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LEONARDO FABBRI

CULTORE DELLA MATERIA
Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto

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Pubblicazioni

2022 - Persistent asthma hospitalisations and deaths require a national asthma prevention plan [Articolo su rivista]
Beghè, Bianca; Fabbri, Leonardo; Clini, Enrico.
abstract

Not available

2021 - Chronic obstructive pulmonary disease exacerbation fundamentals: Diagnosis, treatment, prevention and disease impact [Articolo su rivista]
MacLeod, M.; Papi, A.; Contoli, M.; Beghe', B.; Celli, B. R.; Wedzicha, J. A.; Fabbri, L. M.
abstract

In chronic obstructive pulmonary disease (COPD), exacerbations (ECOPD), characterized by an acute deterioration in respiratory symptoms, are fundamental events impacting negatively upon disease progression, comorbidities, wellbeing and mortality. ECOPD also represent the largest component of the socioeconomic burden of COPD. ECOPDs are currently defined as acute worsening of respiratory symptoms that require additional therapy. Definitions that require worsening of dyspnoea and sputum volume/purulence assume that acute infections, especially respiratory viral infections, and/or exposure to pollutants are the main cause of ECOPD. But other factors may contribute to ECOPD, such as the exacerbation of other respiratory diseases and non-respiratory diseases (e.g., heart failure, thromboembolism). The complexity of worsening dyspnoea has suggested a need to improve the definition of ECOPD using objective measurements such as blood counts and C-reactive protein to improve accuracy of diagnosis and a personalized approach to management. There are three time points when we can intervene to improve outcomes: acutely, to attenuate the length and severity of an established exacerbation; in the aftermath, to prevent early recurrence and readmission, which are common, and in the long-term, establishing preventative measures that reduce the risk of future events. Acute management includes interventions such as corticosteroids or antibiotics and measures to support the respiratory system, including non-invasive ventilation (NIV). Current therapies are broad and better understanding of clinical phenotypes and biomarkers may help to establish a more tailored approach, for example in relation to antibiotic prescription. Other unmet needs include effective treatment for viruses, which commonly cause exacerbations. Preventing early recurrence and readmission to hospital is important and the benefits of interventions such as antibiotics or anti-inflammatories in this period are not established. Domiciliary NIV in those patients who are persistently hypercapnic following discharge and pulmonary rehabilitation can have a positive impact. For long-term prevention, inhaled therapy is key. Dual bronchodilators reduce exacerbation frequency but in patients with continuing exacerbations, triple therapy should be considered, especially if blood eosinophils are elevated. Other options include phosphodiesterase inhibitors and macrolide antibiotics. ECOPD are a key component of the assessment of COPD severity and future outcomes (quality of life, hospitalisations, health care resource utilization, mortality) and are a central component in pharmacological management decisions. Targeted therapies directed towards specific pathways of inflammation are being explored in exacerbation prevention, and this is a promising avenue for future research.

2021 - Combined approach to define the clinical impact and decision making in asthmatics. [Articolo su rivista]
Clini, E; Fabbri, Lm.
abstract

Not available

2021 - Copd, pulmonary fibrosis and ilas in aging smokers: The paradox of striking different responses to the major risk factors [Articolo su rivista]
Beghe', B.; Cerri, S.; Fabbri, L. M.; Marchioni, A.
abstract

Aging and smoking are associated with the progressive development of three main pulmonary diseases: chronic obstructive pulmonary disease (COPD), interstitial lung abnormalities (ILAs), and idiopathic pulmonary fibrosis (IPF). All three manifest mainly after the age of 60 years, but with different natural histories and prevalence: COPD prevalence increases with age to >40%, ILA prevalence is 8%, and IPF, a rare disease, is 0.0005–0.002%. While COPD and ILAs may be associated with gradual progression and mortality, the natural history of IPF remains obscure, with a worse prognosis and life expectancy of 2–5 years from diagnosis. Acute exacerbations are significant events in both COPD and IPF, with a much worse prognosis in IPF. This perspective discusses the paradox of the striking pathological and pathophysiologic responses on the background of the same main risk factors, aging and smoking, suggesting two distinct pathophysiologic processes for COPD and ILAs on one side and IPF on the other side. Pathologically, COPD is characterized by small airways fibrosis and remodeling, with the destruction of the lung parenchyma. By contrast, IPF almost exclusively affects the lung parenchyma and interstitium. ILAs are a heterogenous group of diseases, a minority of which present with the alveolar and interstitial abnormalities of interstitial lung disease.

2021 - Rate of Decline of FEV1 as a Biomarker of Survival? [Articolo su rivista]
Papi, A.; Beghe', B.; Fabbri, L. M.
abstract

2020 - Chronic cough in adults [Abstract in Rivista]
Spanevello, A.; Beghe', B.; Visca, D.; Fabbri, L. M.; Papi, A.
abstract

Cough, a defense mechanism for clearing the airways of secretions, exudate, or foreign bodies, may become a troublesome symptom. Chronic cough, one of the most frequent symptoms requiring medical attention, is often not due to identifiable causes in adults. Chronic productive cough defines chronic bronchitis, and thus is present in 100% of these patients, and frequently in patients with bronchiectasis, cystic fibrosis, and chronic infectious respiratory diseases. However, chronic cough is most frequently dry. Thus, chronic cough in adults is a difficult syndrome requiring multidisciplinary approaches, particularly to diagnose and treat the most frequent identifiable causes, but also to decide which patients may benefit by treating the central cough hypersensitivity by neuromodulatory therapy and/or non-pharmacologic treatment (speech pathology therapy). Recent guidelines provide algorithms for diagnosis and assessment of cough severity; particularly chronic cough in adults. After excluding life-threatening diseases, chronic cough due to identifiable causes (triggers and/or diseases), particularly smoking and/or the most frequent diseases (asthma, chronic bronchitis, chronic obstructive pulmonary disease, eosinophilic bronchitis, and adverse reactions to drugs [angiotensin-converting enzyme inhibitors and sitagliptin]) should be treated by avoiding triggers and/or according to guidelines for each underlying disease. In patients with troublesome chronic cough due to unknown causes or persisting even after adequate avoidance of triggers, and/or treatment of the underlying disease(s), a symptomatic approach with neuromodulators and/or speech pathology therapy should be considered. Additional novel promising neuromodulatory agents in clinical development (e.g., P2X3 inhibitors) will hopefully become available in the near future.

2020 - Management of chronic refractory cough in adults [Articolo su rivista]
Visca, D.; Beghe', B.; Fabbri, L. M.; Papi, A.; Spanevello, A.
abstract

Cough is a common respiratory symptom that is considered to be chronic when it lasts more than eight weeks. When severe, chronic cough may significantly impact an individual's quality of life, and such patients are frequently referred for specialist evaluation. Current international guidelines provide algorithms for the management of chronic cough: in most cases, treatment of the underlying disease is sufficient to improve or resolve cough symptoms. Severe chronic cough may significantly affect patients' quality of life and necessitate frequent referral for specialist evaluations. In this narrative review, we summarize non-pharmacologic and pharmacologic management of adult patients with chronic cough of known cause that persists after proper treatment (chronic refractory cough, CRC) or chronic cough of unknown cause in adult patients. If chronic cough persists even after treatment of the underlying disease, or if the chronic cough is not attributable to any cause, then a symptomatic approach with neuromodulators may be considered, with gabapentin as the first choice, and opioids or macrolides as alternatives. Speech pathology treatment and/or neuromodulators should be discussed with patients and alternative options carefully considered, taking into account risk/benefit. Novel promising drugs are under investigation (e.g. P2×3 inhibitors), but additional studies are needed in this field. Speech pathology can be combined with a neuromodulator to give an enhanced treatment response of longer duration suggesting that non-pharmacologic treatment may play a key role in the management of CRC.

2020 - Multimorbidity in COPD, does sleep matter? [Articolo su rivista]
Vanfleteren, L. E.; Beghe', B.; Andersson, A.; Hansson, D.; Fabbri, L. M.; Grote, L.
abstract

A good night's sleep is a prerequisite for sustainable mental and physical health. Sleep disorders, including sleep disordered breathing, insomnia and sleep related motor dysfunction (e.g., restless legs syndrome), are common in patients with chronic obstructive pulmonary disease (COPD), especially in more severe disease. COPD is commonly associated with multimorbidity, and sleep disorders as a component of this multimorbidity spectrum have a further negative impact on COPD-related comorbidities. Indeed, concomitant diseases in COPD and in obstructive sleep apnea (OSA) are similar, suggesting that the combination of COPD and OSA, the so called OSA-COPD overlap syndrome (OVS), affects patient outcomes. Potential clinically important interactions of OVS exist in cardiovascular and metabolic disease, arthritis, anxiety, depression, neurocognitive disorder and the fatigue syndrome. Correct diagnosis for recognition and treatment of sleep-related disorders in COPD is recommended. However, surprisingly limited information is available and further research and improved diagnostic tools are needed. In the absence of clear evidence, we agree with the recommendation of the Global Initiative on Chronic Obstructive Lung Disease that sleep disorders should be actively searched for and treated in patients with COPD. We believe that both aspects are important components of the holistic approach required in patients with chronic multimorbid conditions.

2019 - Significant chronic airway abnormalities in never-smoking HIV-infected patients [Articolo su rivista]
Besutti, G.; Santoro, A.; Scaglioni, R.; Neri, S.; Zona, S.; Malagoli, A.; Orlando, G.; Beghe, B.; Ligabue, G.; Torricelli, P.; Manfredini, M.; Pellacani, G.; Fabbri, L. M.; Guaraldi, G.
abstract

Objectives The aim of the study was to describe chronic lung disease in HIV-infected never-smokers by looking at clinical, structural and functional abnormalities. Methods This comparative cross-sectional study included 159 HIV-infected never-smoking patients [mean (+/- standard deviation) age 54.6 +/- 9.1 years; 13.2% female; 98.1% with undetectable viral load] and 75 nonmatched never-smoking controls [mean (+/- standard deviation) age 52.6 +/- 6.9 years; 46.7% female]. We examined calcium scoring computer tomography (CT) scans or chest CT scans, all with a lung-dedicated algorithm reconstruction, to assess emphysema and airway disease (respiratory bronchiolitis and/or bronchial wall thickening), tested pulmonary function using spirometry, lung volumes and the diffusion lung capacity of carbon monoxide (DLCO), and assessed respiratory symptoms using the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT). Results Twenty-five (17.2%) of the HIV-infected patients versus two (2.7%) of the controls had a CAT score > 10. Only 5% of the HIV-infected patients showed FEV1% < 80%, and 25% had DLCO CT scans, they had increased prevalences, compared with the controls, of airway disease (37% versus 7.9%, respectively) and emphysema (18% versus 4%, respectively), with more severe and more frequent centrilobular disease. After correction for age, sex and clinical factors, HIV infection was significantly associated with CAT > 10 [odds ratio (OR) 7.7], emphysema (OR 4), airway disease (OR 4.5) and DLCO < 75% of predicted (OR 4). Conclusions Although comparisons were limited by the different enrolment methods used for HIV-infected patients and controls, the results suggest that never-smoking HIV-infected patients may present with chronic lung damage characterized by CT evidence of airway disease. A minority of them showed respiratory symptoms, without significant functional abnormalities.

2019 - Three-year hospitalization and mortality in elderly smokers with COPD or CHF. [Articolo su rivista]
Beghé, B; Fabbri, Lm; Garofalo, M; Schito, M; Verduri, A; Bortolotti, M; Stendardo, M; Ruggieri, V; Fucili, A; Sverzellati, N; Della Casa, G; Maietti, E; Clini, E; Boschetto, P.
abstract

Background: In elderly smokers, COPD and CHF usually present with dyspnoea. COPD and CHF are associated almost invariably with concomitant chronic diseases which contribute to severity and prognosis. Objectives: We investigated similarities and differences in the clinical presentation, concomitant chronic diseases and risk factors for mortality and hospitalization at 3-year follow-up in elderly smokers/ex-smokers with a primary diagnosis of COPD or CHF recruited and followed in specialized centers. Methods: We examined 144 patients with COPD and 96 with CHF, ≥ 65 yrs, ≥20 pack/years, and measured CAT score, mMRC, NYHA, and Charlson Index, routine blood test, eGFR, HRCTscan, 6MWT. In addition, in each patient we actively searched for CHF, COPD, peripheral vascular disease, and metabolic syndrome. Results: COPD and CHF patients had mild to moderate disease, but the majority was symptomatic. Comorbidities were highly prevalent and often unrecognized in both groups. COPD and CHF patients had a similar risk of hospitalization and death at 3 years. Lower glomerular filtration rate, shorter 6MWT and ascending aorta calcification score ≥2 were independent predictors of mortality in COPD, whereas previous 12 month hospitalizations, renal disease and heart diameter were in CHF patients. Lower glomerular filtration rate value, higher CAT score and lower FEV1/FVC ratio were associated with hospitalization in COPD, whilst age, lower FEV1 % predicted and peripheral vascular disease were in CHF. Conclusions: There are relevant similarities and differences between patients with COPD and CHF even when admitted to specialized outpatient centers, suggesting that these patients should be manage in multidisciplinary units.

2018 - Blood eosinophils for the management of COPD patients? [Articolo su rivista]
Fabbri, L. M.; Beghe', B.; Papi, A.
abstract

2018 - Chronic Lung Disease in HIV Patients [Articolo su rivista]
Neri, S; Leung, J; Besutti, G; Santoro, A; Fabbri, Lm; Guaraldi, G
abstract

This narrative review discusses literature on chronic obstructive pulmonary disease (COPD) in people living with HIV (PLWH). Existing data indicate that HIV itself, independent of smoking, constitutes a pathogenic agent implicated in this disease condition. COPD can be viewed not exclusively as a pulmonary disease but rather as a systemic syndrome sparked and fueled by a persistent low-grade HIV-attributable inflammatory state. We speculate that even in the absence of airflow obstruction on spirometry, HIV-related lung disease can manifest with respiratory symptoms and structural lung derangement. Although not fully satisfying the global initiative for obstructive lung disease criteria for COPD, this phenotype of small airways lung disease is related to significant impairment of lung health and is associated with a high comorbidity burden. Within the specific context of the aging epidemic affecting HIV patients characterized by a high burden of comorbidities, frailty, and disabilities HIV-related lung disease has to be fit into the framework of the general comorbidity burden that PLWH experience, due to both HIV infection and to incidental HIV-unrelated risk factors. In this review, we will also provide a list of research gaps and an agenda for future studies in HIV patients.

2018 - Highlights of the 2017 European AIDS Clinical Society (EACS) Guidelines for the treatment of adult HIV-positive persons version 9.0 [Articolo su rivista]
Ryom, L.; Boesecke, C.; Bracchi, M.; Ambrosioni, J.; Pozniak, A.; Arribas, J.; Behrens, G.; Mallon, P. G. M.; Puoti, M.; Rauch, A.; Miro, J. M.; Kirk, O.; Marzolini, C.; Lundgren, J. D.; Battegay, M.; d'Arminio Monforte, A.; Clumeck, N.; Dedes, N.; Gatell, J. M.; Horban, A.; Katlama, C.; McCormack, S.; Molina, J. -M.; Mussini, C.; Raffi, F.; Reiss, P.; Stellbrink, H. -J.; Bower, M.; Cinque, P.; Collins, S.; Compston, J.; De Wit, S.; Fabbri, L. M.; Fux, C. A.; Guaraldi, G.; Martinez, E.; Papapoulos, S.; du Pasquier, R.; Poulter, N.; Williams, I.; Winston, A.; Berenguer, J.; Bhagani, S.; Bruno, R.; Konov, S.; Lacombe, K.; Mauss, S.; Mendao, L.; Peters, L.; Rockstroh, J. K.; Fatkenheuer, G.; Furrer, H.; Mocroft, A.; Morlat, P.; Volny-Anne, A.
abstract

Background: The European AIDS Clinical Society (EACS) Guidelines have since 2005 provided multidisciplinary recommendations for the care of HIV-positive persons in geographically diverse areas. Guideline highlights: Major revisions have been made in all sections of the 2017 Guidelines: antiretroviral treatment (ART), comorbidities, coinfections and opportunistic diseases. Newly added are also a summary of the main changes made, and direct video links to the EACS online course on HIV Management. Recommendations on the clinical situations in which tenofovir alafenamide may be considered over tenofovir disoproxil fumarate are provided, and recommendations on which antiretrovirals can be used safely during pregnancy have been revised. Renal and bone toxicity and hepatitis C virus (HCV) treatment have been added as potential reasons for ART switches in fully virologically suppressed individuals, and dolutegravir/rilpivirine has been included as a treatment option. In contrast, dolutegravir monotherapy is not recommended. New recommendations on non-alcoholic fatty liver disease, chronic lung disease, solid organ transplantation, and prescribing in elderly are included, and human papilloma virus (HPV) vaccination recommendations have been expanded. All drug–drug interaction tables have been updated and new tables are included. Treatment options for direct-acting antivirals (DAAs) have been updated and include the latest combinations of sofosbuvir/velpatasvir/voxilaprevir and glecaprevir/pibrentasvir. Recommendations on management of DAA failure and acute HCV infection have been expanded. For treatment of tuberculosis (TB), it is underlined that intermittent treatment is contraindicated, and for resistant TB new data suggest that using a three-drug combination may be as effective as a five-drug regimen, and may reduce treatment duration from 18-24 to 6-10 months. Conclusions: Version 9.0 of the EACS Guidelines provides a holistic approach to HIV care and is translated into the six most commonly spoken languages.

2018 - Use of adjunctive cardiovascular therapy in patients hospitalized for acute exacerbations of COPD. [Articolo su rivista]
Roversi, S; Tonelli, R; Beghè, Bianca; Banchelli, F; D’Amico, Roberto; Malerba, Mario; Fabbri, Lm; Clini, E.
abstract

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is one of the most frequent diagnoses in patients presenting with acute dyspnea or respiratory failure. According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) document, it is defined clinically, as acute worsening of respiratory symptoms that result in additional therapies, being bronchodilators, corticosteroids, and antibiotics the cornerstone of acute management. However, comorbidities in COPD, including cardiac disease, contribute significantly to heterogeneity of the single acute episode in real-life practice. Therefore, we were interested in evaluating how patients admitted to the hospital with a clinical diagnosis of AECOPD were managed at admission, and we analyzed the therapeutic approach at onset of AECOPD in hospitalized patients, aiming at assessing the adjunctive use of diuretic therapy.

2017 - Peripheral eosinophil count as a biomarker for the management of COPD: not there yet. [Articolo su rivista]
Rabe, Klaus F.; Beghe', Bianca; Fabbri, Leonardo M.
abstract

Chronic obstructive pulmonary disease (COPD) is associated with acute and chronic pulmonary as well as systemic inflammation [1]. Anti-inflammatory treatments, such as inhaled corticosteroids (ICS) and oral roflumilast, are recommended for COPD patients [2]. These drugs are effective agents for the prevention of COPD exacerbations and improvement of lung function and have various effects on health status, but they are associated with adverse events, the most concerning being pneumonia (ICS) and diarrhoea (roflumilast).

2016 - Blood eosinophil count and exacerbations in severe chronic obstructive pulmonary disease after withdrawal of inhaled corticosteroids: a post-hoc analysis of the WISDOM trial [Articolo su rivista]
Watz, Henrik; Tetzlaff, Kay; Wouters, Emiel F. M; Kirsten, Anne; Magnussen, Helgo; Rodriguez Roisin, Roberto; Vogelmeier, Claus; Fabbri, Leonardo; Chanez, Pascal; Dahl, Ronald; Disse, Bernd; Finnigan, Helen; Calverley, Peter M. A.
abstract

Blood eosinophil counts might predict response to inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease (COPD) and a history of exacerbations. We used data from the WISDOM trial to assess whether patients with COPD with higher blood eosinophil counts would be more likely to have exacerbations if ICS treatment was withdrawn.

2016 - Dose-response to inhaled glycopyrrolate delivered with a novel Co-Suspension™ Delivery Technology metered dose inhaler (MDI) in patients with moderate-to-severe COPD [Articolo su rivista]
Fabbri, Leonardo; Kerwin, Edward M; Spangenthal, Selwyn; Ferguson, Gary T; Rodriguez Roisin, Roberto; Pearle, James; Sethi, Sanjay; Orevillo, Chad; Darken, Patrick; St Rose, Earl; Fischer, Tracy; Golden, Michael; Dwivedi, Sarvajna; Reisner, Colin
abstract

This study forms part of the first complete characterization of the dose-response curve for glycopyrrolate (GP) delivered using Co-Suspension™ Delivery Technology via a metered dose inhaler (MDI). We examined the lower GP MDI dose range to determine an optimal dose for patients with moderate-to-severe chronic obstructive pulmonary disease (COPD).

2016 - Insights, attitudes, and perceptions about asthma and its treatment: a multinational survey of patients from Europe and Canada [Articolo su rivista]
Sastre, Joaquin; Fabbri, Leonardo; Price, David; Wahn, Hans Ulrich; Bousquet, Jean; Fish, James E; Murphy, Kevin; Sears, Malcolm R.
abstract

Asthma surveys completed within the past 10 years in the Americas and the Asia-Pacific region have shown significant underassessment of asthma severity in addition to undertreatment of asthma and have suggested the need to improve long-term asthma management. In this study, we examined the frequency of asthma symptoms and severe episodes, patients' perceived asthma control, and use of asthma medications in Europe and Canada.

2016 - Lung Function Abnormalities in Smokers with Ischemic Heart Disease [Articolo su rivista]
Franssen, Frits M. E; Soriano, Joan B; Roche, Nicolas; Bloomfield, Paul H; Brusselle, Guy; Fabbri, Leonardo; García Rio, Francisco; Kearney, Mark T; Kwon, Namhee; Lundbäck, Bo; Rabe, Klaus F; Raillard, Alice; Muellerova, Hana; Cockcroft, John R.
abstract

The aim of the ALICE (Airflow Limitation in Cardiac Diseases in Europe) study was to investigate the prevalence of airflow limitation in patients with ischemic heart disease and the effects on quality of life, healthcare use, and future health risk.

2016 - Scaling up strategies of the chronic respiratory disease programme of the European Innovation Partnership on Active and Healthy Ageing (Action Plan B3: Area 5) [Articolo su rivista]
Bousquet, J; Farrell, J; Crooks, G; Hellings, P; Bel, E. H; Bewick, M; Chavannes, N. H; de Sousa, J. Correia; Cruz, A. A; Haahtela, T; Joos, G; Khaltaev, N; Malva, J; Muraro, A; Nogues, M; Palkonen, S; Pedersen, S; Robalo Cordeiro, C; Samolinski, B; Strandberg, T; Valiulis, A; Yorgancioglu, A; Zuberbier, T; Bedbrook, A; Aberer, W; Adachi, M; Agusti, A; Akdis, C. A; Akdis, M; Ankri, J; Alonso, A; Annesi Maesano, I; Ansotegui, I. J; Anto, J. M; Arnavielhe, S; Arshad, H; Bai, C; Baiardini, I; Bachert, C; Baigenzhin, A. K; Barbara, C; Bateman, E. D; Beghe', Bianca; Kheder, A. Ben; Bennoor, K. S; Benson, M; Bergmann, K. C; Bieber, T; Bindslev Jensen, C; Bjermer, L; Blain, H; Blasi, F; Boner, A. L; Bonini, M; Bonini, S; Bosnic Anticevitch, S; Boulet, L. P; Bourret, R; Bousquet, P. J; Braido, F; Briggs, A. H; Brightling, C. E; Brozek, J; Buhl, R; Burney, P. G; Bush, A; Caballero Fonseca, F; Caimmi, D; Calderon, M. A; Calverley, P. M; Camargos, P. A. M; Canonica, G. W; Camuzat, T; Carlsen, K. H; Carr, W; Carriazo, A; Casale, T; Cepeda Sarabia, A. M; Chatzi, L; Chen, Y. Z; Chiron, R; Chkhartishvili, E; Chuchalin, A. G; Chung, K. F; Ciprandi, G; Cirule, I; Cox, L; Costa, D. J; Custovic, A; Dahl, R; Dahlen, S. E; Darsow, U; De Carlo, G; De Blay, F; Dedeu, T; Deleanu, D; De Manuel Keenoy, E; Demoly, P; Denburg, J. A; Devillier, P; Didier, A; Dinh Xuan, A. T; Djukanovic, R; Dokic, D; Douagui, H; Dray, G; Dubakiene, R; Durham, S. R; Dykewicz, M. S; El Gamal, Y; Emuzyte, R; Fabbri, Leonardo; Fletcher, M; Fiocchi, A; Fink Wagner, A; Fonseca, J; Fokkens, W. J; Forastiere, F; Frith, P; Gaga, M; Gamkrelidze, A; Garces, J; Garcia Aymerich, J; Gemicioğlu, B; Gereda, J. E; González Diaz, S; Gotua, M; Grisle, I; Grouse, L; Gutter, Z; Guzmán, M. A; Heaney, L. G; Hellquist Dahl, B; Henderson, D; Hendry, A; Heinrich, J; Heve, D; Horak, F; Hourihane, J. O' B; Howarth, P; Humbert, M; Hyland, M. E; Illario, M; Ivancevich, J. C; Jardim, J. R; Jares, E. J; Jeandel, C; Jenkins, C; Johnston, S. L; Jonquet, O; Julge, K; Jung, K. S; Just, J; Kaidashev, I; Kaitov, M. R; Kalayci, O; Kalyoncu, A. F; Keil, T; Keith, P. K; Klimek, L; Koffi N'Goran, B; Kolek, V; Koppelman, G. H; Kowalski, M. L; Kull, I; Kuna, P; Kvedariene, V; Lambrecht, B; Lau, S; Larenas Linnemann, D; Laune, D; Le, L. T. T; Lieberman, P; Lipworth, B; Li, J; Lodrup Carlsen, K; Louis, R; Macnee, W; Magard, Y; Magnan, A; Mahboub, B; Mair, A; Majer, I; Makela, M. J; Manning, P; Mara, S; Marshall, G. D; Masjedi, M. R; Matignon, P; Maurer, M; Mavale Manuel, S; Melén, E; Melo Gomes, E; Meltzer, E. O; Menzies Gow, A; Merk, H; Michel, J. P; Miculinic, N; Mihaltan, F; Milenkovic, B; Mohammad, G. M. Y; Molimard, M; Momas, I; Montilla Santana, A; Morais Almeida, M; Morgan, M; Mösges, R; Mullol, J; Nafti, S; Namazova Baranova, L; Naclerio, R; Neou, A; Neffen, H; Nekam, K; Niggemann, B; Ninot, G; Nyembue, T. D; O'Hehir, R. E; Ohta, K; Okamoto, Y; Okubo, K; Ouedraogo, S; Paggiaro, P; Pali Schöll, I; Panzner, P; Papadopoulos, N; Papi, A; Park, H. S; Passalacqua, G; Pavord, I; Pawankar, R; Pengelly, R; Pfaar, O; Picard, R; Pigearias, B; Pin, I; Plavec, D; Poethig, D; Pohl, W; Popov, T. A; Portejoie, F; Potter, P; Postma, D; Price, D; Rabe, K. F; Raciborski, F; Radier Pontal, F; Repka Ramirez, S; Reitamo, S; Rennard, S; Rodenas, F; Roberts, J; Roca, J; Rodriguez Mañas, L; Rolland, C; Roman Rodriguez, M; Romano, A; Rosado Pinto, J; Rosario, N; Rosenwasser, L; Rottem, M; Ryan, D; Sanchez Borges, M; Scadding, G. K; Schunemann, H. J; Serrano, E; Schmid Grendelmeier, P; Schulz, H; Sheikh, A; Shields, M; Siafakas, N; Sibille, Y; Similowski, T; Simons, F. E. R; Sisul, J. C; Skrindo, I; Smit, H. A; Solé, D; Sooronbaev, T; Spranger, O; Stelmach, R; Sterk, P. J; Sunyer, J; Thijs, C; To, T; Todo Bom, A; Triggiani, M; Valenta, R; Valero, A. L; Valia, E; Valovirta, E; Van Ganse, E; van Hage, M; Vandenplas, O; Vasankari, T; Vellas, B; Vestbo, J; Vezzani, G; Vichyanond, P; Viegi, G
abstract

Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) focuses on the integrated care of chronic diseases. Area 5 (Care Pathways) was initiated using chronic respiratory diseases as a model. The chronic respiratory disease action plan includes (1) AIRWAYS integrated care pathways (ICPs), (2) the joint initiative between the Reference site MACVIA-LR (Contre les MAladies Chroniques pour un VIeillissement Actif) and ARIA (Allergic Rhinitis and its Impact on Asthma), (3) Commitments for Action to the European Innovation Partnership on Active and Healthy Ageing and the AIRWAYS ICPs network. It is deployed in collaboration with the World Health Organization Global Alliance against Chronic Respiratory Diseases (GARD). The European Innovation Partnership on Active and Healthy Ageing has proposed a 5-step framework for developing an individual scaling up strategy: (1) what to scale up: (1-a) databases of good practices, (1-b) assessment of viability of the scaling up of good practices, (1-c) classification of good practices for local replication and (2) how to scale up: (2-a) facilitating partnerships for scaling up, (2-b) implementation of key success factors and lessons learnt, including emerging technologies for individualised and predictive medicine. This strategy has already been applied to the chronic respiratory disease action plan of the European Innovation Partnership on Active and Healthy Ageing.

2016 - Smoking, Not COPD, as the Disease [Articolo su rivista]
Fabbri, Leonardo
abstract

Comment on Clinical Significance of Symptoms in Smokers with Preserved Pulmonary Function. [N Engl J Med. 2016] Clinical and Radiologic Disease in Smokers With Normal Spirometry. [JAMA Intern Med. 2015]

2016 - What is the origin of dyspnoea in smokers without airway disease ? [Articolo su rivista]
Clini, Enrico; Beghe', Bianca; Fabbri, Leonardo
abstract

Not available

2015 - An official American Thoracic Society/European Respiratory Society statement: research questions in chronic obstructive pulmonary disease [Articolo su rivista]
Celli, Bartolome R; Decramer, Marc; Wedzicha, Jadwiga A.; Wilson, Kevin C.; Agustí, Alvar; Criner, Gerard J.; Macnee, William; Make, Barry J.; Rennard, Stephen I.; Stockley, Robert A.; Vogelmeier, Claus; Anzueto, Antonio; Au, David H.; Barnes, Peter J.; Burgel, Pierre Regis; Calverley, Peter M.; Casanova, Ciro; Clini, Enrico; Cooper, Christopher B.; Coxson, Harvey O.; Dusser, Daniel J.; Fabbri, Leonardo; Fahy, Bonnie; Ferguson, Gary T.; Fisher, Andrew; Fletcher, Monica J.; Hayot, Maurice; Hurst, John R.; Jones, Paul W.; Mahler, Donald A.; Maltais, François; Mannino, David M.; Martinez, Fernando J.; Miravitlles, Marc; Meek, Paula M.; Papi, Alberto; Rabe, Klaus F.; Roche, Nicolas; Sciurba, Frank C.; Sethi, Sanjay; Siafakas, Nikos; Sin, Don D.; Soriano, Joan B.; Stoller, James K.; Tashkin, Donald P.; Troosters, Thierry; Verleden, Geert M.; Verschakelen, Johny; Vestbo, Jorgen; Walsh, John W.; Washko, George R.; Wise, Robert A.; Wouters, Emiel F. M.; Zuwallack, Richard L.
abstract

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and resource use worldwide. The goal of this Official American Thoracic Society (ATS)/European Respiratory Society (ERS) Research Statement is to describe evidence related to diagnosis, assessment, and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. METHODS: Clinicians, researchers, and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarized, and then salient knowledge gaps were identified. RESULTS: Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. CONCLUSIONS: Great strides have been made in the diagnosis, assessment, and management of COPD as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS Research Statement highlights the types of research that leading clinicians, researchers, and patient advocates believe will have the greatest impact on patient-centered outcomes.

2015 - An official American thoracic society/ European respiratory society statement: Research questions in COPD [Articolo su rivista]
Celli, B. R.; Decramer, M.; Wedzicha, J. A.; Wilson, K. C.; Agusti, A. A.; Criner, G. J.; MacNee, W.; Make, B. J.; Rennard, S. I.; Stockley, R. A.; Vogelmeier, C.; Anzueto, A.; Au, D. H.; Barnes, P. J.; Burgel, P. -R.; Calverley, P. M.; Casanova, C.; Clini, E. M.; Cooper, C. B.; Coxson, H. O.; Dusser, D. J.; Fabbri, L. M.; Fahy, B.; Ferguson, G. T.; Fisher, A.; Fletcher, M. J.; Hayot, M.; Hurst, J. R.; Jones, P. W.; Mahler, D. A.; Maltais, F.; Mannino, D. M.; Martinez, F. J.; Miravitlles, M.; Meek, P. M.; Papi, A.; Rabe, K. F.; Roche, N.; Sciurba, F. C.; Sethi, S.; Siafakas, N.; Sin, D. D.; Soriano, J. B.; Stoller, J. K.; Tashkin, D. P.; Troosters, T.; Verleden, G. M.; Verschakelen, J.; Vestbo, J.; Walsh, J. W.; Washko, G. R.; Wise, R. A.; Wouters, E. F. M.; ZuWallack, R. L.
abstract

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality and resource use worldwide. The goal of this official American Thoracic Society (ATS)/European Respiratory Society (ERS) Research Statement is to describe evidence related to diagnosis, assessment, and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. Clinicians, researchers and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarised, and then salient knowledge gaps were identified. Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. Great strides have been made in the diagnosis, assessment and management of COPD, as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ ERS research statement highlights the types of research that leading clinicians, researchers and patient advocates believe will have the greatest impact on patient-centred outcomes.

2015 - Antibiotic treatment of severe exacerbations of chronic obstructive pulmonary disease with procalcitonin: A randomized noninferiority trial [Articolo su rivista]
Verduri, Alessia; Luppi, Fabrizio; D'Amico, Roberto; Balduzzi, Sara; Vicini, Roberto; Liverani, Anna; Ruggieri, Valentina; Plebani, Mario; Barbaro Foschino, Maria Pia; Spanevello, Antonio; Canonica, Giorgio Walter; Papi, Alberto; Fabbri, Leonardo; Beghe', Bianca
abstract

The duration of antibiotic treatment of exacerbations of COPD (ECOPD) is controversial. Serum procalcitonin (PCT) is a biomarker of bacterial infection used to identify the cause of ECOPD. METHODS AND FINDINGS: We investigated whether a PCT-guided plan would allow a shorter duration of antibiotic treatment in patients with severe ECOPD. For this multicenter, randomized, non-inferiority trial, we enrolled 184 patients hospitalized with ECOPD from 18 hospitals in Italy. Patients were assigned to receive antibiotics for 10 days (standard group) or for either 3 or 10 days (PCT group). The primary outcome was the rate of ECOPD at 6 months. Having planned to recruit 400 patients, we randomized only 183: 93 in the PCT group and 90 in the standard group. Thus, the completed study was underpowered. The ECOPD rate at 6 months between PCT-guided and standard antibiotic treatment was not significant (% difference, 4.04; 90% confidence interval [CI], -7.23 to 15.31), but the CI included the non-inferiority margin of 15. In the PCT-guided group, about 50% of patients were treated for 3 days, and there was no difference in primary or secondary outcomes compared to patients treated for 10 days. CONCLUSIONS: Although the primary and secondary clinical outcomes were no different for patients treated for 3 or 10 days in the PCT group, the conclusion that antibiotics can be safely stopped after 3 days in patients with low serum PCT cannot be substantiated statistically. Thus, the results of this study are inconclusive regarding the noninferiority of the PCT-guided plan compared to the standard antibiotic treatment. The study was funded by Agenzia Italiana del Farmaco (AIFA-FARM58J2XH). Clinical trial registered with www.clinicaltrials.gov (NCT01125098). TRIAL REGISTRATION: ClinicalTrials.gov NCT01125098.

2015 - Breakthroughs in internal and respiratory medicine [Articolo su rivista]
Roversi, Sara; Tonelli, Roberto; Fabbri, Leonardo
abstract

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2015 - Chronic critical illness: the price of survival [Articolo su rivista]
Marchioni, A.; Fantini, Riccardo; Antenora, F.; Clini, Enrico; Fabbri, Leonardo
abstract

BACKGROUND: The evolution of the techniques used in the intensive care setting over the past decades has led on one side to better survival rates in patients with acute conditions and severely impaired vital functions. On the other side, it has resulted in a growing number of patients who survive an acute event, but who then become dependent on one or more life support techniques. Such patients are called chronically critically ill patients. MATERIALS & METHODS: No absolute definition of the disease is currently available, although most patients are characterized by the need for prolonged mechanical ventilation. Mortality rates are still high even after dismissal from intensive care unit (ICU) and transfer to specialized rehabilitation care settings. RESULTS: In recent years, some studies have tried to clarify the pathophysiological characteristics underlying chronic critical illness (CCI), a disease that is also characterized by severe endocrine and inflammatory impairments, partly accounting for the almost constant set of symptoms. DISCUSSION: Currently, no specific treatment is available. However, a strategic early therapeutic approach on ICU admission might try to prevent the progress of the acute disease towards chronic critical illness.

2015 - Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial [Articolo su rivista]
Martinez, Fernando; Calverley, Peter; Goehring, Udo Michael; Brose, Manja; Fabbri, Leonardo; Rabe, Klaus
abstract

Roflumilast reduces exacerbations in patients with severe chronic obstructive pulmonary disease. Its effect in patients using fixed combinations of inhaled corticosteroids and longacting β2 agonists is unknown. We postulated that roflumilast would reduce exacerbations in patients with severe chronic obstructive pulmonary disease at risk for exacerbations, even in combination with inhaled corticosteroid and longacting β2 agonist treatment.

2015 - Eosinophilia in asthma: the easy way is not always the best [Articolo su rivista]
Beghe', Bianca; Spanevello, Antonio; Fabbri, Leonardo
abstract

In this article the role of eosinophilic inflammation is discussed.

2015 - Insufficienza Respiratoria acuta e cronica (cap.21). [Capitolo/Saggio]
Clini, Enrico; Bonsignore, M; Confalonieri, Marco; Corrado, Arianna; Crisafulli, E; Fabbri, Leonardo; Longhini, F; Marchioni, Alessandro; Moretti, Matteo; Navalesi, P; Potena, A; Scala, R; Spanevello, A; Torregiani, C.
abstract

Non disponibile

2015 - Procalcitonin-guided antibiotic therapy: a potentially effective and efficient strategy [Articolo su rivista]
Plebani, Mario; Fabbri, Leonardo
abstract

Comment on Economic evaluation of procalcitonin-guided antibiotic therapy in acute respiratory infections: a US health system perspective. [Clin Chem Lab Med. 2015]

2015 - Regular versus as-needed budesonide and formoterol combination treatment for moderate asthma: a non-inferiority, randomised, double-blind clinical trial [Articolo su rivista]
Papi, Alberto; Marku, Brunilda; Scichilone, Nicola; Maestrelli, Piero; Paggiaro, Pierluigi; Saetta, Marina; Nava, Stefano; Folletti, Ilenia; Bertorelli, Giuseppina; Bertacco, Stefano; Contoli, Marco; Plebani, Mario; Barbaro Foschino, Maria Pia; Spanevello, Antonio; Aliani, Maria; Pannacci, Marco; Morelli, Paolo; Beghe', Bianca; Fabbri, Leonardo
abstract

BACKGROUND: Treatment guidelines for patients with moderate persistent asthma recommend regular therapy with a combination of an inhaled corticosteroid and a longacting β2 agonist plus as-needed rapid-acting bronchodilators. We investigated whether symptom-driven budesonide and formoterol combination therapy administered as needed would be as effective as regular treatment with this combination plus as-needed symptom-driven terbutaline for patients with moderate asthma. METHODS: In this non-inferiority randomised clinical trial, we recruited adult patients (18-65 years of age) with stable moderate persistent asthma, according to 2006 Global Initiative for Asthma guidelines. Patients were recruited from outpatient clinics of secondary and tertiary referral hospitals and university centres. After a 6-week run-in period of inhaled regular budesonide and formoterol plus as-needed terbutaline, the patients were randomly assigned in a 1:1 ratio to receive placebo twice daily plus as-needed treatment with inhaled 160 μg budesonide and 4·5 μg formoterol (as-needed budesonide and formoterol therapy) or twice-daily 160 μg budesonide and 4·5 μg formoterol combination plus symptom-driven 500 μg terbutaline (regular budesonide/formoterol therapy) for 1 year. Randomisation was done according to a list prepared with the use of a random number generator and a balanced-block design stratified by centre. Patients and investigators were masked to treatment assignment. The primary outcome was time to first treatment failure measured after 1 year of treatment using Kaplan-Meier estimates, and the power of the study was calculated based on the rate of treatment failure. Analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00849095. FINDINGS: Between April 20, 2009, and March 31, 2012, we screened 1010 patients with moderate asthma and randomly assigned 866 eligible patients to the two treatment groups (424 to as-needed budesonide and formoterol therapy and 442 to regular budenoside and formoterol therapy). Compared with regular budesonide and formoterol therapy, as-needed budesonide and formoterol treatment was associated with a lower probability of patients having no treatment failure at 1 year (Kaplan-Meier estimates 53·6% for as-needed treatment vs 64·0% for regular treatment; difference 10·3% [95% CI 3·2-17·4], at a predefined non-inferiority limit of 9%). Patients in the as-needed budesonide and formoterol group had shorter time to first treatment failure than those in the regular therapy group (11·86 weeks vs 28·00 weeks for the first quartile [ie, the time until the first 25% of patients experienced treatment failure]). The difference in treatment failures was largely attributable to nocturnal awakenings (82 patients in the as-needed treatment group vs 44 in the regular treatment group). Both treatment regimens were well tolerated. INTERPRETATION: In patients with moderate stable asthma, as-needed budesonide and formoterol therapy is less effective than is the guideline-recommended regular budesonide and formoterol treatment, even though the differences are small. FUNDING: Italian Medicines Agency

2015 - Salmeterol/fluticasone combination instead of indacaterol or vice-versa? [Articolo su rivista]
Fabbri, Leonardo; Agusti, Alvar
abstract

n/a

2015 - Taking Aim at Asthma Around the World: Global Results of the Asthma Insight and Management Survey in the Asia-Pacific Region, Latin America, Europe, Canada, and the United States [Articolo su rivista]
Nathan, Robert A; Thompson, Philip J; Price, David; Fabbri, Leonardo; Salvi, Sundeep; González Díaz, Sandra; Maspero, Jorge F; Moreno Cantu, Jorge J; Fish, James E; Murphy, Kevin
abstract

Asthma, a worldwide health problem, can be controlled if properly diagnosed and managed. Multinational surveys conducted in patients with asthma from 1998 to 2003 indicated that asthma was inadequately controlled. The Asthma Insight and Management (AIM) study represents the largest survey conducted on patients with asthma since 2003.

2014 - Ageing and multimorbidity [Articolo su rivista]
Drazen, Jeffrey; Fabbri, Leonardo
abstract

Although growing old is no fun, it beats the other alternative. Unfortunately we are not built like the famous “One Hoss Shay” of Oliver Wendell Holmes’ poem, The Deacon’s Masterpiece. This marvellous horse drawn carriage ran for one hundred years to the day and then completely fell apart. We are not so lucky; as we age some body systems fail before others, leading to a vast array of morbidities that come into play and interact with each other. Understanding these morbidities, how they reinforce or detract from each other and their overall effects on the lung was a field that was largely ignored until about a decade ago.

2014 - Asthma in the elderly: what we know and what we have yet to know [Articolo su rivista]
Anahí, Yáñez; Sang Hoen, Cho; Joan B., Soriano; Lanny J., Rosenwasser; Gustavo J., Rodrigo; Klaus F., Rabe; Stephen, Peters; Akio, Niimi; Dennis K., Ledford; Rohit, Katial; Fabbri, Leonardo; Juan C., Celedón; Giorgio Walter, Canonica; Paula, Busse; Louis Phillippe, Boulet; Carlos E., Baena Cagnani; Qutayba, Hamid; Claus, Bachert; Ruby, Pawankar; Stephen T., Holgate; the WAO Special Committee on, Asthma
abstract

In the past, asthma was considered mainly as a childhood disease. However, asthma is an important cause of morbidity and mortality in the elderly nowadays. In addition, the burden of asthma is more significant in the elderly than in their younger counterparts, particularly with regard to mortality, hospitalization, medical costs or health-related quality of life. Nevertheless, asthma in the elderly is still been underdiagnosed and undertreated. Therefore, it is an imperative task to recognize our current challenges and to set future directions. This project aims to review the current literature and identify unmet needs in the fields of research and practice for asthma in the elderly. This will enable us to find new research directions, propose new therapeutic strategies, and ultimately improve outcomes for elderly people with asthma. There are data to suggest that asthma in older adults is phenotypically different from young patients, with potential impact on the diagnosis, assessment and management in this population. The diagnosis of AIE in older populations relies on the same clinical findings and diagnostic tests used in younger populations, but the interpretation of the clinical data is more difficult. The challenge today is to encourage new research in AIE but to use the existing knowledge we have to make the diagnosis of AIE, educate the patient, develop a therapeutic approach to control the disease, and ultimately provide a better quality of life to our elderly patients.

2014 - Benralizumab: for asthma, not yet for COPD [Articolo su rivista]
Fabbri, Leonardo
abstract

Asthma and chronic obstructive pulmonary disease (COPD) are two distinct, chronic, inflammatory respiratory diseases.1,2 Asthma develops early in life, mainly in atopic individuals, and is characterised by airway hyper-responsiveness and recurrent wheezing due to a chronic inflammation of the airways caused by a CD4, T-helper type-2, eosinophilic inflammation.1 COPD develops later in life (age >40 years), in smokers, and is characterised by progressive irreversible airflow obstruction, chronic respiratory symptoms, and chronic inflammation of the airways and the lung caused by a CD8, Tc1, neutrophilic inflammation.

2014 - Coronary artery disease concomitant with chronic obstructive pulmonary disease [Articolo su rivista]
Sara, Roversi; Pietro, Roversi; Giuseppe, Spadafora; Rossi, Rosario; Fabbri, Leonardo
abstract

BackgroundNumerous epidemiologic studies have linked the presence of chronic obstructive pulmonary disease (COPD) to coronary artery disease (CAD). However, prevalence, pathological processes, clinical manifestations and therapy are still debated, as progress towards uncovering the link between these two disorders has been hindered by the complex nature of multimorbidity. MethodsArticles targeting CAD in patients with COPD were identified from the searches of MEDLINE and EMBASE databases in July 2013. Three authors reviewed available evidence, focusing on the latest development on disease prevalence, pathogenesis, clinical manifestations and therapeutic strategies. Both clinical trial and previous reviews have been included in this work. ResultsThe most accredited hypothesis asserts that the main common risk factors, that is, cigarette smoke and ageing, elicit a chronic low-grade systemic inflammatory response, which affects both cardiovascular endothelial cells and airways/lung parenchyma. The development of CAD in patients with COPD potentiates the morbidity of COPD, leading to increased hospitalizations, mortality and health costs. Moreover, correct diagnosis is challenging and therapies are not clearly defined. ConclusionsEvidence from recently published articles highlights the importance of multimorbidity in patient management and future research. Moreover, many authors emphasize the importance of low-grade systemic inflammation as a common pathological mechanism and a possible future therapeutic target

2014 - Effect of ADRB2 polymorphisms on the efficacy of salmeterol and tiotropium in preventing COPD exacerbations: a prespecified substudy of the POET-COPD trial [Articolo su rivista]
Rabe, Klaus F; Fabbri, Leonardo; Israel, Elliot; Kögler, Harald; Riemann, Kathrin; Schmidt, Hendrik; Glaab, Thomas; Vogelmeier, Claus
abstract

Background: The effect of β2-adrenergic receptor (ADRB2) polymorphisms on the treatment response to longacting bronchodilators in chronic obstructive pulmonary disease (COPD) is unclear. We aimed to establish whether ADRB2 polymorphisms differentially affected COPD exacerbation outcomes in response to tiotropium versus salmeterol. Methods: We did a prespecified analysis of the ADRB2 polymorphisms Arg16Gly and Gln27Glu within the 1 year randomised, double-blind, double-dummy, parallel-group Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial, comparing the effects of treatment with tiotropium or salmeterol on exacerbations in 7376 patients with COPD. One blood sample was collected for pharmacogenetic testing from each patient who elected to participate in the substudy. Random assignment of patients to treatment groups was not stratified according to genotypes. Genomic DNA was extracted from whole-blood specimens and samples were genotyped for the two SNPs, rs1042713 (Arg16Gly) and rs1042714 (Gln27Glu). All assays were done in technical duplicates and 10% of samples that were randomly chosen were repeated as technical duplicates in a second independent genotyping process. Our primary endpoint was the risk of a first exacerbation of COPD based on time to first exacerbation data. An exacerbation of COPD was defined as the increase or new onset of more than one symptom of COPD (cough, sputum, wheezing, dyspnoea, or chest tightness), with at least one of the symptoms lasting for 3 days or more and needing treatment with antibiotics or systemic glucocorticoids (moderate exacerbations), or admission to hospital (severe exacerbations). POET-COPD is registered with ClinicalTrials.gov, number NCT00563381. Findings: 5125 patients gave informed consent for genotyping. The distributions of ADRB2 genotypes were well matched among groups. Polymorphisms at aminoacid 27 did not affect exacerbation outcomes. In the salmeterol group, patients with Arg16Arg genotype had a significantly reduced exacerbation risk compared with patients with Arg16Gly (p=0·0130) and Gly16Gly (p=0·0018) genotypes (proportion of patients with at least one exacerbation was 32·3% in Arg16Arg, 39·8% in Arg16Gly, and 42·1% in Gly16Gly). By contrast, exacerbation risk was not modified by polymorphisms at aminoacid 16 in the tiotropium group. The effect of the Arg16Gly polymorphism on treatment response to salmeterol was dependent on the use of inhaled corticosteroids (ICS). In patients untreated with ICS at baseline, Arg16Gly and Arg16Arg genotypes were associated with significantly prolonged time to first exacerbation compared with Gly16Gly (vs Arg16Gly p=0·0164; Arg16Arg p=0·0316; proportion of patients with at least one exacerbation was 28·3% in Arg16Arg, 31·6% in Arg16Gly, and 39·2% in Gly16Gly), whereas in patients on ICS at baseline, only the Arg16Arg genotype was associated with significantly prolonged time to first exacerbation compared with Gly16Gly (p=0·0198; not Arg16Gly p=0·64; proportion of patients with at least one exacerbation was 35·9% in Arg16Arg, 46·7% in Arg16Gly, and 44·8% in Gly16Gly). The respiratory disorders, in particular worsening of COPD, were the most common serious adverse events. Interpretation: Patients with the Arg16Arg genotype had better exacerbation outcomes in response to salmeterol than Gly16Gly and Arg16Gly genotypes, suggesting a potential differential Arg16Gly genotype effect on treatment response to longacting β-agonists (LABAs). However, the use of ADRB2 polymorphisms for predicting LABA treatment response is still limited and further prospective validation will be needed to advance the mechanistic understanding of β-adrenergic polymorphisms and their association with clinical features of COPD

2014 - Inhaled steroids in COPD: when should they be used? [Articolo su rivista]
Agusti, Alvar; Fabbri, Leonardo
abstract

Because chronic obstructive pulmonary disease (COPD) is defined as an inflammatory disease,1 anti-inflammatory therapy for these patients makes sense. Inhaled corticosteroids are well established anti-inflammatory drugs in asthma2 but their positioning in COPD is controversial.3 There is consensus that inhaled corticosteroids in combination with long-acting bronchodilators are indicated in patients with COPD at risk of exacerbation and in those with the asthma–COPD overlap syndrome, but never as standalone therapy.

2014 - Moving from the Oslerian paradigm to the post-genomic era: are asthma and COPD outdated terms? [Articolo su rivista]
L. E. G. W., Vanfleteren; J. W. H., Kocks; I. S., Stone; R., Breyer Kohansal; T., Greulich; D., Lacedonia; R., Buhl; Fabbri, Leonardo; I. D., Pavord; N., Barnes; E. F. M., Wouters; A., Agusti
abstract

In the majority of cases, asthma and chronic obstructive pulmonary disease (COPD) are two clearly distinct disease entities. However, in some patients there may be significant overlap between the two conditions. This constitutes an important area of concern because these patients are generally excluded from randomised controlled trials (mostly because of smoking history in the case of asthma or because of significant bronchodilator reversibility in the case of COPD). As a result, their pathobiology, prognosis and response to therapy are largely unknown. This may lead to suboptimal management and can limit the development of more personalised therapeutic options. Emerging genetic and molecular information coupled with new bioinformatics capabilities provide novel information that can pave the way towards a new taxonomy of airway diseases. In this paper we question the current value of the terms 'asthma' and 'COPD' as still useful diagnostic labels; discuss the scientific and clinical progress made over the past few years towards unravelling the complexity of airway diseases, from the definition of clinical phenotypes and endotypes to a better understanding of cellular and molecular networks as key pathogenic elements of human diseases (so-called systems medicine); and summarise a number of ongoing studies with the potential to move the field towards a new taxonomy of airways diseases and, hopefully, a more personalised approach to medicine, in which the focus will shift from the current goal of treating diseases as best as possible to the so-called P4 medicine, a new type of medicine that is predictive, preventive, personalised and participatory.

2014 - Poor adherence to guidelines for long-term oxygen therapy (LTOT) in two Italian university hospitals. [Articolo su rivista]
Verduri, Alessia; L., Ballerin; M., Simoni; M., Cellini; E., Vagnoni; P., Roversi; A., Papi; Clini, Enrico; Fabbri, Leonardo; A., Potena
abstract

Long-term oxygen therapy (LTOT) improves survival in patients with chronic obstructive pulmonary disease (COPD) and severe hypoxemia. Adherence to LTOT guidelines is problematic, both because efficacy has been demonstrated only in specific groups of COPD patients, and because it implies high costs. Introduces treatment high costs. The aim of our study was to examine retrospectively the adherence to LTOT guidelines in a sample of medical records of patients prescribed LTOT between January 2005 and December 2006 in two Italian university hospitals (Ferrara and Modena). Out of a total of 191 medical records of patients prescribed LTOT, only 157 had adequate clinical data considering the three main criteria for appropriateness (arterial blood gas and/or pulse oximetry measurement, oxygen administration, smoking status). Out of these 157 patients, only 73 (46.5 %) fulfilled all three criteria recommended by the guidelines. Adherence was higher for LTOT prescribed by pulmonologists compared to internists. This survey showed that the adherence to LTOT guidelines in a sample of medical records of patients prescribed LTOT is poor. Considering the high costs and the impact on the patients' quality of life of LTOT, these results suggest that the adherence should be carefully monitored.

2014 - Pulmonary disease caused by Mycobacterium marseillense, Italy [Articolo su rivista]
Grottola, Antonella; Roversi, Pietro; Fabio, Anna; Antenora, Federico; Apice, Mariagrazia; Tagliazucchi, Sara; Gennari, William; Serpini, Giulia Fregni; Rumpianesi, Fabio; Fabbri, Leonardo M.; Magnani, Rita; Pecorari, Monica
abstract

Mycobacteriummarseillense was recently described as a new species belonging to the Mycobacterium avium complex (MAC).We describe a case of pulmonary disease caused by M. marseillense in an immunocompetent patient. All strains isolated from the patient were preliminarily identified as M. intracellulare; however, a retrospective molecular analysis corrected the identification to M. marseillense.

2014 - Symptomatic elderly patients. The urgent need for comprehensive assessment and management [Articolo su rivista]
Clini, Enrico; Beghe', Bianca; Fabbri, Leonardo
abstract

Not available

2014 - Systems medicine approaches for the definition of complex phenotypes in chronic diseases and ageing. From concept to implementation and policies [Articolo su rivista]
Bousquet, Jean; Jorgensen, Christian; Dauzat, Michel; Cesario, Alfredo; Camuzat, Thierry; Bourret, Rodolphe; Best, Nicolas; Anto, Josep M; Abecassis, Frederic; Aubas, Pierre; Avignon, Antoine; Badin, Melanie; Bedbrook, Anna; Blain, Hubert; Bourdin, Arnaud; Bringer, Jacques; Camu, William; Cayla, Guilhaume; Costa, David J; Courtet, Philippe; Cristol, Jean Paul; Demoly, Pascal; de la Coussaye, Jean Emmanuel; Fesler, Pierre; Gouzi, Fares; Gris, Jean Christophe; Guillot, Bernard; Hayot, Maurice; Jeandel, Claude; Jonquet, Olivier; Journot, Laurent; Lehmann, Sylvain; Mathieu, Gwenaelle; Morel, Jacques; Ninot, Gregory; Pelissier, Jacques; Picot, Marie Christine; Radier Pontal, Francoise; Robine, Jean Marie; Rodier, Michel; Roubille, Francois; Sultan, Ariane; Wojtusciszyn, Anne; Auffray, Charles; Balling, Rudi; Barbara, Cristina; Cambon Thomsen, Anne; Chavannes, Niels H; Chuchalin, Alexander; Crooks, George; Dedeu, Antoni; Fabbri, Leonardo; Garcia Aymerich, Judith; Hajjam, Jawad; Melo Gomes, Elisabete; Palkonen, Susana; Piette, Francois; Pison, Christophe; Price, David; Samolinski, Boleslaw; Schunemann, Holger J; Sterk, Peter J; Yiallouros, Panayiotis; Roca, Josep; Van de Perre, Philippe; Mercier, Jacques
abstract

Chronic diseases are diseases of long duration and slow progression. Major NCDs (cardiovascular diseases, cancer, chronic respiratory diseases, diabetes, rheumatologic diseases and mental health) represent the predominant health problem of the Century. The prevention and control of NCDs are the priority of the World Health Organization 2008 Action Plan, the United Nations 2010 Resolution and the European Union 2010 Council. The novel trend for the management of NCDs is evolving towards integrative, holistic approaches. NCDs are intertwined with ageing. The European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) has prioritised NCDs. To tackle them in their totality in order to reduce their burden and societal impact, it is proposed that NCDs should be considered as a single expression of disease with different risk factors and entities. An innovative integrated health system built around systems medicine and strategic partnerships is proposed to combat NCDs. It includes (i) understanding the social, economic, environmental, genetic determinants, as well as the molecular and cellular mechanisms underlying NCDs; (ii) primary care and practice-based interprofessional collaboration; (iii) carefully phenotyped patients; (iv) development of unbiased and accurate biomarkers for comorbidities, severity and follow up of patients; (v) socio-economic science; (vi) development of guidelines; (vii) training; and (viii) policy decisions. The results could be applicable to all countries and adapted to local needs, economy and health systems. This paper reviews the complexity of NCDs intertwined with ageing. It gives an overview of the problem and proposes two practical examples of systems medicine (MeDALL) applied to allergy and to NCD co-morbidities (MACVIA-LR, Reference Site of the European Innovation Partnership on Active and Healthy Ageing).

2014 - The Burden of Image Based Emphysema and Bronchiolitis in HIV-Infected Individuals on Antiretroviral Therapy [Articolo su rivista]
Guaraldi, Giovanni; Besutti, Giulia; Scaglioni, Riccardo; Santoro, Antonella; Zona, Stefano; Ligabue, Guido; Marchioni, Alessandro; Orlando, Gabriella; Carli, Federica; Beghe', Bianca; Fabbri, Leonardo; J., Leipsic; D., Don Sin; S. F. P., Man
abstract

Abstract Background: With the widespread use of anti-retroviral therapy (ART), individuals infected with human immune deficiency virus (HIV) are increasingly experiencing morbidity and mortality from respiratory disorders. However, the prevalence or the risk factors associated with emphysema and bronchiolitis are largely unknown. Methods: Thoracic computed tomography (CT) scans were performed in 1,446 patients infected with HIV who were on ART and who attended a tertiary care metabolic clinic (average age 48 years and 29% females). Detailed history and physical examination including anthropometric measurements were performed. Complete pulmonary function tests were performed in a subset of these patients (n = 364). No subjects were acutely ill with a respiratory condition at the time of CT scanning. Findings: Nearly 50% of the subjects had CT evidence for emphysema, bronchiolitis or both with 13% (n = 195) showing bronchiolitis, 19% (n = 274) showing emphysema and 16% (n = 238) revealing both. These phenotypes were synergistically associated with reduced regular physical activity (p for interaction ,.0001). The most significant risk factors for both phenotypes were cigarette smoking, intravenous drug use and peripheral leucocytosis. Together, the area-under-the curve statistics was 0.713 (p = 0.0037) for discriminating those with and without these phenotypes. There were no significant changes in lung volumes or flow rates related to these phenotypes, though the carbon monoxide diffusion capacity was reduced for the emphysema phenotype. Interpretation: Emphysema and bronchiolitis are extremely common in HIV-infected patients who are treated with ART and can be identified by use of thoracic CT scanning.

2013 - Acute exacerbations of chronic obstructive pulmonary disease provide a unique opportunity to take care of patients [Articolo su rivista]
Beghe', Bianca; Garofalo, Martina; Fabbri, Leonardo
abstract

Exacerbation of chronic obstructive pulmonary disease (ECOPD) identifies the acute phase of COPD. The COPD patient is often frail and elderly with concomitant chronic diseases. This requires the physician not only looks at specific symptoms or organs, but to consider the patient in all his or her complexity. ©Copyright B. Beghé et al., 2013 Licensee PAGEPress.

2013 - Asthma [Capitolo/Saggio]
Beghe', Bianca; Fabbri, Leonardo
abstract

Non richiesto

2013 - Beclometasone–formoterol as maintenance and reliever treatment in patients with asthma: a double-blind, randomised controlled trial [Articolo su rivista]
Alberto, Papi; Massimo, Corradi; Catherine Pigeon, Francisco; Roberta, Baronio; Zenon, Siergiejko; Stefano, Petruzzelli; Fabbri, Leonardo; Klaus F., Rabe
abstract

Summary Background According to international treatment guidelines, inhaled rapid-acting β2 agonists should be used for the control of symptoms in patients with asthma. We compared the efficacy and safety of an extrafine combination inhaler containing a corticosteroid (beclometasone) plus a rapid-onset, long-acting β2 agonist (formoterol) with a short-acting β2 agonist (salbutamol) as reliever strategies in patients taking beclometasone–formoterol combination as maintenance treatment. Methods In a double-blind trial undertaken in 183 centres in 14 European countries over 48 weeks, patients (aged ≥18 years) with asthma that was not fully controlled, with a forced expiratory volume in 1 s (FEV1) of at least 60% predicted, had a 2-week run in. During this period, patients were treated with a combination of beclometasone 100 μg and formoterol 6 μg per one inhalation twice daily plus salbutamol 100 μg as required delivered by use of a pressurised metered-dose inhaler. They were then randomly assigned in a 1:1 ratio with a computer-generated randomisation list to receive beclometasone 100 μg plus formoterol 6 μg or salbutamol 100 μg as reliever in addition to maintenance with beclometasone 100 μg plus formoterol 6 μg twice daily. Primary outcome was the time to first severe exacerbation (admission to hospital or visit to emergency department, or use of systemic steroids for ≥3 consecutive days). Secondary outcomes were number of severe exacerbations (events per 100 patients per year), time to and number of mild exacerbations, additional exacerbation variables, lung function, symptom scores, and asthma control. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00861926. Findings 1714 patients were randomly assigned to the as-needed beclometasone–formoterol (n=857) and as-needed salbutamol groups (n=857), and 1701 were analysed (852 and 849, respectively). 326 severe exacerbations were reported by 251 patients during the study, and 99 versus 152 patients had at least one exacerbation during the 48 weeks, respectively. Compared with beclometasone–formoterol plus salbutamol as needed, beclometasone–formoterol for both maintenance and reliever treatment significantly increased the time to first exacerbation (209 days vs 134 days) by 75 days, with a 36% reduction in risk (hazard ratio 0·64 [95% CI 0·49 to 0·82]; p=0·0005), and the estimated probability was 12% and 18%, respectively (p=0·0003). The number of days with mild asthma exacerbations was also lower with as-needed beclometasone–formoterol than with as-needed salbutamol (56·04 days per patient per year vs 65·11 days per patient per year; 0·86 [0·76 to 0·98]; p=0·021). From the run-in period to week 48, both treatments improved symptoms (mean change −1·59 [–1·94 to −1·25] in the as-needed beclometasone–formoterol group vs −1·44 [–1·78 to −1·10] in the as-needed salbutamol group, difference −0·15 [–0·60 to 0·30]; p=0·507), percentage of asthma control days (9·5% [7·3 to 11·8] vs 10·9% [8·7 to 13·1], respectively, −1·4 [–4·3 to 1·6]; p=0·359), use of reliever (–0·29 [–0·38 to −0·20] vs −0·27 [–0·36 to −0·19], respectively, −0·02 [–0·13 to 0·10]; p=0·794), and lung function (FEV1, 0·090 [0·060 to 0·120] vs 0·090 [0·060–0·120], respectively, 0·001 [–0·040 to 0·040]; p=0·969), and were well tolerated (patients with serious adverse events, 32 [4%] and 41 [5%], respectively). Interpretation Our results lend support to the use of the combination of a single inhaled corticosteroid plus a rapid-onset, long-acting β2 agonist for maintenance and relief in patients with moderate to severe asthma and provide encouraging data for the formulation of beclometasone–formoterol for this use.

2013 - Bradykinin-induced asthmatic fibroblast/myofibroblast activities via bradykinin B2 receptor and different MAPK pathways [Articolo su rivista]
Federica, Sabatini; Fabrizio, Luppi; Loredana, Petecchia; Antonino Di, Stefano; Anna M., Longo; Alessandra, Eva; Cristina, Vanni; Pieter S., Hiemstra; Peter J., Sterk; Valentina, Sorbello; Fabbri, Leonardo; Giovanni A., Rossi; Fabio L. M., Ricciardolo
abstract

Bradykinin drives normal lung fibroblasts into myofibroblasts, induces fibroblast proliferation and activates mitogen activated protein kinase pathways (MAPK) but its effects on bronchial fibroblasts from asthmatics (HBAFb) have not been yet studied. We studied bradykinin-induced fibroblast proliferation and differentiation and the related intracellular mechanisms in HBAFb compared to normal bronchial fibroblasts (HNBFb). Bradykinin-stimulated HBAFb and HNBFb were used to assess: bradykinin B-2 receptor expression by Western blot analysis; cell proliferation by [H-3] thymidine incorporation; alpha-smooth muscle actin (SMA) expression/polymerization by Western blot and immunofluorescence; epidermal growth factor (EGF) receptor, extracellular-regulated kinase (ERK) 112 and p38 MAPK activation by immunoprecipitation and Western blot, respectively. Constitutive bradykinin B-2 receptor and alpha-SMA expression was higher in HBAFb as compared to HNBFb. Bradykinin increased bradykinin B-2 receptor expression in HBAFb. Bradykinin, via bradykinin B-2 receptor, significantly increased fibroblast proliferation at lower concentration (10(-11) M) and alpha-SMA expression/polymerization at higher concentration (10(-6) M) in both cells. Bradykinin increased ERK1/2 and p38 phosphorylation via bradykinin B-2 receptor; EGF receptor inhibitor AG1478 and panmetalloproteinase inhibitor GM6001 blocked bradykinin-induced ERK1/2 activation but not p38 phosphorylation. Bradykinin, via bradykinin B-2 receptor, induced EGF receptor phosphorylation that was suppressed by AG1478. In HBAFb AG1478, GM6001, the ERK1/2-inhibitor U0126 and the p38 inhibitor SB203580 suppressed bradykinin-induced cell proliferation, but only SB203580 reduced myofibroblast differentiation. These data indicate that bradykinin is actively involved in asthmatic bronchial fibroblast proliferation and differentiation, through MAPK pathways and EGF receptor transac-tivation, by which bradykinin may contribute to airway remodeling in asthma, opening new horizons for potential therapeutic implications in asthmatic patients. (C) 2013 Elsevier B.V. All rights reserved.

2013 - Changes in Your Breathing Can Change Your Brain [Articolo su rivista]
Roberto Rodriguez, Roisin; Sara, Llufriu; Fabbri, Leonardo
abstract

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2013 - Characterisation of exacerbation risk and exacerbator phenotypes in the POET-COPD trial [Articolo su rivista]
Kai M., Beeh; Thomas, Glaab; Susanne, Stowasser; Hendrik, Schmidt; Fabbri, Leonardo; Klaus F., Rabe; Claus F., Vogelmeier
abstract

Background: Data examining the characteristics of patients with frequent exacerbations of chronic obstructive pulmonary disease (COPD) and associated hospitalisations and mortality are scarce. Methods: Post-hoc analysis of the Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial, targeting exacerbations as the primary endpoint. Patients were classified as non-, infrequent, and frequent exacerbators (0, 1, or >= 2 exacerbations during study treatment), irrespective of study treatment. A multivariate Cox regression model assessed the effect of covariates on time to first exacerbation. Results: In total, 7376 patients were included in the analysis: 63.5% non-exacerbators, 22.9% infrequent, 13.6% frequent exacerbators. Factors significantly associated with exacerbation risk were age, sex, body mass index, COPD duration and severity, smoking history, baseline inhaled corticosteroid use, and preceding antibiotic or systemic corticosteroid courses. Frequent exacerbators had greater severity and duration of COPD, received more pulmonary medication, and >= 2 systemic corticosteroid or antibiotic courses in the preceding year, and were more likely to be female and ex-smokers. The small proportion of frequent exacerbators (13.6%) accounted for 56.6% of exacerbation-related hospitalisations, which, overall, were associated with a three-fold increase in mortality. Conclusion: The frequent exacerbator phenotype was closely associated with exacerbation-related hospitalisations, and exacerbation-related hospitalisations were associated with poorer survival

2013 - Chronic Obstructive Pulmonary Disease is just one component of the complex multimorbidities in patients with COPD. [Articolo su rivista]
Clini, Enrico; Beghe', Bianca; Fabbri, Leonardo
abstract

Not available

2013 - Echocardiography, Spirometry, and Systemic Acute-Phase Inflammatory Proteins in Smokers with COPD or CHF: An Observational Study [Articolo su rivista]
Beghe', Bianca; Verduri, Alessia; Bottazzi, Barbara; Stendardo, Mariarita; Fucili, Alessandro; Balduzzi, Sara; Leuzzi, Chiara; Papi, Alberto; Mantovani, Alberto; Fabbri, Leonardo; Ceconi, Claudio; Boschetto, Piera
abstract

Chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF) may coexist in elderly patients with a history of smoking. Low-grade systemic inflammation induced by smoking may represent the link between these 2 conditions. In this study, we investigated left ventricular dysfunction in patients primarily diagnosed with COPD, and nonreversible airflow limitation in patients primarily diagnosed with CHF. The levels of circulating high-sensitive C-reactive protein (Hs-CRP), pentraxin 3 (PTX3), interleukin-1 beta (IL-1 beta), and soluble type II receptor of IL-1 (sIL-1RII) were also measured as markers of systemic inflammation in these 2 cohorts. Patients aged >= 50 years and with >= 10 pack years of cigarette smoking who presented with a diagnosis of stable COPD (n=70) or stable CHF (n=124) were recruited. All patients underwent echocardiography, N-terminal pro-hormone of brain natriuretic peptide measurements, and post-bronchodilator spirometry. Plasma levels of Hs-CRP, PTX3, IL-1 beta, and sIL-1RII were determined by using a sandwich enzyme-linked immuno-sorbent assay in all patients and in 24 healthy smokers (control subjects). Although we were unable to find a single COPD patient with left ventricular dysfunction, we found nonreversible airflow limitation in 34% of patients with CHF. On the other hand, COPD patients had higher plasma levels of Hs-CRP, IL1 beta, and sIL-1RII compared with CHF patients and control subjects (p < 0.05). None of the inflammatory biomarkers was different between CHF patients and control subjects. In conclusion, although the COPD patients had no evidence of CHF, up to one third of patients with CHF had airflow limitation, suggesting that routine spirometry is warranted in patients with CHF, whereas echocardiography is not required in well characterized patients with COPD. Only smokers with COPD seem to have evidence of systemic inflammation.

2013 - Effect of tiotropium vs. salmeterol on exacerbations: GOLD II and maintenance therapy naïve patients [Articolo su rivista]
Vogelmeier, C; Fabbri, Leonardo; Rabe, Kf; Beeh, Km; Schmidt, H; Metzdorf, N; Glaab, T.
abstract

The objective of this study was to investigate the effect of tiotropium compared with salmeterol on exacerbations in patients with moderate (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage II) chronic obstructive pulmonary disease (COPD) and those naïve to maintenance respiratory therapy in the 1-year Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD(®)) trial (NCT00563381). Time to first exacerbation (primary endpoint) and rates of exacerbations were analyzed using exploratory Cox and Poisson regression (adjusting for time on treatment). Of 7376 randomized patients, 3614 were GOLD stage II (tiotropium n = 1781; salmeterol n = 1833) and 1343 were maintenance therapy naïve (tiotropium n = 672; salmeterol n = 671). Tiotropium significantly increased time to first exacerbation vs. salmeterol in GOLD stage II patients (hazard ratio [HR], 0.88; 95% confidence interval [CI]: 0.79-0.99; p = 0.028) and maintenance therapy naïve patients (HR, 0.79; 95% CI, 0.65-0.97; p = 0.028). Annual exacerbation rates were also significantly lower with tiotropium in the maintenance naïve subgroup compared with salmeterol (rate ratio [RR], 0.77; 95% CI, 0.63-0.94; p = 0.012). In the GOLD stage II subgroup, the rate of hospitalized exacerbations per year was significantly lower with tiotropium than with salmeterol (RR, 0.70; 95% CI, 0.57-0.85; p < 0.001); tiotropium also significantly prolonged time to first hospitalized exacerbation versus salmeterol in this subgroup (HR, 0.66; 95% CI, 0.48-0.91; p = 0.012). In conclusion, results from this prespecified subgroup analysis support the selection of tiotropium as first-choice maintenance therapy for patients with GOLD stage II COPD.

2013 - Exacerbation of respiratory Symptoms in COPD patients may not be exacerbations of COPD [Articolo su rivista]
Beghe', Bianca; Verduri, Alessia; Roca, M; Fabbri, Leonardo
abstract

Exacerbations of chronic obstructive pulmonary disease (COPD) are defined as acute events characterised by a worsening of the patient's respiratory symptoms, particularly dyspnoea, beyond day-to-day variation, leading to a change in medical treatment and/or hospitalisation. Exacerbations of COPD are a leading cause of hospitalisation and healthcare expenditures, particularly in frail, elderly patients. They alter the health-related quality of life and the natural course of disease, increasing the risk of mortality, both during and after the acute event. Patients with COPD frequently have chronic comorbidities. Several of these comorbidities may produce acute events, contributing to the increased morbidity and mortality in COPD exacerbations: acute myocardial infarction, congestive heart failure, cerebrovascular disease, cardiac arrhythmias and pulmonary circulation disorders.

2013 - FAQs about the GOLD 2011 assessment proposal of COPD: a comparative analysis of four different cohorts [Articolo su rivista]
A., Agusti; S., Hurd; P., Jones; Fabbri, Leonardo; F., Martinez; C., Vogelmeier; J., Vestbo; R., Rodriguez Roisin
abstract

Since the publication of the new Global Initiative for Chronic Obstructive Lung Disease (GOLD) proposal for the assessment of chronic obstructive lung disease (COPD), four studies have used existing cohorts to explore the characteristics, temporal variability and/or relationship with outcomes of the four resulting patient categories (A, B, C and D). Here, we compare their results and address a number of frequently asked questions (FAQs) on the topic. The most salient findings were that: 1) the prevalence of these four groups depends on the specific population studied, C being the least prevalent; 2) comorbidities are particularly prevalent in the two "high-symptom" groups (B and D); 3) patients classifiedZ as A or D tend to remain in the same group over time, whereas those classified as B or C change substantially during follow-up; 4) mortality at 3 years was lowest in A and worst in D but surprisingly similar (and intermediate) in B and C; and 5) the incidence of exacerbations during follow-up increases progressively from A to D but that of hospitalisations behave similarly to mortality. These results identify several strengths and shortcomings of the new GOLD assessment proposal, particularly that group B is associated with more morbidity and high mortality

2013 - Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary [Articolo su rivista]
Vestbo, J; Hurd, Ss; Agusti, Ag; Jones, Pw; Vogelmeier, C; Anzueto, A; Barnes, Pj; Fabbri, Leonardo; Martinez, Fj; Nishimura, M; Stockley, Ra; Sin, Dd; Rodriguez Roisin, R.
abstract

Chronic obstructive pulmonary disease (COPD) is a global health problem and since 2001 the Global Initiative for Chronic Obstructive Lung Disease (GOLD) has published its strategy document for the diagnosis and management of COPD. This executive summary presents the main contents of the second 5-year revision of the GOLD document that has implemented some of the vast knowledge about COPD accumulated over the last years. Today, GOLD recommends that spirometry is required for the clinical diagnosis of COPD in order to avoid misdiagnosis and to ensure proper evaluation of severity of airflow limitation. The document highlights that the assessment of the COPD patient should always include assessment of 1) symptoms, 2) severity of airflow limitation, 3) history of exacerbations, and 4) comorbidities. The first three points can be used to evaluate level of symptoms and risk of future exacerbations and this is done in a way that split COPD patients into 4 categories - A, B, C and D. Non-pharmacologic and pharmacologic management of COPD match this assessment in an evidence-based attempt to relieve symptoms and reduce risk of exacerbations. Identification and treatment of comorbidities must have high priority and a separate chapter in the document addresses management of comorbidities as well as COPD in the presence of comorbidities. The revised document also contains a new chapter on exacerbations of COPD. The GOLD initiative will continue to bring COPD to the attention of all relevant shareholders a

2013 - Identifying and Treating COPD in Cardiac Patients [Articolo su rivista]
Carlo, Nozzoli; Beghe', Bianca; Piera, Boschetto; Fabbri, Leonardo
abstract

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2013 - Inhaled Corticosteroids in COPD: Pros and Cons. [Articolo su rivista]
Zervas, E.; Samitas, K.; Gaga, M.; Beghe', Bianca; Fabbri, Leonardo
abstract

Chronic obstructive pulmonary disease (COPD) is a devastating illness characterized by airway and systemic inflammation, progressive airway obstruction and exacerbations. It is a major cause of chronic morbidity and mortality, projected to be the third leading cause of death by the year 2020. Although there is currently no definite cure, COPD is both a preventable and treatable disease. Important changes in our perspective and understanding of the disease have been made that lead to marked improvements in the treatment of COPD, such as the use of long-acting anticholinergics, β2 agonists and inhaled corticosteroids (ICS). Current GOLD guidelines call for the use of ICS in patients with severe and very severe airflow limitation and/or for patients with frequent exacerbations. This population constitutes only around 20% of all COPD patients, however current data show that as much as 70% are prescribed ICS. Although widely used, clinical trials on the efficacy of ICS in COPD have been up to now inconclusive or even contradictory. This has lead to wide confusion and debate regarding their role in the management of COPD. This review summarizes all current knowledge originating from observational studies, randomized clinical trials and expert views regarding ICS therapy in COPD. Arguments in favor and against the use of ICS are presented with respect to airway and systemic inflammation, exacerbation frequency and severity, lung function decline, quality of life, mortality and adverse events

2013 - Long-term macrolide treatment for chronic respiratory disease [Articolo su rivista]
Spagnolo, Paolo; Fabbri, Leonardo; A., Bush
abstract

Long-term macrolide treatment was first shown to alter the natural history of diffuse panbronchiolitis (DPB) in the late 1980s. Since then, macrolides have been demonstrated to exert anti-inflammatory and immunomodulatory activity in addition to being antimicrobial. Indeed, their spectrum of action extends to the regulation of leukocyte function and production of inflammatory mediators, control of mucus hypersecretion, resolution of inflammation and modulation of host defence mechanisms. As such, the potential benefit of macrolide antibiotics has been evaluated in a variety of chronic respiratory diseases. The best studied condition is cystic fibrosis, of which there have been six randomised controlled trials showing evidence of benefit. However, most of the studies were limited by small numbers of patients and short follow-up. More recently, landmark studies have demonstrated the efficacy of azithromycin in reducing the risk of acute exacerbations in patients with chronic obstructive pulmonary disease, but the optimal duration and dosing of macrolide treatment remain uncertain. With the exception of patients with DPB and cystic fibrosis, until clear evidence of efficacy is available, the long-term use of macrolides should be limited to highly selected patients after careful evaluation of benefit and harm, or in the context of randomised controlled clinical trials.

2013 - Mechanisms of acute exacerbation of respiratory symptoms in chronic obstructive pulmonary disease [Articolo su rivista]
Roca, Mihai; Verduri, Alessia; Corbetta, Lorenzo; Clini, Enrico; Fabbri, Leonardo; Beghe', Bianca
abstract

Exacerbations of chronic obstructive respiratory disease (ECOPD) are acute events characterized by worsening of the patient's respiratory symptoms, particularly dyspnoea, leading to change in medical treatment and/or hospitalisation. AECOP are considered respiratory diseases, with reference to the respiratory nature of symptoms and to the involvement of airways and lung. Indeed respiratory infections and/or air pollution are the main causes of ECOPD. They cause an acute inflammation of the airways and the lung on top of the chronic inflammation that is associated with COPD. This acute inflammation is responsible of the development of acute respiratory symptoms (in these cases the term ECOPD is appropriate). However, the acute inflammation caused by infections/pollutants is almost associated with systemic inflammation, that may cause acute respiratory symptoms through decompensation of concomitant chronic diseases (eg acute heart failure, thromboembolism, etc) almost invariably associated with COPD. Most concomitant chronic diseases share with COPD not only the underlying chronic inflammation of the target organs (i.e. lungs, myocardium, vessels, adipose tissue), but also clinical manifestations like fatigue and dyspnoea. For this reason, in patients with multi-morbidity (eg COPD with chronic heart failure and hypertension, etc), the exacerbation of respiratory symptoms may be particularly difficult to investigate, as it may be caused by exacerbation of COPD and/or ≥ comorbidity, (e.g. decompensated heart failure, arrhythmias, thromboembolisms) without necessarily involving the airways and lung. In these cases the term ECOPD is inappropriate and misleading.

2013 - Occurrence and impact of chronic obstructive pulmonary disease in elderly patients with stable heart failure. [Articolo su rivista]
Boschetto, P; Fucili, A; Stendardo, M; Malagù, M; Parrinello, G; Casimirri, E; Potena, A; Ballerin, L; Fabbri, Leonardo; Ferrari, R; Ceconi, C.
abstract

SUMMARY AT A GLANCE: We examined the occurrence of COPD in elderly outpatients with stable heart failure. Longitudinal follow-up over 3 years of study indicated that coexistent COPD did not affect patient survival. ABSTRACT: Background and objective:  The coexistence of chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF) increases with age. We investigated the occurrence, prognosis, and therapeutic implications of concurrent COPD in elderly patients with CHF. Methods:  We enrolled 118 consecutive patients, ≥65 years old with ≥10 pack-years of smoking and with a verified diagnosis of CHF in stable condition. They were followed for a mean of 1029 (range 758-1064) days. All patients had spirometry and the diagnosis and classification of COPD were made according to GOLD Guidelines. Results:  The mean occurrence of COPD was 30% (90% CI 24-37%). At baseline in patients with CHF and COPD, there was a shorter 6-minute walking distance (6MWT), lower arterial oxygen tension, glomerular filtration rate and higher N-terminal B-natriuretic peptide (all p<0.05). The prescription of CHF therapies, including β-blockers, was similar in the two groups. After follow-up the presence of COPD in patients with CHF did not appear to influence survival. Conclusions:  COPD is relatively frequent in elderly patients with CHF. COPD did not alter survival. © 2012 The Authors. Respirology © 2012 Asian Pacific Society of Respirology.

2013 - Phosphodiesterase-4 Inhibitor Therapy for Lung Diseases [Articolo su rivista]
Beghe', Bianca; Rabe, Klaus; Fabbri, Leonardo
abstract

Phosphodiesterases (PDEs) are a superfamily of enzymes that catalyze the breakdown of cAMP and/or cyclic guanosine monophosphate (GMP) to their inactive form. PDE4 is the main selective cAMP-metabolizing enzyme in inflammatory and immune cells. Because PDE4 is highly expressed in leukocytes and other inflammatory cells involved in the pathogenesis of inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD), inhibition of PDE4 has been predicted to have an antiinflammatory effect and thus therapeutic efficacy. The limited and inconsistent efficacy and side effects of the early compounds made their further development less desirable in asthma, given the excellent efficacy/tolerability ratio of inhaled steroids. The lack of effective antiinflammatory drug treatment for COPD has thus shifted the interest in development toward COPD. Roflumilast, the only PDE4 inhibitor that has reached the market because of the good efficacy/tolerability ratio, is recommended for patients with COPD with severe airflow limitation, symptoms of chronic bronchitis, and a history of exacerbations, whose disease is not adequately controlled by long-acting bronchodilators. Albeit safe, it maintains significant side effects (diarrhea, nausea, weight loss) that make it intolerable in some patients. Future developments of PDE4 inhibitors include extended indications of roflumilast (1) in patients with COPD, and(2) in other respiratory (e. g., asthma) and nonrespiratory chronic inflammatory/metabolic conditions (e. g., diabetes), as well as (3) the development of new molecules with PDE4 inhibitory properties with an improved efficacy/tolerability profile.

2013 - Plasma sRAGE and N-(carboxymethyl) lysine in patients with CHF and/or COPD [Articolo su rivista]
Piera, Boschetto; Ilaria, Campo; Mariarita, Stendardo; Enrico, Casimirri; Carmine, Tinelli; Marina, Gorrini; Claudio, Ceconi; Alessandro, Fucili; Alfredo, Potena; Alberto, Papi; Licia, Ballerin; Fabbri, Leonardo; Maurizio, Luisetti
abstract

BACKGROUND: Professional societies, like many other organizations around the world, have recognized the need to use more rigorous processes to ensure that health care recommendations are informed by the best available research evidence. This is the 10th of a series of 14 articles that were prepared to advise guideline developers in respiratory and other diseases. This article deals with how multiple comorbidities (co-existing chronic conditions) may be more effectively integrated into guidelines. METHODS: In this review we addressed the following topics and questions using chronic obstructive pulmonary disease (COPD) as an example. (1) How important are multiple comorbidities for guidelines? (2) How have other organizations involved in the development of guidelines for single chronic disease approached the problem of multiple comorbidities? (3) What are the implications of multiple comorbidities for pharmacological treatment? (4) What are the potential changes induced by multiple comorbidities in guidelines? (5) What are the implications of considering a population of older patients with multiple comorbidities in designing clinical trials? Our conclusions are based on available evidence from the published literature, experience from guideline developers, and workshop discussions. We did not attempt to examine all Clinical Practice Guidelines (CPGs) and relevant literature. Instead, we selected CPGs generated by prominent professional organizations and relevant literature published in widely read journals, which are likely to have a high impact on clinical practice. RESULTS AND CONCLUSIONS: A widening gap exists between the reality of the care of patients with multiple chronic conditions and the practical clinical recommendations driven by CPGs focused on a single disease, such as COPD. Guideline development panels should aim for multidisciplinary representation, especially when contemplating recommendations for individuals aged 65 years or older (who often have multiple comorbidities), and should evaluate the quality of evidence and the strength of recommendations targeted at this population. A priority area for research should be to assess the effect of multiple concomitant medications and assess how their combined effects are altered by genetic, physiological, disease-related, and other factors. One step that should be implemented immediately would be for existing COPD guidelines to add new sections to address the impact of multiple comorbidities on screening, diagnosis, prevention, and management recommendations. Research should focus on the possible interaction of multiple medications. Furthermore, genetic, physiological, disease-related, and other factors that may influence the directness (applicability) of the evidence for the target population in clinical practice guidelines should be examined.

2013 - Prognostic role of clusterin in resected adenocarcinomas of the lung. [Articolo su rivista]
Panico, Francesca; Casali, C; Rossi, Giulio; Rizzi, F; Morandi, Uliano; Bettuzzi, Sara; Davalli, Pierpaola; Corbetta, Lorenzo; Storelli, Es; Corti, Arnaldo; Fabbri, Leonardo; Astancolle, Serenella; Luppi, Fabrizio
abstract

Rationale Clusterin expression may change in various human malignancies, including lung cancer. Patients with resectable non-small cell lung cancer (NSCLC), including adenocarcinoma, have a poor prognosis, with a relapse rate of 30–50% within 5 years. Nuclear factor kB (Nf-kB) is an intracellular protein involved in the initiation and progression of several human cancers, including the lung. Objectives We investigate the role of clusterin and Nf-kB expression in predicting the prognosis of patients with early-stage surgically resected adenocarcinoma of the lung. Findings The level of clusterin gradually decreased from well-differentiated to poorly differentiated adenocarcinomas. Clusterin expression was significantly higher in patients with low-grade adenocarcinoma, in early-stage disease and in women. Clusterin expression was inversely related to relapse and survival in both univariate and multivariate analyses. Finally, we observed an inverse correlation between Nf-kB and clusterin. Conclusions Clusterin expression represents an independent prognostic factor in surgically resected lung adenocarcinoma and was proven to be a useful biomarker for fewer relapses and longer survival in patients in the early stage of disease. The inverse correlation between Nf-kB and clusterin expression confirm the previously reported role of clusterin as potent down regulator of Nf-kB.

2013 - Reply: look at the moon, not just at the finger indicating the moon [Articolo su rivista]
Fabbri, Leonardo; Beghe', Bianca; Agustí, Alvar
abstract

Not available

2013 - Systemic Soluble Receptor for Advanced Glycation Endproducts Is a Biomarker of Emphysema and Associated with AGER Genetic Variants in Patients with Chronic Obstructive Pulmonary Disease [Articolo su rivista]
Donavan T., Cheng; Deog Kyeom, Kim; Debra A., Cockayne; Anton, Belousov; Hans, Bitter; Michael H., Cho; Annelyse, Duvoix; Lisa D., Edwards; David A., Lomas; Bruce E., Miller; Niki, Reynaert; Ruth Tal, Singer; Emiel F. M., Wouters; Alvar, Agustí; Fabbri, Leonardo; Alex, Rames; Sudha, Visvanathan; Stephen I., Rennard; Paul, Jones; Harsukh, Parmar; William, Macnee; Gerhard, Wolff; Edwin K., Silverman; Ruth J., Mayer; Sreekumar G., Pillai
abstract

RATIONALE: Emphysema in chronic obstructive pulmonary disease (COPD) can be characterized by high-resolution chest computed tomography (HRCT); however, the repeated use of HRCT is limited because of concerns regarding radiation exposure and cost. OBJECTIVES: To evaluate biomarkers associated with emphysema and COPD-related clinical characteristics, and to assess the relationships of soluble receptor for advanced glycation endproducts (sRAGE), a candidate systemic biomarker identified in this study, with single-nucleotide polymorphisms (SNPs) in the gene coding for RAGE (AGER locus) and with clinical characteristics. METHODS: Circulating levels of 111 biomarkers were analyzed for association with clinical characteristics in 410 patients with COPD enrolled in the TESRA study. sRAGE was also measured in the ECLIPSE cohort in 1,847 patients with COPD, 298 smokers and 204 nonsmokers. The association between 21 SNPs in the AGER locus with sRAGE levels and clinical characteristics was also investigated. MEASUREMENTS AND MAIN RESULTS: sRAGE was identified as a biomarker of diffusing capacity of carbon monoxide and lung density in the TESRA cohort. In the ECLIPSE cohort, lower sRAGE levels were associated with increased emphysema, increased Global Initiative for Chronic Obstructive Lung Disease stage, and COPD disease status. The associations with emphysema in both cohorts remained significant after covariate adjustment (P < 0.0001). One SNP in the AGER locus, rs2070600, was associated with circulating sRAGE levels both in TESRA (P = 0.0014) and ECLIPSE (7.07 × 10(-16)), which exceeded genome-wide significance threshold. Another SNP (rs2071288) was also associated with sRAGE levels (P = 0.01) and diffusing capacity of carbon monoxide (P = 0.01) in the TESRA study. CONCLUSIONS: Lower circulating sRAGE levels are associated with emphysema severity and genetic polymorphisms in the AGER locus are associated with systemic sRAGE levels. Clinical trial registered with www.clinicaltrials.gov (NCT 00413205 and NCT 00292552).

2012 - COPD and the Solar System:Introducing the Chronic Obstructive Pulmonary Disease Comorbidome [Articolo su rivista]
Fabbri, Leonardo; Beghe', Bianca; A., Agustí
abstract

Chronic obstructive pulmonary disease (COPD) is increasingly recognized as the pulmonary component of a more complex syndrome characterized by structural abnormalities of the airways (bronchiolitis) and lung (emphysema), and also by concomitant disorders (comorbidities) such as cardiovascular disease, metabolic syndrome, osteoporosis, depression, cancer, and inflammatory bowel disease. These comorbidities influence not only the severity of the symptoms and the quality of life of individual patients, but also the risk of hospitalization and eventually death. In turn, COPD is a frequent and important comorbidity of these same chronic conditions (e.g., ischemic heart disease, chronic heart failure, arrhythmia, osteoporosis, and metabolic syndrome). Indeed, only a minority of patients with COPD die of respiratory failure; most die of other conditions, particularly cardiovascular disease, pneumonia, thromboembolism, and cancer (mainly lung cancer)

2012 - COPD in the elderly is almost invariably associated with one or more chronic comorbidities [Relazione in Atti di Convegno]
Verduri, A; Roca, M; Bortolotti, M; Garofalo, M; Balduzzi, S; Veronesi, J; Leuzzi, C; Clini, Enrico; Modena, Maria Grazia; Fabbri, Leonardo; Beghe', Bianca
abstract

non presente

2012 - Do small airway abnormalities characterize asthma phenotypes? In search of proof. [Articolo su rivista]
M., Contoli; M., Kraft; Q., Hamid; J., Bousquet; K. F., Rabe; Fabbri, Leonardo; A., Papi
abstract

The role of small airway abnormalities in asthma pathogenesis has been extensively studied and debated for several decades. However, whether or not small airway abnormalities play a relevant role in specific phenotypes of asthmatic patients and contribute to clinical presentation is largely unknown. In the present review, we evaluated available data on the role of small airways in severe asthma, with a further focus on asthma in smokers and asthma in the elderly. These phenotypes are characterized by a poor response to treatment and they can represent a model of greater small airway impairment. In severe asthmatics, small airway involvement has been shown through evidence of both distal inflammation and of increased air trapping. The few available data on asthmatics who smoke, and elderly asthmatics, similarly suggests that small airway abnormalities contribute to the pathogenesis of the disease. In this perspective, there could be a rationale for specifically assessing small airway impairment in these patients and for clinical studies evaluating whether pharmacological approaches targeting the more peripheral airways result in clinical benefits beyond conventional therapy.

2012 - Does roflumilast decrease exacerbations in severe COPD patients not controlled by inhaled combination therapy? the REACT study protocol. [Articolo su rivista]
P. M., Calverley; F. J., Martinez; Fabbri, Leonardo; U. M., Goehring; K. F., Rabe
abstract

Many patients with chronic obstructive pulmonary disease (COPD) continue to suffer exacerbations, even when treated with maximum recommended therapy (eg, inhaled combinations of long-acting β(2)-agonist and high dose inhaled corticosteroids, with or without a long-acting anticholinergic [long-acting muscarinic antagonist]). Roflumilast is approved to treat severe COPD in patients with chronic bronchitis - and a history of frequent exacerbations - as an add-on to bronchodilators.PURPOSE:The REACT (Roflumilast in the Prevention of COPD Exacerbations While Taking Appropriate Combination Treatment) study (identification number RO-2455-404-RD, clinicaltrials. gov identifier NCT01329029) will investigate whether roflumilast further reduces exacerbations when added to inhaled combination therapy in patients still suffering from frequent exacerbations.PATIENTS AND METHODS:REACT is a 1-year randomized, double-blind, multicenter, phase III/IV study of roflumilast 500 μg once daily or placebo on top of a fixed long-acting β(2)-agonist/inhaled corticosteroid combination. A concomitant long-acting muscarinic antagonist will be allowed at stable doses. The primary outcome is the rate of moderate or severe COPD exacerbations. Using a Poisson regression model with a two-sided significance level of 5%, a sample size of 967 patients per treatment group is needed for 90% power. COPD patients with severe to very severe airflow limitation, symptoms of chronic bronchitis, and at least two exacerbations in the previous year will be recruited.CONCLUSION:It is hypothesized that because roflumilast (a phosphodiesterase-4 inhibitor) has a different mode of action to bronchodilators and inhaled corticosteroids, it may provide additional benefits when added to these treatments in frequent exacerbators. REACT will be important to determine the role of roflumilast in COPD management. Here, the design and rationale for this important study is described.

2012 - Effect of the Phosphodiesterase 4 Inhibitor Roflumilast on Glucose Metabolism in Patients with Treatment-Naive, Newly Diagnosed Type 2 Diabetes Mellitus. [Articolo su rivista]
Wouters, Ef; Bredenbröker, D; Teichmann, P; Brose, M; Rabe, Kf; Fabbri, Leonardo; Göke, B.
abstract

Context:The phosphodiesterase 4 inhibitor roflumilast is a first-in-class antiinflammatory treatment for severe chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis and a history of frequent exacerbations. In previous clinical studies, a transient and reversible weight decrease was reported with roflumilast, suggesting the systemic actions of this drug may impact metabolism.Objective:Our objective was to investigate the effects of roflumilast on glucose homeostasis and body weight.Design and Setting:We conducted a 12-wk, randomized, double-blind, placebo-controlled multicenter study with outpatients.Patients:Patients (n = 205) with newly diagnosed type 2 diabetes mellitus (DM2) but without COPD were included in the study.Interventions:Roflumilast 500 μg or placebo was administered once daily.Primary Outcome:We evaluated mean change in blood glycated hemoglobin levels.Secondary Outcomes:We also evaluated mean change from baseline in the postmeal area under the curve (AUC) for a range of metabolic parameters.Results:Roflumilast was associated with a significantly greater reduction in glycated hemoglobin levels than placebo (least square mean = -0.45%; P < 0.0001) in patients with DM2. In the roflumilast group, postmeal AUC decreased significantly from baseline to last visit for free fatty acids, glycerol, glucose, and glucagon, whereas they slightly increased for C-peptide and insulin. In contrast to roflumilast, the glucagon AUC increased with placebo, and the insulin AUC decreased. Between-treatment analysis revealed statistically significant differences in favor of roflumilast for glucose (P = 0.0082), glycerol (P = 0.0104), and C-peptide levels (P = 0.0033). Patients in both treatment groups lost weight, although the between-treatment difference of the changes from baseline to last visit [-0.7 (0.4) kg] was not statistically significant (P = 0.0584).Conclusion:Roflumilast lowered glucose levels in patients with newly diagnosed DM2 without COPD, suggesting positive effects on glucose homoeostasis.

2012 - Home Oxygen Saturation Monitoring And Quality Of Life Evaluation In Patients With Idiopathic Pulmonary Fibrosis: Preliminary Results From A Prospective Multicenter Trial [Abstract in Rivista]
Cerri, Stefania; Soncini, Francesco; Sdanganelli, Antonia; Aiello, Marina; Chetta, Alfredo Antonio; Lusuardi, Mirco; Dallari, Rossano; Balduzzi, Sara; Campagna, Anselmo; Casolari, Loretta; Fabbri, Leonardo; Richeldi, Luca
abstract

Introduction. Long-term follow-up of patients with idiopathic pulmonary fibrosis (IPF) is an important component of their clinical management. While oxygen saturation (SpO2) measurement is widely used in both routine practice and clinical trials, feasibility and clinical relevance of long-term SpO2 monitoring has not been studied yet. Methods. We designed a 1-year multicenter prospective study aimed at evaluating the long-term feasibility of home daily SpO2 monitoring and its clinical relevance by assessment of correlation with a symptoms and quality of life (QoL) questionnaire. Enrolled patients received a multi-parameter digital recorder (Sally® Personal Assistant, Medigas, Italy), allowing acquisition, transmission and online web-based storage of SpO2 measurements, together with the data of a short questionnaire on symptoms and QoL. SpO2 data were acquired three times a day, for at least one minute, in resting conditions, while answers to the questionnaire were provided once a day. All data were transmitted daily to a dedicated server through the telephone landline. Spearman’s rank correlation coefficient () was used to calculate the correlation between SpO2 values and the QoL scores. Results. Six months interim analysis was based on 21 IPF patients (15 males, mean age 75 years; 9 receiving long-term oxygen therapy): 17 of them (81%) provided valid data for a mean time (± SD) of 175 (±78) days). The majority (66%) of patients provided sufficient data for calculating the correlation coefficient. In most patients (86%) SpO2 values decreased while QoL score increased (i.e. QoL deteriorated): in 5 the correlation was statistically significant. Patients monitored for longer time were more likely to show a statistically significant correlation between these two parameters. Home SpO2 monitoring was accepted positively by all patients; the majority of them (63%) was able to self-perform all required tasks. Missing data accounted for 41% of all expected data and were mostly due to technical issues during the first weeks of study. Conclusions. Non-invasive home daily monitoring of oxygen saturation is feasible and well accepted in IPF patients. SpO2 seems to correlate with changes in symptoms and QoL scores, thus confirming the clinical relevance of this parameter.

2012 - How to Integrate Multiple Comorbidities in Guideline Development [Relazione in Atti di Convegno]
Fabbri, Leonardo; Boyd, Cynthia; Boschetto, Piera; Rabe, Klaus; Buist, Sonia; Yawn, Barbara; Leff, Bruce; Kent, David; Schünemann, Holger
abstract

Professional societies, like many other organizations around the world, have recognized the need to use more rigorous processes to ensure that health care recommendations are informed by the best available research evidence. This is the 10th of a series of 14 articles that were prepared to advise guideline developers in respiratory and other diseases. This article deals with how multiple comorbidities (co-existing chronic conditions) may be more effectively integrated into guidelines. METHODS: In this review we addressed the following topics and questions using chronic obstructive pulmonary disease (COPD) as an example. (1) How important are multiple comorbidities for guidelines? (2) How have other organizations involved in the development of guidelines for single chronic disease approached the problem of multiple comorbidities? (3) What are the implications of multiple comorbidities for pharmacological treatment? (4) What are the potential changes induced by multiple comorbidities in guidelines? (5) What are the implications of considering a population of older patients with multiple comorbidities in designing clinical trials? Our conclusions are based on available evidence from the published literature, experience from guideline developers, and workshop discussions. We did not attempt to examine all Clinical Practice Guidelines (CPGs) and relevant literature. Instead, we selected CPGs generated by prominent professional organizations and relevant literature published in widely read journals, which are likely to have a high impact on clinical practice. RESULTS AND CONCLUSIONS: A widening gap exists between the reality of the care of patients with multiple chronic conditions and the practical clinical recommendations driven by CPGs focused on a single disease, such as COPD. Guideline development panels should aim for multidisciplinary representation, especially when contemplating recommendations for individuals aged 65 years or older (who often have multiple comorbidities), and should evaluate the quality of evidence and the strength of recommendations targeted at this population. A priority area for research should be to assess the effect of multiple concomitant medications and assess how their combined effects are altered by genetic, physiological, disease-related, and other factors. One step that should be implemented immediately would be for existing COPD guidelines to add new sections to address the impact of multiple comorbidities on screening, diagnosis, prevention, and management recommendations. Research should focus on the possible interaction of multiple medications. Furthermore, genetic, physiological, disease-related, and other factors that may influence the directness (applicability) of the evidence for the target population in clinical practice guidelines should be examined.

2012 - Inhaled corticosteroid and long-acting β2-agonist pharmacological profiles: effective asthma therapy in practice [Articolo su rivista]
Tamm, M; Richards, Dh; Beghe', Bianca; Fabbri, Leonardo
abstract

Fixed-dose combinations of inhaled corticosteroids (ICSs) and long-acting b2-agonists (LABAs) have been used to manage asthma for several years. They are the preferred therapy option for patients who do not achieve optimal control of their asthma with lowdose ICS monotherapy. In Europe, four ICS/LABA products are commercially available for asthma maintenance therapy (fluticasone propionate/formoterol fumarate, fluticasone propionate/salmeterol xinafoate, budesonide/formoterol fumarate and beclometasone dipropionate/formoterol fumarate), and other combinations are likely to be developed over the next few years (e.g. mometasone/formoterol fumarate, fluticasone furoate/ vilanterol, mometasone/indacaterol). Data from randomized, controlled, clinical trials do not demonstrate a clear overall efficacy difference among ICS/LABA combinations approved for asthma therapy. Conversely, pharmacological data indicate that there may be certain advantages to using one ICS or LABA over another because of the specific pharmacodynamic and pharmacokinetic profiles associated with particular treatments. This review article summarizes the pharmacological characteristics of the various ICSs and LABAs available for the treatment of asthma, including the potential for ICS and LABA synergy, and gives an insight into the rationale for the development of the latest ICS/LABA combination approved for asthma maintenance therapy.

2012 - Link between chronic obstructive pulmonary disease and coronary artery disease: implication for clinical practice [Articolo su rivista]
Boschetto, P; Beghe', Bianca; Fabbri, Leonardo; Ceconi, C.
abstract

Chronic obstructive pulmonary disease (COPD) and coronary artery disease (CAD) are global epidemics that incur significant morbidity and mortality. These diseases are frequently found in combination, and they can also be found independent of the common causal factors, primarily smoking. Both conditions are systemic disorders with overlapping mechanisms and pathophysiologic processes. CAD has a strong effect on the severity and prognosis of COPD and vice versa, including acute exacerbations. Even the most recent practical clinical recommendations driven by Clinical Practice Guidelines still focus on one disease at a time, and do not provide advice for the management of patients with associated chronic conditions. COPD should be approached in a more comprehensive manner, including the treatment of cardiac comorbidities, particularly CAD. To focus treatment on these comorbidities might modify the natural course of the disease in patients with COPD who may not find relief from treatment of COPD alone.

2012 - Manuale Medico di Diagnostica e Terapia Roversi XI Edizione. (Editori: Renato Lauro, Francesco Rossi e Alberto Zanchetti; Revisore: Gianfranco Pagano) [Monografia/Trattato scientifico]
V., Savarino; A., Craxi; D., Prisco D; G., Di Pasquale; B., Trimarco; Fabbri, Leonardo; A., Dal Canton; A. M., Colao; S., Del Prato; G., Perpignano; R., Scorza; E., Concia; P., Leoni
abstract

Distretto "Apparato Respiratorio"

2012 - Pro-Calcitonin guided antibiotic treatment of acute exacerbations of Chrnic Obstructive Pulmonary Disease [Poster]
A., Veduri; D'Amico, Roberto; Ruggieri, Valentina; P., Vicini; A., Liverani; M., Plebani; A., Papi; Fabbri, Leonardo; Beghe', Bianca
abstract

non presente

2012 - Quantiferon-TB Gold In-Tube Tests In Hospital Health Care Workers: A Five Years Experience [Abstract in Rivista]
Cerri, Stefania; Meccugni, Barbara; Meacci, Marisa; Pietrosemoli, Paola; Balduzzi, Sara; Rumpianesi, Fabio; Marchegiano, Patrizia; Corona, Gianluca; Fabbri, Leonardo; Richeldi, Luca
abstract

Introduction. Interferon Gamma Release Assays (IGRAs) are being largely used worldwide for the screening of tuberculosis infection among subjects likely to undergo multiple testing, such as health care workers (HCW). In theory, IGRAs should overcome the risk of false positive results due to the boosting effect, at difference with the in vivo tuberculin skin test. Evaluation of IGRA results in HCW in a non-experimental setting over several years may provide information on the real-life performance of these tests in daily practice. We reviewed the results of QuantiFERON-TB In-Tube (QTF-IT) tests performed on HCW over nearly five years, with particular focus on repeated tests. Methods: We extracted the anonymised electronic records of all consecutive QFT-IT performed on HCW between May 2006 and December 2010. All tests were done at the Laboratory of Microbiology and Virology of University Hospital of Modena (Italy). Results: A total of 1,531 tests were performed in 1,189 individuals (mean age ± SD: 37±10 years; 29% male). In 226 subjects (37±9 years; 31% male) QFT-IT was repeated at least once. Among subjects who underwent single testing (n=963, 81%), 85% were negative and 14% positive, as compared to the results at first test among subjects with repeated tests (69% negative, 27% positive; p<0.0001). In the majority of cases (84%) a second QFT-IT provided a concordant valid result. Reversion (from positive to negative) occurred more frequently than conversion (from negative to positive) (respectively, 10% vs. 4% of repeated tests). Rate of indeterminate results was extremely low, 0.4% in subjects with single testing and 1.8% at first test in subjects with multiple tests. At second testing, indeterminate QFT-IT results at first testing became negative in all but one case, which remained indeterminate. Conclusions: In this non-experimental routine setting of tuberculosis infection screening in HCW, subjects who underwent repeated tests were more likely to have a positive QFT-IT at first testing, as compared to subjects with single testing. However, a repeated QFT-IT confirmed previous results in almost all cases. Reversions occurred more often than conversions. Rate of indeterminate QFT-IT results was extremely low, thus indicating a very good technical performance of this test in HCW in a low TB prevalence area.

2012 - Repeated Quantiferon-TB Gold In-Tube Tests In Routine Clinical Practice: A Five Years Experience [Abstract in Rivista]
Cerri, Stefania; Meacci, Marisa; Meccugni, Barbara; Pietrosemoli, Paola; Balduzzi, Sara; Rumpianesi, Fabio; Fabbri, Leonardo; Richeldi, Luca
abstract

Introduction. Interferon Gamma Release Assays (IGRAs) are increasingly being used as diagnostic aids for Mycobacterium tuberculosis infection. Although evidence on IGRA performance in different populations is quickly accumulating, data on their use in non-experimental settings may provide information on their performance in routine clinical practice. We reviewed the results of QuantiFERON-TB In-Tube (QTF-IT) tests at our hospital since its introduction in diagnostic routine, with particular focus on repeated tests. Methods: We extracted the anonymised electronic records of all consecutive QFT-IT performed at the Laboratory of Microbiology and Virology of University Hospital of Modena (Italy) between May 2006 and December 2010. All tests performed in both inpatients and outpatients were included in the analysis. Results: A total of 10,812 tests were performed in 8,623 individuals (mean age ± SD: 46±23 years; 52.8% male). Among subjects who underwent single testing (n=7,039, 81.6%), 69.7% were negative, 22.5% positive, 7.4% indeterminate and 0.1% not interpretable due to high background in the negative control (0.3% of all tests were not performed due to missing or inadequate samples). In 1,584 (18.4%) subjects (mean age ± SD: 41±23 years; 56.1% male) QFT-IT was repeated at least once: in this group, there was a significantly higher proportion of indeterminate QFT-IT results (11.6%) at first testing, as compared to subjects with single tests (p<0.0001). In most cases (72.5%) the second QFT-IT provided valid concordant results (53.5% concordant negative; 19.0% concordant positive); conversions (from negative to positive) and reversions (from positive to negative) occurred in 3.7% and 7.3% of patients, respectively. Indeterminate results were more likely to become negative instead of positive (7.1% vs. 0.8%; p<0.0001); 3.8% of negative results became indeterminate at second testing. Conclusions: In this non-experimental routine setting, repeated QFT-IT confirmed previous results in most cases, providing little additional clinical information. Indeterminate QFT-IT results were more frequently negative than positive at repeated testing, thus suggesting that most indeterminate tests do not mask a positive result.

2012 - Sarcoidosis: challenging diagnostic aspects of an old disease. [Articolo su rivista]
Spagnolo, Paolo; F., Luppi; P., Roversi; Cerri, Stefania; Fabbri, Leonardo; Richeldi, Luca
abstract

Over the past few years, there have been substantial advances in our understanding of sarcoidosis immunopathogenesis. Conversely, the etiology of the disease remains obscure for a number of reasons, including heterogeneity of clinical manifestations, often overlapping with other disorders, and insensitive and nonspecific diagnostic tests. While no cause has been definitely confirmed, there is increasing evidence that one or more infectious agents may cause the disease, although the organism may no longer be viable. Here we present 2 cases, in which sarcoidosis preceded tuberculosis and non-Hodgkin lymphoma. Development of new lesions in a patient with chronic/remitting sarcoidosis should be looked at with suspicion and promptly investigated in order to rule out an alternative/concomitant diagnosis. In such cases, tissue confirmation from the most accessible site, and bone marrow biopsy-if lymphoma is in the differential diagnosis-should be performed. In conclusion, we strongly advise that physicians be ready to reconsider the diagnosis of sarcoidosis in the presence of atypical manifestations or persistent/progressive disease despite conventional therapy.

2012 - Spirometric inclusion criteria of COPD patients in randomized clinical trials. [Articolo su rivista]
Fabbri, Leonardo
abstract

I read with interest the paper entitled, “Acute effects of indacaterol on lung hyperinflation in moderate COPD: a comparison with tiotropium”, that has been recently published on line in Respiratory Medicine(1). As I have had in the past a recurrent exchange of opinions with some of the Authors on the spirometric criteria for defining airflow limitation, [2], [3], [4], [5] and [6] and particularly on the relative value of the fixed ratio (FR) FEV1/FVC < 0.7 proposed by the GOLD initiative7versus the Lower Limit of Normal (LLN) of FEV1/VC,8 I carefully read the entry criteria of the study and I was surprised to verify that, similarly to previous studies,9 the same Authors, who heavily criticize the GOLD criteria to the point of requesting the endorsement not only of the Italian “scientific” respiratory societies but also of the Italian Ministry of Health10 continue to use the GOLD criteria in their clinical trials and practice. [1] and [9] I did notice that in this specific study1 they used both the post-bronchodilator FEV1/FVC < 0.7 and the LLN of FEV1/VC related to predicted values,8 but unfortunately they omitted to mention whether the values were pre- or post-bronchodilators, and whether the predicted values used to express the results were pre- or post-bronchodilator. As the methods were not described in details in the paper, I went to the study protocol11 and I found that the LLN of FEV1/VC was not mentioned in the protocol nor in the amendments, and that the only entry criteria for the study were the GOLD criteria.7 As I stated in previous correspondence, [2], [4] and [6] I do not believe that the use of one criterion or the other creates a major problem, but I have to admit that my opinion is not based on evidence. I think it would be interesting to give to the Authors the opportunity to provide this evidence, by publishing the individual data of FR and LLN not reported in the paper, and comment on discrepancies, if any!

2012 - Step-down from high dose fixed combination therapy in asthma patients: a randomized controlled trial. [Articolo su rivista]
Papi, A; Nicolini, G; Crimi, N; Fabbri, Leonardo; Olivieri, D; Rossi, A; Paggiaro, P.
abstract

Asthma guidelines suggest that therapy can be reduced once asthma is controlled. Despite these recommendations, asthmatic patients are seldom stepped down in clinical practice, and questions remain about when and how to reduce asthma therapy. The purpose of the present study was to evaluate lung function and asthma control in patients who were stepped down from the highest recommended dose of inhaled corticosteroid/long acting β2 agonist combination therapy. METHODS: This was a prospective, randomised, controlled, two-arm parallel group study. Asthmatic patients who were fully controlled with a high daily dose (1000/100 μg) of fluticasone/salmeterol were randomly assigned to 6 months of open-label treatment with either 500/100 μg fluticasone/salmeterol Diskus daily or 400/24 μg extrafine beclomethasone/formoterol pMDI daily. The primary outcome was the change in morning peak expiratory flow (PEF) values between baseline and the end of treatment. The secondary outcomes included asthma control and exacerbation frequency. RESULTS: Four hundred twenty-two patients were included in the analysis. The PEF values remained above 95% of the predicted values throughout the study. The end-study morning PEF rates showed equivalence between the groups (difference between means, 2.49 L/min; 95% CI, -13.43 to 18.42). No changes from baseline were detected in PEF and forced expiratory volume in 1 second measured at the clinics, in the symptom scores or in the use of rescue medication. Asthma control was maintained in 95.2% of the patients at 6 months. No significant differences between the groups were detected in any other parameter, including exacerbation frequency and adverse events. CONCLUSIONS: Stepping down patients whose asthma is controlled with the highest recommended dose of fluticasone/salmeterol to either 500/100 μg fluticasone/salmeterol daily or 400/24 μg extra-fine beclomethasone/formoterol daily provides comparable maintenance of lung function and asthma control. TRIAL REGISTRATION: clinicaltrials.gov NCT00497237.

2011 - COPD and comorbidities: The importance of the disease management [Articolo su rivista]
Clini, E. M.; Beghe, B.; Crisafulli, E.; Fabbri, L. M.
abstract

2011 - Cardiovascular mechanisms of death in severe COPD exacerbation: time to think and act beyond guidelines [Articolo su rivista]
Fabbri, Leonardo; Beghe', Bianca; Agusti, Alvar
abstract

This issue of Thorax includes three important studies on acute exacerbations of chronic obstructive pulmonary disease (ECOPD). Two of them, by Chang et al. (1) and Hoiset et al. (2), show the importance of the cardiac biomarkers troponin T and NT-BNP (N-terminal pro-B-type natriuretic peptide) as strong predictors of the increased risk of death of patients hospitalized because of ECOPD (1, 2). The third, by Maclay et al. (3), provides evidence that patients with stable COPD have increased circulating platelet-monocyte aggregates—a potential specific pathogenic mechanism of atherosclerosis—and that they further increase during exacerbations, suggesting a plausible biological mechanism to explain the increased cardiovascular risk seen in ECOPD. Taken together, these studies confirm the view that ECOPD episodes requiring hospitalization must be considered very severe events in the natural course of the disease, since they are associated with such important outcomes as increased risk of mortality, reduced health status, impaired lung function, muscle weakness, and cardiopulmonary complications (4). The studies also suggest that the increased risk of death is often due to acute cardiovascular involvement, and they highlight the limitations of the current definition of ECOPD and the need to move toward a more comprehensive definition, diagnostic approach and treatment.

2011 - Co-trimoxazole effect on human alveolar macrophages of AIDS patients [Articolo su rivista]
Luppi, Fabrizio; M., Covi; G., Velluti; Spagnolo, Paolo; Fabbri, Leonardo; Richeldi, Luca
abstract

Compelling evidence suggests that co-trimoxazole prophylaxis reduces mortality in HIV-infected patients, although it is unclear whether these effects are directly related to antimicrobial activities. We evaluated in vitro phagocytosis and killing of Staphylococcus aureus in alveolar macrophages (AM) obtained from AIDS patients who smoke, treated (n=19) or not treated (n=13) with co-trimoxazole, as compared to non-HIV-infected healthy smokers (n=15). Phagocytosis and killing of Staphylococcus aureus by AM obtained from non-co-trimoxazole treated AIDS patients were significantly lower compared to non-HIV-infected healthy smokers. In contrast, AIDS patients treated with co-trimoxazole prophylaxis showed phagocytosis and killing levels similar to those of healthy controls. These results might help to clarify the observed positive effect of co-trimoxazole on survival in HIV-infected patients.

2011 - Efficacy and safety of once-daily aclidinium in chronic obstructive pulmonary disease. [Articolo su rivista]
Jones, Pw; Rennard, Si; Agusti, A; Chanez, P; Magnussen, H; Fabbri, Leonardo; Donohue, Jf; Bateman, Ed; Gross, Nj; Lamarca, R; Caracta, C; Gil, Eg
abstract

BACKGROUND: The long-term efficacy and safety of aclidinium bromide, a novel, long-acting muscarinic antagonist, were investigated in patients with moderate to severe chronic obstructive pulmonary disease (COPD). METHODS: In two double-blind, 52-week studies, ACCLAIM/COPD I (n=843) and II (n=804), patients were randomised to inhaled aclidinium 200 μg or placebo once-daily. Patients were required to have a post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio of ≤70% and FEV1&lt;80% of the predicted value. The primary endpoint was trough FEV1 at 12 and 28 weeks. Secondary endpoints were health status measured by St George's Respiratory Questionnaire (SGRQ) and time to first moderate or severe COPD exacerbation. RESULTS: At 12 and 28 weeks, aclidinium improved trough FEV1 versus placebo in ACCLAIM/COPD I (by 61 and 67 mL; both p&lt;0.001) and ACCLAIM/COPD II (by 63 and 59 mL; both p&lt;0.001). More patients had a SGRQ improvement≥4 units at 52 weeks with aclidinium versus placebo in ACCLAIM/COPD I (48.1% versus 39.5%; p=0.025) and ACCLAIM/COPD II (39.0% versus 32.8%; p=0.074). The time to first exacerbation was significantly delayed by aclidinium in ACCLAIM/COPD II (hazard ratio [HR] 0.7; 95% confidence interval [CI] 0.55 to 0.92; p=0.01), but not ACCLAIM/COPD I (HR 1.0; 95% CI 0.72 to 1.33; p=0.9). Adverse events were minor in both studies. CONCLUSION: Aclidinium is effective and well tolerated in patients with moderate to severe COPD. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00363896 (ACCLAIM/COPD I) and NCT00358436 (ACCLAIM/COPD II).

2011 - Energy expenditure at rest and during walking in patients with chronic respiratory failure: a prospective two-phase case-control study [Articolo su rivista]
E., Crisafulli; C., Beneventi; V., Bortolotti; N., Kidonias; Fabbri, Leonardo; A., Chetta; Clini, Enrico
abstract

Measurement of Energy Expenditure (EE) at rest (REE) and during physical activities are increasing in interest in chronic patients. In this study we aimed at evaluating the validity/reliability of the SenseWear®Armband (SWA) device in terms of REE and EE during assisted walking in Chronic Respiratory Failure (CRF) patients receiving long-term oxygen therapy (LTOT).In a two-phase prospective protocol we studied 40 severe patients and 35 age-matched healthy controls. In phase-1 we determined the validity and repeatability of REE measured by SWA (REEa) in comparison with standard calorimetry (REEc). In phase-2 we then assessed EE and Metabolic Equivalents-METs by SWA during the 6-minute walking test while breathing oxygen in both assisted (Aid) or unassisted (No-Aid) modalities. When compared with REEc, REEa was slightly lower in patients (1351±169 vs 1413±194 kcal/day respectively, p<0.05), and less repeatable ithan in healthy controls (0.14 and 0.43 coefficient respectively). COPD patients with CRF patients reported a significant gain with Aid as compared with No-Aid modality in terms of meters walked, perceived symptoms and EE.SWA provides a feasible and valid method to assess the energy expenditure in CRF patients on LTOT, and it shows that aided walking results in a substantial energy saving in this population.

2011 - FEV(1)/FVC fixed ratio again [Articolo su rivista]
FABBRI, Leonardo
abstract

letter

2011 - Formoterol by pressurized metered-dose aerosol or dry powder on airway obstruction and lung hyperinflation in partially reversible COPD [Articolo su rivista]
V., Brusasco; G. W., Canonica; R., Dal Negro; G., Scano; P., Paggiaro; Fabbri, Leonardo; G., Barisione; G., D'Amato; G., Varoli; M., Baroffio; M., Milanese; C., Mereu; E., Crimi
abstract

BACKGROUND:We compared the efficacy and safety of formoterol given by a pressurized metered-dose inhaler (pMDI) (Atimos®, Chiesi Farmaceutici, Italy), using a chlorine-free hydrofluoroalkane (HFA-134a) propellant developed to provide stable and uniform dose delivery (Modulite™, Chiesi Farmaceutici, Italy), with formoterol by dry powder inhaler (DPI) (Foradil® Aerolizer®, Novartis Pharmaceuticals) and placebo, in reducing airflow obstruction and lung hyperinflation, in moderate-to-severe, partially reversible chronic obstructive pulmonary disease (COPD).METHODS:Forty-eight patients were randomized to a 1-week, double-blind, double-dummy, three-period crossover study with 12 μg b.i.d. of formoterol given by pMDI or DPI, or placebo. Spirometry, specific airway conductance, and lung volumes were measured at the beginning and at the end of each treatment period from predose to 4 h postdose. A 6-min walking test was carried out 4 h after the first and the last dose, with dyspnea assessed by Borg scale. Safety was assessed through adverse events monitoring electrocardiography and vital signs.RESULTS:The two formulations of formoterol were significantly superior to placebo but not different from each other in increasing 1-sec forced expiratory volume, specific airway conductance, inspiratory capacity, and inspiratory-to-total lung capacity ratio. The two active treatments were also equivalent and superior to placebo in reducing dyspnea at rest and on exertion. No differences in terms of safety between the two active forms and placebo were detected.CONCLUSIONS:Formoterol given with chlorine-free pMDI was equivalent to DPI in reducing airway obstruction and lung hyperinflation in COPD patients. Both formoterol formulations confirmed the good safety profile similar to placebo.

2011 - Functional recovery following physical training in tracheotomised and chronically ventilated patients. An observational prospective cohort study. [Articolo su rivista]
Clini, Enrico; Crisafulli, E; Degli Antoni, F; Beneventi, C; Costi, Stefania; Fabbri, Leonardo; Nava, S.
abstract

Background: Rehabilitation is a non-pharmacological therapy able to restore health status and reversing the patient’s disability. Since the efficacy of this treatment in critically ill patients is not enough documented, the present study aimed to assess whether the degree of change in individual’s functional status after comprehensive rehabilitation may influences the in-hospital clinical outcomes in a population of long-term ventilated patients.Methods: In a prospective cohort study we observed 77 tracheotomized patients (aged 75±7 yrs) admitted for difficult weaning in a regional weaning centre (RICU). Care plan including peripheral muscle training was delivered on a daily basis. Demographic, anthropometric and functional characteristics were measured at admission in all patients. Pre-to-post change in basic activity of daily living score (Δ-BADL), survival and weaning success rate were recorded as clinical outcomes. Pearson’s correlation analysis and a linear regression model with Δ-BADL as the dependent variable were performed to test the predictive power of any measurement taken at baseline.Results: Sixty-seven patients (87%) survived whereas 55 of them (74%) succeded weaning during stay in RICU. Δ-BADL was +2.53 point (SD 2.03, median 2). Performance of the broadest muscle of back (BMB) at baseline predicted Δ-BADL (β 0.388, 95% CI 0.111-1,664, p=0.026). Probability to remain ventilator-free (p=0.043) and to survive (p=0.001) differed across the categories of Δ-BADL (0=no change, 1-2=least improvement, and >2=improvement above median change). Conclusions: Mortality rate and weaning success vary according to the degree of change in basic activities following active training in tracheotomised, ventilated and difficult-to-wean patients. Broadest muscle of back performance was the only significant predictor of change in these activities.

2011 - GPs' role in reducing the risk of bronchospasm in asthma patients undergoing general anesthesia and/or intravascular administration of radiographic contrast media [Articolo su rivista]
G., Liccardi; A., Infantino; P. L., Paggiaro; Fabbri, Leonardo; A., Salzillo; R., Infantino; G., D'Amato
abstract

Research letter

2011 - Heart failure and chronic obstructive pulmonary disease the quandary of Beta-blockers and Beta-agonists. [Articolo su rivista]
N. M., Hawkins; M. C., Petrie; M. R., Macdonald; P. S., Jhund; Fabbri, Leonardo; J., Wikstrand; J. J., Mcmurray
abstract

The combination of heart failure and chronic obstructive pulmonary disease presents many therapeutic challenges. The cornerstones of therapy are beta-blockers and beta-agonists, respectively. Their pharmacological effects are diametrically opposed, and each is purported to adversely affect the alternative condition. The tolerability of beta-blockade in patients with mild and fixed airflow obstruction likely extends to those with more severe disease. However, the evidence is rudimentary. The long-term influence of beta-blockade on pulmonary function, symptoms, and quality of life is unclear. Low-dose initiation and gradual up-titration of cardioselective beta-blockers is currently recommended. Robust clinical trials are needed to provide the answers that may finally allay physicians' mistrust of beta-blockers in patients with chronic obstructive pulmonary disease. Beta-agonists are associated with incident heart failure in patients with pulmonary disease and with increased mortality and hospitalization in those with existing heart failure. These purported adverse effects require further investigation. In the meantime, clinicians should consider carefully the etiology of dyspnea and obtain objective evidence of airflow obstruction before prescribing beta-agonists to patients with heart failure.

2011 - Inhaled Long-Acting {beta}-Agonists Versus Anticholinergics in Older Patients With Chronic Obstructive Pulmonary Disease [Articolo su rivista]
Fabbri, Leonardo; C., Vogelmeier; Kf, Rabe
abstract

letter

2011 - Interleukin-6, but not pentraxin 3, predicts adverse clinical outcomes on short-term prognosis of patients with incipient heart failure [Poster]
Boschetto, P; Bottazzi, B; Fucili, A; Potena, A; Ballerin, L; Stendardo, M; Piva, S; Verduri, Alessia; Beghe', Bianca; Mantovani, A; Fabbri, Leonardo; Ferrari, R; Ceconi, C.
abstract

non previsto

2011 - Roflumilast with long-acting β2-agonists for COPD: influence of exacerbation history [Articolo su rivista]
E. D., Bateman; K. F., Rabe; P. M., Calverley; U. M., Goehring; M., Brose; D., Bredenbröker; Fabbri, Leonardo
abstract

The oral, selective phosphodiesterase type-4 inhibitor roflumilast reduces exacerbations and improves lung function in patients with severe-to-very severe chronic obstructive pulmonary disease (COPD). We investigated the efficacy and safety of roflumilast used concomitantly with long-acting β(2)-agonists (LABAs) to reduce exacerbations, and the influence of exacerbation history. Pooled data were analysed from two 12-month, placebo-controlled roflumilast (500 μg once daily) studies involving 3,091 patients with severe-to-very severe COPD. Approximately half of patients used concomitant LABAs; 39% used concomitant short-acting muscarinic antagonists (SAMAs); 27% were frequent exacerbators (two or more exacerbations per year). Roflumilast reduced the rate of moderate or severe exacerbations, with LABA (rate ratio (RR) 0.79, 95% CI 0.69-0.91; p=0.001) or without LABA (RR 0.85, 95% CI 0.74-0.99; p=0.039) and prolonged time both to first (p=0.035 with LABA, p=0.300 without LABA) and second (p=0.018 with LABA, p=0.049 without LABA) exacerbations. Frequent exacerbators experienced a reduction in moderate or severe exacerbations (RR 0.78, 95% CI 0.66-0.91; p=0.002). Similarly, roflumilast remained effective with concomitant SAMA. No differences arose in adverse events between these subgroups. Roflumilast may be used to reduce exacerbations and improve dyspnoea and lung function, without increasing adverse events in COPD patients receiving concomitant LABAs.

2011 - Roflumilast:un nuovo farmaco per il trattamento della BPCO [Articolo su rivista]
Beghe', Bianca; Verduri, Alessia; Fabbri, Leonardo
abstract

La broncopneumopatia cronica ostruttiva (BPCO) è una malattia respiratoria cronica il cui principale fattore di rischio è il fumo di sigaretta. La patologia è caratterizzata da una progressiva limitazione del flusso aereo non completamente reversibile, da sintomi respiratori quali tosse e dispnea e da frequenti riacutizzazioni cliniche che possono richiedere il ricovero ospedaliero con ulteriore compromissione dello stato di salute, declino della funzionalità respiratoria e aumento del tasso di mortalità. I farmaci attualmente disponibili per il trattamento della BPCO sono i broncodilatatori inalatori a breve (SABA) e a lunga durata d’azione (LABA). Nei pazienti con BPCO grave e molto grave e con frequenti riacutizzazioni i LABA sono somministrati in associazione con gli steroidi inalatori. L’infiammazione cronica dei polmoni gioca un ruolo cruciale nella patogenesi della BPCO. Gli inibitori della fosfodiesterasi 4 (PDE4) sono una nuova classe di farmaci ad azione antinfiammatoria che sono stati sviluppati per controllare l’infiammazione cronica correlata alla BPCO.Gli inibitori della fosfodiesterasi 4 hanno mostrato una buona efficacia e tollerabilità in studi preclinici e clinici condotti nei pazienti con BPCO

2011 - Role Of The QFT-IT Assay For The Diagnosis Of Latent Tuberculosis Infection Among Adult Immigrants [Abstract in Rivista]
Losi, Monica; Dal Monte, Paola; Cagarelli, Roberto; Meacci, Marisa; DEL GIOVANE, Cinzia; Luppi, Fabrizio; Lombardi, Giulia; Spagnolo, Paolo; D'Amico, Roberto; Roversi, Pietro; Cerri, Stefania; Rumpianesi, Fabio; Fabbri, Leonardo; Richeldi, Luca
abstract

Background. Accurate identification and treatment of contacts with latent tuberculosis infection (LTBI) is a desirable goal to achieve effective tuberculosis (TB) control in areas with low prevalence of disease. In immigrants from high prevalence countries, especially in those who are close contacts of active TB cases, the low specificity of the tuberculin skin test (TST) represents an obstacle to the identification of truly infected BCG-vaccinated individuals. The Interferon-Gamma (IFN-g) Release Assays (IGRAs), based on M. tuberculosis -specific antigens, might improve LTBI diagnosis in this population. Methods. In a retrospective study, we assess the performance of the QuantiFERON-TB Gold In-Tube (QFT-IT, Cellestis Ltd., Victoria, Australia) assay and the TST in 84 adult immigrants from high prevalence countries: 68 (80.9%) of those individuals were close contacts of active TB cases. Results. In 84 immigrants (mean age 37.7 ± 11.6 years, 46.3 % were males, 46.3% were BCG-vaccinated) TST was positive in 68 (80.9%) individuals: among these TST-positive individuals, 26 (38.2%) were negative with QFT-IT. QFT-IT assay tested positive in 44 (52.4%) subjects (TST vs QFT-IT: 80.9% vs 52.4%, p< 0.001). Two (2.4%) subjects tested QFT-IT-indeterminate and was TST-positive. Diagnostic overall agreement between TST and QFT-IT was 63.4% (k=0.23). Conclusions. These preliminary data suggest that the rate of LTBI among adult immigrants from TB endemic countries, in our study most of them also close contacts of active TB cases, is significantly lower when detected by QFT-IT, than by TST. Moreover, our findings suggest that using an IGRA test for LTBI screening in this high risk population might reduce the number of candidates to preventive treatment and can provide potential substantial benefits for TB control.

2011 - Short term efficacy of nebulized beclomethasone in mild-to-moderate wheezing episodes in pre-school children [Articolo su rivista]
A., Papi; G., Nicolini; A. L., Boner; E., Baraldi; R., Cutrera; Fabbri, Leonardo; G. A., Rossi
abstract

BACKGROUND:Few data are available on the usefulness of short term treatment with low-medium dose of inhaled corticosteroids (ICS) in pre-school children with wheezing exacerbations.METHODS:To compare the efficacy of one week treatment with 400 μg b.i.d. nebulized beclomethasone dipropionate (BDP), plus nebulized 2500 μg prn salbutamol (BDP group), versus nebulized b.i.d. placebo, plus nebulized prn 2500 μg salbutamol (placebo group), a post-hoc analysis was performed on data obtained in 166 pre-school children with multiple-trigger wheezing, recruited during an acute wheezing episode.RESULTS:The percentage of symptom-free days (SFDs) was significantly higher in the BDP group (54.7%) than in the placebo group (40.5%; p = 0.012), with a 35% relative difference. Day-by-day analysis showed that the percentage of SFDs was already higher in the BDP group after 2 days (7.4%), the difference reaching statistical significance at day 6 (12.3%; p = 0.035). Cough score was also reduced in the BDP group (0.11) as compared with the placebo group (0.39; p = 0.048), the difference reaching statistical significance after 5 days of treatment (0.18 and 0.47 respectively; p = 0.047). The mean number of nebulizations per day of prn salbutamol was lower in the BDP group as compared to the placebo group (0.26 and 0.34, respectively), but the difference was not significant (p = 0.366). There were no differences in positive effects of BDP treatment between children with and without risk factors for asthma.CONCLUSIONS:A 1-week treatment with nebulized BDP and prn salbutamol is effective in increasing SFDs and improving cough in children with wheezing, providing a clinical rationale for the short term use of ICS in episodic wheeze exacerbations in pre-school children.

2011 - Subclinical cardiac dysfunction in moderate to severe COPD patients [Poster]
Verduri, Alessia; Bottazzi, B; Leuzzi, C; Boschetto, P; Modena, Mg; Mantovani, A; Fabbri, Leonardo; Beghe', Bianca
abstract

Non previsto

2011 - Subclinical cardiac dysfunction in moderatw to severe COPD patients [Articolo su rivista]
A., Verduri; B., Bottazzi; C., Leuzzi; P., Boschetto; Modena, Maria Grazia; A., Mantovani; Fabbri, Leonardo; Beghe', Bianca
abstract

BACKGROUND: The co-existence between chronic obstructive pulmonary disease (COPD) and heart failure has been previously described. However, the co-existence between COPD and subclinical left ventricular (LV) dysfunction, without the presence of heart failure symptoms, is less well understood. This study determined the relationship and clinical relevance of COPD and subclinical LV dysfunction in vascular surgery patients. METHODS: 1005 consecutive vascular surgery patients were included in which COPD was determined using spirometry and LV function using echocardiography. Mild COPD was defined as FEV(1)>or=80% of predicted+FEV(1)/FVC-ratio<0.70. Moderate/severe COPD was defined as FEV(1)<80% of predicted+FEV(1)/FVC-ratio<0.70. Systolic LV dysfunction was defined as LV ejection fraction <50% and diastolic LV dysfunction was diagnosed based on E/A-ratio, pulmonary vein flow and deceleration time. Multivariate regression analyses were used to evaluate the impact of COPD and LV dysfunction on all-cause mortality. The mean follow-up time was 2.2+/-1.8 years. RESULTS: Both, mild and moderate/severe COPD were associated with increased risk for subclinical LV dysfunction with odds ratio of 1.6 (95%-CI=1.1-2.3) and 1.7 (95%-CI=1.2-2.4), respectively. Mild- or moderate/severe COPD in combination with LV dysfunction was associated with increased risk for all-cause mortality (mild: hazard ratio 1.7; 95%-CI=1.1-3.6, moderate/severe: hazard ratio 2.5; 95%-CI=1.5-4.7). CONCLUSIONS: COPD was associated with increased risk for subclinical LV dysfunction. COPD+subclinical LV dysfunction was associated with increased risk for all-cause mortality compared to patients with COPD+normal LV function. Echocardiography may be useful to detect subclinical cardiovascular disease and risk-stratify COPD patients undergoing vascular surgery.

2011 - The multiple components of COPD [Capitolo/Saggio]
Fabbri, Leonardo; F., Luppi; Beghe', Bianca; K. F., Rabe
abstract

Recent research suggests that inflammation is not confined to the lungs in COPD: inflammatory cells and mediators generated in the lungs enter the bloodstream and may have systemic effects on other susceptible areas of the body. This may account for the observation that patients with COPD also present with systemic symptoms and comorbid conditions, including muscle weakness, weight loss, cardiovascular disease, osteoporosis, hypertension, depression, cognitive decline, sleep disorders, sexual dysfunction, and possibly diabetes . Considering the systemic nature of the inflammatory response to irritants, particularly cigarette smoke, there is increasing evidence that lung abnormalities may be responsible not only for respiratory symptoms, e.g., dyspnea, but also for the chronic comorbidities that develop along with COPD, particularly chronic heart failure (CHF), coronary and peripheral vascular diseases, and the metabolic syndrome. Comorbidities are highly likely to affect health outcomes in COPD, and COPD patients are more likely to die of cardiovascular complications or cancer than of respiratory failure.

2011 - Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma [Articolo su rivista]
E. D., Bateman; O., Kornmann; P., Schmidt; A., Pivovarova; M., Engel; Fabbri, Leonardo
abstract

BACKGROUND:The efficacy and safety of inhaled long-acting β(2)-adrenergic agonists in asthmatic patients with the B16-Arg/Arg genotype has been questioned, and the use of antimuscarinics has been proposed as an alternative in patients whose symptoms are not controlled by inhaled corticosteroids (ICSs).OBJECTIVE:We compared the efficacy and safety of the long-acting anticholinergic tiotropium with salmeterol and placebo added to an ICS in B16-Arg/Arg patients with asthma that was not controlled by ICSs alone.METHODS:In a double-blind, double-dummy, placebo-controlled trial, after a 4-week run-in period with 50 μg of twice-daily salmeterol administered through a metered-dose inhaler, 388 asthmatic patients were randomized 1:1:1 to 16 weeks of treatment with 5 μg of Respimat tiotropium administered daily in the evening, 50 μg of salmeterol administered twice daily through a metered-dose inhaler, or placebo. Patients aged 18 to 67 years demonstrated reversibility to bronchodilators, and their symptoms were uncontrolled by regular ICSs (400-1000 μg of budesonide/equivalent). ICS regimens were maintained throughout the trial. The mean weekly morning peak expiratory flow (PEF) before randomization was 358 ± 115.7 L/min (range, 80.3-733.0 L/min).RESULTS:Changes in weekly PEF from the last week of the run-in period to the last week of treatment (primary end point: change in PEF) were -3.9 ± 4.87 L/min (n = 128) for tiotropium and -3.2 ± 4.64 L/min (n = 134) for salmeterol, and these were superior to placebo (-24.6 ± 4.84 L/min, n = 125, P < .05). Tiotropium was noninferior to salmeterol (estimated difference, -0.78 L/min [95% CI, -13.096 to 11.53]; P = .002; α = .025, 1-sided; noninferiority, 20 L/min). Tiotropium and salmeterol were numerically superior to placebo in some patient-reported secondary outcomes. Adverse events were comparable across treatments.CONCLUSION:Tiotropium was more effective than placebo and as effective as salmeterol in maintaining improved lung function in B16-Arg/Arg patients with moderate persistent asthma. Safety profiles were comparable.

2011 - Tiotropium versus salmeterol for the prevention of exacerbations of COPD [Articolo su rivista]
Vogelmeier, Claus; Hederer, Bettina; Glaab, Thomas; Schmidt, Hendrik; Mölken, Maureen P. M. H. Rutten van; Beeh, Kai M.; Rabe, Klaus F.; Fabbri, Leonardo
abstract

BACKGROUND:Treatment guidelines recommend the use of inhaled long-acting bronchodilators to alleviate symptoms and reduce the risk of exacerbations in patients with moderate-to-very-severe chronic obstructive pulmonary disease (COPD) but do not specify whether a long-acting anticholinergic drug or a β(2)-agonist is the preferred agent. We investigated whether the anticholinergic drug tiotropium is superior to the β(2)-agonist salmeterol in preventing exacerbations of COPD.METHODS:In a 1-year, randomized, double-blind, double-dummy, parallel-group trial, we compared the effect of treatment with 18 μg of tiotropium once daily with that of 50 μg of salmeterol twice daily on the incidence of moderate or severe exacerbations in patients with moderate-to-very-severe COPD and a history of exacerbations in the preceding year.RESULTS:A total of 7376 patients were randomly assigned to and treated with tiotropium (3707 patients) or salmeterol (3669 patients). Tiotropium, as compared with salmeterol, increased the time to the first exacerbation (187 days vs. 145 days), with a 17% reduction in risk (hazard ratio, 0.83; 95% confidence interval [CI], 0.77 to 0.90; P<0.001). Tiotropium also increased the time to the first severe exacerbation (hazard ratio, 0.72; 95% CI, 0.61 to 0.85; P<0.001), reduced the annual number of moderate or severe exacerbations (0.64 vs. 0.72; rate ratio, 0.89; 95% CI, 0.83 to 0.96; P=0.002), and reduced the annual number of severe exacerbations (0.09 vs. 0.13; rate ratio, 0.73; 95% CI, 0.66 to 0.82; P<0.001). Overall, the incidence of serious adverse events and of adverse events leading to the discontinuation of treatment was similar in the two study groups. There were 64 deaths (1.7%) in the tiotropium group and 78 (2.1%) in the salmeterol group.CONCLUSIONS:These results show that, in patients with moderate-to-very-severe COPD, tiotropium is more effective than salmeterol in preventing exacerbations. (Funded by Boehringer Ingelheim and Pfizer; ClinicalTrials.gov number, NCT00563381.).

2010 - A randomized placebo-controlled study of intravenous montelukast for the treatment of acute asthma. [Articolo su rivista]
Carlos A., Camargo; Deborah M., Gurner; Howard A., Smithline; Rocio, Chapela; Fabbri, Leonardo; Stuart A., Green; Marie Pierre, Malice; Catherine, Legrand; S., Balachandra Dass; Barbara A., Knorr; Theodore F., Reiss
abstract

Background: Current treatments for acute asthma provide inadequate benefit for some patients. Intravenous montelukast may complement existent therapies.Objective: To evaluate efficacy of intravenous montelukast as adjunctive therapy for acute asthma.Methods: A total of 583 adults with acute asthma were treated with standard care during a #60-minute screening period.Patients with FEV1 #50% predicted were randomly allocated to intravenous montelukast 7 mg (n 5 291) or placebo (n 5 292) in addition to standard care. This double-blind treatment period lasted until a decision for discharge, hospital admission, or discontinuation from the study. The primary efficacy endpoint was the time-weighted average change in FEV1 during 60minutes after drug administration. Secondary endpointsincluded the time-weighted average change in FEV1 at various intervals (10-120 minutes) and percentage of patients with treatment failure (defined as hospitalization or lack of decision to discharge by 3 hours postadministration).Results: Montelukast significantly increased FEV1 at 60 minutes postdose; the difference between change from baseline for placebo (least-squares mean of 0.22 L; 95% CI, 0.17, 0.27) and montelukast (0.32 L; 95% CI, 0.27, 0.37) was 0.10 L (95% CI, 0.04, 0.16). Similar improvements in FEV1-related variables were seen at all time points (all P <.05). Although treatment failure did not differ between groups (OR 0.92; 95% CI, 0.63,1.34), a prespecified subgroup analysis suggests likely benefit for intravenous montelukast at US sites.Conclusion: Intravenous montelukast added to standard care in adults with acute asthma produced significant relief of airway obstruction throughout the 2 hours after administration, with an onset of action as early as 10 minutes.

2010 - Asma bronchiale [Capitolo/Saggio]
Beghe', Bianca; Fabbri, Leonardo; A., Papi
abstract

L’asma (parola greca che significa "senza respiro" o "respiro a bocca aperta") bronchiale è una malattia infiammatoria cronica delle vie aeree che si manifesta clinicamente con 1) episodi ricorrenti di respiro sibilante e/o senso di costrizione toracica, dispnea, tosse non produttiva o accompagnata da espettorato bianco e tenace, 2) ostruzione bronchiale reversibile, e 3) iperreattività bronchiale. Il carattere accessuale e reversibile delle manifestazioni clinica e funzionali rappresenta la caratteristica peculiare della malattia. L’infiammazione bronchiale cronica delle vie aeree che sottende le manifestazioni clinico-funzionali dell’asma è costituita da una specifica infiltrazione bronchiale di cellule infiammatorie, in particolare granulociti eosinofili e mastociti, rilascio di mediatori infiammatori, e rimodellamento strutturale delle vie aeree caratterizzato in particolare da ipertrofia/iperplasia della muscolatura liscia e fibrosi sub-epiteliale. .

2010 - Asthma [Capitolo/Saggio]
Beghe', Bianca; Fabbri, Leonardo
abstract

Asthma is a chronic inflammatory disease ofthe airways, characterised clinically byrecurrent respiratory symptoms: dyspnoea,wheezing, chest tightness and/or cough,almost always associated with reversibleairflow limitation.The diagnosis of asthma is based on clinicalhistory and lung function tests, particularlypeak expiratory flow (PEF) and spirometry,with assessment of variable and/or reversibleairflow limitation. Allergy tests are alsousually performed during the first assessmentof a patient with suspected asthma to identifypossible triggers of asthma and to guide theiravoidance.

2010 - CD8+ T cells expressing IL-10 are associated with a favourable prognosis in lung cancer. [Articolo su rivista]
Miotto, D; Cascio, Nl; Stendardo, M; Querzoli, P; Pedriali, M; De Rosa, E; Fabbri, Leonardo; Mapp, Ce; Boschetto, P.
abstract

The dual role of tumour-infiltrating macrophages and lymphocytes on nonsmall cell lung cancer (NSCLC) progression and prognosis may be due to the differential activity of their phenotypes. To investigate the impact of inflammatory cells on NSCLC, we first quantified the number of macrophages (CD68+) and lymphocytes (CD8+ and CD4+) and the percentage of CD8+ cells expressing IL-10 (CD8+/IL-10+) in tumour stroma and epithelium. Then, we evaluated the possible relationships between the numbers of these cells and the clinicopathological features and the overall survival of patients. Paraffin-embedded sections of surgical specimens from 64 patients who had undergone surgery for NSCLC were immunostained with antibodies directed against CD68, CD4, CD8 and IL-10. The percentage of CD8+/IL-10+ cells was higher in cancer stroma of patients with stage I NSCLC than in those with stages II, III, and IV. High percentages of stromal CD8+/IL-10+ cells were associated with longer overall patient survival. In contrast, the number of CD68+, CD8+ and CD4+ cells did not differ between stage I NSCLC and stages II, III, and IV. In conclusion, the survival advantage of patients with stage I NSCLC may be related to the anti-tumour activity of the CD8+/IL-10+ cell phenotype.

2010 - Cardiovascular safety of QVA149, a combination of indacaterol and NVA237, in COPD patients [Articolo su rivista]
B., Van de Maele; Fabbri, Leonardo; C., Martin; R., Horton; M., Dolker; T., Overend
abstract

This study assessed the cardiovascular safety of QVA149, an inhaled, once daily,bronchodilator combination containing two 24-hour bronchodilators, the long-acting β2-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium(NVA237). In this randomised, double-blind, placebo-controlled, parallel-group study,257 patients with moderate-to-severe chronic obstructive pulmonary disease (COPD)were randomised to receive QVA149 (indacaterol/NVA237) 600/100 μg, 300/100 μg or150/100 μg, indacaterol 300 μg or placebo, once daily for 14 days. The primary endpointwas change from baseline in 24-h mean heart rate versus placebo on Day 14. 255patients were included in the safety analysis (mean age 63.8 years, 76.5% male, postbronchodilatorforced expiratory volume in one second [FEV1] 53.2% predicted,FEV1/FVC [forced vital capacity] 50.0%, mean 24-h heart rate 79.6 bpm). There were noclinically significant differences in the 24-h mean heart rate on Day 14 between the threedoses of QVA149 and placebo or indacaterol. The confidence intervals of these treatmentdifferences (contrasts) were within the pre-specified equivalence limit (-5 to 5 bpm). Noclinically relevant differences in QTc interval (Fridericia's) were observed betweengroups on Days 1, 7 and 14. Once-daily QVA149 was well tolerated in COPD patientswith a cardiovascular safety profile and overall AE rates similar to placebo.Page 4 of 36URL: http:/mc.manuscriptcentral.com/copd Email: COPD@njc.orgCOPD: Journal Of Chronic Obstructive Pulmonary Disease

2010 - Chronic obstructive pulmonary disease phenotypes: the future of COPD. [Articolo su rivista]
Han, Mk; Agusti, A; Calverley, Pm; Celli, Br; Criner, G; Curtis, Jl; Fabbri, Leonardo; Goldin, Jg; Jones, Pw; Macnee, W; Make, Bj; Rabe, Kf; Rennard, Si; Sciurba, Fc; Silverman, Ek; Vestbo, J; Washko, Gr; Wouters, Ef; Martinez, Fj
abstract

Significant heterogeneity of clinical presentation and disease progression exists within chronic obstructive pulmonary disease (COPD). Although FEV(1) inadequately describes this heterogeneity, a clear alternative has not emerged. The goal of phenotyping is to identify patient groups with unique prognostic or therapeutic characteristics, but significant variation and confusion surrounds use of the term "phenotype" in COPD. Phenotype classically refers to any observable characteristic of an organism, and up until now, multiple disease characteristics have been termed COPD phenotypes. We, however, propose the following variation on this definition: "a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes (symptoms, exacerbations, response to therapy, rate of disease progression, or death)." This more focused definition allows for classification of patients into distinct prognostic and therapeutic subgroups for both clinical and research purposes. Ideally, individuals sharing a unique phenotype would also ultimately be determined to have a similar underlying biologic or physiologic mechanism(s) to guide the development of therapy where possible. It follows that any proposed phenotype, whether defined by symptoms, radiography, physiology, or cellular or molecular fingerprint will require an iterative validation process in which "candidate" phenotypes are identified before their relevance to clinical outcome is determined. Although this schema represents an ideal construct, we acknowledge any phenotype may be etiologically heterogeneous and that any one individual may manifest multiple phenotypes. We have much yet to learn, but establishing a common language for future research will facilitate our understanding and management of the complexity implicit to this disease.

2010 - Efficacy of standard Rehabilitation in COPD Outpatients with Co-morbidities. [Articolo su rivista]
Crisafulli, E; Gorgone, P; Vagaggini, B; Pagani, M; Rossi, G; Costa, F; Guarriello, V; Paggiaro, P; Chetta, A; de Blasio, F; Olivieri, D; Fabbri, Leonardo; Clini, Enrico
abstract

A prospective study was performed to 1) confirm the prevalence pattern of the most frequent co-morbidities and 2) evaluate whether characteristics of patients, specific co-morbidities, and increasing number of co-morbidities are independently associated with poorer outcomes in a population of complex COPD submitted to rehabilitation (PR). Three-hundred and sixteen outpatients (age 68±7 yrs) were studied. Co-morbidities and proportion of patients with a pre-defined minimally significant change in exercise tolerance (6MWD, +54 mt), breathlessness (MRC score, -1 point) and quality-of-life (SGRQ, -4 points) as outcomes were recorded. Sixty-two % of patients reported co-morbidities; systemic hypertension (35%), dyslipidemia (13%), diabetes (12%), and coronary disease (11%) were the most frequent. Above 45% of them improved over MCID in all the outcomes. In a logistic regression model, baseline 6MWD (OR 0.99 95%CI 0.98-0.99, p=0.001), MRC (OR 12.88 95%CI 6.89-24.00, p=0.001), and PaCO2 (OR 1.08 95%CI 1.00-1.15, p=0.034) related with the proportion of patients who improved 6MWD and MRC, respectively. Presence of osteoporosis reduced the success rate in 6MWD (OR 0.28 95%CI 0.11-0.70, p=0.006). A substantial prevalence of co-morbidities in COPD outpatients referred to rehabilitation was confirmed. The individual’s disability and the presence of osteoporosis only were independently associated with poorer rehabilitation outcomes. (registered at ClinicalTrials.gov: NCT00992498.)

2010 - European Respiratory Society MD PhD programme in respiratory science. [Articolo su rivista]
Eickelberg, O; Laurent, G; Nicod, Lp; Hartl, S; Siafakas, Nm; P., Barnes; S. E., Dahlen; M., Decramer; J. L., Eisele; Fabbri, Leonardo; M., Gaga; J., Gerritsen; G. F., Joos; L. P., Nicod; P., Palange; J. Y., Paton; K., Rabe; W., Wedzicha
abstract

As part of its mission, the European Respiratory Society (ERS) is dedicated to promoting education and scientific endeavour in respiratory medicine. This position statement proposes an important additional activity in this area by coordinating MD PhD degree fellowships in respiratory medicine that will be conducted in European academic centres of excellence. This scheme is aimed at providing the very best training programmes for medical or science graduates within 5 yrs of completing their first qualification. This scheme is directed at the highest level graduates in medicine and science with the aim of educating and training them in the very best laboratories. It is predicted that the scheme is likely to attract medical graduates from Europe. However, in light of ERS outreach to all countries and in recognition of the need to attract young scientists, we suggest that after the initiation and trial period it would be open to medical and science graduates worldwide.

2010 - Fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease: 5-year follow-up. [Articolo su rivista]
Contoli, M; Baraldo, S; Marku, B; Casolari, P; Marwick, Ja; Turato, G; Romagnoli, M; Caramori, G; Saetta, M; Fabbri, Leonardo; Papi, A.
abstract

BACKGROUND: Both smokers and patients with asthma can experience fixed airflow obstruction, which is associated with distinctive patterns of airway pathology. The influence of fixed airflow obstruction on the prognosis of these patients is unknown.OBJECTIVE: We sought to investigate lung function decline and exacerbations in a 5-year prospective study of subjects with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease (COPD). We also sought to explore correlations between functional, pathological, and clinical features.METHODS: Patients with fixed airflow obstruction due to asthma (n = 16) or COPD (n = 21) and a control group of asthmatic patients with fully reversible airflow obstruction (n = 15) were followed for 5 years.RESULTS: The rates of decline in FEV(1) were similar in patients with fixed airflow obstruction caused by asthma (-49.7 +/- 10.6 mL/y) or COPD (-51.4 +/- 9.8 mL/y) and were higher than in asthmatic patients with reversible airflow obstruction (-18.1 +/- 10.1 mL/y, P < .01). Exacerbation rates were also higher in patients with fixed airflow obstruction caused by asthma (1.41 +/- 0.26 per patient-year) or COPD (1.98 +/- 0.3 per patient-year) compared with those seen in asthmatic patients with reversible airflow obstruction (0.53 +/- 0.11 per patient-year, P < .01). Baseline exhaled nitric oxide levels and sputum eosinophil counts correlated with the FEV(1) decline in asthmatic patients with fixed airflow obstruction. By contrast, baseline sputum neutrophil counts, emphysema scores, comorbidities, and exacerbation frequency correlated directly and pulmonary diffusion capacity correlated inversely with the FEV(1) decline in patients with COPD.CONCLUSION: In both patients with asthma and those with COPD, fixed airflow obstruction is associated with increased lung function decline and frequency of exacerbations. Nevertheless, the decline in lung function entails the specific pathological and clinical features of the underlying diseases.

2010 - Genetics, ethics, and the use of long-acting beta-adrenergics to treat asthma. [Articolo su rivista]
Fd, Martinez; Fabbri, Leonardo
abstract

Long-acting β-agonists (LABAs) improve control of persistent asthma that is not well controlled with inhaled corticosteroids (ICS) in adults (1) and children (2), but there are safety concerns related to their continuous use (3–4). Initial pharmacogenetic studies suggested that, during long-term use of short-acting β-agonists, individuals with asthma that are homozygotes for the arginine (Arg) allele at codon 16 of the β2-adrenergic receptor gene (ADRB2) were at increased risk of adverse outcomes when compared with homozygotes for the glycine (Gly) allele or Arg/Gly heterozygotes (5, 6). Retrospective analyses of clinical trials using LABAs, either alone or in combination with ICS, revealed similar adverse outcomes in relation to the Arg/Arg genotype (7). However, other analyses of large LABA clinical trials were unable to reproduce these findings (8).

2010 - La broncopneumopatia cronica ostruttiva nell'anziano [Capitolo/Saggio]
Beghe', Bianca; Fabbri, Leonardo; Clini, Enrico
abstract

La broncopneumopatia cronica ostruttiva (BPCO) rappresenta una affezione a carico dell’apparato respiratorio di frequente riscontro nella popolazione adulta, di elevato impatto epidemiologico nella fascia di età oltre i 50 anni, con manifestazioni cliniche rilevanti in fase avanzata di malattia, in un paziente tipicamente anziano e che presenta, al tempo stesso numerose altre patologie croniche concomitanti, dette comorbilità.Questa caratteristica determina un modello clinico di paziente complesso che, oltre alle caratteristiche legate alla patologia respiratoria, presenta rilevanti effetti patologici extrapolmonari che pure necessitano di essere riconosciuti e trattati.Nel presente capitolo discuteremo appunto, partendo dalla malattia respiratoria, i fondamentali elementi patogenetici, clinici e terapeutici che identificano il paziente anziano con la BPCO.

2010 - La broncopneumopatia cronica ostruttiva nell'anziano. In: M.Mongardi (ed) L'Assistenza all'Anziano. [Monografia/Trattato scientifico]
Beghe', Bianca; Fabbri, Leonardo; Clini, Enrico
abstract

Nel capitolo vengono delineati gli aspetti epidemiologici, diagnostici, clinici e terapeutici della BPCO, patologia di assoluto rilievo nell'età avanzata. Completano il capitolo aspetti di integrazione dell'assistenza professionale nella patologia in oggetto.

2010 - Long-acting beta-agonists in the management of chronic obstructive pulmonary disease: current and future agents [Articolo su rivista]
Tashkin, Dp; Fabbri, Leonardo
abstract

Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation and debilitating symptoms. For patients with moderate-to-severe COPD, long-acting bronchodilators are the mainstay of therapy; as symptoms progress, guidelines recommend combining bronchodilators from different classes to improve efficacy. Inhaled long-acting β2-agonists (LABAs) have been licensed for the treatment of COPD since the late 1990s and include formoterol and salmeterol. They improve lung function, symptoms of breathlessness and exercise limitation, health-related quality of life, and may reduce the rate of exacerbations, although not all patients achieve clinically meaningful improvements in symptoms or health related quality of life. In addition, LABAs have an acceptable safety profile, and are not associated with an increased risk of respiratory mortality, although adverse effects such as palpitations and tremor may limit the dose that can be tolerated. Formoterol and salmeterol have 12-hour durations of action; however, sustained bronchodilation is desirable in COPD. A LABA with a 24-hour duration of action could provide improvements in efficacy, compared with twice-daily LABAs, and the once-daily dosing regimen could help improve compliance. It is also desirable that a new LABA should demonstrate fast onset of action, and a safety profile at least comparable to existing LABAs.A number of novel LABAs with once-daily profiles are in development which may be judged against these criteria. Indacaterol, a LABA with a 24-hour duration of bronchodilation and fast onset of action, is the most advanced of these. Preliminary results from large clinical trials suggest indacaterol improves lung function compared with placebo and other long-acting bronchodilators. Other LABAs with a 24-hour duration of bronchodilation include carmoterol, vilanterol trifenatate and oldaterol, with early results indicating potential for once-daily dosing in humans.The introduction of once-daily LABAs also provides the opportunity to develop combination inhalers of two or more classes of once-daily long-acting bronchodilators, which may be advantageous for COPD patients through simplification of treatment regimens as well as improvements in efficacy. Once-daily LABAs used both alone and in combination with long-acting muscarinic antagonists represent a promising advance in the treatment of COPD, and are likely to further improve outcomes for patients.

2010 - Malattie dell’apparato respiratorioA cura di Leonardo M. Fabbri [Capitolo/Saggio]
Fabbri, Leonardo
abstract

Questa sesta edizione di Medicina Interna Sistematica pur rinnovata nei contenuti e nella veste grafica, ha mantenuto inalterata la struttura di base originale con la quale si è perfettamente armonizzata. Le parti delle precedenti edizioni ritenute ancora attuali, sono state mantenute e incorporate nei testi nuovi e tutti i capitoli sono stati aggiornati alla luce delle più recenti novità.L’approfondimento di molti argomenti rende il testo idoneo anche agli insegnamenti specialistici nell’ambito della medicina interna.

2010 - Mechanisms of bradykinin-induced contraction in human fetal lung fibroblasts. [Articolo su rivista]
Petecchia, L; Sabatini, F; Usai, C; Carnevali, Stefano; Ognibene, M; Vanni, C; Eva, A; Fabbri, Leonardo; Rossi, Giulio; Ricciardolo, F. l.
abstract

Bradykinin (BK) induces fibroblast contraction but the structural changes and intracellular mechanisms involved have not been completely explored.We stimulated HFL-1 fibroblasts with BK to assess: 1) fibroblast contractility; 2) the role of α-smooth muscle actin (SMA) in contraction by small interfering RNA (siRNA); 3) α-SMA protein expression; 4) α-SMA and F-actin structure; 5) intracellular calcium concentration ([Ca2+]i); and 6) phosphorylated myosin light-chain (pMLC) and MLC kinase (MLCK) expression.BK triggered concentration- and time-dependent fibroblast gel contraction in conjunction with α-SMA over expression, but not in α-SMA-siRNA-treated cells. BK also increased α-SMA+ and F-actin+ cell number and stress fibre polymerisation (detectable at 5–60 min). These BK-induced changes were associated with an increase in [Ca2+]i, which peaked within 15 s, and activation of pMLC, which was detectable at 5–60 min. No MLCK content modification was observed. The different manifestations of the BK-induced fibroblast activation were downregulated at different levels (25–100%) by HOE140, a specific BK B2 receptor (B2R) antagonist and by the Ca2+ chelator, EGTA.Thus, BK-induced fibroblast contraction, associated with differentiation into α-SMA+ myofibroblasts, is mediated through the activation of the B2R and involves the Ca2+/calmodulin pMLC-dependent pathway.

2010 - Medicina Interna Sistematica [Monografia/Trattato scientifico]
Rugarli, C.; Nuti, R.; Caligaris Cappio, F.; Cantalamessa, L.; Cappelli, Gianni; Cappellini, M. D.; Cavllo Perin, P.; Corazza, G. R.; Craxì, A.; Crea, F.; Fabbri, Leonardo; Ferraccioli, G.; Giustina, A.; Lazzarin, A.; Stella, A. P.
abstract

Questa sesta edizione di Medicina Interna Sistematica pur rinnovata nei contenuti e nella veste grafica, ha mantenuto inalterata la struttura di base originale con la quale si è perfettamente armonizzata. Le parti delle precedenti edizioni ritenute ancora attuali, sono state mantenute e incorporate nei testi nuovi e tutti i capitoli sono stati aggiornati alla luce delle più recenti novità. L’approfondimento di molti argomenti rende il testo idoneo anche agli insegnamenti specialistici nell’ambito della medicina interna.

2010 - Polymorphisms in IL13 pathway genes in asthma and chronic obstructive pulmonary disease [Articolo su rivista]
Beghe', Bianca; I. P., Hall; M. F., Moffatt; A., Wardlaw; M. J., Connolly; Fabbri, Leonardo; C., Ruse; I., Sayers
abstract

Asthma and chronic obstructive pulmonary disease (COPD) are chronic respiratory diseases involving an interaction between genetic and environmental factors. Interleukin-13 (IL13) has been suggested to have a role in both asthma and COPD. We investigated whether single nucleotide polymorphisms (SNPs) in the IL13 pathway may contribute to the susceptibility and severity of asthma and COPD in adults.Twelve SNPs in IL13 pathway genes -IL4, IL13, IL4RA, IL13RA1, IL13RA2 and STAT6- were genotyped in subjects with asthma (n = 299) and in subjects with COPD or healthy smokers (n = 992). Genetic association was evaluated using genotype and allele models for asthma severity, atopy phenotypes and COPD susceptibility. Linear regression was used to determine the effects of polymorphism on baseline lung function (FEV(1), FEV(1)/FVC).In asthmatics, three IL13 SNPs - rs1881457(-1512), rs1800925(-1111) and rs20541(R130Q) - were associated with atopy risk. One SNP in IL4RA1 [rs1805010(I75V)] was associated with asthma severity, and several IL13 SNPs showed borderline significance. IL13 SNPs rs1881457(-1512) and rs1800925(-1111) were associated with better FEV(1) and FEV(1)/FVC in asthmatics. IL13 SNPs rs2066960(intron 1), rs20541(R130Q) and rs1295685(exon 4) were associated with COPD risk and lower baseline lung function in the recessive model. In females, but not in males, rs2250747 of the IL13RA1 gene was associated with COPD and lower FEV(1).These data suggest that IL13 SNPs (promoter and coding region) and, to a lesser extent, IL4RA SNPs may contribute to atopy and asthma. We also provide tentative evidence that IL13 SNPs in the coding region may be of significance in COPD susceptibility.

2010 - Prioritised research agenda for prevention and control of chronic respiratory diseases [Articolo su rivista]
J., Bousquet; J., Kiley; E. D., Bateman; G., Viegi; A. A., Cruz; N., Khaltaev; N., Aı¨t Khaled; C. E., Baena Cagnani; M. L., Barreto; N., Billo; G. W., Canonica; K. H., Carlsen; N., Chavannes; A., Chuchalin; J., Drazen; Fabbri, Leonardo; M. W., Gerbase; M., Humbert; G., Joos; M. R., Masjedi; S., Makino; K., Rabe; T., To; L., Zhi
abstract

The 2008–2013 World Health Organization (WHO) action plan on noncommunicable diseases (NCDs) includes chronic respiratory diseases as one of its four priorities. Major chronic respiratory diseases (CRDs) include asthma and rhinitis, chronic obstructive pulmonary disease, occupational lung diseases, sleep-disordered breathing, pulmonary hypertension, bronchiectiasis and pulmonary interstitial diseases. A billion people suffer from chronic respiratory diseases, the majority being in developing countries. CRDs have major adverse effects on the life and disability of patients. Effective intervention plans can prevent and control CRDs, thus reducing morbidity and mortality. A prioritised research agenda should encapsulate all of these considerations in the frame of the global fight against NCDs. This requires both CRD-targeted interventions and transverse NCD programmes which include CRDs, with emphasis on health promotion and disease prevention.

2010 - Recent trends in lung cancer and its association with COPD: an analysis using the UK GP Research Database. [Articolo su rivista]
Kiri, Va; Soriano, J; Visick, G; Fabbri, Leonardo
abstract

BACKGROUND: The association between lung cancer and COPD has not been investigated in the primary care setting. METHOD: We determined the recent trends of lung cancer in COPD patients in the UK during the period 1991-2004, by investigating the population aged 45 and over in the General Practice Research Database. RESULTS: The annual-incidence rates of lung cancer per 10,000 person-years were at least four-fold higher in patients with prior COPD (increasing from 45 to 64 in men; 29 to 48 in women) compared with the general population (from 10 to 15 in men; 5 to 10 in women). These lung cancer trends had significant annual increases that were similar in men (5%) and in women (5.5%) with prior COPD; in contrast, the annual increases of lung cancer incidence rates in the general population differed by gender, being 4% in men but double in women (8%). The three-year survival for lung cancer patients among those with prior COPD was almost half that of the general population (15% versus 26%; p<0.01) and the highest mortality was observed in men aged 45-64 (83.79 per 100 person-years; 95% CI: 69.66-97.92). CONCLUSION: These results support the association of COPD and lung cancer observed in other settings.

2010 - Roflumilast [Articolo su rivista]
Fabbri, Leonardo; Beghe', Bianca; Yasothan, U; Kirkpatrick, P.
abstract

In July 2010, roflumilast (Daxas; Nycomed)was granted marketing authorizationby the European Commission for themaintenance treatment of severe chronicobstructive pulmonary disease, as anadd-on to bronchodilator treatment

2010 - The small airways and distal lung compartment in asthma and COPD: a time for reappraisal. [Articolo su rivista]
Contoli, M; Bousquet, J; Fabbri, Leonardo; Magnussen, H; Rabe, Kf; Siafakas, Nm; Hamid, Q; Kraft, M.
abstract

The involvement of small airways in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD) has been debated for a long time. However, a proper definition of small airway disease is still lacking, and neither a widely accepted biomarker nor a functional parameter to assess small airway abnormalities and to explore the effect of tested compounds on small airways is available. Aiming towards increased knowledge and consensus on this topic, this perspective paper intends to (i) strengthen awareness among the scientific community on the role of small airways in asthma and COPD; (ii) examine the pros and cons of some biological, functional and imaging parameters in the assessment of small airway abnormalities; and (iii) discuss the evidence for distal airway pharmacological targeting in asthma and COPD.

2010 - Uniform definition of asthma severity, control, and exacerbations: Document presented for the World Health Organization Consultation on Severe Asthma. [Articolo su rivista]
Bousquet, J; Mantzouranis, E; Cruz, Aa; Aït Khaled, N; Baena Cagnani, Ce; Bleecker, Er; Brightling, Ce; Burney, P; Bush, A; Busse, Ww; Casale, Tb; Chan Yeung, M; Chen, R; Chowdhury, B; Chung, Kf; Dahl, R; Drazen, Jm; Fabbri, Leonardo; Holgate, St; Kauffmann, F; Haahtela, T; Khaltaev, N; Kiley, Jp; Masjedi, Mr; Mohammad, Y; O'Byrne, P; Partridge, Mr; Rabe, Kf; Togias, A; van Weel, C; Wenzel, S; Zhong, N; Zuberbier, T.
abstract

Asthma is a global health problem affecting around 300 millionindividuals of all ages, ethnic groups and countries. It isestimated that around 250,000 people die prematurely each yearas a result of asthma. Concepts of asthma severity and controlare important in evaluating patients and their response totreatment, as well as for public health, registries, and research(clinical trials, epidemiologic, genetic, and mechanistic studies),but the terminology applied is not standardized, and terms areoften used interchangeably. A common international approach isfavored to define severe asthma, uncontrolled asthma, and whenthe 2 coincide, although adaptation may be required inaccordance with local conditions. AWorld Health Organizationmeeting was convened April 5-6, 2009, to propose a uniformdefinition of severe asthma. An article was written by a group ofexperts and reviewed by the Global Alliance against ChronicRespiratory Diseases review group. Severe asthma is defined bythe level of current clinical control and risks as ‘‘Uncontrolledasthma which can result in risk of frequent severe exacerbations(or death) and/or adverse reactions to medications and/orchronic morbidity (including impaired lung function or reducedlung growth in children).’’ Severe asthma includes 3 groups, eachcarrying different public health messages and challenges: (1)untreated severe asthma, (2) difficult-to-treat severe asthma, and(3) treatment-resistant severe asthma. The last group includesasthma for which control is not achieved despite the highest levelof recommended treatment and asthma for which control can bemaintained only with the highest level of recommendedtreatment.

2009 - Clusterin (CLU) and lung cancer. [Articolo su rivista]
Panico, Francesca; F., Rizzi; Fabbri, Leonardo; S., Bettuzzi; Luppi, Fabrizio
abstract

Lung cancer is the leading cause of cancer-related mortality. It is categorized into two histological groups that have distinct clinical behaviors, the nonsmall cell lung cancers (NSCLC) and the small cell lung cancer (SCLC). When identified at an early stage, NSCLC is treated by surgical resection. However, patients who undergo surgical resection still have a relative low survival rate, primarily for tumor recurrence. Unfortunately, advances in cytotoxic therapy have reached a plateau and new approaches to treatment are needed together with new and better parameters for more accurate prediction of the outcome and more precise indication of the efficacy of the treatment. Several in vitro studies have examined the role of Clusterin (CLU) in carcinogenesis, lung cancer progression, and response to chemo- and radiotherapy. Studies performed in lung cancer cell lines and animal models showed that CLU is upregulated after exposure to chemo- and radiotherapy. A potential role proposed for the protein is cytoprotective. In vitro, CLU silencing by antisense oligonucleotides (ASO) and small-interfering RNAs (siRNA) directed against CLU mRNA in CLU-rich lung cancer cell lines sensitized cells to chemotherapy and radiotherapy and decreased their metastatic potential. In vivo, a recent work analyzed the prognostic role of CLU in NSCLC, showing that CLU-positive patients with lung cancer had a better overall survival and disease-free survival than those with CLU-negative tumors. These data are contradictory to the promising in vitro results. From the results of these studies we may hypothesize that in early-stage lung cancers CLU represents a positive biomarker correlating with better overall survival. In advanced patients, already treated with chemo- and radiotherapy, the induction of CLU may confer resistance to the treatments. However, many studies are needed to better understand the role of CLU in early-stage and advanced lung cancers with the aim to discriminate patients and specific local conditions that could benefit for a CLU knocking down treatment.

2009 - Diagnosis of asthma and copd [Capitolo/Saggio]
Luppi, F.; Beghe', B.; Corbetta, L.; Fabbri, L. M.
abstract

The differential diagnosis between asthma and COPD is quite simple when the typical clinical and functional features of either disease are present. The difficulty comes when trying to make a diagnosis of asthma or COPD in a middle-aged or elderly patient, a smoker, who may be atopic or have a history of asthma, who complains of chronic dyspnea but not wheezing, chronic cough, or sputum, and who presents with poorly reversible airflow limitation. It is also difficult to make a diagnosis of asthma or COPD in a middle-aged or elderly patient who has a clear history of atopy and asthma, bronchodilator reversibility, and recurrent wheezing, but who also smokes and has chronic cough and sputum and dyspnea that are not suppressed by inhaled steroids. The diagnosis of asthma or COPD is based on clinical history and lung function tests, particularly peak expiratory flow (PEF) and spirometry, with assessment of spontaneous or postbronchodilator reversibility of airflow limitation. Allergy tests are also usually performed for the diagnosis of asthma, but not of COPD patients, to identify allergens responsible for asthma exacerbations and to consider the opportunity to treat the patient with immunotherapy. While the diagnosis and assessment of severity of asthma and COPD can be fully established on the basis of clinical history and lung function tests, additional tests might be helpful to better characterize individual patients. © 2009 Elsevier Ltd All rights reserved.

2009 - Effects of early inpatient rehabilitation after acute exacerbation of COPD [Articolo su rivista]
Clini, Enrico; Ernesto, Crisafulli; Costi, Stefania; Giuseppina, Rossi; Cristina, Lorenzi; Fabbri, Leonardo; Nicolino, Ambrosino
abstract

We have undertaken an observational retrospective cohort study to assess feasibility and clinical effectiveness of early rehabilitation in patients recovering from acute exacerbation of COPD (AECOPD).A cohort of 1826 inpatients (73% male, age 70±8 yrs, FEV1 50±16% pred.) admitted to a pulmonary rehabilitation (PR) program and completing at least 15 sessions were divided into categories according to their dyspnoea grade (Medical Research Council -MRC scores 2 to 5) as assessed before AECOPD. The pre-post changes in 6 minute walking distance test (6MWD), perceived end-effort dyspnoea (Borg scale), and self-reported quality of life (St George respiratory Questionnaire: SGRQ) were measured throughout. Absolute change in 6MWD (52 [95%CI 45 to 59], 65 [95%CI 60 to 70], 63 [95%CI 59 to 66], and 70 [95%CI 67 to 74] meters in MRC-2 to 5 respectively) and the percentage of patients achieving the minimal clinically important difference (MCID) of +54 m (40, 55, 57, and 61%, respectively, p=0.001) differed across MRC grades. Proportion of patients able to reach ≥350 m at the 6MWD after PR was higher in MRC 4 and 5 (18 and 22%) as compared to MRC 2 and 3 (6 and 15%). Early PR in a cohort of AECOPD patients is feasible and it is associated to clinically meaningful improvement in exercise tolerance independent on the severity of dyspnoea. The proportion of patients reaching the limit of ≥350 m after this intervention is higher in the most severe patients.

2009 - Effects of unsupported upper extremity training in patients with chronic airway obstruction: a randomized clinical trial. [Articolo su rivista]
Costi, Stefania; Ernesto, Crisafulli; Francesca Degli, Antoni; Claudio, Beneventi; Fabbri, Leonardo; Clini, Enrico
abstract

Introduction: Recent guidelines on pulmonary rehabilitation (PR) recommend upper extremity exercise training (UEET) in patients with chronic obstructive pulmonary disease (COPD). However, literature still questions the effectiveness of systematic UEET in this population.Objective: We aimed to verify the effects of unsupported UEET on functional exercise capacity, ability to perform activities of daily living (ADL) and symptoms perceived during activities involving upper extremity in COPD patients.Methods: We conducted a randomized trial comparing the effects of unsupported UEET plus PR (Intervention) to those of PR alone (Control). Change in 6-minute ring test (6MRT) was the primary outcome; ADL field test (4 shuttle stations), dyspnea score as assessed by Medical Research Council (MRC) scale, London Chest Activity of Daily Living scale (LCADL), and 6-minute walked distance (6MWT) served as secondary outcomes of the study . Results: Fifty COPD patients were consecutively randomized into the two groups and completed the study. At the end of rehabilitation period, 6MRT specifically improved in Intervention (p&lt;0.001) but not in Control group; number of rings moved at 6MRT, shuttles completed at the ADL field test, 6MWT and MRC significantly and greatly changed (p&lt;0.01) in Intervention as compared with Control group. At 6-month follow-up, rings moved at 6MRT (p=0.039) and LCADL (p=0.001) were still significantly better in Intervention as compared with Control group.Conclusion: Our trial corroborates the effectiveness of unsupported UEET in specifically improving functional exercise capacity of COPD patients. Moreover, it also provides evidence that this training modality may ameliorate and maintain the patients’ autonomy over and above standard PR.

2009 - Exploring the immune response against Mycobacterium tuberculosis for a better diagnosis of the infection. [Articolo su rivista]
G., Ferrara; M., Losi; Fabbri, Leonardo; G. B., Migliori; Richeldi, Luca; L., Casali
abstract

Tuberculosis (TB) still represents a monumental problem, with more than two million deaths every year worldwide. The current diagnostics for TB offer sub-optimal accuracy both for the active and the latent form of infection and are often based on technologies unaffordable in low-income settings. The tuberculin skin test was the first diagnostic based on an acquired immune response towards Mycobacterium tuberculosis (MTB). Advances in molecular and cellular biology and the elucidation of the mechanisms governing the relation between MTB and the human immune system form the basis for new and more accurate assays, potentially able to fill the gaps and limits of classical diagnostics. However, the process of validating new tests is still complex and hampered by specific questions regarding TB immunology and natural history. We present here a summary of the current approaches to validate new diagnostics based on the detection of immunological biomarkers of TB infection.

2009 - Inhaled corticosteroids and risk of lung cancer among COPD patients who quit smoking [Articolo su rivista]
Victor A., Kiri; Fabbri, Leonardo; Kourtney J., Davis; Joan B., Soriano
abstract

RATIONALE AND OBJECTIVES: COPD is associated with an increased risk of lung cancer. We examined whether inhaled corticosteroids (ICS) used concomitantly with long-acting beta(2)-agonists (LABA) were associated with reduction in lung cancer risk in COPD patients. METHODS: We conducted a retrospective cohort study of patients with a first-time diagnosis of COPD (index date) between 1989 and 2003 who were initially free of lung cancer, had quit smoking, were aged >or=50 years at time of diagnosis, and were regular users of ICS, ICS/LABA concomitantly, or short-acting bronchodilators (SABD). A nested case-control design was applied to overcome the time-varying nature of treatment. RESULTS: We identified 7079 COPD patients who were regular users of the therapies of interest, of whom 127 subsequently had lung cancer and were matched to 1470 controls of same gender and age. Lung cancer was diagnosed in 6.0\% of concomitant ICS/LABA users compared with 7.3\% of ICS and 10.9\% of SABD users. In multivariate analyses, reductions in lung cancer risk were observed, with hazard ratio (HR) 0.50 (95\% confidence interval, 0.27-0.90) in ICS/LABA users and 0.64 (0.42-0.98) in ICS users, compared with SABD users. In assessing 'dose-response' relationships, we found risk reductions: HR of 0.75 (0.33-1.75) and 0.39 (0.19-0.79) in ICS/LABA users with 1-2 and 3+ prescriptions/year, respectively, and 0.88 (0.51-1.52) and 0.51 (0.30-0.84) in ICS users with 1-2 and 3+ prescriptions/year, respectively. CONCLUSIONS: Regular use of ICS, with and without LABA, may reduce the risk of lung cancer among former smokers with diagnosed COPD.

2009 - Leonardo Fabbri: investigating the complexity of COPD. Interview by Kelly Morris. [Articolo su rivista]
Fabbri, Leonardo
abstract

non disponibile

2009 - MUC5AC expression is increased in bronchial submucosal glands of stable COPD patients [Articolo su rivista]
G., Caramori; P., Casolari; C., Di Gregorio; M., Saetta; S., Baraldo; P., Boschetto; K., Ito; Fabbri, Leonardo; P. J., Barnes; I. M., Adcock; G., Cavallesco; K. F., Chung; A., Papi
abstract

AIMS: Mucus expectoration is a common feature of chronic obstructive pulmonary disease (COPD). MUC5AC and MUC5B, the major mucins, are released predominantly from submucosal glands in the central airways. The aim was to investigate gland size and MUC5AC and MUC5B expression in bronchial rings from smokers with COPD compared with control groups. METHODS AND RESULTS: Bronchial rings from 10 non-smoking subjects, 20 smokers with normal lung function and 20 smokers with COPD were studied. Periodic acid-Schiff (PAS) and Alcian blue histochemistry and MUC5AC and MUC5B immunohistochemistry followed by quantification of the immunoreactive area was performed. The area occupied by MUC5AC+ cells in bronchial submucosal glands was increased in COPD [20% (5.5-31.7%) gland area] compared with smokers with normal lung function [9.5% (2.5-17.5%); P < 0.05] and non-smoking subjects [2% (0.4-6.2%); P < 0.05]. The area occupied by MUC5AC+ cells in the bronchial surface epithelium was also increased in smokers (with/without COPD) [73.5% (25-92%) epithelial area] compared with non-smoking subjects [15% (2.7-32%); P < 0.01]. Gland size, PAS, Alcian blue staining and MUC5B expression were not significantly different among groups. MUC5AC expression correlated with the degree of airflow obstruction. MUC5AC and MUC5B expression correlated with pack-years. CONCLUSIONS: COPD is associated with increased MUC5AC expression in submucosal glands, indicating that MUC5AC may be involved in the pathophysiology of the disease.

2009 - Mechanisms of occupational asthma [Articolo su rivista]
P., Maestrelli; P., Boschetto; Fabbri, Leonardo; C. E., Mapp
abstract

Inhalation of agents in the workplace can induce asthma in a relatively small proportion of exposed workers. Like nonoccupational asthma, occupational asthma is probably the result of multiple genetic, environmental, and behavioral influences. It is important that occupational asthma be recognized clinically because it has serious medical and socioeconomic consequences. Environmental factors that can affect the initiation of occupational asthma include the intrinsic characteristics of causative agents as well as the influence of the level and route of exposure at the workplace. The identification of host factors, polymorphisms, and candidate genes associated with occupational asthma may improve our understanding of mechanisms involved in asthma. High-molecular-weight compounds from biological sources and low-molecular-weight chemicals cause occupational asthma after a latent period of exposure. Although the clinical, functional, and pathologic features of occupational asthma caused by low-molecular-weight agents resemble those of allergic asthma, the failure to detect specific IgE antibodies against most low-molecular-weight agents has resulted in a search for alternative or complementary physiopathologic mechanisms leading to airway sensitization. Recent advances have been made in the characterization of the immune response to low-molecular-weight agents. In contrast, the mechanism of the type of occupational asthma that occurs without latency after high-level exposure to irritants remains undetermined.

2009 - Performance of commerical blood tests for the diagnosis of latent tuberculosis infection in children and adolescents [Articolo su rivista]
Bergamini, Barbara Maria; M., Losi; F., Vaienti; D'Amico, Roberto; B., Meccugni; M., Meacci; D., De Giovanni; F., Rumpianesi; Fabbri, Leonardo; F., Balli; Richeldi, Luca
abstract

BACKGROUND: The accurate diagnosis of latent tuberculosis infection reduces the risk of progression to severe disseminated disease. However, in young children, a major limitation of the standard tuberculin skin test is that false-negative results cannot be detected. The new interferon-gamma release assays QuantiFERON-TB Gold (Cellestis Carnegie Victoria, Australia), QuantiFERON-TB In-Tube (Cellestis), and T-SPOT.TB (Oxford Immunotec, Abingdon, United Kingdom) show promise of greater accuracy, but they may also be affected by impaired cellular immunity, resulting in indeterminate results (ie, insufficient response in positive-control wells).OBJECTIVE:To evaluate the impact of age on the performance of interferon-gamma release assays when used in a routine hospital setting among children tested for suspected active or latent TB infection.METHODS:We retrospectively studied 496 children 0 to 19 years of age who had been tested with the tuberculin skin test and at least 1 interferon-gamma release assay: 181 with QuantiFERON-TB Gold and 315 with QuantiFERON-TB In-Tube. In 154 of the children, paired interferon-gamma release assay testing was available: 87 with QuantiFERON-TB Gold/T-SPOT.TB and 67 with QuantiFERON-TB In-Tube/T-SPOT.TB.RESULTS:Compared with T-SPOT.TB, the rates of indeterminate results were significantly higher for both QuantiFERON-TB Gold and QuantiFERON-TB In-Tube. QuantiFERON-TB Gold and QuantiFERON-TB In-Tube also gave indeterminate results more frequently in children <4 years of age than in those >/=4 years of age. Indeterminate results were associated with younger age for both QuantiFERON-TB Gold and QuantiFERON-TB In-Tube but not for T-SPOT.TB. Considering age as a binary variable (<4 and >/=4 years of age), a significantly higher concentration of phytohaemagglutinin-produced interferon-gamma was observed in older children with both QuantiFERON-TB Gold and QuantiFERON-TB In-Tube.CONCLUSIONS:Different blood tests for the diagnosis of latent tuberculosis infection in children seem to perform differently, because both QuantiFERON-TB tests were more likely than T-SPOT.TB to give indeterminate results in children <4 years of age.

2009 - Performance of tests for latent tuberculosis in different groups of immunocompromised patients. [Articolo su rivista]
Richeldi, Luca; Losi, M; D'Amico, Roberto; Luppi, M; Ferrari, A; Mussini, Cristina; Codeluppi, M; Cocchi, S; Prati, F; Paci, V; Meacci, M; Meccugni, B; Rumpianesi, F; Roversi, P; Cerri, Stefania; Luppi, F; Ferrara, G; Latorre, I; Gerunda, Giorgio Enrico; Torelli, G; Esposito, R; Fabbri, Leonardo
abstract

BACKGROUND: Immunocompromised persons infected with Mycobacterium tuberculosis (MTB) have increased risk of tuberculosis (TB) reactivation, but their managementis hampered by the occurrence of false-negative results of the tuberculin skin test (TST). The T-cell interferon (IFN)-gamma release blood assays T-SPOT.TB(TS.TB) [Oxford Immunotec; Abingdon, UK] and QuantiFERON-TB Gold In-Tube (QFT-IT) [Cellestis Ltd; Carnegie, VIC, Australia] might improve diagnostic accuracy forlatent TB infection (LTBI) in high-risk persons, although their performance in different groups of immunocompromised patients is largely unknown.METHODS AND RESULTS: Over a 1-year period, we prospectively enrolled patients in three different immunosuppressed groups, as follows: 120 liver transplantation candidates (LTCs); 116 chronically HIV-infected persons; and 95 patients with hematologic malignancies (HMs). TST, TS.TB, and QFT-IT were simultaneouslyperformed, their results were compared, and intertest agreement was evaluated.Overall, TST provided fewer positive results (10.9%) than TS.TB (18.4%; p <0.001) and QFT-IT (15.1%; p = 0.033). Significantly fewer HIV-infected individuals had at least one positive test (9.5%) compared with LTCs (35.8%; p < 0.001) and patients with HMs (29.5%; p < 0.001). Diagnostic agreement between tests was moderate (kappa = 0.40 to 0.65) and decreased in the HIV-infected group when the results of the TS.TB were compared with either TST (kappa = 0.16) orQFT-IT (kappa = 0.19). Indeterminate blood test results due to low positive control values were significantly more frequent with QFT-IT (7.2%) than with TS.TB (0.6%; p < 0.001).CONCLUSIONS: Blood tests identified significantly more patients as being infected with MTB than TST, although diagnostic agreement varied across groups. Based onthese results, we recommend tailoring application of the new blood IFN-gamma assays for LTBI in different high-risk groups and advise caution in their current use in immunosuppressed patients.

2009 - Regular vs prn nebulized treatment in wheeze preschool children. [Articolo su rivista]
A., Papi; G., Nicolini; E., Baraldi; A. L., Boner; R., Cutrera; G. A., Rossi; Fabbri, Leonardo; B., BEclomethasone Study Group
abstract

International guidelines recommend regular treatment with inhaled glucocorticoids for children with frequent wheezing; however, prn inhaled bronchodilator alone or in combination with glucocorticoid is also often used in practice. We aimed to evaluate whether regular nebulized glucocorticoid plus a prn bronchodilator or a prn nebulized bronchodilator/glucocorticoid combination is more effective than prn bronchodilator alone in preschool children with frequent wheeze.Double-blind, double-dummy, randomized, parallel-group trial. After a 2-week run-in period, 276 symptomatic children with frequent wheeze, aged 1-4 years, were randomly assigned to three groups for a 3-month nebulized treatment: (1) 400 microg beclomethasone bid plus 2500 microg salbutamol prn; (2) placebo bid plus 800 microg beclomethasone/1600 microg salbutamol combination prn; (3) placebo bid plus 2500 microg salbutamol prn. The percentage of symptom-free days was the primary outcome measure. Secondary outcomes included symptom scores, use of relief medication and exacerbation frequency.As compared with prn salbutamol (61.0 +/- 24.83 [SD]), the percentage of symptom-free days was higher with regular beclomethasone (69.6\%, SD 20.89; P = 0.034) but not with prn combination (64.9\%, SD 24.74). Results were no different in children with or without risk factors for developing persistent asthma. The effect of prn combination was no different from that of regular beclomethasone on the primary and on several important secondary outcomes.Regular inhaled glucocorticoid is the most effective treatment for frequent wheezing in preschool children. However, prn bronchodilator/glucocorticoid combination might be an alternative option, but it requires further study.

2009 - Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: Two randomised clinical trials [Articolo su rivista]
Fabbri, Leonardo; Calverley, P. M.; Izquierdo Alonso, J. L.; Bundschuh, D. S.; Brose, M.; Fj, F. J. Martinez; Rabe, K. F. .
abstract

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have few options for treatment. The efficacy and safety of the phosphodiesterase-4 inhibitor roflumilast have been investigated in studies of patients with moderate-to-severe COPD, but not in those concomitantly treated with longacting inhaled bronchodilators. The effect of roflumilast on lung function in patients with COPD that is moderate to severe who are already being treated with salmeterol or tiotropium was investigated. METHODS: In two double-blind, multicentre studies done in an outpatient setting, after a 4-week run-in, patients older than 40 years with moderate-to-severe COPD were randomly assigned to oral roflumilast 500 microg or placebo once a day for 24 weeks, in addition to salmeterol (M2-127 study) or tiotropium (M2-128 study). The primary endpoint was change in prebronchodilator forced expiratory volume in 1 s (FEV(1)). Analysis was by intention to treat. The studies are registered with ClinicalTrials.gov, number NCT00313209 for M2-127, and NCT00424268 for M2-128. FINDINGS: In the salmeterol plus roflumilast trial, 466 patients were assigned to and treated with roflumilast and 467 with placebo; in the tiotropium plus roflumilast trial, 371 patients were assigned to and treated with roflumilast and 372 with placebo. Compared with placebo, roflumilast consistently improved mean prebronchodilator FEV(1) by 49 mL (p<0.0001) in patients treated with salmeterol, and 80 mL (p<0.0001) in those treated with tiotropium. Similar improvement in postbronchodilator FEV(1) was noted in both groups. Furthermore, roflumilast had beneficial effects on other lung function measurements and on selected patient-reported outcomes in both groups. Nausea, diarrhoea, weight loss, and, to a lesser extent, headache were more frequent in patients in the roflumilast groups. These adverse events were associated with increased patient withdrawal. INTERPRETATION: Roflumilast improves lung function in patients with COPD treated with salmeterol or tiotropium, and could become an important treatment for these patients. FUNDING: Nycomed.

2009 - Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials [Articolo su rivista]
P. M., Calverley; K. F., Rabe; U. M., Goehring; S., Kristiansen; Fabbri, Leonardo; F. J., Martinez
abstract

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have few options for treatment. The efficacy and safety of the phosphodiesterase-4 inhibitor roflumilast have been investigated in studies of patients with moderate-to-severe COPD, but not in those concomitantly treated with longacting inhaled bronchodilators. The effect of roflumilast on lung function in patients with COPD that is moderate to severe who are already being treated with salmeterol or tiotropium was investigated. METHODS: In two double-blind, multicentre studies done in an outpatient setting, after a 4-week run-in, patients older than 40 years with moderate-to-severe COPD were randomly assigned to oral roflumilast 500 microg or placebo once a day for 24 weeks, in addition to salmeterol (M2-127 study) or tiotropium (M2-128 study). The primary endpoint was change in prebronchodilator forced expiratory volume in 1 s (FEV(1)). Analysis was by intention to treat. The studies are registered with ClinicalTrials.gov, number NCT00313209 for M2-127, and NCT00424268 for M2-128. FINDINGS: In the salmeterol plus roflumilast trial, 466 patients were assigned to and treated with roflumilast and 467 with placebo; in the tiotropium plus roflumilast trial, 371 patients were assigned to and treated with roflumilast and 372 with placebo. Compared with placebo, roflumilast consistently improved mean prebronchodilator FEV(1) by 49 mL (p&lt;0.0001) in patients treated with salmeterol, and 80 mL (p&lt;0.0001) in those treated with tiotropium. Similar improvement in postbronchodilator FEV(1) was noted in both groups. Furthermore, roflumilast had beneficial effects on other lung function measurements and on selected patient-reported outcomes in both groups. Nausea, diarrhoea, weight loss, and, to a lesser extent, headache were more frequent in patients in the roflumilast groups. These adverse events were associated with increased patient withdrawal. INTERPRETATION: Roflumilast improves lung function in patients with COPD treated with salmeterol or tiotropium, and could become an important treatment for these patients. FUNDING: Nycomed.

2009 - Short-Term Efficacy of Upper-Extremity Exercise Training in Patients With Chronic Airway Obstruction: A Systematic Review. [Articolo su rivista]
Costi, Stefania; M., Di Bari; P., Pillastrini; D'Amico, Roberto; E., Crisafulli; C., Arletti; Fabbri, Leonardo; Clini, Enrico
abstract

Background, Objectives, and Measurements Patients with chronic airway obstruction (CAO) frequently experience dyspnea and fatigue during activities performed by accessory muscles of ventilation, which competitively participate in arm elevation. This systematic review of randomized controlled trials (RCTs) concerning patients with CAO addresses the effects of upper-extremity exercise training (UEET), added to lower-extremity training or comprehensive pulmonary rehabilitation, on the following patient-centered outcomes: exercise capacity, symptoms, ability to perform daily activities, and health-related quality of life. METHODS:/b&gt; Studies were retrieved using comprehensive database and hand-search strategies. Two independent reviewers determined study eligibility based on inclusion criteria. A detailed description of treatments was mandatory. Reviewers rated study quality and extracted information on study methods, design, intervention, and results. RESULTS: /b&gt; Forty publications were evaluated. Four RCTs met the inclusion criteria but had serious methodological limitations, which introduce possible biases that reduce their internal validity. The outcomes measured were heterogeneous, and the results were inconsistent regarding maximal exercise capacity, dyspnea, and health-related quality of life. No effect of UEET was demonstrated for measures of arm fatigue. Limitations and CONCLUSIONS:/b&gt; The limited methodological quality of the studies retrieved prevented us from performing a meta-analysis, the results of which could be misleading. This systematic review shows that there is limited evidence examining UEET and that the evidence available is of poor quality. Therefore, a recommendation for the inclusion or exclusion of UEET in pulmonary rehabilitation programs for individuals with CAO is not possible. Further research is needed to definitively ascertain the effects of this training modality on patient-centered outcomes.

2008 - Beclomethasone/formoterol fixed combination for the management of asthma: patient considerations. [Articolo su rivista]
G., Nicolini; N., Scichilone; A., Bizzi; A., Papi; Fabbri, Leonardo
abstract

Drugs for asthma and other chronic obstructive diseases of the lungs should be preferably delivered by the inhalation route to match therapeutic effects with low systemic exposure. Inhaled drugs are delivered to the lungs via different devices, mainly metered dose inhalers and dry powder inhalers, each characterized by specific inhaler technique and instructions for use. The patient-device interaction is part of the prescribed therapy and can have a relevant impact on adherence and clinical outcomes. The most suitable device should be considered for each patient to assure the correct drug intake and adherence to the prescribed therapy. The development of new drugs/devices in the past decades improved the compliance with inhaler and possibly drug delivery to the bronchi. The present review focuses on the recently developed beclomethasone/formoterol extrafine fixed combination and technical aspects of drug delivery to the lungs in patient's perspective.

2008 - Complex chronic co-morbidities of COPD [Articolo su rivista]
Fabbri, Leonardo; Luppi, Fabrizio; Beghe', Bianca; K. F., Rabe
abstract

Chronic obstructive pulmonary disease (COPD) is defined by fixed airflow limitation associated with an abnormal pulmonary and systemic inflammatory response of the lungs to cigarette smoke. The systemic inflammation induced by smoking may also cause chronic heart failure, metabolic syndrome and other chronic diseases, which may contribute to the clinical manifestations and natural history of COPD. Thus COPD can no longer be considered a disease only of the lungs, as it is often associated with a wide variety of systemic consequences. A better understanding of the origin and consequences of systemic inflammation, and of potential therapies, will most likely lead to better care of patients with COPD. Medical textbooks and clinical guidelines still largely ignore the fact that COPD seldom occurs in isolation. As the diagnosis and assessment of severity of COPD may be greatly affected by the presence of comorbid conditions, the current authors believe that lung function measurement, noninvasive assessment of cardiovascular and metabolic functions, and circulating inflammatory markers (e.g. C-reactive protein) might help to better characterise these patients. Similarly, preventive and therapeutic interventions should address the patient in their complexity.

2008 - Cost-effectiveness of NIV applied to chronic respiratory failure.(Chapter 26). [Monografia/Trattato scientifico]
Clini, Enrico; Crisafulli, E; Moretti, M; Fabbri, Leonardo
abstract

The expansion of HMV in the last 15 yrs was stimulated by the introduction of non-invasive mask ventilation and the recognition that more patient groups could benefit.In the management of health-care resources the costs-analysis currently represents a method to evaluate the expenditure due to the effects on health of a new (or specific) intervention and to assess it in the economic perspective. Disability-adjusted life years (DALYs), healthy year equivalents (HYEs), or quality-adjusted life years (QALYs) are all time-based measures of health that include the impact of interventions on years of life lost due to premature mortality and years of life lived with a non-fatal health outcome, weighted by the severity of that outcome.Despite effectiveness of non-invasive HMV has been addressed so far, the impact of this treatment on the overall costs is not clearly reported nor still demonstrated and very few data based on a true economic analysis in patients under non-invasive HMV are published. Direct and (partially) indirect cost calculation have been observed and reported especially in COPD patients under non-invasive HMV. The most recent data underlie the large impact of non-invasive HMV on both patients’ outcome (reduction of recurrent admissions and increase in quality of life) and families’ burden (unemployment, financial and social issues), thus prompting new studies with appropriate cost-effectiveness and/or cost-utility analysis.

2008 - Cost-effectiveness of NIV applied to chronic respiratory failure.Eur [Capitolo/Saggio]
Clini, Enrico; E., Crisafulli; M., Moretti; Fabbri, Leonardo
abstract

The expansion of home mechanical ventilation (HMV) in the last 15 yrs was stimulated by the introduction of noninvasive mask ventilation and the recognition that more patient groups could benefit.In the management of healthcare resources, cost-analysis currently represents a method for evaluation of the expenditure due to the effects on health of a new (or specific) intervention and for assessing it in the economic perspective. Disabilityadjustedlife-yrs, healthy-yr equivalents and quality-adjusted life-yrs are all time-based measures of health that include the impact of interventions on years of life lost due to premature mortality and years of life lived with a nonfatal health outcome, weightedby the severity of that outcome.Although the effectiveness of noninvasive HMV has been addressed, the impact of this treatment on the overall costs has not been clearly reported or demonstrated and very few data based on a true economic analysis in patients under noninvasive HMV have been published. Direct and (partially) indirect cost calculations have been observed and reported, especially in chronic obstructive pulmonary disease patients under noninvasive HMV. The most recent data underline the large impact ofnoninvasive HMV on both patient outcome (reduction of recurrent admissions and increase in quality of life) and family burden (unemployment, financial and social issues), thus prompting further studies with appropriate cost-effectiveness and/or cost-utility analysis.

2008 - Decreased heme-oxygenase (HO)-1 in the macrophages of non-small cell lung cancer. [Articolo su rivista]
Piera, Boschetto; Elena, Zeni; Lucia, Mazzetti; Deborah, Miotto; Natalina Lo, Cascio; Piero, Maestrelli; Emanuela, Marian; Patrizia, Querzoli; Massimo, Pedriali; Bruno, Murer; Edoardo De, Rosa; Fabbri, Leonardo; Cristina E., Mapp
abstract

Reactive oxygen species (ROS) are important in the initiation and promotion of cells to neoplastic growth. Heme-oxygenase (HO)-1, the inducible form of heme-oxygenase, is a cytoprotective enzyme that plays a central role in the defence against oxidative stress and is implicated in the protection of lung tissue against exogenous oxidant exposure. We investigated whether the expression of HO-1 would be decreased in lung tumour as compared with tumour-free adjacent lung tissues. HO-1 expression was quantified by immunohistochemistry in tumour macrophages, in macrophages of tumour-free lung and in tumour cells of surgical specimens collected from 53 individuals with surgically resectable non-small cell lung cancer (NSCLC). The expression of HO-1 was decreased in tumour as compared with tumour-free lung macrophages. No correlations were observed between the expression of HO-1 and both the clinicopathological characteristics and the overall survival of the examined subjects. In conclusion, our data show that macrophages of non-small cell lung cancer exhibit impaired anti-oxidant defence mechanisms, likely mediated by HO-1. Conversely, HO-1 expression does not seem to be associated with lung tumour progression and prognosis.

2008 - Home-centred physical fitness programme in morbidly obese individuals: a randomized controlled trial [Articolo su rivista]
Riccardo, Tumiati; Gianni, Mazzoni; Ernesto, Crisafulli; Barbara, Serri; Claudio, Beneventi; Cristina M., Lorenzi; Giovanni, Grazzi; Francesco, Prato; Francesco, Conconi; Fabbri, Leonardo; Clini, Enrico
abstract

OBJECTIVE: To assess the effectiveness of domiciliary physical fitness programmes in obese individuals. DESIGN: Nine-month randomized controlled trial. SETTING: Home-based intervention with outpatient visits. SUBJECTS: Morbidly obese subjects (body mass index (BMI) > or = 30) aged 25-65 years suitable for physical activities at home. INTERVENTION: At the end of a preliminary one-month in-hospital rehabilitation programme (baseline), 52 patients were randomly assigned either to a structured educational programme (intervention group) of daily incremental physical activity at home (walking and skeletal muscle resistance training, with booklets and written instructions) or to a programme of general advice (control group) regarding exercise and long-term fitness. MAIN MEASURES: Both groups were evaluated at baseline and every three months for: (1) time, metabolic equivalents (METs), and heart rate reserve (HRR) during a standardized 2-km walking test (2kmWT); (2) anthropometric measures (body weight, BMI, abdominal and neck circumference); (3) the Polar Fitness Test index (PFTI), and (4) time to exhaustion while sustaining consecutive isoload extensions in the dominant leg (isoload LE). Time during 2kmWT was the study primary outcome. RESULTS: Body weight, BMI and abdominal circumference improved significantly (P < 0.05) over time in the intervention group. The cardiopulmonary fitness variables changed significantly (P < 0.05) over time in both study groups. However, all variables improved in the intervention patients, while some worsened or remained stable in the controls. Thus, the mean group difference in changes was significant (P < 0.05) for 2kmWT time (-77.4 seconds), HRR (11.7\%), and PFTI (5.4 points). CONCLUSION: This structured domiciliary fitness programme is feasible and provides sustained anthropometric and physiological benefits in some morbidly obese individuals.

2008 - Increased activation of p38 MAPK in COPD. [Articolo su rivista]
T., Renda; S., Baraldo; G., Pelaia; E., Bazzan; G., Turato; A., Papi; P., Maestrelli; R., Maselli; A., Vatrella; Fabbri, Leonardo; R., Zuin; S. A., Marsico; M., Saetta
abstract

Inflammation, oxidative stress and apoptosis, which are involved in chronic obstructive pulmonary disease (COPD) pathogenesis, may activate the p38 subgroup of mitogen-activated protein kinases (MAPKs). Therefore, the aim of the present study was to evaluate the expression of the phosphorylated, active form of p38 MAPK (phospho-p38) in the lungs of COPD patients. Surgical specimens were obtained from 18 smokers with COPD at different stages of disease severity, plus nine smoking and eight nonsmoking subjects with normal lung function. Phospho-p38+ cells were quantified by immunohistochemistry in both alveolar spaces and alveolar walls. Moreover, a Western blot analysis of phospho-p38 and total p38alpha isoform expressed by alveolar macrophages was performed. Phospho-p38+ alveolar macrophages and phospho-p38+ cells in alveolar walls were increased in patients with severe and mild/moderate COPD, compared with smoking and nonsmoking controls. Moreover, they were inversely correlated to values of forced expiratory volume in one second (FEV(1)) and FEV(1)/forced vital capacity. Western blot analysis showed that phosphorylated p38, but not the total p38alpha isoform, was specifically increased in alveolar macrophages from COPD patients. Activation of the p38 mitogen-activated protein kinase pathway appears to be involved in the pathogenesis of chronic obstructive pulmonary disease. The present findings suggest that this protein may be a suitable pharmacological target for therapeutic intervention.

2008 - Indacaterol provides sustained 24 h bronchodilation on once-daily dosing in asthma: A 7-day dose-ranging study [Articolo su rivista]
C., Laforce; M., Alexander; R., Deckelmann; Fabbri, Leonardo; Z., Aisanov; R., Cameron; R., Owen; M., Higgins
abstract

BACKGROUND: Indacaterol is a novel, once-daily beta(2)-agonist in development for the treatment of asthma and chronic obstructive pulmonary disease. Studies were required to determine optimal dose(s) for continuing investigation. OBJECTIVE: A dose-ranging study was undertaken to evaluate efficacy and safety of indacaterol. METHODS: A total of 436 patients with persistent asthma receiving inhaled corticosteroids were randomized to 7 days treatment with once-daily indacaterol 50, 100, 200, or 400 microg via multi-dose dry-powder inhaler (MDDPI; Certihaler), indacaterol 400 microg via single-dose dry-powder inhaler (SDDPI), or placebo. Serial 24-h spirometry was performed on days 1 and 7. Vital signs, laboratory evaluations, and adverse events were monitored. RESULTS: All doses of indacaterol increased the mean time-standardized area under the curve of forced expiratory volume in 1 s (FEV(1)) from 22 to 24 h postdose (P <or= 0.001 vs placebo) on days 1 and 7, with clinically relevant treatment-placebo differences of 240, 260, 350, 300, and 380 ml on day 1 and 230, 220, 320, 250, and 270 ml on day 7 for indacaterol 50, 100, 200, and 400 microg via MDDPI and 400 microg via SDDPI, respectively. All doses increased mean FEV(1) (P < 0.05 vs placebo) from 5 min to 24 h postdose on days 1 and 7. All doses were well tolerated. Most adverse events were mild-to-moderate in severity: most frequently reported were respiratory, thoracic, and mediastinal disorders. CONCLUSION: Once-daily dosing with indacaterol provided sustained 24-h bronchodilation in patients with moderate-to-severe asthma, with a satisfactory overall safety profile. Indacaterol 200 microg appears the optimum dose, offering the best efficacy/safety balance.

2008 - Inhaled beclometasone dipropionate/formoterol extra-fine fixed combination in the treatment of asthma: Evidence and future perspectives [Articolo su rivista]
Fabbri, Leonardo; Gabriele, Nicolini; Dario, Olivieri; Alberto, Papi
abstract

BACKGROUND: Combinations of a long-acting beta(2)-agonist (LABA) and an inhaled corticosteroid (ICS) are effective and safe options in asthma management. OBJECTIVE: To review available data on a recently developed combination of beclometasone dipropionate (BDP) and formoterol (F) given via a pressurized metered-dose inhaler. METHODS: Published data on preclinical and clinical studies were reviewed. RESULTS/CONCLUSION: In the treatment of asthma, BDP/F was shown to be at least as effective and well-tolerated as other available combinations of ICS and LABA with the advantage of a better cost effectiveness, and more effective in improving asthma control than BDP and formoterol given via separate inhalers. The extra-fine BDP/F combination appears to be a valuable therapeutic option in the management of asthma.

2008 - Mycobacterium tuberculosis induces CCL18 expression in human macrophages [Articolo su rivista]
G., Ferrara; B., Bleck; Richeldi, Luca; J., Reibman; Fabbri, Leonardo; W. N., Rom; R., Condos
abstract

The interaction of Mycobacterium tuberculosis (MTB) with the immune system is mediated by cytokine and chemokine responses of macrophages and/or dendritic cells. Chemokine (C-C motif) ligand 18 (CCL18) and interleukin (IL)-10 are major factors secreted by phagocytes, postulated to recruit naïve T lymphocytes and inhibit pro-inflammatory cells. Our study investigated the role of CCL18 and IL-10 in an in vitro model of infection by MTB in human macrophages. CD14(+) monocytes, obtained from the peripheral blood of eight healthy donors, differentiated in monocyte-derived macrophages (MDM) with monocyte-colony stimulating factor (100 ng/ml) for 6 days, were stimulated in vitro with lipopolysaccharide (LPS) (1 microg/ml) and with heat killed MTB Hv37Ra (multiplicity of infection 1:5) for 24 h. Alveolar macrophages from five healthy donors were infected with MTB Hv37RA. CCL18 protein and mRNA were detected by enzyme-linked immunosorbent assay (ELISA) and real-time PCR, IL-10 levels by ELISA. Stimulation of MDM with LPS or MTB led to a significant increase in CCL18 protein (control 2.67 +/- 0.46 ng/ml, LPS 4.05 +/- 0.56 ng/ml, with MTB 6.70 +/- 1.59 ng/ml, n = 5, P < 0.05) and specific mRNA levels (control 0.09 +/- 0.01, LPS 0.24 +/- 0.11, with MTB 0.34 +/- 0.08 CCL18/Glyceraldehyde 3-phosphate dehydrogenase (GAPDH), n = 3, P < 0.05). A significant increase of the production of CCL18 was observed in infected alveolar macrophages. IL-10 levels increased from 38.52 +/- 26.38 pg/ml in control cells to 1129.32 +/- 235.00 and 974.25 +/- 164.46 pg/ml in LPS and MTB treated cells, respectively (P < 0.05). Up-regulation of CCL18 and IL-10 in macrophages by MTB may be involved in the recruitment of naïve T cells in association with local suppressive immunity against intracellular pathogens. This could represent a mechanism of tolerance during the early phases of infection.

2008 - Nonatopic children with multitrigger wheezing have airway pathology comparable to atopic asthma [Articolo su rivista]
Graziella, Turato; Angelo, Barbato; Simonetta, Baraldo; Maria Elena, Zanin; Erica, Bazzan; Kim Lokar, Oliani; Fiorella, Calabrese; Cristina, Panizzolo; Deborah, Snijders; Piero, Maestrelli; Renzo, Zuin; Fabbri, Leonardo; Marina, Saetta
abstract

RATIONALE: Epidemiologic studies have shown that, in atopic children, wheezing is more likely to persist into adulthood, eventually becoming asthma, whereas it appears to resolve by adolescence in nonatopic children. OBJECTIVES: To investigate whether among children with multitrigger wheeze responsive to bronchodilators the airway pathology would be different in nonatopic wheezers, who are often considered nonasthmatic, compared with atopic wheezers, who are more frequently diagnosed as having asthma. METHODS: Bronchial biopsies were obtained from 55 children undergoing bronchoscopy for appropriate clinical indications: 18 nonatopic children with multitrigger wheeze (median age, 5 yr; range, 2-10 yr), 20 atopic children with multitrigger wheeze (medan age, 5 yr; range, 2-15 yr), and 17 control children with no atopy or wheeze (median age, 4; range, 2-14 yr). By histochemistry and immunohistochemistry, we quantified epithelial loss, basement membrane thickness, angiogenesis, inflammatory cells, IL-4(+,) and IL-5(+) cells in subepithelium. MEASUREMENTS AND MAIN RESULTS: Unexpectedly, all pathologic features examined were similar in atopic and nonatopic wheezing children. Compared with control subjects, both nonatopic and atopic wheezing children had increased epithelial loss (P = 0.03 and P = 0.002, respectively), thickened basement membrane (both P < 0.0001), and increased number of vessels (P = 0.003 and P = 0.03, respectively) and eosinophils (P < 0.0001 and P = 0.002, respectively). Moreover, they had increased cytokine expression, which was highly significant for IL-4 (P = 0.002 and P = 0.0001, respectively) and marginal for IL-5 (P = 0.02 and P = 0.08, respectively). CONCLUSIONS: This study shows that the airway pathology typical of asthma is present in nonatopic wheezing children just as in atopic wheezing children. These results suggest that, when multitrigger wheezing responsive to bronchodilators is present, it is associated with pathologic features of asthma even in nonatopic children.

2008 - Passive smoking and asthma death [Articolo su rivista]
G., Invernizzi; R., Boffi; A., Ruprecht; A., Lazzaro; Fabbri, Leonardo
abstract

letter

2008 - Pharmacological prevention of COPD exacerbations [Capitolo/Saggio]
Beghe', Bianca; F., Luppi; Fabbri, Leonardo
abstract

Exacerbations of COPD are characterized by changes in the patient’s baseline dyspnoea, cough, and/or sputum that are beyond normal day-to-day variations, that are acute in onset, and that may warrant a change in regular medication. The frequency and severity of exacerbations increase with disease severity and are associated with poorer quality of life and health outcomes, with a greater burden on health care, accelerated decline of lung function, and increased risk of death. For all these reasons, exacerbations are a major target of prevention and treatment in patients with COPD.While exacerbations are increasingly used as primary outcome or secondary pre-specified outcome in clinical trials in COPD, major limitations of the studies on COPD exacerbations are that the definition is based on symptoms and not on objective measurements. Furthermore, the definition varies between studies, and often comorbidities are not adequately taken into account. Worsening of daily respiratory symptoms, particularly dyspnoea, could be associated with respiratory events, such as pneumonia, or non respiratory events, such as heart failure, thromboembolisms, and renal failure, among others. Long-acting bronchodilators alone or in combination with inhaled glucocorticosteroids are the most effective treatment for reducing the number and severity of COPD exacerbations—even though caution is required in interpreting the results of some trials. Suissa and coworkers, in their recent papers on methodological issues, suggest that the results of major randomized controlled clinical trials that evaluate the effect of treatment on COPD exacerbations might be biased by the facts that many patients enrolled in the studies are already receiving inhaled therapy before randomization, and that the results could be influenced by withdrawal from the ongoing effective therapy. Another bias might be that patients included in the trials are often not followed after discontinuation of treatment; considering the different rates of withdrawal between treatments and the different causes of withdrawal, this may severely affect the interpretation of the data. Statistical methods are also critical. A statistical approach that does not weight for the length of the follow-up (unweighted approach), and for the within- and between-subject variability of exacerbations, may lead to false-positive results. In particular, this bias applies to all but two trials examining the effect of inhaled glucocorticosteroids on exacerbations, causing the authors of those studies to conclude that the positive effect of inhaled glucocorticosteroids on exacerbations is not supported by solid evidence. With these limitations, however, randomised controlled trials are and will remain the fundamental tools for evaluating the benefit of COPD treatment, and the data collected so far, albeit with the potential biases, are the only evidence available to support treatment recommendations.In this chapter we review the various classes of medications commonly used in treating COPD. We focus on the most effective medications for preventing exacerbations, such as inhaled long-acting bronchodilators alone or in combination with inhaled glucocorticosteroids. Also, considering their importance in the management of COPD, we briefly discuss the effects of smoking cessation and vaccinations on COPD exacerbations. We do not discuss the effects of treatment of exacerbations on subsequent exacerbations—obviously an important clinical aspect. In fact, short-term therapy with oral glucocorticosteroids after hospitalization for a COPD exacerbation reduces the likelihood of readmission for another exacerbation.

2008 - Rehabilitation in patients submitted to lung resection surgery: A retrospective analysis [Articolo su rivista]
Crisafulli, E.; Venturelli, E.; De Biase, A.; Righi, D.; Rizzardi, R.; Lorenzi, C.; Fabbri, L. M.; Clini, E. M.
abstract

Background and aim. Several diseases may affect the thoraco-pulmonary system. In most cases resection surgery represents the elective therapy. To date, consensus is still lacking on the efficacy of post-surgery rehabilitation (PR) in these patients. Aim of our study was, therefore, to evaluate the effectiveness of a PR in patients undergoing thoraco-polmonary resection surgery. Patients and measurements. Forty patients referred for PR "Villa Pineta" Hospital-Rehabilitation Centre (in the period January 2006 to December 2007) after thoraco-pulmonary resection surgery were studied; 24 out of them had been directly transferred from the Surgery Unit (Early Rehabilitation), while other 16 came from their home with surgery having taken place at least 15 days before (Late Rehabilitation). The following outcome measures were recorded at baseline and at the end of PR: respiratory muscle performance (MIP and MEP), arterial blood gases (ABG - PaO2, PaCO2, pH, SatO2, PaO2/FiO2), the distance walked at the 6 minute test (6MWD) with related symptoms (dispnoea and muscle fatigue), scale of chronic dispnoea (MRC), questionnaire of perceived quality of life (SGRQ). Results. After PR, significant improvements (p &lt;0.05) related to MIP-MEP, 6MWD with symptoms, MRC and SGRQ have been recorded in both subgroups. Only patients in the Early Rehabilitation group also showed improvements of blood oxygenation (PaO2, SatO2, PaO2/FiO2). Univariate analysis performed among groups in all the outcomes taking number and percentage of patients improved (as assessed by a pre-defined cut-off), has shown that both dyspnea (p =0.014) and muscle fatigue (p = 0.046) significantly differ in favour of the Early rehabilitation group. Conclusions. Our study suggests that rehabilitation may produce clinically relevant improvements in patients recovering from thoraco-pulmonary resection surgery. Effectiveness is more likely to be higher if program is applied early after surgery.

2008 - Role of comorbidities in a cohort of patients with COPD undergoing pulmonary rehabilitation [Articolo su rivista]
Crisafulli, E; Costi, Stefania; Luppi, Fabrizio; Cirelli, G; Cilione, C; Coletti, O; Fabbri, Leonardo; Clini, Enrico
abstract

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is often associated with other chronic diseases. These patients are often admitted to hospital based rehabilitation programmes. OBJECTIVES: To determine the prevalence of chronic comorbidities in patients with COPD undergoing pulmonary rehabilitation and to assess their influence on outcome. DESIGN: Observational retrospective cohort study. SETTING: A single rehabilitation centre. PATIENTS: 2962 inpatients and outpatients with COPD (73\% male, aged 71 (SD 8) years, forced expiratory volume in 1 s (FEV(1)) 49.3 (SD 14.8)\% of predicted), graded 0, 1 or &gt;/=2 according to the comorbidity categories and included in a pulmonary rehabilitation programme. Measurements: The authors analysed the number of self-reported comorbidities and recorded the Charlson Index. They then calculated the percentage of patients with a predefined positive response to pulmonary rehabilitation (minimum clinically important difference (MCID)), as measured by improvement in exercise tolerance (6 min walking distance test (6MWD)), dyspnoea (Medical Research Council scale) and/or health related quality of life (St George's Respiratory Questionnaire (SGRQ)). RESULTS: 51\% of the patients reported at least one chronic comorbidity added to COPD. Metabolic (systemic hypertension, diabetes and/or dyslipidaemia) and heart diseases (chronic heart failure and/or coronary heart disease) were the most frequently reported comorbid combinations (61\% and 24\%, respectively) among the overall diseases associated with COPD. The prevalence of patients with MCID was different across the comorbidity categories and outcomes. In a multiple categorical logistic regression model, the Charlson Index (OR 0.72 (96\% CI 0.54 to 0.98) and 0.51 (96\% CI 0.38 to 0.68) vs 6MWD and SGRQ, respectively), metabolic diseases (OR 0.57 (96\% CI 0.49 to 0.67) vs 6MWD) and heart diseases (OR 0.67 (96\% CI 0.55 to 0.83) vs SGRQ) reduced the probability to improve outcomes of rehabilitation. CONCLUSIONS: Most patients with COPD undergoing pulmonary rehabilitation have one or more comorbidities. Despite the fact that the presence of comorbidities does not preclude access to rehabilitation, the improvement in exercise tolerance and quality of life after rehabilitation may be reduced depending on the comorbidity.

2008 - Treatment of chronic obstructive pulmonary disease and its comorbidities [Relazione in Atti di Convegno]
Luppi, Fabrizio; Franco, F; Beghe', Bianca; Fabbri, Leonardo
abstract

While chronic obstructive pulmonary disease (COPD) is still characterized and diagnosed by lung function measurements, there is increasing evidence that the chronic diseases that frequently develop with COPD in response to the common risk factors (smoking, aging, obesity) may contribute significantly to its clinical manifestations and severity. Considering that pharmacologic and nonpharmacologic treatments of COPD, such as pulmonary rehabilitation, are primarily symptomatic, it is reasonable to hope that a more comprehensive management of COPD that takes into account its comorbidities may improve the response to treatment and reduce mortality in patients with COPD. Thus, as comorbidities are often underdiagnosed and undertreated, it is important to search for their coexistence in COPD and in all chronic diseases, possibly by adopting recommendations for diagnosis of single diseases. This means that while careful cardiovascular, metabolic, and endocrinologic examinations should be increasingly used in assessing patients with COPD, lung function measurements may become useful in patients with chronic cardiovalscular, metabolic, and endocrinologic diseases. The increasing evidence that active treatment of comorbidities (by, e.g., statins and beta-blockers) may reduce morbidity and mortality in patients with COPD suggests the urgent need for randomized clinical trials that hopefully will provide the evidence for more comprehensive clinical guidelines for these patients.

2007 - An investigation of airway acidification in asthma using induced sputum: a study of feasibility and correlation. [Articolo su rivista]
M., Kodric; A. N., Shah; Fabbri, Leonardo; M., Confalonieri
abstract

RATIONALE: Acidification of the airways seems to be involved in asthma pathophysiology, but its assessment might be difficult. OBJECTIVES: The aim of our study is to assess the feasibility and validity of airway acidification measurement by induced sputum and its clinical significance in asthma. METHODS: Induced-sputum samples were obtained in 57 outpatients with asthma. The between-sample repeatability after 48 hours was measured in an independent population of 14 patients with asthma. pH was measured using a pH meter. The control of asthma was established by the Asthma Control Questionnaire. MEASUREMENTS AND MAIN RESULTS: The pH measurement was feasible in all samples and repeatable both within (intraclass correlation coefficient [ICC], 0.96) and between samples (ICC, 0.621). The mean pH was significantly different between healthy subjects and patients with asthma, including in those with controlled (mean pH: 7.54 in healthy subjects vs. 7.28 in subjects with controlled asthma; p = 0.0105) and uncontrolled disease (mean pH: 7.54 in healthy subjects vs. 7.06 in subjects with uncontrolled disease; p < 0.0001), and between patients with stable asthma and those with poorly controlled asthma (7.28 vs. 7.06, respectively; p = 0.0134). The validity of the method was assessed with the receiver operating characteristic curves and induced-sputum lower pH values (with a cutoff value of 7.3; sensitivity, 72.1%; specificity, 100%). CONCLUSIONS: Patients with asthma show lower pH than healthy subjects. Patients with poorly controlled asthma seem to have the lowest induced-sputum pH, independent of the GINA (Global Initiative for Asthma) severity level. In conclusion, induced sputum is a feasible, repeatable, noninvasive method to measure airway pH. The pH in induced sputum may reflect a different aspect of asthma from sputum eosinophils and be related to different pathophysiologic factors.

2007 - Beclomethasone/formoterol versus budesonide/formoterol combination therapy in asthma. [Articolo su rivista]
A., Papi; Paggiaro, P. L.; G., Nicolini; Vignola, A. M.; Fabbri, Leonardo
abstract

The present study was designed to compare the fixed combination of beclomethasone and formoterol in a hydrofluoroalkane Modulite (Chiesi Farmaceutici, Parma, Italy) pressurised metered-dose inhaler (pMDI), with a combination of budesonide and formoterol administered via a Turbuhaler (AstraZeneca, Lund, Sweden) dry powder inhaler (DPI). This was a phase III, multinational, multicentre, double-blind, double-dummy, randomised, two-arm parallel groups, controlled study design. After a 2-week run-in period, 219 patients with moderate-to-severe asthma were randomised to a 12-week treatment with beclomethasone 200 microg plus formoterol 12 microg b.i.d. delivered via a pMDI or budesonide 400 microg plus formoterol 12 microg b.i.d. delivered via a DPI. The analysis of noninferiority on primary outcome, morning peak expiratory flow in the last 2 weeks of treatment, showed no difference between groups. A statistically significant improvement from baseline in lung function, symptoms and rescue medication use was observed in both groups at all time-points. No differences were observed between treatments in either rate of asthma exacerbations or frequency of adverse events. The new fixed combination of beclomethasone and formoterol in hydrofluoroalkane Modulite pressurised metered-dose inhaler is equivalent to the marketed combination of budesonide and formoterol in terms of efficacy and tolerability profile.

2007 - Beclomethasone/formoterol vs fluticasone/salmeterol inhaled combination in moderate to severe asthma. [Articolo su rivista]
A., Papi; Paggiaro, P. L.; G., Nicolini; Vignola, A. M.; Fabbri, Leonardo; ICAT SE STUDY, Group
abstract

BACKGROUND: Recommended treatment for moderate to severe asthma is the combination of an inhaled corticosteroid and a long-acting beta(2)-agonist. The present study was designed to compare a new fixed combination of extrafine beclomethasone and formoterol, with the fixed combination fluticasone and salmeterol. METHODS: This was a phase III, multinational, multicentre, double-blind, randomized, two-arm parallel groups, controlled study. After a 2-week run-in period, 228 patients with moderate to severe asthma were randomized to a 12-week treatment with either beclomethasone 100 microg plus formoterol 6 microg or fluticasone 125 microg plus salmeterol 25 microg, both delivered two inhalations b.i.d. via a pressurized metered dose inhaler. RESULTS: The analysis of noninferiority on the primary outcome, morning peak expiratory flow in the last 2 weeks of treatment, showed no difference between groups (difference -3.32 l/min; 95% CI -17.92 to 11.28). A significant improvement from baseline in lung function, symptom score and rescue medication use was observed in both groups at all time points. Beclomethasone plus formoterol combination showed a significantly faster onset of bronchodilation when compared with fluticasone plus salmeterol with the difference maintained for up to 1 h postdosing. No differences were observed between treatments in the rate of asthma exacerbations, frequency of adverse events and overnight urinary cortisol/creatinine ratio. CONCLUSIONS: The new combination of extrafine beclomethasone plus formoterol is not inferior to the marketed combination of fluticasone and salmeterol in terms of efficacy and tolerability, with the advantage of a faster onset of bronchodilation. ( ClinicalTrials.gov number, NCT00394368).

2007 - CC ligand 2 levels are increased in LPS-stimulated peripheral monocytes of patients with non-small cell lung cancer. [Articolo su rivista]
D., Miotto; P., Boschetto; I., Bononi; G., Milani; C., Legorini; G., Cavallesco; N., LO CASCIO; E., Zeni; Fabbri, Leonardo; C. E., Mapp
abstract

Non-small cell lung cancer (NSCLC) shows a particular aggressive behaviour. Tumour associated macrophages (TAMs) play an important role in tumour growth and progression and CC ligand 2 (CCL2)/CCR2 axis is markedly involved in their recruitment in the tumour mass from the circulation. The aim of this study was to determine the plasma levels of CCL2 and the expression of CCR2 in the peripheral blood mononuclear cells (PBMCs) of 18 smokers with NSCLC, eight healthy smokers and nine non-smokers. Then, we investigated CCL2 levels in the supernatants of unstimulated and LPS-stimulated PBMC cultures of the same groups of patients. CCL2 levels in plasma and supernatants of PBMC cultures were determined by ELISA. CCR2 expression in PBMC cytospins was assessed by immunocytochemistry. CCL2 plasma levels and CCR2 expression by PBMCs were similar in patients with NSCLC, healthy smokers and non-smokers. In the supernatants of unstimulated PBMC cultures, CCL2 content was not different between the three groups of subjects. Supernatants of LPS-stimulated PBMCs of NSCLC patients showed a higher content of CCL2 as compared to supernatants of non-smokers (p<0.005). CCL2 content increased 28.5-fold vs baseline production in the group of NSCLC patients, 15-fold in healthy smokers and 13-fold in the group of non-smokers. In conclusion, after LPS stimulation, PBMCs of patients with NSCLC release higher levels of CCL2 as compared to those of non-smokers, supporting the hypothesis of a CCL2 involvement in NSCLC biology.

2007 - COPD guidelines: the important thing is not to stop questioning. [Articolo su rivista]
Fabbri, Leonardo; P., BOSCHETTO P; C. E., Mapp
abstract

editoriale

2007 - Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. [Articolo su rivista]
Calverley, Pm; SANCHEZ TORIL, F; Mcivor, A; Teichmann, P; Bredenbroeker, D; Fabbri, Leonardo
abstract

RATIONALE: The oral phosphodiesterase-4 (PDE4) inhibitor, roflumilast, can improve lung function in moderate chronic obstructive pulmonary disease (COPD). Whether treatment is effective in more severe COPD (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stages III and IV) over a longer period is unknown. OBJECTIVES: To determine whether roflumilast improves lung function and decreases exacerbation frequency over 1 year in patients with stable COPD. METHODS: We conducted a randomized, placebo-controlled, double-blind, parallel-group trial for 1 year. We recruited 1,513 patients (mean post-bronchodilator FEV1 41% predicted), 760 receiving oral 500 microg roflumilast and 753 receiving placebo once daily. MEASUREMENTS AND MAIN RESULTS: We recorded post-bronchodilator FEV1, exacerbation rate, St. George's Respiratory Questionnaire total score at the study end point, and number and type of reported adverse events during treatment. Post-bronchodilator FEV1 increased by 39 ml with roflumilast compared with placebo by 52 weeks (p=0.001). The mean exacerbation rate was low and comparable in both treatment groups (0.86 vs. 0.92 exacerbations/patient/yr for roflumilast and placebo, respectively). In a retrospective analysis, the exacerbation rate in patients in GOLD stage IV disease was 36% lower in patients treated with roflumilast than in those treated with placebo (1.01 vs. 1.59 exacerbations/patient/year, respectively; p=0.024). The St. George's Respiratory Questionnaire total score did not differ between treatments. The commonest adverse events related to roflumilast treatment were diarrhea, nausea, and headache, which usually subsided during continued treatment. However, roflumilast resulted in more withdrawals within the first 3 to 4 weeks of administration. CONCLUSIONS: In severe, stable COPD, PDE4 inhibition with roflumilast produced a modest but significant improvement in lung function without changing the exacerbation rate or health status. However, patients with very severe disease experienced fewer exacerbations with roflumilast.

2007 - Effectiveness of erdosteine in elderly patients with bronchiectasis and hypersecretion: A 15-day, prospective, parallel, open-label, pilot study [Articolo su rivista]
Ernesto, Crisafulli; Orietta, Coletti; Costi, Stefania; Emanuela, Zanasi; Cristina, Lorenzi; Sasa, Lucic; Fabbri, Leonardo; Marco, Bertini; Clini, Enrico
abstract

BACKGROUND: Mucus plugging and hypersecretion have been associated with an increased relative risk of death in patients with bronchiectasis who may or may not have chronic obstructive pulmonary disease (COPD), which is of prognostic relevance in the elderly. However, chest physiotherapy and/or the use of mucoactive agents is considered to be an effective therapeutic model in treating patients with COPD and bronchiectasis. OBJECTIVE: The objective of this study was to test the effectiveness of oral erdosteine in treating elderly patients with bronchiectasis and chronic mucus hypersecretion who have been referred to a pulmonary rehabilitation program. METHODS: In this 15-day, prospective, parallel, open label, pilot study, elderly patients with bronchiectasis, hypersecretion, a noncurrent smoking status, who had been consecutively enrolled at Ospedale Villa Pineta's Pulmonary Rehabilitation Center, Pavullo-Modena, Italy, were randomized into 2 treatment groups. Group 1 consisted of those patients receiving PO erdosteine 225 mg BID and chest physiotherapy; group 2 comprised those patients receiving chest physiotherapy alone. Forced lung volumes, arterial blood gases, respiratory muscle strength, walking capacity (as measured by 6-minute walking test [6MWT]), and visual analog scale (VAS) symptoms (cough and dyspnea) were recorded at enrollment and at the conclusion of the study. Mucus density (MD), mucus purulence (MP), and mucus volume produced (MVP) were assessed using a 3-point scale (0 = best or low; 1 = moderate; and 2 = worst or high) at baseline and at 5-day time points during the study period. All measurements were assessed by personnel blinded and not directly associated with the study administration. RESULTS: Thirty patients (21 [70%] male and 9 [30%] female; mean [SD] age, 71 [11] years; and mean [SD] weight, 66 [3] kg) were enrolled. Characteristics were similar in the 2 groups at baseline. At day 15, significant improvements were observed in 6MWT, VAS cough, and VAS dyspnea (P &lt; 0.01) in both groups. However, a significant improvement in forced expiratory volume in 1 second and forced vital capacity (in milliliters) was observed only in group i (0.2 [0.3]; P &lt; 0.05). At day 15, improvement was observed in mean (SD) in MD, MP, and MVP scores for both groups. Significant changes, however, were observed in all 3 measurements in group 1 (-0.80 [0.22], -0.71 [0.51], and 1.01 [0.39], respectively), whereas a significant improvement was observed only in MD (-0.55 [0.44]) and MVP (0.45 [0.62]) in group 2. The improvement in MVP observed in group 1 was significantly better than that observed in group 2 (P &lt; 0.05). CONCLUSION: This pilot study found that a regimen of PO erdosteine 225 mg BID in addition to routine chest physiotherapy provided some physiologic and clinical benefits in the treatment of these elderly patients with bronchiectasis and chronic mucus hyper-secretion.

2007 - Effects of a walking aid in COPD patients receiving oxygen therapy [Articolo su rivista]
E., Crisafulli; Costi, Stefania; F., DE BLASIO; G., Biscione; F., Americi; S., Penza; E., Eutropio; F., Pasqua; Fabbri, Leonardo; Clini, Enrico
abstract

STUDY OBJECTIVES: To elucidate whether a simple walking aid may improve physical performance in COPD patients with chronic respiratory insufficiency who usually carry their own heavy oxygen canister. DESIGN: Randomized crossover trial. SETTING: Physiopathology laboratory of three rehabilitation centers. PATIENTS AND INTERVENTIONS: We studied 60 stable COPD patients (mean age, 70.6 +/- 7.9 years; FEV(1), 44.8 +/- 14.3% of predicted [+/- SD]) with chronic respiratory insufficiency who randomly performed, on 2 consecutive days, a standardized 6-min walking test using two different modalities: a full-weight oxygen canister transported using a small wheeled cart and pulled by the patient (Aid modality) or full-weight oxygen canister carried on the patient's shoulder (No-Aid modality). MEASUREMENTS AND RESULTS: The distance walked, peak effort dyspnea, and leg fatigue scores as primary outcomes, and other cardiorespiratory parameters as secondary outcomes were recorded during both tests. A significant difference (p &lt; 0.05) between the two tests occurred for all the measured outcomes in favor of the Aid modality. Most importantly, significant changes for distance (+ 43 m, p &lt; 0.001), peak effort dyspnea (- 2.0 points, p &lt; 0.001), leg fatigue (- 1.4 points, p &lt; 0.001), as well as for mean and nadir oxygen saturation and heart rate with the Aid modality (but not with the No-Aid modality) were recorded in the subgroup of patients walking &lt; 300 m at baseline. CONCLUSIONS: This study suggests that a simple walking aid may be helpful in COPD patients receiving long-term oxygen therapy, particularly in those with lower residual exercise capacity.

2007 - From COPD to chronic systemic inflammatory syndrome? [Articolo su rivista]
Fabbri, Leonardo; Rabe, Kf
abstract

Chronic obstructive pulmonary disease (COPD) is characterised by poorly reversible airflow limitation that is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases, particularly cigarette smoke.1 A diagnosis of COPD should be considered in any current or previous smoker older than 40 years who has symptoms of cough, sputum production, or dyspnoea.1 Diagnosis and assessment of severity of COPD are based on the degree of airflow limitation at spirometry.1 However, increasing evidence suggests that clinical features of COPD and airflow limitation are poorly correlated and a comprehensive approach, including imaging2 and assessment of exercise tolerance and body-mass index,3 is needed. In this Viewpoint, we aim to convey the message that COPD can no longer be judged a disease only of the lungs. We propose to add the term chronic systemic inflammatory syndrome to the diagnosis of COPD to stimulate discussion around the frequent complex chronic comorbidities in people with COPD and to provoke a new view of the disease in general.

2007 - Increased neurokinin-2 receptor expression in alveolar macrophages of smokers with COPD [Articolo su rivista]
D., Miotto; P., Boschetto; G., Cavallesco; E., Zeni; P., Querzoli; M., Pedriali; S., Chiarelli; Fabbri, Leonardo; C. E., Mapp
abstract

letter

2007 - Macrophage expression of interleukin-10 is a prognostic factor in nonsmall cell lung cancer [Articolo su rivista]
E., Zeni; L., Mazzetti; D., Miotto; N., LO CASCIO; P., Maestrelli; P., Querzoli; M., Pedriali; E., DE ROSA; Fabbri, Leonardo; C. E., Mapp; P., Boschetto
abstract

Interleukin (IL)-10 is expressed in many solid tumours and plays an ambiguous role in controlling cancer growth and metastasis. In order to determine whether IL-10 is involved in tumour progression and prognosis in nonsmall cell lung cancer (NSCLC), IL-10 expression in tumour cells and tumour-associated macrophages (TAMs) and its associations, if any, with clinicopathological features were investigated. Paraffin-embedded sections of surgical specimens obtained from 50 patients who had undergone surgery for NSCLC were immunostained with an antibody directed against IL-10. TAMs and tumour cells positive for IL-10 were subsequently quantified. IL-10-positive TAM percentage was higher in patients with stage II, III and IV NSCLC, and in those with lymph node metastases compared with patients with stage I NSCLC. High IL-10 expression by TAMs was a significant independent predictor of advanced tumour stage, and thus was associated with worse overall survival. Conversely, IL-10 expression by tumour cells did not differ between stages II, III and IV and stage I NSCLC. In conclusion, interleukin-10 expression by tumour-associated macrophages, but not by tumour cells, may play a role in the progression and prognosis of nonsmall cell lung cancer. These results may be useful in the development of novel approaches for anticancer treatments.

2007 - Matrix metalloproteinase-2 protein in lung periphery is related to COPD progression. [Articolo su rivista]
Simonetta, Baraldo; Erica, Bazzan; Maria Elena, Zanin; Graziella, Turato; Spiridione, Garbisa; Piero, Maestrelli; Alberto, Papi; Massimo, Miniati; Fabbri, Leonardo; Renzo, Zuin; Marina, Saetta
abstract

BACKGROUND: There is increasing evidence that matrix metalloproteinases (MMPs) may contribute to the pathogenesis of COPD, but their role in humans is not completely understood. We performed this study to quantify the expression of MMP-2 in a population of COPD patients at different stages of severity. METHODS: We collected surgical specimens from 46 subjects, as follows: 10 smokers with severe COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage III-IV); 13 smokers with mild/moderate COPD (GOLD stage I-II); 12 control smokers; and 11 nonsmoking control subjects. We quantified MMP-2 expression in alveolar macrophages, alveolar walls, peripheral airways, and pulmonary arterioles by immunohistochemistry. RESULTS: In all compartments, MMP-2 expression was increased both in smokers with severe COPD and in smokers with mild/moderate COPD compared to control smokers and nonsmokers (p < 0.05 for all comparisons). Only in alveolar macrophages was MMP-2 expression increased in smokers with severe COPD compared to smokers with mild/moderate COPD (p = c0.002). Moreover, MMP-2 expression was inversely related to values of FEV1/FVC ratio (p < 0.0001; r = -0.71) and Pao2 (in millimeters of Hg) [p = 0.005; r = -0.49], and was positively related to emphysema score (p = 0.01; r = 0.65) and residual volume percent predicted (p = 0.04; r = 0.49). A stepwise increase in the total number of alveolar macrophages was observed in the four groups of subjects examined, with the highest value in those with severe COPD. CONCLUSION: This study shows that MMP-2 expression in the lung periphery progressively increases as lung function worsens and the degree of emphysema increases. These results suggest that MMP-2 may be a key mediator of the mechanisms leading to lung tissue remodeling and inflammation in patients with severe COPD.

2007 - Measurement of exhaled nitric oxide in healthy adults. [Articolo su rivista]
Piero, Maestrelli; Silvia, Ferrazzoni; Annalisa, Visentin; Emanuela, Marian; Davide Dal, Borgo; Rosalba, Accordino; Fabbri, Leonardo
abstract

BACKGROUND AND AIM: Measurement of exhaled nitric oxide (NO) is useful in the diagnosis and management of asthma. The aims of this study were to investigate the effects of physiologic confounders on levels of fractional exhaled NO (FE(NO)) in healthy adults and to establish reference values of FE(NO) measured according to American Thoracic Society (ATS) guidelines. METHODS: FE(NO) was measured in 122 healthy nonsmoking subjects of 20 to 65 years with a chemiluminescence analyser using the single breath online technique and an exhalation flow of 50 mL/s. RESULTS: The geometric mean [SE] FE(NO) was 21.6[1.06] ppb in males and 16.3[1.07] ppb in females (p < 0.01). FE(NO) increased significantly with body size and spirometric indices. In a stepwise regression analysis, body weight was the only variable included in the model (r = 0.36, p < 0.0001) and explained gender differences in FE(NO). When weight-related variables, including BMI, BSA and dead space volume, were analysed in a stepwise regression model, dead space volume gave the best correlation with FE(NO) (R = 0.39; p < 0.0001). CONCLUSION: The present study estimated that mean FE(NO) in healthy Caucasian subjects of 20 to 65 years, measured according to ATS guidelines with the online single breath technique, ranges from 15 to 24 ppb depending on the body weight. We suggest that the volume of dead space may explain the effect of weight on exhaled NO. However, a substantial part of FE(NO) variability in normal subjects remains unexplained.

2007 - Near-fatal asthma phenotype in the ENFUMOSA cohort [Articolo su rivista]
M., Romagnoli; G., Caramori; F., Braccioni; F., Ravenna; E., Barreiro; N. M., Siafakas; A. M., Vignola; P., Chanez; Fabbri, Leonardo; A., Papi; the ENFUMOSA Study, Group
abstract

BACKGROUND: Near-fatal asthma (NFA) is characterized by severe asthma attacks usually requiring intensive care unit admission. This phenotype of asthma has been studied mainly in acute conditions. METHODS: The aim of our study was to compare the clinical, functional and inflammatory characteristics of NFA patients with mild to severe asthmatics in stable conditions. We recruited 155 asthmatic patients from five centres of the European Network for Understanding Mechanisms of Severe Asthma: 67 patients with mild-to-moderate asthma controlled by low/medium doses of inhaled corticosteroids; 64 with severe asthma that, despite treatment with high doses of inhaled corticosteroids, long-acting beta2-agonists and for 1/3 also with regular oral corticosteroids, had at least one asthma exacerbation in the previous year; 24 with an NFA episode in the previous 5 years in the absence of inclusion criteria for the previous groups. All the patients were examined in stable conditions. RESULTS: NFA patients were taking less corticosteroids and were less compliant to prescribed asthma medications than the other two groups of patients. Lung function, blood gases, atopic status, sputum and blood inflammatory cell count of NFA patients were similar to mild-to-moderate, but not severe, asthmatic patients. CONCLUSIONS: In stable conditions patients with an NFA attack in the previous 5 years cannot be distinguished from patients with mild-to-moderate asthma, while they are different from severe asthmatics both in terms of lung function and of airway inflammation. The risk factor that characterizes this group of patients is reduced usage of prophylactic corticosteroids.

2007 - Prevention of death in COPD. [Articolo su rivista]
LA VECCHIA, C; Fabbri, Leonardo
abstract

letter

2007 - Rescue use of beclomethasone and albuterol in a single inhaler for mild asthma [Articolo su rivista]
A., Papi; G. W., Canonica; P., Maestrelli; P., Paggiaro; D., Olivieri; E., Pozzi; N., Crimi; A. M., Vignola; P., Morelli; G., Nicolini; Fabbri, Leonardo
abstract

Background: Treatment guidelines recommend the regular use of inhaled corticosteroids for patients with mild persistent asthma. We investigated whether the symptom-driven use of a combination of beclomethasone dipropionate and albuterol (also known as salbutamol) in a single inhaler would be as effective as the regular use of inhaled beclomethasone and superior to the as-needed use of inhaled albuterol. Methods: We conducted a 6-month, double-blind, double-dummy, randomized, parallel-group trial. After a 4-week run-in, patients with mild asthma were randomly assigned to receive one of four inhaled treatments: placebo twice daily plus 250 microg of beclomethasone and 100 microg of albuterol in a single inhaler as needed (as-needed combination therapy); placebo twice daily plus 100 microg of albuterol as needed (as-needed albuterol therapy); 250 microg of beclomethasone twice daily and 100 microg of albuterol as needed (regular beclomethasone therapy); or 250 microg of beclomethasone and 100 microg of albuterol in a single inhaler twice daily plus 100 microg of albuterol as needed (regular combination therapy). The primary outcome was the morning peak expiratory flow rate. Results: In 455 patients with mild asthma who had a forced expiratory volume in 1 second of 2.96 liters (88.36% of the predicted value), the morning peak expiratory flow rate during the last 2 weeks of the 6-month treatment was higher (P=0.04) and the number of exacerbations during the 6-month treatment was lower (P=0.002) in the as-needed combination therapy group than in the as-needed albuterol therapy group, but the values in the as-needed combination therapy group were not significantly different from those in the groups receiving regular beclomethasone therapy or regular combination therapy. The cumulative dose of inhaled beclomethasone was lower in the as-needed combination therapy group than in the groups receiving regular beclomethasone therapy or regular combination therapy (P < 0.001 for both comparisons). Conclusions: In patients with mild asthma, the symptom-driven use of inhaled beclomethasone (250 microg) and albuterol (100 microg) in a single inhaler is as effective as regular use of inhaled beclomethasone (250 microg twice daily) and is associated with a lower 6-month cumulative dose of the inhaled corticosteroid.

2007 - Respiratory muscles training in COPD patients [Articolo su rivista]
Ernesto, Crisafulli; Costi, Stefania; Fabbri, Leonardo; Clini, Enrico
abstract

It is known that respiratory muscles undergo adaptation in response to overload stimuli during exercise training in stable COPD patients, thus resulting in significant increase of respiratory muscle function as well as the individual's improvements. The present article reviews the most updated evidence with regard to the use of respiratory muscle training (RMT) methods in COPD patients. Basically, three types of RMT (resistive training, pressure threshold loading, and normocapnic hyperpnea) have been reported. Frequency, duration, and intensity of exercise must be carefully considered for a training effect. In contrast with the plentitude of existing data inherent to inspiratory muscle training (IMT), literature is still lacking in showing clinical and physiological studies related to expiratory muscle training (EMT). In particular, while it seems that IMT is slightly superior to EMT in providing additional benefits other than respiratory muscle function such as a reduction in dyspnea, both the effects and the safety of EMT is still to be definitively elucidated in patients with COPD.

2007 - Severe asthma in adults: what are the important questions? [Articolo su rivista]
Chanez, P; Wenzel, Se; Anderson, Gp; Anto, Jm; Bel, Eh; Boulet, Lp; Brightling, Ce; Busse, Ww; Castro, M; Dahlen, B; Dahlen, Se; Fabbri, Leonardo; Holgate, St; Humbert, M; Gaga, M; Joos, Gf; Levy, B; Rabe, Kf; Sterk, Pj; Wilson, Sj; Vachier, I.
abstract

The term severe refractory asthma (SRA) in adults applies to patients who remain difficult to control despite extensive re-evaluation of diagnosis and management following an observational period of at least 6 months by a specialist. Factors that influence asthma control should be recognized and adequately addressed prior to confirming the diagnosis of SRA. This report presents statements according to the literature defining SRA in order address the important questions. Phenotyping SRA will improve our understanding of mechanisms, natural history, and prognosis. Female gender, obesity, and smoking are associated with SRA. Atopy is less frequent in SRA, but occupational sensitizers are common inducers of new-onset SRA. Viruses contribute to severe exacerbations and can persist in the airways for long periods. Inflammatory cells are in the airways of the majority of patients with SRA and persist despite steroid therapy. The T(H)2 immune process alone is inadequate to explain SRA. Reduced responsiveness to corticosteroids is common, and epithelial cell and smooth muscle abnormalities are found, contributing to airway narrowing. Large and small airway wall thickening is observed, but parenchymal abnormalities may influence airway limitation. Inhaled corticosteroids and bronchodilators are the mainstay of treatment, but patients with SRA remain uncontrolled, indicating a need for new therapies.

2007 - Six-minute walk test in patients with chronic obstructive pulmonary disease: Comparison with and without active coaching [Articolo su rivista]
Crisafulli, E.; Lorenzi, M. C.; Gherardini, G.; Eutropio, E.; Beneventi, C.; Fabbri, L. M.; Clini, E. M.
abstract

Aim. To assess the sk-minute walk test (6 MWT) with and without encouragement in patients with severe chronic obstructive pulmonary disease (COPD). Methods. Thirty-eight COPD patients (72 ± 6 years, FEV 37 ± 12% pred.) performed 6 MWT in random order in two non consecutive days. The first test was carried out including encouragement according to the ATS standard procedure (WTE), the second without any phrase of encouragement (WTNE). Subgroup analysis has been also performed by dividing patients on the basis of their own level of exercise tolerance at the baseline test (6 MWT &lt; 300 and &gt; 300 meters). The measured variables included the total distance covered (M), subjective dyspnoea (D) and leg fatigue (F) as assessed by Borg scale, the main cardio-respiratory parameters as recorded along the test. Results. M was significantly higher during WTE than during WTNE (370 ± 78 and 336 ± 79 meters, respectively), whereas D and F only showed a non significant trend to increase during WTE. No significant differences of the other physiological parameters have been recorded between the two tests. Results similar to those obtained in the whole group have also been observed in both pre-defined subgroups of patients. Conclusions. Our study has shown that the encouraged recommended modality of 6 MWT is associated to a better result in terms of walked distance as compared with the non encouraged test in severe COPD patients. This was not associated with a detrimental effect on the cardiopulmonary responses.

2007 - T-cell-based diagnosis of neonatal multidrug-resistant latent tuberculosis infection. [Articolo su rivista]
Richeldi, Luca; K., Ewer; M., Losi; Bergamini, Barbara Maria; K., Millington; Fabbri, Leonardo; A., Lalvani
abstract

Non disponibileYoung children exposed to tuberculosis have a high risk of progression to severe tuberculosis disease, but diagnosis of recent infection is hindered by the poor sensitivity of the tuberculin skin test. Whether new blood tests can detect latent infection in this vulnerable group is unknown because there is no gold standard. We monitored a tuberculin skin test-negative infant whose mother had infectious multidrug-resistant tuberculosis with enzyme-linked immunospot, a blood test that enumerates Mycobacterium tuberculosis-specific T cells. The enzyme-linked immunospot test became persistently positive by 6 months, and 18 months later the child developed active tuberculosis despite appropriate chemoprophylaxis. At this point, the magnitude of the enzyme-linked immunospot response increased >10-fold. Our findings demonstrate that this blood test detected latent infection with dormant, yet viable, bacilli and illustrate how enzyme-linked immunospot could improve diagnosis of childhood tuberculosis infection.

2007 - Update in chronic obstructive pulmonary disease 2006 [Articolo su rivista]
K. F., Rabe; Beghe', Bianca; F., Luppi; Fabbri, Leonardo
abstract

Chronic obstructive pulmonary disease (COPD) is increasinglyrecognized as a major health care problem and the numberof publications in the scientific literature is a reflection of thisincreased awareness. This update cannot do justice to allnewly available information, but it does represent a selection ofarticles that were considered to be of sufficient general interestto warrant further discussion.

2007 - Use of a T-cell interferon-γ release assay for the diagnosis of tuberculous pleurisy [Articolo su rivista]
Losi, Monica; A., Bossink; L., Codecasa; C., Jafari; M., Ernst; S., Thijsen; D., Cirillo; M., Ferrarese; U., Greinert; Fabbri, Leonardo; Richeldi, Luca; C., Lange; European Tuberculosis, Network
abstract

The diagnosis of pleural tuberculosis (plTB) by the analysis of pleural effusions (PEs) with standard diagnostic tools is difficult. In routine clinical practice, the present authors evaluated the performance of a commercially available Mycobacterium tuberculosis (MTB)-specific enzyme-linked immunospot assay on peripheral blood mononuclear cells (PBMCs) and pleural effusion mononuclear cells (PEMCs) in patients with suspect plTB. The T-SPOT.TB test (Oxford Immunotec Ltd, Abingdon, UK) was performed on PBMCs and PEMCs in 20 patients with a clinical and radiological suspect of plTB and in 21 control subjects with a diagnosis of PE of nontuberculous origin at four centres participating in the European Tuberculosis Network. In total, 18 (90%) out of 20 patients with plTB tested T-SPOT.TB-positive on PBMCs and 19 (95%) out of 20 on PEMCs. Among controls, T-SPOT.TB was positive in seven out of 21 (33%) patients when performed on PBMCs (these patients were assumed to be latently infected with MTB) and five (23%) out of 21 when performed on PEMCs. Sensitivity and specificity of T-SPOT.TB for the diagnosis of active plTB when performed on PEMCs were 95 and 76%, respectively. Enumerating Mycobacterium tuberculosis-specific T-cells in pleural effusion mononuclear cells by ELISPOT is feasible in routine clinical practice and may be useful for a rapid and accurate diagnosis of pleural tuberculosis.

2006 - Association between markers of emphysema and more severe chronic obstructive pulmonary disease [Articolo su rivista]
Boschetto, P; Quintavalle, S; Zeni, E; Leprotti, S; Potena, A; Ballerin, L; Papi, A; Palladini, G; Luisetti, M; Annovazzi, L; Iadarola, P; De Rosa, E; Fabbri, Leonardo; Mapp, Ce
abstract

Background: The predominant emphysema phenotype is associated with more severe airflow limitation in patients with chronic obstructive pulmonary disease ( COPD). A study was undertaken to investigate whether COPD patients, with or without emphysema quantitatively confirmed by high resolution computed tomography (HRCT), have different COPD severity as assessed by the BODE index ( body mass index, airflow obstruction, dyspnoea, exercise performance) and inspiratory capacity to total lung capacity ratio (IC/TLC), and by different biological markers of lung parenchymal destruction. Methods: Twenty six outpatients with COPD and eight healthy non-smokers were examined. Each subject underwent HRCT scanning, pulmonary function tests, cell counts, and measurements of neutrophil elastase, matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1 in induced sputum, as well as measurement of desmosine, a marker of elastin degradation in urine, plasma and sputum. Results: Patients with HRCT confirmed emphysema had a higher BODE index and lower IC/TLC ratio than subjects without HRCT confirmed emphysema and controls. Forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity ratio, and carbon monoxide transfer coefficient were lower, whereas the number of eosinophils, MMP-9, and the MMP-9/TIMP-1 ratio in sputum were higher in patients with emphysema. In COPD patients the number of sputum eosinophils was the biological variable that correlated positively with the HRCT score of emphysema (p=0.04). Conclusions: These results suggest that COPD associated with HRCT confirmed emphysema is characterised by more severe lung function impairment, more intense airway inflammation and, possibly, more serious systemic dysfunction than COPD not associated with HRCT confirmed emphysema.

2006 - Blood tests for diagnosis of tuberculosis - Reply [Articolo su rivista]
Ferrara, G; Losi, Monica; Piro, R; Fabbri, Leonardo; Richeldi, Luca
abstract

author reply

2006 - Chronic disease in the elderly: back to the future of internal medicine. [Articolo su rivista]
Fabbri, Leonardo; R., Ferrari
abstract

Elderly people are often affected by two or more chronic diseases, more frequently cardiovascular diseases, chronic respiratory diseases, metabolic syndrome and cancer. Thesemost frequent chronic diseases share largely preventable risk factors, the most important being smoking and obesity, and may be linked to chronic systemic inflammation. Coexistingchronic diseases affect the course of the primary disease and alter the efficacyand safety of its management. Current clinical practice is dominated by the "singledisease"approach, which has major limitations, and there is increasing evidence that a patient-oriented approach that takes into account the several co-existing components of chronic disease is required. This "change of concept" implies the need for medical specialists to extend their expertise to broader diagnostic and treatment approaches that are traditionally the purview of internal medicine. This new approach also requires a differentapproach to clinical research and teaching, followed by extensive rewriting of medical textbooks and remodelling of teaching curricula to reflect the complexity of the patient affected by chronic diseases.

2006 - Clusterin decreases oxidative stress in lung fibroblasts exposed to cigarette smoke [Articolo su rivista]
Carnevali, S; Luppi, Fabrizio; D'Arca, Domenico; Caporali, A; Ruggieri, Mp; Vettori, Mv; Caglieri, A; Astancolle, Serenella; Panico, Francesca; Davalli, Pierpaola; Mutti, A; Fabbri, Leonardo; Corti, Arnaldo
abstract

Rationale: Cigarette smoke causes injury to lung fibroblasts, partly by means of oxidative stress, and oxidative stress can lead to various lung diseases, such as chronic obstructive pulmonary disease. Clusterin is a widely distributed protein with many functions, including cellular protection in response to oxidative stress. Objectives: To determine whether clusterin is involved in the defense of the lung against cigarette smoke, we investigated the effects of cigarette smoke extract on clusterin expression and its protective effect, if any, against oxidative stress. Methods: Fibroblasts were coincubated with conditioned medium and cigarette smoke extract, and bronchial biopsy specimens obtained from nonsmokers, smokers, and ex-smokers were analyzed by immunohistochemistry. Measurements and Main Results: At concentrations of 2.5 and 5.0%, cigarette smoke extract induced oxidative stress. It also markedly increased the expression of two clusterin isoforms (60 and 76-80 kD) and the 76-80-kD isoform was secreted in the incubation medium. Coincubation of fibroblasts with conditioned medium significantly decreased the cellular oxidation caused by the cigarette smoke extract. Immunohistochemical analysis of clusterin on bronchial biopsy specimens obtained from smokers and ex-smokers showed localization of clusterin mainly in the submucosa. Conclusions: We conclude that clusterin may have a protective effect against cigarette smoke-induced oxidative stress in lung fibroblasts.

2006 - Comparative efficacy of once-daily ciclesonide and budesonide in the treatment of persistent asthma [Articolo su rivista]
L. P., Boulet; A., Drollmann; P., Magyar; M., Timar; A., Knight; R., Engelstaetter; Fabbri, Leonardo
abstract

Background: The aim of this study was to compare the efficacy and safety of once-daily ciclesonide, a new-generation, on-site-activated, inhaled corticosteroid, with once-daily budesonide in persistent asthma. Methods: Eligible patients requiring budesonide or equivalent 320-640 mu g (ex-mouthpiece, equivalent to 400-800 mu g; Turbohaler (TM)) daily entered a 2-week baseline, and then a 2- to 4-week pretreatment period (budesonide 1280 mu g/day; ex-mouthpiece, equivalent to 1600 mu g/day). Patients with an increase in forced expiratory volume in 1s (FEV1) of >= 7% or >= 0.15 L were randomised to ciclesonide 320 mu g (ex-actuator, equivalent to 400 mu g ex-valve) via a hydrofluoroalkane-metered dose inhaler (HFA-MDI) without a spacer or budesonide 320 mu g once daily in the morning for 12 weeks. Change in FEV1 was the primary endpoint. Results: In all, 359 patients were randomised. The FEV1 and forced vital capacity (FVC) decreased by 0.18 and 0.12 L, respectively, in the ciclesonide group, and by 0.23 and 0.21 L in the budesonide group. For FEV1, ciclesonide was noninferior and numerically superior to budesonide. For FVC, ciclesonide was statistically superior to budesonide (P = 0.010). Asthma symptom scores were comparable; the median percentage of symptom-free days was significantly higher for ciclesonide (43.6%) versus budesonide (25.8%) (P = 0.017). Rescue medication use decreased significantly only for ciclesonide patients (P = 0.009). Frequency of adverse events was low in both groups. Conclusion: Ciclesonide 320 mu g once daily by HFA-MDI without a spacer was at least as effective as budesonide 320 mu g once daily in persistent asthma.

2006 - Diagnosis of occult tuberculosis in hematological malignancy by enumeration of antigen-specific T cells. [Articolo su rivista]
Richeldi, Luca; Luppi, Mario; Losi, Monica; Luppi, Fabrizio; Potenza, Leonardo; Roversi, P; Cerri, Stefania; Millington, Ka; Ewer, K; Fabbri, Leonardo; Torelli, Giuseppe; Lalvani, A.
abstract

n.d.

2006 - Epithelial damage and angiogenesis in the airways of children with asthma [Articolo su rivista]
Barbato, A; Turato, G; Baraldo, S; Bazzan, E; Calabrese, F; Panizzolo, C; Zanin, Me; Zuin, R; Maestrelli, P; Fabbri, Leonardo; Saetta, M.
abstract

Rationale: Airway remodeling and inflammation are characteristic features of adult asthma that are still poorly investigated in childhood asthma. Objectives: To examine epithelial and vascular changes as well as the inflammatory response in airways of children with asthma. Methods: We analyzed bronchial biopsies obtained from 44 children undergoing bronchoscopy for appropriate clinical indications other than asthma: 17 with mild/moderate asthma (aged 2-15 yr), 12 with atopy without asthma (1-11 yr), and 15 control children without atopy or asthma (1-14 yr). By histochemistry and immunohistochemistry, we quantified epithelial loss, basement membrane thickness, number of vessels, and inflammatory cells in subepithelium. Results: Epithelial loss and basement membrane thickness were increased in children with asthma compared with control subjects (p = 0.005 and p = 0.0002, respectively) and atopic children (p = 0.002 and p = 0.005, respectively). The number of vessels and eosinophils was increased not only in asthmatic children (p = 0.03 and p = 0.0002, respectively) but also in atopic children without asthma (p = 0.03 and p = 0.008, respectively) compared with control subjects. When we stratified the analysis according to age, we observed that children with asthma younger than 6 yr had increased epithelial loss, basement membrane thickening, and eosinophilia compared with control subjects of the same age. Conclusions: Epithelial damage and basement membrane thickening, which are pathologic features characteristic of adult asthma, are present even in childhood asthma. Other changes, such as airway eosinophilia and angiogenesis, were also observed in atopic children without asthma. These observations suggest that pathologic changes occur early in the natural history of asthma and emphasize the concept that some of these lesions may characterize atopy even in the absence of asthmatic symptoms.

2006 - Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations [Articolo su rivista]
Papi, A; Bellettato, Cm; Braccioni, F; Romagnoli, M; Casolari, P; Caramori, G; Fabbri, Leonardo; Johnston, S. L.
abstract

RATIONALE: Severe exacerbations of chronic obstructive pulmonary disease (COPD) are major causes of health care costs mostly related to hospitalization. The role of infections in COPD exacerbations is controversial. OBJECTIVES: We investigated whether COPD exacerbations requiring hospitalization are associated with viral and/or bacterial infection and evaluated relationships among infection, exacerbation severity, assessed by reduction of FEV1, and specific patterns of airway inflammation. METHODS: We examined 64 patients with COPD when hospitalized for exacerbations, and when in stable convalescence. We measured lung function, blood gases, and exhaled nitric oxide, and examined sputum for inflammation and for viral and bacterial infection. RESULTS: Exacerbations were associated with impaired lung function (p < 0.01) and increased sputum neutrophilia (p < 0.001). Viral and/or bacterial infection was detected in 78% of exacerbations: viruses in 48.4% (6.2% when stable, p < 0.001) and bacteria in 54.7% (37.5% when stable, p = 0.08). Patients with infectious exacerbations (29.7% bacterial, 23.4% viral, 25% viral/bacterial coinfection) had longer hospitalizations (p < 0.02) and greater impairment of several measures of lung function (all p < 0.05) than those with noninfectious exacerbations. Patients with exacerbations with coinfection had more marked lung function impairment (p < 0.02) and longer hospitalizations (p = 0.001). Sputum neutrophils were increased in all exacerbations (p < 0.001) and were related to their severity (p < 0.001), independently of the association with viral or bacterial infections; sputum eosinophils were increased during (p < 0.001) virus-associated exacerbations. CONCLUSIONS: Respiratory infections are associated with the majority of COPD exacerbations and their severity, especially those with viral/bacterial coinfection. Airway neutrophilia is related to exacerbation severity regardless of viral and/or bacterial infections. Eosinophilia is a good predictor of viral exacerbations.

2006 - Intrapulmonary percussive ventilation in tracheostomized patients: A randomized controlled trial [Articolo su rivista]
Clini, Enrico; F., Degli Antoni; M., Vitacca; E., Crisafulli; M., Paneroni; S., Chezzi Silva; M., Moretti; L., Trianni; Fabbri, Leonardo
abstract

OBJECTIVE: To investigate whether the addition of intrapulmonary percussive ventilation to the usual chest physiotherapy improves gas exchange and lung mechanics in tracheostomized patients. DESIGN AND SETTING: Randomized multicenter trial in two weaning centers in northern Italy. PATIENTS AND PARTICIPANTS: 46 tracheostomized patients (age 70 +/- 7 years, 28 men, arterial blood pH 7.436 +/- 0.06, PaO(2)/FIO(2) 238 +/- 46) weaned from mechanical ventilation. INTERVENTIONS: Patients were assigned to two treatment groups performing chest physiotherapy (control), or percussive ventilation (IMP2 Breas, Sweden) 10 min twice/day in addition to chest physiotherapy (intervention). MEASUREMENTS AND RESULTS: Arterial blood gases, PaO(2)/FIO(2) ratio, and maximal expiratory pressure were assessed every 5th day for 15 day. Treatment complications that showed up in 1 month of follow-up were recorded. At 15 days the intervention group had a significantly better PaO(2)/FIO(2) ratio and higher maximal expiratory pressure; after follow-up this group also had a lower incidence of pneumonia. CONCLUSIONS: The addition of percussive ventilation to the usual chest physiotherapy regimen in tracheostomized patients improves gas exchange and expiratory muscle performance and reduces the incidence of pneumonia.

2006 - New tools for a better diagnosis of latent tuberculosis infection [Articolo su rivista]
G., Ferrara; Losi, Monica; P., Roversi; Fabbri, Leonardo; Richeldi, Luca
abstract

Two new blood tests are today available for diagnosing latent tuberculosis infection. Both tests are based on the release of interferon-gamma from M. tuberculosis-specific T cells. These tests, QuantiFERON-TB Gold and T-SPOT.TB, are certainly more specific compared to the tuberculin skin test, and possibly more sensitive in some subgroups of patients; they might represent a crucial tool for tuberculosis control and elimination.

2006 - Pathophysiology of exacerbations of chronic obstructive pulmonary disease [Relazione in Atti di Convegno]
A., Papi; F., Luppi; F., Franco; Fabbri, Leonardo
abstract

Smokers with stable chronic obstructive pulmonary disease have a chronic inflammation of the entire tracheobronchial tree characterized by an increased number of macrophages and CD8 T lymphocytes in the airway wall and of neutrophils in the airway lumen. Exacerbations of chronic obstructive pulmonary disease are considered to reflect worsening of the underlying chronic inflammation of the airways, caused mainly by viral and bacterial infections and air pollution. During exacerbations, the inflammatory cellular pattern changes, with a further increase of eosinophils and/or neutrophils and various inflammatory mediators--for example, cytokines (tumor necrosis factor-alpha, RANTES [regulated upon activation normal T cell-expressed and secreted], and eotaxin-1), chemokines (CXCL5 [ENA-78], CXCL8), chemokine receptors (CCR3, CXCR1, and CXCR2), adhesion molecules (E-selectin and ICAM-1), and markers of oxidative stress (H(2)O(2) and 8-isoprostane, glutathione depletion). Worsening of inflammation is considered responsible for the deterioration of lung function and clinical status during exacerbations.

2006 - Pulmonary safety of inhaled insulins: a review of the current data [Articolo su rivista]
Fabbri, Leonardo
abstract

The availability of non-invasive insulin delivery options for patients with diabetes may encourage earlier insulin use, and thus improve glycemic control and help reduce the diabetes burden. Pulmonary insulin delivery is the most promising alternative with several inhaled insulin systems in development, and the inhaled human insulin Exubera* (insulin human [rDNA origin] Inhalation Powder) has been recently approved in the United States and in the European Union for the treatment of adults with type 1 or type 2 diabetes. Pulmonary function is an important aspect of the safety profile for compounds delivered via the lungs. Pulmonary function with Exubera has been extensively investigated in several completed and ongoing Phase 3 studies conducted in patients with type 1 or type 2 diabetes. A small, consistent but clinically non-significant decrease in pulmonary function, occurs early, does not progress during 2 years of continuous therapy, and is reversible after discontinuation. A mild, transient cough occurring after inhalation of Exubera is the most common respiratory adverse event observed. Impaired lung function in asthma and chronic obstructive pulmonary disease may modify the absorption of Exubera, whereas active smoking is associated with increased absorption increasing the risk of hypoglycemia. Limited information is available regarding the pulmonary safety of other inhaled insulins, but comprehensive pulmonary studies are anticipated in the future. In preparing this article, the authors searched for references to inhaled insulin in the Medline database and in congress abstracts from 1998 to 2006.

2006 - Repeated tuberculin testing does not induce false positive ELISPOT results [Articolo su rivista]
Richeldi, Luca; K., Ewer; M., Losi; P., Roversi; Fabbri, Leonardo; A., Lalvani
abstract

Non disponibile

2006 - Transforming growth factor-β type II receptor in pulmonary arteries of patients with very severe COPD [Articolo su rivista]
Beghe', Bianca; E., Bazzan; S., Baraldo; F., Calabrese; F., Rea; M., Loy; P., Maestrelli; R., Zuin; Fabbri, Leonardo; M., Saetta
abstract

A mild-to-moderate increase in pulmonary arterial pressure is often associated with severe chronic obstructive pulmonary disease (COPD). Transforming growth factor (TGF)-beta is a cytokine involved in the maintenance of integrity of vasculature. The aim of the study was to investigate whether the TGF-beta pathway might be involved in the development of pulmonary hypertension associated with COPD. Surgical specimens from 14 patients undergoing lung transplantation for very severe COPD (forced expiratory volume in one second 17 +/- 2% of the predicted value) and from seven donors were examined. The expression of TGF-beta1 and TGF-beta type II receptor (TGF-betaRII), cell proliferation index and structural changes in pulmonary arteries were quantified immunohistochemically. In severe COPD patients, increased expression of TGF-betaRII was observed in both the tunica media and intima, which was associated with a normal proliferation index in both layers. Conversely, significant thickening of the tunica intima, which was not present in the tunica media, was observed, suggesting that mechanisms other than cell proliferation may be involved in intimal thickening. In conclusion, in the pulmonary arteries of patients with severe chronic obstructive pulmonary disease, there is upregulation of transforming growth factor-beta type II receptor expression associated with a normal proliferation index. These findings suggest the activation of an antiproliferative pathway, which might explain the relatively low degree of pulmonary hypertension observed in these subjects.

2006 - Up-regulated membrane and nuclear leukotriene B4 receptors in COPD [Articolo su rivista]
Marian, E; Baraldo, S; Visentin, A; Papi, A; Saetta, M; Fabbri, Leonardo; Maestrelli, P.
abstract

Study objectives: We investigated the role. of two leukotriene B4 (LTB4) receptors, BLT1 and peroxisome proliferator-activated receptor (PPA-R)-alpha, in conferring the susceptibility to develop COPD in smokers. Proinflammatory LTB4 activities are mediated by BLT1, while the inactivation of LTB4 is promoted by PPAR alpha. Patients and methods: BLT1 and PPAR alpha proteins were quantified by immunohistochemistry in specimens obtained during lung surgery from 19 smokers with or without COPD and from 7 nonsmoking subjects. Results: We have shown that the percentages of PPAR alpha-positive alveolar macrophages and PPARa-positive cells in the alveolar wall were increased in COPD patients compared with control subjects. Moreover, the patients with COPD exhibited a significant increase of BLT1-positive alveolar macrophages compared with nonsmokers and an increased number of BLT1-positive cells in the alveolar walls compared with non-COPD smokers. In contrast, BLT1 and PPAR alpha-immunoreactivity did not differ significantly between nonsmokers and non-COPD smokers. Most of BLT1-positive cells in the alveolar,walls were neutrophils and CD8 cells. While the number of neutrophils infiltrating the lung parenchyma was similar among the three groups, the number of CD8 T cells was increased in COPD patients, but there was no evidence that BLT1 was up-regulated specifically on these cells in COPD patients. Conclusion: The results demonstrated that BLT1 and PPAR alpha are detectable in alveolar macrophages and CD8 T cells in human lung tissue, and suggest that the dual LTB4 receptor system is up-regulated in the peripheral lungs of smokers who are susceptible to the development of COPD. This system might represent a novel target for therapeutic intervention in COPD patients.

2006 - Update in Chronic Obstructive Pulmonary Disease 2005 [Articolo su rivista]
Fabbri, Leonardo; F., Luppi; Beghe', Bianca; Kf, Rabe
abstract

Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease that has a large impact on quality of life for patients and their families and kills millions of people worldwide. Even though there have been significant advances in the understanding and management of COPD, suggesting that the disease may be largely preventable, it remains only marginally treatable. This is probably because COPD is due to a slowly progressive destructive process of the lung that is poorly reversible when manifested clinically, and because it has systemic effects and frequent comorbidities that should be managed more comprehensively.The interest in COPD by the medical and scientific community has increased dramatically in the last decade, as reflected by the number of publications in both pulmonary and general medical journals. This review aims to summarize and highlight progress in the understanding of COPD in 2005. Although we found most of the articles interesting, we had to be selective, and we take full responsibility for the choices we have made.

2006 - Upregulation of basic fibroblast growth factor in smokers with chronic bronchitis [Articolo su rivista]
F., Guddo; A. M., Vignola; M., Saetta; S., Baraldo; L., Siena; E., Balestro; R., Zuin; A., Papi; P., Maestrelli; Fabbri, Leonardo; G., Bonsignore; G., Turato
abstract

The aim of the study was to investigate the expression of basic fibroblast growth factor (bFGF) and its receptor, fibroblast growth factor receptor (FGFR)-1, in the central airways of smokers with chronic bronchitis. The lobar bronchi from 17 subjects undergoing thoracotomy for solitary nodules were examined. All had a history of cigarette smoking, nine had symptoms of chronic bronchitis and airflow limitation, and eight were asymptomatic with normal lung function. Using immunohistochemical methods, bFGF and FGFR-1 expression in the total airway wall and the different airway compartments, i.e. bronchial glands, submucosal vessels and smooth muscle, was quantified. Moreover, to investigate the role of bFGF in angiogenesis, the number of submucosal vessels was quantified. Smokers with chronic bronchitis had an increased bFGF expression in the total airway wall compared with asymptomatic smokers, which was mainly due to bFGF upregulation in bronchial glands. By contrast, the expression of FGFR-1 and the number of submucosal vessels was similar in the two groups of subjects examined. In conclusion, smokers with chronic bronchitis have an increased expression of basic fibroblast growth factor in the central airways, which is mainly due to an increased expression in bronchial glands, suggesting the involvement of this growth factor in the pathogenesis of chronic bronchitis.

2006 - Use in routine clinical practice of two commercial blood tests for diagnosis of infection with Mycobacterium tuberculosis: a prospective study [Articolo su rivista]
G., Ferrara; Losi, Monica; D'Amico, Roberto; P., Roversi; R., Piro; M., Meacci; B., Meccugni; Im, Dori; A., Andreani; Bergamini, Barbara Maria; Mussini, Cristina; F., Rumpianesi; Fabbri, Leonardo; Richeldi, Luca
abstract

BACKGROUND: Two commercial blood assays for the diagnosis of latent tuberculosis infection--T-SPOT.TB and QuantiFERON-TB Gold--have been separately compared with the tuberculin skin test. Our aim was to compare the efficacy of all three tests in the same population sample. METHODS: We did a prospective study in 393 consecutively enrolled patients who were tested simultaneously with T-SPOT.TB and QuantiFERON-TB Gold because of suspected latent or active tuberculosis. 318 patients also had results available for a tuberculin skin test. FINDINGS: Overall agreement with the skin test was similar (T-SPOT.TB kappa=0.508, QuantiFERON-TB Gold kappa=0.460), but fewer BCG-vaccinated individuals were identified as positive by the two blood assays than by the tuberculin skin test (p=0.003 for T-SPOT.TB and p&lt;0.0001 for QuantiFERON-TB Gold). Indeterminate results were significantly more frequent with QuantiFERON-TB Gold (11%, 43 of 383) than with T-SPOT.TB (3%, 12 of 383; p&lt;0.0001) and were associated with immunosuppressive treatments for both tests. Age younger than 5 years was significantly associated with indeterminate results with QuantiFERON-TB Gold (p=0.003), but not with T-SPOT.TB. Overall, T-SPOT.TB produced significantly more positive results (38%, n=144, vs 26%, n=100, with QuantiFERON-TB Gold; p&lt;0.0001), and close contacts of patients with active tuberculosis were more likely to be positive with T-SPOT.TB than with QuantiFERON-TB Gold (p=0.0010). INTERPRETATION: T-SPOT.TB and QuantiFERON-TB Gold have higher specificity than the tuberculin skin test. Rates of indeterminate and positive results, however, differ between the blood tests, suggesting that they might provide different results in routine clinical practice.

2006 - Use of commercial interferon-gamma assays in immunocompromised patients for tuberculosis diagnosis [Articolo su rivista]
Richeldi, Luca; Ferrara, G; Losi, Monica; Piro, R; Roversi, P; Fabbri, Leonardo
abstract

Non disponibile

2005 - Allergic rhinitis, asthma, airway biology, and chronic obstructive pulmonary disease in AJRCCM in 2004 [Articolo su rivista]
Fabbri, Leonardo; S. P., Peters; I., Pavord; S. E., Wenzel; S. C., Lazarus; W., Macnee; F. O., Lemaire; E., Abraham
abstract

REVIEW

2005 - CFC phase-out and the Chiesi solution [Articolo su rivista]
G., Huchon; Fabbri, Leonardo
abstract

Since its development in the 1950s, the pressurizedmetered-dose inhaler (pMDI) has become popular withboth patients and clinicians, and it is now available todeliver virtually all drugs used in the treatment of asthmaand chronic obstructive pulmonary disease (COPD).Originally, chlorofl uorocarbons (CFCs) were used as propellantsin these devices, but the Montreal Protocol(1989) has led to the need for CFCs to be replaced bynon-ozone-depleting substances such as the hydrofl uoroalkanes(HFAs) HFA-134a and HFA-227ea. These alternativepropellants, although safe toxicologically, havesignifi cantly different physico-chemical properties ascompared with CFCs, making the transition more complexthan was initially anticipated. Indeed, the transitionfrom CFC- to HFA-based pMDIs has been slow for avariety of reasons, including the need to re-design theinhaler valves to cope with the physico-chemical differencesof solutions with respect to suspensions; thepatent minefi eld imposing constraints on formulationand device design opportunities, and the tighteningof drug delivery performance criteria imposed by regulatoryauthorities.

2005 - Comparison of the tubercolin skin test and the ellispot blood test for the diagnosis of latent tuberculosis infection in pre-transplant dialysis patients [Abstract in Atti di Convegno]
Di Felice, A; Losi, Monica; Roversi, P; Cerri, Stefania; Debbi, Alberto; Ferrari, Federica; Ferramosca, Emiliana; Millington, K; Cappelli, Gianni; Albertazzi, Alberto; Fabbri, Leonardo; Lalvani, A; Richeldi, Luca
abstract

End stage renal disease (ESRD) is a known risk factor for progression to active tuberculosis (TB) from latent tuberculosis infection (LTBI). Kidney transplant and immunosuppressive therapy may increase the risk of TB recurrence. Patients with LTBI undergoing dialysis would therefore benefit from preventive treatment with isoniazid, which often has adverse side effects in this particular group of patients. Therefore it is important to accurately identify ESRD patients with LTBI, mainly if awaiting renal transplantation. The standard tool for diagnosing LTBI is the century-old tuberculin skin test (TST); however, patients with ESRD, as many other immunosuppressedpatients, often have falsely negative TST results. The Enzyme-Linked ImmunoSpot (ELISPOT) test is a new test which enumerates M. tuberculosis-specific T-cells in peripheral blood samples and has been already shown to be more specific and more sensitive than the TST for diagnosis of LTBI. We tested 84 ESRD patients on dialysis treatment with TST and ELISPOT: 26 were on peritoneal dialysis and 57 on hemodialysis; only 1 patient was on conservative treatment. Mean age was 48±14 years (range 23-75); 51 male and 33 female. Simultaneous RD1 Elispot and TST (5 UI PPD) were performed. According to current guidelines, the cut-off value for a positive TST using 5 UI of PPD is 10 mm; based upon previously published studies, the pre- defined positive cut-off for the ELISPOT is 20 spot forming cells per million peripheral blood mononuclear cells. In 64 patients (76%) TST and ELISPOT gave concordant results and in more than 90% were both negative. Only 2 patients tested TST-positive and ELISPOT-negative (one was an immigrant from a high-prevalence Country) while 18 (21%) were TST-negative, but ELISPOT positive. These preliminary results indicate that a significant proportion of ESRD patients on dialysis treatment may have hitherto unrecognised LTBI and an associated increased risk of progression to active disease, mainly after renal transplantation.

2005 - Decreased expression of TGF-beta type II receptor in bronchial glands of smokers with COPD [Articolo su rivista]
S., Baraldo; E., Bazzan; G., Turato; F., Calabrese; Beghe', Bianca; A., Papi; P., Maestrelli; Fabbri, Leonardo; R., Zuin; M., Saetta
abstract

BACKGROUND: The role of transforming growth factor-beta1 (TGF-beta1) in chronic obstructive pulmonary disease is still controversial, but it has been proposed that it may protect from mucus hypersecretion since it is able to downregulate mucin production. A study was undertaken to investigate the expression of TGF-beta1 and its type II receptor (TGF-beta RII) in the bronchial glands of smokers with COPD. METHODS: The expression of TGF-beta and TGF-beta RII were examined immunohistochemically in the bronchial glands of 24 smokers undergoing lung resection for solitary peripheral nodules: 12 with airflow limitation (smokers with COPD) and 12 with normal lung function. RESULTS: The expression of TGF-beta1 in bronchial glands was similar in the two groups of subjects while that of TGF-beta RII was lower in smokers with COPD than in smokers with normal lung function (p=0.004). TGF-beta RII expression was inversely correlated with the values of Reid's index, a measure of gland size (p=0.02, r=-0.50). CONCLUSIONS: In the bronchial glands of smokers with COPD there is decreased expression of TGF-beta RII which is associated with bronchial gland enlargement. These findings support the view that the absence of TGF-beta signalling may induce structural changes in the bronchial glands which, in turn, may promote mucus hypersecretion.

2005 - Does mild persistent asthma require regular treatment? [Articolo su rivista]
Fabbri, Leonardo
abstract

Current national and international guidelines recommend regularly scheduled treatment with inhaled corticosteroids for patients with mild persistent asthma. This recommendation is supported by solid evidence that such treatment achieves and maintains asthma control. Although there is not universal agreement, there are data, reviewed by Vignola, that suggest that continuous suppression of airway inflammation by means of inhaled corticosteroids (referred to as controller therapy) may not only control asthma but also prevent its progression.

2005 - Empoyment of the ELISPOT blood test for the diagnosis of latent tuberculosis infection in dialysis patients awaiting renal transplantation [Abstract in Rivista]
Di Felice, A; Losi, Monica; Roversi, P; Cerri, Stefania; Debbi, A; Ferrari, F; Ferramosca, E; Ravera, F; Millington, K; Cappelli, Gianni; Lucchi, L; Albertazzi, Alberto; Fabbri, Leonardo; Lalvani, A; Richeldi, L.
abstract

Abstract COngresso Internazionale

2005 - Exhaled nitric oxide and asthma [Articolo su rivista]
L., Corbetta; Fabbri, Leonardo
abstract

The landmark study by Smith et al.(May 26 issue) shows that measurement of exhaled nitric oxide (FeNO) can reduce the dose of inhaled corticosteroids in patients with asthma without impairing control of asthma and, in particular, exacerbations of asthma. Because of the high variability of FeNO among both healthy persons and patients with asthma, it may make sense to consider a personalized “best” cutoff FeNO level, as seen after the dose-optimization phase or after administration of a dose of oral prednisone. In addition, the relatively high exhalation flow rate used (250 ml per second), as compared with the recommended flow rate of 50 ml per second, may be a factor. The difference in terms of parts per billion between a patient when in stable condition and the same patient in unstable condition will be much smaller, and perhaps less discriminatory, at 250 ml per second than at 50 ml per second. Finally, the numerical trend seen in the reduction of exacerbations suggests that the study was underpowered to assess this outcome.

2005 - Is mild asthma really 'mild'? [Articolo su rivista]
Fabbri, Leonardo; S., Stoloff
abstract

Current evidence suggests that patients with mild asthma are often under-recognised, and those that are diagnosed can remain with this initial classification and be treated accordingly, despite worsening of their condition. There is considerable overlap between mild and more severe asthma in terms of the underlying pathophysiology and poorly reversible airway changes, such as subepithelial fibrosis and airway wall remodelling, which are present very early in the progression of asthma in patients with normal lung function. Life-threatening exacerbations can also occur in patients with mild asthma. In view of these factors and given that asthma is a two-component disease (airway inflammation and smooth muscle dysfunction), recent studies have examined the effects of both early intervention with steroids and combination therapy comprising an inhaled steroid and a long acting β2-agonist. These studies suggest that early intervention is likely to provide better asthma control and possibly prevent or delay the worsening of disease and fatalities in patients considered to be mild asthmatics.

2005 - Macrolides for chronic asthma. [Articolo su rivista]
Richeldi, Luca; G., Ferrara; Fabbri, Leonardo; T. J., Lasserson; P. G., Gibson
abstract

BACKGROUND: Asthma is a chronic disease of the airways in which inflammation of the respiratory mucosa plays a crucial role. The mechanisms responsible for the maintaining of this inflammatory response are only partially known and there is evidence that a role could be paid by chronic infection by intracellular pathogens (such as Chlamydia pneumoniae). Macrolides are antibiotics with both antimicrobial and anti-inflammatory activities and thus their use in asthmatic patients could lead to reduction of the airways inflammation and therefore improvement of symptoms and pulmonary function. OBJECTIVES: To determine whether macrolides are effective in the management of patients with chronic asthma. SEARCH STRATEGY: We searched MEDLINE, EMBASE and CINAHL up to May 2001. This was also supplemented by manually searching bibliographies of previously published reviews, conference proceedings, and contacting study authors. All languages were included in the initial search. SELECTION CRITERIA: Randomised, controlled clinical trials involving both children and adult patients with chronic asthma treated with macrolides for more than 4 weeks, versus placebo. DATA COLLECTION AND ANALYSIS: Two reviewers independently examined all identified articles. Two reviewers reviewed the full text of any potentially relevant article independently. MAIN RESULTS: The initial search retrieved 95 studies. Preliminary evaluation identified 20 studies that were potentially eligible. Five (357 patients) met the entry criteria. The entry criteria for the primary trials differed, but all recruited a specific subgroup of patients (eg severe oral steroid dependent, aspirin intolerant or evidence of Chlamydia pnuemoniae infection). There was a positive effect on symptoms (Standardised Mean Difference -1.25, 95% Confidence Intervals (CI) -1.80, -0.70) and markers of eosinophilic inflammation; eg sputum eosinophils Weighted Mean difference -78.5, 95%CI -90.8, -66.1). Tests of oral corticosteroid-sparing effects have not yet been performed on the newer agents such as roxithromycin and clarithromycin. REVIEWER'S CONCLUSIONS: Considering the small number of patients studied, there is insufficient evidence to support or to refute the use of macrolides in patients with chronic asthma. Further studies are needed in particular to clarify the potential role of macrolides in some subgroups of asthmatics such as those with evidence of chronic bacterial infection.

2005 - Macrolides in the treatment of asthma and cystic fibrosis [Articolo su rivista]
G., Ferrara; Losi, Monica; F., Franco; L., Corbetta; Fabbri, Leonardo; Richeldi, Luca
abstract

Asthma and cystic fibrosis are two respiratory diseases characterized by chronic inflammation, leading to remodelling of the airways. Macrolides are widely used antibiotics, with a peculiar anti-inflammatory effect. On the basis of the methodologies used by the Cochrane collaboration, this review discusses the evidence for their long-term use as anti-inflammatory agents in these two diseases. Three randomized-controlled trials (RCTs) were identified for both asthma and cystic fibrosis. A positive effect of macrolides on reducing eosinophil numbers and markers of eosinophilic inflammation was demonstrated in patients with asthma. Data on cystic fibrosis demonstrated an effect on lung function with an increase of 5.4% in forced vital capacity (FVC) in patients treated with macrolide vs. placebo, but without a significant effect on FEV1. Side-effects were rare, mild and reversible on withdrawal of treatment. Although preliminary data from small studies are promising, the role of macrolides in the treatment of these chronic disorders needs to be more firmly established with larger, well-designed trials, targeted to investigate major clinical outcomes.

2005 - Management of CAP using a validated risk score [Articolo su rivista]
Richeldi, Luca; M., De Guglielmo; Fabbri, Leonardo; D., Giovanardi; F., Marchetti; M., Larosa; V., Solfrini; M., Altini
abstract

The management of patients with community acquired pneumonia (CAP) is characterised by considerable variation in admission rates, length of hospital stay, and use of institutional resources in different settings. The Pneumonia Severity Index (PSI) is a prediction rule for the short term risk of death in patients with CAP, improving the efficiency of patient care. In the year 2000, 86% of patients with CAP presenting at the emergency department of our hospital were admitted. A retrospective analysis of the PSI scores of these patients showed that 37% of them were in low risk classes (1 and 2) based on their PSI results, so their admissions were potentially avoidable. We therefore designed a prospective study to assess the safety, feasibility, and efficacy of the PSI score for management decisions in patients with CAP. The study was approved by the local ethics committee and written informed consent was obtained from all patients. The study was carried out in the 12 month period from 1 November 2001 to 31 October 2002. One hundred and seventeen adult patients diagnosed in the emergency department with CAP participated in the study and were managed using a computer based score with dedicated software (GesPOrEx, Saxos software, Modena, Italy) for PSI calculation and data collection. CAP was defined as the presence of a pulmonary infiltrate on the chest radiograph and symptoms consistent with pneumonia including cough, dyspnoea, and pleuritic chest pain. Patients with severe immunosuppression, those admitted to hospital in the previous 15 days, and patients infected with HIV were excluded. According to published data, patients with PSI scores of 90 points or lower are recommended for outpatient treatment while those with higher scores are recommended for hospital admission. The score was used only as a guide to the admission decision and did not supersede clinical judgement. Follow up consisted of two visits, the first within 10 days and the second about 1 month after discharge from hospital. The choice of antibiotic treatment, route of administration, duration of antibiotic treatment, and criteria for discharge were according to local guidelines, mainly based on the recommendations of recently published guidelines. None of these interventions changed between the two study periods. To compare data before implementation of the protocol we retrospectively identified 116 consecutive patients admitted with CAP in the preceding year. There were no statistically significant differences in demographic and co-morbidity data between the two groups (table 1). In both groups there was a significant proportion of patients in the lowest risk class; this probably reflects the attitude of patients in our healthcare structure to have frequent access to hospital services, particularly when the "family" doctor is unavailable such as at night or during the weekend. In the group managed after implementation of the protocol, 12 patients (10.3%) were admitted against PSI recommendations: six patients (or their relatives) strongly requested hospital admission, four were admitted for lack of adequate home care support, and two did not provide convincing assurance about compliance with treatment. Three (5.9%) of those admitted died; all were in class V of the PSI and two of the deaths were related to CAP. The implementation of PSI based management reduced the median duration of hospital stay from 9.1 (2.1) days to 7.9 (4.9) days, with a total reduction in bed days from 1070 to 463. Of the 1070 total bed days in the retrospective phase of the study, 348 (32.5%) were attributable to patients admitted with PSI scores in class I or II. All patients treated as outpatients were alive at the 1 month follow up visit and all returned to their usual activities. No adverse clinical outcomes, including admission to hospital or the intensive care unit, mortality or complications were detected. Compared with the historical data in the previous year, the rate of admiss

2005 - Occupational asthma [Articolo su rivista]
Ce, Mapp; P., Boschetto; P., Maestrelli; Fabbri, Leonardo
abstract

Substantial epidemiologic and clinical evidence indicates that agents inhaled at work can induce asthma. In industrialized countries, occupational factors have been implicated in 9 to 15% of all cases of adult asthma. Work-related asthma includes, immunologic occupational asthma (OA), characterized by a latency period before the onset of symptoms; nonimmunologic OA, which occurs after single or multiple exposures to high concentrations of irritant materials; work-aggravated asthma, which is preexisting or concurrent asthma exacerbated by workplace exposures; and variant syndromes. Assessment of the work environment has improved, making it possible to measure concentrations of several high- and low-molecular-weight agents in the workplace. The identification of host factors, polymorphisms, and candidate genes associated with OA is in progress and may improve our understanding of mechanisms involved in OA. A reliable diagnosis of OA should be confirmed by objective testing early after its onset. Removal of the worker from exposure to the causal agent and treatment with inhaled glucocorticoids lead to a better outcome. Finally, strategies for preventing OA should be implemented and their cost-effectiveness examined.

2005 - Role of chemotherapy and the receptor tyrosine kinases KIT, PDGFR alpha, PDGFR beta, and met in large-cell neuroendocrine carcinoma of the lung [Articolo su rivista]
Rossi, Giulio; A., Cavazza; A., Marchioni; L., Longo; Migaldi, Mario; G., Sartori; N., Bigiani; L., Schirosi; C., Casali; Morandi, Uliano; N., Facciolongo; Maiorana, Antonino; M., Bavieri; Fabbri, Leonardo; E., Brambilla
abstract

Purpose Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a relatively uncommon, high-grade neuroendocrine tumor sharing several features with small-cell lung carcinoma (SCLC) but currently considered as a variant of non-SCLC and accordingly treated with poor results. Little is known about the optimal therapy of LCNEC and the possible therapeutic molecular targets. Patients and Methods We reviewed 83 patients with pure pulmonary LCNEC. to investigate their clinicopathologic features, therapeutic strategy, and immunohistorchemical expression and the mutational status of the receptor tyrosine kinases (RTKs) KIT, PDGFR alpha, PDGFR beta, and Met. Results LCNEC histology predicted a dismal outcome (overall median survival, 17 months) even in stage I patients (5-year survival rate, 33%). LCNEC strongly expressed RTKs (KIT in 62.7% of patients, PDGFRa in 60.2%, PDGFR beta in 81.9%, and Met in 47%), but no mutations were detected in the exons encoding for the relevant juxtamembrane domains. Tumor stage and size (>= 3 cm) and Met expression were significantly correlated with survival. At univariate and multivariate analysis, SCLC-based chemotherapy (platinum-etoposide) was the most important variable correlating with survival, both in the adjuvant and metastatic settings (P < .0001). Conclusion Pulmonary LCNEC represents an aggressive tumor requiring multimodal treatment even for resectable stage I disease, and LCNEC seems to respond to adjuvant platinum-etoposide-based chemotherapy, Patients who received this therapy had the best survival rate. Despite our failure in finding mutational events in the tested RTKs, the strong expression of KIT, PDGFR alpha, PDGFR beta, and Met in tumor cells suggests an important role of these RTKs in LCNEC, and these RTKs seem to be attractive therapeutic targets.

2005 - Sputum substance P and neurokinin A are reduced during exacerbations of chronic obstructive pulmonary disease [Articolo su rivista]
P., Boschetto; D., Miotto; I., Bononi; D., Faggian; M., Plebani; A., Papi; C., Creminon; E., De Rosa; Fabbri, Leonardo; Ce, Mapp
abstract

Involvement of tachykinins in airway inflammation has been demonstrated in animal models, but evidence in humans is sparse. The aim of this study was to quantify the levels of substance P and neurokinin A in induced sputum of patients with chronic obstructive pulmonary disease (COPD) and to compare them with the levels in smokers with normal lung function and healthy nonsmokers. Content of tackykinins was measured in 12 sputum samples collected during stable condition and nine sputum samples collected during exacerbations from 13 COPD patients, in eight sputum samples from smokers with normal lung function and in nine from healthy nonsmokers. Patients with COPD exacerbations had a lower sputum content of substance P compared with the other 3 groups (p<0.05). No differences were found between patients with stable COPD, smokers with normal lung function, and nonsmokers. Sputum levels of neurokinin A were trending in the same direction of substance P, but the significant difference was reached for the paired sputum samples collected from the same COPD patients (n=8) during exacerbation and in stable condition. COPD exacerbations are associated with a reduced sputum content of substance P and neurokinin A. These tackykinins might be involved in COPD exacerbations.

2005 - Treatment of mild asthma - Reply [Articolo su rivista]
Fabbri, Leonardo
abstract

letter

2005 - Tubercolosi: Nuove opportunità per controllare una vecchia malattia? [Articolo su rivista]
Ferrara, Giovanni; Cerri, Stefania; Fabbri, Leonardo; Richeldi, Luca
abstract

After the mention of traditional laboratory pathways historically (and still presently) followed for the diagnosis of tuberculosis, the most recent changes to such traditional methods are taken into consideration. The contribution of the microscopic examination with its pros and cons, the bacterial cultures and the advantages deriving from the last generation mediums, the (growing in importance) diagnosis of bacterial resistances and, last not least, the most recent technologies in the field of molecular diagnosis, from polymerase chain reaction to the use of nucleic acid probes, from the molecular typisation of the mycobacterium to the genotypic methods to test antitubercular drug resistances. Particular attention has been put on novel immunologic tests, perhaps yet to be perfectioned but already important and to be considered in the present panel of diagnostic tools, mainly for their relevance in the diagnosis of latent tuberculosis: in this sense both such tests, QuantiFERON-TB GOLD as well as T SPOT-TB (based on the interferon gamma identification) are discussed and compared with the classic Mantoux intradermoreaction.

2004 - Adjustable maintenance dosing with budesonide/formoterol in a single inhaler provides effective asthma symptom control at a lower dose than fixed maintenance dosing [Articolo su rivista]
Gw, Canonica; P., Castellani; M., Cazzola; Fabbri, Leonardo; V., Fogliani; M., Mangrella; A., Moretti; P., Paggiaro; Cm, Sanguinetti; Am, Vignola
abstract

Asthma guidelines suggest a stepwise approach to maintenance pharmacological treatment of persistent asthma until control is attained, and a 3 month review of the fixed maintenance dosing for step-up or step-down adjustment. This 12-week study compared the efficacy and safety of budesonide/formoterol in a single inhaler (Symbicort Turbuhaler 160/4.5 or 80/4.5 microg) given as adjustable maintenance or fixed maintenance dosing. Patients (n = 2358) were randomised to budesonide/formoterol fixed maintenance dosing (two inhalations bid) or adjustable maintenance dosing (two inhalation bid; stepping up to four inhalations bid if asthma worsened for a maximum of 14 days; stepping down to two inhalations once nocte or one inhalation bid if symptoms were controlled) for 12 weeks, following a 4-week run-in period on budesonide/formoterol two inhalations bid. Primary efficacy variables were frequency of asthma exacerbations and changes in patients' asthma symptom severity. Secondary variables were asthma control, safety and health economics. Both adjustable maintenance dosing and fixed maintenance dosing were associated with similar low frequency of exacerbations (5% both groups; ns) and similarly improved lung function, with similarly fewer nocturnal awakenings and less asthma symptoms compared with the mean value of the run-in period. However, patients on adjustable maintenance dosing used 24% fewer study drug compared with fixed maintenance dosing (2.95 versus 3.86 inhalations daily; p < 0.0001) and incurred in a significant (p <0.0001) reduction in total costs (direct+indirect) compared with fixed maintenance dosing. In conclusion, adjustable maintenance dosing with budesonide/formoterol effectively controls asthma at a reduced drug load with lower costs than fixed maintenance dosing.

2004 - COPD increases the risk of squamous histological subtype in smokers who develop non-small cell lung carcinoma [Articolo su rivista]
A., Papi; G., Casoni; G., Caramori; I., Guzzinati; P., Boschetto; F., Ravenna; N., Calia; Petruzzelli, Stefano; L., Corbetta; G., Cavallesco; E., Forini; M., Saetta; A., Ciaccia; Fabbri, Leonardo
abstract

BACKGROUND: Squamous cell carcinoma has a stronger association with tobacco smoking than other non-small cell lung cancers (NSCLC). A study was undertaken to determine whether chronic obstructive pulmonary disease (COPD) is a risk factor for the squamous cell carcinoma histological subtype in smokers with surgically resectable NSCLC. METHODS: Using a case-control design, subjects with a surgically confirmed diagnosis of squamous cell carcinoma were enrolled from smokers undergoing lung resection for NSCLC in the District Hospital of Ferrara, Italy. Control subjects were smokers who underwent lung resection for NSCLC in the same hospital and had a surgically confirmed diagnosis of NSCLC of any histological type other than squamous cell. RESULTS: Eighty six cases and 54 controls (mainly adenocarcinoma, n = 50) were enrolled. The presence of COPD was found to increase the risk for the squamous cell histological subtype by more than four times. Conversely, the presence of chronic bronchitis was found to decrease the risk for this histological subtype by more than four times. Among patients with chronic bronchitis (n = 77), those with COPD had a 3.5 times higher risk of having the squamous cell histological subtype. CONCLUSIONS: These data suggest that, among smokers with surgically resectable NSCLC, COPD is a risk factor for the squamous cell histological subtype and chronic bronchitis, particularly when not associated with COPD, is a risk factor for the adenocarcinoma histological subtype.

2004 - Corticosteroid and immunomodulatory agents in idiopathic pulmonary fibrosis [Articolo su rivista]
F., Luppi; Cerri, Stefania; Beghe', Bianca; Fabbri, Leonardo; Richeldi, Luca
abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive pulmonary disease leading to death within a few years of diagnosis despite medical therapy. On the basis of methodologies of the Cochrane collaboration, this overview discusses the evidence for IPF therapy. Good-quality studies on oral corticosteroids, the most common medical therapy in use for IPF, are lacking. A few small studies have been carried out on the efficacy of many non-steroid immunosuppressive agents, and the results have been generally disappointing. The most extensively studied medical therapy, gamma interferon, showed a significant effect in a small randomized study, but its efficacy was not confirmed in a larger randomized-controlled trial. The long-awaited good news for patients affected by this deadly disease, and for their physicians, could come in the near future from large randomized-controlled trials with gamma interferon or other immunomodulatory agents.

2004 - Early diagnosis of subclinical multi drug-resistant tuberculosis [Articolo su rivista]
Richeldi, Luca; K., Ewer; Losi, Monica; Dm, Hansell; P., Roversi; Fabbri, Leonardo; A., Lalvani
abstract

Background: Tuberculosis control hinges on prompt diagnosis of active cases and screening of contacts by tuberculin skin testing. Rapid blood tests for Mycobacterium tuberculosis infection are a new alternative to the tuberculin skin test, but whether they improve clinical outcomes is unknown. Objective: To describe how a novel T-cell-based test for M. tuberculosis infection helped diagnose tuberculosis in an asymptomatic, immunosuppressed adult with a negative result on a tuberculin skin test. Design: Case report. Setting: Household contact. Patients: Asymptomatic man receiving maintenance azathioprine therapy for Crohn disease whose wife had multidrug-resistant pulmonary tuberculosis. Measurements: Enzyme-linked immunospot (ELISPOT) assay, computed tomography, and bronchoalveolar lavage cultures. Results: The man had a negative tuberculin skin test result and a positive ELISPOT assay result. High-resolution computed tomography of the chest showed consolidation with early cavitation. Bronchoalveolar lavage and culture confirmed multidrug-resistant tuberculosis. Limitations: This single case report is a proof of concept and is not a formal evaluation of clinical utility. Conclusions: A positive ELISPOT assay result helped diagnose subclinical active tuberculosis in an immunosuppressed patient with a false-negative tuberculin skin test result. Large prospective studies that compare benefits and costs of this alternative to tuberculin skin testing are needed.

2004 - Editorial: the Journal of COPD--new directions in disease understanding and management. [Articolo su rivista]
Crapo, Jd; Barnes, Pj; Fabbri, Leonardo; Hurd, S; Make, Bj; Balkissoon, Rc
abstract

non disponibile

2004 - Effect of specific immunotherapy added to pharmacologic treatment and allergen avoidance in asthmatic patients allergic to house dust mite [Articolo su rivista]
P., Maestrelli; L., Zanolla; M., Pozzan; Fabbri, Leonardo
abstract

BACKGROUND: Although several studies support the efficacy of specific immunotherapy in allergic asthma, its benefit compared with that of standardized pharmacologic intervention remains unknown. OBJECTIVE: A double-blind, placebo-controlled trial in 72 patients with mild-to-moderate asthma and allergy to house dust mite (HDM; Dermatophagoides species) was conducted to assess the effects of specific immunotherapy added to guideline-adjusted pharmacologic treatment and allergen avoidance. METHODS: After 1 observational year of pharmacologic treatment and standard measures of HDM avoidance, 2 groups of asthmatic subjects were randomly assigned to receive specific immunotherapy consisting of subcutaneous injections of either a mixture of Dermatophagoides pteronyssinus and Dermatophagoides farinae vaccine (n=41) or placebo (n=31) for 3 years. Medications were adjusted every 3 months according to the Global Initiative for Asthma guidelines. RESULTS: The adjustment of treatment was associated with a reduction in asthma symptom scores in all subjects. The addition of specific immunotherapy was associated with a decrease in the number of subjects requiring rescue bronchodilators, an increase in morning and evening peak expiratory flow, and a reduced skin sensitivity to HDM extracts. The addition of specific immunotherapy had no significant effects on the cumulative dose of inhaled corticosteroids, asthma symptoms, lung volumes, or bronchial responsiveness to methacholine. CONCLUSION: These results suggest that specific immunotherapy added to pharmacologic treatment and HDM avoidance provides marginal but statistically significant clinical benefits, possibly by reducing the allergic response of asthmatic patients sensitized to HDM.

2004 - Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: GOLD Executive Summary updated 2003. [Articolo su rivista]
Fabbri, Leonardo; Pauwels, Ra; Hurd, Ss; GOLD Scientific, Committee
abstract

non disponibile

2004 - Neutrophilic infiltration within the airway smooth muscle in patients with COPD [Articolo su rivista]
S., Baraldo; G., Turato; C., Badin; E., Bazzan; Beghe', Bianca; R., Zuin; F., Calabrese; G., Casoni; P., Maestrelli; A., Papi; Fabbri, Leonardo; M., Saetta
abstract

BACKGROUND: COPD is an inflammatory disorder characterised by chronic airflow limitation, but the extent to which airway inflammation is related to functional abnormalities is still uncertain. The interaction between inflammatory cells and airway smooth muscle may have a crucial role. METHODS: To investigate the microlocalisation of inflammatory cells within the airway smooth muscle in COPD, surgical specimens obtained from 26 subjects undergoing thoracotomy (eight smokers with COPD, 10 smokers with normal lung function, and eight non-smoking controls) were examined. Immunohistochemical analysis was used to quantify the number of neutrophils, macrophages, mast cells, CD4+ and CD8+ cells localised within the smooth muscle of peripheral airways. RESULTS: Smokers with COPD had an increased number of neutrophils and CD8+ cells in the airway smooth muscle compared with non-smokers. Smokers with normal lung function also had a neutrophilic infiltration in the airway smooth muscle, but to a lesser extent. When all the subjects were analysed as one group, neutrophilic infiltration was inversely related to forced expiratory volume in 1 second (% predicted). CONCLUSIONS: Microlocalisation of neutrophils and CD8+ cells in the airway smooth muscle in smokers with COPD suggests a possible role for these cells in the pathogenesis of smoking induced airflow limitation.

2004 - Summary of recommendations for the design of clinical trials and the registration of drugs used in the treatment of asthma [Articolo su rivista]
S. T., Holgate; J., Bousquet; K. F., Chung; H., Bisgaard; R., Pauwels; Fabbri, Leonardo; K., Rabe; M., Doherty; N. J. C., Snell; F., Cuss; M., D'Amato; J. Y., Reginster
abstract

With new drugs being introduced to treat asthma it is timely to review criteria that can be used to assess efficacy in clinical trials. Anti-asthma drugs are classified into symptoms-modifying, symptom preventers and disease modifying agents. Attention is drawn to the types of experimental evidence required in preclinical studies to support further clinical development of a new therapy. Clinical trials demand careful selection of patients to maximise the strength of the efficacy signal according to the type of trial being designed. While provocation tests are useful in suggesting efficacy, negative tests do not necessarily indicate lack of anti-asthma activity. Therapeutic trial designs need to take account of duration of treatment, dose–response relationships and confirmatory trials. Outcome measures include symptoms, lung function, reduction in concomitant medication, exacerbations, quality of life and measures of inflammation. Interpretation of results need to include the clinical relevance of any changes as well as statistical significance. Special consideration needs to be given to the evaluation of drugs for acute severe asthma, asthma in children and older people, co-morbidity such as rhinitis, and inhaler devices. As with all drugs introduced into practice, careful attention needs to be paid to both short- and long-term safety.

2004 - T cell-based tracking of multidrug resistant tuberculosis infection after brief exposure [Articolo su rivista]
Richeldi, Luca; Ewer, K; Losi, M; Bergamini, Barbara Maria; Roversi, P; Deeks, J; Fabbri, Leonardo; Lalvani, A.
abstract

Molecular epidemiology indicates significant transmission of Mycobacterium tuberculosis after casual contact with infectious tuberculosis cases. We investigated M. tuberculosis transmission after brief exposure using a T cell-based assay, the enzyme-linked-immunospot (ELISPOT) for IFN-gamma. After childbirth, a mother was diagnosed with sputum smear-positive multidrug-resistant tuberculosis. Forty-one neonates and 47 adults were present during her admission on the maternity unit; 11 weeks later, all underwent tuberculin skin testing (TST) and ELISPOT. We correlated test results with markers of exposure to the index case. The participants, who were asymptomatic and predominantly had no prior tuberculosis exposure, had 6.05 hours mean exposure (range: 0-65 hours) to the index case. Seventeen individuals, including two newborns, were ELISPOT-positive, and ELISPOT results correlated significantly with three of four predefined measures of tuberculosis exposure. For each hour sharing room air with the index case, the odds of a positive ELISPOT result increased by 1.05 (95% Cl: 1.02-1.09, p = 0.003). Only four adults were TST-positive and TST results did not correlate with exposure. Thus, ELISPOT, but not TST, suggested quite extensive nosocomial transmission of multidrug-resistant M. tuberculosis after brief exposure. These results help to explain the apparent importance of casual contact for tuberculosis transmission, and may have implications for prevention.

2004 - The asthma management gap - why current treatment strategies can fail to provide optimal asthma control [Articolo su rivista]
Fabbri, Leonardo; Boulet, Lp; Kardos, P; Vogelmeier, C.
abstract

Standard asthma management strategies are not always successful at providing optimal control. Despite the availability of effective asthma drugs and the publication of numerous asthma management guidelines, many patients are not adequately controlled and experience frequent asthma symptoms and exacerbations. Current guidelines advocate a stepwise approach to treatment, initially through inhaled corticosteroids, with the addition of a long-acting beta(2)-agonist or another asthma medication when required. Once asthma control has been achieved with an appropriate starting dose, corticosteroids should be reduced to the lowest effective dose with the option to step up during periods of asthma worsening. Such strategies require personalised, written action plans to enable patients to make appropriate changes in medication with less requirement for intervention by the physician. Adjustable maintenance dosing with budesonicle/formoterol in a single inhaler offers an effective means to adapt the medication to the needs of the patient, as indicated in the current guidelines.

2004 - Therapeutic approaches to idiopathic pulmonary fibrosis [Articolo su rivista]
Luppi, Fabrizio; Cerri, Stefania; DE CARLO, Maria Rosaria; Serini, Roberto; Fabbri, Leonardo; Richeldi, Luca
abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive pulmonary disease leading to death within a few years of diagnosis despite medical therapy. Based upon the methodologies of the systematic reviews of the Cochrane collaboration, this article describes the available evidence for the therapy of IPF. Good-quality studies on oral corticosteroids, the most commonly used medical therapy for IPF, are lacking. A few small studies have been carried out on the efficacy of many non-steroid immunosuppressive agents, and the results have been generally disappointing. The most extensively studied medical therapy, γ interferon, showed a significant effect in a first small randomized study, but its effect on survival has not been confirmed in a larger randomized, controlled trial. Preliminary positive data on high doses N-acetylcysteine have also been reported. The long-awaited good news for patients affected by this deadly disease and for their physicians could come in the near future from large randomized, controlled trials using gamma interferon and/or other immunomodulatory agents.

2004 - Triggering receptor expressed on myeloid cells: role in the diagnosis of lung infections [Articolo su rivista]
Richeldi, Luca; M., Mariani; Losi, Monica; F., Maselli; L., Corbetta; C., Buonsanti; M., Colonna; F., Sinigaglia; P., Panina Bordignon; Fabbri, Leonardo
abstract

The triggering receptor expressed on myeloid cells (TREM)-1 is a recently described molecule, which plays an important role in myeloid cell-activated inflammatory responses. TREM-1 is expressed on blood neutrophils and monocytes, and also on alveolar macrophages, thus suggesting a potential role in lung inflammatory responses against infections. To investigate the differential expression of TREM-1 in lung infections, its levels were assessed in bronchoalveolar lavage specimens from patients with community-acquired pneumonia or tuberculosis. TREM-1 was also investigated in patients with interstitial lung diseases, as a model of noninfectious inflammatory disease of the lung. TREM-1 expression was significantly increased in lung neutrophils; and in lung macrophages of patients with pneumonia (n=7; 387.9+/-61.4 and 660.5+/-18.3, respectively) compared with patients with pulmonary tuberculosis (n=7; 59.2+/-13.1 and 80.6+/-291.2) and patients with interstitial lung diseases (n=10; 91.8+/-23.3 and 123.9+/-22.8). In contrast, TREM-1 expression on peripheral blood neutrophils was no different among the three groups. In conclusion, these data suggest that triggering receptor expressed on myeloid cells-1 is selectively expressed in the lungs of patients with pneumonia caused by extracellular bacteria and not in patients with tuberculosis, providing a potential marker for differential diagnosis.

2004 - Vasoactive intestinal peptide receptors in the airways of smokers with chronic bronchitis [Articolo su rivista]
D., Miotto; P., Boschetto; I., Bononi; E., Zeni; G., Cavallesco; Fabbri, Leonardo; C. E., Mapp
abstract

Vasoactive intestinal peptide (VIP) is a neuropeptide involved in the regulation of airway mucus secretion. The biological functions of VIP are mediated through two receptors, the vasoactive intestinal peptide receptor type 1 (VPAC1R) and type 2 (VPAC2R). The aim of this study was to quantify the expression of both VPAC1R and VPAC2R in the central airways of smokers with chronic bronchitis. Surgical specimens were obtained from 33 smokers undergoing thoracotomy for localised pulmonary lesions: 23 smokers with symptoms of chronic bronchitis and 10 asymptomatic smokers with normal lung function. By using immunohistochemical and microscopic analysis, an increased expression of VPAC1R, but not VPAC2R, was found in bronchial epithelium, bronchial glands and vessels of smokers with symptoms of chronic bronchitis compared with asymptomatic smokers. Smokers with symptoms of chronic bronchitis also had an increased number of mononuclear cells positive for both VPAC1R and VPAC2R in the bronchial submucosa. In conclusion, the expression of type 1 and type 2 vasoactive intestinal peptide receptors is increased in the central airways of smokers with chronic bronchitis, suggesting their possible involvement in the pathogenesis of chronic bronchitis.

2004 - Water / electrolyte imbalances in AECOPD. In: Siafakas N, Anthonisen NR, Georgopoulos D. (eds) Acute exacerbations of Chronic Obstrutive Pulmonary Disease. [Monografia/Trattato scientifico]
Moretti, M; Clini, Enrico; Fabbri, Leonardo
abstract

Water and electrolyte imbalance occuring in AECOPD suggests a complex interactions between pulmonary haemodynamics, acid-base balance, hormonal and renal mechanisms. Further studies are required 1) to investigate the contribution of different mechanisms in oedema formation , 2) to select COPD patients at risk of developing chronic right ventricular failure, and 3) to define more effective therapeutical approaches in preventing oedema formation.

2003 - Asthma. European Respiratory Monograph [Monografia/Trattato scientifico]
K. F., Chung; Fabbri, Leonardo
abstract

Despite increasing knowledge about the mechanisms, pathophysiology and treatments in asthma and the implementation of asthma guidelines, "we are only at the dawn of a new beginning". From the patients’ point of view, there are still unmet needs. A recent survey of patients with asthma in Europe revealed that many patients still experience a poor level of control of the disease.This monograph, with contributors predominantly from Europe, focuses on the progress achieved. A lot of information has been gathered concerning asthma in the last 20 years and it is believed that this monograph samples the most pertinent and relevant information needed for the physician and for the researcher.

2003 - Chronic obstructive pulmonary disease: brief review [Articolo su rivista]
Fabbri, Leonardo; Romagnoli, M; Cossi, S; Grassi, V.
abstract

Chronic obstructive pulmonary disease is characterized by airflow limitation that is not fully reversible and is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases, particularly tobacco smoke. Diagnosis of chronic obstructive pulmonary disease is primarily based on a reduction of forced expiratory volume in one second/forced vital capacity ratio < 70% post-bronchodilators. The characteristic symptoms of chronic obstructive pulmonary disease are cough, sputum, and dyspnea upon exertion. Based on airflow limitation as measured by spirometry, chronic obstructive pulmonary disease can be classified as mild, moderate, severe and very severe. Chronic obstructive pulmonary disease can coexist with asthma, although the inflammation characteristic of chronic obstructive pulmonary disease is distinct from that of asthma.

2003 - Chronic obstructive pulmonary disease: definition and classification of severity [Articolo su rivista]
M., Romagnoli; Fabbri, Leonardo
abstract

Chronic obstructive pulmonary disease is characterized by airflow limitation that is not fully reversible and is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases, particularly tobacco smoke. Diagnosis of chronic obstructive pulmonary disease is primarily based on a reduction of forced expiratory volume in one second/forced vital capacity ratio &lt; 70% post-bronchodilators. The characteristic symptoms of chronic obstructive pulmonary disease are cough, sputum, and dyspnea upon exertion. Based on airflow limitation as measured by spirometry, chronic obstructive pulmonary disease can be classified as mild, moderate, severe and very severe. Chronic obstructive pulmonary disease can coexist with asthma, although the inflammation characteristic of chronic obstructive pulmonary disease is distinct from that of asthma.

2003 - Decreased haem oxygenase-1 and increased inducible nitric oxide synthase in the lung of severe COPD patients [Articolo su rivista]
P., Maestrelli; C., Paska; M., Saetta; G., Turato; Y., Nowicki; S., Monti; B., Formichi; M., Miniati; Fabbri, Leonardo
abstract

Oxidant/antioxidant imbalance is implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). The current study examined the expression of antioxidant and pro-oxidant enzymes, haem oxygenases; (140) and inducible nitric oxide synthase (iNOS) respectively, in patients with severe COPD and control smokers without lung function impairment. Immunoreactivity for HO-1, HO-2, iNOS and nitric oxide-derived oxidants expressed as nitrotyrosine (N-Tyr) was quantified in peripheral lung. HO-1+ alveolar macrophages were decreased in severe COPD compared to control smokers, whereas no difference was observed in iNOS+ macrophages. In contrast, severe patients had significantly higher numbers of iNOS+ cells in alveolar walls. These iNOS+ cells were identified as type 2 pneumocytes and their number was inversely related to HO-1+ macrophages. There were no significant differences in N-Tyr immunostaining between the two groups. However, the rate of protein nitration in lung tissue was directly related to iNOS expression and associated with lower values of forced expiratory volume in one second/forced vital capacity. HO-2 was constitutively expressed by type 2 pneumocytes and these cells were increased in severe COPD. In conclusion, the results suggest that the enzymes involved in the oxidative stress response may have a different role in the lung defence and that imbalance between haem oxygenase-1 and inducible nitric oxide synthase may be associated with the development of severe impairment in chronic obstructive pulmonary disease patients.

2003 - Differences in airway inflammation in patients with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease [Articolo su rivista]
Fabbri, Leonardo; M., Romagnoli; L., Corbetta; G., Casoni; K., Busljetic; G., Turato; Ligabue, Guido; A., Ciaccia; M., Saetta; A., Papi
abstract

To determine whether patients with fixed airflow obstruction have distinct pathologic and functional characteristics depending on a history of either asthma or chronic obstructive pulmonary disease (COPD), we characterized 46 consecutive outpatients presenting with fixed airflow obstruction by clinical history, pulmonary function tests, exhaled nitric oxide, sputum analysis, bronchoalveolar lavage, bronchial biopsy, and high-resolution computed tomography chest scans. Subjects with a history of COPD (n = 27) and subjects with a history of asthma (n = 19) had a similar degree of fixed airflow obstruction (FEV1: 56 +/- 2 versus 56 +/- 3% predicted) and airway hyperresponsiveness (PC20FEV1: 2.81 [3.1] versus 1.17 [3.3]). Subjects with a history of asthma had significantly more eosinophils in peripheral blood, sputum, bronchoalveolar lavage, and airway mucosa; fewer neutrophils in sputum and bronchoalveolar lavage fluid; a higher CD4+/CD8+ ratio of T cells infiltrating the airway mucosa; and a thicker reticular layer of the epithelial basement membrane. They also had significantly lower residual volume, higher diffusing capacity, higher exhaled nitric oxide, lower high-resolution computed tomography scan emphysema score, and greater reversibility to bronchodilator and steroids. In conclusion, despite similar fixed airflow obstruction, subjects with a history of asthma have distinct characteristics compared with subjects with a history of COPD and should be properly identified and treated.

2003 - Global Strategy for the Diagnosis, Management and Prevention of COPD: 2003 update. [Articolo su rivista]
Fabbri, Leonardo; S., Hurd
abstract

The Global Initiative for Chronic Obstructive Lung Disease(GOLD) programme was initiated in January 1997 to increaseawareness of chronic obstructive pulmonary disease (COPD)and to decrease morbidity and mortality from this chroniclung disorder. One strategy to help achieve the objectives oftheGOLDprogramme is to provide healthcare workers, healthcareauthorities and the general public with state-of-the-artinformation about COPD and specific recommendations onthe most appropriate management and prevention strategies.The GOLD Workshop Report, Global Strategy for theDiagnosis, Management and Prevention of COPD [1] waspublished in April 2001. It was prepared by a panel of expertsnominated by the National Heart, Lung and Blood Institute(NHLBI), National Institutes of Health and the WorldHealth Organization with the aim of providing the bestvalidated current concepts of COPD pathogenesis and thebest available evidence on the most appropriate managementand prevention strategies. In an effort to keep the GOLDWorkshop Report as up to date as possible, GOLD assembleda Scientific Committee whose aim was to review clinicalresearch that has an impact on COPD management. Theinitial review included publications that were published inJune 2000 (approximately the time of completion of the 2001report) through to March 2003. The results of the first 2 yrs ofactivity were posted on the GOLD website (www.goldcopd.com) in July 2003 [2]. Each year, a new update report will beposted. The GOLD Scientific Committee will also prepare arevision of the entire GOLD Workshop Report approximatelyevery 5 yrs. The process for the first complete revision(to appear in 2006) will be developed in the autumn of2003.

2003 - Increased proportion of CD8(+) T-lymphocytes in the paratracheal lymph nodes of smokers with mild COPD [Articolo su rivista]
M., Saetta; S., Baraldo; G., Turato; Beghe', Bianca; Gl, Casoni; Cm, Bellettato; F., Rea; R., Zuin; Fabbri, Leonardo; A., Papi
abstract

Previous studies have shown an increased number of inflammatory cells and, in particular, of CD8+ T lymphocytes, in central airways, peripheral airways, lung parenchyma and pulmonary arteries of smokers with COPD. In this study we investigated whether this inflammatory process is restricted to the lung tissue or whether a similar process is also present in the lymph nodes of these subjects. We examined paratracheal lymph nodes obtained from 6 smokers with COPD (FEV1/VC < 88% predicted and FEV1/FVC < 70% both before and after 200 microg of inhaled salbutamol) and 6 smokers without COPD (FEV1/VC > 88% predicted and FEV1/FVC > 70%) undergoing lung resection for localised pulmonary lesions. By immunohistochemistry we quantified CD4+ and CD8+ T-lymphocytes in the lymph nodes. Smokers with COPD had a decreased ratio CD4/CD8 compared to smokers without COPD. When all subjects were considered together, the ratio CD4/CD8 showed a positive correlation with the values of FEV1/VC and a negative correlation with cigarette consumption. In conclusion, smokers with COPD have an increased proportion of CD8+ cells in the lymph nodes, indicating that a T-lymphocyte pattern similar to that present in the lung tissue is also present in the lymph nodes of these subjects. This finding suggests that, in COPD, the polarisation of the immune response may occur in the regional lymph nodes, possibly as a consequence of the presentation of an endogenous antigen that remains unknown.

2003 - Interleukin-13 and -4 expression in the central airways of smokers with chronic bronchitis [Articolo su rivista]
D., Miotto; Mp, Ruggieri; P., Boschetto; G., Cavallesco; A., Papi; I., Bononi; C., Piola; B., Murer; Fabbri, Leonardo; Ce, Mapp
abstract

The aim of this study was to determine whether the T-helper 2-type cytokines interleukin (IL)-13 and -4 are involved in mucus hypersecretion, the hallmark of chronic bronchitis (CB). Surgical specimens were examined from 33 subjects undergoing lung resection for localised peripheral malignant pulmonary lesions: 21 smokers with symptoms of CB, 10 asymptomatic smokers (AS) and two nonsmokers with normal lung function. The number of IL-4 and -13 positive (+) cells in the central airways was quantified. To better assess the cytokine profile, a count was also made of IL-5+ and interferon (IFN)-gamma+ cells. Compared to AS, the CB group had an increased number of IL-13+ and -4+ cells in the bronchial submucosa, while the number of IL-5+ and IFN-gamma+ cells were similar in all the groups. No significant associations were found between the number of cells expressing IL-13 or -4 and the number of inflammatory cells. Double labelling showed that 13.2 and 12.9% of IL-13+ cells were also CD8+ and CD4+, whereas 7.5 and 5% of IL-4+ cells were CD8+ and CD4+, respectively. In conclusion, T-helper-2 and -1 protein expression is present in the central airways of smokers and interleukin-4 and -13 could contribute to mucus hypersecretion in chronic bronchitis.

2003 - Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthma exacerbation in adults: one year, double blind, randomised, comparative trial [Articolo su rivista]
L., Bjermer; H., Bisgaard; J., Bousquet; Fabbri, Leonardo; Ap, Greening; T., Haahtela; St, Holgate; C., Picado; J., Menten; Sb, Dass; Ja, Leff; Pg, Polos
abstract

Objectives To assess the effect of montelukast versus salmeterol added to inhaled fluticasone propionate on asthma exacerbation in patients whose symptoms are inadequately controlled with fluticasone alone. Design and setting A 52 week, two period, double blind, multicentre trial during which patients whose symptoms remained uncontrolled by inhaled corticosteroids were randomised to add montelukast or salmeterol. Participants Patients (15-72 years; n = 1490) had a clinical history of chronic asthma for greater than or equal to1 year, a baseline forced expiratory volume in one second (FEV1) value 50-90% predicted, and a beta agonist improvement of greater than or equal to 12% in FEV1. Main outcome measures The primary end point was the percentage of patients with at least one asthma exacerbation. Results 20.1% of the patients in the group receiving montelukast and fluticasone had an asthma exacerbation compared with 19.1% in the group receiving salmeterol and fluticasone; the difference was 1% (95% confidence interval - 3.1% to 5.0%). With a risk ratio (montelukast-fluticasone/ salmeterol-fluticasone) of 1.05 (0.86 to 1.29), treatment with montelukast and fluticasone was shown to be non-inferior to treatment with salmeterol and fluticasone. Salmeterol and fluticasonc significantly increased FEV1 before a beta agonist was used and morning peak expiratory flow compared with montelukast and fluticasone (P less than or equal to0.001), whereas FEV1 after a beta agonist was used and improvements in asthma specific quality of life and nocturnal awakenings were similar between the groups. Montelukast and fluticasone significantly (P = 0.011) reduced peripheral blood eosinophil counts compared with salmeterol and fluticasone. Both treatments were generally well tolerated. Conclusion The addition of montelukast in patients whose symptoms remain uncontrolled by inhaled fluticasone could provide equivalent clinical control to salmeterol.

2003 - Nuclear localisation of p65 in sputum macrophages but not in sputum neutrophils during COPD exacerbations. [Articolo su rivista]
G., Caramori; M., Romagnoli; P., Casolari; C., Bellettato; G., Casoni; P., Boschetto; K. F., Chung; P. J., Barnes; I. M., Adcock; A., Ciaccia; Fabbri, Leonardo; A., Papi
abstract

BACKGROUND: Exacerbations represent an important feature of the clinical manifestation and natural history of chronic obstructive pulmonary disease (COPD). Nuclear localisation of p65 is a signal of nuclear factor-kappaB (NF-kappaB) activation. A study was undertaken to evaluate whether NF-kappaB activation is modified in sputum cells during COPD exacerbations. METHODS: Total and nuclear p65 immunoreactivity was measured by immunocytochemistry in the sputum cells of 11 smokers with moderate COPD during an exacerbation and after 6-8 weeks of clinical stability. RESULTS: Total sputum cell count was significantly increased during exacerbations from a median (IQR) of 880 (510-1865) to 1914.5 (1065-3205) x 10(3)/ml (p&lt;0.05). The main inflammatory cells in the sputum were neutrophils (83.2 (75.4-92.3)%) and macrophages (14.7 (2.6-21.6)%) and their relative proportion did not change during exacerbations. Nuclear staining for p65 was absent in sputum neutrophils, both during exacerbations and in the stable phase. In contrast, the percentage of macrophages expressing nuclear p65 increased significantly during exacerbations from a median (IQR) of 16 (7-24)% to 41.4 (6-69)% (p&lt;0.05). CONCLUSIONS: NF-kappaB appears to be activated in sputum macrophages but not in sputum neutrophils during exacerbations of COPD

2003 - Predominant emphysema phenotype in chronic obstructive pulmonary disease patients [Articolo su rivista]
P., Boschetto; M., Miniati; D., Miotto; F., Braccioni; E., De Rosa; I., Bononi; A., Papi; M., Saetta; Fabbri, Leonardo; Ce, Mapp
abstract

Patients with fixed airflow limitation are grouped under the heading of chronic obstructive pulmonary disease (COPD). The authors investigated whether COPD patients have distinct functional, radiological and sputum cells characteristics depending on the presence or absence of emphysema. Twenty-four COPD outpatients, 12 with and 12 without emphysema on high-resolution computed tomography scan of the chest, were examined. Patients underwent chest radiography, pulmonary function tests and sputum induction and analysis. Subjects with documented emphysema had lower forced expiratory volume in one second (FEV1), FEV1/forced vital capacity ratio, and lower carbon monoxide diffusion constant (KCO), compared with subjects without emphysema. Chest radiograph score of emphysema was higher, chest radiograph score of chronic bronchitis was lower, and the number of sputum lymphocytes was increased in patients with emphysema, who also showed a negative correlation between KCO and pack-yrs. Chronic obstructive pulmonary disease patients with emphysema, documented by high-resolution computed tomography scan, have a different disease phenotype compared with patients without emphysema. Identification of chronic obstructive pulmonary disease-related phenotypes may improve understanding of the natural history and treatment of the disease.

2003 - Reducing agents inhibit the contractile response of isolated guinea-pig main bronchi [Articolo su rivista]
Gl, Casoni; P., Chitano; S., Pinamonti; M., Chicca; A., Ciaccia; Fabbri, Leonardo; A., Papi
abstract

Background Oxidants are involved in many respiratory disorders, including asthma and chronic obstructive pulmonary diseases. Reduced glutathione (GSH), one of the most important antioxidant compounds against oxidant free radicals, is particularly abundant in the respiratory epithelial lining fluid, where its concentration is increased in inflammatory disorders. Objective We hypothesized that reducing agents may have a direct effect on airway smooth muscle. Therefore, we studied the effects of GSH on airway smooth muscle contractility in guinea-pig main bronchi. In parallel, we evaluated superoxide anion generation associated with in vitro bronchial smooth muscle contraction. Methods Guinea-pig main bronchi were mounted in organ baths filled with Krebs-Henseleit solution. Concentration-response curves to acetylcholine (Ach) (10(-9)-10(-3) M), carbachol (10(-9)-10(-4) M), or histamine (10(-9)-10(-3) M) were performed in the presence or absence of either reduced or oxidized glutathione (GSSG) (10(-5)-10(-3) M). We also evaluated the effects of GSH and GSSG on allergen-induced contraction in main bronchi obtained from ovalbumin-sensitized guinea-pig. Superoxide dismutase (SOD)-inhibited cytochrome c reduction kinetics was performed to evaluate superoxide anion (O-2(-)) production during Ach-induced contraction. Results Reduced but not oxidized glutathione significantly decreased smooth muscle contraction induced by Ach, carbachol, and histamine. Similarly, only the reduced form of glutathione attenuated the bronchoconstriction induced by allergen exposure in bronchi from sensitized animals. Finally, SOD-inhibited cytochrome c reduction kinetics demonstrated increased O-2(-) production following bronchial smooth muscle contraction. This production was not affected by epithelium removal. Conclusion Our findings show that GSH decreases bronchial smooth muscle contraction to different stimuli and that oxidant free radicals are produced during bronchial smooth muscle contraction. We suggest that oxidants are involved in the mechanisms of bronchoconstriction and that reducing agents could be a possible therapeutic option for airway obstruction sustained by bronchospasm.

2003 - The pharmacoepidemiology of COPD: recent advances and methodological discussion. [Articolo su rivista]
Burney, P; Suissa, S; Soriano, Jb; Vollmer, Wm; Viegi, G; Sullivan, Sd; Fabbri, Leonardo; Sin, Dd; Ernst, P; Coultas, D; Bourbeau, J; Mapel, Dw; Weiss, K; Mclaughlin, T; Price, D; Sturkenboom, Mc; Taylor, R; Hagan, Gw
abstract

REVIEW

2002 - Actions other than smooth muscle relaxation may play a role in the protective effects of formoterol on the allergen-induced late asthmatic reaction. [Articolo su rivista]
V., Brusasco; E., Crimi; G., Gherson; R., Nardelli; V., Oldani; B., Francucci; G., Della Cioppa; S., Senn; Fabbri, Leonardo
abstract

Long-acting beta(2)-adrenoceptor agonists attenuate the allergen-induced late asthmatic reaction. We evaluated whether other mechanisms in addition to airway smooth muscle relaxation may be implicated in this protective effect. The effects of formoterol (Foradil Aerolizer(TM), 24 microg dry powder) on the late asthmatic reaction were assessed by a randomised crossover factorial study in 24 patients with asthma. Four challenge/treatment combinations were tested: (A) saline/placebo, (B) saline/formoterol, (C) allergen/placebo, (D) allergen/formoterol. Formoterol and placebo were administered double blind after the last inhalation of the allergen or saline. FEV(1) was measured up to 32 h. The bronchodilator effect of formoterol was estimated as (B-A) and the overall protective effect as (D-C). The effect not due to bronchodilation was estimated as [(D-C)-(B-A)]/2. The bronchodilator effect of formoterol was statistically significant up to 5h (all P< or =0.015). Formoterol significantly attenuated the late asthmatic reaction between 3 and 32 h after allergen inhalation (all P< or =0.0012). The difference between this protective effect and the bronchodilator effect was statistically significant at 5 h and between 7 and 28 h after allergen inhalation (all P< or =0.035). Our results suggest that functional antagonism may not be the sole mechanism by which formoterol attenuates the allergen-induced late asthmatic reaction.

2002 - Advances in the understanding and future therapy of COPD [Relazione in Atti di Convegno]
Fabbri, Leonardo; Rennard, A; Leff, A; O’Connors, B.
abstract

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2002 - Airway inflammation in severe chronic obstructive pulmonary disease - Relationship with lung function and radiologic emphysema [Articolo su rivista]
G., Turato; R., Zuin; M., Miniati; S., Baraldo; F., Rea; Beghe', Bianca; S., Monti; B., Formichi; P., Boschetto; S., Harari; A., Papi; P., Maestrelli; Fabbri, Leonardo; M., Saetta
abstract

The lung pathology of severe chronic obstructive pulmonary disease (COPD) has been poorly investigated. We examined surgical specimens obtained from patients with severe (forced expiratory volume in 1 second [FEV1] = 29 +/- 3% predicted, n = 9) or mild/no airflow limitation (FEV1 = 86 +/- 5% predicted, n = 9) and similar smoking history. With histochemical and immunohistochemical methods we quantified the structural changes and the inflammatory cells in small airways and in muscular pulmonary arteries. As compared with smokers with mild/no COPD, smokers with severe COPD had an increased number of leukocytes in the small airways, which showed a positive correlation with the radiologic score of emphysema and with the value of residual volume, and a negative correlation with the values of FEV1 and carbon monoxide diffusing capacity. The inflammatory process was characterized by an increase in CD8(+) and CD4(+) T-lymphocytes in the airway wall and by an increase in macrophages in the airway epithelium. When all smokers were considered together, the smoking history was correlated with both the airway wall and smooth muscle thickness, suggesting that smoking itself may play a role in the development of structural changes. No structural and cellular differences were observed in pulmonary arteries between smokers with severe COPD and smokers with mild/no COPD. In conclusion, in the small airways of smokers with severe COPD, there is an increased number of leukocytes, which is correlated with reduced expiratory flow, lung hyperinflation, carbon monoxide diffusion impairment, and radiologic emphysema, suggesting a role for this inflammatory response in the clinical progression of the disease.

2002 - Churg-Strauss syndrome in a case of asthma [Articolo su rivista]
Richeldi, Luca; G., Rossi; M. P., Ruggieri; L., Corbetta; Fabbri, Leonardo
abstract

Non disponibile

2002 - Clinical use of Levofloxacin in the long-term treatment of drug resistant tuberculosis. [Articolo su rivista]
Richeldi, Luca; M., Covi; G., Ferrara; F., Franco; P., Vailati; E., Meschiari; Fabbri, Leonardo; G., Velluti
abstract

Multidrug-resistant (MDR) tuberculosis (TB) is a form of TB that is resistant to some of the first-line drugs used for the treatment of the disease. It is associated both with a higher incidence of treatment failures and of disease recurrence, as well as with higher mortality than forms of TB sensitive to first-line drugs. Levofloxacin (LFX) represents one of the few second-line drugs recently introduced in the therapeutic regimens for MDR TB. We report our experience concerning in vitro activity and clinical safety of LFX in long term second-line regimens for MDR TB. IN VITRO ACTIVITY ON MYCOBACTERIA: The in vitro activity of ciprofloxacin, ofloxacin and LFX was studied on 28 strains belonging to different species of Mycobacteria. In Dubos medium, LFX inhibited the growth of both library and MDR clinical Mycobacteria strains in a range of 0.25-1 mcg/ml. In International Union Tuberculosis Medium (IUTM) the minimum inhibitory concentrations (MIC) were slightly higher, but LFX activity was not affected by the higher complexity of the medium. CLINICAL EXPERIENCE: Four patients with MDR TB were treated with a second-line regimen comprising oral LFX 500 mg twice daily, for at least 9 months. Two isolates obtained from the patients reported here showed multi resistance to isoniazid and rifampin, one to rifampin and streptomycin and one to isoniazid and ethambutol. During therapy, no significant alteration of either liver function tests, blood tests or any other described side effect of the fluoroquinolone class was observed. The 3 patients with pulmonary MDR TB showed radiologic and clinical improvement. CONCLUSION: We confirm the higher in vitro activity of LFX compared to older fluoroquinolones. Furthermore, in a limited number of MDR TB patients, second-line regimens comprising LFX 500 mg b.i.d. administered in a range of 9-24 months were well tolerated and safe.

2002 - Diagnosis. [Capitolo/Saggio]
M., Romagnoli; Richeldi, Luca; Fabbri, Leonardo
abstract

Non disponibile

2002 - Expression of protease activated receptor-2 (PAR-2) in central airways of smokers and non-smokers [Articolo su rivista]
Miotto, D; Hollenberg, Md; Bunnett, Nw; Papi, A; Braccioni, F; Boschetto, P; Rea, F; Zuin, A; Geppetti, P; Saetta, M; Maestrelli, P; Fabbri, Leonardo; Mapp, Ce
abstract

Background: Protease activated receptor-2 (PAR-2) is a transmembrane G protein coupled receptor preferentially activated by trypsin and tryptase. The protease activated receptors play an important role in most components of injury responses including cell proliferation, migration, matrix remodelling, and inflammation. Cigarette smoking causes an inflammatory process in the central airways, peripheral airways, lung parenchyma, and adventitia of pulmonary arteries. Methods: To quantify the expression of PAR-2 in the central airways of smokers and non-smokers, surgical specimens obtained from 30 subjects undergoing lung resection for localised pulmonary lesions (24 with a history of cigarette smoking and six non-smoking control subjects) were examined. Central airways were immunostained with an antiserum specific for PAR-2 and PAR-2 expression was quantified using light microscopy and image analysis. Results: PAR-2 expression was found in bronchial smooth muscle, epithelium, glands, and in the endothelium and smooth muscle of bronchial vessels. PAR-2 expression was similar in the central airways of smokers and non-smokers, When smokers were divided according to the presence of symptoms of chronic bronchitis and chronic airflow limitation, PAR-2 expression was increased in smooth muscle (median 3.8 (interquartile range 2.9-5.8) and 1.4 (1.07-3.4) respectively); glands (33.3 (18.2-43.8) and 16.2 (11.5-22.2), respectively); and bronchial vessels (54.2 (48.7-56.8) and 40.0 (36-40.4), respectively) of smokers with symptoms of chronic bronchitis with normal lung function compared with smokers with chronic airflow limitation (COPD), but the increase was statistically significant (p&lt;0.005) only for bronchial vessels. Conclusions: PAR-2 is present in bronchial smooth muscle, glands, and bronchial vessels of both smokers and non-smokers. An increased expression of PAR-2 was found in bronchial vessels of patients with bronchitis compared with those with COPD.

2002 - Increased expression of the chemokine receptor CXCR3 and its ligand CXCL10 in peripheral airways of smokers with chronic obstructive pulmonary disease [Articolo su rivista]
M., Saetta; M., Mariani; P., Panina Bordignon; G., Turato; C., Buonsanti; S., Baraldo; C. M., Bellettato; A., Papi; L., Corbetta; R., Zuin; F., Sinigaglia; Fabbri, Leonardo
abstract

CXCR3 is a chemokine receptor preferentially expressed on lymphocytes, particularly on type-1 T-lymphocytes. Smokers who develop chronic obstructive pulmonary disease (COPD) have a chronic bronchopulmonary inflammation that is characterized by an increased infiltration of T-lymphocytes, particularly CD8(+), in the airways and lung parenchyma. To investigate the expression of CXCR3 and its ligand interferon-induced protein 10/CXCL10 in COPD, we counted the number of CXCR3(+) cells and analyzed the expression of CXCL10 in the peripheral airways of 19 patients undergoing lung resection for localized pulmonary lesions. We examined lung specimens from seven smokers with fixed airflow limitation (COPD), five smokers with normal lung function, and seven nonsmoking subjects with normal lung function. The number of CXCR3(+) cells was immunohistochemically quantified in the epithelium, in the submucosa, and in the adventitia of peripheral airways. The number of CXCR3(+) cells in the epithelium and submucosa was increased in smokers with COPD as compared with nonsmoking subjects, but not as compared with smokers with normal lung function. Immunoreactivity for the CXCR3-ligand CXCL10 was present in the bronchiolar epithelium of smokers with COPD but not in the bronchiolar epithelium of smoking and nonsmoking control subjects. Most CXCR3(+) cells coexpressed CD8 and produced interferon gamma. These findings suggest that the CXCR3/CXCL10 axis may be involved in the T cell recruitment that occurs in peripheral airways of smokers with COPD and that these T cells may have a type-1 profile.

2002 - Macrolides for chronic asthma. [Articolo su rivista]
Richeldi, Luca; G., Ferrara; Fabbri, Leonardo; P. G., Gibson
abstract

BACKGROUND: Asthma is a chronic disease of the airways in which inflammation of the respiratory mucosa plays a crucial role. The mechanisms responsible for the maintaining of this inflammatory response are only partially known and there is evidence that a role could be paid by chronic infection by intracellular pathogens (such as Chlamydia pneumoniae). Macrolides are antibiotics with both antimicrobial and anti-inflammatory activities and thus their use in asthmatic patients could lead to reduction of the airways inflammation and therefore improvement of symptoms and pulmonary function. OBJECTIVES: To determine whether macrolides are effective in the management of patients with chronic asthma. SEARCH STRATEGY: We searched MEDLINE, EMBASE and CINAHL up to May 2001. This was also supplemented by manually searching bibliographies of previously published reviews, conference proceedings, and contacting study authors. All languages were included in the initial search. SELECTION CRITERIA: Randomised, controlled clinical trials involving both children and adult patients with chronic asthma treated with macrolides for more than 4 weeks, versus placebo. DATA COLLECTION AND ANALYSIS: Two reviewers independently examined all identified articles. Two reviewers reviewed the full text of any potentially relevant article independently. MAIN RESULTS: The initial search retrieved 95 studies. Preliminary evaluation identified 20 studies that were potentially eligible. Five (357 patients) met the entry criteria. The entry criteria for the primary trials differed, but all recruited a specific subgroup of patients (eg severe oral steroid dependent, aspirin intolerant or evidence of Chlamydia pnuemoniae infection). There was a positive effect on symptoms (Standardised Mean Difference -1.25, 95% Confidence Intervals (CI) -1.80, -0.70) and markers of eosinophilic inflammation; eg sputum eosinophils Weighted Mean difference -78.5, 95%CI -90.8, -66.1). Tests of oral corticosteroid-sparing effects have not yet been performed on the newer agents such as roxithromycin and clarithromycin. REVIEWER'S CONCLUSIONS: Considering the small number of patients studied, there is insufficient evidence to support or to refute the use of macrolides in patients with chronic asthma. Further studies are needed in particular to clarify the potential role of macrolides in some subgroups of asthmatics such as those with evidence of chronic bacterial infection.

2002 - Mild asthma [Articolo su rivista]
M., Romagnoli; Fabbri, Leonardo
abstract

Naureckas and Solway (Oct. 25 issue) discuss the treatment of mild intermittent and mild persistent asthma but do not discuss the importance of indoor allergens. Allergens not only are triggers of symptoms, but some are also regarded as causal factors in the development of the disease. Because they continuously induce allergic inflammation of the airways, allergens may be more important as a cumulative cause of bronchial hyperreactivity than as triggers of acute attacks. Furthermore, longitudinal studies have shown an accelerated decline in the forced expiratory volume in one second in older adults who are exposed to certain allergens. In other diseases that are caused by exposure to foreign substances, such as hypersensitivity pneumonitis, avoidance of exposure to relevant antigens is the first line of treatment. In asthma, environmental control measures to reduce exposure to indoor allergens should be considered a primary antiinflammatory treatment. Such measures should help to prevent the development of chronic airflow limitation and, therefore, reduce the need for further pharmacologic treatment.

2001 - Analysis of sputum in COPD [Articolo su rivista]
P., Maestrelli; Richeldi, Luca; M., Moretti; Fabbri, Leonardo
abstract

A number of studies have suggested a pathogenetic role for airway inflammation in the induction of both chronic sputum production and chronic airflow obstruction in smokers. It is therefore important to characterise and quantify inflammatory changes in the assessment of subjects with chronic obstructive pulmonary disease (COPD). Assessment of inflammation may be achieved by different means including invasive methods such as bronchial biopsies, bronchoalveolar lavage (BAL) or examination of surgical specimens and non-invasive methods such as spontaneous or induced sputum. The induction of sputum by inhalation of hypertonic saline is a safe, reliable, and relatively non-invasive method in COPD, provided the technique is performed in a standardised way and measures are used to prevent adverse reactions. Induced sputum differs from spontaneous sputum by having a higher number of viable cells and less squamous cell contamination. There are no differences between spontaneous and induced samples from patients with COPD or asthma in the total and differential cell counts, but there is poor agreement in the fluid phase components.Bronchial biopsies and BAL can be performed in COPD for investigative use according to the published recommendations.When the different methods of assessing airway inflammation are compared in the same subjects, a different profile of inflammatory cells is obtained depending on the compartment of the lung examined by each techniquethat is, the lumen of the central airways using sputum analysis, the airway wall using bronchial biopsies, and the peripheral airways using BAL. By combining these techniques, integrated and comprehensive information on cell traffic and inflammatory processes in COPD at different levels of the airway can be obtained. Analysis of induced or spontaneous sputum has contributed to the identification of smokers susceptible to developing COPD, to the characterisation of the inflammatory process during exacerbations, and to the effects of intervention with anti-inflammatory drugs or by smoking cessation.

2001 - Cellular and structural bases of chronic obstructive pulmonary disease [Articolo su rivista]
M., Saetta; G., Turato; P., Maestrelli; Ce, Mapp; Fabbri, Leonardo
abstract

Chronic obstructive pulmonary disease (COPD) is defined as a disease state characterized by poorly reversible airflow limitation that is usually both progressive and associated with an abnormal inflammatory response of the lung. Cigarette smoking is the most important risk factor for the development of COPD. However, only a minority of smokers develop COPD and the reason is still unknown. The pathological hallmarks of COPD are inflammation of the peripheral airways and destruction of lung parenchyma or emphysema. The functional consequence of these abnormalities is expiratory airflow limitation. Since the major determinants of expiratory flow are a driving pressure that promotes flow (elastic recoil of the lung) and an opposing resistance that inhibits flow (airway obstruction), the reduction in flow occurring in COPD is more correctly defined as airflow limitation rather than airflow obstruction, since both loss of elastic recoil and increase in airway resistance play an important role in the observed decrease in flow. Emphysema will contribute to the airflow limitation by reducing the elastic recoil of the lung through parenchymal destruction, as well as by reducing the elastic load applied to the airways through destruction of alveolar attachments. On the other hand, inflammation of the peripheral airways will contribute to the airflow limitation by increasing the thickness of the airway wall which, together with fibrosis and smooth muscle hypertrophy, may cause airway narrowing. The role of mucus hypersecretion in the development of chronic airflow limitation is still controversial. The main site of mucus hypersecretion, expressed clinically as chronic bronchitis, is the central airways, and there is increasing evidence that the central airways are inflamed in patients with COPD. Pulmonary hypertension is a common feature in patients with advanced COPD, but the precise mechanisms of increased vascular resistance are unclear. For many years, it has been regarded as a consequence of the hypoxic vasoconstriction that may occur in advanced stages of the disease. However, the lack of reversibility of pulmonary hypertension after hypoxemia correction suggests that it might be due at least in part to the development of pulmonary vascular inflammation and remodeling. In summary, in subjects with COPD, pathological changes can be found in the central airways, the peripheral airways, the lung parenchyma, and pulmonary arteries. Interestingly, some of these changes can already be present in the lungs of "normal" smokers, i.e. smokers with normal lung function, indicating that smoking itself is able to damage the lung even before airflow limitation occurs. In the present article we will focus on the cellular and structural changes present in the lungs of "normal" smokers and on those present in the lungs of smokers with COPD, in an attempt to underline the possible mechanisms contributing to airflow limitation in these patients. We will then review the few studies that described the cellular and structural changes that occur in severe COPD and those that occur during an exacerbation of the disease. Finally, we will address the effect of smoking cessation or antiiflammatory treatment in an attempt to investigate the potential reversibility of the pathologic lesions characteristic of COPD. In advanced COPD, changes in the right heart, the respiratory muscles, and the skeletal non-respiratory muscles as well as cachexia may also occur, but these systemic changes will not be discussed in this article.

2001 - Diagnosis in adults. [Capitolo/Saggio]
A. L., Cogo; Beghe', Bianca; L., Corbetta; Fabbri, Leonardo
abstract

Asthma is a syndrome characterized by recurrent respiratory symptoms, i.e. dyspnoea, wheezing, chest tightness or cough associated with reversible airflow limitation. Familiar predisposition, atopy, and exposure to allergen and sensitising agents are important risk factors for asthma, even the causes of asthma, meaning the factors responsible of the new cases of asthma instead of the exacerbations of asthma, remain largely undetermined

2001 - Exacerbations of Bronchitis: bronchial eosinophilia and gene expression for interleukin-4, interleukin-5, and eosinophil chemoattractants. [Articolo su rivista]
J., Zhu; Y. S., Qiu; S., Majumdar; E., Gamble; D., Matin; G., Turato; Fabbri, Leonardo; N., Barnes; M., Saetta; P. K., Jeffery
abstract

Eosinophilia has been reported during exacerbations of bronchitis, but the mechanisms of tissue recruitment of eosinophils are unclear. We quantified eosinophils and the concurrent expression of cytokines and chemokines probably responsible for the tissue eosinophilia in bronchial biopsies obtained from three groups of nonatopic subjects: (1) healthy nonsmokers (n = 7; FEV1 % predicted = 108 +/- 4 [mean +/- SEM]); (2) nonasthmatic smokers with chronic bronchitis (CB) in a stable phase of their disease (n = 11; FEV1 % predicted: 75 +/- 5); and (3) nonasthmatic subjects with CB who sought medical advice for an exacerbation of their condition (n = 9; FEV(1) % predicted: 61 +/- 8). We applied anti-EG2 antibody and immunostaining to detect and count eosinophils. We performed in situ hybridization to visualize and enumerate cells expressing the genes for interleukin (IL)-4 and IL-5 and the eosinophil chemokines eotaxin, monocyte chemoattractant protein (MCP)-4, or regulated on activation, normal T-cell expressed and secreted (RANTES). We confirmed an increase in EG2-positive eosinophils in patients with CB in exacerbation. We found messenger RNA (mRNA) positivity for IL-4 and IL-5 in CB, but the between-group differences were not statistically significant. However, the numbers of lymphomononuclear cells expressing eotaxin mRNA were significantly greater in the smokers with CB than in the healthy nonsmokers without CB (p < 0.01). Following an exacerbation, RANTES expression was upregulated and this chemokine was strongly expressed in both the surface epithelium and in subepithelial lymphomononuclear cells: only RANTES showed a significant positive correlation with the increasing number of EG2-positive cells (r = 0.51; p < 0.03). In conclusion, an allergic profile of inflammation can also occur in CB: the marked upregulation of RANTES in the epithelium and subepithelium most likely accounts for the increased eosinophilia associated with an exacerbation of bronchitis.

2001 - Increased expression of heme oxygenase (HO)-1 in alveolar spaces and HO-2 in alveolar walls of smokers [Articolo su rivista]
P., Maestrelli; AH El, Messlemani; O., De Fina; Y., Nowicki; M., Saetta; C., Mapp; Fabbri, Leonardo
abstract

It has been suggested that oxidative stress protein heme oxygenase (HO)-1 plays a role in chronic airway diseases including chronic obstructive pulmonary disease (COPD). The inducible isoform HO-1 and the constitutive HO-2 catalyze the same reaction. Their distribution in situ was studied in lungs of 10 nonsmoking subjects, 6 healthy smokers, and 10 smokers with COPD. Paraffin-embedded sections of surgical lung specimens were immunostained with antibodies against HO-1 and HO-2. HO-1 immunoreactivity was observed mainly in alveolar macrophages. HO-1-positive macrophages were increased in smokers with COPD (median: 36%) as compared with nonsmoking subjects (13%; p < 0.02), whereas no differences were observed between patients with COPD and healthy smokers (34%). HO-2 had a more widespread distribution in cells of the alveolar wall, in adventitia of pulmonary arteries and bronchioles, and in vascular smooth muscle. Lower percentages of alveolar macrophages exhibited positive staining for HO-2 without significant differences between the three groups. HO-2(+) cells in the alveolar wall were increased in smokers with (15/mm) and without COPD (12/mm) as compared with nonsmokers (8/mm, p < 0.01). In conclusion, inducible HO-1 and constitutive HO-2 are detectable in human lung tissue and their expression is increased in smokers, suggesting that oxidative stress due to cigarette smoke may increase lung cells expressing HO-1 and HO-2.

2001 - Low domestic exposure to house dust mite allergens (Der p 1) is associated with a reduced non-specific bronchial hyper-responsiveness in mite-sensitized asthmatic subjects under optimal drug treatment [Articolo su rivista]
P., Maestrelli; L., Zanolla; P., Puccinelli; M., Pozzan; Fabbri, Leonardo; Regione Veneto, Study
abstract

BACKGROUND: Airway inflammation in asthma causes symptoms, airflow limitation and bronchial hyper-responsiveness. The strategy of asthma management is to reduce airway inflammation by drug treatment and avoidance of triggers, including allergens. OBJECTIVE: We determined the effect of exposure to house dust mite (HDM) allergens on bronchial responsiveness in asthmatics sensitive to mites while under optimal drug treatment. METHODS: We studied 71 mild to moderate HDM-sensitive asthmatics. Drug treatment sufficient to keep asthma under control was administered to each patient for 1 year. Subjects were divided into two groups, according to the amount of Der p 1 in their bedrooms measured after standard HDM reduction measures: low Der p 1 exposure (0.64 +/- 0.5 microg/g dust) (Group 1, n = 34) and high Der p 1 exposure (12.5 +/- 11.4 microg/g) (Group 2, n = 37). Bronchial responsiveness to methacholine (PD20FEV1) was determined at the beginning and end of the study. RESULTS: In Group 1, PD20FEV1 increased 2.15-fold at the end of the study from 57 to 123 microg (P < 0.05), whereas in Group 2 no significant changes were observed. The subjects in Group 2 tended to increase the use of inhaled steroids and bronchodilators in the autumn months compared with subjects in Group 1, but the difference was not significant. CONCLUSION: This long-term study shows that exposure to lower levels of mite allergens in the bedroom is associated with a decrease of bronchial hyper-responsiveness in sensitized asthmatic subjects under optimal drug treatment.

2001 - New therapeutic indications for Cys-LT1 antagonists: chronic obstructive pulmonary disease. [Relazione in Atti di Convegno]
M., Romagnoli; A., Papi; F., Luppi; Fabbri, Leonardo
abstract

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2001 - Reliability of a questionnaire for evaluating the understanding of asthma. [Articolo su rivista]
G., Bertolotti; M., Carone; S., Viaggi; G., Moscato; M., Neri; C., Rampulla; Fabbri, Leonardo; P., Zanon; C. F., Donner
abstract

The present study was designed to evaluate the repeatability of a questionnaire developed to assess the understanding that asthma patients have of their disease and, on the basis of its variability, estimate the sample size necessary for determining the efficacy of a future structured program on asthma knowledge. The repeatability of the Asthma Questionnaire (AQ) was evaluated by asking 89 patients to complete it twice within a period of 7-10 days without the subject being exposed to any programme on asthma knowledge between the two administrations. The AQ was demonstrated to have good content and face validity. Results showed that neither age nor sex had a significant influence on total scores, and that the degree of reliability was adequate (R = 0.769). The mean percentage of correct answers was observed to be approximately 70% in both sessions, suggesting a consistent area for possible improvement which could be targeted by means of an appropriately structured programme on asthma knowledge. For comparative purposes before and after the programme, or for measuring its efficacy, the AQ should be recommended. In conclusion the Asthma Questionnaire could provide a useful tool for the general practitioner, chest physician and other health professionals, to assess what the patient really does understand or does not, concerning asthma management, and hence be the starting point for a well-tailored educational intervention.

2001 - Remodeling in response to infection and injury. Airway inflammation and hypersecretion of mucus in smoking subjects with chronic obstructive pulmonary disease. [Articolo su rivista]
P., Maestrelli; M., Saetta; C. E., Mapp; Fabbri, Leonardo
abstract

Airway epithelium represents the first line of defense against toxic inhalants. In some subjects, cigarette smoking causes airway inflammation, hypersecretion of mucus, and poorly reversible airflow limitation through mechanisms that are still largely unknown. Likewise, it is unclear why only some smokers develop chronic obstructive pulmonary disease (COPD). Two cell types consistently result in relation to chronic airflow limitation in COPD: neutrophils and CD8(+) cells. Neutrophils are compartmentalized in the mucosal surface of the airways and air spaces, that is, the epithelium and lumen, whereas CD8(+) cells exhibit a more extensive distribution along the subepithelial zone of the airways and lung parenchyma, including alveolar walls and arteries. This pattern of inflammatory cell distribution is observed in mild or moderate COPD, and in patients who have developed COPD, it is not modified by smoking cessation. The number of neutrophils further increases in the submucosa of patients with severe COPD, suggesting a role for these cells in the progression of the disease. Hypersecretion of mucus is a major manifestation in COPD. Mucus is produced by bronchial glands and goblet cells lining the airway epithelium. Unlike mucous gland enlargement, greater mucosal inflammation is associated with sputum production. Whereas neutrophil infiltration of submucosal glands occurs only in smokers with COPD, goblet cell hyperplasia in peripheral airways occurs both in smokers with or without COPD, suggesting that the major determinant of goblet cell hyperplasia is cigarette smoke itself.

2001 - Serum-mediated relaxant response to toluene diisocyanate (TDI) in isolated guinea-pig bronchi [Articolo su rivista]
P., Boschetto; L., Jovine; P., Chitano; N., De Marzo; M., Plebani; D., Faggian; Fabbri, Leonardo; Ce, Mapp
abstract

The present study was designed to evaluate whether pre-incubation with serum, obtained from both control and toluene diisocyanate (TDI)-immunized guinea-pigs, modified the contractile response to TDI in isolated guinea-pig bronchial rings. Guinea-pigs were anaesthetized and the main bronchi dissected in two rings. Bronchial rings were incubated with normal or immune serum (100 mul ml(-1) for 2h) and dose-response curves to TDI (0(.)03-1000 muM) were studied isometrically. Before serum incubation. in eight bronchial rings, epithelium was removed by rubbing the luminal surface gently with a gauze. In control rings. TDI produced a concentration-dependent contraction, whereas in rings pre-incubated with either normal or TDI-immune serum, it produced a concentration-dependent relaxation. Relaxation was 101(.)4 (SEM 17(.)4)% and 94(.)9 (SEM 21)% Of the relaxation induced by isoproterenol (1 mM) respectively with normal and TDI-immune serum. Similarly to the pre-incubation with serum, pre-incubation with albumin produced a concentration-dependent relaxation to TDI. Serum-induced relaxant response to TDI was not affected by capsaicin desensitization. it was only partially inhibited by an NK1-tachykinin antagonist, whereas it was blocked by indomethacin. In bronchial rings without epithelium, pre-incubated with serum. TDI caused contraction at highest doses. while it still induced relaxation at the lowest doses. This study shows that one or more components of the serum modify the contractile response to TDI in isolated guinea-pig bronchi. In bronchial rings without epithelium serum was able to inhibit the contration induced by low doses of TDI.

2001 - Systemic effects of inhaled corticosteroids are milder in asthmatic patients than in normal subjects [Articolo su rivista]
Fabbri, Leonardo; R., Melara
abstract

comment

2001 - The C-C chemokine receptors CCR4 and CCR8 identify airway T cells of allergen-challenged atopic asthmatics [Articolo su rivista]
P., Panina Bordignon; A., Papi; M., Mariani; P., Di Lucia; G., Casoni; C., Bellettato; C., Buonsanti; D., Miotto; C., Mapp; A., Villa; G., Arrigoni; Fabbri, Leonardo; F., Sinigaglia
abstract

In vitro polarized human Th2 cells preferentially express the chemokine receptors CCR3, CCR4, and CCR8 and migrate to their ligands: eotaxin, monocyte-derived chemokine (MDC), thymus- and activation-regulated chemokine (TARC), and I-309. We have studied the expression of chemokines and chemokine receptors in the airway mucosa of atopic asthmatics. Immunofluorescent analysis of endobronchial biopsies from six asthmatics, taken 24 hours after allergen challenge, demonstrates that virtually all T cells express IL-4 and CCR4. CCR8 is coexpressed with CCR4 on 28% of the T cells, while CCR3 is expressed on eosinophils but not on T cells. Expression of the CCR4-specific ligands MDC and TARC is strongly upregulated on airway epithelial cells upon allergen challenge, suggest ing an involvement of this receptor/ligand axis in the regulation of lymphocyte recruitment into the asthmatic bronchi. In contrast to asthma, T cells infiltrating the airways of patients with chronic obstructive pulmonary disease and pulmonary sarcoidosis produce IFN-gamma and express high levels of CXCRS3, while lacking CCR4 and CCR8 expression. These data support the role of CCR4, of its ligands MDC and TARC, and of CCR8 in the pathogenesis of allergen-induced late asthmatic responses and suggest that these molecules could be considered as targets for therapeutic intervention.

2001 - Trattamento farmacologico dell’asma bronchiale. [Capitolo/Saggio]
Beghe', Bianca; A., Papi; I., Guzzinati; Fabbri, Leonardo
abstract

L’asma bronchiale può essere tenuto efficacemente sotto controllo, anche se non può essere guarito, facendo un uso appropriato dei farmaci disponibili. Scopo della terapia è quindi il controllo dell’asma, che consiste nel raggiungere alcuni obbiettivi:rendere il paziente asintomatico,prevenire le riacutizzazioni di asma, e quindi ridurre al minimo il ricorso ai broncodilatatori;normalizzare il quadro funzionale respiratorio, comunque portarlo ai migliori valori possibili; consentire al paziente un normale stile di vita, ivi compresa la normale attività fisica, anche sportiva; rdurre al minimo gli effetti collaterali dei farmaci somministrati.

2000 - Asma Bronchiale [Monografia/Trattato scientifico]
Fabbri, Leonardo
abstract

n/a

2000 - Association between HLA genes and susceptibility to toluene diisocyanate-induced asthma [Articolo su rivista]
C. E., Mapp; Beghe', Bianca; A., Balboni; G., Zamorani; M., Padoan; L., Jovine; O. R., Baricordi; Fabbri, Leonardo
abstract

BACKGROUND: Only a small proportion of subjects exposed to isocyanates develop occupational asthma, suggesting individual predisposition. The human leucocyte antigen (HLA) class II molecules may play a crucial role in the development of the immune response to isocyanates.OBJECTIVES: To investigate the role of HLA class II molecules in the development of toluene diisocyanate (TDI)-induced asthma.SUBJECTS: Sixty-seven asthmatic subjects and 27 asymptomatic exposed subjects (controls) were typed at the HLA class II DQA1, DQB1 and DRB1 loci by polymerase chain reaction (PCR)-based techniques.RESULTS: The frequencies of DQA1*0104 and DQB1*0503 were significantly increased in asthmatics compared with asymptomatic exposed subjects, while DQA1*0101 and DQB1*0501 were significantly increased in asymptomatic exposed subjects. No significant difference was found in the distribution of DRB1 alleles between asthmatics and controls.CONCLUSIONS: The results of this study indicate that HLA-regulated immune mechanisms are involved in TDI-induced asthma and that, in exposed subjects, specific factors may increase or decrease the risk of developing disease

2000 - Delivering effective asthma care--how do we implement asthma guidelines? [Articolo su rivista]
M. R., Partridge; Fabbri, Leonardo; K. F., Chung
abstract

editorial

2000 - Goblet cell hyperplasia and epithelial inflammation in peripheral airways of smokers with both symptoms of chronic bronchitis and chronic airflow limitation [Articolo su rivista]
M., Saetta; G., Turato; S., Baraldo; A., Zanin; F., Braccioni; Ce, Mapp; P., Maestrelli; G., Cavallesco; A., Papi; Fabbri, Leonardo
abstract

To quantify the number of goblet cells and inflammatory cells in the epithelium of peripheral airways in smokers with both symptoms of chronic bronchitis and chronic airflow limitation, we examined surgical specimens obtained from 25 subjects undergoing lung resection for localized pulmonary lesions: 10 smokers with symptoms of chronic bronchitis and chronic airflow limitation, six asymptomatic smokers with normal lung function, and nine nonsmoking control subjects. Peripheral airways were examined with histochemical methods to identify goblet cells and with immunohistochemical methods to identify total leukocytes (CD45+ cells), neutrophils, macrophages, CD4+ and CD8+ cells in the epithelium. When compared with nonsmokers, smokers with both symptoms of chronic bronchitis and chronic airflow limitation had an increased number of goblet cells (p < 0.01), CD45+ cells (p < 0.01), macrophages (p < 0.05), and CD8+ cells (p < 0.01) in the epithelium of peripheral airways. When all the smokers were grouped together, they showed an increased number of neutrophils (p < 0.05) along with an increased number of goblet cells, CD45+ cells, macrophages and CD8+ cells (p < 0.05) compared with nonsmokers. In conclusion, smokers with both symptoms of chronic bronchitis and chronic airflow limitation have an increased number of goblet cells and inflammatory cells in the epithelium of peripheral airways. Saetta M, Turato G, Baraldo S, Zanin A, Braccioni F, Mapp CE, Maestrelli P, Cavallesco G, Papi A, Fabbri LM. Goblet cell hyperplasia and epithelial inflammation in peripheral airways of smokers with both symptoms of chronic bronchitis and chronic airflow limitation.

2000 - Improving patient compliance with asthma therapy. [Articolo su rivista]
Chapman, Kr; Walker, L; Cluley, S; Fabbri, Leonardo
abstract

Patients fail to comply with asthma medication for a variety of reasons. These range from physical inability to use an inhaler, through simple forgetfulness, to a conscious decision not to use medication as prescribed due to internal or cultural health beliefs or socioeconomic factors. In some patients, poor self-care because of deep-rooted psychological factors (i.e. factors of which patients have only limited awareness) can affect compliance. Poor doctor-patient communication can be the cause in many other individuals. Thus, there is no single solution that will improve compliance in all patients. Simplifying the regimen or providing memory aids will be sufficient for some patients, while education or psychological counselling will be more appropriate for others. Doctors can also use a range of communication skills to improve the way in which they present information, motivate patients and reinforce progress. These approaches, plus respect for patients' health beliefs and involving them in treatment decisions, can help foster an atmosphere of mutual responsibility and concordance over medicine taking.

2000 - Montelukast or salmeterol combined with an inhaled steroid in adult asthma: design and rationale of a randomized, double-blind comparative study (the IMPACT Investigation of Montelukast as a Partner Agent for Complementary Therapy-trial) [Articolo su rivista]
L., Bjermer; H., Bisgaard; J., Bousquet; Fabbri, Leonardo; A., Greening; T., Haahtela; St, Holgate; C., Picado; Ja, Leff
abstract

Asthma patients who continue to experience symptoms despite taking regular inhaled corticosteroids represent a management challenge. Leukotrienes play a key role in asthma pathophysiology, and since pro-inflammatory leukutrienes are poorly suppressed by corticosteroids it seems rational to add a leukotriene receptor antagonist (LTRA) when a low to moderate dose of inhaled corticosteroids does not provide sufficient disease control. Long acting beta(2)-agonist (LABA) treatment represents an alternative to LTRAs and both treatment modalities have been shown to provide additional disease control when added to corticosteroid treatment. To compare the relative clinical benefits of adding either a LTRA or a LABA to asthma patients inadequately controlled by inhaled corticosteroids, a randomized, double-blind, multi-centre, 48-week study will be initiated at approximately 120 centres throughout Europe, Latin America, Middle East, Africa and the Asia-Pacific region in early 2000. The study will compare the oral LTRA montelukast with the inhaled LABA salmeterol, each administered on a background of inhaled fluticasone, on asthma attacks, quality of life, lung function, eosinophil levels, healthcare utilization, and safety, in approximately 1200 adult asthmatic patients. The requirements for study enrolment include a history of asthma, FEV1 or PEFR values between 50% and 90% of the predicted value together with greater than or equal to 12% improvement in FEV1 after beta-agonist administration, a minimum pre-determined level of asthma symptoms and daily beta-agonist medication. The study will include a 4-week run-in period, during which patients previously taking inhaled corticosteroids are switched to open-label fluticasone (200 mu g daily), followed by a 48-week double-blind, treatment period in which patients continuing to experience abnormal pulmonary function and daytime symptoms are randomized to receive montelukast (10 mg once daily) and salmeterol placebo, or inhaled salmeterol (100 mu g daily) and montelukast placebo. All patients will continue with inhaled fluticasone (200 mu g daily). During the study, asthma attacks, overnight asthma symptoms, and morning peak expiratory flow rate will be assessed using patient diary cards; quality of life will also be assessed using an asthma-specific quality-of life questionnaire. The results of this study are expected to provide physicians with important clinical evidence to help them make a rational and logical treatment choice for asthmatic patients experiencing breakthrough symptoms on inhaled corticosteroids.

2000 - Partial reversibility of airflow limitation and increased exhaled NO and sputum eosinophilia in chronic obstructive pulmonary disease. [Articolo su rivista]
A., Papi; M., Romagnoli; S., Baraldo; F., Braccioni; I., Guzzinati; M., Saetta; A., Ciaccia; Fabbri, Leonardo
abstract

We investigated the relationship between the reversibility of airflow limitation, the concentration of nitric oxide (NO) in exhaled air, and the inflammatory cells in the sputum of patients with stable chronic obstructive pulmonary disease (COPD). We examined nine normal healthy control subjects and 20 nonatopic patients with COPD. Ten patients had no reversibility of airflow limitation (increase in FEV1 of < 12% and < 200 ml after 200 µg of inhaled salbutamol), and 10 patients had partial reversibility of airflow limitation (increase in FEV1 of < 12% but > 200 ml after 200 µg of inhaled salbutamol). Exhaled NO levels were higher in COPD patients with partial reversibility of airflow limitation than in those with no reversibility of airflow limitation (median 24 [interquartile range 15.3 to 32] ppb versus 8.9 [4.6 to 14.7] ppb; p < 0.01). Compared with healthy control subjects, only COPD patients with partial reversibility of airflow limitation had increased concentrations of sputum eosinophils. We conclude that, in patients with stable COPD, even a partial bronchodilator response to inhaled salbutamol is associated with increased exhaled NO and sputum eosinophilia, suggesting that these patients may have a different response to treatment than do those without reversible airflow limitation.

2000 - Presence and bronchomotor activity of protease-activated receptor-2 in guinea pig airways. [Articolo su rivista]
F. L., Ricciardolo; M., Steinhoff; S., Amadesi; R., Guerrini; M., Tognetto; M., Trevisani; C., Creminon; C., Bertrand; N. W., Bunnett; Fabbri, Leonardo; S., Salvadori; P., Geppetti
abstract

The protease activated receptor-2 (PAR-2) belongs to a family of G-protein-coupled receptors that are activated by proteolysis. Trypsin cleaves PAR-2, exposing an N-terminal tethered ligand (SLIGRL) that activates the receptor. Messenger RNA (mRNA) for PAR-2 was found in guinea pig airway tissue by reverse transcription-polymerase chain reaction, and PAR-2 was found by immunohistochemistry in airway epithelial and smooth-muscle cells. In anesthetized guinea pigs, trypsin and SLIGRL-NH2 (given intratracheally or intravenously) caused a bronchoconstriction that was inhibited by the combination of tachykinin-NK1 and -NK2 receptor antagonists and was potentiated by inhibition of nitric oxide synthase (NOS). Trypsin and SLIGRL-NH2 relaxed isolated trachea and main bronchi, and contracted intrapulmonary bronchi. Relaxation of main bronchi was abolished or reversed to contraction by removal of epithelium, administration of indomethacin, and NOS inhibition. PAR-1, PAR-3, and PAR-4 were not involved in the bronchomotor action of either trypsin or SLIGRL-NH2, because ligands of these receptors were inactive either in vitro or in vivo, and because thrombin (a PAR-1 and PAR-3 agonist) did not show cross-desensitization with PAR-2 agonists in vivo. Thus, we have localized PAR-2 to the guinea-pig airways, and have shown that activation of PAR-2 causes multiple motor effects in these airways, including in vivo bronchoconstriction, which is in part mediated by a neural mechanism.

2000 - The distribution of neurokinin-1 and neurokinin-2 receptors in human central airways. [Articolo su rivista]
C. E., Mapp; D., Miotto; F., Braccioni; M., Saetta; G., Turato; P., Maestrelli; J. E., Krause; V., Karpitskiy; N., Boyd; P., Geppetti; Fabbri, Leonardo
abstract

The precise locations of neurokinin (NK)-1 and NK-2 receptors in human airways, and their role in airway inflammatory diseases, have not been carefully examined. To determine the distribution of NK-1 and NK-2 receptors in human central airways, and to determine whether their distribution was different in smokers, we examined surgical specimens from patients undergoing lung resection for limited lung lesions. We mapped NK-1 and NK-2 receptors in four groups of subjects: four asymptomatic nonsmokers, seven asymptomatic smokers, seven symptomatic smokers with normal lung function, and eight symptomatic smokers with chronic airflow limitation. Tissues were immunostained with anti-NK-1- and anti-NK-2-receptor antibodies. Expression of NK-1 and NK-2 receptors was quantified through light microscopy and image analysis. Both NK-1 and NK-2 receptors were found in bronchial glands, bronchial vessels, and bronchial smooth muscle. Although no receptors were observed in the epithelium, receptors were occasionally found in nerves (NK-1) and in inflammatory cells (NK-2) such as T lymphocytes, macrophages, and mast cells. The distribution of both NK-1 and NK-2 receptors was similar in all the tissues examined in the four groups of subjects. These data show that NK-1 and NK-2 receptors are present in human central airways and that their expression is not modified by cigarette smoking.

2000 - Trattamento farmacologico dell’asma bronchiale [Capitolo/Saggio]
Beghe', Bianca; Papi, A; I., Guzzinati; Fabbri, Leonardo
abstract

L’asma bronchiale è una malattia infiammatoria cronica delle vie aeree caratterizzata da ricorrenti episodi di ostruzione reversibile del flusso aereo responsabili delle crisi di respiro sibilante, senso di costrizione toracica, dispnea e tosse stizzosa.In questo capitolo verrà descritto il trattameto farmacologcio dell'asma

1999 - Antibodies to the IL-12 receptor beta 2 chain mark human Th1 but not Th2 cells in vitro and in vivo. [Articolo su rivista]
L., Rogge; A., Papi; D. H., Presky; M., Biffi; L. J., Minetti; Miotto, Deborah; C., Agostini; G., Semenzato; Fabbri, Leonardo; F., Sinigaglia
abstract

Great attention has been placed on the possibility of distinguishing Th1 from Th2 cells on the basis of differential expression of surface receptors. We have recently shown that the differential expression of the IL-12Rß2 chain in Th1 and Th2 cells, as measured at the mRNA level, accounts for an important regulatory mechanism in the differentiation of the two cell subsets. In this study, we identify IL-12R expression at the protein level. We have generated an anti-IL-12Rß2-specific mAb and analyzed IL-12Rß2 expression on polarized Th cell populations generated in vitro and on T cells derived from patients with Th1- or Th2-mediated inflammatory conditions. Although IL-12Rß2 was absent in freshly isolated PBMC and in cord blood cells, we were able to detect IL-12Rß2 expression selectively in differentiated Th1 and T cytotoxic 1, but not Th2 or T cytotoxic 2 cells. In the presence of IL-12, cell surface expression of the IL-12Rß2 subunit was readily detected on T cells after 24 h, reached the maximum at day 5, and declined thereafter. Most importantly, the anti-IL-12Rß2 mAb recognizes lung T cells from patients with sarcoidosis, a disease characterized by a typical cell-mediated, Th1-type inflammatory response. In contrast, IL-12Rß2 was absent in lung T cells from patients with allergic asthma, a disease characterized by a Th2-type inflammatory response. The mAb reported in this study should represent a powerful tool to investigate the role of Th1 and Th2 cells in inflammatory conditions and to monitor therapies aimed at altering the balance of Th cell subsets.

1999 - Bronchoconstriction induced by citric acid inhalation in guinea pigs: role of tachykinins, bradykinin, and nitric oxide. [Articolo su rivista]
F. L., Ricciardolo; V., Rado; Fabbri, Leonardo; P. J., Sterk; G. U., Di; P., Geppetti
abstract

Gastroesophageal acid reflux into the airways can trigger asthma attacks. Indeed, citric acid inhalationcauses bronchoconstriction in guinea pigs, but the mechanism of this effect has not been fullyclarified. We investigated the role of tachykinins, bradykinin, and nitric oxide (NO) on the citric acid–induced bronchoconstriction in anesthetized and artificially ventilated guinea pigs. Citric acid inhalation(2–20 breaths) caused a dose-dependent increase in total pulmonary resistance (RL). RLvalue obtainedafter 10 breaths of citric acid inhalation was not significantly different from the value obtainedafter 20 breaths (p50.22). The effect produced by a half-submaximum dose of citric acid (5 breaths)was halved by the bradykinin B2receptor antagonist HOE 140 (0.1mmol?kg21, intravenous) andabolished by the tachykinin NK2receptor antagonist SR 48968 (0.3mmol?kg21, intravenous). Bronchoconstrictioninduced by a submaximum dose of citric acid (10 breaths) was partially reduced bythe administration of HOE 140, SR 48968, or the NK1receptor antagonist CP-99,994 (8mmol?kg21,intravenous) alone and completely abolished by the combination of SR 48968 and CP-99,994. Pretreatmentwith the NO synthase inhibitor,L-NMMA (1 mM, 10 breaths every 5 min for 30 min) increasedin anL-arginine–dependent manner the effect of citric acid inhalation on RL. HOE 140 and CP-99,994 markedly reduced theL-NMMA–potentiated bronchoconstriction to inhaled citric acid. Weconclude that citric acid–induced bronchoconstriction is caused by tachykinin release from sensorynerves, which, in part, is mediated by endogenously released bradykinin. Simultaneous release of NOby citric acid inhalation counteracts tachykinin-mediated bronchoconstriction. Our study suggests apossible implication of these mechanisms in asthma associated with gastroesophageal acid reflux anda potential therapeutic role of tachykinin and bradykinin antagonists.

1999 - Bronchopulmonary inflammation and airway smooth muscle hyperresponsiveness induced by nitrogen dioxide in guinea pigs. [Articolo su rivista]
A., Papi; S., Amadesi; P., Chitano; P., Boschetto; A., Ciaccia; P., Geppetti; Fabbri, Leonardo; C. E., Mapp
abstract

We investigated whether acute exposure to nitrogen dioxide (NO2) causes major inflammatory responses (inflammatory cell recruitment, oedema and smooth muscle hyperresponsiveness) in guinea pig airways. Anaesthetised guinea pigs were exposed to 18 ppm NO2 or air for 4 h through a tracheal cannula. Bronchoalveolar lavage was performed and airway microvascular permeability and in vitro bronchial smooth muscle responsiveness were measured. Exposure to NO2 induced a significant increase in eosinophils and neutrophils in bronchoalveolar lavage fluid, microvascular leakage in the trachea and main bronchi (but not in peripheral airways), and a significant in vitro hyperresponsiveness to acetylcholine, electrical field stimulation, and neurokinin A, but not to histamine. Thus, this study shows that in vivo exposure to high concentrations of NO2 induces major inflammatory responses in guinea pig airways that mimic acute bronchitis induced by exposure to irritant gases in man.

1999 - Broncopneumopatie Croniche Ostruttive [Monografia/Trattato scientifico]
Fabbri, Leonardo; Ciaccia, A.
abstract

n/a

1999 - CD8+ve cells in the lungs of smokers with chronic obstructive pulmonary disease. [Articolo su rivista]
M., Saetta; S., Baraldo; L., Corbino; G., Turato; F., Braccioni; F., Rea; G., Cavallesco; G., Tropeano; C. E., Mapp; P., Maestrelli; A., Ciaccia; Fabbri, Leonardo
abstract

Previous studies have shown an increased number of inflammatory cells and, in particular, CD8+ve cells in the airways of smokers with chronic obstructive pulmonary disease (COPD). In this study we investigated whether a similar inflammatory process is also present in the lungs, and particularly in lung parenchyma and pulmonary arteries. We examined surgical specimens from three groups of subjects undergoing lung resection for localized pulmonary lesions: nonsmokers (n = 8), asymptomatic smokers with normal lung function (n = 6), and smokers with COPD (n = 10). Alveolar walls and pulmonary arteries were examined with immunohistochemical methods to identify neutrophils, eosinophils, mast cells, macrophages, and CD4+ve and CD8+ve cells. Smokers with COPD had an increased number of CD8+ve cells in both lung parenchyma (p < 0.05) and pulmonary arteries (p < 0.001) as compared with nonsmokers. CD8+ve cells were also increased in pulmonary arteries of smokers with COPD as compared with smokers with normal lung function (p < 0.01). Other inflammatory cells were no different among the three groups. The number of CD8+ve cells in both lung parenchyma and pulmonary arteries was significantly correlated with the degree of airflow limitation in smokers. These results show that an inflammatory process similar to that present in the conducting airways is also present in lung parenchyma and pulmonary arteries of smokers with COPD.

1999 - Difficult Asthma [Monografia/Trattato scientifico]
Holgate, St; Boushey, Ha; Fabbri, Leonardo
abstract

n/d

1999 - Difficult/therapy-resistant asthma: the need for an integrated approach to define clinical phenotypes, evaluate risk factors, understand pathophysiology and find novel therapies. ERS Task Force on Difficult/Therapy-Resistant Asthma. European Respiratory Society. [Articolo su rivista]
Chung, Kf; Godard, P; Adelroth, E; Ayres, J; Barnes, N; Barnes, P; Bel, E; Burney, P; Chanez, P; Connett, G; Corrigan, C; de Blic, J; Fabbri, Leonardo; Holgate, St; Ind, P; Joos, G; Kerstjens, H; Leuenberger, P; Lofdahl, Cg; Mckenzie, S; Magnussen, H; Postma, D; Saetta, M; Salmeron, S; Sterk, P.
abstract

A Task Force supported by the European Respiratory Society was set up in 1997 in order to address the major issues relevant to difficult/therapy-resistant asthma. Although the group of patients involved is small in comparison to the high numbers of patients with asthma, these patients consume a significant proportion of medical resources in terms of both time and money [1]. The major issues facing the Task Force were how to define "difficult asthma", how the patient with difficult asthma should be evaluated, the pathophysiological mechanisms underlying difficult asthma and the treatments available. The Task Force also concerned itself with defining the areas of research necessary to bring about a greater understanding of the causes of difficult asthma and novel treatments. The document resulting from this Task Force represents a consensus of different opinions, which will form the basis for further research.

1999 - Integrin expression on neutrophils and mononuclear cells in blood and induced sputum in stable asthma. [Articolo su rivista]
P., Maestrelli; O., De Fina; T., Bertin; S., Papiris; M. P., Ruggieri; M., Saetta; C. E., Mapp; Fabbri, Leonardo
abstract

BACKGROUND: We speculated that the expression of integrins in the airway lumen of asthmatic subjects might be altered compared with normal subjects during cell recruitment from circulation. METHODS: To test this hypothesis, we investigated the expression of integrin alpha-chains (CD11a, CD11b, and CD11c) in hypertonic saline-induced sputum and peripheral blood leukocytes in mild to moderate stable asthmatic and control subjects. Immunoreactivity for integrin alpha-chains was assessed by immunocytology on cytospin preparations of sputum and blood. RESULTS: In comparison of the percentages of CD11a+, CD11b+ and CD11c+ mononuclear cells in sputum with their blood counterparts, no significant differences were observed in control subjects, whereas CD11a and CD11b in asthmatic subjects were less expressed on sputum cells. In both control and asthmatic subjects, sputum neutrophils tended to decrease their expression of integrin alpha-chains compared with circulating neutrophils. CONCLUSIONS: We showed that the sputum of asthmatics, unlike normal subjects, is characterized by decreased expression of integrins on mononuclear cells compared with their blood counterparts. The results suggest that downregulation of integrins occurs in asthmatic airways after cell recruitment from circulation.

1999 - Mechanisms of occupational asthma. [Articolo su rivista]
C., Mapp; P., Boschetto; D., Miotto; E., De Rosa; Fabbri, Leonardo
abstract

BACKGROUND: The pathogenesis and the pathologic alterations of occupational asthma are similar to those of nonoccupational asthma. Occupational asthma may therefore represent a useful model of "human asthma" to investigate mechanisms and pathophysiology of asthma in general. In an occupational setting the cause and onset of asthma may be easily identified, and the natural history may be examined in follow-up studies. The mechanisms involved in occupational asthma include genetic predisposition, immunologically mediated responses, as well as nonspecific airway inflammation. In particular, high molecular weight (eg, grain dust, flour) and some low molecular weight sensitizers (eg, acid anhydrides and platinum halide salts) have been shown to induce occupational asthma through an immunoglobulin E (IgE)-dependent mechanism, while cell-dependent immunologic mechanisms are likely to be more relevant for occupational asthma induced by other low molecular weight sensitizers (eg, toluene diisocyanate and plicatic acid contained in western red cedar). The pathology of the airway mucosa of occupational asthma is remarkably similar to the pathology of nonoccupational asthma, ie, characterized by infiltration and accumulation of eosinophils, mast cells, and activated lymphocytes along with subepithelial fibrosis. In this article, the most relevant mechanisms are discussed with particular reference to the similarities and discrepancies between occupational and nonoccupational asthma.

1999 - Nociceptin receptor activation inhibits tachykinergic non adrenergic non cholinergic contraction of guinea pig isolated bronchus. [Articolo su rivista]
Rizzi, A; Calò, G; Trevisani, M; Tognetto, M; Fabbri, Leonardo; Mapp, C; Guerrini, R; Salvadori, S; Regoli, D; Geppetti, P.
abstract

We studied the action of nociceptin (NC) on the atropine-resistant contractions of the guinea pig isolated bronchus evoked by the electrical field stimulation (EFS), an effect that is mediated by the activation of excitatory non adrenergic-non cholinergic (eNANC) nerves and the subsequent release of tachykinins. The functional site by which NC acts in this preparation was investigated using few different NC receptor agonists and the newly discovered NC receptor antagonist, [Phe1psi(CH2-NH)Gly2]NC(1-13)NH2 ([F/G]NC(1-13)NH2). NC inhibited in a concentration dependent manner (pEC50 7.14; Em - 87 +/- 3% of control values) EFS induced contractions. NC effect was mimicked by the NC analogues, NCNH2 and NC(1-13)NH2, but not by NC(1-9)NH2. NC (1 microM) did not affect the contractile effects of exogenously applied neurokinin A (1 microM). [F/G]NC(1-13)NH2 (10 microM) completely prevented the inhibition induced by NC (1 microM), whereas naloxone (1 microM) was found inactive. Both naloxone and ([F/G]NC(1-13)NH2 were per se inactive on basal resting tone as well as on the electrically induced contractions. The present findings show that NC inhibits the atropine-resistant EFS-induced contraction in the guinea pig bronchus by inhibiting eNANC nerves, and suggest the presence of NC receptors, distinct from opioid receptors, on the nerves of the guinea pig bronchus.

1999 - The therapy of bronchial asthma [Articolo su rivista]
Fabbri, Leonardo; A., Papi; L., Corbetta; A., Ciaccia
abstract

Asthma (Greek word that means "breathlessness" or "open-mouth breath") is a chronic inflammatory disorder of the airways, with extensive infiltration of the airway lumen and wall with eosinophils, mast cells, activated T-lymphocytes. Airway inflammation is associated with airway hyperresponsiveness, recurrent episodes of reversible airflow limitation and respiratory symptoms such as wheezing, chest tightness, breathlessness and cough with mucus production. Curiously, asthma worsens particularly at night and in the early hours of the morning. The current consensus on asthma therapy suggests that pharmacological control of asthma can be achieved with antiinflammatory "controller" medications such as inhaled glucocorticoids and cromones. Short-acting bronchodilators act as "reliever" medications and rapidly reverse acute manifestations of asthma. Asthmatic exacerbations require the repetitive administration of inhaled short-acting beta-2-agonist and the early introduction of oral glucocorticoids. Rarely the severity of exacerbation requires the administration of oxygen (that, if available, is not contraindicated), intravenous bronchodilators, glucocorticoids and epinephryne and mechanical ventilation.

1998 - Assessment of airway inflammation: an overview. [Articolo su rivista]
Fabbri, Leonardo; S., Durham; S. T., Holgate; P. M., O'Byrne; D. S., Postma
abstract

review

1998 - CD8+ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. [Articolo su rivista]
M., Saetta; A., Di Stefano; G., Turato; F. M., Facchini; L., Corbino; C. E., Mapp; P., Maestrelli; A., Ciaccia; Fabbri, Leonardo
abstract

To investigate whether the inflammatory process in peripheral airways is different in smokers who develop symptoms of chronic bronchitis and chronic airflow limitation and in asymptomatic smokers who do not develop chronic airflow limitation, we examined surgical specimens obtained from 16 smokers undergoing lung resection for localized pulmonary lesions. Nine had symptoms of chronic bronchitis and chronic airflow limitation and seven were asymptomatic with normal lung function. In peripheral airways, immunohistochemical methods were performed to identify neutrophils, macrophages, CD4+ and CD8+ T-lymphocytes infiltrating the airway wall, and morphometric methods were used to measure the internal perimeter, the airway wall area, and the smooth muscle area. The number of CD8+ T-lymphocytes and the smooth muscle area were increased in smokers with symptoms of chronic bronchitis and chronic airflow limitation as compared with asymptomatic smokers with normal lung function, while the number of neutrophils, macrophages, and CD4+ T-lymphocytes were similar in the two groups of subjects examined. We concluded that smokers who develop symptoms of chronic bronchitis and chronic airflow limitation have an increased number of CD8+ T-lymphocytes and an increased smooth muscle area in the peripheral airways as compared with asymptomatic smokers with normal lung function, supporting the important role of CD8+ T-lymphocytes and airway remodeling in the pathogenesis of chronic obstructive pulmonary disease.

1998 - CHRONIC OBSTRUCTIVE PULMOARY DISEASE INTERNATIONAL GUIDELINES [Articolo su rivista]
Fabbri, Leonardo; G., Caramori; Beghe', Bianca; A., Papi; A., Ciaccia
abstract

Although chronic obstructive pulmonary disease (COPD) has a public health importance similar to asthma, it has received less attention. The first guideline on the management of COPD was released in 1987 by the American Thoracic Society. In 1992 the Canadian Thoracic Society released its guidelines. In 1995 the European Respiratory Society and the Thoracic Society of Australia and New Zealand released their guidelines and the American Thoracic Society updated and expand its COPD guidelines. All these documents were followed in 1997 by the guidelines developed by the British Thoracic Society. These COPD guidelines show many similarities but also have some interesting differences. The aim of this paper is to review these similarities and discrepancies. Like all guidelines, COPD guidelines suffer from the limited amount of evidence-based medicine supporting them, a limitation that, however, provides a strong stimulus for further research.

1998 - Detection of xanthine oxidase activity products by EPR and HPLC in bronchoalveolar lavage fluid from patients with chronic obstructive pulmonary disease. [Articolo su rivista]
S., Pinamonti; M., Leis; A., Barbieri; D., Leoni; M., Muzzoli; S., Sostero; M. C., Chicca; A., Carrieri; F., Ravenna; Fabbri, Leonardo; A., Ciaccia
abstract

Xanthine oxidase (xanthine: oxygen oxidoreductase, EC 1.1.3.22), a molybdenum-containing hydroxylase that produces superoxide and uric acid from purine substrates and molecular oxygen, is involved in the oxidative stress underlying several human pathologies including lung diseases. An enzymatic activity similar to xanthine oxidase was previously reported in bronchoalveolar lavage fluid of patients with chronic obstructive pulmonary disease (COPD-BAL), by fluorometric analysis of DNA unwinding and cytochrome c reduction kinetics. Here we report the detection of xanthine oxidase activity products by electron paramagnetic resonance (EPR) in presence of the spin-trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and reversed-phase high-performance liquid chromatography (RP-HPLC) in COPD-BAL (n = 14, average age of patients 65 years, range 38–81) and BAL from healthy nonsmoker controls (n = 6, average age 64 years, range 44–73). Superoxide DMPO adducts were detected in COPD-BAL and in an in vitro system containing xanthine and xanthine oxidase (XA/XO), but not in BAL controls and when superoxide dismutase (SOD, 1000 I.U./ml) was added to COPD-BAL. The HPLC analyses after addition of xanthine showed production of uric acid in COPD-BAL and in the XA/XO system but not in BAL controls. These results support the involvement of xanthine oxidase in the mechanisms of superoxide production by BAL supernatant, which increases oxidative stress in chronic obstructive pulmonary disease.

1998 - Immunization and challenge with toluene diisocyanate decrease tachykinin and calcitonin gene-related peptide immunoreactivity in guinea pig central airways. [Articolo su rivista]
C. E., Mapp; R. E., Lucchini; Miotto, Deborah; P., Chitano; L., Jovine; M., Saetta; P., Maestrelli; D. R., Springall; J., Polak; Fabbri, Leonardo
abstract

Toluene diisocyanate (TDI) is a potent sensitizer that causes occupational asthma in a significant proportion of subjects exposed. We used an animal model to investigate whether neuropeptide changes occur in the airways of immunized and TDI-challenged guinea pigs. Animals were immunized by weekly intradermal injections, challenged with TDI (5 to 20 ppb) after the third injection, and killed 6 h after exposure. Control guinea pigs received injections of saline. Lung tissue was processed immediately and analyzed for nerves using the streptavidin-biotin complex peroxidase method with antisera to the neural marker protein gene product 9.5 (PGP 9.5), substance P (SP), and calcitonin gene- related peptide (CGRP). We also quantified the inflammatory infiltrate in the submucosa of central airways, and we measured the serum level of specific IgG and IgG1. Specific antibodies against TDI were present only in immunized animals. Immunized as compared with nonimmunized animals had a significant increase in eosinophils in the submucosa of central airways, and a further increase was observed 6 h after TDI challenge. Immunization and TDI challenge did not modify the number of mononuclear cells in the submucosa of central airways in both nonimmunized and immunized animals. TDI exposure did not change the overall innervation in both nonimmunized and immunized animals, but the density of PGP 9.5-positive nerves was significantly different between nonimmunized and immunized TDI-challenged animals. The density of SP-, and CGRP-immunostained nerves was significantly lower in immunized TDI-challenged than in nonimmunized animals. TDI exposure significantly decreased the density of SP-positive nerves in nonimmunized animals. A negative relationship was found between the presence of airway inflammation, as indexed by eosinophil cell infiltration, and the density of PGP 9.5-, SP-, and CGRP-immunostained nerves. In conclusion, TDI produces airway inflammation and neuropeptides changes in the central airways of immunized guinea pigs 6 h after TDI challenge. These findings support an interaction between tachykinins, inflammatory (i.e., eosinophils) and possibly immune cells.

1998 - Intrinsic asthma. Lung Biology in Health and Disease. [Capitolo/Saggio]
Fabbri, Leonardo; G., Caramori; Beghe', Bianca; C., Mapp
abstract

z

1998 - Severity of airflow limitation is associated with severity of airway inflammation in smokers. [Articolo su rivista]
A., Di Stefano; A., Capelli; M., Lusuardi; P., Balbo; C., Vecchio; P., Maestrelli; C. E., Mapp; Fabbri, Leonardo; C. F., Donner; M., Saetta
abstract

To investigate the relationship between airflow limitation and airway inflammation in smokers, we examined paraffin-embedded bronchial biopsies obtained from 30 smokers: 10 with severe airflow limitation, eight with mild/moderate airflow limitation, and 12 control smokers with normal lung function. Histochemical and immunohistochemical methods were performed to assess the number of inflammatory cells in the subepithelium and the expression of CC chemokines macrophage inflammatory protein (MIP)-1 and -1 in the bronchial mucosa. Compared with control smokers, smokers with severe airflow limitation had an increased number of neutrophils (p < 0.02), macrophages (p < 0.03), and NK lymphocytes (p < 0.03) in the subepithelium, and an increased number of MIP-1+ epithelial cells (p < 0.02). When all smokers were considered together, the value of FEV1 was inversely correlated with the number of neutrophils (r = 0.59, p < 0.002), macrophages (r = 047, p < 0.012), NK-lymphocytes (r = 0.51, p < 0.006) in the subepithelium, and with the number of MIP-1+ epithelial cells (r = 0.61, p < 0.003). We conclude that in smokers the severity of airflow limitation is correlated with the severity of airway inflammation and that severe airflow limitation is associated with an increased number of neutrophils, macrophages, NK lymphocytes, and MIP-1+ cells in the bronchial mucosa.

1998 - Similarities and discrepancies between exacerbations of asthma and chronic obstructive pulmonary disease. [Articolo su rivista]
Fabbri, Leonardo; Beghe', Bianca; G., Caramori; A., Papi; M., Saetta
abstract

Asthma is a chronic inflammatory disorder ofthe airways which causes recurrent episodes ofwheezing, breathlessness, chest tightness, andcough, symptoms which are usually associatedwith reversible airflow limitation.1 2 This definitionincludes the recurrence of respiratorysymptoms which might be otherwise classifiedas asthma exacerbations. However, the termasthma exacerbation is usually reserved formore severe and/or more persistent respiratorysymptoms requiring a prolonged increase ofcurrent antiasthma medication.1 2 Chronic obstructivepulmonary disease (COPD) is definedas a progressive airflow limitation, mostlyirreversible.3 4 The term COPD includes patientswith obstructive chronic bronchitisand/or pulmonary emphysema.3 4 Patients withmoderate or severe persistent asthma may alsohave an irreversible component of airflow limitation,and thus they may also be included inthe definition of COPD.3 The definition ofCOPD does not include exacerbations,3–5 evenif exacerbations are the main cause of medicalintervention and admission to hospital in thesepatients.

1998 - What can we learn from late-onset and occupational asthma? [Relazione in Atti di Convegno]
A., Papi; L., Corbetta; Fabbri, Leonardo
abstract

Late-onset asthma and occupational asthma may provide interesting models of human asthma to compare with the most frequent type of atopic early-onset asthma. The discovery of similarities and discrepancies in the aetiology and pathogenesis of these different diseases might provide new insights on different mechanisms producing the same phenotype and, thus, by recognizing the different underlying mechanisms of the different forms of asthma, may allow better targeting of prevention and treatment. Occupational asthma, in addition to being a late-onset asthma, provides the unique opportunity to study the development of asthma under measurable exposure conditions, and consequently to examine the effect of cessation of exposure which, at variance with allergen avoidance, is possible in most of the cases.

1997 - Beta 2 agonists prevent Th1 development by selective inhibition of IL-12 [Articolo su rivista]
P., Panina Bordignon; D., Mazzeo; P., Di Lucia; Dd, D'Ambrosio; R., Lang; Fabbri, Leonardo; C., Self; F., Sinigaglia
abstract

Interleukin 12 (IL-12) plays a central role in the immune system by skewing the immune response towards T helper 1 (Th1) type responses which are characterized by high interferon-gamma and low IL-4 production. In this report we present evidence that beta2-agonists inhibit IL-12 production by both human monocytes in response to lipopolysaccharide (LPS) and dendritic cells stimulated via CD40. Inhibition of IL-12 production is selective, as other cytokines produced by monocytes are unaffected. IL-12 inhibition is dependent on beta2-adrenoceptor stimulation and correlates with increased levels of intracellular cAMP. In conjunction with their ability to suppress IL-12 production, when beta2-agonists are added at priming of neonatal T lymphocytes, they inhibit the development of Th1-type cells, while promoting T helper 2 (Th2) cell differentiation. Further, the in vivo administration of a therapeutic dose of salbutamol results in the selective inhibition of IL-12 production by whole blood lymphocytes stimulated in vitro with LPS. These findings provide new insight into the immunological consequences of the clinical use of beta2-agonists and may suggest new approaches for the treatment of Th1-mediated diseases.

1997 - CD4-positive T-lymphocytes infiltrate the bronchial mucosa of patients with Sjögren's syndrome. [Articolo su rivista]
S. A., Papiris; M., Saetta; G., Turato; R., La Corte; L., Trevisani; C. E., Mapp; P., Maestrelli; Fabbri, Leonardo; A., Potena
abstract

To investigate the degree and the type of inflammation in the bronchial mucosa in patients with Sjögren's syndrome, we examined lobar bronchial biopsies obtained from 10 patients with Sjögren's syndrome (six with primary and four with secondary) and eight control subjects. Histochemistry with hematoxylin-eosin was performed both to identify the number of mononuclear cells and eosinophils and to measure the thickness of the basement membrane. Immunohistochemistry was performed to identify neutrophils (neutrophil-elastase), macrophages (CD68), and T-lymphocyte subpopulations (CD4 and CD8) in the submucosa. Subjects with Sjögren's syndrome presented a greater number of CD4-positive T-lymphocytes than did the normal control subjects (p = 0.0129). Instead, eosinophils, neutrophils, macrophages, CD8 positive T-lymphocytes, and basement membrane thickness were similar in the two groups. There were no differences in cell counts between patients with primary and those with secondary Sjögren's syndrome and between symptomatic and asymptomatic patients. No correlation was found between cell counts, symptoms, lung volumes, and disease duration. This study has shown that patients with Sjögren's syndrome have an increased number of CD4 positive T-lymphocytes in the bronchial mucosa outside of the bronchial glands, supporting the concept that, in the airways, Sjögren's syndrome involves also extraglandular tissues.

1997 - Diagnostic basis of occupational asthma. [Articolo su rivista]
P., Maestrelli; M., Saetta; C., Mapp; Fabbri, Leonardo
abstract

review

1997 - Expression of interleukin (IL)-4 and IL-5 proteins in asthma induced by toluene diisocyanate (TDI). [Articolo su rivista]
P., Maestrelli; P., Occari; G., Turato; S. A., Papiris; A., Di Stefano; C. E., Mapp; G. F., Milani; Fabbri, Leonardo; M., Saetta
abstract

BACKGROUND: TDI-induced asthma exhibits clinical, functional and morphological similarities with allergen-induced asthma, suggesting that an immunological mechanism is involved in the sensitization to TDI. In vitro studies using the technique of cloning lymphocytes demonstrated that a great proportion of T-cell clones derived from bronchial mucosa of subjects with TDI-induced asthma produced IL-5 and interferon-gamma, but not IL-4, upon in vitro stimulation. OBJECTIVES: To investigate in vivo the role of IL-4 and IL-5 on the inflammatory response of the bronchial mucosa to TDI in sensitized subjects, we performed a quantitative analysis of bronchial biopsies. METHODS: We obtained bronchial biopsies from six subjects with TDI asthma 48 h after an asthmatic reaction induced by TDI challenge (challenged group), in six subjects with TDI asthma 1-4 weeks after the last exposure to TDI (chronic group), and in six non-asthmatic controls. The number of eosinophils, mast cells, T-lymphocytes, and IL-4 and IL-5 protein positive cells was determined by immunohistochemistry in the area 100 microm beneath the epithelial basement membrane. RESULTS: The characteristic increase of submucosal eosinophils, but not of mast cells and T-lymphocytes, was observed in the subjects with TDI-induced asthma when compared with controls. No differences were detected between the two groups of asthmatics. In the subjects with TDI-induced asthma, cell immunoreactivity for IL-5 was increased when compared with normal controls. There was no difference in the expression of IL-5 protein between challenged and chronic asthmatics. In contrast, the expression of IL-4 protein was increased only in the asthmatic subjects tested after recent exposure to TDI. CONCLUSIONS: We demonstrated that TDI asthma 48 h after specific bronchial challenge was associated with increased numbers of cells expressing IL-4 and IL-5, whereas chronic TDI asthma was associated with increased expression of IL-5, but not of IL-4. The results suggest that subjects who developed TDI asthma exhibit increased production of IL-5 even in the absence of a recent trigger by the exogenous sensitizer and that production of TH2-like cytokines in TDI-induced asthma may not always be co-ordinately regulated in vivo.

1997 - Human leukocyte antigen associations in occupational asthma induced by isocyanates. [Articolo su rivista]
C. E., Mapp; A., Balboni; R., Baricordi; Fabbri, Leonardo
abstract

Exposure to diisocyanates is recognized as a leading cause of occupational asthma. Occupational asthma induced by isocyanates shares many characteristics with immunoglobulin E (IgE)-mediated asthma: in both, the responsible agent is known, and the clinical presentation, response to inhalation challenge in the laboratory, and response to antiasthma drugs are similar. Although asthma mediated by an IgE mechanism occurs in atopic subjects, occupational asthma induced by isocyanates occurs mostly in nonatopic asthmatics, and an IgE-mediated mechanism has not been consistently demonstrated. However, activated T lymphocytes, methacromatic cells, and eosinophils are increased in the bronchial mucosa of allergic and nonallergic asthmatics and subjects with occupational asthma induced by isocyanates, suggesting similar, probably immunologically mediated mechanisms for both nonoccupational and occupational asthma. Occupational asthma occurs in up to 5-10% of the exposed subjects. Evaluation of major histocompatibility complex (MHC) class II genes in exposed subjects who develop toluene diisocyanate (TDI) asthma has shown a negative association with HLA-DQB1*0501 and a positive association with HLA-DQB1*0503 alleles. In addition, a high proportion of TDI asthmatics express the HLA-DQB1*0503-associated aspartic acid at residue 57, suggesting that HLA-DQ may have a key role in conferring susceptibility. Thus, asthma induced by the low-molecular-weight agent TDI may result from an immunologic reaction due to the interaction of genetic susceptibility with exposure in the workplace. Mapp CE, Balboni A, Baricordi R, Fabbri LM. Human leukocyte antigen associations in occupational asthma induced by isocyanates.

1997 - Il futuro nella terpia dell'asma [Capitolo/Saggio]
Beghe', Bianca; G., Caramori; A., Ciaccia; Fabbri, Leonardo
abstract

L'asma (parola greca che significa "senza respiro" o respiro a bocca aperta") è una malattia infiammatoria cronica delle vie aeree, specificamente caratterizzata da infiltrazione di eosinofili, mastociti e linfociti T attivati e da fibrosi subepiteliale della mucosa tracheobronchiale. Tali alterazioni anatomopatologiche costituiscono il substrato dell'iperresponsività bronchiale e dei ricorrenti episodi di ostruzione del reversibile flusso aereo.La dimostrazione che l'asma non è solo l'espressione di ricorrenti crisi di broncospasmo ma è, anche in fase quiescente, una malattia infiammatoria cronica delle vie aeree, ha imposto un cambiamento radicale all'approccio terapeutico. La moderna terapia antiasmatica a lungo termine consiste di un prolungato trattamento di fondo con glucocorticoidi per via inalatoria o, in alcuni casi, con cromoni per via inalatoria, e di un trattamento sintomatico con farmaci broncodilatatori per via inalatoria, in particolare i beta2 agonisti, prescritti solo per rimuovere i sintomi o per prevenire riacutizzazioni asmatiche causate da stimoli noti quali l'attività fisica.

1997 - Increased VIP-positive nerve fibers in the mucous glands of subjects with chronic bronchitis. [Articolo su rivista]
R. E., Lucchini; F., Facchini; G., Turato; M., Saetta; G., Caramori; A., Ciaccia; P., Maestrelli; D. R., Springall; J. M., Polak; Fabbri, Leonardo; C. E., Mapp
abstract

The presence and distribution of neuropeptide-containing nerves within bronchial surgical specimens has been investigated in bronchitic (n = 12) and in nonbronchitic subjects (n = 7). Lung tissue, obtained from patients undergoing thoracotomy for limited lung lesions, was processed immediately and analyzed for nerves using the streptavidin-biotin complex peroxidase method with antisera to the neural marker protein gene product 9.5 (PGP 9.5) and the neuropeptides vasoactive intestinal peptide (VIP), substance P (SP), calcitonin-gene related peptide (CGRP). There were no significant differences between the two groups with respect to the density of PGP 9.5-, SP-, or CGRP-positive nerves in both the locations assessed (smooth muscle layer and glands). The density of VIP-positive nerves was significantly higher in the glands of bronchitic than in nonbronchitic subjects. A negative relationship was found between the presence of airway inflammation, as indexed by mononuclear cell tissue infiltration, and the density of PGP 9.5-positive nerves in both smooth muscle and glands. Likewise, a relationship was found between the smoking history (packs/yr and age of onset of smoking) and the density of VIP-positive nerves in glands. These findings support a role for VIP in the hallmark of chronic bronchitis, i.e., sputum production.

1997 - Inflammatory cells in the bronchial glands of smokers with chronic bronchitis. [Articolo su rivista]
M., Saetta; G., Turato; F. M., Facchini; L., Corbino; R. E., Lucchini; G., Casoni; P., Maestrelli; C. E., Mapp; A., Ciaccia; Fabbri, Leonardo
abstract

To characterize the inflammatory process in the bronchial glands of smokers with chronic sputum production, we examined lobar bronchi from 18 subjects undergoing lung resection for localized pulmonary lesions, all with a history of cigarette smoking. Nine of the subjects had symptoms of chronic bronchitis and chronic airflow obstruction, and nine were asymptomatic, with normal lung function. The number of neutrophils, eosinophils, mast cells, macrophages, CD4+ and CD8+ T-lymphocytes, and the ratio of CD4+ to CD8+ cells were assessed in the bronchial glands, epithelium, and submucosa. Cells were identified through immunohistochemistry. Smokers with symptoms of chronic bronchitis had an increased number of neutrophils (p = 0.01) and macrophages (p = 0.03) and a decreased CD4+/CD8+ ratio (p = 0.01) in the bronchial glands as compared with asymptomatic smokers. Chronic bronchitic smokers also had an increased number of epithelial neutrophils (p = 0.04), whereas the numbers of macrophages and CD4+ and CD8+ T-lympohcytes in the epithelium and submucosa were similar in the two groups of smokers. No differences in numbers of eosinophils or mast cells were observed between bronchitic and asymptomatic smokers in any of the compartments examined. In conclusion, smokers with chronic sputum production have an increased infiltration of neutrophils and macrophages and an increased proportion of CD8+ T-lymphocytes in their bronchial glands, supporting the important role of bronchial-gland inflammation in the pathogenesis of chronic bronchitis.

1997 - Ipertensione polmonare cronica nell’adulto [Articolo su rivista]
Fabbri, Leonardo; Casoni, Gl; Caramori, G; Ciaccia, A.
abstract

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1997 - Mechanisms of damage in COPD. [Relazione in Atti di Convegno]
M., Saetta; G., Turato; L., Corbino; M. P., Ruggieri; M., Pieno; C. E., Mapp; P., Maestrelli; A., Ciaccia; Fabbri, Leonardo
abstract

review

1997 - Mechanisms of occupational asthma [Articolo su rivista]
P., Maestrelli; M., Saetta; C., Mapp; Fabbri, Leonardo
abstract

review

1997 - Pulmonary vasculitis: classification, clinical features, and management. [Articolo su rivista]
Ciaccia, A; Ferrari, M; Facchini, Fm; Caramori, G; Fabbri, Leonardo
abstract

non disponibile

1997 - Subcutaneous emphysema of the chest wall: a case with unusual presentation. [Articolo su rivista]
A., Fugagnoli; M. L., Castelletti; G., Caramori; M., Romagnoli; Fabbri, Leonardo; A., Ciaccia
abstract

Subcutaneous emphysema (SE) is the presence of air or other gas in the subcutaneous tissue and is generally associated with pneumothorax and/or pneumomediastinum. We describe an unusual presentation of SE of the chest wall without radiological evidence of pneumothorax or pneumomediastinum, which aetiopathogenesis remains open to several hypotheses in spite of an accurate clinical study.

1997 - The rationale for a new approach in asthma treatment [Relazione in Atti di Convegno]
Fabbri, Leonardo; Sterk, Pj
abstract

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1996 - Airflow limitation in chronic bronchitis is associated with T-lymphocyte and macrophage infiltration of the bronchial mucosa [Articolo su rivista]
M., Saetta; A., Di Stefano; G., Turato; P., Maestrelli; Ce, Mapp; Mp, Ruggieri; A., Roggeri; P., Boschetto; Fabbri, Leonardo
abstract

To investigate whether the airway inflammatory process is different in patients with chronic bronchitis with airflow limitation and those with chronic bronchitis without airflow limitation, we obtained bronchial biopsies from 14 subjects with chronic sputum production and fixed airway obstruction, and from 10 subjects with chronic sputum production and normal FEV1, all with a history of cigarette smoking. Paraffin-embedded and frozen bronchial biopsies were examined by immunohistochemistry to identify the number of neutrophils (neutrophil-elastase), eosinophils (antieosinophil cationic protein [EG-2]), mast cells (tryptase), T-lymphocytes (CD3), T-lymphocyte subpopulations (CD4 and CD8), B-lymphocytes, and macrophages (CD68) in the submucosa. Subjects with chronic bronchitis with airflow limitation had a greater number of T-lymphocytes (p < 0.01) and macrophages (p < 0.05) than subjects with chronic bronchitis without airflow limitation, whereas the T-lymphocyte subpopulations and the numbers of B-lymphocytes, neutrophils, eosinophils, and mast cells were similar in the two groups. When all the subjects were considered together, the number of T-lymphocytes correlated inversely with the values of FEV1 (r = 0.46, p < 0.02). In conclusion, airflow limitation in subjects with chronic bronchitis is associated with an increased number of T-lymphocytes and macrophages in the bronchial mucosa.

1996 - Airway eosinophilia and expression of interleukin-5 protein in asthma and in exacerbations of chronic bronchitis. [Articolo su rivista]
M., Saetta; A., Di Stefano; P., Maestrelli; G., Turato; C. E., Mapp; M., Pieno; G., Zanguochi; G., Del Prete; Fabbri, Leonardo
abstract

BACKGROUND: An increased number of eosinophils in the bronchial mucosa has been demonstrated both in asthma and in exacerbations of chronic bronchitis. OBJECTIVE: To investigate whether the airway eosinophilia present in asthma and in chronic bronchitis during exacerbations is associated with interleukin (IL)-5 protein expression in the bronchial mucosa. METHODS: We obtained bronchial biopsies in 18 subjects with asthma (four intrinsic, seven extrinsic and seven occupational) and in 11 subjects with chronic bronchitis examined during an exacerbation. The findings were compared with those of bronchial biopsies from 10 subjects with chronic bronchitis examined under baseline conditions and from seven normal subjects, taken as controls. By immunohistochemistry, we assessed the expression of IL-5 protein and the number of eosinophils (EG2), mast cells (tryptase), and T-lymphocytes (CD3) in the submucosa. RESULTS: As compared with controls, the number of eosinophils was increased to a similar degree in both asthma (P < 0.001) and in exacerbations of chronic bronchitis (P < 0.001), whereas the number of IL-5 immunopositive cells was increased significantly only in asthma (P < 0.01). No differences were observed in the number of mast cells and T-lymphocytes between the four groups of subjects examined. CONCLUSIONS: This study shows that the degree of airway eosinophilia is similar in asthma and in exacerbations of chronic bronchitis, but only in asthma is it associated with an increased expression of IL-5 protein in the bronchial mucosa.

1996 - Airways obstruction, chronic expectoration, and rapid decline of FEV1 in smokers are associated with increased levels of sputum neutrophils. [Articolo su rivista]
D., Stănescu; A., Sanna; C., Veriter; S., Kostianev; P. G., Calcagni; Fabbri, Leonardo; P., Maestrelli
abstract

BACKGROUND: Smoking may cause inflammation of the airways and impairment of lung function. To determine the relationship between the type and degree of airways inflammation and the decline in lung function, leucocytes in the sputum of smokers and ex-smokers were examined. METHODS: Forty six smokers and ex-smokers of median age 64 years (25%; 75% percentiles 62;66) with a smoking history of 40.1 (31.7;53) pack years were studied with lung function tests and a questionnaire at the end of a 15 year follow up period. Sputum was induced by inhalation of hypertonic saline and differential leucocyte counts were performed on cytospin preparations. RESULTS: Adequate sputum samples were obtained in 38 subjects (78%). The ratio of forced expiratory volume in one second (FEV1) to vital capacity (VC) was 67.1 (60; 72)% and the annual decline in FEV1 was 19.4 (12;30) ml/year. Subjects with airways obstruction (FEV1/VC < 63%) had more neutrophils (77 (50;86)%) than those without airways obstruction (60 (43;73)%). The percentage of neutrophils was also significantly greater (77 (62;85)%) in those with chronic expectoration than in those without expectoration (57 (45;75)%. Increased levels of neutrophils in the sputum were correlated with a rapid decline in FEV1 over the 15 year follow up period. CONCLUSIONS: Airways obstruction and chronic expectoration, as well as accelerated decline in lung function, are associated with increased numbers of neutrophils in the sputum of smokers and ex-smokers which suggests that neutrophilic inflammation of the airways may be involved in the pathogenesis of chronic obstructive pulmonary disease.

1996 - Association between toluene diisocyanate-induced asthma and DQB1 markers: a possible role for aspartic acid at position 57. [Articolo su rivista]
A., Balboni; O. R., Baricordi; Fabbri, Leonardo; E., Gandini; A., Ciaccia; C. E., Mapp
abstract

Toluene diisocyanate (TDI) is the most common cause of occupational asthma in western countries. The aim of this study was to investigate whether genetic factors are involved in toluene diisocyanate-induced asthma. We studied the frequency of human leucocyte antigen (HLA) class II genetic markers in three groups of subjects: 1) subjects with TDI-induced asthma (n=30); 2) exposed subjects with no history of TDI-induced asthma (n=12); and 3) normal subjects not exposed to TDI (n=126). Venous blood samples were collected from the three groups and the polymorphic second exon of DQA and DQB genes was amplified by the polymerase chain reaction (PCR) method. Evaluation of HLA class II gene products in TDI-induced asthma cases showed a positive association with HLA-DQB1*0503 and a negative association with HLADQB1* 0501 alleles, which differed at residue 57 for a single amino acid, i.e. aspartic acid in DQB1*0503 and valine in DQB1*0501. No significant difference was found in the distribution of DQA1 alleles between asthmatics and controls. Our results confirm the hypothesis that HLA-DQB1*0503 has a role in conferring susceptibility to TDI-induced asthma and that residue 57 of HLA-DQB1 is a potentially critical location.

1996 - Broncodilatatori nella terapia delle broncopneumopatie croniche ostruttive [Articolo su rivista]
Fabbri, Leonardo; Ferrari, M; Caramori, G; Ciaccia, A.
abstract

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1996 - Controlled-release theophylline inhibits early morning airway obstruction and hyperresponsiveness in asthmatic subjects. [Articolo su rivista]
S., Crescioli; A., Dal Carobbo; P., Maestrelli; P., Boschetto; T., Santagada; V. W., Steinijans; T. S., Hurst; G., Parise; Fabbri, Leonardo
abstract

BACKGROUND: Nocturnal asthma reflects the severity of the disease, and thus its pharmacologic prevention represents one on the main goals of asthma management. SUBJECTS AND METHODS: To determine whether controlled-release theophylline inhibits the development of airway obstruction and/or airway hyperresponsiveness early in the morning, we examined 18 subjects reporting recurrent nocturnal asthma. In each subject, after five days' treatment with an 8 PM increasing dose of oral controlled-release theophylline, up to 10 +/- 1 mg/kg or placebo the night before the study day, we measured serum theophylline, FEV1 and PC20FEV1 at 6 AM, 2 PM and 10 PM. RESULTS: At 6 AM, both FEV1 and PC20FEV1 were significantly higher on theophylline than on placebo (3.52 +/- 0.22 versus 3.17 +/- 0.25 L; P < .005 and 2.76 divided by 3.61 versus 1.55 divided by 3.73 mg/mL; P < .05, respectively). At 2 PM and 10 PM FEV1, but not PC20FEV1, was higher on theophylline than on placebo (3.73 +/- 0.21 versus 3.54 +/- 0.25 L; P < .05 and 3.40 +/- 0.22 versus 3.24 +/- 0.24 L; P < .05). Serum theophylline was 12.8 +/- 1.1 micrograms/ml, 8.9 +/- 0.77 and 9.5 +/- 0.85 at 6 AM, 2 PM and 10 PM, respectively. CONCLUSIONS: We conclude that an evening dose of controlled-release theophyl line inhibits early morning airway obstruction and hyperresponsiveness, and that it may be helpful in the prevention of nocturnal asthma.

1996 - Effect of subchronic in vivo exposure to nitrogen dioxide on lung tissue inflammation, airway microvascular leakage, and in vitro bronchial muscle responsiveness in rats. [Articolo su rivista]
P., Chitano; V., Rado; A., Di Stefano; A., Papi; A., Boniotti; G., Zancuoghi; P., Boschetto; M., Romano; M., Salmona; A., Ciaccia; Fabbri, Leonardo; C. E., Mapp
abstract

OBJECTIVES: In a previous study on bronchoalveolar lavage fluid from rats exposed in vivo for seven days to 10 ppm nitrogen dioxide (NO2), it has been shown that there is an influx of macrophages into the airways. The present study investigated the effect of seven day exposure to 10 ppm NO2, on: (a) lung tissue inflammation and morphology; (b) airway microvascular leakage; (c) in vitro contractile response of main bronchi. METHODS: Lung tissue was studied by light microscopy, after fixing the lungs by inflation with 4% formalin at a pressure of 20 cm H2O. Microvascular leakage was measured by extravasation of Evans blue dye in the larynx, trachea, main bronchi, and intrapulmonary airways. Smooth muscle responsiveness was evaluated by concentration-responses curves to acetylcholine (10(-9)-10(-3) M), serotonin (10(-9)-10(-4) M), and voltage-response curves (12-28 V) to electrical field stimulation. RESULTS: Histology showed an increased total inflammation at the level of respiratory bronchioles and alveoli. No influx of inflammatory cells was found in the main bronchi. A loss of cilia in the epithelium of small airways and ectasia of alveolar capillaries was also found. By contrast, no alterations to microvascular permeability or modification of bronchial smooth muscle responsiveness was found. CONCLUSIONS: Subchronic exposure to 10 ppm NO2 causes airway inflammation and structural damage, but does not cause any persistent alteration to microvascular permeability or bronchial smooth muscle responsiveness in rats.

1996 - Glucocorticoidi per via inalatoria nel trattamento della patologia polmonare dell’adulto. [Articolo su rivista]
Fabbri, Leonardo; Caramori, G; Ciaccia, A.
abstract

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1996 - In vivo exposure to nitrogen dioxide (NO2) induces a decrease in calcitonin gene-related peptide (CGRP) and tachykinin immunoreactivity in guinea-pig peripheral airways. [Articolo su rivista]
R. E., Lucchini; D. R., Springall; P., Chitano; Fabbri, Leonardo; J. M., Polak; C. E., Mapp
abstract

The mammalian respiratory tract is densely innervated by sensory and autonomic fibres. Subsets of the nerves contain bioactive regulatory peptides, such as substance P, calcitonin gene-related peptide (CGRP), and neurokinins. The sensory nervous system responds to inhaled irritants, resulting in a release of neuropeptides and, thus, a decrease in the peptide immunoreactivity of the fibres. We examined the effects of inhaled nitrogen dioxide (NO2), a well-known indoor and outdoor air pollutant, on pulmonary sensory neuropeptides. Guinea-pigs were exposed for 4 h to 18 parts per million (ppm) NO2 or to air (n=5 each). At the end of the exposure, they were killed with urethane and their lungs were fixed in 1% paraformaldehyde in phosphate-buffered saline. Cryostat sections were stained with antisera to an anatomical nerve marker, protein gene product (PGP) 9.5, and to CGRP and tachykinins, utilizing the avidin-biotinylated peroxidase method. In the noncartilaginous airways (diameter <250 µm) of NO2-exposed animals, less tachykinin- and CGRP-immunoreactive nerve fibres were found compared with controls. No change was seen in the total nerve fibre distribution (PGP 9.5). It is concluded that the peptidergic nerves of guinea-pig peripheral airways are a sensitive indicator of exposure to nitrogen dioxide.

1996 - Inflammatory events in the blood and airways of guinea pigs immunized to toluene diisocyanate. [Articolo su rivista]
C. E., Mapp; J. R., Lapa; R. E., Lucchini; P., Chitano; V., Rado; M., Saetta; M., Pretolani; M. H., Karol; P., Maestrelli; Fabbri, Leonardo
abstract

Toluene diisocyanate (TDI)-induced asthma is a common cause of occupational lung disease. We used a model to investigate the course of bronchopulmonary inflammation following immunization with TDI. Guinea pigs were immunized by weekly intradermal injections and challenged with TDI 7 d after the third injection. The animals were killed at different times after challenge and prepared for histologic examination of central and peripheral airways, for immunohistochemical studies of T lymphocyte and eosinophil distribution, and for hematologic and serologic investigations. Specific IgG1 against TDI were present only in immunized animals. In immunized TDI-challenged animals there was a significant increase in the number of metachromatic cells (at 24 h) and a late increase of eosinophils (at 48 h) in the peripheral blood. Mast cells and eosinophils were also increased in the submucosa of central airways of immunized TDI-challenged animals. A similar pattern was observed in the animals' peripheral airways. Additionally, a significant increase of T-lymphocytes and eosinophils was found in the lamina propria at 6 h after exposure in immunized TDI-challenged animals as compared with control animals. In these immunized animals, TDI challenge caused a significant increase of eosinophils, T-lymphocytes, and CD4+ T cells. These findings indicate that intradermal injections of TDI induced a specific antibody response as well as an inflammatory process in both central and peripheral airways. T cells, particularly CD4+ T cells and eosinophils, are the key cells in the immunopathologic alterations induced by TDI in the guinea pig lung.

1996 - Integrin upregulation on sputum neutrophils in smokers with chronic airway obstruction. [Articolo su rivista]
P., Maestrelli; P. G., Calcagni; M., Saetta; T., Bertin; C. E., Mapp; A., Sanna; C., Veriter; Fabbri, Leonardo; D., Stanescu
abstract

To determine the relationship between the expression of leukocyte- specific integrins in the airways and the airway obstruction in smokers, we analyzed hypertonic saline-induced sputum in 33 male subjects, age 64.7 +/- 0.5 yr (mean +/- SEM), with a smoking history of 12 to 94 pack-years, at the end of a 15-yr follow-up study. Average FEV1/VC ratio was 69 +/- 1% at the beginning of the study and 66 +/- 2% at the end of the follow-up period, and annual decline of FEV1 was 20 +/- 3 ml/yr. Fourteen individuals exhibited airway obstruction as assessed by a FEV1/VC ratio lower than 63.3%. Differential leukocyte count was performed on cytospin preparations and the expression of integrin alpha (CD11a, CD11b, CD11c) and beta (CD18) chains was assessed on granulocytes and mononuclear cells by immunocytology. The numbers of neutrophils expressing CD11b and CD18, but not CD11c or CD11a, were increased in the subjects with airway obstruction compared with those without airway obstruction. CD11b- and CD18-positive neutrophils were negatively correlated with FEV1/VC ratio (p < 0.01). No significant correlations were found between CD11a-, CD11b-, CD11c-, CD18-positive mononuclear cells and lung function measurements. In conclusion, our results suggest that leukocyte-specific integrin CD11b/CD18 expressed on sputum polymorphonuclear leukocytes represents a marker for the smokers who develop chronic airway obstruction.

1996 - Is occupational asthma a relevant model? [Articolo su rivista]
Fabbri, Leonardo
abstract

review

1996 - Isotonic smooth muscle response in human bronchi exposed in vitro to nitrogen dioxide. [Articolo su rivista]
P., Chitano; R. E., Lucchini; F., Calabrò; M., Saetta; P., Maestrelli; Fabbri, Leonardo; C. E., Mapp
abstract

Exposure to nitrogen dioxide (NO2), a common oxidant airborne pollutant, has been shown to cause reversible effects on lung function and airway responsiveness, in addition to airways inflammation. However, there have been conflicting reports concerning NO2-induced airway hyperresponsiveness. In the present study, we investigated the isotonic smooth muscle response in isolated human bronchi previously exposed in vitro to NO2. Bronchial segments were obtained from 12 patients who had undergone thoracotomy for lung cancer. Bronchial segments from each patient were exposed to air and to 2.5 parts per million (ppm) NO2 for 4 h. The contractile response of bronchial rings to acetylcholine, neurokinin A (NKA), and substance P was then studied under isotonic conditions. The response to NKA was also studied in rings, with or without epithelium, exposed either to air or 7 ppm NO2. No NO2-induced alteration of the bronchial smooth muscle isotonic response was found under any of the experimental conditions. We conclude that in vitro exposure to up to 7 ppm nitrogen dioxide does not cause alterations of the human bronchial smooth muscle shortening capacity.

1996 - La scoperta dell’ossido nitrico endogeno ha aperto nuove prospettive terapeutiche nella patologia polmonare dell’adulto? [Articolo su rivista]
Fabbri, Leonardo; Cremona, G; Caramori, G; Piattella, M; Romagnoli, M; Beghe', Bianca; Panella, Gl; Ciaccia, A.
abstract

n/d

1996 - Methotrexate in the treatment of systemic glucocorticoid-dependent severe persistent asthma: a word of caution. [Articolo su rivista]
Fabbri, Leonardo; Caramori, G; Cosma, P; Ciaccia, A.
abstract

Methotrexate should not be prescribed to every systemic glucocorticoid-dependent asthmatic. In fact, while methotrexate may be advantageous in selected patients, every attempt to control asthma with regular anti-asthma agents should be made. Most studies on the effects of methotrexate in the treatment of systemic glucocorticoid-dependent asthmatics include small numbers of patients and are all of relatively short duration. Thus, large long-term multicentre trials are urgently needed. In these studies, a uniform accepted definition of systemic glucocorticoid-dependent asthmatics should be used. For the time being, we reinforce the recommendation of the NHLBI/ WHO panel that methotrexate and other systemic glucocorticoid sparing drugs should be considered experimental medications, and used only in selected patients under the supervision of an asthma specialist with previous experimental experience.

1996 - Oral vs inhaled asthma therapy. Pros, cons and combinations. [Articolo su rivista]
Fabbri, Leonardo; M., Piattella; G., Caramori; A., Ciaccia
abstract

A number of oral and inhaled drugs are available for the long term management of patients with persistent asthma, yet the disease continues to be associated with significant morbidity and mortality. Over the past years, inhaled glucocorticoids have become established as a cornerstone of maintenance therapy because of their demonstrated clinical efficacy, ability to reduce bronchial inflammation and good tolerability. Other inhaled drugs (e.g. sodium cromoglycate, nedocromil, long-acting beta 2 agonists) also play a role in the long term treatment of patients with asthma. However, many patients (especially children and the elderly) find inhalers difficult to use, and poor inhalation technique can affect the amount of drug reaching the lungs and response to therapy. Oral drug administration is simple, but, until recently, oral asthma therapy has primarily consisted of sustained-release theophylline and glucocorticoids. Theophylline has a narrow therapeutic index, necessitating regular monitoring of serum drug concentrations, and long term oral glucocorticoid therapy is associated with potentially serious adverse events including osteoporosis with bone fracture. The recent development of orally administered leukotriene receptor antagonists (e.g. zafirlukast) and 5-lipoxygenase inhibitors (e.g. zileuton) offers novel mechanisms of action and potential solutions to compliance issues associated with regular administration of inhaled asthma therapy. These drugs have demonstrated efficacy as maintenance therapy in patients with asthma and, importantly, lack the adverse effects associated with long term systemic glucocorticoid therapy. Further clinical trials and the increasing use of these new therapies will help to establish the precise role of orally administered leukotriene receptor antagonists and 5-lipoxygenase inhibitors in the long term management of patients with asthma.

1996 - Role of leukotrienes in asthma pathogenesis. [Articolo su rivista]
Fabbri, Leonardo; G., Caramori; Beghe', Bianca; A., Ciaccia
abstract

Leukotrienes, products of the 5-lipoxygenase pathway of arachidonic acid, are pro-inflammatory mediators with various biological activities, including mechanisms relevant to the pathogenesis of bronchoobturation in bronchial asthma. This article reviews the evidence on their role in the pathophysiology of asthma as well as on the efficacy of recently developed antileukotriene agents.

1996 - Ruolo dei farmaci beta2-agonisti inalatori nel trattamento dell’asma bronchiale e delle broncopneumopatie croniche ostruttive [Articolo su rivista]
Fabbri, Leonardo; Caramori, G; Ciaccia, A.
abstract

n/d

1996 - Sindrome epatopolmonare [Articolo su rivista]
Fabbri, Leonardo; Ricci, G; Fugagnoli, A; Caramori, G; Alvisi, V; Ciaccia, A.
abstract

n/d

1996 - Xanthine oxidase activity in bronchoalveolar lavage fluid from patients with chronic obstructive pulmonary disease. [Articolo su rivista]
S., Pinamonti; M., Muzzoli; M. C., Chicca; A., Papi; F., Ravenna; Fabbri, Leonardo; A., Ciaccia
abstract

Chronic obstructive pulmonary disease (COPD) is a serious respiratory pathology characterized by irreversible limitation of expiratory flow and includes chronic obstructive bronchitis, chronic airflow limitation, and emphysema. To determine whether xanthine oxidase activity increased in the airspaces of COPD patients, we examined bronchoalveolar lavage fluid (BAL) from COPD patients recruited during a 2-year clinical study. Filtered BAL supernatant from COPD patients and healthy nonsmoking controls was examined by fluorometric analysis of DNA unwinding (FADU) and spectrophotometric assays (cytochrome c reduction kinetics and uric acid kinetics). Compared to controls, filtered BAL supernatant of subjects with COPD exhibited a detectable clastogenic activity probably related to superoxide production. The method of BAL preparation as an acellular system strongly suggests that superoxide production may be due to xanthine oxidase activity.

1995 - Airway wall remodeling after cessation of exposure to isocyanates in sensitized asthmatic subjects. [Articolo su rivista]
M., Saetta; P., Maestrelli; G., Turato; C. E., Mapp; G., Milani; F., Pivirotto; Fabbri, Leonardo; A., Di Stefano
abstract

To determine whether the cessation of exposure to isocyanates is associated with structural changes of the airway wall in sensitized subjects, we studied bronchial biopsies from 10 subjects with occupational asthma induced by toluene diisocyanate (TDI). Bronchial challenges with TDI and methacholine were performed and biopsies were taken on two occasions, at diagnosis and 6 to 21 mo after cessation of exposure to TDI. After bronchoscopy, biopsies were formalin-fixed or snap-frozen in liquid nitrogen and then processed for a quantitative histochemical and immunohistochemical analysis. After cessation of exposure, we observed a significant decrease of the sensitivity to TDI (p < 0.05), of the thickness of subepithelial fibrosis (p < 0.007), and of the numbers of subepithelial fibroblasts (p < 0.05), mast cells (p < 0.02), and lymphocytes (p < 0.03) as compared with values at diagnosis. By contrast, the nonspecific bronchial hyperresponsiveness and the numbers of macrophages and eosinophils did not change. In conclusion, in patients with occupational asthma induced by TDI, the cessation of exposure to the sensitizing agent is associated with a reduced thickness of subepithelial fibrosis and with a reduced number of subepithelial fibroblasts, mast cells, and lymphocytes in the bronchial mucosa, suggesting a remodeling of the airway wall with the avoidance of the specific stimulus.

1995 - Asthma death. [Articolo su rivista]
G., Caramori; Fabbri, Leonardo
abstract

comment

1995 - Comparison of leukocyte counts in sputum, bronchial biopsies, and bronchoalveolar lavage. [Articolo su rivista]
P., Maestrelli; M., Saetta; A., Di Stefano; P. G., Calcagni; G., Turato; M. P., Ruggieri; A., Roggeri; C. E., Mapp; Fabbri, Leonardo
abstract

To determine the relationship between inflammatory cells in sputum, bronchoalveolar lavage (BAL), and bronchial mucosa, we counted the number of leukocytes in sputum, BAL, and bronchial biopsies obtained from subjects with asthma and with chronic bronchitis in stable condition or during exacerbations. Sputum was induced by inhalation of hypertonic saline in the asthma group. Spontaneous sputum was collected in the chronic bronchitis groups. Differential counts of leukocytes were performed on cytospin preparations of sputum and BAL. Eosinophils, macrophages, neutrophils, and lymphocytes were quantified in the submucosa of the bronchial biopsies. In asthma and in stable chronic bronchitis, the percentages of neutrophils were significantly higher in sputum than in BAL, whereas the opposite was true of the percentages of macrophages and lymphocytes. The lymphocyte was the predominant cell infiltrating the bronchial submucosa in all groups. BAL eosinophils correlated with submucosal and sputum eosinophils in the asthma and exacerbated chronic bronchitis groups. A similar trend was observed between submucosal and sputum eosinophils. In conclusion, the relative proportion of inflammatory cells was different in sputum, BAL, and bronchial mucosa. However, there was a fairly good agreement between the number of eosinophils counted with the three techniques in asthmatics and in exacerbated chronic bronchitics, suggesting that sputum cell analysis may be used for a noninvasive assessment of airway eosinophilia.

1995 - Cytokines in the airway mucosa of subjects with asthma induced by toluene diisocyanate. [Articolo su rivista]
P., Maestrelli; A., di Stefano; P., Occari; G., Turato; G., Milani; F., Pivirotto; C. E., Mapp; Fabbri, Leonardo; M., Saetta
abstract

To determine the status of activation of lymphocytes and the role of cytokines on the inflammatory response of the bronchial mucosa in toluene diisocyanate (TDI) asthma, we performed a quantitative analysis of bronchial biopsies obtained from 15 subjects with TDI-induced asthma and seven normal control subjects. Markers of activation of lymphocytes (CD25 and Very Late activation Antigen-1, VLA-1) and expression of Tumor Necrosis Factor-alpha (TNF alpha) and interleukin-1 beta (IL-1 beta) were determined by immunohistology in the submucosa. Moreover, expression of adhesion molecules on endothelium of submucosal vessels was assessed. Asthmatic subjects had increased numbers of cells expressing CD25 and VLA-1 compared with the control group (p < 0.05). TNF alpha and IL-1 beta immunoreactivity was increased in asthmatics compared with control subjects (p < 0.01), whereas the expression of adhesion molecules, ICAM-1 and E-selectin, on vascular endothelium was not significantly different. No significant differences in the morphologic quantifications were observed between the asthmatics who had biopsies taken 2 d after TDI challenge (n = 7) and those with longer interval (21 +/- 8 d) between TDI challenge and biopsy (n = 8), suggesting that the increase in CD25, VLA-1, TNF alpha, and IL-1 beta was not due to an acute effect, but could be considered a part of the chronic inflammatory process of the airways. We conclude that the inflammatory response of the airways in TDI-induced asthma is characterized by persistent activation of lymphocytes and by chronic expression of proinflammatory cytokines.

1995 - Effect of oxidant air pollutants on the respiratory system: insights from experimental animal research. [Articolo su rivista]
P., Chitano; J. J., Hosselet; C. E., Mapp; Fabbri, Leonardo
abstract

In the present paper, we have reviewed experimental animal studies on the effects of the two most important oxidant airborne pollutants, nitrogen dioxide and ozone, on the respiratory system. The toxic effects depend on concentration and length of exposure, and are generally similar for both oxidants, with ozone operative at lower concentrations. High doses of both oxidants cause death due to lung oedema. Exposure to sublethal levels causes functional alterations such as airflow limitation and airway hyperresponsiveness to bronchoconstrictor stimuli. These effects, which are generally reversible, are associated with epithelial injury, oedema and airway and parenchymal infiltration by inflammatory cells. Loss of cilia of airway epithelium and necrosis of type I alveolar epithelial cells are the most prominent consequences at the epithelial level. Inflammation is characterized by early neutrophilic infiltration, followed by an increased number of mononuclear cells, predominantly alveolar macrophages. After long-term exposure, whilst nitrogen dioxide causes predominantly emphysema, ozone produces mainly pulmonary fibrosis. Biochemical effects include lipid peroxidation, increased antioxidant metabolism, and alteration of enzyme activity. Nitrogen dioxide and ozone may also alter the immunological response and reduce the defence against infections, increasing the susceptibility of exposed animals to infections.

1995 - Effect of smoking cessation on airway inflammation in chronic bronchitis. [Articolo su rivista]
G., Turato; A., Di Stefano; P., Maestrelli; C. E., Mapp; M. P., Ruggieri; A., Roggeri; Fabbri, Leonardo; M., Saetta
abstract

To investigate the effect of smoking cessation on the airway inflammatory process present in nonatopic subjects with chronic bronchitis, we obtained bronchial biopsies from nine current smokers and seven exsmokers, all with symptoms of chronic bronchitis at the time of the study, and from seven healthy nonsmoking subjects. The exsmokers had stopped smoking on average 13 yr before the study, yet cough and production of sputum had persisted. Bronchial biopsies were assessed using immunohistochemical techniques to investigate the number of inflammatory cells, the markers of mononuclear cell activation, and the expression of endothelial adhesion molecules and cytokines in the subepithelium. Current smokers and exsmokers had an increased number of macrophages, IL-2R-positive cells, VLA-1-positive cells, ICAM-1-positive vessels, and E-selectin-positive vessels compared with normal nonsmoking subjects, but the number of cells positive for neutrophils, EG-2, CD3, CD4, CD8, TNF-alpha and IL-1 beta were similar among the three groups. No differences were observed between current smokers and exsmokers for any parameter examined. In conclusion, the inflammatory process present in the airway mucosa of current smokers may persist after smoking cessation in subjects who continue to have symptoms of chronic bronchitis.

1995 - Fatal asthma attack during an inhalation challenge with ultrasonically nebulized distilled water. [Articolo su rivista]
M., Saetta; A., Di Stefano; G., Turato; R., De Caro; D., Bordignon; S. T., Holgate; Fabbri, Leonardo
abstract

A 22-year-old man had a history of asthma that was well controlled by regular treatment with inhaled steroids and β-agonists, until a fatal attack occurred during an inhalation challenge in the laboratory with ultrasonically nebulized distilled water.

1995 - HLA class II molecules and asthma induced by toluene diisocyanate. [Articolo su rivista]
Fabbri, Leonardo; C. E., Mapp; A., Balboni; R., Baricordi
abstract

ND

1995 - In-vitro exposure of guinea pig main bronchi to 2.5 ppm of nitrogen dioxide does not alter airway smooth muscle response. [Articolo su rivista]
P., Chitano; R. E., Lucchini; E., Coser; A., Papi; M., Saetta; P., Maestrelli; A., Ciaccia; Fabbri, Leonardo; C. E., Mapp
abstract

In order to investigate whether the oxidant airborne pollutant nitrogen dioxide (NO2) affects airway smooth muscle responsiveness, the contractile response of guinea pig main bronchi after in vitro exposure to 2·5 ppm of nitrogen dioxide was studied. Main bronchi were cannulated and exposed for 2 or 4 h to a constant flow of either NO2 or air. After exposure, bronchial rings were obtained and placed in a 37°C jacketed organ bath filled with Krebs-Henseleit solution. Concentration-response curves were performed for acetylcholine (10−9–10−3 ), substance P (10−9–10−4 ), and neurokinin A (10−10–10−5 ), and voltage-response curves (12–28 V) were performed for electrical field stimulation. There was no significant difference in either the smooth muscle maximal contractile response, or sensitivity between the bronchi exposed to NO2 and those exposed to air. We conclude that in vitro exposure to 2·5 ppm of NO2 does not alter airway smooth muscle responsiveness in guinea pigs.

1995 - Marcatori infiammatori nella diagnosi e nel monitoraggio dell’ asma [Articolo su rivista]
Fabbri, Leonardo; Ferrari, M; Cosma, P; Caramori, G; Ciaccia, A.
abstract

n/d

1995 - Ruolo dei beta2 agonisti a lunga durata di azione nella gestione del paziente asmatico [Articolo su rivista]
Fabbri, Leonardo; Ferrari, M; Caramori, G; Ciaccia, A.
abstract

n/d

1995 - Stato dell’arte degli antileucotrienici nella terapia dell’asma [Articolo su rivista]
Fabbri, Leonardo; Ferrari, M; Caramori, G; Ciaccia, A.
abstract

n/d

1994 - Airway eosinophilia in chronic bronchitis during exacerbations. [Articolo su rivista]
M., Saetta; A., Di Stefano; P., Maestrelli; G., Turato; M. P., Ruggieri; A., Roggeri; P., Calcagni; C. E., Mapp; A., Ciaccia; Fabbri, Leonardo
abstract

To examine the nature and the degree of airway inflammation in chronic bronchitis during exacerbations, bronchial biopsies and sputum were obtained in 11 subjects with chronic bronchitis examined during an exacerbation, and in 12 subjects with chronic bronchitis examined under baseline conditions. All subjects were nonatopic. Lobar bronchial biopsies were assessed using histochemical and immunohistochemical techniques, and sputum was examined for differential cell counts of leukocytes. Subjects with bronchitis during exacerbations had, on average, 30-fold more eosinophils in their bronchial biopsies than did those examined under baseline conditions (p < 0.001). Although to a lesser extent, the numbers of neutrophils (p < 0.01), T-lymphocytes (CD3) (p < 0.05), VLA-1-positive cells (p < 0.01), and TNF-alpha positive cells (p < 0.05) were also increased during exacerbations. By contrast, the T-lymphocyte subpopulations (CD4 and CD8) and the numbers of macrophages, mast cells, IL-2R-positive cells, and IL-1 beta-positive cells were similar in the two groups of subjects, as well as the percentages of ICAM-1- and E-selectin-positive vessels. Eosinophils were also increased in sputum of subjects with exacerbations when compared with those examined under baseline conditions (p < 0.05). In conclusion, exacerbations of chronic bronchitis are associated with a marked airway eosinophilia and with a milder increase in the number of neutrophils, activated T-lymphocytes, and TNF-alpha-positive cells in the bronchial mucosa.

1994 - Airway inflammation in occupational asthma. [Articolo su rivista]
Fabbri, Leonardo
abstract

review

1994 - CD8 T-cell clones producing interleukin-5 and interferon-gamma in bronchial mucosa of patients with asthma induced by toluene diisocyanate. [Articolo su rivista]
P., Maestrelli; G. F., Del; M., De Carli; M. M., D'Elios; M., Saetta; A., Di Stefano; C. E., Mapp; S., Romagnani; Fabbri, Leonardo
abstract

OBJECTIVES--The aims of the present study were to determine whether specific in vivo stimulation of asthmatics sensitized with toluene diisocyanate (TDI) induces the activation of T lymphocytes in bronchial mucosa and to characterize their phenotype and cytokine secretion profile. METHODS--Bronchial biopsies from two subjects with occupational asthma due to TDI were obtained 48 h after an asthmatic reaction induced by an inhalation challenge with TDI and after three months of no exposure to TDI, at the time when the subjects had recovered from their asthma. The fragments of bronchial mucosa were cultured in the presence of interleukin-2 so that the in vivo activated T cells present in the tissue would expand, and T blasts were then cloned under limiting dilution conditions. RESULTS--From the two 48-h specimens, 65 and 63 T-cell clones were obtained. Most of the clones exhibited the CD8 phenotype (82 and 83%). All of the CD8 clones produced interferon-gamma and 44% produced interleukin-5, but only 6% secreted interleukin-4 as well. Three months after the cessation of exposure, growing T cells could not be recovered from bronchial biopsies cultured in interleukin-2. CONCLUSIONS--The results suggest that, in sensitized subjects, exposure to TDI induces the activation of a subset of CD8 lymphocytes producing interferon-gamma and interleukin-5.

1994 - Eosinophil cationic protein (ECP), histamine and tryptase in peripheral blood before and during inhalation challenge with toluene diisocyanate (TDI) in sensitized subjects. [Articolo su rivista]
C. E., Mapp; M., Plebani; D., Faggian; P., Maestrelli; M., Saetta; P., Calcagni; F., Borghesan; Fabbri, Leonardo
abstract

To determine whether the measurement of specific markers of inflammatory cells in peripheral blood might be used to detect the inflammatory activity in the airways in asthma induced by toluene diisocyanate (TDI), we measured the levels of eosinophil cationic protein (ECP), histamine and tryptase in peripheral blood before and during inhalation challenge with TDI or methacholine in two groups of subjects who exhibited or did not exhibit an asthmatic reaction after exposure to toluene diisocyanate in the laboratory. When the subjects developed a late asthmatic reaction after exposure to TDI, they showed an increase in their ECP serum levels. By contrast, there were no significant changes in serum ECP levels after exposure to TDI in the control group or after methacholine challenge in either group. Tryptase levels in serum were not detectable before or during inhalation challenge with TDI or methacholine. There was no significant increase in plasma histamine levels during inhalation challenge with TDI or methacholine. These results suggest that eosinophils are 'activated' in subjects who develop a late asthmatic reaction after exposure to TDI and that the measurement of ECP levels in peripheral blood may be a useful marker to monitor airway inflammation.

1994 - Gli antagonisti dei leucotrieni: nuove speranze nella terapia dell’asma? [Articolo su rivista]
Fabbri, Leonardo; Caramori, G; Guidoboni, A; Ciaccia, A.
abstract

n/d

1994 - HLA class II alleles in isocyanate-induced asthma. [Articolo su rivista]
J. S., Bignon; Y., Aron; L. Y., Ju; M. C., Kopferschmitt; R., Garnier; C., Mapp; Fabbri, Leonardo; G., Pauli; A., Lockhart; D., Charron
abstract

Studying genetic factors that control human immune responsiveness may further our understanding of specific types of asthma in which the role of immune factors is uncertain to date. HLA Class II gene products are involved in the control of immune responses. Therefore, we investigated whether HLA Class II genetic markers contribute to susceptibility or resistance to isocyanate-induced asthma (IAA) in exposed workers. We collected venous blood samples from two groups of unrelated white adults: (1) patients with isocyanate-induced asthma documented by a positive inhalation challenge; and (2) exposed individuals with no history of IAA. The second exon of DQA1, DQB1, DPB1, and DRB genes was selectively amplified by the polymerase chain reaction (PCR) method. HLA typing was carried out by the PCR-RFLP method, which allowed discrimination of most HLA DQA1, DQB1, DPB1, and DRB alleles. No significant difference was found in the distribution of DPB1 alleles between patients and control subjects. Allele DQB1*0503 and allelic combination DQB1*0201/0301 were associated with susceptibility to the disease. Conversely, allele DQB1*0501 and the DQA1*0101-DQB1*0501-DR1 haplotype conferred significant protection to exposed healthy control subjects. Our results are consistent with the hypothesis that immune mechanisms are involved in isocyanate-induced asthma and that specific genetic factors may increase or decrease the risk of developing IAA in exposed workers.

1994 - In vitro exposure to nitrogen dioxide (NO2) does not alter bronchial smooth muscle responsiveness in ovalbumin-sensitized guinea-pigs. [Articolo su rivista]
P., Chitano; E., Coser; R. E., Lucchini; A., Papi; M., Saetta; P., Maestrelli; D., Faggian; M., Plebani; A., Ciaccia; Fabbri, Leonardo
abstract

The aim of this study was to investigate whether in vitro exposure to NO2 affects responsiveness in ovalbumin-sensitized guinea-pig bronchi. Twenty-three animals were sensitized by three weekly intraperitoneal injections of 1 mg ovalbumin in saline with Freund's adjuvant; twenty-one control guinea-pigs received the diluent alone. From each animal, the two main bronchi were obtained and cannulated, then exposed in vitro to a constant intraluminal flow of: (i) either air or 2.5 ppm NO2 with four spikes of 10 ppm NO2 for 2 h; (ii) either air or 10 ppm NO2 for 4 h. A bronchial ring obtained from each animal before exposure was kept in aerated Krebs-Henseleit solution. Rings from bronchi exposed to air, NO2, or kept in Krebs solution were studied isometrically. We performed overall and non-adrenergic non-cholinergic voltage-response curves to electrical field stimulation, concentration-response curves to acetylcholine and to neurokinin A, followed by administration of 10 mg/ml ovalbumin. We did not find any significant difference in bronchial smooth muscle responsiveness between nonexposed, air-exposed and NO2-exposed bronchi, as well as between bronchi from control and sensitized animals. We conclude that in vitro exposure to NO2 does not alter bronchial smooth muscle responsiveness to either specific or non-specific stimuli.

1994 - Low molecular weight pollutants and asthma: pathogenetic mechanisms and genetic factors. [Articolo su rivista]
C. E., Mapp; M., Saetta; P., Maestrelli; A., Ciaccia; Fabbri, Leonardo
abstract

Most studies suggest that asthma prevalence has beenincreasing in children and young adults over the last fourdecades. This increase is not confined to asthmabut includes atopic diseases, such as hay fever and eczema.It has been suggested that a disease is caused bythe interaction of genetic susceptibility and an adverseenvironment. Environmental differences may explainthe variations in the prevalence of asthma found inwestern countries. Several studies have shown an associationbetween the risk of developing respiratory allergyand the season of birth. Other environmentalfactors, such as respiratory viral infection, tobaccosmoke and outdoor pollutants, have been considered asadjuvants for initial sensitization in childhood. Anadverse environment does not necessarily imply an outdoorenvironment, but could be the workplace where asubject spends a substantial part of his life.

1994 - Mechanisms and pathology of occupational asthma. [Articolo su rivista]
C. E., Mapp; M., Saetta; P., Maestrelli; A., Di Stefano; P., Chitano; P., Boschetto; A., Ciaccia; Fabbri, Leonardo
abstract

Since the pathogenesis and the pathological features of occupational asthma are similar to those of nonoccupational asthma, the former represents a very useful model for the investigation of the pathogenesis of asthma in general. More than one mechanism may be operative in occupational asthma. Among the mechanisms proposed, immunological mechanisms and airway inflammation play an important role. There is evidence to confirm that T-lymphocyte activation and local accumulation in the bronchial wall of activated eosinophils occurs in asthma of diverse aetiology, i.e. immunoglobulin E (IgE)-mediated, occupational and intrinsic. Neurogenic pathways should be further investigated as a potential mechanism of modulation and amplification of airway inflammation in occupational asthma.

1994 - Mechanisms of occupational asthma. [Articolo su rivista]
Fabbri, Leonardo; P., Maestrelli; M., Saetta; C. M., Mapp
abstract

review

1994 - Oxygen radical scavengers inhibit clastogenic activity induced by sonication of human serum. [Articolo su rivista]
S., Pinamonti; M. C., Chicca; M., Muzzoli; A., Papi; Fabbri, Leonardo; A., Ciaccia
abstract

Clastogenic factors (CF) are diffusible molecules that damage DNA. They are generated within biological media by a variety of physical and chemical stimuli. Their nature and mechanism of action remain largely unknown. Clastogenic activity can be experimentally generated by pulsed ultrasound treatment of human serum. To investigate whether oxygen radicals are involved in the clastogenic activity induced by sonication of human serum, we examined the effects on such clastogenic activity of different oxygen radical scavengers added to human serum before and after sonication. Human serum was sonicated for 50 min at 24 microW/cm2 by pulsed ultrasound. The clastogenic activity of sonicated human serum was examined in the presence or absence of oxygen radical scavengers by measuring the amount of DNA damage induced in autologous human lymphocytes, assessed with the fluorometric analysis of DNA unwinding (FADU). Sonication of human serum generated significant DNA damage in autologous lymphocytes (DNA unwinding averaged 31.79% +/- 2.1 after sonication vs. 12.82% +/- 2.6 in the controls, p < 0.005). Superoxide dismutase (SOD; 500 I.U./ml), catalase (500 I.U./ml), mannitol (50 mM), and glutathione (50 mM) completely prevented DNA damage when added before serum sonication, whereas only mannitol (86%) and glutathione (90%) almost completely inhibited DNA damage when added after sonication. SOD and catalase had only a partial inhibitory effect when added after sonication (49% and 63%, respectively). The prevention of DNA damage was also obtained by an association of subliminal amounts of glutathione (20 mM) and vitamin E (1 I.U./ml). These results suggest that the clastogenic activity generated by sonication of human serum is mediated by oxygen radicals.

1994 - Postallergen inhaled budesonide reduces late asthmatic response and inhibits the associated increase of airway responsiveness to methacholine in asthmatics. [Articolo su rivista]
P. L., Paggiaro; F. L., Dente; M. C., Morelli; L., Bancalari; A., Di Franco; D., Giannini; B., Vagaggini; E., Bacci; Fabbri, Leonardo; C., Giuntini
abstract

To determine whether inhaled budesonide given after allergen inhalation challenge inhibits the late asthmatic response (LAR) and/or the associated increase of airway responsiveness to methacholine, we performed a double-blind randomized cross-over study in 12 adult asthmatics (eight male, four female; mean age, 20.3 yr; range, 18 to 29 yr) sensitized to Dermatophagoides pteronyssinus (DP) previously shown to develop early and late asthmatic response to allergen challenge with DP. On different days each subject was randomized to receive budesonide 800 micrograms by Turbuhaler or placebo, given three times; (1) after allergen inhalation, after the onset of LAR, when FEV1 had fallen by > or = 15%; (2) 2 h later; (3) 4 h later. Airway responsiveness to methacholine was measured before allergen challenge at 8 to 10 h from allergen inhalation and 24 h after the allergen inhalation. Inhaled budesonide significantly reduced the LAR induced by allergen (maximal % fall in FEV1, delta FEV1%: -23 +/- 6% with budesonide versus -38 +/- 9% with placebo; p < 0.001) and inhibited the associated increase of airway responsiveness (geometric mean of PD20FEV1 methacholine: 0.047 mg after budesonide versus 0.033 mg after placebo at 8 to 10 h, p < 0.05; 0.119 mg after budesonide versus 0.062 mg after placebo at 24 h, p < 0.01). These results suggest that inhaled budesonide may not only prevent but also reduce the late asthmatic response induced by allergen and that it might also be considered in the treatment of exacerbation of asthma.

1994 - Predictive value of airways hyperresponsiveness and circulating IgE for identifying types of responses to toluene diisocyanate inhalation challenge. [Articolo su rivista]
Karol, Mh; Tollerud, Dj; Campbell, Tp; Fabbri, Leonardo; Maestrelli, P; Saetta, M; Mapp, Ce
abstract

Development of asthma after exposure to toluene diisocyanate (TDI) has been recognized in a variety of occupational settings. However, the pathogenesis of isocyanate-induced asthma remains controversial. In particular, the role of IgE in the development of TDI-induced asthma has remained uncertain. To investigate predictive factors for response to inhalation challenge with TDI, we analyzed data from 63 subjects referred for evaluation of respiratory symptoms thought to be related to TDI sensitization. All subjects underwent interview, routine phlebotomy, spirometry, methacholine challenge, and allergy skin testing prior to TDI challenge. Spirometry and methacholine challenge were repeated 1 day after TDI challenge. The cumulative dose of methacholine needed to produce a 20% decrease in FEV1 (PD20) was determined. A PD20 of 1.4 mg or more was considered normal. Subjects were challenged by exposure to 5 to 10 ppb TDI for up to 30 min in a 9 m3 exposure chamber. A positive response was a 20% or more decrease in FEV1 within 1 h (early) or beyond 1 h (late) after TDI exposure. Thirty-four subjects (54%) had a positive response, of whom 12 (35% of responders) had isolated early responses, 13 (38%) had isolated late responses, and the remainder had dual responses. Thirty-two individuals (51%) had a positive response to methacholine (AR+) prior to TDI challenge. AR+ was strongly associated with a positive TDI challenge: 23 AR+ subjects (72%) had a positive TDI challenge, compared with only 11 AR- subjects (35%) (p < 0.01). AR positivity did not predict the time of onset of TDI response

1994 - Sputum eosinophilia after asthmatic responses induced by isocyanates in sensitized subjects. [Articolo su rivista]
P., Maestrelli; P. G., Calcagni; M., Saetta; A., Di Stefano; J. J., Hosselet; A., Santonastaso; Fabbri, Leonardo; C. E., Mapp
abstract

To assess the nature and the time-course of the cellular component of airway inflammation induced by isocyanates, we examined nine subjects with occupational asthma induced by toluene- or methylene diphenyl-diisocyanate (TDI, MDI) and four control subjects never exposed to isocyanates. Sputum was induced by inhalation of ultrasonically nebulized hypertonic saline (3-4% NaCl) before and 8, 24, 48 h after inhalation challenge with TDI or MDI. Expectorated samples were incubated with dithiothreitol, washed and cytocentrifuged. Differential cell counts were obtained on slides stained with May-Grünwald-Giemsa. Metachromatic cells (mast cells and basophils) were counted on slides stained with toluidine blue at pH 0.1. One occupational asthmatic exhibited a dual reaction to TDI, two exhibited a single early asthmatic reaction to MDI, six exhibited a late asthmatic reaction to TDI (n = 5) or MDI (n = 1), whereas no reactions were observed in control subjects after TDI challenge. In sensitized subjects eosinophils increased from a median value (interquartile range) of 5 (15)% before challenge to 29 (29)% (P = 0.014) and to 30 (31)% (P = 0.031) 8 and 24 h after TDI/MDI challenges, respectively. Sputum eosinophilia was observed both in early and late reactors and declined to near to baseline values 48 hr after challenge. Percentages of eosinophils in control subjects did not exceed 7% during the study.

1994 - Structural aspects of airway inflammation in COPD. [Relazione in Atti di Convegno]
M., Saetta; A., Di Stefano; P., Maestrelli; C. E., Mapp; A., Ciaccia; Fabbri, Leonardo
abstract

Descriptions of pathology of chronic bronchitis in the past have been mainly focused on mucous gland hypertrophy, since this was considered the morphologic basis of the disease, but more recent studies have suggested a pathogenetic role for airway inflammation in subjects with chronic bronchitis. In the present review, we briefly summarize the results of these latter studies, which describe the nature of airway inflammation and the state of activation of inflammatory cells in the bronchial mucosa of subjects with chronic bronchitis.

1994 - The effects of toluene diisocyanate and of capsaicin on human bronchial smooth muscle in vitro. [Articolo su rivista]
P., Chitano; P., Di Blasi; R. E., Lucchini; F., Calabrò; M., Saetta; P., Maestrelli; Fabbri, Leonardo; C. E., Mapp
abstract

Toluene diisocyanate contracts guinea-pig bronchial smooth muscle through a mechanism involving capsaicin-sensitive sensory nerves. In the present study, we investigated the effects of toluene diisocyanate, capsaicin and tachykinins on isolated human bronchi. In 44 rings, toluene diisocyanate (0.3 mM) produced a relaxation which averaged 16.9 +/- 1.1%, in ten rings it produced a shortening that was 15.1 +/- 3.3% and in ten preparations it gave no response. A second administration of toluene diisocyanate (0.3 mM) always produced a relaxation (n = 13, 18.1 +/- 3.9%). Capsaicin (0.03 mM) produced shortening in 15 (35 +/- 6.6%) and relaxation in 11 preparations (41 +/- 6.8%), whereas a second administration caused shortening in nine (25.1 +/- 6.1%) and relaxation in 16 rings (36.4 +/- 4.9%). When toluene diisocyanate was given after two consecutive capsaicin administrations, we observed shortening in two rings (10.0 +/- 3.6%), relaxation in ten rings (15.9 +/- 3.6%), and no response in four preparations. To test the role of NK1 and NK2 receptors in these conflicting responses, we performed concentration-response curves to different tachykinins. Substance P, neurokinin A and neurokinin A-(4-10), a specific NK2 receptor agonist, gave a concentration-dependent shortening, with neurokinin A being the most effective and neurokinin A-(4-10) the least. The specific NK1 receptor agonist, [Sar9, Met(O2)11]substance P, produced both shortening and relaxation. We conclude that toluene diisocyanate and capsaicin may produce both shortening and relaxation in isolated human bronchi through NK1 receptors.

1994 - Upregulation of adhesion molecules in the bronchial mucosa of subjects with chronic obstructive bronchitis. [Articolo su rivista]
A., Di Stefano; P., Maestrelli; A., Roggeri; G., Turato; S., Calabro; A., Potena; C. E., Mapp; A., Ciaccia; L., Covacev; Fabbri, Leonardo
abstract

To determine whether adhesion molecules and cytokines are upregulated in the bronchial mucosa of chronic bronchitics, we obtained bronchial biopsies in 16 chronic bronchitics, in eight asymptomatic smokers, and in seven normal nonsmoking subjects. Bronchial biopsies were examined by immunohistochemistry to identify the expression of E-selectin and intercellular adhesion molecular-1 (ICAM-1) on vessels and on bronchial epithelium, and the expression of interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), neutrophil elastase, and eosinophil cationic protein (EG-2) on cells in the submucosa. Chronic bronchitics had an increased number of E-selectin-positive vessels when compared with both asymptomatic smokers (p < 0.05) and normal subjects (p < 0.01). The numbers of ICAM-1-positive vessels, neutrophils, and IL-1 beta, TNF-alpha-, and EG-2-positive cells were not significantly different in the three groups of subjects examined. When the bronchitic group was divided according to the presence or absence of airway obstruction, the increased number of E-selectin-positive vessels persisted only in bronchitics with airway obstruction, who also had an increased expression of ICAM-1 on basal epithelial cells. We concluded that in the bronchial mucosa of chronic bronchitics with airway obstruction, there is an increased expression of E-selectin on vessels and of ICAM-1 on basal epithelial cells, suggesting the involvement of these adhesion molecules in the pathogenesis of the disease.

1993 - Activated T-lymphocytes and macrophages in bronchial mucosa of subjects with chronic bronchitis. [Articolo su rivista]
M., Saetta; A., Di Stefano; P., Maestrelli; A., Ferraresso; R., Drigo; A., Potena; A., Ciaccia; Fabbri, Leonardo
abstract

To examine the nature and the degree of leukocyte infiltration and to determine the state of activation of cells in bronchial mucosa of subjects with chronic bronchitis, bronchoscopy was performed in 10 subjects with a history of cigarette smoking and chronic sputum production and in six normal nonsmoking control subjects. Lobar bronchial biopsies were examined using histochemical and immunohistochemical techniques. Subjects with chronic bronchitis had an increased number of total leukocytes (CD45 positive cells), both in the epithelium and in the lamina propria, than did the control subjects (p < 0.05), whereas the numbers of neutrophils, eosinophils, and mast cells were similar in the two groups. There was a significant increase in the numbers of macrophages (p < 0.01) and of T-lymphocytes (CD3 positive cells) (p < 0.05) in the lamina propria of chronic bronchitics, whereas the relative proportions of CD4 and CD8 positive cells were similar in the bronchitics and the control subjects. Subjects with chronic bronchitis also had an increased expression of markers of lymphocyte activation, i.e., an increased number of interleukin-2 receptor positive cells (CD25 positive cells) (p < 0.05) and an increased number of very late activation antigen (VLA-1) positive cells (p < 0.05). In conclusion, the present study provides evidence for mononuclear cell infiltration and for T-cell activation in bronchial mucosa of subjects with chronic bronchitis, supporting the involvement of these cells in the pathogenesis of the disease.

1993 - Airway responsiveness. Standardized challenge testing with pharmacological, physical and sensitizing stimuli in adults. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. [Articolo su rivista]
P. J., Sterk; Fabbri, Leonardo; P. H., Quanjer; D. W., Cockcroft; P. M., O'Byrne; S. D., Anderson; E. F., Juniper; J. L., Malo
abstract

Review

1993 - Allergen exposure induces the activation of allergen-specific Th2 cells in the airway mucosa of patients with allergic respiratory disorders. [Articolo su rivista]
Del Prete, Gf; De Carli, M; D'Elios, Mm; Maestrelli, P; Ricci, M; Fabbri, Leonardo; Romagnani, S.
abstract

Biopsy specimens were obtained from the bronchial or the nasal mucosa of three patients with grass pollen-induced bronchial asthma or rhinitis 48 h after positive bronchial or nasal provocation test with grass pollen extract. T cell clones (TCC), derived from these and control specimens, were then assessed for their phenotype, allergen-specificity, profile of cytokine secretion and ability to provide B cell help for IgE synthesis. Out of 50 and 61 CD4+ TCC derived from the bronchial mucosa of the two patient with atopic asthma 11 (22%) and 19 (31%), respectively, showed both proliferation and cytokine production in response to grass pollen allergens under major histocompatibility complex-restricted conditions. Of these 21 (70%) exhibited a clear-cut type 2 T helper (Th2) profile and induced IgE synthesis in autologous peripheral blood B cells in the presence of grass allergens. All the other 9 grass-specific clones showed a Th0 pattern of cytokine secretion, but only 1 provided moderate help for IgE synthesis. In contrast, the majority of TCC, derived under the same experimental conditions from the bronchial mucosa of two nonatopic patients with toluene diisocyanate-induced asthma, were CD8+ and most of them produced interferon-gamma or interferon-gamma and interleukin-5, but not interleukin-4, in response to nonspecific stimulation. Of 22 CD4+ TCC3 (14%) derived from the grass-stimulated mucosa of the patient with allergic rhinitis, but none of those derived from the unstimulated nostril of the same patient, exhibited proliferation and cytokine production in response to grass allergens. All had a clear-cut Th2 profile and provided help for IgE synthesis by autologous B cells. These data indicate that inhalation of the relevant allergen results in the activation of allergen-specific Th2 lymphocytes in the airway mucosa of patients with allergic respiratory disorders. These cells may play a central role in determining the nature of the inflammatory response in the airways of atopic patients.

1993 - Comparison of fluticasone propionate with beclomethasone dipropionate in moderate to severe asthma treated for one year. International Study Group. [Articolo su rivista]
Fabbri, Leonardo; Burge, Ps; Croonenborgh, L; Warlies, F; Weeke, B; Ciaccia, A; Parker, C.
abstract

High dose inhaled glucocorticosteroids are increasingly used in the management of patients with moderate to severe asthma. Although effective, they may cause systemic side effects. Fluticasone propionate is a topically active inhaled glucocorticosteroid which has few systemic effects at high doses. METHODS: Fluticasone propionate, 1.5 mg per day, was compared with beclomethasone dipropionate at the same dose for one year in patients with symptomatic moderate to severe asthma; 142 patients received fluticasone propionate and 132 received beclomethasone dipropionate. The study was multicentre, double blind and of a parallel design. For the first three months patients attended the clinic every four weeks and completed daily diary cards. For the next nine months they were only seen at three monthly intervals in the clinic. RESULTS: During the first three months diary card peak expiratory flow (PEF) rate and lung function measurements in the clinic showed significantly greater improvement in patients receiving fluticasone propionate (difference in morning PEF 15 l/min (95% CI 6 to 25)), and these differences were apparent at the end of the first week. The improved lung function was maintained throughout the 12 month period and the number of severe exacerbations in patients receiving fluticasone propionate was reduced by 8% compared with those receiving beclomethasone dipropionate. No significant differences between the two groups were observed in morning plasma cortisol levels, urinary free cortisol levels, or response to synthetic ACTH stimulation. In addition, both the rates of withdrawal and of adverse events were low, and there were fewer exacerbations of asthma with fluticasone propionate than beclomethasone dipropionate. CONCLUSIONS: This study shows that fluticasone propionate in a daily dose of 1.5 mg results in a significantly greater increase in PEF and asthma control than the same dose of beclomethasone dipropionate, with no increase in systemic or other side effects.

1993 - Effect of bumetanide on toluene diisocyanate induced contractions in guinea pig airways. [Articolo su rivista]
C. E., Mapp; A., Boniotti; A., Papi; C. A., Maggi; A., Di Stefano; M., Saetta; A., Ciaccia; Fabbri, Leonardo
abstract

BACKGROUND: The loop diuretic frusemide has been shown to inhibit the bronchoconstrictor response to exercise, inhaled allergen, distilled water, adenosine, and sodium metabisulphite. Toluene diisocyanate contracts smooth muscle by activating capsaicin sensitive nerves and causes asthma that shares many features with allergen induced asthma. METHODS: The study was designed to assess the effect of two loop diuretics, bumetanide (10 and 100 microM) and frusemide (100 microM), on smooth muscle contraction induced by toluene diisocyanate (0.03-1000 microM) in guinea pig airways with and, in the case of bumetanide, without epithelium. The effect of bumetanide on the response to acetylcholine, neurokinin A, and electrical field stimulation in guinea pig bronchial smooth muscle rings was also examined. RESULTS: Bumetanide (10 and 100 microM) had no effect on toluene diisocyanate induced contraction whether airway epithelium was present or not. Frusemide (100 microM) caused no significant inhibition of toluene diisocyanate induced contraction (mean reduction on the entire curve 25%). Bumetanide inhibited non-adrenergic, non-cholinergic contraction induced by electrical field stimulation of bronchi pretreated with atropine (1 microM) and indomethacin (5 microM) and this inhibition was inversely related to the frequency of stimulation, suggesting that bumetanide may be inhibiting transmitter release at the prejunctional level. Bumetanide and frusemide did not inhibit the responses to exogenous acetylcholine (0.1 microM) or neurokinin A (1 nM). CONCLUSIONS: Bumetanide and frusemide in doses that are known to inhibit non-adrenergic, non-cholinergic contraction due to electrical field stimulation failed to inhibit the response to toluene diisocyanate in guinea pig airways.

1993 - Effects of inhaled beclomethasone on airway responsiveness in occupational asthma. Placebo-controlled study of subjects sensitized to toluene diisocyanate. [Articolo su rivista]
P., Maestrelli; N., De Marzo; M., Saetta; M., Boscaro; Fabbri, Leonardo; C. E., Mapp
abstract

We investigated the effect of 5 months of treatment with inhaled beclomethasone dipropionate (BDP) on the airway responsiveness to methacholine (PD20 FEV1) and to toluene diisocyanate (TDI) in 15 sensitized asthmatic subjects who had been removed from occupational exposure to TDI. After the diagnosis was established by a positive inhalation challenge with TDI, each subject was removed from occupational exposure to isocyanates and treated with either BDP (1 mg twice per day, n = 7) or placebo (n = 8) for 5 months. The study was double blind for parallel groups. P20 FEV1 methacholine was measured before and three times during treatment and then at 6 months, that is, 4 wk after cessation of treatment. Airway sensitivity to TDI was assessed with specific inhalation challenge before treatment and at 6 months. Beclomethasone reduced the airway hyperresponsiveness to methacholine but did not affect the response to TDI. In fact, in the subjects on BDP, P20 FEV1 increased from 0.145 to 0.485 mg (p < 0.05) after 2 months of treatment. A further increase was observed at 4 and 5 months (0.548 and 0.629 mg, respectively, p < 0.01), and the improvement in nonspecific airway responsiveness was maintained after a 1-month washout period (0.637 mg, p < 0.01). In contrast, in the subjects on placebo, P20 FEV1 did not change significantly. At the end of the study, the severity of asthmatic reactions induced by bronchial challenge with TDI was significantly reduced in both groups, but no differences were observed between placebo and BDP.

1993 - Identification of epithelial cells in bronchoalveolar lavage. [Articolo su rivista]
S., Finotto; V., Rado; A., Dal Vecchio; G., Milani; Fabbri, Leonardo; P., Maestrelli
abstract

Damage to the bronchial epithelium occurs after the inhalation of toxic substances and allergens, and through virus infections and it may lead to increased desquamation of epithelial cells in bronchoalveolar lavage (BAL). 2. In this study we compared two methods of staining the epithelial cells of BAL, the conventional cytochemical May Grunwald-Giemsa stain (MGG) and an immunocytochemical technique using a monoclonal antibody anti-human cytokeratin (CK) detected with APAAP immuno-alkaline phosphatase. BAL was obtained from 13 subjects and the epithelial cells were cytocentrifuged either immediately after collection (fraction A) or after washing (fraction B). 3. Higher percentages of epithelial cells were identified in fraction A with CK (20.0 +/- 5.1%) than in fraction A with MGG (11.2 +/- 2.3%), which recognized only ciliated epithelial cells. In fact a proportion of CK-positive cells (34%) in fraction A were not ciliated. Underestimation of epithelial cells by MGG compared to CK was more pronounced in fraction B (8.0 +/- 2.9% and 22.9 +/- 3.0%, respectively) as there was a relative loss of ciliated CK+ cells after washings. 4. These results suggest that immunocytochemical staining with an anti-cytokeratin monoclonal antibody is more sensitive than using the MGG stain in detecting epithelial cells in BAL.

1993 - Lack of increase or reduction in circulating platelet factor 4 and heparin-releasable platelet factor 4 in symptomatic patients with asthma. [Articolo su rivista]
Luzzatto, G; Cella, G; Boschetto, P; Fabbri, Leonardo
abstract

We measured circulating platelet factor 4 (PF4) and heparin-releasable platelet factor 4 (HR-PF4) in 13 symptomatic patients suffering from bronchial asthma and in 10 matched normal controls. Neither a difference between patients and controls, nor a correlation between platelet count and HR-PF4 was found (PF4: controls 2.1 +/- 2.9; patients 3.6 +/- 4.4 ng/ml (n.s.); HR-PF4: controls 127 +/- 49, patients 101 +/- 34 ng/ml (n.s.). Therefore, the pathogenetic role of PF4 in the mechanism of bronchial asthma, elsewhere hypothesized, cannot definitely be established.

1993 - Mast cells in the airway mucosa and rapid development of occupational asthma induced by toluene diisocyanate. [Articolo su rivista]
A., Di Stefano; M., Saetta; P., Maestrelli; G., Milani; F., Pivirotto; C. E., Mapp; Fabbri, Leonardo
abstract

We examined lobar bronchial biopsies taken from 18 subjects with occupational asthma induced by toluene diisocyanate (TDI) and from nine nonasthmatic control subjects. Two groups of asthmatics were identified on the basis of the duration of exposure to TDI before the onset of symptoms of asthma. Group A (n = 8) developed asthma after 2.4 +/- 0.4 yr of exposure to TDI, and Group B (n = 10) developed asthma after 21.6 +/- 3.1 yr of exposure to TDI. Both groups of asthmatic subjects had increased numbers of inflammatory cells in the airway mucosa compared with subjects in the nonasthmatic control group. Comparison between Groups A and B showed that subjects who developed asthma after short-term exposure had a significantly increased number of mast cells both in epithelium and in lamina propria than did subjects who developed asthma after long-term exposure to TDI (p < 0.01). Interestingly, the numbers of mast cells both in the epithelium (rs = -0.52, p < 0.05) and in the lamina propria (rs = -0.81, p < 0.001) were inversely correlated with the length of exposure to TDI before the onset of asthma. In conclusion, subjects who develop asthma after short-term exposure to TDI have an increased number of mast cells in the airway mucosa, suggesting that these cells may be associated with individual susceptibility differences to offending agents.

1993 - Occupational asthma and extrinsic alveolitis due to isocyanates: current status and perspectives. [Articolo su rivista]
O., Vandenplas; J. L., Malo; M., Saetta; C. E., Mapp; Fabbri, Leonardo
abstract

Isocyanates are used for the large scale production of polyurethane polymers, which have an almost endless variety of applications in the manufacture of flexible and rigid foams, elastomers, adhesives, and surface coatings. Acute or chronic exposure to high concentrations of isocyanates can result in respiratory health hazards through a direct irritant effect. Isocyanates are of special interest, however, because, in some exposed workers, they can cause occupational asthma or extrinsic alveolitis through an apparently sensitising mechanism.Because of their wide industrial use, isocyanates are the principal cause of occupational asthma which is now the most common respiratory disease linked to the working environment. This review focuses on recently studied aspects of occupational asthma and extrinsic alveolitis related to exposure to isocyanates.

1993 - The effect of compound 48/80 on contractions induced by toluene diisocyanate in isolated guinea-pig bronchus. [Articolo su rivista]
C. E., Mapp; A., Boniotti; A., Papi; P., Chitano; E., Coser; A., Di Stefano; M., Saetta; A., Ciaccia; Fabbri, Leonardo
abstract

We have investigated the ability of compound 48/80 and of histamine H1 and H2 receptor antagonists to inhibit toluene diisocyanate-induced contractions in isolated guinea-pig bronchi. Compound 48/80 (100 micrograms/ml) significantly inhibited toluene diisocyanate-induced contractions. By contrast, the two histamine H1 and H2 receptor antagonists, chlorpheniramine (10 microM) and cimetidine, (10 microM) did not affect toluene diisocyanate-induced contractions, but significantly inhibited contractions induced by exogenously applied histamine (100 microM) and by 48/80. We investigated which mechanisms 48/80 used to inhibit toluene diisocyanate-induced contractions, paying particular attention to the possible involvement of capsaicin-sensitive primary afferents. In vitro capsaicin desensitization (10 microM for 30 min followed by washing) significantly reduced compound 48/80-induced contractions. A capsaicin-resistant component of contraction was also evident. Ruthenium red (3 microM), an inorganic dye which acts as a selective functional antagonist of capsaicin, did not affect 48/80-induced contraction. MEN 10,207 (Tyr5,D-Trp6,8,9,Arg10)-neurokinin A (4-10) (3 microM) a selective antagonist of NK2-tachykinin receptors significantly reduced 48/80-induced contractions. These results show that compound 48/80 inhibits toluene diisocyanate-induced contractions in isolated guinea-pig bronchi. It is likely that two mechanisms are involved in the inhibition: (1) the release of mediators other than histamine by mast cells, (2) an effect of 48/80 on sensory nerves.

1993 - Toluene diisocyanate-stimulated release of arachidonic acid metabolites in the organ bath from guinea-pig airways. [Articolo su rivista]
Mapp, Ce; Boniotti, A; Masiero, M; Plebani, M; Burlina, A; Papi, A; Maestrelli, P; Saetta, M; Ciaccia, A; Fabbri, Leonardo
abstract

This study was designed to evaluate whether metabolites of arachidonic acid play a role in the contractile response to toluene diisocyanate in isolated guinea pig airways. In control experiments we collected the supernatant from an organ bath over a time period of 2 h, after the addition of toluene diisocyanate (100 and 300 microM), and after the addition of toluene diisocyanate (300 microM) in the presence of indomethacin (5 microM). We measured prostaglandin E2, 6-keto-prostaglandin F1 alpha, prostaglandin F2 alpha, thromboxane B2, leukotriene B4, leukotriene C4/D4/E4/F4 by radioimmunoassays. Levels of prostaglandin F2 alpha and 6-keto-prostaglandin F1 alpha increased significantly after addition of toluene diisocyanate in the absence of indomethacin. These results suggest that prostaglandins are involved in toluene diisocyanate-induced contractions in guinea-pig airways.

1992 - Activated T-lymphocytes and eosinophils in the bronchial mucosa in isocyanate-induced asthma. [Articolo su rivista]
A. M., Bentley; P., Maestrelli; M., Saetta; Fabbri, Leonardo; D. S., Robinson; B. L., Bradley; P. K., Jeffery; S. R., Durham; A. B., Kay
abstract

We have studied the phenotype and activation status of leukocytes in the bronchial mucosa in patients with isocyanate-induced asthma. Fiberoptic bronchial biopsy specimens were obtained from nine subjects with occupational (five toluene- and four methylene diisocyanate-sensitive) asthma, 10 subjects with extrinsic asthma, and 12 nonatopic healthy control subjects. Bronchial biopsy specimens were examined by immunohistology with a panel of monoclonal antibodies and the alkaline phosphatase—antialkaline phosphatase method. There was a significant increase in the number of CD25+ cells (interleukin-2 receptor-bearing cells, presumed “activated” T-lymphocytes; p < 0.01) in isocyanate-induced asthma compared with that of control subjects. There were also significant increases in major basic protein (BMK-13)-positive (p < 0.02) and EG2-positive (p < 0.01) cells that represent total and “activated” eosinophil cationic protein—secreting eosinophils, respectively. In agreement with our previous findings, CD25+ (p < 0.01), BMK-13 (p < 0.03), and EG2+ (p < 0.01) cells were also elevated in extrinsic asthma. No significant differences were observed in the numbers of T-lymphocyte phenotypic markers (CD3, CD4, and CD8) between subjects with asthma (isocyanate-induced and extrinsic) and control subjects. Similarly, no significant differences in immunostaining for neutrophil elastase (neutrophils) or CD68 (macrophages) were observed. The results suggest that isocyanate-induced occupational asthma and atopic (extrinsic) asthma have a similar pattern of inflammatory cell infiltrate. The results support the view that T-lymphocyte activation and eosinophil recruitment may be important in asthma of diverse etiology.

1992 - Airway mucosal inflammation in occupational asthma induced by toluene diisocyanate [Articolo su rivista]
M., Saetta; A., Di Stefano; P., Maestrelli; N., De Marzo; G. F., Milani; F., Pivirotto; C. E., Mapp; Fabbri, Leonardo
abstract

We examined the light and electron microscopic structure of lobar bronchial biopsies of nine subjects with occupational asthma induced by toluene diisocyanate (TDI) and of four control nonasthmatic subjects who had never been exposed to TDI. Inflammatory cell numbers were separately assessed in the intact epithelium, in the more superficial layer of the submucosa, and in the total submucosa. Asthmatic subjects had an increased number of inflammatory cells in the airway mucosa compared with control subjects. Eosinophils were significantly increased in all compartments, CD45-positive cells were significantly increased in the epithelium and in the more superficial layer of the submucosa, and mast cells were significantly increased only in epithelium. By electron microscopy eosinophils and mast cells appeared degranulated only in asthmatic patients. In the areas of epithelium that appeared intact by light microscopy, electron microscopy showed that, although the intercellular spaces between columnar cells were similar in asthmatic and control groups, the intercellular spaces between basal cells were significantly wider in patients with asthma. Patients with TDI-induced asthma also had a thicker subepithelial reticular layer, where immunohistochemistry showed the presence of collagen III. In conclusion, in patients with asthma induced by TDI, the airway mucosa shows pathologic features, such as inflammatory cell infiltrate and thickening of subepithelial collagen, similar to those described in atopic asthma.

1992 - Effect of cessation of exposure to toluene diisocyanate (TDI) on bronchial mucosa of subjects with TDI-induced asthma. [Articolo su rivista]
M., Saetta; P., Maestrelli; A., Di Stefano; N., De Marzo; G. F., Milani; F., Pivirotto; C. E., Mapp; Fabbri, Leonardo
abstract

The effect of cessation of exposure to toluene diisocyanate (TDI) was studied in six patients with TDI-induced asthma, proved by a positive inhalation challenge with TDI. Bronchial challenges with TDI and methacholine were performed, and lobar bronchial biopsies were taken at diagnosis and 6 months later, after cessation of exposure. Biopsies from four nonasthmatic control subjects were also examined. At diagnosis, asthmatic subjects had thickened reticular basement membrane (p less than 0.05) and increased numbers of mononuclear cells (p less than 0.05) and eosinophils (p less than 0.05) in the lamina propria when compared with control subjects. Electron microscopy showed degranulation of eosinophils and mast cells in asthmatics. Six months after cessation of exposure, the thickness of reticular basement membrane was significantly reduced compared with that at diagnosis (p less than 0.05), and it decreased to values similar to those of control biopsies. Inflammatory cell numbers in bronchial mucosa of asthmatic subjects did not change significantly 6 months after removal from exposure, and degranulation of eosinophils and mast cells was still present. At the end of the study, airway hyperresponsiveness to methacholine and/or sensitivity to TDI persisted in most of the asthmatic patients despite the cessation of exposure and the disappearance of asthmatic symptoms. In conclusion, in patients with occupational asthma induced by TDI, the avoidance of exposure to the sensitizing agent for 6 months is able to reverse the reticular basement membrane thickening in the bronchial mucosa, but the inflammatory cell infiltrate, the specific sensitivity to TDI, and the nonspecific airway hyperreactivity may persist.

1992 - Increase in vascular permeability produced in rat airways by PAF: potentiation by adrenalectomy. [Articolo su rivista]
P., Boschetto; F. G., Musajo; L., Tognetto; M., Boscaro; C. E., Mapp; P. J., Barnes; Fabbri, Leonardo
abstract

1. The effect of bilateral adrenalectomy on the sensitivity of blood vessels in rat airways to mediators that increase vascular permeability was examined. 2. An increase in vascular permeability was induced by intravenous platelet activating factor (PAF, 50, 100, 500, 1000 ng kg-1) and measured by quantifying the extravasation of Evans blue dye. 3. PAF consistently increased the amount of Evans blue extravasation in the larynx, trachea, main bronchi and intrapulmonary airways in sham-operated rats. 4. The magnitude of this extravasation was significantly greater in the larynx (P less than 0.05), trachea (P less than 0.05) and main bronchi (P less than 0.05) of the adrenalectomized rats than it was in these tissues of the sham-operated rats. 5. When adrenalectomized rats were given subcutaneous dexamethasone (0.2 mg kg-1 4 h before PAF) the amount of plasma extravasation produced by PAF was decreased to the level of the sham-operated rats. 6. We conclude that adrenalectomy potentiates the increase in airway vascular permeability induced by PAF in rats and that this effect may be due to the depletion of endogenous corticosteroids.

1992 - Investigative bronchoscopy in asthma and other airways diseases. [Articolo su rivista]
Fabbri, Leonardo; A., Ciaccia
abstract

editorial

1992 - The effect of phosphoramidon and epithelium removal on toluene diisocyanate-induced contractions in guinea-pig bronchi. [Articolo su rivista]
C. E., Mapp; A., Boniotti; A., Papi; P., Chitano; M., Saetta; A., Di Stefano; A., Ciaccia; Fabbri, Leonardo
abstract

To evaluate the role of airway neutral endopeptidase 24.11 (NEP) and epithelium removal in the contraction of airway smooth muscle in response to toluene diisocyanate (TDI), we studied the effects of the NEP inhibitor, phosphoramidon, on TDI-induced contractions of guinea-pig bronchial rings with intact epithelium and without epithelium. In preparations with intact epithelium, phosphoramidon (10 microM) potentiated the contractile response to TDI (0.3 mM) (mean +/- SEM, 23.7 +/- 2.5% versus 67.9 +/- 10.3%, p less than 0.01). Phosphoramidon also increased TDI-induced contractions in tissues without epithelium (36.9 +/- 4.9% versus 52.5 +/- 7.1%, p less than 0.05). Removal of the epithelium increased the contractile response to TDI (23.7 +/- 2.5% versus 36.9 +/- 4.9%, p less than 0.05). These results demonstrate the response to TDI is increased in epithelium-free compared to intact bronchi and that NEP 24.11 modulates the effects of endogenously released tachykinins by TDI at all of the sites where NEP is found in the airways.

1992 - The products of the reaction between toluene diisocyanate and water contract isolated guinea pig bronchi. [Articolo su rivista]
C. E., Mapp; A., Boniotti; A., Papi; P., Chitano; Fabbri, Leonardo; A., Ciaccia
abstract

We have investigated the ability of the products of the reaction between toluene diisocyanate (TDI) and water to contract bronchial smooth muscle. The experiments were performed in isolated guinea pig bronchi. TDI, both 2,4- and 2,6-toluenediamine (TDA) and mixtures of 2,4- and 2,6-TDA (ratio 80:20 and 20:80) caused concentration-dependent contraction in the isolated bronchi. The mixture of disubstituted urea and biuret also contracted the bronchi, but not in a concentration-dependent fashion. Our results provide evidence that all products of the reaction between toluene diisocyanate and water have the ability to contract isolated bronchial smooth muscle in guinea pigs. Whatever the role of toluenediamine in the adverse respiratory effects induced by exposure to isocyanates, our findings reveal the necessity of in vivo studies on the metabolism of inhaled toluene diisocyanate in humans to improve our understanding of the mechanism of action of isocyanates.

1992 - Theophylline inhibits late asthmatic reactions induced by toluene diisocyanate in sensitised subjects. [Articolo su rivista]
S., Crescioli; N., De Marzo; P., Boschetto; A., Spinazzi; M., Plebani; C. E., Mapp; Fabbri, Leonardo; A., Ciaccia
abstract

Toluene diisocyanate (TDI)-induced asthma is a frequent occupational airway disease. To determine whether a calibrated dosage of oral slow-release theophylline inhibits asthmatic reactions and the associated increase of airway responsiveness to methacholine induced by TDI, we examined six asthmatic subjects who developed a late or a dual asthmatic reaction after TDI inhalation challenge. We administered oral slow-release theophylline or placebo to each subject for 7 days according to a double-blind, randomized, cross-over study design. When the subjects received a placebo, TDI caused a late or a dual asthmatic reaction. When the subjects received theophylline. TDI caused significantly reduced late asthmatic reactions. Mean serum theophylline concentrations were within the therapeutic range. Theophylline neither modified the baseline airway responsiveness to methacholine, nor the increase of airway responsiveness to methacholine induced by TDI. These results suggest that slow-release theophylline may improve TDI-induced late asthmatic reactions, but it does not change the baseline airway responsiveness to methacholine and the increase of airway responsiveness to methacholine induced by TDI.

1991 - Airway inflammation during late asthmatic reactions induced by toluene diisocyanate. [Articolo su rivista]
Fabbri, Leonardo; P., Maestrelli; M., Saetta; C. E., Mapp
abstract

To determine the importance of airway inflammation for the development of late asthmatic reactions, we examined sensitized subjects during late asthmatic reactions induced by exposure to toluene diisocyanate (TDI) in the laboratory. Late asthmatic reactions are associated with a transient increase of bronchial responsiveness and, at the same time, with an increase of neutrophils followed by eosinophils, and of LTB4 and albumin in bronchoalveolar lavage fluid. Late asthmatic reactions, increased bronchial responsiveness, and increase of neutrophils, eosinophils, LTB4, and albumin concentration in bronchoalveolar lavage induced by exposure to TDI are all prevented by pretreatment with prednisone but not with the nonsteroidal anti-inflammatory agent indomethacin. Aerosolized steroids (beclomethasone and dexamethasone isonicotinate) completely inhibit late asthmatic reactions induced by TDI, whereas theophylline has a partial, and verapamil, ketotifen, and cromolyn have no protective effect. These results suggest that late asthmatic reactions induced by TDI may be caused by airway inflammation, and that anti-inflammatory steroids should be recommended in the prophylaxis of TDI asthma.

1991 - Bronchial hyperresponsiveness, airway inflammation and occupational asthma induced by toluene diisocyanate. [Relazione in Atti di Convegno]
Fabbri, Leonardo; C., Mapp
abstract

review

1991 - Bronchial smooth muscle responses evoked by toluene diisocyanate are inhibited by ruthenium red and by indomethacin. [Articolo su rivista]
C. E., Mapp; A., Boniotti; P. D., Graf; P., Chitano; Fabbri, Leonardo; J. A., Nadel
abstract

We have investigated the ability of ruthenium red, an inorganic dye with Ca2+ entry-blocking properties and a selective antagonist of capsaicin, and of indomethacin, a cyclooxygenase inhibitor, to inhibit bronchial smooth muscle responses evoked by toluene diisocyanate in guinea pigs. Previous exposure of isolated guinea pig bronchi to ruthenium red significantly decreased the response produced by toluene diisocyanate. Further, the response to toluene diisocyanate was significantly decreased by pretreatment with indomethacin. These findings provide evidence that toluene diisocyanate-induced contractions of guinea pig bronchi are produced indirectly by generation of a prostanoid that activates capsaicin-sensitive afferents via a ruthenium red-sensitive mechanism.

1991 - Corticosteroid inhibition of airway microvascular leakage. [Articolo su rivista]
P., Boschetto; D. F., Rogers; Fabbri, Leonardo; P. J., Barnes
abstract

We studied the effect of dexamethasone on microvascular leakage (using Evans blue dye as a marker of plasma exudation) induced in rat airways by platelet-activating factor (PAF). Intravenously administered PAF caused a dose-related increase in plasma leakage over the range 0.1 to 1 micrograms/kg. At 500 ng/kg PAF, the response was maximal in the extrapulmonary airways examined with increases in leakage above those in control animals of 312% in the larynx, 295% in the trachea, and 167% in the main bronchi. A maximal response was not achieved in the intrapulmonary airways at the doses of PAF tested: at 1 microgram/kg the increase was 206% above that in control animals. Dexamethasone, given by intraperitoneal injection 24 h and 4 h before PAF at a dose of 0.2 mg/kg on each occasion, partially inhibited leakage induced by PAF (1 microgram/kg) in all airway levels studied by 43 to 65%. At each level the tissue concentration of dye was reduced to a value that was significantly (p less than 0.05) different from either PAF or control values. We also determined whether a high dose (8 mg/kg) of dexamethasone given intraperitoneally would inhibit plasma leakage of dye induced by either PAF or antigen-challenge of sensitized rats. When given 4 h before antigen, dexamethasone completely prevented allergen-induced leakage in the airways showing significant leakage (larynx, trachea, and intrapulmonary airways). Similarly, dexamethasone (4 h before) partially inhibited PAF-induced leakage in the trachea and main bronchi. In summary, in rat airways, both low and high doses of dexamethasone markedly inhibit mediator-induced plasma exudation.

1991 - Increase in numbers of CD8 positive lymphocytes and eosinophils in peripheral blood of subjects with late asthmatic reactions induced by toluene diisocyanate. [Articolo su rivista]
S., Finotto; Fabbri, Leonardo; V., Rado; C. E., Mapp; P., Maestrelli
abstract

Occupational asthma induced by toluene diisocyanate (TDI) shares several features with allergic asthma, but the mechanism of action of TDI is poorly understood. Ten sensitised subjects, previously shown to develop a dual or late asthmatic reaction after inhaling TDI were examined. In each subject, forced expiratory volume in one second (FEV1) was measured and venous blood was taken before, and 30 minutes and eight, 24, 48, and 72 hours after exposure to TDI (0.005-0.015 ppm for 10-30 minutes). Filtered air was used as a control. Differential leucocyte counts were determined and phenotypic analysis was performed by immunofluorescence on mononuclear cells using monoclonal antibodies (anti-CD3, anti-CD4, anti-CD8, and anti-HLA-DR). Five subjects developed a dual asthmatic reaction and five had a late reaction. Percentage of CD8 positive lymphocytes increased significantly eight hours after exposure to TDI (from 27 +/- 3 (SEM) % to 42.1 +/- 5%) in the subjects with an isolated late reaction. A delayed significant further increase in suppressor/cytotoxic T lymphocytes was seen in seven of the 10 subjects 48 hours after active exposure (from 27 +/- 2% to 42 +/- 4.8%), irrespective of the type of asthmatic reaction developed after exposure to TDI. Eosinophil percentage increased from 2.5% +/- 1.0 to 6.4% +/- 1.2 24 hours after exposure to TDI and the increase was sustained for up to 48 hours (4.7 +/- 1.1%). No significant variations of FEV1 or cell percentages were seen in the controls. In conclusion, the events triggered by exposure to TDI in sensitised subjects included changes in lung function and systemic effects which lasted longer than bonchoconstriction and concerned suppressor/cytotoxic lymphocytes and eosinophils. These results suggest that TDI induced late asthmatic reactions may be associated with an immunological response to TDI or to its products.

1991 - Increased bronchial responsiveness in primary Sjögren's syndrome. A sign of tracheobronchial involvement. [Articolo su rivista]
La Corte, R; Potena, A; Bajocchi, G; Fabbri, Leonardo; Trotta, F.
abstract

Thirty-six patients with primary Sjögren's syndrome (pSS) and 60 healthy volunteers underwent provocative bronchial testing with aerosolized dosed methacholine. On the average, pulmonary functions tests performed before bronchial testing were normal. However, 18/36 patients (50%) had bronchial hyper-responsiveness (BH), an incidence higher that that found in our control population (6.6%). No difference between BH and normally responsive patients was found in the duration of disease, immunological abnormalities or symptoms, and only the FEF50 was significantly lower in the BH group. It is therefore hypothesized that in pSS bronchial hyper-responsiveness may be due to lymphocytic inflammation and an alteration in secretion secondary to gland damage.

1991 - Late asthmatic reactions, airway inflammation and chronic asthma in TDI sensitized subjects. [Articolo su rivista]
Fabbri, Leonardo; G., Picotti; C. E., Mapp
abstract

Sensitized subjects may develop symptoms of asthma after exposure to isocyanates in their place of work. After challenge with isocyanates in the laboratory, sensitized subjects develop immediate, late and dual asthmatic reactions. We speculated that toluene diisocyanate (TDI) might cause late asthmatic reactions and increase bronchial responsiveness by causing an acute inflammatory reaction in the airways, and that airway inflammation may be responsible for persistence of occupational asthma induced by isocyanates. To test these hypotheses, we examined sensitized subjects during asthmatic reactions induced by exposure to toluene diisocyanate in the laboratory. We observed that late and dual, but not early, asthmatic reactions are associated with a transient increase of bronchial responsiveness which is associated with an acute inflammatory reaction of the airways characterized by an increase of neutrophils followed by eosinophils, by an increase of leukotriene B4 and albumin in bronchoalveolar lavage fluid, and that all these effects are inhibited by steroids. Longitudinal studies suggest that the majority of subjects with occupational asthma continue to have persistent asthma months and years after the cessation of exposure, and the results of our studies combined with the results of studies performed by others suggest that the persistence of asthma may be related to the persistence of airway inflammation.

1991 - Late asthmatic reactions, airway inflammation and chronic asthma in toluene-diisocyanate-sensitized subjects. [Articolo su rivista]
Fabbri, Leonardo; M., Saetta; G., Picotti; C. E., Mapp
abstract

To determine the importance of airway inflammation for exacerbation and prognosis of asthma induced by toluene diisocyanate (TDI), we first examined sensitized subjects during asthmatic reactions induced by exposure to TDI in the laboratory. We observed that late and dual, but not early, asthmatic reactions induced by TDI are accompanied by a transient increase of airway responsiveness, bronchoalveolar neutrophilia followed by eosinophilia and by an increase of LTB4 and albumin in bronchoalveolar lavage fluid. All these effects were prevented by pretreatment with prednisone. In addition, we examined the lung pathology of 1 sensitized subject who died after exposure at work. The pathologic features of fatal asthma induced by TDI and of chronic asthma induced by TDI suggest the importance of inflammation for the exacerbation and prognosis of the disease.

1991 - Prostacyclin activates tachykinin release from capsaicin-sensitive afferents in guinea-pig bronchi through a ruthenium red-sensitive pathway. [Articolo su rivista]
C. E., Mapp; Fabbri, Leonardo; A., Boniotti; C. A., Maggi
abstract

1. We have investigated the ability of prostacyclin (PGI2) to contract guinea-pig isolated bronchi and the possible involvement of capsaicin-sensitive primary afferents in the response to PGI2. 2. PGI2 (0.1-100 microM) produced concentration-dependent contractions of the guinea-pig isolated bronchi. In vitro capsaicin desensitization (10 microM for 30 min followed by washing) significantly reduced the PGI2-induced contraction at all concentrations tested. A capsaicin-resistant component of contraction (40-60% of the overall response) was also evident. 3. Ruthenium red (3 microM), an inorganic dye which acts as a selective functional antagonist of capsaicin, significantly decreased PGI2-induced contractions, without affecting the response to substance P, neurokinin A or acetylcholine. 4. MEN 10, 207, (Tyr5, D-Trp6,8,9, Arg10)-neurokinin A (4-10) (3 microM), a selective antagonist of NK2-tachykinin receptors, significantly decreased PGI2-induced contractions and neurokinin A-induced contractions, without affecting the response to acetylcholine. 5. The effect of ruthenium red and MEN 10,207 on the one hand, and that of ruthenium red and capsaicin on the other was non additive. 6. These results indicate that PGI2-induced contraction of the guinea-pig isolated bronchi involves two distinct mechanisms, one of which involves transmitter (tachykinins) release from peripheral endings of capsaicin-sensitive primary afferents. In as much as PGI2-activation of primary afferents is sensitive to ruthenium red, we suggest that PGI2 shares a common mechanism of tachykinin release with that activated by capsaicin.

1991 - Quantitative structural analysis of peripheral airways and arteries in sudden fatal asthma. [Articolo su rivista]
M., Saetta; A., Di Stefano; C., Rosina; G., Thiene; Fabbri, Leonardo
abstract

The peripheral airways and the adjacent muscular pulmonary arteries were studied by morphometric methods in the autopsy lungs of six asthmatic subjects who died suddenly during an asthma attack, and they were compared with those of six control subjects who died of other causes and had no history of respiratory diseases. Bronchioles of asthmatic subjects had an increased amount of lumen occlusion (p less than 0.01), smooth muscle thickness (p less than 0.001), and inflammatory infiltrate (p less than 0.001), and both mononuclear cells and eosinophils contributed to this increased inflammation. The muscular pulmonary arteries adjacent to occluded and inflamed bronchioles did not have the morphologic features of chronic hypoxia, as shown by the normal medial and intimal thickness, but they had an important inflammatory process in their walls that was particularly marked at sites adjacent to airways. Although the functional significance of these findings is unknown, they may be responsible in part for the gas exchange abnormalities observed in acute severe asthma.

1991 - Salbutamol plus beclomethasone dipropionate, but not salbutamol alone, completely prevent early and late asthmatic responses to allergen. [Articolo su rivista]
P. L., Paggiaro; F. L., Dente; B., Vagaggini; E., Bacci; D., Talini; R., Testi; C. E., Mapp; Fabbri, Leonardo; C., Giuntini
abstract

The effect of a week treatment with inhaled salbutamol plus placebo (S+P) vs. salbutamol combined with beclomethasone dipropionate (S+BDP) on early and late asthmatic responses to inhaled allergen was studied in ten atopic patients in a randomized, double-blind, cross-over study. All patients had previously shown a dual type response to the specific bronchial provocative test (sBPT). Each patient performed two periods of treatment for a week, with a 15 day interval between them: (a) salbutamol 0.3 mg, tid + placebo; (b) salbutamol 0.3 mg+BDP 0.2 mg, tid; at the end of each treatment period, sBPT was performed and the last treatments were given 1.5-2 h before and 3-4 h after allergen challenge. S + BDP completely prevented both early and late responses to allergen, while S + P reduced but did not completely inhibit early and late responses. The difference between the two treatments was significant for early and late asthmatic responses. Non-specific bronchial hyperresponsiveness to methacholine was performed before each treatment period, after 6 days of treatment before sBPT and the day after sBPT at the end of the treatment period; there was only a mild increase in PD15FEV1 methacholine after 6 days of treatment with S + BDP in comparison with S + P treatment. These results suggest that salbutamol plus beclomethasone may be used effectively in the prophylaxis of early and late asthmatic reactions induced by allergen in sensitized subjects.

1991 - Theophylline inhibits early and late asthmatic reactions induced by allergens in asthmatic subjects. [Articolo su rivista]
S., Crescioli; A., Spinazzi; M., Plebani; M., Pozzani; C. E., Mapp; P., Boschetto; Fabbri, Leonardo
abstract

To determine whether oral slow-release theophylline inhibits asthmatic reactions and the associated increase of airway responsiveness to methacholine induced by allergens, we examined six asthmatic subjects who developed a dual asthmatic reactions after allergen bronchoprovocation with Dermatophagoides pteronyssinus or with grass pollen. We gave oral slow-release theophylline and placebo to each subject for seven days in two series of experiments in a double-blind, randomized, crossover study. The individual daily dose of theophylline (4.7 to 16.6 mg/kg/day, divided into two doses) was calculated for each subject by measuring individual theophylline clearance and optimal daily dosage. During treatment with placebo, the subjects developed dual asthmatic reactions, ie, FEV1 decreased from 4.1 +/- 0.17 L before bronchoprovocation to 3.2 +/- 0.14 L at 15 minutes and to 3.2 +/- 0.19 L at seven hours after allergen bronchoprovocation. By contrast, during active treatment FEV1 decreased from 4.2 +/- 0.28 L to 3.9 +/- 0.26 L at 15 minutes, and to 3.8 +/- 0.13 L at seven hours (both cases, P less than .03 compared with placebo). Mean serum theophylline concentration was 13.2 +/- 0.6 mg/L. Although 1 week's treatment with slow-release theophylline did not modify significantly either prechallenge airway responsiveness to methacholine or its increase after allergen inhalation challenge, in five out of six subjects theophylline significantly inhibited the increase of airway responsiveness to methacholine induced by allergens compared to placebo and control day (P less than .05). These results suggest that slow-release theophylline may inhibit allergen-induced asthmatic reactions and the associated increase of airway responsiveness, suggesting some antiinflammatory effects for this drug.

1990 - Clinical guidelines and indications for bronchoalveolar lavage (BAL): bronchial asthma. [Articolo su rivista]
Fabbri, Leonardo; V., De Rose; P., Godard; G. A., Rossi
abstract

ND

1990 - Clinical guidelines and indications for bronchoalveolar lavage (BAL): chronic bronchitis and emphysema. [Articolo su rivista]
E., Pozzi; V., De Rose; S. I., Rennard; Fabbri, Leonardo
abstract

ND

1990 - Effect of antiasthma drugs on asthmatic reactions induced by toluene diisocyanate in sensitized subjects. [Articolo su rivista]
Fabbri, Leonardo
abstract

To determine the effect of antiasthma drugs on asthmatic reactions and airway inflammation, we studied several groups of sensitized subjects treated with active drugs or placebo before and after exposure to toluene diisocyanate in the laboratory. We observed that the steroidal anti-inflammatory agent prednisone, but not the nonsteroidal anti-inflammatory agent indomethacin, inhibits the late (but not the early) asthmatic reactions induced by TDI. Prednisone also inhibits the increase of bronchial responsiveness and the increase of neutrophils, eosinophils, and albumin in bronchoalveolar lavage fluid that are associated with late asthmatic reactions induced by exposure to TDI. Beclomethasone has a dose-dependent inhibitory effect on TDI-induced late asthmatic reactions, whereas theophylline has a partial inhibitory effect on both early and late asthmatic reactions, and verapamil, ketotifen, cromolyn. Beta 2-adrenergic agonists have variable effects: salbutamol has no effect on early and late asthmatic reactions by itself, but it potentiates the inhibitory effect of low doses of beclomethasone. Broxaterol inhibits early asthmatic reactions, but has no effect on the late asthmatic reactions and the associated inflammatory response. These results suggest that, in sensitized subjects, late asthmatic reactions induced by toluene diisocyanate can be prevented by steroidal anti-inflammatory agents, whereas early asthmatic reactions may be prevented either by an association of inhaled steroids and beta-adrenergic agonists, or by beta-adrenergic agonists (e.g., broxaterol) with more complex mechanisms of action.

1990 - Enfisema polmonare: prospettive di terapia [Articolo su rivista]
Ciaccia, A; Fabbri, Leonardo; Papi, A; Chicca, M; Grandi, G; Pinamonti, S.
abstract

n/d

1990 - Evidence that toluene diisocyanate activates the efferent function of capsaicin-sensitive primary afferents. [Articolo su rivista]
C. E., Mapp; P., Chitano; Fabbri, Leonardo; R., Patacchini; P., Santicioli; P., Geppetti; C. A., Maggi
abstract

Isocyanates are an important cause of occupational asthma. The mechanism of isocyanate-induced asthma is still unknown. To determine whether toluene diisocyanate stimulates the 'efferent' function of peripheral endings of capsaicin-sensitive sensory nerves, we investigated the effect of toluene diisocyanate in the rat isolated urinary bladder, a preparation in which the action of capsaicin has been well characterized. Toluene diisocyanate (0.03-3 mM) produced a concentration-dependent contraction of the bladder strips. Its maximal effect was about 50% of the response to capsaicin (1 microM). Previous exposure of the strips to capsaicin followed by washing out produced complete unresponsiveness, both to the first exposure to toluene diisocyanate and to a second exposure of capsaicin. Further, the response to both toluene diisocyanate and capsaicin was completely prevented by extrinsic bladder denervation, achieved by bilateral removal of pelvic ganglia (72 h before). Repeated exposure of the rat bladder to toluene diisocyanate reduced the capsaicin-evoked release of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI), taken as biochemical marker of activation of these sensory nerves. These experiments provide the first evidence that toluene diisocyanate activates directly or indirectly the efferent function of capsaicin-sensitive primary sensory nerves.

1990 - Increased bronchial responsiveness in primary and secondary Sjögren's syndrome. [Articolo su rivista]
A., Potena; R., La Corte; Fabbri, Leonardo; A., Papi; F., Trotta; A., Ciaccia
abstract

We examined one group of 33 patients with primary Sjögren's syndrome, one group of 17 patients with secondary Sjögren's syndrome, i.e. associated with other connective tissue diseases, and one group of 14 patients with connective tissue diseases but without Sjögren's syndrome. In each patient we obtained chest radiographs and measured lung volumes, carbon monoxide diffusing capacity and airway responsiveness to methacholine. We observed no difference in chest radiograph abnormalities, in lung volumes and in carbon monoxide diffusing capacity among the three groups. However, we found a slight but significant increase of bronchial responsiveness in patients with primary and secondary Sjögren's syndrome compared with patients with connective tissue disorders but without Sjögren's syndrome. Thus PD20FEV1 methacholine was 1.07 mg (1.2) (geometric mean and GSEM) in primary Sjögren's syndrome, 0.91 mg (1.4) in secondary Sjögren's syndrome (NS), and 2.24 mg (1.09) in patients with connective tissue diseases but without Sjögren's syndrome (t = 2.59 and t = 2.8, both p less than 0.05, vs primary and secondary Sjögren's syndrome, respectively). These results show that some patients with Sjögren's syndrome have mild bronchial hyperresponsiveness, which may be related to the specific airway abnormalities of this disease.

1990 - Leukotriene B4 and late asthmatic reactions induced by toluene diisocyanate. [Articolo su rivista]
E., Zocca; Fabbri, Leonardo; P., Boschetto; M., Plebani; M., Masiero; G. F., Milani; F., Pivirotto; C. E., Mapp
abstract

We investigated whether leukotriene B4 (LTB4) is released from the lungs of sensitized subjects during asthmatic reactions induced by toluene diisocyanate (TDI). We examined three groups of TDI-sensitized subjects, one after no exposure to TDI, the second 8 h after an exposure to TDI that caused an early asthmatic reaction, and the third 8 h after an exposure to TDI that caused a late asthmatic reaction. We analyzed bronchoalveolar lavage (BAL) fluid by reverse-phase high-performance liquid chromatography and by specific radioimmunoassay. The mean concentration of LTB4 was higher [0.31 +/- 0.09 (SE) ng/ml, range 0.15-0.51] in BAL fluid of sensitized subjects who developed a late asthmatic reaction than in BAL fluid of subjects who developed an early asthmatic reaction (0.05 +/- 0.04 ng/ml, range 0-0.224), and no LTB4 was detectable in the control subjects. We also performed BAL 8 h after TDI exposure on four TDI-sensitized late-dual reactors who were on steroid treatment. In this group of subjects no LTB4 was detectable. These results suggest that LTB4 may be involved in late asthmatic reactions induced by TDI.

1990 - Pharmacological modulation of the contractile response to toluene diisocyanate in the rat isolated urinary bladder. [Articolo su rivista]
C. E., Mapp; P., Chitano; Fabbri, Leonardo; R., Patacchini; C. A., Maggi
abstract

1. Toluene diisocyanate produced concentration-dependent contractions of the rat isolated urinary bladder. 2. The contractions were tetrodotoxin-resistant and were abolished by previous exposure of the strips to capsaicin. 3. Indomethacin (5 microM) and ruthenium red (30 microM) inhibited toluene diisocyanate-induced contractions. Responses expressed as a percentage of the response obtained with substance P, 30 nM, were respectively 141.6 +/- 24.8% and 20.1 +/- 5.1% in control and indomethacin-treated strips (P less than 0.005); 123.0 +/- 30.2% and 14.0 +/- 6.5% in control and ruthenium red-treated strips (0.01 less than P less than 0.05). 4. These results suggest that toluene diisocyanate-induced contractions of the rat isolated bladder are the result of the release of cyclo-oxygenase products which may act by activating the capsaicin receptor.

1990 - Therapeutic applications of BAL. [Articolo su rivista]
C., Danel; D., Israel Biet; U., Costabel; Fabbri, Leonardo; H., Klech
abstract

review

1990 - Venous blood platelets decrease during allergen-induced asthmatic reactions. [Articolo su rivista]
P., Maestrelli; P., Boschetto; E., Zocca; S., Crescioli; P., Baroldi; C., Mapp; Fabbri, Leonardo
abstract

To determine whether circulating platelets alter during asthmatic reactions induced by allergens, we studied nine subjects previously shown to develop an early or dual asthmatic reaction after inhalation challenge with extracts of house dust mite or grass pollen. In each subject, FEV1, circulating platelets and leucocytes were measured before, 15, 30 and 60 min, and 2, 4, 6 and 8 hr after inhalation of allergen and diluent control administered in a single-blind, randomized fashion. The same procedure was repeated in six of the nine subjects after bronchoconstriction induced by methacholine. Each subject developed an early asthmatic reaction after allergen inhalation challenge, which was followed by a late asthmatic reaction in six subjects and by an equivocal late asthmatic reaction in two of them (fall in FEV1 of 15 and 17% respectively). Compared with the control day, circulating platelets significantly decreased during the allergen-induced early asthmatic reaction (P less than 0.025, at 30 min). Platelet counts returned to baseline values within 4 hr and remained steady thereafter both in subjects who did and did not develop a late asthmatic reaction. No changes in platelet counts occurred after bronchoconstriction induced by methacholine. Diurnal increase of leucocyte numbers occurred after challenge with both allergen and diluent control. These results suggest that platelets may be involved in the pathogenesis of allergen-induced asthmatic reactions.

1989 - Airway smooth muscle biochemistry and asthma. [Articolo su rivista]
N., De Marzo; P., Di Blasi; P., Boschetto; C. E., Mapp; S., Sartore; G., Picotti; Fabbri, Leonardo
abstract

The contractile properties of muscle cells are related to the molecular structure of myosin. The molecular structure and the antigenicity of myosin isoforms is different in skeletal, cardiac, and smooth muscle. We investigated whether different isoforms of myosin heavy chains are present in smooth muscle from human lungs. We observed that the distribution of three isoforms of smooth muscle myosin heavy chains is different in airways compared to pulmonary arteries, and in central airways and arteries compared to lung parenchyma. We also observed that asthmatic subjects have a similar distribution, but different immunoreactivity of myosin heavy chains in bronchial smooth muscle compared to normal subjects. These data suggest that changes in the contractile properties of smooth muscle in human lungs may be associated with changes in myosin heavy chain isoforms.

1989 - Ambroxol inhibits airway hyperresponsiveness induced by ozone in dogs. [Articolo su rivista]
P., Chitano; A., Di Stefano; S., Finotto; G., Zavattini; P., Maestrelli; C., Mapp; Fabbri, Leonardo; L., Allegra
abstract

To follow up previous observations that airway hyperresponsiveness induced by ozone is linked to airway inflammation and particularly to the release of arachidonic acid metabolites, we investigated the effect of ambroxol (a mucoactive and surfactant-stimulating drug that has recently been discovered to inhibit the release of arachidonic acid from cell membrane phospholipids) on airway hyperresponsiveness and bronchoalveolar neutrophilia induced by ozone in dogs. One group of 5 dogs was studied before treatment with nebulized saline and then after exposure to ozone (3 ppm, 1 h); another group of 6 dogs was studied before treatment with ambroxol (100 breaths of a 1% solution) and after exposure to ozone. On each occasion, we measured airway responsiveness to acetylcholine and counted the number of cells in bronchoalveolar lavage fluid. When the dogs were given the saline placebo, ozone induced a marked increase in airway responsiveness to acetylcholine and a marked influx of neutrophils in the airways. When the dogs were given ambroxol, ozone induced the same increase in the number of neutrophils in bronchoalveolar lavage, but did not increase the degree of airway responsiveness to acetylcholine. We conclude that ambroxol inhibits ozone-induced airway hyperresponsiveness in dogs, probably by inhibiting the formation and release of oxygenation products of arachidonic acid from neutrophils.

1989 - Bronchial epithelium and asthma. [Articolo su rivista]
L., Allegra; Fabbri, Leonardo; G., Picotti; S., Mattoli
abstract

The bronchial epithelium has a number of mechanical functions, including mucociliary clearance and protection against noxious agents. It may also modulate the function of the underlying smooth muscle by metabolism and regulation of mediators and the production of relaxant or constrictor substances, and regulate the activation and differentiation of lymphocytes and mast cells by releasing chemotactic factors and cytokines. It is possible that epithelial structural and functional abnormalities may lead via several mechanisms to increased bronchial responsiveness in asthmatic subjects.

1989 - Dexamethasone isonicotinate inhibits dual and late asthmatic reactions but not the increase of airway responsiveness induced by toluene diisocyanate in sensitized subjects. [Articolo su rivista]
L., Tossin; P. C., Corona; G. B., Leproux; N., De Marzo; S., Crescioli; Fabbri, Leonardo; C. E., Mapp
abstract

To determine whether treatment with aerosolized dexamethasone isonicotinate inhibits asthmatic reactions and the associated increase in airway responsiveness induced by toluene diisocyanate (TDI), we studied six sensitized subjects with previously demonstrated dual or late asthmatic reaction after inhalation challenge with TDI. Dexamethasone isonicotinate (four puffs bid for seven days, ie, 0.5 mg bid for seven days; last four puffs 30 minutes before TDI) was administered for seven days before the inhalation challenge with TDI (0.010 to 0.015 ppm for 10 to 30 minutes) to each subject, according to a single-blind study design. When the subjects received no treatment, FEV1 markedly decreased and airway responsiveness increased after exposure to TDI. By contrast, when the subjects were treated with dexamethasone-isonicotinate, FEV1 decreased significantly less, but airway responsiveness still significantly increased after exposure to TDI. These results suggest that aerosolized dexamethasone isonicotinate may be used in the prophylaxis of TDI-induced late asthmatic reactions.

1989 - Fatal asthma in a young patient with severe bronchial hyperresponsiveness but stable peak flow records. [Articolo su rivista]
M., Saetta; G., Thiene; S., Crescioli; Fabbri, Leonardo
abstract

We report the sudden death of a 16 yr old boy with asthma. At presentation, the patient had symptoms of active asthma, mild bronchoconstriction, severe airway hyperresponsiveness to methacholine, and increased variability of peak expiratory flow records. After the patient was placed on inhaled beclomethasone (1 mg b.i.d preceded by inhaled fenoterol 0.4 mg b.i.d) he rapidly felt better, lung function improved, but airway responsiveness remained severe. Four months later, on the day he died, he was well until a fatal attack of asthma occurred around midnight without identifiable precipitating factors. Taken to hospital, he was dead on arrival. Necroscopy and microscopy showed the characteristic features of asthma death. This case report suggests that; a) asthma death may occur suddenly and unexpectedly; b) asthma death may not be prevented by long-term treatment with high-dose inhaled beclomethasone; c) severe bronchial hyperresponsiveness, even in the presence of stable peak flow records, may identify asthmatic patients at risk of sudden death.

1989 - Guidelines for bronchoprovocation on the investigation of occupational asthma. Report of the Subcommittee on Bronchoprovocation for Occupational Asthma. [Articolo su rivista]
A., Cartier; I. L., Bernstein; P. S., Burge; J. R., Cohn; Fabbri, Leonardo; F. E., Hargreave; J. L., Malo; R. T., Mckay; J. E., Salvaggio
abstract

ND

1989 - Ketotifen does not inhibit asthmatic reactions induced by toluene di-isocyanate in sensitized subjects. [Articolo su rivista]
L., Tossin; P., Chiesura Corona; Fabbri, Leonardo; N., De Marzo; G., Picotti; S., Crescioli; C. E., Mapp
abstract

In order to determine whether treatment with ketotifen inhibits asthmatic reactions induced by toluene di-isocyanate (TDI), we studied six sensitized subjects with previously demonstrated dual or late asthmatic reaction after inhalation challenge with TDI. Ketotifen (1 mg b.i.d., orally) or placebo was administered for 7 days to the examined subjects, according to a double-blind, cross-over, placebo-controlled study design. When the subjects were treated with either ketotifen or placebo, FEV1 markedly decreased after exposure to TDI. These results suggest that the anti-asthmatic agent ketotifen is not effective in TDI-induced asthma and suggest that it should not be used in the prophylaxis of asthmatic reactions induced by TDI in sensitized subjects.

1989 - Myosin heavy-chain isoforms in human smooth muscle. [Articolo su rivista]
Sartore, S; De Marzo, N; Borrione, Ac; Zanellato, Am; Saggin, L; Fabbri, Leonardo; Schiaffino, S.
abstract

The myosin heavy-chain composition of human smooth muscle has been investigated by sodium dodecyl sulfate/polyacrylamide gel electrophoresis, enzyme immunoassay, and enzyme-immunoblotting procedures. A polyclonal and a monoclonal antibody specific for smooth muscle myosin heavy chains were used in this study. The two antibodies were unreactive with sarcomeric myosin heavy chains and with platelet myosin heavy chain on enzyme immunoassay and immunoblots, and stained smooth muscle cells but not non-muscle cells in cryosections and cultures processed for indirect immunofluorescence. Two myosin heavy-chain isoforms, designated MHC-1 and MHC-2 (205 kDa and 200 kDa, respectively) were reactive with both antibodies on immunoblots of pyrophosphate extracts from different smooth muscles (arteries, veins, intestinal wall, myometrium) electrophoresed in 4% polyacrylamide gels. In the pulmonary artery, a third myosin heavy-chain isoform (MHC-3, 190 kDa) electrophoretically and antigenically distinguishable from human platelet myosin heavy chain, was specifically recognized by the monoclonal antibody. Analysis of muscle samples, directly solubilized in a sodium dodecyl sulfate solution, and degradation experiments performed on pyrophosphate extracts ruled out the possibility that MHC-3 is a proteolytic artefact. Polypeptides of identical electrophoretic mobility were also present in the other smooth muscle preparations, but were unreactive with this antibody. The presence of three myosin heavy-chain isoforms in the pulmonary artery may be related to the unique physiological properties displayed by the smooth muscle of this artery.

1989 - Neutrophils and asthma. [Articolo su rivista]
P., Boschetto; C. E., Mapp; G., Picotti; Fabbri, Leonardo
abstract

The importance of inflammation in asthma has been recognized for a long time and recently proved in man and animal models. All inflammatory cells are probably involved in exacerbations of asthma. Neutrophils in particular are present in the airways during and after the spontaneous asthma attacks in man and during asthmatic reactions and airway hyperresponsiveness induced experimentally in man and animals. Depletion of neutrophils prevents these effects and repletion with neutrophils reconstitutes them. Moreover, the supernatant from stimulated human neutrophils causes transient hyperresponsiveness. However, neutrophils are not increased in stable asthmatics with hyperreactive airways and are not involved in airway hyperresponsiveness induced experimentally in some animals (e.g. guinea-pigs). The studies reviewed suggest that neutrophils may be involved in the transient increases of airway responsiveness associated with exacerbations of asthma, but not in the long-lasting hyperresponsiveness of stable asthmatics.

1989 - Non-allergic factors of bronchial asthma [Articolo su rivista]
S., Mattoli; Fabbri, Leonardo; C. E., Mapp; L., Allegra
abstract

The functional characteristic of all forms of asthma is the airway hyperresponsiveness to several stimuli. Airway hyperresponsiveness is always present in current asthmatics and can be also documented in some subjects during the symptom-free periods. The mechanisms of the spontaneous or induced increases of airway hyperresponsiveness are probably different from those responsible for stable airway hyperresponsiveness. The transitory increases in airway hyperresponsiveness are associated with an acute inflammatory response of the bronchial mucosa, whereas airway inflammation is not a constant finding in subjects with stable airway hyperresponsiveness. The mechanisms involved in the latter condition might be a functional and/or structural derangement of bronchial epithelium, a functional or structural alteration of airway smooth muscle or alteration in the function of the autonomic nervous system.

1989 - Pathology of bronchial asthma and animal models of asthma. [Articolo su rivista]
M., Saetta; Fabbri, Leonardo; D., Danieli; G., Picotti; L., Allegra
abstract

We reviewed studies on pathology of status asthmaticus, asymptomatic asthma, and of animal models developed to study the pathogenesis of asthma. In status asthmaticus airway occlusion by mucous plugs, desquamed epithelium, goblet cell hyperplasia, submucosal glands hypertrophy, increased smooth muscle, basal membrane thickening, inflammatory infiltration of the bronchial mucosa are observed, together with focal areas of alveolar wall destruction in lung parenchyma. At variance with active asthma, in which almost invariably inflammatory cells infiltrate the mucosa, only scarce airway inflammation is reported in asthmatics between attacks. The majority of the animal models developed so far have been addressed to investigate the mechanism of the transient hyperreactivity that is associated with exacerbations of asthma, while little information is available on the structure-function relationship on long-lasting hyperresponsiveness.

1989 - Response to acetylcholine and myosin content of isolated canine airways. [Articolo su rivista]
C. E., Mapp; P., Chitano; N., De Marzo; P., Di Blasi; M., Saetta; A., Di Stefano; V. M., Bosco; L., Allegra; Fabbri, Leonardo
abstract

Contractility of tracheal smooth muscle strips and spiral strips of fourth to fifth generation bronchi was studied in organ baths. The relationship among contractility, airway smooth muscle myosin, and smooth muscle thickness was also examined. The trachea was divided into three segments, each consisting of 12-14 rings. Smooth muscle strips from each of the three regions (top, middle, and bottom of the trachea) and from fourth to fifth generation bronchi were studied. Acetylcholine (ACh) sensitivity (-log EC50) was 8.1, 7.1, 7.9, and 6.1 for the top, middle, and bottom of the trachea and the bronchi, respectively. At P = 0.01, the EC50 ACh value of the top of the trachea differed from the EC50 value of the bronchi. Maximal tension (Tmax) generated in bronchi (3.2 g) was lower (P less than 0.01) than in the top (10.4 g), middle (7.1 g), and bottom of the trachea (5.1 g). Differences between trachea and bronchi disappeared when Tmax was corrected for smooth muscle myosin content. Thickness of smooth muscle in bronchi was less (P less than 0.01) than in the three regions of trachea. Tmax was significantly correlated with airway smooth muscle thickness (r = 0.56; P less than 0.05). These results suggest that in mongrel dogs sensitivity to ACh shows a gradient from the top of the trachea to the bronchi and that Tmax is greater in the trachea than in the bronchi and is significantly correlated with thickness of smooth muscle.

1989 - Steroid and non-steroid anti-inflammatory agents in asthma. [Articolo su rivista]
C. E., Mapp; P., Boschetto; G., Picotti; N., De Marzo; Fabbri, Leonardo
abstract

Anti-inflammatory steroids are the principal agents for the treatment of asthma. Systemic corticosteroids are recommended for the treatment of acute episodes of asthma, whereas inhaled steroids should be used in the long-term prophylaxis of asthma. Because of their side-effects, there is a need for additional research and development of steroids without systemic activity, and/or other anti-inflammatory agents for use in the long-term prophylaxis of asthma.

1988 - Dose-dependent inhibitory effect of inhaled beclomethasone on late asthmatic reactions and increased responsiveness to methacholine induced by toluene diisocyanate in sensitised subjects. [Articolo su rivista]
N., De Marzo; Fabbri, Leonardo; S., Crescioli; M., Plebani; R., Testi; C. E., Mapp
abstract

To determine whether inhaled beclomethasone, both at low and at high doses, inhibits late asthmatic reactions and the associated increase in airway responsiveness induced by toluene diisocyanate (TDI), we studied 9 sensitised subjects. Low dose beclomethasone (200 micrograms bid), high dose beclomethasone aerosol (1000 micrograms bid), and placebo were administered for 7 days before TDI inhalation challenge to each subject, according to a double-blind, crossover study design. The washout period between the treatments was at least 1 week. When the subjects were treated with placebo, forced expiratory volume in 1 sec (FEV1) markedly decreased after exposure to TDI. By contrast, high dose beclomethasone prevented the late asthmatic reaction and the low dose partially inhibited the reaction. With placebo the mean (+/- SE) value of FEV1 4 h after exposure to TDI was 2.6 +/- 0.17 L, which went to 3.3 +/- 0.12 after low dose beclomethasone, and to 3.5 +/- 0.15 L after high dose of beclomethasone (significant difference in the decrease of FEV1 in the 8 h after exposure to TDI, between treatments: F = 9.87, (P less than 0.001), After treatment with placebo or with low dose beclomethasone, airway responsiveness to methacholine increased 8 h after exposure to TDI. With placebo, the PD20 decreased from 0.66 mg (Geometric Standard Error of the Mean [GSEM], 1.38) to 0.18 mg (GSEM, 1.46); with low dose inhaled beclomethasone, the PD20 decreased from 0.93 mg (GSEM, 1.42) to 0.36 mg (GSEM, 1.63).

1988 - Fatal asthma in a subject sensitized to toluene diisocyanate. [Articolo su rivista]
Fabbri, Leonardo; D., Danieli; S., Crescioli; P., Bevilacqua; S., Meli; M., Saetta; C. E., Mapp
abstract

We report the case of a 43-yr-old car painter who died within 1 h of exposure to a polyurethane paint in the workplace. A diagnosis of asthma induced by toluene diisocyanate (TDI) had been established 6 yr before, when he underwent inhalation challenges with carbachol and with TDI. The subject had airway hyperresponsiveness to carbachol (PD20FEV1 carbachol = 0.32 mg; normal value greater than 1.0 mg) and developed an early and long-lasting asthmatic reaction after exposure to TDI in the laboratory. Although it was recommended that he change his job or stop using paints containing isocyanates, he continued to work as a car painter, taking antiasthmatic drugs both at work and at home to control asthma symptoms. On Monday, October 6, 1986, at 11:30 A. M., he developed a severe attack of asthma while he was mixing the 2 components of a polyurethane paint. Taken to hospital, he was dead on arrival. Autopsy showed no evidence of cardiac or brain disease; lungs were overinflated, the cut surface showed grey glistening mucous plugs in in the airways. Histologic examination showed denudation of airway epithelium and thickening of the basement membrane with infiltration of the lamina propria by polymorphonuclear leukocytes, mainly eosinophils, and diffuse mucous plugging of bronchioles. Bronchial smooth muscle appeared hyperplastic and disarrayed, and lung parenchyma showed focal areas of alveolar destruction adjacent to areas of perfectly intact alveolar walls.

1988 - Occupational asthma due to isocyanates. [Articolo su rivista]
C. E., Mapp; P., Boschetto; L., Dal Vecchio; P., Maestrelli; Fabbri, Leonardo
abstract

162 subjects who had been exposed to isocyanates, who had developed symptoms during the exposure period, or in the evening or night and, therefore, had a history compatible with isocyanate-induced asthma, were studied with inhalation challenge testing to isocyanates (toluene diisocyanate and methylene diphenyl diisocyanate) and methacholine, because they were suspected of having occupational asthma. None of these subjects had symptomatic asthma before employment. The diagnosis of occupational asthma was delayed (duration of symptoms before diagnosis: 3.9 +/- 0.4 yrs). Isocyanate-asthma documented by a positive inhalation challenge to isocyanates was present in 57.4% of the subjects. A higher degree of airway responsiveness to methacholine was present in subjects with a positive isocyanate inhalation challenge compared to subjects with a negative challenge (Gmean and GESM: 0.407 (1.14) vs 0.942 (1.14) mg). The majority of the subjects complained of shortness of breath and cough. The low proportion of atopic subjects (21.5%) and of smokers (7.5%), and the high proportion of subjects with the late component in the asthmatic reaction (71%) appear to be common features in this disease.

1988 - Pathogenesis of bronchial hyperresponsiveness. [Articolo su rivista]
Fabbri, Leonardo; P., Boschetto; E., Zocca; N., De Marzo; S., Crescioli; P., Maestrelli; C. E., Mapp
abstract

In asthmatic subjects, the degree of bronchial hyperresponsiveness correlates with the severity of asthma and the amount of treatment required to control asthma. Both in normal and in asthmatic subjects, the degree of airway responsiveness may increase after viral infections, exposure to oxidant pollutants and allergens or sensitizing agents; however, airway hyperresponsiveness is quite stable in the absence of exposure to inflammatory stimuli, suggesting that there are at least two components in airway hyperresponsiveness: a transient component, caused by airway inflammation, and a long-lasting one, unrelated to exposure to acute inflammatory stimuli, which is hypothesized to be due to changes in the autonomic innervation or in the smooth muscle itself.

1988 - Persistent asthma due to isocyanates. A follow-up study of subjects with occupational asthma due to toluene diisocyanate (TDI). [Articolo su rivista]
Mapp, Ce; Corona, Pc; De Marzo, N; Fabbri, Leonardo
abstract

Thirty-five subjects with occupational asthma due to toluene diisocyanate (TDI) exposure were examined. All the subjects were studied with inhalation challenges with TDI and with methacholine. TDI asthma was documented by a positive inhalation challenge to low levels of TDI. Airway responsiveness to methacholine was in the range of asthmatic patients at the time of diagnosis. After an average follow-up interval of 10 months, all the subjects were re-examined. Of the 35 subjects examined, 30 subjects (85.7%) left the workplace, and 5 remained in the same job. Twenty-seven subjects (77.1%) continued to have asthmatic attacks requiring medication for relief of symptoms. At follow-up examination, TDI asthma was documented by a positive inhalation challenge to TDI in 27 subjects. Of these 27 TDI reactors, 22 subjects were removed from occupational exposure to TDI. The TDI reactors had persistent respiratory symptoms and airway hyperresponsiveness to methacholine. At follow-up visit, 8 subjects (22.9%) lost sensitization to TDI; 5 subjects (62.5%) in this group had also normal airway responsiveness to methacholine after removal from exposure. Only 1 subject among the TDI nonreactors complained of mild respiratory symptoms. At diagnosis, there were no significant differences between subjects who recovered and those who did not with regard to age, smoking habits, atopy, duration of exposure to isocyanates, duration of symptoms, baseline FEV1 (% pred), and baseline airway responsiveness to methacholine.(ABSTRACT TRUNCATED AT 250 WORDS)

1987 - Atropine does not inhibit late asthmatic responses induced by toluene-diisocyanate in sensitized subjects. [Articolo su rivista]
P., Paggiaro; E., Bacci; D., Talini; F. L., Dente; O., Rossi; N., Pulerá; Fabbri, Leonardo; C., Giuntini
abstract

To determine whether early and/or late asthmatic responses induced by toluene diisocyanate (TDI) are caused by a reflex mechanism involving stimulation of muscarinic receptors, we studied the effect of the muscarinic antagonist atropine on early and late airway response induced by TDI. A preliminary study was conducted in asthmatics to assess whether the selected dose of atropine provided adequate muscarinic blockade. On different days we measured the provocation dose (in milligrams) of carbachol causing a 15% decrease in FEV1 (PD15FEV1) without and with atropine premedication (0.008 or 0.012 mg/kg subcutaneous atropine 30 or 90 min before carbachol challenge test). We found that 0.008 to 0.012 mg/kg subcutaneous atropine increased the PD15FEV1 carbachol by 6- to 10-fold, inducing a consistent and prolonged decrease in nonspecific bronchial hyperresponsiveness to cholinergic agent. Then we examined 10 subjects with a history of sensitization to TDI in 2 sets of experiments. In the first set of experiments, we studied the subjects before and after exposure to TDI (0.04 ppm; 30 min) after no treatment. In the second set of experiments, carried out 1 to 2 wk later, we repeated the same procedure after treatment with atropine (0.008 to 0.012 mg/kg atropine sulfate administered subcutaneously 30 min before TDI challenge, and then at 90-min intervals after TDI exposure); all patients showed symptoms of atropine effect (dryness of mouth, cycloplegia, increased heart rate).

1987 - Bronchoalveolar neutrophilia during late asthmatic reactions induced by toluene diisocyanate. [Articolo su rivista]
Fabbri, Leonardo; P., Boschetto; E., Zocca; G., Milani; F., Pivirotto; M., Plebani; A., Burlina; B., Licata; C. E., Mapp
abstract

The mechanism by which late asthmatic reactions are induced by toluene diisocyanate (TDI), a low molecular weight chemical that causes occupational asthma in exposed subjects, is unknown. We investigated whether early and late asthmatic reactions induced by TDI are associated with changes in airway responsiveness to methacholine and airway inflammation as determined by bronchoalveolar lavage. We measured FEV1 before and at regular intervals after exposure to TDI, and performed dose-response curves to methacholine and bronchoalveolar lavage at 8 h after TDI in a group of 6 subjects with late asthmatic reactions and in 6 subjects with only early asthmatic reactions. The same procedure was followed 2 h after TDI in a group of 6 subjects with previously documented late asthmatic reactions and in a group of 6 subjects without any previously documented asthmatic reaction after TDI. In subjects with late asthmatic reactions, neutrophils were increased at both 2 and 8 h, and eosinophils and airway responsiveness were increased only at 8 h. By contrast, neutrophils, eosinophils and airway responsiveness were not increased at 8 h after TDI in subjects with an early asthmatic reaction or at 2 h after TDI in normal control subjects. These results suggest that late asthmatic reactions to TDI, and the associated increase in airway responsiveness, may be caused by airway inflammation.

1987 - Importance of airway inflammation for late asthmatic reactions induced by toluene diisocyanate in sensitized subjects. [Articolo su rivista]
P., Boschetto; E., Zocca; O., Bruchi; G., Cappellazzo; G. F., Milani; F., Pivirotto; C. E., Mapp; Fabbri, Leonardo
abstract

To determine the importance of airway inflammation for late asthmatic reactions and increased airway responsiveness induced by TDI, we investigated whether late asthmatic reactions and increased responsiveness induced by TDI are associated with airway inflammation and whether steroids prevent them by modifying the inflammatory response within the airways. We measured FEV1 before and at regular intervals after exposure to TDI and performed dose-response curves to methacholine and bronchoalveolar lavage 8 hr after TDI in two subjects with previously documented late asthmatic reaction; then we repeated the same procedure a few weeks after treatment with steroids. Airway responsiveness and polymorphonuclear cells were increased in both subjects after the late asthmatic reaction; treatment with steroids prevented late asthmatic reaction and the increase in airway responsiveness and polymorphonuclear cells in bronchoalveolar lavage. These results suggest that late asthmatic reaction induced by TDI may be caused by airway inflammation.

1987 - Prednisone inhibits late asthmatic reactions and airway inflammation induced by toluene diisocyanate in sensitized subjects. [Articolo su rivista]
P., Boschetto; Fabbri, Leonardo; E., Zocca; G., Milani; F., Pivirotto; A., Dal Vecchio; M., Plebani; C. E., Mapp
abstract

To determine the importance of airway inflammation for late asthmatic reactions induced by toluene diisocyanate (TDI), we investigated whether prednisone prevented them [corrected] by modifying the associated airway inflammatory reaction. We measured FEV1 before and at regular intervals after exposure to TDI and performed bronchoalveolar lavage at 8 hours after TDI in two groups of subjects with previously documented late asthmatic reactions, in one group, after no treatment, and in the other group, after treatment with prednisone (50 mg/day for 4 days). After no treatment, each subject developed a late asthmatic reaction, an increase in airway responsiveness, polymorphonuclear leukocytosis, and increased albumin in bronchoalveolar lavage. By contrast, after treatment with prednisone, no subject developed a late asthmatic reaction or an increase in airway responsiveness, and the number of leukocytes and the concentration of albumin were normal in bronchoalveolar lavage. These results suggest that late asthmatic reactions induced by TDI may be caused by airway inflammation and that prednisone may block them [corrected] by inhibiting the inflammatory reaction of the airway induced by TDI in sensitized subjects.

1987 - Protective effect of antiasthma drugs on late asthmatic reactions and increased airway responsiveness induced by toluene diisocyanate in sensitized subjects. [Articolo su rivista]
C., Mapp; P., Boschetto; L., dal Vecchio; S., Crescioli; N., de Marzo; D., Paleari; Fabbri, Leonardo
abstract

To determine whether 4 drugs used in the treatment of asthma inhibit the late asthmatic reaction and the associated increase in airway responsiveness induced by toluene diisocyanate (TDI), we studied 24 sensitized subjects divided into 4 groups. Beclomethasone aerosol (1 mg bid), slow-release theophylline (6.5 mg/kg bid), slow-release verapamil (120 mg bid), and cromolyn (20 mg qid via spinhaler), were administered for 7 days, respectively, to 1 of the 4 groups, according to a double-blind, crossover, placebo-controlled study design. When the subjects were treated with placebo, verapamil, or cromolyn, FEV1 markedly decreased and airway responsiveness increased after exposure to TDI. By contrast, beclomethasone prevented the late asthmatic reaction and the associated increase in airway responsiveness to methacholine induced by TDI. Slow-release theophylline partially inhibited both the immediate and the late asthmatic reactions but had no effect on airway hyperresponsiveness to methacholine. These results suggest that only high-dose inhaled steroids can completely block TDI-induced late asthmatic reactions.

1987 - Rank injustice and academic promotion. [Articolo su rivista]
Fabbri, Leonardo
abstract

comment

1986 - Broncolavaggio nell' asma bronchiale [Articolo su rivista]
Milani, Gf; Pivirotto, F; Licata, B; Dal Vecchio, A; Mapp, C; Fabbri, Leonardo
abstract

n/d

1986 - Late, but not early, asthmatic reactions induced by toluene-diisocyanate are associated with increased airway responsiveness to methacholine. [Articolo su rivista]
C. E., Mapp; G. R., Di; C., Omini; C., Broseghini; Fabbri, Leonardo
abstract

We investigated whether airway responsiveness to methacholine differs in subjects with a history of sensitization to TDI who develop immediate, dual, late, or no asthmatic reactions after exposure to TDI, and also the effect of a TDI inhalation challenge in asthmatic subjects with hyperreactive airways with no history of sensitization to TDI. We measured FEV-1 immediately before and after exposure to TDI (0.018 ppm; 5-30 min) and then hourly for 8 h and the provocative dose (mg) of methacholine that caused a decrease in FEV-1 of 20% (PD20 FEV-1). The results of the present study suggest that the bronchoconstrictor effect of isocyanates is specifically linked to exposure to TDI and subsequent sensitization, excluding a nonspecific irritant effect on the airways. Moreover, they suggest that the increase in airway responsiveness to methacholine associated with the late asthmatic reaction is linked to factors that cause the late component of the asthmatic reaction.

1986 - Long-lasting protective effect of slow-release theophylline on asthma induced by ultrasonically nebulized distilled water. [Articolo su rivista]
Fabbri, Leonardo; M. V., Alessandri; N., De Marzo; E., Zocca; D., Paleari; M., Pozzan; C. E., Mapp
abstract

We investigated the intensity and duration of the effect of a single dose of slow-release theophylline on bronchial hyperresponsiveness to ultrasonically nebulized distilled water in asthma. In six subjects with a history of mild asthma, we measured airway responsiveness to ultrasonically nebulized distilled water and serum theophylline at 4, 8, and 12 hours after treatment with placebo or slow-release theophylline (10 +/- 1 mg/kg, orally). To assess bronchial responsiveness, dose-response curves were established by plotting the baseline value of FEV1 and the largest FEV1 after each doubling dose of nebulized distilled water against the dose of nebulized water. The degree of bronchoconstriction induced by ultrasonically nebulized distilled water was significantly inhibited at 4, 8, and 12 hours after treatment with theophylline, at serum levels of 14.8 +/- 4.6, 14.4 +/- 2.8, and 12.0 +/- 2.5 micrograms/mL theophylline (mean +/- SD). Tremor occurred in three patients and was associated with nausea, epigastric pain, and tachycardia in one of them. We conclude that a single dose of slow-release theophylline has a prolonged protective effect on bronchoconstriction induced by ultrasonically nebulized distilled water, but in some subjects is associated with side effects that limit its clinical usefulness.

1986 - Modification of the methacholine inhalation test and its epidemiologic use in polyurethane workers. [Articolo su rivista]
D. J., Hendrick; Fabbri, Leonardo; J. M., Hughes; D. E., Banks; H. W., Barkman; M. J., Connolly; R. N., Jones; H., Weill
abstract

The dosimeter method of administering doubling cumulative doses of methacholine to measure bronchial responsiveness was standardized to control for the effects of a number of potential influencing variables. The aerodynamic mass median diameter of the challenge aerosol produced from a DeVilbiss 646 nebulizer proved to be 1.2 mu, and the mean output per inhalation 8.9 microliters. Each challenge dose comprised 5 inhalations. Cumulative doses ranged from 0.3 methacholine inhalation units (1 unit = 1 inhalation of aerosol from a 1-mg/ml solution of methacholine, i.e., 8.9 micrograms methacholine) to a possible 640 units, the maximum that was considered reasonable to avoid the risk of unacceptable systemic effects. Responsiveness was expressed as the dose provoking a 20% decline (PD20) in FEV1. Modifications in this full protocol were introduced to facilitate epidemiologic investigations. Physician assessments coupled with baseline measurements of ventilatory function allowed starting at higher dosages for persons with low probability of hyperresponsiveness, thereby shortening the time required for testing to an average of 38 min. In a validation study of 20 persons using both the full and modified protocols, no significant differences were detected between measured PD20 values (geometric means Full versus Modified, 14.83 versus 14.88; r = 0.99). The modified protocol was used to measure bronchial responsiveness in 254 workers exposed to toluene diisocyanate. It proved to be safe and acceptable. Sixty-four workers (25.2%) were found to be reactors. The frequency distribution of the PD20 values exhibited a steadily increasing trend, consistent with a unimodal distribution.

1986 - Reazioni asmatiche ritardate indotte da isocianati ed infiammazione delle vie aeree. [Articolo su rivista]
Mapp, Ce; Dal Vecchio, L; Boschetto, P; De Marzo, N; Zocca, E; Maestrelli, P; Fabbri, Leonardo
abstract

n/d

1986 - The responsiveness of airway smooth muscle in vitro from dogs with airway hyper-responsiveness in vivo. [Articolo su rivista]
E. H., Walters; P. M., O'Byrne; P. D., Graf; Fabbri, Leonardo; J. A., Nadel
abstract

To determine whether smooth muscle from airways made hyper-responsive by ozone exposure is hyper-responsive in vitro, tracheal smooth muscle strips taken from five dogs with airway hyper-responsiveness induced by ozone exposure were compared with strips from five control animals. On 1 day, airway responsiveness was assessed with dose-response curves of acetylcholine aerosol versus pulmonary resistance. On a second day, five dogs were exposed to ozone (3.0 p.p.m. for 2 h) and five were exposed to filtered air. Then airway responsiveness to acetylcholine was reassessed. All dogs were then killed, the trachea was rapidly removed and strips of smooth muscle were prepared from the central one-third of the trachea. The responsiveness of each strip to electrical field stimulation (contractions inhibitable by atropine and tetrodotoxin) and exogenous acetylcholine was assessed after 2 and 6 h of incubation and washing. Ozone caused a marked increase in responsiveness in vivo to acetylcholine with a fall in mean provocation concentration from 0.15 g % to 0.026 g % (P less than 0.001) while sham exposure had no effect. The responsiveness of muscle strips to electrical field stimulation in ozone-exposed dogs after 2 h of incubation and washing was increased when compared with 6 h of incubation and washing and with the control dogs (P less than 0.05 for EF50, the frequency of stimulation giving 50% maximum contraction). However, responsiveness to exogenous acetylcholine was similar in all strips from both ozone-exposed and control dogs.

1986 - Toluene diisocyanate-induced asthma without airway hyperresponsiveness. [Articolo su rivista]
C. E., Mapp; L., Dal Vecchio; P., Boschetto; N., De Marzo; Fabbri, Leonardo
abstract

Six workers with occupational asthma due to toluene diisocyanate (TDI) were studied. For each worker a detailed clinical and occupational history was taken, and lung function measurement and skin intradermal tests for common allergens were carried out. Methacholine inhalation challenge was performed before TDI inhalation, and 8 h after TDI inhalation. Methacholine challenge was within normal limits when performed before TDI inhalation, but went into the asthmatic range after TDI inhalation. These cases provide evidence that asthma can be induced by toluene diisocyanate in the absence of airway hyperresponsiveness. They further demonstrate that an isolated negative methacholine inhalation test cannot be used to exclude sensitization to TDI. Screening and follow-up studies on workers exposed on TDI require serial measurements of airway responsiveness and of variable air-flow obstruction.

1985 - Airway inflammation and asthma. Importance of arachidonate metabolites for airway hyperresponsiveness. [Capitolo/Saggio]
Fabbri, Leonardo
abstract

asthma, inflammation

1985 - An anti-inflammatory drug (BW755C) inhibits airway hyperresponsiveness induced by ozone in dogs. [Articolo su rivista]
Fabbri, Leonardo; H., Aizawa; P. M., O'Byrne; R. A., Bethel; E. H., Walters; M. J., Holtzman; J. A., Nadel
abstract

To follow up our previous observation that airway hyperresponsiveness induced by ozone is linked to airway inflammation, we investigated the effect of BW755C, an anti-inflammatory drug, on ozone-induced hyperresponsiveness in dogs. Airway responsiveness was assessed with dose-response curves of acetylcholine aerosol versus pulmonary resistance in two sets of experiments. In one set (placebo treatment), five dogs were given only saline solution treatment and were studied before treatment or ozone exposure and then after treatment both before and after ozone (3.0 ppm, 2 hours); in another set (BW755C treatment), the same dogs were studied before BW755C treatment or ozone and then after treatment (10 mg/kg intravenously) both before and after ozone. When the dogs were given no BW755C treatment, ozone induced a marked increase in airway responsiveness to acetylcholine. When the dogs were given BW755C, responsiveness was no different during treatment than before treatment but, more importantly, responsiveness did not increase significantly after ozone. We conclude that BW755C markedly inhibits ozone-induced airway hyperresponsiveness in dogs, probably by inhibiting the formation of oxygenation products of arachidonic acid.

1985 - Combined asthma and alveolitis due to diphenylmethane diisocyanate (MDI) with demonstration of no crossed respiratory reactivity to toluene diisocyanate (TDI). [Articolo su rivista]
C. E., Mapp; L., Dal Vecchio; P., Boschetto; Fabbri, Leonardo
abstract

Two workers, who developed asthmatic symptoms, were studied with inhalation provocation tests using diphenylmethane diisocyanate (MDI) and toluene diisocyanate (TDI). The subjects showed specific asthmatic reactions to MDI challenge (more than 20% fall in FEV1), and one also had an alveolar response. Alveolitis was suggested by fever, basal crackles, increased neutrophil counts in venous blood and in bronchoalveolar lavage. The asthmatic reaction to MDI challenge was associated with an increase in airway responsiveness to methacholine in both subjects. We conclude that MDI is a cause of asthma and/or hypersensitivity pneumonitis in workers exposed to diphenylmethane diisocyanate.

1985 - Prednisone inhibits late asthmatic reactions and the associated increase in airway responsiveness induced by toluene-diisocyanate in sensitized subjects. [Articolo su rivista]
Fabbri, Leonardo; P., Chiesura Corona; L., Dal Vecchio; G. R., Di; E., Zocca; N., de Marzo; P., Maestrelli; C. E., Mapp
abstract

To determine whether late asthmatic reactions and the associated increase in airway responsiveness induced by toluene diisocyanate (TDI) are linked to airway inflammation, we investigated whether they are inhibited by prednisone. Ten "sensitized" subjects were studied in 2 sets of experiments. In the first set, each subject was given no treatment and was studied before and for 8 h after exposure to TDI. In the second set, 2 to 4 wk later, each subject was studied before treatment and then during treatment with prednisone (50 mg once a day for 3 days, orally), both before and after exposure to TDI. To assess late asthmatic reactions to TDI, we measured FEV1 immediately before and after exposure, then hourly for 8 h. To assess changes in airway responsiveness, we measured the provocation dose (mg) of methacholine causing a 20% decrease in FEV1 (PD20FEV1) before and 8 h after exposure to TDI. When the subjects received no prednisone treatment, TDI caused late asthmatic reactions and increased airway responsiveness. By contrast, when the subjects received prednisone, TDI caused no late asthmatic reaction or increased airway responsiveness. Prednisone did not change baseline airway caliber or airway responsiveness. These results suggest that late asthmatic reactions and the associated increase in airway responsiveness induced by TDI in "sensitized" subjects may depend on the development of a steroid-responsive acute inflammatory reaction within the airways.

1985 - Prednisone, indomethacin and airway responsiveness in toluene diisocyanate sensitized subjects. [Articolo su rivista]
Fabbri, Leonardo; R., Di Giacomo; L., Dal Vecchio; E., Zocca; N., De Marzo; P., Maestrelli; C. E., Mapp
abstract

We investigated whether late asthmatic reactions and the associated increase in airway responsiveness induced by toluene diisocyanate (TDI) in sensitized subjects are inhibited by indomethacin and/or prednisone. Four sets of experiments were conducted in five subjects sensitized to TDI. To assess late asthmatic reactions to TDI, FEV1 was measured immediately before and after exposure to TDI and then hourly for 8 h. To assess change in airway responsiveness, the provocative dose (mg) of methacholine that caused a decrease in FEV1 of 20% (PD20FEV1) before treatment, and then before and after exposure to TDI was measured. In the first set of experiments, each subject was given no treatment and was studied before and 8 h after exposure to TDI; in the other two sets, each subject was studied before treatment, then during treatment with indomethacin (50 mg q.i.d. for 3 days, orally) or prednisone (50 mg once a day, for 3 days, orally), both before and 8 h after TDI exposure. In a fourth series of experiments, each subject was again given no treatment and studied before and 8 h after TDI. When the subjects were given no treatment or indomethacin, TDI caused late asthmatic reactions and increased airway responsiveness to inhaled methacholine. In contrast, when the subjects were given prednisone, TDI caused neither late asthmatic reactions nor increased airway responsiveness. Treatment with indomethacin and prednisone did not change baseline FEV1 and airway responsiveness. These results suggest that release of prostaglandins does not contribute to late asthmatic reactions and the associated increase in airway responsiveness induced by TDI. Inflammatory mediators inhibited by prednisone but not by indomethacin may be involved.

1985 - Time course of the increase in airway responsiveness associated with late asthmatic reactions to toluene diisocyanate in sensitized subjects. [Articolo su rivista]
C. E., Mapp; R., Polato; P., Maestrelli; D. J., Hendrick; Fabbri, Leonardo
abstract

To understand better the mechanism of the increase in airway responsiveness associated with late asthmatic reactions, we determined the time course of toluene diisocyanate (TDI) effect on airway responsiveness in six sensitized subjects who exhibited a late asthmatic response after TDI exposure (0.018 +/- 0.005 ppm, 30 min) in the laboratory. Airway responsiveness was assessed before TDI exposure and then at 8 hr, 1 day, 1 wk, and 1 mo after TDI exposure. To assess responsiveness we determined the provocative dose of methacholine causing a decrease in FEV1 of 20% (PD20FEV1). The methacholine PD20 decreased from 0.50 mg geometric standard error of the mean (GSEM = 1.54) to 0.06 mg (GSEM = 1.55) (p less than 0.001) at 8 hr after exposure to TDI, was still decreased to 0.15 mg (GSEM = 1.93) (p less than 0.05) at 1 day, returned to 0.26 mg (GSEM = 1.91) (p greater than 0.05) at 1 wk, and returned to 0.43 mg (GSEM = 1.71) at 1 mo, indicating that full recovery occurred within 1 to 4 wk. These results demonstrate that TDI-induced late asthmatic response is associated with a reversible increase in airway responsiveness to methacholine and suggest that the TDI effect is linked to an acute inflammatory response in the airways.

1984 - Airway hyperresponsiveness and changes in cell counts in bronchoalveolar lavage after ozone exposure in dogs. [Articolo su rivista]
Fabbri, Leonardo; H., Aizawa; S. E., Alpert; E. H., Walters; P. M., O'Byrne; B. D., Gold; J. A., Nadel; M. J., Holtzman
abstract

We studied whether airway hyperresponsiveness induced by ozone exposure is associated with changes in the numbers of different types of cells in bronchoalveolar lavage in dogs. Airway responsiveness to acetylcholine and the numbers of cells in lavage fluid were determined 1 wk before and then 1 h and 1 wk after 2-h exposures to filtered air and to ozone (3.0 ppm) in each of 5 dogs. Airway responsiveness and the numbers of cells in lavage fluid did not change after exposure to filtered air. By contrast, airway responsiveness increased markedly 1 h after exposure to ozone and returned to control levels 1 wk later. In addition, the numbers of neutrophils and of ciliated epithelial cells in lavage increased markedly 1 h after ozone and returned to control levels 1 wk later. Our previous study showed that airway hyperresponsiveness induced by ozone is associated with an influx of neutrophils into the most central airways (1); the present results suggest that the hyperresponsiveness is also accompanied by an influx of neutrophils into more distal airways and by desquamation of airway epithelial cells.

1984 - Comparison of ultrasonically nebulized distilled water and hyperventilation with cold air in asthma. [Articolo su rivista]
Fabbri, Leonardo; C. E., Mapp; D. J., Hendrick
abstract

To assess the potential value of brief non-pharmacologic challenge tests in the measurement of bronchial responsiveness and to investigate whether the responses are induced by similar mechanisms, we carried out comparative five-minute inhalation challenges with ultrasonically nebulized distilled water and cold air hyperventilation in nine asthmatic subjects. Decrements in FEV1 following both challenges were closely correlated (r = 0.885) and ranged from 8% to 59% of baseline following challenge with the former and from 6% to 59% following the latter. Each method was therefore equally effective in demonstrating bronchial hyperresponsiveness. Moreover, the strong correlation between the responses to both challenges coupled with previous observations suggests that the two stimuli may act by similar mechanisms.

1984 - Control of neurotransmission by prostaglandins in canine trachealis smooth muscle. [Articolo su rivista]
E. H., Walters; P. M., O'Byrne; Fabbri, Leonardo; P. D., Graf; M. J., Holtzman; J. A., Nadel
abstract

Contractile responses of canine tracheal smooth muscle to electrical field stimulation diminished over a 2-h period of incubation. However, addition of indomethacin (10(-5) M) for a similar time not only prevented this inhibition of contractile response, but actually markedly increased the response to electrical field stimulation, suggesting that prostaglandins were responsible for the time-dependent inhibition. Measured prostaglandin E2 increased in the tissue bath over 2 h in control tissues. Addition of prostaglandin E2 to the tissue produced similar inhibition of contractile responses to electrical field stimulation in a concentration-dependent manner. In contrast, incubation alone, treatment with indomethacin, or addition of prostaglandin E2 had little, if any, effect on contractions induced by acetylcholine. We conclude that the release of prostaglandins from canine tracheal smooth muscle that occurs with time has a predominantly inhibitory effect on cholinergic neurotransmission at a prejunctional site.

1984 - Indomethacin inhibits the airway hyperresponsiveness but not the neutrophil influx induced by ozone in dogs. [Articolo su rivista]
P. M., O'Byrne; E. H., Walters; H., Aizawa; Fabbri, Leonardo; M. J., Holtzman; J. A., Nadel
abstract

To determine whether oxygenation products of arachidonic acid may be involved in the airway hyperresponsiveness induced by ozone exposure, we studied whether ozone-induced hyperresponsiveness could be inhibited by the prostaglandin synthetase inhibitor, indomethacin, in dogs. Airway responsiveness was assessed with dose-response curves of acetylcholine aerosol versus pulmonary resistance in 2 sets of experiments: in one set, 5 dogs were given no indomethacin treatment and were studied both before and after ozone exposure (3.0 ppm, 2 h); in another set, the same dogs were studied before indomethacin treatment or ozone exposure and then during treatment (1 mg/kg every 12 h for 4 days) both before and after ozone exposure. On each occasion, we also determined the number of neutrophils in biopsies of the airway epithelium. When the dogs were not treated with indomethacin, ozone caused a marked increase in responsiveness to acetylcholine and a marked increase in the number of neutrophils in the airway epithelium. When the dogs were given indomethacin, responsiveness was no different during treatment than before treatment, but more importantly, responsiveness did not increase significantly after they were exposed to ozone. Interestingly, indomethacin treatment did not affect either the baseline number of epithelial neutrophils before ozone exposure or the increase in the number of neutrophils after exposure. The results suggest that oxygenation products of arachidonic acid that are sensitive to inhibition by indomethacin play a role in ozone-induced hyperresponsiveness without affecting the influx of neutrophils.

1984 - Neutrophil depletion inhibits airway hyperresponsiveness induced by ozone exposure. [Articolo su rivista]
P. M., O'Byrne; E. H., Walters; B. D., Gold; H. A., Aizawa; Fabbri, Leonardo; S. E., Alpert; J. A., Nadel; M. J., Holtzman
abstract

We studied whether ozone-induced hyperresponsiveness could be inhibited by neutrophil depletion in dogs. Responsiveness was assessed with dose-response curves of acetylcholine aerosol versus pulmonary resistance; depletion was assessed by counting neutrophils in venous blood and in biopsies of the airway epithelium. Responsiveness and neutrophil numbers were determined 5 days and 1 day before ozone and 1 h after ozone (3.0 ppm, 2 h) in 6 untreated dogs and in 6 dogs treated with hydroxyurea (200 mg/kg daily for 5 days starting 5 days before ozone). In untreated dogs, responsiveness and neutrophil numbers 5 days and 1 day before ozone did not change, but responsiveness and epithelial neutrophils increased markedly after ozone. In treated dogs, circulating neutrophils decreased from 8.9 +/- 2.2 to 0.6 +/- 0.01 X 10(3) per mm3 (mean +/- SEM), and responsiveness before ozone did not change. Furthermore, increases in responsiveness and epithelial neutrophils did not occur after ozone. Six wk after stopping hydroxyurea, responsiveness and epithelial neutrophils increased markedly after ozone. The results suggest that ozone-induced hyperresponsiveness may depend on the mobilization of neutrophils into the airways.

1984 - [Bronchial hyperresponsiveness induced by toluene diisocyanate]. [Articolo su rivista]
Mapp, C; Polato, R; Maestrelli, P; Fabbri, Leonardo
abstract

non disponibile

1983 - Antihistaminic versus anticholinergic effects of atropine on canine trachealis muscle. [Articolo su rivista]
B. E., Skoogh; J. A., Nadel; Fabbri, Leonardo; D., Sheppard; M. J., Holtzman
abstract

To determine antihistaminic versus anticholinergic effects of atropine in airway smooth muscle, we used an in vitro preparation of canine trachealis muscle strips and determined atropine's effect on contractile responses induced by histamine or by electrical field stimulation of cholinergic nerves. In the first series of experiments, 53 strips had initial responses to field stimulation determined and were then randomly assigned to a control group or to a group treated with atropine before field stimulation was repeated and histamine was given. Atropine in concentrations of 10(-8), 10(-7), and 10(-6) M decreased the response to field stimulation to 61.4, 10.5, and 0% of the initial response, respectively, but had no effect on the responses to histamine. In the second series of experiments, 24 strips were treated with indomethacin to prevent histamine tachyphylaxis; these strips had initial responses to both field stimulation and histamine determined and were then assigned to a control group or to a group treated with atropine before field stimulation and histamine were repeated. In these experiments, a concentration of atropine (10(-6) M), which again completely blocked the response to field stimulation, still had no effect on histamine-induced contraction. We conclude that atropine in a concentration that completely blocks the response to cholinergic nerve stimulation has no antihistaminic effect.

1983 - Effect of atropine on the bronchial response of asthmatic subjects to the inhalation of ultrasonically nebulized distilled water. [Articolo su rivista]
Fabbri, Leonardo; D. J., Hendrick; J. E., Diem
abstract

To determine whether atropine provides protection against the bronchoconstriction that develops in asthmatic subjects after inhalation of ultrasonically nebulized distilled water, we exposed six asthmatic patients to this stimulus with and without pretreatment with atropine (0.04 mg/kg). The mean FEV1 decreased from 3.32 to 2.39 L (-28%) without and from 3.49 to 3.18 L (-9%) with atropine. This protective effect was statistically significant (p less than 0.05), suggesting that cholinergic pathways are involved in the obstructive response to the inhalation of ultrasonically nebulized distilled water.

1983 - Effect of cromolyn on carbachol-induced bronchoconstriction. [Articolo su rivista]
Fabbri, Leonardo; C. E., Mapp; D. J., Hendrick
abstract

The effect of premedication with cromolyn 40 mg on the bronchial response to inhaled carbachol was investigated in four atopic and four non-atopic subjects with mild asthma. Paired carbachol inhalation tests were carried out on consecutive days in a double-blind fashion following randomized premedication with cromolyn or placebo. Bronchial sensitivity was expressed as the log dose of carbachol provoking a 15% decrease in FEV1 (log PD15 FEV1) or a 30% decrease in FEF25-75 (log PD30 FEF25-75). The mean log PD15 FEV1 was significantly greater following cromolyn compared to placebo (2.34 +/- .22 vs 1.87 +/- .10; mean +/- SE; p less than 0.05) as was log PD30 FEF25-75 (2.30 +/- .16 vs 1.72 +/- .08; p less than 0.005). These results indicate that cromolyn interferes with cholinergic induced bronchoconstriction and support the suggestion that it has an effect at a more fundamental level than the inhibition of antigen induced mediator release from mast cells.

1983 - Importance of airway inflammation for hyperresponsiveness induced by ozone. [Articolo su rivista]
M. J., Holtzman; Fabbri, Leonardo; P. M., O'Byrne; B. D., Gold; H., Aizawa; E. H., Walters; S. E., Alpert; J. A., Nadel
abstract

We studied whether ozone-induced airway hyperresponsiveness correlates with the development of airway inflammation in dogs. To assess airway responsiveness, we determined increases in pulmonary resistance produced by delivering acetylcholine aerosol to the airways. To assess airway inflammation, we biopsied the airway mucosa and counted the number of neutrophils present in the epithelium. Airway responsiveness and inflammation were assessed in anesthetized dogs before ozone exposure and then 1 h and 1 wk after ozone (2.1 ppm, 2 h). Airway responsiveness increased markedly at 1 h after ozone and returned to control levels 1 wk later in each of 6 dogs, but it did not change after ozone in another 4 dogs. Furthermore, dogs that became hyperresponsive also developed a marked and reversible increase in the number of neutrophils in the epithelium, whereas dogs that did not become hyperresponsive had no change in the number of neutrophils. For the group of dogs, the level of airway responsiveness before and after ozone exposure correlated closely with the number of epithelial neutrophils. The results suggest that ozone-induced airway hyperresponsiveness may depend on the development of an acute inflammatory response in the airways.

1983 - Intravenous versus inhaled atropine for inhibiting bronchoconstrictor responses in dogs. [Articolo su rivista]
M. J., Holtzman; M. P., Mcnamara; D., Sheppard; Fabbri, Leonardo; H. L., Hahn; P. D., Graf; J. A., Nadel
abstract

We studied whether the muscarinic antagonist, atropine, given intravenously or by inhalation, inhibits the bronchoconstrictor responses to inhaled acetylcholine and to acetylcholine released by electrical stimulation of the vagus nerves to the same degree. We assessed bronchoconstrictor responses in anesthetized dogs by determining the increase in total pulmonary resistance before and after increasing doses of atropine and then constructing inhibition dose-response curves. Before atropine the responses to the two stimuli were equal in magnitude. After intravenous atropine (initial dose 0.12 micrograms/kg, total dose 16 micrograms/kg) both responses were progressively inhibited to a similar degree. By contrast, after inhaled atropine (initial dose 0.02 micrograms/kg, total dose 2.4 micrograms/kg) the response to acetylcholine inhalation was inhibited to a much greater degree than the response to vagal stimulation. Thus, in studies designed to inhibit bronchoconstriction due to an inhaled muscarinic agonist to the same degree as bronchoconstriction due to a vagal reflex, atropine might better be given intravenously than by inhalation.

1983 - Time course of airway hyperresponsiveness induced by ozone in dogs. [Articolo su rivista]
M. J., Holtzman; Fabbri, Leonardo; B. E., Skoogh; P. M., O'Byrne; E. H., Walters; H., Aizawa; J. A., Nadel
abstract

To better understand the mechanism of ozone-induced airway hyperresponsiveness we determined the time course of the ozone effect in dogs. To do this we assessed airway responsiveness before ozone exposure and then at 1 h, 1 day, and 1 wk after ozone exposure. To assess responsiveness we anesthetized the dogs and obtained dose-response curves of increasing concentrations of acetylcholine or histamine aerosols delivered to the airways vs. pulmonary resistance. Ozone exposures were carried out with the dogs awake and at rest in an exposure chamber for 2 h breathing either through the nose and mouth at a level of 2.2 ppm or through a tracheostomy at a level of 1.0 ppm. For both acetylcholine and histamine and for both routes of ozone delivery airway responsiveness increased most markedly at 1 h after ozone, increased to a lesser degree 1 day later, and returned to control levels by 1 wk. The results are similar to our previous studies in humans that showed that ozone-induced hyperresponsiveness occurs shortly after exposure and is rapidly reversible and suggest that the ozone effect is linked to an acute inflammatory response in the airways.

1983 - [Bronchoconstriction and hypersecretion following sulfur dioxide--a laryngeal reflex?]. [Articolo su rivista]
Hahn, Hl; Fabbri, Leonardo; Graf, Pd; Nadel, Ja
abstract

non disponibile

1982 - Effetto protettivo del fenoterolo sul broncospasmo indotto da mediatori aspecifici [Articolo su rivista]
Rossi, A; Toffanin, R; Saetta, M; Maestrelli, P; Mapp, C; Fabbri, Leonardo
abstract

n/d

1982 - Epidemiologia della bissinosi: problemi inerenti l'uso del questionario e delle prove funzionali respiratorie [Articolo su rivista]
Rossi, A; Maestrelli, P; De Rosa, E; Mapp, C; Fabbri, Leonardo
abstract

n/d

1982 - Lung changes due to chronic exposure to low levels of sulphur dioxide [Articolo su rivista]
Fabbri, Leonardo; Mapp, C; Rossi, A.
abstract

n/d

1982 - Maximal expiratory flow rates and airway resistance in the assessment of bronchoconstriction induced by methacholine and histamine [Articolo su rivista]
Rossi, A; Mapp, C; Maestrelli, P; Polato, R; Fabbri, Leonardo
abstract

n/d

1982 - Reproducibility of lung function tests used in assessing bronchial response [Articolo su rivista]
Fiorentini, F; Sturani, C; Pajello, M; Schiavina, M; Fabbri, Leonardo
abstract

n/d

1982 - Selective effect of general anesthetics on reflex bronchoconstrictor responses in dogs. [Articolo su rivista]
M. J., Holtzman; H. L., Hahn; K., Sasaki; B. E., Skoogh; P. D., Graf; Fabbri, Leonardo; J. A., Nadel
abstract

To determine which part of the parasympathetic bronchoconstrictor pathway is most sensitive to depression by general anesthetics, we stimulated different parts of the pathway in dogs after initial anesthesia with chloralose and urethan and then after additional anesthetic drugs. We stimulated the entire reflex pathway by producing apnea or hypoventilation, the sensory pathway by electrically stimulating the proximal end of cut superior laryngeal nerves, and the motor pathway by stimulating the distal end of a cut cervical vagus nerve. Bronchoconstrictor responses to all stimuli were assessed with a bypassed tracheal segment. When no additional anesthetic was administered, responses to all stimuli increased with time. Small additional doses of anesthetics (thiopental, 1-5 mg/kg; pentobarbital, 1-2 mg/kg; amobarbital, 1-2 mg/kg; or chloralose, 10 mg/kg) decreased responses to reflex and sensory stimulation markedly and reversibly, but they did not affect responses to motor stimulation. Increased doses decreased responses to motor stimulation as well. Our previous study (Skoogh et al., Am. Rev. Respir. Dis. 123: 202, 1981) showed that barbiturates depress parasympathetic ganglionic synapses; the present study suggests that central nervous system synapses may be even more sensitive to depression by general anesthetics.

1982 - Sensitivity and reactivity to cholinergic drugs and histamine in normal, atopic and asthmatic subjects [Articolo su rivista]
Maestrelli, P; Polato, R; Fabbri, Leonardo; Mapp, C; Rossi, A.
abstract

n/d

1981 - Compensating occupational asthma. [Articolo su rivista]
Hendrick, Dj; Fabbri, Leonardo
abstract

Early in 1982, occupational asthma will become a prescribed disease in Britain under the terms of the Social Security Act (1975).1 This is important legislation because occupational asthma is becoming increasingly common as society uses more and more respirable reactive chemicals in its industries. At the same time pneumoconiosis is becoming less common, and it is likely that it will soon give way to asthma as the most frequently compensated occupational disease of the lungs

1981 - L'effetto protettivo e broncodilatante del fenoterolo negli asmatici. PARTE I: Azione protettiva del fenoterolo nel broncospasmo indotto da carbacolo. [Articolo su rivista]
Rossi, A; Toffanin, R; Maestrelli, P; Imoli, P; Fabbri, Leonardo
abstract

n/d

1981 - Tests di provocazione bronchiale specifici ed aspecifici nella diagnostica dell'asma da isocianati. [Articolo su rivista]
Mapp, Ce; Moro, G; Fabbri, Leonardo; Crepet, M.
abstract

n/d

1981 - Variazioni della "densita' dipendenza" dei flussi massimi espiratori nel broncospasmo indotto dal carbacolo. [Articolo su rivista]
Maestrelli, P; Rossi, A; Polato, R; Mapp, C; Fabbri, Leonardo
abstract

n/d

1980 - Effetto del cromoglicato sodico sulla risposta bronchiale al carbacolo di soggetti asmatici e rinitici [Articolo su rivista]
Fabbri, Leonardo; Mapp, C; Sinigaglia, F; Polato, R.
abstract

n/d

1980 - I tests di iperresponsività bronchiale aspecifica in Medicina del lavoro [Articolo su rivista]
Moscato, G; Brunetti, G; Beretta, E; Romano, C; Mapp, C; Fabbri, Leonardo
abstract

n/d

1980 - [Chronic effect on the respiratory function of flax dust exposure]. [Articolo su rivista]
Maestrelli, P; Rossi, A; Mapp, C; Fabbri, Leonardo; De Rosa, E.
abstract

not available

1979 - An epidemiological study of vinyl chloride exposed workers in Italy [Articolo su rivista]
Bertazzi, Pa; Villa, A; Foa', V; Saia, B; Fabbri, Leonardo; Mapp, C; Marcer, G; Manno, M; Marchi, M; Mariani, F; Bottasso, F.
abstract

n/d

1979 - Clinical and electrophysiological studies of acrylamide poisoning [Articolo su rivista]
Mapp, C; Fabbri, Leonardo; Negrin, P.
abstract

n/d

1979 - Lung disease due to inhalation of organic dust in a starch industry. [Articolo su rivista]
Fabbri, Leonardo; Mapp, C; Rossi, A; Moro, G; Pezzini, A.
abstract

n/d

1979 - Pulmonary changes due to low level occupational exposure to ozone. [Articolo su rivista]
Fabbri, Leonardo; Mapp, C; Rossi, A; Sarto, F; Trevisan, A; De Rosa, E.
abstract

not available

1979 - Pulmonary function in men exposed to low levels of ozone. [Articolo su rivista]
Fabbri, Leonardo; Mapp, C; Rossi, A; Sarto, F; Trevisan, A.
abstract

n/d

1979 - Resistenze osmotiche, fosfatasi alcalina e perossidasi leucocitarie in soggetti esposti professionalmente ad ozono [Articolo su rivista]
Sarto, F; Carmignotto, F; Fabbri, Leonardo
abstract

n/d

1979 - Study of some erythrocyte and serum enzyme activities in workers exposed to low ozone concentrations for a long time. [Articolo su rivista]
Sarto, F; Trevisan, A; Gasparotto, G; Rosa, A; Fabbri, Leonardo
abstract

non disponibile

1979 - Tests di provocazione aspecifica e specifica nell'asma bronchiale [Articolo su rivista]
Fabbri, Leonardo; Mapp, C; Saetta, M.
abstract

n/d

1979 - Utilizzazione del "volume di isoflusso" nella diagnosi precoce delle broncopneumopatie. [Articolo su rivista]
Maestrelli, P; Rossi, A; Moro, G; Rossi, M; Mapp, C; Fabbri, Leonardo
abstract

n/d

1979 - [Toluene diisocyanate-induced asthma: specific and non-specific bronchial challenge tests (author's transl)]. [Articolo su rivista]
Mapp, C; Moro, G; Fabbri, Leonardo; Crepet, M.
abstract

non disponibile

1978 - Applicazione epidemiologica dei tests funzionali: confronto fra parametri ventilatori e transfer del CO [Articolo su rivista]
Moro, G; Fabbri, Leonardo
abstract

n/d

1978 - Prove farmacodinamiche: indicazioni metodologiche e tecniche di misura [Articolo su rivista]
Fabbri, Leonardo; Mapp, C; Di, Maria
abstract

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1978 - Riproducibilita' di tests che esplorano la meccanica ventilatoria [Articolo su rivista]
Maestrelli, P; Rossi, A; Fabbri, Leonardo
abstract

n/d

1978 - [Byssinosis, chronic bronchitis and ventilatory dysfunction in a population of workers exposed to flax dust]. [Articolo su rivista]
Rossi, A; Fabbri, Leonardo; Mapp, C; Moro, G; Brighenti, F; De Rosa, E.
abstract

non disponibile

1978 - [Respiratory functional changes caused by chronic exposure to monomeric and polymeric vinyl chloride]. [Articolo su rivista]
Mapp, C; Fabbri, Leonardo; Rossi, A; Moro, G; Cervi, G.
abstract

non disponibile

1978 - [Respiratory pathology due to the production cycle of phosphate fertilizers: 2. Chronic bronchitis and functional respiratory changes]. [Articolo su rivista]
Fabbri, Leonardo; Rossi, A; Mapp, C; De Rosa, E; Brighenti, F; Corrà, P.
abstract

non disponibile

1978 - [Respiratory pathology in the production cycle of phosphate fertilizers. 1. Risk of pneumoconiosis]. [Articolo su rivista]
Rossi, A; Fabbri, Leonardo; Mapp, C; De Rosa, E; Corrà, P; Brighenti, F.
abstract

non disponibile

1978 - [Risk of fluorosis in the manufacture of phosphate fertilizers]. [Articolo su rivista]
Fabbri, Leonardo; De Rosa, E; Potenza, I; Mapp, C; Rossi, A; Brighenti, F; Forin, F.
abstract

not available

1978 - [Value of the study of the flow-volume diagram in the early diagnosis of chronic industrial bronchopneumopathies]. [Articolo su rivista]
Fabbri, Leonardo; Mapp, C; Rossi, A.
abstract

non disponibile

1977 - Alterazioni respiratorie da esposizione cronica a basse concentrazioni di SO2 [Articolo su rivista]
Fabbri, Leonardo; Mapp, C; Furlanis, D.
abstract

n/d

1977 - Transfer del CO in regime stabile [Articolo su rivista]
Fabbri, Leonardo; Maestrelli, P; Mapp, C; Pusinanti, F.
abstract

n/d

1977 - [Changes in the respiratory function of iron-foundry workers]. [Articolo su rivista]
Mapp, C; Rossi, A; Fabbri, Leonardo; Mastrangelo, G; Marcer, G; Saia, B.
abstract

non disponibile

1977 - [Chronic broncopneumopathy and pneumoconiosis in workers employed in phosphoric acid production (author's transl)]. [Articolo su rivista]
Fabbri, Leonardo; Mapp, C; Rossi, A; Cortese, S; Saia, B.
abstract

non disponibile

1977 - [Nervous system disease caused by acrylamide: 1st cases in Italy]. [Articolo su rivista]
Mapp, C; Mazzotta, M; Bartolucci, Gb; Fabbri, Leonardo
abstract

non disponibile

1977 - [Respiratory changes due to chronic exposure to low level concentrations of SO2]. [Articolo su rivista]
Fabbri, Leonardo; Mapp, C; Furlanis, D.
abstract

non disponibile

1976 - Epidemiology of chronic non-specific lung disease in a population exposed to isocyanate. I: Analysis of symptoms. [Articolo su rivista]
Saia, B; Fabbri, Leonardo; Mapp, C; Marcer, G; Mastrangelo, G.
abstract

non disponibile

1976 - Epidemiology of chronic non-specific lung disease in a population exposed to isocyanate. II: Analysis of respiratory impairment. [Articolo su rivista]
Fabbri, Leonardo; Saia, B; Mapp, C; Marcer, G; Mastrangelo, G.
abstract

non disponibile

1974 - Bronchite cronica ed alterazioni funzionali respiratorie nei saldatori. [Articolo su rivista]
Fabbri, Leonardo; Mapp, C; Furlanis, D.
abstract

n/d

1973 - Il transfert del CO nella popolazione operaia esposta a polveri di refrattari [Articolo su rivista]
Fabbri, Leonardo; Mapp, C; Mastrangelo, G; Reggiani, A.
abstract

n/d