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Stefano BUSANI
Professore Associato
Dipartimento Chirurgico, Medico, Odontoiatrico e di Scienze Morfologiche con interesse Trapiantologico, Oncologico e di Medicina Rigenerativa
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Pubblicazioni
2024
- Advances and Challenges in Sepsis Management: Modern Tools and Future Directions
[Articolo su rivista]
Santacroce, Elena; D’Angerio, Miriam; Ciobanu, Alin Liviu; Masini, Linda; Lo Tartaro, Domenico; Coloretti, Irene; Busani, Stefano; Rubio, Ignacio; Meschiari, Marianna; Franceschini, Erica; Mussini, Cristina; Girardis, Massimo; Gibellini, Lara; Cossarizza, Andrea; De Biasi, Sara
abstract
: Sepsis, a critical condition marked by systemic inflammation, profoundly impacts both innate and adaptive immunity, often resulting in lymphopenia. This immune alteration can spare regulatory T cells (Tregs) but significantly affects other lymphocyte subsets, leading to diminished effector functions, altered cytokine profiles, and metabolic changes. The complexity of sepsis stems not only from its pathophysiology but also from the heterogeneity of patient responses, posing significant challenges in developing universally effective therapies. This review emphasizes the importance of phenotyping in sepsis to enhance patient-specific diagnostic and therapeutic strategies. Phenotyping immune cells, which categorizes patients based on clinical and immunological characteristics, is pivotal for tailoring treatment approaches. Flow cytometry emerges as a crucial tool in this endeavor, offering rapid, low cost and detailed analysis of immune cell populations and their functional states. Indeed, this technology facilitates the understanding of immune dysfunctions in sepsis and contributes to the identification of novel biomarkers. Our review underscores the potential of integrating flow cytometry with omics data, machine learning and clinical observations to refine sepsis management, highlighting the shift towards personalized medicine in critical care. This approach could lead to more precise interventions, improving outcomes in this heterogeneously affected patient population.
2024
- The Interplay between Antibiotics and the Host Immune Response in Sepsis: From Basic Mechanisms to Clinical Considerations: A Comprehensive Narrative Review
[Articolo su rivista]
Tosi, M.; Coloretti, I.; Meschiari, M.; De Biasi, S.; Girardis, M.; Busani, S.
abstract
Sepsis poses a significant global health challenge due to immune system dysregulation. This narrative review explores the complex relationship between antibiotics and the immune system, aiming to clarify the involved mechanisms and their clinical impacts. From pre-clinical studies, antibiotics exhibit various immunomodulatory effects, including the regulation of pro-inflammatory cytokine production, interaction with Toll-Like Receptors, modulation of the P38/Pmk-1 Pathway, inhibition of Matrix Metalloproteinases, blockade of nitric oxide synthase, and regulation of caspase-induced apoptosis. Additionally, antibiotic-induced alterations to the microbiome are associated with changes in systemic immunity, affecting cellular and humoral responses. The adjunctive use of antibiotics in sepsis patients, particularly macrolides, has attracted attention due to their immune-regulatory effects. However, there are limited data comparing different types of macrolides. More robust evidence comes from studies on community-acquired pneumonia, especially in severe cases with a hyper-inflammatory response. While studies on septic shock have shown mixed results regarding mortality rates and immune response modulation, conflicting findings are also observed with macrolides in acute respiratory distress syndrome. In conclusion, there is a pressing need to tailor antibiotic therapy based on the patient's immune profile to optimize outcomes in sepsis management.
2023
- A Fatal Case of Pseudomonas aeruginosa Community-Acquired Pneumonia in an Immunocompetent Patient: Clinical and Molecular Characterization and Literature Review
[Articolo su rivista]
Barp, Nicole; Marcacci, Matteo; Biagioni, Emanuela; Serio, Lucia; Busani, Stefano; Ventura, Paolo; Franceschini, Erica; Orlando, Gabriella; Venturelli, Claudia; Menozzi, Ilaria; Tambassi, Martina; Scaltriti, Erika; Pongolini, Stefano; Sarti, Mario; Pietrangelo, Antonello; Girardis, Massimo; Mussini, Cristina; Meschiari, Marianna
abstract
Rare cases of Pseudomonas aeruginosa community-acquired pneumonia (PA-CAP) were
reported in non-immunocompromised patients. We describe a case of Pseudomonas aeruginosa
(PA) necrotizing cavitary CAP with a fatal outcome in a 53-year-old man previously infected with
SARS-CoV-2, who was admitted for dyspnea, fever, cough, hemoptysis, acute respiratory failure
and a right upper lobe opacification. Six hours after admission, despite effective antibiotic therapy,
he experienced multi-organ failure and died. Autopsy confirmed necrotizing pneumonia with
alveolar hemorrhage. Blood and bronchoalveolar lavage cultures were positive for PA serotype
O:9 belonging to ST1184. The strain shares the same virulence factor profile with reference genome
PA01. With the aim to better investigate the clinical and molecular characteristics of PA-CAP, we
considered the literature of the last 13 years concerning this topic. The prevalence of hospitalized
PA-CAP is about 4% and has a mortality rate of 33–66%. Smoking, alcohol abuse and contaminated
fluid exposure were the recognized risk factors; most cases presented the same symptoms described
above and needed intensive care. Co-infection of PA-influenza A is described, which is possibly
caused by influenza-inducing respiratory epithelial cell dysfunction: the same pathophysiological
mechanism could be assumed with SARS-CoV-2 infection. Considering the high rate of fatal
outcomes, additional studies are needed to identify sources of infections and new risk factors, along
with genetic and immunological features. Current CAP guidelines should be revised in light of
these results.
2023
- Accuracy of nasal pressure swing to predict failure of high flow nasal oxygen in patients with acute hypoxemic respiratory failure
[Articolo su rivista]
Tonelli, Roberto; Cortegiani, Andrea; Fantini, Riccardo; Tabbì, Luca; Castaniere, Ivana; Bruzzi, Giulia; Busani, Stefano; Ball, Lorenzo; Clini, Enrico; Marchioni, Alessandro
abstract
Not available
2023
- Association Between Pulmonary Aspergillosis And Cytomegalovirus Reactivation In Critically Ill Covid-19 Patients: A Prospective Observational Cohort Study.
[Articolo su rivista]
Caciagli, Valeria; Coloretti, Irene; Talamonti, Marta; Farinelli, Carlotta; Gatto, Ilenia; Biagioni, Emanuela; Sarti, Mario; Franceschini, Erica; Meschiari, Marianna; Mussini, Cristina; Tonelli, Roberto; Clini, Enrico; Girardis, Massimo; Busani, Stefano
abstract
COVID-19-associated invasive pulmonary aspergillosis (CAPA) is common and is associated with poor outcomes in critically ill patients. This prospective observational study aimed to ex-plore the association between CAPA development and the incidence and prognosis of cytomegalo-virus (CMV) reactivation in critically ill COVID-19 patients. We included all consecutive criti-cally ill adult patients with confirmed COVID-19 infection who were admitted to three COVID-19 intensive care units (ICUs) in an Italian hospital from February 25, 2020, to May 8, 2022. A standardized procedure was employed for early detection of CAPA. Risk factors associ-ated with CAPA and CMV reactivation and the association between CMV recurrence and mor-tality were estimated using adjusted Cox proportional hazard regression models. CAPA oc-curred in 96 patients (16,6%) of the 579 patients analyzed. Among the CAPA population, 40 (41,7%) patients developed CMV blood reactivation with a median time of 18 days (IQR 7-27). The CAPA+CMV group did not exhibit a significantly higher 90-day mortality rate (62.5% vs. 48.2%) than the CAPA alone group (p=0.166). The CAPA+CMV group had a longer ICU stay, few-er ventilation-free days, and a higher rate of secondary bacterial infections than the control group of CAPA alone. In the CAPA population, prior immunosuppression was the only independent risk factor for CMV reactivation (HR 2.33, 95% C.I. 1.21-4.48, p=0.011). In critically ill COVID-19 pa-tients, CMV reactivation is common in those with a previous CAPA diagnosis. Basal immuno-suppression before COVID-19 appeared to be the primary independent variable affecting CMV reactivation in patients with CAPA. Furthermore, the association of CAPA+CMV versus CAPA alone appears to impact ICU length of stay and secondary bacterial infections but not mortality.
2023
- Critical COVID-19 Patients Through First, Second And Third Wave: Retrospective Observational Study Comparing Outcomes In ICU.
[Articolo su rivista]
Coloretti, Irene; Farinelli, Carlotta; Biagioni, Emanuela; Gatto, Ilenia; Munari, Elena; Dall’Ara, Lorenzo; Busani, Stefano; Meschiari, Marianna; Tonelli, Roberto; Mussini, Cristina; Guaraldi, Giovanni; Cossarizza, Andrea; Clini, Enrico; Girardis, Massimo
abstract
Introduction- The time-course of the COVID-19 pandemic was characterized by subsequent waves identified by peaks of Intensive Care Unit (ICU) admission rates. During these periods, progressive knowledge of the disease led to the development of specific therapeutic strategies. This retrospective study investigates whether this led to improvement in outcomes of COVID-19 patients admitted to ICU.
Methods- Outcomes were evaluated in consecutive adult COVID19 patients admitted to our ICU, divided into three waves based on the admission period: the first wave from February 25th, 2020, to July 6th, 2020; the second wave from September 20th, 2020, to February 13th, 2021; the third wave from February 14th, 2021 to April 30th, 2021. Differences were assessed comparing outcomes and by using different multivariable Cox models adjusted for variables related to outcome. Further sensitivity analysis was performed in patients undergoing invasive mechanical ventilation.
Results- Overall, 428 patients were included in the analysis: 102, 169 and 157 patients in the first, second and third wave. The ICU and in-hospital crude mortalities were lower by 7% and 10% in the third wave compared to the other 2 waves (p>0.05). A higher number of ICU and hospital free days at day 90 was found in the third wave when compared to the other 2 waves (p=0.001). Overall, 62.6% underwent invasive ventilation, with decreasing requirement during the waves (p=0.002). The adjusted Cox model showed no difference in the Hazard Ratio for mortality among the waves. In the propensity-matched analysis the hospital mortality rate was reduced by 11% in the third wave (p=0.044).
Conclusions - With application of best practice as known by the time of the first three waves of the pandemic, our study failed to identify a significant improvement in mortality rate when comparing the different waves of the COVID-19 pandemic, notwithstanding, the sub-analyses showed a trend in mortality reduction in the third wave. Rather, our study identified a possible positive effect of dexamethasone on mortality rate reduction and the increased risk of death related to bacterial infections in the three waves.
2023
- Detailed characterization of SARS-CoV-2-specific T and B cells after infection or heterologous vaccination
[Articolo su rivista]
Lo Tartaro, Domenico; Paolini, Annamaria; Mattioli, Marco; Swatler, Julian; Neroni, Anita; Borella, Rebecca; Santacroce, Elena; Di Nella, Alessia; Gozzi, Licia; Busani, Stefano; Cuccorese, Michela; Trenti, Tommaso; Meschiari, Marianna; Guaraldi, Giovanni; Girardis, Massimo; Mussini, Cristina; Piwocka, Katarzyna; Gibellini, Lara; Cossarizza, Andrea; De Biasi, Sara
abstract
: The formation of a robust long-term antigen (Ag)-specific memory, both humoral and cell-mediated, is created following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination. Here, by using polychromatic flow cytometry and complex data analyses, we deeply investigated the magnitude, phenotype, and functionality of SARS-CoV-2-specific immune memory in two groups of healthy subjects after heterologous vaccination compared to a group of subjects who recovered from SARS-CoV-2 infection. We find that coronavirus disease 2019 (COVID-19) recovered patients show different long-term immunological profiles compared to those of donors who had been vaccinated with three doses. Vaccinated individuals display a skewed T helper (Th)1 Ag-specific T cell polarization and a higher percentage of Ag-specific and activated memory B cells expressing immunoglobulin (Ig)G compared to those of patients who recovered from severe COVID-19. Different polyfunctional properties characterize the two groups: recovered individuals show higher percentages of CD4+ T cells producing one or two cytokines simultaneously, while the vaccinated are distinguished by highly polyfunctional populations able to release four molecules, namely, CD107a, interferon (IFN)-γ, tumor necrosis factor (TNF), and interleukin (IL)-2. These data suggest that functional and phenotypic properties of SARS-CoV-2 adaptive immunity differ in recovered COVID-19 individuals and vaccinated ones.
2023
- Do all critically ill patients with COVID-19 disease benefit from adding tocilizumab to glucocorticoids? A retrospective cohort study.
[Articolo su rivista]
Mussini, Cristina; Cozzi-Lepri, Alessandro; Meschiari, Marianna; Franceschini, Erica; Jole Burastero, Giulia; Faltoni, Matteo; Franceschi, Giacomo; Iadisernia, Vittorio; Volpi, Sara; Dessilani, Andrea; Gozzi, Licia; Conti, Jacopo; DEL MONTE, Martina; Milic, Jovana; Borghi, Vanni; Tonelli, Roberto; Brugioni, Lucio; Romagnoli, Elisa; Pietrangelo, Antonello; Corradini, Elena; Girardis, Massimo; Busani, Stefano; Cossarizza, Andrea; Clini, Enrico; Guaraldi, Giovanni
abstract
2023
- Extracorporeal CO 2 Removal During Renal Replacement Therapy to Allow Lung-Protective Ventilation in Patients With COVID-19-Associated Acute Respiratory Distress Syndrome
[Articolo su rivista]
Alessandri, F.; Tonetti, T.; Pistidda, L.; Busani, S.; Borrazzo, C.; Fanelli, V.; Polzoni, M.; Piazza, O.; Lorini, L.; Cattaneo, S.; Ricci, D.; Zanoni, A.; Girardis, M.; Terragni, P.; Tempesta, M.; Di Luca, M.; Pugliese, F.; Ranieri, V. M.
abstract
The aim of this retrospective multicenter observational study is to test the feasibility and safety of a combined extracorporeal CO 2 removal (ECCO 2 R) plus renal replacement therapy (RRT) system to use an ultraprotective ventilator setting while maintaining (1) an effective support of renal function and (2) values of pH within the physiologic limits in a cohort of coronavirus infectious disease 2019 (COVID-19) patients. Among COVID-19 patients admitted to the intensive care unit of 9 participating hospitals, 27 patients with acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI) requiring invasive mechanical ventilation undergoing ECCO 2 R-plus-RRT treatment were included in the analysis. The treatment allowed to reduce V T from 6.0 ± 0.6 mL/kg at baseline to 4.8 ± 0.8, 4.6 ± 1.0, and 4.3 ± 0.3 mL/kg, driving pressure (ΔP) from 19.8 ± 2.5 cm H 2 O to 14.8 ± 3.6, 14.38 ± 4.1 and 10.2 ± 1.6 cm H 2 O after 24 hours, 48 hours, and at discontinuation of ECCO 2 R-plus-RRT (T3), respectively ( p < 0.001). PaCO 2 and pH remained stable. Plasma creatinine decreased over the study period from 3.30 ± 1.27 to 1.90 ± 1.30 and 1.27 ± 0.90 mg/dL after 24 and 48 hours of treatment, respectively ( p < 0.01). No patient-related events associated with the extracorporeal system were reported. These data show that in patients with COVID-19-induced ARDS and AKI, ECCO 2 R-plus-RRT is effective in allowing ultraprotective ventilator settings while maintaining an effective support of renal function and values of pH within physiologic limits.
2023
- Physiological effects of lung protective ventilation in patients with lung fibrosis and usual interstitial pneumonia pattern versus primary ARDS: a matched-control study.
[Articolo su rivista]
Tonelli, Roberto; Grasso, Salvatore; Cortegiani, Andrea; Ball, Lorenzo; Castaniere, Ivana; Tabbì, Luca; Fantini, Riccardo; Andrisani, Dario; Gozzi, Filippo; Moretti, Antonio; Bruzzi, Giulia; Manicardi, Linda; Cerri, Stefania; Samarelli, ANNA VALERIA; Raineri, Giulia; Murgolo, Francesco; Carzoli, Andrea; Di Mussi, Rossella; Busani, Stefano; Rizzoni, Raffaella; Grasselli, Giacomo; Clini, Enrico; Marchioni, Alessandro
abstract
Background- Although patients with interstitial pneumonia pattern (ILD-UIP) and acute exacerbation (AE) leading to severe acute respiratory failure may require invasive mechanical ventilation (MV), physiological data on lung mechanics during MV are lacking. We aimed at describing the physiological effect of lung protective ventilation in patients with AE-ILD-UIP compared with primary ARDS.
Methods- Partitioned lung and chest wall mechanics were assessed in a series of AE-ILD-UIP patients matched 1:1 with primary ARDS as controls (based on BMI and PaO2/FiO2 ratio). Three PEEP levels (zero=ZEEP, 4-8 cmH2O=PEEPLOW, and titrated to achieve positive end-expiratory transpulmonary pressure-PL,EE=PEEPTITRATED) were used for measurements.
Results- Ten AE-ILD-UIP patients and 10 matched ARDS were included. In AE-ILD-UIP median PL,EE at ZEEP was - 4.3 [-7.6 – -2.3] cmH2O and lung elastance (EL) 44 [40 – 51] cmH2O/L. At PEEPLOW, PL,EE remained negative and EL did not change (p=0.995) versus ZEEP. At PEEPTITRATED, PL,EE increased to 0.8 [0.3 – 1.5] cmH2O and EL to 49 [43 – 59] (p=0.004 and p<0.001 compared to ZEEP and PEEPLOW, respectively). PL decreased at PEEPLOW (p=0.018) and increased at PEEPTITRATED (p=0.003). In matched ARDS control PEEP titration to obtain a positive PL,EE did not result in significant changes in EL and PL.
Conclusions- In mechanically ventilated AE-ILD-UIP patients, differently than in patients with primary ARDS, PEEP titrated to obtain a positive PL,EE significantly worsened lung mechanics.
2023
- Prognostic immune markers identifying patients with severe COVID-19 who respond to tocilizumab
[Articolo su rivista]
DE BIASI, Sara; Mattioli, Marco; Meschiari, Marianna; LO TARTARO, Domenico; Paolini, Annamaria; Borella, Rebecca; Neroni, Anita; Fidanza, Lucia; Busani, Stefano; Girardis, Massimo; Coppi, Francesca; Mattioli, Anna Vittoria; Guaraldi, Giovanni; Mussini, Cristina; Cossarizza, Andrea; Gibellini, Lara
abstract
Introduction: A growing number of evidences suggest that the combination of hyperinflammation, dysregulated T and B cell response and cytokine storm play a major role in the immunopathogenesis of severe COVID-19. IL-6 is one of the main pro-inflammatory cytokines and its levels are increased during SARS-CoV-2 infection. Several observational and randomized studies demonstrated that tocilizumab, an IL-6R blocker, improves survival in critically ill patients both in infectious disease and intensive care units. However, despite transforming the treatment options for COVID-19, IL-6R inhibition is still ineffective in a fraction of patients.
Methods: In the present study, we investigated the impact of two doses of tocilizumab in patients with severe COVID-19 who responded or not to the treatment by analyzing a panel of cytokines, chemokines and other soluble factors, along with the composition of peripheral immune cells, paying a particular attention to T and B lymphocytes.
Results: We observed that, in comparison with non-responders, those who responded to tocilizumab had different levels of several cytokines and different T and B cells proportions before starting therapy. Moreover, in these patients, tocilizumab was further able to modify the landscape of the aforementioned soluble molecules and cellular markers.
Conclusions: We found that tocilizumab has pleiotropic effects and that clinical response to this drug remain heterogenous. Our data suggest that it is possible to identify patients who will respond to treatment and that the administration of tocilizumab is able to restore the immune balance through the re-establishment of different cell populations affected by SARS-COV-2 infection, highlighting the importance of temporal examination of the pathological features from the diagnosis.
2023
- Role of selective digestive decontamination in the prevention of VAP in COVID-19 patients: a pre-post observational study.
[Articolo su rivista]
Biagioni, Emanuela; Ferrari, Elena; Gatto, Ilenia; Serio, Lucia; Farinelli, Carlotta; Coloretti, Irene; Talamonti, Marta; Tosi, Martina; Meschiari, Marianna; Tonelli, Roberto; Venturelli, Claudia; Mussini, Cristina; Clini, Enrico; Sarti, Mario; Cossarizza, Andrea; Busani, Stefano; Girardis, Massimo.
abstract
The aim of our study was to evaluate whether the introduction of SDD in a structured protocol for VAP prevention was effective in reducing the occurrence of ventilator associated pneumonia (VAP) in COVID19 patients without changes in the microbiological pattern of antibiotic resistances.
This observational pre-post study including adult patients requiring invasive mechanical ventilation (IMV) for severe respiratory failure related to SARS-CoV-2 admitted in three COVID19 intensive care units (ICUs) in an Italian hospital from February 22, 2020, to March 8, 2022.
Selective digestive decontamination (SDD) was introduced from the end of April 2021 in the structured protocol for VAP prevention. The SDD consisted of a tobramycin sulphate, colistin sulphate and amphotericin B suspension applied in the patient oropharynx and the stomach via nasogastric tube.
Three-hundred forty-eight patients were included in the study. In the 86 patients (32,9%) who received SDD the occurrence of VAP decreased by 7,7% (p = 0,192) compared to patients who did not receive SDD. Onset time of VAP, the occurrence of multidrug-resistant microorganisms AP, the length of invasive mechanical ventilation and hospital mortality were similar in patients who received and who did not receive SDD. The multivariate analysis adjusted for confounders showed that the use of SDD reduces the occurrence of VAP (HR 0,536, CI 0,338-0,851; p = 0,017)
Our pre-post observational study indicates that the use of SDD in a structured protocol for VAP prevention seems to reduce the occurrence of VAP without changes in the incidence of multidrug-resistant bacteria in COVID19 patients.
2023
- Ultra-rare RTEL1 gene variants associate with acute severity of COVID-19 and evolution to pulmonary fibrosis as a specific long COVID disorder
[Articolo su rivista]
Bergantini, L.; Baldassarri, M.; D'Alessandro, M.; Brunelli, G.; Fabbri, G.; Zguro, K.; Degl'Innocenti, A.; Mari, F.; Daga, S.; Meloni, I.; Bruttini, M.; Croci, S.; Lista, M.; Maffeo, D.; Pasquinelli, E.; Serio, V. B.; Antolini, E.; Basso, S. L.; Minetto, S.; Tita, R.; Mencarelli, M. A.; Rizzo, C. L.; Pinto, A. M.; Ariani, F.; Montagnani, F.; Tumbarello, M.; Rancan, I.; Fabbiani, M.; Cameli, P.; Bennett, D.; Anedda, F.; Marcantonio, S.; Scolletta, S.; Franchi, F.; Mazzei, M. A.; Guerrini, S.; Conticini, E.; Cantarini, L.; Frediani, B.; Tacconi, D.; Raffaelli, C. S.; Emiliozzi, A.; Feri, M.; Donati, A.; Scala, R.; Guidelli, L.; Spargi, G.; Corridi, M.; Nencioni, C.; Croci, L.; Caldarelli, G. P.; Romani, D.; Piacentini, P.; Bandini, M.; Desanctis, E.; Cappelli, S.; Canaccini, A.; Verzuri, A.; Anemoli, V.; Pisani, M.; Ognibene, A.; Lorubbio, M.; Pancrazzi, A.; Vaghi, M.; Monforte, A. D. A.; Miraglia, F. G.; Mondelli, M. U.; Mantovani, S.; Bruno, R.; Vecchia, M.; Maffezzoni, M.; Martinelli, E.; Girardis, M.; Busani, S.; Venturelli, S.; Cossarizza, A.; Antinori, A.; Vergori, A.; Rusconi, S.; Siano, M.; Gabrieli, A.; Riva, A.; Francisci, D.; Schiaroli, E.; Pallotto, C.; Parisi, S. G.; Basso, M.; Panese, S.; Baratti, S.; Scotton, P. G.; Andretta, F.; Giobbia, M.; Scaggiante, R.; Gatti, F.; Castelli, F.; Quiros-Roldan, E.; Antoni, M. D.; Zanella, I.; Monica, M.; Piscopo, C.; Capasso, M.; Russo, R.; Andolfo, I.; Iolascon, A.; Fiorentino, G.; Carella, M.; Castori, M.; Merla, G.; Squeo, G. M.; Aucella, F.; Raggi, P.; Perna, R.; Bassetti, M.; Di Biagio, A.; Sanguinetti, M.; Masucci, L.; Guarnaccia, A.; Valente, S.; Di Florio, A.; Mandala, M.; Giorli, A.; Salerni, L.; Zucchi, P.; Parravicini, P.; Menatti, E.; Trotta, T.; Giannattasio, F.; Coiro, G.; Lena, F.; Lacerenza, G.; Mussini, C.; Tavecchia, L.; Crotti, L.; Parati, G.; Mene, R.; Sanarico, M.; Gori, M.; Raimondi, F.; Stella, A.; Biscarini, F.; Bachetti, T.; La Rovere, M. T.; Bussotti, M.; Ludovisi, S.; Capitani, K.; Dei, S.; Ravaglia, S.; Giliberti, A.; Gori, G.; Artuso, R.; Andreucci, E.; Pagliazzi, A.; Fiorentini, E.; Perrella, A.; Bianchi, F.; Bergomi, P.; Catena, E.; Colombo, R.; Luchi, S.; Morelli, G.; Petrocelli, P.; Iacopini, S.; Modica, S.; Baroni, S.; Micheli, G.; Falcone, M.; Urso, D.; Tiseo, G.; Matucci, T.; Grassi, D.; Ferri, C.; Marinangeli, F.; Brancati, F.; Vincenti, A.; Borgo, V.; Lombardi, S.; Lenzi, M.; Di Pietro, M. A.; Vichi, F.; Romanin, B.; Attala, L.; Costa, C.; Gabbuti, A.; Bellucci, A.; Colaneri, M.; Casprini, P.; Pomara, C.; Esposito, M.; Leoncini, R.; Cirianni, M.; Galasso, L.; Bellini, M. A.; Gabbi, C.; Picchiotti, N.; Furini, S.; Fallerini, C.; Bargagli, E.; Renieri, A.
abstract
Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a novel coronavirus that caused an ongoing pandemic of a pathology termed Coronavirus Disease 19 (COVID-19). Several studies reported that both COVID-19 and RTEL1 variants are associated with shorter telomere length, but a direct association between the two is not generally acknowledged. Here we demonstrate that up to 8.6% of severe COVID-19 patients bear RTEL1 ultra-rare variants, and show how this subgroup can be recognized. Methods: A cohort of 2246 SARS-CoV-2-positive subjects, collected within the GEN-COVID Multicenter study, was used in this work. Whole exome sequencing analysis was performed using the NovaSeq6000 System, and machine learning methods were used for candidate gene selection of severity. A nested study, comparing severely affected patients bearing or not variants in the selected gene, was used for the characterisation of specific clinical features connected to variants in both acute and post-acute phases. Results: Our GEN-COVID cohort revealed a total of 151 patients carrying at least one RTEL1 ultra-rare variant, which was selected as a specific acute severity feature. From a clinical point of view, these patients showed higher liver function indices, as well as increased CRP and inflammatory markers, such as IL-6. Moreover, compared to control subjects, they present autoimmune disorders more frequently. Finally, their decreased diffusion lung capacity for carbon monoxide after six months of COVID-19 suggests that RTEL1 variants can contribute to the development of SARS-CoV-2-elicited lung fibrosis. Conclusion: RTEL1 ultra-rare variants can be considered as a predictive marker of COVID-19 severity, as well as a marker of pathological evolution in pulmonary fibrosis in the post-COVID phase. This notion can be used for a rapid screening in hospitalized infected people, for vaccine prioritization, and appropriate follow-up assessment for subjects at risk. Trial Registration NCT04549831 (www.clinicaltrial.org)
2022
- A first update on mapping the human genetic architecture of COVID-19
[Articolo su rivista]
Pathak, Ga; Polimanti, R; Karjalainen, J; Daly, M; Ganna, A; Daly, Mj; Stevens, C; Kanai, M; Liao, Rg; Trankiem, A; Balaconis, Mk; Nguyen, H; Solomonson, M; Veerapen, K; Ripatti, S; Nkambul, L; Bryant, S; Sankaran, Vg; Neale, Bm; Karczewski, Kj; Martin, Ar; Atkinson, Eg; Tsuo, K; Baya, N; Turley, P; Gupta, R; Walters, Rk; Palmer, Ds; Sarma, G; Cheng, N; Lu, W; Churchhouse, C; Goldstein, Ji; King, D; Zhou, W; Seed, C; Finucane, H; Satterstrom, Fk; Andrews, Sj; Sloofman, Lg; Sealfon, Sc; Hoggart, C; Underwood, Sj; Cordioli, M; Pirinen, M; Donner, K; Kivinen, K; Palotie, A; Kaunisto, M; Harerimana, N; Chwialkowska, K; Wolford, B; Roberts, G; Park, D; Ball, Ca; Coignet, M; Mccurdy, S; Knight, S; Partha, R; Rhead, B; Zhang, M; Berkowitz, N; Gaddis, M; Noto, K; Ruiz, L; Pavlovic, M; Hong, El; Rand, K; Girshick, A; Guturu, H; Baltzell, Ah; Niemi, Mek; Pigazzini, S; Rahmouni, S; Georges, M; Belhaj, Y; Guntz, J; Claassen, S; Beguin, Y; Gofflot, S; Nkambule, L; Nkambul, L; Cusick, C; Moutschen, M; Misset, B; Darcis, G; Guiot, J; Azarzar, S; Malaise, O; Huynen, P; Meuris, C; Thys, M; Jacques, J; Leonard, P; Frippiat, F; Giot, Jb; Sauvage, As; Von Frenckell, C; Lambermont, B; Nakanishi, T; Morrison, Dr; Richards, Jb; Butler-Laporte, G; Forgetta, V; Ghosh, B; Laurent, L; Henry, D; Abdullah, T; Adeleye, O; Mamlouk, N; Kimchi, N; Afrasiabi, Z; Rezk, N; Vulesevic, B; Bouab, M; Guzman, C; Petitjean, L; Tselios, C; Xue, Xq; Afilalo, J; Adra, D; Mooser, V; Li, R; Belisle, A; Lepage, P; Ragoussis, J; Auld, D; Lathrop, Gm; Afilalo, M; Oliveira, M; Brenner, B; Brassard, N; Durand, M; Chasse, M; Kaufmann, De; Schurr, E; Hayward, C; Richmond, A; Baillie, Jk; Glessner, Jt; Hakonarson, H; Chang, X; Shaw, Dm; Below, J; Polikowski, H; Lauren, Pe; Chen, Hh; Zhu, Wy; Davis, L; Kerchberger, Ve; Campbell, A; Porteous, Dj; Fawns-Ritchie, C; Morris, M; Mccormick, Jb; North, K; Glessner, Jr; Gignoux, Cr; Wicks, Sj; Crooks, K; Barnes, Kc; Daya, M; Shortt, J; Rafaels, N; Chavan, S; Timmers, Prhj; Wilson, Jf; Tenesa, A; Kerr, Sm; D'Mellow, K; Shahin, D; El-Sherbiny, Ym; El-Jawhari, Jj; von Hohenstaufen, Ka; Sobh, A; Eltoukhy, Mm; Mohamed, Aas; Elhadidy, Ta; Abd Elghafar, Ms; Elnagdy, Mh; Samir, A; Hegazy, Maf; Abdel-Aziz, M; Khafaga, Wt; El-Lawaty, Wm; Torky, Ms; Moahmed, Hs; El-shanshory, Mr; Yassen, Am; Okasha, K; Eid, Ma; Medina-Gomez, C; Uitterlinden, Ag; Ikram, Ma; Magi, R; Milani, L; Metspalu, A; Laisk, T; Lall, K; Lepamets, M; Esko, T; Reimann, E; Alavere, H; Metsalu, K; Puusepp, M; Naaber, P; Laane, E; Pesukova, J; Peterson, P; Kisand, K; Tabri, J; Allos, R; Hensen, K; Starkopf, J; Ringmets, I; Tamm, A; Kallaste, A; Batini, C; Tobin, Md; Venn, Ld; Lee, Ph; Shrine, N; Williams, At; Guyatt, Al; John, C; Packer, Rj; Ali, A; Wang, X; Wain, Lv; Bee, Ce; Adams, El; Free, Rc; Hollox, Ej; Ruotsalainen, S; Kristiansson, K; Koskelainen, S; Perola, M; Rivolta, C; Quinodoz, M; Kamdar, D; Bochud, Py; Boillat, N; Bibert, S; Nussle, Sg; Albrich, W; Suh, N; Neofytos, D; Erard, V; Voide, C; Friolet, R; Vollenweider, P; Pagani, Jl; Oddo, M; zu Bentrup, Fm; Conen, A; Clerc, O; Marchetti, O; Guillet, A; Guyat-Jacques, C; Foucras, S; Rime, M; Chassot, J; Jaquet, M; Viollet, Rm; Lannepoudenx, Y; Portopena, L; Bochud, Py; Desgranges, F; Filippidis, P; Guery, B; Haefliger, D; Kampouri, Ee; Manuel, O; Munting, A; Papadimitriou-Olivgeris, M; Regina, J; Rochat-Stettler, L; Suttels, V; Tadini, E; Tschopp, J; Van Singer, M; Viala, B; Boillat-Blanco, N; Brahier, T; Hugli, O; Meuwly, Jy; Pantet, O; Nussle, Sg; Bochud, M; D'Acremont, V; Younes, Se; Albrich, Wc; Suh, N; Cerny, A; O'Mahony, L; von Mering, C; Frischknecht, M; Kleger, Gr; Filipovic, M; Kahlert, Cr; Wozniak, H; Negro, Tr; Pugin, J; Bouras, K; Knapp, C; Egger, T; Perret, A; Montillier, P; di Bartolomeo, C; Barda, B; de Cid, R; Carreras, A; Galvan-Femenia, I; Blay, N; Farre, X; Sumoy, L; Cortes, B; Moreno, V; Kogevinas, M; Garcia-Aymerich, J; Castano-Vinyals, G; Dobano, C; Mercader, Jm; Mercader, J; Guindo-Martinez, M; Torrents
abstract
2022
- An explainable model of host genetic interactions linked to COVID-19 severity
[Articolo su rivista]
Onoja, A.; Picchiotti, N.; Fallerini, C.; Baldassarri, M.; Fava, F.; Mari, F.; Daga, S.; Benetti, E.; Bruttini, M.; Palmieri, M.; Croci, S.; Amitrano, S.; Meloni, I.; Frullanti, E.; Doddato, G.; Lista, M.; Beligni, G.; Valentino, F.; Zguro, K.; Tita, R.; Giliberti, A.; Mencarelli, M. A.; Rizzo, C. L.; Pinto, A. M.; Ariani, F.; Di Sarno, L.; Montagnani, F.; Tumbarello, M.; Rancan, I.; Fabbiani, M.; Rossetti, B.; Bergantini, L.; D'Alessandro, M.; Cameli, P.; Bennett, D.; Anedda, F.; Marcantonio, S.; Scolletta, S.; Franchi, F.; Mazzei, M. A.; Guerrini, S.; Conticini, E.; Cantarini, L.; Frediani, B.; Tacconi, D.; Raffaelli, C. S.; Feri, M.; Donati, A.; Scala, R.; Guidelli, L.; Spargi, G.; Corridi, M.; Nencioni, C.; Croci, L.; Caldarelli, G. P.; Romani, D.; Piacentini, P.; Bandini, M.; Desanctis, E.; Cappelli, S.; Canaccini, A.; Verzuri, A.; Anemoli, V.; Pisani, M.; Ognibene, A.; Pancrazzi, A.; Lorubbio, M.; Vaghi, M.; D'Arminio Monforte, A.; Miraglia, F. G.; Bruno, R.; Vecchia, M.; Girardis, M.; Venturelli, S.; Busani, S.; Cossarizza, A.; Antinori, A.; Vergori, A.; Emiliozzi, A.; Rusconi, S.; Siano, M.; Gabrieli, A.; Riva, A.; Francisci, D.; Schiaroli, E.; Paciosi, F.; Tommasi, A.; Zuccon, U.; Vietri, L.; Scotton, P. G.; Andretta, F.; Panese, S.; Baratti, S.; Scaggiante, R.; Gatti, F.; Parisi, S. G.; Castelli, F.; Quiros-Roldan, E.; Antoni, M. D.; Zanella, I.; Della Monica, M.; Piscopo, C.; Capasso, M.; Russo, R.; Andolfo, I.; Iolascon, A.; Fiorentino, G.; Carella, M.; Castori, M.; Aucella, F.; Raggi, P.; Perna, R.; Bassetti, M.; Di Biagio, A.; Sanguinetti, M.; Masucci, L.; Guarnaccia, A.; Valente, S.; De Vivo, O.; Bargagli, E.; Mandala, M.; Giorli, A.; Salerni, L.; Zucchi, P.; Parravicini, P.; Menatti, E.; Trotta, T.; Giannattasio, F.; Coiro, G.; Lena, F.; Lacerenza, G.; Coviello, D. A.; Mussini, C.; Martinelli, E.; Tavecchia, L.; Belli, M. A.; Crotti, L.; Parati, G.; Sanarico, M.; Biscarini, F.; Stella, A.; Rizzi, M.; Maggiolo, F.; Ripamonti, D.; Suardi, C.; Bachetti, T.; La Rovere, M. T.; Sarzi-Braga, S.; Bussotti, M.; Capitani, K.; Dei, S.; Ravaglia, S.; Artuso, R.; Andreucci, E.; Gori, G.; Pagliazzi, A.; Fiorentini, E.; Perrella, A.; Bianchi, F.; Bergomi, P.; Catena, E.; Colombo, R.; Luchi, S.; Morelli, G.; Petrocelli, P.; Iacopini, S.; Modica, S.; Baroni, S.; Segala, F. V.; Menichetti, F.; Falcone, M.; Tiseo, G.; Barbieri, C.; Matucci, T.; Grassi, D.; Ferri, C.; Marinangeli, F.; Brancati, F.; Vincenti, A.; Borgo, V.; Lombardi, S.; Lenzi, M.; Di Pietro, M. A.; Vichi, F.; Romanin, B.; Attala, L.; Costa, C.; Gabbuti, A.; Mene, R.; Colaneri, M.; Casprini, P.; Merla, G.; Squeo, G. M.; Maffezzoni, M.; Mantovani, S.; Mondelli, M. U.; Ludovisi, S.; Colombo, F.; Chiaromonte, F.; Renieri, A.; Furini, S.; Raimondi, F.
abstract
We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as “Respiratory or thoracic disease”, supporting their link with COVID-19 severity outcome.
2022
- Association between respiratory distress time and invasive mechanical ventilation in COVID-19 patients: a multicentre regional cohort study.
[Articolo su rivista]
Busani, Stefano; Coloretti, Irene; Baciarello, Marco; Bellini, Valentina; Sarti, Marco; Biagioni, Emanuela; Tonelli, Roberto; Marchioni, Alessandro; Clini, Enrico; Guaraldi, Giovanni; Mussini, Cristina; Meschiari, Marianna; Tonetti, Tommaso; Pisani, Lara; Nava, Stefano; Bignami, Elena; Ranieri, Marco; Girardis, Massimo
abstract
Aim: to determine whether the duration of respiratory distress symptoms in severe COVID-19 pneumonia affects the need for invasive mechanical ventilation and clinical outcomes.
Materials and methods: an observational multicentre cohort study of patients hospitalised in five COVID-19–designated ICUs of the University Hospitals of Emilia-Romagna Region. Patients included were adults with pneumonia due to SARS-CoV-2 with PaO₂/FiO₂ ratio <300 mmHg, respiratory distress symptoms, and need for mechanical ventilation (invasive or non-invasive). Exclusion criteria were an uncertain time of respiratory distress, end-of-life decision, and mechanical respiratory support before hospital admission.
Measurements and main results: we analysed 171 patients stratified into tertiles according to respiratory distress duration (distress time, DT) before application of mechanical ventilation support. The rate of patients requiring invasive mechanical ventilation was significantly different (p<0.001) among the tertiles: 17/57 patients in the shortest duration, 29/57 in the intermediate duration, and 40/57 in the longest duration. The respiratory distress time significantly increased the
risk of invasive ventilation in the univariate analysis (OR 5.5 [CI 2.48–12.35], p = 0.003). Multivariable regression analysis confirmed this association (OR 10.7 [CI 2.89–39.41], p <0.001). Clinical outcomes (mortality and hospital stay) did not show significant differences between DT tertiles.
Discussion: albeit preliminary and retrospective, our data raised the hypothesis that the duration of respiratory distress symptoms may play a role in COVID-19 patients’ need for invasive mechanical ventilation. Furthermore, our observations suggested that specific strategies may be directed towards identifying and managing early symptoms of respiratory distress, regardless of the levels of hypoxemia and the severity of the dyspnoea itself.
2022
- Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19
[Articolo su rivista]
Zguro, K.; Baldassarri, M.; Fava, F.; Beligni, G.; Daga, S.; Leoncini, R.; Galasso, L.; Cirianni, M.; Rusconi, S.; Siano, M.; Francisci, D.; Schiaroli, E.; Luchi, S.; Morelli, G.; Martinelli, E.; Girardis, M.; Busani, S.; Parisi, S. G.; Panese, S.; Piscopo, C.; Capasso, M.; Tacconi, D.; Raffaelli, C. S.; Giliberti, A.; Gori, G.; Katsikis, P. D.; Lorubbio, M.; Calzoni, P.; Ognibene, A.; Bocchia, M.; Tozzi, M.; Bucalossi, A.; Marotta, G.; Furini, S.; Renieri, A.; Fallerini, C.
abstract
Thrombosis of small and large vessels is reported as a key player in COVID-19 severity. However, host genetic determinants of this susceptibility are still unclear. Congenital Thrombotic Thrombocytopenic Purpura is a severe autosomal recessive disorder characterized by uncleaved ultra-large vWF and thrombotic microangiopathy, frequently triggered by infections. Carriers are reported to be asymptomatic. Exome analysis of about 3000 SARS-CoV-2 infected subjects of different severities, belonging to the GEN-COVID cohort, revealed the specific role of vWF cleaving enzyme ADAMTS13 (A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 13). We report here that ultra-rare variants in a heterozygous state lead to a rare form of COVID-19 characterized by hyper-inflammation signs, which segregates in families as an autosomal dominant disorder conditioned by SARS-CoV-2 infection, sex, and age. This has clinical relevance due to the availability of drugs such as Caplacizumab, which inhibits vWF–platelet interaction, and Crizanlizumab, which, by inhibiting P-selectin binding to its ligands, prevents leukocyte recruitment and platelet aggregation at the site of vascular damage.
2022
- Ceftazidime/Avibactam in Ventilator-Associated Pneumonia Due to Difficult-to-Treat Non-Fermenter Gram-Negative Bacteria in COVID-19 Patients: A Case Series and Review of the Literature
[Articolo su rivista]
Burastero, Giulia Jole; Orlando, Gabriella; Santoro, Antonella; Menozzi, Marianna; Franceschini, Erica; Bedini, Andrea; Cervo, Adriana; Faltoni, Matteo; Bacca, Erica; Biagioni, Emanuela; Coloretti, Irene; Melegari, Gabriele; Maccieri, Jessica; Busani, Stefano; Bertellini, Elisabetta; Girardis, Massimo; Ferrarini, Giulia; Rofrano, Laura; Sarti, Mario; Mussini, Cristina; Meschiari, Marianna
abstract
Ventilator-associated pneumonia (VAP) in critically ill patients with COVID-19 represents a very huge global threat due to a higher incidence rate compared to non-COVID-19 patients and almost 50% of the 30-day mortality rate. Pseudomonas aeruginosa was the first pathogen involved but uncommon non-fermenter gram-negative organisms such as Burkholderia cepacea and Stenotrophomonas maltophilia have emerged as other potential etiological causes. Against carbapenem-resistant gram-negative microorganisms, Ceftazidime/avibactam (CZA) is considered a first-line option, even more so in case of a ceftolozane/tazobactam resistance or shortage. The aim of this report was to describe our experience with CZA in a case series of COVID-19 patients hospitalized in the ICU with VAP due to difficult-to-treat (DTT) P. aeruginosa, Burkholderia cepacea, and Stenotrophomonas maltophilia and to compare it with data published in the literature. A total of 23 patients were treated from February 2020 to March 2022: 19/23 (82%) VAPs were caused by Pseudomonas spp. (16/19 DTT), 2 by Burkholderia cepacea, and 6 by Stenotrophomonas maltophilia; 12/23 (52.1%) were polymicrobial. Septic shock was diagnosed in 65.2% of the patients and VAP occurred after a median of 29 days from ICU admission. CZA was prescribed as a combination regimen in 86% of the cases, with either fosfomycin or inhaled amikacin or cotrimoxazole. Microbiological eradication was achieved in 52.3% of the cases and the 30-day overall mortality rate was 14/23 (60.8%). Despite the high mortality of critically ill COVID-19 patients, CZA, especially in combination therapy, could represent a valid treatment option for VAP due to DTT non-fermenter gram-negative bacteria, including uncommon pathogens such as Burkholderia cepacea and Stenotrophomonas maltophilia.
2022
- Correction: Endobronchial valve positioning for alveolar-pleural fistula following ICU management complicating COVID-19 pneumonia (BMC Pulmonary Medicine, (2021), 21, 1, (307), 10.1186/s12890-021-01653-w)
[Articolo su rivista]
Donatelli, P.; Trentacosti, F.; Pellegrino, M. R.; Tonelli, R.; Bruzzi, G.; Andreani, A.; Cappiello, G. F.; Andrisani, D.; Gozzi, F.; Mussini, C.; Busani, S.; Cavaliere, G. V.; Girardis, M.; Bertellini, E.; Clini, E.; Marchioni, A.
abstract
2022
- Cytomegalovirus blood reactivation in COVID-19 critically ill patients: risk factors and impact on mortality.
[Articolo su rivista]
Gatto, Ilenia; Biagioni, Emanuela; Coloretti, Irene; Farinelli, Carlotta; Avoni, Camilla; Caciagli, Valeria; Busani, Stefano; Sarti, Mario; Pecorari, Monica; Gennari, William; Guaraldi, Giovanni; Franceschini, Erica; Meschiari, Marianna; Mussini, Cristina; Tonelli, Roberto; Clini, Enrico; Cossarizza, Andrea; Girardis, Massimo; Gibellini, Lara
abstract
Purpose: Cytomegalovirus (CMV) reactivation in immunocompetent critically ill patients is common
and relates to a worsening outcome. In this large observational study, we evaluated the incidence
and the risk factors associated with CMV reactivation and its effects on mortality in a large cohort of
COVID-19 patients admitted to the intensive care unit (ICU).
Methods: Consecutive patients with confirmed SARS-CoV-2 infection and acute respiratory distress
syndrome admitted to three ICUs from February 2020 to July 2021 were included. The patients were screened at ICU admission and once or twice per week for quantitative CMV-DNAemia in the blood. The risk factors associated with CMV blood reactivation and its association with mortality were estimated by adjusted Cox proportional hazards regression models.
Results: CMV blood reactivation was observed in 88 patients (20,4%) of the 431 patients studied.
SAPS II score (HR 1,031, 95% CI 1,010-1,053, p=0,006), platelet count (HR 0,0996, 95% CI 0,993-0,999, p=0,004), invasive mechanical ventilation (HR 2,611, 95% CI 1,223-5,571, p=0,013) and secondary bacterial infection (HR 5,041; 95% CI 2,852-8,911, p<0,0001) during ICU stay were related to CMV reactivation. Hospital mortality was higher in patients with (67,0%) than in patients without (24,5%) CMV reactivation but the adjusted analysis did not confirm this association (HR 1,141, 95% CI 0,757-1,721, p=0,528).
Conclusion: The severity of illness and the occurrence of secondary bacterial infections were
associated with an increased risk of CMV blood reactivation, which, however, does not seem to
influence the outcome of COVID-19 ICU patients independently.
2022
- Early awake proning in critical and severe COVID-19 patients undergoing noninvasive respiratory support: A retrospective multicenter cohort study
[Articolo su rivista]
Tonelli, R; Pisani, L; Tabbì, L; Comellini, V; Prediletto, I; Fantini, R; Marchioni, A; Andrisani, D; Gozzi, F; Bruzzi, G; Manicardi, L; Busani, S; Mussini, C; Castaniere, I; Bassi, I; Carpano, M; Tagariello, F; Corsi, G; D' amico, R; Girardis, M; Nava, S; Clini, E.
abstract
Introduction- In non-intubated patients with COVID-19 pneumonia, awake prone position associated with non-invasive respiratory support (NRS) demonstrated only physiological benefits. Nonetheless, it might be arguable that at least a selected subset of these patients is going to obtain significant clinical gains.
Methods- This retrospective cohort study was conducted in two teaching hospitals comparing effects of awake prone position in addition to usual care (PP) with standard care alone (SC)in severe and critical COVID-19 patients undergoing NRS. Primary outcome was endotracheal intubation (ETI) rate. In-hospital mortality, time to ETI, tracheostomy, length of RICU and hospital stay served as secondary outcomes. Risk factors associated with ETI were also investigated in PP group.
Results- A cohort of 114 patients (38 and 76 in PP and SC group, respectively) was analyzed. Greater ETI risk reduction rate was observed in PP as compared with SC both at unadjusted estimates (HR=0.45 95%CI [0.2-0.9], p=0.02), and even after adjustment for confounders (HR=0.59 95%CI[0.3-0.94], p=0.03). Compared with SC, PP group also showed a favorable difference in terms of days free from respiratory support, length of RICU and hospital stay, but not in mortality or tracheostomy rate.
Conclusion- Early awake proning in spontaneously breathing Covid-19 patients is associated with a risk reduction of intubation rate.Findings prompt further randomized controlled trials to answer the pending questions on the real efficacy of PP in this setting.
2022
- Editorial: Putting the Spotlight on the Role of Oxygen in Critically-Ill Patients: From Basic Mechanisms to Clinical Effects
[Articolo su rivista]
Busani, S.; Munari, E.; Taccone, F. S.; Donati, A.; Girardis, M.
abstract
2022
- First and second wave among hospitalized COVID-19 patients with severe pneumonia: a comparison of 28-day mortality over 1-year pandemic in a tertiary university hospital in Italy.
[Articolo su rivista]
Meschiari, M; Cozzi-Lepri, A; Tonelli, R; Bacca, E; Menozzi, M; Franceschini, E; Cuomo, G; Bedini, A; Volpi, S; Milic, J; Brugioni, L; Romagnoli, E; Pietrangelo, A; Corradini, E; Coloretti, I; Biagioni, E; Busani, S; Girardis, M; Cossarizza, A; Clini, E; Guaraldi, G; Mussini, C.
abstract
Objectives: The first COVID-19-19 epidemic wave was over the period February-May 2020. Since October 1st, 2020 Italy, as many other European countries, faced a second wave. The aim of this analysis was to compare the 28-day mortality between the two waves among COVID-19 hospitalised patients.
Design: Observational cohort study. Standard survival analysis was performed to compare all-cause mortality within 28 days after hospital admission in the two waves. Kaplan-Meier curves as well as Cox regression model analysis were used. The effect of wave on risk of death was shown by means of hazard ratios (HRs) with 95% confidence intervals (CI). A sensitivity analysis around the impact of the circulating variant as a potential unmeasured confounder was performed.
Setting: University Hospital of Modena, Italy. Patients admitted to hospital for severe COVID-19 pneumonia during the first (February 22nd – May 31st, 2020) and second wave (October 1st- December 31st, 2020) were included.
Results: During the two study periods, a total of 1,472 patients with severe COVID-19 pneumonia were admitted to our hospital, 449 during the first wave and 1,023 during the second. Median age was 70 years (IQR:56-80), 37% females, 49% with PaO /FiO < 250 mmHg, 82% with ≥1 comorbidity, median duration of symptoms was 6 days. 28-day mortality rate was 20.0% (95% CI:16.3-23.7) during the first wave vs. 14.2% (95% CI:12.0-16.3) in the second (log-rank test p-value= 0.03). After including key predictors of death in the multivariable Cox regression model, the data still strongly suggested a lower 28-day mortality rate in the 2nd wave (aHR=0.64, 95% CI: 0.45, 0.90, p- value=0.01).
Conclusions: In our hospitalized COVID-19 patients with severe pneumonia, the 28-day mortality appeared to be reduced by 36% during the second as compared to the first wave. Further studies are needed to identify factors that may have contributed to this improved survival.
2022
- Inspiratory effort and respiratory mechanics in spontaneously breathing patients with acute exacerbation of idiopathic pulmonary fibrosis: a retrospective matched control study.
[Articolo su rivista]
Tonelli, Roberto; Castaniere, Ivana; Cortegiani, Andrea; Tabbì, Luca; Fantini, Riccardo; Andrisani, Dario; Gozzi, Filippo; Moretti, Antonio; Bruzzi, Giulia; Manicardi, Linda; Cerbone, Caterina; Nani, Chiara; Biagioni, Emanuela; Cerri, Stefania; Samarelli, Valeria; Busani, Stefano; Girardis, Massimo; Marchioni, Alessandro; Clini, Enrico
abstract
Background- Patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) may experience severe acute respiratory failure, even requiring ventilatory assistance. Physiological data on lung mechanics during these events are lacking.
Methods- Patients with AE-IPF admitted to Respiratory Intensive Care Unit to receive noninvasive ventilation (NIV) were retrospectively analyzed. Esophageal pressure swing (ΔP es ) and respiratory mechanics before and 2 hours after NIV start were collected as primary outcome. Correlation between positive end-expiratory pressure (PEEP) levels and changes of dynamic compliance (dynC RS ) and PaO 2 /FiO 2 ratio was assessed. Further, an exploratory comparison with a historic cohort of ARDS patients matched 1:1 by age, sequential organ failure assessment score, body mass index and PaO 2 /FiO 2 level was performed.
Results- At baseline, AE-IPF presented high respiratory drive activation with ΔPes = 27 (21–34) cmH2O, respiratory rate (RR) = 34 (30–39) bpm and minute ventilation (VE) = 21 (20–26) L/min. Two hours after NIV application, ΔPes, RR and VE showed a significant reduction (16 [14–24] cmH2O, p<0.0001, 27 [25–30] bpm, p=0.001, and 18 [17–20] L/min, p=0.003, respectively) while no significant change was found for dynamic transpulmonary pressure (27 [21–34] VS 27 [25–36] cmH2O, p=0.2) expiratory tidal volume (Vte) (9.1 [8.7–10.1] VS 9.3 [8.7 – 9.9] mL/kg of predicted boy weight, p=0.2), dynCRS (28 [19–31] VS 26 [18–28] mL/cmH2O, p=0.1) and dynamic mechanical power (71 [49–94] VS 60 [51–74] J/min, p=0.1). PEEP levels negatively correlated with PaO 2 /FiO 2 ratio and dynC RS (r=–0.67, p=0.03 and r=–0.27, p=0.4, respectively). When compared to AE-IPF, ARDS patients presented lower baseline ΔP
es , RR, VE and dynamic mechanical power. At difference with AE-IPF, Vte and dynC RS increased significantly following NIV (p=0.01 and p=0.004 respectively) with PEEP levels directly associated with PaO 2 /FiO 2 ratio and dynC RS (r=0.24, p=0.5 and r=0.65, p=0.04, respectively).
Conclusions- In this study, patients with AE-IPF showed a high inspiratory effort, whose intensity was reduced by NIV application without significant improvement in respiratory mechanics. In an exploratory analysis, AE-IPF patients showed a different mechanical behavior under spontaneous unassisted and assisted breathing compared with ARDS of similar
severity.
2022
- Long-Term Impact of the COVID-19 Pandemic on In-Hospital Antibiotic Consumption and Antibiotic Resistance: A Time Series Analysis (2015-2021)
[Articolo su rivista]
Meschiari, Marianna; Onorato, Lorenzo; Bacca, Erica; Orlando, Gabriella; Menozzi, Marianna; Franceschini, Erica; Bedini, Andrea; Cervo, Adriana; Santoro, Antonella; Sarti, Mario; Venturelli, Claudia; Biagioni, Emanuela; Coloretti, Irene; Busani, Stefano; Girardis, Massimo; Lòpez-Lozano, José-María; Mussini, Cristina
abstract
The coronavirus disease 2019 (COVID-19)-pandemic-related overload of health systems has compromised the application of antimicrobial stewardship (AS) models and infection prevention and control (IPC) programs. We aimed to evaluate the impact of COVID-19 on antimicrobial consumption (AC) and antimicrobial resistance (AMR) in the University Hospital of Modena. A time series analysis with an autoregressive integrated moving average model was conducted from January 2015 to October 2021 to evaluate the AC in the whole hospital and the intensive care unit (ICU), the incidence density (ID) of bloodstream infections (BSIs) due to the main multidrug-resistant organisms, and of C. difficile infections (CDIs). After an initial peak during the COVID-19 period, a decrease in the trend of AC was observed, both at the hospital (CT: -1.104, p = 0.025) and ICU levels (CT: -4.47, p = 0.047), with no significant difference in the single classes. Among the Gram-negative isolates, we observed a significant increase only in the level of BSIs due to carbapenem-susceptible Pseudomonas aeruginosa (CL: 1.477, 95% CI 0.130 to 2.824, p = 0.032). Considering Gram-positive bacteria, an increase in the level of BSIs due to methicillin-resistant Staphylococcus aureus and in the trend of CDIs were observed, though they did not reach statistical significance (CL: 0.72, 95% CI -0.039 to 1.48, p = 0.062; CT: 1.43, 95% CI -0.002 to 2.863, p = 0.051; respectively). Our findings demonstrated that the increases in AMR and AC that appeared in the first COVID-19 wave may be later controlled by restoring IPC and AS programs to pre-epidemic levels. A coordinated healthcare effort is necessary to address the longer-term impact of COVID-19 on AC to avoid irreversible consequences on AMR.
2022
- Metabolic reprograming shapes neutrophil functions in severe COVID-19
[Articolo su rivista]
Borella, Rebecca; De Biasi, Sara; Paolini, Annamaria; Boraldi, Federica; Tartaro, Domenico Lo; Mattioli, Marco; Fidanza, Lucia; Neroni, Anita; Caro-Maldonado, Alfredo; Meschiari, Marianna; Franceschini, Erica; Quaglino, Daniela; Guaraldi, Giovanni; Bertoldi, Carlo; Sita, Marco; Busani, Stefano; Girardis, Massimo; Mussini, Cristina; Cossarizza, Andrea; Gibellini, Lara
abstract
: To better understand the mechanisms at the basis of neutrophil functions during SARS-CoV-2 we studied patients with severe COVID-19 pneumonia. They had high blood proportion of degranulated neutrophils and elevated plasma levels of myeloperoxidase (MPO), elastase and MPO-DNA complexes, which are typical markers of neutrophil extracellular traps (NET). Their neutrophils display dysfunctional mitochondria, defective oxidative burst, increased glycolysis, glycogen accumulation in the cytoplasm, and increase glycogenolysis. Hypoxia-inducible factor 1α (ΗΙF-1α) is stabilized in such cells, and it controls the level of glycogen phosphorylase L (PYGL), a key enzyme in glycogenolysis. Inhibiting PYGL abolishes the ability of neutrophils to produce NET. Patients displayed significant increases of plasma levels of molecules involved in the regulation of neutrophils' function, including CCL2, CXCL10, CCL20, IL-18, IL-3, IL-6, G-CSF, GM-CSF, IFN-γ. Our data suggest that metabolic remodelling is vital for the formation of NET and for boosting neutrophil inflammatory response, thus suggesting that modulating ΗΙF-1α or PYGL could represent a novel approach for innovative therapies. This article is protected by copyright. All rights reserved.
2022
- Molecular and cellular immune features of aged patients with severe COVID-19 pneumonia
[Articolo su rivista]
Lo Tartaro, D.; Neroni, A.; Paolini, A.; Borella, R.; Mattioli, M.; Fidanza, L.; Quong, A.; Petes, C.; Awong, G.; Douglas, S.; Lin, D.; Nieto, J.; Gozzi, L.; Franceschini, E.; Busani, S.; Nasi, M.; Mattioli, A. V.; Trenti, T.; Meschiari, M.; Guaraldi, G.; Girardis, M.; Mussini, C.; Gibellini, L.; Cossarizza, A.; De Biasi, S.
abstract
Aging is a major risk factor for developing severe COVID-19, but few detailed data are available concerning immunological changes after infection in aged individuals. Here we describe main immune characteristics in 31 patients with severe SARS-CoV-2 infection who were >70 years old, compared to 33 subjects <60 years of age. Differences in plasma levels of 62 cytokines, landscape of peripheral blood mononuclear cells, T cell repertoire, transcriptome of central memory CD4+ T cells, specific antibodies are reported along with features of lung macrophages. Elderly subjects have higher levels of pro-inflammatory cytokines, more circulating plasmablasts, reduced plasmatic level of anti-S and anti-RBD IgG3 antibodies, lower proportions of central memory CD4+ T cells, more immature monocytes and CD56+ pro-inflammatory monocytes, lower percentages of circulating follicular helper T cells (cTfh), antigen-specific cTfh cells with a less activated transcriptomic profile, lung resident activated macrophages that promote collagen deposition and fibrosis. Our study underlines the importance of inflammation in the response to SARS-CoV-2 and suggests that inflammaging, coupled with the inability to mount a proper anti-viral response, could exacerbate disease severity and the worst clinical outcome in old patients.
2022
- Nasal pressure swings as the measure of inspiratory effort in spontaneously breathing patients with de novo acute respiratory failure
[Articolo su rivista]
Tonelli, Roberto; Cortegiani, Andrea; Marchioni, Alessandro; Fantini, Riccardo; Tabbì, Luca; Castaniere, Ivana; Biagioni, Emanuela; Busani, Stefano; Nani, Chiara; Cerbone, Caterina; Vermi, Morgana; Gozzi, Filippo; Bruzzi, Giulia; Manicardi, Linda; Rosaria Pellegrino, Maria; Beghè, Bianca; Girardis, Massimo; Pelosi, Paolo; Gregoretti, Cesare; Ball, Lorenzo; Clini, Enrico
abstract
Background- Excessive inspiratory effort could translate into self-inflicted lung injury, thus worsening
clinical outcomes of spontaneously breathing patients with acute respiratory failure (ARF). Although esophageal manometry is a reliable method to estimate the magnitude of inspiratory effort, procedural issues significantly limit its use in daily clinical practice. The aim of this study is to describe the correlation between esophageal pressure swings (ΔP es ) and nasal (ΔP nos ) as a potential measure of inspiratory effort in spontaneously breathing patients with de novo ARF.
Methods- From January 1 st , 2021 to September 1 st , 2021, 61 consecutive patients with ARF (83.6% related to COVID-19) admitted to the Respiratory Intensive Care Unit (RICU) of the University Hospital of Modena (Italy) and candidate to escalation of noninvasive respiratory support (NRS) were enrolled. Clinical features and tidal changes in esophageal and nasal pressure were recorded on admission and 24 hours after starting NRS. Correlation between ΔP es and ΔP nos served as primary outcome. The effect of ΔP nos measurements on respiratory rate and ΔP es was also assessed.
Results- ΔP es and ΔP nos were strongly correlated at admission (R 2 =0.88, p<0.001) and 24 hours apart (R 2 =0.94, p<0.001). The nasal plug insertion and the mouth closure required for ΔP nos measurement did not result in significant change of respiratory rate and ΔP es . The correlation between measures at 24 hours remained significant even after splitting the study population according to the type of NRS (high-flow nasal cannulas [R 2 =0.79, p<0.001] or non-invasive ventilation [R 2 =0.95, p<0.001]).
Conclusions- In a cohort of patients with ARF, nasal pressure swings did not alter respiratory mechanics in the short term and were highly correlated with esophageal pressure swings during spontaneous tidal breathing. ΔP nos might warrant further investigation as a measure of inspiratory effort in patients with ARF.
2022
- Patients Recovering from Severe COVID-19 Develop a Polyfunctional Antigen-Specific CD4+ T Cell Response
[Articolo su rivista]
Paolini, A.; Borella, R.; Neroni, A.; Lo Tartaro, D.; Mattioli, M.; Fidanza, L.; Di Nella, A.; Santacroce, E.; Gozzi, L.; Busani, S.; Trenti, T.; Meschiari, M.; Guaraldi, G.; Girardis, M.; Mussini, C.; Gibellini, L.; De Biasi, S.; Cossarizza, A.
abstract
Specific T cells are crucial to control SARS-CoV-2 infection, avoid reinfection and confer protection after vaccination. We have studied patients with severe or moderate COVID-19 pneumonia, compared to patients who recovered from a severe or moderate infection that had occurred about 4 months before the analyses. In all these subjects, we assessed the polyfunctionality of virus-specific CD4+ and CD8+ T cells by quantifying cytokine production after in vitro stimulation with different SARS-CoV-2 peptide pools covering different proteins (M, N and S). In particular, we quantified the percentage of CD4+ and CD8+ T cells simultaneously producing interferon-γ, tumor necrosis factor, interleukin (IL)-2, IL-17, granzyme B, and expressing CD107a. Recovered patients who experienced a severe disease display high proportions of antigen-specific CD4+ T cells producing Th1 and Th17 cytokines and are characterized by polyfunctional SARS-CoV-2-specific CD4+ T cells. A similar profile was found in patients experiencing a moderate form of COVID-19 pneumonia. No main differences in polyfunctionality were observed among the CD8+ T cell compartments, even if the proportion of responding cells was higher during the infection. The identification of those functional cell subsets that might influence protection can thus help in better understanding the complexity of immune response to SARS-CoV-2.
2022
- Plasma Cytokine Atlas Reveals the Importance of TH2 Polarization and Interferons in Predicting COVID-19 Severity and Survival
[Articolo su rivista]
Gibellini, L.; De Biasi, S.; Meschiari, M.; Gozzi, L.; Paolini, A.; Borella, R.; Mattioli, M.; Lo Tartaro, D.; Fidanza, L.; Neroni, A.; Busani, S.; Girardis, M.; Guaraldi, G.; Mussini, C.; Cozzi-Lepri, A.; Cossarizza, A.
abstract
Although it is now widely accepted that host inflammatory response contributes to COVID-19 immunopathogenesis, the pathways and mechanisms driving disease severity and clinical outcome remain poorly understood. In the effort to identify key soluble mediators that characterize life-threatening COVID-19, we quantified 62 cytokines, chemokines and other factors involved in inflammation and immunity in plasma samples, collected at hospital admission, from 80 hospitalized patients with severe COVID-19 disease who were stratified on the basis of clinical outcome (mechanical ventilation or death by day 28). Our data confirm that age, as well as neutrophilia, lymphocytopenia, procalcitonin, D-dimer and lactate dehydrogenase are strongly associated with the risk of fatal COVID-19. In addition, we found that cytokines related to TH2 regulations (IL-4, IL-13, IL-33), cell metabolism (lep, lep-R) and interferons (IFNα, IFNβ, IFNγ) were also predictive of life-threatening COVID-19.
2022
- Risk factors for pulmonary air leak and clinical prognosis in patients with COVID-19 related acute respiratory failure: a retrospective matched control study.
[Articolo su rivista]
Tonelli, Roberto; Bruzzi, Giulia; Manicardi, Linda; Tabbì, Luca; Fantini, Riccardo; Castaniere, Ivana; Andrisani, Dario; Gozzi, Filippo; Rosaria Pellegrino, Maria; Trentacosti, Fabiana; Dall'Ara, Lorenzo; Busani, Stefano; Franceschini, Erica; Baroncini, Serena; Manco, Gianrocco; Meschiari, Marianna; Mussini, Cristina; Girardis, Massimo; Beghe', Bianca; Marchioni, Alessandro; Clini, Enrico
abstract
Background- The role of excessive inspiratory effort in promoting alveolar and pleural rupture resulting in air leak (AL) in patients with SARS-CoV-2 induced acute respiratory failure (ARF) while on spontaneous breathing is undetermined.
Methods- Among all patients with COVID-19 related ARF admitted to a respiratory intensive care unit (RICU) and receiving non-invasive respiratory support, those developing an AL were and matched 1:1 (by means of PaO2/FiO2 ratio, age, body mass index-BMI and subsequent organ failure assessment [SOFA]) with a comparable population who did not (NAL group). Esophageal pressure (ΔPes) and dynamic transpulmonary pressure (ΔPL) swings were compared between groups. Risk factors affecting AL onset were evaluated. The composite outcome of ventilator-free-days (VFD) at day 28 (including ETI, mortality, tracheostomy) was compared between groups.
Results- AL and NAL groups (n=28) showed similar ΔPes, whereas AL had higher ΔPL (20 [16‐21] and 17 [11‐20], p=0.01 respectively). Higher ΔPL (OR=1.5 95%CI[1‐1.8], p=0.01), positive end‐expiratory pressure (OR=2.4 95%CI[1.2‐5.9], p=0.04) and pressure support (OR=1.8 95%CI[1.1-3.5], p=0.03), D-dimer on admission (OR=2.1 95%CI[1.3-9.8], p=0.03), and features suggestive of consolidation on computed tomography scan (OR=3.8 95%CI[1.1-15], p= 0.04) were all significantly associated with AL. A lower VFD score resulted in a higher risk (HR=3.7 95%CI [1.2-11.3], p=0.01) in the AL group compared with NAL. RICU stay and 90-day mortality were also higher in the AL group compared with NAL.
Conclusions- In spontaneously breathing patients with COVID‐19 related ARF, higher levels of ΔPL, blood D‐dimer, NIV delivery pressures and a consolidative lung pattern were associated with AL onset.
2022
- The PROVENT-C19 registry: A study protocol for international multicenter SIAARTI registry on the use of prone positioning in mechanically ventilated patients with COVID-19 ARDS
[Articolo su rivista]
De Rosa, S.; Sella, N.; Rezoagli, E.; Lorenzoni, G.; Gregori, D.; Bellani, G.; Foti, G.; Pettenuzzo, T.; Baratto, F.; Fullin, G.; Papaccio, F.; Peta, M.; Poole, D.; Toffoletto, F.; Maggiore, S. M.; Navales, P.; Navalesi, P.; Tiberio, I.; Pasin, L.; Godi, I.; Serra, E.; Zarantonello, F.; Andreatta, G.; Boscolo, A.; Persona, P.; Cattin, L.; Forin, E.; Boni, E.; Golino, G.; Danzi, V.; Vetrugno, L.; Cornacchia, N.; Donadello, K.; Gottin, L.; Polati, E.; Campagnolo, M.; Linassi, F.; Panciera, G.; Garofalo, E.; Bruni, A.; Carlon, R.; Pipitone, M.; Serra, E.; Candosin, A.; Badii, F.; Role, S. D.; Girardis, M.; Busani, S.; Gamberini, E.; Tartivita, C. N.; Gamberini, L.; Cortegiani, A.; Frisella, S.; Ippolito, M.; Salvo, F.; Greco, M.; Cecconi, M.; Aceto, R.; Langer, T.; Repishti, M.; Zeduri, A.; Ottolina, D.; Fossali, T.; Colombo, R.; Predonzani, N.; Ferluga, M.; Blasi, S. D.; Zardin, M.; Vergine, S.; Luccarelli, G.; Tritapepe, L.; Francesconi, A. G.; Pagani, M.; Mojoli, F.; Orlando, A.; Mongodi, S.; Bitondo, M.; Johnathan, M.; Maugeri, J.; Bellissima, A.; Guzzardella, A.; Vallecoccia, M. S.; Spadaro, S.; Cricca, V.; Andriolo, E.; Bianchin, A.; Alampi, D.; Rocco, M.; Anchisi, S.; Tenaglia, T.; Nicoletti, R.; Antonini, B.; Zanaty, M.; Mogahed, M.; Ali, A.; Emara, M.; Abdullah, E.; Awad, A. K.; Abdel-Maboud, M.; Hussein, A. M.; Hussein, A. A. R. M.; Mosleh, A. A.; Ahmed, M. G.; Aziz, M. G.; Elsayed, A.; Aldhalia, A.; Elkhatid, A.; Abodina, A. M.; Khalleefah, A.; Shalabi, L. E.; Shamed, H.; Bakeer, H. B.; Hawad, A.; Abuzaid, T.; Alqandouz, R. A. S.; Saliga, A. A.; Haddud, A.; Kredan, A. A.; Shaban, M. S.; Salama, A. A.; Altabit, A. E. R. M.; Alflite, A. O. S.; Hashim, H. T.; Kadhim, Q. M.; Abd-Alreda, A. H.; Al-Juifari, M. A.; Al-Gburi, S. M.; Akram, A.; Laila, A.; Bakri, A.; Abdelmageed, A.; Binnawara, M.; Mohamed, M.; Esaadi, H.; Othman, E.; Said, A.; Alarabi, R.; Alameen, H.; Albouishi, N.; Babaa, K. A.; Salih, R.; Elbakheet, D. E.; Abuelyamen, A.; Perez-Torres, D.; Mattson, J.; Al-Sadawi, M.; Elseidy, S.
abstract
Background The worldwide use of prone position (PP) for invasively ventilated patients with COVID-19 is progressively increasing from the first pandemic wave in everyday clinical practice. Among the suggested treatments for the management of ARDS patients, PP was recommended in the Surviving Sepsis Campaign COVID-19 guidelines as an adjuvant therapy for improving ventilation. In patients with severe classical ARDS, some authors reported that early application of prolonged PP sessions significantly decreases 28-day and 90-day mortality. Methods and analysis Since January 2021, the COVID19 Veneto ICU Network research group has developed and implemented nationally and internationally the "PROVENT-C19 Registry", endorsed by the Italian Society of Anesthesia Analgesia Resuscitation and Intensive Care. . .'(SIAARTI). The PROVENT-C19 Registry wishes to describe 1. The real clinical practice on the use of PP in COVID-19 patients during the pandemic at a National and International level; and 2. Potential baseline and clinical characteristics that identify subpopulations of invasively ventilated patients with COVID-19 that may improve daily from PP therapy. This web-based registry will provide relevant information on how the database research tools may improve our daily clinical practice. Conclusions This multicenter, prospective registry is the first to identify and characterize the role of PP on clinical outcome in COVID-19 patients. In recent years, data emerging from large registries have been increasingly used to provide real-world evidence on the effectiveness, quality, and safety of a clinical intervention. Indeed observation-based registries could be effective tools aimed at identifying specific clusters of patients within a large study population with widely heterogeneous clinical characteristics. Copyright:
2022
- Whole-genome sequencing reveals host factors underlying critical COVID-19
[Articolo su rivista]
Kousathanas, A.; Pairo-Castineira, E.; Rawlik, K.; Stuckey, A.; Odhams, C. A.; Walker, S.; Russell, C. D.; Malinauskas, T.; Wu, Y.; Millar, J.; Shen, X.; Elliott, K. S.; Griffiths, F.; Oosthuyzen, W.; Morrice, K.; Keating, S.; Wang, B.; Rhodes, D.; Klaric, L.; Zechner, M.; Parkinson, N.; Siddiq, A.; Goddard, P.; Donovan, S.; Maslove, D.; Nichol, A.; Semple, M. G.; Zainy, T.; Maleady-Crowe, F.; Todd, L.; Salehi, S.; Knight, J.; Elgar, G.; Chan, G.; Arumugam, P.; Patch, C.; Rendon, A.; Bentley, D.; Kingsley, C.; Kosmicki, J. A.; Horowitz, J. E.; Baras, A.; Abecasis, G. R.; Ferreira, M. A. R.; Justice, A.; Mirshahi, T.; Oetjens, M.; Rader, D. J.; Ritchie, M. D.; Verma, A.; Fowler, T. A.; Shankar-Hari, M.; Summers, C.; Hinds, C.; Horby, P.; Mcauley, D.; Montgomery, H.; Openshaw, P. J. M.; Elliott, P.; Walsh, T.; Tenesa, A.; Fawkes, A.; Murphy, L.; Rowan, K.; Ponting, C. P.; Vitart, V.; Wilson, J. F.; Yang, J.; Bretherick, A. D.; Scott, R. H.; Hendry, S. C.; Moutsianas, L.; Law, A.; Caulfield, M. J.; Baillie, J. K.; Begg, C.; Ling, L.; Millar, J.; Pereira, A. C.; Aravindan, L.; Armstrong, R.; Biggs, H.; Boz, C.; Brown, A.; Clark, R.; Coutts, A.; Coyle, J.; Cullum, L.; Das, S.; Day, N.; Donnelly, L.; Duncan, E.; Finernan, P.; Fourman, M. H.; Furlong, A.; Furniss, J.; Gallagher, B.; Gilchrist, T.; Golightly, A.; Hafezi, K.; Hamilton, D.; Hendry, R.; Law, D.; Law, R.; Law, S.; Lidstone-Scott, R.; Macgillivray, L.; Maclean, A.; Mal, H.; Mccafferty, S.; Mcmaster, E.; Meikle, J.; Moore, S. C.; Murphy, S.; Hellen, M.; Zheng, C.; Chen, J.; Paterson, T.; Schon, K.; Stenhouse, A.; Das, M.; Swets, M.; Szoor-McElhinney, H.; Taneski, F.; Turtle, L.; Wackett, T.; Ward, M.; Weaver, J.; Wrobel, N.; Arbane, G.; Bociek, A.; Campos, S.; Grau, N.; Jones, T. O.; Lim, R.; Marotti, M.; Ostermann, M.; Whitton, C.; Alldis, Z.; Astin-Chamberlain, R.; Bibi, F.; Biddle, J.; Blow, S.; Bolton, M.; Borra, C.; Bowles, R.; Burton, M.; Choudhury, Y.; Collier, D.; Cox, A.; Easthope, A.; Ebano, P.; Fotiadis, S.; Gurasashvili, J.; Halls, R.; Hartridge, P.; Kallon, D.; Kassam, J.; Lancoma-Malcolm, I.; Matharu, M.; May, P.; Mitchelmore, O.; Newman, T.; Patel, M.; Pheby, J.; Pinzuti, I.; Prime, Z.; Prysyazhna, O.; Shiel, J.; Taylor, M.; Tierney, C.; Wood, S.; Zak, A.; Zongo, O.; Bonner, S.; Hugill, K.; Jones, J.; Liggett, S.; Headlam, E.; Bandla, N.; Gellamucho, M.; Davies, M.; Thompson, C.; Abdelrazik, M.; Bakthavatsalam, D.; Elhassan, M.; Ganesan, A.; Haldeos, A.; Moreno-Cuesta, J.; Purohit, D.; Vincent, R.; Xavier, K.; Kumar, R.; Frater, A.; Saleem, M.; Carter, D.; Jenkins, S.; Lamond, Z.; Wall, A.; Fernandez-Roman, J.; Hamilton, D. O.; Johnson, E.; Johnston, B.; Martinez, M. L.; Mulla, S.; Shaw, D.; Waite, A. A. C.; Waugh, V.; Welters, I. D.; Williams, K.; Cavazza, A.; Cockrell, M.; Corcoran, E.; Depante, M.; Finney, C.; Jerome, E.; Mcphail, M.; Nayak, M.; Noble, H.; O'Reilly, K.; Pappa, E.; Saha, R.; Saha, S.; Smith, J.; Knighton, A.; Antcliffe, D.; Banach, D.; Brett, S.; Coghlan, P.; Fernandez, Z.; Gordon, A.; Rojo, R.; Arias, S. S.; Templeton, M.; Meredith, M.; Morris, L.; Ryan, L.; Clark, A.; Sampson, J.; Peters, C.; Dent, M.; Langley, M.; Ashraf, S.; Wei, S.; Andrew, A.; Bashyal, A.; Davidson, N.; Hutton, P.; Mckechnie, S.; Wilson, J.; Baptista, D.; Crowe, R.; Fernandes, R.; Herdman-Grant, R.; Joseph, A.; O'Connor, D.; Allen, M.; Loveridge, A.; Mckenley, I.; Morino, E.; Naranjo, A.; Simms, R.; Sollesta, K.; Swain, A.; Venkatesh, H.; Khera, J.; Fox, J.; Andrew, G.; Barclay, L.; Callaghan, M.; Campbell, R.; Clark, S.; Hope, D.; Marshall, L.; Mcculloch, C.; Briton, K.; Singleton, J.; Birch, S.; Brimfield, L.; Daly, Z.; Pogson, D.; Rose, S.; Nown, A.; Battle, C.; Brinkworth, E.; Harford, R.; Murphy, C.; Newey, L.; Rees, T.; Williams, M.; Arnold, S.; Polgarova, P.; Stroud, K.; Meaney, E.; Jones, M.; Ng, A.; Agrawal, S.; Pathan, N.; White, D.; Daubney, E.; Elston, K.; Grauslyte, L.; Hussain, M.; Phull, M.; Pogreban, T.; Rosaroso, L.; Salciute, E.; Franke, G.; Wong, J.
abstract
Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.
2021
- A five-component infection control bundle to permanently eliminate a carbapenem-resistant Acinetobacter baumannii spreading in an intensive care unit
[Articolo su rivista]
Meschiari, Marianna; Lòpez-Lozano, José-María; Di Pilato, Vincenzo; Gimenez-Esparza, Carola; Vecchi, Elena; Bacca, Erica; Orlando, Gabriella; Franceschini, Erica; Sarti, Mario; Pecorari, Monica; Grottola, Antonella; Venturelli, Claudia; Busani, Stefano; Serio, Lucia; Girardis, Massimo; Rossolini, Gian Maria; Gyssens, Inge C; Monnet, Dominique L; Mussini, Cristina
abstract
Carbapenem-resistant Acinetobacter baumannii (CRAB) infection outbreaks are difficult to control and sometimes require cohorting of CRAB-positive patients or temporary ward closure for environmental cleaning. We aimed at controlling the deadly 2018 CRAB outbreak in a 12 bed- intensive care unit (ICU) including 9 beds in a 220 m2 open space. We implemented a new multimodal approach without ward closure, cohorting or temporarily limiting admissions.
2021
- Adjunctive Immunotherapy With Polyclonal Ig-M Enriched Immunoglobulins for Septic Shock: From Bench to Bedside. The Rationale for a Personalized Treatment Protocol
[Articolo su rivista]
Busani, Stefano; Roat, Erika; Tosi, Martina; Biagioni, Emanuela; Coloretti, Irene; Meschiari, Marianna; Gelmini, Roberta; Brugioni, Lucio; DE BIASI, Sara; Girardis, Massimo
abstract
Septic shock still has a high mortality rate which has not hinted at decreasing in recent
years. Unfortunately, randomized trials failed mainly because the septic patient was
considered as a homogeneous entity. All this creates a sort of therapeutic impotence
in everyday clinical practice in treating patients with septic shock. The need to customize
therapy on each patient with sepsis has now become an established necessity. In this
scenario, adjuvant therapies can help if interpreted as modulators of the immune system.
Indeed, the host’s immune response differs from patient to patient based on the virulence
of the pathogen, comorbidity, infection site, and prolonged hospitalization. In this review,
we summarize the rationale for using immunoglobulins as an adjunctive treatment.
Furthermore, we would like to suggest a possible protocol to personalize treatment in
the different clinical scenarios of the host’s response to serious infectious events.
2021
- Association of toll-like receptor 7 variants with life-threatening COVID-19 disease in males: Findings from a nested case-control study
[Articolo su rivista]
Fallerini, C.; Daga, S.; Mantovani, S.; Benetti, E.; Picchiotti, N.; Francisci, D.; Paciosi, F.; Schiaroli, E.; Baldassarri, M.; Fava, F.; Palmieri, M.; Ludovisi, S.; Castelli, F.; Quiros-Roldan, E.; Vaghi, M.; Rusconi, S.; Siano, M.; Bandini, M.; Spiga, O.; Capitani, K.; Furini, S.; Mari, F.; Renieri, A.; Mondelli, M. U.; Frullanti, E.; Valentino, F.; Doddato, G.; Giliberti, A.; Tita, R.; Amitrano, S.; Bruttini, M.; Croci, S.; Meloni, I.; Mencarelli, M. A.; Rizzo, C. L.; Pinto, A. M.; Sarno, L. D.; Beligni, G.; Tommasi, A.; Iuso, N.; Montagnani, F.; Fabbiani, M.; Rossetti, B.; Zanelli, G.; Bargagli, E.; Bergantini, L.; D'Alessandro, M.; Cameli, P.; Bennett, D.; Anedda, F.; Marcantonio, S.; Scolletta, S.; Franchi, F.; Mazzei, M. A.; Guerrini, S.; Conticini, E.; Cantarini, L.; Frediani, B.; Tacconi, D.; Spertilli, C.; Feri, M.; Donati, A.; Scala, R.; Guidelli, L.; Spargi, G.; Corridi, M.; Nencioni, C.; Croci, L.; Caldarelli, G. P.; Spagnesi, M.; Romani, D.; Piacentini, P.; Desanctis, E.; Cappelli, S.; Canaccini, A.; Verzuri, A.; Anemoli, V.; Ognibene, A.; D'Arminio Monforte, A.; Miraglia, F. G.; Girardis, M.; Venturelli, S.; Busani, S.; Cossarizza, A.; Antinori, A.; Vergori, A.; Emiliozzi, A.; Gabrieli, A.; Riva, A.; Scotton, P. G.; Andretta, F.; Panese, S.; Scaggiante, R.; Gatti, F.; Parisi, S. G.; Baratti, S.; Antoni, M. D.; Monica, M. D.; Piscopo, C.; Capasso, M.; Russo, R.; Andolfo, I.; Iolascon, A.; Fiorentino, G.; Carella, M.; Castori, M.; Merla, G.; Squeo, G. M.; Aucella, F.; Raggi, P.; Marciano, C.; Perna, R.; Bassetti, M.; Biagio, A. D.; Sanguinetti, M.; Masucci, L.; Valente, S.; Mandala, M.; Giorli, A.; Salerni, L.; Zucchi, P.; Parravicini, P.; Menatti, E.; Trotta, T.; Giannattasio, F.; Coiro, G.; Lena, F.; Coviello, D. A.; Mussini, C.; Bosio, G.; Martinelli, E.; Mancarella, S.; Tavecchia, L.; Gori, M.; Crotti, L.; Parati, G.; Gabbi, C.; Zanella, I.; Rizzi, M.; Maggiolo, F.; Ripamonti, D.; Bachetti, T.; Rovere, M. T. L.; Sarzi-Braga, S.; Bussotti, M.; Chiariello, M.; Belli, M. A.; Dei, S.
abstract
Background: Recently, loss-of-function variants in TLR7 were identified in two families in which COVID-19 segregates like an X-linked recessive disorder environmentally conditioned by SARS-CoV-2. We investigated whether the two families represent the tip of the iceberg of a subset of COVID-19 male patients. Methods: This is a nested case-control study in which we compared male participants with extreme phenotype selected from the Italian GEN-COVID cohort of SARS-CoV-2-infected participants (<60 y, 79 severe cases versus 77 control cases). We applied the LASSO Logistic Regression analysis, considering only rare variants on young male subsets with extreme phenotype, picking up TLR7 as the most important susceptibility gene.
2021
- C9orf72 intermediate repeats confer genetic risk for severe covid-19 pneumonia independently of age
[Articolo su rivista]
Zanella, I.; Zacchi, E.; Piva, S.; Filosto, M.; Beligni, G.; Alaverdian, D.; Amitrano, S.; Fava, F.; Baldassarri, M.; Frullanti, E.; Meloni, I.; Renieri, A.; Castelli, F.; Quiros-Roldan, E.; Mari, F.; Daga, S.; Benetti, E.; Furini, S.; Fallerini, C.; Valentino, F.; Doddato, G.; Giliberti, A.; Tita, R.; Bruttini, M.; Croci, S.; Pinto, A. M.; Mencarelli, M. A.; Rizzo, C. L.; Montagnani, F.; Tumbarello, M.; Rancan, I.; Sarno, L. D.; Palmieri, M.; Carriero, M. L.; Fabbiani, M.; Rossetti, B.; Bargagli, E.; Bergantini, L.; D'Alessandro, M.; Cameli, P.; Bennett, D.; Anedda, F.; Marcantonio, S.; Scolletta, S.; Franchi, F.; Mazzei, M. A.; Guerrini, S.; Conticini, E.; Cantarini, L.; Frediani, B.; Tacconi, D.; Raffaelli, C. S.; Feri, M.; Donati, A.; Scala, R.; Guidelli, L.; Spargi, G.; Corridi, M.; Nencioni, C.; Croci, L.; Caldarelli, G. P.; Spagnesi, M.; Piacentini, P.; Bandini, M.; Desanctis, E.; Cappelli, S.; Canac-Cini, A.; Verzuri, A.; Anemoli, V.; Ognibene, A.; Pancrazi, A.; Lorubbio, M.; Vaghi, M.; Monforte, A. D.; Miraglia, F. G.; Mondelli, M. U.; Bruno, R.; Marco, V.; Mantovani, S.; Ludovisi, S.; Girardis, M.; Venturelli, S.; Busani, S.; Cossarizza, A.; Antinori, A.; Vergori, A.; Emiliozzi, A.; Rusconi, S.; Siano, M.; Gabrieli, A.; Riva, A.; Francisci, D.; Schiaroli, E.; Tommasi, A.; Paciosi, F.; Scotton, P. G.; Andretta, F.; Panese, S.; Scaggiante, R.; Gatti, F.; Parisi, S. G.; Antoni, M. D.; Monica, M. D.; Piscopo, C.; Capasso, M.; Russo, R.; Andolfo, I.; Iolascon, A.; Fiorentino, G.; Carella, M.; Castori, M.; Merla, G.; Squeo, G. M.; Aucella, F.; Raggi, P.; Marciano, C.; Perna, R.; Bassetti, M.; Biagio, A. D.; Sanguinetti, M.; Masucci, L.; Valente, S.; Mandala, M.; Giorli, A.; Salerni, L.; Zucchi, P.; Parravicini, P.; Menatti, E.; Baratti, S.; Trotta, T.; Giannattasio, F.; Coiro, G.; Lena, F.; Coviello, D. A.; Mussini, C.; Bosio, G.; Martinelli, E.; Mancarella, S.; Tavecchia, L.; Belli, M. A.; Crotti, L.; Parati, G.; Picchiotti, N.; Gori, M.; Gabbi, C.; Sanarico, M.; Ceri, S.; Pinoli, P.; Raimondi, F.; Bis-Carini, F.; Stella, A.; Rizzi, M.; Maggiolo, F.; Ripamonti, D.; Suardi, C.; Bachetti, T.; Rovere, M. T. L.; Sarzi-Braga, S.; Bussotti, M.; Capitani, K.; Zguro, K.; Dei, S.; Ravaglia, S.; Artuso, R.; Perrella, A.; Bianchi, F.; Bergomi, P.; Catena, E.; Colombo, R.; Perticaroli, V.; Gennarelli, M.; Magri, C.; Basiotto, G.; Zizioli, D.; Giliani, S.; Monti, E.; Foca, E.; Carriero, C.; Latronico, N.; Padovani, A.; Brugnoni, D.
abstract
A cytokine storm, autoimmune features and dysfunctions of myeloid cells significantly contribute to severe coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Genetic background of the host seems to be partly responsible for severe phenotype and genes related to innate immune response seem critical host determinants. The C9orf72 gene has a role in vesicular trafficking, autophagy regulation and lyso-some functions, is highly expressed in myeloid cells and is involved in immune functions, regulating the lysosomal degradation of mediators of innate immunity. A large non-coding hexanucleotide repeat expansion (HRE) in this gene is the main genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), both characterized by neuroinflammation and high systemic levels of proinflammatory cytokines, while HREs of intermediate length, although rare, are more frequent in autoimmune disorders. C9orf72 full mutation results in haploinsufficiency and intermediate HREs seem to modulate gene expression as well and impair autophagy. Herein, we sought to explore whether intermediate HREs in C9orf72 may be a risk factor for severe COVID-19. Although we found intermediate HREs in only a small portion of 240 patients with severe COVID-19 pneumonia, the magnitude of risk for requiring non-invasive or mechanical ventilation conferred by harboring intermediate repeats >10 units in at least one C9orf72 allele was more than twice respect to having shorter expansions, when adjusted for age (odds ratio (OR) 2.36; 95% confidence interval (CI) 1.04–5.37, p = 0.040). The association between intermediate repeats >10 units and more severe clinical outcome (p = 0.025) was also validated in an independent cohort of 201 SARS-CoV-2 infected patients. These data suggest that C9orf72 HREs >10 units may influence the pathogenic process driving more severe COVID-19 phenotypes.
2021
- Effects of cytokine blocking agents on hospital mortality in patients admitted to ICU with acute respiratory distress syndrome by SARS-CoV2 infection: retrospective cohort study.
[Articolo su rivista]
Coloretti, I; Busani, S; Biagioni, E; Venturelli, S; Munari, E; Marco, S; Dall’Ara, L; Tosi, M; Clini, E; Tonelli, R; Fantini, R; Mussini, C; Meschiari, M; Guaraldi, G; Cossarizza, A; Alfano, G; Girardis, M; Gibellini, Lara
abstract
Background- The use of cytokine-blocking agents has been proposed to modulate the inflammatory response in patients with COVID19. Tocilizumab and Anakinra were included in the local protocol as an optional treatment in critically ill patients with acute respiratory distress syndrome (ARDS) by SARS-CoV2 infection. This cohort study evaluated the effects of therapy with cytokine blocking agents on in-hospital mortality in COVID19 patients requiring mechanical ventilation and admitted to intensive care unit.
Methods- The association between therapy with Tocilizumab or Anakinra and in-hospital mortality was assessed in consecutive adult COVID19 patients admitted to our ICU with moderate to severe ARDS. The association was evaluated by comparing patients who receive to those who did not receive Tocilizumab or Anakinra and by using different multivariable Cox models adjusted for variables related to poor outcome, for the propensity to be treated with Tocilizumab or Anakinra and after patient matching.
Results- Sixty-six patients who received immunotherapy (49 Tocilizumab, 17 Anakinra) and 28 patients who did not receive immunotherapy were included. The in-hospital crude mortality was 30,3% in treated patients and 50% in non-treated (OR 0,77, 95% CI 0,56-1,05, p=0,069). The adjusted Cox model showed an association between therapy with immunotherapy and in-hospital mortality (HR 0,40, 95% CI 0,19-0,83, p=0,015). This protective effect was further confirmed in the analysis adjusted for propensity score, in the propensity-matched cohort and in the cohort of patients with invasive mechanical ventilation within 2 hours after ICU admission.
Conclusions- Although important limitations, our study showed that cytokine-blocking agents seem to be safe and to improve survival in COVID-19 patients admitted to ICU with ARDS and the need of mechanical ventilation.
2021
- Endobronchial valve positioning for alveolar-pleural fistula following ICU management of severe COVID-19 pneumonia.
[Articolo su rivista]
Donatelli, P; Trentacosti, F; Pellegrino, Mr; Tonelli, R; Bruzzi, G; Andreani, A; Cappiello, Gf; Andrisani, D; Gozzi, F; Mussini, C; Busani, S; Cavaliere, Gv; Girardis, M; Bertellini, E; Clini, E; Marchioni, A.
abstract
Background- Since December 2019 the outbreak of novel Coronavirus (Severe Acute Respiratory
Sindrome-2, SARS-CoV2) has spread across the world. The main clinical
consequences are respiratory failure even requiring mechanical ventilation, and
pneumonia frequently sharing clinical and radiologic similarities to Acute Respiratory
Distress Syndrome (ARDS). In this context the lung parenchyma is highly prone to
ventilator-related injury, with pneumothorax and persistent air leak as the most serious
adverse events. So far, endobronchial valve (EBV) positioning has proved efficacy in
treating air leaks with high success rate.
Case presentation- We report, for the first time, two cases of patients affected by SARS-CoV2-related
pneumonia suffering from pneumothorax and persistent air leaks after invasive
mechanical ventilation, and successfully treated through EBV positioning.
Conclusions- Persistent air leaks may result from lung tissue damage due to a complex interaction
between inflammation and ventilator-related injury (VILI), especially in the advanced
stages of ARDS. EBV positioning seems to be a feasible and effective least-invasive
therapeutic option for caring this subset of patients.
2021
- Exogenous pulmonary surfactant in COVID-19 ARDS. The similarities to neonatal RDS suggest a new scenario for an 'old' strategy
[Articolo su rivista]
Bhatt, R. M.; Clark, H. W.; Girardis, M.; Busani, S.
abstract
Acute respiratory distress syndrome (ARDS) related to SARS-CoV-2 infection has some unusual characteristics that differentiate it from the pathophysiology described in the more 'typical' ARDS. Among multiple hypotheses, a close similarity has been suggested between COVID-19 ARDS and neonatal respiratory distress syndrome (RDS). With this opinion paper, we investigated the pathophysiological similarities between infant respiratory diseases (RDS and direct neonatal ARDS (NARDS)) and COVID-19 in adults. We also analysed, for the first time, similarities in the response to exogenous surfactant administration in terms of improved static compliance in RDS and direct NARDS, and adult COVID-19 ARDS. In conclusion, we believe that if the pathological processes are similar both from the pathophysiological point of view and from the response in respiratory mechanics to a recruitment treatment such as surfactant, perhaps the latter could be considered a plausible option and lead to recruitment in clinical trials currently ongoing on patients with COVID-19.
2021
- Herpes Simplex re-activation in patients with SARS-CoV2 pneumonia: a prospective observational study.
[Articolo su rivista]
Franceschini, E; Cozzi-Lepri, A; Santoro, A; Bacca, E; Lancellotti, G; Menozzi, M; Gennari, W; Meschiari, M; Bedini, A; Orlando, G; Puzzolante, C; Digaetano, M; Milic, J; Codeluppi, M; Pecorari, M; Carli, F; Cuomo, G; Alfano, G; Corradi, L; Tonelli, R; De Maria, N; Busani, S; Biagioni, E; Coloretti, I; Guaraldi, G; Sarti, M; Luppi, M; Clini, E; Girardis, M; Gyssens, I; Mussini, C.
abstract
Background: Herpes simplex 1 co-infections in patients with COVID-19 are considered relatively uncommon; some reports on re-activations in patients in intensive-care unit have been published. The aim of the study was to analyze herpetic re-activations and their clinical manifestations in hospitalized COVID-19 patients, performing HSV-1 PCR on plasma twice a week.
Methods: We conducted a prospective, observational, single-center study involving 70 consecutive patients with severe/critical SARS-CoV-2 pneumonia tested for HSV-1 hospitalized at Azienda Ospedaliero-Universitaria of Modena.
Results: Of these 70 patients, 21 (30.0%) showed detectable viremia and 13 (62%) had clinically relevant manifestations of HSV-1 infection corresponding to 15 events (4 pneumonia, 5 herpes labialis, 3 gingivostomatitis, one encephalitis and two hepatitis). HSV-1 positive patients were more frequently treated with steroids than HSV-1 negative patients (76.2% vs 49.0%, p 0.036) and more often underwent mechanical ventilation (IMV) (57.1% vs 22.4%, p 0.005). In the unadjusted logistic regression analysis, steroid treatment, IMV, and higher LDH were significantly associated with an increased risk of HSV1 re-activation (odds ratio 3.33, 4.61, and 16.9, respectively). The association with use of steroids was even stronger after controlling for previous use of both tocilizumab and IMV (OR=5.13, 95% CI:1.36-19.32, p=0.016). The effect size was larger when restricting to participants who were treated with high dose of steroids while there was no evidence to support an association with use of tocilizumab.
Conclusions: Our study shows a high incidence of HSV-1 reactivation both virologically and clinically in patients with SARS-CoV-51 2 severe pneumonia, especially in those treated with steroids.
2021
- Hypokalemia in Patients with COVID-19
[Articolo su rivista]
Alfano, G.; Ferrari, A.; Fontana, F.; Perrone, R.; Mori, G.; Ascione, E.; Magistroni, R.; Venturi, G.; Pederzoli, S.; Margiotta, G.; Romeo, M.; Piccinini, F.; Franceschi, G.; Volpi, S.; Faltoni, M.; Ciusa, G.; Bacca, E.; Tutone, M.; Raimondi, A.; Menozzi, M.; Franceschini, E.; Cuomo, G.; Orlando, G.; Santoro, A.; Di Gaetano, M.; Puzzolante, C.; Carli, F.; Bedini, A.; Milic, J.; Meschiari, M.; Mussini, C.; Cappelli, G.; Guaraldi, G.; Borghi, V.; Burastero, G.; Corradi, L.; Di Gaetano, M.; Dolci, G.; Fantini, R.; Iadisernia, V.; Larne, D.; Pellegrino, F.; Rogati, C.; Santoro, A.; Tonelli, R.; Yaacoub, D.; Alfan, S.; Marco, B.; Pulizzi, R.; Leonelli, M.; Facchini, F.; Damiano, F.; Girardis, M.; Andreotti, A.; Biagioni, E.; Bondi, F.; Busani, S.; Chierego, G.; Scotti, M.; Cossarizza, L. S. A.; Bellinazzi, C.; Borella, R.; De Biasi, S.; De Gaetano, A.; Fidanza, L.; Gibellini, L.; Iannone, A.; Tartaro, D. L.; Mattioli, M.; Nasi, M.; Paolini, A.; Pinti, M.
abstract
Background: Patients with COVID-19 experience multiple clinical conditions that may cause electrolyte imbalances. Hypokalemia is a concerning electrolyte disorder closely associated with severe complications. This study aimed to estimate prevalence, risk factors and outcome of hypokalemia in a cohort of patients with confirmed COVID-19. Methods: A retrospective analysis was conducted on 290 non-ICU admitted patients with COVID-19 at the tertiary teaching hospital of Modena, Italy, from February 16 to April 14, 2020. Results: Hypokalemia was detected in 119 out of 290 patients (41%) during hospitalization. Mean serum potassium was 3.1 ± 0.1 meq/L. The majority of patients (90.7%) patients experienced only a mild decrease in serum potassium level (3–3.4 mEq/L). Hypokalemia was associated with hypocalcemia, which was detected in 50% of subjects. Urine potassium-to-creatinine ratio, measured in a small number of patients (n = 45; 36.1%), revealed an increase of urinary potassium excretion in most cases (95.5%). Risk factors for hypokalemia were female sex (odds ratio (OR) 2.44; 95% CI 1.36–4.37; P 0.003) and diuretic therapy (OR 1.94, 95% CI 1.08–3.48; P 0.027). Hypokalemia, adjusted for sex, age and SOFA score, was not associated with ICU transfer (OR 0.52; 95% CI 0.228–1.212; P = 0.131), in-hospital mortality (OR, 0.47; 95% CI 0.170–1.324; P = 0.154) and composite outcome of ICU transfer or in-hospital mortality (OR 0.48; 95% CI 0.222–1.047; P = 0.065) in our cohort of patients. Conclusions: Hypokalemia was a frequent disorder in subjects with COVID-19. Female sex and diuretic therapy were identified as risk factors for low serum potassium levels. Hypokalemia was unrelated to ICU transfer and death in this cohort of patients.
2021
- Inspiratory effort and lung mechanics in spontaneously breathing patients with acute respiratory failure due to COVID-19. A matched control study.
[Articolo su rivista]
Tonelli, R; Busani, S; Tabbì, L; Fantini, R; Castaniere, I; Biagioni, E; Mussini, C; Girardis, M; Clini, E; Marchioni, A.
abstract
Several physical and biological mechanisms can drive progression between the different phases of lung injury due to SARS-CoV-2 infection, thus modifying the mechanical properties and behavior of COVID-19 over time. In this research letter we have presented the findings of a registered clinical trial aimed at describing and comparing the inspiratory effort (primary outcome) and the breathing pattern of spontaneously breathing patients with ARF in COVID-19 and historically matched non-COVID-19 patients, either candidate to NIV. Moreover, we reported the response to a 2 hours NIV trial in the two groups. Spontaneously breathing COVID-19 at their early onset of acute respiratory failure with indication for NIV showed different mechanical characteristics and breathing pattern when compared with non-COVID-19.
2021
- Mapping the human genetic architecture of COVID-19
[Articolo su rivista]
Niemi, M. E. K.; Karjalainen, J.; Liao, R. G.; Neale, B. M.; Daly, M.; Ganna, A.; Pathak, G. A.; Andrews, S. J.; Kanai, M.; Veerapen, K.; Fernandez-Cadenas, I.; Schulte, E. C.; Striano, P.; Marttila, M.; Minica, C.; Marouli, E.; Karim, M. A.; Wendt, F. R.; Savage, J.; Sloofman, L.; Butler-Laporte, G.; Kim, H. -N.; Kanoni, S.; Okada, Y.; Byun, J.; Han, Y.; Uddin, M. J.; Smith, G. D.; Willer, C. J.; Buxbaum, J. D.; Mehtonen, J.; Finucane, H.; Cordioli, M.; Martin, A. R.; Zhou, W.; Pasaniuc, B.; Julienne, H.; Aschard, H.; Shi, H.; Yengo, L.; Polimanti, R.; Ghoussaini, M.; Schwartzentruber, J.; Dunham, I.; Chwialkowska, K.; Francescatto, M.; Trankiem, A.; Balaconis, M. K.; Davis, L.; Lee, S.; Priest, J.; Renieri, A.; Sankaran, V. G.; van Heel, D.; Deelen, P.; Brent Richards, J.; Nakanishi, T.; Biesecker, L.; Eric Kerchberger, V.; Kenneth Baillie, J.; Mari, F.; Bernasconi, A.; Ceri, S.; Canakoglu, A.; Wolford, B.; Faucon, A.; Dutta, A. K.; Schurmann, C.; Harry, E.; Birney, E.; Nguyen, H.; Nasir, J.; Kaunisto, M.; Solomonson, M.; Dueker, N.; Vadgama, N.; Limou, S.; Rahmouni, S.; Mbarek, H.; Darwish, D.; Uddin, M. M.; Albertos, R.; Perez-Tur, J.; Li, R.; Folkersen, L.; Moltke, I.; Koelling, N.; Teumer, A.; Kousathanas, A.; Utrilla, A.; Verdugo, R. A.; Zarate, R.; Medina-Gomez, C.; Gomez-Cabrero, D.; Carnero-Montoro, E.; Cadilla, C. L.; Moreno-Estrada, A.; Garmendia, A.; Moya, L.; Sedaghati-Khayat, B.; Boua, P. R.; Fave, M. -J.; Francioli, L.; Lemacon, A.; Migeotte, I.; Patel, S.; Varnai, R.; Szentpeteri, J. L.; Sipeky, C.; Colombo, F.; von Hohenstaufen, K.; Lio, P.; Vallerga, C.; Wang, Q.; Tanigawa, Y.; Im, H.; Han, C.; Song, H.; Lim, J.; Lee, Y.; Kim, S.; Im, S.; Atanasovska, B.; Ahmad, H. F.; Boer, C.; Jansen, P.; Kaja, E.; Pasko, D.; Kennis-Szilagyi, I.; Kornilov, S. A.; Prijatelj, V.; Prokic, I.; Sivanadhan, I.; Perumal, S.; Esmaeeli, S.; Pearson, N. M.; Auton, A.; Shelton, J. F.; Shastri, A. J.; Filshtein-Sonmez, T.; Coker, D.; Symons, A.; Esparza-Gordillo, J.; Aslibekyan, S.; O'Connell, J.; Ye, C.; Weldon, C. H.; Perera, M.; O'Leary, K.; Tuck, M.; O'Brien, T.; Meltzer, D.; O'Donnell, P.; Nutescu, E.; Yang, G.; Alarcon, C.; Herrmann, S.; Mazurek, S.; Banagan, J.; Hamidi, Z.; Barbour, A.; Raffat, N.; Moreno, D.; Friedman, P.; Ferwerda, B.; van de Beek, D.; Brouwer, M. C.; Vlaar, A. P. J.; Joost Wiersinga, W.; Posthuma, D.; Tissink, E.; Koos Zwinderman, A. H.; Uffelmann, E.; van Agtmael, M.; Algera, A. G.; van Baarle, F.; Bax, D.; Beudel, M.; Bogaard, H. J.; Bomers, M.; Bonta, P. I.; Bos, L.; Botta, M.; de Brabander, J.; de Bree, G.; de Bruin, S.; Bugiani, M.; Bulle, E.; Chouchane, O.; Cloherty, A.; Dongelmans, D.; Elbers, P.; Fleuren, L.; Geerlings, S.; Geerts, B.; Geijtenbeek, T.; Girbes, A.; Goorhuis, B.; Grobusch, M. P.; Hafkamp, F.; Hagens, L.; Hamann, J.; Harris, V.; Hemke, R.; Hermans, S. M.; Heunks, L.; Hollmann, M.; Horn, J.; Hovius, J. W.; de Jong, M. D.; Koning, R.; van Mourik, N.; Nellen, J.; Nossent, E. J.; Paulus, F.; Peters, E.; van der Poll, T.; Preckel, B.; Prins, J. M.; Raasveld, J.; Reijnders, T.; Schinkel, M.; Schultz, M. J.; Schuurman, A.; Sigaloff, K.; Smit, M.; Stijnis, C. S.; Stilma, W.; Teunissen, C.; Thoral, P.; Tsonas, A.; van der Valk, M.; Veelo, D.; de Vries, H.; van Vugt, M.; Wouters, D.; Minnaar, R. P.; Kromhout, A.; van Uffelen, K. W. J.; Wolterman, R. A.; Roberts, G.; Park, D.; Ball, C. A.; Coignet, M.; Mccurdy, S.; Knight, S.; Partha, R.; Rhead, B.; Zhang, M.; Berkowitz, N.; Gaddis, M.; Noto, K.; Ruiz, L.; Pavlovic, M.; Hong, E. L.; Rand, K.; Girshick, A.; Guturu, H.; Baltzell, A. H.; Guntz, J.; Beguin, Y.; Pigazzini, S.; Nkambule, L.; Bouysran, Y.; Busson, A.; Peyrassol, X.; Wilkin, F.; Pichon, B.; Smits, G.; Vandernoot, I.; Goffard, J. -C.; Georges, M.; Moutschen, M.; Misset, B.; Darcis, G.; Guiot, J.; Jadot, L.; Azarzar, S.; Dellot, P.; Gofflot, S.; Claassen, S.; Bertrand, A.; Parzibut, G.; Clarinval, M.; Moermans, C.; Malaise, O.; El Kandoussi, K.; Thonon, R.; Huynen, P.; Mesdagh, A.; Melo, S.
abstract
The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
2021
- Methylprednisolone as rescue therapy after tocilizumab failure in patients with severe COVID-19 pneumonia
[Articolo su rivista]
Guaraldi, Giovanni; Banchelli, Federico; Milic, Jovana; Dolci, Giovanni; Massari, Marco; Corsini, Romina; Meschiari, Marianna; Girardis, Massimo; Busani, Stefano; Cossarizza, Andrea; Salvarani, Carlo; Mussini, Cristina; D'Amico, Roberto
abstract
2021
- Monocyte Distribution Width (MDW) as novel inflammatory marker with prognostic significance in COVID-19 patients
[Articolo su rivista]
Riva, G.; Castellano, S.; Nasillo, V.; Ottomano, A. M.; Bergonzini, G.; Paolini, A.; Lusenti, B.; Milic, J.; De Biasi, S.; Gibellini, L.; Cossarizza, A.; Busani, S.; Girardis, M.; Guaraldi, G.; Mussini, C.; Manfredini, R.; Luppi, M.; Tagliafico, E.; Trenti, T.
abstract
Monocyte Distribution Width (MDW), a new cytometric parameter correlating with cytomorphologic changes occurring upon massive monocyte activation, has recently emerged as promising early biomarker of sepsis. Similar to sepsis, monocyte/macrophage subsets are considered key mediators of the life-threatening hyper-inflammatory disorder characterizing severe COVID-19. In this study, we longitudinally analyzed MDW values in a cohort of 87 COVID-19 patients consecutively admitted to our hospital, showing significant correlations between MDW and common inflammatory markers, namely CRP (p < 0.001), fibrinogen (p < 0.001) and ferritin (p < 0.01). Moreover, high MDW values resulted to be prognostically associated with fatal outcome in COVID-19 patients (AUC = 0.76, 95% CI: 0.66–0.87, sensitivity 0.75, specificity 0.70, MDW threshold 26.4; RR = 4.91, 95% CI: 1.73–13.96; OR = 7.14, 95% CI: 2.06–24.71). This pilot study shows that MDW can be useful in the monitoring of COVID-19 patients, as this innovative hematologic biomarker is: (1) easy to obtain, (2) directly related to the activation state of a fundamental inflammatory cell subset (i.e. monocytes, pivotal in both cytokine storm and sepsis immunopathogenesis), (3) well correlated with clinical severity of COVID-19-associated inflammatory disorder, and, in turn, (4) endowed with relevant prognostic significance. Additional studies are needed to define further the clinical impact of MDW testing in the management of COVID-19 patients.
2021
- Pulmonary stretch and lung mechanotransduction: Implications for progression in the fibrotic lung
[Articolo su rivista]
Marchioni, A; Tonelli, R; Cerri, S; Castaniere, I; Andrisani, D; Gozzi, F; Bruzzi, G; Manicardi, L; Moretti, A; Demurtas, J; Baroncini, S; Andreani, A; Cappiello, G; Busani, S; Fantini, R; Tabbì, L; Samarelli, A; Clini, E.
abstract
Lung fibrosis results from the synergic interplay between regenerative deficits of the alveolar epithelium and dysregulated mechanisms of repair in response to alveolar and vascular damage, followed by progressive fibroblast and myofibroblast proliferation and excessive deposition of extracellular matrix. The increased parenchymal stiffness of fibrotic lungs significantly affects respiratory mechanics, making the lung more fragile and prone to non-physiological stress during spontaneous breathing and mechanical ventilation. Given their parenchymal inhomogeneity, fibrotic lungs may display an anisotropic response to mechanical stresses with different regional deformations (micro-strain). This behavior is not described by the standard stress-strain curve but follows the mechano-elastic models of “squishy balls”, where the elastic limit can be reached due to the excessive deformation of parenchymal areas with normal elasticity, surrounded by inelastic fibrous tissue or collapsed induration areas, which tend to protrude outside the fibrous ring. Increasing evidence has shown that non-physiological mechanical forces applied to fibrotic lungs with as34
sociated abnormal mechanotransduction could favor the progression of pulmonary fibrosis. With this review we aim at summarizing the state of the art on the relation between mechanical forces acting on the lung and biological response in pulmonary fibrosis, with a focus on the progression of damage in the fibrotic lung during spontaneous breathing and assisted ventilatory support.
2021
- Rare variants in Toll-like receptor 7 results in functional impairment and downregulation of cytokine-mediated signaling in COVID-19 patients
[Articolo su rivista]
Mantovani, S.; Daga, S.; Fallerini, C.; Baldassarri, M.; Benetti, E.; Picchiotti, N.; Fava, F.; Galli, A.; Zibellini, S.; Bruttini, M.; Palmieri, M.; Croci, S.; Amitrano, S.; Alaverdian, D.; Capitani, K.; Furini, S.; Mari, F.; Meloni, I.; Montagnani, F.; Tumbarello, M.; Rancan, I.; Fabbiani, M.; Rossetti, B.; Bergantini, L.; D'Alessandro, M.; Cameli, P.; Bennett, D.; Anedda, F.; Marcantonio, S.; Scolletta, S.; Franchi, F.; Mazzei, M. A.; Guerrini, S.; Conticini, E.; Cantarini, L.; Frediani, B.; Tacconi, D.; Raffaelli, C. S.; Feri, M.; Donati, A.; Scala, R.; Guidelli, L.; Spargi, G.; Corridi, M.; Nencioni, C.; Croci, L.; Caldarelli, G. P.; Romani, D.; Piacentini, P.; Bandini, M.; Desanctis, E.; Cappelli, S.; Canaccini, A.; Verzuri, A.; Anemoli, V.; Pisani, M.; Ognibene, A.; Pancrazzi, A.; Lorubbio, M.; Vaghi, M.; D'Arminio Monforte, A.; Miraglia, F. G.; Bruno, R.; Vecchia, M.; Girardis, M.; Venturelli, S.; Busani, S.; Cossarizza, A.; Antinori, A.; Vergori, A.; Emiliozzi, A.; Rusconi, S.; Siano, M.; Gabrieli, A.; Riva, A.; Francisci, D.; Schiaroli, E.; Paciosi, F.; Tommasi, A.; Scotton, P. G.; Andretta, F.; Panese, S.; Baratti, S.; Scaggiante, R.; Gatti, F.; Parisi, S. G.; Castelli, F.; Quiros-Roldan, E.; Antoni, M. D.; Zanella, I.; Della Monica, M.; Piscopo, C.; Capasso, M.; Russo, R.; Andolfo, I.; Iolascon, A.; Fiorentino, G.; Carella, M.; Castori, M.; Aucella, F.; Raggi, P.; Perna, R.; Bassetti, M.; Di Biagio, A.; Sanguinetti, M.; Masucci, L.; Guarnaccia, A.; Valente, S.; De Vivo, O.; Doddato, G.; Lista, M.; Beligni, G.; Valentino, F.; Zguro, K.; Tita, R.; Giliberti, A.; Mencarelli, M. A.; Rizzo, C. L.; Pinto, A. M.; Ariani, F.; Di Sarno, L.; Bargagli, E.; Mandala, M.; Giorli, A.; Salerni, L.; Zucchi, P.; Parravicini, P.; Menatti, E.; Trotta, T.; Giannattasio, F.; Coiro, G.; Lena, F.; Lacerenza, G.; Mussini, C.; Martinelli, E.; Tavecchia, L.; Belli, M. A.; Crotti, L.; Parati, G.; Sanarico, M.; Raimondi, F.; Biscarini, F.; Stella, A.; Bachetti, T.; La Rovere, M. T.; Ludovisi, S.; Bussotti, M.; Dei, S.; Ravaglia, S.; Artuso, R.; Andreucci, E.; Gori, G.; Pagliazzi, A.; Fiorentini, E.; Perrella, A.; Bianchi, F.; Bergomi, P.; Catena, E.; Colombo, R.; Luchi, S.; Morelli, G.; Petrocelli, P.; Iacopini, S.; Modica, S.; Baroni, S.; Segala, F. V.; Falcone, M.; Tiseo, G.; Barbieri, C.; Matucci, T.; Grassi, D.; Ferri, C.; Marinangeli, F.; Brancati, F.; Vincenti, A.; Borgo, V.; Lombardi, S.; Lenzi, M.; Di Pietro, M. A.; Vichi, F.; Romanin, B.; Attala, L.; Costa, C.; Gabbuti, A.; Mene, R.; Colaneri, M.; Casprini, P.; Merla, G.; Squeo, G. M.; Maffezzoni, M.; Frullanti, E.; Mondelli, M. U.; Renieri, A.
abstract
Toll-like receptors (TLR) are crucial components in the initiation of innate immune responses to a variety of pathogens, triggering the production of pro-inflammatory cytokines and type I and II interferons, which are responsible for innate antiviral responses. Among the different TLRs, TLR7 recognizes several single-stranded RNA viruses including SARS-CoV-2. We and others identified rare loss-of-function variants in X-chromosomal TLR7 in young men with severe COVID-19 and with no prior history of major chronic diseases, that were associated with impaired TLR7 signaling as well as type I and II IFN responses. Here, we performed RNA sequencing to investigate transcriptome variations following imiquimod stimulation of peripheral blood mononuclear cells isolated from patients carrying previously identified hypomorphic, hypofunctional, and loss-of-function TLR7 variants. Our investigation revealed a profound impairment of the TLR7 pathway in patients carrying loss-of-function variants. Of note, a failure in IFNγ upregulation following stimulation was also observed in cells harboring the hypofunctional and hypomorphic variants. We also identified new TLR7 variants in severely affected male patients for which a functional characterization of the TLR7 pathway was performed demonstrating a decrease in mRNA levels in the IFNα, IFNγ, RSAD2, ACOD1, IFIT2, and CXCL10 genes.
2021
- Rationale for polyclonal intravenous immunoglobulin adjunctive therapy in covid-19 patients: Report of a structured multidisciplinary consensus
[Articolo su rivista]
Coloretti, I.; Berlot, G.; Busani, S.; De Rosa, F. G.; Donati, A.; Forfori, F.; Grasselli, G.; Mirabella, L.; Tascini, C.; Viale, P.; Girardis, M.
abstract
Introduction: Adjunctive therapy with polyclonal intravenous immunoglobins (IVIg) is currently used for preventing or managing infections and sepsis, especially in immunocompro-mised patients. The pathobiology of COVID-19 and the mechanisms of action of Ig led to the con-sideration of this adjunctive therapy, including in patients with respiratory failure due to the SARSCoV-2 infection. This manuscript reports the rationale, the available data and the results of a structured consensus on intravenous Ig therapy in patients with severe COVID-19. Methods: A panel of multidisciplinary experts defined the clinical phenotypes of COVID-19 patients with severe respiratory failure and, after literature review, voted for the agreement on the rationale and the potential role of IVIg therapy for each phenotype. Due to the scarce evidence available, a modified RAND/UCLA appropriateness method was used. Results: Three different phenotypes of COVID19 patients with severe respiratory failure were identified: patients with an abrupt and dysregulated hyperinflammatory response (early phase), patients with suspected immune paralysis (late phase) and patients with sepsis due to a hospital-acquired superinfection (sepsis by bacterial superinfec-tion). The rationale for intravenous Ig therapy in the early phase was considered uncertain whereas the panelists considered its use in the late phase and patients with sepsis/septic shock by bacterial superinfection appropriate. Conclusion: As with other immunotherapies, IVIg adjunctive therapy may have a potential role in the management of COVID-19 patients. The ongoing trials will clarify the appropriate target population and the true effectiveness.
2021
- Revisited Hyperoxia Pathophysiology in the Perioperative Setting: A Narrative Review
[Articolo su rivista]
Busani, Stefano; Sarti, Marco; Serra, Francesco; Gelmini, Roberta; Venturelli, Sophie; Munari, Elena; Girardis, Massimo
abstract
2021
- SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues
[Articolo su rivista]
D'Antonio, M.; Nguyen, J. P.; Arthur, T. D.; Matsui, H.; D'Antonio-Chronowska, A.; Frazer, K. A.; Neale, B. M.; Daly, M.; Ganna, A.; Stevens, C.; Pathak, G. A.; Andrews, S. J.; Kanai, M.; Cordioli, M.; Ganna, A.; Karjalainen, J.; Pathak, G. A.; Polimanti, R.; Andrews, S. J.; Cordioli, M.; Pirinen, M.; Kanai, M.; Harerimana, N.; Veerapen, K.; Wolford, B.; Nguyen, H.; Solomonson, M.; Stevens, C.; Liao, R. G.; Chwialkowska, K.; Trankiem, A.; Balaconis, M. K.; Hayward, C.; Richmond, A.; Campbell, A.; Morris, M.; Fawns-Ritchie, C.; Glessner, J. T.; Shaw, D. M.; Chang, X.; Polikowski, H.; Lauren, P. E.; Chen, H. -H.; Wanying, Z.; Hakonarson, H.; Porteous, D. J.; Below, J.; North, K.; Mccormick, J. B.; Timmers, P. R. H. J.; Wilson, J. F.; Tenesa, A.; D'Mellow, K.; Kerr, S. M.; Niemi, M. E. K.; Cordioli, M.; Nkambul, L.; von Hohenstaufen, K. A.; Sobh, A.; Eltoukhy, M. M.; Yassen, A. M.; Hegazy, M. A. F.; Okasha, K.; Eid, M. A.; Moahmed, H. S.; Shahin, D.; El-Sherbiny, Y. M.; Elhadidy, T. A.; Abd Elghafar, M. S.; El-Jawhari, J. J.; Mohamed, A. A. S.; Elnagdy, M. H.; Samir, A.; Abdel-Aziz, M.; Khafaga, W. T.; El-Lawaty, W. M.; Torky, M. S.; El-Shanshory, M. R.; Batini, C.; Lee, P. H.; Shrine, N.; Williams, A. T.; Tobin, M. D.; Guyatt, A. L.; John, C.; Packer, R. J.; Ali, A.; Free, R. C.; Wang, X.; Wain, L. V.; Hollox, E. J.; Venn, L. D.; Bee, C. E.; Adams, E. L.; Niemi, M. E. K.; Niavarani, A.; Cordioli, M.; Nkambul, L.; Sharififard, B.; Aliannejad, R.; Amirsavadkouhi, A.; Naderpour, Z.; Tadi, H. A.; Aleagha, A. E.; Ahmadi, S.; Moghaddam, S. B. M.; Adamsara, A.; Saeedi, M.; Abdollahi, H.; Hosseini, A.; Chariyavilaskul, P.; Chamnanphon, M.; Suttichet, T. B.; Shotelersuk, V.; Pongpanich, M.; Phokaew, C.; Chetruengchai, W.; Jantarabenjakul, W.; Putchareon, O.; Torvorapanit, P.; Puthanakit, T.; Suchartlikitwong, P.; Hirankarn, N.; Nilaratanakul, V.; Sodsai, P.; Brumpton, B. M.; Hveem, K.; Willer, C.; Wolford, B.; Zhou, W.; Rogne, T.; Solligard, E.; Asvold, B. O.; Abedalthagafi, M.; Alaamery, M.; Alqahtani, S.; Baraka, D.; Al Harthi, F.; Alsolm, E.; Safieh, L. A.; Alowayn, A. M.; Alqubaishi, F.; Al Mutairi, A.; Mangul, S.; Alshareef, A.; Sawaji, M.; Almutairi, M.; Aljawini, N.; Albesher, N.; Arabi, Y. M.; Mahmoud, E. S.; Khattab, A. K.; Halawani, R. T.; Alahmadey, Z. Z.; Albakri, J. K.; Felemban, W. A.; Suliman, B. A.; Hasanato, R.; Al-Awdah, L.; Alghamdi, J.; Alzahrani, D.; Aljohani, S.; Al-Afghani, H.; Alrashed, M.; Aldhawi, N.; Albardis, H.; Alkwai, S.; Alswailm, M.; Almalki, F.; Albeladi, M.; Almohammed, I.; Barhoush, E.; Albader, A.; Massadeh, S.; Almalik, A.; Alotaibi, S.; Alghamdi, B.; Jung, J.; Fawzy, M. S.; Lee, Y.; Magnus, P.; Trogstad, L. -I. S.; Helgeland, O.; Harris, J. R.; Mangino, M.; Spector, T. D.; Emma, D.; Smieszek, S. P.; Przychodzen, B. P.; Polymeropoulos, C.; Polymeropoulos, V.; Polymeropoulos, M. H.; Fernandez-Cadenas, I.; Perez-Tur, J.; Llucia-Carol, L.; Cullell, N.; Muino, E.; Carcel-Marquez, J.; Dediego, M. L.; Iglesias, L. L.; Planas, A. M.; Soriano, A.; Rico, V.; Aguero, D.; Bedini, J. L.; Lozano, F.; Domingo, C.; Robles, V.; Ruiz-Jaen, F.; Marquez, L.; Gomez, J.; Coto, E.; Albaiceta, G. M.; Garcia-Clemente, M.; Dalmau, D.; Arranz, M. J.; Dietl, B.; Serra-Llovich, A.; Soler, P.; Colobran, R.; Martin-Nalda, A.; Martinez, A. P.; Bernardo, D.; Rojo, S.; Fiz-Lopez, A.; Arribas, E.; de la Cal-Sabater, P.; Segura, T.; Gonzalez-Villa, E.; Serrano-Heras, G.; Marti-Fabregas, J.; Jimenez-Xarrie, E.; de Felipe Mimbrera, A.; Masjuan, J.; Garcia-Madrona, S.; Dominguez-Mayoral, A.; Villalonga, J. M.; Menendez-Valladares, P.; Chasman, D. I.; Buring, J. E.; Ridker, P. M.; Franco, G.; Sesso, H. D.; Manson, J. E.; Chang, X.; Glessner, J. R.; Hakonarson, H.; Hayward, C.; Richmond, A.; Porteous, D. J.; Campbell, A.; Fawns-Ritchie, C.; Medina-Gomez, C.; Uitterlinden, A. G.; Arfan Ikram, M.; Kristiansson, K.; Koskelainen, S.; Perola, M.; Donner, K.; Kivinen, K.; Palotie, A.; Ripatti, S.; Ruotsalainen, S.; Kaunisto, M.; Nakanishi, T.; B
abstract
Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types.
2021
- Spontaneous breathing and evolving phenotypes of lung damage in patients with COVID-19.
[Articolo su rivista]
Tonelli, R; Marchioni, A; Tabbì, L; Fantini, R; Busani, S; Castaniere, I; Andrisani, D; Gozzi, F; Bruzzi, G; Manicardi, L; Demurtas, J; Andreani, A; Cappiello, G; Samarelli, A; Clini, E.
abstract
The mechanisms of acute respiratory failure other than inflammation and complicating the SARS-CoV-2 infection are still far from being fully understood, thus challenging the management of COVID-19 patients in the critical care setting. In this unforeseen scenario, the role of an individual’s excessive spontaneous breathing may acquire critical importance, being one potential and important driver of lung injury and disease progression. The consequences of this acute lung damage may impair lung structure forecasting the model of a fragile respiratory system.
This perspective article aims to analyze the progression of injured lung phenotypes across the SARS-CoV-2 induced respiratory failure, pointing out the role of spontaneous breathing and also tackling the specific respiratory/ventilatory strategy required by the fragile lung type.
2021
- Synergistic effect of static compliance and d-dimers to predict outcome of patients with covid-19-ards: A prospective multicenter study
[Articolo su rivista]
Tonetti, T.; Grasselli, G.; Rucci, P.; Alessandri, F.; Dell'Olio, A.; Boscolo, A.; Pasin, L.; Sella, N.; Mega, C.; Melotti, R. M.; Girardis, M.; Busani, S.; Bellani, G.; Foti, G.; Grieco, D. L.; Scaravilli, V.; Protti, A.; Langer, T.; Mascia, L.; Pugliese, F.; Cecconi, M.; Fumagalli, R.; Nava, S.; Antonelli, M.; Slutsky, A. S.; Navalesi, P.; Pesenti, A.; Ranieri, V. M.
abstract
The synergic combination of D-dimer (as proxy of thrombotic/vascular injury) and static compliance (as proxy of parenchymal injury) in predicting mortality in COVID-19-ARDS has not been systematically evaluated. The objective is to determine whether the combination of elevated D-dimer and low static compliance can predict mortality in patients with COVID-19-ARDS. A “training sample” (March–June 2020) and a “testing sample” (September 2020–January 2021) of adult patients invasively ventilated for COVID-19-ARDS were collected in nine hospitals. D-dimer and compliance in the first 24 h were recorded. Study outcome was all-cause mortality at 28-days. Cutoffs for D-dimer and compliance were identified by receiver operating characteristic curve analysis. Mutually exclusive groups were selected using classification tree analysis with chi-square automatic interaction detection. Time to death in the resulting groups was estimated with Cox regression adjusted for SOFA, sex, age, PaO2/FiO2 ratio, and sample (training/testing). “Training” and “testing” samples amounted to 347 and 296 patients, respectively. Three groups were identified: D-dimer ≤ 1880 ng/mL (LD); D-dimer > 1880 ng/mL and compliance > 41 mL/cmH2O (LD-HC); D-dimer > 1880 ng/mL and compliance ≤ 41 mL/cmH2O (HD-LC). 28-days mortality progressively increased in the three groups (from 24% to 35% and 57% (training) and from 27% to 39% and 60% (testing), respectively; p < 0.01). Adjusted mortality was significantly higher in HD-LC group compared with LD (HR = 0.479, p < 0.001) and HD-HC (HR = 0.542, p < 0.01); no difference was found between LD and HD-HC. In conclusion, combination of high D-dimer and low static compliance identifies a clinical phenotype with high mortality in COVID-19-ARDS.
2021
- The impact of tocilizumab on respiratory support states transition and clinical outcomes in COVID-19 patients. A Markov model multi-state study
[Articolo su rivista]
Milic, J.; Banchelli, F.; Meschiari, M.; Franceschini, E.; Ciusa, G.; Gozzi, L.; Volpi, S.; Faltoni, M.; Franceschi, G.; Iadisernia, V.; Yaacoub, D.; Dolci, G.; Bacca, E.; Rogati, C.; Tutone, M.; Burastero, G.; Raimondi, A.; Menozzi, M.; Cuomo, G.; Corradi, L.; Orlando, G.; Santoro, A.; Digaetano, M.; Puzzolante, C.; Carli, F.; Bedini, A.; Busani, S.; Girardis, M.; Cossarizza, A.; Miglio, R.; Mussini, C.; Guaraldi, G.; D'Amico, R.
abstract
Background The benefit of tocilizumab on mortality and time to recovery in people with severe COVID pneumonia may depend on appropriate timing. The objective was to estimate the impact of tocilizumab administration on switching respiratory support states, mortality and time to recovery. Methods In an observational study, a continuous-time Markov multi-state model was used to describe the sequence of respiratory support states including: no respiratory support (NRS), oxygen therapy (OT), non-invasive ventilation (NIV) or invasive mechanical ventilation (IMV), OT in recovery, NRS in recovery. Results Two hundred seventy-one consecutive adult patients were included in the analyses contributing to 695 transitions across states. The prevalence of patients in each respiratory support state was estimated with stack probability plots, comparing people treated with and without tocilizumab since the beginning of the OT state. A positive effect of tocilizumab on the probability of moving from the invasive and non-invasive mechanical NIV/IMV state to the OT in recovery state (HR = 2.6, 95% CI = 1.2–5.2) was observed. Furthermore, a reduced risk of death was observed in patients in NIV/IMV (HR = 0.3, 95% CI = 0.1–0.7) or in OT (HR = 0.1, 95% CI = 0.0–0.8) treated with tocilizumab. Conclusion To conclude, we were able to show the positive impact of tocilizumab used in different disease stages depicted by respiratory support states. The use of the multi-state Markov model allowed to harmonize the heterogeneous mortality and recovery endpoints and summarize results with stack probability plots. This approach could inform randomized clinical trials regarding tocilizumab, support disease management and hospital decision making.
2021
- Time course of risk factors associated with mortality of 1260 critically ill patients with COVID-19 admitted to 24 Italian intensive care units
[Articolo su rivista]
Zanella, A.; Florio, G.; Antonelli, M.; Bellani, G.; Berselli, A.; Bove, T.; Cabrini, L.; Carlesso, E.; Castelli, G. P.; Cecconi, M.; Citerio, G.; Coloretti, I.; Corti, D.; Dalla Corte, F.; De Robertis, E.; Foti, G.; Fumagalli, R.; Girardis, M.; Giudici, R.; Guiotto, L.; Langer, T.; Mirabella, L.; Pasero, D.; Protti, A.; Ranieri, M. V.; Rona, R.; Scudeller, L.; Severgnini, P.; Spadaro, S.; Stocchetti, N.; Vigano, M.; Pesenti, A.; Grasselli, G.; Aspesi, M.; Baccanelli, F.; Bassi, F.; Bet, A.; Biagioni, E.; Biondo, A.; Bonenti, C.; Bottino, N.; Brazzi, L.; Buquicchio, I.; Busani, S.; Calini, A.; Calligaro, P.; Cantatore, L. P.; Carelli, S.; Carsetti, A.; Cavallini, S.; Cimicchi, G.; Coppadoro, A.; Dall'Ara, L.; Di Gravio, V.; Erba, M.; Evasi, G.; Facchini, A.; Fanelli, V.; Feliciotti, G.; Fusarini, C. F.; Ferraro, G.; Gagliardi, G.; Garberi, R.; Gay, H.; Giacche, L.; Grieco, D.; Guzzardella, A.; Longhini, F.; Manzan, A.; Maraggia, D.; Milani, A.; Mischi, A.; Montalto, C.; Mormina, S.; Noseda, V.; Paleari, C.; Pedeferri, M.; Pezzi, A.; Pizzilli, G.; Pozzi, M.; Properzi, P.; Rauseo, M.; Russotto, V.; Saccarelli, L.; Servillo, G.; Spano, S.; Tagliabue, P.; Tonetti, T.; Tullo, L.; Vetrugno, L.; Vivona, L.; Volta, C. A.; Zambelli, V.; Zanoni, A.
abstract
Purpose: To evaluate the daily values and trends over time of relevant clinical, ventilatory and laboratory parameters during the intensive care unit (ICU) stay and their association with outcome in critically ill patients with coronavirus disease 19 (COVID-19). Methods: In this retrospective–prospective multicentric study, we enrolled COVID-19 patients admitted to Italian ICUs from February 22 to May 31, 2020. Clinical data were daily recorded. The time course of 18 clinical parameters was evaluated by a polynomial maximum likelihood multilevel linear regression model, while a full joint modeling was fit to study the association with ICU outcome. Results: 1260 consecutive critically ill patients with COVID-19 admitted in 24 ICUs were enrolled. 78% were male with a median age of 63 [55–69] years. At ICU admission, the median ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) was 122 [89–175] mmHg. 79% of patients underwent invasive mechanical ventilation. The overall mortality was 34%. Both the daily values and trends of respiratory system compliance, PaO2/FiO2, driving pressure, arterial carbon dioxide partial pressure, creatinine, C-reactive protein, ferritin, neutrophil, neutrophil–lymphocyte ratio, and platelets were associated with survival, while for lactate, pH, bilirubin, lymphocyte, and urea only the daily values were associated with survival. The trends of PaO2/FiO2, respiratory system compliance, driving pressure, creatinine, ferritin, and C-reactive protein showed a higher association with survival compared to the daily values. Conclusion: Daily values or trends over time of parameters associated with acute organ dysfunction, acid–base derangement, coagulation impairment, or systemic inflammation were associated with patient survival.
2021
- Two fatal cases of acute liver failure due to HSV-1 infection in COVID-19 patients following immunomodulatory therapies.
[Articolo su rivista]
Busani, S; Bedini, A; Biagioni, E; Serio, L; Tonelli, R; Meschiari, M; Franceschini, E; Guaraldi, G; Cossarizza, A; Clini, E; Maiorana, A; Gennari, W; De Maria, N; Luppi, M; Mussini, C; Girardis, M.; Gibellini, Lara
abstract
We reported two fatal cases of acute liver failure secondary to Herpes Simplex Virus 1 infection in COVID-19 patients, following tocilizumab and corticosteroid therapy. Screening for and prompt recognition of Herpes Simplex Virus 1 reactivation in these patients, undergoing immunomodulatory treatment, may have potentially relevant clinical consequences.
2021
- Vertebral artery dissection in term pregnancy after cervical spine manipulation: a case report and review the literature
[Articolo su rivista]
Monari, F.; Busani, S.; Imbrogno, M. G.; Neri, I.; Girardis, M.; Ghirardini, A.; Cavalleri, F.; Facchinetti, F.
abstract
Background: Vertebral artery dissection is an uncommon, but potentially fatal, vascular event. This case aimed to describe the pathogenesis and clinical presentation of vertebral artery dissection in a term pregnant patient. Moreover, we focused on the differential diagnosis, reviewing the available evidence. Case presentation: A 39-year-old Caucasian woman presented at 38 + 4 weeks of gestation with a short-term history of vertigo, nausea, and vomiting. Symptoms appeared a few days after cervical spine manipulation by an osteopathic specialist. Urgent magnetic resonance imaging of the head was obtained and revealed an ischemic lesion of the right posterolateral portion of the brain bulb. A subsequent computed tomography angiographic scan of the head and neck showed a right vertebral artery dissection. Based on the correlation of the neurological manifestations and imaging findings, a diagnosis of vertebral artery dissection was established. The patient started low-dose acetylsalicylic acid and prophylactic enoxaparin following an urgent cesarean section. Conclusion: Vertebral artery dissection is a rare but potential cause of neurologic impairments in pregnancy and during the postpartum period. It should be considered in the differential diagnosis for women who present with headache and/or vertigo. Women with a history of migraines, hypertension, or autoimmune disorders in pregnancy are at higher risk, as well as following cervical spine manipulations. Prompt diagnosis and management of vertebral artery dissection are essential to ensure favorable outcomes.
2020
- Altered bioenergetics and mitochondrial dysfunction of monocytes in patients with COVID-19 pneumonia
[Articolo su rivista]
Gibellini, L.; De Biasi, S.; Paolini, A.; Borella, R.; Boraldi, F.; Mattioli, M.; Lo Tartaro, D.; Fidanza, L.; Caro-Maldonado, A.; Meschiari, M.; Iadisernia, V.; Bacca, E.; Riva, G.; Cicchetti, L.; Quaglino, D.; Guaraldi, G.; Busani, S.; Girardis, M.; Mussini, C.; Cossarizza, A.
abstract
In patients infected by SARS-CoV-2 who experience an exaggerated inflammation leading to pneumonia, monocytes likely play a major role but have received poor attention. Thus, we analyzed peripheral blood monocytes from patients with COVID-19 pneumonia and found that these cells show signs of altered bioenergetics and mitochondrial dysfunction, had a reduced basal and maximal respiration, reduced spare respiratory capacity, and decreased proton leak. Basal extracellular acidification rate was also diminished, suggesting reduced capability to perform aerobic glycolysis. Although COVID-19 monocytes had a reduced ability to perform oxidative burst, they were still capable of producing TNF and IFN-γ in vitro. A significantly high amount of monocytes had depolarized mitochondria and abnormal mitochondrial ultrastructure. A redistribution of monocyte subsets, with a significant expansion of intermediate/pro-inflammatory cells, and high amounts of immature monocytes were found, along with a concomitant compression of classical monocytes, and an increased expression of inhibitory checkpoints like PD-1/PD-L1. High plasma levels of several inflammatory cytokines and chemokines, including GM-CSF, IL-18, CCL2, CXCL10, and osteopontin, finally confirm the importance of monocytes in COVID-19 immunopathogenesis.
2020
- Increased Plasma Levels of Mitochondrial DNA and Normal Inflammasome Gene Expression in Monocytes Characterize Patients With Septic Shock Due to Multidrug Resistant Bacteria
[Articolo su rivista]
Busani, Stefano; De Biasi, Sara; Nasi, Milena; Paolini, Annamaria; Venturelli, Sophie; Tosi, Martina; Girardis, Massimo; Cossarizza, Andrea
abstract
Introduction: The activity and regulation of inflammasome is receiving increasing attention in septic shock. Moreover, there is a growing body of evidence suggesting that mitochondrial DNA (mtDNA) can play a role as biomarker of disease severity and even mortality both in adults and children in critically ill setting. However, no data are available on the amount of circulating mtDNA and inflammasome gene expression in multi-drug resistant (MDR) bacteria septic shock. For this reason, the aim of this study was to determine whether plasma mtDNA levels and inflammasome gene expression in monocytes could be related to severity in patients admitted to intensive care unit (ICU) with septic shock due to MDR pathogens. Materials and Methods: Peripheral blood mononuclear cells (PBMC) and plasma were isolated from up to 20 ml of venous blood by density gradient centrifugation in patients admitted to ICU with the diagnosis of septic shock due to MDR-bacteria. Then, CD14+ monocytes were sorted, and RNA and DNA were extracted. NLRP3, PYCARD, AIM2 and NAIP expression level was analyzed by RT-PCR. Plasma circulating mtDNA levels were quantified by digital droplet PCR. Basal and outcome characteristics of the patients were collected. Age-matched healthy subjects were chosen as controls. Results: Nineteen patients with septic shock and 20 healthy subjects were enrolled in the study. A small trend toward an increased expression of inflammasome genes was observed in septic shock patients, who also displayed a marked tendency to an increased expression of IL-18 and IL-1β genes. Circulating mtDNA levels were significantly higher in septic shock patients if compared to healthy subjects, and patients who died in ICU were characterized by higher level of mtDNA if compared to those who were dismissed after 7 days. No correlations were found between mtDNA and inflammasome level and other clinical variables. Conclusion: Despite many limitations, our data suggest that in patients with septic shock caused by MDR pathogens the expression of main inflammasome genes was comparable to that of healthy patients without infection. Furthermore, our data evidence a possible role of mtDNA as a prognostic marker of severity in septic shock from MDR.
2020
- MRI of placenta accreta: diagnostic accuracy and impact of interventional radiology on foetal-maternal delivery outcomes in high-risk women
[Articolo su rivista]
Fiocchi, Federica; Monelli, Filippo; Besutti, Giulia; Casari, Federico; Petrella, Elisabetta; Pecchi, Annarita; Caporali, Cristian; Bertucci, Emma; Busani, Stefano; Botticelli, Laura; Facchinetti, Fabio; Torricelli, Pietro
abstract
To assess accuracy and reproducibility of MRI diagnosis of invasive placentation (IP) in high-risk patients and to evaluate reliability of MRI features. Secondary aim was to evaluate impact of interventional radiology (IR) on delivery outcomes in patients with IP at MRI.
2020
- Machine learning in predicting respiratory failure in patients with COVID-19 pneumonia - challenges, strengths, and opportunities in a global health emergency.
[Articolo su rivista]
Ferrari, D; Milic, J; Tonelli, R; Ghinelli, F; Meschiari, M; Volpi, S; Faltoni, M; Franceschi, G; Iadisernia, V; Yaacoub, D; Ciusa, G; Bacca, E; Rogati, C; Tutone, M; Burastero, G; Raimondi, A; Menozzi, M; Franceschini, E; Cuomo, G; Corradi, L; Orlando, G; Santoro, A; Di Gaetano, M; Puzzolante, C; Carli, F; Borghi, V; Bedini, A; Fantini, R; Tabbì, L; Castaniere, I; Busani, S; Clini, E; Girardis, M; Sarti, M; Cossarizza, A; Mussini, C; Mandreoli, F; Missier, P; Guaraldi, G.
abstract
Aims- The aim of this study was to estimate a 48 hour prediction of moderate to severe respiratory failure, requiring mechanical ventilation, in hospitalized patients with COVID-19 pneumonia.
Methods- This was an observational study that comprised consecutive patients with COVID-19 pneumonia admitted to hospital from 21 February to 6 April 2020. The patients’ medical history, demographic, epidemiologic and clinical data were collected in an electronic patient chart. The dataset was used to train predictive models using an established machine learning framework leveraging a hybrid approach where clinical expertise is applied alongside a data-driven analysis. The study outcome was the onset of moderate to severe respiratory failure defined as PaO 2 /FiO 2 ratio <150 mmHg in at least one of two consecutive arterial blood gas analyses in the following 48 hours. Shapley Additive exPlanations values were used to quantify the positive or negative impact of each variable included in each model on the predicted outcome.
Results- A total of 198 patients contributed to generate 1068 usable observations which allowed to build 3 predictive models based respectively on 31-variables signs and symptoms, 39-variables laboratory biomarkers and 91-variables as a composition of the two. A fourth “boosted mixed model” included 20 variables was selected from the model 3, achieved the best predictive performance (AUC=0.84) without worsening the FN rate. Its clinical performance was applied in a narrative case report as an example.
Conclusion- This study developed a machine model with 84% prediction accuracy, which is able to assist clinicians in decision making process and contribute to develop new analytics to improve care at high technology readiness levels.
2020
- Multi-centre, three arm, randomized controlled trial on the use of methylprednisolone and unfractionated heparin in critically ill ventilated patients with pneumonia from SARS-CoV-2 infection: A structured summary of a study protocol for a randomised controlled trial
[Articolo su rivista]
Busani, S.; Tosi, M.; Mighali, P.; Vandelli, P.; D'Amico, R.; Marietta, M.; Forfori, F.; Donati, A.; Cinnella, G.; De Monte, A.; Pasero, D.; Bellani, G.; Tascini, C.; Foti, G.; Ranieri, M.; Girardis, M.
abstract
OBJECTIVES: To assess the hypothesis that an adjunctive therapy with methylprednisolone and unfractionated heparin (UFH) or with methylprednisolone and low molecular weight heparin (LMWH) are more effective in reducing any-cause mortality in critically-ill ventilated patients with pneumonia from SARS-CoV-2 infection compared to LMWH alone. TRIAL DESIGN: The study is designed as a multi-centre, interventional, parallel group, superiority, randomized, investigator sponsored, three arms study. Patients, who satisfy all inclusion criteria and no exclusion criteria, will be randomly assigned to one of the three treatment groups in a ratio 1:1:1. PARTICIPANTS: Inpatients will be recruited from 8 Italian Academic and non-Academic Intensive Care Units INCLUSION CRITERIA (ALL REQUIRED): 1. Positive SARS-CoV-2 diagnostic (on pharyngeal swab of deep airways material) 2. Positive pressure ventilation (either non-invasive or invasive) from > 24 hours 3. Invasive mechanical ventilation from < 96 hours 4. PaO2/FiO2 ratio lower than 150 mmHg 5. D-dimer level > 6 times the upper limit of normal reference range 6. C-reactive Protein > 6-fold upper the limit of normal reference range EXCLUSION CRITERIA: 1. Age < 18 years 2. On-going treatment with anticoagulant drugs 3. Platelet count < 100.000/mm3 4. History of heparin-induced thrombocytopenia 5. Allergy to sodium enoxaparin or other LMWH, UFH or methylprednisolone 6. Active bleeding or on-going clinical condition deemed at high risk of bleeding contraindicating anticoagulant treatment 7. Recent (in the last 1 month prior to randomization) brain, spinal or ophthalmic surgery 8. Chronic assumption or oral corticosteroids 9. Pregnancy or breastfeeding or positive pregnancy test. In childbearing age women, before inclusion, a pregnancy test will be performed if not available 10. Clinical decision to withhold life-sustaining treatment or "too sick to benefit" 11. Presence of other severe diseases impairing life expectancy (e.g. patients are not expected to survive 28 days given their pre-existing medical condition) 12. Lack or withdrawal of informed consent INTERVENTION AND COMPARATOR: • LMWH group: patients in this group will be administered enoxaparin at standard prophylactic dosage. • LMWH + steroid group: patients in this group will receive enoxaparin at standard prophylactic dosage and methylprednisolone. • UFH + steroid group: patients in this group will receive UFH at therapeutic dosages and methylprednisolone. UFH will be administered intravenously in UFH + steroid group at therapeutic doses. The infusion will be started at an infusion rate of 18 UI/kg/hour and then modified to obtain aPTT Ratio in between the range of 1.5-2.0. aPTT will be periodically checked at intervals no longer than 12 hours. The treatment with UFH will be administered up to ICU discharge. After ICU discharge anticoagulant therapy may be interrupted or switched to prophylaxis with LMWH in the destination ward up to clinical judgement of the attending physician. Enoxaparin will be administered in both LMWH group and LMWH + steroid group at standard prophylactic dose (i.e., 4000 UI once day, increased to 6000 UI once day for patients weighting more than 90 kg). The treatment will be administered subcutaneously once a day up to ICU discharge. After ICU discharge it may be continued or interrupted in the destination ward up to clinical judgement of the attending physician. Methylprednisolone will be administered in both LMWH + steroid group and UHF + steroid group intravenously with an initial bolus of 0,5 mg/kg followed by administration of 0,5 mg/kg 4 times daily for 7 days, 0,5 mg/kg 3 times daily from day 8 to day 10, 0,5 mg/kg 2 times daily at days 11 and 12 and 0,5 mg/kg once daily at days 13 and 14. MAIN OUTCOMES: Primary Efficacy Endpoint: All-cause mortality at day 28 Secondary Efficacy Endpoints: - Ventilation free days (VFDs) at day 28, defined
2020
- Peritoneal dialysis in the time of coronavirus disease 2019
[Articolo su rivista]
Alfano, Gaetano; Fontana, Francesco; Ferrari, Annachiara; Guaraldi, Giovanni; Mussini, Cristina; Magistroni, Riccardo; Cappelli, Gianni; Bacca, Erica; Bedini, Andrea; Borghi, Vanni; Burastero, Giulia; Carli, Federica; Ciusa, Giacomo; Corradi, Luca; Cuomo, Gianluca; Digaetano, Margherita; Dolci, Giovanni; Faltoni, Matteo; Fantini, Riccardo; Franceschi, Giacomo; Franceschini, Ericad; Iadisernia, Vittorio; Larnõ, Damiano; Menozzi, Marianna; Meschiari, Marianna; Milic, Jovana; Orlando, Gabriella; Pellegrino, Francesco; Raimondi, Alessandro; Rogati, Carlotta; Santoro, Antonella; Tonelli, Roberto; Tutone, Marco; Volpi, Sara; Yaacoub, Dina; Aten, G.; Marco, Ballestri; Mori, Giacomo; Girardis, Massimo; Andreotti, Alberto; Biagioni, Emanuela; Bondi, Filippo; Busani, Stefano; Chierego, Giovanni; Scotti, Marzia; Serio, Lucia; Cossarizza, Andrea; Bellinazzi, Caterina; Borella, Rebecca; de Biasi, Sara; de Gaetano, Anna; Fidanza, Lucia; Gibellini, Lara; Iannone, Anna; Lo Tartaro, Domenico; Mattioli, Marco; Nasi, Milena; Paolini, Annamariag; Pinti, Marcello
abstract
In the current setting of global containment, peritoneal dialysis (PD) and home haemodialysis are the best modalities of renal replacement therapy (RRT) to reduce the rate of transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Considering the shorter and easier training programme of PD compared to home haemodialysis, PD appears a practical solution for patients with end-stage renal disease to reduce the risk of hospital-acquired infection. PD offers the advantage of minimizing the risk of viral transmission through interpersonal contact that commonly occurs during the haemodialysis session and while travelling from home to the haemodialysis facility using public transport services. To overcome barriers to health care access due to the containment measures for this emerging disease, telemedicine is a useful and reliable tool for delivering health care without exposing patients to the risk of contact. However, novel issues including handling of potentially infected dialysate, caregivers' infectious risk and adequacy of PD in critically ill patients with acute respiratory distress syndrome remain to be clarified. In conclusion, PD should be preferred to the other modalities of RRT during the coronavirus disease 2019 (COVID-19) outbreak because it can be a solution to cope with the increased number of infected patients worldwide.
2020
- Response Letter to Tuffet S, et al. and to Michard F, et al.
[Articolo su rivista]
Tonelli, R; Tabbì, L; Fantini, R; Castaniere, I; Gozzi, F; Busani, S; Nava, S; Clini, E; Marchioni, A
abstract
Not available
2020
- Response letter to Spinelli E, et al. and Jha
[Articolo su rivista]
Tonelli, R; Castaniere, I; Fantini, R; Tabbì, L; Busani, S; Pisani, L; Nava, S; Clini, E; Marchioni, A.
abstract
Not available
2020
- Surfactant replacement might help recovery of low-compliance lung in severe COVID-19 pneumonia.
[Articolo su rivista]
Busani, S; Dall’Ara, L; Tonelli, R; Clini, E; Munari, E; Venturelli, S; Meschiari, M; Guaraldi, G; Cossarizza, A; Ranieri, Mv; Girardis, M.
abstract
It has been hypothesized that there is a reduced AT2 cells number with low ability to synthesize and secrete endogenous surfactant in COVID-19 patients. To our knowledge, exogenous surfactant replacement has not been described so far in COVID-19 patients. We here report five cases of critically ill COVID-19 undergoing exogenous surfactant instillation through the airways.
2020
- Testicular pain as an unusual presentation of COVID-19: a brief review of SARS-CoV-2 and the testis
[Articolo su rivista]
La Marca, Antonio; Busani, Stefano; Donno, Valeria; Guaraldi, Giovanni; Ligabue, Guido; Girardis, Massimo
abstract
Can the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus induce testis damage and dysfunction?
2019
- Mortality in Patients With Septic Shock by Multidrug Resistant Bacteria: Risk Factors and Impact of Sepsis Treatments
[Articolo su rivista]
Busani, Stefano; Serafini, Giulia; Mantovani, Elena; Venturelli, Claudia; Giannella, Maddalena; Viale, Pierluigi; Mussini, Cristina; Cossarizza, Andrea; Girardis, Massimo
abstract
Background: Patients with septic shock by multidrug resistant (MDR) microorganism maybe considered a specific population of critical patients at very high risk of death in whom the effects of standard sepsis treatment has never been assessed. The objective of this retrospective analysis was to evaluate the risk factors for 30-day mortality and the impact of sepsis management in patients with septic shock caused by MDR bacteria. Methods: Patients with septic shock by MDR bacteria admitted to the mixed intensive care unit (ICU) of Modena University Hospital during a 6-year period were studied. The clinical and microbiological characteristics and sepsis treatments provided were analyzed and compared between survivors (S) and nonsurvivors (NS) at 30 days after septic shock appearance. Results: Ninety-four patients were studied. All therapeutic interventions applied to patients during their ICU stay did not show statistical significance between S and NS groups, except for administration of immunoglobulin M (IgM) preparation which were provided more frequently in S group (P <.05). At the multivariate adjusted analysis, preexisting cancer (odds ratio [OR] = 2.965) and Acinetobacter baumannii infections (OR = 3.197) were independently correlated with an increased risk of 30-day mortality, whereas treatment with IgM preparation was protective (OR = 0.283). Conclusions: This retrospective study showed that in patients with septic shock caused by MDR bacteria, history of cancer and infection sustained by A baumannii increase the risk of mortality and that standard sepsis treatments do not seem to provide any protective effect. Adjunctive therapy with IgM preparation seems to be beneficial, but further appropriate studies are needed to confirm the results observed.
2018
- Erratum to: The Intensive Care Global Study on Severe Acute Respiratory Infection (ICâGLOSSARI): a multicenter, multinational, 14-day inception cohort study (Intensive Care Medicine, (2016), 42, 5, (953), 10.1007/s00134-016-4317-4)
[Articolo su rivista]
Sakr, Yasser; Ferrer, Ricard; Reinhart, Konrad; Beale, Richard; Rhodes, Andrew; Moreno, Rui; Timsit, Jean Francois; Brochard, Laurent; Thompson, B. Taylor; Rezende, Ederlon; Chiche, Jean Daniel; Auer, J.; Schatzl, G.; Mach, K.; Gruber, H.; Schreurs, E.; Vander Laenen, M.; Ceunen, H.; Wauters, J.; Francois, G.; Deschamps, P.; Castanares, D.; Debels, D.; Pierrakos, C.; Vincent, J. L.; Taccone, F.; Vymazal, T.; Gornik, I.; Vujiaklija Brajkovic, A.; Medici, R.; Nielsen, J.; Bendtsen, A.; Siegel, H.; Suonsyrjä, T.; Hraech, S.; Daviaux, F.; Guillot, M.; Castelain, V.; Losser, R. -R.; Novy, E.; Bouadma, L.; Misset, B.; Philippart, F.; Mallat, J.; Zogheib, E.; Miclo, M.; Teboul, J. -L.; Anguel, N.; Darmon, M.; Pham, T.; Barberet, G.; Plantefeve, G.; Floccard, B.; Kheladze, Z.; Bloos, F.; Faltlhauser, A.; Helmes, T.; Zacharowski, K.; Meybohm, P.; Schwarzkopf, K.; Christ, M.; Baumgaertel, M.; John, S.; Nentwich, J.; Deja, M.; Goldmann, A.; Gottschalk, A.; Honig, F.; Siepe, B.; Goebel, U.; Lehmke, J.; Behrens, S.; Fiedler, K.; Sagoschen, I.; Riessen, R.; Haap, M.; Simon, Ph.; Kaisers, U.; Behrens, S.; Niesen, M.; Jaschinski, U.; Hoersch, S.; Jung, A.; Allgaeuer, S.; Haake, H.; Lange, A.; Papanikolaou, M.; Balla, M.; Giannakou, M.; Soultati, I.; Nikos, G.; Koulouras, V.; Kyriazopoulos, G.; Gkika, D.; Vlachogianni, G.; Psaroulis, K.; Mouloudi, E.; Massa, E.; Nichol, A.; Meany, E.; Motherway, C.; Bellani, G.; Pota, V.; Schiavone, V.; Girardis, M.; Busani, S.; Petrucci, N.; Di Pasquale, R.; Mazzini, P.; Molin, A.; Pellerano, G.; Volta, C.; Spadaro, S.; Guarracino, F.; Savioli, M.; Pellis, T.; Chinellato, N.; Gatta, A.; Cecchini, F.; Raineri, S. M.; Cortegiani, A.; Kekstas, G.; Karosas, V.; Anguseva, T.; Mitrev, Z.; Beck, O.; Cimic, N.; Janssen, G.; Bormans, L.; Kuiper, M.; Koopmans, K.; Den Boer, S.; de Groot, M.; Dennesen, P.; van den Bosch, J.; Kluge, G.; Mikaszewska-Sokolewicz, M.; Lazowski, T.; Chruscikowski, M.; Machon, J.; Adamik, B.; Kübler, A.; Wieczorek, A.; Afonso, S.; Matos, R.; Catorze, N.; Araujo, A.; Costa, Z.; Pais-de-Lacerda, A.; Martins, I.; Cardiga, R.; Fernandes, L.; Serra, I.; Martinho, A.; Tomescu, D.; Popescu, M.; Scarlatescu, E.; Stoica, R.; Macri, A.; Filipescu, D.; Rupnik, E.; Tomic, V.; Sifrer, F.; Sole Violan, J.; Ferrer Agüero, J. M.; Izura, J.; Monedero, P.; de Cabo, C. Muños; Aguilar, G.; Belda, F. J.; Blanquer, J.; Nives Carbonell, E.; Lopez-Delgado, J. -C.; Aragon, C.; Joya, C.; Ortiz-Leyba, C.; Fernandez Gonzalez, C. J.; de la Torre-Prados, M. -V.; Puerto-Morlan, A.; Araujo Aguilar, P.; Tomás Marsilla, J. I.; Vera Aratcoz, P.; Olmo, A.; Ferrer Roca, R.; Catalan, R. M.; Garcia Olivares, P.; Albis, A.; Alvarez, M.; Corcoles Gonzalez, V.; Gutierrez Rubio, J. M.; Montoiro Allue, R.; Rubio Mateo-Sidron, J.; Hobrok, M.; Cecconi, M.; Di Tomasso, N.; Raj, A.; Szakmany, T.; Srinivasa, L.; Mathew, S.; Ferguson, A.; Blahut-Zugaj, M.; Watters, M.; Henderson, S.; Sim, M.; Csabi, P.; O’Neill, O.; Nutt, C.; Humphreys, S.; Bhowmick, K.; Donnelly, A.; O’Kane, S.; Garfield, M.; Jha, R.; Unni, N.; Gordon, A.; Rubulotta, F.; Ravi, K.; Lunch, G.; Franco, F.; Higgs, D.; Strandvik, G.; Jonas, A.; Hopkins, Ph.; Hurst, T.; Bellini, A.; Balogun, O.; Srinivasan, R.; Ostermann, M.; Alexander, P.; Mccalman, K.; Bedford, J.; Fulop, M.; Brescia, G.; Strachan, J.; Meyer, J.; Stotz, M.; Brett, S.; Zand, F.; Nikandish, R.; Hashemian, S.; Jamaati, H.; Alsheikhly, A. S.; Almekhlafi, G.; Albarrak, M.; Maghrabi, A.; Salahuddin, N.; Aisa, T.; Atalan, H. K.; Sungur, M.; Hegazi, M.; Bauer, P.; Mukkera, S.; Fried, J.; Barger, M.; Gueret, R.; Gonzalez, C.; Lovesio, C.; Dellera, Ch.; Barrios, D.; Leite Mendes, C.; Gottardo, P.; Caser, E.; Santos, C.; Carvalho, A.; Teixeira, C.; Samaniego, W.; Whittle, S.; Molano, D.; Rojas, A.; Guerra, K.; Villamagua, B.; Salgado-Yepez, E.; Morocho, D.; Remache-Vargas, N.; Ñamendys-Silva, S.; Rodriguez, D.; Dominguez, G.; Barraza, G.; Bermudez-Aceves, E.; Sanchez-Hurtad
abstract
In both the original publication (DOI 10.1007/s00134-015-4206-2) and the first erratum (DOI 10.1007/s00134-016-4317-4), the members of the IC-GLOSSARI Investigators and the ESICM Trials Group were provided in such a way that they could not be indexed as collaborators on PubMed. The publisher apologizes for these errors and is pleased to list the members of the groups here: (Table presented.).
2018
- Purpura Fulminans and Septic Shock due to Capnocytophaga Canimorsus after Dog Bite: A Case Report and Review of the Literature
[Articolo su rivista]
Mantovani, Elena; Busani, Stefano; Biagioni, Emanuela; Venturelli, Claudia; Serio, Lucia; Girardis, Massimo
abstract
Primary infection by Capnocytophaga canimorsus after dog bite is rare but may be difficult to identify and rapidly lethal. We describe a case of fatal septic shock with fulminant purpura occurred in a patient without specific risk factor two days after an irrelevant dog bite. The patient was brought to hospital because of altered mental status, fever, and abdominal pain. In a few hours patient became hypoxic and cyanotic. The patient became extremely hypotensive with shock refractory to an aggressive fluid resuscitation (40 ml/kg crystalloids). She received vasoactive drugs, antibiotic therapy, and blood purification treatment, but cardiac arrest unresponsive to resuscitation maneuvers occurred. Case description and literature review demonstrated that, also in patients without specific risk factors, signs of infection after dog bite should be never underestimated and should be treated with a prompt antibiotic therapy initiation even before occurrence of organ dysfunction.
2017
- Impact of Pre-Analytical Time on the Recovery of Pathogens from Blood Cultures: Results from a Large Retrospective Survey
[Articolo su rivista]
Venturelli, Claudia; Righi, Elena; Borsari, Lucia; Aggazzotti, Gabriella; Busani, Stefano; Mussini, Cristina; Rumpianesi, Fabio; Rossolini, Gian Maria; Girardis, Massimo
abstract
Prompt identification of bloodstream pathogens is essential for optimal management of patients. Significant changes in analytical methods have improved the turnaround time for laboratory diagnosis. Less attention has been paid to the time elapsing from blood collection to incubation and to its potential effect on recovery of pathogens. We evaluated the performance of blood cultures collected under typical hospital conditions in relation to the length of their pre-analytical time. We carried out a large retrospective study including 50,955 blood cultures collected, over a 30-month period, from 7,035 adult septic patients. Cultures were accepted by the laboratory only during opening time (Mon-Fri: 8am±4pm; Sat: 8am±2pm). Samples collected outside laboratory hours were stored at room temperature at clinical wards. All cultures were processed by automated culture systems. Day and time of blood collection and of culture incubation were known for all samples. A maximum pre-analytical interval of 2 hours is recommended by guidelines. When the laboratory
was open, 57% of cultures were processed within 2 h. When the laboratory was closed, 4.9% of cultures were processed within 2 h (P<0.001). Samples collected when the laboratory was closed showed pre-analytical times significantly longer than those collected when laboratory was open (median time: 13 h and 1 h, respectively, P<0.001). The prevalence
of positive cultures was significantly lower for samples collected when the laboratory was closed compared to open (11% vs 13%, P<0.001). The probability of a positive result decreased of 16% when the laboratory was closed (OR:0.84; 95%CI:0.80±0.89, P<0.001). Further, each hour elapsed from blood collection to incubation resulted associated with a
decrease of 0.3% (OR:0.997; 95%CI:0.994±0.999, P<0.001) in the probability of a positive result. Delayed insertions of cultures into automated systems was associated with lower detection rates, with potentially important consequences for patients. In each hospital setting the logistic factors able to shorten pre-analytical time should be carefully investigated and specifically targeted.
2017
- Injury-induced immunosuppression: we are finally on the right track?
[Articolo su rivista]
Busani, Stefano; Cossarizza, Andrea; Girardis, Massimo
abstract
Non abstract
2017
- Oxygen Supplementation Among Patients in the Intensive Care Unit Reply
[Articolo su rivista]
Girardis, M; Busani, S
abstract
No
2017
- The Role of Adjunctive Therapies in Septic Shock by Gram Negative MDR/XDR Infections
[Articolo su rivista]
Busani, Stefano; Roat, Erika; Serafini, Giulia; Mantovani, Elena; Biagioni, Emanuela; Girardis, Massimo
abstract
Patients with septic shock by multidrug resistant microorganisms (MDR) are a specific sepsis population with a high mortality risk. The exposure to an initial inappropriate empiric antibiotic therapy has been considered responsible for the increased mortality, although other factors such as immune-paralysis seem to play a pivotal role. Therefore, beyond conventional early antibiotic therapy and fluid resuscitation, this population may benefit from the use of alternative strategies aimed at supporting the immune system. In this review we present an overview of the relationship between MDR infections and immune response and focus on the rationale and the clinical data available on the possible adjunctive immunotherapies, including blood purification techniques and different pharmacological approaches.
2016
- Dexmedetomidine for agitated delirium in intensive care unit intubated patients
[Articolo su rivista]
Busani, Stefano; Cantaroni, Cosetta; Girardis, Massimo
abstract
No abstract
2016
- Effect of Conservative vs Conventional Oxygen Therapy on Mortality Among Patients in an Intensive Care Unit: The Oxygen-ICU Randomized Clinical Trial
[Articolo su rivista]
Girardis, Massimo; Busani, Stefano; Damiani, Elisa; Donati, Abele; Rinaldi, Laura; Marudi, Andrea; Morelli, Andrea; Antonelli, Massimo; Singer, Mervyn
abstract
Despite suggestions of potential harm from unnecessary oxygen therapy, critically ill patients spend substantial periods in a hyperoxemic state. A strategy of controlled arterial oxygenation is thus rational but has not been validated in clinical practice.
2016
- Intravenous immunoglobulin in septic shock: review of the mechanisms of action and meta-analysis of the clinical effectiveness
[Articolo su rivista]
Busani, Stefano; Damiani, Elisa; Cavazzuti, Ilaria; Donati, Abele; Girardis, Massimo
abstract
Sepsis is characterized by a complex immune response. In this study we aimed to provide a review of the mechanisms of action of immunoglobulin (Ig) related to sepsis and an updated meta-analysis of the clinical effectiveness of the Ig use in septic patients.
2015
- A challenging case of pregnancy with placenta accreta and very rare irregular antibodies versus Cromer blood group system: a case report
[Articolo su rivista]
Busani, Stefano; VOLPI GHIRARDINI, Annamaria; Petrella, Elisabetta; Neri, Isabella; Casari, Federico; Venturelli, Donatella; De Santis, Mario; Montagnani, Giuliano; Facchinetti, Fabio; Girardis, Massimo
abstract
ntroduction: This report describes the challenges of treating a pregnant woman who had a rare case of critical placenta accreta with concurrent Cromer system anti-Tc(a) and anti-Kidd A alloantibodies. No previous case of such alloimmunization in a patient with placenta accreta has been reported. Case presentation: A 28-year-old African woman with anti-Cromer Tc(a) antibodies, anti-Kidd A antibodies and placenta accreta was admitted to the obstetric emergency department at our university hospital with persistent vaginal bleeding. Her rare Cromer blood group system antibodies had been diagnosed 1 month earlier; no compatible blood had been found despite a worldwide search. We performed a cesarean section after placement of Fogarty balloons in her uterine arteries with preoperative endovascular interventional radiology. Other therapeutic interventions included preoperative iron administration to raise hemoglobin and the scheduled predeposit of autologous blood. Intraoperative therapeutic management was aimed at preventing coagulopathy and massive bleeding. With the use of alternative medical techniques determined during perioperative planning, her intraoperative blood loss was only 1000mL, despite the placenta accreta. She was discharged from the hospital 4 days after cesarean section. Conclusions: To the best of our knowledge, this is the first report of an alloimmunized patient with two different alloantibodies and concurrent high risk of bleeding because of placenta accreta. The close collaboration among obstetricians, anesthesiologists, interventional radiologists, blood bank pathologists and intensive care doctors prevented serious consequences in this patient. The exceptional feature of this case is the patient's double risk: the placenta accreta and the inability to transfuse compatible blood. These two extreme situations challenged the multidisciplinary medical team.
2015
- Effect of performance improvement programs on compliance with sepsis bundles and mortality: A systematic review and meta-analysis of observational studies
[Articolo su rivista]
Damiani, Elisa; Donati, Abele; Serafini, Giulia; Rinaldi, Laura; Adrario, Erica; Pelaia, Paolo; Busani, Stefano; Girardis, Massimo
abstract
Background: Several reports suggest that implementation of the Surviving Sepsis Campaign (SSC) guidelines is associated with mortality reduction in sepsis. However, adherence to the guideline-based resuscitation and management sepsis bundles is still poor. Objective: To perform a systematic review of studies evaluating the impact of performance improvement programs on compliance with Surviving Sepsis Campaign (SSC) guideline-based bundles and/or mortality. Data Sources: Medline (PubMed), Scopus and Intercollegiate Studies Institute Web of Knowledge databases from 2004 (first publication of the SSC guidelines) to October 2014. Study Selection: Studies on adult patients with sepsis, severe sepsis or septic shock that evaluated changes in compliance to individual/combined bundle targets and/or mortality following the implementation of performance improvement programs. Interventions may consist of educational programs, process changes or both. Data Extraction: Data from the included studies were extracted independently by two authors. Unadjusted binary data were collected in order to calculate odds ratios (OR) for compliance to individual/combined bundle targets. Adjusted (if available) or unadjusted data of mortality were collected. Random-effects models were used for the data synthesis. Results: Fifty observational studies were selected. Despite high inconsistency across studies, performance improvement programs were associated with increased compliance with the complete 6-hour bundle (OR = 4.12 [95% confidence interval 2.95-5.76], I<sup>2</sup> = 87.72%, k = 25, N = 50,081) and the complete 24-hour bundle (OR = 2.57 [1.74-3.77], I<sup>2</sup> = 85.22%, k = 11, N = 45,846) and with a reduction in mortality (OR = 0.66 [0.61-0.72], I<sup>2</sup> = 87.93%, k = 48, N = 434,447). Funnel plots showed asymmetry. Conclusions: Performance improvement programs are associated with increased adherence to resuscitation and management sepsis bundles and with reduced mortality in patients with sepsis, severe sepsis or septic shock.
2015
- Immune System Dysfunction and Multidrug-resistant Bacteria in Critically Ill Patients: Inflammasones and Future Perspectives
[Capitolo/Saggio]
Girardis, Massimo; Busani, Stefano; DE BIASI, Sara
abstract
Despite the significant improvements in knowledge, technology and pharmacology obtained in the last few decades, we are not yet ready to provide individualized therapy for critically ill patients with sepsis. Clinicians tend to manage patients according to evidence-based guidelines that are derived from large randomized trials in which single patient characteristics and types of infection are rarely considered. But, as is well known, different types of infection in patients with different characteristics may cause different consequences and may need different treatments.
One of the aspects that remains rather unexplored in clinical practice is the immune response of the patient in the intensive care unit (ICU). On a day-to-day basis in the ICU we are dealing with patients who have a higher susceptibility to nosocomial infections with multidrug-resistant (MDR) bacteria without really understanding the cause. Antibiotic therapy alone in these patients is frequently insufficient, so it is necessary to study an alternative way to make sure that the immune response can actively participate in the elimination of the pathogens [1]. Infection with MDR bacteria frequently occurs in debilitated patients, such as those with shock, surgical complications, prolonged antibiotic therapies and immunosuppressive therapy [2]. The association between MDR infection and immunoparalysis is likely due to a disorder of innate and adaptive immune responses in critically ill patients.
2014
- Checklist for anesthesiological process: analysis of risks
[Articolo su rivista]
Ghirardini, A. M; Guerra, Emmanuele; Serio, L; Girardis, Massimo; Pasetto, Alberto; Busani, Stefano
abstract
Several methods are reported in the literature to analyze medically undesirable events during hospital care. Each method has several limitations, so no one has been defined as the standard tool to be able to detect failure during a medical process. The aim of this study was to compare an anesthesiological perioperative checklist with traditional Regional Incident Reporting (RIR) form in detecting and describing failures.
2014
- Early therapy with IgM-enriched polyclonal immunoglobulin in patients with septic shock
[Articolo su rivista]
Cavazzuti, Ilaria; Serafini, Giulia; Busani, Stefano; Rinaldi, Laura; Biagioni, Emanuela; Buoncristiano, Marta; Girardis, Massimo
abstract
To determine whether there was an association between adjunctive therapy with IgM-enriched immunoglobulin (IgM) and the 30-day mortality rate in patients with septic shock.
2014
- Trends in ventilator-associated pneumonia: Impact of a ventilator care bundle in an Italian tertiary care hospital intensive care unit
[Articolo su rivista]
Righi, Elena; Aggazzotti, Gabriella; Elena, Ferrari; Chiara, Giovanardi; Stefano, Busani; Laura, Rinaldi; Girardis, Massimo
abstract
Background: The impact on ventilator-associated pneumonia (VAP) occurrence of a multifaceted program,
including progressive strategies for VAP prevention, implemented in an Italian intensive care unit (ICU) is reported.
Methods: All adults admitted to the ICU in 2004-2010 with a length of stay 72 hours and mechanical ventilation time 48 hours were included in the study. Demographics, clinical information, and data on VAP were extracted from the ICU-acquired infection surveillance dataset. A standardized bundle for VAP prevention was implemented in 2004. In 2008, selective digestive tract decontamination (SDD) was
added to the protocol. Changes in VAP incidence were evaluated.
Results: There were 1,372 subjects included in the study. Overall, 156 (11.4%) developed VAP. In the second part of the study VAP incidence decreased from 15.9% to 6.7% (P <.001). Reductions both in early-onset VAP (6.6% to 1.9%; P < .001) and late-onset VAP (9.3% to 4.7%; P < .001) incidence were observed. Multivariate analysis showed a significant reduction in the risk of developing VAP from multidrug resistant pathogens in the bundle plus SDD period as well (odds ratio, .54; 95% confidence interval,
.31-.91).
Conclusion: The implementation of a standardized approach to patient care, including a number of key
reduction interventions, was associated with a significant reduction in the risk of developing VAP.
2014
- Wernicke's encephalopathy in a malnourished surgical patient: a difficult diagnosis
[Articolo su rivista]
Busani, Stefano; Bonvecchio, Cinzia; Gaspari, Arianna; Malagoli, Marcella; Todeschini, Alessandra; Cautero, Nicola; Girardis, Massimo
abstract
Wernicke's encephalopathy is an acute neurological disorder resulting from thiamine deficiency mainly related to alcohol abuse. Severe thiamine deficiency is an emerging problem in non-alcoholic patients and it may develop in postoperative surgical patients with risk factors.
2013
- Effectiveness of sepsis bundle application in cirrhotic patients with septic shock: A single-center experience
[Articolo su rivista]
Rinaldi, Laura; Ferrari, Elena; Marietta, Marco; Donno, Lara; Trevisan, Davide; Codeluppi, Mauro; Busani, Stefano; Girardis, Massimo
abstract
Purpose: To evaluate the effect of adherence to evidence-based guidelines of the Surviving Sepsis Campaign (SSC) on the outcome of cirrhotic patients with septic shock admitted to the intensive care unit. Methods: This prospective observational cohort study included 38 patients with documented liver cirrhosis and septic shock admitted to a multidisciplinary intensive care unit at a University Hospital from January 2005 to June 2009. In each patient, the compliance to 4 resuscitation (ie, 6-hour bundle) and to 3 management (i.e. 24-hour bundle) interventions recommended by the SSC guidelines and the 30-day mortality were measured. Results: The 6-hour, 24-hour, and all bundles were completed in 50 %, 52%, and 39% of the patients, respectively. The characteristics at admission and the 30-day mortality of patients with all-bundle compliance (n = 15; mortality 86.6%) were similar to those of patients without bundle compliance (n = 23; mortality 78.2%), except for central venous O 2 saturation. Unadjusted and adjusted regression analysis showed that none of the single sepsis interventions and bundles were independently associated with 30-day mortality. Conclusions: In our observational study, the adherence to the interventions recommended by the SSC evidence-based guidelines did not provide an improvement in the survival rate of cirrhotic patients with septic shock. © 2012 Elsevier Inc. All rights reserved.
2013
- Endotoxin activity levels as a prediction tool for risk of deterioration in patients with sepsis not admitted to the intensive care unit: a pilot observational study
[Articolo su rivista]
Biagioni, Emanuela; Venturelli, Claudia; Klein, David J; Buoncristiano, Marta; Rumpianesi, Fabio; Busani, Stefano; Rinaldi, Laura; Donati, Abele; Girardis, Massimo
abstract
The aim of this prospective observational study was to evaluate in patients with sepsis not requiring intensive care unit admission the relationship between the levels of endotoxin activity assay (EAA) early after sepsis recognition and the risk of development of organ dysfunction (OD).
2013
- Unexpected death: anaphylactic intraoperative death due to Thymoglobulin carbohydrate excipient
[Articolo su rivista]
Roncati, Luca; Barbolini, Giuseppe; Scacchetti, Alda Tiziana; Busani, Stefano; Maiorana, Antonino
abstract
Anaphylactic shock is a life-threatening allergic response characterized by severe hypotension, inducing tissue hypoperfusion with possible multi-organ failure and death. We describe the first case of fatal intra-operative anaphylactic shock due to prolonged infusion of Thymoglobulin during Orthotopic Liver Transplantation (OLT), resulting from recruitment of both mastocytes and basophils, activated and degranulated. Post-mortem serological analysis on a preserved, pre-OLT sample of the patient's blood revealed specific IgE against carbohydrate cross-reactive determinants (CCDs), such as MUXF3 and nAna c2, proving that anaphylactic reaction was triggered by the Thymoglobulin carbohydrate excipient (sugar alcohol mannitol), rather than anti-thymocyte globulin itself. Our findings are consistent with scientific data reported in the literature, where only one case of non-fatal anaphylaxis to Thymoglobulin has been described, despite the existence of proven cases of anaphylactic reaction to mannitol. This case highlights the need to pay particular attention in future not only to active substances but also to drug excipients, above all during intra-operative drug delivery. In view of the important role played by basophils in this kind of anaphylaxis, the basophil activation test (BAT) could prove useful in preventing anaphylactic death from CCDs.
2012
- Acute renal failure and liver necrosis associated to allopurinol therapy.
[Articolo su rivista]
Biagioni, E.; Busani, S.; Rinaldi, L.; Marietta, M.; Girardis, Massimo
abstract
no
2012
- Erratum: Acute renal failure and renal replacement therapy in the postoperative period of orthotopic liver transplant patients versus nonelective abdominal surgery patients (Transplantation Proceedings (2011) 43:4 (1145-1147))
[Articolo su rivista]
Biagioni, E.; Cavazzuti, I.; Busani, S.; Trevisan, D.; Zavatti, L.; Ferrari, E.; Girardis, M.
abstract
2012
- Exogenous surfactant, a role in the adult respiratory distress syndrome?
[Articolo su rivista]
Busani, S.; Girardis, Massimo; Pasetto, A.
abstract
x
2012
- Levosimendan in a case of severe peri-myocarditis associated with influenza A/H1N1 virus.
[Articolo su rivista]
S., Busani; A., Pasetto; Ligabue, Guido; V., Malavasi; R., Lugli; Girardis, Massimo
abstract
x
2012
- PSP/reg: a new stone in sepsis biomarkers?
[Articolo su rivista]
S., Busani; Girardis, Massimo
abstract
ABSTRACT: Rapid diagnosis, appropriate management, and time are the key factors for improving survival rate in many emergency clinical scenarios such as acute myocardial infarction, pulmonary embolism, cerebral stroke, and severe sepsis. Clinical signs and electrocardiographic, radiological, and echographic investigations associated with biomarkers usually allow a quick diagnosis in all of the above situations, except severe sepsis, in which the diagnosis in the early phases is often only presumptive. In sepsis, microbiological cultures are still considered the 'gold standard' for diagnosis, whereas the numerous biomarkers investigated are actually valuable only for patient stratification and evaluation of clinical course. In this issue of Critical Care, Que and colleagues describe the prognostic value of pancreatic stone protein/regenerating protein (PSP/reg) concentration in patients with severe infections. The data reported are interesting, but several questions about this biomarker arise, and further studies are needed to understand its role in sepsis and clinical practice.
2012
- Sepsis Stewardship Programs: Methods and Results
[Capitolo/Saggio]
Girardis, Massimo; Busani, S.; Pan, A.
abstract
no
2011
- Acute renal failure and renal replacement therapy in the postoperative period of orthotopic liver transplant patients versus nonelective abdominal surgery patients
[Articolo su rivista]
Biagioni, Emanuela; Cavazzuti, Ilaria; Busani, Stefano; Trevisan, Davide; Zavatti, Laura; Ferrari, Elena; Girardis, Massimo
abstract
Acute renal failure (ARF) often complicates the postoperative period of patients undergoing orthotopic liver transplantation (OLT); it is habitually associated with high mortality rates. Similarly, patients undergoing major nonelective abdominal surgery are prone to ARF because of their frequent preexistent morbidities, abdominal sepsis, and needed for extended surgical procedures. The aim of this study was to evaluate the incidence of ARF and use of renal replacement therapy (RRT) among OLT versus nonelective abdominal surgery patients and associations with clinical outcomes. We studied all the patients admitted to a surgical intensive care unit (ICU) from January 2008 to December 2009 after OLT or nonelective abdominal surgery. The inclusion criteria were an ICU stay of at least 48 hours and without prior end-stage renal failure. OLT patients (n = 84) were younger and less severly ill than surgery patients (n = 60). ARF occurrence was lower among the OLT (29%) than the surgery group (47%) requiring RRT in 71% and 53% of patients due to ARF, respectively. The ICU mortality of ARF patients in both groups (29% OLT and 51% surgery) were greater than among subjects without ARF (2% and 6%). The occurrence of ARF is common among these two patient groups, and associated with increased risk of death among in surgery (+45%) versus in OLT (+27%) patients. © 2011 Elsevier Inc. All rights reserved.
2011
- Emorragia massiva: dalle linee guida ai bundles di trattamento
[Relazione in Atti di Convegno]
Girardis, Massimo; Pedrazzi, P; Braccini, Ms; Busani, S; Marietta, M; Pasetto, A.
abstract
x
2011
- Il politraumatizzato
[Capitolo/Saggio]
Rambaldi, M.; Busani, S.; Baranzoni, M. T.; Girardis, Massimo
abstract
x
2011
- The clinical significance of cardiac output measurement in patients with persistent shock: preliminary result of a randomized trial
[Abstract in Rivista]
Trevisan, D; Zavatti, L; Andreotti, A; Giovannini, S; Busani, S; Girardis, Massimo
abstract
x
2010
- Early use of immunoglobulin in septic shock
[Abstract in Rivista]
Cavazzuti, I; Rinaldi, L; Donno, L; Braccini, Ms; Busani, S; Girardis, Massimo
abstract
x
2010
- Levosimendan in cardiac failure after subarachnoid hemorrhage.
[Articolo su rivista]
Busani, S; Rinaldi, L; Severino, C; Cobelli, M; Pasetto, Alberto; Girardis, Massimo
abstract
The aim of this study is to report the development of cardiac failure after subarachnoid hemorrhage (SAH) with recovery of heart and cerebral function. This is a case report of a 38-year-old woman who was admitted to the intensive care unit (ICU) at Policlinico di Modena, Italy. This woman developed a deep state of coma because of severe SAH. After cerebral hemorrhage, patient showed a cardiogenic shock, which needed invasive monitoring. Cerebral perfusion pressure had to be restored, so fluids, dopamine, norepinephrine, and dobutamine were in administered sequentially. Despite these supportive treatments, hemodynamic parameters further worsened and echocardiography showed a global depressed left ventricular (LV) contraction with poor ejection fraction (EF) and restrictive type of LV relaxation pattern. Twenty-four hours after ICU admission, levosimendan was started with the aim to improve cardiac function because of the refractoriness of all other treatments. Eight hours after levosimendan infusion, cardiac function improved and, within the after 24 hours, EF and LV relaxation pattern recovered. Neurologic state and computed tomography images improved day by day, and after 9 days from the ICU admission, we transferred the patient to the neurosurgical ward with very good neurologic conditions and no deficits in motility. The conventional management of post-SAH cardiovascular failure is based on the use of norepinephrine, dobutamine, and high amount of fluids. This strategy did not provide any improvement, so we decided for levosimendan infusion to counteract myocardial stunning. The improvement in cardiac EF, LV wall motion, and filling pressure observed in our patient could be explained due to the antistunning triple-mechanism action of levosimendan. Data available on the levosimendan effectiveness in patients with SAH and its effect on intracranial pressure are still lacking, but we think that neurogenic cardiac failure can be treated at first with levosimendan. © 2010 Lippincott Williams & Wilkins.
2010
- Liver transplantation in patients aged 65 and over: a case-control study.
[Articolo su rivista]
R., Montalti; G., Rompianesi; DI BENEDETTO, Fabrizio; R., Ballarin; R. C., Gerring; S., Busani; L. D., Pietri; N. D., Ruvo; R. M., Iemmolo; G. P., Guerrini; N., Smerieri; Gerunda, Giorgio Enrico
abstract
INTRODUCTION: The average age of patients undergoing liver transplantation (LT) is consistently increasing. The aim of this case-control study is to evaluate survival and outcome of patients ≥65 yr compared to younger patients undergoing LT. MATERIALS AND METHODS: From 10/00 to 4/08 we performed 330 primary LT, 31 (9.4\%) of these were in patients aged 65-70. Following a case-control approach, we compared these patients with 31 patients aged between 41 and 64 yr and matched according to sex, LT indication, viral status, cadaveric/living donor, LT timing, and Model for End-Stage Liver Disease (MELD) score. RESULTS: There were no statistically significant differences in demographic and surgical donor characteristics. The mean MELD score was under 18 in both groups. Post-LT complications occurred with a similar incidence in the two groups. one-, three-, and five-yr survival was 83.9\%, 80.6\%, and 80.6\%, respectively, for the elderly group, and 80.6\%, 73.8\%, and 73.8\%, respectively, for the young group (p = 0.61). DISCUSSION: Patients aged between 65 and 70 with low MELD score who undergo LT have the same short- and middle-term survival expectancy, morbidity, and outcome quality as younger patients with the same indication and same pre-LT pathology severity, whatever they might be. Thus, chronological age alone should not deter LT workup in patients >65 and <70.
2010
- Posttraumatic massive bleeding: a challenging multidisciplinary task.
[Articolo su rivista]
Marietta, M; Pedrazzi, P; Girardis, Massimo; Busani, S; Torelli, G.
abstract
Massive bleeding is a key issue in the treatment of trauma and surgery. It does in fact account for more than 50% of all trauma-related deaths within the first 48 h following hospital admission, and it can significantly raise the mortality rate of any kind of surgery. Despite this great clinical relevance, evidence on the management of massive bleeding is surprisingly scarce, and its treatment is often based on empirical grounds. Successful treatment of massive haemorrhage depends on better understanding of the associated physiological changes as well as on good team work between the different specialists involved in the management of such a complex condition. The aim of this article is to provide an overview of the pathophysiology as well as of current treatment options of such a condition, including the new concept of "damage control resuscitation", which integrates permissive hypotension, haemostatic resuscitation and damage control surgery.
2010
- Surfactant therapy and intravenous zanamivir in severe respiratory failure due to persistent influenza A/H1N1 2009 virus infection.
[Articolo su rivista]
Busani, S; Girardis, Massimo; Biagioni, E; Pasetto, A; Sambri, V.
abstract
no
2010
- Two-stage liver transplantation: an effective procedure in urgent conditions.
[Articolo su rivista]
Montalti, R.; Busani, S.; Masetti, M.; Girardis, Massimo; Benedetto, F. D.; Begliomini, B.; Rompianesi, G.; Rinaldi, L.; Ballarin, R.; Pasetto, A.; Gerunda, Giorgio Enrico
abstract
Temporary portocaval shunt and total hepatectomy is a technique used in the presence of toxic liver syndrome because of fulminant hepatic failure, hepatic trauma, primary non-function (PNF), and eclampsia. We performed this technique on four patients. An indication for anhepatic state was severe hemodynamic instability in three of them. Etiologies of these three patients were as follows: PNF after liver transplantation, ischemic hepatitis after right hepatic artery embolization, and massive reperfusion syndrome during a liver transplantation. In the fourth patient, during the liver transplantation when hepatic artery was ligated, a kidney carcinoma in the donor graft was discovered. We decided to complete the hepatectomy and to construct a temporary portocaval shunt. Mean anhepatic phases were 19 h and 15 min. All patients survived the two-stage liver transplantation procedure without major complications. Our cases demonstrated that temporary portocaval shunt while awaiting urgent liver transplantation could be an effective "bridge" in selected patients who develop toxic liver syndrome; however, a short time between portocaval shunt and transplantation and careful intensive care managements are mandatory.
2009
- Bronchoalveolar lavage (BAL) and supplementation with exogenous surfactant in adults with acute respiratory distress syndrome (ARDS)
[Abstract in Rivista]
Busani, S; Cavazzuti, I; Fabbri, L; Lumachi, L; Lo Pardo, D; Michielan, F; Vassalli, Pa; Pacini, D; D’Este, G; Girardis, Massimo; Pasetto, Alberto
abstract
x
2009
- Effects of intravenous IGM-enriched immunoglobulins on muscle tissue microcirculation in septic shock: a preliminary report
[Abstract in Rivista]
Cavazzuti, I; Rinaldi, L; Braccini, Ms; Bertolotti, V; Andreotti, A; Busani, S; Girardis, Massimo
abstract
x
2009
- Perioperative red blood cell transfusion and outcome in stable patients after elective major vascular surgery.
[Articolo su rivista]
Bursi, F; Barbieri, A; Politi, L; Di Girolamo, A; Malagoli, A; Grimaldi, T; Rumolo, A; Busani, S; Girardis, Massimo; Jaffe, As; Modena, Maria Grazia
abstract
OBJECTIVES:Definitive evidence that red blood cell transfusion improves outcome after vascular surgery is lacking. The aims of the study were to determine, among stable consecutive patients who underwent elective major vascular surgery, (1) the association between postoperative transfusion and 30-day death, myocardial infarction, and both, and (2) and if this association differs according to the presence of postoperative anaemia (haemoglobin value less than 9.0 g/dL within 7 days after surgery).METHODS:A retrospective observational study was conducted on 359 patients prospectively screened according to the ACC/AHA guidelines for preoperative risk in non-cardiac surgery. Main outcome was 30-day death; secondary outcomes 30-day myocardial infarction, and composite of 30-day myocardial infarction or death.RESULTS:Of the patients included, 95 (26.5%) received at least one unit of red blood cells. Patients who received transfusion had a significantly increased hazard of 30-day death (hazard ratio [HR] 11.72, 95% confidence interval [CI] 3.92-35.10; p<0.0001), myocardial infarction (HR 3.3, 95% CI 1.7-6.1; p=0.0003), and both (HR 4.0 95% CI 2.2-7.3; p<0.0001). Such associations held even after adjusting for baseline characteristics, surgical risk, bleeding, and propensity to receive transfusion. There was a significant interaction between transfusion and postoperative anaemia (p=0.012). In patients without anaemia, transfusion was associated with higher risk of 30-day death (HR 19.20, 95% CI 3.99-92.45; p=0.007), myocardial infarction (HR 5.05, 95% CI 2.23-11.44; p=0.0001), and both. Conversely, in patients with anaemia this association was not significant.CONCLUSIONS:In patients who underwent elective major vascular surgery, perioperative transfusion was associated with a significantly increased risk of 30-day events which was more attributable to patients with lesser degree of anaemia. Our data caution against the use of liberal transfusion in
2008
- Effetto sul microcircolo della terapia con proteina C attivata ricombinante umana in pazienti con shock settico
[Abstract in Rivista]
Cavazzuti, I; Rinaldi, L; Busani, S; Donno, L; Iacomini, E; Girardis, Massimo
abstract
x
2008
- Introduction to the 9th LAIC Meeting
[Articolo su rivista]
Busani, S.; Pasetto, A.
abstract
2008
- Recombinant activated factor VII in critical bleeding after orthotopic liver transplantation.
[Articolo su rivista]
Busani, S; Semeraro, G; Cantaroni, C; Masetti, M; Marietta, M; Girardis, Massimo
abstract
Critical bleeding throughout the intraoperative phase of orthotopic liver transplantation (OLT) strongly increases patient mortality and intensive care unit (ICU) stay. The aim of this study was to report our experience on the use of recombinant activated factor VII (rFVIIa) in postoperative critical bleeding after OLT. In 7 patients with persistent severe bleeding after application of a standard transfusion protocol, we administered a 90 microg/kg bolus of rFVIIa and if necessary eventually repeated it after 3 hours. We recorded the blood loss and the need for transfusions before and after the rFVIIa therapy. Blood losses and need for platelets significantly decreased after rFVIIa administration; a nonsignificant decrease in red blood cells and fresh frozen plasma transfusions also occurred. In 6 patients treatment with rFVIIa was effective; only 1 patient died because of hemorrhagic shock and no thromboses were detected among the treated patients. Awaiting stronger evidence from randomized controlled trials, we suggest that in some challenging cases of massive bleeding rFVIIa should be considered a useful option to control bleeding.
2008
- Strategies to control massive abdominal bleeding.
[Articolo su rivista]
Busani, S; Cavazzuti, I; Marietta, M; Pasetto, A; Girardis, Massimo
abstract
Abdominal trauma is divided into blunt and penetrating causes. Massive intraabdominal hemorrhage after injury represents the most dangerous precipitating factor that can affect survival if not promptly managed. The first target to achieve management of bleeding patients is control of the source, and then adequate resuscitation and optimization of hemostasis. New procoagulant drugs as recombinant activated factor VII (rFVIIa) seem to play an interesting role in bleeding control after trauma. Our experience with rFVIIa in six patients who were refractory to standard treatments demonstrated a good survival rate after massive abdominal bleeding. Regardless of new drugs and new technologies, a multidisciplinary approach is the cornerstone of the primary care of the these patients.
2008
- Use of activated protein C in liver transplantation patients with septic shock.
[Articolo su rivista]
Rinaldi, L; Marietta, M; Mignini, Ma; Donno, L; Busani, S; Codeluppi, M; Masetti, M; Girardis, Massimo
abstract
Recombinant human activated protein C (rhAPC) has been approved for use in patients with severe sepsis at high risk of death. Because of the high risk of bleeding, liver transplantation (LT) patients have been excluded from the randomized control trials that evaluated efficacy and safety of rhAPC and, thus, few data are available on the use of this drug in LT patients with severe sepsis. We describe our experience with 5 LT recipients treated for septic shock with the best conventional therapy and rhAPC. Before rhAPC therapy, all the patients showed septic shock, with ≥3 organ dysfunctions and thrombocytopenia with impairment of coagulation. rhAPC therapy started within 30 hours after septic shock onset in all the patients who recovered from sepsis-induced circulatory failure, improved organ dysfunction, and completed the 96 hours of rhAPC therapy. During rhAPC infusion, 4 patients received fresh'frozen plasma and/or platelet concentrates because of thrombocytopenia and severe hemostasis dysfunction. No major bleeding occurred and only 1 patient presented with minor bleeding events. © 2008 AASLD.
2008
- ∆PCO2 arteriosa e venosa e troponina come markers biologici in terapia intensiva
[Relazione in Atti di Convegno]
Girardis, Massimo; Biagioni, E; Boni, E; Andreotti, A; Scarinci, N; Busani, S; Rinaldi, L.
abstract
x
2007
- Anestesia e coagulazione quale monitoraggio
[Relazione in Atti di Convegno]
Cantaroni, C; Semeraro, G; Braccini, S; Busani, S; Marietta, M; Girardis, Massimo; Pasetto, A.
abstract
x
2007
- Differenza di CO2 nel sangue venoso centrale e nel sangue arterioso come indice precoce di insufficienza d’organo
[Abstract in Rivista]
Biagioni, E; Boni, E; Busani, S; Girardis, Massimo; Pasetto, A.
abstract
x
2007
- Differenze microcircolatorie tra sepsi severa e shock settico rilevate con spettroscopia nel vicino infrarosso
[Abstract in Rivista]
Cavazzuti, I; Rinaldi, L; Busani, S; Donno, L; Girardis, Massimo
abstract
x
2007
- Intracerebral haemorrhage in anticoagulated patients
[Relazione in Atti di Convegno]
Marietta, M; Pedrazzi, P; Busani, S; Girardis, Massimo; Cantaroni, C; Torelli, G.
abstract
x
2007
- Liver transplantation in HIV patients
[Abstract in Rivista]
Masetti, M.; Cocchi, S.; Montalti, R.; Guaraldi, Giovanni; Romano, A.; Codeluppi, M.; Girardis, Massimo; De Ruvo, N.; Busani, S.; Ballarin, R.; DI BENEDETTO, Fabrizio; Guerrini, G. P.; Iemmolo, R. M.; Rompianesi, G.; Gerunda, Giorgio Enrico
abstract
not available
2007
- Peri-operative respiratory failure in a cirrhotic patient: a misleading diagnosis.
[Articolo su rivista]
Busani, S.; Rinaldi, L.; Barbieri, E.; Drago, A.; Barbieri, A.; Girardis, Massimo
abstract
Patients with chronic liver disease may present with different degrees of respiratory dysfunction whose differential diagnosis is important before elective surgery. We report the case of a misleading diagnosis of peri-operative respiratory failure in a cirrhotic patient who underwent mastectomy. Intra-operative respiratory failure was ascribed by the anaesthetic team to pulmonary embolism and after the operation this diagnosis was still suspected. Despite postoperative heparin treatment, pulmonary gas exchange remained severely impaired. On the hypothesis of a right to left shunt, we performed transoesophageal echocardiography with a bubble test and confirmed hepatopulmonary syndrome. We administered anticoagulant therapy to the patient following surgery, increasing the risk of haemorrhage. We also continued orotracheal intubation and mechanical ventilation longer than was needed. Respiratory symptoms in a patient with liver disease should not be underestimated and up to 20\% of these patients may have hepatopulmonary syndrome.
2007
- Pratica Trasfusionale in pazienti con emorragia critica: esperienza del Policlinico di Modena
[Abstract in Rivista]
Cantaroni, C; Semeraro, G; Braccini, S; Busani, S; Marietta, M; De Palma, M; Girardis, Massimo
abstract
x
2006
- Anestesia e disordini vasculo-polmonari nel paziente epatopatico: iter diagnostico e ruolo dello screening precoce
[Relazione in Atti di Convegno]
Busani, S; Rinaldi, L; Girardis, Massimo
abstract
x
2006
- Definizione di protocolli condivisi nell’emorragia critica
[Relazione in Atti di Convegno]
Girardis, Massimo; Busani, S; Cantaroni, C.
abstract
x
2006
- Emorragia critica: clinica, diagnosi e trattamento
[Abstract in Atti di Convegno]
Cantaroni, C; Chierego, G; Busani, S; Marietta, M; Girardis, Massimo
abstract
x
2006
- Intra-abdominal hypertension in nonelective surgery: A preliminary report
[Articolo su rivista]
Busani, S; Soccorsi, Mc; Poma, C; Girardis, Massimo
abstract
Intra-abdominal hypertension (IAH) is recognized to be associated with adverse outcomes in critically ill patients. Etiologic factors for IAH can be divided into three categories: medical, posttraumatic, and surgical/postoperative. No studies have been performed on patients who underwent nonelective surgery, so our aim was to determine prospectively the incidence of IAH among these patients during their intensive care stay to correlate intra-abdominal pressure (IAP) and other parameters. Abdominal pressure was recorded twice daily with the standard method. The study group enrolled 22 patients who underwent an abdominal operation that met urgency criteria and with a postoperative intensive care unit (ICU) stay of at least 48 hours. Several serum and clinical parameters were studied for the first 5 postoperative days as well as during ICU and hospital stay as well as monitored hospital mortality. Our results demonstrated that mortality was definitely higher among patients who developed IAH compared with non-IAH patients. Our results highlighted that a strong correlation existed between increasing values of IAP and worsening serum creatinine and PaO2/FiO(2) quotient among patients who underwent nonelective surgery.
2006
- Living donor liver transplantation and management of portal venous pressure.
[Articolo su rivista]
Busani, S; Marconi, G; Schiavon, L; Rinaldi, L; Del Buono, M; Masetti, Michele; Girardis, Massimo
abstract
Small-for-size syndrome occurs in the presence of a reduced mass of liver that is insufficient to maintain normal liver function. It has been speculated that this dysfunction is principally associated with graft exposure to excessive portal perfusion. The aim of these cases was to evaluate the efficacy of octreotide, a splanchnic vasoconstrictor, and esmolol, a selective beta-blocker, to modify the portal perfusion in the postoperative phase after left living related liver transplantation (LRLT). Four patients who underwent left LRLT with graft-to-recipient weight ratios of 0.60 +/- 0.24 were studied with a catheter placed in a jejunal vein. We observed high basal values of hepatic venous pressure gradient (HVPG) and portal vein flow (PVF). Octreotide infusion decreased HVPG, an effect that was more pronounced when it was combined with esmolol. The administration of both drugs was also associated with an improvement in portal vein oxygen saturation. Despite variation in PVF, the plasma disappearance rate of indocyanin green did not change during the infusion of the two drugs. In conclusion, octreotide and esmolol infusion allowed a manipulation of portal vein pressure that should be measured in left LRLT using a small-for-size graft.
2006
- Muscle oxygenation in septic patients treated with activated protein C
[Abstract in Rivista]
Rinaldi, L; Busani, S; Girardis, Massimo
abstract
x
2006
- New frontiers in critical bleeding
[Relazione in Atti di Convegno]
Busani, S; Donno, L; Girardis, Massimo
abstract
x
2006
- Pathophysiology of Bleeding in Surgery
[Articolo su rivista]
Marietta, M.; Facchini, L.; Pedrazzi, P.; Busani, S.; Torelli, G.
abstract
Bleeding is a major surgical complication. Although mortality rates of 0.1% are observed for surgical procedures, it may be 5% to 8% for elective vascular surgery, and increase to 20% in the presence of severe bleeding. In major surgery for liver diseases, as well as in cardiac surgery, excessive blood loss is associated with increased mortality, morbidity, and intensive care stay. Approximately 75% to 90% of intraoperative and early postoperative bleeding is due to technical factors. However, in some cases either acquired or congenital coagulopathies may favor, if not directly cause, surgical hemorrhage. Uncontrolled bleeding leads to a combination of hemodilution, hypothermia, consumption of clotting factors, and acidosis, which in turn worsen the clotting process, further exacerbating the problem in a vicious bloody circle. At present, the standard treatment for surgical bleeding is the rapid control of the source of bleeding by either surgical or radiological techniques. Blood-derived products as well as hemostatic agents, such as aprotinin, tranexamic acid, and DDAVP, are widely used to improve hemostatic balance in bleeding patients. Recombinant activated factor VII (rFVIIa) has been reported to be effective for the treatment of surgical or traumatic massive bleeding unresponsive to conventional therapy. Although most reports are anecdotal, and therefore exposed to a positive selection bias, the number of cases is impressive, strongly suggesting that in such patients rFVIIa may afford a hemostatic advantage beyond that of conventional replacement therapy.
2006
- Posttransplant cerebral hemorrhage in a patient with familial amyloidotic polyneuropathy
[Articolo su rivista]
L., Rinaldi; S., Busani; Pasetto, Alberto; Girardis, Massimo
abstract
no
2006
- Rectal amputation sparing by haemostatic therapy with recombinant factor Vlla in a patient with cytomegalovirus-related colitis
[Articolo su rivista]
Girardis, Massimo; Marietta, M; Busani, S; Codeluppi, M; Villa, Erica; Pasetto, A.
abstract
The use of rFVIIa allowed to rescue the integrity of intestinal tract
2006
- Sepsis bundles in non intensive care patients
[Abstract in Rivista]
Donno, L; Finelli, M; Rinaldi, L; Marchegiano, P; Cappi, C; Codeluppi, M; Busani, S; Girardis, Massimo
abstract
x
2006
- Thymoglobulin-induced severe cardiovascular reaction and acute renal failure in a patient scheduled for orthotopic liver transplantation
[Articolo su rivista]
Busani, S.; Rinaldi, L.; Begliomini, Bruno; Pasetto, Alberto; Girardis, Massimo
abstract
Antithymocyte globulin (ATG) has been shown to be effective as a pretreatment immunosuppressive agent in liver transplantation because of the ability to wean tacrolimus monotherapy after 4 months in pretreated recipients. However, the use of ATG can be complicated by serious side effects. Reported side effects include severe cardiopulmonary reactions, adult respiratory distress syndrome and hematological disorders. We report a case of a patient with a medical history of cirrhosis scheduled for orthotopic liver transplantation that, during the operation, showed swelling, hyperthermia, tachycardia and hypotension after the administration of ATG. Acute renal failure (ARF) was another serious side effect that our patient developed during ICU star, we ascribed the occurrence of ARF to the serum sickness disease triggered by the ATG administration. only one case has been reported of ARF after ATG-therapy before our experience. Therefore, severe hyperthermia and signs of cardiovascular dysfunction early after the beginning of ATG administration should be carefully evaluated and may need to consider the immediate ATG therapy withdrawal to prevent ARF.
2005
- Muscle PO2 during rhAPC administration in septic shock: a preliminary report
[Abstract in Rivista]
Rinaldi, L.; Busani, S.; Girardis, Massimo
abstract
x
2005
- Severe bleeding in critical care
[Relazione in Atti di Convegno]
Girardis, Massimo; Busani, S.; Marietta, M.
abstract
x
2005
- Use of recombinant factor VIIa in thrombocytopenic patient with spontaneous intracerebral haemorrhage.
[Articolo su rivista]
Busani, S.; Marietta, M.; Pasetto, A.; Girardis, Massimo
abstract
In this report, we describe the use of rFVIIa in a thrombocytopenicpatient with ICH undergoing emergency craniotomy forhematoma evacuation.
2004
- Biochemical markers of sepsis
[Relazione in Atti di Convegno]
Liva, S.; Busani, S.; Rinaldi, L.; Girardis, Massimo
abstract
x
2004
- Intraoperative and post-operative management of living donor liver transplanted patients
[Relazione in Atti di Convegno]
Pasetto, Alberto; Busani, S.; Donno, L.; Fanigliulo, Ma; De Pietri, L.; Siniscalchi, A.; Begliomini, Bruno; Girardis, Massimo
abstract
x
2004
- Non invasive monitoring of dead space and pulmonary capillary blood flow to optimise mechanical ventilation
[Relazione in Atti di Convegno]
Girardis, Massimo; Busani, S.; Rinaldi, L.
abstract
x
2004
- Renal complications after liver transplantation: orthotopic versus living related
[Abstract in Atti di Convegno]
Bondi, F.; Busani, S.; Serio, L.; Girardis, Massimo; Pasetto, Alberto
abstract
x
2004
- Thymoglobulin-induced severe cardiovascular reaction and acute renal failure in a patient scheduled for orthotopic liver transplantation
[Abstract in Atti di Convegno]
Busani, S.; Rinaldi, L.; Serio, L.; Bondi, F.; Begliomini, Bruno; Pasetto, Alberto; Girardis, Massimo
abstract
x
2004
- Use of a new hemostatic drug in the management of severe bleeding in surgical patients
[Relazione in Atti di Convegno]
Girardis, Massimo; Marietta, M.; Busani, S.; Pasetto, Alberto
abstract
x
2004
- Utilizzo di emostatici: approccio corrente e nuove prospettive
[Relazione in Atti di Convegno]
Marietta, M.; Busani, S.; Girardis, Massimo
abstract
x
2004
- rVIIa nelle emorragie incontrollabili: protocolli clinici e sorveglianza uso clinico
[Relazione in Atti di Convegno]
Girardis, Massimo; Busani, S.; Marietta, M.
abstract
x
2003
- Muscle perfusion and oxygen consumption by near-infrared spectroscopy in septic-shock and non-septic-shock patients
[Articolo su rivista]
Girardis, Massimo; Rinaldi, L.; Busani, S.; Flore, I.; Mauro, S.; Pasetto, Alberto
abstract
Objective. To measure muscle blood flow (Qtis) and oxygen consumption (VO(2)tis) in septic and non-septic critically ill patients by near-infrared spectroscopy (NIRS). Setting. Surgical intensive care unit of a university hospital. Patients and participants. Four patients with septic shock, eight post-surgical critically ill patients and ten healthy volunteers. Measurements and results. Oxyhaemoglobin (HbO(2)) and deoxyhaemoglobin (HbH) variations after venous occlusion were measured by NIRS in the brachioradialis muscle. We calculated Qtis by the rate of HbO(2) and HbH increase in the first 30 s of venous occlusion divided by haemoglobin blood concentration. VO(2)tis was calculated by subtraction of the arterial HbH from the initial increase of HbH after venous occlusion extrapolated to 1 min. Tissue oxygenation index [TOI = HbO(2)/(HbO(2)+HbH)] was also measured before venous occlusion. Two measurements in patients with septic shock, and one measurement in non-septic-shock patients and healthy subjects, were obtained. Of the measurements, 35% were repeated because of low-quality NIRS signal. VO(2)tis and Qtis were two times larger (P<0.05) in patients with septic shock than in patients without and in healthy subjects. The TOI was very similar among the three groups. Conclusion. In septic-shock patients the increase in VO(2)tis was associated with an equivalent increase in Qtis. Therefore, tissue O-2 supply does not seem to be a limiting factor for muscle O-2 consumption. NIRS combined with venous occlusion allows a rapid, non-invasive and simultaneous assessment of regional perfusion and oxygen consumption. In case of microcirculatory shunt occurrence, the TOI should be cautiously used to assess tissue oxygenation state.
2003
- Post-transplant cerebral haemorrhage in patient with TTR-FAP
[Abstract in Atti di Convegno]
Rinaldi, L.; Busani, S.; Girardis, Massimo; Serio, L.; Pasetto, A.
abstract
x
2003
- Splanchnic vasoconstrictors and vasodilators in a case of left lobe liver transplantation.
[Abstract in Atti di Convegno]
Busani, S.; Girardis, Massimo; Donno, L.; Rinaldi, L.; Serio, L.; Miller, C.; Pinna, Ad
abstract
x
2003
- Tissue oxygenation by near infrared spectroscopy
[Relazione in Atti di Convegno]
Girardis, Massimo; Rinaldi, L.; Busani, S.
abstract
x
2002
- Flusso capillare polmonare e spazio morto alveolare con metodiche combinate di capnografia volumetrica e CO2 partial rebreathing
[Relazione in Atti di Convegno]
Girardis, Massimo; Busani, S.; Rinaldi, L.; Pasetto, A.
abstract
x
2002
- Hemodynamic effects of different surgical techniques in orthotopic liver transplantation.
[Abstract in Atti di Convegno]
Busani, S.; Roberti, A.; Rinaldi, L.; Siniscalchi, A.; Girardis, Massimo; Pasetto, A.
abstract
x
2002
- Perioperative hemodynamic profile in patients with early allograft dysfunction after liver transplantation
[Relazione in Atti di Convegno]
Roberti, ; Busani, S.; Rinaldi, L.; Baraoni, S.; Girardis, Massimo; Pasetto, A.
abstract
x
2002
- Post-operative respiratory dysfunction after liver transplantation
[Relazione in Atti di Convegno]
Crimi, E.; Donato, P.; Rinaldi, L.; Busani, S.; Girardis, Massimo
abstract
x
2001
- Evaluation of tissue blood flow and oxygenation by near infrared spectroscopy in septic patient
[Abstract in Rivista]
Girardis, Massimo; Rinaldi, L.; Busani, S.; Flore, I.; Mauro, S.; Pasetto, Alberto
abstract
x
2001
- Relationship between oxygen uptake and cardiac output during vascular surgery
[Abstract in Rivista]
Roberti, ; Busani, S.; Rinaldi, L.; Girardis, Massimo; Pasetto, Alberto
abstract
x
2001
- Tissue perfusion and oxygenation in septic patients
[Abstract in Atti di Convegno]
Rinaldi, L.; Busani, S.; Flore, I.; Spampinato, A.; Raffaelli, M.; Girardis, Massimo
abstract
x