2Survival curves according to hydroxychloroquine use. The curves are adjusted by propensity score analysis (inverse probability for treatment weighting) and hospital index as random effect, and are generated using the first imputed dataset. The other imputed datasets are similar and thus omitted.
Subgroup analyses are presented in Table 3. HCQ use remained consistently associated with reduced mortality in almost all subgroups. The inverse association of HCQ with inpatient mortality is slightly more evident in women, elderly and in patients who experienced a higher degree of COVID-19 severity. It was absent in-patient with C-reactive protein <10 mg/L and clearly confined to patients with elevated C-reactive protein (Table 3).Table 3Hazard ratios for mortality according to hydroxychloroquine use in different subgroups.
Abbreviations: HR, hazard ratios; CI, confidence intervals; *Propensity score analysis, inverse probability weighting, including hospital clustering as random effect covariate; multiple imputed analysis.
^Lopinavir/ritonavir or darunavir/cobicistat or tocilizumab or sarilumab or remdesivir or corticosteroids.
**Missing data for N=178. Frequencies and hazard ratios are based on a case complete analysis (N=3,273) without missing data for C-reactive Protein; multiple imputed analysis (N=3,451) yielded very similar results.
4. Discussion
In a large cohort of 3,451 patients hospitalized for COVID-19 in 33 clinical centers all over Italy, covering almost completely the period of the hospitalization for COVID-19, the use of HCQ was associated with a significant better survival. In-hospital crude death rate was 8.9 per 1,000 person-day for patients receiving HCQ and 15.7 for those who did not. After adjustment for known possible confounders, we observed a 30% reduction in the risk of death in patients receiving HCQ therapy as compared with those who did not.
Our findings provide clinical evidence in support of guidelines by Italian and several international Societies suggesting to use HCQ therapy in patients with COVID-19. However, the observed associations should be considered with caution, as the observational design of our study does not allow to fully excluding the possibility of residual confounders. Large randomized clinical trials in well-defined geographical and socio-economic conditions and in well-characterized COVID-19 patients, should evaluate the role of HCQ before any firm conclusion can be reached regarding a potential benefit of this drug in patients with COVID-19.
Over 76% of patients received HCQ either alone or in combination with other drugs. They were more likely to be younger, men and with higher levels of C reactive protein at entry, while less likely had pre-existing comorbidities such as ischemic heart disease, cancer and severe chronic kidney disease, as compared to patients not receiving the drug. We adjusted our analyses for possible confounders, including age, sex, diabetes, hypertension, history of ischemic heart disease, chronic pulmonary disease, chronic kidney disease, C-reactive protein and additional treatments for COVID-19, and took into account possible differences across centres by either adjustment or stratification. To minimize bias due to the observational design, we used different analytical approaches aiming at creating an overall balance between comparison groups. Finally, we tried to limit bias due to missing data by using a multiple imputation approach, but in no case, the result was changed. Despite all these precautions, we recognize the possibility, however, of residual unmeasured confounders affecting results.
Systematic reviews of small clinical trials had reported contrasting results that were however scarcely reliable because of poor designs [20
, 21
, 22
, 23
, 24
, 25
]. The HCQ doses tested in a Chinese randomized clinical trial [25
] were approximately double as compared to that used in our study (1200 mg vs 800 mg as loading dose, 800 mg vs 400 mg as maintenance dose) for twice the time (14-21 days versus 7-10 days). National guidelines in Italy suggest to use HCQ 200 mg twice daily for at least 5-7 days in patients over 70 years and/or with co-morbidities (chronic obstructive pulmonary disease, diabetes, cardiovascular disease) even with mild respiratory symptoms or with radiographically documented pneumonia or in severe patients [36
]. The lower doses of HCQ used in our centers, as suggested by Italian official guidelines [19
,36
], may have been both more effective and safer.
Two recently published large observational studies, both from large hospitals in New York City, showed no association between HCQ use and in-hospital mortality [27
,28
], and deserve specific discussion. In the study of Geleris et al. [27
], the percentage use of HCQ was lower than in Italy; moreover, in both US studies [27
,28
] the drug was more frequently administered to patients with previous illnesses and a more severe presentation of the disease. Our cohort included milder pneumonia patients than the US population, due to between-country differences in indications to the drug for the beginning of therapy (e.g., mild pneumonia in Italy versus only severe pneumonia and ARDS in the US). Concomitant use of other drugs for COVID-19 was very low in one study [27
] and was not reported in the other study [28
]. In our cohort, patients receiving HCQ were more likely treated with another drug for COVID-19 treatment (78.4%), in comparison with non-HCQ patients (46.3%). Anyway, our findings are adjusted for concomitant other drugs use.
While the US studies were confined to one hospital only or a defined relatively small area in the Country, our study included 33 hospitals distributed all over Italy, covering regions with a high number of cases and a high intra-hospital mortality and regions with a lower burden of the disease. The participating Italian clinical centers have different healthcare facilities, different size, specialization, and ownership, and therefore quite closely represent the real-life Italian approach to COVID-19. Moreover, they differed for the percentage of use of HCQ and for the rate of in-hospital mortality that ranged between 34.1 and 1.5 per 1,000 persons/day. To consider this variability, we adjusted the analysis for recruiting center and performed a number of subgroup analyses. In all circumstances, the association between HCQ use and a reduced risk of death of about 30% was maintained. Quite interestingly, the inverse association of HCQ with inpatient mortality was more evident in elderly, in patients who experienced a higher degree of COVID-19 severity or especially having elevated C-reactive protein, suggesting that the anti-inflammatory potential of HCQ may have had more important role rather than its antiviral properties. HCQ, indeed, beside an antiviral activity, may have both anti-inflammatory and anti-thrombotic effects [8
]. This can justify its effect in reducing mortality risk, since Sars-Cov-2 can induce pulmonary microthrombi and coagulopathy, that are a possible cause of its severity [37
,38
] and the lack in preventing SARS-CoV-2 infection after exposure [26
]
Nevertheless, large randomized clinical trials on the efficacy of HCQ on hard end-points are still lacking and the largest observational study showing no effect in reducing mortality has been retracted [16
,17
], Agencies have suspended clinical trials on the efficacy of HCQ on COVID-19 disease or have restricted its use only to patients included in clinical trials, in the absence of an ample, serene and balanced discussion at international level.
Very recently, a large RCT has become available as a pre-print publication [39
], reporting no beneficial effect of HCQ in patients hospitalized with COVID-19. However, the dose of HCQ used in that trial was almost the double of that administered in our real life conditions. A reduced mortality was also observed by other observational studies using low or intermediate doses of HCQ [40
,41
].
Moreover, in our study patients taking HCQ more frequently received other anti-COVID drugs, whose interaction in reducing mortality cannot be completely ruled-out. Of note, despite the higher dosage used, the RCT did not show any excess in ventricular tachycardia or ventricular fibrillation in the HCQ arm (39).
Therefore, it will be very important to compare results of studies with different mode of use and doses of HCQ, different characteristics of treated and untreated patients and different academic or real-world conditions.
4.1 Strengths and limitations
A major strength of this study is the large, unselected patient sample from 33 hospitals, covering the entire Italian territory. Patient sampling covered all the overt epidemic period in Italy. Several statistical approaches were used to overcome biases due to the observational nature of the investigation.
This study has however, several recognized limitations. The study population pertains to Italy, and the results obtained may not be applicable to other populations with a possibly different geographical and socio-economic conditions and natural history of COVID-19. Due to the retrospective nature of the study, some parameters were not available in all patients, and all in-hospital medications might have been not fully recorded. Moreover, although guidelines on the use of HCQ in COVID-19 patients had been published in Italy since the first phase of the pandemic, individual centers could have deviated from recommendations and used different doses or treatment schemes. We have no information on the HCQ doses used individually nor of their possible association with azithromycin. Moreover, adverse events possibly related to drug therapy were not collected, thus we cannot exclude bias due to therapy interruption because of side effects; we do not know whether some deaths could have been due to cardiovascular complications of HCQ. However, recent data on Italian wards showed that COVID-19 patients receiving HCQ and azithromycin had a QTc-interval longer than before therapy, but did not experience, during their hospital stay, any arrhythmic complications, such as syncope or life-threatening ventricular arrhythmias [42
], a finding also reported by the RCT mentioned above (39).
Finally, the possibility of unmeasured residual confounding cannot be completely ruled-out. However, the E-value for the lower boundary of the confidence interval of our main result is 1.67, indicating that the confidence interval could be moved to include the null by a strong unmeasured confounder associated with both HCQ treatment and death with a risk ratio of 1.67-fold for each, above and beyond all the measured confounders. Weaker confounders, however, could not do so.
5. Conclusions
Our study, including a large real life sample of patients hospitalized with COVID-19 all over Italy, shows that HCQ use (200 mg twice/day) was associated with a 30% reduction of overall in-hospital mortality. In the absence of clear-cut results from controlled, randomized clinical trials, our data do not discourage the use of HCQ in inpatients with COVID-19. Given the observational design of our study, however, these results should be transferred with caution to clinical practice.
Source of funding
None.
Declaration of Competing Interests
None.
CRediT authorship contribution statement
Augusto Di Castelnuovo: Conceptualization, Data curation, Investigation, Supervision, Writing - review & editing, Writing - original draft. Simona Costanzo: Investigation, Supervision, Writing - review & editing. Andrea Antinori: Investigation, Supervision, Writing - review & editing. Nausicaa Berselli: Investigation, Supervision, Writing - review & editing. Lorenzo Blandi: Investigation, Supervision, Writing - review & editing. Raffaele Bruno: Investigation, Supervision, Writing - review & editing. Roberto Cauda: Investigation, Supervision, Writing - review & editing. Giovanni Guaraldi: Investigation, Supervision, Writing - review & editing. Lorenzo Menicanti: Investigation, Supervision, Writing - review & editing. Ilaria My: Investigation, Supervision, Writing - review & editing. Giustino Parruti: Investigation, Supervision, Writing - review & editing. Giuseppe Patti: Investigation, Supervision, Writing - review & editing. Stefano Perlini: Investigation, Supervision, Writing - review & editing. Francesca Santilli: Investigation, Supervision, Writing - review & editing. Carlo Signorelli: Investigation, Supervision, Writing - review & editing. Enrico Spinoni: Investigation, Supervision, Writing - review & editing. Giulio G. Stefanini: Investigation, Supervision, Writing - review & editing, Formal analysis. Alessandra Vergori: Investigation, Supervision, Writing - review & editing. Walter Ageno: Investigation, Supervision, Writing - review & editing. Antonella Agodi: Investigation, Supervision, Writing - review & editing. Luca Aiello: Investigation, Supervision, Writing - review & editing. Piergiuseppe Agostoni: Investigation, Supervision, Writing - review & editing. Samir Al Moghazi: Investigation, Supervision, Writing - review & editing. Marinella Astuto: Investigation, Supervision, Writing - review & editing. Filippo Aucella: Investigation, Supervision, Writing - review & editing. Greta Barbieri: Investigation, Supervision, Writing - review & editing. Alessandro Bartoloni: Investigation, Supervision, Writing - review & editing. Marialaura Bonaccio: Investigation, Supervision, Writing - review & editing. Paolo Bonfanti: Investigation, Supervision, Writing - review & editing. Francesco Cacciatore: Investigation, Supervision, Writing - review & editing. Lucia Caiano: Investigation, Supervision, Writing - review & editing. Francesco Cannata: Investigation, Supervision, Writing - review & editing. Laura Carrozzi: Investigation, Supervision, Writing - review & editing. Antonio Cascio: Investigation, Supervision, Writing - review & editing. Arturo Ciccullo: Investigation, Supervision, Writing - review & editing. Antonella Cingolani: Investigation, Supervision, Writing - review & editing. Francesco Cipollone: Investigation, Supervision, Writing - review & editing. Claudia Colomba: Investigation, Supervision, Writing - review & editing. Francesca Crosta: Investigation, Supervision, Writing - review & editing. Chiara Dal Pra: Investigation, Supervision, Writing - review & editing. Gian Battista Danzi: Investigation, Supervision, Writing - review & editing. Damiano D’Ardes: Investigation, Supervision, Writing - review & editing. Katleen de Gaetano Donati: Investigation, Supervision, Writing - review & editing, Writing - original draft. Paola Del Giacomo: Investigation, Supervision, Writing - review & editing. Francesco Di Gennaro: Investigation, Supervision, Writing - review & editing. Giuseppe Di Tano: Investigation, Supervision, Writing - review & editing. Giampiero D’Offizi: Investigation, Supervision, Writing - review & editing. Tommaso Filippini: Investigation, Supervision, Writing - review & editing. Francesco Maria Fusco: Investigation, Supervision, Writing - review & editing. Ivan Gentile: Investigation, Supervision, Writing - review & editing. Alessandro Gialluisi: Investigation, Supervision, Writing - review & editing. Giancarlo Gini: Investigation, Supervision, Writing - review & editing. Elvira Grandone: Investigation, Supervision, Writing - review & editing. Leonardo Grisafi: Investigation, Supervision, Writing - review & editing. Gabriella Guarnieri: Investigation, Supervision, Writing - review & editing. Silvia Lamonica: Investigation, Supervision, Writing - review & editing. Francesco Landi: Investigation, Supervision, Writing - review & editing. Armando Leone: Investigation, Supervision, Writing - review & editing. Gloria Maccagni: Investigation, Supervision, Writing - review & editing. Sandro Maccarella: Investigation, Supervision, Writing - review & editing. Andrea Madaro: Investigation, Supervision, Writing - review & editing. Massimo Mapelli: Investigation, Supervision, Writing - review & editing. Riccardo Maragna: Investigation, Supervision, Writing - review & editing. Lorenzo Marra: Investigation, Supervision, Writing - review & editing. Giulio Maresca: Investigation, Supervision, Writing - review & editing. Claudia Marotta: Investigation, Supervision, Writing - review & editing. Franco Mastroianni: Investigation, Supervision, Writing - review & editing, Methodology. Maria Mazzitelli: Investigation, Supervision, Writing - review & editing. Alessandro Mengozzi: Investigation, Supervision, Writing - review & editing. Francesco Menichetti: Investigation, Supervision, Writing - review & editing. Marianna Meschiari: Investigation, Supervision, Writing - review & editing. Filippo Minutolo: Investigation, Supervision, Writing - review & editing. Arturo Montineri: Investigation, Supervision, Writing - review & editing. Roberta Mussinelli: Investigation, Supervision, Writing - review & editing. Cristina Mussini: Investigation, Supervision, Writing - review & editing. Maria Musso: Investigation, Supervision, Writing - review & editing. Anna Odone: Investigation, Supervision, Writing - review & editing. Marco Olivieri: Investigation, Supervision, Writing - review & editing, Software. Emanuela Pasi: Investigation, Supervision, Writing - review & editing. Francesco Petri: Investigation, Supervision, Writing - review & editing. Biagio Pinchera: Investigation, Supervision, Writing - review & editing. Carlo A. Pivato: Investigation, Supervision, Writing - review & editing. Venerino Poletti: Investigation, Supervision, Writing - review & editing. Claudia Ravaglia: Investigation, Supervision, Writing - review & editing. Massimo Rinaldi: Investigation, Supervision, Writing - review & editing. Andrea Rognoni: Investigation, Supervision, Writing - review & editing. Marco Rossato: Investigation, Supervision, Writing - review & editing. Ilaria Rossi: Investigation, Supervision, Writing - review & editing. Marianna Rossi: Investigation, Supervision, Writing - review & editing. Anna Sabena: Investigation, Supervision, Writing - review & editing. Francesco Salinaro: Investigation, Supervision, Writing - review & editing. Vincenzo Sangiovanni: Investigation, Supervision, Writing - review & editing. Carlo Sanrocco: Investigation, Supervision, Writing - review & editing. Laura Scorzolini: Investigation, Supervision, Writing - review & editing. Raffaella Sgariglia: Investigation, Supervision, Writing - review & editing. Paola Giustina Simeone: Investigation, Supervision, Writing - review & editing. Michele Spinicci: Investigation, Supervision, Writing - review & editing. Enrico Maria Trecarichi: Investigation, Supervision, Writing - review & editing. Amedeo Venezia: Investigation, Supervision, Writing - review & editing. Giovanni Veronesi: Investigation, Supervision, Writing - review & editing, Formal analysis. Roberto Vettor: Investigation, Supervision, Writing - review & editing. Andrea Vianello: Investigation, Supervision, Writing - review & editing. Marco Vinceti: Investigation, Supervision, Writing - review & editing. Laura Vocciante: Investigation, Supervision, Writing - review & editing. Raffaele De Caterina: Conceptualization, Investigation, Supervision, Writing - review & editing, Writing - original draft. Licia Iacoviello: Conceptualization, Data curation, Investigation, Investigation, Supervision, Writing - review & editing, Writing - original draft.
Acknowledgments
We thank the participating clinical centres included in this cohort. This Article is dedicated to all the patients who suffered or died, often in solitude, due to COVID-19; their tragic fate gave us moral strength to initiate and complete this research.
The Authors alone are responsible for the views expressed in this Article. They do not necessarily represent the views, decisions, or policies of the Institutions with which they are affiliated.
Appendix 1
Augusto Di Castelnuovoa, Simona Costanzob, Andrea Antinoric, Nausicaa Bersellid, Lorenzo Blandie, Raffaele Brunof,g, Roberto Caudah,i, Giovanni Guaraldij, Lorenzo Menicantie, Ilaria Myk, Giustino Parrutil, Giuseppe Pattim, Stefano Perlinin,o, Francesca Santillip, Carlo Signorelliq, Enrico Spinonim, Giulio G. Stefaninik, Alessandra Vergorir, Walter Agenos, Antonella Agodit, Luca Aiellou, Piergiuseppe Agostoniv,w, Samir Al Moghazix, Marinella Astutot, Filippo Aucellay, Greta Barbieriz, Alessandro Bartoloniaa, Marialaura Bonacciob, Paolo Bonfantiab,ac, Francesco Cacciatoread, Lucia Caianos, Francesco Cannatak, Laura Carrozziae, Antonio Cascioaf, Arturo Cicculloh, Antonella Cingolanih,i, Francesco Cipollonep, Claudia Colombaaf, Francesca Crostal, Chiara Dal Praag, Gian Battista Danziah, Damiano D'Ardesp, Katleen de Gaetano Donatih, Paola Del Giacomoh, Francesco Di Gennaroai, Giuseppe Di Tanoah, Giampiero D'Offiziaj, Tommaso Filippinid, Francesco Maria Fuscoak, Ivan Gentileal, Alessandro Gialluisib, Giancarlo Ginis, Elvira Grandoney, Leonardo Grisafim, Gabriella Guarnieriam, Silvia Lamonicah, Francesco Landiu, Armando Leonean, Gloria Maccagniah, Sandro Maccarellaao, Andrea Madaroap, Massimo Mapelliv,w, Riccardo Maragnav,w, Lorenzo Marraan, Giulio Marescaaq, Claudia Marottaai, Franco Mastroianniap, Maria Mazzitelliar, Alessandro Mengozziz, Francesco Menichettiz, Marianna Meschiarij, Filippo Minutoloas, Arturo Montineriat, Roberta Mussinelliq, Cristina Mussinij, Maria Mussoau, Anna Odoneq, Marco Olivieriav, Emanuela Pasiaw, Francesco Petriab, Biagio Pincheraal, Carlo A. Pivatok, Venerino Polettiax, Claudia Ravagliaax, Massimo Rinaldiap, Andrea Rognonim, Marco Rossatoag, Ilaria Rossip, Marianna Rossiab, Anna Sabenan, Francesco Salinaron, Vincenzo Sangiovanniak, Carlo Sanroccol, Laura Scorzoliniay, Raffaella Sgarigliaaq, Paola Giustina Simeonel, Michele Spinicciaa, Enrico Maria Trecarichiar, Amedeo Veneziaap, Giovanni Veronesis, Roberto Vettorag, Andrea Vianelloam, Marco Vincetid,az, Laura Voccianteaq, Raffaele De Caterinaai, Licia Iacoviellob,s
aMediterranea Cardiocentro, Napoli. ItalybDepartment of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli (IS). ItalycUOC Immunodeficienze Virali, National Institute for Infectious Diseases “L. Spallanzani”, IRCCS. Roma. ItalydSection of Public Health, Department of Biomedical, Metabolic and Neural Sciences, University of Modenaand Reggio Emilia, Modena. ItalyeIRCCS Policlinico San Donato, San Donato Milanese. ItalyfDivision of Infectious Diseases I, Fondazione IRCCS Policlinico San Matteo, Pavia. ItalygDepartment of Clinical, Surgical, Diagnostic, and Paediatric Sciences, University of Pavia, Pavia. ItalyhFondazione Policlinico Universitario A. Gemelli IRCCS, Roma. ItalyyiUniversità Cattolica del Sacro Cuore- Dipartimento di Sicurezza e Bioetica Sede di Roma, Roma. ItalyjInfectious Disease Unit, Department of Surgical, Medical, Dental and Morphological Sciences, Universityof Modena and Reggio Emilia, Modena. ItalykHumanitas Clinical and Research Hospital IRCCS, Rozzano-Milano. ItalylDepartment of Infectious Disease, Azienda Sanitaria Locale (AUSL) di Pescara, Pescara. ItalymUniversity of Eastern Piedmont, Maggiore della Carità Hospital, Novara. ItalynEmergency Department, IRCCS Policlinico San Matteo Foundation, Pavia. ItalyoDepartment of Internal Medicine, University of Pavia, Pavia. ItalypDepartment of Medicine and Aging, Clinica Medica, “SS. Annunziata” Hospital and University of Chieti,Chieti. ItalyqSchool of Medicine, Vita-Salute San Raffaele University, Milano. ItalyrHIV/AIDS Department, National Institute for Infectious Diseases “Lazzaro Spallanzani”-IRCCS, Roma.ItalysDepartment of Medicine and Surgery, University of Insubria, Varese. ItalytDepartment of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, University ofCatania; AOU Policlinico-Vittorio Emanuele, Catania. ItalyuUOC. Anestesia e Rianimazione. Dipartimento di Chirurgia Generale Ospedale Morgagni-Pierantoni, Forlì.ItalyvCentro Cardiologico Monzino IRCCS, Milano. ItalywDepartment of Clinical Sciences and Community Health, Cardiovascular Section, University of Milano,Milano. ItalyxInfezioni Sistemiche dell'Immunodepresso, National Institute for Infectious Diseases L. Spallanzani,IRCCS, Roma. ItalyyFondazione I.R.C.C.S “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Foggia. ItalyzDepartment of Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria Pisana, andUniversity of Pisa, Pisa. ItalyaaDepartment of Experimental and Clinical Medicine. University of Florence, Firenze. ItalyabUOC Malattie Infettive, Ospedale San Gerardo, ASST Monza, Monza. ItalyacSchool of Medicine and Surgery, University of Milano-Bicocca, Milano. ItalyadDepartment of Translational Medical Sciences. University of Naples, Federico II, Napoli. ItalyaeCardiovascular and Thoracic Department, Azienda Ospedaliero-Universitaria Pisana, and University ofPisa, Pisa. ItalyafInfectious and Tropical Diseases Unit- Department of Health Promotion, Mother and Child Care, InternalMedicine and Medical Specialties (PROMISE) - University of Palermo, Palermo. ItalyagClinica Medica 3, Department of Medicine - DIMED, University hospital of Padova, Padova. ItalyahDepartment of Cardiology, Ospedale di Cremona, Cremona. ItalyaiMedical Direction, IRCCS Neuromed, Pozzilli (IS). ItalyajUOC Malattie Infettive-Epatologia, National Institute for Infectious Diseases L. Spallanzani, IRCCS,Roma. ItalyakUOC Infezioni Sistemiche e dell'Immunodepresso, Azienda Ospedaliera dei Colli, Ospedale Cotugno.Napoli. ItalyalDepartment of Clinical Medicine and Surgery. University of Naples “Federico II”, Napoli. ItalyamRespiratory Pathophysiology Division, Department of Cardiologic, Thoracic and Vascular Sciences,University of Padova, Padova. ItalyanUOC di Pneumologia, P.O. San Giuseppe Moscati, Taranto. ItalyaoASST Milano Nord - Ospedale Edoardo Bassini, Cinisello Balsamo. ItalyapCOVID-19 Unit. EE Ospedale Regionale F. Miulli, Acquaviva delle Fonti (BA). ItalyaqUOC Medicina - PO S. Maria di Loreto Nuovo -ASL Napoli 1 Centro. NapoliarInfectious and Tropical Diseases Unit. Deparment of Medical and Surgical Sciences“Magna Graecia”University, Catanzaro. ItalyasDipartimento di Farmacia, Università di Pisa, Pisa, Italy.atU.O. C. Malattie Infettive e Tropicali, P.O. “San Marco”, AOU Policlinico-Vittorio Emanuele, Catania.ItalyauUOC Malattie Infettive-Apparato Respiratorio, National Institute for Infectious Diseases“L. Spallanzani”,IRCCS, Roma. ItalyavComputer Service, University of Molise, Campobasso. Italy.awMedicina Interna. Ospedale di Ravenna. AUSL della Romagna, Ravenna. ItalyaxUOC Pneumologia. Dipartimento di Malattie Apparato Respiratorio e Torace. Ospedale Morgagni-Pierantoni Forlì, Forlì. ItalyayUOC Malattie Infettive ad Alta Intensità di Cura, National Institute for Infectious Diseases “L.Spallanzani”, IRCCS, Roma. ItalyazDepartment of Epidemiology, Boston University School of Public Health, Boston. USA.
Appendix. Supplementary materials
Cont,
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