Epidemiology of SARS-CoV-2 infection in Italy using real-world data: methodology and cohort description of the second phase of web-based EPICOVID19 study. (preprint)

Digital technologies have been extensively employed in response to the SARS-CoV-2 pandemic worldwide. This study describes the methodology of the two-phase internet-based EPICOVID19 survey, and the characteristics of the adult volunteers respondents who lived in Italy during the first (April - May 2020) and the second wave (January - February 2021) of the epidemic. Validated scales and ad-hoc questionnaires were used to collect socio-demographic, medical and behavioural characteristics, as well as information on COVID-19. Among those who provided email addresses during phase I (105,355), 41,473 participated in phase II (mean age 50.7 years +/- 13.5 SD, 60.6% females). After a median follow-up of ten months, 52.8% had undergone naso-pharyngeal swab (NPS) testing and 13.2% had positive result. More than 40% had undergone serological test (ST) and 11.9% were positive. Out of the 2,073 participants with at least one positive ST, 72.8% had only negative results from NPS or never performed it. These results indicate that a large fraction of individuals remained undiagnosed, possibly contributing to the spread of the virus in the community. Participatory online surveys offer a unique opportunity to collect relevant data at individual level from large samples during confinement.

High Mortality Rate Among Latin American Immigrants With Covid-19 Hospitalised in Milan, Italy: Data From the Luigi Sacco Hospital Registry (preprint)

Background: To assess differences in the probability of COVID-19-related death between native Italians and immigrants hospitalised with COVID-19. Methods This was a retrospective study of prospectively collected data conducted at the ASST Fatebenefratelli-Sacco Hospital in Milan, Italy, between 21 February and 31 November 2020. Uni- and multivariable Cox proportional hazard models were used to assess the impact of the patients' origin on the probability of COVID-19-related death. Results The study population consisted of 1,179 COVID-19 patients: 921 Italians (78.1%) and 258 immigrants (21.9%) from Latin America (99, 38.4%), Asia (72, 27.9%), Africa (50, 19.4%) and central/eastern Europe (37, 14.3%). The Italians were older (p 

Missed opportunities of flu vaccination in Italian target categories: insights from the online EPICOVID 19 survey (preprint)

We aimed to assess the reported rate of flu vaccination in the season 2019/2020 in respondents to the Italian nationwide online EPICOVID 19 survey. A national convenience sample of volunteers aged 18 or older was assessed between 13th April and 2nd June 2020. Flu vaccine rates were calculated for all classes of age. The association between the independent variables and the flu vaccine was assessed by applying a multivariable binary logistic regression model. Of the 198,822 respondents 41,818 (21.0%) reported to have received a flu vaccination shot during the last influenza season. In particular, 15,009 (53.4%) subjects aged 65 years or older received a flu vaccination shot. Being 65 years aged or older (aOR 3.06, 95%CI 2.92-3.20) and having a high education level (aOR 1.34. 95%CI 1.28-1.41) were independently associated to flu vaccination. Heart and lung diseases were the morbidities associated with the higher odds of being vaccinated [aOR 1.97 (95%CI 1.86-2.09) and aOR 1.92 (95%CI 1.84-2.01), respectively]. Nursing home residents aged [≥] 65 years showed a lower odds of being vaccinated [aOR 0.39 (95%CI 0.28-0.54)]. Our data claims for an urgent public heath effort to fill the gap of missed vaccination opportunities reported in the past flu seasons.

Occurrence of Pneumothorax and Pneumomediastinum in Covid-19 patients during non-invasive ventilation with Continuous Positive Airway Pressure (preprint)

Background: Acute Hypoxemic Respiratory Failure (AHRF) is a common complication of Covid-19 related pneumonia, for which non-invasive ventilation (NIV) with Helmet Continuous Positive Airway Pressure (CPAP) is widely used. During past epidemics of SARS and MERS pneumomediastinum (PNM) and pneumothorax (PNX) were common complications (respectively 1.7-12% and 16,4%) either spontaneous or associated to ventilation. Methods: Aim of our retrospective study was to investigate the incidence of PNX/PNM in COVID-19 pneumonia patients treated with CPAP. Moreover, we examined the correlation between PNX/PNM and Positive end-expiratory pressure (PEEP) values. We collected data from patients admitted to Luigi Sacco University Hospital of Milan from 21/02/2020 to 06/05/2020 with COVID-19 pneumonia requiring CPAP. Results: One-hundred-fifty-four patients were enrolled. During hospitalization 3 PNX and 2 PNM occurred (3.2%). Out of these five patients 2 needed invasive ventilation after PNX, two died. In the overall population, 42 patients (27%) were treated with High-PEEP (>10 cmH2O), and 112 with Low-PEEP ([≤]10 cmH2O). All the PNX/PNM occurred in the High-PEEP group (5/37 vs 0/112, p<0,001). Conclusion: The incidence of PNX appears to be lower in COVID-19 than SARS and MERS, but their occurrence is accompanied by high mortality and worsening of clinical conditions. Considering the association of PNX/PNM with high PEEP we suggest using the lower PEEP as possible to prevent these complications.

EPICOVID19: Psychometric assessment and validation of a short diagnostic scale for a rapid Covid-19 screening based on reported symptoms (preprint)

BackgroundConfirmed COVID-19 cases have been registered in more than two hundred countries and regions and of July 28 over 16 million cases of COVID-19, including 650805 deaths, have been reported to WHO. The number of cases changes quickly and varies depending upon which source you use to track, so in the current epidemiological context, the early recognition is critical for the rapid identification of suspected cases (with SARS-CoV-2 infection-like symptoms and signs) to be immediately subjected to quarantine measures. Although surveys are widely used for identifying COVID-19 cases, outcomes and associated risks, no validated epidemiological tool exists for surveying SARS-CoV-2 infection in the population so far. MethodsOur study is the phase II of the EPICOVID19 Italian national survey, launched in April 2020 including a national convenience sample of 201121 adults, who voluntarily filled the EPICOVID19 questionnaire. The phase II questionnaire was mailed to all subjects who underwent tests for COVID-19 by nasopharyngeal swab (NPS) and who accepted to be involved in the second phase of the study, focused on the results reported for NPS and/or serological IgG/IgM tests. We evaluated the capability of the self-reported symptoms collected through the EPICOVID19 questionnaire to discriminate the COVID-19 among symptomatic subjects, in order to identify possible cases to undergo instrumental measurements and clinical examinations. We defined a method for the identification of a total score and validated it with reference to the serological and molecular clinical diagnosis, using four standard steps: identification of critical factors, confirmation of presence of latent variable, development of optimal scoring algorithm and validation of the scoring algorithm. Findings2703 subjects [66% response rate] completed the Phase II questionnaire. Of 2703 individuals, 694 (25.7%) were NPS(+) and of these 84 (12.1% of the 694 NPS(+)) were asymptomatic. In the individuals who performed serological testing, of the 472 who did IgG(+) and 421 who did IgM(+), 22.9% and 11.6% tested positive, respectively. Among IgG(+) 1 of 108 subjects was asymptomatic (0.9%) while 5/49 subjects among IgM(+) were asymptomatic (10.2%). Compared with NPS(-), among NPS(+) subjects there was a higher rate for Fever (421 [60.7%] vs 391[19.5%]; p<0.0001), Loss of Taste and/or Smell (365 [52.6%] vs 239 [11.9%]; p<0.0001) and Cough (352 [50.7%] vs 580 [28.9%]; p<0.0001). Also for other symptoms the frequencies were significantly higher in NPS(+) subjects than in NPS(-) ones (p<0.001). Among groups with serological tests, the symptoms with higher percentages in the subjects IgG(+) were Fever (65 [60.2%] vs 43[11.8%]; p<0.0001) and Pain in muscles, bones, joints (73 [67.6%] vs 71 [19.5%]; p<0.0001). For the COVID-19 self-reported symptoms items, exploratory (proportion variance explained [89.9%]) and confirmatory factor analysis results (SMSR 0.072; RMSEA 0.052) highlights the presence of one latent variable (factor) underlying the symptoms. We define the one-factor solution as EPICOVID19 diagnostic scale and optimal score for each items was identified: Respiratory problems (1.03), Chest pain (1.07), Loss of Taste and/or Smell (0.97) and Tachycardia (palpitations) (1.05) were the most important symptoms. The cut-off score was 2.56 (Sensitivity 76.56%; Specificity 68.24%) in NPS(+) and 2.59 (Se 80.37; Sp 80.17) in IgG(+) subjects. InterpretationWe developed a short diagnostic scale to detect subjects with symptoms potentially associated with COVID-19 among a wide population. Early recognition screening and rapid diagnosis are essential to prevent transmission and provide supportive care in a timely manner and our score supports the potential for identifying individuals who need to seek immediate clinical evaluation. Although these results are referred to the Italian pandemic period, this short diagnostic scale could be optimised and tested as a screening tool in other similar pandemic contexts.

Seroprevalence of SARS-CoV-2 IgG significantly varies with age: results from a mass population screening (SARS-2-SCREEN-CdA). (preprint)

ObjectivesCastiglione DAdda is one of the municipalities more precociously and severely affected by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) epidemic in Lombardy. With our study we aimed to understand the diffusion of the infection by mass seroprevalence screening. MethodsWe searched for SARS-CoV-2 IgGs in the entire voluntary population using lateral flow immune-cromatographic tests on capillary blood (rapid tests). We then performed chemioluminescent serological assays (CLIA) and naso-pharyngeal swabs in a randomized representative sample of 562 subjects and in every subject with a positive rapid test. ResultsBased on CLIA serologies on the representative random sample (509 subjects), we estimated a 23% IgG seroprevalence. We also found a strong correlation between age and prevalence, with the elderly showing the highest probability of a positive serological test. ConclusionsIn an area of unrestricted viral circulation less than one-fourth of the population tested positive for SARS-CoV-2 IgG. Seroprevalence increased with increasing age, possibly suggesting differences in susceptibility to the infection.

Early administration of lopinavir/ritonavir plus hydroxychloroquine does not alter the clinical course of SARS-CoV-2 infection: a retrospective cohort study. (preprint)

Background The potential benefit of a combination therapy with lopinavir/ritonavir (LPV/r) and hydroxychloroquine (HCQ) on COVID-19 has been speculated. We explored the effect of the timing of LPV/r + HCQ initiation on the outcome of patients with COVID-19. Methods A retrospective cohort study was conducted on patients with COVID-19 who started treatment with LPV/r plus HCQ between February 21 and March 20, 2020, at Luigi Sacco Hospital in Milan, Italy. Over time cumulative incidence of clinical improvement was compared between patients who started treatment less than 5 days from the onset of symptoms [early treatment group (ET)] and those who initiated it later [delayed treatment group (DT)]. The association of LPV/r plus HCQ initiation timing on 30-day mortality was also assessed by univariate and multivariate logistic models. Results The study included 172 patients, prevalently males (72%) in their sixties, with a moderate (53.4%) or severe (34.9%) disease. Fourty-three (25%) patients were included in the ET group and and 129 (75%) in the DT group. Severity of disease did not significantly differ between the two groups. Conclusion Timing of LPV/r + HCQ initiation seems to have no impact on COVID-19 clinical course in terms of improvement and 30-day mortality. These findings rise doubts on the clincial efficacy of this regimen.

Dynamics of the SARS-CoV-2 epidemic in the earliest-affected areas in Italy: 1 Mass screening for SARS-CoV-2 serological positivity (SARS-2-SCREEN). (preprint)

Background Several municipalities in the Lombardy Region have been affected by the SARS-CoV-2 infection since the earliest stages of the epidemic. To date, 89442 confirmed cases have been diagnosed in Lombardy, and mortality in several municipalities has already surpassed that of the past decade. Currently, the true extent of the SARS-CoV-2 infection remains unknown as several affected subjects may have been asymptomatic or have presented mild disease, thus not resulting in the identified COVID-19 cases. Methods This cross-sectional study aims to define the spread of infection within the population by determining the seroprevalence of IgG antibodies directed against SARS-CoV-2 by rapid immunochromatographic testing and subsequent confirmation by serology on venous blood by liquid phase immunochemical testing, also allowing to compare the two methods. Testing will be performed on adults and minors residing, domiciled or working in several municipalities of the Lombardy Region, involved in the initial stages of the epidemic. The study will include rapid finger-prick testing and venous sampling for antibodies against SARS-CoV-2, and nasopharyngeal swabbing (NPS). Concurrent notification of test results will occur via the regional healthcare information system (SISS). Discussion This study was developed with the desire to understand the seroprevalence of SARS-CoV-2 infection and the epidemiological transmission characteristics of this virus. Understanding the spread and severity of the disease could help in the implementation of effective infection surveillance containment and countermeasures facilitating the identification of cases that have been exposed to the virus and the traceability of contacts. This study has been approved by the Ethics Committee of the University of Milan (35/2020).

30-day mortality in patients hospitalized with COVID-19 during the first wave of the Italian epidemic: a prospective cohort study (preprint)

Background: Italy was the first European country hit by the COVID-19 pandemic and has the highest number of recorded COVID-19 deaths in Europe. Methods: This prospective cohort study of the correlates of the risk of death in COVID-19 patients was conducted at the Infectious Diseases and Intensive Care units of Luigi Sacco Hospital, Milan, Italy. The clinical characteristics of all the COVID-19 patients hospitalised in the early days of the epidemic (21 February -19 March 2020) were recorded upon admission, and the time-dependent probability of death was evaluated using the Kaplan-Meier method (censored as of 20 April 2020). Cox proportional hazard models were used to assess the factors independently associated with the risk of death. Results: Forty-eight (20.6%) of the 233 patients followed up for a median of 40 days (interquartile range 33-47) died during the follow-up. Most were males (69.1%) and their median age was 61 years (IQR 50-72). The time-dependent probability of death was 19.7% (95% CI 14.6-24.9%) 30 days after hospital admission. Age (adjusted hazard ratio [aHR] 2.08, 95% CI 1.48-2.92 per ten years more) and obesity (aHR 3.04, 95% CI 1.42-6.49) were independently associated with an increased risk of death, which was also associated with critical disease (aHR 8.26, 95% CI 1.41-48.29), C-reactive protein levels (aHR 1.17, 95% CI 1.02-1.35 per 50 mg/L more) and creatinine kinase levels above 185 U/L (aHR 2.58, 95% CI 1.37-4.87) upon admission. Conclusions: Case-fatality rate of patients hospitalized with COVID-19 in the early days of the Italian epidemic was about 20%. Our study adds evidence to the notion that older age, obesity and more advanced illness are factors associated to an increased risk of death among patients hospitalized with COVID-19.