Effect of an enhanced public health contact tracing intervention on the secondary transmission of SARS-CoV-2 in educational settings: the four-way decomposition analysis (preprint)

Background: We assessed the impact of testing contacts immediately instead of at the end of quarantine on the transmission of SARS-CoV-2 in schools in Reggio Emilia Province. Methods: We analysed surveillance data on notification of COVID-19 cases in schools between 1 September 2020 and 4 April 2021. Results: Median tracing delay decreased from 7 to 3.1 days and the percentage of the known infection source increased from 34% to 54.8% (IRR 1.61 1.40-1.86). Implementation of prompt contact tracing was associated with a 10% decrease in the number of secondary cases (excess relative risk, EER -0.1 95%CI -0.35 to 0.15). Knowing the source of infection of the index case led to a decrease in secondary transmission (IRR 0.75 95% CI 0.63-0.91) while the decrease in tracing delay was associated with decreased risk of secondary cases (1/IRR 0.97 95%CI 0.94-1.01 per one day of delay). The direct effect of the intervention accounted for the 29% decrease in the number of secondary cases (EER -0.29 95% -0.61 to 0.03). Conclusions: Prompt contact testing in the community seems to reduce the time of contact tracing and increases the ability to identify the source of infection in school outbreaks. Yet, observed differences can be also due to differences in the force of infection and to other control measures put in place.Funding: This project was carried out with the technical and financial support of the Italian46 Ministry of Health - CCM 2020 and Ricerca Corrente Annual Program 2023

Heat wave, COVID-19, and mortality excess in the 2022 summer: a cohort study on data from Italian surveillances. (preprint)

We aimed to assess differences in the summer excess of mortality by COVID-19 history using data from the mortality and COVID-19 surveillances. We found 4% excess risk in 2022 summer, compared to 2015-2019. A mortality rate ratio of 1.59 (95%CI 1.39-1.82) for COVID-19 survivors compared to naive, was found. Both were higher in people aged >74 years. During the July heat wave, the excess for COVID-19 survivors decreased and disappeared when excluding people living in nursing homes.

The impact of the Covid-19 pandemic on Italian population-based cancer screening activities and test coverage: results from national cross-sectional repeated surveys (preprint)

BackgroundIn Italy, population-based screening programs for breast, cervical and colorectal cancers are mandatory, and Regions are in charge of their delivery. From March to May 2020, a severe lockdown was imposed due to the Covid-19 pandemic by the Italian Ministry of Health, with the suspension of screening programs. This paper describes the impact of the pandemic on Italian screening activities and test coverage in 2020. MethodsThe regional number of subjects invited and of screening tests performed in 2020 were compared with those in 2019. Invitation and examination coverage were also calculated. PASSI surveillance system, through telephone interviews, investigated the population screening test coverage, before and during the pandemic, accordingly to educational attainment, perceived economic difficulties and citizenship. ResultsA reduction of subjects invited and tests performed, with differences among periods and geographic macro areas, was observed in 2020 vs. 2019. The reduction in examination coverage was larger than that in invitation coverage for all screening campaigns. From the second half of 2020, the trend for test coverage showed a decrease in all the macro areas for all the screening campaigns. Compared with the pre-pandemic period, there was a greater difference according to level of education in the odds of having had a test last year vs. never having been screened or not being up to date with screening tests. In addition, foreigners had less access to screening than Italians did. ConclusionsThe lockdown and the ongoing Covid-19 emergency caused an important delay in screening activities. This increased the pre-existing individual and geographical inequalities in access. The opportunistic screening did not mitigate the pandemic impact. FundingThis study was partially supported by Italian Ministry of Health - Ricerca Corrente Annual Program 2023.

Estimation of the incubation period and generation time of SARS-CoV-2 Alpha and Delta variants from contact tracing data (preprint)

Background. During 2021, the COVID-19 pandemic was characterized by the emergence of lineages with increased fitness. For most of these variants, quantitative information is scarce on epidemiological quantities such as the incubation period and generation time, which are critical for both public health decisions and scientific research. Method. We analyzed a dataset collected during contact tracing activities in the province of Reggio Emilia, Italy, throughout 2021. We determined the distributions of the incubation period using information on negative PCR tests and the date of last exposure from 282 symptomatic cases. We estimated the distributions of the intrinsic generation time (the time between the infection dates of an infector and its secondary cases under a fully susceptible population) using a Bayesian inference approach applied to 4,435 SARS-CoV-2 cases clustered in 1,430 households where at least one secondary case was recorded. Results. We estimated a mean incubation period of 4.9 days (95% credible intervals, CrI, 4.4-5.4; 95 percentile of the mean distribution: 1-12) for Alpha and 4.5 days (95%CrI 4.0-5.0; 95 percentile: 1-10) for Delta. The intrinsic generation time was estimated to have a mean of 6.0 days (95% CrI 5.6-6.4; 95 percentile: 1-15) for Alpha and of 6.6 days (95%CrI 6.0-7.3; 95 percentile: 1-18) for Delta. The household serial interval was 2.6 days (95%CrI 2.4-2.7) for Alpha and 2.4 days (95%CrI 2.2-2.6) for Delta, and the estimated proportion of pre-symptomatic transmission was 54-55% for both variants. Conclusions. These results indicate limited differences in the incubation period and intrinsic generation time of SARS-CoV-2 variants Alpha and Delta compared to ancestral lineages.

General and COVID-19-related mortality by pre-existing chronic conditions and care setting during 2020 in Emilia-Romagna region, Italy (preprint)

Background: in the 2020, the number of deaths increased substantially in Italy, mainly because of the COVID-19 pandemic; mortality was among the highest in Europe, with a clear heterogeneity among regions and socio-demographic strata. The present work aims at quantifying excess mortality variability over time and in relation to demographic and pre-existent chronic conditions and care setting in Emilia-Romagna region, Italy. Methods registry-based study, comparing the 2020 observed mortality with the figures of the previous 5 years by age, sex, month, place of death, and pre-existing chronic conditions and including 300 094 deaths referred to 18+ aged people resident in Emilia-Romagna region (Northern Italy). Results excess deaths were higher during the first pandemic wave, particularly among man in March. Age-adjusted risk was similar among both men and women (Mortality Rate Ratio 1.15; IC95% 1.14-1.16). The risk of dying was sensibly higher among females aged 75+ years, in Long-term Care Facilities and at home. Excluding COVID-19 related deaths, differences in the risk of dying estimates tended to disappear. Metabolic and neuropsychiatric diseases were more prevalent among those deceased in 2020 compared to the deaths occurred in 2015-19. Conclusions no particular differences of risk by sex and age were found, despite the heterogeneity of the effect in relation to the sub-periods. Metabolic and neuropsychiatric diseases have been confirmed as elements of increased frailty, such as being in Long-term Care Facilities or private home as place of death. Understanding the impact of the pandemic on overall mortality is relevant in a changing scenario.

Inflammatory Burden and Persistent CT Lung Abnormalities in COVID-19 Patients (preprint)

Inflammatory burden is associated with COVID-19 severity and outcomes. Residual computed tomography (CT) lung abnormalities have been reported after COVID-19. The aim was to evaluate the association between inflammatory burden during COVID-19 and residual lung CT abnormalities collected on follow-up CT scans performed 2–3 and 6–7 months after COVID-19, in severe COVID-19 pneumonia survivors. C-reactive protein (CRP) curves describing inflammatory burden during the clinical course were built, and CRP peaks, velocities of increase, and integrals were calculated. Other putative determinants were age, sex, mechanical ventilation, lowest PaO2/FiO2 ratio, D-dimer peak, and length of hospital stay (LOS). Of the 259 included patients (median age 65 years; 30.5% females), 202 (78%) and 100 (38.6%) had residual, predominantly non-fibrotic, abnormalities at 2-3 and 6-7 months, respectively. In age- and sex-adjusted models, best CRP predictors for residual abnormalities were CRP peak (odds ratio [OR] for one standard deviation [SD] increase=1.79; 95% confidence interval [CI]=1.23-2.62) at 2-3 months and CRP integral (OR for one SD increase=2.24; 95%CI=1.53-3.28) at 6-7 months. Hence, inflammation is associated with short- and medium-term lung damage in COVID-19. Other severity measures, including mechanical ventilation and LOS, but not D-dimer, were mediators of the relationship between CRP and residual abnormalities.

Secondary transmission of SARS-CoV-2 in educational settings in Northern Italy from September 2020 to April 2021: a population-based study (preprint)

BackgroundWe aimed to quantify the risk of transmission of SARS-CoV-2 in the school setting by type of school, characteristics of the index case and calendar period in the Reggio Emilia province (RE), Italy. The secondary aim was to estimate the promptness of contact tracing. MethodsA population-based analysis of surveillance data of all COVID-19 cases occurring in RE, Italy, from September 1, 2020, to April 4th, 2021, for which a school contact and/or exposure was suspected. Indicator of the delay in contact tracing was computed as the time elapsed since positivity of the index case and the date on which the swab for classmates was scheduled (or most were scheduled). ResultsOverall, 30,184 and 13,608 contacts among classmates and teachers/staff, respectively, were identified and received recommendation for testing; 43,214 (98.7%) performed the test. Secondary transmission occurred in about 40% of the investigated classes, and the overall secondary case attack rate was 4%, slightly higher when the index case was a teacher, but with almost no differences by type of school and stable during the study period. Promptness of contact tracing increased during the study period, reducing the time from index case identification and testing of contacts from 7 to 3 days, as well the ability to identify possible source of infection in the index case. ConclusionsDespite the spread of the Alpha variant during the study period in RE, the secondary case attack rate remained stable from school reopening in September 2020 until the beginning of April 2021.

COVID-19 patients and cancer in northern Italy (preprint)

The aim of this population-based work was to evaluate the impact of having had cancer on COVID-19 risk and prognosis during the first wave of the pandemic (27 February - 13 May 2020) in Reggio Emilia Province. Prevalent cancer cases diagnosed between 1996 and 2020 were linked with the provincial COVID-19 surveillance system. We compared cancer survivors cumulative incidence of being tested, testing positive for SARS-CoV-2, and dying of COVID-19 with that of the general population; among COVID-19 patients, we compared cancer survivors risk of dying with that of other patients. During the study period 15,391 people (1,525 cancer survivors - CS) underwent RT-PCR for SARS-CoV-2, of whom 4,541 (449 CS) tested positive; 549 (114 CS) died of COVID-19. The probability of undergoing testing was 29.5% in the general population as well in CS, while the cumulative incidence of being tested, testing positive, and COVID-19 death were lower in CS: age- and sex-adjusted Incidence Rate Ratios were 0.69 [95%CI 0.65-0.73], 0.55 [95%CI 0.50-0.61], and 0.52 [95%CI 0.42-0.64], respectively. Cancer survivors had worse prognosis when diagnosed with COVID-19, particularly those below the age of 70 (odds ratio (OR) of death 4.91 [95%CI 2.38-10.09]), while the OR decreased after age 80 (1.20 [95%CI 0.87-1.65]). The OR was higher for patients with a recent diagnosis (<2 years OR=2.99 [95%CI 1.52-5.89]) or metastases (OR=2.14 [95%CI 0.89-5.16]). Cancer patients may have adopted behaviors that protected them from infection, but they were still at higher risk of death once infected. Novelty and impactCancer survivors during the first wave of the pandemic showed lower COVID-19 cumulative incidence and mortality. When infected, they had worse prognosis, particularly in people younger than age 70, with a recent diagnosis, or with metastases.

Secondary transmission of COVID-19 in preschool and school settings after their reopening in northern Italy: a population-based study (preprint)

BackgroundSchool closures was one of the main measures undertaken to reduce the number of social contacts during the first wave of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. We aimed to describe the data on secondary transmission of SARS-CoV-2 among students and teachers/personnel after the reopening of preschools and schools in Reggio Emilia, Italy. MethodsThis prospective population-based study included all consecutive cases leading to an investigation in 41 classes of 36 educational institutions (8 infant-toddler centres and preschools, 10 primary and 18 secondary schools) in the period September 1 - October 15, 2020, in Reggio Emilia province, Italy. We report the characteristics of the school, of the index case, including the possible source of infection, the number of contacts (students and teachers/personnel) that were identified and tested and the characteristics of secondary cases. ResultsIn the study period, 994 students and 204 teachers were tested during related investigations due to notification of 43 primary cases (38 among students and 5 among teachers). Of these, 10 students and two teachers created 39 secondary cases, resulting in an attack rate of 3.9%. There were no secondary cases among teachers/stuff. Secondary transmission occurred in one primary school and 8 secondary schools. Except for two students and one teacher, the possible source of infection for all index cases was identified as they had all had previous contact with a positive case; the majority of secondary cases did not report any previous close contact with a positive case. The clusters ranged from one to 22 secondary cases. ConclusionsTransmission at school occurred in a non-negligible number of cases, particularly in secondary schools. Prompt testing and isolation of classmates could probably reduce the risk of transmission in school settings.

A Prognostic Model for Death in COVID-19 Patients Presenting to the Emergency Room: The Added Value of Computed Tomography. (preprint)

Objective: The added value of CT in prognostic models for coronavirus disease 2019 (COVID-19) patients is unclear. The aim of this study was to develop a prognostic model for death in COVID-19 patients using clinical and CT variables.Methods: Consecutive patients who presented to the emergency room between February 27 and March 23, 2020 for suspected COVID-19, underwent chest CT, and had a positive swab within 10 days were included in this retrospective study. Age, sex, comorbidities, days from symptom onset, and laboratory data were retrieved from institutional information systems. CT disease extension was visually graded as < 20%, 20-39%, 40-59%, or ≥ 60%. The association between clinical and CT variables with death was estimated with univariable and multivariable Cox proportional hazards models; model performance was assessed using k-fold cross-validation for the area under the ROC curve (CvAUC).Results: Of the 866 included patients (median age 59.8, women 39.2%), 93 (10.74%) died. Clinical variables significantly associated with death in multivariable model were age, male sex, HDL cholesterol, dementia, heart failure, vascular diseases, time from symptom onset, neutrophils, LDH, and oxygen saturation level (SO2). CT disease extension was also independently associated with death (HR=7.56, 95% CI=3.49; 16.38 for ≥ 60% extension). CvAUCs were 0.927 (bootstrap bias corrected-95%CI=0.899-0.947) for the clinical model and 0.936 (bootstrap bias corrected-95%CI=0.912-0.953) when adding CT extension.Conclusions: A prognostic model based on clinical variables is highly accurate in predicting death in COVID-19 patients. Adding CT disease extension to the model scarcely improves its accuracy.

The association between clinical laboratory data and chest CT findings explains disease severity in a large Italian cohort of COVID-19 patients. (preprint)

Background: Laboratory data and computed tomography (CT) have been used during the COVID-19 pandemic, mainly to determine patient prognosis and guide clinical management. The aim of this study was to evaluate the association between CT findings and laboratory data in a cohort of COVID-19 patients.Methods: This was an observational cross-sectional study including consecutive patients presenting to the Reggio Emilia (Italy) province emergency rooms for suspected COVID-19 for one month during the outbreak peak, who underwent chest CT scan and laboratory testing at presentation and resulted positive for SARS-CoV-2.Results: Included were 866 patients. Total leukocytes, neutrophils, C-reactive protein (CRP), creatinine, AST, ALT and LDH increase with worsening parenchymal involvement; an increase in platelets was appreciable with the highest burden of lung involvement. A decrease in lymphocyte counts paralleled worsening parenchymal extension, along with reduced arterial oxygen partial pressure and saturation. After correcting for parenchymal extension, ground-glass opacities were associated with reduced platelets and increased procalcitonin, consolidation with increased CRP and reduced oxygen saturation.Conclusions: Pulmonary lesions induced by SARS-CoV-2 infection were associated with raised inflammatory response, impaired gas exchange and end-organ damage. These data suggest that lung lesions probably exert a central role in COVID-19 pathogenesis and clinical presentation.

Physical Distancing, Face Masks, and Eye Protection to Prevent Person-Person COVID-19 Transmission: A Systematic Review and Meta-Analysis (preprint)

Background: Coronavirus disease 2019 (COVID-19) is spread person to person by virus through close contact. The optimal person-person distance and use of facemasks and/or eye protection to prevent disease transmission in healthcare and non-healthcare settings is debated.Methods: We systematically reviewed the impact of distance, masks, and eye protection on transmission of COVID-19, SARS, or MERS from 21 standard, World Health Organization (WHO)-specific and COVID-19-specific data sources from inception to April 15, 2020 for studies of any design and language 1) comparing different distances between those infected and the people close to them, mask use, or eye protection, or 2) contextual factors of acceptability, feasibility, resource use, and equity of these interventions. We screened studies, extracted data, and assessed risk of bias in duplicate. Frequentist and Bayesian meta-analyses and meta-regression for the main outcome of viral transmission were by random effects. Secondary outcomes were contextual factors. We rated certainty of evidence rating per GRADE. PROSPERO: 177047.Findings: We identified 0 RCTs and 164 relevant observational studies in healthcare and non-healthcare (community) settings from 16 countries across 6 continents. A physical distance of one metre or more compared to less than one metre from those infected was associated with 1) a lower risk of viral transmission (n=7782, 5.3% vs 15.5%; RD -10.2% [95%CI -11.5% to -7.5%], pooled adjusted odds ratio [aOR] 0.18 [95%CI 0.09-0.38], moderate certainty) and 2) incremental benefits with increasing distance, change in relative risk (RR) per metre 1.57 (moderate certainty). Facemask use was associated with less infection (n=2647, 2.7% vs 17.4%; RD -14.% [95% credible interval [CrI] -15.9% to -10.7%]; aOR 0.15 [95%CrI 0.07-0.34], low certainty), with stronger associations with N95 or similar (including powered) respirators compared to disposable surgical or similar (e.g. reusable 12-16-layer cotton) masks, p interaction =0.090; posterior probabilities for RR<1 of N95 vs surgical masks were >95% despite minimally informative priors; moderate certainty). Eye protection was associated with quantitatively similar lower risk of infection in 2 adjusted and 15 unadjusted studies (n=3751, 5.4% vs 16.0%; RD -10.6 [95%CI -12.5% to -7.7%]; RR 0.34 [95%CI 0.22-0.52]; aOR 0.22 [95%CI 0.12-0.39], low certainty).Interpretation: This meta-analysis supports physical distancing by more than one metre and provides quantitative estimates for models and contact tracing to inform policy. Although direct evidence is limited, the optimal use of masks, in particular N95 or similar respirators, may depend on risk assessment and contextual factors. Eye protection may provide significant additional benefits. Globally collaborative, well-conducted studies on preventative and therapeutic strategies are required but are challenging to achieve immediately and, thus, recommendations in the interim to curtail the COVID-19 pandemic should be informed by this systematic appraisal of current evidence.Funding Statement: Commissioned by the World Health Organization as a rapid review on March 25, 2020. The funders of the study helped with defining the scope of the question, but otherwise had no role in study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit it.Declaration of Interests: ML is an investigator of an ongoing clinical trial on medical masks versus N95 respirators for COVID-19 (NCT04296643). All other authors declare no competing interests. Ethics Approval Statement: The authors prospectively submitted the systematic review protocol for registration on PROSPERO (submission number 177047). This study followed PRISMA and MOOSE reporting guidelines.

Survival of hospitalized COVID-19 patients in Northern Italy: a population-based cohort study by the ITA-COVID19 Network (preprint)

BackgroundCOVID-19 case fatality rate in hospitalized patients varies across countries and studies, but reliable estimates specific for age, sex, and comorbidities are needed to design trials for COVID-19 interventions. Aim of this study is to provide population-based survival curves of hospitalized COVID-19 patients. MethodsA cohort study was conducted in Lombardy, Veneto, and Reggio Emilia using COVID-19 registries linked to hospital discharge databases containing patient clinical histories. All patients with positive SARS-CoV-2 RT-PCR test on oral/nasopharyngeal swabs hospitalized from 21st February to 21st April 2020 were identified. Kaplan Meier survival estimates were calculated at 14 and 30 days for death in any setting, stratifying by age, sex and Charlson Index. FindingsOverall, 42,926 hospitalized COVID-19 patients were identified. Patients median age was 69 years (IQR: 57-79), 62{middle dot}6% were males, 69{middle dot}4% had a Charlson Index of 0. In total, 11,205 (26{middle dot}1%) patients died over a median follow-up of 24 days (IQR: 10-35). Survival curves showed that 22{middle dot}0% of patients died within 14 days and 27{middle dot}6% within 30 days of hospitalization. Survival was higher in younger patients and in females. Younger patients with comorbidities had a lower survival than older ones with comorbidities. InterpretationOver 27% of hospitalized COVID-19 patients died within one month in three areas of Northern Italy that were heavily affected by SARS-CoV-2 infection. Such a high fatality rate suggests that trials should focus on survival and have follow-up of at least one month. FundingThe study did not receive any external funding. Research in contextEvidence before this study Two recent systematic reviews with meta-analyses report case fatality rates of three to four percent in COVID-19 patients. Most studies on hospitalized cohorts report only slightly higher figures. These figures do not correspond to those derived from routinely collected clinical data in most European countries, reporting a 10% case fatality rate which has been increasing over time since the epidemic started. Robust and precise survival estimates of hospitalized COVID-19 patients which take into account prognostic factors such as age, sex and burden of comorbidities are needed to design appropriate phase II and phase III clinical studies of drugs targeting COVID-19. Added value of this studyIn this study we present the first survival estimates by age, sex and Charlson index for a large population-based cohort of Italian hospitalized COVID-19 patients. Implications of all the available evidenceOver 27% of COVID-19 patients died within one month from hospital admission. Such a high fatality rate suggests that studies should prioritize mortality as primary outcome. Furthermore, we found that the fatality rate reaches a plateau 30 days after hospitalization, suggesting that studies should have at least one month of follow up to observe deaths; shorter follow-up could lead to overestimation of treatment benefits.

Comparison between CT and RT-PCR in a cohort of symptomatic patients with suspected COVID-19 pneumonia during the outbreak peak in Italy (preprint)

Objective: To assess sensitivity and specificity of CT vs RT-PCR for the diagnosis of COVID-19 pneumonia in a prospective Italian cohort of symptomatic patients during the outbreak peak.Methods: In this cross-sectional study we included all consecutive patients who presented to the ER between March 13th and 23rd for suspected COVID-19 and underwent both CT and RT-PCR within 3 days. Using a structured report, radiologists prospectively classified CTs in highly suggestive, suggestive, and non-suggestive of COVID-19 pneumonia. Ground-glass, consolidation, and visual extension of parenchymal changes were collected. Three different RT-PCR-based reference standard definitions were used. Oxygen saturation level, CRP, LDH, and blood cell counts were collected and compared between CT/RT-PCR classes.Results: The study included 696 patients (41.4% women; age 59±15.8 years): 423/454 (93%) patients with highly suggestive CT, 97/127 (76%) with suggestive CT, and 31/115 (27%) with non-suggestive CT had positive RT-PCR. CT sensitivity ranged from 73% to 77% and from 90% to 94% for high and low positivity threshold, respectively. Specificity ranged from 79% to 84% for high positivity threshold and was about 58% for low positivity threshold. PPV remained ≥90% in all cases. Ground-glass was more frequent in patients with positive RT-PCR in all CT classes. Blood tests were significantly associated with RT-PCR and CT classes. Leukocytes, lymphocytes, neutrophils, and platelets decreased, CRP and LDH increased from non-suggestive to suggestive CT classes.Conclusions: During the outbreak peak, CT presented high PPV and may be considered a good reference to recognize COVID-19 patients while waiting for RT-PCR confirmation.

Characteristics and outcomes of a cohort of SARS-CoV-2 patients in the Province of Reggio Emilia, Italy (preprint)

Objectives. To describe the age- and sex-specific prevalence of SARS-CoV-2 disease (COVID-19) and its prognostic factors. Design. Population-based prospective cohort study on archive data. Setting. Preventive services and hospital care in the province of Reggio Emilia, Northern Italy. Participants. All 2653 symptomatic patients who tested positive for SARS-CoV-2 from February 27 to April 2, 2020 in the province of Reggio Emilia. Main outcome measures. Hospitalization and death up to April 2, 2020. Results. Females had higher prevalence of infection than males below age 50 (2.61 vs. 1.84 per 1000), but lower in older ages (16.49 vs. 20.86 per 1000 over age 80). Case fatality rate reached 20.7% (22/106) in cases with more than 4 weeks follow up. After adjusting for age and comorbidities, men had a higher risk of hospitalization (hazard ratio (HR) 1.4 95% confidence interval (95% CI) 1.2 to 1.6) and of death (HR 1.6, 95% CI 1.2 to 2.1). Patients over age 80 compared to < age 50 had HR 7.1 (95% CI 5.4 to 9.3) and HR 27.8 (95% CI 12.5 to 61.7) for hospitalization and death, respectively. Immigrants had a higher risk of hospitalization (HR 1.3, 95% CI 0.99 to 1.81) than Italians and a similar risk of death. Risk of hospitalization and of death were higher in patients with heart failure (HR 1.6, 95% CI 1.2 to 2.1and HR 2.3, 95% CI 1.6 to 3.2, respectively), arrhythmia (HR 1.5, 95% CI 1.2 to 1.9 and HR 1.8, 95% CI 1.3 to 2.5, respectively), dementia (HR 1.2, 95% CI 0.9 to 1.8 and HR 1.8, 95% CI 1.1 to 2.8, respectively), ischemic heart disease (HR 1.3, 95% CI 1.0 to 1.7 and HR 1.7, 95% CI 1.2 to 2.5, respectively), diabetes (HR 1.5, 95% CI 1.3 to 1.9 and HR 1.6, 95% CI 1.1 to 2.2, respectively), and hypertensions(HR 1.4, 95% CI 1.2 to 2.6 and HR 1.6, 95% CI 1.2 to 2.1, respectively), while COPD increased the risk of hospitalization (HR 1.9, 95% CI 1.4 to 2.5) but not of death (HR 1.1, 95% CI 0.7 to 1.7). Previous use of ACE inhibitors has no effect on risk of death (HR 0.97, 95% CI 0.69 to 1.34) Conclusions. The mechanisms underlying these associations are mostly unknown. A deeper understanding of the causal chain from infection, disease onset, and immune response to outcomes may explain how these prognostic factors act.