Dynamics of viral DNA shedding and culture viral DNA positivity in different clinical samples collected during the 2022 mpox outbreak in Lombardy, Italy.

BACKGROUND: Mpox virus (MPXV) has recently spread outside of sub-Saharan Africa. This large multicentre study was conducted in Lombardy, the most densely populated Italian region accounting for more than 40% of Italian cases. The present study aims to: i) evaluate the presence and the shedding duration of MPXV DNA in different body compartments correlating the MPXV viability with the time to onset of symptoms; ii) provide evidence of MPXV persistence in different body compartment as a source of infection and iii) characterize the MPXV evolution by whole genome sequencing (WGS) during the outbreak occurred in Italy. MATERIAL AND METHODS: The study included 353 patients with a laboratory-confirmed diagnosis of MPXV infection screened in several clinical specimens in the period May 24th - September 1st, 2022. Viral isolation was attempted from different biological matrices and complete genome sequencing was performed for 61 MPXV strains. RESULTS: MPXV DNA detection was more frequent in the skin (94.4%) with the longest median time of viral clearance (16 days). The actively-replicating virus in cell culture was obtained for 123/377 (32.6%) samples with a significant higher viral quantity on isolation positive samples (20 vs 31, p < 0.001). The phylogenetic analysis highlighted the high genetic identity of the MPXV strains collected, both globally and within the Lombardy region. CONCLUSION: Skin lesion is gold standard material and the high viral load and the actively-replicating virus observed in genital sites confirms that sexual contact plays a key role in the viral transmission.

Preliminary results on an autochthonous dengue outbreak in Lombardy Region, Italy, August 2023.

In August 2023, six locally acquired dengue virus 1 infections were detected in Lodi province, Lombardy Region, in northern Italy, where the vector Aedes albopictus is present. Four cases were hospitalised, none died. The viruses clustered with Peruvian and Brazilian strains collected between 2021 and 2023. This preliminary report highlights the importance of continued integrated surveillance of imported vector-borne virus infections and the potential for tropical disease outbreaks in highly populated regions of northern Italy where competent vectors are present.

Reconstructing the impact of COVID-19 on the immunity gap and transmission of respiratory syncytial virus in Lombardy, Italy.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of hospitalisation and mortality in young children globally. The social distancing measures implemented against COVID-19 in Lombardy (Italy) disrupted the typically seasonal RSV circulation during 2019-2021 and caused substantially more hospitalisations during 2021-2022. The primary aim of this study is to quantify the immunity gap-defined as the increased proportion of the population naïve to RSV infection following the relaxation of COVID-19 restrictions in Lombardy, which has been hypothesised to be a potential cause of the increased RSV burden in 2021-2022. METHODS: We developed a catalytic model to reconstruct changes in the age-dependent susceptibility profile of the Lombardy population throughout the COVID-19 pandemic. The model is calibrated to routinely collected hospitalisation, syndromic, and virological surveillance data and tested for alternative assumptions on age-dependencies in the risk of RSV infection throughout the pandemic. FINDINGS: We estimate that the proportion of the Lombardy population naïve to RSV infection increased by 60.8% (95% CrI: 55.2-65.4%) during the COVID-19 pandemic: from 1.4% (95% CrI: 1.3-1.6%) in 2018-2019 to 2.3% (95% CrI: 2.2-2.5%) before the 2021-2022 season, corresponding to an immunity gap of 0.87% (95% CrI: 0.87-0.88%). We found evidence of heterogeneity in RSV transmission by age, suggesting that the COVID-19 restrictions had variable impact on the contact patterns and risk of RSV infection across ages. INTERPRETATION: We estimate a substantial increase in the population-level susceptibility to RSV in Lombardy during 2019-2021, which contributed to an increase in primary RSV infections in 2021-2022. FUNDING: UK Medical Research Council (MRC), UK Foreign, Commonwealth & Development Office (FCDO), EDCTP2 programme, European Union, Wellcome Trust, Royal Society, EU-MUR PNRR INF-ACT.

Estimating SARS-CoV-2 transmission in educational settings: A retrospective cohort study.

BACKGROUND: School closures and distance learning have been extensively adopted to counter the COVID-19 pandemic. However, the contribution of school transmission to the spread of SARS-CoV-2 remains poorly quantified. METHODS: We analyzed transmission patterns associated with 976 SARS-CoV-2 exposure events, involving 460 positive individuals, as identified in early 2021 through routine surveillance and an extensive screening conducted on students, school personnel, and their household members in a small Italian municipality. In addition to population screenings and contact-tracing operations, reactive closures of class and schools were implemented. RESULTS: From the analysis of 152 clear infection episodes and 584 exposure events identified by epidemiological investigations, we estimated that approximately 50%, 21%, and 29% of SARS-CoV-2 transmission was associated with household, school, and community contacts, respectively. We found substantial transmission heterogeneities, with 20% positive individuals causing 75% to 80% of ascertained infection episodes. A higher proportion of infected individuals causing onward transmission was found among students (46.2% vs. 25%, on average), who also caused a markedly higher number of secondary cases (mean: 1.03 vs. 0.35). By reconstructing likely transmission chains from the entire set of exposures identified during contact-tracing operations, we found that clusters originated from students or school personnel were associated with a larger average cluster size (3.32 vs. 1.15) and a larger average number of generations in the transmission chain (1.56 vs. 1.17). CONCLUSIONS: Uncontrolled SARS-CoV-2 transmission at school could disrupt the regular conduct of teaching activities, likely seeding the transmission into other settings, and increasing the burden on contact-tracing operations.

Vulnerability Predictors of Post-Vaccine SARS-CoV-2 Infection and Disease-Empirical Evidence from a Large Population-Based Italian Platform.

We aimed to identify individual features associated with increased risk of post-vaccine SARS-CoV-2 infection and severe COVID-19 illness. We performed a nested case-control study based on 5,350,295 citizens from Lombardy, Italy, aged ≥ 12 years who received a complete anti-COVID-19 vaccination from 17 January 2021 to 31 July 2021, and followed from 14 days after vaccine completion to 11 November 2021. Overall, 17,996 infections and 3023 severe illness cases occurred. For each case, controls were 1:1 (infection cases) or 1:10 (severe illness cases) matched for municipality of residence and date of vaccination completion. The association between selected predictors (sex, age, previous occurrence of SARS-CoV-2 infection, type of vaccine received, number of previous contacts with the Regional Health Service (RHS), and the presence of 59 diseases) and outcomes was assessed by using multivariable conditional logistic regression models. Sex, age, previous SARS-CoV-2 infection, type of vaccine and number of contacts with the RHS were associated with the risk of infection and severe illness. Moreover, higher odds of infection and severe illness were significantly associated with 14 and 34 diseases, respectively, among those investigated. These results can be helpful to clinicians and policy makers for prioritizing interventions.

Reactive vaccination as control strategy for an outbreak of invasive meningococcal disease caused by Neisseria meningitidis C:P1.5-1,10-8:F3-6:ST-11(cc11), Bergamo province, Italy, December 2019 to January 2020.

In Italy, serogroup C meningococci of the clonal complex cc11 (MenC/cc11) have caused several outbreaks of invasive meningococcal disease (IMD) during the past 20 years. Between December 2019 and January 2020, an outbreak of six cases of IMD infected with MenC/cc11 was identified in a limited area in the northern part of Italy. All cases presented a severe clinical picture, and two of them were fatal. This report is focused on the microbiological and molecular analysis of meningococcal isolates with the aim to reconstruct the chain of transmission. It further presents the vaccination strategy adopted to control the outbreak. The phylogenetic evaluation demonstrated the close genetic proximity between the strain involved in this outbreak and a strain responsible for a larger epidemic that had occurred in 2015 and 2016 in the Tuscany Region. The rapid identification and characterisation of IMD cases and an extensive vaccination campaign contributed to the successful control of this outbreak caused by a hyperinvasive meningococcal strain.

Trends in outcomes following COVID-19 symptom onset in Milan: a cohort study.

BACKGROUND: For people with symptomatic COVID-19, the relative risks of hospital admission, death without hospital admission and recovery without admission, and the times to those events, are not well understood. We describe how these quantities varied with individual characteristics, and through the first wave of the pandemic, in Milan, Italy. METHODS: A cohort study of 27 598 people with known COVID-19 symptom onset date in Milan, Italy, testing positive between February and June 2020 and followed up until 17 July 2020. The probabilities of different events, and the times to events, were estimated using a mixture multistate model. RESULTS: The risk of death without hospital admission was higher in March and April (for non-care home residents, 6%-8% compared with 2%-3% in other months) and substantially higher for care home residents (22%-29% in March). For all groups, the probabilities of hospitalisation decreased from February to June. The probabilities of hospitalisation also increased with age, and were higher for men, substantially lower for healthcare workers and care home residents, and higher for people with comorbidities. Times to hospitalisation and confirmed recovery also decreased throughout the first wave. Combining these results with our previously developed model for events following hospitalisation, the overall symptomatic case fatality risk was 15.8% (15.4%-16.2%). CONCLUSIONS: The highest risks of death before hospital admission coincided with periods of severe burden on the healthcare system in Lombardy. Outcomes for care home residents were particularly poor. Outcomes improved as the first wave waned, community healthcare resources were reinforced and testing became more widely available.

Protective action of natural and induced immunization against the occurrence of delta or alpha variants of SARS-CoV-2 infection: a test-negative case-control study.

BACKGROUND: The evolution of SARS-CoV-2 has led to the emergence of several new variants, and few data are available on the impact of vaccination on SARS-CoV-2 variants. We aimed to assess the association between natural (previous infection) and induced (partial or complete vaccination) exposure to SARS-CoV-2 and the onset of new infection supported by the delta variant, and of comparing it with that supported by alpha. METHODS: We performed a test-negative case-control study, by linking population-based registries of confirmed diagnoses of infection with SARS-CoV-2, vaccinations against Covid-19 and healthcare utilization databases of the Italian Lombardy Region. Four hundred ninety-six persons who between 27 December 2020 and 16 July 2021 had an infection by the delta variant were 1:1 matched with citizens affected by alphavariant and 1:10 matched with persons who had a negative molecular test, according to gender, age and date of molecular ascertainment. We used a conditional logistic regression for estimating relative risk reduction of either variants associated with natural and/or induced immunization and corresponding 95% confidence interval (CI). RESULTS: Previous infection was associated with 91% (95% CI 85% to 95%) reduced relative risk of reinfection, without evidence of significant differences between delta and alpha cases (p=0.547). Significant lower vaccinal protection against delta than alpha variant infection was observed with reduced relative risk associated with partial vaccination respectively of 29% (7% to 45%), and 62% (48% to 71%) (p=0.001), and with complete vaccination respectively of 75% (66% to 82%) and 90% (85% to 94%) (p=0.003). CONCLUSIONS: Lower protection towards infections caused by the delta variant with respect to alpha variant was noticed, even after the completion of the vaccination cycle. This finding would support efforts to maximize both vaccine uptake with two doses and fulfilment with individual protection measures, especially as the delta variant is rampant worldwide presently.

[10 years of stagnant clinical research in the Italian academic context.] / Dieci anni di stagnazione della ricerca, non solo clinica, nel contesto accademico italiano.

This article is about current challenges to evidence-based medicine (EMB) in Italy. The authors, who share a 20-year commitment to the field of clinical research, discuss what they define as a phase of "stagnation" in practicing and teaching methods and research tactics, both in clinical and academic settings. Early success of EBM cultural movement was not persistent. The authors reason about how the teaching of EBM has remained a niche, concerning few professionals compared to the needs of the country. The authors identify some reasons that might have led to inconsistent attention to research methodology and address ways to strengthen the contribution of academic medicine to clinical research.

Persistence of protection against SARS-CoV-2 clinical outcomes up to 9 months since vaccine completion: a retrospective observational analysis in Lombardy, Italy.

BACKGROUND: Scarce information is available on the duration of the protective effect of COVID-19 vaccination against the risk of SARS-CoV-2 infection and its severe clinical consequences. We investigated the effect of time since vaccine completion on the SARS-CoV-2 infection and its severe forms. METHODS: In this retrospective observational analysis using the vaccination campaign integrated platform of the Italian region of Lombardy, 5 351 085 individuals aged 12 years or older who received complete vaccination from Jan 17 to July 31, 2021, were followed up from 14 days after vaccine completion until Oct 20, 2021. Changes over time in outcome rates (ie, SARS-CoV-2 infection and severe illness among vaccinated individuals) were analysed with age-period-cohort models. Trends in vaccine effectiveness (ie, outcomes comparison in vaccinated and unvaccinated individuals) were also measured. FINDINGS: Overall, 14 140 infections and 2450 severe illnesses were documented, corresponding to incidence rates of 6·7 (95% CI 6·6-6·8) and 1·2 (1·1-1·2) cases per 10 000 person-months, respectively. From the first to the ninth month since vaccine completion, rates increased from 4·6 to 10·2 infections, and from 1·0 to 1·7 severe illnesses every 10 000 person-months. These figures correspond to relative reduction of vaccine effectiveness of 54·9% (95% CI 48·3-60·6) for infection and of 40·0% (16·2-57·0) for severe illness. The increasing infection rate was greater for individuals aged 60 years or older who received adenovirus-vectored vaccines (from 4·0 to 23·5 cases every 10 000 person-months). The increasing severe illness rates were similar for individuals receiving mRNA-based vaccines (from 1·1 to 1·5 every 10 000 person-months) and adenovirus-vectored vaccines (from 0·5 to 0·9 every 10 000 person-months). INTERPRETATION: Although the risk of infection after vaccination, and even more of severe illness, remains low, the gradual increase in clinical outcomes related to SARS-CoV-2 infection suggests that the booster campaign should be accelerated and that social and individual protection measures against COVID-19 spread should not be abandoned. FUNDING: None.

Pressure on the Health-Care System and Intensive Care Utilization During the COVID-19 Outbreak in the Lombardy Region of Italy: A Retrospective Observational Study in 43,538 Hospitalized Patients.

During the spring of 2020, the coronavirus disease 2019 (COVID-19) epidemic caused an unprecedented demand for intensive-care resources in the Lombardy region of Italy. Using data on 43,538 hospitalized patients admitted between February 21 and July 12, 2020, we evaluated variations in intensive care unit (ICU) admissions and mortality over the course of 3 periods: the early phase of the pandemic (February 21-March 13), the period of highest pressure on the health-care system (March 14-April 25, when numbers of COVID-19 patients exceeded prepandemic ICU bed capacity), and the declining phase (April 26-July 12). Compared with the early phase, patients aged 70 years or more were less often admitted to an ICU during the period of highest pressure on the health-care system (odds ratio (OR) = 0.47, 95% confidence interval (CI): 0.41, 0.54), with longer ICU delays (incidence rate ratio = 1.82, 95% CI: 1.52, 2.18) and lower chances of dying in the ICU (OR = 0.47, 95% CI: 0.34, 0.64). Patients under 56 years of age had more limited changes in the probability of (OR = 0.65, 95% CI: 0.56, 0.76) and delay to (incidence rate ratio = 1.16, 95% CI: 0.95, 1.42) ICU admission and increased mortality (OR = 1.43, 95% CI: 1.00, 2.07). In the declining phase, all quantities decreased for all age groups. These patterns may suggest that limited health-care resources during the peak phase of the epidemic in Lombardy forced a shift in ICU admission criteria to prioritize patients with higher chances of survival.

A quantitative assessment of epidemiological parameters required to investigate COVID-19 burden.

Solid estimates describing the clinical course of SARS-CoV-2 infections are still lacking due to under-ascertainment of asymptomatic and mild-disease cases. In this work, we quantify age-specific probabilities of transitions between stages defining the natural history of SARS-CoV-2 infection from 1965 SARS-CoV-2 positive individuals identified in Italy between March and April 2020 among contacts of confirmed cases. Infected contacts of cases were confirmed via RT-PCR tests as part of contact tracing activities or retrospectively via IgG serological tests and followed-up for symptoms and clinical outcomes. In addition, we provide estimates of time intervals between key events defining the clinical progression of cases as obtained from a larger sample, consisting of 95,371 infections ascertained between February and July 2020. We found that being older than 60 years of age was associated with a 39.9% (95%CI: 36.2-43.6%) likelihood of developing respiratory symptoms or fever ≥ 37.5 °C after SARS-CoV-2 infection; the 22.3% (95%CI: 19.3-25.6%) of the infections in this age group required hospital care and the 1% (95%CI: 0.4-2.1%) were admitted to an intensive care unit (ICU). The corresponding proportions in individuals younger than 60 years were estimated at 27.9% (95%CI: 25.4-30.4%), 8.8% (95%CI: 7.3-10.5%) and 0.4% (95%CI: 0.1-0.9%), respectively. The infection fatality ratio (IFR) ranged from 0.2% (95%CI: 0.0-0.6%) in individuals younger than 60 years to 12.3% (95%CI: 6.9-19.7%) for those aged 80 years or more; the case fatality ratio (CFR) in these two age classes was 0.6% (95%CI: 0.1-2%) and 19.2% (95%CI: 10.9-30.1%), respectively. The median length of stay in hospital was 10 (IQR: 3-21) days; the length of stay in ICU was 11 (IQR: 6-19) days. The obtained estimates provide insights into the epidemiology of COVID-19 and could be instrumental to refine mathematical modeling work supporting public health decisions.

The early phase of the COVID-19 epidemic in Lombardy, Italy.

BACKGROUND: In the night of February 20, 2020, the first epidemic of the novel coronavirus disease (COVID-19) outside Asia was uncovered by the identification of its first patient in Lombardy region, Italy. In the following weeks, Lombardy experienced a sudden increase in the number of ascertained infections and strict measures were imposed to contain the epidemic spread. METHODS: We analyzed official records of cases occurred in Lombardy to characterize the epidemiology of SARS-CoV-2 during the early phase of the outbreak. A line list of laboratory-confirmed cases was set up and later retrospectively consolidated, using standardized interviews to ascertained cases and their close contacts. We provide estimates of the serial interval, of the basic reproduction number, and of the temporal variation of the net reproduction number of SARS-CoV-2. RESULTS: Epidemiological investigations detected over 500 cases (median age: 69, IQR: 57-78) before the first COVID-19 diagnosed patient (February 20, 2020), and suggested that SARS-CoV-2 was already circulating in at least 222 out of 1506 (14.7%) municipalities with sustained transmission across all the Lombardy provinces. We estimated the mean serial interval to be 6.6 days (95% CrI, 0.7-19). Our estimates of the basic reproduction number range from 2.6 in Pavia (95% CI, 2.1-3.2) to 3.3 in Milan (95% CI, 2.9-3.8). A decreasing trend in the net reproduction number was observed following the detection of the first case. CONCLUSIONS: At the time of first case notification, COVID-19 was already widespread in the entire Lombardy region. This may explain the large number of critical cases experienced by this region in a very short timeframe. The slight decrease of the reproduction number observed in the early days after February 20, 2020 might be due to increased population awareness and early interventions implemented before the regional lockdown imposed on March 8, 2020.

Seroprevalence of and Risk Factors Associated With SARS-CoV-2 Infection in Health Care Workers During the Early COVID-19 Pandemic in Italy.

Importance: Identifying health care settings and professionals at increased risk of SARS-CoV-2 infection is crucial to defining appropriate strategies, resource allocation, and protocols to protect health care workers (HCWs) and patients. Moreover, such information is crucial to decrease the risk that HCWs and health care facilities become amplifiers for SARS-CoV-2 transmission in the community. Objective: To assess the association of different health care professional categories and operational units, including in-hospital wards, outpatient facilities, and territorial care departments, with seroprevalence and odds of SARS-CoV-2 infection. Design, Setting, and Participants: This cross-sectional study was conducted using IgG serological tests collected from April 1 through May 26, 2020, in the Lombardy region in Italy. Voluntary serological screening was offered to all clinical and nonclinical staff providing any health care services or support to health care services in the region. Data were analyzed from June 2020 through April 2021. Exposures: Employment in the health care sector. Main Outcomes and Measures: Seroprevalence of positive IgG antibody tests for SARS-CoV-2 was collected, and odds ratios of experiencing infection were calculated. Results: A total of 140 782 professionals employed in the health sector were invited to participate in IgG serological screening, among whom 82 961 individuals (59.0% response rate) were tested for SARS-CoV-2 antibodies, with median (interquartile range [IQR]; range) age, 50 (40-56; 19-83) years and 59 839 (72.1%) women. Among these individuals, 10 115 HCWs (12.2%; 95% CI, 12.0%-12.4%) had positive results (median [IQR; range] age, 50 [39-55; 20-80] years; 7298 [72.2%] women). Statistically significantly higher odds of infection were found among health assistants (adjusted odds ratio [aOR], 1.48; 95% CI, 1.33-1.65) and nurses (aOR, 1.28; 95% CI, 1.17-1.41) compared with administrative staff and among workers employed in internal medicine (aOR, 2.24; 95% CI, 1.87-2.68), palliative care (aOR, 1.84; 95% CI, 1.38-2.44), rehabilitation (aOR, 1.59; 95% CI, 1.33-1.91), and emergency departments (aOR, 1.56; 95% CI, 1.29-1.89) compared with those working as telephone operators. Statistically significantly lower odds of infection were found among individuals working in forensic medicine (aOR, 0.40; 95% CI, 0.19-0.88), histology and anatomical pathology (aOR, 0.71; 95% CI, 0.52-0.97), and medical device sterilization (aOR, 0.54; 95% CI, 0.35-0.84) compared with those working as telephone operators. The odds of infection for physicians and laboratory personnel were not statistically significantly different from those found among administrative staff. The odds of infection for workers employed in intensive care units and infectious disease wards were not statistically significantly different from those of telephone operators. Conclusions and Relevance: These findings suggest that professionals partially accustomed to managing infectious diseases had higher odds of SARS-CoV-2 infection. The findings further suggest that adequate organization of clinical wards and personnel, appropriate personal protective equipment supply, and training of all workers directly and repeatedly exposed to patients with clinical or subclinical COVID-19 should be prioritized to decrease the risk of infection in health care settings.

A comparative study between the incidence and epidemiological features of Influenza-Like Illness and laboratory-confirmed COVID-19 cases in the Italian epicenter (Lombardy).

INTRODUCTION: In Lombardy, the influenza surveillance system relies on sentinel physicians that weekly report data on the number of Influenza-Like Illness (ILI) and a part of them also collect nasopharyngeal samples for virologic analyses. This study aims at comparing the ILI incidence of 2019-2020 influenza season with the incidence of COVID-19 cases in order to better understand the current epidemic and to evaluate whether the implementation of ILI surveillance system could succeed in early detection and monitoring of COVID-19 diffusion. METHODS: The distribution of ILI cases in the seasons 2017-2018, 2018-2019 and 2019-2020 was taken in consideration and the curve trends were compared and analyzed according to geographical areas, age groups and time differences. RESULTS: The curve trends presented a similar pattern up to the 9th week; in fact, a reduction in the ILI incidence rate was observed in the 2017-2018 and 2018-2019 season but in the 2019-2020 an increase in the reported ILI emerged. The relation between the numbers reported by 2019-2020 ILI surveillance and those reported for COVID-19 is supported by the curve trends, the correspondence between age groups, the correspondence by geographical location, and also by the results of the nasopharyngeal swab tests performed. DISCUSSION: The influenza surveillance system is an effective tool for early detection of COVID-19. It may provide timely and high-quality data evaluating the SARS-CoV-2 burden among population with ILI. Implementation of the system has to be prioritized in order to identify any future novel respiratory pathogen with pandemic potential.

Association of Age With Likelihood of Developing Symptoms and Critical Disease Among Close Contacts Exposed to Patients With Confirmed SARS-CoV-2 Infection in Italy.

Importance: Solid estimates of the risk of developing symptoms and of progressing to critical disease in individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are key to interpreting coronavirus disease 2019 (COVID-19) dynamics, identifying the settings and the segments of the population where transmission is more likely to remain undetected, and defining effective control strategies. Objective: To estimate the association of age with the likelihood of developing symptoms and the association of age with the likelihood of progressing to critical illness after SARS-CoV-2 infection. Design, Setting, and Participants: This cohort study analyzed quarantined case contacts, identified between February 20 and April 16, 2020, in the Lombardy region of Italy. Contacts were monitored daily for symptoms and tested for SARS-CoV-2 infection, by either real-time reverse transcriptase-polymerase chain reaction using nasopharyngeal swabs or retrospectively via IgG serological assays. Close contacts of individuals with laboratory-confirmed COVID-19 were selected as those belonging to clusters (ie, groups of contacts associated with an index case) where all individuals were followed up for symptoms and tested for SARS-CoV-2 infection. Data were analyzed from February to June 2020. Exposure: Close contact with individuals with confirmed COVID-19 cases as identified by contact tracing operations. Main Outcomes and Measures: Age-specific estimates of the risk of developing respiratory symptoms or fever greater than or equal to 37.5 °C and of experiencing critical disease (defined as requiring intensive care or resulting in death) in SARS-CoV-2-infected case contacts. Results: In total, 5484 case contacts (median [interquartile range] age, 50 [30-61] years; 3086 female contacts [56.3%]) were analyzed, 2824 of whom (51.5%) tested positive for SARS-CoV-2 (median [interquartile range] age, 53 [34-64] years; 1604 female contacts [56.8%]). The proportion of infected persons who developed symptoms ranged from 18.1% (95% CI, 13.9%-22.9%) among participants younger than 20 years to 64.6% (95% CI, 56.6%-72.0%) for those aged 80 years or older. Most infected contacts (1948 of 2824 individuals [69.0%]) did not develop respiratory symptoms or fever greater than or equal to 37.5 °C. Only 26.1% (95% CI, 24.1%-28.2%) of infected individuals younger than 60 years developed respiratory symptoms or fever greater than or equal to 37.5 °C; among infected participants older than 60 years, 6.6% (95% CI, 5.1%-8.3%) developed critical disease. Female patients were 52.7% (95% CI, 24.4%-70.7%) less likely than male patients to develop critical disease after SARS-CoV-2 infection. Conclusions and Relevance: In this Italian cohort study of close contacts of patients with confirmed SARS-CoV-2 infection, more than one-half of individuals tested positive for the virus. However, most infected individuals did not develop respiratory symptoms or fever. The low proportion of children and young adults who developed symptoms highlights the possible challenges in readily identifying SARS-CoV-2 infections.

Age-specific SARS-CoV-2 infection fatality ratio and associated risk factors, Italy, February to April 2020.

We analysed 5,484 close contacts of coronavirus disease (COVID-19) cases in Italy, all tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Infection fatality ratio was 0.43% (95% confidence interval (CI): 0.21-0.79) for individuals younger than 70 years and 10.5% (95% CI: 8.0-13.6) for older individuals. Risk of death after infection was 62% lower (95% CI: 31-80) in clusters identified after 16 March 2020 and 1.8-fold higher for males (95% CI: 1.03-3.16).

Risk Factors Associated With Mortality Among Patients With COVID-19 in Intensive Care Units in Lombardy, Italy.

Importance: Many patients with coronavirus disease 2019 (COVID-19) are critically ill and require care in the intensive care unit (ICU). Objective: To evaluate the independent risk factors associated with mortality of patients with COVID-19 requiring treatment in ICUs in the Lombardy region of Italy. Design, Setting, and Participants: This retrospective, observational cohort study included 3988 consecutive critically ill patients with laboratory-confirmed COVID-19 referred for ICU admission to the coordinating center (Fondazione IRCCS [Istituto di Ricovero e Cura a Carattere Scientifico] Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy) of the COVID-19 Lombardy ICU Network from February 20 to April 22, 2020. Infection with severe acute respiratory syndrome coronavirus 2 was confirmed by real-time reverse transcriptase-polymerase chain reaction assay of nasopharyngeal swabs. Follow-up was completed on May 30, 2020. Exposures: Baseline characteristics, comorbidities, long-term medications, and ventilatory support at ICU admission. Main Outcomes and Measures: Time to death in days from ICU admission to hospital discharge. The independent risk factors associated with mortality were evaluated with a multivariable Cox proportional hazards regression. Results: Of the 3988 patients included in this cohort study, the median age was 63 (interquartile range [IQR] 56-69) years; 3188 (79.9%; 95% CI, 78.7%-81.1%) were men, and 1998 of 3300 (60.5%; 95% CI, 58.9%-62.2%) had at least 1 comorbidity. At ICU admission, 2929 patients (87.3%; 95% CI, 86.1%-88.4%) required invasive mechanical ventilation (IMV). The median follow-up was 44 (95% CI, 40-47; IQR, 11-69; range, 0-100) days; median time from symptoms onset to ICU admission was 10 (95% CI, 9-10; IQR, 6-14) days; median length of ICU stay was 12 (95% CI, 12-13; IQR, 6-21) days; and median length of IMV was 10 (95% CI, 10-11; IQR, 6-17) days. Cumulative observation time was 164 305 patient-days. Hospital and ICU mortality rates were 12 (95% CI, 11-12) and 27 (95% CI, 26-29) per 1000 patients-days, respectively. In the subgroup of the first 1715 patients, as of May 30, 2020, 865 (50.4%) had been discharged from the ICU, 836 (48.7%) had died in the ICU, and 14 (0.8%) were still in the ICU; overall, 915 patients (53.4%) died in the hospital. Independent risk factors associated with mortality included older age (hazard ratio [HR], 1.75; 95% CI, 1.60-1.92), male sex (HR, 1.57; 95% CI, 1.31-1.88), high fraction of inspired oxygen (Fio2) (HR, 1.14; 95% CI, 1.10-1.19), high positive end-expiratory pressure (HR, 1.04; 95% CI, 1.01-1.06) or low Pao2:Fio2 ratio (HR, 0.80; 95% CI, 0.74-0.87) on ICU admission, and history of chronic obstructive pulmonary disease (HR, 1.68; 95% CI, 1.28-2.19), hypercholesterolemia (HR, 1.25; 95% CI, 1.02-1.52), and type 2 diabetes (HR, 1.18; 95% CI, 1.01-1.39). No medication was independently associated with mortality (angiotensin-converting enzyme inhibitors HR, 1.17; 95% CI, 0.97-1.42; angiotensin receptor blockers HR, 1.05; 95% CI, 0.85-1.29). Conclusions and Relevance: In this retrospective cohort study of critically ill patients admitted to ICUs in Lombardy, Italy, with laboratory-confirmed COVID-19, most patients required IMV. The mortality rate and absolute mortality were high.

Prevalence of SARS-CoV-2 specific neutralising antibodies in blood donors from the Lodi Red Zone in Lombardy, Italy, as at 06 April 2020.

We evaluated SARS-CoV-2 RNA and neutralising antibodies in blood donors (BD) residing in the Lodi Red Zone, Italy. Of 390 BDs recruited after 20 February 2020 - when the first COVID-19 case in Lombardy was identified, 91 (23%) aged 19-70 years were antibody positive. Viral RNA was detected in an additional 17 (4.3%) BDs, yielding ca 28% (108/390) with evidence of virus exposure. Five stored samples collected as early as 12 February were seropositive.

Clinical characteristics of coronavirus disease (COVID-19) early findings from a teaching hospital in Pavia, North Italy, 21 to 28 February 2020.

We describe clinical characteristics, treatments and outcomes of 44 Caucasian patients with coronavirus disease (COVID-19) at a single hospital in Pavia, Italy, from 21-28 February 2020, at the beginning of the outbreak in Europe. Seventeen patients developed severe disease, two died. After a median of 6 days, 14 patients were discharged from hospital. Predictors of lower odds of discharge were age > 65 years, antiviral treatment and for severe disease, lactate dehydrogenase > 300 mg/dL.