SARS-CoV-2 RNA in urban wastewater samples to monitor the COVID-19 epidemic in Lombardy, Italy (March - June 2020) (preprint)

Wastewater-based viral surveillance is a promising approach to monitor the circulation of SARS-CoV-2 in the general population. The aim of this study was to develop an analytical method to detect SARS-CoV-2 RNA in urban wastewater, to be implemented in the framework of a surveillance network in the Lombardy region (Northern Italy). This area was the first hotspot of COVID-19 in Europe. Composite 24h samples were collected weekly in eight cities from end-March to mid-June 2020 (first peak of the epidemic). The method developed and optimized, involved virus concentration, using PEG centrifugation, and one-step real-time RT-PCR for analysis. SARS-CoV-2 RNA was identified in 65 (61%) out of 107 samples, and the viral concentrations (up to 2.1 E +05 copies/L) were highest in March-April. By mid-June, wastewater samples tested negative in all the cities. Viral loads were used for inter- city comparison and Brembate, Ranica and Lodi had the highest. The pattern of decrease of SARS-CoV-2 in wastewater was closely comparable to the decline of active COVID-19 cases in the population, reflecting the effect of lock-down. Wastewater surveillance of SARS-CoV-2 can integrate ongoing virological surveillance of COVID-19, providing information from both symptomatic and asymptomatic individuals, and monitoring the effect of health interventions.

Decreasing hospital burden of COVID-19 during the first wave in Regione Lombardia: an emergency measures context (preprint)

Background: The aim of this study is to quantify the hospital burden of COVID-19 during the first wave and how it changed over calendar time; to interpret the results in light of the emergency measures introduced to manage the strain on secondary healthcare. Methods: : This is a cohort study of hospitalised confirmed cases of COVID-19 admitted from February-June 2020 and followed up till 17th July 2020, analysed using a mixture multi-state model. All hospital patients with confirmed COVID-19 disease in Regione Lombardia were involved, admitted from February-June 2020, with non-missing hospital of admission and non-missing admission date. Results: : The cohort consists of 40,550 patients hospitalised during the first wave. These patients had a median age of 69 (interquartile range 56-80) and were more likely to be men (60%) than women (40%). The hospital-fatality risk, averaged over all pathways through hospital, was 27.5% (95% CI 27.1-28.0%); and steadily decreased from 34.6% (32.5-36.6%) in February to 7.6% (6.3-10.6%) in June. Among surviving patients, median length of stay in hospital was 11.8 (11.6-12.3) days, compared to 8.1 (7.8-8.5) days in non-survivors. Averaged over final outcomes, median length of stay in hospital decreased from 21.4 (20.5-22.8) days in February to 5.2 (4.7-5.8) days in June. Conclusions: : The hospital burden, in terms of both risks of poor outcomes and lengths of stay in hospital, has been demonstrated to have decreased over the months of the first wave, perhaps reflecting improved treatment and management of COVID-19 cases, as well as reduced burden as the first wave waned. The quantified burden allows for planning of hospital beds needed for current and future waves of SARS-CoV-2.

Risk Factors for Severe Hospital Burden During the First Wave of COVID-19 Disease in Regione Lombardia (preprint)

Background: Understanding the risk factors associated with hospital burden of COVID-19 is crucial for healthcare planning for any future waves of infection.Methods: An observational cohort study is performed, using data on all RT-PCR confirmed cases of COVID-19 in Regione Lombardia, Italy, during the first wave of infection from February-June 2020. A multi-state modelling approach is used to simultaneously estimate risks of progression through hospital to final outcomes of either death or discharge, by pathway (via critical care or not) and the times to final events (lengths of stay). Logistic and time-to-event regressions are used to quantify the association of patient and population characteristics with the risks of hospital outcomes and lengths of stay respectively.Findings: Risks of severe outcomes such as ICU admission and mortality have decreased with month of admission and increased with age. Care home residents aged 65+ are at increased risk of hospital mortality and decreased risk of ICU admission. Being a healthcare worker appears to have a protective effect on mortality risk and length of stay. Lengths of stay decrease with month of admission for survivors, but do not appear to vary with month for non-survivors.Interpretation: Improvements in clinical knowledge, treatment, patient and hospital management and public health surveillance, together with the waning of the first wave after the first lockdown, are hypothesised to have contributed to the reduced risks and lengths of stay over time.Funding: This work has been funded by the Medical Research Council (De Angelis, Jackson, Presanis: Unit programme number MC UU 00002/11; Kunzmann: Unit programme number MC_UU_00002/10); and the UKRI-MRC COVID-19 Rapid Call (Presanis, De Angelis, grant no MC_PC_19074).Declaration of Interests: None to declare.

Healthcare strain and intensive care during the COVID-19 outbreak in the Lombardy region: a retrospective observational study on 43,538 hospitalized patients (preprint)

Background. During the spring of 2020, the SARS-CoV-2 epidemic has caused significant resource strain in hospitals of Lombardy, Italy, with the demand for intensive care beds for COVID-19 patients exceeding the overall pre-crisis capacity. In this study, we evaluate the effect of healthcare strain on ICU admission and survival. Methods. We used data on 43,538 patients admitted to a hospital in the region between February 20 and July 12, 2020, of which 3,993 (9.2%) were admitted to an ICU. We applied logistic regression to model the probability of being admitted to an ICU and the probability of survival among ICU patients. Negative binomial regressions were used to model the time between hospital and ICU admission and the length of stay in ICU. Results. During the period of highest hospital strain (March 16 - April 22), individuals older than 70 years had a significantly lower probability of being admitted to an ICU and significantly longer times between hospital and ICU admission, indicating elective admission due to constrained resources. Healthcare strain did not have a clear effect on mortality, with the overall proportion of deaths declining from 52.1% (95%CI 49.8-54.5) for ICU patients admitted to the hospital before March 16, to 43.4% (95%CI 41.5-45.6) between March 16 and April 22, to 27.6% (95%CI 20.0-35.2) after April 22. Conclusions. These data demonstrate and quantify the adoption of elective admission to ICUs during the peak phase of the SARS-CoV-2 epidemic in Lombardy. However, we show that for patients admitted to ICUs, clinical outcomes progressively improved despite the saturation of healthcare resources.

From positive to negative: a time to event analysis during the first COVID 19 epidemic period (preprint)

BackgroundThe ability to identify the positive subjects is crucial for public health practice to reduce transmission and supporting contact tracing and isolation. The reliability of the criteria of the test-based criteria as the required condition for the reintroduction of the asymptomatic and positive patients of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the community was evaluated assessing the time span from positive to negative for RNA detection by Real Time – Polymerase Chain Reaction (RT-PCR). Methods. We used information concerning negative conversion time and the respective times. Cumulative probabilities of negative conversion time during the follow-up were evaluated by Crude Cumulative Incidences (CCIs). Non-parametric estimates of CCIs and respective 95% C.I.s were obtained.Results. We report the results for 52,186 individuals. 33486 subjects resulted negative or potentially negative with a CCI of 75.2% at 70 days from the first swab (95% CI: 74.8% to 75.7%). 11,000 subjects deceased before 14/05/2020 without diagnosis of negative status (CCI 21.9%; 95% CI: 21.5% to 22.3%), at 56 days from the first swab (maximum observed time to death).Conclusions. SARS-CoV-2 positivity is a condition that frequently lasts more than 30 days. More solid studies are required to determinate the significance of a prolonged state of positivity and the consequences on the policies of dismission of quarantine and isolation. 

Infection fatality ratio of SARS-CoV-2 in Italy (preprint)

We analyzed 5,484 close contacts of COVID-19 cases from Italy, all of them tested for SARS-CoV-2 infection. We found an infection fatality ratio of 2.2% (95%CI 1.69-2.81%) and identified male sex, age >70 years, cardiovascular comorbidities, and infection early in the epidemics as risk factors for death.

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.