Post Recovery Impact of the Second and Third Sars-Cov-2 Infection Waves on Healthcare Resource Utilization in Lombardy, Italy (preprint)

Background. The administrative claims database of the Italian region Lombardy, the first in Europe to be hit by the SARS-CoV-2 pandemic, was employed to evaluate the impact on healthcare resource utilization following recovery from the second (mainly alpha-related variant) and third (delta-related) infection waves. Setting and design. 317.164 individuals recovered from the infection and became negative after the second wave, 271.180 after the third. Of them, 1571 (0.5%) and 1575 (0.6%) died in the first 6 post-negativization months. In the remaining cases (315.593 after the second wave and 269.605 after the third),hospitalizations, attendances to emergency rooms and outpatient visits were compared with those recorded in the same pre-pandemic time periods in 2019. Dispensation of drugs as well as of imaging, functional and biochemical diagnostic tests were also compared as additional proxies of the healthcare impact of the second and third SARS-CoV-2 infection waves. Main results. Following both waves, hospitalizations, attendances at emergency rooms and outpatient visits were similar in number and rates to the pre-pandemic periods. However, there was an increased dispensation of drugs and diagnostic tests, particularly those addressing the cardiorespiratory and blood systems. Conclusions. In a large region such as Lombardy taken as a relevant model because early and severely hit by the SARS-CoV-2 pandemic, the post- COVID burden on healthcare facilities was mildly relevant in cases who recovered from the second and third infection waves regarding such pivotal events as deaths, hospitalizations and need for emergency room and outpatient visits, but was high regarding the dispensation of a few drug classes  and types of diagnostic tests.

Post-marketing active surveillance of Guillan Barré Syndrome following vaccination with anti-COVID-19 vaccines in persons aged >=12 years in Italy: a multi-database self-controlled case series study (preprint)

Background Case reports of Guillain Barre syndrome (GBS) following the Coronavirus Disease 2019 (COVID-19) vaccines administration have been reported. This study investigated the risk of GBS after vaccination with anti-COVID-19 vaccines (BNT162b2/Tozinameran; mRNA-1273/Elasomeran, ChAdOx1-S and Ad26.COV2-S) in the population aged [≥]12 years in Italy. Methods We conducted a self-controlled case series study (SCCS) using national data on COVID-19 vaccination linked to emergency care/hospital discharge databases. The outcome was the first diagnosis of GBS between 27 December 2020 and 30 September 2021. Exposure risk period were days 0 (vaccination day) through 42 days following each of the 2 vaccine doses. The remaining periods were considered as non at risk (baseline) period. The SCCS model, adapted to event-dependent exposures, was fitted using unbiased estimating equations to estimate relative incidences (RIs) and excess of cases (EC) per 100,000 vaccinated by dose and vaccine product. Calendar period was included as time-varying confounder in the model. Results The study included 15,986,009 persons who received at least one dose of Covid-19 vaccine. During the 42-day risk interval there were a total of 67 cases of GBS after the first dose and 41 cases after the second dose. In the 42-day risk interval, increased risks were observed after the administration of first dose (RI=6.83; 95% CI 2.14-21.85) and second dose (RI=7.41; 95% CI 2.35-23.38) for mRNA-1273 vaccine, corresponding to 0.4 and 0.3 EC per 100,000 vaccinated, respectively. Increased risk was also observed after the first dose of ChAdOx1-S vaccine (RI=6.52; 95% CI 2.88-14.77), corresponding to 1.0 EC per 100,000 vaccinated. There was no evidence of increased risk of GBS after vaccination with BNT162b2 and Ad26.COV2-S vaccines. In the subgroup analysis by sex an increased risk of GBS was observed among both males and females after mRNA-1273 vaccine. In males an increased risk was observed after the first dose, with a borderline significance (RI=5.26; 95% CI 0.94-29.42, p=0.06) and the second dose (RI=16.50; 95% CI 3.01-90.56) and in females after the first dose (RI=13.44; 95% CI 2.83-63.80). There was also evidence of an increased risk after a first dose of ChAdOx1-S in males (RI=4.94; 95% CI 1.84-13.28) and females (RI=7.14; 95% CI 1.94-26.19). In the subgroup analysis by age, there was evidence of an increased risk of GBS with mRNA-1273 vaccine among those aged [≥]60 years after the first (RI=8.03; 95% CI 2.08-31.03) and second dose (RI=7.71; 95% CI 2.38-24.97). After a first dose of ChAdOx1-S there was evidence of an increased risk of GBS in those aged 40-59 (RI=4.50; 95% CI 1.37-14.79) and in those aged [≥]60 years (RI=6.84; 95% CI 2.56-18.28). There was no evidence of increased risk of GBS after vaccination with BNT162b2 and Ad26.COV2-S vaccines in the subgroup analysis by age and sex. Study limitations include that the outcome was not validated through review of clinical records, the possibility of time-dependent residual confounding and the imprecision of the obtained estimates in the subgroup analysis due to the very low number of events. Conclusions It is important the continuous monitoring of the suspected adverse events of the COVID-19 vaccines as key component of any vaccination program. Results from this large SCCS study showed an increased risk of GBS after first and second dose of mRNA-1273 and first dose of ChAdOx1-S. However, these findings were compatible with a small number of EC. Our data are reassuring regarding BNT162b and Ad26.COV2-S vaccines with respect to GBS outcome. No increased risk of GBS was detected following each of BNT162b vaccine dose nor any increased risk after Ad26.COV2-S vaccine dose.

Pregnancy outcomes in Italy during COVID-19 pandemic: a population-based cohort study. (preprint)

Objective: To compare the estimates of preterm birth (PTB; 22-36 weeks gestational age, GA) and stillbirth rates during COVID-19 pandemic in Italy with those recorded in the three previous years. Design. A population-based cohort study of liveborn and stillborn infants was conducted using data from Regional Health Systems and comparing the pandemic period (March 1st, 2020-March 31st, 2021, N= 362,129) to an historical period (January 2017- February 2020, N=1,117,172). The cohort covered 84.3% of the births in Italy. Methods. Logistic regressions were run in each Region and meta-analyses were performed centrally. We used an interrupted time series regression analysis to study the trend of preterm births from 2017 to 2021. Main Outcome Measures. The primary outcomes were PTB and stillbirths. Secondary outcomes were late PTB (32-36 weeks’ GA), very PTB (<32 weeks’ GA), and extreme PTB (<28 weeks’ GA), overall and stratified into singleton and multiples. Results. The pandemic period compared with the historical one was associated with a reduced risk for PTB (Odds Ratio: 0.90; 95% Confidence Interval, CI: 0.87, 0.93), late PTB (0.91; 0.87, 0.94), very PTB (0.87; 0.84, 0.91), and extreme PTB (0.88; 0.82, 0.94). In multiples, point estimates were not very different, but had wider CIs. No association was found for stillbirths (1.01; 0.90, 1.13). A linear decreasing trend in PTB rate was present in the historical period, with a further reduction after the lockdown. Conclusions We demonstrated a decrease in PTB rate after the introduction of COVID-19 restriction measures, without an increase in stillbirths.

Monitoring the indirect impact of Covid-19 on hospital care pathways in Italy: results from the Mimico-19 network (preprint)

The COVID-19 pandemic has a non-negligible indirect impact on hospital care pathways, which is important to estimate. To this aim, we set up the Mimico-19 network of seven Italian regions (62% of the Italian population) representing different socio-demographic areas of the country with also a different burden of the epidemic. We retrospectively analysed regional hospital discharges data, computing twelve indicators of volumes and performance in three clinical areas: cardiology, oncology and orthopaedics, including time-dependent pathways and elective surgery. Weekly indicators for the period January-July 2020 were compared with the average of the corresponding indicators in 2018 and 2019; comparisons were performed within 3 sub-periods: pre-lockdown, lockdown and post-lockdown. The weekly trend of hospitalizations for ST-segment elevation myocardial infarction (STEMI) showed a 40% reduction, but the proportion of STEMI patients with a primary PTCA did not significantly change from previous years. Volumes of malignant neoplasms surgeries differed substantially by site, with a limited reduction for lung cancer (<20%) and greater declines (30-40%) for breast and prostate cancers. Hospitalizations for femoral neck fracture in the elderly decreased by 20%, but the percentage of timely interventions remained constantly higher than the previous years. General trends did not show important differences across regions, regardless of the different Covid-19 burden. Hospitalizations have generally decreased, but the capacity of a timely and effective response in time-dependent pathways of care was not jeopardized throughout the period. The drop in the care demand for cardiovascular diseases and cancers needs to be further investigated and monitored more thoroughly.

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.