Statins Use in Patients with Cardiovascular Diseases and COVID-19 Outcomes: An Italian Population-Based Cohort Study.

BACKGROUND: The role of statins among patients with established cardiovascular diseases (CVDs) who are hospitalized with COVID-19 is still debated. This study aimed at assessing whether the prior use of statins was associated with a less severe COVID-19 prognosis. METHODS: Subjects with CVDs infected with SARS-CoV-2 and hospitalized between 20 February 2020 and 31 December 2020 were selected. These were classified into two mutually exclusive groups: statins-users and non-users of lipid-lowering therapies (non-LLT users). The relationship between statins exposure and the risk of Mechanical Ventilation (MV), Intensive Care Unit (ICU) access and death were evaluated by using logistic and Cox regressions models. RESULTS: Of 1127 selected patients, 571 were statins-users whereas 556 were non-LLT users. The previous use of statins was not associated with a variation in the risk of need of MV (Odds Ratio [OR]: 1.00; 95% Confidence Intervals [CI]: 0.38-2.67), ICU access (OR: 0.54; 95% CI: 0.22-1.32) and mortality at 14 days (Hazard Ratio [HR]: 0.42; 95% CI: 0.16-1.10). However, a decreased risk of mortality at 30 days (HR: 0.39; 95% CI: 0.18-0.85) was observed in statins-users compared with non-LLT users. CONCLUSIONS: These findings support the clinical advice for patients CVDs to continue their treatment with statins during SARS-CoV-2 infection.

Azithromycin use and outcomes in patients with COVID-19: an observational real-world study.

OBJECTIVES: Previous studies ruled out the benefits of azithromycin for treatment of patients with COVID-19 who are hospitalized. However, the effects of azithromycin for treatment of patients with positive SARS-CoV-2 test results in the community remains a matter of debate. This study aimed to assess whether azithromycin, when used in subjects with positive test results for SARS-CoV-2, is associated with a reduced risk of hospitalization, in-hospital COVID-19 outcomes, and death. METHODS: Two study cohorts were selected. Cohort A included subjects with positive test results for SARS-CoV-2 between February 20, 2020 and December 10, 2020; cohort B included subjects infected with SARS-CoV-2 and hospitalized between February 20, 2020 and December 31, 2020. We compared the risk of hospitalization, intensive care unit access, need for mechanical ventilation, and death in azithromycin users versus nonusers. A clustered Fine-Gray analysis was employed to assess the risk of hospitalization; logistic and Cox regressions were performed to assess the risk of intensive care unit access, mechanical ventilation, and death. RESULTS: In cohort A, among 4861 azithromycin users and 4861 propensity-matched nonusers, azithromycin use was associated with higher risk of hospitalization (hazard ratio [HR] 1.59, 95% confidence interval [CI] 1.45-1.75) compared with nonuse. In cohort B, among 997 subjects selected in both groups, azithromycin use was not significantly associated with intensive care unit access (odds ratio [OR] 1.22, 95% CI 0.93-1.56), mechanical ventilation (OR 1.30, 95% CI 0.99-1.70), 14-day mortality (HR0.88, 95% CI 0.74-1.05), or 30-day mortality (HR 0.89, 95% CI 0.77-1.03). CONCLUSION: Our findings confirm the lack of benefits of azithromycin treatment among community patients infected with SARS-CoV-2, raising concern on potential risks associated with its inappropriate use.

Antidepressants Drug Use during COVID-19 Waves in the Tuscan General Population: An Interrupted Time-Series Analysis.

In Italy, during the COVID-19 waves two lockdowns were implemented to prevent virus diffusion in the general population. Data on antidepressant (AD) use in these periods are still scarce. This study aimed at exploring the impact of COVID-19 lockdowns on prevalence and incidence of antidepressant drug use in the general population. A population-based study using the healthcare administrative database of Tuscany was performed. We selected a dynamic cohort of subjects with at least one ADs dispensing from 1 January 2018 to 27 December 2020. The weekly prevalence and incidence of drug use were estimated across different segments: pre-lockdown (1 January 2018-8 March 2020), first lockdown (9 March 2020-15 June 2020), post-first lockdown (16 June 2020-15 November 2020) and second lockdown (16 November 2020-27 December 2020). An interrupted time-series analysis was used to assess the effect of lockdowns on the observed outcomes. Compared to the pre-lockdown we observed an abrupt reduction of ADs incidence (Incidence-Ratio: 0.82; 95% Confidence-Intervals: 0.74-0.91) and a slight weekly decrease of prevalence (Prevalence-Ratio: 0.997; 0.996-0.999). During the post-first lockdown AD use increased, with higher incidence- and similar prevalence values compared with those expected in the absence of the outbreak. This pandemic has impacted AD drug use in the general population with potential rebound effects during the period between waves. This calls for future studies aimed at exploring the mid-long term effects of this phenomenon.

Impact of COVID-19 Lockdown, during the Two Waves, on Drug Use and Emergency Department Access in People with Epilepsy: An Interrupted Time-Series Analysis.

BACKGROUND: In 2020, during the COVID-19 pandemic, Italy implemented two national lockdowns aimed at reducing virus transmission. We assessed whether these lockdowns affected anti-seizure medication (ASM) use and epilepsy-related access to emergency departments (ED) in the general population. METHODS: We performed a population-based study using the healthcare administrative database of Tuscany. We defined the weekly time series of prevalence and incidence of ASM, along with the incidence of epilepsy-related ED access from 1 January 2018 to 27 December 2020 in the general population. An interrupted time-series analysis was used to assess the effect of lockdowns on the observed outcomes. RESULTS: Compared to pre-lockdown, we observed a relevant reduction of ASM incidence (0.65; 95% Confidence Intervals: 0.59-0.72) and ED access (0.72; 0.64-0.82), and a slight decrease of ASM prevalence (0.95; 0.94-0.96). During the post-lockdown the ASM incidence reported higher values compared to pre-lockdown, whereas ASM prevalence and ED access remained lower. Results also indicate a lower impact of the second lockdown for both ASM prevalence (0.97; 0.96-0.98) and incidence (0.89; 0.80-0.99). CONCLUSION: The lockdowns implemented during the COVID-19 outbreaks significantly affected ASM use and epilepsy-related ED access. The potential consequences of these phenomenon are still unknown, although an increased incidence of epilepsy-related symptoms after the first lockdown has been observed. These findings emphasize the need of ensuring continuous care of epileptic patients in stressful conditions such as the COVID-19 pandemic.

C5a and C5aR1 are key drivers of microvascular platelet aggregation in clinical entities spanning from aHUS to COVID-19.

Unrestrained activation of the complement system till the terminal products, C5a and C5b-9, plays a pathogenetic role in acute and chronic inflammatory diseases. In endothelial cells, complement hyperactivation may translate into cell dysfunction, favoring thrombus formation. The aim of this study was to investigate the role of the C5a/C5aR1 axis as opposed to C5b-9 in inducing endothelial dysfunction and loss of antithrombogenic properties. In vitro and ex vivo assays with serum from patients with atypical hemolytic uremic syndrome (aHUS), a prototype rare disease of complement-mediated microvascular thrombosis due to genetically determined alternative pathway dysregulation, and cultured microvascular endothelial cells, demonstrated that the C5a/C5aR1 axis is a key player in endothelial thromboresistance loss. C5a added to normal human serum fully recapitulated the prothrombotic effects of aHUS serum. Mechanistic studies showed that C5a caused RalA-mediated exocytosis of von Willebrand factor (vWF) and P-selectin from Weibel-Palade bodies, which favored further vWF binding on the endothelium and platelet adhesion and aggregation. In patients with severe COVID-19 who suffered from acute activation of complement triggered by severe acute respiratory syndrome coronavirus 2 infection, we found the same C5a-dependent pathogenic mechanisms. These results highlight C5a/C5aR1 as a common prothrombogenic effector spanning from genetic rare diseases to viral infections, and it may have clinical implications. Selective C5a/C5aR1 blockade could have advantages over C5 inhibition because the former preserves the formation of C5b-9, which is critical for controlling bacterial infections that often develop as comorbidities in severely ill patients. The ACCESS trial registered at www.clinicaltrials.gov as #NCT02464891 accounts for the results related to aHUS patients treated with CCX168.

Response to BNT162b2 mRNA COVID-19 vaccine among healthcare workers in Italy: a 3-month follow-up.

This study investigated the response to BNT162b2 mRNA COVID-19 vaccine among healthcare workers (HCWs) in an Italian teaching hospital. 444 participants were surveyed with either multiple RT-PCR assays for detection of SARS-CoV-2 nucleic acid in nasopharyngeal swabs or serology testing for the research of virus-specific immunoglobulins. Adverse events following immunization (AEFI) were reported. Two weeks after the first dose anti-SARS-CoV-2 antibodies exceeded reactivity cut-off in 82.5% the participants. Four HCWs tested positive at nasopharyngeal swab after 3 months. More than three-quarters reported AEFIs. Our findings offer an insight regarding the vaccine response after 3 months from its administration, with a special focus on effectiveness data, as well as the type and number of AEFIs complained by HCW recipients. The presented study may serve as reference for future research which will be necessary to explore the long-term safety of this vaccine, especially in population at high risk for infection, such as HCWs.

COVID-19 in liver transplant candidates: pretransplant and post-transplant outcomes - an ELITA/ELTR multicentre cohort study.

OBJECTIVE: Explore the impact of COVID-19 on patients on the waiting list for liver transplantation (LT) and on their post-LT course. DESIGN: Data from consecutive adult LT candidates with COVID-19 were collected across Europe in a dedicated registry and were analysed. RESULTS: From 21 February to 20 November 2020, 136 adult cases with laboratory-confirmed SARS-CoV-2 infection from 33 centres in 11 European countries were collected, with 113 having COVID-19. Thirty-seven (37/113, 32.7%) patients died after a median of 18 (10-30) days, with respiratory failure being the major cause (33/37, 89.2%). The 60-day mortality risk did not significantly change between first (35.3%, 95% CI 23.9% to 50.0%) and second (26.0%, 95% CI 16.2% to 40.2%) waves. Multivariable Cox regression analysis showed Laboratory Model for End-stage Liver Disease (Lab-MELD) score of ≥15 (Model for End-stage Liver Disease (MELD) score 15-19, HR 5.46, 95% CI 1.81 to 16.50; MELD score≥20, HR 5.24, 95% CI 1.77 to 15.55) and dyspnoea on presentation (HR 3.89, 95% CI 2.02 to 7.51) being the two negative independent factors for mortality. Twenty-six patients underwent an LT after a median time of 78.5 (IQR 44-102) days, and 25 (96%) were alive after a median follow-up of 118 days (IQR 31-170). CONCLUSIONS: Increased mortality in LT candidates with COVID-19 (32.7%), reaching 45% in those with decompensated cirrhosis (DC) and Lab-MELD score of ≥15, was observed, with no significant difference between first and second waves of the pandemic. Respiratory failure was the major cause of death. The dismal prognosis of patients with DC supports the adoption of strict preventative measures and the urgent testing of vaccination efficacy in this population. Prior SARS-CoV-2 symptomatic infection did not affect early post-transplant survival (96%).

Protective Role of Tacrolimus, Deleterious Role of Age and Comorbidities in Liver Transplant Recipients With Covid-19: Results From the ELITA/ELTR Multi-center European Study.

BACKGROUND AND AIMS: Despite concerns that liver transplant (LT) recipients may be at increased risk of unfavorable outcomes from COVID-19 due the high prevalence of co-morbidities, immunosuppression and ageing, a detailed analysis of their effects in large studies is lacking. METHODS: Data from adult LT recipients with laboratory confirmed SARS-CoV2 infection were collected across Europe. All consecutive patients with symptoms were included in the analysis. RESULTS: Between March 1 and June 27, 2020, data from 243 adult symptomatic cases from 36 centers and 9 countries were collected. Thirty-nine (16%) were managed as outpatients while 204 (84%) required hospitalization including admission to the ICU (39 of 204, 19.1%). Forty-nine (20.2%) patients died after a median of 13.5 (10-23) days, respiratory failure was the major cause. After multivariable Cox regression analysis, age >70 (HR, 4.16; 95% CI, 1.78-9.73) had a negative effect and tacrolimus (TAC) use (HR, 0.55; 95% CI, 0.31-0.99) had a positive independent effect on survival. The role of co-morbidities was strongly influenced by the dominant effect of age where comorbidities increased with the increasing age of the recipients. In a second model excluding age, both diabetes (HR, 1.95; 95% CI, 1.06-3.58) and chronic kidney disease (HR, 1.97; 95% CI, 1.05-3.67) emerged as associated with death CONCLUSIONS: Twenty-five percent of patients requiring hospitalization for COVID-19 died, the risk being higher in patients older than 70 and with medical co-morbidities, such as impaired renal function and diabetes. Conversely, the use of TAC was associated with a better survival thus encouraging clinicians to keep TAC at the usual dose.

Magnitude and time-course of excess mortality during COVID-19 outbreak: population-based empirical evidence from highly impacted provinces in northern Italy.

BACKGROUND: The real impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on overall mortality remains uncertain as surveillance reports have attributed a limited number of deaths to novel coronavirus disease 2019 (COVID-19) during the outbreak. The aim of this study was to assess the excess mortality during the COVID-19 outbreak in highly impacted areas of northern Italy. METHODS: We analysed data on deaths that occurred in the first 4 months of 2020 provided by the health protection agencies (HPAs) of Bergamo and Brescia (Lombardy), building a time-series of daily number of deaths and predicting the daily standardised mortality ratio (SMR) and cumulative number of excess deaths through a Poisson generalised additive model of the observed counts in 2020, using 2019 data as a reference. RESULTS: We estimated that there were 5740 (95% credible set (CS) 5552-5936) excess deaths in the HPA of Bergamo and 3703 (95% CS 3535-3877) in Brescia, corresponding to a 2.55-fold (95% CS 2.50-2.61) and 1.93 (95% CS 1.89-1.98) increase in the number of deaths. The excess death wave started a few days later in Brescia, but the daily estimated SMR peaked at the end of March in both HPAs, roughly 2 weeks after the introduction of lockdown measures, with significantly higher estimates in Bergamo (9.4, 95% CI 9.1-9.7). CONCLUSION: Excess mortality was significantly higher than that officially attributed to COVID-19, disclosing its hidden burden likely due to indirect effects on the health system. Time-series analyses highlighted the impact of lockdown restrictions, with a lower excess mortality in the HPA where there was a smaller delay between the epidemic outbreak and their enforcement.

Estimates of the initial impact of the COVID-19 epidemic on overall mortality: evidence from Italy.

This study provides evidence of the enormous death toll attributable to COVID-19 https://bit.ly/2X4C6a8.