Web-based surveillance of respiratory infection outbreaks: retrospective analysis of Italian COVID-19 epidemic waves using Google Trends.

Introduction: Large-scale diagnostic testing has been proven insufficient to promptly monitor the spread of the Coronavirus disease 2019. Electronic resources may provide better insight into the early detection of epidemics. We aimed to retrospectively explore whether the Google search volume has been useful in detecting Severe Acute Respiratory Syndrome Coronavirus outbreaks early compared to the swab-based surveillance system. Methods: The Google Trends website was used by applying the research to three Italian regions (Lombardy, Marche, and Sicily), covering 16 million Italian citizens. An autoregressive-moving-average model was fitted, and residual charts were plotted to detect outliers in weekly searches of five keywords. Signals that occurred during periods labelled as free from epidemics were used to measure Positive Predictive Values and False Negative Rates in anticipating the epidemic wave occurrence. Results: Signals from "fever," "cough," and "sore throat" showed better performance than those from "loss of smell" and "loss of taste." More than 80% of true epidemic waves were detected early by the occurrence of at least an outlier signal in Lombardy, although this implies a 20% false alarm signals. Performance was poorer for Sicily and Marche. Conclusion: Monitoring the volume of Google searches can be a valuable tool for early detection of respiratory infectious disease outbreaks, particularly in areas with high access to home internet. The inclusion of web-based syndromic keywords is promising as it could facilitate the containment of COVID-19 and perhaps other unknown infectious diseases in the future.

GRAd-COV2 vaccine provides potent and durable humoral and cellular immunity to SARS-CoV-2 in randomized placebo-controlled phase 2 trial.

The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and heterologous immunization approaches implemented worldwide for booster doses call for diversified vaccine portfolios. GRAd-COV2 is a gorilla adenovirus-based COVID-19 vaccine candidate encoding prefusion-stabilized spike. The safety and immunogenicity of GRAd-COV2 is evaluated in a dose- and regimen-finding phase 2 trial (COVITAR study, ClinicalTrials.gov: NCT04791423) whereby 917 eligible participants are randomized to receive a single intramuscular GRAd-COV2 administration followed by placebo, or two vaccine injections, or two doses of placebo, spaced over 3 weeks. Here, we report that GRAd-COV2 is well tolerated and induces robust immune responses after a single immunization; a second administration increases binding and neutralizing antibody titers. Potent, variant of concern (VOC) cross-reactive spike-specific T cell response peaks after the first dose and is characterized by high frequencies of CD8s. T cells maintain immediate effector functions and high proliferative potential over time. Thus, GRAd vector is a valuable platform for genetic vaccine development, especially when robust CD8 response is needed.

Genomic Characterization of Carbapenem-Resistant Acinetobacter baumannii (CRAB) in Mechanically Ventilated COVID-19 Patients and Impact of Infection Control Measures on Reducing CRAB Circulation during the Second Wave of the SARS-CoV-2 Pandemic in Milan, Italy.

COVID-19 has significantly affected hospital infection prevention and control (IPC) practices, especially in intensive care units (ICUs). This frequently caused dissemination of multidrug-resistant organisms (MDROs), including carbapenem-resistant Acinetobacter baumannii (CRAB). Here, we report the management of a CRAB outbreak in a large ICU COVID-19 hub Hospital in Italy, together with retrospective genotypic analysis by whole-genome sequencing (WGS). Bacterial strains obtained from severe COVID-19 mechanically ventilated patients diagnosed with CRAB infection or colonization between October 2020 and May 2021 were analyzed by WGS to assess antimicrobial resistance and virulence genes, along with mobile genetic elements. Phylogenetic analysis in combination with epidemiological data was used to identify putative transmission chains. CRAB infections and colonization were diagnosed in 14/40 (35%) and 26/40 (65%) cases, respectively, with isolation within 48 h from admission in 7 cases (17.5%). All CRAB strains belonged to Pasteur sequence type 2 (ST2) and 5 different Oxford STs and presented blaOXA-23 gene-carrying Tn2006 transposons. Phylogenetic analysis revealed the existence of four transmission chains inside and among ICUs, circulating mainly between November and January 2021. A tailored IPC strategy was composed of a 5-point bundle, including ICU modules' temporary conversion to CRAB-ICUs and dynamic reopening, with limited impact on ICU admission rate. After its implementation, no CRAB transmission chains were detected. Our study underlies the potentiality of integrating classical epidemiological studies with genomic investigation to identify transmission routes during outbreaks, which could represent a valuable tool to ensure IPC strategies and prevent the spread of MDROs. IMPORTANCE Infection prevention and control (IPC) practices are of paramount importance for preventing the spread of multidrug-resistant organisms (MDROs) in hospitals, especially in the intensive care unit (ICU). Whole-genome sequencing (WGS) is seen as a promising tool for IPC, but its employment is currently still limited. COVID-19 pandemics have posed dramatic challenges in IPC practices, causing worldwide several outbreaks of MDROs, including carbapenem-resistant Acinetobacter baumannii (CRAB). We present the management of a CRAB outbreak in a large ICU COVID-19 hub hospital in Italy using a tailored IPC strategy that allowed us to contain CRAB transmission while preventing ICU closure during a critical pandemic period. The analysis of clinical and epidemiological data coupled with retrospective genotypic analysis by WGS identified different putative transmission chains and confirmed the effectiveness of the IPC strategy implemented. This could be a promising approach for future IPC strategies.

Gut and airway microbiota dysbiosis and their role in COVID-19 and long-COVID.

The gut microbiota plays a crucial role in human health and disease. Gut dysbiosis is known to be associated with increased susceptibility to respiratory diseases and modifications in the immune response and homeostasis of the lungs (the so-called gut-lung axis). Furthermore, recent studies have highlighted the possible role of dysbiosis in neurological disturbances, introducing the notion of the "gut-brain axis." During the last 2 years, several studies have described the presence of gut dysbiosis during coronavirus disease 2019 (COVID-19) and its relationship with disease severity, SARS-CoV-2 gastrointestinal replication, and immune inflammation. Moreover, the possible persistence of gut dysbiosis after disease resolution may be linked to long-COVID syndrome and particularly to its neurological manifestations. We reviewed recent evidence on the association between dysbiosis and COVID-19, investigating the possible epidemiologic confounding factors like age, location, sex, sample size, the severity of disease, comorbidities, therapy, and vaccination status on gut and airway microbial dysbiosis in selected studies on both COVID-19 and long-COVID. Moreover, we analyzed the confounding factors strictly related to microbiota, specifically diet investigation and previous use of antibiotics/probiotics, and the methodology used to study the microbiota (α- and ß-diversity parameters and relative abundance tools). Of note, only a few studies focused on longitudinal analyses, especially for long-term observation in long-COVID. Lastly, there is a lack of knowledge regarding the role of microbiota transplantation and other therapeutic approaches and their possible impact on disease progression and severity. Preliminary data seem to suggest that gut and airway dysbiosis might play a role in COVID-19 and in long-COVID neurological symptoms. Indeed, the development and interpretation of these data could have important implications for future preventive and therapeutic strategies.

Plasma Proteomic Variables Related to COVID-19 Severity: An Untargeted nLC-MS/MS Investigation.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection leads to a wide range of clinical manifestations and determines the need for personalized and precision medicine. To better understand the biological determinants of this heterogeneity, we explored the plasma proteome of 43 COVID-19 patients with different outcomes by an untargeted liquid chromatography-mass spectrometry approach. The comparison between asymptomatic or pauci-symptomatic subjects (MILDs), and hospitalised patients in need of oxygen support therapy (SEVEREs) highlighted 29 proteins emerged as differentially expressed: 12 overexpressed in MILDs and 17 in SEVEREs. Moreover, a supervised analysis based on a decision-tree recognised three proteins (Fetuin-A, Ig lambda-2chain-C-region, Vitronectin) that are able to robustly discriminate between the two classes independently from the infection stage. In silico functional annotation of the 29 deregulated proteins pinpointed several functions possibly related to the severity; no pathway was associated exclusively to MILDs, while several only to SEVEREs, and some associated to both MILDs and SEVEREs; SARS-CoV-2 signalling pathway was significantly enriched by proteins up-expressed in SEVEREs (SAA1/2, CRP, HP, LRG1) and in MILDs (GSN, HRG). In conclusion, our analysis could provide key information for 'proteomically' defining possible upstream mechanisms and mediators triggering or limiting the domino effect of the immune-related response and characterizing severe exacerbations.

Spike-specific humoral and cellular immune responses after COVID-19 mRNA vaccination in patients with cirrhosis: A prospective single center study.

BACKGROUND AND AIMS: COVID-19 mRNA vaccines were approved to prevent severe forms of the disease, but their immunogenicity and safety in cirrhosis is poorly known. METHOD: In this prospective single-center study enrolling patients with cirrhosis undergoing COVID-19 vaccination (BNT162b2 and mRNA-1273), we assessed humoral and cellular responses vs healthy controls, the incidence of breakthrough infections and adverse events (AEs). Antibodies against spike- and nucleocapsid-protein (anti-S and anti-N) and Spike-specific T-cells responses were quantified at baseline, 21 days after the first and second doses and during follow-up. RESULTS: 182 cirrhotics (85% SARS-CoV-2-naïve) and 38 controls were enrolled. After 2 doses of vaccine, anti-S titres were significantly lower in cirrhotics vs controls [1,751 (0.4-25,000) U/mL vs 4,523 (259-25,000) U/mL, p=0.012] and in SARS-CoV-2-naïve vs previously infected cirrhotics [999 (0.4-17,329) U/mL vs 7,500 (12.5-25,000) U/mL, (p<0.001)]. T-cell responses in cirrhotics were similar to controls, although with different kinetics. In SARS-CoV-2-naïve cirrhotics, HCC, Child-Pugh B/C and BNT162b2 were independent predictors of low response. Neither unexpected nor severe AEs emerged. During follow-up, 2% turned SARS-CoV-2 positive, all asymptomatic. CONCLUSION: Humoral response to COVID-19 vaccines appeared suboptimal in patients with cirrhosis, particularly in SARS-CoV-2-naïve decompensated cirrhotics, although cellular response appeared preserved, and low breakthrough infections rate was registered.

Evaluation of humoral and cellular response to four vaccines against COVID-19 in different age groups: A longitudinal study.

To date there has been limited head-to-head evaluation of immune responses to different types of COVID-19 vaccines. A real-world population-based longitudinal study was designed with the aim to define the magnitude and duration of immunity induced by each of four different COVID-19 vaccines available in Italy at the time of this study. Overall, 2497 individuals were enrolled at time of their first vaccination (T0). Vaccine-specific antibody responses induced over time by Comirnaty, Spikevax, Vaxzevria, Janssen Ad26.COV2.S and heterologous vaccination were compared up to six months after immunization. On a subset of Comirnaty vaccinees, serology data were correlated with the ability to neutralize a reference SARS-CoV-2 B strain, as well as Delta AY.4 and Omicron BA.1. The frequency of SARS-CoV-2-specific CD4+ T cells, CD8+ T cells, and memory B cells induced by the four different vaccines was assessed six months after the immunization. We found that mRNA vaccines are stronger inducer of anti-Spike IgG and B-memory cell responses. Humoral immune responses are lower in frail elderly subjects. Neutralization of the Delta AY.4 and Omicron BA.1 variants is severely impaired, especially in older individuals. Most vaccinees display a vaccine-specific T-cell memory six months after the vaccination. By describing the immunological response during the first phase of COVID-19 vaccination campaign in different cohorts and considering several aspects of the immunological response, this study allowed to collect key information that could facilitate the implementation of effective prevention and control measures against SARS-CoV-2.

SARS-CoV-2 spike conformation determines plasma neutralizing activity elicited by a wide panel of human vaccines.

Numerous safe and effective COVID-19 vaccines have been developed worldwide that utilize various delivery technologies and engineering strategies. We show here that vaccines containing prefusion-stabilizing S mutations elicit antibody responses in humans with enhanced recognition of S and the S1 subunit relative to postfusion S, as compared to vaccines lacking these mutations or natural infection. Prefusion S and S1 antibody binding titers positively and equivalently correlated with neutralizing activity and depletion of S1-directed antibodies completely abrogated plasma neutralizing activity. We show that neutralizing activity is almost entirely directed to the S1 subunit and that variant cross-neutralization is mediated solely by RBD-specific antibodies. Our data provide a quantitative framework for guiding future S engineering efforts to develop vaccines with higher resilience to the emergence of variants than current technologies.

Increased risk of myocarditis and pericarditis and reduced likelihood of severe clinical outcomes associated with COVID-19 vaccination: a cohort study in Lombardy, Italy.

INTRODUCTION: We aimed to assess harms (post-vaccine myocarditis and pericarditis) and benefits (preventing severe disease) of COVID-19 vaccination. METHODS: We conducted a population-based retrospective cohort study. Using the integrated platform of the vaccination campaign of Lombardy Region (Italy), after the exclusion of 24,188 individuals not beneficiaries of the Regional Health Service, 9,184,146 citizens candidates to vaccine at December 27, 2020 were followed until November 30, 2021 (the loss to follow-up rate was 0.5%). From the date of administration of each vaccine dose to day 28 post-administration, three periods that covered exposure to the first, second, and third dose were defined. The benefit-risk profile of vaccines was performed by comparing the number needed to harm (NNH) and number needed to treat (NNT) by sex, age, and vaccine type. RESULTS: Incidence rates of myocarditis were 9.9 and 5.2 per million person-months during the exposure and no-exposure periods, respectively, and the incidence rates of pericarditis were 19.5 and 15.9 per million person-months, respectively. The risk of myocarditis was highest following exposure to the second dose of the Moderna vaccine (adjusted HR: 5.5, 95% CI: 3.7 to 8.1). Exposure to the Moderna vaccine was also associated with an increased risk of pericarditis (adjusted HR 2.2, 1.5 to 3.1). NNT was higher than NNH (9471 vs. 7213) for 16 to 19-year-old men who received the Moderna vaccine, while all other sex, age, and vaccine subgroups had a favourable harm-benefit profile. CONCLUSIONS: Men 16 to 19 years of age has the highest rates of myocarditis within a few days after receiving the Moderna vaccines. The balance between harms and benefits was almost always in favour of vaccination.

What is the impact of SARS-CoV-2 pandemic on antimicrobial stewardship programs (ASPs)? The results of a survey among a regional network of infectious disease centres.

Discontinuation of antimicrobial stewardship programs (ASPs) and increased antibiotic use were described during SARS-CoV-2 pandemic. In order to measure COVID-19 impact on ASPs in a setting of high multidrug resistance organisms (MDRO) prevalence, a qualitative survey was designed. In July 2021, eighteen ID Units were asked to answer a questionnaire about their hospital characteristics, ASPs implementation status before the pandemic and impact of SARS-CoV-2 pandemic on ASPs after the 1st and 2nd pandemic waves in Italy. Nine ID centres (50%) reported a reduction of ASPs and in 7 cases (38.9%) these were suspended. After the early pandemic waves, the proportion of centres that restarted their ASPs was higher among the ID centres where antimicrobial stewardship was formally identified as a priority objective (9/11, 82%, vs 2/7, 28%). SARS-CoV-2 pandemic had a severe impact in ASPs in a region highly affected by COVID-19 and antimicrobial resistance but weaknesses related to the pre-existent ASPs might have played a role.

Endogenous antibody response to SARS-CoV-2 in patients who received monoclonal antibodies against COVID-19: a systematic review

Passive immunization with mAbs has been employed in COVID-19. We performed a systematic review of the literature assessing the endogenous humoral immune response against SARS-CoV-2 in patients treated with mAbs. Administration of mAbs in seronegative patients led to a reduction in both antibody titres and neutralizing activity against the virus.

Safety Profile and Outcomes of Early COVID-19 Treatments in Immunocompromised Patients: A Single-Centre Cohort Study.

BACKGROUND: Early treatment with remdesivir (RMD) or monoclonal antibodies (mAbs) could be a valuable tool in patients at risk of severe COVID-19 with unsatisfactory responses to vaccination. We aim to assess the safety and clinical outcomes of these treatments among immunocompromised subjects. METHODS: We retrospectively reviewed all nonhospitalized patients who received an early treatment with RMD or mAbs for COVID-19, from 25 November 2021 to 25 January 2022, in a large tertiary hospital. Outcomes included frequency of adverse drug reaction (ADR), duration of symptoms and molecular swab positivity, emergency department access, hospital or intensive care unit admission, and mortality in the 14 days following treatment administration. RESULTS: Early treatments were administered to 143 patients, 106/143 (74.1%) immunocompromised, including 41 solid organ and 6 hematopoietic stem cell transplant recipients. Overall, 23/143 (16.1%) subjects reported ADRs. Median time from treatment start to SARS-CoV-2 nasopharyngeal swab negativity and symptom resolution was 10 (IQR 6-16) and 2.5 days (IQR 1.0-6.0), respectively, without differences between immunocompromised and nonimmunocompromised patients. In the 14 days after treatment administration, 5/143 patients (3.5%) were hospitalized and one died as a result of causes related to COVID-19, all of them were immunocompromised. CONCLUSIONS: RMD and mAbs have minimal ADRs and favourable outcomes in immunocompromised patients.

Lung Transplant for ARDS after COVID-19: Long-Term Outcomes and Considerations about Detrimental Issues.

During the first outbreak of COVID-19 in Italy, based on the only few cases reported from a Chinese centre at the time, we performed lung transplantation in two patients with irreversible acute respiratory distress syndrome (ARDS) after COVID-19 at our centre. After two years, we report the outcomes of these cases and some considerations. The first patient, an 18-year-old male, is in excellent conditions twenty-four months after surgery. The second patient was a 48-year-old man; his airways were colonized by carbapenemase-producing klebsiella pneumoniae at the time of lung transplantation, and he had previously suffered from delirium and hallucinations in the intensive care unit. His postoperative clinical course was complicated by dysexecutive behaviour and then septic shock; he died 62 days after surgery. The recently reported experience of different transplantation centres has led to the inclusion of irreversible acute respiratory distress syndrome (ARDS) after COVID-19 among the indications for lung transplantation in carefully selected patients. Our results confirm the feasibility and the good long-term outcomes of lung transplantation for COVID-19-associated ARDS. Nonetheless, our experience corroborates the need for careful recipient selection: special attention must be paid to the single-organ dysfunction principle, the evaluation of any neuro-psychiatric disorder, and MDR germs colonization, before listing.

Anti-Phospholipid Antibodies and Coronavirus Disease 2019: Vaccination Does Not Trigger Early Autoantibody Production in Healthcare Workers.

A molecular mimicry between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human proteins supports the possibility that autoimmunity takes place during coronavirus disease 2019 (COVID-19) contributing to tissue damage. For example, anti-phospholipid antibodies (aPL) have been reported in COVID-19 as a result of such mimicry and thought to contribute to the immunothrombosis characteristic of the disease. Consistently, active immunization with the virus spike protein may elicit the production of cross-reactive autoantibodies, including aPL. We prospectively looked at the aPL production in healthcare workers vaccinated with RNA- (BNT162b2, n. 100) or adenovirus-based vaccines (ChAdOx1, n. 50). Anti-cardiolipin, anti-beta2 glycoprotein I, anti-phosphatidylserine/prothrombin immunoglobulin G (IgG), IgA, and IgM before and after vaccination were investigated. Anti-platelet factor 4 immunoglobulins were also investigated as autoantibodies associated with COVID-19 vaccination. Additional organ (anti-thyroid) and non-organ (anti-nuclear) autoantibodies and IgG against human proteome were tested as further post-vaccination autoimmunity markers. The antibodies were tested one or three months after the first injection of ChAdOx1 and BNT162b2, respectively; a 12-month clinical follow-up was also performed. Vaccination occasionally induced low titers of aPL and other autoantibodies but did not affect the titer of pre-existing autoantibodies. No significant reactivities against a microarray of approximately 20,000 human proteins were found in a subgroup of ChAdOx1-vaccinees. Consistently, we did not record any clinical manifestation theoretically associated with an underlying autoimmune disorder. The data obtained after the vaccination (two doses for the RNA-based and one dose for the adenovirus-based vaccines), and the clinical follow-up are not supporting the occurrence of an early autoimmune response in this cohort of healthcare workers.

Prognostic Value of Mid-Region Proadrenomedullin and In Vitro Interferon Gamma Production for In-Hospital Mortality in Patients with COVID-19 Pneumonia and Respiratory Failure: An Observational Prospective Study.

Coagulopathy and immune dysregulation have been identified as important causes of adverse outcomes in coronavirus disease (COVID-19). Mid-region proadrenomedullin (MR-proADM) is associated with endothelial damage and has recently been proposed as a prognostic factor in COVID-19. In non-COVID-19 immunocompromised patients, low in vitro interferon gamma (IFNγ) production correlates with infection risk and mortality. This prospective, monocentric, observational study included adult patients consecutively admitted with radiologic evidence of COVID-19 pneumonia and respiratory failure. MR-proADM and in vitro IFNγ production were measured at T0 (day 1 from admission) and T1 (day 7 from enrollment). One hundred patients were enrolled. Thirty-six percent were females, median age 65 (Q1-Q3 54.5-75) years, and 58% had ≥1 comorbidity. Only 16 patients had received COVID-19 vaccination before hospitalization. At admission, the median PaO2:FiO2 ratio was 241 (157-309) mmHg. In-hospital mortality was 13%. MR-proADM levels differed significantly between deceased and survivors both at T0 (1.41 (1.12-1.77) nmol/L vs. 0.79 (0.63-1.03) nmol/L, p < 0.001) and T1 (1.67 (1.08-1.96) nmol/L vs. 0.66 (0.53-0.95) nmol/L, p < 0.001). In vitro IFNγ production at T0 and T1 did not vary between groups. When only the subset of non-vaccinated patients was considered, both biomarkers at T1 resulted significantly associated with in-hospital mortality. AUROC for MR-proADM at T0 to predict in-hospital mortality was 0.87 (95%CI 0.79-0.94), with the best cut-off point at 1.04 nmol/L (92% sensitivity, 75% specificity and 98% negative predictive value). In patients with COVID-19 pneumonia and different degrees of respiratory failure, MR-proADM at admission and during hospitalization resulted strongly associated with in-hospital mortality. Low in vitro IFNγ production after the first week of hospitalization was associated with mortality in non-vaccinated patients possibly identifying the subgroup characterized by a higher degree of immune suppression.

The usefulness of D-dimer as a predictive marker for mortality in patients with COVID-19 hospitalized during the first wave in Italy.

BACKGROUND: The coronavirus disease 2019 (COVID-19) presents an urgent threat to global health. Identification of predictors of poor outcomes will assist medical staff in treatment and allocating limited healthcare resources. AIMS: The primary aim was to study the value of D-dimer as a predictive marker for in-hospital mortality. METHODS: This was a cohort study. The study population consisted of hospitalized patients (age >18 years), who were diagnosed with COVID-19 based on real-time PCR at 9 hospitals during the first COVID-19 wave in Lombardy, Italy (Feb-May 2020). The primary endpoint was in-hospital mortality. Information was obtained from patient records. Statistical analyses were performed using a Fine-Gray competing risk survival model. Model discrimination was assessed using Harrell's C-index and model calibration was assessed using a calibration plot. RESULTS: Out of 1049 patients, 507 patients (46%) had evaluable data. Of these 507 patients, 96 died within 30 days. The cumulative incidence of in-hospital mortality within 30 days was 19% (95CI: 16%-23%), and the majority of deaths occurred within the first 10 days. A prediction model containing D-dimer as the only predictor had a C-index of 0.66 (95%CI: 0.61-0.71). Overall calibration of the model was very poor. The addition of D-dimer to a model containing age, sex and co-morbidities as predictors did not lead to any meaningful improvement in either the C-index or the calibration plot. CONCLUSION: The predictive value of D-dimer alone was moderate, and the addition of D-dimer to a simple model containing basic clinical characteristics did not lead to any improvement in model performance.

Omicron spike function and neutralizing activity elicited by a comprehensive panel of vaccines.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern comprises several sublineages, with BA.2 and BA.2.12.1 having replaced the previously dominant BA.1 and with BA.4 and BA.5 increasing in prevalence worldwide. We show that the large number of Omicron sublineage spike mutations leads to enhanced angiotensin-converting enzyme 2 (ACE2) binding, reduced fusogenicity, and severe dampening of plasma neutralizing activity elicited by infection or seven clinical vaccines relative to the ancestral virus. Administration of a homologous or heterologous booster based on the Wuhan-Hu-1 spike sequence markedly increased neutralizing antibody titers and breadth against BA.1, BA.2, BA.2.12.1, BA.4, and BA.5 across all vaccines evaluated. Our data suggest that although Omicron sublineages evade polyclonal neutralizing antibody responses elicited by primary vaccine series, vaccine boosters may provide sufficient protection against Omicron-induced severe disease.

Detailed stratified GWAS analysis for severe COVID-19 in four European populations.

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended genome-wide association meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12 488 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a ~0.9-Mb inversion polymorphism that creates two highly differentiated haplotypes and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative including non-Caucasian individuals, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.

Remdesivir for the treatment of patients hospitalized with COVID-19 receiving supplemental oxygen: a targeted literature review and meta-analysis.

This network meta-analysis (NMA) assessed the efficacy of remdesivir in hospitalized patients with COVID-19 requiring supplemental oxygen. Randomized controlled trials of hospitalized patients with COVID-19, where patients were receiving supplemental oxygen at baseline and at least one arm received treatment with remdesivir, were identified. Outcomes included mortality, recovery, and no longer requiring supplemental oxygen. NMAs were performed for low-flow oxygen (LFO2); high-flow oxygen (HFO2), including NIV (non-invasive ventilation); or oxygen at any flow (AnyO2) at early (day 14/15) and late (day 28/29) time points. Six studies were included (N = 5245 patients) in the NMA. Remdesivir lowered early and late mortality among AnyO2 patients (risk ratio (RR) 0.52, 95% credible interval (CrI) 0.34-0.79; RR 0.81, 95%CrI 0.69-0.95) and LFO2 patients (RR 0.21, 95%CrI 0.09-0.46; RR 0.24, 95%CrI 0.11-0.48); no improvement was observed among HFO2 patients. Improved early and late recovery was observed among LFO2 patients (RR 1.22, 95%CrI 1.09-1.38; RR 1.17, 95%CrI 1.09-1.28). Remdesivir also lowered the requirement for oxygen support among all patient subgroups. Among hospitalized patients with COVID-19 requiring supplemental oxygen at baseline, use of remdesivir compared to best supportive care is likely to improve the risk of mortality, recovery and need for oxygen support in AnyO2 and LFO2 patients.

External validation of risk scores to predict in-hospital mortality in patients hospitalized due to coronavirus disease 2019.

BACKGROUND: The coronavirus disease 2019 (COVID-19) presents an urgent threat to global health. Prediction models that accurately estimate mortality risk in hospitalized patients could assist medical staff in treatment and allocating limited resources. AIMS: To externally validate two promising previously published risk scores that predict in-hospital mortality among hospitalized COVID-19 patients. METHODS: Two prospective cohorts were available; a cohort of 1028 patients admitted to one of nine hospitals in Lombardy, Italy (the Lombardy cohort) and a cohort of 432 patients admitted to a hospital in Leiden, the Netherlands (the Leiden cohort). The endpoint was in-hospital mortality. All patients were adult and tested COVID-19 PCR-positive. Model discrimination and calibration were assessed. RESULTS: The C-statistic of the 4C mortality score was good in the Lombardy cohort (0.85, 95CI: 0.82-0.89) and in the Leiden cohort (0.87, 95CI: 0.80-0.94). Model calibration was acceptable in the Lombardy cohort but poor in the Leiden cohort due to the model systematically overpredicting the mortality risk for all patients. The C-statistic of the CURB-65 score was good in the Lombardy cohort (0.80, 95CI: 0.75-0.85) and in the Leiden cohort (0.82, 95CI: 0.76-0.88). The mortality rate in the CURB-65 development cohort was much lower than the mortality rate in the Lombardy cohort. A similar but less pronounced trend was found for patients in the Leiden cohort. CONCLUSION: Although performances did not differ greatly, the 4C mortality score showed the best performance. However, because of quickly changing circumstances, model recalibration may be necessary before using the 4C mortality score.