December 20, 2021

Clinical Reports

Outpatient COVID-19 Management Strategies in Children and Adolescents

Given rapidly emerging data, recent increasing rate of COVID-19 hospitalizations, and the fact that many children and adolescents are presenting for medical attention in the outpatient/ambulatory setting, this interim guidance is intended to navigate treatment considerations and challenges and summarize currently available recommendations for the outpatient management of COVID-19 in children and adolescents 

SARS-CoV-2-specific memory B cells can persist in the elderly who have lost detectable neutralising antibodies

Memory B cells (MBC) can provide a recall response able to supplement waning antibodies with an affinity-matured response better able to neutralise variant viruses. We studied a cohort of elderly care home residents and younger staff (median age 87yrs and 56yrs respectively) who had survived COVID-19 outbreaks with only mild/asymptomatic infection. The cohort was selected to enrich for a high proportion who had lost neutralising antibodies (nAb), to specifically investigate the reserve immunity from SARS-CoV-2-specific MBC in this setting. Class-switched spike and RBD-tetramer-binding MBC persisted five months post-mild/asymptomatic SARS-CoV-2 infection, irrespective of age. The majority of spike/RBD-specific MBC had a classical phenotype but activated memory B cells, that may indicate ongoing antigenic stimulation or inflammation, were expanded in the elderly. Spike/RBD-specific MBC remained detectable in the majority who had lost nAb, although at lower frequencies and with a reduced IgG/IgA isotype ratio. Functional spike/S1/RBD-specific recall was also detectable by ELISpot in some who had lost nAb, but was significantly impaired in the elderly. These findings demonstrate a reserve of SARS-CoV-2-specific MBC persists beyond loss of nAb, but highlight the need for careful monitoring of functional defects in spike/RBD-specific B cell immunity in the elderly. 

Science Brief: SARS-CoV-2 Infection-induced and Vaccine-induced Immunity

This brief provides an overview of the current scientific evidence regarding infection-induced and vaccine-induced immunity, including both peer-reviewed and preprint publications, as well as unpublished CDC data. Although comprehensive, it is neither a formal systematic review nor meta-analysis. New data continue to emerge, and recommendations will be updated periodically, as needed. Recovery from many viral infectious diseases is followed by a period of infection-induced immunologic protection against reinfection. This phenomenon is widely observed with many respiratory viral infections, including both influenza and the endemic coronaviruses, for which acquired immunity also wanes over time making individuals susceptible to reinfection. CDC continues to recommend COVID-19 vaccination for all eligible persons, including those who have been previously infected with SARS-CoV-2.

Azithromycin in patients with COVID-19: a systematic review and meta-analysis

Azithromycin has been widely used in the management of COVID-19. However, the evidence on its actual effects remains disperse and difficult to apply in clinical settings. This systematic review and meta-analysis summarizes the available evidence to date on the beneficial and adverse effects of azithromycin in patients with COVID-19.

Methods

The PRISMA 2020 statement criteria were followed. Randomized controlled trials (RCTs) and observational studies comparing clinical outcomes of patients treated with and without azithromycin, indexed until 5 July 2021, were searched in PubMed, Embase, The Web of Science, Scopus, The Cochrane Central Register of Controlled Trials and MedRXivs. Authors used random-effects models to estimate pooled effect size from aggregate data. The initial search produced 4950 results. Finally, 16 studies, 5 RCTs and 11 with an observational design, with a total of 22 984 patients, were included. The meta-analysis showed no difference in mortality for those treated with or without azithromycin, in observational studies [OR: 0.90 (0.66–1.24)], RCTs [OR: 0.97 (0.87–1.08)] and also when both types of studies were pooled together [with an overall OR: 0.95 (0.79–1.13)]. Different individual studies also reported no significant difference for those treated with or without azithromycin in need for hospital admission or time to admission from ambulatory settings, clinical severity, need for intensive care, or adverse effects. The results presented in this systematic review do not support the use of azithromycin in the management of COVID-19. Future research on treatment for patients with COVID-19 may need to focus on other drugs.

Effect of High-Flow Oxygen Therapy vs Conventional Oxygen Therapy on Invasive Mechanical Ventilation and Clinical Recovery in Patients With Severe COVID-19

Authors asked whether the use of high-flow oxygen therapy through a nasal cannula, compared with conventional oxygen therapy, reduce requirement of intubation and time to clinical improvement among patients with severe COVID-19. In this randomized clinical trial that included 220 patients with severe COVID-19, the rate of intubation and mechanical ventilation for those treated with high-flow oxygen therapy through a nasal cannula vs with conventional oxygen therapy was 34.3% vs 51.0%, respectively; the median time to clinical recovery was 11 days vs 14 days. Both comparisons were statistically significant. Among patients with severe COVID-19, treatment with high-flow oxygen therapy compared with conventional oxygen therapy reduced the likelihood of invasive mechanical ventilation and decreased time to clinical recovery.

In non–critically ill patients with COVID-19, therapeutic anticoagulation improved survival to discharge without organ support

Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). Authors hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19. In this open-label, adaptive, multiplatform, controlled trial, authors randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level. The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis. In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis.

Africa's COVID-19 numbers surge, but hospital cases stay low

Africa's COVID-19 cases rose 93% over the past week, with increases occurring across all of the continent's regions, but early signals from South Africa—the Omicron (B.1.1.529) variant epicenter—show that hospitalizations remain low, officials from the World Health Organization (WHO) African regional office said today at a briefing. Meanwhile, at least 57 countries reported cases, with some reporting community spread, including the United Kingdom which announced new "plan B" measures to slow COVID-19 activity, especially as it anticipates rising Omicron levels.

Antiviral Therapeutics and Vaccines

B.1.1.529 escapes the majority of SARS-CoV-2 neutralizing antibodies of diverse epitopes

The SARS-CoV-2 B.1.1.529 variant (Omicron) contains 15 amino acid changes in the receptor-binding domain (RBD). How Omicron would evade RBD neutralizing antibodies (NAbs) and humoral immunity requires immediate investigation. High-throughput yeast display screening was used to determine the RBD escaping mutation profiles for 247 human anti-RBD NAbs identified from SARS-CoV/SARS-CoV-2 convalescents and vaccinees. Based on the results, NAbs could be unsupervised clustered into six epitope groups (A-F), which is highly concordant with knowledge-based structural classifications. Strikingly, various single changes of Omicron could impair NAbs of different epitope groups. Specifically, NAbs in Group A-D, whose epitope overlaps with ACE2-binding motif, are largely escaped by K417N, N440K, G446S, E484A, Q493K, and G496S. Group E (S309 site) and F (CR3022 site) NAbs, which often exhibit broad sarbecovirus neutralizing activity, are less affected by Omicron, but still, a subset of NAbs are escaped by G339D, S371L, and S375F. Furthermore, B.1.1.529 pseudovirus neutralization and RBD binding assay showed that single mutation tolerating NAbs could also be escaped due to multiple synergetic mutations on their epitopes. In total, over 85% of the tested NAbs are escaped by Omicron. Regarding NAb drugs, LY-CoV016/LY-CoV555 cocktail, REGN-CoV2 cocktail, AZD1061/AZD8895 cocktail, and BRII-196 were escaped by Omicron, while VIR7831 and DXP-604 still function at reduced efficacy. Together, data suggest Omicron could cause significant humoral immune evasion, while NAbs targeting the sarbecovirus conserved region remain most effective. These results offer instructions for developing NAb drugs and vaccines against Omicron and future variants.

mRNA booster immunization elicits potent neutralizing serum activity against the SARS-CoV-2 Omicron variant

The Omicron variant of SARS-CoV-2 is causing a rapid increase in infections in various countries. This new variant of concern carries an unusually high number of mutations in key epitopes of neutralizing antibodies on the spike glycoprotein, suggesting potential immune evasion. Authors assessed serum neutralizing capacity in longitudinal cohorts of vaccinated and convalescent individuals, as well as monoclonal antibody activity against Omicron using pseudovirus neutralization assays. A near-complete lack of neutralizing activity was observed against Omicron in polyclonal sera after two doses of the BNT162b2 vaccine, in convalescent individuals, as well as resistance to different monoclonal antibodies in clinical use. However, mRNA booster immunizations in vaccinated and convalescent individuals resulted in a significant increase of serum neutralizing activity against Omicron. These results demonstrate that booster immunizations will be critical to substantially improve the humoral immune response against the Omicron variant.

Protection against Covid-19 by BNT162b2 Booster across Age Groups

After promising initial results from the administration of a third (booster) dose of the BNT162b2 messenger RNA vaccine (Pfizer–BioNTech) to persons 60 years of age or older, the booster campaign in Israel was gradually expanded to persons in younger age groups who had received a second dose at least 5 months earlier. Authors extracted data for the period from July 30 to October 10, 2021, from the Israel Ministry of Health database regarding 4,696,865 persons 16 years of age or older who had received two doses of BNT162b2 at least 5 months earlier. In the primary analysis, rates of confirmed coronavirus disease 2019 (Covid-19), severe illness, and death were compared among those who had received a booster dose at least 12 days earlier (booster group) with the rates among those who had not received a booster (nonbooster group). In a secondary analysis, the rates in the booster group were compared with the rates among those who had received a booster 3 to 7 days earlier (early postbooster group). Poisson regression models were used to estimate rate ratios after adjusting for possible confounding factors. The rate of confirmed infection was lower in the booster group than in the nonbooster group by a factor of approximately 10 (range across five age groups, 9.0 to 17.2) and was lower in the booster group than in the early postbooster group by a factor of 4.9 to 10.8. The adjusted rate difference ranged from 57.0 to 89.5 infections per 100,000 person-days in the primary analysis and from 34.4 to 38.3 in the secondary analysis. The rates of severe illness in the primary and secondary analyses were lower in the booster group by a factor of 17.9 (95% confidence interval [CI], 15.1 to 21.2) and 6.5 (95% CI, 5.1 to 8.2), respectively, among those 60 years of age or older and by a factor of 21.7 (95% CI, 10.6 to 44.2) and 3.7 (95% CI, 1.3 to 10.2) among those 40 to 59 years of age. The adjusted rate difference in the primary and secondary analyses was 5.4 and 1.9 cases of severe illness per 100,000 person-days among those 60 years of age or older and 0.6 and 0.1 among those 40 to 59 years of age. Among those 60 years of age or older, mortality was lower by a factor of 14.7 (95% CI, 10.0 to 21.4) in the primary analysis and 4.9 (95% CI, 3.1 to 7.9) in the secondary analysis. The adjusted rate difference in the primary and secondary analyses was 2.1 and 0.8 deaths per 100,000 person-days. Across the age groups studied, rates of confirmed Covid-19 and severe illness were substantially lower among participants who received a booster dose of the BNT162b2 vaccine than among those who did not.

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