December 28, 2023

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RSV

Outcomes of Pediatric SARS-CoV-2 Omicron Infection vs Influenza and Respiratory Syncytial Virus Infections
These are the results of a multicenter, retrospective cohort study that used five population-based data sources and included all three pediatric EDs in Stockholm, Sweden, covering approximately 500 000 individuals younger than 18 years. They identified individuals younger than 18 years attending the ED from August 1, 2021, to September 15, 2022, with a polymerase chain reaction (PCR) test positive for SARS-CoV-2, influenza A/B, or RSV from one day before to one day after the ED visit. Multiplex PCR testing of all three viruses was introduced February 2021, and more than 99% of the study population was tested for all three viruses. For the cohort with Omicron, only visits from December 27, 2021, onward were included, a period when Omicron was the dominating variant (>99% of sequences from Stockholm). They excluded patients testing positive for more than one virus. They ultimately included 2,596 pediatric patients (896 [34.5%] with Omicron, 426 [16.4%] with influenza A/B, and 1274 [48.0%] with RSV). Of patients with RSV, 990 (77.7%) were younger than 2 years vs 648 (72.3%) with Omicron and 81 (19.0%) with influenza. Hospitalization rates were 31.5% (n = 282) for Omicron, 27.7% (n = 118) for influenza, and 81.7% (n = 1041) for RSV. For infants aged 0 to 1 year, odds ratios (ORs) for hospitalization were 11.29 (95% CI, 8.91-14.38) for RSV vs Omicron and 1.67 (95% CI, 1.03-2.68) for influenza vs Omicron. For children aged 2 to 4 years, ORs were 3.96 (95% CI, 2.25-7.01) and 0.31 (95% CI, 0.15-0.65), respectively. For youths aged 5 to 17 years, ORs were 5.22 (95% CI, 2.40-11.81) and 1.10 (95% CI, 0.69-1.77), respectively. ICU admission rates were 0.7% (n = 6) for Omicron, 0.9% (n = 4) for influenza, and 2.9% (n = 37) for RSV. Three patients died within 30 days: Two (0.2%) with Omicron and one (0.1%) with RSV.
Nirsevimab for Prevention of Hospitalizations Due to RSV in Infants
These are the results of a pragmatic trial, where, infants who were 12 months of age or younger, had been born at a gestational age of at least 29 weeks, and were entering their first RSV season in France, Germany, or the United Kingdom were randomly assigned, in a 1:1 ratio to receive either a single intramuscular injection of nirsevimab or standard care (no intervention) before or during the RSV season. The primary end point was hospitalization for RSV-associated lower respiratory tract infection, defined as hospital admission and an RSV-positive test result. A key secondary end point was very severe RSV-associated lower respiratory tract infection, defined as hospitalization for RSV-associated lower respiratory tract infection with an oxygen saturation of less than 90% and the need for supplemental oxygen. A total of 8,058 infants were randomly assigned to receive nirsevimab (4037 infants) or standard care (4,021 infants). Eleven infants (0.3%) in the nirsevimab group and 60 (1.5%) in the standard-care group were hospitalized for RSV-associated lower respiratory tract infection, which corresponded to a nirsevimab efficacy of 83.2% (95% confidence interval [CI], 67.8 to 92.0; P<0.001). Very severe RSV-associated lower respiratory tract infection occurred in five infants (0.1%) in the nirsevimab group and in 19 (0.5%) in the standard-care group, which represented a nirsevimab efficacy of 75.7% (95% CI, 32.8 to 92.9; P=0.004). The efficacy of nirsevimab against hospitalization for RSV-associated lower respiratory tract infection was 89.6% in France, 74.2% in Germany, and 83.4% in the United Kingdom.

COVID: Children and other Vulnerable Populations

School Absenteeism as a Marker for Community COVID-19 Rates
Here the authors performed an observational study of North Carolina kindergarten through 12th grade schools participating in the ABC Science Collaborative that offered in-school instruction, and contributed severe acute respiratory syndrome coronavirus 2 data for at least two of four weeks monthly for the 2021–2022 academic year. They analyzed publicly available databases including the North Carolina Department of Public Instruction, Centers for Disease Control and Prevention COVID-19 Data Repository, and National Center for Education Statistics. They described community and school COVID-19 infection rates compared with student monthly absenteeism rates to determine if the relationship between community COVID-19 infection rates and student absenteeism varied over time. They reported that for every 1% increase in community infection percentage, they found a 1.68% (1.12–2.25%) increase in absenteeism (P < .001); for every 1 month change in time, they found a 0.12% (0.01–0.24%) increase in absenteeism (P < .05).
Impact of the COVID-19 Pandemic on Pediatric Preventive Health Care Among North Carolina Children Enrolled in Medicaid
The authors used an administrative claims database from North Carolina Medicaid to evaluate the rates of well-child visits and immunization administration for children ≤14 months of age, and used a quasi-Poisson regression model to estimate the rate ratio (RR) of each outcome during the pandemic period (3/15/2020 through 3/15/2021) compared with the pre-pandemic period (3/15/2019 through 3/14/2020). They included 83,442 children during the pre-pandemic period and 96,634 children during the pandemic period. During the pre-pandemic period, 405,295 well-child visits and 715,100 immunization administrations were billed; during the pandemic period, 287,285 well-child visits and 457,144 immunization administrations were billed. The rates of well-child visits (RR 0.64; 95% CI, 0.64–0.64) and vaccine administration (RR 0.55; 95% CI, 0.55–0.55) were lower during the pandemic compared with the pre-pandemic period. The rates of well-child visits and immunization administrations among North Carolina children enrolled in public insurance substantially decreased during the first year of the COVID-19 pandemic.

Ventilation/Transmission

Digital measurement of SARS-CoV-2 transmission risk from 7 million contacts
Here these investigators analyzed 7 million contacts notified by the NHS COVID-19 app in England and Wales. They found that transmissions typically resulted from exposures lasting one hour to several days (median six hours, IQR 1.4-28). They found that contact tracing would have identified 80% of contacts if the duration guideline were one hour or more rather than 15 minutes. They found that time and distance were critical factors and challenge the 15 minute within six feet binary.

COVID: Active Vaccination/Immunity

Antibody response and risk of reinfection over two years among the patients with first wave of COVID-19
The investigators describe the dynamics and factors related with infection alone and hybrid humoral response against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and risk of reinfection among first-wave patients. A prospective longitudinal study with periodic serological follow-up after acute onset of all recovered patients with SARS-CoV-2 infection cared in Udine Hospital (March-May 2020). Nucleocapsid (N) protein and spike receptor-binding domain (S-RBD) antibody tests were used to distinguish natural and vaccine induced response. 153 patients (66 men, mean age 56 years) were followed for a median of 27.3 (IQR 26.9-27.8) months. First-wave patients had durable natural humoral immunity in 40% and anti-S-RBD response in 100% up to two years after infection. But reinfections occurred in 16.3% of the patients, mostly during Omicron circulation. Reinfection rates did not differ significantly between SARS-CoV-2-N IgG seronegative and seropositive patients (14/89, 15.7% vs 10/62, 16.1%, p=0.947). Unvaccinated patients had higher risk of reinfection at 57.1% vs vaccinated at 14.4%, p=0.014). The humoral response induced by infection alone was not protective against reinfections with Omicron SARS-CoV-2 variants, whereas vaccination was effective to reduce the risk of a new infection.
Oral COVID-19 antiviral uptake among a highly vaccinated U.S. cohort of adults with SARS-CoV-2 infection between December 2021 and October 2022
Between 12/2021 and 10/2022 NMV/r uptake was only 13.6% (95% CI: 11.9% – 15.2%) among 1,594 participants and MOV uptake was 1.4%. The highest uptake of NMV/r in the study was among those aged 65 and over (30.2%) which is similar to a study conducted in Massachusetts and New Hampshire. So only a third of the eligible participants with SARS-CoV-2 infection in this study over 65 years received NMV/r.

COVID: Early Viral Phase

SARS-CoV-2 Rebound With and Without Use of COVID-19 Oral Antivirals
Early treatment with a first-line therapy (nirmatrelvir/ritonavir [Paxlovid] or remdesivir) or second-line therapy (molnupiravir) prevents hospitalization and death among patients with mild-to-moderate COVID-19 who are at risk for severe disease and is recommended by the National Institutes of Health COVID-19 Treatment Guidelines. On May 25, 2023, the Food and Drug Administration approved nirmatrelvir/ritonavir (Paxlovid) for treatment of adults at high risk for severe disease. Although antiviral therapies are widely available, they are underutilized, possibly because of reports of SARS-CoV-2 rebound after treatment. To enhance current understanding of rebound, CDC reviewed SARS-CoV-2 rebound studies published during February 1, 2020 – November 29, 2023. Overall, seven of 23 studies that met inclusion criteria, one randomized trial and six observational studies, compared rebound for persons who received antiviral treatment with that for persons who did not receive antiviral treatment. In four studies, including the randomized trial, no statistically significant difference in rebound rates was identified among persons receiving treatment and those not receiving treatment. Depending on the definition used, the prevalence of rebound varied. No hospitalizations or deaths were reported among outpatients who experienced rebound, because COVID-19 signs and symptoms were mild. The review suggests that potential for rebound should not deter clinicians from prescribing lifesaving antiviral treatments when indicated to prevent morbidity and mortality from COVID-19.
Evaluation of SARS-CoV-2 RNA Rebound After Nirmatrelvir/Ritonavir Treatment in Randomized, Double-Blind, Placebo-Controlled Trials — United States and International Sites, 2021–2022
Viral RNA shedding data from two phase 2/3, randomized, double-blind, placebo-controlled clinical trials of nirmatrelvir/ritonavir (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients [EPIC-HR] and Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients [EPIC-SR]) were analyzed to investigate the role of nirmatrelvir/ritonavir treatment in COVID-19 rebound. Rates of rebound of SARS-CoV-2 RNA shedding, identified based on an increase in nasopharyngeal viral RNA levels from day five (end-of-treatment) to day 10 or day 14, were similar between nirmatrelvir/ritonavir and placebo recipients. Among subjects with a virologic response through day five, viral RNA rebound occurred in 6.4%–8.4% of nirmatrelvir/ritonavir recipients and 5.9%–6.5% of placebo recipients across EPIC-HR and the 2021/pre-Omicron and 2022/Omicron enrollment periods of EPIC-SR. Viral RNA rebound after nirmatrelvir/ritonavir treatment was not associated with COVID-19–related hospitalization or death. Data from randomized trials demonstrated that SARS-CoV-2 rebound can occur with or without antiviral treatment, supporting the Food and Drug Administration’s determination of safety and efficacy of nirmatrelvir/ritonavir in eligible patients at high risk for severe COVID-19.
Azvudine and nirmatrelvir–ritonavir in hospitalized patients with moderate-to-severe COVID-19: Emulation of a randomized target trial
Azudine is a prodrug that can be intracellularly converted into FNC triphosphate a nucleoside analogue so it gets incorporated into the RNA of the replicating virus and causes chain termination. It is a potential broad spectrum RdRp inhibitor for RNA viruses. These are the results from a target trial with a multicenter retrospective cohort of hospitalized adults with moderate-to-severe COVID-19 without contraindications for azvudine or nirmatrelvir–ritonavir between December 01, 2022 and January 19, 2023 (during the Omicron BA.5.2 variant wave). Primary composite outcome (all-cause death and initiation of invasive mechanical ventilation), and their separate events were evaluated. Among the 2,262 patients admitted to non-ICU departments with confirmed moderate-to-severe COVID–19 around hospital admission, the primary analysis included 1,154 participants, with 311 receiving azvudine, 165 receiving nirmatrelvir–ritonavir, and 678 not receiving antiviral treatment. Of the 1,154 patients, 27.2% were severe cases. In the intent-to-treat analyses, azvudine reduced all-cause death (Hazard ratio [HR]: 0.31; 95% CI: 0.12–0.78), and its composite with invasive mechanical ventilation (HR: 0.47; 95% CI: 0.24–0.92). Nirmatrelvir–ritonavir reduced invasive mechanical ventilation (HR: 0.42; 95% CI: 0.17–1.05), and its composite with all-cause death (HR: 0.38; 95% CI: 0.18–0.81). Of note: The median days from symptoms onset to receiving treatment was 8 days (IQR: 5–11 days). Hypertension affected 37.3% of participants, followed by diabetes (27.3%), cardiovascular disease (19.8%), and chronic obstructive pulmonary disease (10.3%). At baseline, 86.2% of participants received respiratory support, 68.9% received antibiotics, 24.6% received anticoagulants, 6.8% received nonsteroidal anti-inflammatory drugs, and 48.4% were treated with glucocorticoids. Since over 90% of Chinese adults had been vaccinated before December 2022, these results likely reflect the effectiveness of these two drugs in vaccinated people. Advantages are ease of dosing with one azvudine 5-mg tablet once daily for five days

COVID: Cytokine Storm Week

Simvastatin in Critically Ill Patients with Covid-19
This is more from the REMAP-CAP Investigators. These results are from the ongoing international, multifactorial, adaptive platform, randomized, controlled trial. Authors evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support–free days, assessed on an ordinal scale combining in-hospital death (assigned a value of −1) and days free of organ support through day 21 in survivors. On January 8, 2023, enrollment was closed on the basis of a low anticipated likelihood that prespecified stopping criteria would be met as Covid-19 cases decreased. The final analysis included 2,684 critically ill patients. The median number of organ support–free days was 11 (interquartile range, −1 to 17) in the simvastatin group and seven (interquartile range, −1 to 16) in the control group; the posterior median adjusted odds ratio was 1.15 (95% credible interval, 0.98 to 1.34) for simvastatin as compared with control. Serious adverse events, such as elevated levels of liver enzymes and creatine kinase, were reported more frequently with simvastatin than with control.

COVID: The Late Phase/PASC/Long COVID

COVID-19 mRNA Vaccination Reduces the Occurrence of Post-COVID Conditions in U.S. Children Aged 5-17 Years Following Omicron SARS-CoV-2 Infection, July 2021-September 2022
A multi-site cohort of children enrolled 7/21/2021-9/1/2022 underwent weekly SARS-CoV-2 screening tests and were surveyed via self- or parental report 12/1/2022-5/31/2023 regarding PCC (defined as ≥1 new or on-going symptoms lasting ≥ 1 month after infection). Multivariable logistic regression was performed to estimate the occurrence of PCC by vaccination status among children aged 5–17 years whose first PCR-confirmed SARS-CoV-2 infection occurred in-study with Omicron variant, who completed the survey >60 days from infection, and who were vaccine age-eligible at time of infection per ACIP recommendations. Vaccination status was categorized as vaccinated (at least primary series completed >14 days before infection) and unvaccinated (no vaccine doses before infection). Vaccination status was verified through vaccine registry and/or medical records. Of 622 participants surveyed, 5% (n=28) had PCC and 67% (n=474) were vaccinated. Surveys were completed a median (IQR) of 203.7 days (119.0–293.0) after infection. When comparing children with and without PCC symptoms, COVID-19 mRNA vaccination was associated with a decreased likelihood of >1 PCC symptom (aOR 0.66, 95% CI 0.43-0.99), >2 PCC symptoms (aOR 0.52, 95% 0.32-0.83), and respiratory PCC symptoms (aOR 0.53, 95% CI 0.33-0.87) The adjusted ORs correspond to an estimated 34%, 48%, and 47% reduced likelihood of >1, >2, and respiratory PCC symptoms among vaccinated children, respectively.