Coronavirus COVID-19 Update for April 11, 2021

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Clinical Reports

Croup Associated With SARS-CoV-2: Pediatric Laryngotracheitis During the Omicron Surge
This was a small retrospective analysis, describing weekly croup and corresponding viral prevalence patterns in a pediatric quaternary care system in metropolitan Atlanta. Researchers data show evidence of a croup clinical infectious syndrome associated with SARS-CoV-2 that appears to resemble clinical features of croup caused by other respiratory viruses and increased substantially in frequency during the Omicron variant surge. However, this data also indicates a dramatic increase in frequency of younger children being diagnosed with COVID-19 during ED visits in association with the Omicron variant, when compared with a recent Delta variant surge. Overall, this supports ongoing efforts to immunize younger children, who continue to be adversely affected by COVID-19.
Rhinovirus as the main co-circulating virus during the COVID-19 pandemic in children
The present study's aim was to describe the prevalence of a large array of respiratory pathogens in symptomatic children and adolescents during the pandemic in Southern Brazil. 436 participants were included, with 45 of these hospitalized. Rhinovirus was the most prevalent pathogen (216/436) followed by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, 97/436), with a coinfection of these two viruses occurring in 31/436 participants. The remaining pathogens were found in 24 symptomatic participant (adenovirus, n = 6; Chlamydophila pneumoniae, n = 1; coronavirus NL63, n = 2; human enterovirus, n = 7; human metapneumovirus, n = 2; Mycoplasma pneumoniae, n = 6). Hospitalization was more common among infants (p = 0.004) and those with pathogens other than SARS-CoV-2 (p = 0.001). During the period of social distancing in response to COVID-19, the prevalence of most respiratory pathogens was unusually low. Rhinovirus remained as the main virus co-circulating with SARS-CoV-2. COVID-19 in symptomatic children was less associated with hospitalization than with other respiratory infections in children and adolescents.
Children and COVID-19: State-Level Data Report
A joint report from the American Academy of Pediatrics and the Children’s Hospital Association. Summary of publicly reported data from 49 states, NYC, DC, PR, and GU Version: 5/19/22. The numbers in this report represent cumulative counts since states began reporting. The data are based on how public agencies collect, categorize and post information. All data reported by state/local health departments are preliminary and subject to change and reporting may change over time. Notably, in the summer of 2021 and winter of 2022, some states have revised cases counts previously reported, begun reporting less frequently, or dropped metrics previously reported. For example, due to several changes on their dashboards and the data currently available, AL, TX, HI, DC and MS data in this report are not current (cumulative data through 7/29/21, 8/26/21, 1/13/22, 3/3/22, and 3/10/22 respectively). Readers should consider these factors. States may have additional information on their web sites.

Antiviral Therapeutics and Vaccines

Infectious viral shedding of SARS-CoV-2 Delta following vaccination: a longitudinal cohort study
Researchers compared longitudinal viral shedding dynamics in unvaccinated and fully vaccinated adults. SARS-CoV-2-infected adults were enrolled within 5 days of symptom onset and nasal specimens were self-collected daily for two weeks and intermittently for an additional two weeks. SARS-CoV-2 RNA load and infectious virus were analyzed relative to symptom onset stratified by vaccination status. We tested 1080 nasal specimens from 52 unvaccinated adults enrolled in the pre-Delta period and 32 fully vaccinated adults with predominantly Delta infections. While we observed no differences by vaccination status in maximum RNA levels, maximum infectious titers and the median duration of viral RNA shedding, the rate of decay from the maximum RNA load was faster among vaccinated; maximum infectious titers and maximum RNA levels were highly correlated. Furthermore, amongst participants with infectious virus, median duration of infectious virus detection was reduced from 7.5 days (IQR: 6.0-9.0) in unvaccinated participants to 6 days (IQR: 5.0-8.0) in those vaccinated (P=0.02). Accordingly, the odds of shedding infectious virus from days 6 to 12 post-onset were lower among vaccinated participants than unvaccinated participants (OR 0.42 95% CI 0.19-0.89). These results indicate that vaccination had reduced the probability of shedding infectious virus after 5 days from symptom onset.
Pfizer-BioNTech COVID-19 Vaccine Demonstrates Strong Immune Response, High Efficacy and Favorable Safety in Children 6 Months to Under 5 Years of Age Following Third Dose
In the Phase 2/3 trial, 1,678 children received a third dose of the 3-µg formulation at least two months after the second dose at a time when Omicron was the predominant variant. The immunogenicity analysis of geometric mean titer (GMT) ratio and seroresponse rate was conducted on a subset of study participants one month following the third dose in children 6 months to under 5 years of age, compared to the second dose in the 16- to 25-year-old population. Non-inferiority was met for both the 6- to 24-month-old population and the 2- to under 5-year-old population for both co-primary endpoints. Three 3-µg doses of the Pfizer-BioNTech COVID-19 Vaccine was well-tolerated in this age group, and no new safety signals were identified. The majority of adverse events were mild or moderate. Studies in adults, adolescents, and children over 5 years of age continue to indicate that three doses of the Pfizer-BioNTech COVID-19 Vaccine enhances protection compared to two doses. The safety, immunogenicity and vaccine efficacy data for three doses of the vaccine in children under 5 years of age are consistent with the data seen in adults, suggesting that a third dose will provide similar benefit in children.
Protection of mRNA vaccines against hospitalized COVID-19 in adults over the first year following authorization in the United States
Case control analysis of adults (≥18 years) hospitalized at 21 hospitals in 18 states March 11 – December 15, 2021, including COVID-19 case patients and RT-PCR-negative controls. Study researchers included adults who were unvaccinated or vaccinated with two doses of a mRNA vaccine before the date of illness onset. VE over time was assessed using logistic regression comparing odds of vaccination in cases versus controls, adjusting for confounders. 10,078 patients were included, 4906 cases (23% vaccinated) and 5172 controls (62% vaccinated). Median age was 60 years (IQR 46–70), 56% were non-Hispanic White, and 81% had ≥1 medical condition. Among immunocompetent adults, VE <180 days was 90% (95%CI: 88–91) vs 82% (95%CI: 79–85) at ≥180 days (p < 0.001). VE declined for Pfizer-BioNTech (88% to 79%, p < 0.001) and Moderna (93% to 87%, p < 0.001) products, for younger adults (18-64 years) [91% to 87%, p = 0.005], and for adults ≥65 years of age (87% to 78%, p < 0.001). In models using restricted cubic splines, similar changes were observed. In a period largely pre-dating Omicron variant circulation, effectiveness of two mRNA doses against COVID-19-associated hospitalization was largely sustained through 9 months.
Transfusing convalescent plasma as post-exposure prophylaxis against SARS-CoV-2 infection: a double-blinded, phase 2 randomized, controlled trial
This double-blinded, phase 2 randomized, controlled trial (RCT) compared the efficacy and safety of prophylactic high titer (≥1:320 by Euroimmun ELISA) CCP with standard plasma. Asymptomatic participants aged ≥18 years with close contact exposure to a person with confirmed COVID-19 in the previous 120 hours and negative SARS-CoV-2 test within 24 hours before transfusion were eligible. The primary outcome was new SARS-CoV-2 infection. 180 participants were enrolled; 87 were assigned to CCP and 93 to control plasma, and 170 transfused at 19 sites across the United States from June 2020 to March 2021. Two were excluded for screening SARS-CoV-2 RT-PCR positivity. Of the remaining 168 participants, 12/81 (14·8%) CCP and 13/87 (14·9%) control recipients developed SARS-CoV-2 infection; 6 (7·4%) CCP and 7 (8%) control recipients developed COVID-19 (infection with symptoms). There were no COVID-19-related hospitalizations in CCP and 2 in control recipients. Efficacy by restricted mean infection free time (RMIFT) by 28 days for all SARS-CoV-2 infections (25·3 vs. 25·2 days; p = 0·49) and COVID-19 (26·3 vs. 25·9 days; p = 0·35) was similar for both groups. Administration of high-titer CCP as post-exposure prophylaxis, while appearing safe, did not prevent SARS-CoV-2 infection.
Real-world effectiveness of molnupiravir and nirmatrelvir/ritonavir among COVID-19 inpatients during Hong Kong's Omicron BA.2 wave: an observational study
This retrospective cohort study aims to evaluate the clinical and virologic outcomes associated with molnupiravir and nirmatrelvir/ritonavir use in COVID-19 patients during a pandemic wave dominated by the Omicron BA.2 variant. Study researchers analyzed data from a territory-wide retrospective cohort of hospitalized patients with confirmed diagnosis of SARS-CoV-2 infection from 26th February 2022 to 26th April 2022 in Hong Kong. Oral antiviral users were matched with controls using propensity-score matching in a ratio of 1:4. Study outcomes were a composite outcome of disease progression (all-cause mortality, initiation of invasive mechanical ventilation [IMV], or intensive care unit admission) and their individual outcomes, and lower viral load of cycle threshold (Ct) value ≥30 cycles. Hazard ratios (HR) of event outcomes were estimated using Cox regression models. Among 40,776 hospitalized patients with SARS-CoV-2 infection over a mean follow-up of 41.3 days with 925,713 person-days, 2,359 and 1,000 patients not initially requiring oxygen therapy were initiated with molnupiravir and nirmatrelvir/ritonavir, respectively. The crude incidence rates of all-cause mortality and IMV were 22.24 and 1.06 events per 10,000 person-days among molnupiravir users, 11.04 and 1.75 events per 10,000 person-days among nirmatrelvir/ritonavir users. Oral antiviral use was associated with a significantly lower risk of the composite outcome of disease progression (molnupiravir: HR=0.53, 95%CI=0.46-0.62, p<0.001; nirmatrelvir/ritonavir: HR=0.33, 95%CI=0.24-0.46, p<0.001) than non-use, which was consistently observed for all-cause mortality (molnupiravir: HR=0.55, 95%CI=0.47-0.63, p<0.001; nirmatrelvir/ritonavir: HR=0.32, 95%CI=0.23-0.45, p<0.001). Molnupiravir users had lower risks of IMV (HR=0.31, 95%CI=0.16-0.61, p<0.001). Time to achieving lower viral load was significantly shorter among oral antiviral users than matched controls (molnupiravir: HR=1.21, 95%CI=1.07-1.37, p=0.002; nirmatrelvir/ritonavir: HR=1.25, 95%CI=1.04-1.50, p=0.015). Amongst survivors, nirmatrelvir/ritonavir had shorter length of hospital stay (-0.70 days, 95%CI=-1.37 to -0.04, p=0.039) than matched controls. Head-to-head comparison of molnupiravir and nirmatrelvir/ritonavir reported higher risk of mortality (HR=1.53 95%CI=1.01-2.31, p=0.047) and longer length of hospital stay (0.83 days, 95%CI=0.07-1.58, p=0.032) for molnupiravir users. Against Omicron BA.2, initiation of novel oral antiviral treatment in hospitalized patients not requiring any oxygen therapy was associated with lower risks of disease progression and all-cause mortality, in addition to achieving low viral load faster.
Impact of the Use of Oral Antiviral Agents on the Risk of Hospitalisation in Community COVID-19 Patients
Researchers examined the effectiveness of molnupiravir and nirmatrelvir/ritonavir in reducing hospitalization and deaths in a real-world cohort of non-hospitalised COVID-19 patients. This was a territory-wide retrospective cohort study in Hong Kong. Non-hospitalized COVID-19 patients who attended designated outpatient clinics between 16 February and 31 March 2021 were identified. Patients who were hospitalized on the day of the first appointment at clinic or used both oral antivirals were excluded. The primary endpoint was hospitalization. The secondary endpoint was a composite of intensive care unit admission, invasive mechanical ventilation use, and/or death. Patients’ clinical characteristics were balanced using propensity score weighting. Of 93,883 patients, 83,154 (88·6%), 5,808 (6·2%), and 4,921 (5·2%) were oral antiviral non-users, molnupiravir users, and nirmatrelvir/ritonavir users respectively. Compared to non-users, oral antiviral users were older and had more comorbidities, lower complete vaccination rate, and more hospitalisations in the previous year. Molnupiravir users were older, and had more comorbidities, lower complete vaccination rate, and more hospitalizations in the previous year than nirmatrelvir/ritonavir users. At a median follow-up of 30 days, 1,931 (2·1%) patients were admitted to hospital and 225 (0·2%) patients developed the secondary endpoint. After propensity score weighting, nirmatrelvir/ritonavir use (weighted hazard ratio 0·79, 95% CI 0·65-0·95, P =0·011) but not molnupiravir use (weighted hazard ratio 1·17, 95% CI 0·99-1·39, P =0·062) was associated with a reduced risk of hospitalization than non-users. The use of molnupiravir or nirmatrelvir/ritonavir was not associated with a lower risk of the secondary endpoint as compared to non-users. In the subgroup of patients aged ≥60 years or aged <60 years with comorbidities, nirmatrelvir/ritonavir use but not molnupiravir use was associated with a reduced risk of hospitalization than non-users. The use of nirmatrelvir/ritonavir but not molnupiravir was associated with a reduced risk of hospitalization in real-world non-hospitalized COVID-19 patients.
COVID-19 Rebound After Paxlovid Treatment
Paxlovid continues to be recommended for early-stage treatment of mild to moderate COVID-19 among persons at high risk for progression to severe disease. Paxlovid treatment helps prevent hospitalization and death due to COVID-19. COVID-19 rebound has been reported to occur between 2 and 8 days after initial recovery and is characterized by a recurrence of COVID-19 symptoms or a new positive viral test after having tested negative. A brief return of symptoms may be part of the natural history of SARS-CoV-2 (the virus that causes COVID-19) infection in some persons, independent of treatment with Paxlovid and regardless of vaccination status. Limited information currently available from case reports suggests that persons treated with Paxlovid who experience COVID-19 rebound have had mild illness; there are no reports of severe disease. There is currently no evidence that additional treatment is needed with Paxlovid or other anti-SARS-CoV-2 therapies in cases where COVID-19 rebound is suspected.
Rapid Relapse of Symptomatic Omicron SARS-CoV-2 Infection Following Early Suppression with Nirmatrelvir/Ritonavir
Researchers describe relapse of COVID-19 symptoms and SARS-CoV-2 viral load following nirmatrelvir/ritonavir (NM/R) in 8 non-immunocompromised patients aged 31 to 71-years-old. Most patients improved rapidly after treatment with NM/R and had negative antigen or PCR tests prior to relapse on Days 9-12 of their illness. Relapse symptoms were described most frequently as cold symptoms, though some patients experiencing a recurrence of fatigue and headache. All relapses resolved without additional antiviral treatment. Viral load during relapse was comparable to levels during initial infection. Sequencing in three patients indicated that relapse was not due to a treatment-emergent mutation or infection with a different viral strain. One patient transmitted SARS-CoV-2 to two family members during relapse. The presence of high viral load and the occurrence of one transmission event suggest that patients with relapse should isolate until antigen testing is negative.
Trajectory of long covid symptoms after covid-19 vaccination: community based cohort study
In this observational cohort study, the mean age of participants was 46 years, 55.6% (n=15 760) were women, and 88.7% (n=25 141) were of white ethnicity. Median follow-up was 141 days from first vaccination (among all participants) and 67 days from second vaccination (83.8% of participants). 6729 participants (23.7%) reported long covid symptoms of any severity at least once during follow-up. A first vaccine dose was associated with an initial 12.8% decrease (95% confidence interval −18.6% to −6.6%, P<0.001) in the odds of long covid, with subsequent data compatible with both increases and decreases in the trajectory (0.3% per week, 95% confidence interval −0.6% to 1.2% per week, P=0.51). A second dose was associated with an initial 8.8% decrease (95% confidence interval −14.1% to −3.1%, P=0.003) in the odds of long covid, with a subsequent decrease by 0.8% per week (−1.2% to −0.4% per week, P<0.001). Heterogeneity was not found in associations between vaccination and long covid by sociodemographic characteristics, health status, hospital admission with acute covid-19, vaccine type (adenovirus vector or mRNA), or duration from SARS-CoV-2 infection to vaccination. The likelihood of long covid symptoms was observed to decrease after covid-19 vaccination and evidence suggested sustained improvement after a second dose, at least over the median follow-up of 67 days. Vaccination may contribute to a reduction in the population health burden of long covid, although longer follow-up is needed.

Epidemiology

Excess Mortality in Massachusetts During the Delta and Omicron Waves of COVID-19
During the 23-week Delta period, 1,975 all-cause excess deaths occurred (27,265 observed; 25,290 expected; 95% CI, 671-3297 excess deaths). During the 8-week Omicron period, 2,294 excess deaths occurred (12 231 observed; 9937 expected; 95% CI, 1795-2763 excess deaths). The per-week Omicron to Delta incident rate ratio for excess mortality was 3.34 (95% CI, 3.14-3.54). Statistically significant excess mortality occurred in all adult age groups at various times during the study period and in each period overall. For all adult age groups, the ratio of observed to expected excess mortality increased during the Omicron period compared with the Delta period.
A Longitudinal Study of COVID-19 Sequelae and Immunity: Baseline Findings
In this study, 189 persons with laboratory-documented COVID-19 (12% of whom were hospitalized during acute illness) and 120 antibody-negative control participants were enrolled. At enrollment, symptoms consistent with PASC were reported by 55% of the COVID-19 cohort and 13% of control participants. Increased risk for PASC was noted in women and those with a history of anxiety disorder. Participants with findings meeting the definition of PASC reported lower quality of life on standardized testing. Abnormal findings on physical examination and diagnostic testing were uncommon. Neutralizing antibody levels to spike protein were negative in 27% of the unvaccinated COVID-19 cohort and none of the vaccinated COVID-19 cohort. Exploratory studies found no evidence of persistent viral infection, autoimmunity, or abnormal immune activation in participants with PASC. Most participants with COVID-19 had mild to moderate acute illness that did not require hospitalization. The prevalence of reported PASC was likely overestimated in this cohort because persons with PASC may have been more motivated to enroll. The study did not capture PASC that resolved before enrollment. A high burden of persistent symptoms was observed in persons after COVID-19. Extensive diagnostic evaluation revealed no specific cause of reported symptoms in most cases. Antibody levels were highly variable after COVID-19.
…Post–COVID Conditions Among Adult COVID-19 Survivors Aged 18–64 and ≥65 Years — United States, March 2020–November 2021
These are the results of a retrospective matched cohort design that analyzed EHRs during March 2020–November 2021, from Cerner Real-World Data,* a national, deidentified data set of approximately 63.4 million unique adult records from 110 data contributors in the 50 states. It was reported that COVID-19 survivors have twice the risk for developing pulmonary embolism or respiratory conditions; one in five COVID-19 survivors aged 18–64 years and one in four survivors aged ≥65 years experienced at least one incident condition that might be attributable to previous COVID-19.