Coronavirus COVID-19 Update for April 11, 2021

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Clinical Reports

Long-term Symptoms After SARS-CoV-2 Infection in Children and Adolescents
Ciao Corona is a longitudinal cohort study investigating SARS-CoV-2 seroprevalence in 55 randomly selected schools in the canton of Zurich in Switzerland,⁵^,⁶ which has a linguistically and ethnically diverse population of 1.5 million residents in urban and rural settings. Schools were selected randomly from the 12 cantonal districts, with the number of schools proportional to population size. In Switzerland, children attended schools in person (with protective measures) in 2020-2021, except during a 6-week nationwide lockdown (March 16 to May 10, 2020). Within participating schools, all children of randomly selected classes were invited to participate. Between June 2020 and April 2021, 3 testing phases included a collection of venous blood for serologic analysis and online questionnaires for symptoms. Children who tested positive for SARS-CoV-2 antibodies in October or November 2020 were compared with those who tested negative. Children who were seronegative in October or November 2020 and seroconverted or were not retested by March or April 2021 were excluded. From March to May 2021, parents reported symptoms of their children occurring since October 2020 and lasting for at least 4 weeks, as well as whether the symptoms persisted for more than 12 weeks. The questionnaire contained a list of predefined symptoms and a free-text field. Between October and November 2020 and March and April 2021, 4 of 109 seropositive children (4%) vs 28 of 1246 seronegative ones (2%) reported at least 1 symptom lasting beyond 12 weeks. The most frequently reported symptoms lasting more than 12 weeks among seropositive children were tiredness (3/109, 3%), difficulty concentrating (2/109, 2%), and increased need for sleep (2/109, 2%). None of the seropositive children reported hospitalization after October 2020. Similar proportions of seropositive and seronegative children reported excellent or good health.

Longitudinal Outcomes for Multisystem Inflammatory Syndrome in Children
In spring 2020, a novel hyperinflammatory process associated with severe acute respiratory syndrome coronavirus 2 multisystem inflammatory syndrome in children (MIS-C) was described. The long-term impact remains unknown. Authors report longitudinal outcomes from a New York interdisciplinary follow-up program. All children <21 years of age, admitted to New York-Presbyterian with MIS-C in 2020, were included. Children were followed at 1 to 4 weeks, 1 to 4 months, and 4 to 9 months post-discharge. In total, 45 children were admitted with MIS-C. The median time to the last follow-up was 5.8 months (interquartile range 1.3–6.7). Of those admitted, 76% required intensive care and 64% required vasopressors and/or inotropes. On admission, patients exhibited significant nonspecific inflammation, generalized lymphopenia, and thrombocytopenia. Soluble interleukin (IL) IL-2R, IL-6, IL-10, IL-17, IL-18, and C-X-C Motif Chemokine Ligand 9 were elevated. A total of 80% (n = 36) had at least mild and 44% (n = 20) had moderate-severe echocardiographic abnormalities including coronary abnormalities (9% had a z score of 2–2.5; 7% had a z score > 2.5). Whereas most inflammatory markers normalized by 1 to 4 weeks, 32% (n = 11 of 34) exhibited persistent lymphocytosis, with increased double-negative T cells in 96% of assessed patients (n = 23 of 24). By 1 to 4 weeks, only 18% (n = 7 of 39) had mild echocardiographic findings; all had normal coronaries. At 1 to 4 months, the proportion of double-negative T cells remained elevated at 92% (median 9%). At 4 to 9 months, only 1 child had persistent mild dysfunction. One had mild mitral and/or tricuspid regurgitation. Although the majority of children with MIS-C present critically ill, most inflammatory and cardiac manifestations in our cohort resolved rapidly.

Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection
Immune memory against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) helps to determine protection against reinfection, disease risk, and vaccine efficacy. Using 188 human cases across the range of severity of COVID-19, authors analyzed cross-sectional data describing the dynamics of SARS-CoV-2 memory B cells, CD8⁺ T cells, and CD4⁺ T cells for more than 6 months after infection. The authors found a high degree of heterogeneity in the magnitude of adaptive immune responses that persisted into the immune memory phase of the virus. However, immune memory in three immunological compartments remained measurable in greater than 90% of subjects for more than 5 months after infection. Despite the heterogeneity of immune responses, these results show that durable immunity against secondary COVID-19 disease is a possibility for most individuals.

SARS-CoV-2 infection rates of antibody-positive compared with antibody-negative health-care workers in England: a large, multicentre, prospective cohort study (SIREN)
Increased understanding of whether individuals who have recovered from COVID-19 are protected from future SARS-CoV-2 infection is an urgent requirement. The authors investigated whether antibodies against SARS-CoV-2 were associated with a decreased risk of symptomatic and asymptomatic reinfection. A large, multicentre, prospective cohort study was done, with participants recruited from publicly funded hospitals in all regions of England. All healthcare workers, support staff, and administrative staff working at hospitals who could remain engaged in follow-up for 12 months were eligible to join The SARS-CoV-2 Immunity and Reinfection Evaluation study. Participants were excluded if they had no PCR tests after enrolment, enrolled after Dec 31, 2020, or had insufficient PCR and antibody data for cohort assignment. Participants attended regular SARS-CoV-2 PCR and antibody testing (every 2–4 weeks) and completed questionnaires every 2 weeks on symptoms and exposures. At enrolment, participants were assigned to either the positive cohort (antibody positive, or previous positive PCR or antibody test) or the negative cohort (antibody negative, no previous positive PCR or antibody test). The primary outcome was reinfection in the positive cohort or primary infection in the negative cohort, determined by PCR tests. Potential reinfections were clinically reviewed and classified according to case definitions (confirmed, probable, or possible) and symptom status, depending on the hierarchy of evidence. Primary infections in the negative cohort were defined as a first positive PCR test and seroconversions were excluded when not associated with a positive PCR test. A proportional hazards frailty model using a Poisson distribution was used to estimate incidence rate ratios (IRR) to compare infection rates in the two cohorts. From June 18, 2020, to Dec 31, 2020, 30 625 participants were enrolled in the study. 51 participants withdrew from the study, 4913 were excluded, and 25 661 participants (with linked data on antibody and PCR testing) were included in the analysis. Data were extracted from all sources on Feb 5, 2021, and include data up to and including Jan 11, 2021. 155 infections were detected in the baseline positive cohort of 8278 participants, collectively contributing 2 047 113 person-days of follow-up. This compares with 1704 new PCR positive infections in the negative cohort of 17 383 participants, contributing 2 971 436 person-days of follow-up. The incidence density was 7·6 reinfections per 100 000 person-days in the positive cohort, compared with 57·3 primary infections per 100 000 person-days in the negative cohort, between June 2020, and January 2021. The adjusted IRR was 0·159 for all reinfections (95% CI 0·13–0·19) compared with PCR-confirmed primary infections. The median interval between primary infection and reinfection was more than 200 days. Results indicate that a previous history of SARS-CoV-2 infection was associated with an 84% lower risk of infection, with a median protective effect observed 7 months following primary infection. This time period is the minimum probable effect because seroconversions were not included. This study shows that previous infection with SARS-CoV-2 induces effective immunity to future infections in most individuals.

Post-Discharge Symptoms among Hospitalized COVID-19 Patients in Nigeria: A Single-Center Study
There is a paucity of studies on post-acute COVID-19 syndrome (PCS) among hospitalized COVID-19 survivors from Nigeria. The authors describe the frequency, types, and duration of post-discharge symptoms suggestive of PCS among previously hospitalized COVID-19 patients in a treatment center in Nigeria. A retrospective review of admission and post-discharge follow-up medical records of COVID-19 survivors admitted between April and December 2020 was conducted. A standardized checklist was used to document post-discharge symptoms. PCS was defined as persisting or new post-discharge symptoms lasting at least 3 weeks after initial COVID-19 symptoms. The relationship between study variables and the development of PCS was ascertained by univariate analysis. Thirty of 51 previously hospitalized COVID-19 patients (median age, 46 years; male, 66.7%) were studied. Seventeen (56.7%) of the 30 patients developed features suggestive of PCS. Approximately three post-discharge symptoms were reported per patient over a follow-up period ranging from 3 weeks to 9 months after initial COVID-19 symptoms. Cough, fatigue, and dyspnea were the most common post-discharge symptoms reported. A few patients had symptoms suggestive of thrombosis and COVID-19 reinfection. Among all study variables, baseline COVID-19 severity was the only significant variable associated with the development of PCS. PCS is common in our setting and is characterized by multisystemic signs and symptoms that require vigilance by clinicians for appropriate diagnosis and treatment. Long-term multicenter prospective studies are needed to characterize fully the burden of PCS among COVID-19 survivors in Nigeria.

Clinical Recommendations

American Academy of Pediatrics Updates Recommendations for Opening Schools in Fall 2021
In updated guidance for the 2021-22 school year, the American Academy of Pediatrics strongly recommends in-person learning and urges all who are eligible to be vaccinated to protect against COVID-19. In addition to vaccinations, the AAP recommends a layered approach to make school safe for all students, teachers, and staff. That includes a recommendation that everyone older than age 2 wear masks, regardless of vaccination status. The AAP also amplifies the Centers for Disease Control and Prevention’s recommendations for building ventilation, testing, quarantining, cleaning, and disinfection in the updated guidance. AAP recommends universal masking because a significant portion of the student population is not yet eligible for vaccines, and masking is proven to reduce transmission of the virus and protect those who are not vaccinated. Many schools will not have a system to monitor the vaccine status of students, teachers, and staff, and some communities overall have low vaccination uptake where the virus may be circulating more prominently.

Antiviral Therapeutics and Vaccines

Low dose mRNA-1273 COVID-19 vaccine generates durable T cell memory and antibodies enhanced by pre-existing cross-reactive T cell memory
Authors examined vaccine-specific CD4⁺ T cell, CD8⁺ T cell, binding antibody, and neutralizing antibody responses to the 25 μg Moderna mRNA-1273 vaccine over 7 months post-immunization, including multiple age groups, with a particular interest in assessing whether pre-existing cross-reactive T cell memory impacts vaccine-generated immunity. Low dose (25 μg) mRNA-1273 elicited durable Spike binding antibodies comparable to that of convalescent COVID-19 cases. Vaccine-generated Spike memory CD4⁺ T cells 6 months post-boost were comparable in quantity and quality to COVID-19 cases, including the presence of T_FH cells and IFNγ-expressing cells. Spike CD8⁺ T cells were generated in 88% of subjects, with equivalent percentages of CD8⁺ T cell memory responders at 6 months post-boost compared to COVID-19 cases. Lastly, subjects with pre-existing cross-reactive CD4⁺ T cell memory had increased CD4⁺ T cell and antibody responses to the vaccine, demonstrating a biological relevance of SARS-CoV-2 crossreactive CD4⁺ T cells.
Effect of Oral Azithromycin vs Placebo on COVID-19 Symptoms in Outpatients With SARS-CoV-2 Infection
The question address in this study is whether a single oral dose of azithromycin leads to the absence of symptoms at day 14 in outpatients with COVID-19 compared with placebo. In this randomized trial that included 263 participants with SARS-CoV-2 infection, treatment with a single oral dose of azithromycin, 1.2 g, vs placebo resulted in the self-reported absence of COVID-19 symptoms at day 14 in 50% vs 50%; this was not statistically significant. Among outpatients with SARS-CoV-2 infection, treatment with a single dose of oral azithromycin compared with placebo did not result in a greater likelihood of being free of symptoms at day 14.
COVID-19 Therapeutics for Low- and Middle-Income Countries: A Review of Candidate Agents with Potential for Near-Term Use and Impact
Low- and middle-income countries (LMICs) face significant challenges in the control of COVID-19, given limited resources, especially for inpatient care. In a parallel effort to that for vaccines, the identification of therapeutics that have near-term potential to be available and easily administered is critical. Using the United States, European Union, and WHO clinical trial registries, authors reviewed COVID-19 therapeutic agents currently under investigation. The search was limited to oral or potentially oral agents, with at least a putative anti-SARS-CoV-2 virus mechanism, and with at least five registered trials. The search yielded 1,001, 203, and 1,128 trials, in the United States, European Union, and WHO trial registers, respectively. These trials covered 13 oral or potentially oral repurposed agents that are currently used as antimicrobials and immunomodulatory therapeutics with established safety profiles. The available evidence regarding the proposed mechanism of action, potential limitations, and trial status are summarized. The results of the search demonstrate few published studies of high quality, a low proportion of trials completed, and the vast majority with negative results. These findings reflect limited investment in COVID-19 therapeutics development compared with vaccines. The need for better coordination of trials of accessible agents and their combinations in LMICs was also identified. To prevent COVID-19 from becoming a neglected tropical disease, there is a critical need for rapid and coordinated effort in the evaluation and deployment of those agents found to be efficacious.

Diagnostics

Multidisciplinary assessment of the Abbott BinaxNOW SARS-CoV-2 point-of-care antigen test in the context of emerging viral variants and self-administration
While there has been significant progress in the development of rapid COVID-19 diagnostics, as the pandemic unfolds, new challenges have emerged, including whether these technologies can reliably detect the more infectious variants of concern and be viably deployed in non-clinical settings as “self-tests”. Multidisciplinary evaluation of the Abbott BinaxNOW COVID-19 Ag Card (BinaxNOW, a widely used rapid antigen test, included a limit of detection, variant detection, test performance across different age groups, and usability with self/caregiver administration. While BinaxNOW detected the highly infectious variants, B.1.1.7 (Alpha) was first identified in the UK, B.1.351 (Beta) was first identified in South Africa, P.1 (Gamma) was first identified in Brazil, B.1.617.2 (Delta) was first identified in India and B.1.2, a non-VOC, test sensitivity decreased with decreasing viral loads. Moreover, BinaxNOW sensitivity trended lower when devices were performed by patients/caregivers themselves compared to trained clinical staff, despite universally high usability assessments following self/caregiver-administration among different age groups. Overall, these data indicate that while BinaxNOW accurately detects the new viral variants, as rapid COVID-19 tests enter the home, their already lower sensitivities compared to RT-PCR may decrease even more due to user error.

Rapid, point‐of‐care antigen and molecular‐based tests for diagnosis of SARS‐CoV‐2 infection
The objective of this study was to assess the diagnostic accuracy of point‐of‐care antigen and molecular‐based tests for the diagnosis of SARS‐CoV‐2 infection. Electronic searches of the Cochrane COVID‐19 Study Register and the COVID‐19 Living Evidence Database from the University of Bern (which includes daily updates from PubMed and Embase and preprints from medRxiv and bioRxiv) were undertaken on 30 Sept 2020. Repositories of COVID‐19 publications and included independent evaluations from national reference laboratories, the Foundation for Innovative New Diagnostics and the Diagnostics Global Health website to 16 Nov 2020 were checked. Forty‐eight studies reported 58 evaluations of antigen tests. Estimates of sensitivity varied considerably between studies. There were differences between symptomatic (72.0%, 95% CI 63.7% to 79.0%; 37 evaluations; 15530 samples, 4410 cases) and asymptomatic participants (58.1%, 95% CI 40.2% to 74.1%; 12 evaluations; 1581 samples, 295 cases). Average sensitivity was higher in the first week after symptom onset (78.3%, 95% CI 71.1% to 84.1%; 26 evaluations; 5769 samples, 2320 cases) than in the second week of symptoms (51.0%, 95% CI 40.8% to 61.0%; 22 evaluations; 935 samples, 692 cases). Sensitivity was high in those with cycle threshold (Ct) values on PCR ≤25 (94.5%, 95% CI 91.0% to 96.7%; 36 evaluations; 2613 cases) compared to those with Ct values >25 (40.7%, 95% CI 31.8% to 50.3%; 36 evaluations; 2632 cases). Sensitivity varied between brands. Using data from instructions for use (IFU) compliant evaluations in symptomatic participants, summary sensitivities ranged from 34.1% (95% CI 29.7% to 38.8%; Coris Bio concept) to 88.1% (95% CI 84.2% to 91.1%; SD Biosensor STANDARD Q). Average specificities were high in symptomatic and asymptomatic participants, and for most brands (overall summary specificity 99.6%, 95% CI 99.0% to 99.8%). At 5% prevalence using data for the most sensitive assays in symptomatic people (SD Biosensor STANDARD Q and Abbott Panbio), positive predictive values (PPVs) of 84% to 90% mean that between 1 in 10 and 1 in 6 positive results will be a false positive, and between 1 in 4 and 1 in 8 cases will be missed. At 0.5% prevalence applying the same tests in asymptomatic people would result in PPVs of 11% to 28% meaning that between 7 in 10 and 9 in 10 positive results will be false positives, and between 1 in 2 and 1 in 3 cases will be missed. Thirty studies reported 33 evaluations of five different rapid molecular tests. Sensitivities varied according to the test brand. Most of the data is related to the ID NOW and Xpert Xpress assays. Using data from evaluations following the manufacturer’s instructions for use, the average sensitivity of ID NOW was 73.0% (95% CI 66.8% to 78.4%) and average specificity 99.7% (95% CI 98.7% to 99.9%; 4 evaluations; 812 samples, 222 cases). For Xpert Xpress, the average sensitivity was 100% (95% CI 88.1% to 100%) and average specificity 97.2% (95% CI 89.4% to 99.3%; 2 evaluations; 100 samples, 29 cases). Insufficient data were available to investigate the effect of symptom status or time after symptom onset.

Epidemiology

Viral infection and transmission in a large well-traced outbreak caused by the Delta SARS-CoV-2 variant
The authors report the first local transmission of the Delta SARS-CoV-2 variant in mainland China. All 167 infections could be traced back to the first index case. The investigation on daily sequential PCR testing of the quarantined subjects indicated the viral load of the first positive test of Delta infections was ∼1000 times higher than that of the 19A/19B strains infections back in the initial epidemic wave of 2020, suggesting the potential faster viral replication rate and more infectiousness of the Delta variant at the early stage of the infection. The 126 high-quality sequencing data and reliable epidemiological data indicated some minor intra-host single nucleotide variants (iSNVs) could be transmitted between hosts and finally fixed in the virus population during the outbreak. The minor iSNVs transmission between donor-recipient contribute at least 4 of 31 substitutions identified in the outbreak suggesting some iSNVs could quickly arise and reach fixation when the virus spread rapidly. Disease control measures, including the frequency of population testing, quarantine in the pre-symptomatic phase, and enhancing the genetic surveillance should be adjusted to account for the increasing prevalence of the Delta variant at the global level.