Coronavirus COVID-19 Update for August 2, 2021

VIEW TRANSCRIPT

Clinical Reports

SARS-CoV-2 Infection in Public School District Employees Following a District-Wide Vaccination Program — Philadelphia County, Pennsylvania, March 21–April 23, 2021
Vaccination of school staff members has been highlighted as an important strategy to maximize the safety of in-person education of K–12 students this fall. Weekly SARS-CoV-2 antigen screening tests required of all employees returning for in-school instruction in the School District of Philadelphia found a 95% lower percentage of positive test results among persons who reported receipt of 2 doses of COVID-19 mRNA vaccine (0.09%) than among those who were unvaccinated (1.77%). Efforts to promote COVID-19 vaccination among school staff members before the upcoming 2021–22 school year will be foundational to ensure a safe learning environment.
More kids are being hospitalized for COVID, due to fewer masks, stagnating vaccination rates
The CDC reports that nearly 400 children and adolescents are currently in hospitals across the country with COVID or complications from the virus. More than 16,000 under the age of 18 have been hospitalized from COVID since the start of the pandemic, and more than 300 of them have died from it.
Neurological manifestations of SARS-CoV-2 infection in hospitalised children and adolescents in the UK: a prospective national cohort study
The spectrum of neurological and psychiatric complications associated with paediatric SARS-CoV-2 infection is poorly understood. To analyse the range and prevalence of these complications in hospitalised children and adolescents, a prospective national cohort study in the UK was done using an online network of secure rapid-response notification portals established by the CoroNerve study group. Paediatric neurologists were invited to notify any children and adolescents (age <18 years) admitted to hospital with neurological or psychiatric disorders in whom they considered SARS-CoV-2 infection to be relevant to the presentation. Patients were excluded if they did not have a neurological consultation or neurological investigations or both, or did not meet the definition for confirmed SARS-CoV-2 infection (a positive PCR of respiratory or spinal fluid samples, serology for anti-SARS-CoV-2 IgG, or both), or the Royal College of Paediatrics and Child Health criteria for paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS). Individuals were classified as having either a primary neurological disorder associated with COVID-19 (COVID-19 neurology group) or PIMS-TS with neurological features (PIMS-TS neurology group). The denominator of all hospitalised children and adolescents with COVID-19 was collated from National Health Service England data. Between April 2, 2020, and Feb 1, 2021, 52 cases were identified; in England, there were 51 cases among 1334 children and adolescents hospitalised with COVID-19, giving an estimated prevalence of 3·8 (95% CI 2·9–5·0) cases per 100 paediatric patients. 22 (42%) patients were female and 30 (58%) were male; the median age was 9 years (range 1–17). 36 (69%) patients were Black or Asian, 16 (31%) were White. 27 (52%) of 52 patients were classified into the COVID-19 neurology group and 25 (48%) were classified into the PIMS-TS neurology group. In the COVID-19 neurology group, diagnoses included status epilepticus (n=7), encephalitis (n=5), Guillain-Barré syndrome (n=5), acute demyelinating syndrome (n=3), chorea (n=2), psychosis (n=2), isolated encephalopathy (n=2), and transient ischaemic attack (n=1). The PIMS-TS neurology group more often had multiple features, which included encephalopathy (n=22 [88%]), peripheral nervous system involvement (n=10 [40%]), behavioural change (n=9 [36%]), and hallucinations at presentation (n=6 [24%]). Recognised neuroimmune disorders were more common in the COVID-19 neurology group than in the PIMS-TS neurology group (13 [48%] of 27 patients vs 1 [<1%] of 25 patients, p=0·0003). Compared with the COVID-19 neurology group, more patients in the PIMS-TS neurology group were admitted to intensive care (20 [80%] of 25 patients vs six [22%] of 27 patients, p=0·0001) and received immunomodulatory treatment (22 [88%] patients vs 12 [44%] patients, p=0·045). 17 (33%) patients (10 [37%] in the COVID-19 neurology group and 7 [28%] in the PIMS-TS neurology group) were discharged with disability; one (2%) died (who had stroke, in the PIMS-TS neurology group). This study identified key differences between those with a primary neurological disorder versus those with PIMS-TS. Compared with patients with a primary neurological disorder, more patients with PIMS-TS needed intensive care, but outcomes were similar overall. Further studies should investigate underlying mechanisms for neurological involvement in COVID-19 and the longer-term outcomes.

Clinical Recommendations

Updated masking guidance from CDC
CDC has Updated information for fully vaccinated people given new evidence on the B.1.617.2 (Delta) variant currently circulating in the United States. Added a recommendation for fully vaccinated people to wear a mask in public indoor settings in areas of substantial or high transmission. Added information that fully vaccinated people might choose to wear a mask regardless of the level of transmission, particularly if they are immunocompromised or at increased risk for severe disease from COVID-19, or if they have someone in their household who is immunocompromised, at increased risk of severe disease or not fully vaccinated. Added a recommendation for fully vaccinated people who have a known exposure to someone with suspected or confirmed COVID-19 to be tested 3-5 days after exposure, and to wear a mask in public indoor settings for 14 days or until they receive a negative test result. CDC recommends universal indoor masking for all teachers, staff, students, and visitors to schools, regardless of vaccination status.

Antiviral Therapeutics and Vaccines

Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant
The B.1.617.2 (delta) variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19), has contributed to a surge in cases in India and has now been detected across the globe, including a notable increase in cases in the United Kingdom. The effectiveness of the BNT162b2 and ChAdOx1 nCoV-19 vaccines against this variant has been unclear.A test-negative case–control design was used to estimate the effectiveness of vaccination against symptomatic disease caused by the delta variant or the predominant strain (B.1.1.7, or alpha variant) over the period that the delta variant began circulating. Variants were identified with the use of sequencing and on the basis of the spike (S) gene status. Data on all symptomatic sequenced cases of Covid-19 in England were used to estimate the proportion of cases with either variant according to the patients’ vaccination status. Effectiveness after one dose of vaccine (BNT162b2 or ChAdOx1 nCoV-19) was notably lower among persons with the delta variant (30.7%; 95% confidence interval [CI], 25.2 to 35.7) than among those with the alpha variant (48.7%; 95% CI, 45.5 to 51.7); the results were similar for both vaccines. With the BNT162b2 vaccine, the effectiveness of two doses was 93.7% (95% CI, 91.6 to 95.3) among persons with the alpha variant and 88.0% (95% CI, 85.3 to 90.1) among those with the delta variant. With the ChAdOx1 nCoV-19 vaccine, the effectiveness of two doses was 74.5% (95% CI, 68.4 to 79.4) among persons with the alpha variant and 67.0% (95% CI, 61.3 to 71.8) among those with the delta variant. Only modest differences in vaccine effectiveness were noted with the delta variant as compared with the alpha variant after the receipt of two vaccine doses. Absolute differences in vaccine effectiveness were more marked after the receipt of the first dose.
Covid-19 Breakthrough Infections in Vaccinated Health Care Workers
Despite the high efficacy of the BNT162b2 messenger RNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rare breakthrough infections have been reported, including infections among health care workers. Data are needed to characterize these infections and define correlates of breakthrough and infectivity. At the largest medical center in Israel, breakthrough infections were identified by performing extensive evaluations of health care workers who were symptomatic (including mild symptoms) or had known infection exposure. These evaluations included epidemiologic investigations, repeat reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assays, antigen-detecting rapid diagnostic testing (Ag-RDT), serologic assays, and genomic sequencing. Correlates of breakthrough infection were assessed in a case–control analysis. Patients with breakthrough infection who had antibody titers obtained within a week before SARS-CoV-2 detection (peri-infection period) were matched with four to five uninfected controls and used generalized estimating equations to predict the geometric mean titers among cases and controls and the ratio between the titers in the two groups. The correlation between neutralizing antibody titers and N gene cycle threshold (Ct) values with respect to infectivity was also assessed. Among 1497 fully vaccinated health care workers for whom RT-PCR data were available, 39 SARS-CoV-2 breakthrough infections were documented. Neutralizing antibody titers in case patients during the peri-infection period were lower than those in matched uninfected controls (case-to-control ratio, 0.361; 95% confidence interval, 0.165 to 0.787). Higher peri-infection neutralizing antibody titers were associated with lower infectivity (higher Ct values). Most breakthrough cases were mild or asymptomatic, although 19% had persistent symptoms (>6 weeks). The B.1.1.7 (alpha) variant was found in 85% of samples tested. A total of 74% of case patients had a high viral load (Ct value, <30) at some point during their infection; however, of these patients, only 17 (59%) had a positive result on concurrent Ag-RDT. No secondary infections were documented. Among fully vaccinated health care workers, the occurrence of breakthrough infections with SARS-CoV-2 was correlated with neutralizing antibody titers during the peri-infection period. Most breakthrough infections were mild or asymptomatic, although persistent symptoms did occur.
Antibody Response After a Third Dose of the mRNA-1273 SARS-CoV-2 Vaccine in Kidney Transplant Recipients With Minimal Serologic Response to 2 DosesStudies have reported low seroconversion rates (58% after the second dose) in solid organ transplant recipients who received a messenger RNA (mRNA) SARS-CoV-2 vaccine. Based on this evidence, the French National Authority for Health issued a recommendation in April 2021 to administer a third vaccine dose in immunosuppressed patients who did not respond after 2 doses. Authors examined the antibody responses of kidney transplant recipients who did not respond to 2 doses and received a third dose (100 μg) of the mRNA-1273 vaccine (Moderna). All kidney transplant recipients followed up in the outpatient Kidney Transplantation Department of Strasbourg University Hospital between January 20, 2021, and June 3, 2021, with a negative history for COVID-19 and SARS-CoV-2 antispike IgG levels less than 50 arbitrary units (AU)/mL on the day of the first vaccine injection and 1 month after the second dose were included. All patients received a third vaccine dose between April 9, 2021, and May 12, 2021. The study protocol was approved by the local ethics committee and written informed consent was obtained. Anti–receptor-binding domain IgG response after the third vaccine dose was assessed using the ARCHITECT IgG II Quant test (Abbott). According to the manufacturer, titers greater than 50 AU/mL were considered positive (detection range, 6.8–80 000 AU/mL; positive agreement, 99.4%; negative agreement, 99.6%). The results of this assay have been shown to correlate with in vitro neutralization of SARS-CoV-2. One month after the second dose, 159 kidney transplant recipients had IgG levels less than 50 AU/mL. The median age was 57.6 years (interquartile range [IQR], 49.6-66.1 years), 61.6% were men, and the median time from transplantation was 5.3 years (IQR, 1.9-11.1 years). Ninety-five patients (59.7%) had no antibody response after 2 doses (titers <6.8 AU/mL), and 64 patients (40.3%) showed a response below the positivity limit (titers, 6.8-49.9 AU/mL). The third dose was injected a median of 51 days (IQR, 48-59 days) after the second dose. The antibody response was measured a median of 28 days (IQR, 27-33 days) after the third vaccine injection, and 78 patients (49%) had antibody levels greater than 50 AU/mL (median antibody titers of responders, 586 AU/mL; IQR, 197.2-1920.1 AU/mL). Patients who had a weak response after the second dose were more likely to develop an antibody response after the third dose compared with those without an antibody response (81.3% vs 27.4%, respectively; mean adjusted difference of antibody titers, 894.89 AU/mL [95% CI, 377.41-1410.37]; P = .001). Patients taking tacrolimus, mycophenolate, and steroids were less likely to develop anti–SARS-CoV-2 antibodies than those treated with other regimens (35% vs 63%, respectively; mean adjusted difference of antibody titers, −697.28 AU/mL [95% CI, −1193.00 to −201.56]; P = .006). No severe adverse events were observed after the third dose.
Protection afforded by the BNT162b2 and mRNA-1273 COVID-19 vaccines in fully vaccinated cohorts with and without prior infectionEffect of prior SARS-CoV-2 infection on vaccine protection remains poorly understood. Authors investigated whether persons vaccinated after a prior infection have better protection against future infection than those vaccinated without prior infection. Effect of prior infection was assessed in Qatar’s population, where the Alpha (B.1.1.7) and Beta (B.1.351) variants dominate incidence, using two national retrospective, matched-cohort studies, one for the BNT162b2 (Pfizer-BioNTech) vaccine, and one for the mRNA-1273 (Moderna) vaccine. Incidence rates of infection among BNT162b2-vaccinated persons, with and without prior infection, were estimated, respectively, at 1.66 (95% CI: 1.26-2.18) and 11.02 (95% CI: 9.90-12.26) per 10,000 person-weeks. The incidence rate ratio was 0.15 (95% CI: 0.11-0.20). Analogous incidence rates among mRNA-1273-vaccinated persons were estimated at 1.55 (95% CI: 0.86-2.80) and 1.83 (95% CI: 1.07-3.16) per 10,000 person-weeks. The incidence rate ratio was 0.85 (95% CI: 0.34-2.05). Prior infection enhanced protection of those BNT162b2-vaccinated, but not those mRNA-1273-vaccinated. These findings may have implications for dosing, interval between doses, and potential need for booster vaccination.
Doxycycline for community treatment of suspected COVID-19 in people at high risk of adverse outcomes in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trialDoxycycline is often used for treating COVID-19 respiratory symptoms in the community despite an absence of evidence from clinical trials to support its use. This study was designed to assess the efficacy of doxycycline to treat suspected COVID-19 in the community among people at high risk of adverse outcomes. A national, open-label, multi-arm, adaptive platform randomized trial of interventions against COVID-19 in older people (PRINCIPLE) across primary care centers in the UK was performed. Included were people aged 65 years or older, or 50 years or older with comorbidities (weakened immune system, heart disease, hypertension, asthma or lung disease, diabetes, mild hepatic impairment, stroke or neurological problem, and self-reported obesity or body-mass index of 35 kg/m² or greater), who had been unwell (for ≤14 days) with suspected COVID-19 or a positive PCR test for SARS-CoV-2 infection in the community. Participants were randomly assigned using response adaptive randomization to usual care only, usual care plus oral doxycycline (200 mg on day 1, then 100 mg once daily for the following 6 days), or usual care plus other interventions. The interventions reported in this manuscript are usual care plus doxycycline and usual care only; evaluations of other interventions in this platform trial are ongoing. The coprimary endpoints were time to first self-reported recovery, and hospitalization or death related to COVID-19, both measured over 28 days from randomization and analyzed by intention to treat. This trial is ongoing and is registered with ISRCTN, 86534580. The trial opened on April 2, 2020. Randomisation to doxycycline began on July 24, 2020, and was stopped on Dec 14, 2020, because the prespecified futility criterion was met; 2689 participants were enrolled and randomised between these dates. Of these, 2508 (93·3%) participants contributed follow-up data and were included in the primary analysis: 780 (31·1%) in the usual care plus doxycycline group, 948 in the usual care only group (37·8%), and 780 (31·1%) in the usual care plus other interventions group. Among the 1792 participants randomly assigned to the usual care plus doxycycline and usual care only groups, the mean age was 61·1 years (SD 7·9); 999 (55·7%) participants were female and 790 (44·1%) were male. In the primary analysis model, there was little evidence of difference in median time to first self-reported recovery between the usual care plus doxycycline group and the usual care only group (9·6 [95% Bayesian Credible Interval [BCI] 8·3 to 11·0] days vs 10·1 [8·7 to 11·7] days, hazard ratio 1·04 [95% BCI 0·93 to 1·17]). The estimated benefit in median time to first self-reported recovery was 0·5 days [95% BCI −0·99 to 2·04] and the probability of a clinically meaningful benefit (defined as ≥1·5 days) was 0·10. Hospitalisation or death related to COVID-19 occurred in 41 (crude percentage 5·3%) participants in the usual care plus doxycycline group and 43 (4·5%) in the usual care only group (estimated absolute percentage difference −0·5% [95% BCI −2·6 to 1·4]); there were five deaths (0·6%) in the usual care plus doxycycline group and two (0·2%) in the usual care only group. In patients with suspected COVID-19 in the community in the UK, who were at high risk of adverse outcomes, treatment with doxycycline was not associated with clinically meaningful reductions in time to recovery or hospital admissions or deaths related to COVID-19, and should not be used as a routine treatment for COVID-19.