Coronavirus COVID-19 Update for April 11, 2021

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Clinical Reports

SARS-CoV-2 is associated with changes in brain structure
There is strong evidence of brain-related abnormalities in COVID-19. However, it remains unknown whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can reveal possible mechanisms contributing to brain pathology. Here we investigated brain changes in 785 participants of UK Biobank (aged 51–81 years) who were imaged twice using magnetic resonance imaging, including 401 cases who tested positive for infection with SARS-CoV-2 between their two scans—with 141 days on average separating their diagnosis and the second scan—as well as 384 controls. The availability of pre-infection imaging data reduces the likelihood of pre-existing risk factors being misinterpreted as disease effects. We identified significant longitudinal effects when comparing the two groups, including (1) a greater reduction in grey matter thickness and tissue contrast in the orbitofrontal cortex and parahippocampal gyrus; (2) greater changes in markers of tissue damage in regions that are functionally connected to the primary olfactory cortex; and (3) a greater reduction in global brain size in the SARS-CoV-2 cases. The participants who were infected with SARS-CoV-2 also showed on average a greater cognitive decline between the two time points. Importantly, these imaging and cognitive longitudinal effects were still observed after excluding the 15 patients who had been hospitalized. These mainly limbic brain imaging results may be the in vivo hallmarks of a degenerative spread of the disease through olfactory pathways, of neuroinflammatory events, or of the loss of sensory input due to anosmia. Whether this deleterious effect can be partially reversed, or whether these effects will persist in the long term, remains to be investigated with additional follow-up.
New Onset Dementia Among Survivors of Pneumonia Associated with Severe Acute Respiratory Syndrome Coronavirus 2 Infection
Case series without control groups suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may result in cognitive deficits and dementia in the postinfectious period. This study follow adult pneumonia patients with SARS-CoV-2 infection (index hospitalization) and age-, gender-, and race/ethnicity-matched contemporary control pneumonia patients without SARS-CoV-2 infection were identified from 110 healthcare facilities in United States. The risk of new diagnosis of dementia following >30 days after the index hospitalization event without any previous history of dementia was identified using logistic regression analysis to adjust for potential confounders. Among 10,403 patients with pneumonia associated with SARS-CoV-2 infection, 312 patients (3% [95% confidence interval {CI}, 2.7%–3.4%]) developed new-onset dementia over a median period of 182 days (quartile 1 = 113 days, quartile 3 = 277 days). After adjustment for age, gender, race/ethnicity, hypertension, diabetes mellitus, hyperlipidemia, nicotine dependence/tobacco use, alcohol use/abuse, atrial fibrillation, previous stroke, and congestive heart failure, the risk of new-onset dementia was significantly higher with pneumonia associated with SARS-CoV-2 infection compared with pneumonia unrelated to SARS-CoV-2 infection (odds ratio [OR], 1.3 [95% CI, 1.1–1.5]). The association remained significant after further adjustment for occurrence of stroke, septic shock, and intubation/mechanical ventilation during index hospitalization (OR, 1.3 [95% CI, 1.1–1.5]). Approximately 3% of patients with pneumonia associated with SARS-CoV-2 infection developed new-onset dementia, which was significantly higher than the rate seen with other pneumonias.
Whole genome sequencing reveals host factors underlying critical Covid-19
Critical Covid-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care¹or hospitalisation^2–4 following SARS-CoV-2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from critically-ill cases with population controls in order to find underlying disease mechanisms. Here, researchers use whole genome sequencing in 7,491 critically-ill cases compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical Covid-19. They identify 16 new independent associations, including variants within genes involved in interferon signaling (IL10RB, PLSCR1), leucocyte differentiation (BCL11A), and blood type antigen secretor status (FUT2). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5, CD209) and coagulation factor F8, all of which are potentially druggable targets. The results are broadly consistent with a multi-component model of Covid-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication, or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. It is shown that comparison between critically-ill cases and population controls is highly efficient for detection of therapeutically-relevant mechanisms of disease.
Association Between Dexamethasone Treatment After Hospital Discharge for Patients With COVID-19 Infection and Rates of Hospital Readmission and Mortality
In a cohort of 1164 patients with COVID-19 who received less than 10 days of dexamethasone, 6 mg/d, during hospitalization, the rate of readmission or mortality within 14 days of discharge was 9.1% among patients who continued dexamethasone treatment compared with 11.4% among patients who did not. The difference was not statistically significant. The findings of this study suggest that prescribing dexamethasone at discharge for patients hospitalized with COVID-19 who received less than 10 days of dexamethasone is not associated with a reduction in readmission or mortality.

Antiviral Therapeutics and Vaccines

Pfizer Initiated a Phase 2/3 Study of their Novel COVID-19 Oral Treatment in Pediatric Participants
The Phase 2/3 trial is an open-label, multi-center, single-arm study in approximately 140 pediatric participants under 18 years of age. Initial enrollment features two cohorts; Cohort 1 includes participants aged 6 to 17 weighing at least 40 kg [88 lbs], and Cohort 2 includes those aged 6 to 17 weighing more than 20 kg [44 lbs] and less than 40 kg [88 lbs]. Participants enrolled in Cohort 1 will receive PAXLOVID (nirmatrelvir/ritonavir 300 mg/100 mg) orally twice daily for five days (10 doses total), the current authorized dosing for pediatric patients 12 years of age and older weighing at least 40kg. Participants enrolled in Cohort 2 will receive PAXLOVID (nirmatrelvir/ritonavir 150 mg/100 mg) orally twice daily for five days (10 doses total). Pfizer is also working to develop an age-appropriate formulation for three additional planned cohorts of younger than 6 years old and will enroll the trial to include these younger age groups as data from Cohorts 1 and 2 and the new formulation are available.
Efficacy of Antiviral Agents against the SARS-CoV-2 Omicron Subvariant BA.2
The susceptibilities of omicron/BA.2 (NCD1288) to remdesivir, molnupiravir, and nirmatrelvir were similar to those of the ancestral strain and other variants of concern (i.e., 50% inhibitory concentration values for these three agents that differed by factors of 2.5 to 4.5, 0.7 to 1.6, and 1.5 to 3.3, respectively). Clinical studies are warranted to determine whether these antiviral therapies are indeed effective against omicron/BA.2 infections. Data indicates that some therapeutic monoclonal antibodies (REGN10987–REGN10933, COV2-2196–COV2-2130, and S309) have lower neutralizing activity against omicron/BA.2 than against earlier variant strains.

Diagnostics

Post-acute symptoms, new onset diagnoses and health problems 6 to 12 months after SARS-CoV-2 infection: a nationwide questionnaire study in the adult Danish population
The objective of this study was to identify existing studies on the epidemiology and clinical nature of post-acute COVID-19 symptoms. A considerable number of individuals infected with SARS-CoV-2 continue to experience symptoms after the acute phase. More information on duration and prevalence of these symptoms in nonhospitalized populations is needed. Researchers conducted a nationwide cross-sectional study including 152,880 individuals aged 15-years or older, consisting of RT-PCR confirmed SARS-CoV-2 cases between September 2020-April 2021 (N=61 002) and a corresponding test-negative control group (N=91 878). Data were collected 6, 9 or 12 months after the test using web-based questionnaires. The questionnaire covered acute and post-acute symptoms, selected diagnoses, sick leave and general health, together with demographics and life style at baseline. Risk differences (RDs) between test-positives and -negatives were reported, adjusted for age, sex, single comorbidities, Charlson comorbidity score, obesity and healthcare-occupation. Six to twelve months after the test date, the risks of 18 out of 21 physical symptoms were elevated among test-positives and one third (29.6%) of the test-positives experienced at least one physical post-acute symptom. The largest risk differences were observed for dysosmia (RD = 10.92%, 95%CI 10.68-11.21%), dysgeusia (RD=8.68%, 95%CI 8.43-8.93%), fatigue/exhaustion (RD=8.43%, 95%CI 8.14-8.74%), dyspnea (RD=4.87%, 95%CI 4.65-5.09%) and reduced strength in arms/legs (RD=4.68%, 95%CI 4.45-4.89%). More than half (53.1%) of test-positives reported at least one of the following conditions: concentration difficulties (RD=28.34%, 95%CI 27.34-28.78%), memory issues (RD=27.25%, 95%CI 26.80-27.71%), sleep problems (RD=17.27%, 95%CI 16.81-17.73%), mental (RD=32.58%, 95%CI 32.11-33.09%) or physical exhaustion (RD=40.45%, 95%CI 33.99-40.97%), compared to 11.5% of test-negatives. At the population-level, where the majority of test-positives (96.0%) were not hospitalized during acute infection, a considerable proportion experience post-acute symptoms and sequelae 6-12 months after infection.

Epidemiology

SARS-CoV-2 Incidence in K–12 School Districts with Mask-Required Versus Mask-Optional Policies — Arkansas, August–October 2021Masks are an important part of a multicomponent prevention strategy to limit transmission of SARS-CoV-2. Some school jurisdictions required masks in K–12 schools for fall 2021, while others did not. In Arkansas during August–October 2021, districts with universal mask requirements had a 23% lower incidence of COVID-19 among staff members and students compared with districts without mask requirements.