Coronavirus COVID-19 Update for April 11, 2021

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Clinical Reports

Clinical Manifestations of Infection with Poliomyelitis Virus
Most of the clinical observations on poliomyelitis have been limited to that relatively rare form of the disease which results in residual paralysis. Even here no controlled observations have been published which enable one to say whether a great variety of symptoms are really typical of this disease. For instance, current articles in the foreign and American literature list diarrhea, sore throat, running nose and cough as symptoms of poliomyelitis, but offer no proof. It may be said with safety that outside of paralysis or paresis in a child with an acute febrile illness resulting in head drop, stiff neck and stiff back, and usually accompanied with moderate increase in the spinal fluid protein or cells, no symptoms have been firmly established.
Spike Protein-independent Attenuation of SARS-CoV-2 Omicron Variant in Laboratory Mice
Despite being more transmissible, the severe acute respiratory syndrome coronavirus (SARS3 CoV-2) Omicron variant only causes milder diseases in laboratory animals, often accompanied by a lower viral load compared to previous variants of concern. In this study researchers report the structural basis for a robust interaction between the receptor binding domain of the Omicron spike protein and mouse ACE2. We show that pseudovirus bearing the Omicron spike protein efficiently utilizes mouse ACE2 for entry. By comparing viral load and disease severity among laboratory mice infected by a natural Omicron variant or recombinant ancestral viruses bearing either the entire Omicron Spike or only the N501Y/Q493R mutations in its spike, we find that mutations outside the spike protein in the Omicron variant may be responsible for the observed lower viral load. Together, our results imply that a post-entry block to the Omicron variant exists in laboratory mice.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)–Specific T Cells and Antibodies in Coronavirus Disease 2019 (COVID-19) Protection: A Prospective Study
In 5340 Moscow residents, researchers evaluated anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin M (IgM)/immunoglobulin G (IgG) titers and frequencies of the T cells specific to the membrane, nucleocapsid, and spike proteins of SARS-CoV-2, using interferon gamma (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assay. Additionally, researchers evaluated the fractions of virus-specific CD4⁺and CD8⁺ T cells using intracellular staining of IFN-γ and interleukin 2 followed by flow cytometry. They analyzed the COVID-19 rates as a function of the assessed antibody and T-cell responses, using the Kaplan–Meier estimator method, for up to 300 days postinclusion. Study authors showed that T-cell and antibody responses are closely interconnected and are commonly induced concurrently. Magnitudes of both responses inversely correlated with infection probability. Individuals positive for both responses demonstrated the highest levels of protectivity against the SARS-CoV-2 infection. A comparable level of protection was found in individuals with antibody response only, whereas the T-cell response by itself granted only intermediate protection. Contribution of the virus-specific antibodies to protection against SARS-CoV-2 infection is more pronounced than that of the T cells. The data on the virus-specific IgG titers may be instructive for making decisions in personalized healthcare and public anti–COVID-19 policies.
Distinguishing features of Long COVID identified through immune profiling
SARS-CoV-2 infection can result in the development of a constellation of persistent sequelae following acute disease called post-acute sequelae of COVID-19 (PASC) or Long COVID. Individuals diagnosed with Long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions; however, the basic biological mechanisms responsible for these debilitating symptoms are unclear. Here, 215 individuals were included in an exploratory, cross-sectional study to perform multi-dimensional immune phenotyping in conjunction with machine learning methods to identify key immunological features distinguishing Long COVID. Marked differences were noted in specific circulating myeloid and lymphocyte populations relative to matched control groups, as well as evidence of elevated humoral responses directed against SARS-CoV-2 among participants with Long COVID. Further, unexpected increases were observed in antibody responses directed against non-SARS-CoV-2 viral pathogens, particularly Epstein-Barr virus. Analysis of circulating immune mediators and various hormones also revealed pronounced differences, with levels of cortisol being uniformly lower among participants with Long COVID relative to matched control groups. Integration of immune phenotyping data into unbiased machine learning models identified significant distinguishing features critical in accurate classification of Long COVID, with decreased levels of cortisol being the most significant individual predictor. These findings will help guide additional studies into the pathobiology of Long COVID and may aid in the future development of objective biomarkers for Long COVID.
Unexplained post-acute infection syndromes
SARS-CoV-2 is not unique in its ability to cause post-acute sequelae; certain acute infections have long been associated with an unexplained chronic disability in a minority of patients. These post-acute infection syndromes (PAISs) represent a substantial healthcare burden, but there is a lack of understanding of the underlying mechanisms, representing a significant blind spot in the field of medicine. The relatively similar symptom profiles of individual PAISs, irrespective of the infectious agent, as well as the overlap of clinical features with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), suggest the potential involvement of a common etiopathogenesis. In this Review, we summarize what is known about unexplained PAISs, provide context for post-acute sequelae of SARS-CoV-2 infection (PASC), and delineate the need for basic biomedical research into the underlying mechanisms behind this group of enigmatic chronic illnesses.

Antiviral Therapeutics and Vaccines

Nirmatrelvir Use and Severe Covid-19 Outcomes during the Omicron Surge
The oral protease inhibitor nirmatrelvir has shown substantial efficacy in high-risk, unvaccinated patients infected with the B.1.617.2 (delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Data regarding the effectiveness of nirmatrelvir in preventing severe coronavirus disease 2019 (Covid-19) outcomes from the B.1.1.529 (omicron) variant are limited. Researchers obtained data for all members of Clalit Health Services who were 40 years of age or older at the start of the study period and were assessed as being eligible to receive nirmatrelvir therapy during the omicron surge. A Cox proportional-hazards regression model with time-dependent covariates was used to estimate the association of nirmatrelvir treatment with hospitalization and death due to Covid-19, with adjustment for sociodemographic factors, coexisting conditions, and previous SARS-CoV-2 immunity status. A total of 109,254 patients met the eligibility criteria, of whom 3902 (4%) received nirmatrelvir during the study period. Among patients 65 years of age or older, the rate of hospitalization due to Covid-19 was 14.7 cases per 100,000 person-days among treated patients as compared with 58.9 cases per 100,000 person-days among untreated patients (adjusted hazard ratio, 0.27; 95% confidence interval [CI], 0.15 to 0.49). The adjusted hazard ratio for death due to Covid-19 was 0.21 (95% CI, 0.05 to 0.82). Among patients 40 to 64 years of age, the rate of hospitalization due to Covid-19 was 15.2 cases per 100,000 person-days among treated patients and 15.8 cases per 100,000 person-days among untreated patients (adjusted hazard ratio, 0.74; 95% CI, 0.35 to 1.58). The adjusted hazard ratio for death due to Covid-19 was 1.32 (95% CI, 0.16 to 10.75). Among patients 65 years of age or older, the rates of hospitalization and death due to Covid-19 were significantly lower among those who received nirmatrelvir than among those who did not. No evidence of benefit was found in younger adults.
Vaccine Effectiveness Against Life-Threatening Influenza Illness in US Children
Researchers enrolled children aged <18 years admitted to the intensive care unit with acute respiratory infection across 17 hospitals. Respiratory specimens were tested using reverse-transcription polymerase chain reaction for influenza viruses and sequenced. Using a test-negative design, researchers estimated vaccine effectiveness comparing odds of vaccination in test-positive case patients vs test-negative controls, stratifying by age, virus type, and severity. Life-threating influenza included death or invasive mechanical ventilation, vasopressors, cardiopulmonary resuscitation, dialysis, or extracorporeal membrane oxygenation. Researchers enrolled 159 critically ill influenza case-patients (70% ≤8 years; 51% A/H1N1pdm09 and 25% B-Victoria viruses) and 132 controls (69% were aged ≤8 years). Among 56 sequenced A/H1N1pdm09 viruses, 29 (52%) were vaccine-mismatched (A/H1N1pdm09/5A+156K) and 23 (41%) were vaccine-matched (A/H1N1pdm09/5A+187A,189E). Among sequenced B-lineage viruses, majority (30 of 31) were vaccine-mismatched. Effectiveness against critical influenza was 63% (95% confidence interval [CI], 38% to 78%) and similar by age. Effectiveness was 75% (95% CI, 49% to 88%) against life-threatening influenza vs 57% (95% CI, 24% to 76%) against non-life-threating influenza. Effectiveness was 78% (95% CI, 41% to 92%) against matched A(H1N1)pdm09 viruses, 47% (95% CI, –21% to 77%) against mismatched A(H1N1)pdm09 viruses, and 75% (95% CI, 37% to 90%) against mismatched B-Victoria viruses. During a season when vaccine-mismatched influenza viruses predominated, vaccination was associated with a reduced risk of critical and life-threatening influenza illness in children.
Characteristics of Reported Deaths Among Fully Vaccinated Persons With Coronavirus Disease 2019—United States, January–April 2021
Vaccines against coronavirus disease 2019 (COVID-19) are highly efficacious, but severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections do occur after vaccination. Researchers characterized COVID-19 cases among fully vaccinated persons with an outcome of death. They analyzed COVID-19 cases voluntarily reported to the Centers for Disease Control and Prevention by US health departments from 1 January to 30 April 2021. They included cases among US residents with a positive SARS-CoV-2 test result ≥14 days after completion of an authorized primary vaccine series and who had a known outcome (alive or dead) as of 31 May 2021. When available, specimens were sequenced for viral lineage and death certificates were reviewed for cause(s) of death. Of 8084 fully vaccinated persons with reported COVID-19 during the surveillance period, 245 (3.0%) died. Compared with patients who remained alive, those who died were older (median age, 82 vs 57 years;), more likely to reside in a long-term care facility (51% vs 18%), and more likely to have ≥1 underlying health condition associated with risk for severe disease (64% vs 24%) (all P < .01). Among 245 deaths, 191 (78%) were classified as COVID-19 related. Of 106 deaths with available death certificates, COVID-19 was listed for 81 deaths (77%). There were no differences in the type of vaccine administered or the most common viral lineage (B.1.1.7). COVID-19 deaths are rare in fully vaccinated persons, occurring most commonly in those with risk factors for severe disease, including older age and underlying health conditions. All eligible persons should be fully vaccinated against COVID-19 and follow other prevention measures to mitigate exposure risk.
Real-world effectiveness of early Molnupiravir or nirmatrelvir–ritonavir in hospitalized patients with COVID-19 without supplemental oxygen requirement on admission during Hong Kong's omicron BA.2 wave: a retrospective cohort study
Researchers identified 40 776 patients hospitalized with SARS-CoV-2 infection during the study period, with a mean follow-up of 41·3 days (total 925 713 person-days). After exclusions and propensity-score matching, Researchers included 1856 Molnupiravir recipients and 1856 matched controls, and 890 nirmatrelvir-ritonavir recipients and 890 matched controls. A lower risk of all-cause mortality was observed in Molnupiravir recipients (crude incidence rate per 10 000 person-days 19·98 events [95% CI 16·91–23·45]) versus matched controls (38·07 events [33·85–42·67]; HR 0·48 [95% CI 0·40–0·59], p<0·0001) and in nirmatrelvir–ritonavir recipients (10·28 events [7·03–14·51]) versus matched controls (26·47 events [21·34–32·46]; HR 0·34 [0·23–0·50], p<0·0001). Oral antiviral recipients also had lower risks of the composite disease progression outcome (molnupiravir HR 0·60 [95% CI 0·52–0·69], p<0·0001; nirmatrelvir–ritonavir 0·57 [0·45–0·72], p<0·0001) and need for oxygen therapy (molnupiravir 0·69 [0·57–0·83], p=0·0001; nirmatrelvir–ritonavir 0·73 [0·54–0·97], p=0·032) compared with controls. Time to achieving a low viral burden was significantly shorter among oral antiviral recipients than matched controls (molnupiravir HR 1·38 [95% CI 1·15–1·64], p=0·0005; nirmatrelvir–ritonavir 1·38 [1·07–1·79], p=0·013). Significant differences in initiation of IMV and ICU admission were not found.

Diagnostics

Concordance of SARS-CoV-2 Results in Self-collected Nasal Swabs vs Swabs Collected by Health Care Workers in Children and Adolescents
The primary outcome was SARS-CoV-2 detection and relative quantitation by cycle threshold (Ct) in self-vs health care worker–collected nasal swabs when tested with a real-time reverse transcriptase–polymerase chain reaction test with Emergency Use Authorization. Among the study participants, 108 of 194 (55.7%) were male and the median age was 9 years (IQR, 6-11). Of the 196 participants, 87 (44.4%) tested positive for SARS-CoV-2 and 105 (53.6%) tested negative by both self- and health care worker–collected swabs. Two children tested positive by self- or health care worker–collected swab alone; 1 child had an invalid health care worker swab. Compared with health care worker–collected swabs, self-collected swabs had 97.8% (95% CI, 94.7%-100.0%) and 98.1% (95% CI, 95.6%-100.0%) positive and negative percent agreement, respectively, and SARS-CoV-2 Ct values did not differ significantly between groups (mean [SD] Ct, self-swab: 26.7 [5.4] vs health care worker swab: 26.3 [6.0]; P = .65). After hearing and seeing simple instructional materials, children and adolescents aged 4 to 14 years self-collected nasal swabs that closely agreed on SARS-CoV-2 detection with swabs collected by health care workers.

Epidemiology

Probable Animal-to-Human Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Delta Variant AY.127 Causing a Pet Shop-Related Coronavirus Disease 2019 (COVID-19) Outbreak in Hong Kong
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can infect human and other mammals, including hamsters. Syrian (Mesocricetus auratus) and dwarf (Phodopus) hamsters are susceptible to SARS-CoV-2 infection in the laboratory setting. However, pet shop-related Coronavirus Disease 2019 (COVID-19) outbreaks have not been reported. Researchers conducted an investigation of a pet shop-related COVID-19 outbreak due to Delta variant AY.127 involving at least 3 patients in Hong Kong. Researchers tested samples collected from the patients, environment, and hamsters linked to this outbreak and performed whole genome sequencing analysis of the reverse transcription polymerase chain reaction (RT-PCR)-positive samples. The patients included a pet shop keeper (Patient 1), a female customer of the pet shop (Patient 2), and the husband of Patient 2 (Patient 3). Investigation showed that 17.2% (5/29) and 25.5% (13/51) environmental specimens collected from the pet shop and its related warehouse, respectively, tested positive for SARS-CoV-2 RNA by RT-PCR. Among euthanized hamsters randomly collected from the storehouse, 3% (3/100) tested positive for SARS-CoV-2 RNA by RT-PCR and seropositive for anti-SARS-CoV-2 antibody by enzyme immunoassay. Whole genome analysis showed that although all genomes from the outbreak belonged to the Delta variant AY.127, there were at least 3 nucleotide differences among the genomes from different patients and the hamster cages. Genomic analysis suggests that multiple strains have emerged within the hamster population, and these different strains have likely transmitted to human either via direct contact or via the environment. This study demonstrated probable hamster-to-human transmission of SARS-CoV-2. As pet trading is common around the world, this can represent a route of international spread of this pandemic virus.
Laboratory-Confirmed COVID-19–Associated Hospitalizations Among Adults During SARS-CoV-2 Omicron BA.2 Variant Predominance — COVID-19–Associated Hospitalization Surveillance Network, 14 States, June 20, 2021–May 31, 2022
Older adults and those with underlying medical conditions infected with SARS-CoV-2 have increased risks for hospitalization. Increased hospitalization rates among adults aged ≥65 years compared with rates among younger adults were most pronounced during the Omicron BA.2–predominant period. Among hospitalized nonpregnant patients, 44.1% had received primary vaccination and ≥1 booster or additional dose. Hospitalization rates among unvaccinated adults were approximately triple those of vaccinated adults. Adults should stay up to date with COVID-19 vaccination, including booster doses. Multiple nonpharmaceutical and medical prevention measures should be used to protect persons at high risk for severe SARS-CoV-2, regardless of vaccination status.