December 29, 2022

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Clinical Reports

Antibody-dependent cellular cytotoxicity against SARS-CoV-2 Omicron sub-lineages is reduced in convalescent sera, regardless of the infecting variant
- The SARS-CoV-2 Omicron BA.4 and BA.5 variants caused major waves of infections. Here researchers assess the sensitivity of BA.4 to binding, neutralization and antibody dependent cellular cytotoxicity (ADCC) potential, measured by FcγRIIIa signalling, in convalescent donors infected with four previous variants of SARS-CoV-2, as well as in post-vaccination breakthrough infections (BTIs) caused by Delta or BA.1. Researchers confirm that BA.4 shows high level neutralization resistance, regardless of the infecting variant. However, BTIs retain activity against BA.4, albeit at reduced titers. BA.4 sensitivity to ADCC is reduced compared to other variants but with smaller fold losses compared to neutralization, and similar patterns of cross-reactivity. Overall, the high neutralization resistance of BA.4, even to antibodies from BA.1 infection, provides an immunological mechanism for the rapid spread of BA.4 immediately after a BA.1-dominated wave. Furthermore, although ADCC potential against BA.4 is reduced, residual activity may contribute to observed protection from severe disease.
Structural brain changes in post-acute COVID-19 patients with persistent olfactory dysfunction published in Annals of Clinical and Translational Neurology
- Forty-eight COVID-19 patients were included in the study. Twenty-three were classified as olfactory dysfunction, and 25 as normal olfaction. The olfactory dysfunction group had lower GM volume in a cluster involving the left amygdala, insular cortex, parahippocampal gyrus, frontal superior and inferior orbital gyri, gyrus rectus, olfactory cortex, caudate, and putamen. This group also showed higher MD values in the genu of the corpus callosum, the orbitofrontal area, the anterior thalamic radiation, and the forceps minor; and higher RD values in the anterior corona radiata, the genu of the corpus callosum, and uncinate fasciculus compared with the normal olfaction group.
Persistent post–COVID-19 smell loss is associated with immune cell infiltration and altered gene expression in olfactory epithelium
- SARS-CoV-2 causes profound changes in the sense of smell, including total smell loss. Although these alterations are often transient, many patients with COVID-19 exhibit olfactory dysfunction that lasts months to years. Although animal and human autopsy studies have suggested mechanisms driving acute anosmia, it remains unclear how SARS-CoV-2 causes persistent smell loss in a subset of patients. To address this question, researchers analyzed olfactory epithelial samples collected from 24 biopsies, including from nine patients with objectively quantified long-term smell loss after COVID-19. This biopsy-based approach revealed a diffuse infiltrate of T cells expressing interferon-γ and a shift in myeloid cell population composition, including enrichment of CD207+ dendritic cells and depletion of anti-inflammatory M2 macrophages. Despite the absence of detectable SARS-CoV-2 RNA or protein, gene expression in the barrier supporting cells of the olfactory epithelium, termed sustentacular cells, appeared to reflect a response to ongoing inflammatory signaling, which was accompanied by a reduction in the number of olfactory sensory neurons relative to olfactory epithelial sustentacular cells. These findings indicate that T cell–mediated inflammation persists in the olfactory epithelium long after SARS-CoV-2 has been eliminated from the tissue, suggesting a mechanism for long-term post–COVID-19 smell loss.

Persistent symptoms and sequelae after SARS-CoV-2 infection not requiring hospitalization: Results from Testing Denmark, a Danish cross-sectional survey
- In the fall of 2020, a cross-sectional survey was performed in the adult Danish general population. This included a self-administered point-of-care test for SARS-CoV-2 antibodies, the Short Form Health Survey (SF-12), and COVID-19 associated symptom questions. Non-hospitalized respondents with a positive SARS-CoV-2 PCR-test 12 or more weeks before the survey (cases) were matched (1:10) to seronegative controls on age, sex, and BMI. Propensity score weighted odds ratios (OR) and ORs for risk factors were estimated for each health outcome. In total, 742 cases and 7420 controls were included. The attributable risk of at least one long-COVID symptom was 25·0 per 100 cases (95% confidence interval (CI): 22·2, 27·4). Compared to controls, cases reported worse general health (OR: 5·9, CI: 5·0, 7·0) and had higher odds for a broad range of symptoms, particularly loss of taste (OR: 11·8, CI: 9·5, 14·6) and smell (OR: 11·2, CI: 9·1, 13·9). Physical and Mental Component Summary scores were also significantly reduced with differences of -2·5 (CI: -3·1, -1·8) and -2·0 (CI: -2·7, -1·2) respectively. Female sex and severity of initial infection were major risk factors for long-COVID. Non-hospitalized SARS-CoV-2 PCR-positive individuals had significantly reduced physical and mental health, and one in four reported persistence of at least one long-COVID symptom.

Antiviral Therapeutics and Vaccines

VV116 versus Nirmatrelvir–Ritonavir for Oral Treatment of Covid-19
- Researchers conducted a phase 3, noninferiority, observer-blinded, randomized trial during the outbreak caused by the B.1.1.529 (omicron) variant of SARS-CoV-2. Symptomatic adults with mild-to-moderate Covid-19 with a high risk of progression were assigned to receive a 5-day course of either VV116 or nirmatrelvir–ritonavir. The primary end point was the time to sustained clinical recovery through day 28. Sustained clinical recovery was defined as the alleviation of all Covid-19–related target symptoms to a total score of 0 or 1 for the sum of each symptom (on a scale from 0 to 3, with higher scores indicating greater severity; total scores on the 11-item scale range from 0 to 33) for 2 consecutive days. A lower boundary of the two-sided 95% confidence interval for the hazard ratio of more than 0.8 was considered to indicate noninferiority (with a hazard ratio of >1 indicating a shorter time to sustained clinical recovery with VV116 than with nirmatrelvir–ritonavir). A total of 822 participants underwent randomization, and 771 received VV116 (384 participants) or nirmatrelvir–ritonavir (387 participants). The noninferiority of VV116 to nirmatrelvir–ritonavir with respect to the time to sustained clinical recovery was established in the primary analysis (hazard ratio, 1.17; 95% confidence interval [CI], 1.01 to 1.35) and was maintained in the final analysis (median, 4 days with VV116 and 5 days with nirmatrelvir–ritonavir; hazard ratio, 1.17; 95% CI, 1.02 to 1.36). In the final analysis, the time to sustained symptom resolution (score of 0 for each of the 11 Covid-19–related target symptoms for 2 consecutive days) and to a first negative SARS-CoV-2 test did not differ substantially between the two groups. No participants in either group had died or had had progression to severe Covid-19 by day 28. The incidence of adverse events was lower in the VV116 group than in the nirmatrelvir–ritonavir group (67.4% vs. 77.3%). Among adults with mild-to-moderate Covid-19 who were at risk for progression, VV116 was noninferior to nirmatrelvir–ritonavir with respect to the time to sustained clinical recovery, with fewer safety concerns.
Nirmatrelvir Plus Ritonavir for Early COVID-19 in a Large U.S. Health System
- During the study period, 12 541 (28.1%) patients were prescribed nirmatrelvir plus ritonavir, and 32 010 (71.9%) were not. Patients prescribed nirmatrelvir plus ritonavir were more likely to be older, have more comorbidities, and be vaccinated. The composite outcome of hospitalization or death occurred in 69 (0.55%) patients who were prescribed nirmatrelvir plus ritonavir and 310 (0.97%) who were not (adjusted risk ratio, 0.56 [95% CI, 0.42 to 0.75]). Recipients of nirmatrelvir plus ritonavir had lower risk for hospitalization (adjusted risk ratio, 0.60 [CI, 0.44 to 0.81]) and death (adjusted risk ratio, 0.29 [CI, 0.12 to 0.71]).
Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomized controlled trial
- Between Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalizations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81–1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir. Molnupiravir did not reduce the frequency of COVID-19-associated hospitalizations or death among high-risk vaccinated adults in the community.
Higher dose corticosteroids in hospitalized COVID-19 patients with hypoxia but not requiring ventilatory support (RECOVERY): a randomized, controlled, open-label, platform trial
- In patients hospitalized for COVID-19 with clinical hypoxia but requiring either no oxygen or simple oxygen only, higher dose corticosteroids significantly increased the risk of death compared to usual care, which included low dose corticosteroids. The RECOVERY trial continues to assess the effects of higher dose corticosteroids in patients hospitalized with COVID-19 who require non-invasive ventilation, invasive mechanical ventilation or extra-corporeal membrane oxygenation.
FDA approves Roche’s Actemra (tocilizumab) for the treatment of COVID-19 in hospitalized adults
- Roche today announced that the U.S. Food and Drug Administration (FDA) has approved Actemra® (tocilizumab) intravenous (IV) for the treatment of COVID-19 in hospitalized adult patients who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). Actemra is the first FDA-approved monoclonal antibody to treat COVID-19 and is recommended for use as a single 60-minute IV infusion.
Outpatient treatment of Covid-19 with metformin, ivermectin, and fluvoxamine and the development of Long Covid over 10-month follow-up
- This was a decentralized, remotely delivered trial in the US of 1,125 adults age 30 to 85 with overweight or obesity, fewer than 7 days of symptoms, and enrolled within three days of a documented SARS-CoV-2 infection. Immediate release metformin titrated over 6 days to 1,500mg per day 14 days total; ivermectin 430mcg/kg/day for 3 days; fluvoxamine, 50mg on day one then 50mg twice daily through 14 days. Medical-provider diagnosis of Long Covid, reported by participant by day 300 after randomization was a pre-specified secondary outcome; the primary outcome of the trial was severe Covid by day 14. There was a 42% relative decrease in the incidence of Long Covid in the metformin group compared to its blinded control in a secondary outcome of this randomized phase 3 trial.

Diagnostics

Canine real-time detection of SARS-CoV-2 infections in the context of a mass screening event
- Eight dogs were trained to detect SARS-CoV-2 RT-qPCR-positive samples. Four concerts with a total of 2802 participants were held to evaluate canines’ performance in screening individuals for SARS-CoV-2 infection. Sweat samples were taken from all participants and presented in a line-up setting. In addition, every participant had been tested with a SARS-CoV-2 specific rapid antigen test and a RT-qPCR and they provided information regarding age, sex, vaccination status and medical disease history. The participants’ infection status was unknown at the time of canine testing. Safety measures such as mask wearing and distance keeping were ensured. The SARS-CoV-2 detection dogs achieved a diagnostic specificity of 99.93% (95% CI 99.74% to 99.99%) and a sensitivity of 81.58% (95% CI 66.58% to 90.78%), respectively. The overall rate of concordant results was 99.68%. The majority of the study population was vaccinated with varying vaccines and vaccination schemes, while several participants had chronic diseases and were under chronic medication. This did not influence dogs’ decisions. These results demonstrate that SARS-CoV-2 scent detection dogs achieved high diagnostic accuracy in a real-life scenario. The vaccination status, previous SARS-CoV-2 infection, chronic disease and medication of the participants did not influence the performance of the dogs in detecting the acute infection. This indicates that dogs provide a fast and reliable screening option for public events in which high-throughput screening is required.
Clinical Validation of a Novel T-Cell Receptor Sequencing Assay for Identification of Recent or Prior Severe Acute Respiratory Syndrome Coronavirus 2 Infection
- While diagnostic, therapeutic, and vaccine development in the coronavirus disease 2019 (COVID-19) pandemic has proceeded at unprecedented speed, critical gaps in our understanding of the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain unaddressed by current diagnostic strategies. A statistical classifier for identifying prior SARS-CoV-2 infection was trained using >4000 SARS-CoV-2–associated T-cell receptor (TCR) β sequences identified by comparing 784 cases and 2447 controls from 5 independent cohorts. The T-Detect COVID (Adaptive Biotechnologies) assay applies this classifier to TCR repertoires sequenced from blood samples to yield a binary assessment of past infection. Assay performance was assessed in 2 retrospective (n = 346; n = 69) and 1 prospective cohort (n = 87) to determine positive percent agreement (PPA) and negative percent agreement (NPA). PPA was compared with 2 commercial serology assays, and pathogen cross-reactivity was evaluated. T-Detect COVID demonstrated high PPA in individuals with prior reverse transcription–polymerase chain reaction (RT-PCR)–confirmed SARS-CoV-2 infection (97.1% 15+ days from diagnosis; 94.5% 15+ days from symptom onset), high NPA (∼100%) in presumed or confirmed SARS-CoV-2 negative cases, equivalent or higher PPA than 2 commercial serology tests, and no evidence of pathogen cross-reactivity. T-Detect COVID is a novel T-cell immunosequencing assay demonstrating high clinical performance for identification of recent or prior SARS-CoV-2 infection from blood samples, with implications for clinical management, risk stratification, surveillance, and understanding of protective immunity and long-term sequelae.

Epidemiology

Modelling the adjustment of COVID-19 response and exit from dynamic zero-COVID in China
- Researchers use simulations to assess the respective and combined effectiveness of fourth-dose heterologous boosting, large-scale antiviral treatment and public health and social measures (PHSMs) that might allow China to further adjust COVID-19 response and exit from zero-COVID safely after 7 December 2022. We also assess whether local health systems can cope with the surge of COVID-19 cases posed by reopening, given that chunyun, a 40-day period with extremely high mobility across China associated with Spring Festival, will begin on 7 January 2023. Reopening against Omicron transmission should be supported by the following interventions: 1) fourth-dose heterologous boosting 30-60 days before reopening by vaccinating 4-8% of the population per week with ≥85% uptake across all ages; 2) timely antiviral treatment with ≥60% coverage; 3) moderate PHSMs to reduce transmissibility by 47-69%. With fourth-dose vaccination coverage of 85% and antiviral coverage of 60%, the cumulative mortality burden would be reduced by 26-35% to 448-503 per million, compared with reopening without any of these interventions. Simultaneously reopening all provinces under current PHSMs would still lead to hospitalization demand that are 1.5-2.5 times of surge hospital capacity (2.2 per 10,000 population per day). Although the surge of disease burden posed by reopening in December 2022 – January 2023 would likely overload many local health systems across the country, the combined effect of vaccination, antiviral treatment and PHSMs could substantially reduce COVID-19 morbidity and mortality as China transits from dynamic-zero to normality. Planning for such a nationwide, coordinated reopening should be an urgent priority as part of the global exit from the acute phase of the COVID-19 pandemic.
Two masks can be worse than one: N95 respirator failure caused by an overlying face mask
- Researchers have demonstrated the effect of covering an N95 filtering facepiece respirator (FFR) with an overlying face mask. In total, 100 participants successfully completed quantitative fit testing wearing a 3M 1870+ FFR. Among them, 13 (13%; 95% CI, 7%–22%) failed subsequent fit testing when simultaneously wearing a Halyard 47117 procedural mask over the FFR.
Airflow Patterns in Double-Occupancy Patient Rooms May Contribute to Roommate-to-Roommate Transmission of Severe Acute Respiratory Syndrome Coronavirus 2
- Air flowed from inlet vents in the center of the room to an outlet vent near the door, resulting in air currents flowing toward the bed adjacent to the outlet vent. Fluorescent microspheres (212–250-µm diameter), 5% sodium chloride aerosol, and aerosolized bacteriophage MS2 released from the inner bed were carried on air currents toward the bed adjacent to the outlet vent. Closing curtains between the patient beds reduced transfer of each of the particles. Operation of a portable air cleaner reduced aerosol transfer to the bed adjacent to the outlet vent but did not offer a benefit over closing the curtains alone, and in some situations, resulted in an increase in aerosol exposure. Airflow patterns in double-occupancy patient rooms may contribute to risk for transmission of SARS-CoV-2 between roommates. Keeping curtains closed between beds may be beneficial in reducing risk.
The epidemiology of long COVID in US adults
- An estimated 7.3% (95% CI: 6.1-8.5%) of all respondents reported long COVID, corresponding to approximately 18,828,696 adults. One-quarter (25.3% [18.2-32.4%]) of respondents with long COVID reported their day-to-day activities were impacted ‘a lot’ and 28.9% had SARS-CoV-2 infection >12 months ago. The prevalence of long COVID was higher among respondents who were female (aPR: 1.84 [1.40-2.42]), had comorbidities (aPR: 1.55 [1.19-2.00]) or were not (versus were) boosted (aPR: 1.67 [1.19-2.34]) or not vaccinated (versus boosted) (aPR: 1.41 (1.05-1.91)). Researchers observed a high burden of long COVID, substantial variability in prevalence of SARS-CoV-2 and risk factors unique from SARS-CoV-2 risk, suggesting areas for future research. Population-based surveys are an important surveillance tool and supplement to ongoing efforts to monitor long COVID.