Coronavirus COVID-19 Update for April 11, 2021

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Clinical Reports

Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA suggest prolonged gastrointestinal infection
Gastrointestinal symptoms and SARS-CoV-2 RNA shedding in feces point to the gastrointestinal tract as a possible site of infection in COVID-19. Researchers from Stanford University measured the dynamics of fecal viral RNA in patients with mild to moderate COVID-19 followed for 10 months post-diagnosis. The authors found that fecal viral RNA shedding was correlated with gastrointestinal symptoms in patients who had cleared their respiratory infection. They also observed that fecal shedding can continue to 7 months post-diagnosis. In conjunction with recent related findings, this work presents compelling evidence of SARS-CoV-2 infection in the gastrointestinal tract and suggests a possible role for long-term infection of the gastrointestinal tract in syndromes such as “long COVID.”
The Importance of Understanding the Stages of COVID-19 in Treatment and Trials
COVID-19, caused by SARS-CoV-2, continues to be a major health problem since its first description in Wuhan, China, in December 2019. Multiple drugs have been tried to date in the treatment of COVID-19. Critical to treatment of COVID-19 and advancing therapeutics is an appreciation of the multiple stages of this disease and the importance of timing for investigation and use of various agents. Researchers considered articles related to COVID-19 indexed on PubMed published January 1, 2020-November 15, 2020, and considered papers on the medRxiv preprint server. They identified relevant stages of COVID-19 including three periods: pre-exposure, incubation, and detectable viral replication; and five phases: the viral symptom phase, the early inflammatory phase, the secondary infection phase, the multisystem inflammatory phase, and the tail phase. This common terminology should serve as a framework to guide when COVID-19 therapeutics being studied or currently in use is likely to provide benefit rather than harm.
Supratherapeutic tacrolimus concentrations with Nirmatrelvir/ritonavir in solid organ transplant recipients requiring hospitalization: A case series using rifampin for
Nirmatrelvir/ritonavir was recently granted emergency use authorization for mild-moderate coronavirus disease 2019. Drug-drug interactions between ritonavir and tacrolimus are under-appreciated by non-transplant providers. Researchers describe two solid organ transplant recipients prescribed nirmatrelvir/ritonavir for outpatient use that developed tacrolimus toxicity requiring hospitalization and were managed with rifampin for toxicity reversal. Though rifampin is not without risks ranging from transaminitis to graft rejection secondary to inducement of subtherapeutic concentrations of immunosuppressants, it could greatly improve the calculus in cases of tacrolimus toxicity. The decision to initiate rifampin for reversal should be carefully balanced with these risks against severe or worsening symptomatology (e.g., neuro, cardiac, renal toxicity) of tacrolimus toxicity.
Inflammasome activation in infected macrophages drives COVID-19 pathology
Severe COVID-19 is characterized by persistent lung inflammation, inflammatory cytokine production, viral RNA, and sustained interferon (IFN) response all of which are recapitulated and required for pathology in the SARS-CoV-2 infected MISTRG6-hACE2 humanized mouse model of COVID-19 with a human immune system^1–20. Blocking either viral replication with Remdesivir^21–23or the downstream IFN stimulated cascade with anti-IFNAR2 in vivo in the chronic stages of disease attenuated the overactive immune-inflammatory response, especially inflammatory macrophages. Here, researchers show SARS-CoV-2 infection and replication in lung-resident human macrophages is a critical driver of disease. In response to infection mediated by CD16 and ACE2 receptors, human macrophages activate inflammasomes, release IL-1 and IL-18 and undergo pyroptosis thereby contributing to the hyperinflammatory state of the lungs. Inflammasome activation and its accompanying inflammatory response is necessary for lung inflammation, as inhibition of the NLRP3 inflammasome pathway reverses chronic lung pathology. Remarkably, this same blockade of inflammasome activation leads to the release of infectious virus by the infected macrophages. Thus, inflammasomes oppose host infection by SARS-CoV-2 by production of inflammatory cytokines and suicide by pyroptosis to prevent a productive viral cycle.
Post-acute COVID-19 is characterized by gut viral antigen persistence in inflammatory bowel diseases
Study authors report expression of SARS-CoV-2 RNA in the gut mucosa ~7 months after mild acute COVID-19 in 32 of 46 patients with IBD. Viral nucleocapsid protein persisted in 24 of 46 patients in gut epithelium and CD8+ T cells. Expression of SARS-CoV-2 antigens was not detectable in stool and viral antigen persistence was unrelated to severity of acute COVID-19, immunosuppressive therapy and gut inflammation. Researchers were unable to culture SARS-CoV-2 from gut tissue of patients with viral antigen persistence. Post-acute sequelae of COVID-19 were reported from the majority of patients with viral antigen persistence, but not from patients without viral antigen persistence. These results indicate that SARS-CoV-2 antigen persistence in infected tissues serves as a basis for post-acute COVID-19. The concept that viral antigen persistence instigates immune perturbation and post-acute COVID-19 requires validation in controlled clinical trials.

Antiviral Therapeutics and Vaccines

Limited cross-variant immunity from SARS-CoV-2 Omicron without vaccination
The question arises whether widespread Omicron infections could lead to future cross-variant protection, accelerating the end of the pandemic. In this study, researchers show that without vaccination, infection with Omicron induces a limited humoral immune response in mice and humans. Sera from mice overexpressing the human ACE2 receptor and infected with Omicron neutralize only Omicron, but no other VOCs, whereas broader cross-variant neutralization was observed after WA1 and Delta infections. Unlike WA1 and Delta, Omicron replicates to low levels in the lungs and brains of infected animals, leading to mild disease with reduced pro-inflammatory cytokine expression and diminished activation of lung-resident T cells. Sera from unvaccinated, Omicron-infected individuals show the same limited neutralization of only Omicron itself. In contrast, Omicron breakthrough infections induce overall higher neutralization titers against all VOCs. These results demonstrate that Omicron infection enhances preexisting immunity elicited by vaccines but, on its own, may not confer broad protection against non-Omicron variants in unvaccinated individuals.
FDA expands eligibility for Pfizer-BioNTech COVID-19 Vaccine Booster Dose to Children 5 through 11 years
May 17, 2022, the U.S. Food and Drug Administration amended the emergency use authorization (EUA) for the Pfizer-BioNTech COVID-19 Vaccine, authorizing the use of a single booster dose for administration to individuals 5 through 11 years of age at least five months after completion of a primary series with the Pfizer-BioNTech COVID-19 Vaccine.
FDA Memorandum Explaining Basis for Declining Request for Emergency Use Authorization of Fluvoxamine Maleate
FDA scientific review staff have reviewed available information derived from clinical trials investigating the use of fluvoxamine for the treatment of COVID-19. A summary of the review includes the following. The request is primarily based on results from the TOGETHER trial, a randomized, double-blind, placebo-controlled platform trial in high-risk, symptomatic adult outpatients in Brazil. The primary endpoint was a composite of 1) emergency room visits due to the clinical worsening of COVID-19 (defined as remaining under observation for greater than 6 hours) and 2) hospitalization due to progression of COVID-19 (defined as worsening of viral pneumonia and/or complications), up to 28 days after randomization. While the study met its primary endpoint, the results were primarily driven by a reduction in the emergency department visits lasting greater than 6 hours, and there are uncertainties about the assessment of this endpoint and whether the 6-hour timepoint represents a clinically meaningful threshold. The treatment benefit of fluvoxamine was not persuasive when focusing on clinically meaningful outcomes such as proportion of patients experiencing hospitalizations or hospitalizations and deaths. The STOP COVID and real-world data studies had design limitations, including small size, single center, endpoint selection, and lack of randomization. Two additional trials, STOP COVID 2 (a trial that was several times larger than the STOP COVID trial) and COVID-OUT failed to demonstrate a benefit with fluvoxamine in adults with mild COVID-19 in the outpatient setting, and both were terminated early for futility. Based on the review of available scientific evidence, the FDA has determined that the data are insufficient to conclude that fluvoxamine may be effective in the treatment of non-hospitalized patients with COVID-19 to prevent progression to severe disease and/or hospitalization. Therefore, FDA has determined that the criteria for issuance of an EUA are not met and is declining to issue an EUA covering fluvoxamine for the treatment of COVID-19 at this time.

Diagnostics

Scent dogs in detection of COVID-19: triple-blinded randomized trial and operational real-life screening in airport setting
Four dogs were trained to detect COVID-19 using skin swabs from individuals tested for SARS-CoV-2 by RT-PCR. This controlled triple-blinded validation study comprised four identical sets of 420 parallel samples (from 114 individuals tested positive and 306 negative by RT-PCR), randomly presented to each dog over seven trial sessions. In a real-life setting the dogs screened skin swabs from 303 incoming passengers all concomitantly examined by nasal swab SARS-CoV-2 RT-PCR. Main outcomes were variables of diagnostic accuracy (sensitivity, specificity, positive predictive value, negative predictive value) for scent dog identification in comparison with RT-PCR. This validation experiments had an overall accuracy of 92% (95% CI 90% to 93%), a sensitivity of 92% (95% CI 89% to 94%) and a specificity of 91% (95% CI 89% to 93%) compared with RT-PCR. For the dogs, trained using the wild-type virus, performance was less accurate for the alpha variant.
Antigen Test Positivity After COVID-19 Isolation — Yukon-Kuskokwim Delta Region, Alaska, January–February 2022.
In this study conducted after SARS-CoV-2 infection during emergence of the Omicron variant, the majority of persons with follow-up testing had a positive antigen test result 5–9 days after symptom onset, or, among asymptomatic persons, after the initial positive diagnostic test. The proportion of positive test results declined with time since infection and was lower after asymptomatic than symptomatic infections. The proportion of positive follow-up antigen test results was also lower after previous SARS-CoV-2 infection or vaccination and was lowest among vaccinated persons with a previous infection. However, the percentage of positive test results after SARS-CoV-2 infection among those who had received a booster dose was similar to that among unvaccinated persons; the reasons for this finding are unclear and might reflect differences in testing practices or other individual characteristics. Overall, these findings are consistent with other analyses of positive test results by time since infection, including a recent study in which 43% percent of health care workers with SARS-CoV-2 infection were found to have received a positive antigen test result after 5–10 days.

Epidemiology

High attack rate of SARS-CoV-2 B.1.1.529 among two-dose vaccinated populations in two indoor entertainment setting outbreaks
SARS-CoV-2 B.1.1.529 (Omicron) infection among people attending a nightclub and a graduation ball where >95% had at least 2 vaccine doses. Attack rates were 295/535(55.1%) among people attending a nightclub and 102/189(54.0%) a graduation ball (mean: 5 days post-event). At the ball, attack rates increased with time since vaccination: 12.5% among those vaccinated 1-2 months previously; 68.0% among those vaccinated 3 + months previously; such differences were not found at the nightclub. The authors suggested this emphasized the importance of non-pharmaceutical public health measures in addition to vaccine booster doses to maximize protection in high-risk contexts.