Coronavirus COVID-19 Update for April 11, 2021

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Clinical Reports

Neurovascular injury with complement activation and inflammation in COVID-19
The underlying mechanisms by which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to acute and long-term neurological manifestations remains obscure. Researchers aimed to characterize the neuropathological changes in patients with coronavirus disease 2019 and determine the underlying pathophysiological mechanisms. In this autopsy study of the brain, they characterized the vascular pathology, the neuroinflammatory changes and cellular and humoral immune responses by immunohistochemistry. All patients died during the first wave of the pandemic from March to July 2020. All patients were adults who died after a short duration of the infection, some had died suddenly with minimal respiratory involvement. Infection with SARS-CoV-2 was confirmed on ante-mortem or post-mortem testing. Descriptive analysis of the pathological changes and quantitative analyses of the infiltrates and vascular changes were performed. All patients had multifocal vascular damage as determined by leakage of serum proteins into the brain parenchyma. This was accompanied by widespread endothelial cell activation. Platelet aggregates and microthrombi were found adherent to the endothelial cells along vascular lumina. Immune complexes with activation of the classical complement pathway were found on the endothelial cells and platelets. Perivascular infiltrates consisted of predominantly macrophages and some CD8⁺T cells. Only rare CD4⁺ T cells and CD20⁺ B cells were present. Astrogliosis was also prominent in the perivascular regions. Microglial nodules were predominant in the hindbrain, which were associated with focal neuronal loss and neuronophagia. Antibody-mediated cytotoxicity directed against the endothelial cells is the most likely initiating event that leads to vascular leakage, platelet aggregation, neuroinflammation and neuronal injury. Therapeutic modalities directed against immune complexes should be considered.
Factors Associated with Severe Outcomes Among Immunocompromised Adults Hospitalized for COVID-19 — COVID-NET, 10 States, March 2020–February 2022
Immunocompromise is associated with increased risk for intensive care unit (ICU) admission and in-hospital death after SARS-CoV-2 infection. Population-based descriptions of immunocompromised hospitalized patients and their outcomes are limited. Immunocompromised patients accounted for 12.2% of all adult COVID-19 hospitalizations among 10 states and had increased odds of ICU admission and in-hospital death compared with nonimmunocompromised patients, irrespective of vaccination status. Given the increased odds of severe COVID-19 outcomes among immunocompromised hospitalized patients, multilayered prevention strategies for immunocompromised persons are critical to preventing hospitalization for COVID-19 and subsequent severe outcomes, especially when community levels indicate increased transmission and disease severity. These strategies include implementing nonpharmaceutical interventions; ensuring that immunocompromised persons and their close contacts are up to date with COVID-19 vaccination; urging immunocompromised persons to use effective preexposure prophylactic therapeutics, such as Evusheld; early testing, such as at-home tests; and early disease treatments, such as antiviral medications. Improved access to and use of these measures with considerations for socioeconomically disadvantaged and historically underserved racial and ethnic groups will help ensure health equity. Known multilayered prevention measures, including nonpharmaceutical interventions, up-to-date COVID-19 vaccination, and therapeutics, can prevent hospitalization and subsequent severe COVID-19 outcomes among immunocompromised persons.

Antiviral Therapeutics and Vaccines

Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4, & BA.5
SARS-CoV-2 Omicron subvariants BA.2.12.1 and BA.4/5 have surged dramatically to become dominant in the United States and South Africa, respectively. These novel subvariants carrying additional mutations in their spike proteins raise concerns that they may further evade neutralizing antibodies, thereby further compromising the efficacy of COVID-19 vaccines and therapeutic monoclonals. This report shows findings from a systematic antigenic analysis of these surging Omicron subvariants. BA.2.12.1 is only modestly (1.8-fold) more resistant to sera from vaccinated and boosted individuals than BA.2. However, BA.4/5 is substantially (4.2-fold) more resistant and thus more likely to lead to vaccine breakthrough infections. Mutation at spike residue L452 found in both BA.2.12.1 and BA.4/5 facilitates escape from some antibodies directed to the so-called class 2 and 3 regions of the receptor-binding domain³. The F486V mutation found in BA.4/5 facilitates escape from certain class 1 and 2 antibodies but compromises the spike affinity for the viral receptor. The R493Q reversion mutation, however, restores receptor affinity and consequently the fitness of BA.4/5. Among therapeutic antibodies authorized for clinical use, only bebtelovimab retains full potency against both BA.2.12.1 and BA.4/5. The Omicron lineage of SARS-CoV-2 continues to evolve, successively yielding subvariants that are not only more transmissible but also more evasive to antibodies.
Broadly-Neutralizing Antibodies Against Emerging SARS-CoV-2 Variants
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have become a major concern in the containment of current pandemic. The variants, including B.1.1.7 (Alpha), B.1.351 (Beta), P1 (Gamma) and B.1.617.2 (Delta) have shown reduced sensitivity to monoclonal antibodies, plasma and/or sera obtained from convalescent patients and vaccinated individuals. Development of potent therapeutic monoclonal antibodies (mAbs) with broad neutralizing breadth have become a priority for alleviating the devastating effects of this pandemic. In this study, researchers review some of the most promising broadly neutralizing antibodies obtained from plasma of patients that recovered from early variants of SARS-CoV-2 that may be effective against emerging new variants of the virus. This review summarizes several mAbs, that have been discovered to cross-neutralize across Sarbecoviruses and SARS-CoV-2 escape mutants. Understanding the characteristics that confer this broad and cross-neutralization functions of these mAbs would inform on the development of therapeutic antibodies and guide the discovery of second-generation vaccines. SARS-CoV-2 variants escape neutralization by antibodies from vaccine and natural infection, which highlight the urgent need for a wide range of potently neutralizing antibodies against variants.The ability of SARS-CoV-2 variants to negatively alter the trajectory of the pandemic highlight the urgent need for antibody therapies that can be developed in real time to counter the virus as it evolves. The rapid evolution of SARS-COV-2 escape mutants have resulted in reduced efficacy of most available vaccines and monoclonal antibodies. In this review, we have discussed several monoclonal antibodies characterized from convalescent patients which are potent neutralizers and resistant to mutations. These bnAbs could be used as therapeutic options for the treatment of severe COVID-19 patients and can effectively complement the vaccines in the containment of current pandemic. These passively administered mAb can act in combination with the host immune response to evade the development of severe COVID-19 and limit onward transmission.
Parental COVID-19 Vaccine Hesitancy in Diverse Communities: A National Survey
23% of parents stated that they plan to (or have) vaccinated their children; 30% said that they would not vaccinate their children, and 25% were unsure. Latino/a, Native American, and AAPI parents were generally more likely to vaccinate their children than Black or White parents. After adjusting for demographic factors, AAPI parents were significantly more likely to vaccinate their children than were others. Of parents who said that they would not vaccinate their child, 55% stated it was due to insufficient research. However, over half of parents stated that they would follow their child's healthcare provider's recommendations. After adjusting for demographic factors, trust in their primary care doctor was significantly lower among AAPI, Black, and Native American parents than White parents. Parental vaccine hesitancy was similar overall, but drivers of hesitancy varied by racial/ethnic groups. While the perception that vaccines had been “insufficiently researched” was a major concern among all groups, researchers found that parents are generally inclined to follow health providers’ recommendations. Health professionals can play an important role in COVID-19 vaccine education and should provide access to vaccines.
Oral Sabizabulin for High-Risk, Hospitalized Adults with Covid-19: Interim Analysis
Sabizabulin is an oral, novel microtubule disruptor that has dual antiviral and anti-inflammatory activities in preclinical models. A randomized, multicenter placebo-controlled phase 3 clinical trial was conducted with hospitalized patients with moderate to severe Covid-19 who were at high risk for acute respiratory distress syndrome (ARDS) and death. Patients were randomly assigned (2:1) to 9 mg of oral sabizabulin or placebo daily (up to 21 days). The primary end point was all-cause mortality up to day 60. Key secondary end points were days in the intensive care unit (ICU), days on mechanical ventilation, and days in the hospital. A total of 204 patients were randomly assigned to treatment: 134 to sabizabulin and 70 to placebo. Baseline characteristics were similar. Sabizabulin superiority was demonstrated by a planned interim analysis for the first 150 randomized patients. Sabizabulin treatment resulted in a 24.9 percentage point absolute reduction and a 55.2% relative reduction in deaths compared with placebo (odds ratio, 3.23; 95% CI confidence interval, 1.45 to 7.22; P=0.0042). The mortality rate was 20.2% (19 of 94) for sabizabulin versus 45.1% (23 of 51) for placebo. For the key secondary end points, sabizabulin treatment resulted in a 43% relative reduction in ICU days (P=0.0013), a 49% relative reduction in days on mechanical ventilation (P=0.0013), and a 26% relative reduction in days in the hospital (P=0.0277) versus placebo. Adverse and serious adverse events were lower in the sabizabulin group compared with the placebo group. Sabizabulin treatment resulted in a 24.9% absolute reduction in deaths compared with placebo in hospitalized patients with moderate to severe Covid-19 at high risk for ARDS and death, with a lower incidence of adverse and serious adverse events compared with placebo.

Diagnostics

Rapid Diagnostic Testing for Response to the Monkeypox Outbreak — Laboratory Response Network, United States, May 17–June 30, 2022
During May 17–June 30, 2022, LRN laboratories tested 2,009 specimens from patients with suspected monkeypox. Among these, 730 (36%) specimens from 395 patients were positive for NVO. Specimens from 159 persons with NVO-positive results were confirmed by CDC to be monkeypox; confirmatory testing is pending for 236. LRN laboratories have increased testing capacity from 8,000 per week in June because of NVO assay updates. LRN laboratories’ rapid results enable prompt patient treatment and prevention of further transmission. Expansion of testing to five large national laboratories will increase ease of access to testing.
Evaluating Saliva Sampling with Reverse Transcription Loop-mediated Isothermal Amplification to Improve Access to SARS-CoV-2 Diagnosis in Low-Resource Settings
Standard diagnosis of SARS-CoV-2 by nasopharyngeal swab (NPS) and real-time reverse transcriptase-polymerase chain reaction (PCR) requires a sophisticated laboratory, skilled staff, and expensive reagents that are difficult to establish and maintain in isolated, low-resource settings. In the remote setting of tropical Sumba Island, eastern Indonesia, researchers evaluated alternative sampling with fresh saliva (FS) and testing with colorimetric loop-medicated isothermal amplification (LAMP). Between August 2020 and May 2021, they enrolled 159 patients with suspected SARS-CoV-2 infection, of whom 75 (47%) had a positive PCR on NPS (median cycle threshold [Ct] value: 27.6, interquartile range: 12.5–37.6). PCR on FS had a sensitivity of 72.5% (50/69, 95% confidence interval [CI]: 60.4–82.5) and a specificity of 85.7% (66/77, 95% CI: 75.9–92.6), and positive (PPV) and negative (NPV) predictive values of 82.0% (95% CI: 0.0–90.6) and 77.6% (95% CI: 67.3–86.0), respectively. LAMP on NPS had a sensitivity of 68.0% (51/75, 95% CI: 56.2–78.3) and a specificity of 70.8% (63/84, 95% CI: 58.9–81.0), with PPV 70.8% (95% CI: 58.9-81.0) and NPV 72.4% (95% CI: 61.8–81.5%). LAMP on FS had a sensitivity of 62.3% (43/69, 95% CI: 49.8–73.7%) and a specificity of 72.7% (56/77, 95% CI: 61.4–82.3%), with PPV 67.2% (95% CI: 54.3–78.4) and NPV 68.3% (95% CI: 57.1–78.1%). LAMP sensitivity was higher for NPS and FS specimens with high viral loads (87.1% and 75.0% for Ct value < 26, respectively). Dried saliva on filter paper was stable for 4 days at room temperature. LAMP on either NPS or FS could offer an accessible alternative for SARS-CoV-2 diagnosis in low-resource settings, with potential for optimizing sample collection and processing, and selection of gene targets.

Epidemiology

A More Accurate Measurement of the Burden of COVID-19 Hospitalizations
Researchers proposed utilizing the CDC criteria for severe COVID-19, based on need for supplemental oxygen or oxygen saturation measured below 92%, to define COVID-19 hospitalization (10). To study the impact of this case definition, researchers reviewed medical records of SARS-CoV-2 PCR positive patients admitted to LAC+USC Medical Center, a safety net hospital serving predominantly Latino and low-income patients in Los Angeles, California, during the local Omicron variant surge between 12/10/21 to 1/19/22. Researchers abstracted data on age, vaccination and prior infection history, disease severity assessed by oxygen requirement, hospital length of stay, and mortality via retrospective chart review. Using this case definition based on the CDC criteria for severe disease, 67.5% of SARS-CoV-2 22 PCR positive hospitalized patients would not have met criteria for a COVID-19 hospitalization. These patients had significantly lower median age (44 years vs. 57 years), median hospital length of stay (2 days vs. 3 days), and in-hospital mortality (3.5% vs. 14%). While unadjusted analysis did not show significant association between exposure to vaccine or prior infection and incidental infection (OR=0.79 [0.53-1.17], p=0.24), exposure to vaccine or prior infection was associated with incidental infection upon adjustment for age using logistic regression (OR=0.58 [0.38-0.89], p=0.01).
Leading Causes of Death in the US During the COVID-19 Pandemic, March 2020 to October 2021
From March 2020 to October 2021, COVID-19 accounted for 1 in 8 deaths in the US and was a top 5 cause of death in every age group aged 15 years and older. Cancer and heart disease deaths exceeded COVID-19 deaths overall and in most age groups, whereas accidents were the leading cause of death among those aged 1 to 44 years. Compared with the 2020 time period, deaths from COVID-19 in the 2021 time period decreased in ranking among those aged 85 years or older but increased in ranking among those aged 15 to 54 years, and became the leading cause of death among those aged 45 to 54 years. The increased ranking of COVID-19 as a leading cause of death in some age groups is consistent with a downward age shift in the distribution of COVID-19 deaths in the US in 2021 compared with 2020, perhaps driven by higher COVID-19 vaccination rates in 2021 in the oldest age groups. The pandemic also has had indirect effects on other causes of death in the US. From 2019 to 2020, death rates increased for heart disease, accidents, stroke, Alzheimer disease, and diabetes. Potential explanations are fear of accessing health care or misattribution of COVID-19 deaths to other causes. Accidental deaths (including drug overdoses and unintentional alcohol poisoning), assault, and suicide remain major causes of death in the US, particularly in younger age groups; the pandemic may have contributed to some of these deaths. This analysis was limited by potential misclassification of the cause of death and incomplete death data for 2021, although it included a lag of 6 months to increase the completeness of the provisional data. Moreover, because this analysis only extended through October 2021, it does not include deaths that occurred during the Omicron wave of the pandemic of late 2021 and early 2022.
Lower Risk of Multisystem Inflammatory Syndrome in Children (MIS-C) with the Delta and Omicron variants of SARS-CoV-2
Investigators reported that in Southeast England, MIS-C rates per confirmed SARS-CoV-2 infections in 0-16 years-olds were 56% lower (rate ratio, 0.34; 95%CI, 0.23-0.50) during pre-vaccine Delta, 66% lower (0.44; 0.28-0.69) during post-vaccine Delta and 95% lower (0.05; 0.02-0.10) during the Omicron period.