Coronavirus COVID-19 Update for April 11, 2021

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Clinical Reports

Viral and Symptom Rebound in Untreated COVID-19 Infection
There are reports of viral RNA and symptom rebound in people with COVID-19 treated with nirmatrelvir/ritonavir. Since the natural course of viral and symptom trajectories of COVID-19 has not been well described, we evaluated the incidence of viral and symptom rebound in untreated outpatients with mild-moderate COVID-19. The study population included 568 participants enrolled in the ACTIV-2/A5401 platform trial who received placebo. Anterior nasal swabs were collected for SARS-CoV-2 RNA testing on days 0-14, 21 and 28. Participants recorded the severity of 13 targeted symptoms daily from day 0 to 28. Viral rebound was defined as ≥0.5 log₁₀viral RNA copies/mL increase and symptom rebound was defined as a 4-point total symptom score increase from baseline. Baseline was defined as study day 4 (primary analysis) or 8 days from symptom onset (secondary analysis). In both the primary and secondary analyses, 12% of participants had viral rebound. Viral rebounders were older than non-rebounders (median 54 vs 47 years, P=0.04). Symptom rebound occurred in 27% of participants after initial symptom improvement and in 10% of participants after initial symptom resolution. The combination of high-level viral rebound to ≥5.0 log₁₀ RNA copies/mL and symptom rebound after initial improvement was observed in 1-2% of participants. Viral RNA rebound or symptom relapse in the absence of antiviral treatment is common, but the combination of high-level viral and symptom rebound is rare.
Cognitive Impairment 13 Months After Hospitalization for COVID-19
This study assessed cognitive function 13 months after hospital discharge for coronavirus disease 2019 (COVID-19), using computer-based cognitive tests. Compared to population norms, 14%–25% of patients were impaired in each dimension, and 53% had cognitive impairment in 1 or more of 4 tests. There was some association with acute COVID-19 disease severity.

Antiviral Therapeutics and Vaccines

Pre-exposure prophylaxis with tixagevimab and cilgavimab (Evusheld©) for COVID-19 among 1112 severely immunocompromised patients
Tixagevimab/cilgavimab was administered to 1112 immunocompromised patients. After a median [range] follow-up of 63 [49–73] days, COVID-19 was confirmed in 49/1112 (4.4%) at least 5 days following treatment. During the study period, mean weekly incidence rate was 1669 in 100,000 inhabitants in Ile-de-France and 530 in 100,000 among patients who received tixagevimab/cilgavimab prophylaxis. Among infected patients, 43/49 (88%) had a mild-to moderate form and 6/49 (12%) had a moderate-to-severe form of COVID-19. Patients with moderate-to-severe illnesses were less likely to have received early therapies than patients with mild forms (53.5% vs. 16.7% respectively) and 2/49 (4%) patients died from COVID-19. This study reports a low rate of infections and severe illnesses among immunocompromised patients treated with tixagevimab/cilgavimab. A global preventive strategy including vaccines, preexposure prophylaxis with monoclonal antibodies, and early therapies might be effective to prevent severe forms of COVID-19 among severely immunocompromised patients.
Extended Remdesivir Infusion for Persistent COVID-19 Infection
Persistent SARS-CoV-2 infection patients are difficult to treat. Here, researchers reported a case of 5-month persistent COVID-19 in an immunocompromised patient who was successfully treated with 30 consecutive days of Remdesivir. Prolonged remdesivir infusion with concurrent cycle threshold monitoring might provide a potential solution to cure these difficult patients.
Association between AZD7442 (tixagevimab-cilgavimab) administration and SARS-CoV-2 infection, hospitalization and mortality
Intramuscular AZD7442 (Tixagevimab–Cilgavimab, (Evusheld)) has been found effective among immunocompromised individuals (ICI) in reducing Sars-Cov-2 infection and severe disease in ICIs. We evaluated the association between AZD7442 administration and SARS-CoV-2 infection and severe disease (COVID-19 hospitalization and all-cause mortality) among selected ICIs, during a fifth Omicron-dominated wave of COVID-19 (Dec 2021-April 2022) in Israel. ICIs aged 12 and over identified in the Maccabi HealthCare Services database were invited by SMS/email to receive AZD7442. Demographic information, comorbidities, coronavirus vaccination and prior SARS-CoV-2 infection and COVID-19 outcome data (infection, severe disease), were extracted from the database. Rates of infection and severe disease were compared between those administered AZD7442 and those who did not respond to the invitation, over a three-month period. Of all 825 ICIs administered AZD7442, 29 (3.5%) became infected with SARS-CoV-2 compared to 308 (7.2%) of 4299 ICIs not administered AZD7442 (p < 0.001). After adjustment, the AZD7442 group were half as less likely to become infected with Sars-Cov-2 than the non-administered group (OR: 0.51, 95% CI: 0.30-0.84). One person in the AZD7442 group (0.1%) was hospitalized for COVID-19 compared to 27 (0.6%) in the non-administered group (p = 0.07). No mortality was recorded among the AZD7442 group, compared to 40 deaths (0.9%) in the non-administered group (p = 0.005). After adjustment, ICIs administered AZD7442 were 92% less likely to be hospitalized/die than those not administered AZD7442 (OR: 0.08, 95% CI: 0.01-0.54).AZD7442 among ICI may protect against Omicron variant infection and severe disease, and should be considered for pre-exposure prophylactic AZD7442.
Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomized, controlled, open-label, platform trial and updated meta-analysis
This randomized, controlled, open-label, platform trial (Randomized Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple possible treatments in patients hospitalized with COVID-19 in the UK. Eligible and consenting patients were randomly allocated (1:1) to either usual standard of care alone (usual care group) or usual care plus baricitinib 4 mg once daily by mouth for 10 days or until discharge if sooner (baricitinib group). The primary outcome was 28-day mortality assessed in the intention-to-treat population. A meta-analysis was done, which included the results from the RECOVERY trial and all previous randomized controlled trials of baricitinib or other JAK inhibitor in patients hospitalized with COVID-19. Between Feb 2 and Dec 29, 2021, from 10 852 enrolled, 8156 patients were randomly allocated to receive usual care plus baricitinib versus usual care alone. At randomization, 95% of patients were receiving corticosteroids and 23% were receiving tocilizumab (with planned use within the next 24 h recorded for a further 9%). Overall, 514 (12%) of 4148 patients allocated to baricitinib versus 546 (14%) of 4008 patients allocated to usual care died within 28 days (age-adjusted rate ratio 0·87; 95% CI 0·77–0·99; p=0·028). This 13% proportional reduction in mortality was somewhat smaller than that seen in a meta-analysis of eight previous trials of a JAK inhibitor (involving 3732 patients and 425 deaths), in which allocation to a JAK inhibitor was associated with a 43% proportional reduction in mortality (rate ratio 0·57; 95% CI 0·45–0·72). Including the results from RECOVERY in an updated meta-analysis of all nine completed trials (involving 11 888 randomly assigned patients and 1485 deaths) allocation to baricitinib or another JAK inhibitor was associated with a 20% proportional reduction in mortality (rate ratio 0·80; 95% CI 0·72–0·89; p<0·0001). In RECOVERY, there was no significant excess in death or infection due to non-COVID-19 causes and no significant excess of thrombosis, or other safety outcomes. In patients hospitalized with COVID-19, baricitinib significantly reduced the risk of death but the size of benefit was somewhat smaller than that suggested by previous trials. The total randomized evidence to date suggests that JAK inhibitors (chiefly baricitinib) reduce mortality in patients hospitalized for COVID-19 by about one-fifth.
Repeat subcutaneous administration of casirivimab and imdevimab in adults is well-tolerated and prevents the occurrence of COVID-19
In total, 969 participants received CAS+IMD. Repeat monthly dosing of SC CAS+IMD led to a 92.4% relative risk reduction in clinically defined COVID-19 compared with placebo (3/729 [0.4%] vs 13/240 [5.4%]; odds ratio 0.07 [95% CI 0.01-0.27]), and a 100% reduction in laboratory-confirmed COVID-19 (0/729 vs 10/240 [4.2%]; odds ratio 0.00). Development of anti-drug antibodies occurred in a small proportion of participants (<5%). No grade ≥3 injection-site reactions (ISRs) or hypersensitivity reactions were reported. Slightly more participants reported treatment-emergent adverse events with CAS+IMD (54.9%) than with placebo (48.3%), a finding that was due to grade 1-2 ISRs. Serious adverse events were rare. No deaths were reported in the 6-month treatment period. Repeat monthly administration of 1200 mg SC CAS+IMD was well-tolerated, demonstrated low immunogenicity, and showed a substantial risk reduction in COVID-19 occurrence.

Epidemiology

Is the Omicron variant truly less virulent in Solid Organ Transplant Recipients?
Solid organ transplant (SOT) recipients are at high risk for severe disease with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Emerging variants of concern have disproportionately affected this population. Data on severity and outcomes with the Omicron variant in SOT recipients is limited. Single-center, retrospective cohort study of SOT recipients diagnosed with SARS-CoV-2 infection from December 18, 2021, to January 18, 2022, when prevalence of the Omicron variant was more than 80 - 95% in the community. Univariate and multivariate logistic regression analysis was performed to identify risk factors for hospital admission. We identified 166 SOT patients; 112 (67.5%) kidney, 22 (13.3%) liver, 10 (6.0%) lung, 7 (4.2%) heart, 15 (9.0%) combined transplants. SARS-CoV-2 vaccine series was completed in 59 (35.5%) recipients. Ninety-nine (59.6%) and 13 (7.8%) recipients received casirivimab/imdevimab and sotrovimab, respectively. Fifty-three (32%) recipients required hospital admission, of which 19 (35.8%) required intensive care unit level of care. Median follow up was 50 (IQR, 25 - 59) days, with mortality reported in 6 (3.6%) patients. Risk factors identified for hospital admission were African American race (p<0.001, Odds ratio [OR] 4.00, 95% Confidence Interval [CI] 1.84 – 8.70), history of coronary artery disease (p = 0.031, OR 3.50, 95% CI 1.12 – 10.87), and maintenance immunosuppression with corticosteroids (p = 0.048, OR 2.00, 95% CI 1.01 – 4.00). Contrary to that in the general population, we found a higher hospital admission rate in SOT recipients with omicron variant infection. Further studies to investigate the efficacy of newer treatments are necessary, even as outcomes continue to improve.
Masks for Prevention of Respiratory Virus Infections, Including SARS-CoV-2, in Health Care and Community Settings
Two new cohort studies evaluated mask use and risk for SARS-CoV-2 infection in health care settings. One was a secondary publication for a previously included study. In univariate analysis, it found N95 respirator use associated with increased risk for SARS-CoV-2 infection versus nonuse (OR, 7.8 [CI, 4.0 to 15.2]), but in multivariate analysis, the association between N95 respirator use was not statistically significant enough to be included in the multivariate model (criteria for selecting variables for model not reported); thus, the observed univariate association was likely related to confounding due to increased exposures or other factors in health care workers using N95 masks. The new study did not change the previous assessment of evidence on N95 versus no masks as insufficient. One other new study evaluated the association between consistency of mask use and risk for SARS-CoV-2 infection, but the estimate was very imprecise (for mask use at work all or nearly all of the time versus less than nearly all of the time (adjusted OR, 4.0 [CI, 0.7 to 19.5]). Therefore, the evidence on consistency of mask use remains insufficient.