November 24, 2022

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Clinical Reports

COVID-19 Data Review: Update on COVID-19–Related Mortality
COVID-19 was reported as the underlying cause of death for most COVID-19–related deaths. However, a higher proportion of COVID-19–related deaths had COVID-19 listed as a contributing cause of death during January–September 2022 compared to previous years of the pandemic. This finding was observed among persons dying in hospitals and, to a greater extent, in non-hospital settings such as long-term care facilities and hospice facilities, where a higher proportion of COVID-19–related deaths occurred than earlier in the pandemic. The reasons for these changes are unclear but might signal that 1) people who died outside of the hospital had other health conditions where the severity of those conditions was exacerbated by having COVID-19; 2) people infected with SARS-CoV-2 might have been hospitalized for another condition, but COVID-19 contributed to their death; or 3) that people who survived infection with SARS-CoV-2 continued to suffer COVID-19–related long-term health effects that contributed to their death. Risk of dying while hospitalized for COVID-19 declined steeply during March–April 2022 and remained lower through August 2022 compared to rates observed during June 2021–February 2022. Risk of in-hospital death was highest for patients hospitalized for COVID-19 with ≥5 underlying medical conditions, patients with disabilities, and patients aged ≥80 years. In-hospital death among persons aged 18–49 years hospitalized with COVID-19 during May–August 2022 was rare (1% of COVID-19–associated hospitalizations); most of these patients were unvaccinated. The proportion of patients hospitalized primarily for COVID-19 that had an indicator of severe disease (e.g., required intensive medical intervention) also declined. Less severe COVID-19 disease among hospitalized patients could contribute to the lower rate of in-hospital deaths observed. Decreased use of intensive medical interventions among patients who died in-hospital with COVID-19 could also reflect the increased occurrence of deaths among older people with multiple comorbidities who might not have tolerated or benefited from such interventions or, who did not agree to intensive medical intervention. Early treatment with COVID-19 medication can reduce the risk of COVID-19–related hospitalization and mortality among patients at risk for severe COVID-19. Use of outpatient COVID-19 treatment increased in 2022, particularly during April–July 2022 when nirmatrelvir/ritonavir (Paxlovid), an oral antiviral medication, became widely available. During this period, Paxlovid was the most commonly used outpatient COVID-19 medication among all age groups, with some differences in use by patient age, race and ethnicity, and type of immunocompromising condition.

Antiviral Therapeutics and Vaccines

Effectiveness of the COVID-19 vaccines against hospitalization with Omicron sub-lineages BA.4 and BA.5 in England
This data provides reassuring evidence of the protection conferred by the current vaccines against severe disease with BA.4 and BA.5; researchers found no difference in VE as compared to BA.2 and BNT162b2 and mRNA-1273 boosters provided similarly high levels of protection. This contradicts pre-printed data from a cohort study in Portugal which found VE against severe outcomes was lower for BA.5. This may be due to the small size of the Portuguese study, methodological differences, or differences in classifying hospitalized cases. Here, we use a strict definition as we have previously found broader definitions give lower estimates which likely reflect VE against symptomatic disease. Risk factor status and previous infection will also impact VE; these analyses include adjustment by most recent previous variant and by the risk factor groups offered early vaccination which the Portuguese study did not. Differences in testing policies between countries will also impact local ability to adjust for factors such as previous infection.
Effectiveness of Bivalent mRNA Vaccines in Preventing Symptomatic SARS-CoV-2 Infection — Increasing Community Access to Testing Program, United States, September–November 2022
Monovalent mRNA COVID-19 vaccines were less effective against symptomatic infection during the period of SARS-CoV-2 Omicron variant predominance. In this study of vaccine effectiveness of the U.S.-authorized bivalent mRNA booster formulations, bivalent boosters provided significant additional protection against symptomatic SARS-CoV-2 infection in persons who had previously received 2, 3, or 4 monovalent vaccine doses. Due to waning immunity of monovalent doses, the benefit of the bivalent booster increased with time since receipt of the most recent monovalent vaccine dose. All persons should stay up to date with recommended COVID-19 vaccinations, including bivalent booster doses for eligible persons.
Cardiovascular outcomes after tixagevimab and cilgavimab use for pre-exposure prophylaxis against COVID-19: a population-based propensity-matched cohort study
Tixagevimab and cilgavimab treatment was associated with higher rates of cardiovascular events in a post-hoc analysis of a phase 3 trial. In this large population-based propensity-matched study, we found no increased risk of cardiovascular events up to 90 days after tixagevimab and cilgavimab administration, including in patients with pre-existing cardiovascular disease.
What is the place in therapy for nirmatrelvir/ritonavir?
Based on what is currently known, the benefit from the routine use of nirmatrelvir/ritonavir for immunocompetent patients who are vaccinated and/or have already recovered from COVID-19 on hospitalization or death remains uncertain. While there are an increasing number of retrospective, observational studies supporting use of nirmatrelvir/ritonavir in ‘high-risk’ vaccinated patients, they suffer from varying degrees of immortal time bias, confounding by indication and residual confounding by vaccine status, and therefore, likely represent the most optimistic view of efficacy. Unfortunately, the non-evidence-based approach to use of this oral antiviral agent will continue and likely be exacerbated by full FDA approval. There will remain a critical need for reassessment of what constitutes optimal, cost-effective care with nirmatrelvir/ritonavir. The haste with which COVID-19 therapeutics moved in 2020 and 2021 may no longer be necessary in 2022 and beyond. Unfortunately, SARS-CoV-2 is now here for the long term, and it seems reasonable to make judgements for how we will purchase and prioritize therapies with this in mind prior to repeating lessons from the past.
Paxlovid Associated with Decreased Hospitalization Rate Among Adults with COVID-19 — United States, April–September 2022
Nirmatrelvir-ritonavir (Paxlovid) is an outpatient antiviral medication recommended for adults with mild-to-moderate COVID-19 who have elevated risk of severe illness. Among U.S. adults diagnosed with COVID-19, including those with previous infection or vaccination, persons who were prescribed Paxlovid within 5 days of diagnosis had a 51% lower hospitalization rate within 30 days after diagnosis than those who were not prescribed Paxlovid. Paxlovid should be offered to eligible adults irrespective of vaccination status, especially in groups with the highest risk for severe COVID-19 outcomes, such as older adults and those with multiple underlying health conditions.
Angiotensin receptor blockers for the treatment of covid-19: pragmatic, adaptive, multicenter, phase 3, randomized controlled trial
Between 3 May 2020 and 13 November 2021, 2930 people were screened for eligibility, with 393 randomly assigned to angiotensin receptor blockers (of which 388 (98.7%) to telmisartan 40 mg/day) and 394 to the control group. 787 participants were randomized: 778 (98.9%) from India and nine (1.1%) from Australia. The median WHO scale score at day 14 was 1 (interquartile range 1-1) in 384 participants assigned angiotensin receptor blockers and 1 (1-1) in 382 participants assigned placebo (adjusted odds ratio 1.51 (95% credible interval 1.02 to 2.23), probability of an odds ratio of >1 (Pr(OR>1)=0.98). WHO scale scores at day 28 showed little evidence of difference between groups (1.02 (0.55 to 1.87), Pr(OR>1)=0.53). The trial was stopped when a prespecified futility rule was met. In patients admitted to hospital for covid-19, mostly with mild disease, not requiring oxygen, no evidence of benefit, based on disease severity score, was found for treatment with angiotensin receptor blockers, using predominantly 40 mg/day of telmisartan.

Epidemiology

Human monkeypox virus infection in women and non-binary individuals during the 2022 outbreaks
Collaborators reported data for a total of 136 individuals with monkeypox virus infection who presented between May 11 and Oct 4, 2022, across 15 countries. Overall median age was 34 years (IQR 28–40; range 19–84). The cohort comprised 62 trans women, 69 cis women, and five non-binary individuals (who were, because of small numbers, grouped with cis women to form a category of people assigned female at birth for the purpose of comparison). 121 (89%) of 136 individuals reported sex with men. 37 (27%) of all individuals were living with HIV, with a higher proportion among trans women (31 [50%] of 62) than among cis women and non-binary individuals (six [8%] of 74). Sexual transmission was suspected in 55 (89%) trans women (with the remainder having an unknown route of transmission) and 45 (61%) cis women and non-binary individuals; non-sexual routes of transmission (including household and occupational exposures) were reported only in cis women and non-binary individuals. 25 (34%) of 74 cis women and non-binary individuals submitted to the case series were initially misdiagnosed. Overall, among individuals with available data, rash was described in 124 (93%) of 134 individuals and described as anogenital in 95 (74%) of 129 and as vesiculopustular in 105 (87%) of 121. Median number of lesions was ten (IQR 5-24; range 1–200). Mucosal lesions involving the vagina, anus, or oropharynx or eye occurred in 65 (55%) of 119 individuals with available data. Vaginal and anal sex were associated with lesions at those sites. Monkeypox virus DNA was detected by PCR from vaginal swab samples in all 14 samples tested. 17 (13%) individuals were hospitalized, predominantly for bacterial superinfection of lesions and pain management. 33 (24%) individuals were treated with tecovirimat and six (4%) received post-exposure vaccinations. No deaths were reported. The clinical features of monkeypox in women and non-binary individuals were similar to those described in men, including the presence of anal and genital lesions with prominent mucosal involvement. Anatomically, anogenital lesions were reflective of sexual practices: vulvovaginal lesions predominated in cis women and non-binary individuals and anorectal features predominated in trans women. The prevalence of HIV co-infection in the cohort was high.
Changes in population immunity against infection and severe disease from SARS-CoV-2 Omicron variants in the United States between December 2021 and November 2022
By November 10, 2022, 94% (95% CrI, 79%-99%) of the US population were estimated to have been infected by SARS-CoV-2 at least once. Combined with vaccination, 97% (95%-99%) were estimated to have some prior immunological exposure to SARS-CoV-2. Between December 1, 2021 and November 10, 2022, protection against a new Omicron infection rose from 22% (21%-23%) to 63% (51%-75%) nationally, and protection against an Omicron infection leading to severe disease increased from 61% (59%-64%) to 89% (83%-92%). Increasing first booster uptake to 55% in all states (current US coverage: 34%) and second booster uptake to 22% (current US coverage: 11%) would increase protection against infection by 4.5 percentage points (2.4-7.2) and protection against severe disease by 1.1 percentage points (1.0-1.5). Effective protection against SARS-CoV-2 infection and severe disease in October 2022 was substantially higher than in December 2021. Despite this high level of protection, a more transmissible or immune evading (sub)variant, changes in behavior, or ongoing waning of immunity could lead to a new SARS-CoV-2 wave.
Impact of community masking on COVID-19
A randomized-trial of community-level mask promotion in rural Bangladesh during the COVID-19 pandemic shows that the intervention increased mask usage and reduced symptomatic SARS-CoV-2 infections, demonstrating that promoting community mask-wearing can improve public health.