Mortality Risk Among Patients Hospitalized Primarily for COVID-19 During the Omicron and Delta Variant Pandemic Periods — United States, April 2020–June 2022

Havers F.P., Patel K., Whitaker M., Milucky J., Reingold A., Armistead I., Meek J., Anderson E.J., Weigel A., Reeg L., Seys S., Ropp S.L., Spina N., Felsen C.B., Moran N.E., et. al.

Beginning the week of March 20–26, 2022, the Omicron BA.2 variant of SARS-CoV-2, the virus that causes COVID-19, became the predominant circulating variant in the United States, accounting for >50% of sequenced isolates.* Data from the COVID-19–Associated Hospitalization Surveillance Network (COVID-NET) were analyzed to describe recent COVID-19–associated hospitalization rates among adults aged ≥18 years during the period coinciding with BA.2 predominance (BA.2 period [Omicron BA.2 and BA.2.12.1; March 20–May 31, 2022]). Weekly hospitalization rates (hospitalizations per 100,000 population) among adults aged ≥65 years increased threefold, from 6.9 (week ending April 2, 2022) to 27.6 (week ending May 28, 2022); hospitalization rates in adults aged 18–49 and 50–64 years both increased 1.7-fold during the same time interval. Hospitalization rates among unvaccinated adults were 3.4 times as high as those among vaccinated adults. Among hospitalized nonpregnant patients in this same period, 39.1% had received a primary vaccination series and 1 booster or additional dose; 5.0% had received a primary series and ≥2 boosters or additional doses. All adults should stay up to date† with COVID-19 vaccination, and multiple nonpharmaceutical and medical prevention measures should be used to protect those at high risk for severe COVID-19 illness, irrespective of vaccination status§ (1).Beginning the week of March 20–26, 2022, the Omicron BA.2 variant of SARS-CoV-2, the virus that causes COVID-19, became the predominant circulating variant in the United States, accounting for >50% of sequenced isolates.* Data from the COVID-19–Associated Hospitalization Surveillance Network (COVID-NET) were analyzed to describe recent COVID-19–associated hospitalization rates among adults aged ≥18 years during the period coinciding with BA.2 predominance (BA.2 period [Omicron BA.2 and BA.2.12.1; March 20–May 31, 2022]). Weekly hospitalization rates (hospitalizations per 100,000 population) among adults aged ≥65 years increased threefold, from 6.9 (week ending April 2, 2022) to 27.6 (week ending May 28, 2022); hospitalization rates in adults aged 18–49 and 50–64 years both increased 1.7-fold during the same time interval. Hospitalization rates among unvaccinated adults were 3.4 times as high as those among vaccinated adults. Among hospitalized nonpregnant patients in this same period, 39.1% had received a primary vaccination series and 1 booster or additional dose; 5.0% had received a primary series and ≥2 boosters or additional doses. All adults should stay up to date† with COVID-19 vaccination, and multiple nonpharmaceutical and medical prevention measures should be used to protect those at high risk for severe COVID-19 illness, irrespective of vaccination status§ (1).

Massetti G.M., Jackson B.R., Brooks J.T., Perrine C.G., Reott E., Hall A.J., Lubar D., Williams I.T., Ritchey M.D., Patel P., Liburd L.C., Mahon B.E.

Gold J.A., Kelleher J., Magid J., Jackson B.R., Pennini M.E., Kushner D., Weston E.J., Rasulnia B., Kuwabara S., Bennett K., Mahon B.E., Patel A., Auerbach J.

The COVID-19 pandemic has highlighted and exacerbated long-standing inequities in the social determinants of health (1-3). Ensuring equitable access to effective COVID-19 therapies is essential to reducing health disparities. Molnupiravir (Lagevrio) and nirmatrelvir/ritonavir (Paxlovid) are oral antiviral agents effective at preventing hospitalization and death in patients with mild to moderate COVID-19 who are at high risk* for progression to severe COVID-19 when initiated within 5 days of symptom onset. These medications received Emergency Use Authorization from the Food and Drug Administration (FDA) in December 2021† and were made available at no cost to recipients through the U.S. Department of Health and Human Services (HHS) on December 23, 2021. Beginning March 7, 2022, a series of strategies was implemented to expand COVID-19 oral antiviral access, including the launch of the Test to Treat initiative.§ Data from December 23, 2021-May 21, 2022, were analyzed to describe oral antiviral prescription dispensing overall and by week, stratified by zip code social vulnerability. Zip codes represented areas classified as low, medium, or high social vulnerability; approximately 20% of U.S. residents live in low-, 31% in medium-, and 49% in high-social vulnerability zip codes.¶ During December 23, 2021-May 21, 2022, a total of 1,076,762 oral antiviral prescriptions were dispensed (Lagevrio = 248,838; Paxlovid = 827,924). Most (70.3%) oral antivirals were dispensed during March 7-May 21, 2022. During March 6, 2022-May 21, 2022, the number of oral antivirals dispensed per 100,000 population increased from 3.3 to 77.4 in low-, from 4.5 to 70.0 in medium-, and from 7.8 to 35.7 in high-vulnerability zip codes. The number of oral antivirals dispensed rose substantially during the overall study period, coincident with the onset of initiatives to increase access. However, by the end of the study period, dispensing rates in high-vulnerability zip codes were approximately one half the rates in medium- and low-vulnerability zip codes. Additional public health, regulatory, and policy efforts might help decrease barriers to oral antiviral access, particularly in communities with high social vulnerability.

Clarke K.E., Jones J.M., Deng Y., Nycz E., Lee A., Iachan R., Gundlapalli A.V., Hall A.J., MacNeil A.

In December 2021, the B.1.1.529 (Omicron) variant of SARS-CoV-2, the virus that causes COVID-19, became predominant in the United States. Subsequently, national COVID-19 case rates peaked at their highest recorded levels.* Traditional methods of disease surveillance do not capture all COVID-19 cases because some are asymptomatic, not diagnosed, or not reported; therefore, the proportion of the population with SARS-CoV-2 antibodies (i.e., seroprevalence) can improve understanding of population-level incidence of COVID-19. This report uses data from CDC's national commercial laboratory seroprevalence study and the 2018 American Community Survey to examine U.S. trends in infection-induced SARS-CoV-2 seroprevalence during September 2021-February 2022, by age group.

Plumb I.D., Feldstein L.R., Barkley E., Posner A.B., Bregman H.S., Hagen M.B., Gerhart J.L.

Previous infection with SARS-CoV-2, the virus that causes COVID-19, has been estimated to confer up to 90% protection against reinfection, although this protection was lower against the Omicron variant compared with that against other SARS-CoV-2 variants (1-3). A test-negative design was used to estimate effectiveness of COVID-19 mRNA vaccines in preventing subsequent COVID-19-associated hospitalization among adults aged ≥18 years with a previous positive nucleic acid amplification test (NAAT) or diagnosis of COVID-19.† The analysis used data from Cosmos, an electronic health record (EHR)-aggregated data set (4), and compared vaccination status of 3,761 case-patients (positive NAAT result associated with hospitalization) with 7,522 matched control-patients (negative NAAT result). After previous SARS-CoV-2 infection, estimated vaccine effectiveness (VE) against COVID-19-associated hospitalization was 47.5% (95% CI = 38.8%-54.9%) after 2 vaccine doses and 57.8% (95% CI = 32.1%-73.8%) after a booster dose during the Delta-predominant period (June 20-December 18, 2021), and 34.6% (95% CI = 25.5%-42.5%) after 2 doses and 67.6% (95% CI = 61.4%-72.8%) after a booster dose during the Omicron-predominant period (December 19, 2021-February 24, 2022). Vaccination provides protection against COVID-19-associated hospitalization among adults with previous SARS-CoV-2 infection, with the highest level of protection conferred by a booster dose. All eligible persons, including those with previous SARS-CoV-2 infection, should stay up to date with vaccination to prevent COVID-19-associated hospitalization.

Tenforde M.W., Self W.H., Gaglani M., Ginde A.A., Douin D.J., Talbot H.K., Casey J.D., Mohr N.M., Zepeski A., McNeal T., Ghamande S., Gibbs K.W., Files D.C., Hager D.N., Shehu A., et. al.

COVID-19 mRNA vaccines (BNT162b2 [Pfizer-BioNTech] and mRNA-1273 [Moderna]) are effective at preventing COVID-19-associated hospitalization (1-3). However, how well mRNA vaccines protect against the most severe outcomes of these hospitalizations, including invasive mechanical ventilation (IMV) or death is uncertain. Using a case-control design, mRNA vaccine effectiveness (VE) against COVID-19-associated IMV and in-hospital death was evaluated among adults aged ≥18 years hospitalized at 21 U.S. medical centers during March 11, 2021-January 24, 2022. During this period, the most commonly circulating variants of SARS-CoV-2, the virus that causes COVID-19, were B.1.1.7 (Alpha), B.1.617.2 (Delta), and B.1.1.529 (Omicron). Previous vaccination (2 or 3 versus 0 vaccine doses before illness onset) in prospectively enrolled COVID-19 case-patients who received IMV or died within 28 days of hospitalization was compared with that among hospitalized control patients without COVID-19. Among 1,440 COVID-19 case-patients who received IMV or died, 307 (21%) had received 2 or 3 vaccine doses before illness onset. Among 6,104 control-patients, 4,020 (66%) had received 2 or 3 vaccine doses. Among the 1,440 case-patients who received IMV or died, those who were vaccinated were older (median age = 69 years), more likely to be immunocompromised* (40%), and had more chronic medical conditions compared with unvaccinated case-patients (median age = 55 years; immunocompromised = 10%; p

Ward I.L., Bermingham C., Ayoubkhani D., Gethings O.J., Pouwels K.B., Yates T., Khunti K., Hippisley-Cox J., Banerjee A., Walker A.S., Nafilyan V.

AbstractObjectiveTo assess the risk of death involving COVID-19 following infection from Omicron (B.1.1.539/BA.1) relative to Delta (B.1.617.2).DesignRetrospective cohort study.SettingEngland, UK, 1 December 2021 to 25 January 2022.Participants1,035,163 people aged 18-100 years who tested positive for SARS-CoV-2 in the national surveillance programme, and had an infection identified as either Omicron- or Delta compatible.Main outcome measuresDeath involving COVID-19 as identified from death certification records. The exposure of interest was the SARS-CoV-2 variant identified from NHS Test and Trace PCR positive tests taken in the community (pillar 2) and analysed by Lighthouse laboratories. Cause-specific Cox proportional hazard regression models were adjusted for sex, age, vaccination status, previous infection, calendar time, ethnicity, Index of Multiple Deprivation rank, household deprivation, university degree, keyworker status, country of birth, main language, region, disability, and comorbidities. Additionally, we tested for interactions between variant and sex, age, vaccination status and comorbidities.ResultsThe risk of death involving COVID-19 was 67% lower for Omicron compared to Delta and the reduction in the risk of death involving COVID-19 for Omicron compared to Delta was more pronounced in males than in females and in people under 70 years old than in people aged 70 years or over. Regardless of age, reduction of the risk of death from Omicron relative to Delta more was more pronounced in people who had received a booster than in those having received only two doses.ConclusionsOur results support early work showing the relative reduction in severity of Omicron compared to Delta in terms of hospitalisation and extends this research to assess COVID-19 mortality. Our work also highlights the importance of the vaccination booster campaign, where the reduction in risk of death involving COVID-19 is most pronounced in individuals who had received a booster.What is already known on this topicThe Omicron variant, which refers to the whole lineage (BA.1, BA.2, BA.3) had already been shown to be more transmissible than the Delta variant, but there is emerging evidence suggests that the risk of hospitalisation and risk of death within 28 days after a SARS-COV-2 test is lower. However, with a highly transmissible infection and high levels of population testing, definition of death within 28 days is more likely to be susceptible to misclassification bias due to asymptomatic or co-incidental infection. There is no study so far comparing the risk of COVID-19 death as identified from death certification records, with the cause of death assessed by the physician who attended the patient in the last illness.What this study addsUsing data from a large cohort of COVID-19 infections that occurred in December 2021, we examined the difference in the risk COVID-19 death, as identified from death certification records, between the Delta and Omicron BA.1 variant. Our study shows that risk of death involving COVID-19 was reduced by 67% following infection with the Omicron BA.1 variant relative to the Delta variant after adjusting for a wide range of potential confounders, including vaccination status and comorbidities. Importantly, we found that the relative risk of COVID-19 mortality following Omicron versus Delta infection varied by age and sex, with lower relative risk in younger individuals and for males than females. The reduction in risk of death involving COVID-19 was also most pronounced in individuals who had received a booster.

Hui K.P., Ho J.C., Cheung M., Ng K., Ching R.H., Lai K., Kam T.T., Gu H., Sit K., Hsin M.K., Au T.W., Poon L.L., Peiris M., Nicholls J.M., Chan M.C.

The emergence of SARS-CoV-2 variants of concern with progressively increased transmissibility between humans is a threat to global public health. The Omicron variant of SARS-CoV-2 also evades immunity from natural infection or vaccines1, but it is unclear whether its exceptional transmissibility is due to immune evasion or intrinsic virological properties. Here we compared the replication competence and cellular tropism of the wild-type virus and the D614G, Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2) and Omicron (B.1.1.529) variants in ex vivo explant cultures of human bronchi and lungs. We also evaluated the dependence on TMPRSS2 and cathepsins for infection. We show that Omicron replicates faster than all other SARS-CoV-2 variants studied in the bronchi but less efficiently in the lung parenchyma. All variants of concern have similar cellular tropism compared to the wild type. Omicron is more dependent on cathepsins than the other variants of concern tested, suggesting that the Omicron variant enters cells through a different route compared with the other variants. The lower replication competence of Omicron in the human lungs may explain the reduced severity of Omicron that is now being reported in epidemiological studies, although determinants of severity are multifactorial. These findings provide important biological correlates to previous epidemiological observations. Omicron replicates faster than the wild-type, D614G, Alpha, Beta and Delta SARS-CoV-2 variants in the bronchi but less efficiently in the lung parenchyma.

Iuliano A.D., Brunkard J.M., Boehmer T.K., Peterson E., Adjei S., Binder A.M., Cobb S., Graff P., Hidalgo P., Panaggio M.J., Rainey J.J., Rao P., Soetebier K., Wacaster S., Ai C., et. al.

The B.1.1.529 (Omicron) variant of SARS-CoV-2, the virus that causes COVID-19, was first clinically identified in the United States on December 1, 2021, and spread rapidly. By late December, it became the predominant strain, and by January 15, 2022, it represented 99.5% of sequenced specimens in the United States* (1). The Omicron variant has been shown to be more transmissible and less virulent than previously circulating variants (2,3). To better understand the severity of disease and health care utilization associated with the emergence of the Omicron variant in the United States, CDC examined data from three surveillance systems and a large health care database to assess multiple indicators across three high-COVID-19 transmission periods: December 1, 2020-February 28, 2021 (winter 2020-21); July 15-October 31, 2021 (SARS-CoV-2 B.1.617.2 [Delta] predominance); and December 19, 2021-January 15, 2022 (Omicron predominance). The highest daily 7-day moving average to date of cases (798,976 daily cases during January 9-15, 2022), emergency department (ED) visits (48,238), and admissions (21,586) were reported during the Omicron period, however, the highest daily 7-day moving average of deaths (1,854) was lower than during previous periods. During the Omicron period, a maximum of 20.6% of staffed inpatient beds were in use for COVID-19 patients, 3.4 and 7.2 percentage points higher than during the winter 2020-21 and Delta periods, respectively. However, intensive care unit (ICU) bed use did not increase to the same degree: 30.4% of staffed ICU beds were in use for COVID-19 patients during the Omicron period, 0.5 percentage points lower than during the winter 2020-21 period and 1.2 percentage points higher than during the Delta period. The ratio of peak ED visits to cases (event-to-case ratios) (87 per 1,000 cases), hospital admissions (27 per 1,000 cases), and deaths (nine per 1,000 cases [lagged by 3 weeks]) during the Omicron period were lower than those observed during the winter 2020-21 (92, 68, and 16 respectively) and Delta (167, 78, and 13, respectively) periods. Further, among hospitalized COVID-19 patients from 199 U.S. hospitals, the mean length of stay and percentages who were admitted to an ICU, received invasive mechanical ventilation (IMV), and died while in the hospital were lower during the Omicron period than during previous periods. COVID-19 disease severity appears to be lower during the Omicron period than during previous periods of high transmission, likely related to higher vaccination coverage,† which reduces disease severity (4), lower virulence of the Omicron variant (3,5,6), and infection-acquired immunity (3,7). Although disease severity appears lower with the Omicron variant, the high volume of ED visits and hospitalizations can strain local health care systems in the United States, and the average daily number of deaths remains substantial.§ This underscores the importance of national emergency preparedness, specifically, hospital surge capacity and the ability to adequately staff local health care systems. In addition, being up to date on vaccination and following other recommended prevention strategies are critical to preventing infections, severe illness, or death from COVID-19.

Everaert S., Godderis L., Raquez J., Schoeters G., Spanoghe P., Moens J., Hens L., Michel O., Adang D., Fraeyman N.

The use of face masks has proven to be an effective preventive measure during the COVID-19 pandemic. However, concerns have emerged regarding the safety of metal (nano)particles incorporated into face masks for antimicrobial purposes. Specifically, this review examines the risks associated with TiO2 nanoparticles (NPs), which are classified as a possible human carcinogen. The inhalation of TiO2 NPs can cause multiple adverse effects, including oxidative stress, pulmonary inflammation, histopathological changes, and (secondary) genotoxicity. Different aspects are discussed, such as the composition and filtration efficiency of face masks, the antimicrobial mode of action and effectiveness of various metals, and the hazards of TiO2 NPs to human health, including exposure limits. A conservative risk assessment was conducted using different worst-case scenarios of potential (sub)chronic TiO2 exposure, derived from published leaching experiments. Most face masks are considered safe, especially for occasional or single use. However, the nanosafety of a minority of face masks on the European market may be inadequate for prolonged and intensive use. Important uncertainties remain, including the risks of combined exposure to TiO2 NPs and silver biocides, and the lack of direct exposure measurements. Considering the potential safety issues and the limited added protective value of TiO2 NPs, it is recommended to ban all applications of TiO2 in face masks based on the precautionary principle.

Hurst J.H., Mohan A.A., Dalapati T., George I.A., Aquino J.N., Lugo D.J., Pfeiffer T.S., Rodriguez J., Rotta A.T., Turner N.A., Burke T.W., McClain M.T., Henao R., DeMarco C.T., Louzao R., et. al.

Abstract Age is among the strongest risk factors for severe outcomes from SARS-CoV-2 infection. Here we describe upper respiratory tract (URT) and peripheral blood transcriptomes of 202 participants (age range of 1 week to 83 years), including 137 non-hospitalized individuals with mild SARS-CoV-2 infection and 65 healthy individuals. Among healthy children and adolescents, younger age is associated with higher URT expression of innate and adaptive immune pathways. SARS-CoV-2 infection induces broad upregulation of URT innate and adaptive immune responses among children and adolescents. Peripheral blood responses among SARS-CoV-2-infected children and adolescents are dominated by interferon pathways, while upregulation of myeloid activation, inflammatory, and coagulation pathways is observed only in adults. Among SARS-CoV-2-infected individuals, fever is associated with blunted URT immune responses and more pronounced systemic immune activation. These findings demonstrate that immune responses to SARS-CoV-2 differ across the lifespan, from distinct signatures in childhood and adolescence to age-associated alterations in adults.

Ge J., Far A., Digitale J.C., Pletcher M.J., Lai J.C., Wilcox A.B., Lee A.M., Graves A., Anzalone A.(., Manna A., Saha A., Olex A., Zhou A., Williams A.E., Southerland A., et. al.

The virulence and severity of SARS-CoV-2 infections have decreased over time in the general population due to vaccinations and improved antiviral treatments. Whether a similar trend has occurred in patients with cirrhosis is unclear. We used the National COVID Cohort Collaborative (N3C) to describe the outcomes over time.

Van Eijndhoven D.A., Vos R., Bos S.

Coronavirus disease 2019 (COVID-19) has significantly impacted lung transplant recipients (LTR), who remain vulnerable to severe COVID-19 despite vaccination, prompting the use of monoclonal antibodies (mAbs) as a treatment option. This systematic review summarizes the clinical efficacy of mAbs against COVID-19 in adult LTR and provides a perspective on the role of mAbs for infectious diseases in the future. A systematic search of PubMed/MEDLINE, Embase and Cochrane was conducted for studies reporting clinical outcomes of adult LTR or solid organ transplant recipients (SOTR) including LTR with drug-specific outcomes. Twelve studies were included. Pre-exposure prophylaxis with mAbs reduced COVID-19 breakthrough infection in LTR. Early treatment of COVID-19 with mAbs correlated with a reduced incidence of severe COVID-19 outcomes, although statistical significance varied among studies. Overall, observational studies have demonstrated a potential benefit of mAbs in the treatment of COVID-19 in LTR, both in prophylaxis and early treatment, as well as the importance of early administration. Moreover, mAb therapy appeared safe and could be a viable option against other pathogens, a route that warrants further investigation.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=382133, identifier CRD42022382133.

Ramos-Rincón J., Sánchez-Paya J., González-De-La-Aleja P., Rodríguez-Díaz J., Merino E.

ObjectivesThe study aimed to analyze in-hospital mortality (IHM) among all COVID-19 patients hospitalized in Spain between March 1, 2020, and December 31, 2021, and to compare two distinct periods: the prevaccination period (March 1, 2020, to January 31, 2021) and the vaccination period (February 1, 2021, to December 31, 2021). The objective was to assess the impact of vaccination on IHM and identify associated risk factors, using data from Spain’s national hospitalization registry.MethodsThis retrospective analysis used data from the Spanish National Surveillance System for Hospital Data. The primary outcome was in-hospital mortality (IHM). Multivariate logistic regression identified risk factors across the overall study period, as well as during the prevaccination and vaccination periods. Risk factors included age (in 20-year intervals), sex, comorbidities (e.g., hypertension, diabetes, chronic kidney failure, obesity, neurodegenerative disorders, and others), and admission to the intensive care unit.ResultsA total of 524,314 COVID-19 hospitalizations were recorded in Spain, with 329,690 during the prevaccination period and 194,624 during the vaccination period. Hospitalization rates dropped from 697/100,000 people to 411/100,000, and in-hospital mortality (IHM) decreased from 16.2 to 11.5% (adjusted odds ratio [AOR]: 0.71, 95% CI: 0.70–0.73, p < 0.001). IHM rose with age, from 0.8% in patients aged 18–39 to 31.7% in those ≥80 years (p < 0.001), but significant decreases were observed across all age groups after vaccination, especially in those ≥80 years (AOR: 0.76, 95% CI: 0.75–0.79, p < 0.001). Risk factors for IHM remained consistent, with leukemia, neoplasm, and lymphoma posing the highest risks, while female sex (AOR: 0.75, 95% CI: 0.74–0.77, p < 0.001) and dyslipidemia (AOR: 0.85, 95% CI: 0.32–0.86, p < 0.001) were protective factors.ConclusionDuring the vaccination period, the risk of in-hospital mortality (IHM) was 29% lower than in the prevaccination period, after adjusting for sex, age, and comorbidities. This reduced risk was observed across sexes, age groups, and comorbidities. The risk factors for IHM remained consistent between the two periods, with age as the main risk factor, while female sex and dyslipidemia were identified as protective factors.

Mizuno T., Suzuki J., Takahashi S., Imai H., Itagaki H., Yoshida M., Endo S.

Systemic baricitinib and corticosteroids play important roles in treating severely and critically ill patients with coronavirus disease 2019 (COVID-19). However, the efficacy of the combination of baricitinib and corticosteroids compared to that of corticosteroid monotherapy in severely and critically ill hospitalized patients with COVID-19 remains unclear.

Rodriguez L., Zamora J.L., Han D., Moshiri J., Peinovich N., Martinez C., Ho P.Y., Li J., Aeschbacher T., Martin R., Pekosz A., Bilello J.P., Perry J.K., Hedskog C.

As new SARS-CoV-2 variants continue to emerge, it is important to evaluate the potency of antiviral drugs to support their continued use. Remdesivir (RDV; VEKLURY®) an approved antiviral treatment for COVID-19, and obeldesivir (ODV) are inhibitors of the SARS-CoV-2 RNA-dependent RNA polymerase Nsp12. Here we show these two compounds retain antiviral activity against the Omicron variants BA.2.86, BF.7, BQ.1, CH.1.1, EG.1.2, EG.5.1, EG.5.1.4, FL.22, HK.3, HV.1, JN.1, JN.1.7, JN.1.18, KP.2, KP.3, LB.1, XBB.1.5, XBB.1.5.72, XBB.1.16, XBB.2.3.2, XBC.1.6, and XBF when compared with reference strains. Genomic analysis identified 29 Nsp12 polymorphisms in these and previous Omicron variants. Phenotypic analysis of these polymorphisms confirmed no impact on the antiviral activity of RDV or ODV and suggests Omicron variants containing these Nsp12 polymorphisms remain susceptible to both compounds. These data support the continued use of RDV in the context of circulating SARS-CoV-2 variants and the development of ODV as an antiviral therapeutic.

Cheng H., Chang K., Wu B., Teo M., Hung W., Wu H., Huang A.C., Lin C., Lin T., Lin H., Chiu C., Lin S.

Scott A., Puzniak L., Murphy M.V., Benjumea D., Rava A., Benigno M., Allen K.E., Stanford R.H., Manuel F., Chambers R., Reimbaeva M., Ansari W., Cha-Silva A.S., Draica F.

Goldwasser J., Hu A.J., Bilinski A., McDonald D.J., Tibshirani R.J.

AbstractSeverity rates like the case-fatality rate and infection-fatality rate are key metrics in public health. To guide decision-making in response to changes like new variants or vaccines, it is imperative to understand how these rates shift in real time. In practice, time-varying severity rates are typically estimated using a ratio of aggregate counts. We demonstrate that these estimators are capable of exhibiting large statistical biases, with concerning implications for public health practice, as they may fail to detect heightened risks or falsely signal nonexistent surges. We supplement our mathematical analyses with experimental results on real and simulated COVID-19 data. Finally, we briefly discuss strategies to mitigate this bias, drawing connections with effective reproduction number (Rt) estimation.

Dinh T., Ross J., James S., Klein K., Chandran A.U., Larios O., Strong D., Conly J.M.

Background: With initial waves of COVID-19, many public health systems assumed each COVID-19 positive hospitalization was a direct cause from COVID-19 infection. Since January 2022, Alberta Health Services Communicable Disease Control Hospitalization Team (CDC-HT) implemented an admission criteria algorithm to adjudicate COVID-19 as a direct, contributing, or unrelated cause for all COVID-19 admissions in Alberta. Methods: This quality improvement initiative sought to improve the admission algorithm's precision in reporting COVID-19 admissions. Patient hospitalization records from January-February 2022 with a positive COVID-19 test in the last 30 days were proportionally sampled in a geographically stratified manner across Alberta health zones. 261 patient records were sampled and determination of COVID-19 attribution by CDC-HT algorithm was compared to adjudication by a panel of infectious diseases physicians with extensive COVID-19 clinical experience. Results: Of 261 sampled COVID-19 admissions, blinded physician adjudication determined 39.9% were direct-cause, 17.2% contributing-cause, and 37.6% unrelated-cause. Within the same cohort the CDC-HT admission algorithm adjudicated 42.9% direct-cause, 24.5% contributing-cause, and 30.3% unrelated-cause. Cohen's kappa was 0.475, providing only moderate agreement. The majority of discrepancy was from over-attribution of unrelated hospitalizations as contributing cause. Implementation of this algorithm in Alberta throughout 2022 showed a fluctuating proportion of direct plus contributing COVID-19 hospitalizations as low as 40%. Conclusion: There was misattribution bias in COVID-19 hospitalization determination using the admission algorithm. The findings from this analysis led to improvements in the algorithm to improve precision. Public health jurisdictions should review their COVID-19 hospitalization reporting approaches to ensure validity and consideration of incidental cases.

Yuan W., Liu Y., Zhan H., Wei F., Zhang Q., Gao H., Yan H., Huang T., Li Y., Dai E.

ObjectiveThe aim of this study was to explore the clinical characteristics of patients infected with different Omicron subvariants presenting non-severe disease, evaluate the safety and efficacy of Azvudine for treatment of COVID-19, in order to broaden understanding of Omicron subvariant infections.MethodA total of 244 individuals with Omicron subvariant (BA.2.76, n = 158; BA.5.1, n = 86) were included in the study. Demographic, clinical, and laboratory data of the study participants were collected and analyzed.ResultPatients infected with BA.5.1 exhibited a higher incidence of clinical symptoms like fatigue (25.58% vs. 2.53%, p < 0.001), headache/dizziness (12.79% vs. 4.43%, p = 0.017), nausea/vomiting (10.47% vs. 1.27%, p = 0.002), viral loads and inflammatory factors, and shorter virus shedding time than those with BA.2.76. There are 28.1% patients reporting mild adverse events following Azvudine administration. After treatment, the levels of anti-SARS-CoV-2 IgG/IgM, white blood cell, and lymphocyte obviously increased, while C-reactive protein, procalcitonin, and D-dimer reduced. Azvudine speeded up the time for virus clearance compared to control treatment (10 vs. 11 days, p = 0.032). Low lymphocyte counts (odd ratio (OR) = 0.607, p = 0.001) and anti-SARS-CoV-2 IgG titer (OR = 0.990, p = 0.028) were the independent risk factors for long nucleic acid negativization duration after infection. Patients with pneumonia were often accompanied by dyspnea, fatigue and high level of D-dimer. Dyspnea (OR = 10.176, p = 0.019) could be used to identify the occurrence of pneumonia in patients infected with Omicron.ConclusionThe study demonstrated the difference in clinical and laboratory parameters between patients infected with Omicron BA.2.76 and BA.5.1, as well as the safety and efficacy of Azvudine therapy. Our study linked patient manifestations to Omicron subvariant, treatment, and clinical outcomes, which is conducive to healthcare providers/policymakers to revise and implement appropriate countermeasures, facilitating appropriately advise for individuals with Omicron subvariant infections.

Stremel T., Schnaidt S., Bihrer N., Fröling E., Jacob C., Kisser A.

Individuals at increased risk of severe coronavirus disease 2019 (COVID-19) progression have a higher probability of being hospitalized. Nirmatrelvir/ritonavir (NMV/r) is an antiviral drug aiming to prevent severe disease courses. Our study aimed to assess the resource utilization and costs of adults hospitalized for COVID-19 at high risk for severe disease progression. A retrospective study was conducted using German claims data. The presence of high-risk criteria was determined through recorded diagnoses, operations, procedures, and prescriptions. Individuals at high risk for severe COVID-19 progression, primarily hospitalized for COVID-19, required a recorded diagnosis for COVID-19 and additionally a diagnosis of sepsis, pulmonary embolism, acute respiratory failure, pneumonia, or a remdesivir prescription. Patients were grouped by eligibility for NMV/r treatment (eligible, eligible with restrictions, and not eligible). The outcomes of interest were reported for the timeframe of the last dominant virus variant available in the database, i.e., Delta (June 21, 2021 to December 31, 2021). Of approximately 3.7 million individuals continuously observable in the database, about 60% were identified as being at high risk for severe COVID-19 progression. Among high-risk individuals, 2938 patients were primarily hospitalized for COVID-19 between June 21, 2021, and December 31, 2021, two-thirds of which were suitable for NMV/r treatment (half without restrictions). Advanced age (86.3%) and cardiovascular conditions (83.9%) were the most prevalent of the predefined risk factors. Identified patients stayed, on average, 11.3 days in hospital, with inpatient mortality of 18.9%. These COVID-19-related hospitalizations resulted in mean healthcare costs of €8728. This study reflects the economic burden of hospitalized adult individuals with COVID-19 at high risk for severe disease progression from payer’s perspective in Germany. Our findings highlight the need to prevent severe disease courses and associated hospitalizations to relieve healthcare systems regarding costs and resource allocation.

Atienza-Diez I., Rodriguez-Maroto G., Ares S., Manrubia S.

The limited availability of COVID-19 vaccines has prompted extensive research on optimal vaccination strategies. Previous studies have considered various non-pharmaceutical interventions, vaccine efficacy and distribution strategies. In this work, we address the combined effects of inter-group contacts and vaccination rates under contact reduction, analysing the Spanish population’s demographic and age group contact patterns and incorporating reinfection dynamics. We conduct an exhaustive analysis, evaluating 362 880 permutations of nine age groups across six vaccination rates and two distinct, empirically quantified scenarios for social contacts. Our results show that at intermediate-to-high vaccination rates with unrestricted social contacts, optimal age-based vaccination strategies only slightly deviate from older-to-younger prioritization, yielding marginal reductions in deaths and infections. However, when significant reductions in social contacts are enforced—similar to the lockdowns in 2020—there are substantial improvements, particularly at moderate vaccination rates. These restrictions lead to a transition where infection propagation is halted, a scenario that became achievable during the pandemic with the observed vaccination rates. Our findings emphasize the importance of combining appropriate social contact reductions with vaccination to optimize age-based vaccination strategies, underscoring the complex, nonlinear dynamics involved in pandemic dynamics and the necessity for tailored context-specific interventions.

Collins S.P., Shotwell M.S., Strich J.R., Gibbs K.W., de Wit M., Files D.C., Harkins M., Hudock K., Merck L.H., Moskowitz A., Apodaca K.D., Barksdale A., Safdar B., Javaheri A., Sturek J.M., et. al.

ImportanceFostamatinib, a spleen tyrosine kinase inhibitor, has been reported to improve outcomes of COVID-19.ObjectiveTo evaluate the efficacy and safety of fostamatinib in adults hospitalized with COVID-19 and hypoxemia.Design, Setting, and ParticipantsThis multicenter, phase 3, placebo-controlled, double-blinded randomized clinical trial was conducted at 41 US sites and 21 international sites between November 17, 2021, and September 27, 2023; the last follow-up visit was December 31, 2023. Participants were adults aged 18 years or older hospitalized with acute SARS-CoV-2 infection and hypoxemia. Data were analyzed between January 10 and March 8, 2024.InterventionsFostamatinib, 150 mg orally twice daily for 14 days, or placebo.Main Outcomes and MeasuresThe primary outcome was oxygen-free days, an ordinal outcome classifying a participant’s status at day 28 based on mortality and duration of supplemental oxygen use. An adjusted odds ratio (AOR) greater than 1.0 was considered to indicate superiority of fostamatinib over placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included elevated transaminase values, neutropenia, and hypertension.ResultsOf the 400 participants randomized (median age, 67 years [IQR, 58-76 years]; 210 [52.5%] men), 199 received fostamatinib and 201 received placebo. The mean (SD) number of oxygen-free days was 13.4 (12.4) in the fostamatinib group and 14.2 (12.1) in the placebo group (unadjusted mean difference, −1.26 days [95% CI, −3.52 to 1.00 days]; AOR, 0.82 [95% credible interval (CrI), 0.58-1.17]). Mortality at 28 days occurred in 22 of 195 patients (11.3%) in the fostamatinib group and 16 of 197 (8.1%) in the placebo group (AOR, 1.44; 95% CrI, 0.72-2.90). Aspartate aminotransferase elevation occurred more commonly in the fostamatinib group (23 [11.6%]) than in the placebo group (11 [5.5%]; AOR, 2.28; 95% CrI, 1.07-4.84). Other safety outcomes were similar between groups.Conclusions and RelevanceIn this randomized clinical trial of adults hospitalized with COVID-19 and hypoxemia, fostamatinib did not increase the number of oxygen-free days compared with placebo. These results do not support the hypothesis that fostamatinib improves outcomes among adults hospitalized with hypoxemia during the Omicron era.Trial RegistrationClinicalTrials.gov Identifier: NCT04924660