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Objectives: National guidelines in Botswana recommend baseline CD4 count measurement and both CD4 and HIV viral load (VL) monitoring post‐antiretroviral therapy (ART) initiation. We evaluated the utility of CD4 count measurement in Botswana in the era of universal ART. Methods: CD4 and VL data were analysed for HIV‐infected adults undergoing CD4 count measurement in 2015–2017 at the Botswana Harvard HIV‐Reference Laboratory. We determined (1) the proportion of individuals with advanced HIV disease (CD4 count < 200 cells/µL) at initial CD4 assessment, (2) the proportion with an initial CD4 count ≥ 200 cells/µL experiencing a subsequent decline in CD4 count to < 200 cells/µL, and (3) the proportion of these immunologically failing individuals who had virological failure. Logistic regression modelling examined factors associated with advanced HIV disease. CD4 count trajectories were assessed using locally weighted scatterplot smoothing (LOWESS) regression. Results: Twenty‐five per cent (3571/14 423) of individuals with an initial CD4 assessment during the study period had advanced HIV disease at baseline. Older age [≥ 35 years; adjusted odds ratio (aOR) 1.9; 95% confidence interval (CI) 1.8–2.1] and male sex were associated with advanced HIV disease. Fifty per cent (7163/14 423) of individuals had at least two CD4 counts during the study period. Of those with an initial CD4 count ≥ 200 cells/µL, 4% (180/5061) experienced a decline in CD4 count to < 200 cells/µL; the majority of CD4 count declines were in virologically suppressed individuals and transient. Conclusions: One‐quarter of HIV‐positive individuals in Botswana still present with advanced HIV disease, highlighting the importance of baseline CD4 count measurement to identify this at‐risk population. Few with a baseline CD4 count ≥ 200 cells/µL experienced a drop below 200 cells/µL, suggesting limited utility for ongoing CD4 monitoring. [ABSTRACT FROM AUTHOR]

Test-negative designs (TNDs) are used to assess vaccine effectiveness (VE). Protection from infection-induced immunity may confound the association between case and vaccination status, but collecting reliable infection history can be challenging. If vaccinated individuals have less infection-induced protection than unvaccinated individuals, failure to account for infection history could underestimate VE, though the bias is not well understood. We simulated individual-level SARS-CoV-2 infection and COVID-19 vaccination histories and a TND. VE against symptomatic infection and VE against severe disease estimates unadjusted for infection history underestimated VE compared to estimates adjusted for infection history, and unadjusted estimates were more likely to be below 0%, which could lead to an incorrect interpretation that COVID-19 vaccines are harmful. TNDs assessing VE immediately following vaccine rollout introduced the largest bias and potential for negative VE against symptomatic infection. Despite the potential for bias, VE estimates from TNDs without prior infection information are useful because underestimation is rarely more than 8 percentage points., Competing Interests: Competing interests: The authors declare that they do not have any commercial or other associations that might pose a conflict of interest., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Respiratory syncytial virus vaccines first recommended for use during 2023 were efficacious against lower respiratory tract disease in clinical trials. Limited real-world data regarding respiratory syncytial virus vaccine effectiveness are available. To inform vaccine policy and address gaps in evidence from the clinical trials, we aimed to assess the effectiveness against respiratory syncytial virus-associated hospitalisations and emergency department encounters among adults aged at least 60 years., Methods: We conducted a test-negative design analysis in an electronic health records-based network in eight states in the USA, including hospitalisations and emergency department encounters with respiratory syncytial virus-like illness among adults aged at least 60 years who underwent respiratory syncytial virus testing from Oct 1, 2023, to March 31, 2024. Respiratory syncytial virus vaccination status at the time of the encounter was derived from electronic health record documentation, state and city immunisation registries, and, for some sites, medical claims. Vaccine effectiveness was estimated by immunocompromise status, comparing the odds of vaccination among respiratory syncytial virus-positive case patients and respiratory syncytial virus-negative control patients, and adjusting for age, race and ethnicity, sex, calendar day, social vulnerability index, number of underlying non-respiratory medical conditions, presence of respiratory underlying medical conditions, and geographical region., Findings: Among 28 271 hospitalisations for respiratory syncytial virus-like illness among adults aged at least 60 years without immunocompromising conditions, vaccine effectiveness was 80% (95% CI 71-85) against respiratory syncytial virus-associated hospitalisations, and vaccine effectiveness was 81% (52-92) against respiratory syncytial virus-associated critical illness (ICU admission or death, or both). Among 8435 hospitalisations for respiratory syncytial virus-like illness among adults with immunocompromising conditions, vaccine effectiveness was 73% (48-85) against associated hospitalisation. Among 36 521 emergency department encounters for respiratory syncytial virus-like illness among adults aged at least 60 years without an immunocompromising condition, vaccine effectiveness was 77% (70-83) against respiratory syncytial virus-associated emergency department encounters. Vaccine effectiveness estimates were similar by age group and product type., Interpretation: Respiratory syncytial virus vaccination was effective in preventing respiratory syncytial virus-associated hospitalisations and emergency department encounters among adults aged at least 60 years in the USA during the 2023-24 respiratory syncytial virus season, which was the first season after respiratory syncytial virus vaccine was approved., Funding: The Centers for Disease Control and Prevention., Competing Interests: Declaration of interests NPK reports support for other work from Sanofi Pasteur, Merck, Pfizer, Seqirus, and GSK, unpaid expert panel membership for a planned hepatitis E phase 2 vaccine clinical trial among pregnant women in Pakistan, and unpaid membership on the Western States COVID-19 Scientific Safety Review Workgroup, Board on Population Health and Public Health Practice, National Academies of Science, Engineering, and Medicine, and National Vaccine Advisory Committee Safety Subcommittee. SJG reports funding from the National Institutes of Health's National Center for Advancing Translation Sciences and National Institute of Mental Health. TCO reports consulting fees from Regenstrief Institute as a domain expert in patient matching in global health informatics, travel support from Regenstrief Institute and Patient-Centered Outcomes Research institute, and holds a patent (patent number PCT/US2018/047961). MBD, BED, and WFF report an additional CDC contract for the Vaccine Safety Datalink. TS reports unpaid participation as a member of the Advisory Committee on the Immunization Practices Influenza Vaccine Work Group, is chief of the Utah Adult Immunization Coalition, and is a member of the Utah Department of Health and Human Services Scientific Advisory Committee on Vaccines. OZ reports funding from the National Institute of Allergy and Infectious Diseases (grant number R01AI168373). NPK, JT, and KG report a CDC contract for VISION (contract number 75D30123C17595). SR reports funding from Biofire and GSK. MB reports speaker bureau participation for Innoviva Specialty Therapeutics. CEM reports funding from AstraZeneca, GSK, National Institutes of Health, US Department of Defense, and Patient-Centered Outcomes Research Institute, payment or honoraria for a lecture from Pri-Med, and leadership on the American Lung Association of Minnesota board, the Minnesota Department of Health Long COVID Advisory Committee, and on the Minnesota Department of Health Asthma Care Advisory Committee. JAW, PKM, SWB, SER, and EAKR report a CDC contract for VISION (contract number 75D30121D12779). KD, SAI, SJG, TCO, MBD, KN, BED, WFF, CR, KSA, and CEM report payments made to their institution by CDC via Westat. All other authors declare no competing interests., (Copyright © 2024 Published by Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: The role of computed tomography (CT) before lumbar puncture (LP) is unclear, with limited evidence for a causal link between LP and cerebral herniation or for the ability of CT to identify individuals at risk of herniation. The risks of LP delay or deferral are potentially greater in high-HIV prevalence, resource-limited settings; we analyzed data from such a setting to determine the impact of CT on time to LP and treatment, as well as mortality., Methods: Adults with suspected central nervous system (CNS) infection were enrolled prospectively into the Botswana National Meningitis Survey between 2016 and 2019. Inpatient mortality and clinical data including time of treatment initiation and CT were captured from medical records. Associations between preceding CT and outcomes were assessed using logistic regression., Results: LPs were performed in 711 patients with suspected CNS infection; 27% had a CT before LP, and 73% were HIV positive. Time from admission to LP and time from admission to appropriate treatment were significantly longer in patients who had a CT before LP compared with those who did not (2.8 hours and 13.2 hours, respectively). There was some evidence for treatment delays being associated with increased mortality; however, there was no significant difference in mortality between those who had or did not have CT., Conclusions: Patients who had a CT had delays to diagnostic LP and initiation of appropriate treatment; although treatment delays were associated with increased mortality, our observational study could not demonstrate a causal association between delays in diagnosis and treatment introduced by CT and mortality., Competing Interests: Potential conflicts of interest. J.M., G.M.B., and J.N.J. have received investigator-initiated funding from bioMérieux. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Tuberculous meningitis (TBM) disproportionately impacts high-HIV prevalence, resource-limited settings where diagnosis is challenging. The GeneXpert platform has utility in TBM diagnosis, but uptake remains limited. In Botswana, before the introduction of GeneXpert, tuberculosis (TB) testing was only available through mycobacterial culture at the National TB Reference Laboratory. Data describing routine use of Xpert MTB/RIF for cerebrospinal fluid (CSF) testing in resource-limited settings are scarce., Methods: Electronic records for patients with CSF tested in government facilities in Botswana between 2016 and 2022 were obtained from a central online repository as part of ongoing national meningitis surveillance. Samples were excluded from 1 site where Xpert MTB/RIF is performed universally. The proportion receiving TB-specific investigation on CSF and the number positive for Mycobacterium tuberculosis following increased Xpert MTB/RIF capacity were determined., Results: The proportion of CSF samples receiving TB-specific investigation increased from 4.5% (58/1288) in 2016 to 29.0% (201/693) in 2022, primarily due to increased analysis with Xpert MTB/RIF from 0.9% (11/1288) to 23.2% (161/693). There was an overall decline in the annual number of CSF samples analyzed, but the proportion with microbiologically confirmed TBM increased from 0.4% to 1.2%. The proportion of samples tested for TB that were collected from health care facilities >100 km from the National TB Reference Laboratory increased with Xpert MTB/RIF rollout from 65.9% (87/132) to 78.0% (494/633)., Conclusions: In Botswana, access to TB culture is challenging in remote populations; more accessible near-patient testing using Xpert MTB/RIF increased the number of patients receiving TB-specific testing on CSF and the number of confirmed TBM cases., Competing Interests: Potential conflicts of interest. J.M. and J.N.J. have received investigator-initiated funding from bioMerieux. A.A. has received research support from ViiV Healthcare and Viatris Pharmaceuticals. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Pneumonia is common in adults hospitalized with laboratory-confirmed influenza, but the association between timeliness of influenza antiviral treatment and severe clinical outcomes in patients with influenza-associated pneumonia is not well characterized., Methods: We included adults aged ≥18 years hospitalized with laboratory-confirmed influenza and a discharge diagnosis of pneumonia over 7 influenza seasons (2012-2019) sampled from a multi-state population-based surveillance network. We evaluated 3 treatment groups based on timing of influenza antiviral initiation relative to admission date (day 0, day 1, days 2-5). Baseline characteristics and clinical outcomes were compared across groups using unweighted counts and weighted percentages accounting for the complex survey design. Logistic regression models were generated to evaluate the association between delayed treatment and 30-day all-cause mortality., Results: 26,233 adults were sampled in the analysis. Median age was 71 years and most (92.2%) had ≥1 non-immunocompromising condition. Overall, 60.9% started antiviral treatment on day 0, 29.5% on day 1, and 9.7% on days 2-5 (median 2 days). Baseline characteristics were similar across groups. Thirty-day mortality occurred in 7.5%, 8.5%, and 10.2% of patients who started treatment on day 0, day 1, and days 2-5, respectively. Compared to those treated on day 0, adjusted OR for death was 1.14 (95%CI: 1.01-1.27) in those starting treatment on day 1 and 1.40 (95%CI: 1.17-1.66) in those starting on days 2-5., Discussion: Delayed initiation of antiviral treatment in patients hospitalized with influenza-associated pneumonia was associated with higher risk of death, highlighting the importance of timely initiation of antiviral treatment at admission., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Background: Cryptococcal meningitis (CM) causes substantial mortality in African countries with a high prevalence of human immunodeficiency virus (HIV), despite advances in disease management and increasing antiretroviral therapy (ART) coverage. Reliable diagnosis of CM is cheap and more accessible than other indicators of advanced HIV disease burden such as CD4 testing or investigation for disseminated tuberculosis; therefore, monitoring CM incidence has the potential to serve as a valuable metric of HIV programmatic success., Methods: Botswana national meningitis surveillance data from 2015 to 2022 were obtained from electronic health records. All electronic laboratory records from cerebrospinal fluid samples analyzed within government healthcare facilities in Botswana were extracted from a central online repository. Adjustments for missing data were made through triangulation with prospective cohort study datasets. CM case frequency was enumerated using a case definition and incidence calculated using national census data., Results: A total of 1744 episodes of CM were identified; incidence declined from 15.0 (95% confidence interval [CI], 13.4-16.7) cases/100 000 person-years in 2015 to 7.4 (95% CI, 6.4-8.6) cases/100 000 person-years in 2022. However, the rate of decline slowed following the introduction of universal treatment in 2016. The highest incidence was observed in men and individuals aged 40-44 years. The proportion of cases diagnosed through cryptococcal antigen testing increased from 35.5% to 86.3%., Conclusions: CM incidence has decreased in Botswana following expansion of ART coverage but persists at a stubbornly high incidence. Most cases are now diagnosed through the cheap and easy-to-use cryptococcal antigen test, highlighting the potential of using CM as key metric of program success in the Treat All era., Competing Interests: Potential conflicts of interest. J. M. and J. N. J. have received investigator-initiated funding from bioMérieux. J. N. J. has received grants from the Centers for Disease Control and Prevention (CDC). D. S. L. has received salary support from Janssen, CDC, and NIHR. A. A. has received research support from ViiV Healthcare; research support and support for meetings and/or travel from Viatris Pharmaceuticals; contract from Botswana Harvard Health Partnership; consulting fees from UNAIDS; participation on an advisory board and support for meetings and/or travel from the World Health Organization; and membership on the University of Botswana Institutional Review Board. S. E. reports support for meetings and/or travel from the International AIDS Society. J. O. reports support for meetings and/or travel from the Clinton Health Access Initiative. I. M. reports support for meetings and/or travel from the Jill & Herbert Hunt Scholarship, Oxford University. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The 2022-2023 United States influenza season had unusually early influenza activity with high hospitalization rates. Vaccine-matched A(H3N2) viruses predominated, with lower levels of A(H1N1)pdm09 activity also observed., Methods: Using the test-negative design, we evaluated influenza vaccine effectiveness (VE) during the 2022-2023 season against influenza A-associated emergency department/urgent care (ED/UC) visits and hospitalizations from October 2022 to March 2023 among adults (aged ≥18 years) with acute respiratory illness (ARI). VE was estimated by comparing odds of seasonal influenza vaccination among case-patients (influenza A test positive by molecular assay) and controls (influenza test negative), applying inverse-propensity-to-be-vaccinated weights., Results: The analysis included 85 389 ED/UC ARI encounters (17.0% influenza A positive; 37.8% vaccinated overall) and 19 751 hospitalizations (9.5% influenza A positive; 52.8% vaccinated overall). VE against influenza A-associated ED/UC encounters was 44% (95% confidence interval [CI], 40%-47%) overall and 45% and 41% among adults aged 18-64 and ≥65 years, respectively. VE against influenza A-associated hospitalizations was 35% (95% CI, 27%-43%) overall and 23% and 41% among adults aged 18-64 and ≥65 years, respectively., Conclusions: VE was moderate during the 2022-2023 influenza season, a season characterized with increased burden of influenza and co-circulation with other respiratory viruses. Vaccination is likely to substantially reduce morbidity, mortality, and strain on healthcare resources., Competing Interests: Potential conflicts of interest. During the conduct of the study, all Westat- and Kaiser Permanente Northern California Division of Research–affiliated authors reported receiving contractual support from the CDC via payments made to their respective institutions. Additionally, all authors affiliated with Baylor Scott & White Health, Children's Minnesota, Columbia University Irving Medical Center, HealthPartners Institute, Intermountain Healthcare, Kaiser Permanente Center for Health Research, Regenstrief Institute, University of Colorado Anschutz Medical Campus, and Vanderbilt University Medical Center reported receiving contractual support from the CDC during the conduct of the study, via subcontracts from Westat, Inc, with payments made to their respective institutions. Unrelated to the submitted work, the following disclosures were reported from the past 36 months: A. L. N. received grants from Pfizer and Vir Biotechnology; M. N. received grants directly from CDC and from CDC via subcontracts from Abt Associates and Vanderbilt University Medical Center to her institution; C. E. M. received grants AstraZeneca; S. R. received grants from GSK; and N. P. K. received research support from Pfizer, Merck, GlaxoSmithKline, Sanofi Pasteur, and Seqirus. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Competing Interests: Disclosures: Authors have reported no disclosures of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L24-0142.

In September 2023, CDC's Advisory Committee on Immunization Practices recommended updated 2023-2024 (monovalent XBB.1.5) COVID-19 vaccination for all persons aged ≥6 months to prevent COVID-19, including severe disease. As with past COVID-19 vaccines, additional doses may be considered for persons with immunocompromising conditions, who are at higher risk for severe COVID-19 and might have decreased response to vaccination. In this analysis, vaccine effectiveness (VE) of an updated COVID-19 vaccine dose against COVID-19-associated hospitalization was evaluated during September 2023-February 2024 using data from the VISION VE network. Among adults aged ≥18 years with immunocompromising conditions, VE against COVID-19-associated hospitalization was 38% in the 7-59 days after receipt of an updated vaccine dose and 34% in the 60-119 days after receipt of an updated dose. Few persons (18%) in this high-risk study population had received updated COVID-19 vaccine. All persons aged ≥6 months should receive updated 2023-2024 COVID-19 vaccination; persons with immunocompromising conditions may get additional updated COVID-19 vaccine doses ≥2 months after the last recommended COVID-19 vaccine., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Brian E. Dixon reports institutional support from the National Institutes of Health (NIH) and the U.S. Department of Veterans Affairs and royalties from Elsevier, Inc. for a book on health information technology and from Springer Nature for a book on health information technology. Nicola P. Klein reports institutional support from Sanofi Pasteur, Merck, Pfizer, Seqiris, and GSK; uncompensated membership on an expert panel for a planned Hepatitis E Phase II vaccine clinical trial among pregnant women in Pakistan, sponsored by the International Vaccine Institute; unpaid membership on the Western States COVID-19 Scientific Safety Review Workgroup, the Board on Population Health and Public Health Practice, the National Academies of Science, Engineering and Medicine, and the National Vaccine Advisory Committee Safety Subcommittee. Charlene E. McEvoy reports grants or contracts from NIH, the Department of Defense, Patient-Centered Outcomes Research Institute, Astra Zeneca, and GSK; payment or honorarium from Pri-Med for a lecture on incorporation of ACT and CAT into electronic health records to improve outcomes in patients with asthma and chronic obstructive pulmonary disease; and uncompensated participation on the American Lung Association of Minnesota Board, the Minnesota Department of Health Long COVID Advisory Committee, and the Minnesota Department of Health Asthma Care Advisory Committee. Tamara Sheffield reports uncompensated membership on CDC’s Advisory Committee on Immunization Practices Influenza Vaccine Work Group, chairmanship of the Utah Adult Immunization Coalition vaccine quality improvement and advocacy group, and membership on the Utah Department of Health and Human Services Scientific Advisory Committee on Vaccines. Ousseny Zerbo reports a grant from the National Institute of Allergy and Infectious Diseases. Suchitra Rao reports grants from Biofire and GSK. No other potential conflicts of interest were disclosed.

Background: During the 2022-2023 influenza season, the United States experienced the highest influenza-associated pediatric hospitalization rate since 2010-2011. Influenza A/H3N2 infections were predominant., Methods: We analyzed acute respiratory illness (ARI)-associated emergency department or urgent care (ED/UC) encounters or hospitalizations at 3 health systems among children and adolescents aged 6 months-17 years who had influenza molecular testing during October 2022-March 2023. We estimated influenza A vaccine effectiveness (VE) using a test-negative approach. The odds of vaccination among influenza-A-positive cases and influenza-negative controls were compared after adjusting for confounders and applying inverse-propensity-to-be-vaccinated weights. We developed overall and age-stratified VE models., Results: Overall, 13 547 of 44 787 (30.2%) eligible ED/UC encounters and 263 of 1862 (14.1%) hospitalizations were influenza-A-positive cases. Among ED/UC patients, 15.2% of influenza-positive versus 27.1% of influenza-negative patients were vaccinated; VE was 48% (95% confidence interval [CI], 44-52%) overall, 53% (95% CI, 47-58%) among children aged 6 months-4 years, and 38% (95% CI, 30-45%) among those aged 9-17 years. Among hospitalizations, 17.5% of influenza-positive versus 33.4% of influenza-negative patients were vaccinated; VE was 40% (95% CI, 6-61%) overall, 56% (95% CI, 23-75%) among children ages 6 months-4 years, and 46% (95% CI, 2-70%) among those 5-17 years., Conclusions: During the 2022-2023 influenza season, vaccination reduced the risk of influenza-associated ED/UC encounters and hospitalizations by almost half (overall VE, 40-48%). Influenza vaccination is a critical tool to prevent moderate-to-severe influenza illness in children and adolescents., Competing Interests: Potential conflicts of interest . N. P. K. reports research support from Sanofi Pasteur and Seqirus for unrelated adult influenza vaccine effectiveness studies, and from Pfizer, Merck, and GlaxoSmithKline for unrelated studies. S. R. received funds from GlaxoSmithKline. M. G. reports a research grant and contract for the CDC Ambulatory US Flu/COVID VE Network, a grant for HAIVEN Adult Inpatient Flu/COVID VE, a contract for SYNERGY FLU/COVID study, and subcontracts for the IVY COVID/FLU VE PHS project and RECOVER-PROTECT COVID Cohort studies. D.-H. Y., L. K., M. M. D., S. W. B., and Z. A. W. report payments made to Westat via CDC contract number 200-2019-F-06819. A. B. K., A. L. N., J. A., K. D., K. N., M. B. D., M. G., N. G., P. J. E., S. A. I, S. J. G., S. R., and T. C. O. report payments made to their institution by CDC via Westat. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Background: Although psychiatric disorders have been associated with reduced immune responses to other vaccines, it remains unknown whether they influence COVID-19 vaccine effectiveness (VE). This study evaluated risk of COVID-19 hospitalization and estimated mRNA VE stratified by psychiatric disorder status., Methods: In a retrospective cohort analysis of the VISION Network in four US states, the rate of laboratory-confirmed COVID-19-associated hospitalization between December 2021 and August 2022 was compared across psychiatric diagnoses and by monovalent mRNA COVID-19 vaccination status using Cox proportional hazards regression., Results: Among 2,436,999 adults, 22.1% had ≥1 psychiatric disorder. The incidence of COVID-19-associated hospitalization was higher among patients with any versus no psychiatric disorder (394 vs. 156 per 100,000 person-years, p < 0.001). Any psychiatric disorder (adjusted hazard ratio [aHR], 1.27; 95% CI, 1.18-1.37) and mood (aHR, 1.25; 95% CI, 1.15-1.36), anxiety (aHR, 1.33, 95% CI, 1.22-1.45), and psychotic (aHR, 1.41; 95% CI, 1.14-1.74) disorders were each significant independent predictors of hospitalization. Among patients with any psychiatric disorder, aHRs for the association between vaccination and hospitalization were 0.35 (95% CI, 0.25-0.49) after a recent second dose, 0.08 (95% CI, 0.06-0.11) after a recent third dose, and 0.33 (95% CI, 0.17-0.66) after a recent fourth dose, compared to unvaccinated patients. Corresponding VE estimates were 65%, 92%, and 67%, respectively, and were similar among patients with no psychiatric disorder (68%, 92%, and 79%)., Conclusion: Psychiatric disorders were associated with increased risk of COVID-19-associated hospitalization. However, mRNA vaccination provided similar protection regardless of psychiatric disorder status, highlighting its benefit for individuals with psychiatric disorders., (© 2024 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

In September 2023, CDC's Advisory Committee on Immunization Practices recommended updated 2023-2024 (monovalent XBB.1.5) COVID-19 vaccination for all persons aged ≥6 months to prevent COVID-19, including severe disease. However, few estimates of updated vaccine effectiveness (VE) against medically attended illness are available. This analysis evaluated VE of an updated COVID-19 vaccine dose against COVID-19-associated emergency department (ED) or urgent care (UC) encounters and hospitalization among immunocompetent adults aged ≥18 years during September 2023-January 2024 using a test-negative, case-control design with data from two CDC VE networks. VE against COVID-19-associated ED/UC encounters was 51% (95% CI = 47%-54%) during the first 7-59 days after an updated dose and 39% (95% CI = 33%-45%) during the 60-119 days after an updated dose. VE estimates against COVID-19-associated hospitalization from two CDC VE networks were 52% (95% CI = 47%-57%) and 43% (95% CI = 27%-56%), with a median interval from updated dose of 42 and 47 days, respectively. Updated COVID-19 vaccine provided increased protection against COVID-19-associated ED/UC encounters and hospitalization among immunocompetent adults. These results support CDC recommendations for updated 2023-2024 COVID-19 vaccination. All persons aged ≥6 months should receive updated 2023-2024 COVID-19 vaccine., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Steven Y. Chang reports consulting fees from PureTech Health and Kiniksa Pharmaceuticals, and participation on the data safety monitoring board for an unrelated, local study at Ronald Reagan UCLA Medical Center, outside the submitted work. Manjusha Gaglani reports serving as the Texas Pediatric Society, Texas Chapter of the American Academy of Pediatrics co-chair of the ID and Immunization Committee, outside the submitted work. Adit A. Ginde reports support from Biomeme and Seastar, outside the submitted work. Carlos G. Grijalva reports other funding from Merck, contracts from Syneos Health and the Food and Drug Administration, and grants from National Institutes of Health (NIH) and Agency for Health Care Research and Quality, outside the submitted work. Akram Khan reports grant funding from 4DMedical, Dompe Pharmaceuticals, Ely Lilly, and Roche Pharmaceuticals, outside the submitted work. Adam S. Lauring reports research support from the National Institute of Allergy and Infectious Diseases, Michigan Department of Health and Human Services, Burroughs Wellcome Fund, Flu Lab, and consulting fees from Roche, outside the submitted work. Christopher Mallow reports medical legal consulting, outside the submitted work. Emily T. Martin reports research funding from Merck, outside the submitted work. Ithan D. Peltan reports grant support from NIH, Intermountain Research and Medical Foundation, and Janssen Pharmaceuticals, and funding to his institution from Bluejay Diagnostics and Regeneron, outside the submitted work. Karthik Natarajan reports institutional support from NIH, Office of the Director, the National Center for Advancing Translational Sciences, and the National Heart, Lung, and Blood Institute. Brian E. Dixon reports Institutional support from NIH, National Library of Medicine in the form of a T15 training grant in biomedical informatics, salary support from the U.S. Department of Veterans Affairs, royalties from Elsevier, Inc. for a book on health information technology and from Springer Nature for a book on health information technology. Nicola P. Klein reports support from GSK, Merck, Pfizer, Sanofi Pasteur, and Seqirus for work unrelated to this report. No other potential conflicts of interest were disclosed.

Surveillance data can provide rapid, within-season influenza vaccine effectiveness (VE) estimates to guide public health recommendations. Mandatory reporting of influenza vaccine administration to California's immunization information registry began January 1, 2023, and mandatory reporting of all influenza laboratory test results, including negative results, was instituted in California on June 15, 2023. These data, collected by the California Department of Public Health during October 1, 2023-January 31, 2024, were used to calculate interim influenza VE against laboratory-confirmed influenza by comparing the odds of vaccination among case-patients (persons who received a positive influenza laboratory test result) and control patients (those who received a negative influenza laboratory test result). VE was calculated as 1 - adjusted odds ratio using mixed-effects logistic regression, with age, race, and ethnicity as fixed effects and specimen collection week and county as random effects. Overall, during October 1, 2023-January 31, 2024, estimated VE was 45% among persons aged ≥6 months, 56% among children and adolescents aged 6 months-17 years, 48% among adults aged 18-49 years, 36% among those aged 50-64 years, and 30% among those aged ≥65 years. Consistent with some previous influenza seasons, influenza vaccination provided moderate protection against laboratory-confirmed influenza among infants, children, adolescents, and adults. All persons aged ≥6 months without a contraindication to vaccination should receive annual influenza vaccination to reduce influenza illness, severe influenza, and strain on health care resources. Influenza vaccination remains the best way to prevent influenza., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

In the United States, annual influenza vaccination is recommended for all persons aged ≥6 months. Using data from four vaccine effectiveness (VE) networks during the 2023-24 influenza season, interim influenza VE was estimated among patients aged ≥6 months with acute respiratory illness-associated medical encounters using a test-negative case-control study design. Among children and adolescents aged 6 months-17 years, VE against influenza-associated outpatient visits ranged from 59% to 67% and against influenza-associated hospitalization ranged from 52% to 61%. Among adults aged ≥18 years, VE against influenza-associated outpatient visits ranged from 33% to 49% and against hospitalization from 41% to 44%. VE against influenza A ranged from 46% to 59% for children and adolescents and from 27% to 46% for adults across settings. VE against influenza B ranged from 64% to 89% for pediatric patients in outpatient settings and from 60% to 78% for all adults across settings. These findings demonstrate that the 2023-24 seasonal influenza vaccine is effective at reducing the risk for medically attended influenza virus infection. CDC recommends that all persons aged ≥6 months who have not yet been vaccinated this season get vaccinated while influenza circulates locally., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Emmanuel B. Walter reports institutional support from Pfizer, Moderna, Seqiris, Clinetic, and Najit Technologies Inc., consulting fees from ILiAD Biotechnologies, payment from the College of Diplomates of the American Board of Pediatric Dentistry, travel support from the American Academy of Pediatrics, and paid compensation for participation on the Vaxcyte Scientific Advisory Board. Yuwei Zhu reports participation on a Vanderbilt University Medical Center Data Safety Monitoring Board. Sara Y. Tartof reports institutional support from Pfizer and Genentech. Samantha M. Olson reports travel support from the Gates Foundation. Nicola P. Klein reports institutional support from Sanofi Pasteur, Merck, Pfizer, Seqirus, and GlaxoSmithKline; membership on an expert panel for a planned hepatitis E Phase II vaccine clinical trial among pregnant women in Pakistan; membership in Western States COVID-19 Scientific Safety Review Workgroup, Board on Population Health and Public Health Practice, National Academies of Science, Engineering and Medicine, and National Vaccine Advisory Committee Safety Subcommittee. Manjusha Gaglani reports receipt of honorarium for educational webinar presentation on respiratory viruses from the Texas Pediatric Society, Texas Chapter of the American Academy of Pediatrics, and serving as co-chair of the Infectious Diseases and Immunization Committee and Chair of the Texas Respiratory Syncytial Virus Taskforce, Texas Pediatric Society. Kevin W. Gibbs reports grants or contracts from the Department of Defense and the National Institutes of Health (NIH) and service as chair of the Vanderbilt University Medical Center Data Safety Monitoring Board. Adit A. Ginde reports institutional support from the NIH, the Department of Defense, AbbVie, and Faron Pharmaceuticals, consulting fees (paid to institution) from Biomeme and Seastar, and participation on data safety monitoring boards for the NIH and Emory University. Richard K. Zimmerman reports institutional support from the NIH and Sanofi Pasteur, and honorarium from Clinical Educational Alliance. Mary A. Staat reports institutional support from NIH, Pfizer, and Merck and royalties for Up-to-Date chapter on International Adoption. Stacey House reports institutional support from Seegene, Inc., Abbot, Healgen, Roche, CorDx, Hologic, Cepheid, Janssen, and Wondfo Biotech. Geoffrey A. Weinberg reports institutional support from the New York State Department of Health AIDS Institute, consulting fees from Inhalon Biopharma for participation on a Scientific Advisory Board, and honoraria from Merck & Company for textbook chapters. Marian G. Michaels reports institutional support from the National Institute on Allergy and Infectious Diseases and complimentary meeting attendance for presentation at the American Transplant Congress on respiratory viruses. Emily T. Martin reports receipt of grants or contracts from Merck. Natasha B. Halasa reports receipt of grants from Sanofi, Quidell, and Merck. Elie A. Saade reports institutional support from Protein Sciences Corporation, consulting fees, honoraria, and travel support from Johnson & Johnson and participation on a Johnson & Johnson Data Safety Monitoring Board. No other potential conflicts of interest were disclosed.

Background: The epidemiology of coronavirus disease 2019 (COVID-19) continues to develop with emerging variants, expanding population-level immunity, and advances in clinical care. We describe changes in the clinical epidemiology of COVID-19 hospitalizations and risk factors for critical outcomes over time., Methods: We included adults aged ≥18 years from 10 states hospitalized with COVID-19 June 2021-March 2023. We evaluated changes in demographics, clinical characteristics, and critical outcomes (intensive care unit admission and/or death) and evaluated critical outcomes risk factors (risk ratios [RRs]), stratified by COVID-19 vaccination status., Results: A total of 60 488 COVID-19-associated hospitalizations were included in the analysis. Among those hospitalized, median age increased from 60 to 75 years, proportion vaccinated increased from 18.2% to 70.1%, and critical outcomes declined from 24.8% to 19.4% (all P < .001) between the Delta (June-December, 2021) and post-BA.4/BA.5 (September 2022-March 2023) periods. Hospitalization events with critical outcomes had a higher proportion of ≥4 categories of medical condition categories assessed (32.8%) compared to all hospitalizations (23.0%). Critical outcome risk factors were similar for unvaccinated and vaccinated populations; presence of ≥4 medical condition categories was most strongly associated with risk of critical outcomes regardless of vaccine status (unvaccinated: adjusted RR, 2.27 [95% confidence interval {CI}, 2.14-2.41]; vaccinated: adjusted RR, 1.73 [95% CI, 1.56-1.92]) across periods., Conclusions: The proportion of adults hospitalized with COVID-19 who experienced critical outcomes decreased with time, and median patient age increased with time. Multimorbidity was most strongly associated with critical outcomes., Competing Interests: Potential conflicts of interest. M. G. reports additional grants or institutional contracts with the CDC Ambulatory US Flu/COVID Vaccine Effectiveness (VE) Network, Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN) Adult Inpatient Flu/COVID VE, Investigating Respiratory Viruses in the Acutely Ill Public Health Surveillance Network, and Researching COVID to Enhance Recovery and Health and Human Services Protect. C. M. reports an institutional grant or contract from AstraZeneca (AZD1222) for a COVID-19 vaccination trial. A. L. N. reports institutional research funding from Pfizer for an unrelated study of meningococcal B vaccine safety during pregnancy and Vir Biotechnology for an unrelated influenza study. S. A. I. reports an additional pending contract with CDC (200-2012-53584, Vaccine Safety Datalink). G. V.-B. reports grants or contracts from CDC (Vaccine Safety Datalink) and Sanofi (Tdap Vaccine Safety). A. B. K. reports a subcontract through HealthPartners for VISION payment made to Children's Minnesota. B. E. D. reports a grant from the National Institutes of Health to evaluate Health Information Exchange (HIE) technologies, a grant from CDC to use HIE data for public health surveillance, an R21 grant from the US Agency for Healthcare Research and Quality to evaluate HIE technologies, a grant from the US Department of Veterans Affairs to evaluate HIE technologies, royalties from Elsevier and Springer Nature for books on HIE and public health informatics, and consulting fees for advisory panel on human papillomavirus vaccination from Merck and Co. K. M. reports 2 additional contracts with CDC (Ambulatory US Flu VE Network and HAIVEN). N. P. K. has received grants from Pfizer, Merck, GlaxoSmithKline, and Sanofi Pasteur. S. R. has received grant funds from GlaxoSmithKline. P. K. M., V. L., and E. B. report payments made to Westat via CDC (contract number 200-2019-F-06819). C. M., C. R., D. K., E. S., G. V.-B., J. A., J. Han., K. S. A., K. N., K. D., M. B., M. B. D., M. M., M. S. S., N. G., N. R. V., P. J. E., S. G., T. C. O., and W. F. F. report payments made to their institution by CDC via Westat. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Competing Interests: Disclosures: All relevant financial relationships have been mitigated. Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=A23-0004.

Background: People with HIV (PWH) are at increased risk for venous thromboembolism (VTE). We conducted this study to characterize VTE including provoking factors among PWH in the current treatment era., Methods: We included PWH with VTE between 2010 and 2020 at 6 sites in the CFAR Network of Integrated Clinical Systems cohort. We ascertained for possible VTE using diagnosis, VTE-related imaging, and VTE-related procedure codes, followed by centralized adjudication of primary data by expert physician reviewers. We evaluated sensitivity and positive predictive value of VTE ascertainment approaches. VTEs were classified by type and anatomic location. Reviewers identified provoking factors such as hospitalizations, infections, and other potential predisposing factors such as smoking., Results: We identified 557 PWH with adjudicated VTE: 239 (43%) had pulmonary embolism with or without deep venous thrombosis, and 318 (57%) had deep venous thrombosis alone. Ascertainment with clinical diagnoses alone missed 6% of VTEs identified with multiple ascertainment approaches. DVTs not associated with intravenous lines were most often in the proximal lower extremities. Among PWH with VTE, common provoking factors included recent hospitalization (n = 134, 42%), infection (n = 133, 42%), and immobilization/bed rest (n = 78, 25%). Only 57 (10%) PWH had no provoking factor identified. Smoking (46%), HIV viremia (27%), and injection drug use (22%) were also common., Conclusions: We conducted a robust adjudication process that demonstrated the benefits of multiple ascertainment approaches followed by adjudication. Provoked VTEs were more common than unprovoked events. Nontraditional and modifiable potential predisposing factors such as viremia and smoking were common., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Severe outcomes were common among adults hospitalized for COVID-19 or influenza, while the percentage of COVID-19 hospitalizations involving critical care decreased from October 2021 to September 2022. During the Omicron BA.5 period, intensive care unit admission frequency was similar for COVID-19 and influenza, although patients with COVID-19 had a higher frequency of in-hospital death., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Test-negative-design COVID-19 vaccine effectiveness (VE) studies use symptomatic SARS-CoV-2-positive individuals as cases and symptomatic SARS-CoV-2-negative individuals as controls to evaluate COVID-19 VE. To evaluate the potential bias introduced by the correlation of COVID-19 and influenza vaccination behaviors, we assessed changes in estimates of VE of bivalent vaccines against COVID-19-associated hospitalizations and emergency department/urgent care (ED/UC) encounters when considering influenza vaccination status or including or excluding influenza-positive controls using data from the multi-state VISION vaccine effectiveness network. Analyses included encounters during October 2022 - February 2023, a period of SARS-CoV-2 and influenza cocirculation. When considering influenza vaccination status or including or excluding influenza-positive controls, COVID-19 VE estimates were robust, with most VE estimates against COVID-19-associated hospitalization and ED/UC encounters changing less than 5 percentage points. Higher proportions of influenza-positive patients among controls, influenza vaccination coverage, or VE could impact these findings; the potential bias should continue to be assessed., Competing Interests: Declaration of Competing Interest Allison L. Naleway reports institutional support from Pfizer for an unrelated study of meningococcal B vaccine safety during pregnancy and from Vir Biotechnology for an unrelated influenza study.  Nicola P. Klein reports institutional support from Pfizer, Merck, GSK, Sanofi Pasteur, and Seqirus.  Manjusha Gaglani reports institutional funding from CDC for the Ambulatory US Flu/COVID VE Network and the HAIVEN Adult Inpatient Flu/COVID VE study and institutional subcontracts for the IVY-3 PHS project and RECOVER study.  All other authors have no conflicts of interest to report., (Published by Elsevier Ltd.)

Adults with disabilities are at increased risk for severe coronavirus disease 2019 (COVID-19). Using data across 9 states during Delta- and Omicron-predominant periods (June 2021-September 2022), we evaluated the effectiveness of the original monovalent COVID-19 messenger RNA vaccines among 521 206 emergency department/urgent care encounters (11 471 [2%] in patients with a documented disability) and 139 548 hospitalizations (16 569 [12%] in patients with a disability) for laboratory-confirmed COVID-19 illness in adults (aged ≥18 years). Across variant periods and for the primary series or booster doses, vaccine effectiveness was similar in those with and those without a disability. These findings highlight the importance of adults with disabilities staying up to date with COVID-19 vaccinations., Competing Interests: Potential conflicts of interest. A. L. N. reports institutional support from Pfizer for an unrelated study of meningococcal B vaccine safety during pregnancy. N. P. K. reports institutional support from Pfizer, Merck, GlaxoSmithKline (GSK), Sanofi Pasteur, and Protein Sciences (now Sanofi Pasteur) for unrelated studies and institutional support from Pfizer for coronavirus disease 2019 vaccine clinical trials. All other authors report no potential conflicts., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Introduction: Understanding the changing epidemiology of adults hospitalized with coronavirus disease 2019 (COVID-19) informs research priorities and public health policies., Methods: Among adults (≥18 years) hospitalized with laboratory-confirmed, acute COVID-19 between 11 March 2021, and 31 August 2022 at 21 hospitals in 18 states, those hospitalized during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron-predominant period (BA.1, BA.2, BA.4/BA.5) were compared to those from earlier Alpha- and Delta-predominant periods. Demographic characteristics, biomarkers within 24 hours of admission, and outcomes, including oxygen support and death, were assessed., Results: Among 9825 patients, median (interquartile range [IQR]) age was 60 years (47-72), 47% were women, and 21% non-Hispanic Black. From the Alpha-predominant period (Mar-Jul 2021; N = 1312) to the Omicron BA.4/BA.5 sublineage-predominant period (Jun-Aug 2022; N = 1307): the percentage of patients who had ≥4 categories of underlying medical conditions increased from 11% to 21%; those vaccinated with at least a primary COVID-19 vaccine series increased from 7% to 67%; those ≥75 years old increased from 11% to 33%; those who did not receive any supplemental oxygen increased from 18% to 42%. Median (IQR) highest C-reactive protein and D-dimer concentration decreased from 42.0 mg/L (9.9-122.0) to 11.5 mg/L (2.7-42.8) and 3.1 mcg/mL (0.8-640.0) to 1.0 mcg/mL (0.5-2.2), respectively. In-hospital death peaked at 12% in the Delta-predominant period and declined to 4% during the BA.4/BA.5-predominant period., Conclusions: Compared to adults hospitalized during early COVID-19 variant periods, those hospitalized during Omicron-variant COVID-19 were older, had multiple co-morbidities, were more likely to be vaccinated, and less likely to experience severe respiratory disease, systemic inflammation, coagulopathy, and death., Competing Interests: Potential conflicts of interest. J. C. reports grants from the National Institutes of Health (NIH) and Department of Defense (DoD), outside the submitted work. J. C. reports receiving grants from the NIH, DoD, outside the submitted work. A. D, reports grants from the NIH and National Heart, Lung, and Blood Institute (NHLBI) for the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) platform and Prevention and Early Treatment of Acute Lung Injury (PETAL) network respectively, as well as consulting fees for Alung Technologies, outside the submitted work. S. C. reports receiving consulting fees from PureTech Health and Kiniksa Pharmaceuticals and participating as a Data and Safety Monitoring Board (DSMB) member for a neuromodulation study at University of California, Los Angeles, outside the submitted work. M. E. reports grants from NIH and Regeneron, personal funds for speaking at the ASPEN conference for Abbott Labs, and payment for testimony from Medical Legal Expert Witness, outside the submitted work. M. G. reports receiving grants from CDC, CDC-Abt Associates, CDC-Westat, and Janssen, and served as co-chair of the Infectious Diseases and Immunization Committee for the Texas Pediatric Society, outside the submitted work. K. G. reports grants from NIH and DoD, outside the submitted work. A. G. reports receiving grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals, outside the submitted work. M. N. G. reports grants from NHLBI, CDC, Agency for Healthcare Research and Quality (AHRQ), speaking at medicine grand rounds at New York Medical College, travel support for the American Thoracic Society (ATS) executive meeting and serving as ATS Chair Critical Care Assembly, DSMB membership fees from Regeneron, and participating on the scientific advisory panel for Endpoint, outside the submitted work. D. H. reports receiving grants from NHLBI, outside the submitted work. A. K. reports receiving grants from United Therapeutics, Johnson & Johnson, 4D Medical, Eli Lily, Dompe Pharmaceuticals, and GlaxoSmithKline; and serves on the guidelines committee for Chest, outside the submitted work. J. K. reports a grant from NIH, outside the submitted work A. L. reports receiving grants from CDC, National Institute of Allergy and Infectious Diseases (NIAID), and Burroughs Wellcome Fund, Michigan Department of Health and Human Services, Flu Lab, and consulting fees from Sanofi and Roche for consulting on oseltamivir and baloxavir respectively, outside the submitted work. E. M. reports grants from Flu Lab, Merck, and NIH outside the submitted work. T. N. reports receiving a grant from CDC, receiving a one-time payment for participating as a virtual webinar panelist for Clinical Updates in Heart Failure, and being a Practice Management Committee member for Society of Hospital Medicine, outside the submitted work. I. D, P. reports grants from NIH/NHLBI, Janssen Pharmaceuticals and institutional support from Regeneron, outside the submitted work. J. S. reports a grant from NHLBI, outside the submitted work. W. B. S, reports grants from NIH/NHLBI, outside the submitted work. J. W. reports a grant from NIH/NHLBI, payment for the American College of Emergency Physicians speaker honorarium and participating on the American Board of Internal Medicine Critical Care Exam Committee, outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

On June 19, 2022, the original monovalent mRNA COVID-19 vaccines were approved as a primary series for children aged 6 months-4 years (Pfizer-BioNTech) and 6 months-5 years (Moderna) based on safety, immunobridging, and limited efficacy data from clinical trials. On December 9, 2022, CDC expanded recommendations for use of updated bivalent vaccines to children aged ≥6 months. mRNA COVID-19 vaccine effectiveness (VE) against emergency department or urgent care (ED/UC) encounters was evaluated within the VISION Network during July 4, 2022-June 17, 2023, among children with COVID-19-like illness aged 6 months-5 years. Among children aged 6 months-5 years who received molecular SARS-CoV-2 testing during August 1, 2022-June 17, 2023, VE of 2 monovalent Moderna doses against ED/UC encounters was 29% (95% CI = 12%-42%) ≥14 days after dose 2 (median = 100 days after dose 2; IQR = 63-155 days). Among children aged 6 months-4 years with a COVID-19-like illness who received molecular testing during September 19, 2022-June 17, 2023, VE of 3 monovalent Pfizer-BioNTech doses was 43% (95% CI = 17%-61%) ≥14 days after dose 3 (median = 75 days after dose 3; IQR = 40-139 days). Effectiveness of ≥1 bivalent dose, comparing children with at least a complete primary series and ≥1 bivalent dose to unvaccinated children, irrespective of vaccine manufacturer, was 80% (95% CI = 42%-96%) among children aged 6 months-5 years a median of 58 days (IQR = 32-83 days) after the dose. All children should stay up to date with recommended COVID-19 vaccines, including initiation of COVID-19 vaccination immediately when they are eligible., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Nicola P. Klein reports institutional support from Pfizer, Merck, GSK, Sanofi Pasteur, and Protein Sciences (now Sanofi Pasteur). Allison L. Naleway reports institutional support from Pfizer for an unrelated study of meningococcal B vaccine safety during pregnancy study and from Vir Biotechnology for an unrelated influenza study. Suchitra Rao reports grant support from GSK. No other potential conflicts of interest were disclosed.

Background: Following historically low influenza activity during the 2020-2021 season, the United States saw an increase in influenza circulating during the 2021-2022 season. Most viruses belonged to the influenza A(H3N2) 3C.2a1b 2a.2 subclade., Methods: We conducted a test-negative case-control analysis among adults ≥18 years of age at 3 sites within the VISION Network. Encounters included emergency department/urgent care (ED/UC) visits or hospitalizations with ≥1 acute respiratory illness (ARI) discharge diagnosis codes and molecular testing for influenza. Vaccine effectiveness (VE) was calculated by comparing the odds of influenza vaccination ≥14 days before the encounter date between influenza-positive cases (type A) and influenza-negative and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-negative controls, applying inverse probability-to-be-vaccinated weights, and adjusting for confounders., Results: In total, 86 732 ED/UC ARI-associated encounters (7696 [9%] cases) and 16 805 hospitalized ARI-associated encounters (649 [4%] cases) were included. VE against influenza-associated ED/UC encounters was 25% (95% confidence interval (CI), 20%-29%) and 25% (95% CI, 11%-37%) against influenza-associated hospitalizations. VE against ED/UC encounters was lower in adults ≥65 years of age (7%; 95% CI, -5% to 17%) or with immunocompromising conditions (4%; 95% CI, -45% to 36%)., Conclusions: During an influenza A(H3N2)-predominant influenza season, modest VE was observed. These findings highlight the need for improved vaccines, particularly for A(H3N2) viruses that are historically associated with lower VE., Competing Interests: Potential conflicts of interest. S. R. received grants from GlaxoSmithKline. A. L. N. received grants from Pfizer and Vir Biotechnology. C. M. received grants from AstraZeneca. N. P. K. received grants from Pfizer, Merck, GlaxoSmithKline, and Sanofi Pasteur. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Background: Understanding the usefulness of additional COVID-19 vaccine doses-particularly given varying disease incidence-is needed to support public health policy. We characterize the benefits of COVID-19 booster doses using number needed to vaccinate (NNV) to prevent one COVID-19-associated hospitalization or emergency department encounter., Methods: We conducted a retrospective cohort study of immunocompetent adults at five health systems in four U.S. states during SARS-CoV-2 Omicron BA.1 predominance (December 2021-February 2022). Included patients completed a primary mRNA COVID-19 vaccine series and were either eligible to or received a booster dose. NNV were estimated using hazard ratios for each outcome (hospitalization and emergency department encounters), with results stratified by three 25-day periods and site., Findings: 1,285,032 patients contributed 938 hospitalizations and 2076 emergency department encounters. 555,729 (43.2%) patients were aged 18-49 years, 363,299 (28.3%) 50-64 years, and 366,004 (28.5%) ≥65 years. Most patients were female (n = 765,728, 59.6%), White (n = 990,224, 77.1%), and non-Hispanic (n = 1,063,964, 82.8%). 37.2% of patients received a booster and 62.8% received only two doses. Median estimated NNV to prevent one hospitalization was 205 (range 44-615) and NNV was lower across study periods for adults aged ≥65 years (110, 46, and 88, respectively) and those with underlying medical conditions (163, 69, and 131, respectively). Median estimated NNV to prevent one emergency department encounter was 156 (range 75-592)., Interpretation: The number of patients needed to receive a booster dose was highly dependent on local disease incidence, outcome severity, and patient risk factors for moderate-to-severe disease., Funding: Funding was provided by the Centers for Disease Control and Prevention though contract 75D30120C07986 to Westat, Inc. and contract 75D30120C07765 to Kaiser Foundation Hospitals., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. M.G. reports additional contracts with CDC Ambulatory US Flu/COVID VE Network, HAIVEN Adult Inpatient Flu/COVID VE, IVY-3 PHS, and RECOVER. A.L.N. reports research funding from Pfizer for an unrelated study of meningococcal B vaccine safety during pregnancy and Vir Biotechnology for an unrelated influenza study. S.A.I. reports an additional contract with Centers for Disease Control and Prevention, 200-2012-53584 (Vaccine Safety Datalink). A.K. reports a subcontract through HealthPartners for VISION payment made to Children’s Minnesota. B.E.D. reports a grant from NIH to evaluate HIE technologies, a grant from CDC to use HIE data for public health surveillance, an R21 grant from U.S. Agency for Healthcare Research Quality to evaluate HIE technologies, a grant from the U.S Department of Veterans Affairs to evaluate HIE technologies, royalties from Elsevier and Springer Nature for books on HIE and Public Health Informatics, and consulting fees for advisory panel on HPV vaccination from Merk and Co. K.M. reports two additional contracts with CDC: Ambulatory US Flu VE Network and HAIVEN Hospitalized Adult Influenza Vaccine Effectiveness Network. J.J.R., E.A.K.R., A.H., J.K., S.W.B., and M.M.D. report payments made to Westat via CDC Contract #200-2019-F-06819. B.F., E.H., E.S., K.N., K.D., C.R., C.S-A., M.B.D., T.C.O., N.G., J.N., J.A., N.R.V., and P.J.E. report payments made to their institution by CDC via Westat. No other potential conflicts of interest were disclosed.

Background: Accurate determination of COVID-19 vaccination status is necessary to produce reliable COVID-19 vaccine effectiveness (VE) estimates. Data comparing differences in COVID-19 VE by vaccination sources (i.e., immunization information systems [IIS], electronic medical records [EMR], and self-report) are limited. We compared the number of mRNA COVID-19 vaccine doses identified by each of these sources to assess agreement as well as differences in VE estimates using vaccination data from each individual source and vaccination data adjudicated from all sources combined., Methods: Adults aged ≥18 years who were hospitalized with COVID-like illness at 21 hospitals in 18 U.S. states participating in the IVY Network during February 1-August 31, 2022, were enrolled. Numbers of COVID-19 vaccine doses identified by IIS, EMR, and self-report were compared in kappa agreement analyses. Effectiveness of mRNA COVID-19 vaccines against COVID-19-associated hospitalization was estimated using multivariable logistic regression models to compare the odds of COVID-19 vaccination between SARS-CoV-2-positive case-patients and SARS-CoV-2-negative control-patients. VE was estimated using each source of vaccination data separately and all sources combined., Results: A total of 4499 patients were included. Patients with ≥1 mRNA COVID-19 vaccine dose were identified most frequently by self-report (n = 3570, 79 %), followed by IIS (n = 3272, 73 %) and EMR (n = 3057, 68 %). Agreement was highest between IIS and self-report for 4 doses with a kappa of 0.77 (95 % CI = 0.73-0.81). VE point estimates of 3 doses against COVID-19 hospitalization were substantially lower when using vaccination data from EMR only (VE = 31 %, 95 % CI = 16 %-43 %) than when using all sources combined (VE = 53 %, 95 % CI = 41 %-62%)., Conclusion: Vaccination data from EMR only may substantially underestimate COVID-19 VE., Competing Interests: Declaration of Competing Interest All authors have completed and submitted the International Committee of Medical Journal Editors (ICJME) disclosure form. Funding for this work was provided to all participating sites by the United States Centers for Disease Control and Prevention. The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: Samuel Brown reports institutional funds from Janssen for influenza research. Jonathan Casey reports a travel grant from Fischer and Paykel, outside the submitted work. Steven Chang reports consulting fees from PureTech Health and Kiniksa Pharmaceuticals and participating as a DSMB member for a study at UCLA, outside the submitted work. Manjusha Gaglani reports grants from CDC, CDC-Abt Associates, CDC-Westat, and Janssen, and served as co-chair of the Infectious Diseases and Immunization Committee for the Texas Pediatric Society, outside the submitted work. Kevin Gibbs reports grants from NIH and DoD, as well as support for MHSRS 2022 travel from the DoD, outside the submitted work. Adit Ginde reports receiving grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals, outside the submitted work. Michelle N. Gong reports grants from NHLBI, CDC, AHRQ, speaking at medicine grand rounds at New York Medical College, travel support for the ATS executive meeting and serving as ATS Chair Critical Care Assembly, DSMB membership fees from Regeneron, and participating on the scientific advisory panel for Endpoint, outside the submitted work. Carlos Grijalva reports grants from NIH, CDC, AHRQ, FDA, Campbell Alliance/Syneos Health; receiving consulting fees from and participating on a DSMB for Merck, outside the submitted work. David Hager reports receiving grants from NIH, outside the submitted work. Akram Khan reports receiving grants from United Therapeutics, Johnson & Johnson, 4D Medical, Eli Lily, Dompe Pharmaceuticals, and GlaxoSmithKline; and serves on the guidelines committee for Chest, outside the submitted work. Adam Lauring reports receiving grants from CDC, FluLab, NIAID, and Burroughs Wellcome Fund, and consulting fees from Sanofi and Roche for consulting on oseltamivir and baloxavir respectively, outside the submitted work. Emily Martin reports grants from Merck and NIH, outside the submitted work. Tresa McNeal reports receiving a grant from CDC, receiving a one-time payment for participating as a virtual webinar panelist for Clinical Updates in Heart Failure, and being a Practice Management Committee member for Society of Hospital Medicine, outside the submitted work. Ithan D. Peltan reports grants from NIH, Janssen Pharmaceuticals and institutional support from Asahi Kasei Pharma and Regeneron, outside the submitted work. Jennifer Wilson reports grants from NHLBI, outside the submitted work. No other potential conflicts of interest were disclosed., (Published by Elsevier Ltd.)

Background: Cardiac function of critically ill patients with COVID-19 generally has been reported from clinically obtained data. Echocardiographic deformation imaging can identify ventricular dysfunction missed by traditional echocardiographic assessment., Research Question: What is the prevalence of ventricular dysfunction and what are its implications for the natural history of critical COVID-19?, Study Design and Methods: This is a multicenter prospective cohort of critically ill patients with COVID-19. We performed serial echocardiography and lower extremity vascular ultrasound on hospitalization days 1, 3, and 8. We defined left ventricular (LV) dysfunction as the absolute value of longitudinal strain of < 17% or left ventricle ejection fraction (LVEF) of < 50%. Primary clinical outcome was inpatient survival., Results: We enrolled 110 patients. Thirty-nine (35.5%) died before hospital discharge. LV dysfunction was present at admission in 38 patients (34.5%) and in 21 patients (36.2%) on day 8 ( P  = .59). Median baseline LVEF was 62% (interquartile range [IQR], 52%-69%), whereas median absolute value of baseline LV strain was 16% (IQR, 14%-19%). Survivors and nonsurvivors did not differ statistically significantly with respect to day 1 LV strain (17.9% vs 14.4%; P  = .12) or day 1 LVEF (60.5% vs 65%; P  = .06). Nonsurvivors showed worse day 1 right ventricle (RV) strain than survivors (16.3% vs 21.2%; P  = .04)., Interpretation: Among patients with critical COVID-19, LV and RV dysfunction is common, frequently identified only through deformation imaging, and early (day 1) RV dysfunction may be associated with clinical outcome., (© 2023 The Authors.)

Background: Coronavirus disease 2019 (COVID-19) vaccination coverage remains lower in communities with higher social vulnerability. Factors such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure risk and access to healthcare are often correlated with social vulnerability and may therefore contribute to a relationship between vulnerability and observed vaccine effectiveness (VE). Understanding whether these factors impact VE could contribute to our understanding of real-world VE., Methods: We used electronic health record data from 7 health systems to assess vaccination coverage among patients with medically attended COVID-19-like illness. We then used a test-negative design to assess VE for 2- and 3-dose messenger RNA (mRNA) adult (≥18 years) vaccine recipients across Social Vulnerability Index (SVI) quartiles. SVI rankings were determined by geocoding patient addresses to census tracts; rankings were grouped into quartiles for analysis., Results: In July 2021, primary series vaccination coverage was higher in the least vulnerable quartile than in the most vulnerable quartile (56% vs 36%, respectively). In February 2022, booster dose coverage among persons who had completed a primary series was higher in the least vulnerable quartile than in the most vulnerable quartile (43% vs 30%). VE among 2-dose and 3-dose recipients during the Delta and Omicron BA.1 periods of predominance was similar across SVI quartiles., Conclusions: COVID-19 vaccination coverage varied substantially by SVI. Differences in VE estimates by SVI were minimal across groups after adjusting for baseline patient factors. However, lower vaccination coverage among more socially vulnerable groups means that the burden of illness is still disproportionately borne by the most socially vulnerable populations., Competing Interests: Potential conflicts of interest. B. E. D. reported consulting fees for advisory panel on HPV vaccination from Merck & Co and book royalties from Elsevier (book on HIE) as well as Springer Nature (book on Public Health Informatics), and grant to evaluate HIE technologies from US National Institutes of Health (NIH), grant to use HIE data for public health surveillance from CDC, R21 grant to evaluate HIE technologies from US Agency for Healthcare Research and Quality, grant to evaluate HIE technologies from US Department of Veterans Affairs. G. V. B. reported grants or contracts from Sanofi for Tdap Vaccine Safety and from CDC for Vaccine Safety Datalink. A. I. N. received institutional support from Pfizer for an unrelated study of meningococcal B vaccine safety during pregnancy and institutional research funding from Vir Biotechnology for unrelated influenza study. S. Rao received grant funding from GlaxoSmithKline. S. A. I. reports contract no. 200-2012-53584 (Vaccine Safety Datalink) from CDC. M. B. reports Columbia University is part of the VISION surveillance network and receives funding from Westat to support work done at Columbia as part of VISION. M. G. reports Ambulatory US Flu/COVID VE Network institutional grant, HAIVEN Adult Inpatient Flu/COVID VE institutional grant from CDC, IVY-3 PHS project institutional subcontract from CDC-Vanderbilt, and RECOVER study institutional subcontract from CDC-Abt. K. M. reports contracts or grants paid to institution from US CDC Ambulatory US Flu VE Network and US CDC HAIVEN—Hospitalized Adult Influenza Vaccine Effectiveness Network. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Objectives: We assessed BNT162b2 vaccine effectiveness (VE) against mild to moderate and severe coronavirus disease 2019 (COVID-19) in children and adolescents through the Omicron BA.4/BA.5 period., Methods: Using VISION Network records from April 2021 to September 2022, we conducted a test-negative, case-control study assessing VE against COVID-19-associated emergency department/urgent care (ED/UC) encounters and hospitalizations using logistic regression, conditioned on month and site, adjusted for covariates., Results: We compared 9800 ED/UC cases with 70 232 controls, and 305 hospitalized cases with 2612 controls. During Delta, 2-dose VE against ED/UC encounters at 12 to 15 years was initially 93% (95% confidence interval 89 to 95), waning to 77% (69% to 84%) after ≥150 days. At ages 16 to 17, VE was initially 93% (86% to 97%), waning to 72% (63% to 79%) after ≥150 days. During Omicron, VE at ages 12 to 15 was initially 64% (44% to 77%), waning to 13% (3% to 23%) after ≥150 days; at ages 16 to 17 VE was 31% (10% to 47%) during days 60 to 149, waning to 7% (-8 to 20%) after 150 days. A monovalent booster increased VE to 54% (40% to 65%) at ages 12 to 15 and 46% (30% to 58%) at ages 16 to 17. At ages 5 to 11, 2-dose VE was 49% (33% to 61%) initially and 41% (29% to 51%) after 150 days. During Delta, VE against hospitalizations at ages 12 to 17 was high (>97%), and at ages 16 to 17 remained 98% (73% to 100%) beyond 150 days; during Omicron, hospitalizations were too infrequent to precisely estimate VE., Conclusions: BNT162b2 protected children and adolescents against mild to moderate and severe COVID-19. VE was lower during Omicron predominance including BA.4/BA.5, waned after dose 2 but increased after a monovalent booster. Children and adolescents should receive all recommended COVID-19 vaccinations., (Copyright © 2023 by the American Academy of Pediatrics.)

Competing Interests: We declare no competing interests. The views expressed here are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention. Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

Background: We assessed coronavirus disease 2019 (COVID-19) vaccination impact on illness severity among adults hospitalized with COVID-19, August 2021-March 2022., Methods: We evaluated differences in intensive care unit (ICU) admission, in-hospital death, and length of stay among vaccinated (2 or 3 mRNA vaccine doses) versus unvaccinated patients aged ≥18 years hospitalized for ≥24 hours with COVID-19-like illness and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) molecular testing. We calculated odds ratios (ORs) for ICU admission and death and subdistribution hazard ratios (SHR) for time to hospital discharge adjusted for age, geographic region, calendar time, and local virus circulation., Results: We included 27 149 SARS-CoV-2-positive hospitalizations. During both Delta- and Omicron-predominant periods, protection against ICU admission was strongest among 3-dose vaccinees compared with unvaccinated patients (Delta OR, 0.52 [95% CI, .28-.96]; Omicron OR, 0.69 [95% CI, .54-.87]). During both periods, risk of in-hospital death was lower among vaccinated compared with unvaccinated patients but ORs overlapped across vaccination strata. We observed SHR >1 across all vaccination strata in both periods indicating faster discharge for vaccinated patients., Conclusions: COVID-19 vaccination was associated with lower rates of ICU admission and in-hospital death in both Delta and Omicron periods compared with being unvaccinated., Competing Interests: Potential conflicts of interest. N. P. K. reported receiving grants from Pfizer, Merck, GlaxoSmithKline, Sanofi Pasteur, and Protein Science (now Sanofi Pasteur) outside the submitted work. B. E. D. reported consulting fees for advisory panel on HPV vaccination from Merck & Co and book royalties from Elsevier as well as Springer Nature. A. L. N. received institutional support from Pfizer for an unrelated study of meningococcal B vaccine safety during pregnancy and from Vir Biotechnology for an unrelated influenza study. S. R. received grant funding from GlaxoSmithKline. C. M. received institutional support from AstraZeneca for a COVID vaccine trial. G. V.-B. reported Sanofi for Tdap Vaccine Safety. M. G. reported receiving institutional support from CDC for the ambulatory US Flu/COVID VE network and HAIVEN adult inpatient flu/COVID VE network; from CDC-Vanderbilt for the IVY-3 PHS project and from CDC-Abt for the RECOVER study. All other authors declare no financial relationships with any organizations that might have an interest in the submitted work in the previous three years, and no other relationships or activities that could appear to have influenced the submitted work. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.)

Background: Although most adults infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) fully recover, a proportion have ongoing symptoms, or post-COVID conditions (PCC), after infection. The objective of this analysis was to estimate the number of United States (US) adults with activity-limiting PCC on 1 November 2021., Methods: We modeled the prevalence of PCC using reported infections occurring from 1 February 2020 to 30 September 2021, and population-based, household survey data on new activity-limiting symptoms ≥1 month following SARS-CoV-2 infection. From these data sources, we estimated the number and proportion of US adults with activity-limiting PCC on 1 November 2021 as 95% uncertainty intervals, stratified by sex and age. Sensitivity analyses adjusted for underascertainment of infections and uncertainty about symptom duration., Results: On 1 November 2021, at least 3.0-5.0 million US adults, or 1.2%-1.9% of the US adult population, were estimated to have activity-limiting PCC of ≥1 month's duration. Population prevalence was higher in females (1.4%-2.2%) than males. The estimated prevalence after adjusting for underascertainment of infections was 1.7%-3.8%., Conclusions: Millions of US adults were estimated to have activity-limiting PCC. These estimates can support future efforts to address the impact of PCC on the US population., Competing Interests: Potential conflicts of interest. This project was funded by the CDC, and CDC co-authors took part in the project design, conduct, analysis, and manuscript preparation. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.)

Background: The purpose of this systematic review is to provide updated evidence on the preferred induction therapy for the treatment of HIV-associated cryptococcal meningitis considering the most recent evidence available in order to inform the need for updates to WHO guidelines., Methods: We searched Medline via PubMed, EMBASE, the Cochrane Library and clinicaltrials.gov for published or completed randomized clinical trials that evaluated induction treatment of first episode HIV-associated cryptococcal meningitis from 9 July 2018 (date of last search) to 1 September 2021., Results: One randomized clinical trial of 844 people with HIV-associated cryptococcal meningitis met the inclusion criteria. Participants were randomized to: (1) amphotericin deoxycholate for 7 days, with flucytosine and fluconazole (control); or (2) a single dose of liposomal amphotericin 10 mg/kg with flucytosine and fluconazole (intervention). In the intention-to-treat analysis, 10-week mortality was 24.8% [95% confidence interval (CI): 20.7-29.3%] in the single-dose liposomal amphotericin group compared with 28.7% (95% CI: 24.4-33.4%) in the control group. The absolute difference in 10-week mortality was -3.9% with an upper one-sided 95% CI of 1.2%, within the 10% pre-specified non-inferiority margin. Fewer participants had grade 3 and 4 adverse events in the intervention arm compared with the control arm (50.0% vs. 62.3%, p < 0.001)., Conclusions: In the single study included in this systematic review, single high-dose liposomal amphotericin B with flucytosine and fluconazole was non-inferior to the WHO-recommended standard of care induction therapy for HIV-associated cryptococcal meningitis, with significantly fewer adverse events., (© 2022 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Background: The COVID-19 pandemic was associated with historically low influenza circulation during the 2020-2021 season, followed by an increase in influenza circulation during the 2021-2022 US season. The 2a.2 subgroup of the influenza A(H3N2) 3C.2a1b subclade that predominated was antigenically different from the vaccine strain., Methods: To understand the effectiveness of the 2021-2022 vaccine against hospitalized influenza illness, a multistate sentinel surveillance network enrolled adults aged ≥18 years hospitalized with acute respiratory illness and tested for influenza by a molecular assay. Using the test-negative design, vaccine effectiveness (VE) was measured by comparing the odds of current-season influenza vaccination in influenza-positive case-patients and influenza-negative, SARS-CoV-2-negative controls, adjusting for confounders. A separate analysis was performed to illustrate bias introduced by including SARS-CoV-2-positive controls., Results: A total of 2334 patients, including 295 influenza cases (47% vaccinated), 1175 influenza- and SARS-CoV-2-negative controls (53% vaccinated), and 864 influenza-negative and SARS-CoV-2-positive controls (49% vaccinated), were analyzed. Influenza VE was 26% (95% CI: -14% to 52%) among adults aged 18-64 years, -3% (-54% to 31%) among adults aged ≥65 years, and 50% (15-71%) among adults aged 18-64 years without immunocompromising conditions. Estimated VE decreased with inclusion of SARS-CoV-2-positive controls., Conclusions: During a season where influenza A(H3N2) was antigenically different from the vaccine virus, vaccination was associated with a reduced risk of influenza hospitalization in younger immunocompetent adults. However, vaccination did not provide protection in adults ≥65 years of age. Improvements in vaccines, antivirals, and prevention strategies are warranted., Competing Interests: Potential conflicts of interest. M. G. reports grants from the Centers for Disease Control and Prevention (CDC), CDC-Abt Associates, CDC-Westat, and Janssen, and a leadership position as co-chair of the Infection Diseases and Immunizations Committee. J. S. S. reports a grant from the National Institutes of Health (NIH). A. D. reports grants from the NIH-PETAL Network, ACTIV-3b, ACTIV-4d, and GRAIL and consulting fees from Alung Technologies. M. E. P. reports a grant from the US Department of Defense and support for speaking at the 2022 North American Congress of Clinical Toxicology. I. D. P. reports grants from NIH, Janssen, Regeneron, and Asahi Kasei Pharma. D. N. H. reports grants from NIH (ACTIV-4d and Host Tissue-Nectar Trial). M. N. G. reports a grant from the National Heart, Lung, and Blood Institute (NHLBI); consulting fees for scientific advisory from Endpoint; support for attending an ATS Board of Executives Meeting; and participation in a Regeneron Data Safety and Monitoring Board (DSMB) for a monoclonal antibody trial. M. C. E. reports grants from NIH, Regeneron Pharmaceuticals, and payment from Abbott Labs for attending/lecture at the ASPEN Annual Meeting and on an Abbott webinar on nutrition in patients with COVID019. A. A. G. reports grants from NIH, Department of Defense, AbbVie, and Faron Pharmaceuticals. N. M. M. reports grants from the US CDC. E. T. M. reports grants from NIH and Merck and payment for lectures from the Michigan Infectious Diseases Society. K. W. G. reports grants from the Department of Defense and NIH support for ACTIV-4HT and Department of Defence support for Military Health System Research Symposium 2022 travel. J. H. K. is supported by grant 1K23AI137321-01A1 from the National Institute of Allergy and Infectious Diseases. N. H. reports grants from Sanofi and Quidel. A. S. L. reports grants from the US CDC, National Institute of Allergy and Infectious Diseases, and Burroughs Wellcome Fund; consulting fees from Sanofi and Roche; and membership on the American Society of Virology governing council (unpaid). C. J. L. reports grants from NIH, Department of Defense, CDC, bioMerieux, Entegrion Inc, Endpoint Health, Astra Zeneca, and AbbVie; patents for risk stratification in sepsis and septic shock issued to the Cincinnati Children's Hospital Medical Center; participation on DSMBs for clinical trials for Study Principal Investigators unrelated to the current work; and stock options in Bioscape Digital unrelated to the current work. C. G. G. reports grants from NIH, CDC, the Food and Drug Administration, the Agency for Healthcare Research and Quality, Sanofi, and Syneos Health and consulting fees from Pfizer, Merck, and Sanofi. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.)

During June-October 2022, the SARS-CoV-2 Omicron BA.5 sublineage accounted for most of the sequenced viral genomes in the United States, with further Omicron sublineage diversification through November 2022.* Bivalent mRNA vaccines contain an ancestral SARS-CoV-2 strain component plus an updated component of the Omicron BA.4/BA.5 sublineages. On September 1, 2022, a single bivalent booster dose was recommended for adults who had completed a primary vaccination series (with or without subsequent booster doses), with the last dose administered ≥2 months earlier (1). During September 13-November 18, the VISION Network evaluated vaccine effectiveness (VE) of a bivalent mRNA booster dose (after 2, 3, or 4 monovalent doses) compared with 1) no previous vaccination and 2) previous receipt of 2, 3, or 4 monovalent-only mRNA vaccine doses, among immunocompetent adults aged ≥18 years with an emergency department/urgent care (ED/UC) encounter or hospitalization for a COVID-19-like illness. † VE of a bivalent booster dose (after 2, 3, or 4 monovalent doses) against COVID-19-associated ED/UC encounters was 56% compared with no vaccination, 32% compared with monovalent vaccination only with last dose 2-4 months earlier, and 50% compared with monovalent vaccination only with last dose ≥11 months earlier. VE of a bivalent booster dose (after 2, 3, or 4 monovalent doses) against COVID-19-associated hospitalizations was 59% compared with no vaccination, 42% compared with monovalent vaccination only with last dose 5-7 months earlier, and 48% compared with monovalent vaccination only with last dose ≥11 months earlier. Bivalent vaccines administered after 2, 3, or 4 monovalent doses were effective in preventing medically attended COVID-19 compared with no vaccination and provided additional protection compared with past monovalent vaccination only, with relative protection increasing with time since receipt of the last monovalent dose. All eligible persons should stay up to date with recommended COVID-19 vaccinations, including receiving a bivalent booster dose. Persons should also consider taking additional precautions to avoid respiratory illness this winter season, such as masking in public indoor spaces, especially in areas where COVID-19 community levels are high., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Nicola P. Klein received grants from Pfizer, Merck, GlaxoSmithKline, and Sanofi Pasteur. Allison L. Naleway received grants from Pfizer and Vir Biotechnology. Suchitra Rao received grants from GlaxoSmithKline. Charlene McEvoy received grants from AztraZeneca. No other potential conflicts of interest were disclosed.

Importance: Recent SARS-CoV-2 Omicron variant sublineages, including BA.4 and BA.5, may be associated with greater immune evasion and less protection against COVID-19 after vaccination., Objectives: To evaluate the estimated vaccine effectiveness (VE) of 2, 3, or 4 doses of COVID-19 mRNA vaccination among immunocompetent adults during a period of BA.4 or BA.5 predominant circulation; and to evaluate the relative severity of COVID-19 in hospitalized patients across Omicron BA.1, BA.2 or BA.2.12.1, and BA.4 or BA.5 sublineage periods., Design, Setting, and Participants: This test-negative case-control study was conducted in 10 states with data from emergency department (ED) and urgent care (UC) encounters and hospitalizations from December 16, 2021, to August 20, 2022. Participants included adults with COVID-19-like illness and molecular testing for SARS-CoV-2. Data were analyzed from August 2 to September 21, 2022., Exposures: mRNA COVID-19 vaccination., Main Outcomes and Measures: The outcomes of interest were COVID-19 ED or UC encounters, hospitalizations, and admission to the intensive care unit (ICU) or in-hospital death. VE associated with protection against medically attended COVID-19 was estimated, stratified by care setting and vaccine doses (2, 3, or 4 doses vs 0 doses as the reference group). Among hospitalized patients with COVID-19, demographic and clinical characteristics and in-hospital outcomes were compared across sublineage periods., Results: During the BA.4 and BA.5 predominant period, there were 82 229 eligible ED and UC encounters among patients with COVID-19-like illness (median [IQR] age, 51 [33-70] years; 49 682 [60.4%] female patients), and 19 114 patients (23.2%) had test results positive for SARS-CoV-2; among 21 007 hospitalized patients (median [IQR] age, 71 [58-81] years; 11 209 [53.4%] female patients), 3583 (17.1 %) had test results positive for SARS-CoV-2. Estimated VE against hospitalization was 25% (95% CI, 17%-32%) for receipt of 2 vaccine doses at 150 days or more after receipt, 68% (95% CI, 50%-80%) for a third dose 7 to 119 days after receipt, and 36% (95% CI, 29%-42%) for a third dose 120 days or more (median [IQR], 235 [204-262] days) after receipt. Among patients aged 65 years or older who had received a fourth vaccine dose, VE was 66% (95% CI, 53%-75%) at 7 to 59 days after vaccination and 57% (95% CI, 44%-66%) at 60 days or more (median [IQR], 88 [75-105] days) after vaccination. Among hospitalized patients with COVID-19, ICU admission or in-hospital death occurred in 21.4% of patients during the BA.1 period vs 14.7% during the BA.4 and BA.5 period (standardized mean difference: 0.17)., Conclusions and Relevance: In this case-control study of COVID-19 vaccines and illness, VE associated with protection against medically attended COVID-19 illness was lower with increasing time since last dose; estimated VE was higher after receipt of 1 or 2 booster doses compared with a primary series alone.

Background: Coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccines were authorized in the United States in December 2020. Although vaccine effectiveness (VE) against mild infection declines markedly after several months, limited understanding exists on the long-term durability of protection against COVID-19-associated hospitalization., Methods: Case-control analysis of adults (≥18 years) hospitalized at 21 hospitals in 18 states 11 March-15 December 2021, including COVID-19 case patients and reverse transcriptase-polymerase chain reaction-negative controls. We included adults who were unvaccinated or vaccinated with 2 doses of a mRNA vaccine before the date of illness onset. VE over time was assessed using logistic regression comparing odds of vaccination in cases versus controls, adjusting for confounders. Models included dichotomous time (<180 vs ≥180 days since dose 2) and continuous time modeled using restricted cubic splines., Results: A total of 10 078 patients were included, 4906 cases (23% vaccinated) and 5172 controls (62% vaccinated). Median age was 60 years (interquartile range, 46-70), 56% were non-Hispanic White, and 81% had ≥1 medical condition. Among immunocompetent adults, VE <180 days was 90% (95% confidence interval [CI], 88-91) versus 82% (95% CI, 79-85) at ≥180 days (P < .001). VE declined for Pfizer-BioNTech (88% to 79%, P < .001) and Moderna (93% to 87%, P < .001) products, for younger adults (18-64 years) (91% to 87%, P = .005), and for adults ≥65 years of age (87% to 78%, P < .001). In models using restricted cubic splines, similar changes were observed., Conclusions: In a period largely predating Omicron variant circulation, effectiveness of 2 mRNA doses against COVID-19-associated hospitalization was largely sustained through 9 months., Competing Interests: Potential conflicts of interest. All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. W. H. S. reports grant funding from the Centers for Disease Control and Prevention (CDC) for this work, grants and consultant fees from Merck (for research on the surveillance of pneumococcal infections) and Gilead Sciences (for research on the surveillance of hepatitis C virus infections) outside this work. M. G. reports grant support from CDC (Ambulatory US Flu/COVID VE Network and Adult Inpatient Flu/COVID VE Network, HAIVEN), CDC-Abt Associates (Flu Vax Immunogenitiy RCT and RECVOERPROTECT COVID/Flu VE studies), CDC-Westat (VISION COVID Study), and Janssen (Johnson & Johnson) (RSV Severity App Birth Cohort Study). A. A. G. reports grant support from CDC, National Institute of Health (NIH), Department of Defense (DoD), AbbVie, and Faron Pharmaceuticals. J. D. C. reports grants from the CDC, NIH (K23HL153584), and Department of Defense. N. M. reports grants from the CDC (funded two other multicenter COVID-related projects separate from this work through payments to my institution). T. M. reports a grant from CDC and fees from the Society of Hospital Medicine for a talk about managing patients with congestive heart failure. K. G. reports grants from the CDC and the received grant funding for participation in executive committee of COVID-19 therapeutics from the NIH (ACTIV-4HT NECTAR Trial). D. C. F. reports grant support from CDC, consultant fees from Cytovale, and membership on a Medpace Data Safety Monitoring Board (DSMB). D. N. H. reports contracts from CDC, National Heart, Lung, and Blood Institute (NHLBI; funding for participation in the ACTIV4d - Host Tissue Trial), and Incyte Corporation (funding to enroll in RUCOVID-DEVENT) and membership on the SAFE EVICT Trial of VIT C in COVID-19 as DSMB chair. M. C. E. reports talks on nutrition in COVID pneumonia at the American Society of Parenteral and Enteral Nutrition (ASPEN) conference sponsored by Abbott Labs. M. N. G. reports grant support from CDC, NHLBI, NIH, and Agency for Healthcare Research and Quality (AHRQ), travel support for American Thoracic Society board meeting, and membership on the Regeneron DSMB for monoclonal antibodies in COVID-19. N. J. reports grants from CDC, NIH/NHLBI/NINDS, and University of Washington Royalty Research Fund, and payment for expert testimony from the Washington Department of Health. I. D. P. reports grants from CDC, NIH, Intermountain Research & Medical Foundation, and Janssen Pharmaceuticals, and institutional fees from Asahi Kasei Pharma and from Regeneron Pharmaceuticals. S. M. B. reports grants from CDC, NIH (for trials and other research activities related to COVID), and DoD (to study COVID); fees from Hamilton ventilators for chairing a DSMB; and personal fees from New York University for service on a DSMB. E. T. M. reports a grant from Merck outside the submitted work. A. M. reports grant support from CDC, NIH, NIAID, and membership on a DSMB for the Food and Drug Administration (FDA). A. K. reports grants from CDC, Gilead Sciences, Ely Lily, United Therapeutics, BOA-Medical, and 4D Medical and membership on the Guidelines Committee for Chest. C. L. H. reports grants from CDC, NIH, and the American Lung Association. A. D. reports a grant from the CDC and consulting fees from ALung Technologies (Steering Committee). J. W. reports grants from the CDC and NIH (ARREST Pneumonia Trial UH3HL141722, ACTIV3a and 3b trials, and ACTIV4a trial), and membership on the American Board of Internal Medicine Critical Care Medicine exam committee. S. Y. C. reports grants from CDC and Regeneron (for 6R88-COV-2040 trial) and consulting fees from PureTech Health (for COVID study) and Kiniska (for possible ARDS study). J. H. K. reports grant support from CDC and NIH (1K23 AI137321-01A1). A. S. L. reports grants from the CDC, NIH, and Burroughs Wellcome Fund, consultant fees for antiviral drugs from Sanofi and fees from Roche for membership on a baloxavir trial steering committee. N. H. reports grants from CDC, NIH, Sanofi, and Quidel and honoraria for speaking at a continuing medical education event at American Academy of Pediatrics. C. G. G. reports consultant fees from Pfizer, Merck, and Sanofi and grants from Syneos Health, CDC, NIH, FDA, AHRQ, and Sanofi. T. R. reports grants from CDC and Abbvie Inc, consultant fees from Cytovale, Inc. and Cumberland Pharmaceuticals Inc., membership on a Sanofi, Inc. DSMB, a voluntary role as the Immediate Past President of ASPEN and stock in Cumberland Pharmaceuticals, Inc. I. J. reports grants/contracts from the CDC, NIH, Quidel, and Sanofi. C. J. L. reports grants/contracts from CDC, NIH, DoD, bioMerieux, Endpoint Health, Entegrion, Inc., and AbbVie; a patent issued to Cincinnati Children’s Hospital Medical Center for risk stratification in sepsis and septic shock, membership on a Study Principal Investigators DSMB for clinical trials unrelated to the current work, Executive Committee; Immediate Past President, Member, Board of Directors, Association for Clinical and Translational Science, and stock options in Bioscape Digita unrelated to the current work. W. B. S. reports a grant from the CDC and NIH (5K12HL133117-05). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2022.)

Background: Coronavirus disease 2019 (COVID-19) vaccine effectiveness (VE) studies are increasingly reporting relative VE (rVE) comparing a primary series plus booster doses with a primary series only. Interpretation of rVE differs from traditional studies measuring absolute VE (aVE) of a vaccine regimen against an unvaccinated referent group. We estimated aVE and rVE against COVID-19 hospitalization in primary-series plus first-booster recipients of COVID-19 vaccines., Methods: Booster-eligible immunocompetent adults hospitalized at 21 medical centers in the United States during December 25, 2021-April 4, 2022 were included. In a test-negative design, logistic regression with case status as the outcome and completion of primary vaccine series or primary series plus 1 booster dose as the predictors, adjusted for potential confounders, were used to estimate aVE and rVE., Results: A total of 2060 patients were analyzed, including 1104 COVID-19 cases and 956 controls. Relative VE against COVID-19 hospitalization in boosted mRNA vaccine recipients versus primary series only was 66% (95% confidence interval [CI], 55%-74%); aVE was 81% (95% CI, 75%-86%) for boosted versus 46% (95% CI, 30%-58%) for primary. For boosted Janssen vaccine recipients versus primary series, rVE was 49% (95% CI, -9% to 76%); aVE was 62% (95% CI, 33%-79%) for boosted versus 36% (95% CI, -4% to 60%) for primary., Conclusions: Vaccine booster doses increased protection against COVID-19 hospitalization compared with a primary series. Comparing rVE measures across studies can lead to flawed interpretations of the added value of a new vaccination regimen, whereas difference in aVE, when available, may be a more useful metric., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

During June-October 2022, the SARS-CoV-2 Omicron BA.5 sublineage accounted for most of the sequenced viral genomes in the United States, with further Omicron sublineage diversification through November 2022.* Bivalent mRNA vaccines contain an ancestral SARS-CoV-2 strain component plus an updated component of the Omicron BA.4/BA.5 sublineages. On September 1, 2022, a single bivalent booster dose was recommended for adults who had completed a primary vaccination series (with or without subsequent booster doses), with the last dose administered ≥2 months earlier (1). During September 13-November 18, the VISION Network evaluated vaccine effectiveness (VE) of a bivalent mRNA booster dose (after 2, 3, or 4 monovalent doses) compared with 1) no previous vaccination and 2) previous receipt of 2, 3, or 4 monovalent-only mRNA vaccine doses, among immunocompetent adults aged ≥18 years with an emergency department/urgent care (ED/UC) encounter or hospitalization for a COVID-19-like illness. † VE of a bivalent booster dose (after 2, 3, or 4 monovalent doses) against COVID-19-associated ED/UC encounters was 56% compared with no vaccination, 31% compared with monovalent vaccination only with last dose 2-4 months earlier, and 50% compared with monovalent vaccination only with last dose ≥11 months earlier. VE of a bivalent booster dose (after 2, 3, or 4 monovalent doses) against COVID-19-associated hospitalizations was 57% compared with no vaccination, 38% compared with monovalent vaccination only with last dose 5-7 months earlier, and 45% compared with monovalent vaccination only with last dose ≥11 months earlier. Bivalent vaccines administered after 2, 3, or 4 monovalent doses were effective in preventing medically attended COVID-19 compared with no vaccination and provided additional protection compared with past monovalent vaccination only, with relative protection increasing with time since receipt of the last monovalent dose. All eligible persons should stay up to date with recommended COVID-19 vaccinations, including receiving a bivalent booster dose. Persons should also consider taking additional precautions to avoid respiratory illness this winter season, such as masking in public indoor spaces, especially in areas where COVID-19 community levels are high., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Nicola P. Klein received grants from Pfizer, Merck, GlaxoSmithKline, and Sanofi Pasteur. Allison L. Naleway received grants from Pfizer and Vir Biotechnology. Suchitra Rao received grants from GlaxoSmithKline. Charlene McEvoy received grants from AztraZeneca. No other potential conflicts of interest were disclosed.

From surveillance data of patients hospitalized with laboratory-confirmed influenza in the United States during the 2015-2016 through 2018-2019 seasons, initiation of antiviral treatment increased from 86% to 94%, with increases seen across all age groups. However, 62% started therapy ≥3 days after illness onset, driven by late presentation to care., Competing Interests: Potential conflicts of interest. E.A. has received received grants for clinical trials from Pfizer, Merck, PaxVax, Micron, Sanofi-Pasteur, Janssen, MedImmune, and GSK, has been a consultant for Sanofi-Pasteur, Pfizer, Medscape, Janssen, GSK, and Moderna, has been a member of the data safety monitoring board for Kentucky Bioprocessing and Sanofi-Pasteur, and has been a member of the endpoint adjudication committee for WCG and ACI Clinical. His institution has also received funding from the NIH to conduct clinical trials of COVID-19 vaccines. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.)

Background: Advanced HIV disease (AHD; CD4 counts <200 cells/µL) remains common in many low- and middle-income settings. An instrument-free point-of-care test to rapidly identify patients with AHD would facilitate implementation of the World Health Organization (WHO) recommended package of care. We performed a laboratory-based validation study to evaluate the performance of the VISITECT CD4 Advanced Disease assay in Botswana., Setting: A laboratory validation study., Methods: Venous blood samples from people living with HIV having baseline CD4 testing in Gaborone, Botswana, underwent routine testing using flow cytometry, followed by testing with the VISITECT CD4 Advanced Disease assay by a laboratory scientist blinded to the flow cytometry result with a visual read to determine whether the CD4 count was below 200 cells/µL. A second independent investigator conducted a visual read blinded to the results of flow cytometry and the initial visual read. The sensitivity and specificity of the VISITECT for detection of AHD were determined using flow cytometry as a reference standard, and interrater agreement in VISITECT visual reads assessed., Results: One thousand fifty-three samples were included in the analysis. The VISITECT test correctly identified 112/119 samples as having a CD4 count <200 cells/µL, giving a sensitivity of 94.1% (95% confidence interval: 88.3% to 97.6%) and specificity of 85.9% (95% confidence interval: 83.5% to 88.0%) compared with flow cytometry. Interrater agreement between the 2 independent readers was 97.5%, Kappa 0.92 ( P < 0.001)., Conclusions: The VISITECT CD4 advanced disease reliably identified individuals with low CD4 counts and could facilitate implementation of the WHO recommended package of interventions for AHD., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Test-negative design (TND) studies have produced validated estimates of vaccine effectiveness (VE) for influenza vaccine studies. However, syndrome-negative controls have been proposed for differentiating bias and true estimates in VE evaluations for COVID-19. To understand the use of alternative control groups, we compared characteristics and VE estimates of syndrome-negative and test-negative VE controls., Methods: Adults hospitalized at 21 medical centers in 18 states March 11-August 31, 2021 were eligible for analysis. Case patients had symptomatic acute respiratory infection (ARI) and tested positive for SARS-CoV-2. Control groups were test-negative patients with ARI but negative SARS-CoV-2 testing, and syndrome-negative controls were without ARI and negative SARS-CoV-2 testing. Chi square and Wilcoxon rank sum tests were used to detect differences in baseline characteristics. VE against COVID-19 hospitalization was calculated using logistic regression comparing adjusted odds of prior mRNA vaccination between cases hospitalized with COVID-19 and each control group., Results: 5811 adults (2726 cases, 1696 test-negative controls, and 1389 syndrome-negative controls) were included. Control groups differed across characteristics including age, race/ethnicity, employment, previous hospitalizations, medical conditions, and immunosuppression. However, control-group-specific VE estimates were very similar. Among immunocompetent patients aged 18-64 years, VE was 93 % (95 % CI: 90-94) using syndrome-negative controls and 91 % (95 % CI: 88-93) using test-negative controls., Conclusions: Despite demographic and clinical differences between control groups, the use of either control group produced similar VE estimates across age groups and immunosuppression status. These findings support the use of test-negative controls and increase confidence in COVID-19 VE estimates produced by test-negative design studies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors have completed and submitted the International Committee of Medical Journal Editors (ICMJE) disclosure form. Funding for this work was provided to all participating sites by the United States Centers for Disease Control and Prevention. Samuel Brown reports grants from National Institutes of Health (NIH) and Department of Defense (DoD), participation as the DSMB chair for Hamilton Ventilators, and participation as a member of the DSMB for New York University COVID clinical trials. Jonathan Casey reports funding from NIH and DoD. Steven Chang reports consulting fees from La Jolla Pharmaceuticals, PureTech Health, and Kiniska Pharmaceuticals, payment/honoraria from La Jolla Pharmaceuticals, and participation on a DSMB for an investigator-initiated study conducted at UCLA. James Chappell reports grants and other support from NIH. Abhijit Duggal reports consulting fees from ALung technologies. Matthew Exline reports payment/honorariua from Abbott Lab for sponsored talks. D. Clark Files reports consulting fees from Cytovale and participation on a DSMB for Medpace. Anne Frosch reports grants from NIH. Manjusha Gaglani reports grants from Centers for Disease Control and Prevention (CDC), CDC-Abt Associates, CDC-Westat, and Janssen, and a leadership role as co-chair of the Infectious Disease and Immunization Committee of the Texas Pediatric Society, Texas Chapter of American Academy of Pediatrics. Kevin Gibbs reports funding from NIH/ National Heart, Lung, and Blood Institute (NHLBI) for the ACTIV-4HT NECTAR trial. Nicholas Mohr reports grants from the CDC (funded 2 other multicenter COVID-related projects separate from this work through payments to author’s institution). Adit Ginde reports grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals. Michelle Gong reports grants from NIH/NHLBI and Agency for Healthcare Research and Quality (AHRQ), consulting fees from Endpoint, a leadership role on the American Thoracic Society (ATS) executive committee and board as well as support from ATS for meeting travel expenses, and participation on a DSMB for Regeneron. Carlos Grijalva reports grants from NIH, CDC, Food and Drug Administration (FDA), AHRQ, Sanofi, and Syneos Health and consulting fees from Pfizer, Merck, and Sanofi. David Hager reports grants from NIH/NHLBI for the ACTIV-4HT NECTAR trial and Incyte Corporation and participation as a DSMB chair for the SAFE EVICT Trial of vitamin C in COVID-19. Jennifer Wilson reports grants from the CDC and NIH (ARREST Pneumonia Trial UH3HL141722, ACTIV3a and 3b trials, and ACTIV4a trial), and membership on the American Board of Internal Medicine Critical Care Medicine exam committee. Natasha Halasa reports grants from NIH, Quidel, and Sanofi and honoraria for speaking at the American Academy of Pediatrics (AAP) conference. Nicholas Johnson reports grants from NIH/NHLBI/NINDS and the University of Washington Royalty Research Fund and payment for expert testimony for the Washington Department of Health. Akram Khan reports grants from United Therapeutics, Gilead Sciences, and 4D Medical and a leadership role on the guidelines committee for Chest. Jennie Kwon reports grants from NIH/NIAID. Adam Lauring reports grants from CDC, NIH/NIAID, and Burroughs Wellcome Fund and consulting fees from Sanofi and Roche. Christopher Lindsell reports grants from NIH, DoD, CDC, bioMerieux, Entegrion Inc., Endpoint Health, and AbbVie, patents for risk stratification in sepsis and septic shock, participation on DSMBs for clinical trials unrelated to the current work, a leadership role on the executive committee for the Board of Directors of the Association for Clinical and Translational Science, and stock options in Bioscape Digita. Emily Martin reports grants from Merck, CDC, and NIH and payment/honoraria from the Michigan Infectious Disease Society. Tresa McNeal reports payment/honoraria from the Society of Hospital Medicine. Ithan Peltan reports grants from NIH, Janssen, Regeneron, and Asahi Kasei Pharma. Todd Rice reports grants from AbbVie Inc., consulting fees from Cumberland Pharmaceuticals, Inc. and Cytovale, Inc., membership on a DSMB for Sanofi, Inc., a leadership role as immediate past president of the American Society of Parenteral and Enteral Nutrition, and stock options in Cumberland Pharmaceuticals, Inc. Wesley Self reports receiving the primary funding for this project from the United States Centers for Disease Control and Prevention, and research funding from Merck and Gilead Sciences. William Stubblefield reports grants from the NIH/NHLBI., (Published by Elsevier Ltd.)