Search

Background: During the COVID-19 pandemic, self-reported COVID-19 vaccination might facilitate rapid evaluations of vaccine effectiveness (VE) when source documentation (e.g., immunization information systems [IIS]) is not readily available. We evaluated the concordance of COVID-19 vaccination status ascertained by self-report versus source documentation and its impact on VE estimates., Methods: Hospitalized adults (≥18 years) admitted to 18 U.S. medical centers March-June 2021 were enrolled, including COVID-19 cases and SARS-CoV-2 negative controls. Patients were interviewed about COVID-19 vaccination. Abstractors simultaneously searched IIS, medical records, and other sources for vaccination information. To compare vaccination status by self-report and documentation, we estimated percent agreement and unweighted kappa with 95% confidence intervals (CIs). We then calculated VE in preventing COVID-19 hospitalization of full vaccination (2 doses of mRNA product ≥14 days prior to illness onset) independently using data from self-report or source documentation., Results: Of 2520 patients, 594 (24%) did not have self-reported vaccination information to assign vaccination group; these patients tended to be more severely ill. Among 1924 patients with both self-report and source documentation information, 95.0% (95% CI: 93.9-95.9%) agreement was observed, with a kappa of 0.9127 (95% CI: 0.9109-0.9145). VE was 86% (95% CI: 81-90%) by self-report data only and 85% (95% CI: 81-89%) by source documentation data only., Conclusions: Approximately one-quarter of hospitalized patients could not provide self-report COVID-19 vaccination status. Among patients with self-report information, there was high concordance with source documented status. Self-report may be a reasonable source of COVID-19 vaccination information for timely VE assessment for public health action., (© 2022 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: We estimated SARS-CoV-2 Delta- and Omicron-specific effectiveness of two and three mRNA COVID-19 vaccine doses in adults against symptomatic illness in US outpatient settings., Methods: Between October 1, 2021, and February 12, 2022, research staff consented and enrolled eligible participants who had fever, cough, or loss of taste or smell and sought outpatient medical care or clinical SARS-CoV-2 testing within 10 days of illness onset. Using the test-negative design, we compared the odds of receiving two or three mRNA COVID-19 vaccine doses among SARS-CoV-2 cases versus controls using logistic regression. Regression models were adjusted for study site, age, onset week, and prior SARS-CoV-2 infection. Vaccine effectiveness (VE) was calculated as (1 - adjusted odds ratio) × 100%., Results: Among 3847 participants included for analysis, 574 (32%) of 1775 tested positive for SARS-CoV-2 during the Delta predominant period and 1006 (56%) of 1794 participants tested positive during the Omicron predominant period. When Delta predominated, VE against symptomatic illness in outpatient settings was 63% (95% CI: 51% to 72%) among mRNA two-dose recipients and 96% (95% CI: 93% to 98%) for three-dose recipients. When Omicron predominated, VE was 21% (95% CI: -6% to 41%) among two-dose recipients and 62% (95% CI: 48% to 72%) among three-dose recipients., Conclusions: In this adult population, three mRNA COVID-19 vaccine doses provided substantial protection against symptomatic illness in outpatient settings when the Omicron variant became the predominant cause of COVID-19 in the United States. These findings support the recommendation for a third mRNA COVID-19 vaccine dose., Competing Interests: Ana Florea reports unrelated institutional grant support for research from Gilead, GlaxoSmithKline, Moderna, and Pfizer. Carlos G. Grijalva reports consulting fees from Merck, Pfizer, and Sanofi Pasteur, and institutional grant support from the Agency for Health Care Research and Quality, Campbell Alliance/Syneos Health, the Food and Drug Administration, and the National Institutes of Health. Emily T. Martin reports institutional grant support from Merck. Arnold S. Monto reports personal fees from Sanofi and non‐financial support from Seqirus. Mary Patricia Nowalk reports unrelated institutional grant support and personal fees from Merck Sharp & Dohme and institutional investigator‐initiated grant support from Sanofi Pasteur. Sara Y. Tartof reports unrelated institutional grant support from Pfizer and GlaxoSmithKline. No other potential conflicts of interest were disclosed., (Published 2022. This article is a U.S. Government work and is in the public domain in the USA. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

The SARS-CoV-2 Omicron variant (B.1.1.529 or BA.1) became predominant in the United States by late December 2021 (1). BA.1 has since been replaced by emerging lineages BA.2 (including BA.2.12.1) in March 2022, followed by BA.4 and BA.5, which have accounted for a majority of SARS-CoV-2 infections since late June 2022 (1). Data on the effectiveness of monovalent mRNA COVID-19 vaccines against BA.4/BA.5-associated hospitalizations are limited, and their interpretation is complicated by waning of vaccine-induced immunity (2-5). Further, infections with earlier Omicron lineages, including BA.1 and BA.2, reduce vaccine effectiveness (VE) estimates because certain persons in the referent unvaccinated group have protection from infection-induced immunity. The IVY Network † assessed effectiveness of 2, 3, and 4 doses of monovalent mRNA vaccines compared with no vaccination against COVID-19-associated hospitalization among immunocompetent adults aged ≥18 years during December 26, 2021-August 31, 2022. During the BA.1/BA.2 period, VE 14-150 days after a second dose was 63% and decreased to 34% after 150 days. Similarly, VE 7-120 days after a third dose was 79% and decreased to 41% after 120 days. VE 7-120 days after a fourth dose was 61%. During the BA.4/BA.5 period, similar trends were observed, although CIs for VE estimates between categories of time since the last dose overlapped. VE 14-150 days and >150 days after a second dose was 83% and 37%, respectively. VE 7-120 days and >120 days after a third dose was 60%and 29%, respectively. VE 7-120 days after the fourth dose was 61%. Protection against COVID-19-associated hospitalization waned even after a third dose. The newly authorized bivalent COVID-19 vaccines include mRNA from the ancestral SARS-CoV-2 strain and from shared mRNA components between BA.4 and BA.5 lineages and are expected to be more immunogenic against BA.4/BA.5 than monovalent mRNA COVID-19 vaccines (6-8). All eligible adults aged ≥18 years § should receive a booster dose, which currently consists of a bivalent mRNA vaccine, to maximize protection against BA.4/BA.5 and prevent COVID-19-associated hospitalization., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Samuel M. Brown reports personal fees from Hamilton Ventilators outside the submitted work. Jonathan D. Casey reports grants from the National Institutes of Health (NIH) and U.S. Department of Defense (DoD), outside the submitted work. Steven Y. Chang reports consulting for PureTech Health in 2020 and Kiniksa Pharmaceuticals and membership on the safety monitoring board (DSMB) for an investigator-initiated study at UCLA. James D. Chappell reports grants from NIH and DoD during the conduct of the study. David J. Douin reports grants received from NIH and National Institute of General Medical Sciences, outside the submitted work. Abhijit Duggal reports grants from NIH and participation on a steering committee for ALung technologies, outside the submitted work. Matthew C. Exline reports grants from the NIH and Regeneron, as well as support from Abbott Labs for sponsored talks, outside the submitted work. D. Clark Files reports personal consultant fees from Cytovale and membership on DSMB from Medpace, outside the submitted work. Anne P. Frosch reports grants from NIH, outside the submitted work. Manjusha Gaglani reports grants from Abt Associates, Westat, Janssen, and participation as co-chair on the Infection Diseases and Immunizations Committee for the Texas Pediatric Society, outside the submitted work. Kevin W. Gibbs reports grants from NIH and DoD, and DoD funds for Military Health System Research Symposium travel in 2022, outside the submitted work. Adit A. Ginde reports grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals, outside the submitted work. Michelle N. Gong reports grants from NIH, speaking at medicine grand rounds at New York Medical College, travel support for the American Thoracic Society executive meeting, DSMB membership fees from Regeneron, and participation on the scientific advisory panel for Endpoint, outside the submitted work. Carlos G. Grijalva reports consultancy fees from Pfizer, Merck, and Sanofi-Pasteur; grants from Campbell Alliance/Syneos Health, NIH, the Food and Drug Administration, Agency for Healthcare Research and Quality, and Sanofi, outside the submitted work. David N. Hager grants from NIH, outside the submitted work. Natasha Halasa reports grants and nonfinancial support from Sanofi, and grants from Quidel outside the submitted work. Nicholas J. Johnson reports grants from the NIH, DoD, University of Washington, and Medic One Foundation, outside the submitted work. Akram Khan reports grants from United Therapeutics, Johnson & Johnson, Ely Lilly, 4D Medical, Dompe Pharmaceuticals, and GlaxoSmithKline, outside the submitted work. Jennie H. Kwon reports grants from National Institute of Allergy and Infectious Diseases (NIAID), outside the submitted work. Adam S. Lauring reports personal fees from Sanofi and Roche and grants from NIAID, Burroughs Wellcome Fund, Flu Lab, outside the submitted work. Emily T. Martin reports grants from Merck, outside the submitted work. Tresa McNeal reports participation as a webinar invited panelist and 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. Todd W. Rice reports grants from Abbvie Inc, and personal fees from Cumberland Pharmaceuticals, Inc, Cytovale, Inc., and Sanofi, Inc., outside the submitted work. William B. Stubblefield reports grants from NIH, outside the submitted work. Jennifer G. Wilson reports grants from NIH, and personal funds from the American College of Emergency Physicians and American Board of Internal Medicine, outside the submitted work. No other potential conflicts of interest were disclosed.

Persons with moderate-to-severe immunocompromising conditions might have reduced protection after COVID-19 vaccination, compared with persons without immunocompromising conditions (1-3). On August 13, 2021, the Advisory Committee on Immunization Practices (ACIP) recommended that adults with immunocompromising conditions receive an expanded primary series of 3 doses of an mRNA COVID-19 vaccine. ACIP followed with recommendations on September 23, 2021, for a fourth (booster) dose and on September 1, 2022, for a new bivalent mRNA COVID-19 vaccine booster dose, containing components of the BA.4 and BA.5 sublineages of the Omicron (B.1.1.529) variant (4). Data on vaccine effectiveness (VE) of monovalent COVID-19 vaccines among persons with immunocompromising conditions since the emergence of the Omicron variant in December 2021 are limited. In the multistate VISION Network, § monovalent 2-, 3-, and 4-dose mRNA VE against COVID-19-related hospitalization were estimated among adults with immunocompromising conditions ¶ hospitalized with COVID-19-like illness,** using a test-negative design comparing odds of previous vaccination among persons with a positive or negative molecular test result (case-patients and control-patients) for SARS-CoV-2 (the virus that causes COVID-19). During December 16, 2021-August 20, 2022, among SARS-CoV-2 test-positive case-patients, 1,815 (36.3%), 1,387 (27.7%), 1,552 (31.0%), and 251 (5.0%) received 0, 2, 3, and 4 mRNA COVID-19 vaccine doses, respectively. Among test-negative control-patients during this period, 6,928 (23.7%), 7,411 (25.4%), 12,734 (43.6%), and 2,142 (7.3%) received these respective doses. Overall, VE against COVID-19-related hospitalization among adults with immunocompromising conditions hospitalized for COVID-like illness during Omicron predominance was 36% ≥14 days after dose 2, 69% 7-89 days after dose 3, and 44% ≥90 days after dose 3. Restricting the analysis to later periods when Omicron sublineages BA.2/BA.2.12.1 and BA.4/BA.5 were predominant and 3-dose recipients were eligible to receive a fourth dose, VE was 32% ≥90 days after dose 3 and 43% ≥7 days after dose 4. Protection offered by vaccination among persons with immunocompromising conditions during Omicron predominance was moderate even after a 3-dose monovalent primary series or booster dose. Given the incomplete protection against hospitalization afforded by monovalent COVID-19 vaccines, persons with immunocompromising conditions might benefit from updated bivalent vaccine booster doses that target recently circulating Omicron sublineages, in line with ACIP recommendations. Further, additional protective recommendations for persons with immunocompromising conditions, including the use of prophylactic antibody therapy, early access to and use of antivirals, and enhanced nonpharmaceutical interventions such as well-fitting masks or respirators, should also be considered., 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 reported grant support from the National Institutes of Health, Agency for Healthcare Research and Quality, and the U.S. Department of Veterans Affairs; personal fees from Elsevier and Springer Nature; and consulting fees from Merck. Nicola P. Klein reported institutional grant support from Pfizer, Inc., Merck, GSK, and Sanofi Pasteur. Allison L. Naleway reported institutional support from Pfizer, Inc. and Vir Biotechnology. Suchitra Rao reported grant support from GSK. Charlene McEvoy reported institutional support from AstraZeneca. No other potential conflicts of interest were disclosed.

Background . Adults in the United States (US) began receiving the adenovirus vector coronavirus disease 2019 (COVID-19) vaccine, Ad26.COV2.S (Johnson & Johnson [Janssen]), in February 2021. We evaluated Ad26.COV2.S vaccine effectiveness (VE) against COVID-19 hospitalization and high disease severity during the first 10 months of its use. Methods . In a multicenter case-control analysis of US adults (≥18 years) hospitalized 11 March to 15 December 2021, we estimated VE against susceptibility to COVID-19 hospitalization (VEs), comparing odds of prior vaccination with a single dose Ad26.COV2.S vaccine between hospitalized cases with COVID-19 and controls without COVID-19. Among hospitalized patients with COVID-19, we estimated VE against disease progression (VEp) to death or invasive mechanical ventilation (IMV), comparing odds of prior vaccination between patients with and without progression. Results . After excluding patients receiving mRNA vaccines, among 3979 COVID-19 case-patients (5% vaccinated with Ad26.COV2.S) and 2229 controls (13% vaccinated with Ad26.COV2.S), VEs of Ad26.COV2.S against COVID-19 hospitalization was 70% (95% confidence interval [CI]: 63-75%) overall, including 55% (29-72%) among immunocompromised patients, and 72% (64-77%) among immunocompetent patients, for whom VEs was similar at 14-90 days (73% [59-82%]), 91-180 days (71% [60-80%]), and 181-274 days (70% [54-81%]) postvaccination. Among hospitalized COVID-19 case-patients, VEp was 46% (18-65%) among immunocompetent patients. Conclusions . The Ad26.COV2.S COVID-19 vaccine reduced the risk of COVID-19 hospitalization by 72% among immunocompetent adults without waning through 6 months postvaccination. After hospitalization for COVID-19, vaccinated immunocompetent patients were less likely to require IMV or die compared to unvaccinated immunocompetent patients., Competing Interests: Potential conflicts of interest. M. G.: CDC: Baylor Scott & White Health (BSWH) US Flu/COVID VE Network, HAIVEN, Synergy studies; CDC-Abt: BSWH FluVax Trial and RECOVER-PROTECT Cohort Studies; CDC-Westat: BSWH VISION COVID-Flu VE Study; Janssen: BSWH Respiratory Syncytial Virus (RSV) Severity App Birth Cohort Study; Co-Chair of Infectious Diseases and Immunization Committee—Texas Pediatric Society—Texas Chapter of American Academy of Pediatrics. A. G.: National Institutes of Health (NIH), Department of Defense; Faron Pharmaceuticals; AbbVie; D Douin: NIH/National Institute of General Medical Sciences (NIGMS) Institutional Training Grant. J. C.: NIH and Department of Defense grants unrelated to this work. T. A. M.: Panelist for Society of Hospital Medicine Updates in Heart Failure; Board member for Scott & White Clinic Physicians Board of Directors. K. G.: NECTAR Executive Committee member ACTIV4-HT; D. C. F.: Cytovale consulting fees; Medpace Data Safety Monitoring Board. D. N. H.: National Heart, Lung, and Blood Institute (NIHLBI) participant in the ACTIV4d-Host Tissue Trial; Chair DSMD—SAFE EVICT Trial of VIT C in COVID-19. M. N. G.: Grants from NHLBI and Agency for Healthcare Research and Quality (AHRQ); Consulting fees for Endpoint for scientific advisory panel; Honoraria—Medicine Grand Rounds from Westchester Medical Center; Support for attending ATS Board of Directors meeting; Data and Safety Monitoring Board (DSMB) for Regeneron study and REPLENISH trial. N. J. J.: IH grants paid to University of Washington Royalty Research Fund; Department of Defense grants; Medic One Foundation grants; WA Department of Health expert testimony payment; DSMB for Opticyte, Inc.; Chair, ACEP Critical Care Section. I. P.: NIH grants; Regeneron Pharmaceuticals grant; Intermountain Research & Medical Foundation grant; Asahi Kasei Pharma grant; Janssen Pharmaceuticals grant. S. B.: NIH grants and Department of Defense grants; DSMB for Hamilton ventilators and NYU. E. T. M.: Merck grant. A. S. M.: NIH grant. A. K.: NIH grants; United Therapeutics grants; Eli Lily grants; Johnson & Johnson—BOA Medical—4DMedical research grants; rA. D.: Center PI for PETAL network through NHLBI grant; on steering committee for A Lung technologies. J. G. W.: NIH/NHLBI funding for ACTIV-3 and ACTIV-4 trials; American Board of Internal Medicine—member of Critical Care Exam Committee. S. Y. C.: Consulting fees for PureTech Health and Kiniska Pharmaceuticals; Honoraria for La Jolla. H. M. B.: CDC grant for HCP COVID vaccine effectiveness. J. H. K.: NIAID grant. M. C. E.: Abbott Labs honoraria for speaking on ASPEN on nutrition in critical illness from COVID. A. L.: grants from CDC, NIH, and Burroughs Wellcome Fund; consulting fees from Sanofi on antiviral drugs and for Roche on baloxavir trial steering committee. N. H.: grants from NIH, Quidel, and Sanofi; Honoraria for speaking at CME event at AAP. C. G. G.: grants from Campbell Alliance/Syneos Health, Sanofi, CDC, AHRQ, NIH, and FDA; consulting fees from Merck, Pfizer, and Sanofi-Pasteur. T. W. R.: grants from NIH, Department of Defense and AbbVie; consulting fees for Cumberland Pharmaceuticals, Inc. and Cytovale, Inc.; DSMB for Sanofi, Inc.; Immediate Past President—ASPEN; Stock in Cumberland Pharmaceuticals, Inc. for consulting work. W. B. S.: NIH training grants. C. J. L.: grants from NIH, Department of Defense; CDC; bioMerieux; Entegrion, Inc.; Endpoint Health; AbbVie; Patents for risk stratification in sepsis and septic shock issued to Cincinnati Children’s Hospital Medical Center; DSMBs for clinical trials for Study Principal Investigators; Association for Clinical and Translational Science (Executive Committee, Immediate Past President, and Board of Directors); stock options in Bioscape Digita. 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: The study objective was to evaluate 2- and 3-dose coronavirus disease 2019 (COVID-19) mRNA vaccine effectiveness (VE) in preventing COVID-19 hospitalization among adult solid organ transplant (SOT) recipients., Methods: We conducted a 21-site case-control analysis of 10 425 adults hospitalized in March to December 2021. Cases were hospitalized with COVID-19; controls were hospitalized for an alternative diagnosis (severe acute respiratory syndrome coronavirus 2-negative). Participants were classified as follows: SOT recipient (n = 440), other immunocompromising condition (n = 1684), or immunocompetent (n = 8301). The VE against COVID-19-associated hospitalization was calculated as 1-adjusted odds ratio of prior vaccination among cases compared with controls., Results: Among SOT recipients, VE was 29% (95% confidence interval [CI], -19% to 58%) for 2 doses and 77% (95% CI, 48% to 90%) for 3 doses. Among patients with other immunocompromising conditions, VE was 72% (95% CI, 64% to 79%) for 2 doses and 92% (95% CI, 85% to 95%) for 3 doses. Among immunocompetent patients, VE was 88% (95% CI, 87% to 90%) for 2 doses and 96% (95% CI, 83% to 99%) for 3 doses., Conclusions: Effectiveness of COVID-19 mRNA vaccines was lower for SOT recipients than immunocompetent adults and those with other immunocompromising conditions. Among SOT recipients, vaccination with 3 doses of an mRNA vaccine led to substantially greater protection than 2 doses., 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. J. H. K. reports grant support from National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (1K23 AI137321-01A1). M. G. reports grant support from CDC, CDC-Abt, CDC-Westat, and Janssen and a role as the Co-Chair of the Infectious Diseases and Immunization Committee, Texas Pediatric Society, Texas Chapter of American Academy of Pediatrics (AAP). H. K. T. reports a grant from CDC. A. A. G. reports grant support from CDC, NIH, US Department of Defense (DOD), AbbVie, and Faron Pharmaceuticals. T. M. reports payments as a panelist for the Society of Hospital Medicine Updates in Heart Failure (August 25, 2021) and as a board member of the Scott & White Clinic Physicians Board of Directors. D. J. D. reports grant support from NIH/National Institute of General Medical Sciences (T32GM135169). J. D. C. reports grants from the NIH and DOD. K. W. G. reports grant support as a NECTAR Executive Committee member ACTIV-4HT. D. C. F. reports consultant fees from Cytovale and membership on a Medpace Data Safety Monitoring Board (DSMB). D. N. H. reports a contract from CDC and grant support from National Heart, Lung, and Blood Institute (NHLBI) for participation in the ACTIV4d-Host Tissue Trial. M. C. E. reports talks on nutrition in COVID pneumonia at ASPEN conference sponsored by Abbott Laboratories. M. N. G. reports grant support from the CDC, funding from NHLBI and Agency for Healthcare Research and Quality (AHRQ), and fees from Endpoint for participating on a scientific advisory panel, payment for Medicine Grand Rounds at Westchester Medical Center, travel support for attending the ATS Board of Directors meeting, and participation on a DSMB for Regeneron and REPLINISH trial. N. J. J. reports grants from the NIH, DOD, and Medic One Foundation, payment for expert testimony from the Washington Department of Health, participation on DSMBs for Opticyte Inc., Multi-Center, Randomized Control Trial to Study the Effectiveness of Hyperbaric Oxygen for COVID-19 patients with Moderate to Severe Hypoxemia (NCT04619719), and Remote Ischemic Conditioning to Enhance Resuscitation (RICE) Pilot (NCT04265807), and participation as Chair of the ACEP Critical Care Section. I. D. P. reports grants from the CDC, NIH, Janssen Pharmaceuticals, and Intermountain Research & Medical Foundation, institutional fees from Asahi Kasei Pharma and from Regeneron Pharmaceuticals. S. M. B. reports grants from the CDC, NIH, and DOD, 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. K. reports grants from the NIH, Ely Lily, United Therapeutics, Johnson & Johnson, BOA Medical, and 4D Medical. A. D. reports funding as the Center PI for PETAL network through NHLBI grant and for participation on a steering committee for ALung technologies. J. G. W. reports grant support from NIH/NHLBI for ACTIV-3 and ACTIV-4 trials and membership on the American Board of Internal Medicine Critical Care Exam Committee. S. Y. C. reports payment as a speaker for La Jolla Pharmaceuticals and consultant fees for PureTech Health and Kiniska Pharmaceuticals. H. M. B. reports grants from the CDC. A. S. L. reports grants from the CDC, NIH, and Burroughs Wellcome Fund, consultant fees from Sanofi, and fees from Roche for membership on a trial steering committee. N. H. reports grants from the CDC, NIH, Sanofi, and Quidel and honoraria for speaking at Continuing Medical Education event at AAP. J. D. C. reports grant support from the CDC. C. G. G. reports consultant fees from Pfizer, Merck, and Sanofi-Pasteur and grants from Campbell Alliance/Syneos Health, CDC, NIH, US Food and Drug Administration, AHRQ, and Sanofi. T. W. R. reports grants from the NIH, DOD, and AbbVie, personal fees from Cumberland Pharmaceuticals as the Director of Medical Affairs, consultant fees from Cytovale, Inc., personal fees from Sanofi, Inc. for serving as a DSMB board member, a role as the Immediate Past President of the American Society of Parenteral and Enteral Nutrition (ASPEN), and stock from Cumberland Pharmaceuticals for consulting work. C J. L. reports grants/contracts from the CDC, NIH, DOD, bioMerieux, Endpoint LLC, Entegrion, Inc., and AbbVie, a patent issued to Cincinnati Children’s Hospital Medical Center for risk stratification in sepsis and septic shock, participation on DSMBS for Study Principal Investigators, roles on the Executive Committee, Immediate Past President, Member, Board of Directors for the Association of Clinical and Translational Science, and stock options in Bioscape Digita. W. H. S. reports grant funding from the CDC for this 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., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objectives: To evaluate risk factors for postdischarge sequelae in children and adolescents hospitalized for acute coronavirus disease 2019 (COVID-19) or multisystem inflammatory syndrome in children (MIS-C)., Methods: Multicenter prospective cohort study conducted in 25 United States pediatric hospitals. Patients <21-years-old, hospitalized May 2020 to May 2021 for acute COVID-19 or MIS-C with follow-up 2 to 4 months after admission. We assessed readmissions, persistent symptoms or activity impairment, and new morbidities. Multivariable regression was used to calculate adjusted risk ratios (aRR) and 95% confidence intervals (CI)., Results: Of 358 eligible patients, 2 to 4 month survey data were available for 119 of 155 (76.8%) with acute COVID-19 and 160 of 203 (78.8%) with MIS-C. Thirteen (11%) patients with acute COVID-19 and 12 (8%) with MIS-C had a readmission. Thirty-two (26.9%) patients with acute COVID-19 had persistent symptoms (22.7%) or activity impairment (14.3%) and 48 (30.0%) with MIS-C had persistent symptoms (20.0%) or activity impairment (21.3%). For patients with acute COVID-19, persistent symptoms (aRR, 1.29 [95% CI, 1.04-1.59]) and activity impairment (aRR, 1.37 [95% CI, 1.06-1.78]) were associated with more organ systems involved. Patients with MIS-C and pre-existing respiratory conditions more frequently had persistent symptoms (aRR, 3.09 [95% CI, 1.55-6.14]) and those with obesity more frequently had activity impairment (aRR, 2.52 [95% CI, 1.35-4.69]). New morbidities were infrequent (9% COVID-19, 1% MIS-C)., Conclusions: Over 1 in 4 children hospitalized with acute COVID-19 or MIS-C experienced persistent symptoms or activity impairment for at least 2 months. Patients with MIS-C and respiratory conditions or obesity are at higher risk of prolonged recovery.

The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in the emergence of new variant lineages that have exacerbated the COVID-19 pandemic. Some of those variants were designated as variants of concern/interest (VOC/VOI) by national or international authorities based on many factors including their potential impact on vaccine-mediated protection from disease. To ascertain and rank the risk of VOCs and VOIs, we analyze the ability of 14 variants (614G, Alpha, Beta, Gamma, Delta, Epsilon, Zeta, Eta, Theta, Iota, Kappa, Lambda, Mu, and Omicron) to escape from mRNA vaccine-induced antibodies. The variants show differential reductions in neutralization and replication by post-vaccination sera. Although the Omicron variant (BA.1, BA.1.1, and BA.2) shows the most escape from neutralization, sera collected after a third dose of vaccine (booster sera) retain moderate neutralizing activity against that variant. Therefore, vaccination remains an effective strategy during the COVID-19 pandemic., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The Omicron variant (B.1.1.529) of SARS-CoV-2, the virus that causes COVID-19, was first identified in the United States in November 2021, with the BA.1 sublineage (including BA.1.1) causing the largest surge in COVID-19 cases to date. Omicron sublineages BA.2 and BA.2.12.1 emerged later and by late April 2022, accounted for most cases.* Estimates of COVID-19 vaccine effectiveness (VE) can be reduced by newly emerging variants or sublineages that evade vaccine-induced immunity (1), protection from previous SARS-CoV-2 infection in unvaccinated persons (2), or increasing time since vaccination (3). Real-world data comparing VE during the periods when the BA.1 and BA.2/BA.2.12.1 predominated (BA.1 period and BA.2/BA.2.12.1 period, respectively) are limited. The VISION network † examined 214,487 emergency department/urgent care (ED/UC) visits and 58,782 hospitalizations with a COVID-19-like illness § diagnosis among 10 states during December 18, 2021-June 10, 2022, to evaluate VE of 2, 3, and 4 doses of mRNA COVID-19 vaccines (BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]) compared with no vaccination among adults without immunocompromising conditions. VE against COVID-19-associated hospitalization 7-119 days and ≥120 days after receipt of dose 3 was 92% (95% CI = 91%-93%) and 85% (95% CI = 81%-89%), respectively, during the BA.1 period, compared with 69% (95% CI = 58%-76%) and 52% (95% CI = 44%-59%), respectively, during the BA.2/BA.2.12.1 period. Patterns were similar for ED/UC encounters. Among adults aged ≥50 years, VE against COVID-19-associated hospitalization ≥120 days after receipt of dose 3 was 55% (95% CI = 46%-62%) and ≥7 days (median = 27 days) after a fourth dose was 80% (95% CI = 71%-85%) during BA.2/BA.2.12.1 predominance. Immunocompetent persons should receive recommended COVID-19 booster doses to prevent moderate to severe COVID-19, including a first booster dose for all eligible persons and second booster dose for adults aged ≥50 years at least 4 months after an initial booster dose. Booster doses should be obtained immediately when persons become eligible. ¶ ., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Stephanie A. Irving reports institutional support from Westat. Nicola P. Klein reports institutional support from Pfizer, Merck, GlaxoSmithKline, Sanofi Pasteur, and Protein Science, unrelated to the current work, and institutional support from Pfizer for COVID-19 vaccine clinical trials. Allison L. Naleway reports institutional support from Pfizer for a study of meningococcal B vaccine safety during pregnancy, unrelated to the current work. Charlene McEvoy reports institutional support from AstraZeneca for an AZD1222 COVID-19 vaccine trial. Suchitra Rao reports grant support from GlaxoSmithKline and Biofire Diagnostics. No other potential conflicts of interest were disclosed.

Background: We sought to assess whether persistent COVID-19 symptoms beyond 6 months (Long-COVID) among patients with mild COVID-19 is associated with poorer health status, quality of life, and psychological distress., Methods: This was a multicenter prospective cohort study that included adult outpatients with acute COVID-19 from eight sites during 2-week sampling periods from April 1 and July 28, 2020. Participants were contacted 6-11 months after their first positive SARS-CoV-2 to complete a survey, which collected information on the severity of eight COVID-19 symptoms using a 4-point scale ranging from 0 (not present) to 3 (severe) at 1 month before COVID-19 (pre-illness) and at follow-up; the difference for each was calculated as an attributable persistent symptom severity score. A total attributable persistent COVID-19 symptom burden score was calculated by summing the attributable persistent severity scores for all eight symptoms. Outcomes measured at long-term follow-up comprised overall health status (EuroQol visual analogue scale), quality of life (EQ-5D-5L), and psychological distress (Patient Health Questionnaire-4). The association between the total attributable persistent COVID-19 burden score and each outcome was analyzed using multivariable proportional odds regression., Results: Of the 2092 outpatients with COVID-19, 436 (21%) responded to the survey. The median (IQR) attributable persistent COVID-19 symptom burden score was 2 (0, 4); higher scores were associated with lower overall health status (aOR 0.63; 95% CI: 0.57-0.69), lower quality of life (aOR: 0.65; 95%CI: 0.59-0.72), and higher psychological distress (aOR: 1.40; 95%CI, 1.28-1.54) after adjusting for age, race, ethnicity, education, and income., Conclusions: In participants with mild acute COVID-19, the burden of persistent symptoms was significantly associated with poorer long-term health status, poorer quality of life, and psychological distress., (© 2022 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 (omicron) variant, which led to increased U.S. hospitalizations for coronavirus disease 2019 (Covid-19), generated concern about immune evasion and the duration of protection from vaccines in children and adolescents., Methods: Using a case-control, test-negative design, we assessed vaccine effectiveness against laboratory-confirmed Covid-19 leading to hospitalization and against critical Covid-19 (i.e., leading to receipt of life support or to death). From July 1, 2021, to February 17, 2022, we enrolled case patients with Covid-19 and controls without Covid-19 at 31 hospitals in 23 states. We estimated vaccine effectiveness by comparing the odds of antecedent full vaccination (two doses of BNT162b2 messenger RNA vaccine) at least 14 days before illness among case patients and controls, according to time since vaccination for patients 12 to 18 years of age and in periods coinciding with circulation of B.1.617.2 (delta) (July 1, 2021, to December 18, 2021) and omicron (December 19, 2021, to February 17, 2022) among patients 5 to 11 and 12 to 18 years of age., Results: We enrolled 1185 case patients (1043 [88%] of whom were unvaccinated, 291 [25%] of whom received life support, and 14 of whom died) and 1627 controls. During the delta-predominant period, vaccine effectiveness against hospitalization for Covid-19 among adolescents 12 to 18 years of age was 93% (95% confidence interval [CI], 89 to 95) 2 to 22 weeks after vaccination and was 92% (95% CI, 80 to 97) at 23 to 44 weeks. Among adolescents 12 to 18 years of age (median interval since vaccination, 162 days) during the omicron-predominant period, vaccine effectiveness was 40% (95% CI, 9 to 60) against hospitalization for Covid-19, 79% (95% CI, 51 to 91) against critical Covid-19, and 20% (95% CI, -25 to 49) against noncritical Covid-19. During the omicron period, vaccine effectiveness against hospitalization among children 5 to 11 years of age was 68% (95% CI, 42 to 82; median interval since vaccination, 34 days)., Conclusions: BNT162b2 vaccination reduced the risk of omicron-associated hospitalization by two thirds among children 5 to 11 years of age. Although two doses provided lower protection against omicron-associated hospitalization than against delta-associated hospitalization among adolescents 12 to 18 years of age, vaccination prevented critical illness caused by either variant. (Funded by the Centers for Disease Control and Prevention.)., (Copyright © 2022 Massachusetts Medical Society.)

The prevalence and clinical relevance of human herpesvirus-6 (HHV-6) detection in cerebrospinal fluid (CSF) using multiplex polymerase chain reaction (PCR) testing in patients with suspected meningoencephalitis in high human immunodeficiency virus-prevalence African settings are not known. We describe the clinical and laboratory characteristics of 13 patients with HHV-6 CSF PCR positivity in Botswana., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Vaccine effectiveness (VE) against COVID-19 hospitalization was evaluated among immunocompetent adults (≥18 years) during March-August 2021 using a case-control design. Among 1669 hospitalized COVID-19 cases (11% fully vaccinated) and 1950 RT-PCR-negative controls (54% fully vaccinated), VE was 96% (95% confidence interval [CI], 93%-98%) among patients with no chronic medical conditions and 83% (95% CI, 76%-88%) among patients with ≥ 3 categories of conditions. VE was similar between those aged 18-64 years versus ≥65 years (P > .05). VE against severe COVID-19 was very high among adults without chronic conditions and lessened with increasing comorbidity burden., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)

Background: As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination coverage increases in the United States, there is a need to understand the real-world effectiveness against severe coronavirus disease 2019 (COVID-19) and among people at increased risk for poor outcomes., Methods: In a multicenter case-control analysis of US adults hospitalized March 11-May 5, 2021, we evaluated vaccine effectiveness to prevent COVID-19 hospitalizations by comparing odds of prior vaccination with a messenger RNA (mRNA) vaccine (Pfizer-BioNTech or Moderna) between cases hospitalized with COVID-19 and hospital-based controls who tested negative for SARS-CoV-2., Results: Among 1212 participants, including 593 cases and 619 controls, median age was 58 years, 22.8% were Black, 13.9% were Hispanic, and 21.0% had immunosuppression. SARS-CoV-2 lineage B0.1.1.7 (Alpha) was the most common variant (67.9% of viruses with lineage determined). Full vaccination (receipt of 2 vaccine doses ≥14 days before illness onset) had been received by 8.2% of cases and 36.4% of controls. Overall vaccine effectiveness was 87.1% (95% confidence interval [CI], 80.7-91.3). Vaccine effectiveness was similar for Pfizer-BioNTech and Moderna vaccines, and highest in adults aged 18-49 years (97.4%; 95% CI, 79.3-9.7). Among 45 patients with vaccine-breakthrough COVID hospitalizations, 44 (97.8%) were ≥50 years old and 20 (44.4%) had immunosuppression. Vaccine effectiveness was lower among patients with immunosuppression (62.9%; 95% CI,20.8-82.6) than without immunosuppression (91.3%; 95% CI, 85.6-94.8)., Conclusion: During March-May 2021, SARS-CoV-2 mRNA vaccines were highly effective for preventing COVID-19 hospitalizations among US adults. SARS-CoV-2 vaccination was beneficial for patients with immunosuppression, but effectiveness was lower in the immunosuppressed population., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Early in the COVID-19 pandemic, the World Health Organization stressed the importance of daily clinical assessments of infected patients, yet current approaches frequently consider cross-sectional timepoints, cumulative summary measures, or time-to-event analyses. Statistical methods are available that make use of the rich information content of longitudinal assessments. We demonstrate the use of a multistate transition model to assess the dynamic nature of COVID-19-associated critical illness using daily evaluations of COVID-19 patients from 9 academic hospitals. We describe the accessibility and utility of methods that consider the clinical trajectory of critically ill COVID-19 patients., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Dr Ginde reports grants from CDC, during the conduct of the study; grants from NIH, grants from Department of Defense, grants from AbbVie, grants from Faron Pharmaceuticals, outside the submitted work. Matthew C. Exline reports talks on nutrition in COVID pneumonia at APEN conference sponsored by Abbott Labs. Akram Khan reports grants from United Therapeutics, Johnson & Johnson, 4D Medical, Lung LLC, and Reata Pharmaceuticals. D. Clark Files reports consultant fees from Cytovale and membership on a Medpace Data Safety Monitoring Board (DSMB). Dr Rice reports grants from Centers for Disease Control (CDC), during the conduct of the study; personal fees from Cumberland Pharmaceuticals, Inc., personal fees from Cytovale, Inc., personal fees from Sanofi, Inc., outside the submitted work. Jonathan D. Casey reports a grant (N23HL153584) from the National Institutes of Health (NIH). Daniel J. Henning reports consulting fees from Cytovale and Opticyte. Samuel M. Brown reports fees from Hamilton for chairing a DSMB, and institutional fees from Faron, Sedana, and Janssen; grants from Sedana, Janssen, NIH, and the Department of Defense (DoD); book royalties from Oxford University and Brigham Young University; and personal fees from New York University for service on a DSMB. Wesley H. Self reports grant funding from CDC for this work; grants and consultant fees from Merck outside this work and consultant fees from Aerpio Pharmaceuticals outside this work. Christopher J. Lindsell reports grants from NIH, DoD, and the Marcus Foundation; organizational contract fees from bioMerieux, Endpoint LLC, and Entegrion, Inc.; and a patent issued to Cincinnati Children’s Hospital Medical Center for risk stratification in sepsis and septic shock. No other potential conflicts of interest were disclosed., (© The Author(s) 2022.)

COVID-19 mRNA vaccines (BNT162b2 [Pfizer-BioNTech] and mRNA-1273 [Moderna]) are effective at preventing COVID-19-associated hospitalization (1-3). However, how well mRNA vaccines protect against the most severe outcomes of these hospitalizations, including invasive mechanical ventilation (IMV) or death is uncertain. Using a case-control design, mRNA vaccine effectiveness (VE) against COVID-19-associated IMV and in-hospital death was evaluated among adults aged ≥18 years hospitalized at 21 U.S. medical centers during March 11, 2021-January 24, 2022. During this period, the most commonly circulating variants of SARS-CoV-2, the virus that causes COVID-19, were B.1.1.7 (Alpha), B.1.617.2 (Delta), and B.1.1.529 (Omicron). Previous vaccination (2 or 3 versus 0 vaccine doses before illness onset) in prospectively enrolled COVID-19 case-patients who received IMV or died within 28 days of hospitalization was compared with that among hospitalized control patients without COVID-19. Among 1,440 COVID-19 case-patients who received IMV or died, 307 (21%) had received 2 or 3 vaccine doses before illness onset. Among 6,104 control-patients, 4,020 (66%) had received 2 or 3 vaccine doses. Among the 1,440 case-patients who received IMV or died, those who were vaccinated were older (median age = 69 years), more likely to be immunocompromised* (40%), and had more chronic medical conditions compared with unvaccinated case-patients (median age = 55 years; immunocompromised = 10%; p<0.001 for both). VE against IMV or in-hospital death was 90% (95% CI = 88%-91%) overall, including 88% (95% CI = 86%-90%) for 2 doses and 94% (95% CI = 91%-96%) for 3 doses, and 94% (95% CI = 88%-97%) for 3 doses during the Omicron-predominant period. COVID-19 mRNA vaccines are highly effective in preventing COVID-19-associated death and respiratory failure treated with IMV. CDC recommends that all persons eligible for vaccination get vaccinated and stay up to date with COVID-19 vaccination (4)., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Samuel M. Brown reports personal fees from Hamilton ventilators, and grants from the National Institutes of Health (NIH) and the U.S. Department of Defense (DoD). Jonathan D. Casey reports grants from the NIH and DoD. Steven Y. Chang was a speaker for La Jolla Pharmaceuticals in 2018, consulted for PureTech Health in 2020, and consulted for Kiniska Pharmaceuticals in December 2021. David J. Douin reports a grant from NIH/National Institute of General Medical Sciences. Abhijit Duggal reports grants from NIH and participation on a Steering Committee for ALung Technologies. Matthew C. Exline reports support from Abbott Labs for sponsored talks. D. Clark Files reports personal consultant fees from Cytovale and membership on a data and safety monitoring board (DSMB) from Medpace. Anne E. Frosch reports grants from NIH/National Institute of Allergy and Infectious Diseases (NIAID), NIH/National Heart, Lung, and Blood Institute (NHLBI), and NIH/INSIGHT/ICC. Manjusha Gaglani reports grants from Abt Associates, Westat, and Janssen. Adit A. Ginde reports grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals. Michelle N. Gong reports grants from NIH and the Agency for Healthcare Research and Quality (AHRQ), and DSMB membership fees from Regeneron, outside the submitted work. Carlos G. Grijalva reports consultancy fees from Pfizer, Merck, and Sanofi-Pasteur; grants from Campbell Alliance/Syneos Health, NIH, the Food and Drug Administration, AHRQ, and Sanofi. David N. Hager reports grants from NIH/NHLBI. Natasha Halasa reports grants and nonfinancial support from Sanofi, and grants from Quidel and NIH. Nicholas J. Johnson reports grants from NIH, DoD, and Medic One Foundation. Akram Khan reports grants from United Therapeutics, Johnson & Johnson, and Eli Lilly. Jennie H. Kwon reports grants from NIH/NIAID. Adam S. Lauring reports personal fees from Sanofi and Roche, and grants from NIH and Burroughs Wellcome Fund. Christopher J. Lindsell reports grants from NIH, DoD, and the Marcus Foundation; contract fees from bioMerieux, Endpoint Health, Entegrion Inc, and AbbVie; and a patent for risk stratification in sepsis and septic shock. Emily T. Martin reports grants from Merck. Arnold S. Monto reports a grant from NIH. Ithan D. Peltan reports grants from NIH, Janssen Pharmaceuticals, and Intermountain Research and Medical Foundation, and institutional support from Asahi Kasei Pharma and Regeneron. Todd W. Rice reports grants from NIH, DoD, and AbbVie and personal fees from Cumberland Pharmaceuticals, Inc., and Cytovale, Inc. No other potential conflicts of interest were disclosed.

COVID-19 mRNA vaccines (BNT162b2 [Pfizer-BioNTech] and mRNA-1273 [Moderna]) provide protection against infection with SARS-CoV-2, the virus that causes COVID-19, and are highly effective against COVID-19-associated hospitalization among eligible persons who receive 2 doses (1,2). However, vaccine effectiveness (VE) among persons with immunocompromising conditions* is lower than that among immunocompetent persons (2), and VE declines after several months among all persons (3). On August 12, 2021, the Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for a third mRNA vaccine dose as part of a primary series ≥28 days after dose 2 for persons aged ≥12 years with immunocompromising conditions, and, on November 19, 2021, as a booster dose for all adults aged ≥18 years at least 6 months after dose 2, changed to ≥5 months after dose 2 on January 3, 2022 (4,5,6). Among 2,952 adults (including 1,385 COVID-19 case-patients and 1,567 COVID-19-negative controls) hospitalized at 21 U.S. hospitals during August 19-December 15, 2021, effectiveness of mRNA vaccines against COVID-19-associated hospitalization was compared between adults eligible for but who had not received a third vaccine dose (1,251) and vaccine-eligible adults who received a third dose ≥7 days before illness onset (312). Among 1,875 adults without immunocompromising conditions (including 1,065 [57%] unvaccinated, 679 [36%] 2-dose recipients, and 131 [7%] 3-dose [booster] recipients), VE against COVID-19 hospitalization was higher among those who received a booster dose (97%; 95% CI = 95%-99%) compared with that among 2-dose recipients (82%; 95% CI = 77%-86%) (p <0.001). Among 1,077 adults with immunocompromising conditions (including 324 [30%] unvaccinated, 572 [53%] 2-dose recipients, and 181 [17%] 3-dose recipients), VE was higher among those who received a third dose to complete a primary series (88%; 95% CI = 81%-93%) compared with 2-dose recipients (69%; 95% CI = 57%-78%) (p <0.001). Administration of a third COVID-19 mRNA vaccine dose as part of a primary series among immunocompromised adults, or as a booster dose among immunocompetent adults, provides improved protection against COVID-19-associated hospitalization., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Samuel M. Brown reports personal fees from Hamilton, institutional fees from Faron Pharmaceuticals and Sedana, grants from Janssen, the National Institutes of Health (NIH), the Department of Defense (DoD), book royalties from Oxford University and Brigham Young University, outside the submitted work. Steven Y. Chang was a speaker for La Jolla Pharmaceuticals in 2018 and consulted for PureTech Health in 2020. James D. Chappell reports grants from NIH during the conduct of the study. Abhijit Duggal reports grants from NIH and participation on a steering committee for ALung Technologies, Inc., outside the submitted work. Matthew C. Exline reports support from Abbott Labs for sponsored talks, outside the submitted work. D. Clark Files reports personal consultant fees from Cytovale and is a data and safety monitoring board (DSMB) member from Medpace, outside the submitted work. Manjusha Gaglani reports grants from CDC-Vanderbilt University Medical Center for the submitted work, CDC-Abt Associates, CDC-Westat, Janssen and Pfizer, outside the submitted work. Adit A. Ginde reports grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals, outside the submitted work. Michelle N. Gong reports grants from NIH and the Agency for Healthcare Research and Quality (AHRQ), DSMB membership fees from Regeneron, outside the submitted work. Carlos G. Grijalva reports consultancy fees from Pfizer, Merck, and Sanofi-Pasteur; grants from Campbell Alliance/Syneos Health, NIH, the Food and Drug Administration, AHRQ, and Sanofi, outside the submitted work. David N. Hager reports salary support from Incyte Corporation and EMPACT Precision Medicine via Vanderbilt University Medical Center and grants from NHLBI, outside the submitted work. Natasha Halasa reports grants and nonfinancial support from Sanofi, and grants from Quidel outside the submitted work. Akram Khan reports grants from United Therapeutics, Johnson & Johnson, Ely Lilly, and GlaxoSmithKline, outside the submitted work. Adam S. Lauring reports personal fees from Sanofi and Roche, outside the submitted work. Christopher J. Lindsell reports grants from NIH, DoD, and the Marcus Foundation; contract fees from bioMerieux, Endpoint LLC, and Entegrion Inc, outside the submitted work; in addition, Dr. Lindsell has a patent for risk stratification in sepsis and septic shock issued. Emily T. Martin reports personal fees from Pfizer and grants from Merck, 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. Todd W. Rice reports personal fees from Cumberland Pharmaceuticals, Inc, Cytovale, Inc., and Sanofi, Inc., outside the submitted work. Wesley H. Self reports consulting fees from Aeprio Pharmaceuticals and Merck, outside the submitted work. No other potential conflicts of interest were disclosed.

At nine US hospitals that enrolled children hospitalized with acute respiratory illness (ARI) during 2015-2016 through 2017-2018 influenza seasons, 50% of children with ARI received clinician-initiated testing for influenza and 35% of cases went undiagnosed due to lack of clinician-initiated testing. Marked heterogeneity in testing practice was observed across sites., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

To test the hypothesis that relatively lower clot strength on thromboelastography maximum amplitude (MA) is associated with development of venous thromboembolism (VTE) in critically ill patients with COVID-19., Design: Prospective, observational cohort study., Setting: Tertiary care, academic medical center in Nashville, TN., Patients: Patients with acute respiratory failure from COVID-19 pneumonia admitted to the adult medical ICU without known VTE at enrollment., Interventions: None., Measurements and Main Results: Ninety-eight consecutive critically ill adults with laboratory-confirmed COVID-19 were enrolled. Thromboelastography parameters and conventional coagulation parameters were measured on days 0 (within 48 hr of ICU admission), 3, 5, and 7 after enrollment. The primary outcome was diagnosis of VTE with confirmed deep venous thrombosis and/or pulmonary embolism by clinical imaging or autopsy. Twenty-six patients developed a VTE. Multivariable regression controlling for antiplatelet exposure and anticoagulation dose with death as a competing risk found that lower MA was associated with increased risk of VTE. Each 1 mm increase in enrollment and peak MA was associated with an 8% and 14% decrease in the risk of VTE, respectively (enrollment MA: subdistribution hazard ratio [SHR], 0.92; 95% CI, 0.87-0.97; p = 0.003 and peak MA: SHR, 0.86; 95% CI, 0.81-0.91; p < 0.001). Lower enrollment platelet counts and fibrinogen levels were also associated with increased risk of VTE ( p = 0.002 and p = 0.01, respectively). Platelet count and fibrinogen level were positively associated with MA (multivariable model: adjusted R 2 = 0.51; p < 0.001)., Conclusions: When controlling for the competing risk of death, lower enrollment and peak MA were associated with increased risk of VTE. Lower platelet counts and fibrinogen levels at enrollment were associated with increased risk of VTE. The association of diminished MA, platelet counts, and fibrinogen with VTE may suggest a relative consumptive coagulopathy in critically ill patients with COVID-19., Competing Interests: Dr. Marvi was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH) under Award Number R38HL143619. Dr. Grijalva was supported in part by National Institute for Allergy and Infectious Diseases K24 AI148459; he has received unrelated consulting fees from Pfizer, Sanofi, and Merck; and he has received research support from Sanofi-Pasteur, Campbell Alliance, the Centers for Disease Control and Prevention, NIH, The Food and Drug Administration, and the Agency for Healthcare Research and Quality. Dr. Rice is supported in part by the NIH U01HL123009; he has received unrelated consulting fees from Cumberland Pharmaceuticals, Cytovale, and Sanofi. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Cryptococcal antigen (CrAg) screening in individuals with advanced HIV reduces cryptococcal meningitis (CM) cases and deaths. The World Health Organization recently recommended increasing screening thresholds from CD4 ≤100 cells/µL to ≤200 cells/µL. CrAg screening at CD4 ≤100 cells/µL is cost-effective; however, the cost-effectiveness of screening patients with CD4 101-200 cells/µL requires evaluation. Methods: Using a decision analytic model with Botswana-specific cost and clinical estimates, we evaluated CrAg screening and treatment among individuals with CD4 counts of 101-200 cells/µL. We estimated the number of CM cases and deaths nationally and treatment costs without screening. For screening we modeled the number of CrAg tests performed, number of CrAg-positive patients identified, proportion started on pre-emptive fluconazole, CM cases and deaths. Screening and treatment costs were estimated and cost per death averted or disability-adjusted life year (DALY) saved compared with no screening. Results: Without screening, we estimated 142 CM cases and 85 deaths annually among individuals with CD4 101-200 cells/µL, with treatment costs of $368,982. With CrAg screening, an estimated 33,036 CrAg tests are performed, and 48 deaths avoided (1,017 DALYs saved).  While CrAg screening costs an additional $155,601, overall treatment costs fall by $39,600 (preemptive and hospital-based CM treatment), yielding a net increase of $116,001. Compared to no screening, high coverage of CrAg screening and pre-emptive treatment for CrAg-positive individuals in this population avoids one death for $2440 and $114 per DALY saved. In sensitivity analyses assuming a higher proportion of antiretroviral therapy (ART)-naïve patients (75% versus 15%), cost per death averted was $1472; $69 per DALY saved. Conclusions: CrAg screening for individuals with CD4 101-200 cells/µL was estimated to have a modest impact, involve additional costs, and be less cost-effective than screening populations with CD4 counts ≤100 cells/µL. Additional CrAg screening costs must be considered against other health system priorities., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Tenforde MW et al.)

Background: At the start of the 2019-2020 influenza season, concern arose that circulating B/Victoria viruses of the globally emerging clade V1A.3 were antigenically drifted from the strain included in the vaccine. Intense B/Victoria activity was followed by circulation of genetically diverse A(H1N1)pdm09 viruses that were also antigenically drifted. We measured vaccine effectiveness (VE) in the United States against illness from these emerging viruses., Methods: We enrolled outpatients aged ≥6 months with acute respiratory illness at 5 sites. Respiratory specimens were tested for influenza by reverse-transcriptase polymerase chain reaction (RT-PCR). Using the test-negative design, we determined influenza VE by virus subtype/lineage and genetic subclades by comparing odds of vaccination in influenza cases versus test-negative controls., Results: Among 8845 enrollees, 2722 (31%) tested positive for influenza, including 1209 (44%) for B/Victoria and 1405 (51%) for A(H1N1)pdm09. Effectiveness against any influenza illness was 39% (95% confidence interval [CI]: 32-44), 45% (95% CI: 37-52) against B/Victoria and 30% (95% CI: 21-39) against A(H1N1)pdm09-associated illness. Vaccination offered no protection against A(H1N1)pdm09 viruses with antigenically drifted clade 6B.1A 183P-5A+156K HA genes (VE 7%; 95% CI: -14 to 23%) which predominated after January., Conclusions: Vaccination provided protection against influenza illness, mainly due to infections from B/Victoria viruses. Vaccine protection against illness from A(H1N1)pdm09 was lower than historically observed effectiveness of 40%-60%, due to late-season vaccine mismatch following emergence of antigenically drifted viruses. The effect of drift on vaccine protection is not easy to predict and, even in drifted years, significant protection can be observed., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

Influenza vaccination and antiviral therapeutics may attenuate disease, decreasing severity of illness in vaccinated and treated persons. Standardized assessment tools, definitions of disease severity, and clinical endpoints would support characterizing the attenuating effects of influenza vaccines and antivirals. We review potential clinical parameters and endpoints that may be useful for ordinal scales evaluating attenuating effects of influenza vaccines and antivirals in hospital-based studies. In studies of influenza and community-acquired pneumonia, common physiologic parameters that predicted outcomes such as mortality, ICU admission, complications, and duration of stay included vital signs (hypotension, tachypnea, fever, hypoxia), laboratory results (blood urea nitrogen, platelets, serum sodium), and radiographic findings of infiltrates or effusions. Ordinal scales based on these parameters may be useful endpoints for evaluating attenuating effects of influenza vaccines and therapeutics. Factors such as clinical and policy relevance, reproducibility, and specificity of measurements should be considered when creating a standardized ordinal scale for assessment.

Importance: A comprehensive understanding of the benefits of COVID-19 vaccination requires consideration of disease attenuation, determined as whether people who develop COVID-19 despite vaccination have lower disease severity than unvaccinated people., Objective: To evaluate the association between vaccination with mRNA COVID-19 vaccines-mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech)-and COVID-19 hospitalization, and, among patients hospitalized with COVID-19, the association with progression to critical disease., Design, Setting, and Participants: A US 21-site case-control analysis of 4513 adults hospitalized between March 11 and August 15, 2021, with 28-day outcome data on death and mechanical ventilation available for patients enrolled through July 14, 2021. Date of final follow-up was August 8, 2021., Exposures: COVID-19 vaccination., Main Outcomes and Measures: Associations were evaluated between prior vaccination and (1) hospitalization for COVID-19, in which case patients were those hospitalized for COVID-19 and control patients were those hospitalized for an alternative diagnosis; and (2) disease progression among patients hospitalized for COVID-19, in which cases and controls were COVID-19 patients with and without progression to death or mechanical ventilation, respectively. Associations were measured with multivariable logistic regression., Results: Among 4513 patients (median age, 59 years [IQR, 45-69]; 2202 [48.8%] women; 23.0% non-Hispanic Black individuals, 15.9% Hispanic individuals, and 20.1% with an immunocompromising condition), 1983 were case patients with COVID-19 and 2530 were controls without COVID-19. Unvaccinated patients accounted for 84.2% (1669/1983) of COVID-19 hospitalizations. Hospitalization for COVID-19 was significantly associated with decreased likelihood of vaccination (cases, 15.8%; controls, 54.8%; adjusted OR, 0.15; 95% CI, 0.13-0.18), including for sequenced SARS-CoV-2 Alpha (8.7% vs 51.7%; aOR, 0.10; 95% CI, 0.06-0.16) and Delta variants (21.9% vs 61.8%; aOR, 0.14; 95% CI, 0.10-0.21). This association was stronger for immunocompetent patients (11.2% vs 53.5%; aOR, 0.10; 95% CI, 0.09-0.13) than immunocompromised patients (40.1% vs 58.8%; aOR, 0.49; 95% CI, 0.35-0.69) (P < .001) and weaker at more than 120 days since vaccination with BNT162b2 (5.8% vs 11.5%; aOR, 0.36; 95% CI, 0.27-0.49) than with mRNA-1273 (1.9% vs 8.3%; aOR, 0.15; 95% CI, 0.09-0.23) (P < .001). Among 1197 patients hospitalized with COVID-19, death or invasive mechanical ventilation by day 28 was associated with decreased likelihood of vaccination (12.0% vs 24.7%; aOR, 0.33; 95% CI, 0.19-0.58)., Conclusions and Relevance: Vaccination with an mRNA COVID-19 vaccine was significantly less likely among patients with COVID-19 hospitalization and disease progression to death or mechanical ventilation. These findings are consistent with risk reduction among vaccine breakthrough infections compared with absence of vaccination.

Evaluations of vaccine effectiveness (VE) are important to monitor as coronavirus disease 2019 (COVID-19) vaccines are introduced in the general population. Research staff enrolled symptomatic participants seeking outpatient medical care for COVID-19-like illness or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing from a multisite network. VE was evaluated using the test-negative design. Among 236 SARS-CoV-2 nucleic acid amplification test-positive and 576 test-negative participants aged ≥16 years, the VE of messenger RNA vaccines against COVID-19 was 91% (95% confidence interval, 83%-95%) for full vaccination and 75% (55%-87%) for partial vaccination. Vaccination was associated with prevention of most COVID-19 cases among people seeking outpatient medical care., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)

Background: Experimental studies have shown that vaccination can reduce viral replication to attenuate progression of influenza-associated lower respiratory tract illness (LRTI). However, clinical studies are conflicting, possibly due to use of non-specific outcomes reflecting a mix of large and small airway LRTI lacking specificity for acute lung or organ injury., Methods: We developed a global ordinal scale to differentiate large and small airway LRTI in hospitalized adults with influenza using physiologic features and interventions (PFIs): vital signs, laboratory and radiographic findings, and clinical interventions. We reviewed the literature to identify common PFIs across 9 existing scales of pneumonia and sepsis severity. To characterize patients using this scale, we applied the scale to an antiviral clinical trial dataset where these PFIs were measured through routine clinical care in adults hospitalized with influenza-associated LRTI during the 2010-2013 seasons., Results: We evaluated 12 clinical parameters among 1020 adults; 210 (21%) had laboratory-confirmed influenza, with a median severity score of 4.5 (interquartile range, 2-8). Among influenza cases, median age was 63 years, 20% were hospitalized in the prior 90 days, 50% had chronic obstructive pulmonary disease, and 22% had congestive heart failure. Primary influencers of higher score included pulmonary infiltrates on imaging (48.1%), heart rate ≥110 beats/minute (41.4%), oxygen saturation <93% (47.6%) and respiratory rate >24 breaths/minute (21.0%). Key PFIs distinguishing patients with severity < or ≥8 (upper quartile) included infiltrates (27.1% vs 90.0%), temperature ≥ 39.1°C or <36.0°C (7.1% vs 27.1%), respiratory rate >24 breaths/minute (7.9% vs 47.1%), heart rate ≥110 beats/minute (29.3% vs 65.7%), oxygen saturation <90% (14.3% vs 31.4%), white blood cell count >15,000 (5.0% vs 27.2%), and need for invasive or non-invasive mechanical ventilation (2.1% vs 15.7%)., Conclusion: We developed a scale in adults hospitalized with influenza-associated LRTI demonstrating a broad distribution of physiologic severity which may be useful for future studies evaluating the disease attenuating effects of influenza vaccination or other therapeutics., Competing Interests: The authors have declared that no competing interests exist.

Background: Influenza vaccine effectiveness (VE) against a spectrum of severe disease, including critical illness and death, remains poorly characterized., Methods: We conducted a test-negative study in an intensive care unit (ICU) network at 10 US hospitals to evaluate VE for preventing influenza-associated severe acute respiratory infection (SARI) during the 2019-2020 season, which was characterized by circulation of drifted A/H1N1 and B-lineage viruses. Cases were adults hospitalized in the ICU and a targeted number outside the ICU (to capture a spectrum of severity) with laboratory-confirmed, influenza-associated SARI. Test-negative controls were frequency-matched based on hospital, timing of admission, and care location (ICU vs non-ICU). Estimates were adjusted for age, comorbidities, and other confounders., Results: Among 638 patients, the median (interquartile) age was 57 (44-68) years; 286 (44.8%) patients were treated in the ICU and 42 (6.6%) died during hospitalization. Forty-five percent of cases and 61% of controls were vaccinated, which resulted in an overall VE of 32% (95% CI: 2-53%), including 28% (-9% to 52%) against influenza A and 52% (13-74%) against influenza B. VE was higher in adults 18-49 years old (62%; 95% CI: 27-81%) than those aged 50-64 years (20%; -48% to 57%) and ≥65 years old (-3%; 95% CI: -97% to 46%) (P = .0789 for interaction). VE was significantly higher against influenza-associated death (80%; 95% CI: 4-96%) than nonfatal influenza illness., Conclusions: During a season with drifted viruses, vaccination reduced severe influenza-associated illness among adults by 32%. VE was high among young adults., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Multisystem inflammatory syndrome in children (MIS-C) consensus criteria were designed for maximal sensitivity and therefore capture patients with acute COVID-19 pneumonia., Methods: We performed unsupervised clustering on data from 1,526 patients (684 labeled MIS-C by clinicians) <21 years old hospitalized with COVID-19-related illness admitted between 15 March 2020 and 31 December 2020. We compared prevalence of assigned MIS-C labels and clinical features among clusters, followed by recursive feature elimination to identify characteristics of potentially misclassified MIS-C-labeled patients., Findings: Of 94 clinical features tested, 46 were retained for clustering. Cluster 1 patients ( N  = 498; 92% labeled MIS-C) were mostly previously healthy (71%), with mean age 7·2 ± 0·4 years, predominant cardiovascular (77%) and/or mucocutaneous (82%) involvement, high inflammatory biomarkers, and mostly SARS-CoV-2 PCR negative (60%). Cluster 2 patients ( N  = 445; 27% labeled MIS-C) frequently had pre-existing conditions (79%, with 39% respiratory), were similarly 7·4 ± 2·1 years old, and commonly had chest radiograph infiltrates (79%) and positive PCR testing (90%). Cluster 3 patients ( N  = 583; 19% labeled MIS-C) were younger (2·8 ± 2·0 y), PCR positive (86%), with less inflammation. Radiographic findings of pulmonary infiltrates and positive SARS-CoV-2 PCR accurately distinguished cluster 2 MIS-C labeled patients from cluster 1 patients., Interpretation: Using a data driven, unsupervised approach, we identified features that cluster patients into a group with high likelihood of having MIS-C. Other features identified a cluster of patients more likely to have acute severe COVID-19 pulmonary disease, and patients in this cluster labeled by clinicians as MIS-C may be misclassified. These data driven phenotypes may help refine the diagnosis of MIS-C., Competing Interests: All authors report receiving funding from the Centers for Disease Control and Prevention for the current study. AG reports receiving grants from the NIH outside of the submitted work. ABM reports receiving grants from the Francis Family Foundation and from the NIH/NICHD (K23HD096018) outside of the submitted work. CVH reports receiving consulting fees from DYNAMED and BIOFIRE outside of the submitted work. JES reports receiving grants from Merck outside of the submitted work. NBH reports receiving grants from Sanofi, Quidel, the NIH, and the CDC; consulting fees from Moderna; and an educational grant from Genetech outside of the submitted work. CMR reports receiving grants from the NIH/NHLBI (K23HL150244) outside of the submitted work. NZC reports receiving grants or contracts from Boston Children's Hospital and Cincinnati Children's Hospital and Medical Center outside of the submitted work. JCF reports receiving grants from the NIH outside of the submitted work. HD reports payments from Delex Pharma International Inc. outside of the submitted work. PMM reports receiving grants from the NIH and serving as a member of data safety monitoring board for the NIH supported KIDS-DOT trial outside of the submitted work. AGR reports receiving royalties from UpToDate outside of the submitted work. All other authors have nothing to declare., (© 2021 The Authors.)

Three COVID-19 vaccines are authorized or approved for use among adults in the United States (1,2). Two 2-dose mRNA vaccines, mRNA-1273 from Moderna and BNT162b2 from Pfizer-BioNTech, received Emergency Use Authorization (EUA) by the Food and Drug Administration (FDA) in December 2020 for persons aged ≥18 years and aged ≥16 years, respectively. A 1-dose viral vector vaccine (Ad26.COV2 from Janssen [Johnson & Johnson]) received EUA in February 2021 for persons aged ≥18 years (3). The Pfizer-BioNTech vaccine received FDA approval for persons aged ≥16 years on August 23, 2021 (4). Current guidelines from FDA and CDC recommend vaccination of eligible persons with one of these three products, without preference for any specific vaccine (4,5). To assess vaccine effectiveness (VE) of these three products in preventing COVID-19 hospitalization, CDC and collaborators conducted a case-control analysis among 3,689 adults aged ≥18 years who were hospitalized at 21 U.S. hospitals across 18 states during March 11-August 15, 2021. An additional analysis compared serum antibody levels (anti-spike immunoglobulin G [IgG] and anti-receptor binding domain [RBD] IgG) to SARS-CoV-2, the virus that causes COVID-19, among 100 healthy volunteers enrolled at three hospitals 2-6 weeks after full vaccination with the Moderna, Pfizer-BioNTech, or Janssen COVID-19 vaccine. Patients with immunocompromising conditions were excluded. VE against COVID-19 hospitalizations was higher for the Moderna vaccine (93%; 95% confidence interval [CI] = 91%-95%) than for the Pfizer-BioNTech vaccine (88%; 95% CI = 85%-91%) (p = 0.011); VE for both mRNA vaccines was higher than that for the Janssen vaccine (71%; 95% CI = 56%-81%) (all p<0.001). Protection for the Pfizer-BioNTech vaccine declined 4 months after vaccination. Postvaccination anti-spike IgG and anti-RBD IgG levels were significantly lower in persons vaccinated with the Janssen vaccine than the Moderna or Pfizer-BioNTech vaccines. Although these real-world data suggest some variation in levels of protection by vaccine, all FDA-approved or authorized COVID-19 vaccines provide substantial protection against COVID-19 hospitalization., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Wesley H. Self reports grants and consultant fees from Merck and consultant fees from Aerpio Pharmaceuticals. Adit A. Ginde reports grant support from AbbVie and Faron Pharmaceuticals. Jonathan D. Casey reports a grant (N23HL153584) from the National Institutes of Health (NIH). D. Clark Files reports consultant fees from Cytovale and membership on a Medpace Data Safety Monitoring Board (DSMB). David N. Hager reports salary support from Incyte Corporation, EMPACT Precision Medicine, and the Marcus Foundation. Michelle N. Gong reports grant support from NIH and the Agency for Healthcare Research and Quality (AHRQ) and fees for participating on a DSMB for Regeneron and for participating on a scientific advisory panel for Philips Healthcare. Daniel J. Henning reports consulting fees from Cytovale and Opticyte. Ithan D. Peltan reports grants from NIH and Janssen Pharmaceuticals, institutional fees from Asahi Kasei Pharma and from Regeneron. Samuel M. Brown reports fees from Hamilton for chairing a DSMB, and institutional fees from Faron, Sedana, and Janssen; grants from Sedana, Janssen, NIH, and the Department of Defense (DoD); book royalties from Oxford University and Brigham Young University; and personal fees from New York University for service on a DSMB. Emily T. Martin reports personal fees from Pfizer for unrelated work and a grant from Merck for unrelated work. Akram Khan reports grants from United Therapeutics, Johnson & Johnson, 4D Medical, Lung LLC, and Reata Pharmaceuticals. Arnold S. Monto reports consulting fees from Sanofi-Pasteur and Seqirus. Steven Y. Chang was a speaker for La Jolla Pharmaceuticals and a Consultant for PureTech Health. Jennie H. Kwon reports grant support from NIH. Matthew C. Exline reports talks on nutrition in COVID pneumonia at APEN conference sponsored by Abbott Labs. Natasha Halasa reports grants from Sanofi and Quidel. James D. Chappell reports a grant from the National Center for Advancing Translational Sciences, NIH. Adam S. Lauring reports consultant fees from Sanofi and fees from Roche for membership on a trial steering committee. Carlos G. Grijalva reports consultant fees from Pfizer, Merck, and Sanofi-Pasteur and grants from Campbell Alliance/Syneos Health, NIH, the Food and Drug Administration, AHRQ, and Sanofi. Todd W. Rice reports personal fees from Cumberland Pharmaceuticals, Inc., as the Director of Medical Affairs, consultant fees from Avisa Pharma, LLC; and DSMB membership fees from Sanofi. Christopher J. Lindsell reports grants from NIH, DoD, and the Marcus Foundation; organizational contract fees from bioMerieux, Endpoint LLC, and Entegrion, Inc.; and a patent issued to Cincinnati Children’s Hospital Medical Center for risk stratification in sepsis and septic shock. No other potential conflicts of interest were disclosed.

Background: Influenza causes significant morbidity and mortality and stresses hospital resources during periods of increased circulation. We evaluated the effectiveness of the 2019-2020 influenza vaccine against influenza-associated hospitalization in the United States., Methods: We included adults hospitalized with acute respiratory illness at 14 hospitals and tested for influenza viruses by reserve-transcription polymerase chain reaction. Vaccine effectiveness (VE) was estimated by comparing the odds of current-season influenza vaccination in test-positive influenza cases vs test-negative controls, adjusting for confounders. VE was stratified by age and major circulating influenza types along with A(H1N1)pdm09 genetic subgroups., Results: A total of 3116 participants were included, including 18% (n = 553) influenza-positive cases. Median age was 63 years. Sixty-seven percent (n = 2079) received vaccination. Overall adjusted VE against influenza viruses was 41% (95% confidence interval [CI], 27%-52%). VE against A(H1N1)pdm09 viruses was 40% (95% CI, 24%-53%) and 33% against B viruses (95% CI, 0-56%). Of the 2 major A(H1N1)pdm09 subgroups (representing 90% of sequenced H1N1 viruses), VE against one group (5A + 187A,189E) was 59% (95% CI, 34%-75%) whereas no VE was observed against the other group (5A + 156K) (-1% [95% CI, -61% to 37%])., Conclusions: In a primarily older population, influenza vaccination was associated with a 41% reduction in risk of hospitalized influenza illness., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

Introduction: Understanding patient factors associated with not being vaccinated is essential for successful implementation of influenza vaccination programs., Methods: We enrolled adults hospitalized with severe acute respiratory illness at 10 United States (US) hospitals during the 2019-2020 influenza season. We interviewed patients to collect data about influenza vaccination, sociodemographic characteristics, and vaccine perceptions., Results: Among 679 participants, 264 (38.9%) reported not receiving influenza vaccination. Among those not vaccinated, 135 (51.1%) reported choosing not to receive a vaccine because of perceived ineffectiveness (36.7%) or risk (14.4%) of influenza vaccination. Sociodemographic factors associated with not being vaccinated included no medical insurance (aOR = 6.42; 95% CI: 2.52-16.38) and being non-White or Hispanic (aOR = 1.54, 95% CI: 1.02-2.32)., Conclusions: Optimizing uptake of influenza vaccination in the US may be improved by educational programs regarding vaccine safety and effectiveness and enhancing vaccine access, particularly among non-White and Hispanic Americans and those without medical insurance., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Dr. Brown reports grants from CDC, during the conduct of the study; personal fees from Hamilton, other from Faron, other from Sedana, grants from Janssen, grants from NIH, grants from DoD, other from Oxford University, other from Brigham Young University, outside the submitted work. Dr. Grijalva reports other from Pfizer, other from Merck, other from Sanofi-Pasteur, grants from Campbell Alliance, grants from Centers for Disease Control and Prevention, grants from National Institutes of Health, grants from Food and Drug Administration, grants from Agency for Health Care Research and Quality, grants from Sanofi, outside the submitted work. Dr. Files reports grants from CDC, during the conduct of the study; personal fees from Cytovale, personal fees from Medpace, outside the submitted work. Dr. Lindsell reports grants from CDC, during the conduct of the study; grants from NIH, grants from DoD, grants from CDC, other from Entegrion Inc., other from Endpoint LLC, other from bioMerieux, grants from Marcus Foundation, outside the submitted work. The other authors declare no potential competing interests.]., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Real-world evaluations have demonstrated high effectiveness of vaccines against COVID-19-associated hospitalizations (1-4) measured shortly after vaccination; longer follow-up is needed to assess durability of protection. In an evaluation at 21 hospitals in 18 states, the duration of mRNA vaccine (Pfizer-BioNTech or Moderna) effectiveness (VE) against COVID-19-associated hospitalizations was assessed among adults aged ≥18 years. Among 3,089 hospitalized adults (including 1,194 COVID-19 case-patients and 1,895 non-COVID-19 control-patients), the median age was 59 years, 48.7% were female, and 21.1% had an immunocompromising condition. Overall, 141 (11.8%) case-patients and 988 (52.1%) controls were fully vaccinated (defined as receipt of the second dose of Pfizer-BioNTech or Moderna mRNA COVID-19 vaccines ≥14 days before illness onset), with a median interval of 65 days (range = 14-166 days) after receipt of second dose. VE against COVID-19-associated hospitalization during the full surveillance period was 86% (95% confidence interval [CI] = 82%-88%) overall and 90% (95% CI = 87%-92%) among adults without immunocompromising conditions. VE against COVID-19- associated hospitalization was 86% (95% CI = 82%-90%) 2-12 weeks and 84% (95% CI = 77%-90%) 13-24 weeks from receipt of the second vaccine dose, with no significant change between these periods (p = 0.854). Whole genome sequencing of 454 case-patient specimens found that 242 (53.3%) belonged to the B.1.1.7 (Alpha) lineage and 74 (16.3%) to the B.1.617.2 (Delta) lineage. Effectiveness of mRNA vaccines against COVID-19-associated hospitalization was sustained over a 24-week period, including among groups at higher risk for severe COVID-19; ongoing monitoring is needed as new SARS-CoV-2 variants emerge. To reduce their risk for hospitalization, all eligible persons should be offered COVID-19 vaccination., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Samuel M. Brown reports personal fees from Hamilton, institutional fees from Faron Pharmaceuticals and Sedana, grants from Janssen, the National Institutes of Health (NIH), and the Department of Defense (DoD), book royalties from Oxford University and Brigham Young University, outside the submitted work. Jonathan D. Casey reports grants from NIH, outside the submitted work. Steven Y. Chang was a speaker for La Jolla Pharmaceuticals in 2018 and consulted for PureTech Health in 2020. James D. Chappell reports grants from NIH during the conduct of the study. Matthew C. Exline reports support from Abbott Labs for sponsored talks, outside the submitted work. D. Clark Files reports personal consultant fees from Cytovale and is a data and safety monitoring board (DSMB) member from Medpace, outside the submitted work. Adit A. Ginde reports grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals, outside the submitted work. Michelle N. Gong reports grants from NIH and the Agency for Healthcare Research and Quality (AHRQ), DSMB membership fees from Regeneron, and personal fees from Philips Healthcare, outside the submitted work. Carlos G. Grijalva reports consultancy fees from Pfizer, Merck, and Sanofi-Pasteur; grants from Campbell Alliance/Syneos Health, NIH, the Food and Drug Administration, AHQR, and Sanofi, outside the submitted work. David N. Hager reports salary support from Incyte Corporation, the Marcus Foundation, and EMPACT Precision Medicine via Vanderbilt University Medical Center, outside the submitted work. Natasha Halasa reports grants and nonfinancial support from Sanofi, and Quidel outside the submitted work. Daniel J. Henning reports personal consultant fees from Cytovale and Opticyte. Akram Khan reports grants from United Therapeutics, Johnson & Johnson, 4D Medical, Lung LLC, and Reata Pharmaceuticals, outside the submitted work. Adam S. Lauring reports personal fees from Sanofi and Roche, outside the submitted work. Christopher J. Lindsell reports grants from NIH, DoD, and the Marcus Foundation; contract fees from bioMerieux, Endpoint LLC, and Entegrion Inc, outside the submitted work and has a patent for risk stratification in sepsis and septic shock issued. Emily T. Martin reports personal fees from Pfizer and grants from Merck, outside the submitted work. Arnold S. Monto reports consulting fees from Sanofi-Pasteur and Seqirus outside the submitted work. Ithan D. Peltan reports grants from NIH and Janssen Pharmaceuticals and institutional support from Asahi Kasei Pharma and Regeneron, outside the submitted work. Todd W. Rice reports personal fees from Cumberland Pharmaceuticals, Inc. and personal fees from Avisa Pharma, LLC and Sanofi, outside the submitted work. Wesley H. Self reports consulting fees from Aeprio Pharmaceuticals and Merck outside the submitted work. No other potential conflicts of interest were disclosed.

Background: Demonstration of influenza vaccine effectiveness (VE) against hospitalized illness in addition to milder outpatient illness may strengthen vaccination messaging. Our objective was to compare patient characteristics and VE between United States (US) inpatient and outpatient VE networks., Methods: We tested adults with acute respiratory illness (ARI) for influenza within 1 outpatient-based and 1 hospital-based VE network from 2015 through 2018. We compared age, sex, and high-risk conditions. The test-negative design was used to compare vaccination odds in influenza-positive cases vs influenza-negative controls. We estimated VE using logistic regression adjusting for site, age, sex, race/ethnicity, peak influenza activity, time to testing from, season (overall VE), and underlying conditions. VE differences (ΔVE) were assessed with 95% confidence intervals (CIs) determined through bootstrapping with significance defined as excluding the null., Results: The networks enrolled 14 573 (4144 influenza-positive) outpatients and 6769 (1452 influenza-positive) inpatients. Inpatients were older (median, 62 years vs 49 years) and had more high-risk conditions (median, 4 vs 1). Overall VE across seasons was 31% (95% CI, 26%-37%) among outpatients and 36% (95% CI, 27%-44%) among inpatients. Strain-specific VE (95% CI) among outpatients vs inpatients was 37% (25%-47%) vs 53% (37%-64%) against H1N1pdm09; 19% (9%-27%) vs 23% (8%-35%) against H3N2; and 46% (38%-53%) vs 46% (31%-58%) against B viruses. ΔVE was not significant for any comparison across all sites., Conclusions: Inpatients and outpatients with ARI represent distinct populations. Despite comparatively poor health among inpatients, influenza vaccination was effective in preventing influenza-associated hospitalizations., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

Background: Because of the increased risk for severe coronavirus disease 2019 (COVID-19), the Advisory Committee on Immunization Practices (ACIP) initially prioritized COVID-19 vaccination for persons in long-term care facilities (LTCF), persons aged ≥65 years, and persons aged 16-64 years with high-risk medical conditions when there is limited vaccine supply. We compared characteristics and severe outcomes of hospitalized patients with COVID-19 in the United States between early and later in the pandemic categorized by groups at higher risk of severe COVID-19., Methods: Observational study of sampled patients aged ≥18 years who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and admitted to one of 14 academic hospitals in the United States during March-June and October-December 2020. Demographic and clinical information were gathered from electronic health record data., Results: Among 647 patients, 91% met ≥1 of the following risk factors for severe COVID-19 [91% March-June (n = 434); 90% October-December (n = 213)]; 19% were LTCF residents, 45% were aged ≥65-years, and 84% had ≥1 high-risk condition. The proportion of patients who resided in a LTCF declined significantly (25% vs 6%) from early to later pandemic periods. Compared with patients at lower risk for severe COVID-19, in-hospital mortality was higher among patients at high risk for severe COVID-19 (20% vs 7%); these differences were consistently observed between March-June and October-December., Conclusions: Most adults hospitalized with COVID-19 were those recommended to be prioritized for vaccination based on risk for developing severe COVID-19. These findings highlight the continued urgency to vaccinate patients at high risk for severe COVID-19 and monitor vaccination impact on hospitalizations and outcomes., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)

Background: The epidemiology of Pneumocystis jirovecii, known to colonize the respiratory tract and cause a life-threatening HIV-associated pneumonia (PCP), is poorly described in Africa. We conducted a systematic review to evaluate P. jirovecii prevalence in African HIV-positive adults with or without respiratory symptoms., Methods: We searched Medline, Embase, Cochrane library, Africa-Wide, and Web of Science for studies employing PCR and/or microscopy for P. jirovecii detection in respiratory samples from HIV-positive adults in Africa between 1995 and 2020. Prevalence with respiratory symptoms was pooled using random-effect meta-analysis, and stratified by laboratory method, sample tested, study setting, CD4 count, and trimethoprim/sulfamethoxazole prophylaxis. Colonization prevalence in asymptomatic adults and in adults with non-PCP respiratory disease was described, and quantitative PCR (qPCR) thresholds to distinguish colonization from microscopy-confirmed PCP reviewed., Results: Thirty-two studies were included, with 27 studies (87%) at high risk of selection bias. P. jirovecii was detected in 19% [95% confidence interval (CI): 12-27%] of 3583 symptomatic and in 9% [95% CI: 0-45%] of 140 asymptomatic adults. Among symptomatic adults, prevalence was 22% [95% CI: 12-35%] by PCR and 15% [95% CI: 9-23%] by microscopy. Seven percent of 435 symptomatic adults had PCR-detected Pneumocystis colonization without evidence of PCP [95% CI: 5-10%, four studies]. One study established a qPCR cutoff of 78 copies/5μl of DNA in 305 induced sputum samples to distinguish Pneumocystis colonization from microscopy-confirmed PCP., Conclusion: Despite widened access to HIV services, P. jirovecii remains common in Africa. Prevalence estimates and qPCR-based definitions of colonization are limited, and overall quality of studies is low., (© The Author(s) 2021. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Observational studies of the effectiveness of vaccines to prevent COVID-19 are needed to inform real-world use. Such studies are now underway amid the ongoing rollout of SARS-CoV-2 vaccines globally. Although traditional case-control and test-negative design studies feature prominently among strategies used to assess vaccine effectiveness, such studies may encounter important threats to validity. Here, we review the theoretical basis for estimation of vaccine direct effects under traditional case-control and test-negative design frameworks, addressing specific natural history parameters of SARS-CoV-2 infection and COVID-19 relevant to these designs. Bias may be introduced by misclassification of cases and controls, particularly when clinical case criteria include common, nonspecific indicators of COVID-19. When using diagnostic assays with high analytical sensitivity for SARS-CoV-2 detection, individuals testing positive may be counted as cases even if their symptoms are due to other causes. The traditional case-control design may be particularly prone to confounding due to associations of vaccination with healthcare-seeking behavior or risk of infection. The test-negative design reduces but may not eliminate this confounding, for instance, if individuals who receive vaccination seek care or testing for less-severe illness. These circumstances indicate the two study designs cannot be applied naively to datasets gathered through public health surveillance or administrative sources. We suggest practical strategies to reduce bias in vaccine effectiveness estimates at the study design and analysis stages., Competing Interests: J.A.L. has received grants and consulting fees from Pfizer, Inc., unrelated to this research. The remaining authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Evidence to inform cryptococcal antigen (CrAg)-screening guidelines among ART-experienced populations is lacking. We performed a study evaluating the utility of reflex CrAg screening in Gaborone, Botswana., Methods: CD4 count data were collected from the HIV reference laboratory from 2014-2016. CrAg screening was performed on samples with CD4 ≤100 cells/µL beginning January 2015. The proportion of CD4 counts ≤100 cells/µL was determined and the frequency of repeat CrAg testing described. Analyses ascertained the impact of ART status on CrAg prevalence and outcomes, and whether CrAg titers could be used for risk stratification., Results: Overall, 5.6% (3335/59 300) of individuals tested had CD4 ≤100 cells/μL; 2108 samples with CD4 ≤100 cells/μL from 1645 unique patients were CrAg tested. Over half of samples were from ART-experienced individuals: 40.9% (863) on ART and 12.1% (255) defaulters; 22% (463) of CrAg tests were on repeat samples. CrAg prevalence was 4.8% (72/1494; 95% CI, 3.8-6.0%) among outpatients and 21.9% (32/151; 95% CI, 15.3-28.5%) among inpatients. CrAg prevalence rates did not differ by ART status, but 6-month mortality was significantly lower in CrAg-positive individuals on ART at screening. Ten CrAg positives were identified through repeat testing. A CrAg titer cutoff ≥1:80 provided the best discrimination for 6-month survival., Conclusions: CrAg-positivity rates in an ART-experienced population were comparable to those seen in ART-naive populations. Repeat screening identified individuals who seroconverted to CrAg positivity and were at risk of cryptococcal disease. CrAg titers ≥1:80 can help identify the individuals at highest risk of death for more intensive management., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Adults aged ≥65 years are at increased risk for severe outcomes from COVID-19 and were identified as a priority group to receive the first COVID-19 vaccines approved for use under an Emergency Use Authorization (EUA) in the United States (1-3). In an evaluation at 24 hospitals in 14 states,* the effectiveness of partial or full vaccination † with Pfizer-BioNTech or Moderna vaccines against COVID-19-associated hospitalization was assessed among adults aged ≥65 years. Among 417 hospitalized adults aged ≥65 years (including 187 case-patients and 230 controls), the median age was 73 years, 48% were female, 73% were non-Hispanic White, 17% were non-Hispanic Black, 6% were Hispanic, and 4% lived in a long-term care facility. Adjusted vaccine effectiveness (VE) against COVID-19-associated hospitalization among adults aged ≥65 years was estimated to be 94% (95% confidence interval [CI] = 49%-99%) for full vaccination and 64% (95% CI = 28%-82%) for partial vaccination. These findings are consistent with efficacy determined from clinical trials in the subgroup of adults aged ≥65 years (4,5). This multisite U.S. evaluation under real-world conditions suggests that vaccination provided protection against COVID-19-associated hospitalization among adults aged ≥65 years. Vaccination is a critical tool for reducing severe COVID-19 in groups at high risk., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Christopher J. Lindsell reports grants from National Institutes of Health, U.S. Department of Defense, Marcus Foundation, Endpoint Health, Entegrion, bioMerieux, and Bioscape Digital, outside the submitted work. Jay S. Steingrub reports grants from National Institutes of Health, outside the submitted work. Akram Khan reports grants from United Therapeutics, Actelion Pharmaceuticals, Regeneron, and Reata Pharmaceuticals, outside the submitted work. Samuel M. Brown reports grants from National Institutes of Health, U.S. Department of Defense, Intermountain Research and Medical Foundation, and Janssen, and consulting fees paid to his employer from Faron and Sedana, all outside the submitted work. Ithan D. Peltan reports grants from National Institutes of Health and, outside the submitted work, grants from Asahi Kasei Pharma, Janssen Pharmaceuticals, and Regeneron. Adit A. Ginde reports grants from National Institutes of Health, U.S. Department of Defense and AbbVie, outside the submitted work. Carlos G. Grijalva reports consulting fees from Pfizer, Merck, and Sanofi-Pasteur, grants from Campbell Alliance/Syneos Health, National Institutes of Health, Food and Drug Administration, and Agency for Health Care Research and Quality, outside the submitted work. Michelle N. Gong reports grants from National Institutes of Health, Agency for Healthcare Research and Quality, and consulting fees from Regeneron, Philips Healthcare, all outside the submitted work. Steven Y. Chang reports consulting fees from PureTech Health and speaker fees from La Jolla Pharmaceuticals, both outside the submitted work. Jonathan D. Casey reports grants from National Institutes of Health, outside the submitted work. Todd W. Rice reports grants from National Institutes of Health and Endpoint Health, consulting work for Cumberland Pharmaceuticals, Inc, and Sanofi, Inc., outside the submitted work. Manjusha Gaglani reports grants from CDC-Abt Associates, outside the submitted work. Emily T. Martin reports personal fees from Pfizer and grants from Merck, outside the submitted work. Anurag Malani reports shareholder of Pfizer pharmaceuticals. Arnold S. Monto reports personal fees from Sanofi Pasteur and Seqirus, outside the submitted work. Fernanda P. Silveira reports grants from Shire, Qiagen, Ansun, and Novartis, outside the submitted work. Richard K. Zimmerman reports grants from Sanofi Pasteur, outside the submitted work. Donald B. Middleton reports grants and personal fees from Pfizer and personal fees from Seqirus, Sanofi Pasteur, and GlaxoSmithKline, outside the submitted work. No other potential conflicts of interest were disclosed.

Increasing the CD4-count threshold for cryptococcal antigen (CrAg) screening from ≤100 to ≤200 cells/µL resulted in a 3-fold increase in numbers screened. CrAg-prevalence was 3.5% at CD4 101-200 and 6.2% ≤100 cells/µL. Six-month mortality was 21.4% (9/42) in CrAg-positive CD4 ≤100 cells/µL and 3.2% (1/31) in CrAg-positive CD4 101-200 cells/µL., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Among 249 healthcare personnel who worked in hospital units with COVID-19 patients for 1 month, 19 (7.6%) tested positive for SARS-CoV-2 antibodies. Only 11 (57.9%) of the 19 personnel with positive serology reported symptoms of a prior illness, suggesting asymptomatic healthcare personnel could be an important source of SARS-CoV-2 transmission., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Symptoms of mild COVID-19 illness are non-specific and may persist for prolonged periods. Effects on quality of life of persistent poor physical or mental health associated with COVID-19 are not well understood., Methods: Adults aged ≥18 years with laboratory-confirmed COVID-19 and matched control patients who tested negative for SARS-CoV-2 infection at outpatient facilities associated with 11 medical centers in the United States were interviewed to assess symptoms, illness duration, and health-related quality of life. Duration of symptoms, health-related quality of life measures, and days of poor physical health by symptoms experienced during illness were compared between case patients and controls using Wilcoxon rank-sum tests. Symptoms associated with COVID-19 case status were evaluated by multivariable logistic regression., Results: Among 320 participants included, 157 were COVID-19 cases and 163 were SARS-CoV-2 negative controls. Loss of taste or smell was reported by 63% of cases and 6% of controls and was strongly associated with COVID-19 in logistic regression models (adjusted odds ratio [aOR] = 32.4; 95% confidence interval [CI], 12.6-83.1). COVID-19 cases were more likely than controls to have experienced fever, body aches, weakness, or fatigue during illness, and to report ≥1 persistent symptom more than 14 days after symptom onset (50% vs 32%, P < .001). Cases reported significantly more days of poor physical health during the past 14 days than controls (P < .01)., Conclusions: Differentiating COVID-19 from other acute illnesses will require widespread diagnostic testing, especially during influenza seasons. Persistent COVID-19-related symptoms may negatively affect quality of life, even among those initially presenting with mild illness., (© Published 2020. This article is a U.S. Government work and is in the public domain in the USA. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Importance: Coronavirus disease 2019 (COVID-19) affects the nervous system in adult patients. The spectrum of neurologic involvement in children and adolescents is unclear., Objective: To understand the range and severity of neurologic involvement among children and adolescents associated with COVID-19., Setting, Design, and Participants: Case series of patients (age <21 years) hospitalized between March 15, 2020, and December 15, 2020, with positive severe acute respiratory syndrome coronavirus 2 test result (reverse transcriptase-polymerase chain reaction and/or antibody) at 61 US hospitals in the Overcoming COVID-19 public health registry, including 616 (36%) meeting criteria for multisystem inflammatory syndrome in children. Patients with neurologic involvement had acute neurologic signs, symptoms, or diseases on presentation or during hospitalization. Life-threatening involvement was adjudicated by experts based on clinical and/or neuroradiologic features., Exposures: Severe acute respiratory syndrome coronavirus 2., Main Outcomes and Measures: Type and severity of neurologic involvement, laboratory and imaging data, and outcomes (death or survival with new neurologic deficits) at hospital discharge., Results: Of 1695 patients (909 [54%] male; median [interquartile range] age, 9.1 [2.4-15.3] years), 365 (22%) from 52 sites had documented neurologic involvement. Patients with neurologic involvement were more likely to have underlying neurologic disorders (81 of 365 [22%]) compared with those without (113 of 1330 [8%]), but a similar number were previously healthy (195 [53%] vs 723 [54%]) and met criteria for multisystem inflammatory syndrome in children (126 [35%] vs 490 [37%]). Among those with neurologic involvement, 322 (88%) had transient symptoms and survived, and 43 (12%) developed life-threatening conditions clinically adjudicated to be associated with COVID-19, including severe encephalopathy (n = 15; 5 with splenial lesions), stroke (n = 12), central nervous system infection/demyelination (n = 8), Guillain-Barré syndrome/variants (n = 4), and acute fulminant cerebral edema (n = 4). Compared with those without life-threatening conditions (n = 322), those with life-threatening neurologic conditions had higher neutrophil-to-lymphocyte ratios (median, 12.2 vs 4.4) and higher reported frequency of D-dimer greater than 3 μg/mL fibrinogen equivalent units (21 [49%] vs 72 [22%]). Of 43 patients who developed COVID-19-related life-threatening neurologic involvement, 17 survivors (40%) had new neurologic deficits at hospital discharge, and 11 patients (26%) died., Conclusions and Relevance: In this study, many children and adolescents hospitalized for COVID-19 or multisystem inflammatory syndrome in children had neurologic involvement, mostly transient symptoms. A range of life-threatening and fatal neurologic conditions associated with COVID-19 infrequently occurred. Effects on long-term neurodevelopmental outcomes are unknown.

Objectives: Determine if thromboelastography parameters and platelet count on the day of ICU admission are associated with the development of venous thromboembolism in patients with coronavirus disease 2019., Design: Prospective, observational cohort study., Setting: Tertiary-care, academic medical center in Nashville, TN., Patients: Patients with coronavirus disease 2019 pneumonia and acute respiratory failure admitted to the adult ICU without venous thromboembolism at the time of ICU admission., Intervention: None., Measurements and Main Results: The primary outcome was development of venous thromboembolism during the index hospitalization. Venous thromboembolism was defined by clinical imaging or autopsy, demonstrating deep vein thrombosis or pulmonary embolism. Forty consecutive critically ill adults with laboratory-confirmed coronavirus disease 2019 were enrolled; 37 (92.5%) were hypercoagulable by at least one thromboelastography parameter at the time of ICU admission and 12 (30%) met the primary outcome of venous thromboembolism during the index hospitalization. Patients who developed venous thromboembolism had decreased measures of clotting (maximum amplitude, alpha angle, shear elastic modulus parameter, and clotting index) on ICU admission thromboelastography compared with patients who did not develop venous thromboembolism ( p < 0.05 for all measures). For each individual thromboelastography parameter used to dichotomize patients as hypercoagulable, the rate of venous thromboembolism was not higher in those identified as hypercoagulable; in fact, the venous thromboembolism rate was higher in patients who were not hypercoagulable by thromboelastography for maximum amplitude ( p = 0.04) and alpha angle ( p = 0.001). Platelet count was positively correlated with maximum amplitude, alpha angle, G parameter, and clotting index, and significantly lower in patients who developed venous thromboembolism than those who did not (median 186 vs 278 10 3 /μL, p = 0.046). Venous thromboembolism was associated with inhospital mortality (odds ratio, 6.3; 95% CI, 1.4-29; p = 0.02)., Conclusions: Our data do not support the use of thromboelastography to risk stratify critically ill adults with coronavirus disease 2019 for the development of venous thromboembolism or to guide decisions about anticoagulation. Lower platelet count on ICU admission, which may reflect platelet aggregation, was associated with venous thromboembolism., Competing Interests: Dr. Marvi was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number R38HL143619. Dr. Grijalva was supported in part by the National Institute for Allergy and Infectious Diseases K24 AI148459, and has received unrelated consulting fees from Pfizer, Sanofi, and Merck and research support from Sanofi-Pasteur, Campbell Alliance, the Centers for Disease Control and Prevention, National Institutes of Health, The Food and Drug Administration, and the Agency for Healthcare Research and Quality. Dr. Rice is supported in part by the National Institutes of Health U01HL123009. He has received unrelated consulting fees from Cumberland Pharmaceuticals, Cytovale, and Avisa Pharma, LLC. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Importance: Refinement of criteria for multisystem inflammatory syndrome in children (MIS-C) may inform efforts to improve health outcomes., Objective: To compare clinical characteristics and outcomes of children and adolescents with MIS-C vs those with severe coronavirus disease 2019 (COVID-19)., Setting, Design, and Participants: Case series of 1116 patients aged younger than 21 years hospitalized between March 15 and October 31, 2020, at 66 US hospitals in 31 states. Final date of follow-up was January 5, 2021. Patients with MIS-C had fever, inflammation, multisystem involvement, and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase-polymerase chain reaction (RT-PCR) or antibody test results or recent exposure with no alternate diagnosis. Patients with COVID-19 had positive RT-PCR test results and severe organ system involvement., Exposure: SARS-CoV-2., Main Outcomes and Measures: Presenting symptoms, organ system complications, laboratory biomarkers, interventions, and clinical outcomes. Multivariable regression was used to compute adjusted risk ratios (aRRs) of factors associated with MIS-C vs COVID-19., Results: Of 1116 patients (median age, 9.7 years; 45% female), 539 (48%) were diagnosed with MIS-C and 577 (52%) with COVID-19. Compared with patients with COVID-19, patients with MIS-C were more likely to be 6 to 12 years old (40.8% vs 19.4%; absolute risk difference [RD], 21.4% [95% CI, 16.1%-26.7%]; aRR, 1.51 [95% CI, 1.33-1.72] vs 0-5 years) and non-Hispanic Black (32.3% vs 21.5%; RD, 10.8% [95% CI, 5.6%-16.0%]; aRR, 1.43 [95% CI, 1.17-1.76] vs White). Compared with patients with COVID-19, patients with MIS-C were more likely to have cardiorespiratory involvement (56.0% vs 8.8%; RD, 47.2% [95% CI, 42.4%-52.0%]; aRR, 2.99 [95% CI, 2.55-3.50] vs respiratory involvement), cardiovascular without respiratory involvement (10.6% vs 2.9%; RD, 7.7% [95% CI, 4.7%-10.6%]; aRR, 2.49 [95% CI, 2.05-3.02] vs respiratory involvement), and mucocutaneous without cardiorespiratory involvement (7.1% vs 2.3%; RD, 4.8% [95% CI, 2.3%-7.3%]; aRR, 2.29 [95% CI, 1.84-2.85] vs respiratory involvement). Patients with MIS-C had higher neutrophil to lymphocyte ratio (median, 6.4 vs 2.7, P < .001), higher C-reactive protein level (median, 152 mg/L vs 33 mg/L; P < .001), and lower platelet count (<150 ×103 cells/μL [212/523 {41%} vs 84/486 {17%}, P < .001]). A total of 398 patients (73.8%) with MIS-C and 253 (43.8%) with COVID-19 were admitted to the intensive care unit, and 10 (1.9%) with MIS-C and 8 (1.4%) with COVID-19 died during hospitalization. Among patients with MIS-C with reduced left ventricular systolic function (172/503, 34.2%) and coronary artery aneurysm (57/424, 13.4%), an estimated 91.0% (95% CI, 86.0%-94.7%) and 79.1% (95% CI, 67.1%-89.1%), respectively, normalized within 30 days., Conclusions and Relevance: This case series of patients with MIS-C and with COVID-19 identified patterns of clinical presentation and organ system involvement. These patterns may help differentiate between MIS-C and COVID-19.

Objectives: Given finite ICU bed capacity, knowledge of ICU bed utilization during the coronavirus disease 2019 pandemic is critical to ensure future strategies for resource allocation and utilization. We sought to examine ICU census trends in relation to ICU bed capacity during the rapid increase in severe coronavirus disease 2019 cases early during the pandemic., Design: Observational cohort study., Setting: Thirteen geographically dispersed academic medical centers in the United States., Patients/subjects: We obtained daily ICU censuses from March 26 to June 30, 2020, as well as prepandemic ICU bed capacities. The primary outcome was daily census of ICU patients stratified by coronavirus disease 2019 and mechanical ventilation status in relation to ICU capacity., Interventions: None., Measurements and Main Results: Prepandemic overall ICU capacity ranged from 62 to 225 beds (median 109). During the study period, the median daily coronavirus disease 2019 ICU census per hospital ranged from 1 to 84 patients, and the daily ICU census exceeded overall ICU capacity for at least 1 day at five institutions. The number of critically ill patients exceeded ICU capacity for a median (interquartile range) of 17 (12-50) of 97 days at these five sites. All 13 institutions experienced decreases in their noncoronavirus disease ICU population, whereas local coronavirus disease 2019 cases increased. Coronavirus disease 2019 patients reached their greatest proportion of ICU capacity on April 12, 2020, when they accounted for 44% of ICU patients across all participating hospitals. Maximum ICU census ranged from 52% to 289% of overall ICU capacity, with three sites less than 80%, four sites 80-100%, five sites 100-128%, and one site 289%., Conclusions: From March to June 2020, the coronavirus disease 2019 pandemic led to ICU censuses greater than ICU bed capacity at fives of 13 institutions evaluated. These findings demonstrate the short-term adaptability of U.S. healthcare institutions in redirecting limited resources to accommodate a public health emergency., Competing Interests: Dr. Lindsell reports grants from National Institutes of Health and the Department of Defense and other support from Marcus Foundation, Endpoint Health, Entegrion, bioMerieux, and Bioscape Digital, outside the submitted work. Dr. Brown reports grants from National Institutes of Health, Department of Defense, Intermountain Research and Medical Foundation, and Janssen and consulting fees paid to his employer from Faron and Sedana, outside the submitted work. Dr. Peltan reports grants from the National Institutes of Health, Asahi Kasei Pharma, Immunexpress Inc., Janssen Pharmaceuticals, and Regeneron, outside the submitted work. Dr. Rice reports grants from the National Institutes of Health, personal fees from Cumberland Pharmaceuticals, Inc, Cytovale, Inc, and Avisa, LLC, outside the submitted work. Dr. Henning reports personal fees from CytoVale and grants from Baxter, outside the submitted work. Dr. Self reports research funding for the current work from the Centers for Disease Control and Prevention. Dr. Ginde reports grants from the National Institutes of Health and Department of Defense, outside the submitted work. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)