Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection

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Abstract

Importance

SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals.

Objective

To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections.

Design, Setting, and Participants

Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling.

Exposure

SARS-CoV-2 infection.

Main Outcomes and Measures

PASC and 44 participant-reported symptoms (with severity thresholds).

Results

A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months.

Conclusions and Relevance

A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.

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Most cited references 26

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6-month consequences of COVID-19 in patients discharged from hospital: a cohort study

Chaolin Huang, Lixue Huang, Yeming Wang … (2021)

Background The long-term health consequences of COVID-19 remain largely unclear. The aim of this study was to describe the long-term health consequences of patients with COVID-19 who have been discharged from hospital and investigate the associated risk factors, in particular disease severity. Methods We did an ambidirectional cohort study of patients with confirmed COVID-19 who had been discharged from Jin Yin-tan Hospital (Wuhan, China) between Jan 7, 2020, and May 29, 2020. Patients who died before follow-up, patients for whom follow-up would be difficult because of psychotic disorders, dementia, or re-admission to hospital, those who were unable to move freely due to concomitant osteoarthropathy or immobile before or after discharge due to diseases such as stroke or pulmonary embolism, those who declined to participate, those who could not be contacted, and those living outside of Wuhan or in nursing or welfare homes were all excluded. All patients were interviewed with a series of questionnaires for evaluation of symptoms and health-related quality of life, underwent physical examinations and a 6-min walking test, and received blood tests. A stratified sampling procedure was used to sample patients according to their highest seven-category scale during their hospital stay as 3, 4, and 5–6, to receive pulmonary function test, high resolution CT of the chest, and ultrasonography. Enrolled patients who had participated in the Lopinavir Trial for Suppression of SARS-CoV-2 in China received severe acute respiratory syndrome coronavirus 2 antibody tests. Multivariable adjusted linear or logistic regression models were used to evaluate the association between disease severity and long-term health consequences. Findings In total, 1733 of 2469 discharged patients with COVID-19 were enrolled after 736 were excluded. Patients had a median age of 57·0 (IQR 47·0–65·0) years and 897 (52%) were men. The follow-up study was done from June 16, to Sept 3, 2020, and the median follow-up time after symptom onset was 186·0 (175·0–199·0) days. Fatigue or muscle weakness (63%, 1038 of 1655) and sleep difficulties (26%, 437 of 1655) were the most common symptoms. Anxiety or depression was reported among 23% (367 of 1617) of patients. The proportions of median 6-min walking distance less than the lower limit of the normal range were 24% for those at severity scale 3, 22% for severity scale 4, and 29% for severity scale 5–6. The corresponding proportions of patients with diffusion impairment were 22% for severity scale 3, 29% for scale 4, and 56% for scale 5–6, and median CT scores were 3·0 (IQR 2·0–5·0) for severity scale 3, 4·0 (3·0–5·0) for scale 4, and 5·0 (4·0–6·0) for scale 5–6. After multivariable adjustment, patients showed an odds ratio (OR) 1·61 (95% CI 0·80–3·25) for scale 4 versus scale 3 and 4·60 (1·85–11·48) for scale 5–6 versus scale 3 for diffusion impairment; OR 0·88 (0·66–1·17) for scale 4 versus scale 3 and OR 1·77 (1·05–2·97) for scale 5–6 versus scale 3 for anxiety or depression, and OR 0·74 (0·58–0·96) for scale 4 versus scale 3 and 2·69 (1·46–4·96) for scale 5–6 versus scale 3 for fatigue or muscle weakness. Of 94 patients with blood antibodies tested at follow-up, the seropositivity (96·2% vs 58·5%) and median titres (19·0 vs 10·0) of the neutralising antibodies were significantly lower compared with at the acute phase. 107 of 822 participants without acute kidney injury and with estimated glomerular filtration rate (eGFR) 90 mL/min per 1·73 m2 or more at acute phase had eGFR less than 90 mL/min per 1·73 m2 at follow-up. Interpretation At 6 months after acute infection, COVID-19 survivors were mainly troubled with fatigue or muscle weakness, sleep difficulties, and anxiety or depression. Patients who were more severely ill during their hospital stay had more severe impaired pulmonary diffusion capacities and abnormal chest imaging manifestations, and are the main target population for intervention of long-term recovery. Funding National Natural Science Foundation of China, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, National Key Research and Development Program of China, Major Projects of National Science and Technology on New Drug Creation and Development of Pulmonary Tuberculosis, and Peking Union Medical College Foundation.

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The Elements of Statistical Learning

Trevor J. Hastie, Robert Tibshirani, Jerome Friedman (2009)

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Characterizing long COVID in an international cohort: 7 months of symptoms and their impact

Hannah Davis, Gina Assaf, Lisa McCorkell … (2021)

Background A significant number of patients with COVID-19 experience prolonged symptoms, known as Long COVID. Few systematic studies have investigated this population, particularly in outpatient settings. Hence, relatively little is known about symptom makeup and severity, expected clinical course, impact on daily functioning, and return to baseline health. Methods We conducted an online survey of people with suspected and confirmed COVID-19, distributed via COVID-19 support groups (e.g. Body Politic, Long COVID Support Group, Long Haul COVID Fighters) and social media (e.g. Twitter, Facebook). Data were collected from September 6, 2020 to November 25, 2020. We analyzed responses from 3762 participants with confirmed (diagnostic/antibody positive; 1020) or suspected (diagnostic/antibody negative or untested; 2742) COVID-19, from 56 countries, with illness lasting over 28 days and onset prior to June 2020. We estimated the prevalence of 203 symptoms in 10 organ systems and traced 66 symptoms over seven months. We measured the impact on life, work, and return to baseline health. Findings For the majority of respondents (>91%), the time to recovery exceeded 35 weeks. During their illness, participants experienced an average of 55.9+/- 25.5 (mean+/-STD) symptoms, across an average of 9.1 organ systems. The most frequent symptoms after month 6 were fatigue, post-exertional malaise, and cognitive dysfunction. Symptoms varied in their prevalence over time, and we identified three symptom clusters, each with a characteristic temporal profile. 85.9% of participants (95% CI, 84.8% to 87.0%) experienced relapses, primarily triggered by exercise, physical or mental activity, and stress. 86.7% (85.6% to 92.5%) of unrecovered respondents were experiencing fatigue at the time of survey, compared to 44.7% (38.5% to 50.5%) of recovered respondents. 1700 respondents (45.2%) required a reduced work schedule compared to pre-illness, and an additional 839 (22.3%) were not working at the time of survey due to illness. Cognitive dysfunction or memory issues were common across all age groups (~88%). Except for loss of smell and taste, the prevalence and trajectory of all symptoms were similar between groups with confirmed and suspected COVID-19. Interpretation Patients with Long COVID report prolonged, multisystem involvement and significant disability. By seven months, many patients have not yet recovered (mainly from systemic and neurological/cognitive symptoms), have not returned to previous levels of work, and continue to experience significant symptom burden. Funding All authors contributed to this work in a voluntary capacity. The cost of survey hosting (on Qualtrics) and publication fee was covered by AA's research grant (Wellcome Trust/Gatsby Charity via Sainsbury Wellcome center, UCL).

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Author and article information

Journal

Title: JAMA

Abbreviated Title: JAMA

Publisher: American Medical Association (AMA)

ISSN (Print): 0098-7484

Publication date (Electronic): May 25 2023

Affiliations

[1 ]Massachusetts General Hospital, Boston

[2 ]Harvard Medical School, Boston, Massachusetts

[3 ]University of Colorado Anschutz Medical Campus, Aurora

[4 ]Brigham and Women’s Hospital, Boston, Massachusetts

[5 ]University of Alabama at Birmingham

[6 ]Case Western Reserve University, Cleveland, Ohio

[7 ]Patient-Led Research Collaborative, Calabasas, California

[8 ]Icahn School of Medicine at Mount Sinai, New York, New York

[9 ]The University of Arizona College of Medicine, Tucson

[10 ]Stanford University School of Medicine, Stanford, California

[11 ]Emory University School of Medicine, Atlanta, Georgia

[12 ]Mass General Brigham, Boston, Massachusetts

[13 ]New York University Grossman School of Medicine, New York

[14 ]for the RECOVER Consortium

[15 ]University of Washington, Seattle

[16 ]University of California, San Francisco

[17 ]Howard University, Washington, DC

[18 ]Bateman Horne Center, Salt Lake City, Utah

[19 ]Stanford University, Stanford, California

[20 ]Kaiser Foundation Health Plan of Georgia Inc, Atlanta

[21 ]University of Kansas Medical Center, Kansas City

[22 ]Cedars-Sinai Medical Center, Los Angeles, California

[23 ]University of Washington School of Medicine, Seattle

[24 ]George Washington University, Washington, DC

[25 ]The Ohio State University, Columbus

[26 ]Universidad de Puerto Rico Recinto de Ciencias Medicas, San Juan, Puerto Rico

[27 ]Swedish Medical Center, Seattle, Washington

[28 ]MaineHealth, Portland

[29 ]The University of Arizona, Tucson

[30 ]Emory University, Atlanta, Georgia

[31 ]The University of Texas Health Science Center at San Antonio

[32 ]University of Illinois Chicago

[33 ]Tulane University Health Sciences Center, New Orleans, Louisiana

[34 ]Partners HealthCare Systems, Boston, Massachusetts

[35 ]Kaiser Permanente Georgia, Atlanta

[36 ]Denver Health, Denver, Colorado

[37 ]MetroHealth Medical Center, Cleveland, Ohio

[38 ]Pennington Biomedical Research Center, Baton Rouge, Louisiana

[39 ]TriHealth, Cincinnati, Ohio

[40 ]University of Illinois Chicago College of Medicine

[41 ]University of Illinois College of Medicine at Peoria

[42 ]Institute for Systems Biology, Seattle, Washington

[43 ]UH Cleveland Medical Center, Cleveland, Ohio

[44 ]University of Utah Schools of the Health Sciences, Salt Lake City

[45 ]West Virginia Clinical and Translational Science Institute, Morgantown

[46 ]Christiana Care Health Services Inc, Newark, Delaware

[47 ]Sanford Health, Sioux Falls, South Dakota

[48 ]Duke University, Durham, North Carolina

[49 ]Cambridge Health Alliance, Cambridge, Massachusetts

[50 ]Tufts Medical Center, Boston, Massachusetts

[51 ]MetroHealth Campus of Case Western Reserve University, Cleveland, Ohio

[52 ]The University of Arizona College of Medicine, Phoenix

[53 ]University of Illinois Hospital and Health Sciences System, Chicago

[54 ]Howard University College of Medicine, Washington, DC

[55 ]Tulane University, New Orleans, Louisiana

[56 ]Tulane School of Medicine, New Orleans, Louisiana

[57 ]Universidad de Puerto Rico, San Juan, Puerto Rico

[58 ]Beth Israel Deaconess Medical Center, Boston, Massachusetts

[59 ]Boston University, Boston, Massachusetts

[60 ]University of Mississippi, Oxford

[61 ]McGovern Medical School at The University of Texas Health Science Center at Houston

[62 ]University of Utah Health, Salt Lake City

[63 ]University of Arizona, Tucson

[64 ]Case Western Reserve University School of Medicine, Cleveland, Ohio

[65 ]Morehouse School of Medicine, Atlanta, Georgia

[66 ]Medical College of Wisconsin, Milwaukee

[67 ]Saint Peter’s University Hospital, Brunswick, New Jersey

[68 ]Cedars-Sinai Health System, Los Angeles, California

[69 ]University of Pennsylvania, Philadelphia

[70 ]Yale School of Medicine, New Haven, Connecticut

[71 ]NorthShore University HealthSystem, Evanston, Illinois

[72 ]Warren Alpert Medical School, Brown University, Providence, Rhode Island

[73 ]Columbia University Irving Medical Center, New York, New York

[74 ]West Virginia University School of Medicine, Morgantown

[75 ]Department of Medicine, The University of Texas Health Science Center at San Antonio

[76 ]Banner Alzheimer’s Institute, Phoenix, Arizona

[77 ]Banner University Medical Center Tucson, Arizona

[78 ]Brown University, Providence, Rhode Island

[79 ]The University of Kansas Medical Center, Kansas City

[80 ]Eastern Virginia Medical School, Norfolk

[81 ]Milken Institute of Public Health, The George Washington University, Washington, DC

[82 ]Boston University School of Medicine, Boston, Massachusetts

[83 ]University of Pittsburgh, Pittsburgh, Pennsylvania

[84 ]Weill Cornell Medicine, New York, New York

[85 ]The University of Oklahoma, Norman

[86 ]The University of North Carolina at Chapel Hill

[87 ]Mercy Medical Center, Baltimore, Maryland

[88 ]University of Alabama, Birmingham

[89 ]University of Oklahoma Health Sciences Center, Oklahoma City

[90 ]University of Nebraska Medical Center, Omaha

[91 ]The George Washington University Biostatistics Center, Rockville, Maryland

[92 ]West Virginia University, Morgantown

[93 ]University of Kentucky, Lexington

[94 ]Feinberg School of Medicine, Northwestern University, Chicago, Illinois

Article

DOI: 10.1001/jama.2023.8823

PubMed ID: 37278994

SO-VID: 0d084e55-e5ba-4f80-9b9e-4c19600e45f0

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Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection

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Abstract

Importance

Objective

Design, Setting, and Participants

Exposure

Main Outcomes and Measures

Results

Conclusions and Relevance

Related collections

Novel Coronavirus Disease COVID-19

Most cited references 26

6-month consequences of COVID-19 in patients discharged from hospital: a cohort study

The Elements of Statistical Learning

Characterizing long COVID in an international cohort: 7 months of symptoms and their impact

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Similar content 712

Cited by 108

Most referenced authors 651