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. 2023 Jun 13;329(22):1934-1946.
doi: 10.1001/jama.2023.8823.

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

Tanayott Thaweethai  1   2 , Sarah E Jolley  3 , Elizabeth W Karlson  4 , Emily B Levitan  5 , Bruce Levy  2   4 , Grace A McComsey  6 , Lisa McCorkell  7 , Girish N Nadkarni  8 , Sairam Parthasarathy  9 , Upinder Singh  10 , Tiffany A Walker  11 , Caitlin A Selvaggi  1 , Daniel J Shinnick  1 , Carolin C M Schulte  1 , Rachel Atchley-Challenner  12 , George A Alba  1 , Radica Alicic  13 , Natasha Altman  3 , Khamal Anglin  14 , Urania Argueta  14 , Hassan Ashktorab  15 , Gaston Baslet  4 , Ingrid V Bassett  1 , Lucinda Bateman  16 , Brahmchetna Bedi  11 , Shamik Bhattacharyya  4 , Marie-Abele Bind  1 , Andra L Blomkalns  17 , Hector Bonilla  17 , Hassan Brim  18 , Patricia A Bush  19 , Mario Castro  20 , James Chan  1 , Alexander W Charney  8 , Peter Chen  21 , Lori B Chibnik  1 , Helen Y Chu  22 , Rebecca G Clifton  23 , Maged M Costantine  24 , Sushma K Cribbs  11 , Sylvia I Davila Nieves  25 , Steven G Deeks  14 , Alexandria Duven  26 , Ivette F Emery  27 , Nathan Erdmann  5 , Kristine M Erlandson  3 , Kacey C Ernst  28 , Rachael Farah-Abraham  29 , Cheryl E Farner  30 , Elen M Feuerriegel  3 , Judes Fleurimont  31 , Vivian Fonseca  32 , Nicholas Franko  13 , Vivian Gainer  33 , Jennifer C Gander  34 , Edward M Gardner  35 , Linda N Geng  17 , Kelly S Gibson  36 , Minjoung Go  10 , Jason D Goldman  26 , Halle Grebe  14 , Frank L Greenway  37 , Mounira Habli  38 , John Hafner  39 , Jenny E Han  11 , Keith A Hanson  40 , James Heath  41 , Carla Hernandez  42 , Rachel Hess  43 , Sally L Hodder  44 , Matthew K Hoffman  45 , Susan E Hoover  46 , Beatrice Huang  14 , Brenna L Hughes  47 , Prasanna Jagannathan  17 , Janice John  48 , Michael R Jordan  49 , Stuart D Katz  50 , Elizabeth S Kaufman  51 , John D Kelly  14 , Sara W Kelly  40 , Megan M Kemp  13 , John P Kirwan  37 , Jonathan D Klein  31 , Kenneth S Knox  52 , Jerry A Krishnan  53 , Andre Kumar  10 , Adeyinka O Laiyemo  54 , Allison A Lambert  13 , Margaret Lanca  2 , Joyce K Lee-Iannotti  52 , Brian P Logarbo  55 , Michele T Longo  56 , Carlos A Luciano  57 , Karen Lutrick  28 , Jason H Maley  58 , Gail Mallett  59 , Jai G Marathe  60 , Vincent Marconi  29 , Gailen D Marshall  61 , Christopher F Martin  29 , Yuri Matusov  21 , Alem Mehari  54 , Hector Mendez-Figueroa  62 , Robin Mermelstein  31 , Torri D Metz  63 , Richard Morse  1 , Jarrod Mosier  64 , Christian Mouchati  65 , Janet Mullington  2 , Shawn N Murphy  1 , Robert B Neuman  19 , Janko Z Nikolich  28 , Ighovwerha Ofotokun  11 , Elizabeth Ojemakinde  66 , Anna Palatnik  67 , Kristy Palomares  68 , Tanyalak Parimon  69 , Samuel Parry  70 , Jan E Patterson  30 , Thomas F Patterson  30 , Rachel E Patzer  29 , Michael J Peluso  14 , Priscilla Pemu  66 , Christian M Pettker  71 , Beth A Plunkett  2   72 , Kristen Pogreba-Brown  28 , Athena Poppas  73 , John G Quigley  31 , Uma Reddy  74 , Rebecca Reece  75 , Harrison Reeder  1 , W B Reeves  76 , Eric M Reiman  77 , Franz Rischard  78 , Jonathan Rosand  1 , Dwight J Rouse  79 , Adam Ruff  80 , George Saade  81 , Grecio J Sandoval  82 , Jorge L Santana  83 , Shannon M Schlater  63 , Frank C Sciurba  84 , Fitzgerald Shepherd  85 , Zaki A Sherif  54 , Hyagriv Simhan  86 , Nora G Singer  36 , Daniel W Skupski  87 , Amber Sowles  63 , Jeffrey A Sparks  4 , Fatima I Sukhera  88 , Barbara S Taylor  30 , Larissa Teunis  29 , Robert J Thomas  58 , John M Thorp  89 , Paul Thuluvath  90 , Amberly Ticotsky  48 , Alan T Tita  91 , Katherine R Tuttle  13 , Alfredo E Urdaneta  10 , Daisy Valdivieso  14 , Timothy M VanWagoner  92 , Andrew Vasey  93 , Monica Verduzco-Gutierrez  30 , Zachary S Wallace  1 , Honorine D Ward  49 , David E Warren  93 , Steven J Weiner  94 , Shelley Welch  95 , Sidney W Whiteheart  96 , Zanthia Wiley  29 , Juan P Wisnivesky  8 , Lynn M Yee  97 , Sokratis Zisis  6 , Leora I Horwitz  50 , Andrea S Foulkes  1   2 ; RECOVER Consortium
Collaborators, Affiliations

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

Tanayott Thaweethai et al. JAMA. .

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Thaweethai reported receiving grants from the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) and serving as co-investigator of the RECOVER Data Resource Core. Dr Jolley reported receiving grants from the NIH/NHLBI. Dr Karlson reported receiving grants from the NIH. Dr Levitan reported receiving grants from the NIH and Amgen. Dr Levy reported receiving grants from the NHLBI and personal fees or research support from Entrinsic Bioscience, Nocion Therapeutics, Gossamer Bio, AstraZeneca, Novartis, Sanofi, Amgen, Genentech, Pieris Pharmaceuticals, and SRA. Dr McComsey reported serving as a consultant for Gilead, Merck, Janssen, and GlaxoSmithKline and receiving research support from Pfizer, Genentech, and Roche. Ms McCorkell reported receiving personal fees from NIH RECOVER and research funding as a subcontractor from the NIH and the Patient-Centered Outcomes Research Institute (PCORI). Dr Parthasarathy reported receiving grants from the NIH, NHLBI, Sergey-Brin Foundation, and Regeneron and personal fees from Jazz Pharmaceuticals. Dr Singh reported receiving grants from Pfizer and serving as an advisor to Regeneron and Gilead. Dr Walker reported receiving grants from the NHLBI. Mr Shinnick reported receiving grants from the NIH/NHLBI. Dr Horwitz reported receiving grants from the NIH and serving on an ad hoc committee for the National Academy of Medicine. Dr Foulkes reported receiving grants from the NIH/NHLBI and personal fees from the Round Table Group and serving as principal investigator of the RECOVER Data Resource Core. Dr Alba reported receiving personal fees from Minerva Biotechnologies. Dr Alicic reported receiving grants from the NIH, the Centers for Disease Control and Prevention, and Travere Therapeutics and personal fees from Boehringer Ingelheim. Dr Ashktorab reported receiving grants from the NIH. Dr Bhattacharyya reported receiving grants from NIH RECOVER, Alexion Pharmaceuticals, UCB, and Massachusetts Consortium on Pathogen Readiness and personal fees from American Academy of Neurology and UpToDate. Dr Castro reported receiving grants from the NIH, American Lung Association, PCORI, AstraZeneca, Gala Therapeutics, Genentech, GlaxoSmithKline, Novartis, Pulmatrix, Sanofi, Shionogi, and Theravance Biopharma; personal fees from Allakos, Amgen, OM Pharma, Pfizer, Pioneering Medicines, AstraZeneca, GlaxoSmithKline, Genentech, Teva Pharmaceutical Industries, Sanofi, Merck, Novartis, Arrowhead Pharmaceuticals, and Regeneron; stock options from Aer Therapeutics; and royalties from Elsevier. Dr Chu reported receiving grants from the NIH and personal fees from Merck, Vir Biotechnology, AbbVie, Ellume, Pfizer, and the Bill and Melinda Gates Foundation; serving on advisory boards for Merck and AbbVie; conducting CME teaching with Medscape, Vindico, and Clinical Care Options; and receiving research funding from Gates Ventures and support and reagents from Ellume and Cepheid. Dr Clifton reported receiving grants from the NIH. Dr Costantine reported receiving grants from the NIH, Baxter International, and Siemens Healthcare and personal fees from Quidel, Progenity, and Siemens Healthcare. Dr Davila Nieves reported receiving grants from the NIH. Dr Deeks reported receiving grants from the NIH. Dr Emery reported receiving grants from the NIH. Dr Erdmann reported receiving grants from the NIH and personal fees from Perspectum and having a patent for Plantform. Dr Erlandson reported receiving grant funding and advisory fee payments from Gilead Sciences (paid to the University of Colorado) and advisory fee payments from Merck and ViiV (paid to the University of Colorado) in the last 3 years. Ms Gainer reported receiving grants from NIH RECOVER. Dr Geng reported receiving grants from Pfizer and personal fees from UnitedHealthcare. Dr Gibson reported receiving grants from the NIH. Dr Go reported receiving grants from the NIH. Dr Goldman reported receiving grants from Gilead Sciences and Merck; personal fees from Gilead Sciences and Eli Lilly; contracted research from Gilead Sciences, Eli Lilly, and Regeneron Pharmaceuticals; and nonfinancial support from Adaptive Biotechnologies, Labcorp, and Monogram Biosciences. Dr Greenway reported receiving grants from the NIH. Dr Heath reported receiving grants from Merck and Gilead Sciences, personal fees from Regeneron Pharmaceuticals, and being a board member for IsoPlexis. Dr Hess reported receiving grants from the NIH and being a member of a data and safety monitoring board for Astellas Pharmaceuticals. Dr Hodder reported receiving grants from the NHLBI. Dr Hoffman reported receiving grants from the NHLBI. Dr Hughes reported receiving honorarium from UpToDate and personal fees from AMAG Pharmaceuticals. Ms John reported receiving grants from the NIH. Dr Katz reported receiving grants from the NIH. Dr Klein reported receiving grants from NIH RECOVER and consulting fees from Gilead Sciences. Dr Knox reported receiving grants from the NIH. Dr Krishnan reported receiving grants from the NIH/NHLBI; personal fees from GlaxoSmithKline, AstraZeneca, CereVu Medical, BData, Propeller, ResMed, American Board of Internal Medicine, American Academy of Allergy, Asthma, and Immunology; and research funding from the NIH, PCORI, American Lung Association, COPD Foundation, and the Sergey Brin Family Foundation. Dr Laiyemo reported receiving grants from the NIH. Dr Lambert reported receiving grants from the NIH and the PCORI and serving as a site principal investigator for trials funded by Vertex and Aceragan. Dr Luciano reported receiving grants from the NIH and speaker fees from Sanofi-Genzyme. Ms Mallett reported receiving grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr Marathe reported receiving grants from NIH RECOVER and funding from Boston Medical Center. Dr Marconi reported receiving grants from the Centers for Disease Control and Prevention, Veteran Affairs, and the NIH; grants, personal fees, nonfinancial support, and other from Eli Lilly and Gilead; grants and personal fees from ViiV; and nonfinancial support from Bayer. Dr Marshall reported receiving grants from the NIH. Mr Martin reported receiving grants from the NIH. Dr Metz reported receiving grants from the NIH and Pfizer and personal fees from Pfizer. Mr Morse reported receiving grants from the NIH/NHLBI. Dr Mullington reported receiving grants from the NIH and Open Medicine Foundation and speaker and book chapter contribution for Idorsia Pharmaceuticals. Dr Murphy reported receiving grants from the NIH/NHLBI. Dr Nikolich reported receiving grants from the NIH/NHLBI. Dr Ojemakinde reported receiving grants from the NIH. Dr Parry reported receiving grants from NIH RECOVER paid to Penn and funding from the Sergey Brin Family Foundation. Dr Peluso reported receiving personal fees from Gilead Sciences and AstraZeneca. Dr Pogreba-Brown reported receiving grants from NIH RECOVER. Dr Poppas reported owning stock in GE and serving as an UpToDate contributor and co-editor of Hurst and Fuster’s The Heart. Dr Quigley reported receiving grants from the NIH, Pfizer, AbbVie, and Teva Pharmaceutical Industries and personal fees from Alexion Pharmaceuticals, Servier Laboratories, Agios Pharmaceuticals, and Rigel Pharmaceuticals. Dr Reiman reported receiving grants from the NIH. Dr Rischard reported receiving grants from the NIH/NHLBI, Bayer, Janssen, Merck, Aerovate Therapeutics, and Respira Therapeutics and consulting relationships with Acceleron Pharma and United Therapeutics. Dr Rosand reported receiving grants from the NIH and the American Heart Association and personal fees from the National Football League and Takeda Pharmaceutical Co. Dr Shepherd reported receiving grants from NIH RECOVER. Dr Simhan reported receiving grants from the NIH. Dr Singer reported receiving grants from Case Western Reserve University and MetroHealth. Dr Sparks reported receiving grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the R. Bruce and Joan M. Mickey Research Scholar Fund, the Llura Gund Award for Rheumatoid Arthritis Research and Care, Brigham and Women’s Hospital, and Bristol Myers Squibb and personal fees from Bristol Myers Squibb, AbbVie, Amgen, Boehringer Ingelheim, Gilead Sciences, Inova Diagnostics, Janssen, Optum, and Pfizer. Dr Thomas reported receiving personal fees from Guidepoint Global and GLG Councils and having a patent for ECG-spectrogram with royalties paid from MyCardio LLC through Beth Israel Deaconess Medical Center. Dr Thuluvath reported receiving grants from Mercy Medical Center. Dr Tita reported receiving grants from Pfizer. Dr VanWagoner reported receiving grants from the NIH. Dr Vasey reported receiving grants from NIH RECOVER. Dr Wallace reported receiving grants from Bristol Myers Squibb, Sanofi, and Horizon Therapeutics and personal fees from Sanofi, Novartis, Shionogi, Visterra, Horizon Therapeutics, PPD Inc, Zenas BioPharma, and Medpace. Dr Warren reported receiving grants from the NIH. Mr Weiner reported receiving grants from the NIH. Ms Welch reported receiving grants from the NIH. Dr Wisnivesky reported receiving personal fees from PPD Inc, Banook, Sanofi, Atea Pharmaceuticals, and Prospero and grants from Regeneron Pharmaceuticals, Axella, Sanofi, and Arnold. Dr Yee reported receiving grants from the NIH. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. RECOVER Adult Analysis Cohort
aUninfected included acute cohort (n = 1092) and postacute cohort (n = 999) participants. Uninfected participants had no known history of SARS-CoV-2 infection. Acute uninfected participants were enrolled within 30 days of a SARS-CoV-2 negative test result, while postacute uninfected participants were enrolled more than 30 days after a SARS-CoV-2 negative test result. bParticipants who completed visit without reaching end of visit window were included in this count.
Figure 2.
Figure 2.. Defining the Postacute Sequelae of SARS-CoV-2 Infection (PASC) Score and a Decision Rule
A, Optimal score cutoff for classifying a participant as PASC positive using cross-validation (eMethods in Supplement 3). The decision rule based on symptoms is intended to identify participants with PASC. PASC status for participants not meeting the score threshold requires consideration of additional data inputs. B, Symptom frequencies among PASC-positive participants for symptoms that contribute to the PASC score. Many other symptoms have high frequency in PASC-positive participants (eTable 8 in Supplement 3). C, Distribution of Patient-Reported Outcomes Measurement Information System (PROMIS) Global 10 responses among participants with a zero PASC score and among participants within nonzero PASC score quintiles. The PROMIS Global 10 provides an assessment of quality of life along 10 dimensions, each rated on a 5-point scale. The shading corresponds to frequency within each column on a scale from 0% to 100%. aAdditional severity criteria required (eTables 1 and 2 in Supplement 3).
Figure 3.
Figure 3.. Identification of Postacute Sequelae of SARS-CoV-2 Infection (PASC) Subgroups and Their Characteristics
A, Dendrogram illustrating how PASC-positive participants with similar symptom profiles cluster. Each branch in the dendrogram represents a participant, and each cluster represents a subgroup of participants. B. Heatmap of symptom frequencies within PASC unspecified and within each PASC-positive subgroup. The shading corresponds to frequency within each column on a scale from 0% to 100%. aAlthough unsupervised learning uses 12 symptoms selected by least absolute shrinkage and selection operator (LASSO) (Figure 2), many other symptoms occur in combination with these 12.
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