2024 Update of the RECOVER-Adult Long COVID Research Index

Linda N Geng; Kristine M Erlandson; Mady Hornig; Rebecca Letts; Caitlin Selvaggi; Hassan Ashktorab; Ornina Atieh; Logan Bartram; Hassan Brim; Shari B Brosnahan; Jeanette Brown; Mario Castro; Alexander Charney; Peter Chen; Steven G Deeks; Nathaniel Erdmann; Valerie J Flaherman; Maher A Ghamloush; Paul Goepfert; Jason D Goldman; Jenny E Han; Rachel Hess; Ellie Hirshberg; Susan E Hoover; Stuart D Katz; J Daniel Kelly; Jonathan D Klein; Jerry A Krishnan; Joyce Lee-Iannotti; Emily B Levitan; Vincent C Marconi; Torri D Metz; Matthew E Modes; Janko Ž Nikolich; Richard M Novak; Igho Ofotokun; Megumi J Okumura; Sairam Parthasarathy; Thomas F Patterson; Michael J Peluso; Athena Poppas; Orlando Quintero Cardona; Jake Scott; Judd Shellito; Zaki A Sherif; Nora G Singer; Barbara S Taylor; Tanayott Thaweethai; Monica Verduzco-Gutierrez; Juan Wisnivesky; Grace A McComsey; Leora I Horwitz; Andrea S Foulkes

doi:10.1001/jama.2024.24184

. 2024 Dec 18;333(8):694–700. doi: 10.1001/jama.2024.24184

2024 Update of the RECOVER-Adult Long COVID Research Index

Linda N Geng ¹, Kristine M Erlandson ², Mady Hornig ^3,⁴, Rebecca Letts ⁵, Caitlin Selvaggi ⁶, Hassan Ashktorab ⁷, Ornina Atieh ⁸, Logan Bartram ⁹, Hassan Brim ⁷, Shari B Brosnahan ¹⁰, Jeanette Brown ¹¹, Mario Castro ¹², Alexander Charney ⁹, Peter Chen ^13,¹⁴, Steven G Deeks ¹⁵, Nathaniel Erdmann ¹⁶, Valerie J Flaherman ¹⁷, Maher A Ghamloush ¹⁸, Paul Goepfert ¹⁶, Jason D Goldman ¹⁹, Jenny E Han ²⁰, Rachel Hess ²¹, Ellie Hirshberg ²², Susan E Hoover ²³, Stuart D Katz ¹⁰, J Daniel Kelly ¹⁵, Jonathan D Klein ^24,²⁵, Jerry A Krishnan ^24,²⁶, Joyce Lee-Iannotti ²⁷, Emily B Levitan ²⁸, Vincent C Marconi ^29,^30,³¹, Torri D Metz ³², Matthew E Modes ³³, Janko Ž Nikolich ³⁴, Richard M Novak ^24,²⁶, Igho Ofotokun ²⁹, Megumi J Okumura ³⁵, Sairam Parthasarathy ³⁶, Thomas F Patterson ³⁷, Michael J Peluso ¹⁵, Athena Poppas ³⁸, Orlando Quintero Cardona ³⁹, Jake Scott ³⁹, Judd Shellito ⁴⁰, Zaki A Sherif ⁷, Nora G Singer ⁴¹, Barbara S Taylor ³⁷, Tanayott Thaweethai ^6,⁴², Monica Verduzco-Gutierrez ³⁷, Juan Wisnivesky ⁹, Grace A McComsey ⁴³, Leora I Horwitz ^10,^44,^✉, Andrea S Foulkes ^6,^42,⁴⁵, for the RECOVER Consortium

¹Department of Medicine, School of Medicine, Stanford University, Stanford, California

²Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora

³RECOVER patient representative, New York, New York

⁴CORe Community Inc (COVID Recovery through Community), New York, New York

⁵RECOVER patient/caregiver representative, New York, New York

⁶Massachusetts General Hospital Biostatistics, Boston

⁷College of Medicine, Howard University, Washington, DC

⁸Case Western Reserve University, Cleveland, Ohio

⁹Icahn School of Medicine at Mount Sinai, New York, New York

¹⁰Department of Medicine, NYU Grossman School of Medicine, New York, New York

¹¹University of Utah Health, Salt Lake City

¹²Department of Medicine, University of Kansas Medical Center, Kansas City

¹³Department of Medicine, Women’s Guild Lung Institute, Los Angeles, California

¹⁴Cedars-Sinai Medical Center, Los Angeles, California

¹⁵University of California, San Francisco

¹⁶Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham

¹⁷Department of Pediatrics, University of California San Francisco

¹⁸Tufts Medical Center, Boston, Massachusetts

¹⁹Swedish Center for Research and Innovation, Providence Swedish Medical Center, Seattle, Washington

²⁰Division of Pulmonary and Critical Care, Department of Medicine, School of Medicine, Emory University, Atlanta, Georgia

²¹Departments of Population Health Sciences and Internal Medicine, Spencer Fox Eccles School of Medicine, University of Utah, Salt Lake City

²²Intermountain Health, Salt Lake City, Utah

²³Sanford Health, Sioux Falls, South Dakota

²⁴ILLInet RECOVER, Chicago, Illinois

²⁵Department of Pediatrics, Stanford University, Stanford, California

²⁶University of Illinois, Chicago

²⁷College of Medicine, University of Arizona, Phoenix

²⁸Department of Epidemiology, School of Public Health, University of Alabama at Birmingham

²⁹Division of Infectious Diseases, Department of Medicine, School of Medicine, Emory University, Atlanta, Georgia

³⁰Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia

³¹Atlanta Veterans Affairs Medical Center, Atlanta, Georgia

³²Department of Obstetrics and Gynecology, University of Utah Health, Salt Lake City

³³Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California

³⁴Department of Immunobiology, College of Medicine, University of Arizona, Tucson

³⁵Departments of Pediatrics, Internal Medicine, and Health Policy, University of California, San Francisco

³⁶College of Medicine, University of Arizona, Tucson

³⁷University of Texas Health Science Center at San Antonio

³⁸Warren Alpert Medical School, Brown University, Providence, Rhode Island

³⁹Stanford Tri-Valley Section, Stanford Hospital Medicine, Pleasanton, California

⁴⁰Louisiana State University, New Orleans

⁴¹Case Western Reserve University and Metrohealth Medical Center, Cleveland, Ohio

⁴²Department of Medicine, Harvard Medical School, Harvard University, Boston, Massachusetts

⁴³Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio

⁴⁴Department of Population Health, NYU Grossman School of Medicine, New York, New York

⁴⁵Department of Biostatistics, T. H. Chan School of Public Health, Harvard University, Boston, Massachusetts

Group Information: The members of the RECOVER Consortium are listed in Supplement 2.

Accepted for Publication: October 28, 2024.

Published Online: December 18, 2024. doi:10.1001/jama.2024.24184

^✉

Corresponding Author: Leora I. Horwitz, MD, MHS, NYU Grossman School of Medicine, 550 First Ave, New York, NY 10016 (leora.horwitz@nyulangone.org).

Author Contributions: Dr Foulkes had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Geng and Erlandson are co-first authors. Drs McComsey, Horwitz, and Foulkes are co-senior authors.

Concept and design: Geng, Erlandson, Letts, Brim, Brosnahan, Brown, Charney, Erdmann, Hess, Katz, Kelly, Lee-Iannotti, Metz, Nikolich, Ofotokun, Parthasarathy, Shellito, Taylor, Thaweethai, Verduzco-Gutierrez, McComsey, Horwitz, Foulkes.

Acquisition, analysis, or interpretation of data: Geng, Erlandson, Hornig, Selvaggi, Ashktorab, Atieh, Bartram, Brim, Castro, Charney, Chen, Deeks, Erdmann, Flaherman, Ghamloush, Goepfert, Goldman, Han, Hess, Hirshberg, Hoover, Katz, Kelly, Klein, Krishnan, Lee-Iannotti, Levitan, Marconi, Metz, Modes, Novak, Ofotokun, Okumura, Patterson, Peluso, Poppas, Quintero Cardona, Scott, Sherif, Singer, Taylor, Thaweethai, Wisnivesky, McComsey, Horwitz, Foulkes.

Drafting of the manuscript: Geng, Selvaggi, Brosnahan, Goepfert, Han, Parthasarathy, Scott, Shellito, Thaweethai, McComsey, Horwitz, Foulkes.

Critical review of the manuscript for important intellectual content: Geng, Erlandson, Hornig, Letts, Selvaggi, Ashktorab, Atieh, Bartram, Brim, Brown, Castro, Charney, Chen, Deeks, Erdmann, Flaherman, Ghamloush, Goldman, Han, Hess, Hirshberg, Hoover, Katz, Kelly, Klein, Krishnan, Lee-Iannotti, Levitan, Marconi, Metz, Modes, Nikolich, Novak, Ofotokun, Okumura, Parthasarathy, Patterson, Peluso, Poppas, Quintero Cardona, Sherif, Singer, Taylor, Thaweethai, Verduzco-Gutierrez, Wisnivesky, McComsey, Foulkes.

Statistical analysis: Selvaggi, Han, Thaweethai, McComsey, Foulkes.

Obtained funding: Erlandson, Ashktorab, Brim, Charney, Erdmann, Katz, Kelly, Krishnan, Nikolich, Ofotokun, Parthasarathy, Sherif, Taylor, Wisnivesky, McComsey, Horwitz, Foulkes.

Administrative, technical, or material support: Geng, Erlandson, Ashktorab, Bartram, Brosnahan, Brown, Charney, Chen, Deeks, Flaherman, Goldman, Han, Katz, Kelly, Klein, Krishnan, Modes, Ofotokun, Okumura, Parthasarathy, Poppas, Taylor, Wisnivesky, McComsey, Horwitz, Foulkes.

Supervision: Geng, Brim, Castro, Deeks, Erdmann, Goepfert, Han, Kelly, Krishnan, Lee-Iannotti, Nikolich, Novak, Ofotokun, Parthasarathy, Quintero Cardona, Thaweethai, McComsey, Horwitz, Foulkes.

Conflict of Interest Disclosures: Dr Geng reported receiving research support from Pfizer that was paid directly to her institution and receiving personal fees from UnitedHealth Group. Dr Erlandson reported receiving grants from Gilead Sciences paid to directly to her institution and receiving personal fees from Gilead Sciences, ViiV, and Merck. Dr Brown reported receiving personal fees from Breas Medical. Dr Castro reported receiving grants from ALA, AstraZeneca, GSK, Novartis, Pulmatrix, Sanofi-Aventis, Shionogi, Teva, Gala Therapeutics, Theravance, Nocion, and Genentech and receiving personal fees from Allakos, Amgen, Apogee, Apreo Health, Arrowhead Pharmaceuticals, Blueprint Medicines, Connect Biopharma, Evommune, Jasper, Kinaset, Merck, Novartis, OM Pharma, Pfizer, Pioneering Medicines, Sanofi-Aventis, Teva, Third Rock Ventures, Upstream Bio, Verona Pharmaceuticals, and Aer Therapeutics. Dr Deeks reported receiving personal fees from BioVie Pharma, Enanta, and Pfizer and receiving nonfinancial support from Aerium, Eli Lilly, and Gilead. Dr Erdmann reported receiving personal fees from Pfizer and having a patent for human neutralizing antibodies that was licensed to PlantForm. Dr Ghamloush reported receiving grants from 4DMedical. Dr Goepfert reported having a patent for COVID-19 monoclonal antibody that was licensed to Aridis Pharmaceuticals. Dr Goldman reported having research contracts with Gilead, Regeneron, and Helix; receiving grants from Gilead and BARDA (Merck); serving as a speaker or advisory board member for Gilead, Merck, and Invivyd; and having collaborative service agreements with Adaptive Biotechnologies and Monogram Biosciences/Labcorp. Dr Hess reported receiving personal fees from Astellas Pharmaceuticals. Dr Hirshberg reported receiving grants from Intermountain Health. Dr Krishnan reported receiving grants from the Patient-Centered Outcomes Research Institute, the COPD Foundation, the American Lung Association, and Verily that were paid directly to his institution. Dr Levitan reported receiving research support from Amgen that was paid directly to her institution and receiving personal fees from the University of Pittsburgh. Dr Marconi reported receiving research support and consultation fees from Eli Lilly, Bayer, Gilead Sciences, Merck, and ViiV that were paid directly to his institution. Dr Metz reported receiving grants from Pfizer. Dr Novak reported receiving personal fees from Gilead and Moderna. Dr Parthasarathy reported receiving grants from Verily Lifesciences, Philips, and Regeneron that were paid directly to his institution and receiving personal fees from AbbVie, Apria Healthcare, and Jazz Pharmaceuticals. Dr Peluso reported receiving research support from Aerium Therapeutics that was paid directly to his institution; receiving personal fees from Gilead Sciences, AstraZeneca, BioNTech, BioVie, and Apellis Pharmaceuticals; and receiving nonfinancial support from Aerium Therapeutics and Shionogi. Dr Verduzco-Gutierrez reported receiving research support from Ipsen that was paid directly to her institution and receiving personal fees from Ipsen, AbbVie, Merz, Revance, and Pfizer. Dr Wisnivesky reported receiving personal fees from Sanofi, ThermoFisher Scientific/PPD, Banook, the American Medical Association, and BioNTech and receiving grants from Sanofi, Regeneron, and Axella. Dr McComsey reported receiving research support from Astellas, Roche, Genentech, Pfizer, Redhill, and Cognivue and receiving personal fees from GSK/ViiV, Gilead, Janssen, and Merck. No other disclosures were reported.

Funding/Support: This research was funded by agreements OTA OT2HL161847, OT2HL161841, and OT2HL156812 and grant R01 HL162373 (awarded to Drs Thaweethai and Foulkes) from the National Institutes of Health as part of the Researching COVID to Enhance Recovery (RECOVER) Research Initiative. Additional research support was provided by the Emory Center for AIDS Research (grant P30AI050409 awarded to Dr Marconi) and the Clinical and Translational Science Collaborative of Northern Ohio (grant UM1TR004528 awarded to Dr McComsey).

Role of the Funder/Sponsor: The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The members of the RECOVER Consortium are listed in Supplement 2.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We thank the national community engagement group, caregivers, community representatives, and the participants enrolled in the RECOVER Initiative.

^✉

Corresponding author.

PMCID: PMC11862971 PMID: 39693079

Key Points

Question

How do updated data from nearly 4000 additional participants and expanded symptom questionnaires inform the prior research classification for long COVID (LC) or post–COVID-19 condition?

Findings

In this prospective, observational cohort study, data from 13 647 adults participating in the Researching COVID to Enhance Recovery (RECOVER-Adult) study were used to update the research index for classifying symptomatic LC and 5 symptom subtypes that differ in associated demographic features and quality of life.

Meaning

The 2024 LC research index may help researchers identify people with symptomatic LC and its symptom subtypes. Refinement of the index will be needed as research advances and the understanding of LC deepens.

Abstract

Importance

Classification of persons with long COVID (LC) or post–COVID-19 condition must encompass the complexity and heterogeneity of the condition. Iterative refinement of the classification index for research is needed to incorporate newly available data as the field rapidly evolves.

Objective

To update the 2023 research index for adults with LC using additional participant data from the Researching COVID to Enhance Recovery (RECOVER-Adult) study and an expanded symptom list based on input from patient communities.

Design, Setting, and Participants

Prospective, observational cohort study including adults 18 years or older with or without known prior SARS-CoV-2 infection who were enrolled at 83 sites in the US and Puerto Rico. Included participants had at least 1 study visit taking place 4.5 months after first SARS-CoV-2 infection or later, and not within 30 days of a reinfection. The study visits took place between October 2021 and March 2024.

Exposure

SARS-CoV-2 infection.

Main Outcomes and Measures

Presence of LC and participant-reported symptoms.

Results

A total of 13 647 participants (11 743 with known SARS-CoV-2 infection and 1904 without known prior SARS-CoV-2 infection; median age, 45 years [IQR, 34-69 years]; and 73% were female) were included. Using the least absolute shrinkage and selection operator analysis regression approach from the 2023 model, symptoms contributing to the updated 2024 index included postexertional malaise, fatigue, brain fog, dizziness, palpitations, change in smell or taste, thirst, chronic cough, chest pain, shortness of breath, and sleep apnea. For the 2024 LC research index, the optimal threshold to identify participants with highly symptomatic LC was a score of 11 or greater. The 2024 index classified 20% of participants with known prior SARS-CoV-2 infection and 4% of those without known prior SARS-CoV-2 infection as having likely LC (vs 21% and 5%, respectively, using the 2023 index) and 39% of participants with known prior SARS-CoV-2 infection as having possible LC, which is a new category for the 2024 model. Cluster analysis identified 5 LC subtypes that tracked quality-of-life measures.

Conclusions and Relevance

The 2024 LC research index for adults builds on the 2023 index with additional data and symptoms to help researchers classify symptomatic LC and its symptom subtypes. Continued future refinement of the index will be needed as the understanding of LC evolves.

This prospective, observational cohort study uses data from the Researching COVID to Enhance Recovery adult cohort to assess post–COVID-19 condition (or long COVID) with additional participant data and an expanded symptom list.

Introduction

Long COVID (LC) or post–COVID-19 condition is a major public health issue.^1,2 The National Academies of Sciences, Engineering, and Medicine (NASEM) defines LC as a heterogeneous, infection-associated chronic condition present for at least 3 months after SARS-CoV-2 infection.³ The NASEM definition is broadly inclusive and does not require or exclude any symptoms or conditions. However, a granular index for LC is needed to (1) support rigorous and reproducible research and (2) identify biomarkers and treatments.⁴ Challenges to the establishment of such a research index for LC include the nonspecific nature of many symptoms; the complex and often fluctuating illness trajectory; uncertainty about SARS-CoV-2 infection history; and shifts in virus, immunity, reinfections, and treatments that may be altering the nature of the condition itself.

As part of the National Institutes of Health–funded Researching COVID to Enhance Recovery (RECOVER) Initiative (https://recovercovid.org/), we published details regarding a preliminary research index⁵ to identify symptomatic LC based on the symptoms reported by the first 9764 adults enrolled in the RECOVER-Adult study, anticipating refinement of the index after acquisition of additional data. Since then, 3883 additional participants were enrolled in the RECOVER-Adult study or had qualifying visits. Based on patient and community input, data on symptoms of 3 syndromes (myalgic encephalomyelitis/chronic fatigue syndrome,⁶ dysautonomia,⁷ and mast cell activation syndrome⁸) that overlap with LC were collected. The current analysis compares the 2023 symptom-based LC research index with the 2024 index.

Methods

The NYU Grossman School of Medicine institutional review board provided approval. All participants provided written informed consent. Adults with or without known prior SARS-CoV-2 infection were enrolled at 83 sites in the US and Puerto Rico and completed symptom surveys every 90 days.^9,10 Included participants had at least 1 study visit taking place 4.5 months after the first SARS-CoV-2 infection or later, and not within 30 days of a reinfection; visits occurred between October 2021 and March 2024 (eMethods in Supplement 1). Eight symptoms were added in June 2023 (eTable 1 in Supplement 1).

Balancing weights were used to account for differences in the distributions for age, sex, and race and ethnicity between participants with vs without known prior SARS-CoV-2 infection. Frequencies of each symptom by SARS-CoV-2 infection status and adjusted odds ratios were calculated using weighted logistic regression. The least absolute shrinkage and selection operator (LASSO) regression approach was used to assign points to each symptom.^5,11

The original 44 participant-reported symptoms were used for the LASSO regression approach. The participant-level LC research index was defined as the sum of the points for each reported symptom. An optimal LC index threshold was selected based on the estimated false-positive rate (eMethods in Supplement 1); participants above this threshold were classified as having likely LC. Participants with at least 1 symptom selected by the LASSO regression approach, but not above the threshold were classified as having possible LC. Participants with likely LC were classified into subtypes using the LASSO-selected symptoms as previously described.⁵ All 52 symptoms were reported overall and by subtypes.

Results

A total of 13 647 participants (11 743 [86%] with known prior SARS-CoV-2 infection and 1904 [14%] without known prior SARS-CoV-2 infection; median age, 45 years [IQR, 34-69 years]; and 73% were female) were included (eFigure 1 and eTable 2 in Supplement 1). All symptoms were more prevalent in participants with vs without prior SARS-CoV-2 infection (adjusted odds ratio >1) (eFigure 2 in Supplement 1).

2024 LC Research Index

Compared with the 2023 LC research index,⁵ there were 3 symptoms (lack of sexual desire or capacity, gastrointestinal symptoms, and abnormal movements) excluded from the 2024 LC research index and 2 symptoms added (shortness of breath and snoring or sleep apnea). The scores were consistent with the 2023 index (Table). For the 2024 LC research index, the optimal threshold to identify participants with highly symptomatic LC was a score of 11 or greater (eFigure 3 in Supplement 1). The 2024 index classified 20% of participants with known prior SARS-CoV-2 infection and 4% of participants without known prior SARS-CoV-2 infection as having likely LC (vs 21% and 5%, respectively, using the 2023 index) and 39% of participants with known prior SARS-CoV-2 infection as having possible LC (scores ≥1-<11), which is a new category for the 2024 model (Figure 1 and eTable 3 in Supplement 1).

Table. Model-Selected Symptoms and Associated Points^a.

Symptom	2024 analysis^b		2023 analysis^c
Symptom	Log odds ratio	Points^d	Log odds ratio	Points^d
Score contributors to the 2024 model
Loss of smell or taste	0.734	7	0.776	8
Postexertional malaise	0.599	6	0.674	7
Chronic cough	0.436	4	0.438	4
Brain fog^e	0.273	3	0.325	3
Thirst	0.062	1	0.255	3
Palpitations	0.234	2	0.238	2
Chest pain^e	0.132	1	0.233	2
Fatigue^e	0.138	1	0.148	1
Dizziness	0.168	2	0.121	1
Shortness of breath	0.182	2	0	0
Snoring or sleep apnea	0.060	1	0	0
Score contributors to the 2023 but not 2024 model
Lack of sexual desire or capacity	0	0	0.126	1
Gastrointestinal symptoms	0	0	0.085	1
Abnormal movements	0.010	0	0.072	1
Hair loss	0	0	0.049	0
Sleep disturbance	0.038	0	0	0

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^{^a}

The least absolute shrinkage and selection operator (LASSO) regression models were fitted using SARS-CoV-2 infection status as the outcome. The 44 original symptoms were used for the LASSO regression models, but the 8 symptoms added to the expanded questionnaire were excluded.

^{^b}

Based on 13 647 adults enrolled in the Researching COVID to Enhance Recovery (RECOVER-Adult) cohort study prior to March 15, 2024, with at least 1 visit taking place at least 135 days (approximately 4.5 months) after the index SARS-CoV-2 infection, and not within 30 days of a reinfection.

^{^c}

Based on 9764 participants enrolled in RECOVER-Adult prior to April 10, 2023, with at least 1 visit taking place at least 135 days (approximately 4.5 months) after the index SARS-CoV-2 infection.

^{^d}

Determined by multiplying the corresponding estimated log odds ratio by 10 and rounding to the nearest integer.⁵

^{^e}

Required additional severity measure to be considered present in the analysis.⁵

Among participants with prior SARS-CoV-2 infection, 2213 (18.8%) met both the 2023 and 2024 thresholds, 121 (1.0%) met the 2024 but not the 2023 threshold, and 200 (1.7%) met the 2023 but not the 2024 threshold (Figure 1). The proportion meeting the 2024 threshold was greater among participants with SARS-CoV-2 infection before circulation of the Omicron variant (33.8%) vs during Omicron variant circulation (12.7%). The most common symptoms in participants with likely LC were fatigue (85.8% [2002/2334]), postexertional malaise (87.4% [2041/2334]), postexertional soreness (75.0% [225/300]), dizziness (65.8% [1535/2334]), brain fog (63.8% [1488/2334]), gastrointestinal symptoms (59.3% [1385/2334]), and palpitations (58.0% [1353/2334]) (Figure 2).

Symptom Subtypes for LC

Among participants with likely LC and prior known SARS-CoV-2 infection, 5 symptom subtypes were identified (Figure 2). Fatigue and postexertional malaise were prominent in all but subtype 1. Additional prominent features included change in smell or taste (subtype 1), chronic cough (subtype 2), brain fog (subtype 3), palpitations (subtype 4), and postexertional soreness, dizziness, and gastrointestinal symptoms (subtype 5). Participants with a high burden of multisystem symptoms (subtype 5) more often reported worse quality of life, physical health, and daily function than those in the other subtypes (Figure 2 and eFigure 4 in Supplement 1).

Compared with males, a lower proportion of females were classified as having subtype 3 and a higher proportion were classified as having subtype 4 or 5 (eTable 4 in Supplement 1). A higher proportion of Hispanic and multiracial participants were classified as having subtype 5. Higher proportions of unvaccinated participants and those with SARS-CoV-2 infection before circulation of the Omicron variant were in subtype 5.

Discussion

The 2024 index builds upon the 2023 index with additional data from 3883 participants and additional symptoms to provide a classification for research use within the broader NASEM definition of LC.^3,5 Compared with the 2023 index, the 2024 index refines the LC classification, consolidates candidate organ systems, increases symptom specificity (replacing broad categories of abnormal movements and gastrointestinal symptoms with more specific symptoms such as shortness of breath and sleep apnea), and further differentiates symptoms into 5 subtypes that track quality-of-life measures.⁵ The 2024 index does not include postinfection routine laboratory data because these were not meaningfully associated with prior SARS-CoV-2 infection status.¹² Individuals not meeting the 2024 index threshold of 11 or greater may still have LC. The index is not designed for clinical diagnosis and researchers may select different thresholds tailored to their needs.

The 2024 and 2023 index models are overall aligned, as evidenced by the positive correlation of LC indices and worsening quality of life as symptom burden increases among subtypes (Figure 1). Fatigue and postexertional malaise were common, suggesting some shared pathways with other infection–associated chronic conditions such as myalgic encephalomyelitis/chronic fatigue syndrome.^6,13 The symptom subtypes reflect the heterogeneity of LC, and mechanistic studies will be critical to understand the distinct disease processes. For instance, subtype 5 (the most severe form) was more prevalent among individuals infected before the Omicron variant or before vaccination, potentially suggesting distinct mechanisms of disease. Similarly, when the same method was used to derive a pediatric index, its use resulted in comparable though not identical component symptoms.¹⁴

Strengths of this study include large sample size, prospective collection of symptoms, and comparison of participants with vs without known prior SARS-CoV-2 infection. The symptom subtypes may facilitate recognition of the variety of presentations for LC. Inclusion of symptoms related to other infection–associated conditions aligns with patient and community feedback. Within the broader NASEM framework, the 2024 index offers granularity for research use when specificity and control groups are needed.

Limitations

This study has several limitations. First, we cannot distinguish time-dependent effects on symptoms and illness trajectory. Second, decreased testing, milder acute disease, and waning antibody levels could have misclassified some participants in the uninfected group. Third, symptoms from other conditions and medications may have confounded the index. Fourth, selection and attrition biases may have affected cohort characteristics and the relative representation of different variants.⁵

Conclusions

Supplement 1.

eMethods

eTable 1. Symptoms added to survey and considered in determining index threshold

eTable 2. Demographic characteristics of cohort by infection status at analysis visit

eTable 3. Participants meeting Long COVID (LC) index thresholds

eTable 4. Demographics by Long COVID (LC) phenotype cluster among participants with a history of infection and an LC Index score of ≥ 11

eFigure 1. Cohort Development

eFigure 2. Adjusted Odds Ratios for symptoms between infected and uninfected groups

eFigure 3. Selection criteria for determining optimal Long COVID (LC) Index threshold

eFigure 4. Quality of life and function measures across clusters

eReferences

jama-e2424184-s001.pdf^{(1.2MB, pdf)}

Supplement 2.

Nonauthor collaborators

jama-e2424184-s002.pdf^{(372.4KB, pdf)}

Supplement 3.

Data sharing statement

jama-e2424184-s003.pdf^{(16.2KB, pdf)}

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12.Erlandson KM, Geng LN, Selvaggi CA, et al. ; RECOVER-Adult Cohort . Differentiation of prior SARS-CoV-2 infection and postacute sequelae by standard clinical laboratory measurements in the RECOVER cohort. Ann Intern Med. 2024;177(9):1209-1221. doi: 10.7326/M24-0737 [DOI] [PMC free article] [PubMed] [Google Scholar]
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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eMethods

eTable 1. Symptoms added to survey and considered in determining index threshold

eTable 2. Demographic characteristics of cohort by infection status at analysis visit

eTable 3. Participants meeting Long COVID (LC) index thresholds

eTable 4. Demographics by Long COVID (LC) phenotype cluster among participants with a history of infection and an LC Index score of ≥ 11

eFigure 1. Cohort Development

eFigure 2. Adjusted Odds Ratios for symptoms between infected and uninfected groups

eFigure 3. Selection criteria for determining optimal Long COVID (LC) Index threshold

eFigure 4. Quality of life and function measures across clusters

eReferences

jama-e2424184-s001.pdf^{(1.2MB, pdf)}

Supplement 2.

Nonauthor collaborators

jama-e2424184-s002.pdf^{(372.4KB, pdf)}

Supplement 3.

Data sharing statement

jama-e2424184-s003.pdf^{(16.2KB, pdf)}

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PERMALINK

2024 Update of the RECOVER-Adult Long COVID Research Index

Linda N Geng, MD, PhD

Kristine M Erlandson, MD, MSc

Mady Hornig, MA, MD

Rebecca Letts, BA

Caitlin Selvaggi, MS

Hassan Ashktorab, PhD

Ornina Atieh, MD

Logan Bartram, MD

Hassan Brim, PhD

Shari B Brosnahan, MD, MSc

Jeanette Brown, MD, PhD

Mario Castro, MD

Alexander Charney, MD, PhD

Peter Chen, MD

Steven G Deeks, MD

Nathaniel Erdmann, MD, PhD

Valerie J Flaherman, MD, MPH

Maher A Ghamloush, MD

Paul Goepfert, MD

Jason D Goldman, MD, MPH

Jenny E Han, MD, MSc

Rachel Hess, MD, MS

Ellie Hirshberg, MD

Susan E Hoover, MD

Stuart D Katz, MD

J Daniel Kelly, MD, PhD

Jonathan D Klein, MD, MPH

Jerry A Krishnan, MD, PhD

Joyce Lee-Iannotti, MD

Emily B Levitan, ScD

Vincent C Marconi, MD

Torri D Metz, MD, MS

Matthew E Modes, MD, MPP, MS

Janko Ž Nikolich, MD, PhD

Richard M Novak, MD

Igho Ofotokun, MD, MSc

Megumi J Okumura, MD, MAS

Sairam Parthasarathy, MD

Thomas F Patterson, MD

Michael J Peluso, MD

Athena Poppas, MD

Orlando Quintero Cardona, MD

Jake Scott, MD

Judd Shellito, MD

Zaki A Sherif, PhD

Nora G Singer, MD

Barbara S Taylor, MD

Tanayott Thaweethai, PhD

Monica Verduzco-Gutierrez, MD

Juan Wisnivesky, MD, DrPH

Grace A McComsey, MD

Leora I Horwitz, MD, MHS

Andrea S Foulkes, ScD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Exposure

Main Outcomes and Measures

Results

Conclusions and Relevance

Introduction

Methods

Results

2024 LC Research Index

Table. Model-Selected Symptoms and Associated Pointsa.

Figure 1. Relationship Between 2023 and 2024 Research Index for Long COVID (LC) Among Adult Participants With a History of SARS-CoV-2 Infection.

Figure 2. Symptom Frequency by Long COVID (LC) Status and History of SARS-CoV-2 Infection.

Symptom Subtypes for LC

Discussion

Limitations

Conclusions

References

Associated Data

Table. Model-Selected Symptoms and Associated Points^a.