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Cardiology

Use of Cardiopulmonary Exercise Testing to Evaluate Long COVID-19 Symptoms in AdultsA Systematic Review and Meta-analysis

Educational Objective
To identify the key insights or developments described in this article

1 Credit CME

JAMA Network Open

Published Online: October 12, 2022

Original Investigation

Article Information and Disclosures

Matthew S. Durstenfeld, MD, MAS^1,2;

Kaiwen Sun, MD¹;

Peggy Tahir, MLIS, MA³;

Michael J. Peluso, MD, MHS, MPhil, DTMH^1,4;

Steven G. Deeks, MD^1,4;

Mandar A. Aras, MD, PhD^1,5;

Donald J. Grandis, MD^1,5;

Carlin S. Long, MD^1,5;

Alexis Beatty, MD^1,5,6;

Priscilla Y. Hsue, MD^1,2

Author Affiliations

¹Department of Medicine, University of California, San Francisco
²Division of Cardiology, Zuckerberg San Francisco General Hospital, San Francisco, California
³UCSF Library, University of California, San Francisco
⁴Division of HIV, Infectious Diseases, and Global Medicine, Zuckerberg San Francisco General Hospital, University of California, San Francisco
⁵Division of Cardiology, UCSF Health, University of California, San Francisco
⁶Department of Epidemiology and Biostatistics, University of California, San Francisco

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Key Points

Question Is exercise capacity reduced more than 3 months after SARS-CoV-2 infection among those with long COVID-19 (LC) symptoms compared with recovered individuals without symptoms, and what patterns of limitations on cardiopulmonary exercise testing (CPET) are common?

Findings In this systematic review and meta-analysis of 38 studies comprising 2160 participants, exercise capacity was reduced by 4.9 mL/kg/min among individuals with symptoms consistent with LC compared with individuals without symptoms more than 3 months after SARS-CoV-2 infection. Findings among individuals with exertional intolerance suggest that deconditioning, dysfunctional breathing, chronotropic incompetence, and abnormal peripheral oxygen extraction and/or use may contribute to reduced exercise capacity.

Meaning These findings suggest that CPET may provide insight into the mechanisms for reduced exercise capacity among individuals with LC.

Abstract

Importance Reduced exercise capacity is commonly reported among individuals with COVID-19 symptoms more than 3 months after SARS-CoV-2 infection (long COVID-19 [LC]). Cardiopulmonary exercise testing (CPET) is the criterion standard to measure exercise capacity and identify patterns of exertional intolerance.

Objectives To estimate the difference in exercise capacity among individuals with and without LC symptoms and characterize physiological patterns of limitations to elucidate possible mechanisms of LC.

Data Sources A search of PubMed, EMBASE, Web of Science, preprint servers, conference abstracts, and cited references was performed on December 20, 2021, and again on May 24, 2022. A preprint search of medrxiv.org, biorxiv.org, and researchsquare.com was performed on June 9, 2022.

Study Selection Studies of adults with SARS-CoV-2 infection more than 3 months earlier that included CPET-measured peak oxygen consumption (V̇o₂) were screened independently by 2 blinded reviewers; 72 (2%) were selected for full-text review, and 35 (1%) met the inclusion criteria. An additional 3 studies were identified from preprint servers.

Data Extraction and Synthesis Data extraction was performed by 2 independent reviewers according to the PRISMA reporting guideline. Data were pooled using random-effects models.

Main Outcomes and Measures Difference in peak V̇o₂ (in mL/kg/min) among individuals with and without persistent COVID-19 symptoms more than 3 months after SARS-CoV-2 infection.

Results A total of 38 studies were identified that performed CPET on 2160 individuals 3 to 18 months after SARS-CoV-2 infection, including 1228 with symptoms consistent with LC. Most studies were case series of individuals with LC or cross-sectional assessments within posthospitalization cohorts. Based on a meta-analysis of 9 studies including 464 individuals with LC symptoms and 359 without symptoms, the mean peak V̇o₂ was −4.9 (95% CI, −6.4 to −3.4) mL/kg/min among those with symptoms with a low degree of certainty. Deconditioning and peripheral limitations (abnormal oxygen extraction) were common, but dysfunctional breathing and chronotropic incompetence were also described. The existing literature was limited by small sample sizes, selection bias, confounding, and varying symptom definitions and CPET interpretations, resulting in high risk of bias and heterogeneity.

Conclusions and Relevance The findings of this systematic review and meta-analysis study suggest that exercise capacity was reduced more than 3 months after SARS-CoV-2 infection among individuals with symptoms consistent with LC compared with individuals without LC symptoms, with low confidence. Potential mechanisms for exertional intolerance other than deconditioning include altered autonomic function (eg, chronotropic incompetence, dysfunctional breathing), endothelial dysfunction, and muscular or mitochondrial pathology.

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Article Information

Accepted for Publication: August 25, 2022.

Published: October 12, 2022. doi:10.1001/jamanetworkopen.2022.36057

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Durstenfeld MS et al. JAMA Network Open.

Corresponding Author: Matthew S. Durstenfeld, MD, MAS, Division of Cardiology, University of California, San Francisco at Zuckerberg San Francisco General Hospital, 1001 Potrero Ave, Room 5G8, San Francisco, CA 94110 (matthew.durstenfeld@ucsf.edu).

Author Contributions: Dr Durstenfeld 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.

Concept and design: Durstenfeld, Sun, Peluso, Long, Hsue.

Acquisition, analysis, or interpretation of data: Durstenfeld, Tahir, Peluso, Deeks, Aras, Grandis, Beatty, Hsue.

Drafting of the manuscript: Durstenfeld, Sun, Tahir.

Critical revision of the manuscript for important intellectual content: Tahir, Peluso, Deeks, Aras, Grandis, Long, Beatty, Hsue.

Statistical analysis: Durstenfeld, Sun, Peluso.

Obtained funding: Durstenfeld, Peluso, Grandis, Long.

Administrative, technical, or material support: Durstenfeld, Tahir, Peluso, Deeks.

Supervision: Peluso, Aras, Grandis, Beatty, Hsue.

Conflict of Interest Disclosures: Dr Beatty reported receiving a salary in 2018 and 2019 and stock from 2019 to 2021 from Apple Inc and receiving grants from the National Heart, Lung, and Blood Institute (NHLBI) outside the submitted work. Dr Hsue reported receiving honoraria from Gilead Sciences Inc and Merck & Co Inc and receiving grants from Novartis AG outside the submitted work. No other disclosures were reported.

Funding/Support: This study was funded by grant K12 HL143961 from the NHLBI.

Role of the Funder/Sponsor: The sponsor 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.

AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
1.00 credit toward the CME of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.