Key PointsQuestion
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.
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.
After SARS-CoV-2 infection, a substantial proportion of survivors with long COVID-19 (LC) experience persistent cardiopulmonary symptoms and exercise intolerance. Long COVID-19 may occur in 3% to 30% of individuals after SARS-CoV-2 infection,1-5 including nonhospitalized and vaccinated individuals,6,7 and can persist for at least 12 months.8
Cardiopulmonary exercise testing (CPET) is the criterion standard for measuring exercise capacity and aiding in the differential diagnosis of exercise limitations.9-11 After measuring resting cardiopulmonary parameters, participants exercise on a cycle ergometer or a treadmill with measurement of gas exchange and cardiopulmonary monitoring. Measuring oxygen consumption (V̇o2) allows for objective and reproducible determination of exercise capacity, determination of anaerobic threshold, and classification of limitations. Research CPET has provided insight into persistent symptoms after SARS,12 dyspnea in people living with HIV,13 and exercise intolerance in myalgic encephalitis and/or chronic fatigue syndrome (ME/CFS).14-16 Clinically, CPET is useful diagnostically for unexplained dyspnea9 and prognostically in heart failure,17 lung disease,9 and preoperative evaluations.18
Case series suggest that SARS-CoV-2 infection is associated with reduced exercise capacity.19,20 A prior narrative review of 11 studies including 581 patients21 suggested that deconditioning was a major cause of reduced exercise capacity after COVID-19 hospitalization, with literature limited by confounding and lack of controls; however, to our knowledge, no systematic review on the role of CPET in LC has been published. Whether exercise intolerance persists and is associated with LC and the pathophysiology of exertional intolerance in LC, especially among individuals who are not hospitalized, is uncertain. Therefore, the objectives of this systematic review and meta-analysis were to address whether adults with persistent COVID-19 symptoms more than 3 months after SARS-CoV-2 infection22 have reduced exercise capacity on results of CPET compared with recovered individuals without symptoms and to identify potential causal pathways for the reduced exercise capacity after SARS-CoV-2 infection.
This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline and was registered prospectively on PROSPERO (CRD42021299842) before beginning the literature search. Because the study did not constitute human participants research, the University of California, San Francisco Institutional Review Board deemed it exempt from approval and waived informed consent.
We included studies that performed CPET measurement of peak V̇o2 among adults at least 3 months after SARS-CoV-2 infection, including case series (only symptomatic individuals), cohort studies (both symptomatic and recovered individuals), and baseline data from interventional studies. Of 3256 studies that were screened by title and abstract, we selected 72 (2%) for full-text review, (1%) of which met the inclusion criteria. Studies were excluded if participants were studied less than 3 months after infection or if they did not measure V̇o2. For the first objective, we only included studies that compared individuals with and without prevalent symptoms consistent with LC at the time of CPET; for the second objective, we included studies that classified participants with exercise limitations or explored specific mechanisms of limitations.
A comprehensive search was planned with a research librarian (P.T.) to identify all studies that used CPET to evaluate exercise capacity among adults more than 3 months after SARS-CoV-2 infection, including studies published since 2020, abstracts from conference proceedings, and indexed preprints without language restrictions. We searched PubMed, EMBASE, Web of Science, and references of included studies. We additionally searched medrxiv.org, biorxiv.org, and researchsquare.com for nonindexed preprints. The search strategy included terms and synonyms for the following: COVID or SARS-CoV-2 along with cardiopulmonary exercise test, CPET or CPX or CPEX, exercise capacity, V̇o2, and anaerobic threshold tailored to each search engine (eTable 1 in the Supplement). Searches were conducted on December 20, 2021, and rerun on May 24, 2022; the preprint search was performed on June 9, 2022.
The searches were conducted by the research librarian (P.T.), with results downloaded and imported into a commercially available systemic reviews tool. After duplicates were automatically removed, 2 independent reviewers (M.S.D. and K.S.) screened each title and abstract using the systemic reviews tool and were blinded to each other’s decision regarding full-text review. Studies for which both reviewers agreed to full-text review or disagreed after reconciliation discussion underwent full-text review. After full-text review and consensus discussion, there were no disagreements regarding study inclusion. Data extraction was performed independently, in duplicate, using REDCap (eMethods and eAppendix in the Supplement). Discrepancies were corrected by the first 2 authors (M.S.D. and K.S.) reviewing the full text together.
Quality was assessed independently by 2 reviewers (M.S.D. and K.S.) using Cochrane’s Quality in Prognostic Studies tool23 to assess study populations (inclusion criteria and control group), measurement quality (CPET exercise protocols, peak V̇o2 assessment, submaximal test results, and interpretation of CPET), outcome (symptom assessment), confounding, and statistical analysis and reporting, followed by discussion and tabulation of consensus results. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) framework was used to guide a consensus discussion for overall outcome assessment.24
Owing to expected differences in study inclusion criteria, we used random-effects meta-analysis to estimate the mean difference in peak V̇o2 (in mL/kg/min) between those with and without prevalent LC symptoms as defined by each study using a restricted maximum likelihood variance estimator and Wald-type confidence intervals. For 2 studies that only reported median and IQR, the distance between the median and IQR upper and lower bounds were similar, so medians were taken as the mean and SD was estimated as the IQR divided by 1.3525; subgroups were combined among studies only reporting results by groups.25 Heterogeneity was assessed by examining forest plots, funnel plots, heterogeneity variance (τ2 statistic), and inconsistency (I2 statistic). Prespecified subgroup analyses by proportion hospitalized and time since infection were performed. Because of the small number of studies, tests for publication bias were not performed.
To synthesize findings for our second objective, we recorded the predominant explanatory finding for reduced exercise capacity, including deconditioning, ventilatory limitation, cardiac limitations, chronotropic incompetence, dysfunctional breathing/ventilatory inefficiency, or other limitations, and the number and proportion with each if reported. Meta-analysis was performed using Stata, version 17.1 (StataCorp LLC); 2-sided P < .05 indicated statistical significance.
We identified 41 reports of 38 observational studies in which CPET was performed among 2160 individuals 3 to 18 months after SARS-CoV-2 infection,26-66 including 1228 individuals with symptoms consistent with LC. The studies included 33 published reports, 2 conference abstracts, and 3 preprints (Figure 1). We identified 1 interventional study of cardiac rehabilitation67 with baseline CPET reported in an included study.68
Description of Included Studies
Table 1 lists study-level characteristics; eTable 2 and eTable 3 in the Supplement include the risk of bias assessments. Most studies (32 [84.2%]) were single-center case series of patients attending LC clinics or referred for clinical CPET (only symptomatic individuals) or cross-sectional assessments within COVID-19 recovery cohorts (with and without current symptoms). Most studies performed CPET 3 to 6 months after infection; only 1 study26 investigated individuals more than 1 year after infection. Fourteen studies (36.8%)27,30,33,35,36,44,47,49,52,55,56,62,66,68 only included individuals who were hospitalized for acute infection (median, 70% [range, 0-100%] hospitalized), and 15 studies (39.5%)30,32,39-43,50,51,54,55,57,59,61,64 included individuals with prevalent symptoms at CPET (median, 95% [range, 38%-100%] symptomatic).
Exercise Capacity in Symptomatic Compared With Recovered Individuals
Nine studies26,29,31,33,37,38,44,45,47,58 included both individuals with prevalent symptoms (n = 464) and recovered individuals without prevalent symptoms (n = 359) (Table 2), with the risk of bias rated for each study in eTable 2 in the Supplement and overall quality in the eResults in the Supplement. Because definitions of LC and postacute sequelae of COVID-19 have evolved, studies used different symptom definitions, mostly based on prevalent symptoms at CPET (dyspnea, fatigue, or exertional intolerance). From meta-analyses of these 9 studies, mean peak V̇o2 is estimated to be –4.9 (95% CI, –6.4 to –3.4) mL/kg/min among individuals with symptoms (P < .001) (Figure 2). The I2 statistic and funnel plot (eFigure 1 in the Supplement) suggest moderate heterogeneity. Two studies that did not find a statistically significant difference in symptom prevalence by reduced or preserved peak V̇o268 or by association between improvement in peak V̇o2 and symptoms27 were excluded for not reporting peak V̇o2 by symptoms.
Clinical and methodologic variability likely contribute to heterogeneity. Clinical variability may result from the spectrum of LC severity and symptoms.70 Most studies recruited before widespread vaccination, but 1 study28 reported lower peak V̇o2 among unvaccinated compared with vaccinated individuals. In addition, methodologic variability in the definition of LC26,29 and CPET exercise modality (treadmill, upright cycle ergometer, or supine cycle ergometer) may also contribute. Most studies suggest higher acuity during acute infection (intensive care unit–treated vs hospitalized vs nonhospitalized patients) is associated with worse exercise capacity,30-34 although this is not a universal finding.35,36 Subgroup analyses by proportion hospitalized or time after SARS-CoV-2 infection were not significantly different compared with the overall result (eResults in the Supplement).
Residual confounding may also contribute to heterogeneity. Age, sex, body mass index, and prior fitness are highly associated with peak V̇o2 and likely associated with LC, but few studies addressed confounding. Margalit et al37 reported that age, sex, pre–COVID-19 fitness, body mass index, and reduction in exercise time per week were similar among those with and without LC. Barbagaleta et al38 adjusted for sex, cardiovascular history, use of β-blockers, and use of aspirin but not body mass index or age, and mean estimated peak V̇o2 was 3.2 (95% CI, 0.9-5.5) mL/min/kg lower in LC. Durstenfeld et al26 estimated that mean peak V̇o2 was 5.9 (95% CI, 2.3-9.6) mL/kg/min lower in LC adjusted for age, sex, body mass index, time since infection, and hospitalization.
Patterns of Reduced Exercise Capacity
We included 37 studies with at least 714 people with reduced exercise capacity that classified patterns or limitations or investigated specific mechanisms (Table 3).26,27,29-31,33-66,68,69 Nearly all studies defined reduced exercise capacity as less than 80% or less than 85% of predicted levels. Approaches to CPET interpretation may differ, but few studies reported using specific guidelines or algorithms or their classification approach, so notable differences emerge between studies even with similar objective findings.
Deconditioning was reported as the most prevalent pattern by 10 studies,27,33,35,36,46,59,61-64 with alterations in muscular oxygen utilization acknowledged as an alternative explanation by some. Eight studies27,33,35,36,46,62-64 reporting deconditioning included mostly individuals hospitalized for severe acute COVID-19. Deconditioning may be more common among those hospitalized with other patterns (peripheral, ventilatory inefficiency) predominant among nonhospitalized patients.31 Muscular and/or peripheral oxygen extraction abnormalities were also commonly reported. Distinguishing deconditioning from altered oxygen delivery, mitochondrial dysfunction, muscular pathology, and obesity can be challenging with noninvasive CPET without adjunctive testing or pre–COVID-19 CPET for comparison. Using invasive CPET, Singh et al39 found reduced peripheral oxygen extraction, and others40,41 reported alterations in metabolism and lactate production. Importantly, none of the studies that included adjunctive cardiac imaging or right heart catheterization during exercise testing attributed their findings to deconditioning.29,39,42-44
Cardiac limitations were uncommon, but studies with adjunctive cardiac testing identified reduced stroke volume augmentation that was likely attributable to preload failure29,43,44; Singh et al39 did not find evidence of preload failure. Five studies26,29,37,45,69 identified chronotropic incompetence as a contributor.
Although ventilatory limitations were uncommon, dysfunctional breathing, hyperventilation, or ventilatory inefficiency (V/Q mismatch) were commonly noted.43,46-51 One study each specifically reported dysautonomia,69 pulmonary fibrosis,52 pulmonary vascular limitation,53 impaired microcirculation,54 endothelial dysfunction,55 and loss of mechanical efficiency56 as the primary cause of reduced exercise capacity. Despite concerns about pulmonary thromboembolism during acute infection, pulmonary vascular limitations were uncommon.
Four studies27,54,57,67 performed longitudinal CPET in a subset, including 1 interventional study. Cassar et al27 reported CPET at 2 to 3 and at 6 months; median peak V̇o2 improved from 18.0 (IQR, 14.4-21.9) to 20.5 (IQR, 17.5-26.1) mL/kg/min but remained lower than that of controls (28.1 [95% CI, 22.1-34.0] mL/kg/min; P ≤ .001 for all). Evers et al54 found no change in peak V̇o2 during 3 months among 23 individuals with reduced exercise capacity who underwent repeated CPET (mean [SD] CPET 1: 86% [19%] of predicted levels; CPET 2: 85% [21%] of predicted levels; P = .55). Moulson et al57 found improved peak V̇o2 among young symptomatic athletes 5 months after the index study, which correlated with symptom resolution. Barbara et al67 found that mean (SD) peak V̇o2 improved from 17.8 (4.6) to 20.5 (4.5) mL/kg/min after 8 weeks of cardiac rehabilitation (P < .001).
This meta-analysis and systematic review found 38 studies that reported CPET on 2160 individuals after SARS-CoV-2 infection, including 1228 with prevalent symptoms possibly consistent with LC and 714 with reduced exercise capacity. In our meta-analysis of symptomatic vs recovered individuals more than 3 months after SARS-CoV-2 infection, we found a modest but consistent effect suggesting that exercise capacity was reduced among individuals with LC, with very low certainty in the magnitude of the effect size by GRADE (eResults in the Supplement). Given the low certainty by GRADE, we identified classifications of exercise limitations without a single conclusive mechanism. Despite the large number of participants included, the overall quality of the evidence is poor owing to the small sample size of most studies, selection bias, variability in symptom ascertainment and CPET interpretation, inadequate methods to address confounding, and lack of appropriate statistical methods.
Challenges to Estimating the Association of LC With Exercise Capacity
Selection bias was a major challenge; the included studies oversampled hospitalized individuals with greater acute severity, more comorbidities, and lower baseline fitness. Hospitalization or need for intensive care during acute infection was associated with reduced peak V̇o2 and with LC,30-34 but most patients with LC were not hospitalized.71 Differential selection bias may occur among individuals who are hospitalized, are referred for clinical CPET, or attend CPET after joining a cohort, which may result in overestimation of the proportion of individuals with reduced exercise capacity.
Few studies addressed confounding; the most commonly used strategies included (1) reporting the percentage of predicted peak V̇o2 that implicitly adjusts for age, sex, height, and weight; (2) group matching on age, sex, and weight; and (3) excluding individuals with comorbid cardiac, pulmonary, and musculoskeletal conditions. Preinfection fitness was an unmeasured confounder in all but 1 study37; no studies had preinfection CPET to compare within-individual change. Two excluded studies among military recruits and professional athletes found reduced peak V̇o2 at 45 to 60 days after infection compared with before infection.72,73 A few studies used stepwise regression despite small sample sizes and colinear variables, resulting in exclusion of important confounders. Only 2 studies26,38 estimated an adjusted difference in peak V̇o2 between individuals with and without LC symptoms.
Using the GRADE framework, we have low confidence in our meta-analysis estimate of the difference in exercise capacity among individuals with and without LC symptoms. The included studies provided evidence of a clinically significant, mild to moderate decrease in exercise capacity among individuals with LC compared with infected individuals without LC symptoms despite different definitions of LC.
Insights Into Mechanisms of Reduced Exercise Capacity in LC
These studies should provide insight into mechanisms of LC, yet no consistent etiology of reduced exercise capacity has emerged, likely because of heterogeneity in inclusion criteria, variability in interpretation (measurement error), and the presence of multiple mechanisms of reduced exercise capacity in LC. Deconditioning, which occurs to some degree after any illness but especially during and after hospitalization, was commonly identified. On results of noninvasive CPET, peripheral mechanisms related to oxygen delivery and/or extraction due to muscular, mitochondrial, or vascular pathology can be misattributed to deconditioning. Use of invasive CPET, stress echocardiography, or stress magnetic resonance imaging allows for measurement or approximation of cardiac output, preload, pulmonary hypertension, and peripheral oxygen extraction and may therefore allow for more accurate classification. Overall, we found consistent evidence that deconditioning is not the only explanation of reduced exercise capacity in LC, especially among individuals who were not hospitalized.
Apart from peripheral mechanisms, other commonly reported patterns include (1) dysfunctional breathing or hyperventilation unexplained by baseline pulmonary function tests or findings on cross-sectional imaging, (2) chronotropic incompetence, and (3) preload failure despite normal resting cardiac function. Ventilatory, pulmonary vascular, and cardiac limitations are uncommon, suggesting that direct heart or lung damage (especially given other negative testing results) are not major drivers of exercise limitations in LC. From the diversity of interpretations, different phenotypes resulting in exertional intolerance seem more likely than a single unifying mechanism.
Autonomic dysfunction and endothelial dysfunction are possible mechanisms for these findings and could be caused by SARS-CoV-2 infection of neurons and endothelial cells, chronic inflammation, or autoimmune mechanisms. One included study found endothelial dysfunction55 and 2 suggested dysautonomia37,69 to be associated with reduced exercise capacity in LC. Dysfunctional breathing may also be a manifestation of dysautonomia.69 Autonomic nervous system and endothelial interaction may regulate peripheral vasomotor tone16; together, they may explain differences in peripheral extraction and preload failure. Small-fiber neuropathy among individuals who have LC symptoms with postural orthostatic tachycardia syndrome may be associated with reduced cerebral blood flow and postural symptoms.74,75 No published studies included comprehensive autonomic testing, endothelial testing, and CPET.
Myalgic encephalitis/chronic fatigue syndrome is associated with reduced peak V̇o2, lower ventilatory efficiency, higher perceived exertion, and lower peak heart rates,15 and chronotropic incompetence may contribute to exercise limitations.14 Alternatively, small-fiber neuropathy causing peripheral shunting reduces exercise capacity in ME/CFS.16 Postexertional malaise (PEM; recurrence or worsening of symptoms after exercise) has been reported in LC, similar to ME/CFS.76,77 The overlap between ME/CFS and LC and whether LC has similar pathophysiology to ME/CFS remain unknown.
Recommendations for CPET for LC Clinical Care and Research
Given the heterogeneity of phenotypes of LC and lack of a single mechanism, CPET is clinically useful to narrow the differential diagnosis of exertional dyspnea in LC. A CPET result within reference range without cardiopulmonary limitations will reassure some individuals with LC and increase comfort with physical activity. For those with objective limitations, identifying a cardiac or ventilatory limitation could provide clues for further diagnostic testing and treatment. Risk of PEM should be considered in evaluation of the risk-benefit ratio of CPET among individuals reporting PEM.
With regard to research, determining the prevalence of exercise intolerance requires intentional sampling. Selection of control groups requires particular attention tailored to the research question. We recommend that CPET be performed as a maximal test that allows for assessment of chronotropy except for individuals with significant PEM, with adjunctive measures as per local expertise. Careful postexertional symptom assessment, including after CPET and 2-day CPET protocols, may provide insights into PEM in individuals with LC symptoms. Correlative data with autonomical testing may provide mechanistic insights. Given high reproducibility within individuals and reduced exercise capacity among individuals with LC symptoms, CPET may be a useful objective measure to include in interventional trials for potential LC therapeutics.
This study has some limitations. The search plan was not peer reviewed, and the search was not limited to peer-reviewed studies. We may have missed studies that met our inclusion criteria, especially recent preprints. Many included studies were case series, which contributed only to classification of exercise limitations. Because of selection bias, we could not estimate the prevalence of reduced exercise capacity. There was moderate heterogeneity in the included studies. Additionally, we cannot rule out publication bias contributing to exaggeration of effect estimates, especially because 2 excluded studies did not find an association, although we mitigated this by including preprints and conference abstracts.
In this meta-analysis and systematic review, we found evidence that exercise capacity is reduced after SARS-CoV-2 infection among individuals who have symptoms consistent with LC, with a low confidence in the effect size. Further research should include longitudinal assessments to understand the trajectory of exercise capacity. Interventional trials of potential therapies are urgently needed, including studies of rehabilitation to address deconditioning, as well as further mechanistic investigation into dysfunctional breathing, autonomic dysfunction, chronotropic incompetence, impaired oxygen uptake or utilization, and preload failure to identify treatments for LC.
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.
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