Cardiopulmonary Exercise Testing in Patients With Long COVID

Abstract

BackgroundAfter COVID-19, some patients present with ongoing symptoms (eg, breathlessness, exercise limitations), even after mild acute infection.Research QuestionWhat is the exercise capacity of patients diagnosed with long COVID and does it change from baseline to 1-year follow-up?Study Design and MethodsThis retrospective case series included patients with persistent symptoms after a confirmed diagnosis of COVID-19. Exercise capacity was examined by cardiopulmonary exercise testing (CPET), and parameters related to performance, ventilation, circulation, and gas exchange were compared with predicted values. A subgroup of patients was retested 1 year after baseline, and self-reported physical fitness was assessed at follow-up.ResultsIn total, 169 patients completed baseline CPET and 41 patients completed 1-year follow-up. Mean maximum workload was 172 W (95% CI, 161-182), with 19% not achieving at least 84% predicted workload. Mean peak oxygen uptake was 24.4 mL/kg/min (95% CI, 23.1-25.7), and 36% had a value below % predicted. Oxygen uptake/workload slope below the normal threshold of 8.4 mL/min/W was observed in 54% of patients. The 1-year follow-up results showed no statistically significant changes in any of the CPET parameters, which correspond to lack of improvement in self-reported physical fitness.InterpretationPatients with long COVID demonstrated lowered peak oxygen uptake, oxygen uptake/workload slope, and/or ventilatory equivalent for carbon dioxide, but different parameters were lowered in different patients, illustrating a heterogeneous study population. No improvements in any parameters were found at 1-year follow-up. After COVID-19, some patients present with ongoing symptoms (eg, breathlessness, exercise limitations), even after mild acute infection. What is the exercise capacity of patients diagnosed with long COVID and does it change from baseline to 1-year follow-up? This retrospective case series included patients with persistent symptoms after a confirmed diagnosis of COVID-19. Exercise capacity was examined by cardiopulmonary exercise testing (CPET), and parameters related to performance, ventilation, circulation, and gas exchange were compared with predicted values. A subgroup of patients was retested 1 year after baseline, and self-reported physical fitness was assessed at follow-up. In total, 169 patients completed baseline CPET and 41 patients completed 1-year follow-up. Mean maximum workload was 172 W (95% CI, 161-182), with 19% not achieving at least 84% predicted workload. Mean peak oxygen uptake was 24.4 mL/kg/min (95% CI, 23.1-25.7), and 36% had a value below % predicted. Oxygen uptake/workload slope below the normal threshold of 8.4 mL/min/W was observed in 54% of patients. The 1-year follow-up results showed no statistically significant changes in any of the CPET parameters, which correspond to lack of improvement in self-reported physical fitness. Patients with long COVID demonstrated lowered peak oxygen uptake, oxygen uptake/workload slope, and/or ventilatory equivalent for carbon dioxide, but different parameters were lowered in different patients, illustrating a heterogeneous study population. No improvements in any parameters were found at 1-year follow-up. Take-Home PointStudy Question: What is the exercise capacity of patients diagnosed with long COVID and does it change from baseline to 1-year follow-up?Results: No changes in cardiopulmonary exercise testing parameters were found at 1-year follow-up.Interpretations: Patients diagnosed with long COVID demonstrated lowered values across various cardiopulmonary exercise testing parameters, illustrating a heterogeneous study population with no improvements observed over time. Study Question: What is the exercise capacity of patients diagnosed with long COVID and does it change from baseline to 1-year follow-up? Results: No changes in cardiopulmonary exercise testing parameters were found at 1-year follow-up. Interpretations: Patients diagnosed with long COVID demonstrated lowered values across various cardiopulmonary exercise testing parameters, illustrating a heterogeneous study population with no improvements observed over time. COVID-19, caused by SARS-CoV-2 infection, is associated with multiple organ involvement.1Dennis A. Wamil M. Alberts J. et al.Multiorgan impairment in low-risk individuals with post-COVID-19 syndrome: a prospective, community-based study.BMJ Open. 2021; 11e048391Crossref Scopus (296) Google Scholar Although most patients recover within a few weeks, approximately 80% of those infected experience mild symptoms or remain asymptomatic during the acute phase.2World Health OrganizationClinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected: interim guidance. World Health Organization, 2020Crossref Scopus (80) Google Scholar However, persistent symptoms (eg, fatigue, breathlessness, muscle weakness, chest pain, cognitive dysfunction) are common among a subset of both hospitalized and nonhospitalized patients.3Bosworth M.P.P. Ayoubkhani D. Prevalence of ongoing symptoms following coronavirus (COVID-19) infection in the UK: 2 February 2023.https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/prevalenceofongoingsymptomsfollowingcoronaviruscovid19infectionintheuk/2february2023Date accessed: February 3, 2023Google Scholar, 4Carfì A. Bernabei R. Landi F. Persistent symptoms in patients after acute COVID-19.JAMA. 2020; 324: 603-605Crossref PubMed Scopus (2652) Google Scholar, 5Clavario P. De Marzo V. Lotti R. et al.Cardiopulmonary exercise testing in COVID-19 patients at 3 months follow-up.Int J Cardiol. 2021; 340: 113-118Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 6Raman B. Cassar M.P. Tunnicliffe E.M. et al.Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health, post-hospital discharge.EClinicalMedicine. 2021; 31100683Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar, 7Malik P. Patel K. Pinto C. et al.Post-acute COVID-19 syndrome (PCS) and health-related quality of life (HRQoL)-a systematic review and meta-analysis.J Med Virol. 2022; 94: 253-262Crossref PubMed Scopus (229) Google Scholar, 8Heightman M. Prashar J. Hillman T.E. et al.Post-COVID-19 assessment in a specialist clinical service: a 12-month, single-centre, prospective study in 1325 individuals.BMJ Open Respir Res. 2021; 8Google Scholar These symptoms cause impaired physical function, reduced quality of life, and compromised mental health, often persisting for months or even years after recovery from the acute infection.9Dennis A. Cuthbertson D.J. Wootton D. et al.Multi-organ impairment and long COVID: a 1-year prospective, longitudinal cohort study.J R Soc Med. 2023; 116: 97-112Crossref Scopus (23) Google Scholar In line with World Health Organization recommendations, ongoing symptoms 3 months from disease onset are referred to as long COVID.10Soriano J.B. Murthy S. Marshall J.C. Relan P. Diaz J.V. A clinical case definition of post-COVID-19 condition by a Delphi consensus.Lancet Infect Dis. 2021; Google Scholar Multiple studies have aimed to understand the etiology and pathophysiology of long COVID, and its impact on cardiopulmonary function and reduced exercise capacity. Often, assessments of pulmonary function and cardiac performance at rest have not revealed abnormalities.11Wood G. Kirkevang T.S. Agergaard J. et al.Cardiac performance and cardiopulmonary fitness after infection with SARS-CoV-2.Front Cardiovasc Med. 2022; 9871603Crossref Scopus (4) Google Scholar, 12Beaudry R.I. Brotto A.R. Varughese R.A. et al.Persistent dyspnea after COVID-19 is not related to cardiopulmonary impairment; a cross-sectional study of persistently dyspneic COVID-19, non-dyspneic COVID-19 and controls.Front Physiol. 2022; 13917886Crossref Scopus (11) Google Scholar, 13Singh I. Joseph P. Heerdt P.M. et al.Persistent exertional intolerance after COVID-19: insights from invasive cardiopulmonary exercise testing.Chest. 2022; 161: 54-63Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar Cardiopulmonary exercise testing (CPET) has emerged as the preferred method to quantify the degree of exercise impairment and facilitate differential diagnosis.14Herdy A.H. Ritt L.E. Stein R. et al.Cardiopulmonary exercise test: background, applicability and interpretation.Arq Bras Cardiol. 2016; 107: 467-481PubMed Google Scholar,15Mezzani A. Cardiopulmonary exercise testing: basics of methodology and measurements.Ann Am Thorac Soc. 2017; 14: S3-S11Crossref Scopus (159) Google Scholar Therefore, utilization of CPET in patients with long COVID is optimal for evaluating exercise capacity and providing important insights on cardiovascular, respiratory, muscular, and metabolic limitations during physical activity.12Beaudry R.I. Brotto A.R. Varughese R.A. et al.Persistent dyspnea after COVID-19 is not related to cardiopulmonary impairment; a cross-sectional study of persistently dyspneic COVID-19, non-dyspneic COVID-19 and controls.Front Physiol. 2022; 13917886Crossref Scopus (11) Google Scholar,16Mancini D.M. Brunjes D.L. Lala A. Trivieri M.G. Contreras J.P. Natelson B.H. Use of cardiopulmonary stress testing for patients with unexplained dyspnea post-coronavirus disease.JACC Heart Fail. 2021; 9: 927-937Crossref PubMed Scopus (103) Google Scholar, 17Skjørten I. Ankerstjerne O.A.W. Trebinjac D. et al.Cardiopulmonary exercise capacity and limitations 3 months after COVID-19 hospitalisation.Eur Respir J. 2021; 58Crossref Scopus (107) Google Scholar, 18Evers G. Schulze A.B. Osiaevi I. et al.Sustained impairment in cardiopulmonary exercise capacity testing in patients after COVID-19: a single center experience.Can Respir J. 2022; 20222466789Crossref PubMed Scopus (11) Google Scholar, 19Sakellaropoulos S.G. Ali M. Papadis A. Mohammed M. Mitsis A. Zivzivadze Z. Is long COVID syndrome a transient mitochondriopathy newly discovered: implications of CPET.Cardiol Res. 2022; 13: 264-267Crossref Google Scholar In this study, we aimed to investigate the exercise capacity of patients diagnosed with long COVID and determine changes in exercise capacity from baseline to 1-year follow-up. This retrospective case series included patients with persistent symptoms for a minimum of 3 months after a confirmed diagnosis of COVID-19, as determined by a positive polymerase chain reaction or antibody test for SARS-CoV-2. Patients were evaluated and diagnosed with long COVID at the long COVID clinic, Department of Infectious Diseases, Aarhus University Hospital, Denmark, after referral from their general practitioner. Patients exhibiting physical limitations (eg, dyspnea, chest pain, muscle pain or weakness) were referred to the Department of Physiotherapy and Occupational Therapy for CPET. Patients were tested between April 2021 and May 2023, and the 1-year follow-up CPET assessments were performed until May 2023. Sociodemographic and clinical data were collected through hospital medical records, electronic questionnaires, and clinical visits. The study data were managed using the REDCap tool hosted at Aarhus University, a secure web-based software platform for building and managing online databases and surveys.20Barbagelata L. Masson W. Iglesias D. et al.Cardiopulmonary exercise testing in patients with post-COVID-19 syndrome.Med Clin (Barc). 2021; Google Scholar,21Baratto C. Caravita S. Faini A. et al.Impact of COVID-19 on exercise pathophysiology: a combined cardiopulmonary and echocardiographic exercise study.J Appl Physiol (1985). 2021; 130: 1470-1478Crossref PubMed Scopus (88) Google Scholar CPET was performed using a cycle ergometer (Lode Corival CPET; Lode BV) and continuous breath-by-breath respiratory gas exchange analysis with Vyaire Vyntus CPX and SentrySuite software v3.10 (CareFusion). The system was calibrated prior to each test. After a 2-min resting phase for preexercise measurements, the incremental bicycle test started at an initial workload of 20 to 40 W and increased by 10 to 25 W each minute until the participants reached exhaustion. The workload protocol was selected based on the goal of reaching exhaustion in 8 to 12 min. ECG, oxygen saturation, and BP were measured during the test. Data were averaged every 15 s. No tests were stopped for medical reasons. Oxygen uptake (V̇o2)/workload slope, peak oxygen uptake (Vo2peak), and body weight-indexed Vo2peak (Vo2peak/kg) were considered abnormal if values were ≤ 84% predicted, maximum heart rate was ≤ predicted, and oxygen was ≤ 80% J.B. B. Persistent exertional dyspnea and exercise intolerance after mild COVID-19: A for 2022; PubMed Scopus Google Scholar The slope was measured from the 2 to the workload 8.4 mL/min/W were considered A. K. and of an abnormal during cardiopulmonary exercise testing in with persistent symptoms following COVID-19 2022; Scopus (11) Google Scholar Patients were based on normal or abnormal was from the ventilatory equivalent for carbon were considered J.B. B. Persistent exertional dyspnea and exercise intolerance after mild COVID-19: A for 2022; PubMed Scopus Google Scholar The as was to the as minute to a and was considered J.B. B. Persistent exertional dyspnea and exercise intolerance after mild COVID-19: A for 2022; PubMed Scopus Google Scholar threshold was as the at which and was considered abnormal if at was ≤ 40 % of at peak J.B. B. Persistent exertional dyspnea and exercise intolerance after mild COVID-19: A for 2022; PubMed Scopus Google Scholar In the clinic, patients diagnosed with long COVID performed a pulmonary function test with of were performed to R. R. J. electronic data methodology and for providing PubMed Scopus Google Scholar The is a 15 and symptoms with of and in is with a from to 3 in a from to A of mental has R. et REDCap building an of software platform PubMed Scopus Google Scholar The was completed at patients were by a to their physical exercise and physical fitness both the SARS-CoV-2 infection and at the of baseline and follow-up CPET. were using were for normal by and data are as values or with are as with A was to CPET between patients with abnormal respiratory exchange and slope and patients with normal values at and were included in the test was to Vo2peak % predicted and slope between patients years of and patients years of Patients were based on their and Mean values with of Vo2peak % predicted and were across each and between were using A test was to continuous from CPET between baseline test and follow-up CPET. 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Brotto A.R. Varughese R.A. et al.Persistent dyspnea after COVID-19 is not related to cardiopulmonary impairment; a cross-sectional study of persistently dyspneic COVID-19, non-dyspneic COVID-19 and controls.Front Physiol. 2022; 13917886Crossref Scopus (11) Google Scholar,16Mancini D.M. Brunjes D.L. Lala A. Trivieri M.G. Contreras J.P. Natelson B.H. Use of cardiopulmonary stress testing for patients with unexplained dyspnea post-coronavirus disease.JACC Heart Fail. 2021; 9: 927-937Crossref PubMed Scopus (103) Google G. Schulze A.B. Osiaevi I. et al.Sustained impairment in cardiopulmonary exercise capacity testing in patients after COVID-19: a single center experience.Can Respir J. 2022; 20222466789Crossref PubMed Scopus (11) Google S. G. et on of cardiopulmonary exercise testing in Respir PubMed Scopus Google of on cardiopulmonary exercise J Respir Med. PubMed Scopus Google Scholar studies normal G. Kirkevang T.S. Agergaard J. et al.Cardiac performance and cardiopulmonary fitness after infection with SARS-CoV-2.Front Cardiovasc Med. 2022; 9871603Crossref Scopus (4) Google I. Joseph P. Heerdt P.M. et al.Persistent exertional intolerance after COVID-19: insights from invasive cardiopulmonary exercise testing.Chest. 2022; 161: 54-63Abstract Full Text Full Text PDF PubMed Scopus (154) Google of exercise testing and pathophysiology and clinical Scholar In this case of patients had an at peak abnormal ventilatory R.I. Brotto A.R. Varughese R.A. et al.Persistent dyspnea after COVID-19 is not related to cardiopulmonary impairment; a cross-sectional study of persistently dyspneic COVID-19, non-dyspneic COVID-19 and controls.Front Physiol. 2022; 13917886Crossref Scopus (11) Google Scholar,16Mancini D.M. Brunjes D.L. Lala A. Trivieri M.G. Contreras J.P. Natelson B.H. Use of cardiopulmonary stress testing for patients with unexplained dyspnea post-coronavirus disease.JACC Heart Fail. 2021; 9: 927-937Crossref PubMed Scopus (103) Google S. G. et on of cardiopulmonary exercise testing in Respir PubMed Scopus Google of exercise testing and pathophysiology and clinical Scholar and oxygen D.M. Brunjes D.L. Lala A. Trivieri M.G. Contreras J.P. Natelson B.H. Use of cardiopulmonary stress testing for patients with unexplained dyspnea post-coronavirus disease.JACC Heart Fail. 2021; 9: 927-937Crossref PubMed Scopus (103) Google G. Schulze A.B. Osiaevi I. et al.Sustained impairment in cardiopulmonary exercise capacity testing in patients after COVID-19: a single center experience.Can Respir J. 2022; 20222466789Crossref PubMed Scopus (11) Google Scholar have observed during CPET in patients with long In study, most of the patients with normal oxygen values and normal BP during heart disease to cause exercise of participants a peak predicted. 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K. and of an abnormal during cardiopulmonary exercise testing in with persistent symptoms following COVID-19 2022; Scopus (11) Google Scholar invasive peak oxygen in a oxygen was a oxygen utilization R.I. Brotto A.R. Varughese R.A. et al.Persistent dyspnea after COVID-19 is not related to cardiopulmonary impairment; a cross-sectional study of persistently dyspneic COVID-19, non-dyspneic COVID-19 and controls.Front Physiol. 2022; 13917886Crossref Scopus (11) Google Scholar on the and not this was by et S. 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