Cardiopulmonary Exercise Testing in Patients With Long COVID
2024; Elsevier BV; Volume: 2; Issue: 2 Linguagem: Inglês
10.1016/j.chpulm.2024.100036
ISSN2949-7892
AutoresLotte Sørensen, Camilla Lundgren Pedersen, Mads J. Andersen, Johannes Martin Schmid, Lisa Gregersen Oestergaard, Berit Schiøttz-Christensen, Søren Pedersen,
Tópico(s)Thermal Regulation in Medicine
ResumoBackgroundAfter 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 (HR) was ≤ 90% predicted, and oxygen pulse was ≤ 80% predicted.22van Voorthuizen E.L. van Helvoort H.A.C. Peters J.B. van den Heuvel M.M. van den Borst B. Persistent exertional dyspnea and perceived exercise intolerance after mild COVID-19: A critical role for breathing dysregulation?.Phys Ther. 2022; 102Crossref PubMed Scopus (10) Google Scholar The V̇o2/workload slope was measured from the third (after 2 min) to the second-to-last workload step. Values < 8.4 mL/min/W were considered abnormal.23von Gruenewaldt A. Nylander E. Hedman K. Classification and occurrence of an abnormal breathing pattern during cardiopulmonary exercise testing in subjects with persistent symptoms following COVID-19 disease.Physiol Rep. 2022; 10e15197Crossref Scopus (11) Google Scholar Patients were divided into subgroups based on normal or abnormal V̇o2/workload relationship. Ventilatory efficiency was estimated from the ventilatory equivalent for carbon dioxide (Ve/Vco2) slope. Values ≥ 34 were considered abnormal.22van Voorthuizen E.L. van Helvoort H.A.C. Peters J.B. van den Heuvel M.M. van den Borst B. Persistent exertional dyspnea and perceived exercise intolerance after mild COVID-19: A critical role for breathing dysregulation?.Phys Ther. 2022; 102Crossref PubMed Scopus (10) Google Scholar The indirect maximal voluntary ventilation (MVV), calculated as FEV1 × 40, was used to estimate the breathing reserve (%) as follows: (MMV − minute ventilation [Ve])/MVV) × 100). Ve close to MVV indicates a low breathing reserve, and breathing reserve < 15% was considered abnormal.22van Voorthuizen E.L. van Helvoort H.A.C. Peters J.B. van den Heuvel M.M. van den Borst B. Persistent exertional dyspnea and perceived exercise intolerance after mild COVID-19: A critical role for breathing dysregulation?.Phys Ther. 2022; 102Crossref PubMed Scopus (10) Google Scholar Ventilatory threshold (VT) was identified as the point at which CO2 output exceeded Vo2 and was considered abnormal if V̇o2 at VT was ≤ 40 % of V̇o2 at peak exercise.22van Voorthuizen E.L. van Helvoort H.A.C. Peters J.B. van den Heuvel M.M. van den Borst B. Persistent exertional dyspnea and perceived exercise intolerance after mild COVID-19: A critical role for breathing dysregulation?.Phys Ther. 2022; 102Crossref PubMed Scopus (10) Google Scholar In the outpatient clinic, patients diagnosed with long COVID performed a pulmonary function test with registration of FEV1. Tests were performed according to ERS/ATS guidelines.24Harris P.A. Taylor R. Thielke R. Payne J. Gonzalez N. Conde J.G. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support.J Biomed Inform. 2009; 42: 377-381Crossref PubMed Scopus (29101) Google Scholar The Mental Fatigue Scale is a questionnaire containing 15 items about affective, cognitive, and sensory symptoms along with duration of sleep and daytime variation in symptom severity. Each item is answered with a score rating from 0 (normal function) to 3 (maximal symptom), resulting in a sum score from 0 to 45. A cutoff score of 10.5 indicating mental fatigue has been suggested.25Harris P.A. Taylor R. Minor B.L. et al.The REDCap consortium: building an international community of software platform partners.J Biomed Inform. 2019; 95103208Crossref PubMed Scopus (9300) Google Scholar The Mental Fatigue Scale was completed electronically at baseline. At follow-up, patients were asked by a physiotherapist to assess their physical activity level, exercise habits, and physical fitness both before the SARS-CoV-2 infection and at the time of baseline and follow-up CPET. Statistical analyses were conducted using Stata (version 17.0; StataCorp). Continuous variables were checked for normal distribution by histogram and Q-Q plots. Normally distributed data are presented as mean values ± SD or 95% CIs. Variables with nonnormal distribution are presented as median with interquartile range. A multivariable regression model was used to compare CPET outcomes between patients with abnormal respiratory exchange ratio (RER) and V̇o2/workload slope and patients with normal values at baseline. Variables age, BMI, and gender were included in the analysis. An unpaired t test was used to compare Vo2peak (mL/kg/min) % predicted and Vo2/workload slope between younger patients (˂ 49 years of age) and older patients (≥ 49 years of age). Patients were categorized into three groups based on their BMI: healthy weight (BMI 18.5-24.9 kg/m2), overweight (BMI 25.0-29.9 kg/m2), and obese (BMI ≥ 30 kg/m2). Mean values with 95% CIs of Vo2peak (mL/kg/min) % predicted and V̇o2/workload were reported across each group, and differences between BMI categories were quantified using linear regression models. A paired Student t test was used to compare continuous outcomes from CPET between baseline test and follow-up CPET. The distribution of differences was checked by Bland-Altman plot. McNemar test was used to compare binary outcomes between tests yielding a risk difference. To account for multiple tests, a Bonferroni-corrected threshold of P < .0026 (α = 0.05/19 outcomes) was applied. P values were reported to three decimals, and P < .001 was reported as < .001. Patients were included after giving written informed consent, and the study was approved by The Danish Data Protection Agency (No. 1-16-02-655-20). The study did not require approval from a research ethics committee. In total, 169 patients completed baseline CPET. The mean age ± SD was 46.7 ± 12.5 years, and most patients were females (62%). The mean BMI ± SD was 27.2 ± 5.4 kg/m2, with 41% being categorized as overweight (BMI 25.0-29.9 kg/m2) and 28% categorized as obese (BMI ≥ 30 kg/m2). Pulmonary function testing was performed in 64 patients, with a mean FEV1 % predicted ± SD of 98% ± 13%. FEV1 % predicted was > 80% predicted in 58 patients (91%). The mean Mental Fatigue Scale score ± SD was 18.8 ± 5.6. Of 47 patients invited to 1-year follow-up, 41 patients completed the follow-up (87%). Reasons for not completing were work (n = 1), sickness (n = 1), and not willing to participate (n = 4). Patient characteristics are shown in Table 1.Table 1Characteristic of the Study Population at Baseline (N = 169)CharacteristicValueAge, y46.7 ± 12.5Gender Male64 (38) Female105 (62)BMI, kg/m2 Overall27.2 ± 5.4 Underweight(< 18.5)3 (2) Healthy weight(18.5-24.9)48 (28) Overweight(25.0-29.9)69 (41) Obesity(≥ 30)47 (28)Time since infection, d359 (233-468)Patients hospitalized12 (7)FEV1, L/min (n = 64)3.39 ± 0.65FEV1, % predicted (n = 64)98 ± 13Educational level Low55 (37) Medium64 (43) High30 (20)Work status Working/studying same hours as before54 (38) Sick leave75 (54) Unemployed11 (8)Mental Fatigue Scale score18.8 ± 5.6Data are presented as No. (%), mean ± SD, or median (interquartile range). Open table in a new tab Data are presented as No. (%), mean ± SD, or median (interquartile range). The mean maximum workload was 172 W (95% CI, 161-182), with 19% not achieving at least 84% of the predicted workload. In total, 36% had a Vo2peak (mL/kg/min) % predicted below the normal threshold. Overall, 77 patients (46%) had a peak HR < 90% predicted. The mean V̇o2/workload slope was 8.1 (95% CI, 7.8-8.4), with 91 patients (54%) having a Vo2/workload slope below the normal threshold (Table 2).Table 2Baseline Cardiopulmonary Exercise Testing Parameters at Peak Exercise (N = 169)Mean (95% CI)Cutoff Abnormal ValueAbnormal ValuesPerformance Workload (peak), W172 (162-182)…… Workload, % predicted125 (119-132)≤ 84%32 (19) Vo2peak, mL/min2,008 (1,908-2,108)…… Vo2peak, mL/kg/min24.4 (23.1-25.7)…… Vo2, mL/kg/min, % predicted97 (92-101)≤ 84%60 (36)Circulation Peak HR, beats/min155 (152-159)…… HR, % predicted90 (88-91)≤ 90%77 (46) Oxygen pulse peak, mL/bpm12.9 (12.3-13.5)…… Oxygen pulse, % predicted107 (103-112)≤ 80%28 (17) Vo2/workload slope, mL/min/W8.1 (7.8-8.4)< 8.4 mL/min/W91 (54) Peak systolic BP, mm Hg184 (179-190)…… Peak diastolic BP, mm Hg85.1 (82.9-87.2)……Ventilation Peak Ve, L/min77.9 (73.7-82.2)…… Ve, % predicted77 (73-81)< 85%115 (68) Peak breathing frequency35 (34-36)≥ 60 breaths/min2 (1) Breathing reserve, % (n = 65)39 (35-44)< 15%5 (8) Peak RER1.18 (1.17-1.20)< 1.1027 (16)Gas exchange Ve/Vco2 slope29.2 (28.2-30.1)≥ 3426 (15) Lowest Sao2, %99 (98-100)aMedian (interquartile range).< 95%7 (4) Vo2 at VT/Vo2peak, %71 (69-73)≤ 40%0 (0)Data are presented as mean (95% CI), No. (%), or as otherwise indicated. HR = heart rate; RER = respiratory exchange ratio; Sao2 = oxygen saturation; Ve = minute ventilation; Ve/Vco2 = ventilatory equivalent for carbon dioxide; Vo2 = oxygen uptake; Vo2peak = peak oxygen uptake; VT = ventilatory threshold.a Median (interquartile range). Open table in a new tab Data are presented as mean (95% CI), No. (%), or as otherwise indicated. HR = heart rate; RER = respiratory exchange ratio; Sao2 = oxygen saturation; Ve = minute ventilation; Ve/Vco2 = ventilatory equivalent for carbon dioxide; Vo2 = oxygen uptake; Vo2peak = peak oxygen uptake; VT = ventilatory threshold. Maximum Ve was 77% predicted (95% CI, 73-81), with 68% having a Ve < 85% predicted. A breathing reserve < 15% predicted was found in five patients (8%). Ventilatory efficiency measured by Ve/Vco2 slope was 29.2 (95% CI, 28.2-30.1), with 26 patients (15%) scoring a Ve/Vco2 ≥ 34 (Table 2). Multivariable analysis revealed significant differences in outcomes between patients with a RER < 1.10 and those with a RER ≥ 1.10. In patients with a RER < 1.10, there was a reduction in Vo2peak of 270 mL/min (95% CI, 37-504; P = .024), a decrease in HR of 15 beats/min (95% CI, 7-23; P < .001), and a decrease in Ve of 14 L/min (95%). Meanwhile, Ve/Vco2 increased by 5.6 (95% CI, 3.1-8.1; P < .001) (Table 3).Table 3Comparison of Cardiopulmonary Exercise Testing Parameters Between Patients With Abnormal RER and Vo2/Workload Slope and Patients With Normal Values at BaselineRER < 1.10 (n = 27)RER ≥ 1.10 (n = 142)Mean Difference, (95% CI), P ValueVo2/Workload Slope < 8.4 (n = 91)Vo2/Workload Slope ≥ 8.4 (n = 78)Mean Difference, (95% CI), P ValuePerformance Peak workload, W138 (111-165)179 (168-190)37 (14 to 59), .002162 (147-177)184 (171-197)25 (9 to 42), .003 Workload, % predicted106 (90-121)129 (122-136)25 (8 to 41), .004115 (106-123)137 (128-147)23 (11 to 35), < .001 Vo2peak, mL/min1,799 (1,526-2,071)2,048 (1,940-2,155)270 (37 to 504), .0241,794 (1,662-1,927)2,257 (2,123-2,390)463 (305 to 622), < .001 Vo2peak, mL/kg/min19.7 (16.7-22.8)25.3 (23.9-26.7)3.0 (−0.0 to 6.1), .05222.5 (20.9-24.1)26.7 (24.7-28.6)5.9 (3.8 to 7.9), < .001 Vo2, mL/kg/min, % predicted87 (77-98)99 (94-103)12 (1 to 24), .03486 (81-91)110 (103-116)24 (16 to 32), < .001Circulation Peak HR, beats/min141 (133-150)158 (155-161)15 (7 to 23), < .001156 (151-160)155 (151-160)3 (−3 to 9), .279 HR, % predicted83 (78-88)91 (89-93)8 (3 to 13), .00189 (86-91)91 (89-93)2 (−2 to 5), .271 Vo2/workload slope, mL/min/W8.9 (8.1-9.7)7.9 (7.6-8.2)−0.8 (−1.6 to 0.0), .0526.8 (6.5-7.1)9.6 (9.5-9.8)2.8 (2.5 to 3.2) < .001Ventilation Peak Ve, L/min67 (58-76)80 (75-85)14 (4 to 24), .00771 (64-77)87 (81-92)15 (8 to 22), < .001 Ve, % predicted69 (61-78)78 (74-82)10 (0 to 21), .04370 (65-75)85 (80-90)14 (7 to 21), < .001 Breathing reserve, % (n = 65)43 (30-56)39 (34-44)−3 (−16 to 9), .58346 (39-52)31 (26-35)−14 (−23 to −6), .001 Peak breathing frequency33 (30-36)36 (34-37)3 (−16 to 9), .58334 (32-36)36 (35-38)2 (−0 to 5), .085 Peak RER1.0 (1.0-1.1)1.2 (1.2-1.2)0.2 (0.1 to 0.2), < .0011.2 (1.2-1.2)1.2 (1.1-1.2)−0.0 (−0.1 to 0.0), .125Gas exchange Ve/Vco2 slope34.0 (30.6-37.4)28.2 (27.4-29.1)−5.6 (−8.1 to −3.1), < .00129.5 (28.1-30.8)28.8 (27.5-30.1)−1.3 (−3.2 to 0.6), .176 Vo2 at VT/Vo2peak, %77 (70-83)70 (68-72)−5 (−10 to 1), .08372 (70-75)70 (67-73)4 (0 to 8), .043Data are mean (95% CI) or as otherwise indicated. A multivariable regression model was used to compare outcomes between patients with abnormal RER and Vo2/workload slope with patients with normal values at baseline. Variables age, BMI, and gender were included in the analysis. HR = heart rate; RER = respiratory exchange ratio; Ve = minute ventilation; Ve/Vco2 = ventilatory equivalent for carbon dioxide; Vo2 = oxygen uptake; Vo2peak = peak oxygen uptake; VT = ventilatory threshold. Open table in a new tab Data are mean (95% CI) or as otherwise indicated. A multivariable regression model was used to compare outcomes between patients with abnormal RER and Vo2/workload slope with patients with normal values at baseline. Variables age, BMI, and gender were included in the analysis. HR = heart rate; RER = respiratory exchange ratio; Ve = minute ventilation; Ve/Vco2 = ventilatory equivalent for carbon dioxide; Vo2 = oxygen uptake; Vo2peak = peak oxygen uptake; VT = ventilatory threshold. Similarly, multivariable analysis revealed significant differences in outcomes between patients with a V̇o2/workload slope < 8.4 and those with a V̇o2/workload slope ≥ 8. In patients with a V̇o2/workload slope < 8.4, there was a reduction in Vo2peak of 463 mL/min (95% CI, 305-622; P < .001) and a decrease in Ve of 15 L/min (95% CI, 8-22; P < .001). No difference in the RER was found between the two groups (−0.0; 95% CI, −0.1 to 0.0; P = .125) (Table 3). The overlap of patients with an abnormal Vo2peak (mL/kg/min) % predicted, V̇o2/workload slope, and Ve/Vco2 slope is illustrated in Figure 1. End-tidal oxygen and end-tidal CO2 were normal at rest, the VT, and the time of peak exercise (e-Table 1). The difference in Vo2peak (mL/kg/min) % predicted between younger patients (< 49 years of age) and older patients (≥ 49 years of age) was 7.5% (95% CI, −16.2 to 1.2; P = .09), with younger patients having the lowest Vo2peak (mL/kg/min) % predicted of 93% (95% CI, 87-98). Similarly, V̇o2/workload slope was 7.9 (95% CI, 7.5-8.3) in younger patients compared with 8.3 (95% CI, 7.9-8.7; P = .11) in older patients. Patients with a healthy weight (BMI 18.5-24.9 kg/m2) had a mean Vo2peak (mL/kg/min) % predicted of 101.3 (95% CI, 91.9-110.8), with Vo2peak (mL/kg/min) % predicted being 6.2% (95% CI, −16.6 to 4.2; P = .24) lower in patients who were overweight (BMI 25.0-29.9 kg/m2) and 7.1% predicted (95% CI, −18.5 to 4.3; P = .22) lower in patients who were obese (BMI ≥ 30 kg/m2). The V̇o2/workload slope in patients with a healthy weight was 7.9 (95% CI, 7.5-8.4), 7.8 (95% CI, 7.2-8.3) in patients who were overweight, and 8.8 (95% CI, 8.3-9.2) in patients who were obese. At 1-year follow-up CPET, no significant changes in parameters related to performance, ventilation, circulation, or gas exchange were found (Table 4).Table 4Cardiopulmonary Exercise Testing Parameters at Peak Exercise: Baseline and 1-Year Follow-up (n = 41)Baseline1-y Follow-upMean Difference, (95% CI), P ValuePerformance Work load, W199 (176-222)202 (178-227)3.3 (−4.5 to 11.1), .399 Work load, % predicted128 (114-141)131 (118-145)3.7 (−2.0 to 9.5), .199 Vo2, mL/min2,309 (2,070-2,549)2,322 (2,092-2,552)12.8 (−117.7 to 143.2), .844 Vo2, mL/kg/min27.7 (24.7-30.8)27.6 (24.7-30.5)−0.1 (−1.8 to 1.5), .870 Vo2, mL/kg/min, % predicted102 (92-112)103 (94-111)0.9 (−4.9 to 6.6), .759Circulation HR, beats/min157 (151-164)156 (149-163)−1.4 (−8.4 to 5.5), .679 HR, % predicted89 (86-93)92 (87-97)2.8 (−2.8 to 8.3), .323 Oxygen pulse, mL/bpm14.7 (13.3-16.1)14.9 (13.4-16.4)0.2 (−0.7 to 1.1), .641 Oxygen pulse, mL/bpm, % predicted112 (101-122)115 (106-124)3.0 (−4.4 to 10.6), .409 Vo2/workload slope, mL/min/W8.4 (7.7-9.0)8.2 (7.5-8.8)−0.2 (−0.9 to 0.6), .606Ventilation Ve, L/min87 (77-98)87 (77-98)0.0 (−6.5 to 6.7), .988 Ve, % predicted74 (67-82)81 (73-90)7.1 (−1.6 to 15.9), .107 Breathing frequency36 (33-38)37 (34-39)0.7 (−2.0 to 3.4), .613 Breathing reserve, % predicted (n = 27)36 (28-45)38 (31-46)1.9 (−2.8 to 6.8), .409 RER1.2 (1.1-1.2)1.2 (1.2-1.2)0.0 (0.0 to 0.1), .018 Vo2 at VT, % predicted102 (92-112)103 (94-111)0.9 (−4.9 to 6.6), .759 Lowest Sao2, %97 (96-98)aMedian (interquartile range).98 (96-99)aMedian (interquartile range).0.3 (−0.6 to 1.2), .558Gas exchange Ve/Vco2 slope28.5 (26.4-30.7)27.0 (25.9-28.1)−1.5 (−3.5 to 0.5), .128 Vo2 at VT/Vo2peak, %70 (66-75)71 (65-76)0 (−5 to 5), .764Data are mean (95% CI) or as otherwise indicated. A paired t test was used to compare continuous outcomes between baseline and 1-year follow-up. HR = heart rate; RER = respiratory exchange ratio; Sao2 = oxygen saturation; Ve = minute ventilation; Ve/Vco2 = ventilatory equivalent for carbon dioxide; V̇o2 = oxygen uptake; Vo2peak = peak oxygen uptake; VT = ventilatory threshold.a Median (interquartile range). Open table in a new tab Data are mean (95% CI) or as otherwise indicated. A paired t test was used to compare continuous outcomes between baseline and 1-year follow-up. HR = heart rate; RER = respiratory exchange ratio; Sao2 = oxygen saturation; Ve = minute ventilation; Ve/Vco2 = ventilatory equivalent for carbon dioxide; V̇o2 = oxygen uptake; Vo2peak = peak oxygen uptake; VT = ventilatory threshold. A considerable decline in both physical activity and physical fitness was observed from the time prior to infection to ba
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