Functional Limitations and Exercise Intolerance in Patients With Post-COVID Condition: A Randomized Crossover Clinical Trial

Abstract

Importance: Many patients with post-COVID condition (PCC) experience persistent fatigue, muscle pain, and cognitive problems that worsen after exertion (referred to as postexertional malaise). Recommendations currently advise against exercise in this population to prevent symptom worsening; however, prolonged inactivity is associated with risk of long-term health deterioration.

Objective: To assess postexertional symptoms in patients with PCC after exercise compared with control participants and to comprehensively investigate the physiologic mechanisms underlying PCC.

Design, setting, and participants: In this randomized crossover clinical trial, nonhospitalized patients without concomitant diseases and with persistent (≥3 months) symptoms, including postexertional malaise, after SARS-CoV-2 infection were recruited in Sweden from September 2022 to July 2023. Age- and sex-matched control participants were also recruited.

Interventions: After comprehensive physiologic characterization, participants completed 3 exercise trials (high-intensity interval training [HIIT], moderate-intensity continuous training [MICT], and strength training [ST]) in a randomized order. Symptoms were reported at baseline, immediately after exercise, and 48 hours after exercise.

Main outcomes and measures: The primary outcome was between-group differences in changes in fatigue symptoms from baseline to 48 hours after exercise, assessed via the visual analog scale (VAS). Questionnaires, cardiopulmonary exercise testing, inflammatory markers, and physiologic characterization provided information on the physiologic function of patients with PCC.

Results: Thirty-one patients with PCC (mean [SD] age, 46.6 [10.0] years; 24 [77%] women) and 31 healthy control participants (mean [SD] age, 47.3 [8.9] years; 23 [74%] women) were included. Patients with PCC reported more symptoms than controls at all time points. However, there was no difference between the groups in the worsening of fatigue in response to the different exercises (mean [SD] VAS ranks for HIIT: PCC, 29.3 [19.5]; controls, 28.7 [11.4]; P = .08; MICT: PCC, 31.2 [17.0]; controls, 24.6 [11.7]; P = .09; ST: PCC, 31.0 [19.7]; controls, 28.1 [12.2]; P = .49). Patients with PCC had greater exacerbation of muscle pain after HIIT (mean [SD] VAS ranks, 33.4 [17.7] vs 25.0 [11.3]; P = .04) and reported more concentration difficulties after MICT (mean [SD] VAS ranks, 33.0 [17.1] vs 23.3 [10.6]; P = .03) compared with controls. At baseline, patients with PCC showed preserved lung and heart function but had a 21% lower peak volume of oxygen consumption (mean difference: -6.8 mL/kg/min; 95% CI, -10.7 to -2.9 mL/kg/min; P < .001) and less isometric knee extension muscle strength (mean difference: -37 Nm; 95% CI, -67 to -7 Nm; P = .02) compared with controls. Patients with PCC spent 43% less time on moderate to vigorous physical activity (mean difference, -26.5 minutes/d; 95% CI, -42.0 to -11.1 minutes/d; P = .001). Of note, 4 patients with PCC (13%) had postural orthostatic tachycardia, and 18 of 29 (62%) showed signs of myopathy as determined by neurophysiologic testing.

Conclusions and relevance: In this study, nonhospitalized patients with PCC generally tolerated exercise with preserved cardiovascular function but showed lower aerobic capacity and less muscle strength than the control group. They also showed signs of postural orthostatic tachycardia and myopathy. The findings suggest cautious exercise adoption could be recommended to prevent further skeletal muscle deconditioning and health impairment in patients with PCC.

Trial registration: ClinicalTrials.gov Identifier: NCT05445830.

Figure 1.. Study Flowchart

HIIT indicates high-intensity interval training; MICT, moderate-intensity continous training; PCC, post-COVID condition; and ST, strength training.

Figure 2.. Fatigue and Muscle Pain Responses to 3 Different Exercise Sessions

High-intensity interval training (HIIT), moderate-intensity continuous training (MICT), and strength training (ST) were conducted in a randomized crossover design in patients with post-COVID condition (PCC) (n = 30) and age- and sex-matched healthy controls (n = 31). Differences in changes from baseline to 48 hours following each exercise trial in the fatigue visual analog scale (VAS; score range, 0 [no feeling] to 10 [worst possible feeling]) (A) and the muscle pain VAS (B) were compared between patients with PCC and controls. Differences in changes 48 hours after exercise in the fatigue VAS score (C) and the muscle pain VAS score (D) among 3 exercise trials were compared in the group with PCC and the control group separately, and individual post hoc tests were used to compare exercise sessions when a main effect of exercise was found. Change in the muscle pain VAS score 48 hours after ST exercise was also compared between patients with PCC and controls. Horizontal bars indicate medians; lower and upper ends of the boxes, the first and third quartiles; and whiskers, minimum and maximum values. ^aP < .05. ^bP > .05 (not significant). ^cP < .001.

Figure 3.. Aerobic Capacity and Inflammatory Responses to 3 Different Exercise Sessions

A and B, Aerobic capacity, presented as the peak volume of oxygen consumption (V̇O₂), and the percentage of individuals reaching ventilatory threshold (VT), both of which were assessed via cardiopulmonary exercise testing 48 hours after 3 exercise sessions (high-intensity interval training [HIIT], moderate-intensity continuous training [MICT], and strength training [ST]) in patients with post-COVID condition (PCC) (n = 30) and age- and sex-matched healthy controls (n = 31). C and D, For group, P = .37; exercise, P = .18; time, P = .02; group × exercise, P = .04; group × time, P = .49; exercise × time, P = .31; group × exercise × time, P = .92. E and F, For group, P = .06; exercise, P < .001; time, P = .27; group × exercise, P = .52; group × time, P = .26; exercise × time P = .004; group × exercise × time, P = .054. Bars represent means; whiskers, SDs; and dots, individual data. CK indicates creatine kinase; IL-6, interleukin 6. To convert CK to U/L, divide by 0.0167. ^aP < .05.