Persistent dyspnea is a debilitating symptom in the SARS-coronavirus-2 disease 19 (COVID-19).1 Patients with symptoms lasting more than 4 weeks have post-acute sequelae of COVID-19, commonly known as Long-COVID.1,2 In a study of 4,299 individuals hospitalized for COVID-19, 72% experienced dyspnea 5 months after discharge, which persisted or worsened in 63% of them at 1 year follow-up.1 Given that pulmonary rehabilitation (PR) improves dyspnea among individuals with respiratory conditions, such as chronic obstructive pulmonary disease (COPD), it is a potential therapy for Long-COVID patients with respiratory complaints.2–5
While research has begun evaluating the effects of PR on physical and psychological functioning on Long-COVID, evidence that PR is associated with dyspnea improvements in this population remains limited.
A recent systematic review reported that while PR is associated with reduced dyspnea in Long-COVID, there were no differences between patients that underwent PR and controls.6 The lack of efficacy in the group referred to PR may result from several factors, such as different setting (outpatient vs. inpatient), heterogeneity of PR programs, and dyspnea measures. Therefore, further research is needed to better understand whether PR is an appropriate and effective treatment for dyspnea in Long-COVID.
Accordingly, the first aim of this retrospective study was to evaluate changes in dyspnea following completion of PR in Long-COVID patients. We hypothesized that dyspnea symptoms would reach a clinically meaningful improvement in this group at the end of the program. We also aimed to compare the degree of dyspnea reduction in Long-COVID subjects with two groups, one including individuals with COPD and a second including individuals with both Long-COVID and at least one chronic respiratory disease (Long-COVID+CRD). We hypothesized that Long-COVID+CRD would be associated with attenuated dyspnea improvements after PR compared to individuals with Long-COVID alone.
METHODS
The study included outpatients from The Miriam Hospital’s Pulmonary Rehabilitation Program in Providence, RI. Main inclusion criteria were a PR referral for the primary diagnosis of Long-COVID or COPD, and completion of PR between June 2020 and April 2022. Once eligibility was confirmed, participants were assigned to one of three diagnostic groups: Long-COVID, Long-COVID+CRD, or COPD. The COPD group was selected as an appropriate comparator group (see Supplementary materials).
Participants attended PR 2 – 3 times per week for 8 weeks, on average. The PR program was comprised of exercise (aerobic and resistance training), breathing retraining, and multi-disciplinary education. Participant characteristics, pulmonary function, medical and smoking history, dyspnea symptoms, and six-minute walk distance were extracted from medical records. Dyspnea was assessed by the dyspnea subscale of the self-reported Chronic Respiratory Questionnaire (CRQ-SR)7 and the Modified Medical Research Questionnaire8 (see Supplementary materials).
One-way ANOVA, with Bonferroni post-hoc, was used to detect baseline differences across groups. Chi square tests were conducted to evaluate between-group differences on categorical variables. Within group changes in the CRQ-SR and the Modified Medical Research Questionnaire were analyzed with the Wilcoxon Signed Rank Tests. Alpha was set at 0.05.
RESULTS
Based on study inclusion criteria, of 92 people referred, 18 dropped out, and 74 completed the program and were allocated to analysis: 17 Long-COVID, 28 COPD (FEV1 % predicted 46.8 ± 15.9), and 29 Long-COVID+CRD. At intake, there were no differences in gender, race, supplemental oxygen use, or 6 minute walk distance across groups. Individuals with COPD were older (P = .005) and had a greater smoking history than those with Long-COVID (P = .03) (Table). Mean number and range of sessions attended were not statistically different across groups [Long-COVID 23 (18–33), COPD 23 (20–33), and Long-COVID+COPD 24 (20–35)]. All groups had significant (P < .01) improvements in dyspnea as assessed by the CRQ-SR, meeting the minimal clinically important difference at the end of PR. The Long-COVID participants had a larger improvement in dyspnea on the CRQ-SR compared to those with Long-COVID+CRD and COPD who experienced moderate and minimal clinically significant improvements, respectively. Moreover, Long-COVID was the only group to show a clinically significant reduction in Modified Medical Research Questionnaire scores (P = .002). No group differences in 6 minute walk distance improvement at discharge were detected (P = .34).
Table:
Comparison of Personal Characteristics, Dyspnea Scores, and Six Minute Walk Distances between Individuals with COPD, Long-COVID, and Long-COVID+CRD at Enrollment (June 2020) and on Completion (April 2022) of Pulmonary Rehabilitation
| COPD | Long-COVID | Long-COVID+CRD | |
|---|---|---|---|
| Personal characteristics | |||
| N (% male) | 28 (43) | 17 (53) | 29 (48) |
| Age, yr | 71 ± 8.0 | 63 ± 13.9 | 63 ± 12.4c |
| Race (W/AA/O), n | 25/0/3 | 14/1/2 | 24/1/4 |
| BMI, kg/m2 | 26.6 ± 4.6 | 32.3 ± 7.8c | 31.5 ± 6.0c |
| Smoking status (N/F/C), n | 3/19/6 | 11/6/0 | 10/19/0 |
| Smoking history, pack-years | 56.9 ± 48.6 | 9.7 ± 9.3c | 48.5 ± 37.0 |
| Supplemental oxygen, n (%) | 2 (7) | 1 (6) | 2 (7) |
| CRQ-SR dyspnea a | |||
| Intake | 3.16 ± 1.03 | 3.76 ± 1.12 | 3.17 ± 1.33 |
| Discharge | 3.78 ± 1.37 | 5.32 ± 1.11 | 4.42 ± 1.17 |
| Δ | .62 ± 1.29 | 1.56 ± 1.03 | 1.26 ± 1.21 |
| mMRC dyspnea b | |||
| Intake | 2.21 ± 1.00 | 2.06 ± 1.14 | 1.90 ± .90 |
| Discharge | 1.39 ± .83 | .76 ± .83 | 1.31 ± .76 |
| Δ | -0.82 ± .90 | -1.29 ± 1.10 | -0.59 ± .87 |
| 6MWD, m | |||
| Intake | 308.22 ± 103.74 | 337.53 ± 140.74 | 366.49 ± 139.01 |
| Discharge | 373.40 ± 98.82 | 422.36 ± 138.60 | 417.71 ± 115.00 |
| Δ | 65.18 ± 58.21 | 84.82 ± 83.63 | 51.22 ± 76.45 |
Data are presented as mean ± SD unless otherwise indicated. Abbreviations: AA, African American; BMI, body mass index; C, current smoker; COPD, chronic obstructive pulmonary disease; CRD, Chronic Respiratory Disease; CRQ-SR, Self-Reported Chronic Respiratory Questionnaire; Δ, changes between pulmonary rehabilitation discharge and intake; F, former smoker; mMRC, Modified Medical Research Council Dyspnea Scale; N, never smoker individual; O, other race; 6MWD, six minutes walking distance test; W, White Caucasian.
Higher scores on Self-Reported Chronic Respiratory Questionnaire indicate less dyspnea
Lower scores on Modified Medical Research Council indicate less dyspnea
P≤ 0.05 compared to COPD. Minimal clinically important differences: CRQ-SR ≥ 0.5; mMRC ≥ 1; 6MWD ≥ 30 m.
DISCUSSION
Consistent with our hypothesis, this retrospective study suggests that PR is associated with significant and clinically important improvements in dyspnea in people with Long-COVID. This group also reported significant improvements in 6 minute walk distance (+85 m) which was very similar to another group of Long-COVID patients completing 8 – 12 weeks of PR,2 reinforcing the evidence of PR-induced benefits on exercise performance in this population. In our study, the other two groups also showed an association of PR with clinically significant changes in dyspnea, despite the Long-COVID+CRD having only a moderate reduction. Ours is the first study to evaluate changes in Long-COVID dyspnea using the CRQ-SR subscale (commonly used in COPD7) following outpatient PR and to compare changes across different respiratory diseases.
However, given the retrospective nature of this study, it is unknown if potential confounding variables might mask the extent to which PR directly contributes to dyspnea improvements. Potential confounders include the natural history of respiratory symptom improvements in Long-COVID over time regardless of PR; the unclear timing of PR enrollment relative to diagnosis of acute COVID-19; additional factors, such as patient motivation, flare-up and hospitalization, work-related obligations that conflict with PR participation, and the choice of selecting COPD as control group, given COPD is a progressive, chronic disease. In addition, for this group we did not further delineate presence of other comorbidities, which limits the ability to account for the effects of COPD alone. Among study limitations, COVID-19 testing was not conducted to confirm infection prior to PR intake, nor did we have access to the appropriate medical records to quantify the time between infection and PR intake. Nevertheless, all Long-COVID patients were seen at most 15 months after time of infection.
In conclusion, our study reported a significant decrease in dyspnea in all individuals completing PR, and those with Long-COVID reported the largest improvement. Future randomized controlled studies are necessary to draw more conclusive evidence around the effects of PR on reducing dyspnea in Long-COVID. Additionally, validation studies are recommended to assess the reliability of the use of CRQ-SR in this population.
Supplementary Material
Acknowledgements
The authors thank Julianne DeAngelis and Christopher Breault for data management and data extraction.
Funding
Maria Buckley has no financial disclosures
Andrea Wycoff is funded by NIH T32AA007459 (Miranda/Monti).
Kayla Mahoney has no financial disclosures
Jacqueline Pierce has no financial disclosures
James Simmons has no financial disclosures
Alessandra Adami is funded by a National Heart, Lung, and Blood Institute (NHLBI) grant (R01HL151452).
Andrea Wycoff is funded by NIH T32 AA007459 (Miranda/Monti). Alessandra Adami is funded by NIH R01HL151452 (Rossiter/Adami).
Footnotes
Conflict of Interest
The authors declare no conflict of interest. The results of the study are presented clearly, honestly and without fabrication, falsification, or inappropriate data manipulation.
All authors declare no conflicts of interest.
All authors meet the 4 ICMJE criteria for authorship.
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