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Study design and patients
This was a prospective, randomized, parallel-group, and single-blind (assessor blind) study conducted between September 2021 and December 2022. Volunteers were randomized 1:1 into an IG and a waiting CG using a computer-based list of random numbers generated by the software SPSS. Variable block length with block sizes of 2, 4, and 6, was used to avoid selection bias due to predictability. Study nurses and physicians screening volunteers and assessing the primary outcome at baseline and after 6 months were blinded for the randomization sequence. We recruited eligible patients who consulted the pneumological post-COVID-19 outpatient clinic or the Department of Rheumatology and Immunology of Hannover Medical School. Patients were referred by general practitioners or pneumologists due to persisting symptoms ≥ 3 months after SARS-CoV-2 infection.
According to pre-study defined criteria, we included female and male volunteers aged 18 years or older who reported a continuing impairment of physical or mental health after COVID − 19 (detection by polymerase chain reaction) infection with a fatigue assessment scale (FAS) score ≥ 22 points. Non-inclusion criteria were current participation in another intervention study, clinically relevant acute or chronic infections, pregnancy, preceding surgery less than 8 weeks prior to recruitment, joint replacement that is less than 6 months old, tumor -associated diseases in the last 5 years, or any illnesses or functional impairments which preclude participation in a physical training intervention.
Our randomized clinical trial (RCT) was carried out in accordance with the Declaration of Helsinki, and was registered at German Clinical Trials Register (registration number: DRKS00026245). The institutional ethics review board of Hannover Medical School approved the study (No.9822_BO_S_2021) and written informed consent was obtained prior to the inclusion of patients. All methods were performed in accordance with the relevant guidelines and regulations. This study adhered to CONSORT guidelines [10].
Primary outcome
The primary outcome of our study was the change in V̇O2peak during an exercise test, recorded at baseline, and after the 3-month intervention period compared with controls. Body weight-normalized values for V̇O2peak and for maximum power output were also expressed as a percentage of age- and sex-adjusted reference values [11, 12]. As V̇O2max (defined as maximum volume of oxygen the body can utilize under maximum load conditions and accompanied by V̇O2 plateau formation) is often achieved only by competitive athletes or highly motivated subjects, we used V̇O2peak as an alternative (highest oxygen uptake over a 30s interval attained during a particular test).
Secondary outcomes
Secondary outcomes included the FAS score, HrQoL, severity of depression and anxiety, work ability, body weight, and spirometric parameters. These data were assessed at baseline and after the 3-month intervention period and compared with changes assessed within the control group.
Assessments
After study inclusion, all patients completed a comprehensive medical evaluation including pulmonary function testing by body plethysmography according to international technical standard [13]. We assessed height and weight in a standardized fashion and estimated fat and fat-free mass with a bioimpedance analysis (InBody 720, Biospace, Seoul, Korea). To determine steps per day, patients received a wearable activity tracker (Forerunner 45, Garmin, Olathe, United States).
For testing parameters of exercise capacity, including the primary outcome (i.e. V̇O2peak), patients performed an incremental exercise test using a spirometric system (Oxycon CPX, CareFusion, Würzburg, Germany) on a speed-independent bicycle ergometer (Ergoline P150, Bitz, Germany) with 60 to 70 revolutions per minute. The incremental exercise tests were conducted in an air-conditioned room. To ensure consistent testing conditions, ambient conditions were maintained. To avoid overexerting patients with anticipated low performance, we adopted a testing procedure for the majority of cases based on an individually defined starting load with load increases following evaluation by the investigating physician. With the exception of 6 examinations, the incremental test started with a load of 20 W (W) increasing by 10 W steps every minute and was stopped with the onset of subjective overexertion due to peripheral muscle fatigue and/or pulmonary limitations (4 subjects started with a load of 50 W increasing by 10 W steps every minute, two started with a load of 50 W increasing by 16.67 W steps every minute). Heart rate (12-channel electrocardiogram) and oxygen uptake (breath by breath) were continuously recorded. The subjective perceived exertion was assessed by the Borg scale, with values ranging from 6 to 20 [14]. This scale is validated and used in many languages including the here used German version [15], and based on the assumption that the perception of exertion at maximal voluntary exhaustion is related to an individuals’ heart rate [14].
Self-reported outcomes were recorded via validated questionnaires in German to be completed by patients at home. Fatigue was estimated with the FAS as recommended by the German Society for Pneumology and Respiratory Medicine [16]. Higher numbers refer to more severe fatigue. An FAS score of at least 22 points indicates fatigue, while a score of at least 35 points indicates extreme fatigue [17]. We distributed the authorized version (Hofgrefe Publishing GmbH, Göttingen, Germany) of the short form 36 questionnaire (SF-36) for the estimation of HrQoL [18]. The SF-36 uses eight subscales, each with a scale ranging from 0 to 100, culminating in two summated scales, the mental and physical component score. A higher mental and physical component score corresponds to a better HrQol. We compared the component scores with normative values from the German population [19]. We used the German version of the Hospital Anxiety and Depression Scale (HADS-D), a validated questionnaire to assess the severity of depression and anxiety [20, 21]. Scores for the anxiety and depression subscales range from 0 to 21, higher scores indicating more severe anxiety or depression. Values between 8 and 10 are suggestive for a mood disorder, scores > 10 indicate depressive symptoms and/ or anxiety. To estimate work ability we distributed the work ability index questionnaire [22]. This questionnaire contains seven questions concerning work, work ability and health, resulting in a total score ranging from seven to 49, with higher values representing greater work ability. We estimated daily physical activity characteristics, using the Freiburger activity questionnaire which estimates the total and exercise-related physical activity of adults, both of which are specified as metabolic equivalent of task (MET)-hours per week [23]. All outcome data at baseline and after the intervention were assessed at the Department of Rehabilitation and Sports Medicine at Hannover Medical School. The study intervention was conducted as an online-supported telerehabilitation with the use of the activity tracker (see paragraph “Study Intervention”).
Study intervention
Patients allocated to the 3-month intervention received an exercise plan recommending 150 min of moderate physical activity per week (60–75% of the maximum heart rate measured during the incremental exercise test). The exercise plan was individually designed by the exercise scientist based on the results of the assessment, personal preferences and needs, as well as the patient’s exercise tolerance. The exercise plan consistently included a defined exercise heart rate, periods of endurance (e.g. cycling, walking, indoor cycling, cross-training, swimming or jogging), strength (e.g. equipment-based training at a gym or home, single-limb strength training, stability training or fitness videos focused on strengthening the body) and recovery (e.g. meditation, stretching exercises, breathing exercises, yoga or relaxation retreats). In addition, once a week, more intense exercise was scheduled in the form of three to ten minutes of stair climbing or one to three minutes of sit-to-stand exercises that allowed patients to exceed their exercise heart rate limit, if tolerated. Patients performed the training independently at home. The control group did not receive any specific instructions and were asked to continue with their current lifestyle and everyday activities.
All patients were provided with Garmin activity trackers to record their exercise, activity intensity, and associated parameters such as sleep duration. The trackers were worn on the non-dominant hand during the study period, connected to the Garmin Connect app, and activity data was stored on the Garmin server. Consent from the patient allowed the exercise scientist and the patient to view the activities through the app. In weeks one, four, and eight of the intervention, scheduled face-to-face exercise consultations were conducted via telephone or video call with an exercise scientist to adjust the exercise plan considering current exercise levels and fatigue severity as needed. The patients’ self-assessment of their previous training session and the corresponding heart rate of the training units was the basis for adapting the training plan during the exercise consultation. The exercise scientist also contacted patients to clarify and discuss possible adjustments when discrepancies from the scheduled training plan were detected. For instance, if the exercise scientist finds that the wearable activity device was not worn, or that activities were not recorded or were recorded incorrectly. Patients were free to contact their exercise scientist by telephone or e-mail with questions or needs at any time.
Statistical analysis
We did not calculate an a priori sample size due to the lack of appropriate studies in that field at the time. Data were first tested for normal distribution and variance homogeneity with Kolmogorov-Smirnov test and the Levene test, respectively. For all outcomes the analysis was carried out with the per-protocol population, including all cases with complete data at baseline and after the intervention for the primary outcome. For the analysis of the primary and all secondary outcomes, an analysis of covariance model was used with the change in the parameter of interest (3 months-baseline) as the response variable and eta quadrat η² as the effect size. Explanatory variables were sex, the respective parameter at baseline, and the study group (intervention vs. control). To test for within-group differences from baseline to end of intervention, a two-sided Students T-Test or a Wilcoxon-Test with Cohens d as the effect size were used. An exploratory sub-group analysis was performed based on the subdivision of the FAS score into fatigue (< 35 points) and extreme fatigue (≥ 35 points). Within-subgroup differences for changes from baseline to end of intervention in terms of V̇O2peak were tested using a Students T-test or Wilcoxon test. The type-I-error was set to 5% (two-sided). All statistical analyses were performed with IBM SPSS 27 Statistics (IBM Corporation, New York, USA). Unless otherwise stated, values are given as mean ± SD.
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