Daily life physical activity in patients with chronic stage IV sarcoidosis: A multicenter cohort study

Abstract Background and objectives Little is known about the consequences of chronic sarcoidosis on daily life physical activity (DLPA). The aim of this prospective study was to measure DLPA in patients with chronic sarcoidosis and to determine its relationship to clinical and functional parameters. Methods Fifty‐three patients with chronic sarcoidosis and 28 healthy control subjects were enrolled in this multicenter prospective study. Two markers of DLPA (number of steps walked per day [SPD]) and total daily energy expenditure (TEE) were assessed for five consecutive days with a physical activity monitor. Pulmonary function, aerobic capacity (maximal oxygen uptake [VO2max]), exercise capacity (6‐min walk test [6MWT]), and quality of life (self‐reported questionnaires) were also evaluated. Comparisons of DLPA parameters between the two groups were performed using an analysis of covariance adjusted for age, sex, and body mass index (BMI). Relationships between DLPA parameters and patient characteristics were assessed in multivariable linear regression models. Results Patients with sarcoidosis walked significantly fewer SPD than did the control subjects (6395 ± 4119 and 11 817 ± 3600, respectively; P < 0.001 after adjustment for age, BMI, and sex). TEE was not significantly different between patients with sarcoidosis and healthy controls (median [interquartile range]: 2369 [2004‐2827] and 2387 [2319‐2876] kcal/day, respectively, P = 0.054 adjusted for age, BMI, and sex). SPD showed significant positive correlations with 6MWT distance (Pearson's correlation, r = 0.32, 95% confidence intervals [95%CI] = 0.06, 0.55; P = 0.019), VO2max (r = 0.44, 95%CI = 0.17, 0.65; P = 0.002), and Visual Simplified Respiratory Questionnaire score (r = 0.44, 95%CI = 0.19, 0.64; P = 0.001), and a significant negative correlation with modified Medical Research Council questionnaire score (r = −0.38, 95%CI = −0.60, −0.10; P = 0.009). TEE was significantly correlated with BMI (r = 0.38, 95%CI = 0.13, 0.59; P = 0.004), forced expiratory volume in 1 second (r = 0.55, 95%CI = 0.33, 0.71; P < 0.001), total lung capacity (r = 0.44, 95%CI = 0.18, 0.64; P = 0.001), and forced vital capacity (r = 0.56, 95%CI = 0.34, 0.72; P < 0.001). In multivariable analysis, SPD remained associated only with VO2max. Conclusion Patients with chronic sarcoidosis appear to have reduced DLPA mainly because of compromised VO2max.


Conclusion:
Patients with chronic sarcoidosis appear to have reduced DL PA mainly because of compromised VO 2 max. KEYWORDS aerobic capacity, anxiety, daily life physical activity, depression, fatigue, pulmonary function test, Sarcoidosis is a systemic disease of unknown cause that can affect many organs but that most frequently (90%-95% of cases) affects the lungs. 1 Together, sarcoidosis and idiopathic pulmonary fibrosis represent the two most common etiologies of interstitial lung disease. 1 Histologically, sarcoidosis is characterized by the formation of epithelioid and giant cell granulomas without caseous necrosis, 2 and it is usually classified in five stages based on radiological findings.
Stage IV corresponds to the chronic fibrosing form of the disease, which accounts for approximately 5.4% of pulmonary sarcoidosis cases. 3 Patients with chronic respiratory diseases often display disabling dyspnea associated with a progressive reduction in daily life physical activity (DL PA ), as has previously been demonstrated in patients with interstitial lung diseases, including idiopathic pulmonary fibrosis. 4 Reduced physical activity is an important clinical parameter related to increased morbidity, mortality, and hospitalizations in many chronic diseases. 5 Little is known about DL PA in patients with chronic sarcoidosis. [6][7][8][9] Saligan showed a reduction in physical activity associated with fatigue, depressive symptoms, and a shorter distance in the 6-minute walk test (6MWT), 9 whereas Bahmer et al found a significant association with 6MWT distance and quality of life scores but only a weak association with fatigue. 6 However, these studies examined patients with a variety of respiratory conditions, and relatively few of them had chronic fibrotic disease.
With this in mind, we sought to quantify DL PA in patients with stage IV chronic sarcoidosis and determine the relationships between two-defined DL PA parameters and a number of pulmonary function, aerobic capacity, and quality of life measures. The main objective of this work was to evaluate DL PA in patients with chronic stage IV sarcoidosis compared with healthy control subjects. The secondary objective was to determine the factors associated with DL PA in patients with chronic sarcoidosis.

| Patients
Fifty-three patients with stage IV chronic sarcoidosis 10 were enrolled in the study. Of these, 29  bullae, and emphysema. In addition, we enrolled 28 healthy volunteers who were students or relatives of employees at the hospital. The controls were selected to be comparable in age and sex ratio. All control subjects had normal spirometry results. None of the patients or control subjects was engaged in exercise training programs prior to the study. All individuals gave informed consent, and approval for the use of the data was provided by the Institutional Review Board of the French Learned Society for Pulmonology (CEPRO 2017-007).

| Assessment of daily life physical activity
Subjects were equipped with a physical activity monitor (SenseWear Pro armband and SenseWear software version 8.0; BodyMedia Inc., Pittsburgh, Pennsylvania, United States) and instructed to wear the device continuously, except while showering or bathing, for five consecutive days (three weekdays and two weekend days). The device was positioned on the upper right arm at the midpoint between the acromion and the olecranon, as previously described. 11 DL PA was assessed by measuring the number of steps per day (SPD) and the total daily energy expenditure (TEE, in kcal/day). All functional tests and questionnaires were performed on the same day, prior to the 5-day DL PA monitoring.

| Six-minute walk test (6MWT)
The 6MWT was performed in accordance with international recommendations 15 using a 30-m indoor corridor in our hospital. Two 6MWT were performed and the results of the second ISWT were recorded for analysis. Pulse O 2 saturation (SpO 2 ) and heart rate were monitored continuously using a Novametrix 513 Pulse Oximeter (Wallingford, Connecticut, United States).

| Cardiopulmonary exercise test
Subjects completed a triangular exercise test on a cycle ergometer (Ergometrics 800; Ergoline, Bitz, Germany), with blood pressure and electrocardiographic monitoring (Medcard; Medisoft, Sorrine, Belgium) according to a standardized protocol, as detailed previously. 16 We focused on aerobic capacity assessed by maximal oxygen uptake (VO 2 max), and the results are expressed as mL O 2 /kg/min and the percentage of predicted values. 17

| Dyspnea
Dyspnea occurring during the patients' daily lives was assessed using the modified Medical Research Council (mMRC) self-administered questionnaire, which consists of five questions about perceived breathlessness and is scored on a scale from 0 (not troubled by breathlessness except during strenuous exercise) to 4 (very severe dyspnea: too breathless to leave the house or breathless when dressing or undressing). 18

| Fatigue
Fatigue occurring during the patients' daily lives was assessed using the Fatigue Assessment Scale (FAS) questionnaire, in which a score greater than 22 (on a scale of 10-50) is considered clinically significant. 19

| Quality of life
The patients indicated their overall quality of life using the Visual Simplified Respiratory Questionnaire (VSRQ). A score of at least 80 (on a scale of 0-100) indicates a satisfactory quality of life. 20

| Anxiety and depression
The Hospital Anxiety and Depression Scale (HADS) was designed to identify and quantify the two most common forms of psychological disorders in medical patients. 21 For both subscales, a score of 8 to 10 (on a scale of 0-21) is indicative of uncertain symptoms, and a score greater than 11 is indicative of clinically relevant symptoms.

| Statistical analysis
Continuous variables are expressed as means (SD) for normally distributed data and medians (interquartile range [IQR]) for other data.
Categorical variables are expressed as numbers (percentage). Normality of distribution was assessed visually using histograms and statistically using the Shapiro-Wilk test. Patient characteristics were compared with those of healthy control subjects using student's t test for quantitative variables and Chi-square test for sex. DL PA parameters were compared between patients and control subjects using an analy-

| RESULTS
The characteristics of the patients with sarcoidosis and healthy control subjects are summarized in Tables 1 and Table 2. Pulmonary function tests showed that DLco was reduced (<80% predicted) in 46 of the 53 (87%) patients with sarcoidosis. A restrictive pattern (TLC < 80% predicted) was observed in 20 patients (38%), and an obstructive pattern (FEV 1 /FVC < 70%) was seen in 31 patients (58%). Twenty-two patients (41%) displayed significant fatigue (FAS score > 22), 14 (26%) had a significant HADS anxiety score (≥11), and 11 (20%) had   Since the difference in TEE was considered not to be clinically significant, the multivariable analysis were not performed.

| DISCUSSION
The results of this study show that DL PA is decreased in adult patients with stage IV sarcoidosis and that SPD is significantly associated with   and SF-12 questionnaires). 6 However, it is important to note that Bahmer et al included only three patients with chronic sarcoidosis stage IV in their study cohort, which could explain the differences between their and our results. Indeed, the mean (±SD) SPD recorded in that study (7490 ± 3007) 6 was higher than in our study (6395 ± 4119).
Our data suggest that submaximal stress tests are insufficient to evaluate the mechanisms underlying the reduced DL PA in patients with sarcoidosis. To our knowledge, only one study has previously evaluated parameters other than SPD to quantify DL PA in patients with chronic sarcoidosis. 7 Although daily energy expenditure was also associated with VO 2 max in that study, only patients with less severe disease (stage II) were evaluated. 7 We also found that total daily expenditure was correlated with FEV 1 . Bahmer et al 6 found that FEV 1 was associated with the 6MWT distance but not with SPD in patients with sarcoidosis. However, the mean FEV 1 in that study was less severe than in our study. Similar findings to ours have been reported in patients with chronic obstructive pulmonary disease, who display a progressive decrease in FEV 1 that is paralleled by a decrease in physical activity. 23 Our study is the first to show that the obstructive ventilatory defect is correlated with DL PA in patients with sarcoidosis and might explain part of the reduction in daily TEE.
Interestingly, both the pulmonary function pattern and the high per-   In addition to the limitations inherent to the observational exploratory design, our study has several weaknesses. There was no formal sample size calculation, so we cannot exclude the possibility that differences may have been overlooked because of inadequate statistical power. In a posterior power calculation, the smallest significant difference that our sample size (53 patients with sarcoidosis and 28 healthy controls) allowed us to detect with 80% power was 0.7 (standardized mean difference), which is interpreted as a large effect size. 32 The lack of a validation dataset was also a limitation. Additionally, we also cannot exclude response bias in the questionnaires.  All variables associated with number of steps per day in the univariable analyses (at P < 0.10) were considered as candidate variables for multivariable analysis. The multivariable analysis was conducted using a forwardstepwise selection approach, as specified in the statistical analysis section, by including pre-specified confounders as forced variables (age, BMI, and sex).