Effects of different exercise training programs on the functional performance in fibrosing interstitial lung diseases: A randomized trial.

OBJECTIVES: We aimed to compare the effects of different aerobic exercise training (ET) programs on respiratory performance, exercise capacity, and quality of life in fibrosing interstitial lung diseases (f-ILD).
METHODS: A case-control study where 31 patients with f-ILD diagnosis based on chest high-resolution computed tomography were recruited from Main Alexandria University hospital-Egypt. Ten patients were randomly assigned for only lower limbs (LL) endurance training program, and 10 patients for upper limbs, lower limbs, and breathing exercises (ULB) program for consecutive 18 sessions (3 sessions/week for 6 consecutive weeks). Eleven patients who refused to participate in the ET program were considered as control. All patients were subjected for St George's respiratory questionnaire (SGRQ), 6-minute walk test (6-MWT), forced spirometry and cardiopulmonary exercise testing (CPET) before and after ET programs.
RESULTS: Fibrosing non-specific interstitial pneumonia (NSIP) and collagenic associated-ILD were the commonest pathologies among the ET groups (30% each) with mean age of 44.4±12.25 and 41.90±7.58 years for LL and ULB groups respectively and moderate-to-severe lung restriction. 6-MWT and SGRQ significantly improved after both ET programs (p<0.001). Peak oxygen consumption (VO2) improved significantly after both LL training (median of 22 (interquartile range (IQR) = 17.0-24.0) vs. 17.5 (IQR = 13.0-23.0) ml/kg/min, p = 0.032) and ULB training (median of 13.5 (IQR = 11.0-21.0) vs. 10.5 (IQR = 5.0-16.0) ml/kg/min, p = 0.018). Further, maximal work load and minute ventilation (VE) significantly improved after both types of ET training (p<0.05); however, neither ventilation equivalent (VE/VCO2) nor FVC% improved after ET (p = 0.052 and 0.259 respectively). There were no statistically significant important differences between LL and ULB training programs regarding 6-MWT, SGRQ or CPET parameters (p>0.05).
CONCLUSIONS: ET was associated with improvements in exercise capacity and quality of life in f-ILD patients irrespective of the type of ET program provided.

Introduction

Interstitial lung diseases (ILDs) are a heterogeneous group of diseases characterized by pulmonary parenchymal inflammation and fibrosis [1]. Various subtypes of ILDs are referred to as fibrotic ILDs (f-ILDs) with overlapping in the clinical features, since they have an insidious onset of dry cough, shortness of breath, especially progressive exertion, and bibasilar crackles. They also share morphological characteristics and typical pathological mechanisms, as they are distinguished by the existence of diffuse and permanent fibrous lesions of the lung interstitium and alveolar parenchyma leading to the concept of a progressive fibrosing phenotype that can be applied to a variety of f-ILDs [1].

Idiopathic pulmonary fibrosis (IPF) is the most common subtype of f-ILDs [2]. However, other ILD subtypes also have a progressive fibrosing phenotype. These include fibrotic hypersensitivity pneumonitis (HP), unclassifiable ILD, non-specific interstitial pneumonia (NSIP), connective tissue diseases associated ILDs, organizing pneumonia, ILD associated with occupational exposures and rarely sarcoidosis. Progressive f-ILDs are associated with high mortality [3-5]. Decline in lung function and worsening of symptoms are reflecting the cardinal features of progressive f-ILDs which results in exercise limitation and marked deterioration of health-related quality of life (HRQoL) [6-8].

Exercise limitation in ILDs is multifactorial, with contributions of impairment of gas exchange and pulmonary circulation [9], ventilatory limitation [10], and peripheral muscle dysfunction [11, 12]. Pulmonary rehabilitation (PR) is gaining wide acceptance in the management of chronic respiratory diseases especially chronic obstructive pulmonary disease (COPD) in the last years [13]. Exercise training (ET) is an integral component of PR for ILDs, including resistance and endurance training which is important in increasing cardiorespiratory fitness and exercise capacity [14]. Despite weak recommendation for PR in the guidelines of management of IPF [15], PR has shown benefits in patients with ILDs irrespective of the underlying pathology in terms of reduce the severity of symptoms, improvement of functional exercise capacity and HRQoL [16].

We hypothesized that patients with f-ILDs could get benefits from various types of ET. We aimed to compare the effects of different aerobic ET programs (namely lower limbs only (LL) versus upper limbs, lower limbs, and breathing exercises (ULB)) on respiratory performance, exercise capacity, and HRQoL in f-ILDs patients.

Materials and methods

Study design and ethics

A prospective randomized case-control study with short-term follow-up that enrolled patients with diagnosis of f-ILDs based on chest high-resolution computed tomography (HRCT). The study was conducted at Alexandria Main University hospitals, Alexandria, Egypt between January 2020 and January 2021. The study was approved by local ethical committee of Alexandria Faculty of Medicine of Egypt (protocol ID: 0201313). The protocol was registered in ClinicalTrials.gov (ID number: NCT05227443). All the participants signed an informed written consent.

Patients’ characteristics

Adult patients aged more than 18 years–with age range between 25 to 70 years–who were previously diagnosed as f-ILDs based on HRCT radiological features, in addition to the restrictive or mixed pattern in spirometric results were enrolled. Patients with motor disabilities, cardiovascular diseases (as acute heart failure, unstable angina or recent myocardial infarction), cognitive impairments, history of cerebrovascular accident, active cancer, and a life expectancy below 3 months were excluded from the study. Thirty-one patients with f-ILDs were enrolled, of whom 11 patients refused to participate in ET programs or unable to participate due to morbid obesity or living outside the influence of the hospital or voluntary withdrew from the study were considered as control group (Fig 1) whom met the same inclusion and exclusion criteria of the study. Accordingly, 20 patients were randomized equally for either LL only aerobic ET or ULB and further reanalyzed.

Fig 1

Flow chart of the studied population.

All patients were subjected to complete history including modified Medical Research Council (mMRC) dyspnea scale [17] (with detailed description in S1 File) and smoking history; complete physical examination including anthropometric measures and body mass index (BMI); and HRCT of chest. A detailed drug history was also taken from all participants including the use of oral corticosteroids, immunosuppressive medication and antifibrotic treatment; and we did not modify either the dose or pharmacological drug was taken by any patient throughout the study duration to avoid any risk bias in our results. Forced spirometry and 6-minute walk test (6MWT) [18] according to international guidelines were performed for all patients before ET. St. George’s Respiratory Questionnaire (SGRQ) [19] for assessment of HRQoL was obtained also before ET which includes 3 categories: symptoms component (frequency and severity), activity component and impact component (social functioning, psychological disturbances). mMRC dyspnea scale, forced spirometry, 6MWT, and SGRQ were repeated by the end of ET program. Regarding the control group, they were followed up by phone calls for symptomatology change and exacerbations history due to the COVID-19 pandemic state.

Cardiopulmonary exercise test (CPET)

CPET was performed for all the patients before and after the sessions of ET. CPET was performed using the Ergocard clinical exercise testing system (Ergocard Clinical, Medisoft, Sorinnes, Belgium) according to American Thoracic Society (ATS) guidelines [20]. The reference values of Jones et al [21] were considered. Incremental CPET protocol was conducted on an electronically braked cycle ergometer using ExpAir software (ExpAir, version 1.34, Medisoft, Sorinnes, Belgium). All CPET parameters were recorded at baseline (i.e., at zero watts during the warming phase of CPET just before starting the incremental increase of work load) and at maximum work load (WL) achieved by the participants. These parameters included: work load (WL), minute ventilation (VE), oxygen consumption (VO2), oxygen consumption / kilogram (VO2/kg; which is considered as the peak VO2 at the maximal WL), carbon dioxide output (VCO2), heart rate (HR), respiratory rate (RR), oxygen pulse (VO2/HR), dead space (VD), tidal volume (VT), systolic blood pressure (SBP), diastolic blood pressure (DBP), breathing reserve (BR), respiratory quotient (RQ), end-tidal carbon dioxide pressure (PETCO2), end-tidal oxygen pressure (PETO2), and oxygen saturation (SpO2). The VE/VCO2 was calculated.

Exercise training (ET)

Twenty patients enrolled in ET programs: 10 patients performed LL only training and 10 patients performed ULB training. ET protocols were consistent with those recommended for use in PR programs for people with COPD [22]. The program continued for 6 weeks where the patients had 3 supervised sessions/week (a total of 18 sessions). Lower limb aerobic training was performed on a treadmill (S1 Fig in S1 File). The standards of exercise prescription were applied as previously described for chronic lung diseases [22, 23]. The program was individualized; as the initial duration, the initial intensity, and the rate of progression varied among patients based on their exercise tolerance.

The exercise intensity was measured as the percentage of the maximum heart rate determined from the equation (220 –age of the participant) [24]. During the 1st week, the patients exercised initially at low intensity exercise i.e., 50–60% of their maximum heart rate and short duration of usually 10 minutes that was broken into shorter intervals if needed (as cycles of 3 minutes training followed by 1–2 minutes of rest period). The 2nd week, an attempt was made to increase the performed work during training by increasing the duration of session by 5 minutes every 2 sessions with decreasing the intervals between training, and increasing the workload by 5% every 2–3 sessions according to patient’s tolerance. The 3rd week, most patients were able to continue 30 minutes of aerobic exercise as 2 cycles of continuous 15 minutes aerobic training separated by one interval of rest at moderate exercise intensity of 64–76% of their maximum heart rate. The 4th– 6th week, the ET continued the achievement of 3rd week whereas most patients were able to exercise 30 minutes continuously at moderate exercise intensity which was the main target to achieve.

Upper limb exercise was performed on a wheel (S2 Fig in S1 File). Each session lasted for 15 minutes of continuous exercise which was well tolerated by patients (workload is less demanding). For breathing exercises, an incentive spirometry was used [25].

During ET session, SpO2 and HR were measured regularly to ensure safety. Those on long term oxygen therapy (LTOT) performed the ET while continuously used their level of L/min. The patients who desaturated below predetermined cutoff values (often SpO2 < 90%) and known to be on with acceptable SpO2 on room air, supplemental oxygen was used to exercise safely. In patients who kept on desaturating despite adequate oxygen support, the exercise session was divided into multiple short bouts in order to allow SpO2 to recover and stay in a safe range [26].

Outcomes

The changes of CPET parameters, mMRC dyspnea scale, 6-minute walk distance (6MWD), SGRQ, and forced spirometry were recorded as primary outcomes. Further, mortality and disease exacerbation during the follow up time were recorded as secondary outcomes.

Statistical analysis

All the data were expressed as median and interquartile range (IQR) for the non-normal distribution of continuous data or mean ± standard deviation (SD) for the normal distribution of continuous data. Frequencies and percentages (%) were used to report categorical data. Chi-square test, one-way ANOVA test and Kruskal-Wallis test were used in the comparison between 3 groups as appropriate; while Student independent t-test, Paired t-test, Mann-Whitney test, Wilcoxon signed rank test were used as appropriate when comparing between 2 groups. Further, a multivariate logistic regression in relation to outcome was conducted using forward method after adjustment to the significant baseline covariates found between the control group and ET intervention groups. Odd ratio (OR) and confidence interval (CI) 95% was shown. A two-tailed p-value < 0.05 was considered statistically significant. SPSS package (Version 22.0. Armonk, NY: IBM Corp) was used for all analyses.

Results

Table 1 shows the demographics and baseline clinical characteristics of all the participants. The patients involved in ET program appeared to be significantly younger in age (p = 0.004, Table 1), more males in LL program and control rather than ULB program (p = 0.048, Table 1), and mostly non-smokers (p = 0.035, Table 1). There was no statistically significant difference between groups regarding presence of comorbidities, associated pulmonary hypertension, duration of illness, mMRC dyspnea scale, baseline 6-minute walk distance (6MWD), baseline SGRQ and baseline spirometric parameters (p > 0.05, Table 1). The mean FVC was 49.0 ± 12.30% predicted in LL group, and 49.9 ± 11.89% predicted in ULB group indicated a moderate to severe lung restriction.

Table 1

Baseline characteristics of the studied groups.

Character	Control group (n = 11)	LL group (n = 10)	ULB group (n = 10)	Sig. (p value)
Age (yrs); mean (±SD)	57.91 ± 11.74	44.40 ± 12.25	41.90 ± 7.58	0.004*
Gender; (n, %)	7 (63.6) / 4 (36.4)	6 (60) / 4 (40)	2 (20) / 8 (80)	0.048*
Male / Female
BMI (kg/m 2 ); mean (±SD)	28.24 ± 8.10	25.33 ± 5.36	27.89 ± 6.92	0.590
Smoking status; (n, %)	4 (36.4) / 7 (63.6)	2 (20) / 8 (80)	0 (0) / 10 (100)	0.035*
Active smoker/ non-smoker
Smoking index (pk/yr); median (IQR)	72.5 (57.5–80.0)	80 (50.0–110.0)	0 (0)	0.625
Duration of the disease (months)	19.0 ± 13.8	24 ± 9.80	17.3 ± 15.39	0.508
Comorbidities (Y); (n, %)	5 (45.5)	3 (30)	4 (40)	0.784
Hypertension	1 (9.1)	1 (10)	1 (10)	0.918
DM	2 (18.2)	2 (20)	2 (20)
Both	2 (18.2)	0 (0)	1 (10)
Associated PHT	7 (63.6)	6 (60)	8 (80)	0.433
mMRC dyspnea scale; mean (±SD)	NA	2.90 ± 0.74	3 ± 0.67	0.754
SGRQ (total)	64.3 ± 17.4	74.6 ± 16.73	75.8 ± 18.78	0.272
6MWD (meter)	243.82 ± 138.99	276.0 ± 130.06	264.0 ± 95.13	0.834
Diagnosis; (n, %)
IPF	4 (36.4)	2 (20)	0 (0)	0.166
Chronic HP	5 (45.5)	1 (10)	4 (40)
Fibrotic NSIP	2 (18.2)	3 (30)	3 (30)
Collagenic ILD	0 (0)	3 (30)	3 (30)
Chronic Sarcoidosis	0 (0)	1 (10)	0 (0)
Spirometry; mean (±SD)
FVC (L)	1.46 ± 0.57	1.97 ± 0.60	1.93 ± 0.53	0.140
FVC (% predicted)	44.4 ± 15.13	49.0 ± 12.30	49.9 ± 11.89	0.592
FEV1 (L)	2.0 ± 0.95	1.99 ± 0.58	1.694 ± 0.38	0.523
FEV1 (% predicted)	51.69 ± 28.04	55.7 ± 14.69	55.2 ± 13.56	0.894
FEV1 / FVC	93.9 ± 6.9	91.1 ± 9.15	88.1 ± 8.43	0.374
Baseline medications; (n, %)
Corticosteroids	6 (54.5)	9 (90)	9 (90)	0.049*
Pirfenidone	1 (9.1)	0 (0)	0 (0)	0.232
Immunosuppressive steroid sparing	0 (0)	3 (30)	2 (20)	0.199
Acetyl cysteine	5 (45.5)	5 (50)	5 (50)	0.833
LTOT	4 (36.4)	2 (20)	6 (60)	0.285

Abbreviations; yrs: years, pk/yr: pack/ year, Y: yes; SD: standard deviation, n: number, NA: not assessed, IQR: interquartile range, BMI: body mass index, DM: diabetes mellitus, IPF: idiopathic pulmonary fibrosis, HP: hypersensitivity pneumonitis, ILD: interstitial lung disease, NSIP: non-specific idiopathic pneumonitis, PHT: pulmonary hypertension, FVC: forced vital capacity, FEV1: forced expiratory volume in 1 second, LTOT: long term oxygen therapy, 6MWD: 6-minute walk distance.

* Significant p value < 0.05.

Fibrosing NSIP and collagenic associated-ILD were the commonest pathologies followed by chronic HP among ET groups while IPF and chronic HP were the commonest pathologies among control group without statistically significant difference (p = 0.138, Table 1). Corticosteroids was the commonest prescribed medication among all groups whereas six patients (54.5%) in the control group and 18 patients (90%) in the ET groups were treated with corticosteroids (p = 0.049, Table 1). Eight patients (40% of both ET groups) and 4 patients (36.4%) of control group were on LTOT (p = 0.285).

CPET

The various parameters of CPET both at baseline (at 0 watts of WL) and maximal exercise before starting ET programs are shown in S1 Table in S1 File and Table 2 respectively. The VO2, VO2% predicted, VO2/kg and oxygen pulse (VO2/HR) at baseline (at 0 watts of WL) were significantly lower among ULB groups when compared to LL group and control group (p < 0.05, S1 Table in S1 File). At maximal WL during CPET, SpO2 of the control group was significantly lower when compared to LL and ULB training groups (p = 0.025, Table 2) while VO2/HR (i.e., oxygen pulse) was significantly lower among ULB group versus both LL and control groups (p = 0.044, Table 2). However, there was no statistically significant difference regarding work load, VO2, VO2% predicted, VCO2, peak VO2, VE, breathing reserve, PETO2, PETCO2, VD/VT, respiratory rate, heart rate, RER and ventilation equivalent (VE/VCO2 slope) at maximal exercise (p > 0.05, Table 2).

Table 2

CPET variables at maximal exercise workload before ET among the studied groups.

Variable	Control group (n = 11)	LL group (n = 10)	ULB group (n = 10)	Sig. (p value)
Time (min)	6.63 ± 1.16	6.61 ± 1.30	7.61 ± 1.61	0.203
Work load (watts)	48.22 ± 23.24	49.20 ± 14.48	37.88 ± 21.62	0.441
Work load%	35.2 ± 16.59	33.7 ± 14.94	30.4 ± 19.32	0.837
VE (L/min)	44.50 ± 18.41	44.18 ± 11.50	31.81 ± 7.78	0.067
VE%	40.6 ± 19.62	42.1 ± 14.87	33.0 ± 9.38	0.353
Breathing reserve (%)	46.56 ± 17.56	46.5 ± 16.59	58.30 ± 16.99	0.228
VD/VT ratio	0.27 (0.20–0.30)	0.22 (0.20–0.25)	0.22 (0.21–0.24)	0.258
VO2 (L/min)	1.17 (0.64–1.38)	1.19 (0.94–1.39)	0.79 (0.56–1.10)	0.123
VO 2 %	69 (29–88)	63.0 (46.0–72.0)	36.5 (29.0–46.0)	0.090
VO 2 /kg (ml/kg/min)	19 (10–20)	17.5 (13.0–23.0)	10.5 (5.0–16.0)	0.160
VCO2 (L/min)	0.69 (0.47–1.08)	0.93 (0.64–1.03)	0.63 (0.36–0.68)	0.064
Respiratory rate (br/min)	47.21 ± 14.46	47.50 ± 7.89	40.0 ± 9.38	0.236
RER	0.64 ± 0.21	0.79 ± 0.12	0.70 ± 0.32	0.366
HR (b/min)	119 (104–120)	140 (122.25–144)	122 (103.5–139.5)	0.288
HR%	77 (65.0–80.0)	78 (69.2–84.8)	69 (65.0–82.3)	0.708
VE/VCO 2	43.19 ± 10.66	40.85 ± 14.22	45.83 ± 10.96	0.675
VO 2 /HR (ml/beat)	10.2 (4.10–10.40)	8.7 (6.85–10.0)	3.9 (3.80–5.65)$	0.044*
VO 2 /HR%	71.2 (47.9–71.5)	70.4 (0.56–0.85)	47.9 (0.45–0.64)	0.133
PETCO2 (mmHg)	23.67 ± 6.16	25.9 ± 4.77	26.6 ± 6.15	0.520
PETO2 (mmHg)	118.44 ± 5.32	114.5 ± 8.96	117.5 ± 9.64	0.557
SpO2 (%)	82.11 ± 1.97$	86.8 ± 5.25	87.8 ± 5.2	0.025*

Abbreviations; VE: minute ventilation, br/min: breath/minute, VO2: oxygen consumption, VCO2: carbon dioxide output, HR: heart rate, VO2/HR: oxygen pulse, VD: dead space, VT: tidal volume, RER: respiratory exchange ratio, PETCO2: end-tidal carbon dioxide pressure, SpO2: oxygen saturation, SD: standard deviation.

*Significant p value < 0.05.

$ Significance between this group and the others.

ET programs

Tables 3 and 4 display the measures following ET compared to that before ET. There was no statistically significant change in FVC, FVC% predicted, FEV1, FEV1 / FVC before and after ET either in LL or ULB groups (p >0.05, Table 3). However, the FEV1% predicted significantly improved among ULB group after ET (55.2 ± 13.56% vs. 61.9 ± 12.07 before and after ET respectively, p = 0.035, Table 3). Further, SpO2 significantly improved after ET training among ULB (median of 92.5% (IQR = 92.0–93.0) before vs. 93.5% (IQR = 91.0–94.0) after ET, p = 0.035, Table 3).

Table 3

Comparison between spirometric parameters, SpO2, 6MWT, and SGRQ before and after ET among group LL and ULB.

Test	LL group before ET (n = 10)	LL group after ET (n = 10)	Sig. (p)#	ULB group before ET (n = 10)	ULB group after ET (n = 10)	Sig. (p) #	Sig. (p)$
Spirometry:
FVC (L)	1.97 ± 0.60	2.01 ± 0.58	0.266	1.93 ± 0.53	2.16 ± 0.49	0.087	0.545
FVC (% predicted)	49.0 ± 12.30	53.9 ± 11.4	0.104	49.9 ± 11.89	56.5 (54.0–58.0)	0.085	0.186
FEV1 (L)	1.99 ± 0.58	2.34 ± 0.86	0.580	1.694 ± 0.38	2.10 ± 0.52	0.056	0.456
FEV1 (% predicted)	55.7 ± 14.69	60.0 ± 16.18	0.247	55.2 ± 13.56	61.9 ± 12.07	0.035*	0.778
FEV1 / FVC	91.1 ± 9.15	95.6 ± 10.83	0.494	88.1 ± 8.43	88.1 ± 7.25	0.714	0.093
SpO2 (%); median (IQR)	93.0 (92.0–96.0)	94.0 (92.0–96.0)	0.066	92.5 (92.0–93.0)	93.5 (91.0–94.0	0.035*	0.468
6MWD (meter)	276.0 ± 130.06	438.0 ± 128.74	<0.001*	264.0 ± 95.13	414.0 ± 132.35	<0.001*	0.686
SGRQ questionnaire (%, total); mean (±SD)	74.6 ± 16.73	26.7 ± 8.70	<0.001*	75.8 ± 18.78	32.5 ± 5.93	<0.001*	0.102
SGRQ (%, activity)	0.76 (0.69–0.76)	37.4 (30.0–76.0)	0.011*	0.75 (0.74–0.76)	44.9 (44.9–76.0)	0.028*	0.390
SGRQ (%, impact)	67.4 ± 17.33	10.7 ± 5.33	<0.001*	64.1 ± 17.26	11.3 ± 3.53	<0.001*	0.757
SGRQ (%, symptoms); median (IQR)	74.3 (70.7–78.1)	54.4 (51.4–57.5)	0.005*	76.7 (72.4–77.2)	57.5 (57.5–57.5)	0.021*	0.204
mMRC dyspnea scale	2.90 ± 0.74	2.0 ± 0.94	0.001*	3.0 ± 0.67	1.8 ± 0.79	<0.001*	0.613

Abbreviations; FVC: forced vital capacity, FEV1: forced expiratory volume in 1 second, 6MWD: 6-minute walk distance, SGRQ: St. George’s Respiratory Questionnaire, SpO2: oxygen saturation, mMRC dyspnea scale: modified medical research council dyspnea scale.

* Significant p value < 0.05

$ Comparison between LL and ULB groups after ET

Comparison between the same group after ET.

Table 4

Comparison between CPET at maximal exercise before and after ET among group LL and ULB.

Variable	LL group before ET (n = 10)	LL group after ET (n = 10)	Sig. (p) #	ULB group before ET (n = 10)	ULB group after ET (n = 10)	Sig. (p) #	Sig. (p) $
Work load (watts)	49.20 ± 14.48	64.7 ± 11.51	0.009*	37.88 ± 21.62	51.2 ± 20.36	0.006*	0.085
Work load%	33.7 ± 14.94	45.8 ± 14.66	0.038*	30.4 ± 19.32	38.3 ± 19.98	0.048*	0.353
VE (l/min)	44.18 ± 11.50	54.67 ± 8.72	0.017*	31.81 ± 7.78	44.47 ± 7.0	0.003*	0.010*
VE%	42.1 ± 14.87	53.6 ± 10.16	0.021*	33.0 ± 9.38	44.9 ± 5.96	0.005*	0.034*
Breathing reserve (%)	46.5 ± 16.59	53.0 ± 10.79	0.284	58.30 ± 16.99	58.7 ± 4.85	0.936	0.145
VT	0.98 ± 0.21	1.16 ± 0.24	0.037*	0.82 ± 0.19	1.08 ± 0.31	0.017*	0.538
VD/VT ratio	0.22 ± 0.06	0.22 ± 0.03	0.726	0.21 ± 0.05	0.23 ± 0.04	0.112	0.296
VO2 (L/min)	1.19 (0.94–1.39)	1.34 (1.04–1.86)	0.169	0.79 (0.56–1.10)	0.94 (0.88–1.06)	0.139	0.140
VO 2 %	63.0 (46.0–72.0)	76 (57.0–85.0)	0.066	36.5 (29.0–46.0)	49.5 (39.0–60.0)	0.022*	0.050
VO 2 /kg (ml/kg/min)	17.5 (13.0–23.0)	22 (17.0–24.0)	0.032*	10.5 (5.0–16.0)	13.5 (11.0–21.0)	0.018*	0.075
VCO2 (L/min)	0.93 (0.64–1.03)	1.09 (0.95–1.26)	0.051	0.63 (0.36–0.68)	0.87 (0.74–1.09)	0.009*	0.120
Respiratory rate (br/min)	47.50 ± 7.89	46.55 ± 7.86	0.695	40.0 ± 9.38	43.63 ± 7.58	0.240	0.409
RER	0.81 (0.72–0.83)	0.74 (0.67–0.84)	0.507	0.80 (0.64–0.89)	0.83 (0.67–0.88)	0.540	0.402
HR (b/min)	140 (122.25–144)	140.5 (119.5–147.0)	0.715	122 (103.5–139.5)	130 (127.0–145.5)	0.046*	0.705
HR%	78 (69.2–84.8)	80.8 (66.9–85.4)	0.715	69 (65.0–82.3)	80.1 (74.0–84.5)	0.063	1.00
SBP (mmHg)	138.8 ± 7.74	138.5 ± 9.73	0.879	143 ± 10.01	143 ± 7.89	1.0	0.271
DBP (mmHg)	93.5 ± 10.01	94.5 ± 8.64	0.509	98.5 ± 10.56	98.5 ± 7.09	1.0	0.273
VE/VCO 2	40.85 ± 14.22	38.35 ± 14.69	0.265	45.83 ± 10.96	38.14 ± 9.84	0.097	0.477
VO 2 /HR (ml/beat)	8.7 (6.23–10.15)	7.5 (6.9–8.3)	0.715	3.9 (3.80–6.08)	6.9 (5.78–7.98)	0.128	0.390
VO 2 /HR%	70.4 (0.56–0.85)	73.5 (66.4–82.3)	1.00	47.9 (0.45–0.64)	74.7 (59.0–86.9)	0.128	0.705
PETCO2 (mmHg)	24.5 (23.0–30.0)	25 (22.0–29.0)	0.610	27.0 (23.0–33.0)	27.5 (25.0–29.0)	0.812	0.518
PETO2 (mmHg)	116.0 (106.0–121.0)	120.5 (113.0–127.0)	0.858	122.0 (113.0–126.0)	116.5 (111.0–121.0)	0.138	0.306
SpO2 (%)	86.8 ± 5.25	89.3 ± 5.50	0.179	87.8 ± 5.2	87.5 ± 5.76	0.883	0.484

Abbreviations; VE: minute ventilation, br/min: breath/minute, VO2: oxygen consumption, VCO2: carbon dioxide output, HR: heart rate, VO2/HR: oxygen pulse, VD: dead space, HR: heart rate, VT: tidal volume, RER: respiratory exchange ratio, PETCO2: end-tidal carbon dioxide pressure, SpO2: oxygen saturation, SBP: systolic blood pressure, DBP: diastolic blood pressure, SD: standard deviation

*significant p value < 0.05

$ Comparison between LL and ULB groups after ET

Comparison between the same group after ET.

The absolute change in the average distance covered at the 6MWD after ET was significantly improved from 276.0 ± 130.06 meters to 438.0 ± 128.74 meters for LL group with a mean difference > 100 meters (p < 0.001, Table 3), and from 264.0 ± 95.13 meters to 414.0 ± 132.35 meters in ULB group with a mean difference > 100 meters (p < 0.001, Table 3). Notably, SGRQ score improved significantly in all its categories as well as total score after ET among both LL and ULB groups (p < 0.05, Table 3). Furthermore, the mean mMRC dyspnea scale reduced significantly from 2.90 ± 0.74 to 2.0 ± 0.94 after ET (p = 0.001) in LL group, and from 3.0 ± 0.67 to 1.8 ± 0.79 (p <0.001) in ULB group.

VO2, VO2% predicted, VO2/HR% predicted and SpO2 at baseline (at 0 watts of WL) significantly improved after ET training among ULB group (p < 0.05, S2 Table in S1 File) but not after LL only training program (p > 0.05, S2 Table in S1 File). After training, at baseline CPET (0 watts of WL), resting HR in both groups were reduced and VT increased but not at a significant level (p > 0.05, S2 Table in S1 File). At maximal exercise, there was statistically significant increase of WL, WL% predicted, VE, VE% predicted, VT, and peak VO2 (i.e., VO2/kg at maximal WL) after ET in both groups (LL only and ULB) (p < 0.05, Table 4). Moreover, VO2% predicted, VCO2 and HR significantly increased among ULB training group (p < 0.05, Table 4) but not LL training group. However, neither ventilation equivalent (VE/VCO2 slope) despite apparent decrease nor SpO2 despite apparent increase had statistically significant difference after ET in both groups (p > 0.05, Table 4).

There were no statistically significant differences between LL training and ULB training programs regarding pulmonary function testing, SpO2 at rest, 6MWT and SGRQ (p > 0.05, Table 3). Further, there was no statistically significant differences between LL and ULB training programs in terms of CPET parameters (p > 0.05, Table 4) except for VE and VE% predicted that was significantly higher in LL vs. ULB after termination of ET training sessions (p = 0.01 and 0.034 respectively, Table 4). We did not report any serious adverse events during any of the ET programs.

Outcome

Regarding the control group, one patient (9.1%) died and 5 patients (45.5%) reported exacerbations of their underlying disease (Fig 1). Further, the patients of the control group did not report change of their dyspnea level or other associated symptomatology during their follow up through phone calls despite of continuing medical therapy prescribed by their physicians for at least 3 months. Regarding the ET groups, none of the patients died while one patient (5%) experienced exacerbation of symptoms during the follow-up duration (Fig 1). Moreover, ET (either LL only or ULB) was an independent significant protective factor against underlying disease exacerbations or mortality (p = 0.020, OR = 0.063, CI95% = 0.006–0.652) after adjusting to age, gender, smoking status, and corticosteroids use (S3 Table in S1 File).

Discussion

We found that the f-ILD patients, regardless of the etiology, whom were subjected to ET either LL or ULB training program had improved in term of functional capacity as being assessed by CPET and 6MWT as well as HRQoL. There was no significant improvement of FVC; however, dyspnea level and SpO2 significantly improved after ET. Further, we did not find significant difference between LL and ULB training programs regarding the follow-up assessment except for peak VE.

Holland et al [27] found that 6MWD and dyspnea improved significantly after ET without significant difference between the IPF patients and non-IPF. Vainshelboim et al [23] found in their clinical trial that 6MWD, dyspnea, quality of life, peak VO2 and work rate assessed by CPET improved significantly in IPF population after ET. Also, Kozu et al [28] and Dowman et al [29] found that dyspnea, 6 MWD and quality of life improved in IPF and other ILD after ET. Similarly, Perez-Bogerd et al [30] found in their cohort of ILD that 6MWD, SGRQ and peak work rate increased significantly after PR. Our results are in accordance with these findings.

Treatment options for ILD are limited. Available drug therapy has significant toxic side effects and may not be suitable for many patients with no evidence that current drug therapies for f-ILD can improve quality of life and symptoms [31]. Interestingly, the 6MWD in the current study exceeded the increases observed in most of the previous studies (>100 m vs. 25–45 m respectively) [23, 27–30]. This could be explained by patients’ motivation and the adherence to the ET sessions as well as the lesser proportion of participants diagnosed with IPF who experienced minimal change in 6MWD in other studies [23, 27–30].. Further, the younger age in the ET groups rather than the control group (Table 1) could be another factor that encouraged the participants to stuck to our ET programs.

In contrast to the study of Vainshelboim et al [23], we did not report improvement in pulmonary functions especially FVC after both modalities of ET. However, Holland et al [27] did not find improvement of FVC of their studied IPF population subjected to PR program, similar to our results. This difference could be attributed to the heterogeneity of our f-ILD population, the severity of the disease and the difference of the duration of the ET provided as well as the various training programs in the studies. Up to date, there is no standardized ET recommended for ILD patient and various programs of ET were applied in clinical trials [11, 23, 27, 29, 32]. Further, pulmonary function did not typically improve after PR in other respiratory diseases as COPD which could not be considered as primary outcome in ET programs.

Further, beside the significant improvements in peak VO2, the gold standard for cardiorespiratory capacity evaluation, we showed also significant improvements in WL, VE, and VT at maximal exercise as well as SpO2 at rest. In contrast to our findings, Holland et al [27] and Arizono et al [33] did not report difference in peak VO2 after ET, but they found significant improvements of other CPET parameters in their IPF patients. The effect of ET on improvement of physiological outcomes as detected with CPET and the clinical outcome as being reflected by HRQoL and dyspnea improvements in our patients can be explained by several mechanisms. Firstly, repetitive stimulation of high ventilatory demands and stretching of the thoracic muscles during ET sessions as well as chest expansion during exercises resulted in efficient breathing, improvement of respiratory muscles strength, enhancement of the pleural elasticity and pulmonary compliance resulting in increase of peak VE and VT [23, 34–37] and so amelioration of dyspnea perception. Secondly, enhancement of the ventilatory responses that occurred after the ET could be a cause of recruitment of more alveoli and so increased alveolar oxygen tension and improved alveolar ventilation / perfusion mismatch, resulting in increasing peak VO2 [34, 35].

We have shown that ET with the targeted intensity reached during the training sessions indicate that ET is safe and feasible to be implemented in f-ILD in a similar way as in COPD and other chronic respiratory condition [38]. Moreover, in the current study we demonstrated 2 modalities of ET (LL only and ULB). To our knowledge, this is the first study that evaluates 2 different training programs in f-ILD patients. Interestingly, we found no clinically significant important difference between the two groups. This had the importance of implication of ET with only LL program which would be time and effort saving, especially for f-ILD patients whom have a low exercise tolerance, and in our developing country that has limited resources.

Limitations

The current study had some limitations. Firstly, we did not assess the peripheral muscle strength in the current study. Peripheral muscle weakness is predictive of exercise limitation and intolerance in ILD and further studies still required to assess this factor [39]. Secondly, the current study included only one component of PR, the ET, as we did incorporate the educational and nutritional components which has been shown to be associated with comparable even greater clinical outcomes compared with ET alone in some studies [26]. However, still ET constitutes the main bulk of all PR programs, as reported in previous studies of COPD patient [23, 40]. Thirdly, we did not provide objective follow-up of the control group (using either CPET or 6MWT) and we considered only subjective follow-up through phone calls. However, dyspnea assessed by mMRC was important predictor of mortality among chronic ILD either the baseline level or longitudinal increases of dyspnea degree [41]. Fourthly, we did not include the diffusion capacity (DLCO) in the evaluation of our participant due to lack of this facility in our institute. DLCO is crucial for ILD evaluation; however, FVC variability is associated with disease progression and widely accepted as single factor for monitoring of disease in clinical trials [42, 43]. Lastly, the sample size of the current study is quietly small which could limit the external validity, increase the risk of statistical error and did not allow to conduct power analysis despite the high debate regarding power analysis validity in case of significant data [44, 45]; so further studies are still needed to confirm the current results.

Conclusions

ET in f-ILD is safe, tolerable and results in improving the functional exercise capacity, dyspnea, oxygen saturation, and HRQoL which highlights the effective of ET for f-ILD population. Further, LL only training program is effective as ULB program. This can be of advantage especially in low economic countries that had low resources and to decrease the effort needed by those patients with similar results.

(DOC)

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Supplemental material.

The file contains methods, S1-S3 Tables and S1, S2 Figs legends.

(DOCX)

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(PDF)

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10 Mar 2022

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Reviewer #1: The authors conduct a case-control study to compare the effects of different exercise training programs (two exercise programs: LL endurance training, and ULB program, and one control group) on the functional performance in fibrosing interstitial lung diseases with 31 subjects. The results show that exercise training programs were associated with improved exercise capacity and quality of life.

1. Line 96. 11 patients who refused to participate in ET programs or unable to participate due to certain reasons were considered as a control group. In other words, the selection of control groups were not randomized. How do we know the significant results from intervention or other reasons? Such self-selection and non-randomization seems to violate the spirit of randomized trial.

2. Line 163. There were significant difference in ET group and control at baseline. Were these significant covariates adjusted in later analysis? If not, the final results or conclusions might be questionable in terms of generalizability?

Reviewer #2: Thank you for your submission. This kind of long term studies are challenging and necessary to advance the field. I appreciate the hard work and effort and a well written article in all aspects. But I think there is problem in methodology especially in standardisation of groups and risk of selection bias. I'm undecided in accepting this article, I'm half and half.

I believe these major revisions below will make the article much more effective for the readers:

Comments

1) In abstract section,

Only 18 sessions were written as exercises. İf it is possible, the number of days, whether there is a break, etc. should be emphasized more clearly in the abstract and material method section.

2) The introduction section,

is well written. The purpose is well emphasized.

3) Method section:

Write the population age groups more clearly, is it the elderly group or the adults?

How did you measure exercise intensity with? Please explain it.

Increasing exercise intensity and durations should have been more standardized, it seems not objective and clear. Please explain week by week.

4) Statistical analysis section,

Power analysis should be done, the strength of the study should be specified, such as ( post hoc analysis )

5) Results section,

include bias risk (corticosteroid use). It is risky to include users and non-users in the same group or comparative groups in the results.

6) Please check the references like (28) Is it necessarry to highlight it?

7) Table section,

Please delete the dollar sign under the control group in Table 1.

The age difference between the control group and the experimental groups is very large.And also it is obvious thatcontrol group are in worse physical condition than other groups.

Reviewer #3: �  Abstract:

In my opinion, unit forVO2should be added.

�  In methods section :

I thought it would be better if images about aerobic exercise tests were used ( the monitor of the device, etc.)

DLCO is crucial in interstitial lung diseases. Is there any particular reason for not mentioning about it?

The literature or information about mMRC dispnea scale should be added.

�  InStatistical analysis:

Line 153‘All the data were expressed as median and interquartile range (IQR) or mean . standard deviation(SD) according to the normal distribution of continuous data’.

This sentence hasa missing part. “Median and interquartile rangefor non-normal distribution“should be added.

�  In the Results:

Table 1 has both weight and BMI values. In my opinion, emphasizing “weight” as a separate entity is not necessary. Also, “Y/N” statements for comorbidities have only Y statement in the table. So, “N” statement should be removed.

In Table 1CPEE is considered to be a phenotype of IPF, so it can be merged.

182

“The VO2, VO2% predicted,VO2/kg and oxygen pulse (VO2/HR) at baseline were significantly lower among ULB groups compared to LL group and control group (p < 0.05, table S1 online supplement)”Could you please check this sentence? Only VO2/HR is statistically significant according to Table 1.

184-185“At maximal exercise, SpO2 of the control group was significantly lower when…”Isn’t the control group selected from the ones do not exercise??

186-187 ‘while the oxygen pulse was significantly lower among ULB group

versus both LL and control groups (p= 0.045, table 2)’ I didn’t see these results in table 2.

210-211‘VO2, VO2% predicted, VO2/HR% predicted and SpO2 at baseline significantly improved after ET training among ULB group (p < 0.05, table S2, online supplement) but not after LL only training program (p > 0.05, table S2, online supplement)’.

In table 4, VO2 and VO2/HR%, are not statistically significant for ULB group.

212-213

‘After training, resting HR in both groups were reduced and VT increased but not at a significant level (p > 0.05, table S2, online supplement’

Could you please check this sentence? VT is decreased significantly in table 4. HR results for both groups are different.

215- ‘peak VO2 after ET in both groups (LL only and ULB) (p < 0.05, table 4)’ Could you pleasecheck this sentence? This statement is not statistically significant according to table 4.

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Reviewer #1: No

Reviewer #2: Yes: Esedullah AKARAS

Reviewer #3: No

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Submitted filename: Plos One f-ILD (2).docx

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24 Apr 2022

Dear Dr. Walid Kamal Abdelbasset; Academic Editor

I would like to thank the editor in-chief, the academic editor, the editorial office, and the reviewers for your time and effort in reviewing the paper and the valuable comments. We truly think that the manuscript has improved sensibly after your suggestions. We would like to respond all reviewer’s comments point by point and fulfil all the journal requirements.

Journal Requirements:

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

Response. The style of manuscript has been ajusted to meet PLOS ONE's style requirements.

2. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly.

Response. After reviewing the legal or ethical restrictions on sharing data publicly, we included the dataset of the current study in one the public repository (Fig share). URL https://figshare.com/s/fd724ded44c70a86cef5 and doi: 10.6084/m9.figshare.19640214.

The dataset is currently as a private link that will be available as public on acceptance. We provided this point in a new cover letter submitted with the revised version.

Reviewer #1:

Thank you for your valuable evaluation and your time.

1. Line 96. 11 patients who refused to participate in ET programs or unable to participate due to certain reasons were considered as a control group. In other words, the selection of control groups were not randomized. How do we know the significant results from intervention or other reasons? Such self-selection and non-randomization seems to violate the spirit of randomized trial.

Response. The benefits of rehabilitation and exercise training (ET) in patients with ILD in terms of improvement of functional exercise capacity and quality of life was previously shown in various studies (Dowman LM et al. The evidence of benefits of exercise training in interstitial lung disease: a randomised controlled trial. Thorax. 2017;72(7):610-9; Huppmann P et al. Effects of inpatient pulmonary rehabilitation in patients with interstitial lung disease. Eur Respir J. 2013;42(2):444-53). So, we think that it is unethical to choose a randomized control group among our studied population and we have a specialized ET program of care for ILD patients. Further, the aim of the current study was to compare the effects of different ET programs on the respiratory performance, exercise capacity and quality of life in progressively fibrosed ILD patients rather than to explore the general effect of ET in ILD patients compared to usual care.

Accordingly, we offered our ET program to all participants and those who refused to participate in ET programs or unable to participate due to morbid obesity or living outside the influence of the hospital or voluntary withdrew from the study as we mentioned was considered as control; while those who agreed to participate in ET programs were totally randomized to one of ET (LL only or ULB program) who were included in the subsequent analysis later and we assure that there was no self-selection or non-randomization among the interventions groups. Moreover, the inclusion and exclusion criteria for 3 groups were the same with no statistical difference regarding duration of disease, associated comorbidities, underlying pathological ILD disease and severity of lung fibrosis (assessed by spirometry) as we showed in table 1; so, we think that the significant results (provided in tables 3-4 and S1 file online supplement) were related to the provided intervention rather than the influence of other factors. We clarified this point in the methodology. (Line 104 -109)

2. Line 163. There were significant difference in ET group and control at baseline. Were these significant covariates adjusted in later analysis? If not, the final results or conclusions might be questionable in terms of generalizability?

Response Following the reviewer’s recommendation, we conducted a multivariate logistic regression adjusted to the significant baseline covariates shown in table 1 and corresponding text (namely age, gender, smoking status, corticosteroids) using forward method. We found that only ET (either LL only or ULB) was an independent significant protective factor against underlying ILD disease exacerbations or mortality (p= 0.020, odd ratio= 0.063, confidence interval 95%= 0.006 – 0.652) after adjusting to age, gender, smoking status, and corticosteroids use which were insignificant in regression model. Accordingly, this data supports our conclusion regarding the benefits of ET among f-ILD and reject the terms of generalizability. We included this part in the results section (outcome section, Lines 291 - 294) and online supplement as table S3 with explanation of statistical method in methodology (Lines 205 - 208).

Reviewer #2:

Thank you for your valuable evaluation and your time.

1) In abstract section,

Only 18 sessions were written as exercises. İf it is possible, the number of days, whether there is a break, etc. should be emphasized more clearly in the abstract and material method section.

Response. Following the reviewer’s recommendation, we emphasized more clearly the exercise sessions in the abstract in terms of number of days and weeks as we had 3 supervised sessions of exercise training / week for total duration of 6 consecutive weeks (total number 18 sessions). And we provided details of the exercise training protocol in the methodology as being suggested later by the reviewer. (Line 29 in Abstract and Lines 149 – 150 in methods)

2) The introduction section,

is well written. The purpose is well emphasized.

Response. We would like to thank the reviewer for his comment.

3) Method section:

Write the population age groups more clearly, is it the elderly group or the adults?

How did you measure exercise intensity with? Please explain it.

Increasing exercise intensity and durations should have been more standardized, it seems not objective and clear. Please explain week by week.

Response. Regarding the population age groups, we included adult patients not elderly groups. The mean age of our studied population was 40s (as we showed in table 1), with age range between 25 to 70 years, rather than older than 65 years which represented the elderly group. We clarified this point in the methodology and we provided the age range of the studied population. (Line 99)

Regarding the exercise intensity, it was measured as a percentage of maximum heart rate determined from the equation (220 – age of the participant). We clarified this point in the methodology (Lines 154 – 155) and supported by reference 24.

Following the reviewer’s recommendation, we provided a detailed description of ET program in the methodology week by week. Our ET program followed the standards of exercise prescription were applied as previously described for chronic lung diseases (Bolton CE, et al. British Thoracic Society guideline on pulmonary rehabilitation in adults. Thorax. 2013;68 Suppl 2:ii1-30). The program was individualized; as the initial duration, the initial intensity, and the rate of progression varied among patients based on their exercise tolerance which is widely accepted by previous publication (Dowman LM, et al. The evidence of benefits of exercise training in interstitial lung disease: a randomised controlled trial. Thorax. 2017 Jul;72(7):610-619; Vainshelboim B, et al. Exercise training-based pulmonary rehabilitation program is clinically beneficial for idiopathic pulmonary fibrosis. Respiration. 2014;88(5):378-88.) During 1st week, the patients exercised initially at low intensity exercise i.e., 50-60% of their maximum heart rate and short duration of usually 10 minutes that was broken into shorter intervals if needed (as cycles of 3 minutes training followed by 1-2 minutes of rest period). The 2nd week, an attempt was made to increase the performed work during training by increasing the duration of session by 5 minutes every 2 sessions with decreasing the intervals between training, and increasing the workload by 5% every 2 – 3 sessions according to patient’s tolerance. The 3rd week, most patients were able to continue 30 minutes of aerobic exercise as 2 cycles of continuous 15 minutes aerobic training separated by one interval of rest at moderate exercise intensity of 64 –76% of their maximum heart rate. The 4th – 6th week, the ET continued the achievement of 3rd week whereas most patients were able to exercise 30 minutes continuously at moderate exercise intensity which was the main target to achieve. This part was added with details in the methodology section (ET program subtitle, Lines 151 – 169 and references 22 – 24) and supported with figures in the supplemental material (S1 file, fig S1 and S2) as being suggested by the reviewer #3.

4) Statistical analysis section,

Power analysis should be done, the strength of the study should be specified, such as (post hoc analysis)

Response. We agree with the reviewer that power analysis as post hoc analysis increase the strength of the study; however, post-hoc analysis is usually conducted on negative data (insignificant p value) as a method to show that a “non-significant” hypothesis test failed to achieve significance because it wasn’t powerful enough. Further, it is well documented that post hoc power calculations are not useful and could be misleading (Goodman and Berlin. The use of predicted confidence intervals when planning experiments and the misuse of power when interpreting results. Ann Intern Med. 1994 Aug 1;121(3):200-6; Hoenig and Heisey. The Abuse of Power: The Pervasive Fallacy of Power Calculations for Data Analysis. The American Statistician, February 2001, Vol. 55, No. 1: 19-24; Althouse AD. Post Hoc Power: Not Empowering, Just Misleading. J Surg Res, 2021; 259: A3-A6). In the current study, there was statistically significant improvement in health quality-of-life evaluation, reduction of dyspnea (as assessed by mMRC), improvement of respiratory performance and exercise capacity that was assessed by CPET and 6-minute walk test (p <0.05, tables 3-4 and S2) and only few parameters were not significant during the analysis which we think did not influence the power of the study. However, following the reviewer’s recommendations, we calculated post-hoc power on one of insignificant parameters; and we found that achieved statistical power 60% to detect 3% in the mean improvement of maximal SpO2 after ET between 2 groups at level of significance of 0.05 using 2-sided independent t test (data not shown). We assumed that the power of 60% was due to low sample size of our study; however, our sample size is based on the prevalence of the ILD disease in our community (Shafiek H, et al. Transbronchial cryobiopsy validity in diagnosing diffuse parenchymal lung diseases in Egyptian population. J Multidiscip Healthc. 2019 Aug 30;12:719-726; El-Hoffy MM, et al. High resolution multi-detector row computed tomography in imaging of interstitial lung diseases. Alexandria J Med. 2008;44(2):1–7) as well as the relatively uncommon f-ILD worldwide and its high variability (Kaul B, et al. Variability in Global Prevalence of Interstitial Lung Disease. Front Med (Lausanne). 2021;8:751181). We highlighted this point and relatively small sample size in the limitation of the study. (Lines 369-373)

5) Results section,

include bias risk (corticosteroid use). It is risky to include users and non-users in the same group or comparative groups in the results.

Response. We agree with the reviewer that inclusion of users and non-users of corticosteroids in the groups could raise a bias risk; however, as we showed in table 1 that 90% of the participants in ET programs were on oral corticosteroids on inclusion in the study which was equal between both exercise training groups as the significant difference was between the control group and the experimental groups (as we shown in table 1), with no statistically significant difference regarding the duration of the disease in the studied groups. Further, as being suggested by reviewer #1, we conducted a multivariate regression analysis with adjustment to all significant baseline covariates and we found that corticosteroids use did not influence the benefits of ET regarding the outcome. In addition, our study focused on patients with fibrotic progressive ILD, where the rule of corticosteroid use is variable and questionable (Richeldi L et al. European Respiratory Review Dec 2018, 27 (150) 180074; DOI: 10.1183/16000617.0074-2018); and we did not modify any line of the treatment was considered by the patients at the time of inclusion to our programs in order to avoid any bias in our results. Accordingly, we think that there was no bias risk in the current results. We highlighted this point in the methodology (Lines 113 – 116, and 205 – 208) and results (lines 291 – 294, table 1, table S3 – supplemental material file S1).

6) Please check the references like (28) Is it necessarry to highlight it?

Response. We agree with the reviewer that it is not necessary to highlight reference 28. The reference has been corrected and became reference 30.

7) Table section,

Please delete the dollar sign under the control group in Table 1.

The age difference between the control group and the experimental groups is very large. And also it is obvious thatcontrol group are in worse physical condition than other groups.

Response. Following the reviewer’s recommendation, we deleted the dollar sign under the control group in Table 1 and its comment in the table note.

Secondly, we agree with the reviewer that the age group is large and there is significant age difference between the control group and the experimental groups; however, the control group is not in worse physical condition than the experimental groups based on the insignificant difference between various groups regarding the pulmonary function test (spirometry), health related quality of life evaluation, 6-minute walk distance achieved and CPET data that we described in tables 1 and 2. Further and as being suggested by reviewer #1, we conducted a multivariate analysis model with adjustment to all significant baseline covariates and we found that age did not influence the benefits of ET regarding the outcome. In addition, we think that the younger age of the experimental groups could be an important factor that encouraged the participants to stuck to our exercise training programs. We highlighted this point in the methods (Lines 205 – 208), results (Lines 291 – 294, table 1, table S3 – supplemental material file S1) and discussion (Lines 317 – 319).

Reviewer #3:

Thank you for your valuable evaluation and your time.

Abstract:

- In my opinion, unit for VO2 should be added.

Response. Following the reviewer’s recommendation, we included the unit change for VO2 in both exercise training modalities in abstract (Lines 36 – 40).

In methods section:

- I thought it would be better if images about aerobic exercise tests were used (the monitor of the device, etc.) DLCO is crucial in interstitial lung diseases. Is there any particular reason for not mentioning about it?

Response. Following the reviewer’s recommendation, we included images of the aerobic exercise tests (lower and upper limbs training) provided to our participants along with the monitoring device used mainly in case of LL training in the File S1 supplemental material (Figures S1 – S2). Secondly, we totally agree with the reviewer that DLCO is crucial in interstitial lung diseases; however, due to lack of this test in our institute during the duration of the study, we did not mention this test in our study. However, FVC variability is associated with disease progression (Veit T, et al. Variability of forced vital capacity in progressive interstitial lung disease: a prospective observational study. Respir Res. 2020 Oct 19;21(1):270. doi: 10.1186/s12931-020-01524-8) and FVC decline was considered as single primary end-point for response to therapy among progressive fibrotic ILD patients in clinical trials (Behr J et al. Pirfenidone in patients with progressive fibrotic interstitial lung diseases other than idiopathic pulmonary fibrosis (RELIEF): a double-blind, randomised, placebo-controlled, phase 2b trial. Lancet Respir Med. 2021 May;9(5):476-486. doi: 10.1016/S2213-2600(20)30554-3.). We highlighted this point in the limitation of the study (Lines 366 – 369, references 43 – 44).

- The literature or information about mMRC dispnea scale should be added.

Response. Following the reviewer’s recommendation, we added a reference about mMRC dyspnea scale (reference 17) with detailed information about mMRC dispnea scale in the supplemental material (S1 file) with a highlighted note in the main text (Line 111).

In Statistical analysis:

- Line 153‘All the data were expressed as median and interquartile range (IQR) or mean. standard deviation(SD) according to the normal distribution of continuous data’.

This sentence hasa missing part. “Median and interquartile rangefor non-normal distribution“should be added.

Response. We agree with the reviewer that this part “median and interquartile range for non-normal distribution” was missing and has been added. (Lines 200 – 201)

In the Results:

- Table 1 has both weight and BMI values. In my opinion, emphasizing “weight” as a separate entity is not necessary. Also, “Y/N” statements for comorbidities have only Y statement in the table. So, “N” statement should be removed.

Response. We agree with the reviewer that emphasizing “weight” as a separate entity is not necessary, so we removed the weight from table 1. Also, we agree that “N” statement in “Y/N” statements for comorbidities is not necessary and we removed “N” for comorbidities in table 1 as being recommended by the reviewer.

- In Table 1 CPEE is considered to be a phenotype of IPF, so it can be merged.

Response. We agree with the reviewer that CPEE is considered to be a phenotype of IPF, so we merged it with IPF (in table 1) as being recommended by the reviewer and we re-calculated the p value. (Table 1)

- 182 “The VO2, VO2% predicted, VO2/kg and oxygen pulse (VO2/HR) at baseline were significantly lower among ULB groups compared to LL group and control group (p < 0.05, table S1 online supplement)” Could you please check this sentence? Only VO2/HR is statistically significant according to Table 1.

Response. In table S1 of the supplemental material, we provided the baseline CPET parameters that was recorded before starting the incremental increase in work load of CPET (i.e., during the warming stage of CPET at workload of zero watts). Accordingly, we found that the VO2, VO2% predicted, VO2/kg and oxygen pulse (VO2/HR) at baseline (at 0 watts of workload) were significantly lower among ULB groups compared to LL group and control group (as we showed in the main text). However, only VO2/HR is statistically significant at maximal workload of CPET among ULB groups compared to LL group and control group as we shown in table 2 (not table 1). We clarified this point in the methodology with the addition of a description of baseline phase of CPET in order to avoid conflicts regarding the data provided (Lines 136 – 138) as well as short description in the heading of table S1 (supplemental material S1 file) and in results section (Lines 234 – 236).

- 184-185 “At maximal exercise, SpO2 of the control group was significantly lower when...”Isn’t the control group selected from the ones do not exercise??

Response. Yes, the control group were selected from the ones who did not exercise training as mentioned by the reviewer; however, all the groups including the control group had the CPET on recruitment in the study as we meant by “At maximal exercise” the maximal workload during CPET. We corrected the word “maximal exercise” to “maximal work load during CPET” to avoid conflicts. (Line 238)

- 186-187 ‘while the oxygen pulse was significantly lower among ULB group

versus both LL and control groups (p= 0.045, table 2)’ I didn’t see these results in table 2.

Response. In table 2, the oxygen pulse (which is VO2/HR) was significantly lower among ULB group (median of 3.9 (IQR= 3.80 – 5.65) ml/beat) versus both LL (median of 8.7 (IQR= 6.85 – 10.0) ml/ beat) and control groups (median of 10.2 (IQR= 4.1 – 10.4) ml/beat) and p value of 0.044 rather than 0.045 as written in the text. This point has been clarified in the text and p value was corrected. (Lines 239 – 240)

- 210-211 ‘VO2, VO2% predicted, VO2/HR% predicted and SpO2 at baseline significantly improved after ET training among ULB group (p < 0.05, table S2, online supplement) but not after LL only training program (p > 0.05, table S2, online supplement)’.

In table 4, VO2 and VO2/HR%, are not statistically significant for ULB group.

Response. In table S2 of online supplement, we provided a comparison between ET groups regarding the baseline CPET parameters that was recorded during the warming phase of CPET with a workload of zero watts, and before starting the incremental increase of workload. Accordingly, the baseline variables (VO2, VO2% predicted, VO2/HR% predicted and SpO2 measured at 0 watts of workload) significantly improved after ET training among ULB group but not after after LL only training program. However, in table 4, we provided the CPET at maximal workload achieved by the participants during CPET and as was mentioned by the reviewer neither VO2 nor VO2/HR% were statistically significant for ULB group. We clarified this point in the methodology with the addition of a description of baseline phase of CPET (Lines 136 – 138) in order to avoid conflicts regarding the data provided as well as short description in the heading of table S2 (supplemental material S1 file) and in results section (Lines 267 – 269).

- 212-213 ‘After training, resting HR in both groups were reduced and VT increased but not at a significant level (p > 0.05, table S2, online supplement’

Could you please check this sentence? VT is decreased significantly in table 4. HR results for both groups are different.

Response. As being suggested by the reviewer, we checked the sentence in lines 212-213 and we found the data is correct with no contradictory between the data in table S2 and table 4. The resting HR in both groups (ULB and LL) were reduced and VT increased but not at a significant level at baseline CPET (i.e., workload of zero watts) as being shown in table S2 (supplemental material S1 file); however, VT is increased significantly after ET training among both groups as shown in table 4 and prescribed in the text. Regarding HR, the results for both groups are different as being mentioned by the reviewer whereas HR at maximal exercise among ULB increased significantly (p= 0.046, table 4) but not after LL training (p= 0.715, table 4). We clarified this point in the text (Lines 269 – 270) and we added a description of baseline phase of CPET in methodology (Lines 136 – 138).

- 215- ‘peak VO2 after ET in both groups (LL only and ULB) (p < 0.05, table 4)’ Could you please check this sentence? This statement is not statistically significant according to table 4.

Response. As being suggested by the reviewer, we checked the sentence in line 215. We agree with the reviewer that the word “peak VO2” could have some conflict, as we meant by the word “peak VO2” as VO2/kg at maximal work load which is statistically significant after ET in LL and ULB groups according to table 4 (p= 0.032 and 0.018 respectively). We clarified this point in the text (result section, Line 272) and we provided also a clear definition of peak VO2 in the methodology (Lines 139 – 140).

Submitted filename: ILD- response to reviwers.docx

Click here for additional data file.

3 May 2022

Effects of different exercise training programs on the functional performance in fibrosing interstitial lung diseases: a randomized trial

PONE-D-21-37890R1

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18 May 2022

PONE-D-21-37890R1

Effects of different exercise training programs on the functional performance in fibrosing interstitial lung diseases: a randomized trial

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