Effect of supervised exercise training on exercise capacity,pulmonary function and growth differentiation factor 15 levels in patients with interstitial lung disease: A preliminary study

Abstract

BACKGROUND:

Interstitial lung disease is characterized by exertion dyspnea, exercise limitation and reduced quality of life. The role of exercise training in this diverse patient group is unclear. The growth differentiation factor 15 (GDF15) is a stress-sensitive circulating factor that regulates systemic energy balance and could be a possible biomarker in interstitial lung disease.

OBJECTIVE:

To evaluate the effect of supervised exercise (endurance and resistance) training (SET) on exercise capacity, pulmonary function parameters and GDF15 levels in patients with interstitial lung disease (PwILD).

METHODS:

In this non-randomized case-control trial, the experimental group comprised of 10 PwILD (7 women and 3 men) while the control group consisted of of 18 apparently healthy participants s 11 women and 7 men). All subjects completed an 8-week supervised exercise training program, at a rate of twice a week. Dyspnea was evaluated using the Shortness of Breath Respiratory Questionnaire. Exercise capacity was measured using the 6-min walk test while the heart rate (HR) was monitored before and after the exercise training. GDF15 levels were measured by Enzyme-Linked Immunosorbent Assay (ELISA).

RESULTS:

PwILD had significantly shorter 6-min walk distance than the control subjects at both the 1 ${}^{\text{st}}$ and the 15 ${}^{\text{th}}$ visit. However, both groups improved significantly in this test. The change (pre to post-exercise) in HR value was smaller in PwILD compared to the controls. Moreover, PwILD had higher Shortness of Breath Respiratory Questionnaire score than controls. The mean pre and post GDF15 values in both groups remained statistically unchanged. However the GDF15 values of the PwILD patients were significantly higher compared to the controls with respect to pre and post exercise training respectively.

CONCLUSION:

Supervised exercise training did not affect GDF15 levels in both patient and control groups but its values in PwILD were significantly higher compared to those of controls ( $p\leqslant 0.05$ ). The exercise capacity and dyspnea in these patients improved after exercise training program.

Keywords

Exercise capacity growth differentiation factor 15 interstitial lung disease supervised exercise training pulmonary function parameters

1. Introduction

Physical exercise improves the quality of life and decreases the risk of several diseases [1]. Exercise training is an essential constituent of evidence based management programs for many chronic cardiac and respiratory conditions. Interstitial lung disease (ILD) is a group of disabling chronic lung conditions consisting of more than 200 different disease entities [2]. They are normally associated with interstitial inflammation, [3] and fibrosis. Stressful dyspnea, insightful exhaustion and reduced exercise tolerance are common [4] with subsequent decline in health associated quality of life. Therapeutic choices are often restricted and patients go through cumulative exercise control as their condition advances. There are few well described studies reported on the importance of exercise training in interstitial lung disease (ILD) [5]. The respiratory imbalance noticed in ILD patients is more apparent during exercise. Pathophysiological mechanisms responsible for exertional dyspnea and reduced exercise tolearnce include changed respiratory mechanics, compromised gas exchange, cardiovascular abnormalities and peripheral muscle dysfunction [6].

Exercise training rules in chronic respiratory diseases are same as defined for healthy individuals, including personalized exercise recommendation and evolution of training load [7]. There is a significant indication that a minimum of 8 weeks of exercise training bring considerable improvement in exercise tolerance and clinically important changes in exercise capacity and quality of life [8]. Physical exercise is potentially useful as a treatment for subjects with ILD, [9] with advancements in six-minute walk distance (6MWD), dyspnea, and exercise capacity [5].

Several studies reported positive results of exercise training on fortitude and quality of life [10]. However, very few explored the effect of exercise training on exercise capacity and pulmonary function in patients with ILD [11, 12, 13, 14]. Recently our group assessed [15] the impact of supervised exercise training (SET) on pulmonary function Parameters, exercise capacity and Irisin biomarker in ILD patients.

Growth differentiation factor 15 is a distant member of the transforming growth factor- $\beta$ cytokine superfamily [16]. In the usual state, GDF-15 is expressed in low concentrations in most organs and upregulated because of injury of organs such as liver, kidney, heart and lung [17]. GDF15 levels have been reported to be as a useful biomarker in chronic obstructive pulmonary disease, lung fibrosis and pulmonary arterial hypertension and predict disease severity, decline in lung function and mortality. GDF15 expression increases during pathological states including inflammation, aging, smoking, cancer, oxidative stress, and hypoxia [18, 19, 20]. Moreover, elevated serum levels have been correlated with inflammatory biomarkers, suggesting a link between GDF-15 and inflammation and it may act as pro- or anti-inflammatory depending on the context, organ, and timing [21, 24].

The biological effects of GDF-15 are condition based and may differ with the phase of the disease [22]. GDF-15 concentrations increase with age in healthy old aged subjects [23]. The circulating levels of GDF-15 are increased in acute pulmonary embolism [24] and in idiopathic pulmonary arterial hypertension provide predictive information about the long-term risk of death or lung transplantation [25].

Growth differentiation factor 15 contributes to the loss of muscle in COPD which elevated levels of this cytokine translate into reduced exercise ability in subjects with COPD. Labaki et al. [26] examined the link between GDF-15 levels and 6MWD and assumed that higher GDF-15 levels are associated with lower six minutes walking distance (6MWD). Yazisiz et al. [27] defined the function of GDF-15 in the development of pulmonary fibrosis and reported serum GDF-15 levels in ILD patients with connective tissue disorders (CTD) and CTD without ILD which were significantly higher than healthy controls. Raised serum GDF-15 level was found [28] to estimate an adverse result individually in subjects with COPD exacerbation, proposing the probability that serum GDF-15 could be used as a predictive biomarker of COPD exacerbation.

We hypothesized that GDF-15 could play a pathogenic role in interstitial inflammation in patients with ILD (PwILD). These findings have directed us to explore biological markers that may permit prior discovery of ILD. Since plasma levels of GDF-15 in patients with ILD have never been reported previously, the main object of present study was to discover a possible role for GDF-15 in patients with ILD before and after exercise training and also to evaluate the impact of SET on pulmonary function and exercise capacity in ILD patients.

2. Method

2.1 Participants

Interstitial Lung Disease patients ( $n=$ 10, male $=$ 3; female 7) with stable condition and healthy controls ( $n=$ 18, male $=$ 7; female $=$ 11) aged from18 years and above were recruited in this study. Interstitial Lung Disease patients were referred from pulmonary clinic at King Khalid University Hospital (KKUH) and Controls were recruited from the staff at the King Saud University. This study was conducted at the Department of Physiology, Faculty of Medicine, King Khalid University Hospital (KKUH), King Saud University, Riyadh, Saudi Arabia, from October 2018 to February 2019.

2.2 Study design

This is a non-randomized case control interventional study (single-arm clinical trial (SACT).

Figure 1.

Distribution of medical diagnosis for patients who participated in the study.

2.3 Inclusion/exclusion criteria

The inclusion criteria for SET program in ILD has been broad and participants have had a wide range of ILD diagnoses (Fig. 1). The patients with stable condition, non-smokers, having dyspnea on exertion, on medical treatment and not involved in any exercise program in the last 12 months were included. All participants were free from any serious risk of exercise training according to the guidelines of ACC/AHA for exercise testing [29]. The control subjects were medically free, non-smokers and their pulmonary function tests were normal. Patients with ILD with long term Oxygen (O ${}_{2}$ ) supply, predominant respiratory disease other than ILD, unstable cardiac disease (such as active Ischemic Heart disease, arrhythmia, and pacemaker). Also, subjects who had a musculoskeletal disability (e.g., active arthritis), any comorbidities that prevent exercise, a history of syncope on exertion, communication or transport difficulties and history of arterial SaO ${}_{2}$ during exercise (equal or less than 90% on peak exercise), were all excluded from the study.

2.4 Study protocol

Both patients and healthy subjects received the same exercise training program. All exercise protocol was supervised and performed with oxygen supplementation 2 L/min via intranasal cannula to avoid unwanted shortness of breath (SOB). Full written consent obtained from the participants prior to the study. Adequate level of confidentiality and privacy of subjects was established. The study protocol was approved by the College of Medicine King Saud University Institutional Review Board (Ref. No. 17/0591/IRB, dated Oct. 5, 2017). The pulmonary function test (PFT) was carried out according to previously recommended techniques [30]. Measurements of participant’s body mass composition, blood pressure, oxygen desaturation SpO2, were recorded before and after the exercise.

2.5 Supervised exercise training (SET)

Endurance and resistance training are the main applied modalities in typical exercise training programs. Participants attended a SET program twice-weekly for eight weeks which consisted of endurance training (cycle ergometer and arm ergometer) and resistance training (upper and lower limb) exercise training as described previously [29, 31].

2.5.1 Endurance training

The endurance training program involved flexibility and aerobic exercises. We relied on the Rating of perceived exertion (PRE) scale and complemented by HR monitor (polar watch 430) for monitoring the training intensity. In the initial visit, exercise intensities for endurance training were targeted to the level that patients could exercise at. This meant just lower than the Borg breathlessness rating based on RPE (12–13/20 progressing to 14–15/20, moderate to vigorous, respectively which depended on the ability of subjects and symptom of Borg RPE scale. The target HR was calculated using the HR reserve method such that during the activity the HR was kept below 60% of HR reserve.

2.5.2 Training in cycle ergometer

Participants had performed exercise training in cycle ergometer (ergoline GmbH – Type: ergoselect 200 p mit BD) at an intensity which was initially equivalent to 60% of baseline HR reserve with 20 seconds work interspersed with 20 seconds rest for a maximum time 15 min. The workload was increased according to the subject’s ability and exercise intensity (RPE and HR) for about (5 to 10) watts at each exercise session.

2.5.3 Training in arm-ergometer

Participants have performed exercise training in arm ergometer at interval training. (ergoline GmbH – Type: ergoselect 400 p) at an intensity which was initially equivalent to 60% of baseline HR reserve with 20 seconds work interspersed with 20 seconds rest for a maximum time 15 min. The workload was increased according to the subject’s ability and exercise intensity (RPE and HR) for about 5 watts at each exercise session.

2.5.4 The resistance training

The resistance training session comprised three sets of leg extension and front raise. The intensity-based on one repetition maximum (1RM) (40% to 50%) for one to three sets with 10 to 15 repetitions per set with one min of rest between the sets. The progression of resistance training was expressed by the weight in kgf, that participant worked against in each visit. Most of the subjects trained with 5–20 kgf, depending on their individual ability and symptoms of RPE.

All outcome measures were determined at baseline (visit 1) and after completion of eight weeks of the exercise intervention (visit 15). The following variable indicators were measured before and after SET.

2.6 Outcome measures

2.6.1 Shortness of breath questionnaire (SOBQ)

Both patients and healthy subjects were asked to fill the SOBQ. It is a multi-dimensional instrument to measure the three factors of dyspnea (intensity, quality and emotional responses to this sensation). It is a valid and reliable tool used to indicate severity of shortness of breath previously [32]. The (SOBQ) involves twelve descriptor items on a scale of none (0), mild (1), moderate (2), or severe (3). Total scores from the (SOBQ) range from 0 to 36, with higher scores showing greater severity.

2.6.2 Six minutes walk test (6MWT)

The 6MWT was used for estimating exercise capacity in both ILD patients and controls. The reproducibility of the 6MWD has been confirmed in ILD [33]. Participants were trained to walk from one end to the other of long uncrowded 50 m long hallway at their own speed, while trying to cover as much as possible f a distance in 6 min. Finally covering distance was recorded at the end of six-minute waking before and after SET program.

2.6.3 Heart rate (HR)

Polar heart rate monitor was used to assess the heart rate (HR) of all participants before and after exercise session.

2.6.4 Blood sample collection and analysis

Blood samples from the 10 ILD patients and 18 matched healthy controls were drawn after overnight fasting. Blood was taken into 3 mL EDTA containing tubes for blood collection. The samples were centrifuged directly after the blood sampling for 20 min at 4 ${}^{\circ}$ C at 3000 $\times$ g and the plasma was kept at $-$ 80 ${}^{\circ}$ C until analysis. GDF-15 concentrations were measured in the plasma of all subjects using a commercially available sandwich ELISA kit (Cusabio Biotech Co. Ltd., Wuhan, China).

2.7 Statistical analysis

Data were analysed by using the statistical software package SPSS, version 21 and it will presented as mean $\pm$ SD. The percentage difference in physiological variables before and after training interventions were calculated. The within and between-group differences were analysed using repeated measures analysis of variance. Between groups comparisons of baseline characteristics will carried out using an unpaired $t$ -test, after checking for normal distribution. The level of significance will set at $p\leqslant$ 0.05. GDF-15 protein values were not normally distributed, therefore Mann-Whitney test was used.

3. Results

3.1 Demographic characteristics of study groups

The demographic characteristics of the sampled study groups are presented in Table 1.

0pt 0pt

Table 1
Personal characteristics and Body mass index of the sampled study groups

Bio-demographic data		Group
		Patient ( $n=$ 10)		Control ( $n=$ 18)
		$n$	%	$n$	%
Gender	Male	3	30 %	7	39%
	Female	7	70 %	11	61%
Age in years	30–39	2	20 %	13	72%
Age in years	40 $+$	8	80 %	5	28%
Body mass index	Normal	2	20 %	9	50%
Body mass index	Overweight	4	40 %	6	33%
	Obese	4	40 %	3	17%

3.2 Six minutes walk test (6MWT)

The findings of the 6MWT are outlined in Table 2. The PwILD had significantly lower 6MWD values than control group at 1st visit (395 $\pm$ 68 vs. 517 $\pm$ 84, $p=$ 0.001) and 15 ${}^{\text{th}}$ visit (459 $\pm$ 87 $\pm$ 562 $\pm$ 82, $p=$ 0.03) respectively. However, both PwILD and controls improved, by 64 and 45 m, respectively ( $p=$ 0.001).

Table 2
Six minutes walk test (6MWT) of the sampled study groups

6MWT distance		Groups		$p^{1}$
(meter)		Patient ( $n=$ 10)	Control ( $n=$ 18)
Visit 1	Range	300–550 m	392–656 m	0.001*
	Mean (SD)	395 (68)	517 (84)
Visit 15	Range	350–600 m	420–670 m	0.013*
	Mean (SD)	459 (87)	562 (82)
$p^{2}$		0.001*	0.001*

$p^{1}$ : Adjusted $p$ value of independent $t$ -test between control and patient group. $p^{2}$ : Adjusted $p$ value of paired $t$ -test between same groups. * $p<$ 0.05 (significant).

3.3 Shortness of breath respiratory questionnaire (SOBQ) score

The overall change in SOBQ score of Dyspnea-12 using questionnaire (D-12) before and after SET program is presented in Table 3 and Fig. 2 for both PwILD and controls. Patients had higher D-12 score at baseline than the controls and the score was reduced significantly ( $p=$ 0.01) after SET i.e. there was a significant improvement in dyspnea symptoms in the patients following SET ( $P=$ 0.012). Almost 40% of the participants reported having moderate or severe SOB before SET as compared to 50% of PwILD who had mild to moderate SOB while none of the participant had severe SOB after SET. However, in the control group, the D-12 questionnaire demonstrated no significant decreases in dyspnea after SET ( $p=$ 0.24).

Table 3
Overall change in shortness of breath respiratory questionnaire (D-12) items before and after SET according to the study groups

Group	Overall	Before		After		$p$
	SOBQ	$n$	%	$n$	%
Patient	None	0	0.0%	5	50.0%	0.01*
	Mild	6	60.0%	4	40.0%
	Moderate	3	30.0%	1	10.0%
	Severe	1	10.0%	0	0.0%
Control	None	11	61.1%	12	66.7%	0.24
	Mild	4	22.2%	6	33.3%
	Moderate	3	16.7%	0	0.0%
	Severe	0	0.0%	0	0.0%

Table 4

Change in GDF15 levels before and after intervention among the study groups

GDF15 (pg/ml)		Groups		$p^{1}$
		Patient	Control
Before SET	Range	59.4–267.8	25.4–106.4	0.05*
	Mean (SD)	120.9 (63.3)	78.3 (23.5)
After SET	Range	58.2–234.8	32.7–136.3	0.02*
	Mean (SD)	129.7 (56.4)	83.1 (27.1)
$p^{2}$		0.54	0.51

$p^{1}$ : Adjusted $p$ value of independent $t$ -test between control and patient group. $p^{2}$ : Adjusted $p$ value of paired $t$ -test between same groups. * $p<$ 0.05 (significant).

Figure 2.

Change in overall shortness of breath respiratory questionnaire (SOBQ) score before and after intervention among the study groups.

3.4 Heart rate (HR)

Trends in HR before and after SET were recorded at each visit among the study groups. The patients comparatively had higher HR than the controls before starting SET and after completing the SET. Figure 3 shows the overall change (difference between pre and post SET) in heart rate (HR) of patients (30–35 bpm) compared to controls (40–45 bpm) at each visit.

Figure 3.

Trend in HR change (difference between pre and post SET) at each visit among the study groups.

3.5 Growth differentiation factor 15 (GDF-15) levels

The mean pre exercise and post exercise training GDF15 levels are presented in Table 4. Pre and post mean GDF15 values of ILD patients (120.9 $\pm$ 63.3 pg/ml, 129.7 $\pm$ 56.4 pg/ml) and controls (78.3 $\pm$ 23.5 pg/ml, 83.1 $\pm$ 27.1 pg/ml) did not change significantly ( $p=$ 0.537, $p=$ 0.508). However, GDF15 values of the PwILDs were significantly higher (120.9 $\pm$ 63.3 and 129.7 $\pm$ 56.4 pg/ml) compared to controls (78.3 $\pm$ 23.5 and 83.1 $\pm$ 27.1 pg/ml) ( $p=$ 0.21 $p=$ 0.048.) before and after SET respectively.

4. Discussion

Recently, there is increasing evidence that exercise training is a vital element of pulmonary rehabilitation (PR), and efficient intervention to improve dyspnea, exercise capacity and functional status in PwILD. In the present case-control interventional design study we evaluated the effect of SET on exercise capacity, dyspnea and GDF-15 plasma levels in PwILD and normal healthy subjects.

This study demonstrate that all Pw ILD improved the 6MWD significantly which is consistent with earlier reports [34]. Our results indicate an overall mean improvement of 64 meters in 6MWD which was greater than the minimal clinically important difference (MCID) (30–33 m) [5] previously reported for PwILD [13, 35, 36, 37, 38]. Though increases in 6MWD beyond the MCID has been described [34] after exercise training (ET) in PwILD the mechanism by which this increase was arbitrated was not unfolded. The smaller improvement by the controls (44 m) may be due to the latter having achieved long distances at baseline with limited capacity for further improvement.

In spite of the limited improvement in PwILD, some symptomatic benefit was attained with variations in SOBQ and HR symptoms beyond the MCID. Generally, the SOBQ and HR score improved after exercise. The overall score of D-12 questionnaire at baseline was high and then declined post-SET, while minimum changes in the score of overall D-12 questionnaire were found in the control group having low scores at baseline. This significant improvement in dyspnea was associated with the observed gains in exercise capacity in the PwILD. Similar improvements in dyspnea were obtained in other studies [11, 13, 34] using Chronic Respiratory Disease Questionnaire (CRDQ) that achieved the minimum important difference (MID). To our knowledge, no previous study adopted the D-12 Questionnaire to evaluate the effect of an exercise training program in dyspnea improvement for these patients. Further investigation is necessary to explain the usefulness of the SOBQ in determining change in dyspnea in PwILD. These facts have important clinical significance and practical associations, since proven and effective therapies for ILD are restricted.

Numerous mechanisms may explaine the effect of exercise training on the physiological and clinical outcomes in PwILD. It is possible that frequent stimuli of high ventilation required during exercise sessions, stretching of the thoracic muscles and chest expansion during deep breathing exercises resulted in a more effective breathing pattern, enhance pulmonary compliance and pleural elasticity within the lung tissue, increased strength of respiratory muscles and decreased dyspnea perception following exercise training [39].

Since no suitable biomarker for the diagnosis of ILD exists the main object of our study was to evaluate the effect of SET on GDF15 biomarker in patients with ILD. Our results show significantly higher GDF15 levels as compared to controls both pre and post SET. However, no significant change in GDF15 values has been observed within PwILD and controls after SET innervation. Similar trend in increase of GDF15 levels were reported after playing different sports [40, 41]. So far no single study reported the effect of exercise on GDF15 concentration in these patients. However, previously increased GDF15 levels associated with both COPD [42] and lung injury [43] have been reported. Since GDF15 is not lung specific it is difficult to tell whether the source of GDF15 is from lung tissue or other organ systems.

This study has some limitations. First, the small sample size prevents generalization. Additional confirmation of the findings in a larger, extensive group of PwILD is necessary. Second, the sample was heterogeneous with respect to enclosure of patients with numerous ILD etiologies. The sample size was inadequate for subgroup analyses based on etiology. This again may obstruct the ability to generalize data over the entire ILD group.

This study hints that the SET program may be effective for patients with ILD, providing significant clinical improvements in exercise capacity, dyspnea and functional status for these patients. This strengthens the recommendation for the role of exercise training as part of a standard comprehensive treatment for ILD patients. The described SET seems to be safe and well tolerated by the patients. However, the exact underlying mechanisms of training adaptation, long-term impact, the ideal program modalities, and other issues still need to be elaborated in further studies.

5. Conclusions

This study provided evidence that patients with ILD completing SET program established progress in exercise capacity (6MWT) and dyspnea. The results also indicate that SET does not affect circulating GDF-15 levels in PwILD although their GDF15 values were significantly greater than the control group’s before and after SET. Moreover, these values may be considered clinically significant. Our results provide preliminary support for introducing SET programs to increase pulmonary function and exercise capacity in patients with PwILD, but maintenance strategies are warranted to preserve the outcomes. From a clinical perception, the results of this study offer evidence that exercise training is safe and well tolerated by PwILD and that participation may improve their exercise performance.

Author contributions

CONCEPTION: Abdulrahman Mohammed Alhwoikan

PERFORMANCE OF WORK: Rahmah Mohammad Alyami

INTERPRETATION OR ANALYSIS OF DATA: Rahmah Mohammad Alyami

PREPARATION OF THE MANUSCRIPT: Rahmah Mohammad Alyami

REVISION FOR IMPORTANT INTELLECTUAL CONTENT: Abdulrahman Mohammed Alhwoikan

SUPERVISION: Abdulrahman Mohammed Alhwoikan

Ethical considerations

Institutional Review Board approval number; E-17-2630 Dated: 5 ${}^{\text{th}}$ Oct, 2018. Informed consent was obtained from all patients and controls participating in the study.

Funding

National Plan for Science and Technology and Innovation (MAARIFAH), and Vice Deanship of Research Chairs, at King Saud University, Kingdom of Saudi Arabia for financial support.

Footnotes

Acknowledgments

We thank National Plan for Science and Technology and Innovation (MAARIFAH), and Vice Deanship of Research Chairs, at King Saud University, Kingdom of Saudi Arabia for financial support.

Conflict of interest

The authors have no conflicts of interest to report.

References

Grygiel-Górniak

Puszczewicz

. Review on irisin, a new protagonist that mediates muscle-adipose-bone-neuron connectivity. Eur Rev Med Pharmacol Sci. 2017; 21(20): 4687-4693.

Demedts

Wells

Antó

Costabel

Hubbard

Cullinan

, et al. Interstitial lung disease. An epidemiological overview. Eur Respir J. 2001; 18: 2s-16s.

Meyer

. Diagnosis and management of interstitial lung disease. Transl Respir Med. 2014; 2: 4. doi: 10.1186/2213-0802-2-4.

Holland

. Exercise limitation in interstitial lung disease mechanisms, significance and therapeutic options. Chron Respir Dis 2010; 7: 101-111.

Dowman

Hill

Holland

. Pulmonary rehabilitation for interstitial lung disease. Cochrane Database Syst Rev. 2014; (10): CD006322.

Bonini

, Fiorenzano, G. Exertional dyspnea in interstitial lung diseases: The clinical utility of cardiopulmonary exercise testing. Eur Respir Rev. 2017; 21; 26(143): 160099. doi: 10.1183/16000617.0099-2016.

Spruit

Singh

Garvey

ZuWallack

Nici

Rochester

, et al. ATS/ERS task force on pulmonary rehabilitation. An official American Thoracic Society/European Respiratory Society statement: Key concepts and advances in pulmonary rehabilitation. American Journal of Respiratory and Critical Care Medicine. 2013; 188(8): E13-E64.

Ries

Bauldoff

Carlin

Casaburi

Emery

Mahler

Make

Rochester

Zuwallack

Herrerias

. Pulmonary rehabilitation: Joint ACCP/AACVPR evidence-based clinical practice guidelines. CHEST Journal. 2007; 131(5 suppl): 4S-42S.

Nakazawa

Cox

Holland

. Current best practice in rehabilitation in interstitial lung disease. Ther Adv Respir Dis. 2017; 11(2): 115-128.

10.

Poletti

Ravaglia

Buccioli

Tantalocco

Piciucchi

Dubini

, et al. Idiopathic pulmonary fibrosis: Diagnosis and prognostic evaluation. Respiration. 2013; 86: 5-12.

11.

Ryerson

Cayou

Topp

Hilling

Camp

Wilcox

Khalil

Collard

Garvey

. Pulmonary rehabilitation improves longterm outcomes in interstitial lung disease: A prospective cohort study. Respir Med. 2014; 108(1): 203-210.

12.

Sciriha

Lungaro-Mifsud

Fsadni

Scerri

Montefort

. Pulmonary rehabilitation in patients with interstitial lung disease: The effects of a 12-week programme. Respir Med. 2019; 146: 49-56.

13.

Holland

Hill

Conron

Munro

McDonald

. Short term improvement in exercise capacity and symptoms following exercise training in interstitial lung disease. Thorax. 2008; 63: 549-554.

14.

Keyser

Woolstenhulme

Chin

Nathan

Weir

Connors

, et al. Cardiorespiratory function before and after aerobic exercise training in patients with interstitial lung disease. J Cardiopulm Rehabil Prev 2015; 35: 47-55.

15.

Alyami

Alhowikan

Alharbi

AL-Nafisah

. Impact of supervised exercise training on pulmonary function parameters, exercise capacity and Irisin Biomarker in Interstitial lung disease patients. Pak J Med Sci 2020; 36(5): 1089-1095.

16.

Meadows

Risbano

Zhang

Geraci

Tuder

Collier

, et al. Increased expression of growth differentiation factor-15 in systemic sclerosis-associated pulmonary arterial hypertension. Chest 2011; 139: 994-1002.

17.

Ago

Sadoshima

. GDF15, a cardioprotective TGF-beta superfamily protein. Circulation Research. 2006; 98(3): 294-297.

18.

Al-Mudares

Reddick

Ren

Venkatesh

Zhao

Lingappan

. Role of growth differentiation factor 15 in lung disease and senescence: Potential role across the lifespan. Front Med; 2020. https://doi.org/10.3389/fmed.2020.594137.

19.

Zhang

Jiang

Nouraie

Roth

Tabib

Spencer Winters

. GDF15 is an epithelial-derived biomarker of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2019; 317(4): L510-L521.

20.

Walter

Gordon

Pescatello

. ACSM’s guidelines for exercise testing and prescription. Lippincott Williams & Wilkins, Philadelphia. 2010.

21.

de Jager

SCA

Bermúdez

Bot

Koenen

Bot

Kavelaars

, et al. Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis. J Exp. 2011; 208(2): 217-225.

22.

Tsai

Lin

Brown

Salis

Breit

. Anorexiacachexia and obesity treatment may be two sides of the same coin: Role of the TGF- superfamily cytokine MIC- 1/GDF15. Int J Obes 2016; 40: 193-197.

23.

Kempf

Horn-Wichmann

Brabant

Peter

Allhoff

Klein

, et al. Circulating concentrations of growth differentiation factor 15 in apparently healthy elderly individuals and patients with chronic heart failure as assessed by a new immunoradiometric sandwich assay. Clin Chem 2007; 53: 284-291.

24.

Lankeit

Kempf

Dellas

Cuny

Tapken

Peter

, et al. Growth differentiation factor-15 for prognostic assessment of patients with acute pulmonary embolism. Am J Respir Crit Care Med 2008; 177: 1018-1025.

25.

Nickel

Kempf

Tapken

Tongers

Laenger

Lehmann

, et al. Growth differentiation factor-15 in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2008; 178: 534-541.

26.

Labaki

Martinez

Freeman

Martinez

Wells

Bhatt

, et al. Higher levels of growth differentiation factor 15 (GDF-15) are associated with lower walking distance and exercice capacity in COPD: An analysis of the SPIROMICS cohort. American Journal of Respiratory and Critical Care Medicine. 2018; 197: A3124.

27.

Yazisiz

Oygen

Çavusoglu

Kahraman

Gök

Karahan

Uçar

Terzioglu

. The role of growth differentiation factor (gdf)-15 and transforming growth factor (tgf)-β in the development of pulmonary fibrosis. Anals of the Rheumatic Diseases. 2017; 76: 1066.

28.

Kim

Cha

Choi

Shin

Lim

Yoo

Lee

Kim

Park

Yang

. Prognostic value of serum growth differentiation factor-15 in patients with chronic obstructive pulmonary disease exacerbation. Tuberc Respir Dis (Seoul). 2014; 77(6): 243-250.

29.

Medicine ACoS. ACSM’s guidelines for exercise testing and prescription: Lippincott Williams & Wilkins, 2013.

30.

Gardner

Hankinson

Clausen

Crapo

Johnson

, Jr Epler

. XFS statement on standardization of spirom-etry-1987 update. Am Rev Respir Dis. 1987; 136: 1285-1298.

31.

Walter

Gordon

Pescatello

. ACSM’s guidelines for exercise testing and prescription. Lippincott Williams & Wilkins, Philadelphia; 2010.

32.

Alyami

Jenkins

Lababidi

Hill

. Reliability and validity of an arabic version of the dyspnea-12 questionnaire for Saudi nationals with chronic obstructive pulmonary disease. Annals of thoracic medicine. 2015; 10(2): 112-117.

33.

Singh

Puhan

Andrianopoulos

Hernandes

Mitchell

Hill

, et al. An official systematic review of the European Respiratory Society/American Thoracic Society: Measurement properties of field walking tests in chronic respiratory disease. Eur Respir J. 2014; 44: 1447-1478.

34.

Holland

Hill

Glaspole

Goh

McDonald

. Predictors of benefit following pulmonary rehabilitation for interstitial lung disease. Respir Med. 2012; 106: 429-435.

35.

Dowman

McDonald

Hill

Lee

Barker

Boote

, et al. The evidence of benefits of exercise training in interstitial lung disease: A randomised controlled trial Thorax: Thoraxjnl. 2017; 2016-208638.

36.

Dowman

Hill

and Holland

. Pulmonary rehabilitation for interstitial lung disease. Cochrane Database of Systematic Reviews. 2014; (10).

37.

Huppmann

Sczepanski

Boensch

Winterkamp

Schönheit-Kenn

Neurohr

, et al. Effects of inpatient pulmonary rehabilitation in patients with interstitial lung disease. European Respiratory Journal. 2013; 42(2): 444-453.

38.

Ferreira

Garvey

Connors

Hilling

Rigler

Farrell

, et al. Pulmonary rehabilitation in interstitial lung disease: Benefits and predictors of response. Chest. 2009; 135(2): 442-447.

39.

Vainshelboim

Oliveira

Yehoshua

Weiss

Fox

Fruchter

, et al. Exercise training-based pulmonary rehabilitation program is clinically beneficial for idiopathic pulmonary fibrosis. Respiration. 2014; 88(5): 378-388.

40.

Isabelle

Margeli

Tsironi

Skenderi

Barnet

Kanaka-Gantenbein

, et al. Growth-differentiation factor-15, endoglin and N-terminal pro-brain natriuretic peptide induction in athletes participating in an ultramarathon foot race. Biomarkers. 2009; 14(6): 418-422.

41.

Emanuela

Lombardi

Monica

Grasso

Vianello

Pozzoni

, et al. Acute exercise in elite rugby players increases the circulating level of the cardiovascular biomarker GDF-15. Scandinavian Journal of Clinical and Laboratory Investigation. 2014; 74(6): 492-499.

42.

Mutlu

Altintas

Aydin

Tulubas

Oran

Kucukyalin

, et al. Growth differentiation factor-15 is a novel biomarker predicting acute exacerbation of chronic obstructive pulmonary disease. Inflammation. 2015; 38: 1805-1813.

43.

Zimmers

Jin

Hsiao

McGrath

Esquela

Koniaris

. Growth differentiation factor-15/macrophage inhibitory cytokine-1 induction after kidney and lung injury. Shock. 2005; 23(6): 543-548.

Effect of supervised exercise training on exercise capacity,pulmonary function and growth differentiation factor 15 levels in patients with interstitial lung disease: A preliminary study

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSION:

Keywords

1. Introduction

2. Method

2.1 Participants

2.2 Study design

2.4 Study protocol

2.5 Supervised exercise training (SET)

2.5.1 Endurance training

2.5.2 Training in cycle ergometer

2.5.3 Training in arm-ergometer

2.5.4 The resistance training

2.6 Outcome measures

2.6.1 Shortness of breath questionnaire (SOBQ)

2.6.2 Six minutes walk test (6MWT)

2.6.3 Heart rate (HR)

2.6.4 Blood sample collection and analysis

2.7 Statistical analysis

3. Results

3.1 Demographic characteristics of study groups

Table 1 Personal characteristics and Body mass index of the sampled study groups

Table 2 Six minutes walk test (6MWT) of the sampled study groups

Table 3 Overall change in shortness of breath respiratory questionnaire (D-12) items before and after SET according to the study groups

4. Discussion

5. Conclusions

Author contributions

Ethical considerations

Funding

Footnotes

Acknowledgments

Conflict of interest

References

Table 1
Personal characteristics and Body mass index of the sampled study groups

Table 2
Six minutes walk test (6MWT) of the sampled study groups

Table 3
Overall change in shortness of breath respiratory questionnaire (D-12) items before and after SET according to the study groups