Six-minute walk test and factors affecting exercise capacity in children with cystic fibrosis

Abstract

PURPOSE:

This study aimed to compare the result of the six-minute walk test (6MWT) in patients with cystic fibrosis (CF) aged < 20 years old and individuals without CF.

METHODS:

In this cross-sectional study, 50 children and adolescents with CF and 20 children and adolescents without CF underwent the 6MWT. Vital signs before and immediately after the 6MWT and six-minute walk distance (6MWD) were evaluated.

RESULTS:

The mean change in heart rate, percentage of peripheral oxygen saturation (SpO2%), systolic blood pressure, respiratory rate, and dyspnea severity during the 6MWT was significantly higher in patients with CF. In the case group, 6MWD was associated with regular chest physical therapy (CPT) and forced expiratory volume (FEV)> 80%. Patients with CF receiving regular CPT or mechanical vibration and with FEV in the first second > 80% showed better physical capacity during the 6MWT (smaller Sp02% decline and lower dyspnea perception).

CONCLUSION:

Children and adolescents with CF have lower physical capacity compared to individuals without CF. CPT and mechanical vibration could be used to increase physical capacity in this population.

Keywords

Cystic fibrosis physical capacity six-minute walk test chest physical therapy

Abbreviations

Cystic Fibrosis

ADLs

Activities of Daily Living

CPET

Cardiopulmonary Exercise Test

6MWT

Six-Minute Walk Test

CPT

Chest Physical Therapy

Vibration Modality

BMI

Body Mass Index

Heart Rate

SpO2%

Percentage of Peripheral Oxygen Saturation

Blood Pressure

Respiratory Rate

FEV1

Forced Expiratory Volume in the first second

FVC

Forced Vital Capacity

6MWD

Six-Minute Walk Distance

VO_2max

Maximum Oxygen Uptake

W_max

Maximum Workload

Odds Ratio

1 Introduction

Cystic fibrosis (CF) is a progressive genetic disease with autosomal recessive inheritance characterized by generalized dysfunction of the exocrine glands [1, 2]. In patients with CF, the CF transmembrane conductance regulator gene is defective at the epithelial cell, resulting in dysfunction of chloride transport, decreased chloride secretion, increased sodium and water reabsorption, and thus, thicker mucus [3]. The respiratory and digestive systems are the main organs affected by CF, leading to chronic pulmonary disorders, pancreatic enzyme insufficiency, malnutrition, and decreased muscle strength [4].

The combination of deterioration in nutritional status and severe respiratory dysfunction causes important physical limitations, intolerance to exercise, and reduced functional capacity [5, 6]. Regular evaluation of physical capacity is recommended to assess disease prognosis and its effects on activities of daily living (ADLs) [7]. Higher levels of physical capacity are associated with improved survival rate [8]. Thus, identifying valid tests to assess cardiopulmonary status is vital in the CF population [9].

A standardized cardiopulmonary exercise test (CPET) is considered the gold standard method to assess functional capacity in this population [10]. The CPET is an expensive, energy-consuming, technically demanding assessment and can only be performed in a center with the necessary equipment and trained staff [11]. Due to these shortcomings, simple and less expensive field exercise tests including the six-minute walk test (6MWT) and incremental shuttle walk test have been reliably utilized as alternative assessment tools in these patients [12].

The 6MWT is a submaximal and safe test used to evaluate functional capacity, to monitor treatment interventions, and to gain prognostic information in various chronic respiratory disorders including CF [13]. Although it has been routinely studied in adult patients [14], there are limited reports on the prognostic value of the 6MWT in children with CF [6].

Furthermore, several chest physical modalities have been described in the literature to be applied for patients with CF, including percussion, postural drainage, and vibration. Chest physical therapy (CPT) can limit the progression of CF and reduce the decline of respiratory function. Routine pulmonary clearance modalities are important interventions for maintaining pulmonary health. Improved pulmonary function is linked with pulmonary fitness and exercise capacity [15].

Considering the limited available evidence on evaluating physical capacity in children with CF using the submaximal 6MWT and given that there is a lack of information in Iran regarding exercise tolerance of this population, this study aimed to perform the 6MWT in participants with CF aged < 20 years old and compare its results with healthy individuals. Also, due to the theoretical importance of CPT in patients with CF, the correlation between its application and physical capacity in children with CF was evaluated.

2 Materials and methods

2.1 Study design

This cross-sectional study was conducted on children and adolescents with CF who regularly visited in the out-patient department at a university referral hospital from September 2016 to February 2017. This project was approved by the Research Ethics Committee of the Tabriz University of Medical Sciences (TUOMS), under Protocol No. #94/3–5/2.

Prior to the study, informed written consent was obtained from all participants≥18 years or guardians’ of all participants < 18 years of age. The research was carried out according to the Helsinki Declaration.

2.2 Study participants

Subjects with a confirmed CF diagnosis (clinical manifestations and sweat test [sweat chloride concentration > 60 mEq / L] and/or the presence of two mutations in the gene regulating CF membrane) were included. The exclusion criteria were antibiotics administration during the last month, orthopedic and neuromuscular disorders, physical disability, severe heart failure (New York Heart Association class III and IV), history of heart or lung transplantation, and smoking. The healthy group included students and volunteers without CF, aged seven to 20 years, who were non-smokers and non-athletes with no previous history of cardiovascular, neuromuscular, respiratory or orthopedic disorders. The study participants were group-level matched in terms of age and sex.

2.3 Study protocol

Evaluations were performed on two different days with a gap of 2–4 days. On the first day, participants in the CF group were referred to a pulmonologist for spirometric evaluations. Day two assessment was performed by a trained assessor in three stages in all participants (both the CF and non-CF group): first stage - assessment of demographic, anthropometric, and physiological characteristics at rest (ten minutes); second stage - 6MWT; and third stage - re-evaluation of physiological characteristics ten minutes after the 6MWT. In addition, CPT history (regular or irregular use) and the application of mechanical vibration modality (VM) were recorded.

2.4 Study measurement

2.4.1 Demographic characteristics and anthropometric indices

In this study, age, sex, body weight, and height were collected. Body mass index (BMI) was calculated using participants’ weight and height and was categorized according to percentile criteria for underweight (5^th), normal (5^th to < 85^th), overweight (85^th to < 95^th), obesity (> = 95^th) and severe obesity (> = 120×95^th percentile) [16].

2.4.2 Physiological characteristics

Patients’ heart rate (HR) and percentage of peripheral oxygen saturation (SpO2%) as measured by a finger pulse oximeter, systolic and diastolic blood pressure (BP), and respiratory rate (RR) were measured. The Borg CR10 scale was used to measure dyspnea with a 0–10 range (zero equals no shortness of breath and ten equals the most severe dyspnea) [17, 18].

2.4.3 Spirometric indices

Before the 6MWT, all participants with CF underwent spirometry tests using a Microloop MK 8 spirometer (Micro Medical, England). The average of three attempts for forced expiratory volume in the first minute (FEV1) and forced vital capacity (FVC) were reported [19].

2.4.4 6MWT and six-minute walk distance (6MWD)

The 6MWT was performed using protocols, which have been described in detail by the American Thoracic Society [20] and Li et al. [21]. Before the course, physiological variables were recorded (in sitting position for both groups). At the end of the 6MWT, the participants were asked to stand still. At this point, the physiological variables were re-measured and then the distance traveled in meters (i.e., 6MWD) was calculated [20, 21].

2.4.5 CPT

In the present study, if CPT was performed twice a day for more than three times a week, it was considered regular, and therapy with fewer repetitions was reported as irregular [15].

2.5 Sample size

In this study, CF patients were recruited based on a census method, and all 50 patients meeting the inclusion criteria who were referred to the hospital in the determined period were included in the study. The sample size of non-CF individuals was determined by obtaining descriptive data related to the 6MWT from Okuro et al.’s study [6]. Considering the power of 80% confidence of 95% and the possibility of 5% loss of samples, 20 subjects were estimated.

2.6 Statistical analysis

In this study, data were analyzed using SPSS software, V24. In order to describe continuous variables that were normally distributed, mean and standard deviation were used and categorical variables were described using frequency and percent. The normality of the variables was examined by the Kolmogorov-Smirnov test. A chi-squared or Fisher’s exact test was used to compare the relative frequencies between the study groups. To identify between group differences in terms of normally distributed continuous variables, the independent samples t-test was used. Also, Mann-Whitney and Kruskal-Wallis tests were used to compare non-normally distributed continuous variables among groups. In the case of Kruskal-Wallis test significancy, the Bonferroni correction procedure was used to adjust P-values for pairwise comparisons. To identify predictors of 6MWD in individuals with CF and without CF, separate regression models for CF and non-CF subjects were developed. Significant predictors at P-value < 0.2 in a simple linear regression model were included in a multiple regression model in order to build the prediction equation. P-values were compared to a significance level of 0.05.

3 Results

The CF group included 22 (44.0%) females and 28 (56.0%) males in whom the mean age was 10.67±2.85 years. In the non-CF group, there were 10 (50.0%) females and 10 (50.0%) males, and the mean age of participants was 12.16±3.98 years. There was no statistically significant difference between the two study groups in terms of gender and age. Baseline BMI, systolic BP, and diastolic BP values were all significantly higher in the non-CF group compared to the CF group, while HR and RR values were significantly elevated in the CF group. There was no significant difference between the groups in terms of SpO2% before the 6MWT. The prevalence of underweight was significantly higher in the CF group. Baseline values are demonstrated in Table 1 in detail.

Table 1
Demographic information, baseline physiological values, and spirometric

indices of individuals with and without CF

Variable CF group (n = 50) Group without CF (n = 20) P-value

Female 22 (44.0%) 10 (50.0%) 0.649^*

Age, years 10.67±2.85(8 to 17) 12.16±3.98(10 to 18) 0.146 ‡

BMI^¥ 16.20±2.22 18.26±2.50 0.001 †

Underweight 14 (28.0%) 0 (0.0%) 0.014^**

Normal 32 (64.0%) 19 (95.1%)

Overweight 2 (4.0%) 0 (0.0%)

Obese 2 (4.0%) 1 (5.0%)

HR 80.73±7.9880 (70 to 107) 75.32±4.4976 (68 to 81) 0.004 ‡

SpO2% 97.27±1.1598 (94 to 99) 97.58±0.6998 (96 to 98) 0.383 ‡

SYS BP (mmHg) 89.51±10.979 (70 to 115) 96.84±8.03100 (80 to 110) 0.006 ‡

DYS BP(mmHg) 61.71±11.9660 (50 to 80) 65.79±6.2965 (60 to 80) 0.037 ‡

RR 17.12±1.3117 (15 to 20) 16.32±0.9516 (14 to 18) 0.017 ‡

Regular physical therapy 34 (68.0%) N/A N/A

Vibration modality 14 (28.0%) N/A N/A

FEV1 75.46±15.7478 (23 to 105) N/A N/A

FEV1 < 80% 27 (54.0%) N/A N/A

FEV1/FVC 102.34±9.11101.50 (84 to 117) N/A N/A

Variable	CF group (n = 50)	Group without CF (n = 20)	P-value
Female	22 (44.0%)	10 (50.0%)	0.649^*
Age, years	10.67±2.85(8 to 17)	12.16±3.98(10 to 18)	0.146 ‡
BMI^¥	16.20±2.22	18.26±2.50	0.001 †
Underweight	14 (28.0%)	0 (0.0%)	0.014^**
Normal	32 (64.0%)	19 (95.1%)
Overweight	2 (4.0%)	0 (0.0%)
Obese	2 (4.0%)	1 (5.0%)
HR	80.73±7.9880 (70 to 107)	75.32±4.4976 (68 to 81)	0.004 ‡
SpO2%	97.27±1.1598 (94 to 99)	97.58±0.6998 (96 to 98)	0.383 ‡
SYS BP (mmHg)	89.51±10.979 (70 to 115)	96.84±8.03100 (80 to 110)	0.006 ‡
DYS BP(mmHg)	61.71±11.9660 (50 to 80)	65.79±6.2965 (60 to 80)	0.037 ‡
RR	17.12±1.3117 (15 to 20)	16.32±0.9516 (14 to 18)	0.017 ‡
Regular physical therapy	34 (68.0%)	N/A	N/A
Vibration modality	14 (28.0%)	N/A	N/A
FEV1	75.46±15.7478 (23 to 105)	N/A	N/A
FEV1 < 80%	27 (54.0%)	N/A	N/A
FEV1/FVC	102.34±9.11101.50 (84 to 117)	N/A	N/A

Note: All values are presented as mean±SD, median (minimum to maximum), or n (%). ¥BMI was categorized according to the standards of the Centers for Disease Control for pediatric BMI which is based on percentile criteria for underweight (5^th), normal (5^th to < 85^th), overweight (85^th to < 95^th), obesity (> = 95^th) and severe obesity (> = 120×95^th percentile) by taking gender and age into account. †Independent samples t-test. ‡Mann-Whitney U test. ^*Chi-squared test. ^** Fisher’s exact test. Abbreviations CF: cystic fibrosis; BMI: body mass index; HR: heart rate; SpO2: saturation of peripheral oxygen; SYS BP: systolic blood pressure; DYS BP: diastolic blood pressure; RR: respiratory rate; N/A: not applicable; FEV1: forced expiratory volume in the first second; FVC: forced vital capacity Significance: P < 0.05.

The 6MWD was significantly higher in the non-CF group compared to the CF group (628.42±53.88 vs. 410.98±94.77, P < 0.001).

After the 6MWT, participants with CF showed a significantly greater change in HR (mean ranks [MR]: 41.96 vs. 19.35, P < 0.001), SpO2% (MR: 44.16 vs. 13.85, P < 0.001), systolic BP (MR: 40.27 vs. 21.13, P < 0.001), and RR (MR: 42.46 vs. 18.10, P < 0.001). Also, in the CF group, a higher dyspnea severity was observed (MR: 36.87 vs. 30.08; P < 0.001) (Table 2).

Table 2

Comparison of physiological changes before and after the 6MWT in individuals with and without CF

Variable		CF group(n = 50)	Group withoutCF (n = 20)	P-value
HR	Before 6MWT	80.73±7.98	75.32±4.49
		80 (70 to 107)	76 (68 to 81)
	After 6MWT	123.31±10.99	122 (100 to 142)
		106.79±8.35	108 (92 to 120)
	Changes	42.59±9.73	31.47±6.31
		42 (22 to 60)	30 (20 to 40)
		41.96^†	19.35^†	< 0.0001 ‡
SpO2%	Before 6MWT	97.27±1.15	97.58±0.69
		98 (94 to 99)	98 (96 to 98)
	After 6MWT	89.18±4.58	93.11±1.33
		60 (19 to 94)	93 (90 to 95)
	Changes	8.10±4.45	4.47±1.39
		8 (3 to 37)	4 (2 to 7)
		44.16^†	13.85^†	< 0.001 ‡
SYS BP (mmHg)	Before 6MWT	89.51±10.97	96.84±8.03
		90 (70 to 115)	100 (80 to 110)
	After 6MWT	108.04±10.35	108.61±9.20
		110 (90 to 125)	110 (90 to 125)
	Changes	18.53±6.95	11.94±4.89
		20 (10 to 35)	10 (5 to 20)
		40.27^†	21.13^†	< 0.001 ‡
DYS BP (mmHg)	Before 6MWT	61.71±6.96	71.94±6.67
		60 (50 to 80)	70 (60 to 85)
	After 6MWT	69.71±8.45	71.94±6.67
		70 (50 to 85)	70 (60 to 85)
	Changes	7.75±6.43	5.83±6.70
		10 (5 to 25)	5 (5 to 20)
		36.87^†	30.08^†	0.301 ‡
RR	Before 6MWT	17.12±1.31	16.32±0.95
		17 (15 to 20)	16 (14 to 18)
	After 6MWT	28.06±2.51	24.48±1.43
		28 (23 to 33)	24 (22 to 27)
	Changes	10.94±2.28	8.16±1.26
		11 (6 to 15)	8 (6 to 10)
		42.46^†	18.10^†	< 0.001 ‡

Note All values are presented as mean±SD or median (minimum to maximum). †Mean rank Abbreviations CF: cystic fibrosis; HR: heart rate; SpO2: saturation of peripheral oxygen; SYS BP: systolic blood pressure; DYS BP: diastolic blood pressure; RR: respiratory rate. ‡Mann-Whitney U test. Significance: P < 0.05.

After the test, participants in the CF group with a FEV1 < 80% showed significantly higher changes in HR, RR, SpO2% and dyspnea compared to other participants in the CF group and participants in the non-CF group (all with P < 0.05). The decrease in SpO2% in the non-CF group was significantly lower compared to participants in the CF group with FEV1 < 80% (P < 0.001) or FEV1 > 80% (P < 0.001) (Table 3).

Table 3

Comparison of physiological changes in individuals with and without CF and the relationship with FEV1

Variable	CF group with FEV1 < 80% (n = 27)	CF group with FEV1 > 80% (n = 23)	Group without CF (n = 20)	P-value†	Pairwise comparisons ‡
					FEV1 < 80% Vs. group without CF	FEV1 > 80% Vs. group without CF	FEV1 < 80% Vs. FEV1 > 80%
Increase in HR	46.61±9.9149 (28 to 80)	37.70±7.0039 (22 to 50)	31.47±6.3130 (20 to 40)	< 0.001	< 0.001	0.081	< 0.001
Increase in dyspnea	7.18±0.867 (5 to 8)	5.87±0.816 (5 to 8)	5.37±0.55 (5 to 6)	< 0.001	< 0.001	0.205	< 0.001
Decrease in SpO2%	8.29±1.498 (3 to 10)	7.87±6.497 (4 to 37)	4.47±1.394 (2 to 7)	< 0.001	< 0.001	< 0.001	< 0.001
Increase in SYS BP	18.75±6.8920 (10 to 35)	18.26 7.1720 (10 to 35)	11.49±4.8910 (5 to 50)	0.002	0.001	0.002	0.653
Increase in DYS BP	9.29±6.3410 (5 to 25)	5.87±6.155 (0 to 20)	5.83±6.705 (5 to 20)	0.067	–	–	–
Increase in RR	11.89±1.7912 (8 to 14)	9.78±2.3210 (6 to 15)	8.16±1.268 (6 to 10)	< 0.001	< 0.001	0.083	0.001

Note: All values are presented as mean±SD or median (minimum to maximum). Abbreviations: CF: cystic fibrosis; HR: heart rate; SpO2: saturation of peripheral oxygen; SYS BP: systolic blood pressure; DYS BP: diastolic blood pressure; RR: respiratory rate. †Kruskal-Wallis test. ‡Mann-Whitney U test. Significance: P < 0.05.

The participants with CF who received irregular CPT showed significantly greater increases in regard to HR, dyspnea, and RR compared to both the participants with CF with regular CPT and the non-CF participants. In looking more closely, the results revealed that the decrease in SpO2% was significantly smaller in the non-CF group compared to the participants with CF with regular and irregular CPT (P < 0.001). While there was not a significant difference in elevated diastolic BP among the three groups (P = 0.434), the participants with CF with regular and irregular CPT showed a considerable increase in their systolic BP compared to the non-CF participants (P = 0.001) (Table 4).

Table 4

Comparison of physiological changes in individuals with and without CF and the relationship with CPT and mechanical vibration

Variable	CF group with regular CPT (n = 34)	CF group with irregular CPT (n = 16)	Group without CF (n = 20)	P-value†	Pairwise comparisons‡
					Regular CPT vs. group without CF	Irregular CPT vs. group without CF	Regular CPT vs. irregular CPT
Increase in HR	41.20±9.5040 (22 to 60)	45.63±9.8450 (28 to 59)	31.47±6.3130 (20 to 40)	< 0.001	< 0.001	0.001	0.012
Increase in dyspnea	6.23±0.976 (5 to 8)	7.38±0.818 (6 to 8)	5.37±0.505 (5 to 6)	< 0.001	< 0.001	< 0.001	< 0.001
Decrease in SpO2%	7.86±5.317 (3 to 37)	8.63±1.209 (7 to 10)	4.47±1.394 (2 to 7)	< 0.001	< 0.001	< 0.001	0.005
Increase in SYS BP	18.14±7.2820 (10 to 35)	19.38±6.2920 (10 to 30)	11.49±4.8910 (5 to 20)	0.001	0.001	0.001	0.004
Increase in DYS BP	8.14±6.1910 (0 to 25)	6.88±7.045 (0 to 20)	5.3±6.705 (5 to 20)	0.434	–	–	–
Increase in RR	10.17±2.0810 (6 to 14)	12.63±1.7813 (8 to 15)	8.16±1.268 (6 to 10)	< 0.001	< 0.001	< 0.001	< 0.001
Variable	CF group with vibration (n = 14)	CF group without vibration (n = 36)	Group without CF (n = 20)	P-value†	Pairwise comparisons‡
					Vibration vs. group without CF	No vibration vs. group without CF	Vibration vs. no vibration
Increase in HR	40.07±8.0740 (28 to 57)	43.54±10.2243 (22 to 60)	31.47±6.3130 (20 to 40)	< 0.001	0.041	< 0.001	0.144
Increase in dyspnea	5.71±0.736 (5 to 7)	6.92±0.987 (5 to 8)	5.37±0.505 (5 to 6)	< 0.001	0.192	< 0.001	< 0.001
Decrease in Spo2%	6.50±1.226.5 (5 to 8)	8.86±5.038 (4 to 37)	4.35±1.464 (2 to 7)	< 0.001	< 0.001	< 0.001	0.001
Increase in SYS BP	18.93±5.6120 (10 to 30)	18.47±7.5420 (10 to 35)	11.84±4.7810 (5 to 20)	0.002	0.001	0.001	0.706
Increase in DYS BP	5.36±4.325 (0 to 10)	8.61±6.210 (5 to 25)	5.26±3.265 (5 to 20)	0.175	–	–	–
Increase in RR	9.36±2.029.5 (6 to 13)	11.61±2.0812 (7 to 15)	8.15±1.228 (6 to 10)	< 0.001	0.071	< 0.001	0.002

Note: All values are presented as mean±SD or median (minimum to maximum). Abbreviations: CF: cystic fibrosis; CPT: chest physical therapy; HR: heart rate; SpO2: saturation of peripheral oxygen; SYS BP: systolic blood pressure; DYS BP: diastolic blood pressure; RR: respiratory rate. †Kruskal-Wallis test. ‡Mann-Whitney U test. Significance: P < 0.05.

The application of mechanical VM was also associated with notable results after the 6MWT. The non-CF group showed a considerably smaller increase in HR compared to the participants with CF without vibration (P_{CF group without vibration VS . Non - CF group}< 0.001). Although the increase in the non-CF group’s HR was smaller compared to the participants with CF with vibration, this difference was not meaningfully significant (P_{CF group without}_{vibration VS . Non - CF group} = 0.041). It can be observed that the non-CF group showed a considerably smaller increase in their systolic BP (P_CF group_{without vibration VS . Non - CF group} = 0.001 and P_CF group_{without vibration VS . Non - CF group} = 0.001). Increase in dyspnea and RR was greater for the participants with CF who did not receive VM compared to the non-CF group and those participants with CF who received vibration. The participants with CF who did not receive mechanical vibration showed a statistically greater decrease in their SpO2% compared to the two other groups (P_{CF group without vibration}_{VS . CF group with vibration} = 0.001 and P_{CF group without}_{vibration VS . Non - CF group} < 0.001) (Table 4).

Based on simple linear regression models, gender had no significant effect on the average 6MWD in either group (P = 0.297). With increase in age, the average 6MWD in the CF group significantly decreased (P = 0.023). However, increasing age led to an increase in average 6MWD in the non-CF group (P = 0.049). With increase in height, the average 6MWD decreased in the CF group (P = 0.041) and increased in the non-CF group (P = 0.007). BMI did not explain a significant amount of a variance in average 6MWD either in the CF group (P = 0.312) or in the non-CF group (P = 0.429). The results indicated that FEV1 was a significant predictor of average 6MWD in the participants with CF (P < 0.001). Also, the average 6MWD for participants with regular CPT was significantly longer compared to others in the CF group (449.14±88.30 vs. 327.50±37.86, P < 0.001) (Table 5). The following equations could be used to determine the average 6MWD that patients with CF should be expected to walk based on age, BMI, and FEV1:

Table 5

Simple linear regression to identify demographic, anthropometric, and spirometric characteristics affecting six-minute walk distance in individuals with and without CF

Variable	Statistic	CF	Without CF
Gender	β(SE)	26.23 (24.90)	16.00 (23.81)
	P-value (95% CI)	0.297 (–23.84 to 76.31)	0.510 (–34.03 to 66.03)
Age	β(SE)	–6.27 (2.36)	5.91 (2.79)
	P-value (95% CI)	0.023 (–15.04 to –1.51)	0.049 (0.42 to 11.78)
Height	β(SE)	–0.14 (0.03)	1.82 (0.60)
	P-value (95% CI)	0.041 (–1.10 to 0.02)	0.007 (0.55 to 3.08)
BMI	β(SE)	5.74 (5.62)	3.89 (4.81)
	P-value (95% CI)	0.312 (–5.56 to 17.04)	0.429 (–6.21 to 13.99)
Chest physical therapy	Regular	mean±SD	449.14±88.30
	Irregular	mean±SD	327.50±37.86	NA
	β(SE)		–114.85 (21.06)
	P-value (95% CI)		< 0.001 (–157.21 to –72.50)
Vibration modality	Yes	mean±SD	501.43±59.98
	No	mean±SD	368.33±65.44	NA
	β(SE)		133.09 (20.16)
	P-value (95% CI)		< 0.001 (92.56 to 173.63)
FEV1		β(SE)	4.21 (0.53)	NA
		P-value (95% CI)	< 0.001 (3.15 to 5.26)
FEV1/FVC		β(SE)	2.32 (1.35)	NA
		P-value (95% CI)	0.091 (–0.39 to 5.02)
FEV1 < 80%	Yes	mean±SD	353.33±63.73
	No	mean±SD	433.96±70.48	NA
	β(SE)		113.62 (18.99)
	P-value (95% CI)		< 0.001 (75.45 to 151.80)

Abbreviations: CF: cystic fibrosis; BMI: body mass index; SE: standard error; SD: standard deviation; FEV1: forced expiratory volume in the first second; FVC: forced vital capacity. Significance: P < 0.05. NA: Not applicable.

6MWD_CF = 472.92 –6.27 Age

6MWD_CF = 312.38 + 5.74 BMI

6MWD_CF = 88.39 + 4.21 FEV1

The result of multiple regression revealed that CPT, VM, and FEV1 played a significant role in predicting the 6MWD in the patients with CF. All above-mentioned variables were included to the prediction equation. These variables statistically significantly predicted 6MWD: F (3. 46) = 46.01, P < 0.001, R-square = 0.73. (Model 1). In order to verify the results of multiple regression, a power analysis was performed to calculate the actual power of the presented model. Considering R-square = 0.73, the effect size was calculated as 2.70. Consequently, with α= 0.05, power = 0.8, and number of predictors = 3, the estimated actual power was 0.89 for the provided model for the CF group. For individuals without CF, height (P = 0.007) was the only significant predictor in building the equation model for 6MWD: F (1,18) = 9.14, P = 0.007, R2 = 0.34 (Model 2).

6MWD_CF = 245.39 –42.30 CPT + 71.62

VM + 2.60 FEV1 Model 1

6MWD_non - CF = 361.98 + 1.82 height Model 2

In order to better describe the patients with CF, a sub-analysis with regard to FEV1 and BMI in the older patients was performed. The results indicated that there was a weak and positive correlation between age and BMI among patients with CF; however, this relationship was not statistically significant (r = 0.27, n = 50, p = 0.058). Additionally, a moderate and negative correlation was observed between age and FEV1 within the CF group (r = –0.35, n = 50, p = 0.014). This result revealed that there was a lower FEV1 in the older patients within the CF group.

4 Discussion

In this study, multiple linear regression was used to predict the variables affecting 6MWT results. A multiple regression investigates the effect of more than one independent variable on some of the results of interest. This model evaluates the relative effect of these independent variables on the dependent variable when all other variables are constant. The advantage of this approach is that it may lead to a more accurate and precise understanding of the relationship of each individual factor to the outcome.

Based on the literature, exercise capacity is one of the major aspects affected by CF such that higher physical capacity is associated with better prognosis and survival and lower mortality and morbidity rate [22]. Few studies have reported the predictive value of physical capacity in the prognosis of children with CF [23, 24]. Routine assessment of physical fitness in patients with CF could be helpful to measure the impact of this disease on the patient’s life [6]. By evaluating physical capacity, proper intervention could be applied to prevent further decline [25].

In this study, the physical capacity of a cohort of individuals with CF was evaluated using the 6MWT; the results were compared with healthy individuals. Although the gold standard for evaluation of physical response is CPET, the 6MWT could provide physicians with a more realistic view of patients’ capacity, due to the demanding nature of CPET and the fact that most ADLs are performed at the submaximal level. Additionally, the 6MWT is well tolerated by patients with cardiopulmonary disorders, including chronic obstructive pulmonary disease, heart failure, and interstitial lung disease [6 , 27]. Several studies have been conducted to evaluate the role of the 6MWT in the CF population. According to Gulmans et al. [22], the 6MWT is a valid and reliable test in pediatric patients with CF with mild to moderate symptoms, and the 6MWD is in agreement with maximum oxygen uptake (VO_2max) and maximum workload (W_max) obtained via cycle ergometry. Cunha et al. [5] reported that 6MWD is reproducible in CF cases. According to several studies, 6MWD is the estimation of individual response to incremental maximal exercise and is associated with exercise tolerance of patients with respiratory disorders [28, 29].

According to the findings of the present study, children and adolescents with CF covered a significantly lower distance in six minutes compared to healthy individuals. Furthermore, patients with CF demonstrated lower exercise tolerance as observed as greater dyspnea severity, and a greater decrease in SpO2% was observed in this group. Also, the MR in HR, systolic BP, and RR were significantly greater in the CF group. These findings showed lower exercise capacity and tolerance in the CF group, and they were in line with the results of other studies.

According to Okuro et al. [6], patients with CF have slower pace (94.71±12.89 m/min vs. 104.55±9.13 m/min) and shorter 6MWD (568.02±76.31 m vs. 627.54±54.81 m) compared to healthy participants.

In Chetta et al.’s study [30], no difference in mean 6MWD was observed between 25 adult patients with mild to moderate CF and 22 healthy individuals (626±49 m vs. 652±46 m, respectively). Furthermore, lower mean SpO2% and higher dyspnea severity were observed after the 6MWT in the CF group. The difference in the 6MWD between the two studies could be interpreted according to the differences in the included populations (adult vs. pediatric). According to the authors, in adults with chronically stable lung disorders, 6MWD is poorly associated with baseline respiratory function.

According to Ziegler et al.’s study [31], patients with CF (aged > 15 years) covered less distance during the 6MWT compared to healthy individuals (mean: 517.0±100.0 m vs. 577.5±76.1 m). Patients with CF also demonstrated lower physical tolerance as shown by higher oxygen desaturation (3% mean decline in post-test SpO2% vs. 0.4%) and greater post-exercise dyspnea severity (median [interquartile range]: (1.9 [0–9] vs. 1.1 [0–4])). The difference in dyspnea perception was non-significant and smaller compared to the present study. This could be due to the difference in included populations (children vs. adult) and contributed to by the fact that patients who have CF for a longer duration have a diminished perception of dyspnea [32].

In the present study, 6MWD had a positive correlation with FEV1 and a negative correlation with age and height in the CF group. The positive correlation of FEV1 and 6MWD has been observed by different authors, though this relationship is controversial in patients with CF [20]. Li et al. [20] reported that 6MWD is positively correlated with FEV1 in healthy Chinese individuals aged 7–16 years (with a weak correlation: r = 0.328 in males and r = 0.170 in females). In Martin et al.’s study [13] of 286 adult patients with CF, a multivariable logistic regression model found lower odds of 6MWD≤475 m when FEV1 increased by 10% (odds ratio [OR] = 0.70, confidence interval [CI]: [0.58, 0.85]) and when SpO2% increased by 1% (OR = 0.88, CI: [0.76, 1.00]). Gulmans et al. [22] reported a positive but statistically non-significant correlation between 6MWD and FEV1 (r = 0.45). In Cunha et al.’s study [5] of children with CF, 6MWD was not associated with age, height, BMI, or FEV1 and was positively correlated with peak HR (r = 0.59), dyspnea severity (r = 0.55), cardiac double product (r = 0.59), and peak expiratory pressures (r = 0.60). In Okuro et al.’s study [6], although longer 6MWD was observed in patients with better FEV1, this association was not significant. In Nixon et al.’s study of children with severe cardiopulmonary disorders [23], 6MWD was not associated with FEV1 (r = 0.26), but when only subjects with obstructive lung disorders were evaluated, the correlation was significant (r = 0.75). Conversely, Lima et al. [33] suggested that 6MWD is not correlated with FEV1 in pediatric patients with CF. The authors stated that, due to the pathophysiological complexity of CF, several variable mechanisms besides lung function can affect the physical capacity of the CF population. It should be noted that, in this systematic review, only one of the included studies mentioned and assessed the relationship between FEV1 and 6MWD, and thus, the lack of correlation between 6MWD and FEV1 was reached on limited evidence. These differences and controversies might be explained by the inclusion of varied populations, especially considering age, gender, number of patients, the severity of airflow limitation, and severity of disease [22].

As previously mentioned, 6MWD had a negative relationship with age and height. This finding could be explained according to the natural progression of the disease, which leads to a greater decline in respiratory function, and thus, lower physical tolerance over the years. According to Liou et al. [34], adolescents with CF are at higher risk of FEV1 decline as patients with CF who are 6–15 years old tend to lose respiratory function at a higher rate (i.e., twice the median year-to-year loss in adults). Vandenbranden et al. [35] reported a year-to-year decline of FEV1 in adolescents and young adults with CF. This decline accelerated in late adolescence and early adulthood. Earnest et al. [36] also reported the year-to-year loss of respiratory function in children and adults with CF. Several risk factors have been described for the respiratory decline in CF patients, including lower BMI (lower nutritional status), FEV1 variability, male gender, and lung infections [35].

In the present study, respiratory function was evaluated via the FEV1. The findings demonstrated that lower exercise tolerance (greater oxygen desaturation measured as a decline in SpO2% more severe dyspnea, and a higher increase in HR and RR after the 6MWT) was observed in patients with FEV1 < 80%. Also, 6MWD was positively associated with FEV1 (and not FEV1/FVC), and patients with FEV1 < 80% covered a significantly shorter distance compared to other patients (353.33±63.73 m vs. 433.96±70.48 m). In Chetta et al.’s study [30], FEV1 appeared to be correlated with SpO2% in the adult CF population with r = 0.69. Freeman et al. [37] suggested that adult patients with CF with FEV1 < 60% are vulnerable to significant clinical oxygen desaturation during exercise. Martin et al. [13] also suggested that there is a correlation between FEV1 and oxygen desaturation after exercise and reported that SpO2% < 90% during the 6MWT was observed only in patients withFEV < 60%.

This study also evaluated the role of regular CPT. Individuals within the CF group who participated in regular CPT demonstrated better exercise tolerance than those with no history of regular CPT. Furthermore, regular CPT was associated with a significantly longer 6MWD (449.14±88.30 m vs. 327.50±37.86 m). Additionally, the application of VM as a means of airway clearance was associated with lower oxygen desaturation and dyspnea perception and longer 6MWD (501.43±59.98 m vs. 368.33±65.44 m). CPT can limit the progression of CF and reduce the decline of respiratory function, but there is limited evidence on the superiority of different modalities [38]. McIlwaine et al. [39] suggested that CPT is associated with slower respiratory function decline, lower dyspnea perception, improved muscle strength and physical response, and better quality of life in patients with CF. According to a 2019 Cochrane review, airway clearance techniques should be considered in the management of all individuals with CF [40]. These statements are in agreement with the current study’s findings. According to these findings and considering the positive effects of regular CPT, this intervention appears to be a good treatment for children with CF and can be performed to improve quality of life and physical tolerance.

In the present study, the lower physical capacity (evaluated by the 6MWT) of children and adolescents with CF compared to healthy individuals was demonstrated. According to this study finding, 6MWD has a positive correlation with FEV1, regular CPT, and the application of VM and a negative correlation with age and height. Patients with FEV > 80% and with a history of regular CPT showed better exercise tolerance.

The results of the present study should be interpreted in light of its limitations. The main limitation was the small sample size. Furthermore, only 6MWD and FEV1 were included for assessment of physical capacity and respiratory function, respectively. Although 6MWD is a valuable index, it is associated with several limitations in children and adolescents, e.g., the variability of anthropometric characteristics, lack of reference values for this age group, and lack of a specific minimum difference of 6MWD [6]. One way that anthropomorphic variations might be normalized for in 6MWD would be to calculate a normalized walk speed by dividing gait speed by body height, which would help to minimize the variation that might occur given that a study population’s step/stride length will increase proportionally to their size. Due to this shortcoming, additional indices, including six-minute walk work [distance x weight], mean velocity, etc., should be investigated in further studies. Grouping the participants as pre-pubertal and post-pubertal would have improved the study. Also in future studies, other spirometry variables besides FEV1 should be included.

Conclusions

Children and adolescents with CF have lower physical capacity compared to healthy individuals, according to 6MWT results. In the present study, 6MWD had a negative association with age and height and a positive association with FEV1. Longer 6MWD was observed in patients with FEV1 > 80% patients who received regular CPT, and patients who used mechanical vibration as an airway clearance technique.

Footnotes

Acknowledgments

We would like to thank the Clinical Research Development Unit of Children Educational Research and Treatment Center, Tabriz University of Medical Sciences, Tabriz, Iran, for their support.

This study did not receive any financial support.

Conflict of interest

No conflicts are declared.

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