Cardiorespiratory fitness in patients with post-infectious bronchiolitis obliterans: a cross-sectional study

Abstract

Background

Post-infectious bronchiolitis obliterans (PIBO) arises after lower respiratory tract infection during childhood and is marked by impaired lung function. Despite possible impacts on exercise capacity, cardiorespiratory fitness in PIBO patients remain largely unknown. This study aimed to examine cardiorespiratory fitness and identify possible demographic and clinical–functional associations.

Methods

The following variables were examined in a multicentre, cross-sectional study conducted in clinically stable PIBO patients aged 6–20 years: cardiorespiratory fitness (exercise testing), lung function (spirometry and impulse oscillometry), muscle strength (handgrip, upper and lower extremities), functional capacity (30-s sit-to-stand (STS) test), physical activity level (physical activity questionnaire adolescents and children; PAQ-A-C), body mass index (BMI), quality of life (Saint George's respiratory questionnaire; SGRQ) and dyspnoea perception (modified Medical Research Council scale).

Results

51 patients were enrolled (mean age 13.2±4.2 years, 49% female). BMI z-score was 0.06±1.20. Lung function tests indicated moderate-to-severe obstruction (forced expiratory volume in 1 s (FEV₁) z-score −3.55±1.30) and elevated airway resistance (R5 Hz 165.8±53.64%). Peak oxygen consumption (V′_O2peak) was 36.8±8.58 mL·kg⁻¹·min⁻¹ (47% ≤10 percentile) and breathing reserve 7.08±8.29%, indicating ventilatory limitation. Handgrip strength was 0.49±0.14 kg·kg⁻¹. The 30-s STS test was 27.2±5.7 repetitions. PAQ-A/PAQ-C was 1.89±0.46 indicating a low physical activity level. SGRQ was 20.1±10.8%. There was no resting dyspnoea. Multivariate regression identified significant associations between V′_O2peak and FEV₁ (p<0.001), BMI (p<0.001), SGRQ (p=0.005), female sex (p=0.002) and age (p=0.033).

Conclusions

In these patients, cardiorespiratory fitness was impaired mainly due to ventilatory limitations. Lung function, upper and lower limb muscle strength, BMI, quality of life, sex and age were all associated with fitness level.

Shareable abstract

Children and adolescents with PIBO exhibit reduced cardiorespiratory fitness due to ventilatory limitations. This impairment is associated with lung function, muscle strength, age, body mass index, quality of life and female sex. https://bit.ly/40dErkr

Introduction

Post-infectious bronchiolitis obliterans (PIBO) is a chronic inflammatory disease of the small airways and is the consequence of damage to the respiratory tract caused by a viral infection during childhood. Adenovirus is the most frequently implicated agent. Irreversible airway obstruction and diminished lung function are characteristic features [1]. The respiratory infection that leads to PIBO is usually severe, often requiring hospital admission, oxygen therapy, and, in some cases, mechanical ventilation [2]. The disease is described as non-progressive, as hospital admissions and symptom exacerbations decline with age. However, its morbidity rate remains high, especially in the early years of PIBO [2].

Paediatric populations with different chronic diseases generally show lower levels of physical activity compared with their healthy peers, directly impacting their exercise capacity [3]. Physical activity is of vital importance for a child's healthy development due to the significant physiological, anatomical and psychological transformations that take place during childhood [4]. Hence, an improved exercise capacity can bring numerous health benefits [5], including improved cardiorespiratory fitness (CRF), muscle strength, quality of life, body composition [5, 6], and prevention or control of chronic diseases [3]. Particularly in chronic respiratory diseases, CRF measured as peak oxygen consumption (V′_O2peak) through cardiopulmonary exercise testing (CPET) has been linked to airway obstruction severity, quality of life [7, 8] and dyspnoea [9]. However, this evidence is limited for patients with PIBO. Some findings have confirmed reduced functional exercise capacity in submaximal field tests [10], but CPET has been only used in two studies with small sample sizes [11, 12]. While the benefits for individuals with chronic respiratory diseases of improving CRF have been confirmed, literature data regarding fitness levels of patients are still lacking, and the main underlying mechanisms and associations with important clinical variables remain poorly understood.

As patients with PIBO may well show reduced exercise capacity [6], it is essential to examine their levels of CRF and its influencing factors. Knowledge about these aspects may contribute to a better understanding of the physical challenges they face and help in the design of more effective therapeutic strategies targeting prevention and treatment. The aim of the present study was thus to assess the CRF of children and adolescents with PIBO and examine its association with demographic and clinical–functional variables. We hypothesised that CRF would be impaired due to a limited ventilatory capacity and that this would correlate with lung function.

Methods

Study design and setting

This multicentre cross-sectional study was approved by the ethic committees of three hospitals: Hospital Universitario Niño Jesús (R-0087/22), Hospital Universitario Vall d'Hebron (PR(AMI)457/2022) and Hospital Universitario Donostia (PI2023108). To participate in this study, it was required that all legal guardians and subjects over 18 years signed an informed consent form. The recruitment of participants was during the period from May 2023 to July 2024. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement was used to produce this manuscript [13].

Participants

We used a non-probabilistic convenience sampling procedure to recruit children and adolescents with PIBO. Inclusion criteria were (1) a previous diagnosis of PIBO (based on clinical, radiological and functional criteria, confirmed by a paediatric pulmonologist at each centre); (2) clinical stability at the time of assessment; and (3) age between 6 and 20 years. Exclusion criteria were (2) respiratory symptom exacerbations 4 weeks before the examination; (3) diagnosis of other lung diseases causing persistent respiratory dysfunction; (3) musculoskeletal alterations, difficulties in understanding, or any other disorder that could affect exercise capacity; (4) pregnancy; and (5) inclusion in a transplant list. Compliance with these criteria was verified by members of the research team.

Variables

All variables were measured in one visit to the CPET laboratory of each participating hospital. The study's main outcome measure was CRF. Secondary outcomes were lung function, muscle strength and functionality, physical activity level, body composition, quality of life and dyspnoea perception. The demographic and clinical variables recorded were sex, age, high-resolution computed tomography (HRCT) findings, age at diagnosis and PIBO disease aetiology. All collected data were managed using Research Electronic Data Capture (REDCap) [14].

Procedures

Cardiorespiratory fitness

This was determined in a treadmill (RAM 870 Medisoft, Sorinnes-Belgium) incremental exercise test following the recommendations of the European Respiratory Society (ERS) [15]. Treadmill speed began at 2.5 km·h⁻¹ (patient height <120 cm) or 3.5 km·h⁻¹ (patient height >120 cm). The incline was set at 0.5%. The protocol consisted of a 3-min warm-up involving speed increments of 0.2 to 0.6 km.h⁻¹, depending on the patient's initial forced expiratory volume in 1 s (FEV₁) and 0.5% incline increments every 60 s. Gas exchange data were measured breath-by-breath via open-circuit spirometry (Ergocard CPX; Medisoft ExpAIR, Sorinnes-Belgium). The variables recorded included V′_O2peak, ventilation (V′_E), respiratory exchange ratio (RER), ventilatory equivalent for oxygen and carbon dioxide (V′_E/V′_O2 and V′_E/V′_CO2), breathing reserve (BR), peripheral oxygen saturation (S_pO2) and maximum heart rate (HR_max). V′_O2peak was recorded as the highest value obtained for any continuous 20 s period and is presented in both absolute and percentile values [16]. The BR was calculated as the difference between maximum voluntary volume (MVV) and the maximum V′_E at peak exercise. An indirect estimate was used to predict MVV by multiplying FEV₁ by 40 [15]. We also measured HR_max (Polar, Kempele, Finland), S_pO2 (Nonin, Plymouth, USA), blood pressure (manual sphygmomanometer, Riester, Jungingen, Germany) and rating of perceived exertion for the lower extremities and dyspnoea (modified Borg scale 0 to 10) at the time points baseline, immediately after the end of the test, and after 1 and 3 min of recovery. The ventilatory threshold (VT₁) was determined noninvasively by the ventilatory equivalent method [15]. The test was considered maximal if at least two of the following criteria were met: visible exhaustion; RER >1.05; HR_max >85% of predicted maximum (208 – age × 0.7); ventilatory limitation (BR<20%), and presence of a plateau in V′_O2 [15]. Tests were interrupted if S_pO2 ≤85% [15].

Lung function

Lung function was assessed by spirometry (Ergocard CPX; Medisoft ExpAIR, Sorinnes-Belgium) following American Thoracic Society (ATS)/ERS guidelines [17]. The main variables collected were FEV₁, forced vital capacity (FVC), FEV₁/FVC ratio and forced expiratory flow at 25–75% of FVC (FEF_25–75%). All data were expressed as absolute values and z-scores were calculated using the Global Lung Initiative method [18].

Impulse oscillometry was performed (Jaeger, Erich Jaeger, Germany) according to ERS/ATS guidelines [19]. The variables recorded were respiratory impedance (Z5), total (R5) and central airway resistance (R20), reactance to 5 Hz (X5), reactance area (AX) and resonance frequency (F_res). Data were obtained in 30 patients at two centres with the same measurement devices. Z-scores were calculated according to reference values.

Muscle strength and functional capacity

Handgrip strength was assessed with a hand dynamometer (Jamar, Lafayette Instrument, Lafayette, IN, USA) in a seated position (elbow at 90°) [20]. A digital handheld dynamometer (MicroFET 2, Hoggan–Health Industries, West Jordan, UT, USA) was used to assess the strength of the arms (in a supine decubitus position with 90° arm flexion) and legs (seated with the hip at 90° and the knees flexed to determine isometric strength for both leg extension and flexion) [21]. The highest value was recorded and then adjusted for body weight.

Functional capacity was assessed in the 30-s sit-to-stand (STS) test. Participants were instructed to stand up and sit down and to perform as many cycles of sit–stand–sit as possible in 30 s with their arms crossed over the chest [22]. Two trials with a 60-s rest period were performed.

Physical activity

To measure physical activity levels, we used the Physical Activity Questionnaires for adolescents (PAQ-A) and children (PAQ-C) [23]. Each item is scored on a five-point scale and the total score is an average of the scores of all items. Total scores range from 1 (very low levels) to 5 (higher levels).

Body composition

Body weight and fat percentage were measured through bioelectrical impedance analysis (Tanita BC-545n, Tokyo, Japan). Height was measured with a stadiometer. The waist–hip ratio was calculated using the waist circumference (at the belly button) divided by the circumference of the fullest curve of the hip measured with wrap tape. The body mass index (BMI) was calculated as kg·m⁻². Weight, height and BMI data were expressed as absolute values and z-scores [24].

Quality of life

The Saint George Respiratory Questionnaire (SGRQ) grades 50 items divided into three subscales: symptoms, activity and impacts. Results are presented as an overall score from 0–100, where zero indicates no respiratory impairment [25].

Dyspnoea

To assess basal dyspnoea levels during daily life activities we used the five-point modified British Medical Research Council scale (mMRC). Participants were asked about their perceived breathlessness according to descriptive statements and classified according to their mMRC dyspnoea scores (from 0 to 4) [26].

Demographic and clinical variables

Demographic and clinical data were collected both directly from the participants and from their medical records.

Sample size

The sample size needed to detect a minimum correlation of 0.45 [11] between V′_O2peak (% predicted) and FEV₁ (% predicted), with a significance of 0.05 and a power of 90%, was estimated at 48 participants.

Statistical analysis

R statistical software was used. Descriptive data for the participants are first presented as total numbers and percentages for categorical variables, and mean±sd for continuous variables. To examine the association between the main outcome measure (CRF) and each of the secondary variables, age and sex, we used univariate linear regression models where the dependent variable was the V′_O2peak and the independent variables were each of the secondary variables along with age and sex. Next, we built a multiple regression model with all the secondary outcomes, age and sex as covariates. Model selection was performed using a stepwise method based on the Akaike information criterion. We assessed the validity of the models by checking the different application assumptions (linearity, homoscedasticity, normality and independence). The degree of association was calculated as the model coefficient for each of the secondary variables and its 95% confidence interval. Finally, we stratified descriptive data according to the level of airway obstruction [17] and sex and compared groups using a t-test.

Results

Participants were 51 children and adolescents (49% female) with PIBO enrolled as described in the supplementary figure. The characteristics of the study sample together with their lung function data are shown in table 1. Mean±sd participant age was 13.2±4.2 years. Age at PIBO diagnosis was 4.2±3.5 years. 33 patients had an identifiable infectious agent at diagnosis. Upon HRCT, participants showed a mosaic pattern of bronchiectasis, and air trapping. Two patients required lung biopsy to confirm their diagnosis. Lung function impairment in the study population was moderate-to-severe (FEV₁) and airway resistance was elevated (R5 Hz and R20 Hz). The CPET variables recorded are provided in table 2. These data indicated reduced CRF (V′_O2peak), but a good endurance potential, as reflected by the %V′_O2 at VT₁ (59,9% of V′_O2peak). In 43 patients (84%), BR at peak exercise was below 15%, and in 23 patients (45%), BR at peak exercise was zero. While none of the patients had a baseline S_pO2 <94%, 16 completed the test with an S_pO2 ≤90%, and three exhibited a desaturation to ≤85%. No patient presented any adverse events during or after the test, and all patients met the maximum effort criteria.

TABLE 1.

Study sample characteristics and lung function data

Demographics (n=51)
Age, years	13.2±4.2
Female	25 (49)
Anthropometrics (n=51)
Weight, kg	48.7±17.0
Weight, z-score	−0.12±1.17
Height, cm	154.1±17.1
Height, z-score	−0.38±1.00
BMI, kg·m−2	19.8±4.1
BMI, z-score	0.06±1.20
Fat mass, %	22.1±7.6
WHR	0.82±0.06
Parental education level (n=102)
Elementary school	14 (14)
High school	13 (13)
Short-cycle tertiary	27 (26)
Master's/Doctorate	42 (41)
Other	6 (6)
Medical history (n=51)
Adenovirus	16 (31)
RSV	9 (18)
Other	8 (16)
Unknown	18 (35)
Number of co-infections	9 (18)
Lung function (n=51)
Spirometry
FVC, L	2.7±1.09
FVC, z-score	−1.65±1.26
FEV1, L	1.63±0.67
FEV1, z-score	−3.6±1.30
FEV1/FVC	0.61±0.13
FEF25–75%, L·min−1	1.09±0.73
FEF25–75%, z-score	−3.8±1.55
Oscillometry (n=30)
R5 Hz, kPa·L−1·s−1	0.85±0.35
R5 Hz, %	165.8±53.6
R20 Hz, kPa·L−1·s−1	0.48±0.12
R20 Hz, %	120.5±30.7
X5 Hz, kPa·L−1·s−1	−0.29±0.19
X5 Hz, %	6.5±943.4

Data are presented as mean±sd or n (%). The education level of parents includes the mother and father of each patient (n=102). BMI: body mass index; WHR: waist–hip ratio; RSV: respiratory syncytial virus; FVC: forced vital capacity; FEV₁: forced expiratory volume in 1 s; FEF_25–75%: forced mid-expiratory flow between 25% and 75% of FVC; R: resistance; X: reactance.

TABLE 2.

Cardiopulmonary exercise testing variables

Variable	n=51
Rest
HR, beats·min−1	89.9±14.9
SpO2, %	97.8±1.62
RER	0.72±0.06
VT1
HR, beats·min−1	137.2±14.2
RER	0.84±0.07
V′O2, L·min−1	2.1±8.0
V′O2, mL·kg−1·min−1	21.5±5.5
V′O2, % of peak	59.9±12.8
V′E, L·min−1	30.0±9.8
V′E/V′O2	26.9±5.0
V′E/V′CO2	32.0±5.2
Peak
HR, beats·min−1	183.1±14.2
SpO2, %	92.0±5.3
RER	1.02±0.12
BR, %	7.1±8.3
V′O2, L·min−1	1.76±0.68
V′O2, mL·kg−1·min−1	36.8±8.6
V′O2, centile
≤10	24 (47)
11–25	13 (25)
25–75	9 (18)
≥76	5 (10)
V′E, L·min−1	62.4±24.6
V′E/V′O2	32.4±7.2
V′E/V′CO2	32.5±5.2
PETCO2, mmHg	34.7±6.5
O2 pulse, mL·beat−1	9.5±3.5
1-min recovery
HR, beats·min−1	159.3±20.2
SpO2, %	95.5±3.6

Data are presented as mean±sd or n (%). HR: heart rate; S_pO2: oxyhaemoglobin saturation by pulse oximetry; RER: respiratory exchange ratio; VT₁: first ventilatory threshold; V′_O2: oxygen consumption; V′_E: ventilation; V′_CO2: carbon dioxide output; BR: breathing reserve; P_ETO2: end-tidal oxygen; P_ETCO2: end-tidal carbon dioxide.

The secondary variables recorded are shown in table 3. Upper body strength was good, as indicated by handgrip strength levels in the 40th percentile. Functional capacity was also good (30-s STS). However, in the PAQ-A and PAQ-C questionnaires, 59% of participants scored between 1 and 1.99 points (very low level of physical activity), whereas the remaining 41% scored between 2 and 2.99 (low level). Quality of life (SGRQ) and dyspnoea scale (mMRC) scores were both low.

TABLE 3.

Muscle strength, functional capacity, physical activity level, quality of life and dyspnoea

Variable (n=51)
Muscle strength
Upper limbs, kg·kg−1
Right handgrip	0.48±0.14
Left handgrip	0.45±0.12
Dominant handgrip	0.49±0.14
Right arm flexion	0.36±0.11
Left arm flexion	0.34±0.11
Dominant arm flexion	0.36±0.11
Lower limbs, kg·kg−1
Right leg extension	0.63±0.19
Left leg extension	0.61±0.21
Dominant leg extension	0.62±0.20
Right leg flexion	0.40±0.16
Left leg flexion	0.40±0.16
Dominant leg flexion	0.41±0.17
Functional capacity
30-s STS
Number of repetitions	27.2±5.7
Questionnaires
Physical activity
PAQ-A-C, points	1.89±0.46
Quality of life, SGRQ score, %
Symptoms	33.6±17.7
Activity	26.0±17.4
Impact	12.2±9.9
Total	20.1±10.8
Dyspnoea scale mMRC
Dyspnoea 0	25 (49)
Dyspnoea 1	26 (51)

Data are presented as mean±sd or n (%). 30-s STS: 30-s sit-to-stand test; PAQ-A-C: physical activity questionnaire for adolescents or children; SGRQ: St. George's respiratory questionnaire; mMRC: modified Medical Research Council scale.

Associations between CRF and clinical–functional variables are shown in table 4. A significant relationship was found between V′_O2peak and FEV₁, quality of life, BMI, dominant handgrip strength and dominant leg flexion muscle strength. No significant associations were found for the remaining variables. Multiple regression analysis revealed a significant association between the main outcome measure and FEV₁, BMI, sex, quality of life and age.

TABLE 4.

Linear regression analysis of associations between clinical–functional variables and cardiorespiratory fitness

	V′O2peak (mL·kg−1·min−1)
	β-coefficient	95% CI	p-value
Univariate regression#
FEV1, z-score	3.55	1.88–5.22	<0.001
Dominant handgrip, kg·kg−1	21.99	5.13–38.86	0.012
Dominant arm flexion, kg·kg−1	12.61	−8.98–34.21	0.246
Dominant leg extension, kg·kg−1	10.33	−1.46–22.12	0.085
Dominant leg flexion, kg·kg−1	15.27	1.08–29.45	0.036
30-s STS, repetitions	0.36	−0.06–0.78	0.093
BMI, z-score	−2.79	−4.68– −0.91	0.005
SGRQ, score (%)	−0.36	−0.57– −0.16	<0.001
Dyspnoea scale mMRC	−3.33	−7.24–0.58	0.094
PAQ, points	4.51	−0.74–9.76	0.091
Sex, female	−3.53	−8.30–1.24	0.144
Age, years	0.09	−0.50–0.68	0.772
Multiple regression¶
FEV1, z-score	4.41	3.16–5.68	<0.001
BMI, z-score	−2.96	−4.28– −1.64	<0.001
SGRQ, score (%)	−0.20	−0.34– −0.06	0.005
Sex, female	−4.94	−8.04– −1.84	0.002
Age, years	0.39	0.03–0.74	0.033

V′_O2: oxygen consumption; FEV₁: forced expiratory volume in 1 s; 30-s STS: 30-s sit-to-stand test; BMI: body mass index; SGRQ: St. George's respiratory questionnaire; mMRC: modified Medical Research Council scale; PAQ: physical activity questionnaire. ^#: Summary of univariate linear regression models with V′_O2peak (mL·kg⁻¹·min⁻¹) as the dependent variable and other relevant variables as independents. ^¶: Summary of multivariate linear regression model with V′_O2peak (mL·kg⁻¹·min⁻¹) as the dependent variable, and as independent variables those that following backward stepwise regression variable selection gave rise to the model with the lower Akaike information criterion. Significant values are highlighted in bold.

As V′_O2peak is strongly associated with FEV₁, we conducted additional subgroup analyses (table 5) based on the level of airway obstruction (FEV₁ z-score >−3.5 and ≤−3.5). The group with the lower level of airway obstruction showed significantly higher values of V′_O2peak, S_pO2 at peak, RER at VT₁ and peak, V′_E at peak, V′_E/V′_O2 at peak and end-tidal oxygen tension (P_ETO2) at peak. Additionally, this group showed significantly lower dominant arm flexion strength, % of V′_O2 at VT₁, and end-tidal carbon dioxide tension (P_ETCO2) at peak. No significant differences were found between the two groups for the remaining variables. Descriptive data by participant sex are provided in the supplementary table. These data indicated lower lung function and higher muscle strength for the male participants.

TABLE 5.

Main variables examined according to lung function impairment (moderate-to-mild or moderate severe-to-severe FEV₁ reduction).

Variable	FEV1 z-score >−3.5 (n=29)	FEV1 z-score ≤−3.5 (n=22)	p-value
Demographics
Age, years	13.0±4.1	13.6±4.4	0.614
Female	18 (62)	7 (32)
Anthropometrics
BMI, z-score	0.20±0.98	−0.13±1.44	0.340
Muscle strength, kg·kg−1
Dominant handgrip	0.47±0.11	0.51±0.17	0.386
Dominant leg extension	0.59±0.13	0.67±0.27	0.149
Dominant leg flexion	0.39±0.09	0.43±0.23	0.428
Dominant arm flexion	0.32±0.05	0.40±0.15	0.016
Functional capacity
30-s STS, repetitions	28.3±4.9	25.8±6.4	0.109
Aerobic fitness
VT1
HR, beats·min−1	136.5±13.1	127.1±43.1	0.273
V′O2, L·min−1	3.02±10.6	0.97±0.34	0.370
V′O2, mL·kg−1·min−1	22.3±5.9	20.5±4.8	0.243
V′O2, % of peak	56.8±13.1	64.2±11.3	0.039
V′E, L·min−1	31.8±10.4	27.7±8.5	0.138
RER	0.85±0.07	0.82±0.06	0.042
V′E/V′O2	28.0±4.9	25.3±4.8	0.052
V′E/V′CO2	32.8±5.5	31.0±4.8	0.212
Peak
HR, beats·min−1	185.7±12.2	179.6±16.2	0.136
SpO2, %	94.1±3.5	89.2±5.9	0.001
V′O2, L·min−1	1.87±0.62	1.61±0.73	0.169
V′O2, mL·kg−1·min−1	39.7±7.1	32.9±9.0	0.005
V′O2, centile
≤10	9 (31)	15 (68)
11–25	7 (24)	6 (27)
25–75	9 (31)	0 (0)
≥76	4 (14)	1 (5)
V′E, L·min−1	69.9±23.9	52.5±22.4	0.011
RER	1.07±0.11	0.95±0.10	<0.001
BR, %	8.5±8.2	5.2±8.3	0.168
V′E/V′O2	34.5±6.1	29.5±7.7	0.014
V′E/V′CO2	33.1±4.1	31.6±6.3	0.316
PETCO2, mmHg	33.0±5.7	36.8±7.0	0.039
O2 pulse, mL·beat−1	10.0±3.1	8.9±3.9	0.247
Other
Dyspnoea mMRC
0 points	15 (52)	10 (45)
1 point	14 (48)	12 (55)
PAQ-A-C, points	1.86±0.41	1.93±0.52	0.554
SGRQ total score, %	19.3±10.2	21.1±11.8	0.582

Data are presented as mean±sd or n (%). FEV₁: forced expiratory volume in 1 s; BMI: body mass index; 30-s STS: 30-s sit-to-stand test; VT₁: first ventilatory threshold; HR: heart rate; V′_O2: oxygen consumption; V′_E: minute ventilation; RER: respiratory exchange ratio; V′_CO2: carbon dioxide output; S_pO2: oxyhaemoglobin saturation by pulse oximetry; BR: breathing reserve; P_ETO2: end-tidal oxygen; P_ETCO2: end-tidal carbon dioxide; PAQ-A-C: physical activity questionnaire for adolescents or children; SGRQ: St. George's respiratory questionnaire. Significant values are highlighted in bold.

Discussion

The findings of our study indicate that children and adolescents with PIBO show lower V′_O2peak values than normal. This translates to reduced CRF, mostly due to ventilatory limitations. Additionally, the lower V′_O2peak value observed in our study population was significantly associated with reduced lung function (FEV₁), reduced arm and leg muscle strength, younger age, higher BMI, poorer quality of life score and female sex.

Participants with PIBO presented a mean V′_O2peak of 36.8±8.6 mL·kg⁻¹·min⁻¹, which is similar to that reported in the literature for children and adolescents with asthma [27] and cystic fibrosis [28]. Although we lack local reference CPET values for paediatric subjects, according to percentiles based on sex and age [16], 47% of the present study sample was below the 10th percentile. A lower exercise capacity was also observed in the only two studies that have assessed CPET in children and adolescents with PIBO [11, 12], as also noted in submaximal tests [10, 12]. However, despite their low CRF level, we observed good endurance potential as indicated by %V′_O2 values recorded at VT₁. These last findings are similar to data reported for sedentary healthy individuals, in whom VT₁ occurs at around 50–60% of V′_O2peak [15]. These findings are also in line with previous guidelines for exercise testing in subjects with chronic lung disease, indicating that patients with respiratory limitations may show a reduced V′_O2peak but normal %V′_O2 at VT₁ [15]. Another important finding of the present study related to the main mechanisms involved in the exercise intolerance shown here was that most participants (84%) ended the CPET with a BR of less than 15%, suggesting significant ventilatory impairment. Similar data have been reported by other authors for PIBO patients compared with healthy subjects (BR at peak 9% versus 43%) [12]. To the best of our knowledge, no other study performed in PIBO patients has examined these variables. Patients with cystic fibrosis may have a lower peak BR compared with healthy subjects or individuals with asthma [29]. However, our data suggest that patients with PIBO may show even more severe ventilatory limitations.

The present study, along with others conducted in patients with PIBO, shows that FEV₁ may be significantly associated with CRF, as measured in both maximal [11, 30] and submaximal [10, 31] tests. While this relationship has not been observed in patients with asthma [32], findings in those with cystic fibrosis have been contradictory [30, 31]. We also observed here that CRF was associated with quality of life (SGRQ). This association has been also shown in patients with idiopathic pulmonary fibrosis [33], although conflicting results have been obtained in asthma patients [34] using a disease-specific questionnaire. Additionally, we found significant links between CRF and both handgrip and leg flexion muscle strength, similar to observations in children with pulmonary hypertension [35]. Body composition (BMI) and sex were also here found related to V′_O2peak. Moreover, we observed a higher percentage of males (57% versus 36%) with a V′_O2peak below the 10th percentile. This difference could be attributed to the fact that our male participants featured significantly worse lung function (FEV₁) and significantly greater airway reactance (X5 Hz) than females.

Most of our PIBO patients (57%) had moderate-to-mild airway obstruction (FEV₁ z-score >−3.5) according to the ERS/ATS classification [17]. This contrasts with the lower airway obstruction scores reported in a meta-analysis of children with PIBO [36], and in children and adolescents with primary ciliary dyskinesia and cystic fibrosis [37]. We also observed a mean±sd FEV₁/FVC of 0.61±0.13 similar to previously reported values [36] indicating an obstructive pattern. When we divided our study population into those with moderate-to-mild airway obstruction (FEV₁ z-score >−3.5) and those with moderate severe-to-severe (FEV₁ z-score ≤-3.5) obstruction, we found a significantly lower V′_O2peak in the latter group. Peak S_pO2 was also significantly lower in these patients. Interestingly, participants in the poorer lung function group showed significantly greater strength when flexing the dominant arm. The differences found at VT₁ (V′_O2% of peak) and at peak exercise (V′_E and V′_E/V′_O2) could indicate that patients with a worse clinical condition may undergo peripheral chronic adaptations to exercise and, therefore, feature a higher V′_E/V′_O2. Notwithstanding, a shorter test duration due to ventilatory limitations albeit maximal could also have influenced these findings.

Muscle function plays a key role in patients with chronic respiratory diseases [38]. Patients with PIBO generally show good upper body strength with handgrip strength levels in the 40th percentile [39]. For knee flexion/extension, and elbow flexion muscle strength, we have found no reference values for the age range of our sample. Further, our functional capacity results indicated no limitations when compared with a cohort of healthy children and adolescents [39]. However, according to the PAQ-A and PAQ-C questionnaires, participants reported low levels of physical activity, with no significant correlation observed with V′_O2peak. This may be attributed to the self-reported nature of the PAQ, as previous studies have shown that it does not always correlate strongly with objective measures of physical fitness or conditioning – such as cardiorespiratory fitness (V′_O2peak) – particularly in paediatric and adolescent populations, where the perception and reporting of physical activity can be inconsistent or influenced by external factors [40].

Quality of life is an important factor in various chronic diseases [7, 31, 34]. We found improved quality of life levels in patients with PIBO (SGRQ) over those with cystic fibrosis, as assessed by a disease-specific questionnaire [31]. Our mean SGRQ score was, however, lower than that observed in patients with bronchiolitis obliterans syndrome after lung transplantation [41]. We also obtained good scores when assessing dyspnoea, as 49% of our PIBO patient population reported no shortness of breath, except during intense exercise. In contrast, 51% reported breathlessness when walking quickly or up a hill. Other authors have reported similar respiratory symptoms [11] indicating these patients experience no significant dyspnoea when performing daily activities involving lower energy expenditure.

Strengths and limitations

This is the first multicentre large-sample study performed in children and adolescents with PIBO. Among its limitations we should mention that while all participants had a confirmed diagnosis of PIBO, we were not able to obtain information on viral aetiology in all patients. Also, the quality-of-life questionnaire employed here is usually administered to adults, although it has also been used in children and adolescents [7]. To minimise the potential bias introduced by this factor, we provided detailed instructions on the questionnaire to all participants. Another limitation was that one of the participating centres used a different oscillometry device, so it was not possible to pool these data for the whole study sample.

Conclusions

Individuals with PIBO show reduced CRF, mainly due to ventilatory limitations, and this impairment is associated with lower lung function (FEV₁), upper and lower limb muscle strength and age, and a higher BMI and quality of life score, and female sex. This is the largest multicentre study including children and adolescents with PIBO to provide CRF data for this population as well as evidence for mechanisms of exercise intolerance, and associations with other clinical–functional variables. Our findings could serve to improve the clinical management of PIBO by identifying the main factors limiting exercise and functional capacity and thus help personalise exercise prescription.

Supplementary material

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Supplementary figure

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Supplementary table

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