2025 临床建议：呼吸系统疾病儿童的心肺运动试验（更新版）

ABSTRACT

Introduction: Cardiopulmonary exercise testing (CPET) is a diagnostic-integrated tool for evaluating cardiovascular, ventilatory, and metabolic functional limitations in children with respiratory diseases. Recently, novel applications have emerged, revealing dynamic abnormalities that may go unnoticed in standard static cardiac and pulmonary function tests. Given its clinical importance and novel research findings, updated recommendations are warranted.

Areas covered: We conducted a narrative review based on a literature search up to April 2025. This review provides an update on the application of CPET in pediatric respiratory diseases, covering physiological differences to adults, non-traditional CPET metrics such as the oxygen uptake efficiency slope (OUES), tidal volume to inspiratory time ratio (VT/Ti), and recent reference values. Indications, contraindications, and standardized protocols are discussed, alongside emerging trends in CPET technology.

Expert opinion: CPET is a potent tool for assessing, evaluating, and diagnosing pediatric respiratory diseases. Standardized protocols, age-specific reference values, and novel CPET parameters enhance clinical utility. Future research should refine interpretation, integrate artificial intelligence for data analysis, and facilitate CPET for younger children.

ARTICLE HISTORY

Received 6 March 2025 Accepted 8 August 2025

KEYWORDS

Exercise; physiology; respiration; children; lung disease

1. Introduction

1.1. Background and significance

This review provides an update on the application of cardio-pulmonary exercise testing (CPET) in pediatric respiratory diseases of our previous article on this topic [1]. CPET plays a vital role in assessing and evaluating exercise capacity, with a special focus on respiratory functioning in children with respiratory diseases. Static lung function tests are valuable for diagnosing and monitoring respiratory conditions as they assess key parameters like lung volume, capacity, and airflow. These tests provide a snapshot of the lungs' overall function, helping to identify obstructive or restrictive lung diseases, such as asthma and pulmonary fibrosis. While they offer important insights into lung health, static lung function tests may not detect dynamic changes in lung function that occur during physical activity, which is why they are often complemented by more advanced tests like CPET [2]. CPET assesses the integrated physiological response to exercise and a comprehensive approach measure ventilation, gas exchange, and cardiovascular performance under stress, offering insights into real-world functional capacity and exercise limitations. In the context of pediatric respiratory conditions, this intergraded approach assesses e.g. ventilation, gas

exchange, and cardiovascular performance under stress, providing dynamic evaluation of respiratory efficiency, functional capacity, experienced exercise limitations, and highlight potential areas for intervention of the pediatric patient. This assessment is essential for children with a respiratory disease, as exercise capacity is a key determinant of physical health, quality of life, psychosocial development, and well-being [3].

Advances in pediatric respiratory disease management increasingly leverage on CPET to guide personalized care. By identifying specific deficits – whether ventilatory, cardiovascular, muscular, or metabolic – clinicians can tailor exercise prescriptions and monitor therapeutic and interventional responses more effectively. Furthermore, CPET helps detect early signs of disease progression, enabling timely adjustments to treatment plans and assessing breathing patterns.

As research continues to refine CPET protocols, utilization, and interpretation, its integration into pediatric medicine holds promise for improving diagnostic value, outcomes, and promoting physical activity in children with respiratory conditions. Therefore, the objective of this review is to provide an updated overview of clinical application and recommendations and highlight recent advancements and consensus guidelines

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Article highlights

$\bullet$ CPET enables dynamic, integrated assessment of cardiopulmonary function in children with respiratory disease.

$\bullet$ Recent advancements include novel CPET metrics such as OUES and VT/Ti, which may enhance diagnostic precision.

* New pediatric reference values improve the interpretation of CPET results across age groups and environments

Non-traditional indications such as dysfunctional breathing and ElLO benefit from detailed CPET pattern recognition.

* Artificial intelligence may support automated interpretation and improve [vCD] utility and accessibility.

* Standardization of protocols and improved accessibility are key for broader CPET adoption in pediatric care.

1.2. Methods

We performed a comprehensive literature search on PubMed and Embase. The search included studies published between 1 January 2010 and 30 April 2025. We used a combination of Medical Subject Headings (MeSH) and free-text terms related to 'cardiopulmonary exercise testing,' 'children,' and 'respiratory diseases.' The search was limited to English-language publications. Additional relevant articles were identified by screening the reference lists of included studies.

2. Physiological basis of CPET in children

2.1. Overview of pediatric exercise Physiology

Children are not simply small adults. As growth and development bring anatomical, psychological, and physiological changes that influence exercise responses, children cannot simply be regarded as small adults. Almost all hemodynamic, ventilatory, and metabolic exercise parameters differ in children compared to adults. Correspondingly, large gender differences appear after the onset of puberty [4], implying that girls are not just small boys from the same age [5]. During puberty, boys appear to have a greater development in status and body composition. This makes that their exercise capacity increases more overtime compared to girls. Also, the differences in exercise response like breathing pattern will differ between girls and boys from the onset of puberty [4].

2.2. Differences between pediatric and adult ventilatory responses

As most physiological systems, the respiratory system also undergoes significant growth and development during childhood and adolescence. This includes increases in lung size, alveolar surface area, and respiratory muscle strength, all of which influence ventilatory response during exercise. In contrast, pulmonary function in adults is fully developed and remains largely unchanged despite improvements of muscular and circulatory efficiency due to physical training.

2.2.1. Ventilatory control mechanisms

Research indicates that both central and peripheral control mechanisms for ventilation continue to mature through

adolescence, affecting the precision of ventilatory responses. The respiratory center in the medulla oblongata, which regulates breathing rate in response to changes in blood levels of carbon dioxide, oxygen, and pH, undergoes developmental changes during this period. This maturation contributes to the observed decrease in normal respiratory rates from childhood to adolescence.

As children grow, anatomical and physiological changes lead to a progressive reduction in the dead space-to-tidal volume ratio (VD/VT). Neonates and infants exhibit relatively high VD/VT due to their proportionally larger upper airways and lower tidal volumes. With increasing age, airway dimensions scale with lung volume, and tidal volume increases, resulting in a lower VD/VT ratio and more efficient gas exchange during exercise. This developmental trajectory contributes to improved ventilatory efficiency, which can be captured in CPET variables such as VE/VCO₂. Understanding these maturational changes is essential for interpreting ventilatory parameters in pediatric exercise testing.

The ventilatory equivalent of carbon dioxide (VE/VCO₂) is influenced by two principal physiological determinants: the arterial partial pressure of carbon dioxide (PaCO₂) and the dead space to tidal volume ratio (VD/VT). According to the alveolar ventilation equation, VE/VCO₂ is inversely related to PaCO₂ and directly related to VD/VT. In children, PaCO₂ is tightly regulated via central and peripheral chemoreceptors; during exercise, hyperventilation may occur to maintain or slightly lower PaCO₂ especially in the presence of increased dead space or impaired perfusion. The VD/VT ratio tends to decrease with increasing tidal volume and improved alveolar ventilation as children grow; however, in conditions like cystic fibrosis or interstitial lung disease, a persistently elevated VD/VT can drive VE/VCO₂ higher, reflecting ventilatory inefficiency. Therefore, both an elevated VD/VT and a decreased ability to reduce PaCO₂ can independently and synergistically increase the VE/VCO₂ ratio, making this parameter particularly informative in the assessment of pulmonary pathophysiology in pediatric populations.

Additionally, studies have shown that ventilatory responses during exercise evolve with maturation [6,7]. Between the ages of 11 and 17, there is a significant increase in ventilation (VE) and tidal volume (VT), while breathing frequency (BF) tends to decrease. These changes suggest that as children grow, their ventilatory control mechanisms become more efficient, leading to more precise regulation of breathing during physical activity. Understanding these developmental trajectories is crucial for assessing pediatric respiratory health and tailoring interventions appropriately.

2.2.2. Breathing reserve (BR)

In healthy adolescents, BR is generally above 30% at peak exercise. This indicates that the ventilatory system rarely reaches its capacity during maximal exercise. However, pre-pubertal children might reach a lower BR compared to adolescents (see also section 2.3.5 Breathing Reserve).

In healthy adult males, BR can be as low as 10–15% during intense exercise. Highly fit endurance athletes may reach ventilatory rates comparable to their maximum voluntary ventilation (MVV), reflecting the greater ventilatory demand in highly

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trained subjects. It should be reminded that lung structure is not significantly changed by exercise training [8].

2.2.3. Ventilatory limitation

Pediatric patients with respiratory diseases (e.g. cystic fibrosis) may experience ventilatory limitations if their resting forced expiratory volume in 1 s (FEV₁) drops below ± 70% of predicted. In this case, the BR at the end of the CPET may be below 15% or even below 0% (i.e. negative value). Adults with respiratory conditions may show a similar pattern, but due to larger lung capacity and more developed pulmonary function, they might tolerate higher ventilatory workloads before limitations arise.

In summary, pediatric ventilatory responses are characterized by developmental changes in efficiency, lung mechanics, and BR, while adults show more stable and efficient breathing patterns with potentially lower BR at maximal exertion.

2.3. Non-traditional respiratory CPET metrics

In our previous review, we described several CPET parameters that can be used in pediatric patients with respiratory disease [1]. Here, we describe an additional five non-traditional CPET metrics for assessing and evaluating respiratory dysfunction during exercise:

2.3.1. Oxygen uptake efficiency slope

The Oxygen Uptake Efficiency Slope (OUES) was originally developed by Baba et al. [9] to evaluate the exercise capacity in patients with congenital heart disease. The OUES quantifies the relationship between oxygen uptake ($VO_2$) and minute ventilation ($VE$) during exercise. It is expressed as the slope of the logarithmic relationship:

$$\dot{V} O_2=a\log(\dot{V} E)+b\dot{V} O_2=a\log(\dot{V} E)+b$$

Where $\dot{V}O_2$ stands for oxygen uptake (mL/min), $\dot{VE} = \text{minute}$ ventilation (L/min), a = OUES (slope), and b = Intercept.

The OUES is a metric for the assessment of ventilatory efficiency. The OUES measures how effectively the body extracts oxygen relative to the amount of air ventilated. A higher OUES value indicates better ventilatory efficiency and cardiorespiratory function. The OUES was initially developed as a submaximal, effort-independent metric. Unlike peak oxygen uptake ($VO_{2\text{peak}}$), OUES can be assessed at submaximal exercise levels, making it particularly useful for pediatric populations where achieving maximal effort may be challenging.

Normalizing for body size is required when one wants to compare persons with different body sizes or track OUES values over time. To normalize OUES values, it can be adjusted for body surface area (BSA) or body weight to enhance comparability between children of different ages and sizes. Also, the allometric scaling method has been advised [10].

Advantages of the OUES in pediatric CPET are that this metric does have a minimal effort dependency [5]. OUES is reliable even if the child does not reach maximal exertion, providing a more accurate assessment of cardiopulmonary function under real-world conditions. Changes in OUES

might detect early signs of ventilatory inefficiency before overt clinical symptoms appear, aiding in early intervention planning.

In summary, OUES is a well-researched, effort-independent parameter that offers valuable insights into ventilatory efficiency, also in pediatric populations with respiratory diseases. It complements traditional CPET metrics like $\text{VO}_2$ and $\text{VE}/\text{VCO}_2$-slope, enhancing diagnostic accuracy and disease monitoring. However, the OUES is not yet widely implemented in regular clinical exercise testing equipment, and its validity is questioned in some populations.

2.3.2. Intercept of the VE/VCO₂-slope

The VE/VCO₂ relationship during exercise provides insight into ventilatory efficiency and is typically assessed through the slope, intercept, and nadir. The VE/VCO₂ slope reflects the rate of increase in ventilation relative to carbon dioxide output and is elevated in conditions with impaired ventilation- perfusion matching, increased physiological dead space, or heightened chemosensitivity. A steep slope (> 34) may suggest underlying pulmonary or cardiovascular limitations. The nadir, or lowest VE/VCO₂ value reached during exercise, typically occurs near the anaerobic threshold and is considered a robust index of ventilatory efficiency. In healthy children, the VE/VCO₂ nadir generally decreases with age due to reductions in VD/VT and improved pulmonary mechanics. In contrast, in pediatric patients with chronic respiratory diseases, an elevated nadir is associated with worse clinical status and can provide prognostic information. The intercept represents the hypothetical ventilation at zero CO₂ production (hypothetical VCO₂ = 0) and is thought to reflect baseline ventilatory demand and dead space ventilation at rest. Thus, interpreting these three elements together can enhance understanding of disease severity and ventilatory limitation during exercise.

The intercept is derived from the linear regression equation of the $\dot{VE/VCO_2}$ relationship:

$$\dot{V}E=m\left(\dot{V}CO_{2}\right)+b\dot{V}E=m\left(\dot{V}CO_{2}\right)+b$$

Where m is the slope and b is the intercept.

The $\dot{VE}/\dot{VC}_2$-intercept is an independent indicator for the ventilatory drive. The intercept reflects intrinsic ventilatory drive or the baseline breathing pattern, independent of metabolic load. A high intercept suggests increased resting ventilatory drive, potentially due to pulmonary vascular disease, elevated central respiratory drive (e.g. in severe COPD or interstitial lung disease), or poor ventilatory efficiency or deadspace ventilation.

While the $\dot{VE}/\dot{CO}_2$-slope indicates the efficiency of gas exchange during incremental exercise, the intercept provides additional diagnostic information by highlighting issues that are present at rest or during low-intensity exertion.

The intercept is not yet researched in the pediatric population. However, research by Nagano et al. [11] is indicating that children breathe relatively more because of a slightly but lower $PaCO_2$ set point. We think that this might be an interesting

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parameter to use in the pediatric age group. However, more research on this parameter is needed.

2.3.3. Oxygen breath

The oxygen breath (OB) was recently described by Stavrou et al. [12]. The OB reflects the amount of oxygen taken up per breath. Higher values suggest a more efficient oxygen extraction, while lower values may indicate shallow breathing or poor gas exchange, common in respiratory dysfunction. OB might provide insights into the progression of chronic respiratory conditions, complementing parameters like VE/VCO₂-slope and OUES.

The Oxygen Breath (OB) is calculated as:

$$\text{Oxygen Breath}\left(OB\right)=\dot{VO}_{2}/\dot{BF}$$

Where:

$$ \dot{VO}_2 = \text{Oxygen uptake (mL/min)} $$

BF = respiratory rate (breaths/min)

In children with respiratory conditions such as cystic fibrosis or asthma, a low OB value can signal ventilatory inefficiency: increased respiratory rate without proportional oxygen uptake, and restrictive lung disease: inability to increase tidal volume effectively.

In pediatric populations, OB measurements across different exercise intensities may differentiate normal physiological adaptations (e.g. growth-related changes) from pathological respiratory responses. This parameter might add additional depth to the interpretation of CPET data, offering insights into both ventilatory efficiency and gas exchange abnormalities in children with respiratory diseases. More research on this parameter in pediatric populations is required.

2.3.4. Breathing pattern (BP) analysis

2.3.4.1. Duty cycle of the respiratory system. The Inspiration Time/Total Respiratory Cycle Time (Ti/Tot ratio), also known as the duty cycle of the respiratory system, represents the fraction of the total respiratory cycle spent on inspiration. It was already described by Lind & Hesser in 1984 [13] in the context of CPET but has rarely been reported in the CPET literature. A recent report on CPET in long-COVID patients showed its application in adult patients with respiratory disease [14].

It is calculated as:

$Ti/Tot = \text{Inspiratory Time (Ti)/Total Time (Ttot)}$

Where:

Ti (Inspiratory Time) = Duration of the respiratory phase (in seconds).

Tot (Total Time) = Total duration of one complete respiratory cycle (inspiration + expiration) (in seconds).

The Ti/Ttot ratio provides insight into ventilatory muscle function and breathing control. Increased ratios suggest prolonged respiratory effort, often seen in respiratory muscle fatigue or obstructive lung diseases. In adults, a cutoff of 0.38 has been proposed [14].

Higher Ti/Ttot values correlate with increased perception of breathlessness (dyspnea), especially during incremental exercise. In healthy adults at rest, the Ti/Ttot typically ranges between 0.30 and 0.40, indicating that inspiration constitutes 30% to 40% of the total respiratory cycle. Specific normative values for adolescents are less well-defined in the literature. However, it is understood that as children mature, their respiratory patterns gradually align with adult norms. Therefore, by late adolescence, the Ti/Ttot ratio is expected to approximate the adult range of 0.30 to 0.40 [15].

During exercise, the Ti/Ttot ratio typically decreases, reflecting a shorter inspiratory phase to accommodate the increased breathing rate. In healthy adults, this ratio often approaches 0.50 (inverse I: E ratio of 1.0) at or near peak exercise. In adolescents, the Ti/Ttot ratio during exercise may be higher compared to adults, reflecting ongoing maturation of respiratory control mechanisms. However, specific normative values for adolescents during exercise are not well-established in the available literature. It is important to note that individual variations can occur due to factors such as physical fitness, respiratory health, and measurement conditions. Clinicians should consider these factors when interpreting Ti/Ttot ratios in both adults and adolescents.

In healthy individuals, the ratio remains relatively stable across moderate exercise but increases with intense exertion. In patients with chronic obstructive pulmonary disease (COPD) or asthma, an abnormal increase suggests inefficient breathing patterns.

Studies indicate that a disproportionately high Ti/Ttot ratio during CPET can predict exercise intolerance and ventilatory limitations. It reflects mechanical constraints on breathing, contributing to early termination of exercise. In children with respiratory diseases, assessing Ti/Ttot provides noninvasive data on breathing patterns during (sub)maximal exercise.

In summary, the Ti/Ttot ratio is an interesting parameter during CPET, particularly for assessing breathing patterns in patients with respiratory diseases. However, this parameter has not yet been reported in children. Future studies should investigate its clinical relevance to early detection of breathing inefficiency and predicting exercise intolerance in children with respiratory diseases.

2.3.5. Mean inspiratory flow

In the context of CPET in patients with respiratory disease, the mean respiratory flow, calculated as the ratio of tidal volume to inspiratory time (VT/Ti), is a parameter reflecting ventilatory efficiency and respiratory mechanics. A higher VT/Ti ratio suggests more efficient ventilation, as a greater volume of air is moved with less time spent in the inspiratory phase. Conversely, a lower ratio may indicate less efficient ventilation.

The parameter is calculated as:

VT/Ti = Tidal Volume (VT; mL/breath)/Inspiratory Time (Ti; sec).

While the specific normative values for the VT/Ti ratio are not well-defined for children [15], understanding the components of this ratio can aid in assessing respiratory function. It is

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important to note that individual variations can occur due to factors such as age, sex, physical fitness, and underlying lung conditions. Clinicians should consider these factors when interpreting the VT/Ti ratio in both adults and adolescents.

This ratio represents the mean inspiratory flow and provides insight into the ability of the respiratory system to meet metabolic demands during exercise. In healthy individuals, an appropriate increase in VT/Ti allows for efficient gas exchange with minimal ventilatory burden. The VT/Ti increases linearly with increased ventilation during exercise.

However, in respiratory diseases such as chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), or long-COVID, limitations in tidal volume expansion, and a disproportionate reduction in inspiratory time can lead to dynamic hyperinflation, increased work of breathing, and exertional dyspnea. A significantly lower VT/Ti has been observed during exercise in Long-COVID patients, but not in resting conditions [14].

In some cases, especially among elite athletes, maximum inspiratory flow (MIF) can rise markedly due to high ventilatory demands and superior cardiovascular conditioning. However, this may reach a critical threshold at which supraglottic ELO occurs due to powerful negative inspiratory pressures and suction forces. Alternatively, dysfunctional glottic closure patterns may emerge (primary or secondary), resulting in a sudden collapse of MIF. Recognizing such patterns requires a careful interpretation of flow – volume loops in conjunction with clinical features and, when appropriate, laryngoscopic confirmation [16].

Analyzing VT/Ti during CPET can help identify ventilatory constraints, assess disease severity, and guide therapeutic interventions aimed at optimizing respiratory mechanics and exercise tolerance. More research is needed to investigate the mean inspiratory flow during exercise among pediatric patients with respiratory diseases.

2.3.6. Breathing reserve (BR)

In pediatric CPET, ventilatory limitation can be assessed by the breathing reserve (BR) at peak exercise, which compares peak minute ventilation (VEepeak) to maximum voluntary ventilation (MVV). It is calculated as:

$$VR=(MVV-\dot{V} e_{\text{peak}})/MVV\times 100\%$$

Although it is common to report this value in adults, it is less frequently reported in pediatric populations. Fit children may reach ventilatory rates comparable to MVV, highlighting the importance of optimal breathing patterns since lung function does not significantly improve with training.

The BR is an essential parameter in CPET for assessing ventilatory capacity in children. It represents the difference between the maximum voluntary ventilation (MVV) and the minute ventilation VE achieved at peak exercise, typically expressed as a percentage of MVV. In healthy children, the BR usually remains above 25% [0%; 45%] in boys and 30% [0%; 52%] in girls, indicating adequate ventilatory capacity even at

maximal exertion in most children [17]. However, several healthy children might have a low (< 15%) BR. In children, the BR is not significantly affected by anthropometric variables [17].

A low BR (<15%) during CPET suggests that a child is approaching or has reached their ventilatory limit. This finding is particularly relevant for children with respiratory conditions like asthma, cystic fibrosis, or restrictive lung diseases, where ventilatory constraints may limit exercise performance. A reduced BR indicates that ventilatory capacity is insufficient to meet the increased demands of exercise, contributing to early-onset dyspnea.

BR helps distinguish between cardiac and pulmonary limitations. In children with normal BR, but reduced exercise capacity, the limitation is likely cardiovascular. Conversely, a low BR with significant ventilatory distress points to a respiratory cause. In chronic respiratory diseases such as bronchopulmonary dysplasia or interstitial lung disease, serial evaluation of BR (together with a worsening in spiritometric values) can track changes in ventilatory function over time. A progressively declining BR may indicate worsening lung function or ineffective treatment.

A low BR is associated with a higher risk of developing exercise-induced dyspnea or hyperinflation, especially in children with obstructive lung diseases. It can help clinicians advise on safe levels of physical activity and the need for interventions like bronchodilator therapy before exercise. Therefore, we strongly recommend that a forced spirometry maneuver be performed during recovery, especially when the BR is low, as it is essential for accurately assessing exercise-induced bronchoconstriction (EIB).

MVW is often estimated as FEV₁ times 35–40 in children. We advise to use FEV₁ times 35 [18]. Accurate interpretation of BR requires age-specific reference values, as ventilatory capacity and reserve change with growth and development. Recent studies, such as those by Griffith et al. [19] and Amedro et al. [17], provide updated reference values for pediatric CPET parameters, including BR.

BR is a vital CPET parameter for assessing ventilatory limitations in children with respiratory diseases. It helps differentiate the underlying causes of exercise intolerance, monitors disease progression, and guides therapeutic interventions, contributing significantly to the management of pediatric patients with pulmonary conditions.

2.3.7. Evaluating dynamic operating lung volumes

Measuring inspiratory capacity (IC) at rest and during CPET, followed by the calculation of end-expiratory lung volume (EELV), end-inspiratory lung volume (EILV), inspiratory reserve volume (IRV), and the tidal volume/inspiratory capacity (VT/IC) ratio, offers the most physiologically and clinically relevant approach to identify ventilatory limitations during exercise and explore the mechanisms behind exertional dyspnea [20]. Individuals are asked to make maximal inspiratory efforts to total lung capacity (TLC) from EELV at rest before exercise begins and at regular intervals throughout the CPET.

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Practically, these IC maneuvers should be performed close to when dyspnea intensity ratings are taken so that exercise-induced changes in dyspnea can be directly correlated with changes in lung volumes. Assuming the TLC remains constant from rest to peak exercise, IC is used to calculate EELV and EILV, where:

$$ \begin{align*} \text{ELV} &= \text{TLC} - \text{IC} \\ \text{and} \\ \text{ELV} &= \text{EELV} + \text{VT} \text{ (or TLC} - \text{IRV}, \\ \text{where } \text{RV} &= \text{IC} - \text{VT}. \end{align*} $$

Combining these measurements provides a comprehensive view of potential dynamic mechanical constraints on tidal volume (VT) expansion [20]. For instance, as EILV approaches TLC (or IRV decreases toward 0 L), VT is forced to expand within the noncompliant upper part of the respiratory system's pressure-volume curve. In this case, the inspiratory muscles (e.g. diaphragm) shorten and weaken while simultaneously generating higher intrapulmonary pressures to overcome the greater elastic recoil forces of the lung. This increased inspiratory neural drive required to support ventilation would result in significantly elevated exertional dyspnea and exercise intolerance.

Evaluating dynamic operating lung volumes is clinically relevant because it provides critical insights into how the lungs function during both rest and physical activity, helping to identify ventilatory limitations and mechanisms of exertional dyspnea (shortness of breath). The dynamic operating lung volumes can be used for the following indications:

Identifying Ventilatory Limitations: By assessing dynamic lung volumes, clinicians can identify whether respiratory limitations (such as restrictive lung disease or airway obstruction) are impairing the ability to meet the increased demands during exercise. This can guide treatment strategies for conditions like asthma or pulmonary fibrosis.

Understanding the Mechanisms of Dyspnea: Evaluating lung volumes helps determine whether dyspnea during exercise is due to mechanical constraints on ventilation (e.g. decreased inspiratory reserve volume) or other factors like ventilatory inefficiency or poor gas exchange. This information can help pinpoint the underlying cause of exertional shortness of breath and tailor interventions.

Assessing Respiratory Muscle Function: Dynamic lung volume measurements can reveal whether the inspiratory muscles (like the diaphragm) are functioning effectively or becoming overstrained. When VT-expansion is limited due to lung volume restrictions, the muscles may work harder, leading to increased exertion and fatigue.

Improving Treatment and Management Plans: By understanding the relationship between lung volume changes and symptoms during exercise, healthcare providers can better manage respiratory conditions through targeted interventions like pulmonary rehabilitation, medication optimization, or adjustments in physical activity levels.

Predicting Disease Progression: In chronic lung diseases, monitoring changes in dynamic lung volumes over time can provide early indications of disease progression or worsening symptoms, enabling more proactive management and intervention to prevent further deterioration.

2.3.8. Expiratory flow limitation

Measuring inspiratory capacity (IC) is crucial for generating exercise flow-volume loops, which can be incorporated into a maximum flow-volume loop (MFVL). These exercise flow-volume loops are useful for assessing the presence and severity of expiratory flow limitation (EFL) during cardiopulmonary exercise testing (CPET), which occurs when the expiratory portion of the tidal exercise flow-volume loop intersects or exceeds that of the MFVL [20]. Most commercially available breath-by-breath CPET systems allow users to construct these loops, enabling healthcare providers to easily visualize EFL and dynamic operating volumes.

However, exercise flow-volume loops have some important limitations. The MFVL, typically generated at rest before the start of CPET, may be inaccurate because it does not account for potential exercise-induced bronchodilation or constriction. Therefore, it is important to generate an MFVL as close to the end of exercise as possible. Additionally, dynamic airway compression can occur while generating the MFVL, leading to an overestimation of the prevalence and severity of EFL during exercise, as it underestimates expiratory flow for any given lung volume. This can be corrected by either having patients perform graded expirations from total lung capacity (TLC) to residual volume at different efforts and then reconstructing the MFVL, or by performing the maneuver in a body displacement plethysmograph. However, these approaches are rarely used in the clinical CPET laboratory. Therefore, the evaluation of EFL should be interpreted with caution unless factors like bronchodilation (or constriction), and thoracic gas compression artifacts have been accounted for.

3. Indications and contraindications for CPET in pediatric respiratory diseases

3.1. Indications

As previously stated by van Brussel et al. [21] the CPET can be used as a diagnostic test, an assessment of disease severity, a prognostic test, and a monitoring test for pediatric patients with respiratory diseases.

3.1.1. Diagnostic test

When children present with symptoms such as dyspnea, generalized or exertional fatigue, shortness of breath, dizziness, or chest pain during exercise, routine cardiopulmonary testings such as exercise challenge tests [22], may fail to identify a clear etiology. In such cases, the CPET can provide valuable insights as it allows for an objective assessment of

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symptoms synchronized with exercise intensity. Therefore, it can capture the symptom onset and progression across the different exercise intensities such as the start of the exercise, 1st ventilatory threshold, submaximal, or maximal intensity. This comprehensive evaluation helps differentiate between cardiovascular, respiratory, and metabolic diseases in children. For diagnosing exercise-induced bronchoconstriction (EIB) specifically, a submaximal exercise challenge test performed in a cooled (10°C) room is preferable to CPET, as it better mimics the environmental conditions that trigger EIB. Furthermore, the incremental exercise of the CPET is less suitable for diagnosing EIB as preferably submaximal exercise intensity is used (either heart rate 85-95% of the predicted heart rate or minute ventilation greater than 21 times forced expiratory volume in 1 s ($FEV_1$) for 4 consecutive minutes).

3.1.2. Assessing disease severity

CPET testing in children with respiratory diseases can help evaluate the severity of the disease, their functional capacity, gas exchange, and the presence of exercise-induced cardiopulmonary abnormalities. By measuring the VO₂peak, ventilatory efficiency, and oxygen saturation, CPET tests can help determine how far a patient can safely push their physical limits during regular sports activities, training, and pulmonary and cardiac rehabilitation. Additionally, it allows for the identification of gas exchange impairments, including abnormal ventilatory responses and exercise-induced hypoxia, which may indicate disease progression in patients with cystic fibrosis, bronchopulmonary dysplasia, or interstitial lung disease. In more severe cases, CPET findings can be used to assess the need for further interventions such as lung transplantation by objectively quantifying the patient's respiratory and cardiovascular limitations [23].

3.1.3. Prognostic test

The CPET test can be used as a prognostic test in the long-term management of children with respiratory disease by providing an objective and quantifiable measure of disease progression. In pediatric patients with cystic fibrosis, regular CPET assessments can allow for early detection of functional decline, enabling timely interventions to slow disease progression and optimize their treatment. Furthermore, CPET testing can aid in identifying patients at other risk for complications or hospitalizations by revealing abnormalities in their oxygen uptake and ventilatory efficiency. This risk stratification can support clinical decision-making, guiding the need for intensified monitoring or treatment. Furthermore, CPET can aid in preoperative and pre-treatment screening, particularly in candidates for lung transplantation or chemotherapy. By establishing a baseline of cardiopulmonary function, CPET helps identify patients at higher risk for perioperative complications and allows for personalized treatment planning to optimize outcomes

3.1.4. Monitoring test

For patients with dysfunctional breathing who receive physiotherapy and breathing exercises, the CPET test can be used to evaluate the therapeutic intervention's effectiveness. Furthermore, in patients with deconditioning, the CPET test can help as a motivational tool to objectify the progress of the physiotherapy. It also provides insights into the efficacy of specific medications potentially affecting the cardiorespiratory response (such as beta blockers) by assessing improvements in oxygen uptake and ventilatory response during exercise. In addition to guiding treatment adjustments, CPET can aid in preoperative and pre-treatment screening, particularly in candidates for lung transplantation or chemotherapy. By establishing a baseline of cardiopulmonary function, CPET helps identify patients at higher risk for perioperative complications and allows for personalized treatment planning to optimize outcomes.

3.2. Contraindications and safety considerations

As stated by Takken et al. [24] the absolute contraindications include active inflammatory heart disease, hepatitis, myocardial infarction, pneumonia, severe systemic hypertension for age, and acute orthopedic injury to an exercise muscle group. The aforementioned relative contraindications are severe left or right ventricular outflow obstruction, congestive heart disease, pulmonary vascular obstructive disease, severe aortic or mitral stenosis, ischemic coronary artery disease, cardiomyopathy, and several arrhythmia syndromes. While these latter conditions do not preclude CPET testing, they ask for close monitoring and individualized assessment.

Furthermore, children with a forced expiratory volume in 1 s below 70% of the predicted value or 20% below their individual baseline are at an increased risk of exacerbation, particularly in pediatric asthma patients. In such cases, CPET should be performed with caution. If lung function varies significantly, CPET may still be feasible, but it is crucial to have bronchodilators, such as salbutamol, readily available for symptom relief post-exercise.

Patients with a history of syncope should also undergo CPET with caution, and an evaluation for potential cardiac causes should be conducted before testing. To minimize risks, proper safety measures must be in place, including fall prevention strategies such as the presence of additional healthcare professionals to assist in case of collapse. In some cases, having a cardiologist (or a cardiologist in training) present can be beneficial to provide detailed real-time cardiac monitoring.

Oxygen desaturation is another critical factor to consider when determining a patient's suitability for CPET. A pulse oximetry reading below 85-90% indicates significantly reduced arterial oxygen partial pressure, as reflected by the oxygen dissociation curve, potentially leading to impaired tissue oxygenation. In such cases, a thorough reassessment of the indication for CPET is necessary to evaluate

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whether the test remains appropriate or if alternative assessments should be considered.

4. Methodology and protocols

4.1. Standard CPET protocols for children

CPET in children requires protocols tailored to their physiological characteristics, developmental stage, and cooperation levels. The two primary modalities used in pediatric CPET are the treadmill and cycle ergometer, each with distinct advantages and respiratory demands. Treadmill protocols are often preferred for younger children because walking and running are natural activities.

Treadmill testing elicits a higher ventilatory demand due to greater muscle involvement and weight-bearing activity, leading to a more pronounced respiratory response. However, variations in gait and coordination may affect reproducibility, and handrail support can influence workload assessment. In contrast, cycle ergometry, performed using ramp or incremental step protocols, offers more controlled workload increments and direct work rate measurements, but may impose a relatively lower respiratory demand. This modality is particularly advantageous for children with coordination difficulties or musculoskeletal limitations. Age-appropriate modifications – including adjustable equipment, smaller ergometers, and engaging motivational strategies – are essential to optimize test feasibility, ensure gradual increases in exercise intensity, and achieve valid, comparable CPET results in pediatric populations.

4.2. Equipment and calibration

Recently, van Hooren et al. [25] conducted an important study of the accuracy of commercially available CPET systems. Although this study did not specifically focus on pediatric usage of the equipment, its findings are important and applicable to this group. The study demonstrates significant differences in accuracy among various CPET systems when measuring respiratory variables such as minute ventilation (VE), breathing frequency (BF), oxygen uptake (VO₂), and carbon dioxide production (VO₂). Absolute error percentages ranged widely, with some systems performing consistently better than others, but overall, there was considerable variability in measurement accuracy.

The results indicated that portable CPET systems were not necessarily less accurate than stationary systems. Certain portable devices demonstrated accuracy comparable to their stationary counterparts, whereas others showed significantly lower accuracy. In addition, some systems showed considerable variability between sessions, which could impact longitudinal assessments.

The study emphasizes the critical role of proper calibration. In general, CPET systems perform better when calibrated with certified gases rather than relying solely on ambient air calibration [25]. The authors stress also the importance of a well-ventilated testing room since CO₂ can be easily build up in the testing rooms, especially when there

are several persons in the room (e.g. parents, siblings, and personnel).

The work by van Hooren et al. [25] underscores the importance of selecting and interpreting CPET results with caution. Users should be aware of the limitations of different systems, ensure proper calibration, and an intended use in children and adolescents. For example, when testing children the equipment should be sensitive to measure low minute ventilations (VE below 40 L/min). Also, calibration of the flow sensor using low airflows should be available in equipment intended for pediatric use.

4.3. Interpretation of CPET data in children

Several recent studies have developed reference values for pediatric CPET that are essential for the interpretation of respiratory response during exercise in children with chronic diseases. Older pediatric CPET reference values can be found elsewhere [26].

The study by Burstein et al. established normative values for 28 CPET-parameters using ramp cycle ergometry in children and adolescents 6–18-year-old [27]. It offers reference ranges for key parameters such as VO₂peak, ventilatory equivalents, dead space-to-tidal volume ratio, minute ventilation, respiratory rate, tidal volume, breathing reserve, PETO₂, PETCO₂, and VE/VCO₂ slope. These values provide a framework for interpreting CPET results, particularly in diagnosing and monitoring pediatric patients with respiratory diseases. The study emphasizes the importance of age, sex, and body size in establishing accurate benchmarks, aiding clinicians in detecting abnormal respiratory responses during exercise testing.

Griffith et al. provided age-specific reference values for VO₂ peak in children aged 6–18 years during treadmill testing [19]. Reference values for VO₂ peak/kg were reported as well as endurance time. However, no other respiratory parameters were reported.

The study by Amedro et al. reported among others, several respiratory efficiency parameters in 5–18-year-old children [17]. They reported the VE/VCO₂-slope, oxygen uptake efficiency slope (OUES), and maximum tidal volume, respiratory rate, breathing reserve, and ventilatory equivalent for CO₂ and O₂.

Poosala et al. [28] contributed with a study on pediatric CPET reference values. In children who were referred for exercise testing and without a history of cardiac/respiratory diseases were analyzed. The reported on the following respiratory parameters at peak exercise: breathing frequency, tidal volume, end-tidal CO₂, death space ventilation, oxygen saturation, VCO₂, VE/VO₂ and VO₂.

Rottermann et al. contributed by introducing outdoor CPET for preschoolers, making CPET more accessible and relevant in early childhood for diagnosing respiratory limitations [29]. These reference values allow for a more accurate interpretation of exercise-induced changes in lung function, helping clinicians to better monitor disease progression, adjust treatment plans, and optimize rehabilitation strategies in young pediatric patients with respiratory diseases.

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A recent study provided reference values for treadmill and cycle ergometer-based CPETs for children (6–18 years) living at altitude (1580 m to 2111 m above sea-level) [30]. This is important to consider, since altitude significantly influences exercise capacity in this age range.

In summary, these recent studies have established reference values for pediatric CPET in addition to the existing literature [26], and provide essential benchmarks for assessing respiratory function during exercise in children with respiratory diseases.

5. Clinical application of CPET in specific respiratory diseases

5.1. CPET and Dysfunctional breathing

Dysfunctional breathing (DB) is an umbrella term used to describe a collection of conditions where the normal biomechanical pattern of breathing is disrupted, resulting in dyspnea and associated respiratory and non-respiratory symptoms that cannot be explained by disease pathophysiology [31]. The prevalence of DB in asthma is disproportionately high (30%) compared to the overall prevalence which is estimated to be 5-10% [32]. DB can be caused or influenced by psychological and physiological triggers or a combination, and exercise is a frequent trigger for DB in children. Prevalent symptoms of DB during exercise besides breathlessness include chest tightness, pain, and dizziness, but the list is endless. Commonly in DB breathing frequency increases inappropriately quickly at low exercise intensities, while tidal volume remains unchanged or even decreases, in contrast to healthy children who first increase VT aligning with the production of CO₂, minimizing dead space ventilation. CPET will reveal this pattern by measuring VT in conjunction with VE and BF, and show a high VE/VCO₂-slope, indicating ventilatory inefficiency [33]. In exercise induced DB, this pattern may be interrupted by sighing and inspiratory gasps, resulting in an erratic breathing pattern and periodic spikes in ventilation that do not align with oxygen consumption needs. Although incidental sighing is a physiologic phenomenon in rest reducing bronchial tone, it should cease during exercise. Breathing in DB can be primarily driven by the chest rather than the diaphragm reflected by a lack of costal expansion. This predominant thoracic breathing and high reliance on the supportive breathing muscles during inspiration leads to dynamic hyperinflation and

inefficient ventilation, contributing to early sensation of dyspnea as well. Thoracic dominant breathing also leads to less effective gas exchange. This will be reflected in a higher-than-expected heart rate for the amount of work being done during exercise. CPET may show signs of ventilatory inefficiency (high VE/VCO₂ slope) and a lower OUES. Most subtypes of dysfunctional breathing lead to early fatigue and shortness of breath and in extreme cases to dizziness or collapse immediately post-exercise, but the underlying mechanisms can vary. Collapse during exercise is a clinical red flag prompting cardiac evaluation, as during exercise respiratory alkalosis is prevented by metabolic activity of the muscles.

CPET can investigate the above-mentioned specific breathing patterns, which can exist together or merge into each other. Specific symptoms and CPET variables for DB, Asthma, and CF are provided in Table 1.

Consider the multidimensionality of breathing and the complexity of DB diagnosis, variable intra- and inter-individually presentation. Due to the perceived stress, relying on a single criterion is inadequate. On the contrary, a multicomponent assessment is recommended, which includes a detailed history, physical examination, additional diagnostic procedures, and subjective variables.

Also, symptoms of DB overlap with symptoms of other pulmonary diseases such as asthma leading to missed diagnosis or symptoms being attributed to respiratory diseases. CPET has been put forward as a tool to diagnose DB, as it can rule out cardiac, respiratory, metabolic, and organic pathology [34].

In conclusion, CPET can provide objective measurements which can identify and disentangle aberrant breathing patterns compatible with DB, when clinical evaluation of DB is inconclu- sive. This can pave the way for targeted breathing technique therapy.

5.2. CPET and EILO

Exercise-Induced Laryngeal Obstruction (EILO) is a common but under-recognized cause of exertional dyspnea in both children and young adults, arising during high-intensity exercise. EILO is caused by a narrowing of the laryngeal structures during inspiration, which normally opens during exercise. The larynx may obstruct at the glottic or at the supraglottic level, which may induce glottic narrowing. Symptoms such as dyspnea, not being able to inhale completely, chest or throat tightness, noisy breathing, stridor, or sudden chocking may

|Symptoms|Dysfunctional breathing|Asthma|CF|| |---|---|---|---|---| |Stress influence|++|±|±|–| |Wheezing|–|±|±|±| |Stridor|±|±|±|–| |Salbutamol bronchoprotection during exercise|–|++|–|–| |CPET variables||||| |$paCO_{2}$ at rest|normal/low|normal|normal|normal/high| |$O_{2}$ saturation|normal|normal|normal|normal/low| |$paCO_{2}$ at peak exercise|typically low|normal|normal|normal/high| |$VE/VCO_{2}$ slope|typically high|normal/high*|normal/high*|normal/low|

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appear. However, not all patients with EILO experience or report these typical symptoms and there is an overlap in symptoms with other exercise induced respiratory disorders. EILO prevalence among the general adolescent population is 5-8% [35], while prevalence of EILO among adults with asthma ranges from 13% to 47% [36]. In their retrospective study, Walsted et al. [37] showed that, 12-31% of the children and adolescents (age 8-24 years) with EILO, simultaneously had asthma.

Symptoms of ElLO can mimic asthma and DB, leading to misdiagnosis and ineffective treatment. The exercise-induced airflow constraint in patients with ElLO usually occurs during peak exercise when the ventilation requirement is high, while EIB usually peaks after exercise and DB at the start of exercise. ElLO has been classified as an extra-thoracic form of dysfunctional breathing [38], and signs of dysfunctional breathing may prelude ElLO symptoms. Continuous laryngoscopy during exercise (CLE) is considered the reference standard for diagnosing ElLO [16]. During this test, the larynx is continuously visualized during exercise, while trying to provoke symptoms by increasing exercise intensity to maximal intensity. An ECT performed to assess EIB does not always provoke ElLO as it is submaximal. A CLE test can be performed in conjunction with a CPET as both tests are maximal and can reveal and disentangle the causes and sequence of events leading to symptoms.

5.3. CPET and Cystic fibrosis (CF)

CPET has for decades been the designated tool to monitor disease progression in people with CF [39].

Consistently, VO₂peak has shown prognostic significance for mortality and risk of hospitalization. CF is characterized by chronic airway inflammation, mucus retention, and airway remodeling, reducing the efficiency of the ventilation. Moreover, in CF patients, muscle atrophy and weakness are prevalent and associated with reduced aerobic and anaerobic capacity. Patients with severe CF may therefore experience symptoms and discomfort when attempting to perform a maximum test as it induces mucus mobilization causing cough and large airway obstruction. Since the introduction of neonatal screening programs and novel disease changing medication, the burden of the disease in the pediatric age group has declined, facilitating the performance of exercise challenge tests [40]. Some aerobic fitness variables other than VO₂peak that can be acquired from submaximal exercise tests and provide prognostic significance have been proposed; VE/VO₂ and VE/VO₂ at the ventilatory threshold, reflecting the inefficiency of ventilation, were associated with the time to a first exacerbation [41]. This could be relevant for clinical decision making, as impaired ventilatory efficiency can be present in patients with CF with normal lung function. This confirms the high sensitivity of exercise testing in detecting early lung disease compared with unprovoked routine spirometry.

The OUES has been suggested as a metric of aerobic fitness in persons who are not able or allowed to perform a maximal effort. However, the validity of the OUES as

a submaximal measure of VO₂peak in conditions like CF has been questioned, because of low correlations with VO₂ peak and other aerobic fitness measures [9,10], as well as the observation that the OUES behaves nonlinearly during progressive exercise in CF-patients [10].

5.4. CPET and asthma

Asthma is the most common chronic disease in children worldwide, and its symptoms may limit the patient's ability to be physically active, impairing quality of life. In 1980, the WHO stated that functional capacity explorations, such as CPET, best reflected the impact of chronic disease on health-related quality of life [42].

Although limited data about cardiopulmonary fitness in large cohorts of children with asthma are available, a recent study found that cardiopulmonary fitness in children with asthma was moderate but significantly reduced in comparison with healthy children [17]. VO₂ peak was markedly impaired in one-fourth of children with asthma, which was four times higher than in a matched control group (24% vs $6\%$, $p<0.01$). A decreased VO₂ peak was associated with female gender, high BMI, low ventilatory threshold, and low FEV₁. Nearly one-third of children with asthma had low ventilatory threshold values (<55%), which was three times higher in the asthma group than in a matched control group (31% vs 11%, $p<0.01$), suggesting an increased risk of physical deconditioning. Children with asthma were prone to ventilatory inefficiency during exercise, which may be due to dynamic hyperinflation, as in the majority of children bronchoconstriction starts during exercise (Breakthrough EIB) and not after exercise, as is often assumed [43]. In female asthmatic children with age VO₂ peak decreased significantly faster than in controls, whilst no difference was observed in male subjects [17]. The reference exercise test for asthma is a submaximal exercise challenge test preferably on a treadmill under standardized conditions, which aims to rapidly increase ventilation to provide a hyperosmotic stimulus to the lining of the airways. In summary, CPET can identify the asthmatic children most at risk of physical deconditioning contributing to targeted cardiopulmonary rehabilitation.

6. Emerging technologies and trends

6.1. Portable devices & wearable technology

Several portable CPET devices are commercially available. However, they are not suited for home-monitoring of respiratory function during exercise because of the costs of a unit and wearing a unit might be cumbersome for children. Recent developments of inexpensive devices such as the Calibre™ can make home or field-monitoring affordable [25].

In the last couple of years several wearable sensors for measuring breathing patterns during exercise have been developed. The general intended use of those wearables is the monitoring of respiratory rates during sports activities. Those sports respiratory wearables are incorporated in shirts or in flexible chest bands [44]. Examples are the Tyme

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Wear™ [45], Hexoskin™ smart shirts [46] and the Breathpal (https://breathpal.nl) chest straps. Some of these systems even provide a value for the VE, ventilatory thresholds and VO2 peak and other metabolic parameters during exercise. However, validation studies for measuring metabolic parameters during exercise in children are warranted.

Wearable technology can also be used for therapeutic purposes in dysfunctional breathing in children and adolescents, particularly through the use of real-time, individualized respiratory feedback during exercises. Smithy et al. [47] presents a laboratory-based real-time feedback system using opto-electronic plethysmography (OEP). This system visualizes thoracoabdominal coordination during breathing by displaying volume changes and phase angles between the ribcage and abdomen via Konno - Mead loops. This approach led to significant improvements in breathing synchrony and reductions in respiratory rate. Another example is the Wearable Breathing Trainer (WBT), which is designed to enhance respiratory symptom monitoring and physical therapy assessment in children with dysfunctional breathing [48]. Utilizing textiles integrated with sensors, this device measures key respiratory parameters and provides real-time haptic and visual feedback during breathing exercises. This technology may support children to actively engage in their own therapy. The integration with a mobile application enhances motivation and adherence, allowing both patients and healthcare providers to have access to data on symptom progression and treatment efficacy and potentially bring therapy toward the home-setting.

6.2. Integration with other diagnostic modalities

Respiratory Rate Recovery Time (RRRT) is a physiological marker that has the potential to enhance asthma monitoring and management, particularly in children, as they are physically active in play and sports [49]. Measured using continuous raw ECG data, the RRRT quantifies the time needed for respiratory rate to return to baseline after physical exercise. RRRT is significantly prolonged in children with uncontrolled asthma, with recovery taking almost twice as long compared to those with controlled asthma. This delay in recovery may reflect bronchoconstriction severity, which in children usually starts during or directly after exercise and consequent impaired ventilation. This makes the RRRT a promising and reproducible indicator of asthma control even more so because children primarily rely on respiratory rate adjustment after exercise, as opposed to tidal volume for adults. The integration of wearable home-monitoring devices could enable real-time, longitudinal tracking of RRRT [50,51]. Future advancements in automated detection methods or Artificial Intelligence could further refine RRRT measurement and analysis.

6.3. Artificial intelligence and respiratory diseases

The addition of (at home) CPET data to Artificial Intelligence (AI) models for pediatric respiratory disease, such as asthma and CF, may offer additional insight into

future exacerbation risk, lung development, and analysis of a combination of complex clinical data. Al is emerging as a powerful tool in pediatric respiratory disease management, offering new possibilities for predicting pediatric exacerbations [52]. Al-driven models can analyze complementing information including anamnesis, literature-based risk factors, and physiological data from CPET and additional lung function to provide a better understanding of the complex factors influencing disease control [53]. These models have the potential to enhance early detection of personal signals preceding exacerbations, addressing a gap in the current clinical practice. Potential applications include a personal risk dashboard for self-management, a risk dashboard for pediatricians to optimize outpatient care, and an eHealth monitoring tool for continuous tracking of asthma control. Additionally, given its success in predicting exacerbations in CF [54], integrating AI with CPET data and physiological and physical activity data acquired from home diagnostics may offer new insights into asthma control and future risk.

In addition, a recent paper by Kleinhendler et al. showed the possibilities of ChatGPT to perform the interpretation of CPET data in adult patient [55]. The authors showed that ChatGP models 3.5 and 4.0 were able to accurately classify tests into normal, cardiovascular limitation, pulmonary limitation, or other. Furthermore, Zignoli et al. showed the application of their AI model Oxynet to predict the first and second ventilatory thresholds of CPET. However, this analysis was performed on adult CPET data and CPET data of patients with lower aerobic fitness yielded lesser performance. Increased variability of CPET data with increasing age in children and lower aerobic fitness in children with respiratory conditions complicates AI application. This research was continued with a focus on explainability of the model, improving its practicality and usability [56]. Thus, this method may hold the potential to perform the interpretation of CPET data [57] when using extensive pediatric and adult datasets. Since the power of AI models is evolving rapidly, we think that CPET interpretation using AI will develop very rapidly by helping in combining clinical available data with CPET and assessing temporal CPET.

Thus, AI technology may have the potential to complement current respiratory care, with future research focusing on the effect of complementary AI analysis on long-term outcomes.

7. Challenges and limitations in pediatric CPET

7.1. Technical and logistical challenges

There are some pediatric-specific issues in test execution. One of the main challenges is effort and motivation variability. Young children may struggle with giving a maximal 'cardio-pulmonary' effort during CPET due to lack of motivation, fear, unfamiliarity with the test environment, or a lack of leg muscle strength. Unlike adults, their ability to understand and follow pacing instructions can vary, which may lead to submaximal of suboptimal test results. Some children will find it hard to keep a constant cadence throughout the test. A variability in cadence will also result in a higher variability in the gas-

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exchange data. Encouragement and engaging protocols (e.g. visual feedback or gamification) can help improve compliance. Applications for exergames are already available.

Further, size-appropriate equipment and protocols are required. Standard CPET equipment (e.g. ergometers, masks, and mouthpieces) is often designed for adults and may not fit smaller children properly, leading to discomfort and potential measurement inaccuracies. Treadmills and cycle ergometers must also accommodate lower body weight and shorter limb lengths to ensure valid results. Rottermann et al. [29] developed an outdoor test protocol to test young (preschoolers) without the need to use a treadmill of cycle ergometer.

As stated above, children have a unique physiological response to exercise. The higher breathing frequencies, lower tidal volumes, and a lower stroke volume compared to adults will influence CPET variables such as VO₂-kinetics, ventilatory thresholds, and heart rate responses. Published age- and sex-specific reference values are essential to accurately interpret pediatric CPET results and distinguish between normal physiological responses and pathology (see also 7.2).

7.2. Interpretation challenges

A review by Tomlinson and colleagues showed that there is a high variance in the use of reference values among researchers working with children and adults with CF [58]. The use of different reference values sets impedes the comparability of results between studies. Waterfall and colleagues have shown the risk of applying different reference values set to a CPET performed in the same pediatric patient [59]. This can lead to different conclusions. We want to stress the importance of using uniform reference sets among centers in the same geographic regions where this is applicable.

Another challenge is how to account for differences in growth and development among children. Children with pulmonary disease might have a growth retardation (lower weight, smaller height) compared to peers. The current recommendation is to evaluate both absolute (L/min) and relative (ml/kg/min) parameters as well as an allometrically scaled factor for the specific population, and as a percentage of predicted with stating the explicit equation(s) [58].

8. Clinical practice recommendations

8.1. Summary of updated guidelines

The most recent guidelines on pediatric exercise testing were published by the Brazilian Association for Cardiology [60]. The guidelines are mostly focused on patients with heart disease. Many of the methodologies in CPET are comparable for heart and lung patients. Furthermore, many children with congenital heart disease will often experience exercise-induced dyspnea, and testing can help to differentiated between cardiac and pulmonary limitations.

Also, the British Association for Respiratory Technology & Physiology (ARTP) has published a guideline on exercise testing including a section on pediatric exercise testing [61]. Both guidelines are helpful in optimizing CPET testing in children in

addition to previously published guidelines like the ERS guide- line on CPET in chronic lung diseases [62].

8.2. Recommendations for implementation in clinical practice

For the implementation of CPET in pediatric respiratory disease, we recommend the following:

Always perform baseline spirometry. Assess FEV₁, FVC, and FEV₂/FVC ratio before exercise to determine resting pulmonary function. When testing an asthmatic child, consider pre- and post-bronchodilator spirometry to evaluate reversibility.

Conduct post-exercise spirometry (FEV₁ at 1, 3-, 5-, 10-, and 15-min posttest) to assess for EIB. Cool, dry environments can trigger EIB. If triggering EIB is the aim of the test, consider indoor testing in a controlled room with cold dry air.

Monitor oxygen desaturation using pulse oximetry throughout the test, especially in conditions like CF or ILD.

Record flow-volume loops during CPET.

9. Conclusion

CPET is an essential tool in pediatric respiratory disease management, providing comprehensive insights into ventilatory, cardiovascular, and metabolic limitations beyond static lung function tests.

Recent advancements in CPET include novel respiratory parameters to, such as the oxygen uptake efficiency slope, and tidal volume to inspiratory time ratio, enhancing clinical assessment.

Age-specific reference values are critical for accurate interpretation, with recent studies improving normative data for children across different modalities and environments, including high-altitude populations.

Standardized CPET protocols for children should consider developmental differences, with treadmill tests eliciting higher respiratory demand and cycle ergometry offering better workload control.

CPET plays a pivotal role in identifying disease progression and treatment response, particularly in conditions like asthma, cystic fibrosis, and interstitial lung disease.

9.1. Implications for future practice and research

Greater standardization of CPET protocols and reference values is needed to improve comparability across clinical centers. Machine learning and artificial intelligence applications may enhance CPET data interpretation, improving diagnostic precision and personalized treatment strategies.

More research on non-traditional CPET metrics in pediatric populations could refine assessments of respiratory dysfunction and exercise intolerance. Expanding CPET accessibility to younger children and those with severe disease through innovative approaches like outdoor testing or wearable technology may improve clinical utility.

Longitudinal studies linking CPET parameters to long-term health outcomes could further establish its prognostic value in pediatric respiratory disease management.

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10. Expert opinion

CPET is increasingly recognized as a valuable tool in pediatric respiratory medicine, providing insights into functional impairments that static lung function tests cannot detect. The advances in CPET protocols and the incorporation of novel parameters such as the oxygen uptake efficiency slope (OUES) and tidal volume to inspiratory time ratio (VT/Ti) may provide additional insights into the diagnosis, prognosis, and management of pediatric respiratory disease. However, while these advancements show promise, their integration into routine clinical practice remains inconsistent due to logistical, technological, and interpretative challenges.

10.1. Impact on real-world outcomes

The implementation of CPET in pediatric respiratory medicine has the potential to refine disease classification, enhance personalized treatment strategies, and improve the monitoring of therapeutic interventions. For example, in CF, CPET can detect early declines in ventilatory efficiency before they manifest in traditional spirometric measures, allowing for earlier interventions. In asthma, CPET can differentiate between exercise-induced bronchoconstriction, dysfunctional breathing, and deconditioning, leading to more targeted treatment strategies. The challenge, however, lies in the accessibility of CPET, as it requires specialized equipment, trained personnel, pediatric expertise, and age-specific reference values, which are not universally available. Adoption into routine clinical practice is hindered by these resource constraints, necessitating broader dissemination of CPET expertise and cost-effective alternatives such as portable monitoring devices.

10.2. Key areas for improvement

One of the primary barriers to the widespread clinical use of CPET is the lack of standardization in protocols, data interpretation, and reference values. While significant progress has been made in developing pediatric-specific reference norms, variability between laboratories remains a concern. Harmonization of methodologies and the development of universally accepted reference standards should be prioritized to ensure comparability of results across institutions. Technological advancements, including machine learning-driven analysis and interpretation of CPET data, could aid in reducing interobserver variability and improving diagnostic accuracy. Furthermore, expanding CPET accessibility through the development of field-based exercise testing protocols or wearable technology could bridge the gap for patients who lack access to specialized centers.

10.3. Future research potential

CPET research holds considerable promise, with potential applications extending beyond traditional respiratory disease diagnostics. For instance, emerging evidence suggests that CPET-data like VO₂peak could serve as a biomarker for systemic inflammation and cardiovascular dysfunction in pediatric chronic diseases beyond the respiratory domain.

Additionally, AI algorithms could facilitate automated pattern recognition in CPET data, enabling more precise identification of subclinical abnormalities. The integration of CPET with other physiological monitoring techniques, such as continuous laryngoscopy for ELO or wearable biosensors for at-home exercise assessment, could further expand its clinical utility.

10.4. Long-term evolution of the field

Over the next five to 10 years, CPET is likely to become more widely implemented in pediatric pulmonology, particularly as technology advances and standardization efforts gain traction. Machine learning-based CPET analysis may become an integral part of diagnostic workflows, reducing reliance on expert interpretation. Wearable respiratory monitors and low-cost portable CPET systems may enable longitudinal tracking of respiratory function outside the laboratory setting, enhancing real-world disease monitoring and management. Despite these advancements, challenges in cost, accessibility, and training will remain key hurdles to overcome. However, with continued investment in research and innovation, CPET is poised to become a cornerstone of precision medicine in pediatric respiratory care.

Funding

This paper was not funded.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

(In compliance with the International Committee of Medical Journal Editors (ICM) recommendations, the authors provide the following disclosure regarding the utilization of AI services in this work: ChatGPT 4.0 was used for spelling and language correction.

ORCID

Tim Takken ID http://orcid.org/0000-0002-7737-118X Tamara Ruuls ID http://orcid.org/0009-0004-6856-8468 Mattienne Van der Kamp D http://orcid.org/0000-0003-3053-2342 Marco van Brussel ID http://orcid.org/0000-0003-1837-0643 Erik H.J. Hulzebos ID http://orcid.org/0000-0003-3149-3998

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