Cystic fibrosis (CF) is an autosomal recessive disease most found in Caucasian populations.1 The most prevalent mutation is F508del, of which 88% of patients have at least one copy.2 F508del is classified as a class II mutation, which are characterized by a misfolding of the CFTR protein making it unable to reach the cell surface.3 During the last decade, research has been focusing on the underlying dysfunction of the CFTR gene using new drugs, so called CFTR modulators. The highly effective modulator combination elexacaftor/tezacaftor/ivacaftor (ETI) was approved in Spain for people with CF (pwCF)>12 years in 2020, and the age of use was reduced to over 6 years old from September 2022.4

The meta-analysis done by Kapuni et al. highlights a substantial increase in forced expiratory volume (FEV1) in both children and adults in multiple studies.3 It was also found to increase quality of life of patients, reduce pulmonary exacerbations and increase weight gain.3 Although FEV1 has been considered as the best predictor of mortality in both CF children and adults, it should not be forgotten that CF is a multisystemic disease affecting other systems such as the cardiovascular system as well as the peripheral muscles.5,6 Adding a test for aerobic fitness would enable to have a complete picture for the prognosis. Peak oxygen consumption (VO2 peak), which is measured during a cardiopulmonary exercise test (CPET), is the main parameter in the evaluation of aerobic capacity and has been found to be a good predictor of survival in pwCF.7,8 Patients with lower VO2 peak rates showed a 4.9-fold increased risk for a fatal outcome.8

As of today, only a few studies have measured aerobic fitness with CPET in patients under ETI treatment, showing a clinical improvement9,10 or no effect.11

Data on treatment response on exercise capacity after initiation of ETI is still quite scarce. Therefore, the general objective of this study was to assess the evolution of aerobic capacity of children before and during treatment with ETI in real-life conditions. A second objective was to assess if those same variables would be affected by a previous CFTR modulator treatment.

Our hypothesis was that ETI would not improve aerobic capacity in patients with CF although an increase could be observed in the pulmonary function. Also, that the difference of the variables over time would be lower in patients which already received a CFTR treatment previously.

The present study evaluated the effects of an ETI treatment on exercise capacity in children with CF in real life conditions. Few published data exist on the impact of new modulators on cardiorespiratory fitness in pwCF, particularly with ETI and in children of our age range. This study also examined the possible difference in response between patients who had received previous CFTR modulator therapy and those who didn’t. The hypotheses were that ETI would not improve cardiorespiratory fitness although an increase could be observed in the pulmonary function. Also, the difference over time would be lower in patients who had already received a CFTR treatment previously.

No improvements were observed in VO2 peak, the main parameter for evaluating cardiorespiratory fitness. There were also no significant improvements when separated into modulator-naive patients and patients with previous CFTR treatment. Previous research has also investigated the impact of CFTR modulators on VO2 peak (ml/kg/min) in pwCF and conclusions are quite different. Ahmed et al. observed no significant difference in VO2 peak in a cohort of 19 adolescents, 4–8 months after treatment.19 They also found no significant differences when splitting the group into naive and previously treated patients. Similarly, Gur et al. found no significant improvements in VO2 peak three months after the initiation of ETI.20 Wilson et al. studied the impact of lumacaftor/ivacaftor on exercise tolerance in pwCF compared to patients on placebo and found no significant improvement in VO2 peak.11 However, some studies observed improvements in VO2 peak.9,10,21,22 Philipsen et al., in a study involving 229 CF patients aged 12 and older, found significant improvements in VO2 peak (+0.6ml/kg/min, 95% CI (0.1–1.1)) and other cardiopulmonary variables after one year of ETI treatment.21 Causer et al. also showed an improvement in peak VO2 with 6 weeks of ETI treatment in three adolescents with CF.9 They explained that those with more severe lung disease and lowest fitness levels had the greatest improvements. Studies using second generation CFTR-modulator treatment such as ETI also found improvements in VO2 peak after 1 year and 2 years of treatment.10,22 In our study, exercise capacity did not improve despite an improvement in lung function. Our patients have mild lung function impairment, which may influence the results; however, it is possible that patients with severe lung disease experience ventilatory limitations during exercise, reaching a respiratory reserve close to 0, and may see improvements following the use of the modulator.23

To determine if CPET was done maximally, a VO2 plateau is mostly looked for, which is difficult to obtain in healthy populations and even harder in pwCF. Therefore, secondary variables such as the respiratory exchange ratio (RER) help to determine a maximal effort. An RER of 1.1 or higher during CPET is a commonly accepted criterion indicating maximal effort. For children with CF it is set at 1.05. In this case, a significant increase in RER was observed from T1 (0.98 (0.08)) to T3 (1.03 (0.08)) in the whole cohort. RER is getting closer to 1.05, meaning that the patients are closer to performing maximally during exercise testing. All test were done at 85% of maximum heart rate at all three timepoints during this study.

A decrease in VE/VO2 is generally a positive indicator of respiratory efficiency and overall fitness, meaning that the body is becoming more efficient at extracting and utilizing oxygen.24 Unexpectedly, in this case, an increase in the VE/VO2 was observed in the group that had previous treatment, which is the opposite of what was found by Philipsen et al. and Gur et al. for example.20,21 This unexpected result could simply be explained by the small sample number, but an explanation could also be found at peripheral muscle level and more precisely at the endothelial cells where CFTR also plays a role.9 Adequate physical activity may play a more significant role in overall improvements than enhancements in lung function and the better functioning of the CFTR, highlighting the importance of a correct dose of physical exercise rather than focusing solely on pulmonary function improvements.

Improvements were also observed in BR in the whole cohort and in the patient group that received previous treatment. Ahmed et al. also found improvements in BR after 4 to 8 months on ETI treatment, particularly un modulator-naive patients.19 A low BR and low VO2 peak are suggested to be related to respiratory pathologies.13 As CF progresses, it limits ventilation and therefore, also limits exercise capacity.23 BR could be used as marker to follow the progression of CF.

As expected, lung function improved with ETI. Significant improvement in FEV1 was found in the whole cohort and in the group with no previous treatment. There are few studies that have investigated this parameter in real life conditions and in this age group, but under different settings, similar results were found in previous research.19–21,25,26

In summary, cardiorespiratory fitness depends on central factors (heart and lungs) and peripheral factors (muscular bioenergetics). Although our patients show improved pulmonary function following the initiation of ETI, their baseline impairment is mild. Therefore, their exercise intolerance is primarily due to muscular bioenergetic deficiencies.27 Addressing muscular alterations requires more time and potentially the integration of a stimulus, such as appropriately tailored high-intensity physical exercise.28

To assess the impact of ETI treatment on quality-of-life, the CFQ-R questionnaire was used. In this study a significant improvement was found in three domains for the whole cohort; emotion, eat and respiratory. Same improvements were also found in the modulator-naive group. McNally et al. for example, assessed quality of life over 1-year ETI treatment in 117 pwCF (12 years and older) in real-world conditions, showed a 14.2 points (95% CI, 11.3, 17.2) improvement for the respiratory domain.29 The responses can vary depending on the severity of the disease, where pwCF that are more severely affected have a bigger room for improvement. It needs to be mentioned this study was done in children and that age can play a major role in the perception of certain aspects, which could explain why the emotional domain improved in this case. Generally, it seems that the respiratory domain benefits the most of the ETI therapy.

Functional capacity was assessed using the 30CST, stair climb test and 10MWT. The whole cohort improved in all of them. Gur et al. found a significant improvement in the 6MWT but mentions that firm conclusions cannot be drawn to small sample size.20 Aubriot et al. found improvements in the 1STST but no improvements in the 6MWT.30

Several studies have shown improvements in BMI which could be explained by an improved nutritional status.9,20 A better functioning of the CFTR protein would lead to better pancreatic function and improved digestion and absorption of nutrients.9,20 In this study, despite good adherence to the Mediterranean diet, no significant improvements were observed regarding BMI – for –age – z-score, body fat and lean mass percentages. These results may be related to the measurement and comparison of these parameters in absolute value, instead of using BMI – for –age – z-score.

There are some limitations to be considered in this study. The main limitation is the small sample size. Especially when separated into two subgroup “modulator-naive” and “previous CFTR treatment”, where the “previous CFTR treatment” group consisted of only nine patients. Additionally, the lack of randomization may have introduced selection bias, potentially affecting the comparability of groups and the generalizability of the findings.

The strength of this study is that is the first study to measure exercise capacity in children 6–11 years old under ETI treatment in real life conditions.

This study confirms that there is a beneficial effect of ETI on lung function in children 6–11 years old with pwCF. However, those improvements were not translated to cardiorespiratory fitness parameters even though patients increased physical activity. More research is needed to understand the other factors that can play a role in exercise capacity such as muscle oxidative capacity.

M.P.R.: Methodology, Writing-Original Draft, Formal analysis.

M.B.: Formal Analysis, Investigation, Data Curation, Writing-Original Draft.

P.F.G.: Clinical trial sample recruitment, Resources, Writing-Review & Editing, Funding acquisition.

C.M.G.: Methodology, Writing-Review & Editing.

A.M.T.: Clinical trial sample recruitment.

A.L.N.: Methodology, Writing-Review & Editing.

M.R.V.: Clinical trial sample recruitment.

M.R.: Investigation, Formal analysis, Data Curation, Writing-Review & Editing.

V.S.S.: Conceptualization, Methodology, Supervision, Funding acquisition, Writing-Review & Editing, Project administration.

Margarita Pérez-Ruiz, Alejandro López-Neyra and Verónica Sanz-Santiago have received speaking fees from Vertex Pharmaceuticals®.