INTRODUCTION

Cystic fibrosis (CF) is a genetic disease caused by dysfunction of the CF transmembrane conductance regulatory (CFTR) protein, which results in the accumulation of viscous mucus in several organs^1,2. The respiratory system is particularly affected and often impacted by mucus, whereby the ensuing complications can lead to reductions in both life expectancy and health-related quality of life (HRQL)². The treatment approach involving a combination of three CFTR modulators (elexacaftor, tezacaftor, ivacaftor) is causal, easy to administer and has shown very promising results. Most importantly, this treatment approach has been shown to significantly improve lung function, as evidenced by an improvement in forced expiratory volume in one second (FEV₁)^3,4.

Nonetheless, the impact of this combination regimen on respiratory physiology needs to be investigated further, since lung function has so far mostly been evaluated by spirometry. For this reason, the present study investigated adult cystic fibrosis patients after (follow-up) the initiation of triple therapy with elexacaftor/tezacaftor/ivacaftor. Spirometry, full body plethysmography, and the assessment of the diffusion capacity were performed in all subjects, in line with previously established recommendations^5-7.

METHODS

This retrospective single center study investigated adult cystic fibrosis patients after the initiation of triple CFTR therapy between July 2020 and March 2021 to explore the change of body plethysmography parameters together with measurements of exercise capacity and quality of life.

The two-tailed t-test for dependent samples with Bonferroni correction was used to compare outcomes between the two visits. Primary endpoint was the change in effective specific airway resistance (sRAWeff). Additional spirometry and body plethysmography parameters, 6-minute walking test and the Cystic Fibrosis Questionnaire–Revised (CFQ-R) served as secondary outcomes. Pearson’s correlation coefficient (r) was calculated for changes in sRAWeff, residual volume (RV), FEV1, the CFQ-R respiratory domain, and the 6-minute walking distance (6MWD).

RESULTS

A total of 38 patients were included: 20 females (52.6%); mean age 37.2 ± 11.6 years; body mass index 21.6 ± 5.1 kg/m²; FEV₁ 60.2 ± 20.3; intrathoracic gas volume (ITGV) 147 ± 33; residual volume (RV) 169.9 ± 59.9; total lung capacity (TLC) 112.8 ± 20.4 and sRAWeff: 282 ± 161, each percent predicted; 6MWD 583.1 ± 90.8 m; and CFQ-R respiratory domain 62.6 ± 18.3 points. Phe508del mutations were homozygous in 50% (n=19). The mean time between the compared visits was 16 ± 4 weeks, the mean time between the first visit and therapy initiation was 4 ± 3 weeks. In one patient, the first visit was seven days after the first dose of triple therapy. Time to the follow-up visits after triple therapy initiation was 13 ± 2 weeks.

The main results are summarized in Table 1 and are as follows: The analysis shows significant improvements in FEV₁ and vital capacity (VC). Therefore, the Tiffeneau-Index (FEV₁/VC) only showed a minor increase from 59 ± 14% to 62 ± 13%. Hyperinflation (RV) and the primary outcome (sRAWeff) significantly improved such as exercise capacity and CFQ-R. sRAWeff showed a strong significant association with an improvement in exercise capacity (6MWD) (Pearson’s r=0.593; 95% CI: 0.296–0.786, p<0.001) and FEV₁ (Pearson’s r=0.560; 95% CI: 0.292–0.746, p<0.001) while all other parameters did not show significant correlations.

DISCUSSION

The additional assessment of sRAWeff in CF treatment offers three potential advantages: Firstly, sRAWeff measurements occur during quiet breathing, are directly assessed by breathing loops and therefore independent from the forced respiratory maneuvers. This has proven to be advantageous in children and other patients with limited ability to perform spirometry or with non-reproducible spirometry results. Secondly, sRAWeff measurements address the interplay of airway obstruction and lung volume⁷. Thus, sRAWeff is suggested to represent a flow-standardized, volume-related work of breathing⁷. It is therefore conceivable that changes in sRAWeff are closely related to exercise capacity, as assessed by the 6MWD and as suggested by the present data.

Based on these findings, CFTR modulator treatment has the potential to improve both airway obstruction and hyperinflation, and these intricate lung function improvements are not fully detectable by spirometric measurements alone. However, in view of the current finding, improvements in FEV₁ are suggested to reflect two different changes in respiratory mechanics: 1) an improvement in airway obstruction, 2) a recruitment in lung volumes as a consequence of an improved VC at a cost of a reduced RV (mucus clearance).

These observations also confirm previous radiological findings that showed areas with reduced mucus impaction following treatment and significantly augment research that identified the peripheral lung as an important site of therapy effect^8,9.

Therefore, thirdly, the assessment of sRAWeff and RV is another method to easily determine if mucus is impacting the respiratory tract. Since the aim of CFTR modulation is to liquefy mucus and to reduce its amount, the success of CFTR modulation therapy might be enhanced when treatment is supplemented with intensified airway clearance techniques, which should be investigated in future studies.

CONCLUSIONS

Triple CFTR modulation therapy and airway clearance techniques improve airway resistance and pulmonary gas trapping. This is reliably assessed by measuring sRAWeff, which is associated with exercise capacity. Future studies should incorporate body plethysmography to understand their relationship, especially if FEV₁ does not improve after therapy initiation.