BACKGROUND: Physical activity is a crucial demand on cystic fibrosis treatment management. The highest value of oxygen uptake (VO2peak) is an appropriate tool to evaluate the physical activity in these patients. However, there are several other valuable CPET parameters describing exercise tolerance (Wpeak, VO2VT1, VO2VT2, VO2/HRpeak, etc.), and helping to better understand the effect of specific treatment (VE, VT, VD/VT etc.). Limited data showed ambiguous results of this improvement after CFTR modulator treatment. Elexacaftor/tezacaftor/ivacaftor medication improves pulmonary function and quality of life, whereas its effect on CPET has yet to be sufficiently demonstrated. METHODS: We performed a single group prospective observational study of 10 adolescent patients with cystic fibrosis who completed two CPET measurements between January 2019 and February 2023. During this period, elexacaftor/tezacaftor/ivacaftor treatment was initiated in all of them. The first CPET at the baseline was followed by controlled CPET at least one year after medication commencement. We focused on interpreting the data on their influence by the novel therapy. We hypothesized improvements in cardiorespiratory fitness following treatment. We applied the Wilcoxon signed-rank test. The data were adjusted for age at the time of CPET to eliminate bias of aging in adolescent patients. RESULTS: We observed significant improvement in peak workload, VO2 peak, VO2VT1, VO2VT2, VE/VCO2 slope, VE, VT, RQ, VO2/HR peak and RR peak. The mean change in VO2 peak was 5.7 mL/kg/min, or 15.9% of the reference value (SD ± 16.6; p= 0.014). VO2VT1 improved by 15% of the reference value (SD ± 0.1; p= 0.014), VO2VT2 improved by 0.5 (SD ± 0.4; p= 0.01). There were no differences in other parameters. CONCLUSION: Exercise tolerance improved after elexacaftor/tezacaftor/ivacaftor treatment initiation. We suggest that the CFTR modulator alone is not enough for recovering physical decondition, but should be supplemented with physical activity and respiratory physiotherapy. Further studies are needed to examine the effect of CFTR modulators and physical therapy on cardiopulmonary exercise tolerance.

Department of Paediatric Infectious Diseases University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Pulmonology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Pulmonology University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Sports Medicine and Rehabilitation St Anne's University Hospital and Faculty of Medicine Masaryk University Brno Czech Republic

Faculty of Medicine Masaryk University Brno Czech Republic

Institute of Biostatistics and Analyses Ltd and Faculty of Medicine Masaryk University Brno Czech Republic

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Cerny FJ, Pullano TP, Cropp GJ. Cardiorespiratory adaptations to exercise in cystic fibrosis. Am Rev Respir Dis. 1982;126(2):217–220. PubMed

Thin AG, Dodd JD, Gallagher CG, Fitzgerald MX, Mcloughlin P. Effect of respiratory rate on airway deadspace ventilation during exercise in cystic fibrosis. Respir Med. 2004;98(11):1063–1070. doi: 10.1016/j.rmed.2004.03.016. PubMed DOI

Regnis JA, Donnelly PM, Robinson M, Alison JA, Bye PT. Ventilatory mechanics at rest and during exercise in patients with cystic fibrosis. Am J Respir Crit Care Med. 1996;154(5):1418–1425. doi: 10.1164/ajrccm.154.5.8912758. PubMed DOI

Nixon PA, Joswiak ML, Fricker FJ. A six-minute walk test for assessing exercise tolerance in severely ill children. J Pediatr. 1996;129(3):362–366. doi: 10.1016/S0022-3476(96)70067-7. PubMed DOI

Pastré J, Prévotat A, Tardif C, Langlois C, Duhamel A, Wallaert B. Determinants of exercise capacity in cystic fibrosis patients with mild-to-moderate lung disease. BMC Pulm Med. 2014;14:74. doi: 10.1186/1471-2466-14-74. PubMed DOI PMC

Pianosi P, Pelech A. Stroke volume during exercise in cystic fibrosis. Am J Respir Crit Care Med. 1996;153(3):1105–1109. doi: 10.1164/ajrccm.153.3.8630552. PubMed DOI

Szollosi I, King SJ, Wilson JW, Naughton MT. Tachycardia in adults with cystic fibrosis is associated with normal autonomic function. Intern Med J. 2011;41(6):455–461. doi: 10.1111/j.1445-5994.2009.02039.x. PubMed DOI

Hebestreit H, Hulzebos EHJ, Schneiderman JE, Karila C, Boas SR, Kriemler S, et al. Cardiopulmonary Exercise Testing Provides Additional Prognostic Information in Cystic Fibrosis. Am J Respir Crit Care Med. 2019;199(8):987–995. doi: 10.1164/rccm.201806-1110OC. PubMed DOI

Edgeworth D, Keating D, Ellis M, Button B, Williams E, Clark D, et al. Improvement in exercise duration, lung function and well-being in G551D-cystic fibrosis patients: a double-blind, placebo-controlled, randomized, cross-over study with ivacaftor treatment. Clin Sci (Lond) 2017;131(15):2037–45. doi: 10.1042/CS20170995. PubMed DOI

Wilson J, You X, Ellis M, Urquhart DS, Jha L, Duncan M, et al. VO2max as an exercise tolerance endpoint in people with cystic fibrosis: Lessons from a lumacaftor/ivacaftor trial. J Cyst Fibros Off J Eur Cyst Fibros Soc. 2021;20(3):499–505. doi: 10.1016/j.jcf.2020.12.006. PubMed DOI

Saynor ZL, Barker AR, Oades PJ, Williams CA. The effect of ivacaftor in adolescents with cystic fibrosis (G551D mutation): an exercise physiology perspective. Pediatr Phys Ther Off Publ Sect Pediatr Am Phys Ther Assoc. 2014;26(4):454–461. PubMed

Savi D, Schiavetto S, Simmonds NJ, Righelli D, Palange P. Effects of Lumacaftor/Ivacaftor on physical activity and exercise tolerance in three adults with cystic fibrosis. J Cyst Fibros Off J Eur Cyst Fibros Soc. 2019;18(3):420–424. doi: 10.1016/j.jcf.2019.03.001. PubMed DOI

Ahmed MI, Dayman N, Madge J, Gaillard E. P91 Cardiopulmonary exercise testing in CF adolescents after starting Tezacaftor/Ivacaftor. Thorax. 2021;76(Suppl 1):A136–A136.

Middleton PG, Mall MA, Dřevínek P, Lands LC, McKone EF, Polineni D, et al. Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. N Engl J Med. 2019;381(19):1809–1819. doi: 10.1056/NEJMoa1908639. PubMed DOI PMC

Snowball JE, Flight WG, Heath L, Koutoukidis DA. A paradigm shift in cystic fibrosis nutritional care: clinicians’ views on the management of patients with overweight and obesity. J Cyst Fibros. 2023;0(0). 10.1016/j.jcf.2023.03.011. PubMed

Causer AJ, Shute JK, Cummings MH, Shepherd AI, Wallbanks SR, Pulsford RM, et al. Elexacaftor-Tezacaftor-Ivacaftor improves exercise capacity in adolescents with cystic fibrosis. Pediatr Pulmonol. 2022;57(11):2652–2658. doi: 10.1002/ppul.26078. PubMed DOI PMC

Hebestreit H, Arets HGM, Aurora P, Boas S, Cerny F, Hulzebos EHJ, et al. Statement on exercise testing in cystic fibrosis. Respir Int Rev Thorac Dis. 2015;90(4):332–351. PubMed

Rysgaard UK, Pedersen CL, Jensen JH, Sørensen L, Philipsen LKD, Leo-Hansen C, et al. Change in exercise capacity measured by Cardio-pulmonary Exercise Testing (CPET) in Danish people with cystic fibrosis after initiation of treatment with Lumacaftor/Ivacaftor and Tezacaftor/Ivacaftor. J Cyst Fibros Off J Eur Cyst Fibros Soc. 2022;21(5):844–849. doi: 10.1016/j.jcf.2022.05.009. PubMed DOI

Caterini JE, Ratjen F, Barker AR, Williams CA, Rendall K, Schneiderman JE, et al. Exercise intolerance in cystic fibrosis-the role of CFTR modulator therapies. J Cyst Fibros Off J Eur Cyst Fibros Soc. 2022;21(2):282–292. doi: 10.1016/j.jcf.2021.11.011. PubMed DOI

Warth JD, Collier ML, Hart P, Geary Y, Gelband CH, Chapman T, et al. CFTR chloride channels in human and simian heart. Cardiovasc Res. 1996;31(4):615–624. doi: 10.1016/S0008-6363(95)00245-6. PubMed DOI

Robert R, Norez C, Becq F. Disruption of CFTR chloride channel alters mechanical properties and cAMP-dependent Cl- transport of mouse aortic smooth muscle cells. J Physiol. 2005;568(Pt 2):483–495. doi: 10.1113/jphysiol.2005.085019. PubMed DOI PMC

Lamhonwah AM, Bear CE, Huan LJ, Kim Chiaw P, Ackerley CA, Tein I. Cystic fibrosis transmembrane conductance regulator in human muscle: Dysfunction causes abnormal metabolic recovery in exercise. Ann Neurol. 2010;67(6):802–808. doi: 10.1002/ana.21982. PubMed DOI

Malik FA, Meissner A, Semenkov I, Molinski S, Pasyk S, Ahmadi S, et al. Sphingosine-1-phosphate is a novel regulator of cystic fibrosis transmembrane conductance regulator (CFTR) activity. PLoS One . 2015;10(6):e0130313. PubMed PMC

Madácsy T, Pallagi P, Maleth J. Cystic fibrosis of the pancreas: the role of CFTR channel in the regulation of intracellular Ca2+ signaling and mitochondrial function in the exocrine pancreas. Front Physiol. 2018;9:1585. doi: 10.3389/fphys.2018.01585. PubMed DOI PMC

Velsor LW, Kariya C, Kachadourian R, Day BJ. Mitochondrial oxidative stress in the lungs of cystic fibrosis transmembrane conductance regulator protein mutant mice. Am J Respir Cell Mol Biol. 2006;35(5):579–586. doi: 10.1165/rcmb.2005-0473OC. PubMed DOI PMC

van de Weert-van Leeuwen PB, Slieker MG, Hulzebos HJ, Kruitwagen CLJJ, van der Ent CK, Arets HGM. Chronic infection and inflammation affect exercise capacity in cystic fibrosis. Eur Respir J. 2012;39(4):893–898. doi: 10.1183/09031936.00086211. PubMed DOI

Casey M, Gabillard-Lefort C, McElvaney OF, McElvaney OJ, Carroll T, Heeney RC, et al. Effect of elexacaftor/tezacaftor/ivacaftor on airway and systemic inflammation in cystic fibrosis. Thorax. 2023;78(8):835–839. doi: 10.1136/thorax-2022-219943. PubMed DOI

Divangahi M, Balghi H, Danialou G, Comtois AS, Demoule A, Ernest S, et al. Lack of CFTR in skeletal muscle predisposes to muscle wasting and diaphragm muscle pump failure in cystic fibrosis mice. PLoS Genet. 2009;5(7):e1000586. doi: 10.1371/journal.pgen.1000586. PubMed DOI PMC