The Impact of CFTR Modulating Therapy on Chronic Lung Infection in Patients with Cystic Fibrosis


  • Joana Rodrigues Faculdade de Medicina. Universidade do Porto. Porto.
  • Rita Boaventura Faculdade de Medicina. Universidade do Porto. Porto; Serviço de Pneumologia. Centro Hospitalar e Universitário São João. Porto.
  • Gabriela Fernandes Faculdade de Medicina. Universidade do Porto. Porto; Serviço de Pneumologia. Centro Hospitalar e Universitário São João. Porto.
  • Adelina Amorim Faculdade de Medicina. Universidade do Porto. Porto; Serviço de Pneumologia. Centro Hospitalar e Universitário São João. Porto.



Cystic Fibrosis Transmembrane Conductance Regulator/therapeutic, Cystic Fibrosis/drug therapy, Respiratory Tract Infections/drug therapy


Cystic fibrosis is the most common lethal genetic disease in the white population, affecting approximately 80 000 people worldwide. It is an autosomal recessive, monogenic, and multisystemic disease, with over 2000 mutations described in the CFTR protein gene. The dysfunction of this protein leads to a decrease in the secretion of chlorine and bicarbonate, sodium hyperabsorption, and consequent water absorption, resulting in the thickening of secretions and accumulation of pathogens. These changes culminate in inflammation, chronic pulmonary infection, and recurrent exacerbations, with lung disease being the main cause of morbidity and mortality. In the early stages of the disease, Staphylococcus aureus is generally the agent responsible for chronic infection. Over time, Pseudomonas aeruginosa becomes more prevalent, being the most frequent bacteria in adults. However, in up to 70% of patients, colonization is polymicrobial, with frequent isolation of S. aureus and P. aeruginosa, associated with Haemophilus influenzae or Streptococcus pneumoniae, as well as isolation of other bacterial agents, viruses, or fungi. In recent years, drugs modulating CFTR have been developed which have shown a positive effect on lung function, body mass index, exacerbation rate, chlorine concentration, and quality of life. Currently, four drugs are approved that act by improving the function or increasing the amount of protein produced and consequently the ion transport. [...]


Download data is not yet available.


Meoli A, Fainardi V, Deolmi M, Chiopris G, Marinelli F, Caminiti C, et al. State of the art on approved cystic fibrosis transmembrane conductance regulator (CFTR) modulators and triple-combination therapy. Pharmaceuticals. 2021;14:928. DOI:

Bessonova L, Volkova N, Higgins M, Bengtsson L, Tian S, Simard C, et al. Data from the US and UK cystic fibrosis registries support disease modification by CFTR modulation with ivacaftor. Thorax. 2018;73:731-40. DOI:

Bierlaagh MC, Muilwijk D, Beekman JM, van der Ent CK. A new era for people with cystic fibrosis. Eur J Pediatr. 2021;180:2731-9. DOI:

Harvey C, Weldon S, Elborn S, Downey DG, Taggart C. The effect of CFTR modulators on airway infection in cystic fibrosis. Int J Mol Sci. 2022;23:3513. DOI:

Lopes-Pacheco M. CFTR modulators: the changing face of cystic fibrosis in the era of precision medicine. Front Pharmacol. 2019;10:1662. DOI:

Shteinberg M, Haq IJ, Polineni D, Davies JC. Cystic fibrosis. Lancet. 2021;397:2195-211. DOI:

Haq I, Almulhem M, Soars S, Poulton D, Brodlie M. Precision medicine based on CFTR genotype for people with cystic fibrosis. Pharmgenomics Pers Med. 2022;15:91-104. DOI:

King JA, Nichols AL, Bentley S, Carr SB, Davies JC. An update on CFTR modulators as new therapies for cystic fibrosis. Paediatr Drugs. 2022;24:321-33. DOI:

Brochiero E, Dagenais A, Privé A, Berthiaume Y, Grygorczyk R. Evidence of a functional CFTR Cl(-) channel in adult alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2004;287:L382-92. DOI:

Kirwan L, Fletcher G, Harrington M, Jeleniewska P, Zhou S, Casserly B, et al. Longitudinal trends in real-world outcomes after initiation of ivacaftor. A cohort study from the Cystic Fibrosis Registry of Ireland. Ann Am Thorac Soc. 2019;16:209-16. DOI:

Leigh MW, Kylander JE, Yankaskas JR, Boucher RC. Cell proliferation in bronchial epithelium and submucosal glands of cystic fibrosis patients. Am J Respir Cell Mol Biol. 1995;12:605-12. DOI:

Ballard ST, Trout L, Bebök Z, Sorscher EJ, Crews A. CFTR involvement in chloride, bicarbonate, and liquid secretion by airway submucosal glands. Am J Physiol. 1999;277:L694-9. DOI:

McShane D, Davies JC, Wodehouse T, Bush A, Geddes D, Alton EW. Normal nasal mucociliary clearance in CF children: evidence against a CFTRrelated defect. Eur Respir J. 2004;24:95-100. DOI:

Muhlebach MS, Stewart PW, Leigh MW, Noah TL. Quantitation of inflammatory responses to bacteria in young cystic fibrosis and control patients. Am J Respir Crit Care Med. 1999;160:186-91. DOI:

Khan TZ, Wagener JS, Bost T, Martinez J, Accurso FJ, Riches DW. Early pulmonary inflammation in infants with cystic fibrosis. Am J Respir Crit Care Med. 1995;151:1075-82. DOI:

Wagener JS, Kahn TZ, Copenhaver SC, Accurso FJ. Early inflammation and the development of pulmonary disease in cystic fibrosis. Pediatr Pulmonol Suppl. 1997;16:267-8. DOI:

Dean TP, Dai Y, Shute JK, Church MK, Warner JO. Interleukin-8 concentrations are elevated in bronchoalveolar lavage, sputum, and sera of children with cystic fibrosis. Pediatr Res. 1993;34:159-61. DOI:

Tabary O, Zahm JM, Hinnrasky J, Couetil JP, Cornillet P, Guenounou M, et al. Selective up-regulation of chemokine IL-8 expression in cystic fibrosis bronchial gland cells in vivo and in vitro. Am J Pathol. 1998;153:921-30. DOI:

Bonfield TL, Konstan MW, Burfeind P, Panuska JR, Hilliard JB, Berger M. Normal bronchial epithelial cells constitutively produce the anti-inflammatory cytokine interleukin-10, which is downregulated in cystic fibrosis. Am J Respir Cell Mol Biol. 1995;13:257-61. DOI:

Wooldridge JL, Deutsch GH, Sontag MK, Osberg I, Chase DR, Silkoff PE, et al. NO pathway in CF and non-CF children. Pediatr Pulmonol. 2004;37:338-50. DOI:

Konstan MW, Hilliard KA, Norvell TM, Berger M. Bronchoalveolar lavage findings in cystic fibrosis patients with stable, clinically mild lung disease suggest ongoing infection and inflammation. Am J Respir Crit Care Med. 1994;150:448-54. DOI:

Birrer P, McElvaney NG, Rüdeberg A, Sommer CW, Liechti-Gallati S, Kraemer R, et al. Protease-antiprotease imbalance in the lungs of children with cystic fibrosis. Am J Respir Crit Care Med. 1994;150:207-13. DOI:

DiMango E, Zar HJ, Bryan R, Prince A. Diverse Pseudomonas aeruginosa gene products stimulate respiratory epithelial cells to produce interleukin-8. J Clin Invest. 1995;96:2204-10. DOI:

Roum JH, Buhl R, McElvaney NG, Borok Z, Crystal RG. Systemic deficiency of glutathione in cystic fibrosis. J Appl Physiol. 1993;75:2419-24. DOI:

Koller DY, Urbanek R, Götz M. Increased degranulation of eosinophil and neutrophil granulocytes in cystic fibrosis. Am J Respir Crit Care Med. 1995;152:629-33. DOI:

Bell SC, Mall MA, Gutierrez H, Macek M, Madge S, Davies JC, et al. The future of cystic fibrosis care: a global perspective. Lancet Respir Med. 2020;8:65-124. DOI:

Harrison F. Microbial ecology of the cystic fibrosis lung. Microbiology. 2007;153:917-23. DOI:

del Campo R, Morosini MI, de la Pedrosa EG, Fenoll A, Muñoz-Almagro C, Máiz L, et al. Population structure, antimicrobial resistance, and mutation frequencies of Streptococcus pneumoniae isolates from cystic fibrosis patients. J Clin Microbiol. 2005;43:2207-14. DOI:

Román F, Cantón R, Pérez-Vázquez M, Baquero F, Campos J. Dynamics of long-term colonization of respiratory tract by Haemophilus influenzae in cystic fibrosis patients shows a marked increase in hypermutable strains. J Clin Microbiol. 2004;42:1450-9. DOI:

Silva Filho LV, Ferreira F de A, Reis FJ, Britto MC, Levy CE, Clark O, et al. Pseudomonas aeruginosa infection in patients with cystic fibrosis: scientific evidence regarding clinical impact, diagnosis, and treatment. J Bras Pneumol. 2013;39:495-512. DOI:

Smith EE, Buckley DG, Wu Z, Saenphimmachak C, Hoffman LR, D’Argenio DA, et al. Genetic adaptation by Pseudomonas aeruginosa to the airways of cystic fibrosis patients. Proc Natl Acad Sci U S A. 2006;103:8487-92. DOI:

Govan JR, Brown AR, Jones AM. Evolving epidemiology of Pseudomonas aeruginosa and the Burkholderia cepacia complex in cystic fibrosis lung infection. Future Microbiol. 2007;2:153-64. DOI:

Blanchard AC, Waters VJ. Microbiology of cystic fibrosis airway disease. Semin Respir Crit Care Med. 2019;40:727-36. DOI:

Oliver A, Alarcón T, Caballero E, Cantón R. Diagnóstico microbiológico de la colonización-infección broncopulmonar en el paciente con fibrosis quística. Enferm Infecc Microbiol Clin. 2009;27:89-104. DOI:

Bardin E, Pastor A, Semeraro M, Golec A, Hayes K, Chevalier B, et al. Modulators of CFTR. Updates on clinical development and future directions. Eur J Med Chem. 2021;213:113195. DOI:

Tewkesbury DH, Robey RC, Barry PJ. Progress in precision medicine in cystic fibrosis: a focus on CFTR modulator therapy. Breathe. 2021;17:210112. DOI:

Rowe SM, Daines C, Ringshausen FC, Kerem E, Wilson J, Tullis E, et al. Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med. 2017;377:2024-35. DOI:

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;381:1809-19. DOI:

Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365:1663-72. DOI:

Flume PA, Liou TG, Borowitz DS, Li H, Yen K, Ordoñez CL, et al. Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation. Chest. 2012;142:718-24. DOI:

Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli M, et al. Lumacaftor-Ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med. 2015;373:220-31. DOI:

Taylor-Cousar JL, Munck A, McKone EF, van der Ent CK, Moeller A, Simard C, et al. Tezacaftor-Ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N Engl J Med. 2017;377:2013-23. DOI:

Walker S, Flume P, McNamara J, Solomon M, Chilvers M, Chmiel J, et al. A phase 3 study of tezacaftor in combination with ivacaftor in children aged 6 through 11 years with cystic fibrosis. J Cyst Fibros. 2019;18:708-13. DOI:

Heijerman HG, McKone EF, Downey DG, Van Braeckel E, Rowe SM, Tullis E, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Lancet. 2019;394:1940-8. DOI:

Mall MA, Brugha R, Gartner S, Legg J, Moeller A, Mondejar-Lopez P, et al. Efficacy and safety of elexacaftor/tezacaftor/ivacaftor in children 6 through 11 years of age with cystic fibrosis heterozygous for f508del and a minimal function mutation: a phase 3b, randomized, placebo-controlled study. Am J Respir Crit Care Med. 2022;206:1361-9. DOI:

Reznikov LR, Abou Alaiwa MH, Dohrn CL, Gansemer ND, Diekema DJ, Stoltz DA, et al. Antibacterial properties of the CFTR potentiator ivacaftor. J Cyst Fibros. 2014;13:515-9. DOI:

Heeb S, Fletcher MP, Chhabra SR, Diggle SP, Williams P, Cámara M. Quinolones: from antibiotics to autoinducers. FEMS Microbiol Rev. 2011;35:247-74. DOI:

Hisert KB, Heltshe SL, Pope C, Jorth P, Wu X, Edwards RM, et al. Restoring cystic fibrosis transmembrane conductance regulator function reduces airway bacteria and inflammation in people with cystic fibrosis and chronic lung infections. Am J Respir Crit Care Med. 2017;195:1617-28. DOI:

Durfey SL, Pipavath S, Li A, Vo AT, Ratjen A, Carter S, et al. Combining ivacaftor and intensive antibiotics achieves limited clearance of cystic fibrosis infections. mBio. 2021;12:e0314821. DOI:

Rowe SM, Heltshe SL, Gonska T, Donaldson SH, Borowitz D, Gelfond D, et al. Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med. 2014;190:175-84. DOI:

Volkova N, Moy K, Evans J, Campbell D, Tian S, Simard C, et al. Disease progression in patients with cystic fibrosis treated with ivacaftor: data from national US and UK registries. J Cyst Fibros. 2020;19:68-79. DOI:

Frost FJ, Nazareth DS, Charman SC, Winstanley C, Walshaw MJ. Ivacaftor is associated with reduced lung infection by key cystic fibrosis pathogens. a cohort study using national registry data. Ann Am Thorac Soc. 2019;16:1375-82. DOI:

Neerincx AH, Whiteson K, Phan JL, Brinkman P, Abdel-Aziz MI, Weersink EJ, et al. Lumacaftor/ivacaftor changes the lung microbiome and metabolome in cystic fibrosis patients. ERJ Open Res. 2021;7:731-2020. DOI:

Elborn JS, Ahuja S, Springman E, Mershon J, Grosswald R, Rowe SM. EMPIRE-CF: a phase II randomized placebo-controlled trial of once-daily, oral acebilustat in adult patients with cystic fibrosis - study design and patient demographics. Contemp Clin Trials. 2018;72:86-94. DOI:

Sosinski LM, H CM, Neugebauer KA, Ghuneim LJ, Guzior DV, Castillo-Bahena A, et al. A restructuring of microbiome niche space is associated with elexacaftor-tezacaftor-ivacaftor therapy in the cystic fibrosis lung. J Cyst Fibros. 2022;21:996-1005. DOI:

Loughlin DW, Coughlan S, De Gascun CF, McNally P, Cox DW. The role of rhinovirus infections in young children with cystic fibrosis. J Clin Virol. 2020;129:104478. DOI:

van Ewijk BE, van der Zalm MM, Wolfs TF, Fleer A, Kimpen JL, Wilbrink B, et al. Prevalence and impact of respiratory viral infections in young children with cystic fibrosis: prospective cohort study. Pediatrics. 2008;122:1171-6. DOI:

De Jong E, Garratt LW, Looi K, Lee AH, Ling KM, Smith ML, et al. Ivacaftor or lumacaftor/ivacaftor treatment does not alter the core cf airway epithelial gene response to rhinovirus. J Cyst Fibros. 2021;20:97-105. DOI:

Mayer-Hamblett N, Ramsey BW, Kulasekara HD, Wolter DJ, Houston LS, Pope CE, et al. Pseudomonas aeruginosa phenotypes associated with eradication failure in children with cystic fibrosis. Clin Infect Dis. 2014;59:624-31. DOI:

Yi B, Dalpke AH, Boutin S. Changes in the cystic fibrosis airway microbiome in response to cftr modulator therapy. Front Cell Infect Microbiol. 2021;11:548613. DOI:

Jarosz-Griffiths HH, Scambler T, Wong CH, Lara-Reyna S, Holbrook J, Martinon F, et al. Different CFTR modulator combinations downregulate inflammation differently in cystic fibrosis. Elife. 2020;9:e54556. DOI:

Soto SM. Role of efflux pumps in the antibiotic resistance of bacteria embedded in a biofilm. Virulence. 2013;4:223-9. DOI:

Cho DY, Lim DJ, Mackey C, Skinner D, Zhang S, McCormick J, et al. Ivacaftor, a cystic fibrosis transmembrane conductance regulator potentiator, enhances ciprofloxacin activity against pseudomonas aeruginosa. Am J Rhinol Allergy. 2019;33:129-36. DOI:

Schneider EK, Reyes-Ortega F, Wilson JW, Kotsimbos T, Keating D, Li J, et al. Development of HPLC and LC-MS/MS methods for the analysis of ivacaftor, its major metabolites and lumacaftor in plasma and sputum of cystic fibrosis patients treated with ORKAMBI or KALYDECO. J Chromatogr B Analyt Technol Biomed Life Sci. 2016;1038:57-62. DOI:

Maillé É, Ruffin M, Adam D, Messaoud H, Lafayette SL, McKay G, et al. Quorum sensing down-regulation counteracts the negative impact of pseudomonas aeruginosa on CFTR channel expression, function and rescue in human airway epithelial cells. Front Cell Infect Microbiol. 2017;7:470. DOI:

Laselva O, Stone TA, Bear CE, Deber CM. Anti-Infectives restore ORKAMBI® rescue of f508del-CFTR function in human bronchial epithelial cells infected with clinical strains of P. aeruginosa. Biomolecules. 2020;10:334. DOI:

European Medicines Agency. Kalydeco. [consultado 2023 ago 06]. Disponível em:

Cystic Fibrosis Foundation. CFTR modulator therapies. [consultado 2023 ago 06]. Disponível em:



How to Cite

Rodrigues J, Boaventura R, Fernandes G, Amorim A. The Impact of CFTR Modulating Therapy on Chronic Lung Infection in Patients with Cystic Fibrosis. Acta Med Port [Internet]. 2023 Sep. 23 [cited 2024 Apr. 13];36(12):826-34. Available from:



Review Articles