Speaker's Highlight

• Don Sin University of British Columbia, St. Paul Hospital (Canada)
  Kenneth R. Chapman Toronto General Hospital Research Institute (Canada)
• Parameswaran Nair McMaster University (Canada)
  Carolyn Calfee UCSF (U.S.A.)
• Gregory P. Downey University of Colorado School of Medicine (U.S.A.)
  David A. Schwartz University of Colorado School of Medicine (U.S.A.)
• Neil Schluger Tuberculosis Control Branch, California Department of Public Health (U.S.A.)
  Nick Kim Critical Care & Sleep Medicine, University of California San Diego (U.S.A.)
• Nicola Hananiah Baylor College of Medicine (U.S.A.)
  Jae-Joon Yim Seoul National University College of Medicine (Republic of Korea)
• Koichiro Asano Tokai University School of Medicine (Japan)
  Diahn-Warng Perng Taipei Veterans General Hospital (Taiwan)
• Konstantinos Kostikas University of Ioannina (Greece)
  Karin Klooster University Medical Center Groningen (Kingdom of the Netherlands)

• Cystic fibrosis modulator therapies in modern respiratory care

  Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies have changed the management of cystic fibrosis (CF) by targeting the molecular defect behind the disease. Instead of treating only airway obstruction, infection, and inflammation, these medicines can improve the function, production, or stability of the defective CFTR protein.

  The clinical impact extends across respiratory medicine. Many people with CF experience better lung function, fewer pulmonary exacerbations, improved nutritional status, and a lower treatment burden after starting an appropriate modulator. However, treatment selection remains individualized and depends on the patient’s CFTR variant, age, organ involvement, drug interactions, and access to specialist monitoring.

  Discussions at respiratory medicine congresses such as APSR 2022 and meetings connected with KATRD help place these advances in a broader clinical context. They also highlight the importance of multidisciplinary care, long-term follow-up, and equitable access to precision therapies.

  How CFTR modulators work

  CFTR is an epithelial ion channel that regulates chloride and bicarbonate movement across cell membranes. When the protein is absent, poorly formed, unstable, or inefficient, airway surface liquid becomes dehydrated. Thick mucus then obstructs the airways and supports chronic infection and inflammation.

  CFTR correctors help the protein fold and reach the cell surface, while potentiators improve channel opening once the protein is present. Some treatment regimens combine two correctors with a potentiator to address several defects simultaneously. The result may be improved mucociliary clearance and more effective airway defense.

  Main treatment categories

  Ivacaftor was the first widely used CFTR potentiator and remains important for people with specific gating or residual-function variants. By increasing the probability that CFTR channels remain open, it can produce meaningful improvements in sweat chloride concentration, lung function, and symptoms for eligible patients.

  Corrector-potentiator combinations include lumacaftor/ivacaftor and tezacaftor/ivacaftor. Elexacaftor/tezacaftor/ivacaftor, commonly described as triple-combination therapy, offers broader variant coverage and has become a major development in CF care. Eligibility varies by country and regulatory approval, so genetic confirmation and local prescribing guidance are essential.

  Selecting therapy through precision medicine

  Genotyping is central to treatment decisions. A complete CFTR variant analysis can identify whether a patient is likely to respond to a potentiator, a corrector combination, or a newer triple regimen. Clinical teams should also consider age, baseline pulmonary function, liver health, pregnancy considerations, and the ability to maintain regular follow-up.

  Response is assessed through several measures rather than a single test. Spirometry, weight, pulmonary exacerbation frequency, sweat chloride, respiratory symptoms, and patient-reported quality of life can all provide useful evidence. A rapid improvement in lung function may occur, but benefits can also include fewer infections and slower disease progression over time.

  Benefits and limitations in respiratory care

  Clinical trials and real-world studies have associated CFTR modulators with improved forced expiratory volume, reduced pulmonary exacerbations, better body mass index, and enhanced daily functioning in eligible populations. Some patients report less cough and sputum production, although established structural lung damage may not fully reverse.

  These medicines are not a cure and do not eliminate the need for airway clearance, inhaled therapies, nutritional support, vaccination, or infection management. Access may also be limited by cost, reimbursement policies, age restrictions, or the absence of an approved indication for a particular variant. People with rare or very uncommon mutations may require specialist evaluation and additional research-based options.

  Therapy approach	Primary action	Typical clinical role	Important monitoring
  Ivacaftor	Increases CFTR channel opening	Selected gating and residual-function variants	Liver enzymes, drug interactions, eye examinations in children
  Lumacaftor/ivacaftor	Corrects protein processing and increases channel activity	Certain two-copy F508del genotypes	Liver function, respiratory symptoms, interactions
  Tezacaftor/ivacaftor	Improves CFTR processing and channel activity	Selected responsive variants	Liver function and concomitant medicines
  Elexacaftor/tezacaftor/ivacaftor	Combines two correctors with a potentiator	Broad eligibility among responsive genotypes	Liver function, mood or sleep changes, interactions

  Safety, monitoring, and adherence

  CFTR modulators are generally well tolerated, but adverse effects require active surveillance. Liver enzyme elevations can occur, particularly in people with pre-existing hepatic disease or when medicines affecting hepatic metabolism are used at the same time. Clinicians should review all prescriptions, over-the-counter products, and herbal supplements for interactions.

  Other reported concerns may include rash, headache, gastrointestinal symptoms, changes in sleep, and mood-related effects. Eye examinations are recommended for some children receiving ivacaftor-containing treatment. Clear education helps patients understand dosing with fat-containing food when required, recognize potential adverse effects, and maintain adherence.

  Integrating modulators into lifelong care

  A modulator should be incorporated into a comprehensive CF care plan rather than viewed as a replacement for established respiratory treatment. Airway clearance, inhaled mucolytics, exercise, nutrition, pancreatic enzyme replacement, diabetes screening, bone health assessment, and psychosocial support remain important.

  Multidisciplinary teams are especially valuable when patients have advanced lung disease, liver complications, CF-related diabetes, fertility concerns, or a history of transplantation. Communication between CF centers, primary care clinicians, pharmacists, and respiratory specialists can prevent interruptions and identify complications early.

  Practical priorities for clinical teams

  Treatment pathways should be transparent and responsive to the patient’s genetic and clinical profile. Teams can strengthen care by combining objective monitoring with the patient’s experience of breathlessness, fatigue, treatment workload, and daily activity.

  Useful priorities include:

  • Confirm the CFTR genotype and review current regulatory eligibility before prescribing.
  • Establish baseline spirometry, liver tests, medication history, nutrition measures, and symptom scores.
  • Reassess clinical response regularly instead of relying on short-term lung function changes alone.
  • Educate patients about dosing, adherence, adverse effects, and clinically important drug interactions.
  • Preserve airway clearance, infection prevention, nutrition support, and routine CF surveillance.

  The expansion of CFTR-targeted treatment demonstrates how molecular diagnosis can reshape respiratory medicine. Continued research is needed for people with nonresponsive variants, advanced disease, and populations underrepresented in clinical trials. Conference programs, invited expert sessions, and professional discussion can help clinicians translate emerging evidence into safe, equitable care.

  Explore the APSR 2022 congress program, committee resources, and invited-speaker content to engage with developments in cystic fibrosis, respiratory therapeutics, and multidisciplinary pulmonary practice.

  Richard Russell Nuffield Department of Clinical Medicine, University of Oxford (United Kingdom)
• Mona Bafadhel King’s College London (United Kingdom)
  David Jackson Guy’s and St Thomas’ Hospital, King’s College London (United Kingdom)
• James Chalmers University of Dundee (United Kingdom)
  David Price University of Aberdeen (United Kingdom)