Residual disease activity in cystic fibrosis lung disease: implications for clinical management and research

The advent of cystic fibrosis transmembrane conductance regulator (CFTR) modulators is fundamentally reshaping research and care for people with cystic fibrosis (CF). Despite unprecedented improvements in lung function and predicted survival, a substantial proportion of people with CF continue to exhibit residual disease activity (RDA) across multiple biological and clinical domains. Persistent abnormalities in CFTR function, mucus properties, mucociliary clearance, airway infection, inflammation, and symptom burden indicate that CFTR modulation does not fully normalize airway physiology or eliminate the pathological processes underlying CF lung disease. This review proposes RDA as a conceptual framework for identifying ongoing, potentially modifiable disease processes in people receiving CFTR modulators. Candidate measures across complementary mechanistic and clinical domains are examined, and their potential multidimensional interpretation as a means of supporting more individualized monitoring and treatment decisions is discussed. We consider the implications of RDA for clinical research by identifying key evidence gaps, outlining a stepwise pathway for its definition and validation. We further explore the potential to inform sensitive endpoint selection, enrich study populations, and guide the development of therapies targeting disease processes that persist despite CFTR modulation. As the CF population ages and disease trajectories evolve, care models and research priorities must move beyond conventional measures of disease severity alone. A better understanding and systematic evaluation of RDA may help align long-term clinical management and future trial design with the changing needs of people with CF, while ensuring that therapeutic advances translate into sustained health gains.

Target Audience

Pulmonologists, critical care specialists, translational researchers, and clinicians

Learning Objectives

  • Distinguish residual disease activity from disease severity in people with cystic fibrosis and recognize the major domains of residual disease activity that may persist despite cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy
  • Apply a multidomain approach to identify and longitudinally monitor residual disease activity, including residual CFTR dysfunction, mucociliary impairment, airway infection, inflammation, and respiratory symptoms
  • Use the residual disease activity framework to test its validity in stratifying patients and individualize management strategies aimed at limiting disease progression and treatment burden in people with cystic fibrosis

Course summary

Available credit: 
  • 1.00 AMA PRA Category 1 Credit(s)™

    The American Thoracic Society designates this Journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

  • 1.00 Participation
Publication Date: 
09/30/2026
Credit Expires: 
09/30/2028
Cost:
$25.00
Rating: 
0

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The American Thoracic Society is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

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Article Authorship Disclosures (as submitted to the ATS prior to article publication date)

Andrea Gramegna, M.D. (Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy and Respiratory and Cystic Fibrosis Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, Italy) reports grants from AstraZeneca and Insmed; consulting fees from Menarini and Vertex Pharmaceuticals; payment or honoraria for lectures from AstraZeneca, Chiesi, GSK, Guidotti, Grifols, Insmed, Menarini, Vertex Pharmaceuticals, and Zambon; travel reimbursement received for participation in advisory board meetings or congresses for Vertex Pharmaceuticals, Insmed, Chiesi, and Neupharma. He is the Chair of the European Cystic Fibrosis Society Standards-of-Care Working Group.

Gianmarco Putti, M.D. (Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy) reported no relevant financial relationships with ineligible companies.

Gianfranco Alicandro, Ph.D. (Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy and Mother and Child Department, Cystic Fibrosis Centre, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy) reported no relevant financial relationships with ineligible companies.

Marcus A. Mall, M.D. (Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany; German Center for Child and Adolescent Health (DZKJ), partner site Berlin, Berlin, Germany; German Center for Lung Research (DZL), associated partner site Berlin, Berlin, Germany; and Cluster of Excellence ImmunoPreCept, Charité - Universitätsmedizin Berlin, Berlin, Germany) reports grants or contracts from German Ministry of Research, Technology and Space (BMFTR), German Research Foundation (DFG), Boehringer Ingelheim, Enterprise Therapeutics, and Vertex Pharmaceuticals with payments made to his institution; consultancy fees from Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotech, Pari, Splisense, and Vertex Pharmaceuticals; payment or honoraria for lectures from Boehringer Ingelheim and Vertex Pharmaceuticals; travel reimbursement received for participation in advisory board meetings for Boehringer Ingelheim and Vertex Pharmaceuticals; and fees for participation on an advisory board from Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotech, Pari, Splisense, and Vertex Pharmaceuticals. He is an unpaid fellow of the European Respiratory Society.

Francesco Blasi, M.D., Ph.D. (Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy, and Respiratory and Cystic Fibrosis Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, Italy) reports grants or contracts from AstraZeneca, Insmed, and Chiesi with payments made to his institution; consultancy fees from Menarini, OM Pharma, and Boehringer; payment or honoraria for lectures from AstraZeneca, Chiesi, GSK, Guidotti, Grifols, Insmed, Menarini, Novartis, OM Pharma, Pfizer, Sanofi, Vertex Pharmaceuticals, Viatris, and Zambon; travel reimbursement received for participation in advisory board meetings for Novartis, Pfizer, Sanofi, Vertex Pharmaceuticals, Viatris, and Zambon; and fees for participation on an advisory board from Novartis, GSK, Pfizer, Sanofi, Vertex Pharmaceuticals, and Zambon. He is an unpaid fellow of the European Respiratory Society.

 

AJRCCM CME Planner

Edward J. Schenck, M.D. (New York Presbyterian Hospital/Weill Cornell Medical College, New York, New York) Dr. Schenck is a consultant for Axle Informatics

Off-Label Usage Disclosure

Emerging anti-inflammatory therapies such as DPP-1 inhibitors are discussed as a potential complement to CFTR modulation and to help address persistent disease activity (refs 66–68).

All relevant financial relationships have been reviewed and mitigated.

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Available Credit

  • 1.00 AMA PRA Category 1 Credit(s)™

    The American Thoracic Society designates this Journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

  • 1.00 Participation

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