European Respiratory Society
Cystic Fibrosis

Cystic fibrosis (CF) is one of the most common fatal hereditary diseases. The discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene 25 years ago set the stage for unraveling the pathogenesis of CF lung disease, continuous refinement of symptomatic treatments and the development of mutation-specific therapies, which are now becoming available for a subgroup of patients. This ERS Monograph provides an update on all aspects of CF lung disease, from infancy to adulthood, including current concepts on disease process, improvements in early diagnosis and monitoring, therapeutic approaches, and patient care. The book highlights important recent developments and discusses the next steps that will be required for further improvement of the life expectancy and quality of life of CF patients. It will be an essential reference for basic and clinical scientists and all members of the CF team.

  • ERS Monograph
  1. Page ix
  2. Page xi
  3. Page xiii
    1. Page 1
      Correspondence: Marcus A. Mall, Dept of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), University of Heidelberg, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany. E-mail:

      Chronic obstructive lung disease starting in the first months of life remains the major cause of morbidity and mortality in patients with cystic fibrosis (CF). The discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene 25 years ago paved the way for investigation of the molecular and cellular basis of CF lung disease, and the generation of animal models for in vivo studies of pathogenesis. In this chapter, we focus on major advances in the understanding of the link between mutations in CFTR and the predictable development of chronic mucus obstruction, inflammation and infection of CF airways. We discuss evidence from translational studies supporting the concept that increased mucus concentration (i.e. dehydration) and reduced pH of the airway surface layer are key abnormalities underlying impaired innate defence of the CF lung. Novel therapeutic strategies targeting these defects may be successful for the prevention and treatment of CF lung disease independent of the patient’s CF genotype.

    2. Page 14
      Correspondence: Noel Gerard McElvaney, Education and Research Centre, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland. E-mail:

      Cystic fibrosis (CF) is a multisystem disorder with significantly shortened life expectancy. The major cause of mortality and morbidity is lung disease. Inflammation is seen in the CF airways from a very early age and contributes significantly to symptoms and disease progression. It is unknown whether this inflammation is intrinsically driven by defective immune regulation or is a result of bacterial infection, but it is probably a combination of both. Abnormal cystic fibrosis transmembrane conductance regulator (CFTR) function affects elements of the innate immune system including neutrophils, monocytes/macrophages, lymphocytes and epithelial cells, and the interaction of these cells with bacteria, viruses and fungi, all of which contribute to the eventual parenchymal destruction that is the hallmark of this condition. There are numerous methods to measure the degree of airway inflammation; however, many are limited by either reliability or ease of use. Therapeutic interventions for CF have improved significantly in the last 20 years and now there are therapies targeted towards specific elements of inflammation, which may impact upon exacerbation frequency, symptoms and eventually mortality due to lung disease.

    3. Page 32
      Correspondence: John J. LiPuma, Dept of Pediatrics and Communicable Diseases, 8323 MSRB III, 1150 W. Medical Center Drive, Ann Arbor, MI, 48109, USA. E-mail:

      The use of culture-independent microbiomic analyses is expanding our view of respiratory tract infection in cystic fibrosis (CF). Recent studies demonstrate that the airways of persons with CF harbour complex polymicrobial communities. Ongoing studies are assessing how the composition and dynamics of these communities relate to clinical states and lung disease progression. Interest is now also focusing on better understanding the network of microbe–microbe and microbe–host interactions inherent in these communities. This deeper appreciation of how microbial airway communities are structured and how they function has potential to drive advances in our management of lung infection in CF.

    4. Page 47
      Correspondence: Burkhard Tümmler, Clinical Research Group “Molecular Pathology of Cystic Fibrosis”, Clinic for Paediatric Pneumology, Allergology and Neonatology, OE 6710, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany. E-mail:

      Contemporary cystic fibrosis (CF) has become a chronic disorder that is shaped by a complex network of cystic fibrosis transmembrane conductance regulator (CFTR) mutations, other genes and nongenetic influences. Environmental modifiers and non-CFTR genetic variants each account for about 50% of the pulmonary phenotypic variability in Phe508del homozygous CF patients. The organisation and funding of domestic healthcare systems, the access to and provision of qualified CF care, adherence to treatment and sex-related issues, such as body image and sex hormones, are major modifiers of CF disease outcomes. Climate and microbes are important environmental determinants of CF disease. The disease-causing CFTR mutations, the haplotype of the CFTR linkage group and non-CFTR genetic variants contribute to the inherited components of CF. Genome-wide and candidate gene approaches have identified genetic modifiers of the processing, trafficking and activity of mutant CFTR and have resolved inherited risk factors for meconium ileus, liver disease and CF-related diabetes mellitus (CFRD) that explain a substantial part of the variance of these clinical phenotypes.

  4. Page 65
    1. Page 65
      Correspondence: Anil Mehta, Medical Research Institute, Ninewells Hospital Medical School, University of Dundee, Dundee, DD1 9SY, UK. E-mail:

      Newborn screening for cystic fibrosis (CF) is a reasonable public health strategy, when modified criteria for assessing such a programme are taken into account. A variety of protocols is employed, although all use measurement of immunoreactive trypsinogen (IRT) in the first week of life as a first step. Second-tier testing varies and there are insufficient data to critically compare strategies. In this chapter, we provide a subjective assessment of each protocol from the best available evidence, with the aim of highlighting how changes in protocol impact performance; for example, a strategy may improve specificity but at the expense of increased recognition of infants with an inconclusive diagnosis. Protocol selection is a matter of balancing priorities. Alternative strategies, such as measuring pancreatitis-associated protein (PAP), may improve performance, but further work is required to determine the optimal strategy. It is important that programmes continue to monitor performance against standards and aim to reduce unnecessary negative impact.

    2. Page 77
      Correspondence: Stephen M. Stick, Dept of Respiratory Medicine, Princess Margaret Hospital for Children, Roberts Road, Subiaco 6008, Perth, Australia. E-mail:

      Lung disease was recognised as an early component of cystic fibrosis (CF) when it was first described as a syndrome. However, until midway through the 20th century, when the generalised mucous abnormality was identified, it was considered secondary to low vitamin A due to malabsorption of fat. Improved nutrition resulting from pancreatic enzyme replacement and comprehensive care in specialist clinics has resulted in improved survival, and lung disease is now the major determinant of morbidity and mortality. Early surveillance studies have demonstrated the very early onset of lung disease associated with neutrophilic airway inflammation and indicate potential strategies to prevent or slow the onset of structural lung disease.

    3. Page 88
      Correspondence: Harm A.W.M. Tiddens, Dept of Paediatric Pulmonology and Allergology, Erasmus Medical Centre Sophia Children’s Hospital, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands. E-mail:

      Cystic fibrosis (CF) lung disease starts early in life and is characterised by chronic lung inflammation and infection that persists throughout life. Both inflammation and infection lead to early irreversible structural lung damage. The most important pathological changes are bronchiectasis and bronchiolitis obliterans-like changes of the small airways. The course of disease and spectrum of the structural changes vary widely between patients due to genotypic and environmental differences.

      The primary aim of CF therapy is to prevent any structural damage and to conserve lung function. Adequate monitoring of CF lung disease is paramount to tailoring treatment to a patient’s need. Imaging techniques are needed to visualise the structural changes related to CF lung disease. Chest computed tomography (CT) is currently the best validated and most sensitive imaging modality to detect and monitor structural lung abnormalities. Magnetic resonance imaging (MRI) is a promising technique that is of specific interest for studying dynamic aspects of the lung.

    4. Page 104
      Correspondence: Kris De Boeck, Paediatric Pulmonology, Dept of Pediatrics, University Hospital Leuven, Herestraat 49, 3000 Leuven, Belgium. E-mail:

      The development of new treatments for patients with cystic fibrosis (CF) was paralleled by a renewed interest in the development and critical evaluation of new and existing end-points. The improved outcome of patients was the main reason why mortality, and even forced expiratory volume in 1 s (FEV1) could no longer be used as sensitive outcome measures.

      In this chapter, we review the pros and cons of commonly used outcome measures in clinical trials, as well as the factors that determine the choice of end-points in a specific trial. We then “put the theory into practice” by elaborating on scenarios for CF clinical trials addressing different aspects of CF lung disease.

      Since CF is a rare disorder, phase III clinical trials require multicentre cooperation. The development of clinical trial networks and task forces striving for rigorous standardisation and agreement on detailed standard operating procedures for outcome measures are other important steps in bridging the gap between drug discovery and robust evaluation of drug benefit.

  5. Page 116
    1. Page 116
      Correspondence: Luis J.V. Galietta, U.O.C. Genetica Medica, Istituto Giannina Gaslini, via Gerolamo Gaslini 5, 16147 Genova, Italy. E-mail:

      The basic defect in cystic fibrosis (CF) is the loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated ion channel permeable to chloride and bicarbonate. Correction of the basic defect may be obtained by rescuing the mutant CFTR proteins with drugs that specifically target the alterations caused by CF mutations. For example, small molecules known as “potentiators” are able to improve the activity of CFTR proteins with channel gating mutations. Instead, “correctors” may contrast the destabilising effects that the Phe508del mutation, the most frequent among CF patients, causes to CFTR protein. Recent studies suggest the possibility that a high extent of Phe508del-CFTR rescue may only be obtained by a combination of correctors having different mechanisms of action. Alternative strategies to correct the CF ion-transport defect are based on the stimulation of alternative chloride channels, such as TMEM16A or SLC26A9, or the improvement of airway surface hydration using osmotically active agents.

    2. Page 129
      Correspondence: Isabelle Sermet-Gaudelus, INSERM 1151 and Centre de Ressources et de Compétence de Mucoviscidose, Unité de Pneumo-Allergologie Pédiatrique, Hôpital Necker, 149 rue de Sévres, Paris 75015, France. E-mail:

      Recent data have established proof of concept that rescue of the underlying defects in the cellular processing and channel function of mutant cystic fibrosis transmembrane conductance regulator (CFTR) can result in clinical benefit. Modulators of the CFTR protein include: correctors, which are mainly targeted at rescuing the Phe508del-CFTR at the plasma membrane; and potentiators, which aim to restore activity of mutants that impair channel gating. The potentiator ivacaftor proved safe in patients carrying the Gly551Asp mutation and demonstrated a significant change in sweat chloride and an improvement in lung function; an effect that was maintained for up to 144 weeks. This clinical benefit has also been demonstrated in patients with other mutations that resulted in defective channel gating or conductance. Ivacaftor acts as a modest potentiator for the small amount of Phe508del-CFTR channels trafficked to the cell surface. However its combination with the corrector lumacaftor resulted in improvement in the forced expiratory volume in 1 s (FEV1) in Phe508del homozygote patients. Such treatments provide rationale for a personalised medicine strategy in the treatment of cystic fibrosis (CF).

    3. Page 150
      Correspondence: Uta Griesenbach, Dept of Gene Therapy, Imperial College London, Manresa Road, London, SW3 6LR, UK, E-mail:

      In this chapter, we will review key studies that have contributed to our current know-how on the feasibility of gene therapy in cystic fibrosis (CF). We have learnt that the lung is a more difficult target organ than originally anticipated and have gathered significant information on the strengths and weaknesses of the different gene transfer vectors in pre-clinical and clinical research. The important question of whether nonviral gene transfer can improve CF lung disease has not yet been answered, but a large multidose clinical trial is currently ongoing to address this question. Cell therapy, defined as the administration of stem/progenitor cells to correct cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction in the lung, is a comparatively new concept and may be an alternative or an addition to gene therapy. Key studies related to cell therapy and bioengineering will also be discussed.

    4. Page 169
      Correspondence: Judy M. Bradley, 1F117 University of Ulster, Shore Road, Newtownabbey, BT37 0QB, UK. E-mail:

      In cystic fibrosis (CF) the mucociliary clearance mechanism is impaired and airway clearance techniques aim to compensate for this by promoting secretion clearance. A substantial body of research has been unable to provide clear evidence for one technique over another. This is in part due to limitations in the study designs used to assess the effects of the techniques. There is great variability in the airway clearance techniques used at patient, centre and country level. Adherence to airway clearance techniques is consistently low and there is an urgent need to focus research on interventions to overcome key barriers to non-adherence. Airway clearance techniques also need to be coordinated with mucoactive medications to ensure the overall effect is optimised. Recent trials have identified the challenges related to using forced expiratory volume in 1 s (FEV1) as a primary outcome measure for airway clearance trials. New testing methods, for example multiple-breath washout and radio-imaging studies, may improve our understanding of the mechanisms underlying airway clearance as well as offering potential alternate clinical end-points.

    5. Page 188
      Correspondence: Diana Bilton, Dept of Adult CF, Royal Brompton Hospital, Sydney Street, London, SW3 6NP, UK. E-mail:

      Cystic fibrosis (CF) is a complex multisystem genetic disorder, with the major burden of morbidity and mortality resulting from destructive pulmonary disease associated with chronic airway infections. Successful treatment of pulmonary infections is one of the major reasons for improved life expectancy. In the past decades, we have embraced the principles of early treatment of infection and successful eradication regimens aimed at reducing the number of patients with chronic Pseudomonas aeruginosa infection.

      In this chapter, we discuss current strategies and possible future developments for management of airway infection, focusing mainly on P. aeruginosa as the most prevalent pathogen. The principles of antibiotic therapy derived from treating P. aeruginosa infection are discussed with regard to other pathogens.

    6. Page 203
      Correspondence: Helge Hebestreit, Paediatrics, University of Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany. E-mail:

      Physical activity and exercise have become part of standard treatment in many centres caring for people with cystic fibrosis (CF). Observed benefits include positive effects on exercise capacity, pulmonary disease and health-related quality of life (HRQoL). Furthermore, some data also suggest improvements in bone mineral density and psychological well-being. However, exercise may carry some risks in CF. Most of the adverse events associated with exercise are more common in individuals with advanced disease. In addition to knowing a patient’s medical history and actual health status, standardised cardiopulmonary exercise testing can identify patients at risk for many of the potential complications, as well as the reasons for a reduced exercise capacity. The Godfrey protocol for cycle ergometry is employed by many international experts. A proper individual risk assessment, as well as patient education and counselling, will foster an active and healthy lifestyle.

    7. Page 219
      Correspondence: Barry J. Plant, Adult Cystic Fibrosis Centre, Dept of Medicine, Cork University Hospital, University College Cork, Cork, Ireland. E-mail:

      This chapter details the key manifestations of extrapulmonary cystic fibrosis (CF), which include the following. 1) Nasal polyposis: an increasing prevalence from 18% in patients aged <6 years to 45% in adolescents/adults. 2) Focal biliary fibrosis: progresses to multilobular biliary cirrhosis in 5–10% of affected individuals. 3) Pancreatic insufficiency: occurs in 80–85% of infants and leads to malabsorption. 4) CF-related diabetes mellitus: an increasing prevalence from 2–3% in patients aged 6–10 years to 13.5–17.5% in patients aged 18–24 years. 5) Acute kidney injury: common with an estimated incidence of 4.6–10.1 cases in 10 000 children per year; chronic kidney disease is concentrated in adults. 6) Gastro-oesophageal reflux disease: observed in up to 80% of CF patients. 7) Obstructive azoospermia: results in infertility in ∼98% of males with CF. Stress urinary incontinence remains an under-reported issue in female CF patients. 8) Osteoporosis: suggested to have a pooled prevalence of 23.5% in adult CF patients. 9) Gastro-intestinal cancer: risk was found to be significantly increased in CF patient cohorts. 10) Macrovascular complications: emerging issue for CF patients. 11) Anxiety and depression: rates range from 10% to 30%.

    8. Page 236
      Correspondence: Jens Gottlieb, Hannover Medical School, Dept of Respiratory Medicine OE6870, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. E-mail:

      The vast majority of adult cystic fibrosis (CF) patients will develop respiratory failure. Lung transplantation in CF represents an established treatment option in end-stage lung disease. Both adolescents and children can receive transplants successfully. Due to donor shortage and increasing waiting time, early referral of possible candidates to transplant centres is of critical importance. During the process of candidate selection, presumed improvements in quality of life and survival benefit should be weighed against contraindications. Lung transplantation in CF needs special consideration with regard to candidate selection, surgery and post-operative follow-up care. Centre-based follow-up and close cooperation with primary care providers are key factors for success.

  6. Page 246
    1. Page 246
      Correspondence: Eitan Kerem, Dept of Pediatrics and CF Center, Hadassah Hebrew University Medical Center, Jerusalem, 91240, Israel. E-mail:

      Standards of care define the optimal service provision necessary to deliver the best outcomes possible for patients. People with cystic fibrosis (CF) have complex care needs that demand extensive medical and allied healthcare expertise. Several guidelines have been written to assist CF caregivers in the evaluation and monitoring of patients, detection of complications and prevention of clinical deterioration. The better clinical status and improved survival of patients with CF is a result of understanding of the molecular mechanisms of CF and the development of therapeutic strategies that are based on insights into the natural course of the disease. Current CF treatments that target respiratory infections, inflammation, mucociliary clearance and nutritional status are associated with improved pulmonary function and reduced exacerbations. Patients benefit from treatment at specialised CF centres by a multidisciplinary dedicated team, with emphasis being placed on frequent visits, periodic testing and monitoring adherence to therapy. However, the current published standards of care in Europe and North America cannot be fully implemented in populations or countries with limited resources and where CF services are in the early stages of development.

    2. Page 262
      Correspondence: Edward F. McKone, National Referral Centre for Adult Cystic Fibrosis, School of Medical Sciences, University College Dublin, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland. E-mail:

      Since their first introduction almost 50 years ago, cystic fibrosis (CF) registries have become an essential tool in improving our understanding of CF. More recently, CF registries have become important in the direct management of CF patients and have been developed to supply detailed information on how CF care is delivered throughout the world. This chapter will focus on the role of CF registries in improving quality of care for patients with CF. We will review the outcome variation and its interpretation in CF and the present and future role of CF patient registries in improving healthcare delivery through benchmarking, pharmaco-epidemiology and comparative effectiveness research.

    3. Page 272
      Correspondence: Alexandra L. Quittner, Dept of Psychology, University of Miami, 5665 Ponce de Leon Blvd, Coral Gables, FL 33146, USA, E-mail:

      Currently, there are no consistent procedures for transitioning adolescents from paediatric to adult cystic fibrosis (CF) care, and little empirical evidence exists on the best practices for transition. Given increased survival among patients with CF, a more formalised transition process is necessary to ensure continuity of care across the lifespan. This chapter reviews current transition practices and makes specific recommendations for more gradual, developmentally appropriate procedures involving all members of the CF care team. To ensure successful transition, providers should be aware of the normative milestones of adolescence and emerging adulthood, and how CF disrupts youths’ navigation of these milestones. Age-appropriate guidance should be given to adolescents and their families in gradual doses, beginning in early childhood and continuing until early adulthood. Importantly, the success of these recommendations depends on clear and active communication between paediatric and adult care teams, parents, and adolescents.

    4. Page 286
      Correspondence: Scott C. Bell, Adult Cystic Fibrosis Centre, The Prince Charles Hospital, Chermside, Queensland, 4032, Australia. E-mail:

      The number of adults with cystic fibrosis (CF) equals or exceeds that of children in many parts of the world. Consequently the size and number of adult centres has grown. In association with these increased numbers, the complexity of care of the adult has also increased. Emerging complications are commonplace and include diabetes, drug allergy and toxicity, difficulties with venous access and multiresistant infections. Strategies to enhance self-management require further evaluation in the setting of therapy requirements, which are increasingly complex. Planning for the provision of facilities and resources for the care of adults with CF, including training of multidisciplinary healthcare members, has been variable within and between countries. Novel models for the delivery of adult CF care may provide the opportunity to continue to deliver effective management to a rapidly growing population.

    5. Page 304
      Correspondence: Milan Macek Jr, Dept of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University, V Uvalu 84, Prague 5, CZ15006, Czech Republic. E-mail: Milan.Macek.Jr@LFmotol.Cuni.Cz

      There is an increasing need to manage cost-effectiveness issues of novel or relatively expensive technologies that are currently in use or being proposed for the treatment of cystic fibrosis (CF) (e.g. cystic fibrosis transmembrane conductance regulator (CFTR) modulation therapy). Health-economic evaluations of rising pharmacotherapeutic costs, as the major driver of overall cost, have to be part of the cost analysis of chronic and progressive (rare) diseases like CF that may require lifelong therapy. Total costs include not only direct healthcare costs but also the cost of lost productivity by both patients and family caregivers. When considering the results of cost-effectiveness analysis of new technologies associated with the management of CF, it is unreasonable to expect that the incremental cost-effectiveness ratio to be less than the generally applied thresholds (willingness to pay) for other common diseases. Therefore, when assessing CF and other rare diseases, such analyses should include complex health technology assessment approaches, which evaluate comparative treatment effectiveness (novel and established), as well as wider social benefits and ethical aspects.