European Respiratory Society
Cystic Fibrosis (out of print)

This book has been superseded by a newer edition.

When CF was first described the disease was found to be affecting children who died as a result of it within the first few years of their life. However, it became clear that the CF phenotype differs between individuals and this may, in parallel with improved treatment, explain why certain affected individuals appear to have a more beneficial prognosis with prolonged survival. The knowledge regarding CF has increased tremendously. It is now clear that the disease is caused by a mutation in the gene coding for CF transmembrane conductance regulator, an ion channel responsible for chlorine transport in epithelial cells. The treatment has improved substantially and life expectancy has increased from approximately 6 months to 30 yrs. Treatment of airway infections and obstructions, nutritional repletion, anti-inflammatory therapy and lung transplantation have contributed to improve survival outcomes with the possibility of gene therapy soon becoming a probable option. In the present issue of the European Respiratory Monograph, current knowledge regarding CF has been acquired by authors who are true specialists in the field. Most aspects of CF have been covered and this Monograph will be an inestimable source of information for pulmonary physicians and scientists within the field.

  • European Respiratory Society Monographs
  1. Page vii
  2. Page viii
  3. Page 1
    Correspondence: G. Döring, Institute of Medical Microbiology and Hygiene, University of Tübingen, Wilhelmstrasse 3, 72074 Tübingen, Germany. Fax: 49 7071293011; Email:

    The complexity of lung disease in cystic fibrosis (CF) is thought to result from the combination of various mutations in the CF transmembrane conductance regulator gene and other, mainly unknown, disease-modifying genes. Several hypotheses have been put forward to link the basic defect in CF to chronic bacterial lung infection. As a consequence of mutated chloride channel, it has been proposed that bacteria cause infection in CF airways because defensins are inactivated, mucociliary clearance is defective, an increased number of receptors for bacterial pathogens are present on respiratory epithelial cells, killing of bacteria in epithelial cells is impaired, or airway inflammation precedes infection. A better understanding of the development of lung disease in CF will have a pronounced impact on therapeutic interventions.

  4. Page 21
    Correspondence: K.G. Brownlee, Leeds Teaching Hospitals Trust, St James’ University Hospital, Beckett Street, Leeds, LS9 7TF, UK. Fax: 44 1132067011 E-mail:

    The outcome for patients with cystic fibrosis (CF) has improved significantly over the last two decades and it is now unusual for children to die as a result of CF. However, the process of CF lung disease begins soon after birth and progresses throughout childhood. The small airways have been referred to as the Achilles heel of patients with CF because they are especially vulnerable to the triad of infection, inflammation and obstruction that characterises CF lung disease. The classical clinical picture of a chronic productive cough, chronic Pseudomonas aeruginosa infection, severe bronchiectasis and severe clubbing is now less common in children. Increasingly patients are seen with severe obstructive lung function, no regular pathogens in respiratory secretions, and a nonproductive cough and wheeze. Do these patients represent the severe end of the spectrum of small airways disease despite controlled airway infection? Airway wall thickening and lumen obstruction begins very early in the course of CF lung disease. However, because the small airways are responsible for only a small proportion of total airway resistance and under normal circumstances there is substantial respiratory reserve, their loss and obstruction can go unnoticed. Once spirometry is abnormal and significant symptoms are present substantial damage has already occurred. Respiratory function and radiological techniques are beginning to be developed that are sensitive to early change in the small airways and are applicable to young children. To achieve the next significant improvement in outcome of patients with CF, it is likely that small airway obstruction and inflammation need to be targeted early with drugs that are effective and safe.

  5. Page 38
    Correspondence: K.W. Southern, Institute of Child Health, University of Liverpool, Royal Liverpool Children’s Hospital, Eaton Road, Alder Hey, Liverpool L12 2AP, UK. Fax: 44 1512525456; E-mail:

    Cystic fibrosis (CF) is a recessively inherited condition caused by mutation of the CF transmembrane conductance regulator (CFTR) gene. Characterisation of the genetic defect has improved understanding of the condition and, in the majority of cases, diagnosis is straightforward. However, in a significant number diagnosis remains a challenge. This article will explore these issues, in particular reflecting on the pre-symptomatic child identified through screening and older patients with atypical presentations. The importance of a thorough clinical assessment and sweat testing will be highlighted. In addition, further investigations that may help in determining CFTR function, such as nasal potential difference measurement, will be considered. There is increasing evidence that mild CFTR dysfunction may be associated with single organ pathology; congenital bilateral absence of the vas deferens, chronic rhinosinusitis and chronic pancreatitis are three such conditions. In some cases, these presentations represent mild CF phenotypes (and further investigation reveals involvement of other organs); however, the evidence suggests that heterozygotes may be predisposed.

  6. Page 50
    Correspondence: H. Grasemann, Division of Respiratory Medicine, The Hospital for Sick Children, 555 University Ave, Toronto, M58 1XA ON, Canada. Fax: 1 416 813 6246; E-mail:

    Phenotypic variability in monogenic disorders can often not be explained by mutations in the disease-causing gene alone. Several examples show that other nondisease causing genes can alter the course of monogenic disorders. Defining these so-called modifier genes and their relative contribution to disease phenotype will not only improve our understanding of pathological processes but will also help to identify new therapeutic targets. Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene that encodes for a chloride ion channel. CFTR mutations lead to multi-organ disease, although primary morbidity and mortality is related to lung. However, the course of CF lung disease is highly variable even in siblings and twins carrying the same CFTR mutations, supporting the concept that other genetic factors modify the phenotypic appearance of the disease. Studies in recent years, therefore, have been aimed at identifying disease modifier genes in CF. Several candidates have been under investigation, including genes that may affect CFTR function, protein folding and stability, ion transport by alternative channels, innate and adopted immune response, oxidative stress, airway inflammation and progression of chronic lung disease, as well as genes involved in defence mechanisms against bacteria.

  7. Page 66
    Correspondence: N. Høiby, Dept Clinical Microbiology, 9301 Rigshospitalet, Juliane Maries Vej 22, 2100, Copenhagen, Denmark. Fax: 45 35456412; E-mail:

    The mean life expectancy for cystic fibrosis (CF) patients has improved significantly due to improved treatment, especially concerning respiratory infections. Although Pseudomonas. aeruginosa and Staphylococcus aureus are still the most important pathogens concerning morbidity and mortality, a number of other bacteria have emerged as probable or possible pathogens that give rise to increasing diagnostic and therapeutic problems. These pathogens comprise members of the normal pharyngeal flora such as Moraxella sp. and bacteria from the environment, such as Burkholderia cepacia complex, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, Pandoraea sp., Nontuberculous mycobacteria, and a few other species.

    Some of these bacteria have the capacity to spread from patient to patient and some give rise to chronic infection resembling chronic P. aeruginosa infection with a pronounced antibody response. Most of these bacteria are still found in a few CF patients in individual CF centres and consequently larger clinical investigations cannot be undertaken unless networks of centers cooperate.

    Since the situation concerning P. aeruginosa in CF patients was similar 35 yrs previously, where the clinical importance of these bacteria was uncertain, a systematic strategy is suggested whereby the pathogenic property of a given emerging pathogen may be identified in CF patients. This strategy has proven efficient in CF patients colonised or infected with P. aeruginosa.

  8. Page 79
    Correspondence: J.C. Davies, Dept of Gene Therapy, Imperial College, Emanuel Kaye Building, Manresa Rd, London SW3 6LR, UK. Fax: 44 2073518340; E-mail:

    The last decade has brought with it great advances in understanding the hurdles to successful cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy. Some of these have been overcome whilst others remain as significant challenges. Alongside the improvements in gene transfer agents (GTAs) and plasmids being engineered at the bench, there is an urgent need for clinicians to develop and validate a collection of sensitive assays correlating with clinical outcome. Without this groundwork there is a very real possibility that the study design will prove inadequate to allow a clinically useful product to be recognised as such.

    The UK Cystic Fibrosis Gene Therapy Consortium (, comprising the present authors’ groups and those from Oxford and Edinburgh, UK, was recently formed to take CFTR gene therapy forward into clinical trial. It is believed, based on the evidence presented above, that at the current time, the only possible way forward is with the use of nonviral GTAs, which can be repeatedly administered. The present authors have previously demonstrated proof-of-concept of gene transfer to the lower airways using this approach and are moving forward into a multidose clinical trial, looking, for the first time, for clinical benefit. Prior to this, much effort had been focused on developing robust end-point assays, ranging from the molecular through to clinical. Whilst recognising that this trial may not be with the perfect product in its final form, it will provide the much needed opportunity to address the crucial question of whether clinical benefit can be achieved by this approach, and will enable a tie in of molecular and clinical end-points, thus, greatly improving trial design for future, refined GTAs. Only by pooling resources, avoiding duplication of effort and playing to individual strengths in a collaboration such as this, can the very substantial hurdles be overcome and the promise of gene therapy for cystic fibrosis be fulfilled.

  9. Page 88
    Correspondence: L.J.V. Galietta, Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, L.go G. Gaslini 5, 16148 Genova, Italy. Fax: 39 0103779797; Email:

    Cystic fibrosis (CF) is caused by mutations in the gene coding for the CF transmembrane conductance regulator (CFTR), a membrane channel mediating cyclic adenosine monophosphate-dependent chloride ion transport in epithelial cells. CF mutations alter CFTR protein structure/function in many different ways. Deletion of phenylalanine 508 (F508del), the most frequent mutation in CF patients, alters CFTR structure so that it is largely unable to escape the endoplasmic reticulum and to reach the plasma membrane. In addition, when targeted to the plasma membrane, F508del protein shows also a reduced ability of channel opening, and an accelerated rate of internalisation compared with wild-type CFTR. Other CF mutations may impair the channel opening process without alteration of the trafficking or may cause premature truncation of protein synthesis. Recent studies have shown the feasibility of a pharmacological approach aimed at correcting the CFTR primary defect caused by CF mutations. Various chemical compounds called CFTR potentiators or openers show the ability to stimulate the opening of mutant CFTR channels by a possible mechanism involving direct interaction with the defective protein itself. Other types of compounds, called F508del correctors, have the effect of improving the trafficking of the mutant protein to the plasma membrane, thus increasing the amount of CFTR protein available for Cl transport. Finally, other types of compounds, e.g. aminoglycosides antibiotics, can induce the read-through of stop codon mutations, thus allowing synthesis of almost normal full-length CFTR protein. In conclusion, there is an emerging number of small molecules that are promising as possible pharmacological tools with which to treat CF patients.

  10. Page 105
    Correspondence: S.C. Bell, Adult Cystic Fibrosis Centre, The Prince Charles Hospital, Chermside, Brisbane, 4032, Australia. Fax: 61 732125630; Email:

    Pseudomonas aeruginosa is the principal pathogen for individuals with cystic fibrosis (CF). Historically, cross-infection by P. aeruginosa was not thought to be a problem in CF. However, recently compelling evidence for P. aeruginosa cross-infection has emerged at some CF centres in Australia and Europe. Some clonal strains appear confined to single specialist CF centres, whilst other clonal strains have been isolated from patients at a number of geographically distinct centres. The findings of a number of studies suggest that patient-to-patient transmission may be a mode of spread. Microbiological surveillance for P. aeruginosa cross-infection is dependent on molecular typing of isolates coupled with epidemiological findings. The optimal molecular method and frequency of strain typing is unknown. Data from early studies indicates that infection with clonal strains may increase patient morbidity. It is probable that virulence is strain specific. A small number of cases in which patients with non-CF chronic lung disease acquired infection with clonal P. aeruginosa strains, which have previously been isolated from CF patients, have also been described. The introduction of infection control policies, in particular cohort segregation to control the spread of clonal strains, remains contentious. The implementation of measures to combat spread of clonal P. aeruginosa strains will challenge the currently available resources of all large specialist CF centres.

  11. Page 127
    Correspondence: B. Fauroux, Armand Trousseau Hospital, Assistance Publique – Hôpitaux de Paris, 28 avenue du Docteur Arnold Netter 75012 Paris, France. Fax: 33 144736718; Email:

    Cystic fibrosis (CF) lung disease is characterised by a progressive decline in lung function which eventually leads to progressive end-stage respiratory failure. A physiological rationale has been developed for the use of noninvasive positive-pressure ventilation (NPPV) in CF patients with advanced lung disease. Indeed, as lung disease progresses, as reflected by a fall in the forced expiratory volume in one second, there is an increase in the respiratory muscle load. As a result, the patients develop a rapid shallow breathing pattern in an attempt to reduce the increase in load and maintain the level of ventilation. Despite the preservation of diaphragmatic strength, this increase in respiratory load translates into progressive alveolar hypoventilation with a rise in partial arterial carbon dioxide pressure.

    Short-term physiological studies, during wakefulness and sleep, have demonstrated that NPPV reduces respiratory muscle load and work of breathing, and increases minute ventilation, thus improving alveolar ventilation and gas exchange. NPPV has been shown to reduce oxygen desaturation during exercise and chest physiotherapy. Different ventilatory modes have been used with success in patients with CF.

    Future studies need to assess the long-term benefits of NPPV on survival, decline of lung function and quality of life, as well as clarify the criteria as to when NPPV should be initiated in patients with CF.

  12. Page 139

    Lung transplantation has become an accepted therapeutic option for patients with cystic fibrosis (CF) and advanced lung disease. This presents a challenge for the physician who cares for CF patients. Which patients are suitable for consideration of transplantation? What are the absolute and relative contra-indications? When do I refer my patient for transplantation?

    This article deals with difficult issues currently facing transplant physicians as they attempt to maximise both the number of patients who are suitable for transplantation and the long-term success for recipients. There are sections on microbiology (particularly with respect to Burkholderia cenocepacia, fungi and mycobacterial disease), liver disease and Clostridium difficile colitis. Finally the manuscript discusses indications for referral and timing of transplant listing.

  13. Page 150
    Correspondence: C.S. Haworth, Adult Cystic Fibrosis Centre, Papworth Hospital NHS Foundation Trust, Cambridge CB3 8RE, UK. Fax: 44 1480364330; E-mail:

    Low bone mineral density (BMD) was first reported in patients with cystic fibrosis (CF) over 25 yrs ago and, since that time, research has concentrated on documenting the prevalence, natural history, prevention and treatment of CF-related low BMD. These studies show that 15-25% of CF adults have a BMD Z score below -2 in the lumbar spine or proximal femur when measured by dual energy X-ray absorptiometry. Histomorphometry confirms that the low BMD identified by densitometry in CF adults is real. A few patients have osteomalacia, and measuring the 25-hydroxyvitamin D (25OHD) and parathyroid hormone concentrations should identify these individuals. Reduced bone formation appears to be the predominant problem possibly due to inhibition of mature osteoblasts or increased osteoblast apoptosis. It is likely that increased bone resorption occurs during periods of ill health/infection and as disease severity worsens. This is supported by data from bone turnover markers. The aetiology of the documented low BMD appears complex. Numerous studies have found associations with low BMD and forced expiratory volume in one second, body mass index and intravenous antibiotic use. These factors are likely surrogates for disease severity and more recent data suggest that cytokines may play a role in bone loss. Many studies document low levels of 25OHD; however few have found low 25OH vitamin D to correlate with low BMD. It is highly probable that low serum 25OHD levels contribute to the loss of bone by causing intermittent secondary hyperparathyroidism and a consequent increase in bone turnover. Recent data demonstrate difficulty in achieving adequate serum levels of 25OHD with wide variability in vitamin absorption. More interest has also being shown in elucidating the role of low serum vitamin K and decreased bone formation.

    In this chapter, current knowledge is summarised, the authors’ thoughts on management are outlined, and current areas of uncertainty that require further research are discussed.

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