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Over 7000 people have cystic fibrosis in the United Kingdom. It is the commonest genetically inherited disease in white populations (1 in 2500 newborns), although it is increasingly recognised as being important in non-white populations. However, most general practitioners have only one or two patients on their list, and as management generally takes place in specialist centres, many general paediatricians will be involved in the care of only a small number of patients.
Progress in our understanding of the disease and the impact of this on management has been rapid over the past 20 years. Cystic fibrosis used to be a digestive and lung disease of young children but more recently has become a complex, multisystem disease extending into adulthood; there will soon be more adults than children with the condition. The predicted median survival for babies born in the 21st century is now more than 50 years.1 This increased survival—together with changes in standard treatment, the increasing implementation of newborn screening, and the focus on new therapeutic strategies—leads us to consider that an update on this albeit relatively rare disease may be of general interest.
Cystic fibrosis is an autosomal recessive disease. It is caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene.2 The commonest mutation is the deletion of phenylalanine at codon 508 (phe508del, until recently known as ΔF508). This occurs in about 70% of patients with cystic fibrosis (www.ornl.gov/sci/techresources/Human_Genome/posters/chromosome/cftr.shtml). Over 1600 mutations of the CFTR gene have been described. Different mutations in this gene have varying effects on CFTR function and can result in different phenotypes of the disease. Some mutations will result in milder forms of the disease, although there is not enough evidence about these rarer mutations to counsel patients about their prognosis. The CFTR protein is expressed in many cells and has several functions, not all of which have been linked with disease. The primary function of the CFTR protein is as an ion channel that regulates liquid volume on epithelial surfaces through chloride secretion and inhibition of sodium absorption.
The commonly accepted explanation for airway disease in cystic fibrosis is the “low volume” hypothesis. A reduced volume of airway surface liquid causes failure of mucociliary clearance, the lungs’ innate defence mechanism.3 The mucociliary dysfunction means that a patient with cystic fibrosis cannot effectively clear inhaled bacteria. In addition, there is an excessive inflammatory response to pathogens. For a given bacterial load, a person with cystic fibrosis will have up to 10 times more inflammation than a person with a lower respiratory tract infection but without the disease. This may also be the case for other insults such as viruses or even for airborne particulate matter and pollutants. The reasons for the excessive inflammatory response to pathogens are not fully understood. The abnormal composition and secretion of mucus may also be important. At birth, the airway is uninfected and probably uninflamed, although some controversy exists in this area,4 but the end result of the abnormalities described above is irreversible airway damage with bronchiectasis and respiratory failure in most patients (fig 11).). Ion and water abnormalities may also cause disease in other epithelia-lined organs (see tables 11,, 33,, 44).”
Disease manifests in many organs, but most notably the upper and lower airways, pancreas, bowel, and reproductive tracts (table 11).5 For most patients, lung disease is the most important problem in terms of symptoms and the treatment required and the fact that it is the most likely cause of death. Table 11 outlines the clinical presentation, which varies according to age.
The optimal diagnostic test for cystic fibrosis is the measurement of sweat electrolyte levels.6 Patients with the disease have raised concentrations of sodium and chloride (>60 mmol/l, diagnostic; 40-60 mmol/l, intermediate (but more likely to be diagnostic in infants); <40 mmol/l, normal). However, undoubted cases of cystic fibrosis with normal sweat electrolytes have been described. Newer techniques have reduced the amount of sweat needed (fig 33).). The test needs to be done by someone trained and experienced. For this reason the diagnosis will usually be made in secondary and tertiary centres, although primary care professionals play a vital role in identifying the patients who need investigation. In the rare cases where the diagnosis remains in doubt, other diagnostic tests are available—for example, measurement of the nasal potential difference to assess altered salt transport is available in a few specialist centres in the UK.7
The UK now has a programme for screening all newborns for cystic fibrosis using the Guthrie blood spot test.8 The initial screen is for raised concentrations of immunoreactive trypsinogen. Positive samples will be tested for common CFTR gene mutations followed by a second screen for immunoreactive trypsinogen if required. Screen positive infants will be referred for sweat testing.
Screening programmes have been in place in some parts of the world for many years, but they may be inappropriate in countries with a low prevalence of CFTR gene mutations. The advantages of early diagnosis include nutritional benefits; early access to specialised care; a reduction in the time of diagnostic uncertainty; and the ability to counsel parents for prenatal testing.
Screening programmes have some negative aspects, however. Programmes will identify some healthy heterozygote carriers as potential patients. This may have psychological implications and stress for the family until the diagnosis is excluded. Moreover, some patients, even those with classic cystic fibrosis, will be missed.
Once a diagnosis has been confirmed, other family members may be offered screening. All siblings need to be screened for the disease, which may be presymptomatic or unrecognised. Asymptomatic adult relatives, may wish to be screened for carrier status to enable them to make informed choices about prenatal screening. In our experience, screening and counselling of other family membersis most readily facilitated through primary care but requires coordination between genetic laboratories to ensure rapid and cost efficient testing.
Most patients in the UK and Europe receive care coordinated by a tertiary cystic fibrosis centre, which improves outcomes. However, patients benefit greatly from links with and access to local care, in many cases having formalised “shared care” with local clinics. Primary care teams can provide valuable help with surveillance and early treatment of infection; dietary and nutritional support; and social and psychological support for patients and families. Primary care also provides continuity during the difficult transition from paediatric to adult care; an informative patient’s perspective of the issues encountered during this period has recently been published.9
Much of the current clinical practice has evolved over decades without being subjected to high quality randomised controlled trials. Tables 2-42-4 outline the various treatments and indicate those that are based on randomised controlled trials, meta-analyses, or systematic review and those that are treatments for which we consider consensus is lacking.
The aims of treating the lungs at different stages of disease vary; table 22 outlines the conventional management at each of these stages. Many of the treatment options have been discussed in systematic reviews. Respiratory treatments represent the greatest challenge to patients and families: doing physiotherapy and taking inhaled drugs such as antibiotics often takes up a lot of time—more than an hour a day during periods of good health and much longer during a respiratory exacerbation.
Patients with cystic fibrosis often have gastrointestinal problems; table 33 outlines the nature and management of these (management should be in close collaboration with a specialist dietician). Table 44 lists other complications of the disease, plus their management strategies.
Cystic fibrosis clearly poses a huge burden to patients and families in terms of the life shortening nature of the disease, the time consuming treatments prescribed, and the ongoing morbidity. Times of particular stress include diagnosis, adolescence (when adherence to treatment can often be poor), and end of life. Support and coping strategies from clinical psychologists with experience of the disease are often invaluable.20
We searched PubMed for the terms “cystic fibrosis”, “therapy”, “treatment”, “management”, “complications”, and “diagnosis” in various combinations. We also searched all entries under “cystic fibrosis” in the Cochrane Library. From this search, we selected randomised controlled trials, high quality journal reviews and meta-analyses. We also drew from our own personal archives of references from known leaders in this field.
Contributors: JCD wrote the original draft of this paper and all authors contributed to subsequent drafts. Jackie Francis provided certain photographic images. JCD acts as guarantor for the article.
Competing interests: JCD and EWFWA are members of the UK Cystic Fibrosis Gene Therapy Consortium.
Provenance and peer review: Commissioned; externally peer reviewed.