Clinical manifestations and consequences

Diagnosis of CF

Diagnosis is increasingly by newborn screening, measuring immunoreactive trypsin (iRT) and one or more ethnically appropriate genes on the routine heel-prick sample taken from the baby at 7–10 days of life. Diagnosis should always be confirmed with a sweat test. In patients with suspicious symptoms, diagnosis can almost always be made by a sweat test performed in an experienced centre (> 98% of cases), and the sweat test should be the first-line investigation. It should be noted that false-positive and false-negative tests will invariably occur at inexperienced centres. There are rare cases of genuine CF with equivocal or even normal sweat electrolytes. In these cases, ancillary diagnostic methods are needed, including genetic testing and measurement of transepithelial potential differences (in vivo in the nose, the usual method; in the lower airway; or in vitro on a rectal biopsy). These tests are only available in very few centres. Diagnostic algorithms have been published in Europe and the USA; they are very similar (see Further reading).

A further diagnostic issue is the spectrum of ‘CFTR-related’ disorders, and their relationship with CF. It is known that patients with idiopathic bronchiectasis, congenital bilateral absence of the vas deferens, idiopathic (non-alcoholic) pancreatitis, and severe sinusitis (all conditions seen in established CF) have a higher prevalence of CF mutations than would be expected; and indeed, in some adults, these are actually the first presentation of true CF. Most usually, the patient has a single CF mutation, a normal sweat test, and a single-organ manifestation such as bronchiectasis. In time, in some subjects, a second disease-producing mutation may be discovered, confirming the diagnosis of CF. The remainder are classed as having a CFTR-related disorder; in practice, the treatment of the single organ manifestation is driven by the nature of the disease, not by the diagnostic label.

Manifestations of CF

The basic details of the disease are described in standard books and monographs. When first described, CF was considered a pulmonary and digestive disease; now, it is known to affect most body systems. The important manifestations of CF, especially in longer-surviving patients, are shown in table 3.

Lower airway Chronic infection, especially with Staphylococcus aureus , Haemophilus influenzae and, in particular, Pseudomonas aeruginosa , together with a widening range of other Gramnegative rods; acute exacerbations; atypical mycobacterial infection; bronchiectasis; haemoptysis; pneumothorax; allergic bronchopulmonary aspergillosis
Upper airway Nasal polyps, sinusitis, rarely mucocele
Liver Biliary cirrhosis, portal hypertension, gall stones, bile duct stricture
Gastrointestinal comorbidity and complications Severe constipation, distal intestinal obstruction syndrome, Crohn’s disease, coeliac disease, giardiasis, cow’s milk protein intolerance, increased incidence of malignancy
Endocrine pancreatic failure Insulin deficiency, which adversely impacts on clinical state before frank diabetes mellitus develops
Bone disease Related to: CF itself (CFTR is expressed in bone), malabsorption of vitamin D and vitamin K, immobility, poor calcium intake, pubertal delay, gonadal failure, and the systemic effects of pro-inflammatory cytokines
Genito-urinary Infertility due to bilateral absence of the vas deferens, stress incontinence, vaginal candidiasis
Sweat gland Electrolyte depletion in the sweat (pseudo-Bartter’s syndrome)
Table 3 – Multi-organ complications of cystic fibrosis (CF). CFTR: CF transmembrane regulator.

Most of the morbidity and mortality of CF is still due to respiratory disease. The lungs are essentially normal at birth, but soon become chronically infected and inflamed. The conventional view is that the initial pathogens are usually Staphylococcus aureus and Haemophilus influenzae . Subsequently, chronic infection with Pseudomonas aeruginosa becomes established in most patients, although the prevalence of chronic infection is being reduced by attention to prevention of cross-infection in hospitals, and aggressive eradication regimes at the time of first isolation. This conventional view is having to be widened. Firstly, the aggressive use of antibiotics has led to the emergence of other Gram-negative bacilli, including the Burkholderia cepacia complex, Stenotrophomonas maltophilia , Achromobacter xylosidans and Pandoria apiospermum. Secondly, the use of anaerobic cultures has shown that lower airway flora contain at least as many anaerobes as P. aeruginosa . Finally, molecular microbiology (16s rRNA, for example) has shown a far more diverse bacterial and fungal flora in the lower airways of CF patients than was previously suspected. It is unclear whether the CF airway is intrinsically pro-inflammatory in the absence of infection, or whether there is an exaggerated response to infection or some other dysregulation of the control and resolution of infection. What is clear is that the intense inflammatory response is itself harmful, and, combined with chronic infection, leads to bronchiectasis, cor pulmonale and death from respiratory failure unless the patient receives a lung transplant.

In addition to chronic infection, there are periods of acute deterioration of respiratory symptoms, termed ‘pulmonary exacerbations’, or better, ‘CF lung attacks’. There is no agreed definition of a pulmonary exacerbation, despite the fact that reduction in frequency is commonly used as an end-point in clinical trials. They are common, and effects include: 1) a marked adverse effect on quality of life; 2) failure to recover baseline lung function in up to one-third of exacerbations; 3) an association with accelerated deterioration in lung function; and 4) an adverse impact on prognosis. Other important respiratory complications include allergic bronchopulmonary aspergillosis, pneumothorax (which carries a bad prognosis because of associated severe lung disease), massive haemoptysis, and lung or lobar collapse.

Many patients have malabsorption of nutrients caused by pancreatic insufficiency from diagnosis; ultimately, 85% of patients become pancreatic insufficient. Malabsorption should not be assumed to be due to pancreatic disease: coeliac disease, inflammatory bowel disease and the complications of neonatal surgery may all lead to steatorrhoea (an excess of fat in the faeces). A relatively common intestinal complication is distal intestinal obstruction syndrome (DIOS), caused by accumulation of thick tenacious secretions and malabsorbed fat in the terminal ileum. This must be distinguished from constipation, to which CF patients are also prone. Another more unusual gastrointestinal complication is biliary cirrhosis leading to portal hypertension.

As patients survive longer, systemic complications become more prominent. These include: CF-related diabetes, which eventually affects nearly half the pancreatic-insufficient CF population; bone disease leading to pathological fractures; and, particularly in women, stress incontinence.

Finally, although standard advice is that CF carriers are as healthy as the general population, there is a higher prevalence of CFTR mutations (i.e. more carriers) in groups of patients with single organ, CF-like disease.

Impact of CF on the individual

The diagnosis of CF, whether in the patient him/herself or a family member, may have a considerable economic impact. In particular, a woman who has become the mother of a CF child may refocus her career intentions, and opt to remain at home caring for the CF child rather than pursuing a career. Although many young people and adults with CF are in full- time education or employment, progression of the disease may curtail these activities. A spouse or parent may need to give up work, and rely on social security payments, as the patient becomes sicker. The other main fiscal costs for adults are time off work, community support and, for the rare really ill child, home tutoring. In the UK, adults will attain an employment rate that is 80% of that seen in a control population matched for age and sex. Half of CF adults are in paid employment, and around a quarter are in full-time education ( However, calculating the costs of CF to society should also take account of loss of productive working years in individuals with CF and their carers.

Costs of CF treatments: impact on health services and society

The costs of care vary with the stage of the illness, being highest in the year following diagnosis, and again rising later as the disease worsens. The vast majority (90%) of patients will use pancreatic enzyme replacement supplements, and many will use rhDNAse and nebulised antibiotics (tobramycin or colomycin), each costing several thousand euros per patient per year. These antibiotics are also now available in dry powder delivery devices, but this has not brought down the cost. Newer treatments are likely to be even more expensive. The emerging issue of the costs of genotype-specific treatments will be discussed in detail later.

It should also be noted that there are marked regional differences in the use of expensive treatments, suggesting that cost may be a factor in what patients receive. rhDNase was used in between 2% (Hungary) and 87% (Belgium) of patients in 2007, and nebulised antibiotics in 5% (Hungary) to nearly 50% (UK, Belgium, Germany). Chronic oral macrolide use ranges 0–35%.

The costs of treatment escalate as the patient becomes sicker. Treatment of lung disease is likely to involve repeated courses of expensive intravenous antibiotics. Patients being treated for atypical Mycobacteria are prescribed particularly expensive medications. As respiratory disease worsens, home oxygen and noninvasive ventilation may be required, and eventually very prolonged hospital stays are likely. Maintenance of good nutrition may require placement of a gastrostomy for supplemental enteral feeds. Treatment of CF-related diabetes, liver disease and bone disease adds to the rising costs, and these may culminate in the costs of lung transplantation.

Costs of emerging treatments: a new challenge

The cost of illness is likely to increase greatly with the advent of novel, expensive medications. Ivacaftor (VX-770) is a class III channel-opening small molecule, which has been tested in CF patients carrying at least one copy of the G551D mutation in a recent double-blind, placebo-controlled, 24-week trial. Patients receiving the active compound saw an increase of more than 10% in forced expiratory volume in 1 second (FEV1) (a key measurement of lung function), were half as likely to have a pulmonary exacerbation, gained on average 2.7 kg in weight, and, almost incredibly, halved their sweat chloride concentrations. This medication is licensed in the USA, where it costs $294 000 (about €220 000) per patient per year. The impact will depend initially on the country prevalence of CF, and the percentage of patients who carry the G551D mutation (Ireland has the highest prevalence, with 7.6% of its total CF population carrying G551D). In the UK, if all of the 5% of the CF population who carry at least one copy of G551D were prescribed the medication, the cost would be €75 million per year, raising the cost of CF care by about 50%. It is likely that VX-770 will be useful in other class III mutations, and possibly in some more common mutations in combination with a corrector such as VX-809, which facilitates the trafficking of misfolded class II mutations such as ΔF508 to the apical cell membrane. Strategies will be needed to decide who will benefit from these novel small molecule therapies, and how they will be financed.

See the entire Cystic Fibrosis Chapter