Case 7.5 – Cystic Fibrosis [SDL]

A correlation may be made between the mutation and the patient's clinical condition. Based on current knowledge of the association between genotype and phenotype, the clinical characteristics of patients with cystic fibrosis (CF) are divided into severe, milder than severe, and variable phenotypes.

The affected organs include:

Respiratory tract:

• Ask about cough, chronic or recurrent cough, which can be dry and hacking at the beginning and later mucoid (early) and purulent (later) sputum
• Other respiratory symptoms may include wheezing, recurrent pneumonia, atypical asthma, pneumothorax, hemoptysis, and digital clubbing are all complications and may be the initial manifestation
• Check for increasing shortness of breath

Pancreatic dysfunction:

• Check for use of pancreatic supplements and the adequacy of replacement
• Steatorrhea is characterized by frequent, poorly formed, large, bulky, foul-smelling, greasy stools that float in water
• Check for weight loss, recurrent abdominal pain, and abdominal distention

Hepatobiliary:

• Check for symptoms of biliary dysfunction such as nausea, vomiting, dark urine, bleeding
• Patients may present with a history of jaundice or gastrointestinal tract bleeding

Urogenital tract manifestations:

• Males are frequently sterile because of the absence of the vas deferens
• Undescended testicles or hydrocele may exist

Physical examination includes:

• Nose: Rhinitis, nasal polyps
• Respiratory system: Tachypnea, degree of distress, wheeze or crackles, cough, sputum, diameter of chest, clubbing, cyanosis, crackles
• Gastrointestinal tract: Abdominal distention, hepatosplenomegaly, rectal prolapse

Respiratory:

• Infective exacerbations of bronchiectasis
• Spontaneous pneumothorax
• Haemoptysis
• Nasal polyps
• Respiratory failure
• Cor pulmonale
• Lobar collapse due to secretions

Gastrointestinal:

• Malabsorption and steatorrhoea
• Distal intestinal obstruction syndrome
• Biliary cirrhosis and portal hypertension
• Gallstones

Others:

• Diabetes (25% of adults)
• Delayed puberty
• Male infertility
• Stress incontinence
• Psychosocial problems
• Osteoporosis
• Arthropathy

The lungs are macroscopically normal at birth, however bronchiolar inflammation and infections usually lead to bronchiectasis in childhood.

The lungs become infected, most commonly with Staphylococcus aureus. Later, the majority of patients have Pseudomonas aeruginosa infection by the time they reach adolescence. Recurrent exacerbations of bronchiectasis, initially in the upper lobes but subsequently throughout both lungs, cause progressive lung damage resulting ultimately in death from respiratory failure.

Other clinical manifestations of the gene defect include intestinal obstruction, exocrine pancreatic failure with malabsorption, diabetes and hepatic cirrhosis.

Most men with CF are infertile due to failure of development of the vas deferens, but microsurgical sperm aspiration and in vitro fertilisation are now possible.

The genotype is a poor predictor of severity of disease in most individuals; even siblings with matching genotypes may have quite different phenotypes. This suggests that other 'modifier genes' (as yet unidentified) influence clinical outcome.

Chest physiotherapy:

Regular chest physiotherapy is essential to maintain airway clearance.

Treat infections:

• While infections with Staph. aureus can often be managed with oral antibiotics, intravenous treatment is needed for Pseudomonas species
• Nebulised antibiotic therapy, mainly with colomycin or tobramycin is used between exacerbations in an attempt to suppress chronic Pseudomonas infection
• Unfortunately, the bronchi of many CF patients eventually become colonised with pathogens which are resistant to most antibiotics
• Resistant strains of P. aeruginosa, Stenotrophomonas maltophilia and Burkholderia cepacia are the main culprits, and may require prolonged treatment with unusual combinations of antibiotics
• Aspergillus and 'atypical mycobacteria' are also frequently found in the sputum of CF patients, but in most cases these behave as benign 'colonisers' of the bronchiectatic airways and do not require specific therapy

Treat co-incidental airways diseases:

Treat co-incidental airways diseases such as asthma if present.

Nebulised DNase:

• Treatment with nebulised recombinant human deoxyribonuclease (DNase) has been available since 1994
• The aim of this is to liquify the sputum by breaking up the excess viscous DNA derived from disintegrated inflammatory cells
• Careful monitoring of response to treatment is appropriate as this treatment is very expensive

Non-respiratory aspects of CF must be considered:

• There is a clear link between good nutrition and prognosis in CF
• Malabsorption is treated with oral vitamins and pancreatic enzyme supplements and the increased calorie requirements of CF patients are met by supplemental feeding including nasogastric or gastrostomy tube feeding if required
• Diabetes will eventually appear in about 25% of patients and often requires insulin therapy
• Osteoporosis secondary to malabsorption and chronic ill health should be sought and treated

Long term treatments:

• For advanced CF lung disease, home oxygen and non-invasive ventilation may be necessary to treat respiratory failure
• Ultimately, lung transplantation can produce dramatic improvements but is limited by donor organ availability

The discovery of the CF gene and the fact that the lethal defect is located in the respiratory epithelium (which is accessible by inhaled therapy) presents an exciting opportunity for gene therapy.

Manufactured normal CF gene can be 'packaged' within a viral or liposome vector and delivered to the respiratory epithelium to correct the genetic defect.

Initial trials in the nasal and bronchial epithelium have shown some effect, and further trials of nebulised bronchial delivery are planned.

Improved gene transfer efficiency is needed before this will become a practical clinical treatment.

Abbreviation	Stands for
FEV1	Forced expiratory volume in 1 second
FVC	Forced vital capacity
VC	Vital capacity (relaxed)
PEF	Peak (maximum) expiratory flow
TLC	Total lung capacity
FRC	Functional residual capacity
RV	Residual volume
TLCO	Gas transfer factor for carbon monoxide
KCO	Gas transfer per unit lung volume