Cystic fibrosis - Suppurative lung disorders

Suppurative lung disorders

Cystic fibrosis

Definition

Autosomal recessive disorder with multisystem involvement including chronic suppurative lung disease, pancreatic insufficiency and liver cirrhosis.

Incidence

1 in 2500 births are homozygous, 1 in 25 carriers (heterozygous) in Caucasians.

Age

90% diagnosed in childhood, and 10% in adolescents and adults.

Sex

M = F

Geography

More common in Caucasians, uncommon in Orientals and Afro Caribbeans.

Aetiology

The condition is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene carried on the long arm of chromosome 7.

Seventy per cent of North European patients have the F508 mutation, which is a specific codon deletion resulting in deletion of a phenylalanine at position 508 within the amino acid sequence of the CFTR protein. Over 1000 other mutations have now been identified. There is poor correlation between the genetics and the clinical disease.

Pathophysiology

In normal mucus secreting epithelium the CFTR acts as an important cAMP-regulated chloride channel to facilitate secretion of sodium chloride and hence water, which results in low viscosity mucus. The mutation results in defective ion transport and nearly all exocrine glands are involved to a varying extent:

1.     In the lungs, which appear to be histologically normal at birth, increased production of thick viscous mucus plugs airways, leading to inflammation and secondary infection. Bronchiectasis (thickened, dilated bronchial walls) filled with purulent, thick secretions and areas of atelectasis develop. There may also be immunemediated damage by an influx of neutrophils releasing proteases.

2.     Viscous or solid material also obstructs the lumen of pancreas, small and large intestine, intrahepatic bile ducts and gallbladder.

3.     There is increased Na and Cl concentration in the sweat.

4.     There is also obstruction or maldevelopment of the vas deferens causing most males to be infertile, and increased viscosity of cervical secretions impairs fertility in some women.

Clinical features

10% of patients escape detection until adolescence or early adulthood.

Presentation:

·        40% with respiratory disease

·        25% with failure to thrive and malabsorption

·        15% at birth with meconium ileus due to viscous meconium

·        10% with liver disease

·        10% with rectal prolapse

With later disease, patients show use of accessory muscles of respiration, a barrelchest deformity, clubbing and cyanosis. Auscultation of the chest shows widespread coarse crackles.

Investigations

·        Diagnosis is by the sweat test which is positive if the Cl is above 60 mmol/L on two sweat tests in at least 75 mg of sweat (preferably 100 mg). Testing involves pilocarpin iontophoresis. Occasionally false positives or negatives occur.

·        Prenatal DNA screening by mutation analysis is possible for those with a previous sibling with CF. Widespread prenatal screening is not yet recommended.

·        Chest X-ray is initially normal, later there is generalised bronchial wall thickening and hyperinflation. Sputum culture for chest infection and lung function testing are useful.

Management

1. Non-pharmacological: Postural drainage, other manoeuvres and exercise, close liaison with a physiotherapist is essential.

2. Pharmacological:

Antibiotics used on the basis of regular sputum culture (prophylactic flucloxacillin may be used in first 2 years of life). Respiratory exacerbations should be treated with high-dose antibiotic courses lasting 2 weeks. Oral ciprofloxacin is useful for Pseudomonas aeruginosa infections. Regular nebulised gentamicin may be useful.

Bronchodilators may prove useful in those with reversible airways obstruction.

Agents to reduce the viscosity of the sputum may be used including acetylcysteine, triphosphate nucleotide and inhaled recombinant human deoxyribonuclease (rhDNase).

Malabsorption is treated with pancreatic enzyme supplements taken with all meals and snacks. Vitamin A, D and E supplements are used. NG or gastrostomy feeding is possible with either whole or partially digested food.

Appropriate vaccination against influenza, H. in fluenzae Strep pneumoniae, measles, pertussis and varicella.

Gene therapy is currently being researched in an attempt to ‘infect’ individuals with a retrovirus carrying the normal CF gene.

3. Surgical treatment: If the patient has a life expectancy of less than 18 months, lung (or heart–lung) transplantation is used with good result. Liver transplantation has been used in patients with endstage liver disease.

Prognosis

Median age of survival is 31 years but is expected to rise with improving therapies.