Cystic Fibrosis And Bronchiectasis
Cystic ﬁbrosis (CF) is the primary cause of severe chronic lung disease in children, although 90% of children now survive into their second decade (Fig. 34a). CF is characterized by chronic bronchopulmonary infection and airway obstruction (Fig. 34b) and by exocrine pancreatic insufﬁciency with consequent effects on gut function, nutrition and development. The key feature of CF is increased viscosity and subsequent stasis of epithelial mucus. There is usually an increased salt content of sweat. Figure 34c shows some associated disorders.
CF is an autosomal recessive trait that is the most common genetic cause of morbidity and mortality in the white population, with a prevalence of approximately 1 in 2000 live births; nearly 5% of white people of European descent are heterozygous carriers. Prevalence is far less in others, being approximately 1 in 17 000 for those of African descent. CF is due to mutations in a gene on chromosome 7 encoding for the cystic ﬁbrosis transmembrane conductance regulator (CFTR), a cyclic adenosine monophosphate (cAMP)-regulated epithelial chloride channel that can also alter activity of other ionic transporters. Dysfunction of CFTR impairs epithelial chloride, sodium and water transfer and thus causes reduced mucus hydration and increased viscosity (Chapter 18). Over 800 mutations in the CFTR gene have been described, but the most common, found in approximately 65% of patients with CF, is deletion of the phenylalanine codon at position 508, the .6F508 mutation.
The lungs of neonates with CF are often normal, but rapid development of respiratory symptoms, including refractory cough and infections, is usual. CF patients nearly always have an increased lung volume and ﬁnger clubbing (increased curvature of the nail and loss of normal angle between nail and nail bed) (Chapter 19). Recurrent bronchopulmonary infections, primarily as a result of defective mucus clearance, are rarely cleared once established and eventually result in bronchiectasis (see below), extensive lung damage and dysfunction. Spontaneous pneumothorax (Chapter 35) and haemoptysis (spitting blood; Chapter 45) are not uncommon. About 10% of neonates present with meconium ileus (failure to pass meconium), which can cause death in the firs day of life; 20% of older patients exhibit a similar ileal obstruction (meconium ileus equivalent, MIE). Eighty-five percent of patients have steatorrhoea (high fat stools) as a result of pancreatic insuff ciency. Some patients have only mild respiratory symptoms for many years, but this is inevitably followed by a characteristic increase in the frequency and severity of periods of exacerbation of symptoms (cough, dyspnoea, loss of appetite). Eventually, severe restrictions in activity herald the end-stage disease, followed by respiratory failure, hypoxaemia, pulmonary hypertension and death.
Several factors need to be taken into account, including a family history of the disease and the presence of typical respiratory and gastrointestinal disorders (Fig. 34c). A sweat chloride or sodium concentration above 60 mmol/L is diagnostic when coupled with such disorders, although approximately 1% of CF patients may have normal sweat electrolytes. DNA analysis can detect known mutations (e.g. .6F508), but is limited by the high number of unknown mutations. In later disease, chest X-rays can detect bronchiectasis (see below). Neonates can be screened for CF by blood immunoreactive trypsin, which can detect many, but not all cases.
The primary objectives of treatment are to control infection, promote mucus clearance and improve nutrition. Early antibiotic therapy is crucial to inhibit progression of the disease. Choice of antibiotic is determined following identificatio of infecting organisms. The dosage should be higher in CF patients and the course longer. Development of resistance is a key problem and is transferable; segregation of patients is thus advisable. Adequate immunization for measles, pertussis and influenz is important, as these organisms are particularly dangerous in CF.
Clearance: Training by physiotherapists in postural drainage (tip-ping the body so that the infected lobe is uppermost) is vital, coupled with chest percussion to mobilize secretions to the upper airways where they can be coughed up. Such treatment is prescribed one to four times a day. Recently introduced therapies include inhalation of DNase, an enzyme that breaks down DNA from dead cells, which contributes to mucus viscosity. Inhalation of aerosolized saline may improve mucus hydration, as may blockade of sodium reabsorption with amiloride or stimulation of chloride secretion with nucleotide triphosphates. Cough should never be suppressed, as it is an important method of clearance. Other therapies: Bronchodilators (β-agonists) may improve lung function, and corticosteroids may assist inflammatio in some patients. A potential therapy under intense investigation is gene transfer of the normal CFTR gene. In end-stage respiratory disease, a lung transplant should be considered.
Nutrition: Most patients with CF require pancreatic enzymes with meals, supplemented with vitamins. High-calorifi foods should be advised.
Bronchiectasis is an abnormal and permanent dilatation of proximal (>2 mm) bronchi due to inflammatio and subsequent destruction of the elastic and muscular components of their walls (Chapter 44). It is normally associated with defects in mucociliary clearance (Chapter 18) and persistent respiratory infections. Onset is often in childhood, following pulmonary infections complicating measles or pertussis. Since the introduction of antibiotics, the most common cause of bronchiectasis is now CF (Fig. 34d), except in poorly resourced countries. Symptoms depend on the severity and location of diseased bronchi, but commonly include persistent productive cough, with large quantities of foul-smelling purulent sputum as the disease worsens. Severity has been correlated with the volume of sputum produced, but not with dyspnoea. Haemoptysis and recurrent pneumonia or abscesses are common; haemoptysis is normally mild, but can become life-threatening, particularly in CF patients. Fever, anaemia and weight loss may accompany the disease. Patients often develop f nger clubbing, metastatic abscesses, respiratory failure and amyloidosis. Chest X-rays and high-resolution computed tomography (HRCT) can often detect the dilated and thickened bronchi (Chapter 45). Management is similar to that for CF, although without the nutritional uirements.