Cystic fibrosis

Overview

Cystic fibrosis (CF) is an inherited multisystem disease of exocrine glands. It is the major cause of severe chronic lung disease in children and the commonest cause of exocrine pancreatic insufficiency in early life (Akbar). Nelson gives it as much rarer in people of Asian heritage than in whites, but CF belongs in the differential of any child with chronic respiratory or gut symptoms, especially with clubbing.

Genetics, inheritance and pathophysiology

Genetics

• Autosomal recessive: both parents are carriers; each child has a 1 in 4 chance of being affected.
• Gene on the long arm of chromosome 7, coding for the cystic fibrosis transmembrane conductance regulator (CFTR).
• The commonest mutation is delta F508 (loss of phenylalanine at position 508); more than 1500 CFTR mutations are known (Nelson).
• CFTR is a cAMP-regulated chloride channel in the epithelium of the airways, pancreas, biliary tree, intestine, sweat glands and genital tract.

Pathophysiology

• Airways: cells cannot secrete chloride, so salt and water do not move onto the surface. The fluid layer around the cilia is too thin, mucus becomes dry, sticky and rubbery and cannot be cleared. Small airway obstruction is the earliest lung change, then infection, inflammation and bronchiectasis.
• Pancreas and bile ducts: the same thick secretions block the ducts, causing pancreatic damage and focal biliary fibrosis.
• Intestine: viscid meconium blocks the ileum (meconium ileus).
• Sweat glands: the duct normally reabsorbs chloride; in CF it cannot, so sweat is very salty. This is the basis of the sweat test.

Airway organisms

Staphylococcus aureus, Pseudomonas aeruginosa and Burkholderia cepacia; virulent Burkholderia strains are hard to treat and can speed deterioration (Nelson). Finding S. aureus or Pseudomonas in a child's sputum strongly suggests CF.

Clinical manifestations

Respiratory

• Cough, at first dry, later productive of purulent sputum.
• Recurrent chest infections, wheeze, breathlessness, exercise intolerance.
• Barrel chest, hyperresonance, coarse crackles, digital clubbing, cyanosis in advanced disease.
• Nasal polyps and pansinusitis.

Gastrointestinal

• Meconium ileus in 15 to 20% of affected newborns (Akbar; Nelson about 10%): abdominal distension, vomiting, failure to pass meconium in the first 48 hours.
• Pancreatic insufficiency in more than 85% (Nelson about 90%): frequent, bulky, greasy, foul-smelling stools; failure to gain weight; protein loss can cause hypoproteinaemia and oedema in early infancy (Nelson).
• Fat-soluble vitamin deficiency (A, D, E, K).
• Rectal prolapse.
• Biliary cirrhosis becomes symptomatic in 2 to 3% (jaundice, ascites, haematemesis from varices); cholestatic jaundice can be the first sign in infancy (Nelson).
• Pancreatitis, gallstones.

Sweat glands

• Heavy salt loss, especially in hot weather and during gastroenteritis: hyponatraemia and hypochloraemic metabolic alkalosis.

Reproductive

• Almost all males are infertile from congenital absence (obliteration) of the vas deferens.
• Females have reduced fertility from thick cervical mucus.

Diagnosis

Sweat test (standard test)

• Sweat is stimulated by pilocarpine iontophoresis (a small electric current carries pilocarpine into the forearm skin), collected on filter paper for 30 to 60 minutes and its chloride measured.
• Positive: chloride above 60 mEq/L. Normal: below 40 mEq/L (Akbar). Nelson calls 40-60 mEq/L borderline, requires an adequate sweat collection, and finds the test positive in 99% of patients with CF; cut-offs may be lower in infants under 6 months.
• Can be done after the first 48 hours of life, though infants under 2 weeks may not produce enough sweat.
• A positive result must be confirmed; a negative result is repeated if suspicion remains.

Diagnostic criteria

One or more of:

• typical clinical features (respiratory, gastrointestinal or genitourinary), or
• a sibling with CF, or
• a positive newborn screening test (raised immunoreactive trypsinogen),

plus laboratory evidence of CFTR dysfunction:

• two raised sweat chloride results on separate days, or
• two CF mutations on DNA testing, or
• an abnormal nasal potential difference.

Other tests

Sweat test pitfalls

Differential diagnosis

Nelson lists the presentations that should prompt a sweat test, and so the conditions CF must be separated from:

• Chest: recurrent bronchiolitis, recurrent wheeze or difficult asthma, persistent atelectasis, haemoptysis, Pseudomonas in the airway without another explanation.
• Gut: meconium ileus, other neonatal intestinal obstruction (meconium plug, atresia), steatorrhoea and malabsorption, childhood cirrhosis, prolonged cholestatic jaundice, pancreatitis, rectal prolapse.
• Other: failure to thrive, digital clubbing, nasal polyps, recurrent sinusitis, hyponatraemic hypochloraemic alkalosis in an infant, a sibling or cousin with CF, a salty taste of the skin.
• Akbar adds CF to the differential of bronchiolitis (repeated chest infections, malabsorption, raised sweat chloride).

Multidisciplinary management

Care is best coordinated by a multidisciplinary team at a CF centre (Nelson), with education of the child and parents and review every 1 to 3 months (Akbar). The aim is to keep the child stable for as long as possible.

Lungs

• Chest physiotherapy 2 to 4 times a day: breathing exercises, postural drainage with or without percussion.
• Antibiotics to prevent and treat infection, chosen by sputum culture; courses of 2 weeks or more at full doses (Nelson: 2-3 week IV courses for exacerbations).
• Inhaled therapy: bronchodilators, inhaled steroids, cromolyn.
• Nebulised 7% hypertonic saline 2 to 4 times daily improves mucus clearance.
• Recombinant human DNase (dornase alfa) 2.5 mg once daily by nebuliser thins secretions and improves lung function; N-acetylcysteine as a mucolytic.
• Nebulised tobramycin or aztreonam for Pseudomonas colonisation.
• Alternate-day steroids reduce inflammation.
• Bronchoscopic lavage of blocked airways in selected cases.
• Lung transplantation for end-stage disease.

Nutrition and gut

• High-calorie, high-protein diet: children with CF need more calories than usual to grow.
• Pancreatic enzyme replacement (lipase, amylase, protease) with feeds and meals. Lipase should not exceed 2,500 units/kg per meal; excessive doses cause colonic strictures.
• Vitamins A, D, E and K daily; zinc (to prevent acrodermatitis) and iron.
• Night-time tube feeds or gastrostomy, or short-term IV nutrition, when weight gain fails; growth hormone can improve height and weight velocity.
• Stool softeners; surgery for meconium ileus.
• Plenty of fluid and salt, especially in hot weather or with gastroenteritis; treat dehydration early, intravenously if needed.

Targeted and newer treatment

• Ivacaftor, a CFTR potentiator, for children with the G551D mutation (from 6 years; 150 mg twice daily orally): fewer exacerbations, lower sweat chloride, better weight.
• Gene therapy and drugs that boost chloride secretion are under study.

Complications

Long-term care, prognosis and prevention

• CF remains life-limiting: lung disease progresses slowly but eventually becomes disabling; Nelson gives a median survival in the mid-30s.
• With good medical and psychosocial support, many children reach a productive adult life.
• Long-term care: follow-up every 1 to 3 months, regular airway cultures to guide antibiotics (Nelson), nutrition and growth checks.
• Prevention: carrier detection (testing finds more than 90% of carriers) and prenatal DNA testing offered to families with an affected child, by amniocentesis or chorionic villus sampling (Nelson); newborn screening identifies many infants.

Quick revision

• Autosomal recessive; CFTR on chromosome 7q; delta F508 commonest.
• Thick secretions in lungs, pancreas, bile ducts, gut; salty sweat.
• Recurrent infections, bronchiectasis, clubbing, nasal polyps.
• Meconium ileus 15 to 20%; pancreatic insufficiency over 85%; vitamins A, D, E, K low.
• Salt loss: hyponatraemia with hypochloraemic metabolic alkalosis.
• Sweat chloride above 60 positive, below 40 normal, confirm on two days.
• Newborn screen: immunoreactive trypsinogen.
• Organisms: S. aureus, Pseudomonas, Burkholderia cepacia.
• Physiotherapy, antibiotics by culture, DNase 2.5 mg daily, 7% saline, tobramycin.
• Enzymes (lipase max 2,500 units/kg per meal), high-calorie diet, vitamins; males infertile.

Written by The House Job from standard references (Basis of Paediatrics by Pervez Akbar; Nelson Essentials of Paediatrics).

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