CYSTIC FIBROSIS

Cystic fibrosis (CF), the commonest cause of chronic lung disease and malabsorption syndrome in western countries, is rare in India though being increasing diagnosed in recent years on genetic testing.

Pathogenesis: CF is an autosomal recessive disorder of cystic fibrosis transmembrane conductance regulator protein (CFTR) gene on chromosome 7, with a pathognomonic defect in transport of salts (Na⁺ and Cl^-) and water across secretary epithelia, leading to:

• Desiccation of respiratory mucus, causing airway obstruction and chronic lung disease

• Desiccation of pancreatic and biliary secretions, causing obstruction of respective ducts with malabsorption/ biliary cirrhosis

• Desiccation of sweat, with increase in sweat Na⁺ and Cl^- contents.

• Similar abnormalities in other exocrine ducts, e.g. vas deferens (azoospermia), etc.

Carriers with single pathogenic variant may be asymptomatic or occasionally develop a disease limited to one organ system, known as CFTR-related disorder.

Clinically, CF is a multisystemic disease though respi­ratory manifestations are predominant cause of morbi­dity and mortality with variable time course.

Meconium ileus is the earliest presentation in ~10-20% newborns leading to intestinal obstruction, though most cases present beyond neonatal period with:

• Respiratory manifestations, e.g. recurrent infections and wheeze in early infancy, followed by secondary complications, e.g. bronchiectasis or recurrent pneu­mothorax. Sinusitis and nasal polyps are common.

• GIT manifestations, e.g. malabsorption due to exocrine pancreatic insufficiency, with failure to thrive, steatorrhea, hypoproteinemia, etc. Intermittent abdo­minal pain and intestinal obstruction is common.

• Skin manifestations, e.g. salty frost or taste over the skin. Excessive loss of salts in sweat also leads to hyponatremia and dehydration, specially in hot weather or febrile children.

• Late manifestations, e.g. biliary cirrhosis, diabetes, delayed puberty or sterility/infertility may develop in surviving adolescents.

Diagnosis depends on following criteria (A and B both): A. Presence of at least one of the following:

± At least one phenotype with chronic pulmonary disease, chronic sinusitis, characteristic gastro­intestinal and nutritional abnormalities, salt-loss syndromes or obstructive azoospermia;

± History of CF in a sibling;

± Positive newborn screening test.

B. PLUS at least one of the following:

± Elevated sweat chloride concentration (gt;60 mEq/L):

± Two CFTR gene mutations, known to cause CF on separate alleles:

± Abnormalities in nasal potential difference (NPD) testing typical for CF-NPD, suggesting abnormalities in ion transport across the nasal epithelium

For Sweat chloride test, minimum 50 mg of sweat is collected on a filter paper wrapped around the forearm or back, after stimulating sweat production by 3 mA current passed through pilocarpine (pilocarpine iontophoresis).

Prenatal diagnosis is possible with ~90% sensitivity, though neonatal screening in high-risk cases is more cost-effective for early diagnosis. It involves a spot-test to detect immunoreactive trypsinogen in cord-blood, though diagnosis must be further confirmed by sweat- chloride test or molecular studies.

Management aims to prevent/treat pulmonary compli­cations and secondary infections as well as to maintain adequate nutrition, as follows:

• Prevention of pulmonary complications with:

± Frequent nebulizations with hypertonic saline, to liquefy mucus followed by chest physiotherapy.

± Prolonged antibiotic therapy, specially to cover Pseudomonas and staphylococci-predominant pathogens in CF. Aerosolized tobramycin or aztreonam therapy 2-3 times a day on alternate months has been recommended in cases with chronic pseudomonas colonization to reduce morbidity.

± Treatment of acute exacerbations with oral or IV antibiotics, intensified airway clearance therapies, and respiratory support.

± Endoscopic removal of airway obstruction, e.g. mucus with bronchopulmonary lavage. Intra­bronchial antibiotics may also be instilled.

± Early diagnosis and treatment of complications, e.g. collapse, pneumothorax, hemoptysis, etc.

± Steroids, mucolytics and expectorants, though commonly used, are of limited value in CF.

• Nutritional therapy with adequate dietary support, pancreatic enzyme replacements, vitamin and mineral supplements, etc.

• Fluid and electrolyte correction in cases with significant salt depletion. Hypochloremic alkalosis is the commonest metabolic abnormality in CF.

• Treatment of other complications, e.g. meconium ileus, intestinal obstruction, pancreatitis, rectal prolapse, nasal polyps and liver disease, etc.

CFTR modulator therapy with many drugs, e.g. Ivacaftor, Lumacaftor, Tezacaftor and Elexacaftor,

has been recently approved for use in selected cases depending on the age and genotype, to modulate CFTR gene functions, either alone or in combinations.

Prognosis: Untreated cases succumb in early childhood due to lung problems, though supportive therapy has improved life span in recent years.

16.10.4