Cystic fibrosis (CF) is an autosomal-recessive disorder caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR), a gene located on chromosome 7.
- CF is the most common lethal genetic disease in whites, with an incidence of 1 in 3,200 live births in the United States. Although CF is less common in nonwhites, the diagnosis needs to be considered in patients of diverse backgrounds.
- The diagnosis of CF is typically made during childhood, but 8% of patients are diagnosed during adolescence or adulthood.
- With improved therapy, the median survival has been extended to approximately 35 years.
- Predictors of increased mortality include age, female gender, low weight, low forced expiratory volume in 1 second (FEV1), pancreatic insufficiency, diabetes mellitus, infection with Burkholderia cepacia, and the number of acute exacerbations.
- CFTR normally regulates and participates in the transport of electrolytes across epithelial cell and intracellular membranes. The primary pulmonary manifestations of disease are thought to be related to abnormal electrolyte transport in the airway, which results in desiccated airway secretions and impaired mucociliary clearance. Secretions become infected, and a vicious cycle of infection, inflammation, and chronic airway obstruction ensues, resulting in bronchiectasis, chronic infection, and ultimately premature death.
The diagnosis of CF is based on a compatible clinical and family history and persistently elevated concentrations of sweat chloride, two known disease-causing CF mutations, or nasal transepithelial potential difference
measurements that are typical of CF. Atypical patients may lack classic symptoms and signs or have normal sweat tests. Although genotyping may assist in the diagnosis, it alone cannot establish or rule out the diagnosis of CF, and the initial test of choice remains the sweat test.
- Pulmonary symptoms lead to consideration of the diagnosis of CF in 50% of cases. In almost all patients, chronic (sino) pulmonary disease eventually develops, most notable for bronchiectasis and chronic airflow obstruction.Symptoms initially include cough and purulent sputum production. Dyspnea ensues as the disease progresses. Acute pulmonary disease exacerbations may lead to significant deterioration and subsequent hospitalization. Isolation of mucoid variants of Pseudomonas aeruginosa from the respiratory tract occurs frequently.
- Extrapulmonary manifestations of CF include pancreatic exocrine insufficiency, which is seen in 90% of patients and leads to fat malabsorption and malnutrition. Pancreatitis occasionally develops. Gastrointestinal (GI) complications include distal intestinal obstruction syndrome, volvulus, intussusception, and rectal prolapse. CF also affects the endocrine pancreatic (diabetes mellitus in approximately 20% of adults), the hepatobiliary system (fatty liver, cirrhosis, portal hypertension, cholelithiasis, and cholecystitis), the genitourinary (male infertility and epididymitis), and the skeletal (retardation of growth, osteoarthropathy, osteopenia) systems. Digital clubbing appears in childhood in virtually all symptomatic patients. Although fertility may be decreased in women with CF secondary to thickened cervical mucus, many women with CF have tolerated pregnancy well.
- Skin sweat testing with a standardized quantitative pilocarpine iontophoresis method remains the gold standard for the diagnosis of CF.
- A sweat chloride concentration of >60 mmol/L is consistent with the diagnosis of CF. However, the diagnosis requires an elevated sweat chloride concentration on two separate occasions in a patient with a typical phenotype or with a history of CF in a sibling. Borderline sweat test results (40-60 mmol/L sweat chloride) or nondiagnostic results in the setting of high clinical suspicion should also lead to repeat sweat testing, nasal potential difference testing, or genetic testing. Sweat testing should be performed at a CF care center to ensure reliability of results. Abnormal sweat chloride concentrations are rarely detected in non-CF patients (e.g., Addison disease and untreated hypothyroidism).
- Genetic tests have detected more than 1,000 putative CF mutations.
- Two recessive genes must be abnormal to cause CF. The most commonly encountered CF mutation is the CFTR mutation, which is present inapproximately 70% of alleles in affected individuals.
- Commercially available probes identify more than 90% of the abnormalgenes in a white Northern European population, although they test for only aminority of the known CF genes.
- Sputum cultures typically identify P. aeruginosa or Staphylococcus aureus , or both, and sputum sensitivity testing should direct therapy.
- Testing for malabsorption due to pancreatic exocrine insufficiency is often not formally performed, because clinical evidence (the presence of foul-smelling, bulky, and loose stools; low fat-soluble vitamin levels [vitamins A, D, and E]; and a prolonged prothrombin time [vitamin K dependent]) and a clear response to pancreatic enzyme treatment are usually considered sufficient for the diagnosis.
- Tests that identify chronic sinusitis or infertility, especially obstructiveazoospermia in men, would also support the diagnosis of CF.
- Monitoring of electrolytes is indicated in patients with a history of electrolyte abnormalities or renal insufficiency.
- Typically chest radiography eventually shows enlarged lung volumes, with cystic lung disease and bronchiectasis, especially in the upper lobes.
- Pulmonary function tests eventually show expiratory airflow obstruction with increased residual volume and total lung capacity. Impairment of alveolar gas exchange may be present as well, progressing to oxyhemoglobin desaturation with exertion, hypoxemia, and hypercapnia.
- High-resolution CT scan may be helpful in evaluating patients with early or mild disease.
- Respiratory tract disease is characterized by neutrophil-dominated airway inflammation with the development of bronchiectasis. Airway obstruction may lead to focal pneumonia and areas of cavitation within the lung.
- Interstitial fibrosis is seen with more advanced disease.
- Primary ciliary dyskinesia or immunoglobulin deficiency may lead to bronchiectasis, sinusitis, and infertility. However, limited GI symptoms and normal sweat electrolytes distinguish these diseases from CF.
- Shwachman syndrome, consisting of pancreatic insufficiency and cyclic neutropenia, may also lead to lung disease, but sweat chloride concentrations are normal and the neutropenia is distinguishing.
- Men with Young syndrome have bronchiectasis, sinusitis, and azoospermia, but this disorder only has mild respiratory symptoms, lacks GI symptoms, and has normal sweat chloride levels.
CF therapy aims to improve quality of life and functioning, decrease the number of exacerbations and hospitalizations, avoid complications associated with therapy, and decrease mortality. A comprehensive program addressing multiple organ/system derangements, as provided at CF care centers, is recommended.
The greatest number of adults with CF have significant lung disease and a large portion of therapy is focused on clearing pulmonary secretions and controlling infection.
- Avoidance of irritating inhaled fumes, dusts, or chemicals including second-hand smoke is recommended.
- Inhaled bronchodilators such as b-adrenergic agonists (albuterol metered-dose inhaler [MDI], two to four puffs; salmeterol or formoterol,one dry powder inhalation bid) are used to treat the reversible components of airflow obstruction and facilitate mucus clearance (see Chronic Obstructive Pulmonary Disease). These agents are contraindicated in the rare patient with associated paradoxical deterioration of airflow after their use.
- Airway clearance for pulmonary disease may be accomplished by various airway clearance techniques, including postural drainage with chest percussion and vibration, with or without mechanical devices (flutter valves, high-frequency chest oscillation vests, low- and high-pressure positive expiratory pressure devices, etc.), and breathing and coughing exercises.
- Recombinant human deoxyribonuclease (Dnase, dornase, Pulmozyme) digests extracellular DNA, decreasing the viscoelasticity of the sputum. It improves pulmonary function and decreases the incidence of respiratory tract infections that require parenteral antibiotics.The recommended dose is 2.5 mg (one ampule) per day inhaled using a jet nebulizer. Adverse effects may include pharyngitis, laryngitis, rash, chest pain, and conjunctivitis.
- Hypertonic saline. A recent study showed fewer exacerbations and possible improvement in lung function in patients treated with 4 mL of inhaled 7% saline twice daily. Inhaled bronchodilators should be administered prior to treatments to avoid treatment-induced bronchospasm.
- Antibiotics. P. aeruginosa is the most frequent pulmonary pathogen. A combination of an IV semisynthetic penicillin, a third- or fourth-generation cephalosporin, or a quinolone and an aminoglycoside is typically recommended during acute exacerbations. Sputum culture sensitivities should guide therapy.
- Patients with CF have atypical pharmacokinetics and often require higher drug doses at more frequent intervals. In patients with CF, for example, cefepime is often dosed at 2 g IV q8h and gentamicin or tobramycin is often dosed at 3 mg/kg IV q8h (aiming for peak levels of 10 mg/mL and trough levels of <2 mg/mL). Once-daily aminoglycoside dosing should be guided by pharmacokinetic testing.
- Antibacterial Agents, Anti-inflammatory therapy. The anti-inflammatory effects of short courses of glucocorticoid therapy may be helpful to some patients, but long-term therapy should be avoided to minimize the side effects that include glucose intolerance, osteopenia, and growth retardation. High-dose ibuprofen has been used as a chronic anti-inflammatory in patients with mild impairment of lung function.
- Azithromycin. Recent studies have shown that chronic PO azithromycin (500 mg PO Mon, Wed, Fri) mildly improves lung function and reduces days in the hospital for treatment of respiratory exacerbations in patients who are chronically infectedwith P. aeruginosa .
- Pulmonary rehabilitation that includes exercise rehabilitation may improve functioning.
- Oxygen therapy is indicated based on standard recommendations (see Chronic Obstructive Pulmonary Disease). Rest and exercise oxygen assessments should be performed as clinically indicated.
- Noninvasive ventilation for chronic respiratory failure due to CF-related bronchiectasis has not been clearly demonstrated to provide a survival benefit, although it may provide symptomatic relief or it can be used as a bridge to transplantation.
- Lung transplantation The majority of patients with CF die from pulmonary disease. FEV1 is a strong predictor of mortality and has been helpful in deciding when to refer patients for lung transplantation. However, other factors such as marked alveolar gas exchange abnormalities (resting hypoxemia or hypercapnia), evidence of PH, or increased frequency or severity of pulmonary exacerbations should also be considered when deciding on referral for transplantation.
- Massive hemoptysis is usually controlled with bronchial artery embolization. Surgical lung resection is rarely needed.
- Pancreatic insufficiency is managed with pancreatic enzyme supplementation.
- Enzyme dose should be titrated to achieve one to two semisolid stools per day, and to maintain adequate growth and nutrition. Enzymes are taken immediately before meals and snacks. Dosing of pancreatic enzymes should be initiated at 500 Units lipase/kg/meal and should not exceed 2,500 Units lipase/kg/meal. High doses (6,000 Units lipase/kg/meal) have been associated with chronic intestinal strictures.58 Generic enzyme substitutes
- may not provide adequate lipase needed for absorption. Gastric acid suppression may enhance enzyme activity.
- Vitamin supplementation is recommended in extrapulmonary disease, especially with fat-soluble vitamins that are not well absorbed in the setting of pancreatic insufficiency. Vitamins A, D, E, and K can all be taken orally on amregular basis (see Table 2-4 in Chapter 2). Iron-deficiency anemia requires iron supplementation.
- Treatment of CF-related diabetes mellitus is usually accomplished with insulin (see Chapter 21, Diabetes Mellitus and Related Disorders), but typical diabetic dietary restrictions are liberalized (high-calorie diet with unrestricted fat) to meet the increased energy requirements of patients with CF and to encourage appropriate growth and weight maintenance.
- Osteopenia screening should be routinely performed on patients with CF, and if present may be managed with calcium, vitamin D supplementation, and bisphosphonate therapy as clinically indicated.
- Sinusitis regimens are used in the typical fashion for extrapulmonary disease. nMany patients will benefit from chronic nasal steroid administration. Patients whose symptoms cannot be controlled with medical management may benefit from functional endoscopic sinus surgery and nasal polypectomy.
- Yearly influenza vaccination (0.5 mL IM) decreases the incidence of infection and subsequent deterioration.60 Pneumovax (0.5 mL IM) may also provide benefit (see Appendix C, Immunizations and Postexposure Therapies).
- Other pulmonary complications of CF may include allergic bronchopulmonary aspergillosis, massive hemoptysis, and pneumothorax.