Cystic Fibrosis

DESCRIPTION

Cystic fibrosis (CF) is an inherited, autosomal recessive disorder, characterized by chronic obstructive lung disease, pancreatic exocrine insufficiency, and elevated sweat chlorideconcentration.

CLINICAL:

• Most common pitfall is failure to diagnose. Neonatal screening is not performed in all states.

• Not uncommon to delay making the diagnosis in patients with mild symptoms

GENERAL PREVENTION

Prepregnancy carrier detection

EPIDEMIOLOGY

• Most common lethal inherited disease in the Caucasian population

• Carrier frequency of mutations in the CF transmembrane conductance regulator (CFTR) gene:

1. 1:29 in Caucasians

2. 1:49 in Hispanics

3. 1:53 in Native Americans

4. 1:62 in African Americans

5. 1:90 in Asians

Incidence

• 1:3,300 in Caucasians

• 1:9,500 in Hispanics

• 1:11,200 in Native Americans

• 1:15,300 in African Americans

• 1:32,100 in Asians

RISK FACTORS

Genetics

CFTR gene:

• Located on the long arm of chromosome 7

• Most common mutation results in deletion of phenylalanine at position 508 in the CFTR glycoprotein. This Δ508

mutation occurs in ~70% of CF patients.

• >1,500 mutations have been reported in the CFTR gene.

PATHOPHYSIOLOGY

• CFTR:

1. Membrane glycoprotein, which functions as a cyclic AMP-activated chloride channel at the apical surface of epithelial cells

2. An abnormality in CFTR results in defective chloride conductance.

3. May have other roles in the regulation of membrane channels and the pH of intracellular organelles. May

affect cell apical sodium channel regulation

• In the respiratory system:

1. Lungs are morphologically normal at birth.

2. Increased viscosity of mucus

3. Early bacterial colonization despite a robust neutrophilic inflammatory response

4. Mucus plugging and atelectasis

5. Bronchiectasis and emphysema develop

6. Abnormal nasal sinus development

• In the GI tract:

1. Exocrine pancreatic insufficiency

2. Focal biliary cirrhosis of the liver

3. Hypoplasia of the gallbladder

Diagnosis

SIGNS AND SYMPTOMS

History

• Most common presenting respiratory symptoms: Chronic cough, recurrent pneumonia, nasal polyps, chronic pansinusitis

• Most common presenting GI symptoms: Meconium ileus (15–20% of patients present with this symptom); pancreatic insufficiency occurs in 85% of patients. In infants, fat malabsorption may lead to failure to thrive. In

older patients, pancreatitis, rectal prolapse (occurs in 2% of the patients, must consider CF until proven otherwise, commonly seen between 1 and 5 years of age); distal obstruction of the small intestine (meconium ileus, seen in

older children and adults)

• Evidence of heat intolerance: In summer, increased sweating may lead to dehydration with hyponatremia or

hypochloremic metabolic alkalosis.

Physical Exam

• Respiratory findings:

1. Frequent cough, often productive of mucopurulent sputum

2. Rhonchi, crackles, wheezing, hyperresonance to percussion

3. Nasal polyposis

• Other common findings:

1. Digital clubbing

2. Hepatosplenomegaly in patients with cirrhosis

3. Growth retardation

4. Hypertrophic osteoarthropathy

5. Delayed puberty

6. Osteoporosis

TESTS

LABORATORY

• Sweat test: Keystone for the diagnosis of CF; sweat chloride >60 mEq/L is abnormal.

1. Other causes of elevated sweat chloride:

• Malnutrition

• Adrenal insufficiency

• Nephrogenic diabetes insipidus

• Ectodermal dysplasia

• Fucosidosis

• Hypogammaglobulinemia

• False negatives seen in: CF patients with edema

• Mutation analysis: Can detect >90% of CF patients. Failure to identify 2 mutations reduces, but does not eliminate, the possibility of CF. Immunoreactive Trypsinogen Test (IRT) is used for newborn screening. In the IRT test, blood

drawn 2–3 days after birth is analyzed for trypsinogen. Positive IRT tests must be confirmed by sweat test and/or genetic testing.

• Frequently recovered organisms in sputum cultures:

1. Haemophilus influenzae

2. Staphylococcus aureus

3. MRSA (methicillin resistant Staphylococcus aureus)

4. Pseudomonas aeruginosa(nonmucoid and mucoid)

5. Burkholderia cepacia

6. Stenotrophomonas maltophilia

7. Aspergillus species

• Pulmonary function test: Usually reveals obstructive lung disease, although some patients may have a restrictive pattern

• Analysis of stimulated pancreatic secretions: Degree of pancreatic exocrine deficiency

• Fecal elastase measurements can detect pancreatic insufficiency

• 72-hour fecal fat measurement: Fat malabsorption

IMAGING

• Chest radiography:

1. Typical features include: Hyperinflation, peribronchial thickening, atelectasis, bronchiectasis

• CT scan:

1. Early bronchiectasis

DIFFERENTIAL DIAGNOSIS

• Pulmonary:

1. Recurrent pneumonia or bronchitis

2. Asthma

3. Aspiration pneumonia

4. Ciliary dyskinesia

• GI:

1. Failure to thrive

2. Celiac disease

3. Protein-losing enteropathy

• Other:

1. Metabolic alkalosis

2. Immune deficiency

Treatment

GENERAL MEASURES

DIET

• High-calorie diet with added salt

• Lifelong nutritional support usually required

• Duration of antibiotic therapy is controversial; more frequent use is required as pulmonary function deteriorates

MEDICATIONS

• Antibiotic therapy based on sputum culture results and clinical improvement:

1. Oral antibiotics:

• Cephalexin

• Cefaclor

• Trimethoprim–sulfamethoxazole

• Ciprofloxacin

• Inhaled

• Tobramycin or colistin in selected patients

2. IV antibiotics:

• To treat Staphylococcus aureus,consider oxacillin, ticarcillin with clavulanic acid, linezolid or vancomycin.

• To treat Pseudomonas aeruginosa and Burkholderia cepacia, consider aminoglycoside plus ticarcillin, ceftazidime, or piperacillin.

3. Severe cases with resistant strains may benefit from aztreonam, imipenem, or meropenem.

4. Synergistic antibiotic studies should be performed in patients with multiresistant organisms.

• Clearance of pulmonary secretions:

1. Chest physiotherapy with postural drainage and vibrations given manually, or with high-frequency

oscillatory vest device. Adjunct therapy such as Flutter valve, Accapela or PEP mask may also be used.

2. Bronchodilator: Aerosol or metered-dose inhaler (β2-agonist)

3. Mucolytics: RhDNase

4. Anti-inflammatory: Cromolyn sodium, steroid (inhaled or short-term oral)

5. Hypertonic saline

• GI disease:

1. Pancreatic enzyme replacement therapy: Used in CF patients who are pancreatic insufficient; dosage

adjusted for frequency and character of the stools and for growth pattern; generic substitutes are not bioequivalent to name brands. The maximum recommended dose is 2,500 U of lipase/kg per meal.

2. Vitamin supplements: Multivitamin supplement, fat-soluble vitaminsA,D,E and K

3. Patients with cholestasis may benefit from therapy with ursodeoxycholic acid.

Follow-up Recommendations

EXPECTED COURSE/PROGNOSIS

• Current median survival is ~36 years.

• Variable course of the disease

• The median survival has been increasing for the past 4 decades, although the rate of increase in age has slowed in the past decade.

POSSIBLE COMPLICATIONS

• Respiratory complications:

1. Recurrent bronchitis and pneumonia

2. Atelectasis

3. Bronchiectasis

4. Pneumothorax

5. Hemoptysis

6. Chronic sinusitis and nasal polyps

• GI complications:

1. Pancreatic insufficiency in 85–90% of CF patients

2. Patients usually have steatorrhea, poor growth, and poor nutritional status.

3. Decreased levels of vitamins A, E, D, and K

4. Rectal prolapse

5. 10–15% of patients have meconium ileus.

6. Distal intestinal obstruction syndrome

7. Clinically significant focal biliary cirrhosis; hepatobiliary disease in 5% of CF patients

8. Esophageal varices

9. Splenomegaly

10. Hypersplenism

11. Cholestasis

• Reproductive complications:

1. Sterility in 98% of males, due to absence or atresia of the vas deferens

2. Slight decrease in fertility for females secondary to abnormalities of cervical mucus

• Endocrine complications:

1. CF-related diabetes occurs with increasing frequency in adolescent and adult patients

• Skeletal complications:

1. Osteoporosis

PATIENT MONITORING

• Specialized care should be at a CF center.

• Frequency of visits depends on age and severity of illness:

1. Infants should be seen at least once monthly for 1st 12 months then every 2–3 months thereafter.

Frequently Asked Questions

• Q: Should relatives be tested?

• A: All siblings should have a sweat test.

• Q: How well will a child with CF do?

• A: The course of the illness is variable. It is difficult to predict the course of disease in an individual.

• Q: How should a borderline sweat test be interpreted?

• A: Borderline sweat tests should always be correlated with other findings such as physical examination, sputum

cultures, pulmonary function, radiographic findings, nutritional evaluation, and/or mutation analysis.