Basics
Description
Cystic fibrosis (CF) is an inherited autosomal recessive disorder, characterized by chronic obstructive lung disease, pancreatic exocrine insufficiency, and elevated sweat chloride concentration.
Alert
- 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
Epidemiology
- Most common lethal inherited disease in the Caucasian population
- Carrier frequency of mutations in the CF transmembrane conductance regulator (CFTR) gene:
- 1:29 in Caucasians
- 1:49 in Hispanics
- 1:53 in Native Americans
- 1:62 in African Americans
- 1:90 in Asians
Prevalence
- 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.
- The Δ508 mutation occurs in ~70% of CF patients.
- >1,500 mutations have been reported in the CFTR gene.
- Presence of gene modifiers may cause incomplete phenotypic presentations.
General Prevention
Prepregnancy carrier detection
Pathophysiology
- CFTR
- Membrane glycoprotein, which functions as a cyclic AMP-activated chloride channel at the apical surface of epithelial cells
- An abnormality in CFTR results in defective chloride conductance.
- May have other roles in the regulation of membrane channels and the pH of intracellular organelles; may affect cell apical sodium channel regulation
- CFTR abnormalities may act as binding sites for Pseudomonas aeruginosa, promoting proinflammatory responses in the lung.
- In the respiratory system
- Increased mucus viscosity
- Early bacterial colonization despite a robust neutrophilic inflammatory response
- Mucous plugging and atelectasis
- Bronchiectasis and emphysema develop.
- Abnormal nasal sinus development
- In the GI tract
- Progressive pancreatic damage leads to exocrine pancreatic insufficiency.
- Endocrine pancreatic dysfunction
- Focal biliary cirrhosis of the liver
- Hypoplasia of the gallbladder and impaired bile flow
Diagnosis
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 chronic diarrhea and failure to thrive.
- In older patients, pancreatitis, rectal prolapse (occurs in 2% of the patients; must consider CF until proven otherwise)
- Distal obstruction of the small intestine (meconium ileus equivalent, 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:
- Frequent cough, often productive of mucopurulent sputum
- Rhonchi, crackles, wheezing, hyperresonance to percussion
- Nasal polyposis
- Other common findings:
- Digital clubbing
- Hepatosplenomegaly in patients with cirrhosis
- Growth retardation
- Delayed puberty
- Osteoporosis
Diagnostic Tests & Interpretation
Lab
- Sweat test: keystone for the diagnosis of CF
- Sweat chloride >60 mEq/L is abnormal.
- <40 mmol/L: negative
- 40-60 mmol/L: borderline
- >60 mmol/L: consistent with CF
- In infants up to 6 months of age
- 30-60 mmol/L: borderline
- 60 mmol/L: consistent with CF
- Diagnostic criteria include the following:
- One or more phenotypic features of CF or a sibling with CF or a positive newborn screening test
- PLUS
- 2 positive sweat tests or 2 CF mutations on genetic screening or nasal potential difference (NPD) consistent with CF
- 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 CF diagnosis.
- Immunoreactive trypsinogen test (IRT) is used for newborn screening. Blood drawn 2-3 days after birth is analyzed for trypsinogen.
- Positive IRT tests must be confirmed by sweat test and/or genetic testing.
- IRT testing may be normal in the presence of meconium ileus
- Frequently recovered organisms in sputum cultures:
- Haemophilus influenzae
- Staphylococcus aureus
- Methicillin-resistant Staphylococcus aureus (MRSA)
- P. aeruginosa (nonmucoid and mucoid)
- Burkholderia cepacia
- Stenotrophomonas maltophilia
- Aspergillus and other fungal species
- Nontuberculous mycobacterial 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
- Typical features include hyperinflation, peribronchial thickening, atelectasis, and bronchiectasis.
- CT scan
- Bronchiectasis
- Cystic and interstitial changes
- Focal consolidation or scarring
Differential Diagnosis
- Pulmonary
- Recurrent pneumonia or bronchitis
- Asthma
- Aspiration pneumonia
- Ciliary dyskinesia
- Airway anomalies
- Chronic sinusitis
- Chronic aspiration
- Non-CF bronchiectasis
- Allergic bronchopulmonary aspergillosis
- α1-Antitrypsin disease
- GI
- Celiac disease
- Protein-losing enteropathy
- GERD
- Chronic pancreatitis
- Other:
- Metabolic alkalosis
- Immune deficiency
- Shwachman-Diamond syndrome
Treatment
Medication
First Line
- Antibiotic therapy based on sputum culture results and clinical improvement:
- Oral antibiotics:
- Cephalexin
- Linezolid
- Trimethoprim-sulfamethoxazole
- Ciprofloxacin, inhaled tobramycin, colistin, or aztreonam in selected patients
- IV antibiotics:
- To treat S. aureus, consider oxacillin, ticarcillin with clavulanic acid, linezolid, or vancomycin.
- To treat P. aeruginosa and B. cepacia, consider aminoglycoside plus ticarcillin, ceftazidime, or piperacillin.
- Severe cases with resistant strains may benefit from aztreonam, imipenem, or meropenem.
- Two or more antibiotics may be used during treatment of pulmonary exacerbations.
- The use of regular azithromycin is controversial due to emerging mycobacterial resistance.
- Indwelling catheters may be needed for frequent antibiotic therapy
- Clearance of pulmonary secretions
- Chest physical therapy or with high-frequency oscillatory vest device. Adjunct therapy such as flutter valve, Acapella, or PEP mask may also be used.
- Bronchodilator: aerosol or metered-dose inhaler (β2-agonist)
- Mucolytics: RhDNase
- Anti-inflammatory: short-term oral steroid course. Inhaled corticosteroids may benefit patients with asthma and/or those demonstrating an oral steroid response.
- Hypertonic saline
- GI disease
- 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 and 10,000 U of lipase/kg/24 h.
- Vitamin supplements: multivitamin, fat-soluble vitamins A, D, E, and K
- Salt supplementation
- Patients with cholestasis may benefit from therapy with ursodeoxycholic acid.
Other Medications
- CFTR potentiators
- G551D mutations treated with ivacaftor will improve lung function, decrease exacerbations, and, in some cases, normalize sweat test.
- Ongoing research is underway to determine if other CF genotypes may benefit from this targeted therapy or other therapies.
Ongoing Care
Follow-up Recommendations
Patient Monitoring
- Specialized care should be at a CF center.
- Frequency of visits depends on age and severity of illness:
- Infants should be seen at least monthly for the first 12 months, then every 2-3 months.
Diet
- High-calorie diet with added salt
- Lifelong nutritional support usually required
- Gastrostomy tube placement may be necessary to increase caloric intake and maintain growth.
Respiratory
- Throat and sputum cultures for fungi, acid-fast bacteria, and aerobic organisms are used to direct antimicrobial therapy.
- Duration of antibiotic therapy is controversial; more frequent use is required as pulmonary function deteriorates.
Prognosis
- Current median survival is ~38 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.
Complications
- Respiratory complications:
- Recurrent bronchitis and pneumonia
- Atelectasis
- Bronchiectasis
- Pneumothorax
- Hemoptysis
- Chronic sinusitis and nasal polyps
- CV complications:
- Pulmonary hypertension in older patients
- GI complications:
- Pancreatic insufficiency in 85-90% of CF patients
- Patients usually have steatorrhea and poor growth and nutritional status.
- Decreased levels of vitamins A, E, D, and K
- Rectal prolapse
- 10-15% of patients have meconium ileus.
- Distal intestinal obstruction syndrome
- Clinically significant focal biliary cirrhosis; hepatobiliary disease in 5% of CF patients
- Esophageal varices
- Splenomegaly
- Hypersplenism
- Cholestasis
- Reproductive complications:
- Sterility in 98% of males due to absence or atresia of the vas deferens
- Slight decrease in fertility for females secondary to abnormalities of cervical mucus
- Endocrine complications:
- Glucose intolerance
- CF-related diabetes occurs with increasing frequency in adolescent and adult patients.
- Skeletal complications:
Additional Reading
- Baumer JH. Evidence based guidelines for the performance of the sweat test for the investigation of cystic fibrosis in the UK. Arch Dis Child. 2003;88(12):1126-1127. [View Abstract]
- Farrell MH, Farrell PM. Newborn screening for cystic fibrosis: ensuring more good than harm. J Pediatr. 2003;143(6):707-712. [View Abstract]
- Flume PA, O'Sullivan BP, Robinson KA, et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2007;176(10):957-969. [View Abstract]
- Hammond KB, Abman SH, Sokol RJ, et al. Efficacy of statewide neonatal screening for cystic fibrosis by assay of trypsinogen concentrations. N Engl J Med. 1991;325(11):769-774. [View Abstract]
- Pier GB. CFTR mutations and host susceptibility to Pseudomonas aeruginosa lung infection. Curr Opin Microbiol. 2002;5(1):81-86. [View Abstract]
- Rowe SM, Verkman AS. Cystic fibrosis transmembrane regulator correctors and potentiators. Cold Spring Harb Perspect Med. 2013;3(7):a009761. [View Abstract]
- Ryan G, Mukhopadhyay S, Singh M. Nebulised anti-pseudomonal antibiotics for cystic fibrosis. Cochrane Database Syst Rev. 2003;(3):CD001021. [View Abstract]
- Smyth A, Walters S. Prophylactic antibiotics for cystic fibrosis. Cochrane Database Syst Rev. 2000;(2):CD001912. [View Abstract]
- Southern KW, Barker PM. Azithromycin for cystic fibrosis. Eur Respir J. 2004;24(5):834-838. [View Abstract]
- Stallings VA, Stark LJ, Robinson KA, et al. Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. J Am Diet Assoc. 2008;108(5):832-839. [View Abstract]
- Yankaskas JR, Marshall BC, Sufian B, et al. Cystic fibrosis adult care: consensus conference report. Chest. 2004;125(1)(Suppl):1S-39S. [View Abstract]
Codes
ICD09
- 277.00 Cystic fibrosis without mention of meconium ileus
- 277.02 Cystic fibrosis with pulmonary manifestations
- 277.01 Cystic fibrosis with meconium ileus
- 277.03 Cystic fibrosis with gastrointestinal manifestations
- 277.0 Cystic fibrosis
- 277.09 Cystic fibrosis with other manifestations
ICD10
- E84.9 Cystic fibrosis, unspecified
- E84.0 Cystic fibrosis with pulmonary manifestations
- E84.11 Meconium ileus in cystic fibrosis
- E84.19 Cystic fibrosis with other intestinal manifestations
- E84.8 Cystic fibrosis with other manifestations
SNOMED
- 190905008 Cystic fibrosis (disorder)
- 86555001 Cystic fibrosis of the lung (disorder)
- 86092005 Cystic fibrosis with meconium ileus (disorder)
- 190909002 Cystic fibrosis with intestinal manifestations (disorder)
- 81423003 Cystic fibrosis without meconium ileus (disorder)
FAQ
- 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 exam, sputum cultures, pulmonary function, radiographic findings, nutritional evaluation, and/or mutation analysis.