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Cystic Fibrosis
Brandon W. Bonds, MD
Tatiana P. Ivan, MD
image BASICS
DESCRIPTION
  • Cystic fibrosis (CF) is an autosomal recessive genetic mutation (CFTR gene) that most prominently affects the pulmonary and pancreatic systems.
  • The GI, endocrine, and reproductive systems as well as the liver, sinuses, and skin can all be involved.
  • Initially a pediatric disease, CF has become a chronic pediatric and adult medical condition as improvements in medical care have led to a dramatic increase in long-term survival.
EPIDEMIOLOGY
CF is the most common lethal inherited disease in Caucasians and is found in every racial group.
Incidence
Number of infants born with CF in relation to the total number of live births in the United States
  • 1 in 3,000 Caucasians
  • 1 in 4,000 to 10,000 Latin Americans
  • 1 in 15,000 to 20,000 African Americans
  • 1 in 30,000 Asian Americans
Prevalence
  • 30,000 patients with CF living in the United States
  • ˜1,000 new diagnoses are made annually.
ETIOLOGY AND PATHOPHYSIOLOGY
  • Abnormal CFTR function leads to abnormally viscous secretions that alter organ function.
  • The lungs: obstruction, infection, and inflammation negatively affect lung growth, structure, and function
    • Decreased mucociliary clearance
    • Infection is accompanied by an intense neutrophilic response.
    • Degradation of supporting tissues causes bronchiectasis and eventual failure.
Genetics
CFTR gene (cystic fibrosis transmembrane conductance regulator): >1,500 mutations exist that can cause varying severity of phenotypic CF, all of which are recessively inherited. Most common is loss of the phenylalanine residue at 508th position (deltaF508), which accounts for 8.7% of affected alleles in the CF population in the United States. G551D mutation accounts for 4.3% of affected alleles.
RISK FACTORS
CF is a single-gene disorder. The severity of the phenotype can be affected by the specific CFTR mutation (most predictive of pancreatic disease), other modifier genes (CFTM1 for meconium ileus), gastroesophageal reflux disease (GERD), severe respiratory virus infection, and environmental factors such as tobacco smoke exposure.
GENERAL PREVENTION
Preconception counseling
  • American Congress of Obstetricians and Gynecologists (ACOG) recommends preconception or early (1st/2nd trimester) genetic analysis for all North American couples planning a pregnancy, with appropriate counseling to identified carriers and genetic analysis of siblings of known CF patients.
  • Universal newborn screening (NBS) has been integral in early diagnosis (62% of new CF diagnosis in 2013 were found by NBS)
  • Patients diagnosed prior to onset of symptoms have better lung function, nutritional outcomes, and should receive referral and early intervention services by an accredited regional CF center.
Pregnancy Considerations
  • Pulmonary disease may worsen during pregnancy.
  • CF may cause increased incidence of preterm delivery, IUGR, and cesarean section (1)[A].
  • Advances in fertility treatments now allow men with CF to father children (2)[A].
image DIAGNOSIS
PHYSICAL EXAM
  • Respiratory
    • Rhonchi and/or crackles
    • Hyperresonance on percussion
    • Nasal polyps
  • GI: Hepatosplenomegaly when cirrhosis is present.
  • Other: digital clubbing, growth retardation, and pubertal delay
COMMONLY ASSOCIATED CONDITIONS
  • CF-related diabetes (CFRD)
    • May present as steady decline in weight, lung function, or increased frequency of exacerbation
    • Leading comorbid complication (20.3%)
    • Result of progressive insulin deficiency
    • Early screening and treatment may improve reduced survival found in CFRD (4)[A].
  • Upper respiratory
    • Rhinosinusitis is seen in up to 100% of patients with CF.
    • Nasal polyps are seen in up to 86% of patients.
  • The GI tract
    • Pancreatic exocrine insufficiency (85-90%) (1)[A]
    • Malabsorption of fat, protein, and fat-soluble vitamins (A, D, E, and K)
    • Hepatobiliary disease (10.8%)
    • Focal biliary cirrhosis
    • Cholelithiasis
    • Meconium ileus at birth (10-15%) (5)[A]
    • Distal intestinal obstruction syndrome (DIOS): intestinal blockage that typically occurs in older children and adults (5.1%) (2)[A]
    • GERD (31.3%) (2)[A]
  • Endocrine
    • Bone mineral disease (14.8%) (2)[A]
    • Joint disease (2.9%) (2)[A]
    • Hypogonadism
    • Frequent low testosterone levels in men
    • Menstrual irregularities are common.
  • Reproductive organs
    • Congenital bilateral absence of the vas deferens: obstructive azoospermia in 98% of males
  • Depression (12%) (2)[A]
DIFFERENTIAL DIAGNOSIS
  • Immunologic
    • Severe Combined Immunodeficiency
  • Pulmonary
    • Difficult-to-manage asthma
    • COPD
    • Recurrent pneumonia
    • Chronic/recurrent sinusitis
    • Primary ciliary dyskinesia
  • Gastrointestinal
    • Celiac disease
    • Protein-losing enteropathy
    • Pancreatitis of unknown etiology
    • Shwachman-Diamond syndrome
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • NBS tests blood levels of immunoreactive trypsin (IRT) (2)[A].
  • Patients must have clinical symptoms of CF involving at least one organ system
  • Sweat test (gold standard)
    • Sweat chloride
      • >60 mmol/L (on 2 occasions) is (+) for CF.
      • <40 mmol/L is normal.
    • CFTR mutation analysis
    • Limited panel testing: Allele-specific polymerase chain reaction (PCR) identifies >90% of mutations; finite chance of false-negative finding. Full-sequence testing is more costly and time-consuming.
    • Nasal potential difference (when sweat test and DNA testing inconclusive)
    • CXR
Follow-Up Tests & Special Considerations
To further investigate the presence of CF-related complications, these tests are generally ordered:
  • Sputum culture (common CF organisms)
  • Pulmonary function tests (PFTs)
  • 72-hour fecal fat, stool elastase
  • Oral glucose tolerance test (OGTT) annually after age 10 years
  • P.253

  • Head CT: Abnormal sinus CT findings are nearly universal in CF and may include mucosal thickening, intraluminal sinus polyps, and sinus effusions.
  • Chest CT (not routine): useful when unusual findings noted on CXR
Diagnostic Procedures/Other
  • Flexible bronchoscopy
  • Bronchoalveolar lavage
image TREATMENT
GENERAL MEASURES
  • CF Foundation Guidelines call for yearly evaluation:
    • 4 office visits, 4 respiratory cultures, PFTs q6mo, and at least 1 evaluation by a multidisciplinary team including dietician, GI, and social worker
    • PFT goals: >75% predicted for adults, >100% predicted for children <18 years old
    • Annual screening for ABPA for patients >6 years old with total serum IgE concentration
    • Annual influenza vaccination for all CF patients age >6 months and all other age appropriate recommended vaccines
    • Screen all adults for osteoporosis with a DXA scan.
    • Annual measurement of fat soluble vitamins to rule out vitamin deficiencies
    • Annual LFTs
    • Decrease exposure to tobacco smoke
    • All patients should be followed in a CF center (accredited sites are listed at www.cff.org).
  • Infant care:
    • Monthly visits for first 6 months of life and then every 2 months until 1 year of life
    • Fecal elastase testing and salt supplementation after diagnosis
    • Consider palivizumab for RSV prophylaxis in infants with CF <2 years (6)[A].
    • Avoidance of smoke
MEDICATION
  • Pulmonary infections:
    • Antibiotics, oral
      • Staphylococcus aureus: Bactrim (MRSA), doxycycline (MRSA) or cephalexin
      • Pseudomonas aeruginosa: fluoroquinolones
    • Antibiotics, inhaled
      • TOBI (tobramycin): for P. aeruginosa, nebulizer twice daily for 28 days; stop for 28 days, then resume use (7)[A]
      • Colistin (more commonly used in Europe)
      • Cayston (aerosolized aztreonam) (7)[A]
    • Antibiotics, IV
      • S. aureus: Cefazolin or nafcillin
      • Methicillin-resistant S. aureus (MRSA): vancomycin or linezolid
      • P. aeruginosa: Zosyn or ceftazidime plus aminoglycoside (tobramycin)
      • Dual therapy synergistic
  • Medications recommended for chronic use in pulmonary disease:
    • Recombinant human DNAse (Dornase alpha) (7)[A]
    • Hypertonic saline
    • High-dose ibuprofen in patients 6 to 17 years old with FEV1 ≤60 PPV
    • Inhaled tobramycin or aztreonam in P. aeruginosa positive patients
    • Azithromycin in P. aeruginosa positive patients
    • Ivacaftor (VX770): A small-molecule CFTR potentiator shown to improve lung function and improve risk of pulmonary exacerbations in patients 6 years and older with at least one copy of G551D mutation (7)[A].
  • Inhaled steroids are not recommended for chronic use in the absence of asthma or ABPA.
  • Insufficient evidence to recommend for or against chonic use: inhaled &bgr;-agonist, inhaled anticholinergics, leukotriene modifiers, inhaled colistin
    • Pancreatic enzymes (87.3%) (2)[A]
      • Often combined with H2 blocker or PPI to increase effectiveness
    • Fat-soluble vitamin supplementation (A, D, E, and K)
    • Liver disease (cholestasis)
      • Ursodeoxycholic acid has not been proven effective.
ADDITIONAL THERAPIES
  • High frequency chest wall oscillation vest is the most widely used airway clearance technique.
  • Aerobic exercise is used as an adjunct therapy for airway clearance (8)[A].
    • CF-related bone disease: Consider bisphosphonate therapy.
SURGERY/OTHER PROCEDURES
  • Timing for lung transplantation (bilateral) is polyfactorial (9)[A].
  • 5-year posttransplant survival is up to 62%.
  • Liver transplantation is reserved for progressive liver failure ± portal hypertension with GI bleeding.
  • Nasal polypectomy in 4.5% of CF patients (2)[A]
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
  • CF exacerbations should always be admitted on contact precautions and private rooms.
  • Pulmonary exacerbation (most common reason for admission)
  • Bowel obstruction (due to DIOS, previously known as meconium ileus equivalent [MIE])
  • Pancreatitis (in pancreatic-sufficient patients)
  • Nasal cannula oxygen when SaO2 <90%
IV Fluids
  • Increased salt loss increases risk of hyponatremic hypochloremic dehydration.
  • Cautious use of IV fluids
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
  • Upon discharge for a pulmonary exacerbation, follow-up with CF provider within 2 to 4 weeks
  • Routine clinic visits every 3 months, with airway cultures and pulmonary function testing
  • Annual comprehensive nutritional evaluation (5)[A]
DIET
High-calorie, high-fat diet titrated to specific BMI goals established by the CF Foundation nutrition guidelines. If not meeting nutritional goals, dietician, pancreatize enzyme, and oral or tube supplemental feeding should be considered if indicated (8)[A].
PATIENT EDUCATION
Cystic Fibrosis Foundation: www.cff.org
PROGNOSIS
  • Median survival is 40.7 years.
  • Progression of lung disease usually determines length of survival.
REFERENCES
1. Grigoriadis C, Tympa A, Theodoraki K. Cystic fibrosis and pregnancy: counseling, obstetrical management and perinatal outcome. Invest Clin. 2015;56(1):66-73.
2. Cystic Fibrosis Foundation Patient Registry. Annual Data Report. Bethesda, MD: Cystic Fibrosis Foundation; 2013.
3. Gilljam M, Ellis L, Corey M, et al. Clinical manifestations of cystic fibrosis among patients with diagnosis in adulthood. Chest. 2004;126(4): 1215-1224.
4. Moran A, Brunzell C, Cohen RC, et al. Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society. Diabetes Care. 2010;33(12):2697-2708.
5. O'Sullivan BP, Freedman SD. Cystic fibrosis. Lancet. 2009;373(9678):1891-1904.
6. Borowitz D, Robinson KA, Rosenfeld M, et al. Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis. J Pediatr. 2009;155(6)(Suppl):S73-S93.
7. Mogayzel PJ Jr, Naureckas ET, Robinson KA, et al. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2013;187(7):680-689.
8. Flume PA, Robinson KA, O'Sullivan BP, et al. Cystic fibrosis pulmonary guidelines: airway clearance therapies. Respir Care. 2009;54(4):522-537.
9. Weill D, Benden C, Corris PA, et al. A consensus document for the selection of lung transplant candidates: 2014—an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2015;34(1):1-15.
Codes
&NA;
ICD10
  • E84.9 Cystic fibrosis, unspecified
  • E84.11 Meconium ileus in cystic fibrosis
  • E84.0 Cystic fibrosis with pulmonary manifestations
Clinical Pearls
&NA;
  • Meconium ileus is virtually pathognomonic for CF.
  • When sweat test is equivocal, CFTR genetic testing is diagnostic.
  • CF must be considered in any child with chronic diarrhea, especially if associated with poor growth or failure to thrive.
  • All children with nasal polyps, digital clubbing, or bronchiectasis should be evaluated.
  • A rapid decline in pulmonary function suggests the acquisition of resistant organisms (e.g., Burkholderia cepacia), CFRD, allergic bronchopulmonary aspergillosis (ABPA), or GERD.