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Cystic Fibrosis

- Hx during infancy - Failure to thrive - Chronic diarrhea - Anasarca/hypoproteinemia - Pseudotumor cerebri (vitamin A deficiency) - Hemolytic anemia (vitamin E deficiency)

- Respiratory - Rhonchi and/or crackles - Hyperresonance on percussion - Nasal polyps

- 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].

- 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

- Immunologic - Severe Combined Immunodeficiency

- Gastrointestinal - Celiac disease - Protein-losing enteropathy - Pancreatitis of unknown etiology - Shwachman-Diamond syndrome

- 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

- 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).

- Pulmonary infections: - Antibiotics, oral - Staphylococcus aureus: Bactrim (MRSA), doxycycline (MRSA) or cephalexin - Pseudomonas aeruginosa: fluoroquinolones

- 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].

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  • 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].

DIAGNOSIS

HISTORY

  • Suspect with failure to thrive, steatorrhea, and recurrent respiratory problemsChronic/recurrent respiratory symptoms, including airway obstruction and infections**Persistent infiltrates on chest x-rays (CXRs)Hypochloremic metabolic acidosis
  • Hx during neonatal periodMeconium ileus (20%) (generally considered pathopneumonic for CF)Prolonged jaundice
  • Hx during infancyFailure to thriveChronic diarrheaAnasarca/hypoproteinemiaPseudotumor cerebri (vitamin A deficiency)Hemolytic anemia (vitamin E deficiency)
  • Hx during childhoodRecurrent endobronchial infectionBronchiectasisChronic pansinusitisSteatorrheaPoor growthDIOSAllergic bronchopulmonary aspergillosis
  • Hx for adolescence and adulthood (7% diagnosed >18 years old) (3)[A]Recurrent endobronchial infectionBronchiectasisAllergic bronchopulmonary aspergillosisChronic sinusitisHemoptysisPancreatitisPortal hypertensionAzoospermiaDelayed puberty

PHYSICAL EXAM

  • RespiratoryRhonchi and/or cracklesHyperresonance on percussionNasal 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 exacerbationLeading comorbid complication (20.3%)Result of progressive insulin deficiencyEarly screening and treatment may improve reduced survival found in CFRD (4)[A].
  • Upper respiratoryRhinosinusitis is seen in up to 100% of patients with CF.Nasal polyps are seen in up to 86% of patients.
  • The GI tractPancreatic 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 cirrhosisCholelithiasisMeconium 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]
  • EndocrineBone mineral disease (14.8%) (2)[A]Joint disease (2.9%) (2)[A]HypogonadismFrequent low testosterone levels in menMenstrual irregularities are common.
  • Reproductive organsCongenital bilateral absence of the vas deferens: obstructive azoospermia in 98% of males
  • Depression (12%) (2)[A]

DIFFERENTIAL DIAGNOSIS

  • ImmunologicSevere Combined Immunodeficiency
  • PulmonaryDifficult-to-manage asthmaCOPDRecurrent pneumoniaChronic/recurrent sinusitisPrimary ciliary dyskinesia
  • GastrointestinalCeliac diseaseProtein-losing enteropathyPancreatitis of unknown etiologyShwachman-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 analysisLimited 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
  • 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

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 workerPFT goals: >75% predicted for adults, >100% predicted for children <18 years oldAnnual screening for ABPA for patients >6 years old with total serum IgE concentrationAnnual influenza vaccination for all CF patients age >6 months and all other age appropriate recommended vaccinesScreen all adults for osteoporosis with a DXA scan.Annual measurement of fat soluble vitamins to rule out vitamin deficienciesAnnual LFTsDecrease exposure to tobacco smokeAll 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 lifeFecal elastase testing and salt supplementation after diagnosisConsider palivizumab for RSV prophylaxis in infants with CF <2 years (6)[A].Avoidance of smoke

MEDICATION

  • Pulmonary infections:Antibiotics, oralStaphylococcus aureus: Bactrim (MRSA), doxycycline (MRSA) or cephalexinPseudomonas aeruginosa: fluoroquinolonesAntibiotics, inhaledTOBI (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, IVS. aureus: Cefazolin or nafcillinMethicillin-resistant S. aureus (MRSA): vancomycin or linezolidP. 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 salineHigh-dose ibuprofen in patients 6 to 17 years old with FEV1 ≤60 PPVInhaled tobramycin or aztreonam in P. aeruginosa positive patientsAzithromycin in P. aeruginosa positive patientsIvacaftor (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 β-agonist, inhaled anticholinergics, leukotriene modifiers, inhaled colistinPancreatic enzymes (87.3%) (2)[A]Often combined with H2 blocker or PPI to increase effectivenessFat-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

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, 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

11 Grigoriadis C, Tympa A, Theodoraki K. Cystic fibrosis and pregnancy: counseling, obstetrical management and perinatal outcome. Invest Clin. 2015;56(1):66-73.22 Cystic Fibrosis Foundation Patient Registry. Annual Data Report. Bethesda, MD: Cystic Fibrosis Foundation; 2013.33 Gilljam M, Ellis L, Corey M, et al. Clinical manifestations of cystic fibrosis among patients with diagnosis in adulthood. Chest. 2004;126(4):1215-1224.44 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):2697-2708.55 O'Sullivan BP, Freedman SD. Cystic fibrosis. Lancet. 2009;373(9678):1891-1904.66 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-S93.77 Mogayzel PJJr, 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):680-689.88 Flume PA, Robinson KA, O'Sullivan BP, et al. Cystic fibrosis pulmonary guidelines: airway clearance therapies. Respir Care. 2009;54(4):522-537.99 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

ICD10

  • E84.9 Cystic fibrosis, unspecified
  • E84.11 Meconium ileus in cystic fibrosis
  • E84.0 Cystic fibrosis with pulmonary manifestations
  • E84.19 Cystic fibrosis with other intestinal manifestations
  • E84.8 Cystic fibrosis with other manifestations

ICD9

  • 277.00 Cystic fibrosis without mention of meconium ileus
  • 277.01 Cystic fibrosis with meconium ileus
  • 277.02 Cystic fibrosis with pulmonary manifestations
  • 277.03 Cystic fibrosis with gastrointestinal manifestations
  • 277.09 Cystic fibrosis with other manifestations

SNOMED

  • 190905008 Cystic fibrosis (disorder)
  • 86092005 Cystic fibrosis with meconium ileus (disorder)
  • 86555001 Cystic fibrosis of the lung (disorder)
  • 190909002 Cystic fibrosis with intestinal manifestations (disorder)
  • 81423003 Cystic fibrosis without meconium ileus (disorder)

CLINICAL PEARLS

  • 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.