Cystic Fibrosis, Emergency Medicine

Basics

Description

Defect of the cystic fibrosis transmembrane conductance regulator (CFTR)
CFTR functions as an ATP-regulated chloride channel that regulates the activity of chloride and sodium channels on the cell surface:
- Abnormal electrolyte transport in exocrine glands and secretory epithelia
- Decreased exocrine pancreatic function with malabsorption
- Thickened mucus, recurrent pulmonary infections, and progressive obstructive damage to the lungs
- Recurrent sinus disease
Occurs in 1:3,600 live births in White population, 1:29,000 in African American population; 1:6,500 in Hispanic population
30% of cases diagnosed by newborn screening
75% cases diagnosed in the 1st 2 yr of life
~30,000 children and young adults in US have CF.
Median life expectancy in US about 40 yr.
40% of CF patients are older than 18 yr.
10 million Americans are unknown, asymptomatic carriers of the defective gene.
16% of lung transplants in US due to CF

Risk Factors

Genetics
Recessively inherited genetic disease, involving the CFTR gene on the long arm of chromosome 7: �

Different mutations; variable phenotypes.
Classic disease: Homozygous DF508 mutation.
Most common lethal genetic disease in US

Etiology

Common organisms in patients with pneumonia; often multiple drug resistance: �

Staphylococcus aureus:
- MSSA/MRSA
Pseudomonas aeruginosa:
- Prevalence increases with age; >70% of adults are chronically infected.
Haemophilus influenzae
Stenotrophomonas maltophilia
Burkholderia cepacia:
- Prevalence 3%
- Associated with rapid clinical deterioration
Achromobacter xylosoxidans
Mycobacteria (nontuberculous):
- Mycobacterium avium complex, Mycobacterium abscessus
Aspergillus

Diagnosis

Signs and Symptoms

General:
- Failure to thrive
- Recurrent respiratory tract infections
- Anasarca in infancy
- Salty taste of skin
Head, ears, eyes, nose, and throat (HEENT):
- Nasal polyps; severe headaches due to sinusitis; otitis media
Pulmonary:
- Persistent cough. Initially dry, then productive
- Recurrent pneumonitis or bronchiolitis in 1st yr of life
- Wheezing
- Hemoptysis
- Pneumonia
- Chronic bronchitis
- Bronchiectasis
- Respiratory distress
- Pneumothorax
- Pneumomediastinum
- Most common cause of CF hospitalization
Cardiac:
- CHF
- Cor pulmonale; pulmonary hypertension
GI:
- Abdominal pain
- Meconium ileus
- Distal intestinal obstructive syndrome (DIOS) or "meconium ileus equivalent"�
- Gastroesophageal reflux
- Cholelithiasis
- Pancreatitis/pancreatic insufficiency
- Ileocecal intussusception
- Foul smelling, fatty stools
- Jaundice/cirrhosis
- Rectal prolapse
- Hematemesis
- Small intestine bacterial overgrowth
Extremities:
- Bone pain
- Edema/joint effusions
- Decreased thickness of cortical bone
Recurrent venous thrombosis
Cardiorespiratory failure is most common cause of death.

Essential Workup

Sweat chloride test
DNA analysis if sweat test equivocal
Nasal potential difference if DNA inconclusive

Diagnosis Tests & Interpretation

Lab

Sweat chloride test:
- Chloride concentration >60 mEq/L
- With classic signs and symptoms, a positive test result confirms the diagnosis.
Stool sample:
- Decreased elastase, trypsin, or chymotrypsin
- Increased fat in 72-hr fecal fat excretion
Immunoreactive trypsin (IRT):
- Defines increased risk and/or diagnosis
- May be falsely positive or negative
DNA analysis:
- Indicated if symptoms are highly suggestive, but sweat test result is negative
- 90% of CF chromosomes identified
- Positive if 2 abnormal genes present
- Genotyping cannot establish the diagnosis.
- 1,300 CTFR mutations listed
- Ameliorating or neutralizing 2nd mutation may be present.
CBC:
- Thrombocytopenia
Serum electrolytes:
- Hyponatremic, hypochloremic alkalosis
Serum glucose:
- Hyperglycemia and new-onset diabetes in adolescents and adults; ketoacidosis is rare.
Liver function tests and PT:
- Obtain if hematemesis or hemoptysis or signs of liver failure
ABG:
- Hypoxemia. Metabolic alkalosis
Sputum culture:
- May have pseudomonal colonization.
Studies indicated in high-risk patients with unclear diagnosis:
- Nasal potential-difference measurements:
  - Complex and time-consuming study
- Semen analysis:
  - Azoospermia

Imaging

Chest radiograph:
- Hyperaeration
- Peribronchial thickening
- Atelectasis
- Hilar lymphadenopathy
- Pneumothorax/pneumomediastinum
- Bronchiectasis
- Blebs
- Chest CT identifies blebs/bronchiectasis
Abdominal radiographs and/or CT:
- Indicated if abdominal pain, vomiting, or abdominal distention
- Distal intestinal obstruction syndrome
- Intussusception
Barium enema:
- Indicated if suspicion of intussusception
Sinus films:
- Limited use because routine sinus films are always cloudy
- CT scan is needed to assess sinuses for pre-operative planning.

Diagnostic Procedures/Surgery
Bronchoalveolar lavage: �

High percentage of neutrophils and absolute neutrophil count
Unnecessary if obvious pulmonary symptoms

Differential Diagnosis

Respiratory:
- Asthma
- Recurrent pneumonia
- Bronchiectasis
- Pertussis
- Immunodeficiency
- Foreign body aspiration
- α1-Antitrypsin deficiency
- Ciliary agenesis
GI:
- Chronic diarrhea
- Gastroenteritis
- Milk allergy
Elevated electrolyte levels in sweat:
- Fucosidosis
- Glycogen storage disease type I
- Mucopolysaccharidosis
- Hypothyroidism
- Vasopressin-resistant diabetes insipidus
- Adrenal insufficiency
- Familial cholestasis
- Familial hypoparathyroidism
- Malnutrition
- Ectodermal dysplasia
- Atopic dermatitis
- Infusion of prostaglandin E1

Treatment

Pre-Hospital

Transcutaneous pacing for unstable type II 2nd- or 3rd-degree block
Atropine:
- Avoid with type II 2nd-degree block because it may precipitate 3rd-degree block.

Ed Treatment/Procedures

Stabilize airway, breathing, and circulation:
- Correct fluid, respiratory, electrolyte, and glucose abnormalities.
- Bronchodilators/steroids if wheezing.
Pneumothorax:
- Observe if <5-10%.
- Thoracostomy
Consultation with the primary CF physician or pulmonary specialist
Right heart failure:
- Diuretics
Hemoptysis:
- Blood products as indicated (check INR)
- Ventilatory support
DIOS:
- Usually requires surgery
Hematemesis:
- Packed RBCs
- Blood products for coagulation abnormalities
- Early consultation with endoscopist
Intussusception:
- Correct with barium/air enema
- May require surgery
Rectal prolapse:
- Manual reduction
- Consider surgical consult
Respiratory care:
- Pulmonary toilet/physical therapy
- Mucous thinning inhaled agents
Antibiotics for pneumonia:
- Based on culture and sensitivity
- S. aureus (MSSA):
  - Cephalothin or Nafcillin
- S. aureus (MRSA):
  - Vancomycin or linezolid
- P. aeruginosa:
  - (Tobramycin or amikacin or colistin) + (piperacillin/tazobactam or ticarcillin/clavulanate or ceftazidime or imipenem/cilastatin or meropenem)
- S. aureus (MSSA) and P. aeruginosa:
  - (Piperacillin/tazobactam or ticarcillin/clavulanate or cefepime or imipenem/cilastatin or meropenem) + (tobramycin or amikacin or colistin)
- S. aureus (MRSA) and P. aeruginosa:
  - (Vancomycin or linezolid) + coverage for Pseudomonas alone
- B. cepacia:
  - Trimethoprim-sulfamethoxazole and/or meropenem and/or cipro and/or minocycline and/or chloramphenicol
- H. influenzae:
  - Cefotaxime or ceftriaxone
- Sinusitis
- Based on cultures and sensitivities

Note: Ciprofloxacin may replace the aminoglycoside if sensitive pseudomonas �

CFTR modulation: Ivacaftor
- Repair of protein function
Restore airway surface liquid:
- Nebulized hypertonic saline
Mucous alteration:
- Dornase alpha to thin mucus in lungs
Future directions:
- Gene therapy: Compacted DNA
- Anti-inflammatory: High-dose ibuprofen
- Anti-infective agents:
  - Inhaled tobramycin, aztreonam, colistin
  - Continuous vancomycin infusion
- Transplantation: Inhaled cyclosporine
- Nutrition and exercise

Medication

Amikacin: 7.5-10 mg/kg IV q8h
Cefazolin: 100 mg/kg/d IV (max.: 6 g/d)
Cefepime: 50 mg/kg IV q8h (max.: 2 g/8hr)
Ceftazidime: 50 mg/kg IV q8h (max.: 6 g/d)
Colistin: 2.5-5 mg/kg/d IV, div. BID-QID
Imipenem/cilastatin: 15-25 mg/kg IV q6h
Meropenem: 40 mg/kg IV q8h (max.: 2 g/8hr)
Nafcillin: 25-50 mg/kg IV q6h (max. 2-3 g q6h)
Piperacillin/tazobactam: 350-450 mg/kg/d IV (max.: 4.5 g q6h)
Ticarcillin/clavulanate:300-400 mg/kg/d IV q6h
Tobramycin: 2.5-3.3 mg/kg/dose IV q8h
TMP-SMX: 5-10 mg/kg IV q12h (max.: 160 mg TMP q12h)
Vancomycin: 15 mg/kg q6h (max.: 1 g q6h)
Note: Because many patients are undernourished, pharmacokinetics of antibiotics (especially aminoglycosides, penicillins, and cephalosporins) may be altered, requiring careful monitoring.

Follow-Up

Disposition

Admission Criteria

Pulmonary exacerbation with significant deterioration from baseline, hypoxemia, resistant bacteria, failure of outpatient therapy
Pneumothorax
Hemoptysis
Hematemesis
Intussusception or unexplained abdominal pain or bowel obstruction
Hyperglycemia

Discharge Criteria

Close follow-up to verify the sensitivities of culture results and change therapy as needed
Avoid hot weather.
Oral salt supplement when profuse sweating

Issues for Referral
All patients followed by a pediatric pulmonary center. Consultation during acute exacerbations. �

Follow-Up Recommendations

Team approach of specialists
Breathing treatments, chest PT, exercise programs, antibiotics, replacement of pancreatic enzymes

Pearls and Pitfalls

With CF patients in respiratory distress, always consider pneumothorax: Obtain CXR.
For CF patients with abdominal pain/vomiting, always consider DIOS and intussusception

Additional Reading

Hoffman �LR, Ramsey �BW. Cystic fibrosis therapeutics: The road ahead. Chest. 2013;143:207-213.
Ryan �G, Jahnke �N, Remmington �T. Inhaled antibiotics for pulmonary exacerbations in cystic fibrosis. Cochrane Database Syst Rev. 2012.
Willey-Courand �DB, Marshall �BC. Cystic Fibrosis. AAP: Pediatric Care Online 2013, www.pediatriccareonline.org.

Codes

ICD9

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

ICD10

E84.0 Cystic fibrosis with pulmonary manifestations
E84.9 Cystic fibrosis, unspecified
E84.19 Cystic fibrosis with other intestinal manifestations
E84.11 Meconium ileus in cystic fibrosis
E84.1 Cystic fibrosis with intestinal manifestations
E84.8 Cystic fibrosis with other manifestations
E84 Cystic fibrosis

SNOMED

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

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