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Cystic Fibrosis, Pediatric

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Cystic Fibrosis, Pediatric

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.

  • 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 Caucasians1:49 in Hispanics1:53 in Native Americans1:62 in African Americans1:90 in Asians
  • 1:29 in Caucasians
  • 1:49 in Hispanics
  • 1:53 in Native Americans
  • 1:62 in African Americans
  • 1:90 in Asians
  • 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

  • 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

Pathophysiology

  • CFTRMembrane glycoprotein, which functions as a cyclic AMP-activated chloride channel at the apical surface of epithelial cellsAn 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 regulationCFTR abnormalities may act as binding sites for Pseudomonas aeruginosa, promoting proinflammatory responses in the lung.
  • In the respiratory systemIncreased mucus viscosityEarly bacterial colonization despite a robust neutrophilic inflammatory responseMucous plugging and atelectasisBronchiectasis and emphysema develop.Abnormal nasal sinus development
  • In the GI tractProgressive pancreatic damage leads to exocrine pancreatic insufficiency.Endocrine pancreatic dysfunctionFocal biliary cirrhosis of the liverHypoplasia of the gallbladder and impaired bile flow
  • 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.
  • Increased mucus viscosity
  • Early bacterial colonization despite a robust neutrophilic inflammatory response
  • Mucous plugging and atelectasis
  • Bronchiectasis and emphysema develop.
  • Abnormal nasal sinus development
  • 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.
  • 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)

Physical Exam

  • Respiratory findings:Frequent cough, often productive of mucopurulent sputumRhonchi, crackles, wheezing, hyperresonance to percussionNasal polyposis
  • Other common findings:Digital clubbingHepatosplenomegaly in patients with cirrhosisGrowth retardationDelayed pubertyOsteoporosis
  • Frequent cough, often productive of mucopurulent sputum
  • Rhonchi, crackles, wheezing, hyperresonance to percussion
  • Nasal polyposis
  • Digital clubbing
  • Hepatosplenomegaly in patients with cirrhosis
  • Growth retardation
  • Delayed puberty
  • Osteoporosis

Diagnostic Tests & Interpretation

  • Sweat test: keystone for the diagnosis of CFSweat chloride >60 mEq/L is abnormal.<40 mmol/L: negative40-60 mmol/L: borderline>60 mmol/L: consistent with CFIn infants up to 6 months of age30-60 mmol/L: borderline60 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 testPLUS2 positive sweat tests or 2 CF mutations on genetic screening or nasal potential difference (NPD) consistent with CF
  • Other causes of elevated sweat chloride:MalnutritionAdrenal insufficiencyNephrogenic diabetes insipidusEctodermal dysplasiaFucosidosisHypogammaglobulinemiaFalse 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 influenzaeStaphylococcus aureusMethicillin-resistant Staphylococcus aureus (MRSA)P. aeruginosa (nonmucoid and mucoid)Burkholderia cepaciaStenotrophomonas maltophiliaAspergillus and other fungal speciesNontuberculous 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
  • Sweat chloride >60 mEq/L is abnormal.<40 mmol/L: negative40-60 mmol/L: borderline>60 mmol/L: consistent with CF
  • In infants up to 6 months of age30-60 mmol/L: borderline60 mmol/L: consistent with CF
  • <40 mmol/L: negative
  • 40-60 mmol/L: borderline
  • >60 mmol/L: consistent with CF
  • 30-60 mmol/L: borderline
  • 60 mmol/L: consistent with CF
  • 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
  • Malnutrition
  • Adrenal insufficiency
  • Nephrogenic diabetes insipidus
  • Ectodermal dysplasia
  • Fucosidosis
  • Hypogammaglobulinemia
  • False negatives seen in CF patients with edema
  • Positive IRT tests must be confirmed by sweat test and/or genetic testing.
  • IRT testing may be normal in the presence of meconium ileus
  • 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
  • Chest radiographyTypical features include hyperinflation, peribronchial thickening, atelectasis, and bronchiectasis.
  • CT scanBronchiectasisCystic and interstitial changesFocal consolidation or scarring
  • Typical features include hyperinflation, peribronchial thickening, atelectasis, and bronchiectasis.
  • Bronchiectasis
  • Cystic and interstitial changes
  • Focal consolidation or scarring

Differential Diagnosis

  • PulmonaryRecurrent pneumonia or bronchitisAsthmaAspiration pneumoniaCiliary dyskinesiaAirway anomaliesChronic sinusitisChronic aspirationNon-CF bronchiectasisAllergic bronchopulmonary aspergillosisα1-Antitrypsin disease
  • GICeliac diseaseProtein-losing enteropathyGERDChronic pancreatitis
  • Other:Metabolic alkalosisImmune deficiencyShwachman-Diamond syndrome
  • Recurrent pneumonia or bronchitis
  • Asthma
  • Aspiration pneumonia
  • Ciliary dyskinesia
  • Airway anomalies
  • Chronic sinusitis
  • Chronic aspiration
  • Non-CF bronchiectasis
  • Allergic bronchopulmonary aspergillosis
  • α1-Antitrypsin disease
  • Celiac disease
  • Protein-losing enteropathy
  • GERD
  • Chronic pancreatitis
  • Metabolic alkalosis
  • Immune deficiency
  • Shwachman-Diamond syndrome

Treatment

Medication

  • Antibiotic therapy based on sputum culture results and clinical improvement:Oral antibiotics:CephalexinLinezolidTrimethoprim-sulfamethoxazoleCiprofloxacin, inhaled tobramycin, colistin, or aztreonam in selected patientsIV 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 secretionsChest 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: RhDNaseAnti-inflammatory: short-term oral steroid course. Inhaled corticosteroids may benefit patients with asthma and/or those demonstrating an oral steroid response.Hypertonic saline
  • GI diseasePancreatic 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 KSalt supplementationPatients with cholestasis may benefit from therapy with ursodeoxycholic acid.
  • Oral antibiotics:CephalexinLinezolidTrimethoprim-sulfamethoxazoleCiprofloxacin, 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
  • Cephalexin
  • Linezolid
  • Trimethoprim-sulfamethoxazole
  • Ciprofloxacin, inhaled tobramycin, colistin, or aztreonam in selected patients
  • 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.
  • 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
  • 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 potentiatorsG551D 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.
  • 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

  • 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.
  • 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 pneumoniaAtelectasisBronchiectasisPneumothoraxHemoptysisChronic sinusitis and nasal polyps
  • CV complications:Pulmonary hypertension in older patients
  • GI complications:Pancreatic insufficiency in 85-90% of CF patientsPatients usually have steatorrhea and poor growth and nutritional status.Decreased levels of vitamins A, E, D, and KRectal prolapse10-15% of patients have meconium ileus.Distal intestinal obstruction syndromeClinically significant focal biliary cirrhosis; hepatobiliary disease in 5% of CF patientsEsophageal varicesSplenomegalyHypersplenismCholestasis
  • Reproductive complications:Sterility in 98% of males due to absence or atresia of the vas deferensSlight decrease in fertility for females secondary to abnormalities of cervical mucus
  • Endocrine complications:Glucose intoleranceCF-related diabetes occurs with increasing frequency in adolescent and adult patients.
  • Skeletal complications:Osteoporosis
  • Recurrent bronchitis and pneumonia
  • Atelectasis
  • Bronchiectasis
  • Pneumothorax
  • Hemoptysis
  • Chronic sinusitis and nasal polyps
  • Pulmonary hypertension in older patients
  • 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
  • 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
  • Glucose intolerance
  • CF-related diabetes occurs with increasing frequency in adolescent and adult patients.
  • Osteoporosis

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.