Cystic Fibrosis

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12 Interesting Facts of Cystic Fibrosis 

  1. Cystic fibrosis is an autosomal recessive, multisystem disorder caused by pathologic variants in the CFTR (cystic fibrosis transmembrane conductance regulator) gene resulting in altered chloride and bicarbonate transport across many epithelial tissues
  2. Disease primarily affects the upper and lower airways, pancreas, gastrointestinal tract (eg, intestine, hepatobiliary system), reproductive organs, and exocrine sweat glands
  3. Early consequences include impaired airway function with chronic endobronchial infection and progressive airway obstruction, and exocrine pancreatic dysfunction with resultant malabsorption of fat and fat-soluble vitamins
  4. Later consequences are numerous and often include irreversible bronchiectasis eventually leading to respiratory failure and premature death
  5. Presentation is highly variable; manifestations at the time of presentation depend on the age of patient and, to some degree, genotype
  6. Diagnosis is usually initially established by documenting CFTR dysfunction with an elevated sweat chloride level (gold standard); establishing genetic diagnosis is often involved in the second phase of testing
  7. Refer all patients with suspected cystic fibrosis to an accredited cystic fibrosis center immediately for further diagnostic recommendations, treatment considerations, and monitoring
  8. Long-term maintenance therapy is individualized; often involves:
    • Nutritional support and treatment of pancreatic exocrine insufficiency with pancreatic enzyme replacement therapy; fat-soluble A, D, E, and K vitamin supplementation; and high-calorie, high-fat diet
    • Airway secretion clearance therapy with airway clearance techniques, inhaled hydrator therapy (eg, hypertonic saline), and mucolytics (eg, dornase alfa)
    • Treatment of chronic airway Pseudomonas species infection with inhaled antibiotics (eg, tobramycin, aztreonam, colistin)
    • Antiinflammatory medications such as azithromycin, ibuprofen, and inhaled bronchodilators
    • CFTR modulator treatment (eg, ivacaftor, lumacaftor-ivacaftor, tezacaftor-ivacaftor) for certain genotypes
  9. Treat complications expediently
    • Treatment of pulmonary exacerbations includes individualized antibiotic regimens for lung infection, along with focus on increasing intensity of airway clearance techniques and optimizing nutritional status 
  10. Lung transplant is the standard of care for end-stage lung disease
  11. Median survival rates exceed age 40 years in most developed countries and age 50 years in some; most common cause of death is respiratory failure secondary to pulmonary insufficiency 
  12. Universal newborn screening is recommended; numerous screening protocols exist; initial test is usually immunoreactive trypsinogen

Pitfalls

  • Newborn screening is not foolproof; false-negative results do occur and diagnosis can be missed by newborn screening protocols 
    • Additionally, be aware that universal newborn screening in all 50 United States has been in effect since 2010; patients born before 2010 may not have been subject to newborn screening
  • Diagnosis is complex in a minority (less than 5%) of patients, usually those with milder or limited phenotype, because initial diagnostic testing is inconclusive (eg, sweat chloride result in intermediate range, fewer than 2 CFTR pathologic variants associated with disease identified) 
  • Standard 23-mutation panel for genetic testing contains pathologic variants associated with disease most often noted in primarily White populations and may not be appropriate for testing patients of other ethnic backgrounds; alternative testing may be needed 
  • Maintain awareness that a positive newborn screening result does not establish diagnosis of cystic fibrosis 
    • Asymptomatic infants with a positive newborn screening result in which diagnosis is not confirmed by functional CFTR testing (ie, sweat chloride, nasal potential difference, intestinal current measurement) or detection of 2 CFTR disease–causing pathologic variants are classified as CFTR-related metabolic syndrome (cystic fibrosis screen positive, inconclusive diagnosis)
    • Some patients will eventually develop symptoms or findings that meet qualifications for cystic fibrosis diagnosis; therefore, patients require periodic monitoring for additional disease manifestations
  • Meconium ileus is associated with false-negative newborn screening results but is highly likely to be associated with cystic fibrosis 
    • All infants with meconium ileus carry presumptive diagnosis and require confirmatory testing starting with sweat chloride test irrespective of newborn screening results
  • Cystic fibrosis is an autosomal recessive, multisystem disorder caused by pathologic variants in the CFTR (cystic fibrosis transmembrane conductance regulator) gene; results in altered chloride and bicarbonate transport across many epithelial tissues, giving rise to decreased moisture in luminal secretions 
  • Disease primarily affects the upper and lower airways, pancreas, gastrointestinal tract (eg, intestine, hepatobiliary system), exocrine sweat glands, and vas deferens 
  • Early consequences include impaired airway function with chronic endobronchial infection and progressive airway obstruction and exocrine pancreatic dysfunction with resultant fat and fat-soluble vitamin malabsorption
  • Delayed complications are numerous and often include resultant irreversible bronchiectasis eventually leading to respiratory failure and premature death

Classification

  • CFTR mutations are classified into groups by effect on maturation and function of CFTR protein; classification aids in determining therapy and prognosis 
    • Caveats regarding classification scheme
      • Some mutations are rare and therefore class is unknown
      • Some mutations are of unknown or varying consequence
    • Patients with more severe mutations (class I-III genotypes) typically experience more severe complications and disease manifestations, with manifestations beginning at a very early age, compared with those who have milder mutations (class IV-VI genotypes) and usually delayed onset of measurable abnormalities 
      • Class I to III genotypes
        • Patients experience more severe complications and disease manifestations than those with milder (class IV-VI genotypes) CFTR mutations; manifestations often begin at a very early age
      • Class IV to VI genotypes
        • Patients typically experience less severe complications and disease manifestations than those with more severe CFTR mutations (class I-III genotypes), or at least experience delayed onset of measurable abnormalities
    • General groupings
      • Pathologic variants commonly associated with pancreatic insufficiency and severe phenotype
        • Class I: absent CFTR protein production
          • Mutations result in absent or defective protein production
          • Represents about 10% of patients worldwide 
        • Class II: CFTR protein trafficking defects
          • Mutations lead to improper processing of CFTR protein, preventing transport to apical cell membrane 
          • Phe508del mutation represents at least 1 allele in up to 73% of patients with disease 
        • Class III: defective CFTR channel regulation (gating)
          • Gating mutations hinder CFTR activation and chloride movement through channel in apical membrane 
          • Represents about 4% to 5% of patients worldwide 
          • G551D mutation is the most common 
      • Pathologic variants commonly associated with pancreatic sufficiency and milder phenotype 
        • Class IV: decreased CFTR channel conductance
          • Mutations decrease conductance properties of protein, resulting in a partially-functioning CFTR protein located in the apical membrane 
          • Represents about 3% of patients worldwide 
        • Class V: reduced CFTR synthesis
          • Mutations cause decreased quantity of normal CFTR protein 
          • Represents about 3% of patients worldwide 
        • Class VI: decreased CFTR stability
          • Mutations decrease stability of CFTR protein, leading to high turnover at the apical membrane surface 
  • Diagnostic terminology of genetically related allelic disorders
    • CFTR-related metabolic syndrome (cystic fibrosis screen positive, inconclusive diagnosis)
      • Refers to asymptomatic newborns with abnormal newborn screening results for cystic fibrosis and inconclusive CFTR functional (sweat test) and genetic testing 
      • A significant proportion of these infants will ultimately convert to diagnosis of cystic fibrosis based on genetic testing or sweat chloride testing later in childhood 
    • CFTR-related disorder
      • Refers to patients with some symptomatic manifestations compatible with disease and some evidence of CFTR dysfunction but who do not meet full diagnostic criteria 

Symptoms and Clinical Presentation of Cystic Fibrosis

History

  • Presentation is variable
    • Presenting manifestation or combination of manifestations often depend on age of patient and, to some degree, class of pathologic variant responsible for disease
      • Age at presentation by class and pancreatic functional status
        • Pancreatic insufficiency (classes I-III): neonates, infants, and young children
        • Pancreatic sufficiency (classes IV-VI): later in life, sometimes as adults 
      • Common presenting manifestations by age group
        • Neonates
          • Gastrointestinal and hepatobiliary: meconium ileus, prolonged neonatal jaundice, possible intestinal atresia
        • Infants
          • Gastrointestinal and hepatobiliary: failure to thrive and manifestations related to pancreatic insufficiency, rectal prolapse, fat-soluble vitamin deficiency
          • Pulmonary: chronic cough, recurrent pneumonia (especially Haemophilus influenzae or Staphylococcus aureus), persistent infiltrates on chest imaging, recurrent bronchiolitis, wheezing 
        • Children, adolescents, and adults
          • Gastrointestinal and hepatobiliary: idiopathic recurrent or chronic pancreatitis, cirrhosis, chronic constipation, rectal prolapse, distal ileal obstruction syndrome
          • Pulmonary: chronic cough and sputum production, idiopathic bronchiectasis, chronic sinusitis, nasal polyposis, hemoptysis, exercise intolerance, dyspnea, recurrent pneumonia
            • Commonly encountered pneumonia pathogen profile by age
              • About 10 years or younger: most commonly Haemophilus influenzae or Staphylococcus aureus
              • About 10 years or older: predominately Pseudomonas aeruginosa and other atypical gram-negative pathogens
    • Wide spectrum of initial presenting manifestations; may include any of the following:
      • Known prenatal diagnosis based on positive genetic test result
        • Echogenic bowel is suggestive of disease on prenatal ultrasonography, particularly when associated with dilated bowel and absent visualized gallbladder
      • Asymptomatic or minimally symptomatic neonate or infant with positive newborn screening result 
      • Asymptomatic or minimally symptomatic patient with family history of disease 
      • Most common symptomatic manifestations dominating presentation include: 
        • Chronic or recurrent respiratory problems (eg, infection, cough, sputum, idiopathic bronchiectasis)
        • Malabsorption (fat, protein malabsorption, or both with failure to thrive, weight loss, steatorrhea, chronic diarrhea, edema, fat-soluble vitamin deficiency)
      • Other presentations
        • Salt loss syndromes (eg, acute-onset dehydration and electrolyte imbalance on hot days; progressive dehydration secondary to higher salt requirement than breast milk and infant formula can adequately replace)
          • Dehydration with the development of hypochloremic metabolic alkalosis is characteristic; may be associated with hyponatremia
        • Intestinal obstruction in neonate (ie, meconium ileus) or older patient (ie, distal ileal obstruction syndrome)
          • About 15% of infants with cystic fibrosis are born with meconium ileus (eg, failure to pass meconium, bilious emesis, abdominal bloating)
        • Liver disease (eg, hepatic steatosis, cirrhosis)
          • Usually presents with hepatosplenomegaly and obstructive jaundice
        • Pancreatitis (eg, recurrent acute; chronic)
        • Chronic sinusitis with or without nasal polyps
        • Male infertility secondary to azoospermia and absence of vas deferens
        • Allergic bronchopulmonary aspergillosis
        • Salty skin
        • Manifestations consistent with fat-soluble vitamin deficiency; most common include: 
          • Dry skin or pseudotumor cerebri (eg, papilledema) associated with vitamin A deficiency
          • Hemolytic anemia associated with vitamin E deficiency
        • Delayed puberty 

Physical examination

  • General findings
    • Dehydration may be present, demonstrated by dry skin, sunken eyes, or lack of tears
    • Growth restriction or failure to thrive with inadequate weight gain and poor linear growth 
    • Anasarca associated with hypoproteinemia
  • Findings related to gastrointestinal tract
    • Meconium ileus in neonates and distal ileal obstruction syndrome in patients outside of the neonatal period; typically presents with abdominal distention and palpable mass in the lower right quadrant 
    • Prolonged obstructive jaundice is common in neonates, often lasting at least 2 to 3 weeks 
    • Cirrhosis with or without portal hypertension presents with hepatosplenomegaly, ascites, or jaundice
    • Rectal prolapse is a common finding during childhood; presents with protruding rectal mucosa and a thick, concentric mucosal ring
  • Findings related to respiratory system
    • Pulmonary findings may include tachypnea, decreased breath sounds, crackles, wheezing, hypoxia, and increased anteroposterior diameter of chest
    • Nasal polyps are typically found in paranasal sinuses with mucopurulent discharge from middle meatus 
    • Digital clubbing may develop in older children

Associated congenital anomalies

  • Bilateral congenital absence of vas deferens 
  • Intestinal atresia 

Causes and Risk Factors

What Causes Cystic Fibrosis?

  • Pathologic variant of CFTR gene (OMIM #219700, OMIM *602421) at cytogenetic location 7q31.2 causes disease 
    • Over 2000 mutations in CFTR are known; however, molecular alteration in DNA sequence does not always result in defective protein and clinical disease 
    • Over 300 known pathologic variants are associated with disease
      • Comprehensive and updated list of pathologic variants is maintained on CFTR2 database 
        • Mutations are categorized as disease causing, not disease causing, mutation of variable clinical significance, or mutation of unknown clinical significance
        • Available information pertaining to clinical and functional phenotypic severity (eg, sweat chloride concentrations, lung function, pancreatic status, Pseudomonas infection rates) is provided in database
    • Manifestations of cystic fibrosis develop when a person has 2 disease-causing pathologic variants of the CFTR gene present on distinct chromosomes 
    • Absence or dysfunction of CFTR protein primarily alters chloride and bicarbonate transport across apical membrane of many epithelial tissues 
      • Lack of chloride and bicarbonate secretion alters osmotic gradient, causing surface liquid depletion 
      • Other CFTR protein functions include:
        • Regulation of sodium transport across membrane; dysfunction leads to excessive sodium absorption, exacerbating depletion of surface liquid 
        • Regulation of cellular pathways affecting inflammation; dysfunction leads to exaggerated immune responses
    • Clinical consequences of defective CFTR protein function most notably affect the respiratory and gastrointestinal systems
      • Respiratory system
        • Mucus obstruction
          • Depletion of airway surface liquid impairs mucociliary clearance, and thickened mucus accumulates in distal airways
        • Infection and inflammation
          • Altered surface pH impairs innate ability to effectively destroy pathogens, and exaggerated inflammatory response promotes disease progression 
        • Repeated infections; progressive airway obstruction and irreversible bronchiectasis ensue, resulting in loss of lung function
          • Infections tend to be diverse, frequently polymicrobial, and constantly evolving. Staphylococcus aureus predominates in young patients and Pseudomonas aeruginosa in older patients. Organisms of the Burkholderia cepacia complex occur, are difficult to treat, and are associated with increased morbidity and mortality 
      • Gastrointestinal system
        • Luminal obstruction
          • Deficient surface fluid and bicarbonate efflux result in viscous and acidic secretions; inspissation of viscous secretions and luminal obstruction may occur 
        • Consequences of intestinal, pancreatic, and/or biliary duct luminal obstruction
          • Intestinal obstruction, exocrine and endocrine pancreatic dysfunction, and cholestasis
    • Classes of CFTR mutations that cause cystic fibrosis
      • Class I: absent CFTR protein production (about 10% of patients with disease)
        • Mutations include premature stop codon mutations, frameshift mutations, and large deletions 
        • Cause RNA splicing defects that result in truncated and unstable mRNA; subsequently, no functional protein is produced 
        • Specific examples include Trp1282X, Gly542X, Arg553X, W1282X, and 621+1G→T 
      • Class II: protein trafficking defects
        • Mutations include missense and amino acid deletions
        • Defects prevent proper protein folding, which results in premature protein degradation; very low amount of protein is expressed at apical membrane surface and function is poor
        • Phe508del (F508del) is the most common mutation
          • 1 copy of F508del is present in about 73% of affected patients; 2 copies are present in about 38% 
        • Specific examples include N1303K, Asn1303Lys, Ile507del, and Arg560Thr 
      • Class III: defective CFTR regulation (gating)
        • Mutations include missense and amino acid changes 
        • Protein is synthesized but has defective regulation; CFTR protein channel is unable to be activated by ATP or cyclic AMP; ion channel is localized to the plasma membrane but function is poor 
        • Specific examples include G551D(gly551Asp), Gly178Arg, Gly551Ser, and Ser549Asn 
      • Class IV: decreased CFTR conductance
        • Mutations include missense and amino acid changes 
        • Abnormal protein is produced and localized to the apical membrane with reduced functional ability to transport chloride
        • Specific examples include R117H(Arg117His), Arg347Pro, Arg117Cys, and Arg334Trp 
      • Class V: reduced CFTR synthesis
        • Mutation types include missense and splicing defects 
        • Defects cause reduced production of normal CFTR protein or moderate decrease in trafficking; result is normally-functioning protein but reduced expression at apical membrane 
        • Specific examples include A455E, 3849+10kb C→T, 2789+5G→A, and 3120+1G→A 
      • Class VI: decreased CFTR stability
        • Mutation types include missense and amino acid changes 
        • Defects lead to high turnover at the apical membrane surface; result is normally-functioning protein but reduced expression at apical membrane 
        • Specific examples include 120del23, N287Y, 4326delTC, Gln1412X, and 4279insA 
    • Phenotypic variability
      • Extensive phenotypic variability is present among patients with cystic fibrosis
      • Some variability is related to genotype; among manifestations, pancreatic functional status correlates best with genotype 
      • Individual variability (eg, particular manifestation profile, severity of manifestations) is high even among patients with the same genotype; in particular, genotype accounts for only a portion of respiratory phenotype 
      • Non–cystic fibrosis modifier genes and environmental factors appear to influence progression of lung disease 
        • Certain polymorphisms in mannose-binding lectin-2 and transforming growth factor β1 genes are associated with more severe lung disease 

Risk factors and/or associations

Age
  • Overall
    • Approximately 70% of patients are diagnosed by age 1 year 
    • A minority of patients (up to 10%) are diagnosed in adulthood
      • Most often milder phenotypes with pancreatic sufficiency
      • Initial diagnosis rarely extends through the 6th and 7th decades of life 
  • Regions with universal newborn screening program
    • Diagnosis is most common in neonates and young infants
  • Regions without universal newborn screening program
    • Median age at diagnosis ranges from age 4 months to 2 years 
Sex
  • Historically, females are at an overall survival disadvantage compared to males; based on most recent data, survival rate discrepancy may be resolving 
Genetics
  • Inheritance is autosomal recessive 
Ethnicity/race
  • Over 90% of affected patients are White individuals 
  • Occurrence among populations in the United States
    • About 1 in 3000 to 4000 White people
    • About 1 in 4000 to 10,000 Hispanic people
    • About 1 in 15,000 to 20,000 Black people
    • Least common among Asian people
Other risk factors/associations
  • Parent carriers of 2 or more cystic fibrosis–causing mutations on distinct chromosomes
  • Sibling with cystic fibrosis
  • Family history of cystic fibrosis

Diagnostic Procedures

Primary diagnostic tools

  • Overview of diagnosis
    • Cystic fibrosis is diagnosed when patient has both clinical presentation consistent with disease and evidence of CFTR dysfunction 
    • Evaluate all neonates with a presumptive diagnosis at an accredited cystic fibrosis center within 24 to 72 hours for initiation of treatment pending formal diagnosis or exclusion of diagnosis 
      • Presumptive diagnosis includes neonates with:
        • Positive newborn screening result with clinical manifestations of cystic fibrosis
        • Positive newborn screening result and 2 identified pathologic variants associated with disease
        • Meconium ileus with or without positive newborn screening result
          • Neonates with meconium ileus have an increased rate of false-negative newborn screening test results 
    • Establishing definitive diagnosis is straightforward in most patients once diagnosis is suspected
      • Confirm diagnosis with demonstration of CFTR dysfunction 
      • Pursue genetic diagnosis in all patients with evidence of CFTR dysfunction for genetic counseling and prognostic purposes, as well as potential treatment implications 
      • In most patients, a clear clinical presentation (eg, positive newborn screening result, chronic respiratory symptoms coupled with malabsorption), sweat chloride level of 60 mmol/L or higher, and 2 pathologic variants associated with disease confirm diagnosis 
      • In less than 5% of patients (ie, those with a milder or limited phenotype), diagnostic process is more complex owing to inconclusive initial diagnostic test results (ie, sweat chloride in intermediate range, less than 2 pathologic variants associated with disease identified, or both) 
        • Refer to accredited cystic fibrosis center for further diagnostic recommendations (eg, specialized physiologic testing of CFTR function with nasal potential difference or intestinal current measurement) 
        • When diagnosis remains unresolved, consider the following diagnosis while continuing to monitor and manage patient closely for development of manifestations that qualify for definitive cystic fibrosis diagnosis: 
          • CFTR-related metabolic syndrome (cystic fibrosis screen positive, inconclusive diagnosis) for newborns with positive newborn screening result
          • CFTR-related disorder: older symptomatic patients
    • Cystic Fibrosis Foundation provides several clinical care guidelines related to diagnosis of cystic fibrosis 
  • Suspect diagnosis with any of the following clinical presentations of disease: 
    • Abnormal newborn screening results
      • Most diagnoses in areas with newborn screening in place occur among asymptomatic or minimally symptomatic infants with high immunoreactive trypsinogen level on newborn screening 
      • In the United States, newborn screening was introduced by different states at different times, and was not adopted by all states until 2010; therefore, children born before 2010 have not necessarily been tested at birth 
      • Neonates with meconium ileus have an increased rate of false-negative newborn screening test results 
    • Family history of disease 
    • Clinical manifestations suggestive of disease; may include: 
      • Chronic sinopulmonary disease (eg, chronic cough, obstructive lung disease, colonization with pathogens common to patients with disease, persistent chest radiography abnormalities, nasal polyps, chronic pansinusitis)
      • Characteristic gastrointestinal abnormalities (eg, meconium ileus and intestinal obstruction, rectal prolapse, pancreatitis, prolonged neonatal jaundice, liver disease, hypoproteinemia, edema)
      • Nutritional abnormalities (eg, failure to thrive, fat and/or protein malabsorption, steatorrhea, fat-soluble vitamin deficiencies)
      • Male infertility with obstructive azoospermia and congenital absence of vas deferens
      • Salt loss syndromes (eg, acute salt depletion, chronic metabolic alkalosis, hyponatremic-hypochloremia dehydration)
  • Diagnostic progression
    • Gold standard first phase of testing to evaluate CFTR function is sweat chloride test, ideally performed at an accredited cystic fibrosis center 
      • Definitive diagnosis is established with sweat chloride value of 60 mmol/L or higher in patients with positive newborn screening result, clinical features consistent with disease, or family history of disease 
        • Follow with CFTR genetic testing and refer to accredited cystic fibrosis center for treatment
      • Sweat chloride values between 30 and 59 mmol/L are within intermediate range and considered inconclusive or equivocal 
        • Patients presenting with a positive newborn screening result or symptoms of disease with intermediate sweat chloride levels on 2 separate occasions may have cystic fibrosis
        • Obtain CFTR genetic testing and refer to accredited cystic fibrosis center for initiation of treatment pending definitive diagnosis or exclusion of diagnosis
        • Further specialized physiologic testing of CFTR function (ie, nasal potential differences or intestinal current measurement) may be required to further evaluate risk for developing features of cystic fibrosis lung disease 
      • Sweat chloride value of 29 mmol/L or lower is within reference range 
        • Neonates with positive newborn screening result
          • Diagnosis is unlikely; sweat chloride testing may be repeated if indicated by family history or if symptoms suggestive of disease occur 
        • All populations with clinical features that may be consistent with disease
          • Indicates disease is less likely 
          • Rarely patients may be diagnosed with cystic fibrosis after exclusion of alternate disease when clinical criteria and other confirmatory tests support diagnosis of cystic fibrosis (ie, CFTR genotyping, specialized physiologic testing of CFTR function) 
    • Second phase of testing involves CFTR genetic analysis
      • Rationale for genetic testing includes obtaining pertinent information regarding targeted treatment options, prognosis, and genetic counseling
      • First line genetic testing usually involves targeted analysis for CFTR pathologic variants with standard mutation panel
      • Indicated for patients with high (60 mmol/L or higher) or inconclusive (30-59 mmol/L) sweat chloride measurements 
      • Results
        • Identification of 2 pathologic variants associated with disease on 2 distinct chromosomes is consistent with diagnosis 
        • If only a single CFTR pathologic variant is identified, expanded (extended) CFTR testing is indicated 
        • Undefined CFTR genotype or known mutation of varying clinical consequence indicates cystic fibrosis is possible and requires further specialized physiologic testing of CFTR function 
        • If only non–cystic fibrosis causing variants are found, cystic fibrosis is unlikely 
    • Other tests to assess for disease complications commonly obtained at time of diagnosis include:
      • Chest imaging (eg, chest radiograph, chest CT)
      • Electrolyte panel to assess for electrolyte abnormalities, particularly with episodes of dehydration
      • Serum chemistry panel to assess for evidence of malabsorption and liver disease, and as a baseline for later monitoring
      • Serum levels of fat-soluble vitamins A, D, E, and K
      • Stool studies to assess for pancreatic insufficiency (ie, 72-hour fecal fat, fecal elastase)
      • Clinical criteria for diagnosis of pulmonary exacerbation (ie, Fuchs criteria for exacerbation of respiratory symptoms, FEV₁ measurement)
      • Diagnostic criteria for allergic bronchopulmonary aspergillosis
  • Refer all patients with suspected cystic fibrosis to an accredited cystic fibrosis center immediately if disease is suspected; may include: 
    • Patients with positive or intermediate/equivocal sweat chloride test
    • Patients for which there is a high clinical suspicion for disease but testing results are within reference range
    • Patients for which genetic testing reveals 1 or more cystic fibrosis mutations

Laboratory

  • Immunoreactive trypsinogen
    • First test used in most neonatal screening protocols
    • Part of neonatal screening in combination with other methods, including DNA mutation analysis, double immunoreactive trypsinogen testing, and pancreatitis-associated protein testing 
    • Cutoff based on the 96th percentile (single day’s batch of specimens) found a sensitivity of 96.2% and a specificity of 94.7% 
  • Genetic testing for CFTR mutation
    • First stage of testing usually includes targeted analysis for CFTR pathologic variants 
      • Standard CFTR mutation panel should include the most common disease-causing mutations (covering 80%-85% of all mutations) in a given population 
      • Recommended panel in the United States tests for 23 cystic fibrosis–causing pathologic variants 
        • Sensitivity of this test varies among ethnic groups; most sensitive in non-Hispanic white and Ashkenazi Jewish populations. 
      • Several commercially available expanded mutation panels are available to enhance sensitivity for carrier detection in racial and ethnic groups with a lower prevalence of cystic fibrosis and less common mutations 
    • Second stage of testing is usually sequence analysis of CFTR, followed by gene-targeted deletion/duplication analysis 
      • Expanded (extended) CFTR testing involves extensive sequencing of entire gene with assessment for large deletions and insertions 
      • Indicated as second line test when 2 disease-causing pathologic variants are not identified with first line testing strategy when diagnosis is almost certain (eg, sweat chloride greater than 60 mmol/L) or highly probable (eg, suggestive clinical presentation) 
      • May be the initial preferred diagnostic test in certain clinical scenarios, including: 
        • Ethnicity with low sensitivity for standard targeted analysis
        • Prenatal testing in high-risk fetus
        • Prenatal testing in low-risk fetus with echogenic bowel on prenatal ultrasonogram
        • Infant with elevated immunoreactive trypsinogen on newborn screening and intermediate sweat chloride level (ie, 30-59 mEq/L)
        • Symptomatic infant (eg, meconium ileus) who is too young to produce adequate volume of sweat for sweat chloride testing
    • Comprehensive and updated list of pathologic variants associated with disease is maintained on CFTR2 database 
      • Mutations are categorized as disease causing, not disease causing, mutation of variable significance, or mutation of unknown clinical significance
      • Not all disease-causing mutations have been characterized; a small fraction of affected patients carry at least 1 unidentifiable mutation responsible for disease 
    • Genotypic criteria for diagnosis include identification of 2 pathologic variants associated with disease on 2 separate chromosomes 
  • Electrolytes
    • Hypochloremic metabolic alkalosis is the characteristic electrolyte pattern associated with dehydration; concomitant hyponatremia may occur 
  • Fat-soluble vitamins
    • Levels of vitamins A, D, E, and/or K may be low in the presence of fat malabsorption
  • Assessment for pancreatic insufficiency and fat malabsorption
    • Common tests include fecal elastase measurement, 72-hour fecal fat collection, or both
      • Fecal elastase
        • Enzyme excreted by pancreas that is not altered by gut transit; therefore, represents a measure of pancreatic exocrine function
        • Stool levels below 200 mcg/g
          • Indicate pancreatic insufficiency
          • Suggest need for pancreatic enzyme replacement therapy
          • Less effective for diagnosis of mild to moderate insufficiency 
        • Stool levels below 50 mcg/g
          • Consistent with severe insufficiency 
          • 72% sensitive and 90% specific for diagnosis of severe insufficiency 
        • False-positive test result may occur with watery diarrhea and in patients with diabetes 
      • 72-hour quantitative fecal fat collection
        • Measure for fat malabsorption
        • Stool is collected while patient consumes standard high-fat diet (ie, 100 g fat/day or 3 g fat/kg/day); stool markers (eg, blue dye) are given orally at the beginning and end of the dietary period to signal when stool collection should begin and end 
        • Markedly abnormal fat absorption is noted in patients with untreated or ineffectively treated pancreatic insufficiency
  • Protein malabsorption may be indicated by hypoproteinemia, hypoalbuminemia, or both

Imaging

  • Chest radiograph
    • Nonspecific findings suggestive of cystic fibrosis
      • Hyperinflation
      • Mucus plugging
      • Bronchial wall thickening
      • Bronchiectasis
      • Atelectasis
      • Persistent infiltrate or consolidation
      • Flattening of diaphragm
    • Obtain at time of diagnosis, annually as part of routine monitoring, and with clinical concern for pulmonary complications (eg, exacerbation, pneumothorax) 
  • Chest CT
    • Consider ordering on an individual basis
    • More sensitive to presence and severity of pulmonary disease than spirometry FEV₁
    • Shows improvement with effective therapy and predicts future disease progression

Functional testing

  • Sweat chloride test
    • Gold standard test to evaluate CFTR function 
    • Testing procedure
      • Patient should be normally hydrated, not acutely ill, and at least 48 hours of age 
      • Sweat production is stimulated via iontophoresis using transdermally applied pilocarpine 
      • Sweat is collected on gauze or filter paper (requires about 75 mg of sweat) or in a Macroduct coil (requires 50 μL of sweat); collection time is about 30 minutes 
      • Sweat chloride concentration is then quantified
      • Special considerations for testing in neonates
        • To optimize likelihood of adequate sweat collection, perform test:
          • Bilaterally (ie, from both arms) and analyze results separately in the 2 samples 
          • When neonate is at least 36 weeks corrected gestational age and weight is greater than 2 kg 
        • Preferred timing for test is between ages 2 and 4 weeks 
    • Results
      • Level higher than 60 mmol/L: generally diagnostic of disease
        • Second confirmatory sweat test after an initial positive test is no longer considered necessary when 2 disease-causing mutations are identified on genetic testing; more than 1 sweat test may be necessary when genetic information is incomplete 
      • Level between 30 to 59 mmol/L: intermediate range, inconclusive 
      • Level lower than 30 mmol/L: reference range for all ages (with limited exceptions) 
    • Test characteristics
      • False-positive result (uncommon)
        • Causes include malnutrition, eczema, congenital adrenal hyperplasia, adrenal insufficiency, hypothyroidism, fucosidosis, Mauriac syndrome, ectodermal dysplasia, nephrogenic diabetes insipidus, and environmental deprivation 
      • False-negative result
        • Causes include malnutrition, dilution of sample, hypoproteinemia, dehydration, and CFTR mutations with preserved sweat duct function
  • Specialized physiologic testing of CFTR function
    • Refer to cystic fibrosis center for specialized physiologic testing; tests are technically challenging and not widely available 
    • Useful to diagnose or exclude diagnosis in patients with intermediate sweat chloride results, less than 2 identified disease-causing CFTR pathologic variants, and CFTR mutations of unknown significance 
    • Tests indirectly assess for alterations in electrolyte transport across epithelial tissue that are characteristic for patients with cystic fibrosis
    • Nasal transepithelial potential difference
      • In vivo testing for altered transmucosal voltage potential of nasal mucosal tissue that results from increased sodium absorption and defective chloride secretion in patients with cystic fibrosis 
      • Various solutions are applied to nasal mucosal surface and voltmeter is used to measure response 
      • General results consistent with cystic fibrosis
        • More negative basal nasal potential and a larger change in potential when sodium channel is blocked with amiloride
        • Little or no change in potential when the CFTR channel is stimulated by zero chloride solution and isoproterenol
      • Limitations
        • Lack of universal reference values and large test-to-test intrasubject variability
        • Limited number of sites offer test
        • Most feasible in cooperative patients (ie, older than 6 years); however, may be performed on infants with modified protocols
    • Intestinal current measurement
      • Ex vivo testing for altered intestinal transmucosal voltage potential or altered electrical current performed on rectal biopsy tissue 
      • Currents are evoked using various solutions and measured in an open circuit 
      • Abnormal reversal of current conduction is consistent with disease 
  • Spirometry
    • FEV₁ (forced expiratory volume in 1 second) demonstrates and quantifies airway obstruction
      • Expressed as percent of a predicted value derived from models based on height, age, and ethnic group 
      • Important measure for:
        • Defining lung disease severity (percent of predicted value) 
          • Reference range: 95% or higher
          • Mild: 70% to 94%
          • Moderate: 60% to 90%
          • Moderately severe: 50% to 59%
          • Severe: 35% to 49%
          • Very severe: less than 35%
        • Diagnosing pulmonary exacerbation
        • Assessing treatment response
        • Determining efficacy endpoint in clinical trials
        • Predicting future mortality 
      • Limitations
        • Poor sensitivity for early (mild) cystic fibrosis lung disease 
        • Limited use in children younger than 6 years; young children are usually not capable of reliably performing spirometry testing. May be attempted beginning at age 3 years 
          • Options for younger children are limited but include:
            • Chest imaging (eg, chest radiograph, chest CT) 
            • Infant pulmonary function tests, modified preschool spirometry protocols and interpretation, and lung clearance index (typically available only in research settings) 
      • Low-radiation chest CT may be a more sensitive tool to assess disease progression; however, FEV₁ is more commonly used because no radiation exposure is required for measurement

Other diagnostic tools

  • Fuchs criteria for exacerbation of respiratory symptoms
    • 4 of the following 12 manifestations suggest need for parenteral antibiotics:
      • Change in sputum
      • New or increased hemoptysis
      • Increased cough
      • Increased dyspnea
      • Malaise, fatigue, or lethargy
      • Temperature above 38 °C
      • Anorexia or weight loss
      • Sinus pain or tenderness
      • Change in sinus discharge
      • Change in physical examination of chest
      • Decrease in pulmonary function (FEV₁) by 10% or more from a previously recorded value
      • Radiographic changes indicative of pulmonary infection
  • Minimal diagnostic criteria for allergic bronchopulmonary aspergillosis 
    • Acute or subacute deterioration not attributable to another cause
    • Elevated total serum IgE concentration (greater than 500 international units/mL or greater than 1200 ng/mL) when patient is not receiving systemic corticosteroids
    • Immediate cutaneous reactivity to Aspergillus species (wheal greater than 3 mm with surrounding erythema when patient is not receiving systemic antihistamines) or in vitro demonstration of serum IgE to Aspergillus fumigatus
    • At least 1 of the following:
      • Presence of in vitro serum IgG to Aspergillus fumigatus or precipitating antibodies to Aspergillus fumigatus
      • New abnormalities on chest radiography (pulmonary infiltrates or mucus plugging) or chest CT (bronchiectasis) that have not cleared with antibiotics and standard chest physiotherapy

Differential Diagnosis

Most common

  • CFTR genetically related allelic disorders
    • CFTR-related metabolic syndrome (cystic fibrosis screen positive, inconclusive diagnosis)
      • Diagnosis includes asymptomatic newborns with abnormal newborn screening findings for cystic fibrosis (ie, high immunoreactive trypsinogen level), plus inconclusive CFTR functional (eg, sweat chloride) and genetic testing (ie, absence of 2 known pathologic variants associated with disease) 
      • A minority of patients eventually meet diagnostic criteria for cystic fibrosis (possibly up to about 10%) 
        • Patients require periodic monitoring and follow-up at an accredited cystic fibrosis center 
        • Currently, outcomes are not well characterized 
        • Infants may be at risk for developing CFTR-related disorder 
    • CFTR-related disorder
      • Diagnosis includes patients with some manifestations compatible with disease and some evidence of CFTR dysfunction (eg, intermediate sweat chloride values) but not fulfilling full diagnostic criteria (eg, identification of only 1 CFTR pathologic variant associated with known disease) 
      • Manifestations often associated with this diagnosis include presenting findings limited to a single organ system such as bronchiectasis, congenital bilateral absence of vas deferens, chronic sinusitis, or acute or recurrent pancreatitis 
  • Asthma
    • Chronic inflammatory disease of the airways of the lungs characterized by variable and recurring episodes of reversible airflow obstruction
    • Presents similarly with chronic cough and persistent wheeze, particularly in association with and after respiratory infection
    • Can be a comorbidity associated with cystic fibrosis; comorbid diagnosis can be problematic. No accepted criteria exist for diagnosing comorbid asthma in patients with cystic fibrosis
    • Presence of atopy (eg, eczema, allergic rhinitis, food allergy) or family history of asthma or atopic disease suggests diagnosis of asthma
    • Patients with asthma alone often improve significantly with asthma-specific treatment, have normal growth and weight gain, are not colonized with cystic fibrosis–related bacteria, experience fewer recurrent pneumonias, and do not have malabsorptive issues (eg, steatorrhea) 
    • Diagnosis of asthma is based on clinical presentation and documentation of reversible airway obstruction
  • Gastroesophageal reflux disease 
    • Symptoms resulting from the reflux of gastric contents into the esophagus
    • Presents similarly to cystic fibrosis in infants, with chronic cough, failure to thrive, and possible chronic tracheal aspiration
    • Unlike cystic fibrosis, in patients with gastroesophageal reflux disease there is a temporal relationship of coughing to feedings, chest radiography may show focal densities if aspiration occurs, but is not likely to show air trapping; in addition, gastroesophageal reflux disease does not present with stool abnormalities
    • Definitive diagnosis of gastroesophageal reflux disease is obtained with esophageal pH monitoring; endoscopy may be used as adjunct to document presence of inflammation
  • Pulmonary malformations
    • Includes disorders such as congenital pulmonary airway malformation, bronchopulmonary sequestration, bronchial atresia, bronchogenic cyst, and congenital lobar emphysema
    • May present similarly with chronic cough, wheezing, and recurrent pneumonia in childhood
    • Anomalies involving the extrathoracic airway are often associated with recurrent stridor, which is uncommon in children with cystic fibrosis
    • Gastrointestinal problems and nutritional deficiencies are not associated with anatomical pulmonary malformations
    • Most pulmonary malformations are detectable with antenatal fetal ultrasonography; postnatal diagnosis is based on imaging (eg, chest radiograph, chest CT, chest MRI)
  • Primary biliary atresia
    • Obliterative cholangiopathy that presents in neonates with obstructive jaundice (conjugated hyperbilirubinemia) and acholic stools
    • May present similarly to cystic fibrosis with prolonged obstructive jaundice in an otherwise clinically asymptomatic neonate
    • Primary biliary atresia may present as part of a syndrome (eg, Mitchell-Riley, cat-eye, Zimmermann-Laband, Fanconi, Martinez-Frias, Lambert-Eaton)
    • Unlike in neonates with cystic fibrosis, test results for serum immunoreactive trypsinogen, fecal elastase, and sweat chloride are within reference range in those with primary biliary atresia 
    • Other tests that may help differentiate biliary atresia from cystic fibrosis include abdominal ultrasonography, hepatobiliary scintigraphy, and liver biopsy
    • Gold standard test to confirm diagnosis of biliary atresia is cholangiogram
  • Congenital tracheoesophageal fistula
    • Congenital anomaly of the esophagus in which an abnormal connection and anatomic configuration are established during embryogenesis between the esophagus and trachea; esophageal atresia may be present
    • 6 classifications (types A-E) are recognized based on various abnormal anatomical relationships between esophagus and trachea 
    • Associated congenital malformations are present in about 50% of patients and may include VACTERL (vertebral/vascular, anorectal, cardiac, tracheoesophageal, radial/renal, and limb deformities) association 
    • Diagnosis may be suggested by abnormal prenatal ultrasonography findings (eg, polyhydramnios, prominent esophageal pouch, small or absent stomach)
    • Similar presenting manifestations may include chronic cough and failure to thrive; recurrent pneumonia may develop
    • Choking with feeding is characteristic of tracheoesophageal fistula, unlike cystic fibrosis; when placed, nasogastric tube may follow abnormal course, suggesting tracheoesophageal fistula
    • Diagnosis of tracheoesophageal fistula also depends on type; several diagnostic modalities may be necessary to characterize anatomy, including upper gastrointestinal tract series with water-soluble contrast material, 3-dimensional chest CT scan, and endoscopy (bronchoscopy and esophageal endoscopy) with use of methylene blue injections
  • Severe combined immunodeficiency disorders
    • Group of rare, genetically heterogeneous disorders characterized by a lack of T cell, B cell, and sometimes natural killer cell responses to infection
    • Molecular basis for disorders is diverse; X-linked disorder caused by a dysfunctional IL2RG gene 
    • Manifests similarly to failure to thrive, chronic persistent respiratory symptoms (eg, cough, nasal congestion), frequent or recalcitrant infection (eg, fever, upper respiratory tract infection, pneumonia, sepsis), and chronic gastrointestinal symptoms (eg, diarrhea); patients may present with a positive newborn screen result for severe combined immunodeficiency disorders
    • Unlike in cystic fibrosis, patients develop other recalcitrant and recurrent nonrespiratory infections (eg, oral thrush, cellulitis, otitis media), lymphocyte counts are low (eg, absolute lymphocyte count less than 2000 cells/mm²), serum immunoglobulin levels are typically low, T cells lack response to antigen skin testing, and minimal or no lymph node tissue (eg, tonsils) is appreciated on examination 
    • Differentiate severe combined immunodeficiency disorder from cystic fibrosis by clinical presentation and abnormal laboratory test results (eg, lymphopenia, absent T cell response to mitogens, low serum immunoglobulin levels) 
    • Diagnostic criteria exist for disorder (eg, absence or very low number of T cells [less than 300 CD3 T cells/mm³] and no or very low T cell function [less than 10% of the lower limit of reference range] or the presence of T cells of maternal origin); molecular diagnosis may be established by genetic testing 
  • Shwachman-Diamond syndrome
    • Autosomal recessive disorder caused by a mutation in the SBDS gene characterized by: 
      • Exocrine pancreatic dysfunction (eg, malabsorption, malnutrition) and failure to thrive
      • Single- or multilineage cytopenias (eg, anemia, neutropenia, thrombocytopenia, pancytopenia) and increased risk for myelodysplastic syndrome and leukemia
      • Bony abnormalities (eg, chondrodysplasia, asphyxiating thoracic dystrophy, metaphyseal dysostosis)
      • Craniofacial abnormalities and syndactyly may be present
    • Patients present similarly to those with cystic fibrosis plus exocrine pancreatic insufficiency (eg, steatorrhea, malabsorption) and failure to thrive; occasionally respiratory symptoms (eg, cough, dyspnea) may be present secondary to chest wall hypoplasia
    • Unlike cystic fibrosis, patients with Shwachman-Diamond syndrome have various hematologic abnormalities (eg, cytopenias) and characteristic bony abnormalities 
    • Diagnosis is confirmed by detection of biallelic pathologic variants of SBDS gene associated with disease 
  • Primary ciliary dyskinesia
    • Rare, genetically diverse, autosomal recessive disorder characterized by abnormal or immotile cilia affecting primarily the respiratory tract and sperm; situs inversus occurs in up to 50% of patients 
    • Presents with chronic cough, persistent respiratory tract infections (eg, sinusitis, otitis media, pneumonia), opportunistic respiratory infections (eg, Pseudomonas), and infertility in males owing to abnormal sperm motility; progressive lung injury occurs, resulting in chronic bronchiectasis and digital clubbing 
    • Unlike cystic fibrosis, patients with primary ciliary dyskinesia often experience recalcitrant otitis media resulting in hearing loss and lack of gastrointestinal manifestations (eg, malabsorption, steatorrhea); situs inversus is highly suggestive of primary ciliary dyskinesia 
    • Diagnosis is often based on a combination of modalities: low nasal nitric oxide measurements; abnormalities detected by high-speed video microscopy analysis of ciliary beat frequency and pattern; and tissue biopsy with transmission electron microscopy analysis of ciliary ultrastructure 
    • Molecular diagnosis may be confirmed in about two-thirds of patients by identifying pathologic variants known to be associated with disease (eg, DNAH5, DNAH11, CCDC39, DNAIl, CCDC40) 

Treatment Goals

  • Mainstay of treatment is symptomatic with focus on optimizing pulmonary function and nutritional status to maintain health and quality of life, and increase life expectancy 
    • Compensate for pancreatic insufficiency with pancreatic enzyme replacement therapy to minimize malabsorption
    • Optimize nutrition with high-fat, high-calorie diet to attain age-appropriate growth; minimize risk of fat-soluble vitamin deficiency with vitamin A, D, E, and K supplements as appropriate
    • Delay lung disease progression and pulmonary function decline with inhaled and physical therapies intended to improve airway clearance
    • Initiate small-molecule CFTR modulator therapy when indicated for certain genotypes
    • Individualize antibiotic treatment of pulmonary exacerbation
  • Monitor for, prevent, and manage the numerous complications and manifestations commonly associated with disease 

Disposition

Admission criteria

Pulmonary exacerbation requiring IV antibiotics 

Certain complications require admission for further diagnostic testing and treatment; may include:

  • Large pneumothorax (greater than 3 cm) 
  • Concern for bowel obstruction (eg, distal ileal obstruction syndrome, fibrosing colonopathy)
  • Pancreatitis
  • Severe malnutrition and failure to thrive
  • Dehydration with significant electrolyte abnormalities unresponsive to initial hydration efforts
Criteria for ICU admission
  • Respiratory failure requiring invasive ventilation or noninvasive respiratory support
  • Postoperative lung and liver transplant recipients
  • ICU level of care may be required for patients with life-threatening complications, such as:
    • Massive hemoptysis 
    • Pneumothorax with significant respiratory compromise
    • Acute pancreatitis with hemodynamic instability
    • Bleeding esophageal varices secondary to portal hypertension 
    • Meconium ileus (managed in the neonatal ICU)

Recommendations for specialist referral

  • Refer to an accredited cystic fibrosis center if disease is suspected (clinically or based on positive newborn screen result) for further multidisciplinary team diagnostic and individualized treatment recommendations
    • Accredited centers follow Cystic Fibrosis Foundation guidelines, deliver multidisciplinary care, and have appropriate inpatient and outpatient medical and diagnostic facilities 
    • There are over 120 accredited centers throughout the United States 
  • Multidisciplinary treatment team usually includes the following specialists: 
    • Gastroenterologist
    • Hepatologist
    • Pulmonologist
    • Infectious disease specialist
    • Endocrinologist
    • Specialized nursing staff and care coordinators
    • Psychologist and psychiatrist
    • Nutritionist or dietitian
    • Respiratory therapist and cystic fibrosis physiotherapist
    • Social worker
    • Primary care physician for continuity of medical care (ie, medical home) and collaboration with treatment team specialists
  • Genetic counseling may be indicated for discussion of carrier testing, potential risks to offspring, and reproductive options 
    • Offer to affected young adults, carriers, and patients at risk of being carriers

Treatment Options

As cystic fibrosis is a multisystem disease, management of these patients includes measures to optimize respiratory function and nutritional status; treat pulmonary, pancreatic, and other organ system complications; and prevent infection

  • Cystic Fibrosis Foundation provides several clinical care guidelines related to treatment of respiratory and other manifestations of cystic fibrosis and care of specific age groups from infants to adults 

Maintenance of respiratory health is the main focus of cystic fibrosis treatment as pulmonary disease is the leading cause of morbidity and mortality 

  • Airway secretion clearance therapy
    • Airway clearance techniques
      • Standard therapy despite limited evidence supporting efficacy 
      • May include specialized breathing techniques, positive expiratory pressure devices, oscillatory devices, external percussion and vibration, or noninvasive ventilation 
      • Daily therapy is recommended; choice of particular method is individualized 
      • Clinical modifications may be required for certain complications
        • Temporarily discontinue airway clearance therapies in patients with massive hemoptysis and large pneumothorax 
        • Intensify treatments during periods of pulmonary exacerbation
    • Inhaled hydrator therapy
      • Osmotic agents to rehydrate viscous sputum 
        • Hypertonic saline (7%)
          • Regular use reduces frequency of pulmonary exacerbation frequency in adults and children aged 6 years or older and may result in short-term improvement in lung function and quality of life 
            • May be used selectively in younger children based on individual circumstances 
              • Has been shown to improve lung clearance index in children aged 3 to 6 years 
              • There is evidence that hypertonic saline inhalation initiated in early months of life may lead to improvements in lung clearance and weight gain in infants with cystic fibrosis; however, there was no significant effect on pulmonary exacerbations 
          • May be administered before, during, or after airway clearance techniques; timing of inhalation has little to no effect on lung function but patients may perceive better efficacy when used before or during airway clearance 
          • Pretreatment with albuterol may facilitate delivery 
          • Patients with massive hemoptysis should temporarily discontinue aerosolized hypertonic saline 
        • Mannitol
          • Administered via a breath-actuated dry-powder inhaler 
          • Improves lung function and may be more convenient to use than nebulized agents 
    • Mucolytics
      • Dornase alfa
        • Mechanism of action is by degradation of DNA released by neutrophils, thereby diminishing viscosity of mucus 
        • Generally administered 30 minutes before airway clearance techniques 
        • Improves lung function and quality of life, and diminishes exacerbation frequency in children aged 6 years or older 
          • Use in young children is individualized 
        • Insufficient evidence to determine whether benefits of dornase alfa are superior to those with inhaled hyperosmolar agents 
  • Treatment of chronic airway infection
    • Inhaled antibiotics
      • Most data support use in patients colonized with Pseudomonas aeruginosa; includes inhaled tobramycin, colistin, and aztreonam 
        • Phase II and III trials are underway involving levofloxacin, liposomal amikacin, and combination treatments (eg, fosfomycin-tobramycin)
      • Prophylactic therapy is controversial and recommendations differ between guidelines 
      • Low-quality evidence suggests inhaled antipseudomonal therapy improves lung function and reduces exacerbation rates; however, magnitude of benefit is unclear 
      • Treatment team recommendations regarding antibiotic choice are often tailored to infection severity and chronicity, lung function response, and tolerance of treatments 
        • Goal for treating newly acquired Pseudomonas aeruginosa is eradication of infection; however, persistent colonization is common and maintenance antibiotic therapy is often prescribed indefinitely in these cases 
        • In cases of chronic infection or colonization with Pseudomonas aeruginosa and other gram-negative pathogens, treatment may include more than 1 inhaled antibiotic class concurrently or different classes of antibiotics alternating between different months 
      • Optimal antibiotic choice for Pseudomonas aeruginosa infection is unclear; treatment is individualized and several options exist 
        • Inhaled tobramycin
          • Initial Pseudomonas aeruginosa eradication protocol often involves daily use for 28 days 
          • Often used in 28-day on and off cycles for chronic suppression of Pseudomonas aeruginosa 
          • Use of tobramycin inhaled solution increases FEV₁ by a mean of 10% from baseline; patients are less likely to require hospitalization and IV antibiotics than those not receiving it 
        • Inhaled aztreonam
          • Data suggest efficacy is similar to inhaled tobramycin for chronic Pseudomonas aeruginosa growth; however, requires 3-times daily dosing 
          • Eradication of Burkholderia cepacia has been studied, but data to support efficacy are lacking 
        • Inhaled colistin
          • Limited data suggest that efficacy is similar to inhaled tobramycin for chronic Pseudomonas aeruginosa growth 
  • Antiinflammatory medications
    • Azithromycin
      • Only antiinflammatory medication in wide use with strong data to support efficacy; antiinflammatory mechanism of action is not well defined 
      • Recommended for patients aged 6 years or older for airway inflammation (with or without persistent Pseudomonas aeruginosa present in airway cultures) 
      • Guidelines recommend screening for nontuberculous mycobacteria before initiating therapy owing to concerns about developing resistance among colonized patients; withhold in the presence of active nontuberculous mycobacterium infection 
      • Some increase in erythromycin resistance in Staphylococcus aureus and clarithromycin resistance in Haemophilus species is noted among patients with long-term use 
    • NSAIDs
      • Recommended for use by patients aged 6 to 17 years with FEV₁ greater than 60%; high-dose NSAID use is limited by adverse effect and toxicity profile 
      • May slow progression of lung disease, particularly in children 
      • Despite recommendation, clinical use remains low owing to concerns regarding potential adverse effects; discontinuation of regimen secondary to adverse effects is not uncommon 
      • Temporarily discontinue NSAIDs in patients with hemoptysis or signs of bleeding, and during administration of aminoglycosides or other potentially nephrotoxic agents 
    • Inhaled corticosteroids
      • Used extensively by some experts despite limited data to support efficacy 
      • Other experts advise avoidance of routine use in the absence of clear indication, such as concomitant asthma or allergic bronchopulmonary aspergillosis 
  • Inhaled bronchodilators
    • Inhaled β-agonists are indicated for some patients older than 6 years; treatment requires individualization 
  • Sequence for inhaled medications
    • Recommendations are varied; standard sequence includes bronchodilator, followed by hypertonic saline, dornase alfa, airway clearance technique, inhaled corticosteroid when used, and lastly, aerosolized antibiotic 

CFTR modulator therapy can partially restore function in mutated CFTR 

  • Treatment with small molecules targeting mutation-specific defects in the CFTR protein with aim to restore functional ion transport
  • Most data indicate that treatment diminishes exacerbation frequency and improves lung function, pancreatic exocrine function, and nutritional status 
  • Considered part of standard care in patients with certain gating mutations 
  • Monotherapy
    • Ivacaftor
      • Referred to as a CFTR potentiator; mechanism of action involves increasing probability of CFTR channel opening (gating) to enhance chloride transport 
      • Approved for treatment in patients aged 2 years or older with at least 1 class III gating mutation (G551D) or class IV (R117H) mutation 
        • Evidence does not support the use of ivacaftor in people with the class II mutation (F508del) mutation 
  • Combination therapies
    • Combination of a CFTR corrector(s) plus CFTR potentiator result in improvements in quality of life and respiratory function and lower pulmonary exacerbation rates 
      • Lumacaftor-ivacaftor
        • Lumacaftor is referred to as a F508del-CFTR corrector; mechanism of action involves increasing production of CFTR protein
        • Combination of drugs addresses protein trafficking defect (lumacaftor) along with gating defect (ivacaftor) associated with defective F508del allele
        • Approved for treatment in patients aged 6 years or older with homozygous class II F508del (Phe508del) genotype 
      • Tezacaftor-ivacaftor
        • Tezacaftor is an F508del-CFTR corrector that facilitates delivery of CFTR to the cell surface
        • Approved for patients aged 6 years or older who are homozygous for the F508del mutation or who have at least 1 mutation in the CFTR gene that is responsive to the combination drug
        • May have better safety profile than lumacaftor-ivacaftor 
      • Elexacaftor-tezacaftor-ivacaftor 
        • Triple therapy is effective in patients aged 6 years or older who have one or two F508del variants
  • Available drugs are subject to numerous interactions (eg, antifungal agents, glucocorticoids, contraceptives) and prescribing precautions
  • Monitor for significant adverse effects, including respiratory symptoms, increased pulmonary secretions, hypersensitivity reactions, hypertension, biliary colic, neurocognitive or neuropsychiatric changes, and cataract formation 
    • Baseline and periodic ophthalmologic examination and hepatic function tests are recommended, among other precautions

Management of advanced cystic fibrosis lung disease

  • Treatment continues in a similar manner to that of other patients with cystic fibrosis and includes CFTR modulator therapy in eligible patients 
    • In some patients, improvement in lung function with elexacaftor-tezacaftor-ivacaftor was sufficient to remove them from consideration for lung transplant 
  • Screen patients with advanced cystic fibrosis lung disease or hypoxemia on exertion and sleep, hypercarbia, and pulmonary hypertension 
    • Supplemental oxygen is recommended for exercise-induced or nocturnal hypoxemia
    • Consider nocturnal noninvasive ventilation for patients with chronic hypercarbia
  • Lung transplantation is a recommended treatment option if indications for referral are present and consistent with individualized goals of care 
    • Short- and long-term outcomes are excellent (better than outcomes for other transplant indications) 
  • Management is described in depth in Cystic Fibrosis Foundation consensus guidelines for the care of individuals with advanced cystic fibrosis lung disease 

Management of pulmonary exacerbations

  • Paucity of data regarding optimum treatment; regional standard of care and guidelines may differ in specific recommended approach 
  • General management
    • Antibiotics
      • Combination of oral (for mild exacerbation), IV (for severe exacerbation), or inhaled therapies may be used 
      • Sputum pathogen profile, severity of illness, and patient allergy profile are primary determinants of antibiotic regimen 
      • Standard treatment in patients chronically infected with Pseudomonas species involves use of combination antibiotic therapy with 2 or more antipseudomonal drugs selected on the basis of prevailing antimicrobial susceptibility patterns and patient’s previous antibiotic use; aminoglycoside and antipseudomonal β-lactam are often used for IV treatment 
      • Once-daily dosing of aminoglycosides is preferable to 3-times daily dosing for treatment of exacerbation 
      • Optimal duration of antibiotic therapy is not standardized and is based on individual clinical response to therapy; typical duration is 10 to 14 days 
      • Consider fungal and atypical mycobacterial organisms, allergic bronchopulmonary aspergillosis, viral infection, or bacterial resistance when there is lack of response to usual therapy
    • Optimize and adjust maintenance therapies and chronic medications on an individual basis 
    • Intensify airway clearance therapy by increasing time for each treatment and frequency of treatments 
      • Mucolytic agents such as hypertonic saline are used as an adjunct to physiotherapy 
    • Focus on optimizing nutritional status 
    • Routine corticosteroid treatment is discouraged owing to lack of evidence of benefit; treatment with short course of corticosteroids may be individualized 
      • There is limited evidence that short courses of steroids may reduce symptoms and possibly improve lung function; this is currently being studied 

Other aspects of maintenance therapy in cystic fibrosis patients include the following: 

  • Fluid, electrolytes, and nutrition therapy
    • High-calorie, high-fat diet
    • Daily fat-soluble vitamin A, D, E, and K supplements
    • Sodium chloride supplementation
  • Treatment of exocrine pancreatic insufficiency
    • Pancreatic enzyme replacement therapy
      • Initiate once pancreatic insufficiency is documented 
      • Administer enzyme replacement with every meal, milk product, and snack 
      • Porcine-derived product; multiple formulations are available with variable units of lipase, amylase, and protease 
      • Some formulations contain bicarbonate to optimize enzyme activity 
    • Proton pump inhibitors, H₂-blockers, and antacids
      • May be added to normalize duodenal pH and augment exogenous pancreatic enzyme function 

Management of other complications is usually in same fashion as those in patients without cystic fibrosis

Drug therapy

  • General
    • Pharmacokinetics, particularly for antibiotics, may be altered because of increased renal clearance of drugs and high proportion of lean body mass 
    • Appropriate, modified cystic fibrosis dosing is individualized and may require additional monitoring 
  • Pancreatic enzyme replacement therapy
    • Dosing is based on units of lipase
    • General standard recommended starting dose is about 2500 units of lipase per kg per meal (or 10,000 units of lipase per kg per day), and smaller doses for snacks 
    • Alternative approach is to dose based on grams of fat ingested on average per day (4000 units of lipase per gram of fat per day) 
    • Adjustments may be required based on clinical response to treatment (eg, improved weight gain, diminished steatorrhea) and measured response by stool studies (eg, 72-hour fecal fat collection, fecal elastase measurement)
    • Some formulations contain bicarbonate to optimize enzyme activity 
    • Note: the various pancrelipase brands are not interchangeable with other pancrelipase products, unless the specific manufacturer FDA-approved label notes interchangeability
      • Delayed-release preparation
        • Lipase (Porcine), Protease (Porcine), Amylase (Porcine) Oral capsule, gastro-resistant pellets; Neonates and Infants: 2,600 lipase units per 120 mL formula or per breastfeeding PO for Pancreaze; 3,000 lipase units per 120 mL formula or per breastfeeding PO for Creon and Zenpep. Do not mix directly into formula or breast milk.
        • Lipase (Porcine), Protease (Porcine), Amylase (Porcine) Oral capsule, gastro-resistant pellets; Children 1 to 3 years: Initially, 1,000 lipase units/kg/meal PO. Titrate dose as needed. Max: 2,500 lipase units/kg/meal or 10,000 lipase units/kg/day or 4,000 lipase units/gram fat ingested/day. Give half mealtime dose with snacks.
        • Lipase (Porcine), Protease (Porcine), Amylase (Porcine) Oral capsule, gastro-resistant pellets; Children and Adolescents 4 years and older: Initially, 500 lipase units/kg/meal PO. Titrate dose PRN. Max: 2,500 lipase units/kg/meal or 10,000 lipase units/kg/day or 4,000 lipase units/gram fat ingested/day. Give half mealtime dose with snacks.
        • Lipase (Porcine), Protease (Porcine), Amylase (Porcine) Oral capsule, gastro-resistant pellets; Adults: Initially, 500 lipase units/kg/meal PO. Titrate dose PRN. Max: 2,500 lipase units/kg/meal (10,000 lipase units/kg/day or less or less than 4,000 lipase units/gram fat ingested/day). Give half mealtime dose with snacks. Doses of 72,000 lipase units/meal PO were studied in adults aged 32 to 75 years with chronic pancreatitis.
  • Inhaled hydrators and mucolytics
    • Dornase alfa (deoxyribonuclease)
      • Nebulized once daily; generally 30 minutes before performing airway clearance 
      • Dornase alfa Nebulizer solution; Infants and Children 3 months to 4 years: 2.5 mg via oral inhalation once daily (based on limited data).
      • Dornase alfa Nebulizer solution; Children and Adolescents 5 to 17 years: 2.5 mg via oral inhalation once daily; patients with FVC more than 85% may benefit from 2.5 mg via oral inhalation twice daily.
      • Dornase alfa Nebulizer solution; Adults: 2.5 mg via oral inhalation once daily; patients older than 21 years and/or with FVC more than 85% may benefit from 2.5 mg via oral inhalation twice daily.
    • Inhaled hypertonic saline (7%)
      • Sodium Chloride Nebulizer solution; Children and Adolescents 6 to 17 years: 4 mL/dose via oral inhalation twice daily. To prevent bronchospasm, administer after a bronchodilator (e.g., albuterol).
      • Sodium Chloride Nebulizer solution; Adults: 4 mL/dose via oral inhalation twice daily. To prevent bronchospasm, administer after a bronchodilator (e.g., albuterol).
    • Inhaled mannitol
      • Mannitol Inhalation powder, capsule; Adults: 400 mg (contents of 10 inhalation capsules containing 40 mg mannitol/capsule) via oral inhalation twice daily (morning and evening, with evening dose at least 2 to 3 hours before bedtime). Administer an inhaled short-acting bronchodilator 5 to 15 minutes before every dose. LIMIT OF USE: Use only in patients who have passed the BRONCHITOL Tolerance Test.
  • Inhaled antibiotics
    • Tobramycin
      • Nebulized solution
        • Tobramycin Nebulizer solution; Children and Adolescents 6 to 17 years: 300 mg via inhalation twice daily for 28 days in alternating 28-day periods.
        • Tobramycin Nebulizer solution; Adults: 300 mg via inhalation twice daily for 28 days in alternating 28-day periods.
        • Clinical use of tobramycin nebulizer solution is common in younger age groups in consultation with specialist; specifics regarding dosing are directed by specialist
      • Dry powder
        • Tobramycin Inhalation powder, capsule; Adults: 112 mg (4 caps) via oral inhalation every 12 hours for 28 days in alternating 28-day periods.
    • Aztreonam
      • Aztreonam Nebulizer solution; Children and Adolescents 7 to 17 years: 75 mg nebulized 3 times daily for 28 days then 28 days off therapy. Administer doses at least 4 hours apart; inhaled therapy order of administration: bronchodilator, mucolytic, aztreonam.
      • Aztreonam Nebulizer solution; Adults: 75 mg nebulized 3 times daily for 28 days then 28 days off therapy. Administer doses at least 4 hours apart; inhaled therapy order of administration: bronchodilator, mucolytic, aztreonam.
    • Colistin (colistimethate, an inactive prodrug of colistin)
      • Note: colistimethate sodium should be reconstituted just before administration in order to avoid excessive conversion to colistin, which can cause airway or alveolar injury 
      • Colistimethate for injection must only be prescribed as colistin in terms of base activity to prevent dosing errors 
      • Colistimethate Sodium Solution for injection; Children and Adolescents: 75 mg colistin base activity or 2.5 mg/kg/dose colistin base activity nebulized every 12 hours.
      • Colistimethate Sodium Solution for injection; Adults: 75 to 150 mg colistin base activity nebulized every 12 hours.
  • Antiinflammatory medications
    • Do not use as single-drug therapy in patients with active infection with nontuberculous mycobacteria
    • Azithromycin
      • Azithromycin Oral tablet; Children and Adolescents 6 to 17 years weighing 40 kg or more: 500 mg PO 3 times weekly. Optimal dosing not well established and various regimens used; some centers prefer daily dosing.
      • Azithromycin Oral tablet; Children and Adolescents 6 to 17 years weighing less than 40 kg: 250 mg PO 3 times weekly. Optimal dosing not well established and various regimens used; some centers prefer daily dosing.
      • Azithromycin Oral tablet; Adults: 500 mg PO 3 times weekly. Optimal dosing not well established and various regimens used; some centers prefer daily dosing.
    • NSAIDs
      • Ibuprofen
        • Ibuprofen Oral suspension; Children and Adolescents 6 to 17 years: 20 to 30 mg/kg/dose (Max: 1,600 mg/dose) PO twice daily adjusted to maintain a peak serum concentration of 50 to 100 mcg/mL.
        • Ibuprofen Oral tablet; Adults: 20 to 30 mg/kg/dose (Max: 1,600 mg/dose) PO twice daily adjusted to maintain a peak serum concentration of 50 to 100 mcg/mL.
    • Inhaled corticosteroids
      • Type of inhaled corticosteroid and dosing is highly individualized
  • Inhaled bronchodilators (β₂-adrenergic receptor agonists)
    • Albuterol (standard dosing for bronchospasm prophylaxis)
      • Albuterol Inhalation powder; Adults, Adolescents, and Children 6 years and older: 180 mcg (2 oral inhalations) every 4 to 6 hours as needed. 90 mcg (1 oral inhalation) every 4 hours may be sufficient in some patients. FDA-approved labeling recommends to not exceed 12 inhalations/day. Note: do not use the device with a spacer or volume holding chamber.
  • CFTR modulators
    • Ivacaftor
      • FDA-approved for treatment in patients aged 2 years or older with at least 1 of the 23 CFTR mutations, including G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, and R117H 
      • Ivacaftor Oral granules; Infants 4 to 5 months weighing 5 kg or more: 25 mg PO every 12 hours with fat-containing food. Coadministration of certain drugs may need to be avoided; review drug interactions.
      • Ivacaftor Oral granules; Infants and Children 6 months to 5 years weighing 5 kg to less than 7 kg: 25 mg PO every 12 hours with fat-containing food. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Ivacaftor Oral granules; Infants and Children 6 months to 5 years weighing 7 kg to less than 14 kg: 50 mg PO every 12 hours with fat-containing food. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Ivacaftor Oral granules; Infants and Children 6 months to 5 years weighing 14 kg or more: 75 mg PO every 12 hours with fat-containing food. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Ivacaftor Oral tablet; Children and Adolescents 6 to 17 years: 150 mg PO every 12 hour with fat-containing food. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Ivacaftor Oral tablet; Adults: 150 mg PO every 12 hour with fat-containing food. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • Lumacaftor-ivacaftor combination therapy
      • FDA-approved for treatment in patients aged 2 years or older with homozygous F508del CFTR genotype 
      • Lumacaftor, Ivacaftor Oral granules; Children 2 to 5 years weighing less than 14 kg: One packet of oral granules (containing lumacaftor 100 mg and ivacaftor 125 mg) PO every 12 hours with fat-containing food. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Lumacaftor, Ivacaftor Oral granules; Children 2 to 5 years weighing 14 kg or more: One packet of oral granules (containing lumacaftor 150 mg and ivacaftor 188 mg) PO every 12 hours with fat-containing food. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Lumacaftor, Ivacaftor Oral tablet; Children 6 to 11 years: 2 tablets (each containing lumacaftor 100 mg and ivacaftor 125 mg) PO every 12 hours with fat-containing food. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Lumacaftor, Ivacaftor Oral tablet; Children and Adolescents 12 years and older: 2 tablets (each containing lumacaftor 200 mg and ivacaftor 125 mg) PO every 12 hours with fat-containing food. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Lumacaftor, Ivacaftor Oral tablet; Adults: 2 tablets (each containing lumacaftor 200 mg and ivacaftor 125 mg) PO every 12 hours with fat-containing food. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • Tezacaftor-ivacaftor combination therapy
      • Approved for patients aged 6 years or older who are homozygous for the F508del mutation or who have at least 1 mutation in the CFTR gene that is responsive to the combination drug
      • Ivacaftor Oral tablet, Tezacaftor, Ivacaftor Oral tablet; Children 6 to 11 years weighing less than 30 kg: 1 tablet (containing tezacaftor 50 mg/ivacaftor 75 mg) PO in the morning and 1 tablet (containing ivacaftor 75 mg) PO in the evening, approximately 12 hours apart and given with fat-containing food. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Ivacaftor Oral tablet, Tezacaftor, Ivacaftor Oral tablet; Children 6 to 11 years weighing 30 kg or more: 1 tablet (containing tezacaftor 100 mg/ivacaftor 150 mg) PO in the morning and 1 tablet (containing ivacaftor 150 mg) PO in the evening, approximately 12 hours apart and given with fat-containing food. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Ivacaftor Oral tablet, Tezacaftor, Ivacaftor Oral tablet; Children and Adolescents 12 to 17 years: 1 tablet (containing tezacaftor 100 mg/ivacaftor 150 mg) PO in the morning and 1 tablet (containing ivacaftor 150 mg) PO in the evening, approximately 12 hours apart and given with fat-containing food. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Ivacaftor Oral tablet, Tezacaftor, Ivacaftor Oral tablet; Adults: 1 tablet (containing tezacaftor 100 mg/ivacaftor 150 mg) PO in the morning and 1 tablet (containing ivacaftor 150 mg) PO in the evening, approximately 12 hours apart and given with fat-containing food. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • Elexacaftor-tezacaftor-ivacaftor combination therapy
      • Approved for patients aged 6 years or older who have at least 1 F508del mutation in the CFTR gene
      • Elexacaftor, Tezacaftor, Ivacaftor Oral tablet, Ivacaftor Oral tablet; Children and Adolescents 12 to 17 years: 2 tablets (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) PO in the morning and 1 tablet (containing ivacaftor 150 mg) PO in the evening, approximately 12 hours apart and given with fat-containing food. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Elexacaftor, Tezacaftor, Ivacaftor Oral tablet, Ivacaftor Oral tablet; Adults: 2 tablets (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) PO in the morning and 1 tablet (containing ivacaftor 150 mg) PO in the evening, approximately 12 hours apart and given with fat-containing food. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Nondrug and supportive care

Nutrition

  • Caloric intake and energy requirements
    • Process for determining caloric energy requirements is standardized; recommendations are given in consultation with a nutrition specialist familiar with treating patients with cystic fibrosis 
      • Energy requirements are increased to about 110% to 200% of typical requirements for healthy population of similar sex, age, and size 
    • Enteral tube feedings may be required for patients with disease unresponsive to pancreatic enzyme replacement therapy and high-calorie, high-fat diet; a capsule of pancreatic enzymes can be included in the tube feeding 
    • Other options for improving suboptimal nutritional status may include behavioral therapy and pharmacotherapy (eg, cyproheptadine, megestrol acetate, dronabinol) 
    • May be necessary to exclude alternative causes of malabsorption in patients with disease unresponsive to pancreatic enzyme replacement therapy and high-calorie, high-fat diet 
  • Fat-soluble vitamin supplementation
    • Commercially available combination A/D/E/K products with ideal dosing for most fat-soluble vitamins are available 
    • Standardized recommendations for age-based fat-soluble vitamin supplementation are as follows:
      • Vitamin A
        • Age 0 to 12 months: 450 mcg (1500 international units)/day
        • Age 1 to 3 years: 1500 mcg (5000 international units)/day
        • Age 4 to 8 years: 1500 to 3000 mcg (5000-10,000 international units)/day
        • Age older than 8 years: 3000 mcg (10,000 international units)/day
      • Vitamin D
        • Initial dose
          • Age 0 to 12 months: 10 mcg (400 international units)/day of vitamin D₃ (cholecalciferol)
          • All other ages: at least 10 to 20 mcg (400-800 international units)/day of vitamin D₃ (cholecalciferol) 
        • Maintenance dose
          • Increase dose in increments to maintain 25-hydroxyvitamin D in optimal range (lower limit goal: greater than 30 ng/mL)
          • Most children and adults require between 25 to 50 mcg (1000-2000 international units) daily to maintain 25-hydroxyvitamin D in optimal range
      • Vitamin E
        • Age 0 to 12 months: 26.8 to 33.5 mg (40-50 international units)/day 
        • Age 1 to 3 years: 53.6 to 100 mg (80-150 international units)/day
        • Age 4 to 8 years: 67 to 134 mg (100-200 international units)/day
        • Age older than 8 years: 134 to 268 mg (200-400 international units)/day
      • Vitamin K
        • All ages: 0.3 to 0.5 mg/day
        • Most commercially available products contain less than the optimal dose of vitamin K
    • Dosing adjustments may be required based on screening vitamin concentrations 
  • Sodium chloride supplementation
    • Excessive salt loss through skin may lead to hyponatremia, particularity in association with dehydration
    • Recommended table salt supplementation
      • Age younger than 6 months: 0.125 tsp daily (290.5 mg) 
      • Age 6 months and older: 0.25 tsp daily (581 mg) 
      • Older patients should routinely consume a high-salt diet 
      • Older patients in warm environments during periods of activity should supplement with 0.25 tsp (581 mg) of salt added to 12-ounce (30 mL) electrolyte sports drink 
  • Other elements
    • Calcium
      • Intestinal absorption of calcium is not affected by disease and patients should consume minimum daily requirement of 1000 to 1500 mg of elemental calcium in divided doses daily (either in diet or via supplementation) 
    • Zinc
      • Empiric zinc supplementation for 6 months is recommended for patients with short stature or failure to thrive because fat malabsorption negatively affects zinc absorption 
  • Probiotics
    • Probiotics may be considered to improve intestinal health in children and adults
      • Shown to reduce levels of fecal calprotectin, a marker of intestinal inflammation; however, clinical implications of this are unclear
    • Probiotics have little or no effect on lung function or rates of pulmonary exacerbation
  • Academy of Nutrition and Dietetics Cystic Fibrosis Evidence-Based Nutrition Practice Guidelines provide recommendations on nutrition assessments and interventions for children and adults with cystic fibrosis

Airway clearance techniques

  • Goal is to mobilize airway secretions and diminish infectious burden by removing bacteria and other airway irritants 
  • There are no data to suggest that one form of airway clearance is more effective than another; therapy is individualized according to ease of administration, comfort, convenience, cost, and patient satisfaction to maximize adherence 
  • Intensify treatments during times of pulmonary exacerbation; temporarily discontinue for patients with certain complications (eg, massive hemoptysis, large pneumothorax) 
  • Specific techniques may include:
    • Percussion and postural drainage
      • Only method available for infants and young children; may be used in patients of any age 
      • Avoid head-down position in infants and children younger than 2 years; head-down position may exacerbate gastrointestinal reflux 
    • High-frequency chest wall oscillation vest
      • Useful for patients aged 18 months or older 
      • Vest vibrates airways to loosens mucus, expediting effective cough and mucus expulsion 
    • Positive expiratory pressure
      • Often used in children about 3 years or older; young children may require assistance 
      • Device attached to nebulizer designed to reinflate atelectatic lung; involves breathing against pressure on expiration 
    • Active cycle of breathing techniques
      • Often used in children about age 3 years or older; young children may require assistance 
      • Thoracic expansion exercises followed by controlled breathing and forced expiratory techniques 
    • Autogenic drainage
      • Useful in patients aged 12 years or older 
      • Respiratory exercise involving a series of huffs and coughs to dislodge and expel mucus 
    • Oscillatory positive expiratory pressure
      • Useful for adolescents and adults 
      • Specialized equipment, in some cases attached to nebulizer, that causes air to vibrate to move mucus 

Exercise

  • Important airway clearance adjunct 
  • Optimal mode, duration, frequency, intensity, and type of exercise is not rigorously established
  • Regular regimen is individualized and directed by cystic fibrosis physiotherapist; often includes 30 minutes of aerobic exercise and strength training 3 to 5 times weekly 
  • Role of specific respiratory muscle training is unclear 
  • Supplemental oxygen is recommended for desaturation below 90% during exercise 

Oxygen

  • Supplemental oxygen may be used in patients with cystic fibrosis for treatment of intermittent or chronic hypoxemia

Noninvasive positive pressure ventilation

  • BPAP may be used in patients with advanced cystic fibrosis who have hypercapnic respiratory failure, particularly in the following: 
    • Infants
    • Patients with reversible cause for respiratory failure
    • Accepted lung transplant candidates
  • No effect on lung function, but can improve pulmonary symptoms, exertional dyspnea, nocturnal hypoventilation, and peak exercise capacity

Psychological support

  • Regular assessment for psychological distress and mental health issues is routine
  • Focused intervention may be indicated, including:
    • Desensitization, distraction, and healthy coping strategies to help contend with painful procedures
    • Counseling or pharmacotherapy for mental health issues such as anxiety and depression

Infection prevention and control measures

  • Strict infection prevention and control measures are required for hospitalized patients and those attending specialized clinics 
  • Goal is to diminish risk of transmissible pathogen exposure, especially with highly pathogenic organisms (eg, Burkholderia cenocepacia) and highly resistant organisms (eg, Pseudomonas aeruginosa, Mycobacterium abscessus) 

Agents and exposures to avoid

  • Airway irritants (eg, cigarette smoke, dust) 
  • Contact with people with respiratory infections 
  • Excessive vitamin A intake 
  • Excessive alcohol intake 

Routine health care and immunizations

  • Perform routine, age-based, well-child care according to American Academy of Pediatrics guidelines 
  • Administer all routine, age-appropriate immunizations, including seasonal influenza vaccine to patients younger than 6 months and household contacts 
  • Administer first pneumococcal polysaccharide vaccine (PPSV23) at least 8 weeks after last pneumococcal conjugate vaccine (PCV13) 
  • Consider use of palivizumab for prophylaxis of respiratory syncytial virus in children younger than 2 years; routine use in cystic fibrosis is not recommended unless other indications are apparent (eg, prematurity, immunocompromised state, hemodynamically significant congenital heart disease, chronic lung disease) 
    • In children with cystic fibrosis, use of palivizumab does not appear to influence age at first positive Pseudomonas aeruginosa culture, annual risk of hospitalization, or lung function at age 7 years 

Transition to adult care

  • Begin preparation of patient and family early; some experts suggest beginning discussion in early childhood, up to age 12 years at the latest 
  • Patient and family checklists are used by many cystic fibrosis centers to assist transition process to adult care team 

Lung transplant

  • Consider for treatment of end-stage lung disease 
  • Cystic Fibrosis Foundation has published detailed indications for referral to a lung transplant center 
  • Mechanical ventilation and extracorporeal membrane oxygenation may be required as a bridge to lung transplant

Liver transplant

  • Consider for treatment of end-stage liver disease associated with any of the following: 
    • Intractable variceal bleeding recalcitrant to other therapy
    • Marked ascites and jaundice
    • Hepatopulmonary syndrome
    • Portopulmonary hypertension
    • Hypoalbuminemia with coagulopathy
    • Deteriorating pulmonary function
    • Severe malnutrition

End-stage palliative care

  • Focuses on symptom management, communication, and support of patient and family with goal of improving quality of life despite prognosis 
  • Options include medical, psychological, and spiritual modes of intervention 
Procedures
Lung transplant

General explanation

  • Total replacement of lung tissue by a donor organ is the final therapeutic option for end-stage lung disease caused by cystic fibrosis 
  • Some patients with both advanced pulmonary and liver disease undergo simultaneous lung-liver transplant; dual organ transplant is rare owing to the complexity of the procedure

Indication

  • Cystic Fibrosis Foundation has published detailed indications for referral to a lung transplant center; these include: 
    • FEV₁ less than 50% predicted for those with a rapidly declining FEV₁
    • FEV₁ less than 40% (less than 50% for patients younger than 18 years) predicted with markers of shortened survival (greater than 2 exacerbations per year, massive hemoptysis, pneumothorax, BMI less than 18 kg/m²)
    • FEV₁ less than 30% (less than 40% for patients younger than 18 years) predicted
    • Any of the following, regardless of FEV₁
      • 6-minute walk test less than 400 m
      • Hypoxemia (SpO₂ less than 88% or PaO₂ less than 55 mm Hg)
      • Hypercapnia (PaCO₂ greater than 50 mm Hg) 
      • Pulmonary hypertension (pulmonary artery systolic pressure greater than 50 mm Hg on echocardiogram) 
      • Any exacerbation requiring positive pressure ventilation

Contraindications

  • Each transplant center has individualized contraindications to transplant; general contraindications may include: 
    • Malignancy within 2 years
    • Chronic extrapulmonary infection
    • Severe skeletal deformity
    • Substance use disorder
    • No consistent social support system
    • Untreatable psychological condition that impairs adherence to therapy
    • Inconsistent clinic attendance
    • Chronic infection with Burkholderia cenocepacia, Burkholderia gladioli, Mycobacterium abscessus, or Lomentospora prolificans 
    • Acute respiratory failure (intubated and mechanically ventilated) 
    • Osteoporosis 

Comorbidities

  • Asthma
    • Diagnosis of comorbid asthma is challenging and complex
      • No accepted criteria exist for diagnosis of comorbid asthma in patients with cystic fibrosis 
      • Presence of atopy may help identify some patients with concurrent asthma 

Special populations

  • Pregnant patients
    • Careful family planning is required in consultation with high-risk obstetrician and cystic fibrosis treatment team; preimplantation genetic diagnosis may be possible when reproductive partner is a carrier of a CFTR pathologic variant associated with disease
    • Pregnancy outcomes are good in patients with good respiratory and nutritional status; however, pregnant patients with FEV₁ less than 60% of predicted have a higher rate of preterm deliveries and smaller infants, and maternal complications, while rare, are more common than in patients without cystic fibrosis
    • Pregnancy is managed in close consultation with both high-risk obstetrician and cystic fibrosis treatment team 
    • European Respiratory Society/Thoracic Society of Australia and New Zealand has published guidelines for management of reproduction and pregnancy in women with airways diseases such as cystic fibrosis 
    • Enhanced monitoring for development of diabetes during pregnancy is suggested (ie, screening in each trimester) 
    • Closely monitor and optimize maternal nutritional status and weight gain; treat pulmonary exacerbations early and aggressively 
    • Preferred mode of delivery is based on usual obstetric indications 

Monitoring

  • General routine monitoring of growth, nutrition, and pulmonary status
    • Perform clinical assessments every 3 months and at the time of any clinical deterioration; more frequent assessments are necessary in the first year of life and early childhood 
      • Monitor height, weight, and BMI
        • Plot growth parameters on standard WHO (patients younger than 2 years) and CDC growth charts (patients aged 2-20 years) 
          • Younger than 2 years: goal weight for length is greater than 50th percentile 
          • Older than 2 years: goal BMI is 50th percentile or higher 
          • Adult females: goal BMI is at least 22 kg/m² 
          • Adult males: goal BMI is at least 23 kg/m² 
      • Obtain bacterial airway cultures every 3 months for routine surveillance 
      • Assess and review airway clearance, inhalation techniques, and exercise regimen 
      • Monitor for adherence to treatment regimen
        • Airway clearance techniques and nebulized treatments are the most common therapies associated with nonadherence 
    • Monitor pulmonary function at each clinic visit
      • FEV₁ is gold standard for patients able to perform test (from age 5 or 6 years) 
      • Assess pre- and postbronchodilator spirometry 
    • Obtain chest radiograph at least every other year 
    • Consider bronchoscopy to obtain cultures, evaluate airway inflammation, and assess for anatomic abnormalities in patients with decline in FEV₁ and/or recurrent pulmonary exacerbation despite standard therapy 
  • Monitoring for complications and manifestations commonly associated with disease
    • Pancreatic insufficiency
      • In patients with pancreatic insufficiency who are receiving pancreatic enzyme replacement therapy, monitor efficacy indirectly by nutritional status (BMI, vitamin levels) and stool characteristics
      • In patients with pancreatic sufficiency at diagnosis, some authorities recommend annual fecal elastase
    • Nutritional status
      • Assess for fat-soluble vitamin deficiency (vitamins A, D, E, and K) with baseline levels at time of initial diagnosis and annually; test the following:
        • Vitamin A (retinol)
        • 25-hydroxyvitamin D
        • Vitamin E (α-tocopherol)
        • If clinically indicated, vitamin K (PIVKA-II or prothrombin time)
      • Evaluate for iron deficiency with hemoglobin and hematocrit at time of initial diagnosis and annually 
      • Monitor protein stores with albumin at the time of initial diagnosis and annually 
      • Evaluate electrolytes annually 
    • Cystic fibrosis–related diabetes
      • Annual oral glucose tolerance test during periods of stability is recommended after age 10 years 
      • Role of hemoglobin A1C for screening of cystic fibrosis–related diabetes is controversial owing to high false-negative rate in certain clinical scenarios among patients with cystic fibrosis 
        • May be used to monitor glycemic control in patients receiving insulin 
      • Monitoring for hypoglycemia in patients started on CFTR modulator therapy
        • Increased monitoring intensity may be indicated; hypoglycemia may develop with improved insulin secretion after beginning CFTR modulator therapy 
    • Cystic fibrosis–related liver disease
      • Annual screening is recommended; obtain baseline liver function biochemistry at time of initial diagnosis
      • Screening involves abdominal examination to assess for hepatomegaly and other signs of liver disease, and biochemical assessment (ie, AST, ALT, γ-glutamyl transferase, albumin, prothrombin time, platelet count); abdominal ultrasonography is recommended by most experts for patients with known hepatic disease or persistent abnormalities on examination or laboratory testing 
      • Patients with liver disease and portal hypertension require screening with upper gastrointestinal endoscopy to assess for development of esophageal varices 
    • Bone disease
      • Begin screening bone mineral density for osteopenia and osteoporosis with DXA 
      • Suggested frequency of screening depends on severity of bone mineral density loss and fracture history 
        • Z score greater than −1: every 5 years
        • Z score between −2 and −1: every 2 to 4 years
        • Z score greater than −2: at least annually
      • Monitor vitamin D intake; measure vitamin D level annually. Goal serum 25-hydroxyvitamin D level is greater than 30 ng/mL 
    • Depression and anxiety
      • Annual screening is recommended for adolescents and adults, as well as parents of children from time of diagnosis until at least age 17 years 
      • Untreated mental health issues lead to increased risk of nonadherence to medical regimen 
    • Male hypogonadism
      • Obtain testosterone level with clinical concern for hypogonadism and as part of osteoporosis evaluation in men 
      • Obtain morning level; avoid obtaining level during period of acute illness 
    • Pulmonary hypertension
      • Consider screening with transthoracic echocardiogram in patients with advanced lung disease, signs of right-sided heart failure, and at time of lung transplant 
    • Allergic bronchopulmonary aspergillosis
      • Begin annual screening in children older than 6 years with total serum IgE levels and peripheral eosinophil counts 
      • Further testing is recommended if total serum IgE level is greater than 500 international units/mL. Obtain cutaneous reactivity to Aspergillus species; serum IgE to Aspergillus fumigatus; serum IgG to Aspergillus fumigatus or precipitins to Aspergillus fumigatus; and/or chest imaging 
      • Close follow-up is indicated if total IgE level is borderline (ie, 200-500 international units/mL); obtain repeat total IgE level in 1 to 3 months if clinical suspicion for allergic bronchopulmonary aspergillosis is present 
    • Colon polyposis and malignancy screening
      • Monitoring is not standardized; however, colonoscopy screening is recommended to start in patients older than 40 years and in persistently symptomatic patients without identifiable alternative explanation for symptoms 
        • Posttransplant patients require more intensive monitoring; consider initial screening colonoscopy at age 30 years 
      • Suggested follow-up colonoscopy interval is every 5 years in the absence of abnormal findings and every 3 years in patients with evidence of adenomatous polyps 
  • Monitoring for patients on drug therapy
    • Ivacaftor
      • Limited data suggest that increased transaminase levels may occur in up to 15% of younger children aged 2 to 5 years; monitoring may be indicated 
      • Monitor for improvement in clinical parameters (eg, blood glucose levels in patients requiring insulin) as clinical manifestations may change with institution of medication
      • Some data suggest possible association with cataract development; baseline and follow-up ophthalmologic examinations are recommended 
    • Aminoglycosides
      • Periodic monitoring of drug concentration is recommended with adjustments to dosing as necessary 
      • Periodic assessments for toxicity with creatinine level and audiogram are recommended on individual basis 
    • Azithromycin
      • Screen for nontuberculous mycobacterium at 6- or 12-month intervals; withhold azithromycin in the presence of active infection 
  • Patients designated with CFTR-related metabolic syndrome (cystic fibrosis screen positive, inconclusive diagnosis)
    • Periodic clinical monitoring for developing disease manifestations is required, preferably at an accredited cystic fibrosis center 
      • Frequency and duration of follow-up are not rigorously standardized 
    • Most experts recommend repeat sweat testing at ages 6 months and 2 years 

Complications

  • Pulmonary complications
    • Chronic cough and sputum production
    • Frequent, recurrent, or recalcitrant pneumonia
    • Severe bronchiolitis and bronchitis
    • Bronchiectasis
    • Colonization and chronic endobronchial infection with a variety of respiratory pathogens
      • Bacterial pathogens
        • Most common pathogens early in life include Staphylococcus aureus and Haemophilus influenzae
        • Later in life, typically transitions to predominantly Pseudomonas aeruginosa
          • 50% to 70% of adults are chronically infected with Pseudomonas aeruginosa 
          • Conversion to mucoid phenotype of Pseudomonas is associated with poor prognosis 
        • Other notable pathogens, often associated with deteriorating lung function, include Achromobacter xylosoxidans, Stenotrophomonas maltophilia, Burkholderia cepacia complex, MRSA, and Mycobacterium abscessus 
      • Fungal species commonly encountered include Candida and Aspergillus 
      • Numerous viral pathogens are commonly identified in airways; may trigger pulmonary exacerbation 
    • Pulmonary exacerbations
      • Viral and bacterial pathogens often trigger clinical deterioration; exaggerated inflammatory response exacerbates process
      • Staphylococcus aureus and Haemophilus influenzae are most common causative pathogens in children 
      • Pseudomonas aeruginosa is the most common pathogen in adults, with Stenotrophomonas maltophilia and infections becoming increasingly common
      • Risk factors include increasing age and severity of baseline FEV₁, female sex, chronic endobronchial infections, allergic bronchopulmonary aspergillosis, cystic fibrosis–related diabetes, and history of having been treated for a pulmonary exacerbation 
      • Presents clinically with changes in respiratory (eg, increased cough, sputum, dyspnea, hemoptysis, decline in FEV₁) or systemic (eg, weight loss, fever, anorexia, fatigue) status 
      • No clear diagnostic criteria exist to define; Fuchs criteria are often used clinically despite lack of validation 
      • Exacerbations are associated with:
        • Development of cystic fibrosis–related diabetes, sleep disturbances, and diminished health-related quality of life parameters
        • Hastening in overall decline of pulmonary function and diminished survival rates
      • Frequent exacerbations are a marker of increasing disease severity 
      • Treatment involves antibiotics, intensifying airway clearance techniques, and optimizing both chronic medications and maintenance therapy 
        • Selection of empiric antibiotics is based on likely pathogens (eg, Pseudomonas aeruginosa, Burkholderia complex, Staphylococcus aureus), patient history of antibiotic exposure, and prevailing antimicrobial susceptibility patterns
    • Allergic bronchopulmonary aspergillosis
      • Immune-mediated (IgE and IgG) allergic response to Aspergillus fumigatus leading to bronchial airway obstruction
      • 8% to 9% of adult patients with cystic fibrosis develop this condition 
      • Associated with increased cough, wheeze, exercise intolerance, pulmonary infiltrates, high-attenuation mucus plugging, central bronchiectasis, and pulmonary fibrosis with decreased FEV₁
      • Consider with clinical deterioration during presumed pulmonary exacerbation that does not respond to usual treatment with antibiotics; diagnostic criteria are available 
      • Recurrent exacerbations of clinical manifestations occur during typical course of allergic bronchopulmonary aspergillosis, which is commonly protracted
      • Associated with a greater decline in lung function than typical pulmonary exacerbation and can progress to respiratory failure 
      • High-dose corticosteroids are mainstay of treatment along with simultaneous standard treatment of pulmonary exacerbation 
    • Advanced cystic fibrosis lung disease
      • Progressive pulmonary obstructive disease and declining lung function eventually leads to respiratory failure
      • Patients experience worsening clinical symptoms, increased exacerbations, and reduced quality of life 
      • Risk of developing complications such as hemoptysis, pneumothorax, pulmonary hypertension, and chronic respiratory failure, increases as lung disease progresses 
      • Patients are considered to have advanced cystic fibrosis lung disease if any of the following criterion are met: 
        • FEV₁ less than 40% when stable
        • Referred for lung transplant evaluation
        • One or more of the following characteristics:
          • Previous intensive care unit admission for respiratory failure
          • Hypercarbia (PaCO₂ greater than 50 mmHg on arterial blood gas or PvCO₂ greater than 56 mm Hg on venous blood gas)
          • Daytime oxygen requirement at rest (excluding nocturnal use only)
          • Pulmonary hypertension (pulmonary artery systolic pressure greater than 50 mm Hg on echocardiogram or evidence of right ventricular dysfunction in the absence of a tricuspid regurgitant jet)
          • Severe functional impairment from respiratory disease (New York Heart Association Class IV)
          • 6-minute walk test distance less than 400 m
      • Management is described in depth in Cystic Fibrosis Foundation consensus guidelines for the care of individuals with advanced cystic fibrosis lung disease
    • Pneumothorax
      • About 3.4% of patients develop at least 1 pneumothorax; estimated annual incidence is 0.64% 
      • May occur during pulmonary exacerbation and recurrence is common 
      • Risk factors include FEV₁ less than 30% to 40%, older age, pancreatic insufficiency, massive hemoptysis, allergic bronchopulmonary aspergillosis, and sputum colonization with Pseudomonas aeruginosa, Burkholderia cepacia complex, or aspergillus 
      • Small pneumothorax (less than 2 cm) may be treated conservatively; larger pneumothorax requires chest tube insertion and possibly pleurodesis or partial pleurectomy 
      • Modification of mechanical airway clearance techniques may be required 
    • Hemoptysis
      • Annual incidence is 1% to 2%; up to about 4% of patients develop massive hemoptysis during lifetime 
      • Risk factors include sputum colonization with Staphylococcus aureus and cystic fibrosis–related diabetes; massive hemoptysis is associated with older age and lower FEV₁ 
      • May be associated with pulmonary exacerbation or rupture of pulmonary vessel into airway 
      • Management depends on cause and severity of hemoptysis
        • Minor bleeding with small volumes (less than 5 mL)
          • Requires no specific management outside of addressing possibility of pulmonary exacerbation 
        • Larger volume or recurrent episodes
          • May require holding nebulized treatments, adapting airway clearance techniques, pulmonary exacerbation treatment with antibiotics, and possibly tranexamic acid or ε-aminocaproic acid 
        • Massive hemoptysis (greater than 240 mL in 24 hours or recurrent hemoptysis over several days with greater than 100 mL per day) 
          • Often requires standard resuscitation and bronchial artery embolization 
    • Pulmonary hypertension
      • Reportedly develops in 20% to 63% of patients depending on population and definitions 
      • Correlates with hypoxia and severe lung dysfunction
      • Absolute contraindication to pregnancy 
      • May result in right-sided heart failure and cor pulmonale
    • Pulmonary venous thrombosis
      • Relatively uncommon and may be associated with central venous catheters
  • Pancreatic complications
    • Pancreatic insufficiency
      • Prevalence is 85% to 90% and increases with age
        • May be present at birth and usually evident in the first few months of life; evident at time of diagnosis in most patients with class I to III CFTR mutations 
        • Late-onset exocrine pancreatic insufficiency may develop in patients with previous pancreatic sufficiency and in those with milder phenotypes (class IV and V CFTR mutations); monitoring for development is indicated
      • Obstruction of pancreatic ducts results in pancreatic autodigestion and insufficiency; process is progressive 
        • Consequences include undernutrition, poor weight gain, and failure to thrive
          • Fat malabsorption occurs secondary to reduced intestinal pH and lack of lipolytic pancreatic enzyme secretion; symptoms may include bloating, greasy stools, steatorrhea, and flatulence 
          • Malabsorption of fat-soluble vitamins (A, D, E, K) 
          • Protein malabsorption occurs secondary to inadequate proteolytic pancreatic enzyme secretion; severe edema may develop if untreated 
      • Diagnosis may involve assessment of symptoms (eg, poor weight gain, bloating, abnormal stools), steatocrit, 72-hour quantitative fecal fat collection, and/or fecal elastase measurement 
      • Treatment includes optimizing pancreatic enzyme replacement therapy; high-calorie, high-fat diet; fat-soluble vitamin supplementation; and normalization of intestinal pH with proton pump inhibitors. Ivacaftor may improve exocrine pancreatic function, particularly in younger patients 
    • Pancreatitis
      • Recurrent acute pancreatitis occurs in 10% to 15% of patients; more common in patients with pancreatic sufficiency 
      • Typically occurs in patients with milder CFTR pathologic variants (ie, classes IV-VI) 
      • More common in patients with recurrent pulmonary exacerbations, viral infections, and after surgery 
      • Exclusion of additional cause of pancreatitis (eg, alcohol-induced, biliary stone) is indicated 
      • Treatment is conservative with bowel rest, pain management, IV fluid hydration, nasogastric tube for persistent vomiting, and sometimes antibiotics 
      • Patients are at higher risk for development of pancreatic insufficiency and cystic fibrosis–related diabetes 
    • Cystic fibrosis–related diabetes
      • Most common comorbidity associated with cystic fibrosis 
      • Prevalence is 20% in adolescents and up to 50% in adults; more common in patients with pancreatic insufficiency and patients with class I to III CFTR mutations 
      • Can occur in patients of any age, including infants; prevalence increases with age 
      • Distinct from type 1 and type 2 diabetes
        • Insulin deficiency is severe but not complete and onset is gradual rather than abrupt 
          • Results from progressive and gradual decrease in β-cell insulin production secondary to decreased β-cell mass (rather than abrupt decrease and onset as seen in type 1 diabetes) 
          • Patients do not usually develop ketoacidosis because sufficient endogenous insulin is produced to avoid ketosis 
          • Patients may be asymptomatic because production of insulin declines gradually 
          • Autoantibodies found in type 1 diabetes are not present 
        • Insulin sensitivity is usually normal 
      • Associated with accelerated decline in FEV₁, increased pulmonary exacerbation frequency, and poorer nutritional status; early recognition and treatment improves survival. Monitoring is indicated 
      • Diagnosis can be made in a symptomatic patient (eg, polyuria, polydipsia) with plasma glucose level of 200 mg/dL or higher or in an asymptomatic patient through routine screening with oral glucose tolerance test; hemoglobin A1C is not recommended for screening 
      • Prolonged fasting hyperglycemia may result in diabetic retinopathy and nephropathy; autonomic neuropathy and gastrointestinal manifestations secondary to cystic fibrosis–related diabetes may develop irrespective of fasting hyperglycemia 
      • Management is similar to type 1 diabetes with insulin-based therapy and careful individualized dosing adjustments to compensate for high-calorie diet in consultation with an endocrinologist 
        • Oral diabetes medications are considered to be less effective than insulin and not recommended for cystic fibrosis–associated diabetes; however, a Cochrane review did not find conclusive evidence that any agent was superior in terms of controlling hyperglycemia or improving outcomes 
        • In eligible patients, ivacaftor, alone or in combination with other CFTR-modulating agents, may improve insulin secretion profile and possibly reverse cystic fibrosis–related diabetes 
      • Management of cystic-fibrosis related diabetes is discussed in detail in International Society for Pediatric and Adolescent Diabetes guidelines for management of cystic fibrosis–related diabetes in children and adolescents and the American Diabetes Association/Cystic Fibrosis Foundation Clinical Care Guidelines for Cystic Fibrosis–Related Diabetes 
      • Cystic fibrosis–specific complications improve with treatment 
  • Hepatobiliary complications
    • Cystic fibrosis–related liver disease
      • Liver disease usually develops before age 18 years when de novo (ie, related to CFTR dysfunction) 
        • Risk factors include male sex, history of meconium ileus, and presence of severe mutations (classes I-III) 
        • Hepatic steatosis occurs in 23% to 75% of patients 
        • Severe cirrhosis develops in 5% to 8% of patients 
          • Stagnation of biliary secretion and subsequent ductal obstruction lead to cirrhosis 
          • Primary manifestations include hepatosplenomegaly and portal hypertension; synthetic dysfunction is rare 
          • Esophageal varices and ascites may develop; upper gastrointestinal monitoring for esophageal varices is indicated 
      • There is little consensus regarding strict definition of cystic fibrosis–related liver disease 
        • Transient elevations of liver function test results are frequent and do not necessarily signify underlying liver disease directly secondary to cystic fibrosis 
          • Drug interactions and drug (eg, ivacaftor)-induced hepatic disease are frequent causes of liver function test result abnormalities
        • Guidelines suggest consideration of diagnosis with at least 2 of the following: 
          • Evidence of hepatomegaly, splenomegaly, or both on clinical examination
          • Hepatic transaminases and γ-glutamyl transferase elevation on at least 3 consecutive occasions over a 12-month period after exclusion of other causes of liver disease
          • Structural evidence of liver disease on ultrasonographic imaging
        • Decreased platelet count suggests disease 
        • Elastography may be useful measure to assess for hepatic fibrosis 
        • Liver biopsy may be needed to confirm when diagnostic uncertainty exists 
      • Management
        • Optimizing pancreatic enzyme replacement therapy, caloric intake, fat-soluble vitamin supplementation, and avoiding hepatotoxic drugs 
        • Ursodeoxycholic acid is used clinically despite limited evidence; in eligible patients, ivacaftor may improve hepatic steatosis. Portosystemic shunting or liver transplant may be required for severe disease 
      • Consider β-blockers in patients with portal hypertension while taking care to monitor for development of hypotension and bronchospasm 
    • Gallbladder-related abnormalities occur in up to 50% of patients
      • Recurrent subacute cholecystitis leads to contracted and poorly functioning gallbladder in about one-third of patients 
      • Cholelithiasis occurs in up to 10% of patients 
      • Other complications may include biliary tract stenosis and sclerosing cholangitis 
      • Management is similar to general population without cystic fibrosis; cholecystectomy may be required when complications exist (eg, cholecystitis, bile duct obstruction) 
    • Neonatal obstructive jaundice
      • Affects less than 2% of patients and is often prolonged 
      • Usually resolves within about 3 months 
      • Management includes optimizing pancreatic enzyme replacement therapy, nutritional support, and short-term use of ursodeoxycholic acid 
  • Gastrointestinal complications
    • Meconium ileus
      • Bowel obstruction presenting at birth secondary to accumulation of inspissated mucus and fecal material
      • Occurs in 10% to 15% of patients; condition is highly suggestive of cystic fibrosis, but most affected infants have a false-negative newborn screening result 
      • Simple obstruction presents with failure to pass meconium in the first 48 hours of life without findings consistent with complex disease 
        • Complex disease includes perforation, meconium peritonitis, and/or volvulus; occurs in up to 40% of patients with meconium ileus 
      • Management for simple obstruction includes hyperosmolar enemas, IV hydration, and nasogastric decompression; complex disease and obstruction not resolving with medical therapy require surgical intervention 
    • Distal ileal obstruction syndrome
      • Acute or subacute bowel obstruction presenting in children outside of neonatal period and adults secondary to accumulation of inspissated mucus and fecal material; may be complete or incomplete (impending) obstruction and usually occurs at the ileocecal junction
        • Complete is defined by evidence of obstruction (eg, bilious emesis, distended small bowel with air fluid levels on radiographs) associated with abdominal pain and/or abdominal distention, and often a palpable ileocecal mass 
        • Incomplete (impending) is defined by a history of abdominal pain and/or distention and often a palpable ileocecal mass without evidence of obstruction
      • Estimated prevalence is between 10% to 47%; early recognition and treatment is important because delayed intervention is associated with significant morbidity 
      • Risk factors include history of meconium ileus, pancreatic insufficiency, chronic constipation, cystic fibrosis–related liver disease, cystic fibrosis–related diabetes, sputum colonization with Pseudomonas aeruginosa, dehydration, and nonadherence to pancreatic enzyme replacement therapy 
      • Management often includes a combination of oral laxatives (eg, polyethylene glycol), sodium meglumine diatrizoate enemas (eg, Gastrografin), N-acetyl-cysteine, analgesia, IV fluid rehydration, and bowel decompression for complete obstruction (eg, nasogastric tube); surgical treatment is required for obstruction refractory to medical treatment 
      • Prevention includes adequate administration of pancreatic replacement enzyme therapy, adequate hydration, and salt replacement, especially in summer months and tropical climates 
    • Constipation
      • Up to 50% of children and most adults are affected; usually more chronic than distal intestinal obstruction syndrome 
      • Associated with pancreatic insufficiency, history of meconium ileus, and fat malabsorption 
      • Treatment includes increasing enteral fluid intake, dietary modification with adequate fiber (but not increased fiber), optimization of pancreatic enzyme replacement therapy and salt replacement, osmotic laxatives, and stool softeners (eg, polyethylene glycol) 
      • Prevention includes adequate administration of pancreatic replacement enzyme therapy, adequate hydration, and salt replacement, especially in summer months and tropical climates 
    • Gastroesophageal reflux disease
      • Prevalence of up to 25% in infants and 85% of children and adults; at least 50% of those affected require medical therapy for symptom control 
      • May be asymptomatic 
      • Associated with increased cough frequency, faster decline in FEV₁, and increased risk of gastric content microaspiration 
      • First line treatment is proton pump inhibitors; severe cases may require prokinetic agent (eg, domperidone); recalcitrant cases may require surgical fundoplication after confirmation of physiology with esophageal pH monitoring and manometry 
    • Clostridium difficile infection
      • Carrier rates approach 50% (with up to two-thirds of carriers being toxin-positive); however, symptomatic disease is rare in nontransplant population 
      • About 1% to 2% of hospitalized patients are affected with symptomatic disease; up to 30% of posttransplant patients develop symptomatic disease 
      • Treatment includes effective hand hygiene for caregivers and oral metronidazole or vancomycin for symptomatic patients 
    • Gastrointestinal tract neoplasms and malignancy
      • Up to 23-fold increased risk than general population for colon, small bowel, biliary tract, and gastroesophageal carcinoma 
      • Risk of colorectal cancer is 5 to 10 times greater in adults with cystic fibrosis compared to the general population 
        • Increased risk for bowel cancer is associated with male sex, more severe CFTR mutations, patients with history of distal intestinal obstruction syndrome, and posttransplant status 
      • Adenomatous polyps in the colon are increasingly prevalent in older patients (older than 40 years); monitoring is recommended 
        • Risk factors include cystic fibrosis–related diabetes and homozygosity for Phe508 deletion; male sex and lung transplant are risks for advanced or multiple adenomas 
      • Posttransplant patients are at very high risk for gastrointestinal cancer, particularly colon cancer
        • Risk of colorectal cancer is 25 to 30 times greater in patients with cystic fibrosis after an organ transplantation compared to the general population 
      • Colorectal cancer screening with colonoscopy should be commenced at age 40 years (30 years or within 2 years of transplant in organ transplant recipients) 
        • Rescreening at 5 years, then every 3 years (unless shorter interval is indicated), and use of cystic fibrosis–specific intensive bowel preparation is recommended 
    • Other gastrointestinal disease reported at increased frequency compared to general population, including:
      • Rectal prolapse
      • Small-bowel bacterial overgrowth 
      • Celiac disease 
      • Intussusception 
      • Fibrosing colonopathy 
  • Renal complications
    • Nephrolithiasis
      • Common complication
      • Contributing factors include hyperoxaluria, hyperuricosuria, hypercalciuria, salt depletion, dehydration, and low urine volume
      • Treatment is similar to general population with renal stones, with additional dietary modification and increased enteral fluid intake 
    • Acute kidney injury
      • Not common (incidence 4.6-10.1 cases per 10,000 children per year) but about 100-fold increased risk compared with general population 
      • Risk factors include treatment with aminoglycosides and dehydration
    • Chronic kidney disease
      • Prevalence rises with increasing age
      • Risk factors include insulin therapy, female sex, lower FEV₁, previous acute kidney injury, F508del homozygosity, and organ transplant 
      • Up to 10% of lung transplant recipients require renal replacement therapy 
    • Other less common complications include IgA nephropathy with resultant glomerulonephritis and amyloidosis with secondary nephrotic syndrome 
  • General growth, development, and nutritional consequences
    • Failure to thrive and growth failure secondary to nutritional deficiency and malabsorption 
      • Malabsorption is usually caused by pancreatic exocrine insufficiency
      • Alternate causes include bacterial overgrowth, gastroesophageal reflux disease, Clostridium difficile–induced colitis, inflammatory bowel disease, celiac disease, constipation, and distal intestinal obstruction syndrome 
      • Poor nutritional status is associated with increased morbidity and mortality in all age groups 
      • Delayed puberty and amenorrhea are not uncommon, particularly in undernourished patients 
    • Reduced linear growth
      • Short stature is a risk for patients with untreated nutritional deficiency; chronic inflammation, chronic infection, chronic insulin insufficiency, and exposure to inhaled and systemic glucocorticoids may contribute 
      • Consider treatable causes (eg, malabsorption, cystic fibrosis–related diabetes); optimize maintenance treatments (eg, pancreatic replacement enzyme therapy) and nutritional regimen 
      • Consider non–cystic fibrosis–related diagnosis such as thyroid dysfunction, growth hormone deficiency, celiac or inflammatory bowel disease 
      • Recombinant human growth hormone therapy has been proposed as a possible intervention; effective in improving height, weight, and lean body mass attained in children with cystic fibrosis; may also result in improvement in some measures of pulmonary function 
    • Fat-soluble vitamin deficiency states
      • Patients are at increased risk owing to pancreatic insufficiency, liver disease, and intestinal malabsorption; monitoring is recommended 
        • Vitamin A deficiency can cause night blindness, skin changes, and impaired immune response
        • Vitamin D deficiency can cause osteoporosis and increased risk of infection; rarely, may cause rickets
        • Vitamin E deficiency can cause cognitive defects, peripheral neuropathy, ataxia, retinopathy, hemolytic anemia, and reduced immunity
        • Vitamin K deficiency can cause coagulopathy and poor bone health
    • Dehydration
      • Excess salt and water losses may quickly lead to severe dehydration, especially when exposed to climate with high temperature 
      • Development of hyponatremic hypochloremic metabolic alkalosis is characteristic
      • Preventative measures include ensuring adequate intake of salt and fluid 
    • Hypoglycemia
      • Patients may develop hypoglycemia in the absence of cystic fibrosis–related diabetes or insulin treatment 
  • Genitourinary complications
    • Male hypogonadism
      • Low testosterone levels may be present in up to 25% of young men and may negatively impact bone mineral density 
      • Assess for low testosterone levels in men during evaluation for osteoporosis and when symptoms of hypogonadism are present 
      • Confirm low testosterone with at least 2 morning measurements before considering testosterone therapy 
    • Male infertility
      • Occurs in 98% of patients secondary to bilateral absence of vas deferens 
      • Spermatogenesis is normal; semen analysis is required to definitively determine fertility status because a minority of CFTR pathologic variants are associated with preserved fertility 
      • Intracytoplasmic sperm injection after testicular epididymal sperm aspiration may enable fathering a child 
    • Female infertility
      • Females can get pregnant; however, thickened cervical mucus may lead to diminished fertility in some
      • Pregnancy is well tolerated by most women with cystic fibrosis; adverse outcomes occur more frequently in women with severe lung disease (FEV₁ less than 50% of predicted), poor nutritional status, and/or poorly controlled diabetes 
    • Urinary stress incontinence
      • Occurs in 30% to 74% of females and 15% of males 
      • Prevalence increases with declining FEV₁ and increasing age 
      • Chest physiotherapy may exacerbate incontinence and lead to diminished chest physiotherapy adherence 
      • Associated with increased levels of anxiety and depression 
      • Treatment includes patient education, modifying airway clearance techniques, and treatment of exacerbating factors (eg, constipation) 
  • Sinus disease
    • Rhinosinusitis
      • Prevalence is estimated at up to 65% 
      • Sinuses may serve as reservoir for pathogens
      • Treatment includes saline rinses, intranasal steroids, antibiotics for bacterial infection when present, and potentially surgical intervention; in eligible patients, ivacaftor may improve sinus disease 
    • Nasal polyps
      • Prevalence is estimated between 25% to 45% 
      • Treatment may involve surgical polypectomy 
  • Bone disease
    • Osteopenia and osteoporosis
      • Prevalence of osteopenia is about 38% and osteoporosis is about 23%; monitoring is recommended 
      • Increased fracture rates are common, especially in patients with severe lung disease, undernutrition, and inadequate physical activity 
      • Contributing factors include pancreatic insufficiency; use of corticosteroids; cystic fibrosis–related diabetes; pulmonary exacerbations; deficiencies of calcium, vitamin D, and vitamin K; sex steroid deficiency; altered growth hormone axis; and chronic inflammation 
      • Prevention strategies important for maintenance of skeletal health include: 
        • Optimizing nutritional status and maintaining recommended levels of vitamin D, calcium, vitamin K, magnesium, and phosphorus 
        • Encouraging weight-bearing exercises 
        • Minimizing duration of corticosteroid treatment courses 
      • Consider bisphosphonate treatment in consultation with endocrinologist if DXA is consistent with osteoporosis or low trauma fracture; treat any causes of secondary osteoporosis such as hypogonadism and low vitamin D 
      • Preliminary data suggest ivacaftor may improve bone health in patients for whom it is otherwise indicated 
    • Hypertrophic pulmonary osteoarthropathy
      • Occurs in up to 7% of patients and overall risk increases with age 
      • Often affects adults with poor lung function 
      • Manifests as digital clubbing and pain of distal long bones (eg, wrist, ankles, knees), usually in patients with increasingly severe lung disease; pulmonary exacerbation often worsens pain; periosteal elevation may be present on radiographs
      • Treatment includes NSAIDs, bisphosphonates, and management of pulmonary exacerbations 
    • Cystic fibrosis–related arthropathy
      • Occurs in up to 8.5% of patients; usual onset is adolescence or adulthood 
      • Severity and activity of lung disease does not appear to be associated with development 
      • Manifests with recurrent, intermittent episodic joint pain, swelling, and stiffness involving 1 or multiple joints; usually evolves over 12 to 24 hours but may wax and wane in a pattern similar to rheumatoid arthritis; associated fever and rash may be present; radiographic findings are often normal 
      • Management includes joint rest, NSAIDs, discontinuation of medications that may worsen joint symptoms when possible (eg, quinolones, cimetidine), and sometimes course of corticosteroids 
  • Cutaneous manifestations
    • Aquagenic palmoplantar keratoderma (aquagenic wrinkling of palms)
      • Benign condition; may be fairly common 
      • Manifests as transient, excessive wrinkling of palms after water immersion; self-limited pruritus, burning, tingling, or discomfort may accompany findings; resolves within minutes to hours
  • Coronary artery disease
    • Patients appear to have increased arterial stiffness measured by augmentation index; patients may be subject to premature vascular aging 
    • Increasingly prevalent complication as longevity increases among patients with cystic fibrosis
    • Preliminary data suggest that in otherwise eligible patients, ivacaftor may improve (reduce) augmentation index 
  • Mental health issues
    • Depression and anxiety
      • Prevalence of depression ranges from 8% to 29% among children and 13% to 33% among adults 
      • Prevalence of depression among care givers is 20% to 35%; caregiver depression linked to increased risk of anxiety and depression among children with disease 
      • Risk factors include older age, female sex, worse disease severity (eg, lower FEV₁, lower BMI), poorer adherence to medical regimen, recent decline in health status (within 6 months), and increased hospitalization 
      • Untreated mental health issues are associated with nonadherence to medical regimen, increased risk of pulmonary exacerbation, and worsening lung disease
      • Management includes psychological and pharmacologic treatment; selective serotonin reuptake inhibitors are first line pharmacologic agents 
  • Malignancy
    • In addition to increased risk for gastrointestinal tract malignancy, standardized incidence ratios are higher than general population for testicular cancers and lymphoid leukemia 
  • Anemia
    • May be multifactorial; common causes include anemia of chronic disease, iron deficiency anemia, and vitamin E malabsorption
    • Annual monitoring with hemoglobin and hematocrit is recommended 

Prognosis

  • Morbidity
    • Pulmonary disease
      • Lung disease begins to develop in early infancy in most patients with disease 
      • Structural lung disease that develops in infants and young children progresses throughout life 
      • Major cause of morbidity owing to development of progressive obstructive lung disease with bronchiectasis 
        • Annual decline in lung function is variable but estimated at around 1% to 3% yearly depending on age, genotype, sputum microbiology, frequency of pulmonary exacerbation, and other factors 
          • Patients with no or 1 copy of F508del experience slower decline in lung function 
          • About 25% to 50% of patients treated for pulmonary exacerbation do not return to baseline preexacerbation lung function 
          • More rapid decline in lung function is associated with frequent pulmonary exacerbations, low BMI, female sex, and low socioeconomic status 
        • Mild lung disease (measured by FEV₁) develops by age 18 years in most effectively treated patients in the United States 
      • Frequent hospitalizations are required for pulmonary exacerbations, advancing pulmonary disease, and pulmonary complications
    • Pancreatic insufficiency
      • Pancreatic insufficiency preventing absorption of fat, protein, and fat-soluble vitamins is usually present at birth among patients with pancreatic insufficient phenotypes 
        • Leads to clinically evident malabsorption with malnutrition and failure to thrive as early as the first few weeks after birth 
        • Presence of malnutrition further exacerbates clinical status and negatively impacts declining pulmonary function 
    • Growth
      • Early growth deficiency secondary to malabsorption and malnutrition is not uncommon, particularly in untreated patients 
      • Median BMI approaches lower limit of healthy BMI range for older children and adults with disease because of focus on improved nutritional status among cystic fibrosis treatment centers 
    • The many complications and manifestations commonly associated with disease add to impact of overall patient morbidity
  • Mortality
    • Average median age of survival exceeds age 40 years in most developed countries and age 50 years in some 
    • Predicted median survival among patients born in 2010 is approximately age 56 years 
    • Most common cause of death (up to 80%) is respiratory failure secondary to pulmonary insufficiency 
    • Most common nonrespiratory cause of death is hepatic cirrhosis 
    • Factors associated with poor prognosis and increased mortality risk include:
      • Development of pneumothorax (4-year mortality: about 50%) 
      • Massive hemoptysis (1-year mortality: about 35%) 
      • Presence of pulmonary hypertension, including subclinical pulmonary hypertension 
      • Acquisition of high-risk organisms (eg, Burkholderia cepacia, Pseudomonas aeruginosa, MRSA) 
        • Conversion to Pseudomonas of mucoid phenotype is predictive of poor prognosis 
      • Development of cystic fibrosis–related diabetes 
      • Increasing frequency of or refractory pulmonary exacerbations 
      • FEV₁ less than 30% (about a 10% per year probability of death is associated with FEV₁ below 30%) 
      • Severe malnutrition and poorer nutritional status 
      • Data suggest that survival for females is worse than for males, particularly among patients aged 1 to 20 years 
        • Most recent data suggest observed difference in survival rate among females compared to males may be diminishing
      • Residence in low-income region and certain ethnic backgrounds (eg, Hispanic) 
  • Factors associated with improved survival and decreased morbidity
    • Early diagnosis and implementation of treatment
    • Comprehensive multidisciplinary care
    • Aggressive nutritional supplementation
    • New inhaled therapies
    • Pseudomonas aeruginosa eradication
    • Lung transplant
    • CFTR modulator therapies are expected to further increase life expectancy
  • Transplant-related patient survival
    • Lung transplant
      • Patients experience higher waiting list mortality rates than other patients on lung transplant waiting list; however, posttransplant survival rates are higher than many patients transplanted for other reasons 
      • Survival rates after lung transplant
        • Data are surprisingly scarce; median posttransplant survival is estimated to be about 8.6 years 
        • 1-year posttransplant survival rate in the United States is reported to approach 90% 
        • 3-year posttransplant survival rate in the United States is reported to approach 70% 
        • 10-year posttransplant survival probability in Canada is reported at approximately 50% 
        • Posttransplant survival for patients with infection due to Burkholderia cepacia complex or Mycobacterium abscessus is much lower than those without 
          • Mean survival for patients with Burkholderia cepacia complex is roughly 3.3 years compared to 12.4 years 
        • Acute rejection and infection are primary cause of death in the first year posttransplant; after the first year, chronic rejection manifesting with bronchiolitis obliterans syndrome and infection are primary cause of death 
          • Malignancy associated with antirejection drugs accounts for up to 15% of deaths 5 years posttransplant and beyond 
    • Liver transplant
      • Survival rates after liver transplant
        • Approximately 86% in pediatric patients and 73% in adult patients 5 years after successful transplant 
        • Liver transplant does not appear to negatively impact pulmonary function 

Screening

At-risk populations

  • Newborn screening
    • Recommended for all newborns (universal screening)
    • Mandatory universal newborn screening has been active in all 50 United States since 2010 
  • Carrier screening
    • Offer carrier screening to all women considering pregnancy or who are already pregnant, regardless of ethnic background; most patients affected by disease do not have a family history of disease 
      • Carrier frequencies by ethnicity include:
        • Non-Hispanic White individuals and Ashkenazi Jews: approximately 1:30
        • Hispanic Americans: approximately 1:46
        • Black Americans: approximately 1:65
        • Asian Americans: approximately 1:90
    • If the potential mother is found to be a carrier, offer carrier screening to her reproductive partner 
    • Couples who carry pathologic variants associated with disease should receive genetic counseling to discuss reproductive options (eg, preimplantation diagnosis, donor gametes, prenatal screening) 
    • Carrier screening does not identify all mutations
  • Prenatal testing
    • Offer prenatal testing for fetuses considered to be at high risk of cystic fibrosis in consultation with genetic counselor 
      • Both parents are known carriers of at least one pathogenic CFTR variant, or a fetal echogenic bowel is noted at second-trimester ultrasound screening 
        • It is estimated that 0.8–13.3% of fetuses with fetal echogenic bowel will have cystic fibrosis
        • When both parents are carriers of pathogenic CFTR variants, there is 25% risk of cystic fibrosis in the fetus
  • Offer screening to all siblings and at-risk relatives of affected proband 

Screening tests

  • Newborn cystic fibrosis screening
    • Rationale for cystic fibrosis newborn screening
      • Early diagnosis leads to early treatment and improved outcomes
      • Allows for genetic counseling and informed decisions regarding future prenatal planning
    • Goal of screening is to expedite diagnosis and initiate treatment by age 1 month 
    • A number of regional screening algorithms are used and protocols are subject to frequent modification 
      • Immunoreactive trypsinogen is the first-tier screening test
        • Performed on dry blood spot obtained by heel prick at the time of other routine newborn screening tests 
        • Elevated immunoreactive trypsinogen is a marker of pancreatic injury 
        • Falsely elevated initial immunoreactive trypsinogen is not uncommon and may be caused by perinatal stress, low Apgar scores, prematurity, critical illness, CFTR mutation carrier status, infants of African ethnicity, and chromosomal abnormality, among other causes 
        • Falsely low immunoreactive trypsinogen is associated with meconium ileus at birth 
      • Second-tier test differs between regional algorithms
        • Various algorithms are adopted to improve positive predictive value of testing based on target population 
        • Strategies may include any of the following:
          • CFTR mutation analysis panel
            • Most common second-stage test in the United States; usually performed on initial dry blood spot sample used for immunoreactive trypsinogen screening 
            • Panels are individualized by region to incorporate mutations most frequently encountered in screened population
            • Protocols that incorporate DNA analysis risk higher rates of inconclusive diagnosis and carrier status rates, yet improve timeliness and positive predictive value of screening program 
          • Repeat immunoreactive trypsinogen between 2 to 4 weeks of life
            • Values decrease in infants without cystic fibrosis over the first 4 weeks of life but remain elevated in infants with cystic fibrosis 
          • Measurement of pancreas-associated protein is less commonly performed
            • Often applicable to populations when mutation frequencies in screened population are unknown or use of genetic analysis is restricted 
        • Positive second-tier screening results are indicated by:
          • 2 elevated consecutive immunoreactive trypsinogen results
          • Initial elevated immunoreactive trypsinogen result and identification of at least 1 CFTR mutation
          • Elevated immunoreactive trypsinogen and abnormal pancreas-associated protein testing
      • Third-tier, and even fourth-tier, testing is incorporated into some screening algorithms 
        • May involve extended genetic CFTR sequencing analysis
          • Disadvantages of this screening approach include a dramatic increase in inconclusive diagnoses and identification of mutations with unclear phenotypic significance 
    • No screening protocol is foolproof; sensitivity and specificity of individual screening protocols are variable 
      • Some diagnoses are not detected by newborn screening and diagnosis is not confirmed in all patients with positive screening result
    • Formal diagnostic testing, starting with gold standard sweat chloride testing, is required for patients with positive screening algorithm results 
      • Confirmation of diagnosis requires a positive sweat test result, detection of 2 CFTR pathologic variants associated with disease, or rarely by specialized physiologic testing of CFTR function (ie, nasal transepithelial potential difference or intestinal current measurement) 
    • Drawbacks to newborn screening for cystic fibrosis
      • Increased number of inconclusive diagnoses 
      • Detection of carrier state 
      • Missed cases in screening population 
  • Carrier screening
    • General population carrier screening for patients without family history of disease
      • Panels should include all mutations with frequency of 0.5% to 1% or more in the cystic fibrosis population 
      • Mutation panel recommended by American College of Medical Genetics and Genomics includes 23 CFTR pathologic variants associated with disease 
      • General carrier screening may not be appropriate preconception testing for patients with family history of disease 
    • Focused carrier screening for patients with family history of disease
      • Perform in consultation with genetic counselor 
      • Test for specific pathologic variants when CFTR mutation in family is known 
      • If the familial variant is not known and the other member of the couple is a carrier, more extensive molecular analysis (eg, expanded mutation panel; sequencing, deletion, and/or duplication analysis) may be recommended 
  • Prenatal screening
    • Possible if CFTR pathologic variants in the family are known
    • Invasive screening methods include: 
      • Chorionic villus sampling is usually accomplished around 10 to 12 weeks of gestation 
      • Amniocentesis is usually accomplished around 16 to 18 weeks of gestation 
    • Noninvasive alternative is evaluation of fetal cell-free DNA isolated from the maternal bloodstream 
      • Method is not definitive; positive screening results require confirmation by means of amniocentesis and chorionic villus sampling
  • Screening for all siblings and at-risk relatives of affected proband
    • Offer genetic testing if CFTR pathologic variants in the family are known 
    • Offer sweat chloride testing if pathologic variants in the family are not known 

Evaluations after initial diagnosis

  • May include the following, dependent on age and symptoms at presentation: 
    • Spirometry to assess FEV₁
    • Chest imaging (eg, chest radiography, chest CT)
    • Sputum culture with or without bronchoscopy
    • Sinus CT in symptomatic patients
    • Fecal elastase and/or 72-hour fecal fat content
    • Fat-soluble vitamin levels and prothrombin time
    • Random glucose testing
    • CBC with differential
    • Electrolyte, BUN, and creatinine levels
    • Liver function testing with albumin and total protein measurement
    • Genetic counselor consultation

Prevention

  • Preimplantation genetic diagnosis is possible when pathologic variant associated with disease is known
    • Most frequent indication for preimplantation genetic diagnosis is cystic fibrosis
    • Preimplantation genetic diagnosis testing usually screens for over 50 different CFTR mutations 

References

Sanders DB et al: Background and epidemiology. Pediatr Clin North Am. 63(4):567-84, 2016

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