Cystic Fibrosis

Cystic fibrosis (CF) is a serious autosomal recessive disease that affects approximately one in every 4,000 newborns in the United States,  but may also be diagnosed later in childhood or in adulthood. Symptoms of CF include lung disease, liver disease, and exocrine and endocrine pancreatic insufficiency.  Age of onset, severity of symptoms, and manifestations of CF vary widely.  CF is caused by pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.  More than 2,000 CFTR variants have been reported,  but most are very rare and of unknown significance, presenting a diagnostic challenge. The gold standard for diagnostic testing of CF is sweat chloride testing. The immunoreactive trypsinogen (IRT) test is a preliminary assay used for newborn screening. Molecular testing (ie, DNA analysis) can be used for carrier screening, newborn screening, and diagnostic testing.

Quick Answers for Clinicians

How does the diagnostic testing strategy for cystic fibrosis differ between adult and pediatric patients?

Testing recommendations for adult and pediatric populations are the same, regardless of whether the suspicion for cystic fibrosis (CF) arises from newborn screening or symptomatic presentation. Both the Cystic Fibrosis Foundation and European Cystic Fibrosis Society recommend sweat chloride testing.   Two elevated (positive) sweat chloride test results on 2 different days are diagnostic for CF; if sweat chloride values are borderline, CFTR genetic testing is recommended.   The identification of two severe pathogenic CFTR variants on opposite chromosomes is also diagnostic for CF; however, the absence of a positive genetic result does not exclude CF.  

What laboratory tests for cystic fibrosis are appropriate to perform before birth?

If carrier screening reveals that both members of a couple are cystic fibrosis (CF) carriers, the parents should be offered the option of preimplantation genetic diagnosis or prenatal diagnosis.

What is the definition of CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis (CRMS/CFSPID)?

CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis (CRMS/CFSPID) refers to the combination of a positive newborn screen (high IRT), inconclusive sweat chloride test, and inconclusive genetic testing results.  Newborns with CRMS/CFSPID may never develop any symptoms of CF, but are at risk for CFTR-related disorders such as bilateral absence of the vas deferens, lung disease, or pancreatic insufficiency.

Indications for Testing

Molecular testing for CF is indicated for the following    :

  • Carrier screening in couples who are pregnant or planning a pregnancy
  • Carrier screening in individuals with a family history of CF or CFTR-related conditions
  • Diagnosis in newborns with a positive newborn screening result
  • Diagnosis in adult or pediatric patients with signs or symptoms or a family history of CF
  • Confirmation of the causative CFTR gene variants in a known affected individual to determine eligibility for CFTR variant-specific treatment

Laboratory testing is also used to monitor complications in patients with an established diagnosis of CF.

Criteria for Diagnosis

The Cystic Fibrosis Foundation  proposes the following diagnostic criteria for CF in an individual with a positive newborn screening test, signs and/or symptoms of CF, or a family history of CF:

  • A positive sweat chloride test result of at least 60 mmol/L
  • Identification of two CF-causing variants on separate chromosomes and a sweat chloride value of at least 30 mmol/L
  • Demonstrated CFTR dysfunction (ie, a sweat chloride test result of at least 60 mmol/L or CF-typical nasal potential difference or intestinal current measurement), regardless of whether or not two molecular pathogenic variants can be identified

Laboratory Testing

Carrier Screening

Carrier screening for CF is recommended for all women who are pregnant or planning a pregnancy, individuals with a family history of CF, and men with isolated congenital bilateral absence of the vas deferens.   A panel test for the 23 most common CF-causing variants is recommended for carrier screening  ; each of these variants occurs with a frequency of more than one in 1,000 in a panethnic U.S. population. For more information on the genetics of CF, see the Cystic Fibrosis Test Fact Sheet.

Newborn Screening

Screening for CF is recommended for all newborns in the U.S.  Screening is performed using a measurement of IRT in blood spots; depending on the results, a reflex test for a panel of common pathogenic CFTR gene variants may be performed.   False-negative results occur at an increased rate in infants with meconium ileus. 

Diagnosis

In individuals with a positive IRT test, positive CFTR genetic test, or suggestive symptoms (see Test Fact Sheet), sweat chloride testing is recommended.  A sweat chloride result of ≥60 mmol/L is diagnostic for CF, and no further testing is required.  A sweat chloride result of <30 mmol/L suggests that CF is unlikely, and further testing is not indicated unless clinical suspicion persists.  An intermediate sweat chloride test result of 30-59 mmol/L should be clarified with CFTR genetic analysis.  CFTR gene sequencing and deletion/duplication analysis should be performed if one or no pathogenic variants are identified on a CF panel of selected variants.  If CFTR sequencing and deletion/duplication testing fails to identify two causative variants, functional analysis (nasal potential difference and intestinal current measurement) is recommended.  If results are inconclusive, a diagnosis of CRMS/CFSPID is appropriate. 

Monitoring

CF has numerous complications that require careful monitoring:

Laboratory Tests for Monitoring of Complications in CF
Complication Laboratory Tests Recommended Frequency
Liver disease Liver enzyme tests (and liver function tests in patients with cirrhosis) Periodically
Exocrine pancreatic insufficiency Fecal pancreatic elastase-1 Annually during infancy and childhood; during periods of failure to thrive, weight loss, or diarrhea
Pancreatitis Lipase, amylase tests On presentation with recurrent unexplained pain and associated nausea/vomiting
Diabetes mellitus Oral glucose tolerance test (confirm with second test) Annually beginning at 10 yrs of age; more frequently in cases of pulmonary exacerbation, initiation of glucocorticoids, enteral tube feeding, planning for pregnancy, pregnancy, planned organ transplantation, and if symptomatic
Nutritional deficiency Essential fatty acid status (if testing is available), fat-soluble vitamin testing Annually
Allergic bronchopulmonary aspergillosis Allergy skin testing, serum IgE, Aspergillus-specific IgE, Aspergillus serum precipitins tests On presentation with symptoms
Airway fungal infections Airway cultures Every clinic visit
Bacterial infection (eg, with Pseudomonas aeruginosa or Staphylococcus aureus) Cultures On presentation with acute exacerbation of lung function and to ensure eradication after treatment
Nephrolithiasis Urinalysis On presentation with signs and symptoms
Medication toxicity According to standard therapeutic drug monitoring protocols When taking aminoglycosides

IgE, immunoglobulin E

Source: ECFS, 2018 

ARUP Lab Tests

Genetic Tests
Preferred Carrier Screening Test

Carrier screening for expectant couples and those planning a pregnancy; diagnostic for symptomatic individuals

Preferred Diagnostic Tests

For individuals with suspected CF, not indicated for carrier screening

Additional Tests

For individuals with suspected CF but without two pathogenic variants detected by the CFTR 165 pathogenic variants test

For individuals with suspected CF but without two pathogenic variants detected by the CFTR 165 pathogenic variants test

If sequencing identifies fewer than two pathogenic variants, CFTR deletion/duplication will be performed

For fetal testing when both parents are known carriers of a variant on the CFTR 165 variants test or if fetus has an echogenic bowel

Useful when a pathogenic familial variant identifiable by sequencing is known

Monitoring Tests

Monitor for liver disease

Components: albumin; alkaline phosphatase (ALP); aspartate transaminase (AST); alanine aminotransferase (ALT); bilirubin, direct; protein, total; and bilirubin, total

Screen for exocrine pancreatic insufficiency

Monitor for pancreatitis

Monitor for diabetes mellitus

Monitor nutritional status

Monitor for allergic bronchopulmonary aspergillosis

Identify respiratory infection

Important informationLimited to the University of Utah Health Sciences Center only

Medical Experts

Contributor

Mao

Rong Mao, MD, FACMG
Professor of Clinical Pathology; Adjunct Associate Professor, Pediatrics; and Co-Director, Clinical Molecular Genetics Fellowship Program, University of Utah
Section Chief, Molecular Genetics and Genomics, ARUP Laboratories
Contributor

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®