The sweat chloride test is the primary assessment that supports a diagnosis of cystic fibrosis (CF). A chloride concentration of 60 mmol/L or higher on sweat testing confirms CF in a person who has a positive newborn screen, symptoms consistent with the disease, or a family history. This single test has remained the gold standard for decades, and the Cystic Fibrosis Foundation’s diagnostic guidelines, last reviewed in July 2025, reaffirm it as the cornerstone of diagnosis. When sweat test results fall in a borderline range, genetic testing and specialized functional assessments can help clarify the picture.
The Sweat Chloride Test
CF affects a protein that moves chloride (a component of salt) in and out of cells. When this protein doesn’t work properly, sweat contains abnormally high levels of chloride. The sweat chloride test measures this directly by collecting a small sample of sweat, usually from the forearm, after stimulating the skin with a mild chemical and a weak electrical current. The process is painless and takes about 30 to 45 minutes.
Results fall into three categories:
- Normal: Below 30 mmol/L in infants (below 39 mmol/L in older children and adults). CF is unlikely.
- Intermediate: 30 to 59 mmol/L. CF is possible but not confirmed. Further testing is needed.
- Positive: 60 mmol/L or higher. This confirms CF when paired with clinical suspicion or a positive newborn screen.
At a level of 70 mmol/L or above, both the sensitivity and specificity of the test approach 100%, meaning false results are extremely rare at that threshold. When results land in the intermediate zone on two separate occasions, guidelines recommend extended genetic analysis or functional testing to reach a definitive answer.
Newborn Screening
Most countries with established screening programs test newborns for CF within the first few days of life using a blood spot taken from the heel. This initial test measures immunoreactive trypsinogen (IRT), a pancreatic enzyme that is elevated in babies with CF because mucus blocks the pancreatic ducts before birth. If the first IRT level is elevated (typically at or above 70 ng/mL), a second sample is collected, ideally between 10 and 21 days after birth.
If the second IRT is also elevated, the infant is referred for a sweat chloride test at a CF care center. Newborn screening is not a diagnosis on its own. It identifies babies who need confirmatory testing. The IRT/IRT screening approach has roughly 80% sensitivity, meaning it catches about 4 out of 5 affected newborns, with very high specificity so that almost no unaffected babies are falsely flagged. Some screening programs add a DNA step between the two IRT samples, testing for common CF-causing mutations to improve accuracy before ordering a sweat test.
Genetic Testing for CFTR Mutations
CF is caused by mutations in the CFTR gene, and a person needs two disease-causing mutations (one inherited from each parent) to have the condition. Genetic testing can identify these mutations and plays a key role in diagnosis, especially when sweat chloride results are borderline.
Initial genetic panels typically screen for the 23 to 36 most common mutations, depending on the commercial assay used. These panels catch about 85% of CF cases. The most common mutation, known as F508del, accounts for a large share of diagnoses. If a standard panel finds only one mutation or none, extended sequencing of the entire CFTR gene can search for rarer variants. Even with full gene sequencing, roughly 15% of people with CF may not receive a clear-cut genetic answer, because some mutations are not yet well characterized.
Two confirmed disease-causing mutations in trans (one on each copy of the gene) support a CF diagnosis even when sweat chloride is borderline or, in rare cases, normal. This is particularly important for people with atypical CF, who may carry mutations that allow partial protein function.
Clinical Signs That Prompt Testing
Outside of newborn screening, CF is suspected based on a pattern of symptoms. In newborns, meconium ileus (a bowel obstruction caused by thick, sticky first stool) is one of the earliest and most recognizable signs. Prolonged newborn jaundice and early lung infections also raise suspicion.
In infants and young children, the hallmarks include failure to thrive with poor weight gain, greasy and foul-smelling stools from fat malabsorption, recurrent respiratory infections, and chronic cough. Boys may have undescended testicles. Older children and adults with atypical CF can present with symptoms in only one organ system, such as chronic sinusitis, unexplained bronchiectasis, or male infertility. These milder presentations can go undiagnosed for years, sometimes into adulthood, because they don’t match the classic childhood picture.
Nasal Potential Difference Testing
When sweat chloride results are inconclusive and genetic testing doesn’t provide two clear mutations, nasal potential difference (NPD) measurement can help. This test evaluates how well the CFTR protein is actually working by measuring electrical voltage across the nasal lining as different solutions are applied.
In a healthy person, the nasal lining responds to chloride-free solutions and certain stimulants by changing its electrical charge in a predictable way. In someone with CF, this response is absent or dramatically reduced because the chloride channels don’t open properly. A scoring method called the Wilschanski index combines sodium and chloride transport measurements, with a value above 0.70 suggesting CF. NPD testing is available only at specialized CF centers and is most useful for confirming or ruling out atypical cases that other tests can’t resolve.
Assessing Pancreatic Function
Pancreatic insufficiency affects the majority of people with CF and contributes to the malnutrition and poor growth that characterize the disease. While it doesn’t diagnose CF on its own, testing for it helps define the severity of the condition and guides treatment decisions.
The standard assessment is a fecal elastase test, which measures the concentration of a digestive enzyme in a stool sample. Results above 200 mcg/g are normal. Levels between 100 and 200 mcg/g suggest moderate pancreatic insufficiency, and levels below 100 mcg/g indicate severe insufficiency. This test is simple to perform, requiring only a single stool sample, and it reliably distinguishes between people who need enzyme replacement with meals and those whose pancreas is still functioning adequately.
Diagnosis in Adults With Atypical CF
Adults who were never screened as newborns can develop CF symptoms that are subtle or limited to a single organ. Chronic respiratory infections, nasal polyps, pancreatitis, or infertility in men may be the only clue. Because these symptoms overlap with many other conditions, CF can go unrecognized for years.
The diagnostic approach for adults follows the same sequence: sweat chloride testing first, followed by genetic analysis if needed. One complicating factor is that people with atypical CF sometimes have sweat chloride values in the intermediate or even normal range despite carrying two CFTR mutations. In these cases, NPD testing or extended genetic sequencing becomes essential. The stakes of a missed diagnosis are real. People with undiagnosed atypical CF experience progressive lung damage and nutritional decline that could be slowed with appropriate treatment.