How Cystic Fibrosis Is Diagnosed

There are two tests commonly used to diagnose cystic fibrosis (CF): a sweat test, which measures the amount of chloride in sweat, and a genetic test, which detects chromosomal mutations associated with the disease. Because of the severity of CF and the need for proactive treatment, newborns are routinely screened. While the majority of diagnoses are made this way, around a third are only confirmed during childhood or much later in life. Cystic fibrosis is inherited from parents who are carriers of the defective gene, and couples can be screened to see if their child could be at risk.

cystic fibrosis diagnosis
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Sweat Chloride Test

The sweat test, more appropriately referred to as the sweat chloride test, has been considered the test of choice since it was first introduced back in 1959. The test is highly accurate with a correct positive rate of 98 percent.

How the Test Works

One of the primary symptoms of CF is salty-tasting skin. This is caused when a defective form of a protein, known as cystic fibrosis transmembrane regulator (CTFR), obstructs the normal flow of water and mineral ions in and out of cells.

When this occurs in the sweat glands, it prevents sodium from being reabsorbed into cells and causes chloride to accumulate in the sweat ducts. As the excessive amounts of sodium and chloride get pushed close to the surface of the skin, they combine to form salt. The level of accumulation on the skin—specifically, the chloride content—can be used diagnostically to confirm CF.

How the Test Is Performed

The sweat test is quick, painless, and non-invasive. It can be used to diagnose people of any age, although infants under two weeks or seven pounds may not be able to produce enough sweat to render an accurate result. Similarly, a common condition known as edema, characterized by fluid retention, may dilute a sweat sample and trigger a false-negative result.

The sweat test is usually performed on the forearm but may be done on the thigh of babies and smaller children. The procedure takes around an hour.

To perform a sweat test:

  1. The lab technician places two electrodes on the skin, one of which contains a disc with a sweat-inducing gel called pilocarpine.
  2. A small electrical current is then delivered through the electrodes to stimulate drug activity. This causes a mild tingling sensation, but little to no discomfort.
  3. After around 10 minutes, the current is shut off and the electrodes are removed. The skin is wiped cleaned, and a piece of filter paper is applied to the area.
  4. When a sufficient amount of sweat has been collected, usually after 30 to 45 minutes, the patch is removed and sent to the lab for evaluation.

There are variations of the procedure, some of which use a single device called a Macroduct coil to both perform the electrical stimulation and collect the sweat.

Test results are usually returned within a day or so. To ensure accuracy, a sweat test should be performed at a clinic certified by the non-profit Cystic Fibrosis Foundation (CFF).

Interpreting the Results

The sweat test is able to diagnose CF by the concentration of chloride in the collected sample.

For newborns under six months, the diagnostic ranges are interpreted as follows:

  • Negative (CF is ruled out): less than 30 mmol/L
  • Borderline (inconclusive): between 30 and 59 mmol/L
  • Positive (CF is confirmed): 60 mmol/L or greater

For all other children and adults, the diagnostic ranges are:

  • Negative: less than 40 mmol/L
  • Borderline: between 40 and 59 mmol/L
  • Positive: 60 mmol/L or greater

If a positive result is returned, the CFF recommends that a second sweat test or an independent genetic test be performed to confirm the results.

A genetic test may be preferred if the sweat test is strongly positive, but the symptoms are not entirely consistent with CF. This is because there are other genetic disorders associated with high chloride levels that may trigger a false-positive result.

If a borderline result is returned, a second sweat test should be performed in the event there was either a lab error or an inadequate sweat collection sample. Genetic testing may also be considered.

Genetic Testing

Genetic testing can also be used to diagnose cystic fibrosis by detecting specific genetic mutations associated with the disease. To date, scientists have identified well over 2,000 mutations that can cause CF by producing defective forms of the CFTR protein.

How the Test Works

Cystic fibrosis is an autosomal recessive disorder, meaning that you need to inherit the CFTR mutation from both parents to have the disease. If you inherit only one mutation, you won't have CF but are a carrier who is able to pass the mutation to your children.

Because there are so many different CTFR mutations, there is no single test able to detect all variations. The standard genetic test, called the ACMG/AGOG panel, is designed to detect the 23 most common CFTR mutations. The mutations were selected based on the joint recommendation of the American College of Medical Genetics and Genomics (ACMG) and the American College of Obstetricians and Gynecologists (ACOG).

How the Test Is Performed

Genetic testing for CF is usually performed on a blood sample but may also be done by taking a swab of cells from the inside of your cheek. Results are usually received within three to five working days.

Interpreting the Results

If the test is used to diagnose CF, a positive result means that you have two copies of the CFTR mutation and, as a result, have cystic fibrosis.

Based on the types of mutations you have, the test may also be used to predict how serious the disease may be. For example, of the 2,000-plus CTFR mutations, the deltaf508 mutation will be found in around 70 percent of cases. If you inherit two of these from your parents, you will likely have a greater respiratory obstruction, thicker mucus discharge, and a poorer functioning pancreas.

Based on your genetic profile, a genetic counselor can provide you more information about your specific mutations and work with your doctor to determine the way forward.

Prenatal/Preconception Testing

In addition to diagnosing cystic fibrosis, genetic testing can be used to help parents find out what their chances are of having a baby with CF. When used for this purpose, the test is referred to as carrier screening.

Carrier screening may be used for couples planning to get pregnant or those who are currently pregnant. To this end, both the ACMG and ACOG endorse carrier screening as a routine part of prenatal care. The test can either be performed on its own (especially if a person has a family history of CF) or as part of an expanded panel of multiple genetic tests.

How the Test Is Performed

The test can determine whether one or both of you have a CFTR mutation. Having the mutation is not as uncommon as you might think, with some racial groups being at far greater risk than others.

Statistically speaking, the number of people who carry a CFTR mutation in the United States is about:

  • 1 in 29 Caucasian-Americans (translating to a 1 in 3,500 risk)
  • 1 in 46 Hispanic-Americans (1 in 10,000 risk)
  • 1 in 65 African-Americans (1 in 20,000 risk)
  • 1 in 90 Asian-Americans (1 in 100,000 risk)

Testing is initially performed on one partner, typically the woman if she is pregnant. Since it takes two copies of the mutations for CF to occur, a negative result means that you, as a couple, are at no risk of having a baby with CF. However, if you are positive, your partner needs to be tested.

If you both end up having a CFTR mutation, it means that your baby has a 25 percent chance of having cystic fibrosis (two mutations); a 50 percent chance of being a carrier (one mutation; and a 25 percent chance of being unaffected (no mutations).

There is, unfortunately, nothing you can do as parents to influence the odds one way or the other.

Prenatal Diagnostic Testing

If genetic testing is performed during pregnancy and both of you are positive for the CFTR mutation, additional tests are needed to determine whether the fetus has cystic fibrosis.

Prenatal diagnostic testing can tell you with a high degree of certainty whether the fetus has the disease or is simply a carrier. There are two procedures that can be used to collect a sample for testing:

  • Amniocentesis is a procedure in which a small amount of fluid is extracted from the sac surrounding the fetus. This is usually done between 15 and 20 weeks of pregnancy but can be performed right up until the time of delivery.
  • Chorionic villus sampling (CVS) is another procedure in which cells from the finger-like projections on the placenta are obtained for evaluation. CVS can be performed between 10 and 13 weeks of pregnancy.

If the investigation confirms that your baby has CF, you'll meet with a genetic counselor and your OB-GYN to discuss your options.

Newborn Screening

Newborn screening of cystic fibrosis is routinely performed so that treatment can be started early to prevent many of the more serious manifestations of the disease.

While all 50 states and the District of Columbia now have laws mandating the routine screening of CF in newborns, the testing protocols vary by state. Since the implementation of universal screening in 2010, the rate of CF diagnoses in newborns has increased from 10 percent in 2006 to well over 60 percent by 2013.

How the Test Is Performed

Newborns are typically tested in the first or second day of life. A blood sample is drawn from a needle prick on the baby's heel and placed on a card (called a Guthrie card) and sent to a state lab for analysis.

The screening is performed in three stages:

  • The first test looks for a pancreatic enzyme known as immunoreactive trypsinogen (IRT), which is a marker for the disease. While an elevated IRT is strongly suggestive of CF, other conditions can trigger an increase, including premature birth. As such, it is not so much diagnostic of CF as it a red flag of the disease.
  • If the IRT is high, a genetic test is then performed. If the test is positive, it means that the baby either has CF or is a carrier.
  • To definitively confirm the diagnosis, a sweat test is performed.

While this is the ideal method of screening, not all states mandate genetic testing as part of the routine assessment. Some states only require an IRT. In this instance, instead of moving to genetic testing, the baby is retested when it is two weeks old. If the second IRT is high, the baby is stepped directly to a sweat test.

Other states dictate the use of both IRT and genetic testing, eliminating the need for a second visit (and a potentially missed diagnosis).

Differential Diagnoses

While the tests used to diagnose cystic fibrosis are highly accurate, there may be times when the results are inconclusive. It may be that there was an error in the lab or that the symptoms, while suggestive of cystic fibrosis, are actually something else.

In such cases, your doctor may want to explore other possible causes. Among them:

  • Asthma can mimic and sometimes co-exist with the respiratory symptoms of CF. Because there are no diagnostic tests for asthma, it may only be differentiated by the absence of finger clubbing (common in people with CF) or the absence of mucus during an acute respiratory attack.
  • Bronchiectasis is a condition in which damage caused to your lungs makes it hard to clear mucus. While CF can cause bronchiectasis, so can pneumonia, tuberculosis, and whooping cough. To differentiate between causes, the doctor may perform a sputum test to check for viruses, fungi, or bacteria, or order a blood or skin test for tuberculosis.
  • Celiac disease shares similar gastrointestinal symptoms with CF. It can usually be differentiated by an intestinal biopsy. Moreover, people with celiac disease generally see improvement in their symptoms when gluten is removed from their diets.
  • Failure to thrive means that your baby is not gaining weight as would be expected. In some cases, malnutrition can trigger a false-positive sweat test result. The absence of respiratory symptoms is usually a clue that it is not CF.
  • Primary ciliary dyskinesia (PCD) is a rare genetic disorder in which the microscopic cells of the respiratory system, called the cilia, do not function. It can be differentiated from CF by low IRT levels.
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