New Guidelines for CF Diagnosis Draw on New Understanding of Disease and Its Mutations

Guidelines for diagnosing cystic fibrosis (CF) were recently updated to give doctors firmer direction in determining signs of this disease, especially in those not diagnosed as newborns, and in being able to recommend the best treatment for each patient.

The update, the work of 32 experts from nine countries, includes more information on mutations leading to CF and how the results of a sweat test (used to help diagnose the disease) should be interpreted, a change that could lead to more people with elevated sweat test results being considered as possibly having CF.

The guidelines were published in the article, “Diagnosis Of Cystic Fibrosis: Consensus Guidelines From The Cystic Fibrosis Foundation” in The Journal of Pediatrics, along with two supplemental articles on the data used to crease these guidelines and their implications.

“We’ve more precisely defined what cystic fibrosis is,” Patrick Sosnay, MD and senior author of the report, said in a news release. “That precision was a result of the genetic research we did and from studying the many mutations associated with cystic fibrosis.”

CF is caused by mutations in the CFTR gene, which encodes the CFTR protein. When faulty, this protein contributes to the accumulation of mucus in several organs, which potentiates bacterial growth and infection, especially in the lungs.

For a long time, CF diagnosis relied on evidence of symptoms, but the introduction of CF newborn screening (NBS) and prenatal tests in many countries led to more diagnoses being made before symptoms occur.

However, while a CF diagnosis for most infants whose screenings are positive is validated with a sweat test, the diagnosis is not as clear for others. Further complicating this, newborn CF screenings were only recently made a requirement in the U.S., and children born before 2010 were not screened. In fact, more than one-third of all the CF cases in 2014 were not diagnosed via newborn screenings.

The age of onset and severity of symptoms are also highly variable, and subsequently difficult for doctors to interpret.

To date, more than 2,000 mutations associated with the disease have been identified, but not all have been clinically described. In 2008, researchers started a project called CFTR2 (the Clinical and Functional TRanslation of CFTR) to compile and describe CF mutations using data from patients from across the globe.

So far, CFTR2 has led to a better understanding of 300 of the 2,000 known mutations, which have been now been categorized into different classes, including CF-causing, mutations of varying clinical consequence, non-cystic fibrosis causing, or unknown. Mutations are categorized according to whether they meet clinical criteria and the probability that someone with such mutation would develop CF.

The updated guidelines standardized diagnostic criteria for people diagnosed outside of a newborn screening, and recommend that doctors use CFTR2 to help determine whether a patient has signs of CF.

“The stakes in categorizing a mutation are particularly high,” Sosnay said. “For example, claiming that a mutation 100 percent causes cystic fibrosis may affect people’s reproductive decisions if they believe their child will have the mutation.”

According to Sosnay, the new guidelines provide a better understanding of the disease-causing factors, and can result in  better and more informed healthcare decisions for each patient.

“Therapies exist for individuals with certain mutations,” he said. “The compilation and availability of all this data can lead to more personalized medicine if people know what mutation(s) they have and seek appropriate care.”

Based on data from CFTR2 and other research, the new guidelines also include new recommendations for interpreting a sweat test in which high levels of chloride provide direct evidence that the CFTR protein is not working properly.

In this test, the normal range for chloride concentration in sweat is 10 to 20 millimoles per liter, and 60 millimoles per liter indicates CF. The updated guidelines recommend that people with chloride levels between 30 to 40 millimoles per liter should also be considered as “possibly” having CF or a related disease.