A team of 32 international researchers have collaborated on an update of guidelines for diagnosing cystic fibrosis, and hope that their revisions will better guide clinicians in making not only correct diagnoses, but in recommending personalized treatment. Their updates and two supplemental articles on the implications and data used for the updates can both be found in theJournal of Pediatrics.
“We’ve more precisely defined what cystic fibrosis is. That precision was a result of the genetic research we did and from studying the many mutations associated with cystic fibrosis,” says co-author Patrick Sosnay, MD, assistant professor of medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
In 2008, the CFTR2 project (Clinical and Functional Translation of cystic fibrosis transmembrane conductance regulator [CFTR]) was begun by Dr. Sosnay and fellow researchers, who gathered data from patients in North America, Europe, Australia, the Middle East, Asia, and South American in efforts to better define cystic fibrosis and categorize the mutations associated with it.
To date, they have described approximately 300 of the 2,000 known mutations responsible for cystic fibrosis, for the most comprehensive compilation and evaluation of disease liability for all genetic diseases. Based on the CFTR2 project, mutations are now categorized as either cystic fibrosis causing, mutations of varying clinical consequence, non-cystic fibrosis causing, or unknown. They categorized all mutations according to whether the mutation meets clinical criteria and the likelihood that someone with the mutation will have cystic fibrosis.
In these updated diagnosis consensus guidelines, they recommend using CFTR2 as an aid to determine whether a patient has the genetic evidence of cystic fibrosis, a substantial update from the 23-mutation panel by the American College of Medical Genetics and Genomics and the American Congress of Obstetricians and Gynecologists used since 2004.
“The stakes in categorizing a mutation are particularly high. For example, claiming that a mutation 100% causes cystic fibrosis may affect people’s reproductive decisions if they believe their child will have the mutation,” said Dr. Sosnay.
By providing patients with all of the available information on cystic fibrosis, these guidelines will hopefully lead to more informed health care decisions and a better understanding of the wide spectrum of CFTR-related disease, he stressed.
“Therapies exist for individuals with certain mutations. 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,” added Dr. Sosnay.
Newborn screening was begun in the US in the 1980s, and rapidly adopted in the 1990s and 2000s. It is comprised of a standard blood test performed soon after birth, and accounts for the majority of cystic fibrosis diagnoses, but has not been consistently performed worldwide. Even in the US, the possibility of a false negative exists.
In the new guidelines, diagnostic criteria for those diagnosed outside of newborn screening have also been standardized, which is of importance since over one-third of all US cystic fibrosis diagnoses in 2014 did not occur during newborn screening. This screening is focused on the symptoms and signs of CFTR dysfunction, usually indicated by testing the amount of chloride in a patient’s sweat. Elevated levels of chloride are considered direct evidence that the CFTR protein is dysfunctional, and therefore, this is the primary diagnostic test for cystic fibrosis.
The normal range of chloride concentration in sweat is 10 to 20 mM/L. In these new guidelines, Dr. Sosnay and colleagues lowered the threshold for “possible” cystic fibrosis from 40 mM/L to 30 mM/L for all ages. A measurement of 60 mM/L constitutes a cystic fibrosis diagnosis.
Dr. Sosnay’s co-authors on these papers include Karen S. Raraigh, Johns Hopkins University School of Medicine; Terry B. White, Sarah E. Hempstead and Bruce C. Marshall, Cystic Fibrosis Foundation; Philip M. Farrell, University of Wisconsin School of Medicine and Public Health; Clement L. Ren and Michelle S. Howenstine, Indiana University School of Medicine; Nico Derichs, Charité University Berlin; Jerry Nick, the National Jewish Center; Kris De Boeck, University of Leuven; Danieli B. Salinas, University of Southern California Keck School of Medicine; Emmanuelle Girodon, Groupe Hospitalier Cochin; and Carlo Castellani, Ospedale Civile Maggiore.
Dr. Sosnay receives funding from the Cystic Fibrosis Foundation.