Updated guidelines for the diagnosis and treatment of cystic fibrosis (CF) include two major changes.
The first important update is that clinicians use the latest classifications of the specific CF transmembrane conductance regulator (CFTR) gene mutations, from the Clinical and Functional TRanslation of CFTR (CFTR2) database, to aid with making a CF diagnosis in any patient, newborn to adult. The other of these changes relates to the chloride concentration level used to confirm CF diagnosis through a sweat test. Under the new guidelines, the sweat chloride threshold for “possible” CF or a CF-related disease was reduced to 30 mmol/L of chloride concentration from 40 mmol/L across all ages. The guidelines, written by an international team of collaborators and published by the Cystic Fibrosis Foundation, are available online in the Journal of Pediatrics (J Pediatr 2017 Feb;181(suppl):S4-S15.e1. doi: 10.1016/j.jpeds.2016.09.064).
Since its inception in 2008, the CFTR2 project has described 300 of the 2,000 known CF-related mutations and their various functional and clinical impacts. The project involves amassing phenotypic and genotypic information from patient registries to collect, quantify, and describe mutations reported in individuals with CF. Such mutations are categorized as CF-causing, carrying a variety of potential clinical consequences, non–cystic fibrosis causing, or unknown. The previous guidelines, written in 2008, relied on a 23-mutation panel from the American College of Medical Genetics and Genomics and the American Congress of Obstetricians and Gynecologists.
“We’ve more precisely defined what cystic fibrosis is,” Patrick R. Sosnay, MD, assistant professor of medicine at Johns Hopkins University, Baltimore, and coauthor of the guidelines, said in a statement. “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.”
In the CFTR2 project, the “disease-liability” of each mutation is evaluated through a combination of sweat chloride and functional activity identified in cell-based systems, according to a supplement published simultaneously with the updated guidelines (J Pediatr 2017 Feb;181(suppl):S52-S57.e2. doi: 10.1016/j.jpeds.2016.09.068). Data from this project led to the discovery of a cohort of 746 persons diagnosed with CF despite sweat chloride levels less than 60 mmol/L. These findings were the basis for the guideline authors’ decision to lower the threshold of chloride concentration in sweat in order for an individual to be considered having a possible CF diagnosis, according to the supplement.
The guidelines include 27 approved consensus statements spanning four overlapping categories, and applying to screened and nonscreened populations; newborn screened populations and fetuses undergoing prenatal testing; infants with an uncertain diagnosis and designated as having either CFTR gene-related metabolic syndrome or being CF-screen positive, inconclusive diagnosis; and nonscreened patients who present with symptoms, including children before newborn screening implementation, those with false negative tests and older, nonscreened patients.
Although not specified in the consensus statements, the authors of a second supplement published simultaneously with the updated guidelines (J Pediatr 2017;181(suppl):S27-S32.e1. doi: 10.1016/j.jpeds.2016.09.063), wrote that they supported genotyping all individuals diagnosed with CF, even if physiologic tests establish the diagnosis, to better understand the disease’s genetic epidemiology and to refine future therapies. “If the identified mutations are known to be associated with variable outcomes, or have unknown consequence, that genotype may not result in a CF phenotype. In these cases, other tests of CFTR function may help,” this supplement’s authors concluded.
The updated guideline authors recommend avoiding the use of terms such as “atypical” or “nonclassical” CF, as there is no consensus on the specific taxonomy of CF, since the genetic data are still emerging.
When administering a newborn test, the guidelines warn that the heterogenous nature of newborn screening often leads to false positive results, thus the need for the sweat test. Although obtaining an adequate sweat specimen for chloride measurements can be difficult, the authors say it is possible, especially in full-term infants aged 1 month. Repeat sweat testing is recommended, as is nasal potential difference (NPD) and intestinal current measurement (ICM) in some cases.
Another change to the guidelines is that newborns with a high immunoreactive trypsinogen level and inconclusive CFTR functional and genetic testing may now be designated as having CFTR-related metabolic syndrome/CF screen positive inconclusive diagnosis (CRMS/CFSPID), instead of CFTR-related metabolic syndrome or CF screen positive, inconclusive diagnosis. Regarding changes to screening for CRMS/CFSPID, the older guidelines called for such an assessment by age 2 months, repeated every 6-12 months, while the new guidelines say their recommendation on the duration and frequency of follow-up “remains to be determined.”
The authors of the first supplement decry the lack of standardized CF diagnostic criteria for those diagnosed with CF outside of the neonatal period, and urge clinicians to rely on clinical evidence including organ pathologies typical in CF, such as bronchiectasis or pancreatic insufficiency, along with testing for the presence of CFTR dysfunction with sweat chloride testing, CFTR molecular genetic analysis, or CFTR physiologic tests.
In contrast, the second supplement states that “clinical suspicion should always take precedence” in making a CF diagnoses for individuals in this age group.
Dr. Sosnay and Philip M. Farrell, MD, PhD, a coauthor of the guidelines, received funds from the Cystic Fibrosis Foundation, where guideline coauthor Terry B. White, PhD, is an employee. Kris De Boeck, MD, a coauthor of the first supplement, receives funding from Vertex Pharmaceuticals, Ablynx, Aptalis, Galapagos, Gilead, Pharmaxis, and PTC Therapeutics. The guideline and supplements’ other authors have no disclosures.
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