CF Guidelines: Greater Reliance on Mutation Classifications

Diana Phillips

February 13, 2017

New consensus guidelines for the diagnosis of cystic fibrosis (CF) further standardize the diagnostic criteria for infants through adults and may inform targeted treatment based on specific genetic variants of the pulmonary disease.

Of particular note, the consensus recommendations, developed for the Cystic Fibrosis Foundation by an international panel of experts and published online in the Journal of Pediatrics, recommend that clinicians use the most recent classifications for CF transmembrane conductance regulator (CFTR) mutations to diagnose the disease in patients of all ages.

As in the previous guideline, published in 2008, the primary diagnostic criteria in the new document are clinical presentation and evidence of CFTR dysfunction. However, the revised guidelines rely on advances in CFTR mutation interpretation and annotation gained through the Clinical and Functional Translation of CFTR (CFTR2) project. The CFTR2 project characterizes CFTR mutations from patients with CF globally according to whether they meet clinical criteria and the probability that someone with such a mutation would develop CF.

To date, the CFTR2 project, which is described in an accompanying article, has described 300 of the approximately 2000 known CF-related mutations, whereas the previous guidelines relied on a panel comprising 23 mutations, according to lead author Philip Farrell, MD, PhD, professor of pediatrics and population health sciences from the University of Wisconsin School of Medicine and Public Health, Madison.

The interpretation of CFTR variants "is a major step forward," and can influence diagnostic and treatment considerations "because not every CFTR genetic change will result in CF," Dr Farrell explained in an interview with Medscape Medical News. The various genetic mutations can have different implications in terms of "disease liability," he said. Some are characterized as CF-causing, and others as non-CF-causing, and some have unknown consequences. Incorporating this information into diagnostic consideration can help clinicians identify whether patients need additional diagnostic studies and, in some cases, which treatment protocols might be most beneficial.

Another major change in the updated guideline is the reduction of the threshold for sweat chloride concentration used to indicate a possible cystic fibrosis diagnosis. Across all ages, the threshold has been reduced to 30 mmol/L from the earlier recommendation of 40 mmol/L.

The normal range for sweat chloride is 10 to 20 mmol/L, and a concentration of 60 mmol/L indicates a definite CF diagnosis, the authors explain. Previously, researchers believed that a concentration of 40 mmol/L indicated that the CFTR was not working, but they have lowered that threshold "because patients have been definitively diagnosed with CF with chloride values in the 30-39 mmol/L range."

For this reason, patients with sweat chloride levels higher than 30 mmol/L should be considered for further evaluation, including extended CFTR gene analysis and/or CFTR functional analysis "to establish or rule out a CF diagnosis," the authors write.

In total, the guideline includes 27 consensus statements that apply to screened and nonscreened patient populations, newborn screened populations and fetuses undergoing prenatal testing, infants with uncertain diagnoses designated as CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis, and patients with clinical presentation of CF who were either not screened or had false-negative screening tests.

Additional changes to the guidelines include the following recommendations:

  • Treatment for CF can be started while awaiting sweat-test confirmation based on a presumptive diagnosis in the case of a positive newborn screen and the presence of any of the following: two CF mutations, signs and symptoms of CF, or meconium ileus.

  • Newborn infants with a high level of immunoreactive trypsinogen and inconclusive CFTR testing results should be designated as CFTR-related metabolic syndrome/inconclusive diagnosis, although "further research is needed to determine their prognosis, best practice, and frequency of follow-up."

  • Clinicians should avoid using the terms classic/nonclassic CF, typical/atypical CF, and delayed CF, "because these terms have no harmonized definition and could be confusing for families or caregivers."

Several other related papers were published with the guidelines, including one on the diagnosis of CF in unscreened populations, and an overview of the challenges and lessons learned in 40 years of CF research.

The guideline and supplement authors disclosed received funds from the Cystic Fibrosis Foundation, Vertex Pharmaceuticals, Ablynx, Aptalis, Galapagos, Gilead, Pharmaxis, and PTC Therapeutics.

J Pediatr. 2017;181:S4-S15, S27-S32. Guidelines full text, Article full text

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