1. In a prospective multi-center study, 21% of children with cystic fibrosis screen positive, inconclusive diagnosis (CFSPID) at birth were later reclassified to a diagnosis of cystic fibrosis (CF).
2. Initial sweat chloride value on the high end of normal predicted eventual diagnosis of CF.
Evidence Rating Level: 2 (Good)
Study Rundown: Screening for cystic fibrosis (CF) has been part of routine newborn care for decades in the United States and Canada. After a positive screening for elevated immunoreactive trypsinogen, the diagnosis of CF is typically made based on genetic testing for disease-causing variants of the CFTR gene as well as elevated sweat chloride. Infants with cystic fibrosis screen positive, inconclusive diagnosis (CFSPID) have either 2 CFTR gene variants, at least 1 of which is not known to be CF-causing, or borderline sweat chloride values of 30 to 59 mmol/L. This ongoing, longitudinal, multi-center study examined long-term outcomes for children across Canada falling into this diagnostic gray area. These children were compared to controls with diagnosed CF, with and without pancreatic insufficiency. At a mean follow-up time of 7.7 years, 21% of 115 children with CFSPID were eventually diagnosed with CF based on either reinterpretation of gene variants or increased sweat chloride. Children with CFSPID had normal heights and weights at age 6, and normal lung function. Children with CFSPID and initial sweat chloride 40 mmol/L or greater were more likely to eventually be diagnosed with CF. This study’s limitations include its relatively small sample size and the timing of this interim analysis, as differences in growth, pulmonary function, and pancreatic function due to CF may not manifest until early adulthood. However, this study presents compelling evidence supporting the use of sweat chloride as a biomarker to predict a future diagnosis of CF in children with CFSPID.
Relevant Reading: Cystic fibrosis screen positive, inconclusive diagnosis (CFSPID): A new designation and management recommendations for infants with an inconclusive diagnosis following newborn screening
In-Depth [prospective cohort]: The CFTR2 database was used to determine whether individual CFTR gene variants were pathogenic. 27% of the original cohort with CFSPID was lost to follow-up. Linear regression models were used for analysis of anthropometric and pulmonary function measures. Pulmonary function was assessed using both FEV1 and lung clearance index (LCI). FEV1 was not significantly different between CFSPID and CF. LCI was lower in CFSPID than in CF patients. Respiratory bacteria were also sampled, and were overall similar between CFSPID and CF patients though with low frequency of positive cultures in both groups. A proportional hazards model was used to analyze sweat chloride as a possible predictor of CF diagnosis. The hazard ratio for conversion to CF in CFSPID patients with initial sweat chloride 40 or greater compared to <40 mmol/L was 12.1 (95% confidence interval 2.6-55.6). Immunoreactive trypsinogen screening values did not predict later CF diagnosis in a similar analysis.
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