Cystic Fibrosis Diagnosis in Newborns, Children, and Adults

Carlo Castellani, MD; Barry Linnane, MB, BCh, BAO, DCH, MRCPI, MRCPCH, MD; Iwona Pranke, PhD; Federico Cresta, MD; Isabelle Sermet-Gaudelus, MD, PhD; Daniel Peckham, MD


Semin Respir Crit Care Med. 2019;40(6):701-714. 

In This Article

Initial IRT-based Screening

The initial proof of concept studies used a retrospective design, retrieving the blood spots collected as a part of screening for phenylketonuria and other inborn errors of metabolism, of cases with an established diagnosis of CF.[55] The IRT levels were compared with randomly selected cards taken as controls. The study successfully demonstrated high levels of serum IRT in children with CF, whether or not active trypsin was detected in their stool, thus giving an abnormal result even in infants with residual pancreatic function at the time of testing. The study also supported the hypothesis that the pancreatic duct is progressively blocked resulting in "back-leakage" of acinar contents into the plasma.[55]

Small pilot studies demonstrated the IRT assay could be used for neonatal screening, and larger screening studies ensued.[56–63] In Australia, Wilcken et al described the findings of screening 75,000 infants prospectively.[61] Bloodspots, sampled in batches of 250 to 500, were considered abnormal when the IRT value was greater than the 98th percentile for the batch or exceeded 200 arbitrary units (AU) per liter. In the assay an AU equated with 1 μg of purified trypsin extract. If the IRT was found to be high a repeat heel prick sample was taken, and if this was >220 AU/L a sweat test was performed. The study confirmed IRT could distinguish between CF and non-CF with excellent (although not perfect) sensitivity. Specificity was suboptimal in the newborn period, but improved with repeat sampling at 4 to 7 weeks. In Colorado, Hammond et al, screened almost 280,000 infants and demonstrated that 95% of the CF infants (confidence interval, 85–99%) could be identified using an IRT cut-off value of 140 μg/L on initial testing and at 80 μg/L on repeat testing.[62]