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

IRT: Factors Influencing the Measured Value

Several important variables can influence IRT values measured in dried blood spots, as described in a 10-year review by the Wisconsin group.[72]

Variation Between Reagent Lots

The Wisconsin group demonstrated variations in IRT values between reagent lot numbers of up to 14 ng/mL for the 95th percentile cut-off, possibly as a consequence of the assay calibration.[72] CF NBS programs need to be aware of this issue when they change assay kits. Using a fixed IRT cut-off value could result in an error, hence the variation between lots is one of the two reasons to advocate for a "floating" cut-off level, based on the percentile (e.g., 95th) of a batch.[72]

Seasonal Variation

IRT values are higher in winter (mean IRT 61 ng/mL) and lower in summer (mean 57 ng/mL).[72] This appears to be a consequence of degradation of IRT in the bloodspot with higher environmental temperatures and humidity. The precise relationship is difficult to predict and so CF NBS programs, even in temperate climates, should investigate local seasonal effects on IRT. This seasonal variability is the second reason a "floating" cut-off level is advocated.[72]

Age at Time of Testing

Infants unaffected by CF show a minor drop in IRT in the first 24 hours of life, followed by a 2-week period of relative stability, and then a gradual decrease in IRT beyond 2-weeks postnatal age.[72] Setting cut-off IRT values for infants over a month of age is therefore problematic, particularly for programs using an IRT in tier two. By contrast, most infants with CF continue to have a substantially raised IRT for approximately a year after birth.[62,72] However, this is not the case for all infants with CF, and beyond 30 days of age IRT values can overlap with infants without CF.[73,74]

Prematurity, Low Birth Weight, and Sick Neonates

The Wisconsin group used low birth weight as a surrogate for prematurity. They, and others, demonstrated, somewhat surprisingly, that IRT values tend to be slightly higher in low birth weight infants, possibly as a consequence of stress, immaturity, or other illnesses.[72,73,75,76] The Wisconsin group demonstrated that infants with a birth weight <2,500 g had an average IRT 32 ng/mL compared with 29 ng/mL for those >2,500 g. The difference is unlikely to have a material effect on performance of a CF NBS program, and the findings demonstrate an important issue, that IRT could be used to screen infants born prematurely. Illnesses which can result in some variability to IRT values in the neonatal period in term infants, in particular raising the IRT and potentially resulting in false positive values, are: bowel atresia, physiological stress, respiratory distress, hypoglycemia, congenital infection, sepsis, asphyxia, cardiac surgery, extracorporeal membrane oxygenation, and chromosomal abnormalities.[72,73,75,76]

Meconium Ileus

Infants presenting with meconium ileus (MI) deserve special mention. MI is the earliest clinical manifestation of CF, typically occurring within the first few days of life with features of bowel obstruction, and even earlier if one includes the observation of hyperechogenic bowel on antenatal ultrasound scanning.[15,77–79] CF NBS programs were never going to be able to identify these infants before they presented clinically. Somewhat paradoxically, given that MI is a cardinal sign of CF representing up to 20% of the cases, infants with MI are more likely to produce a false negative NBS result, with the initial IRT below the cut-off level.[21,62,72,80,81] How extensive the issue is, is somewhat unclear, nor is there a clear explanation as to the cause.[62,80] Therefore it is important that teams caring for these infants, such as surgeons, general pediatricians, and neonatologists, should not be falsely reassured by a negative CF NBS result in an infant in whom they suspect MI. All these infants require further assessment, which may include genetic testing, review by a CF specialist and sweat testing.