Newborn Screening
CF newborn screening (NBS) is a pertinent area of research interest,
with work in the past year published related to optimization of both the
diagnostic pathway as well as clinical care delivery for both CF and CF
related metabolic syndrome/CF screen positive inconclusive diagnosis
(CRMS/CF-SPID) patients.
NBS has been available in every state in the US since 2010 and other
countries with variable initiation dates. NBS varies by location, but an
ongoing awareness of each state/country’s outcomes are critical. The
European CF Society Neonatal Screening Workgroup published key
performance outcome parameters with clear definitions to help assess and
monitor NBS programs76.
Several locations have shared their experiences with valuable lessons
shared. In a report from Colorado, 8 cases were missed over 5
years71. Upon data review, use of a fixed cut off for
IRT (60 ng/ml) explained the missed cases, as over time, IRT values
gradually decreased. To account for known variations seen with IRT
levels, Colorado changed to a 96%ile floating cutoff and 50ng/ml fixed
cutoff, which would have prevented these missed cases. New York state
changed to an IRT/DNA sequencing algorithm in 2017 and demonstrated the
ability to use customizable targeted sequencing of all clinically
relevant CFTR variants in an effort to decrease false positive
testing77. In Germany, to reduce identification of
carriers, the use of IRT, pancreatitis associated protein (PAP) with an
IRT dependent safety net was compared to IRT-DNA method over the years
2008-2016. The PAP method had good sensitivity and the advantage of
detecting no carriers, however had a low positive predictive value
(PPV), leading authors to conclude that DNA may be necessary as a third
tier to improve the PPV78. Poland identified 11
patients with a false negative NBS, with many due to lack of SC testing
in subsequent siblings, infants with meconium ileus, and patients with
symptoms consistent with CF despite normal NBS
results79. These reports highlight the role of ongoing
data monitoring, false negatives in NBS including from known variation
in IRT levels, advancing to CFTR sequencing and use of PAP in NBS for
CF.
The use of palmar aquagenic wrinkling is a possible screening method for
CF80. To test this hypothesis, children less than 2
years of age were examined. Time to wrinkle was much shorter in PwCF
compared to carriers/controls and correlated with IRT, SC levels, and
CFTR mutations. These results may be of benefit in countries with
financial and geographic limitations to NBS implementation, whereby use
of time to wrinkle can serve as a screening tool to determine those
patients who need earlier referral for diagnostic testing.
Once a NBS is positive, patient care pathways are important to optimize
outcomes. The CF Newborn Screening Genetic Counselling Workgroup, a
cross disciplinary expert group, recommends that centers ensure access
to a trained genetic specialist for parents of infants with a positive
NBS74.
The first 9 years of NBS in the US were reviewed in 6,354 infants from
the CFF PR73. The first event (defined as earliest SC
test, clinic visit or hospitalization) for NBS positive infants was
withing the first 30 days for 77% yet 10% still had their age at first
event at >60 days. The percent with age at first event
beyond 60 days has decreased over the 9 years, from 11% in 2010-2012 to
7.8% in 2016-2018. It is critically important for long term clinical
outcomes to have an earlier age at first event, especially with the
importance of early nutrition. It was notable that 40% of these infants
had a weight for age of <10% at their first visit,
demonstrating early evidence of nutritional concern. This evaluation of
NBS over time in the US serves as a reminder to clinicians of the
importance of early diagnosis/evaluation (prior to 30 days of age) and
the critical importance of nutritional monitoring
Long term follow-up regarding the benefits of NBS were explored in PwCF
diagnosed as part of the Wisconsin CF Neonatal Screening Project who
have been followed up to 26 years75. No difference in
mortality was seen at age 25 (89% of screened vs. 85% diagnosed
symptomatically). In those diagnosed by NBS, the FEV1pp rate of decline
was greater between ages 7-26 years (-1.76 vs. 1.43% per year),
however, was concluded to be partially due to earlier PA acquisition.
The authors concluded that CF NBS was not significant enough to improve
longitudinal lung function decline.