Quantity not sufficient rates and delays in sweat testing in US infants
with cystic fibrosis
Susanna A. McColley, MD1; Alexander Elbert,
PhD2; Runyu Wu, MS2; Clement L. Ren,
MD3; Marci K. Sontag, PhD4; Vicky A.
LeGrys, DA, MT(ASCP)5.
- Department of Pediatrics, Northwestern University Feinberg School of
Medicine; Stanley Manne Children’s Research Institute, Ann & Robert
H. Lurie Children’s Hospital of Chicago, Chicago, IL.
- Cystic Fibrosis Foundation, Bethesda, MD.
- Department of Pediatrics, Indiana University; Riley Children’s
Hospital, Indianapolis, Indiana.
- Center for Public Health Innovation, Littleton, Colorado; Department
of Epidemiology, University of Colorado, Denver.
- Department of Allied Health Science, University of North Carolina,
Chapel Hill, NC.
Abstract
Background: Diagnostic sweat testing is required for infants with
positive newborn screening (NBS) tests for cystic fibrosis (CF). Infants
have “quantity not sufficient” (QNS) sweat volumes more often than
older children. A comprehensive study of QNS sweat volumes in infants
has not previously been reported. Methods: We surveyed US CF Centers to
obtain QNS rates in all infants who had sweat testing at< 14 days and < 3 months of age. We
then calculated QNS rates reported to the Cystic Fibrosis Foundation
Patient Registry (CFFPR) 2010-2018 in 10-day increments from 1 to 60
days of life. We compared QNS sweat tests rates in preterm (<
37 weeks gestational age) versus term infants. We assessed age at sweat
test and proportion of infants who did not have a sweat test reported by
60 days of age. Results: Thirty-nine of 144 (27%) of CF Centers
reported a mean QNS rate of 10.5 % (range, 0-100) in infants< 14 days old. CFFPR data showed highest QNS rates in
the youngest infants and in those born < 37 weeks gestation.
The median age at sweat testing decreased over time, but >
22% of infants did not have a sweat test reported by 60 days.
Conclusion: Higher QNS rates are seen in the youngest infants with CF,
but > 80% of infants < 2 weeks of age have
adequate sweat volumes. Sweat testing should not be delayed in infants
with a positive CF NBS test.
Introduction
During the last decade, cystic fibrosis (CF) newborn screening (NBS) has
been adopted throughout the United States (US) and in many other nations
and regions. A positive NBS result may be reported before 2 weeks of age
when a single dried blood spot is used for screening. Quantitative
pilocarpine iontophoresis sweat chloride testing is recommended for
evaluation of infants with a positive NBS1 and
guidelines have been updated to enhance sweat testing in
infants2. However, young infants are at increased risk
of having quantity not sufficient (QNS) sweat volumes (or weights)
compared to older infants and children3-5.
Surveys of QNS rates in US CF Care Centers led to guidance that CF
Centers should have quantity not sufficient rates of <10% in infants under 3 months of age and < 5% in
older patients6. These data were collected before CF
NBS was implemented in all states. Risk factors for QNS sweat tests in
infants include gestational age < 38 weeks, postnatal age
< 14 days, and weight < 2 kg (3-5.
Variability in QNS rates and high QNS rates in infants have been
observed in the US6 and Europe7. We
hypothesized that sweat testing QNS rates are higher in infants less
than 14 days old or less than 37 weeks gestational age. We evaluated QNS
rates and age at sweat testing in infants in the US seen at Cystic
Fibrosis Foundation (CFF) -accredited Care Centers after initiation of
NBS in all US states, utilizing a survey of CF Center Directors and data
from the Cystic Fibrosis Foundation Patient Registry (CFFPR). We also
evaluated delays in sweat testing in infants reported to the CFFPR.
Methods
For preliminary data, we surveyed Cystic Fibrosis Foundation accredited
CF Center pediatric and affiliate program directors to estimate QNS
rates in infants presenting for evaluation of a positive NBS test. Based
on prior literature, we aimed to assess rates for infants who were
< 30 days old, and of the subset who were < 14 days
old, at time of sweat testing. The 6-question survey (table 1) was sent
via email directly from the CFF to 144 pediatric and affiliate program
directors by the CFF. Participation was encouraged, but voluntary. This
study was deemed exempt by the Ann & Robert H. Lurie Children’s
Hospital of Chicago Institutional Review Board.
Based on our initial findings, we evaluated data submitted to CFFPR from
January 1 2010-December 31 2018 to calculate sweat test QNS rates in
infants with CF who had a sweat test recorded before 60 days of age. The
CFFPR structure has been previously described (Knapp). The year 2010 was
chosen since it was the first full year in which all US states screened
infants for CF. Rates of QNS sweat tests were calculated for infants in
10-day increments from 0- <10 days to 50-60 days. We also
compared QNS rates for infants born at 37 weeks (pre-term) to those born> 37 weeks gestation (term). Finally, we compared
data submitted to the CFFPR to evaluate the age at first sweat test for
infants in three time periods: 2010-2012, 2013-2015, and 2016-2018. Data
entry into the CFF patient registry is approved by local or central
institutional review boards, and legal guardians of minors provide
informed consent for participation.
Statistical analysis
Descriptive statistics were generated for the survey questions. Changes
in the median age at sweat test were compared using the Wilcoxon rank
sum test. Comparisons of QNS rates across postnatal age and gestational
age categories was compared using the Chi-square test. P < .05
was considered statistically significant.
Results
The CF Center survey, conducted between June 6 and July 4 2016, was
completed by 39 (27%) of CF center directors (table 2). There was great
variability in the number of sweat tests performed by responding
programs. Infants < 14 days of age comprised a minority of
those tested, and one third of programs had no tests performed in
infants in this age group. In infants < 14 days, the mean QNS
rate was 10.5 (SD = 22.2%; range, 0-100%).
During the time period from January 1, 2010 and December 31, 2018, 5392
infants with CF were reported in the CFFPR. The QNS rate in infants
< 10 days of age was 16.4%. With each 10-day increment, the
QNS rate decreased (table 3). There were 3418 infants born> 37 weeks gestation and 287 infants born
< 37 weeks gestation. Quantity not sufficient sweat tests were
reported in 224 (6.6%) term infants and 56 (19.5%) of preterm infants
(p < 0.001, Chi-square test). Variation by gestational age or
age at sweat test were not evaluated due to the small number of preterm
infants. There was a decrease in median age at sweat test over time
(table 5). Among infants reported, 1204 (23.8%) had no sweat test
reported before 60 days of age. The percentage of patients with no sweat
test before 60 days decreased slightly over time.
Discussion
This is the first large study of sweat test QNS rates and delayed sweat
testing in infants and are important for center assessment of sweat
testing, quality improvement efforts, and communicating with parents of
infants with positive newborn screening tests. Newborn screening
identifies infants at risk for CF. Prompt diagnostic testing is critical
to identify infants with CF and to resolve the diagnosis in infants who
do not have CF. Delays in diagnostic confirmation are associated with
parental psychological distress8 and in treatment. The
quantitative pilocarpine iontophoresis sweat test is recommended for CF
diagnosis9,10. It confirms CFTR dysfunction, has a
rapid turnaround time, and is widely available.
The center director survey provides evidence that QNS rates are higher
in younger infants and confirms previous findings that there is high
variability in QNS rates between CF Centers 6. Because
only 27% of CF centers responded, the overall population QNS rates
cannot be adequately estimated from these data. Data may not be
representative of CF Centers, since those with better rates may have
been more likely to respond. However, the large number and broad range
of QNS results show significant variability in sweat test performance
and include QNS rates in infants with and without CF.
Consistent with other studies 3-5, we found that QNS
rates are highest in infants during the first 10 days and in infants
born prematurely. A novel finding is that sweat test QNS rate decreased
over each subsequent 10-day increment. We did not evaluate infant weight
at the time of sweat testing as it is not available in the registry. We
did not assess other potential factors influencing QNS rates that have
been inconsistent between studies. These include sweat collection
methodology 4,11 and African-American
race3,4. Some infants in the CFFPR may have had QNS
sweat tests that were not entered into the registry, underestimating the
overall QNS rates. Therefore, we caution against using these rates to
set QNS goals for quality assurance until additional prospective data
are collected.
We found that while the median and mean age of sweat testing decreased
over time, more than 1:5 infants seen at US CFF Care Centers during
2010-2018 did not have a sweat test by 60 days of age. This may be due
to intentional delays in infants who have two CFTR mutations reported on
NBS or by prenatal testing. However, some infants with two mutations may
not have CF12, and there is a theoretical risk of NBS
specimens being misattributed during collection or in a laboratory.
Since most infants < 10 days old or < 37 weeks
gestation had sufficient sweat quantities, sweat testing should not be
delayed because of chronological or gestational age if the infant is
physiologically stable and large enough for the test. Those who have a
QNS test or are unable to undergo sweat testing due to illness or small
size should be evaluated for signs and symptoms of CF. Empiric therapy
with sodium chloride and pancreatic enzymes should be considered in
these circumstances and later withdrawn if the sweat test is normal.
Additional testing, such as fecal pancreatic elastase or confirmatory or
expanded CFTR genotyping on a sample from the infant, may also be useful
if sweat tests are persistently QNS.
Due to the potential that CF Centers or their associated laboratories
might discourage testing in young infants fearing an increased QNS rate,
the CFF has modified the reporting system for accredited centers.
Effective 2019, QNS rates are being evaluated for patients between 6
weeks to 3 months of age with a benchmark of 10% and patients over 3
months of age with a benchmark of 5%. QNS rates in patients less than 6
weeks of age will be collected and evaluated for establishment of an
appropriate standard.
Finally, even with sweat test improvement efforts, a proportion of
infants with positive NBS tests will have a QNS sweat test. Guidelines
for diagnosis of CF in screened populations 9recommend prompt evaluation of infants with a positive NBS test and
presumptive treatment of infants who have signs and symptoms, including
poor growth or abnormal stools, to reduce the risk of growth failure,
hyponatremia and other complications. We further recommend presumptive
treatment in infants with 2 copies of disease causing CFTR mutations.
For infants at risk for pancreatic insufficiency, treatment with
pancreatic enzyme replacement therapy has few side effects and may be
lifesaving. Sodium chloride supplementation is low cost, widely
available in the form of table salt, and can avoid life-threatening
hyponatremia.
Conclusion: Young and premature infants have higher QNS sweat test rates
than older infants. Sweat testing should not be delayed and is often
successful even before 10 days of age. Evaluation of sweat collection
proficiency should account for the proportion of young and premature
infants evaluated and requires expansion beyond this report. Regardless
of the ultimate standard set for QNS rates, ongoing quality improvement
work should be undertaken to minimize sweat test QNS rates. This will
improve timing of diagnostic resolution and benefit infants with
positive NBS tests, their families, and the healthcare system.
Funding sources: This work was funded by Cystic Fibrosis Foundation
grants MCCOLL15QI0 and MCCOLL19QI0.
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