The Need for Quality Improvement in Sweat Testing Infants after Newborn Screening for Cystic Fibrosis

doi:10.1016/j.jpeds.2010.07.053

The Journal of Pediatrics

Volume 157, Issue 6, December 2010, Pages 1035-1037

https://doi.org/10.1016/j.jpeds.2010.07.053 Get rights and content

The proportion of insufficient sweat tests after positive newborn screening for cystic fibrosis was determined. Infants ≤3 months old had a mean (±standard deviation) rate of 7.2% (±7.6) (range, 0% to 40%). Collection methods did not affect the rates. The high and variable rates indicate a need for quality improvement.

Section snippets

Methods

Three sets of data concerning QNS rates were collected and analyzed in 2009 and 2010: a national survey of 110 pediatric CFF accredited care centers (“CFF Annual Application”); a national survey to 48 state leaders involved in newborn screening for CF (NBS Special Interest Group (“NBS-SIG”); and a review of sweat test data prospectively collected by the Illinois Department of Public Health NBS program, which includes 13 Illinois and 2 Missouri sites performing sweat testing for Illinois infants

Results

We found that QNS rates were often high and generally variable in the national survey (Table I). The t tests were performed comparing the QNS rate with regard to collection method of pad (gauze or filter paper) versus Macroduct coil according to age . For infants ≤3 months, t = 1; P = .321, with a 95% CI of 1.46 to 4.38. For individuals >3 months of age, t = 1.75; P = .086, with a 95% CI of -0.15 to 2.3. It can be inferred that with regard to QNS rates, no one collection method is superior to

Discussion

Determining QNS rates is important because a very high rate signifies a problem in sweat collection. Routine monitoring of the QNS rate should trigger evaluation of the sweat testing protocol. The CFF annual application and the NBS-SIG data reveal that young infants can be successfully sweat tested. On average, 92.8% of individuals yielded sufficient sweat for analysis. The CFF annual application, the NBS-SIG data, and the Illinois data all support the QNS metric for infants 3 months of age and

References (5)

R.B. Parad et al.
Sweat testing infants detected by cystic fibrosis newborn screening
J Pediatr
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P.M. Farrell et al.
Sweat chloride concentrations in infants homozygous or heterozygous for F508 cystic fibrosis
Pediatrics
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There are more references available in the full text version of this article.

Cited by (37)

Variability of the sweat test in children with Cystic Fibrosis previously CRMS/CFSPID: A retrospective monocenter experience
2023, Journal of Cystic Fibrosis
Some studies have evaluated the sweat test (ST) intra individual variability in CRMS/CFSPID. Here, we retrospectively evaluated this in a cohort followed at the CF center in Florence, Italy. We enrolled 37 CRMS/CFSPID and 37 CF children, born between 2011 and 2019. A total of 327 ST were retrospectively recovered, of which 17 (5.2%) were quantity not sufficient. After a median follow-up of 33.8 months (range 1.7–88.2), 11 (24.3%) became CF with at least two pathological sweat chloride (SC) values at a median age of 46.9 months (range 1.4–49). The coefficient of variation was 6.2% in CF patients and 32.5% in the CRMS/CFSPID that transitioned to CF (P<.001). Our data highlight a more variability of SC values in CRMS/CFSPID, especially in those that transitioned to a diagnosis of CF. Further studies are needed to understand whether it is correct to define an asymptomatic CRMS/CFSPID with pathological SC as CF.
Standards of care guidance for sweat testing; phase two of the ECFS quality improvement programme
2022, Journal of Cystic Fibrosis
Citation Excerpt :
A high proportion of QNS is indicative of possible methodological shortcomings requiring action such as: training of personnel, re-evaluation of procedures and/or technical inspection of devices. Strategies to minimize QNS rates are outlined in Appendix A [18]. Sweat may be collected at remote sites and transported to the laboratory for analysis as long as strict storage conditions can be adhered to.
More than five decades after the introduction of the quantitative pilocarpine iontophoresis technique, surveys still highlight inconsistencies in the performance and reporting of sweat tests in Europe. The sweat test remains key for the Cystic Fibrosis (CF) diagnostic pathway for all age groups, as it reflects the basic pathophysiological defect in the sweat gland. It is also critical following newborn screening as a confirmatory diagnostic step. Despite its importance, sweat test quality is variable whether performed in the laboratory or as a point of care test. The ECFS DNWG aims to improve sweat test performance, taking into account the barriers and issues identified in the European survey; the previous step in the ECFS sweat test project. This manuscript proposes a grading of sweat test guidance from "acceptable" to "optimal", aiming to pragmatically improve quality while taking into account local situations, especially in resource-limited settings.
A paper-based length of stain analytical device for naked eye (readout-free) detection of cystic fibrosis
2019, Analytica Chimica Acta
Citation Excerpt :
The minimum acceptable amount required for an accurate test is 75 mg of sweat collected on 2 × 2-inch pads or 15 μL of sweat collected in Macroduct coils. Lower amounts are not sufficient for analysis [3]. Also many false positive and false negative results may occur, mainly due to the presence of such unmeasured anions as lactate and bicarbonate [4].
The test of sweat chloride is routinely performed as a worldwide newborn screening (NBS) to the diagnosis of cystic fibrosis (CF) in infants. However, the available methods for measurement of chloride in sweat suffer from such limitations as either low selectivity and/or requiring relatively large sample size. In this work, we have designed an analytical ruler that can measure chloride ion in sweat and hence can be used for the diagnosis of cystic fibrosis. This micro-pad (μ-PAD) device is fabricated by making hydrophilic micro-channel on a filter paper impregnated with silver dichromate. After addition of chloride ion-containing sweat sample, it moves through the channel, leading to the formation of an AgCl sediment, which deposits as a white color stain, the length of which in the channel being proportional to the amount of chloride ion in sweat. A well-defined linear relation was observed between the length of white color stain and the concentration of chloride ion in the sample solutions with a relative standard deviation of 3.6% (n = 3) for an artificial sweat sample containing 100 mM chloride ion. The possible interfering effects of several different cations and anions on the detection of chloride ion were investigated and the results well-confirmed the selectivity of the proposed method. With the use of only 2.0 μL of the sample solution, the μPAD was able to measure the chloride content of sweat over a concentration range of 20.0–100.0 mM, which covers both the healthy range (˂ 40 mM) and the risky range (˃60 mM) of chloride ion. Analysis of chloride content of sweat samples by the μPAD agreed well with those obtained by a standard electrochemical method (with relative errors of lower than 10%).
Sweat test for cystic fibrosis: Wearable sweat sensor vs. standard laboratory test
2018, Journal of Cystic Fibrosis
Citation Excerpt :
For laboratory analysis of sweat concentration using the Macroduct device, a minimum sweat volume of 15 μL is required, and samples with smaller volumes are designated “quantity not sufficient” (QNS). QNS is frequently encountered in conventional sweat tests, especially in infants younger than 3 months [9,10]. The wearable sensor directly measures the chloride concentration of a thin layer of sweat between the sensor and skin, and hence does not require a large volume.
Sweat chloride testing for diagnosis of cystic fibrosis (CF) involves sweat induction, collection and handling, and measurement in an analytical lab. We have developed a wearable sensor with an integrated salt bridge for real-time measurement of sweat chloride concentration. Here, in a proof-of-concept study, we compare the performance of the sensor to current clinical practice in CF patients and healthy subjects.
Sweat was induced on both forearms of 10 individuals with CF and 10 healthy subjects using pilocarpine iontophoresis. A Macroduct sweat collection device was attached to one arm and sweat was collected for 30 min and then sent for laboratory analysis. A sensor was attached to the other arm and the chloride ion concentration monitored in real time for 30 min using a Bluetooth transceiver and smart phone app.
Stable sweat chloride measurements were obtained within 15 min following sweat induction using the wearable sensor. We define the detection time as the time at which the standard deviation of the real-time chloride ion concentration remained below 2 mEq/L for 5 min. The sweat volume for sensor measurements at the detection time was 13.1 ± 11.4 μL (SD), in many cases lower than the minimum sweat volume of 15 μL for conventional testing. The mean difference between sweat chloride concentrations measured by the sensor and the conventional laboratory practice was 6.2 ± 9.5 mEq/L (SD), close to the arm-to-arm variation of about 3 mEq/L. The Pearson correlation coefficient between the two measurements was 0.97 highlighting the excellent agreement between the two methods.
A wearable sensor can be used to make real-time measurements of sweat chloride within 15 min following sweat induction, requiring a small sweat volume, and with excellent agreement to standard methods.
Feasibility and normal values of an integrated conductivity (Nanoduct™) sweat test system in healthy newborns
2017, Journal of Cystic Fibrosis
Citation Excerpt :
Collecting sufficient sweat for analysis is a challenge in small infants and some guidelines recommend delaying the test until the infant is more than two weeks of age or weighs more than 3 kg [3–5]. Although for infants below three months of age test failure rates of up to 40% have been reported [6–10], North American recommendations aim for a failure rate of 10% or less for sweat tests in NBS programs [2,6]. Since the invention of the sweat test based on the pad method by Gibson and Cooke 60 years ago [11,12], sweat testing has evolved.
Nanoduct™ is a simple and practical sweat analysis system measuring conductivity in situ. It requires only three microlitres of sweat, making it especially applicable to newborns.
We measured conductivity in 260 healthy term infants at the age of four days, and again at four weeks to determine the proportion of successful tests, test duration, and normal values for sweat conductivity in newborns.
Sufficient sweat was collected in 159/260 of four-day olds (61%), and in 225/239 of four-week olds (94%). Mean (sd) test duration was 27 (5) and 25 (5) min. Mean (sd, range) conductivity was 53 mmol/l (16, 8–114) at age four days, and 36 (9, 12–64) at four weeks.
Determination of sweat conductivity using Nanoduct™ cannot be recommended for four-day old newborns. However, at the age of four weeks the success rate is high (94%), and conductivity values at that age are comparable to older healthy children.
Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation
2017, Journal of Pediatrics
Cystic fibrosis (CF), caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, continues to present diagnostic challenges. Newborn screening and an evolving understanding of CF genetics have prompted a reconsideration of the diagnosis criteria.
To improve diagnosis and achieve standardized definitions worldwide, the CF Foundation convened a committee of 32 experts in CF diagnosis from 9 countries to develop clear and actionable consensus guidelines on the diagnosis of CF and to clarify diagnostic criteria and terminology for other disorders associated with CFTR mutations. An a priori threshold of ≥80% affirmative votes was required for acceptance of each recommendation statement.
After reviewing relevant literature, the committee convened to review evidence and cases. Following the conference, consensus statements were developed by an executive subcommittee. The entire consensus committee voted and approved 27 of 28 statements, 7 of which needed revisions and a second round of voting.
It is recommended that diagnoses associated with CFTR mutations in all individuals, from newborn to adult, be established by evaluation of CFTR function with a sweat chloride test. The latest mutation classifications annotated in the Clinical and Functional Translation of CFTR project (http://www.cftr2.org/index.php) should be used to aid in diagnosis. Newborns with a high immunoreactive trypsinogen level and inconclusive CFTR functional and genetic testing may be designated CFTR-related metabolic syndrome or CF screen positive, inconclusive diagnosis; these terms are now merged and equivalent, and CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis may be used. International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes for use in diagnoses associated with CFTR mutations are included.

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: V.L. serves as a consultant regarding sweat testing performance and receives honoraria for this activity. S.M. serves as an advisor and speaker’s bureau member for Genentech, for which she has received honoraria, and is a member of the Illinois Department of Public Health Genetic and Metabolic Diseases Advisory Committee. P.F. is the CFF National Facilitator for Newborn Screening and receives honoraria for that work. Z.L. declares no conflicts of interest.

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Clinical and Laboratory ObservationThe Need for Quality Improvement in Sweat Testing Infants after Newborn Screening for Cystic Fibrosis

Section snippets

Methods

Results

Discussion

Sweat testing infants detected by cystic fibrosis newborn screening

J Pediatr

Sweat chloride concentrations in infants homozygous or heterozygous for F508 cystic fibrosis

Pediatrics

Clinical and Laboratory Observation
The Need for Quality Improvement in Sweat Testing Infants after Newborn Screening for Cystic Fibrosis