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Objective: To describe the clinical course of children who have intermediate sweat chloride values on initial screening for cystic fibrosis (CF)., Study Design: We performed a retrospective review of children with intermediate sweat chloride values (raised immunoreactive trypsinogen/1 copy of p.F508del CF mutation on newborn screening (NBS)/sweat chloride value of 30-59 mmol/L) presenting to The Children's Hospital at Westmead over 15 years. Patients with an intermediate sweat chloride evolving to a formal diagnosis of CF (termed "delayed CF") were matched (2:1) with NBS positive patients with CF (termed "NBS positive CF"). Clinical outcomes were compared., Results: Fourteen of 29 (48%, 95% CI 0.3-0.66) patients with intermediate sweat chloride value evolved to a diagnosis of CF and were matched with 28 NBS positive patients with CF. Delayed CF had less pancreatic insufficiency (OR 0.06, 95% CI 0.01-0.44, P = .006), less colonization with nonmucoid Pseudomonas aeruginosa (OR 0.04, 95% CI 0.01-0.38, P = .005), milder obstructive lung disease (forced expiratory volume in 1 second/forced vital capacity ratio), and overall disease severity (Shwachman scores) at 10 years (mean difference 5.93, 95% CI 0.39-11.46, P = .04; mean difference 4.72, 95% CI 0.9-8.53, P = .015, respectively). Nutritional outcomes were better at 2 years for delayed CF but did not persist to later ages., Conclusions: In this cohort, approximately one-half of infants with intermediate sweat chloride value were later diagnosed with CF. The clinical course of delayed CF was milder in some aspects compared with NBS positive CF. These results emphasize the importance of ongoing follow-up of infants with intermediate sweat chloride values., (Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.)

Objective: To assess whether reporting "possible cystic fibrosis (CF)" newborn screening (NBS) results via fax plus simultaneous telephone contact with primary care providers (PCPs) versus fax alone influenced 3 outcomes: undergoing a sweat chloride test, age at sweat chloride testing, and undergoing sweat testing before age 8 weeks., Study Design: This was a retrospective cohort comparison of infants born in Wisconsin whose PCP received a telephone intervention (n = 301) versus recent historical controls whose PCP did not (n = 355). Intervention data were collected during a longitudinal research and quality improvement effort; deidentified comparison data were constructed from auxiliary NBS tracking information. Parametric and nonparametric statistical analyses were performed for group differences., Results: Most infants (92%) with "possible CF" NBS results whose PCP lacked telephone intervention ultimately underwent sweat testing, underlining efficacy for fax-only reporting. Telephone intervention was significantly associated with improvements in the infants undergoing sweat testing at age ≤6 weeks and <8 weeks and a slight, statistically nonsignificant 3.5-day reduction in the infants' age at sweat testing. The effect of telephone intervention was greater for PCPs whose patients underwent sweat testing at community-affiliated medical centers versus those whose patients did so at academic medical centers (P = .008)., Conclusion: Reporting "possible CF" NBS results via fax plus simultaneous telephone follow-up with PCPs increases the rate of sweat chloride testing before 8 weeks of age, when affected infants are more likely to receive full benefits of early diagnosis and treatment., (Copyright © 2013 Mosby, Inc. All rights reserved.)

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., (Copyright © 2010 Mosby, Inc. All rights reserved.)

Objective: To evaluate parental stress after a false-positive result at the time of the cystic fibrosis (CF) newborn screening (NBS), attributable to heterozygotism or persistent hypertrypsinemia., Study Design: A prospective study was conducted in 86 French families at 3, 12, and 24 months after NBS. A psychologist conducted interviews with a questionnaire, the Perceived Stress Scale, and the Vulnerable Child Scale., Results: Overall, 96.5% of parents said they had been anxious at the time of the sweat test. However, 86% felt entirely reassured 3 months after the test. The mean Perceived Stress Scale score did not differ from that observed in the French population. Mean Vulnerable Child Scale scores were high, associated with a low Parental Perception of Child Vulnerability. These results did not differ significantly at 1 and 2 years. In total, 86% to 100% of families no longer worried about CF. All parents stated that they would have the test performed again for another child., Conclusions: CF NBS can lead to false-positive results, causing parental anxiety, which quickly decreases after a sweat test performed soon after the phone call.

Objective: To develop reference intervals (RIs) for sweat chloride and sodium in healthy children, adolescents, and adults., Study Design: Healthy, unrelated subjects aged from 5 to >50 years and subjects who were pancreatic insufficient with cystic fibrosis (CF) were recruited. Sweat collection was performed on all subjects with the Wescor Macroduct system. Sweat electrolytes were analyzed with direct ion selective electrodes. DeltaF508 mutation analysis was performed on the healthy subjects >/=15 years old., Results: A total of 282 healthy and 40 subjects with CF were included for analysis. There was no overlap of sweat chloride between the group with CF and the group without CF, but there was some overlap of sweat sodium. Sweat chloride increased with age, with the rate of increase slowing progressively to zero after the age of 19 years. The estimated median (95% RI) for sweat chloride were: 5 to 9 years, 13 mmol/L (1-39 mmol/L); 10 to 14 years, 18mmol/L (3-47 mmol/L); 15 to 19 years, 20 mmol/L (3-51mmol/L); and 20+ years 23 mmol/L (5-56mmol/L)., Conclusions: We have successfully developed the age-related RI for sweat electrolytes, which will be useful for clinicians interpreting sweat test results from children, adolescents, and adults.

The reference ranges for sweat [C1(-)] were reevaluated in 300 infants referred to our Center as carriers of at least 1 cystic fibrosis mutation identified through newborn screening. The recommended borderline range of 30 to 59 mmol/L failed to identify all individuals who were compound heterozygotes. Our data support using a borderline range of 24 to 59 mmol/L.

Newborn screening (NBS) for cystic fibrosis (CF) is increasingly being implemented and is soon likely to be in use throughout the United States, because early detection permits access to specialized medical care and improves outcomes. The diagnosis of CF is not always straightforward, however. The sweat chloride test remains the gold standard for CF diagnosis but does not always give a clear answer. Genotype analysis also does not always provide clarity; more than 1500 mutations have been identified in the CF transmembrane conductance regulator (CFTR) gene, not all of which result in CF. Harmful mutations in the gene can present as a spectrum of pathology ranging from sinusitis in adulthood to severe lung, pancreatic, or liver disease in infancy. Thus, CF identified postnatally must remain a clinical diagnosis. To provide guidance for the diagnosis of both infants with positive NBS results and older patients presenting with an indistinct clinical picture, the Cystic Fibrosis Foundation convened a meeting of experts in the field of CF diagnosis. Their recommendations, presented herein, involve a combination of clinical presentation, laboratory testing, and genetics to confirm a diagnosis of CF.

Objective: To determine whether primary sclerosing cholangitis (PSC) in childhood is associated with abnormalities in cystic fibrosis transmembrane conductance regulator (CFTR)., Study Design: Subjects with PSC diagnosed in childhood (n = 20) were recruited from Children's Hospital. Subjects had testing with sweat chloride concentration, nasal transmembrane potential difference, and extensive genetic analysis of the CFTR gene. Disease control subjects consisted of 14 patients with inflammatory bowel disease alone and no liver disease. t tests were performed to determine statistical significance., Results: In the PSC group, CFTR chloride channel function (deltaChloride free + isoproterenol) was markedly diminished at -8.6 +/- 8.2 mV (reference range: -24.6 +/- 10.4 mV). In contrast, disease control subjects had normal function, at -17.8 +/- 9.7 mV (P = .008). Sweat chloride concentration in subjects with PSC was greater than in disease control subjects (20.8 +/- 3.4 mmol/L vs 12.0 +/- 1.6 mmol/L, P = .045). Comprehensive CFTR genotyping revealed that 5 of 19 (26.3%) subjects with PSC had a CFTR mutation or variant, compared with 6 of 14 (42.9%) disease control subjects., Conclusions: There is a high prevalence of CFTR-mediated ion transport dysfunction in subjects with childhood PSC.

Objectives: To characterize the time course and physiologic significance of decline in serum immunoreactive trypsinogen (IRT) levels in infants with cystic fibrosis (CF) by mode of diagnosis and genotype, and to examine IRT heritability., Study Design: We studied longitudinal IRT measurements in 317 children with CF. We developed statistical models to describe IRT decline. Pancreatic disease severity (Mild or Severe) was assigned using CF genotype and was confirmed in 47 infants through fat malabsorption studies., Results: Infants with severe disease exhibited IRT decline with non-detectable levels typically seen by 5 years of age. Infants with mild disease exhibited a decline in the first 2 years, asymptomatically approaching a level greater than published norms. IRT and fecal fat were inversely correlated. IRT values in infants with meconium ileus (MI) were significantly lower than newborn-screened infants at birth. The high proportion of shared variation in predicted IRT values among sibling pairs with severe disease suggests that IRT is heritable., Conclusions: IRT declines characteristically in infants with CF. Lower IRT values in newborns with MI suggest increased pancreatic injury. Furthermore, IRT is heritable among patients with severe disease suggesting genetic modifiers of early CF pancreatic injury. This study demonstrates heritability of a statistically modeled quantitative phenotype.

Objective: To quantitate the proportion of infants identified through cystic fibrosis (CF) newborn screening (NBS) by an immunoreactive trypsinogen (IRT)/DNA screening algorithm who have an unclear diagnosis as defined by the findings of an elevated IRT level and either 1) 2 CF gene (CFTR) mutations detected and sweat chloride level <60 mEq/L; or 2) 0 or 1 CFTR mutations and a "borderline" sweat chloride level >or=30 and <60 mEq/L., Study Design: Using the 4-year cohort of CF-affected infants recently described by the Massachusetts CF NBS program, we identified and described the number of infants with the diagnostic characteristics (diagnostic dilemmas) aforementioned., Results: Of infants with positive results on CF NBS who had 1 CFTR mutation detected and a borderline sweat chloride concentration, nearly 20% displayed a second CFTR mutation on further evaluation. Of all infants with positive CF NBS results considered affected with CF, 11% had a diagnosis that fell into 1 of the diagnostic dilemma categories aforementioned., Conclusions: Four problematic diagnostic categories generated by CF NBS are defined. In the absence of data on the natural history of such infants, careful follow-up is recommended for infants in whom a definitive diagnosis is elusive.

Objective: To examine immunoreactive trypsinogen (IRT)-based screening for cystic fibrosis (CF) for recall rate, genotype distribution, and "borderline" sweat test results., Study Design: CF newborn screening in Colorado began in 1982, and >1,153,000 infants were screened through 2002 with an IRT-based screen (IRT/IRT)., Results: We have identified 313 infants with CF, giving an overall incidence of 1 in 3684 and a Hispanic incidence of 1 in 6495. Fifty-five infants with meconium ileus (17.6%) were excluded from analysis. Fourteen infants with false-negative results were identified (5.4%). The average recall rate was 0.6%, with a positive predictive value of 4.7%. Ninety-three percent of the infants had at least 1 DeltaF508 mutation, and 98% of the infants had at least 1 mutation from the American College of Medical Genetics recommended panel. Six infants had hypertrypsinogenemia and borderline results on sweat tests (30-60 mmol/L). Increased variability in sweat chloride levels were seen in these infants compared with infants with homozygous DeltaF508. Three children with initial borderline results on sweat tests had CF diagnosed., Conclusions: The recall and false-negative rates of our IRT/IRT CF screening program are reported. Additionally, genotypes of the patients identified mirror the CF population genotypes, reflecting similar disease severity in the screened population. Finally, infants with persistent hypertrypsinogenemia and borderline sweat test results need long-term follow-up.

Objectives: To provide a model of the information processes instigated by a positive result on a newborn screening for cystic fibrosis and to analyze their implications for future research., Method: We reviewed research conducted at Wisconsin and elsewhere., Results: We identified 6 distinct phases of information flow., Conclusion: Although continued attention to genetic counseling is clearly warranted, research on information flow after newborn screening should: 1) look beyond genetic counseling to include a variety of information sources including family, friends, and the Internet; 2) appreciate that families vary in their willingness to acquire cystic fibrosis-related information; and 3) should seek to better understand how this information moves through social networks.

Objective: Describe and define limitations of early pilocarpine iontophoresis (sweat testing) for cystic fibrosis (CF) newborn screening (NBS)., Study Design: Population-based results from follow-up of CF NBS-positive newborns., Results: Insufficient quantity of sweat is more likely if the sweat test is done too early, but testing is generally successful after 2 weeks of age. Sweat chloride levels drop over the first weeks of life. CF carriers have higher sweat chloride concentrations than non-carriers., Conclusions: Sweat testing can be performed effectively after 2 weeks of age for CF NBS-positive newborns. Earlier testing has a higher risk of insufficient sweat for completing testing.

Objective: To describe the development and follow-up confirmatory results of the routine cystic fibrosis (CF) newborn screening (NBS) program in Wisconsin., Methods: CF NBS has been performed on a routine clinical basis in Wisconsin since July 1994. The 2-tiered immunoreactive trypsinogen (IRT)/DNA technique was used on dried blood on filter paper spots. From July 1994 to February 2002, mutation analysis was for the DeltaF508 allele. Beginning in March 2002, multimutation analysis of 25 CF mutations was performed. Infants with a positive result on NBS were seen in certified CF centers for sweat testing by means of quantitative pilocarpine iontophoresis, and families received genetic counseling., Results: From July 1994 to February 2002, there were 120 cases of CF detected by means of NBS (509,794 infants screened), with 53 DeltaF508 homozygotes and 67 compound heterozygotes. There were 8 clinically diagnosed cases of CF (no DeltaF508 allele). The CF incidence was 1:3983 (95%CI, 1:3373-1:4774). From March 2002 to June 2003, multimutation analysis identified 21 cases of classic CF (90,142 infants screened). Sweat tests were successfully performed in infants younger than 1 month., Conclusions: Early diagnosis of CF through NBS was successfully performed, with an estimated sensitivity rate of 99% using the IRT/25 CFTR multimutation assay.

Objectives: To compare the cost of diagnosing cystic fibrosis (CF) through a newborn screening program with the traditional method and to estimate the cost of CF diagnosis if a national newborn screening program is implemented., Study Design: Surveys were conducted to determine the annual number of sweat tests in 1991 and in 2000 after implementation of statewide screening. A national survey of sweat test costs was used to estimate the annual expense for diagnosing CF in the United States through newborn screening., Results: Since the introduction of newborn screening for CF, the numbers of sweat tests ordered annually have decreased from 1670 to 804 (including 134 follow-up tests from screening). The current estimated annual cost of Wisconsin CF newborn screening and diagnosis is $4.58 per newborn infant. The estimated annual cost per newly diagnosed CF infant using the traditional method is $4.97 per newborn infant. If no additional sweat tests were ordered outside of the newborn screening program, the estimated annual cost of a Wisconsin CF newborn screening and diagnosis is $2.66 per newborn and $2.47 per newborn for a national CF newborn screening program., Conclusions: A CF newborn screening program provides a potentially cost-saving alternative to the traditional method of diagnosis of CF.

The diagnosis of cystic fibrosis (CF) is not always certain, despite extensive clinical evaluation, multiple sweat chloride tests, and genotype analysis. We hypothesized that nasal transepithelial potential difference measurements have a useful role in this situation. In 11 patients without an established diagnosis of CF, results of simultaneous nasal potential difference (PD) and sweat chloride measurements were compared with those from control subjects, obligate CF heterozygotes, and patients with a confirmed diagnosis of CF. Two patients conformed to the PD profile for CF patients, whereas nine had values corresponding to those of the healthy control subjects. Subsequently the 5-thymidine (IVS8-5T) CF gene variant was identified in the two patients with abnormal PD measurements.

The diagnostic criteria proposed here are not likely to cover every possible clinical scenario, and there will be clinical dilemmas. For the vast majority of patients with CF, the diagnosis will be suggested by the presence of one or more characteristic clinical features, a history of CF in a sibling, or a positive newborn screening test result and will then be confirmed by laboratory evidence of CFTR dysfunction (Table V). Abnormal CFTR function will usually be documented by two elevated sweat chloride concentrations obtained on separate days or identification of two CF mutations. For patients in whom sweat chloride concentrations are normal or borderline and in whom two CF mutations are not identified, an abnormal nasal PD measurement recorded on 2 separate days can be used as evidence of CFTR dysfunction. Clinical judgment will continue to be essential in patients who have typical or "atypical" clinical features but who lack conclusive evidence of CFTR dysfunction. Such patients will require close clinical follow-up along with laboratory reevaluation as appropriate.

Most pediatricians eventually encounter a patient with a clinical presentation that warrants the consideration of a sweat test to rule out of confirm the diagnosis of cystic fibrosis. This article discusses, in a series of questions and answers, the currently available sweat testing methods and describes the various methods' reliability, limitations, and frequency of use. In addition, sweat testing utilization and the interpretation and evaluation of test results are discussed so that the clinician can critically analyze the laboratory data.

Objective: To compare differences in epithelial chloride conductance according to class of mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene., Methods: We evaluated the relationship between the functional classes of CFTR mutations and chloride conductance using the first diagnostic sweat chloride concentration in a large cystic fibrosis (CF) population., Results: There was no difference in sweat chloride value value between classes of CFTR mutations that produce no protein (class I), fail to reach the apical membrane because of defective processing (class II), or produce protein that fails to respond to cyclic adenosine monophosphate (class III). Those mutations that produce a cyclic adenosine monophosphate-responsive channel with reduced conductance (class IV) were associated with a significantly lower, intermediate sweat chloride value. However, patients with the mutations that cause reduced synthesis or partially defective processing of normal CFTR (class V) had sweat chloride concentrations similar to those in classes I to III., Conclusion: Studies of differences in chloride conductance between functional classes of CFTR mutations provide insight into phenotypic expression of the disease.

Elevated sweat chloride concentration in a patient with Mauriac syndrome has been reported only once. The authors of that report regarded their patient's underlying malnutrition, and not Mauriac syndrome per se, as the cause of the elevated sweat chloride concentration. We describe a second example of transient elevation of sweat chloride concentration, which confirms that the malnutrition intrinsic to Mauriac syndrome, rather than the syndrome itself, was the probable cause of elevated sweat chloride values.

The purposes of this study were to compare sweat tests used in diagnosing cystic fibrosis (CF), as performed with the Macroduct collection system, with those utilizing the more laborious quantitative pilocarpine iontophoresis test (QPIT), and to ascertain the efficacy of the Sweat-Chek conductivity analyzer in eliminating some possibly unnecessary chloride analyses. A Macroduct sweat test was performed on one arm and a QPIT on the other on 1090 patients, 93 of whom had CF. Of these, 514 patients (43 with CF) also had a conductivity determination on the Macroduct sweat sample. All subjects were referred to the laboratory of one of us (K.B.H.) for sweat testing. Of the QPIT samples, 0.7% were inadequate, as were 6.1% of those from the Macroduct system. When sodium and chloride concentrations from the two tests were compared, the standard errors of the estimate were 3.90 and 3.85, respectively. Agreement within 8 mEq/L could then be expected with 95% confidence limits. With use of the Sweat-Chek analyzer, no patient with CF was found to have a conductivity of less than 90 mmol/L, whereas 430 (91%) of the non-CF subjects had a conductivity of less than 50 mmol/L. None of those 430 subjects had a sweat chloride value > 32 mmol/L. We conclude that the Macroduct collection system provides results equally as satisfactory as those provided by the QPIT and that the Sweat-Chek analyzer frequently eliminates the necessity of measuring chloride concentrations.