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Newborn screening for cystic fibrosis (CF-NBS) using an IRT-DNA algorithm with a 12 CFTR-variant panel and an IRT/IRT failsafe was officially implemented in the French-speaking Community of Belgium in January 2020. This screening protocol was evaluated after 4 years according to the criteria defined by the European Cystic Fibrosis Society's working group on neonatal screening. Immunoreactive trypsinogen concentration (IRT) was measured on dried blood spots collected between the second and the fourth day of life. CFTR variants genotyping was initiated when IRT ≥ 99th percentile (P99). If at least 1 variant was identified, the child was referred to a CF center for a sweat test (ST). If IRT ≥ 99.9th percentile with no variant identified, a failsafe was provided with IRT repeated on day 21 and subsequent ST in case of persistent IRT > P99. Extensive Gene Analysis was initiated if sweat chloride level was ≥ 30 mmol/L. Over a period of 4 years, 212.979 newborns were screened. Forty-two were diagnosed with CF: 34 by CF-NBS, 3 following a meconium ileus, 3 by family history and 2 missed cases. Additionally, 112 healthy carriers and 14 CFSPID were identified. The median age at the first consultation was 23 days. The sensitivity of our CF-NBS is 95% (target ≥ 95%), the positive predictive value 18% (target ≥ 30%) and CF/CFSPID ratio 2.8., Conclusion:  Although follow-up is limited, this first evaluation demonstrates encouraging sensitivity and early management before one month of age., What Is Known: • Newborn screening for cystic fibrosis improves the prognosis of patients., What Is New: • This article presents an initial assessment of our screening after 4 years., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: New York (NY) State implemented a new cystic fibrosis (CF) newborn screen (NBS) algorithm in December 2017 with improvement in positive predictive value and unanticipated increased identification of infants with cystic fibrosis transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS). Repeat sweat testing is recommended in infants with CRMS. During the COVID-19 pandemic infants with CRMS were lost to follow up. With this quality improvement (QI) initiative, we aimed to perform repeat sweat testing in 25% of infants lost to follow up. We also describe consensus recommendations for CRMS from the NY CF NBS Consortium., Methods: Our QI team identified the primary drivers contributing to absent follow up, outreached to families, and created a questionnaire to evaluate parental understanding of CRMS using QI-based strategies., Results: Of 350 infants diagnosed with CRMS during the study period, 179 (51.1%) infants were lost to follow up. A total of 31 (17.3%) were scheduled for repeat sweat tests and followed up at CF Centers. Families reported high satisfaction with the CRMS knowledge questionnaire., Conclusions: With this QI-based approach, we effectively recaptured infants with CRMS previously lost to follow up during the COVID-19 pandemic. Ongoing concerns about infection risk and lack of understanding on the part of families and pediatricians likely contributed to patients with CRMS lost to follow up. Consensus recommendations for CRMS include annual visits with repeat sweat testing until 2-6 years of age and education for adolescents about clinical and reproductive implications of CRMS., (© 2024 Wiley Periodicals LLC.)

Since screening for cystic fibrosis (CF) was incorporated into the newborn screening program, the number of recognised variants in the CF transmembrane conductance regulator (CFTR ) gene has significantly increased. This has led to the discovery of combinations of gene variants with an uncertain prognosis. One outcome is the designation of 'cystic fibrosis screen positive inconclusive diagnosis' (CFSPID). While the majority of these children are expected to be unaffected by their CFTR variants, a small proportion have been seen to develop symptoms or increasing sweat chloride levels over time, which may reflect dysfunction of the CFTR protein.As the number of children with CFSPID increases, paediatricians and those working in primary care are more likely to encounter them in their practice. It is important that professionals have an understanding of CFSPID: what it is and, importantly, what it is not (ie, they do not have CF). In this article, we hope to explore this using some example cases, illustrating the ways in which these children may present symptomatically and how to manage them., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Wales has an immunoreactive trypsin (IRT)-DNA cystic fibrosis (CF) newborn screening (NBS) programme. Most CF NBS false negative cases are due to an IRT concentration below the screening threshold. The accuracy of IRT results is dependent on the quality of the dried bloodspot (DBS) sample. The aim of this study was to determine the cause of false negative cases in CF NBS and their relationship to DBS quality., Design: Longitudinal birth cohort., Setting: Wales 1996-2016., Patients: Children with CF., Interventions: Identification of all CF patients with triangulation of multiple data sources to detect false negative cases., Main Outcome Measures: False negative cases., Results: Over 20 years, 673 952 infants were screened and 239 were diagnosed with CF (incidence 1:2819). The sensitivity of the programme was 0.958, and positive predictive value was 0.476. Eighteen potential false negatives were identified, of whom eight were excluded: four screened outside Wales, two had complex comorbidities, no identified cystic fibrosis transmembrane conductance regulator (CFTR) variants on extended analysis and thus not considered to have CF and two were diagnosed after their 16th birthday. Of the 10 false negatives, 9 had a low DBS IRT and at least one common CFTR variant and thus should have received a sweat test under the programme. DBS cards were available for inspection for five of the nine false negative cases-all were classified as small/insufficient or poor quality., Conclusions: The majority of false negatives had a low bloodspot IRT, and this was associated with poor quality DBS. The optimal means to improve the sensitivity of our CF NBS programme would be to improve DBS sample quality., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To characterize the phenotypic expression of children with conductance regulator-related metabolic syndrome (CRMS)/cystic fibrosis screen positive inconclusive diagnosis (CFSPID) designation after positive newborn screening, reassign labeling if applicable and better define these children's prognosis., Methods: A multicenter cohort with CRMS/CFSPID designation was matched with cystic fibrosis (CF)-diagnosed cohort. Cohorts were prospectively compared on baseline characteristics, cumulative data and when they reached 6 to 7 years at endpoint assessment., Results: Compared to infants with CF (n = 63), the CRMS/CFSPID cohort (n = 63) had initially lower immunoreactive trypsinogen (IRT) and sweat chloride (SC) values, delayed visits, less symptoms, and better nutritional status; during follow-up, they had fewer hospitalizations, Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus identification, CF comorbidities, and treatment burden. At endpoint assessment, they presented a milder pulmonary phenotype on Brody computed tomography scores (0.0[0.0; 2.0] vs 13[2.0; 31.0]; P < .0001, respectively), Wisconsin and Brasfield chest radiograph scores, pulmonary function tests, and improved nutritional status. Among the inconclusive CF diagnosis cohort, 28 cases (44%) converted to CF diagnosis based on genotype (44%), SC (28%) or both (28%); yet, comparing those with or without final CF diagnosis, we found no differences, possibly related to their young age and mild degree of lung disease. In the total cohort, we found significant associations between Brody scores and IRT, SC values, genotype, Wisconsin and Brasfield score and spirometry., Conclusions: The matched CRMS/CFSPID and CF cohorts showed differences in outcomes. By a mean age of 7.6 years, a high proportion of the CRMS/CFSPID cohort converted to CF. Our results highlight that monitoring at CF clinics until at least 6 years is needed as well as further studies., (© 2020 Wiley Periodicals, Inc.)

Newborn screening (NBS) for cystic fibrosis (CF) was implemented throughout France since 2002, with a 3-tiered strategy consisting in an immunoreactive trypsinogen (IRT) measurement at day-3, a search for the most common mutations responsible for CF when the IRT value is above the cut-off level, and, if necessary, a safetynet retesting of IRT at day-21. Coordination and follow-up are ensured at the national level and NBS is carried out through a regional organization involving NBS centers, biochemical and molecular genetics laboratories. Sweat testing and comprehensive mutation gene analysis are then performed according to a defined algorithm. Between 2002 and 2014, screening for the 30 most common mutations identified 87% of the alleles and comprehensive mutation gene analysis performed when applicable identified more than 300 additional mutations and resulted in a detection rate of 99.8% of the mutated alleles. Program surveillance ensured at a national level allowed to carry out adaptation of cut-off levels and removal of the p.Arg117His mutation. Thanks to these modifications, the performance of the French NBS program for CF meets the European guideline standards regarding positive predictive values, sensitivity and time to initial visit at the CF center, thus making the strategy effective. © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved., (© 2020 Elsevier Masson SAS. Tous droits réservés.)

Competing Interests: Competing interests: None declared.

Newborn screening for cystic fibrosis (CF) has become a widely accepted and endorsed public health strategy in economically developed countries, although there is little consensus on optimal screening methods and gene panels. Increasing understanding of CFTR genetics and consequent unpredictability of phenotypic and clinical outcomes lead to diagnostic uncertainty, and emergence of Cystic Fibrosis Screen Positive Inconclusive Diagnosis (CF-SPID). Many of these children are clinically well or have a mild phenotype yet may still experience the psychosocial impact of a CF diagnosis. This questions the role of newborn screening and how best to manage those it identifies with CF-SPID., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Cystic fibrosis (CF) is an autosomal recessive genetic disorder resulting from a mutation in the gene which encodes a cellular transmembrane protein channel known as the CF transmembrane conductance regulator. Located systemically on the surface of numerous cells, these altered channels yield multisystem dysfunction. Typical manifestations seen are chronic, progressive, obstructive lung disease, pancreatic insufficiency, CF-related diabetes mellitus, malabsorption and malnutrition, liver disease, and infertility.Once considered a pediatric disorder, through developments in innovative care and therapeutic modalities, CF now spans the life continuum and has established itself as an ageless disease. Facing management of maturing-life issues, advanced practice nurses (APNs) in pediatrics now find themselves needing to collaborate with or facilitate transition of care to other APNs, such as nurse midwives and adult APNs, as well as their counterpart specialists in medicine, all while maintaining open communication with the patient, family and managing CF center., (Copyright © 2018 National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved.)

Objectives: In the national newborn screening programme for CF in Switzerland, we compared the performance of two sweat test methods, by investigating the feasibility and diagnostic performance of the Macroduct ® collection method (with chloride mesurement) and Nanoduct ® test (measuring conductivity) for diagnosing CF., Study-Design: We included all newborns with a positive screening result between 2011 and 2015 who were referred to a CF-centre for sweat testing. In the CF-centre, a Macroduct and Nanoduct sweat test were performed simultaneously. If sweat test results were positive or borderline, a DNA analysis was performed. Final diagnosis was based on genetic mutations., Results: Over 5 years, 445 children were screened positive and in 413 (114 with CF) at least one sweat test was performed (median age at first test, 22 days); both tests were performed in 371 children. A sweat test result was more often available with the Nanoduct compared to the Macroduct (79 vs 60%, P < 0.001). The Nanoduct was equally sensitive as the Macroduct in identifying newborns with CF (sensitivity 98 vs 99%) but less specific (specificity 79 vs 93%; P-value comparing ROC curves = 0.033)., Conclusions: This national multicentre study revealed high failure rates for Macroduct and Nanoduct in newborns in real life practice. While this needs to be addressed, our results suggested that performing the Nanoduct in addition to the Macroduct might speed up the diagnostic process because it more often yields valid results with comparable diagnostic performance. The addition of the Nanoduct sweat test can therefore help to reduce the stressful time of uncertainty for parents and to start appropriate treatment earlier., (© 2019 Wiley Periodicals, Inc.)

Expanded newborn screening of inborn errors of metabolism (IEM) based on tandem mass spectrometry (MS/MS) technology is one of the most successful preventative healthcare initiatives for presymptomatic diagnosis and treatment of rare yet treatable genetic diseases in the population. However, confirmatory testing of presumptive screen-positive cases is required using high efficiency separations for improved specificity in order to improve the positive predictive value (PPV) for certain classes of IEMs. Here, we describe recent advances using capillary electrophoresis-mass spectrometry (CE-MS) for reliable second-tier screening or confirmatory testing based on targeted analysis of amino acids, acylcarnitines, nucleosides, and other classes of polar metabolites associated with IEMs. Additionally, nontargeted metabolite profiling enables the identification of unknown biomarkers of clinical significance for other genetic diseases that are currently screened by bioassays and/or mutation panels, such as cystic fibrosis (CF). Noteworthy, CE-MS allows for resolution of isobaric/isomeric interferences without complicated sample handling that is ideal when analyzing volume-restricted biospecimens from neonates/infants, including dried blood spots and sweat specimens. New developments to improve concentration sensitivity, as well as enhance sample throughput and quality control for unambiguous confirmatory testing of IEMs will also be discussed when using multiplexed separations based on multisegment injection-CE-MS.

Newborn babies positively screened for cystic fibrosis (CF) (high serum immunoreactive trypsin (IRT) with DNA analysis) are referred for a diagnostic sweat test, which may be normal (sweat chloride <30 mmol/L). Unless two gene mutations are identified during Newborn screening (NBS), the babies are discharged from follow-up. We wished to check that none had subsequently developed symptoms suggestive of CF. We retrospectively reviewed patient notes and contacted general practitioners of all babies with a negative sweat test, conducted in one of the four paediatric specialist CF centres in London, over the first 6 years of screening in South East England.Of 511 babies referred, 95 (19%) had a normal sweat test. Five (5%) had CF diagnosed genetically, two of them on extended genome sequencing after clinical suspicion. Eleven (12%) were designated as CF screen positive inconclusive diagnosis (CFSPID); one of the five CF children was originally designated as CFSPID. Seventy-nine (83%) were assumed to be false-positive cases and discharged; follow-up data were available for 51/79 (65%); 32/51 (63%) had no health issues, 19/51 (37%) had other significant non-CF pathology.These results are reassuring in that within the limitations of those lost to follow-up, CF symptoms have not emerged in the discharged children. The high non-CF morbidity in these children may relate to known causes of high IRT at birth. Clinicians need to be aware that a child can have CF despite a normal sweat test following NBS, and if symptoms suggest the diagnosis, further testing, including extended genome sequencing, is required., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Significant gaps have been identified in parental understanding of CF newborn screening and the consequences of carrying an altered CF gene. Seven potential causes of psychosocial adversity arising from false positive newborn screening for CF have been identified. The current study aimed to increase parents understanding of CF, reduce their levels of stress, and investigate psychosocial adversity arising from false-positive screening. This national study was run over one year in the Republic of Ireland. Parents were recruited for the study following a diagnostic sweat test confirming their child carried a single altered CF gene. Parents were randomly assigned into a control and intervention group, with those in the intervention group receiving a carefully designed information pack. All parents took part in semi-structured interviews. Parents (n = 16) who received an information pack had significantly higher CF knowledge scores than parents (n = 16) in the control group. 66% of parents in the control group misunderstood the health implications of carrying an altered CF gene, no parents in the intervention group had the same misunderstanding. There was no significant difference in stress scores between the groups. Parents of infants who had more than one sweat test due to insufficient sweat quantity had higher overall stress percentiles (50%), than parents of infants who had one sweat test (30%), indicating greater parental stress. The combination of written and audio-visual information contained in the information pack successfully increased parents comprehension of CF. The study also evaluates the potential for psychosocial adversity following false positive newborn screening for CF.

Objectives To evaluate the French cystic fibrosis newborn screening algorithm, based on data tracked by a centralized monitoring process, from 2002 to 2014. The programme aimed to attain European Standards in terms of positive predictive value, sensitivity, the ratio of screen positive patients diagnosed with cystic fibrosis to infants who screen positive but with inconclusive diagnosis (CFSPID), and time to diagnosis. Methods Retrospective analysis of programme performance, compliance with the algorithm, and changes in screening strategy. Results Modifications in the flow chart protocol improved the positive predictive value to 0.31 while maintaining the sensitivity at 0.95. Among infants diagnosed with cystic fibrosis, or identified as CFSPID, sweat test results were obtained for 94%, and two mutations were identified after exhaustive screening for the gene, when applicable, in 99.6%. The rate of pending diagnosis was very low (0.5%). The ratio of infants with cystic fibrosis:CFSPID was 6.3:1. Age at initial visit at the CF centre was ≤ 35 days, respectively, in 53%/26%. Conclusion Performances were in agreement with European standards, but timeliness of initial visit needed improvement. Our data complement an accumulating body of evidence demonstrating that attention must be paid to such ethical considerations as limiting carrier detection and inconclusive diagnosis. Newborn screening programmes should have a rigorous centralized monitoring process to warrant adjustments for improving performance to attain consensus guidelines.

Neonatal screening for cystic fibrosis (CF) may detect infants with elevated immunoreactive trypsinogen (IRT) levels but with inconclusive sweat tests and/or DNA results. This includes cases associating (1) either the presence of at most one CF-causing mutation and sweat chloride values between 30 and 59mmol/L or (2) two CFTR mutations with at least one of unknown pathogenicity and a sweat chloride below 60mmol/L. This encompasses different clinical situations whose progression cannot be predicted. These cases require redoing the sweat test at 12 months and if possible at 6 and 24 months of life. This must be associated with extended genotyping. CFTR functional explorations can also help by investigating CFTR dysfunction. These infants must be initially evaluated in dedicated CF centers including bacteriological sputum analysis, chest radiology and fecal elastase dosage. A home practitioner must be informed of the specificity of follow-up. These infants will be reviewed in the CF center at 3, 6 and 12 months and every year. Any CF-related symptom requires reevaluation of the diagnosis. These guidelines were established by the "neonatal screening and difficult diagnoses" working group of the French CF Society. They aim to standardize management of infants with unclear diagnosis in French CF centers., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Clinical heterogeneity in cystic fibrosis (CF) often causes diagnostic uncertainty in infants without symptoms and in older patients with milder phenotypes. We performed a cross-sectional evaluation of a comprehensive set of clinical and laboratory descriptors in a physician-defined cohort (N = 376; Children's Hospital of Wisconsin and the American Family Children's Hospital CF centers in Milwaukee and Madison, WI, USA) to determine the robustness of categorizing CF (N = 300), cystic fibrosis transmembrane conductance regulator (CFTR)-related disorder (N = 19), and CFTR-related (CRMS) metabolic syndrome (N = 57) according to current consensus guidelines. Outcome measures included patient demographics, clinical measures, sweat chloride levels, CFTR genotype, age at diagnosis, airway microbiology, pancreatic function, infection, and nutritional status. The CF cohort had a significantly higher median sweat chloride level (105 mmol/l) than CFTR-related disorder patients (43 mmol/l) and CFTR-related metabolic syndrome patients (35 mmol/l; p ≤ 0.001). Patient groups significantly differed in pancreatic sufficiency, immunoreactive trypsinogen levels, sweat chloride values, genotype, and positive Pseudomonas aeruginosa cultures (p ≤ 0.001). An automated classification algorithm using recursive partitioning demonstrated concordance between physician diagnoses and consensus guidelines. Our analysis suggests that integrating clinical information with sweat chloride levels, CFTR genotype, and pancreatic sufficiency provides a context for continued longitudinal monitoring of patients for personalized and effective treatment., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The influence of the generalization of cystic fibrosis newborn screening (CFNBS) in France on sweat test (ST) prescription is unknown. In this French retrospective, descriptive, and multicenter study, we studied the indications, number, methods, and results of STs prescribed by a pediatric pulmonologist in children who had a negative CFNBS and an ST for respiratory symptoms in 2012. We included 502 children with 523 STs, performed with four different methods. The main indication was asthma (71.3 %), then chronic cough (52.4 %), atypical lower airway infections (42.2 %), and bronchiectasis (7 %). Four children had a diagnosis of CF (0.8 %), all presenting with chronic productive cough and recurrent respiratory infections., Conclusion: Asthma is the most frequent indication of ST in our cohort. Because of the systematic CFNBS in France, some prescriptions should be avoided, particularly in case of severe or moderate asthma with no other associated symptom. Moreover, methods of STs often do not follow the guidelines and need standardization., What Is Known: • Newborn screening (NBS) has become the most frequent circumstance of the diagnosis of cystic fibrosis (CF) in France after its generalization. • The prescription of sweat test (ST) in children with respiratory symptoms who already had a negative NBS has not been studied., What Is New: • In children with a negative CF NBS referred to a university hospital for respiratory diseases, despite important variations of ST methods, only 4 children among 502 have been diagnosed as CF. • Despite recommendations, ST prescription should be avoided in children with moderate to severe asthma and no other associated symptom.

Unlabelled: After a positive newborn screening test for cystic fibrosis (CF), a sweat test is performed to confirm the diagnosis. The success rate of the generally acknowledged methods (Macroduct/Gibson and Cooke) in newborns varies between 73 and 99%. The Nanoduct sweat test system is easier to perform and less sweat is needed. The main aim of this study was to measure the success rate of the Nanoduct compared to current approved sweat test methods in a newborn population. After informed consent of the parents, newborns with a positive screening test for CF were included. The Macroduct or Gibson and Cooke and Nanoduct were performed in all infants, during the same appointment. The chloride concentration was determined by standard coulorimetry; conductivity was measured directly and converted to a NaCl molarity. One hundred eight newborns were included: 17 with CF, 7 with cystic fibrosis transmembrane regulator (CFTR)-related metabolic syndrome (CRMS), and 84 healthy children. The success rate of the Nanoduct was 93% and for the Macroduct/Gibson and Cooke 79% (McNemar, p = 0.002). The Nanoduct detected the same CF patients as the Macroduct/Gibson and Cooke; one CF patient had an equivocal result for both tests, and no patients were missed. The area under the receiver operating characteristic curve for detection of CF with the Nanoduct was 0.999, with ideal cutoff levels of 91 and 66 mmol/l, comparable to former studies., Conclusion: The success rate of the Nanoduct to collect sufficient sweat in infants was higher compared to the Macroduct and Gibson and Cooke.

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.)

Aim: This study developed a clinical decision rule (CDR) to rule in or rule out cystic fibrosis (CF) in the first weeks of life., Methods: We combined a two-step nonconcurrent birth cohort and a cross-sectional controlled study in which observers and mothers were blinded to confirmatory sweat test results. Neonates from uncomplicated pregnancies and deliveries, with two subsequent tests for immunoreactive trypsinogen (IRT) higher than 70 ng/mL, were eligible to take part., Results: We included 49 CF-affected and 177 CF-unaffected infants with an average age of 34 days. CF-affected infants demonstrated statistically significant differences in weight gain, stool frequency and salty tasting skin from birth. Multivariate analysis showed that the main predictors of CF were salty tasting skin (odds ratio 17.2) and weight gain of <10.5 g per day (odds ratio 4.6). Depending on the CDR score, we obtained the following results: sensitivity (42.9-61.2%), specificity (89.6-96.5%), positive (62.5-77.8%) and negative (85.6-89.1%) predictive value and positive (5.8-12.3) and negative (0.4-0.6) likelihood ratio., Conclusion: The CDR could provide a reliable index of clinical suspicion and timely referral for sweat testing in settings without newborn screening programmes and may also be applied to false-negative individuals where such programmes already exist., (©2015 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Introduction: Neonatal cystic fibrosis screening contributes to an early diagnosis of cystic fibrosis and to implementing appropriate therapeutic management. Long-standing screening tests have made it possible to identify a group of newborns in whom the diagnosis was ambiguous and required further specialised tests., Aim: The aim is to present cases of patients with a positive result of newborn screening for cystic fibrosis who were found to be carriers of the mutation in both alleles, however the lack of clinical symptoms and correct sweat testing values did not lead doctors to diagnosing cystic fibrosis and by the same token implementing the treatment., Material and Methods: The analysis encompassed a group of 22 infants and children 3 months to 3 years of age, in whom, in spite of a positive result of newborn screening for cystic fibrosis and the presence of 2 mutations in the CFTR gene, the diagnosis of cystic fibrosis was not made, and appropriate treatment was not administered because of diagnostic doubts (due to correct concentration of chlorides in sweat, correct IRT level and lack of clinical signs of cystic fibrosis). The control group consisted of 55 children treated in our centre, in whom neonatal screening for cystic fibrosis was positive and the diagnosis was confirmed by genetic testing, sweat chloride testing and IRT concentration., Results: There were no differences in birth body weight between the groups. The differences in chlorideion levels in sweat secretion tests and mean IRT values were statistically significant and were: 97.5 for the control group and 26.4 for the test group. At the present time there are no clinical symptoms to give a diagnosis of cystic fibrosis and start treatment in the test group., Conclusions: Newborn screening contributes not only to an early diagnosis of cystic fibrosis but also to CFTR-related metabolic syndromes (CRMS), which is a phenomenon requiring further observation. This fact constitutes a definite psychological problem for the parents of these patients. .

Newly implemented newborn screening (NBS) programs in California have resulted in a large subset of patients in whom at least two cystic fibrosis transmembrane conductance regulator (CFTR) mutations are identified, but subsequent sweat chloride analysis reveals normal or indeterminate values. These patients are diagnosed with CFTR-Related Metabolic Syndrome (CRMS). However, the natural progression and management of these patients are not clearly understood and frequently after the age of 1-year these patients are lost to follow-up with Cystic Fibrosis (CF) Centers. We present the first case of an infant who was referred to Miller Children's Hospital for a NBS positive for CF and subsequent discovery of identical mutations in six of his seven older brothers. Several siblings had positive sweat chloride results on repeat testing after the age of 3 years. We suggest the need for continued follow-up of CRMS in a CF center with diagnostic evaluation including repeat sweat chloride testing, beyond the currently recommended period., (© 2013 Wiley Periodicals, Inc.)

Background: Switzerland introduced newborn screening (NBS) for CF in 2011, using an IRT/DNA/IRT protocol. This paper describes the results of the first year and compares two versions of the protocol with different IRT cut-offs, particularly effects on recall rate, sensitivity and specificity., Methods: IRT cut-offs were >45 ng/ml (99.0th percentile) in period 1 (months 1-4) and >50 ng/ml (99.2nd percentile) in period 2 (months 5-12). In period 2 we abstained from recalls when none of the 7 most common CF mutations were detected and IRT was <60 ng/ml., Results: In periods 1 and 2, 26,535 and 56,663 tests were performed. Recall rates were 0.94% and 0.48%, respectively (p<0.001), PPV increased from 23% to 47% (p=0.024) and sensitivity was 90% and 100%., Conclusions: Raising initial IRT cut-off from the 99.0th to the 99.2nd percentile and abstaining from recalls for children with an IRT<60 ng/ml and carrying no major CFTR mutation significantly reduced the recall rate without affecting sensitivity., (Copyright © 2013 European Cystic Fibrosis Society. Published by Elsevier B.V. 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.)

Unlabelled: Cystic fibrosis (CF) is a life-threatening disease for which early diagnosis following newborn screening (NBS) improves the prognosis. We performed a prospective assessment of the immunoreactive trypsinogen (IRT)/DNA/IRT protocol currently in use nationwide, versus the IRT/pancreatitis-associated protein (PAP) and IRT/PAP/DNA CF NBS protocols. Dried blood spots (DBS) from 106,522 Czech newborns were examined for IRT concentrations. In the IRT/DNA/IRT protocol, DNA-testing was performed for IRT ≥ 65 ng/mL. Newborns with IRT ≥ 200 ng/mL and no detected cystic fibrosis transmembrane conductance regulator gene (CFTR) mutations were recalled for a repeat IRT. In the same group of newborns, for both parallel protocols, PAP was measured in DBS with IRT ≥ 50 ng/mL. In PAP-positive newborns (i.e., ≥1.8 if IRT 50-99.9 or ≥1.0 if IRT ≥ 100, all in ng/mL), DNA-testing followed as part of the IRT/PAP/DNA protocol. Newborns with at least one CFTR mutation in the IRT/DNA/IRT and IRT/PAP/DNA protocols; a positive PAP in IRT/PAP; or a high repeat IRT in IRT/DNA/IRT were referred for sweat testing., Conclusion: the combined results of the utilized protocols led to the detection of 21 CF patients, 19 of which were identified using the IRT/DNA/IRT protocol, 16 using IRT/PAP, and 15 using IRT/PAP/DNA. Decreased cut-offs for PAP within the IRT/PAP protocol would lead to higher sensitivity but would increase false positives. Within the IRT/PAP/DNA protocol, decreased PAP cut-offs would result in high sensitivity, an acceptable number of false positives, and would reduce the number of DNA analyses. Thus, we concluded that the IRT/PAP/DNA protocol would represent the most suitable protocol in our conditions.

When new technical possibilities arise in health care, often attunement is needed between different actors from the perspectives of research, health care providers, patients, ethics and policy. For cystic fibrosis (CF) such a process of attunement in the Netherlands started in a committee of the Health Council on neonatal screening in 2005. In the balancing of pros and cons according to Wilson and Jungner criteria, the advantages for the CF patient were considered clear, even though CF remains a severe health problem with treatment. Nevertheless, screening was not started then, mainly since the specificity of the tests available at that time was considered too low. Many healthy infants would have been referred for sweat testing and much uncertainty would arise in their parents. Also the limited sensitivity for immigrants and the detection of less severe phenotypes and carriers were considered problematic. The Health Council recommended a pilot screening project which was subsequently performed in some provinces, leading to a 4-step protocol: IRT, PAP, screening for a CFTR mutation panel, and sequencing of the CFTR gene. This would lead to the identification of 23 cases of classical CF, two infants with less severe forms and 12 carriers per year in the Netherlands. Thus many CF patients can be diagnosed early, while limiting the number of referrals, the number of infants with less severe forms diagnosed and the number of carriers identified. Technical solutions were found to limit the ethical problems. A nationwide program using this four step protocol started by 1 May 2011.

Purpose of Review: Newborn screening for cystic fibrosis (CF) is now universal in the US and many other countries. The rapid expansion of screening has resulted in numerous publications identifying new challenges for healthcare providers. This review provides an overview of these publications and includes ideas on managing these challenges., Recent Findings: Most CF newborn screening algorithms involve DNA mutation analysis. As screening has expanded, new challenges have been identified related to carrier detection and inconclusive diagnoses. Early descriptions of infants with CF-related metabolic syndrome (CRMS) indicate that the natural history of this condition cannot be predicted. Early identification has also provided an opportunity to better understand the pathophysiology of CF. However, few studies have been conducted in infants with CF to determine optimal therapy and recommendations are largely anecdotal., Summary: Newborn screening provides an opportunity to identify and begin treatment early in individuals with CF. Whereas a single, optimal approach to screening does not exist, all programs can benefit from new findings regarding sweat testing, carrier detection, early pathophysiology, and clinical outcomes.

We examined the relation between the number of (TG) repeats at the (IVS8)-(TG)m(T)5 locus of the CFTR gene with neonatal serum immunoreactive trypsinogen (IRT) and sweat chloride (SC) concentrations in hypertrypsinogenemic infants with genotype ΔF508-9T/5T identified by California cystic fibrosis newborn screening. SC and IRT distributions increased with increasing (TG) repeats., (Copyright © 2011 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

With newborn screening for cystic fibrosis (CF) now accessible in every state in the US, more infants are being diagnosed. Currently, no large-scale randomized studies are available to assist clinicians in providing evidence-based medical care for the youngest CF patients. We review the standard of diagnostic evaluation, the sweat test, showing a slightly altered range for infants less than 6 months of age. Cystic fibrosis transmembrane conductance regulator (CFTR) metabolic syndrome is an entity that can be clinically challenging for parents and caregivers. Simply indentifying infants with CF can be challenging. This review tries to clarify the CFTR gene and its expressions and the additional benefits that may be drawn from newborn screening. We searched literature to review guidelines for care of infants with CF, and we reviewed newborn screening methods and diagnosis. We focused on early nutritional intervention and lung protective strategies to improve growth and lung function outcomes.

Background: Newborn screening (NBS) for CF has become widespread, although there are multiple strategies. Little is known about outcomes such as age of diagnosis after different NBS methods., Methods: We used the U.S. Cystic Fibrosis Foundation Patient Registry to identify infants with CF born between 2001 and 2008 in states that utilized NBS. We compared ages at diagnosis, genotyping, sweat test, and first visit to a CF Centre between states that used serial immunoreactive trypsinogen (IRT/IRT) levels and states that used IRT and DNA analysis (IRT/DNA)., Results: We identified 1288 infants with CF. Compared to infants born in IRT/IRT states, infants born in IRT/DNA states were younger at the time of diagnosis (median 2.3 weeks versus 4.0 weeks in IRT/IRT states, p<0.001), genotyping (0.7 weeks versus 5.3 weeks, p<0.001), and initial CF Centre visit (5.9 weeks versus 7.7 weeks, p=0.008)., Conclusions: Although there is room to improve outcomes with both strategies, infants born in IRT/DNA states have treatment initiated at a younger age than infants born in IRT/IRT states., (Copyright © 2011 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Objective: To compare three cystic fibrosis (CF) newborn screening strategies used in Victoria since 1989., Design, Setting and Participants: Retrospective review of newborn screening and clinical records for people with CF born in Victoria between 1989 and 2008 to compare screening strategies: repeat immunoreactive trypsinogen (IRT) testing (IRT/IRT, 1989-1990), IRT and p.F508del mutation analysis (IRT/p.F508del, 1991-2006) and IRT with analysis of 12 CFTR mutations (IRT/12 mutations, 2007-2008)., Main Outcome Measures: Total number of infants screened, people identified with CF (by screening or clinical diagnosis), number of CF-affected terminations of pregnancy, and number of carriers detected., Results: There were 420 people born with CF (live-birth prevalence, 1/3139; 95% CI, 1/2853-1/3462) and 78 CF-affected pregnancy terminations (overall prevalence, 1/2647; 95% CI, 1/2425-1/2896). Of the babies born with CF, 283 (67.4%) were detected by newborn screening alone, 61 (14.5%) had meconium ileus, 33 (7.9%) had a family history of CF, nine (2.1%) were diagnosed antenatally, and 34 (8.1%) were missed by screening (17 missed because IRT level was < 99th percentile, two with repeat IRT level not elevated, 14 without a screened CFTR mutation, and one with missing data). The sensitivities of the protocols were 86.6% for IRT/IRT, 89.9% for IRT/p.F508del, and 95.8% for IRT/12 mutations. Including 12 mutations in the analysis detected one patient who would otherwise have been missed and, had this protocol been implemented from 1989, it would have detected four others., Conclusion: Most babies with CF without meconium ileus, a family history or antenatal diagnosis are detected by newborn screening. Despite improved sensitivity with the 12-mutation analysis, most infants detected would have been diagnosed using the IRT/p.F508del protocol.

Newborn screening is a public health policy program involving the centralized testing laboratory, infant and their family, primary care provider, and subspecialist for confirmatory testing and follow-up of abnormal results. Cystic fibrosis (CF) newborn screening has now been enacted in all 50 states and the District of Columbia and throughout many countries in the world. Although CF neonatal screening will identify the vast majority of infants with CF, there are many factors in the newborn screening system that can lead to a missed diagnosis of CF. To inform clinicians, this article summarizes the CF newborn screening system and highlights 14 factors that can account for a missed diagnosis of CF. Care providers should maintain a high suspicion for CF if there are compatible symptoms, regardless of the results of the newborn screening test. These factors in newborn screening programs leading to a missed diagnosis of CF present opportunities for quality improvement in specimen collection, laboratory analysis of immunoreactive tryspinogen (IRT) and CF mutation testing, communication, and sweat testing., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: Newborn screening for cystic fibrosis (CF) in Illinois uses an immunoreactive trypsinogen/DNA methodology; most false-positive results identify unaffected carriers., Methods: Parents whose child received a negative result from the sweat test after a positive newborn screening for CF were surveyed ≥ 6 weeks later by telephone. All parents received genetic counseling while waiting for the sweat-test results., Results: A total of 90 parents participated. Overall knowledge of CF was high (78%), but the ability to understand the CF screening results was mixed. Although 94% of the parents understood that their child did not have CF, only 79% (62 of 78) of participants whose child had a mutation knew their child was definitely a carrier, and only 1 of 12 parents whose child had no mutation understood that the child may be a carrier. Respondents stated that most relatives were not interested in genetic testing. Both parents had been tested in only 13 couples. Fewer than half (36 of 77 [47%]) of the untested couples expressed interest in genetic testing. Although most participants were satisfied with the process, parents expressed frustration because of the lack of prospective newborn screening discussions by prenatal and pediatric providers and lack of knowledge and sensitivity by those who initially notified them of the abnormal newborn screening results. Speaking to a genetic counselor when scheduling the sweat test decreased anxiety for many parents (53 of 73 [73%] were "very worried" at notification versus 18 of 73 [25%] after scheduling; P < .001)., Conclusions: Parental knowledge about CF is high, but confusion about the child's carrier status and the concept of residual risk persist despite genetic counseling. Relatives express low interest in carrier testing.

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.)

Purpose of Review: There has been a rise in the introduction of cystic fibrosis (CF) newborn screening (NBS) programs in recent years. Despite many long running and successful programs with established protocols, new strategies are being developed in an effort to improve sensitivity and specificity. In light of the emerging issues of NBS, new algorithms have been implemented and are reviewed here., Recent Findings: The increase in mixing of populations affects both immunoreactive trypsinogen values and sensitivity of genetic analysis in NBS. Adjustments to the mutation panel are not always possible. Algorithms adding nongenetic tiers may prove to be an alternative. The interpretation of the sweat test in neonates has been changing too, and there is now agreement that the upper limit of a normal sweat chloride is 29 mmol/l. Infants identified by NBS with a sweat chloride of 30-59 mmol/l and no evidence of two CF-causing mutations require further evaluation and often a long clinical follow-up before CF may be confirmed or excluded. Some NBS programs have reported a steady reduction in the incidence of CF, traceable to prenatal diagnosis on subsequent pregnancies and population-based carrier screening., Summary: Although there is not one universal CF NBS protocol that will suit the heterogeneous needs of diverse regions, many options for adjusting algorithms to local conditions are now available.

Newborn screening (NBS) for cystic fibrosis (CF) offers the opportunity for early diagnosis and improved outcomes in patients with CF and has been universally available in the state of Massachusetts since 1999 using an immunoreactive trypsinogen (IRT)-DNA algorithm. Ideally, CF NBS is incorporated as part of an integrated NBS system that allows for comprehensive and coordinated education, laboratory screening, clinical follow-up, and evaluation so that evidence-based data can be used to maximize quality improvements and optimize the screening algorithm. The New England Newborn Screening Program (NENSP) retrospectively analyzed Massachusetts's CF newborn screening data that yielded decisions to eliminate a screen-positive category, maintain the IRT cutoff value that prompts the second tier DNA testing, and communicate CF relative risk to primary care providers (PCPs) based on categorization of positive CF NBS results.

Background: Ethical concerns and disadvantages of newborn screening (NBS) for cystic fibrosis (CF) related to genetic testing have raised controversies and impeded implementation of CF NBS in some countries. In the present study, we used a prospective and sequential immunoreactive trypsinogene (IRT)/pancreatitis-associated protein (PAP) strategy, with IRT as first and PAP as second tier, and validated this biochemical approach against the widely used IRT/DNA protocol in a population-based NBS study in southwest Germany., Methods: Prospective quantitation of PAP and genetic analysis for the presence of four mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene most prevalent in southwest Germany (F508del, R553X, G551D, G542X) were performed in all newborns with IRT > 99.0th percentile. NBS was rated positive when either PAP was ≥1.0 ng/mL and/or at least one CFTR mutation was detected. In addition, IRT > 99.9th percentile was also considered a positive rating. Positive rating led to referral to a CF centre for testing of sweat Cl(-) concentration., Findings: Out of 73,759 newborns tested, 98 (0.13%) were positive with IRT/PAP and 56 (0.08%) with IRT/DNA. After sweat testing of 135 CF NBS-positive infants, 13 were diagnosed with CF. Detection rates were similar for both IRT/PAP and IRT/DNA. One of the 13 diagnosed CF newborns had a PAP concentration <1.0 ng/mL., Conclusions: Sequential measurement of IRT/PAP provides good sensitivity and specificity and allows reliable and cost-effective CF NBS which circumvents the necessity of genetic testing with its inherent ethical problems.

Infants with positive CF newborn screening (NBS) results are called to a CF Centre for verification. Those, in whom the sweat test is elevated, undergo further medical procedures. The aim of our study was to evaluate the applicability of Nanoduct - a new system measuring sweat conductivity and giving immediate results in a CF NBS protocol. Measurements with Nanoduct were compared with the classic pilocarpine method. During 3 years 487 infants from CF NBS had both sweat tests performed on the same day, at the same CF centre. CF infants had a mean conductivity of 99.8 ± 1 8.8 mmol/L and a mean chloride concentration of 74.0 ± 18.4 mmol/L. Non-CF infants values were 29.8 ± 7.7 mmol/L and 19.2 ± 6.6 mmol/L respectively. A good correlation between both tests was found (95% confidence level (CI); r=0.87). The optimal cut off, based on follow up experience of screened children, for conductivity tests was 50 mmol/L and for chloride concentration was 34 mmol/L (no lost CF, 11 false positive) with 100% sensitivity and 97.5 % specificity. In conclusion Nanoduct is a very useful and reliable tool in CF NBS protocol, allowing more time efficient organization of the diagnostic and training procedures. Simultaneous bilateral sweat testing with two different methods (concentration and conductivity) provides an extra quality control system.

These guidelines aim to standardize the standard operating procedures for the sweat test in newborn cystic fibrosis (CF) screening. They have been implemented by the national Neonatal Screening working group of the French Federation for Cystic Fibrosis. It is recommended that the sweat test be performed when the infant weighs more than 3 kg and is at least 3 weeks of age. Sweat gland secretion is stimulated by transdermal administration of pilocarpine by iontophoresis. Sweat is preferentially collected in a Macroduct coil. Diagnosis of CF is based on the sweat chloride level. A sweat chloride level below 30 mmol/l very probably rules out CF; 60 mmol/l or higher supports the diagnosis of CF. Values between 30 and 60 mmol/l are considered abnormal., (Copyright © 2010 Elsevier Masson SAS. 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.