Search

BACKGROUND Infants with a positive cystic fibrosis (CF) newborn screen, only one identified CFTR mutation (NBS+/1 mut), and an initial intermediate sweat chloride (30-59 mmol/L) should have repeat sweat chloride testing (SCT). However, the outcome of repeat SCT and the relationship between initial sweat Cl and subsequent CF diagnosis have not been reported. OBJECTIVE The objective of this study was to analyze the outcomes of repeat SCT and subsequent CF diagnosis in NBS+/1 mut infants based on their initial sweat chloride concentration. METHODS We retrospectively identified all infants born in Indiana from 2007 to 2017 with NBS+/1 mut and initial SCT in the intermediate range. For each infant, we recorded the initial and repeat SCT results and/or a final CF diagnosis. RESULTS From 2007 through 2017 there were 2822 NBS+/1 mut infants of which 2613 (82%) had at least one SCT result. No infants with an initial SCT of 30-39 mmol/L were subsequently diagnosed with CF. Of the 31 infants with an initial SCT of 40-49 mmol/L, only 1 was subsequently diagnosed with CF. In contrast, 61% of those with SCTs of 50-59 mmol/L were later diagnosed with CF. CONCLUSION These results suggest that infants with a positive NBS for CF and one CFTR mutationwhose initial sweat chloride concentration is 50-59 mmol/L need to be monitored more closely forCF with strong consideration for earlier repeat SCTs and immediate genotyping.

BACKGROUND Diagnostic sweat testing is required for infants with positive newborn-screening (NBS) tests for cystic fibrosis (CF). Infants have "quantity not sufficient" (QNS) sweat volumes more often than older children. A comprehensive study of QNS sweat volumes in infants has not previously been reported. METHODS We surveyed US CF Centers to obtain QNS rates in all infants who had sweat testing at under 14 days and under 3 months of age. We then calculated QNS rates reported to the Cystic Fibrosis Foundation Patient Registry (CFFPR) 2010-2018 in 10-day increments from 1 to 60 days of life. We compared QNS sweat test rates in preterm (

Objective We evaluated the prevalence, Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene profile, clinical data, management and outcome for infants with a CFTR-related metabolic syndrome/CF Screen Positive, Inconclusive Diagnosis (CRMS/CFSPID) designation from six Italian centres. Methods All newborn bloodspot screening (NBS) positive infants born from January 2011 to August 2018 with a CF diagnosis or a CRMS/CFSPID designation were enrolled. Data on sweat testing, genetics, clinical course and management were collected. Results We enrolled 257 CF patientsand 336 infants with a CRMS/CFSPID designation (CF: CRMS/CFSPID ratio of 1:1.30).Blood immuno-reactive trypsinogen (IRT) was significantly lower in CRMS/CFSPID infants and the F508del variant accounted for only 20% of alleles. Children with CRMS/CFSPID showed a milder clinical course, pancreatic sufficiency compared to CF infants. Varied practice across centres was identified regarding sweat testing, chest radiograph (8-100%) and salt supplementation (11-90%). Eighteen (5.3%) CRMS/CFSPID infants converted or were reclassified to diagnosis of CF. Four infants (1.3%) developed a clinical feature consistent with a CFTR-related disorder (1.2%). Twenty-seven were re-classified as healthy carriers (8.0%) and 16 as healthy infants (4.8%). Conclusions We have identified considerable variability in the evaluation and management of infants with an inconclusive diagnosis following NBS across six Italian centres. CRMS/CFSPID is more regularly seen in this population compared to countries with higher prevalence of F508del.Conversion to a CF diagnosis was recorded in 18 (5.3%) of CRMS/CFSPID infants and in 16 was as a result of increasing sweat chloride concentration.

Cystic fibrosis (CF) is the most common life-threatening autosomal-recessive disease affecting Caucasians in the western world. The sweat test is the main diagnostic test for CF. It is indicated as part of the clinical assessment for infants that have picked up on the national neonatal screening programme. It may also be requested where clinical suspicion of a diagnosis of CF exists despite normal screening results. This article outlines the physiological basis behind sweat testing and the technical aspects of performing the test. Indications for performing the test are also considered. The article aims to provide clinicians with a guide to interpretation of results.

Cystic fibrosis (CF) is the most common fatal genetic disease of the Caucasian population. Sweat testing is the principal diagnostic test for CF, and it is used for the evaluation of infants with positive CF newborn screening (NBS) and in patients with clinical findings suggesting CF. This article describes the classical sweat test method in detail and also provides an overwiew of recent advances.

The sweat test is the gold standard for the diagnosis of cystic fibrosis (CF). The test utilizes iontophoresis to administer pilocarpine to the skin to induce sweating for measurement of chloride concentration in sweat. However, the sweat test procedure needs to be conducted in an accredited lab with dedicated instrumentation, and it can lead to inadequate sweat samples being collected in newborn babies and young children due to variable sweat production with pilocarpine iontophoresis. We tested the feasibility of using microneedle (MN) patches as an alternative to iontophoresis to administer pilocarpine to induce sweating. Pilocarpine‐loaded MN patches were developed. Both MN patches and iontophoresis were applied on horses to induce sweating. The sweat was collected to compare the sweat volume and chloride concentration. The patches contained an array of 100 MNs measuring 600 μm long that were made of water‐soluble materials encapsulating pilocarpine nitrate. When manually pressed to the skin, the MN patches delivered >0.5 mg/cm2 pilocarpine, which was double that administered by iontophoresis. When administered to horses, MN patches generated the same volume of sweat when normalized to drug dose and more sweat when normalized to skin area compared to iontophoresis using a commercial device. Moreover, both MN patches and iontophoresis generated sweat with comparable chloride concentration. These results suggest that administration of pilocarpine by MN patches may provide a simpler and more‐accessible alternative to iontophoresis for performing a sweat test for the diagnosis of CF.

Background The sweat test has been the "gold standard" diagnostic test for cystic fibrosis for more than 40 years. We hypothesized that there would be a change in the pattern of sweat testing in Ireland since the introduction of cystic fibrosis newborn screening in 2011, when practices were last reviewed. This is a follow up survey looking at sweat testing numbers and practices. Methods A national survey compiled data on sweat collection, conductivity and sweat chloride testing in all hospitals previously identified as performing sweat tests. Results All 13 centres in Ireland performing sweat testing in 2018 responded to the survey (100% return rate). Our results indicate that 1007 sweat tests were performed in 2018 compared to 2555 in 2011, equating to a 61% reduction. Seven out of 13 centres are performing less than 50 sweat tests per year. Nine out of 13 centres (69%) had a sweat test failure rate greater than the recommended allowable rate of ≤ 10%. We detected a trend of sweat testing in patients with an existing diagnosis of CF who had commenced cystic fibrosis transmembrane conductance regulator (CFTR) modulators. Conclusions There has been a significant reduction in the number of sweat tests performed in Ireland since the introduction of newborn screening for CF. There remains a lack of standardisation in many aspects of the service ranging from sample collection to reporting of results. We have identified a new trend of sweat testing in the cystic fibrosis transmembrane conductance regulator modulator era.

Background: Benefits of early Cystic Fibrosis (CF) detection using newborn screening (NBS) lead to widespread use in NBS programs. Since 2002, a two-stage immunoreactive trypsinogen (IRT/IRT) screening strategy has been used as CFNBS method in all public maternities in the City of Buenos Aires, Argentina. However, novel screening strategies may be more efficient. The aim of the study is to prospectively compare two CFNBS strategies, IRT/IRT and IRT/PAP (pancreatitis-associated protein). Methods: A two-year prospective study was performed. IRT was measured in dried blood samples collected 48–72 hours after birth. When IRT value was abnormal, PAP was determined, and a second visit was scheduled to obtain another sample for IRT before 25 days of life. Newborns with a positive CFNBS were referred for confirmatory sweat test. Results: There were 69,827 births in the City of Buenos Aires during the period studied; 918 (1.31%) had an abnormal IRT. A total of 207 children (22.5%) failed to return for the second IRT, but only two PAP (0.2%) were not performed. IRT/IRT was more likely to lead to a referral for sweat testing than IRT/PAP (OR 2.3 [95% CI 1.8;2.9], p

Aim To audit the delivery of sweat testing in a district general hospital against national standards To develop recommendations for local practice. Method In our NHS Trust which cares for 300 000 children a retrospective audit against national (RCPCH endorsed) clinical and laboratory standards was performed over 12 months beginning January 2017. Records of sweat tests and laboratory procedures were obtained from the biochemistry laboratory. Clinical indications for sweat testing were obtained from patient electronic notes. The audit was registered with the audit department. Results 43 sweat tests were performed in 41 children whose age ranged from 3 months to 18 years. The most common indications were respiratory 27 (65.9%), failure to thrive 7 (17.1%) and bowel symptoms 5 (12.2%). Out of 39 sweat tests (excluding repeat tests), 13 failed (33%) mostly due to insufficient sweat volume. All the sweat tests showed normal results except for one borderline result that when repeated showed a normal result. Conclusion Despite the high number of sweat tests still being requested by paediatricians there has been no single case of cystic fibrosis (CF) diagnosed in our Trust for 10 years, suggesting the newborn CF screening program in our region is effective. Should hospitals like ours that do not run CF clinics and/or receive newborn CF screening results be doing sweat tests? Also we wonder if the indications and threshold for sweat testing require redefining in the post newborn CF screening era. Our sweat testing failure rate of 33% was very high against the recommended failure rate of

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

Cystic fibrosis (CF) is a genetic disease caused by a bi-allelic mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. When the diagnosis cannot be confirmed by a positive sweat test or/and the identification of two CF-causing variants, international guidelines recommend the use of CFTR functional assays. These tests assess whether CFTR activity is normal or diminished/absent through measurement of CFTR-mediated chloride secretion/absorption., CFTR functional assays are not only useful for diagnostic purposes but can also serve as a surrogate outcome for clinical trials of CFTR modulators, which are emerging therapeutic agents designed to correct the malfunctioning protein. In the near future they could also be used as precision-medicine techniques, to help guidance and optimisation of treatment., Until now, sweat testing has been the only CFTR functional assay available in Switzerland. Since 2020, the Centre Hospitalier Universitaire Vaudois (CHUV) at Lausanne and the Lucerne Children's Hospital perform nasal potential difference measurement. Moreover, The Ecole Poly-technique Federale de Lausanne (EPFL) established a reliable procedure to generate adult intestinal organoids, i.e., stem cell-derived in-vitro grown mini tissues, extracted from rectal biopsies, which can be used to assess CFTR function in vitro., This narrative review describes the most popular CFTR functional assays, as well as their indications, limitations and availability in Switzerland.

In Germany, screening for cystic fibrosis (CF) is part of the newborn screening since September 2016. The risk of psychological harm due to false-positive screening results is a longstanding concern. We investigated the parents' perception of the CF screening process in Bavaria and the communication after positive screening results with a questionnaire. Until August 2018, 192 children went through a final diagnostic testing after a positive CF screening result, and 105 (54.7%) families completed the questionnaire. Of these, only 30 parents obtained information about the newborn screening by a physician, despite this being mandatory in Germany. Parents being informed by a CF specialist (28.6%) about the positive screening result were more satisfied with the given information (80.0 versus 50% informed by the maternity ward), and the delay until the final diagnostic testing was shorter. More than 3 days between the information about the screening result and the diagnostic testing was too long for 77.7% of the families.Conclusion: Performing final diagnostic testing with only short delays and receiving satisfactory information is important. Therefore, parents should be informed directly by a CF center about positive screening results and only when sweat testing is possible within the next days. What is Known: • The risk of psychological harm due to false-positive screening results is a longstanding concern. • Satisfactory information about the positive CF screening result seem to reduce the parental stress. What is New: • Parents being informed directly by a CF specialist were more satisfied with the given information and the delay until the final diagnostic testing was shorter. • Our data support the concept that parents should better be informed directly by a CF specialist about positive screening results and only when sweat testing is possible within the next days to reduce parental stress.

Background: The objective of the study was to assess the diagnostic efficacy of the coulometric endpoint method and compare it with classic Gibson&Cooke and chloridometer methods. Methods: This study is a prospective clinical study comparing two conventional sweat testing methods with the coulometric endpoint method in previously diagnosed cystic fibrosis (CF) patients and a non-CF control group. All individuals underwent two simultaneous sweat collections. One sample of sweat, collected by the CF Delta collector coil system, was analyzed by two methods: the titrimetric Cl- measurement (Sherwood (R) Chloridometer 926S, Sherwood Scientific Ltd., Cambridge, UK) and the coulometric endpoint method (CF Delta Collection System (R), UTSAT/Turkey); the second sample was collected from the other forearm by the Gibson&Cooke method and the collected sweat was analyzed by manual titration in accordance with the Schales&Schales method. Within-run and between-run imprecisions were evaluated via Cl- concentrations of 40, 70, and 130 mmol/L samples. Results: One hundred and seventy (60 CF and 110 controls) subjects were included in the study. All three sweat test methods discriminated CF subjects from the healthy individuals. The mean difference between the coulometric endpoint and titrimetric Cl - measurement methods was -1.5 mmol/L, (95% confidence limits of agreement, ranging from -8.9 to 15.9 mmol/L); the mean difference between manual titration vs. coulometric endpoint methods was 12.8 mmol/L, (95% confidence limits of agreement ranging from -9.7 to 45.3 mmol/L) and the mean difference between the manual titration and titrimetric Cl - measurement methods was 11.3 mmol/L, (95% confidence limits of agreement ranging from -7.8 to 40.5 mmol/L) based on a Bland-Altman analysis. In the Receiver operating characteristic (ROC) analysis, made on the basis that Cl- concentration values

Summary Newborn screening for Cystic Fibrosis (CF) began in New York in October, 2002 using immunoreactive trypsinogen (IRT)/DNA methodology. Infants with at least one CFTR mutation or very high IRT and no mutations (VHIRT) are referred for sweat testing. In a preliminary analysis, we noted a very low positive predictive value (PPV) and preponderance of Hispanic infants in the group of infants with CF referred for VHIRT, which led to a decision to revise, but not eliminate, the VHIRT category. Automatic referral for specimens with VHIRT collected on the day of birth was eliminated, and the VHIRT threshold was raised from 0.2% to 0.1%. In this report, we describe outcomes from VHIRT referrals among 2.4 million infants screened between March 2003 and February 2013. Following the algorithm change, referrals decreased by 37.8% overall (annual mean 1,485 vs. 923), and the VHIRT PPV improved (0.6–1.0%). The number of infants diagnosed has remained consistent at 1 in 4,400 births. The proportion of Black/Hispanic/Asian/Other infants with confirmed CF, CFTR-related metabolic syndrome (CRMS), or possible CF/CRMS was 21.3% in infants with 1–2 mutations, but 75.8% in the VHIRT group. In conclusion, although the PPV among VHIRT referrals remains low, had this category never been implemented, 24 infants with confirmed CF, and 9 infants with CRMS or possible CF/CRMS, most of whom were Hispanic, would have been missed over the 10 years. Information from this study may be helpful in assessing the need for the VHIRT category and algorithm changes in other screening programs. Pediatr Pulmonol. 2015; 50:771–780. © 2015 Wiley Periodicals, Inc.

Evidence based guidelines exist for sweat testing, which remains a key component of a diagnosis of cystic fibrosis (CF), especially following newborn bloodspot screening (NBS). There are emerging challenges with respect to maintaining a valid sweat test service, notably a smaller number of sweat tests ordered in regions with established NBS programmes where Pediatricians refer less children for sweat testing, younger patients and equipment becoming obsolete. The ECFS Diagnostic Network Working Group has undertaken a comprehensive survey to better define sweat test practice across Europe. The survey was completed by 136 European respondents representing a CF center or laboratory providing a sweat test service (65% from regions with NBS for CF). There was considerable variance in practice, often not consistent with guidelines. In particular collection of sweat from two sites was rarely reported in European centres in contrast to US guidelines. There was a range of different references quoted for cut-off for both a positive and intermediate test. Most responses suggest cost is becoming an increasing issue and is not sufficiently reimbursed. This work will inform best practice guidelines and resources to sustain and improve sweat testing in Europe.

Background: There are several complementary English-language guidelines for the performance of the sweat chloride test. These guidelines also incorporate information for the collection of conductivity samples. However, recommendations for the measurement and reporting of sweat conductivity are less clear than for sweat chloride. The aim of the study was to develop an understanding of the testing and reporting practices of sweat conductivity in Australasian laboratories. Methods: A survey specifically directed at conductivity testing was sent to the 12 laboratories registered with the Royal College of Pathologists of Australasia Quality Assurance Programs. Results: Nine (75%) laboratories participated in the survey, seven of whom used Wescor Macroduct® for collecting sweat and the Wescor SWEAT·CHEK™ for conductivity testing, and the remaining two used the Wescor Nanoduct®. There was considerable variation in frequency and staffing for this test. Likewise, criteria about which patients it was inappropriate to test, definitions of adequate collection sweat rate, cutoffs and actions recommended on the basis of the result showed variations between laboratories. Conclusions: Variations in sweat conductivity testing and reporting reflect many of the same issues that were revealed in sweat chloride test audits and have the potential to lead to uncertainty about the result and the proper action in response to the result. We recommend that sweat testing guidelines should include clearer statements about the use of sweat conductivity.

The sweat test remains important as a diagnostic test for cystic fibrosis (CF) and has contributed greatly to our understanding of CF as a disease of epithelial electrolyte transport. The standardization of the sweat test, by Gibson and Cooke [Gibson and Cooke (1959) Pediatrics 1959;23:5], followed observations of excessive dehydration amongst patients with CF and confirmed the utility as a diagnostic test. Quantitative pilocarpine iontophoresis remains the gold standard for sweat induction, but there are a number of collection and analytical methods. The pathophysiology of electrolyte transport in sweat was described by Quinton [Quinton (1983) Nature 1983;301:421-422], and this complemented the developments in genetics that discovered the cystic fibrosis transmembrane conductance regulator (CFTR), an epithelial-based electrolyte transport protein. Knowledge of CF has since increased rapidly and further developments in sweat testing include: new collection methods, further standardization of the technique with international recommendations and age related reference intervals. More recently, sweat chloride values have been used as proof of effect for the new drugs that activate CFTR. However, there remain issues with adherence to sweat test guidelines in many countries and there are gaps in our knowledge, including reference intervals for some age groups and stability of sweat samples in transport. Furthermore, modern methods of elemental quantification need to be explored as alternatives to the original analytical methods for sweat electrolyte measurement. The purpose of this review is therefore to describe the development of the sweat test and consider future directions.

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.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.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 and8 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).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.

Introduction: Sweat test has a diagnostic role in evaluation of cystic fibrosis. Its performance includes sweat stimulation, collection and analysis. All listed may be sources of inconsistencies in everyday practice. The aim of this study was an evaluation of external quality assessment (EQA) of sweat chloride measurement including sweat test performance in medical biochemistry laboratories in Croatia. Materials and methods: EQA for sweat chloride measurement was provided by Croatian Centre for Quality Assessment in Laboratory Medicine (CROQALM) in five consecutive exercises to medical biochemistry laboratories (MBL) that offered sweat testing. A questionnaire regarding all phases of testing was mailed to involved MBL (N = 10). Survey results were compared to current guidelines for sweat test performance. Results: Reported results of EQA in 2015 exercises showed coefficients of variation (CV) from 28.9%, 29.0% to 35.3%, respectively. An introduction of uniform sweat chloride measurement protocol resulted in CV of 15.5% and 14.7% reported in following two exercises in 2016. All MBL included in this study replied to the questionnaire. Results reported by MBL indicated: lack of patient information policy (7/10), use of unacceptable electrodes (6/9), misuse of minimum of acceptable sweat weight (6/9), lack of internal quality assessment (5/9) and recommended reference ranges (5/9 and 4/9). Agreements to guidelines were found in approach to unsuitable patients (9/10) and sweat collection (8/9). Conclusion: Presented results indicate major weak points of current practice in sweat test performance in Croatian MBL and stress the need for its standardization on a national level.

Objectives Rapid and reliable confirmatory sweat testing following a positive newborn screen (NBS) for cystic fibrosis (CF) is preferred to allow for early diagnosis and to decrease parental anxiety. The Cystic Fibrosis Foundation (CFF) recently recommended a quantity not sufficient (QNS) rate of ≤ 10% in infants < 3 months of age referred for quantitative sweat chloride analysis. Two CFF-approved methods are available by which to quantitatively measure chloride concentration in sweat. Our objective was to compare the performance of the Macroduct® sweat collection system (MSCS) with the Gibson and Cooke technique (GCT) in the acquisition of samples for the determination of sweat chloride concentration in infants with a positive Minnesota State NBS for cystic fibrosis.

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.

Background Accurate measurement of sweat chloride concentration is essential for the diagnosis of cystic fibrosis (CF). We surveyed all laboratories enrolled in the Royal College of Pathologists of Australasia Quality Assurance Program (QAP) for Sweat Electrolytes to determine how closely they comply with the Australian Guidelines for the performance of the sweat test for the diagnosis of CF. Methods A detailed questionnaire covering most aspects of sweat collection and analysis was sent to all participating laboratories in 2007. Results Twenty out of 38 laboratories completed the questionnaire. While adherence to accepted guidelines was noted in many areas, the following main variations were recorded: some laboratories were not doing enough sweat tests to maintain expertise; some were not collecting sweat for the recommended collection time; sweat conductivity was the only test available in some laboratories; there was a lack of agreement between the sweat chloride concentration used to indicate CF or define an equivocal result. Conclusions There is room for improvement in the performance of the sweat test in some laboratories in Australasia. The Sweat Testing Working Party of the Australasian Association of Clinical Biochemists is the appropriate body to address the problems involved in sweat testing and to bring about change.

Screening newborns for cystic fibrosis (CF) is considered to be an ethical undertaking in regions with a significant incidence of the condition. Current screening protocols result in recognition of infants with an equivocal diagnosis. A survey of European practice suggested inconsistencies in the evaluation and management of these infants.We have undertaken a consensus process using a modified Delphi method. This has enabled input of CF specialists from a wide geographical area to a rigorous process that has provided a clear pathway to a consensus statement. A core group produced 21 statements, which were modified over a series of three rounds (including a meeting arranged at the European CF Conference). A final document of 19 statements was produced, all of which achieved a satisfactory level of consensus. The statements cover four themes; sweat testing, further assessments and investigations, review arrangements and database.This consensus document will provide guidance to CF specialists with established screening programmes and those who are in the process of implementing newborn screening in their region.

There are few data on sweat analysis in Down's syndrome. We studied 25 children with Down's syndrome and obtained sweat samples by pilocarpine iontophoresis. Sweat osmolality was elevated in Down's syndrome compared to normal. The results of sweat testing must be regarded with caution when cystic fibrosis is suspected in children with Down's syndrome.

This review focuses on the pathobiology of the gastrointestinal and hepatic manifestations of cystic fibrosis (CF) disease in relation to their genetic basis in mutations of the CF transmembrane conductance regulator (CFTR) gene. It reviews the nature of the CFTR protein, a categorization of the types of gene mutations underlying CF's various manifestations, and the ways in which absent or reduced CFTR produces various functional abnormalities in the different organs affected by CF. Subsequently, the particular organ-related clinical manifestations of CF directly associated with loss of CFTR function are addressed. Thereafter, the review discusses some of the complexities of the genotype-phenotype relationships related to milder mutations or complex genetic disorders in which CFTR abnormalities interact with other genetic and environmental factors, and the potential diagnostic roles of sweat testing or other electrophysiologic testing. This discussion examines secondary gastrointestinal manifestations of CF and the particular cases of diseases that may be related to abnormalities of CFTR.

BACKGROUND: Surveys in USA and UK have shown inconsistencies between practice of sweat testing and guidelines of the National Committee for Clinical Laboratory Standards (NCCLS), which could increase the risk of false-positive and -negative results. To determine the current practice of sweat testing in German cystic fibrosis (CF)-centres a survey was performed. METHOD: A questionnaire was mailed to all 123 German CF-centres that join the German CF-register. The results were compared with the NCCLS-guidelines. RESULTS: 88 out of 113 responding centres perform 30-1100 (median 200) sweat tests by pilocarpine iontophoresis per year. The recommended sweat sample time of 20-30 min was accepted by 33% of all centres. Minimum acceptable sweat rates were quoted between 100 and 7500 (median 1000) mg/m 2 /min differing from the recommended 1000 mg/m 2 /min. Osmolality was measured in 3%, sodium in 24% and conductivity in 53% of the centres. Chloride, the only accepted diagnostic measurement by the NCCLS, was investigated by only 58% of all centres. The recommended chloride CF-reference value of >60 mmol/l was used in 78% of centres that perform chloride testing. CONCLUSIONS: Major areas of inconsistencies between sweat testing practice in German CF-centres and NCCLS-guidelines are sweat collection, analyzing method and reference values. Chloride, the only accepted diagnostic measurement by the NCCLS, was investigated only by 58% of all centres.

Newborn screening for cystic fibrosis (CF NBS) has been introduced in almost all of the Western countries, and most of the children with CF are now being identified via CF NBS before disease-related symptoms develop. This review summarizes the evidence that has been generated to date to support the benefit of CF NBS and the various screening algorithms that are used in different jurisdictions. A special focus is directed towards the challenges arising from false-negative and -positive screening results. Finally, we review the emerging data reporting on positively-screened newborns, in whom confirmatory sweat testing resulted in an inconclusive diagnosis for CF.

BACKGROUND Sweat testing in young infants (≤ 3 months) with a positive newborn screen for Cystic Fibrosis (CF) can yield higher rates of inadequate sweat collection. The role of salt supplements in improving sweat collection has not been studied before. METHODS All young infants referred to our CF center for sweat testing were randomized to either receive salt supplements {1/8th teaspoon salt (750 mg)} mixed in formula feeds 1 day prior to sweat testing (study group) or no salt supplement (controls). RESULTS Of the 151 young infants that underwent sweat testing over 18 months, 75 received salt supplements, while 76 did not. A total of 9 (11.8%) infants in the salt supplement group had inadequate sweat collection, as compared to 4 (5.2%) infants in the control group (p = 0.16, Fisher's Exact Test). CONCLUSIONS Oral salt supplementation for young infants prior to sweat testing does not help to reduce the rates of inadequate sweat collection.

Background: Evolving diagnostic criteria for cystic fibrosis, broadening of the populations being tested and the need to interpret intermediate sweat test results have imposed a much greater need to standardize the collection and analysis of sweat. Aim: To identify variations in sweat testing in New Zealand laboratories and compare these with guidelines from the UK and the USA. Methods: All laboratories in New Zealand offering sweat testing were identified and data collected from these laboratories by structured questionnaire. Results: There were no New Zealand laboratories that conformed to either set of guidelines. Inconsistencies were observed in minimum sweat quantities, the nature of the iontophoresis solution, the sweat electrolytes analysed, quoted reference ranges and recommendations made as a consequence of the result. Conclusions: Conformity to the guidelines would help to minimize variation in sweat testing in New Zealand. Performance of a sufficient number of tests to maintain expertise is critical, but geographical constraints make patient travel to distant centres difficult in a small, scattered population. A possible solution, where numbers permit, may be the collection of sweat locally, with referral to a major laboratory for analysis. This is only possible with adequate training in collection and follow-up audit of the sweat testing procedure both in the collection and in the analytical phase.

Objectives To evaluate the performance of a strategy in which, after immunoreactive trypsinogen (IRT) determination, genetic analysis is replaced by a biological test, the pancreatitis-associated protein (PAP) enzyme-linked immunosorbent assay (ELISA). Study design The French newborn screening program includes cystic fibrosis (CF) screening by the IRT/CFTR mutation strategy. PAP was assayed on screening cards, in parallel with IRT, in all newborns from 5 French regions (n = 204,749). Analysis of PAP values in CF and non-CF newborns with elevated IRT allowed direct comparison between the current strategy and the proposed IRT/PAP strategy. Results A protocol in which newborns with IRT >50 ng/mL and PAP >1.8 ng/mL and those with IRT >100 ng/mL and PAP >1.0 ng/mL are directly recalled for sweat testing would have the same performance as the IRT/CFTR mutation strategy. Conclusions The IRT/PAP strategy is an alternative for CF newborn screening, which avoids the drawbacks of genetic analysis and is cheaper and easier to implement than the current IRT/CFTR mutation strategy.

Sweat-testing remains a key component of the diagnostic workup for cystic fibrosis. However, it is technically challenging, especially in young children. This review covers technical aspects related to the devices and protocols associated with conducting successful tests.