40 Longitudinal values of sweat chloride concentration among infants identified by cystic fibrosis (CF) newborn screening (NBS) in California

Abstract There is a widely accepted consensus on the benefits of newborn screening (NBS) for cystic fibrosis (CF) in terms of reduced disease severity, improved quality of life, lower treatment burden, and reduced costs. More and more countries in the world are introducing NBS for CF as a national preventive health program. Newborn screening for CF was introduced in the Republic of North Macedonia (RNM) in April, 2019, after a pilot study of 6 months in 2018. A two-step immunoreactive trysinogen (IRT-IRT) algorithm is performed, and then a sweat test for confirmation/exclusion of the CF diagnosis when the IRT values were both over the cutoff (70.0 and 45.0 ng/mL, respectively). In cases with confirmed diagnosis of CF (a sweat chloride concentration >60.0 mmol/L) or with intermediate sweat test results (a sweat chloride concentration of between 30.0 and 59.0 mmol/L), CF transmembrane conductance regulator (CFTR) mutation analysis is performed. By the end of 2020, over a period of 27 months, including the pilot study period, a total number of 43,139 newborns were screened for CF. Seventeen (0.039%) newborns were diagnosed with CF. In all newly discovered CF cases by screening, the diagnosis was confirmed by determination of the CFTR mutations. The most common CFTR mutation, F508del, was found with an overall incidence of 70.6%. Other more frequent mutations were G542X (11.8%) and N1303K (5.9%). Four mutations were found in one CFTR allele each: G1349D, G126D, 457TAT>G and CFTRdupexon22, with the last one being newly discovered with unknown consequences. An incredibly large difference was found in the incidence of the disease between the Macedonian and Albanian neonatal population, with almost four time higher prevalence among Albanians (1:4530 vs. 1:1284).

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Test for the Concentration of Electrolytes in Cystic Fibrosis of the Pancreas Utilizing Pilocarpine by Iontophoresis, by Lewis E. Gibson and Robert E. Cooke,Pediatrics; 1959;24:545–549

PEDIATRICS ◽

10.1542/peds.102.s1.230 ◽

1998 ◽

Vol 102 (Supplement_1) ◽

pp. 230-231

Author(s):

Victor Chernick

Keyword(s):

Cystic Fibrosis ◽

Filter Paper ◽

Direct Injection ◽

Heat Stroke ◽

Chloride Concentration ◽

Hot Water ◽

Sweat Test ◽

High Concentration ◽

Sweat Chloride ◽

Plastic Bag

Aim. To develop a method for stimulating sweating that is rapid, painless, and avoids the risk of heat stress. Background. Since the discovery that there is a high concentration of sodium and chloride in the sweat of patients with cystic fibrosis of the pancreas in 1953, the sweat test has been performed by placing the patient's body in a plastic bag with or without hot water bottles to stimulate sweating. This method is unsatisfactory because of complications such as hyperpyrexia and heat stroke. Direct injection of a cholinergic agent intradermally is painful and therefore not practical. Methods. A rheostat with a milliampere meter was constructed at a cost of ∼$7 that allowed the iontophoresis of pilocarpine into the skin using negative and positive (2-cm diameter) electrocardiography electrodes. The positive electrode was placed on the flexor surface of the arm over a filter paper soaked in 0.2 mL of 0.2% pilocarpine nitrate. Current (0.2 mA) was applied for 5 minutes and then sweat was collected onto a preweighed filter paper for 30 minutes. Sweat chloride was determined by a polarographic method. Sweat tests were performed on 25 patients with cystic fibrosis (CF), 17 asymptomatic relatives and 27 control patients. Patients with CF had sweat chloride concentration >80 mEq/L; relatives, 32.5 mEq/L (highest 57 mEq/L); and control subjects, 21.1 mEq/L (highest 60 mEq/L). Conclusions. The iontophoresis of pilocarpine into the skin is a rapid, painless, safe, and reliable method for stimulating sweating and facilitating the determination of sweat chloride concentration.

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Negative Effects of Oral Fatty Acid Supplementation on Sweat Chloride in Cystic Fibrosis

PEDIATRICS ◽

10.1542/peds.64.1.50 ◽

1979 ◽

Vol 64 (1) ◽

pp. 50-52

Author(s):

John D. Lloyd-Still ◽

Stuart H. Simon ◽

Hans U. Wessel ◽

Lewis E. Gibson

Keyword(s):

Cystic Fibrosis ◽

Fatty Acid ◽

Sweat Rate ◽

Chloride Concentration ◽

Control Group ◽

Safflower Oil ◽

Negative Effects ◽

Fatty Acid Supplementation ◽

Acid Supplementation ◽

Sweat Chloride

Essential fatty acid supplementation with oral safflower oil (1 gm/kg/day) to 11 cystic fibrosis patients (aged 6 months to 14 years) for one year produced no significant change in sweat chloride concentration (mEq/liter) or sweat rate (gm/min/m2). Addition of vitamin E (10 mg/kg/day) to the safflower oil had no effect on sweat chloride concentration or rate compared to placebo. No clinical improvement could be detected compared to a control group. These results do not support previous reports of the effects of fatty acid supplementation on sweat electrolyte concentrations in cystic fibrosis.

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Variability of sweat chloride concentration in subjects with cystic fibrosis and G551D mutations

Journal of Cystic Fibrosis ◽

10.1016/j.jcf.2016.02.015 ◽

2017 ◽

Vol 16 (1) ◽

pp. 36-40 ◽

Cited By ~ 17

Author(s):

F. Vermeulen ◽

C. Le Camus ◽

J.C. Davies ◽

D. Bilton ◽

D. Milenković ◽

...

Keyword(s):

Cystic Fibrosis ◽

Chloride Concentration ◽

Sweat Chloride

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Relation of sweat chloride concentration to severity of lung disease in cystic fibrosis

Pediatric Pulmonology ◽

10.1002/ppul.20054 ◽

2004 ◽

Vol 38 (3) ◽

pp. 204-209 ◽

Cited By ~ 25

Author(s):

Pamela B. Davis ◽

Mark D. Schluchter ◽

Michael W. Konstan

Keyword(s):

Cystic Fibrosis ◽

Lung Disease ◽

Chloride Concentration ◽

Sweat Chloride

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Correlation of Sweat Chloride Concentration with Genotypes in Cystic Fibrosis Patients in Saguenay Lac-Saint-Jean, Quebec, Canada

Clinical Biochemistry ◽

10.1016/s0009-9120(97)00138-0 ◽

1998 ◽

Vol 31 (1) ◽

pp. 33-36 ◽

Cited By ~ 2

Author(s):

Marc De Braekeleer ◽

Christian Allard ◽

Jean-Pierre Leblanc ◽

Gervais Aubin ◽

Fernand Simard

Keyword(s):

Cystic Fibrosis ◽

Chloride Concentration ◽

Sweat Chloride

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Cystic fibrosis newborn screening: outcome of infants with normal sweat tests

Archives of Disease in Childhood ◽

10.1136/archdischild-2017-313290 ◽

2017 ◽

Vol 103 (8) ◽

pp. 753-756 ◽

Cited By ~ 6

Author(s):

Claire Edmondson ◽

Christopher Grime ◽

Ammani Prasad ◽

Jacqui Cowlard ◽

Chinedu E C Nwokoro ◽

...

Keyword(s):

Cystic Fibrosis ◽

Newborn Screening ◽

Genome Sequencing ◽

Dna Analysis ◽

Gene Mutations ◽

High Serum ◽

Sweat Test ◽

Sweat Chloride ◽

South East England

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.

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Case Report: Japanese Siblings of Cystic Fibrosis With a Novel Large Heterozygous Deletion in the CFTR Gene

Frontiers in Pediatrics ◽

10.3389/fped.2021.800095 ◽

2022 ◽

Vol 9 ◽

Author(s):

Mayumi Kawase ◽

Masato Ogawa ◽

Takayuki Hoshina ◽

Masumi Kojiro ◽

Miyuki Nakakuki ◽

...

Keyword(s):

Cystic Fibrosis ◽

Direct Sequencing ◽

Chloride Concentration ◽

Conventional Polymerase Chain Reaction ◽

Large Deletion ◽

Heterozygous Deletion ◽

Real Time Quantitative Pcr ◽

Sweat Chloride ◽

Exon 1 ◽

Fecal Pancreatic Elastase

Cystic fibrosis (CF) is a rare disease in the Japanese. The most common CFTR variant in Japanese CF patients is a large heterozygous deletion that can easily avoid detection by standard gene sequencing methods. We herein report a novel large heterozygous deletion in the CFTR gene in Japanese siblings with CF. A genetic analysis was performed in two patients (9-year-old boy and 5-month-old girl) who were clinically diagnosed with CF because of the positive result for the rapid fecal pancreatic elastase antigen test and the elevation of the sweat chloride concentration. In addition to conventional polymerase chain reaction (PCR) and direct sequencing, multiplex ligation-dependent probe amplification (MLPA) was performed to check for a large deletion and duplication of the CFTR gene. Based on MLPA findings, the breakpoint of heterozygous deletion was identified by real-time quantitative PCR followed by the sequence of the amplified junction fragment. In MLPA, the numbers of the fragments corresponding to exons 1, 16, 17a, and 17b and 234 nt and 747 nt upstream from the translation initiation codon of exon 1 in the CFTR gene and exon 3 in the ASZ1 gene were reduced by almost half. The c.2908+1085_3367+260del7201 variant (exon 16-17b deletion) was identified in one allele. The other allele had a large 137,567-bp deletion from g.117,361,112 (ASZ1 3′ flanking region) to g.117,498,678 (CFTR intron 1) on chromosome 7. Since the deletion variant lacked the entire promoter region of CFTR, CFTR mRNA would not be transcribed from the allele, indicating it to be a novel pathogenic variant causing CF. As large mutations are frequently detected in Japanese CF patients, MPLA can be useful when searching for variants.

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Intermediate-range sweat chloride concentration and Pseudomonas bronchitis. A cystic fibrosis variant with preservation of exocrine pancreatic function

JAMA ◽

10.1001/jama.239.25.2676 ◽

1978 ◽

Vol 239 (25) ◽

pp. 2676-2680 ◽

Cited By ~ 30

Author(s):

R. C. Stern

Keyword(s):

Cystic Fibrosis ◽

Chloride Concentration ◽

Exocrine Pancreatic Function ◽

Pancreatic Function ◽

Intermediate Range ◽

Sweat Chloride

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Newborn Screening for Cystic Fibrosis Is Complicated by Age-Related Decline in Immunoreactive Trypsinogen Levels

PEDIATRICS ◽

10.1542/peds.85.6.1001 ◽

1990 ◽

Vol 85 (6) ◽

pp. 1001-1007 ◽

Cited By ~ 1

Author(s):

Michael J. Rock ◽

Elaine H. Mischler ◽

Philip M. Farrell ◽

Lee-Jen Wei ◽

W. Theodore Bruns ◽

...

Keyword(s):

Cystic Fibrosis ◽

Newborn Screening ◽

Cutoff Point ◽

Controlled Study ◽

Negative Results ◽

Sweat Chloride ◽

Age Related ◽

Comparison Groups ◽

Neonatal Blood Spots ◽

Immunoreactive Trypsinogen

Detection of elevated levels of immunoreactive trypsinogen (IRT) in dried neonatal blood spots has been used as a screening test for cystic fibrosis. In other cystic fibrosis newborn-screening studies, a sweat chloride test is generally performed only if an infant has a persistent IRT level above a selected cutoff value on both the initial and subsequent specimens. Neither the timing of the second specimen nor the value of the cutoff point for the second specimen has been comprehensively evaluated. In this randomized, controlled study, 145 024 infants were screened in the neonatal period for cystic fibrosis using the 99.8 percentile (180 ng/mL) as the neonatal cutoff point. A total of 129 infants had elevated neonatal IRT levels and had negative results on sweat tests (false-positive by IRT screening). A total of 54 children with cystic fibrosis were identified in the screened and comparison groups. Excluding patients with meconium ileus, 4 infants with cystic fibrosis had neonatal IRT values less than 180 ng/mL, and an additional 9 infants with cystic fibrosis had values decline to less than 180 ng/mL within the first 2½ months of age. The IRT values of infants with and without cystic fibrosis overlapped considerably beyond 30 days of age. These findings suggest that further refinement of cystic fibrosis screening methodology will be necessary to achieve an acceptable sensitivity and specificity.

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