The Journal of Pediatrics
Volume 153, Issue 6 , Pages 735-736, December 2008

By the Sweat of Our Brows: How Salty Should a Person Be?

  • Brian P. O'Sullivan, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Brian P. O'Sullivan, MD, Department of Pediatrics, University of Massachusetts Medical School, UMass Memorial Health Care, 55 Lake Avenue North, Worcester, MA 01655
    • ,
  • Robert G. Zwerdling, MD

Department of Pediatrics, University of Massachusetts Medical School, UMass Memorial Health Care, Worcester, Massachusetts

Article Outline

Abbreviations: CF, Cystic fibrosis

 

Traditionally, a sweat chloride value > 60 mmol/L (60 mEq/L) has been considered to be diagnostic of cystic fibrosis (CF), a value < 40 mmol/L to be negative for CF, and values between 40 and 60 mmol/L to be borderline.1 For very young infants undergoing a sweat test because of a positive newborn screening test, a borderline range of 30 to 60 mmol/L may be more appropriate.1, 2, 3 Two articles in this issue of The Journal add both clarity and confusion to interpreting what remains the gold standard for the diagnosis of CF.4, 5

See related articles, p 758 and p 857

The Australian group led by Massie has tracked a large cohort of patients and screened infants closely over many years. Now this group has created a database that allows appropriate interpretation of sweat chloride measurements over a wide range of ages.4 Surprisingly, such normative information has been lacking previously.6 This group now reports sweat chloride and sodium determinations in 40 people in each of 6 age categories.4 They excluded carriers of the ΔF508 mutation, relatives of known patients with CF, and individuals with chronic respiratory symptoms, thereby minimizing the likelihood of including results of subjects with mild forms of CF in their reference data. Impressively, the traditional cutoff value for a normal sweat chloride value in a child, < 40 mmol/L, is in almost perfect agreement with their data. Beyond childhood, these investigators noted a gradual but significant rise in normal sweat electrolyte values with age. By young adulthood, the median sweat chloride value in unaffected individuals was 22.7 mmol/L (95th percentile = 59.6 mmol/L). Again, this value is consistent with the accepted belief that a sweat test value > 60 mmol/L is diagnostic of CF. But many unaffected adults in this cohort had sweat chloride values in the range of 40 to 60 mmol/L, which are considered borderline using traditional reference ranges. This is a critical piece of information. Because more adults with chronic respiratory, reproductive, and pancreatic symptoms are rightly undergoing sweat testing, it is vital that these tests be interpreted in an age-appropriate manner. Sharing the results of the study by Mishra et al4 with adult care providers is imperative to avoid unnecessary follow-up testing in patients without CF with sweat chloride values > 40 mmol/L.

In a related article, Soultan et al5 address the other end of the age spectrum. They argue that we should consider lowering the accepted upper limit of normal for screened infants with 1 known CF mutation from 30 mmol/L to 24 mmol/L. They propose this value based on their observations in the first 50 infants referred to their center after institution of CF newborn screening. But their proposed lower limit of normal is not consistent with reports from 3 other, larger newborn screening groups. Massie et al7 found ΔF508 carriers had a mean sweat chloride value of 15.5 ± 6.2 mmol/L (n = 270), Farrell et al8 reported a mean sweat chloride value of 14 .9 ± 8.4 mmol/L in carriers of this mutation (n = 128), and Parad et al2 reported an almost identical value (14.7 ± 7.1 mmol/L) in carriers of 1 CF mutation (n = 882). Using these values and Soultan et al's method of mean plus 3 standard deviations makes the acceptable upper limit for a carrier for 1 CF mutation higher, not lower, than the 30 mmol/L currently in use.

Out of nearly 300 children tested, Soultan et al identified 3 with sweat chloride values between 24 and 30 mmol/L. In most centers, these children would be deemed unaffected carriers. These children underwent extensive (and expensive) genetic testing and were found to be heterozygous for the ΔF508 mutation and the 5T-12TG variant, which may or may not be associated with disease. Although a small number of children with an additional CF variant may be detected by expanding the borderline range, any benefit to knowing about these variants at this time is purely speculative. Will the child ever develop fulminate CF? If so, will it manifest in childhood? Will an intervention in childhood change the course or lifetime burden of illness? Based on the few case reports of people carrying this genetic combination (ΔF508/5T-12TG) and the large pool of people who likely have the same genetic background but no illness,9 it appears that the answer to all 3 questions is “no.”

Given our current knowledge, we feel that the proposed change in the sweat test reference range for infants is not warranted and may indeed be harmful, for several reasons: (1) possible development of the “vulnerable child syndrome”10, 11 (to quote Sultan et al, “we tell parents…that their infants are at risk of developing CF-like disease”); (2) performance of unnecessary, costly, and anxiety-provoking genetic testing;12, 13 (3) impact on future reproductive decisions;13, 14 (4) potential unnecessary diagnostic evaluations, possibly including high-resolution computed tomography scans with their attendant radiation risks;15 and (5) exposure to possible adverse events from therapeutic interventions that have not yet been tested in infants with classical CF, never mind in children with forme fruste CF.

It is important for CF care providers to recognize that newborn screening generally is implemented to identify children at risk of a severe disease for which there is an intervention that will improve quality of life and which, if delayed, will lead to irreversible damage. In our opinion, insufficient data are available to justify changing clinical practice at this time. The New York study raises an important issue that is amenable to a prospective, perhaps multistate or even multinational, evaluation. We will never know the true nature of the risk faced by children carrying CF gene variants if they are not identified and followed through their lifetime; however, such a study should be done in a prospective manner with safeguards in place, such as use of knowledgeable genetic counselors trained to help families understand nuances of genetic tests. Adopting new reference ranges and identifying children who may not have disease as part of a newborn screening algorithm is inappropriate. For more than 40 years, pediatricians have been aware of “phenylketonuria anxiety” generated in families of children with false-positive newborn screens.16 We should be careful to not create “CF anxiety.”

Back to Article Outline

References 

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  2. Parad RB, Comeau AM, Dorkin HL, Dovey M, Gerstle R, Martin T, et al. Sweat testing infants detected by cystic fibrosis newborn screening. J Pediatr. 2005;147:S69–S72
  3. Massie J, Clements B. Diagnosis of cystic fibrosis after newborn screening: the Australasian experience, twenty years and five million babies later (A consensus statement from the Australasian Paediatric Respiratory Group). Pediatr Pulmonol. 2005;39:440–446
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PII: S0022-3476(08)00775-0

doi:10.1016/j.jpeds.2008.09.010

Refers to article:

  • Diagnosis of Cystic Fibrosis by Sweat Testing: Age-Specific Reference Intervals , 01 July 2008

    Avantika Mishra, Ronda Greaves, Katherine Smith, John B. Carlin, Andrew Wootton, Rob Stirling, John Massie
    The Journal of Pediatrics December 2008 (Vol. 153, Issue 6, Pages 758-763.e1)

  • Sweat Chloride Testing in Infants Identified as Heterozygote Carriers by Newborn Screening

    Zafer N. Soultan, Mary M. Foster, Nancy B. Newman, Ran D. Anbar
    The Journal of Pediatrics December 2008 (Vol. 153, Issue 6, Pages 857-859)

The Journal of Pediatrics
Volume 153, Issue 6 , Pages 735-736, December 2008

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