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Thorax. 2007 May; 62(5): 463.
PMCID: PMC2117191

Authors' reply

We thank Dr Naehrlich for commenting on the Cystic Fibrosis Diagnostic Network consensus.1 The first comment is correct. Adequacy of sweat collection is dealt with clearly in the guidance for performing sweat tests for investigating cystic fibrosis (CF) in the UK. The Multidisciplinary Working Group gives calculations for assessing the adequacy of collection (http//:www.acb.org.uk). A minimum sweat rate of 1 g/m2/min is required. This does indeed relate to the sampling surface and an error occurred in the published paper.

With regard to the method of sampling, the members of the Diagnostic Network Group did discuss this in detail. There is increasing evidence that the Macroduct system gives an acceptable collection, but direct comparison with the method of Gibson and Cooke shows that an inadequate sweat collection is more likely with the Macroduct system (6.1% vs 0.7%). Also, where the Macroduct collection is linked to analysis using conductivity (which measures total ionic concentration rather than chloride), there is a higher rate of false positivity (results falling within the borderline range) than with the traditional Gibson and Cooke method, and this is a particular concern when investigating non‐classic disease. However, there is no increased likelihood of false negative results with the Macroduct technique.

In the UK even laboratories currently using the Macroduct system continue to analyse chloride conductivity to comply with the National Quality Control regulations. Two large studies using capillary collections linked with conductivity showed good correlation between this methodology and iontophoresis with determination of chloride concentration.2 However, the technique has not been examined critically in patients with non‐classic disease and, because of this and the increased likelihood of obtaining an inadequate sweat collection, the Diagnostic Network Group continues to advocate the Gibson and Cooke method in combination with direct measurements of chloride.

The evidence that a proportion of CF patients with chloride concentrations of 30–60 mmol/l will be found to have two CFTR mutations is recent and has evolved following CFTR mutation testing. These data would not have been available before the development of mutation testing, and this information supersedes previous data on the limits of sweat test chloride concentrations. As shown by Lebecque et al,3 sweat test results between 30 and 60 mmol/l are uncommon—about 4% of more than 2300 sweat tests performed. It is the only paper in which mutation scanning was done using the range 30–60 mmol/l. Indeed, most studies have focused on a chloride range of 40–60 mmol/l and cannot state any conclusion about the range 30–60 mmol/l.4 But when one reads the papers carefully, it is obvious that others also regularly report and diagnose CF by detection of two CFTR mutations in patients with sweat chloride values below 40 mmol/l.

Josserand et al5 studied 50 men with congenital bilateral absence of the vas deferens. Three of the 11 patients in whom two CFTR mutations were detected had a sweat chloride level below 40 mmol/l. Highsmith et al6 reported a novel mutation in patients with pulmonary disease and “normal” sweat chloride concentrations. Again, 3 of the 13 patients had a sweat chloride level of 30–39 mmol/l and 7 had levels between 40 and 59 mmol/l.

In the UK guidelines on sweat testing, 40 mmol/l is considered as the lower limit but the data supporting this were only graded B evidence level 2b and 3. The majority of the studies referred to in the UK document date from the time before genotype analysis and—as stated in the document—“the normals could include some persons with CF or CF‐related disorders”. Only two papers report CF mutations and sweat chloride levels.7,8 The study by Farrell and Koscik7 only concerns newborns, while the study by the CF Genotype‐Phenotype Consortium8 only explores specific genotypes and does not report values for healthy individuals. Furthermore, we do not state that patients with a sweat chloride level above 30 mmol/l suffer from CF. We simply state that, in symptomatic individuals with a sweat chloride level of, for example, 35 mmol/l, further investigation is warranted.

References

1. De Boeck K, Wilschanski M, Castellani C. et al Cystic fibrosis: terminology and diagnostic algorithms. Thorax 2006. 61627–635.635 [PMC free article] [PubMed]
2. Mastella G, DiCesare G, Borruso A. et al Reliability of sweat‐testing by the Macroduct collection method combined with conductivity analysis in comparison with the classic Gibson and Cooke technique. Acta Paediatr 2000. 89933–937.937 [PubMed]
3. Lebecque P, Leal T, DeBoeck C. et al Mutations of the cystic fibrosis gene and intermediate sweat chloride levels in children. Am J Respir Crit Care Med 2002. 165757–761.761 [PubMed]
4. Desmarquest P, Feldmann D, Tamalat A. et al Genotype analysis and phenotypic manifestation of children with intermediate sweat chloride test results. Chest 2000. 1181591–1597.1597 [PubMed]
5. Josserand R N, Bey‐Omar F, Rollet J. et al Cystic fibrosis phenotype evaluation and paternity outcome in 50 males with congenital bilateral absence of vas deferens. Hum Reprod 2001. 102093–2097.2097 [PubMed]
6. Highsmith W E, Burch L H, Zhou Z. et al A novel mutation in the cystic fibrosis gene in patients with pulmonary disease but normal sweat chloride concentrations. N Engl J Med 1994. 331974–980.980 [PubMed]
7. Farrell P M, Koscik R E. Sweat chloride concentrations in infants homozygous or heterozygous for F508 cystic fibrosis. Pediatrics 1996. 97524–528.528 [PubMed]
8. CF Genotype‐Phenotype Consortium Correlation between genotype and phenotype in patients with cystic fibrosis. N Engl J Med 1993. 3291308–1313.1313 [PubMed]

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