Sixty-five years since the New York heat wave: Advances in sweat testing for cystic fibrosis

Abstract

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.

A randomised, double-blind, placebo-controlled trial of repeated nebulisation of non-viral cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy in patients with cystic fibrosis

“…Lack of chloride ion reabsorption by CFTR in the sweat gland leads to high levels being lost in the sweat, typically > 100 mmol/l in comparison with values of < 30 mmol/l in healthy individuals. 9 Diagnosis can also be established on CFTR mutation testing, although, because of the large number of mutations, a negative test cannot rule out the diagnosis unless the entire CFTR gene has been sequenced; this is rarely employed as a first-line diagnostic tool and is reserved for difficult diagnoses. However, whereas previously it may have been sufficient to secure a diagnosis on the basis of a sweat test, with the recent development of mutation-specific small-molecule treatments, 10 it is becoming increasingly necessary for a patient's mutation(s) to be defined.…”

Targeting ion channels in cystic fibrosis

“…CFTR malfunction also causes obstruction of pancreatic and biliary ducts (resulting in nutrient malabsorption and liver disease), infertility (particularly in men), meconium ileus at birth, and diabetes [15][16][17][18]. Another characteristic feature of most CF patients is the elevated concentration of sodium chloride in sweat [19]. Restoration of anion transport in defective cells is therefore considered as an important goal of therapeutic strategies in CF.…”

Sources of Variation in Sweat Chloride Measurements in Cystic Fibrosis

“…This variation is likely not unique to individuals with CF, because studies of all patients presenting for sweat chloride testing found within-subject variability ranging between 8.3 and 20.2% (median coefficient of variation) (22,39). Site-to-site differences in measurement cause further variation among individuals with identical CFTR genotypes, particularly if different techniques are used for measurement (40,41). Although testing variability seems to be decreasing with time, revisiting methods to standardize sweat testing among centers could address this tractable source of variation.…”