The predictive potential of the sweat chloride test in cystic fibrosis patients with the G551D mutation

Seliger, Verena; Rodman, David M.; Goor, Fredrick Van; Schmelz, Andreas; Mueller, Peter S.

doi:10.1016/j.jcf.2013.03.004

Cited by 25 publications

(20 citation statements)

References 25 publications

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“…Sweat chloride changes occur within days of ivacaftor, as seen in G551D patients, so that by the end of 2 weeks a steady state response has been achieved. Decreased sweat chloride concentration at 2 weeks is predictive of long‐term improvements in pulmonary function and weight gain in patients with gating mutations . However, other studies of ivacaftor in R117H mutation also failed to show an improvement in pulmonary function with long courses of ivacaftor despite improvements in sweat chloride concentration .…”

Section: Discussionmentioning

confidence: 96%

In vivo and in vitro ivacaftor response in cystic fibrosis patients with residual CFTR function: N‐of‐1 studies

McGarry

Illek²,

et al. 2017

Pediatric Pulmonology

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Summary Rationale: Ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, decreases sweat chloride concentration, and improves pulmonary function in 6% of cystic fibrosis (CF) patients with specific CFTR mutations. Ivacaftor increases chloride transport in many other CFTR mutations in non-human cells, if CFTR is in the epithelium. Some CF patients have CFTR in the epithelium with residual CFTR function. The effect of ivacaftor in these patients is unknown. Methods: This was a series of randomized, crossover N-of-1 trials of ivacaftor and placebo in CF patients ≥8 years old with potential residual CFTR function (intermediate sweat chloride concentration, pancreatic sufficient, or mild bronchiectasis on chest CT). Human nasal epithelium (HNE) was obtained via nasal brushing and cultured. Sweat chloride concentration change was the in vivo outcome. Chloride current change in HNE cultures with ivacaftor was the in vitro outcome. Results: Three subjects had decreased sweat chloride concentration (−14.8 to −40.8 mmol/L, P<0.01). Two subjects had unchanged sweat chloride concentration. Two subjects had increased sweat chloride concentration (+23.8 and +27.3 mmol/L, P<0.001); both were heterozygous for A455E and pancreatic sufficient. Only subjects with decreased sweat chloride concentration had increased chloride current in HNE cultures. Conclusions: Some CF patients with residual CFTR function have decreased sweat chloride concentration with ivacaftor. Increased chloride current in HNE cultures among subjects with decreased sweat chloride concentrations may predict clinical response to ivacaftor. Ivacaftor can increase sweat chloride concentration in certain mutations with unclear clinical effect.

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Section: Discussionmentioning

confidence: 96%

In vivo and in vitro ivacaftor response in cystic fibrosis patients with residual CFTR function: N‐of‐1 studies

McGarry

Illek²,

et al. 2017

Pediatric Pulmonology

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“…The sweat secretion test could not, however, detect a difference between pancreatic-sufficient and -insufficient patients with CF and did not find a difference in most patients with CFTR-related disorders, whereas sweat chloride concentration and NPD show a difference between these groups. There is evidence to suggest that early sweat chloride response may indicate a higher likelihood of longer-term sweat chloride change (up to Week 16) in patients treated with a CFTR potentiator (31). While sweat chloride may be a useful activity biomarker in clinical studies of CFTR potentiators, there has been no correlation between changes in sweat chloride concentration and clinical outcomes (30).…”

Section: Discussionmentioning

confidence: 99%

Sweat chloride as a biomarker of CFTR activity: Proof of concept and ivacaftor clinical trial data

Accurso

Goor

Zha

et al. 2014

Journal of Cystic Fibrosis

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Background We examined data from a Phase 2 trial {NCT00457821 } of ivacaftor, a CFTR potentiator, in cystic fibrosis (CF) patients with a G551D mutation to evaluate standardized approaches to sweat chloride measurement and to explore the use of sweat chloride and nasal potential difference (NPD) to estimate CFTR activity. Methods Sweat chloride and NPD were secondary endpoints in this placebo-controlled, multicenter trial. Standardization of sweat collection, processing, and analysis was employed for the first time.. Sweat chloride and chloride ion transport (NPD) were integrated into a model of CFTR activity. Results Within-patient sweat chloride determinations showed sufficient precision to detect differences between dose-groups and assess ivacaftor treatment effects. Analysis of changes in sweat chloride and NPD demonstrated that patients treated with ivacaftor achieved CFTR activity equivalent to approximately 35%–40% of normal. Conclusions Sweat chloride is useful in multicenter trials as a biomarker of CFTR activity and to test the effect of CFTR potentiators.

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“…By reporting on relative changes, our data may better account for a potentially heterogeneous group at baseline and enhances the fact that no correlation exists. Additionally, although sweat chloride has been proposed as a sensitive and specific predictor of subsequent improvement in lung function for patients treated with Ivacaftor, the thresholds for response were lower than those required by UK commissioners and the poor negative predictive value of the sweat chloride response meant that it was unsuitable as a clinical test 3. Finally, as a marker of adherence, sweat chloride appears to be excessively sensitive to individual missed doses and gives no useful information about longer-term adherence.…”

Section: Discussionmentioning

confidence: 99%

Sweat chloride is not a useful marker of clinical response to Ivacaftor

Barry

Jones

Webb

et al. 2013

Thorax

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The predictive potential of the sweat chloride test in cystic fibrosis patients with the G551D mutation

Abstract: Changes in sweat chloride concentration at day 15 following treatment with ivacaftor may have sufficient predictive potential to identify individuals that show improvement in pulmonary function and weight gain after 16 weeks of treatment.

Cited by 25 publications

References 25 publications

In vivo and in vitro ivacaftor response in cystic fibrosis patients with residual CFTR function: N‐of‐1 studies

In vivo and in vitro ivacaftor response in cystic fibrosis patients with residual CFTR function: N‐of‐1 studies

Sweat chloride as a biomarker of CFTR activity: Proof of concept and ivacaftor clinical trial data

Sweat chloride is not a useful marker of clinical response to Ivacaftor

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