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Correspondence |

Understanding the Relationship Between Sweat Chloride and Lung Function in Cystic FibrosisCystic Fibrosis Sweat Chloride and Lung Function FREE TO VIEW

Sonya L. Heltshe, PhD; Nicole Mayer-Hamblett, PhD; Steven M. Rowe, MD, MSPH
Author and Funding Information

From the Departments of Pediatrics (Drs Heltshe and Mayer-Hamblett) and Biostatistics (Dr Mayer-Hamblett), University of Washington; Seattle Children’s Research Institute (Drs Heltshe and Mayer-Hamblett); and Department of Pediatrics, University of Alabama at Birmingham (Dr Rowe).

Correspondence to: Sonya L. Heltshe, PhD, Seattle Children’s Research Institute, M/S CW8-5B, PO Box 5371, Seattle, WA 98145-5005; e-mail: Sonya.Heltshe@seattlechildrens.org


Editor’s Note: Authors are invited to respond to Correspondence that cites their previously published work. Those responses appear after the related letter. In cases where there is no response, the author of the original article declined to respond or did not reply to our invitation.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Heltshe has received research grant funding from the Cystic Fibrosis Foundation Therapeutics, Inc and the National Institutes of Health. Dr Mayer-Hamblett has received research grant funding from the Cystic Fibrosis Foundation Therapeutics, Inc, the National Institutes of Health, Novartis Corporation, and Vertex Pharmaceuticals Incorporated, and has also served on an advisory board for Insmed. Dr Rowe has received research grant funding from the Cystic Fibrosis Foundation Therapeutics, Inc, the National Institutes of Health, Vertex Pharmaceuticals Incorporated, Novartis Corporation, and PTC Therapeutics and contracts for clinical trials from PTC Therapeutics and Vertex Pharmaceuticals Incorporated, and has provided consulting services for PTC Therapeutics, Vertex Pharmaceuticals Incorporated, and The Cystic Fibrosis Foundation.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;144(4):1418. doi:10.1378/chest.13-1320
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To the Editor:

In a recent issue of CHEST (January 2013), Durmowicz et al1 highlight the finding that despite improvement in both cystic fibrosis (CF) transmembrane conductance regulator (CFTR) and pulmonary function in clinical trials of ivacaftor (recently approved by the US Food and Drug Administration for individuals with CF and the G551D mutation), there does not appear to be a direct correlation between changes in sweat chloride (a measure of CFTR function) and changes in FEV1 (an established efficacy measure). They also were unable to identify a minimum threshold for change in sweat chloride that was associated with FEV1 improvement.

Despite the findings, lack of a linear correlation between the changes in these outcome measures should not diminish the potential utility of sweat chloride for predicting clinical outcomes. Although the data presented failed to show a population level threshold for change in sweat chloride, the absolute sweat chloride concentrations after treatment in the two ivacaftor trials were not assessed. While adult sweat chloride values are highly variable across CF and healthy control subjects,2 concentrations < 60 mM are typical among individuals without CF, and intermediate values are associated with a more benign clinical course. In reanalysis of the ivacaftor trial data, Seliger et al3 show that nearly every participant has a resulting sweat chloride ≤ 80 mM after 2 weeks of treatment, which does not provide the spectrum of response required to readily establish a linear correlation with another outcome. Thus, correlation between changes in sweat chloride and change in FEV1 may not fully capture the predictive ability of sweat chloride.

There is no doubt that FEV1 variability across and within individuals poses a challenge for clinical research in CF. That variability comes from years of infection, inflammation, and structural damage to the lung and can confound treatment effects. Before a meaningful quantitative relationship between CFTR activity and lung function or other clinical outcomes can be established, more work must be done to better understand the complex collection and interaction of physiologic and clinical measures in CF, particularly across diverse patient populations. The evaluation of younger patient populations with mild disease (and for whom lung function cannot be reliably measured nor acute changes expected) poses a particular challenge and highlights the need for robust pharmacodynamic parameters predictive of clinical response. Further discussions between regulatory agencies, trial sponsors, and community advocates will be necessary for monitoring the evolution of biomarkers in the regulatory approval process to ensure availability of beneficial and safe therapies.

References

Durmowicz AG, Witzmann KA, Rosebraugh CJ, Chowdhury BA. Change in sweat chloride as a clinical end point in cystic fibrosis clinical trials: the ivacaftor experience. Chest. 2013;143(1):14-18. [CrossRef] [PubMed]
 
Farrell PM, Rosenstein BJ, White TB, et al; Cystic Fibrosis Foundation. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report. J Pediatr. 2008;153(2):S4-S14. [CrossRef] [PubMed]
 
Seliger VI, Rodman D, Van Goor F, Schmelz A, Mueller P. The predictive potential of the sweat chloride test in cystic fibrosis patients with the G551D mutation [published online ahead of print April 26, 2013]. J Cyst Fibros. doi: 10.1016/j.jcf.2013.03.004.
 

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References

Durmowicz AG, Witzmann KA, Rosebraugh CJ, Chowdhury BA. Change in sweat chloride as a clinical end point in cystic fibrosis clinical trials: the ivacaftor experience. Chest. 2013;143(1):14-18. [CrossRef] [PubMed]
 
Farrell PM, Rosenstein BJ, White TB, et al; Cystic Fibrosis Foundation. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report. J Pediatr. 2008;153(2):S4-S14. [CrossRef] [PubMed]
 
Seliger VI, Rodman D, Van Goor F, Schmelz A, Mueller P. The predictive potential of the sweat chloride test in cystic fibrosis patients with the G551D mutation [published online ahead of print April 26, 2013]. J Cyst Fibros. doi: 10.1016/j.jcf.2013.03.004.
 
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