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Sweat Chloride & Disease Severity

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Impact of CFTR Dysfunction SwCl and Lung Function SwCl and BMI SwCl and Mortality

CFTR function, SwCl concentration, and disease severity are closely linked

Impaired cystic fibrosis transmembrane conductance regulator (CFTR) protein function initiates a cascade of pathologic effects throughout the body, including in the lungs1-5:

Defective or deficient CFTR protein followed by impaired chloride transport followed by thickened fluid secretions followed by inflammation, inflection, structural changes, followed by reduced organ function Defective or deficient CFTR protein followed by impaired chloride transport followed by thickened fluid secretions followed by inflammation, inflection, structural changes, followed by reduced organ function

Increased SwCl concentration reflects impaired chloride transport, the earliest defect in this cascade.1,6,7

CFTR function can be classified as normal to low, with corresponding sweat chloride (SwCl) concentrations2,3,8-14

Chart showing how sweat chloride concentration is linked to CF diagnosis, and how reducing CFTR function is related to the emergence of CF-related clinical features. Chart showing how sweat chloride concentration is linked to CF diagnosis, and how reducing CFTR function is related to the emergence of CF-related clinical features.

*When accompanied by clinical suspicion, such as positive newborn screen, clinical features, and/or family history of CF.9

Retrospective analysis from McKone et al

Study design15

  • This single retrospective analysis of Cystic Fibrosis Foundation Patient Registry data conducted by McKone et al examined associations between SwCl concentration at the time of CF diagnosis and lung function, nutritional outcomes, and mortality risk over time
  • Analysis included 25,753 patients enrolled between January 1, 1996, and December 31, 2009 who were genotyped and had a sweat chloride concentration measured during the follow-up period
    • Analysis was conducted with data collected in the pre-CFTR modulator era, and thus reflects the natural history of CF
  • SwCl concentration was grouped into three categories of <60, 60 to <80, or ≥80 mmol/L
    • Patients with SwCl concentrations <10 or >160 mmol/L were excluded from the analysis population as these concentrations are outside the range of the test
    • The ≥80 mmol/L category was selected because prior research suggested that ~80 mmol/L may be a possible threshold for increased risk of mortality when considering the natural history of CF

Study limitations15

  • SwCl concentrations in the US Cystic Fibrosis Foundation Patient Registry are not validated, and testing practices may differ between centers
  • SwCl concentrations were measured at diagnosis and thus could be measured at any age
  • Since this analysis was conducted with population-level data, it cannot be directly correlated to the experiences of individual patients

Retrospective analysis from McKone et al

Annual rate of ppFEV1 Decline by SwCl Concentration

Higher CFTR function, as measured by lower SwCl concentration in patients untreated by CFTR modulators, was associated with better lung function (ppFEV1) among groups of patients analyzed15

  • Genotype determines level of CFTR function; as SwCl is a measure of CFTR function, the two variables are highly correlated
  • When genotype and SwCl were entered into the model, the SwCl relationship was no longer statistically significant. Thus, SwCl does not provide additional information regarding future clinical outcomes when genotype is known
Bar graph showing lower rates of annual ppFEV1 decline in patients with lower sweat chloride concentrations Bar graph showing lower rates of annual ppFEV1 decline in patients with lower sweat chloride concentrations

Patients with SwCl concentration <60 mmol/L also had higher mean ppFEV₁ and ppFVC, compared with those patients with higher SwCl concentrations16

Several factors impact pulmonary outcomes in CF, including history of infections, microbial colonization, pulmonary exacerbations, and other comorbidities.3

Retrospective analysis from McKone et al

BMI Percentile by SwCl Concentration

Higher CFTR function, as measured by lower SwCl concentration in patients untreated by CFTR modulators, was associated with higher BMI among groups of patients analyzed15,16

  • Genotype determines level of CFTR function; as SwCl is a measure of CFTR function, the two variables are highly correlated
  • When genotype and SwCl were entered into the model, the SwCl relationship was no longer statistically significant. Thus, SwCl does not provide additional information regarding future clinical outcomes when genotype is known
Bar graph showing higher BMI percentile in patients with lower sweat chloride concentrations. Bar graph showing higher BMI percentile in patients with lower sweat chloride concentrations.

Patients with SwCl concentrations in the <60 mmol/L category had BMIs in the ~50th percentile16

Several factors can impact nutritional outcomes in CF, including time at which nutritional support was initiated, level of pancreatic insufficiency, caloric intake, and nutrient absorption.17

Retrospective analysis from McKone et al

Risk of Mortality Over Time by SwCl Concentration

Higher CFTR function, as measured by lower SwCl concentration in patients untreated by CFTR modulators, was associated with lower risk of mortality among groups of patients analyzed15

  • Genotype determines level of CFTR function; as SwCl is a measure of CFTR function, the two variables are highly correlated
  • When genotype and SwCl were entered into the model, the SwCl relationship was no longer statistically significant. Thus, SwCl does not provide additional information regarding future clinical outcomes when genotype is known
Kaplan-Meier curves showing risk of mortality in patients with sweat chloride concentration <60 mmol/L, 60->80 mmol/L, and ≥80 mmol/L Kaplan-Meier curves showing risk of mortality in patients with sweat chloride concentration <60 mmol/L, 60->80 mmol/L, and ≥80 mmol/L

Adapted from McKone et al, 2015.

Patients with SwCl concentration <60 mmol/L had 51% lower risk of mortality, compared with those with SwCl concentration ≥80 mmol/L (unadjusted hazard ratio 0.49, 95% CI 0.39–0.63)15

BMI, body mass index; CFSPID, CF screen positive, inconclusive diagnosis; CI, confidence interval; CRMS, CFTR-related metabolic syndrome; HR, hazard ratio; ppFEV1, percent predicted forced expiratory volume in 1 second; ppFVC, percent predicted forced vital capacity.

References: 1. Naehrig S, Chao CM, Naehrlich L. Cystic fibrosis: diagnosis and treatment. Dtsch Arztebl Int. 2017;114(33-34):564-574. doi:10.3238/arztebl.2017.0564 2. Ratjen F, Bell SC, Rowe SM, Goss CH, Quittner AL, Bush A. Cystic fibrosis. Nat Rev Dis Primers. 2015;1:15010. doi:10.1038/nrdp.2015.10 3. O’Sullivan BP, Freedman SD. Cystic fibrosis. Lancet. 2009;373:1895-1904. doi:10.1016/S0140-6736(09)60327-5 4. Sakiani S, Kleiner DE, Heller T, Koh C. Hepatic manifestations of cystic fibrosis. Clin Liver Dis. 2019;23(2):263-277. doi:10.1016/j.cld.2018.12.008 5. Colombo C, Ellemunter H, Houwen R, Munck A, Taylor C, Wilschanski M. Guidelines for the diagnosis and management of distal intestinal obstruction syndrome in cystic fibrosis patients. J Cyst Fibros. 2011;10(Suppl 2):S24-S28. doi:10.1016/S1569-1993(11)60005-2 6. Muhlebach MS, Clancy JP, Heltshe SL, et al. Biomarkers for cystic fibrosis drug development. J Cyst Fibros. 2016;15:714-723. 7. Sontag MK. Sweat chloride: the critical biomarker for cystic fibrosis trials. Am J Resp Crit Care Med. 2016;194(1):1311-1312. 8. Farrell PM, White TB, Ren CL, et al. Diagnosis of cystic fibrosis: Consensus guidelines from the Cystic Fibrosis Foundation. J Pediatr. 2017;181S:S4-15. doi:10.1016/j.jpeds.2016.09.064 9. Cystic Fibrosis Foundation. Clinical care guide for diagnosis of cystic fibrosis. https://www.cff.org/sites/default/files/2021-10/Clinical-Care-Guide-for-Diagnosis-of-CF.pdf. Accessed April 1, 2024. 10. Wine JJ. How the sweat gland reveals levels of CFTR activity. J Cyst Fibros. 2022;21:396-406. doi:10.1016/j.jcf.2022.02.001 11. Mishra A, Greaves R, Massie J. The relevance of sweat testing for the diagnosis of cystic fibrosis in the genomic era. Clin Biochem Rev. 2005;26:135-153. 12. Bell SC, Mall MA, Gutierrez H. The Lancet Respiratory Medicine Commission on the future of care of cystic fibrosis. Lancet Respir Med. 2020;8(1):65-124. 13. Pagin A, Sermet-Gaudelus I, Burgel P-R. Genetic diagnosis in practice: From cystic fibrosis to CFTR-related disorders. Arch Pediatr. 2020;27:eS25-eS29. doi: 10.1016/S0929-693X(20)30047-6 14. Barben J, Castellani C, Munck A, et al. Updated guidance on the management of children with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID). J Cyst Fibros. 2021;20:810-819. doi:10.1016/j.jcf.2020.11.006 15. McKone EF, Velentgas P, Swenson AJ, Goss CH. Association of sweat chloride concentration at time of diagnosis and CFTR genotype with mortality and cystic fibrosis phenotype. J Cyst Fibros. 2015;14:580-586. doi:10.1016/j.jcf.2015.01.005 16. Supplement to: McKone EF, Velentgas P, Swenson AJ, Goss CH. Association of sweat chloride concentration at time of diagnosis and CFTR genotype with mortality and cystic fibrosis phenotype. J Cyst Fibros. 2015;14:580-586. doi:10.1016/j.jcf.2015.01.005 17. Zani EM, Grandinetti R, Cunico D, et al. Nutritional care in children with cystic fibrosis. Nutrients. 2023;15:479. doi:10.3390/nu15030479