Skip to main content
Thorax logoLink to Thorax
. 2004 Jul;59(7):608–612. doi: 10.1136/thx.2003.012906

Reduced pH and chloride levels in exhaled breath condensate of patients with chronic cough

A Niimi 1, L Nguyen 1, O Usmani 1, B Mann 1, K Chung 1
PMCID: PMC1747079  PMID: 15223872

Abstract

Background: Increased hydrogen and reduced chloride ionic environments of the airways are conducive to the stimulation of cough. However, the constituents of the local milieu of the airways of patients with chronic cough are unknown.

Methods: The pH and chloride levels in exhaled breath condensate and capsaicin cough threshold (C5) were measured in 50 patients with chronic cough and in 16 healthy controls. pH and chloride measurements were repeated after capsaicin challenge in those with cough. The cause of cough was asthma (n = 13), postnasal drip/rhinitis (n = 7), gastro-oesophageal reflux (n = 5), bronchiectasis (n = 5), but remained unidentified in 20.

Results: Compared with controls, patients with chronic cough had lower pH (mean 7.9 v 8.3, 95% CI of difference –0.5 to –0.2, p<0.0001), chloride levels (median 4 v 6 mmol/l, 95% CI –3.1 to –0.2, p = 0.007), and C5 (median 3.9 v 125 µM, 95% CI –270.0 to –17.6, p = 0.002). The pH levels were different in the six subgroups including controls, and were reduced in all diagnostic subgroups of patients with cough compared with controls but did not differ between them. Chloride levels were significantly different in the six subgroups but were lower than controls in only the gastro-oesophageal reflux subgroup. There was a weak but significant correlation between chloride levels and C5 when all participants were analysed together, but not between pH and C5 or chloride levels. pH and chloride levels did not change after capsaicin challenge.

Conclusions: The epithelial lining fluid of patients with chronic cough has a reduced pH and reduced chloride levels which could contribute to the enhanced cough reflex.

Full Text

The Full Text of this article is available as a PDF (125.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bennett W. D., Chapman W. F., Mascarella J. M. The acute effect of ipratropium bromide bronchodilator therapy on cough clearance in COPD. Chest. 1993 Feb;103(2):488–495. doi: 10.1378/chest.103.2.488. [DOI] [PubMed] [Google Scholar]
  2. Boulet L. P., Milot J., Boutet M., St Georges F., Laviolette M. Airway inflammation in nonasthmatic subjects with chronic cough. Am J Respir Crit Care Med. 1994 Feb;149(2 Pt 1):482–489. doi: 10.1164/ajrccm.149.2.8306050. [DOI] [PubMed] [Google Scholar]
  3. Brightling C. E., Symon F. A., Birring S. S., Bradding P., Wardlaw A. J., Pavord I. D. Comparison of airway immunopathology of eosinophilic bronchitis and asthma. Thorax. 2003 Jun;58(6):528–532. doi: 10.1136/thorax.58.6.528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Choudry N. B., Fuller R. W. Sensitivity of the cough reflex in patients with chronic cough. Eur Respir J. 1992 Mar;5(3):296–300. [PubMed] [Google Scholar]
  5. Chung K. F. Cough: potential pharmacological developments. Expert Opin Investig Drugs. 2002 Jul;11(7):955–963. doi: 10.1517/13543784.11.7.955. [DOI] [PubMed] [Google Scholar]
  6. Chung K. F., Lalloo U. G. Diagnosis and management of chronic persistent dry cough. Postgrad Med J. 1996 Oct;72(852):594–598. doi: 10.1136/pgmj.72.852.594. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fox A. J., Barnes P. J., Dray A. Stimulation of guinea-pig tracheal afferent fibres by non-isosmotic and low-chloride stimuli and the effect of frusemide. J Physiol. 1995 Jan 1;482(Pt 1):179–187. doi: 10.1113/jphysiol.1995.sp020508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fox A. J., Urban L., Barnes P. J., Dray A. Effects of capsazepine against capsaicin- and proton-evoked excitation of single airway C-fibres and vagus nerve from the guinea-pig. Neuroscience. 1995 Aug;67(3):741–752. doi: 10.1016/0306-4522(95)00115-y. [DOI] [PubMed] [Google Scholar]
  9. Gibson P. G., Fujimura M., Niimi A. Eosinophilic bronchitis: clinical manifestations and implications for treatment. Thorax. 2002 Feb;57(2):178–182. doi: 10.1136/thorax.57.2.178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Grodzicky T., Elkon K. B. Apoptosis in rheumatic diseases. Am J Med. 2000 Jan;108(1):73–82. doi: 10.1016/s0002-9343(99)00332-0. [DOI] [PubMed] [Google Scholar]
  11. Hunt J. F., Fang K., Malik R., Snyder A., Malhotra N., Platts-Mills T. A., Gaston B. Endogenous airway acidification. Implications for asthma pathophysiology. Am J Respir Crit Care Med. 2000 Mar;161(3 Pt 1):694–699. doi: 10.1164/ajrccm.161.3.9911005. [DOI] [PubMed] [Google Scholar]
  12. Hunt John F., Erwin Elizabeth, Palmer Lisa, Vaughan John, Malhotra Neil, Platts-Mills Thomas A. E., Gaston Benjamin. Expression and activity of pH-regulatory glutaminase in the human airway epithelium. Am J Respir Crit Care Med. 2002 Jan 1;165(1):101–107. doi: 10.1164/ajrccm.165.1.2104131. [DOI] [PubMed] [Google Scholar]
  13. Irwin R. S., Curley F. J., French C. L. Chronic cough. The spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy. Am Rev Respir Dis. 1990 Mar;141(3):640–647. doi: 10.1164/ajrccm/141.3.640. [DOI] [PubMed] [Google Scholar]
  14. Jatakanon A., Lalloo U. G., Lim S., Chung K. F., Barnes P. J. Increased neutrophils and cytokines, TNF-alpha and IL-8, in induced sputum of non-asthmatic patients with chronic dry cough. Thorax. 1999 Mar;54(3):234–237. doi: 10.1136/thx.54.3.234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Jayaraman S., Joo N. S., Reitz B., Wine J. J., Verkman A. S. Submucosal gland secretions in airways from cystic fibrosis patients have normal [Na(+)] and pH but elevated viscosity. Proc Natl Acad Sci U S A. 2001 Jun 26;98(14):8119–8123. doi: 10.1073/pnas.131087598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Jordt S. E., Tominaga M., Julius D. Acid potentiation of the capsaicin receptor determined by a key extracellular site. Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):8134–8139. doi: 10.1073/pnas.100129497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kastelik Jack A., Thompson Rachel H., Aziz Imran, Ojoo Josephine C., Redington Anthony E., Morice Alyn H. Sex-related differences in cough reflex sensitivity in patients with chronic cough. Am J Respir Crit Care Med. 2002 Oct 1;166(7):961–964. doi: 10.1164/rccm.2109061. [DOI] [PubMed] [Google Scholar]
  18. Kharitonov S. A., Barnes P. J. Exhaled markers of pulmonary disease. Am J Respir Crit Care Med. 2001 Jun;163(7):1693–1722. doi: 10.1164/ajrccm.163.7.2009041. [DOI] [PubMed] [Google Scholar]
  19. Kollarik Marian, Undem Bradley J. Mechanisms of acid-induced activation of airway afferent nerve fibres in guinea-pig. J Physiol. 2002 Sep 1;543(Pt 2):591–600. doi: 10.1113/jphysiol.2002.022848. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kostikas Konstantinos, Papatheodorou Georgios, Ganas Konstantinos, Psathakis Konstantinos, Panagou Panos, Loukides Stelios. pH in expired breath condensate of patients with inflammatory airway diseases. Am J Respir Crit Care Med. 2002 May 15;165(10):1364–1370. doi: 10.1164/rccm.200111-068OC. [DOI] [PubMed] [Google Scholar]
  21. Lalloo U. G., Lim S., DuBois R., Barnes P. J., Chung K. F. Increased sensitivity of the cough reflex in progressive systemic sclerosis patients with interstitial lung disease. Eur Respir J. 1998 Mar;11(3):702–705. [PubMed] [Google Scholar]
  22. Laude E. A., Higgins K. S., Morice A. H. A comparative study of the effects of citric acid, capsaicin and resiniferatoxin on the cough challenge in guinea-pig and man. Pulm Pharmacol. 1993 Sep;6(3):171–175. doi: 10.1006/pulp.1993.1023. [DOI] [PubMed] [Google Scholar]
  23. Lowry R. H., Wood A. M., Higenbottam T. W. Effects of pH and osmolarity on aerosol-induced cough in normal volunteers. Clin Sci (Lond) 1988 Apr;74(4):373–376. doi: 10.1042/cs0740373. [DOI] [PubMed] [Google Scholar]
  24. McGarvey L. P., Forsythe P., Heaney L. G., MacMahon J., Ennis M. Bronchoalveolar lavage findings in patients with chronic nonproductive cough. Eur Respir J. 1999 Jan;13(1):59–65. doi: 10.1183/09031936.99.13105999. [DOI] [PubMed] [Google Scholar]
  25. McShane D., Davies J. C., Davies M. G., Bush A., Geddes D. M., Alton E. W. F. W. Airway surface pH in subjects with cystic fibrosis. Eur Respir J. 2003 Jan;21(1):37–42. doi: 10.1183/09031936.03.00027603. [DOI] [PubMed] [Google Scholar]
  26. Morice Alyn H. Epidemiology of cough. Pulm Pharmacol Ther. 2002;15(3):253–259. doi: 10.1006/pupt.2002.0352. [DOI] [PubMed] [Google Scholar]
  27. Niimi A., Amitani R., Suzuki K., Tanaka E., Murayama T., Kuze F. Eosinophilic inflammation in cough variant asthma. Eur Respir J. 1998 May;11(5):1064–1069. doi: 10.1183/09031936.98.11051064. [DOI] [PubMed] [Google Scholar]
  28. Niimi A., Matsumoto H., Minakuchi M., Kitaichi M., Amitani R. Airway remodelling in cough-variant asthma. Lancet. 2000 Aug 12;356(9229):564–565. doi: 10.1016/S0140-6736(00)02584-8. [DOI] [PubMed] [Google Scholar]
  29. Sasse S. A., Causing L. A., Mulligan M. E., Light R. W. Serial pleural fluid analysis in a new experimental model of empyema. Chest. 1996 Apr;109(4):1043–1048. doi: 10.1378/chest.109.4.1043. [DOI] [PubMed] [Google Scholar]
  30. Tate S., MacGregor G., Davis M., Innes J. A., Greening A. P. Airways in cystic fibrosis are acidified: detection by exhaled breath condensate. Thorax. 2002 Nov;57(11):926–929. doi: 10.1136/thorax.57.11.926. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Tominaga M., Caterina M. J., Malmberg A. B., Rosen T. A., Gilbert H., Skinner K., Raumann B. E., Basbaum A. I., Julius D. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron. 1998 Sep;21(3):531–543. doi: 10.1016/s0896-6273(00)80564-4. [DOI] [PubMed] [Google Scholar]
  32. Ventresca P. G., Nichol G. M., Barnes P. J., Chung K. F. Inhaled furosemide inhibits cough induced by low chloride content solutions but not by capsaicin. Am Rev Respir Dis. 1990 Jul;142(1):143–146. doi: 10.1164/ajrccm/142.1.143. [DOI] [PubMed] [Google Scholar]
  33. Wong C. H., Matai R., Morice A. H. Cough induced by low pH. Respir Med. 1999 Jan;93(1):58–61. doi: 10.1016/s0954-6111(99)90078-1. [DOI] [PubMed] [Google Scholar]

Articles from Thorax are provided here courtesy of BMJ Publishing Group

RESOURCES