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Editorial |

The Problem of Treating Unexplained Chronic Cough FREE TO VIEW

Eva Millqvist, MD, PhD
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FINANCIAL/NONFINANCIAL DISCLOSURES: None declared.

CORRESPONDENCE TO: Eva Millqvist, MD, PhD, Department of Internal Medicine/Respiratory Medicine and Allergology, Sahlgrenska University Hospital, University of Gothenburg, SE 413 45 Gothenburg, Sweden


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;149(3):613-614. doi:10.1016/j.chest.2015.12.008
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Various terms are used to describe a chronic cough that has no obvious medical explanation; these terms include chronic refractory cough, chronic idiopathic cough, and chronic persistent cough. The terminology in this topic is challenging and a general problem in scientific reports, all of which describe a condition that is often misdiagnosed and unsuccessfully treated.

FOR RELATED ARTICLE SEE PAGE 639

Unexplained chronic cough (UCC) is a frustrating condition not only for the patients but also for physicians involved in efforts to treat these patients. Although non-life-threatening, chronic cough influences social activity and quality of life. Most patients with significant symptoms have been extensively examined and have tried a variety of asthma, COPD, and cough medications. Treatment failure is more the rule than the exception, despite evident links between a number of respiratory conditions and aspects of coughing. In recent years, a new concept of cough hypersensitivity as a clinically useful paradigm has been developed to categorize patients with chronic cough under the “umbrella” of cough hypersensitivity syndrome (CHS). CHS comprises patients who have a chronic cough that is often triggered by low levels of thermal, mechanical, or chemical exposure, with or without pathologic medical findings. CHS is closely related to the condition described as laryngeal hypersensitivity syndrome.

The key to successful management of chronic cough may be to disregard old concepts (eg, use of asthma medications such as β2-agonists and inhaled steroids) as cures for UCC. There is growing evidence that in many cases, UCC is not caused by eosinophilic asthmatic inflammation (which we have developed an expertise in treating during the last decades) or the neutrophilic inflammation found in COPD. Instead, assessing how similar conditions in other organ systems are explained and managed could lead to greater treatment success. Chronic pain and chronic itch may be the result of various neuropathic disorders and have several similarities to chronic cough. As a parallel to the treatment of pain and itch, UCC should now perhaps be treated as a sensory neuropathic disorder, in concordance with earlier findings of neurogenic inflammation in such cough., Transient receptor potential (TRP) ion channels on airway sensory nerves are key players in the cough reflex, and the TRPs have gained much interest during the last decade as possible targets for various airway conditions, among them chronic cough following cough reflex sensitization and increased expression of TRPs. Although the current results are not in unison, research regarding TRP inhibitors in the treatment of cough is quickly developing. The findings of a cough reflex desensitization with the use of orally administered capsaicin indicate the possibility of improving both cough symptoms and cough reflex sensitivity, although it is not clear whether the effect mechanism is peripheral or central.

Centrally acting drugs such as codeine and morphine can influence the central reflex control of coughing but are associated with well-known adverse effects. Cough hypersensitivity may occur at both the peripheral and central levels, or both; in accordance with the use of gabapentin for neuropathic pain, such medications in chronic cough also exerted positive effects on cough symptoms. In this issue of CHEST (see page 639), Vertigan et al found that a combination of pregabalin and speech therapy improved cough severity, cough frequency, and cough quality of life in patients with UCC. The study included patients with earlier treatment failure and no obvious medical explanation for coughing. By using a cough monitor and measuring cough severity with validated instruments such as a visual analogue scale and the Leicester Cough Questionnaire, the authors produced reliable results supporting the treatment of chronic cough with a centrally acting neuromodulatory drug, together with speech therapy probably targeting peripheral mechanisms. The findings remind us to use nonpharmacologic methods as options for managing difficult-to-treat conditions. Although it is necessary to be aware of potential adverse effects when using centrally acting medications, the article by Vertigan et al gives important signals for physicians to try new methods in cough treatment and the need for new guidelines in chronic cough. Such guidelines, suggesting a new way to assess and treat UCC, are now being developed based on a systematic review of randomized controlled clinical trials using CHEST organization methodology. An expert panel valued the efficacy of treatment compared with customary care on cough severity, cough frequency, and cough-related quality of life. Both speech pathology-based cough suppression and neuromodulatory drugs were suggested as treatment options. The guidelines also highlight our current limited knowledge and suggest UCC as an area for future research for determining uniformed terminology, methods of investigations, and treatment policy.

References

Irwin R.S. .French C.T. .Fletcher K.E. . Quality of life in coughers. Pulm Pharmacol Ther. 2002;15:283-286 [PubMed]journal. [CrossRef] [PubMed]
 
Morice A.H. .Millqvist E. .Belvisi M.G. .et al Expert opinion on the cough hypersensitivity syndrome in respiratory medicine. Eur Respir J. 2014;44:1132-1148 [PubMed]journal. [CrossRef] [PubMed]
 
Vertigan A.E. .Bone S.L. .Gibson P.G. . Laryngeal sensory dysfunction in laryngeal hypersensitivity syndrome. Respirology. 2013;18:948-956 [PubMed]journal. [CrossRef] [PubMed]
 
Ji R.R. . Neuroimmune interactions in itch: Do chronic itch, chronic pain, and chronic cough share similar mechanisms? Pulm Pharmacol Ther. 2015;35:81-86 [PubMed]journal. [CrossRef] [PubMed]
 
Chung K. .McGarvey L. .Mazzone S. . Chronic cough as a neuropathic disorder. Lancet Respir Med. 2013;1:412-422 [PubMed]journal
 
Niimi A. .Torrego A. .Nicholson A.G. .Cosio B.G. .Oates T.B. .Chung K.F. . Nature of airway inflammation and remodeling in chronic cough. J Allergy Clin Immunol. 2005;116:565-570 [PubMed]journal. [CrossRef] [PubMed]
 
Caterina M.J. .Schumacher M.A. .Tominaga M. .Rosen T.A. .Levine J.D. .Julius D. . The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature. 1997;389:816-824 [PubMed]journal. [CrossRef] [PubMed]
 
Kaneko Y. .Szallasi A. . Transient receptor potential (TRP) channels: a clinical perspective. Br J Pharmacol. 2014;171:2474-2507 [PubMed]journal. [CrossRef] [PubMed]
 
Bonvini S.J. .Birrell M.A. .Smith J.A. .Belvisi M.G. . Targeting TRP channels for chronic cough: from bench to bedside. Naunyn Schmiedebergs Arch Pharmacol. 2015;388:401-420 [PubMed]journal. [CrossRef] [PubMed]
 
Ternesten-Hasseus E. .Johansson E.L. .Millqvist E. . Cough reduction using capsaicin. Respir Med. 2015;109:27-37 [PubMed]journal. [CrossRef] [PubMed]
 
Ryan N.M. .Birring S.S. .Gibson P.G. . Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial. Lancet. 2012;380:1583-1589 [PubMed]journal. [CrossRef] [PubMed]
 
Vertigan A.E. .Kapela S.L. .Ryan N.M. .Birring S.S. .McElduff P. .Gibson P.G. . Pregabalin and speech pathology combination therapy for refractory chronic cough: a randomized controlled trial. Chest. 2016;149:639-648 [PubMed]journal
 
Gibson P. .Wang G. .McGarvey L. .Vertigan A.E. .Altman K.W. .Birring S.S. . Treatment of unexplained chronic cough: CHEST guideline and expert panel report. Chest. 2016;149:27-44 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Tables

References

Irwin R.S. .French C.T. .Fletcher K.E. . Quality of life in coughers. Pulm Pharmacol Ther. 2002;15:283-286 [PubMed]journal. [CrossRef] [PubMed]
 
Morice A.H. .Millqvist E. .Belvisi M.G. .et al Expert opinion on the cough hypersensitivity syndrome in respiratory medicine. Eur Respir J. 2014;44:1132-1148 [PubMed]journal. [CrossRef] [PubMed]
 
Vertigan A.E. .Bone S.L. .Gibson P.G. . Laryngeal sensory dysfunction in laryngeal hypersensitivity syndrome. Respirology. 2013;18:948-956 [PubMed]journal. [CrossRef] [PubMed]
 
Ji R.R. . Neuroimmune interactions in itch: Do chronic itch, chronic pain, and chronic cough share similar mechanisms? Pulm Pharmacol Ther. 2015;35:81-86 [PubMed]journal. [CrossRef] [PubMed]
 
Chung K. .McGarvey L. .Mazzone S. . Chronic cough as a neuropathic disorder. Lancet Respir Med. 2013;1:412-422 [PubMed]journal
 
Niimi A. .Torrego A. .Nicholson A.G. .Cosio B.G. .Oates T.B. .Chung K.F. . Nature of airway inflammation and remodeling in chronic cough. J Allergy Clin Immunol. 2005;116:565-570 [PubMed]journal. [CrossRef] [PubMed]
 
Caterina M.J. .Schumacher M.A. .Tominaga M. .Rosen T.A. .Levine J.D. .Julius D. . The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature. 1997;389:816-824 [PubMed]journal. [CrossRef] [PubMed]
 
Kaneko Y. .Szallasi A. . Transient receptor potential (TRP) channels: a clinical perspective. Br J Pharmacol. 2014;171:2474-2507 [PubMed]journal. [CrossRef] [PubMed]
 
Bonvini S.J. .Birrell M.A. .Smith J.A. .Belvisi M.G. . Targeting TRP channels for chronic cough: from bench to bedside. Naunyn Schmiedebergs Arch Pharmacol. 2015;388:401-420 [PubMed]journal. [CrossRef] [PubMed]
 
Ternesten-Hasseus E. .Johansson E.L. .Millqvist E. . Cough reduction using capsaicin. Respir Med. 2015;109:27-37 [PubMed]journal. [CrossRef] [PubMed]
 
Ryan N.M. .Birring S.S. .Gibson P.G. . Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial. Lancet. 2012;380:1583-1589 [PubMed]journal. [CrossRef] [PubMed]
 
Vertigan A.E. .Kapela S.L. .Ryan N.M. .Birring S.S. .McElduff P. .Gibson P.G. . Pregabalin and speech pathology combination therapy for refractory chronic cough: a randomized controlled trial. Chest. 2016;149:639-648 [PubMed]journal
 
Gibson P. .Wang G. .McGarvey L. .Vertigan A.E. .Altman K.W. .Birring S.S. . Treatment of unexplained chronic cough: CHEST guideline and expert panel report. Chest. 2016;149:27-44 [PubMed]journal. [CrossRef] [PubMed]
 
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