Highlights
- •Cough is a defense mechanism for clearing the airways but may become troublesome.
- •Chronic cough of known and unknown cause(s) frequently requires medical attention.
- •Chronic cough of known cause(s) must be treated according to guidelines.
- •Chronic refractory cough may benefit from neuromodulatory/speech pathology therapy.
- •Novel promising neuromodulatory agents are in clinical development.
Abstract
Cough, a defense mechanism for clearing the airways of secretions, exudate, or foreign
bodies, may become a troublesome symptom. Chronic cough, one of the most frequent
symptoms requiring medical attention, is often not due to identifiable causes in adults.
Chronic productive cough defines chronic bronchitis, and thus is present in 100% of
these patients, and frequently in patients with bronchiectasis, cystic fibrosis, and
chronic infectious respiratory diseases. However, chronic cough is most frequently
dry. Thus, chronic cough in adults is a difficult syndrome requiring multidisciplinary
approaches, particularly to diagnose and treat the most frequent identifiable causes,
but also to decide which patients may benefit by treating the central cough hypersensitivity
by neuromodulatory therapy and/or non-pharmacologic treatment (speech pathology therapy).
Recent guidelines provide algorithms for diagnosis and assessment of cough severity;
particularly chronic cough in adults. After excluding life-threatening diseases, chronic
cough due to identifiable causes (triggers and/or diseases), particularly smoking
and/or the most frequent diseases (asthma, chronic bronchitis, chronic obstructive
pulmonary disease, eosinophilic bronchitis, and adverse reactions to drugs [angiotensin-converting
enzyme inhibitors and sitagliptin]) should be treated by avoiding triggers and/or
according to guidelines for each underlying disease. In patients with troublesome
chronic cough due to unknown causes or persisting even after adequate avoidance of
triggers, and/or treatment of the underlying disease(s), a symptomatic approach with
neuromodulators and/or speech pathology therapy should be considered. Additional novel
promising neuromodulatory agents in clinical development (e.g., P2X3 inhibitors) will
hopefully become available in the near future.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to European Journal of Internal MedicineAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Heterogeneity of cough neurobiology: clinical implications.Pulm Pharmacol Ther. 2019; 55: 62-66https://doi.org/10.1016/j.pupt.2019.02.002
- Translational review: neuroimmune mechanisms in cough and emerging therapeutic targets.J Allergy Clin Immunol. 2018; 142: 1392-1402https://doi.org/10.1016/j.jaci.2018.09.004
- Managing chronic cough as a symptom in children and management algorithms: chest guideline and expert panel report.Chest. 2020; ([Epub ahead of print])https://doi.org/10.1016/j.chest.2020.01.042
- ERS guidelines on the diagnosis and treatment of chronic cough in adults and children.Eur Respir J. 2020; 55 (pii: 1901136)https://doi.org/10.1183/13993003.01136-2019
- Chronic cough in individuals with COPD: a population-based cohort study.Chest. 2020; (pii: S0012-3692(20)30130-6[Epub ahead of print])https://doi.org/10.1016/j.chest.2019.12.038
- Causes of chronic productive cough: an approach to management.Respir Med. 2015; 109: 1105-1113https://doi.org/10.1016/j.rmed.2015.05.020
- Muco-obstructive lung diseases.N Engl J Med. 2019; 380: 1941-1953https://doi.org/10.1056/NEJMra1813799
- Cough due to TB and other chronic infections: chest guideline and expert panel report.Chest. 2018; 153: 467-497https://doi.org/10.1016/j.chest.2017.11.018
- Chronic cough due to tuberculosis and other infections: ACCP evidence-based clinical practice guidelines.Chest. 2006; 129: 197S-201Shttps://doi.org/10.1378/chest.129.1_suppl.197S
- Epidemiology and impact of chronic bronchitis in chronic obstructive pulmonary disease.Eur Respir J. 2017; 50 (pii: 1602470)https://doi.org/10.1183/13993003.02470-2016
- Role and impact of chronic cough in individuals with asthma from the general population.J Allergy Clin Immunol Pract. 2019; 7 (–92.e8): 1783https://doi.org/10.1016/j.jaip.2019.02.021
- ERS guidelines on the assessment of cough.Eur Respir J. 2007; 29: 1256-1276https://doi.org/10.1183/09031936.00101006
- Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines.Chest. 2006; 129: 1S-23Shttps://doi.org/10.1378/chest.129.1_suppl.1S
- Classification of cough as a symptom in adults and management algorithms: chest guideline and expert panel report.Chest. 2018; 153: 196-209https://doi.org/10.1016/j.chest.2017.10.016
- Cough hypersensitivity syndrome: a few more steps forward.Allergy Asthma Immunol Res. 2017; 9: 394-402https://doi.org/10.4168/aair.2017.9.5.394
- Management of cough.J Allergy Clin Immunol Pract. 2019; 7: 1724-1729https://doi.org/10.1016/j.jaip.2019.03.050
- Recent advances in severe asthma: from phenotypes to personalized medicine.Chest. 2019; 2020: 516-528https://doi.org/10.1016/j.chest.2019.10.009
- Multimorbidity in COPD, does sleep matter?.Eur J Intern Med. 2020; 73: 7-15
- Clinical features of the urge-to-cough in patients with chronic cough.Respir Med. 2015; 109: 701-707https://doi.org/10.1016/j.rmed.2015.03.011
- Laryngeal dysfunction in cough hypersensitivity syndrome: a cross-sectional observational study.J Allergy Clin Immunol Pract. 2018; 6: 2087-2095https://doi.org/10.1016/j.jaip.2018.04.015
- Mechanisms of cough.Curr Opin Allergy Clin Immunol. 2014; 14: 55-61https://doi.org/10.1097/ACI.0000000000000027
- Vagal afferent innervation of the airways in health and disease.Physiol Rev. 2016; 96: 975-1024https://doi.org/10.1152/physrev.00039.2015
- Laryngeal sensory dysfunction in laryngeal hypersensitivity syndrome.Respirology. 2013; 18: 948-956https://doi.org/10.1111/resp.12103
- Distinct brainstem and forebrain circuits receiving tracheal sensory neuron inputs revealed using a novel conditional anterograde transsynaptic viral tracing system.J Neurosci. 2015; 35: 7041-7055https://doi.org/10.1523/JNEUROSCI.5128-14.2015
- Investigation of the neural control of cough and cough suppression in humans using functional brain imaging.J Neurosci. 2011; 31: 2948-2958https://doi.org/10.1523/JNEUROSCI.4597-10.2011
- Chronic cough as a neuropathic disorder.Lancet Respir Med. 2013; 1: 414-422https://doi.org/10.1016/S2213-2600(13)70043-2
- Neuroimmune interactions in itch: do chronic itch, chronic pain, and chronic cough share similar mechanisms?.Pulm Pharmacol Ther. 2015; 35: 81-86https://doi.org/10.1016/j.pupt.2015.09.001
- Central mechanisms of airway sensation and cough hypersensitivity.Pulm Pharmacol Ther. 2017; 47: 9-15https://doi.org/10.1016/j.pupt.2017.01.010
- Transient receptor potential cation channel, subfamily V, member 4 and airway sensory afferent activation: role of adenosine triphosphate.J Allergy Clin Immunol. 2016; 138: 249-261https://doi.org/10.1016/j.jaci.2015.10.044
- In pursuit of P2X3 antagonists: novel therapeutics for chronic pain and afferent sensitization.Purinergic Signal. 2012; 8: 3-26https://doi.org/10.1007/s11302-011-9271-6
- P2X3 449 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study.Lancet. 2015; 385: 1198-1205https://doi.org/10.1016/S0140-6736(14)61255-1
- The effect of gefapixant, a P2X3 antagonist, on cough reflex sensitivity: a randomised placebo-controlled study.Eur Respir J. 2019; 541900439https://doi.org/10.1183/13993003.00439-2019
- Neural correlates of cough hypersensitivity in humans: evidence for central sensitisation and dysfunctional inhibitory control.Thorax. 2016; 71: 323-329https://doi.org/10.1136/thoraxjnl-2015-207425
- Increased expression of transient receptor potential vanilloid-1 in airway nerves of chronic cough.Am J Respir Crit Care Med. 2004; 170: 1276-1280https://doi.org/10.1164/rccm.200402-174OC
- Neuropeptide levels in nasal secretions from patients with and without chronic cough.Ann Allergy Asthma Immunol. 2011; 107: 360-363https://doi.org/10.1016/j.anai.2011.07.010
- Vagal afferent stimulation activates astrocytes in the nucleus of the solitary tract via AMPA receptors: evidence of an atypical neural-glial interaction in the brainstem.J Neurosci. 2011; 31: 14037-14045https://doi.org/10.1523/JNEUROSCI.2855-11.2011
- Chronic cough.N Engl J Med. 2016; 375: 1544-1551https://doi.org/10.1056/NEJMcp1414215
- Therapeutic targets for the treatment of chronic cough.Curr Otorhinolaryngol Rep. 2019; 7 (–28): 116https://doi.org/10.1007/s40136-019-00239-9
- A retrospective survey of diagnosis and management of patients presenting with chronic cough to a general chest clinic.Int J Clin Pract. 1998; 52: 158-161
- An algorithmic approach to chronic cough.Ann Intern Med. 1993; 119: 977-983https://doi.org/10.7326/0003-4819-119-10-199311150-00003
- Cough. 6: which investigations are most useful in the diagnosis of chronic cough?.Thorax. 2004; 59: 342-346https://doi.org/10.1136/thx.2004.021832
- A pathogenic triad in chronic cough: asthma, postnasal drip syndrome and gastroesophageal reflux disease.Chest. 1999; 116: 279-284https://doi.org/10.1378/chest.116.2.279
- Eosinophilic bronchitis is an important cause of chronic cough.Am J Respir Crit Care Med. 1999; 160: 406-410https://doi.org/10.1164/ajrccm.160.2.9810100
- An update on speech pathology management of chronic refractory cough.J Allergy Clin Immunol Pract. 2019; 7: 1756-1761https://doi.org/10.1016/j.jaip.2019.03.030
- Development and validation of the Newcastle laryngeal hypersensitivity questionnaire.Cough. 2014; 10: 1https://doi.org/10.1186/1745-9974-10-1
- Evaluation of a cough-specific quality-of-life questionnaire.Chest. 2002; 121: 1123-1131https://doi.org/10.1378/chest.121.4.1123
- Development of a symptom specific health status measure for patients with chronic cough: leicester cough questionnaire (LCQ).Thorax. 2003; 58: 339-343https://doi.org/10.1136/thorax.58.4.339
- The leicester cough monitor: preliminary validation of an automated cough detection system in chronic cough.Eur Respir J. 2008; 31: 1013-1018https://doi.org/10.1183/09031936.00057407
- Tools for assessing outcomes in studies of chronic cough: chest guideline and expert panel report.Chest. 2015; 147: 804-814https://doi.org/10.1378/chest.14-2506
- Can peak expiratory flow measurements reliably identify the presence of obstruction and bronchodilator response as assessed by FEV1 in primary care patients presenting with a persistent cough?.Thorax. 1999; 54: 1055-1060https://doi.org/10.1136/thx.54.12.1055
- Exhaled nitric oxide as a noninvasive assessment of chronic cough.Am J Respir Crit Care Med. 1999; 159: 1810-1813https://doi.org/10.1164/ajrccm.159.6.9809047
- Rhinovirus infection in nonasthmatic subjects: effects on intrapulmonary airways.Eur Respir J. 2002; 20: 274-279https://doi.org/10.1183/09031936.02.00247202
- A causal relationship between cough and gastroesophageal reflux disease (GERD) has been established: a pro/con debate.Lung. 2014; 192: 39-46https://doi.org/10.1007/s00408-013-9528-7
- Chronic cough due to gastroesophageal reflux disease: accp evidence-based clinical practice guidelines.Chest. 2006; 129: 80S-94Shttps://doi.org/10.1378/chest.129.1_suppl.80S
- Chronic cough due to gastroesophageal reflux. Clinical, diagnostic, and pathogenetic aspects.Chest. 1993; 104: 1511-1517https://doi.org/10.1378/chest.104.5.1511
- Evaluation and outcome of patients with chronic non-productive cough using a comprehensive diagnostic protocol.Thorax. 1998; 53: 738-743https://doi.org/10.1136/thx.53.9.738
- Chronic cough and obstructive sleep apnoea in a sleep laboratory-based pulmonary practice.Cough. 2013; 9: 24https://doi.org/10.1186/1745-9974-9-24
- Chronic tonsillar enlargement and cough: preliminary evidence of a novel and treatable cause of chronic cough.Eur Respir J. 2004; 23: 199-201https://doi.org/10.1183/09031936.03.00066403
- The pathogenetic mechanisms of cough in idiopathic pulmonary fibrosis.Intern Emerg Med. 2019; 14: 39-43https://doi.org/10.1007/s11739-018-1960-5
- Airway abnormalities at flexible bronchoscopy in patients with chronic cough.Eur Respir J. 2007; 30: 1138-1142https://doi.org/10.1183/09031936.00034807
- Opiate therapy in chronic cough.Am J Respir Crit Care Med. 2007; 175: 312-315https://doi.org/10.1164/rccm.200607-892OC
- Multimorbidity: assessment, prioritisation and management of care for people with commonly occurring multimorbidity.National Institute for Health and Care Excellence (UK), London2016 (NICE Guideline NG56, https://www.ncbi.nlm.nih.gov/books/NBK385543/; [accessed 21 January 2020])
- Cough: new pharmacology.J Allergy Clin Immunol Pract. 2019; 7: 1731-1738https://doi.org/10.1016/j.jaip.2019.04.027
Global Initiative for Asthma (GINA), https://www.ginasthma.org; 2019[accessed 11 January 2020].
- Chronic cough due to nonasthmatic eosinophilic bronchitis: ACCP evidence-based clinical practice guidelines.Chest. 2006; 129 (-21S): 116https://doi.org/10.1378/chest.129.1_suppl.116S
- Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease.N Engl J Med. 2007; 356: 775-789https://doi.org/10.1056/NEJMoa063070
- Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial.Lancet. 2012; 380: 1583-1589https://doi.org/10.1016/S0140-6736(12)60776-4
- Pregabalin and speech pathology combination therapy for refractory chronic cough: a randomized controlled trial.Chest. 2016; 149: 639-648https://doi.org/10.1378/chest.15-1271
- Central regulation of the cough reflex: therapeutic implications.Pulm Pharmacol Ther. 2009; 22: 75-81https://doi.org/10.1016/j.pupt.2009.01.003
- A randomized clinical trial comparing the effects of antitussive agents on respiratory center output in patients with chronic cough.Chest. 2017; 151: 1288-1294https://doi.org/10.1016/j.chest.2017.02.001
- Mucolytic agents versus placebo for chronic bronchitis or chronic obstructive pulmonary disease.Cochrane Database Syst Rev. 2019; 5CD001287https://doi.org/10.1002/14651858.CD001287
- Efficacy of speech pathology management for chronic cough: a randomised placebo controlled trial of treatment efficacy.Thorax. 2006; 61: 1065-1069https://doi.org/10.1136/thx.2006.064337
- Cough suppression therapy: does it work?.Pulm Pharmacol Ther. 2013; 26: 524-527https://doi.org/10.1016/j.pupt.2013.03.012
- Advances in mechanisms and management of chronic cough: the ninth London International Cough Symposium 2016.Pulm Pharmacol Ther. 2017; 47: 2-8https://doi.org/10.1016/j.pupt.2017.02.003
- Positive expiratory pressure therapy versus other airway clearance techniques for bronchiectasis.Cochrane Database Syst Rev. 2017; 9CD011699https://doi.org/10.1002/14651858.CD011699.pub2
- Cough reduction using capsaicin.Respir Med. 2015; 109: 27-37https://doi.org/10.1016/j.rmed.2014.11.001
- XEN-D0501, a novel transient receptor potential vanilloid 1 antagonist, does not reduce cough in patients with refractory cough.Am J Respir Crit Care Med. 2017; 196: 1255-1263https://doi.org/10.1164/rccm.201704-0769OC
- TRPA1 receptors in chronic cough.Pulm Pharmacol Ther. 2017; 47: 42-44https://doi.org/10.1016/j.pupt.2017.05.004
- Aprepitant for cough suppression in advanced lung cancer: a randomized trial.Chest. 2020; ([Epub ahead of print])https://doi.org/10.1016/j.chest.2019.11.048
- Update on the clinical development of gefapixant, a P2X3 receptor antagonist for the treatment of refractory chronic cough.Pulm Pharmacol Ther. 2019; 56: 75-78https://doi.org/10.1016/j.pupt.2019.03.006
Article info
Publication history
Published online: May 17, 2020
Accepted:
March 19,
2020
Received in revised form:
March 17,
2020
Received:
January 24,
2020
Identification
Copyright
© 2020 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
