It’s More Than Just a Cough: Navigating the Diagnosis of Refractory Chronic Cough
Developed in collaboration with Lorcan McGarvey, Queen’s University Belfast, UK. This fictional case study has been organised and funded by GSK and is for healthcare professionals only. Technical and medical writer support was provided by EMJ and funded by GSK.
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Allergy & Immunology, Respiratory
This interactive, fictional case study was developed with support from Lorcan McGarvey, Professor of Respiratory Medicine, Queen’s University Belfast, UK, was organised and funded by GSK, and is for healthcare professionals only. Technical and medical writer support was provided by EMJ and funded by GSK.
This is a hypothetical patient case and outcomes may not be reflective of clinical studies or real-life circumstances. This includes reference to agents that may be used off-label or for unlicensed indications. The mention of these agents and their uses is intended solely for educational purposes and should not be considered an endorsement or recommendation for their use outside approved indications. Please always consult guidelines and local prescribing information in your country of practice, as information may vary.
NX-GBL-RS-PRST-260003 | August 2026
Short summary: A patient workup for chronic cough should include a physical examination, chest X-ray, and assessment of various patient factors (i.e., medical history, red flags, cough characteristics).1,2 Patients should be evaluated for common cough-related aetiologies (i.e., UACS, asthma, NAEB, GORD) that may be contributing to the chronic cough.1,3 Neuronal hypersensitivity is when the nervous system reacts with heightened intensity to sensory input, or has an exaggerated response to low-level stimuli.4-7 Identifying clinical features of RCC suggestive of cough hypersensitivity syndrome (i.e., hypertussia, allotussia, laryngeal paraesthesia) may aid in timely diagnosis.8-10
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References and abbreviations
Keywords: Chronic cough, clinical features, cough hypersensitivity, cough hypersensitivity syndrome, habit cough, idiopathic cough, neural hypersensitivity, neurogenic cough, neuronal hypersensitivity, persistent cough, psychogenic cough, refractory chronic cough (RCC), unexplained chronic cough.
x
GORD: gastro-oesophageal reflux disease; NAEB: non-asthmatic eosinophilic bronchitis; RCC: refractory chronic cough; UACS: upper airway cough syndrome. 1. Irwin RS et al. Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report. Chest. 2018;153(1):196-209. 2. Dicpinigaitis PV et al. Interdisciplinary collaboration in the diagnosis and management of chronic cough: the role and importance of primary care providers. Curr Med Res Opin. 2023;39(10):1375-81. 3. Satia I et al. The clinical approach to chronic cough. J Allergy Clin Immunol Pract. 2025;13(3):454-66. 4. Irwin RS, Madison JM. Unexplained or refractory chronic cough in adults. N Engl J Med. 2025;392(12):1203-14. 5. Morice A et al. Chronic cough: new insights and future prospects. Eur Respir Rev. 2021;30(162):210127. 6. Moe AAK et al. Brainstem processing of cough sensory inputs in chronic cough hypersensitivity. EBioMedicine. 2024;100:104976. 7. Satia I et al. Towards understanding and managing chronic cough. Clin Med (Lond). 2016;16(Suppl 6):s92-7. 8. Peters AT et al. Therapeutic and mechanistic advances in chronic cough. Ann Allergy Asthma Immunol. 2025;134(6):639-48. 9. Morice AH et al. ERS guidelines on the diagnosis and treatment of chronic cough in adults and children. Eur Respir J. 2020;55(1):1901136. 10. Chung KF et al. Cough hypersensitivity and chronic cough. Nat Rev Dis Primers. 2022;8(1):45.
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Learning objective 1: Understand that RCC is a disease likely driven by neuronal hypersensitivity.1-5
Learning objective 2: Optimise the diagnosis of RCC by conducting a thorough assessment of potential underlying conditions/factors, recognising key clinical features of cough hypersensitivity syndrome, and understanding which investigations to request.
Learning objective 3: Understand different treatment and management options available.
Learning objective
RCC: refractory chronic cough. 1. Morice AH et al. ERS guidelines on the diagnosis and treatment of chronic cough in adults and children. Eur Respir J. 2020;55(1):1901136. 2. Chung KF et al. Cough hypersensitivity and chronic cough. Nat Rev Dis Primers. 2022;8(1):45. 3. Gibson PG, Vertigan AE. Management of chronic refractory cough. BMJ. 2015:351:h5590. 4. Chung KF et al. Chronic cough as a disease: implications for practice, research, and health care. Lancet Respir Med. 2025;13(2):110-2. 5. Irwin RS, Madison JM. Unexplained or refractory chronic cough in adults. N Engl J Med. 2025;392(12):1203-14.
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Abbreviations and footnotes
A 60-year-old White female has been referred by her PCP to the pulmonologist for “investigation and treatment of worsening asthma.”* The referral note states that the patient has had a dry cough over the last 6 months, with no haemoptysis, and no other respiratory symptoms. She is a lifetime non-smoker and has recently taken a 5-day course of oral prednisolone with no improvement.
Cough Assessment
Past medical history: Asthma, controlled for 10 years Hypertension, controlled for 20 years GORD, controlled for 5 years
Current medications: Losartan 50 mg daily Budesonide/formoterol 200/6 mcg one puff BID Montelukast 10 mg daily Omeprazole 20 mg daily
Investigations: Spirometry and FeNO performed 5 years ago; reported as normal No previous chest radiology
*This is a fictional patient case study. BID: twice daily; FeNO: fractional exhaled nitric oxide; GORD: gastro-oesophageal reflux disease; PCP: primary care physician.
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What would be the next best approach? 1. Repeat course of steroids, increase inhaler dose, and follow up in 6 weeks 2. Take a detailed history and perform a physical examination 3. Ask the patient to record severity of cough on a 0–10 rating scale 4. Order a chest X-ray 5. Order spirometry and FeNO
2 and 5
D
B
1, 2, 4, and 5
A
1
2, 3, 4, and 5
C
ERS: European Respiratory Society; FeNO: fractional exhaled nitric oxide; HCP: healthcare provider; T2: Type 2. 1. Morice AH et al. ERS guidelines on the diagnosis and treatment of chronic cough in adults and children. Eur Respir J. 2020;55(1):1901136. 2. de la Orden Abad M et al. The Severity of Chronic Cough Diary (SCCD): development and content validation of a novel patient-reported outcome instrument for evaluating the symptom experience of chronic cough. J Patient Rep Outcomes. 2023;7(1):65. 3. Global Initiative for Asthma. Global strategy for asthma management and prevention. 2026. Available at: 2026/05/GINA-2026-Strategy-Report-WMS.pdf. Last accessed: 18 May 2026. 4. Irwin RS et al. Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report. Chest. 2018;153(1):196-209.
Answer rationale:1-4 HCPs should avoid repeating trials of therapy or escalating the dose without supportive history or findings on investigation. As part of the initial workup, patients should be assessed for red flags with inquiries regarding haemoptysis, weight loss, and fever. Recording a patient’s rating of cough severity serves as a useful baseline assessment. A chest X-ray is an important examination as part of the assessment for potential red flags. Updated spirometry and FeNO is important to assess current asthma (T2 inflammation) status.
To assess the impact of cough severity, ERS guidelines recommend using a rating scale (0–10) or visual analogue scale. Questionnaires and cough diaries are also used to collect patient-reported outcomes.1,2
Worst possible cough
No cough
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The patient describes her cough as follows: Persists daily and is mainly dry, although occasionally productive with small amounts of clear phlegm. An itchy, tickly sensation in the throat which feels like something is draining down from the back of her nose. She thinks the cough is worse when visiting her daughter, who has a cat.
The patient describes her cough as follows: Persists daily and is mainly dry, although occasionally productive with small amounts of clear phlegm. An itchy, tickly sensation in the throat which feels like something is draining down from the back of her nose. She thinks the cough is worse when visiting her daughter, who has a cat. Cough severity: 9/10 Cough triggers: Cold air, talking and laughing, cooking and food odours
HCPs should ask patients about their cough triggers.1 Cough triggers in chronic cough can include:2-4 Smoke/perfume Talking, shouting, laughing Lying down or change in position Eating or drinking Cold temperatures Dry atmosphere Asking patients about cough triggers can help identify clinical features of cough hypersensitivity.5
Feels depressed
Symptoms:
Cold air
Talking
Laughing
Food odours
Cooking
Tickle in throat
Rib pain
Urinary incontinence
The patient shares that she feels depressed when she misses social activities due to her cough. Chronic cough may cause a wide range of negative psychosocial outcomes, including:6-9 Interference with daily functioning Social isolation Anxiety Depression
HCP: healthcare provider. 1. Morice AH et al. ERS guidelines on the diagnosis and treatment of chronic cough in adults and children. Eur Respir J. 2020;55(1):1901136. 2. Hilton E et al. Clinical features of the urge-to-cough in patients with chronic cough. Respir Med. 2015;109(6):701-7. 3. Chung KF et al. Cough hypersensitivity and chronic cough. Nat Rev Dis Primers. 2022;8(1):45. 4. Bali V et al. Patient-reported experiences with refractory or unexplained chronic cough: a qualitative analysis. Ther Adv Respir Dis. 2024;18:1-15. 5. Dicpinigaitis PV et al. Interdisciplinary collaboration in the diagnosis and management of chronic cough: the role and importance of primary care providers. Curr Med Res Opin. 2023;39(10):1375-81. 6. French CL et al. Impact of chronic cough on quality of life. Arch Intern Med. 1998;158(15):1657-61. 7. Coles T et al. Quality of life in adults with chronic cough: a mixed methods study informing the development of a quantitative patient preference study. Patient. 2024;17(3):253-62. 8. Hari G et al. Anxiety and depression diagnoses and the cough severity index: a retrospective study. Ear Nose Throat J. 2026;105(1):23-8. 9. Iyer VN, Lim KG. Chronic cough: an update. Mayo Clin Proc. 2013;88(10):1115-26. 10. Irwin RS et al. Life-threatening and non-life-threatening complications associated with coughing: A scoping review. Chest. 2020;158(5):2058-73.
The patient also reports rib pain from coughing, and urinary incontinence. Chronic cough may cause a wide range of negative physical outcomes, including:6,7,10 Insomnia Urinary incontinence Vomiting/retching
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On further examination, there is no haemoptysis or persistent hoarseness, and no fever or night sweats are reported. The patient’s weight is steady and she feels otherwise well, looks normal, and is comfortable at rest. Height: 5’4”; Weight: 128 lb; BMI: 22 kg/m2 There is no finger clubbing or lymphadenopathy. No findings on chest examination (inspection, palpation, percussion, and auscultation). BP: 124/80 mmHg; Pulse: 80 bpm, regular Direct inspection of the patient's nasal passages, ears, and throat are all unremarkable. Chest X-ray: Reported normal Spirometry: Normal FeNO: 21 ppb
Physical Examination and Updated Investigations
FeNO should be evaluated to assess for eosinophilic airway disease.4 The BTS guidelines recommend a short trial of ICS for 4 weeks for patients with FeNO >25 ppb and blood eosinophil count ≥0.3x109 /L, with no other symptoms or airflow obstruction.4
BP: blood pressure; BTS: British Thoracic Society; FeNO: fractional exhaled nitric oxide; ICS: inhaled corticosteroid. 1. Dicpinigaitis PV et al. Interdisciplinary collaboration in the diagnosis and management of chronic cough: the role and importance of primary care providers. Curr Med Res Opin. 2023;39(10):1375-81. 2. Irwin RS et al. Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report. Chest. 2018;153(1):196-209. 3. Michaudet C, Malaty J. Chronic cough: evaluation and management. Am Fam Physician. 2017;96(9):575-80. 4. Parker SM et al. British Thoracic Society Clinical Statement on chronic cough in adults. Thorax. 2023;78(Suppl 6):s3-19.
Red flags are essential to evaluate because they may signal life-threatening conditions.1-3 Haemoptysis Weight loss Fever Recurrent pneumonia Abnormal X-ray Hoarseness
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What would be the next best approach? 1. Add a LAMA therapy and review in 6 weeks 2. Double dose of PPI and add in an H2 antagonist 3. Refer to gastroenterologist for oesophageal pH testing 4. Refer to allergist/ENT in view of throat symptoms and possible cat allergy
4
2
2 and 3
ACE: angiotensin converting enzyme; ENT: ear, nose, and throat; GORD: gastro-oesophageal reflux disease; LAMA: long-acting muscarinic antagonist; NAEB: non-asthmatic eosinophilic bronchitis; PPI: proton pump inhibitor; UACS: upper airway cough syndrome. 1. Global Initiative for Asthma. Global strategy for asthma management and prevention. 2026. Available at: 2026/05/GINA-2026-Strategy-Report-WMS.pdf. Last accessed: 18 May 2026. 2. Morice AH et al. ERS guidelines on the diagnosis and treatment of chronic cough in adults and children. Eur Respir J. 2020;55(1):1901136. 3. Parker SM et al. British Thoracic Society Clinical Statement on chronic cough in adults. Thorax. 2023;78(Suppl 6):s3-19. 4. Irwin RS et al. Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines. Chest. 2006;129(Suppl 1):1S-23S. 5. Satia I et al. The clinical approach to chronic cough. J Allergy Clin Immunol Pract. 2025;13(3):454-66.
Answer rationale: No features in history, examination, or lung function findings to suggest that adding inhaled LAMA is likely to be effective.1 No features in history to suggest active acid reflux or volume reflux. Symptoms are well controlled on current PPI therapy.2-4 ENT/allergy evaluation is a reasonable next best approach.3,5
During patient workup for chronic cough, guidelines recommend a thorough assessment of various conditions/factors that may be the underlying cause, including:3,5 Asthma, NAEB GORD UACS Modifiable risk factors (e.g., use of ACE inhibitors, smoking) Red flags
Figure modified from Satia et al.5
Assessment of Underlying Causes of Cough
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The patient is still coughing, which is very disruptive to her daily life. She rates her cough severity as 9/10. She also tells you that she independently saw a gastroenterologist a few weeks ago, where she had an endoscopy and 24-hour oesophageal pH testing: both were normal.
Review of Specialist Investigations (Visit #2)
Abbreviations
CBC: complete blood count; ENT: ear, nose, and throat; IgE: Immunoglobulin E.
Summary of ENT/allergy visit: No findings on indirect laryngoscopy Skin prick test: mildly positive to pollen and dust mites CBC: normal IgE blood test: normal A trial of first-generation antihistamine therapy did not improve the patient's cough symptoms
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What should you do next? 1. Explain to the patient that her cough is likely to be a habit and refer her to a clinical psychologist. 2. Explain that there is nothing serious causing the cough and discharge her from the clinic. 3. Explain that she has clinical features of cough hypersensitivity syndrome associated with RCC. Manage according to guidelines or consider referral to a specialist with interest in chronic cough/cough clinic. 4. Prescribe another trial of oral steroids and switch to alternative ICS/LABA combination.
3
Clinical Features of Cough Hypersensitivity Syndrome
GORD: gastro-oesophageal reflux disease; ICS: inhaled corticosteroid; LABA: long-acting β2-agonist; RCC: refractory chronic cough; UACS: upper airway cough syndrome. 1. Parker SM et al. British Thoracic Society Clinical Statement on chronic cough in adults. Thorax. 2023;78(Suppl 6):s3-19. 2. Satia I et al. The clinical approach to chronic cough. J Allergy Clin Immunol Pract. 2025;13(3):454-66. 3. Irwin RS et al. Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report. Chest. 2018;153(1):196-209.
Answer rationale: UACS, GORD, and inadequately controlled asthma have been considered/ investigated as potential causes of the patient's chronic cough. There are no features in the history, examination, and investigations to suggest any other underlying lung condition. It would not be appropriate to escalate treatment or order further investigations at this time.1,2 It is important to consider RCC as the probable diagnosis, explain this to the patient, and follow current guidance on treatment options, including a referral (if available) to a specialist with an interest in chronic cough or to a cough clinic.1,3
Laryngeal paraesthesia
Hypertussia
Allotussia
abnormal irritation (itch or tickle sensation) in the throat
increased coughing in response to low levels of tussive stimuli
cough in response to nontussive (innocuous) stimuli
Dysregulation of the normal cough reflex in RCC is associated with neuronal hypersensitivity and manifests clinically as cough hypersensitivity syndrome.1-4 Neuronal hypersensitivity is where the nervous system reacts with heightened intensity to sensory input, or has an exaggerated response to low-level stimuli.1,2,5 Clinical features of cough hypersensitivity syndrome include:2,6-11
RCC: refractory chronic cough. 1. Irwin RS, Madison JM. Unexplained or refractory chronic cough in adults. N Engl J Med. 2025;392(12):1203-14. 2. Chung KF et al. Cough hypersensitivity and chronic cough. Nat Rev Dis Primers. 2022;8(1):45. 3. Chung KF et al. Chronic cough as a disease: implications for practice, research, and health care. Lancet Respir Med. 2025;13(2):110-2. 4. Morice AH et al. ERS guidelines on the diagnosis and treatment of chronic cough in adults and children. Eur Respir J. 2020;55(1):1901136. 5. Moe AAK et al. Brainstem processing of cough sensory inputs in chronic cough hypersensitivity. EBioMedicine. 2024;100:104976. 6. Smith JA et al. Mini-review: hypertussivity and allotussivity in chronic cough endotypes. Neurosci Lett. 2023;792:136934. 7. Vertigan AE et al. Laryngeal sensory dysfunction in laryngeal hypersensitivity syndrome. Respirology. 2013;18(6):948-56. 8. Vertigan AE et al. Chronic refractory cough as a sensory neuropathy: evidence from a reinterpretation of cough triggers. J Voice. 2011:25(5):596-601. 9. Hilton E et al. Clinical features of the urge-to-cough in patients with chronic cough. Respir Med. 2015;109(6):701-7. 10. Won HK et al. Cough-related laryngeal sensations and triggers in adults with chronic cough: symptom profile and impact. Allergy Asthma Immunol Res. 2019;11(5):622-31. 11. Koskela HO et al. Cluster analysis in 975 patients with current cough identifies a phenotype with several cough triggers, many background disorders, and low quality of life. Respir Res. 2020;21(1):219.
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History, physical examination, and chest X-ray1,2
Assessment Refresh
Physical examination is unremarkable1,2
No red flags identified1,2
Reversible causes have been addressed1,3
Clinical features of cough hypersensitivity syndrome rule in possible RCC diagnosis4-8
Cough hypersensitivity syndrome5-8
Gastro-oesophageal reflux disease
Asthma, non-asthmatic eosinophilic bronchitis
Upper airway cough syndrome
Common cough-related aetiologies adequately treated or ruled out1
Figure reproduced with permission from Irwin et al.1 RCC: refractory chronic cough. 1. Irwin RS et al. Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report. Chest. 2018;153(1):196-209. 2. Dicpinigaitis PV et al. Interdisciplinary collaboration in the diagnosis and management of chronic cough: the role and importance of primary care providers. Curr Med Res Opin. 2023;39(10):1375-81. 3. Domingo C et al. Basic assessment of chronic cough in primary care and referral pathways of patients to different specialists. Ther Adv Respir Dis. 2023:17:17534666231178694. 4. Smith JA et al. Mini-review: hypertussivity and allotussivity in chronic cough endotypes. Neurosci Lett. 2023;792:136934. 5. Chung KF et al. Cough hypersensitivity and chronic cough. Nat Rev Dis Primers. 2022;8(1):45. 6. Irwin RS, Madison JM. Unexplained or refractory chronic cough in adults. N Engl J Med. 2025;392(12):1203-14. 7. Chung KF et al. Chronic cough as a disease: implications for practice, research, and health care. Lancet Respir Med. 2025;13(2):110-2. 8. Won HK et al. Cough-related laryngeal sensations and triggers in adults with chronic cough: symptom profile and impact. Allergy Asthma Immunol Res. 2019;11(5):622-31.
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The pulmonologist diagnoses the patient with RCC, defined as a disease identified in a subset of people who experience chronic cough (lasting >8 weeks) that persists despite adequate treatment for common cough-related aetiologies.1-5 Patients with RCC are predominantly females in their 50's or 60's.6-9
Diagnosis of Refractory Chronic Cough
Figure reproduced with permission from Irwin et al.10 RCC: refractory chronic cough. 1. Morice AH et al. ERS guidelines on the diagnosis and treatment of chronic cough in adults and children. Eur Respir J. 2020;55(1):1901136. 2. Chung KF et al. Cough hypersensitivity and chronic cough. Nat Rev Dis Primers. 2022;8(1):45. 3. Gibson PG, Vertigan AE. Management of chronic refractory cough. BMJ. 2015:351:h5590. 4. Chung KF et al. Chronic cough as a disease: implications for practice, research, and health care. Lancet Respir Med. 2025;13(2):110-2. 5. Irwin RS, Madison JM. Unexplained or refractory chronic cough in adults. N Engl J Med. 2025;392(12):1203-14. 6. Abozid H et al. Distribution of chronic cough phenotypes in the general population: a cross-sectional analysis of the LEAD cohort in Austria. Respir Med. 2022;192:106726. 7. Rouette J et al. Epidemiology of refractory chronic cough and unexplained chronic cough: a systematic literature review. Original Investigation Poster. CHEST Annual Meeting, 19-22 October, 2025. 8. Brister D et al. Burden of disease associated with refractory and unexplained chronic cough in Canada: results from a national survey. Lung. 2024;202(4):415-24. 9. Walz L et al. Characteristics, demographics, and epidemiology of possible chronic cough in Sweden: a nationwide register-based cohort study. PLoS One. 2024;19(7):e0303804. 10. Irwin RS et al. Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report. Chest. 2018;153(1):196-209. 11. Dicpinigaitis PV et al. Interdisciplinary collaboration in the diagnosis and management of chronic cough: the role and importance of primary care providers. Curr Med Res Opin. 2023;39(10):1375-81.
RCC
Consider RCC
Consider referring to a cough specialist or cough clinic to confirm diagnosis10,11
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Which treatments could you try first based on guidelines?
Gabapentin 300 mg PO QD
Speech and language therapy
Slow-release morphine 5 mg PO BID
SLN block injections
Answer rationale: Given the lack of widely accessible treatments for RCC, off-label treatments (e.g., opioids, neuromodulators) and non-pharmacological therapies (e.g., physiotherapy, speech and language therapy) are recommended by the ERS and CHEST guidelines.1-4 Low-dose, slow-release morphine can reduce cough frequency, cough severity, and cough-related QoL;2,5 however, opioids are associated with risks of misuse or addiction.6,7 Speech and language therapy is a non-pharmacological approach that provides training on techniques to help suppress the urge to cough, as well as psychological support and education for patients with chronic cough.8 Limited evidence based on small sample size studies is...
• Given the lack of widely accessible treatments for RCC, off-label treatments (e.g., opioids, neuromodulators) and non-pharmacological therapies (e.g., physiotherapy, speech and language therapy) are recommended by the ERS and CHEST guidelines.1-4 • Low-dose, slow-release morphine can reduce cough frequency, cough severity, and cough-related QoL;2,5 however, opioids are associated with risks of misuse or addiction.6,7 • Speech and language therapy is a non-pharmacological approach that provides training on techniques to help suppress the urge to cough, as well as psychological support and education for patients with chronic cough.8 • Limited evidence based on small sample size studies is available to support the efficacy of speech and language therapy in RCC.8 • Several studies have demonstrated short-term benefit of SLN block injections for chronic cough; however, repeat injections are often required, and long-term benefit is unknown.9,10 • Limited, small trials have demonstrated some effectiveness of centrally acting neuromodulators in RCC.11-15 • Neuromodulators are often discontinued due to tachyphylaxis and side effects.11-13
Answer rationale:1-4
All of the above
E
BID: twice daily; CHEST: American College of Chest Physicians; ERS: European Respiratory Society; PO: by mouth; QD: daily; QoL: quality of life; RCC: refractory chronic cough; SLN: superior laryngeal nerve. 1. Gibson P et al. Treatment of unexplained chronic cough: CHEST guideline and expert panel report. Chest. 2016;149(1):27-44. 2. Morice AH et al. ERS guidelines on the diagnosis and treatment of chronic cough in adults and children. Eur Respir J. 2020;55(1):1901136. 3. Smith JA. The therapeutic landscape in chronic cough. Lung. 2024;202(1):5-16. 4. Morice A et al. Chronic cough: new insights and future prospects. Eur Respir Rev. 2021;30(162):210127. 5. Morice AH et al. Opiate therapy in chronic cough. Am J Respir Crit Care Med. 2007;175(4):312-5. 6. Oh JY et al. Codeine prescription pattern and treatment responses in patients with chronic cough: a routinely collected institutional database analysis. J Thorac Dis. 2023;15(4):2344-54. 7. Visca D et al. Management of chronic refractory cough in adults. Eur J Intern Med. 2020;81:15-21. 8. Slinger C et al. Speech and language therapy for management of chronic cough. Cochrane Database Syst Rev. 2019;7(7):CD013067. 9. Quinton BA et al. The role of bilateral superior laryngeal nerve block in managing refractory chronic cough. Laryngoscope. 2024;134(4):1773-7. 10. Peachman AT et al. Prospective study of long-term outcomes and the patient experience with superior laryngeal nerve block for chronic cough. Laryngoscope. 2026;136(1):262-72. 11. Bowen AJ et al. Short- and long-term effects of neuromodulators for unexplained chronic cough. Otolaryngol Head Neck Surg. 2018;159(3):508-15. 12. Ryan NM et al. Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial. Lancet. 2012;380(9853):1583-9. 13. Ryan MA, Cohen SM. Long-term follow-up of amitriptyline treatment for idiopathic cough. Laryngoscope. 2016;126(12):2758-63. 14. Xu X et al. Successful resolution of refractory chronic cough induced by gastroesophageal reflux with treatment of baclofen. Cough. 2012;8(1):8. 15. Dicpinigaitis PV, Rauf K. Treatment of chronic, refractory cough with baclofen. Respiration. 1998;65(1):86-8.
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Given the lack of widely accessible treatments for RCC, clinicians have little choice but to prescribe off-label treatments and non-pharmacological therapies based on low-quality clinical evidence.1-3
Treatment of Refractory Chronic Cough
Guideline recommendations:
Non-pharmacological therapies such as physiotherapy and speech and language therapy.4-6
Off-label treatments include neuromodulators, opioids, and anaesthetics.5,7,8
RCC-specific treatment options are limited.9-11 Numerous targeted therapy options for RCC are in development.1
BID: twice daily; QD: daily; RCC: refractory chronic cough. 1. Mazzone SB, McGarvey L. Mechanisms and rationale for targeted therapies in refractory and unexplained chronic cough. Clin Pharmacol Ther. 2021;109(3):619-36. 2. Smith JA. The therapeutic landscape in chronic cough. Lung. 2024;202(1):5-16. 3. Morice A et al. Chronic cough: new insights and future prospects. Eur Respir Rev. 2021;30(162):210127. 4. Morice AH et al. ERS guidelines on the diagnosis and treatment of chronic cough in adults and children. Eur Respir J. 2020;55(1):1901136. 5. Gibson P et al. Treatment of unexplained chronic cough: CHEST guideline and expert panel report. Chest. 2016;149(1):27-44. 6. Slinger C et al. Speech and language therapy for management of chronic cough. Cochrane Database Syst Rev. 2019;7(7):CD013067. 7. Ryan NM et al. An update and systematic review on drug therapies for the treatment of refractory chronic cough. Expert Opin Pharmacother. 2018;19(7):687-711. 8. Quinton BA et al. The role of bilateral superior laryngeal nerve block in managing refractory chronic cough. Laryngoscope. 2024;134(4):1773-7. 9. Abdulqawi R et al. P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 2015;385(9974):1198-205. 10. Smith JA et al. Safety and efficacy of BLU-5937 in the treatment of refractory chronic cough from the phase 2b Soothe trial. Am J Respir Crit Care Med. 2022;205:A5778. 11. Smith J et al. Improvements in cough frequency over 24 hours with BLU-5937, a selective P2X3 antagonist, in patient subgroups defined by baseline awake cough frequencies. Am J Respir Crit Care Med. 2021;203:A1019.
CHEST guidelines5
ERS guidelines4
Gabapentin (300 mg QD, titrate up to 1,800 mg daily in two divided doses)
Gabapentin (up to 1,800 mg QD)/pregabalin (300 mg QD)
Physiotherapy/speech and language therapy
Low-dose, slow-release morphine (5–10 mg BID)
–
Speech therapy
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Take-Home Messages
GORD: gastro-oesophageal reflux disease; HCP: healthcare provider; QoL: quality of life; RCC: refractory chronic cough; UACS: upper airway cough syndrome. 1. Morice AH et al. ERS guidelines on the diagnosis and treatment of chronic cough in adults and children. Eur Respir J. 2020;55(1):1901136. 2. Chung KF et al. Cough hypersensitivity and chronic cough. Nat Rev Dis Primers. 2022;8(1):45. 3. Gibson PG, Vertigan AE. Management of chronic refractory cough. BMJ. 2015:351:h5590. 4. Chung KF et al. Chronic cough as a disease: implications for practice, research, and health care. Lancet Respir Med. 2025;13(2):110-2. 5. Irwin RS, Madison JM. Unexplained or refractory chronic cough in adults. N Engl J Med. 2025;392(12):1203-14. 6. Morice A et al. Chronic cough: new insights and future prospects. Eur Respir Rev. 2021;30(162):210127. 7. Moe AAK et al. Brainstem processing of cough sensory inputs in chronic cough hypersensitivity. EBioMedicine. 2024;100:104976. 8. Satia I et al. Towards understanding and managing chronic cough. Clin Med (Lond). 2016;16(Suppl 6):s92-7. 9. Bali V et al. Patient-reported experiences with refractory or unexplained chronic cough: a qualitative analysis. Ther Adv Respir Dis. 2024;18:1-15. 10. Puente-Maestu L et al. Burden of refractory and unexplained chronic cough on patients' lives: a cohort study. ERJ Open Res. 2023;9(5):00425-2023. 11. Dicpinigaitis PV et al. Poster. CHEST Annual Meeting, 16-19 October, 2022. 12. Smith JA. The therapeutic landscape in chronic cough. Lung. 2024;202(1):5-16.
RCC is a disease identified in a subset of people who experience chronic cough (lasting >8 weeks) that persists despite adequate treatment for known cough-related aetiologies (e.g., UACS, GORD, asthma).1-5
RCC is often associated with neuronal hypersensitivity,1-5 which is when the nervous system reacts with heightened intensity to sensory input, or has an exaggerated response to low-level stimuli.5-8
Identifying clinical features of RCC suggestive of cough hypersensitivity syndrome (i.e., hypertussia, allotussia, laryngeal paraesthesia) may aid in timely diagnosis.1,2
Physical and psychosocial impacts, along with a lengthy and complex diagnostic journey, can adversely affect the QoL of patients with RCC.9-11 The journey to a diagnosis of RCC often includes numerous visits to HCPs, diagnostic tests, and trials of therapies.11
Most current guideline-recommended treatments for RCC are used off-label.6,12
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Episode 1: Unmasking the Unrelenting Cough: Refractory Chronic Cough Through Patient and Practitioner Eyes
Episode 2: Why the Cough Won’t Stop: Neuronal Hypersensitivity in Refractory Chronic Cough
Episode 3: Tools, Trials, and Treatments: Navigating RCC in Real Life
