What is the best approach to managing refractory chronic cough (RCC)?

Understanding Refractory Chronic Cough: Epidemiology, Pathophysiology, and Burden

Refractory chronic cough (RCC) represents a distinct clinical entity affecting up to 15-50% of patients with chronic cough who fail to respond to treatment of identifiable causes, with a striking female predominance (two-thirds of cases) and represents a condition of neuronal hypersensitivity rather than simply untreated underlying disease. 1, 2, 3

Epidemiology and Patient Demographics

• Chronic cough overall affects 5-11% of adults, with peak incidence between 60-80 years of age 2
• Among patients with chronic cough, 15-50% remain undiagnosed or refractory to treatment despite thorough evaluation and appropriate therapy 1, 2, 3
• Women comprise approximately two-thirds of RCC patients, suggesting sex-specific mechanisms in cough hypersensitivity 2
• The typical RCC patient is an immunocompetent nonsmoker who is otherwise healthy, with normal or insignificant chest radiograph findings 4

Pathophysiology: The Cough Hypersensitivity Syndrome

The current understanding has shifted dramatically from viewing RCC as simply "unexplained" or "idiopathic" cough to recognizing it as a neurological disorder:

• The key abnormality in RCC is dysfunctional, hypersensitive sensory nerves in the airways, analogous to neuropathic pain conditions and laryngeal hypersensitivity 3
• A typical lymphocytic airways inflammation is seen in idiopathic cough, suggesting immune-mediated neuronal sensitization 4
• The pathophysiology involves neuronal activation, sensitization, and altered signal processing in the brain, creating a self-perpetuating cough reflex 3
• ATP signaling through P2X3 receptors on sensory nerve terminals plays a central mechanistic role in cough hypersensitivity 5

This represents a fundamental departure from older models that assumed RCC was simply undertreated upper airway cough syndrome (UACS), asthma, or gastroesophageal reflux disease (GERD).

Clinical Burden and Impact

The burden of RCC extends far beyond the symptom itself:

• RCC significantly impairs quality of life to a degree comparable to other chronic diseases such as cardiac and gastrointestinal conditions 4
• Approximately 80% of children with chronic cough presenting to specialists have seen more than 5 doctors for their cough, indicating substantial healthcare utilization 4
• The condition causes high healthcare burden with frequent specialist referrals and extensive, often unrevealing diagnostic workups 4, 1
• Cough can be debilitating in many common acute and chronic respiratory diseases, with suppression being relatively contraindicated when cough clearance is important 4

Distinguishing RCC from Treatable Chronic Cough

A critical concept is that RCC should only be diagnosed after systematic exclusion of treatable causes:

• The three most common causes of chronic cough—UACS, asthma, and GERD—account for the vast majority of cases in descending order of prevalence 4
• Nonasthmatic eosinophilic bronchitis (NAEB) is frequent enough to warrant early consideration 4
• Chronic cough is often multifactorial, with patients having two or all three common diagnoses simultaneously, requiring treatment of all identified causes for resolution 4
• RCC is defined as chronic cough of known cause that persists after proper treatment, or chronic cough of unknown cause after thorough evaluation 1

Common Pitfalls in Understanding RCC

Several misconceptions persist that delay appropriate management:

• Failure to recognize that cough may be the only clinical manifestation of asthma, GERD, or UACS leads to underdiagnosis of treatable conditions 4
• No currently available tests of airway function can reliably exclude a corticosteroid-responsive cough, necessitating empiric trials 4
• The clinical history of reflux cough is often present in patients labeled as having idiopathic cough, suggesting inadequate GERD treatment rather than true refractoriness 4
• Chronic cough should only be considered idiopathic or refractory following thorough assessment at a specialist cough clinic 4

Implications for Management Approach

Understanding RCC as a neurological hypersensitivity disorder has transformed treatment strategies:

• When diagnostic tests and specific directed treatments fail to control chronic cough, neuromodulators (gabapentin preferred, with morphine, pregabalin as alternatives) and/or speech pathology are recommended 1, 2, 3
• Novel P2X3 receptor antagonists (gefapixant, camlipixant) show the most promise for RCC treatment by targeting the ATP-mediated neuronal hypersensitivity 3, 5
• Speech pathology combined with neuromodulators provides enhanced treatment response of longer duration, suggesting non-pharmacologic treatment plays a key role 1
• Current treatment for refractory cough remains limited to symptomatic management rather than disease modification 2