New therapies and a fresh focus are reshaping care for refractory cases, say researchers.
Relief may finally be within reach for patients with refractory chronic cough, researchers say.
Once considered an intractable symptom, persistent cough lasting more than eight weeks despite treatment of underlying conditions is now recognised as a distinct neuropathic disorder, and new therapies are transforming the clinical landscape.
Writing a comment in The Lancet Respiratory Medicine, researchers said gefapixant, the first targeted therapy licensed in the EU, UK, Switzerland and Japan, showed robust efficacy, with indications of sustained benefit even after discontinuation.
These advances raised urgent questions about how clinicians define treatment success and whether the cough process has resolved, remains active, or entered remission, they said.
Gefapixant, a P2X3 receptor antagonist, is not yet approved for use in Australia and is still considered an investigational drug. It is currently being investigated further in Australian clinical trials to understand its mechanism and long-term effects.
Despite the historical neglect of remission as a concept in RCC, longitudinal studies suggest that approximately half of patients may achieve cough resolution over five years.
Remission is well established in other chronic conditions such as asthma, malignancy, and chronic pain, where it is defined by minimal disease activity sustained over time and measured by clinical, functional and sometimes biological markers.
Applying a similar framework to RCC was challenging, given gaps in understanding of disease phenotypes, optimal measures of pathological burden and reliable biomarkers, the researchers wrote.
The complexity is compounded by the natural variability of cough. As a protective reflex, coughing shows substantial heterogeneity even in healthy individuals, is influenced by sex, infections and environmental triggers and can fluctuate over time.
“Considerable deficits remain in our understanding of the phenotypic or endotypic features, of optimal measures of pathological burden, and of appropriate biological surrogates for assessing disease activity,” the researchers wrote.
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“In chronic cough, the complexity of this issue is further compounded by the substantial overlap of markers of disease in RCC and healthy patients without cough.”
Any definition of remission must account for these natural variations and establish thresholds beyond which cough is pathological, they said.
Patient-reported outcome measures (PROs) offered a practical approach. Severity visual analogue scores of 20 mm or less correspond with minimal or absent symptoms, while numerical rating scales of two or less provided a convenient alternative.
Multi-item PROs, including severity diaries and cough-specific quality-of-life instruments, captured the broader impact of cough on daily function and psychosocial well-being, the researchers noted.
Objective measures could complement PROs. Clinical trials often assess 24-hour cough frequency, but this approach is intrusive and subject to variability. Emerging automated monitoring systems using neural networks promise longer-term, less burdensome assessment.
Laboratory-based cough challenge tests and PROs assessing triggers provide insights into cough hypersensitivity, a hallmark of RCC, while experimental imaging and histological studies reveal peripheral nerve changes and central processing deficits. Whether these biological features regress with treatment remains unknown.
Lessons from other neuropathic disorders may guide RCC management, the researchers suggested.
“To conclude, remission is an emerging reality for many patients with chronic cough and is the most desirable outcome for both patients and clinicians; patients do not want their cough to improve by half, they want their pathological cough to fully resolve,” the researchers wrote.
“Thus, for researchers engaged in this area, recognising and defining this concept is key, and for now, might be best realised with subjective PROs until practical biomarkers can be identified.
“Establishing remission criteria will help shape any future approach to understanding the underlying disease process, defining treatment success in terms recognised by patients, and quantifying the economic implications of novel treatments.”
