Evaluating Treatment Efficacy in Chronic Cough: From 'Responders' to 'Controlled'

Key Points
Research Question:
We examined whether cough control could be defined using thresholds based on patient-reported assessments and what proportion of patients reach this state after treatment.
Results:
Based on patient assessments, cough control was defined as follows:
・Cough Frequency (CF) ≤ 10 coughs/hour
・Cough Severity VAS (CS-VAS) ≤ 30 mm
・Leicester Cough Questionnaire (LCQ) ≥ 16

After treatment, only 26% of patients met all three criteria and achieved **Controlled Cough (ConCC)**. Conversely, the proportion of patients meeting individual outcome thresholds was higher.

Interpretation:
Using composite thresholds based on patient assessments results in significantly fewer patients being classified as having controlled cough compared to traditional definitions of 'treatment response.' These results highlight the need for more effective treatments and clinically meaningful outcome measures.

Background
Treatment response in refractory chronic cough (RCC) is often defined by the **minimally important difference (MID)**. However, the MID indicates the minimum change in an outcome that a patient feels is important, not whether the cough has improved to a sufficiently controlled level. Therefore, defining criteria for cough control could serve as a complementary benchmark for evaluating treatment success.

Research Question
How can cough control be defined using thresholds based on a state where patients feel they have 'improved sufficiently'? We also examined what proportion of patients reach this state after treatment.

Study Design and Methods
PROCOUGH is a prospective, single-center observational cohort study conducted at McMaster University. Patients were treated according to ERS guidelines and evaluated before and after treatment.
A post-hoc analysis was performed to derive cough control criteria using:
・The 90th percentile of scores in patients reporting 6–7 on the Global Rating of Change Scale (GROC)
・A question regarding treatment response: 'Is your cough sufficiently controlled that you do not require additional treatment?'
・Patients who did not meet the cough control criteria were classified as having RCC.

Results
100 patients completed the follow-up. Patient characteristics were as follows:
・Age: 58±14 years
・Female: 58%
・Median cough duration: 7 years

Post-treatment **Controlled Cough (ConCC)** was defined by the following three criteria:
・24-hour Cough Frequency (CF) ≤ 10 coughs/hour
・Cough Severity VAS (CS-VAS) ≤ 30 mm
・Leicester Cough Questionnaire (LCQ) ≥ 16

After treatment, 26% of patients met all three criteria, while 74% were classified as having RCC.

Using only two patient-reported outcome (PRO) measures, 32% met the ConCC criteria. Individual criteria were achieved at the following rates:

Interpretation
In this study, cough control criteria based on patient assessments, combining objective and subjective outcomes, were derived. Specifically, the criteria are:
・24-hour Cough Frequency ≤ 10 coughs/hour
・Cough Severity VAS ≤ 30 mm
・LCQ ≥ 16
When these composite thresholds were applied as a definition for chronic cough control, only 26% of patients achieved cough control, despite relatively high rates of patients meeting individual treatment response criteria.

This discrepancy indicates that more effective treatments and more clinically meaningful outcome definitions are necessary to appropriately capture the cough control experienced by patients.

This is an attempt to shift the paradigm of evaluating treatment efficacy in chronic cough from 'responder' to 'controlled'. The novelty lies in introducing the concept of 'control' into cough clinical practice, following the same logic as the evolution from 'symptom improvement' to 'controlled state (ACT/ACQ)' in asthma.

Specific Clinical Value for Pulmonologists

1. Numerical goals that can be used immediately in outpatient settings
Until now, treatment efficacy for refractory chronic cough (RCC) has been discussed in terms of MID, focusing on 'amount of change' such as '1.3-point improvement in LCQ' or '30% reduction in CF.' However, patients want to know 'is this enough?' rather than 'how much better did it get?' This paper presents the following targets based on the patient's perspective:
24-hour Cough Frequency (CF) ≤ 10 coughs/hour
Cough Severity VAS (CS-VAS) ≤ 30 mm
Leicester Cough Questionnaire (LCQ) ≥ 16

In particular, LCQ ≥ 16 can be easily obtained in outpatient settings using a 10-item self-administered questionnaire, making it highly feasible as a decision-making criterion for 'continue vs. intensify treatment' in daily practice.

2. Visualizing the reality that 'being treated ≠ being controlled'
Even with treatment compliant with ERS guidelines, only 26% meet all three criteria(74% remain RCC). Since 36–50% are judged as improved when looking at single metrics, the composite endpoint corrects for an overestimation of approximately two-fold.

This is persuasive in clinical settings in the following scenarios:
Explaining to patients: 'Even if we change your medication, only 1 in 4 people can truly say they are 'cured.' Let's set a goal based on the premise of a long-term relationship.'
Rationale for the necessity of new drugs (e.g., P2X3 antagonists like gefapixant): Can demonstrate the limitations of existing treatments with numbers.
Threshold for specialist referral: Can be used as a criterion for referring patients who do not meet the above even after primary treatment.

3. Potential to change endpoint design in clinical research
Pharmaceutical companies' P2X3 antagonist trials have previously used % reduction in CF as the primary endpoint, but if regulatory authorities and academic societies adopt 'control achievement rate' as a secondary or primary endpoint, trial design and efficacy labeling will change. In the context of medical AI development, this also provides a basis for redesigning outcome definitions for cough monitoring devices/apps to 'threshold achievement (binary)'.

Points to consider in clinical practice as limitations
N=100, single-center, observational study: Replication in multi-center and multi-ethnic (especially Asian) populations is necessary. There are reports that Japanese people tend to have higher cough sensitivity, so thresholds like CF ≤ 10/h may not be directly applicable.
Post-hoc analysis and patient-anchored: The definition treating GROC 6–7 as 'sufficiently controlled' depends on patient expectations, which vary by culture and healthcare system.
Assumes 24-hour cough count (CF): In Japan, objective cough monitors like VitaloJAK / Leicester Cough Monitor are still at the research level. Clinical introduction faces challenges regarding insurance reimbursement/widespread adoption of devices. In the implementation phase, the 2-PRO (CS-VAS + LCQ) version (32% achievement rate) is more realistic.
Longitudinal stability of 'control' is unverified: Research extending this to a concept of sustained control, like asthma's 'well-controlled,' is needed in the future.

For the first time, a second metric, 'controlled state (ConCC),' has been operationally defined alongside 'treatment response (responder)' for chronic cough management.
LCQ ≥ 16, CS-VAS ≤ 30 mm, CF ≤ 10/h is a set of three criteria worth remembering, and LCQ ≥ 16 in particular can be used as a 'treatment goal' starting from today's outpatient clinic. At the same time, the fact that 74% remain RCC even under guideline-based treatment clarifies the profile of patients waiting for new treatments.