Chronic Refractory Cough: A Disorder of the Brain and the Respiratory System (Editorial)

Chronic refractory cough (CRC) increasingly is recognised as a distinct clinical entity; cough that persists despite addressing potential aggravating factors (eg, asthma, acid reflux, angiotensin-converting enzyme medication).1 CRC is associated with considerable physical and psychosocial morbidity, and its underlying mechanisms remain enigmatic.1,2 Peripheral hypersensitivity of airway nerves is very likely of key importance, but the failure of central-located mechanisms, which normally act to regulate the cough reflex, may also have an important role in CRC.3,4No Full Tex

Cough and Pain: More Similar Than at First Glance (Editorial)

Cough and pain appear at first glance to be two common, yet very distinct, symptoms. However, further consideration and a review of the current literature rapidly reveals analogies and deeper similarities between the two. At a basic level, both symptoms represent physiologic responses that are protective and adaptive, but in chronic pathologic states, they can become maladaptive.1,2 Chronic pain and chronic cough are both associated with substantial impacts on quality of life and are challenging to manage.2No Full Tex

Chronic cough: is the end nigh?

Chronic cough (lasting more than 8 weeks) is a common condition with substantial psychosocial impact. Despite huge efforts following robust guidelines, chronic cough in many patients remains refractory or unexplained (RU-CC). Recent insights support a significant role for cough hypersensitivity in RU-CC, including neuropathophysiological evidence from inhalational cough challenge testing, functional magnetic resonance imaging, and airway nerve biopsy. Along with improved approaches to measuring cough, this knowledge has developed in tandem with repurposing neuromodulator medications, including gabapentin, and evidence for non-pharmacological treatments. Most significantly, there is now a pipeline for novel classes of drugs specifically for chronic cough. The P2X3 receptor antagonist gefapixant is the first such drug to be approved in Europe. However, challenges persist. The field of chronic cough needs more robust epidemiological data, enhanced diagnostic tools, further well-designed clinical trials accounting for the effects of placebo, and treatments with minimal side-effects. Addressing these challenges are novel chronic cough registries, improved International Classification of Diseases (10th revision) coding, genetic testing options and further mechanistic studies. This Viewpoint article discusses these facets and considers how, whilst the end of chronic cough may not be imminent for all patients, the evolving landscape looks increasingly optimistic.Full Tex

Patient-reported assessments of chronic cough in clinical trials: accessory or primary endpoints?

Chronic cough is a complex disorder that affects up to 5-10% of the general population. It can be challenging to manage as there are few effective treatments, although several novel antitussives are in clinical development. The endpoints used to assess their efficacy in clinical trials should be optimal; most large clinical trials currently use objective measures as the primary outcome, especially cough frequency. There are strengths in this approach, although taking the view that other measures of chronic cough are less important, including patient-rated cough severity, psychosocial impact and other associated symptoms. Patient-reported outcome measures (PROMs) explore patients' personal experiences of health and disease, and the effects of particular conditions on their lives. Numerous validated PROMs exist for chronic cough, from simple visual analogue scales, to those that focus on cough hypersensitivity and cough-specific quality of life. Medicine regulators in the European Union (EU) and United States of America (USA) encourage the use of PROMs in clinical trials but have voiced concerns over their content validity, clinically meaningful thresholds for change, and discordance with objective measures. There are recent and ongoing studies to address these limitations. This review discusses currently available PROMs used to assess chronic cough and discusses their potential role as primary outcome measures in clinical trials.Full Tex

Cough hypersensitivity and suppression in COPD

Cough reflex hypersensitivity and impaired cough suppression are features of chronic refractory cough (CRC). Little is known about cough suppression and cough reflex hypersensitivity in cough associated with chronic obstructive pulmonary disease (COPD). This study investigated the ability of patients with COPD to suppress cough during a cough challenge test in comparison to patients with CRC and healthy subjects. This study also investigated whether cough reflex hypersensitivity is associated with chronic cough in COPD. Participants with COPD (n=27) and CRC (n=11) and healthy subjects (n=13) underwent capsaicin challenge tests with and without attempts to self-suppress cough in a randomised order over two visits, 5 days apart. For patients with COPD, the presence of self-reported chronic cough was documented, and objective 24-h cough frequency was measured. Amongst patients with COPD, those with chronic cough (n=16) demonstrated heightened cough reflex sensitivity compared to those without chronic cough (n=11): geometric mean±sd capsaicin dose thresholds for five coughs (C5) 3.36±6.88 µmol·L−1 versus 44.50±5.90 µmol·L−1, respectively (p=0.003). Participants with CRC also had heightened cough reflex sensitivity compared to healthy participants: geometric mean±sd C5 3.86±5.13 µmol·L−1 versus 45.89±3.95 µmol·L−1, respectively (p<0.001). Participants with COPD were able to suppress capsaicin-evoked cough, regardless of the presence or absence of chronic cough: geometric mean±sd capsaicin dose thresholds for 5 coughs without self-suppression attempts (C5) and with (CS5) were 3.36±6.88 µmol·L−1 versus 12.80±8.33 µmol·L−1 (p<0.001) and 44.50±5.90 µmol·L−1 versus 183.2±6.37 µmol·L−1 (p=0.006), respectively. This was also the case for healthy participants (C5 versus CS5: 45.89±3.95 µmol·L−1 versus 254.40±3.78 µmol·L−1, p=0.033), but not those with CRC, who were unable to suppress capsaicin-evoked cough (C5 versus CS5: 3.86±5.13 µmol·L−1 versus 3.34±5.04 µmol·L−1, p=0.922). C5 and CS5 were associated with objective 24-h cough frequency in patients with COPD: ρ= −0.430, p=0.036 and ρ= −0.420, p=0.041, respectively. Patients with COPD-chronic cough and CRC both had heightened cough reflex sensitivity but only patients with CRC were unable to suppress capsaicin-evoked cough. This suggests differing mechanisms of cough between patients with COPD and CRC, and the need for disease-specific approaches to its management.No Full Tex

Patient Global Impression of Severity Scale in Chronic Cough: Validation and Formulation of Symptom Severity Categories

Background The Patient Global Impression of Severity (PGI-S) scale is a self-reported, single-item categorical scale that is increasingly used when assessing chronic cough (CC). Objective This study aimed to establish validity, repeatability, and responsiveness of the PGI-S scale in CC and use the scale to define discrete categories of severity when measured with other commonly used patient-reported outcome (PRO) tools. Methods Consecutive patients with CC completed the PGI-S scale, cough severity and urge to cough visual analog scales (VAS), and cough-specific health status Leicester Cough Questionnaire (LCQ) at a clinic visit. Validity, repeatability, and responsiveness were assessed, and threshold scores for PRO severity categories determined. Results A total of 482 participants completed the assessments; the median (interquartile range [IQR]) age was 57 (46-67) years, 71% were female, and the median (IQR) duration of cough was 48 (24-120) months. They reported a median (IQR) PGI-S score of 3 (3-4; moderate severity), cough severity VAS of 57 (31-75) mm, urge to cough VAS of 62 (40-81) mm, and LCQ of 11.5 (8.7-14.4). There were strong associations between PGI-S scores and cough severity VAS (ρ = 0.81), urge to cough VAS (ρ = 0.73), and LCQ (ρ = −0.73) (all P < .001). Repeatability of the PGI-S scale was high (n = 77); the intraclass correlation coefficient (95% confidence interval) was 0.85 (0.77-0.91) ( P < .001). The PGI-S scale was responsive in participants with a treatment response ( P < .001). The suggested PRO thresholds to define severe cough are ≥61 mm (cough severity VAS), ≥71 mm (urge to cough VAS), and ≤10 (LCQ). Conclusion The PGI-S scale is a simple and valid tool that characterizes cough severity and is repeatable and responsive in CC. The proposed categorical severity thresholds for VAS and LCQ can provide intuitive meaning for patients and clinicians.Full Tex