Tackling chronic cough – pathogenic mechanisms and novel therapeutics

Chronic cough, defined as a cough lasting more than eight weeks in duration, is “really common” and affects up to one-in-10 adults, heard the Irish Thoracic Society Annual Scientific Meeting.

Prof Jacky Smith, National Institute for Health and Care Research (NIHR) Senior Investigator, Director of the NIHR Manchester Clinical Research Facility, Respiratory Theme Lead in the NIHR Manchester Biomedical Research Centre, UK, and leading expert in pathological cough, shared her knowledge and insights into the mechanisms of refractory chronic cough and developing management strategies.

Prof Smith described an increased prevalence of chronic cough in people who smoke, women, and older people, noting that “patients with no obvious cause are tricky to treat”. She presented a typical case history to demonstrate the complexity of managing the condition and discussed associated demographics and clinical features. “It’s incredibly disruptive and really impacts quality-of-life,” she said.

Healthy people cough typically 10-15 times per day, Prof Smith told delegates, and went on differentiate between coughing in health vs coughing in disease. She described an array of mechanical and chemical triggers, and presented neuroanatomical diagrams depicting somatosensory vagal fibres to explain the sensory disturbances felt by patients in the throat.

Delegates heard that many patients are commonly experiencing asthma, nasal disease, gastro-oesophageal reflux disease, and eosinophilic bronchitis, and that challenges arise when a cough persists despite treatment of these underlying conditions. “There must be some kind of different pathology going on here, and the best way to think about this is to look at innovation of the airways and how cough might be being evoked,” said Prof Smith, who presented in detail on the neuro-physical pathways controlling cough.

“C-fibres characteristically respond to capsaicin, the pungent extract of chilli pepper,” said Prof Smith about the unmyelinated nerve fibres. She described this as “an important tool” in the study of chronic cough.

“That [capsaicin] acts through a receptor known as TRPV1 [transient receptor potential vanilloid 1, a receptor found on airway sensory nerves] to evoke action potentials and produce coughing. It’s also temperature sensitive, as is the channel next to it, which is the TRPA1 sensor, and that also responds to lots of irritant chemicals…. These C-fibres also express a very large number of receptors that will respond to inflammatory mediators, including P2X3, which responds to ATP [adenosine triphosphate], and that has turned out to be quite an important receptor.”

Prof Smith elaborated further on various other chemo- and mechano-sensitive pathways, and explained that tonicity also activates these nerve fibres. “Hypotonicity is releasing ATP through activation of TRPV4, that’s activating the nerves, and that’s subsequently able to cause cough,” she explained. “In our human hypotonic challenges, this occurred in our chronic refractory cough patients and not the healthy volunteers, which is why P2X3 antagonists are effective in this patient group and may be effective in subgroups of patients with other diseases.”

Prof Smith concluded that there is “quite a bit of evidence to support the concept that the airways are hypersensitive and inhibitory mechanisms are impaired” in chronic cough, before moving on to examine current and novel treatment strategies for the condition.

Treatment

The conference heard that standard therapies such as low-dose morphine and gabapentin “have been shown in studies to be effective, but have side-effects and significant abuse potential”. Prof Smith noted that speech and language therapy can also benefit some patients, but is not always widely available.

“There’s a number of ways in which these pathways are abnormal, so there are a number of ways to address treatment,” she said.

“You can try to reduce airway nerve activation, reduce conduction in those vagal afferent fibres, and try to interfere with upregulation of inhibitory pathways in the central nervous system [CNS],” Prof Smith told delegates, highlighting that most CNS-targeting drugs are associated with multiple side-effects. “Most efforts have been focusing on peripheral mechanisms, and we see the most success in blocking P2X3 ion channels that are activated by ATP.”

Prof Smith presented an overview of findings from her own research using the oral P2X3 receptor antagonist gefapixant to treat chronic cough. “The drug at 45mg had quite a dramatic effect on cough from baseline, reducing the amount of coughing by about 60-to-65 per cent, but it [the control group] also had a substantial placebo effect.” The drug has been licensed in Europe and the UK, but not by the US Food and Drug Administration (FDA). The FDA was not convinced of its benefit versus the large placebo response in the control arm in clinical trials and was concerned about the taste side-effects.

The conference heard that the treatment has not yet been funded in Ireland and is only available on private prescription at present. Prof Smith concluded by saying that “hyperexcitability of the neuronal pathways is the main problem” in refractory chronic cough, and that blocking peripheral pathways is making “substantial differences” to patients. “Hopefully these therapies will be available to prescribe in clinic for our patients soon.”