New understanding in the treatment of cough (NEUROCOUGH) ERS Clinical Research Collaboration: improving care and treatment for patients with cough

What is the clinical rationale for NEUROCOUGH?

Chronic cough, defined as one persisting for more than 8 weeks, is among the most common clinical problems encountered by doctors in both general and hospital practice [1]. Chronic cough is recognised globally as an important clinical problem and to address the extent of this, a number of the NEUROCOUGH researchers undertook a review of over 10 000 patients to determine the demographic profile attending specialist cough clinics worldwide [8]. Particularly evident from this study were the characteristics of patients seeking specialist help for cough. In many cases the cough had persisted for years and with no effective treatments available, many such patients are left frustrated, with their clinicians unsure how best to manage this condition. To understand the scope of the problem more completely, the NEUROCOUGH researchers also undertook a survey in collaboration with the European Lung Foundation (ELF) involving almost 2000 people throughout Europe living with chronic cough. Key findings were that the cough impacted considerably on patients' daily-life activities, with many reporting deterioration in health-related quality of life and feeling fed-up and depressed [9]. Many of those surveyed reported a complete lack of awareness among their primary care physicians of cough as a distinct clinical problem and reported seeing numerous clinicians and undergoing many failed trials of therapy. While there is some consensus on the use of systematic protocols for the diagnosis and treatment of chronic cough, standardisation across centres is variable [10]. Furthermore, chronic cough can exist as a distinct clinical entity termed “refractory”, “unexplained” or “idiopathic” chronic cough, when no associated cause is apparent, or treatment of any associated causes is ineffective.

Cough can also be a prominent and troublesome symptom for patients with common lung conditions including asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and bronchiectasis. Cough is also considered as one of the potential treatable traits of airway disease and acknowledging this more widely may help clinicians adopt a more individualised approach to treating their patients [11]. For example, in asthma, patients with cough are often given oral corticosteroids; however, this may not deliver adequate control and exposes patients to the unacceptable side-effects of high-dose steroids. In COPD, cough is reported in 70% of patients [12], and many consider it to be extremely severe [13], contributing to impaired quality of life [14]. Cough is also a central clinical feature of bronchiectasis, and during an exacerbation the cough can become much worse and contribute to impaired health status [15]. In sarcoidosis, chronic cough is a common symptom and is associated with a heightened cough reflex [16]. In IPF, a chronic dry cough is as troublesome as breathlessness and remains difficult to treat [17]. Chronic cough remains difficult to manage and many patients self-medicate with “over the counter” (OTC) cough therapies, despite a lack of evidence supporting their efficacy [18, 19]. Current estimates suggest that almost 3 billion Euros are spent annually throughout Europe on OTC therapies that have little anti-tussive effect [20].

How can NEUROCOUGH improve mechanistic understanding of cough?

There is a growing recognition that chronic cough is a heterogeneous condition in terms of its presentation and causes and the underlying mechanisms are poorly understood, representing a significant knowledge gap [21]. A number of the NEUROCOUGH researchers have been instrumental in developing the concept that the common pathophysiological mechanism of cough, regardless of the aetiology, is an inflammation-induced injurious effect of the nervous system (neuro-inflammation). This leads to a cough hypersensitivity syndrome whereby neural pathways (in the airway and the brain) become damaged by factors including viral infection, and physical and chemical irritants [22, 23]. This neural damage (neuropathy), analogous to that driving some forms of chronic pain, is central to the clinical problem of cough. The challenge is in defining the complex and heterogeneous neuronal mechanisms responsible, to help identify targets for suppressing problematic cough whilst maintaining the protective cough that is essential for normal lung health. Recent work has led to greater understanding of the fundamental mechanisms of cough pathophysiology [24–28] and recent international collaboration through a European Respiratory Society (ERS) initiative has led to the innovative concept of cough hypersensitivity syndrome [23]. While evidence for this concept needs to be strengthened, the emerging potential in this field is underpinned by recent and remarkable progress in novel target discovery in neurobiology [2], highlighting the timely nature of the NEUROCOUGH initiative.

How can NEUROCOUGH help to deliver better treatments for cough?

A key unmet need is the lack of effective anti-tussives and, to date, assessment of novel targets in early “proof of concept” clinical studies has come with mixed success. Although efficacy has been observed with gabapentin [29] and the blocker of the ATP receptor, P2X3 [2, 7], in subsets of cough patients, compounds directed at a range of potentially promising targets including TRPV1 [3], TRPA1 [4] and voltage-gated sodium channels [6] have failed. This has raised two important issues. First, can we improve the predictive value of existing pre-clinical cough model systems? In this regard, it is our ambition that partnership activities initiated through NEUROCOUGH will pave a way forward to enhance translation of basic discoveries into clinical success. Secondly, how can we identify the genetic and biological characteristics that define the subgroups of “responsive” cough patients to novel anti-tussive therapies? Establishing a pan-European registry of well-phenotyped patients as detailed in our second core objective (see later section) will provide future capacity for multicentre studies to determine pathophysiological mechanisms and enable translation into later phase precision medicine clinical trials.

Why do we need NEUROCOUGH now?

Europe's cough researchers and clinicians have no formal mechanism to develop common investigative and management approaches or to facilitate collaboration either with each other or with partners from industry. Individual centres of cough expertise have been set up in many countries across Europe but, to date, there has been no means to standardise and harmonise the activity in these specialist clinics. In simple terms, we have no idea currently how patients with chronic cough are evaluated and managed between countries within Europe. In addition, while there have been efforts to provide consensus on the optimal management strategies, this has been largely at an individual national level, e.g. in Germany, Spain, the UK and France [30–33]. Recently an ERS Task Force on Cough has been established, with the first meeting of members held at the 2017 ERS Scientific Assembly in Milan, Italy, and the resulting publication soon to be published. A number of Task Force members are National Leads for NEUROCOUGH and will champion the Task Force recommendations within their respective countries. Finally, and perhaps most importantly, the vast majority of single- and multicentre clinical trials of novel anti-tussives have, to date, been conducted in the UK and USA [2–7]. As the number of potential novel compounds for cough is growing and the need to conduct large phase III studies of the most promising compounds is pressing, there is an opportunity for Europe to play a leading role as the ideal environment for such studies by creating a unified approach to patient management and phenotyping. To deliver on this objective, the NEUROCOUGH CRC will support the establishment of new specialist cough clinics, creating much-needed clinical trial infrastructure throughout Europe.

In summary, recent advances in mechanistic understanding of cough, coupled with interest in its neurobiology and the development of novel therapeutic options, have provided the perfect environment in which to establish a CRC for cough. We strongly believe the NEUROCOUGH network will advance cough research and clinical management throughout Europe and generate a framework for future clinical trials.

NEUROCOUGH objectives

NEUROCOUGH seeks to achieve the following four core objectives.

Objective 2: Establish a chronic cough patient registry

We aim to establish the first Europe-wide chronic cough patient registry comprising pre-specified clinical, physiological and biological data. An electronic data collection form for all these variables is being developed in conjunction with the Health Informatics Centre based at the University of Dundee (UK). NEUROCOUGH will generate a registry of carefully characterised chronic cough patients (including those with refractory and unexplained cough) at existing first-wave sites (figure 1) and then, through an “open-door” policy, encourage second-wave cough centres across Europe to join NEUROCOUGH and enter data.

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FIGURE 1

New understanding in the treatment of cough (NEUROCOUGH): first-wave specialist cough centres participating in the Europe-wide registry of chronic cough patients.

Anticipated output

This resource will provide, for the first time, a Europe-wide registry of “clinical trial ready” chronic cough patients suitable for multicentre experimental medicine studies and later phase precision medicine clinical trials.

How will NEUROCOUGH achieve its objectives?

NEUROCOUGH has assembled a multidisciplinary team of leading cough specialist clinicians, together with clinical and basic science researchers from both academia and industry, to work with patients and the public in an integrated fashion.

The NEUROCOUGH CRC is composed of a Steering Committee comprising the co-chairs, three members of the Committee of National Leads (rotating on an annual basis), a member of the PAG and the Early Career Member responsible for the oversight of the CRC as well as for reporting to ERS. The Steering Committee will work closely with the appointed representatives from each of the industry partners. A NEUROCOUGH Registry Scientific Committee responsible for the running of the registry will be developed. The Registry Scientific Committee will have direct responsibility for the conduct of the registry, including ensuring compliance with the protocol. The Registry Scientific Committee will work with the Steering Committee to provide direction on the strategic development of the registry and the monitoring of core activities (figure 2).

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FIGURE 2

New understanding in the treatment of cough (NEUROCOUGH) structure: an operational model for the Clinical Research Collaboration. ERS: European Respiratory Society; CNL: members of the Committee of National Leads; PAG: Patient Advisory Group.

Looking forwards with NEUROCOUGH

It is anticipated that NEUROCOUGH, in collaboration with the ERS Research Agency, will seek external funding support to develop a programme of work designed to address the research priorities in cough and the unmet needs in the development of novel anti-tussives. A number of these are listed in table 1. Furthermore, there is a need to raise awareness of cough as an important and difficult-to-manage clinical problem in lung diseases including COPD, asthma, IPF and bronchiectasis. The NEUROCOUGH CRC envisages fruitful collaborations with others within the ERS CRC family, including but not limited to EMBARC [34], SHARP [35], CADSET [36] and Ariane-IPF [37].

Conclusion

The NEUROCOUGH CRC brings together, for the first time, clinicians, scientists, patients and industry, to work in partnership with a vision to advance clinical management of chronic cough throughout Europe, enhance research capability and generate a framework for clinical trials. The purpose of this editorial is to inform and invite all who are interested in the field of cough to join us in achieving these goals.