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Chronic cough in Idiopathic Pulmonary Fibrosis (IPF)

Highly distressing symptom in IPF with strong impact on quality of life

A chronic, dry cough is one of the major symptoms of idiopathic pulmonary fibrosis (IPF) and is experienced by up to 80% of IPF patients. With a frequency of up to 100 coughs per hour it has a major impact on affected IPF patients’ quality of life, and many report cough together with shortness of breath and fatigue as the most burdensome aspects of their disease.

Chronic cough is defined as cough for more than 8 weeks.

Even after exclusion or treatment of alternative causes of cough including gastro-esophageal reflux disease, asthma and medications such as ACE inhibitors, a significant number of IPF patients continue to suffer from debilitating cough.

Inadequate treatment options despite large unmet need

There are no good treatment options for refractory cough in IPF - despite the large unmet clinical need. Historically, opioids have been commonly prescribed to reduce cough, but given the epidemic of opioid abuse and related deaths, as well as the significant risks of dependency and side effects, this option is becoming less available to patients. Cough in IPF has both psychosocial and physiological consequences. • The psychosocial consequences of cough in IPF can include depression and anxiety, disruption of daily activities, social embarrassment, relational problems, and impaired ability to work. Cough attacks can worsen breathlessness, which can lead to a vicious cycle of increasing anxiety, shortness of breath and coughing. • Refractory cough can lead to significant physiological consequences such as chest pain, urinary incontinence, rib fracture, sleep disturbance, and vomiting. Since persons affected by IPF can often be frail and elderly, these serious consequences can be particularly strenuous and further reduce life quality.

Pathophysiology is not completely understood

Under normal conditions, the coughing reflex is an important physiological mechanism protecting the airways from aspiration and irritants. Chronic cough, on the other hand, is characterised by hypersensitivity of cough receptors to minor environmental stimuli and physiological triggers such as mild exertion and emotional stress. It is assumed that neurogenic inflammation initiated by the activation of hypersensitive peripheral nervous system C-fibre neurons in the lungs contributes to the perpetuation of chronic cough in IPF. • Cough receptors are stimulated by thermal, chemical or mechanical factors and afferent impulses reach the so-called cough centre in the medulla region of the brainstem via the vagus nerve. • Activation of cough-sensitive nerve ending is presumed to happen predominantly through TRPV1 and TRPA1 ion channels. Functional upregulation of the nerve endings’ sensory capability may lead to chronic cough by sending activation signals to the cough centre in the brain in response to otherwise harmless stimuli Mechanical parenchymal distortion has also been suggested to contribute to sensory fibre hyperreactivity and chronic cough in IPF appears to be partly driven by worsening parenchymal fibrosis. Another contributing factor is presumed to be altered respiratory epithelium secreting neurotrophins. Neurotrophins such as brain-derived neurotrophic factor and nerve growh factor mediate inflammatory hyperalgesia and can reduce the cough threshold, which may contribute to respiratory tract hypersensitivity.

Chronic cough in IPF may contribute to faster disease progression

Refractory cough in IPF may contribute to disease progression and faster lung function decline. • Recurrent stress injuries and pressure differences caused by chronic cough have been hypothesized to lead to traction and shear stress causing lung damage and increased pulmonary fibrosis. • Study results on whether chronic cough in IPF contributes to worse survival have been contradictory. However, it is likely that the direct physiological and psychosocial effects of uncontrolled cough hasten the course of IPF. A negative spiral between increasing fibrosis driving chronic cough, which in turn hastens pro-fibrotic processes, can develop. A safe, well-tolerated and effective treatment for chronic cough in IPF might therefore not only significantly improve affected person’s quality of life but might also slow disease progression.


Current management is unsatisfactory

In the absence of approved treatments and broadly effective therapies for cough in IPF, current management is highly unsatisfactory and often guided by trial and error. Having treated and/or excluded modifiable causes of cough (such as gastro-esophageal reflux disease), the next step is to attempt symptomatic treatment with conventional anti-cough therapies (antitussives) such as dextromethorphan and codeine, which, however, do not provide satisfactory symptom relief in most patients. There is a suggestive role of immunosuppressive drugs such as corticosteroids and off-label treatment with thalidomide for reducing cough symptoms in IPF; however, there is insufficient evidence supporting their effectiveness and their side effect profiles limit their use. There is some limited evidence suggesting a positive effects of the antifibrotic drug pirfenidone on cough counts and cough-related quality of life. Yet, unfortunately, most patient with IPF who experience chronic cough do not experience adequate symptom control with currently available treatment options.


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