Idiopathic pulmonary fibrosis: a nervous cough?

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Abstract

Little is known about the mechanisms which generate cough in patients with diffuse parenchymal lung disease. This article outlines some of the possible mechanisms which cause cough in patients with idiopathic pulmonary fibrosis (IPF). It goes on to discuss what is currently known about the enhanced cough reflex which afflicts patients with this condition, and describes recent evidence for enhanced expression of neurotrophins in the lungs of these patients. Preliminary data indicating that corticosteroids can reduce the cough reflex response to capsaicin and substance P in IPF offer hope that more specific therapies may be developed in the future.

Introduction

The cough reflex is the respiratory tract's first line of defence against unwanted inhaled particles such as foreign bodies, toxic fumes and infectious agents. Patients with an impaired cough reflex are predisposed to aspiration of gastric contents and respiratory tract infections.

The sensory afferent nerves within the human respiratory tract are thought to be of two types: the rapidly adapting receptors (RARs) which respond to mechanical stimuli and mucus within the airways and C-fibre receptors which are responsive to chemical stimulation and react to agents such as capsiacin. Activation of C-fibres is thought to result in the antidromic release of neuropeptides such as substance P and neurokinin A, which in turn activate the RARs to feed into the central cough mechanisms. The human airway is richly innervated with such nerves, particularly the trachea, carina and the branching points of the bronchi [1].

The majority of respiratory conditions associated with cough, such as chronic bronchitis, asthma and acute viral infections, predominantly affect the bronchi and or bronchioles where innervation is known to be exuberant. By contrast, IPF is characterized by fibroblastic proliferation and extracellular matrix deposition in the pulmonary interstitium together with a mononuclear cell alveolitis. Patients with IPF typically present with progressive breathlessness but, in approximately 80% of cases, this is associated with an irritating dry cough which usually proves resistant to conventional anti-tussive therapies [2]. It therefore seems anomalous that a condition primarily affecting alveoli, where innervation is known to be sparse [3], should cause a symptom more commonly related to airway disease.

Section snippets

Gastro-oesophageal reflux

The association between gastro-oesophageal reflux (GOR) and IPF was studied extensively by Tobin et al. [4] who found that patients with IPF had a high prevalence of oesophageal acid exposure, particularly at night, but without typical symptoms. They proposed that GOR may be relevant to the pathogenesis of IPF. Given that GOR is well known to be a cause of chronic cough [5], it seems likely that it may also be a causative factor per se for cough in some patients with IPF. However, other

Treatment of cough in IPF

Treatment of cough in IPF often proves difficult as the symptom responds poorly to conventional anti-tussive therapies. Anecdotal evidence suggests that corticosteroids may be beneficial, but there have been no formal trials to substantiate this. We recently demonstrated that administration of high dose oral prednisolone to a small group of patients with IPF caused significant reduction in their cough symptoms, a reduction in cough sensitivity to capsaicin and an abrogation of cough response to

Conclusions

It seems likely that there are a number of mechanisms which can explain the cough of patients with IPF. It is hoped that this review may progress our understanding of the condition, particularly the role of neurotrophins, which could potentially link the fibroproliferative processes with neuronal abnormalities associated with an enhanced cough reflex. Whilst IPF continues to present a challenge both to scientists and clinicians, such an understanding should ultimately lead to the development of

Acknowledgements

The author would like to thank Dr Ben Hope-Gill who helped generate much of the data discussed in this article [13] and for interesting discussions on the causes of cough in IPF. I am also grateful to Dr Robin McAnulty and Dr Steve Bottoms for providing the photomicrograph for Fig. 3.

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    Vibration transmitted through the small airways that begins with talking—and in our experience, laughing and breathing deep and/or fast—may act as a stimulus for overly sensitive RARs and SARs.34 In addition, nerves that inhibit the cough reflex arc may be selectively destroyed by fibrosis.35 Direct stimulation of the chest wall by mechanical percussion induced cough in 85% of patients with IPF vs 17% of control subjects (P < .0001) and at a lower frequency (20 vs 40 or 60 Hz) posteriorly than at other positions.34

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    For instance, more than 50% of patients with interstitial lung disease could have cough caused by other causes such as asthma, rhinitis or gastro-oesophageal reflux [18,19]. However, IIP may directly cause cough as inflammation is not limited to the parenchyma, and disrupted airway epithelium [20] with inflammatory mediators known to provoke cough having been detected in such patients [17,18]. A further possible cause of cough in patients with IIP is airway distortion secondary to interstitial fibrosis, which results in traction bronchiectasis [21].

  • Cough in interstitial lung disease

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    Up-regulation of the neurological pathways of cough is likely to play a crucial role. Heightened cough reflex to inhaled capsaicin and substance P, independent of volume restriction, is observed in patients with IPF [53,54] and is paralleled by elevated levels of neurotrophin factors, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), in induced sputum [54] and immunostaining of lung tissue [55], suggesting upregulation of sensory C-fibres and/or a lowered threshold to neuronal stimulation of the cough reflex in more proximal airways, giving rise to the concept of airway neuroplasticity [29,56]. The recent discovery of an altered lung microbiome in patients with IPF [57] could suggest epithelial disruption and sensory nerve exposure as another potential mechanism for an exaggerated cough response, as has been observed in otherwise healthy Japanese subjects exposed to substance P following an upper respiratory tract infection [58].

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    However, the effects of pirfenidone on cough in patients with IPF have not been adequately investigated. Researchers have proposed several theories [4,6] on the mechanisms which generate cough in patients with IPF: airway mechanical distortion secondary to fibrosis leading to sensitized rapidly adapting receptors (RARs) in small airways; modulation of nerves in larger airways by increased expression of neurotrophins; coexistence of GERD; and enhanced cough reflex sensitivity. Previous studies have also reported that patients with IPF have increased cough reflex sensitivity to capsaicin compared to healthy people [8,27].

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