Cough in interstitial lung disease

Cough in interstitial lung disease

Pulmonary Pharmacology & Therapeutics 35 (2015) 122–128 Contents lists available at ScienceDirect Pulmonary Pharmacology & Therapeutics j o u r n a ...

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Pulmonary Pharmacology & Therapeutics 35 (2015) 122–128

Contents lists available at ScienceDirect

Pulmonary Pharmacology & Therapeutics j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y p u p t

Cough in interstitial lung disease Justin Garner a,*, Peter M. George a,b, Elisabetta Renzoni a,b a b

Interstitial Lung Disease Unit, Royal Brompton and Harefield NHS Trust, United Kingdom National Heart and Lung Institute, Imperial College London, United Kingdom

A R T I C L E

I N F O

Article history: Received 5 October 2015 Received in revised form 22 October 2015 Accepted 23 October 2015 Available online 3 November 2015 Keywords: Cough Interstitial lung disease Lung fibrosis Mechanisms

A B S T R A C T

Cough in the context of interstitial lung disease (ILD) has not been the focus of many studies. However, chronic cough has a major impact on quality of life in a significant proportion of patients with ILD. For the purpose of this review, we have chosen to highlight some of the more frequently encountered diffuse lung diseases including idiopathic pulmonary fibrosis, sarcoidosis, hypersensitivity pneumonitis and systemic sclerosis associated ILD. Many of the underlying mechanisms remain speculative and further research is now required to elucidate the complex pathways involved in the pathogenesis of chronic cough in ILD. This will hopefully pave the way for the identification of new therapeutic agents to alleviate this distressing and often intractable symptom. © 2015 Elsevier Ltd. All rights reserved.

Up to one third of the general population have experienced a chronic cough, defined as a cough persisting for more than 8 weeks. Most commonly, cough is post-infective or attributable to conditions such as upper airways cough syndrome (rhinosinusitis), gastrooesophageal reflux, eosinophilic airways disease, and chronic obstructive airways disease (COPD) [1]. Many causes for cough are self-limiting or manageable, but more than four hundred million pounds are spent on over-the-counter medications per annum. The persisting cough afflicting many patients with interstitial lung disease (ILD), however, is characteristically intractable, and exerts a major impact on physical, psychological, and social wellbeing [2]. 1. Cough reflex Cough is a protective mechanism clearing the airways of noxious substances and accumulated secretions to preserve gas exchange, and is defined by three phases: inspiration, forced expiration against a closed glottis, and finally opening of the glottis [3]. It is triggered by both mechanical and chemical stimuli. The cough reflex arc comprises the following; 1) an afferent vagal sensory limb usually originating from the upper and lower airways (particularly the larynx and tracheo-bronchial tree); 2) convergence of signals in the nucleus tractus solitarius and processing in the central respiratory generator of the medulla oblongata; and 3) efferent motor limbs in the vagus (glottis closure), phrenic and spinal nerves supplying the laryngo-thoraco-abdomino-pelvic muscles [4,5]. Higher cortical centres can modify the cough response [6]. Several afferent nerve

* Corresponding author. E-mail address: [email protected] (J. Garner). http://dx.doi.org/10.1016/j.pupt.2015.10.009 1094-5539/© 2015 Elsevier Ltd. All rights reserved.

pathways have been identified in sub-serving this role and can be broadly classified into: -

• •

Mechanically-evoked pathways (tracheal touch-sensitive A-delta fibres or cough receptors and rapidly and slowly adapting airway mechanosensors) and Chemically-evoked pathways (bronchopulmonary unmyelinated C-fibres and chemosensitive A-delta fibres).

The reader is directed to several excellent reviews on this topic [7–10]. Activation of cough receptors and bronchopulmonary C-fibres initiates coughing: Cough receptors are insensitive to capsaicin and anaesthesia in contrast to bronchopulmonary C-fibres, lending support to the existence of parallel pathways regulating cough [7]. C-fibres originating from the lungs can be inhibitory to cough and so further research is needed to clarify their involvement in homeostasis versus a pathological state, and thus identification of potential therapeutic targets. Members of the transient receptor potential (TRP) family, including TRP channel subfamily vanilloid member 1 (TRPV1), TRP channel melastatin member 8 (TRPM8) and TRP channel subfamily A member 1 (TRPA1), are expressed on airway sensory nerves, and are directly activated by mechanical, chemical and thermal stimuli [11]. For example, capsaicin stimulates bronchopulmonary C-fibres via the TRPV1 receptor [12]. The TRPV1 receptor also responds to other noxious stimuli including heat and low pH. TRPV1 is overexpressed in patients with chronic cough [13], and with severe asthma [14]. Of likely relevance also to interstitial lung diseases, TRPV1 and/or TRPA1 can be sensitised indirectly by a range of inflammatory mediators, including bradykinin, nerve growth factor and PGE2, which act by decreasing the TRP activation potential [15].

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TRPV1 activation triggers the release of neuropeptides mediating vessel dilatation and permeability, such as substance P and neurokinin A [16]. Furthermore, substance P and neurokinin may in turn induce activation and chemotaxis of fibroblasts, thereby contributing to the fibrotic process [17]. P2X2/3 receptors are also expressed on sensory afferents innervating the airways and are recognised as important in transducing signals from the lung periphery to the central nervous system including from the visceral pleura in animal models [18–20]. Perhaps surprisingly, no studies have yet been performed to address the distribution or response to activation of the TRP family or P2X2/3 receptors in pulmonary fibrosis. This is clearly an area that requires dedicated research, given the heavy burden of cough on quality of life of patients with ILD. 2. Cough in interstitial lung disease Cough in the context of interstitial lung disease has not been the focus of many studies [21]. From the >300 existing ILD entities, for the purpose of this review, we have chosen to highlight only a few of the more frequently encountered conditions including: Idiopathic pulmonary fibrosis, sarcoidosis, hypersensitivity pneumonitis and systemic sclerosis associated ILD. 2.1. Idiopathic pulmonary fibrosis (IPF) Idiopathic pulmonary fibrosis (IPF) is the most frequent of the idiopathic interstitial pneumonias (IIPs), causing more than 5000 deaths each year in the UK alone [22,23]. It is more common in older men with a history of cigarette smoking. IPF is a dismal disease, characterised by progressive parenchymal distortion and scarring, with a median survival of only 3 years, although a wide variability in disease course is increasingly recognised [23]. Histologically, IPF is defined by a usual interstitial pneumonia (UIP) pattern, characterised by temporal and spatial heterogeneity, fibroblastic foci and areas of microscopic honeycombing, dilated airspaces surrounded by fibrosis [24]. IPF is thought to result from the complex interaction between genetic susceptibility, increasingly well defined [24–27], and environmental insults, with cigarette smoke the most powerful environmental risk factor described to date [28]. Recurrent micro-injuries to the alveolar epithelial cell are believed to initiate a cascade of events leading to a progressive fibro-proliferative response [29–31]. More than 80% of patients with idiopathic pulmonary fibrosis suffer from chronic cough [21]. Ryerson et al. compiled a prospective database of 242 patients with IPF and examined the clinical associations and prognostic value of cough. Intriguingly, cough was more common in never smokers as well as in individuals with more advanced disease, and was found to be an independent predictor of disease progression [32]. Similar to other respiratory conditions [33,34], cough in IPF occurs predominantly during the daytime. [35]. This may well be due to the fact that sleep itself is potently inhibitory to cough [36]. In IPF, intractable cough [37,38], in addition to disabling shortness of breath [39], has a major impact on quality of life and should not be underestimated. Health-related quality of life measures provide invaluable information in addition to physiological parameters and are increasingly employed in research as part of a drive towards targeting of patient-centred outcomes in what is a debilitating and extremely challenging condition to treat. It may seem somewhat surprising that cough is such a prominent symptom in patients with IPF, a disease which has been traditionally thought to exclusively involve the alveolar interstitium, where neuronal innervation is sparse. However, there are a number of mechanisms which are likely to play a role in the pathogenesis of cough. The striking genetic association between a promoter

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polymorphism in the MUC5B gene (encoding one of the main airway mucins) and both familial and sporadic IPF, and the overexpression of MUC5B in the small airways and honeycomb cysts in IPF [26,40–47], highlights a role for the peripheral airways in IPF which had been hitherto under-recognised. Interestingly, the minor (T) allele is associated with a greatly increased risk of IPF, but is also linked to a slower rate of decline [42] and improved survival [29]. Interestingly, the increased expression of MUC5B in distal airways is not observed in fibrotic NSIP pattern, whether idiopathic or associated with scleroderma, suggesting that this mechanism is specific to IPF [48]. Whether the MUC5B variant is also associated with an increased prevalence of cough as suggested by Scholand et al., will require further confirmatory studies [49]. Proliferation of bronchiolar cells specific to IPF compared to other ILD patterns had been originally reported by Chilosi et al. [50]. Very recent studies further support a key role for bronchiolar proliferation/small airway involvement in IPF [51,52]. 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]. Additional mechanisms are likely to include traction bronchiectasis, a dilatation of the larger airways associated with surrounding fibrosis, easily identified on CT, linked to alterations to the structure of the airways which could significantly contribute to cough pathogenesis. Mechanical chest wall percussion using a cutaneous electrical oscillator has also been shown to induce cough in patients with IPF compared to healthy controls, in particular when applied to the basal zones, which are preferentially involved [59]. These observations support the hypothesis that architectural distortion of the bronchial tree may either sensitise or upregulate mechanical sensors of the cough reflex arc or disrupt coughinhibitory C-fibre subtype neuronal pathways, resulting in an exuberant coughing response in these individuals [29]. 2.2. Granulomatous ILD 2.2.1. Sarcoidosis Sarcoidosis is a condition characterised by non-caseating granulomatous inflammation in the absence of an infective or infiltrative cause [60]. The prevalence of sarcoidosis is 10–20 per 100,000 individuals and more commonly occurs in the Afro-Caribbean population [61,62]. A genetic predisposition (HLA DR 11, 12, 14, 15, and 17) [63,64] and environmental triggers (infections for example, propionibacterium and mycobacterium, and various organic/ inorganic agents) [60,63] have been implicated by association. Sarcoidosis presents with an extensive range of symptoms reflecting the potential for multisystem involvement. Pulmonary involvement is observed in over 90% of patients with sarcoidosis and can affect both the upper and lower respiratory tracts [65]. The prevalence of cough is estimated at between 30 and 50% [56]. The pathogenesis of cough is thought to mainly relate to a combination of parenchymal involvement leading to airway distortion, and granulomatous mucosal inflammation causing airflow limitation and hyper-responsiveness [21,66,67]. Indeed, sarcoid granulomas

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tend to follow a peri-lymphatic distribution and are thus abundant in association with the bronchiolo-arterial bundles. An almost two-fold increased burden of cough is observed among sarcoid patients with biopsy-proven granulomatous tracheitis compared to those without. Further, the occurrence of airway involvement increases as the parenchymal disease progresses [68]. Increased expression of neurotrophins (nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3) and high affinity neurotrophin receptor transcripts (TrkA-C) have been measured in bronchoalveolar lavage immune cells (macrophages, CD4 and CD8 T-cell populations) and granulomas from patients with sarcoidosis [69–71], suggesting airway neuromodulation as a potential mechanism for a heightened cough reflex. Adenopathy causing extrinsic compression may rarely be the main cause of symptoms [67]. Airway hyperreactivity has been reported at varying rates by a number of studies, with the most frequently reported estimate being approximately 20% [72], and may be the cause of cough in a proportion of patients. 2.2.2. Hypersensitivity pneumonitis Hypersensitivity pneumonitis (HP) is characterised by bronchocentric granulomatous inflammation driven by an overzealous immune response (predominantly type IV) to the repeated inhalation of an antigen. HP is traditionally classified into acute, subacute, and chronic (fibrotic) forms, all of which are associated with cough [21]. The pathogenesis of cough in this condition is poorly understood and thought to relate in part to airflow limitation due to bronchiolitis in non-fibrotic disease [73,74]. It is quite possible that several of the cough mechanisms operating in IPF may be relevant to other fibrotic ILDs, including fibrotic HP. Indeed, a proportion of patients with fibrotic HP have a clinical course and progression of disease akin to individuals with IPF [73]. 2.3. Connective tissue disease associated ILD Pulmonary manifestations relating to an underlying rheumatic disease form a significant proportion of patients reviewed in the respiratory clinic. In addition to cough associated with an ILD, there are a number of potential contributory mechanisms. In Sjogren’s syndrome, cough can occur as a consequence of lymphocytic destruction of the glandular epithelial mucosa of the trachea causing airway desiccation or xerotrachea [75], or can be associated with lymphocytic inflammation with bronchial hyperresponsiveness [75–78]. The distinction between the two is relevant as treatment varies, for example topical lubrication in the form of nebulised saline for xerotrachea, and either inhaled or systemic corticosteroid therapy for lymphocytic inflammation [79,80]. As SSc is the CTD most commonly associated with ILD, it has been the most studied, also in terms of mechanisms of chronic cough. A heightened cough reflex is observed in patients with systemic sclerosis following inhalation of capsaicin and chloride-deficient solutions [81], and this is mediated by non-myelinated C and myelinated A-delta fibres in the guinea pig [82]. Sensory innervation is predominantly of the proximal airways, and the mechanisms of neurogenic stimulation in patients with systemic sclerosis may relate to an inflammatory milieu as identified on bronchoalveolar lavage [83,84] or injury to pulmonary C-fibres, which inihibit the cough reflex in anaesthetised cats [85]. There is a positive correlation between the extent of fibrosis and the frequency and severity of cough, which is responsive to immunosuppressive therapy with Cyclophosphamide [86]. Thus architectural distortion of the airways may also promote neuroplasticity in a similar manner as hypothesised in IPF. In addition, patients frequently have oesophageal dysmotility and dilatation with gastro-oesophageal reflux, and the significance of this is explored in more detail below.

3. Co-factors contributing to cough in ILD A number of common conditions may aggravate the cough in interstitial lung disease and a thorough evaluation should be made in the clinical work upto include: upper airways cough syndrome (rhinosinusitis), gastro-oesophageal reflux (see below), and drugrelated cough (e.g. angiotensin-converting enzyme (ACE) inhibitor) [3]. Rhinosinusitis is characterised by a post-nasal drip (PND) with throat clearing in the context of either nasal discharge or congestion and can be treated with an intranasal steroid, antihistamine or decongestant (e.g. pseudoephedrine). However, it has been argued that PND is not necessarily a cause of cough, rather an index of coexisting pathology [87,88]. ACE inhibitors are commonly used in cardiovascular disease and can cause a chronic cough secondary to bradykinin accumulation [89]. The onset of an ACE-inhibitor related cough should prompt replacement of the culprit drug with an alternative agent. This often results in resolution of cough, but not necessarily with immediate effect. 3.1. The role of gastro-oesophageal reflux disease (GORD) in ILD It is now well established that GORD is one of the most common causes of chronic cough [90,91]. GORD can induce cough through a number of pathobiological mechanisms. Acid and non-acid reflux can irritate the respiratory tract acting as a direct cough stimulant. The larynx is poorly protected from the effects of GORD and is vulnerable to exposure to gastric contents, including highly irritant molecules such as proteolytic enzymes and bile salts [92]. If gastric contents do manage to traverse the larynx to access the lower airway, the cough reflex is once again stimulated. Along with these direct mechanisms, there are also indirect mechanisms which implicate the shared vagal afferents between the oesophagus and the airway which converge at the brainstem. This crosstalk between the oesophagus and airway has been termed the oesophageal-bronchial reflex and work in this field has led to the suggestion that stimulation of the distal oesophagus with gastric contents is sufficient in its own right to cause cough [93]. GORD is very common in patients with ILD. In a study of 65 wellcharacterised patients with idiopathic pulmonary fibrosis (IPF), abnormal levels of acid reflux were found in 87% of those studied [94]. Interestingly in many of these patients, acid reflux was clinically silent and in 12 of 19 patients already receiving proton pump inhibitor (PPI) treatment for GORD, acid reflux persisted. Savarino and colleagues compared the presence of GORD and gastric aspiration in consecutive patients with IPF, patients with non-IPF ILDs and healthy controls demonstrating that patients with IPF had significantly more gastro-oesophageal reflux (both acid and nonacid) than patients with non IPF ILDs, who in turn had more than controls [95]. The group found higher bile acid and pepsin levels in the bronchoalveolar lavage (BAL) fluid of the IPF patient group concluding that this group is at higher risk of pulmonary aspiration of gastric contents. GORD is particularly relevant in patients with systemic sclerosis (SSc) where it is estimated that oesophageal dysmotility is an issue in over 85% of patients [96]. In patients with SSc associated ILD (SSc-ILD), worsening GORD has been associated with more severe pulmonary fibrosis [97,98]. However, in a subsequent study of patients with SSc-ILD by Gilson and colleagues, severity of oesophageal involvement was not associated with lung function decline, once baseline ILD severity was taken into account, although only a small number of patients had extensive ILD [99]. Whilst none of these studies focused specifically on cough, rather pulmonary fibrosis, the disparate results observed suggest that GORD may be relevant in a subset of individuals with SScILD. A currently recruiting prospective observational trial aims to examine the relationship between GORD and severity of lung fibrosis, markers of micro-aspiration into the lungs and longitudinal

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behaviour of pulmonary fibrosis in the context of SSc. This should allow a better characterisation of the relationship between gut and lung involvement in SSc-ILD (NCT02136394). There is yet to be a large controlled interventional study of GORD treatment in ILD to assess for benefits on pulmonary fibrosis or cough. In a retrospective analysis of data from three randomized controlled IPF trials, Lee and colleagues divided patients in the placebo arms into two groups; those taking a PPI or an H2 blocker and those not taking anti-acid treatment. At 30 weeks, patients on acid suppression treatment at baseline had a significant reduction in lung function decline, with a mean FVC decline of 60 mL compared to 120 mL for those not on treatment [100]. However, two abstracts presented at the 2015 European Respiratory Society conference reported no difference in survival or disease progression between patients with or without PPI treatment in the recent large placebo arms of the Pirfenidone [101] and Nintedanib trials [102]. It is worth noting that in a recent small study of IPF patients where oesophageal impedance was measured, the majority of reflux was non-acid as opposed to acid. Treatment with high dose PPIs paradoxically increased non-acid reflux and although reducing acid reflux, had no effect on cough [103].

rently recruiting to specifically assess the effects of pirfenidone on cough in IPF (NCT02009293). Thalidomide is a potent immunomodulatory agent with antiangiogenic potential [114]. In an early study designed to assess the potential for thalidomide as an IPF drug, it was noted that patients on treatment experienced an improvement in symptoms of cough [115]. Although this study was not powered to assess this end point, it provided the basis for a formal randomized control trial designed to assess the efficacy of thalidomide as an anti-tussive agent in IPF. In this double blind cross-over 24 week trial, thalidomide was found to reduce cough as measured by the Cough Quality of Life Questionnaire, cough visual analogue score and St George’s Respiratory Questionnaire [116]. Adverse events were more common in the treatment arm (74%) as compared to placebo (22%). The commonest side effects were constipation, dizziness and malaise. Although limited by small numbers (only 20 patients completed both arms) and its nature as a single centre study, this study supports the use of thalidomide in IPF-induced cough. Taken together, further research is needed to exploit potential therapeutic targets for what is a very distressing symptom in patients with IPF [113].

4. Treatment of cough in interstitial lung disease

4.2. Granulomatous ILD

Treatment of cough is aimed at the underlying interstitial process, whenever possible, in addition to targeting co-factors such as rhinosinusitis and gastro-oesphageal reflux. Depending on the underlying ILD type, there may be an element of reversible disease, and treatment of the underlying ILD (and/or removal of potential causative exposures in the case of HP) can also lead to improvement in the cough. However, unfortunately, alleviation of cough remains challenging in the majority of patients with ILD, also owing to the progressive and irreversible nature of the scarring process in ILDs such as IPF. In addition, we have a limited understanding of the pathogenic mechanisms involved and potential drugtargets which could be exploited. Opioid medications are frequently prescribed but with limited benefit, although their use in combination with other palliative therapies remains important in the more advanced stages of lung fibrosis [104].

No dedicated randomised controlled trials on the treatment of cough in patients with granulomatous ILD have been performed. A systematic review evaluating the efficacy of corticosteroid (oral or inhaled) in individuals with pulmonary sarcoidosis included 13 randomised controlled trials of variable methodology [117]. The authors concluded an improvement in symptoms (including cough), chest x-ray appearances, and spirometry over a 3–24 month period, though the results could not be reliably extrapolated to determine effect on disease progression beyond 2 years. A risk benefit assessment must be made on the value of introducing steroid therapy, particularly if given orally, and the attendant side-effects of therapy [21]. In patients with hypersensitivity pneumonitis, the mainstay of treatment rests with management of the underlying condition, with avoidance of the sensitising agent, in the cases where this is identified, alongside corticosteroids± immunosuppressive therapy [118,119].

4.1. Idiopathic pulmonary fibrosis 4.3. Systemic sclerosis Hope-Gill et al. demonstrated reduced cough severity and sensitivity to inhaled capsaicin and substance P following one month of prednisolone 40 mg once daily in all 6 treated patients with IPF [54]. However, steroids can cause significant side-effects and the 2006 ACCP guidelines therefore recommend a risk-benefit assessment should be made before introduction [21]. Furthermore. the PANTHER trial provides evidence against combined immunosuppression using high dose steroid in patients with mild to moderate impairment of lung function, with increased mortality and increased rates of hospital admissions observed in subjects in the triple therapy arm compared to placebo [105]. Treatment with low dose oral interferon-alpha, which inhibits proliferating fibroblasts, was assessed as part of a proof of concept study. Five of six patients reported a significant symptomatic improvement in cough. However, the study was limited by small numbers and the lack of a control group [106]. Furthermore, type I interferon has been associated with the development of pulmonary arterial hypertension [107,108], a grave complication of interstitial lung disease. Pirfenidone, an anti-fibrotic agent, and Nintedanib, a tyrosine kinase inhibitor, are the only drugs that have been shown to slow progression in patients with IPF to date [109–112]. There is limited data to suggest Pirfenidone may alleviate cough in a subset of patients with mild to moderate lung function impairment [113]. A multicentre European study is cur-

In patients with progressive SSc-ILD, cyclophosphamide treatment [120,121] is associated with stabilization of forced vital capacity (FVC) at one year compared to placebo, with more marked benefits compared to placebo seen in patients with greater baseline ILD severity. In the Scleroderma Lung Study (SLS I), cough frequency and severity responded favourably to 12 months treatment with oral Cyclophosphamide. This benefit was no longer present one year following discontinuation of treatment, in parallel with the loss in FVC benefit, suggesting ongoing treatment with alternative immunosuppressive agents is required [86]. Improvement in the cough is likely to result from the treatment of the underlying ILD process. However, there is a substantial number of patients with troublesome cough that does not respond satisfactorily to available treatments. 5. Targeting of nervous pathways A neuropathic aetiology for cough is suggested by improvement in chronic idiopathic cough after treatment with Amitriptyline [122] and Gabapentin [123] and a central nervous system action is thought to mediate this effect in part [124]. Nebulised lidocaine has been found to be beneficial in patients with refractory cough [125] although its use in interstitial lung disease is anecdotal.

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The TRP family of receptors present on vagal sensory afferents of the cough reflex arc offer one such pharmacological target and opens the door to novel antagonists [12,15,126,127]. An exciting development is a P2X3 receptor antagonist, AF-219, which has been shown to reduce cough frequency by 75% in patients with chronic idiopathic cough [128] and might be of benefit in other causes of cough such as ILD. 6. Conclusion Progress has been made in understanding the pathology of chronic cough. However, many of the mechanisms for cough in interstitial lung disease remain speculative. Further research is now required to elucidate the complex pathways involved in the pathogenesis of chronic cough in ILD. This will hopefully pave the way for the identification of new therapeutic agents to alleviate this distressing and often intractable symptom. References [1] W.J. Song, Y.S. Chang, S. Faruqi, et al., The global epidemiology of chronic cough in adults: a systematic review and meta-analysis, Eur. Respir. J. 45 (5) (2015) 1479–1481. [2] S. Faruqi, R.D. Murdoch, F. Allum, A.H. Morice, On the definition of chronic cough and current treatment pathways: an international qualitative study, Cough 10 (2014) 5. [3] K.F. Chung, I.D. Pavord, Prevalence, pathogenesis, and causes of chronic cough, Lancet 371 (9621) (2008) 1364–1374. [4] J.G. Widdicombe, Neurophysiology of the cough reflex, Eur. Respir. J. 8 (7) (1995) 1193–1202. [5] R. Shannon, D.M. Baekey, K.F. Morris, Z. Li, B.G. Lindsey, Functional connectivity among ventrolateral medullary respiratory neurones and responses during fictive cough in the cat, J. Physiol. 525 (Pt 1) (2000) 207–224. [6] J. Widdicombe, R. Eccles, G. Fontana, Supramedullary influences on cough, Respir. Physiol. Neurobiol. 152 (3) (2006) 320–328. [7] B.J. Canning, Y.L. Chou, Cough sensors. I. Physiological and pharmacological properties of the afferent nerves regulating cough, Handb. Exp. Pharmacol. 187 (2009) 23–47. [8] S.B. Mazzone, B.J. Undem, Cough sensors. V. Pharmacological modulation of cough sensors, Handb. Exp. Pharmacol. 187 (2009) 99–127. [9] B.J. Canning, Functional implications of the multiple afferent pathways regulating cough, Pulm. Pharmacol. Ther. 24 (3) (2011) 295–299. [10] D. Spina, C.P. Page, Regulating cough through modulation of sensory nerve function in the airways, Pulm. Pharmacol. Ther. 26 (5) (2013) 486–490. [11] L. Vay, C. Gu, P.A. McNaughton, The thermo-TRP ion channel family: properties and therapeutic implications, Br. J. Pharmacol. 165 (4) (2012) 787–801. [12] M.S. Grace, E. Dubuis, M.A. Birrell, M.G. Belvisi, TRP channel antagonists as potential antitussives, Lung 190 (1) (2012) 11–15. [13] D.A. Groneberg, A. Niimi, Q.T. Dinh, et al., Increased expression of transient receptor potential vanilloid-1 in airway nerves of chronic cough, Am. J. Respir. Crit. Care Med. 170 (12) (2004) 1276–1280. [14] L.P. McGarvey, C.A. Butler, S. Stokesberry, et al., Increased expression of bronchial epithelial transient receptor potential vanilloid 1 channels in patients with severe asthma, J. Allergy Clin. Immunol. 133 (3) (2014) 704–712, e4. [15] M. Grace, M.A. Birrell, E. Dubuis, S.A. Maher, M.G. Belvisi, Transient receptor potential channels mediate the tussive response to prostaglandin E2 and bradykinin, Thorax 67 (10) (2012) 891–900. [16] J. Springer, P. Geppetti, A. Fischer, D.A. Groneberg, Calcitonin gene-related peptide as inflammatory mediator, Pulm. Pharmacol. Ther. 16 (3) (2003) 121–130. [17] N.K. Harrison, K.E. Dawes, O.J. Kwon, P.J. Barnes, G.J. Laurent, K.F. Chung, Effects of neuropeptides on human lung fibroblast proliferation and chemotaxis, Am. J. Physiol. 268 (2 Pt 1) (1995) L278–L283. [18] I. Pintelon, I. Brouns, I. De Proost, F. Van Meir, J.P. Timmermans, D. Adriaensen, Sensory receptors in the visceral pleura: neurochemical coding and live staining in whole mounts, Am. J. Respir. Cell Mol. Biol. 36 (5) (2007) 541– 551. [19] I. Brouns, I. Pintelon, J.P. Timmermans, D. Adriaensen, Novel insights in the neurochemistry and function of pulmonary sensory receptors, Adv. Anat. Embryol. Cell Biol. 211 (2012) 1–115, vii. [20] D. Adriaensen, I. Brouns, J.P. Timmermans, Sensory input to the central nervous system from the lungs and airways: a prominent role for purinergic signalling via P2X2/3 receptors, Auton. Neurosci. 191 (2015) 39–47. [21] K.K. Brown, Chronic cough due to chronic interstitial pulmonary diseases: ACCP evidence-based clinical practice guidelines, Chest 129 (suppl. 1) (2006), 180S-5S. [22] V. Navaratnam, K.M. Fleming, J. West, et al., The rising incidence of idiopathic pulmonary fibrosis in the U.K., Thorax 66 (6) (2011) 462–467.

[23] J. Gribbin, R.B. Hubbard, I. Le Jeune, C.J. Smith, J. West, L.J. Tata, Incidence and mortality of idiopathic pulmonary fibrosis and sarcoidosis in the UK, Thorax 61 (11) (2006) 980–985. [24] Y. Wang, P.J. Kuan, C. Xing, et al., Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer, Am. J. Hum. Genet. 84 (1) (2009) 52–59. [25] C.H. van Moorsel, M.F. van Oosterhout, N.P. Barlo, et al., Surfactant protein C mutations are the basis of a significant portion of adult familial pulmonary fibrosis in a dutch cohort, Am. J. Respir. Crit. Care Med. 182 (11) (2010) 1419–1425. [26] A.L. Peljto, Y. Zhang, T.E. Fingerlin, et al., Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis, JAMA 309 (21) (2013) 2232–2239. [27] I. Noth, Y. Zhang, S.F. Ma, et al., Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study, Lancet Respir. Med. 1 (4) (2013) 309–317. [28] P.D. Mitchell, J.P. Das, D.J. Murphy, et al., Idiopathic pulmonary fibrosis with emphysema: evidence of synergy among emphysema and idiopathic pulmonary fibrosis in smokers, Respir. Care 60 (2) (2015) 259–268. [29] N.K. Harrison, Idiopathic pulmonary fibrosis: a nervous cough?, Pulm. Pharmacol. Ther. 17 (6) (2004) 347–350. [30] H. Kage, Z. Borok, EMT and interstitial lung disease: a mysterious relationship, Curr. Opin. Pulm. Med. 18 (5) (2012) 517–523. [31] I.E. Fernandez, O. Eickelberg, The impact of TGF-β on lung fibrosis: from targeting to biomarkers, Proc. Am. Thorac. Soc. 9 (3) (2012) 111–116. [32] C.J. Ryerson, M. Abbritti, B. Ley, B.M. Elicker, K.D. Jones, H.R. Collard, Cough predicts prognosis in idiopathic pulmonary fibrosis, Respirology 16 (6) (2011) 969–975. [33] P.A. Marsden, J.A. Smith, A.A. Kelsall, et al., A comparison of objective and subjective measures of cough in asthma, J. Allergy Clin. Immunol. 122 (5) (2008) 903–907. [34] J.J. Stephenson, Q. Cai, M. Mocarski, H. Tan, J.A. Doshi, S.D. Sullivan, Impact and factors associated with nighttime and early morning symptoms among patients with chronic obstructive pulmonary disease, Int. J. Chron. Obstruct Pulmon. Dis. 10 (2015) 577–586. [35] A.L. Key, K. Holt, A. Hamilton, J.A. Smith, J.E. Earis, Objective cough frequency in Idiopathic Pulmonary Fibrosis, Cough 6 (2010) 4. [36] C.E. Sullivan, E. Murphy, L.F. Kozar, E.A. Phillipson, Waking and ventilatory responses to laryngeal stimulation in sleeping dogs, J. Appl. Physiol. Respir. Environ. Exerc Physiol. 45 (5) (1978) 681–689. [37] J.J. Swigris, A.L. Stewart, M.K. Gould, S.R. Wilson, Patients’ perspectives on how idiopathic pulmonary fibrosis affects the quality of their lives, Health Qual. Life Outcomes 3 (2005) 61. [38] A. Belkin, J.J. Swigris, Health-related quality of life in idiopathic pulmonary fibrosis: where are we now?, Curr. Opin. Pulm. Med. 19 (5) (2013) 474–479. [39] O. Nishiyama, H. Taniguchi, Y. Kondoh, et al., Health-related quality of life in patients with idiopathic pulmonary fibrosis. What is the main contributing factor?, Respir. Med. 99 (4) (2005) 408–414. [40] M.A. Seibold, A.L. Wise, M.C. Speer, et al., A common MUC5B promoter polymorphism and pulmonary fibrosis, N. Engl. J. Med. 364 (16) (2011) 1503–1512. [41] L. Plantier, B. Crestani, S.E. Wert, et al., Ectopic respiratory epithelial cell differentiation in bronchiolised distal airspaces in idiopathic pulmonary fibrosis, Thorax 66 (8) (2011) 651–657. [42] C.J. Stock, H. Sato, C. Fonseca, et al., Mucin 5B promoter polymorphism is associated with idiopathic pulmonary fibrosis but not with development of lung fibrosis in systemic sclerosis or sarcoidosis, Thorax 68 (5) (2013) 436– 441. [43] R. Borie, B. Crestani, P. Dieude, et al., The MUC5B variant is associated with idiopathic pulmonary fibrosis but not with systemic sclerosis interstitial lung disease in the European Caucasian population, PLoS One 8 (8) (2013) e70621. [44] R. Wei, C. Li, M. Zhang, et al., Association between MUC5B and TERT polymorphisms and different interstitial lung disease phenotypes, Transl. Res. 163 (5) (2014) 494–502. [45] C. Wang, Y. Zhuang, W. Guo, et al., Mucin 5B promoter polymorphism is associated with susceptibility to interstitial lung diseases in Chinese males, PLoS One 9 (8) (2014) e104919. [46] A.L. Peljto, M. Selman, D.S. Kim, et al., The MUC5B promoter polymorphism is associated with idiopathic pulmonary fibrosis in a Mexican cohort but is rare among Asian ancestries, Chest 147 (2) (2015) 460–464. [47] Y. Horimasu, S. Ohshimo, F. Bonella, et al., MUC5B promoter polymorphism in Japanese patients with idiopathic pulmonary fibrosis, Respirology 20 (3) (2015) 439–444. [48] C. Conti, A. Montero-Fernandez, A.G. Nicholson, et al., Distribution of Mucins MUC5B and MUC5AC in distal airways and honeycomb spaces: comparison between uip and other ild patterns, Am. J. Respir. Crit. Care Med 191 (2015) A2161, in press. [49] M.B. Scholand, R. Wolff, P.F. Crossno, et al., Severity of cough in idiopathic pulmonary fibrosis is associated with MUC5 B genotype, Cough 10 (2014) 3. [50] M. Chilosi, V. Poletti, A. Zamò, et al., Aberrant Wnt/beta-catenin pathway activation in idiopathic pulmonary fibrosis, Am. J. Pathol. 162 (5) (2003) 1495–1502. [51] A. Prasse, Unexpected contribution of airway-derived epithelial cells to IPF progression, in: ERS Congress Symposium, 2015. [52] W. Wuyts, Unexpected results of imaging in IPF, in: ERS Congress Symposium, 2015.

J. Garner et al./Pulmonary Pharmacology & Therapeutics 35 (2015) 122–128

[53] M.J. Doherty, R. Mister, M.G. Pearson, P.M. Calverley, Capsaicin induced cough in cryptogenic fibrosing alveolitis, Thorax 55 (12) (2000) 1028–1032. [54] B.D. Hope-Gill, S. Hilldrup, C. Davies, R.P. Newton, N.K. Harrison, A study of the cough reflex in idiopathic pulmonary fibrosis, Am. J. Respir. Crit. Care Med. 168 (8) (2003) 995–1002. [55] A. Ricci, P. Graziano, E. Bronzetti, et al., Increased pulmonary neurotrophin protein expression in idiopathic interstitial pneumonias, Sarcoidosis Vasc. Diffus. Lung Dis. 24 (1) (2007) 13–23. [56] N.K. Harrison, Cough, sarcoidosis and idiopathic pulmonary fibrosis: raw nerves and bad vibrations, Cough 9 (1) (2013) 9. [57] P.L. Molyneaux, M.J. Cox, S.A. Willis-Owen, et al., The role of bacteria in the pathogenesis and progression of idiopathic pulmonary fibrosis, Am. J. Respir. Crit. Care Med. 190 (8) (2014) 906–913. [58] U. Katsumata, K. Sekizawa, H. Inoue, H. Sasaki, T. Takishima, Inhibitory actions of procaterol, a beta-2 stimulant, on substance P-induced cough in normal subjects during upper respiratory tract infection, Tohoku J. Exp. Med. 158 (1) (1989) 105–106. [59] R.M. Jones, S. Hilldrup, B.D. Hope-Gill, R. Eccles, N.K. Harrison, Mechanical induction of cough in Idiopathic Pulmonary Fibrosis, Cough 7 (2011) 2. [60] R.P. Baughman, E.E. Lower, R.M. du Bois, Sarcoidosis. Lancet 361 (9363) (2003) 1111–1118. [61] B.A. Rybicki, M. Major, J. Popovich, M.J. Maliarik, M.C. Iannuzzi, Racial differences in sarcoidosis incidence: a 5-year study in a health maintenance organization, Am. J. Epidemiol. 145 (3) (1997) 234–241. [62] R. Heinle, C. Chang, Diagnostic criteria for sarcoidosis, Autoimmun. Rev. 13 (4–5) (2014) 383–387. [63] A. Fischer, J. Grunewald, P. Spagnolo, A. Nebel, S. Schreiber, J. Müller-Quernheim, Genetics of sarcoidosis, Semin. Respir. Crit. Care Med. 35 (3) (2014) 296–306. [64] J. Grunewald, Review: role of genetics in susceptibility and outcome of sarcoidosis, Semin. Respir. Crit. Care Med. 31 (4) (2010) 380–389. [65] G.W. Hunninghake, U. Costabel, M. Ando, et al., ATS/ERS/WASOG statement on sarcoidosis. American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders, Sarcoidosis Vasc. Diffus. Lung Dis. 16 (2) (1999) 149–173. [66] V.S. Polychronopoulos, U.B. Prakash, Airway involvement in sarcoidosis, Chest 136 (5) (2009) 1371–1380. [67] R.P. Baughman, R. Shipley, S. Desai, et al., Changes in chest roentgenogram of sarcoidosis patients during a clinical trial of infliximab therapy: comparison of different methods of evaluation, Chest 136 (2) (2009) 526–535. [68] B.D. Harrison, J.M. Shaylor, T.C. Stokes, A.R. Wilkes, Airflow limitation in sarcoidosis–a study of pulmonary function in 107 patients with newly diagnosed disease, Respir. Med. 85 (1) (1991) 59–64. [69] D. Xin-Min, X. Qin-Zhi, D. Yun-You, et al., Impact of tracheal mucosa involvement on clinical characteristics of sarcoidosis, South Med. J. 104 (5) (2011) 315–318. [70] A. Ricci, S. Mariotta, C. Saltini, et al., Neurotrophin system activation in bronchoalveolar lavage fluid immune cells in pulmonary sarcoidosis, Sarcoidosis Vasc. Diffus. Lung Dis. 22 (3) (2005) 186–194. [71] C. Dagnell, J. Grunewald, F. Idali, et al., Increased levels of nerve growth factor in the airways of patients with sarcoidosis, J. Intern. Med. 264 (5) (2008) 463–471. [72] F. Shora, A. Menzies-Gow, N. Goh, E. Renzoni, The airways and Sarcoidosis, in: D. Mitchell, A. Wells, S. Spiro, D. Moller (Eds), Sarcoidosis, Hodder Arnold, United Kingdon, 2012, pp. 203–213. [73] J.S. Vourlekis, M.I. Schwarz, R.M. Cherniack, et al., The effect of pulmonary fibrosis on survival in patients with hypersensitivity pneumonitis, Am. J. Med. 116 (10) (2004) 662–668. [74] Y. Lacasse, M. Girard, Y. Cormier, Recent advances in hypersensitivity pneumonitis, Chest 142 (1) (2012) 208–217. [75] S.A. Papiris, M. Saetta, G. Turato, et al., CD4-positive T-lymphocytes infiltrate the bronchial mucosa of patients with Sjögren’s syndrome, Am. J. Respir. Crit. Care Med. 156 (2 Pt 1) (1997) 637–641. [76] B. Gudbjörnsson, H. Hedenström, G. Stålenheim, R. Hällgren, Bronchial hyperresponsiveness to methacholine in patients with primary Sjögren’s syndrome, Ann. Rheum. Dis. 50 (1) (1991) 36–40. [77] D. Lúdvíksdóttir, C. Janson, M. Högman, et al., Increased nitric oxide in expired air in patients with Sjögren’s syndrome. BHR study group. Bronchial hyperresponsiveness, Eur. Respir. J. 13 (4) (1999) 739–743. [78] K. Amin, D. Lúdvíksdóttir, C. Janson, et al., Inflammation and structural changes in the airways of patients with primary Sjögren’s syndrome, Respir. Med. 95 (11) (2001) 904–910. [79] M. Kokosi, E.C. Riemer, K.B. Highland, Pulmonary involvement in Sjögren syndrome, Clin. Chest Med. 31 (3) (2010) 489–500. [80] P.Y. Hatron, I. Tillie-Leblond, D. Launay, E. Hachulla, A.L. Fauchais, B. Wallaert, Pulmonary manifestations of Sjögren’s syndrome, Presse Med. 40 (1 Pt 2) (2011) e49–64. [81] U.G. Lalloo, S. Lim, R. DuBois, P.J. Barnes, K.F. Chung, Increased sensitivity of the cough reflex in progressive systemic sclerosis patients with interstitial lung disease, Eur. Respir. J. 11 (3) (1998) 702–705. [82] A.J. Fox, P.J. Barnes, A. Dray, Stimulation of guinea-pig tracheal afferent fibres by non-isosmotic and low-chloride stimuli and the effect of frusemide, J. Physiol. 482 (Pt 1) (1995) 179–187. [83] R.M. Silver, K.S. Miller, M.B. Kinsella, E.A. Smith, S.I. Schabel, Evaluation and management of scleroderma lung disease using bronchoalveolar lavage, Am. J. Med. 88 (5) (1990) 470–476.

127

[84] A.U. Wells, D.M. Hansell, M.B. Rubens, et al., Fibrosing alveolitis in systemic sclerosis. Bronchoalveolar lavage findings in relation to computed tomographic appearance, Am. J. Respir. Crit. Care Med. 150 (2) (1994) 462–468. [85] M. Tatar, S.E. Webber, J.G. Widdicombe, Lung C-fibre receptor activation and defensive reflexes in anaesthetized cats, J. Physiol. 402 (1988) 411–420. [86] A.C. Theodore, C.H. Tseng, N. Li, R.M. Elashoff, D.P. Tashkin, Correlation of cough with disease activity and treatment with cyclophosphamide in scleroderma interstitial lung disease: findings from the Scleroderma Lung Study, Chest 142 (3) (2012) 614–621. [87] A.H. Morice, Post-nasal drip syndrome–a symptom to be sniffed at?, Pulm. Pharmacol. Ther. 17 (6) (2004) 343–345. [88] L.I. Landau, Acute and chronic cough, Paediatr. Respir. Rev. 7 (Suppl 1) (2006) S64–S67. [89] K.E. Berkin, S.G. Ball, Cough and angiotensin converting enzyme inhibition, Br. Med. J. Clin. Res. Ed. 296 (6632) (1988) 1279. [90] L.P. McGarvey, L.G. Heaney, J.T. Lawson, et al., Evaluation and outcome of patients with chronic non-productive cough using a comprehensive diagnostic protocol, Thorax 53 (9) (1998) 738–743. [91] R.S. Irwin, Chronic cough due to gastroesophageal reflux disease: ACCP evidence-based clinical practice guidelines, Chest 129 (suppl. 1) (2006), 80S-94S. [92] G.S. Sandhu, R. Kuchai, The larynx in cough, Cough 9 (1) (2013) 16. [93] J.A. Smith, L.A. Houghton, The oesophagus and cough: laryngo-pharyngeal reflux, microaspiration and vagal reflexes, Cough 9 (1) (2013) 12. [94] G. Raghu, T.D. Freudenberger, S. Yang, et al., High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis, Eur. Respir. J. 27 (1) (2006) 136–142. [95] E. Savarino, R. Carbone, E. Marabotto, et al., Gastro-oesophageal reflux and gastric aspiration in idiopathic pulmonary fibrosis patients, Eur. Respir. J. 42 (5) (2013) 1322–1331. [96] S. Weston, M. Thumshirn, J. Wiste, M. Camilleri, Clinical and upper gastrointestinal motility features in systemic sclerosis and related disorders, Am. J. Gastroenterol. 93 (7) (1998) 1085–1089. [97] I. Marie, S. Dominique, H. Levesque, et al., Esophageal involvement and pulmonary manifestations in systemic sclerosis, Arthritis Rheum. 45 (4) (2001) 346–354. [98] E. Savarino, M. Bazzica, P. Zentilin, et al., Gastroesophageal reflux and pulmonary fibrosis in scleroderma: a study using pH-impedance monitoring, Am. J. Respir. Crit. Care Med. 179 (5) (2009) 408–413. [99] M. Gilson, D. Zerkak, J. Wipff, et al., Prognostic factors for lung function in systemic sclerosis: prospective study of 105 cases, Eur. Respir. J. 35 (1) (2010) 112–117. [100] J.S. Lee, H.R. Collard, K.J. Anstrom, et al., Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomised controlled trials, Lancet Respir. Med. 1 (5) (2013) 369–376. [101] M. Kreuter, W. Wuyts, E. Renzoni, et al., Antacid therapy and progression free survival in idiopathic pulmonary fibrosis (IPF), in: ERS Congress Symposium, 2015. [102] G. Raghu, B. Crestani, Z. Bailes, R. Schlenker-Herceg, U. Costabel, Effect of anti-acid medication on reduction in FVC decline with nintedanib, in: ERS Congress Symposium, 2015. [103] C.E. Kilduff, M.J. Counter, G.A. Thomas, N.K. Harrison, B.D. Hope-Gill, Effect of acid suppression therapy on gastroesophageal reflux and cough in idiopathic pulmonary fibrosis: an intervention study, Cough 10 (2014) 4. [104] NICE, Diagnosis and Management of Suspected Idiopathic Pulmonary Fibrosis: Idiopathic Pulmonary Fibrosis, 2013. [105] G. Raghu, K.J. Anstrom, T.E. King, J.A. Lasky, F.J. Martinez, I.P.F.C.R. Network, Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis, N. Engl. J. Med. 366 (21) (2012), 1968–77. [106] L.O. Lutherer, K.M. Nugent, B.W. Schoettle, et al., Low-dose oral interferon α possibly retards the progression of idiopathic pulmonary fibrosis and alleviates associated cough in some patients, Thorax 66 (5) (2011) 446–447. [107] G. Simonneau, M.A. Gatzoulis, I. Adatia, et al., Updated clinical classification of pulmonary hypertension, J. Am. Coll. Cardiol. 62 (25 Suppl) (2013) D34– D41. [108] P.M. George, E. Oliver, P. Dorfmuller, et al., Evidence for the involvement of type I interferon in pulmonary arterial hypertension, Circ. Res. 114 (4) (2014) 677–688. [109] A. Azuma, T. Nukiwa, E. Tsuboi, et al., Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis, Am. J. Respir. Crit. Care Med. 171 (9) (2005) 1040–1047. [110] H. Taniguchi, M. Ebina, Y. Kondoh, et al., Pirfenidone in idiopathic pulmonary fibrosis, Eur. Respir. J. 35 (4) (2010) 821–829. [111] T.E. King, W.Z. Bradford, S. Castro-Bernardini, et al., A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis, N. Engl. J. Med. 370 (22) (2014), 2083–92. [112] L. Richeldi, R.M. du Bois, G. Raghu, et al., Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis, N. Engl. J. Med. 370 (22) (2014), 2071– 82. [113] A. Azuma, Y. Taguchi, T. Ogura, et al., Exploratory analysis of a phase III trial of pirfenidone identifies a subpopulation of patients with idiopathic pulmonary fibrosis as benefiting from treatment, Respir. Res. 12 (2011) 143. [114] S. Singhal, J. Mehta, R. Desikan, et al., Antitumor activity of thalidomide in refractory multiple myeloma, N. Engl. J. Med. 341 (21) (1999) 1565–1571. [115] M.R. Horton, S.K. Danoff, N. Lechtzin, Thalidomide inhibits the intractable cough of idiopathic pulmonary fibrosis, Thorax 63 (8) (2008) 749.

128

J. Garner et al./Pulmonary Pharmacology & Therapeutics 35 (2015) 122–128

[116] M.R. Horton, V. Santopietro, L. Mathew, et al., Thalidomide for the treatment of cough in idiopathic pulmonary fibrosis: a randomized trial, Ann. Intern Med. 157 (6) (2012) 398–406. [117] N.S. Paramothayan, T.J. Lasserson, P.W. Jones, Corticosteroids for pulmonary sarcoidosis, Cochrane Database Syst. Rev. (2005), (2): CD001114. [118] J.I. Kokkarinen, H.O. Tukiainen, E.O. Terho, Effect of corticosteroid treatment on the recovery of pulmonary function in farmer’s lung, Am. Rev. Respir. Dis. 145 (1) (1992) 3–5. [119] W. Wuyts, M. Sterclova, M. Vasakova, Pitfalls in diagnosis and management of hypersensitivity pneumonitis, Curr. Opin. Pulm. Med. 21 (5) (2015) 490– 498. [120] R.K. Hoyles, R.W. Ellis, J. Wellsbury, et al., A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma, Arthritis Rheum. 54 (12) (2006) 3962–3970. [121] D.P. Tashkin, R. Elashoff, P.J. Clements, et al., Cyclophosphamide versus placebo in scleroderma lung disease, N. Engl. J. Med. 354 (25) (2006) 2655– 2666.

[122] R.W. Bastian, A.M. Vaidya, K.G. Delsupehe, Sensory neuropathic cough: a common and treatable cause of chronic cough, Otolaryngol. Head. Neck Surg. 135 (1) (2006) 17–21. [123] N.M. Ryan, S.S. Birring, P.G. Gibson, Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial, Lancet 380 (9853) (2012) 1583–1589. [124] K.F. Chung, Approach to chronic cough: the neuropathic basis for cough hypersensitivity syndrome, J. Thorac. Dis. 6 (suppl. 7) (2014) S699–S707. [125] K.G. Lim, M.A. Rank, P.Y. Hahn, K.A. Keogh, T.I. Morgenthaler, E.J. Olson, Long-term safety of nebulized lidocaine for adults with difficult-to-control chronic cough: a case series, Chest 143 (4) (2013) 1060–1065. [126] S.J. Bonvini, M.A. Birrell, J.A. Smith, M.G. Belvisi, Targeting TRP channels for chronic cough: from bench to bedside, Naunyn Schmiedeb. Arch. Pharmacol. 388 (4) (2015) 401–420. [127] S.A. Maher, M.A. Birrell, J.J. Adcock, et al., Prostaglandin D2 and the role of the DP1, DP2 and TP receptors in the control of airway reflex events, Eur. Respir. J. 45 (4) (2015) 1108–1118. [128] R. Abdulqawi, R. Dockry, K. Holt, et al., P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study, Lancet 385 (9974) (2015) 1198–1205.