Effect of acid suppression therapy on gastroesophageal reflux and cough in idiopathic pulmonary fibrosis: an intervention study

Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrotic interstitial lung disease of unknown origin associated with the histological and/or radiological pattern of usual interstitial pneumonia [1]. It typically presents with progressive breathlessness and more than 70% of patients also complain of a persistent, troublesome cough, which is resistant to conventional antitussive therapy [2]. Cough is an airway defence mechanism which is mediated via vagal sensory nerves that are mainly located within the central and proximal airways [3]. It is therefore interesting that cough should be such a prominent symptom in IPF which predominantly affects peripheral lung parenchyma. A recent study using 24-hour cough monitors has shown that patients with IPF have higher cough counts than both normal controls and asthmatics; and that the cough counts correlate well with subjective assessments of cough [4]. It has also been demonstrated that cough has a significant, detrimental effect on quality of life in patients with IPF [5].

The mechanisms underlying the pathogenesis of IPF remain unknown. However, one hypothesis proposes that chronic aspiration of gastric contents may cause repeated injury to alveolar epithelium resulting in the pathological abnormalities of usual interstitial pneumonia [6]. This hypothesis has recently received support from studies using 24-hour oesophageal pH monitoring and oesophageal manometry. The largest of these found that 87% of patients with IPF had abnormal acid gastroesophageal reflux (GOR) which was often clinically silent and occurred despite treatment with acid suppression therapy [7]. Furthermore, two small, retrospective, observational studies have reported clinical stabilisation of patients with IPF following strategies aimed at the management of GOR [8, 9]. Consequently, international guidelines recommend that the majority of patients with IPF and asymptomatic acid reflux should receive medical treatment with acid suppression therapy, whilst acknowledging that the evidence to support such a recommendation is weak [10, 11]. Despite the widespread use of acid suppression therapy in patients with IPF, the impact of such treatment on GOR and cough in this condition has not been investigated.

Gastroesophageal reflux has long been known to be an important cause of chronic cough [12]. Indeed a diagnosis of acid GOR-associated cough is often made following a successful, empirical trial of high-dose acid suppression therapy [13]. Thus, a particular attraction of the reflux hypothesis is that it could explain both the pathogenesis of IPF and the associated symptom of cough.

Despite the accumulating body of evidence linking IPF, cough and acid reflux, less is known about non-acid reflux in this context. A recent advance in the assessment of non-acid reflux is the technique of combined oesophageal pH and impedance monitoring. This provides a means of detecting and characterizing all reflux episodes regardless of pH [14]. Using this technique a recent study has shown a high prevalence of non-acid gastroesophageal reflux in patients with IPF compared with controls [15]. A study using pH-impedance monitoring in patients with systemic sclerosis, a condition complicated by oesophageal dysmotility and GOR, showed a positive relationship between the degree of acid and non-acid GOR and extent of pulmonary fibrosis estimated on CT scan [16].

Cough reflex sensitivity to capsaicin is known to be increased in IPF suggesting there is up-regulation of sensory C-fibres in the airways in IPF [17]. Cough reflex sensitivity to capsaicin is similarly increased in patients with both acid and non-acid reflux [18].

In this context, the objective of the present study was to investigate the impact of high-dose acid suppressant therapy on GOR and cough in this condition.

This is the first study to investigate the effect of acid suppression therapy on gastroesophageal reflux and cough in patients with IPF. We have confirmed recent findings that non-acid reflux is prevalent and that proximal oesophageal reflux occurs in the majority of patients. This observation may be important because non-acid reflux (pH ≥7) is known to be rare in healthy individuals [20, 26].

A potential mechanism for chronic cough in patients with IPF and GOR is enhancement of cough reflex sensitivity due to neuronal changes within the airways induced by gastroesophageal refluxate. It has been demonstrated that induced sputum from patients with IPF contains higher levels of the neurotrophins, nerve growth factor and brain-derived neurotrophic factor, compared with normal controls [17]. Furthermore, a study investigating pulmonary neurotrophin expression in patients with idiopathic interstitial pneumonia found evidence of enhanced expression of neurotrophins in the lungs of patients with IPF compared to other interstitial lung diseases, with fibroblastic foci in particular showing intense immunostaining for brain-derived neurotrophic factor and its receptor TrkB [27]. The cause of the enhanced neurotrophin expression in the lungs and airways of patients with IPF is unknown; however these observations raise the possibility that the neurotrophins may influence neuronal proliferation and differentiation in more proximal airways.

Gastric juice is a complex mixture of gastric acid, gastric enzymes such as pepsin; and bile acids and pancreatic enzymes from the duodenum. Hence, it may be of acid, neutral or alkaline pH. The pH of refluxate influences its biochemical activity and cellular toxicity. For example, animal studies have shown that within an acidic milieu pepsin potentiates the degree of acid-induced injury to oesophageal epithelial cells, but that at neutral pH pepsin is inactive and its oesophageal epithelial toxicity is ameliorated [28]. The toxicity of individual bile acids also varies with pH and conjugation. Animal studies have shown that conjugated bile acids cause injury to the oesophageal mucosa at acidic pH, whereas unconjugated bile acids are more injurious at a neutral pH [29]. In-vitro studies have shown that human airway epithelial cells exposed to unconjugated bile salts produce increased levels of the fibrogenic cytokine Transforming Growth Factor-β1 [30]. There is also preliminary data to suggest that airway epithelial cells exposed to pepsin can undergo epithelial-mesenchymal transformation, a process which is implicated in the pathogenesis of IPF [31]. In this context, our finding of frequent proximal reflux events in IPF subjects might be important because it demonstrates a potential mechanism by which alveolar epithelial cells could come into contact with the many components of gastric juice outlined above. A rodent model of chronic aspiration has shown that lung injury was caused by pH-neutral gastric constituents but not by hydrochloric acid [32]. Therefore, it is possible that incremental lung injury caused by chronic microaspiration is due to the non-acid components of gastric juice.

Supine reflux from the stomach into the oesophagus is rare in normal human subjects [20, 26] probably because lower oesophageal sphincter relaxations are uncommon during sleep [33]. By contrast, reflux from the duodenum into the stomach is a normal, physiological, postprandial event and it also occurs nocturnally [29]. A previous study in patients with GORD found increased levels of bile acids in oesophageal aspirates compared with normal controls, particularly postprandially and in the supine position [34]. Hence, it is also of interest that reflux occurred in the supine position in the majority of our cohort.

As might be predicted, the present study objectively demonstrated a marked decrease in acid reflux following treatment with high-dose proton pump inhibitors (PPIs) and H2-receptor antagonists in the majority of patients with IPF. However, an unexpected finding was that this was consistently associated with an increase in non-acid reflux. Proton pump inhibitors are widely prescribed for acid suppression therapy in patients with IPF; therefore our findings that increased non-acid reflux may be a consequence of PPI therapy in such patients is an important observation.

The effect of PPIs on duodeno-gastroesophageal reflux is complex. Whilst they reduce gastric volume, which should reduce reflux into the oesophagus, they also delay gastric emptying which might enhance reflux [35]. It has been shown that PPIs have no effect on levels of pepsin or bile acids in bronchoalveolar lavage from patients after lung transplantation, despite reducing oesophageal acid exposure [36]. We were careful to exclude other known causes of cough in this patient cohort. Therefore, our observation that cough can occur despite verifying low levels of oesophageal acidity; and that cough counts do not diminish following high dose acid suppression therapy, suggests that acid-GOR per se is not the sole cause of cough in IPF. This finding is in keeping with negative randomized, controlled trials of acid suppression therapy in patients with GOR and chronic cough [37, 38].

The exclusion of confounding causes of cough and the invasive nature of the investigations performed has limited the size of the study cohort and also resulted in a high withdrawal rate for the second pH-impedance assessment. A combination of the small sample size and day to day variations in reflux frequency [39] may explain the unexpectedly low rates of acid reflux observed in our population compared with previous larger studies [7, 40]. In addition, a previous study has shown that objective cough frequency and subjective cough severity are both reduced by the presence of an oesophageal catheter [41]. Such an inhibitory effect may have influenced the detection of a difference in cough count before and after acid suppression therapy. However, given that an oesophageal catheter was in situ both at baseline and eight weeks in the present study and the absence of a trend towards reduced cough after acid suppression therapy a type two error of this nature seems unlikely.

Despite these limitations, the careful subject selection process means that relevant observations about the relationship between cough, gastroesophageal reflux and acid suppression therapy in this condition can be made. The invasive nature of the investigations also made attempts to recruit a suitable control group unrewarding. However, the normal ranges for impedance detected reflux parameters have been well defined in both North American [20] and European populations [26]. Three subjects were also treated with prokinetic therapy and whilst no clear evidence of additional effect was observed, the group is too small to draw conclusions from.

In conclusion, proximal, non-acid reflux is prevalent in patients with IPF and may be implicated in both the pathogenesis of pulmonary fibrosis and sensitisation of the cough reflex in this condition. The lack of improvement in cough symptoms despite effective acid suppression therapy indicates that acid GOR reflux alone is not responsible for cough in the majority of patients with IPF. The finding that acid suppression consistently increases the frequency of non-acid reflux cautions against the widespread empirical use of acid suppression in IPF and GOR in the absence of objective pH or impedance testing. Our findings suggest that strategies for treating GOR in patients with IPF should target both acid and non-acid reflux, perhaps by including prokinetic therapies, rather than acid suppression therapy alone.

CEK is a clinical research fellow and specialty trainee in respiratory medicine.

MJC is a gastro-intestinal physiologist. GAT is a consultant in general and gastrointestinal medicine with an interest in gastroesophageal reflux. NKH is a consultant in general and respiratory medicine with an interest in interstitial lung disease. BHG is consultant in general and respiratory medicine with an interest in interstitial lung disease.