The prevalence of gastro-esophageal reflux disease and esophageal dysmotility in Chinese patients with idiopathic pulmonary fibrosis

The last ten years has seen considerable advances in the sensitivity of techniques to study esophageal motor disorders and GERD, which have collectively revealed clinical features that can help explore the pathophysiology of various conditions in great detail [9,10]. Impedance monitoring is a new method that allows detection of bolus transit. It does so by detecting a change in the resistance to current flow between pairs of electrodes when a liquid and/or gas bolus bridges them. When a liquid bolus bridges the two electrode rings, impedance decreases directly with the degree of bolus ionization. By contrast, a gas bolus increases impedance. These differences in impedance characteristic allows the differentiation of liquid, gas and combined liquid–gas (mixed) boluses. In addition, combining impedance with pH monitoring can determine bolus exposure time, composition, and proximal extent of the refluxate. Both of these measures can be used to assess the risk for micro-aspiration [7].

In this study, we found that the prevalence of GERD in Chinese patients with IPF was high (i.e., 62.3%), but GERD symptoms were found to be a poor predictor of the presence of reflux within the group. The sensitivity and specificity of any typical symptoms (e.g., heartburn, regurgitation and chest pain) was 58.1% and 61.6%, positive predictive value, and the negative predictive value was 71.4% and 47.1%. These data confirm that Chinese patients with IPF have a similar profile as those seen in other countries in previous studies [4,15-17]. The relatively poor sensitivity and specificity of using symptoms alone outlines the importance of performing objective assessments of esophageal function and reflux status in IPF as opposed to empirically treating GERD in the entire cohort.

Although the cause of IPF remains unknown, several associations have been described, including cigarette smoking, exposure to wood and metal dusts, chronic viral infection, exposure to some drugs (e.g., antidepressants) and hereditary factors and mutations in the genes encoding telomerase components [2,18]. Recent emerging data supports a role for chronic micro-aspiration (e.g., subclinical aspiration of small droplets due to GERD) which may cause repetitive subclinical injury to the lung leading to pulmonary fibrosis [3,7]. Studies [19,20] have been described that show IPF patients that presented with increased prevalence of hiatal hernia and IPF patients that presented with hiatal hernia had a greater physiological impairment on pulmonary function testing. Mays et al. [21] suggested that repeated small tracheobronchial aspiration of gastric secretions over a long period of time could lead to lung fibrosis. Lee et al. [22] detected pepsin, a biomarker of micro-aspiration, in bronchial alveolar lavage (BAL) fluid from patients with IPF, and it was direct evidence that showed that gastric contents can reach the lower respiratory tract without an overt aspiration. The observed association of hiatal hernia and abnormal GERD coupled with the detection of pepsin in BAL specimens retrieved from the distal pulmonary parenchyma supports the long-standing hypothesis that micro-aspiration is a causative role in the development of IPF and may trigger episodes of acute execrations of IPF.

For several decades, esophageal specialists have postulated that altered respiratory mechanics in patients with end-stage lung disease may cause reflux. Specifically, increases in positive intra-abdominal pressure and negative intrathoracic pressure (with a corresponding increase in the transdiaphragmatic pressure gradient) could cause a gradient-favoring reflux [23,24]. Survival analysis [25] showed that identifying the presence of gastro-esophageal symptoms, providing a reflux diagnosis, medication use, and Nissen fundoplication were all collectively associated with longer survival in IPF.

In this study, we also found that patients with IPF presented with lower LESP and UESP, higher prevalence of hypotensive LESP and hiatal hernia, and combined impedance showed that in addition to 46.4% of patients having weak peristalsis, 33.3% of patients had abnormal distal reflux events, 37.7% of patients had abnormal proximal reflux events, and moreover, IPF patients presented with higher TBTT and lower CBTR which meant that the bolus transit was impaired.

The esophagus comprises striated muscle in the proximal third of the esophageal body and smooth muscle in the distal two-thirds. Where these two types of muscle meet there is a ‘transition zone’ which can lead to a ‘break’ in the peristaltic wave as it travels distally. This occurs in healthy individuals under normal conditions, but it has been shown that if this break is greater than 2 cm, it can lead to the bolus not being completely transported and cleared into the stomach. In patients with weak peristalsis, these breaks can often be characterized as small (2–5 cm) or large (>5 cm). It has been demonstrated that among healthy volunteers weak peristalsis of the esophageal body has predicted incomplete bolus clearance [26] and might account for delayed bolus transit and impaired esophageal reflux clearance in patients with GERD [27,28]. In addition, weak peristalsis with large breaks is associated with high acid exposure and delayed reflux clearance in the supine position in GERD patients [28]. Moreover, GERD patients with IPF, have presented with lower UESP, lower CBTR and a higher bolus exposure time than GERD patients without IPF. This means that there is an increasing possibility of small droplets from the esophagus that are capable of being aspirated into the trachea, and supports the hypothesis that GERD and chronic micro-aspiration may play a major role in the pathobiology of IPF.

GERD has long been known to be an important cause of chronic cough. Indeed a diagnosis of gastro-esophageal acid reflux-associated cough (GERC) is often made following a successful, empirical trial of high-dose acid suppression therapy. Thus, a particular attraction of the reflux hypothesis is that it could explain both the pathogenesis of IPF and the associated symptom of cough. However, the lack of improved cough symptoms despite effective acid suppression therapy indicates that gastroesophageal acid reflux alone is not wholly responsible for cough in the majority of patients with IPF. A recent advance in the assessment of non-acid reflux is the technique of combined esophageal pH and impedance monitoring, which provides a means of detecting acid and non-acid reflux. Savarino et al. [29] reported a high frequency of occurrence of acid reflux events, non-acid reflux events, and reflux reaching the proximal esophagus in patients with systemic sclerosis and interstitial lung disease. Our study also found that patients with IPF had more distal and proximal reflux events, especially non-acid reflux, which showed combined impedance and pH recordings that provided a more accurate assessment of the specific pattern of reflux.

Mise et al. [30] reported lower DLCO in patients with recently diagnosed GERD in comparison with healthy controls. Bonacin et al. [31] showed statistically significant increases in FVC in the GERD group as compared with the non-GERD group. Among the GERD group, values of DLCO and DLCO/VA were significantly lower, and intrapulmonary shunt was significantly higher in comparison with the non-GERD group, which confirmed the correlation between GERD and damaged lung function. The results of that study suggested an additional pathological mechanism in the development of intrapulmonary shunt, due in part, to microatelectasis resulting from surfactant damage caused by micro-aspiration of the stomach contents. Both of the aforementioned studies stated the need for early lung function tests in all GERD patients. In our study, esophageal function parameters in IPF patients presenting with GERD did not correlate with worsened pulmonary function (FVC or DLCO). We also did not find a significant correlation in our research between FVC or DLCO and motility or reflux. This may be due to the relatively small numbers of research subjects that were recruited to this study (i.e., when comparing quite variable parameters, as the study was not powered to detect these changes), and the inclusion of IPF patients at the milder end of the spectrum. Some researchers [32-34] have showed that anti-reflux surgery can improve lung function of GERD patients so further studies are required to determine whether anti-reflux surgery or using PPI might improve the prognosis of IPF patients.

Our study also has some limitations. All subjects were recruited from one hospital and in only one city, which might have a potential selection bias. Besides, the small number of patients limited the statistical power of the study. The life signs of all 346 patients were stable but in some of the severe presenting patients who needed inspired oxygen management, we decided that they should not undertake the procedure. Whilst this means there is somewhat the risk of a selection bias for patients at the mild end of the IPF spectrum, we felt justified to use these inclusion criteria on the grounds of patient safety and to exclude the confounders of other underlying diseases (e.g., connective tissue disease) to esophageal motility. Healthy Chinese volunteers were younger than IPF patients, and we used the diagnostic criteria of abnormal acid exposure from the USA. However, we do have sufficient merit to demonstrate that it is important to screen GERD in IPF patients, even if there do not present with typical reflux symptoms.