Interstitial lung diseases (ILDs) refer to a group of lung diseases characterized in alveolar inflammation and interstitial fibrotic lesions (Travis et al., 2013). The etiology of ILDs is complex and diverse. Idiopathic pulmonary fibrosis (IPF) and connective tissue disease-related interstitial lung disease (CTD-ILD) are the most common types of ILD (Hu et al., 2016). The main respiratory symptoms of IPF include irritating cough and breathing difficulty.

Gastroesophageal reflux disease (GERD) is caused by the reflux of gastric acid and other stomach contents into the esophagus, and one of its typical clinical symptoms is cough (Cohen et al., 2002; Hom and Vaezi, 2013; Lai et al., 2013). GERD has been recognized as a common cause for chronic cough (Lai et al., 2013). International diagnosis and treatment guidelines for IPF suggest an association between GERD and IPF onset and thus recommend anti-acid treatments for patients with IPF (Raghu et al., 2006; Lee et al., 2011; Raghu et al., 2011; Raghu et al., 2015). However, a previous report has shown that anti-acid treatments do not reduce the all-cause mortality and the rate of hospitalization of patients with IPF (Lee et al., 2013). Moreover, Raghu and colleagues have found that approximately half of patients with IPF did not present gastroesophageal reflux (GER) symptoms, such as heartburn and sour regurgitation (Raghu et al., 2011). Extraesophageal reflux (EER) or laryngopharyngeal reflux (LPR) is the reflux of stomach contents into the throat and larynx, and patients with LPR usually do not present the classic symptoms of GERD (Hom and Vaezi, 2013). An accurate diagnosis of LPR remains challenging in clinical practice.

LPR is the reflux of stomach contents into the area above the upper esophageal sphincter, such as the nasal cavity, mouth, throat, trachea, and lung (Koufman, 2002). Patients with LPR disease (LPRD) often presents cough, laryngopharyngeal discomfort, and breathing difficulty (Cohen et al., 2002; Koufman, 2002; Ayazi et al., 2009). Similar to GERD, LPRD can also cause chronic cough. Gaseous refluxate in the airway reduces the pH of the upper airway to <6.5, which activates the pepsin that is from the refluxate and deposited on the airway mucosal epithelial cells and consequently induces nonspecific inflammation in the airway mucosa (Cohen et al., 2002; Koufman, 2002). Previous studies have demonstrated that 32–84% of patients with bronchial asthma had GERD and 50% of the patients with GERD did not present any obvious reflux symptoms such as heartburn and sour regurgitation (Harding et al., 2000; Mastronarde et al., 2009). GERD can exacerbate asthma. Antacids and gastric pro-motility drugs can alleviate asthma symptoms in patients with GERD (Sharma et al., 2007; DiMango et al., 2009; Liang et al., 2013). The association between LPR and IPF remains unclear, and monitoring upper airway pH in patients with IPF is essential to understand such association and may shed light on therapeutic strategies for LPR in patients with IPF.

IPF is a progressive lung disease with an unknown etiology. The pathology of IPF is characterized by slowly progressive diffuse alveolar inflammation and/or alveolar structural disorders, which eventually damage alveolar structure and result in pulmonary fibrosis and honeycomb lung. IPF has a poor prognosis and the survival time of patients with IPF is approximately 3–5 years (Loomis-King et al., 2013). IPF ultimately lead to scars in lung tissues.

Previous studies have suggested that IPF may be highly associated with GERD [(Raghu et al., 2011), (Lee et al., 2011)]. Chronic inhalation of gaseous refluxate is a risk factor for airway and pulmonary inflammation and could induce or exacerbate IPF. Antacids, such as proton pump inhibitors and histamine H2-receptor antagonists, have been found to reduce the risk of GER-associated pulmonary damages (Raghu et al., 2006; Lee et al., 2011). Clinicians have routinely prescribed anti-acid drugs for patients with IPF (Raghu et al., 2011; Raghu et al., 2015). GER is caused by abnormal lower esophageal sphincter relaxation, which allows stomach contents to flow back to the esophagus. The majority of the stomach contents in GER are liquid and stay inside the esophagus. Patients with GER and LPR may experience gaseous reflux into the upper airway. LPR is caused by abnormal upper esophageal sphincter relaxation and is mainly gaseous reflux into the throat, nose, and ear. The gaseous refluxate can then enter the lower airway and alveoli during breathing. Thus, compared with GER, LPR appears more likely to adversely affect the lower airway and lung parenchyma and exacerbate IPF.

The etiology of GERD is associated with the dysfunction of gastric cardia and lower part of the esophagus. The clinical presentations of GERD are mainly digestive tract symptoms and occasional airway symptoms. The pathophysiology of GERD is characterized by acidic or basic gastric liquid and gaseous reflux into the esophagus and into the airway in severe cases. The etiology of LPR is associated with gastric empty dysfunction. LPR causes pathological changes in the airway. The clinical presentations of LPR are mainly airway symptoms but not digestive tract symptoms. The pathophysiology of LPR is characterized by acidic or basic gaseous reflux into the airway. Only 20% of patients with LPRD and GERD show low esophageal pH (the duration of pH < 4.0 is more than 4% of the total measurement time). Therefore, only monitoring esophageal pH could miss the diagnosis of LPRD in 80% of patients with LPRD (Ford, 2005; Yuksel and Vaezi, 2013). The 24 h laryngopharyngeal pH monitoring (DX-pH) has been used to diagnose LPRD (Sun et al., 2009; Wiener et al., 2009; Vailati et al., 2013). The diagnostic criteria for LPR based on DX-pH are the Ryan index at upright position >9.41 and/or at supine position >6.79.

In the current study, we monitored the laryngopharyngeal pH of 44 patients with IPF and 30 healthy individuals for 24 h and explored the association between IPF and LPR. The analysis of the overall 24 h laryngopharyngeal pH showed that 61.3, 27.3, and 11.4% of the 44 IPF patients had neutral, basic, and acidic laryngopharyngeal pH, respectively. 93.4, 3.3, and 3.3% of the 30 healthy individuals had neutral, basic, and acidic laryngopharyngeal pH. The proportion of pH > 7.5 group in IPF patients was higher than control group. The normal pH in the lower airway is 7.0–7.5. Thus, both basic reflux (pH > 7.5) and acidic reflux (pH < 6.5) appear to occur in patients with IPF. According to the diagnostic criteria for LPR (Ryan index at upright position >9.41), only 7 IPF patients met the criteria.

The normal pH in the lung is 7.0–7.5. pH > 7.5 may reduce enzyme activity in the lung tissues or even denature enzymes. Thus, basic reflux could affect lung function adversely, particularly for patients with IPF, who often have poor pulmonary elasticity because of lung fibrosis. Patients with IPF may have to inhale deeply to expand the alveoli because of the poor pulmonary elasticity. The deep inhalation may cause excessive negative pressure in the chest, which in turn may cause the basic contents including bile and pancreatic juice flow from the duodenal to the throat. The speed of this basic reflux may be too fast to allow the basic contents to be neutralized by gastric acid and to be cleared from the throat. The contents of basic refluxate and the adverse effects of basic refluxate on the laryngopharyngeal mucosa, the lower airway, and the lung need to be further investigated. Acidic reflux could activate the pepsin that has been deposited on the lower airway mucosa and alveoli and consequently result in nonspecific inflammation and trigger IPF.

The analysis of the pH at supine position showed that 54.5, 27.3, and 18.2% of the 44 IPF patients had neutral, acidic, and basic laryngopharyngeal pH, respectively. 90.0, 6.7, and 3.3% of the 30 healthy individuals had neutral, acidic, and basic laryngopharyngeal pH. The proportion of pH < 6.5 group in ILD patients was higher than control group. The supine position may actually facilitate gastric acid reflux into the throat. We found that using Ryan index only diagnosed 7 cases of LPR. For the entire pH monitoring duration and the duration at upright position, about 30% of the patients showed basic laryngopharyngeal pH, whereas for the duration at supine position, approximately 30% of the patients had acidic laryngopharyngeal pH. These findings indicate that the cut-off value of Ryan index for positive LPR (pH < 5.5 at upright position and/or pH < 5.0 at supine position) may not reflect LPR effectively in patients with IPF. In addition, we found that only five of the 44 patients showed significant difference between the average pH at coughing and the overall average pH. This suggests that cough appears more likely to be associated with IPF but not with LPR in patients with IPF. But it is not definitely clear whether the correlation between chronic cough and laryngopharyngeal pH changes is the causal effect or just correlation. We will further explore it in our future study. This study is an exploratory research. The sample size was relatively small. Idiopathic pulmonary fibrosis is a rare disease. Researches about laryngopharyngeal pH monitoring in patients with IPF were rarer. However, we still got some valuable findings in a limited number of study participants. Although the interpretation of the data is limited by small number of study participants, the current study was first to explore the possible association between LPR and IPF. In addition, we will investigate the composition of gaseous refluxate and study possible mechanism underlying the adverse effects of LPR on IPF initiation and development in our future study.

We found that 50–60% of the patients had neutral laryngopharyngeal pH and did not need anti-acid treatments. Basic LPR may likely occur at upright position, whereas acidic LPR may probably occur at supine position. Patients with acidic LPR may use antacids (Park et al., 2005; Sato, 2006; Naik and Vaezi, 2013) and gastric pro-motility drugs (Glicksman et al., 2014). Patients with basic LPR may only need gastric pro-motility drugs. Ryan index score calculated based on acidic LPR may not reflect LPR accurately in patients with IPF.

CRP, c-reactive protein; CSS, cough symptom score; CTD-ILD, connective tissue disease-related interstitial lung disease; D_LCO % pred, carbon monoxide diffusing capacity of the lung expressed as a percentage of predicted; EER, extraesophageal reflux; ESR, erythrocyte sedimentation rate; FVC % pred, force vital capacity expressed as a percentage of predicted; FVC, force vital capacity; GERD, gastroesophageal reflux disease; ILD, interstitial lung diseases; IPF, idiopathic pulmonary fibrosis; LPR, laryngopharyngeal reflux; PaCO₂, partial pressure of carbon dioxide; PaO₂, partial pressure of oxygen; SaO₂, oxygen saturation.