Gastroesophageal reflux and lung disease

Abstract

Gastroesophageal reflux (GER) can cause respiratory symptoms and may trigger, drive and/or worsen airway disorders, interstitial lung diseases and lung allograft dysfunction. Whether lifestyle changes and acid suppression alone can counter and prevent the adverse effects of GER on the respiratory tract remains unclear. Recent data suggest that antireflux surgery may be more effective in preventing lung disease progression in patients with idiopathic pulmonary fibrosis or lung transplant recipients who have evidence of allograft dysfunction associated with the presence of excessive GER. Additional research and clinical trials are needed to determine the role of GER in various lung disorders and identify which interventions are most efficacious in preventing the respiratory consequences of gastroesophageal reflux disease. In addition, measuring biomarkers that indicate that gastric refluxate has been aspirated into the lower respiratory tract (e.g., pepsin and bile acid concentrations in bronchoalveolar lavage fluid) may prove helpful in both diagnosis and therapeutic decision making.

Keywords:

• gastroesophageal reflux
• gastroesophageal reflux disease
• lung disease
• pulmonary fibrosis
• respiratory aspiration

Gastroesophageal reflux (GER) is estimated to affect up to 10% of the adult population in the USA on a daily basis [1]. GER events commonly occur in infants, children and adults, but such GER is not necessarily pathologic. Normal adults can have up to 50 brief episodes of GER (with pH below 4) in a 24-hour period, but, if rapidly cleared by intact defense mechanisms, these secretions do not reach the proximal esophagus and larynx and place an individual at risk for an aspiration event. Rapid buffering of gastric acid and clearance of refluxed gastroduodenal secretions from the esophagus can prevent esophageal damage and/or respiratory tract complications. However, reflux of gastroduodenal secretions (which usually have low pH and contain pepsin and possibly bile acids) into the esophagus places individuals at risk of developing esophageal (e.g., ulceration, Barrett’s esophagus, stricture) or respiratory tract disorders. If these complications of GER are detected, a diagnosis of gastroesophageal reflux disease (GERD) can be made.

The primary cause of GER/GERD is dysfunction of the lower esophageal sphincter (LES) and the antireflux barrier complex (the angulation formed by the esophagus, diaphragmatic hiatus and the cardia of the stomach), which are particularly dysfunctional when a hiatal hernia is present. In addition, reflux can be intensified by esophageal dysmotility or delayed gastric emptying. Hiatal hernias tend to gradually increase in size over time due to pressure and increased stress on the diaphragm, which can be caused by factors such as chronic cough, repetitive straining, pregnancy or obesity. Elderly individuals are more likely to develop hiatal hernias, compromised LES function and GER. Although symptoms and/or syndromes associated with GER generally become more prevalent in the elderly, symptoms of GER also tend to wane such that significant reflux events can often be ‘silent’.

How can pathologic GER be detected?

Refluxate is rapidly cleared from the esophagus in normal individuals. More prolonged and more frequent episodes may reach the threshold that is considered significant and can usually be detected by ambulatory pH monitoring, which has been established for decades as the gold standard test for detecting significant GER and diagnosing GERD. However, refluxed gastric secretions can also be weakly acidic or nonacidic such that refluxate would not be sensed by a pH catheter; impedance monitoring can detect esophageal reflux whether acidic or not and can be combined with pH testing. Other testing can also contribute valuable information. Esophageal manometry can assist in placing the pH probe in the proper location (5 cm above the LES) for pH or pH/impedance testing and define the physiologic characteristics of the esophagus and LES. Other testing may also provide valuable information; flexible endoscopy of the esophagus and stomach can identify anatomic causes of GER and identify pathologic changes due to GERD, and a fluoroscopic upper gastrointestinal esophagram can locate the gastroesophageal junction, identify gastric herniation or detect esophageal motility disorders. Finally, the detection of pepsin or bile acids in sputum or bronchoalveolar lavage fluid (BAL) can serve as a biomarker for microaspiration into the respiratory tract.

Can GER cause upper airway disorders?

Extraesophageal reflux may reach the upper airway (often termed laryngopharyngeal reflux) yet not give typical reflux symptoms (such as heartburn and epigastric discomfort) but cause symptoms that suggest laryngitis or sinusitis. Such reflux is not seen in normal individuals, and up to 10% of patients seen in otolaryngology clinics have evidence of reflux-associated disorders or symptoms that include hoarseness, cough, throat clearing, post-nasal drainage, dysphonia, excessive phlegm production or chronic laryngitis.

Is GER a significant issue for infants & children?

Reflux is common in infants, and aspiration of refluxed gastric contents into the lungs can occur [1,2]. Reflux may cause an exacerbation of asthma or be a cause of recurrent pneumonia or vocal cord dysfunction. Chronic cough is a common manifestation of GERD in children, and other signs such as wheezing, gagging, hoarseness or stridor may be caused by GER. However, because many infants and children do not display more obvious symptoms and signs of reflux, the diagnosis can be challenging. Diagnostic evaluation is similar to that for adults, but diagnostic criteria for GERD are age dependent. An empiric trial of antireflux therapy may prove diagnostic, but other testing such as upper gastrointestinal fluoroscopy may be required to make a diagnosis.

What is the role of GER in obstructive lung disease?

GER has been linked to chronic cough, vocal cord dysfunction and lower respiratory tract airway disorders [1–5]. GER can precipitate cough directly via microaspiration or indirectly by activating an esophageobronchial reflex or by increasing the sensitivity of the cough reflex (both mediated by the vagus nerve). Many investigations have shown that GER/GERD is highly prevalent (34–89%) in patients with asthma, and GER has been reported as a risk factor for hospitalizations due to asthma exacerbations in the elderly. The association of GER/GERD with chronic obstructive pulmonary disease is less well studied, but GER is highly prevalent and has been associated with disease severity and increased risk of chronic obstructive pulmonary disease exacerbation.

GER/GERD has also been associated with both cystic fibrosis (CF) and non-CF bronchiectasis [1,5]. Various studies have shown that pathologic GER is highly prevalent in patients with CF (both children and adults with prevalence up to 90%). GER is frequently asymptomatic, but both pepsin and bile acids are significantly higher in BAL fluid or sputum/saliva from patients with CF versus controls. Studies have also shown pathologic GER prevalence to range up to 50% in patients with non-CF bronchiectasis.

What is the role of GER in interstitial lung diseases?

Carefully performed case series and observational studies have suggested that GERD is a risk factor for disease progression in idiopathic pulmonary fibrosis (IPF), and recently published studies have suggested that antireflux therapies can prolong survival and may decrease the incidence of acute disease exacerbation events in patients with IPF [6–12]. Studies have shown that increased concentrations of pepsin and bile acids are highly prevalent in patients with IPF, but up to half of patients with significant GER do not have typical symptoms or are asymptomatic. In addition, pH/impedance studies and BAL analyses have shown that patients with scleroderma, who usually have exophageal dysmotility, are also at very high risk for reflux and aspiration, and significant GER may also be present in patients with other forms of connective tissue disease. Finally, aspiration can clearly play a role in other parenchymal fibrotic disorders in both children and adults [13], and diagnosis can be challenging.

Are lung transplant recipients at risk for complications due to GER?

Patients with various forms of advanced lung disease are likely to have pathologic reflux when referred for lung transplantation [14–16]. Recurrent reflux following successful transplantation has been identified in a substantial proportion of transplant recipients by both pH/impedance testing and by detection of pepsin and bile acids in BAL fluid, and persistent or new onset post-transplant GERD has been implicated in chronic lung allograft dysfunction.

Does sleep-disordered breathing cause GER?

GER during sleep is associated with arousals, unrefreshing sleep, awakenings, insomnia, excessive sleepiness in the wakeful state and impaired daytime functioning. Sleep-related GER is common in patients with obstructive sleep apnea, and successful treatment with continuous airway pressure can lessen sleep-related GER. Medical treatment of GER may improve a number of outcomes, but such therapy, which only buffers or decreases acid secretion and does not affect esophageal motility, may allow nonacid GER to persist despite such therapy.

Do medications cause GER/GERD?

Elderly patients are increasingly likely to be taking drug therapies for a number of indications, and many medications can cause increased risk of dysphagia and GERD (or worsening of GERD if already present). These include antihypertensive medications, anticholinergics, bisphosphonates, nitrates, antidepressants, amiodarone, phenothiazines, pirfenidone, antiparkinson agents, antiepileptics, bisphonates, benzodiazepines and others.

How can pathologic GER be treated or prevented?

The goals of managing GERD include preventing complications and relieving symptoms. Because the pathophysiology of GERD is multifactorial, treatment strategies would ideally address all underlying factors that lead to GERD. Anatomic factors can be addressed to some degree by positioning (elevated head of bed when sleeping), and lifestyle changes can be helpful (avoiding stimuli that can promote reflux such as caffeine, alcohol or nicotine, avoiding ingestion of food 2–3 h prior to sleep). Stomach acid reduction can be achieved with acid-suppressing medications (proton pump inhibitors or histamine type 2 receptor antagonists), and acid-neutralizing medications such as antacids or alginic acid can also be used. Treating the acid component of reflux can not only neutralize the caustic nature of gastric refluxate but also indirectly alter the activity of pepsin and bile acids, which can induce a greater degree of mucosal damage when pH is low. However, nonsurgical approaches may not be effective for some patients, especially if anatomic changes, such as the presence of a large hiatal hernia, cause other approaches to be ineffective in preventing reflux. Gastric fundoplication may be required to prevent excessive GER and its consequences, and such can be done safely for carefully selected patients by an experienced surgeon.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.