Probing Questions: When Is Gastroesophageal Reflux the Cause of Symptoms?

Occasional episodes of gastroesophageal reflux (GER) occur in asymptomatic infants, children, and adults. Rarely, GER causes symptoms or signs such as chest pain, esophagitis, laryngitis, or recurrent pneumonia, and the term gastroesophageal reflux disease (GERD) is applied. Unfortunately, GER is now frequently invoked as the cause of a large variety of symptoms, but the best approach for establishing GER as the causative factor remains elusive. In pediatric practice, it is likely that we frequently blame GER inappropriately for disorders ranging from irritability to recurrent sinusitis, but we also may mistakenly exclude GER as the cause of symptoms on the basis of normal findings in a pH probe study and/or negative endoscopy findings.

In this issue of JPGN, Snel et al. (page XXX) describe their studies in which they attempted to correlate behavioral changes with episodes of GER in preterm infants. Careful analysis using a synchronized videotape system and esophageal pH probe recording failed to demonstrate an association between any purported “reflux-induced behavior” (hiccuping, sneezing, coughing, or gagging, thumb sucking or head retraction) and episodes of GER. The infants selected for study were normal infants at a mean corrected gestational age of 35 weeks who were not considered “clinically” to have GERD.

In contrast, Feranchak et al. ⁽¹⁾ studied 10 patients, aged 2 to 32 weeks. These infants underwent pH probe for the evaluation of symptoms suggestive of GERD. All had abnormal esophageal pH probe recordings with pH less than 4 for 18% to 44% of the total recording time (values well above the normal adult and pediatric ranges). Eight of the 10 infants had esophageal biopsies performed, and all had esophagitis. In these symptomatic patients, behavior, including apparent discomfort, emission, yawning, stretching, stridor, or mouthing, was shown to be associated with onset of esophageal acidification. In another pediatric study, discomfort was described as an initial symptom in 85% of a series of infants with esophagitis ⁽²⁾. Thus, in older infants with esophagitis, the symptom of irritability and some other behavioral changes appear to be correlated with esophageal acidification, but in normal premature infants, no association of behavior and esophageal acidification are observed.

These conflicting results could be explained by speculating that the premature infant is simply immature, and this results in an altered or absent behavioral response to GER episodes. However, normal asymptomatic older infants and adults experience many episodes of esophageal acidification each day, with no perception of the events and no discernible behavioral changes. This conundrum highlights the possible variability in individual symptom responses to episodes of esophageal acidification. One patient may have no perception of esophageal acidification, whereas another may experience discomfort or pain in response to the same stimulus. Similarly, some patients with severe esophagitis may have no significant history of dysphagia or pain.

Studies in adult populations demonstrate a troubling inability of the pH probe to adequately separate patients with typical symptoms of GER from those without symptoms of GER ⁽³⁾. This can probably be explained by individual variations in sensory pain thresholds causing some people to experience discomfort during normal reflux events ⁽⁴⁾. Thus, a patient may have normal esophageal acid exposure with no esophagitis, and yet the patient may experience pain during episodes of esophageal acidification. Treatment of GER may provide substantial relief, despite normal findings in pH probe studies and endoscopy ⁽⁵⁾.

Ambulatory pH monitoring can be combined with symptom recording to examine the association of a specific symptom with episodes of esophageal acidification using either a symptom index (percentage of symptom episodes associated with esophageal acidification) ⁽⁶⁾ or a symptom-association probability index, for which a contingency table is used to calculate the probability that symptom episodes are associated with GER ⁽⁷⁾. Although these studies support the contention that some adult patients with esophageal pain can have normal pH probe results, the analysis methods are far from perfect and are particularly problematic if symptoms occur infrequently. Results in one study ⁽⁸⁾ demonstrated that patients with a positive symptom index improve with proton pump therapy, whereas those with a negative symptom index are less likely to improve. In clinical practice, no method for demonstrating a symptom–reflux association has been prospectively evaluated against an independent criteria, such as the response to proton pump therapy. Furthermore, symptoms such as hoarseness or pneumonia may be caused by an inflammatory reaction to very infrequent episodes of GER, so that persistent symptoms are not temporally related to individual reflux events. In these instances, pH probe findings are of limited value in discriminating normal patients from those in whom GER is contributing to symptoms.

Recognition that there is no correlation between symptoms and pH probe results has led to recommendations to empirically treat adult patients with a proton pump inhibitor to determine whether GER is causing symptoms ⁽⁹⁾. If there is concern about possible esophagitis, upper endoscopy with biopsy is the most reasonable test. As in adults, the severity of esophagitis in children does not correlate with the degree of abnormality on esophageal pH monitoring ^(10,11). Furthermore, in almost all pediatric studies there are some patients with a normal pH probe result that show evidence of esophagitis in specimen analysis ⁽¹²⁾, so that a normal pH probe does not assure absence of esophagitis. Even in patients without esophagitis or pH probe abnormalities, airway and other symptoms may improve after antireflux surgery ⁽¹³⁾.

Esophageal pH recording can be considered the gold standard for determining whether GER occurs. However, it is not reasonable to use esophageal pH monitoring as a gold standard for determining whether GER is causing symptoms or disease. Although a positive pH probe result may increase the probability that a particular symptom is caused by reflux, there are numerous examples of patients with normal pH probe measurements improving after medical or surgical treatment of GER. To assess whether pain or infant irritability is caused by GER, it may be most reasonable to assess the response to empiric medical reflux therapy. Unfortunately, there is a potentially large placebo effect in routine clinical practice, and empiric therapy in infants has not been evaluated in a prospective double-blind manner. Clearly, more data are needed to provide guidance on the best approach to determining whether a specific symptom is caused by GER.