Nancy M. Bauman, MD, FAAP, FACS, is Professor of Otolaryngology-Head and Neck Surgery at Children’s National Medical Center and George Washington University in Washington, DC. She may be reached at firstname.lastname@example.org.
Pediatric extraesophageal reflux disease (EERD) refers to the manifestations of gastroesophageal reflux that arise outside of the gastrointestinal tract. Of the many manifestations of EERD, the most common observed in pediatric patients are chronic cough, sore throat, apnea, wheezing, stridor, recurrent pneumonia/bronchitis, and hoarseness. The term EERD is preferred to the terms supraesophageal or laryngopharyngeal reflux disease, as it encompasses pulmonary manifestations as well. In this editorial, I will discuss salient features of the pathophysiology, diagnosis, and treatment of this entity, with an emphasis on the pitfalls and controversies in our current understanding of EERD.
The pathophysiology of EERD is multifactorial. The mucosa of the upper and lower airways is particularly vulnerable to injury from contact with noxious gastroesophageal refluxate. Other mechanisms of EERD are often overlooked but are important to recognize, especially in pediatric patients. In 1994, we described potent vagal airway reflexes that can be induced by chemical stimulation of sensory nerve endings in the distal esophagus.1 The laryngospasm and central apnea elicited were far more pronounced in developing animals than in mature animals. This observation mirrors our clinical experience, as apnea from reflux disease is seen in infants, but typically not in older children. Finally, chemical neuromediators that are likely released from injured esophageal mucosa and their systemic effect on the aerodigestive tract remain to be identified. Discoveries in this area of medicine may unravel novel pharmacologic approaches to treating reflux disease by blocking the end-organ effect, as opposed to merely reducing gastric acid output.
The diagnosis of EERD requires a high index of suspicion. The manifestations are diverse, and suggestive clues such as heartburn and water brash are often lacking in pediatric patients. Observations can be drawn from the trends seen in clinical practice to improve the diagnostic yield. Just as reflux-induced apnea demonstrates an age predilection for infants, other manifestations of EERD also show an age predilection. Chronic sore throat is an uncommon sign of EERD in toddlers and young children, but is one of the most common presenting symptoms in adolescents, particularly those with nocturnal reflux symptoms. Chronic cough, bronchitis, and recurrent pneumonia from reflux disease are most frequently observed in toddlers and young children.
The true incidence of EERD is unknown, but it certainly appears to be a condition that is overdiagnosed. I believe that the overdiagnosis is inadvertent, and can be attributed to several factors. Most at fault is the lack of a sensitive and specific diagnostic test for reflux disease. For many years, pH probe testing, considered superior to radiographic studies, was touted as the gold standard for diagnosing GERD. Its shortfall in diagnosing EERD was readily apparent to those of us who frequently observed children who responded well to antireflux medication despite having normal single, or even double, pH probe studies.2 Interestingly, despite the pH probe’s widespread use, the criteria for pathologic reflux at the upper probe were never established by controlled outcome studies.
The low sensitivity, the lack of reproducibility, and the burden of obtaining a pH probe study prompted the emergence of the next phase of diagnosis-using the response to empiric antireflux therapy as a primary diagnostic test. The relative inefficacy and the early development of tolerance to H2 receptor antagonists justified the rationale for initiating treatment with proton pump inhibitors (PPIs). Insurance companies often failed to approve PPI therapy in the absence of a prior trial of H2 receptor antagonists, or a letter of medical necessity, validating the use of this superior class of antireflux medications. Although a trial of empiric therapy is cheaper than a diagnostic study for reflux disease, it is nevertheless a costly approach. At a local large chain pharmacy in the Washington, DC, area, a 12-week supply of Zantac suspension (rantidine hydrochloride, 15 mg/mL, 45 mg) for a 20-kg child costs $490, while a similar supply of Prevacid (lansoprazole) is $495 (30 mg Solutab) or $558 (30 mg capsule). (The price difference for a three-month supply is not as striking as one would suspect, given the reluctance of insurance companies to approve first-line PPI therapy.)
The difficulty obtaining insurance approval for PPIs is not their only shortcoming. They must be administered in a careful fashion to ensure their efficacy. Although it is common knowledge that PPIs block hydrogen ion production by the gastric parietal cells, it is less well known that their effect is systemic and not local at the gastric level. Consequently, PPIs must be administered 30 minutes before a meal to allow for absorption from the duodenum into the systemic system. Prior to the advent of pleasant-tasting suspensions and soluble tablets, the content of PPI capsules was sometimes sprinkled into a concealing, palatable food before administration. However, placement of the enteric coated beads of PPIs in something other than a weakly acidic solution, such as applesauce or yogurt, rendered the medication inactive. Inappropriate administration lessened the value of using PPI therapy as a diagnostic study.
Other Diagnostic Methods
Newer on our horizon, and yet to be refuted as a valuable study, is the multichannel intraluminal impedance (MII) test. While it is similar to pH probe testing, this relatively new study allows the detection of both acidic and nonacidic reflux events by measuring changes in impedance along a series of ring electrodes on an esophageal catheter. Nonacidic reflux events may account for up to four-fifths of reflux events in pediatric patients, particularly infants, and may explain the insensitivity of pH probe testing, as well as the relative inefficacy of acid-reducing antireflux medications.3 Institutions are understandably a bit cautious about purchasing this relatively new, expensive equipment and software to replace their functioning pH probe equipment at a cost of nearly $25,000. Reviewing the MII study after it has been scored by the software program is relatively labor-intensive but will likely become less so as technology improves.
We must not overlook the diagnostic value of endoscopy in evaluating pediatric patients with suspected reflux disease.4 While systematically evaluating the larynx and trachea for pathology, we must realize that most laryngeal and tracheal signs attributed to reflux disease in the literature are actually nonspecific findings indicative of inflammation from a variety of potential causes. Findings such as pseudosulcus vocalis, edema of the vocal folds or posterior glottis, and follicular bronchitis of the trachea are nonspecific signs that certainly can be seen with reflux disease, but can also be seen with a variety of other conditions, including infectious, allergic, or inflammatory causes. I recall authoring a manuscript about follicular bronchitis observed in several children from a variety of causes and stating that cobblestoning of the trachea was a nonspecific finding arising from hyperplasia of lymphoid follicles. I was surprised to later see the manuscript quoted as equating follicular bronchitis to reflux disease! Until outcome studies show us that laryngeal and tracheal findings resolve with antireflux therapy, these findings must be viewed as suspicious for reflux disease, but not diagnostic.
The value of laryngoscopy and bronchoscopy is further enhanced when combined with esophagoscopy and biopsy. Preoperatively obtaining consent from patients for esophagoscopy can prove particularly fruitful intraoperatively in the event that laryngoscopy and bronchoscopy findings are normal. Evaluating the esophagus for erythema, ulceration, linear furrows, trachealization, and white patches should be combined with biopsying the distal, mid, and proximal esophagus to detect eosinophilic esophagitis (EE) as well as reflux esophagitis. Although both flexible and rigid esophagoscopy are adequate for obtaining biopsies, flexible esophagoscopy offers improved insufflation, advanced fiberoptics to assess the submucosal esophageal vascularity, and the ability to proceed with simultaneous gastroscopy and duodenoscopy. I often coordinate endoscopy with our pediatric gastroenterologists who not only offer flexible esophagoscopy, but also provide great insight in managing our complicated mutual patients.
Eosinophilic esophagitis is a relatively recently described phenomenon that usually presents with dysphagia and/or food impaction but can also have associated airway symptoms. Radioallergosorbent testing (RAST) for common food allergens is not always positive in patients with EE, which renders detection difficult. Recognizing this dilemma, the American Gastroenterology Association recently published diagnostic criteria for EE based on both histologic and clinical findings. Patients with EE respond best to swallowed inhalational steroids, but some patients also respond to antireflux medication, further confusing the diagnosis between the two disease processes. Scattered eosinophils within the mucosa of the esophagus is diagnostic of reflux esophagitis, but aggregates of eosinophils, or more than 15 per high-power field, are diagnostic of EE. It is likely that many patients with EE were diagnosed historically with reflux disease before the quantification of eosinophils was determined to be a differentiating factor. Consideration for EE lends further support to the value of esophagoscopy with biopsy.
Avoiding overzealous diagnosis while still maintaining EERD in the differential diagnosis is critical to managing our patients. Of a survey of the 265 ASPO members regarding reflux disease conducted by John Little, MD, from East Tennessee Children’s Hospital, in which 25% responded, more than 90% felt that reflux is a significant diagnosis in their pediatric otolaryngology practices. I was pleased to discover from this enlightening survey that most pediatric otolaryngologists do not believe reflux is a significant cause of vocal cord nodules, sinusitis, or otitis media. However, I was surprised to learn that two-thirds of responders prescribe antireflux medication for infants with laryngomalacia. I have not found treatment to be particularly effective in enough infants with laryngomalacia to warrant treating all, and find that very few with overt regurgitation even respond to treatment. I was also surprised to find that few pediatric otolaryngologists believe that reflux plays a role in causing apnea, an association that I believe is a relatively significant one.
It is easy to understand how reflux is an overdiagnosed phenomenon. The literature is replete with case reports of reflux-related disease in pediatric patients, and the tendency to consider this diagnosis in patients with difficult-to-manage conditions is a natural one. We pride ourselves in helping patients, and there is nothing quite so rewarding as observing a patient improve on antireflux medication after he or she has seen numerous physicians and been treated unsuccessfully with inhalers, steroids, and antibiotics. These rewarding examples make us hopeful that reflux is the culprit in many of our patients with difficult pathology. Sometimes it is the culprit and sometimes it is not.
Controlled studies correlating symptoms, diagnostic results, and outcome of antireflux therapy are lacking in the pediatric otolaryngology literature. Although completing such studies is an arduous task, it remains an essential one. Multidisciplinary clinics among gastroenterologists, pulmonologists, and otolaryngologists are a credit to institutions establishing them. These clinics sacrifice productivity of their physicians for improved patient care and convenience. Such centers will continue to drive our understanding of reflux disease in the future.
- Bauman NM, Sandler AD, Maher JH, Schmidt C, Smith RJH. Reflex laryngospasm induced by stimulation of distal esophageal afferents. Laryngoscope 1994;104:209-14.
- Bauman NM, Bishop WP, Sandler AD, Smith RJ. Value of pH probe testing in pediatric patients with extraesophageal manifestations of gastroesophageal reflux disease: a retrospective review. Ann Otol Rhinol Laryngol Suppl 2000;184:18-24.
- Wenzl TG, Silny J, Schenke S, Peschgens T, Heimann G, Skopnik H. Gastroesophageal reflux and respiratory phenomena in infants: status of the intraluminal impedance technique. J Pediatr Gastroenterol Nutr 1999;28:423-8.
- Orenstein S, DiLorenzo C, Hassall E, Bauman NM. Controversies and cases: issues in diagnosis and management of pediatric GERD. American Academy of CME, Suppl Contemp Pediatr 24(2):1-6.
©2008 The Triological Society