Evaluation

Numerous tests are available for evaluation of children with laryngeal disease and presumed GERD. It is essential to understand the strengths and limitations of these tests to ensure judicious utilization and optimize clinical outcomes. Categories include 1) historic instruments and questionnaires, 2) direct measurements of reflux and acidity, 3) imaging, 4) endoscopic and microscopic evaluation of the upper GI mucosa, and 5) direct visual inspection of the airway.

Validated questionnaires such as infant GER instruments (I-GERQ-R) are useful for standardization in clinical research but are seldom used in clinical practice. Esophageal manometry measures the internal pressures of the esophagus to evaluate for adequate relaxation and contraction of the esophagus. Manometry may be abnormal in patients with GERD, but its specificity and sensitivity for GERD are low. Esophageal pH testing (standard pH-metry) as an isolated test has limitations that include poor specificity in correlating low pH with actual physiologic GER and the inability to detect nonacid reflux. Impedance monitoring measures intraluminal bolus movement through the esophagus, and impedance can be combined with both manometry and pH probe. Combined pH and multichannel intraluminal impedance (pH/MII) testing is preferred because it is identifies acid and nonacid reflux and provides better correlation with respiratory events. Whereas standards across the pediatric spectrum are evolving, combined pH/MII testing has clearly supplanted pH-metry in the evaluation of reflux disease.

Imaging for children with GERD may include contrast fluoroscopy and nuclear scintigraphy studies. The upper GI series should be considered a study of anatomy and is aimed at the assessment of esophageal caliber, gastric anatomy, and presence of diaphragmatic defects or possible malrotation. Although reflux is often described during an upper GI series, the refluxate may be nonspecific and may be the result of positioning for the study. The videofluoroscopic swallow study may serve as a functional screen to assess for dysphagia with aspiration or to identify impaired or dysfunctional relaxation of the cricopharyngeal musculature as may be noted with cranial nerve and posterior fossa defects. Nuclear scintigraphy, also known as a milk scan, may be useful to document postprandial retrograde transit of food and to track the contents into the lungs if aspiration occurs with reflux. However, the utility of scintigraphy testing in the evaluation of GERD is low, and the technique is not recommended for routine testing. As with all pediatric radiographic studies, proper technique should be utilized to judiciously limit the radiation exposure to the child.

Esophagogastroduodenoscopy (EGD) with biopsy is useful to identify EoE, esophageal pathology related to GERD, and gastric outlet obstructions and hiatal hernias that may promote reflux and vomiting. Direct sequelae of chronic exposure to refluxate include esophageal erythema and/or linear erosions and, in more severe cases, marked patchy erythema with intestinal metaplasia (Barrett esophagus), esophageal scarring, or stricturing. EGD with biopsy may also diagnose diseases that require alternative therapies.

Classically, indirect or direct laryngoscopy findings, such as posterior glottic and arytenoid erythema and edema or posterior cobblestoning, have been attributed to GERD, but standardized criteria are lacking. A weak correlation has been found between signs consistent with reflux laryngitis (glottic edema, laryngeal erythema) on direct microlaryngoscopy and results from dual-probe pH studies and posterior cricoid biopsies with histologic changes for reflux. A high frequency of GERD in children with laryngeal pathology was found when utilizing scintigraphy and an upper GI series for GERD diagnosis, but these methods undoubtedly overestimated the incidence of GERD in the study population. A landmark study in adults found that laryngeal signs suggestive of GERD improved after fundoplication but symptoms of GERD did not, which suggests that visual findings of laryngeal disease and symptoms of GERD may not be correlated.

Flexible bronchoscopy may be utilized with bronchoalveolar lavage (BAL) and aspiration of secretions for further analysis. The lipid-laden macrophage index determines the contents of 100 consecutive macrophages scored with a scale from 0 to 4, with a summative score of 0 to 400; a value greater than 100 may be associated with the highest risk of GERD. The presence of lipid-laden macrophages on BAL as a sign of aspiration from GERD has low sensitivity and specificity. The Western blot analysis for pepsin is a promising tool for the evaluation of GER in patients with airway disease and suspected extra­esophageal reflux disease. Pepsin has been shown to be a causative agent of laryngeal damage in acidic and nonacidic reflux. Pepsin in laryngeal epithelium may more accurately link laryngopharyngeal reflux with GERD. In a small prospective study, seven of eight adults experienced improvement in symptoms and elimination of pepsin from laryngeal biopsies after antireflux surgery. Pepsin and exposure to gastric refluxate were found in 59% of biopsies performed in adults with idiopathic (nonautoimmune) SGS. However, results of adult studies may be difficult to extrapolate to children. Increased concentrations of pepsin have been shown in tracheal aspirates in preterm infants who developed bronchopulmonary dysplasia. In a small study on children undergoing bronchoscopy, pepsin was more sensitive than lipid-laden macrophages for the detection of aspiration. Pepsin appears to be a more specific biomarker for aspiration extraesophageal reflux compared with the presence of lipid-laden macrophages in BAL or tracheostomy aspirates in children with chronic lung disease.

Clinical Presentation

GERD-related disease within general pediatrics encompasses three general categories of pathology: 1) failure to gain weight secondary to GER, typically from vomiting; 2) pain related to esophageal inflammation; and 3) extraesophageal manifestations that include both airway and pulmonary disease. In particular, laryngeal disease as a manifestation of GERD will present in different ways in children of various ages.

Infants and young toddlers may present with apnea, stridor, croup, hoarseness, and aspiration. In one study of 202 infants with stridor, half had laryngopharyngeal reflux associated with their condition. Approximately 75% of cases of infantile stridor are secondary to laryngomalacia, and the incidence of GER has been reported to be as high as 90% in these infants.

Given the natural history of GER in infants, the coexistence of GER and laryngomalacia is not surprising, but it is unclear whether it is coincidental or reflects a predisposition. GERD may also alter laryngeal tone and sensorimotor function of the larynx, and one theory suggests that increased intrathoracic pressure as a result of airway obstruction in laryngomalacia promotes increased GER. Furthermore, the altered vagal tone that affects the larynx in laryngomalacia may have similar effects on the vagal tone of the lower esophageal sphincter and on esophageal motility. Yet a systematic review of 1295 neonates with coexisting acid reflux and laryngomalacia failed to identify a causal relationship.

Apnea or apparent life-threatening events (ALTEs) in infants and young children have been associated with GERD; however, most studies fail to correlate ALTEs with the frequency, duration, or acidity of reflux episodes in any way that supports a causal mechanism. A recent systematic review found that routine GER testing was unnecessary in children with ALTEs. If events recur, pH/MII monitoring with symptom monitoring is recommended to formally assess GER in children with ALTEs. In the unusual infant in whom GER and ALTEs appear to be causally related, antireflux surgery may be indicated.

In older children, dysphonia, cough, and pharyngitis are the predominant presenting symptoms of laryngeal manifestations of GERD. No association between extraesophageal signs and symptoms and GER episodes as measured by pH/MII monitoring was demonstrated in a study of 63 children. A study of 254 children with hoarseness found that only 25% of children with vocal cord nodules had GER. Moreover, no association between esophageal biopsy, BAL, and laryngoscopy findings was found in a series of children with hoarseness. GERD has been implicated as a cause for paradoxic vocal cord motion, but the causative association is still unclear. According to a recent clinical practice guideline, antireflux medication should not be prescribed for patients with hoarseness without overt signs or symptoms of GERD. Thus while GERD may play a role in dysphonia and hoarseness, a direct causal relationship has not been established.

Whether or not laryngeal sequelae of reflux disease can occur in the absence of esophageal sequelae has been a controversial topic. Because esophageal mucosa is organized with tight junctions, it may be more resistant to esophageal refluxate; this refluxate may be effectively confined within the esophageal lumen, which prevents it from irritating the deeper layers of the esophageal wall. Furthermore, contractile waves frequently clear esophageal gastric contents into the stomach, further minimizing the esophageal exposure to refluxate. Nonacid elements of refluxate, such as bile and pancreatic enzymes, may contribute to extraesophageal disease, but it has not been well studied in children.

Unlike adults, the role GER plays in children with chronic cough is unclear. GERD was the third most common cause of chronic cough among 72 children, but it occurred in only 15%; the most common causes were cough-variant asthma and sinusitis. Esophageal vagal reflexes are thought to mediate cough and GERD via esophageal irritation that precipitates vagal signals to the brainstem that promote bronchoconstriction and trigger cough. Others have proposed that microaspiration may be the trigger for chronic cough. However, prospective evaluation of patients with chronic cough by bronchoscopy and BAL found that protracted bacterial bronchitis was most prevalent (39%) and that GERD was an infrequent cause (3%). Thus the role of GERD in chronic cough in children may be minor relative to that of other causes.

Most authors recommend preoperative GER evaluation and treatment to optimize success in laryngotracheal recon­struction. However, one review of children who underwent laryngotracheal reconstructions recommended against routine perioperative evaluation for GERD because pathologic reflux did not contribute to operative outcome. Experimental gastric exposure directly leading to SGS and airway pathology has been demonstrated in animal models. A systematic review of endoscopic evaluation of the larynx and trachea in the pediatric population with the incidence of GERD found that SGS was frequently identified in patients with GERD. Adult studies have demonstrated pepsin in subglottic scar and larynges of idiopathic adult SGS patients, but this did not correlate with dual-probe pH studies. In summary, GERD may play a role in SGS and may interfere with laryngotracheal reconstruction, but further study is needed.

Taken together, the variations in the presentation of pediatric laryngeal disease associated with GERD; the conflicting, albeit well-executed pediatric studies; and the inability to reliably extrapolate data from adult studies highlight the importance of good clinical judgment in the successful management of such patients.