Laryngospasm and pediatric eosinophilic esophagitis

1. Introduction 

Eosinophilic esophagitis (EoE) is an inflammatory condition characterized by eosinophilic infiltration of the esophageal wall. It is predominant in males and occurs in both the pediatric and adult population. Historically, EoE was described as a distinct clinical and histopathologic diagnosis with more noticeable eosinophilic infiltration than that found with gastroesophageal reflux disease (GERD) [1], [2], [3], [4], [5]. While GERD is far more common, the diagnosis of EoE is sought when patients have GERD refractory to treatment, recurrent food impaction or esophageal stricture. The pediatric population has a bimodal distribution that peaks in infancy and adolescence [6], [7], [8]. In infants and toddlers, symptoms commonly include solid food dysphagia, frequent emesis, regurgitation, failure to thrive, and feeding difficulties. Adolescents, similar to adults, may present with emesis, abdominal pain, heartburn or chest pain, solid food dysphagia with associated food impaction, esophageal stricture and need for dilation [9], [10].

Airway symptoms in the presence of EoE were first noted by Orenstein et al. [11]. Since then, EoE has been related to asthma, allergy, rhinosinusitis and other upper airway complaints [6], [12], [13]. In the last decade there has been an escalating interest in EoE and its otolaryngologic manifestations. Pharyngolaryngeal complaints presenting to the otolaryngologist include recurrent cough or choking, hoarseness and globus sensation, dyspnea, stridor, and sleep-disordered breathing [6].

Currently, there are no reports in the literature associating laryngospasm with the diagnosis of EoE. Based on the pathophysiology of laryngospasm and the proposed theory of EoE, one can envision the relationship between the two. This study explores EoE in 2 patients presenting with laryngospasm.

2. Case reports 

Two patients were discovered this past year that had laryngospasm and EoE. Following IRB approval their charts were reviewed. Their cases are described herein.

Patient 1: A 6-month-old girl presented with a history high-pitched biphasic (primarily inspiratory) stridor, intermittent apneic episodes, reflux, and rhinitis of infancy. The parents reported frequent emesis partially controlled with anti-reflux and pro-motility medication. During flexible fiberoptic laryngoscopy (FFL), the patient was noted to have hyperadduction of the true vocal cords consistent with laryngospasm. Her supraglottic larynx was erythematous and edematous. Direct laryngoscopy, bronchoscopy, and esophagoscopy (DLB/E) with biopsy were performed 4–6 weeks later after failure of maximal reflux management with lansoprazole 7.5mg twice daily. The airway revealed laryngeal edema, erythema, and congenital grade I subglottic stenosis. The patient had numerous laryngospasms during ventilation. The esophagus had linear furrowing and erythema (Fig. 1). Proximal and distal esophageal biopsies were obtained. The distal biopsies showed >20 eosinophils per high power field. Once the diagnosis had been made, swallowed fluticasone therapy was initiated and she was referred to the gastroenterology service for definitive therapy. This patient had negative responses to common food and aeroallergen radioallergosorbent test (RAST) testing. Six weeks after treatment the patient had complete resolution of airway symptoms.

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Fig. 1. Esophagoscopy on patient 1. Picture shows white exudates, linear furrowing, and erythema.

Patient 2: A 3½-year-old girl presented with a history of intermittent nighttime apnea associated with a decrease in oxygen saturation on pulse oximetry. Additional symptoms included coughing, choking, stridor and restless sleep. She had an overnight sleep study prior to the initial ENT clinic visit that showed an apnea/hypopnea index of 0.4, lowest oxygen saturation 88%, and an elevated arousal index. She had a negative reflux work-up by technetium 99 scanning, but was empirically treated for GERD with lansoprazole 7.5mg twice daily. During the otolaryngology encounter adenotonsillar hypertrophy was noted and laryngospasm was found during FFL. Adenotonsillectomy with DLB/E with biopsy was performed. Airway evaluation from supraglottis to carina was within normal limits. Esophageal evaluation revealed linear furrowing and erythema. Proximal and distal biopsies were obtained. Eosinophil count was >100 per high power field. Swallowed fluticasone was initiated and she was referred to gastroenterology for definitive therapy. The patient underwent allergy testing. The patient was strongly positive to fungus, wheat, tomato, milk, egg, and strawberry. She also had a strong family history of milk hypersensitivity and anaphylaxis. After follow-up 3–4 months later, symptoms were resolved.

3. Discussion 

The American Gastroenterology Association (AGA) Institute provided diagnostic guidelines for EoE in 2007 [14]. They define EoE as a clinicopathologic disorder of the esophagus. Patients should have clinical symptoms of esophageal dysfunction (i.e. dysphagia, or food impaction), lack of responsiveness to high-dose proton pump inhibitors, and the absence of pathologic GERD as evidenced by normal ph-probe monitoring. Pathologically, the last of the diagnostic guidelines include greater than or equal to 15 eosinophils per high power field on microscopy. The typical presenting symptoms of EoE are gastrointestinal in nature. Both patients in this series were at or below the 30th percentile for weight gain and were positive for clinical reflux, regurgitation and poor eating. Both met pathologic criteria. One patient had a negative reflux work-up and both lacked a clinical response to anti-reflux medication.

Histologically, eosinophilic inflammation infiltrates the epithelial layer causing microabscesses, superficial layering of eosinophils, and basal zone hyperplasia [1], [6]. This is important when obtaining biopsy specimens as the superficial mucosal layer may look normal, though more than 80% of patients have common endoscopic appearances [1], [6]. Once the clinical history (esophageal dysfunction, lack of responsiveness to proton pump inhibitors, or absence of pathologic reflux on pH-monitoring) has been provided, it is confirmed by esophageal biopsy and histopathologic determination [1], [6], [14]. No standardized criteria have been set forth, however, the consensus statement put forth by the AGA, recommends ≥15 intraepithelial eosinophils per high powered field (HPF) as an absolute minimum number to make the diagnosis of EoE in the proper clinical context [14].

On esophagoscopy, most patients show tissue remodeling consistent with trachealization, rings, strictures, white exudates, linear furrowing, and erythema (Fig. 1). Trachealization refers to circular rings within the esophagus related to inflammation and inflammatory mediators that cause submucosal fibrosis [6]. A systematic review of 26 EoE reports identified trachealization, and rings or strictures present in over 80% of patients, while radiographic strictures were noted in over 60% of patients [6], [13]. While none of the features are pathognomonic of EoE, they are commonly reported by pediatric endoscopists. These findings are related to eosinophilic degradation products like major basic protein (MBP). This is found histologically in the intracellular and extracellular mileu of EoE patients [6]. Dauer et al. reported MBP effects which include smooth muscle contraction leading to esophageal dysmotility and subsequent dysphagia as well as eliciting tissue injury and edema leading to strictures, food impaction and other endoscopic signs [6].

Many clinicians feel that EoE is simply an additional system manifestation of allergy. There is usually a strong family history of allergy and atopic disease, most commonly allergic rhinitis and asthma. Studies have shown that over 70–80% of patients will have positive allergy testing and atopic dermatologic disorders with aeroallergens and food allergens [1], [11], wheat, rye, milk and egg have the strongest clinical association [15]. Immunologically, EE develops in response to the same inflammatory mediators involved in allergic airway and skin disease and responds to the same anti-allergy or anti-reactive airway management [15]. In addition to allergic rhinitis and asthma, sinusitis and pneumonia have been linked in previous reports, but otolaryngologic airway symptoms of EE have only recently been noted in the literature [11]. The first report described a young girl with subglottic stenosis refractory to surgical management in the presence of uncontrolled reflux. Once diagnosed and treated, the patient was able to be decannulated [16]. More recently, Dauer et al., explored other airway manifestations including apneic spells and dyspnea on exertion [6]. However, there is a relative paucity of literature linking laryngospasm as a presenting symptom of EoE as documented by the two children in this series.

Debate exists regarding the appropriate treatment of EoE which include systemic steroids, topical steroids, biologics, leukotriene inhibitors, immunomodulators, elemental/elimination diet, and endoscopic dilation. The most promising treatment for EoE is topical steroids, namely fluticasone. Swallowed fluticasone has been found to alleviate symptoms and proven to be as equally efficacious as systemic steroids without the adverse side effects [14]. Elemental and/or elimination diet is also very important for the management of EoE [14]. Due to the strong association of EoE as another systemic allergic manifestation there is a high incidence of RAST positive allergens. One patient had significant positives on RAST testing. The AGA consensus statement recommends allergy evaluation and testing for all patients diagnosed with EoE [14].

Laryngospasm is a vagally mediated involuntary muscle contraction or hyperadduction of the thyroarytenoid (TA) muscle. Afferent nerves in the supraglottis carried by the superior laryngeal nerve relay information to the brain stem while efferent nerves carry the response to the TA muscle through the recurrent laryngeal nerves (RLN) [17]. This leads to repetitive discharges of the RLN that cause a sustained contraction of the true vocal cords [18].

Clinically, laryngospasm is characterized by stridor and airway obstruction. The condition typically lasts 30–60s and causes difficulty with inspiration. GERD has historically been associated as one of its causes. Sensory testing in animal studies have reliably reproduced laryngospasm when acidic solutions (pH 2.5 or less) are instilled into the larynx [17]. Other animal studies have used sensory testing to show a correlation with distal esophageal afferents in the etiology of laryngospasm related to a vagally mediated efferent mechanism [19].

In this study we revealed 2 patients with laryngospasm recalcitrant to reflux management with clinicohistopathologic evidence of EoE. The inflammatory reaction of EoE and the eosinophilic degradation products may be linked to the chemosensory vagally mediated mechanism [6]. We postulate that inflammation from the degratory products of mucosal eosinophilia (such as major basic protein) irritate the superficial and deep layers of the esophagus causing a chronic inflammatory response that directly stimulates vagally mediated esophageal afferents that lead to laryngospasm. Another potential mechanism is the release of substance ‘p’ from allergens leading to neural hypersensitivity and laryngospasm. The chronic inflammatory response (dysmotility and tissue injury) may also alter upper and lower esophageal sphincter pressures giving rise to the extraesophageal reflux symptoms of dysphagia, frequent regurgitation, emesis, and/or sleep-disturbed breathing.

4. Conclusion 

Laryngospasm secondary to EoE has not been reported. We found 2 patients with laryngospasm as the presenting symptom of EoE. This study illustrates another airway symptom related to EoE. Pediatric EoE should be considered in the differential diagnosis of patients with laryngospasm, dysphagia, and GERD refractory to anti-reflux therapy.