Middle ear fluid histamine and leukotriene B4 in acute otitis media: effect of antihistamine or corticosteroid treatment

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Abstract

Objective: Two potent mediators of acute inflammation, histamine and leukotriene B4 (LTB4), have been shown to play important roles in the pathogenesis and clinical course of acute otitis media (AOM) in children. The purpose of this study was to evaluate the ability of adjuvant drugs, antihistamine and corticosteroid, in reduction of the levels of histamine and LTB4 in the middle ear and their ability to improve outcomes of AOM. Methods: Eighty children with AOM (aged 3 months to 6 years) were enrolled in a prospective, randomized, double-blind, placebo controlled study. All children received one dose of intramuscular ceftriaxone and were randomly assigned to receive either chlorpheniramine maleate (0.35 mg/kg per day) and/or prednisolone (2 mg/kg per day) or placebos three times a day for 5 days. Tympanocentesis was performed at enrollment and after 5 days of adjuvant drug treatment. MEFs were collected for bacterial and viral studies and histamine and LTB4 levels. The subjects were followed for the duration of middle ear effusion or up to 3 months. Results: Histamine or LTB4 levels in the MEF after 5 days of treatment were not significantly reduced by adjuvant drug treatment. However, subjects receiving corticosteroid had a lower rate of treatment failure during the first 2 weeks and shorter duration of middle ear effusion. Conclusions: Five day of antihistamine or corticosteroid treatment does not reduce the levels of histamine or leukotriene B4 in the MEF of children with AOM. Positive clinical outcomes of AOM cases associated with corticosteroid treatment needs to be confirmed in a larger clinical trial of children with intact tympanic membranes, who do not receive tympanocentesis.

Introduction

The middle ear fluids (MEFs) of both experimental animals and patients with acute otitis media (AOM) have been shown to contain numerous cytokines and inflammatory mediators, including IL-1β, IL-6, IL-8, TNF-α, histamine, leukotrienes and prostaglandins [1], [2], [3], [4], [5], [6]. These substances are involved in induction and/or mediation of inflammation in the middle ear that leads to clinical signs and symptoms of AOM. Inflammatory mediators can induce inflammation even in the absence of a pathogen [7]. Higher levels of some mediators have been associated specifically with young age [2], type and load of pathogens [5], [6], viability of bacteria [8], purulent MEF [9] and specific cellular products of nonviable bacteria [10].

Previous studies in our laboratory have shown high levels of two potent inflammatory mediators, histamine and leukotriene B4 (LTB4), in bacteria- and/or virus-positive MEF samples from children with AOM [3], [4]. High concentrations of the mediators tended to be associated with persistent otitis. Two to 5 days of antibiotic treatment alone had no effect on the concentrations of histamine or LTB4 in the MEF. These observations led to the hypothesis that adjuvant treatment with drugs directed against these inflammatory mediators might improve outcomes of AOM by reducing the degree of inflammation in the middle ear.

Antihistamines are a group of drugs called H1 receptor antagonists, that work as competitive inhibitors at end organ receptors. To a certain extent, H1 antagonists also inhibit the release of histamine from basophils/mast cells [11], [12]. Corticosteroids are potent anti-inflammatory drugs that inhibit the synthesis and/or release of numerous inflammatory mediators and cytokines, including interleukin-1, interleukin-6, tumor necrosis factor (TNF) and arachidonic acid metabolites, such as prostaglandins and leukotrienes [13]. In order to evaluate the ability of antihistamine and corticosteroid to reduce the levels of inflammatory mediators in the middle ear and thereby improve outcomes of AOM, we performed a randomized, double-blind, placebo-controlled trial in 80 subjects with AOM.

Section snippets

Subjects and clinical assessment

We recruited subjects aged 3 months to 6 years with AOM from our pediatric clinic between September 1995 and May 1998. The clinical diagnosis of AOM was based on acute symptoms (fever, irritability, earache or poor feeding/poor sleep), signs of acute tympanic membrane inflammation (red, yellow or bulging of the tympanic membrane) and the presence of MEF as documented by tympanocentesis. Exclusion criteria were: (a) treatment for AOM within the past 30 days; (b) antibiotic treatment during the

Demographic data and risk factors

The study population consisted of 80 subjects. Tympanocentesis was performed on 127 ears at enrollment. Demographic and risk factor data were as follows: mean age 20.2 months (range 3–73 months); 59% male; 44% African-American, 36% Caucasian, 20% Hispanic; 38% attended day care; 25% breast fed; 43% exposed to tobacco smoke at home; prior AOM episodes: 31% none, 29% 1–2, 29% >2, 11% unknown; 10% with prior history of pressure-equalizing tube surgery; and season of enrollment: 34% spring, 7%

Discussion

In this study, we evaluated the effect of adjuvant drugs, antihistamine and corticosteroid, on reduction of histamine and LTB4 levels in the MEF. Our hypothesis was that anti-inflammatory drugs help improve AOM outcomes by reducing the degree of inflammation in the middle ear through lowering the local concentration of inflammatory mediators. All patients in this study received two tympanocentesis procedures and the MEFs were collected pre- and post-adjuvant treatment to document changes in

Acknowledgements

Financial support was provided by the National Institutes of Health, Grant R01 DC 02620. The study was conducted at the General Clinical Research Center at the University of Texas Medical Branch at Galveston, funded by Grant M01 RR 00073 from the National Center for Research Resources, NIH, USPHS. We thank Dr Mary Owen and Dr Monica Thint for their invaluable input and assistance with patient evaluation; Dr Avelina Dimaandal and Dr Ralph W. Noble, UTMB ambulatory pediatric faculty and pediatric

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