Middle ear fluid histamine and leukotriene B4 in acute otitis media: effect of antihistamine or corticosteroid treatment
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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2003, Journal of PediatricsCitation Excerpt :In experimental animals,14 antihistamine prevents the increased tissue permeability caused by histamine but has no effect on vasodilation or swelling of the eustachian tube. In a separate study of 80 children with AOM that we performed in parallel with the study reported here,36 MEE was collected preadjunctive and postadjunctive treatment for determination of changes in histamine and LTB4 levels. We found that histamine levels in the MEE were significantly reduced after 5 days of treatment with antibiotic but that reduction was not associated with antihistamine treatment.
Systemic cytokine response profiles associated with respiratory virus-induced acute otitis media
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Presently at the University of Turku, Finland.