Secretory otitis media, first described by Politzer in 1869, received little mention in the literature until 1931 when Proetz noted a relationship between patients with allergic rhinitis and chronic OM.[102] Koch's study of 222 patients was the first to include observations of eosinophilia in otorrhea "supporting the contention that the middle ear takes part in allergic reactions similar to those seen in the nose and sinuses".[66] Observations as to its incidence, etiology, pathology and therapy were reported with increased frequency through the 50's and 60's as the use of Armstrong's ventilation tube, antibiotics and research in immunology flourished. Hays[52] urged investigation of systemic factors such as allergy and hormonal disturbance in patients with otitis.
Investigators including Boor, Suechs, Senturia, Lim, and Reisman[18],[72],[116],[126],[106] concluded that there is an imposing lack of evidence to substantiate the claim of an allergic cause in the majority of cases of OM. Senturia critically analyzed the literature in the early 60"s and although he did not disagree with the fact that many patients with MEE may be allergic, he found no clinical or pathologic basis from which to correlate nasal allergy with recurrent otitis media.
Fernandez and McGovern in 1965 suggested that an allergic mechanism is not only the major cause of chronic otitis media, but is a predisposing factor in as many as 85% of children with acute otitis as well. Shambaugh suspected allergy as an etiology of chronic draining mastoid cavities or middle ears of patients with OME, citing empirical data. He cautioned that: "surgical mastoidectomy, simple or radical is not indicated. With competent allergic diagnosis and management, preferably by the otologist trained in allergic methods, the otorrhea is finally brought under control."[117]
The middle ear is not a privileged site, devoid of immune response mechanisms, as thought in the 1960's. Although the middle ear is unusual in that it contains no lymphoid tissue and normally has a very weak response to antigen challenge, a previously sensitized middle ear does respond with a vigorous immune response when antigen is presented to it.[58],[61]
Several possible mechanisms of systemic immune response in the ear have been proposed to explain how antigen can stimulate the middle ear, despite its inability to enter that cavity directly. In all middle ears various mediators are produced during the acute infection. These mediators may persist some time in the middle ear after the acute episode has subsided. In normals this does not matter, but in subjects who have primed eosinophils and neutrophils circulating in their blood, mediators present in the middle ear will attract and activate those cells, with the resultant chronic release of ECP as observed in this study. Allergic reactions, infectious inflammation and local immunologic response associated with persistence of pathogenic bacteria, bacterial components or viruses have been considered factors responsible for preemptive dysfunction of the eustachian tube (ET) leading to OME.[83] Repeated antigen exposure may alter inflammatory reactivity to strengthen eosinophil participation in the late-phase reaction while neutrophil involvement diminishes.[94]
Inflammation is exclusively an in vivo phenomenon that only occurs in living tissues with an active microcirculation.[98] Perpetuation of that inflammation, regardless of origin, is the crucial difference between RAOM and OME. Eosinophils are much more toxic than neutrophils, making them particularly harmful to host tissues.[109] In addition to ECP, other cytotoxic proteases, enzymes, lysozymes, and oxidizers are released simultaneously from their respective cells. Allergy has been proven to be almost as potent as bacterial infection in producing an inflammatory response in the middle ear.[57],[86] This may explain why the allergic patient, in addition to exhibiting increased ET dysfunction, is particularly unable to clear the resultant fluid spontaneously, as compared to the non-allergic patient. Perhaps it is the child with allergy who is "otitis prone" and only in the ear of such an allergic patient does a bacterial or viral induced OM proceed to the development of refractory effusion.
Several reviews include critical analyses of decades of studies, both clinical and histological, that have been designed to evaluate the relation between allergy and OM.[5],[35],[92],[154],[17],[138] Unfortunately many reports including those published since the discovery of IgE are often less than critical, quote old data,[15],[70] are not based on present day standardized methods of allergy testing, apply allergy treatments to all patients regardless of diagnosis, or narrowly define their clinical population of "allergic" to include only those with a history of rhinitis.[10],[154] Tomonaga criticized many of the aforementioned works. He found 21% of 605 allergy patients had OME, but among 259 OME patients, 87% were allergic by skin testing, although only 50% of these had nasal allergy.[138] He determined the incidence of allergies among patients with OME to be 4 to 5 times that expected in a similar age-adjusted population of normal individuals. This suggests that the relationship may be more than coincidental.
The symptoms of OME are due at least in part to both inflammation of the middle ear mucosa and/or to eustachian tube (ET) dysfunction with failure to ventilate the middle ear cleft, allergic reactions, and local immune dysfunction associated with persistence of pathogenic bacteria or bacterial components.[83] The ET is involved functionally and morphologically in Type I reactions of the nose.[120] Friedman[40] used a double-blind protocol to show that a provocative intranasal pollen challenge of allergic individuals produced allergic rhinitis followed by ET obstruction. Placebo patients did not obstruct. He demonstrated that allergic reactions in the nose and nasopharynx inhibit even transient dilations of the eustachian tube during swallowing. Double-blind protocols also show that provocative intranasal challenges with allergens or histamine produce severe functional obstruction of the eustachian tube.[120],[34],[1],[10]
Few challenge studies in humans or animals lead to the development of OME. Fireman and Bluestone demonstrated that exposure of the nose to antigen leads to ET obstruction and is dose dependent. The authors are careful to point out that: "The fact that OME did not occur in our preselected adult patient cohort was anticipated and an expectation of our experimental design." They chose allergic adults who had no history of OME "so as to avoid creating complications".[1] This type of dose dependent mucosal edema is acutely produced only by inflammatory mediators such as bradykinin, histamine, leukotrienes, or granular proteins from the eosinophil.[98],[142]
Experiments with Rhesus monkeys produced ET obstruction after a 4 day challenge with ragweed. These animals failed to develop OME, perhaps because MEE does not form in monkeys without transection of the tensor veli palatini muscle.[23] Experiments with chinchillas and mice are more successful in producing MEE.[86],[128],[58] Surgical obstruction of the ET successfully produces OME in only 25% of chinchillas.[86] Failure to find an animal model does not in itself prove that allergy cannot cause OME in humans. These results may just attest to Darwinian selection against the survival of animals that easily develop effusion and hearing loss.
Chronic inflammation is the prerequisite for the development of persistent OME. It is not surprising that the histologic features of chronic otitis are non-specific and may be produced by acute infections or mimicked by other non-specific mechanisms; as middle ear mucosa has a limited repertoire of responses to injury, different triggers and pathogenic mechanisms may lead to similar outcomes. Normally the tympanic mucosa is a low cuboidal epithelium, devoid of lymphoid tissue and eosinophils are not described. The submucosa is often just thick enough to transport vessels, nerves and lymph channels.[36] Research attempting to analyze inflammation based on conventional histologic tests is difficult because obtaining a biopsy of middle ear mucosa in normal or diseased patients raises ethical concerns and cannot always be approved. Furthermore a biopsy constitutes a very limited sample of a large area of mucosa.
Conventional histology does not readily detect degranulated or activated neutrophils or eosinophils and leads to various conclusions.[82],[95], [92],[128] There is also disagreement as to whether mediators in middle ear effusion come from the plasma or local tissue. Palva found that OME is a local process and stated that it "may be assumed that the fluid cytology and the biopsy cell make-up give an accurate picture of the ongoing immune biological events."[96] Using animal studies Nakata found few eosinophils in the effusion of immunized chinchillas in the acute phase of inflammation but did conclude that "middle ear effusion is a local product of the middle ear mucosa rather than a transudate from plasma".[86] Histopathologic examination of effusion demonstrates that eosinophils and neutrophils are integral components in these secretions,[61],[95] but not necessarily present in the mucosal lining. Koch initially described cytologic changes in chronic OM and found eosinophils in mucosa from 52 of 62 cases of allergic otitis.[66]
Modern methods of immunofluorescence staining techniques using mono or polyclonal antibodys have made the identification of specific cells more precise. Mice ears with a chronic immune response show an extensive mucosal hyperplasia consisting of lymphocytes and neutrophils in the submucosa with neutrophils, macrophages and diffuse eosinophilic material in the cellular effusions accompanied by numerous IL-5+ cells in both the subepithelial tissue and effusion in the chronic stages.[13] Using these methods histological studies indicating eosinophil reaction have been described in allergic inflammation involving tissue damage of skin, kidney, lung and nasal mucosa.[39],[28],[100],[30] Inflammation involved in otitis can similarily be characterized from biopsies using immunohistochemical stains that are more sensitive and specific than conventional histologic methods and were used in Study IV.