The Role of Allergy

in Otitis Media
w i t h E ff u s i o n
David S. Hurst, MD, PhD*

KEYWORDS
 Allergy  Otitis media with effusion  Immunotherapy  Atopy
 Eustachian tube

Key Points: ALLERGY IN OTITIS MEDIA

 The middle ear, as part of the unified airway, can be a target organ of allergy.
 OME is frequently an IgE-mediated, late phase allergic disease.
 Allergy can cause eustachian tube dysfunction.
 SPT underestimates the incidence of allergy among patients with OME.
 Once patients are identified as being atopic, aggressive treatment of their allergies with
immunotherapy can frequently resolve the underlying middle ear disease.

Otitis media with effusion (OME) is the major form of chronic relapsing inflammatory
disease of the middle ear. It is a clinical disease defined as the presence of fluid in
the middle ear behind an intact tympanic membrane with no active infection. For 70
years, the concept of the cause of this disease had been founded on clinical observa-
tion. The emergence of molecularly based diagnostic tools in genetics, cell biology,
and immunology over the last decade has now enabled us to better understand the
pathophysiology of OME and develop new therapies for OME based on the improved
understanding.

Portions of this article were previously published in: Hurst DS. Efficacy of allergy immuno-
therapy as a treatment for patients with chronic otitis media with effusion. Int J Pediatr
Otorhinolaryngol 2008;72(8):1215–23; with permission; and Hurst DS. The middle ear: the
inflammatory response in children with otitis media with effusion and the impact of atopy.
Clinical and histochemical studies. In: Comprehensive Summaries of Uppsala Dissertations
from the Faculty of Medicine, Dept of Immunology and Clinical Chemistry #978. Uppsala
(Sweden): Uppsala University Sweden; 2000; with permission.
Tufts University, Department of Otolaryngology/Head and Neck Surgery, 800 Washington
Street, Box 850, Boston, MA 02111, USA
* Private Practice, 43 Carson Drive, Gorham, ME 04038.
E-mail address: [email protected]

Otolaryngol Clin N Am 44 (2011) 637–654

doi:10.1016/j.otc.2011.03.009 oto.theclinics.com
0030-6665/11/$ – see front matter Ó 2011 Elsevier Inc. All rights reserved.
638 Hurst

Chronic OME is associated with hearing loss and delayed speech development and
may cause permanent middle ear damage with mucosal changes.1 It is a disease of
immense social and financial impact among families of young children, accounting
for more than 16 million office visits a year at an annual cost of more than $3.5 billion
(2003) in the United States alone.2 Children with hearing loss secondary to OME
constitute the largest group of people in the world with a reversible learning disorder.
Among the 35% of preschool children who experience otitis media (OM), 50%
maintain the effusion 14 days after initial treatment.3 In another study the effusion
was found to persist in 70% at 2 weeks, in 40% at 1 month, and in 20% beyond 2
months.4 Chronic middle ear disease represents an entity with multiple contributing
environmental factors interacting with a complex web of immunologic, genetic,
mechanical, and inflammatory components.
Many otologists do not embrace a role of allergy in chronic middle ear disease. A
recent clinical practice discussion and literature review states that “the relation
between allergy and OME will remain controversial until well controlled clinical studies
are conducted documenting that in select populations antiallergy therapy is
efficacious in preventing or limiting the duration of OME.”5

TERMINOLOGY AND DEFINITIONS

OM describes a symptom, not a disease. It is used to categorize a broad spectrum of

middle ear abnormalities, which may involve recurrent acute infections occurring
sporadically or extend to conditions of prolonged, ris intact, perforated, or draining.
Chronic suppurative OM (CSOM) refers to a chronic discharge through a perforation
of the tympanic membrane. OME is defined by the current gGuidelines as “fluid in the
middle ear without signs or symptoms of infection; OME is not to be confused with
acute OM (inflammation of the middle ear with signs of infection).”6 Confusion occurs
when practitioners mistakenly equate inflammation with infection.
Allergy refers to symptoms of asthma, rhinitis, or otitis versus atopy, which is a sensi-
tivity as reflected by elevated IgE antibody levels to various allergens without the
patient necessarily having the symptoms.7 There is little research on the role of allergy
in OME. Of more than 10,570 articles published from 2001 to 2006 in the 2 major
allergy journals (Allergy and Journal of Allergy and Clinical Immunology) and the 3
major ear, nose, and throat journals (Otolaryngology, Head and Neck Surgery;
Laryngoscope; and Annals of Otolaryngology), only 16 articles addressed the link of
allergy to middle ear disease.

IMMUNOLOGY OF ALLERGY

If the nomenclature published by both the European Academy of Allergy and Clinical
Immunology and the American Academy of Allergy Asthma and Immunologyguide-
lines in 2001 and 2003, respectively,7 for asthma or sinusitis as being either allergic
or nonallergic, is extended to categorize inflammation in the middle ear, which is
a direct extension of the mucosa-lined respiratory tract, allergic otitis inflammation
could be divided into “IgE- or non–IgE-mediated” disease (Fig. 1).
All normal individuals, atopic or not, when exposed during an infection to bacterial
antigen stimulate a cell-mediated TH1 response that is activated by the cytokines
interferon g and interleukin (IL) 2.8,9 In the TH2 allergic reaction, allergens trigger the
naive T cell to take a different pathway to become a TH2 cell (Fig. 2). The immunology
of IgE-mediated disease is detailed by Calhoun and Schofieldelsewhere in this
issue. Although in summary, IgE-mediated disease is characterized by mast cell
 The Role of Allergy in Otitis Media with Effusion 639

Fig. 1. AAAAI and EAACI classification of the inflammation of asthma or sinusitis. AAAAI,
American Academy of Allergy Asthma and Immunology; EAACI, European Academy of
Allergy and Clinical Immunology. (From Johansson SG, Bieber T, Dahl R, et al. Revised
nomenclature for allergy for global use: report of the nomenclature review committee of
the world allergy organization, October 2003. J Allergy Clin Immunol 2004;113(5):834;
with permission.)

degranulation and a classic early phase of symptoms occurring within an hour of

antigen exposure, the late phase occurs several hours later and is mediated by the
recruitment of eosinophils attracted by IL-5 as well as other cytokines generated
during the early phase response. This eosinophil response can be present chronically

Fig. 2. A representation of current concepts of T, B, and antigen-presenting cell (APC) inter-

relationships. Bacterial antigen-induced (TH1) and allergen-induced (TH2) reactions lead to
the release of cell mediators such as tryptase, eosinophil cationic protein (ECP) and MPO.
APCs include macrophages (Mac), B cells, and dendritic cells. Cells in the trapezoid constitute
the IgE-mediated early phase TH2 response. Eosinophils and IL-5 are expressions of non—
IgE-mediated late phase disease. Eos, eosinophils; INF, interferon; MHC, major histocompat-
ibility complex; TCR, T cell receptor. (Adapted from Hurst DS, Venge P. The impact of atopy
on neutrophil activity in middle ear effusion from children and adults with chronic otitis
media. Arch Otolaryngol Head Neck Surg 2002;128:561; with permission.)
640 Hurst

in ongoing disease. The presence of eosinophils does not in itself implicate IgE-
mediated disease but rather reflects non—IgE-mediated hypersensitivity. Influx of
eosinophils and their mediators eosinophil cationic protein (ECP) and major basic
protein (MBP) are typical of some of the most refractory subtypes of asthma and rhi-
nosinusitis and have been documented in the effusion of OME.9

HISTORICAL PERSPECTIVE

In 1931, Proetz10 noted a relationship of middle ear disease with allergic rhinitis. In
1947, Koch11 observed eosinophilia in the otorrhea from 222 children, “supporting
the contention that the middle ear takes part in allergic reactions similar to those
seen in the nose and sinuses.” In 1965, Fernandez and McGovern12 suggested that
an allergic mechanism, although not the major cause of chronic OME, was a predis-
posing factor in as many as 85% of children with acute otitis. Shambaugh13 suspected
allergy as a cause of chronic draining mastoid cavities or middle ears in patients with
OME and 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.”13
Objective information on the allergic status of patients with OME is lacking in available
otitis databases in Minnesota or Norway (Casselbrant M, personal communication,
2007), making the true incidence of allergy unknown. In studies from 1952 to 1984,
Suehs,14 Senturia and colleagues,15 Boor,16 Siirala,17 Lim and Brick,18 and Reisman
and Bernstein19 using the techniques of their day, could not find any clinical basis of
allergy in the formation of OME. Suehs14 reported an absence of eosinophils in the
middle ear effusion (MEE) of 50 patients, as did Senturia20 in 1960. Sade and
colleagues21 attributed the basic cause of OME to infection in the nasopharynx with
retrograde contamination of the middle ear and edema of the eustachian tube (ET).
This thinking has dominated otology to this day.

ALLERGY TESTING

Studies that find no increased allergy in subjects with OME often rely on less-objective
criteria than actual skin testing to arrive at a diagnosis of allergy. Tomonaga and
colleagues22 criticized many of these methodologically flawed studies in the “Discus-
sion” section of of their work. The study revealed that 21% of 605 patients with allergy
had OME, but among 259 patients with OME, 87% were atopic by skin testing, even
though only 50% of them had nasal allergy.
The study by Bernstein and colleagues23 in 1981, although sentinel in being among
the first to link allergy to otitis, probably underestimated the role of allergy in OME
because it reported that less than 30% of OME was related to allergy. This low
percentage results from the very narrow definition of atopy, which required both
rhinitis and a total IgE level greater than 100 mg/L or positive results of prick testing.
Ten years ago, the author’s group showed that the mean total IgE level among atopic
patients was 93.8 mg/L, with two-thirds of atopic patients with OME having a serum
IgE level less than 100 mg/L.24 Otitis is thus similar to rhinitis. It is a “low level IgE
disease” having no relation to the total IgE level, unlike asthma, which does show
a correlation with IgE levels.25 Because OME is a low-level IgE disease, prick testing
misses more than 80% of patients with OME whose disease actually resolves when
those particular allergens that give positive results on intradermal testing are included
in their immunotherapy (IT).26 The reported prevalence of atopy of 81% to 100% by the
author among the group of more than 240 patients with OME9,24,26 may reflect the
 The Role of Allergy in Otitis Media with Effusion 641

increased sensitivity of intradermal testing compared with results obtained from

specific IgE in vitro testing,27,28 and/or its equivalent skin prick testing (SPT).
There are several large literature reviews of the relationship of allergy to OME.
Ojala29 surmised that “It would seem that atopy is probably one cause of persistent
therapy-resistant otitis media and it must be taken into account when considering
the treatment of a chronic ear.” Sprinkle and Veltri30 found “solid evidence..to
suggest that (Gell Coombs) Type I immune injury can be considered a major contrib-
uting factor to persistent middle ear effusion.,” and that type III hypersensitivity reac-
tions that require the presence of microorganisms were “very important,” and type IV
reactions may also “play a role in causing and potentiating serous otitis media in man.”
Doyle31 concluded that “it has been reasonably well demonstrated that allergy is a risk
factor for otitis media.” Skoner and colleagues32 in his article on OM, with more than
209 references note that “evidence that allergy contributes to the pathogenesis of
OME is derived from epidemiologic, mechanistic, and therapeutic lines of investiga-
tion.” Tewfik and Mazer5 concluded “in-vitro and clinical evidence now indicates
that, as in asthma and allergic rhinitis, Th2 mediated allergic inflammation is found
in middle ear effusion in some patients with OME. As in asthma, this may be a result
of direct allergen exposure.”

EPIDEMIOLOGY

OME is a multifactorial disease, of which allergy is only 1 risk factor. Parental smoking,
day care classrooms having more than 6 students, asthma, and viral upper respiratory
tract infection are also known to predispose one for OME. Yet allergy adds unique
comorbidity and is by far a greater risk factor than other identified factors, conferring
a 2- to 4.5-fold increased incidence of OME compared with the incidence of OME in
nonallergic people.33,34 Thus a child who has an episode of acute OM is up to 3 times
more likely to develop OME if that same child is also allergic.
Epidemiologic studies in Japan22 and Sweden35 have shown a significant relation of
allergy to OME. Although only 6% to 20% of the general population is atopic and
among atopic patients only 21% have OME, more than 87% of patients with OME
were found to be atopic and/or have allergy symptoms.22 Irander and colleagues35
found that among 54 Swedish infants, 38% with OME had respiratory tract allergy.
Infants with allergic symptoms were 5 times more likely to develop OME than nona-
topic patients. Jero and colleagues36 found similar results in Finland where allergy
posed a risk factor of 4.4 for children failing to clear an acute otitis. Allergy certainly
puts a patient at risk for recurrent sinus infections because it adds to conditions
that can lead to an environment that is suitable for mucostasis, bacterial overgrowth,
and chronic inflammation.37 The author’s group has found that among 97 patients with
OME, 62% had documentation of additional atopic signs and symptoms, including
asthma in 22%, allergic rhinitis in 48%, eczema in 4%, and chronic nasal congestion
in 8%.24
Based on SPT, a Greek study34 found a much higher incidence of allergy among 88
children with chronic OME than in the controls. It was concluded that allergy is an
independent risk factor for developing OME. A study in Mexico found that 15% of
80 children with positive skin test result to dust, corn, and cockroach had abnormal
tympanograms when compared with 50 controls all of who had normal Type A tympa-
nograms and negative results of SPT for the same 3 allergens. Among children with
rhinitis, allergy presented an increased risk for difficulty in opening their ET.38
Doner and colleagues39 evaluated 22 children who required an myringotomy and
tubes (M&T) and adenoidectomy. Only 8% of those with no recurrence of their middle
642 Hurst

ear disease had positive skin test result. This result compared with those of 22 children
who had recurrent middle ear effusions requiring repeat M&T. Thirty-eight percent of
this group had positive SPT result. The investigators concluded that allergy seemed to
be a major contributing factor for recurrent disease.
Viral infections seem to be a trigger for OME. Chonmaitree and colleagues40 found
that 39% of 84 children with MEE had positive viral cultures of their effusion and/or
nasal lavage at the time of their acute episode. Only 15% of the patients had no path-
ogen (bacteria or virus) in the effusion. Other studies showed that human rhinovirus
RNA is present in 30% of the effusions of children with OME.41 Endotoxin has been
demonstrated in 52% to 87% of effusions.42 Polymerase chain reaction has detected
the presence of various bacteria in as many as 85% of the cases.43
Viral sensitization may contribute to the initial inflammatory process leading to OME.
Respiratory syncytial virus (RSV), a common virus in the middle ear and nasopharynx,
induces a state of IgE-mediated allergy in the nasopharynx44 wherein patients with
elevated number of mast cells in the adenoid bed are more prone to OME on viral
exposure.45 RSV enhances the synthesis of proinflammatory cytokines (IL-1b, tumor
necrosis factor-a, IL-6) and cell adhesion molecules (ICAM-1, ELAM-1, VCAM-1)46
in the middle ear of infected individuals. Ohashi and colleagues47 found VCAM-1 levels
to be significantly more elevated in the ears of atopic patients. It has been suggested
that both a respiratory virus infection and the presence of bacteria in the nasopharynx
are required for the development of acute otitis. Garofalo and colleagues48 examined
the effusion from 20 children with acute otitis. They found that tryptase levels were
elevated in 79% of the patients. Samples that were negative for viral culture did not
contain detectable levels of tryptase. It was suggested that viral pathogens were
“an essential trigger or priming factor for mast cell degranulation.” Neither virus nor
bacteria alone seems to be capable of causing otitis as frequently as the 2 combined,
especially in atopic patients.

HISTOLOGIC STUDIES

Inflammation is exclusively an in vivo phenomenon that only occurs in living tissues

with an active microcirculation.49 Purulence in the middle ear has previously been
shown to elevate levels of both eosinophil and neutrophil mediators.9 Perpetuation
of inflammation, regardless of origin, is the crucial difference between recurrent acute
OM and OME. A basic question is whether the middle ear inflammation was the result
of infection, allergy, or both. Atopy seems to have a significant relationship to whatever
produces a response from eosinophils and mast cells in the middle ear.24 This is
a significant observation not only in regard to the association to allergy but also
because human eosinophils are much more toxic than neutrophils, making them
particularly harmful to host tissues.50
The fact that conventional histology does not readily detect degranulated or acti-
vated neutrophils, mast cells, or eosinophils has led to various conclusions29,51–53
and is the major reason this controversy has been perpetuated. There is also
disagreement as to whether mediators in MEE come from the plasma or local tissue.
In the initial stages of serous otitis, mast cells are found in the lamina propria and the
pars flacida of diseased human middle ears.54 Mast cells release inflammatory medi-
ators producing vasodilatation and mucosal edema, as well as neutrophil chemo-
taxis. Using animal studies, Nakata and colleagues55 found few eosinophils in the
effusion of immunized chinchillas in the acute phase of inflammation but also
concluded that “middle ear effusion is a local product of the middle ear mucosa
rather than a transudate from plasma.” Histopathologic examination of effusion
 The Role of Allergy in Otitis Media with Effusion 643

demonstrates that eosinophils and neutrophils are integral components in these

secretions.52,56
In addition to the cytotoxic effects of ECP, myeloperoxidase (MPO), and tryptase,
these mediators are always accompanied by the other proteases, lysozomasol
enzymes, and oxidizers that are released simultaneously from their respective cells.
ECP attracts other inflammatory cells, including neutrophils, and also delays
apoptosis. This may be why the atopic patient continues to produce additional fluid,
when compared with the nonatopic patient. This condition was seen in allergic
mice, which produced twice the amount of MEE as nonallergic mice on antigen
challenge.57 ECP has also been shown to decrease ciliary function and impair ET
clearance.
The very high concentrations of mediators released by eosinophils and mast cells
may also account for the great destruction, osteitis, and granulation tissue described
on histologic examination of temporal bones from patients with chronic OME.51 Both
heparin and tryptase contribute to fibrosis and bone resorption.58 This finding may
have added significance in understanding the pathophysiology of chronic scarring
in the middle ear as well as in the bone destruction observed in cholesteatoma. A
prospective study of 117 patients found that “patients with cholesteatoma had a higher
prevalence of IgE-mediated hypersensitivity than patients without that condition.” The
researchers concluded that “allergy might contribute to chronic otitis media especially
in cases with a cholesteatoma.”59
One of the unique features of the middle ear response in OME is the involvement of
neutrophils. Most atopic patients have increased levels of MPO in addition to ECP in
their ear effusion, even though there is no evidence of acute inflammation.24 Paired
samples confirm that in an acutely infected ear, purulent otitis is associated with
a significant elevation of both mediators, but with a disproportionately greater eleva-
tion of MPO in the infected side when compared with the nonpurulent ear.60 Yet even
in the nonpurulent ear, the levels of MPO were much higher in atopic patients than in
nonatopic patients. The inflammatory response to putative inciting agents such as
bacterial and viral products may be amplified in atopy, perhaps via IL-8. Another
explanation for the increased MPO level reported in nonpurulent MEE is that an
increase in neutrophils may occur as a result of weak stimulation of these cells
because bacteria are being cleared from the site of inflammation.61 Bacterial
messenger RNA (mRNA) present in otherwise sterile MEE may serve as a stimulus
to T-cell activation.62 Regardless of whether the relationship between allergy and
OME is direct or indirect, marked elevation of effusion MPO levels in atopic patients,
but very low levels in nonatopic patients, suggests that atopy may contribute to
elevated levels of neutrophil activity in OME to a disproportionate degree among
atopic patients.60
Neutrophils are reported in IgE-mediated late phase reactions in the nose and
skin.63 Thus the presence of neutrophils in MEE is not necessarily an argument against
OME being an allergic disease. Atopy contributes to the elevated levels of MPO by
causing the atopic child to respond differently to the products of acute inflammation
because of its primed inflammatory cells. This is demonstrated most vividly in the
classroom struck by a viral upper respiratory tract infection. Whereas most normal
children only experience a cold, their atopic classmates frequently go on to trigger
asthma attacks requiring nebulizer treatments.
The destructive potential of these mediators in effusion is often overlooked, as is
hearing loss, yet serves as a further justification for the removal of this fluid at the
time of myringotomy and for prevention of its reoccurrence by appropriate surgical
and allergy management. Allergy testing is frequently recommended in children
644 Hurst

requiring a second set of tubes, in order that this common predisposing factor for
OME can be addressed.

ET DYSFUNCTION

ET dysfunction (ETD), either extrinsic or intrinsic, is regarded as the underlying path-

ophysiologic event that leads to most cases of chronic middle ear disease. Causes of
ETD include ciliary dysmotility, nasopharynx carcinoma, cleft palate, gastroesopha-
geal reflux,64 and adenoid hypertrophy, but these causes only account for a minority
of patients. Allergy and reflux are the best explanations for the intermittent nature of
ETD. Bluestone65 outlined 4 hypothetical mechanisms by which allergy could be
responsible for ETD leading to the production of OME. These mechanisms included
(1) the middle ear functioning directly as a shock organ, (2) ETD due to intrinsic
mechanical obstruction from inflammatory swelling of the ET itself, (3) inflammatory
obstruction of the nose, or (4) aspiration of bacteria-laden allergic secretions from
the nasopharynx into the middle ear. As hypothesized, these explanations have all
been documented to occur at times because of allergy.
Obstruction of the ET in humans has been clearly demonstrated to result from
antigen challenge.66 The ET has been shown to be involved functionally and morpho-
logically in type I reactions of the nose.67 In a double-blind protocol, Friedman and
colleagues68 demonstrated that intranasal pollen challenge of atopic individuals
produced allergic rhinitis followed by ET obstruction, which did not occur with the
placebo. The allergic reaction inhibited even transient dilations of the ET during swal-
lowing. Several other double-blind protocols with intranasal allergen or histamine
challenge produced similar severe functional obstruction of the ET.69 All these results
confirm the hypothesis that the ET may become dysfunctional due to allergic inflam-
mation causing intrinsic mucosal edema and obstruction. Skoner and colleagues32 in
their review state, “much of the research into OM pathophysiology has indicated that
there is a pivotal role for allergen-induced dysfunction of the Eustachian tube.
Allergen-induced blockage subverts the normal mechanism of gas exchange between
the middle ear and the environment, thus setting the stage for development of middle
ear underpressured OME.”
The most frequently cited objection of past decades to the allergy hypothesis is that
an allergen is unlikely to get into the middle ear itself because of the structural gate-
keeper function of the ET.70 Possible mechanisms of immune response in the ear
have been proposed. Secretory immunity does not rely on the premise of direct
allergen transport to the middle ear, but rather depends on the newer understanding
of both humoral and cell-mediated immunology. These concepts are best explained in
the section “Unified Airway.”
Evidence-based medicine has dispelled previously held assumptions. It has been
shown that “there are no substantial differences in ET function between ears that
develop OME recurrence and ears that do not.”71 It is also a commonly held myth
that the ET will grow to normal size as children mature despite evidence that there
is no difference in the size of either the isthmus or the pharyngeal portion of the ET
in children with OME versus normals.72 Sade and colleagues72 showed that the ET
of patients with OM does not have an “immature morphology.” Parents are also falsely
told that their otitis-prone children cannot equalize the pressure in their middle ears,
yet the fact is that there is no organic obstruction or stenosis of the ET in patients
with OME. Only 11% of patients with active OME have abnormally high opening
pressures.73 Finally, there is the myth of antibiotics. Rosenfeld and Bluestone74
have shown that a meta-analysis of all treatment studies demonstrate antibiotics to
 The Role of Allergy in Otitis Media with Effusion 645

be no better than placebo in treating chronic OME. Chronic OME is usually not an
infection.

UNIFIED AIRWAY

The middle ear is not a privileged site devoid of immune response mechanisms as was
taught in the 1960s. Middle ear mucosa, which evolves from the same ectoderm as the
rest of the upper respiratory tract epithelium, has been found in animal studies to have
the same active intrinsic immunologic responsiveness to antigenic stimulus as do the
nasal tract, sinuses, and bronchi.62 It is now recognized that human nasal airway
mucosa is the focus of absorption of allergens as well as microorganisms that activate
the mucosal defense systems. Secretory immunity is the best-defined effector mech-
anism of antigen presentation and stimulation of the immune system in humans and is
elegantly described by Jahnsen and Brandtzaeg.75
Since 2000, both the European Academy of Allergy and Clinical Immunology and the
American Allergy Academy of Allergy Asthma and Immunology have come to view the
upper respiratory tract as a unified airway system. The underlying concept is that
allergy can affect different target organs at different ages. So, just as most asthmas
are hyper reactive diseases of the airway mucosa, all allergic diseases, including
OME, are hyper reactive mucosal diseases regardless of the location of the mucous
membrane within the respiratory tract. This concept is developed in detail by
Krouse.76 Extrapolating from the landmark study by Braunstahl and colleagues77 in
which nonasthmatic patients with allergic rhinitis were administered nasal provocation
with pollen, he demonstrated eosinophilic infiltration in the lungs, through bronchial
washings, even though the lungs were never stimulated with antigen. He concluded
that the upper respiratory tract responded as one unified airway.
Similarly, Hamid and colleague78 simultaneously took biopsies from the middle ear
mucosa and the nasopharyngeal mucosa just next to the ET orifice. He measured
eosinophils, CD3 T cells, IL-4 levels, and mRNA levels for IL-5 and found them all to
be elevated at both ends of the ET. He concluded that the middle ear may behave
in a “similar manner to the lungs under allergic inflammatory insults” and that the
“middle ear may be included in the united airways.”

OM: AN ALLERGIC DISEASE

Because asthma is heterogeneous, some forms are categorized predominantly with

a non–IgE-mediated eosinophilic histotype. Current medical therapy for asthma now
relies on antileukotrienes and steroid inhalers as agents to downregulate the eosino-
phil mediators and activation. Exactly the same cells and chemical mediators found in
the lung and sinuses in allergic disease are also found in the middle ear.
Proof of the hypothesis that chronic OME is an allergic disease requires the
following 4 steps.
The first is to establish a relevant, associated, objective diagnosis of atopy in
patients with persistent effusion or middle ear drainage. The low sensitivity of conven-
tional prick or radioallergosorbent testing hampers the diagnosis of this low-level IgE-
mediated disease.26,79 As mentioned, investigators using objective intradermal testing
demonstrate that 72% to 100% of children with OME are atopic (Table 1).
The second step is to establish an association of allergic TH2 immune-mediated
histochemical reactivity within the target organ itself. The concept that active immuno-
logic processes may be a localized phenomena in the middle ear has been established
in animal models57 as well as in humans. Lymphocytes necessary for antibody
production are recruited nonspecifically into the mucosa in OM. T lymphocytes are
646 Hurst

Table 1
Studies of patients with OME with allergy confirmed by skin testing

Number with % Improved with

References Positive Skin Test % of Positive Tests Allergy Therapy
Dohlman,80 1943 178 56% —
Mao,81 1942 252 29% of pathologically —
deaf children
2% of normal
children
Jordan,82 1949 123 74% 98%
Solow,83 1958 50 72% —
Lecks,84 1961 82 88% —
Fernandez and 113 55% 95%
McGovern,12 1965
Whitcomb,85 1965 38 100% 87%
Draper,86 1967 340 53% 91%
Hall and Lukat,87 1981 92 100% 82%
McMahan et al,88,a 1981 119 93% 86%
Sanz et al,89,a 1986 20 30% —
Tomonaga et al,22 1988 259 72% of OME cases
Hurst,90,b 1990 20 100% 100%
Becker et al,91 1991 35 34% SPT
Nsouli et al,92,a 1994 104 78% 86%
Corey et al,93,a 1994 89 61% —
Hurst,9 1996 73 87% —
Psifidis et al,94 1998 148 59% 78%
Doner et al,39 2004 22 38% SPT
Lasisi et al,95 2008 80 80% SPT
Hurst,26,b 2008 89 100% 89% of OME resolve
0% of controls
a
In vitro testing.
b
Patients not included in previous study.
Data from Hurst DS. The middle ear: the inflammatory response in children with otitis media
with effusion and the impact of atopy. Clinical and histochemical studies. In: Comprehensive
Summaries of Uppsala Dissertations from the Faculty of Medicine, Dept of Immunology and Clinical
Chemistry #978. Uppsala (Sweden): Uppsala University Sweden; 2000. p. 14; as modified in Hurst
DS. Freedom from Chronic Ear Infections: The Role of Allergies and the Way to a Cure. Portsmouth,
NH: Back Channel Press; 2011. p. 130; with permission.

common in serous or mucoid effusions.96 IL-5 is produced predominately by stimu-

lated TH2 and not TH1 cells (see Fig. 2),97 and its levels are increased during the
late phase reaction of chronic middle ear disease.98 IL-5 mRNA in middle ear mucosa
biopsies provides strong evidence that the middle ear is actively participating in a TH2
response.99
Proof of a relation of allergy to asthma or sinus disease required researchers to
demonstrate tryptase from mast cells and, more importantly, ECP or MBP from eosin-
ophils in the lung and sinuses. Similarly, studies in China, Japan, the United States,
Canada, and Sweden have demonstrated that all the mediators required for a TH2
inflammatory response, including ECP, tryptase, and/or IL-5 mRNA cells, CD31T
 The Role of Allergy in Otitis Media with Effusion 647

cells,99 eosinophils,100 mast cells,101 Rantes,102 prostaglandins,78 and specific IgE for
foods and inhalants103 are present in most ears with chronic effusion. Antitryptase
antibody (AA1) staining101 has shown that mast cells are present in the mucosa and
submucosa in atopic patients and not in controls. Lasisi and colleagues103 studied
the secretion of IgE in the middle ear of patients with CSOM and controls. They found
that “allergy appears to play a contributory role in CSOM and elevated IgE in the
middle ear secretions suggests a likely mucosal response.”103 Furthermore, they
found that a positive skin reaction in 80% of patients with CSOM suggested
a “substantial potentiating role of allergy in SOM.”
The third step needed to prove that the middle ear behaves as a target organ of
allergy is to demonstrate that the inflammation within the middle ear is truly allergic
in nature, and not merely coincidental. This demonstration requires an examination
of the epidemiologic mechanisms and treatment studies for patients with chronic
OME. These studies were reviewed earlier under the section “Etiology.”
Direct demonstration of serum and middle ear immunoglobulins being associated
with a TH2 response in the middle ear itself has been provided by Hamid,78 Lasisi
and colleagues,103 and Hurst and colleagues.104 The evidence is conclusive enough
for the 2004 guidelines published by the academies of Pediatrics, Family Practice,
and Otolaryngology-Head and Neck Surgery to conclude that the middle ear epithe-
lium of atopic patients has all the components required to behave in a manner similar
to that of the rest of the upper respiratory system, and that “like other parts of respi-
ratory mucosa, the mucosa lining the middle ear cleft is capable of an allergic
response.”105 Roland’s review106 surmised that significant data supports “the concept
that chronic OME in atopic patients represents a local Th2 allergy response.”
The fourth and final step needed to prove the hypothesis of an allergy connection
requires direct evidence of a dose-response curve and consistency of results. A
call for treatment studies has been made every 4 years at the International
Symposia on Middle Ear Disease as well as by the Committee on Guidelines which
states, “no recommendation is made regarding allergy management.based on
insufficient evidence of therapeutic efficacy or causal relationship between allergy
and OME.”105

EFFICACY OF IMMUNOTHERAPY FOR OME

Sporadic reports of therapeutic efficacy of IT for OME have lacked documented

controls until recently. In a study of 89 patients aged 4 to 70 years with intractable
middle ear disease who presented with chronic effusion or chronic draining perfora-
tions or tubes all proved to be atopic by intradermal skin testing. All were offered
allergy IT based on the results of their intradermal testing. A total of 21 individuals
self-selected to be a “control cohort” by choosing not to proceed with IT for a variety
of reasons. Specific allergy IT completely resolved 85% of 127 diseased ears and
significantly improved an additional 5.5%. The condition in all children younger than
15 years and most adults resolved within 4 months and they remained free of disease
while on allergy IT for 2 to 8 years of follow-up. None of the controls’ 39 ears resolved
spontaneously (P<.001). The average patient with OME proved to be sensitive to 9
allergens (range 4–15). This study documented that in a select population, antiallergy
therapy is efficacious in preventing or limiting the duration of OME while comparing
treatment patients to a control cohort.26 These findings are in keeping with other
studies (see Table 1) that although lacking a control group, have demonstrated that
when a patient’s allergies are properly treated with IT and/or diet elimination, the effu-
sion resolves in most patients.
648 Hurst

Because chronic otitis has been shown to be a low-level IgE-mediated disease

similar to allergic rhinitis, with two-thirds of patients with OME having a serum IgE level
less than 100 mg/L (mean 93.8 mg/L),24 intradermal testing was chosen for its greater
sensitivity and reproducibility as the test for atopy. IT was chosen to treat the underlying
allergy because it has been shown to have a long-lasting effect on T lymphocytes, it
acts in the earliest stages of immunologic response, and it can revert an atopic patient
from a TH2 response back to being a normal TH1 responder.107 This has been docu-
mented in cases of asthma, allergic sinusitis, and, now, clinically in chronic OME.78
This cohort study demonstrated conclusively that almost all patients with OME were
atopic. Eighty-seven percent of patients with chronic middle ear fluid who presented
with draining tubes, draining perforations, or a history of OME showed resolution of the
disease and stayed free of disease from 1 to 8 years follow-up on allergy IT, whereas
none of the controls had disease resolution spontaneously. Direct proof that allergy
contributes to chronic OME and/or other manifestations of chronic middle ear disease
is best given by a randomized, double-blind placebo-controlled trial. None have been
published.
Not all OMEs are the result of allergy. What makes the middle ear mucosa the target
organ of some allergies and the lung, sinuses, or skin the target of others is unknown.
Allergy seems to play a role in more than 85% of those adults or children who present
with chronic OME.
Several reviewers suggest that otolaryngologists consider the possible use of allergy
treatment for chronic middle ear disease. Lieberman and Blaiss108 conclude that “in
patients with OME in which allergy may be a contributing factor, appropriate allergy
treatment of avoidance of particular allergens, medications, and immunotherapy
may be indicated.” The review by Tewfik and Mazer5 suggests that it may be prudent
to screen every child with OME for allergic rhinitis and, ultimately, to manage those with
allergic inflammation differently than nonatopic individuals with OME.

SUMMARY

Current medical evidence supports the link between allergy and OME. The application
of newly gained knowledge of inflammation provided by modern immunology and
cellular biology gleaned from the study of chronic mucosal inflammatory diseases of
the unified airway helps us to understand the pathophysiology underlying chronic
middle ear disease. Histologic, epidemiologic, and clinical studies based on objective
allergy testing have thus far achieved the following:
1. Established that most patients with OME (see Table 1) are atopic
2. Demonstrated that all the mediators necessary for a TH2 allergic response are
present in the middle ear
3. Provided medical evidence to support the conclusion that “the middle ear (mucosa)
is capable of an allergic response”105
4. Shown using intradermal testing that patients with OME are almost universally
atopic and that their chronic middle ear disease does resolve with IT in more
than 85% of cases when compared with 0% of a control cohort (P<.001).26

Review of recent medical evidence supports the hypothesis that chronic OME is an
allergic disease. It raises a call for further studies to confirm that treatment using
immunotherapy, an established conventional modality recognized to be effective in
treating and reversing allergic rhinitis and asthma, is worth considering for the treat-
ment of the otherwise frequently intractable middle ear disease.
 The Role of Allergy in Otitis Media with Effusion 649

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