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The Impact of Atopy on Neutrophil Activity in Middle Ear Effusion From Children and Adults With Chronic Otitis Media
David S. Hurst, MD, PhD;
Per Venge, MD, PhD
Arch Otolaryngol Head Neck Surg. 2002;128:561-566.
ABSTRACT
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Objective To identify the relationship of neutrophil activity to allergy as reflected
by the level of myeloperoxidase (MPO) in ears of atopic patients with chronic
otitis media with effusion (OME) by objective testing.
Design Evidence of neutrophils was measured in the effusion of atopic patients
with chronic OME. Atopy was determined by intradermal and/or in vitro testing
of allergic reaction to 10 inhalants, 2 molds, and 5 foods.
Subjects Effusion MPO was measured prospectively in 138 ears from 106 consecutive
patients with chronic OME.
Results A total of 86 (81%) of 106 patients with OME tested atopic by in vitro
or in vivo testing. Excluding 36 ears with purulence, the mean MPO level was
3132 µg/L in 84 atopic vs 142 µg/L in 18 nonatopic ears (P<.001). A total of 78 (90%) of 87 patients with OME
were atopic.
Conclusions The surprising finding of marked elevation of effusion MPO in atopic
patients but very low levels in nonatopic patients (P<.001)
suggests that atopy may contribute to elevated levels of neutrophil activity
in OME. An atopic patient may respond differently from a nonatopic one to
the microbial or viral products of acute inflammation owing to the presence
of primed inflammatory cells. This study provides confirmation on a cellular
level that neutrophils are an integral part of the inflammatory process in
OME to a disproportionate degree among atopic patients.
INTRODUCTION
IDENTIFICATION OF the factors responsible for the chronic nature of
otitis media is an essential step in developing treatment and ultimate prevention
strategies for this disease. Histopathologic studies have demonstrated that
neutrophils and eosinophils are integral components in middle ear infiltrates.1
A role for the neutrophil in the allergen-induced inflammatory process
seems counterintuitive because the presence of neutrophils, unlike that of
eosinophils, is not normally associated with an atopic helper T–cell
(TH) 2 inflammatory response. The predominance of neutrophils in
middle ear effusion(MEE) thus serves as a major refutation of the hypothesis
that allergy might be a significant contributing factor to the pathogenesis
of otitis media with effusion (OME) and supports the theory that chronic otitis
is predominantly a response to infection. However, it is disturbing to recognize
that after 25 years of working under the "infection hypothesis," evidence-based
medicine confirms that otitis media resolves within 2 months of initial infection
in 70% of children regardless of antibiotic treatment.2
Among those 30% of children in whom it progresses to chronic OME, more than
85% have been proven atopic by objective testing.3-4
The objectives of this study were (1) to investigate the relationship of neutrophil
activity to allergy, as reflected by the levels of myeloperoxidase (MPO) in
ears with OME, and (2) to determine if there is a difference in the inflammatory
response in an OME ear in atopic vs nonatopic patients, as determined by objective
in vitro or in vivo testing.
SUBJECTS AND METHODS
EFFUSION SUBJECTS
To characterize the relationship of the neutrophil response to allergy
or infection in OME, we measured MPO levels in effusion from 106 individuals
who presented with refractory effusion to a solo-practitioner, community-based
otolaryngologist. Fifty-one young children (aged 14 months to 6 years), 36
children of school age (6-18 years), and 19 adults were selected in a consecutive,
prospective manner. None was immunodeficient or exhibited congenital malformations.
All had documented hearing loss, flat tympanograms, and effusion of a minimum
of 3 months' duration that was unresponsive to antibiotic and/or decongestant
therapy. Middle ear effusions were collected at the time the patients underwent
routine myringotomy and placement of tympanostomy tubes (M&T). The patients
were tested for allergy only after they were entered into the study to avoid
preselection bias. The study proceeded following approval of the Franklin
Memorial Hospital (Farmington, Me) Committee on Ethics and Human Experimentation
and patient or parental consent.
The effusion from 138 ears, including 32 pairs, was collected quantitatively
in a Juhn Tym-Tap (Xomed, Jacksonville, Fla) and diluted with precisely 2
mL of isotonic sodium chloride solution. Supernatants of diluted, centrifuged
specimens were pipetted, stored at -20°C, and later tested for MPO.
Variation in the volume of middle ear fluid was previously considered by measuring
14 samples containing lithium chloride. Effusion volumes collected by our
method were quite similar, ranging from 0.11 to 0.43 mL (mean ± 2 SDs,
0.32 ± 0.11 mL).5 That analysis demonstrated
that any statistically significant differences observed between group means
were unlikely to be explained by variation of volumes and dilution of MEE
alone.
Some patients designated as having OME had also experienced a superimposed
acute ear infection within 2 weeks prior to their M&T. These patients
represent a mixed, purulent type of otitis (PUR). Any patient with pus in
his or her effusion, or even a hyperemic tympanic membrane at the time of
myringotomy, was included in this PUR group and evaluated separately. Ears
that typified episodes of recurrent acute otitis media that quickly resolved
between infections were excluded from the study. Among the 97 diseased patients
were several children with no known antecedent infections who presented after
failing a school hearing test. Typical patient histories and allergens have
been described previously.5 The results were
sorted by patient type (ie, atopic vs nonatopic) as well as by MPO, total
serum IgE, and age (Table 1 and Table 2).
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Table 1. Demographics and Myeloperoxidase (MPO) Levels in Nonatopic
and Atopic Patients With Various Mediator Levels*
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Table 2. Mediator Levels Found in Study Subjects*
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DIAGNOSIS OF ATOPY
After undergoing M&T, all patients in both groups were evaluated
for allergies by in vitro and/or in vivo testing for specific IgE with a battery
of 15 allergens (dust mites der P and der F, cat, dog, Timothy grass, short
ragweed, birch, oak, Alternaria, Hormodendrum, milk, wheat, corn, soy, and egg). Patients were categorized
as atopic if they reacted positively to at least 2 antigens at a modified
radioallergosorbent test (RAST) class 2 or higher by either testing method.
This definition resulted in an intentional bias to exclude borderline atopic
patients.
In vitro testing used either RAST (Immuno-CAP; Pharmacia-Upjohn, Uppsala,
Sweden) or Thabest (Integrative Medicine Inc, Denville, NJ) IgE micro–enzyme-linked
immunosorbent assay (micro-ELISA) testing of serum. Intradermal skin testing
for the same battery of 10 inhalants, 2 molds, and 5 foods was performed by
injection of an allergenic extract in volumes of 0.01 mL to produce a 4-mm
wheal. The skin tests were performed with 1:500 wt/vol or serial 5-fold weaker
dilutions of the allergenic extracts. Results were considered positive when
a wheal diameter of 7 mm or larger was observed that was at least 2 mm larger
than the wheal from a glycerin control of the same dilution strength after
10 minutes.
IN VITRO TESTING
Serum RAST or micro-ELISA testing was performed for specific serum IgE
in all patients. Atopy was determined without knowledge of the mediator results
so as to have a single-blind study.
TITRATION OF MEDIATORS IN EFFUSION
Myeloperoxidase levels were measured by a double antibody radioimmunoassay
(Pharmacia-Upjohn Diagnostic AB, Uppsala, Sweden) according to the instructions
of the manufacturer. The MPO interassay coefficient of variation varied between
6% and 10%, and levels under 8 µg/L were undetectable. The stability
of MPO in middle ear fluid was verified by incubating a known amount of MPO
(8-1000 µg/L) into 1 of the ear samples for 1 hour. This was then assayed
for the protein. The mean ± 2 SDs recovery rate for MPO was 102.9%
± 5.3% (n = 7). Effusion mediator levels were considered abnormally
elevated if the MPO level was greater than 407 µg/L (ie, the nonatopic
mean + 2 SDs). Initially, MPO levels were measured using radioimmunoassay
technique at a research facility in Sweden.
STATISTICAL ANALYSIS
Statistical analyses were carried out by means of nonparametric tests.
The Mann-Whitney U test with the Bonferroni correction
was used to compare the different groups (atopic vs nonatopic). Results are
given as mean ± SEM. Statistical calculations were performed using
the InStat statistical package (GraphPad Software Inc, San Diego, Calif) with
a Power Mac 7200 personal computer (Apple Computer Inc, Cupertino, Calif).
RESULTS
The demographic characteristics regarding age distribution and atopic
status are given in Table 1. Eighty-five
of the 106 patients were classified as having only refractory, nonacute OME;
15 patients had signs of a recent infection (PUR); and 6 more presented with
1 PUR and 1 non-PUR ear.
ATOPIC STATUS
A total of 86 (81%) of 106 patients with OME were atopic by in vitro
or in vivo testing. Among the 19 adults the prevalence of atopy at 42% (8/19)
was higher than that found in the general population. Among the children,
78 (90%) of 87 were atopic (Table 1). Evaluation of the type and number of antigens to which atopic patients had
a positive intratermal skin testing reaction and/or had in vitro analyses
that elicited a class 2 or higher response revealed that for inhalants, 37
(42%) reacted to 2 to 5 antigens, and 34 (39%) had antibodies to 6 or more.
Additionally, 61 (70%) reacted at class 2 or higher to both molds, 5 (6%)
to just 1, and 44 (51%) had significant reactions to foods. Thirty-two children
(37%) demonstrated antibodies to 1 or 2 foods and 12 (14%) to 3 to 5 foods.
Retrospective review of the 54 charts, including written inquiry to the referring
physician, revealed that 33 (61%) of the 54 children had documentation of
additional atopic signs and symptoms including asthma (n = 12; 22%), allergic
rhinitis (n = 26; 48%), eczema (n = 2; 4%), and chronic nasal congestion (n
= 4; 7%). Otitis media with effusion was the sole symptom of allergy in 18
children (33%).
MEDIATOR LEVELS IN EFFUSIONS
The inflammatory response by neutrophils in the middle ear of atopic
patients was distinctly different than it was in nonatopic patients (Figure 1). The mean MPO level in atopic patients
was 3132 µg/L vs 142 µg/L in nonatopic patients (P<.001). The highest levels of MPO (mean, 15 140 µg/L)
were found in PUR ears at the time of myringotomy. Among non-PUR ears, the
mean MPO level of atopic patients was 22 times higher than that of nonatopic
subjects (Figure 1, Table 2).
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Figure 1. A scatterplot comparison of myeloperoxidase
(MPO) levels found in ears of atopic and nonatopic subjects. The horizontal
line represents the mean + 2 SDs MPO level of nonatopic subjects (400 µg/L).
PUR indicates a patient who experienced a superimposed acute ear infection
within 2 weeks prior to the routine myringotomy and placement of tympanostomy
tubes. P<.001 for the difference in MPO levels
between atopic and nonatopic subjects.
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Most atopic patients had a serum IgE level lower than 100 µg/L.
Total IgE levels did not differ between atopic (mean, 91.6 µg/L) and
nonatopic subjects (mean, 44.7 µg/L; P = .74)
(Table 2).
COMMENT
Our data indicate a unique response by neutrophils in the middle ear
of atopic vs nonatopic subjects. In humans, the influx of neutrophils correlates
with levels of interleukin (IL) 8. Many investigators have described IL-8
in middle ear fluid,1 but the implications
of this occurence, especially as might relate to our findings, has not been
appreciated. Interleukin 8 controls initiation and maintenance of the inflammatory
process in various tissues and acts as a chemotactic cytokine for neutrophils
and primed eosinophils.6 Significant sources
of IL-8 include endothelial cells, fibroblasts, macrophages, epithelial cells,
and primed eosinophils.7-8 Neutrophils
and eosinophils express IL-8 messenger RNA7
and serve as a source of other cytokines into the site of inflammation. Interleukin
8 affects neutrophils by inducing activation of the motile apparatus, directional
migration, expression of surface adhesion molecules, and production of reactive
oxygen metabolites and by causing the release of storage enzymes,9 including MPO. In allergic bronchial asthma and dermatitis,
IL-8 is a chemoattractant for T lymphocytes and basophils and induces histamine
release from primed basophils.8 An increase
in IL-8 secretion is associated with the nasal allergic reaction after allergen
challenge in atopic patients but not controls.6
Thus, IL-8 activity is amplified in the allergic response (Figure 2) and may explain the elevation of neutrophils we recorded
in the ears of atopic patients.
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Figure 2. A graphic representation of current
concepts of T-, B-, and antigen-presenting cell (APC) interrelationships,
with emphasis on neutrophil (Neut) chemotaxis under the influence of interleukin
(IL) 8 expressed by macrophages, injured epithelium, and sensitized eosinophils.
Bacterial antigen-induced (TH1) and allergen-induced (TH2)
reactions lead to the release of cell mediators tryptase, eosinophil cationic
protein (ECP), and myeloperoxidase (MPO). APCs include macrophages (Mac),
B cells, and dendritic cells. IFN- indicates interferon gamma; MHC,
major histocompatibility complex; TH, helper T cell; and TCR, T-cell
antigen receptor.
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Neutrophil involvement is not unknown in other allergic diseases. A
difference in neutrophil response has been reported among atopic vs nonatopic
humans in allergic asthma, rhinitis, and atopic dermatitis. Neutrophil inflammation
contributes to the pathophysiology of asthma under natural allergen exposure.10 The late asthmatic response in animal models is dependent
on neutrophil availability and neutrophil chemotactic factor. Styrt et al11 found that "the neutrophil from atopics may be both
easier to stimulate and more difficult to suppress than cells from normals."
In mice, neutrophils are recruited to the lung early after allergen challenge,
whereas eosinophil recruitment occurs at a later time.12
Interleukin 8 also contributes to selective eosinophil recruitment in
allergic inflammatory responses in vivo.8 The
eosinophil, an important cell in the late-phase allergic reaction, is both
an effector and a responder and has been found in high concentrations in the
MEE of atopic patients.5 Only sensitized eosinophils
from atopic patients with asthma seem to respond to IL-8, which has been shown
to induce eosinophil migration in a dose-dependent manner in pollen-allergic
blood donors but not in nonatopic subjects.7, 13
In the middle ear, IL-8 may be responsible for prolongation of the inflammatory
process, as its concentration in chronic mucoid OME is reportedly 5 times
that found in acute purulent otitis.14 The
closed middle ear space seems to act like a trap for IL-8, unlike the lung
where the cytokine is not concentrated. Maxwell et al1
hypothesized that "IL-8 is crucial in the leukocyte response in the middle
ear and is pivotal in the maintenance of inflammation in chronic OME." The
total number and percentage of neutrophils in MEE correlate with the concentration
of IL-8 in MEE.15 Interleukin 8 is present
in MEE from children and adults9 with no difference
reported among mucoid, seromucinous, or serous effusions.1
The presence of IL-8 is strongly correlated with levels of IL-1b and tumor
necrosis factor  , both known inducers of IL-8 production.
One hypothesis offered to explain the observed levels of MPO in MEE
of allergic patients at 22 times that of the levels in nonatopic subjects
(Figure 1) is that OME is a disease
merely associated with atopy. The inflammatory cells in the middle ear of
atopic subjects in general are more responsive and produce more cytokines,
etc, as is seen in allergic asthma, rhinitis, and dermatitis.6, 13
Why this should be remains to be determined.
Regardless of a patient's atopic status, antigens retained in MEE after
an acute infection are responsible for activating T cells and subsequent cytokine
production,16 particularly IL-1b, IL-2, IL-6,
tumor necrosis factor , interferon , and IL-8.9
Interleukin 8 induces a rapid influx of polymorpholeukocytes into the middle
ear, but the inflammation is not sustained, suggesting that the effect is
temporary unless continued IL-8 expression is present. Persistent reactivity
in atopic subjects with resulting high levels of MPO might result from the
high concentration of eosinophils in atopic ears,5
as IL-8 is constitutively expressed by human resting eosinophils.7 The eosinophil is not only an effector cell but also
takes part actively in a cytokine network and in regulating the immune response.
Most important, it seems that only eosinophils from symptomatic, pollen-allergic
patients with asthma, not those from nonallergic subjects, respond to IL-8.13 Eosinophils from patients with symptomatic seasonal
rhinitis migrate toward IL-8 in a dose-dependent fashion also.13
Interleukin 5, a specific activator for eosinophils with no effect on neutrophils
or monocytes, seems to act as a cofactor in initiating or enhancing the eosinophil
response to other chemotactic factors, including IL-8.13
Interleukin 5 has recently been demonstrated to be present in the mucosa of
patients with chronic OME.17
An alternative hypothesis is that OME is due to a true allergic response
in which the middle ear, like the nose and lung, participates in a type 1,
TH2 immune–mediated allergic reaction. If the middle ear
were to participate in a true allergic response, one would then expect to
find the results we report: namely, that mediators from eosinophils and mast
cells, capable of epithelial damage, might lead to increased IL-8 release
and the attraction of neutrophils uniquely among atopic patients. The middle
ear mucosus is similar to that of the rest of the upper respiratory tract
and is capable itself of an allergic response.18
Effusion and mucosal biopsy studies demonstrate that many of the mediators
and cells essential to the production of a TH2 immune–mediated
response, including eosinophil cationic protein, tryptase and/or IL-5 messenger
RNA cells, CD3+ T cells,17 eosinophils,5 and mast cells18-19
are all present in ears with chronic OME. Indeed, Labadie et al20
found in animal studies that allergen-sensitized and -challenged mice respond
by producing more middle ear fluids to a secondary stimulus than do nonsensitized
and unchallenged animals. They showed that allergen challenge per se did not
induce any fluid production, which is in agreement with others.21
The unique reactivity of atopic ears has also been documented in humans with
the demonstration of higher fluid levels of vascular cell adhesion molecule
1 than is found in nonatopic subjects.22 Messenger
RNA for IL-8 is actively produced in the cells found in MEE associated with
viral infections but is not found to arise from mucosal cells.23
Biopsy studies demonstrate a greater number of eosinophils and neutrophils
in the mucus than in the mucosa of ears of atopic patients with chronic OME
and a significant and similar ratio of neutrophils and eosinophils both in
the mucus and mucosa,24 indicating a proportional
influx by both cells into the middle ear of atopic patients.
The tendency of purulence in middle-ear disease to elevate neutrophil
mediators5 was expected and confirmed in children
and adults (Figure 1, Table 1). Because of the distortion of MPO levels by purulence,
data used to demonstrate a relationship of MPO levels to atopy excluded purulent
ears (Table 2).
Clinically, the diagnosis of type 1 hypersensitivity is based on the
detection of allergen-specific IgE by means of skin testing and/or in vitro
testing. In the present study, 86 (81%) of the 106 patients (78 [90%] of the
87 children) with chronic OME were deemed to be atopic by in vitro (n = 65),
in vivo (n = 41), or both (n = 22) testing types. With intradermal testing
as the standard, Thabest proved to have a greater sensitivity (92% vs 35%)
in detecting atopy than RAST in 23 patients for whom all 3 assay methods were
used. This was evident especially among those children whose total serum IgE
levels were lower than 30 µg/L.
Among nonpurulent ears, 66 (81%) of 81 atopic patients had MPO levels
that exceeded the mean + 2 SDs (407 µg/L) of nonatopic subjects (Table 2, Figure 1), indicating a very significant difference between the
groups (P<.001). Although MPO was present, its
levels were not elevated in all atopic patients, suggesting that an elevated
effusion MPO level reflects a local activation of neutrophils, not a general
systemic atopic response. Twenty-six patients with paired samples had different
MPO values in the opposing ears (eg, patient 16: 1480 µg/L in the right,
5604 µg/L in the left), which also suggests a local response.
Although our study is not an epidemologic study, it clearly shows that
OME is predominantly a disease of children (>90% of reported cases) and that
it presents differently among adults. Only 8 (42%) of the adults in the present
study were atopic vs 78 (90%) of the children. The populations differed. Most
adults were seen earlier, perhaps because they were able to self-refer. Twelve
of the 19 sought care after a single upper respiratory tract infection or
with eustachian tube dysfunction following an airplane ride. Neutrophil response
was significantly different between adults and children, whether atopic (980
µg/L vs 3296 µg/L) or nonatopic (64 µg/L vs 274 µg/L)
(P>.01). The response was generally less pronounced
among adults, which might reflect either a less chronic nature of the middle-ear
disease or a true muting by age of adult tissue inflammatory response (57%
of the adults were older than 50 years). Regardless, even after omitting the
adult ears, our observations are statistically unchanged.
Studies 20 years ago that led otolaryngologists to believe that fewer
than 30% of OME cases were related to allergy had been based on definitions
of atopy requiring both rhinitis and total serum IgE levels higher than 100
µg/L25 or results of skin-prick testing,
the sensitivity of which (43%26) is less than
chance. Our data show that the mean serum IgE level among atopic patients
was 91.6 µg/L, with 61 of 84 atopic patients with OME having a serum
IgE level lower than 100 µg/L (Table
2). Otitis is thus similar to rhinitis in having no relation to
total IgE, unlike asthma, which does show correlation.27
These results are in keeping with the high percentage of patients with OME
reported to be atopic in other studies (Tomonaga et al,3
72%; Nsouli et al,28 86%; and Hurst,4 87.5%) that used positive skin testing or RAST results
to define allergy. We believe this to be a reflection of increased sensitivity
and objectivity of modern RAST, ELISA, and intradermal skin testing methods,
not selection bias.
Our data support 2 observations that may be keys to understanding the
development of OME. First, there is some unique quality associated with being
atopic, as it is only atopic patients who have elevated levels of MPO (Figure 1) in addition to the expected TH2 mediators previously described.5, 17-18
This quality is most likely related to a patient's allergen sensitivity and
exposure to that allergen. This may help explain why it is that among those
children in day care with an acute otitis, it is predominantly the atopic
child who has a 3 to 5 times disproportionate tendency to develop chronic
OME.29-30
Second, elevated MPO levels in effusion suggests that the inflammatory
response in atopic ears is not restricted to those cells and mediators involved
in the classic TH2 allergic reaction in which neutrophils are usually
nonparticipants. These excessively increased levels of MPO in atopic patients
suggest that the general inflammatory response to putative inciting agents
such as bacterial and viral products may be amplified in atopy, perhaps via
IL-8. The allergic status of the host deserves as much attention as the virulence
of the infecting bacteria or virus and holds a key to successful management
of OME.28, 31
In conclusion, regardless of whether the relationship between allergy
and OME is direct or indirect, marked elevation of effusion MPO levels in
atopic patients (Figure 1) but very
low levels in nonatopic subjects (P<.001) suggests
that atopy may contribute to elevated levels of neutrophil activity in OME.
A total of 78 (90%) of the 87 children with OME were atopic. This study provides
confirmation on a cellular level that neutrophils are an integral part of
the inflammatory process in OME to a disproportionate degree among atopic
patients.
AUTHOR INFORMATION
Accepted for publication October 5, 2001.
This study was presented at the American Society of Pediatric Otolaryngology,
Scottsdale, Ariz, May 11, 2001.
We would like to thank Patty Welles, BS, for skin-testing the patients,
Melissa Weekley, MD, for technical review of the manuscript, and Kerstin Lindblad,
BS, for measuring myeloperoxidase levels.
Corresponding author and reprints: David S. Hurst, MD, PhD, 176 Livermore
Falls Rd, Farmington, ME 04938 (e-mail: meear{at}earthlink.net).
From the Laboratory for Inflammation Research, Department of Medical
Sciences, University Hospital, Uppsala University, Uppsala, Sweden (Dr Venge).
Dr Hurst is in private practice in Farmington, Me.
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