CHAPTER SIX
Pathogenesis
It is beyond doubt that sometimes in excessive swelling of the tubal mucous membrane and impermeability of the Eustachian tube there
occurs in consequence of the consecutive rarefaction of the air in the tympanum, a transudation of serous fluid.
—Adam Politzer (1835–1920)
Pathogenesis of middle-ear effusion owing to the
hydrops ex vacuo theory is now evidence-based from
studies in humans and animals.
As summarized in Chapter 1, “Introduction,” many factors have
been identified as being involved in the etiology and pathogenesis of middle-ear disease, other than dysfunction of the
Eustachian tube (see Figure 1–7). The most important of these
other factors would be host related, such as genetic predisposition, age, prematurity, gender, race, allergy, immunocompetence, and craniofacial abnormalities. Environmental factors are
also important, such as upper respiratory tract infection, season
of the year, attendance in child day care, number of siblings,
exposure to smoking, absence of breast-feeding, socioeconomic
status, and use of a pacifier (see Chapter 2, “Epidemiology”). In
this chapter, I discuss the role of the dysfunctional Eustachian
tube system in the pathogenesis of otitis media and certain related diseases and disorders. I proposed a few of these concepts
many years ago,1 but now we have studies in both humans and
animals to confirm some of the more common pathogenic
sequences of events leading to otitis media. The reader should
review my presentation of the pathophysiology of the
Eustachian tubes system in Chapter 5, “Pathophysiology,” to better understand the role of the tubal system in the pathogenesis
of disease presented in this chapter; I also included some discussion of pathogenesis in that chapter.
As detailed in Chapter 5, many abnormalities of the
Eustachian tube system can be attributed to the pathogenesis of
middle-ear disease, some of which do not necessarily have to
involve the existence of pathophysiology or pathology of the
Eustachian tube itself to be present. The most obvious example
of middle-ear infection that does not involve dysfunction of the
tube in its pathogenesis is when there is a traumatic perforation
of the tympanic membrane in an individual who has a
Eustachian tube that functions normally; despite normal tubal
function, the posterior, middle ear end of the system is open.
These patients frequently develop an attack of acute otitis
media, with otorrhea, at the onset of an upper respiratory tract
infection. Infected nasopharyngeal secretions can reflux
through the tube into the middle ear owing to the loss of the
middle ear–mastoid gas cushion. Also, these patients can insufflate nasopharyngeal secretions through a normal tube into the
middle ear by vigorously blowing the nose.
But, most commonly, Eustachian tube dysfunction is
involved in the pathogenesis of middle-ear disease. I describe in
detail the recent studies that have provided convincing evidence-based confirmation that the hydrops ex vacuo theory,
first advanced by Adam Politzer over 100 years ago,2 is the most
logical explanation for the development of middle-ear underpressures, which is the stage that precedes the most frequently
encountered types of middle-ear disease: acute otitis media and
otitis media with effusion. Clinical studies in adult volunteers
and experiments in animal models have shown that Eustachian
tube dysfunction is involved in the pathogenesis of middle-ear
underpressures, otitis media with effusion, and acute otitis
media. But first I provide an overview of the pathogenesis of
middle-ear disease related to the various abnormalities of the
Eustachian tube system as described in Chapter 5.
Overview of Pathogenesis Related to the
Pathophysiology of the Eustachian Tube System
As summarized in Chapter 5, the Eustachian tube system can be
either too closed or too open, or there is abnormal pressure at
either end. The most common result of a dysfunction of the system is development of middle-ear underpressures, which can
progress into middle-ear disease. But, as stated above, there are
circumstances in which negative middle-ear pressure is not
involved in the pathogenesis, such as when acute otitis media,
94 / Eustachian Tube: Structure, Function, Role in Otitis Media
with otorrhea, occurs when the tympanic membrane is not
intact, owing either to a perforation, a tympanostomy tube in
place, or when the patient has had a radical mastoidectomy. The
middle ear and mastoid can be infected by two major routes:
reflux of infected secretions from the nasopharynx or contamination of the middle-ear cleft from the external auditory canal,
most commonly from water in the ear canal. If the acute otitis
media does not resolve spontaneously or following treatment,
the acute disease can progress to chronic suppurative otitis
media, as I discuss in this chapter. But dysfunction of the
Eustachian tube system is most frequently the cause of underpressures developing in the middle ear, which can progress to
middle-ear disease.
Primary and Secondary Causes of Middle-Ear
Underpressure Owing to Dysfunctions of the
Eustachian Tube System
Dysfunction of the system may be a primary or a secondary
cause of middle-ear negative pressure. Abnormalities of the system that are a primary cause are due to either anatomic or functional obstruction of the tube or both. Anatomic obstruction is
most frequently caused by inflammation, which is most commonly viral in etiology. Evidence for viruses as the cause of tubal
dysfunction and middle-ear negative pressure has been demonstrated in studies that involved adult volunteers. However, as
described below, subjects who had preexisting tubal dysfunction
were at highest risk of developing middle-ear underpressures
after being challenged with a respiratory virus inoculated into
the nasal cavity. Development of underpressures in the middle
ear could be from any of the intrinsic or extrinsic anatomic conditions that are related to pathophysiology of the tube itself
(such as allergic inflammation); at either end of the tubal system, such as obstruction at the nasopharyngeal end, as might be
caused by adenoids or tumor; or at the middle ear end of the
system, such as cholesteatoma or polypoid granulation tissue.
Functional obstruction of the tube within its system can
also cause primary development of middle-ear negative pressure. The possible underlying causes of functional obstruction
of the tube are presented in Chapter 5 but include a floppy cartilage, dysfunction of the tensor veli palatini muscle, and constriction of the tube during swallowing.3 Functional obstruction
of the tube has been identified by our team4–7 and confirmed by
other investigators.8–10 A more dramatic and rapid example of a
primary cause of middle-ear negative pressure by functional (as
opposed to anatomic) obstruction is otitic barotrauma owing to
“locking” of the tube during descent in an airplane, scuba diving, and hyperbaric oxygen therapy; the sudden negative pressure at the middle ear end of the tubal system functionally
obstructs the tube. Patients who have preexisting dysfunction of
the Eustachian tubes are at highest risk.11 Functional tubal dysfunction can also be induced at the proximal end of the tubal
system and cause middle-ear negative pressure by either func-
tionally obstructing the tube at the nasopharynx (the Toynbee
phenomenon or in infants using a pacifier, thumb sucking, or
sucking on a nonventilated milk bottle) or by aspirating gas out
of the middle ear by sniffing.
A secondary cause of middle-ear underpressures would
not be primarily related to anatomic or functional obstruction
but secondarily to inflammation that occurs in the middle ear.
Because middle-ear inflammation can obstruct the osseous portion of the tube, preventing adequate pressure regulation of the
middle ear (anatomic obstruction at the middle ear end of the
system, which can impair the pressure regulatory and clearance
functions of the Eustachian tube), secretions are trapped in the
middle ear. From my description of the inverted flask in Chapter
5, as liquid flows down the narrow neck, negative pressure
develops in the bulbous portion of the flask. Negative middleear pressure has been identified in children who have otitis
media with effusion.12 The most likely cause of inflammation
occurring within the middle ear in this scenario is either from
reflux (the tube is too open, too short, or both) of nasopharyngeal secretions into the middle ear or by insufflation of secretions from the nasopharynx into the middle-ear cavity by nose
blowing or crying in infants or from the Toynbee phenomenon
(if positive pressure is transmitted to the middle ear). From
knowledge of fluid dynamics through a collapsible tube, liquid
flows more readily than gas. Thus, if positive pressure has been
identified in the middle ear during these events, nasopharyngeal
secretions are even more likely to be forced into the middle ear.
Middle Ear Negative Pressure Can Cause Otitis
Media with Effusion and Acute Otitis Media
The next step in the sequence of events leading to otitis media is
the development of middle-ear effusion owing to the presence
of underpressures in the middle ear; various mechanisms causing these pressures are discussed above. As postulated by
Politzer, middle-ear negative pressure can cause transudation of
fluid from the middle-ear mucosa into the cavity of the middle
ear. Since his time, subsequent observations and now studies in
humans and animals have provided evidence to support his
hydrops ex vacuo theory.2 Obviously not available to Politzer
100 years ago, development of barotitis is a now a well-known
complication of flying in an airplane (especially when the cabin
is not pressurized), scuba diving, and during hyperbaric oxygen
treatment in a pressure chamber.11,13–15 Another dramatic example of how middle-ear negative pressure can cause transudation
of an effusion was shown by Ingelstedt and colleagues in which
they aspirated the middle ear and mastoid with a syringe in aviators and produced middle-ear effusion.16
Even though these rapid alterations in pressures are
impressive examples of effusion developing in the middle-ear
cleft owing to the extreme and rapid onset of negative middleear pressure, they are not related to the pathogenesis of middleear disease in children and adults who have not been exposed to
Pathogenesis / 95
these conditions. Therefore, we must turn to the studies in
humans and animals described below. Also, the originally proposed classic ex vacuo theory does not explain if middle-ear
negative pressure is a stage prior to an attack of viral or bacterial acute otitis media. But as shown below, following intranasal
inoculation of a virus in an adult volunteer, Eustachian tube
obstruction occurred, followed by middle-ear negative underpressure and the subject developing an attack of acute viral and
bacterial otitis media.17 It is probable that the nasopharyngeal
pathogens were aspirated into the middle ear. Thus, development of negative pressure in the middle ear can be an
antecedent event for the pathogenesis of both otitis media with
effusion and acute otitis media. As stated above, acute otitis
media can be caused by other dysfunctions of the tube and
pathogenetic mechanisms, such as reflux or insufflation of
nasopharyngeal secretions into the middle ear, which do not
have to have underpressures in the middle ear to occur.
However, if negative middle-ear pressure is present, it will
enhance reflux and insufflation into the middle ear.
Viral Nasal Challenge Studies in Adult
Volunteers
Clinical studies of adult volunteers at our center have assessed
nasal and Eustachian tube functions and the status of the middle ear following intranasal challenge with viruses. These studies demonstrated the role that the Eustachian tube plays in the
pathogenesis of middle-ear underpressures, otitis media with
effusion, and acute otitis media and are summarized in
Table 6–1.17–23
In an early study, Doyle and colleagues determined the
effect of an upper respiratory tract infection (a cold) on
Eustachian tube function and the status of the middle ear after
intranasal challenge of rhinovirus in a group of 40 adult volunteers.18 After rhinovirus was inoculated into the nose, all subjects were found to be infected, but only 80% developed the
signs and symptoms of a clinical illness. Before and periodically after this nasal challenge, assessments were made of
Eustachian tube function (using sonotubometry and the ninestep test), middle-ear pressure (using tympanometry), and nasal
patency (using active posterior rhinometry). All subjects who
had a cold had decreased nasal patency, 50% had Eustachian
tube obstruction, and 30% had abnormal negative middle-ear
pressure for approximately 1 week after the inoculation. All outcomes completely resolved within 16 days, but none of the volunteers developed a middle-ear effusion.
In a subsequent study by McBride and colleagues that
employed similar methods and design as described in the abovecited study, 32 adult volunteers were recruited.19 After the challenge with rhinovirus, abnormal findings were limited to the 24
(75%) subjects who developed clinical signs and symptoms of
infection. After 2 days, 80% had Eustachian tube obstruction,
50% had high negative middle-ear pressure, and 46% had
decreased nasal patency. Again, none of the subjects developed a
middle-ear effusion. These abnormal findings resolved 6 to 10
days after the challenge.
A similar study by Buchman and colleagues evaluated 60
adult volunteers using a design and methods similar to the previous two studies.20 Figure 6–1 shows that after nasal inoculation with rhinovirus, 95% became infected and 60% had a clinical cold. Before the nasal challenge, three volunteers (5%) had
abnormal middle-ear pressure, and in two of these subjects, a
middle-ear effusion developed. Of the 60 subjects, 22 (39%) had
high negative middle-ear pressure. None of the subjects who
had normal middle-ear pressure before the challenge developed
an effusion, indicating that a rhinovirus infection may result in
a middle-ear effusion if the patient has a preexisting dysfunction of the Eustachian tube.
In still another study, but with a different respiratory
virus, Doyle and colleagues reported that intranasal challenge
with influenza A virus in 33 healthy adult volunteers resulted in
Table 6–1. Effect of Nasal Virus Challenge on Eustachian Tube and Middle-Ear Status in Human Volunteers
Outcomes, %
Experiment
Reference
1
2
3
4
5
6
7
Doyle et al, 198818
McBride et al, 198919
Buchman et al, 199420
Doyle et al, 199421
Buchman et al, 199517
Doyle et al, 200022
Buchman et al, 200223
Number of Subjects
Virus
ET OBS
HNP
MEE
AOM
40
32
60
33
27
18
32
Rhinovirus
Rhinovirus
Rhinovirus
Influenza A
Influenza A
Influenza A
Respiratory syncytial virus
50
80
NT
80
NT
Yes/no*
NT
30
50
39
80
59
Yes/no*
54
0
0
3
23
25
0
0
0
0
0
0
4
0
0
Adapted from Bluestone CD.78
AOM = acute otitis media; ET OBS = Eustachian tube obstruction; HNP = high negative pressure; MEE = middle-ear effusion; NT = not tested.
*Eustachian tube dysfunction and abnormal middle-ear pressures in individuals are more prevalent when the tube is found to have poor function prior to challenge (see text).
96 / Eustachian Tube: Structure, Function, Role in Otitis Media
80% demonstrating Eustachian tube obstruction and 80% having negative middle-ear pressure.21 However, with this virus, 5
(23%) of 21 infected subjects also developed a middle-ear effusion. Most likely, influenza A virus is more virulent than rhinovirus in the pathogenesis of Eustachian tube and middle-ear
abnormalities.
In a highly enlightening study, Buchman and colleagues
demonstrated the events leading to the development of not only
otitis media with effusion but, more importantly, an acute otitis
media that developed in one subject.17 Using a design similar to
the previous studies, they recruited 27 adult volunteers, in
whom influenza A was inoculated into the nose. Figure 6–2
shows that all subjects developed a nasal infection and 16 (59%)
subsequently developed high negative middle-ear pressure. In
one subject, acute otitis media was present. Using polymerase
chain reaction, a middle-ear aspirate revealed the virus and
Streptococcus pneumoniae; traditional viral and bacterial culture
methods failed to grow these organisms from the middle-ear
effusion. It is possible that these microorganisms were aspirated
from the nasopharynx into the middle-ear cavity owing to the
high negative middle-ear pressure.
FIGURE 6–1. Outcomes of an adult volunteer study following intranasal
inoculation of rhinovirus related to development of negative middle-ear
pressures and effusion in subjects who did and did not have preexisting
abnormal middle-ear pressures. Adapted from Buchman CA et al.20
In a more recent study, Doyle and colleagues infected 18
adult subjects with influenza A, showing that those individuals
who had preexisting good Eustachian tube function reduced the
otologic complications of the viral upper respiratory tract infection.22 Also, Buchman and colleagues inoculated respiratory
syncytial virus into the nasal cavities of 32 adult volunteers.23
Only 56% had detectable infection, but all of the subjects who
did have infection had rather substantial signs and symptoms,
and 54% of these subjects developed abnormal middle-ear
pressures.
These studies in adult volunteers were unique because
they demonstrated the relationship of viral upper respiratory
FIGURE 6–2. Outcomes of an adult volunteer study following intranasal
inoculation of influenza A virus demonstrating not only development of
abnormal middle-ear pressures and middle-ear effusion but also, importantly, an attack of viral and bacterial acute otitis media in one subject.
Adapted from Buchman CA et al.17
Pathogenesis / 97
tract infection, middle-ear negative pressure and effusion, and
acute otitis media.
Studies of Upper Respiratory Tract Infections
in Children
An informative clinical investigation by Moody and colleagues
also demonstrated a similar sequence of events in children, as
was documented in adult volunteers.24 In this study, the parents
of 20 children between the ages of 2 and 6 years monitored the
middle-ear status of their children every day using a tympanometer. They reported that when an upper respiratory tract
infection developed in the children, many soon also developed
middle-ear underpressures, and some then developed a middleear effusion.
In a follow-up study, Antonio and colleagues prospectively followed 40 children in their homes, using daily tympanometry, symptom diaries, and weekly otoscopic examinations, during the respiratory seasons (fall, winter, and early spring) and
during periods of common cold, which occurred in 22%; 63%
of all otitis media episodes occurred during an upper respiratory tract infection.25 Interestingly, 30% of the episodes of otitis
media were evident 1 to 7 days prior to the onset of the cold,
whereas in 26%, the middle-ear disease occurred between 8 and
14 days after the onset of the cold; the remaining 44% had otitis media on the same day or up to the seventh day after the
onset of the cold. These prospective studies in children who
developed a “wild cold”—not induced by intranasal inoculation
of viruses, as in the adult studies—showed that almost onethird of episodes of middle-ear effusion occurred prior to the
signs and symptoms being apparent. Thus, the virus had already
caused Eustachian tube dysfunction and otitis media.
There is now equally convincing evidence from studies in
adult volunteers that the Eustachian tube is involved in the
pathogenesis of otitis media. These six experiments show that
the Eustachian tube has an important role in the development
of otitis media in animal models. This is described below.
Experiments in Animals
In our laboratory over the past 30 years, we successfully produced both underpressures and middle-ear effusion in animal
models using several methods. Some of our more important
studies are summarized in Table 6–2.26–31
We demonstrated that when the tensor veli palatini muscle is experimentally impaired (altered or inactivated) in animal
models, active opening of the Eustachian tube is impaired. This
results in negative middle-ear pressure followed by middle-ear
effusion. In one experiment, excision of a portion of the tensor
veli palatini muscle at the pterygoid hamulus in the palate
resulted in negative pressure in the middle ear followed by an
effusion.26 A similar experiment in which the muscle was completely excised, the superficial muscle bundle was transected, or
the tendon medial to the hamular process was transposed had
comparable outcomes.27 Figure 6–3 shows the surgical procedures used and the number of animals in each group. Complete
excision of the tensor tendon resulted in middle-ear underpressures followed by persistent middle-ear effusion. Transection of
the muscle resulted in negative middle-ear pressure, or effusion,
or both (and in some animals, the middle ear returned to nor-
Table 6–2. Animal Models of High Negative Middle-Ear Pressure and Middle-Ear Effusion
Outcomes
Experiment
Reference
Animal
Diagnostic Method
1
2
Cantekin et al, 197726
Cantekin et al, 198027
Monkey
Monkey
Otomicroscope and tympanometry
Otomicroscope and tympanometry
3
Casselbrant et al, 198828 Monkey
Otomicroscope and tympanometry
4
Buchman et al, 199529
Ferret
Otomicroscope and tympanometry
5
Swarts et al, 199530
Monkey
MRI
6
Alper et al, 199731
Monkey
MRI
Method
TVP excised
TVP
Excised
Transected
Transposed
Botulinum into
TVP
Influenza A
nasal inoculation
CO2 insufflation
into ME
Botulinum into
TVP
Resolved
Long Term
HNP
MEE
Yes
Yes
Yes
Yes
Yes
Yes
No
No
No
No
No/yes
Yes
Yes
No
Yes
Yes
Yes
NA
Yes
Yes
Yes
Adapted from Bluestone CD.78
HNP = high negative middle-ear pressure; MEE = middle-ear effusion; TVP = tensor veli palatini muscle; ME = middle ear; MRI = magnetic
resonance imaging; NA = not applicable (acute experiment).
98 / Eustachian Tube: Structure, Function, Role in Otitis Media
FIGURE 6–3. Three methods of surgically altering the
tendon of the tensor veli palatini muscle in the monkey
that resulted in varying degrees and types of middle-ear
abnormalities, including development of negative pressure and effusion in the middle ear. Reproduced with
permission from Cantekin EI et al.27
mal after the muscle healed). When the tendon was transposed,
outcomes were similar to surgical alteration, but the middle ear
rapidly returned to normal in a few weeks. Using a noninvasive
method, Casselbrant and colleagues injected botulinum toxin
into the tensor muscle, which resulted in negative pressure and
then effusion.28 When the effect of the botulinum toxin
resolved, the middle-ear status returned to normal.
In these earlier studies, middle-ear status was diagnosed
with otomicroscopy and tympanometry. We have also used
magnetic resonance imaging (MRI) to more accurately diagnose
the presence of effusion in the middle ear and mastoid.
Figure 6–4 shows the flow diagrams for two such studies in the
monkey. Alper and colleagues used MRI and tympanometry to
identify middle-ear and mastoid effusion.31 These investigators
also injected botulinum toxin into the tensor veli palatini muscle of monkeys, resulting in a Eustachian tube that failed to
open, middle-ear underpressure, and effusion. In ears that
developed underpressure within the middle ear, increased vascular permeability was observed on the MRI. These experiments
created a functional obstruction of the Eustachian tube (ie, an
impairment of the active opening of the tube) impeding pressure regulation of the middle ear and resulting in an effusion. As
in the earlier study, when the effect of the botulinum toxin
resolved, the middle-ear status returned to normal.
Using a different approach, Swarts and colleagues were
also able to produce unilateral middle-ear effusion in the monkey shortly after inducing middle-ear negative pressure by
inflating the middle ear with carbon dioxide.30 Increased vascular permeability was identified on the MRI using a contrast
agent. None of these changes were found in the contralateral
(control) ear. When the middle-ear cleft was flushed with oxygen, lesser middle-ear underpressures developed, but no middle-ear effusion or other changes on the MRI scan developed.
Even though the Eustachian tube was not altered in this experiment, the study showed the effect of middle-ear negative pressure in the development of middle-ear effusion.
Buchman and colleagues, using a ferret, evaluated the
effect of influenza A virus nasal challenge on the function of the
Eustachian tube.29 The results were assessed by forced-response
and inflation-deflation tests, and middle-ear status was evaluated by otomicroscopy and tympanometry. All 10 animals in the
experiment became infected, and all had Eustachian tube dysfunction associated with middle-ear underpressures, although
no middle-ear effusion developed in any of the ferrets. The
investigation also showed that even though the Eustachian tube
did not become totally obstructed, abnormally high negative
pressures developed in the middle ear.
In an earlier study by Giebink and colleagues, the
nasopharynx of 29 chinchillas was inoculated with influenza A,
which resulted in histopathologic evidence of inflammation of
the Eustachian tube and tympanic membrane; middle-ear
underpressures were also documented by tympanometry.32 More
recently, Piltcher and colleagues, in our laboratory, completely
obstructed the Eustachian tubes of 164 rats, which resulted in
tympanic membrane retraction and middle-ear effusion.33
FIGURE 6–4. Outcomes of two studies in monkeys that support the hydrops
ex vacuo theory of the pathogenesis of middle-ear effusion. MEE = middle-ear effusion; MRI = magnetic resonance imaging. Left flow diagram
adapted from Swarts JD et al30; right flow diagram adapted from Alper
CM et al.31
Pathogenesis / 99
Summary and Conclusions from Human and
Animal Studies
These studies in both humans and animal models support the
causal relationship between a viral upper respiratory tract infection, partial Eustachian tube obstruction, abnormal middle-ear
underpressures, and otitis media with effusion and acute otitis
media (Figure 6–5). It is important to note that this pathogenic
sequence of events in humans affected subjects who had preexisting dysfunction of the Eustachian tube and that those whose
function was normal had little or no middle-ear sequelae following induced viral upper respiratory tract infection. It is
assumed that functional obstruction of the tube is the dysfunction that is present, which makes these individuals more susceptible than normal. Future research should be directed
toward uncovering the underlying pathophysiology of functional Eustachian tube obstruction and reducing the severity, if
not the occurrence, of viral upper respiratory tract infections.
These studies lend convincing support for the hydrops ex vacuo
theory.
Clinical Aspects of the Pathogenesis of Otitis
Media and Certain Related Conditions
Acute otitis media, otitis media with effusion, Eustachian tube
dysfunction, and chronic suppurative otitis media are the most
frequent middle-ear diseases that clinicians encounter.
Following the onset of either acute otitis media or otitis media
with effusion, persistent middle-ear effusion may develop. The
following describes these clinical types and stages of otitis
media and relates them to the pathophysiology and pathogenesis related to the Eustachian tube, as described in this chapter
and in Chapter 5. The pathogenesis of chronic suppurative otitis media, atelectasis, retraction pocket, and cholesteatoma is
described in Chapter 10, “Role in Certain Complications and
Sequelae of Otitis Media,” because management is related to
pathogenesis.
Acute Otitis Media
As described above, the pathogenesis of acute otitis media usually occurs with the following pattern in most children: the
patient has an antecedent event (usually an upper respiratory
viral infection) that results in congestion of the respiratory
mucosa of the upper respiratory tract, including the nasopharynx and Eustachian tube. Congestion of the mucosa of the
Eustachian tube is followed by negative middle-ear pressure,
and, if prolonged, potential pathogens (viruses and bacteria) are
aspirated from the nasopharynx into the middle ear. Because
the Eustachian tube is obstructed, the middle-ear effusion,
owing to the infection, accumulates in the middle ear, and the
clearance function of the tube is impaired. Microbial pathogens
proliferate in the secretions, resulting in a suppurative and
symptomatic acute otitis media.
For children with recurrent acute otitis media, an
anatomic or physiologic abnormality of the Eustachian tube
appears to be an important factor, if not the most important
factor. In Sweden, Stenstrom and colleagues studied the pathogenesis of recurrent acute otitis media in 50 otitis-prone children (defined as greater than 11 episodes of acute otitis media).9
Using the pressure chamber to test Eustachian tube function,
they found the otitis-prone children to have significantly poorer active tubal function than 49 normal (control) children who
had no history of acute otitis media. This finding indicates that
the pathogenesis of recurrent acute otitis media is the result of
functional obstruction of the Eustachian tube, as opposed to
mechanical obstruction. However, it is likely that infants and
young children with their short, floppy Eustachian tubes can
reflux or insufflate nasopharyngeal secretions into the middle
ear during a viral upper respiratory tract infection. Another
possible mechanism is an infection that progressively ascends
from the nasopharynx into the mucosa of the Eustachian tube.
This most likely occurs when an indwelling obstructing foreign
object is in the nasopharynx, such as a nasogastric or nasotracheal tube.
Evidence-Based Virus-Induced Pathogenesis of Otitis Media
Upper respiratory tract infection
(Moody et al. 1998; Antonio et al. 2002)
Abnormal middle-ear under-pressure
(Giebink et al. 1986)*
Pre-existing Eustachian tube dysfunction
(Buchnan et al. 1994)
No
Yes
Resolution of abnormal
middle-ear pressure
Virus/bacteria from
nasopharynx
aspirated into middle
ear via Eustachian
tube
(Buchnan et al. 1994)
Transudation of middle-ear
effusion
(Doyle et al;
unpublished data)
(Swarts et al. 1995; Alper et al. 1997)
Otitis media with effusion
(Buchnan et al. 1994; Doyle et al 1998)
Acute otitis media
(Buchnan et al. 1994)
*Histologic animal experiment
FIGURE 6–5. Flow diagram of evidence-based pathogenesis of otitis
media.
100 / Eustachian Tube: Structure, Function, Role in Otitis Media
Otitis Media with Effusion
At the onset of an episode of otitis media with effusion, the
patient is usually asymptomatic (except for presence of hearing
loss), but usually this condition has a sequence of events similar
to that described above for acute otitis media. Bacteria can be
isolated from middle-ear effusions of patients with otitis media
with effusion,34–36 but prolonged negative pressure within the
middle ear can cause a sterile middle-ear effusion. As described
above, otitis media with effusion has been produced in the monkey animal model following excision of the tensor veli palatini
muscle26 and injection of botulinum toxin into the tensor veli
palatini muscle,28,31 which resulted in the Eustachian tube failing
to open, middle-ear underpressures, and effusion. These experiments confirm the hydrops ex vacuo theory of the pathogenesis of middle-ear effusion. This theory postulates that when the
Eustachian tube does not open, the gas exchange from the middle ear into the microcirculation of the mucous membrane
causes a middle-ear underpressure, followed by transudation of
effusion. Swarts and colleagues were also able to produce middle-ear effusion in the monkey by flushing the middle ear with
carbon dioxide shortly after inducing middle-ear negative pressure.30 In the studies cited above by McBride and colleagues and
Buchman and colleagues that involved adult volunteers, nasal
challenge with rhinovirus resulted in Eustachian tube obstruction, negative middle-ear pressure, and, in two subjects, middleear effusion.19,20 Doyle and colleagues also demonstrated that
intranasal challenge of influenza A virus in adult volunteers
resulted in Eustachian tube obstruction, negative middle-ear
pressure, and, in infected subjects, middle-ear effusion.21 Most
likely, influenza A virus is more virulent than rhinovirus. Also,
preexisting poor Eustachian tube function predisposes the individual to obstruction of the tube and middle-ear abnormalities.20,22
Episodes of upper respiratory tract infection can then
result in atelectasis of the tympanic membrane–middle ear (ie,
high negative middle-ear pressure), sterile otitis media with
effusion, or acute bacterial otitis media. Because the tube can
open when there is a middle ear with an effusion, nasopharyngeal secretions can be aspirated, creating the clinical condition
in which otitis media with effusion and acute bacterial otitis
media occur together.
In a study of Eustachian tube function in 163 ears of
Japanese children and adults who had otitis media with effusion
and chronic otitis media, Iwano and colleagues found an
impaired active opening function of the tube in children and
adults.37 They concluded that the tube was functionally
obstructed. But organic (mechanical or anatomic) obstruction
was also considered to be involved in the pathogenesis in adults.
Persistent Middle-Ear Effusion
The pathogenesis of persistent middle-ear effusion after the initial stage of a viral or bacterial infection in the middle ear or fol-
lowing transudation of effusion is multifactorial. In addition to
impairment of clearance function of the tube and inflammatory obstruction at the protympanic (osseous) portion of the
tube, cytokines are stimulated, such as interleukins 1, 2, and 6;
tumor necrosis factor; interferon- from inflammatory cells of
the middle-ear mucous membrane; and growth factors,38–44 followed by two pathways of inflammation: (1) up-regulation of
submucosal receptors, primarily selectins and integrins that trap
lymphocytes into the mucosa, which also produce cytokines and
inflammatory mediators, and (2) stimulation of inflammatory
mediators, such as leukotrienes, prostaglandins, thromboxane,
prostacycline, and platelet-activating factor,45,46 which, in turn,
can promote fluid leakage from the mucous membrane. Nitric
oxide47 and free radicals48,49 have also been implicated in the
pathogenesis of persistent middle-ear effusion. At this stage,
there is probably an increase in blood flow within the mucous
membrane owing to engorgement of blood vessels and angioneogenesis. This then results in further negative pressure within
the middle ear owing to an increase in N2 into the microcirculation of the mucosa.50 There is some evidence that infection
caused by Haemophilus influenzae predisposes the middle-ear
cleft to persistent effusion.51 In addition, the effusion that is produced is “trapped” in the middle ear owing to the anatomy of
the system, that is, a closed space with a narrow outlet—the
Eustachian tube. Also, the mucociliary system and the pumping
action of the tube are most likely impaired, causing persistent
middle-ear effusion.
Eustachian Tube Dysfunction
Symptomatic Eustachian tube dysfunction can be due to either
an obstruction (anatomic or functional or both) of the tube
(too closed) or a patulous tube (too open). Signs and symptoms
are referable to the ear, despite the lack of a middle-ear effusion.
Obstruction of the tube can cause middle-ear negative pressure,
retraction of the tympanic membrane, hearing loss, and, in its
severe form, atelectasis of the middle ear (loss of the middle-ear
space). Obstruction can be due to inflammation or failure of the
opening mechanism. Obstruction can be acute or chronic, but
infrequent periodic tubal opening probably occurs to prevent
the accumulation of an effusion. A patulous tube can cause
patients to complain of autophony and hearing their own
breathing. Both conditions have been documented during the
last trimester of pregnancy.52 Eustachian tube obstruction is
common in girls during puberty and may be related to hormonal changes, but we do not know the underlying cause of this
problem (see Chapter 5).
Role of Allergy in Etiology and Pathogenesis
Allergy is thought to be one of the etiologic factors in otitis
media because otitis media occurs frequently in allergic individuals.53 The mechanism by which allergy might cause otitis
media is hypothetical and controversial.54,55 Figure 6–6 illus-
Pathogenesis / 101
trates my concepts of allergy’s role in the etiology and pathogenesis of otitis media by one or more of the following mechanisms56:
• The middle-ear mucosa functioning as a shock (target)
organ
• Inflammatory swelling of the Eustachian tube mucosa
• Inflammatory obstruction of the nose
• Aspiration of bacteria-laden allergic nasopharyngeal
secretions into the middle-ear cavity
Doyle has also proposed another possible mechanism.57
This hypothesis is based on the possible increase in circulating
inflammatory mediators from local allergic reactions in the
mucosa of the nose or stomach, which, in turn, could alter the
middle-ear mucosal permeability and result in altered gas
exchange. Ohashi and colleagues found that allergic responses
did not impair mucociliary activity but could adversely affect
the structure of the Eustachian tube’s mucus blanket.58 More
recently, investigators from Finland reported a higher incidence
of recurrent otitis media in children who had a cow’s milk allergy in infancy.59
As presented in Chapter 5, Bernstein and colleagues provided evidence that the Eustachian tube may be adversely
affected by allergy, as opposed to the middle ear as a target
organ (see Table 5–5).54 More recently, Hurst and Venge
assessed the inflammatory response by eosinophils, neutrophils,
and mast cells in the middle ear and found a difference between
atopic and nonatopic individuals, which led to their conclusion
that the middle-ear mucosa is capable of an allergic response,
similar to other portions of the respiratory tract.60 But if the
middle ear is a target organ, why is it that following tympanostomy tube placement in children who have allergic rhinitis and
otitis media, a postoperative otorrhea is not a common complication? The target organ is the Eustachian tube.
Studies at the Children’s Hospital of Pittsburgh involving
adult volunteers demonstrated a relationship between
intranasal antigen challenge, allergic rhinitis, and Eustachian
tube obstruction.61–63 Table 6–3 summarizes studies that
demonstrated a relationship among intranasal challenge with
allergens, virus, and mediators in volunteers who did and did
not have allergic rhinitis and the effect on their nasal and
Eustachian tube function.61–67 None of these allergy studies produced otitis media in the volunteers, but none had preexisting
Eustachian tube dysfunction; we were concerned that challenging a volunteer with a susceptibility to middle-ear effusion (a
preexisting Eustachian tube dysfunction) could be hazardous. It
is possible that repeated challenge with antigen over a prolonged period of time would cause individuals who are hypersensitive to the specific antigen and who also have poor
Eustachian tube function to develop middle-ear effusion (see
Chapter 11, “Future Directions”). It seems reasonable that children with signs and symptoms of upper respiratory allergy may
have otitis media as a result of the allergic condition, especially
if they have underlying dysfunction of the tubal system.
Gastroesophageal Reflux
There has been a suggestion in the past that gastroesophageal
reflux disease may be involved in the pathogenesis of Eustachian
tube–middle-ear pathology.68 In the last few years, several
reports have shown an association of otitis media with gastroesophageal disease in humans and animal models.69,70 In animals, Heavner and colleagues were able to demonstrate a transient inflammation of the Eustachian tube secondary to multiple exposures of a gastroesophageal refluxant instilled into the
middle ears of a rat model.71 In a similar study, White and colleagues instilled gastric juice into the nasopharynx of the rat
model that resulted in Eustachian tube dysfunction.72 In
humans, Tasker and colleagues measured pepsin concentrations
in middle-ear effusions from children using enzyme-linked
Table 6–3. Studies at Children’s Hospital of Pittsburgh that
Evaluated the Effect of Nasal Challenge on Nasal and
Eustachian Tube Function
Nasal Provocation
Allergens
(pollens, mite)
Mediators
Histamine
PGD2
Methacholine
FIGURE 6–6. Possible anatomic sites related to allergic etiology and pathogenesis of otitis media.
Nasal Function
Eustachian Tube Function
Nonallergic Allergic
Nonallergic Allergic
0
+
0
+
+
+
+
+
+
+
0
0
0
+
+
0
Adapted from Friedman PA et al61; Ackerman MN et al62; Doyle WJ et
al63; Skoner DP et al66; Skoner DP et al64; Stillwagon PK et al.65
+ = adverse effect; 0 = little effect; PGD2 = prostaglandin D2.
102 / Eustachian Tube: Structure, Function, Role in Otitis Media
immunosorbent assay and enzyme activity assays; of the 54
specimens, 45 (83%) were positive.69 In another report from the
same research group, Tasker and colleagues assessed the levels of
pepsin and pepsinogen protein in 65 middle-ear effusions of
children; 59 had levels 1,000-fold higher than serum levels,
which were attributed to reflux of gastric contents into the middle ear.73 Poelmans and colleagues performed tests for reflux in
adults who had chronic otitis media with effusion or Eustachian
tube dysfunction and reported that there was an association and
that treatment with antireflux medication was effective in
relieving the otologic symptoms.74 This was not a randomized
clinical trial. At this time, it is still uncertain that gastroesophageal reflux is involved in the pathogenesis of Eustachian
tube–middle-ear disease, even though there appears to be an
association in both humans and an animal model.75 These issues
are future research goals (see Chapter 11).76
I routinely include questions concerning symptoms of
reflux disease (arching the back and frequent vomiting in the
infant, chronic or recurrent hoarseness, frequent belching and
clearing the throat, recurrent croup, heartburn, stomach discomfort) in children who have recurrent acute otitis media and
chronic otitis media with effusion. All young infants are especially prone to reflux because of their relatively short esophagus
and other factors related to being “born too soon.”77 Even if a
cause-and-effect relationship between the two is lacking, there
may be a cause-and-effect relationship in symptomatic patients.
Thus, I treat these children for both diseases; even if there is only
an association, both usually require management (see Chapter
9, “Role in Management of Otitis Media”).
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CHAPTER 6: ADDITIONAL FIGURES