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1 Denitions, Terminology, andClassication
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tion that this is more than just a “nal classication” written
in stone; it has represented, over the years, a “consensus or
working agreement” between different clinicians and investigators who have different viewpoints and perspectives. In
other words, as Cicero stated centuries ago: “Every rational
discussion of anything whatsoever should begin with a denition in order to make clear what is the subject of dispute.”
The classication is as follows:
1. Myringitis, which is an inammation of the tympanic
membrane that occurs alone or in association with external otitis or otitis media
2. Acute suppurative otitis media (acute purulent otitis
media (POM) or acute otitis media), which refers to a
clinically identiable infection of the middle ear with
sudden onset and short duration
3. Otitis media with effusion or secretory otitis media
(chronic otitis media with effusion, otitis media with effusion, nonsuppurative otitis media, catarrh, serous otitis
media (SOM), serotympanum, mucoid otitis media
(MOM), mucositis, or mucotympanum), which refers to
the presence of middle ear effusion (MEE) behind an intact
tympanic membrane without any acute signs or symptoms.
This broad term includes nonsuppurative or clinically noninfectious forms of OM.However, evidence suggests that
effusions are, for the most part, infectious. Cultures of
serous effusions yield between 22% and 52% positively,
percentages that increase to 77.3% if PCR is used [6].
4. Chronic suppurative otitis media (chronic otitis media),
which refers to a chronic discharge from the middle ear
through a perforation of the tympanic membrane.
Suppurative refers to an active clinical infection. A perforation without discharge can be an inactive stage of the infection (but not of the underlying histopathological process).
Over time, a new entity was incorporated:
5. Recurrent otitis media, which refers to repeated epi-
sodes of acute otitis media in between periods of “apparent remission” (three episodes in 6 months or four
episodes in 1year)
In addition, the denition of “chronic” can also be applied
to otitis with an intact tympanic membrane, as in the cases of
masked mastoiditis [7] and silent otitis media [8, 9].
Based on its duration, this disease can be divided into
acute (up to 3weeks), subacute (from 3weeks to 3months),
and chronic (more than 3months) [10].
Two other types can be added: hemorrhagic and any combination of the previously mentioned effusions. In practice, it
is unusual to see a pure effusion because effusions reect a
dynamic process in which some forms evolve into others.
This will depend on the interaction between defensive and
aggressive forces (e.g., the aggressive forces prevail in the
more infectious phases, whereas the defensive forces prevail
in the noninfectious phases). Moreover, uid composition
represents what is going on in the underlying mucoperiosteum, as will be described in Chap. 5.
Histopathological Classication
Histopathologically an inltration by polymorphonuclear
cells is a sign of acute inammmation, and an inltration by
round cells is a sign of chronic inammation. The term
“chronic” implies inltration of the mucoperiosteum by
round cells or the cells of chronic inammation. However,
studies of the histopathological process of otitis media provide much more comprehensive knowledge and understanding that goes much further than the practical clinical terms
“acute” and “chronic.” These histopathological changes are
described in Chap. 5.
Complications andSequelae
In addition to the acute and chronic involvement of the mucoperiosteum by the otitis media process, there are potential
complications and sequelae. A complication occurs when the
inammatory process extends beyond the mucoperiosteum.
Sequelae refer to histopathological changes that are secondary
to the otitis media process that remain within the mucoperiosteum and have the capacity or potential to develop a complication [11]. For example, the granulation tissue is a sequela
(active sequela), but erosion of bone and stula by the granulation tissue is a complication. In addition, the overall consequences of a localized problem (e.g., ossicular disruption
causing conductive hearing loss) can have signicant effects
on a person and their relationship with others (lack of communication, isolation, learning problems, and so forth).
Complications and sequelae are described in Table1.1.
The Concept ofOverall Involvement
Middle Ear Eusions
Otitis media is associated with the presence of middle ear
uid (effusion). Basically, three types of effusions are found:
(1) serous otitis media (SOM), (2) mucoid otitis media
(MOM), and (3) purulent otitis media (POM).
An essential concept in otitis media is that the otitis media
process involves not only the middle ear cavity but also the
Eustachian tube and the mastoid. This manifests by changes
in the whole mucoperiosteum covering these cavities—
including osteitis of the underlying bone—(Fig. 1.3) and in
the uids that the cavities contain (middle ear effusions). In
addition, effusions are not stagnant spillage but are dynamic
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Fig. 1.3 Middle ear cavity
with middle ear effusion
(Copyright Marcos Y
Goycoolea 2023; all rights
reserved). The inammatory
process involves all the walls,
cavities, and anatomical
structures that these contain
as well as the
mucoperiosteum that lines
these cavities and structures
M. V. Goycoolea et al.
forms that evolve and change in response to and as part of the
overall mucoperiosteal changes [11, 12]. We see the inammatory changes as a continuum, with some forms evolving
or resolving into other forms and, at times, resulting in complications and sequelae, depending on the multiple factors
involved. Viewed from this perspective, it becomes obvious
that otitis media implies much more than uid behind the
tympanic membrane.
References
1. Paparella MM, Goycoolea MV, Jung TK. Otitis media with effusion. In: Paparella MM, Shumrick DA, Gluckman JL, Meyerhoff
WL, editors. Otolaryngology, vol. II.Philadelphia: WB Saunders;
1991. p.1317–42.
2. Goycoolea MV, Jung TK. Complications of suppurative otitis
media. In: Paparella MM, Shumrick DA, Gluckman JL, Meyerhoff
WL, editors. Otolaryngology, vol. II.Philadelphia: Saunders; 1991.
p.1381–403.
3. Goycoolea MV, Hueb MM, Ruah CB. Otitis Media. Denitions
and terminology. In: Goycoolea MV, editor. Otitis media. The
pathogenesis approach, The otolaryngologic clinics of NA, vol. 24.
Philadelphia: WB Saunders; 1991. p.757–61.
4. Klein JO, Tos M, Hussl B, etal. Denition and classication. Ann
Otol Rhinol Laryngol. 1989;98(Suppl 139):10.
5. Bluestone C, Ogra P, Paparella M, etal. Denitions, terminology and
classication of otitis media. In: Lim DJ, editor. Recent advances in
otitis media. Report of the Seventh Research Conference. Ann Otol
Rhinol Laryngol 2002; 111 (suppl.111): 8–18.
6. Liu YS, Lim DJ, Lang R, etal. Microorganisms in chronic otitis
media with effusion. Ann Otol Rhinol Laryngol. 1976;85(Suppl
25):245.
7. Mawson SR.Latent mastoiditis. In: Mawson SR, editor. Diseases
of the ear. Baltimore: Williams and Wilkins; 1963. p.286, 344.
8. Paparella MM, Bluestone CD, Arnold W, etal. Denition and classication. Ann Otol Rhinol Laryngol. 1985;94(Suppl 116):8.
9. Paparella MM, Goycoolea MV, Bassiouni M, et al. Silent otitis
media: clinical applications. Laryngoscope. 1986;96:978.
10. Paparella MM, Senturia BH, Bluestone CD, Lim DJ, etal. Report
of the ad hoc committee on denition and classication of otitis
media and otitis media with effusion. Ann Otol Rhinol Laryngol.
1980;89(Suppl 68):3–4.
11. Goycoolea MV, Paparella MM, Juhn SK, Carpenter AM. The
cells involved in the middle ear defense system. Ann Otol Rhinol
Laryngol. 1980;89(Suppl. 68):121–1980.
12. Goycoolea MV. Surgical procedures in different forms of otitis
media. Summary of concepts. In: Goycoolea MV, et al., editors.
Atlas of otologic surgery, vol. 1. New Delhi: Jaypee Brothers
Medical Publishers Ltd; 2012. p.463–89.
Otitis Media: Basic Concepts
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andFundamentals
SadySelaimenda Costa andRafaelda CostaMonsanto
2
“Acute pain of the ear, with continued strong fever, is to be
dreaded, for there is danger that man may become delirious and
die.” Hippocrates
Introduction
The term “otitis media (OM)” describes a multifactorial
inammatory process that involves not only the middle ear
but also the Eustachian tube and the mastoid. It is one of the
most prevalent infectious diseases, being considered a worldwide public health problem [1–6]. In the United States alone,
more than 5 billion dollars are spent annually to treat OM.It
is estimated that 30 million dollars are spent toward antibiotic treatment of OM. In 2006, OM-related expenditure with
outpatients alone in the United States was around 2.8 billion
dollars [7]. The National Ambulatory Medical Care
Survey and the National Hospital Ambulatory Medical
Care Survey in the USA indicated that—in 2019 only—
more than one million emergency department visits were
patients with OM.In Germany (2014–2019), the population
under 16years of age only represented more than 900,000
S. S. da Costa (*)
Otolaryngology and Head and Neck Surgery, School of Medicine,
Federal University of Rio Grande do Sul,
Porto Alegre, Rio Grande do Sul, Brazil
Service of Otolaryngology and Head and Neck Surgery, Hospital
de Clínicas, Porto Alegre, Rio Grande do Sul, Brazil
Brazilian Association of Otorhinolaryngology and Cervico-Facial
Surgery, São Paulo, SP, Brazil
Brazilian Society of Otology, São Paulo, SP, Brazil
International Hearing Foundation, Minneapolis, MN, USA
International Advisory Board—American Academy of
Otolaryngology and Head & Neck Surgery, Alexandria, VA, USA
Collegium Oto-Rhino-Laryngologicum Amicitiae Sacrum,
Helsinki, Finland
R. da CostaMonsanto
Department of Otolaryngology, Head & Neck Surgery, University
of Minnesota, Minneapolis, MN, USA
e-mail: rdacosta@umn.edu
episodes of OM, 15% of which were identied as recurrent
[8, 9]. A study in Boston showed that, out of 17,000 pediatric
outpatient consultations performed during the rst year of
life, acute otitis media (AOM) constituted one-third of them
[10]. According to Lanphear etal. [11], the number of outpatient consultations due to OM in preschoolers, which has
always been traditionally high, increased even more in the
past decade. In the United States, half a million patients
undergo tympanostomy tube surgery every year, either for
OM with effusion (OME) or recurrent acute OM (AOM) that
is refractory to conventional clinical treatments [12].
Tympanostomy tube insertion is the most frequent surgical
procedure performed under general anesthesia in American
children [13].
OM is a dynamic disease in which some forms lead to
others, resulting at times in complications and sequelae. The
progression of middle ear inammation and tissue changes is
inuenced by many factors, including the anatomy and physiology of the middle ear, mastoid, and Eustachian tube, and
the host’s immunological response to environmental factors.
In addition to local factors, this process is directly inuenced
not only by the neighboring anatomical structures but also by
the host’s relationship with the environment.
Classication andDenitions
Otitis media can be classied on a clinical or histopathological basis. Although these elements have been already
addressed in Chap. 1, they will be duplicated here in order to
stress their importance in the understanding of many concepts that will be discussed in the next paragraphs.
Clinical Classication
OM was classied on the clinical basis by both the “Task
Force of the Fourth International Symposium of Otitis
Media” (June 1987, Bal Harbor, Florida) and the “Task Force
of the Seventh Symposium in 1999” [14]. For purposes of
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
M. V. Goycoolea et al. (eds.), Textbook of Otitis Media, https://doi.org/10.1007/978-3-031-40949-3_2
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S. S. da Costa and R. da CostaMonsanto
consistency, we have followed this classication throughout
this chapter. However, it is important to highlight that this is
a working classication that allows a “common language” in
the subject. These denitions represent a “consensus or
working agreement” between different clinicians and investigators who have different viewpoints and perspectives. In
other words, as Cicero stated centuries ago: “Every rational
discussion of anything whatsoever should begin with a denition in order to make clear what is the subject of dispute.”
The classication is as follows:
• Myringitis: Inammation of the tympanic membrane that
occurs alone or in association with external otitis or otitis
media
• Acute suppurative otitis media (acute purulent otitis
media, acute otitis media): A clinically identiable infection of the middle ear with sudden onset and short
duration
• Secretory otitis media (chronic otitis media (COM) with
effusion, otitis media with effusion, nonsuppurative otitis
media, catarrh, serous otitis media, serotympanum,
mucoid otitis media, mucositis, mucotympanum): The
presence of middle ear effusion (MEE) behind an intact
tympanic membrane without any acute signs or symptoms. This broad term includes nonsuppurative or clinically noninfectious forms of OM. However, evidence
suggests that effusions are, for the most part, infectious.
Cultures of serous effusions yield between 22% and 52%
positively, percentages that increase to 77.3% if PCR is
used [15].
• Chronic suppurative otitis media (CSOM) (chronic otitis
media): Chronic discharge from the middle ear through a
perforation of the tympanic membrane. Suppurative refers
to an active clinical infection. A perforation without discharge can be an inactive stage of the infection (but not of
the underlying histopathological process).
Later, other terms were incorporated into this
classication:
• Recurrent otitis media: Repeated episodes of acute otitis
media in between periods of “apparent remission” (three
episodes in 6months or four episodes in 1year)
• Silent (or “masked”) otitis media: The presence of a
chronic inflammatory process affecting the middle
ear and the mastoid behind an intact tympanic membrane [16]
Additionally, OM can be classied based on its duration
into acute (up to 3 weeks), subacute (from 3 weeks to
3months), and chronic (more than 3months) [17].
Middle Ear Eusions
Otitis media is associated with the presence of middle ear
effusion. Three types of effusions can be found in OM cases:
(1) serous, which comprises a thin, pale transudate; (2)
mucoid, which is a thick exudate that is the result of goblet
cells present in the metaplastic epithelium; and (3) purulent,
which is characterized by the presence of inammatory cells.
In addition, two other types can be included: hemorrhagic,
when red blood cells are present, and middle ear effusions
that can appear as a combination of any of these.
Histopathological Classication
Histopathologically, the term “acute” refers to inltration by
polymorphonuclear cells, characterized by classic signs of
acute inammation. The term “chronic” implies the presence
of clinically intractable tissue changes affecting the middle
ear and/or the mastoid. Histopathological changes secondary
to OM are described in Chap. 5.
Basic Concepts
Otitis media is a multifaceted pathology, and, therefore, its
complete understanding can only be achieved through analysis and meticulous study of each of its small facets. These
studies will have to be skilled enough to dissect the individual aspects of this disease without, however, denying the fact
that they are organically and evolutionarily interconnected.
Analogously, it would be as if we tried to understand a chain
by examining only one of its links and extrapolating that to
include every form of the disease. For this reason, we will
dedicate the next paragraphs to dive deeper into the basic
concepts that we consider essential for addressing issues relevant to the etiology, classication, pathogenesis, and treatment of this prevalent disease.
As mentioned in the “Introduction” section, OM is dened
as the presence of an inammatory process (which may or
may not be infectious) affecting the middle ear and the mastoid. However, before navigating through the more specic
aspects of this disease, it is important to further discuss denitions. To do so, it is necessary to review foundations related
to general pathology and primary anatomy and physiology,
which is critical to the global understanding of this entire
fascinating process.
Inammation is a nonspecic biological process that is
inherent to organisms, which occurs in response to pathogenic stimuli of different nature. These stimuli include
chemical, physical, or biological agents. Although inammation is essentially a defense mechanism, it can sometimes
result in damage to the body. In clinical practice, it is more
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frequently associated with trauma, infections, deposits of
crystals, or antigen–antibody complexes.
The rst description of inammation, an important milestone in the history of medicine, is attributed to Celsus in the
rst century AD, who described four cardinal signs: heat,
redness, pain, and tumor. A century later, Galen added
another sign: loss of function. The inammatory process
begins with a more or less intense nonspecic tissue injury.
As a result, there is local activation of the complement system, which is an enzymatic cascade, constituted by several
elements endowed with biological activity [18].
At the histopathological level, two different stages of
inammation occur, namely, acute and chronic. The rst is
characterized by arteriolar and venular vasodilation, with
increased hydrostatic pressure in the microcirculation and
uid leakage into the interstitial tissues (edema); increased
permeability in microvascularization, by cell contraction in
the venular endothelium (fenestration), with protein escape
that decreases vascular oncotic pressure and favors the formation of inammatory exudates in the tissue; migration of
polymorphonuclear cells (chemotaxis), initially; and accumulation of macrophages at the injury site, approximately
24h later. The chronic phase of inammation begins 36–48h
after the inammatory stimulus, where leukocyte migration
continues, with a predominance of monocytes, lymphocytes,
plasmocytes, and broblasts and signs of regeneration and
reconstruction of the connective matrix. At the molecular
level, there is protein denaturation, from lytic enzymes,
released by the rupture of the lysosome membrane, due to
the action of phagocytes. Protein alteration is the starting
point for the activation of a series of systems that synthesize
and release substances such as histamine, serotonin, bradykinin, prostaglandins, leukotrienes, and various chemotactic
factors, which are responsible for vasodilation, increased
vascular permeability, leukocyte migration, and platelet
aggregation, in addition to other manifestations of the acute
inammatory process.
One of several characteristics that differentiate inammation from infection is that the latter only exists in the presence of biological agents and microorganisms, which include
bacteria, viruses, and fungi. The infectious process includes
an inammatory response of the body, but as seen, not every
inammatory process is caused by an infectious agent. An
infection can be dened through Koch’s principles, which
establish criteria for relating a specic microorganism to a
given disease: (1) the organism is regularly found in disease
lesions, (2) the organism can be isolated in colonies on a
solid medium, (3) inoculation of this culture causes lesions
in an experimental animal, and (4) the organism can be
recovered from lesions in the animals. In the last 10years,
advances in molecular biology have led to a change in Koch’s
postulates that link a particular characteristic of an organism
to a particular disease: (1) the phenotype or characteristic
should be associated with virulent strains of the microorganism and not with strains that are not virulent; (2) the specic
inactivation of the gene associated with virulence, replacing
the wild-type gene with a mutant, can lead to a measurable
decrease in the pathogenicity of the microorganism; and (3)
replacing the mutant gene with the wild-type gene can restore
the pathogenicity of the organism.
The infectious process can be didactically divided into the
following stages:
(a) Interactions between the agent and the host: The infec-
tious agent can be exogenous, such as the u virus or
Pseudomonas bacteria, or endogenous, colonizing
agents of the organism, which, for some reason, become
pathogenic.
(b) Tissue invasion: Penetration of the microorganism can
occur through a rupture of the epithelial barrier or, in
some situations, through the intact epithelium. The
microorganism can also enter through inhalation and
ingestion.
(c) Dissemination: The microorganism propagates from the
original site of entry to the adjacent or distant tissues. In
any case, microorganisms only disseminate and proliferate if they overcome the host’s defenses. Dissemination
depends on the anatomical factors of the host and also on
the characteristics of the invading agent.
(d) Tissue damage: The degree of tissue damage mainly
depends on the pathogenicity of the invading agent.
Damage due to the infectious process may be due to
mechanical causes, cell death, pharmacological changes
in metabolism, and exaggerated host responses.
(e) Outcome: This is the end result of the entire process. It
can culminate in elimination of the infectious agent,
death, or chronic colonization of the host [19].
In COM, the bacterial ora found in the middle ear is
mixed, deriving either from the upper aerodigestive tract
and/or through tympanic perforation. The Gram-negative
bacteria Pseudomonas aeruginosa and Hemophilus inuen-
zae are the most frequently identied bacteria in patients
with COM, whereas the Gram-positive bacteria Streptococcus
pneumoniae and Staphylococcus aureus and anaerobic
microorganisms are less frequent [20].
There is a correlation between the strain of bacteria present in the middle ear during an episode of infection and those
found in the nasopharynx. In children with upper airway
infections, the microbiota of the upper aerodigestive tract
seems to be less biodiverse as compared with to that in children without infections. The presence of lower airway disease (asthma, for example) is also correlated with lower
biodiversity of the middle ear microbiota. After an episode of
AOM, the bacteria in the middle ear cleft and nasopharynx
can form a biolm, thus passing to a saprophytic state in the
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S. S. da Costa and R. da CostaMonsanto
local mucosa. A few days after the initial infection, the biolm matrix is matured by the pathogen. The formation of
biolms protects bacterial colonies and also increases their
defense against host immunity and antibiotic treatments.
Thus, it seems to play a role in the chronicity of otitis media
[6, 21].
This imbalance in the local bacterial ora plays a decisive
role in the pathophysiology and perpetuation of COM.More
recently, vaccinations against Hemophilus inuenzae and
Streptococcus pneumoniae seem to have increased the relevance of other bacteria in this process. Alloiococcus otitidis
and Turicella otitidis, previously considered normal participants of the middle ear ora, have now been detected as possible pathogens in COM, including helping in the formation
of biolms.
Some bacteria seem to have the means of bypassing the
host’s immune pathways. The presence of intracellular
Gram-positive cocci in the middle ear of children with OME
has already been veried, which could imply greater bacterial resistance and perpetuation of inammatory cascades.
Innate immunity is the rst line of defense against these
microorganisms. It consists of nonspecic barriers (that is,
not directed at specic pathogens) that range from mucociliary ow to proinammatory molecules. Among these, we
highlight the role of lysozymes, defensins, complement factors, cytokines, and chemokines in the middle ear. Bacteria
and viruses act as triggers for the activation of inammatory
mediators in the nasopharynx, auditory tube, and middle ear
cleft. Cellular receptors, such as Toll-like receptors (TLRs),
detect the presence of pathogenic antigens, triggering an
immunoinammatory cascade. Adding certain bacterial biolms (mainly Pseudomonas aeruginosa and Staphylococcus
aureus) to the innate immune system receptors that are in a
state of upregulation results in the middle ear being in a constant inammatory state. The clinical effects of this prolonged inammation translate into what we call chronic
otitis media [6, 22, 23].
As for humoral immunity, its role in ghting middle ear
infection is mainly through immunoglobulin (Ig)A (present
in the mucous membranes) and IgG (found in tissue plasmocytes). These molecules act by adhering to the bacterial wall,
in a process called “coating.” One factor that could explain
the colonization of P. aeruginosa in the middle ear clefts in
COM is that this pathogen easily prevents the “coating” of
immunoglobulins. Children with secretory COM seem to
have deciency in the local production of IgA, whose role in
the defense of the middle ear mucosa is reduction of adherence and colonization of potentially pathogenic microorganisms. IgG facilitates the phagocytosis of microorganisms and
stimulates the complement system. Some children with
recurrent respiratory tract infections may also be decient in
specic IgGs, such as IgG2.
However, an individual’s immune response and susceptibility to the chronicity of otitis media does not exclusively
depend on the presence of microorganisms. Several other
genetic and molecular factors as well as environmental exposure to pollution and cigarette smoke are well-established as
an integral part of this process. External factors trigger the
onset of an immune-mediated inammatory cascade in the
middle ear cleft. Models in rats also suggest that alterations
in the recruitment of neutrophils and macrophages, as well
as a decient phagocytic function, seem to be linked to the
prolongation of the inammatory process in the middle ear.
Deciencies in the tympanic membrane plasminogen, in
these specimens, lead to a decient regeneration after an episode of tympanic perforation. On the other hand, inammatory pathways that act in local protection against
microorganisms, when overexpressed, lead to a high secretion of cytokines that can also lead to tissue damage and
chronicity of the otitis media process.
Molecular biology techniques have identied several
genes that act in the process of perpetuating the inammation that occurs in AOM and its subsequent progression to
COM.Middle ear inammation caused by AOM reduces the
availability of oxygen to the middle ear mucosa, perpetuating the inammatory process through production of reactive
oxygen species. Hypoxia is a trigger to the nuclear factor
kappa B (NF-κB) pathway, releasing further inammatory
mediators such as vascular endothelial growth factor
(VEGF), which increases neoangiogenesis, propagates
inammation, and results in production of exudates. This
further results in the upregulation of inammatory gene
expression, propagating the inammatory process and
increasing the risks of development of COM.Individual variations in inammatory response and gene expression also
play a role in this process. Polymorphisms of the FBX011
and TGIF1 genes, for example, modulate transforming
growth factor beta (TGF-β) expression during inammatory
processes. Interleukin (IL) regulatory genes have also been
identied as participants in this process. In COM, polymorphisms of receptor regulatory genes, such as Toll-like and
Nod-like, are also found in the middle ear mucosa that is in a
state of upregulation. Overexpression of the inammasome
NLRP3 (nucleotide-binding domain, leucine-rich- containing
family, pyrin domain–containing-3), a subtype of the Nodlike receptor, results in alterations in the inammatory
pathway of IL-1β and IL-18. The IL-17 inammatory pathway also appears to be more active in the mucosa of patients
with COM and sinusitis. Its deregulation can lead to overexpression of cytokines and chronic inammation in chronic
mucosal diseases. IL-17 also appears to be increased in the
effusions and peripheral blood samples from children with
OME.The Toll-like receptor (TLR)-2 is capable of recognizing lipoproteins from Gram-positive bacteria and mediating
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the inammatory immune response. TLR-4, on the other
hand, recognizes lipopolysaccharides, a cell membrane component of Gram-negative-bacteria present in the middle ear
of patients with otitis media. It has been shown that the transtympanic injection of lipopolysaccharides into rat ears generates IL-1β production [24–26].
Conversely, some genes that mediate host innate immunity and signaling pathways, have anti-inammatory properties and mediate middle ear regeneration after an acute
inammatory episode. The TGF-β pathway, for example,
helps minimize a possible exaggerated inammatory process, modulating the action of these proteins. The balance of
molecular forces seems to be at the core of links that are still
not well-understood in the pathogenesis of COM [27].
Mucins, which are highly glycosylated glycoproteins that are
present in the granules of mucus-producing cells, can also
prevent bacterial invasion in mouse ear models. Exposure of
the human middle ear to live bacteria or bacterial lysates
from S. pneumonia, non-typeable H. inuenzae, and
Moraxella catarrhalis induces regulation of mucin production via messenger RNA.These pathways are responsible for
epithelial metaplasia that transforms the middle ear epithelium into mucus-producing cells. Pollution particles seem to
have the same effect on the middle ear epithelium.
In acute otitis media, the ossicles undergo an initial reabsorption and posterior remodeling process, which can alter
their sound conduction capacity. The activity of osteoclasts
responsible for bone remodeling seems to be mediated by
lipopolysaccharides. Ossicular destruction in the middle ear
of rats is much more strong when the osteoprotegerin cytokine receptor is absent. Some pathogens have the ability to
bypass the round window barrier and cause migration of
inammatory cells to the scala tympani. Pneumococcus, for
example, when producing the pneumolysin enzyme, caused
tissue damage in the inner ear of examined rats [28, 29].
Development, Anatomy, andPhysiology
oftheMiddle Ear
Phylogenetic Evolution oftheMiddle Ear
Communication is a key factor in the interrelationship
between numerous animal groups. This ability came about as
the demands for survival in the environment led to the emergence and improvement of structures adapted for the production and capture of sound energy. Thousands of years of
evolution have made this exchange of information indissoluble, at rst rudimentary, but largely responsible for the perpetuation of these animals in the biosphere. The structures
responsible for sound production and capture show a wide
range of variations across species.
Regarding the capture of sounds from the environment,
the crucial moment in the renement of the auditory system
occurs when life-forms born in water start to inhabit the terrestrial environment. Thus, the sound waves previously captured through vibrations in the aquatic environment must
overcome the resistance of a different medium, such as air, to
be perceived. It was with the intention of improving this process that the evolution occurred from purely sensory structures in aquatic beings to those with much more elaborate
auditory functions.
Among sh, the sense of hearing is demonstrably more
evolved in the teleost group, including carp, catsh, and
goldsh, which have auditory structures somewhat similar to
those of tetrapods [30]. These sh have developed the socalled swim bladder, which works as a hydrophone that captures sound waves transmitted by the water [31]. From the
anterior portion of this organ arises pairs of bones derived
from the ribs, called the Weberian ossicles, which transmit
and amplify vibrations to the perilymphatic space adjacent to
the sensory epithelium of the saccule, a rudimentary hearing
organ, in addition to its role in maintaining the vestibular balance [30, 32, 33]. This ingenious primitive mechanism of
transmission of sound vibrations to a sensorial epithelium
through a true bone bridge nds an analogy with the tympanic membrane and middle ear ossicles found in tetrapods.
Conversely, other sh have openings called spiracles, which
open into the mouth to transport oxygen from the external
environment, in addition to the hyomandibular bone, which
is adjacent to the inner ear and participates in sound transmission from the aquatic environment [32]. Theoretically,
during the evolutionary process, the spiracles gave way to
the middle ear and the hyomandibular bone was modied in
the columella found in amphibians [34].
Even in the most primitive amphibians, a tympanic membrane is found on the outer surface of the head. In the middle
ear, a single bone (“columella”) connects the tympanic membrane to the inner ear. This bone is interposed between the
supercial region of the head and the inner ear, and its most
proximal portion has already been called stapes by some
authors [35]. Similar to the eardrums of amphibians, in sh,
communication takes place between the throat and the external environment through the spiracle, an orice that is
located adjacent to the hyomandibular bone and that transmits sound from the cranial vault to the inner ear [34]. This
topographic location allows us to deduce the evolution of the
spiracle into the auditory tube and middle ear chamber and
the hyomandibular bone into the columella, as we nd in
most modern amphibians. In the most primitive reptiles, for
example, lizards, some modications have been observed.
We observed that the columella remains isolated while communicating sounds to the inner ear, with no further involvement of the mandible bones. In addition, the columella can
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become complicated in its most external portion in the extracolumella when it becomes cartilaginous and adapts to the
eardrum, thus playing the role of a sound-capturing organ. A
small external depression is also observed, which would be
an outline of the external acoustic meatus, compared to that
found in more evolved vertebrates.
In addition to a well-developed cochlea, mammals as a
whole also have particularities in the middle ear. In this
chamber, there are three typical ossicles, namely, the malleus, the anvil, and the stirrup, whose basic function is to
conduct and amplify many times the vibrations captured
from the air environment. Much was debated about the phylogenetic origin of such structures, until a joint study between
comparative anatomy and paleontology claried the issue.
As already mentioned, primitive reptiles had two bones
forming the mandibular joint: the quadrate and the articular.
It seems that the rst mammals developed other bones of
their own for articulation, with which such elements were
relegated to exclusive functions in the middle ear. The quadrate, conserving its connection with the eardrum, became the
malleus, whereas the articulation placed between it and the
stapes was modied into the incus [32]. The biggest stimulus
for these changes seems to have been improving hearing in
order to capture prey and escape from predators not in the
direct line of sight. This was especially striking for the rst
mammals that survived the tyranny of reptiles in the
Mesozoic era, when nocturnal behavior emphasized auditory
and olfactory perception [36].
Embryology
The Middle Ear Cleft
Between the third and seventh months of gestation, four
endothelial pouches evaginate from the rst branchial arch to
form the tympanic cavity. At the points where these bags
come into contact, mucous folds and suspensory ligaments
of the ossicles are formed, thus generating compartmentalization of the middle ear [37].
The middle sac, occasionally with a contribution from the
anterior sac, forms the epitympanum, as described by Jackler
[38]. It is divided into three saccules: anterior, middle, and
posterior. The middle saccule forms Prussak’s space—
bounded by Shrapnell’s membrane, the neck, and the lateral
process of the malleus and the lateral malleolar fold—and
the superior incudal space (laterosuperior to the malleus
head and body of the incus) [38].
The posterior saccule pneumatizes the petrous portion of
the mastoid cell system. The anterior saccule often gives rise
to the anterior compartment of the epitympanum. At these
times, the anterior and posterior epitympanic compartments
are conuent and separated from the anterior mesotympanum by the tensor tympani fold. The anterior epitympanum
can also derive from the saccus anticus when the anterior
saccule delays its expansion in this direction. When this
occurs, the saccus anticus—which is already responsible for
the formation of the anterior mesotympanum and the anterior space of Von Trölscht—also forms the so-called supratubal recess that freely communicates with the protympanum,
since the tympanic tensor fold is incomplete in these cases.
The saccus superior forms the inferior incudal space (below
the body of the incus) and proceeds to pneumatize the squamous portion of the temporal bone. The limit of mastoid
pneumatization proceeding from the superior saccus—squamous—and from the saccus medius—petrous—may become
evident as a bone plate known as the petrosquamous plate or
Körner’s septum, a reference point in the posterior approach
to the antrum. The saccus posticus forms the posterior mesotympanum and hypotympanum.
The Otic Capsule
The embryological development of the otic capsule is no less
complex, being unique in several aspects. In all bones of the
human body, the ossication process takes place concomitantly with the deposition of new cartilage plates. In the otic
capsule, however, this pattern is not followed since ossication takes place only after the cartilaginous matrix has
reached its denitive stage. By the time the ossication of
the otic capsule is complete, all inner ear structures must
have reached their adult size since the bony framework thus
formed does not allow for further growth. The other peculiarity of this region (and of the ossicles) is that the endochondral bone initially formed will never be removed and replaced
by the Haversian periosteal bone, as occurs in other bones. In
this way, it will continue throughout life as a relatively avascular bone, of stony consistency, poor in osteogenic responses
and exhibiting discreet remodeling activity [39].
The rst ossication center appears around the cochlea
when it reaches the adult state around the 16th week. The last
center appears around the semicircular canals in the 20th
week of intrauterine life. Once initiated, ossication progresses at an accelerated pace until the 23rd week when it
should be complete, except for a small area over the posterior
semicircular canal and a reniform area around the oval window and the ante fenestram ssula [40].
The Ossicles
In an 8-week-old embryo, the tympanic cavity corresponds
to only the lower half of the future middle ear, and its upper
half is completely lled with the mesenchymal tissue. The
ossicles originate from small cartilaginous condensations
found in the mesenchyme of the rst and second branchial
arches (hammer and incus predominantly of the rst and stapes of the second branchial arch). Initially, the malleus,
2 Otitis Media: Basic Concepts andFundamentals
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incus, and cartilaginous mandible are interconnected as the
Meckel’s cartilage of the rst branchial arch, whereas the
styloid process, hyoid bone, stapes, lenticular process of the
incus, and malleus handle make up the so-called cartilage of
the incus. Reichert’s cartilage is formed in the second branchial arch. The primitive ossicles quickly separate from the
cartilages from which they originated and begin independent
development. The ossicles, as well as the otic capsule and the
labyrinth, grow only until the rst half of intrauterine life
when, then, they ossify each one from a single ossication
center that appears in the 16th week in the incus, between the
16th and 17th weeks in the malleus, and in the 18th week of
intrauterine life in the stapes. Interestingly, the hammer and
anvil remain solid and structurally constant after the ossication process. The stapes, on the other hand, develops a curious process of erosion and remodeling right after its
ossication. The result of this process is the less robust and a
much more delicate appearance of the adult stirrup when
compared to the fetal one.
Anatomy
At the beginning of this chapter, we dened otitis media as
an inammatory process, infectious or noninfectious, located
in the middle ear cleft. It is important to state that the term
“middle ear cleft” should be preferred over “middle ear.” As
we will discuss below, this deliberate substitution has precise
clinicopathological reasons, echoing modern concepts of
classication and pathogenesis of otitis, not constituting,
therefore, just a semantic caprice. This concern makes sense
when we verify that the dimensions of the middle ear have
been inadequately compressed to the region subjected to otomicroscopic inspection. In other words, the universe of
inammatory and infectious alterations that are characteristic of this disease would be limited to the mesotympanum,
which is clearly exposed through the transparency or even
the absence of the tympanic membrane. It is clear that the
middle ear is multi-compartmental and that the mesotympanum represents only one of these compartments; however,
we note that the conception of this scope is facilitated with
the introduction of a new concept, namely, the middle ear
cleft, which includes the bony portion of the auditory tube in
all its extension as well as its opening next to the protympanum. This association, which may even be debatable from a
strictly anatomical point of view, makes sense insofar as this
entire complex reacts en bloc when it is subjected to an insult
of an inammatory nature.
The Middle Ear Cleft
When reviewing and summarizing the anatomy of this
region, it is convenient to remember that it is represented by
two aerated cavities, an anterior cuboid—the middle ear cleft
with its three oors, epitympanum or attic, mesotympanum,
and hypotympanum, and the tympanic portion of the auditory tube—and a grossly posterior pyramidal—the cell complex of the mastoid with its largest cell: the mastoid antrum.
These cavities are continuous and are joined by a small triangular opening called an adyte. The upper boundary of the
tympanic cavity is the tegmen tympani, a thin bony roof that
separates it from the dura of the middle fossa, communicates
inferiorly with another bony lamina in close relationship
with the jugular gulf, anteriorly with the tympanic orice of
the Eustachian tube, which connects the middle ear with the
nasopharynx, anteromedially with the vertical segment of
the petrous portion of the internal carotid artery, posteriorly
with the aditus, a passage that connects the upper oor of the
tympanic cavity (the epitympanum or attic) with the cells of
the mastoid, laterally with the tympanic membrane that separates it from the external auditory canal, and medially with
the otic capsule that protects the inner ear and its two windows, oval and round, lled, respectively, by the footplate of
the stapes and the membrane of the round window. In addition, the tympanic cavity has a set of small articulated bones,
the ossicular chain, constituted by the malleus, incus, and
stapes, which, attached to muscles and ligaments, transmits
and amplies the sounds that reach the tympanic membrane
and are conducted to the eardrum through the oval window
[41]. All the structures described above are covered by the
respiratory epithelium, which modies its ciliary and glandular histological structure according to the region it covers
or the pathological alterations to which it adapts [41].
The Eustachian Tube
The Eustachian tube consists of a canal comprised part by
bone and part by brocartilaginous tissue that runs from the
nasopharynx to the middle ear. The bony part and the brocartilaginous part are connected at the level of the isthmus,
which is the narrowest part of the Eustachian tube, with an
approximate diameter of 1.5mm. Thus, the Eustachian tube
has an hourglass shape, with its tympanic and nasopharyngeal orices being much larger than the isthmus. In adults,
the Eustachian tube is longer, more inclined, and narrower
than in children, which seems to indicate one of the reasons
why AOM is more frequent in childhood, when there would
be less protection against infected nasopharyngeal secretions. While the bony part of the Eustachian tube is, under
normal conditions, permanently open, the brocartilaginous
portion is closed most of the times. The brocartilaginous
portion opening mechanism involves a complex muscular
contraction in which the tensor and levator palate muscles
play a preponderant role [42, 43]. These muscles contract
during physiological actions such as swallowing, which happens every minute when the individual is awake and every
5 min when sleeping, by reex arc, as well as the act of
yawning. This dilation causes air to pass from the nasophar-
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ynx to the middle ear cleft, renewing its air content and balancing its pressure with atmospheric pressure, thus keeping
the tympanic membrane and ossicular chain in a balanced
position, with minimum impedance. The brocartilaginous
portion of the Eustachian tube can also be passively dilated,
as in the act of sneezing or in the Valsalva maneuver when,
regardless of muscle action, air is forced into the middle ear
cleft. The Eustachian tube has three main functions (ventilation, drainage, and protection) that will be discussed below.
Tubal Physiology
Ventilation oftheMiddle Ear andtheMastoid
As previously mentioned, the middle ear ossicles originated
in vertebrates when they became terrestrial in order to
recover the loss of energy resulting from the passage of
sound from an air medium to a liquid medium or, in other
words, to overcome the so-called interface of air–bone
impedances [34]. To fulll this function properly, the tympanic–ossicular system requires minimal friction between its
various components and the presence of a physically inert
environment. Such an environment is provided by the middle
ear cleft, which is a structure analogous to a gas bag.
Biological gas sacs are not rare in the animal world, as they
are present in a multitude of forms and with the most varied
functions: birds have respiratory air sacs that can extend to
the bones in order to facilitate ight, sh have swim bladders
with the function of oating, and mammals have intestines,
paranasal sinuses, and tympanic cavities [34]. In fact, the
middle ear cleft and the Eustachian tube can be roughly compared to the lower airways, with the former representing a
sort of a “mini lung.” All these air bags face a common problem, which is the possibility of collapsing if they fail to compensate for pressure variations veried inside them caused
by the continuous gaseous exchanges carried out with the
adjacent circulation. A second problem characteristic of
these structures is the absolute need to maintain their selfcleaning properties. These two attributions, namely, ventilation and drainage, and the overlapping function of protection,
are carried out in the middle ear by the Eustachian tube [44].
There are some general principles that regulate the socalled gaseous economy of the middle ear or any other bag
of biological gas. The presence of a certain gas in a gaseous
environment is expressed in terms of its partial pressure (PP).
The sum of all the partial pressures of the gases that make up
this mixture corresponds to the total pressure (TP) of this
environment. Under normal conditions of temperature and
pressure, ambient air is composed of a combination of ve
gases: nitrogen (N2), argon (Ar), oxygen (O2), carbon dioxide (CO2), and water vapor. The same gases are found in different dilutions in blood, tissues and, obviously, in the
tympanic cavity. Thus, the TP of ambient air at sea level is
10,000mm of water (H2O) or 760mm of mercury (Hg), and
its composition at a temperature of 37°C (when saturated by
water vapor) is 150mmHg of O2, practically zero CO2, and
approximately 563mmHg N2. The amount of water vapor
present in one or another environment will dilute or concentrate the other gases in direct dependence on its degree of
saturation and also on the function of the temperature where
this system is found. The PP of gases present in the alveoli
and the TP of inspired air are practically identical and in balance with those found in the arterial blood leaving the alveolar capillaries. As the blood transits the circulation toward
the tissues, several changes occur in the composition of these
gases. Thus, volumetrically speaking, O2 is consumed more
proportionally at the cellular level than CO2 is produced [44].
This difference can be expressed through a typical equation
or as the CO2/O2 respiratory quotient less than one (0.85).
The PP of CO2 is also inuenced by the lower solubility of
this gas in tissues and blood when compared to O2. This
asymmetry between the solubility and the shape of the O2
and CO2 saturation curves in the blood results in a sharp drop
in O2 levels and, on the other hand, in only a slight increase
in the CO2 concentration in the transition from the arterial to
the venous compartment. For example, partial pressure of
oxygen (PO2) decreases from 102 mmHg in the alveoli to
approximately 93 mmHg in arterial blood, plummeting to
38mmHg in venous blood. On the other hand, partial pressure of carbon dioxide (PCO2) has a slight increase from
39 mmHg in the alveoli to only 44 mmHg in the venous
level. Thus, while the metabolic consumption of oxygen
causes the PO2 to decrease by 55mmHg, the tissue production of carbon dioxide raises the PCO2 by only 5 mmHg.
This difference corresponds to a gaseous pressure decit
found in the venous blood that circulates in the tympanic
cavity and with which this structure has to adapt. These PO2
and PCO2 variations between arterial and venous blood are
not accompanied by corresponding changes in N2 levels
since this gas hardly participates in metabolic processes. As
an example, the partial pressure of nitrogen (PN2) of alveolar
air is 572mmHg, whereas in the venous system, this number
rises by only 3mmHg (575mmHg). Thus, the behavior of
the gases in the transition from alveolar air to the arterial and
then venous system will show a considerable drop in PO2, a
slight increase in PCO2, and maintenance of PN2.
Consequently, the venous environment surrounding the
middle ear has, at sea level, a TP lower than the atmospheric
pressure found in the light of the tympanic cavity [44].
The particles of a gas have the tendency to transfer from
an environment of high pressure to that of low pressure until
the balance between these two systems is reached. This transfer occurs in any permeable medium at rates specic to uids,
tissues, blood walls, and epithelial surfaces. In this way, the
gases that ll the tympanic cavity “strive” to nd a balance
with the corresponding pressures in the adjacent venous cap-
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