This document discusses the formation and management of granulation tissue in the middle ear in cases of chronic ear disease. It begins by describing the multi-stage process of granulation tissue formation, starting with a break in the epithelial cell basement membrane allowing inflammatory cells to enter the middle ear space. It then discusses factors that promote the growth of granulation tissue like endothelial growth factors. The document outlines methods to control granulation tissue including aural toilet, anti-infectives, steroids, and cautery/debridement. It also discusses granulation tissue in the context of tympanostomy tubes and other chronic ear diseases.

1. The formation and management
of middle ear granulation tissue
in chronic ear disease

2. First
stage
The formation of
granulation tissue
in the middle ear
space begins with
a break in the
basement
membrane of
surface epithelial
cells.
Inflammatory cells in
the underlying
lamina propria
traverse through the
broken basement
membrane and enter
the lumen of the
middle ear space.
The rupture of the
basement membrane
and epithelial cell lining
is caused by bacterial
toxins, inflammatory
mediators produced by
ruptured lysozymes, and
the accumulation of
subepithelial fluid and
vacuoles, all of which
exert pressure on the
surface epithelium.

3. Second
stage
The second step in the
formation of
granulation tissue
occurs when a small
piece of the herniated
lamina propria
extrudes through the
ruptured area of the
epithelial cell surface
The result of this
extrusion is that the
affected tissue is no
longer epithelialized.
In some cases,
angiogenic growth -
incite capillary budding,
vascular
hyperpermeability, and
fibroblast recruitment. If
the growth of
granulation tissue is
vigorous and aggressive,
polyps can form (figure
3).

4. Growth of granulation tissue
• endothelial growth factor,
• tissue growth factors
• alpha and particularly beta,
• vascular endothelial growth factor,
• prostaglandin growth factor

5. • Following the rupture of the lamina propria into the middle
ear space, re-epithelialization begins.
• Re-epithelialization is a continuous process, although it
occurs at different rates and is often incomplete.
• When the epithelium surrounds a polyp, it can become
metaplastic. Microsectioning of these polyps generally
reveals the presence of a variety of different types of
epithelial surfaces in different portions of the polyp.
• The presence or absence of a significant amount of
keratinizing epithelium on a polyp surface during biopsy
analysis can provide clues to the polyp's etiology.
• The presence of significant keratinizing epithelium
indicates that the cause of the polyp is a cholesteatoma, as
opposed to a purely infectious process. On the other hand,
the absence of squamous keratinizing epithelium is a fairly
reliable sign that no cholesteatoma is present.

6. Tympanostomy-tube-related
granulation tissue
• Kay et al performed a meta-analysis of more than 7,000
ears and found that the mean incidence of granulation
tissue in patients with tympanostomy tubes was slightly
less than 5%.
• Of these, 8.1% required surgical debridement.
• El-Bitar et al found that the incidence of granulation tissue
was 13.8% in tympanostomy tubes
• had been in place for 2 to 3 years and more than 40%
tubes that had been in place for more than 5 years.-60%
• They also noted that children who were older than 7 years
were much more likely to have granulation tissue than
were younger children, regardless /of how long the tubes
had been in place.

7. Etiology.
• The etiology of tympanostomy-tube-related granulation
tissue is still disputed.
• In some cases, of course, its development is almost
certainly the result of the actual middle ear infection itself.
• Granulation tissue might also arise as a direct response to
the presence of the foreign body in the tympanic
membrane, or it might represent a direct response to
trapped squamous epithelium that has become lodged
between the flange of the tube and the tympanic
membrane.
• Post suggested that tympanostomy-tube-related
granulation tissue might be related to the development of
bacterial biofilms that adhere to the surface of the tube.3

9. Consequences.
• There are several potential consequences of
tympanostomytube-related granulation tissue.
• One is that it might impede the delivery of topical antibiotic
solution to the site of infection so that the eardrop cannot
penetrate into the middle ear space, which, of course,
would result in a treatment failure.
• Another complication is that the granulation tissue can
cause bloody otorrhea. This in itself is not serious, but it
can alarm the child's parents and lead them to seek
emergency treatment, which significantly drives up the cost
of care.
• Finally, over long periods of time, granulation tissue can
fibrose and lead to permanent/тогтмол байнгийн/
scarring.

10. Granulation tissue in other types of
chronic ear disease
• Meyerhoff et al reported that granulation tissue
develops in 94% of all cases of chronic suppurative
otitis media (CSOM),
• usually in the epitympanum, and in 100% of cases of
CSOM that are characterized by intracranial
complications.4
• Granulation tissue also develops in many cases of
chronic otitis externa.
• Finally, chronic granular myringitis is, in effect, a
granulation tissue disease-that is, granulation tissue is
essentially its only manifestation.

12. Control and management
The control and management of granulation
tissue involves the use of four modalities:
1. aural toilet
2. antiinfectives
3. steroids
4. cautery -silver nitrate wrong site - paralysis FN
or debridement.

13. Aural toilet.
• The easiest method of aural toilet is irrigation, which,
of course, can be performed by virtually anyone in any
setting. The best results are achieved with one or two
syringefuls or bulbfuls of either full-strength (3%) or
half-strength hydrogen peroxide, which is safe and
generally painless. Flushing of the ear should take
place 15 to 20 minutes prior to the administration of
therapeutic eardrops so that the irrigation solution has
had sufficient time to dissipate. Once the ear is dry, the
therapeutic eardrops will be able to penetrate to the
source of the granulation tissue.

14. Chart shows that ciprofloxacin/dexamethasone was significantly more
effective than ofloxacin alone in eradicating granulation tissue in 90 children
with acute otitis media with otorrhea at 11 and 18 days from the initiation of
treatment

15. Bilateral nontuberculous
mycobacterial middle ear infection:
A rare case
Case report

16. Abstract
• Nontuberculous Mycobacterium (NTM) middle ear
infection is a rare cause of chronic bilateral intermittent
otorrhea. We report a rare case of bilateral NTM
middle ear infection in which a 55-year-old woman
presented with intermittent otorrhea of 40 years'
duration. The patient was treated medically with
success. We conclude that NTM is a rare but probably
under-recognized cause of chronic otitis media. A high
index of suspicion is needed for the diagnosis to avoid
prolonged morbidity. Treatment includes surgical
clearance of infected tissue with appropriate
antimycobacterial drugs, which are selected based on
culture and sensitivity.

17. Introduction
• Nontuberculous mycobacteria (NTM) are related to but are
different species from Mycobacterium
tuberculosis and Mycobacterium leprae.1,2 They are
important low-virulence, environmental pathogens that
have been associated with human diseases, particularly in
immunocompromised patients. They are found in soil,
biofilms, drinking water, and
aerosols.3 Otorhinolaryngologic (ORL) infections due to
NTM are rare. The most common ORL nontuberculous
mycobacterial infections are head and neck lymphadenitis
and middle ear infections; these infections always target
healthy young children. We report a case of NTM middle
ear infection in a 55-year-old woman who had experienced
bilateral otorrhea intermittently for 40 years.
•

18. • A 55-year-old woman was referred to our ORL clinic for
chronic intermittent bilateral otorrhea lasting 40 years; it
was associated with decreased hearing bilaterally. She had
only sought medical advice from general practitioners
when her ear discharge increased or bothered her. She
claimed multiple oral antibiotics and local otic drops had
been prescribed for her, but none of these medications had
completely dried her ears.
• The patient underwent left myringoplasty in 1982 in a
private hospital, but the graft failed. Since then, she had
been followed inconsistently in a private clinic. In 2001, she
underwent a left modified radical mastoidectomy, but it did
not solve her problem. She was then referred to our ORL
clinic in 2003.
• At the patient's presentation to our clinic, her symptoms
were still persistent despite the multiple treatments she
had been given. Her medical history was otherwise
unremarkable, and she had no evidence of
immunodeficiency.

19. • Clinical examination revealed bilateral intact
facial nerves. Her ear examination revealed
bilateral mucopus discharge with bilateral
subtotal tympanic membrane perforation. There
was minimal granulation tissue noted in the
middle ears bilaterally.
• Multiple biopsies of granulation tissue, as well as
culture and sensitivity swabs, were taken from
both ears. The biopsy revealed acute-on-chronic
inflammation of nonspecific origin and no growth
culture from the granulation tissue. The culture
and sensitivity swabs grew Staphylococcus
aureus.

20. • The patient was treated with oral antibiotics and local
otic drops based on culture results, but the otorrhea
persisted.
• She was then scheduled for an otoscopic examination
under anesthesia and underwent mastoidectomy
revision surgery to clear the remaining granulation
tissue.
• Granulation tissue obtained from both ears yielded
rapidly growing Mycobacterium
abscessus andMycobacterium fortuitum that were
resistant to trimethoprim-sulfamethoxazole but
sensitive to imipenem, clarithromycin, and
azithromycin.

21. • High-resolution computed tomography (HRCT) and
gallium scans revealed bilateral temporoparietal
osteitis.
• The patient was given intravenous imipenem 500 mg
three times daily and oral clarithromycin 500 mg twice
daily. Amikacin was added to the treatment regimen
for a synergistic effect, but the patient was unable to
tolerate it. Therefore, the dual treatment was
continued for a total of 40 days without any
complications. The patient was then continued on oral
doxycycline 100 mg twice daily, clarithromycin 500 mg
twice daily, and moxifloxacin 400 mg once daily. The
medications were continued for 1 year after her illness
had resolved, during follow-up.
•

22. . Axial HRCT of the temporal bone shows soft-tissue thickening in the left external auditory canal
posteriorly (arrow). Osteitis changes are noted in the left temporal bone. The presence of left
mastoid air cells indicates previous surgery

23. Repeat axial HRCT of the temporal bone
obtained 1 year after treatment reveals no
evidence of recurrence of the otitis media and
osteitis.
Six months after the
treatment with the three
oral antibiotics, both of the
patient's ears were dry and
her hearing had improved. A
repeat gallium scan revealed
a significant response to
treatment. HRCT of the
temporal bones was
performed 1 year after
completion of the three oral
antibiotics; it revealed no
evidence of recurrence of
otitis media and osteitis

24. Discussion
• Runyon identified NTM species as human pathogens in 1959.5 He
classified NTM into four groups depending on the speed of growth,
morphology, and carotenoid pigmentation of colonies of solid media, as
well as biochemical reactions. The Runyon group IV was identified based
on rapid growth characteristics and nonpigmented colonies. Three species
from Runyon group IV-M fortuitum, Mycobacterium chelonae, and M
abscessus-can cause human disease in any part of the body.6
• NTM species are low-virulence, opportunistic pathogens that can cause
disseminated disease in immunocompromised individuals and localized
disease in otherwise normal hosts. Localized NTM infection is usually
precipitated by penetrating trauma or surgery. Most NTM infections
present as chronic cervical lymphadenitis in healthy children with ORL
infection. Tympanomastoid infection due to NTM is rare. Nearly all the
cases of NTM middle ear infection are caused by the M fortuitumcomplex
(which includes M fortuitum, M chelonae, and M abscessus; 67%) or by
theMycobacterium avium complex (27%).7 In our case, the middle ear
infection was caused by M abscessus.
• Entry of NTM into the middle ear is most probably by direct inoculation via
the external ear canal. Other possible entry routes include the eustachian
tube and hematogenous or direct spread.8 Most of the studies show
tympanostomy tubes as the most preferential route of entry of NTM.4,6-8

25. • In our case, there was no history of ventilation tube
insertion, but our patient had undergone two left ear
operations. These operations might have been the route of
direct inoculation of NTM into the middle ear when it was
exposed to the ambient environment.
• Clinical suspicion of NTM middle ear infection should be
raised in any chronically draining ear unresponsive to
standard antibiotic therapy regardless of a patient's age or
immune system status. Clinical examination of an ear that
shows persistent otorrhea with granulation tissue will add
more suspicion for an NTM infection.
• Redaelli de Zinis et al reported that NTM infections
appeared to develop over a preexistent chronic or
recurrent middle ear inflammatory disease.7 However,
there is no direct evidence that these conditions were not
actually NTM infections that had been misdiagnosed. The
incubation time varies from 1 week to 2 years, but most of
the infections manifest themselves within 1 month. There is
no evidence of human cross-infection.

26. • Flint et al8 and Franklin et al6 reported bone erosion
caused by the progression of NTM infection. The
eroded bones, identified by CT, were the cortical
mastoid, tegmen, posterior ear canal, and middle ear
ossicles. Although CT of the temporal bone cannot
confirm the diagnosis, it can detect the extent of the
lesion, bone erosion, and intracranial extension. In our
case, both HRCT of the temporal bone and a gallium
bone scan revealed bilateral temporoparietal osteitis
without any intracranial complications.
• Histopathologic examination of NTM infection shows
noncaseous granulomatous changes of the tissue
specimens, but acid-fast bacilli staining will be
negative. However, the diagnosis can only be
confirmed by a positive culture from the infected tissue
or ear discharge

27. • . Because of the small numbers of this microorganism
and its slow growth rate, the organism cannot always
be detected. It often takes 2 to 6 weeks before the
species can be identified biochemically. This issue has
been emphasized in almost all the literature reviews
regarding NTM infection.2,4,6-8 With the aid of
polymerase chain reaction testing, it is possible to
make a more rapid identification of the type of NTM.9
• Management of NTM middle ear infection is
challenging. The ideal treatment is complete surgical
excision of the infected tissue8 and long-term
antibiotic therapy.6,7 However, because of the
complicated anatomy of the middle ear, complete
surgical excision is rarely possible. (In our case, some
granulation tissue was left to avoid injury to the facial
nerve and cochlea.)

28. • Moreover, the rate of resistance to antibiotics is high,
and they should be continued for a long period until
repeated cultures are negative or there is dramatic
improvement in the clinical signs and symptoms.
• Antibiotic therapy that should be given intravenously is
high-dose cefoxitin or imipenem for 3 to 6 weeks,
together with clarithromycin and intravenous amikacin.
It should later be followed by at least 4 to 6 months of
clarithromycin. However, this therapy should be based
on individual organism susceptibilities and clinical
response.2 In our case, the patient was also given
doxycycline and moxifloxacin for 1 year of long-term
therapy because one of the tissue specimens grew M
fortuitum.

29. • A common suggestion for medical therapy from the literature is to
provide multidrug treatment based on cultural examinations to
avoid antibiotic resistance for a period varying from 1 to 3 months
after the patient is disease-free.4,7,8
• In conclusion, NTM is a rare and probably under-recognized cause
of chronic otitis media. A high index of suspicion is needed for the
diagnosis to avoid prolonged morbidity. A thorough history and
physical examination, along with appropriate investigations, are
needed to diagnose NTM infection in the middle ear. Tissue
specimens from granulation tissue for histology and culture should
be obtained in cases of chronic otitis media unresponsive to
conventional antibiotic therapy. The diagnosis of NTM only can be
confirmed by growth of the NTM species. Treatment includes
surgical clearance of infected tissue with appropriate
antimycobacterial drugs based on culture and sensitivity.
•