The formation and management of

middle ear granulation tissue in

chronic ear disease

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.

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).

Growth of granulation tissue

• endothelial growth factor,

• tissue growth factors

• alpha and particularly beta,

• vascular endothelial growth factor,

• prostaglandin growth factor

• 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.

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.

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

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.

Granulation tissue in other types of chronic ear disease

• Meyerhoff et al reported that granulation tissue develops in 94% of all cases of chronic suppurativeotitis 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.

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.

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.

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

Bilateral nontuberculousmycobacterial middle ear infection:

A rare case

Case report

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.

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 nontuberculousmycobacterial 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.

•

• 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.

• 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.

• The patient was treated with oral antibiotics and local otic drops based on culture results, but the otorrheapersisted.

• She was then scheduled for an otoscopic examination under anesthesia and underwent mastoidectomyrevision 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.

• High-resolution computed tomography (HRCT) and gallium scans revealed bilateral temporoparietalosteitis.

• 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.

•

. 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

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

Discussion• Runyon identified NTM species as human pathogens in 1959. 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.

• 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%). 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 eustachiantube and hematogenous or direct spread. Most of the studies show tympanostomy tubes as the most preferential route of entry of NTM.

• 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. 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.

• Flint et al and Franklin et al 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 osteitiswithout 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

• . 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.With the aid of polymerase chain reaction testing, it is possible to make a more rapid identification of the type of NTM.

• Management of NTM middle ear infection is challenging. The ideal treatment is complete surgical excision of the infected tissue and long-term antibiotic therapy. 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.)

• 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. 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.

• 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.

• 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.