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

The formation of granulation tissue in the middle ear space begins with a break in the basement membrane of surface epithelial cells (figure 1). 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.

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 (figure 2). The result of this extrusion is that the affected tissue is no longer epithelialized. In some cases, angiogenic growth factors--such as endothelial growth factor, tissue growth factors alpha and particularly beta, vascular endothelial growth factor, and prostaglandin-derived growth factor--incite capillary budding, vascular hyperpermeability, and fibroblast recruitment. If the growth of granulation tissue is vigorous and aggressive, polyps can form (figure 3).

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 Incidence. Granulation tissue is involved in several types of chronic ear disease, particularly in patients who have tympanostomy tubes. 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%. (1) Of these, 8.1% required surgical debridement. El-Bitar et al found that the incidence of granulation tissue was 13.8% in tympanostomy tubes that had been in place for 2 to 3 years and more than 40% in tubes that had been in place for more than 5 years. (2) 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 tympanostomy-tube-related granulation tissue. One is that it might impede the delivery of topical antibiotic solution to the site of infection so that the ear-drop 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 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 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.

Control and management

The control and management of granulation tissue involves the use of four modalities: aural toilet, anti-infectives, steroids, and cautery 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.

Anti-infectives. The fluoroquinolone and the amino-glycoside antibiotics are the mainstays of the management of chronic granulation tissue because the ultimate etiology of the abnormality is infectious. For middle ear disease, the quinolones are preferred because they lack the potential for ototoxicity.

Topical antibiotics have a great advantage over other dosage forms with respect to the higher concentration of medication that can be delivered. For example, a 3- to 5-drop dose of a topical antibiotic delivers a total of approximately 1 to 1.5 mg of medication, but the concentration of that medication is 3,000 [micro]g/ml. This concentration exceeds the minimum inhibitory concentration necessary to eradicate any known relevant pathogens. The concentration of systemic antibiotics that can be delivered to middle ear fluid is much lower. For example, administration of high-dose amoxicillin--90 to 100 mg/kg/day--delivers a concentration of only 8 to 10 [micro]g/ml to the middle ear fluid. A similar dose of cefuroxime delivers 2 to 4 [micro]g/ml to the middle ear fluid. Pediatricians are enamored with intramuscular ceftriaxone because it delivers a concentration as high as 25 to 30 [micro]g/ml to the middle ear fluid, but even this concentration pales in significance when compared with the 3,000 [micro]g/ml achieved with topical drops.

Steroids. For many years, most otolaryngologists have held as an article of faith the belief that steroids are important in suppressing, eliminating, and preventing granulation tissue. We are not alone; dermatologists, plastic surgeons, veterinarians, and a wide variety of other physicians have long believed this to be the case. The more potent steroids are preferred over the weaker ones.

Several animal studies have found that steroids are effective in controlling keloids and hypertrophic scarring (5) and in reducing angiogenesis and subsequent granulation. (6) In rabbits, Hashimoto et al showed that steroids suppress the formation of granulation tissue (1) by reducing vascular permeability, (2) by decreasing extravasation and the migration of inflammatory cells to the site of infection, (3) by inhibiting the production of a variety of chemotactic factors (especially complement factors and lymphocyte-derived factors), and (4) by acting on growth factors such as vascular endothelial growth factor and transforming growth factor beta. (6)

Steroids appear to be effective in humans, as well. We conducted a randomized, controlled, double-blind drug comparison study of 599 children with patent tympanostomy tubes and acute otitis media with otorrhea of 3 weeks' or less duration. (7,8) Patients were treated with either a quinolone plus a steroid (ciprofloxacin/dexarnethasone at 4 drops twice a day for 7 days) or a quinolone alone (ofloxacin at 5 drops twice a day for 10 days). Not only did the combination product prove to be significantly more effective in establishing clinical and microbiologic cure in all patients, (7) it was also significantly more effective in treating a subgroup of 90 children who had granulation tissue at baseline (figure 4). (8)

Powders. Topical powders are also widely used to control granulation tissue in any of the chronic ear conditions. They can be administered twice a week to twice a month in the office or at home, and they are relatively inexpensive. Another of their virtues is that they adhere to moist surfaces, so their dwell-time in and around the infective tissue appears to be relatively prolonged. These powders are made up of a variety of different combinations of an antibiotic (a quinolone, a sulfonamide, or chloramphenicol), an antifungal (clotrimazole or ampnotericin B), and a steroid (dexamethasone or hydrocortisone).

Cautery. Chemical cautery is usually performed with silver nitrate, although other agents such as trichloroacetic acid are sometimes used. Keep in mind, however, that chemical cautery is in effect a burn, and control over the depth and severity of that burn is somewhat limited. Every few years, we see a report of a case of facial nerve paralysis that occurred because the cauterizing agent, usually silver nitrate, was applied too aggressively at the wrong site.

Debridement. Debridement can be performed in the office setting with a microscope and small Bellucci's scissors. Avulsing a polyp is usually not recommended, because when it is removed, the otolaryngologist might find that the stapes is attached to the end of the polyp. Using sharp techniques will help avoid injury. Tympanomastoid surgery for chronic otitis media is, in effect, an aggressive form of debridement, and it is quite effective.

Summary

Granulation tissue is an important pathogenic feature of all types of chronic ear disease, and it can be controlled and treated with good aural toilet, appropriate antibiotic therapy, topical steroids, and chemical cautery or surgical debridement.

References

(1.) Kay DJ. Nalson M, Rosenfeld RM. Meta-analysis of tympanostomy tube sequelae. Otolaryngol Head Neck Surg 2001; 124:374-80.

(2.) El-Bitar MA, Pena MT, Choi SS, Zalzal GH. Retalned ventilation tubes: Should they be removed at 2 years? Arch Otolaryngol Head Neck Surg 2002; 128:1357-60.

(3.) Post JC. Direct evidence of bacterial biofilms in otitis media. Laryngoscope 2001; l11:2083-94.

(4.) Meyerhoff WL, Kim CS, Paparella MM. Pathology of chronic otitis media. Ann Otol Rhinol Laryngol 1978;87:749-60.

(5.) Bertone AL. Management of exuberant granulation tissue. Vet Clin North Am Equine Pract 1989;5:551-62.

(6.) Hashimoto I, Nakanishi H, Shono Y, et al. Angiostatic effects of corticosteroid on wound healing of the rabbit ear. J Med Invest 2002;49:61-6.

(7.) Roland PS, Kreisler LS, Reese B, et al. Topical ciprofloxacir/ dexamethasone otic suspension is superior to ofloxacin otic solution in the treatment of children with acute otitis media with otorrhea through tympanostomy tubes. Pediatrics 2004; 113:40-6.

(8.) Roland PS, Dohar JE, Lanier BJ, et al. Ciprofloxacin/dexamethasone versus ofloxacin for granulation tissue in AOMT patients. Presented at the annual meeting of the American Academy of Otolaryngology--Head and Neck Surgery; Sept. 22, 2003; Orlando, Fla.