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Controversial etiopathologic agents in otitis media.

In a number of recent articles, authors have made claims of etiopathology for a variety of organisms that are not conventionally thought to be pathogens in ear disease. What follows is a review of some of those claims.

New organisms

Three new bacteria have been proposed as important pathogens in otitis media: Corynebacterium mucifaciens, Pseudomonas otitidis, and Alloiococcus otitidis:

Corynebacterium mucifaciens. In 2006, Morinaka et al reported "the unexpectedly frequent isolation of C mucifaciens." (1) In their study of 88 children, they collected specimens from the ears and noses of patients with otitis media with effusion (OME) and chronic sinusitis, respectively. The specimens were cultured in highly selective media that contained vancomycin, trimethoprim/sulfamethoxazole, polymyxin B, cefsulodin, and amphotericin B. The authors found 9 C mucifaciens isolates--5 in the middle ear effusion of 4 OME patients (1 case was bilateral) and 4 in the nasal discharge or nasal polyps of the sinusitis patients. Alter the cessation of treatment, 3 of the 4 C mucifaciens-positive OME patients experienced a relapse of their otorrhea. As a result of these findings, the authors proposed that C mucifaciens is an etiopathologic agent in otitis media.

Such findings have not been established by other investigators. For example, in two large earlier series, C mucifaciens was cultured from only 1 of 2,646 specimens obtained from patients with either acute otitis externa (AOE) (2) or acute otitis media through tympanostomy tubes (AOMT). (3) In these two studies, we found a total of 73 Corynebacterium isolates; Corynebacterium auris was the most common organism in patients with AOE, and Corynebacterium amycolatum and Corynebacterium pseudodiphtheriticum were the most common isolates in patients with middle ear infection. However, because highly selective media were not used in these series, it is unlikely that C mucifaciens would have been recovered even if it had been present.

Simonet et al (4) and Poetker et al (5) also reported culturing C mucifaciens from patients with middle ear effusion, and Funke et al (6) reported that C mucifaciens was recovered from infected blood and joint fluid, supporting its possible role as a pathogen.

Pseudomonas otitidis. P otitidis is a recently described novel organism that has been recovered from adults and children with otic infections. Clark et al recovered this organism from 34 patients with AOE, from 6 patients with acute OME, and from 1 patient with chronic suppurative otitis media. (7) Genetic analysis indicated that the isolate belonged to the genus Pseudomonas but not to any known species. Analysis of 16S rRNA gene sequences and studies of DNAhybridization indicate that this bacterium is closely related to but different from Pseudomonas aeruginosa.

Alloiococcus otitidis. A otitidis is a slowly growing, fastidious, aerobic gram-positive bacterium. It was first described in 1989 by Faden and Dryja, who isolated it from the ears of 10 children with persistent OME. (8) Since then, it has been reported in 20 to 60% of middle ear effusions on polymerase chain reaction assay (PCR). (9) It is rarely detected via culture because it is slow growing and fastidious. There is some uncertainty as to whether A otitidis is a true pathogen or simply a commensal of the external auditory canal. Evidence of a local antibody response to A otitidis in the middle ear fluid of children with OME has been observed; the initiation of an inflammatory response suggests that A otitidis may well be a pathogen. On the other hand, an evaluation of healthy ears by Stroman et al found that 48 of 164 subjects (29.3%) had A otitidis as a saprophyte in the normal external auditory canal. (10)

At the 2007 Combined Otolaryngological Spring Meetings, Vijayasekaran et al reported a high recovery rate of A otitidis in children undergoing middle ear surgery. (9) Samples of middle ear effusion were taken from 25 children (39 ears) who were undergoing tympanostomy tube insertion or myringoplasty. The fluid was analyzed by standard culture techniques and by 16S rRNA sequencing of extracted DNA. Of the 54 organisms that were identified, 19 (35.2%) were A otitidis isolates.

Other organisms

Microbacterium spp. The Microbacterium genus is a member of the Corynebacterium group. Microbacterium spp are generally believed to be normal saprophytes of the external auditory canal, although one study showed that they were present in 9.5% of pretherapy AOE isolates. (2) In contrast, only 6 specimens were recovered from 624 isolates (0.96%) in the study of normal external auditory canals by Stroman et al. (10) Thus, the recovery rate was 10 times higher in the diseased ears than in the normal ears. Moreover, in the former study, the recovery rate of Microbacterium spp was higher when it appeared as a single isolate rather than as one of several isolates. (2) These organisms are often the only recovered species in cases of treatment failure and recurrent infections. Therefore, although Microbacterium spp are generally categorized as harmless skin saprophytes, they can be pathogenic in patients with external otitis.

Staphylococcus epidermidis. S epidermidis may be a pathogen in individuals with AOE. S epidermidis is almost universally regarded as a saprophyte and a probable contaminant of middle ear cultures. However, in our large series of more than 1,000 patients with AOE, it was the fifth most common organism (10.2% of isolates). (2) S epidermidis was present in 3 of 13 treatment failures (23.1%), a rate that is higher than its prevalence in normal external auditory canals (16.4%). (10) Moreover, Stroman has shown that a significant white cell response is found in patients in whom S epidermidis is recovered as a single isolate (oral communication, May 2007). Therefore, in some cases, S epidermidis may be a significant pathogen in AOE. (2)

Anaerobes

In our initial studies of AOMT, we found almost no anaerobic organisms. (3) However, large clinical trials currently under way have already yielded 111 anaerobes from more than 1,600 patients (unpublished data). This finding is related to a change in transport media that makes recovery of anaerobic organisms much more likely. Again, the etiopathologic significance of anaerobes remains unclear.

Viral co-infection

More than a dozen articles in the ENT literature report the presence of virus in children with acute otitis media (AOM). Reported rates of bacterial and viral co-infection range from as low as 5% to as high as 66%. (11)

In a study published in late 2006, Ruohola et al evaluated 79 children with AOMT within 48 hours of the onset of otorrhea: 73% of these children were evaluated within 24 hours. (11) In addition to aural discharge, common presenting symptoms included rhinitis (97% of patients) and cough (87%). Bacteria were sought by culture and PCR, and viruses were sought by culture, PCR, and antigen detection.

An infectious etiology was identified in 96% of these children:

Bacteria. Some 80% of these children were bacteria-positive on culture, and an additional 12% were bacteria-positive on PCR. The most frequently isolated bacteria were the usual culprits: Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.

Viruses. Viruses were present in 70% of patients. The most common of these (41% of cases) were picornaviruses, which belong to the family Picornaviridae. The 41% included Rhinovirus spp (20%) and Enterovirus spp (10%); the remaining 11% were nontypeable. The incidence of picornavirus infection was much higher than the incidence of respiratory syncytial virus (14%) in this study. Other viral organisms that were identified included parainfluenza virus, Influenzavirus A, Bocavirus spp, Metapneumovirus spp, and Coronavirus spp.

Co-infection. Bacterial and viral co-infection was present in 66% of these children. No association was noted between any particular bacteria and any particular viruses.

It has been noted that viruses are recovered more often in persistent and severe AOM infections than in milder cases. Chonmaitree and colleagues reported an increase in inflammation when both bacteria and viruses were present. (12-14) Likewise, Giebink et al showed that otitis media could be induced in chinchillas more easily when both a bacterium and a virus were introduced. (15) In their study, otitis media developed in only 21% of animals inoculated with S pneumoniae and 4%, of those inoculated with influenza A virus. But among those who were inoculated with both organisms, otitis media occurred in 67%. This suggests that viruses are important etiopathologic agents in the development of bacterial AOM.

Conclusion

The identification of these "new" organisms has often depended on either a significant change in laboratory technique (i.e., selective media, genetic analysis) or special diligence. So, to a considerable extent, it is reasonable to assert that what you find depends on how (or how hard) you look.

The identification of organisms previously unrecognized in subjects with AOM raises several questions. Foremost among them is, Are they or are they not important in the etiopathology of the disease?

The traditional method of determining causality has been the application of Koch's postulates. However, Koch's postulates cannot be applied to children, so we need to develop other methods of determining the pathologic significance of organisms recovered from infected middle ears. Answers to the following questions may help determine the pathogenicity of isolates:

* Are the organisms more common in diseased and infected ears?

* Are they frequently present in treatment failures?

* Are they often isolated alone (or apparently alone)?

* Are they associated with an inflammatory response?

* Does genetic analysis indicate the presence or absence of specific virulence factors?

In the end, however, the clinical impact of these controversial agents is actually quite minimal because (1) clinical laboratories do not find these agents, (2) pathogenicity has not been established, (3) most of the identified agents will respond to topical treatment regimens, and (4) viral components are believed to resolve spontaneously.

References

(1.) Morinaka S, Kurokawa M, Nukina M, Nakamura H. Unusual Corynebacterium mucifaciens isolated from ear and nasal specimens. Otolaryngol Head Neck Surg 2006;135(3):392-6.

(2.) Roland PS, Stroman DW. Microbiology of acute otitis externa. Laryngoscope 2002; 112(7 Pt 1): 1166-77.

(3.) Roland PS, Parry DA, Stroman DW. Microbiology of acute otitis media with tympanostomy tubes. Otolaryngol Head Neck Surg 2005:133(4):585-95.

(4.) Simonet M, De Briel D, Boucot I, et al. Coryneform bacteria isolated from middle ear fluid. J Clin Microbiol 1993;31 (6): 1667-8.

(5.) Poetker DM, Lindstrom DR, Edmiston CE, et al. Microbiology of middle ear effusions from 292 patients undergoing tympanostomy tube placement for middle ear disease. Int J Pediatr Otorhinolaryngol 2005;69(6):799-804.

(6.) Funke G, Lawson PA, Collins MD. Corynebacterium mucifaciens sp. nov., an unusual species from human clinical material, int J Syst Bacteriol 1997:47(4):952-7.

(7.) Clark LL, Dajcs JJ, McLean CH, et al. Pseudomonas otitidis sp. nov., isolated from patients with otic infections. Int J Syst Evol Microbiol 2006;56(Pt 4):709-14.

(8.) Faden H, Dryja D. Recovery of a unique bacterial organism in human middle ear fluid and its possible role in chronic otitis media. J Clin Microbiol 1989;27(11):2488-91.

(9.) Vijayasekaran S. Thornton R, Prosser K, et al. Alloiococcus otitidis in otitis media. Presented at the annual meeting of the American Society of Pediatric Otolaryngology; April 29, 2007: San Diego.

(10.) Stroman DW, Roland PS, Dohar J, Burr W. Microbiology of normal external auditory canal. Laryngoscope 2001;111(11 Pt 1):2054-9.

(11.) Ruohola A, Meurman O. Nikkari S, et al. Microbiology of acute otitis media in children with tympanostomy tubes: Prevalence of bacteria and viruses. Clin Infect Dis 2006:43(11):1417-22.

(12.) Chonmaitree T, Owen M J, Howie VM. Respiratory viruses interfere with bacteriologic response to antibiotic in children with acute otitis media. J Infect Dis 1990:162(2):546-9.

(13.) Chonmaitree T, Owen M J, Patel JA, et al. Effect of viral respiratory tract infection on outcome of acute otitis media. J Pediatr 1992: 120(6):856-62.

(14.) Chonmaitree T. Patel JA, Sire T, et al. Role of leukotriene B4 and interleukin-8 in acute bacterial and viral otitis media. Ann Otol Rhinol Laryngol 1996:105(12):968-74.

(15.) Giebink GS, Berzins IK, Marker SC, Schiffman G. Experimental otitis media after nasal inoculation of Streptococcus pneumoniae and influenza A virus in chinchillas. Infect Immun 1980;30(2): 445-50.

Peter S. Roland, MD
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Author:Roland, Peter S.
Publication:Ear, Nose and Throat Journal
Date:Nov 1, 2007
Words:2013
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