- Email: [email protected]
Otitis media with effusion: disease or defense?
International Journal of Pediatric Otorhinolaryngology (2004) 68, 331—339
Otitis media with effusion: disease or defense? A review of the literature J.A. de Ru a,*, J.J. Grote b a
Department of Otorhinolaryngology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands b Department of Otorhinolaryngology, Leiden University Medical Center, Leiden, The Netherlands Received 21 May 2003 ; received in revised form 2 November 2003; accepted 9 November 2003
KEYWORDS Middle ear effusion; Immune system; Infection; Eustachian tube; Ventilation tube
Summary Many studies of otitis media with effusion (OME) have been published, most of them dealing with risk factors. The literature correlates this condition with various patient characteristics and socio-economic factors, but none of these have been identified as the sole causative factor. A review of the literature suggests that otitis media with effusion is a response to pathogenic bacteria and thus a normal protective reaction of the body. Therefore, the decision on whether or not treatment is indicated should take the natural course of that response into account. In light of the literature reviewed here, we conclude that there is usually no need to treat middle ear effusion in young children. © 2003 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Acute otitis media (AOM) is a bacterial infection of the middle ear that causes fever and pain, has a risk of acute complications, and manifests itself as an erythematous, bulging tympanic membrane. If the membrane is perforated, a bloodstained discharge may be present. This picture differs from that of otitis media with effusion (OME). OME causes temporary hearing loss; in the long run, it is said to cause bone resorption and retraction pockets. However, the patient shows no signs of illness like pain or fever. In general, it is self-limiting and most often it does not leave the patient with a functional hearing impairment.
* Corresponding author. Tel.: +31-30-2509111; fax: +31-30-2541922. E-mail address: [email protected] (J.A. de Ru).
The greatest risk of developing OME is in the first 2 years of life, and it affects 80% of pre-school children at least once. OME is still the most common reason for surgery in children. Many studies have been performed on the pathophysiology of this disease, but the precise etiology remains unclear. Therefore, the guidelines for treatment are still open to interpretation. In our opinion, the viscous type of OME in children should not be considered as a disease that needs treatment. Instead, we propose that it should be seen as a necessary reaction by the middle ear to an infectious focus, and that it generally is a well-balanced response that is regulated by our innate and acquired immune system. Because the thick mucus contains many factors of our immune system, it is a hostile environment for micro-organisms. This reaction sets up a line of defense against bacteria coming from the nasopharynx. In this light, it seems that OME could develop when other protective barriers (mucocil-
0165-5876/$ — see front matter © 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2003.11.003
332 iary system, immune system, and eustachian tube) are not yet functioning properly or not offering enough resistance to pathogenic bacteria. In short, we think that OME is the body’s way to protect the ear until other mechanisms have developed fully. In the Netherlands, OME is responsible for about 30% of all pediatric healthcare visits by children under the age of 2 years. Taking the standpoint that OME is just a normal protective response would have several advantages: it would allow many children to avoid an operation for grommet insertion; it would reduce exposure to the risks of surgery; and it would prevent all late complications of grommet insertion (note that retention of ventilation tubes for more than 2 years causes higher complication rates [1]). Moreover, it would mean considerable savings in time and money for the healthcare system.
2. The mucociliary system The mucociliary system is one of the airways’ most important defenses against inhaled or invading particles such as dust, bacteria, viruses, and allergens [2]. It prevents colonization by inhaled bacteria in three ways: (1) physical removal by ciliar clearance, (2) the presence of broad-spectrum antimicrobial agents in the mucus, and (3) the recruitment of phagocytic cells and an inflammatory response. Moreover, the epithelial cells that line the airways play a role in the immune defense against micro-organisms, an innate response on which the body depends to prevent onset of infection [3,4]. The anterior half of the middle ear mucosa, like part of the hypotympanum and the orifice of the eustachian tube, is cilia-bearing. Normally, this membrane secretes mucus, which is transported by the cilia across the middle ear mucosa and down the eustachian tube to be swallowed [5—7]. This transport helps prevent bacteria from ascending from the nasopharynx to the middle ear. In addition, the mucus can bind bacteria and influence adhesion to the epithelium by providing points of attachment that mimic cell surface attachment sites [5,6]. Then, mucin-bacterial interactions may facilitate the removal of bacteria [8]. Ciliary activity is sensitive to a variety of pathological agents, including bacteria, bacterial toxins, and irradiation [2]. Nonetheless, children with OME were found to have a normal ciliary beat frequency [6]. On the other hand, middle ear effusions are common in patients with impaired mucociliary function, specifically Kartagener’s syndrome [9]. These studies suggest that normal mucociliary function is necessary for a middle ear cavity to be healthy.
J.A. de Ru, J.J. Grote
3. The eustachian tube 3.1. Obstruction or infection Early theories stated that OME starts with a mechanical obstruction to airflow through the eustachian tube. As oxygen is absorbed, negative pressure builds up, causing the middle ear to fill with fluid. This is called the ‘ex vacuo’ theory [10,11]. Recently, this theory has been challenged by Sadé [11], who argued that tubal occlusion is an unlikely explanation. In cases of nasopharyngeal carcinoma, he found that OME usually occurred when no air could pass through the eustachian tube for the reason that its muscles had been affected, not because its opening was blocked. Thus, even small carcinomas can cause OME. Even so, large polyps that fill the nasopharynx are usually not associated with middle ear effusions [11]. Furthermore, the effusions are generally more serous in adults with nasopharyngeal carcinoma. In children with a predominantly inflammatory etiology, the effusions are mostly viscous [12]. Also, Kuijpers et al. found that the increased activity encountered in secretory otitis media cannot be attributed solely to tubal occlusion. Rather, they thought it was the result of an infective process [13]. Adenoidectomy has been shown to be effective in OME, assuming that it removes the source of infection. The presence of adenoid tissue around the torus tubarius is associated with OME, although the size of the adenoids is not [14—16]. The above studies suggest that OME in young children is more likely to be the result of an infectious focus than of a mechanical obstruction.
3.2. Function In otologically normal children, the active eustachian tube function is not as good as in adults, while the passive function is similar. In children with a history of otitis media, the active eustachian tube function is worse than in otologically normal children [17]. Because the opening function of the tube is poor, negative pressure builds up in the middle ear. The ability to equilibrate middle ear pressure and atmospheric pressure upon swallowing improves with age. Improvement is most pronounced among children 3—7 years old. In that age group, the incidence of OME decreases, possibly because the function of the tensor veli palatini and levator veli palatini muscles improves at that age [18]. When the opening function of the eustachian tube is impaired, as it is in patients with a cleft palate, the incidence of OME is high [19]. Poor eustachian
Otitis media with effusion: disease or defense? A review of the literature tube function, as evidenced by persistent negative middle ear pressure, is commonly seen in older subjects with un-operated cleft palates [20]. It is our opinion that not all OME in children with a cleft palate or lip should be treated. There is some evidence that the insertion of a ventilation tube in these children produces more long-term sequelae of OME than a conservative approach [21]. Furthermore, OME is very common in syndromes affecting the nasopharynx and skull base [22]. It is important to note that the tube’s position is more horizontal in children than in adults, as well as in children with Down’s syndrome compared to normal children. This position might give bacteria from the nasopharynx easier access to the middle ear. In infancy, when the tube is shorter and wider, this route is easily accessible to potentially harmful germs [23]. Moreover, reflux of gastric juice into the tube is easier because of the angle and immaturity of the tube, but also because of the supine position in which infants are often placed [24]. Reflux might cause transient damage to the eustachian tube and the middle ear mucosa, resulting in ideal conditions for secondary bacterial colonization [24]. Like other investigators, we conclude that hypofunction of the tube may be an underlying factor in the development of OME [17]. It is possible that eustachian tube function is sub-optimal to some degree in most children. Nonetheless, those with more abnormality than others (cleft palate, Down’s syndrome) run an even greater risk of developing OME [10]. These studies clearly indicate that a normally functioning eustachian tube should be seen as a line of defense. Besides regulating middle ear pressure, the eustachian tube protects the middle ear from nasopharyngeal secretions and regulates the clearance of fluids accumulating in the middle ear [25].
4. Effusion In patients with OME, the middle ear mucosa shows vascular proliferation with an infiltrate of plasma cells and lymphocytes in the submucosa. There is metaplasia of the middle ear epithelium to a secretory type with proliferation of goblet cells [26,27]. Histology shows fewer mucus-secreting cells in the middle ear mucosa in serous compared to viscous OME [10]. Mucus contains water, cells, cell debris, high molecular weight compounds (mucins, proteins, and lipids), immunoglobulins, lysozyme, lactoferrin and complement components, antimicrobial peptides, leukotrienes and cytokines [3,10,28—32]. These chemical defenses ensure
333
that an antimicrobial milieu is constantly present [3]. Mucins are found in association with epithelia throughout the body. Their function, in general terms, is to lubricate, prevent dehydration, and protect [10]. Mucin is actively secreted into the effusion, which means that effusions are not simply passive transudates of fluid. In OME, the viscosity of the effusion has been shown to correlate with the concentration of mucin [33]. Furthermore, ever since Fleming’s discovery that human nasal secretions harbor antimicrobial activity, lysozyme has been considered one of the most important of the host defense molecules [3]. Also, IgA and IgG are secreted into the middle ear effusion in excess of plasma levels [10,34,35]. Antigen-specific antibody-producing cells can be induced in the middle ear mucosa of previously sensitized animals [36]. Breast-feeding protects against OME, probably through the effect of maternal antibodies on middle ear pathogens [37—40]. In view of these chemical properties, we conclude that the thick ‘glue’ found in the middle ear of young children is a defensive barrier that is actively secreted by the middle ear mucosa.
5. Immunology Cytokines, which control the acute inflammatory response, are intercellular messenger molecules produced by inflammatory cells. Many of these messengers, including IL-1, IL-2, IL-8, and TNF-␣, are present in the effusion, where they regulate the inflammatory response [26,28,32,41]. In blood sera, most of the cytokines are either absent or occur only at the lowest levels that can be detected. This implies that the cytokines found in middle ear effusions are produced locally. Moreover, the levels of cytokines are correlated with the type of effusion; the concentration is significantly higher in mucopurulent secretions [29,41,42]. Another important mediator is transforming growth factor  (TGF-). This is an extremely potent mononuclear leukocyte chemotactic factor. It controls the recruitment and activation of monocytes and lymphocytes in many inflammatory diseases. Another one is platelet activating factor (PAF) [43,44]. PAF is released from human neutrophils, platelets, eosinophils, macrophages, mast cells, and vascular epithelial cells. It can induce OME even when the eustachian tube is functioning normally [44]. Like cytokines, PAF is found in higher concentrations in mucoid than in serous effusions. Polymorphonuclear leukocytes are known to generate an oxygen-dependent bactericidal system.
334 They do so by using a series of oxidants to destroy invading micro-organisms [45]. However, as a side effect, superoxide radicals might damage the membrane of the host cell. To protect the host from these oxygen radicals, an important role is played by superoxide dismutase, which is present in higher levels in mucoid than in serous effusions [45]. These findings suggest that the immune system plays an active and well-balanced role in the body’s response to OME.
6. Inner ear protection Otitis media can also produce functional and pathological changes in the cochlea. The round and oval windows are possible routes through which noxious substances may pass from the middle to the inner ear [46,47]. Morphologic evidence suggests that membrane layers of the round window participate in the absorption and secretion of substances into and out of the inner ear [47]. Post-mortem studies of patients with a history of otitis media give evidence of a defensive action in this region. At the oval window, the squamous epithelium on the middle ear side of the footplate of the stapes was taller than normal. Furthermore, the connective tissue layer was thicker than normal and infiltrated by inflammatory cells [47]. In contrast, the vestibular side of the footplate had remained unchanged. At the round window outer epithelium, the normally low cuboidal cells were taller. There was also an increase in mitochondria and rough endoplasmatic reticulum in this region. While microvilli are normally sparse, their number was increased. At the core of the connective tissue, there was evidence of cellular infiltration by neutrophils, macrophages, and plasma cells. Immunoactive cells were observed surrounding the capillary vessels [47]. On the one hand, these histopathological changes during OME would clearly influence the function of the membrane. On the other hand, they constitute a defensive reaction of the membrane. This reaction includes a possible decrease in permeability once the histological changes are established [47].
7. Micro-organisms OME might be initiated by an acute infection caused by gram-negative bacteria containing endotoxin, a lipopolysaccharide in the membrane of bacteria that is released by growth or lysis [29,31]. Endotoxin reduces the mucociliary activity, induces effusion, and stimulates mucin production
J.A. de Ru, J.J. Grote [31,48,49]. Moreover, it exerts a strong stimulus on the proliferation of middle ear epithelium [50]. Endotoxin concentrations are significantly higher in muco-purulent than in serous effusions [42]. Animal models support the idea that the inflammatory stimulus for OME is bacterial endotoxin. This substance stimulates the production of tumor necrosis factor ␣ (TNF-␣) and interleukin 1 (IL-1) [28,29,31,49,50—53]. The levels of TNF-␣ are higher in effusions containing gram-negative bacteria than in those without bacteria [29]. TNF-␣ has been shown to evoke mucus secretion by up-regulating mucin genes [54]. High TNF-␣ levels in middle ear effusions have been associated with the persistence of OME [55].
7.1. Bacteria Bacteria, especially Haemophilus influenzae and Streptococcus pneumoniae (normal residents of the nasopharynx), have been cultured from up to 40% of the effusions studied [29,31,56—58]. Under direct microscopy, bacteria are more often visible in mucoid than in serous effusions [59]. Other studies have shown bacterial DNA by polymerase chain reaction in up to 80% of effusions in the absence of viable organisms on culture [60,61]. The presence of H. influenzae mRNA was demonstrated in 43% of 93 middle ear effusions from children whose OME had lasted 3 months or more, even though only 12% of these cases were positive on culture. Bacterial mRNAs have a half-life of mere seconds. Thus, their presence indicates viable and metabolically active bacteria. To explain this discrepancy it was argued that the negative cultures are caused by the bacteria existing as a biofilm, which is a state of very low metabolic activity. While bacteria in this state may be resistant to antibiotics, they can still evoke an immune response [62].
7.2. Viruses Viral infections may stimulate inflammation in the middle ear. Indeed a short-lived middle ear effusion is not uncommon in the course of the common cold. Viral respiratory infections, particularly those caused by respiratory syncytial virus (RSV), adenovirus, and influenza virus type A or B, have been linked etiologically with OME [10,63]. RSV, rhinovirus, and adenovirus nucleic acids have been identified in effusions [55,64,65]. Viral sequences were highly detectable in effusions of patients from whose nasopharynges RSV was isolated [55]. In some cases, the viruses were present alone, while in others co-existing bacteria were found. It is unclear whether viruses act alone to
Otitis media with effusion: disease or defense? A review of the literature produce inflammation or merely predispose to bacterial superinfection [10,32]. Several studies have demonstrated that viral infection of the upper respiratory tract may have a substantial impact on the bacterial colonization of the nasopharynx and the adherence of bacteria to epithelial cells [66—69]. Recently, Sadé et al. suggested that the bimodal peak prevalence distribution might be the result of different types of infection. They discriminated between two groups of children: one, of predominantly younger children, 2.6 years of age, with bacterial OMA resulting in OME; and the other, 5 years of age, with a possible viral infection as etiological factor [70]. The above mentioned studies consistently show that both bacterial and viral infections may play a very important role in the etiology of OME.
8. Allergy Controlled studies have failed to show any increase in the prevalence of an atopic history or positive skin prick tests in children with OME compared to normal children. Middle ear effusions contain mediators of the allergic response, such as IgE and eosinophil cationic protein. Their concentrations in the effusions are usually similar to, or lower than, those in serum, suggesting that they are not produced locally. Most studies do not support the notion that middle ear mucosa serves as the target organ for allergy. Middle ear challenge with antigenic material does not produce an effusion in an animal model [59]. If allergy plays any role in OME, it is probably in the form of allergic rhinitis delaying the resolution of a middle ear effusion by affecting the eustachian tube function [10]. Furthermore, an allergic reaction might cause damage to the mucosa in the nasopharynx, thereby predisposing an individual for secondary bacterial infection. In our opinion, allergy may exert some influence on the development of OME, but we do not believe it is the sole causative factor.
9. Environmental factors Disease states and environmental exposure can inhibit the operation of the body’s defenses and responses, thus allowing unimpeded growth of pathogenic micro-organisms [3]. In addition, various social factors have been implicated in the etiology of OME. All of these factors are probably mediated by an increased propensity to infection.
335
It is postulated that greater exposure to respiratory pathogens is the reason for this increase. Children who attend daycare centers have a higher risk of OME. The more time spent in daycare, the greater the risk [10,40,71]. The same mechanism may explain the increased incidence of OME in children with several siblings at home [40]. This suggests that infection status plays an important role. There is also seasonal variation in the incidence of OME. The winter preponderance may be attributed to an overall increase in respiratory infections and perhaps also to keeping children indoors close together [10,72]. Patients with OME who have been exposed to cigarette smoke have a significantly lower ciliary beat frequency than those who have not been exposed [73]. In animals, however, exposure to smoke has never been shown to lead to middle ear effusions. Studies show that smoke has no effect on the resolution of experimentally induced middle ear effusions in rats and chinchillas [73,74]. Otitis media with effusion is more common in children exposed to cigarette smoke [75,76]. This higher incidence might be a knock-on effect of the more frequent upper respiratory tract infections found among smokers and the less well functioning first line of defense, i.e. reduced ciliary beat.
10. Acute otitis media and otitis media with effusion We would agree with most authors that OME could develop after a period of AOM. In 50% of the cases, the middle ear effusion directly follows an episode of infection, indicating a close connection. Some research shows that children with OME have up to five times more episodes of acute otitis media than those without OME, suggesting a reverse causality [72]. The flaw in that argument seems to be that most of the children in the study already had twice as many acute episodes before the OME set in. These children could thus be prone to chronic infection and would therefore just need to protect their middle ear more than others.
11. Discussion and conclusions The pathogenesis of inflammatory disease is more complex than can be explained by a single cause-and-effect relationship. It probably represents an interaction between genetically predisposing factors (innate and acquired immune system), exogenous triggers (amount of exposure
336 to bacteria, daycare centers), and endogenous triggers (local inflammatory response). The outcome of these interactions is a spontaneously relapsing and remitting inflammatory process [77]. It is still unclear whether mucoid and serous effusions represent different stages of the same disease or in fact different diseases. One reason why a mucoid effusion is generally found in children and a serous one in adults might be that a fully developed immune system would not need to mount an overwhelming reaction. However, it is more likely that we are dealing with different entities [5]. Mucoid effusions contain on average more bacterial toxins, and other markers of inflammation than serous ones. Accordingly, mucoid secretions are formed if there is an infectious component. As Maw has suggested, the thick mucoid secretion developing within the middle ear may ultimately obstruct the eustachian tube. Acting as a barrier to ascending infection, the thick mucus would isolate the middle ear from the ambient environment [22]. Sadé et al. distinguished between different kinds of middle ear effusions in a group of 809 children. In one of these groups, the effusion was almost always sterile, consisting mainly of lymphocytes and macrophages. This suggested a viral upper respiratory tract infection [70]. For some reason, serous otitis, as seen in patients with nasopharyngeal carcinoma or in irradiated ears, seems to fit the ‘ex vacuo’ theory (negative middle ear pressure with subsequent effusion of sterile fluid). But the serous effusion in this group, often consisting of immuno-compromised patients, could also be a late form of the general ‘mucositis’ mentioned by Sadé et al. Viral upper respiratory tract infection can lead to eustachian tube opening failure, middle ear underpressure, and OME [78—84]. It has been suggested that the observed increase in tubal resistance that accompanies viral infections in the upper respiratory tract may be a reflexive up-regulation of the protective function at the expense of the pressure-regulating function of the eustachian tube [23]. This review of the literature provides convincing evidence that the viscous type of OME in children should not be considered a disease. Instead, it should be seen as a necessary protective reaction by the middle ear to an infectious focus in children. Therefore, we conclude that OME in young children usually does not require treatment of any kind. Most OME will subside through the gradual maturation of the child’s immune system and eustachian tube function [85]. Meanwhile, as Rosenfeld proposed, since nature will ‘cure’ OME, the best treatment is reassurance, avoidance of unproved therapies, and
J.A. de Ru, J.J. Grote parental education about the prevalence and natural history of OME [85]. There are, of course, examples of adaptive and defensive natural processes going out of control and thereby causing disease. In general, however, we believe that OME is a well-balanced, self-limiting response. In some cases, treatment could be necessary, though. For instance, it could be necessary in cases of prolonged and severe delay in language development in school children. And it might be indicated in children with a combined congenital perceptive hearing loss and OME. However, we concur with Gates, who suggested that the treatment of choice should be adenoidectomy to remove the infectious focus [86]. The effect of anti-reflux therapy remains to be investigated [87]. Encouraging breast-feeding and parental advice to stop smoking to reduce the number of upper respiratory tract infections may reduce the incidence and morbidity of OME. Furthermore, the natural course of OME has to be incorporated in the decision on whether treatment is warranted or not. If OME does not resolve itself in the natural way, clinical history-taking and examination to ascertain an underlying reason (immuno-deficiencies, URTI, etc.) should be performed.
Acknowledgements The authors like to thank Marja J. Nell and Anne G.M. Schilder for their critical reading of the manuscript.
References [1] M. El-Bitar, M.T. Pena, S.S. Choi, G.H. Zalzal, Retained ventilation tubes, should they be removed at 2 years? Arch. Otolaryngol. Head Neck Surg. 128 (2002) 1357—1360. [2] Y. Ohashi, Y. Nakai, Current concepts of mucociliary dysfunction in otitis media with effusion, Acta Otolaryngol. (Stockh.) 486 (Suppl.) (1991) 149—161. [3] G. Diamond, D. Legarda, L.K. Ryan, The innate immune response of the respiratory epithelium, Immunol. Rev. 173 (2000) 27—38. [4] R.E.W. Hancock, G. Diamond, The role of cationic antimicrobial peptides in innate host defences, Trends Microbiol. 8 (2000) 402—410. [5] J. Sadé, Middle ear mucosa, Arch. Otolaryngol. 84 (1966) 137—143. [6] M. Wake, L.A. Smallman, Ciliary beat frequency of nasal and middle ear mucosa in children with otitis media with effusion, Clin. Otolaryngol. 17 (1992) 155—157. [7] W. Kuijpers, J.M.H. Van Der Beek, The role of microorganisms in experimental Eustachian tube obstruction, Acta Otolaryngol. (Stockh.) 414 (Suppl.) (1984) 58—66. [8] M.S. Reddy, T.F. Murphy, H.S. Faden, J.M. Bernstein, Middle ear mucin glycoprotein: purification and interaction
Otitis media with effusion: disease or defense? A review of the literature
[9] [10] [11] [12] [13]
[14]
[15] [16] [17] [18] [19] [20] [21]
[22] [23]
[24] [25] [26] [27] [28] [29]
with non typable Haemophilus influenzae and Moraxella catarrhalis, Otolaryngol. Head Neck Surg. 116 (1997) 175— 180. T.J. Fisher, Middle ear ciliary defect in Kartagener’s syndrome, Pediatrics 62 (1978) 443. H. Kubba, J.P. Pearson, J.P. Birchall, The aetiology of otitis media with effusion, Clin. Otolaryngol. 25 (2000) 81— 94. J. Sadé, The nasopharynx, eustachian tube and otitis media, J. Laryngol. Otol. 108 (1994) 95—100. W.I. Wei, V.J. Lund, D.J. Howard, Serous otitis media in malignancies of the nasopharynx and maxilla, J. Laryngol. Otol. 102 (1988) 129—132. W. Kuijpers, J.M.H. Van der Beek, P.H.K. Jap, E.L.G. Tonnaer, The structure of the middle ear epithelium of the rat and the effect of Eustachian tube obstruction, Histochem. J. 16 (1984) 807—818. G.A. Gates, C.A. Avery, T.J. Prihoda, J.C. Cooper, Effectiveness of adenoidectomy and tympanostomy tubes in the treatment of chronic otitis media with effusion, N. Engl. J. Med. 317 (1987) 1444—1451. E.D. Wright, A.J. Pear, J.J. Manoukian, Laterally hypertrophic adenoids as a contributing factor in otitis media, Int. J. Pediatr. Otorhinolaryngol. 45 (1998) 207—214. N. Roydhouse, Adenoidectomy for otitis media with mucoid effusion, Ann. Otol. Rhinol. Laryngol. 89 (Suppl. 68) (1980) 312—313. A. Bylander, Function and dysfunction of the eustachian tube in children, Acta Otorhinolaryngol. Belg. 38 (1984) 238—245. C.A. Holborow, Eustachian tubal function changes through childhood and neuromuscular control, J. Laryngol. Otol. 89 (1975) 47—55. P.J. Robinson, S. Lodge, B.M. Jones, C.C. Walker, H.R. Grant, The effect of palate repair on otitis media with effusion, Plast Reconstr. Surg. 89 (1992) 640—645. A. Gopalakrishna, K.S. Goleria, A. Raje, Middle ear function in cleft palate, Br. J. Plast. Surg. 37 (1984) 558—565. P. Sheahan, A.W. Blaney, J.N. Sheahan, M.J. Earley, Sequelae of otitis media with effusion among children with cleft lip and/or cleft palate, Clin. Otolaryngol. 27 (2002) 494—500. A.R. Maw, in: A.G. Kerr (Ed.), Scott-Brown’s Otolaryngology, vol. 6, sixth ed., Butterworth—Heinemann, Oxford, 1997 (Chapter 7). D. Passali, Immunobiology in otorhinolaryngology–—progress of a decade, in: G. Mogi, J.E. Veldman, H.C. Kawauchi (Eds.), Proceedings of the 4th International Academic Conference Oita, Japan, 4—7 April 1994, Kugler Publications, Amsterdam, 1994, pp. 83—87. A. Tasker, P.W. Dettmar, M. Panetti, J.A. Koufman, J.P. Birchall, J.P. Pearson, Reflux of gastric juice and glue ear in children, Lancet 359 (2002) 493—495. C.D. Bluestone, Pathogenesis of otitis media: role of eustachian tube, Pediatr. Infect. Dis. J. 15 (1996) 281—291. G. Zechner, Auditory tube and middle ear mucosa in nonpurulent otitis media, Ann. Otol. Rhinol. Laryngol. 89 (Suppl.) (1980) 87—90. T. Ishii, M. Toriyama, J.I. Suzuki, Histopathological study of otitis media with effusion, Ann. Otol. Rhinol. Laryngol. 89 (1980) 83—86. K.S. Maxwell, J.E. Fitzgerald, J.A. Burleson, G. Leonard, R. Carpenter, D.L. Kreutzer, Interleukin-8 expression in otitis media, Laryngoscope 104 (1994) 989—995. D.N. Willett, R.P. Rezaee, J.M. Billy, M.B. Tighe, T.T. De Maria, Relationship of endotoxin to tumor-necrosisfactoralpha and interleukin-1 beta in children with otitis media
[30] [31] [32]
[33]
[34] [35]
[36]
[37]
[38]
[39]
[40]
[41] [42] [43]
[44] [45] [46] [47]
337
with effusion, Ann. Otol. Rhinol. Laryngol. 107 (1998) 28— 33. E. Hentzer, Ultrastructure of the middle-ear mucosa in secretory otitis media, Acta Otolaryngol. 73 (1972) 394— 401. T. Ovesen, T. Ledet, Bacteria and endotoxin in middle ear fluid and the course of secretory otitis media, Clin. Otolaryngol. 17 (1992) 531—534. R.F. Yellon, G. Leonard, P.T. Marucha, R. Craven, R.J. Carpenter, W.B. Lehmann, et al., Characterization of cytokines present in middle ear effusions, Laryngoscope 101 (1991) 165—169. S. Carrie, D.A. Hutton, J.P. Birchall, G.G.R. Green, J.P. Pearson, Otitis media with effusion: components which contribute to the viscous properties, Acta Otolaryngol. (Stockh.) 112 (1992) 504—511. E.A. Jones Jr., L.R. Thomas, N.C. Davis, The significance of secretory IgA in middle ear fluid, Ann. Allergy 42 (1979) 236—240. S. Jeep, Correlation of immunoglobulins, the complement system and inflammatory mediators with reference to the pathogenesis of serous otitis media, Laryngo-rhino-otologie 69 (1990) 201—207. N. Watanabe, H. Yoshimura, G. Mogi, Induction of antigen-specific IgA-forming cells in the middle ear mucosa, Arch. Otolaryngol. Head Neck Surg 114 (1988) 758— 762. L.C. Duffy, H. Faden, R. Wasielewski, J. Wolf, D. Krystofik, Exclusive breastfeeding protects against bacterial colonization and day care exposure to otitis media, Pediatrics 100 (1997) E7. J.M. Bernstein, Y. Harabuchi, N. Yamanaka, H.S. Faden, Immunobiology in otorhinolaryngology–—progress of a decade, in: G.J.E. Mogi, J.E. Veldman, H.C. Kawauchi (Eds.), Proceedings of the 4th International Academic Conference Oita, Japan, 4—7 April 1994, Kugler Publications, Amsterdam, 1994, pp. 25—36. M.J. Owen, C.D. Baldwin, P.R. Swank, A.K. Pannu, D.L. Johnson, V.M. Howie, Relation of infant feeding practices cigarette smoke exposure and group childcare to the onset and duration of otitis media with effusion in the first two years of life, J. Pediatr. 123 (1993) 702—711. J.L. Paradise, H.E. Rockette, D.K. Colborn, B.S. Bernard, C.G. Smith, M. Kurs-Lasky, et al., Otitis media in 2235 Pittsburgh infants: prevalence and risk factors during the first two years of life, Pediatrics 99 (1997) 318—333. M. Hotomi, T. Samukawa, N. Yamanaka, Interleukin 8 in otitis media with effusion, Acta Otolaryngol. (Stockh.) 114 (1994) 406—409. M.J. Nell, J.J. Grote, Endotoxin and tumor necrosis factor-␣ in middle ear effusions in relation to upper airway infection, Laryngoscope 109 (1999) 1815—1819. M.S. Cooter, R.J. Eisma, J.A. Burleson, G. Leonard, D. Lafreniere, D.L. Kreutzer, Transforming growth factor beta expression in otitis media with effusion, Laryngoscope 108 (1998) 1066—1070. C.K. Rhee, T.T. Jung, S. Miller, D. Weeks, Experimental Otitis media with effusion induced by platelet activating factor, Ann. Otol. Rhinol. Laryngol. 102 (1993) 600—605. H. Shigemi, Y. Kurono, T. Egashira, G. Mogi, Role of superoxide dismutase in otitis media with effusion, Ann. Otol. Rhinol. Laryngol. 107 (1998) 327—331. M.V. Goycoolea, Oval and round window membrane changes in otitis media in the human, Acta Otolaryngol. (Stockh.) 115 (1995) 282—283. M.V. Goycoolea, D. Muchow, P. Schachern, Experimental studies on round window structure: function
338
[48]
[49]
[50]
[51]
[52]
[53] [54]
[55]
[56] [57]
[58] [59] [60]
[61]
[62]
[63]
J.A. de Ru, J.J. Grote and permeability, Laryngoscope (Suppl. 44) (1988) 1— 20. A.S. Rose, J. Prazma, S.H. Randell, H.C. Baggett, A.P. Lane, H.C. Pillsbury, Nitric oxide mediates mucin secretion in endotoxin-induced otitis media with effusion, Otolaryngol. Head Neck Surg. 116 (1997) 308—316. M.J. Nell, B.M. Albers, H.K. Koerten, J.J. Grote, Inhibition of endotoxin effects on cultured human middle ear epithelium by batericidal permeability-increasing protein, Am. J. Otol. 23 (2000) 625—630. S.C. Hesseling, C.A. Van Blitterswijk, D.J. Lim, T.F. DeMaria, L.O. Bakaletz, J.J. Grote, Effect of Endotoxin on cultured rat middle ear epithelium, rat meatal epidermis and human keratinocytes, Am. J. Otol. 15 (1994) 762— 768. J.J. Grote, S.C. Hesseling, G.J.M. Tjebbes, C.A. Van Blitterswijk, Effect of HA-1A monoclonal IgM antibody on endotoxin-induced proliferation of cultured rat middle ear epithelium, Ann. Otol. Rhinol. Laryngol. 104 (1995) 226— 230. T.F. DeMaria, B.R. Briggs, D.J. Lim, et al., Experimental otitis media with effusion following middle ear inoculation of nonviable Haemophilus influenzae, Ann. Otol. Rhinol. Laryngol. 93 (1984) 52—56. M.J. Nell, B.M. Op’t Hof, H.K. Koerten, J.J. Grote, Effect of endotoxin on cultured human middle ear epithelium, ORL 61 (1999) 201—205. S.J. Levine, P. Larivee, C. Logun, C.W. Angus, F.P. Ognibene, J.H. Shelhamer, Tumour necrosis factor a induces mucin hypersecretion and MUC 2 gene expression in human airway epithelial cells, Am. J. Resp. Cell Mol. Biol. 12 (1995) 196—204. Y. Okamoto, K. Kudo, K. Shirotori, M. Nakazewa, E. Ito, K. Togawa, et al., Detection of genomic sequences of respiratory syncytial virus in otitis media with effusion in children, Ann. Otol. Rhinol. Laryngol. 157 (Suppl.) (1992) 7— 10. T. Palva, T. Lehtinen, J. Rinne, Immune complexes in middle ear fluid in chronic secretory otitis media, Ann. Otol. Rhinol. Laryngol. 92 (1983) 42—44. T. Palva, T. Lehtinen, H. Kirtanen, Immune complexes in middle ear fluid and adenoid tissue in chronic secretory otitis media, Acta Otolaryngol. (Stockh.) 95 (1983) 539— 543. I. Brook, P. Yocum, K. Shah, B. Feldman, S. Epstein, Aerobic and anaerobic bacteriologic features of serous otitis media in children, Am. J. Otol. 4 (1983) 389—392. P. Van Cauwenberge, M. Rysselaere, P. Kluyskens, New perspectives in the direct microscopic examination of middle ear effusions, Am. J. Otol. 6 (1985) 191—195. M. Hotomi, T. Tabata, H. Kakiuchi, M. Kunimoto, Detection of Haemophilus influenzae in middle ear of otitis media with effusion by polymerase chain reaction, Int J. Ped. Otorhinolaryngol. 27 (1993) 119—126. J.C. Post, R.A. Preston, J.J. Aul, M. Larkins-Pettigrew, J. Rydquist-White, K.W. Anderson, et al., Molecular analysis of bacterial pathogens in otitis media with effusion, JAMA 273 (1995) 1598—1604. M. Rayner, Y. Zhang, M.C. Gorry, Y. Chen, J.C. Post, G.D. Ehrlich, Evidence for bacterial activity in culture–—negative otitis media with effusion, JAMA 279 (1998) 296— 299. F.W. Henderson, A.M. Collier, M.A. Sanyal, J.M. Watkins, D.L. Fairclough, W.A. Clyde, et al., A longitudinal study of respiratory viruses and bacteria in the etiology of otitis media with effusion, N. Engl. J. Med. 306 (1982) 1377— 1383.
[64] C.B. Shaw, N. Obermyer, S.J. Wetmore, G.A. Spirou, R.W. Farr, Incidence of adenovirus and respiratory syncitial virus in chronic otitis media with effusion using the polymerase chain reaction, Otolaryngol. Head Neck Surg. 113 (1995) 234—241. [65] M. Arola, T. Ziegler, H. Puhakka, O. Lehtonen, O. Ruuskanen, Rhinovirus in otitis media with effusion, Ann. Otol. Rhinol. Laryngol. 99 (1990) 451—453. [66] T. Heikkinen, T. Chonmaitree, Increasing importance of viruses in acute otitis media, Ann. Med. 32 (2000) 157— 163. [67] J. Patel, H. Faden, S. Sharma, P.L. Ogra, Effect of respiratory syncytial virus on adherence, colonization and immunity of non-typable Haemophilus influenzae: implications for otitis media, Int. J. Pediatr. Otorhinolaryngol. 23 (1992) 15—23. [68] V. Fainstein, D.M. Musher, T.R. Cate, Bacterial adherence to pharyngeal cells during viral infection, J. Infect. Dis. 141 (1980) 172—176. [69] J.S. Abramson, J.G. Wheeler, Virus-induced neutrophil dysfunction: role in the pathogenesis of bacterial infections, Pediatr. Infect. Dis. J. 13 (1994) 643—652. [70] J. Sadé, C. Fuchs, E. Russo, D. Cohen, Is secretory otitis media a single disease entity? Ann. Otol. Rhinol. Laryngol. 112 (2003) 342—347. [71] M.M. Rovers, G.A. Zielhuis, H. Straatman, K. Ingels, G.J. Van de Wilt, P. Van den Broek, Prognostic factors for persistent otitis media with effusion in infants, Arch. Otolaryngol. Head Neck Surg. 125 (1999) 1203—1207. [72] O.P. Alho, H. Oja, M. Koivu, M. Sorri, Chronic otitis media with effusion in infancy. How frequent is it? How does it develop, Arch. Otolaryngol. Head Neck Surg. 121 (1995) 432—436. [73] A.M. Agius, M. Wake, A. Pahor, L.A. Smallman, Smoking and middle ear ciliary beat frequency in otitis media with effusion, Acta Otolaryngol. (Stockh.) 115 (1995) 44— 49. [74] P.J. Antonelli, K.A. Daly, S.K. Juhn, E.J. Veum, G.L. Adams, G.S. Giebink, Tobacco smoke and otitis media in the chinchilla model, Otolaryngol. Head Neck Surg. 111 (1994) 513—518. [75] A.E. Hinton, G. Buckley, Parental smoking and middle ear effusions in chidren, J. Laryngol. Otol. 102 (1988) 992— 996. [76] D.P. Strachan, Impedance tympanometry and the home environment in 7-year-old children, J. Laryngol. Otol. 104 (1990) 4—8. [77] D.S. Hurst, P. Venge, Levels of eosinophil cationic protein and myeloperoxidase from chronic middle ear effusions in patients with allergy and/or acute infection, Otolaryngol. Head Neck Surg. 114 (1996) 531—544. [78] M.A. Sanyal, F.W. Henderson, E.C. Stempel, A.M. Collier, F.W. Denny, Effect of upper respiratory tract infection on Eustachian tube ventilatory function in preschool children, Pediatrics 87 (1980) 11—15. [79] A. Bylander, Upper respiratory tract infection and eustachian tube function in children, Acta Otolaryngol. (Stockh.) 97 (1984) 343—349. [80] S.A. Moody, C.M. Alper, W.J. Doyle, Daily tympanometry in children during the cold season: association of otitis media with upper respiratory tract infections, Int. J. Ped. Otoplaryngol. 45 (1998) 143—150. [81] T.P. McBride, W.J. Doyle, F.G. Hayden, J.M. Gwaltney, Alteration of Eustachian tube function middle ear pressure and nasal patency in response to an experimental rhinovirus challenge, Arch. Otolaryngol. Head Neck Surg. 115 (1989) 1054—1059.
Otitis media with effusion: disease or defense? A review of the literature [82] C.A. Buchman, W.J. Doyle, D. Skoner, P. Fireman, J.M. Gwaltney, Otologic manifestations of experimental rhinovirus infection, Laryngoscope 104 (1994) 1295—1299. [83] W.J. Doyle, D.P. Skoner, F. Hayden, C. Buchman, J.T. Seroky, P. Fireman, Nasal and otologic effects of experimental influenza A virus infection, Ann. Otol. Rhinol. Laryngol. 103 (1994) 59—69. [84] C.A. Buchman, W.J. Doyle, D.P. Skoner, J.C. Post, C.M. Alper, J.M. Seroky, K. Anderson, R.A. Preston, F. Hayden, P. Fireman, G.D. Ehrlich, Influenza A virus induced acute otitis media, J. Infect Dis. 172 (1995) 1348—1351.
339
[85] R.M. Rosenfeld, Amusing parents while nature cures otitis media with effusion, Int. J. Pediatr. Otorhinolaryngol. 43 (1998) 189—192. [86] G.A. Gates, C.A. Avery, T.J. Prihoda, Effect of adenoidectomy upon children with chronic otitis media with effusion, Laryngoscope 98 (1988) 58—63. [87] A. Tasker, P.W. Dettmar, M. Panetti, J.A. Koufman, J.P. Birchall, J.P. Pearson, Is gastric reflux a cause of otitis media with effusion in children? Laryngoscope 112 (2002) 1930—1934.
Otitis media with effusion: disease or defense? A review of the literature J.A. de Ru a,*, J.J. Grote b a
Department of Otorhinolaryngology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands b Department of Otorhinolaryngology, Leiden University Medical Center, Leiden, The Netherlands Received 21 May 2003 ; received in revised form 2 November 2003; accepted 9 November 2003
KEYWORDS Middle ear effusion; Immune system; Infection; Eustachian tube; Ventilation tube
Summary Many studies of otitis media with effusion (OME) have been published, most of them dealing with risk factors. The literature correlates this condition with various patient characteristics and socio-economic factors, but none of these have been identified as the sole causative factor. A review of the literature suggests that otitis media with effusion is a response to pathogenic bacteria and thus a normal protective reaction of the body. Therefore, the decision on whether or not treatment is indicated should take the natural course of that response into account. In light of the literature reviewed here, we conclude that there is usually no need to treat middle ear effusion in young children. © 2003 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Acute otitis media (AOM) is a bacterial infection of the middle ear that causes fever and pain, has a risk of acute complications, and manifests itself as an erythematous, bulging tympanic membrane. If the membrane is perforated, a bloodstained discharge may be present. This picture differs from that of otitis media with effusion (OME). OME causes temporary hearing loss; in the long run, it is said to cause bone resorption and retraction pockets. However, the patient shows no signs of illness like pain or fever. In general, it is self-limiting and most often it does not leave the patient with a functional hearing impairment.
* Corresponding author. Tel.: +31-30-2509111; fax: +31-30-2541922. E-mail address: [email protected] (J.A. de Ru).
The greatest risk of developing OME is in the first 2 years of life, and it affects 80% of pre-school children at least once. OME is still the most common reason for surgery in children. Many studies have been performed on the pathophysiology of this disease, but the precise etiology remains unclear. Therefore, the guidelines for treatment are still open to interpretation. In our opinion, the viscous type of OME in children should not be considered as a disease that needs treatment. Instead, we propose that it should be seen as a necessary reaction by the middle ear to an infectious focus, and that it generally is a well-balanced response that is regulated by our innate and acquired immune system. Because the thick mucus contains many factors of our immune system, it is a hostile environment for micro-organisms. This reaction sets up a line of defense against bacteria coming from the nasopharynx. In this light, it seems that OME could develop when other protective barriers (mucocil-
0165-5876/$ — see front matter © 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2003.11.003
332 iary system, immune system, and eustachian tube) are not yet functioning properly or not offering enough resistance to pathogenic bacteria. In short, we think that OME is the body’s way to protect the ear until other mechanisms have developed fully. In the Netherlands, OME is responsible for about 30% of all pediatric healthcare visits by children under the age of 2 years. Taking the standpoint that OME is just a normal protective response would have several advantages: it would allow many children to avoid an operation for grommet insertion; it would reduce exposure to the risks of surgery; and it would prevent all late complications of grommet insertion (note that retention of ventilation tubes for more than 2 years causes higher complication rates [1]). Moreover, it would mean considerable savings in time and money for the healthcare system.
2. The mucociliary system The mucociliary system is one of the airways’ most important defenses against inhaled or invading particles such as dust, bacteria, viruses, and allergens [2]. It prevents colonization by inhaled bacteria in three ways: (1) physical removal by ciliar clearance, (2) the presence of broad-spectrum antimicrobial agents in the mucus, and (3) the recruitment of phagocytic cells and an inflammatory response. Moreover, the epithelial cells that line the airways play a role in the immune defense against micro-organisms, an innate response on which the body depends to prevent onset of infection [3,4]. The anterior half of the middle ear mucosa, like part of the hypotympanum and the orifice of the eustachian tube, is cilia-bearing. Normally, this membrane secretes mucus, which is transported by the cilia across the middle ear mucosa and down the eustachian tube to be swallowed [5—7]. This transport helps prevent bacteria from ascending from the nasopharynx to the middle ear. In addition, the mucus can bind bacteria and influence adhesion to the epithelium by providing points of attachment that mimic cell surface attachment sites [5,6]. Then, mucin-bacterial interactions may facilitate the removal of bacteria [8]. Ciliary activity is sensitive to a variety of pathological agents, including bacteria, bacterial toxins, and irradiation [2]. Nonetheless, children with OME were found to have a normal ciliary beat frequency [6]. On the other hand, middle ear effusions are common in patients with impaired mucociliary function, specifically Kartagener’s syndrome [9]. These studies suggest that normal mucociliary function is necessary for a middle ear cavity to be healthy.
J.A. de Ru, J.J. Grote
3. The eustachian tube 3.1. Obstruction or infection Early theories stated that OME starts with a mechanical obstruction to airflow through the eustachian tube. As oxygen is absorbed, negative pressure builds up, causing the middle ear to fill with fluid. This is called the ‘ex vacuo’ theory [10,11]. Recently, this theory has been challenged by Sadé [11], who argued that tubal occlusion is an unlikely explanation. In cases of nasopharyngeal carcinoma, he found that OME usually occurred when no air could pass through the eustachian tube for the reason that its muscles had been affected, not because its opening was blocked. Thus, even small carcinomas can cause OME. Even so, large polyps that fill the nasopharynx are usually not associated with middle ear effusions [11]. Furthermore, the effusions are generally more serous in adults with nasopharyngeal carcinoma. In children with a predominantly inflammatory etiology, the effusions are mostly viscous [12]. Also, Kuijpers et al. found that the increased activity encountered in secretory otitis media cannot be attributed solely to tubal occlusion. Rather, they thought it was the result of an infective process [13]. Adenoidectomy has been shown to be effective in OME, assuming that it removes the source of infection. The presence of adenoid tissue around the torus tubarius is associated with OME, although the size of the adenoids is not [14—16]. The above studies suggest that OME in young children is more likely to be the result of an infectious focus than of a mechanical obstruction.
3.2. Function In otologically normal children, the active eustachian tube function is not as good as in adults, while the passive function is similar. In children with a history of otitis media, the active eustachian tube function is worse than in otologically normal children [17]. Because the opening function of the tube is poor, negative pressure builds up in the middle ear. The ability to equilibrate middle ear pressure and atmospheric pressure upon swallowing improves with age. Improvement is most pronounced among children 3—7 years old. In that age group, the incidence of OME decreases, possibly because the function of the tensor veli palatini and levator veli palatini muscles improves at that age [18]. When the opening function of the eustachian tube is impaired, as it is in patients with a cleft palate, the incidence of OME is high [19]. Poor eustachian
Otitis media with effusion: disease or defense? A review of the literature tube function, as evidenced by persistent negative middle ear pressure, is commonly seen in older subjects with un-operated cleft palates [20]. It is our opinion that not all OME in children with a cleft palate or lip should be treated. There is some evidence that the insertion of a ventilation tube in these children produces more long-term sequelae of OME than a conservative approach [21]. Furthermore, OME is very common in syndromes affecting the nasopharynx and skull base [22]. It is important to note that the tube’s position is more horizontal in children than in adults, as well as in children with Down’s syndrome compared to normal children. This position might give bacteria from the nasopharynx easier access to the middle ear. In infancy, when the tube is shorter and wider, this route is easily accessible to potentially harmful germs [23]. Moreover, reflux of gastric juice into the tube is easier because of the angle and immaturity of the tube, but also because of the supine position in which infants are often placed [24]. Reflux might cause transient damage to the eustachian tube and the middle ear mucosa, resulting in ideal conditions for secondary bacterial colonization [24]. Like other investigators, we conclude that hypofunction of the tube may be an underlying factor in the development of OME [17]. It is possible that eustachian tube function is sub-optimal to some degree in most children. Nonetheless, those with more abnormality than others (cleft palate, Down’s syndrome) run an even greater risk of developing OME [10]. These studies clearly indicate that a normally functioning eustachian tube should be seen as a line of defense. Besides regulating middle ear pressure, the eustachian tube protects the middle ear from nasopharyngeal secretions and regulates the clearance of fluids accumulating in the middle ear [25].
4. Effusion In patients with OME, the middle ear mucosa shows vascular proliferation with an infiltrate of plasma cells and lymphocytes in the submucosa. There is metaplasia of the middle ear epithelium to a secretory type with proliferation of goblet cells [26,27]. Histology shows fewer mucus-secreting cells in the middle ear mucosa in serous compared to viscous OME [10]. Mucus contains water, cells, cell debris, high molecular weight compounds (mucins, proteins, and lipids), immunoglobulins, lysozyme, lactoferrin and complement components, antimicrobial peptides, leukotrienes and cytokines [3,10,28—32]. These chemical defenses ensure
333
that an antimicrobial milieu is constantly present [3]. Mucins are found in association with epithelia throughout the body. Their function, in general terms, is to lubricate, prevent dehydration, and protect [10]. Mucin is actively secreted into the effusion, which means that effusions are not simply passive transudates of fluid. In OME, the viscosity of the effusion has been shown to correlate with the concentration of mucin [33]. Furthermore, ever since Fleming’s discovery that human nasal secretions harbor antimicrobial activity, lysozyme has been considered one of the most important of the host defense molecules [3]. Also, IgA and IgG are secreted into the middle ear effusion in excess of plasma levels [10,34,35]. Antigen-specific antibody-producing cells can be induced in the middle ear mucosa of previously sensitized animals [36]. Breast-feeding protects against OME, probably through the effect of maternal antibodies on middle ear pathogens [37—40]. In view of these chemical properties, we conclude that the thick ‘glue’ found in the middle ear of young children is a defensive barrier that is actively secreted by the middle ear mucosa.
5. Immunology Cytokines, which control the acute inflammatory response, are intercellular messenger molecules produced by inflammatory cells. Many of these messengers, including IL-1, IL-2, IL-8, and TNF-␣, are present in the effusion, where they regulate the inflammatory response [26,28,32,41]. In blood sera, most of the cytokines are either absent or occur only at the lowest levels that can be detected. This implies that the cytokines found in middle ear effusions are produced locally. Moreover, the levels of cytokines are correlated with the type of effusion; the concentration is significantly higher in mucopurulent secretions [29,41,42]. Another important mediator is transforming growth factor  (TGF-). This is an extremely potent mononuclear leukocyte chemotactic factor. It controls the recruitment and activation of monocytes and lymphocytes in many inflammatory diseases. Another one is platelet activating factor (PAF) [43,44]. PAF is released from human neutrophils, platelets, eosinophils, macrophages, mast cells, and vascular epithelial cells. It can induce OME even when the eustachian tube is functioning normally [44]. Like cytokines, PAF is found in higher concentrations in mucoid than in serous effusions. Polymorphonuclear leukocytes are known to generate an oxygen-dependent bactericidal system.
334 They do so by using a series of oxidants to destroy invading micro-organisms [45]. However, as a side effect, superoxide radicals might damage the membrane of the host cell. To protect the host from these oxygen radicals, an important role is played by superoxide dismutase, which is present in higher levels in mucoid than in serous effusions [45]. These findings suggest that the immune system plays an active and well-balanced role in the body’s response to OME.
6. Inner ear protection Otitis media can also produce functional and pathological changes in the cochlea. The round and oval windows are possible routes through which noxious substances may pass from the middle to the inner ear [46,47]. Morphologic evidence suggests that membrane layers of the round window participate in the absorption and secretion of substances into and out of the inner ear [47]. Post-mortem studies of patients with a history of otitis media give evidence of a defensive action in this region. At the oval window, the squamous epithelium on the middle ear side of the footplate of the stapes was taller than normal. Furthermore, the connective tissue layer was thicker than normal and infiltrated by inflammatory cells [47]. In contrast, the vestibular side of the footplate had remained unchanged. At the round window outer epithelium, the normally low cuboidal cells were taller. There was also an increase in mitochondria and rough endoplasmatic reticulum in this region. While microvilli are normally sparse, their number was increased. At the core of the connective tissue, there was evidence of cellular infiltration by neutrophils, macrophages, and plasma cells. Immunoactive cells were observed surrounding the capillary vessels [47]. On the one hand, these histopathological changes during OME would clearly influence the function of the membrane. On the other hand, they constitute a defensive reaction of the membrane. This reaction includes a possible decrease in permeability once the histological changes are established [47].
7. Micro-organisms OME might be initiated by an acute infection caused by gram-negative bacteria containing endotoxin, a lipopolysaccharide in the membrane of bacteria that is released by growth or lysis [29,31]. Endotoxin reduces the mucociliary activity, induces effusion, and stimulates mucin production
J.A. de Ru, J.J. Grote [31,48,49]. Moreover, it exerts a strong stimulus on the proliferation of middle ear epithelium [50]. Endotoxin concentrations are significantly higher in muco-purulent than in serous effusions [42]. Animal models support the idea that the inflammatory stimulus for OME is bacterial endotoxin. This substance stimulates the production of tumor necrosis factor ␣ (TNF-␣) and interleukin 1 (IL-1) [28,29,31,49,50—53]. The levels of TNF-␣ are higher in effusions containing gram-negative bacteria than in those without bacteria [29]. TNF-␣ has been shown to evoke mucus secretion by up-regulating mucin genes [54]. High TNF-␣ levels in middle ear effusions have been associated with the persistence of OME [55].
7.1. Bacteria Bacteria, especially Haemophilus influenzae and Streptococcus pneumoniae (normal residents of the nasopharynx), have been cultured from up to 40% of the effusions studied [29,31,56—58]. Under direct microscopy, bacteria are more often visible in mucoid than in serous effusions [59]. Other studies have shown bacterial DNA by polymerase chain reaction in up to 80% of effusions in the absence of viable organisms on culture [60,61]. The presence of H. influenzae mRNA was demonstrated in 43% of 93 middle ear effusions from children whose OME had lasted 3 months or more, even though only 12% of these cases were positive on culture. Bacterial mRNAs have a half-life of mere seconds. Thus, their presence indicates viable and metabolically active bacteria. To explain this discrepancy it was argued that the negative cultures are caused by the bacteria existing as a biofilm, which is a state of very low metabolic activity. While bacteria in this state may be resistant to antibiotics, they can still evoke an immune response [62].
7.2. Viruses Viral infections may stimulate inflammation in the middle ear. Indeed a short-lived middle ear effusion is not uncommon in the course of the common cold. Viral respiratory infections, particularly those caused by respiratory syncytial virus (RSV), adenovirus, and influenza virus type A or B, have been linked etiologically with OME [10,63]. RSV, rhinovirus, and adenovirus nucleic acids have been identified in effusions [55,64,65]. Viral sequences were highly detectable in effusions of patients from whose nasopharynges RSV was isolated [55]. In some cases, the viruses were present alone, while in others co-existing bacteria were found. It is unclear whether viruses act alone to
Otitis media with effusion: disease or defense? A review of the literature produce inflammation or merely predispose to bacterial superinfection [10,32]. Several studies have demonstrated that viral infection of the upper respiratory tract may have a substantial impact on the bacterial colonization of the nasopharynx and the adherence of bacteria to epithelial cells [66—69]. Recently, Sadé et al. suggested that the bimodal peak prevalence distribution might be the result of different types of infection. They discriminated between two groups of children: one, of predominantly younger children, 2.6 years of age, with bacterial OMA resulting in OME; and the other, 5 years of age, with a possible viral infection as etiological factor [70]. The above mentioned studies consistently show that both bacterial and viral infections may play a very important role in the etiology of OME.
8. Allergy Controlled studies have failed to show any increase in the prevalence of an atopic history or positive skin prick tests in children with OME compared to normal children. Middle ear effusions contain mediators of the allergic response, such as IgE and eosinophil cationic protein. Their concentrations in the effusions are usually similar to, or lower than, those in serum, suggesting that they are not produced locally. Most studies do not support the notion that middle ear mucosa serves as the target organ for allergy. Middle ear challenge with antigenic material does not produce an effusion in an animal model [59]. If allergy plays any role in OME, it is probably in the form of allergic rhinitis delaying the resolution of a middle ear effusion by affecting the eustachian tube function [10]. Furthermore, an allergic reaction might cause damage to the mucosa in the nasopharynx, thereby predisposing an individual for secondary bacterial infection. In our opinion, allergy may exert some influence on the development of OME, but we do not believe it is the sole causative factor.
9. Environmental factors Disease states and environmental exposure can inhibit the operation of the body’s defenses and responses, thus allowing unimpeded growth of pathogenic micro-organisms [3]. In addition, various social factors have been implicated in the etiology of OME. All of these factors are probably mediated by an increased propensity to infection.
335
It is postulated that greater exposure to respiratory pathogens is the reason for this increase. Children who attend daycare centers have a higher risk of OME. The more time spent in daycare, the greater the risk [10,40,71]. The same mechanism may explain the increased incidence of OME in children with several siblings at home [40]. This suggests that infection status plays an important role. There is also seasonal variation in the incidence of OME. The winter preponderance may be attributed to an overall increase in respiratory infections and perhaps also to keeping children indoors close together [10,72]. Patients with OME who have been exposed to cigarette smoke have a significantly lower ciliary beat frequency than those who have not been exposed [73]. In animals, however, exposure to smoke has never been shown to lead to middle ear effusions. Studies show that smoke has no effect on the resolution of experimentally induced middle ear effusions in rats and chinchillas [73,74]. Otitis media with effusion is more common in children exposed to cigarette smoke [75,76]. This higher incidence might be a knock-on effect of the more frequent upper respiratory tract infections found among smokers and the less well functioning first line of defense, i.e. reduced ciliary beat.
10. Acute otitis media and otitis media with effusion We would agree with most authors that OME could develop after a period of AOM. In 50% of the cases, the middle ear effusion directly follows an episode of infection, indicating a close connection. Some research shows that children with OME have up to five times more episodes of acute otitis media than those without OME, suggesting a reverse causality [72]. The flaw in that argument seems to be that most of the children in the study already had twice as many acute episodes before the OME set in. These children could thus be prone to chronic infection and would therefore just need to protect their middle ear more than others.
11. Discussion and conclusions The pathogenesis of inflammatory disease is more complex than can be explained by a single cause-and-effect relationship. It probably represents an interaction between genetically predisposing factors (innate and acquired immune system), exogenous triggers (amount of exposure
336 to bacteria, daycare centers), and endogenous triggers (local inflammatory response). The outcome of these interactions is a spontaneously relapsing and remitting inflammatory process [77]. It is still unclear whether mucoid and serous effusions represent different stages of the same disease or in fact different diseases. One reason why a mucoid effusion is generally found in children and a serous one in adults might be that a fully developed immune system would not need to mount an overwhelming reaction. However, it is more likely that we are dealing with different entities [5]. Mucoid effusions contain on average more bacterial toxins, and other markers of inflammation than serous ones. Accordingly, mucoid secretions are formed if there is an infectious component. As Maw has suggested, the thick mucoid secretion developing within the middle ear may ultimately obstruct the eustachian tube. Acting as a barrier to ascending infection, the thick mucus would isolate the middle ear from the ambient environment [22]. Sadé et al. distinguished between different kinds of middle ear effusions in a group of 809 children. In one of these groups, the effusion was almost always sterile, consisting mainly of lymphocytes and macrophages. This suggested a viral upper respiratory tract infection [70]. For some reason, serous otitis, as seen in patients with nasopharyngeal carcinoma or in irradiated ears, seems to fit the ‘ex vacuo’ theory (negative middle ear pressure with subsequent effusion of sterile fluid). But the serous effusion in this group, often consisting of immuno-compromised patients, could also be a late form of the general ‘mucositis’ mentioned by Sadé et al. Viral upper respiratory tract infection can lead to eustachian tube opening failure, middle ear underpressure, and OME [78—84]. It has been suggested that the observed increase in tubal resistance that accompanies viral infections in the upper respiratory tract may be a reflexive up-regulation of the protective function at the expense of the pressure-regulating function of the eustachian tube [23]. This review of the literature provides convincing evidence that the viscous type of OME in children should not be considered a disease. Instead, it should be seen as a necessary protective reaction by the middle ear to an infectious focus in children. Therefore, we conclude that OME in young children usually does not require treatment of any kind. Most OME will subside through the gradual maturation of the child’s immune system and eustachian tube function [85]. Meanwhile, as Rosenfeld proposed, since nature will ‘cure’ OME, the best treatment is reassurance, avoidance of unproved therapies, and
J.A. de Ru, J.J. Grote parental education about the prevalence and natural history of OME [85]. There are, of course, examples of adaptive and defensive natural processes going out of control and thereby causing disease. In general, however, we believe that OME is a well-balanced, self-limiting response. In some cases, treatment could be necessary, though. For instance, it could be necessary in cases of prolonged and severe delay in language development in school children. And it might be indicated in children with a combined congenital perceptive hearing loss and OME. However, we concur with Gates, who suggested that the treatment of choice should be adenoidectomy to remove the infectious focus [86]. The effect of anti-reflux therapy remains to be investigated [87]. Encouraging breast-feeding and parental advice to stop smoking to reduce the number of upper respiratory tract infections may reduce the incidence and morbidity of OME. Furthermore, the natural course of OME has to be incorporated in the decision on whether treatment is warranted or not. If OME does not resolve itself in the natural way, clinical history-taking and examination to ascertain an underlying reason (immuno-deficiencies, URTI, etc.) should be performed.
Acknowledgements The authors like to thank Marja J. Nell and Anne G.M. Schilder for their critical reading of the manuscript.
References [1] M. El-Bitar, M.T. Pena, S.S. Choi, G.H. Zalzal, Retained ventilation tubes, should they be removed at 2 years? Arch. Otolaryngol. Head Neck Surg. 128 (2002) 1357—1360. [2] Y. Ohashi, Y. Nakai, Current concepts of mucociliary dysfunction in otitis media with effusion, Acta Otolaryngol. (Stockh.) 486 (Suppl.) (1991) 149—161. [3] G. Diamond, D. Legarda, L.K. Ryan, The innate immune response of the respiratory epithelium, Immunol. Rev. 173 (2000) 27—38. [4] R.E.W. Hancock, G. Diamond, The role of cationic antimicrobial peptides in innate host defences, Trends Microbiol. 8 (2000) 402—410. [5] J. Sadé, Middle ear mucosa, Arch. Otolaryngol. 84 (1966) 137—143. [6] M. Wake, L.A. Smallman, Ciliary beat frequency of nasal and middle ear mucosa in children with otitis media with effusion, Clin. Otolaryngol. 17 (1992) 155—157. [7] W. Kuijpers, J.M.H. Van Der Beek, The role of microorganisms in experimental Eustachian tube obstruction, Acta Otolaryngol. (Stockh.) 414 (Suppl.) (1984) 58—66. [8] M.S. Reddy, T.F. Murphy, H.S. Faden, J.M. Bernstein, Middle ear mucin glycoprotein: purification and interaction
Otitis media with effusion: disease or defense? A review of the literature
[9] [10] [11] [12] [13]
[14]
[15] [16] [17] [18] [19] [20] [21]
[22] [23]
[24] [25] [26] [27] [28] [29]
with non typable Haemophilus influenzae and Moraxella catarrhalis, Otolaryngol. Head Neck Surg. 116 (1997) 175— 180. T.J. Fisher, Middle ear ciliary defect in Kartagener’s syndrome, Pediatrics 62 (1978) 443. H. Kubba, J.P. Pearson, J.P. Birchall, The aetiology of otitis media with effusion, Clin. Otolaryngol. 25 (2000) 81— 94. J. Sadé, The nasopharynx, eustachian tube and otitis media, J. Laryngol. Otol. 108 (1994) 95—100. W.I. Wei, V.J. Lund, D.J. Howard, Serous otitis media in malignancies of the nasopharynx and maxilla, J. Laryngol. Otol. 102 (1988) 129—132. W. Kuijpers, J.M.H. Van der Beek, P.H.K. Jap, E.L.G. Tonnaer, The structure of the middle ear epithelium of the rat and the effect of Eustachian tube obstruction, Histochem. J. 16 (1984) 807—818. G.A. Gates, C.A. Avery, T.J. Prihoda, J.C. Cooper, Effectiveness of adenoidectomy and tympanostomy tubes in the treatment of chronic otitis media with effusion, N. Engl. J. Med. 317 (1987) 1444—1451. E.D. Wright, A.J. Pear, J.J. Manoukian, Laterally hypertrophic adenoids as a contributing factor in otitis media, Int. J. Pediatr. Otorhinolaryngol. 45 (1998) 207—214. N. Roydhouse, Adenoidectomy for otitis media with mucoid effusion, Ann. Otol. Rhinol. Laryngol. 89 (Suppl. 68) (1980) 312—313. A. Bylander, Function and dysfunction of the eustachian tube in children, Acta Otorhinolaryngol. Belg. 38 (1984) 238—245. C.A. Holborow, Eustachian tubal function changes through childhood and neuromuscular control, J. Laryngol. Otol. 89 (1975) 47—55. P.J. Robinson, S. Lodge, B.M. Jones, C.C. Walker, H.R. Grant, The effect of palate repair on otitis media with effusion, Plast Reconstr. Surg. 89 (1992) 640—645. A. Gopalakrishna, K.S. Goleria, A. Raje, Middle ear function in cleft palate, Br. J. Plast. Surg. 37 (1984) 558—565. P. Sheahan, A.W. Blaney, J.N. Sheahan, M.J. Earley, Sequelae of otitis media with effusion among children with cleft lip and/or cleft palate, Clin. Otolaryngol. 27 (2002) 494—500. A.R. Maw, in: A.G. Kerr (Ed.), Scott-Brown’s Otolaryngology, vol. 6, sixth ed., Butterworth—Heinemann, Oxford, 1997 (Chapter 7). D. Passali, Immunobiology in otorhinolaryngology–—progress of a decade, in: G. Mogi, J.E. Veldman, H.C. Kawauchi (Eds.), Proceedings of the 4th International Academic Conference Oita, Japan, 4—7 April 1994, Kugler Publications, Amsterdam, 1994, pp. 83—87. A. Tasker, P.W. Dettmar, M. Panetti, J.A. Koufman, J.P. Birchall, J.P. Pearson, Reflux of gastric juice and glue ear in children, Lancet 359 (2002) 493—495. C.D. Bluestone, Pathogenesis of otitis media: role of eustachian tube, Pediatr. Infect. Dis. J. 15 (1996) 281—291. G. Zechner, Auditory tube and middle ear mucosa in nonpurulent otitis media, Ann. Otol. Rhinol. Laryngol. 89 (Suppl.) (1980) 87—90. T. Ishii, M. Toriyama, J.I. Suzuki, Histopathological study of otitis media with effusion, Ann. Otol. Rhinol. Laryngol. 89 (1980) 83—86. K.S. Maxwell, J.E. Fitzgerald, J.A. Burleson, G. Leonard, R. Carpenter, D.L. Kreutzer, Interleukin-8 expression in otitis media, Laryngoscope 104 (1994) 989—995. D.N. Willett, R.P. Rezaee, J.M. Billy, M.B. Tighe, T.T. De Maria, Relationship of endotoxin to tumor-necrosisfactoralpha and interleukin-1 beta in children with otitis media
[30] [31] [32]
[33]
[34] [35]
[36]
[37]
[38]
[39]
[40]
[41] [42] [43]
[44] [45] [46] [47]
337
with effusion, Ann. Otol. Rhinol. Laryngol. 107 (1998) 28— 33. E. Hentzer, Ultrastructure of the middle-ear mucosa in secretory otitis media, Acta Otolaryngol. 73 (1972) 394— 401. T. Ovesen, T. Ledet, Bacteria and endotoxin in middle ear fluid and the course of secretory otitis media, Clin. Otolaryngol. 17 (1992) 531—534. R.F. Yellon, G. Leonard, P.T. Marucha, R. Craven, R.J. Carpenter, W.B. Lehmann, et al., Characterization of cytokines present in middle ear effusions, Laryngoscope 101 (1991) 165—169. S. Carrie, D.A. Hutton, J.P. Birchall, G.G.R. Green, J.P. Pearson, Otitis media with effusion: components which contribute to the viscous properties, Acta Otolaryngol. (Stockh.) 112 (1992) 504—511. E.A. Jones Jr., L.R. Thomas, N.C. Davis, The significance of secretory IgA in middle ear fluid, Ann. Allergy 42 (1979) 236—240. S. Jeep, Correlation of immunoglobulins, the complement system and inflammatory mediators with reference to the pathogenesis of serous otitis media, Laryngo-rhino-otologie 69 (1990) 201—207. N. Watanabe, H. Yoshimura, G. Mogi, Induction of antigen-specific IgA-forming cells in the middle ear mucosa, Arch. Otolaryngol. Head Neck Surg 114 (1988) 758— 762. L.C. Duffy, H. Faden, R. Wasielewski, J. Wolf, D. Krystofik, Exclusive breastfeeding protects against bacterial colonization and day care exposure to otitis media, Pediatrics 100 (1997) E7. J.M. Bernstein, Y. Harabuchi, N. Yamanaka, H.S. Faden, Immunobiology in otorhinolaryngology–—progress of a decade, in: G.J.E. Mogi, J.E. Veldman, H.C. Kawauchi (Eds.), Proceedings of the 4th International Academic Conference Oita, Japan, 4—7 April 1994, Kugler Publications, Amsterdam, 1994, pp. 25—36. M.J. Owen, C.D. Baldwin, P.R. Swank, A.K. Pannu, D.L. Johnson, V.M. Howie, Relation of infant feeding practices cigarette smoke exposure and group childcare to the onset and duration of otitis media with effusion in the first two years of life, J. Pediatr. 123 (1993) 702—711. J.L. Paradise, H.E. Rockette, D.K. Colborn, B.S. Bernard, C.G. Smith, M. Kurs-Lasky, et al., Otitis media in 2235 Pittsburgh infants: prevalence and risk factors during the first two years of life, Pediatrics 99 (1997) 318—333. M. Hotomi, T. Samukawa, N. Yamanaka, Interleukin 8 in otitis media with effusion, Acta Otolaryngol. (Stockh.) 114 (1994) 406—409. M.J. Nell, J.J. Grote, Endotoxin and tumor necrosis factor-␣ in middle ear effusions in relation to upper airway infection, Laryngoscope 109 (1999) 1815—1819. M.S. Cooter, R.J. Eisma, J.A. Burleson, G. Leonard, D. Lafreniere, D.L. Kreutzer, Transforming growth factor beta expression in otitis media with effusion, Laryngoscope 108 (1998) 1066—1070. C.K. Rhee, T.T. Jung, S. Miller, D. Weeks, Experimental Otitis media with effusion induced by platelet activating factor, Ann. Otol. Rhinol. Laryngol. 102 (1993) 600—605. H. Shigemi, Y. Kurono, T. Egashira, G. Mogi, Role of superoxide dismutase in otitis media with effusion, Ann. Otol. Rhinol. Laryngol. 107 (1998) 327—331. M.V. Goycoolea, Oval and round window membrane changes in otitis media in the human, Acta Otolaryngol. (Stockh.) 115 (1995) 282—283. M.V. Goycoolea, D. Muchow, P. Schachern, Experimental studies on round window structure: function
338
[48]
[49]
[50]
[51]
[52]
[53] [54]
[55]
[56] [57]
[58] [59] [60]
[61]
[62]
[63]
J.A. de Ru, J.J. Grote and permeability, Laryngoscope (Suppl. 44) (1988) 1— 20. A.S. Rose, J. Prazma, S.H. Randell, H.C. Baggett, A.P. Lane, H.C. Pillsbury, Nitric oxide mediates mucin secretion in endotoxin-induced otitis media with effusion, Otolaryngol. Head Neck Surg. 116 (1997) 308—316. M.J. Nell, B.M. Albers, H.K. Koerten, J.J. Grote, Inhibition of endotoxin effects on cultured human middle ear epithelium by batericidal permeability-increasing protein, Am. J. Otol. 23 (2000) 625—630. S.C. Hesseling, C.A. Van Blitterswijk, D.J. Lim, T.F. DeMaria, L.O. Bakaletz, J.J. Grote, Effect of Endotoxin on cultured rat middle ear epithelium, rat meatal epidermis and human keratinocytes, Am. J. Otol. 15 (1994) 762— 768. J.J. Grote, S.C. Hesseling, G.J.M. Tjebbes, C.A. Van Blitterswijk, Effect of HA-1A monoclonal IgM antibody on endotoxin-induced proliferation of cultured rat middle ear epithelium, Ann. Otol. Rhinol. Laryngol. 104 (1995) 226— 230. T.F. DeMaria, B.R. Briggs, D.J. Lim, et al., Experimental otitis media with effusion following middle ear inoculation of nonviable Haemophilus influenzae, Ann. Otol. Rhinol. Laryngol. 93 (1984) 52—56. M.J. Nell, B.M. Op’t Hof, H.K. Koerten, J.J. Grote, Effect of endotoxin on cultured human middle ear epithelium, ORL 61 (1999) 201—205. S.J. Levine, P. Larivee, C. Logun, C.W. Angus, F.P. Ognibene, J.H. Shelhamer, Tumour necrosis factor a induces mucin hypersecretion and MUC 2 gene expression in human airway epithelial cells, Am. J. Resp. Cell Mol. Biol. 12 (1995) 196—204. Y. Okamoto, K. Kudo, K. Shirotori, M. Nakazewa, E. Ito, K. Togawa, et al., Detection of genomic sequences of respiratory syncytial virus in otitis media with effusion in children, Ann. Otol. Rhinol. Laryngol. 157 (Suppl.) (1992) 7— 10. T. Palva, T. Lehtinen, J. Rinne, Immune complexes in middle ear fluid in chronic secretory otitis media, Ann. Otol. Rhinol. Laryngol. 92 (1983) 42—44. T. Palva, T. Lehtinen, H. Kirtanen, Immune complexes in middle ear fluid and adenoid tissue in chronic secretory otitis media, Acta Otolaryngol. (Stockh.) 95 (1983) 539— 543. I. Brook, P. Yocum, K. Shah, B. Feldman, S. Epstein, Aerobic and anaerobic bacteriologic features of serous otitis media in children, Am. J. Otol. 4 (1983) 389—392. P. Van Cauwenberge, M. Rysselaere, P. Kluyskens, New perspectives in the direct microscopic examination of middle ear effusions, Am. J. Otol. 6 (1985) 191—195. M. Hotomi, T. Tabata, H. Kakiuchi, M. Kunimoto, Detection of Haemophilus influenzae in middle ear of otitis media with effusion by polymerase chain reaction, Int J. Ped. Otorhinolaryngol. 27 (1993) 119—126. J.C. Post, R.A. Preston, J.J. Aul, M. Larkins-Pettigrew, J. Rydquist-White, K.W. Anderson, et al., Molecular analysis of bacterial pathogens in otitis media with effusion, JAMA 273 (1995) 1598—1604. M. Rayner, Y. Zhang, M.C. Gorry, Y. Chen, J.C. Post, G.D. Ehrlich, Evidence for bacterial activity in culture–—negative otitis media with effusion, JAMA 279 (1998) 296— 299. F.W. Henderson, A.M. Collier, M.A. Sanyal, J.M. Watkins, D.L. Fairclough, W.A. Clyde, et al., A longitudinal study of respiratory viruses and bacteria in the etiology of otitis media with effusion, N. Engl. J. Med. 306 (1982) 1377— 1383.
[64] C.B. Shaw, N. Obermyer, S.J. Wetmore, G.A. Spirou, R.W. Farr, Incidence of adenovirus and respiratory syncitial virus in chronic otitis media with effusion using the polymerase chain reaction, Otolaryngol. Head Neck Surg. 113 (1995) 234—241. [65] M. Arola, T. Ziegler, H. Puhakka, O. Lehtonen, O. Ruuskanen, Rhinovirus in otitis media with effusion, Ann. Otol. Rhinol. Laryngol. 99 (1990) 451—453. [66] T. Heikkinen, T. Chonmaitree, Increasing importance of viruses in acute otitis media, Ann. Med. 32 (2000) 157— 163. [67] J. Patel, H. Faden, S. Sharma, P.L. Ogra, Effect of respiratory syncytial virus on adherence, colonization and immunity of non-typable Haemophilus influenzae: implications for otitis media, Int. J. Pediatr. Otorhinolaryngol. 23 (1992) 15—23. [68] V. Fainstein, D.M. Musher, T.R. Cate, Bacterial adherence to pharyngeal cells during viral infection, J. Infect. Dis. 141 (1980) 172—176. [69] J.S. Abramson, J.G. Wheeler, Virus-induced neutrophil dysfunction: role in the pathogenesis of bacterial infections, Pediatr. Infect. Dis. J. 13 (1994) 643—652. [70] J. Sadé, C. Fuchs, E. Russo, D. Cohen, Is secretory otitis media a single disease entity? Ann. Otol. Rhinol. Laryngol. 112 (2003) 342—347. [71] M.M. Rovers, G.A. Zielhuis, H. Straatman, K. Ingels, G.J. Van de Wilt, P. Van den Broek, Prognostic factors for persistent otitis media with effusion in infants, Arch. Otolaryngol. Head Neck Surg. 125 (1999) 1203—1207. [72] O.P. Alho, H. Oja, M. Koivu, M. Sorri, Chronic otitis media with effusion in infancy. How frequent is it? How does it develop, Arch. Otolaryngol. Head Neck Surg. 121 (1995) 432—436. [73] A.M. Agius, M. Wake, A. Pahor, L.A. Smallman, Smoking and middle ear ciliary beat frequency in otitis media with effusion, Acta Otolaryngol. (Stockh.) 115 (1995) 44— 49. [74] P.J. Antonelli, K.A. Daly, S.K. Juhn, E.J. Veum, G.L. Adams, G.S. Giebink, Tobacco smoke and otitis media in the chinchilla model, Otolaryngol. Head Neck Surg. 111 (1994) 513—518. [75] A.E. Hinton, G. Buckley, Parental smoking and middle ear effusions in chidren, J. Laryngol. Otol. 102 (1988) 992— 996. [76] D.P. Strachan, Impedance tympanometry and the home environment in 7-year-old children, J. Laryngol. Otol. 104 (1990) 4—8. [77] D.S. Hurst, P. Venge, Levels of eosinophil cationic protein and myeloperoxidase from chronic middle ear effusions in patients with allergy and/or acute infection, Otolaryngol. Head Neck Surg. 114 (1996) 531—544. [78] M.A. Sanyal, F.W. Henderson, E.C. Stempel, A.M. Collier, F.W. Denny, Effect of upper respiratory tract infection on Eustachian tube ventilatory function in preschool children, Pediatrics 87 (1980) 11—15. [79] A. Bylander, Upper respiratory tract infection and eustachian tube function in children, Acta Otolaryngol. (Stockh.) 97 (1984) 343—349. [80] S.A. Moody, C.M. Alper, W.J. Doyle, Daily tympanometry in children during the cold season: association of otitis media with upper respiratory tract infections, Int. J. Ped. Otoplaryngol. 45 (1998) 143—150. [81] T.P. McBride, W.J. Doyle, F.G. Hayden, J.M. Gwaltney, Alteration of Eustachian tube function middle ear pressure and nasal patency in response to an experimental rhinovirus challenge, Arch. Otolaryngol. Head Neck Surg. 115 (1989) 1054—1059.
Otitis media with effusion: disease or defense? A review of the literature [82] C.A. Buchman, W.J. Doyle, D. Skoner, P. Fireman, J.M. Gwaltney, Otologic manifestations of experimental rhinovirus infection, Laryngoscope 104 (1994) 1295—1299. [83] W.J. Doyle, D.P. Skoner, F. Hayden, C. Buchman, J.T. Seroky, P. Fireman, Nasal and otologic effects of experimental influenza A virus infection, Ann. Otol. Rhinol. Laryngol. 103 (1994) 59—69. [84] C.A. Buchman, W.J. Doyle, D.P. Skoner, J.C. Post, C.M. Alper, J.M. Seroky, K. Anderson, R.A. Preston, F. Hayden, P. Fireman, G.D. Ehrlich, Influenza A virus induced acute otitis media, J. Infect Dis. 172 (1995) 1348—1351.
339
[85] R.M. Rosenfeld, Amusing parents while nature cures otitis media with effusion, Int. J. Pediatr. Otorhinolaryngol. 43 (1998) 189—192. [86] G.A. Gates, C.A. Avery, T.J. Prihoda, Effect of adenoidectomy upon children with chronic otitis media with effusion, Laryngoscope 98 (1988) 58—63. [87] A. Tasker, P.W. Dettmar, M. Panetti, J.A. Koufman, J.P. Birchall, J.P. Pearson, Is gastric reflux a cause of otitis media with effusion in children? Laryngoscope 112 (2002) 1930—1934.