key: cord-0873605-smstf1m1
authors: Heikkinen, Terho; Chonmaitree, Tasnee
title: Viral-bacterial synergy in otitis media: Implications for management
date: 2000
journal: Curr Infect Dis Rep
DOI: 10.1007/s11908-000-0028-6
sha: 5a7c7a830e8ba4ab7ec1a612b063737167fdbb6e
doc_id: 873605
cord_uid: smstf1m1

Despite the extensive use of broad-spectrum antibiotics, poor clinical response to the treatment of acute otitis media is common. Evidence derived from numerous studies during the past two decades supports a crucial role for respiratory viruses in the etiology and pathogenesis of acute otitis media, and recent studies indicate that viruses may also have a profound adverse effect on the resolution of this disease. Viruses seem to interact with bacteria and enhance the local inflammatory process in the middle ear. Effective adjuvant therapies are needed to improve outcome in children with otitis media. Increasing knowledge of the role of viruses, viral-bacterial interaction, and host inflammatory mechanisms in otitis media may lead to major improvements in the management of this disease.

Acute otitis media (AOM) is a major health care problem of childhood and the most common reason for outpatient antibiotic therapy in children in the United States and many other parts of the world. Wang et al. [1] analyzed computerized databases for physician visits and antibiotic prescriptions for different respiratory infections in preschool children in Canada. AOM accounted for 33% of all physician visits and 39% of all antibiotic prescriptions in children younger than 5 years of age.

Although AOM is usually considered a bacterial infection and is therefore treated with antibiotics, there is convincing evidence that respiratory viruses play a crucial role in the etiopathogenesis of this disease [2] . AOM usually occurs in conjunction with a viral upper respiratory infection (URI) and in the vast majority of cases can be clearly regarded as a complication of a viral URI. Koivunen et al. [3] recently corroborated earlier findings about the temporal development of AOM in the course of URI. Of 250 episodes of AOM in children, the incidence was highest during days 2 through 5 after the onset of respiratory symptoms. The distinctive role of URI in the development of AOM was also demonstrated by Daly et al. [4] , who followed 596 infants from birth to age 6 months. Respiratory tract infection was the most important predictor for early AOM, indisputably outweighing other risk factors (eg, daycare attendance). The strongest evidence for the decisive role of viruses in the etiopathogenesis of AOM is, however, provided by direct intervention trials investigating the efficacy of viral vaccination in the prevention of AOM. Studies with influenza vaccine have demonstrated that prevention of the preceding viral URI is an effective way to prevent the development of AOM as a complication [5,6,7••] .

Although the close association between URI and AOM is well established, the detection rates of respiratory viruses in nasopharyngeal specimens from children with AOM have usually ranged from 30% to 50% [2] . In previous studies, detection of respiratory viruses has been based on virus culture and/or viral antigen detection methods, and it is obvious that limitations in these techniques have resulted in underdetection of viruses in the specimens. The recent development of polymerase chain reaction (PCR)-based assays for several respiratory viruses may substantially increase the rates of viral detection in nasopharyngeal specimens [8•,9] . Pitkäranta et al. [10•] studied 92 children with AOM using PCR for detection of rhinovirus, respiratory syncytial virus (RSV), and coronavirus and found at least one of these viruses in the nasopharyngeal aspirates from 62% of the children. In a recent study from the University of Turku, Finland, we searched for viruses in nasopharyngeal aspirates with rapid antigen detection for RSV, influenza virus, parainfluenza virus, and adenovirus and with PCR for rhinovirus, enterovirus, and coronavirus. By these methods, viral infection could be documented in 90% of 67 children with AOM (A. Ruohola et al., Unpublished data).

Dysfunction of the eustachian tube is generally considered the most important factor in the pathogenesis of AOM. Numerous studies in both animals and humans have provided strong evidence of a causal role for respiratory viruses in the disruption of normal eustachian tube function [2] . One plausible mechanism by which viruses may cause eustachian tube dysfunction is that viruses are known to induce the release of cytokines and other inflam-Despite the extensive use of broad-spectrum antibiotics, poor clinical response to the treatment of acute otitis media is common. Evidence derived from numerous studies during the past two decades supports a crucial role for respiratory viruses in the etiology and pathogenesis of acute otitis media, and recent studies indicate that viruses may also have a profound adverse effect on the resolution of this disease. Viruses seem to interact with bacteria and enhance the local inflammatory process in the middle ear. Effective adjuvant therapies are needed to improve outcome in children with otitis media. Increasing knowledge of the role of viruses, viral-bacterial interaction, and host inflammatory mechanisms in otitis media may lead to major improvements in the management of this disease. matory mediators from target cells in the nasopharynx [11, 12] . After intranasal challenge, many of these mediators have been shown to provoke eustachian tube dysfunction [13] . In a recent study of adult volunteers, Fritz et al. [14] reported that nasal lavage fluid levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon-γ, and IL-10 increased in response to influenza virus infection, and the levels correlated significantly with the magnitude and time course of the symptoms. The host-response mechanisms triggered by a viral infection are, however, extremely complex, involving a network of factors that affect each other in a time-dependent manner. Patel et al. [15•] showed that the production of IL-8 by respiratory epithelial cells during an RSV infection was primarily regulated by IL-1α. Further, IL-1β and TNF-α induced the synthesis of IL-8 at 24 hours but partially inhibited the synthesis of this cytokine at 48 hours. Another study by the same group demonstrated the existence of a similar autocrine regulation of IL-6 production during RSV infection [16] . Despite the rapidly increasing knowledge of the host inflammatory response during a viral URI, it is likely that many essential factors contributing to the inflammatory processes in the nasopharynx remain to be identified.

Several recent studies have shown 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 [17, 18] . Recently, Jiang et al. [19] showed that RSV infection significantly enhanced the attachment of nontypeable Haemophilus influenzae to human respiratory epithelial cells. They also demonstrated that P5-fimbriae of H. influenzae were essential for this increased attachment because no similar effect of RSV infection was observed with P5-fimbriae-deficient mutant strains of H. influenzae.

The detailed mechanisms by which bacteria enter the middle ear during AOM are still poorly understood. Some light was shed on this issue by Miyamoto and Bakaletz [20] , who studied the kinetics of ascension of nontypeable H. influenzae from the nasopharynx to the middle ear in adenovirus-infected chinchillas. The bacteria entered the middle ear 7 to 10 days after intranasal inoculation. Interestingly, while the bacteria were in the eustachian tube, they preferentially adhered to the mucus instead of the epithelial cells in the eustachian tube.

The fact that pathogenic bacteria, mainly Streptococcus pneumoniae, H. influenzae, and Moraxella catarrhalis, can be isolated from the middle-ear fluid (MEF) in only about 70% of AOM cases [21] has prompted investigators to search for viruses directly in the MEF. During the 1950s and 1960s, when culture was the only available method for virus detection, viruses were rarely found in the MEF. Since the 1980s, improved viral culture techniques and the development of viral antigen detection methods has allowed demonstration of viruses in the MEF in approximately 20% of AOM cases (Table 1) [22] [23] [24] [25] [26] [27] [28] [29] [30] . A wide array of viruses has been identified in the MEF, including RSV, influenza and parainfluenza viruses, adenovirus, enterovirus, rhinovirus, cytomegalovirus, rotavirus, and herpes simplex virus.

During recent years, the use of PCR has dramatically increased the rates of virus detection in the MEF. Okamoto et al. [31] found RSV genomic sequences in 53% of 44 MEF samples from children with AOM. Pitkäranta et al. [10•] used PCR for rhinovirus, RSV, and coronavirus and recovered RNA from at least one of these viruses in the MEF of 48% of 92 children with AOM. In a study by Cone et al. [32] , DNA from human herpesvirus 6 was detected in 71% of MEFs from 49 children with AOM. These high rates of viral detection have inevitably raised the question of the real significance of these findings. Because of the very high sensitivity of the PCR technique, the question has arisen The specific viral cause of the URI could be determined in 41% of the cases. In children with AOM during a documented RSV infection, the same virus could be detected in the MEF in 74% of cases. The relative prevalence of RSV in the MEF was significantly higher than that of parainfluenza (52%) or influenza viruses (42%), which in turn were found significantly more often in the MEF than were enteroviruses (11%) or adenoviruses (4%). This study has two major implications. First, the results indicate that RSV has a particularly strong ability to invade the middle ear. Second, the different relative prevalences of the viruses in the MEF suggest that while some viruses may indeed enter the middle ear passively along with nasal secretions, others actively invade the middle ear and may contribute to the inflammatory process in the middle-ear mucosa. If all viruses found in the MEF were only "innocent bystanders" without any active role, they should be detected in the MEF at roughly equal rates during different viral infections. In this study, the relative importance of rhinoviruses could not be determined because the incidence of rhinovirus infections was too low for a meaningful analysis [33••] . However, a study by Pitkäranta et al. [10•] , who used PCR to detect viruses in the MEF, suggested that the prevalence of rhinoviruses in the MEF may be similar to that of RSV.

In about two thirds of cases in which virus has been detected in the MEF by culture or antigen detection methods, bacteria have also been isolated (Table 1) . Interestingly, S. pneumoniae was cultured significantly more often in MEFs containing influenza viruses than in those containing RSV or parainfluenza viruses [33••] . Overall, mixed viral-bacterial infections represent approximately 15% of all cases of AOM. Current estimates of either sole viral or mixed viral-bacterial AOM may not, however, represent the true occurrence of viruses in the middle ear because it is obvious that underdetection of viruses is still common. Further, it has also been suggested that the bacteriologic techniques routinely used are not sensitive enough for full detection of bacteria in the MEF [34] . Therefore, it is possible that with the increasing availability of the more sensitive techniques for detection of both viruses and bacteria, our current concept of the relative distribution of viral and/or bacterial causes of AOM will be transformed in the near future [8•,9,34,35] .

Despite proper antibiotic treatment of AOM in children, poor clinical response is a frequent phenomenon. This often results in a change in the antibiotic or even the use of several courses of different antibiotics for the same episode because physicians assume that the cause of the failure is bacterial resistance to the antibiotic used. It has been shown, however, that resistant bacteria account for only a small proportion (about 20%) of these cases [36] . During the past decade, much attention has been focused on the potential role of viruses in treatment failure. Although viruses are often found in the MEF, the importance of this finding has been questioned because viral replication in the human middle-ear epithelium during AOM has not been demonstrated. Nevertheless, the results of clinical studies from Texas and Finland strongly suggest that viruses play a significant role in the outcome of otitis media.

In a study of the effect of viruses on the outcome of AOM, MEF samples were obtained from 58 children before and 2 to 4 days after initiation of antibiotic treatment [28] . Although the bacteria in the MEF were susceptible to the antibiotic used, bacteriologic failure at the second tympanocentesis was observed in 33% of the children who had both bacteria and virus in the initial MEF compared with 3% of children with only bacteria in the MEF. The effect of viruses on the outcome of otitis media was further supported by a subsequent larger study of 271 children [29] . In this study, otitis media persisted in a significantly higher proportion of children with combined viral and bacterial infection than in those with bacteria alone in the MEF. Arola et al. [27] studied 22 children with AOM who had failed to improve after 2 days of antibiotic therapy. Bacteria were found in the MEF in only four of these children, and only one isolate was resistant to the antibiotic used. Viruses were detected in the MEF of 32% of these children compared with 15% of children in a comparison group with newly diagnosed, untreated AOM. Whether different viruses have a varying impact on the clinical outcome of otitis media is not known, but Sung et al. [37] suggested that rhinoviruses may be more commonly associated with bacteriologic failure than are other respiratory viruses.

The mechanisms by which the presence of viruses in the middle ear might interfere with the resolution of otitis media are still unclear. Some respiratory viruses, particularly influenza viruses, are known to have a suppressive effect on polymorphonuclear leukocyte function [38] , potentially resulting in delayed clearance of bacteria from the middle ear. Another hypothesis is that viral infection of the middle-ear epithelium causes local inflammation that interferes with the penetration of antibiotics into the middle ear, resulting in lower concentrations of antibiotics. Although some data are available to support this theory [39, 40] , additional studies are needed.

Perhaps the most plausible explanation for the adverse effect of viruses on the outcome of otitis media is provided by studies demonstrating that viruses increase the production of cytokines and inflammatory mediators in the middle ear. Numerous inflammatory mediators (eg, IL-1β, IL-2, IL-6, IL-8, TNF, histamine, leukotrienes, prostaglan-dins) have been detected in the MEF of patients with otitis media [41] [42] [43] . In a study of 248 children with AOM [44] , histamine concentrations in the MEF were higher in those with evidence of concurrent viral infection than in those without and bacteria and viruses appeared to have an additive effect on the histamine content in the MEF. Further, 3 to 5 days of antibiotic treatment did not decrease the histamine concentrations, and the pretreatment levels tended to be higher in children with persistent otitis media than in those who had a good response to treatment. In another study [30] , the concentrations of leukotriene B4 (LTB4) and IL-8 were measured in 271 MEF samples from 106 children. The highest concentrations of these mediators were found in MEFs containing both bacteria and virus. In five children who had bilateral AOM and similar bacterial findings in both ears, LTB4 and IL-8 levels were higher in the ear that contained virus than in the contralateral ear. High concentrations of LTB4 at the time of AOM diagnosis and initiation of antibiotic treatment were associated with an increased rate of treatment failure. Antibiotic treatment had no effect on the levels of these mediators. Similarly, in a study of two chemokines, macrophage inflammatory protein-1α and monocyte chemotactic protein-1 (which are considered histamine-releasing factors), higher concentrations of these substances were found in MEF samples containing both bacteria and virus than in samples with bacteria alone [45] .

Our increasing knowledge of the role of viruses and the detailed inflammatory mechanisms in the middle ear during AOM may have a substantial impact on the management of this disease in the future. Considering the rapidly increasing antimicrobial resistance of bacteria and the frequently observed poor clinical response to antibiotic treatment, it is clear that effective adjuvant therapies are needed to improve outcome. Various inflammatory mediators, whether induced by bacteria, viruses, or both, appear to play a prominent role in the enhancement or prolongation of the inflammatory process in the middle ear. Because these mediators cannot be controlled by antibiotics, it is understandable that the inflammatory process in the middle ear may persist long after the elimination of the bacteria.

Previous trials have failed to demonstrate any efficacy of antihistamines, decongestants, or prostaglandin inhibitors for the treatment of otitis media. Recently, Ruohola et al. [46• ] investigated the efficacy of oral steroid treatment as adjuvant therapy in AOM. In children with AOM draining through tympanostomy tubes, a 3-day course of prednisolone combined with standard antibiotic treatment significantly shortened the duration of otorrhea compared with antibiotic treatment alone. Whether short-term use of steroids early in the course of AOM would also improve the outcome of AOM in children with intact tympanic membranes remains to be determined.

In addition to suppression of the inflammatory process in the middle ear, the role of specific antiviral treatments may come into consideration in the future. The recently developed neuraminidase inhibitors zanamivir and oseltamivir are well tolerated, safe, and effective against influenza A and B infections in adults and older children, but no data are available on the use of these drugs in young children [47] . Another new antiviral agent with theoretic potential for use in otitis media is pleconaril, which is effective against enteroviruses and most clinically important serotypes of rhinoviruses (Hayden et al., Paper pres e n t e d a t t h e 3 9 t h I n t e r s c i e n c e C o n f e r e n c e o n Antimicrobial Agents and Chemotherapy, San Francisco, 1999). However, even though antivirals were shown to be effective adjuvant treatments of otitis media, their successful use in clinical situations would require the availability of easy, rapid, and accurate methods to determine the specific viral cause of the infection.

Because approximately one third of AOM cases have no proven bacterial cause, withholding antibiotic treatment in nonbacterial AOM might be safe and would reduce unnecessary use of antibiotics. Previous studies have shown that serum levels of C-reactive protein and IL-6 are significantly higher in bacterial than in nonbacterial AOM [48, 49] . Because of substantial overlap, however, neither of these markers is a reliable screening test for clinical purposes.

Rather than being a simple bacterial infection that is effectively treated with antibiotics, otitis media is a very complex disease. The etiopathogenesis of AOM involves viruses, bacteria, and a large network of other factors that affect each other in a time-dependent manner. Respiratory viruses play a crucial role in initiating the whole cascade of events that ultimately lead to the development of AOM. In the middle ear, viruses seem to interact with bacteria and enhance the local inflammatory process, which in turn may significantly impair the outcome of the disease. It is obvious that effective adjuvant treatments for otitis media are needed. The development of new innovative strategies for management of this disease will require further research into respiratory viruses, viral-bacterial interaction, and the host immune and inflammatory response during otitis media.

Antibiotic prescribing for Canadian preschool children: evidence of overprescribing for viral respiratory infections

Role of viruses in middle-ear disease

Time to development of acute otitis media during an upper respiratory tract infection in children

Epidemiology of otitis media onset by six months of age

Influenza vaccination in the prevention of acute otitis media in children

Influenza A vaccine decreases the incidence of otitis media in 6-to 30-monthold children in day care

The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children

This extensive, well-conducted study confirms that a substantial number of acute otitis media cases can be prevented by viral vaccination

Rapid simultaneous diagnosis of infections with respiratory syncytial viruses A and B, influenza viruses A and B, and human parainfluenza virus types 1, 2, and 3 by multiplex quantitative reverse transcription-polymerase chain reaction-enzyme hybridization assay (Hexaplex)

This study demonstrates the development of a sensitive and specific method for detecting several respiratory viruses in a single test

Molecular diagnosis of human rhinovirus infections: comparison with virus isolation

Detection of rhinovirus, respiratory syncytial virus, and coronavirus infections in acute otitis media by reverse transcriptase polymerase chain reaction

This study shows the great potential of the PCR technique in clinical otitis media research

Nasal cytokine production in viral acute upper respiratory infection of childhood

Development of interleukin 6 and tumor necrosis factor alpha activity in nasopharyngeal secretions of infants and children during infection with respiratory syncytial virus

Physiologic responses to intranasal dose-response challenges with histamine, methacholine, bradykinin, and prostaglandin in adult volunteers with and without nasal allergy

Nasal cytokine and chemokine responses in experimental influenza A virus infection: results of a placebo-controlled trial of intravenous zanamivir treatment

Autocrine regulation of interleukin-8 by interleukin-1␣ ␣ ␣ ␣ in respiratory syncytial virus-infected pulmonary epithelial cells in vitro

This is a nice example of the complex network of factors in the host inflammatory response during viral infection

Autocrine regulation and experimental modulation of interleukin-6 expression by human pulmonary epithelial cells infected with respiratory syncytial virus

Effect of experimental influenza A virus infection on isolation of Streptococcus pneumoniae and other aerobic bacteria from the oropharynges of allergic and nonallergic adult subjects

Adenovirus infection enhances in vitro adherence of Streptococcus pneumoniae

Fimbria-mediated enhanced attachment of nontypeable Haemophilus influenzae to respiratory syncytial virus-infected respiratory epithelial cells

Kinetics of the ascension of NTHi from the nasopharynx to the middle ear coincident with adenovirus-induced compromise in the chinchilla

Bacteriology of otitis media

The role of respiratory syncytial virus and other viral pathogens in acute otitis media

Demonstration of viral antigens in middle ear secretions of children with acute otitis media

Identification of respiratory virus antigens in middle ear fluids of children with acute otitis media

Presence of respiratory viruses in middle ear fluids and nasal wash specimens from children with acute otitis media

Rhinovirus in acute otitis media

Respiratory virus infection as a cause of prolonged symptoms in acute otitis media

Respiratory viruses interfere with bacteriologic response to antibiotic in children with acute otitis media

Effect of viral respiratory tract infection on outcome of acute otitis media

Role of leukotriene B4 and interleukin-8 in acute bacterial and viral otitis media

Presence of respiratory syncytial virus genomic sequences in middle ear fluid and its relationship to expression of cytokines and cell adhesion molecules

Human herpesvirus 6 variant B in acute otitis media

Prevalence of various respiratory viruses in the middle ear during acute otitis media

This is the largest series to date demonstrating the active role of viruses and the differences between respiratory viruses in the pathogenesis of AOM

Comparison of PCR assay with bacterial culture for detecting Streptococcus pneumoniae in middle ear fluid of children with acute otitis media

Blinded multiplex PCR analyses of middle ear and nasopharyngeal fluids from chinchilla models of single-and mixed-pathogen-induced otitis media

Persistent acute otitis media: I. Causative pathogens

Association of rhinovirus infection with poor bacteriologic outcome of bacterial-viral otitis media

Virus-induced neutrophil dysfunction: role in the pathogenesis of bacterial infections

Effect of Streptococcus pneumoniae and influenza A virus on middle ear antimicrobial pharmacokinetics in experimental otitis media

Amoxicillin middle ear fluid penetration and pharmacokinetics in children with acute otitis media

Arachidonic acid metabolites in middle ear effusions of children

Cytokines, immunoglobulins, and bacterial pathogens in middle ear effusions

Cytokine analysis of middle ear effusions during acute otitis media: significant reduction in tumor necrosis factor alpha concentrations correlates with bacterial eradication

Virus and bacteria enhance histamine production in middle ear fluids of children with acute otitis media

Influence of viral infection on middle ear chemokine response in acute otitis media

Oral prednisolone is an effective adjuvant therapy for acute otitis media with discharge through tympanostomy tubes

This is the first clinical study to indicate that suppression of the inflammatory reaction in the middle ear during AOM reduces the duration of middle-ear effusion

New approaches to influenza chemotherapy: neuraminidase inhibitors

Use of C-reactive protein in differentiation between acute bacterial and viral otitis media

Serum interleukin-6 in bacterial and nonbacterial acute otitis media

This work was partly supported by the Academy of Finland; the Jenny and Antti Wihuri Foundation; and the National Institutes of Health (R01 DC 02620).