Background Vaccines against respiratory viruses may be ableto reduce the frequency of acute otitis media. Although therole of respiratory viruses in the pathogenesis of acute otitismedia is well established, the relative importance of variousviruses is unknown.
Methods We determined the prevalence of various respiratoryviruses in the middle-ear fluid in 456 children (age, two monthsto seven years) with acute otitis media. At enrollment and aftertwo to five days of antibiotic therapy, specimens of middle-earfluid and nasal-wash specimens were obtained for viral and bacterialcultures and the detection of viral antigens. The viral causeof the infections was also assessed by serologic studies ofserum samples obtained during the acute illness and convalescence.
Results A specific viral cause of the respiratory tract infectionswas identified in 186 of the 456 children (41 percent). Respiratorysyncytial virus was the most common virus identified in middle-earfluid: it was detected in the middle-ear fluid of 48 of the65 children (74 percent) infected by this virus (P0.04 for thecomparison with any other virus). Parainfluenza viruses (15of 29 children [52 percent]) and influenzaviruses (10 of 24children [42 percent]) were detected in the middle-ear fluidsignificantly more often than enteroviruses (3 of 27 children[11 percent]) or adenoviruses (1 of 23 children [4 percent])(P0.01 for all comparisons).
Conclusions Respiratory syncytial virus is the principal virusinvading the middle ear during acute otitis media. An effectivevaccine against upper respiratory tract infections caused byrespiratory syncytial virus may reduce the incidence of acuteotitis media in children.
Acute otitis media is the most common bacterial infection amongchildren and the most frequent reason for outpatient antibiotictherapy.1 Despite proper antibiotic treatment, middle-ear effusionmay persist for weeks or months,2,3 often resulting in repeatedcourses of antibiotics and, eventually, surgical intervention.4In the United States, the annual costs of otitis media havebeen estimated to exceed $3.5 billion.5 Although acute otitismedia is generally considered a bacterial infection, there isample evidence that respiratory viruses have a crucial rolein the etiology and pathogenesis of this disease.6,7 Moreover,viruses may also profoundly affect the outcome of acute otitismedia.7,8,9,10 A better understanding of the effect of virusesand the mechanisms of interactions between viruses and bacteriain otitis media is essential if major improvements are to bemade in the management and prevention of this disease.
Several studies have documented the presence of viruses in themiddle-ear fluid of children with acute otitis media,8,9,10,11,12,13,14,15,16but it is not known whether there are differences in the abilityof various respiratory viruses to invade the middle ear. Knowledgeof the relative frequencies of viral involvement in the middleear would be important for the development of effective strategiesto prevent otitis media. Vaccination against influenzavirusdecreases the incidence of acute otitis media in infants andchildren,17,18,19 and vaccines against other respiratory viruses,particularly respiratory syncytial virus, are being developed.20,21,22,23Vaccines against the viruses that are found most frequentlyin the middle ear will probably have the greatest potentialfor reducing the incidence of acute otitis media. We soughtto determine the rates of middle-ear invasion by common respiratoryviruses in children with acute otitis media and a concurrent,documented viral infection of the upper respiratory tract.
Methods
Study Subjects
We studied 456 children (age, two months to seven years) withacute otitis media who were enrolled in various antibiotic trialsbetween 1989 and 1993.10,16 All the children were otherwisegenerally healthy and were seen at our primary care clinics.None of the children had received antibiotics during the weekpreceding the study. The diagnosis of acute otitis media wasbased on symptoms of fever, irritability, or earache; signsof inflammation of the tympanic membrane (red or yellow coloror bulging of the membrane); and the presence of fluid in themiddle ear on tympanocentesis. Informed consent was obtainedfrom the parents or guardians of all the children, and all proceduresconformed to the guidelines established by the Department ofHealth and Human Services and the institutional review boardof the University of Texas Medical Branch.
Specimens
At enrollment (visit 1), middle-ear fluid was obtained for bacterialand viral studies by needle tympanocentesis. After tympanocentesis,a nasal-wash specimen was collected for viral studies by flushingthe nostril with 3 to 5 ml of phosphate-buffered saline solutionin a 30-ml tapered rubber bulb.24 Venous blood was also obtainedfor serologic studies during the acute illness.
Follow-up visits were scheduled two to five days after the initiationof therapy (visit 2), at the end of therapy (visit 3; days 9to 12), and approximately one month after the initiation oftherapy (visit 4). During the second visit, a second tympanocentesiswas routinely performed and a second nasal-wash specimen wascollected for viral studies. Venous blood was obtained duringthe third visit to assess antibody responses to viruses duringconvalescence.
Processing of Specimens and Virologic Procedures
Immediately after collection, portions of the specimens of middle-earfluid were inoculated onto blood-agar, chocolate-agar, and MacConkey-agarplates and into meat broth to test for aerobic bacteria. Theremaining middle-ear fluid was diluted with 1.0 to 1.2 ml ofphosphate-buffered saline solution and inoculated into cellcultures within two to three hours after collection. For viralculture of middle-ear fluid and nasal-wash specimens, each specimenwas inoculated in two tubes each of primary monkey-kidney cellsand human fibroblasts (MRC-5 cells). In addition, Hep-2 cellsand Buffalo green-monkey–kidney cells were used duringrespiratory syncytial virus and enterovirus seasons, respectively.For each cell line, one tube was incubated at 33°C and theother at 36°C, and they were observed daily for 10 daysfor cytopathic effects. Hemadsorption was performed three times,and the final identification of viruses was made according tostandard methods.
Rapid viral antigen testing was performed on specimens of middle-earfluid and nasal-wash specimens. For middle-ear fluid, the presenceof respiratory syncytial virus antigens was assessed by enzymeimmunoassay (Respiratory Syncytial Virus Enzyme ImmunoassayDiagnostic Kit, Abbott Laboratories, North Chicago, Ill., orOrtho Respiratory Syncytial Virus Antigen Enzyme-Linked ImmunoassayTest, Ortho Diagnostic Systems, Raritan, N.J.). For nasal-washspecimens, the cell pellet from the centrifuged specimen wassmeared onto microscope slides and subjected to an indirectfluorescence antibody assay with commercially available antiserumfor respiratory syncytial virus, influenza A and B viruses,adenoviruses, and parainfluenza virus types 1, 2, and 3 (BartelsViral Respiratory Panel, Baxter Healthcare, West Sacramento,Calif.). Serologic tests for the same respiratory viruses werealso performed by the same indirect fluorescence antibody technique.Serum samples obtained from a patient during the acute illnessand convalescence were tested at the same time.
Definitions
The presence of a viral infection of the respiratory tract wasconsidered to be confirmed if the results of viral culture orantigen-detection tests of either nasal-wash or middle-ear specimensobtained during the first or second visit were positive. Anincrease in viral titers by a factor of at least 4 from thetime of acute illness to convalescence was also considered proofof a viral infection.
When we calculated the prevalence of the various viruses inthe specimens of middle-ear fluid, we regarded the dual viralinfections in nine children as separate infections. In 25 childrenwith evidence of a viral infection on analysis of the middle-earfluid, the specimens from the left and right ears had been combinedbefore viral culture or antigen detection, and they were thereforeexcluded from the analysis of specific combinations of virusesand bacteria in the middle ear.
Statistical Analysis
Comparison of proportions between the groups was done by thestandard chi-square test and Fisher's exact test. The Mann–WhitneyU test and Kruskal–Wallis one-way analysis of varianceaccording to rank were used to compare nonparametric continuousdata between the groups. A P value of less than 0.05 was consideredto indicate statistical significance.
Results
Of the 456 children analyzed, the specific viral cause of therespiratory tract infections was determined in 186 (41 percent);these children had a total of 208 viral infections (18 childreneach were infected by two viruses, and 2 children each by threeviruses). Of these 208 infections, 168 (81 percent) were causedby respiratory syncytial virus, parainfluenza virus type 1,2, or 3, influenza A or B virus, enteroviruses, or adenoviruses(Table 1). There were no significant differences in sex, raceor ethnic group, duration of respiratory symptoms, or age amongthe groups with specific viral illnesses or between these childrenand the group of children as a whole, except that children withinfluenzavirus infection were significantly older than the otherchildren.
Table 1. Characteristics of the Group of Children as a Whole and According to the Specific Viral Infections.
Respiratory syncytial virus was the most common virus identifiedin middle-ear fluid: the virus was detected in the middle-earfluid of 74 percent of the children infected by this virus (P=0.04for the comparison with parainfluenza viruses and P0.005 forthe comparison with any of the other viral groups) (Table 2).Also, parainfluenza viruses (52 percent) or influenzaviruses(42 percent) were found in the middle-ear fluid significantlymore often than enteroviruses (11 percent) or adenoviruses (4percent) (P0.01 for all comparisons). The relative differencesin the prevalences remained regardless of whether the rateswere calculated per patient or per infected ear. There wereno statistically significant differences in age, sex, race orethnic group, or duration of respiratory symptoms between thechildren with viruses in middle-ear fluid and those withoutviruses.
Table 2. Prevalence of Various Respiratory Viruses in the Middle Ear in Children with Acute Otitis Media.
The 456 children had a total of 815 ears with acute otitis media.Streptococcus pneumoniae was isolated from the middle-ear fluidof 203 of these ears (25 percent), Haemophilus influenzae from190 ears (23 percent), and Moraxella catarrhalis from 122 ears(15 percent); 82 ears (10 percent) had either two or all threeof these bacterial pathogens at the same time. Sixty-six earsfrom which viruses were detected in the middle-ear fluid couldbe analyzed for the presence of bacteria; both virus and bacteriawere found in 43 of these ears (65 percent). In these combinedviral and bacterial infections, S. pneumoniae was cultured significantlymore often in middle-ear fluid containing influenzaviruses (100percent) than in those containing respiratory syncytial virus(36 percent) or parainfluenza viruses (10 percent) (Table 3).No statistically significant differences were observed in therates of detection of H. influenzae or M. catarrhalis in combinationwith any of these three viruses. Virus as the sole middle-earpathogen (without bacteria) was found in 14 of 36 ears withrespiratory syncytial virus (39 percent), 6 of 16 ears withparainfluenza viruses (38 percent), and 2 of 10 ears with influenzaviruses(20 percent) (no significant differences among the groups).
Table 3. Specific Microorganisms in the 43 Samples of Middle-Ear Fluid That Contained Both Bacteria and Viruses.
Discussion
We used tympanocentesis together with comprehensive viral andbacterial diagnostic methods in 456 children with acute otitismedia to determine and compare the relative frequencies of respiratoryviruses in the middle-ear fluid. Our results suggest that therates of middle-ear invasion by the common respiratory virusesvary significantly during acute otitis media and that respiratorysyncytial virus has a particularly strong ability to invadethe middle ear. Our results also provide additional evidenceof the active role of viruses in the pathogenesis of acute otitismedia. The different prevalences of the viruses suggest thatsome viruses enter the middle ear passively along with nasalsecretions, whereas other viruses actively invade the middleear and contribute to the inflammatory process in the middle-earmucosa. If the viruses found in the middle-ear fluid were onlyinnocent bystanders with no active role, they should be detectedin the middle-ear fluid at roughly equal rates during differentviral infections.
Previous studies have demonstrated a wide array of viruses inthe middle-ear fluids of infants and children with acute otitismedia.8,9,10,11,12,13,14,15,16,25,26 However, none of thesestudies have been able to determine the relative importanceof the various viruses to otitis media. Obviously, the likelihoodof detecting particular viruses in the middle-ear fluid duringacute otitis media is dependent on the overall prevalence ofthose infections in the study population; therefore, the ratesof viral detection in middle-ear fluid in different studiesare not directly comparable. Furthermore, differences in themethods of viral detection used in earlier studies limit thecomparability of the frequencies. The strength of the presentstudy is that we consistently used similar methods of viraldetection in a large number of children over several respiratoryvirus seasons. It could be argued, however, that we might haveoverestimated the differences in the rates of detection in middle-earfluid between respiratory syncytial virus and the other virusesbecause we used antigen detection only to identify respiratorysyncytial virus and not the other viruses in middle-ear fluid.The use of antigen detection for respiratory syncytial viruswas essential, because unlike other respiratory viruses, thisvirus is relatively labile, and thus, the sensitivity of cell-culturetechnique for this virus is considerably lower than those ofvarious rapid antigen techniques.27 Although in theory the useof viral-antigen detection in nasopharyngeal specimens but notin middle-ear specimens could have resulted in falsely low ratesof detection of influenzaviruses, parainfluenza viruses, andadenoviruses in the middle ear, this possibility did not affectour results or conclusions, because only one influenzavirusinfection and two adenovirus infections were diagnosed solelyon the basis of antigen detection in the nasopharyngeal specimens.
Our results are in accordance with those of previous epidemiologicstudies of the association of viral infections with acute otitismedia. Several reports have indicated that respiratory syncytialvirus may be the type of virus that is most likely to predisposea child to acute otitis media.28,29,30,31 The relative abilityof different respiratory viruses to predispose a person to acuteotitis media is, however, difficult to determine, because thedevelopment of acute otitis media depends on multiple factors.In particular, the age of the child is an important confoundingfactor that has not been adjusted for in many studies. Nonetheless,our results clearly corroborate the view that respiratory syncytialvirus is an important cause of acute otitis media in children.We could not determine the relative importance of rhinovirusesin acute otitis media, because the incidence of rhinovirus infectionswas too low for any meaningful analysis. Rhinoviruses accountfor approximately one third of all infections of the upper respiratorytract,32 and previous studies have demonstrated that rhinovirusescan also be found in middle-ear fluid in children with acuteotitis media.14,15 A recent study, which used a reverse-transcriptase–polymerase-chain-reactionassay to detect respiratory viruses, suggested that the prevalenceof rhinoviruses in middle-ear fluid during acute otitis mediamay be similar to that of respiratory syncytial virus.33 Ingeneral, the development of nucleic acid–based assaysfor a wide range of respiratory viruses may provide researcherswith more sensitive methods for studying the role of respiratoryviruses in acute otitis media.
The presence of viruses in the middle-ear fluid is importantnot only in regard to the etiology and pathogenesis of acuteotitis media, but also in regard to the outcome of the disease.7Clinical studies have indicated that the presence of virusesin the middle ear may considerably worsen both the clinicaland bacteriologic outcomes of otitis media.8,9,10 The mechanismsby which viruses enhance or prolong the inflammation in themiddle ear are still unclear, but studies have shown that thereare higher concentrations of some inflammatory mediators inmiddle-ear fluid containing both bacteria and virus than inmiddle-ear fluid containing bacteria alone.16,34,35
The enormous impact of otitis media on society has made preventionof this disease a high priority of research, and bacterial andviral vaccines are considered to hold the greatest promise forthe ultimate prevention of acute otitis media.36,37 Previousstudies have clearly demonstrated that both inactivated andlive, attenuated influenzavirus vaccines reduce the incidenceof acute otitis media in infants and children.17,18,19 Our resultssuggest that an effective vaccine against respiratory syncytialvirus might have a major effect on the incidence of acute otitismedia, together with the more serious manifestations of respiratorysyncytial virus infection. It is apparent, however, that toprevent acute otitis media, such a vaccine should protect notonly the lower respiratory tract but also the upper respiratorytract.
Supported by grants from the National Institutes of Health (R01DC 02620), the Academy of Finland, and the Maud Kuistila MemorialFoundation. Dr. Heikkinen is the recipient of a European Societyfor Paediatric Infectious Diseases Fellowship Award sponsoredby Bristol-Myers Squibb.
We are indebted to Drs. Virgil M. Howie and Mary J. Owen fortheir contributions to the clinical part of the study.
Source Information
From the Department of Pediatrics, University of Texas Medical Branch, Galveston, TX 77555-0371, where reprint requests should be addressed to Dr. Chonmaitree (e-mail address: tchonmai{at}utmb.edu).
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Respiratory Viruses and Acute Otitis Media
Pitkäranta A., Hayden F. G., Damoiseaux R. A.M.J., van Balen F. A.M., Verheij T. J.M., Heikkinen T., Chonmaitree T., Thint M.
Extract |
Full Text
N Engl J Med 1999;
340:2001-2002, Jun 24, 1999.
Correspondence
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0.04 for the comparison with any other virus). Parainfluenza viruses (15 of 29 children [52 percent]) and influenzaviruses (10 of 24 children [42 percent]) were detected in the middle-ear fluid significantly more often than enteroviruses (3 of 27 children [11 percent]) or adenoviruses (1 of 23 children [4 percent]) (P
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