Nonetheless, certain observations were consistent in both PCV7-CRM–vaccinated and unvaccinated children, and were significant in pooled analysis. Neither pathogen was more or less likely to be associated with the youngest age group (Table 2, Fig., Supplemental Digital Content 1, http://links.lww.com/INF/C612) than with older ages. Hflu was less likely to be identified in the first episode (RR: 0.71; 0.60–0.84) than in subsequent episodes and more likely to be associated with recurrent rather than sporadic disease (RR: 1.40; 1.00–1.96). In contrast, Spn was less likely to be associated with recurrent disease (RR: 0.76; 0.61–0.97).
Clinical Severity by Etiology
Encapsulated Hflu isolates were more frequently associated with high severity of tympanic membrane bulging and inflammation (73% were OS-6/7), compared with Spn or NTHi or Mcat (30%–35% OS-6/7), whereas Spyo cases were only infrequently severe (8%–9%, Table, Supplemental Digital Content 2, http://links.lww.com/INF/C613). Conjunctivitis was more commonly identified in NTHi cases, but otherwise reported symptoms were similar between Spn and NTHi cases. Ear tugging and trouble sleeping were less frequently observed in cases caused by encapsulated Hflu than NTHi.
Both major otopathogens were thus associated with a range of disease severity (Table 2, Fig., Supplemental Digital Content 1, http://links.lww.com/INF/C612): Hflu was more likely to be identified in cases with an OS-6 or 7 than in less severe cases (RR: 1.35; 1.06–1.71), and Spn was more likely to be identified in children with reported ear pain or a temperature ≥38.5°C (RR: 1.42; 1.01–2.01). Spyo was more likely (RR: 8.61; 4.74–15.63) and Mcat less likely (RR: 0.17; 0.04–0.69) to be found in MEF samples collected from otorrhea than by tympanocentesis.
Observations According to Vaccination Status
Some observations were statistically significant only in vaccinated or only in unvaccinated children, with little indication of a similar trend in the other group. For example, in PCV7-CRM–vaccinated children, Spn was more likely to be found in otorrhea rather than in tympanocentesis samples (RR: 1.66; 1.23–2.25) and in cases with severe tympanic membrane inflammation (RR: 3.58; 1.34–9.61). It was also more likely to be isolated from a treatment failure (RR: 1.63; 1.32–2.01) in vaccinated but not in unvaccinated children, and less likely to be identified in a first-reported episode in the youngest children (RR: 0.58; 0.37–0.91) (Table 2, Fig., Supplemental Digital Content 1, http://links.lww.com/INF/C612).
In vaccinated children, Hflu was less likely to be isolated by otorrhea than by tympanocentesis (RR: 0.63; 0.47–0.85). In unvaccinated children, Hflu was less likely to be found in a child with severe symptoms such as ear pain or high fever (RR: 0.63; 0.43–0.91) than the one with milder symptoms (Table 2, Fig., Supplemental Digital Content 1, http://links.lww.com/INF/C612). However, in none of the above examples was a similar association apparent in the other group.
In unvaccinated children, the proportions of Spn and Hflu cases presenting with severe symptoms were 37.5% (30.6%–46.0%) and 17.0% (10.1%–28.6%), respectively, but in vaccinated children 28.3% (20.1%–39.9%) of the Spn cases and 33.8% (22.4%–50.9%) of the Hflu cases were severe.
Not surprisingly, serotype distribution also differed according to vaccination status (Fig. 1, right). PCV7-CRM types (including 6A) were less likely to be identified in PCV7-CRM–vaccinated children compared with unvaccinated [RR: 0.38 (0.24–0.61)]. Serotype 19A appeared to be more frequently identified in children who were PCV7-CRM vaccinated, although this did not achieve statistical significance (RR: 2.27; 0.93–5.56). In contrast, there was no obvious association of vaccination status with the proportion of serotype 3 (RR: 1.15; 0.58–2.27), that of the group of 1, 5 and 7F (RR: 0.70; 0.19–2.63), or the proportion of other non-PCV7-CRM types (RR: 1.08; 0.50–2.33).
Nonsusceptibility (Table 3) to first-line therapies such as aminopenicillin was 18.5% (10.3%–33.2%) among Spn isolates and 20.0% (11.8%–33.7%) for Hflu isolates. Nonsusceptibility to alternate first-line therapies differed: Spn isolates were rarely nonsusceptible to cefotaxime (9.8%; 4.6%–20.7%) but were frequently nonsusceptible to azithromycin (69.9%; 45.2%–100.0%). Small proportions of Hflu isolates were nonsusceptible to cefotaxime (0.9%; 0.3%–2.9%) and azithromycin (6.2%; 2.7%–14.2%). Spn and Hflu were also frequently nonsusceptible to second-line agents such as tetracycline and co-trimoxazole but were largely susceptible to amoxicillin/clavulanate. The percentage of Hflu isolates that were beta-lactamase negative was 74.6% (57.9%–96.0%), and 3.7% (1.7%–8.0%) were both beta-lactamase negative and ampicillin resistant. There were generally no significant differences in nonsusceptibility according to vaccination status, except for tetracycline nonsusceptible Hflu isolates, which were less likely to be found in vaccinated children [RR: 0.31 (0.11–0.92)], and trimethoprim/sulfamethoxazole nonsusceptible isolates, which were more likely to be observed in vaccinated children [RR: 1.37 (1.08–1.75)].
This analysis focused on 10 recent studies that had been implemented with similar study designs and characteristics so that a pooled analysis could assess the relative importance of different pathogens worldwide. It, thus, complements and extends previous reviews of pneumococcal serotype data from contemporaneous pediatric AOM studies,14,34 as well as other reviews of bacterial AOM etiology.13 The finding that Spn and Hflu were the 2 major pathogens in the pooled analysis is consistent with results from each of the included studies and provides a more definitive confirmation of what has been reported in most other published single-country studies.35,36 The increased proportion of Hflu and moderately decreased proportion of Spn among cases who were PCV7-CRM vaccinated were also consistent with previous reports.37,38 Comparable results were observed within an eleventh individual study sharing the same design and conducted in Costa Rica; the results of that study were unfortunately not available at the time the pooling analysis was performed.39
Because individual patient information was included in this pooled analysis, it was possible to explore more completely than usually possible in single studies the role that other covariates play in etiology. For example, Hflu is sometimes thought to cause only mild AOM but in this study, approximately 25% of Hflu AOM cases presented with more severe symptoms and almost one-third presented with severe inflammation of tympanic membranes. In addition, there appeared to be differences associated with vaccination status. While in unvaccinated children the percentage of Hflu AOM cases presenting with severe symptoms (17%; 10.1%–28.6%) appeared lower than that of Spn cases (37.5%; 30.6%–46.0%), in vaccinated children the percentages were more similar [33.8% (22.4%–50.9%) and 28.3% (20.1%–39.9%), respectively], a finding for which we have no straightforward explanation. As previously reported, conjunctivitis was also particularly associated with NTHi AOM.13
A noteworthy observation is that although Hflu was less likely to be reported as the cause of a first AOM episode than of later episodes and more likely to be identified as recurrent, it nonetheless still comprised 20.2% (9.7%–41.8%) of first-reported AOM episodes in unvaccinated children of <12 months of age, a proportion not much different from that seen for Spn (30.5%; 29.3%–31.7%). This finding, in addition to >20% of isolates being nonsusceptible to first-line therapy with aminopenicillin, suggests that Hflu is an important target for primary prevention of AOM. Similar observations regarding NTHi were made in a study assessing AOM cases in children with single otopathogen in their nasopharyngeal carriage.40 Conversely, the observation that Spn (along with Hflu) remains a prominent AOM pathogen even in children 3 or 4 years of age implies that duration of protection would be an important attribute of any PCV in the prevention of childhood AOM.
The shift in pneumococcal serotype distribution toward nonvaccine types in AOM cases who were PCV7-CRM vaccinated was expected and similar to results seen in US studies.37,38 It is tempting to speculate that the predominantly non-PCV7-CRM types causing pneumococcal AOM in PCV7-CRM–vaccinated children, especially 19A and 3, are responsible for some of the other findings observed here—specifically, that only in PCV-CRM-vaccinated children was Spn more often found in otorrhea than in tympanocentesis samples, more often associated with severe tympanic membrane inflammation than mild, and more often from treatment failures than other cases.
The observation that Spyo is more likely and Mcat is less likely to be associated with spontaneous otorrhea rather than tympanocentesis is consistent with reports from other investigators.41–43 Spyo appeared less likely to be isolated in PCV7-CRM–vaccinated than in unvaccinated children, but unless prior infection with the serotypes contained in PCV7-CRM selectively predisposes the child to a subsequent Spyo infection, this appears a chance finding.
This pooled analysis is subject to limitations. First, there was statistically significant heterogeneity among the studies included, despite the use of similar protocols. For example, heterogeneity of PCV7-CRM use across the included studies limits broad interpretation of potential serotype and pathogen replacement. In an attempt to control for this, subgroup analyses were performed, the results were weighted, a random effect model was used and vaccination status was accounted for whenever possible when formulating the presented conclusions. Nonetheless, some countries had experienced a broad uptake of PCV7-CRM before the conduct of the study, and thus the contribution of herd effects was impossible to factor in. Evaluation after vaccination for a longer duration would be important.
As noted earlier, the pooling methodology relies solely on intrastudy comparisons, meaning that some pooled RR or proportion estimations did not include data from individual studies where such a comparison was not possible. It could, therefore, be argued that this introduces additional bias. However, the strength of the pooling methodology lies precisely in its focus on the consistency (or not) of the comparisons of the values obtained within each study. This should minimize variability that could otherwise arise from inclusion of values from only 1 group lacking a comparison set of value.
Second, despite efforts to standardize the design across studies, there were important differences in local guidelines for MEF collection. This is a recognized limitation of such prospectively planned pooled studies.26 One country required MEF to be collected only in cases that were considered to be recurrent. There are likely differences in care-seeking practices for AOM in other countries that could have affected the severity of cases enrolled. Nonetheless, a significant finding of this study is that despite these differences, no evidence suggested major setting-related differences in etiology.
Third, bacterial etiology was not determined with molecular techniques and the true contribution of these bacteria to AOM is likely higher than reported here (as previously described).19 It is also possible that culture-negative but polymerase chain reaction–positive samples may show different clinical severity or age tropisms compared with those described here.
Finally, although this analysis included 10 countries, most countries and regions are naturally not represented, including North America, most of Asia and sub-Saharan Africa, as well as native high-risk populations. Consequently, the generalizability of some of our findings may be limited to the health-care–seeking pediatric population in the countries included. However, as already noted, the identity of the most prominent etiologic pathogens as determined in the pooled analysis was largely consistent between the studies included, as well with other published reports, so those results may be considered to be more broadly applicable.
Despite differences in PCV7-CRM use and clinical management of AOM, this pooled analysis indicates that Spn and Hflu remain the leading causes of AOM in the different regions investigated. Both pathogens cause disease in the youngest and the oldest children, and it is known that early AOM cases are associated with more AOM cases/recurrence. Infants, thus, remain important targets for vaccination for either pathogen. Both pathogens are responsible for both mild and more severe AOM, as assessed by different measures and so are clinically significant. Finally, both pathogens are associated with antibiotic resistance. Although most serotypes in PCV7-CRM-vaccinated children now could be covered by 1 or both expanded serotype PCVs, one can note that already >20% of isolates were not covered by any currently licensed PCV, and this proportion will certainly increase as higher valency vaccines are fully implemented. The availability of next-generation PCVs should address some residual disease burden, but replacement and antibiotic resistance make elimination an elusive target. Continued evaluation of otopathogens is needed to support up-to-date treatment guidelines and inform decision making for new prevention strategies.
The authors wish to thank Cyrille Cartier (4 Clinics for GSK Vaccines) for his involvement in performing the statistical analyses and Thomas Déplanque (XPE Pharma & Science for GSK Vaccines) for his excellent suggestions and manuscript coordination.
R.C., S.A.M., A.R., M.M.P., K.A-M., G.G., P.L., L.N., F.P. and N.S. were primary investigators of the studies included in the pooled analysis reported in this article and contributed to the acquisition of data. M.K.V.D., J-Y.P., R.C., S.A.M. and W.P.H. participated in the conception/design/planning of the study. M.K.V.D., J-Y.P. and W.P.H. were involved in the assembling of the data and performed or supervised the analyses. M.K.V.D., J-Y.P., R.C., S.A.M., A.R., M.M.P., K.A-M. and W.P.H. contributed to interpretation of the results. All co-authors participated in drafting or revision of the submitted article. All authors approved the manuscript for the content and the submission and agreed to take responsibility for their contributions as presented in the manuscript.
W.P.H. was an employee of the GSK group of companies at the time of initial development of this article and own stocks/stock options of GSK group of companies. M.K.V.D. and J-Y.P. are currently employees of the GSK group of companies. R.C. declares having received money for consultancy and payment for lectures and his institution having received grants from GSK, Pfizer, Novartis, SP-MSD and AstraZeneca. S.A.M. declares his institution having received money for the conduct of the study in South Africa included in this pooled analysis. He reports personal fees for development of educational presentations from Medscape (about PCV, rotavirus and pertussis topics) consultancy in advisory board from GSK and Pfizer, payment for lectures from Sanofi Pasteur (in relation with Hexaxim), GSK (pneumococcal and rotavirus vaccines) and Pfizer (PCV), and his institution received grants from Novartis (GBS) and GSK (PCV). A.R. reports him and his institution having received grants for the conduct of the study in Chile included in this pooled analysis. M.M.P. reports grants to her institution for participation in protocols of trials from the following companies: Novartis, Sanofi Pasteur, Bayer, MSD (phase III), GSK (phase III and Pharmacoeconomics) and Pfizer (phase IIb and phase III). She declares having received consulting fees for lectures from Sanofi Pasteur, support for travel to meeting (Congresses) from GSK, Sanofi Pasteur, Pfizer and MSD, and fees for participation to advisory boards from GSK and Novartis. K.A-M. declares his institution having received grants for the conduct of the study in Saudi Arabia included in this pooled analysis, and he received support for travel to meeting from the GSK group of companies. P.L. declares his institution having received a grant from GSK for the conduct of the study in Colombia included in this pooled analysis. L.N. declares her institution having received money for the conduct of the study in Venezuela included in this pooled analysis. She is currently an employee of the GSK group of companies. N.S. declares having received grant, consultancy fees, payment for lectures and support for travel to meetings during conduct of the study in Thailand included in this pooled analysis. W.P.H. is a co-holder of a patent for 13-valent PCV licensed to Pfizer/Wyeth, but receives no royalties as per industry practice. He is currently an independent consultant. R.C. (France), S.A.M. (South Africa), A.R. (Chile), M.M.P. (Mexico), K.A-M. (Saudi Arabia), G.G. (Germany), P.L. (Colombia), L.N. (Venezuela), F.P. (Spain) and N.S. (Thailand) were investigators of the studies included in this pooled analysis. G.G. and F.P. have no conflicts of interest to disclose.
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