Pneumococcal Phenotype and Interaction with Nontypeable Haemophilus influenzae as Determinants of Otitis Media Progression

Abstract

All-cause otitis media (OM) incidence has declined in numerous settings following introduction of pneumococcal conjugate vaccines (PCVs) despite increases in carriage of nonvaccine pneumococcal serotypes escaping immune pressure. To understand the basis for the declining incidence, we assessed the intrinsic capacity of pneumococcal serotypes to cause OM independently and in polymicrobial infections involving nontypeable (NTHi) using samples obtained from middle ear fluid and nasopharyngeal cultures before PCV7/13 rollout. Data included samples from OM episodes (11,811) submitted for cultures during a 10-year prospective study in southern Israel and nasopharyngeal samples (1,588) from unvaccinated asymptomatic children in the same population. We compared data representing pneumococcal serotype diversity across carriage and disease isolates with and without NTHi coisolation. We also measured associations between the pneumococcal phenotype and the rate of progression from colonization to OM in the presence and absence of NTHi. Whereas pneumococcal serotype diversity was lower in single-species OM than in single-species colonization, levels of serotype diversity did not differ significantly between colonization and OM in mixed-species episodes. Serotypes differed roughly 100-fold in progression rates, and those differences were attenuated in polymicrobial episodes. Vaccine serotype pneumococci had higher rates of progression than nonvaccine serotypes. While serotype invasiveness was a weak predictor of the OM progression rate, efficient capsular metabolic properties-traditionally thought to serve as an advantage in colonization-predicted an enhanced rate of progression to complex OM. The lower capacity of nonvaccine serotypes to cause OM may partially account for reductions in all-cause OM incidence despite serotype replacement in carriage following rollout of PCVs.

Bacterial causes of otitis media with spontaneous perforation of the tympanic membrane in the era of 13 valent pneumococcal conjugate vaccine

“…We found that with Sp isolated with other otopathogens, the frequency of NVTs was higher than with Sp alone (p = 0.017). These findings also support the results of Lewnard et al: PCV13 serotypes were less frequently associated with NTHi than were non-PCV13 serotypes, which suggests that interactions with NTHi may change serotype-specific virulence for AOM [31]. Serotype 3 being the leading VT may indicate that this serotype is among the most virulent in terms of progression from carriage to AOM and for which a lower effectiveness of PCV13 has been demonstrated in other pneumococcal diseases [32, 33].…”

“…Similar results were observed in Italy 4 years after PCV13 implementation, with 77.1% of NVTs [30]. Lewnard et al recently found that PCV13 serotypes were among the most virulent in terms of progression from carriage to AOM, contrary to non-PCV13 serotypes, which explains in part the reduced benefit for incidence of AOM after PCV implementation, despite a complete serotype replacement in NP carriage [10, 31]. We found that with Sp isolated with other otopathogens, the frequency of NVTs was higher than with Sp alone (p = 0.017).…”

An empirical Bayes method for serotype case-carrier ratios, with an application to Group B streptococcus

“…While not available for this analysis, prior distributions of both serotype frequencies and measures of pathogenicity can be incorporated into the calculation of posterior probabilities. For instance, phenotypic aspects of S. pneumoniae such as capsule width, molecular content, and charge predict serotype associations with carriage prevalence as well as risk of invasive infection, 45 death, 25 and otitis media; 15,46 estimates of such associations could provide prior distributions on prevalence or invasiveness parameters for rare serotypes. Whereas we have assumed statistically-independent distributions of serotypes in carriage and disease within each setting, the model could also be extended to account for Dirichlet prior distributions of serotypes by geographic setting in addition to carriage or disease status.…”

Translating Recent Microbiome Insights in Otitis Media into Probiotic Strategies

“…Vaccines such as the PCV variants or the 10-valent pneumococcal H. influenzae protein D conjugate vaccine (PHiD-CV10) have already shown a decrease in the incidence of OM (273,274). For these preventive strategies to reduce OM episodes, probiotic bacteria can also be included as vaccine adjuvants.…”