By Patrick T. Kiessling and Philip R. Fischer, MD, DTM&H

Dr. Fischer is Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN. Mr. Kiessling is a student at Mayo Clinic School of Medicine.

Dr. Fischer and Mr. Kiessling report no financial relationships relevant to this field of study.

SYNOPSIS: Surveillance data collected prospectively in Israel reveal a decline in progression from pneumococcal carriage to complex otitis media in both vaccine-targeted and non-vaccine serotypes following implementation of routine use of pneumococcal conjugate vaccines. Vaccinating against pneumococcal serotypes causing early-life infections may reduce the risk of subsequently developing complex otitis media due to other organisms.

SOURCE: Lewnard JA, Givon-Lavi N, Weinberger DM, et al. Pan-serotype reduction in progression of Streptococcus pneumoniae to otitis media after rollout of pneumococcal conjugate vaccines. Clin Infect Dis 2017;65:1853-1861.

Especially in infancy, Streptococcus pneumoniae is a major bacterial cause of otitis media (OM). Although originally licensed to combat invasive pneumococcal disease, pneumococcal conjugate vaccines (PCVs) target serotypes most commonly implicated in invasive disease but also show efficacy against vaccine-serotype OM. Most young children carry S. pneumoniae and other otopathogens, which can progress from colonization to symptomatic OM, including recurrent and nonresponsive infection. Reductions in OM incidence following rollout of PCV exceeded expectations, suggesting that PCVs affect the progression of both vaccine-targeted and non-vaccine serotypes. By preventing tissue damage sustained from early-life middle ear infections caused by vaccine-serotype pneumococci, PCVs may halt the cascade to complex OM from non-vaccine serotypes.

Pre-implementation studies of PCV demonstrated efficacy against complex OM, resulting in more than 30% reduction in the need for ventilation tubes. Further, rates of OM caused by Moraxella catarrhalis, non-typable Haemophilus influenzae, and S. pyogenes declined following PCV rollout, although the underlying mechanism behind these secondary benefits of vaccination is unknown. With this background information in mind, investigators in Israel attempted to further explore changes in progression from colonization to illness by analyzing pneumococcal carriage and complex OM incidence among Bedouin and Jewish children before and after PCV introduction.

Before and after introduction of PCV programs in southern Israel, investigators used the medical center that provided care to nearly all children in the region to collect data, and no changes in access to care occurred following vaccine implementation. Pneumococcal carriage prevalence before PCV implementation was measured in unvaccinated Jewish and Bedouin children either enrolled in a hepatitis A trial or a pre-implementation PCV dosing trial. Pneumococcal carriage prevalence after vaccine rollout was estimated by sampling Jewish and Bedouin children presenting to the emergency department with diagnoses unrelated to any potential pneumococcal carriage. OM incidence was measured by the number of episodes at this medical center necessitating middle ear fluid culture (primarily indicating complex OM), both before and after PCV implementation. The progression rate was measured as the rate of OM incidence divided by carriage prevalence for each serotype.

Following PCV implementation, the incidence of middle ear fluid culture episodes from pneumococcal OM declined regardless of ethnicity. Rates of progression from carriage to OM in the first year of life decreased for PCV-targeted serotypes. For non-vaccine serotypes, the progression rate in the first year of life declined by 74% in Bedouin children and by 43% in Jewish children. The incidence of non-vaccine serotype OM decreased by 68% in Bedouin children younger than 12 months of age. Following vaccine rollout, no pneumococcal serotype demonstrated a statistically significant increase in progression. Therefore, the epidemiologic relationship between pneumococcal carriage and OM changed significantly following introduction of PCV. Damage sustained during early-life pneumococcal infections opens the door to less-virulent bacterial pathogens to progress to complex OM at older ages. Therefore, by inhibiting the establishment of early-life infection, vaccination against PCV serotypes may reduce overall complex OM burden.

COMMENTARY

Otitis media remains one of the most common infections seen in pediatric patients. A leading cause of both pediatric healthcare visits and pediatric antimicrobial prescribing in high-income countries, OM creates an estimated $2.88 billion in additional healthcare costs in the United States alone.1,2 Close to 20% of children contract recurrent or persistent acute OM, while approximately one-third of acute OM infections are caused by Streptococcus pneumoniae, representing a significant burden on pediatric patients.3,4 Pneumococcal conjugate vaccination is associated with protection against OM, coinciding with a continued decline in physician visits for acute OM, potentially representing a decreased burden of OM resulting from PCV rollout.5

The inspiration for this study stemmed from the desire to gain a greater understanding of the mechanism(s) by which pneumococcal vaccines exceeded impact predictions. PCV provided direct protection against progression of vaccine-targeted serotypes, as well as decreased progression rates for non-vaccine serotypes. Since vaccine-targeted serotypes primarily cause early-life infection, the subsequent reduction in non-vaccine serotypes following vaccine rollout revealed an unexpected relationship between early and later childhood pneumococcal infections.

Early-life pneumococcal infections cause damage and essentially stick a “foot in the door” to facilitate infection at older ages progressing to complex OM. This newfound relationship coincides with the “two-hit hypothesis” seen in other infectious diseases. Singly infected patients are made more susceptible to infection from a “hit” sustained by another infection. Epstein-Barr virus alone cannot cause endemic Burkitt lymphoma, but coinfection with Plasmodium falciparum malaria creates an environment suitable to this pediatric cancer.6 Acute respiratory viral infections, such as influenza, facilitate conditions that allow pathogenic bacteria such as Staphylococcus aureus to invade and cause tracheitis.7 Additionally, HIV infection predisposes susceptibility to infection by Mycobacterium tuberculosis, as well as progression from infection to active disease.8 PCV prevented early “hits” from vaccine-targeted pneumococcal serotypes, and therefore established greater protection against non-vaccine serotypes that take advantage of the damage sustained by early-life pneumococcal infection.

The multifactorial nature of OM can be observed further in the differing responses to vaccine rollout seen in Bedouin and Jewish children. As reported in the paper by Lewnard, Bedouin children are subject to “larger family sizes, higher rates of overcrowding, and lower socioeconomic status.” In the first year of life, Bedouin children exhibited higher OM incidence and higher pneumococcal carriage than their Jewish counterparts prior to vaccine rollout, perhaps related to some of these lifestyle issues. Then, following implementation of PCV, Bedouin children in the first year of life exhibited greater decreases in rates of progression from pneumococcal carriage to OM compared to Jewish children. During this time, they also experienced a decrease in the progression rate of serotypes not targeted by PCV that was nearly twice the decrease seen in Jewish children.

Not surprisingly, children at higher risk of pneumococcal disease demonstrated greater benefit from vaccination. Dysregulated inflammation of the middle ear can facilitate development and subsequent progression of OM.9 Therefore, if lifestyle variations and medical interventions available to Jewish children limited middle ear inflammation, they may have decreased the susceptibility of Jewish children to pneumococcal carriage and OM infection. Thus, greater reductions in pneumococcal carriage and progression rates were observed in Bedouin children following PCV rollout.

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