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Pediatric Infectious Disease Journal:
doi: 10.1097/INF.0b013e318154b287
Article

Prospects for Prevention of Otitis Media

Pelton, Stephen I. MD

Free Access
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Author Information

From the Boston University Schools of Medicine and Public Health, Pediatric Infectious Disease, Boston Medical Center, Boston, MA.

Accepted for publication July 17, 2007.

Stephen I. Pelton, MD has indicated that he has received grant/research support from Sanofi-Aventis; serves as a consultant for GlaxoSmithKline and Wyeth, and has been on the Speakers Bureau for Sanofi-Aventis. Dr. Pelton does not plan to discuss off-label/investigational uses of a commercial product.

Address for correspondence: Stephen I. Pelton, MD, Boston University School of Medicine, 774 Albany Street – Suite 506, Boston, MA. E-mail: spelton@bu.edu.

CME Overview

Accreditation and Certification

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Boston University School of Medicine and The Physicians Academy for Clinical and Management Excellence. Boston University School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Boston University School of Medicine designates this educational activity for a maximum of 1.25 AMA PRA Category 1 CreditsTM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Statements of credit will be provided by mail within six weeks following activity participation and upon completion and return of evaluation form to Boston University School of Medicine at BUSM CME, E.PCV11PA07, 715 Albany St., A-305, Boston, MA 02118, Fax: 617-638-4905. For CME questions, please call BUSM CME at 617-638-4605.

Intended Audience

This activity has been designed for adult and pediatric clinical infectious disease specialists, microbiologists, and vaccinologists. It will provide material that is relevant to the concerns of clinicians and researchers who are interested in the treatment and management of infectious disease and how these strategies impact on patient outcomes.

Educational Needs Addressed

Acute otitis media (AOM) is one of the most common afflictions affecting children under the age of 5 years of age. In developed countries, nearly every child becomes a nasopharyngeal carrier of S. pneumoniae (SP) during the first year of life and the pathogen persists in the nasopharynx, which is significant as most cases of AOM result from a middle ear reflux from the nasopharynx. In developing countries, SP is one of the most notable bacterial pathogens for children under 6 months of age. Based upon available data, SP is estimated to kill one million children under five years of age worldwide. New vaccines are needed to provide the protective immunity necessary against the large number of SP serotypes that exist globally. The changing microbiology of SP disease, with a shift from SP to non-typeable H. influenzae (NTHi), likely based on the impact of currently available vaccine, demonstrates the even greater need for education on the use of existing and emergent conjugate vaccines in treating AOM. Success will also require expanded coverage against additional otopathogens, especially NTHi. A meaningful educational and action-oriented approach will enhance the global ability to prevent and treat AOM and its sequelae.

1. World Health Organization. World Development Report 1993: Investing in Health. Oxford: Oxford University Press; 1993:215-222.

2. Poehling KA, Lafleur BJ, Szilagyi PG, et al. Population-based impact of pneumococcal conjugate vaccine in young children. Pediatrics. 2004;114:755-761.

3. Acuin J. Chronic suppurative otitis media: burden of illness and management options. World Health Organization (WHO). 2006 update.

4. Belshe RB, Edwards KM, Vesikari T, et al. Live attenuated versus inactivated influenza vaccine in infants and young children. N Engl J Med. 2007;356:685-696.

Educational Objectives

Upon completion of this educational activity participant should be better able to:

1. Describe the global demographics and burden of Acute Otitis Media citing current available data.

2. Discuss the management of children with recurrent and relapsing respiratory tract disease, specifically Acute Otitis Media.

3. Outline the impact of Pneumococcal Conjugate Vaccine on Acute Otitis Media in the US and discuss the global implication of a vaccine targeting both pneumococcal and H. influenzae (NTHi) respiratory infections.

Release date   October 1, 2007   Expiration date   September 30, 2008

Estimated Time to Complete This Activity

1 hour and 15 minutes

Method of Participation

In order to successfully complete this activity, participants are required to read the entire supplement and complete and submit the test answer sheet by September 30, 2008. CME credit will be awarded provided a score of 70% or better is achieved. Statements of credit will be provided by mail within six weeks of receipt of the test answers to those who successfully complete the examination.

Course Director

Stephen I. Pelton, MD

Chief, Pediatric Infectious Disease

Boston Medical School

Professor of Pediatrics and Epidemiology

Boston University School of Medicine

Faculty

Lauren O. Bakaletz, PhD

Professor of Pediatrics

The Ohio State University, College of Medicine

Director, Center for Microbial Pathogenesis

Columbus Children's Research Institute

Janet R. Casey, MD

Legacy Pediatrics, PLLC

University of Rochester, School of Medicine and Dentistry

Amanda J. Leach, PhD

Ear and Respiratory Health Unit

Tropical and Infectious Diseases Division

Menzies School of Health Research

Charles Darwin University

Eugene Leibovitz, MD

Pediatric Infectious Disease Unit

Soroka Medical Center and The Faculty of Health Sciences

Ben-Gurion University of the Negev

Peter S. Morris, MBBS, FRACP, PhD

Deputy Leader of Child Health Division

Menzies School of Health Research

Charles Darwin University

Associate Professor of Pediatrics

Flinders University

Michael E. Pichichero, MD

Professor of Microbiology and Immunology

Professor of Pediatrics and Professor of Medicine

University of Rochester, School of Medicine and Dentistry

Disclosure Policy

Boston University School of Medicine asks all individuals involved in the development and presentation of Continuing Medical Education (CME) activities to disclose all relationships with commercial interests. This information is disclosed to CME activity participants. Boston University School of Medicine has procedures to resolve apparent conflicts of interest. In addition, faculty members are asked to disclose when any discussion of unapproved use of pharmaceuticals and devices is being discussed.

Disclosures

Stephen I. Pelton, MD has indicated that he has received grant/research support from Sanofi-Aventis; serves as a consultant for GlaxoSmithKline and Wyeth; and has been on the Speakers Bureau for Sanofi-Aventis. Dr. Pelton does not plan to discuss off-label/investigational uses of commercial products.

Amanda J. Leach, PhD has no relevant financial relationships to disclose. Dr. Leach does not plan to discuss off-labeled/investigational uses of commercial products.

Peter S. Morris, PhD has no relevant financial relationships to disclose. Dr. Morris does not plan to discuss off-label/investigational uses of commercial products.

Eugene Leibovitz, MD has no relevant financial relationships to disclose. Dr. Leibovitz does not plan to discuss off-label/investigational uses of commercial products.

Michael E. Pichichero, MD has indicated that he has received grant/research support from Abbott, GlaxoSmithKline, MedImmune, Sanofi-Aventis, and Sanofi-Pasteur; Honoraria from Abbott, GlaxoSmithKline, Sanofi-Aventis, and Sanofi-Pastuer. Dr. Pichichero does not plan to discuss off-label/investigational uses of commercial products.

Janet R. Casey, MD has indicated that she has been a single-day consultant for Abbott, GlaxoSmithKline, Sanofi-Aventis, and Sanofi-Pasteur. Dr. Casey does not plan to discuss off-label/investigational uses of commercial products.

Lauren Bakaletz, PhD has indicated that she has received grant/research support from GlaxoSmithKline Biologicals. Dr. Bakaletz does not plan to discuss off-label/investigational uses of commercial products.

Planning Committee: Mary Deering, Barry A. Fiedel, PhD, Heidi J. Katz, RPh, Amy Klopfenstien, MS and Kelly McPherson of Physicians Academy, along with Julie White, MS, Elizabeth Gifford and Elizabeth D. Barnett, MD of Boston University School of Medicine have no relevant financial relationships to disclose.

These materials and all other materials provided in conjunction with continuing medical education activities are intended solely for purposes of supplementing continuing medical education programs for qualified health care professionals. Anyone using the materials assumes full responsibility and all risk for their appropriate use. Trustees of Boston University makes no warranties or representations whatsoever regarding the accuracy, completeness, currentness, noninfringements, merchantability or fitness for a particular purpose of the materials. In no event will Trustees of Boston University be liable to anyone for any decision made or action taken in reliance on the materials. In no event should the information in the materials be used as a substitute for professional care.

For questions regarding CME, please contact cme@bu.edu

Boston University Privacy Policy: http://www.bu.edu/cme/policies/privacy_policy.html

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Abstract

Abstract: Understanding the pathogenesis of acute otitis media provides insight into strategies for immunoprophylaxis. This article evaluates the interactions between pathogen and host defense, and identifies potential bacterial and viral vaccine targets. Discussed in detail are the attributes for a candidate antigen necessary to achieve a greater reduction in the burden of middle ear disease. These include: (1) the need to target a broad spectrum of otopathogens; (2) antigens need to be shared across all (or most) isolates within a bacterial species; (3) antigens need to be surface exposed during middle ear infection; and (4) preferred antigens have an essential function such that nonexpressing bacterial mutants have reduced virulence. A vaccine candidate (Pnc-PD) that encompasses these “attributes” is discussed from the perspective of how it may provide additional protection from middle ear disease if further studies confirm initial data on efficacy.

The pathogenesis of acute otitis media (AOM) is complex, requiring bacterial otopathogens in the nasopharynx to evade host defenses and ascend the Eustachian tube into the middle ear space. These events are most likely to occur in infants and toddlers less than 3 years of age because of immunologic naiveté and incomplete maturation of Eustachian tube function. The likelihood of these events occurring are enhanced in the presence of viral respiratory tract infection; which appears to increase the density of nasopharyngeal colonization with otopathogens and further compromise Eustachian tube function because of mucosal edema.1–3 Such viral respiratory tract infections may also impair immune function (eg, decreased neutrophil function during Influenza A infection).4

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UNDERSTANDING THE PATHOGENESIS OF AOM

Understanding the pathogenesis of AOM provides insight into strategies for immunoprophylaxis. Prevention of viral respiratory tract infections reduces acute otitis events occurring in conjunction with viral infection. Recent studies of intranasal live-attenuated influenza vaccine in children 6 to 59 months of age have demonstrated the potential of this strategy.5 There were 54.9% fewer cases of culture-confirmed influenza in children that received live-attenuated vaccine than in the group that received inactivated vaccine (153 versus 338 cases, P < 0.001). There were fewer cases of AOM with culture-confirmed influenza among the children who were immunized with intranasal live-attenuated vaccine (attack rate of 0.7% versus 1.4%; relative efficacy of 50.6% favoring live-attenuated vaccine). The major limitation of this strategy is that the spectrum of viruses causing respiratory tract infection is large and only a relatively small proportion of AOM episodes overall are associated with influenza infection. A greater reduction in the burden of AOM could be achieved with use of vaccines that prevent other viral upper respiratory tract infections, especially those associated with Respiratory Syncytial or Para-influenza virus. To date, the development of effective and safe vaccines for these pathogens remains elusive.

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A SECOND STRATEGY FOR PREVENTING AOM

A second strategy for prevention of AOM is to target bacterial otopathogens by preventing nasopharyngeal colonization; or enhancing the ability of host defenses to rapidly clear bacteria from the middle ear. Current evidence suggests that both strategies have the potential to be effective. Immunization with pneumococcal conjugate vaccine results in prevention of new colonization events due to bacterial serotypes within the vaccine. Multiple investigators, including our group, have documented the decline in colonization with vaccine serotypes after universal immunization in infants and the increase in colonization with nonvaccine serotypes of Streptococcus pneumoniae (Fig. 1). 6 Dagan and colleagues demonstrated a negative correlation between serum antibody concentration and new acquisition(s) of serotypes 9V, 14, 19F, or 23F, indicating that higher serum antibody concentrations lead to the decreased probability of a new acquisition.7 The decline in nasopharyngeal colonization with vaccine serotypes only results in a decrease in AOM if “replacement” serotypes are less likely to ascend the Eustachian tube and produce an inflammatory exudate. In the FinOM study, the efficacy of PCV7 against pneumococcal otitis media was partially offset by the 33% increase in disease due to nonvaccine serotypes resulting in an overall decline of 34%.8 These data suggested that nonvaccine serotypes have the capacity to invade the middle ear. An analysis of vaccine and nonvaccine serotypes from Finland and Israel compared the frequency of a given serotype among carriage isolates with the frequency of recovery of a given serotype from the middle ear of children with AOM (to determine the relative virulence).9,10 Serotypes 3, 5, and 1 were identified as having a high virulence for AOM but only small differences were observed between most other serotypes, supporting the view that nonvaccine serotypes can cause disease as observed in the FinOM study.

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TYPE-SPECIFIC ANTIBODY AND PROTECTION AGAINST AOM

Alternatively, immunization can elicit antibody that enhances host clearance of bacteria that gain entry into the middle ear. The proof of concept for the ability of type-specific antibody to protect against pneumococcal otitis was demonstrated using bacterial polysaccharide immune globulin administered to chinchillas before challenge with serotype 7F S. pneumoniae. Passively immunized chinchillas were protected after direct intrabullar challenge with serotype 7F S. pneumoniae compared with controls, which all developed culture-positive experimental otitis media.11 Further, the FinOM study provided definitive evidence that systemic immunization can elicit sufficient antibody to prevent type-specific infection, where a 57% reduction in type-specific and a 51% reduction in vaccine-related serotypes were observed.8 However, the burden of otitis was only reduced by 6% overall as an increase in AOM due to nonvaccine S. pneumoniae serotypes and nontypable Haemophilus influenzae was observed. Studies of PCV7 from the Northern California Kaiser Permanente using clinical episodes of AOM as the end point found a similar (∼7%) reduction in middle ear disease.12 These results demonstrate the limitations of immunoprophylaxis that targets a restricted spectrum of otopathogens (eg, vaccine type S. pneumoniae).

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MOVING TO THE FUTURE

Achieving a greater reduction in the burden of middle ear disease will require vaccines that target a broader spectrum of otopathogens. It appears a successful approach will require the identification of antigens that are shared across all (or most) isolates within a bacterial species; that are surface exposed during middle ear infection; that preferably have an essential function so that nonexpressing bacterial mutants have reduced virulence; and finally are immunogenic in children (Table 1). Lipoprotein D from nontypable H. influenzae has been reported to be antigenically conserved across all isolates of nontypable H. influenzae; it is immunogenic in infants, and has an essential function rendering protein d-deficient mutants less virulent.13,14 Prymula et al recently published the results of a clinical trial with a 10-valent polysaccharide vaccine conjugated to protein D for prevention of AOM.15 Children immunized with Pnc-PD had 52% fewer episodes of pneumococcal otitis and 32.7% few episodes of hemophilus otitis (Fig. 2). Overall, a 42% reduction in culture-confirmed episodes of AOM and a 33% decline in clinical episodes were observed (Table 2). Further studies will be necessary to confirm the efficacy of protein D and understand its limitations.

Table 1
Table 1
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Figure 2
Figure 2
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Table 2
Table 2
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CONCLUDING COMMENTS

Prevention of AOM will require a different strategy than preventing invasive infections as nonvaccine serotypes of S. pneumoniae possess significant ability to ascend the Eustachian tube and invade the middle ear. Vaccines with broader coverage against the major bacterial otopathogens seems achievable, including more serotypes of S. pneumoniae and/or an antigen (Protein D) capable of targeting disease due to nontypable H. influenzae. However, further studies that provide greater understanding of the mechanism(s) of protection, the expression of protein D (and other antigen candidates) at various sites of infection and colonization, and its role in pathogenesis, will be necessary as we develop second-generation vaccines with even greater effectiveness in preventing AOM.

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REFERENCES

1.Chonmaitree T. Viral and bacterial interaction in acute otitis media. Pediatr Infect Dis. 2000;19:S24–S30.

2.Sanyal MA, Henderson FW, Stempel EC, et al. Effect of upper respiratory tract infection on eustachian tube ventilatory function in the preschool child. J Pediatr. 1980;97:11–15.

3.Doyle WJ, Skoner DP, Hayden F, et al. Otologic manifestations of experimental rhino virus infection. Laryngoscope. 1994;104:1295–1299.

4.Abramson JS, Wheeler HG. Virus-induced neutrophil dysfunction: role in the pathogenesis of bacterial infections. Pediatr Infect Dis J. 1994;13:643–652.

5.Belshe RB, Edwards KM, Vesikari T, et al. Live attenuated versus inactivated influenza vaccine in infants and young children. N Engl J Med. 2007;356:685–696.

6.Pelton SI, Loughlin AM, Marchant CD. Seven valent pneumococcal conjugate vaccine immunization in two Boston communities: changes in serotypes and antimicrobial susceptibility among Streptococcus pneumoniae isolates. Pediatr Infect Dis J. 2004;23:1015–1022.

7.Dagan R, Givon-Lavi N, Fraser D, et al. Serum serotype-specific pneumococcal anticapsular immunoglobulin G concentrations after immunization with a 9-valent conjugate pneumococcal vaccine correlate with nasopharyngeal acquisition of pneumococcus. J Infect Dis. 2005;192:367–376.

8.Eskola J, Kilpi T, Palmu A, et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med. 2001;344:403–409.

9.Shouval DS, Greenberg D, Givon-Lavi N, et al. Site-specific disease potential of individual Streptococcus pneumoniae serotypes in pediatric invasive disease, acute otitis media and acute conjunctivitis. Pediatr Infect Dis J. 2006;25:602–607.

10.Hanage WP, Auranen K, Syrjanen R, et al. Ability of pneumococcal serotypes and clones to cause acute otitis media: implications for the prevention of otitis media by conjugate vaccine. Infect Immun. 2004;72:76–81.

11.Shurin PA, Giebink GS, Wegman DL, et al. Prevention of pneumococcal otitis media in chinchillas with human bacterial polysaccharide immune globulin. J Clin Microbiol. 1988;26:755–759.

12.Fireman B, Black SB, Shinefield HR, et al. Impact of the pneumococcal conjugate vaccine on otitis media. Ped Infect Dis J. 2003;22:10–16.

13.Ruan MR, Akkoyunlu M, Grubb A, et al. Protein D of Haemophilus influenzae: a novel bacterial surface protein with affinity for human IgD. J Immunol. 1990;145:3379–3384.

14.Song XM, Forsgren A, Janson H. The gene encoding protein D (hpd) is highly conserved among Haemophilus influenzae type b and nontypeable strains. Infect Immun. 1995;63:696–699.

15.Prymula R, Peeters P, Chrobok V, et al. Pneumococcal capsular polysaccharides conjugated to protein D for prevention of acute otitis media caused by both Streptococcus pneumoniae and non-typable Haemophilus influenzae: a randomised double-blind efficacy study. Lancet. 2006;367:740–748.

Keywords:

acute otitis media; host clearance; lipoprotein D; serotypes; vaccines

© 2007 Lippincott Williams & Wilkins, Inc.

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