Skip to main content
SpringerLink
Log in

Cellular Immune Response in Young Children Accounts for Recurrent Acute Otitis Media

  • OTITIS (DP SKONER, SECTION EDITOR)
  • Published:
Current Allergy and Asthma Reports Aims and scope Submit manuscript

Abstract

Acute otitis media (AOM) is a common disease in young children. Streptococcus pneumoniae (Spn) and Haemophilus influenzae (NTHi) are the two most common pathogens that cause AOM. Over the past 5 years, our group has been studying the immunologic profile of children that experience repeated AOM infections despite tympanocentesis drainage of middle ear fluid and individualized antibiotic treatment; we call these children stringently-defined otitis-prone (sOP). Although protection against AOM is primarily mediated by ototpathogen-specific antibody, our recent studies suggest that suboptimal memory B and T cell responses and an immaturity in antigen-presenting cells may play a significant role in the propensity to recurrent AOM infections. This review focuses on the studies performed to define immunologic dysfunction in sOP children.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Acuin J. Chronic suppurative otitis media. Clin Evid. 2004;12:710–29.

    PubMed  Google Scholar 

  2. Pichichero ME. Recurrent and persistent otitis media. Pediatr Infect Dis J. 2000;19(9):911–6.

    Article  PubMed  CAS  Google Scholar 

  3. Berman S. Otitis media in developing countries. Pediatrics. 1995;96(1):126–31.

    PubMed  CAS  Google Scholar 

  4. Poehling KA, Szilagyi PG, Grijalva CG, et al. Reduction of frequent otitis media and pressure-equalizing tube insertions in children after introduction of pneumococcal conjugate vaccine. Pediatrics. 2007;119(4):707–15.

    Article  PubMed  Google Scholar 

  5. Pichichero ME, Casey JR. Evolving microbiology and molecular epidemiology of acute otitis media in the pneumococcal conjugate vaccine era. Pediatr Infect Dis J. 2007;26(10 Suppl):S12–6.

    PubMed  Google Scholar 

  6. Kaur R, Adlowitz DG, Casey JR, Zeng M, Pichichero ME. Simultaneous assay for four bacterial species including Alloiococcus otitidis using multiplex-PCR in children with culture negative acute otitis media. Pediatr Infect Dis J. 2010;29(8):741–5.

    Article  PubMed  Google Scholar 

  7. Kaur R, Chang A, Xu Q, Casey JR, Pichichero ME. Phylogenetic relatedness and diversity of non-typable Haemophilus influenzae in the nasopharynx and middle ear fluid of children with acute otitis media. J Med Microbiol. 2011;60(Pt 12):1841–8.

    Article  PubMed  Google Scholar 

  8. •• Xu Q, Almudevar A, Casey JR, Pichichero ME. Nasopharyngeal bacterial interactions in children. Emerg Infect Dis. 2012;18(11):1738–45. Article mentions epidemiological changes in the multiple nasopharyngeal colonization of young children over time.

    Article  PubMed  Google Scholar 

  9. Xu Q, Casey JR, Chang A, Pichichero ME. When co-colonizing the nasopharynx haemophilus influenzae predominates over Streptococcus pneumoniae except serotype 19A strains to cause acute otitis media. Pediatr Infect Dis J. 2012;31(6):638–40.

    Article  PubMed  Google Scholar 

  10. Xu Q, Kaur R, Casey JR, Adlowitz DG, Pichichero ME, Zeng M. Identification of Streptococcus pneumoniae and Haemophilus influenzae in culture-negative middle ear fluids from children with acute otitis media by combination of multiplex PCR and multi-locus sequencing typing. Int J Pediatr Otorhinolaryngol. 2011;75(2):239–44.

    Article  PubMed  Google Scholar 

  11. Xu Q, Kaur R, Casey JR, Sabharwal V, Pelton S, Pichichero ME. Nontypeable Streptococcus pneumoniae as an otopathogen. Diagn Microbiol Infect Dis. 2011;69(2):200–4.

    Article  PubMed  Google Scholar 

  12. Chang A, Adlowitz DG, Yellamatty E, Pichichero ME. Haemophilus influenzae outer membrane protein P6 molecular characterization may not differentiate all strains of H. Influenzae from H. haemolyticus. J Clin Microbiol. 2010;48(10):3756–7.

    Article  PubMed  Google Scholar 

  13. Chang A, Kaur R, Michel LV, Casey JR, Pichichero ME. Haemophilus influenzae vaccine candidate outer membrane protein P6 is not conserved in all strains. Hum Vaccine. 2011;7(1):102–5.

    Article  CAS  Google Scholar 

  14. Casey JR, Adlowitz DG, Pichichero ME. New patterns in the otopathogens causing acute otitis media six to eight years after introduction of pneumococcal conjugate vaccine. Pediatr Infect Dis J. 2010;29(4):304–9.

    PubMed  Google Scholar 

  15. Friedel V, Chang A, Wills J, Vargas R, Xu Q, Pichichero ME. Impact of respiratory viral infections on alpha-hemolytic streptococci and otopathogens in the nasopharynx of young children. Pediatr Infect Dis J. 2013;32(1):27–31.

    Article  PubMed  Google Scholar 

  16. Liu K, Pichichero ME. Clinical significance of serum S100A12 in acute otitis media in young children. Pediatr Infect Dis J. 2012;31(3):e56–8.

    Article  PubMed  Google Scholar 

  17. Pichichero ME. Bacterial conjunctivitis in children: antibacterial treatment options in an era of increasing drug resistance. Clin Pediatr (Phila). 2011;50(1):7–13.

    Article  Google Scholar 

  18. Michel LV, Kalmeta B, McCreary M, Snyder J, Craig P, Pichichero ME. Vaccine candidate P6 of nontypable Haemophilus influenzae is not a transmembrane protein based on protein structural analysis. Vaccine. 2011;29(8):1624–7.

    Article  PubMed  CAS  Google Scholar 

  19. •• Pichichero ME, Casey JR, Almudevar A. Reducing the frequency of acute otitis media by individualized care. Pediatr Infect Dis J. 2013;Jan 21 [Epub ahead of print]. This article defines immunological changes that may predispose young children for recurrent acute otitis media.

  20. Sabirov A, Casey JR, Murphy T, Pichichero ME. Breast-feeding is associated with a reduced frequency of acute otitis media and high serum antibody levels against NTHi and outer membrane protein vaccine antigen candidate P6. Pediatr Res. 2009;66(5):565–70.

    Article  PubMed  Google Scholar 

  21. •• Sharma SK, Casey JR, Pichichero ME. Reduced memory CD4+ T-cell generation in the circulation of young children may contribute to the otitis-prone condition. J Infect Dis. 2011;204(4):645–53. This key manuscript demonstrates poor generation of anamnestic T cell responses in children that were prone to otitis-media.

    Article  PubMed  CAS  Google Scholar 

  22. • Sharma SK, Casey JR, Pichichero ME. Reduced serum IgG responses to pneumococcal antigens in otitis-prone children may be due to poor memory B-cell generation. J Infect Dis. 2012;205(8):1225–9. An important and concise paper defining poor memory B cell population in young children with recurrent acute otitis media.

    Article  PubMed  CAS  Google Scholar 

  23. Khan MN, Kaur R, Pichichero ME. Bactericidal antibody response against P6, protein D, and OMP26 of nontypeable Haemophilus influenzae after acute otitis media in otitis-prone children. FEMS Immunol Med Microbiol. 2012;65(3):439–47.

    Article  PubMed  CAS  Google Scholar 

  24. •• Liu K, Chen LL, Kaur R, Pichichero ME. Transcriptome signature in young children with acute otitis media due to non-typeable Haemophilus influenzae. Int Immunol. 2013;Feb 14 [Epub ahead of print]. This describes immunological changes in the children with ongoing AOM at the transcriptional level.

  25. Liu K, Kaur R, Almudevar A, Pichichero ME. Higher serum levels of interleukin 10 occur at onset of acute otitis media caused by streptococcus pneumoniae compared to haemophilus influenzae and moraxella catarrhalis. Laryngoscope. 2013;Feb 12 [Epub ahead of print].

  26. •• Kaur R, Casey JR, Pichichero ME. Serum antibody response to three non-typeable Haemophilus influenzae outer membrane proteins during acute otitis media and nasopharyngeal colonization in otitis prone and non-otitis prone children. Vaccine. 2011;29(5):1023–8. The article describes poor antigen-specific IgG responses to NTHi among children that had reccurent AOM compared to normal children.

    Article  PubMed  CAS  Google Scholar 

  27. •• Kaur R, Casey JR, Pichichero ME. Serum antibody response to five Streptococcus pneumoniae proteins during acute otitis media in otitis-prone and non-otitis-prone children. Pediatr Infect Dis J. 2011;30(8):645–50. This article, in conjunction with the preceding one, describes how otitis-prone children have lower levels of antibodies (IgG) that were specific to pneumococcal antigens.

    Article  PubMed  Google Scholar 

  28. Kaur R, Kim T, Casey JR, Pichichero ME. Antibody in middle ear fluid of children originates predominantly from sera and nasopharyngeal secretions. Clin Vaccine Immunol. 2012;19(10):1593–6.

    Article  PubMed  CAS  Google Scholar 

  29. • Pichichero ME, Kaur R, Casey JR, Sabirov A, Khan MN, Almudevar A. Antibody response to Haemophilus influenzae outer membrane protein D, P6, and OMP26 after nasopharyngeal colonization and acute otitis media in children. Vaccine. 2010;28(44):7184–92. This article depicts the role of bactericidal antibodies in preventing AOM in children.

    Article  PubMed  CAS  Google Scholar 

  30. •• Verhoeven D, Nesselbush M, Pichichero ME. Lower nasopharyngeal epithelial cell repair and diminished innate inflammation responses contribute to the onset of acute otitis media in otitis-prone children. Med Microbiol Immunol. 2013;April 11 [Epub ahead of print]. An important article that demonstrates alternation in local inflammation during AOM in otitis-prone children.

  31. Faden H. The microbiologic and immunologic basis for recurrent otitis media in children. Eur J Pediatr. 2001;160(7):407–13.

    Article  PubMed  CAS  Google Scholar 

  32. Cripps AW, Otczyk DC. Prospects for a vaccine against otitis media. Expert Rev Vaccines. 2006;5(4):517–34.

    Article  PubMed  CAS  Google Scholar 

  33. Arkwright PD. Atopic eczema is associated with delayed maturation of the antibody response to pneumococcal vaccine. Clin Exp Immunol. 2000;122(1):16–9.

    Article  PubMed  CAS  Google Scholar 

  34. Holt PG. Developmental factors as determinants of risk for infections and atopy in childhood. Eur Respir Rev. 2005;14(95):5.

    Article  Google Scholar 

  35. McKinstry KK, Strutt TM, Swain SL. The potential of CD4 T-cell memory. Immunology. 2010;130(1):1–9.

    Article  PubMed  CAS  Google Scholar 

  36. Kelly DF, Pollard AJ, Moxon ER. Immunological memory: the role of B cells in long-term protection against invasive bacterial pathogens. JAMA. 2005;294(23):3019–23.

    Article  PubMed  CAS  Google Scholar 

  37. Pichichero ME. Booster vaccinations: can immunologic memory outpace disease pathogenesis? Pediatrics. 2009;124(6):1633–41.

    Article  PubMed  Google Scholar 

  38. Fietta P, Delsante G. The effector T helper cell triade. Riv Biol. 2009;102(1):61–74.

    PubMed  Google Scholar 

  39. Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996;17(3):138–46.

    Article  PubMed  CAS  Google Scholar 

  40. Korn T. IL-17 and Th17 Cells. Annu Rev Immunol. 2009;27:485–517.

    Article  PubMed  CAS  Google Scholar 

  41. Kaplan MH. Th9 cells: differentiation and disease. Immunol Rev. 2013;252(1):104–15.

    Article  PubMed  Google Scholar 

  42. Ramiscal RR, Vinuesa CG. T-cell subsets in the germinal center. Immunol Rev. 2013;252(1):146–55.

    Article  PubMed  Google Scholar 

  43. • Sharma SK, Almudevar A, Mosmann T, Pichichero ME. CD4+ T-cell responses among adults and young children in response to streptococcus pneumoniae and haemophilus influenzae vaccine candidate protein antigens. Vaccine. 2013;In Press. In this article, the divergence in pneumococci-specific CD4+ T cell responses among adults and young children have been shown. The weaker T cell responses in young children may be responsible for their susceptibility to AOM infections.

  44. Mureithi MW, Finn A, Ota MO, et al. T cell memory response to pneumococcal protein antigens in an area of high pneumococcal carriage and disease. J Infect Dis. 2009;200(5):783–93.

    Article  PubMed  CAS  Google Scholar 

  45. Zhang Q, Bagrade L, Bernatoniene J, et al. Low CD4 T cell immunity to pneumolysin is associated with nasopharyngeal carriage of pneumococci in children. J Infect Dis. 2007;195(8):1194–202.

    Article  PubMed  CAS  Google Scholar 

  46. de Bree GJ, Daniels H, Schilfgaade MV, et al. Characterization of CD4+ memory T cell responses directed against common respiratory pathogens in peripheral blood and lung. J Infect Dis. 2007;195(11):1718–25.

    Article  PubMed  Google Scholar 

  47. King PT, Hutchinson PE, Johnson PD, et al. Adaptive immunity to nontypeable Haemophilus influenzae. Am J Respir Crit Care Med. 2003;167(4):587–92.

    Article  PubMed  Google Scholar 

  48. Malley R, Srivastava A, Lipsitch M, et al. Antibody-independent, interleukin-17A-mediated, cross-serotype immunity to pneumococci in mice immunized intranasally with the cell wall polysaccharide. Infect Immun. 2006;74(4):2187–95.

    Article  PubMed  CAS  Google Scholar 

  49. Kodama H, Faden H, Harabuchi Y, Kataura A, Bernstein JM, Brodsky L. Cellular immune response of adenoidal and tonsillar lymphocytes to the P6 outer membrane protein of non-typeable Haemophilus influenzae and its relation to otitis media. Acta Otolaryngol. 1999;119(3):377–83.

    Article  PubMed  CAS  Google Scholar 

  50. Avanzini AM, Castellazzi AM, Marconi M, et al. Children with recurrent otitis show defective IFN gamma-producing cells in adenoids. Pediatr Allergy Immunol. 2008;19(6):523–6.

    Article  PubMed  Google Scholar 

  51. Kaminkova J, Lange CF. Transfer factor and repeated otitis media. Cell Immunol. 1984;89(1):259–64.

    Article  PubMed  CAS  Google Scholar 

  52. Mattila PS, Nykanen A, Eloranta M, Tarkkanen J. Adenoids provide a microenvironment for the generation of CD4(+), CD45RO(+), L-selectin(−), CXCR4(+), CCR5(+) T lymphocytes, a lymphocyte phenotype found in the middle ear effusion. Int Immunol. 2000;12(9):1235–43.

    Article  PubMed  CAS  Google Scholar 

  53. Skotnicka B, Stasiak-Barmuta A, Hassmann-Poznanska E, Kasprzycka E. Lymphocyte subpopulations in middle ear effusions: flow cytometry analysis. Otol Neurotol. 2005;26(4):567–71.

    Article  PubMed  Google Scholar 

  54. Lewis M, Tarlton JF, Cose S. Memory versus naive T-cell migration. Immunol Cell Biol. 2008;86(3):226–31.

    Article  PubMed  CAS  Google Scholar 

  55. Jecker P, Pabst R, Westermann J. Proliferating macrophages, dendritic cells, natural killer cells, T and B lymphocytes in the middle ear and Eustachian tube mucosa during experimental acute otitis media in the rat. Clin Exp Immunol. 2000;126(3):421–5.

    Article  Google Scholar 

  56. Forseni MD, Bagger-Sjoback D, Hultcrantz M. A study of inflammatory mediators in the human tympanosclerotic middle ear. Arch Otolaryngol Head Neck Surg. 2001;127(5):559–64.

    Article  PubMed  CAS  Google Scholar 

  57. Lagging E, Papatziamos G, Hallden G, et al. T-cell subsets in adenoids and peripheral blood related to age, otitis media with effusion and allergy. APMIS. 1998;106(3):354–60.

    Article  PubMed  CAS  Google Scholar 

  58. Bernstein JM, Ballow M, Xiang S, O'Neil K. Th1/Th2 cytokine profiles in the nasopharyngeal lymphoid tissues of children with recurrent otitis media. Ann Otol Rhinol Laryngol. 1998;107(1):22–7.

    PubMed  CAS  Google Scholar 

  59. von Andrian UH, Mempel TR. Homing and cellular traffic in lymph nodes. Nat Rev Immunol. 2003;3(11):867–78.

    Article  Google Scholar 

  60. Yamane H, Paul WE. Early signaling events that underlie fate decisions of naive CD4(+) T cells toward distinct T-helper cell subsets. Immunol Rev. 2013;252(1):12–23.

    Article  PubMed  Google Scholar 

  61. Cella M, Salio M, Sakakibarn Y, Langen H, Julkunen I, Lanzavecchia A. Maturation, activation, and protection of dendritic cells induced by double-stranded RNA. J Exp Med. 1999;189(5):821–9.

    Article  PubMed  CAS  Google Scholar 

  62. Hertz CJ, Kiertscher SM, Godowski PT, et al. Microbial lipopeptides stimulate dendritic cell maturation via Toll-like receptor 2. J Immunol. 2001;166(4):2444–50.

    PubMed  CAS  Google Scholar 

  63. Cho HJ, Hayashi T, Datta SK. IFN-alpha beta promote priming of antigen-specific CD8+ and CD4+ T lymphocytes by immunostimulatory DNA-based vaccines. J Immunol. 2002;168(10):4907–13.

    PubMed  CAS  Google Scholar 

  64. Emonts M, Veenhoven RH, Wiertsema SP, et al. Genetic polymorphisms in immunoresponse genes TNFA, IL6, IL10, and TLR4 are associated with recurrent acute otitis media. Pediatrics. 2007;120(4):814–23.

    Article  PubMed  Google Scholar 

  65. Revai K, Patel JA, Grady JJ, Nair S, Matalon R, Chonmaitree T. Association between cytokine gene polymorphisms and risk for upper respiratory tract infection and acute otitis media. Clin Infect Dis. 2009;49(2):257–61.

    Article  PubMed  CAS  Google Scholar 

  66. Pichichero ME, Kaur R, Casey JR, Xu X, Almudvar A, Ochs M. Antibody response to Streptococcus pneumoniae proteins PhtD, LytB, PcpA, PhtE and Ply after nasopharyngeal colonization and acute otitis media in children. Hum Vaccin Immunother. 2012;8(6):799–805.

    Article  PubMed  CAS  Google Scholar 

  67. Prellner K, Hartsen G, Lofgren B, Christenson B, Heldrup J. Responses to rubella, tetanus, and diphtheria vaccines in otitis-prone and non-otitis-prone children. Ann Otol Rhinol Laryngol. 1990;99(8):628–32.

    PubMed  CAS  Google Scholar 

  68. Wiertsema SP, Sanders EA, Veenhoven RH, et al. Antibody levels after regular childhood vaccinations in the immunological screening of children with recurrent otitis media. J Clin Immunol. 2004;24(4):354–60.

    Article  PubMed  CAS  Google Scholar 

  69. Barnett ED, Pelton SI, Cabral HJ, et al. Immune response to pneumococcal conjugate and polysaccharide vaccines in otitis-prone and otitis-free children. Clin Infect Dis. 1999;29(1):191–2.

    Article  PubMed  CAS  Google Scholar 

  70. •• Pichichero ME, Casey JR, Almudevar A. Non- protective responses to pediatric vaccines occur in children who are otitis prone. Pediatr Infect Dis J. 2013;In press. This article reports a broad immunological immaturity among otitis-prone children. OP children exhibit reduced IgG response to routine pediatric vaccination compared to normal children.

  71. Sharma SK, Pichichero ME. Functional deficits of pertussis-specific CD4+ T cells in infants compared to adults following DTaP vaccination. Clin Exp Immunol. 2012;169(3):281–91.

    Article  PubMed  CAS  Google Scholar 

  72. Adkins B, Leclerc C, Marshall-Clarke S. Neonatal adaptive immunity comes of age. Nat Rev Immunol. 2004;4(7):553–64.

    Article  PubMed  CAS  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Sharad K. Sharma and Michael E. Pichichero declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Center for Infectious Disease and Vaccine Immunology, Research Institute, Rochester General Hospital, 1425 Portland Ave, Rochester, NY, 14621, USA

    Sharad K. Sharma & Michael E. Pichichero

Authors
  1. Sharad K. Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael E. Pichichero
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael E. Pichichero.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sharma, S.K., Pichichero, M.E. Cellular Immune Response in Young Children Accounts for Recurrent Acute Otitis Media. Curr Allergy Asthma Rep 13, 495–500 (2013). https://doi.org/10.1007/s11882-013-0370-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11882-013-0370-z

Keywords

Search

Navigation