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Current Allergy and Asthma Reports

, Volume 13, Issue 5, pp 495–500 | Cite as

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

  • Sharad K. Sharma
  • Michael E. PichicheroEmail author
OTITIS (DP SKONER, SECTION EDITOR)

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.

Keywords

Acute otitis media Cellular immune response Recurrent otitis media Streptococcus pneumoniae Haemophilus influenzae Memory T cells Memory B cells Cytokine response Dendritic cells 

Notes

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.

References

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

  1. 1.
    Acuin J. Chronic suppurative otitis media. Clin Evid. 2004;12:710–29.PubMedGoogle Scholar
  2. 2.
    Pichichero ME. Recurrent and persistent otitis media. Pediatr Infect Dis J. 2000;19(9):911–6.PubMedCrossRefGoogle Scholar
  3. 3.
    Berman S. Otitis media in developing countries. Pediatrics. 1995;96(1):126–31.PubMedGoogle Scholar
  4. 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.PubMedCrossRefGoogle Scholar
  5. 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.PubMedGoogle Scholar
  6. 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.PubMedCrossRefGoogle Scholar
  7. 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.PubMedCrossRefGoogle Scholar
  8. 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.PubMedCrossRefGoogle Scholar
  9. 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.PubMedCrossRefGoogle Scholar
  10. 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.PubMedCrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. 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.CrossRefGoogle Scholar
  14. 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.PubMedGoogle Scholar
  15. 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.PubMedCrossRefGoogle Scholar
  16. 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.PubMedCrossRefGoogle Scholar
  17. 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.CrossRefGoogle Scholar
  18. 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.PubMedCrossRefGoogle Scholar
  19. 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. Google Scholar
  20. 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.PubMedCrossRefGoogle Scholar
  21. 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.PubMedCrossRefGoogle Scholar
  22. 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.PubMedCrossRefGoogle Scholar
  23. 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.PubMedCrossRefGoogle Scholar
  24. 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. Google Scholar
  25. 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].Google Scholar
  26. 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.PubMedCrossRefGoogle Scholar
  27. 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.PubMedCrossRefGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. 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. Google Scholar
  31. 31.
    Faden H. The microbiologic and immunologic basis for recurrent otitis media in children. Eur J Pediatr. 2001;160(7):407–13.PubMedCrossRefGoogle Scholar
  32. 32.
    Cripps AW, Otczyk DC. Prospects for a vaccine against otitis media. Expert Rev Vaccines. 2006;5(4):517–34.PubMedCrossRefGoogle Scholar
  33. 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.PubMedCrossRefGoogle Scholar
  34. 34.
    Holt PG. Developmental factors as determinants of risk for infections and atopy in childhood. Eur Respir Rev. 2005;14(95):5.CrossRefGoogle Scholar
  35. 35.
    McKinstry KK, Strutt TM, Swain SL. The potential of CD4 T-cell memory. Immunology. 2010;130(1):1–9.PubMedCrossRefGoogle Scholar
  36. 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.PubMedCrossRefGoogle Scholar
  37. 37.
    Pichichero ME. Booster vaccinations: can immunologic memory outpace disease pathogenesis? Pediatrics. 2009;124(6):1633–41.PubMedCrossRefGoogle Scholar
  38. 38.
    Fietta P, Delsante G. The effector T helper cell triade. Riv Biol. 2009;102(1):61–74.PubMedGoogle Scholar
  39. 39.
    Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996;17(3):138–46.PubMedCrossRefGoogle Scholar
  40. 40.
    Korn T. IL-17 and Th17 Cells. Annu Rev Immunol. 2009;27:485–517.PubMedCrossRefGoogle Scholar
  41. 41.
    Kaplan MH. Th9 cells: differentiation and disease. Immunol Rev. 2013;252(1):104–15.PubMedCrossRefGoogle Scholar
  42. 42.
    Ramiscal RR, Vinuesa CG. T-cell subsets in the germinal center. Immunol Rev. 2013;252(1):146–55.PubMedCrossRefGoogle Scholar
  43. 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. Google Scholar
  44. 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.PubMedCrossRefGoogle Scholar
  45. 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.PubMedCrossRefGoogle Scholar
  46. 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.PubMedCrossRefGoogle Scholar
  47. 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.PubMedCrossRefGoogle Scholar
  48. 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.PubMedCrossRefGoogle Scholar
  49. 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.PubMedCrossRefGoogle Scholar
  50. 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.PubMedCrossRefGoogle Scholar
  51. 51.
    Kaminkova J, Lange CF. Transfer factor and repeated otitis media. Cell Immunol. 1984;89(1):259–64.PubMedCrossRefGoogle Scholar
  52. 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.PubMedCrossRefGoogle Scholar
  53. 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.PubMedCrossRefGoogle Scholar
  54. 54.
    Lewis M, Tarlton JF, Cose S. Memory versus naive T-cell migration. Immunol Cell Biol. 2008;86(3):226–31.PubMedCrossRefGoogle Scholar
  55. 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.CrossRefGoogle Scholar
  56. 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.PubMedCrossRefGoogle Scholar
  57. 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.PubMedCrossRefGoogle Scholar
  58. 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.PubMedGoogle Scholar
  59. 59.
    von Andrian UH, Mempel TR. Homing and cellular traffic in lymph nodes. Nat Rev Immunol. 2003;3(11):867–78.CrossRefGoogle Scholar
  60. 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.PubMedCrossRefGoogle Scholar
  61. 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.PubMedCrossRefGoogle Scholar
  62. 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.PubMedGoogle Scholar
  63. 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.PubMedGoogle Scholar
  64. 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.PubMedCrossRefGoogle Scholar
  65. 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.PubMedCrossRefGoogle Scholar
  66. 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.PubMedCrossRefGoogle Scholar
  67. 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.PubMedGoogle Scholar
  68. 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.PubMedCrossRefGoogle Scholar
  69. 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.PubMedCrossRefGoogle Scholar
  70. 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. Google Scholar
  71. 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.PubMedCrossRefGoogle Scholar
  72. 72.
    Adkins B, Leclerc C, Marshall-Clarke S. Neonatal adaptive immunity comes of age. Nat Rev Immunol. 2004;4(7):553–64.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Center for Infectious Disease and Vaccine ImmunologyResearch Institute, Rochester General HospitalRochesterUSA

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