Transmission Model Analysis of Nontypeable Haemophilus Influenzae

  • James S. Koopman
  • Ximin Lin
  • Stephen E. Chick
  • Janet R. Gilsdorf
Part of the International Series in Operations Research & Management Science book series (ISOR, volume 70)


The effects of immunity stimulated by natural colonization with Nontypeable Haemophilus influenzae (NTHi) were assessed using population models of transmission and data from the literature on NTHi colonization prevalence by age, NTHi acute otitis media (AOM) incidence by age, NTHi antibody levels, and colonization duration. The models allowed both contact patterns and immunity to influence colonization and disease patterns by age. To fit the data, the models required colonization to stimulate immunity affecting both transmission (susceptibility and contagiousness) and pathogenicity (AOM given colonization). Model analysis demonstrated that immunity affecting transmission influenced AOM incidence in the first year of life from 4.6 to 39.5 times as much as immunity reducing pathogenicity. This differential decreased with age until age three and then rose again. It was important, however, across all age groups. The conclusion that immunity affecting transmission had larger effects on AOM incidence than immunity affecting pathogenicity was robust to model form and to reasonable variation in the data. Because sensitivity to NTHi strain interactions and age patterns of infection by strain could not be assessed and because data on the distribution of NTHi strains across all ages are deficient, this conclusion must still be viewed as tentative. Nonetheless, these results make it imperative that trials of potential NTHi vaccines be designed to insure accurate assessment of effects on transmission. The models presented here provide the basis for the construction of discrete individual simulation models for use in designing the most informative and powerful vaccine trials.

Key words

Infection Models Vaccines Transmission Bacteria 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. [1]
    Poolman, J.T., et al. (2000). Developing a nontypeable Haemophilus influenzae (NTHi) vaccine. Vaccine, 19, S108–S115.CrossRefPubMedGoogle Scholar
  2. [2]
    Barbour, M.M.-W., R.T. Coles, C. Crook, and D.W.M. Moxon. (1995). The impact of conjugate vaccine on carriage of Haemophilus influenzae type b. Journal of Infectious Diseases, 171, 93–98.PubMedGoogle Scholar
  3. [3]
    Eskola, J., et al. (2001). Efficacy of a pneumococcal conjugate vaccine against acute otitis media. New England Journal of Medicine, 344, 403–409.CrossRefPubMedGoogle Scholar
  4. [4]
    Heikkinen, T., M. Thint, and T. Chonmaitree (1999). Prevalence of various respiratory viruses in the middle ear during acute otitis media. New England Journal of Medicine, 340, 260–264.CrossRefPubMedGoogle Scholar
  5. [5]
    Bluestone, C.D. (1982). Otitis media in children: to treat or not to treat? New England Journal of Medicine, 306, 1399–1404.PubMedCrossRefGoogle Scholar
  6. [6]
    Teele, D.W., J.O. Klein, and B.A. Rosner (1980). Epidemiology of otitis media in children. Annals of Otology, Rhinology, & Laryngology-Supplement, 89, 5–6.Google Scholar
  7. [7]
    Del Beccaro, M.A., et al. (1992). Bacteriology of acute otitis media: a new perspective. Journal of Pediatrics, 120, 81–84.PubMedCrossRefGoogle Scholar
  8. [8]
    Howard, A.J., K.T. Dunkin, and G.W. Millar (1988). Nasopharyngeal carriage and antibiotic resistance of Haemophilus influenzae in healthy children. Epidemiology & Infection, 100, 193–203.CrossRefGoogle Scholar
  9. [9]
    St. Sauver, J.L., C. Marrs, B. Foxman, P. Somsel, R. Madera, and J.R. Gilsdorf. (2000). Relationship of otitis media risk factors to carriage of multiple strains of H. influenzae and S. pneumoniae. Emerging Infectious Diseases, 6, 622–630.PubMedCrossRefGoogle Scholar
  10. [10]
    Faden, H., L. Duffy, A. Williams, D.A. Krystofik, and J. Wolf (1996). Epidemiology of nasopharyngeal colonization with nontypeable Haemophilus influenzae in the first two years of life. Acta Oto-Laryngologica-Supplement, 523, 128–129.Google Scholar
  11. [11]
    Gunnarsson, R.K., S.E. Holm, and M. Soderstrom (2000). The prevalence of potentially pathogenic bacteria in nasopharyngeal samples from individuals with a long-standing cough-clinical value of a nasopharyngeal sample. Family Practice, 17, 150–155.CrossRefPubMedGoogle Scholar
  12. [12]
    Fontanals, D., et al. (2000). Prevalence of Haemophilius influenzae carriers in the Catalan preschool population. Working Group on Invasive Disease Caused by Haemophilus influenzae. European Journal of Clinical Microbiology & Infectious Diseases, 19, 301–304.CrossRefGoogle Scholar
  13. [13]
    Principi, N., P. Marchisio, G.C. Schito, and S. Mannelli (1999). Risk factors for carriage of respiratory pathogens in the nasopharynx of healthy children. Ascanius Project Collaborative Group. Pediatric Infectious Disease Journal, 18, 517–523.PubMedCrossRefGoogle Scholar
  14. [14]
    Peerbooms, P.E., M.N. Stokman, D.A. van Benthem, B.H. van Weert, M.L. Bruisten, S.M. van Belkum, and R.A. Coutinho (2002). Nasopharyngeal carriage of potential bacterial pathogens related to day care attendance, with special reference to the molecular epidemiology of Haemophilus influenzae. Journal of Clinical Microbiology, 40, 2832–2836.CrossRefPubMedGoogle Scholar
  15. [15]
    Lundgren, K. and L. Ingvarsson (1983). Epidemiology of acute otitis media in children. Scandinavian Journal of Infectious Diseases-Supplementum, 39, 19–25.PubMedGoogle Scholar
  16. [16]
    Teele, D.W., J.O. Klein, and B. Rosner (1989). Epidemiology of otitis media during the first seven years of life in children in greater Boston: a prospective, cohort study. Journal of Infectious Diseases, 160, 83–94.PubMedGoogle Scholar
  17. [17]
    Alho, O.P., M. Koivu, M. Sorri, and P. Rantakallio (1991). The occurrence of acute otitis media in infants. A life-table analysis. International Journal of Pediatric Otorhinolaryngology, 21, 7–14.PubMedCrossRefGoogle Scholar
  18. [18]
    U.S. Bureau of the Census (1998). Childcare Arrangements for Preschoolers by Family Characteristics: Fall 1995 Percentages.
  19. [19]
    Jacquez, J.A., C.P. Simon, and J.S. Koopman (1989). Structured Mixing: Heterogeneous Mixing by the Definition of Activity Groups. Springer-Verlag Lecture Notes in Biomathematics.Google Scholar
  20. [20]
    Macey, R. and G. Oster (2003). Berkeley Madonna-Modeling and Analysis of Dynamic Systems.
  21. [21]
    Yamanaka, N. and H. Faden (1993). Antibody response to outer membrane protein of nontypeable Haemophilus influenzae in otitisprone children. Journal of Pediatrics, 122, 212–218.PubMedCrossRefGoogle Scholar
  22. [22]
    Harabuchi, Y., et al. (1994). Nasopharyngeal colonization with nontypeable Haemophilus influenzae and recurrent otitis media. Tonawanda/Williamsville Pediatrics. Journal of Infectious Diseases, 170, 862–866.PubMedGoogle Scholar
  23. [23]
    Yamanaka, N. and H. Faden (1993). Local antibody response to P6 of nontypeable Haemophilus influenzae in otitis-prone and normal children. Acta Oto-Laryngologica, 113, 524–529.PubMedCrossRefGoogle Scholar
  24. [24]
    Williams, R. and R. Gibbons (1972). Inhibition of bacterial adherence by secretory immunoglobulin A: a mechanism of antigen disposal. Science, 177, 697–699.ADSPubMedCrossRefGoogle Scholar
  25. [25]
    Rao, V.K., G.P. Krasan, D.R. Hendrixson, S. Dawid, and J.W. St. Geme, 3rd (1999). Molecular determinants of the pathogenesis of disease due to non-typeable Haemophilus influenzae. In FEMS Microbiology Reviews.Google Scholar
  26. [26]
    Koopman, J.S., I.M. Longini, J.A. Jacquez, C.P Simon, D. Ostrow, W.R. Martin, and D.M. Woodcock (1991). Assessing risk factors for transmission. American Journal of Epidemiology, 133, 1199–1209.PubMedGoogle Scholar
  27. [27]
    Koopman, J.S., S.E. Chick, C.P. Riolo, C.P. Simon, and G. Jacquez (2002). Stochastic effects of disseminating versus local infection transmission. Mathematical Biosciences, 180, 49–71.CrossRefPubMedMathSciNetGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • James S. Koopman
    • 1
    • 2
  • Ximin Lin
    • 1
  • Stephen E. Chick
    • 3
    • 4
  • Janet R. Gilsdorf
    • 1
    • 5
  1. 1.Department of EpidemiologyUniversity of MichiganAnn Arbor
  2. 2.Center for the Study of Complex SystemsUniversity of MichiganAnn Arbor
  3. 3.Department of Industrial and Operations EngineeringUniversity of MichiganAnn Arbor
  4. 4.INSEADFontainbleauFrance
  5. 5.Department of PediatricsUniversity of MichiganAnn Arbor

Personalised recommendations