The interaction between Streptococcus pneumoniae and
other respiratory pathogens, including viruses and bacteria
commonly colonizing the nasopharynx
Dissertation (170 pages)
Committee Chair / Thesis Advisers: Klugman, Keith P; Flanders, W Dana
Committee Members: McGowan Jr., John E ; Sullivan, Patrick S ; Levin, Bruce ; McGee, Lesley (Respiratory Diseases Branch, CDC);
Research Fields: Health Sciences, Epidemiology; Health Sciences, Public Health
Keywords: Streptococcus pneumoniae; Influenza ; pandemic; nasopharyngeal colonization; bacterial interaction; co-infection
Program: Laney Graduate School, Epidemiology
This dissertation includes three studies, each assessing the interaction of Streptococcus pneumoniae and other respiratory pathogens using different approaches. The first study assessed the importance of secondary bacterial infections, especially pneumococcal infections, in the 1918 influenza pandemic. A systematic review of antemortem cultures from normally sterile sites during the 1918 influenza pandemic was performed, showing that the majority of pneumonias and deaths were caused by secondary pneumococcal pneumonia. A meta-analysis of bacterial vaccine studies during the 1918 pandemic was also performed, suggesting that the efficacy of whole-cell killed pneumococcal vaccine was 59% (95% CI 43-70%) for prevention of pneumonia and 70% (95% CI 50% - 82%) for prevention of death. In the second study, a deterministic compartment model was developed to investigate the interaction of S. pneumoniae and influenza virus and the usefulness of antibacterial interventions in a future "1918-like" influenza pandemic. The model predicts that such a pandemic will result in many fewer deaths in current developed countries than in 1918 simply due to the decline in pneumococcal carriage and the herd immunity provided by the widespread use of pneumococcal conjugate vaccines. Antibiotic treatment of patients with secondary pneumonia can greatly reduce mortality; antibiotic prophylaxis will be less useful because the number needed to treat is too high. The findings of these two studies will help set up a more conservative upper bound on the disease burden of a 1918 - like influenza pandemic and have the potential to lead to substantial changes in pandemic planning.
The third study investigated the interaction of Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus in the nasopharynx using data from a longitudinal study in Peru. A positive association between S. pneumoniae and H. influenzae and a negative association between S. pneumoniae and S. aureus were found, no matter whether culture or real-time quantitative polymerase chain reaction (qPCR) was used to determine the colonization status. The densities of S. pneumoniae and H. influenzae were also positively correlated. These findings suggest that bacterial interactions in the nasopharynx are complex and thus vaccines and antimicrobials which target specific bacteria and may unexpectedly influence the bacterial flora.
Table of Contents
List of Figures
List of Tables
Chapter 1. Introduction...1
Chapter 2. Background information and review of literature...3
Epidemiology of S. pneumoniae...3
The interaction between influenza virus and respiratory bacteria...7
Bacterial co-infections in pandemic influenza...10
Bacterial interactions in the nasopharynx...15
Chapter 3. Organization and objectives of the dissertation...26
Chapter 4. Study #1-1 Evidence from Ante-mortem Cultures for a Major Role of the Pneumococcus and Other Bacterial Pathogens in Mortality during the 1918 Influenza Pandemic...28
Submitted to the New England Journal of Medicine in July, 2009. A Shortened version of this manuscript was published in December, 2009. See Appendix.
Chapter 5. Study #1-2 Efficacy of Whole-cell Killed Bacterial Vaccines in Preventing Pneumonia and Death during the 1918 Influenza Pandemic...50
Published. Journal of Infectious Diseases. 2010;202(11):1639-48 Â©2010. Oxford University Press. Reproduced by Permission.
Chapter 6. Study #2 The anticipated severity of a "1918-like" influenza pandemic in contemporary populations: the contribution of antibacterial interventions...79
Submitted to American Epidemiological Society, 2011 for oral presentation. To be submitted to PLoS Medicine.
Chapter 7. Study #3 The nasopharyngeal interaction of Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus among young children living in the Peruvian Andes: comparison of culture and Real-time quantitative polymerase chain reaction...118
To be submitted to the Pediatric Infectious Disease Journal.
Chapter 8. Summary...152
Appendix: Published version for Study #1-1. "Bacterial Pathogens and Mortality during the 1918 Influenza Pandemic." New England Journal of Medicine. 2009; 361(26):2582-3...155
Â©2009. Massachusetts Medical Society
Reproduced by Permission.