Difference between revisions of "Coxiella burnetii: Dose Response Models"

Revision as of 15:07, 5 October 2011

Coxiella burnetii

General overview of Coxiella burnetii and Q fever

Coxiella burnetii (C. burnetii), an obligate intracellular gram-negative bacterium, is the causative agent of Q fever. C. burnetii multiplies only within the phagolysosomal vacuoles, particularly the macrophages of the host. During natural infections, the organism grows to high numbers in placental tissues of animals such as goats, sheep, and cows. The Center for Disease Control and Prevention (CDC) has classified C. burnetii as a category B biological terrorist agent because it consistently causes disability, can be manufactured on a large scale, remains stable under production, storage, and transportation conditions, can be efficiently disseminated and remains viable for years after dissemination.

Q fever, a zoonotic disease found worldwide, may manifest as acute or chronic disease. The acute form is generally not fatal and manifests as self-controlled febrile illness. Chronic Q fever is usually characterized by endocarditis. Many animal models, including humans, have been studied for Q fever infection through various exposure routes.

Humans are infected primarily through inhalation of aerosolized C. burnetii with as few as 10 organisms causing disease. Aerosols, or airborne particles, easily cause infection even without contact with infected animals, whereas person-to-person infection is rare. Ingestion of contaminated dairy products or bites from infected ticks may also lead to infection but these modes of transmission are very rare. However, there have been some recorded cases of human Q fever caused by the consumption of unpasteurized goat milk products (Tamrakar et al. 2011).

Summary Data

Williams and Cantrell interperitoneally inoculated groups of C57BL/10ScN male mice with 11 different doses of C. burnetii phase I Ohio strain to develop a vaccine against Q fever.

Scott and Williams examined the susceptibility of inbred mice to infection by C. burnetii Nine mile phase I strain. As many as 47 strains of inbred mice were evaluated. Groups of resistant C57BL/6J mice were inoculated with mean doses ranging from 10^−1.3 to 10⁷ organisms. The mortalities at various doses were recorded.

Table 4.1. Summary of the Coxiella burnetii data and best fits

The data from different experiments were not able to be statistically pooled.

^*Recommended Model

It is recommended that experiment 1 should be used as the best dose-response model. A more virulent strain in experiment 1 can be more meaningful for emergency preparedness. Also, single host strain was used in experiment 1 instead of multiple strains as in experiment 2.

Optimized Models and Fitting Analyses

Optimization Output for experiment 1

Figure 4.1 Parameter scatter plot for beta Poisson model ellipses signify the 0.9, 0.95 and 0.99 confidence of the parameters.

Figure 4.2 beta Poisson model plot, with confidence bounds around optimized model

Optimized Models and Fitting Analyses

Optimization Output for experiment 2

Figure 4.3 Parameter histogram for exponential model (uncertainty of the parameter)

Figure 4.4 Exponential model plot, with confidence bounds around optimized model

Summary

Noting an apparent difference of LD₅₀ between the experiment 1 (4.93x10⁸) and experiment 2 (1.22 x10¹⁰) routes has been identified. This may reflect the difference of susceptibilities associated with different host and pathogen strains.

References

Scott, G. and J. C. Williams (1987). "Pathological responses of inbred mice to phase I Coxiella Burnetii." Journal of General Microbiology 133(3): 691–700.

Tamrakar, S. B., A. Haluska, C. N. Haas and T. A. Bartrand (2011). "Dose-Response Model of Coxiella burnetii (Q Fever)." Risk Analysis 31(1): 120-128.

Williams, J. C. and J. L. Cantrell (1982). "Biological and immunological properties of Coxiella burnetii vaccines in C57BL/1OScN endotoxin-nonresponder mice." Infection and Immunity 35(3): 1091–1102.