Modeling low-dose mortality and disease incubation period of inhalational anthrax in the rabbit

• Published in: Journal of theoretical biology 2013-07, Vol.329, p.20-31
• Main Authors: Gutting, Bradford W., Marchette, David, Sherwood, Robert, Andrews, George A., Director-Myska, Alison, Channel, Stephen R., Wolfe, Daniel, Berger, Alan E., Mackie, Ryan S., Watson, Brent J., Rukhin, Andrey
• Format: Article
• Language: English
• Subjects: Ames; Animals; Anthrax - microbiology; Anthrax - prevention & control; Anthrax Vaccines; Bacillus anthracis - pathogenicity; Bacillus anthracis - physiology; Bacterial Load; Disease Models, Animal; Dose–response; Infectious Disease Incubation Period; Inhalational anthrax; Lung - microbiology; Male; Models, Biological; Rabbit; Rabbits; Respiratory Tract Infections - microbiology; Respiratory Tract Infections - prevention & control; Risk Assessment - methods; Spores, Bacterial - pathogenicity; Spores, Bacterial - physiology; Stochastic model
• ISSN: 0022-5193; 1095-8541
• DOI: 10.1016/j.jtbi.2013.03.020

There is a need to advance our ability to conduct credible human risk assessments for inhalational anthrax associated with exposure to a low number of bacteria. Combining animal data with computational models of disease will be central in the low-dose and cross-species extrapolations required in achieving this goal. The objective of the current work was to apply and advance the competing risks (CR) computational model of inhalational anthrax where data was collected from NZW rabbits exposed to aerosols of Ames strain Bacillus anthracis. An initial aim was to parameterize the CR model using high-dose rabbit data and then conduct a low-dose extrapolation. The CR low-dose attack rate was then compared against known low-dose rabbit data as well as the low-dose curve obtained when the entire rabbit dose–response data set was fitted to an exponential dose–response (EDR) model. The CR model predictions demonstrated excellent agreement with actual low-dose rabbit data. We next used a modified CR model (MCR) to examine disease incubation period (the time to reach a fever >40°C). The MCR model predicted a germination period of 14.5h following exposure to a low spore dose, which was confirmed by monitoring spore germination in the rabbit lung using PCR, and predicted a low-dose disease incubation period in the rabbit between 14.7 and 16.8 days. Overall, the CR and MCR model appeared to describe rabbit inhalational anthrax well. These results are discussed in the context of conducting laboratory studies in other relevant animal models, combining the CR/MCR model with other computation models of inhalational anthrax, and using the resulting information towards extrapolating a low-dose response prediction for man. •Data were collected from NZW rabbits exposed to high doses of B. anthracis Ames spore aerosols.•The data were modeled using the Competing Risks model of inhalational anthrax.•The low dose-response (lethality) extrapolation data agreed with known dose–response data.•The model predicted a 14.5h median low-dose germination period.•The model predicted a low-dose disease incubation period between 14.7 and 16.8 days.