A dynamic dose-response model to account for exposure patterns in risk assessment: a case study in inhalation anthrax.

The most commonly used dose-response models implicitly assume that accumulation of dose is a time-independent process where each pathogen has a fixed risk of initiating infection. Immune particle neutralization of pathogens, however, may create strong time dependence; i.e. temporally clustered pathogens have a better chance of overwhelming the immune particles than pathogen exposures that occur at lower levels for longer periods of time. In environmental transmission systems, we expect different routes of transmission to elicit different dose-timing patterns and thus potentially different realizations of risk. We present a dose-response model that captures time dependence in a manner that incorporates the dynamics of initial immune response. We then demonstrate the parameter estimation of our model in a dose-response survival analysis using empirical time-series data of inhalational anthrax in monkeys in which we find slight dose-timing effects. Future dose-response experiments should include varying the time pattern of exposure in addition to varying the total doses delivered. Ultimately, the dynamic dose-response paradigm presented here will improve modelling of environmental transmission systems where different systems have different time patterns of exposure.

Estimating the location and spatial extent of a covert anthrax release.

Rapidly identifying the features of a covert release of an agent such as anthrax could help to inform the planning of public health mitigation strategies. Previous studies have sought to estimate the time and size of a bioterror attack based on the symptomatic onset dates of early cases. We extend the scope of these methods by proposing a method for characterizing the time, strength, and also the location of an aerosolized pathogen release. A back-calculation method is developed allowing the characterization of the release based on the data on the first few observed cases of the subsequent outbreak, meteorological data, population densities, and data on population travel patterns. We evaluate this method on small simulated anthrax outbreaks (about 25-35 cases) and show that it could date and localize a release after a few cases have been observed, although misspecifications of the spore dispersion model, or the within-host dynamics model, on which the method relies can bias the estimates. Our method could also provide an estimate of the outbreak's geographical extent and, as a consequence, could help to identify populations at risk and, therefore, requiring prophylactic treatment. Our analysis demonstrates that while estimates based on the first ten or 15 observed cases were more accurate and less sensitive to model misspecifications than those based on five cases, overall mortality is minimized by targeting prophylactic treatment early on the basis of estimates made using data on the first five cases. The method we propose could provide early estimates of the time, strength, and location of an aerosolized anthrax release and the geographical extent of the subsequent outbreak. In addition, estimates of release features could be used to parameterize more detailed models allowing the simulation of control strategies and intervention logistics.

Private and public economic incentives for the control of animal diseases: the case of anthrax in livestock.

This study examined the roles of the public and private sectors as economic components of anthrax control with direct reference to the 2005 anthrax outbreak in livestock in North Dakota. Anthrax is an endemic disease in North Dakota, which often causes disease outbreaks in livestock, leading to economic losses to the livestock industry. The economic incentives and interests behind public and private control of an anthrax outbreak are investigated. Anthrax management is most effective with the participation of public and private firms. As anthrax is an infectious disease, its control also brings positive economic externalities, which are not accounted for in a producer's decision to protect animals. Therefore, public programs designed to control the disease must be implemented. The government can change producer response to anthrax by setting up policies and incentives that encourage their participation. However, these interventions must encourage compliance and not discourage producers from actively taking part in anthrax management. Producers have economy-based interests and personal reasons for controlling anthrax in their farms. The main reason behind government intervention is to provide assurance to the public who consume livestock products. Another reason is to assist producers and veterinarians, and to achieve biosecurity and biosafety objectives. The contribution of each animal healthcare partner in making anthrax management a success in North Dakota is discussed.

Is 60 days of ciprofloxacin administration necessary for postexposure prophylaxis for Bacillus anthracis?

Sixty days of ciprofloxacin administration at 500 mg every 12 h is currently recommended for the prophylaxis of inhalational exposure to Bacillus anthracis. We examined Bacillus anthracis (Delta-Sterne strain) in our hollow-fiber infection model. We measured the ciprofloxacin concentrations achieved and the number of organisms present before heat shock (total population) and after heat shock (spore population). We fit a mathematical model to these data. Monte Carlo simulation with differing initial spore burdens (3, 5, and 6.9 log(10) CFU/ml) demonstrated that 35 days of this regimen would completely clear the spore burden in 95% of patients. Durations of 110 days did not achieve 99.9% eradication, irrespective of initial burden, because of between-patient variance in drug pharmacokinetics. Given the absence of person-to-person transmission for Bacillus anthracis, adverse drug effects with long-term ciprofloxacin administration, and the possibility of engendering resistance in bodily flora, shorter prophylaxis duration should be given consideration, along with careful monitoring of all exposed individuals.

Evaluating detection of an inhalational anthrax outbreak.

Timely detection of an inhalational anthrax outbreak is critical for clinical and public health management. Syndromic surveillance has received considerable investment, but little is known about how it will perform relative to routine clinical case finding for detection of an inhalational anthrax outbreak. We conducted a simulation study to compare clinical case finding with syndromic surveillance for detection of an outbreak of inhalational anthrax. After simulated release of 1 kg of anthrax spores, the proportion of outbreaks detected first by syndromic surveillance was 0.59 at a specificity of 0.9 and 0.28 at a specificity of 0.975. The mean detection benefit of syndromic surveillance was 1.0 day at a specificity of 0.9 and 0.32 days at a specificity of 0.975. When syndromic surveillance was sufficiently sensitive to detect a substantial proportion of outbreaks before clinical case finding, it generated frequent false alarms.

Biological warfare and infection control.

Though many agents have been proposed as potential biological weapons, the feasibility of biological warfare is largely a matter of conjecture. The unpredictable and indiscriminate devastation caused by natural epidemics during wartime should warn us of the dangers of employing microbes as weapons.