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Sverdlovsk revisited: modeling human inhalation anthrax.

ABSTRACT: Several models have been proposed for the dose-response function and the incubation period distribution for human inhalation anthrax. These models give very different predictions for the severity of a hypothetical bioterror attack, when an attack might be detected from clinical cases, the efficacy of medical intervention and the requirements for decontamination. Using data from the 1979 accidental atmospheric release of anthrax in Sverdlovsk, Russia, and limited nonhuman primate data, this paper eliminates two of the contending models and derives parameters for the other two, thereby narrowing the range of models that accurately predict the effects of human inhalation anthrax. Dose-response functions that exhibit a threshold for infectivity are contraindicated by the Sverdlovsk data. Dose-dependent incubation period distributions explain the 10-day median incubation period observed at Sverdlovsk and the 1- to 5-day incubation period observed in nonhuman primate experiments.

SUBMITTER: Wilkening DA

PROVIDER: S-EPMC1564296 | biostudies-literature | 2006 May

REPOSITORIES: biostudies-literature

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Sverdlovsk revisited: modeling human inhalation anthrax.

Wilkening Dean A DA

Proceedings of the National Academy of Sciences of the United States of America 20060505 20

Several models have been proposed for the dose-response function and the incubation period distribution for human inhalation anthrax. These models give very different predictions for the severity of a hypothetical bioterror attack, when an attack might be detected from clinical cases, the efficacy of medical intervention and the requirements for decontamination. Using data from the 1979 accidental atmospheric release of anthrax in Sverdlovsk, Russia, and limited nonhuman primate data, this paper ...[more]

PMID: 16679412

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Project description:Inhalation anthrax has three clinical stages: early-prodromal, intermediate-progressive, and late-fulminant. We report the comprehensive characterization of anthrax toxins, including total protective antigen (PA), total lethal factor (LF), total edema factor (EF), and their toxin complexes, lethal toxin and edema toxin in plasma, during the course of inhalation anthrax in 23 cynomolgus macaques. The toxin kinetics were predominantly triphasic with an early rise (phase-1), a plateau/decline (phase-2), and a final rapid rise (phase-3). Eleven animals had shorter survival times, mean±standard deviation of 58.7±7.6 hours (fast progression), 11 animals had longer survival times, 113±34.4 hours (slow progression), and one animal survived. Median (lower-upper quartile) LF levels at the end-of-phase-1 were significantly higher in animals with fast progression [138 (54.9-326) ng/mL], than in those with slow progression [23.8 (15.6-26.3) ng/mL] (p = 0.0002), and the survivor (11.1 ng/mL). The differences were also observed for other toxins and bacteremia. Animals with slow progression had an extended phase-2 plateau, with low variability of LF levels across all time points and animals. Characterization of phase-2 toxin levels defined upper thresholds; critical levels for exiting phase-2 and entering the critical phase-3, 342 ng/mL (PA), 35.8 ng/mL (LF), and 1.10 ng/mL (EF). The thresholds were exceeded earlier in animals with fast progression (38.5±7.4 hours) and later in animals with slow progression (78.7±15.2 hours). Once the threshold was passed, toxin levels rose rapidly in both groups to the terminal stage. The time from threshold to terminal was rapid and similar; 20.8±7.4 hours for fast and 19.9±7.5 hours for slow progression. The three toxemic phases were aligned with the three clinical stages of anthrax for fast and slow progression which showed that anthrax progression is toxin- rather than time-dependent. This first comprehensive evaluation of anthrax toxins provides new insights into disease progression.

Dataset Information

Sverdlovsk revisited: modeling human inhalation anthrax.

Publications

Sverdlovsk revisited: modeling human inhalation anthrax.

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