Human Dose–Response Data for Francisella tularensis and a Dose‐ and Time‐Dependent Mathematical Model of Early‐Phase Fever Associated with Tularemia After Inhalation Exposure

Abstract

Military health risk assessors, medical planners, operational planners, and defense system developers require knowledge of human responses to doses of biothreat agents to support force health protection and chemical, biological, radiological, nuclear (CBRN) defense missions. This article reviews extensive data from 118 human volunteers administered aerosols of the bacterial agent Francisella tularensis, strain Schu S4, which causes tularemia. The data set includes incidence of early-phase febrile illness following administration of well-characterized inhaled doses of F. tularensis. Supplemental data on human body temperature profiles over time available from de-identified case reports is also presented. A unified, logically consistent model of early-phase febrile illness is described as a lognormal dose-response function for febrile illness linked with a stochastic time profile of fever. Three parameters are estimated from the human data to describe the time profile: incubation period or onset time for fever; rise time of fever; and near-maximum body temperature. Inhaled dose-dependence and variability are characterized for each of the three parameters. These parameters enable a stochastic model for the response of an exposed population through incorporation of individual-by-individual variability by drawing random samples from the statistical distributions of these three parameters for each individual. This model provides risk assessors and medical decisionmakers reliable representations of the predicted health impacts of early-phase febrile illness for as long as one week after aerosol exposures of human populations to F. tularensis.

Using mixture density networks to emulate a stochastic within-host model of Francisella tularensis infection

“…Beginning in the 1950s, Operation Whitecoat was a vaccine research program investigating the human response to potential biothreat agents, including F. tularensis [ 23 ]. During this program, human volunteers were exposed by inhalation to the highly infectious Schu S4 strain and observed for symptoms associated with pneumonic tularemia [ 24 ].…”

“…For the 118 individuals that were exposed to F. tularensis , McClellan et al . provides records of whether or not they developed febrile illness [ 23 ]. At doses above 46 CFUs, febrile illness was observed in all individuals, suggesting that the majority of the data-set is redundant when considering the dose-response relationship.…”

“…febrile illness [23]. At doses above 46 CFUs, febrile illness was observed in all individuals, suggesting that the majority of the data-set is redundant when considering the dose-response relationship.…”

“…The only exception to this is the one individual who, despite being exposed to a high initial dose, did not develop symptoms until a week later. As a comparison, the 95% confidence regions from a statistical model by McClellan et al are also provided [23]. In this model, the logarithm of the incubation time is assumed to follow a Gaussian distribution with constant variance and a mean that is a decreasing function of dose.…”

Mediastinale Lymphadenopathie – Tuberkulose oder Tularämie?

“…Die Hasenpest genannte Zoonose wird von infizierten Hasen, Kaninchen und kleinen Nagetieren übertragen [1]. Die Übertragung erfolgt direkt durch Kontakt mit infizierten Tieren oder indirekt durch Stiche von Zecken oder Mücken [2], durch die Ingestion von kontaminiertem Wasser oder frisch gepresstem Traubenmost [3] oder durch die Inhalation von kontagiösem Staub [4]. Infektionsdosis sind 10 -50 Erreger bei Inhalation oder intrakutaner Inokulation [5].…”