Death Due to Bioterrorism-Related Inhalational Anthrax

Borio, Luciana; Frank, Dennis; Mani, Venkat; Chiriboga, Carlos; Pollanen, Michael S.; Ripple, Mary G.; Ali, Sana; DiAngelo, Constance; Lee, Jacqueline; Arden, Jonathan; Titus, Jack M.; Fowler, David L.; O’Toole, Tara; Masur, Henry; Bartlett, John G.; Inglesby, Thomas V.

doi:10.1001/jama.286.20.2554

Cited by 171 publications

(129 citation statements)

References 2 publications

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“…3 These clinical observations strongly indicate that procoagulant and inflammatory responses coincide with bacteremia and toxemia. In the baboons, we observed a significant increase in vascular permeability coincident with hemostatic imbalances manifested by thrombocytopenia, transient leucopenia, and an aggressive DIC.…”

Section: Discussionmentioning

confidence: 91%

Sepsis and Pathophysiology of Anthrax in a Nonhuman Primate Model

Stearns-Kurosawa

Lupu

Taylor

et al. 2006

The American Journal of Pathology

103

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Studies that define natural responses to bacterial sepsis assumed new relevance after the lethal bioterrorist attacks with Bacillus anthracis (anthrax), a spore-forming, toxigenic gram-positive bacillus. Considerable effort has focused on identifying adjunctive therapeutics and vaccines to prevent future deaths, but translation of promising compounds into the clinical setting necessitates an animal model that recapitulates responses observed in humans. Here we describe a nonhuman primate (Papio c. cynocephalus) model of B. anthracis infection using infusion of toxigenic B. anthracis Sterne 34F2 bacteria (5 ؋ 10 5 to 6.5 ؋ 10 9 CFU/kg). Similar to that seen in human patients, we observed changes in vascular permeability, disseminated intravascular coagulation, and systemic inflammation. The lung was a primary target organ with serosanguinous pleural effusions, intra-alveolar edema, and hemorrhagic lesions. This animal model reveals that a fatal outcome is dominated by the host septic response, thereby providing important insights into approaches for treatment and prevention of anthrax in humans. (Am J Pathol

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Section: Discussionmentioning

confidence: 91%

Sepsis and Pathophysiology of Anthrax in a Nonhuman Primate Model

Stearns-Kurosawa

Lupu

Taylor

et al. 2006

The American Journal of Pathology

103

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“…A report of two patients who died of bioterrorism-related inhalation anthrax emphasized the need for specific diagnostic tools that can be used in the clinical setting where infection is likely to be encountered (20). Immunoassay for bacterial capsular antigens in body f luids is a proven technology.…”

Section: Discussionmentioning

confidence: 99%

mAbs toBacillus anthraciscapsular antigen for immunoprotection in anthrax and detection of antigenemia

Kozel

Murphy

Brandt

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

109

117

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Bacillus anthracis is surrounded by an antiphagocytic polypeptide capsule composed of poly ␥-D-glutamic acid (␥DPGA). ␥DPGA has been identified recently as a potential target for vaccine development. Studies of the role of ␥DPGA in disease have been hampered by the poor Ab response to this antigen and the lack of immunochemical reagents. As a consequence, neither the extent of ␥DPGA production during anthrax nor the protective activity of ␥DPGA Abs in inhalation anthrax are known. Here we report production of IgG Abs to ␥DPGA in mice following an immunization regimen using ␥DPGA in combination with agonist mAbs to CD40. mAbs were produced that are specific for ␥DPGA. Passive immunization with ␥DPGA mAbs protected >90% of mice in a pulmonary model of anthrax that was lethal in control mice (P < 0.0001). Use of ␥DPGA mAb in an antigen detection immunoassay found that the appearance of ␥DPGA in serum coincided with the emergence of bacteremia. These studies identify CD40 stimulation as a means for production of Ab and generation of mAbs against a weakly immunogenic antigen and demonstrate that the capsule is an effective target for immunoprotection and for antigen detection in the diagnosis of anthrax.

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“…INHALATIONAL Bacillus anthracis infection is a highly lethal disease and a major bioterrorism health threat today (3,10,21,22). In the recent outbreak of inhalational B. anthracis in the United States, death was complicated by progressive shock despite treatment with appropriate antibiotics and aggressive hemodynamic and pulmonary support (3,22).…”

mentioning

confidence: 99%

Lethality during continuous anthrax lethal toxin infusion is associated with circulatory shock but not inflammatory cytokine or nitric oxide release in rats

Cui¹,

Moayeri²,

Li³

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

114

172

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. Lethality during continuous anthrax lethal toxin infusion is associated with circulatory shock but not inflammatory cytokine or nitric oxide release in rats. Am J Physiol Regul Integr Comp Physiol 286: R699-R709, 2004. First published January 8, 2004 10.1152/ajpregu.00593.2003.-Although circulatory shock related to lethal toxin (LeTx) may play a primary role in lethality due to Bacillus anthracis infection, its mechanisms are unclear. We investigated whether LeTx-induced shock is associated with inflammatory cytokine and nitric oxide (NO) release. SpragueDawley rats with central venous and arterial catheters received 24-h infusions of LeTx (lethal factor 100 g/kg; protective antigen 200 g/kg) that produced death beginning at 9 h and a 7-day mortality rate of 53%. By 9 h, mean arterial blood pressure, heart rate, pH, and base excess were decreased and lactate and hemoglobin levels were increased in LeTx nonsurvivors compared with LeTx survivors and controls (diluent only) (P Յ 0.05 for each comparing the 3 groups). Despite these changes, arterial oxygen and circulating leukocytes and platelets were not decreased and TNF-␣, IL-1␤, IL-6, and IL-10 levels were not increased comparing either LeTx nonsurvivors or survivors to controls. Nitrate/nitrite levels and tissue histology also did not differ comparing LeTx animals and controls. In additional experiments, although 24-h infusions of LeTx and Esherichia coli LPS produced similar mortality rates (54 and 56%, respectively) and times to death (13.2 Ϯ 0.8 vs. 11.0 Ϯ 1.7 h, respectively) compared with controls, only LPS reduced circulating leukocytes, platelets, and IL-2 levels and increased TNF-␣, IL-1␣ and -1␤, IL-6, IL-10, interferon-␥, granulocyte macrophage-colony stimulating factor, RANTES, migratory inhibitory protein-1␣, -2, and -3, and monocyte chemotactic protein-1, as well as nitrate/nitrite levels (all P Յ 0.05 for the effects of LPS). Thus, in contrast to LPS, excessive inflammatory cytokine and NO release does not appear to contribute to the circulatory shock and lethality occurring with LeTx in this rat model. Although therapies to modulate these host mediators may be applicable for shock caused by LPS or other bacterial toxins, they may not with LeTx.

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Death Due to Bioterrorism-Related Inhalational Anthrax

Cited by 171 publications

References 2 publications

Sepsis and Pathophysiology of Anthrax in a Nonhuman Primate Model

Sepsis and Pathophysiology of Anthrax in a Nonhuman Primate Model

mAbs toBacillus anthraciscapsular antigen for immunoprotection in anthrax and detection of antigenemia

Lethality during continuous anthrax lethal toxin infusion is associated with circulatory shock but not inflammatory cytokine or nitric oxide release in rats

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