About Anthrax

Anthrax

Anthrax is a disease caused by Bacillus anthracis.1,2 While it is primarily a disease of animals, cases of anthrax in humans occur through contact with infected animals or animal products or through intentional spread of B. anthracis spores as a biowarfare or bioterrorism agent.

The Threat of Anthrax

Anthrax is regarded as a top (“Category A”) biological warfare and bioterrorism threat for a number of reasons:1,3-4

The causative agent, B. anthracis, is widely available. The spores are hardy and tolerant to temperature, humidity, and light.
Techniques for mass production and aerosol dissemination of anthrax have been developed.
Multi-drug resistant (MDR) B. anthracis is recognized by Public Health Emergency Medical Countermeasures Enterprise as a high-priority threat5.
B. anthracis has been used in the past as a biological weapon.

To prepare for the possibility of the use of B. anthracis as a biological weapon, the US government acquires and maintains equipment and medical countermeasures for anthrax treatment and prevention as part of CDC’s Strategic National Stockpile (SNS).4,6 The SNS is a national repository of large quantities of medicines, vaccines, and other medical supplies stored in strategic locations around the nation. These assets are designed to supplement state and local public health departments in the event of a large-scale public health emergency that causes local supplies to run out. Medical countermeasures for anthrax maintained in the SNS include antibiotics, antitoxins, and vaccines. Antitoxins would be expected to maintain their effectiveness in case of antibiotic resistance.7,8

Transmission and Spread of Anthrax

B. anthracis spores introduced through the lungs lead to inhalational anthrax.9

Inhalational anthrax is particularly deadly in humans.9 Untreated, the mortality rate exceeds 90%.10 Despite the medical care administered to victims of the 2001 attacks in the US, which included multidrug regimens, pleural fluid drainage, and intensive care support, the associated fatality rate was approximately 45%.11,12 ‬‬‬‬‬‬‬‬

Symptoms of Inhalational Anthrax

The median incubation period is 10 days (range 2 – 43 days).2,13 The disease develops in two phases; initially, patients experience a period of flu-like symptoms with a median duration of 3.9 days (range, 3.5 to 4.4 days).11 Nonspecific symptoms reported in this phase include fever, malaise, sweats, cough, dyspnea, altered mental state, nausea and vomiting, headache, and muscle aches.1 A transition to severe illness follows abruptly, with high fever, dyspnea, diaphoresis, and shock.2

Chest imaging reveals widening of the mediastinum, mediastinal lymphadenopathy, infiltrates, and pleural effusions.1 Because the progression from non-specific to severe, life-threatening symptoms is rapid, the treatment window for inhalational anthrax is brief.

Stage 1

Anthrax Toxin Production

Following infection, Bacillus anthracis produces anthrax toxin, which consists of protective antigen (PA83), lethal factor (LF), and edema factor (EF).

Stage 2

Receptor Binding & Activation

PA83 binds to anthrax toxin receptors (ATR) on host cells and is cleaved by cellular furin, releasing PA20 and generating the active PA63 fragment.

Stage 3

Pore Formation

Cell-bound PA63 assembles into a heptameric complex that creates a pore, enabling toxin components to enter the cell.

Stage 4

Cellular Entry

PA63 binds lethal factor (LF) and edema factor (EF), facilitating endocytosis and delivery of these toxin components into the intracellular environment.

Stage 5

Cellular Damage

LF disrupts cellular signaling pathways by cleaving MAP kinase kinases (MAPKKs), while EF elevates intracellular cAMP levels, increasing membrane permeability and contributing to edema.

About Anthrax

How it Works

Anthrax toxin mediated cell death and edema

Treatment

Hospitalization is warranted for all patients with suspected inhalational anthrax.9 The CDC guidance for treatment is summarized here.
Antibiotics target B. anthracis but have no direct effect on toxins that have been released, or the systemic damage they cause. Antitoxins are a class of FDA-approved drugs that complement antibiotics for anthrax treatment by preventing toxins from entering cells and exerting their deleterious effects.

Prevention

Pre-exposure prophylaxis: Currently, FDA-approved options for the pre-exposure prevention of anthrax include a vaccine and antitoxins (immediate prophylaxis only).
Post-exposure prophylaxis: For persons who may have been exposed to aerosolized B. anthracis spores but are not showing signs or symptoms of anthrax infection, recommended post-exposure prophylaxis includes antimicrobial therapy or vaccine administration combined with antimicrobial therapy. When alternative therapies are not available, appropriate antitoxins can be used. In this situation, antitoxins would be expected to maintain their treatment effectiveness by preventing toxin formation.

References

1 Turnbull, PC. Anthrax in humans and animals, 4th ed. Geneva, Switzerland: World Health Organization. 2008.

2 Inglesby TV, O’Toole T, Henderson DA, et al. Anthrax as a biological weapon, 2002: updated recommendations for management. JAMA 2002;287:2236–52.

3 CDC Bioterrorism agents. http://fas.org/biosecurity/resource/documents/CDC_Bioterrorism_Agents.pdf. Accessed January 22, 2016.

4 Bower WA, Hendricks K, Pillai S, Guarnizo J, Meaney-Delman D. Clinical Framework and Medical Countermeasure Use During an Anthrax Mass-Casualty Incident. MMWR Recomm Rep. 2015 Dec 4;64(4):1-22. doi: 10.15585/mmwr.rr6404a1.

5 2015 Public Health Emergency Medical Countermeasures Enterprise Strategy and Implementation Plan. US Department of Health and Human Services. http://www.phe.gov/Preparedness/mcm/phemce/Documents/2015-PHEMCE-SIP.pdf. Accessed January 13, 2016.

6 DSNS Fact Sheet. 2014. Accessed December 14, 2015.

7 Froude JW, Thullier P, Pelat T. Antibodies against anthrax: mechanisms of action and clinical applications. Toxins. 2011; 3(11):1433-1452.

8 IOM (Institute of Medicine). 2012. Prepositioning antibiotics for anthrax. Washington, DC: The National Academies Press.

9 Hendricks KA, Wright ME, Shadomy SV, Bradley JS, Morrow MG, Pavia AT, et al. Centers for Disease Control and Prevention expert panel meetings on prevention and treatment of anthrax in adults. Emerg Infect Dis [Internet]. 2014 Feb [Accessed December 14, 2015]. http://dx.doi.org/10.3201/eid2002.130687

10 Barr JR, Boyer AE, Quinn CP. Anthrax: modern exposure science combats a deadly, ancient disease. J Expo Sci Environ Epidzemiol. 2010;20(7):573-4. doi: 10.1038/jes.2010.49.

11 Holty JE, Bravata DM, Liu H, et al. Systematic review: a century of inhalational anthrax cases from 1900 to 2005. Ann Intern Med 2006;144:270–80.

12 Jernigan DB, Raghunathan, PL, Bell, BP, et al. Investigation of bioterrorism-related anthrax, United States, 2001: epidemiologic findings. Emerg Infect Dis. 2002;8:1019-28.

13 Brookmeyer R, Johnson E, Barry S. Modelling the incubation period of anthrax. Stat Med. 2005;28:531–542