There are three major anthrax syndromes: cutaneous, inhalational, and gastrointestinal anthrax. Cutaneous anthrax, which makes up 95% of naturally occurring infections, begins as a painless, pruritic papule that develops into a vesicle within 2 days.
As the vesicle enlarges, striking edema may form around it, and there is regional lymphadenopathy. After the vesicle ruptures, the remaining ulcer becomes covered with a characteristic black eschar, which dries and falls off as the patient recovers. Bacteremia is rare with cutaneous anthrax.
Inhalational anthrax occurs when spores are inhaled. The organism grows and is carried to lymph nodes by phagocytes where the spores germinate, and the release of toxins causes hemorrhagic mediastinitis.
After a prodromal illness of 1 to 6 days characterized by fever, cough, and chest or abdominal pain, there is abrupt onset of increased fever, hypoxia, and sweating. Frequently, anthrax meningitis develops due to bacteremia. Inhalational anthrax rapidly leads to shock and frequently death within 1 to 2 days.
Gastrointestinal anthrax is an uncommon form of this infection that is usually contracted by eating undercooked meat contaminated with B. anthracis. Initially, the patient has nausea, abdominal pain, and vomiting. Severe, bloody diarrhea rapidly develops, and mortality is over 50%.
Pathogeny
Anthrax lethal toxin lyses macrophages derived from certain inbred mice but not others, forming the basis of a bioassay widely used in the development of antibodies and drugs to treat anthrax.
Two genes essential for this lysis have been identified, revealing potential links between toxin-induced proteolysis and cellular killing.
B. anthracis produces potent toxins and a polyglutamyl capsule that is antiphagocytic. The anthrax toxin, produced by B. anthracis, is well understood.
The B subunit is referred to as the protective antigen because antibodies against this protein protect animals against the toxin. The protective antigen binds to a cell surface protein, and then a host protease clips off a 20-kDa fragment of the B subunit.
The remaining 63-kDa fragments associate to form a heptamer. Anthrax toxin has two alternate A subunits: edema factor (EF) and lethal factor (LF), each named for the effect of the toxin in experimental animals.
Three A subunits bind to the B heptamer, and this complex is endocytosed into the host cell. The low pH of the endosome causes a conformational change in the protective antigen heptamer, which then forms a selective channel in the endosome membrane through which EF and LF move into the cytoplasm. In the cytoplasm, EF binds to calcium and calmodulin to form an adenylate cyclase.
The active EF converts adenosine triphosphate to cyclic adenosine monophosphate (cAMP). cAMP is an important signaling molecule in cells, and elevated cAMP leads to efflux of water from the cell to form edema. LF has a different mechanism of action.
LF is a protease that destroys mitogen-activated protein kinase kinases (MAPKKs). MAPKKs regulate the activity of mitogen-activated protein kinases, which are important regulators of cell growth and differentiation (Chapter 3). The mechanism of cell death due to deregulation of mitogen-activated protein kinases is not understood.
Morphology. Anthrax lesions at any site are typified by necrosis and exudative inflammation with infiltration of neutrophils and macrophages. The presence of large, boxcar-shaped Gram-positive extracellular bacteria in chains, seen histopathologically or recovered in culture, should suggest the diagnosis.
Inhalational anthrax causes numerous foci of hemorrhage in the mediastinum with hemorrhagic, enlarged hilar and peribronchial lymph nodes. Microscopic examination of the lungs typically shows perihilar interstitial pneumonia with infiltration of macrophages and neutrophils and pulmonary vasculitis.
Hemorrhagic lesions associated with vasculitis are also present in about half of cases. Mediastinal lymph nodes show lymphocytosis, with phagocytosis of apoptotic lymphocytes by macrophages and a fibrin-rich edema.
B. anthracis is present predominantly in the alveolar capillaries and venules and, to a lesser degree, within the alveolar space. In fatal cases, B. anthracis is evident in multiple organs (spleen, liver, intestines, kidneys, adrenal glands, and meninges).
References
Boyden ED, Dietrich WF. Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat Genet. 2006 Feb;38(2):240-4. PMID: 16429160
Bugge TH, Leppla SH. Anthrax target in macrophages unveiled. Nat Genet. 2006 Feb;38(2):137-138. PMID: 16444249
Chensue SW. Exposing a killer: pathologists angle for anthrax. Am J Pathol. 2003 Nov;163(5):1699-702. PMID: 14578167