eMedicine - Anthrax : Article by Burke A Cunha, MD, MACP

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Anthrax

Last Updated: May 2, 2006

Synonyms and related keywords: anthrax, malignant pustule, woolsorter's disease, black bane, charbon, murrain, black blood

AUTHOR INFORMATION Section 1 of 10

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Author: Burke A Cunha, MD, MACP, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Burke A Cunha, MD, MACP, is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America

Editor(s): Douglas A Drevets, MD, Assistant Professor, Department of Medicine, Section of Infectious Disease, Oklahoma University Health Sciences Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Michael Stuart Bronze, MD, Professor, Stewart G Wolf Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Eleftherios Mylonakis, MD, PhD, Assistant Professor of Medicine, Harvard Medical School, Assistant in Medicine, Division of Infectious Disease, Massachusetts General Hospital; and Michael E Zevitz, MD, Assistant Professor of Medicine, Finch University of the Health Sciences, The Chicago Medical School; Consulting Staff, Private Practice

Disclosure

INTRODUCTION

Section 2 of 10

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Background: Anthrax is described in the early literature of the Greeks, Romans, and Hindus. The fifth plague described in the book of Genesis may be among the earliest descriptions of anthrax.

Most of the terms associated with anthrax relate to cutaneous or respiratory anthrax. Cutaneous anthrax results from exposure to the spores of Bacillus anthracis after handling sick animals or contaminated wool, hair, or animal hides. Pulmonary anthrax results from inhaling anthrax spores. Intestinal anthrax results from ingesting meat products that contain anthrax. Anthrax is present in animal grazing areas, particularly those of herbivores.

Pathophysiology: Anthrax primarily is a disease of herbivores (eg, cattle, sheep, goats, horses). Pigs are not immune, but they are more resistant, as are dogs and cats. Birds usually are naturally resistant to anthrax. Buzzards and vultures are naturally resistant to anthrax but may transmit the spores on their talons and beaks.

Humans are relatively resistant to cutaneous invasion by B anthracis, but the organisms may gain access through microscopic or gross breaks in the skin. In cutaneous anthrax, a "malignant pustule" develops at the site of the infection. This pustule is a central area of coagulation necrosis (ulcer) surrounded by a rim of vesicles filled with bloody or clear fluid. A black eschar forms at the ulcer site. Extensive edema surrounds the lesion. The organisms multiply locally and may spread to the bloodstream or other organs (eg, spleen) via the efferent lymphatics. Dissemination from the liver, spleen, and kidneys back into the bloodstream may result in bacteremia. In bacteremic anthrax, hemorrhagic lesions may develop anywhere on the body. Bacteremic anthrax with hematogenous spread most commonly follows inhalational anthrax.

B anthracis remains in the capillaries of invaded organs, and the local and fatal effects of the infection result, in large part, to the toxins elaborated by B anthracis. Anthrax in the spore stage can exist indefinitely in the environment. Optimal growth conditions result in a vegetative phase and bacterial multiplication. Secondary hemorrhagic intestinal foci of anthrax result from B anthracis bacteremia.

Primary intestinal anthrax predominantly affects the cecum and produces a local lesion not unlike the lesion that results from the cutaneous form. Oropharyngeal anthrax is a variant of intestinal anthrax and occurs in the oropharynx after ingesting meat products contaminated by anthrax. Oropharyngeal anthrax is characterized by throat pain and difficulty in swallowing. The lesion at the site of entry into the oropharynx resembles the cutaneous ulcer.

Inhalational anthrax occurs after inhaling spores into the lungs. Spores are ingested by alveolar macrophages and are carried to the mediastinal lymph nodes. Anthrax in the lungs does not cause pneumonia, but it does cause hemorrhagic mediastinitis and pulmonary edema. Hemorrhagic pleural effusions frequently accompany inhalational anthrax.

Anthrax meningitis may occur after bacteremic seeding from any form of anthrax.

Septicemic anthrax refers to overwhelming infection resulting from bloodstream invasion secondary to inhalational or intestinal anthrax. Death from anthrax occurs as a result of the effects of lethal toxins. Near death or just after death, animals bleed from all body orifices.

Frequency:

In the US: Natural incidence is rare, but infection is an occupational hazard for veterinarians, farmers, and individuals who handle animal wool, hair, hides, or bone meal products.

Internationally: Anthrax is uncommon in western Europe, but the disease is not uncommon in the Middle East, the Indian subcontinent, Africa, Asia, and Latin America. Anthrax used in bioterrorism (ie, weapon-grade anthrax) may be dispersed as an aerosol for mass effect or by focal spore contamination via letters or packages.

Mortality/Morbidity: Most cases are cutaneous anthrax, are mild, and resolve with/without treatment. However, other forms of anthrax are potentially fatal.

Septicemic anthrax and inhalational anthrax have the highest mortality. Inhalational anthrax is a rapid fulminating disease that nearly always is fatal with or without antibiotic therapy (mortality rate >90%).

Cutaneous anthrax is readily curable if treated early with appropriate antibiotics (mortality rate <1%).

Intestinal anthrax is difficult to diagnose and is associated with higher morbidity (mortality rate 20-60%).

Race:

No racial predilection for, or protection from, anthrax exists.

Sex:

No sex predilection exists.

Age:

No age predilection exists, but because anthrax often is related to industrial exposure and farming, the disease most often affects young-to-middle-aged adults.

Persons of any age can be affected if anthrax is used as a bioterrorist weapon.

CLINICAL

Section 3 of 10

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History:

Cutaneous anthrax

Cutaneous anthrax occurs 1-7 days (usually 2-5) after skin exposure and penetration of B anthracis spores.

This form most commonly affects the exposed areas of the upper extremities and, to a lesser extent, the head and neck.

Hematogenous dissemination occurs in 5-10% of untreated cases.

Oropharyngeal anthrax

Ingestion of B anthracis spores may result in oropharyngeal anthrax 2-7 days after exposure.

Patients with oropharyngeal anthrax may complain of unilateral sore throat/difficulty swallowing.

Intestinal anthrax

Ingesting B anthracis spores may cause intestinal anthrax 2-5 days following ingestion.

Patients with intestinal anthrax complain of nausea, vomiting, malaise, anorexia, abdominal pain, hematemesis, and bloody diarrhea, which are accompanied by fever.

Inhalational anthrax

Inhalational anthrax begins abruptly, 1-60 days (usually 1-3 d) after inhaling large concentrations (8000-10,000) of anthrax spores 1-5 mm in diameter.

As evidenced by the recent US anthrax cases, it appears that fewer spores of weapon-grade anthrax may be required to cause inhalational anthrax.

This form presents initially with nonspecific symptoms, including a low-grade fever and a nonproductive cough.

Patients may complain of substernal discomfort early in the illness.

Patients may improve temporarily before rapidly deteriorating clinically with hemorrhagic mediastinitis.

After initial improvement, inhalational anthrax progresses rapidly with high fever, severe shortness of breath, tachypnea, cyanosis, profuse diaphoresis, hematemesis, and chest pain, which may be so severe as to mimic an acute myocardial infarction.

Septicemic anthrax

Septicemic anthrax refers to overwhelming infection by anthrax bacilli and may complicate inhalational anthrax.
Internal organs become darkly colored with widespread petechiae and hemorrhage.
The anthrax bacilli multiply in the blood and achieve numbers in excess of the red blood cells present. Another name for anthrax is black blood, which refers to the very dark color of the blood of animals or humans with overwhelming septicemic anthrax.
Because humans are relatively resistant to invasion by B anthracis, most cases of septicemic anthrax occur following inhalational anthrax. The number of organisms released from the liver or spleen into the bloodstream overwhelms host defenses and produces massive amounts of lethal toxin that result in shock and death.

Anthrax meningitis: Anthrax meningitis may complicate any form of anthrax, with bacteremia and hematogenous spread to the CNS.

Physical:

Cutaneous anthrax

Cutaneous anthrax begins as a pruritic papule that enlarges in 24-48 hours to form an ulcer surrounded by a satellite bulbus/lesion edematous halo. The cutaneous anthrax lesion usually measures approximately 2-3 cm in diameter and has a round, regular, and raised edge.

Regional lymphadenopathy of the nodes draining the infected area may occur.

The cutaneous anthrax ulcer characteristically is pruritic but not painful. The adenopathy associated with cutaneous anthrax may be painful.

The membrane/exudate of the ulcer contains numerous anthrax bacilli.

The anthrax ulcer and surrounding edema evolve into a black eschar in 7-10 days and last for 7-14 days before separating and leaving a permanent scar. The edema surrounding the ulcer may persist through the eschar stage.

Lymphadenopathy associated with cutaneous anthrax may persist long after disappearance of the ulcer/eschar.

If the lesions of cutaneous anthrax affect the neck, neck swelling resulting from edema and enlarged cervical lymph nodes may impinge on the trachea and cause stridor and respiratory distress and, if severe, may be accompanied by asphyxiation.

Oropharyngeal anthrax

Oropharyngeal anthrax is the proximal GI manifestation of intestinal anthrax. Mouth lesions may affect the hard palate or pharyngeal walls.

The anthrax ulcer in the oropharynx may be accompanied by a membrane and is associated with local edema and cervical adenopathy.

Death may result from asphyxiation due to neck edema or toxemia.

Intestinal anthrax

Patients with intestinal anthrax may have severe abdominal pain, hematemesis, or bloody diarrhea.

Multiple anthrax ulcerative lesions are found throughout the GI tract secondary to hematogenous spread.

Primary intestinal anthrax has a local lesion resembling the ulcer of oropharyngeal anthrax.

Intestinal anthrax is difficult to recognize, and shock and death may occur 2-5 days after onset.

Inhalational anthrax

Chest percussion or radiographs reveal a widened mediastinum.
Obtain a chest CT scan or MRI as soon as possible in patients with a flulike illness and substernal discomfort.
Pulmonary infiltrates are not present because inhalational anthrax presents as hemorrhagic mediastinitis, not pneumonia, which may be associated with bloody pleural effusions.
Inhalational anthrax usually is fatal; the patient succumbs to shock and to the effects of lethal toxin.

Septicemic anthrax: This is the most severe form and may complicate any other form of anthrax, particularly inhalational anthrax.
Anthrax meningitis
- Cerebrospinal fluid (CSF) anthrax is distinguished by hemorrhagic leptomeningitis.
- Anthrax is present in other locations of the body, and patients develop hemorrhagic leptomeningitis (Cardinal's cap).

Causes: Anthrax is caused by B anthracis, a gram-positive bacillus. B anthracis measures 1 by 3 mm and usually is straight but may be slightly curved. The ends of the bacilli are truncated, not rounded. Anthrax bacilli tend to form into long chains and may appear similar to streptobacilli when cultured. B anthracis produces a capsule that is easily visualized using a methylene blue or India ink stain. Ground-glass–appearing colonies are adherent and gray/white in color on blood agar. B anthracis is catalase-positive. Bacilli grow optimally in an atmosphere of enhanced carbon dioxide and are nonmotile. Capsule formation may help differentiate B anthracis and other nonpathogenic bacilli.

The most important presumptive test for B anthracis is the lack of motility in broth and hemolysis on blood agar.

Table 1. Microbiological Differences Between B anthracis and Non-B anthracis Bacilli

B anthracis Non-B anthracis bacilli (pseudoanthrax bacilli)

� Nonmotile long chains � Generally motile short chains

� Capsule formation on bicarbonate agar � No capsule formation in bicarbonate

� No growth on penicillin agar
(10 mcg/mL) � Usually good growth on penicillin agar

� Growth in gelatin resembles inverted fir tree � Growth in gelatin absent or resembles atypical fir tree

� Gelatin liquefaction slow � Gelatin liquefaction usually rapid

� No hemolysis of sheep RBCs � Hemolysis of sheep RBCs

� Ferments salicin slowly or not at all � Usually ferments salicin rapidly

� Pathogenic to laboratory animals � Nonpathogenic to laboratory animals

Adapted from Cunha CB: Anthrax: Ancient Plague, Persistent Problem. Infectious Disease Practice 1999; 23(4):35-9.

Table 2. Toxins and Protein Toxins of B anthracis

PA = Protective antigen
EF = Edema factor
LF = Lethal factor
EF + LF = Host cell penetration by B anthracis
EF + PA = Edema toxin
LF + PA = Lethal toxin (primary virulence factor of B anthracis)
Edema toxin + lethal toxin = Inhibited polymorphonuclear function and phagocytosis

Anthrax exotoxins are produced in the vegetative phase and are composed of proteins. Lethal toxin is the single most important virulence factor and is the primary cause of death. Lethal toxin is a combination of PA and LF. EF and lethal toxin inhibit phagocytosis and polymorphonuclear (PMN) function.

The other major anthrax virulence factor is its antiphagocytic poly-D-glutamic acid capsule.

DIFFERENTIALS Section 4 of 10

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Other Problems to be Considered:

Cutaneous anthrax

Physicians must differentiate cutaneous anthrax and bubonic plague or lymphocutaneous tularemia. Patients with plague have painful adenopathy, usually in the groin or axilla. No ulcer is present, and ulcer edema and eschar characteristic of anthrax are absent. Patients with bubonic plague appear more toxemic than patients with uncomplicated cutaneous anthrax. Patients with anthrax have an appropriate history of contact with animal products. In contrast, patients with bubonic plague have a history of contact with infected cats that may be in contact with sylvatic rodents in plague-endemic areas. Patients with bubonic plague also may provide a history of contact with armadillos or infected prairie dogs in the western United States.

Ulceroglandular tularemia and primary syphilis

Ulceroglandular tularemia is characterized by purple ulcerative lesions that are painful, not pruritic, and not surrounded by a gelatinous edematous halo. Patients with anthrax, tularemia, or plague may complain of headache and have fever associated with shaking chills. The chancre of primary syphilis also may be confused with cutaneous anthrax. The chancre of primary syphilis is painless, as is the lesion of cutaneous anthrax, but the syphilitic chancre is not pruritic and is not surrounded by an edematous halo. Generalized rather than local adenopathy accompanies syphilis, which is the opposite of what is expected with cutaneous anthrax. Exudates from the ulcers of both ulceroglandular tularemia and cutaneous anthrax reveal organisms when properly stained. The ulcer of syphilis does not reveal organisms, but Treponema pallidum may be visualized using dark-field examination.

Inhalational anthrax

Do not confuse inhalational anthrax with the zoonotic atypical pneumonias. Pulmonary tularemia usually presents as a community-acquired pneumonia with bilateral hilar adenopathy and bloody pleural effusion. The primary clinical manifestation of inhalational anthrax is hemorrhagic mediastinitis with bloody pleural effusions. No pulmonary infiltrate is present, and a widened mediastinum is observed on early chest CT scans. Mediastinitis very closely resembles inhalational anthrax on chest radiographs, but their clinical presentations are different.

Bacterial mediastinitis is a serious infectious process usually secondary to thoracic surgery or esophageal perforation. The initial phase of inhalational anthrax may resemble bacterial mediastinitis, but it is associated with hemoptysis, severe substernal chest pain, and shock, which is very different from bacterial mediastinitis. Patients with bacterial mediastinitis give a history of previous esophageal tear or may have recently had a thoracic surgical procedure, which can result in mediastinitis. Patients with inhalational anthrax have a history of exposure to inhaling anthrax spores.

Intestinal anthrax

Intestinal anthrax is a difficult diagnosis that must be distinguished from dysentery. Dysentery may present with bloody diarrhea, as does intestinal anthrax, and may be accompanied by abdominal pain (ie, in cases of Shigella or amebic dysentery). A history of ingesting meat possibly contaminated with anthrax is helpful if suspecting intestinal anthrax. In tropical areas where bacillary and amebic dysentery are common, clinically differentiating intestinal anthrax and these endemic causes of dysentery is very difficult unless a cluster of dysentery cases or an outbreak is known to exist. Stool examination rapidly rules in bacillary or amebic dysentery. Stools negative for amebic cysts or trophs and for Shigella suggest the possibility of intestinal anthrax in patients residing near areas where anthrax is endemic (ie, in pastures where herbivores graze) or after ingestion of spores from hand/food contact.

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WORKUP

Section 5 of 10

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Lab Studies:

The preferred diagnostic procedure for cutaneous anthrax is staining the ulcer exudate with methylene blue or Giemsa stain. B anthracis readily grows on blood agar, and staining will microbiologically differentiate the organism and nonanthracis bacilli species. Warn laboratory personnel that contracting anthrax from specimens is a possibility and that they must take appropriate biohazard (level II) precautions.

In patients with cutaneous anthrax who have fever and systemic symptoms that suggest extracutaneous spread, blood culture may be indicated. Treat blood cultures as biohazard II specimens.

Imaging Studies:

If inhalational anthrax is suspected, obtain a chest radiograph or CT scan. The appearance on chest x-ray/CT scan may suggest the diagnosis, especially if other predisposing disorders that might result in a widening mediastinum (eg, dissecting aortic aneurysm, bacterial mediastinitis) are absent.

Other Tests:

B anthracis is present in high numbers in the ulcer/eschar of cutaneous anthrax, bloody pleural fluid, the CSF in anthrax meningitis, or the blood in septicemic anthrax. Specimens may be stained/cultured to demonstrate the organism. Culture on sheep blood or peptone agar.

The diagnosis of cutaneous anthrax usually is suggested by the characteristic appearance of skin lesions.

Enzyme-linked immunosorbent assay (ELISA) serological diagnosis also is available. The ELISA measures titers to edema and lethal toxins, and the test is positive if a single acute-phase titer is highly elevated or if a 4-fold greater rise in the titer is observed between acute and convalescent specimens.

Procedures:

If anthrax meningitis is suspected, perform a lumbar puncture to obtain CSF for stain and culture. The CSF is grossly hemorrhagic with few PMN neutrophils and numerous gram-positive bacilli. Again, advise laboratory personnel to handle specimens with biohazard level II precautions.

Histologic Findings: The characteristic finding in anthrax is the presence of the organisms in the capillaries at the infection site; therefore, if a patient is infected, expect B anthracis in the capillaries of the skin, intestines, liver, spleen, lungs, or leptomeninges.

Pathological findings are not in proportion to the numbers of bacilli present, which is best explained by the effects of one or more of the toxins associated with B anthracis.

The histology of inhalational anthrax is that of hemorrhagic mediastinitis, with few, if any, PMN neutrophils. No endobronchial ulcers/eschars are present.

TREATMENT Section 6 of 10

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Medical Care:

The preferred agent used to treat anthrax is penicillin. Penicillin is the preferred agent to treat inhalational anthrax/anthrax meningitis. Use meningeal doses for inhalational anthrax because meningitis often is present as well.

Ampicillin (meningeal doses), doxycycline, and chloramphenicol penetrate the CSF, which is important in meningeal anthrax.

Doxycycline also is a preferred agent. With doxycycline, a loading regimen should be used (200 mg PO/IV q12h for 72 h). In severely ill patients, 200 mg IV q12h may be continued (without toxicity) for the duration of therapy.

Oral doxycycline and quinolones have excellent bioavailability; the same blood/tissue levels are obtained with PO and IV therapy.
No previous clinical experience exists with using quinolones (eg, ciprofloxacin) in human anthrax.
Use any quinolone for patients unable to take penicillin or doxycycline.
Treatment ordinarily continues for 1-2 weeks.

Postexposure prophylaxis to prevent inhalation anthrax should be continued for 60 days.
Use amoxicillin, doxycycline, or any quinolone (eg, ciprofloxacin, levofloxacin, gatifloxacin) for postexposure prophylaxis to prevent inhalation anthrax.

Prophylaxis is continued for 60 days to prevent inhalation anthrax from any anthrax exposure.
Other antibiotics that may be useful include erythromycin, first-generation cephalosporins, chloramphenicol, clindamycin, vancomycin, carbapenems, cefoperazone, and extended-spectrum penicillins or trimethoprim-sulfamethoxazole (TMP-SMX).
Avoid aztreonam and second-generation and third-generation cephalosporins (except cefoperazone).
No reason exists for instituting double-drug coverage against B anthracis, which is a very sensitive organism.
Clindamycin may be used to treat anthrax or may be added to another antianthrax antibiotic because of its potential antianthrax exotoxin properties.

Consultations: Obtain consultation with an infectious disease specialist for any patient with suspected anthrax.

MEDICATION Section 7 of 10

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The goals of pharmacotherapy are to eradicate the infection, reduce morbidity, and prevent complications.

Further Inpatient Care:

With cutaneous anthrax, 80% of patients who are not treated recover. However, a fatal outcome is the rule in inhalational, meningeal, or septicemic anthrax.

Antimicrobial therapy renders lesions culture-negative within hours, but the lethal effects of anthrax are related to the effects of the organism's toxin.

Perform a tracheostomy on patients with anthrax involving the head or neck who have respiratory compromise. This procedure ensures the patient has an adequate airway.

Treat patients with hemorrhagic mediastinitis and pulmonary edema resulting from inhalational anthrax who are on a ventilator with cardiopulmonary supportive measures and appropriate antimicrobial therapy.

In/Out Patient Meds:

Treat patients with cutaneous anthrax as outpatients, using oral doxycycline.

Alternatively, any quinolone can be used for a total course of 7-14 days.

Deterrence/Prevention:

Anthrax vaccine

A vaccine exists but is not readily available.

Administer human anthrax vaccine in a dose of 0.5 mL subcutaneously, and repeat at 2 weeks and at 1, 6, 12, and 18 months following the initial immunization.

Administer a booster of 0.5 mL of human anthrax vaccine annually. Administer to individuals who have exposure to anthrax-containing animals or animal products.

Assess the efficacy of the vaccine using the anthracin skin test.

Chemoprophylaxis

To prevent infection from aerosolized spores of B anthracis, use amoxicillin or doxycycline chemoprophylaxis 60 days postexposure.

Alternatively, any quinolone may be used for postexposure chemoprophylaxis.

Complications:

Patients with cutaneous anthrax have a persistent circular scar at the point of eschar formation.

Patients with inhalational, oropharyngeal, or cutaneous (neck) anthrax may develop an airway obstruction.

Patients with septicemic anthrax may develop overwhelming toxicity or shock.

Patients with inhalational anthrax also often develop hemorrhagic leptomeningitis.

Prognosis:

If treated early, patients with cutaneous anthrax have a good prognosis.

Patients with inhalational anthrax have the worst prognosis.

The prognosis for patients with oropharyngeal or intestinal anthrax is not as favorable as the prognosis for patients with cutaneous anthrax but is more favorable than for patients with inhalational anthrax.

Patient Education:

For excellent patient education resources, visit eMedicine's Bioterrorism and Warfare Center. Also, see eMedicine's patient education articles Biological Warfare, Anthrax, and Personal Protective Equipment.

PICTURES

Section 9 of 10

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Anthrax excerpt