BASICS
DESCRIPTION
- A highly infectious disease caused by the bacteria Bacillus anthracis that primarily infects ruminant animals (cows, goats, and sheep). Cutaneous (95% of United States cases), inhalational, and GI forms cause human disease.
- Synonym(s) for cutaneous anthrax: charbon; malignant pustule; Siberian ulcer; malignant edema; splenic fever; Milzbrand
- Synonym(s) for inhalational anthrax: ragpicker disease; woolsorter disease
EPIDEMIOLOGY
- Total of 235 anthrax cases (224 cutaneous and 11 inhalational) occurred in the United States between 1955 and 1994, resulting in 20 fatalities.
- Cutaneous: 95% of cases in the United States; cutaneous anthrax without appropriate exposure risk raises concern for bioterrorism.
- 5-20% of untreated cases result in death; case fatality rate is <1% with antibiotic therapy.
- GI: very rare in the United States
- Mortality rate is estimated to be 25-60%.
- Inhalational anthrax is rare in the United States; in absence of occupational exposures to animal hides or products, U.S. cases of inhalational anthrax should be considered a bioterrorist event until proven otherwise.
- 99% of untreated cases result in death. Fatality rates are still 45-80% in patients with severe symptoms who are treated in state-of-the-art medical facilities.
- From October to November 2001, 11 cases of inhalational anthrax and 11 cases of cutaneous anthrax resulted from the bioterrorist release of B. anthracis along the east coast of the United States.
- "Injectional anthrax"Ł B. anthracis as a pharmaceutical contaminant; >50 recognized cases occurred in the United Kingdom between December 2009 and December 2010, with 33% fatality rate.
- Anthrax is most common in agricultural regions of the Middle East, Asia, Southern and Eastern Europe, Africa, South and Central America, and the Caribbean.
ETIOLOGY AND PATHOPHYSIOLOGY
- B. anthracis is a soil-based, spore-forming, gram-positive bacterium found worldwide. Anthracis derived from Greek word for "coal,"Ł describing characteristic black cutaneous lesions.
- B. anthracis has three known virulence factors: an antiphagocytic capsule and two protein toxins (edema factor and lethal factor)
- The capsule provides resistance to phagocytosis.
- A protective antigen protein binds to host cell surface. After protease cleavage, a binding site is created for lethal factor and edema factor; protective antigen is required for the action of these two protein toxins.
- B. anthracis spores are phagocytosed at the exposure site by macrophages where they germinate into vegetative forms and produce virulence factors.
- Cutaneous anthrax occurs when B. anthracis enters the skin through a cut or abrasion during the handling of infected animal products (e.g., meat, wool,hides)
- GI: ingestion of contaminated meat
- Inhalational: inhalation of aerosolized spores (1 to 2 ╬╝ diameter)
RISK FACTORS
- Contact with infected animals/animal products
- Bioweapon/bioterrorism: military, mail handlers, response workers
- Travelers to endemic areas with appropriate exposure
- Drug users
GENERAL PREVENTION
- Vaccine protects against all forms of anthrax. The vaccine causes minimal local reactions, no long-term sequelae, and is effective against naturally occurring and biologically engineered strains (1)[A].
- Vaccine has been established as safe by the FDA, the CDC, and the National Academy of Sciences.
- Vaccine schedule: 5 IM doses at 0, 4 weeks; and 6, 12, and 18 months with annual boosters. IM (vs. SC) route reduces the incidence of local adverse events.
- Anthrax vaccine adsorbed (BioThrax) is FDA approved for ages 18 to 65 years; pregnancy Category D.
- If behind schedule, do not restart series; pick-up where left off (delays do not diminish protection) (2)[B].
- Individuals are not protected until they have completed the full series.
- The most common adverse reactions are tenderness, pain, erythema, and a temporary limitation of arm motion at the site of injection (~10%). The most common systemic reactions are muscle aches, fatigue, and headache (~5%).
- The Advisory Committee on Immunization Practices (ACIP) recommends vaccination for the following (3)[C]:
- Laboratory personnel working with B. anthracis
- Persons working with imported animal hides or furs in areas with insufficient measures to prevent exposure to anthrax spores
- Persons who handle potentially infected animal products in high-incidence areas
- Military personnel deployed to areas with high risk for exposure to biologic warfare
- Pregnant women should be vaccinated only if absolutely necessary.
- Proper public health and first responder preparation can limit exposure. (4)[C].
DIAGNOSIS
- Cutaneous: Incubation period is brief (1 day); begins as a pruritic spot, followed by a red-brown papule that enlarges with peripheral erythema, vesiculation, and induration. This is followed by black eschar formation within 7 to 10 days of the initial lesion.
- The papule, blister, and eschar are painless. Cutaneous symptoms may be accompanied by fever, malaise, and headache.
- A black eschar with significant edema is essentially pathognomonic for cutaneous anthrax (5).
- GI: Incubation period is usually 1 to 7 days; presents as oropharyngeal or abdominal syndrome
- Oropharyngeal syndrome includes fever, edema, oral ulceration, sore throat, and cervical lymphadenopathy with marked neck swelling.
- Abdominal syndrome presents with fever, malaise, hematemesis, anorexia, severe abdominal pain, hematochezia, or melena; 2 to 4 days after onset of symptoms, pain begins to subside and ascites develops, shock and death often within days.
- Inhalational: Incubation period is usually <1 week but may be up to 60 days; biphasic presentation, with initial phase featuring nonspecific influenza-like symptoms (low-grade fever, chills, headache, nonproductive cough, diaphoresis, malaise, chest discomfort, nausea, vomiting, diarrhea, abdominal pain)
- This initial phase is followed in 1 to 5 days by a fulminant phase. Characterized by the abrupt onset of high fever, severe dyspnea, hypoxia, hypotension, and death within 24 to 36 hours (2).
HISTORY
- A thorough occupational and exposure history is central to the diagnosis of anthrax (particularly in cases of inhalational disease).
- Cutaneous: Clinical clues include rapidly evolving skin lesions, which are painless, edematous, and exhibit pathognomonic black eschar (5).
- GI: 2 to 4 days after onset of symptoms, ascites develops as abdominal pain decreases. Shock and death occur within 2 to 5 days after onset of symptoms.
- Inhalational: Incubation period is usually <1 week but may be as long as 2 months. Second portion of the biphasic presentation begins 1 to 5 days after onset of initial symptoms. There may be a 1- to 3-day period of improvement after the first phase and before the second phase begins. Shock and death occur within 24 to 36 hours after onset of the second phase.
PHYSICAL EXAM
- Cutaneous: red-brown papule, vesicles, or black eschar
- GI: Acute abdomen with rebound tenderness may occur. Ascites presents later in course.
- Inhalational: hemodynamic instability; pulmonary findings consistent with acute respiratory distress (rales, rhonchi, crackles)
DIFFERENTIAL DIAGNOSIS
- Depends on form
- Cellulitis
- Brown recluse spider bite
- Cat-scratch disease
- Rat bite fever
- Rickettsial spotted fever
- Carbuncle
- Cowpox
- Bullous erysipelas
- Tularemia vasculitides
- Ecthyma gangrenosum
- Orf (viral disease of goats and sheep)
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
Gram stain and culture. Obtain specimens for culture before initiating antimicrobial therapy. B. anthracis is easily isolated from blood cultures in <24 hours. A presumptive diagnosis can be made if nonmotile, nonhemolytic, and encapsulated (India ink). Gram-positive rods. If antibiotics have been given for >24 hours, immunohistochemical staining and/or polymerase chain reaction (PCR). á
- Testing for anthrax should be sent to a CDC-verified lab. Anthrax is a reportable disease (1).
- Inhalational: CXR for suspected inhalational anthrax Widened mediastinum and pleural effusions are common; infiltrates are rare.
- Chest CT if inhalational anthrax suspected but CXR normal (2)[C]
- GI: Mesenteric adenopathy on CT scan is likely.
- Lumbar puncture if meningitis is suspected (6)[C].
TREATMENT
GENERAL MEASURES
- While inhalational and GI anthrax have not been shown to spread from person to person, universal precautions should still be enforced (4,7)[C].
- Avoid contact with the wound or wound drainage in cases of cutaneous anthrax (4)[C].
- Patients with a likely inhalational exposure history, but no symptoms, are candidates for postexposure prophylaxis with either ciprofloxacin 500 mg PO BID or doxycycline 100 mg PO BID for 60 days. Levofloxacin is also FDA approved for patients over 18. Consider 3 doses of anthrax vaccine (0, 2 weeks, 4 weeks), under an Investigational New Drug application. Prophylactic medications are not indicated for prevention of cutaneous anthrax (5)[C].
MEDICATION
First Line
- Cutaneous: ciprofloxacin 500 mg PO BID or doxycycline 100 mg PO BID for 7 to 10 days for localized or uncomplicated cases of naturally acquired cutaneous anthrax. Treat for 7 to 10 days with IV instead for severe cases of naturally acquired cutaneous anthrax with signs of systemic involvement, extensive edema, or lesions of the head and neck.
- If cutaneous disease is localized or uncomplicated and is bioterrorism-related, patients must be treated for 60 days with PO ciprofloxacin or doxycycline as they are also at risk for inhalational anthrax.
- Patients with bioterrorism-related cutaneous anthrax who show signs of systemic involvement, massive edema, or lesions on the head or neck should be treated as having inhalational anthrax.
- A shorter course of antibiotics lasting just 3 to 5 days may be as effective as the standard 7- to 10-day course in uncomplicated cases of cutaneous anthrax not related to bioterrorism (4,5)[C].
- Inhalational and GI: IV ciprofloxacin 400 mg q12h (first line) or IV doxycycline 100 mg q12h (second line) PLUS 1 or 2 of the following: rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, meropenem, clindamycin (4,6)[B]
- Ciprofloxacin is first line for systemic disease due to good CNS penetration.
- Clindamycin is a suitable adjunct to use with ciprofloxacin for systemic infection (4)[C].
- May switch to PO when clinically appropriate
- Must complete 60-day course (combined PO and IV) in cases of inhalational anthrax
- Early and aggressive pleural fluid drainage is recommended for all cases of inhalational anthrax (4)[B].
Second Line
- Patients being treated for anthrax may also benefit from vaccination.
- Raxibacunab is an IV antitoxin that can be administered as monotherapy or incombination with antimicrobials. One time dose 40 mg/kg, can be considered for postexposure prophylaxis (4)[C].
- Anthrax immune globulin appears to be a safe adjunct available under Investigation New Drug Protocol or Emergency Use Authorization (4)[C].
- Thravixa is an experimental monoclonal antibody developed as an adjunct therapy for anthrax. It has shown benefit in animals when antibiotic therapy was delayed (6)[B].
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
Monitor patients for 60 days to ensure treatment is completed. á
PROGNOSIS
- Cutaneous: death in 5-20% of untreated cases, but the case fatality rate is <1% with antibiotic therapy
- GI: mortality rates as high as 50% reported
- Inhalational: death in 45-80% of patients with severe symptoms who are treated in a state-of-the-art facility; case fatality rate approaches 99% in untreated cases.
REFERENCES
11 Centers for Disease Control and Prevention. Anthrax. http://www.bt.cdc.gov/agent/anthrax/. Accessed 2015.22 Donegan áS, Bellamy áR, Gamble áCL. Vaccines for preventing anthrax. Cochrane Database Syst Rev. 2009;(2):CD006403.33 Wright áJG, Quinn áCP, Shadomy áS, et al. Use of anthrax vaccine in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009. MMWR Recomm Rep. 2010;59(RR-6):1-30.44 D'Amelio áE, Gentile áB, Lista áF, et al. Historical evolution of human anthrax from occupational disease to potentially global threat as bioweapon. Environ Int. 2015;85:133-146.55 Stern áEJ, Uhde áKB, Shadomy áSV, et al. Conference report on public health and clinical guidelines for anthrax. Emerg Infect Dis. 2008;14(4):pii.070969.66 Malkevich áNV, Hopkins áRJ, Bernton áE, et al. Efficacy and safety of AVP-21D9, an anthrax monoclonal antibody, in animal models and humans. Antimicrob Agents Chemother. 2014;58(7):3618-3625.77 Hendricks áKA, Wright áME, Shadomy áSV, et al. Centers for Disease Control and Prevention Expert Panel meetings on prevention and treatment of anthrax in adults. Emerg Infect Dis. 2014;20(2):e130687.
ADDITIONAL READING
- Centers for Disease Control and Prevention. Update: investigation of bioterrorism-related anthrax and interim guidelines for exposure management and antimicrobial therapy, October 2001. MMWR Morb Mortal Wkly Rep. 2001;50(42):909-919.
- Defense Health Agency. Immunization Healthcare Branch. http://www.vaccines.mil.
- Jernigan áDB, Raghunathan áPL, Bell áBP, et al. Investigation of bioterrorism-related anthrax, United States, 2001: epidemiologic findings. Emerg Infect Dis. 2002;8(10):1019-1028.
- Kayabas áU, Karahocagil áMK, Ozkurt áZ, et al. Naturally occurring cutaneous anthrax: antibiotic treatment and outcome. Chemotherapy. 2012;58(1):34-43.
- Marano áN, Plikaytis áBD, Martin áSW, et al. Effects of a reduced dose schedule and intramuscular administration of anthrax vaccine adsorbed on immunogenicity and safety at 7 months: a randomized trial. JAMA. 2008;300(13):1532-1543.
- Sweeney áDA, Hicks áCW, Cui áX, et al. Anthrax infection. Am J Respir Crit Care Med. 2011;184(12):1333-1341.
CODES
ICD10
- A22.9 Anthrax, unspecified
- A22.0 Cutaneous anthrax
- A22.1 Pulmonary anthrax
- A22.2 Gastrointestinal anthrax
- A22.7 Anthrax sepsis
- A22.8 Other forms of anthrax
ICD9
- 022.9 Anthrax, unspecified
- 022.0 Cutaneous anthrax
- 022.1 Pulmonary anthrax
- 022.2 Gastrointestinal anthrax
- 022.3 Anthrax septicemia
- 022.8 Other specified manifestations of anthrax
SNOMED
- Anthrax (disorder)
- Cutaneous anthrax (disorder)
- Inhalational anthrax (disorder)
- Gastrointestinal anthrax (disorder)
- Sepsis due to Bacillus anthracis (disorder)
CLINICAL PEARLS
- Inhalational anthrax is rare in the United States and requires a high degree of clinical suspicion for diagnosis. If no occupational exposures to animal hides or products, it should be considered a bioterrorist event until proven otherwise.
- Widened mediastinum on CXR should raise suspicion for inhalational anthrax in the appropriate clinical setting.
- Ciprofloxacin is the drug of choice for initial treatment.
- Anthrax vaccine (recommended for high-risk groups) is safe and protects against all forms of anthrax.