Anthrax

• Samaan Rafeq, M.D.

 Basic Information

Definition

Anthrax is an acute infectious disease caused by the spore-forming bacterium Bacillus anthracis.

ICD-10CM CODES
A22.0	Cutaneous anthrax
A22.1	Pulmonary anthrax
A22.2	Gastrointestinal anthrax
A22.7	Anthrax sepsis

Epidemiology & Demographics

1. •

   Anthrax most commonly occurs in hoofed animals and can only incidentally infect human beings who come in contact with infected animals or animal products. Between 20,000 and 100,000 cases of cutaneous anthrax occur worldwide annually. Twenty-three cases of anthrax were reported to the CDC from 1972 through 2000.

2. •

   Until the bioterrorism attack in 2001, most cases of anthrax occurred in industrial environments (contaminated raw materials used in manufacturing process) or in agriculture.

3. •

   There were 22 anthrax cases with 5 deaths (all inhalational) after a 2001 attack in which anthrax spores were sent through U.S. mail (Fig. E1).

   

4. •

   Traditionally, there are three major anthrax syndromes: cutaneous, inhalational, and gastrointestinal anthrax. A fourth type, injectional anthrax, was recognized after the 2009 to 2010 European outbreak from heroin-injecting drug users. This type of infection has not been reported in the United States.

5. •

   Direct person-to-person spread of anthrax is extremely unlikely, if it occurs at all; therefore, there is no need to immunize or treat contacts of persons ill with anthrax, such as household contacts, friends, or coworkers, unless they also were exposed to the same source of infection.

Physical Findings & Clinical Presentation

1. •

   Inhalation anthrax is the most lethal form. It begins with a brief prodrome resembling a viral respiratory illness without rhinorrhea. The incubation period may be as short as 1 day to 6 weeks. Host factors, dose of exposure, and chemoprophylaxis may affect the duration of the incubation period. A severe advanced phase of fever, shock, and respiratory distress follow the prodromal stage. Inhalational anthrax does not cause pneumonia but can progress to acute respiratory distress syndrome. Radiographic evidence of mediastinal widening and pleural and pericardial effusions can also occur. Mortality is higher when infection spreads to the meninges.

2. •

   Cutaneous anthrax (Fig. E2) is characterized by a skin lesion evolving from a papule, through a vesicular stage, to a depressed black eschar. The incubation period ranges from 1 to 12 days. The lesion is usually painless, but patients also may have fever, malaise, headache, and regional lymphadenopathy. The eschar dries and falls off in 1 to 2 wk with little scarring.

   

3. •

   Gastrointestinal anthrax usually follows eating raw or undercooked contaminated meat and can have an incubation period of 1 to 7 days. Disease presentation may be divided into two phases: oropharyngeal and lower gastrointestinal. Involvement of the pharynx is usually characterized by lesions at the base of the tongue, dysphagia, fever, and regional lymphadenopathy. Lower bowel inflammation typically causes nausea, loss of appetite, and fever followed by abdominal pain, hematemesis, and bloody diarrhea. Gastric ulcers may occur and may be associated with hematemesis.

4. •

   Injectional anthrax may have similar skin lesions present with IV drug users. These may progress rapidly with systemic dissemination. Unlike cutaneous anthrax, the injectional type is not associated with eschar formation on the skin.

Etiology

The disease is caused by B. anthracis, a gram-positive, spore-forming bacillus. It is aerobic, nonmotile, nonhemolytic on sheep’s blood agar and grows readily at a temperature of 37° C, forming large colonies with irregularly tapered outgrowths (a Medusa’s head appearance). In the host, it appears as single organisms or chains of two or three bacilli (Fig. E3).

Diagnosis

Differential Diagnosis

1. •

   Inhalation anthrax must be distinguished from influenza-like illness (ILI) and tularemia. Most cases of ILI are associated with nasal congestion and rhinorrhea, which are unusual in inhalation anthrax. Additional distinguishing factors are the usual absence of abnormal chest radiograph in ILI (see the following).

2. •

   Cutaneous anthrax should be distinguished from staphylococcal disease, ecthyma, ecthyma gangrenosum, plague, brown recluse spider bite, and tularemia.

3. •

   The differential diagnosis of gastrointestinal anthrax includes viral gastroenteritis, shigellosis, and yersiniosis.

Laboratory Tests

1. •

   Presumptive identification is based on Gram stain of material from skin lesion, CSF, or blood showing encapsulated gram-positive bacilli.

2. •

   Confirmatory tests are performed at specialized laboratories. Virulent strains grow on nutrient agar in the presence of 5% CO₂. Susceptibility to lysis by gamma phage and direct fluorescent antibody (DFA) staining of cell-wall polysaccharide antigen are also useful confirmatory tests.

3. •

   Nasal swab culture to determine inhalation exposure is of limited diagnostic value. A negative result does not exclude the possibility of exposure. It may be used by public health officials to assist in epidemiologic investigations of exposed persons to evaluate the dispersion of spores.

4. •

   Serologic testing by enzyme-linked immunosorbent assay (ELISA) can confirm the diagnosis.

5. •

   A skin test (Anthracin test) that detects anthrax cell-mediated immunity is also available in specialized laboratories.

6. •

   Depending on disease severity, laboratory studies may also demonstrate hemoconcentration, elevated liver enzymes, anemia, thrombocytopenia, and coagulopathy.

Imaging Studies

Chest radiographs usually reveal mediastinal widening. Additional findings include infiltrates and pleural effusion. An echocardiogram may reveal pericardial effusion.

Treatment

Nonpharmacologic Rx

IV hydration and ventilator support may be necessary with inhalation anthrax.

Acute General Rx

1. •

   Uncomplicated cutaneous anthrax can be treated with an oral fluoroquinolone or doxycycline for 7 to 10 days. When inhalation of spores has occurred, the duration should be extended to 60 days.

2. •

   CDC recommendations (MMWR 64(4), 2015) for a clinical framework and medical countermeasure use during an anthrax mass-casualty incident are summarized in Figs. E4 through E6 and Boxes E1 through E3.

   

   

   

   BOX E1Diagnostic Criteria for Sepsis and Severe Sepsis^∗

   Sepsis—documented or suspected infection plus one or more of the following:

   General variables

   1. •

      Fever (>38.3° C)

   2. •

      Hypothermia (core temperature <36° C)

   3. •

      Heart rate >90/min or >2 SD above normal value for age

   4. •

      Tachypnea

   5. •

      Altered mental status

   6. •

      Significant edema or positive fluid balance (>20 mL/kg over 24 hr)

   7. •

      Hyperglycemia (plasma glucose >140 mg/dL or 7.7 mmol/L) in the absence of diabetes

   Inflammatory variables

   1. •

      Leukocytosis (WBC count >12 x10³/μL)

   2. •

      Leukopenia (WBC count <4 x 10³/μL)

   3. •

      Normal WBC count with greater than 10% immature forms

   4. •

      Plasma C-reactive protein >2 SD above normal value

   5. •

      Plasma procalcitonin >2 SD above normal value

   Hemodynamic variables

   1. •

      Arterial hypotension (SBP <90 mm Hg, MAP <70 mm Hg, or an SBP decrease >40 mm Hg in adults or <2 SD below normal value for age)

   Organ dysfunction variables

   1. •

      Arterial hypoxemia (PaO2/FiO₂ <300)

   2. •

      Acute oliguria (urine output <0.5 mL/kg/hr for at least 2 hours despite adequate fluid resuscitation)

   3. •

      Creatinine increase >0.5 mg/dL or >44.2 μmol/L

   4. •

      Coagulation abnormalities (INR >1.5 or aPTT >60 s)

   5. •

      Ileus (absent bowel sounds)

   6. •

      Thrombocytopenia (platelet count <100 x 10³/μL)

   7. •

      Hyperbilirubinemia (plasma total bilirubin >4 mg/dL or >70 μmol/L)

   Tissue perfusion variables

   1. •

      Hyperlactatemia (>1 mmol/L)

   2. •

      Decreased capillary refill or mottling

   Severe sepsis—documented or suspected infection resulting in tissue hypoperfusion or organ dysfunction documented by one or more of the following

   1. •

      Sepsis-induced hypotension

   2. •

      Lactate above upper normal limits of laboratory

   3. •

      Urine output <0.5 mL/kg/hr for >2 hours despite adequate fluid resuscitation

   4. •

      Acute lung injury with PaO2/FiO₂ <250 in the absence of pneumonia as infection source

   5. •

      Acute lung injury with PaO2/FiO₂ <200 in the presence of pneumonia as infection source

   6. •

      Creatinine >2.0 mg/dL (176.8 μmol/L)

   7. •

      Bilirubin >2 mg/dL (34.2 μmol/L)

   8. •

      Platelet count <100 x 10³/μL

   9. •

      Coagulopathy (international normalized ratio >1.5)

   aPTT, Activated partial thromboplastin time; INR, international normalized ratio; MAP, mean arterial pressure; SBP, systolic blood pressure; SD, standard deviation; WBC, white blood cell.

   Adapted with permission from Dellinger RP, et al: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012, Crit Care Med 41:580–637, 2013, from Centers for Disease Control and Prevention: Clinical framework and medical countermeasure use during an anthrax mass-casualty incident, MMWR 64(RR04):1-28, 2015.

   BOX E2Parenteral Antimicrobial Choice for Treatment of Systemic Anthrax in Conventional, Contingency, and Crisis Standards of Care

   Conventional setting

   1. •

      Patients with probable, confirmed, or suspected meningitis should be treated with three recommended antimicrobials with good central nervous system penetration.

   2. •

      Patients without evidence of meningitis should be treated with a minimum of one bactericidal agent plus one protein synthesis inhibitor.

   3. •

      Parenteral combination treatment of systemic anthrax should be provided for at least two weeks or until the patient is clinically stable, whichever is longer; at that point, the patient may be transitioned to oral monotherapy for prophylaxis against ungerminated spores.

   Contingency setting

   1. •

      Same as conventional setting, except that alternatives to first-line antimicrobial treatment recommendations may be used.

   Crisis setting

   1. •

      If triple antimicrobial therapy is not available, patients with probable, confirmed, or suspected meningitis may be treated with two recommended antimicrobials (one bactericidal agent and one protein synthesis inhibitor; both with good central nervous system penetration).

   2. •

      Patients without evidence of meningitis

      1. ○

         Should be treated with a bactericidal antimicrobial combined with a protein synthesis inhibitor.

      2. ○

         Parenteral therapy may be stopped based on clinical judgment that the patient is clinically stable and improving; at that point, the patient may be transitioned to oral monotherapy for prophylaxis against ungerminated spores.

   3. •

      Patients with confirmed or suspected meningitis are recommended to receive at least 14 days of antimicrobials and be clinically stable and improving, before considering transition to oral monotherapy for prophylaxis against ungerminated spores.

   Centers for Disease Control and Prevention: Clinical framework and medical countermeasure use during an anthrax mass-casualty incident, MMWR 64(RR04):1-28, 2015.

   BOX E3Antitoxin Prioritization for Treatment of Systemic Anthrax in Conventional, Contingency, and Crisis Standards of Care

   Conventional setting

   An antitoxin should be added to the combination antimicrobial treatment for patients for whom there is a high level of clinical suspicion for systemic anthrax.

   Contingency setting

   1. •

      Patients for whom there is a high level of clinical suspicion of systemic anthrax, with clinical symptoms or signs consistent with any of the general or inflammatory sepsis variables and in whom severe sepsis has not been diagnosed, should receive.

      1. ○

         Combination parenteral antimicrobial therapy.

      2. ○

         Short term re-evaluation and observation is recommended.

      3. ○

         Based on the clinical judgment of the local triage team, an antitoxin may be added to the antimicrobial regimen for patients who do not display rapid clinical improvement or who demonstrate any signs or symptoms of clinical deterioration.

   2. •

      Patients for whom there is a high level of clinical suspicion for systemic anthrax, with clinical signs or symptoms consistent with severe sepsis or septic shock with a reasonable expectation of survival based on clinical judgment of the local triage team, should receive combination parenteral antimicrobial therapy plus antitoxin without delay.

   3. •

      Patients with probable, confirmed, or suspected meningitis should receive combination parenteral antimicrobial therapy plus antitoxin without delay.

   4. •

      Mechanisms should be in place to capture critical care and organ dysfunction measurements among septic anthrax patients, including measurements included in the sequential organ failure assessment (SOFA) score and other objective scoring systems.

   5. •

      Disease-specific prognostic indicators should be defined based on real-time data and may inform and augment decisions of the local triage team regarding resource allocation.

   Crisis setting

   1. •

      Same as contingency setting.

   Centers for Disease Control and Prevention: Clinical framework and medical countermeasure use during an anthrax mass-casualty incident, MMWR 64(RR04):1-28, 2015.

3. •

   If meningitis has not been ruled out, the IV antimicrobial regimen should include a fluoroquinolone plus a bactericidal with good CNS penetration (meropenem) plus a protein synthesis inhibitor (linezolid).

4. •

   If meningitis has been ruled out, a two-drug regimen that includes a fluoroquinolone plus linezolid or clindamycin is recommended. The addition of glucocorticoids should be in accordance with the bacterial meningitis protocol.

5. •

   Adjunct therapies include the use of antibodies directed against anthrax toxins: raxibacumab and anthrax immune globulin (Anthrasil) for systemic disease. Anthrasil is available in 50 ml vials, recommended dose is 420 unites (7 vials) administered by slow IV infusion using an infusion pump. Drainage of toxin-laden fluids (pleural, pericardial effusions and ascites) is also recommended.

6. •

   Initial postexposure prophylaxis therapy in adults is with ciprofloxacin, 500 mg PO bid, doxycycline 100 mg bid, or levofloxacin 500 mg daily. The total duration of treatment is 60 days. Administration of anthrax vaccine adsorbed (AVA), an inactivated cell-free filtrate of an avirulent strain available from the CDC in a series of three SC injections at 2-wk intervals, is also recommended for known or suspected inhalation exposure to anthrax in adults.

7. •

   A single dose of raxibacumab, a human monoclonal antibody directed against protective antigen, has been reported effective in animal studies with symptomatic inhalational anthrax. This can be used when no other option is available.

Prognosis

1. •

   Case fatality estimates for inhalation anthrax are extremely high (>90%).

2. •

   During the 2001 bioterrorism attacks, the case fatality rate was lower at 45%. The decrease was linked to improvement in critical care management, drainage of effusions, and antimicrobial therapy.

3. •

   The case fatality rate for cutaneous anthrax when left untreated is less than 1%.

4. •

   The case fatality rate for gastrointestinal anthrax is estimated to be 25% to 60%.

5. •

   Even with treatment, the mortality rate for injectional anthrax is 34%.

Referral

Consultation with an infectious disease specialist is recommended in all cases of anthrax. Local and state authorities should also be notified of suspected cases of anthrax.

Pearls & Considerations

Comments

1. •

   Postexposure prophylaxis: If the exposure to B. anthracis is confirmed and anthrax vaccine is available, three doses of the vaccine should be given at 0, 2, and 4 wk, and antibiotics should be continued throughout the 4-wk period. If vaccine is not available, antibiotics should be continued for 60 days.

2. •

   Preexposure vaccination is limited to groups at risk for repeated exposures to B. anthracis spores, such as bioterrorism level B laboratories and workers who will be making repeated entries into known B. anthracis spore-contaminated areas.

3. •

   The U.S. anthrax vaccine is an inactivated cell-free product licensed to be given in a six-dose series.

Suggested Reading

• A.A. Adalja, et al.: Clinical management of potential bioterrorism-related conditions. N Engl J Med. 372:954–962 2015 25738671

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