Anthrax

Overview

Definition

Anthrax is an infectious disease caused by Bacillus anthracis (B. anthracis) and can have cutaneous, respiratory, and gastrointestinal manifestations.

Epidemiology

• Zoonotic disease
• Common hosts: wild or domestic livestock, such as sheep, cattle, horses, and goats
• Endemic in agricultural regions of the world, although rare in the United States
• Centers for Disease Control reports < 5 cases/year in the United States. 
• Men are at higher risk than women due to them being in higher risk occupations.
• Outbreaks can be seasonal: usually in an enzootic area receiving rain after a period of drought

Etiology

• Etiologic agent is B. anthracis:
  • Gram-positive rods
  • Forms spores that can persist in soil in a dormant state for a long time
• Animals become infected by inhaling spores or ingesting them → bacteria multiply in their body and they excrete more spores
• Spores can enter humans in 3 ways:
  • Inhalation (inhalation anthrax)
  • Ingestion (gastrointestinal anthrax)
  • Direct contact with the skin (cutaneous anthrax)
• Humans usually become infected through contact with animals or their products.
• Laboratory accidents with documented cases of infection have been reported.
• Biological warfare uses specialized refinement of anthrax spores to make the spores extra fine and easily aerosolized, so the spores are easily inhaled.

Pathophysiology and Clinical Presentation

Pathogenesis

• Depends on the production of 2 potent exotoxins:
  • Edema toxin (ET):
    • Increases cyclic adenosine monophosphate (cAMP) levels
    • Causes edema and black eschar of cutaneous anthrax
    • Induces multiorgan hemorrhage
  • Lethal toxin (LT):
    • Protease (cleaves mitogen-activated protein (MAP) kinase)
    • Causes tissue necrosis
• Protective antigen (PA) binds with both toxins and allows ET and LT to enter cells.
• B. anthracis capsule allows the bacterium to avoid phagocytosis.
• Toxins inhibit neutrophils, dendritic cells, and macrophage recruitment.
• Endothelial cells may also be affected (vascular leakage).

Clinical presentation

Cutaneous anthrax:

• 95% of anthrax cases
• Enters the body through a cut or other sore on the skin 
• Incubation period: 5–7 days
• Mildest form of anthrax: With appropriate treatment, it is rarely fatal.
• Signs and symptoms:
  • A raised, itchy bump resembling an insect bite that quickly develops into a painless sore with a black eschar
  • Lymphadenopathy, lymphangitis, and surrounding edema
  • Systemic symptoms can occur: fever, malaise, headache

Gastrointestinal anthrax:

• From eating undercooked meat from an infected animal or drinking contaminated water
• Incubation period: 1–6 days
• Causes necrotic ulcers in the gastrointestinal tract, anywhere from mouth to ascending colon
• Signs and symptoms:
  • Nausea
  • Vomiting
  • Abdominal pain
  • Headache
  • Loss of appetite
  • Fever
  • Severe, bloody diarrhea in the later stages of the disease
  • Oropharyngeal form:
    • Sore throat
    • Difficulty swallowing
    • Swollen neck (lymphadenopathy)

Inhalation anthrax (“woolsorter’s disease”):

• From inhaling anthrax spores
• Reported incubation period varies from 1–60 days.
• Biphasic illness:
  • Prodromal phase (flu-like symptoms):
    • Sore throat 
    • Mild fever
    • Fatigue and muscle aches
    • Some hemoptysis, nausea, dyspnea, odynophagia may be present.
  • Fulminant phase:
    • Rapidly progressive respiratory failure
    • Bacteremia/shock
    • Meningitis (in up to 50%)
    • Almost universally fatal

Injection anthrax:

• Most recently identified route of anthrax infection
• Contracted through injecting illegal drugs
• Signs and symptoms:
  • Redness at the area of injection (typically without a black eschar)
  • Significant swelling
  • Fever
  • Abscess at injection site

Diagnosis

History

• Exposure to animal products
• Laboratory exposure
• Potential exposure to bioterrorism
• Injection drug use
• Typical cutaneous, gastrointestinal, or respiratory symptoms

Physical exam

• Skin lesions with significant edema and black eschars
• Fever

Laboratory studies

• Diagnosis is made by measuring levels of antibodies or toxins in the blood or direct testing of biological specimens. 
• Samples must be taken before the patient starts treatment.
• Culture, Gram stain, polymerase chain reaction (PCR), and immunohistochemical staining can be performed.
• Specimens to test:
  • Cutaneous anthrax:
    • Fluid from blisters 
    • Full-thickness punch biopsy
    • Blood
    • Cerebrospinal fluid (CSF)
  • Inhalation anthrax:
    • Pleural fluid
    • Respiratory secretions
    • Blood
    • CSF
  • Gastrointestinal anthrax:
    • Oral and rectal secretions
    • Ascitic fluid
    • Splenic or mesenteric lymph node biopsy
    • Blood
    • CSF
• Supporting tests:
  • Complete blood cell count (CBC): anemia, leukocytosis
  • Electrolytes
  • Blood urea nitrogen (BUN)/creatinine
  • Liver enzymes
  • Coagulation studies

Imaging studies

• X-ray or computed tomography (CT) of the chest for inhalational anthrax:
  • Mediastinal widening 
  • Perihilar interstitial pneumonia
  • Pleural effusion
•  CT of the abdomen for gastrointestinal anthrax:
  • Ascites
  • Mesenteric inflammation and edema 
  • Bowel wall edema

Management

Initial approach

• Blood and other appropriate cultures should be obtained prior to treatment.
• All systemic anthrax cases should be hospitalized (cutaneous with systemic symptoms and all other forms).
• Close hemodynamic monitoring should be performed due to risk of rapid deterioration.
• Supportive management for sepsis (fluid resuscitation, blood transfusion, vasopressors, mechanical ventilation)
• Lumbar puncture should be performed to rule out meningitis unless contraindicated.

Antibiotics

• Should be started urgently
• Meningitis: ciprofloxacin + meropenem + linezolid
• Systemic anthrax without meningitis:
  • Ciprofloxacin + clindamycin
  • Ciprofloxacin + linezolid
• Cutaneous anthrax without systemic signs and head or neck involvement: single therapy with fluoroquinolones, doxycycline, or clindamycin

Antitoxins

• Should be started urgently for systemic anthrax
• Monoclonal antibodies: raxibacumab, obiltoxaximab
• Anthrax immunoglobulin

Other measures

• Glucocorticoids
• Drainage of pleural and pericardial effusions for inhalation anthrax
• Drainage of ascites for gastrointestinal anthrax

Prognosis

• Mortality from meningitis is nearly 100%.
• Case fatality for cutaneous anthrax is < 2% with appropriate antibiotic therapy.
• Mortality for inhalation or gastrointestinal anthrax remains > 40% even with appropriate therapy.

Prevention

• Vaccination of animals
• Proper disposal of infected animals
• Anthrax vaccine adsorbed (AVA) is the only vaccine approved for humans.
• Provides active immunization for at-risk groups:
  • Military personnel at risk
  • Fur and wool handlers
  • Veterinarians handling potentially infected animals 
  • Laboratory workers with exposure to B. anthracis
  • Endemic areas

Differential Diagnosis

Cutaneous anthrax:

• Insect or spider bite: may present as an area of localized erythema and swelling, often with eschar. Sometimes associated with fever/chills. Diagnosis is often made based on history and exam. Management is frequently supportive, sometimes involves antibiotics and surgical debridement.
• Cellulitis or abscess in injection drug users: deep dermis and soft tissue infection presenting with erythema, edema, purulent drainage (abscess), and sometimes systemic signs. Frequent in injection drug users. Causative organisms are confirmed by culture.

Inhalation anthrax:

• Pneumonia: infection of the lung parenchyma most commonly caused by bacteria or viruses. Pneumonia is community acquired in 80% of the cases. Diagnosis is based on a clinical presentation of fever, productive cough, dyspnea, rales, and consolidation on chest X-ray. Atypical pneumonia may present with milder symptoms and less remarkable imaging. Management is with empiric antibiotic treatment.
• Tuberculosis (TB): a disease caused by bacteria of Mycobacterium tuberculosis complex. The bacteria usually attack the lungs but can also damage other parts of the body. Tuberculosis is airborne and can be a latent infection for decades, posing a challenge to diagnosis, therapy, and prevention. Management is with multiple antibiotics over a long period of time.
• Pleural effusion: the accumulation of fluid in the lungs, between the layers of the parietal and visceral pleural membranes. Pleural effusion can be caused by infection due to a virus, pneumonia, or heart failure. Clinical manifestations include chest pain, dry and non-productive cough, dyspnea, and orthopnea. Treatment is dependent on the underlying condition and severity of symptoms.

Gastrointestinal anthrax:

• Intestinal ischemia: vascular compromise of the small bowel caused most commonly by arterial or venous thromboembolic events. Presents with severe abdominal pain, sometimes nausea/vomiting, and bloody diarrhea in late stages. Diagnosis is established with CT angiogram. Management involves anticoagulation and surgery. 
• Gastroenteritis: acute inflammation of gastrointestinal mucosa usually caused by viral infection. Presents with abdominal pain, nausea/vomiting, and diarrhea. Diagnosis is established clinically, and management is largely supportive.