Anthrax

Anthrax is an infection caused by the bacterium Bacillus anthracis, which usually targets the skin, lungs, or intestines. Anthrax is a zoonotic disease and is usually transmitted to humans from animals or through animal products. The Bacillus spores can persist in soil for a long time. The Bacillus spores have also been used as a biological weapon. Symptoms depend on which organ system is affected. The skin forms small blisters with surrounding swelling that often turn into a painless ulcer with a black center. Inhalational exposure causes severe fulminant pneumonia. Intestinal exposure causes mucosal ulcers, bloody diarrhea, abdominal pain, nausea, and vomiting. Diagnosis is established with cultures, tissue examination, and polymerase chain reaction (PCR). Management involves antibiotics, antitoxins, and frequently hospital/critical care admission. Mortality from systemic disease remains high.

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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.
Anthrax Cycle

The anthrax cycle:
Bacillus anthracis (anthrax) spores infect humans or mammals via different processes: either via ingestion, inhalation, or through cutaneous pathways by bites from an infected insect. Anthrax spores originate from vegetation in excreted waste from cattle that is exposed to oxygen.

Image by Lecturio.

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
Inhalational anthrax

Pulmonary anthrax: Chest X-ray shows mediastinal widening.

Image: “Inhalational anthrax” by JoJan. License: Public Domain

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
Gram stain of Bacillus anthracis

Gram stain of B. anthracis

Image: “Photomicrograph of a Gram stain of the bacterium Bacillus anthracis” by CDC. License: Public Domain

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.

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References

  1. Akbayram S, Dogan M, Akgün C, et al. (2010). Clinical findings in children with cutaneous anthrax in eastern Turkey. Pediatr Dermatol 27(6):600-6.
  2. Beatty ME, Ashford DA, Griffin PM, Tauxe RV, Sobel J. (2003). Gastrointestinal anthrax: review of the literature. Arch Intern Med 163 (20):2527-31. 
  3. Doganay M, Metan G, Alp E. (2010). A review of cutaneous anthrax and its outcome. J Infect Public Health 3 (3):98-105. 
  4. Wilson K. (2020). Clinical manifestations and diagnosis of anthrax. Retrieved 21 January 2021, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-anthrax
  5. Wilson K. (2020). Microbiology, pathogenesis, and epidemiology of anthrax. Retrieved 21 January, 2021, from https://www.uptodate.com/contents/microbiology-pathogenesis-and-epidemiology-of-anthrax
  6. Wilson K. (2019). Treatment of anthrax. Retrieved 3 February 2021, from https://www.uptodate.com/contents/treatment-of-anthrax

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