Anthrax overview

# Overview
Anthrax (Greek  for coal) is an acute infectious disease in humans and animals that is caused by the bacterium Bacillus anthracis and is highly lethal in some forms. Anthrax is one of only a few bacteria that can form long lived spores. When the bacteria s life cycle is threatened by factors such as lack of food caused by their host dying or by a change of temperature, the bacteria turn themselves into a dormant spores to wait for another host to continue their life cycle.
When breathing, ingesting or getting anthrax spores in a cut in the skin, these spores reactivate themselves and multiply in their new host very rapidly. The anthrax spores in the soil are very tough, can live many decades and are known to occur on all continents except Antarctica. Anthrax most commonly occurs in wild and domestic grass eating mammals (ruminants) who ingest or breathe in the spores while eating grass. Anthrax  can also infect humans when they are exposed to dead infected animals, eat tissue from infected animals, or are exposed to a high density of anthrax spores from an animal's fur, hide, or wool. Anthrax spores can be grown outside the body and used as a biological weapon. Anthrax cannot spread directly from human to human; but anthrax spores can be transported by human clothing, shoes, among others. If a person dies of anthrax their body can be a very dangerous source of anthrax spores. The word anthrax is  the Greek word for coal, the germ's name is derived from anthrakitis, the Greek word for anthracite, in reference to the black skin lesions victims develop in a cutaneous skin infection.

# Historical Perspective
Anthrax, caused by Bacillus anthracis, is thought to have originated in Egypt around 1250 BC. Described as being a disease affecting horses, camels and sheep, anthrax had an impact on great civilizations, such as the Greek and Roman. It was described clinically for the first time by Maret in 1752 and Fournier in 1769. In 1877, based upon his studies with Bacillus anthracis, Robert Koch was able to demonstrate what became known as Kochs postulates. In 1881, Louis Pasteur worked to create a vaccine for anthrax, which he was able to test with success in animals. In 1900, due to the great amount of knowledge gathered during the 1800s, anthrax cases were well documented in the US, UK and Germany. In 1944, penicillin was first used to treat anthrax.  The first commercial vaccine to prevent anthrax in humans was created in 1950s. In the past 10 years there have been a few reported cases in the US, specifically in 2006 in NYC, 2009 in Connecticut and in 2011 in Florida. Anthrax has also been used throughout history as a biologic weapon and there has been efforts to create and enforce legislation to avoid disastrous outbreaks of the disease.  For that, a Convention on the Prohibition of the Development, Production, and Stockpiling of Biological and Toxin Weapons and on Their Destruction was created and later ratified in April of 1972, with more than 100 nations signing it, including Iraq, the United States, and the Soviet Union.

# Pathophysiology
The genetic material of Bacillus anthracis is coded within 1 chromosome and 2 plasmids, which are fundamental for its toxicity. The spores of B. anthracis are the infectious form and can remain dormant in the environment for decades. The disease may be transmitted through the skin, gastrointestinal or respiratory systems. The bacterium causes disease through 2 mechanisms: toxemia and bacterial infection.  B. anthracis begins to produce toxins within hours of germination.  Protective antigen (PA) and edema factor (EF) combine to form edema toxin (ET), and PA and lethal factor (LF) combine to form lethal toxin (LT), the active toxins. Bacterial toxins have a direct cytotoxic effect by interfering with cellular pathways, being also responsible for weakening the immune system, so the initial systemic infection may occur. Anthrax lesions at any site are characterized by lymphadenopathy, extensive edema, necrosis and confluent exudate containing macrophages and neutrophils. If not stopped, the infection may affect different organs, causing septicemia and potentially death.

# Causes
The causative agent of anthrax is B. anthracis, a nonmotile, Gram-positive, aerobic or facultatively anaerobic, endospore-forming, rod-shaped bacterium. The spores of B. anthracis, which can remain dormant in the environment for decades, are the infectious form, but this vegetative B. anthracis rarely causes disease. The Bacillus may enter the body through the skin, lungs, gastrointestinal system or by injection, after which they will travel to the lymph nodes. The virulence factors will facilitate the translocation of the toxins to the cytosol. The natural reservoirs of Bacillus anthracis include humans, mammals, herbivores, reptiles, and birds.

# Differentiating Anthrax from other Diseases
The differential diagnosis of anthrax includes a wide range of infectious and non-infectious conditions. Depending on the mode of anthrax exposure in the patient (cutaneous, ingestion, inhalation or injection), there will be different forms of the disease. A history of exposure to contaminated animal materials, occupational exposure, and living in an endemic area, is crucial when considering the diagnosis of anthrax. Additional tests to isolate Bacillus anthracis are required to differentiate anthrax from other diagnoses, thereby confirming the correct etiologic agent.

# Epidemiology and Demographics
Incidence of the natural disease in humans is dependent on the level of exposure to affected animals and, for any one country, national incidence data for non-industrial cases reflect the livestock situation.  Human case rates for anthrax are highest in Africa and Central and Southern Asia.  While, statistically, in Northern Europe and countries with similar epidemiological situations, there is one human cutaneous case per every 10 livestock carcasses butchered, there can be some 10 human cutaneous and enteric cases per single carcass butchered in Africa, India, and the Southern Russian Federation.

# Risk Factors
Risk factors for contracting anthrax include handling of livestock or livestock products, playing animal hide drums, working in a laboratory researching anthrax, and traveling to an endemic region such as Central and South America, Sub-Saharan Africa, Central and southwestern Asia, Southern and eastern Europe, or the Caribbean. Risk factors for anthrax in the setting of bioterrorism are: working as a mail handler, military personnel, or response worker.

# Natural History, Complications and Prognosis
The natural history of anthrax depends on the mode of exposure to the disease (cutaneous, ingestion, inhalation, or injection). In cutaneous anthrax, a small painless skin sore develops into a blister and later into a skin ulcer, with a central black area. The resolution of the lesion takes several weeks, depending on its size, location and severity. The anthrax lesions might lead to scarring and contractures. Inhalation anthrax is characterized by a mild initial phase of nonspecific symptoms, that is followed by sudden development of dyspnea, cyanosis, disorientation with coma, and death. In oropharyngeal anthrax, the lesion is generally localized in the oral cavity. This type may progress rapidly, and edema around the lymph nodes may result in extensive swelling of the neck and anterior chest wall.  The gastrointestinal anthrax lesions may occur anywhere within the gastrointestinal tract, potentially bleeding, and lead to fatal hemorrhage. Some cases are complicated by massive ascites,shock and death.  The prognosis of anthrax depends on the form of the disease, how early it is diagnosed, the strain of bacteria, the patient's age and his health condition. Pulmonary anthrax has the highest mortality rate.

# Diagnosis

## History and Symptoms
The symptoms of anthrax infection depend on the mode of anthrax exposure in the patient (cutaneous, ingestion, inhalation, injection).  The cutaneous type of anthrax is characterized by a skin blister that evolves into an ulcer with a black center, muscle pains, fever, and vomiting.  The gastrointestinal type may include symptoms of fever, chills, sore throat, painful swallowing, and abdominal pain.  The symptoms of the inhalation type of anthrax are fever, chills, fatigue, sore throat, and shortness of breath.  The symptoms of the injection type are usually similar to those of cutaneous anthrax; however, the disease may spread through the body faster. The symptoms of the injection type of anthrax include fever, chills, skin ulcer, and subcutaneous or muscular abscess.  A history of exposure to contaminated animal materials, occupational exposure, and living in an endemic area is crucial when considering a diagnosis of anthrax.

## Physical Examination
The physical findings of anthrax infection depend on the mode of anthrax exposure in the patient (cutaneous, ingestion, inhalation, injection). Common findings associated with cutaneous anthrax infection include fever, tachycardia, skin rash with formation of a typical scar, edema and lymphadenopathy; with gastrointestinal anthrax infection include fever, tachycardia, mucosal ulcer and edema in case of oropharyngeal lesion and edema and pallor in more severe cases; with inhalation anthrax infection includes: fever, tachycardia, bradypnea in severe cases, pallor, cyanosis and decreased heart and lung sounds in the presence of pleural effusion; and with anthrax infection due to injection include fever, typical skin scar at the site of injection, edema and subcutaneous and/or muscular abscess.

## Laboratory Findings
Initial evaluation of patients suspected of having anthrax should be similar to the standard evaluation for patients with an acute febrile illness and should have an emphasis on obtaining pre-treatment blood and other appropriate cultures.  When systemic anthrax is present, abnormalities in laboratory tests include anemia, thrombocytopenia, and leukocytosis particularly in the latter stages of the disease.  Other laboratory findings are hyponatremia, increased BUN, elevated transaminase levels, hypoalbuminemia, and elevated troponin.  Cell cultures from the initial skin lesion, blood, CSF, or pleural fluid can identify the organism and possibly the toxins.  In injection anthrax, the typical laboratory finding is an inflammatory pattern with a low CRP.  A normal PT/PTT at admission does not exclude coagulopathy nor DIC.

## Chest X Ray
Chest X-ray is a sensitive diagnostic test for inhalation anthrax.  Chest X-ray abnormalities associated with inhalation anthrax include mediastinal widening, paratracheal fullness, pleural effusions, parenchymal infiltrates, and mediastinal lymphadenopathy.

## CT
The chest CT scan findings in anthrax include mediastinal widening, hyperdense lymph nodes, and edema of the mediastinal fat.

## Other Diagnostic Studies
Several studies are used for the diagnosis and monitoring of anthrax.  The polymerase chain reaction (PCR) test is ordered to confirm the virulence of the organism.  In addition, lumbar puncture should be performed on admission when it is not contraindicated to search for the organism in the cerebrospinal fluid (CSF) and to to exclude other alternative diagnoses.  Other diagnostic studies include an electrocardiogram and an echocardiogram to assess possible complications of anthrax such as atrial fibrillation and pericardial effusion.

# Treatment

## Medical Therapy
Medical therapy of anthrax infection includes antibiotic and antitoxin drugs.  Uncomplicated cutaneous anthrax is treated with a single oral antimicrobial drug for a duration of 7-10 days for naturally acquired anthrax and 60 days for bioterrorism-related exposure.  In case of systemic anthrax without meningitis, the initial treatment should include 2 antimicrobial drugs for 2 weeks or until the patient is clinically stable, whichever is longer.  In case of systemic anthrax with suspected or confirmed meningitis, the initial treatment should include 3 antimicrobial drugs for 2 weeks or until the patient is clinically stable, whichever is longer.  Once patients with systemic illness who were exposed to aerosolized spores have completed initial combination treatment, they should be transitioned to single-agent oral treatment to prevent relapse from surviving B. anthracis spores.  These patients should be monitored at all times to evaluate the need for supportive care measures, such as hemodynamic support, mechanical ventilation, corticosteroids, procedures, and surgical interventions in certain occasions.  An antitoxin should be added to combination antibiotic treatment.  Currently there are 2 antitoxins in the CDC Strategic National Stockpile: raxibacumab and Anthrax Immune Globulin Intravenous (AIGIV).

## Prevention
Prevention of anthrax infection can be achieved with post-exposure prophylaxis antibiotics and vaccination. The US Advisory Committee on Immunization Practices recommended 60 days of antibiotic drug prophylaxis for immediate protection and a 3-dose series of Anthrax Vaccine Adsorbed (AVA) for long-term protection.  Postexposure prophylaxis of asymptomatic persons should start as soon as possible after exposure because its effectiveness decreases with delay in implementation.  Everyone exposed to aerosolized B. anthracis spores should receive a full 60 days of post-exposure prophylaxis antimicrobial drugs, whether they are unvaccinated, partially vaccinated, or fully vaccinated.  Protective measures should also be implemented to prevent the transmission of the disease.

## Cost-Effectiveness of Therapy
Given the morbidity and mortality associated with Anthrax infection, and the low cost of safe and effective antibiotics, current pharmacotherapy to treat anthrax is relatively cost-effective.

## Future or Investigational Therapies
Given the safety and efficacy of current vaccines and antibiotics, there are not a large number of new agents under development to treat anthrax.