Anthrax differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

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.

Differential Diagnosis

Cutaneous Anthrax

• A history of exposure to contaminated animal materials, occupational exposure, and living in an endemic area is crucial when considering a diagnosis of anthrax. A painless, pruritic papule, surrounding vesicles and edema, usually on an exposed region of the body should raise concern of cutaneous anthrax, which is confirmed by the demonstration of Gram-positive encapsulated bacilli on the lesion, and/or positive culture for Bacillus anthracis and/or positive specialized tests.

• The differential diagnosis of the anthrax eschar includes a wide range of infectious and non-infectious conditions, including:

Disease	Findings
Boil (early lesion)	Skin disease caused by the inflammation of hair follicles, thus resulting in the localized accumulation of pus and necrotic tissue. Individual boils may cluster together and form an interconnected network of boils called carbuncles. In severe cases, boils may develop to form abscesses.
Arachnid bites	Spider bites can cause allergic reactions. Symptoms of a spider bite may include erythema, pain and edema of the site.
Erysipelas	Acute streptococcus bacterial infection of the dermis, resulting in inflammation and characteristically extending into underlying fat tissue. Erythematous skin lesion that enlarges rapidly and has a sharply demarcated raised edge. It appears as a red, swollen, warm, hardened and painful rash, similar in consistency to an orange peel. More severe infections can result in vesicles, bullae, and petechiae, with possible skin necrosis. Lymph nodes may be swollen, and lymphedema may occur. Occasionally, a red streak extending to the lymph node can be seen. The infection may occur on any part of the skin including the face, arms, fingers, legs and toes, but it tends to favor the extremities. Fat tissue is most susceptible to infection, along with facial areas typically around the eyes, ears, and cheeks. Repeated infection of the extremities can lead to chronic lymphadenitis.
Glanders	Infectious disease that occurs primarily in horses, mules, and donkeys. It is caused by infection by the bacterium Burkholderia mallei, usually by ingestion of contaminated food or water. Symptoms of glanders include the formation of nodular lesions in the lungs and ulceration of the mucous membranes in the upper respiratory tract. The acute form results in coughing, fever and the release of infectious nasal discharge, followed by septicemia and death within days. In the chronic form, nasal and subcutaneous nodules develop, eventually ulcerating. Death can occur within months, while survivors act as carriers.
Plague	Yersinia pestis infection is an infectious disease of animals and humans caused by a bacterium named Yersinia pestis. The typical sign of the most common form of human plague is a swollen and very tender lymph gland, accompanied by pain. The swollen gland is called a "bubo." Bubonic plague should be suspected when a person develops a swollen gland, fever, chills, headache, and extreme exhaustion, and has a history of possible exposure to infected rodents, rabbits, or fleas. A person usually becomes ill with bubonic plague 2 to 6 days after being infected.
Syphilitic chancre	Painless ulceration formed during the primary stage of syphilis. This infectious lesion forms approximately 21 days after the initial exposure to Treponema pallidum, the gram-negative spirochaete bacterium yielding syphilis. Chancres transmit syphilis through direct physical contact. These ulcers usually form on or around the anus, mouth, penis, and vagina.
Ulceroglandular tularemia	Infectious disease caused by the bacterium Francisella tularensis. Symptoms of tularemia depend on how a person was exposed to the tularemia bacteria. These symptoms can include ulcers on the skin or mouth, swollen and painful lymph glands, swollen and painful eyes, and a sore throat.
Rickettsial diseases	Non-motile, Gram-negative, non-sporeforming, highly pleomorphic, obligate intracellular parasites that can present as cocci, rods or thread-like bacteria. May cause conditions, such as the Rocky Mountain spotted fever.
Rhizomucor infections	May cause conditions such as Zygomucosis, which causes necrosis of infected tissues and neural invasion. It is a rare disease often found in patients' lungs with a weakeaned immune system which will create a higher fatal outcome.
Orf	Or "Sore mouth infection” is a viral infection caused by a member of the poxvirus group and is an infection primarily of sheep and goats. Early in the infection, sores appear as blisters and then become crusty scabs. These may be typically found on the lips or mouth.
Vaccinia	Vaccinia virus infection is very mild and is typically asymptomatic in healthy individuals, but it may cause a mild rash and fever.
Cowpox	Skin disease caused by the Cowpox virus that is related to the Vaccinia virus, also causing a skin rash and fever.
Rat-bite fever	Commonly presents with fever, chills, open sore at the site of the bite and rash, which may show red or purple plaques.
Leishmaniasis	Cutaneous leishmaniasis is characterized by one or more cutaneous lesions. Individuals who have cutaneous leishmaniasis have one or more sores on the skin. The sores can change in size and appearance over time. They often end up looking somewhat like a "volcano", with a raised edge and central depression. A scab covers some sores. The sores can be painless or painful. Some people have swollen glands near the sores.
Ecthyma gangrenosum	Ecthyma gangrenosum is an infection of the skin typically caused by Pseudomonas aeruginosa. It is often seen in immunocompromised patients such as those with neutropenia. Ecthyma gangrenosum presents as a round or oval lesion, 1 to 15cm in diameter, with a halo of erythema. A necrotic center is usually present with a surrounding erythematous edge, representing where the organism invaded blood vessels and caused infarctions. These ulcerous lesions are single or multiple, and heal with scar formation, although sepsis resulting from other gram negative bacteria can also cause this condition.
Herpes	Caused by the Varicella-zoster virus, it commonly starts as a painful rash on one side of the face or body. The rash forms blisters that typically scab over in 7-10 days and clears up within 2-4 weeks.

• Generally there are other diseases and conditions lack the characteristic edema of anthrax. The absence of pus, the lack of pain, and the patient’s occupation may provide further diagnostic clues. The outbreak of Rift Valley fever, initially thought to be anthrax in livestock, also affected numerous humans.

• In the differential diagnosis of the severe forms, orbital cellulitis, dacryocystitis and deep tissue infection of the neck, should be considered in the case of severe anthrax lesions involving the face, neck and anterior chest wall. Necrotizing soft tissue infections, particularly group A streptococcal infections and gas gangrene, and severe cellulitis due to staphylococci, should also be considered in the differential diagnosis of severe forms of cutaneous anthrax. Gas and abscess formation are not observed in patients with cutaneous anthrax. Abscess formation is only seen when the lesion is infected with other bacteria, such as streptococci or staphylococci.

Ingestional Anthrax (Oropharyngeal and Gastrointestinal Anthrax)

Oropharyngeal Anthrax

• The list of differential diagnosis of oropharyngeal anthrax includes:

Disease	Findings
Diphtheria	Upper respiratory tract illness characterized by sore throat, low-grade fever, and an adherent membrane (a pseudomembrane) on thetonsils, pharynx, and/or nasal cavity. A milder form of diphtheria can be restricted to the skin. It is caused by Corynebacterium diphtheriae, a facultatively anaerobicGram-positive bacterium
Complicated tonsillitis	Infection of the tonsils which may often cause sore throat and fever. Causes may include adenovirus, rhinovirus, influenza, coronavirus, and respiratory syncytial virus.
Streptococcal pharyngitis	Also known as streptococcal sore throat (Strep throat), is a form of group A streptococcal infection that affects the pharynx, and possibly the larynx and tonsils. It may cause Sudden and severe sore throat, red and enlarged tonsils, yellow and white patches in the throat, dysphagia, tender cervical lymphadenopathy, fever, rash and abdominal pain.
Vincent's angina	Also known as trench mouth, is a polymicrobial infection of the gums leading to inflammation, bleeding, deep ulceration, necrotic gum tissue, and possibly fever.
Ludwig's angina	Serious, potentially life-threatening infection of the tissues of the floor of the mouth, usually occurring in adults with concomitant dental infections. Although other bacteria may be responsible, common agents include streptococci or staphylococci. Common symptoms include swelling, pain and raising of the tongue, swelling of the neck and the tissues of the submandibular and sublingual spaces, malaise, fever, dysphagia (difficulty swallowing) and, in severe cases, stridor or difficulty breathing. Swelling of the submandibular and/or sublingual spaces are distinctive in that they are hard and classically 'board like'. Important signs include the patient not being able to swallow his/her own saliva and the presence of audible stridor as these strongly suggest that airway compromise is imminent.
Parapharyngeal abscess	Collection of pus that has accumulated in a cavity formed by the tissue on the basis of an infectious process (usually caused by bacteria or parasites) or other foreign materials. Common symptoms include pain at the site of the abscess, fever, chills, general discomfort, uneasiness, or ill feeling, headache, local swelling and hardening of tissue.
Deep-tissue infection of the neck	Refers to an infection or abscess located deep in the neck, near the blood vessels, nerves, and muscles. Common causes of deep neck infections include retropharyngeal abscess, parapharyngeal abscess, Ludwig's angina, among others. Symptoms may include asymmetric swelling of the neck face, under the jaw or back of the throat, fever, dysphagia, drooling, voice change, decreased ability to move the neck and sick appearance.

Gastrointestinal Anthrax

• The list of differential diagnosis of gastrointestinal anthrax includes:

Disease	Findings
Food poisoning (in the early stages of intestinal anthrax)	True food poisoning occurs when a person ingests a contaminating chemical or a natural toxin, while most cases of foodborne illness are actually food infection caused by a variety of foodborne pathogenic bacteria, viruses, prions or parasites. Common symptoms include nausea, abdominal pain, vomiting, diarrhea, gastroenteritis, fever, headache, fatigue.
Acute abdomen	Refers to a sudden, severe pain in the abdomen that is less than 24 hours in duration. It is in many cases an emergency condition requiring urgent and specific diagnosis, and the treatment usually involves surgery. Common symptoms include diffuse abdominal pain, bowel distension and bloody diarrhea.
Hemorrhagic gastroenteritis	Although the cause is uncertain, suspected causes include abnormal responses to bacteria or bacterial endotoxin, or a hypersensitivity to food. Profuse vomiting is usually the first symptom, followed by depression and bloody diarrhea with a foul odor. Severe hypovolemia is one of the hallmarks of the disease, and severe hemoconcentration is considered necessary for diagnosis. The progression of HGE is so rapid that hypovolemic shock and death can occur within 24 hours. Disseminated intravascular coagulation (DIC) is a possible sequela of HGE.
Necrotizing enteritis caused by Clostridium perfringens	Some strains of Clostridium perfringens produce toxins which cause food poisoning if ingested. Common symptoms include nausea, abdominal pain, vomiting, diarrhea, gastroenteritis, fever, headache, fatigue.
Dysentery (amebic or bacterial)	A cause of bloody diarrhea, any diarrheal episode in which the loose or watery stools contain visible red blood. Dysentery is most often caused by Shigella species (bacillary dysentery) or Entamoeba histolytica (amoebic dysentery).

Inhalational Anthrax (Pulmonary, Mediastinal, and Respiratory Anthrax)

• The list of differential diagnosis of inhalation anthrax includes:

Disease	Findings
Mycoplasma pneumoniae	A form of bacterial pneumonia which is caused by bacteria of the Mycoplasma genus. Symptoms are generally mild and appear over a period of 1 to 3 weeks. Common symptoms include: chest; chills; cough; excessive sweating; fever; headache; sore throat.
Legionnaires' disease	Infectious disease caused by bacteria belonging to the genus Legionella. Symptoms of Legionnaires' disease may include: chest pain; coughing up blood; fever; gastrointestinal symptoms, such as diarrhea, nausea, vomiting, and abdominal pain; general discomfort, uneasiness, or malaise; headache; joint pain; ataxia; loss of energy; muscle pain and stiffness; nonproductive cough; chills and shortness of breath.
Psittacosis	Zoonotic infectious disease caused by a bacterium called Chlamydophila psittaci (formerly Chlamydia psittaci) and contracted from parrots and other birds. Psittacosis symptoms are due to secondary bacteremia from reticuloendothelial system. It is associated with constitutional symptoms such as: fever; headache; chills; malaise; fatigue; symptoms of pneumonia/respiratory system: dry cough; shortness of breath; blood-tinged sputum at times; sore throat; and epistaxis.
Tularemia	Infectious disease caused by the bacterium Francisella tularensis. Symptoms of tularemia depend on how a person was exposed to the tularemia bacteria. These symptoms can include ulcers on the skin or mouth, swollen and painful lymph glands, swollen and painful eyes, and a sore throat.
Q fever	Caused by infection with Coxiella burnetii. Common symptoms include: dry cough; fever; headache; arthralgia; muscle pain; abdominal pain; chest pain; jaundice and rash.
Viral pneumonia	Inflammation of the lung caused by a virus. Symptoms of viral pneumonia often begin slowly and may not be severe at first. The most common symptoms of pneumonia include: cough; fever; chills and shortness of breath.
Histoplasmosis	Disease caused by the fungus Histoplasma capsulatum. Its symptoms vary greatly, but the disease primarily affects the lungs. Common symptoms include: chills; cough; fever; shortness of breath; and unintentional weight loss.
Coccidiomycosis	Fungal disease caused by Coccidioides immitis or C. posadasii. It can be caused by breathing coccidioides spores in the air, especially after a soil disturbance. Symptomatic infection usually presents as an influenza-like illness with fever, cough, headaches, rash, and myalgia. Some patients fail to recover and develop chronic pulmonary infection or widespread disseminated infection (affecting meninges, soft tissues, joints, and bone).
Malignancy	Disease where epithelial (internal lining) tissue in the lung grows out of control. Symptoms of lung cancer (bone pain, fever, weight loss) are nonspecific; in the elderly, these may be attributed to comorbid illness.

Anthrax Meningitis

• Meningitis is a potential complication of anthrax infection. The list of differential diagnosis of anthrax meningitis includes:

Disease	Findings
Acute meningitis	Inflammation of the protective membranes covering the central nervous system, known collectively as the meninges. Common symptoms include: headache is the most common symptom of meningitis; nuchal rigidity; fever; and altered mental status.
Cerebral malaria	Mosquito-borne infectious disease of humans and other animals caused by parasitic protozoans of the genus Plasmodium. Common signs and symptoms may include: fever, no rash, no lymphadenopathy; hypoglycemia and seizures.
Subarachnoid hemorrhage	Bleeding into the subarachnoid space surrounding the brain. The classic symptom of subarachnoid hemorrhage is thunderclap headache. Other symptoms may include: double vision; nausea and vomiting; neck pain; numbness; personality changes such as confusion and irritability; speech disturbance; sudden or decreased consciousness; weakness on one side of the body and severe headache: commonly starts suddenly and after a popping or snapping feeling in the head.

• The definitive diagnosis is obtained by visualization of the capsulated bacilli in the cerebrospinal fluid and/or by culture.

Anthrax Sepsis

• Sepsis is a potential complication of anthrax infection.

Disease

Findings

Sepsis

Whole-body inflammatory state caused by infection. Symptoms of sepsis are often related to the underlying infectious process. When the infection crosses into the bloodstream the resulting symptoms of sepsis occur: fever and capillary leak syndrome can develop with severe swelling, edema, and third spacing of fluids. General symptoms can include flu-like symptoms, as well as chills or rigors. If the respiratory system is the primary source for sepsis then sore throat, productive cough, and pleuritic chest pain may be present.

• The definitive diagnosis of anthrax is made by the isolation of Bacillus anthracis from the primary lesion, from blood cultures or by detection of the toxin or DNA of B. anthracis in these specimens.