Diagnosis Synopsis
Inhalational anthrax is an often-fatal bacterial infection caused by Bacillus anthracis, an encapsulated, gram-positive, spore-forming bacillus. Extremely rare in normal circumstances, inhalational anthrax reaches a mortality rate of nearly 90% if treatment is not started in the prodromal phase.

B. anthracis has been classified by the CDC as a Category A bioterrorism agent due to its high lethality, hardiness, and ease of weaponization. The spores, which are resistant to heat, UV light, microwave radiation and many otherwise useful disinfectants, can remain dormant in soil for years. If anthrax were to be weaponized, the most likely method of dispersal would be by aerosol release, however the anthrax events of 2001 proved that dissemination of anthrax powder by mail is also an effective dispersal method.

A single case of inhalational anthrax may represent a bioterrorist threat and a public health emergency. The incubation period for inhalational anthrax is usually 1 to 13 days, and rarely up to 60 days. In the past there were considered to be two stages of Anthrax (early and late). Based upon the clinical, radiologic and microbiologic findings of the 11 inhalational anthrax victims in 2001, three stages have been identified:

Early-prodromal: The first stage consists of nonspecific symptoms such as fever, dyspnea, cough, headache, vomiting, chills, weakness, abdominal pain, and chest pain. Laboratory tests are also nonspecific at this stage. If diagnosed in the early prodrome stage the prognosis is very good if the appropriate antibiotics are instituted. These initial symptoms occur for 24 to 48 hours and the patient may show signs of transient improvement after 2 to 4 days.

Intermediate-progressive: Inclusion criteria can be any one of the following: positive blood cultures, mediastinal adenopathy or pleural effusions. Patient may also have non-specific findings such as high fever, dyspnea, confusion, syncope, and nausea/vomiting. If diagnosed in this stage the prognosis is still good if antibiotics are administered, pleural fluid is drained, and supportive care is provided.

Late-fulminant: Inclusion criteria can be one of the following: meningitis, respiratory failure (requiring mechanical ventilation), or shock. Findings from the previous stages may be present. These latter fatal manifestations are believed to be the result of exotoxins secreted by the anthrax bacilli (lethal factor, edema factor, protective antigen). If diagnosed in this stage the prognosis is poor; survival is much less likely.

Exact mortality rates are hard to determine. Historically, mortality rates have been as high as 89%, but many of these cases were before the development of critical care units or even antibiotics. Prior to the events of 2001, there had not been a reported case of inhalational anthrax since 1978. In 2001 there were 11 cases of inhalational anthrax attributed to the terrorist events, 5 of which resulted in death.

B. Anthracis is present in both domestic and wild animals throughout the world (mainly in agricultural regions of South and Central America, Southern and Eastern Europe, Asia, Africa, the Caribbean, and the Middle East) and can be transmitted by their meat, wool or hides. Therefore, veterinarians and those in the meat, wool or hide processing industries are the most at risk for contracting naturally occurring inhalational anthrax. Inhalational anthrax should be considered in postal workers and those who handle mail or packages when the patient presentation includes the symptoms listed above. Anthrax is rarely found in animals in the United States. Person-to-person transmission of inhalational anthrax does not occur.

The anthrax vaccine is a cell-free filtrate vaccine. The CDC regulates its use. In 2002, the United States Department of Defense reintroduced the vaccination of military personnel and essential emergency civilians against anthrax.

Suspected or confirmed cases of inhalational anthrax must be reported immediately to your local or state department of health. The CDC recommends standard contact precautions (gloves, gown, mask, eye protection, and frequent hand washing).

Look For
Chest x-ray or CT shows enlarged, high-density mediastinal and hilar lymphadenopathy along with pleural effusions. Pulmonic infiltrates may be seen but are not common. The late-fulminant stage may include meningitis, respiratory failure, or shock.

Initial symptoms are followed by a sudden onset of high fever and severe respiratory distress along with cyanosis, hypotension, shock, respiratory failure, and sudden death.

Diagnostic Pearls
Pulmonic infiltrates, previously thought rare, were seen in the patients infected in 2001. Rhonchi may be present. Although nasal congestion and rhinorrhea occur often in influenza and influenza-like illnesses, only rarely are they seen in patients with inhalational anthrax.

Differential Diagnosis & Pitfalls
Patients with tularemia are far more likely than those with anthrax to have pulmonary infiltrates.
Acute bacterial mediastinitis
Mycoplasma pneumonia
Legionnaire's disease
Psittacosis
Tularemia
Q fever
Viral pneumonia
Brucellosis
Blastomycosis
Histoplasmosis
Coccidioidomycosis
Ruptured aortic aneurysm
Superior vena cava syndrome

Best Tests
Chest x-ray or CT to look for widened mediastinum, pleural effusions, etc.
Gram stain.
Blood culture (obtain before instituting antibiotic therapy).
PCR.
If this is a lethal event, obtain permission for autopsy and alert the pathologist to the possibility of anthrax.

Note: Coordinate all aspects of testing, packaging, and transporting with public health laboratory/Laboratory Response Network (LRN).

Management Pearls
Early antibiotic therapy and cardio-respiratory support are needed. A chest tube or drainage of pleural effusions may be necessary.
In addition, a strong public health response after identification of a single early case may allow for antibiotic prophylaxis with a concomitant vaccine series for other asymptomatic exposed individuals. This can be life saving.

Therapy
Ciprofloxacin or doxycycline should be considered an essential part of first line therapy for inhalational anthrax. Initiate treatment based on a history of exposure or contact, not laboratory test results. Steroids may be considered as an adjunct therapy for patients with severe edema and for meningitis based on experience with bacterial meningitis of other etiologies.

If meningitis is suspected, doxycycline may be less optimal because of poor central nervous system penetration. If intravenous ciprofloxacin is not available, oral ciprofloxacin may be acceptable because it is rapidly and well absorbed from the gastrointestinal tract with no substantial loss by first-pass metabolism. Maximum serum concentrations are attained 1 to 2 hours after oral dosing but may not be achieved if vomiting or ileus is present. There are anecdotal reports of multiple IV drug therapy leading to recovery in two of the 2001 inhalational anthrax patients in the US.

Because of the danger that laboratory manipulated strains will show antibiotic resistance, the CDC recommends the following treatment.

Adults:
IV treatment initially.
Ciprofloxacin, 400 mg IV every 12 hours
or
Doxycycline* 100 mg IV every 12 hours and one or two additional antimicrobials (other agents with in vitro activity such as rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, imipenem, clindamycin, and clarithromycin. Because of concerns of constitutive and inducible beta-lactamases in B. anthracis, penicillin and ampicillin should not be used alone.) Consultation with an infectious disease specialist is advised.

Switch to oral antimicrobial therapy when clinically appropriate:
Ciprofloxacin 500 mg po bid or doxycycline 100 mg po bid.
Duration of treatment: 60 days (IV and po combined) because of the potential persistence of spores after an aerosol exposure.

* Doxycycline may be less optimal if meningitis is suspected because of poor central nervous system penetration.

Children:
IV treatment initially.
Ciprofloxacin 10 to 15 mg/kg IV every 12 hours (not to exceed 1 g/day)
or
Doxycycline*:
>8 years and > 45 kg: 100 mg IV every 12 hours
>8 years and < 45 kg: 2.2 mg/kg IV every 12 hours
<8 years: 2.2 mg/kg IV every 12 hours and one or two additional antimicrobials (other agents with in vitro activity such as rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, imipenem, clindamycin, and clarithromycin. Because of concerns of constitutive and inducible beta-lactamases in B. anthracis, penicillin and ampicillin should not be used alone.) Consultation with an infectious disease specialist is advised.

Switch to oral antimicrobial therapy when clinically appropriate:
Ciprofloxacin 10 to 15 mg/kg po every 12 hours (not to exceed 1 g/day).
or
Doxycycline*:
>8 years and > 45 kg: 100 mg po bid
>8 years and < 45 kg: 2.2 mg/kg po bid
>8 years and < 45 kg: 2.2 mg/kg po bid
Duration of treatment: 60 days (IV and po combined) because of the potential persistence of spores after an aerosol exposure.

* Doxycycline may be less optimal if meningitis is suspected because of poor central nervous system penetration. The American Academy of Pediatrics recommends treatment of young children with tetracyclines for serious infections (e.g., Rocky Mountain spotted fever).

Pregnant women and the immunocompromised:
Same dosages as listed above for adults and children. Although tetracyclines or ciprofloxacin are not recommended during pregnancy, their use may be indicated for life-threatening illness. Adverse effects on developing teeth and bones are dose related; therefore, doxycycline might be used for a short time (7 to 14 days) before 6 months of gestation.

Medical Disclaimer:
The information contained in this web page is intended to be an adjunct to traditional medical information sources. It is not intended to be a substitute for professional medical judgment.

Authors and Editors:
Tener Goodwin Veenema PhD, MPH, MS, CPNP