JAMA Consensus Statement: Anthrax as a Biological Weapon. (Special Feature).

The full text of the following feature was published in: Inglesby, TV, Henderson DA, Bartlett JG, et al, for the Working Group on Civilian Biodefense: Anthrax as a biological weapon: medical and public health management. JAMA, Volume 281, No. 18, May 12, 1999, pp 1735-1745.

HISTORY OF CURRENT THREAT

* Anthrax is one of the most crippling biological weapons and one of the most feared terrorist scenarios.

* Aerosol dispersal could inflict widespread disease because of its odorless, invisible spores and ability to penetrate through buildings and travel many kilometers before disseminating.

* At least 17 nations, including Iraq and the former Soviet Union, are known to have or are suspected of having biowarfare programs.

* Historical experience consists of accidental release of anthrax in the former Soviet Union in 1979, which caused 68 deaths, and 8 separate aerosol attacks of anthrax and botulism in Japan, which did not produce illness.

* The US Congressional Office of Technology Assessment and the World Health Organization (WHO) estimate that 50 kg to 100 kg of anthrax could cause 100,000 to 3 million deaths in a heavily populated area-more lethal than a hydrogen bomb.

EPIDEMIOLOGY

* In animals, anthrax occurs most often in herbivores, which ingest spores from plants.

* Although animal vaccination has been effective, soil samples throughout the world continue to show contamination of anthrax spores.

* Little information on food and water contamination is available.

* Types of human anthrax infections are inhalational, cutaneous, and gastrointestinal.

* The cutaneous form is the most common, with 224 cases reported in the US between 1944 and 1994 (10,000 cases in Zimbabwe 1979 to 1985). It is easier to recognize, simpler to treat, and less likely to be fatal.

* The gastrointestinal form is rarely reported, although outbreaks caused by eating undercooked contaminated meat occurred in Africa and Asia in the 1980s.

* Inhalational anthrax is rarest, with only 18 reported cases in the US between 1900 and 1978. The majority of these cases occurred in high-risk groups, such as industrial mill or laboratory workers. This is the form most likely to be dispersed as an aerosolized weapon.

MICROBIOLOGY

* Bacillus anthracis is an aerobic, gram-positive, spore-forming, nonmotile Bacillus species. The name derives from the Greek anthrakis, meaning coal, because the disease causes black skin lesions.

* The vegetative cell is 1-8 [mu]m x 1-1.5 [mu]m in size.

* Spores are about 1 [mu]m, and grow readily on ordinary laboratory media with a "jointed bamboo-rod" cellular appearance and a "curled-hair" colonial appearance. Spores germinate in amino acid, nucleoside, and glucose environments, such as that of human blood or tissue.

Unlike vegetative bacteria, the hardy B anthracis spore can survive for years.

PATHOGENESIS AND CLINICAL MANIFESTATIONS

Inhalational

* Incomplete data from the 18 cases [at the time this paper was published] of inhalational anthrax in the US in this century make early diagnosis difficult. In the initial stage, lasting from hours to a few days, patients developed symptoms including fever, dyspnea, cough, headache, vomiting, chills, weakness, abdominal pain, and chest pain. Some patients appeared to briefly recover, while others progressed quickly to the second stage, with fever, dyspnea, diaphoresis, and shock. Death sometimes occurred within hours.

* Modern medical therapy might decrease the 89% mortality rate reported in previous cases. Clincal records from the former Soviet Union are not available, and most of the US cases occurred before the development of antibiotics and/or critical care units.

* Animal studies suggest that mortality rates could also improve with correction of electrolyte disturbances/acid-base imbalance, glucose infusion, and early mechanical ventilation/vasopressor administration in conjunction with antibiotics.

Cutaneous

* Cutaneous anthrax most often affects areas of cuts or abrasions on skin in exposed areas such as the arms, hands, face, and neck.

* Twelve days is the longest latency period recorded.

* Stages include local edema, a macule or papule enlarging into a round ulcer by the second day, 1-mm to 3-mm vesicles, and a painless, depressed black eschar, which dries and falls off within 1 to 2 weeks.

* Antibiotics do not change eschar formation and healing but prevent the likelihood of systemic disease and death. Without antibiotics, the mortality rate is 20%.

Gastrointestinal

* Gastrointestinal anthrax is the result of the deposition and germination of spores in the upper or lower gastrointestinal tract.

* Symptoms include nausea, vomiting, and malaise, progressing to bloody diarrhea, acute abdomen, or sepsis, and occasionally massive ascites. Advanced infection may appear similar to the sepsis syndrome in the two other forms of anthrax.

* Mortality rate would be high because early diagnosis is difficult, although some professionals believe medical intervention similar to that used for inhalational anthrax may be effective.

DIAGNOSIS

* Diagnosis of anthrax may be made from an unusual radiologic finding, identification in the microbiology laboratory, or recognition of specific pathologic findings. For example, flu-like symptoms along with a widened mediastinum on chest x-ray in a previously healthy patient should prompt immediate action.

* Since rapid diagnostic tests for anthrax are available only at national reference laboratories, the most useful test is the standard blood culture. If the possibility of anthrax is suspected, a preliminary diagnosis can be made within 36 to 48 hours.

* If the laboratory has not been alerted to the possibility of anthrax, B anthracis may not be correctly identified.

* A Gram stain and culture of vesicular fluid will confirm cutaneous anthrax.

* The first evidence of biological warfare most likely will occur from patients with inhalational anthrax symptoms.

* Suspicion of an anthrax illness must be reported immediately to the local or state health department, local hospital epidemiologist, and local or state health laboratory. Definitive tests can then be arranged through a reference laboratory and/or the US Army Medical Research Institute of Infectious Diseases (USAMRIID) at Fort Detrick, Maryland.

VACCINATION

* The US anthrax vaccine is made from the cell-free filtrate of a nonencapsulated attenuated strain of B anthracis at Bioport Corp in Lansing, Michigan.

* The principal antigen providing immunity is the protective antigen.

* Required for all US military active- and reserve-duty personnel, the vaccine is given in a six-dose series. No serious side effects occurred in the 590,000 doses administered to US Armed Forces through March 1, 1999.

* Current production rates would require years to provide sufficient quantities for civilians, and populationwide vaccination has not been recommended. However, vaccination of some essential service personnel should be considered.

* In the event of a biological attack, postexposure vaccination, if available, should be used along with antibiotic administration.

THERAPY

* No clinical studies have been conducted on the treatment of inhalational anthrax in humans.

* Because resistance to penicillin- and tetracycline-class antibiotics is possible, it is recommended that ciprofloxacin or other fluoroquinolone therapy be initiated in adults with presumed inhalational anthrax infection.

* When the B anthracis strain has been identified, the most widely available, efficacious, and least toxic antibiotic should be administered as soon as possible. A delay of even hours decreases the survival rate.

* Although other antibiotics have been effective against B anthracis in vitro, they have not been tested in humans or animal studies and should be used only if the previously mentioned ones are not available.

* Sulfamethoxazole, trimethoprim, cefuroxirne, cefotaxime sodium, aztreonam, and ceftazidime should not be used because of natural resistance of B anthracis.

* Cutaneous anthrax may be treated with oral fluoroquinolone or tetracycline antibiotics, as well as amoxicillin. In bioterrorism circumstances with aerosol exposure, treatment should last 60 days.

* The same guidelines apply for immunosuppressed adults and children.

POSTEXPOSURE PROPHYLAXIS

* The FDA has no guidelines regarding postexposure antibiotics.

* The same regimen as prescribed above applies: continue prophylaxis for 60 days.

* National, state, and local health agencies should develop guidelines immediately following the use of anthrax as a biological weapon.

MANAGEMENT OF SPECIAL GROUPS

* The working group recommends cipro-floxacin or other fluoroquinolones and doxycycline for treating anthrax in children and pregnant women.

* Penicillin should be substituted for fluoroquinolone where possible.

* The serious risk of infection following an anthrax attack supersedes normal precautions in the use of these drugs; but doxycydine should be administered only if antibiotic susceptibility testing, exhaustion of drug supplies, or allergic reaction precludes use of penicillin or ciprofloxacin.

* Since these antibiotics are excreted in breast milk? a breast-feeding mother and infant should be treated with the same antibiotic, based on safety and effectiveness for the child.

* Although the US vaccine is approved for adult use only, it is likely to be effective in children.

INFECTION CONTROL

* Anthrax is not contagious, and normal precautions are adequate.

* Standard hospital disinfectants are effective in cleaning contaminated surfaces.

* At the first indication of anthrax attack, local hospital microbiology laboratories should be notified.

* Cremation is the preferred treatment of human or animal bodies after death, and autopsy instruments should be autoclaved or incinerated.

DECONTAMINATION

* The greatest risk to humans is during the time anthrax spores remain airborne, called primary aerosolization. The length of this period depends on meteorologic conditions and type of aerosol used.

* Onset of disease has occurred as late as 43 days after contact.

* Onset after 7 days may be due to secondary aerosolization, originating from the soil or other surfaces, but this risk is low. Although decontamination of buildings and large areas reduces the risk of acquiring anthrax by secondary aerosolization, this task would be difficult and is not indicated.

* Anyone who has been in contact with a substance alleged to be anthrax should thoroughly wash exposed skin and articles of clothing with soap and water and receive antibiotic prophylaxis while the substance is being identified.

* Upon positive identification of anthrax, the CDC and USAMRIID should be notified.

ADDITIONAL RESEARCH

* An effective response to a bioterrorist attack involving anthrax will require additional knowledge of the organism and its genetics and pathogenesis, improved rapid diagnostic techniques, improved prophylactic and therapeutic regimens, and an improved second-generation vaccine.