Overview of Anthrax
(Splenic fever, Siberian ulcer, Charbon, Milzbrand)
Anthrax is a zoonotic disease caused by the sporeforming bacterium Bacillus anthracis. Anthrax is most common in wild and domestic herbivores (eg, cattle, sheep, goats, camels, antelopes) but can also be seen in people exposed to tissue from infected animals, to contaminated animal products, or directly to B anthracis spores under certain conditions. Depending on the route of infection, host factors, and potentially strain-specific factors, anthrax can have several different clinical presentations. In herbivores, anthrax commonly presents as an acute septicemia with a high fatality rate, often accompanied by hemorrhagic lymphadenitis. In dogs, people, horses, and pigs, it is usually less acute although still potentially fatal.
B anthracis spores can remain viable in soil for many years. During this time, they are a potential source of infection for grazing livestock but generally do not represent a direct risk of infection for people. Grazing animals may become infected when they ingest sufficient quantities of these spores from the soil. In addition to direct transmission, biting flies may mechanically transmit B anthracis spores from one animal to another. The latter follows when there have been rains encouraging a high fly hatch and reporting has been delayed on the index ranch, such that there are 4–6 moribund or dead cattle for the flies to feed on. Feed contaminated with bone or other meal from infected animals can serve as a source of infection for livestock, as can hay muddy with contaminated soil. Raw or poorly cooked contaminated meat is a source of infection for zoo carnivores and omnivores; anthrax resulting from contaminated meat consumption has been reported in pigs, dogs, cats, mink, wild carnivores, and people.
Underdiagnosis and unreliable reporting make it difficult to estimate the true incidence of anthrax worldwide. However, anthrax has been reported from nearly every continent and is most common in agricultural regions with neutral or alkaline, calcareous soils. In these regions, anthrax periodically emerges as epizootics among susceptible domesticated and wild animals. These epizootics are usually associated with drought, flooding, or soil disturbance, and many years may pass between outbreaks. During interepidemic periods, sporadic cases may help maintain soil contamination. But it is now absent from some countries in western Europe, north Africa, and east of the Mississippi in the USA.
Human cases may follow contact with contaminated carcasses or animal products. The risk of human disease in these settings is comparatively small in developed countries, partly because people are relatively resistant to infection. However, in developing countries, each affected cow can result in up to 10 human cases because of home slaughter and sanitation issues. In cases of natural transmission, people exhibit primarily cutaneous disease (>95% of all cases). GI anthrax (including pharyngeal anthrax) may be seen among human populations after consumption of contaminated raw or undercooked meat. Under certain artificial conditions (eg, laboratories, animal hair processing facilities, exposure to weaponized spore products), people may develop a highly fatal form of disease known as inhalational anthrax or woolsorter’s disease. Inhalational anthrax is an acute hemorrhagic lymphadenitis of the mediastinal lymph nodes, often accompanied by hemorrhagic pleural effusions, severe septicemia, meningitis, and a high mortality rate. Of late, injection anthrax has emerged in conjunction with contaminated heroin.
The precise incidence of anthrax among animals in the USA is unknown. Throughout the past hundred years, animal infections have been seen in nearly all states, with highest frequency from the Midwest and West. Presently, anthrax is enzootic in west Texas and northwest Minnesota; sporadic in south Texas, Montana, eastern North and South Dakota; and only occasionally seen elsewhere. The annual incidence of human anthrax in the USA has declined from ~130 cases annually in the beginning of the last century to no reported cases in 2004–2005.
In addition to causing naturally occurring anthrax, B anthracis has been manufactured as a biologic warfare agent. B anthracis was used successfully as a weapon of terrorism in 2001, killing 5 people and causing disease in 22. Probably because of the method of delivery (via mail), no known animal disease resulted from this attack. Weaponized spores represent a threat to both human and animal populations. The World Health Organization has estimated that 50 kg of B anthracis released upwind of a population center of 500,000 could result in 95,000 deaths and 125,000 hospitalizations. The effect on animal populations has not been estimated, but because livestock are more susceptible to B anthracis infection than primates, the outcome of an aerosol attack with B anthracis spores against livestock would result in higher and earlier mortality and morbidity rates than among a human population. Subsequent to the 1979 Severdlovsk incident, human cases were seen up to 4 km from the source, but dead sheep were noted 64 km downwind, and in villages between.
After wound inoculation, ingestion, or inhalation, spores infect macrophages, germinate, and proliferate. In cutaneous and GI infection, proliferation can occur at the site of infection and in the lymph nodes draining the site of infection. Lethal toxin and edema toxin are produced by B anthracis and respectively cause local necrosis and extensive edema, which are frequent characteristics of the disease. As the bacteria multiply in the lymph nodes, toxemia progresses and bacteremia may ensue. With the increase in toxin production, the potential for disseminated tissue destruction and organ failure increases. After vegetative bacilli are discharged from an animal after death (by carcass bloating, scavengers, or postmortem examination), the oxygen content of air induces sporulation. Spores are relatively resistant to extremes of temperature, chemical disinfection, and dessication. Necropsy is discouraged because of the potential for blood spillage and vegetative cells to be exposed to air, resulting in large numbers of spores being produced. Because of the rapid pH change after death and decomposition, vegetative cells in an unopened carcass quickly die without sporulating.
Typically, the incubation period is 3–7 days (range 1−14 days). The clinical course ranges from peracute to chronic. The peracute form (common in cattle and sheep) is characterized by sudden onset and a rapidly fatal course. Staggering, dyspnea, trembling, collapse, a few convulsive movements, and death may occur in cattle, sheep, or goats with only a brief evidence of illness.
In acute anthrax of cattle and sheep, there is an abrupt fever and a period of excitement followed by depression, stupor, respiratory or cardiac distress, staggering, convulsions, and death. Often, the course of disease is so rapid that illness is not observed and animals are found dead. Body temperature may reach 107°F (41.5°C), rumination ceases, milk production is materially reduced, and pregnant animals may abort. There may be bloody discharges from the natural body openings. Some infections are characterized by localized, subcutaneous, edematous swelling that can be quite extensive. Areas most frequently involved are the ventral neck, thorax, and shoulders.
The disease in horses may be acute. Signs may include fever, chills, severe colic, anorexia, depression, weakness, bloody diarrhea, and swellings of the neck, sternum, lower abdomen, and external genitalia. Death usually occurs within 2–3 days of onset.
Although relatively resistant, pigs may develop an acute septicemia after ingestion of B anthracis, characterized by sudden death, oropharyngitis, or more usually a mild chronic form. Oropharyngeal anthrax is characterized by rapidly progressive swelling of the throat, which may cause death by suffocation. In the chronic form, pigs show systemic signs of illness and gradually recover with treatment. Some later show evidence of anthrax infection in the cervical lymph nodes and tonsils when slaughtered (as apparently healthy animals). Intestinal involvement is seldom recognized and has nonspecific clinical characteristics of anorexia, vomiting, diarrhea (sometimes bloody), or constipation.
In dogs, cats, and wild carnivores, the disease resembles that seen in pigs. In wild herbivorous animals, the expected course of illness and lesions varies by species but resembles, for the most part, anthrax in cattle.
Rigor mortis is frequently absent or incomplete. Dark blood may ooze from the mouth, nostrils, and anus with marked bloating and rapid body decomposition. If the carcass is inadvertently opened, septicemic lesions are seen. The blood is dark and thickened and fails to clot readily. Hemorrhages of various sizes are common on the serosal surfaces of the abdomen and thorax as well as on the epicardium and endocardium. Edematous, red-tinged effusions commonly are present under the serosa of various organs, between skeletal muscle groups, and in the subcutis. Hemorrhages frequently occur along the GI tract mucosa, and ulcers, particularly over Peyer’s patches, may be present. An enlarged, dark red or black, soft, semifluid spleen is common. The liver, kidneys, and lymph nodes usually are congested and enlarged. Meningitis may be found if the skull is opened.
In pigs with chronic anthrax, the lesions usually are restricted to the tonsils, cervical lymph nodes, and surrounding tissues. The lymphatic tissues of the area are enlarged and are a mottled salmon to brick-red color on cut surface. Diphtheritic membranes or ulcers may be present over the surface of the tonsils. The area around involved lymphatic tissues generally is gelatinous and edematous. A chronic intestinal form involving the mesenteric lymph nodes is also recognized.
A diagnosis based on clinical signs alone is difficult. Confirmatory laboratory examination should be attempted if anthrax is suspected. Because the vegetative cell is not robust and will not survive 3 days in transit, the optimal sample is a cotton swab dipped in the blood and allowed to dry. This results in sporulation and the death of other bacteria and contaminants. For carcasses dead >3 days, either the nasal turbinates should be swabbed or turbinate samples removed. Pigs with localized disease are rarely bacteremic, so a small piece of affected lymphatic tissue that has been collected aseptically should be submitted. Before submission, the receiving reference laboratory should be contacted regarding appropriate specimen labelling, handling, and shipping procedures.
Specific diagnostic tests include bacterial culture, PCR tests, and fluorescent antibody stains to demonstrate the agent in blood films or tissues. Western blot and ELISA tests for antibody detection are available in some reference laboratories. Lacking other tests, fixed blood smears stained with Loeffler’s or MacFadean stains can be used and the capsule visualized; however, this can result in ~20% false positives.
In livestock, anthrax must be differentiated from other conditions that cause sudden death. In cattle and sheep, clostridial infections, bloat, and lightning strike (or any cause of sudden death) may be confused with anthrax. Also, acute leptospirosis, bacillary hemoglobinuria, anaplasmosis, and acute poisonings by bracken fern, sweet clover, and lead must be considered in cattle. In horses, acute infectious anemia, purpura, colic, lead poisoning, lightning strike, and sunstroke may resemble anthrax. In pigs, acute classical swine fever, African swine fever, and pharyngeal malignant edema are diagnostic considerations. In dogs, acute systemic infections and pharyngeal swellings due to other causes must be considered.
Anthrax is controlled through vaccination programs, rapid detection and reporting, quarantine, treatment of asymptomatic animals (postexposure prophylaxis), and burning or burial of suspect and confirmed cases. In livestock, anthrax can be controlled largely by annual vaccination of all grazing animals in the endemic area and by implementation of control measures during epizootics. The nonencapsulated Sterne-strain vaccine is used almost universally for livestock immunization. Vaccination should be done at least 2–4 wk before the season when outbreaks may be expected. Because this is a live vaccine, antibiotics should not be administered within 1 wk of vaccination. Before vaccination of dairy cattle during an outbreak, all of the procedures required by local laws should be reviewed and followed. Human anthrax vaccines currently licensed and used in the USA and Europe are based on filtrates of artificially cultivated B anthracis.
Early treatment and vigorous implementation of a preventive program are essential to reduce losses among livestock. Livestock at risk should be immediately treated with a long-acting antibiotic to stop all potential incubating infections. This is followed by vaccination ~7–10 days after antibiotic treatment. Any animals becoming sick after initial treatment and/or vaccination should be retreated immediately and revaccinated a month later. Simultaneous use of antibiotics and vaccine is inappropriate, because available commercial vaccines for animals in the USA are live vaccines. Animals should be moved to another pasture away from where the bodies had lain and any possible soil contamination. Suspected contaminated feed should be immediately removed. Domestic livestock respond well to penicillin if treated in the early stages of the disease. Oxytetracycline given daily in divided doses also is effective. Other antibacterials, including amoxicillin, chloramphenicol, ciprofloxacin, doxycycline, erythromycin, gentamicin, streptomycin, and sulfonamides also can be used, but their effectiveness in comparison with penicillin and the tetracyclines has not been evaluated under field conditions.
In addition to therapy and immunization, specific control procedures are necessary to contain the disease and prevent its spread. These include the following: 1) notification of the appropriate regulatory officials; 2) rigid enforcement of quarantine (after vaccination, 2 wk before movement off the farm, 6 wk if going to slaughter); 3) prompt disposal of dead animals, manure, bedding, or other contaminated material by cremation (preferable) or deep burial; 4) isolation of sick animals and removal of well animals from the contaminated areas; 5) cleaning and disinfection of stables, pens, milking barns, and equipment used on livestock; 6) use of insect repellents; 7) control of scavengers that feed on animals dead from the disease; and 8) observation of general sanitary procedures by people who handle diseased animals, both for their own safety and to prevent spread of disease. Contaminated soils are very difficult to completely decontaminate, but formaldehyde will be successful if the level is not excessive. The process generally requires removal of soil.
Human infection is controlled through reducing infection in livestock, veterinary supervision of animal production and slaughter to reduce human contact with potentially infected livestock or animal products, and in some settings either pre- or postexposure prophylaxis. In countries where anthrax is common and vaccination coverage in livestock is low, people should avoid contact with livestock and animal products that were not inspected before and after slaughter. In general, consumption of meat from animals that have exhibited sudden death, meat obtained via emergency slaughter, and meat of uncertain origin should be avoided. Routine vaccination against anthrax is indicated for individuals engaged in work involving large quantities or concentrations of B anthracis cultures or activities with a high potential for aerosol production. Laboratory workers using standard Biosafety Level 2 practices in the routine processing of clinical samples are not at increased risk of exposure to B anthracis spores. The risk for workers who come into contact with imported animal hides, furs, bone meal, wool, animal hair, or bristles has been reduced by improvements in industry standards and import restrictions. Routine preexposure vaccination is recommended for people in this group only when these standards and restrictions are insufficient to prevent exposure to anthrax spores. Routine vaccination of veterinarians in the USA is not recommended because of the low incidence of animal cases. However, vaccination may be indicated for veterinarians and other high-risk individuals handling potentially infected animals in areas where there is a high incidence of anthrax cases.
The CDC has recommended that those at risk of repeated exposure to B anthracis spores in response to a bioterrorism attack should be vaccinated. Those groups include some emergency first responders, federal responders, and laboratory workers. Vaccination in anticipation of a terrorist attack is not recommended for other populations.
For people, postexposure prophylaxis against B anthracis is recommended after an aerosol exposure to B anthracis spores. Prophylaxis may consist of antibiotic therapy alone or the combination of antibiotic therapy and vaccination, if vaccine is available (most human vaccines are not live). Although there is no approved regimen, the CDC has suggested that antibiotics may be discontinued after three doses of vaccine have been administered according to the standard schedule (0, 2, and 4 wk). Because of availability and ease of dosing, doxycycline or ciprofloxacin may be chosen initially for antibiotic chemoprophylaxis until the susceptibility of the infecting organism is determined. Penicillin and doxycycline are approved by the FDA for treatment of anthrax in people and have traditionally been considered the drugs of choice. Both ciprofloxacin and ofloxacin have demonstrated in vitro activity against B anthracis. Although naturally occurring B anthracis resistance to penicillin is infrequent, it is reported; resistance to other antibiotics has been noted. Antibiotics are effective against the germinated form of B anthracis but are not effective against the spore form of the organism. Spores may survive in the mediastinal lymph nodes in the lungs for months without germination in nonhuman primates.
There are currently no approved vaccination regimens for postexposure prophylaxis after B anthracis exposures. Although postexposure chemoprophylaxis using antibiotics alone has been effective in animal models, the definitive length of treatment remains unclear. Antibiotic chemoprophylaxis may be switched to penicillin VK or amoxicillin in children or pregnant women once antibiotic susceptibilities are known and the organism is found to be susceptible to penicillin. The safety and efficacy of anthrax vaccine in children or pregnant women has not been studied; therefore, a recommendation for use of vaccine in these groups cannot be made. Although the shortened vaccine regimen has been effective when used in a postexposure regimen that includes antibiotics, the duration of protection from vaccination is not known. The existing evidence suggests that vaccine protection is adequate for 12 mo. If subsequent exposures occur, additional vaccinations may be required.
There are no definitive recommendations for postexposure prophylaxis after cutaneous or GI exposures of people to B anthracis. Based on the slow progression of disease, low fatality rate, and ease of antibiotic treatment of cutaneous anthrax, and the general low risk of cutaneous disease after natural exposure, postexposure prophylaxis is not recommended after direct cutaneous exposure to contaminated animals or animal products. However, immediate washing of the exposed areas is advised. Those exposed should be advised of the signs of cutaneous anthrax (ie, an inflamed but painless area with or without circumferential small vesicles, enlargement of the regional lymph nodes) and should seek medical assistance if illness develops. Because of the high fatality rate and rapid progression of GI anthrax, serious consideration should be given to initiating postexposure antibiotic prophylaxis for those who consume contaminated undercooked or raw meat. There is no current indication for vaccination after either cutaneous exposure or ingestion.