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CHAPTER 318 BRUCELLOSIS 1891 318 BRUCELLOSIS ROBERT A. SALATA DEFINITION Bacteria of the genus Brucella cause disease with protean manifestations. Infection is transmied to humans from animals as a consequence of occu- pational exposure or ingestion of contaminated milk products. Despite the aempt to institute effective control measures, brucellosis remains a signifi- cant health and economic burden in many countries. The Pathogen Brucellae are slow-growing, small, aerobic, nonmotile, nonencapsulated, non-spore-forming, gram-negative coccobacilli. Brucella abortus, Brucella suis, Brucella melitensis, and Brucella canis are best known to infect humans and are typed on the basis of biochemical, metabolic, and immunologic cri- teria. DNA hybridization analysis shows a high degree of homology among strains. EPIDEMIOLOGY Etiology ere are differences in virulence among the four major species. B. abortus, with a reservoir in cale, is usually associated with mild to moderate sporadic disease; suppurative or disabling complications are rare. B. suis infection, resulting from swine contact, is oſten associated with destructive, suppurative lesions and may have a prolonged course. B. melitensis, with a reservoir in sheep, goats, and camels, may cause severe, acute disease and disabling com- plications. B. canis, spread to humans from infected dogs, causes disease with an insidious onset, frequent relapse, and a chronic course that is indistin- guishable from that of infection related to B. abortus. Studies indicate that there are two new species, Brucella pinnipediae and Brucella cetaceae, related to seals and cetaceans, respectively. Two human cases of marine-associated Brucella infection have been reported. Brucella microti, with high pathogenic- ity, was recently isolated from the common vole, red fox, and soil. No instances of human infection have been reported. Brucellae are also potential agents for bioterrorism. Incidence and Prevalence More than 500,000 cases of brucellosis are reported yearly to the World Health Organization from 100 countries. B. melitensis infection accounts for the majority of cases, distributed primarily in the Mediterranean region (par- ticularly Spain and Greece), Latin America, the Arabian Gulf, and the Indian subcontinent. B. abortus infection occurs worldwide but has been effectively eradicated in several European countries, Japan, and Israel. B. suis occurs mainly in the Midwestern United States, South America, and Southeast Asia, whereas B. canis infection is most common in North America, South America, Japan, and central Europe. Identification of the Brucella species recovered in humans can provide clues to the likely source of infection. In animals, brucellosis is a chronic infection that persists for life. In associa- tion with effective control programs in animals, human brucellosis has decreased dramatically in the United States, from more than 6000 cases in 1947 to fewer than 200 cases each year since 1980. States reporting the great- est number of cases include Texas, California, Virginia, and Florida. In North America, brucellosis occurs mainly in the spring and summer and is more common in men, usually related to occupational exposure. Brucella infection in the United States occurs mostly through direct contact with animals or their secretions in high-risk groups, including slaughterhouse workers, farmers and dairy workers, veterinarians, travelers to endemic areas, and laboratory workers handling the organisms. More than half the reported cases are associated with the meat-processing industry, particularly the kill areas, where infection is spread through abraded or lacerated skin; the con- junctiva, possibly by aerosolization; and, rarely, by ingestion of infected tissue. Many cases of B. abortus infection in veterinarians have resulted acci- dentally through exposure to the strain 19 vaccine used to immunize cale. In the southern United States, 20% of feral swine are positive for B. suis, and human infections in hunters have been reported. B. melitensis infection, trans- mied through the ingestion of goat’s milk cheese, has been seen in U.S. travelers to and immigrants from Mexico. Brucellosis contracted abroad may not become symptomatic until the patient returns to the United States. Although persons with human immunodeficiency virus (HIV) infection are at risk for intracellular pathogens, the clinical manifestations of brucellosis in HIV-infected and noninfected individuals are similar in the few cases reported. ere are increased reports of sexually transmied brucellosis. Brucellosis in pregnancy has been associated with spontaneous abortions, possible congenital abnormalities, and neonatal infections. Brucellosis in children accounts for only 3 to 10% of all reported cases worldwide; it is common in endemic areas (where it may account for 20 to 25% of cases) and is oſten a mild, self-limited process. Infection occurs most frequently in school-aged children and in familial outbreaks. PATHOBIOLOGY Pathogenesis Aſter penetrating the epithelial cells of human skin, conjunctiva, pharynx, or lung, Brucella organisms initially induce an exuberant polymorphonuclear neutrophil response in the submucosa. Aſter ingestion of organisms by neu- trophils and tissue macrophages, spread to regional lymph nodes occurs. If host defenses within the lymph nodes are overwhelmed, bacteremia follows. e usual incubation period between infection and bacteremia is 1.5 to 3 weeks. Bacteremia is accompanied by phagocytosis of free Brucella organisms by neutrophils and localization of bacteria primarily to the spleen, liver, and bone marrow, with the formation of granulomas. If the inoculum is large and the patient receives no treatment, large granu- lomas may form, suppurate, and serve as a source of persistent bacteremia, with the potential for multiorgan spread. e primary virulence factor of Brucella appears to be cell wall lipopolysaccharide. Both virulent and aenuated strains of Brucella are readily phagocytized by neutrophils aſter opsonization with normal human serum. Whole bacteria and extracts of Brucella species may inhibit neutrophil oxidative burst activity and degranulation. Intracellular killing of ingested bacteria has been demon- strated with B. abortus but not B. melitensis; this may explain differences in pathogenicity between these species. e major cell wall antigen and viru- lence factor of Brucella is the smooth lipopolysaccharide containing A and M antigens, which also dominates antibody production. Immunity Humoral factors may be important in the host defense against Brucella. Even in the absence of specific agglutinating antibody, normal human serum is bactericidal for Brucella organisms; B. abortus is more susceptible to serum lysis than is B. melitensis. e intracellular location within macrophages of the organism may provide a means for the bacteria to escape the lethal effects of serum. Specific serum agglutinating antibody has opsonic activity but does not correlate with the development of protective immunity. A role for mononuclear phagocytes and cell-mediated immunity in brucel- losis has been demonstrated. Protection against Brucella infection in animals is associated with preceding infection with Listeria monocytogenes or Myco- bacterium tuberculosis, both of which stimulate cell-mediated immune mechanisms. Skin testing with Brucella proteins elicits a typical delayed hypersensitivity response in infected individuals. Macrophages, activated

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CHAPTER  318  BRUCELLOSIS  1891

318 BRUCELLOSIS ROBERT A. SALATA

DEFINITIONBacteria of the genus Brucella cause disease with protean manifestations. Infection is transmitted to humans from animals as a consequence of occu-pational exposure or ingestion of contaminated milk products. Despite the attempt to institute effective control measures, brucellosis remains a signifi-cant health and economic burden in many countries.

The PathogenBrucellae are slow-growing, small, aerobic, nonmotile, nonencapsulated, non-spore-forming, gram-negative coccobacilli. Brucella abortus, Brucella suis, Brucella melitensis, and Brucella canis are best known to infect humans and are typed on the basis of biochemical, metabolic, and immunologic cri-teria. DNA hybridization analysis shows a high degree of homology among strains.

EPIDEMIOLOGYEtiologyThere are differences in virulence among the four major species. B. abortus, with a reservoir in cattle, is usually associated with mild to moderate sporadic disease; suppurative or disabling complications are rare. B. suis infection, resulting from swine contact, is often associated with destructive, suppurative lesions and may have a prolonged course. B. melitensis, with a reservoir in sheep, goats, and camels, may cause severe, acute disease and disabling com-plications. B. canis, spread to humans from infected dogs, causes disease with an insidious onset, frequent relapse, and a chronic course that is indistin-guishable from that of infection related to B. abortus. Studies indicate that there are two new species, Brucella pinnipediae and Brucella cetaceae, related to seals and cetaceans, respectively. Two human cases of marine-associated Brucella infection have been reported. Brucella microti, with high pathogenic-ity, was recently isolated from the common vole, red fox, and soil. No instances of human infection have been reported. Brucellae are also potential agents for bioterrorism.

Incidence and PrevalenceMore than 500,000 cases of brucellosis are reported yearly to the World Health Organization from 100 countries. B. melitensis infection accounts for the majority of cases, distributed primarily in the Mediterranean region (par-ticularly Spain and Greece), Latin America, the Arabian Gulf, and the Indian subcontinent. B. abortus infection occurs worldwide but has been effectively eradicated in several European countries, Japan, and Israel. B. suis occurs mainly in the Midwestern United States, South America, and Southeast Asia, whereas B. canis infection is most common in North America, South America,

Japan, and central Europe. Identification of the Brucella species recovered in humans can provide clues to the likely source of infection.

In animals, brucellosis is a chronic infection that persists for life. In associa-tion with effective control programs in animals, human brucellosis has decreased dramatically in the United States, from more than 6000 cases in 1947 to fewer than 200 cases each year since 1980. States reporting the great-est number of cases include Texas, California, Virginia, and Florida. In North America, brucellosis occurs mainly in the spring and summer and is more common in men, usually related to occupational exposure.

Brucella infection in the United States occurs mostly through direct contact with animals or their secretions in high-risk groups, including slaughterhouse workers, farmers and dairy workers, veterinarians, travelers to endemic areas, and laboratory workers handling the organisms. More than half the reported cases are associated with the meat-processing industry, particularly the kill areas, where infection is spread through abraded or lacerated skin; the con-junctiva, possibly by aerosolization; and, rarely, by ingestion of infected tissue. Many cases of B. abortus infection in veterinarians have resulted acci-dentally through exposure to the strain 19 vaccine used to immunize cattle. In the southern United States, 20% of feral swine are positive for B. suis, and human infections in hunters have been reported. B. melitensis infection, trans-mitted through the ingestion of goat’s milk cheese, has been seen in U.S. travelers to and immigrants from Mexico. Brucellosis contracted abroad may not become symptomatic until the patient returns to the United States. Although persons with human immunodeficiency virus (HIV) infection are at risk for intracellular pathogens, the clinical manifestations of brucellosis in HIV-infected and noninfected individuals are similar in the few cases reported. There are increased reports of sexually transmitted brucellosis.

Brucellosis in pregnancy has been associated with spontaneous abortions, possible congenital abnormalities, and neonatal infections. Brucellosis in children accounts for only 3 to 10% of all reported cases worldwide; it is common in endemic areas (where it may account for 20 to 25% of cases) and is often a mild, self-limited process. Infection occurs most frequently in school-aged children and in familial outbreaks.

PATHOBIOLOGYPathogenesisAfter penetrating the epithelial cells of human skin, conjunctiva, pharynx, or lung, Brucella organisms initially induce an exuberant polymorphonuclear neutrophil response in the submucosa. After ingestion of organisms by neu-trophils and tissue macrophages, spread to regional lymph nodes occurs. If host defenses within the lymph nodes are overwhelmed, bacteremia follows. The usual incubation period between infection and bacteremia is 1.5 to 3 weeks. Bacteremia is accompanied by phagocytosis of free Brucella organisms by neutrophils and localization of bacteria primarily to the spleen, liver, and bone marrow, with the formation of granulomas.

If the inoculum is large and the patient receives no treatment, large granu-lomas may form, suppurate, and serve as a source of persistent bacteremia, with the potential for multiorgan spread. The primary virulence factor of Brucella appears to be cell wall lipopolysaccharide.

Both virulent and attenuated strains of Brucella are readily phagocytized by neutrophils after opsonization with normal human serum. Whole bacteria and extracts of Brucella species may inhibit neutrophil oxidative burst activity and degranulation. Intracellular killing of ingested bacteria has been demon-strated with B. abortus but not B. melitensis; this may explain differences in pathogenicity between these species. The major cell wall antigen and viru-lence factor of Brucella is the smooth lipopolysaccharide containing A and M antigens, which also dominates antibody production.

ImmunityHumoral factors may be important in the host defense against Brucella. Even in the absence of specific agglutinating antibody, normal human serum is bactericidal for Brucella organisms; B. abortus is more susceptible to serum lysis than is B. melitensis. The intracellular location within macrophages of the organism may provide a means for the bacteria to escape the lethal effects of serum. Specific serum agglutinating antibody has opsonic activity but does not correlate with the development of protective immunity.

A role for mononuclear phagocytes and cell-mediated immunity in brucel-losis has been demonstrated. Protection against Brucella infection in animals is associated with preceding infection with Listeria monocytogenes or Myco-bacterium tuberculosis, both of which stimulate cell-mediated immune mechanisms. Skin testing with Brucella proteins elicits a typical delayed hypersensitivity response in infected individuals. Macrophages, activated

CHAPTER  318  BRUCELLOSIS 1892

with T helper 1 (TH1)–type cytokines (e.g., interferon-γ, tumor necrosis factor-α, interleukin-1, interleukin-12), kill Brucella. Recent studies have shown that, despite high levels of TH1 cytokine production, including interferon-γ, deficient effector phagocytic activity persists.

CLINICAL MANIFESTATIONSClinically, human brucellosis can be conveniently but arbitrarily divided into subclinical illness, acute or subacute disease, localized disease and complica-tions, relapsing infection, and chronic disease (Table 318-1).

Subclinical IllnessDetected only by serologic testing, asymptomatic or clinically unrecognized human brucellosis often occurs in high-risk groups, including slaughterhouse workers, farmers, and veterinarians. More than 50% of abattoir workers and up to 33% of veterinarians have high anti-Brucella antibody titers but no history of recognized clinical infection. Children in endemic areas frequently have subclinical illness.

Acute and Subacute DiseaseAfter an incubation period of several weeks or months, acute brucellosis may occur as a mild, transient illness (B. abortus or B. canis) or as an explosive, toxic illness with the potential for multiple complications (B. melitensis). Approximately 50% of patients have an abrupt onset over days, whereas the remainder have an insidious onset over weeks. Symptoms in brucellosis are protean and nonspecific. More than 90% of patients experience malaise, chills, sweats, fatigue, and weakness. More than 50% of patients have myal-gias, anorexia, and weight loss. Fewer patients complain of arthralgias, cough, testicular pain, dysuria, ocular pain, or visual blurring. Likewise, few localiz-ing physical signs are apparent. Fever, with temperatures often greater than 39.4° C (103° F), occurs in 95% of patients. An undulating or intermittent fever pattern is unusual. A pulse-temperature deficit (i.e., relative bradycar-dia) may occur. Splenomegaly is present in 10 to 15% of cases, and lymph-adenopathy occurs in up to 14% (axillary, cervical, and supraclavicular locations are most frequent, related to hand wound or oropharyngeal routes of infection); hepatomegaly is less frequent. Other laboratory findings in acute or subacute disease may include mild anemia, lymphopenia or neutro-penia (especially with bacteremia), lymphocytosis, thrombocytopenia, or (rarely) pancytopenia. The majority of infected individuals recover com-pletely without sequelae if the appropriate diagnosis is made and prompt therapy is initiated.

Localized Disease and ComplicationsBrucella organisms can localize in almost any organ, but they most commonly localize in bone, joint, central nervous system, heart, lung, spleen, testis, liver, gallbladder, kidney, prostate, pancreas, and skin. Localized disease may occur simultaneously at multiple sites. Localized complications most often appear in association with a more chronic course of illness, although complications may occur with acute disease caused by B. melitensis or B. suis. In the United States, localized disease is most frequently related to B. suis. Osteoarticular complications are most frequent and are reported in 10 to 80% of series. The most common site is sacroiliitis in younger persons and spondylitis in older

TABLE 318-1 CLINICALCLASSIFICATIONOFHUMANBRUCELLOSIS

CLASSIFICATIONDURATION OF SYMPTOMS 

BEFORE DIAGNOSIS MAJOR SYMPTOMS AND SIGNS DIAGNOSIS COMMENTSSubclinical — Asymptomatic Positive (low titer) serology,

negative culturesOccurs in abattoir workers, farmers, and

veterinariansAcute and subacute Up to 2-3 mo and 3 mo–1 yr Malaise, chills, sweats, fatigue,

headache, anorexia, arthralgias, fever, splenomegaly, lymphadenopathy, hepatomegaly

Positive serology, positive blood or bone marrow cultures

Presentation can be mild, self-limited (B. abortus) or fulminant with severe complications (B. melitensis)

Localized Occurs with acute or chronic untreated disease

Related to involved organs Positive serology, positive cultures in specific tissues

Bone or joint, genitourinary, hepatosplenic involvement most common

Relapsing 2-3 mo after initial episode Same as acute illness but may have higher fever and more fatigue, weakness, chills, and sweats

Positive serology, positive cultures

May be extremely difficult to distinguish relapse from reinfection

Chronic >1 yr Nonspecific presentation but neuropsychiatric symptoms and low-grade fever most common

Low titer or negative serology, negative cultures

Most controversial classification; localized disease may be associated

persons. Vertebral osteomyelitis (most often in the lumbar area) is also well recognized and can be associated with paravertebral, epidural, and psoas abscesses.

Relapsing InfectionUp to 10% of patients with brucellosis experience relapses after antimicrobial therapy. Relapses usually occur 3 to 6 months after completion of therapy but may be seen up to 2 years after treatment. Relapses are often associated with antimicrobial resistance and the intracellular location of organisms, which protects the bacteria from certain antibiotics and host defense mechanisms. Relapsing infection is difficult to distinguish from reinfection in high-risk groups with continued exposure. Studies have shown that relapses are associ-ated with inappropriate or insufficient antimicrobial therapy, positive blood cultures on initial presentation, and an acute onset of disease.

Chronic DiseaseDisease with a duration of more than 1 year has been called chronic brucellosis. A majority of patients classified as having chronic brucellosis really have persistent disease caused by inadequate treatment of the initial episode, or they have focal disease in bone, liver, or spleen. About 20% of patients diag-nosed with chronic brucellosis complain of persistent fatigue, malaise, and depression; in many respects, this condition resembles chronic fatigue syn-drome. These symptoms are frequently not associated with clinical, micro-biologic, or serologic evidence of active infection and may represent a preexisting psychoneurosis.

DIAGNOSISCultureMany more common illnesses mimic the clinical presentation of brucellosis, and a thorough history is needed, including occupation, travel to endemic areas, avocations, and ingestion of at-risk food and beverages. The most con-clusive means of establishing the diagnosis of brucellosis is positive culture from normally sterile body fluid or tissue. Rates of positive cultures have ranged from 15 to 90%, depending on the methods employed and the speci-men type. The culture of Brucella organisms is potentially hazardous to labo-ratory personnel.

In acute brucellosis, positive blood cultures are obtained in 10 to 30% of cases (as high as 85% with B. melitensis). Blood culture positivity decreases with increasing duration of illness. With B. melitensis infection, bone marrow cultures are of higher yield than blood cultures. Blood processed in radiomet-ric detection or isolator systems may yield positive cultures in less than 10 days. With localized brucellosis (e.g., lymph nodes, spleen, liver, skeletal system), cultures of purulent material or tissues usually yield Brucella organ-isms. Culture of cerebrospinal fluid is positive in 45% of patients with men-ingitis. Antibody against Brucella may be demonstrated in cerebrospinal fluid by enzyme-linked immunosorbent assay (ELISA).

Standard Tube AgglutinationIn the absence of microbiologic confirmation, a presumptive diagnosis can be made by history and serology. The most frequently used test is the stan-dard tube agglutination (STA) test, measuring antibody to B. abortus antigen.

A four-fold or greater rise in titer to 1 : 160 or higher is considered significant. A presumptive case is one in which the agglutination titer is positive (1 : 160) in single or serial specimens, with symptoms consistent with brucellosis. By 3 weeks of illness, more than 97% of patients demonstrate serologic evidence of infection. This test detects antibodies to B. abortus, B. suis, and B. melitensis but not to B. canis. Serologic confirmation of B. canis infection requires B. canis or Brucella ovis antigen. Despite adequate antibiotic treatment, signifi-cant STA titers can persist for up to 2 years in 5 to 7% of cases. Because the STA titer may remain elevated, it is not useful in differentiating relapsing infection from other febrile illnesses in patients with past Brucella infections. Individuals with subclinical infection may demonstrate significant STA titers. In chronic localized brucellosis, STA titers may appear absent or low owing to a prozone phenomenon. This prozone effect appears to be related to the presence of immunoglobulin G or immunoglobulin A blocking antibodies; it can be eliminated if dilutions are carried out to at least 1 : 1280. False-positive STA titers related to immunologic cross-reactivity have been associ-ated with Brucella skin testing, cholera vaccination, or infection with Vibrio cholerae, Francisella tularensis, or Yersinia enterocolitica.

Other TestsCertain newer antibody tests, including ELISA, are more sensitive and spe-cific than STA and are being used more widely. Preliminary studies of the diagnosis of brucellosis using polymerase chain reaction with random or selected primers of blood and other fluids or tissues have been promising, but additional evaluation is necessary, and access to this diagnostic technol-ogy is still limited.

TABLE 318-2 TREATMENTFORBRUCELLOSISTREATMENT COMMENTS

Acute, with no endocarditis or central nervous system involvement

Doxycycline (200 mg/day) plus rifampin (600-900 mg/day) for 6 wk

Treatment of choice by World Health Organization; widely used; low rate of relapse; intramuscular administration of streptomycin may be difficult

orTetracycline (2 g/day) for 6 wk plus streptomycin (1 g/day)

or gentamicin for 1 wkAlternative agents: chloramphenicol, fluoroquinolones,

trimethoprim-sulfamethoxazole, imipenem

Combination therapy still preferred; fluoroquinolones plus rifampin is an alternative

In children Trimethoprim-sulfamethoxazole plus rifampinCentral nervous system Doxycycline plus rifampin and trimethoprim-sulfamethoxazole Third-generation cephalosporin can be substituted

if susceptible in vitroLocalized Surgically drain abscesses plus antimicrobial therapy for ≥6 wkBrucella endocarditis Bactericidal drugs; early valve replacement may be necessary Possible aortic valve destruction and/or major

arterial emboli

EffectivetreatmentofBrucella infectionrequiresantibiotics thatcanpen-etrate intracellularly, are available for prolonged therapy to prevent relapse,and are bactericidal in order to treat central nervous system infection andendocarditis.Thereisstillconsiderabledebateoverwhichantibioticregimenissuperior,butthecombinationoforaldoxycyclinefor45daysor8weeksplusintramuscular gentamicin for 5 to 7 days is equally effective as traditionaltherapy using doxycycline for 45 days plus streptomycin for 14 days.1TheWorldHealthOrganizationrecommendsdoxycyclineplusrifampinorallyfor6weeks.Thisregimenislesseffectiveforcasesofspondylitis.Monotherapywithfluoroquinoloneshasbeendisappointing,andiftheseagentsareused,theyshouldalwaysbecombinedwithanotheractiveagent.Recentinvitrostudieshavedemonstratedsignificantactivityandsynergyoftigecyclinewithgenta-micin and rifampin; these observations must be supported in clinical trials.RecommendationsaregiveninTable318-2.

TREATMENT

humans. There is controversy about the effectiveness of postexposure antimi-crobial prophylaxis.

PROGNOSISBrucellosis that is treated appropriately within the first month of symptom onset is curable. Acute brucellosis often produces severe weakness and fatigue, and patients are frequently unable to work for up to 2 months. Immu-nity to reinfection follows initial Brucella infection in the majority of indi-viduals. With early antimicrobial therapy, cases of chronic brucellosis or localized disease and complications are rare. Of the patients who die of bru-cellosis, 84% have endocarditis involving a previously abnormal aortic valve, often associated with severe congestive heart failure.

1. Roushan MR, Amiri MJ, Janmohammadi N, et al. Comparison of the efficacy of gentamicin for 5 days plus doxycycline for 8 weeks versus streptomycin for 2 weeks plus doxycycline for 45 days in the treatment of human brucellosis: a randomized clinical trial. J Antimicrob Chemother. 2010;65:1028-1035.

SUGGESTED READINGS

Buzgan T, Karahocagil MK, Irmak H, et al. Clinical manifestations and complications in 1028 cases of brucellosis: a retrospective evaluation and review of the literature. Int J Infect Dis. 2010;14:e469-e478. About 50% of patients were engaged in raising livestock, and the main risk factor in others was consumption of raw milk and dairy products; the STA was positive in 99% of cases.

Eales KM, Norton RE, Ketheesan N. Brucellosis in northern Australia. Am J Trop Med Hyg. 2010;83:876-887. Fever (94%), fatigue (78%), and arthralgia (78%) were the main features, with a median 2-week diagnostic delay.

Seleem MN, Boyle SM, Sriranganathan N. Brucellosis: a re-emerging zoonosis. Vet Microbiol. 2010;140;392-398. Review of the epidemiology of the more than 500,000 human cases reported annually.

PREVENTIONThe control of human brucellosis is directly related to prevention programs in domestic animals and the avoidance of unpasteurized milk and milk prod-ucts. In slaughterhouses, important means of prevention include careful wound dressing, the wearing of protective glasses and clothing, the prohibi-tion of raw meat ingestion, and the use of previously infected (immune) individuals in high-risk areas. Work is ongoing to find an effective vaccine for