General Characteristics

Brucellae are small, facultative, intracellular, nonmotile, aerobic, gram-negative coccobacilli or short rods that stain poorly by conventional Gram stain. Many isolates require supplementary carbon dioxide (CO₂) for growth, especially on primary isolation. Brucella spp. are closely related to Bartonella, Rhizobium, and Agrobacterium spp.

Epidemiology and Pathogenesis

The disease brucellosis occurs worldwide, especially in Mediterranean and Persian Gulf countries, India, and parts of Mexico and Central and South America. The organisms are capable of survival for extended periods (e.g., soil, 10 weeks; aborted fetuses, 11 weeks; bovine stool, 17 weeks, milk and ice cream, 3 weeks); they can survive in fresh cheese for several months. Brucellosis is a zoonosis and is recognized as a cause of devastating economic loss among domestic livestock.

Each of the four Brucella spp. that are pathogenic for humans has a limited number of preferred animal hosts (Table 36-1). In the host, Brucella tend to localize in tissues rich in erythritol (e.g., placental tissue), a four-carbon alcohol that enhances their growth. Humans become infected by four primary routes:

Rare cases of transmission by blood and bone marrow transplantation and by sexual intercourse, in addition to neonatal brucellosis, have been reported. Individuals considered at risk for contracting brucellosis include dairy farmers, livestock handlers, slaughterhouse employees, veterinarians, and laboratory personnel. The organism has a very low infectious dose (100 organisms or fewer). Mishandling and misidentification of the organism is often associated with laboratory transmission of the organism.

Brucella spp. are facultative, intracellular parasites that are able to exist in both intracellular and extracellular environments. Other bacteria classified as facultative intracellular infectious agents include Salmonella, Shigella, Yersinia, Listeria, and Francisella spp. After infecting a host, brucellae are ingested by neutrophils, within which they replicate, causing cell lysis. Neutrophils containing viable organisms circulate in the bloodstream and are subsequently phagocytized by reticuloendothelial cells in the spleen, liver, and bone marrow. If the infection goes untreated, granulomas develop in these organs, and the brucellae survive in monocytes and macrophages. Brucellae tend to show a tendency to invade and persist in the human host by inhibiting apoptosis (programmed cell death). Resolution of the infection depends on the host’s nutritional and immune status, the size of the inoculum and route of infection, and the Brucella species causing the infection; in general, B. melitensis and B. abortus are more virulent for humans.

Survival and multiplication of Brucella organisms in phagocytic cells are features essential to the establishment, development, and chronicity of the disease. The mechanisms by which brucellae avoid intracellular killing are not completely understood. Brucella spp. can change from a smooth to a rough colonial morphology based on the composition of their cell wall lipopolysaccharide O-side chain (LPS); those with a smooth LPS are more resistant to intracellular killing by neutrophils than those with a rough LPS. The smooth phenotype has been identified in B. abortus and B. melitensis. Brucellae ensure intracellular survival by interfering with the phagosome-lysosome fusion in macrophages and epithelial cells. In addition, as do Legionella spp. (see Chapter 35), brucellae use a type IV secretion system, VirB, for intracellular survival and replication. Unlike Legionella spp., however, brucellae modulate phagosome transport to avoid being delivered to lysosomes. Essentially, VirB is involved in controlling the maturation of the Brucella vacuole into an organelle that allows replication. In the mouse model, if mutations occur in this gene region, B. abortus is unable to establish chronic infections. In addition, Brucella spp. produce urease, which provides protection during passage through the digestive system when the organism is ingested in food products. Urease breaks down urea, producing ammonia, and neutralizes the gastric pH. Despite our current knowledge, many questions remain about the pathogenesis of disease caused by Brucella spp.

Spectrum of Disease

The clinical manifestations of brucellosis vary greatly, ranging from asymptomatic infection to serious, debilitating disease. For the most part, brucellosis is a systemic infection that can involve any organ of the body. Symptoms, which are nonspecific, include fever, chills, weight loss, sweats, headache, muscle aches, fatigue, and depression. Lymphadenopathy and splenomegaly are common physical findings. After an incubation period of about 2 to 4 weeks, the onset of disease is commonly insidious. Complications can occur, such as arthritis; spondylitis (inflammation of the spinal cord); genital, pulmonary, and renal complications; and endocarditis. Relapse is considered an important feature of brucellosis; it is associated with delayed initiation of treatment, ineffective antibiotic therapy, and positive blood culture findings during the initial presentation.

A definitive diagnosis of brucellosis requires isolation of the organisms in cultures of blood, bone marrow, cerebrospinal fluid (CSF), pleural and synovial fluids, urine, abscesses, or other tissues. If processing will be delayed, the specimen may be held in the refrigerator.

It is essential that the clinical microbiology laboratory be notified whenever brucellosis is suspected:

Blood for culture can be collected routinely (see Chapter 68) into most commercially available blood culture bottles and the lysis-centrifugation system (Isolator; Alere, Waltham, MA). For other clinical specimens, no special requirements must be met for collection, transport, or processing.

Direct Detection Methods

Direct stains of clinical specimens are not particularly useful for the diagnosis of brucellosis. Conventional and real-time polymerase chain reaction (PCR) assays are reliable and specific means of directly detecting Brucella organisms in clinical specimens. Sensitivity varies among assays, ranging from 50% to 100%. Several gene targets have been used, including a cell surface protein (BCS P31), a periplasmic protein (BP26), 16S rRNA, and transposon insertion sequence 711(IS711). Molecular assays currently are not available in routine laboratory testing; therefore, use of a reference laboratory may be required.

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