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Brucellosis (Mediterranean Fever, Gibralter fever, Malta Fever, Cyprus Fever, Undulant Fever, Typhomalarial Fever)


Updated 11/2001

Primary Distribution: Worldwide, especially Mediterranean basin, Arabian Gulf, and Indian subcontinent. Brucellosis is also found in Mexico and Central and South America; and is found in higher rates on the United States/Mexican border than elsewhere in the U.S. (Doyle & Bryan, 2000). The global incidence is estimated to be around 500,000 cases/year, but brucellosis is undereported at a ratio of about 1:26 (one reported to 26 unreported) (Araj, 1999).

Agent and Vector: Brucella species (gram negative coccobacilli) are transmitted through ingestion of contaminated (unpasteurized) milk or cheese and other contaminated animal products. Persons involved in animal husbandry, slaughtering, or treatment of sick animals can be infected through the respiratory route, skin, or conjunctiva. Laboratory workers are also at risk. Brucella species, including B. melitensis and B. suis, are considered to be potential agents of biological terrorism and are classified as Category B agents (Centers for Disease Control [CDC], 2000A; CDC, 2000B). See Bioterror box below.

Incubation: Usually 1-4 weeks, and up to several months.

Clinical Findings and Treatment

Signs and Symptoms: Onset may be gradual or sudden. Brucellosis typically presents as a mild nonspecific illness with fever, which may be intermittent. There may be a wide range of complaints, with common symptoms/signs including lethargy, night sweats with a moldy odor, fatigue, headache, cough and pharyngitis, nausea and vomiting, hepatosplenomegaly, myalgia, and lymphadenopathy. Arthritis, especially of large joints, is common and may be severe. Vertebral abscesses, orchitis, epididymitis, pyelonephritis, and glomerulonephritis may also occur. The most commonly affected systems (with a variety of manifestations) include cardiac, respiratory, gastrointestinal (including as acute abdomen), genitourinary, and central nervous system. The illness also occurs in a chronic form, waxing and waning over many years.

Bioterror Considerations

Brucella species are considered by the CDC to be Category B biological warfare (BW) agents. Category B agents are moderately easy to disseminate and cause moderate morbidity and low mortality (CDC, 2000B). Brucellosis has been documented as one of the agents in Iraq's biological warfare program and has been produced and/or investigated by other countries (Shoham, 2000). The BW route of infection is most likely aerosol. Person-to-person transmission does not occur in nature (Federation of American Scientists, 2000). Treatment of mass casualties would be some variation on the below - especially doxycycline + rifampin.

Complications: Bone and joint lesions, suppurative arthritic lesions, endocarditis, meningoencephalitis, chronic neurological deficits.

Common Laboratory Findings: Lymphocytosis, elevated agglutination titre, increased ESR, abnormal liver function.

Diagnosis: Brucella sp. are found in the blood, urine, CSF, and bone marrow in acute, but often are not discernable in chronic infections. The laboratory should be notified if brucellosis is suspected as cultures take 21-28 days to grow. The least expensive and most common test is serum agglutination test (SAT). Increased level of Brucella agglutinin (>1:160) confirms an acute episode and lower levels indicate earlier infection. ELISA is the test of choice for complicated and/or chronic cases. With acute brucellosis, there are elevations of brucella-specific IgG, IgM, IgA, IgE, IgG1, and IgG3. Patients with chronic brucellosis show elevations of IgG, IgA, IgE, IgG1, and IgG4. In laboratories that do not perform the ELISA, the indirect Coombs has been diagnostic after a negative SAT. Advances in polymerase chain reaction assays have resulted in high sensitivity in detecting brucella antibodies, but currently these are used primarily in research facilities (Araj, 1999; Schutze & Jacobs, 2000).

Differential Diagnosis: Acute febrile illnesses such as influenza, tularemia, Q fever, mononucleosis, enteric fever, rheumatic fever, typhoid fever, cat scratch fever; and also cholecystitis, thronmbophlebitis, auto-immune diseases and cancer (lymphoma). Chronic brucellosis is may be confused with lymphoma, tuberculosis, HIV, malaria, and disseminated fungal infections.

Treatment: Prognosis is good with treatment. Adults and children > eight years of age may be treated with doxycycline 100 mg po bid x 6 weeks + streptomycin 500 mg IM bid for 7-14 days OR gentamycin 3-5 mg/kg/24 hours IM or IV for 7-14 days. An alternative treatment is doxycycline 100 mg po bid x 6 weeks + rifampin 600-900 mg/24 hours po/day x 6 weeks. If organ-specific complications occur, such as meningitis, osteomyelitis, or endocarditis, treatment may include doxycycline 100 mg po bid for 4-6 months + streptomycin or gentamycin one gram/24 hours IM for 4-6 months + rifampin 600-900 mg/24 hours po/day x 6 weeks. Children <8 years may be treated with TMP/SMX 10 mg/kg/24 hours (trimethoprim maximum of 480 mg/24 hours, and sulfamethoxazole maximum of 2.4 gram/24 hours) + rifampin 15-20 mg/kg/24 hours po x 45 days. Some sources (e.g., Madkour, 1998 and Schutze & Jacobs, 2000) recommend at least eight weeks of therapy (doxycycline 100 mg po bid + an aminoglycoside for four weeks followed by doxycycline 100 mg po bid + rifampin 600-900 mg po daily for 4-8 more weeks).

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Authors: Amy Roberts, FNP & Charles Kemp, FNP

References

Araj, G.F. (1991). Human brucellosis: A classical infectious disease with persistent diagnostic challenges. Clinical Laboratory Science, 12(4), 207-212.

Centers for Disease Control and Prevention (2000A). Suspected brucellosis case prompts investigation of possible bioterrorism-related activity: New Hampshire and Massachusetts, 1999. MMWR: Morbidity and Mortality Weekly Report, 49(23), 509-512.

Centers for Disease Control and Prevention. (2000B). Biological and chemical terrorism: Strategic plan for preparedness and response. MMWR: Morbidity and Mortality Weekly Report, 49(RR-4), 1-14.

Centers for Disease Control and Prevention: Brucellosis. Retrieved January May 14, 2000, from the World Wide Web: http://www.cdc.gov/dbmd/diseaseinfo/brucellosis_t.htm.

Chambers, H.F. (1999). Infectious diseases: Bacterial & chlamydial. In L.M. Tierney, S.J. McPhee, & M.A. Papadakis (Eds.), Current medical diagnosis & treatment (38th ed.) (pp. 1317-1318, 1432). Stamford Connecticut: Appleton & Lange.

Doyle, T.J. & Bryan, R.T. (2000). Infectious disease morbidity in the U.S. region bordering Mexico, 1990-1998. Journal of Infectious Diseases, 182(5), 1503-1510.

Federation of American Scientists. (2000). Biological weapons. Retrieved October 31, 2001, from the World Wide Web: http://www.fas.org/index.html

Madkour, M.M. (1998). Brucellosis. In A.S. Fauci, E. Braunwald, K.J. Isselbacher, J.D. Wilson, J. B. Martin, D.L. Kasper, S.L. Hauser, & D.L. Longo (Eds.). Harrison's principles of internal medicine (14th ed.) (pp. 969-971). New York: McGraw-Hill.

Schutze, G. & Jacobs, R. (2000). Brucella. In R. Behrman, R. Kliegman, & H. Jenson (Eds.). Nelson textbook of pediatrics (16th ed.) (pp. 867-869). Philadelphia: W.B. Saunders Company.

Shoham, D. (2000). Iraq's biological warfare agents: A comprehensive analysis. Critical Reviews in Microbiology, 26(3), 179-204.

Wright, S.G. & Al-Aska, A.K. (1991). Brucellosis. In G.T. Strickland (Ed.), Hunter's tropical medicine (7th ed.) (pp. 421-426). Philadelphia: W.B. Saunders Company.