Brucellosis

Summary

Signs and Symptoms: Incubation period from 5-60 days; average of 1-2 months. Highly variable. Acute and subacute brucellosis are non-specific. Irregular fever, headache, profound weakness and fatigue, chills, sweating, arthralgias, mylagias. Depression and mental status changes. Osteoarticular findings (i.e., sacroiliitis, vertebral osteomyleitis). Fatalities are uncommon.

Diagnosis: Blood cultures require a prolonged period of incubation in the acute phase. Bone marrow cultures produce a higher yield. Confirmation requires phage-typing, oxidative metabolism, or genotyping procedures. ELISA’s followed by Western blotting are used.

Treatment: Doxycycline and rifampin for a minimum of six weeks. Ofloxacin + rifampin is also effective. Therapy with rifampin, a tetracycline, and an aminoglycoside is indicated for infections with complications such as endocarditis or meningoencephalitis.

Prophylaxis: No approved human vaccine is available. Avoid consumption of unpasteurized milk and cheese.

Isolation and Decontamination: Standard precautions for healthcare workers. Person-to-person transmission via tissue transplantation and sexual contact have been reported but are insignificant. Environmental decontamination can be accomplished with a 0.5% hypochlorite solution.

Overview

The Brucellae are a group of gram-negative cocco-baccillary organisms, of which four species are pathogenic in humans. Abattoir and laboratory worker infections suggest that Brucella spp. are highly infectious via the aerosol route. It is estimated that inhalation of only 10 to 100 bacteria is sufficient to cause disease in man. The relatively long and variable incubation period (5-60 days) and the fact that many infections are asymptomatic under natural conditions has made it a less desirable agent for weaponization, although large aerosol doses may shorten the incubation period and increase the clinical attack rate. Brucellosis infection has a low mortality rate (5% of untreated cases) with most deaths caused by endocarditis or meningitis. It is an incapacitating and disabling disease in its natural form.

History and Significance

Marston described disease caused by B. melitensis among British soldiers on Malta during the Crimean War as "Mediterranean gastric remittent fever". Work by the Mediterranean Fever Commission identified goats as the source of human brucella infection on Malta, and restriction of the ingestion of unpasteurized goats milk and cheese soon decreased the number of cases of brucellosis among military personnel.

In 1997, most cases were associated with ingestion of unpasteurized dairy products and abattoir and veterinary work. In the United States most cases are reported from Florida, California, Virginia, and Texas. It is a rare disease in the United States with an incidence of 0.5 per 100,000 population.

In 1954, Brucella suis became the first agent weaponized by the U.S. in the days of its offensive BW program at the newly constructed Pine Bluff Arsenal. Despite this, B. melitensis actually produces more severe human disease.

Clinical Features

Brucellosis may present as a nonspecific febrile illness which resembles influenza. Fever, headache, myalgia, arthralgia, back pain, sweats, chills, and generalized weakness and malaise are common complaints. Cough and pleuritic chest pain may occur in up to twenty percent of cases, but these are usually not associated with acute pneumonitis. Pulmonary symptoms may not correlate with radiographic findings. The chest x-ray may be normal, or show lung abscesses, single or miliary nodules, bronchopneumonia, enlarged hilar lymph nodes, and pleural effusions. Gastrointestinal symptoms occur in up to 70 percent of adult cases, and less frequently in children. These include anorexia, nausea, vomiting, diarrhea and constipation. Ileitis, colitis and granulomatous or a mononuclear infiltrative hepatitis may occur. Lumbar pain and tenderness can occur in up to 60% of cases and is due to various osteoarticular infections of the axial skeletal system. Paravertebral abscesses may occur and can be imaged by CT scan or MRI. CT scans often show vertebral sclerosis. Vertebral and disc space destruction may occur in chronic cases. One or, less frequently, both sacroiliac joints may be infected causing low back and buttock pain that is intensified by stressing the sacroiliac joints on physical exam. Hepatomegaly and splenomegaly can occur in up to 45-63 percent of cases. Peripheral joint involvement may vary from pain on range of motion testing to joint immobility and effusion. Peripheral joint effusions usually show a mononuclear cell predominance and organisms can be isolated in up to 50% of cases. The hip joints are the most commonly involved peripheral joints, but ankle, knee, and sternoclavicular joint infection may occur. Plain radiographs of involved sacroiliac joints usually show blurring of articular margins and widening of the joint space. Technetium or Gallium-67 bone scans are 90% sensitive for detecting sacroileitis and will also detect other sites of bone and joint involvement; they are also useful for differentiating sacroiliac from hip joint involvement.

Meningitis occurs in less than 5% of cases and may be an acute presenting illness of a chronic syndrome occurring late in the course of a persistent infection. The cerebrospinal fluid contains an increased number of lymphocytes and a low to normal glucose. Culture of the CSF has sensitivity of 50%, and specific brucella antibodies can be detected in the fluid in a higher percentage of cases. Encephalitis, peripheral neuropathy, radiculoneuropathy and meningovascular syndromes have also been observed in rare cases. Behavioral disturbances in children and psychoses may occur in the meningoencephalitic form of the disease. Epididymo-orchitis may occur in men as the most frequent genitourinary form of brucellosis. Rashes occur in less than 5% if cases and include macules, papules, ulcers, purpura, petechiae, and erythema nodosum.

Diagnosis

The leukocyte count is usually normal but may be low. Anemia and thrombocytopenia may occur. Blood and bone marrow culture during the acute febrile phase of the illness will yield a positivity rate of 15-70% and 92% respectively. A biphasic culture method for blood (Castaneda bottle) may increase the number of isolates. The serum agglutination test (SAT) will detect both IgM and IgG antibodies. A titer of 1:160 or greater is indicative of active disease. The IgM titer can be measured by adding a reduced agent such as 2-mercaptoethanol to the serum. This will destroy the agglutinability of IgM allowing the IgM titer to be measured by subtracting the now lower titer from the total serum agglutinin titer. A dot-ELISA using an autoclaved extract of B. abortus has been found to be a sensitive and specific screening test for detection of Brucella antibodies under field conditions. ELISA tests for antibody detection require standardization using a specific antigen before they will be widely available. Antigen detection on DNA extracted from blood mononuclear cells has been accomplished using PCR analysis of a target sequence on the 31-kilodalton B. abortus protein BCSP 31. This test has been proven to be rapid and specific and may replace blood culture in the future, since the latter may require incubation for up to 6 weeks. PCR for Brucella species is not available at this time except in research laboratories, but shows promise for future use.

Medical Management

Isolation is not required other than contact isolation for draining lesions. Person to person transmission is possible via contact with such lesions. Biosafety level 3 practices should be used for suspected brucella cultures in the laboratory because of the danger of inhalation infection. Antibiotic therapy is recommended as the sole therapy unless there are surgical indications for the treatment of localized diseases (e.g., valve replacement for endocarditis).

The treatment recommended by the World Health Organization for acute brucellosis in adults is doxycycline 200 mg/day p.o. plus rifampin 600-900 mg/day for a minimum of six weeks. The previously established regimen of intramuscular streptomycin along with an oral tetracycline may give fewer relapses but is no longer the primary recommendation. Ofloxacin 400 mg/day and rifampin 600 mg/day p.o. is also an effective combination. Combination therapy with rifampin, a tetracycline, and an aminoglycoside is indicated for infections with complications such as meningoencephalitis or endocarditis. Doxycycline clearance is increased in the presence of rifampin and plasma levels are lower than when streptomycin is used instead of rifampin.

Prophylaxis

Live animal vaccines are used widely. Consumption of unpasteurized milk and cheese should be avoided. No approved human brucella vaccine is available. An experimental human brucellosis vaccine has been tested on 271 subjects with a 25% rate of unpleasant acute side effects, but no long term adverse side effects.