( Malta fever. Undulant fever. Mediterranean fever)
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Bacterial zoonosis, bacterial genus Brucellae .
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Brucella species: o coccobacill, o gram-negative o intracellular aerobes o nonencapsulated, non– spore forming o slow-growing
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Survive well in aerosols and resist drying.
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Transmission occurs: o after occupational exposure (farmers, veterinarians, slaughterhouse workers) o through direct contact with animals, their carcasses or excreta, or by-products of abortion o infection can follow inhalation of contaminated aerosols or dusts o may penetrate through damaged skin o through ingestion of contaminated food products (dairy products - cheese, butter, ice cream, meat, or, rarely, water) o have not been directly transmitted from human to human
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There is seasonal variation in incidence in temperate climates, coinciding with animal parturition times. It is a year-round infection in the tropics.
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Brucellosis has become a rare entity in many industrialized nations because of animal vaccination
Organism
B melitensis
B abortus bovis
Specific animal reservoir and geographic distribution
Animal Reservoir
Goats, sheep, camels, horses, elands
Cattle, buffalo, camels, yaks, sheep, rarely in pigs
Geographic Distribution
Mediterranean (especially in Israel, Italy, Spain, southern
France, and Malta), Asia, and Latin America
North America (especially in Texas and New Mexico), Mexico,
South America, New Zealand, and other cattle areas
B suis sows, hogs, rarely in horses, cows, dogs, fowl
South America, Southeast Asia, and midwestern United States
B canis the result of a laboratory accident
Cosmopolitan, but human infection is usually accidental
Pathophysiology:
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Brucella are ingested by neutrophils and tissue macrophages (can be maintained intracellularly within phagosomes), which, in turn, transport them to local lymph nodes then into the bloodstream.
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The enlargement of regional nodes may result, and the organism is disseminated primarily to the spleen, liver, bone marrow, brain, but may affect any organ or tissue.
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In organisms, in reticuloendothelial system, the formation of granulomas ensues.
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Large granulomas serve as a source for persistent bacteremia.
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It is characteristic of brucellosis that, in the spine, the intervertebral discs are involved rapidly by granulomatous tissue starting from the bone marrow, extending through the trabeculae and cartilage, and invading the disc. Bone repair occurs rapidly and the osteophytes are evidence of this.
History:
 Symptoms of brucellosis are protean in nature, and none are specific enough to make the diagnosis: o Fever (intermittent, undulant) can be associated with:
 chills, sweats and relative bradycardia. o Constitutional symptoms:
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o o o o o o o o o o o o
 anorexia, asthenia, fatigue, weakness, and malaise.
Neuropsychiatric symptoms:
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 headache, depression, fatigue, emotional instability, irritability.
Diffuse CNS involvement - spasticity, hyperreflexia, clonus, extensor plantar response, sensorineural hearing loss, cranial nerve involvement, and cerebellar signs
Peripheral polyradiculoneuropathy – Hypotonia, areflexia, paraparesis, absence of sensory involvement
Pain in the spine is an early and constant symptom, either in the neck or over the lumbar area:
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Spinal tenderness, often muscle spasm limiting spinal movement.
The pain from involvement of the nerve roots.
More than half of those with spinal disease are in the 40 to 60-year age group, and less than
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1% are under the age of 20 years.
The lumbar spine is affected more frequently than the thoracic and cervical regions.
When the disease affects the peripheral joints, it is usually in children under the age of 10 years; it is more frequent in the:
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 hips, knees and sacroiliac joints, but wrists, elbows, sternoclavicular, and costochondral joints may also be affected.
Osteoarticular findings:
 Tenderness, swelling over affected joints, bursitis, decreased range of motion, joint effusion
(rare).
Abdominal tenderness is associated with enlargement of the liver and/or the spleen. Cirrhosis is unlikely.
Clinical examination also demonstrates lymphadenopathy, particularly in the cervical and axillary nodes, which are soft and remain discrete and slightly tender.
Urinary infections occur but have no distinguishing features:
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 pyelo- and glomerulonephritis may develop.
Brucella organisms may be found in the urine.
Orchitis and epididymitis are not infrequent.
Older patients may develop congestive cardiac failure. Pericardial effusions can occur.
Lung infection is uncommon and may only occur when there has been inhalation.
A papular skin rash, skin ulcers, and soft tissue abscesses may all occur.
It is known that Brucella organism may survive in man for many years and remain dormant, only to erupt unexpectedly; it can be difficult to be sure that a cure has been finally effected.
 Clinically, brucellosis can be classified as: o subclinical (asymptomatic, diagnosis usually is found incidentally with serologic screening) o acute (disease can be mild and self-limited or severe with complications). Associated symptoms o o can be present at 2-3 months subacute, Associated symptoms can be present at 3-12 months chronic infections (Diagnosis typically is made after symptoms have been present for 1 year or more.). Low-grade fevers and neuropsychiatric complaints predominate.
 Localized complications o o are observed in patients with acute disease or chronic untreated infection.
Osteoarticular, genitourinary, and hepatosplenic involvement are most common.
Lab Studies:
 Leukopenia with a relative lymphocytosis. Pancytopenia - in as many as 20% of patients.
 Liver function studies are mildly abnormal
 Culture o Isolation of the organism in culture is the definitive diagnostic procedure. o Standard culturing techniques require prolonged incubation periods (30 days) under special conditions;
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o o o o o
Newer radiometric blood culturing techniques have decreased isolation time to less than 10 days.
Sensitivity of blood cultures ranges from 17-85%, depending on the strain involved.
Sensitivity decreases for all strains as the disease duration progresses.
Bone marrow cultures typically are more sensitive than blood cultures.
Synovial fluid demonstrates mononuclear cell predominance with the organisms isolated in
50% of patients. o Cerebrospinal fluid (CSF) isolation is rare.
 Serum tube agglutination test (the most commonly used test for brucellosis diagnosis) o o
The serum tube agglutination test detect IgG and IgM directed against smooth LPS.
Results are considered positive when titers are greater than or equal to 1:160 or when a 4-fold
 o o rise in titer is demonstrated in convalescent sera.
Blocking antibodies can cause a false-positive result. Coombs testing for Brucella species can clarify results in suspicious cases.
A prozone effect caused by hyperantigenemia can result in a negative titer. Prior to testing, routine dilution of serum beyond 1:320 can alleviate this problem. o Cross-reactivity with Afipia clevelandensis, Vibrio cholerae, Francisella tularensis, Salmonella species, and Yersinia enterocolitica can cause a false-positive result because of the presence of
LPS.
Enzyme-linked immunoassay (the most sensitive of all available tests) o The use of LPS-depleted, cytoplasmic, protein antigen allows for more accurate evaluation of o patient relapse because LPS antigenemia persists for longer periods than protein antigens.
ELISA is especially useful for the diagnosis of neurobrucellosis by CSF evaluation.
Imaging Studies:
 Spinal radiography o Radiographic findings in patients with osteoarticular disease occur later in the course of illness, o o usually 2-3 weeks after the onset of symptoms.
The most characteristic radiological findings are seen in the spine, especially in the lower dorsal and lumbar regions, but even these are nonspecific.
The lesions may occur at the periphery or in the center of the vertebral body.
 Radiological changes may affect one or more vertebrae.
 Peripheral vertebral lesions tend to occur early in the infection and affect the
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 anterosuperior margin of the vertebral body
Loss of the intervertebral disc space occurs early
Dense sclerosis and ankylosis often develop within 1 or 2-years after the initial bone infection
 Radionuclide scintigraphy o This study is more sensitive for detecting skeletal abnormalities, especially early in the disease.
Medical Care:
 Multidrug antimicrobial regimens are the mainstay of therapy because of high relapse rates reported with monotherapeutic approaches:
 Adults and children older than 8 years:
 doxycycline + rifampin for 4-6 weeks is the therapy of choice. Relapse rate is 5-10%.
 Children younger than 8 years:
 rifampin + TMP-SMX for 6 weeks is the therapy of choice. Relapse rate -5% or less.
 For patients with spondylitis:
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 doxycycline + rifampin + an aminoglycoside (gentamicin) for the initial 2-3 weeks followed by 6 weeks of rifampin + doxycycline.
 Patients with meningoencephalitis doxycycline + rifampin and/or TMP-SMX. A brief course of adjunctive corticosteroid
 therapy has been used to control the inflammatory process.
Patients with endocarditis require aggressive therapy:
 Aminoglycoside + doxycycline + rifampin + TMP-SMX for at least 4 weeks followed by at least 2-3 active agents (without aminoglycosides) for another 8-12 weeks is preferred.
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Complications:
 Osteoarticular (20-60%): o o o o sacroiliitis spondylitis, arthritis, osteomyelitis, bursitis, and tenosynovitis paraspinal pyogenic complications peripheral joint involvement (knees, hips, ankles, and shoulders), can be monoarticular or
 polyarticular.
Hepatobiliary o hepatitis, hepatic abscess, and acute cholecystitis.
 o gastrointestinal complications rarely include ileitis, colitis, and spontaneous peritonitis.
Genitourinary o orchitis or epididymo-orchitis. o renal involvement is rare (glomerulonephritis and pyelonephritis are reported). o Infection in patients who are pregnant is rare and is associated with first trimester abortions.
 Neurobrucellosis (5%)
 o Acute meningoencephalitis. o Other forms of neurobrucellosis typically present after at least 3 months of gradual symptoms.
Cardiovascular o o o o
Endocarditis (2% worldwide; 7-10% - in endemic areas).
The aortic valve is affected in 75% of patients,
Pericarditis, myocarditis, and mycotic aneurysms of the aorta and cerebral vessels
Primary pericarditis and myocarditis also are reported and have a more favorable outcome.
 Pulmonary (0.3-1%) o pneumonia and pleural effusion.
Prognosis:
 Although initial symptoms may be debilitating, if the symptoms are treated appropriately and within the first few months of onset, this disease is easily curable with a low risk of relapse or chronic disease.
For persons presenting with congestive heart failure from endocarditis, the prognosis is poor, with a mortality rate approaching 85%.
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