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Brucellosis
OVERVIEW: Systemic bacterial infection caused by Brucella species in infected animal products, or vaccine. Incubation period usually 5-60 days, but highly variable and may be several months. Characterized by intermittent or irregular fevers, with symptoms ranging from subclinical disease to infection of almost any organ system. Bone and joint involvement common. May be chronic or recurrent. Case fatality untreated less than 2%.
System(s) affected: Endocrine/Metabolic, Gastrointestinal, Renal/Urologic, Pulmonary, Nervous, Skin/Exocrine, Musculoskeletal, Cardiovascular
Genetics: None; some evidence for intrauterine transmission
Incidence/Prevalence in USA: About 100/year (105 cases in 1992; 0.34/100,000), but probably underreported; common in developing countries. Recent cases reported from exposure to dairy products from Mexico. Reportable in all states except Nevada.
Predominant age: All ages, but especially 20-60 (occupational exposure), sometimes children (milk-related outbreaks)
Predominant sex:
• Male > Female (occupational exposure)
• Female Male (milk exposure)
SIGNS AND SYMPTOMS: • Fever (may be undulant, increased in afternoon and evening, maximum 101-104° daily); weakness; headache; sweating; chills; generalized aching; arthralgia (90%)
• Also common - weight loss, depression, irritability, hepatosplenomegaly (20-30%)
• Hepatic dysfunction (abnormal liver function test) 30-60%
• Gastrointestinal symptoms (unusual)
• Lymphadenopathy, especially cervical, inguinal (12-21%)
• Orchitis, epididymitis (normal urinalysis) (2-40%)
• Nephritis, prostatitis (rare)
• Cystitis
• Pulmonary - cough or other pulmonary symptoms, x-ray may be normal (15-25%)
• Cutaneous - many transient, non-specific rashes have been described; also, purpura from thrombopenia (5%)
• Visual disturbances, eye pain
• Chronic fatigue syndrome and various neuro-psychiatric symptoms described. Unclear relationship.
• Also localized suppurative infections (see Complications)
CAUSES: • Brucella ingestion from tissue or milk
• Worst disease: B. melitensis, B. suis; also B. canis, B. abortus. Enter through mucous membrane, broken skin, occasionally inhaled. Facultative intracellular parasite, releases endotoxin when destroyed.
• Person-to-person transmission rare; sexual, vertical, possibly breast milk
RISK FACTORS: • In US, from occupational exposure to infected animals (especially cattle, sheep). Veterinarians, meat processors, farm workers; who may experience accidental exposure to vaccine. 18 case outbreak in pork processing plant, 1992.
• Consumer exposure to unpasteurized milk products, cheese
• Exposure while traveling in countries where endemic (Mediterranean, N. and E. Africa, central Asia, India, Mexico, Central and South America)
• Worse in chronically ill, immunosuppressed, malnourished
• Iron deficiency increases susceptibility
DIAGNOSIS DIFFERENTIAL DIAGNOSIS: • Many non-specific systemic febrile illnesses; a great mimic
• Tularemia
• Psittacosis
• Rickettsial disease
• Tuberculosis
• Visceral leishmaniasis
• Other disease of infected organs
• HIV infection
LABORATORY: • Isolation of organism from blood, discharge, bone or other tissue. Fastidious and slow-growing. Watch 3-4 weeks, with periodic subcultures. Automated systems shorten time, but not all recognize brucellosis. PCR exists, but not available in most clinical labs. Skin tests not standardized, not recommended for diagnosis.
• Acute illness: Blood culture is positive 70%, bone 90%
• May have thrombopenia, disseminated intravascular coagulation; granulopenia, lymphopenia, lymphocytosis. 30-60% with abnormal liver function test. 72% have normal.
• Serology: Brucella standard tube agglutination (STA) paired sera, > 1:160 or 4 x rise (cheapest). An easy, rapid dipstick test is being developed.
• More effective ELISA, indirect fluorescent antibody test (IFAT), Coombs tests. With ELISA, IgM, IgG or IGA may be present at low levels > 1 year even if treated.
• IgM increased initially for several weeks, declines by 3 months
• IgG begins rise 2 weeks, may stay up (low levels) > 1 yr if treated or not treated (though IgM increase may be lower or gone by 6 months if treated, but can also persist > 1 year at low levels). IgG titer rises again with reinfection or reactivation. IgG and IGA titer > 1:160 at 1 year implies ongoing infection.
• New research: gene cloning and amplification for discriminatory markers detection and strain differences
Drugs that may alter lab results: None
Disorders that may alter lab results: Serologic cross-reaction with F. tularensis, Yersinia enterocolitica, V. cholerae, or vaccinated patients. It has been misdiagnosed in culture as Moraxella phenylpyruvica.
PATHOLOGICAL FINDINGS: • Facultative intracellular; can survive inside phagocytic cells, circulate to regional lymph nodes, and into circulation. (Cell-mediated immunity necessary to kill intracellular organism.)
• Macrophages kill, releasing endotoxin that may cause symptoms of acute disease
• Variable tissue reaction depending on site, organisms. Causes local microabscesses; possibly some immune reaction in arthritis, including elevated C3, C4; ANA, RF
SPECIAL TESTS: Echocardiogram depending on location
IMAGING: • Bone scan, CT, depending on location
• Chest x-ray - pleural effusion, lung cavitation
• Joint x-rays frequently normal, requiring scan or MRI
DIAGNOSTIC PROCEDURES: Biopsy, aspiration depending on location
TREATMENT APPROPRIATE HEALTH CARE: Outpatient in mild cases, hospitalization in severe illness. Cardiac care unit in patients with complicating cardiac disease.
GENERAL MEASURES: • Supportive care
• In milk-related outbreak, look for other cases
SURGICAL MEASURES: Specific complications may require surgical drainage, or valve replacement in endocarditis
ACTIVITY: Bedrest during febrile periods and restricted activity in acute cases
DIET: No special diet. May need to provide supplemental foods, e.g., milk shakes, to counter weight loss.
PATIENT EDUCATION: Food Safety and Inspection Service, Office of Public Awareness, Dept. of Agriculture, Room 1165-S, Washington, DC 20205, (202)447-9351
MEDICATIONS DRUG(S) OF CHOICE: Optimal therapy includes two drugs, at least one with good intracellular penetration
• Rifampin 600-900 mg and doxycycline 200 mg given together every day for at least 6 weeks (possible for several months with severe complications). 5% relapse rate, not related to drug resistance - use same drugs for relapse. Usual cause is localized sequestration of organisms, or noncompliance with medication.
• Steroids in Herxheimer's reaction, severe illness, pancytopenia
Contraindications: Avoid doxycycline in children, pregnant women
Precautions: May get Herxheimer's reaction when therapy initiated
Significant possible interactions:
• Rifampin is a potent inducer for the hepatic P450 enzyme system, and may increase metabolism of many drugs metabolized by the liver
• Doxycycline: Antacids, anticoagulants, barbiturates, carbamazepine, hydantoins, cimetidine, digoxin insulin, iron salts, lithium, methoxyflurane, oral contraceptives, penicillins, sodium bicarbonate
ALTERNATIVE DRUGS: • In recent studies, ciprofloxacin 1 gm/qd and rifampin 600 mg/day for 30 days as effective as rifampin/doxycycline for 45 days
• Doxycycline orally bid and streptomycin by injection - very effective. (Streptomycin currently not available in the USA except by special request from CDC in Atlanta.) Slightly more effective than doxycycline/rifampin, especially with spondylitis, but more toxic and less convenient.
• In children, trimethoprim-sulfamethoxazole (cotrimoxazole) plus rifampin 15 mg/kg (don't use alone) - higher relapse rate
• In children and pregnant women, rifampin 15 mg/kg for 45 weeks plus trimethoprim-sulfamethoxazole for 6 weeks or gentamicin for 7 days or netilmicin 5-6 mg/kg IM
• Ofloxacin plus rifampin effective in recent study
• No single drug is effective alone
FOLLOW UP PATIENT MONITORING: Check serology at 6 months and 1 year for chronic disease (difficult to evaluate if continuing exposure). Investigate any evidence of complication, recurrence.
PREVENTION/AVOIDANCE: • Avoid infected milk
• For occupational exposure - caution, animal vaccination, use of protective goggles, protective gloves. Possible future human vaccine.
POSSIBLE COMPLICATIONS: • Relapse (5% overall)
• Localized suppurative infections - osteo-articular (20-85%). Includes arthritis (possibly also immune effect), bursitis, tenosynovitis, osteomyelitis, sacroiliitis, vertebral or paraspinous abscess.
• Endocarditis - rare, but main cause of death in brucellosis
• Thrombophlebitis
• Neuro-brucellosis - most are meningeal. Also peripheral neuritis (usually single, bilateral is possible), encephalitis, myelitis, radiculopathy. Possibly neuro-psychiatric symptoms; a chronic fatigue type syndrome may exist which may or may not represent organic disease.
• Intrinsic ocular lesions - uveitis, retinal thrombophlebitis, nummular keratitis
• Pneumonitis with pleural effusion
• Hepatitis
• Cholecystitis
• Chronic infection. Persistent (> 1 year) signs of infection, elevated titers, occasional bacteria in blood or tissue. Chronic fatigue syndrome with everything negative is controversial.
EXPECTED COURSE AND PROGNOSIS: • Untreated case fatality < 2%
• Most cases resolve with treatment. 2-3 weeks for acute uncomplicated cases, but at least 6 weeks treatment recommended
• Relapse rate overall, 5%
MISCELLANEOUS ASSOCIATED CONDITIONS: N/A
AGE-RELATED FACTORS:
Pediatric: May be mild, subclinical
Geriatric: N/A
Others: Worse in chronically ill, immunosuppressed
PREGNANCY: May cause miscarriage or abortion, even in subclinical cases
SYNONYMS: • Undulant fever
• Malta fever
ICD-9-CM: 023.9 Brucellosis, unspecified
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Chronic fatigue syndrome
Abortion, spontaneous
Thrombosis, deep vein (DVT)
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