BRUCELLOSIS

BRUCELLOSIS - Nancy Snapp, MD, MPH
BASICS
DESCRIPTION
• 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
• System(s) Affected: Cardiovascular; Endocrine/Metabolic; Gastrointestinal; Musculoskeletal; Nervous; Pulmonary; Renal/Urologic; Skin/Exocrine
• Synonym(s): Undulant fever; Malta fever
ALERT
Pediatric Considerations
May be mild, subclinical
Pregnancy Considerations
High rates of miscarriage or abortion (can occur in subclinical cases). Early antibiotic treatment is preventive.
GENERAL PREVENTION
• Avoid infected dairy products.
• For occupational exposure, use caution, animal vaccination, protective goggles, protective gloves. There is a possibility of future human vaccine.
• Postexposure prophylaxis same as treatment in large-scale exposure such as bioterrorism
• Susceptible to heat, disinfectant, but can survive in dust, soil, or water for weeks
EPIDEMIOLOGY
• Predominant age: All ages, but especially ages 20-60 years (occupational exposure), sometimes children (milk-related outbreaks)
• Predominant sex:
- Male > Female (occupational exposure)
- Female  Male (milk exposure)
Incidence
~100 per year (0.34/100,000), but probably underreported (1,2)
Prevalence
• Common in developing countries; consider in immigrants
• Highest rates in Hispanic population, along US-Mexico border
• Considered a potential biological terror agent in aerosolized form
• Reportable in all states except Nevada
RISK FACTORS
• In the US, from occupational exposure to infected animals (especially cattle, sheep) veterinarians, meat processors, farm workers who may experience accidental exposure to vaccine.
• Consumer exposure to unpasteurized milk products, cheese, especially in Hispanics along US-Mexico border
• Exposure while traveling in countries where endemic (Mediterranean, Middle East, North and East Africa, Central Asia, India, Mexico, and Central and South America)
• Worse in chronically ill, immunosuppressed, and malnourished
• Iron deficiency increases susceptibility
Genetics
• Some evidence for intrauterine transmission
• Some complications may have genetic predisposition (2)
ETIOLOGY
• Brucella ingestion from tissue or milk
• Worst disease: B. melitensis, B. suis; also B. canis, B. abortus. Enters through mucous membrane or broken skin; occasionally inhaled.
• Facultative intracellular parasite
• Person-to-person transmission rare; sexual, vertical, and possibly breast milk; case report of neonatal brucellosis from a blood transfusion
• Potential air-borne biologic weapon


DIAGNOSIS
SIGNS AND SYMPTOMS
• Fever (may be undulant, increased in afternoon and evening, maximum 101-104F daily); weakness; headache; sweating; chills; generalized aching; arthralgia (90%) (2)[A]
• 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; radiograph may be normal (15-25%)
• Cutaneousmany transient, nonspecific rashes have been described; also, purpura from thrombopenia (5%)
• Visual disturbances, eye pain
• Chronic fatigue syndrome and various neuropsychiatric symptoms described. Relationship is unclear.
• Also localized supurative infections (see "Complications")
• Malodorous perspiration (2)
History
Exposure
TESTS
Echocardiogram, depending on location
Lab
• Isolation of organism from blood, discharge, bone, or other tissue (3)[C]
- Fastidious and slow growing
- Watch for 3-4 weeks, with periodic subcultures
- Automated systems shorten time, but not all recognize brucellosis.
- Polymerase chain reaction (PCR) accurate, including nonblood samples, but not available in most clinical labs (3)[C]
- Skin tests not standardized, not recommended for diagnosis
• Acute illness: Blood culture positive 70%, bone marrow 90%
• May have thrombocytopenia, disseminated intravascular coagulation; granulopenia, lymphopenia, lymphocytosis. 30-60% with abnormal liver function test. Up to 70% may have normal labs.
• Serology: Use at least 2 tests to confirm (4)[C]
- Brucella standard tube agglutination paired sera, >1:160 or 4 rise (cheapest)
- Easy, accurate, and rapid dipstick for IgM now exists for developing countries
• More effective enzyme-linked immunosorbent assay (ELISA), indirect fluorescent antibody test, Coombs tests, immunocapture-agglutination (Brucellacapt). 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 to rise in 2 weeks, may stay up (low levels) >1 year if treated or not treated (though IgM increase may be lower or gone by 6 months if treated, 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 disease. (4)[C]
• New research: Gene cloning and amplification for discriminatory markers detection and strain differences; PCR-ELISA
• 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
- Has been misdiagnosed in culture as Moraxella phenylpyruvica
Imaging
• Bone scan, CT, depending on location
• Chest radiographpleural effusion, lung cavitation
• Joint radiographs frequently normal, requiring scan or MRI
Diagnostic Procedures/Surgery
Biopsy, aspiration, depending on location
Pathological Findings
• Facultative intracellular Gram-negative coccobacillus; can survive inside phagocytic cells, circulate to regional lymph nodes, and into circulation
• Variable tissue reaction depending on site, organisms. Causes local microabscesses; noncaseating granulomas; (1) possibly some immune reaction in arthritis, including elevated C3, C4; antinuclear antibody, and rheumatoid factor.
DIFFERENTIAL DIAGNOSIS
• Many nonspecific systemic febrile illnesses; a great mimic
• Tularemia
• Psittacosis
• Rickettsial disease
• Tuberculosis
• Visceral leishmaniasis
• Other disease of infected organs
• HIV infection
TREATMENT
• Outpatient in mild cases, hospitalization in severe illness
• Cardiac care unit for patients with complicating cardiac disease
GENERAL MEASURES
• Supportive care
• In milk-related or occupational outbreak, look for other cases.
Diet
• No special diet
• May need to provide supplemental foods, such as milk shakes, to counter weight loss
Activity
Bed rest during febrile periods and restricted activity in acute cases
Nursing
Patient comfort, education
IV Fluids
If cardiac complications
MEDICATION (DRUGS)
First Line
• Optimal therapy includes 2 drugs, at least 1 with good intracellular penetration. In some cases, 3 drugs may give a better long-term cure.
• Longer courses (months) may improve relapse rate in complicated disease.
• Rifampin 600-900 mg and doxycycline 200 mg given together every day for at least 6 weeks (possibly for several months with severe complications); 5-10% relapse rate, not related to drug resistanceuse same drugs for relapse. Usual cause is localized sequestration of organisms or noncompliance with medication (5)[C].
• Steroids in Herxheimer reaction, severe illness, and pancytopenia
• Contraindications
- Avoid doxycycline in children and pregnant women (affects bone).
• Precautions:
- May get Herxheimer 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
Second Line
• In recent studies, ciprofloxacin 1 g daily and rifampin 600 mg/d for 30 days as effective as rifampin/doxycycline for 4-5 weeks (2,6)[A]
• Doxycycline PO b.i.d. and streptomycin by injectionvery effective (streptomycin currently not available in the US except by special request from Centers for Disease Control and Prevention); slightly more effective than doxycycline/rifampin, especially with spondylitis, but more toxic and less convenient (5)
• In children and pregnant women, rifampin 15 mg/kg for 4-5 weeks plus cotrimoxazole for 6 weeks or gentamicin for 7 days or netilmicin 5-6 mg/kg IM. Significant cotrimoxazole resistance in some countries (1,6)[C]
• Ofloxacin plus rifampin effective in recent study
• Sensitivities frequently don't reflect in vivo action (2)[C]
SURGERY
Specific complications may require surgical drainage or valve replacement (endocarditis).
FOLLOW-UP
PROGNOSIS
• Untreated case fatality 2%
• Most cases resolve with treatment in 2-3 weeks in acute uncomplicated cases, but at least 6 weeks treatment recommended
COMPLICATIONS
• Relapse rate overall: 5-10% (6)[C]
• Complications present 10-15% (4)[C]
• 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 neuropsychiatric symptoms
• 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.
PATIENT MONITORING
• Check serology at 6 months and 1 year for chronic disease (difficult to evaluate if continuing exposure).
• Investigate any evidence of complication or recurrence.
• PCR recently shown to be sensitive and specific for monitoring treatment relapse
REFERENCES
1. Sauret J, Vilissova N. Human brucellosis. J Amer Board Fam Pract. 2002;15:401-406.
2. Pappas, Georgios, et al. Brucellosis. N Eng J Med. 2005;352(22);2325-2336.
3. Al Dahouk S, Tomaso H, et al. Laboratory-based diagnosis of brucellosisa review of the literature. Part I: Techniques for direct detection and identification of Brucella spp. Clin Lab. 2003;49:487-505.
4. Al Dahouk S, Tomaso H, et al. Laboratory-based diagnosis of brucellosisa review of the literature. Part II: Serological tests for brucellosis. Clin Lab. 2003;49:577-589.
5. Montejo JM, et al. Open randomized therapeutic trial of six antimicrobial regimens in brucellosis. Clin Infect Dis. 1993;16:671-676.
6. Pappas, Georgios, et al. New approaches to the antibiotic treatment of brucellosis. Intl J Antimicrob Ag. 2005;26(2);101-105.
MISCELLANEOUS
See also: Abortion, Spontaneous; Chronic Fatigue Syndrome; Thrombosis, Deep Vein (DVT)