para>May be mild, subclinical
Boys infected more than girls (animal handling)
Children often present with refusal to walk or bear weight secondary to pain.
Children respond better to antibiotic treatment than adults.
�
ALERT
Can have high rates of miscarriage or abortion (can occur in subclinical cases). Early antibiotic treatment is preventive.
�
EPIDEMIOLOGY
- Predominant age: 20 to 45 years (occupational exposure); sometimes children (milk-related outbreaks) but can occur at all ages
- Predominant gender:
- male > female (occupational exposure)
- female ≥ male (milk exposure)
Incidence
- >500,000 new cases yearly (likely underreported)
- <100 U.S. cases reported annually to the CDC
Prevalence
- Common in developing countries; highest in Turkey, Syria, and Iran; some countries report case rates as high as 10/100,000; present in all inhabited continents
- Highest rates in the United States are in Hispanic populations along U.S.-Mexico border; also Wyoming, North Carolina, Illinois, Florida, and Iowa
- Reportable in all states
ETIOLOGY AND PATHOPHYSIOLOGY
- Brucella ingestion from raw or undercooked tissue or unpasteurized milk products. Susceptible to heat and disinfectant but can survive for several weeks in frozen food and weeks to months in dust, soil, or water.
- Facultative intracellular parasite: gram-negative, nonmotile, non-spore-forming coccobacillus
- Most virulent disease: Brucella melitensis, Brucella suis; also Brucella canis, Brucella abortus; can enter via mucous membrane or broken skin; occasionally inhaled
- Laboratory workers at high risk of infection if specimens handled improperly
- Person-to-person transmission is rare; sexual, vertical, and possibly, breast milk; blood transfusion
- Potential airborne biologic weapon
- Affects most domesticated ungulates (goats, cattle, camels, pigs, sheep) and also wild bison and elk. Marine mammals are also implicated in zoonotic transmission.
- Infection increases abortion rate in animals, less so in humans.
Genetics
- Some evidence for intrauterine transmission but causes no birth defects
- Some complications may have genetic predisposition.
RISK FACTORS
- In the United States, occupational exposure to infected animals (especially cattle and sheep): veterinarians, meat processors, farm workers who may experience accidental exposure to vaccine, lab technicians
- Consumer exposure to unpasteurized dairy products and cheese, especially along U.S.-Mexico border
- Exposure while traveling in endemic countries (Mediterranean, Middle East, North and East Africa, Central Asia, India, Mexico, Central and South America)
- Chronically ill and malnourished
- Potential acceleration of HIV disease
- Iron deficiency increases susceptibility.
- Bison and elk are infected with brucellosis near Yellowstone Park.
GENERAL PREVENTION
- Avoid infected, unpasteurized dairy products.
- Use caution handling animal vaccines. Use protective goggles and protective gloves in handling tissue.
- Possibility exists for future human vaccine.
- Postexposure prophylaxis same as treatment
DIAGNOSIS
HISTORY
- Nonspecific systemic febrile illnesses; "great mimic"�
- Constellation of fever (often high, undulant-increased in afternoon and evening), weakness, headache, sweating, chills, generalized aching, arthralgia (90%)
- Arthralgia (65%)
- Myalgia (56%)
- Back pain (49%)
- Epididymo-orchitis in 10% of men
- Weight loss, depression, irritability
- Dyspepsia and abdominal pain
- Cough or other pulmonary symptoms
- Visual disturbances, eye pain
- Chronic fatigue and various neuropsychiatric symptoms (chronic infection)
PHYSICAL EXAM
- Fever (78%)
- Malodorous perspiration: pathognomonic
- Hepatosplenomegaly (20-30%)
- Arthritis is the most common complication.
- Lymphadenopathy, cervical and inguinal (12-21%)
- Orchitis, epididymitis (normal urinalysis) (2-40%)
- Cystitis, nephritis, prostatitis (rare)
- Cutaneous: transient, nonspecific rash; purpura from thrombopenia (5%)
- Localized suppurative infections
- Noncaseating granulomas
- Endocarditis (2%): most common cause of death
- Hepatic dysfunction (abnormal LFT): 30-60%
- Pulmonary: Radiograph may be normal (15-25%).
- Neurologic: motor tics, cranial nerve deficits, sciatica, peripheral weakness
DIFFERENTIAL DIAGNOSIS
- Tularemia
- Psittacosis
- Rickettsial disease
- Tuberculosis
- Visceral leishmaniasis
- HIV infection
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- Microbiologic:
- Isolation of organism from blood, pus, bone, or other tissue: Bone marrow is gold standard:
- Fastidious and slow-growing-culture for 3 to 4 weeks with repeated subcultures
- Low sensitivity (50-90%) of culture in acute disease (1)[C]; not all labs have suitable culture material.
- Culture often negative in longstanding disease.
- Skin tests not standardized or recommended for diagnosis
- Serologic:
- Because of difficulty with culture, serology used more often; need at least two tests to confirm (1)[C],(2)[B]
- In absence of appropriate culture facilities, rapid bedside testing often used initially and then confirmed by serum agglutination testing:
- Rose Bengal Test useful for acute disease but less so in patients with prior disease (3)[C]
- Brucella IgM/IgG lateral flow assay is a simple rapid bedside test using a drop of blood collected by fingerprick, more sensitive than serology (3)[C].
- Serologic confirmatory testing: Brucella standard tube agglutination paired sera at least 2 weeks apart- >1:160 or 4 times rise (cheapest) (2)[B],(3)[C]
- ELISA, indirect fluorescent antibody test, Coombs tests, immunocapture-agglutination (Brucella apt) are also helpful. With ELISA-IgM, IgG, or IgA may be present at low levels >1 year, even if treated. IgM increases during initial weeks and declines by 3 months.
- ELISA: IgG begins to rise in 2 weeks; may stay elevated (low levels) for >1 year. (IgM increase may resolve 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 disease.
- Molecular:
- Gene cloning and amplification for discriminatory detection and strain differences; polymerase chain reaction (PCR)-ELISA
- PCR: accurate and more rapid than culture; becoming more available in most clinical labs (2)[B]
- Disorders that may alter lab results:
- Serologic cross-reaction with Francisella tularensis, Yersinia enterocolitica, Vibrio cholerae, or vaccinated patients
- Has been misdiagnosed in culture as Moraxella phenylpyruvica
- Other findings:
- May have thrombocytopenia, disseminated intravascular coagulation, granulopenia, lymphopenia (40%), relative lymphocytosis
- 30-60% with abnormal liver transaminases
- Bone scan, MRI, CT-depending on location
- Chest x-ray: pleural effusion, lung cavitation
- Joint radiographs frequently normal
Diagnostic Procedures/Other
Bone marrow biopsy; tissue biopsy of affected area �
Test Interpretation
- Facultative intracellular gram-negative coccobacillus; can survive inside phagocytic cells, lymph nodes, and into circulation
- Variable tissue reaction, depending on site and organisms; causes local microabscesses
TREATMENT
GENERAL MEASURES
- Supportive care
- In milk-related or occupational outbreak, case surveillance as public health measure.
- Bed rest during febrile periods and restricted activity in acute cases
MEDICATION
First Line
- Optimal therapy includes two drugs, one with good intracellular penetration (typically an aminoglycoside). In some cases, three drugs may give a better long-term cure.
- Longer courses (months) may improve relapse rate in complicated disease.
- For individuals >8 years of age: rifampin 600 to 1,200 mg once daily and doxycycline 100 mg BID for at least 6 weeks (possibly, for several months with severe complications) (3,4)[C]:
- 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.
- Streptomycin 1 g/day IM for 2 to 3 weeks and doxycycline 100 mg PO BID for 6 weeks are acceptable alternatives shown to have less relapse than rifampin/doxycycline (4)[C],(5)[A].
- In children <8 years old, rifampin plus TMP-SMX for 6 weeks (2,3)[C]
- For pregnant women: Rifampin daily with or without trimethoprim/sulfamethoxazole for 6 weeks; caution with use of trimethoprim/sulfamethoxazole in last trimester of pregnancy.
- In patients with spondylitis or sacroiliitis, gentamicin (2 weeks) should be given initially with doxycycline and rifampin (continued for full 6 weeks) (5)[A].
- Chronic brucellosis is treated with triple therapy, typically rifampin, doxycycline, and streptomycin.
- Contraindications:
- Avoid doxycycline in children <8 years old and pregnant women.
- Precautions:
- Observe for Herxheimer reaction when therapy initiated.
- Significant possible interactions:
- Rifampin induces the hepatic P450 system which may alter metabolism of other hepatically metabolized drugs: doxycycline, antacids, anticoagulants, barbiturates, carbamazepine, hydantoins cimetidine, digoxin, insulin, iron salts, lithium, methoxyflurane, oral contraceptives, penicillins, sodium bicarbonate.
- Concern for development of resistance to rifampin in tuberculosis-endemic areas
Second Line
- Doxycycline PO BID and streptomycin by injection is very effective (streptomycin currently not available in the United States except by special request from the CDC); slightly more effective than doxycycline/rifampin (5)[A], especially with spondylitis but more toxic and less convenient
- Ofloxacin or ciprofloxacin plus doxycycline or rifampin effective in a recent study but not as effective as first-line treatment (5)[A].
- Use of triple-drug therapy with doxycycline, rifampin, and a 7- to 10-day course of gentamicin markedly reduced relapse but not current standard as only studied in uncomplicated, acute disease (5)[A].
ISSUES FOR REFERRAL
Need for surgical intervention �
SURGERY/OTHER PROCEDURES
Specific complications (neurologic deficit, spinal instability, localized abscess) may require surgical drainage or valve replacement (endocarditis). �
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
- Outpatient in mild cases; hospitalization in severe illness. Consider consultation with infectious disease specialist.
- Cardiac care unit for patients with complicating cardiac disease
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- Check serology at 6 months and 1 year for chronic disease (difficult to evaluate if continuing exposure).
- Investigate any suspicion of recurrence.
- PCR was recently shown to be sensitive and specific for monitoring treatment relapse.
DIET
- No special diet
- May need to provide supplemental foods, such as milkshakes, to counter weight loss
PATIENT EDUCATION
- Food Safety and Inspection Service, Office of Public Awareness, Department of Agriculture: Room 1165-S, Washington, DC 20205; (202)720-9904; www.fsis.usda.gov/
- Education about exposure
PROGNOSIS
- Untreated case fatality <5%; mostly from endocarditis
- Most cases resolve with treatment in 2 to 3 weeks in acute uncomplicated cases but at least 6-week treatment recommended.
COMPLICATIONS
- Relapse rate overall: 5-10%
- Severe complications present: 10-15%
- Localized suppurative infections: osteoarticular (20-85%); includes arthritis (possibly also immune effect), bursitis, tenosynovitis, osteomyelitis, sacroiliitis, vertebral, or paraspinous abscess
- Endocarditis: rare but main cause of death
- Thrombophlebitis
- Neurobrucellosis: meningitis, peripheral neuritis, encephalitis, myelitis, radiculopathy; possibly neuropsychiatric symptoms
- Intrinsic ocular lesions: uveitis, retinal thrombophlebitis, nummular keratitis
- Pneumonitis with pleural effusion
- Hepatitis; cholecystitis
- Chronic infection
REFERENCES
11 Ciocchini �AE, Rey Serantes �DA, Melli �LJ, et al. Development and validation of a novel diagnostic test for human brucellosis using a glyco-engineered antigen coupled to magnetic beads. PLoS Negl Trop Dis. 2013;7(2):e2048.22 Sanjuan-Jimenez �R, Morata �P, Berm �dez �P, et al. Comparative clinical study of different multiplex real time PCR strategies for the simultaneous differential diagnosis between extrapulmonary tuberculosis and focal complications of brucellosis. PLoS Negl Trop Dis. 2013;7(12):e2593.33 Al Dahouk �S, N �ckler �K. Implications of laboratory diagnosis on brucellosis therapy. Expert Rev Anti Infect Ther. 2011;9(7):833-845.44 Yousefi-Nooraie �R, Mortaz-Hejri �S, Mehrani �M, et al. Antibiotics for treating human brucellosis. Cochrane Database Syst Rev. 2012;(10):CD007179.55 Sol �s Garc �a del Pozo �J, Solera �J. Systematic review and meta-analysis of randomized clinical trials in the treatment of human brucellosis. PLoS One. 2012;7(2):e32090.
ADDITIONAL READING
- Dean �AS, Crump �L, Greter �H, et al. Clinical manifestations of human brucellosis: a systematic review and meta-analysis. PLoS Negl Trop Dis. 2012;6(12):e1929.
- Pappas �G, Akritidis �N, Bosilkovski �M, et al. Brucellosis. N Engl J Med. 2005;352(22):2325-2336.
- Pappas �G, Papadimitriou �P, Akritidis �N, et al. The new global map of human brucellosis. Lancet Infect Dis. 2006;6(2):91-99.
- Skalsky �K, Yahav �D, Bishara �J, et al. Treatment of human brucellosis: systematic review and meta-analysis of randomised controlled trials. BMJ. 2008;336(7646):701-704.
CODES
ICD10
- A23.9 Brucellosis, unspecified
- A23.8 Other brucellosis
- A23.0 Brucellosis due to Brucella melitensis
- A23.2 Brucellosis due to Brucella suis
- A23.1 Brucellosis due to Brucella abortus
- A23.3 Brucellosis due to Brucella canis
ICD9
- 023.9 Brucellosis, unspecified
- 023.8 Other brucellosis
- 023.0 Brucella melitensis
- 023.2 Brucella suis
- 023.3 Brucella canis
- 023.1 Brucella abortus
SNOMED
- Brucellosis (disorder)
- Brucellosis of skin
- Infection due to Brucella melitensis
- Infection due to Brucella suis
- Infection due to Brucella canis
- Infection due to Brucella abortus
- Brucella infection of the central nervous system
CLINICAL PEARLS
- Diagnosis of brucellosis can be challenging. Brucellosis is characterized by intermittent or irregular fevers, with symptoms ranging from subclinical disease to infection of almost any organ system.
- Diagnosis is based on serologies and confirmed by culture.
- Rifampin and doxycycline are used most commonly to treat brucellosis.
- Brucellosis is a reportable disease and a potential agent of bioterrorism.