Brucella/Brucellosis

Brucellosis (also known as undulant fever, Mediterranean fever, or Malta fever) is a zoonotic infection that spreads predominantly through ingestion of unpasteurized dairy products or direct contact with infected animal products. Clinical manifestations include fever, arthralgias, malaise, lymphadenopathy, and hepatosplenomegaly. The clinical manifestations, exposure history, serology, and culture data are used in the diagnosis. Treatment involves a combination of antibiotics, including doxycycline, rifampin, and aminoglycosides. Preventative measures include avoiding unpasteurized dairy products, vaccinating livestock, and using caution around animals.

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General Characteristics of Brucella

General characteristics

  • Gram-negative coccobacilli
  • Facultative intracellular
  • Aerobic
  • Requires carbon dioxide (CO2)
  • Non-motile
  • Unencapsulated
  • Non-spore forming
  • Oxidase and urease positive
  • Require enriched media for culture growth (Thayer-Martin medium)
    • Improved with blood or serum
    • Optimum temperature: 35–37°C (95–98.6°F)

Brucellae are poorly staining, gram-negative coccobacilli. They are mostly seen as tiny, single cells that look like “fine sand.”

Image: “Brucella spp” by CDC. License: Public Domain

Clinically relevant species

  • B. melitensis
  • B. abortus 
  • B. suis 
  • B. canis

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Epidemiology and Risk Factors

Epidemiology

  • Most common zoonotic infection worldwide and a significant public health problem in many developing countries:
    • Endemic areas: 
      • Mediterranean
      • Middle East 
      • Central Asia 
      • China 
      • Mexico 
      • Central and South America
    • Rare in the United States, mostly seen in:
      • California
      • Florida
      • Texas
      • Virginia
  • Prevalence:
    • Worldwide: approximately 500,000 cases annually
    • United States: 100–200 cases annually
    • Increasing due to international tourism and migration
  • Affects all age groups

Occupations at high risk

  • Veterinarians 
  • Dairy farmers 
  • Shepherds
  • Slaughterhouse workers
  • Laboratory personnel

Pathogenesis

Reservoirs

  • Sheep, goats, camels → B. melitensis
  • Cattle → B. abortus
  • Swine → B. suis
  • Dogs → B. canis

Transmission

  • Ingestion of unpasteurized animal products (most common)
  • Skin contact with mucous membranes of infected animal tissues or fluids 
  • Inhalation of aerosolized particles (more common in laboratory workers)
  • Rarely, human-to-human transmission

Virulence factors

  • Lipopolysaccharide (LPS)
    • Inhibits: 
      • Phagosomal fusion and lysosomal destruction → allows intracellular survival
      • Complement deposition
    • “Non-classical”
      • Less toxic than in other species of bacteria
      • Weak immune system inducer
  • Superoxide dismutase and catalase: provides defense against oxidative burst activity → allows intracellular survival
  • Type IV secretion system
    • Multi-protein complex
    • Allows Brucella to reach and replicate within a cell’s endoplasmic reticulum

Pathophysiology

  • Bacteria translocate across mucosal epithelium.
  • Engulfed by macrophages
    • Approximately 10% of bacteria survive.
    • Replication occurs in the endoplasmic reticulum.
  • Transported to the lymphatic system → disseminate throughout the body
  • Hemolysins allow for release of bacteria from the macrophage → cell apoptosis → triggers an immune response
  • Antigens are presented to T lymphocytes → cytokine production 
    • Activation of macrophages → ↑ bactericidal effect
    • Attracts more immune cells → granuloma formation
  • Antibodies and natural killer cells play a smaller role in the immune response.

Pathogenesis of brucellosis due to Brucella

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Clinical Presentation

General signs and symptoms

  • Average incubation period is 2–4 weeks.
  • Symptoms:
    • “Undulant fever” 
      • Comes in waves
      • Can vary in presentation
      • Persists 1‒5 weeks
    • Night sweats: associated with a strong, moldy odor
    • Malaise
    • Arthralgias
    • Headache
    • Loss of appetite
    • Weight loss
    • Symptoms may disappear and then return after weeks or months.
  • Physical exam (nonspecific):
    • Hepatomegaly
    • Splenomegaly
    • Painful lymphadenopathy

Complications

  • Osteoarticular (70% of patients):
    • Arthritis
    • Sacroiliitis
    • Spondylitis
    • Osteomyelitis
  • Genitourinary:
    • Orchitis
    • Epididymitis
    • Cystitis
    • Interstitial nephritis and glomerulonephritis
    • ↑ Risk of spontaneous abortion in pregnancy
  • Neurobrucellosis:
    • Meningitis
    • Encephalitis
    • Neuritis
    • Brain abscess
  • Cardiovascular:
    • Endocarditis (main cause of death)
    • Myocarditis
    • Pericarditis
  • Pulmonary:
    • Bronchitis
    • Interstitial pneumonitis
    • Pneumonia
    • Pleural effusion
  • Abdominal:
    • Cholecystitis
    • Hepatic abscess
    • Splenic abscess
    • Pancreatitis
    • Ileitis and colitis
  • Ocular: uveitis
  • Cutaneous: rash (varying presentation)

Relapse can occur in 4%–24% of patients, usually within 1 year.

Diagnosis

Diagnostic algorithm

As this diagram illustrates, testing modalities that provide a definitive diagnosis usually require a considerable amount of time. While waiting for the results of these modalities, other testing measures can be used to provide a presumptive diagnosis.
CSF: cerebrospinal fluid
PCR: polymerase chain reaction

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Diagnostic testing

  • Culture
    • Definitive
    • Blood cultures are usually obtained in all patients.
    • Bone marrow is considered the gold standard (most sensitive).
    • Requires special culture techniques
  • Serum tube agglutination test (SAT)
    • Measures antibodies against a Brucella antigen (smooth lipopolysaccharide)
    • Evolution titers (fourfold increase in the titer between acute and convalescent serum obtained ≥ 2 weeks apart)
      • Provides a definitive diagnosis
      • Limited by the time required
    • Positive titers providing a presumptive diagnosis: 
      • > 1:160 outside endemic regions 
      • > 1:320 within endemic regions
    • Cannot be used for B. canis
  • Enzyme-linked immunosorbent assay (ELISA)
    • Comparable sensitivity and specificity to SAT
    • Tests for immunoglobulins against cytoplasmic proteins
  • Rose Bengal agglutination
    • Can be used as a screening tool
    • Rapid
  • Polymerase chain reaction (PCR)
    • Detects Brucella DNA
    • Can provide a presumptive diagnosis

Additional workup

The testing performed is guided by the patient’s clinical presentation and any concerns for complications.

  • Laboratory testing (nonspecific)
    • Complete blood count:
      • Anemia 
      • Leukopenia with ↑ lymphocytes
      • Thrombocytopenia
    • ↑ Liver function tests 
    • Synovial fluid:
      • May be tested in patients with arthritis
      • White blood cell (WBC) count ≤ 15,000 cells/µL
      • Culture will grow Brucella
    • CSF:
      • May be tested in patients with neurologic involvement
      • 10‒200 WBC with mononuclear cell predominance
      • ↑ Protein
      • Antibody or agglutination testing may be done.
    • Urinalysis
      • ↑ WBC
      • Brucella may be grown on culture.
  • Imaging
    • Radiographs
      • Arthritis
      • Interstitial pneumonitis, pleural effusion, or pneumonia
    • Computerized tomography (CT)
      • Abscess
    • Magnetic resonance imaging (MRI)
      • Spondylitis
      • Osteomyelitis
    • Echocardiography 
      • Endocarditis
      • Myocarditis

Management and Prevention

Management

  • Antibiotics
    • Adults: doxycycline plus an aminoglycoside or rifampin
    • Children < 8 years: trimethoprim-sulfamethoxazole (TMP-SMX) plus rifampin
    • Neurobrucellosis: ceftriaxone plus rifampin and doxycycline for 12 weeks
    • Endocarditis: aminoglycoside plus rifampin and doxycycline for 12 weeks
  • 5%–15% of patients relapse.
    • All patients should have close clinical follow-up.
    • Repeat serologic studies for 1 year.
    • Treat relapse with a repeat course of the standard antibiotic regimen.
  • Immunity lasts for only 2 years after the disease.

Prevention

  • Brucellosis is a reportable disease.
  • Post-exposure prophylaxis for high-risk patients: doxycycline plus rifampin
  • Avoid unpasteurized dairy products.
  • Wear gloves, gowns, and goggles when handling animals and carcasses.
  • Vaccination of livestock (do not give to humans, as can cause infection)

Comparison of Gram-negative Coccobacilli

Table: Comparison of similar Gram-negative coccobacilli
OrganismBrucellaHaemophilusBordetella
Clinically relevant species
  • B. melitensis
  • B. abortus
  • B. suis
  • B. canis
  • H. influenzae
  • H. ducreyi
  • B. pertussis
  • B. parapertussis
  • B. bronchiseptica
Microbiology features
  • Facultative intracellular
  • Aerobic
  • Requires CO2
  • Non-motile
  • Unencapsulated
  • Non-spore forming
  • Facultative anaerobe
  • Non-motile
  • Encapsulated and unencapsulated
  • Non-spore forming
  • Isolated on chocolate agar
  • Obligate aerobe
  • Non-motile
  • Encapsulated
  • Non-spore forming
Virulence factors
  • LPS
  • Superoxide dismutase and catalase
  • IgA protease
  • Capsular polysaccharides
  • Capsule
  • Beta-lactamase
  • FHA
  • Pertussis toxin
Reservoir
  • Farm animals
  • Dogs
HumansHumans
TransmissionContact with animal products
  • Respiratory droplets
  • Sexual contact
Respiratory droplets
Clinical presentation
  • Undulant fever
  • Neurobrucellosis
  • Endocarditis
  • Meningitis
  • Otitis media
  • Epiglottitis
  • Pneumonia
  • Chancroid
Pertussis
Diagnosis
  • Culture
  • SAT
  • ELISA
Culture
  • Culture
  • PCR
Management
  • Doxycycline
  • Aminoglycosides
  • Rifampin
  • Ceftriaxone
  • Amoxicillin
  • Azithromycin
  • Azithromycin
  • TMP-SMX

ELISA: enzyme-linked immunosorbent assay

FHA: filamentous hemagglutinin

IgA: immunoglobulin A

LPS: lipopolysaccharide

PCR: polymerase chain reaction

SAT: serum tube agglutination test

TMP-SMX: trimethoprim-sulfamethoxazole

Differential Diagnosis

  • Malaria: an infection due to Plasmodium. Patients may present with periodic fever similar to brucellosis. Other symptoms include rigors, night sweats, diarrhea, abdominal pain, seizure, hemolytic anemia, and splenomegaly. The diagnosis is confirmed by visualizing Plasmodium on a peripheral smear and with rapid test detection of Plasmodium antigens. Treatment with antimalarials depends on the species. 
  • Tuberculosis: a mycobacterial infection, most commonly affecting the lungs. Symptoms include fever, night sweats, weight loss, malaise, and cough. The diagnosis is made with a sputum smear and culture detecting acid-fast bacilli. Treatment involves combination therapy with isoniazid, rifampin, pyrazinamide, and ethambutol.
  • Endocarditis: an inflammatory condition of the endocardium, usually due to an infection. The heart valves are typically affected. Patients present with fever and a new heart murmur. Endocarditis is diagnosed with blood cultures and echocardiography. Prolonged antibiotics are required for infectious causes, and surgery may be required.
  • Typhoid fever: a systemic disease caused by Salmonella enterica serotype Typhi. Patients may have a high fever, abdominal pain, and rose spots (rash) on the body. Unlike brucellosis, typhoid predominantly manifests with gastrointestinal symptoms. The diagnosis is based on the clinical presentation and confirmed by culture. Antibiotics are used to treat typhoid fever, and include ceftriaxone, fluoroquinolones, and azithromycin.
  • Rheumatic fever: a nonsuppurative, inflammatory complication of streptococcal pharyngitis. The disease is rare in developed countries. Patients can have a high fever, arthritis, pancarditis, and erythema marginatum, and often have preceding symptoms of sore throat or skin infection. Diagnosis is based on the clinical presentation, modified Jones criteria, and laboratory testing. Treatment includes aspirin, corticosteroids, and antibiotics.

References

  1. Bosilkovski, M. (2020). Brucellosis: Epidemiology, microbiology, clinical manifestations, and diagnosis. In Baron, E.L. (Ed.), UpToDate. Retrieved December 8, 2020, from https://www.uptodate.com/contents/brucellosis-epidemiology-microbiology-clinical-manifestations-and-diagnosis
  2. Bosilkovski, M. (2019). Brucellosis: Treatment and prevention. In Baron, E.L. (Ed.), Retrieved December 8, 2020, from https://www.uptodate.com/contents/brucellosis-treatment-and-prevention
  3. Al-Nassir, W., Lisgaris, M.V., Salata, R.A, and Bennett, N.J. (2018). Brucellosis. In Bronze, M.S. (Ed.), Medscape. Retrieved December 8, 2020, from https://emedicine.medscape.com/article/213430-overview
  4. Bush, L.M., and Vazquez-Pertejo, M.T. (2020). Brucellosis. [online] MSD Manual Professional Version. Retrieved December 8, 2020, from https://www.msdmanuals.com/professional/infectious-diseases/gram-negative-bacilli/brucellosis

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