AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

The first clinical case compatible with brucellosis was credited to JA Maston, an assistant surgeon in the Royal Army Medical Corps. Brucellosis in an alphaproteobacteria that was discovered in 1887 by David Bruce, an English doctor working with British soldiers in Malta, by microscopic examination of a spleen from a fatal case.

Brucellosis is primarily a zoonotic infectious disease found in both domestic and wild animals. Humans are accidental hosts, but brucellosis continues to be a major public health concern worldwide and is the most common zoonotic infection. Brucellosis has been known by various names, including Mediterranean fever, Malta fever, gastric remittent fever, and undulant fever.

Brucellosis can be acquired via exposure to infected animals or infected food. The primary means of prevention is the pasteurization of dairy products, but slaughter campaigns of infected cattle have also been used to control the infection at its source in some countries.

Pathophysiology

Brucella species are facultative intracellular pathogens that are capable of surviving and replicating within phagocytic cells of the host. Shortly after gaining entry to the body, brucellae are ingested by polymorphonuclear leukocytes (PMLs), which are attracted to the site of inoculation. The principal virulence factor is cell wall lipopolysaccharide (LPS). Normal serum factors, including complement, are involved in opsonization of the organisms to allow phagocytosis, but PMLs have limited ability to kill bacteria within phagocytes. A copper-zinc superoxide dismutase, o-polysaccharide, and nucleotidelike substances are among the factors that protect brucellae from being killed by PMLs.

Brucellae that are not killed by PMLs are ingested by macrophages, where they become localized within organs of the reticuloendothelial system (ie, liver, spleen, bone marrow) and multiply in macrophages and monocytes. However, any organ system can be involved in brucellosis (ie, CNS, heart, joints, genitourinary system, pulmonary system, and skin), and localization of the process may cause focal symptoms or findings.

Shortly after infection, humoral antibodies directed against LPS and other cell wall antigens are produced. However, development of cell-mediated immunity is the principle mechanism of recovery. The host response to infection with Brucella abortus is characterized by the development of tissue granulomas indistinguishable from those of sarcoidosis. In contrast, infection with the more virulent species (Brucella melitensis, Brucella suis) more commonly results in visceral microabscesses.

Frequency

United States

Brucellosis is still a reportable disease in the United States, although the Centers for Disease Control and Prevention (CDC) has received reports of only 100-200 cases annually (a rate of 0.4 per one million population) in the last several years. Texas has the highest incidence of cases (1.38 per one million population). Nationally, the infection is due to 2 main sources: importation of disease (from infected food products or international travel) and cross-border spread¹ (mostly B melitensis) from Mexico into neighboring states (mostly affecting Hispanics).

International

The geographic distribution of brucellosis is limited by effective public and animal health programs, and prevalence of the disease widely varies from country to country.² Brucellosis is still endemic in the Mediterranean countries, the Arabian Peninsula, Western Asia, Eastern Europe, and parts of Africa and Latin America. Control campaigns have effectively removed it from countries like the United Kingdom and Ireland. Early vaccination attempts were problematic; the vaccine controlled symptoms of the disease but did not actually prevent infection.

A clear (although nonlinear) association between gross domestic product (GDP) and rates of brucellosis is evident according to European Union (EU) data. No countries with a GDP above 90% of the mean had an incidence above 10 annual cases per million population.

In very resource-poor countries (such as some African countries) in which brucellosis is endemic, control through animal slaughter is a poor option because of the fragile nature of the food supply.

Mortality/Morbidity

Duration of symptoms for more than 30 days before diagnosis is the major risk factor for developing focal disease. Mortality is low (<2%) and is most frequently found in those with endocarditis due to brucellosis.

• The most common focal complications are as follows:
• • Osteoarticular complications - Especially, sacroiliitis (20-30% - but rarer in children)
  • Genitourinary tract complications - Especially, epididymoorchitis in males (2-49%)
  • Neurobrucellosis³ - Meningitis⁴ (1-2%) and, less commonly, papilledema, optic neuropathy, radiculopathy, stroke, and intracranial hemorrhage
  • Endocarditis (1%) - Responsible for most mortality associated with the disease
  • Hepatic abscess (1%)
• Other less common complications include the following:
• • Splenic abscess
  • Thyroid abscess
  • Epidural abscess
  • Pneumonitis
  • Pleural empyema
  • Uveitis
  • Aneurysm of the aorta
  • Aneurysm of the cerebral vessels
  • Peritonitis

Race

No racial predilection is known (however, see United States for information about cross-border cases).

Sex

Food-borne brucellosis is not limited according to age or sex and is found in women and men in equal numbers.

Age

Farmers, ranchers, veterinarians, and meat inspectors have the highest risk; however, people of all ages are susceptible. Childhood brucellosis is more common in countries where B melitensis is the prevalent species; in the United States, only about 10% of cases occur in people younger than 19 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

In children, brucellosis is frequently a mild self-limiting illness and is less chronic than in adults. A key element in the history is exposure to an infected animal or food. Symptoms are nonspecific, usually occurring within 2-4 weeks of inoculation.

• Symptoms include weakness, excessive sweating, lethargy, anorexia, weight loss, arthralgia, myalgia, abdominal pain, and headache.⁵
• Symptoms in young children include refusal to eat, lassitude, refusal to bear weight, and failure to thrive.
• Brucellosis can present as a fever of unknown origin,⁶ and the fever may undulate, repeatedly coming and going (hence, the term "undulant fever").
• In the chronic form, with longer than 1 year of illness (undiagnosed and untreated brucellosis), an afebrile pattern is typical, with a history of myalgia, fatigue, depression, and arthralgias (chronic fatigue syndrome is the most important disease in the differential diagnosis). The chronic form is primarily caused by B melitensis and usually affects adults older than 30 years. The chronic form is rare in children.

Physical

Physical abnormalities can be minimal. Fever and minimal lymphadenopathy are the most common physical findings. Occasionally, hepatosplenomegaly may be present. Disease is infrequently localized; physical findings are predominately related to a single organ.

• Physical examination reveals hot swollen tender joints, with limited movement in patients with arthritis (most commonly knees, ankles, and hips).
• A point of tenderness and limited movement is present in patients with osteomyelitis.
• Sacroiliitis is rare in children.
• Nuchal rigidity, Kerning sign, and Brudzinski sign are seen if meningitis is the focal point.
• Papilledema, cranial nerve palsy, and focal neurologic deficits may be present in patients with increased intracranial pressure or brain abscess.
• Generalized tenderness, rebound tenderness, and sluggish or absent bowel sounds can be expected in patients with peritonitis.
• A tender swollen scrotum with erythema is present in patients with epididymoorchitis.
• A new or changing murmur may be detected in patients with infective endocarditis.
• A pericardial rub is present in patients with pericarditis.

Causes

Brucella species are small, fastidious, non–spore-forming, gram-negative coccobacilli. They lack flagella, endospores, capsules, and naturally occurring plasmids. Their metabolism is oxidative, and all strains are aerobic, although some species require carbon dioxide for primary isolation.
 
Brucellae have catalase activity, but oxidase activity varies. Most strains reduce nitrate to nitrite. Hydrogen sulfide production and urase activity also vary. The bacteria can be grown on various laboratory media, including serum dextrose, blood, and chocolate agar. Four species are pathogenic to humans: B abortus, B melitensis, B suis, and Brucella canis.

Table 1. Animal Hosts for Brucella Species

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Acute brucellosis

Typhoid fever
Tularemia
Rickettsial diseases
Tuberculosis
Influenza
Infectious mononucleosis
Histoplasmosis
Coccidioidomycosis

Chronic brucellosis

Malignant histocytosis
Lymphoma
Fever of unknown origin

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Diagnosis is definitive when Brucella organisms are recovered from blood, bone marrow, or other tissue. Some Brucella species require 5-10% carbon dioxide for primary isolation. In vitro replication is fairly slow; therefore, alert laboratory personnel to maintain cultures for 4 weeks or longer. Blood culture results can be positive in 75% of patients with acute disease, while bone marrow culture allows isolation in 90% of patients.
• The serum agglutination test (SAT) uses killed B abortus cells as antigen. SAT is the most commonly used serologic test and detects antibodies against B abortus, B suis, and B melitensis. B canis–specific antigen is used to detect its antibodies. SAT titers of 1:160 or higher indicate active infection. Repeat serologic tests are recommended if the initial titers are low.
• The 2-mercaptoethanol test detects immunoglobulin G (IgG), and titers higher than 1:80 define active infection. A high IgG antibody titer or a titer that is higher after treatment suggests persistent infection or relapse. Prozone inhibition can cause false-negative results in the presence of sera with high titers, and dilution of sera is necessary to avoid this problem. Brucella antibodies can possibly cross-react with other organisms, such as Yersinia enterocolitica serotype O9, Francisella tularensis, and Vibrio cholera. Enzyme immunoassay (EIA) is the most sensitive method for detection of immunoglobulin M (IgM), immunoglobulin A (IgA), and IgG anti-Brucella antibodies.
• Polymerase chain reaction (PCR) tests have been developed for the detection and rapid diagnosis of Brucella species in human blood specimens but are only available in specialist laboratories.⁷
• WBC counts in patients with brucellosis are usually within reference range or lower. Anemia is reported in 75% of patients, thrombocytopenia is reported in 40%, and pancytopenia is reported in 6% of patients.
• Elevated levels of liver enzymes may reflect the severity of hepatic involvement and correlate clinically with hepatomegaly.

Imaging Studies

• Scanning techniques, including CT scanning and MRI, can be used for diagnosis of an occult focus of infection.

Other Tests

• Bone marrow examination may reveal erythrophagocytosis. Microangiopathic hemolytic anemia, thrombocytopenic purpura,⁸ and Coombs-positive hemolytic anemia have been reported in brucellosis.
• Neurobrucellosis: Cerebral spinal fluid (CSF) reveals pleocytosis, elevated protein levels, and hypoglycorrhea. CSF culture results are positive in fewer than 50% of patients. CSF antibodies are present in most patients.

Procedures

• Bone marrow aspiration and lumbar puncture can be performed, if indicated.

Histologic Findings

• Analysis of liver biopsy specimens may reveal granulomatous hepatitis and hepatic microabscesses. Specimens from bone marrow biopsy may test positive for granulomas, hemophagocytosis, or both.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

See Medication.

Surgical Care

Surgical intervention may be required to drain pyogenic joint effusions or rare paraspinal abscesses. Valve replacement surgery is often recommended in addition to a prolonged course of antibiotics.

Consultations

• Infectious disease specialist: Consult an infectious disease specialist regarding treatment in patients with brucellosis.
• Surgeon: Consult with a surgeon, if indicated.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug Category: Antibiotics

Despite extensive studies, optimal antibiotic therapy for brucellosis remains under dispute. For acute brucellosis in adults and children older than 8 years, World Health Organization (WHO) guidelines recommend rifampin (600-900 mg) and doxycycline (200 mg) daily for a minimum of 6 weeks. Treatment in children younger than 8 years requires rifampin and cotrimoxazole.^{9, 10} Treatment of meningoencephalitis or endocarditis requires combination therapy with rifampin, a tetracycline, and an aminoglycoside.

Table 2. Age-related Dosing of Antimicrobial Agents in Brucellosis

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Further outpatient care is essential in brucellosis to enhance patient compliance in taking the medicine and to ensure that response to treatment is good and antibody titers are decreasing.
• Continue outpatient care until the infection is cured and laboratory findings return to reference ranges.

Deterrence/Prevention

• Prevention of brucellosis in humans depends on eradication or control of the disease in animals. Pasteurization of milk and diary products for human consumption is an important element of disease prevention in children. In endemic areas, immunization, surveillance, and testing are needed in all animals. Public awareness and education play major roles in prevention of the disease.
• Live attenuated vaccine strains are available for B abortus and B melitensis¹¹ but can cause infection in humans and are not recommended.

Complications

• Arthritis¹² and osteomyelitis
• Meningoencephalitis, myelitis, and cranial neuropathy
• Hepatic abscesses and peritonitis
• Epididymoorchitis
• Infective endocarditis, pericarditis, and myocarditis
• Pneumonia and empyema
• Aneurysms of the aorta and cerebral vessels
• Uveitis

Prognosis

• Complete recovery after specific therapy is by far the most common outcome in patients with brucellosis; however, some patients may have relapse with recurrence of symptoms.
• In the vast majority of patients, relapse is not the result of emergence of antibiotic resistance; therefore, careful long-term follow-up monitoring is recommended.
• The case-fatality rate in patients who go untreated is approximately 3%.

Patient Education

Education should address the following issues:

• The nature of the disease, routes of transmission, and preventive measures
• Symptoms, complications, and relapse of the disease if the patient does not receive adequate treatment
• The importance of taking the medications as prescribed, completing the full course of treatment, and scheduling outpatient visits
• Potential adverse effects of the medications

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Signs and symptoms of brucellosis can be nonspecific and can mimic many other diseases; therefore, meticulous attention is needed in making the diagnosis and in treating patients.
• Advise laboratory personnel to maintain cultures for at least 4 weeks, otherwise, negative results are reported.
• Repeated serologic testing is recommended if the initial titer is low.
• False-negative results can result from sera with high titers; therefore, dilution is recommended if the clinical index of suspicion is high.
• Use of a combination of antibiotics, a prolonged treatment course, and follow-up care are recommended.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Doyle TJ, Bryan RT. Infectious disease morbidity in the US region bordering Mexico, 1990-1998. J Infect Dis. Nov 2000;182(5):1503-10. [Medline].
2. Pappas G, Papadimitriou P, Akritidis N, Christou L, Tsianos EV. The new global map of human brucellosis. Lancet Infect Dis. Feb 2006;6(2):91-9. [Medline]. [Full Text].
3. Shakir RA. Neurobrucellosis. Postgrad Med J. Dec 1986;62(734):1077-9. [Medline].
4. Tena D, Gonzalez-Praetorius A, Lopez-Alonso A, et al. Acute meningitis due to Brucella spp. Eur J Pediatr. May 12 2006;[Medline].
5. al-Eissa YA, Kambal AM, al-Nasser MN, et al. Childhood brucellosis: a study of 102 cases. Pediatr Infect Dis J. Feb 1990;9(2):74-9. [Medline].
6. Sharda DC, Lubani M. A study of brucellosis in childhood. Clin Pediatr (Phila). Oct 1986;25(10):492-5. [Medline].
7. Mitka S, Anetakis C, Souliou E, Diza E, Kansouzidou A. Evaluation of different PCR assays for early detection of acute and relapsing brucellosis in humans in comparison with conventional methods. J Clin Microbiol. Apr 2007;45(4):1211-8. [Medline].
8. Young EJ, Tarry A, Genta RM, et al. Thrombocytopenic purpura associated with brucellosis: report of 2 cases and literature review. Clin Infect Dis. Oct 2000;31(4):904-9. [Medline].
9. Lubani MM, Dudin KI, Sharda DC, et al. A multicenter therapeutic study of 1100 children with brucellosis. Pediatr Infect Dis J. Feb 1989;8(2):75-8. [Medline].
10. Roushan MR, Mohraz M, Janmohammadi N, Hajiahmadi M. Efficacy of cotrimoxazole and rifampin for 6 or 8 weeks of therapy in childhood brucellosis. Pediatr Infect Dis J. Jun 2006;25(6):544-5. [Medline].
11. Corbel MJ. Vaccines against bacterial zoonoses. J Med Microbiol. Apr 1997;46(4):267-9. [Medline].
12. Lubani M, Sharda D, Helin I. Brucella arthritis in children. Infection. Sep-Oct 1986;14(5):233-6. [Medline].
13. al-Eissa YA, al-Mofada SM. Congenital brucellosis. Pediatr Infect Dis J. Aug 1992;11(8):667-71. [Medline].
14. Committee on Infectious Diseases. Brucellosis. In: Red Book. 27th Ed. 2006:235-237.
15. Schultze GE, Jacobs RF. Brucella. In: Behrman RE, Kliegman R, Jenson HB, eds. Nelson Textbook of Pediatrics. 16^th ed. Philadelphia, Pa: WB Saunders; 2000:868-9.
16. Trifiletti RR, Restivo DA, Pavone P, et al. Diabetes insipidus in neurobrucellosis. Clin Neurol Neurosurg. Sep 2000;102(3):163-5. [Medline].
17. Young EJ. An overview of human brucellosis. Clin Infect Dis. Aug 1995;21(2):283-9; quiz 290. [Medline].

Article Last Updated: Jan 25, 2008