Brucellosis

OVERVIEW: What every practitioner needs to know

Are you sure your patient has brucellosis? What should you expect to find?

Brucellosis in humans is a zoonotic infection with a gram-negative intracellular bacillus of the genus Brucella. Brucella melitensis is the most common species causing human disease.
The clinical presentation can range from asymptomatic infection to very severe illness.
After an incubation period of several weeks, generalized symptoms, including fever, anorexia, fatigue, sweats, arthralgias, myalgias, headache, and gastrointestinal (GI) complaints, may occur in acute infection.

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Even in acute infection, onset of symptoms is usually gradual.
Brucellosis can present as a fever of unknown origin.
In less than 40% of patients, localized infection can occur, resulting in joint pain (arthritis), especially of the joints of the lower extremity, sacroiliitis, or vertebral osteomyelitis (infectious spondylitis), testicular or scrotal pain (orchitis, epididymitis, testicular abscess), or abdominal or pelvic pain (nephritis, renal, or tuboovarian abscess).
A classic symptom is malodorous sweat.
Patients can also have bronchitis, pneumonia, pleural effusion, or empyema.
Abdominal pain may indicate hepatitis, hepatic or splenic abscesses, pancreatitis, colitis, or peritonitis.
Meningitis can occur as well as encephalitis, myelitis, and neuritis.
Other manifestations include endocarditis, myocarditis, pericarditis, mycotic aneurysm, uveitis, keratoconjunctivitis, endophthalmitis, and skin findings, including rashes, ulcerations, petechiae, purpurae, and abscesses
The physical exam findings vary according to the organ system affected.
Fever, generalized lymphadenopathy, and hepatosplenomegaly are commonly noted.

How did the patient develop brucellosis? What was the primary source from which the infection spread?

Human infections with Brucella species are primarily from infected domestic animals that excrete bacteria in their placentas, products of abortion, urine, and milk.
Because many infections are asymptomatic, the true prevalence of infection is likely higher than the 500,000 human cases reported worldwide annually.
The species of brucella varies by animal. Brucella melitensis, the most common human pathogenic species, is found in sheep or goats.
Brucella suis, which occurs in pigs, is the second most common human pathogen. Brucella canis occurs in dogs and Brucella abortus in cattle, and both usually cause less severe human disease.
There are other species that infect other animals, preferentially.
Infection is transmitted by eating unpasteurized milk products from infected animals or by eating meat not fully cooked.
Other routes include inhalation of dust or ingestion of secretions.
Human to human transmission is uncommon but has been reported in organ transplantation; congenital and nosocomial cases have been described.

Which individuals are of greater risk of developing brucellosis?

Individuals who practice animal husbandry and who come in contact with infected sheep, goats, or pigs or their secretions are at greatest risk.
Family members of infected individuals are also often infected, not from human to human transmission, but because they likely had similar exposures to animals.
Children and adults are equally affected, as are men and women.
Older patients and those with chronic disease are more likely to develop spondylitis.
In the United States, eating unpasteurized dairy products is one of the major risk factors for infection.
Clinical laboratory workers are at risk for laboratory acquired brucellosis. Laboratory workers should be advised if this is a possible diagnosis in a patient for whom samples have been sent for culture so that they can perform all tasks in accordance with biosafety level 3.

Beware: there are other diseases that can mimic brucellosis:

Other diseases may mimic brucellosis and should be considered depending on the specific clinical manifestations. This includes tuberculosis, HIV, malaria, influenza, tularemia, Q fever, endocarditis, Epstein-Barr virus (EBV), Cytomegalovirus (CMV), and occult abscesses. There can also be non-infectious entities that mimic brucellosis, including malignancy and connective tissue diseases.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

General laboratory results are generally not helpful in making the diagnosis.
Pancytopenia may occur, or the complete blood count (CBC) can be entirely normal.
Mild elevations of hepatic enzymes can occur.
Cerebrospinal fluid (CSF) in neurobrucellosis has a profile similar to aseptic meningitis, with a mildly elevated, predominately mononuclear white blood cell (WBC) count, elevated protein, and mildly decreased glucose.

Results that confirm the diagnosis

Blood cultures, when positive, confirm the diagnosis. Studies using older cultures techniques found positive cultures in 15-70% of cases.
Newer, automatic blood culture systems have improved sensitivity and time to positive (3 days versus 14 days with the older manual culture systems). This is true for both acute and chronic Brucella infections.
Bone marrow culture is the gold standard for diagnosis but is reserved for patients with fever of unknown origin and evidence of bone marrow involvement.
Serologic tests can be helpful to confirm the diagnosis, but interpretation can be challenging. Detecting a rise in titers is most helpful, but acute and convalescent titers are not always available.
A variety of methods have been developed. Serum agglutination testing (SAT) is the most studied test method. Positive titers are defined as greater than 1:160 in endemic areas and greater than 1:80 in non-endemic areas.
However, SAT can be falsely positive in the presence of other infections, including those due to F. tularensis, E. coli, Y. enterocolitica, V. cholerae, and others.
Enzyme-linked immunosorbent assay (ELISA) is commonly used and easier to perform than SAT, but there are data that suggest it does not have equal diagnostic sensitivity.
Polymerase chain reaction (PCR) is not yet widely available or standardized but offers rapid and sensitive diagnosis from a variety of patient specimens.
Synovial fluid analysis and culture does not usually confirm brucellosis, but the cell count is usually less than for other bacterial arthritides (10,000-15,000 cells/uL) and has a lymphocyte predominance.

What imaging studies will be helpful in making or excluding the diagnosis of brucellosis?

Radiographs can be helpful in patients who have joint pain.
Those with back pain should have an MRI to evaluate for spondylitis and to rule out paraspinal or epidural infections that could result in spinal cord compression.
A characteristic CT finding is “snowflake” calcifications in the liver and spleen in chronic infection.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has brucellosis what therapies should you initiate immediately?

1. Anti-infective agents (see Table I)

If I am not sure what pathogen is causing the infection what anti-infective should I order?

Because there are so many entities in the differential diagnosis and Brucella infections rarely present with a fulminant course but require long courses of antibiotic treatment, it is best to confirm a diagnosis prior to committing a patient to therapy.

If a patient is acutely ill, cover empirically as described in the chapter on Sepsis, while starting the complete work-up.

2. Other key therapeutic modalities.

General supportive care is important in addition to antibiotic therapy.
Corticosteroids for neurobrucellosis is controversial and is not generally recommended but have been used in certain cases.

What complications could arise as a consequence of brucellosis?

What should you tell the family about the patient's prognosis?

Relapsing disease can occur in up to 10-15% of patients after treatment; this usually occurs within the first 6 months.
Endocarditis is a rare clinical manifestation but is the most common cause of death in brucellosis.

How do you contract brucellosis and how frequent is this disease?

Individuals who practice animal husbandry and who come in contact with infected sheep, goats, or pigs or their secretions are at greatest risk.

Family members of infected individuals are also often infected, not from human to human transmission, but because they likely had similar exposures to animals.

Children and adults are equally affected, as are men and women.

Because many infections are asymptomatic, the true prevalence of infection is likely higher than the 500,000 human cases reported worldwide annually.

There is no seasonal variation.

Human infections with Brucella species are primarily from infected domestic animals that excrete bacteria in their placentas, products of abortion, urine, and milk.

Infection is transmitted by eating unpasteurized milk products from infected animals or by eating meat fully cooked.

Other routes include inhalation of dust or ingestion of secretions.

The species of brucella varies by animal.

Brucella melitensis, the most common human pathogenic species, is found in sheep and goats.

Brucella suis, which occurs in in pigs, is the second most common human pathogen.

Brucella canis occurs in dogs.

Brucella abortus occurs in cattle.

What pathogens are responsible for this disease?

Brucella melitensis
Brucella suis
Brucella canis
Brucella abortus

How do Brucella species cause disease?

After ingestion or inhalation, the bacteria initially replicate in lymph nodes and then go to the reticuloendothelial system (i.e., spleen, liver, bone marrow).

Brucella is an intracellular organism and has developed mechanisms to exist inside phagocytic cells, yet avoiding destruction by polymorphonuclear leukocytes. The mechanisms of this are not fully understood. Factors believed to assist with this are adenosine and guanine monophosphate and a superoxide dismutase.

The major virulence factor is smooth lipopolysaccharide (S-LPS), which confers resistance to lysis. Strains without S-LPS are more easily cleared from establishing infection.

The 1 cell mediated immunity plays a key role in clearing infection, as do cytokines IL-1, IL-12, TNF-α, TNF-γ.

What other clinical manifestations may help me to diagnose and manage brucellosis?

Exposure to animals (cows, sheep, goats, pigs, dogs)
Eating unpasteurized milk products from infected animals
Eating meat not fully cooked
Fever, generalized lymphadenopathy, and hepatosplenomegaly are commonly noted.
In less than 40% of patients, localized infection can occur, resulting in joint pain (arthritis), especially of the joints of the lower extremity, sacroiliitis, or vertebral osteomyelitis (infectious spondylitis), testicular or scrotal pain (orchitis, epididymitis, testicular abscess), or abdominal or pelvic pain (nephritis, renal, or tuboovarian abscess).
A classic symptom is “malodorous sweat.”
Patients can also have bronchitis, pneumonia, pleural effusion, or empyema.
Abdominal pain may indicate hepatitis, hepatic or splenic abscesses, pancreatitis, colitis, or peritonitis.
Meningitis can occur, as well as encephalitis, myelitis, and neuritis.
Other manifestations include endocarditis, myocarditis, pericarditis, mycotic aneurysm, uveitis, keratoconjunctivitis, endophthalmitis, and skin findings, including rashes, ulcerations, petechiae, purpurae, and abscesses.
The physical exam findings vary according to the organ system affected.

How can brucellosis be prevented?

There are currently live, attenuated animal vaccines for sheep, goats (B. melitensis), and cattle (B. abortus), but not for pigs (B. suis).

There are no human vaccines, and it is possible for accidental infection to occur after accidental inoculation with vaccine. Those individuals should have post exposure prophylaxis (see Table I).

Abattoir workers can be protected by proper air handling mechanisms in buildings and by wearing protective clothing and masks.

Laboratory workers should be advised of potential cultures that could contain Brucella, so they can use high level (BSL-3) biosafety precautions.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Atluri, VL, Xavier, MN, de Jong, MF, den Hartigh, AB, Tsolis, RE. “Interactions of the human pathogenic Brucella species with their hosts”. Annu Rev Microbiol. vol. 65. 2011. pp. 523-41.

Araj, GF. “Update on laboratory diagnosis of human brucellosis”. Int J Antimicrob Agents. vol. 36. 2010 Nov. pp. S12-7. (This source discusses in detail the pros and cons of different diagnostic methods.)

Franco, MP, Mulder, M, Gilman, RH, Smits, HL. “Human brucellosis”. Lancet Infect Dis. vol. 7. 2007 Dec. pp. 775-86. (This is an excellent general overview.)

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