Introduction
Background
Brucellosis is believed to be an ancient disease that was described more than 2000 years ago by the Romans. Bruce first isolated Brucella melitensis in 1887. Since then, brucellosis has become an emerging disease in many parts of the world.
Brucellosis is a worldwide zoonosis caused by infection with the bacterial genus Brucella. These organisms, which are small aerobic intracellular coccobacilli, localize in the reproductive organs of host animals, causing abortions and sterility. They are shed in large numbers in the animal's urine, milk, placental fluid, and other fluids. Exposure to infected animals and animal products causes brucellosis in humans.
The global burden of human brucellosis remains enormous; it causes more than 500,000 infections per year worldwide. The annual number of reported cases in United States (now approximately 100 cases) has dropped significantly because of aggressive animal vaccination programs and milk pasteurization. Most of the US cases are now due to the consumption of illegally imported unpasteurized dairy products from Mexico. Approximately 60% of human brucellosis cases in the United States now occur in California and Texas.
The interest in brucellosis has been increasing because of the growing phenomena of international tourism and migration, in addition to the potential use of Brucella as a biological weapon.1 (For more information, see the article CBRNE - Brucellosis in eMedicine’s Emergency Medicine volume.) Familiarity with the manifestations of brucellosis and the optimal laboratory studies is essential for physicians to recognize this re-emerging zoonosis.
Recently, B melitensis, Brucella abortus, and Brucella suis have been completely sequenced, which will help improve our understanding of the complex pathogenesis and the diverse manifestations of this complex disease.
The traditional classification of Brucella species is based largely on the preferred hosts.
Table 1. The 7 Currently Recognized Brucella Species
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Table
| Organism | Animal Reservoir | Geographic Distribution |
|---|---|---|
| B melitensis | Goats, sheep, camels | Mediterranean, Asia, Latin America, parts of Africa and some southern European countries |
| B abortus | Cows, buffalo, camels, yaks | Worldwide |
| B suis | Pigs (biotype 1-3) | South America, Southeast Asia, United States |
| Brucella canis | Canines | Cosmopolitan |
| Brucella ovis | Sheep | No known human cases |
| Brucella neotomae | Rodents | Not known to cause human disease |
| Brucella pinnipediae and Brucella cetaceae | Marine animals, minke whales, dolphins, seals | Recent case reports describing some human cases (mainly neurobrucellosis) |
| Organism | Animal Reservoir | Geographic Distribution |
|---|---|---|
| B melitensis | Goats, sheep, camels | Mediterranean, Asia, Latin America, parts of Africa and some southern European countries |
| B abortus | Cows, buffalo, camels, yaks | Worldwide |
| B suis | Pigs (biotype 1-3) | South America, Southeast Asia, United States |
| Brucella canis | Canines | Cosmopolitan |
| Brucella ovis | Sheep | No known human cases |
| Brucella neotomae | Rodents | Not known to cause human disease |
| Brucella pinnipediae and Brucella cetaceae | Marine animals, minke whales, dolphins, seals | Recent case reports describing some human cases (mainly neurobrucellosis) |
Among the 4 Brucella species known to cause disease in humans (B abortus, B melitensis, B canis, B suis), B melitensis is thought to be the most virulent and causes the most severe and acute cases of brucellosis. B melitensis is also the most prevalent worldwide. A prolonged course of illness, often associated with suppurative destructive lesions, is associated with B suis infections. B abortus is associated with mild-to-moderate sporadic disease that rarely causes complications. B canis infection has a disease course that is indistinguishable from B abortus infection. B canis infection has an insidious onset, causes frequent relapses, and does not commonly cause chronic brucellosis. B pinnipediae and B cetaceae are distinctive species that typically affect marine animals; however, these strains were recently described to cause disease in humans, mainly neurobrucellosis.
Definitive diagnosis of brucellosis is based on culture, serologic techniques, or both. Clinically, identification to the genus level is adequate to initiate therapy, and the type of Brucella species involved does not alter the therapeutic agents used; however, speciation is necessary for epidemiologic surveillance and requires more detailed biochemical, metabolic, and immunologic testing.
Pathophysiology
Brucella species have a unique ability of invading both phagocytic and nonphagocytic cells and surviving in the intracellular environment by avoiding the immune system in different ways, explaining why brucellosis is a systemic disease and can involve almost every organ system.
After ingestion by phagocytes, approximately 15-30% of Brucella organisms survive. In polymorphonuclear or mononuclear phagocytic cells, the bacteria use numerous mechanisms to avoid or suppress bactericidal responses. Based on animal models, the lipopolysaccharide (LPS; smooth in B melitensis, B abortus, and B suis and rough in B canis) was found likely to play a substantial role in intracellular survival, perhaps because of adenine and guanine monophosphate production, which inhibits phagosomal fusion and oxidative burst activity. In addition, Brucella species have relatively low virulence, toxicity, and pyrogenicity, making them a poor inducer of some inflammatory cytokines such as tumor necrosis factor (TNF) and interferons. Also, the bacteria do not activate the alternative complement system. Finally, it is thought to inhibit programmed cell death.
After replication in the endoplasmic reticulum, the brucellae are released with the help of hemolysins and induced cell necrosis.
Susceptibility to intracellular killing differs among species, with B abortus readily killed and B melitensis rarely affected; this might explain the differences in pathogenicity and clinical manifestations in human cases of brucellosis.2
Frequency
United States
Brucellosis has become a rare disease because of the institution of veterinary control measures (eg, routine screening of domestic livestock, vaccination programs). Now, fewer than 100 cases are reported annually to the Centers for Disease Control and Prevention (CDC). The most common reporting states include California, Florida, Texas, and Virginia.
International
Brucellosis causes more than 500,000 infections per year worldwide. The heaviest disease burden lies in countries of the Mediterranean basin and Arabian Peninsula, and the disease is also common in India, Mexico, and South and Central America. Although some countries have effectively controlled brucellosis, new areas of human brucellosis have emerged in areas such as central Asia. Disease incidence and prevalence rates vary widely among nations. Because of variable reporting, true estimates in endemic areas are unknown. Incidence rates of 1.2-70 cases per 100,000 people are reported.
Mortality/Morbidity
Human brucellosis carries a low mortality rate (<5%), mostly secondary to endocarditis, which is a rare complication of brucellosis. However, brucellosis can cause chronic debilitating illness with extensive morbidity.
Sex
Worldwide, brucellosis is more common in males than in females, with a ratio of 5:2-3 in endemic areas.
Age
- In multiple large series, persons in their third to fifth decades of life were most commonly affected.
- Brucellosis in children comprises 3-10% of reported cases worldwide, with a heavier burden in endemic areas. (For more information on pediatric brucellosis, see the article Brucellosis in eMedicine’s Pediatrics: General Medicine volume.)
- Elderly persons typically develop chronic brucellosis.
Clinical
History
Symptoms of brucellosis are protean in nature, and none is specific enough to support the diagnosis. Table 2 lists symptoms and signs compiled from large studies that were conducted in regions hyperendemic for brucellosis.
- Fever is the most common symptom and sign of brucellosis, occurring in 80-100% of cases. It is intermittent in 60% of patients with acute and chronic brucellosis and undulant in 60% of patients with subacute brucellosis. Fever can be associated with a relative bradycardia. Fever of unknown origin (FUO) is a common initial diagnosis in patients in areas of low endemicity. It is associated with chills in almost 80% of cases.
- Constitutional symptoms of brucellosis include anorexia, asthenia, fatigue, weakness, and malaise and are very common (>90% of cases).
- Bone and joint symptoms include arthralgias, low back pain, spine and joint pain, and, rarely, joint swelling. These symptoms affect as many as 55-80% of patients.
- Neuropsychiatric symptoms of brucellosis are common despite the rare involvement of the nervous system. Headache, depression, and fatigue are the most frequently reported neuropsychiatric symptoms.
- Gastrointestinal symptoms, present in 50% of patients, include abdominal pain, constipation, diarrhea, and vomiting.
- Neurologic symptoms of brucellosis can include weakness, dizziness, unsteadiness of gait, and urinary retention. Symptoms associated with cranial nerve dysfunction may affect persons with chronic CNS involvement. For more information on neurologic manifestations of brucellosis, see the article Brucellosis in eMedicine’s Neurology volume.
- Cough and dyspnea develop in up to 19% of persons with brucellosis; however, these symptoms are rarely associated with active pulmonary involvement. Pleuritic chest pain may affect patients with underlying empyema.3
a Anorexia, asthenia, fatigue, weakness, malaise.
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Table
Study | Total Number of Patients | Fever or Chills | Arthralgia or Arthritis | Sweating | Constitutional symptoms a | Hepatomegaly | Splenomegaly |
Memish et al (2000) 5 | 160 | 146 (91.3%) | 105 (65.6%) | 30 (18.8%) | 70 (43.8%) | 9 (5.6%) | 11 (6.9%) |
Kokoglu et al (2006) 6 | 138 | 108 (78.3%) | 107 (77.5%) | 100 (72.5%) | 98 (71%) | 37 (26.8%) | 50 (36.2%) |
Mantur et al (2006) 7 | 495 | 417 (84.2%) | 117 (23.6%) | 19 (3.8%) | 6 (1.2%) | 56 (11.3%) | 95 (19.2%) |
Ruiz-Mesa et al (2005) 8 | 711 | 702 (98.7%) | 353 (49.6%) | 597 (84%) | 533 (75%) | 250 (35.2%) | 148 (20.8%) |
Barroso Garcia et al (2002) 9 | 565 | 441 (78.1%) | 248 (43.9%) | 483 (85.5%) | 472 (83.5%) | 422 (74.7%) | 152 (26.9%) |
Hasanjani Roushan et al (2004) 10 | 469 | 314 (67%) | 252 (53.7%) | 357 (76.1%) | ... | ... | 27 (5.8%) |
Pappas et al (2005) 11 | 100 | 91 (91%) | 44 (44%) | .. | 26 (26%) | 7 (7%) | 16 (16%) |
Troy et al (2005) 12 | 28 | 25 (89%) | 15 (54%) | .. | 13 (46%) | 8 (29%) | 5 (18%) |
Andriopoulos et al (2007) 13 | 144 | 144 (100%) | 125 (86.8%) | 138 (95.8%) | 140 (97.2%) | ... | 74 (51.4%) |
Giannakopoulos et al (2006) 14 | 52 | 42 (81%) | 43 (83%) | 8 (15%) | 7 (13%) | ... | ... |
Mantur et al (2004) 15 | 93 | 49 (53%) | 19 (20%) | ... | ... | ... | ... |
Tsolia et al (2002) 16 | 39 | 27 (69%) | 27 (69%) | 8 (21%) | 13 (33%) | 11 (28%) | 15 (38%) |
Study | Total Number of Patients | Fever or Chills | Arthralgia or Arthritis | Sweating | Constitutional symptoms a | Hepatomegaly | Splenomegaly |
Memish et al (2000) 5 | 160 | 146 (91.3%) | 105 (65.6%) | 30 (18.8%) | 70 (43.8%) | 9 (5.6%) | 11 (6.9%) |
Kokoglu et al (2006) 6 | 138 | 108 (78.3%) | 107 (77.5%) | 100 (72.5%) | 98 (71%) | 37 (26.8%) | 50 (36.2%) |
Mantur et al (2006) 7 | 495 | 417 (84.2%) | 117 (23.6%) | 19 (3.8%) | 6 (1.2%) | 56 (11.3%) | 95 (19.2%) |
Ruiz-Mesa et al (2005) 8 | 711 | 702 (98.7%) | 353 (49.6%) | 597 (84%) | 533 (75%) | 250 (35.2%) | 148 (20.8%) |
Barroso Garcia et al (2002) 9 | 565 | 441 (78.1%) | 248 (43.9%) | 483 (85.5%) | 472 (83.5%) | 422 (74.7%) | 152 (26.9%) |
Hasanjani Roushan et al (2004) 10 | 469 | 314 (67%) | 252 (53.7%) | 357 (76.1%) | ... | ... | 27 (5.8%) |
Pappas et al (2005) 11 | 100 | 91 (91%) | 44 (44%) | .. | 26 (26%) | 7 (7%) | 16 (16%) |
Troy et al (2005) 12 | 28 | 25 (89%) | 15 (54%) | .. | 13 (46%) | 8 (29%) | 5 (18%) |
Andriopoulos et al (2007) 13 | 144 | 144 (100%) | 125 (86.8%) | 138 (95.8%) | 140 (97.2%) | ... | 74 (51.4%) |
Giannakopoulos et al (2006) 14 | 52 | 42 (81%) | 43 (83%) | 8 (15%) | 7 (13%) | ... | ... |
Mantur et al (2004) 15 | 93 | 49 (53%) | 19 (20%) | ... | ... | ... | ... |
Tsolia et al (2002) 16 | 39 | 27 (69%) | 27 (69%) | 8 (21%) | 13 (33%) | 11 (28%) | 15 (38%) |
Physical
- Subclinical, acute, subacute, and chronic infections are the classic categorizations of brucellosis. Localized and relapsing forms have also been described. This classification system is subjective and has limited clinical use.
- Subclinical brucellosis: Disease is usually asymptomatic, and the diagnosis is usually established incidentally after serologic screening of persons at high risk of exposure. Culture data are usually unrevealing.
- Acute or subacute brucellosis: Disease can be mild and self-limited (eg, B abortus) or fulminant with severe complications (eg, B melitensis). Associated symptoms can develop at 2-3 months and 3-12 months prior to diagnosis, respectively. The most common symptoms and signs are listed in Table 2.
- Chronic brucellosis: The diagnosis is typically made after symptoms have persisted for 1 year or more. Low-grade fevers and neuropsychiatric symptoms predominate. Results of serologic studies and cultures are often negative; without confirmatory evidence, many authorities doubt the existence of chronic disease. Many patients have persistent disease caused by inadequate initial therapy, and underlying localized disease may be present.
- Localized complications of brucellosis are typically observed in patients with acute disease or chronic untreated infection. Osteoarticular, genitourinary, and hepatosplenic involvement are most common. Cultures of involved tissue sites and serology can be diagnostic. (See Complications.)
- Relapsing brucellosis may be difficult to distinguish from reinfection. Presenting symptoms typically reflect the initial disease; however, these symptoms are more severe. Symptoms typically develop 2-3 months after therapy completion. Culture results are typically positive, and serology may be difficult to interpret, but enzyme-linked immunoassay (ELISA) testing may be more helpful.
- Physical findings in patients with brucellosis vary and are nonspecific for the disease.
- The most common findings include hepatosplenomegaly (or isolated hepatomegaly or splenomegaly) and osteoarticular involvement. Table 2 displays the range of signs observed.
- Osteoarticular findings can include tenderness and swelling over affected joints, bursitis, decreased range of motion, and joint effusion (rare). Maneuvers that isolate the sacroiliac joint may cause pain.
- Neurologic findings vary according to the presentation of neurologic disease, as follows:
- Acute meningoencephalitis (most common neurological manifestation) - Depressed level of consciousness, meningeal irritation, cranial nerve involvement, coma, seizure, and respiratory depression
- Peripheral polyradiculoneuropathy - Hypotonia and areflexia in most cases, paraparesis, and an absence of sensory involvement
- Diffuse CNS involvement - Spasticity, hyperreflexia, clonus, extensor plantar response, sensorineural hearing loss, cranial nerve involvement, and cerebellar signs
- Cutaneous manifestations develop in 5-10% of patients, are transient and nonspecific, resolve with therapy, and do not alter the prognosis. Lesions reported in association with brucellosis are as follows:17
- Erythema nodosum, abscesses, and papulonodular eruptions (most common)
- Impetigo, psoriatic, eczematous, and pityriasis rosea –like lesions
- Macular, maculopapular, and scarlatiniform rashes
- Vasculitic lesions (eg, petechiae, purpura, thrombophlebitis)
- Ocular findings can include the following:18
Causes
- Ingestion of unpasteurized goat milk and related dairy products is the main route of B melitensis transmission to humans.
- Slaughterhouse workers, primarily those in the kill areas, become inoculated through aerosolization of fluids, contamination of skin abrasions, and splashing of mucous membranes. Farmers and shepherds have similar exposure risks, and they also have exposure to aborted animals.
- Veterinarians are usually infected by inadvertent inoculation of animal vaccines against B abortus and B melitensis.
- Laboratory workers (microbiologists) are exposed by processing specimens (aerosols) without special precautions.
More on Brucellosis |
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Further Reading
Keywords
brucellosis, Malta fever, Brucella melitensis, human brucellosis, bang disease, Brucella abortus, undulant fever, B melitensis, B abortus, Brucella suis, B suis, Brucella canis, B canis, bacterial zoonosis, neurobrucellosis, chronic brucellosis, acute brucellosis, subclinical brucellosis, subacute brucellosis, localized brucellosis, relapsing brucellosis
