A careful history is the most helpful tool in the diagnosis of brucellosis. The history should include both assessment of any risk factors present and evaluation of any symptoms reported. Unless exposure to Brucella is due to a weaponized attack,  almost every case of brucellosis involves exposure to an affected animal in some fashion, either directly or indirectly.
The risk factors for brucellosis differ somewhat, depending upon whether a given individual resides in or has recently visited a region of endemic disease.
Brucellosis should be considered in any patient whose place of residence or dietary, travel, or occupational history suggests a risk for the infection and who is experiencing any of the various known neurologic or nonneurologic complications of brucellosis. It must be borne in mind that the latency period from infection to onset of symptoms of primary brucellosis may be as long as months.
The threshold for consideration of brucellosis is low in regions of endemic disease, where diagnostic testing is undertaken for any of the many atypical presentations or unusual complications.
A dietary history is especially helpful for diagnosing brucellosis in individuals who live in or visit regions of endemic disease. Unpasteurized dairy products, especially goat’s cheese, frequently are implicated as sources of human infection. Raw or poorly cooked meats are also important sources of infection in regions of endemic disease.
Occasional person-to-person transmission has been reported, including transmission to infants via breastfeeding. There is a little evidence for sexual transmission of brucellosis.
Laboratory transmission of brucellosis may occur, especially in regions of endemic disease. It is estimated that 12% of laboratory workers in Spain acquire brucellosis. 
Brucellosis poses a particular diagnostic challenge in persons not from regions of endemic disease. In areas of the world where brucellosis is rare, the diagnosis may be missed even in patients who manifest typical signs, such as otherwise uncomplicated persistent undulating fever. The possibility of brucellosis is even less likely to be recognized promptly in cases that present atypically.
A dietary history is important in evaluating for the possibility of brucellosis among individuals who live in regions where the disease is not endemic because the disease may be acquired through ingestion of infected foods shipped from regions of endemic disease. Ingestion of unpasteurized milk from cows or goats enhances risk of infection in both regions of endemic disease and regions in which the disease is not endemic.
Although various potential intermediate hosts have harbored brucellosis in the extra-Mediterranean world, dairy cattle infected with B abortus have been particularly important hosts in North America. The infection is often symptomatic in cattle. Outbreaks of epizootic bovine abortion due to B abortus should alert health care providers to the possibility of human brucellosis. Some cases in humans in North America have been traced to pork from hogs infected with B suis. In Scandinavia and Alaska, reindeer are an important source of brucellosis.
Brucellosis has developed in infants who have been breastfed from mothers who either visited regions of endemic disease or ingested foodstuffs shipped from such regions.
In nonendemic regions, as in endemic regions, physicians, veterinarians, pathologists, and laboratory personal exposed to tissues from infected animals (including humans) are at particular risk for brucellosis.  Surprisingly, infection with Brucella species accounts for as many as 10% of laboratory-acquired infections, 24% of laboratory-acquired bacterial infections, and 11% of occupational-exposure deaths in the United States. 
Aside from laboratory workers, individuals at greatest risk for brucellosis are those exposed to goats, sheep, cows, camels, pigs, reindeer, rabbits, or hares, both in areas of endemic disease and in areas where the disease is not endemic. Such individuals include herders, hunters, farmers, dairy workers, veterinarians, abattoir workers, and meatpackers.
Brucella has the potential to be used as a biologic weapon,  but to date, these organisms have not been implicated in any major bioterrorism incident. Were they used in such a way, however, patients might not present until several weeks later. Because of this potential, and in view of the rarity of brucellosis in the United States, especially in more urban areas, any clustering of brucellosis cases should be thoroughly investigated and reported to public health officials.
Table 2. Symptoms and Signs of Brucellosis (Open Table in a new window)
|Study||No. of Patients||Fever or Chills||Arthralgia or Arthritis||Sweating||Constitutional symptoms*||Hepatomegaly||Splenomegaly|
|Memish et al (2000) ||160||146 (91.3%)||105 (65.6%)||30 (18.8%)||70 (43.8%)||9 (5.6%)||11 (6.9%)|
|Kokoglu et al (2006) ||138||108 (78.3%)||107 (77.5%)||100 (72.5%)||98 (71%)||37 (26.8%)||50 (36.2%)|
|Mantur et al (2006) ||495||417 (84.2%)||117 (23.6%)||19 (3.8%)||6 (1.2%)||56 (11.3%)||95 (19.2%)|
|Ruiz-Mesa et al (2005) ||711||702 (98.7%)||353 (49.6%)||597 (84%)||533 (75%)||250 (35.2%)||148 (20.8%)|
|Barroso Garcia et al (2002) ||565||441 (78.1%)||248 (43.9%)||483 (85.5%)||472 (83.5%)||422 (74.7%)||152 (26.9%)|
|Hasanjani Roushan et al (2004) ||469||314 (67%)||252 (53.7%)||357 (76.1%)||...||...||27 (5.8%)|
|Pappas et al (2005) ||100||91 (91%)||44 (44%)||..||26 (26%)||7 (7%)||16 (16%)|
|Troy et al (2005) ||28||25 (89%)||15 (54%)||..||13 (46%)||8 (29%)||5 (18%)|
|Andriopoulos et al (2007) ||144||144 (100%)||125 (86.8%)||138 (95.8%)||140 (97.2%)||...||74 (51.4%)|
|Giannakopoulos et al (2006) ||52||42 (81%)||43 (83%)||8 (15%)||7 (13%)||...||...|
|Mantur et al (2004) ||93||49 (53%)||19 (20%)||...||...||...||...|
|Tsolia et al (2002) ||39||27 (69%)||27 (69%)||8 (21%)||13 (33%)||11 (28%)||15 (38%)|
|* Anorexia, asthenia, fatigue, weakness, malaise.|
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 weight loss 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. Arthralgias may be diffuse or localized, with a predilection for bone ends and the sacroiliac joint. Acute monoarticular arthritis is uncommon but may be part of the presentation.
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. In patients with advanced disease who have meningoencephalitis, these complaints may include changes in mental status, coma, neurologic deficit, nuchal rigidity, or seizures.
A significant percentage (approximately 50%) of patients have gastrointestinal (GI) complaints, primarily dyspepsia, though abdominal pain from hepatic abscesses may occur. Hepatic abscesses should be suspected in patients with signs of systemic toxicity and persistently elevated liver enzymes. The abscess can serve as a source of bacteremic seeding. Spontaneous bacterial peritonitis secondary to brucellosis infection has been reported. Constipation, diarrhea, and vomiting may occur.
Genitourinary infections with brucellae have been reported and include orchitis, urinary tract infection (UTI), and glomerulonephritis. Frank renal failure or sepsis is rare.
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 central nervous system (CNS) involvement.
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. 
Endocarditis from brucellae is reported, with septic embolization a common complication of this form of brucellosis. Other cardiac complications, such as pulmonary edema or dysrhythmias, are rare. Brucella endocarditis is the form most commonly associated with fatalities.
With the chronic form of brucellosis, in which the illness has lasted longer than 1 year (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.
Generally, physical examination findings are normal or only minimally abnormal (see below), and the diagnosis is made on the basis of the history and serologic studies.
Categorization of disease
Traditionally, brucellosis has been classified as subclinical, acute, subacute, or chronic; localized and relapsing forms have also been described. This classification system, though commonly used, is subjective and of limited clinical utility.
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 and subacute brucellosis
Disease can be mild and self-limited (eg, B abortus) or fulminant with severe complications (eg, B melitensis). Associated symptoms can develop 2-3 months before diagnosis in mild cases and 3-12 months before diagnosis in severe cases.
Usually, acute brucellosis occurs without focal abnormalities. Nonfocal weakness may be noted. The tissues overlying the spine or peripheral nerves may be tender to percussion. Tenderness, swelling, or effusion of joints may be evident. In some instances, orchitis appears after a few days of illness. Testicular swelling and tenderness in the wake of chills and high fever thus resemble mumps orchitis.
Some patients manifest constipation. Occasionally, abdominal tenderness suggests an acute abdomen. In some more severe cases, tender enlargement of the spleen may be detected.
Murmurs, friction rubs, acute-onset blindness or visual field disturbance, tachycardia, oropharyngeal or conjunctival petechiae (some with pale centers), Roth spots, splinter hemorrhages of the nail beds, Osler nodes, Janeway lesions, or hepatosplenomegaly may develop as manifestations of bacterial endocarditis, a complication that is much rarer as an aspect of acute or subacute brucellosis than as an element of focal or diffuse chronic brucellosis.
Rarely, disease of the lungs or pleura is a feature of acute brucellosis, manifestations of which could include rales, wheezes, abnormalities of percussion or egophony, or pleural friction rubs.
Meningismus, papilledema, mental status changes, and long-tract signs are found in a small fraction of cases of acute brucellosis as manifestations of acute neurobrucellosis.
Radicular sensory or motor changes may arise in individuals with brucellotic osteomyelitis with associated epidural abscess. Focal tenderness or pain in the perispinous region may precede fever and objective sensory or motor findings. Brucellotic cervical epidural abscess may produce tenderness and movement restriction without the classic triad (fever, neck pain, and radiculopathy) of streptococcal or other types of epidural abscess. However, such findings may eventually develop, prompting delayed consideration of this diagnostic entity. 
The diagnosis of chronic brucellosis 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 and relapsing brucellosis
Localized complications of brucellosis are typically observed in patients with acute disease or chronic untreated infection. Osteoarticular, genitourinary, and hepatosplenic involvement are most common (see Complications). Cultures of involved tissue sites and serology can be diagnostic.
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.
Among the most common findings is hepatosplenomegaly (or isolated hepatomegaly or splenomegaly). Right upper quadrant pain and jaundice may indicate hepatic abscess. Generalized tenderness, rebound tenderness, and sluggish or absent bowel sounds can be expected in patients with peritonitis.
Osteoarticular involvement is also common. Focal infection of bones or joints may present with localized abnormal physical findings (eg, swelling, tenderness, and limited motion) in the affected areas. Arthritis, joint effusions, or, in severe cases, costovertebral angle tenderness may be observed. Focal osteomyelitis of the vertebrae, tibia, and, especially, the knee has also been associated with brucellosis infection even in the absence of other significant systemic symptoms. Maneuvers that isolate the sacroiliac joint may cause pain.
Focal infection of the genitourinary system may also present with localized abnormal physical findings. Epididymo-orchitis has been described in association with brucellosis; a tender, swollen scrotum with erythema is present in these patients. Urethritis has been reported. Testicular abscess, mimicking tumor, has also been known to occur.
Endocarditis may present with new or changing murmurs, and mycotic aneurysms of ventricles, brain, and aorta have been observed. A pericardial rub is present in patients with pericarditis.
Although pulmonary complaints are frequently present in patients with brucellosis, physical examination of this organ system almost always yields normal findings.
Neurologic findings vary according to the presentation of neurologic disease and may include the following:
Acute meningoencephalitis (most common neurologic manifestation) - Depressed level of consciousness, meningeal irritation, cranial nerve involvement, coma, seizure, and respiratory depression
Meningitis – Nuchal rigidity, Kerning sign, and Brudzinski sign
Increased intracranial pressure (ICP) or brain abscess – Papilledema, cranial nerve palsy, and focal neurologic deficits
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 include the following  :
Erythema nodosum, abscesses, and papulonodular eruptions (most common)
Macular, maculopapular, and scarlatiniform rashes
Vasculitic lesions (eg, petechiae, purpura, and thrombophlebitis)
Ocular findings can include the following  :
Complications are rare in the patient who is treated appropriately, though relapse of infection may occur in 10% of patients. The major risk factor for the development of focal complications is symptom duration greater than 30 days before diagnosis. The most common focal complications fall into the following categories:
Hepatobiliary and GI
Other, less common complications include the following:
Osteoarticular symptoms affect 20-60% of patients with brucellosis and are the most commonly reported complications; sacroiliitis is the most common (though rarer in children). Spondylitis, arthritis, osteomyelitis, bursitis, and tenosynovitis have been reported. Paraspinal pyogenic complications are often associated with spondylitis, especially in elderly persons. Peripheral joint involvement usually includes the knees, hips, ankles, and shoulders and can be monoarticular or polyarticular.
Hepatobiliary complications include hepatitis, hepatic abscess, and acute cholecystitis. The rarely reported GI complications include ileitis, colitis, and spontaneous peritonitis.
Genitourinary complications usually manifest as orchitis or epididymo-orchitis.  Renal involvement is rare, although glomerulonephritis and pyelonephritis have been reported.  Infection in pregnant patients is rare and is associated with first-trimester abortions. The frequency of this complication is not substantially different from its frequency when associated with other bacterial infections.
Neurobrucellosis occurs more frequently in endemic regions and develops in approximately 5% of cases. Meningitis  (1-2%) and, less commonly, papilledema, optic neuropathy, radiculopathy, stroke, and intracranial hemorrhage may be seen.
Acute meningoencephalitis presents with a prehospital symptom duration of less than 7 days, and clinical findings progress rapidly. With appropriate aggressive therapy, symptoms resolve quickly, and patients are rarely left with residual sequelae. Other forms of neurobrucellosis typically present after at least 3 months of gradual symptoms. After successful therapy, residual deficits are not uncommon; however, they are rarely debilitating.
Worldwide, endocarditis occurs in less than 2% of patients with brucellosis; however, in endemic areas, it may affect 7-10% of patients. The aortic valve is affected in 75% of patients, and 50% of affected valves were previously healthy. Endocarditis is responsible for most of the mortality associated with brucellosis.
Pericarditis, myocarditis, and mycotic aneurysms of the aorta and cerebral vessels may complicate endocarditis. Primary pericarditis and myocarditis are also reported and have a more favorable outcome.
Pulmonary complications are reported in 0.3-1% of patients with brucellosis (less commonly in children) and include pneumonia and pleural effusion. These complications are less common in children. Pneumonitis and pleural empyema have been reported.
Hematologic complications are not typically associated with severe sequelae and resolve with appropriate therapy. Reports of disseminated intravascular coagulation (DIC) and the hemophagocytic syndrome have been published. Splenic abscess has been reported.
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