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History
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,[3]
almost every case of brucellosis involves exposure to an affected animal in some
fashion, either directly or indirectly.
Risk factors
The risk factors for brucellosis differ somewhat, depending upon whether a given
individual resides in or has recently visited a region of endemic disease.
Endemic exposure
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
goats 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.
[5]
Nonendemic exposure
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.
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Symptoms
Symptoms of brucellosis are protean in nature, and none is specific enough to
support the diagnosis (see Table 2, below).[11, 12]
Table 2. Symptoms and Signs of Brucellosis (Open Table in a new window)
Study
Fever
No. of
or
Patients
Chills
Arthralgia
Constitutional
or
Sweating
Hepatomegaly Splenomegaly
symptoms*
Arthritis
Memish et al
(2000)[13]
160
146
105
(91.3%) (65.6%)
30
(18.8%)
70 (43.8%)
9 (5.6%)
11 (6.9%)
Kokoglu et al
(2006)[14]
138
108
107
(78.3%) (77.5%)
100
(72.5%)
98 (71%)
37 (26.8%)
50 (36.2%)
Mantur et al
(2006)[15]
495
417
117
(84.2%) (23.6%)
19 (3.8%) 6 (1.2%)
56 (11.3%)
95 (19.2%)
Ruiz-Mesa et al
711
(2005)[16]
702
353
(98.7%) (49.6%)
597
(84%)
533 (75%)
250 (35.2%)
148 (20.8%)
Barroso Garcia
565
et al (2002)[17]
441
248
(78.1%) (43.9%)
483
(85.5%)
472 (83.5%)
422 (74.7%)
152 (26.9%)
Hasanjani
Roushan et al
(2004)[18]
469
314
(67%)
252
(53.7%)
357
(76.1%)
...
...
27 (5.8%)
Pappas et al
(2005)[19]
100
91
(91%)
44 (44%)
..
26 (26%)
7 (7%)
16 (16%)
Troy et al
(2005)[20]
28
25
(89%)
15 (54%)
..
13 (46%)
8 (29%)
5 (18%)
Andriopoulos et
144
al (2007)[21]
144
125
(100%) (86.8%)
138
(95.8%)
140 (97.2%)
...
74 (51.4%)
Giannakopoulos
52
et al (2006)[22]
42
(81%)
43 (83%)
8 (15%)
7 (13%)
...
...
Mantur et al
(2004)[23]
93
49
(53%)
19 (20%)
...
...
...
...
Tsolia et al
(2002)[24]
39
27
(69%)
27 (69%)
8 (21%)
13 (33%)
11 (28%)
15 (38%)
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.[25] 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
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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.[26]
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.
Physical Examination
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.
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 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),
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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.[10]
Chronic brucellosis
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 enzymelinked immunoassay (ELISA) testing may be more helpful.
Physical findings
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
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Complications
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:
Osteoarticular [31]
Hepatobiliary and GI
Genitourinary
Neurobrucellosis
Cardiovascular
Pulmonary
Hematologic [32]
Other, less common complications include the following:
Splenic abscess
Thyroid abscess
Epidural abscess
Uveitis
Osteoarticular
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
Hepatobiliary complications include hepatitis, hepatic abscess, and acute
cholecystitis. The rarely reported GI complications include ileitis, colitis, and
spontaneous peritonitis.
Genitourinary
Genitourinary complications usually manifest as orchitis or epididymo-orchitis.[33]
Renal involvement is rare, although glomerulonephritis and pyelonephritis have
been reported.[34] Infection in pregnant patients is rare and is associated with firsttrimester abortions. The frequency of this complication is not substantially different
from its frequency when associated with other bacterial infections.
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Neurobrucellosis
Neurobrucellosis occurs more frequently in endemic regions and develops in
approximately 5% of cases. Meningitis[35] (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.
Cardiovascular
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
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
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.
Differential Diagnoses
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