Version May 2024
INTRODUCTION — Brucellosis (also known as 'undulant fever,' 'Mediterranean fever,' or 'Malta fever') is a zoonotic infection transmitted to humans from infected animals (cattle, sheep, goats, camels, pigs, or other animals) by ingestion of food products (such as unpasteurized dairy products) or by contact with tissue or fluids. It is the most common zoonosis worldwide and is an important public health problem in many resource-limited settings [1-3].
The epidemiology, microbiology, clinical manifestations, and diagnosis of brucellosis will be reviewed here. The treatment and prevention of brucellosis are discussed separately. (See "Brucellosis: Treatment and prevention".)
EPIDEMIOLOGY
Geographic distribution — Endemic areas for brucellosis include countries of the Mediterranean basin, Middle East, Central Asia, China, the Indian subcontinent, sub-Saharan Africa, and parts of Mexico and Central and South America (table 1) [4,5].
Worldwide, approximately 500,000 cases are reported annually [6], and there are an estimated 2.4 billion people at risk [7]. All age groups are affected. The prevalence of brucellosis has been increasing due to growing international tourism, trade, and migration [8,9].
In the United States, 100 to 200 cases of human brucellosis are reported annually; most of them are due to Brucella melitensis [4]. However, true incidence has been estimated at 5 to 12 times greater, mainly attributable to foodborne illness [10]. Imported unpasteurized dairy products, such as fresh goat or sheep cheese from neighboring countries (particularly Mexico), are an important source of infection [4,9,11]. In addition, transmission of brucellosis in association with consumption of unpasteurized milk from domestic sources has been described [12-14].
Brucellosis has been reported among wildlife in some regions [15]. In Australia and the United States, Brucella suis has been observed in approximately 20 percent of feral swine, and infection among hunters has been described [16-18]. Approximately 25 to 30 of cases reported annually to the United States Centers for Disease Control are due to B. suis; nationwide, 18 to 53 percent of feral swine are carriers of B. suis [19] and almost all cases are diagnosed in feral swine hunters [3].
Transmission — The most common mechanisms for transmission of brucellosis to humans are [1,2]:
●Consumption of infected, unpasteurized animal products
●Contact of skin or mucous membranes with infected animal tissue (such as placenta or miscarriage products) or infected animal fluids (such as blood, urine, or milk)
●Inhalation of infected aerosolized particles
Consumption of unpasteurized dairy products (especially raw milk, soft cheese, butter, and ice cream) is the most common means of transmission [1,20-22]. Hard cheese, yogurt, and sour milk are less hazardous, since fermentation takes place. Infection due to Brucella RB51 (a live attenuated cattle vaccine strain that can be shed in milk) has been acquired via consumption of unpasteurized milk [23]. Consumption of raw or undercooked muscle tissue or organ meat (such as liver and spleen) are less common modes of transmission [1].
Brucellosis is an occupational disease in shepherds, abattoir workers, veterinarians, dairy-industry professionals, and laboratory personnel (including laboratory workers handling Brucella cultures and workers preparing brucellosis vaccines for animal use) (table 2).
Rare cases of human-to-human transmission via blood transfusion, tissue transplantation, breastfeeding, sexual contact, congenital transmission, and nosocomial infection have been described [24-27]. Congenital brucellosis is rare; transmission may occur transplacentally during maternal bacteremia. Neonatal brucellosis may be acquired via contact with body fluids during delivery or via breastfeeding in the postpartum period [3,25,28]. Nosocomial transmission has occurred among health care workers who did not adhere to precautions and acquired the infection during obstetrical delivery or while caring for patients [24,25].
MICROBIOLOGY
Taxonomy — Several species are recognized within the Brucella genus [29,30].
Four Brucella species can cause human disease: B. melitensis (isolated from small ruminants such as sheep and goats, as well as camels), B. abortus (isolated from cattle), B. suis (isolated from swine), and B. canis (isolated from dogs). Worldwide, most human cases are caused by B. melitensis [1]. In general, human infection due to B. melitensis and B. suis is more virulent than human infection due to B. abortus or B. canis [2,31-33]. However, one study noted similar severity between infection due to B. melitensis and B. abortus [34].
Additional Brucella species have been isolated from animals or humans and detected as sporadic human pathogens; these include B. pinipedialis and B. ceti (isolated from marine mammals), B. microti (isolated from wildlife animals), B. papionis (isolated from baboons), B. inopinata (isolated from a human breast implant wound), B. vulpis (isolated from red foxes), B. ovis (isolated from sheep), B. neotomae (isolated from desert wood rats), and B. pseudogrignonensis (isolated from humans) [35-43].
Laboratory identification — Laboratory workers should be informed about the diagnostic possibility of brucellosis in order to implement appropriate precautions and special culture techniques (table 2).
Brucellae are small, nonmotile, facultative intracellular aerobic rods, 0.5 to 0.7 micron in diameter and 0.6 to 1.5 micron in length [44,45]. Gram staining demonstrates single, tiny, gram-negative coccobacilli [46].
Most strains require complex media for growth, which may be improved by adding serum or blood [46]. The optimum growth temperature is 35 to 37°C. Some biovars of B. abortus and B. suis require supplementary carbon dioxide [47]. Colonies are usually raised, convex, and 0.5 to 1.0 mm in diameter with a smooth, shiny surface [46].
The biphasic (solid and liquid) blood culture technique of Ruiz-Castaneda is still used in some resource-limited settings, but automated blood culture systems are more effective [1]. The biphasic technique requires 6 weeks of incubation; the yield is variable (40 to 90 percent in acute disease versus 5 to 20 percent in chronic, focal, and complicated disease) [48]. Most blood cultures are positive between 7 and 21 days [49]; subcultures should be performed for at least 4 weeks [1].
The semiautomatic blood culture systems (Bactec and BacTAlert) shorten the detection time considerably; the presence of Brucella can be detected by the third day of incubation [2,11,50,51]. With automated blood culture systems, most isolates are recovered in one week; there is no need to incubate bottles longer than two weeks [48,52]. Cultures of other fluids or tissues (other than blood) may take up to three weeks to grow on plated media.
Brucella organisms can survive up to two days in milk at 8°C, up to three weeks in frozen meat, and up to three months in goat cheese. Brucellae shed in animal excretions may remain viable for >40 days if the soil is damp. The organisms are sensitive to heat, ionizing radiation, most commonly used disinfectants, and pasteurization [47,53,54].
CLINICAL MANIFESTATIONS
Signs and symptoms — Brucellae are taken up by local tissue lymphocytes, enter the circulation via regional lymph nodes, and seed throughout the body, with tropism for the reticuloendothelial system. The incubation period (from acquisition to clinical manifestations) is usually two to four weeks; occasionally, it may be as long as several months [1,20].
Brucellosis typically presents with insidious onset of fever, malaise, night sweats (associated with a strong, peculiar, moldy odor), and arthralgias (table 3) [1,22]. The fever pattern is variable; it may be spiking and accompanied by rigors, or may be relapsing, mild, or protracted. Additional symptoms may include weight loss, arthralgia, low back pain, headache, dizziness, anorexia, dyspepsia, abdominal pain, cough, and depression [1,11]. Physical findings are variable and nonspecific; hepatomegaly, splenomegaly, and/or lymphadenopathy may be observed.
The clinical manifestations of brucellosis in patients with HIV infection are the same as in patients without HIV infection [55].
Complications — Complications of brucellosis include infection involving one or more focal sites; the likelihood of focal involvement ranges from 6 to 92 percent and is usually about 30 percent [22,56-60]. Complications of brucellosis occur more frequently in adults than in children [61,62].
Brucellosis can affect any organ system [20]:
●Osteoarticular disease is the most common form of focal brucellosis; it occurs in up to 70 percent of patients with brucellosis [61,63-65]. Forms include peripheral arthritis, sacroiliitis, and spondylitis. The sacroiliac (up to 80 percent of those with osteoarticular disease) and spinal joints (up to 54 percent) are the most commonly affected sites [66]. Sacroiliitis is important manifestation in young adults [64,67]; it is unilateral in almost 80 percent of cases [64,68,69]. Peripheral arthritis and sacroiliitis occur in the context of acute disease. Peripheral arthritis usually involves the knees, hips, and ankles [63,64,70]. Prosthetic joints can also be affected.
Spondylitis is a serious complication of brucellosis; it is more prevalent in older patients and patients with prolonged illness prior to treatment [63]. The lumbar vertebrae are involved more frequently than the thoracic and cervical vertebrae, and associated paravertebral, epidural, and psoas abscesses have been described [71-73]. Spondylitis is frequently associated with residual damage following treatment.
●Genitourinary involvement is the second most common form of focal brucellosis; it occurs in up to 10 percent of cases [48,74]. In males, orchitis and/or epididymitis are the most common presentation; prostatitis and testicular abscess occur less commonly. In women, tubo-ovarian abscess has been described. Additional manifestations include cystitis, interstitial nephritis, glomerulonephritis, and renal abscess [21].
Brucellosis in pregnant women has been associated with the risk of spontaneous abortion, intrauterine fetal death, premature delivery, and intrauterine infection with possible fetal death [28,47,75-77]. In one study including more than 240 pregnant women with brucellosis, the obstetric complication rate was 14 percent; spontaneous abortion was the most common complication (6 percent of cases) [77].
●Neurologic involvement occurs in up to 10 percent of cases [48,74]. Manifestations include meningitis (acute or chronic), encephalitis, brain abscess, myelitis, radiculitis, and/or neuritis (with involvement of cranial or peripheral nerves) [20,21,47].
●Cardiovascular involvement occurs in up to 3 percent of cases [48]; it may include endocarditis, myocarditis, pericarditis, endarteritis [78], thrombophlebitis, and/or mycotic aneurysm of the aorta or ventricles. Endocarditis is the most common cardiovascular complication (1 to 2 percent of cases) and is the main cause of death attributable to brucellosis [20,47,58].
●Pulmonary involvement occurs in up to 2 percent of cases [48]. Bronchitis, interstitial pneumonitis, lobar pneumonia, lung nodules, pleural effusion, hilar lymphadenopathy, empyema, or abscesses may be observed [58,79-81].
●Intra-abdominal manifestations are rare; these may include hepatic or splenic abscess, cholecystitis, pancreatitis, ileitis, colitis, and peritonitis.
●Ocular involvement is rare; uveitis is the most common form. Other manifestations include keratoconjunctivitis, corneal ulcers, iridocyclitis, nummular keratitis, choroiditis, optic neuritis, papilledema, and endophthalmitis [82].
●Dermatologic manifestations occur in up to 10 percent of cases. Findings may include macular, maculopapular, scarlatiniform, papulonodular, and erythema nodosum-like eruptions, ulcerations, petechiae, purpura, granulomatous vasculitis, and abscesses [47,58,83].
In the absence of a specific definition for chronic brucellosis by the United States Centers for Disease Control and Prevention and the World Health Organization [84], clinicians typically consider patients with clinical manifestations for more than one year after the diagnosis of brucellosis is established to have chronic brucellosis [11,85].
Patients suffering from chronic brucellosis may be divided into two categories [86]:
●Those with a focal complication (such as spondylitis, osteomyelitis, tissue abscess, or uveitis) and objective evidence of infection (such as elevated antibody titers and/or recovery of Brucellae from blood or tissue culture)
●Those with persistent symptoms in the absence of objective signs of infection (such as positive serology or cultures); symptoms may include malaise, psychiatric complaints (such as depression, anxiety, emotional lability), insomnia, sexual disturbances, tremor, or arthralgias
Relapse — The rate of relapse following treatment is 5 to 15 percent [87]. Relapse usually occurs within the first six months following completion of treatment, but may occur up to 12 months later [88-90].
In a multivariate model for predicting relapse, independent predictors included temperature ≥38.3°C, duration of symptoms <10 days prior to treatment, and positive blood cultures at baseline [91]. In areas with ongoing exposure, differentiation between relapse and reinfection can be difficult [11,90,92].
Causes of relapse include an inadequate antibiotic regimen, inadequate duration of antibiotic therapy, lack of adherence, or localized foci of infection [63]. Relapse may also occur in the absence of the preceding factors. Relapse due to antibiotic resistance is rare.
Laboratory findings — Laboratory findings of brucellosis may include elevated transaminases and hematologic abnormalities including anemia, leukopenia or leukocytosis with relative lymphocytosis, and thrombocytopenia (table 3) [1,22,47,93,94].
In the setting of Brucella arthritis, the synovial fluid white blood cell count is usually ≤15,000 cells/microL (lymphocyte-predominant) [95-98]. The organism can be grown in synovial fluid [68,98,99].
In the setting of brucellosis with neurologic involvement, cerebrospinal fluid findings include a pleocytosis (10 to 200 white blood cells, predominantly mononuclear cells), mild to moderately elevated protein levels (mean 330±490 mg/dL in one study [100]), and hypoglycorrhachia [101,102]. Measurement of the cerebrospinal fluid (CSF) adenosine deaminase (ADA) level may be a useful adjunctive test for diagnosis of central nervous system brucellosis [103]. However, elevated CSF ADA levels may also be observed in the setting of tuberculosis and other infections, and there is no clear threshold to distinguish neurobrucellosis from meningitis caused by other infectious agents [104,105]. Uncommonly, the organism may be recovered in CSF culture; the yield of Brucella CSF culture ranges from 4 to 38 percent [102,106,107]. More frequently antibody or agglutination testing of spinal fluid may be used to establish the diagnosis [102].
In the setting of genitourinary involvement, pyuria may be observed; the organism may be grown in urine culture [108,109].
DIAGNOSIS
Clinical approach — Brucellosis should be suspected in patients with relevant signs and symptoms (fever, malaise, night sweats, and arthralgia) in the setting of relevant epidemiologic exposure (consumption of unpasteurized dairy products, animal exposure in an endemic area, and/or occupational exposure). (See 'Epidemiology' above.)
A definitive diagnosis of brucellosis may be made via either of the following [3,98,110-112]:
●Culture of the organism from blood, body fluids (urine, cerebrospinal fluid, synovial fluid, and pleural fluid), or tissue (such as bone marrow or liver biopsy). However, this method is time consuming and hazardous (table 2) [113].
●A fourfold or greater rise in Brucella antibody titer between acute and convalescent phase serum specimens obtained ≥2 weeks apart
A presumptive diagnosis of brucellosis may be made via either of the following [3]:
●Brucella total antibody titer ≥1:160 by standard tube agglutination test (SAT) in serum specimen obtained after onset of symptoms
●Detection of Brucella DNA in a clinical specimen by polymerase chain reaction assay
Obtaining diagnostic studies — For patients with suspected brucellosis, blood cultures and serologic testing should be performed. In addition, laboratory studies including complete blood count and liver function tests should be obtained. Laboratory workers should be informed about the diagnostic possibility of brucellosis in order to implement special culture techniques and appropriate precautions (table 2).
For patients with negative blood cultures and negative serologic studies, further investigation should be guided by the clinical presentation, tailored to individual circumstances. As an example, patients with signs and symptoms of osteoarticular disease warrant synovial fluid analysis and radiographic imaging. Patients with neurologic manifestations warrant lumbar puncture; this procedure usually does not enable definitive diagnosis but may be useful to distinguish brucellosis from other causes of disease. (See 'Laboratory findings' above and 'Imaging' below.)
If the above evaluation is unrevealing, bone marrow biopsy for culture and histopathology is warranted [1,47]. If bone marrow evaluation is not diagnostic and there is evidence for liver involvement (based on liver function tests and/or radiographic imaging), liver biopsy is warranted. (See 'Adjunctive tools' below.)
Diagnostic tests
Culture — The sensitivity of blood culture for diagnosis of brucellosis is 15 to 70 percent [114]. Automated blood culture systems are most effective; biphasic (solid and liquid) blood culture (Ruiz-Castaneda technique) is still used in some resource-limited settings [1]. Blood cultures are often negative in the setting of chronic disease [2]. Issues related to blood cultures are discussed further above. (See 'Laboratory identification' above.)
Bone marrow culture is more sensitive than blood culture and is considered the gold standard for diagnosis of brucellosis [1]. In one study including 50 patients diagnosed with brucellosis, bone marrow culture was positive in 92 percent of cases [115]. Bone marrow culture has a shorter time to detection than blood culture, and its sensitivity is not diminished by prior antibiotic use [115].
Serologic tests — A variety of serologic methods that enable antibody detection against lipopolysaccharide or other antigens have been used for diagnosis of brucellosis. Serologic results must be interpreted in context of clinical presentation and epidemiologic data [112]. The most common tests are SAT and enzyme-linked immunosorbent assays (ELISAs). Additional tests include screening tests (Rose Bengal agglutination test and the immunochromatographic lateral flow assay). Tests that may be most useful for patients with complicated and/or chronic infection include the 2-mercaptoethanol (2-ME) agglutination test, the immunocapture agglutination (Brucellacapt) test, and the indirect Coombs test.
To optimize the likelihood of diagnosis, it may be useful to use a combination of two serologic tests (such as SAT with 2-ME, SAT with Brucellacapt, SAT with indirect Coombs, or ELISA for immunoglobulin [Ig]G and IgM); this approach allows antibody detection at different stages of disease. In acute disease, any of the assays may be positive; in chronic or complicated disease, SAT may be negative while 2-ME, Brucellacapt, Coombs, and ELISA IgG may be positive.
The SAT is the serologic method for which there is the greatest experience [11,20,116]. In general, positive SAT titers consist of >1:160 outside endemic regions and >1:320 within endemic areas [1]. Evolution of titers (eg, a fourfold or greater rise in titer between acute and convalescent phase serum specimens obtained ≥2 weeks apart) may be used as a diagnostic tool [44]; however, this definition is clinically impractical and may delay therapy. The sensitivity and specificity of SAT are high (95 and 100 percent, respectively, in one study) [117]. In patients with chronic Brucella infection, nonagglutinating antibodies progressively become more abundant than the agglutinating ones and the SAT may give false-negative results [112]. SAT may not be used for diagnosis of B. canis infection; B. canis serology should be requested specifically if brucellosis is suspected but the SAT is negative, or if there is clinical suspicion for B. canis infection [50,118].
ELISAs measure IgM, IgG, and IgA, and typically use whole cells or sonicate, purified lipopolysaccharide (LPS), protein extracts, or other antigens [48]. In one study including more than 130 patients, the sensitivity of ELISA IgM or IgG were lower than SAT (45 and 79 versus 95 percent, respectively); when ELISA IgM and IgG were used in combination, the sensitivity and specificity were comparable with SAT (94 and 97 percent, respectively) [117]. ELISA with smooth LPS is a promising test but there are problems of interlaboratory variability; standard reference materials are needed [2,11,110]. ELISA is preferred for diagnosis of neurobrucellosis, and may be used to distinguish from other infections that give false positive serologic results due to cross reaction [112].
Serologic tests with short turnaround time that may be used as screening tools include the Rose Bengal agglutination test (sensitivity and specificity 87 and 100 percent, respectively, in one study) [119] and the immunochromatographic lateral flow assay (sensitivity and specificity 92 and 97 percent, respectively) [39,48,84].
Serologic tests that may be useful for patients with complicated and/or chronic infection include the 2-ME agglutination test, the immunocapture agglutination (Brucellacapt) test, and the indirect Coombs test [110,120,121]. The Brucellacapt and indirect Coombs tests have similar sensitivity and specificity; the Brucellacapt is more rapid and less cumbersome to perform [48]. In one study including 82 patients with brucellosis, the specificities of the Brucellacapt, Coombs, and SAT were 81, 96, and 100 percent, respectively [122]. (See "Brucellosis: Treatment and prevention", section on 'Limited role of follow-up serology'.)
There are a number of disadvantages associated with serologic tests. Cross-reactivity with other bacteria is a problem with standard tube agglutination; cross-reacting organisms include Francisella tularensis, Yersinia enterocolitica, Escherichia coli, Salmonella urbana, Vibrio cholerae, and others [1,123]. False-negative results are common early in the course of infection, in the setting of immunosuppression, and in the presence of incomplete or blocking antibodies (serum agglutination) [124-126]. In addition, a "prozone" phenomenon (eg, inhibition of agglutination at low dilutions due to an excess of antibodies or to nonspecific serum factors) may also be observed with serum agglutination testing [11,123].
The interpretation of serologic tests can be difficult in the setting of chronic infection, reinfection, relapse, and in endemic areas where a high proportion of the population has antibodies against brucellosis [80]. Positive serologic test results can persist long after recovery in treated individuals, so it is not always possible to distinguish serologically between active and past infection [110,120,127].
Issues related to use of serologic tests in the context of follow-up are discussed further separately. (See "Brucellosis: Treatment and prevention", section on 'Limited role of follow-up serology'.)
Molecular tests — Thus far, development of molecular testing for diagnosis of brucellosis is promising, but this is not yet a routine diagnostic [20,128-132]. Molecular tests can be a valuable diagnostic method in patients with seronegative tests [133]. Positive molecular test results cannot discriminate between active disease and prior (resolved) brucellar infection [132]. All Brucella 16S rRNA gene sequences have been determined to be identical; therefore, 16S rRNA gene sequencing is useful for genus identification, but cannot be used for species identification [131].
A multiplex PCR, Bruce-ladder, can identify and differentiate between Brucella species and vaccine strains; it can be used in epidemiologic analysis and for confirmation of relapse and laboratory-acquired infection [86,130].
Adjunctive tools
Imaging — Radiographic imaging may be useful for evaluation of patients with signs and symptoms of brucellosis, but does not enable definitive diagnosis.
For evaluation of spondylitis, magnetic resonance imaging is the preferred imaging study; other modalities include plain radiography, computed tomography (CT), and bone scintigraphy [66,134].
●Radiographic and CT findings of brucellar spondylitis include intervertebral disk narrowing, epiphysitis of the antero-superior angle with step-like deformities (the Pons sign), osteoporosis, dense sclerosis, parrot beak osteophytes with vertebral "bridging," and interapophyseal involvement. Findings of progressive disease may include osteolysis with vertebral body destruction and abscess (paravertebral or epidural) [63,135].
●MRI findings include decreased signal intensity in the intervertebral disc, while the adjacent vertebral bodies appear hypointense on T-1 weighted images and hyperintense on T-2 weighted images [136,137]. The radiographic findings of sacroiliitis include blurred joint margins, narrowing or widening of the joint space, subchondral erosion or sclerosis. For peripheral arthritis, these findings encompass joint space narrowing or widening, subchondral erosion, sclerosis, and soft tissue swelling [63].
For patients with brucellosis who present with fever of uncertain etiology and undergo CT scan, hepatosplenic disease with localized calcification may be observed (image 1) [138].
In the setting of suspected endocarditis, echocardiography should be pursued. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis" and "Prosthetic valve endocarditis: Epidemiology, clinical manifestations, and diagnosis".)
Histopathology — Bone marrow biopsy and liver biopsy may demonstrate noncaseating granulomas (consisting of epithelioid cells, polymorphonuclear leukocytes, lymphocytes, and some giant cells) in the setting of infection due to B. melitensis and B. abortus; in B. melitensis infection, the granulomata are very small. B. suis infection is often accompanied by chronic abscess formation [47].
DIFFERENTIAL DIAGNOSIS — Given the protean manifestations of brucellosis, the differential diagnosis varies depending on the clinical presentation. In patients with undifferentiated fever, the differential diagnosis includes:
●Malaria – Malaria is characterized by fever, malaise, nausea, vomiting, abdominal pain, diarrhea, myalgia, and anemia. Transmission is via mosquito; the disease occurs throughout most tropical regions. The diagnosis of malaria is established by visualization of parasites on peripheral smear. (See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children" and "Laboratory tools for diagnosis of malaria".)
●Tuberculosis – Tuberculosis (TB) is characterized by cough, lymphadenopathy, fevers, night sweats, and weight loss. In addition, TB may present with extrapulmonary manifestations including musculoskeletal and central nervous system involvement. Transmission is human to human, and infection occurs worldwide. Diagnostic evaluation includes chest radiography and sputum microbiology; further investigation is tailored to clinical manifestations. (See "Pulmonary tuberculosis: Clinical manifestations and complications" and "Diagnosis of pulmonary tuberculosis in adults" and "Bone and joint tuberculosis" and "Central nervous system tuberculosis: An overview".)
●Visceral leishmaniasis – Visceral leishmaniasis is characterized by subacute progression of malaise, fever, weight loss, and splenomegaly (with or without hepatomegaly) over a period of months. Transmission occurs via sand fly bites, and endemic areas include the Mediterranean, the Middle East, Afghanistan, Iran, Pakistan, East Africa, India, Nepal, Bangladesh, and Brazil. The diagnosis is established by histopathology, culture, or serology. (See "Visceral leishmaniasis: Clinical manifestations and diagnosis".)
●Endocarditis – Endocarditis is characterized by fever, often associated with chills, anorexia, and weight loss. Other common symptoms include malaise, headache, myalgias, arthralgias, night sweats, abdominal pain, and dyspnea. The diagnosis is established based on clinical manifestations, blood cultures (or other microbiologic data), and echocardiography. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis".)
●HIV infection – Acute HIV infection is commonly characterized by fever, lymphadenopathy, sore throat, rash, myalgia/arthralgia, and headache. The infection is transmitted sexually, and infection occurs worldwide. The diagnosis is established via immunoassay and viral load. (See "Acute and early HIV infection: Clinical manifestations and diagnosis".)
●Enteric fever – Enteric fever (caused by Salmonella enterica serotype Typhi [formerly Salmonella typhi] and S. enterica serovar Paratyphi A, B, and C) is characterized by abdominal pain, fever, and chills. Classic manifestations include relative bradycardia, pulse-temperature dissociation, and "rose spots" (faint macules on the trunk and abdomen). Hepatosplenomegaly, intestinal bleeding, and perforation may occur, leading to secondary bacteremia and peritonitis. The disease occurs worldwide; regions of highest incidence include South Asia, Southeast Asia, and southern Africa. Transmission is fecal-oral. The diagnosis is established via culture. (See "Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis".)
●Q fever – Q fever is a zoonotic infection caused by Coxiella burnetii. Clinical manifestations include flu-like illness, pneumonia, granulomatous hepatitis, and endocarditis. Q fever is mainly occupational disease that may occur through inhalation of contaminated aerosols or intradermal inoculation. The diagnosis is established via serology and polymerase chain reaction.
●Malignancy – The most common malignancies presenting with fever of unknown origin include lymphoma, leukemia, renal cell carcinoma and hepatocellular carcinoma, or other tumors metastatic to the liver. (See "Fever of unknown origin in adults: Etiologies", section on 'Malignancies'.)
In patients with osteoarticular manifestations, additional diagnostic considerations include:
●Spondyloarthritis – Spondyloarthritis refers to a group of diseases that share clinical features including chronic low back pain, heel enthesitis, dactylitis, and oligoarthritis. The diagnosis is established based on clinical manifestations, radiographic findings, and laboratory tests. (See "Overview of the clinical manifestations and classification of spondyloarthritis" and "Diagnosis and differential diagnosis of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults".)
●Reactive arthritis – Reactive arthritis is a form of arthritis associated with a coexisting or recent antecedent extra-articular infection. Enteric and genitourinary pathogens capable of causing reactive arthritis include Chlamydia trachomatis, Yersinia, Salmonella, Shigella, Campylobacter, Clostridioides difficile, and Chlamydia pneumoniae. Synovial fluid findings are similar to those seen in patients with arthritis associated with brucellosis. The diagnosis is based on clinical presentation and exclusion of other causes. (See "Reactive arthritis".)
●Septic arthritis – Septic arthritis refers to infection in a joint; it is usually caused by bacteria but can also be caused by other microorganisms. Most commonly, septic arthritis arises via hematogenous seeding; it may also develop as a result of direct inoculation of bacteria into the joint. Rarely, septic arthritis develops via extension of infection into the joint space from adjacent tissues. The diagnosis is established based on synovial fluid analysis and culture. (See "Septic arthritis in adults".)
●Lyme disease – Lyme disease is caused by Borrelia burgdorferi. In late disease, clinical manifestations may include intermittent or persistent arthritis of the large joints. The diagnosis is suspected based clinical presentation and tick exposure; it is confirmed via serology and/or polymerase chain reaction. (See "Clinical manifestations of Lyme disease in adults".)
●Viral infections – Viral infections may cause arthritis, fever, and other constitutional manifestations; agents include chikungunya fever virus, rubella, parvovirus B19, hepatitis B virus, and others. The diagnosis is established via serology and polymerase chain reaction. (See "Viral arthritis: Causes and approach to evaluation and management".)
●Systemic lupus erythematosus – Systemic lupus erythematosus is characterized by fever, rash, and inflammatory polyarthritis or arthralgias. The diagnosis is established via presence of antinuclear antibodies and other characteristic systemic manifestations. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults".)
Rheumatoid arthritis – Rheumatoid arthritis is a symmetric, inflammatory, peripheral polyarthritis involving peripheral joints; extra-articular features may include anemia, fatigue, subcutaneous nodules, pleuropericarditis, parenchymal lung diseases, neuropathy, and renal involvement. The diagnosis can be made via clinical criteria and laboratory and serologic tests. (See "Clinical manifestations of rheumatoid arthritis" and "Diagnosis and differential diagnosis of rheumatoid arthritis".)
In patients with biopsy demonstrating noncaseating granulomas, the differential diagnosis includes:
●Sarcoidosis – Sarcoidosis is a multisystem disorder of unknown etiology; it most frequently involves the lung but can involve all organ systems. The diagnosis requires compatible clinical and radiographic manifestations, exclusion of other diseases that may present similarly, and histopathologic detection of noncaseating granulomas. (See "Clinical manifestations and diagnosis of sarcoidosis" and "Overview of extrapulmonary manifestations of sarcoidosis".)
●Fungal infection – Fungal infections (eg, histoplasmosis, blastomycosis) may be associated with granulomatous disease. In the setting of suspected fungal infection, biopsy specimens should be evaluated with fungal stains and culture. In the setting of relevant epidemiologic exposure for histoplasmosis, urine and serum antigen testing should also be performed. (See "Diagnosis and treatment of pulmonary histoplasmosis" and "Clinical manifestations and diagnosis of blastomycosis".)
SUMMARY
●General principles – Brucellosis is a zoonotic infection transmitted to humans from infected animals (cattle, sheep, goats, camels, pigs, or other animals) by ingestion of food products (such as unpasteurized dairy products) or by contact with tissue or fluids. It is the most common zoonosis worldwide and is an important public health problem in many resource-limited settings. (See 'Introduction' above.)
●Epidemiology – Endemic areas for brucellosis include countries of the Mediterranean basin, Middle East, Central Asia, China, the Indian subcontinent, sub-Saharan Africa, and parts of Mexico and Central and South America (table 1). Worldwide, approximately 500,000 cases are reported annually. (See 'Epidemiology' above.)
●Transmission – The most common mechanisms for transmission of brucellosis to humans are consumption of infected, unpasteurized animal products, contact of skin or mucous membranes with infected animal tissue (such as placenta or miscarriage products) or infected animal fluids (such as blood, urine, or milk), and inhalation of infected aerosolized particles. Laboratory workers should be informed about the diagnostic possibility of brucellosis in order to implement special culture techniques and appropriate precautions (table 2). (See 'Transmission' above.)
●Clinical manifestations – (See 'Clinical manifestations' above.)
•Signs and symptoms – The incubation period is usually two to four weeks; occasionally, it may be as long as several months. Brucellosis typically presents with insidious onset of fever, malaise, night sweats (associated with a strong, peculiar, moldy odor), and arthralgias (table 3). Physical findings are variable and nonspecific; hepatomegaly, splenomegaly, and/or lymphadenopathy may be observed. Laboratory findings of brucellosis may include elevated transaminases and hematologic abnormalities including anemia, leukopenia or leukocytosis with relative lymphocytosis, and thrombocytopenia. (See 'Signs and symptoms' above.)
•Complications – Complications of brucellosis include infection involving one or more focal sites; any organ system can be affected. Osteoarticular disease is the most common form of focal brucellosis; it occurs in up to 70 percent of patients with brucellosis. (See 'Complications' above.)
●Diagnosis
•Clinical approach – Brucellosis should be suspected in patients with relevant signs and symptoms (fever, malaise, night sweats, and arthralgia) in the setting of relevant epidemiologic exposure (consumption of unpasteurized dairy products, animal exposure in an endemic area, and/or occupational exposure). A definitive diagnosis may be made by culture of the organism (from blood, body fluids, or tissue), or ≥4-fold rise in Brucella antibody titer between acute and convalescent phase serum specimens obtained ≥2 weeks apart. A presumptive diagnosis may be made by antibody titer ≥1:160 via standard tube agglutination test or by polymerase chain reaction detection of Brucella DNA in a clinical specimen. (See 'Clinical approach' above.)
•Obtaining diagnostic studies – For patients with suspected brucellosis, blood cultures and serologic testing should be performed. In addition, laboratory studies including complete blood count and liver function tests should be obtained. For patients with negative blood cultures and negative serologic studies, further investigation should be guided by the clinical presentation, tailored to individual circumstances. (See 'Obtaining diagnostic studies' above.)
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