Approach

Brucellosis is known as a great imitator, as it can mimic any disease and affect any organ or system.[1][4] It has been reported to affect the genitourinary, gastrointestinal, hepatobiliary, reticuloendothelial, cardiovascular, and musculoskeletal systems, as well as the central and peripheral nervous system. When clinical features relate to predominantly one organ system, this is defined as localised or focal disease.[75] Diagnosis is based on clinical presentation in conjunction with laboratory investigations.

Brucellosis is a reportable condition in some countries.

History

Eliciting a history of exposure to animals or their products, consumption or inhalation of possibly infected material (e.g., unpasteurised milk, cheese, other milk products, raw meat), and/or travel to an endemic area is essential to the diagnosis of brucellosis. A history of travel to an endemic area should always be asked about, and migrants from endemic areas should be asked specifically about consumption of imported dairy products.[69][70][71] Close contact with an infected person should also be established; a family member has similar symptoms in up to 50% of cases in endemic areas.[19][20]

Occupational history is of particular importance, as farmers, animal handlers, abattoir workers, veterinarians, and laboratory personnel have a greater risk of infection than the general population.

The length and type of symptoms may help localise focal disease and target further investigations. A history of fever or chills is the most common symptom, occurring in 53% to 100% of infections, and if left untreated can show an undulating pattern.[4][80] Profuse sweating is also common, especially at night. Non-specific constitutional symptoms, such as lethargy and weight loss are extremely common, affecting up to 97% of patients.[81]

Arthralgia, particularly affecting the hips, knees, or spine, is associated with 20% to 83% of infections.[81][82] Young children may present with difficulty walking, mimicking an irritable hip.

Gastrointestinal symptoms include nausea, vomiting, abdominal pain, constipation, and diarrhoea. A minority of patients have pulmonary symptoms such as a dry cough. Men may present with testicular pain.

Although focal central nervous system involvement is rare, mild to moderate neuropsychiatric symptoms frequently occur, and include headache, fatigue, and depression.

Asymptomatic disease is possible and may be diagnosed following serological screening of high-risk people. During a follow-up period of up to 18 months, 40% of patients remained asymptomatic and 15% of patients appeared symptomatic.[83]

Physical examination

The temperature is raised in more than 90% of patients. Patients usually look miserable and may have overt depression, but they rarely appear septic. They may be pale owing to underlying anaemia.

Osteoarticular findings are present in 40% to 50% of patients and include joint swelling and tenderness, bursitis, decreased joint range of motion, and, rarely, joint effusion.[82][84] The spine or sacroiliac joints may be tender, but gross deformity is unusual and more suggestive of tuberculosis.

One third of patients have palpable hepatomegaly and/or splenomegaly.[85] Lymphadenopathy is present in about 10% of adult cases but has been reported in up to two-thirds of children with brucellosis.[85] Between 5% and 10% of male patients have orchitis, which is occasionally the predominant clinical feature.[1]

Up to 4% of patients present with signs of meningoencephalitis (e.g., neck stiffness), and occasionally may have clinical signs associated with focal vasculitic brain lesions or cranial nerve lesions (focal neurological deficits).[82] Long-tract neurological signs are unusual. Ocular involvement, suggested by the presence of a red eye (uveitis or conjunctivitis), is rare.

Endocarditis is a rare but serious problem (about 1% of patients), which usually affects the aortic valve and is responsible for a large proportion of the 1% to 5% mortality rate of brucellosis.[82][86] Pulmonary signs suggesting consolidation or effusion occur infrequently and include dullness to percussion, decreased air entry, and crepitations on auscultation.[87][88]​​ It is more common for patients with a cough to have few clinical signs in the chest.

A variety of non-specific maculopapular or vasculitic skin rashes may occasionally be seen.[89]

Laboratory investigations

Cultures are required for confirmation of the disease. The microbiology laboratory should be informed that brucellosis is suspected to ensure safe handling of Brucella species cultures.

Blood cultures are the mainstay of diagnosis and should, therefore, be the first tests ordered.[90] The sensitivity of blood cultures depends largely on previous antibiotic use, the phase of the disease, and the method of culturing.[91][92][93] Traditional culture sensitivity is improved by using sensitive methods such as lysis-centrifugation or specialised culture media (e.g., Castañeda's medium) and by extending culture duration to 6 weeks. Modern culture systems are more sensitive and usually become positive within 1 week, but subcultures should be maintained for up to 3 weeks.[93] Bone marrow cultures have a greater positive yield than blood cultures, as the organism is intracellular and localised in the bone marrow and, therefore, may be considered in difficult cases (e.g., negative blood cultures, negative serology, and brucellosis suspected).[91]

Cultures are not always available or successful, so at least one serological test is usually indicated, typically an agglutination test or enzyme-linked immunosorbent assay (ELISA). Serological tests are usually based on the traditional (Wright) standard agglutination test (SAT) or tube agglutination test (TAT), modified in some laboratories to be performed in small ELISA plates as the microagglutination test (MAT).[94] All these tests rely on agglutination of crude preparations of smooth Brucella lipopolysaccharide antigens in increasing dilutions of antibody in the patient's serum. However, the techniques suffer from lack of standardisation and are notoriously affected by the prozone phenomenon, caused by blocking immunoglobulin (Ig)A antibodies, yielding false negative results at low dilutions of patient serum.[1] Rose Bengal agglutination tests, developed for veterinary practice, are used in some countries to screen human sera; they have high sensitivity but require subsequent confirmatory testing.[95][94] Several groups prefer to use locally prepared ELISA tests, which usually have high sensitivity but variable specificity.[84][94][96] These may have a role in reference laboratories. Point-of-care tests are being developed but require further evaluation.[97]

There is considerable cross-reactivity between Brucella species; therefore, species diagnosis by serology is not reliable. All serological tests can also cross-react with other gram-negative bacteria, such as Escherichia coli and Yersinia species, as well as with previous cholera vaccinations, increasing the rate of false positive tests.[98] In endemic areas, a high background level of antibodies may be present due to subclinical infection, which affects test interpretation.[99] Human infections with the live animal vaccine do not generate antibody responses, and B canis infections are not usually detected by conventional serological tests that are based on antigens present in smooth phase Brucella variants, which B canis lacks as it forms rough (mucoid) colonies.​[1][84][100]​[101]​ In addition, serological tests remain variably positive for months to years after infection and may not be reliable for the diagnosis of re-infection or relapse.

Molecular tests such as polymerase chain reaction (PCR) should be more rapid than blood culture and have sensitivity reported to approach 100%, with a specificity of 98.3%.[102] PCR may be particularly useful in patients with relapse or re-infection and has been used in trials to monitor the progress of treated patients and to assess disease relapse.[103] However, PCR methods are still not standardised, are susceptible to contamination, and have yielded contradictory results with prolonged positivity in some settings, so their full potential has yet to be realised.[104]

There is increasing evidence for the use of matrix-assisted laser desorption/ionisation time of flight mass spectrometry (MALDI-TOF-MS) for rapid analysis and identification of Brucella species in blood and pure cultures; however, this is still considered an emerging test.[105][106][107]

Clinically affected organs and tissues can be biopsied, particularly lymph nodes, liver, and, occasionally, synovium. This is done partly to obtain material for culture to exclude tuberculosis (TB). Histology usually reveals non-caseating granulomata, but these may be difficult to distinguish from caseating granulomata as found, for example, in TB.

Examination of cerebrospinal fluid (CSF) via lumbar puncture should be performed in patients with neurological signs and symptoms to exclude meningoencephalitis. Results usually show a predominance of lymphocytes; culture is rarely positive but is improved by use of automated culture systems, and CSF serological tests are difficult to interpret, but the SAT is usually positive.[1][108][109] Synovial fluid analysis obtained via aspiration is indicated in all patients with joint effusion and shows cellular changes similar to those in TB. As with CSF, synovial fluid should always be cultured for suspected brucellosis.[110]

A routine full blood count should be requested in all patients; it gives non-specific clues, as anaemia and/or thrombocytopenia occur in 30% to 75% of infected patients.[111][112]​ In addition, leukopenia or leukocytosis is found in 22% and 7% of patients, respectively.[111] Serum electrolyte levels may reveal hyponatraemia.[113] Routine liver function tests are also necessary in all patients; results are commonly disturbed, with mild elevation of transaminases.[1][84]

Imaging

Imaging studies are largely supportive and are not indicated for all patients. Plain film x-ray changes in the axial skeleton and peripheral joints appear late in the course of the disease and typically include small erosions near affected joints, moderate sclerosis of bone adjacent to infected joints, and little joint destruction or loss of joint space.[1] Bone scan is sensitive and may reveal subclinical joint infection.[114] This study may be of use early in the disease, when abnormalities are usually not visible on plain film radiographs, and should be considered for patients with musculoskeletal manifestations. Furthermore, bone scan may help distinguish hip involvement from sacroiliitis.[115]

Chest x-ray findings are usually normal but may show consolidation or pleural effusion; they are usually reserved for patients with pulmonary signs or symptoms.

Computed tomography (CT) and particularly magnetic resonance imaging (MRI) scans of the spine are useful for delineating infection of the spine and paraspinal tissues. In addition, intracranial collections, calcification, or hydrocephalus may be revealed with head CT or MRI in rare cases of central nervous system infection.

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