Update on laboratory diagnosis of human brucellosis

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Abstract

The persistent worldwide prevalence of human brucellosis causes serious public health concerns and economic loss to communities. The multisystem involvement and the protean and unusual clinical presentations of the disease pose significant diagnostic challenges. The clinical features are non-specific and can overlap with a wide spectrum of other infectious and non-infectious diseases, leading to brucellosis being labelled the ‘disease of mistakes’. Protracted chronicity and serious complications can result and mislead physicians onto a path of costly laboratory and radiological investigations. To reach a diagnosis clinicians must use a wide range of non-specific routine haematological and biochemical tests in addition to Brucella-specific assays. The latter are microbiological (culture), serological (e.g. slide or tube agglutination, Coombs test, immunocapture agglutination, Brucellacapt, immunochromatographic lateral flow, enzyme-linked immunosorbent assays and the indirect fluorescent antibody test) and molecular (e.g. polymerase chain reaction (PCR) and real-time PCR). Each of these tests has advantages and limitations, and thus requires careful interpretation. Since brucellosis can have several presentations and phases (acute, subacute, chronic, relapsed, active and inactive), the search for reliable, discriminatory diagnostic and prognostic markers, especially for monitoring disease evolution, are ongoing. Although much progress has been made, further challenges remain to the accurate diagnosis of this historic but still common global zoonotic disease.

Section snippets

Brucella species

Brucella spp. are small (0.5–1.5 μm), facultative, intracellular Gram-negative coccobacilli that lack capsules, flagellae, endospores or native plasmids. They are aerobic, do not ferment sugars and are positive in a few oxidative metabolic tests. They can grow on a wide range of culture media and colonies generally appear after 24–48 h incubation [11], [12].

To date, six terrestrial and three marine Brucella species have been recognized: B. melitensis (preferred hosts are goats, sheep, camels), B.

Antigenic components

Several antigenic components have been identified and determined to be involved in a variety of roles, including pathogenesis and the immune response, and are potentially useful in diagnosis of the disease. Lipopolysaccharide (LPS) is the major antigen and can exist in two partially shared antigenic epitopes: A (B. abortus) and M (B. melitensis). The O-specific side chains of the LPS molecule are considered the cause of the reported cross-reactions in both the agglutination and complement

Transmission

Ingesting unpasteurized animal milk (goat, sheep, cow or camel) or its products, e.g. soft cheese, account for most cases worldwide [4], [5], [22]. Occupational infection (mostly in veterinarians, workers in clinical, research and production laboratories, and abattoir workers) is primarily associated with respiratory, conjunctival and skin routes of infection, e.g. through inhalation, sprays and aerosols; abrasions, accidental inoculation or cuts; and mishandling and misidentification of the

Virulence and pathogenesis

The virulence and pathogenesis of Brucella infection and the bacterium's avoidance of the immune system remain to be clarified and resolved [24]. The incubation period is variable, but generally is 1–4 weeks. Its intracellular survival within polymorphonuclear and mononuclear phagocytes, escaping phagosome–lysosome fusion and the immune response, is facilitated by factors including its ability to produce urease, which offers protection from stomach acid, Brucella-containing vacuoles, where the

Clinical features

The clinical diagnosis of brucellosis remains a considerable challenge, and to the unaware physician the diagnosis becomes a protracted problem for months and sometimes years. This difficulty can be attributed to several aspects of infection, including the prolonged and variable incubation period, its frequent presentation as a non-specific febrile syndrome in adults and children (periodic or undulant fever, including muscle aches, back pain, sweating and fatigue), the varied evolution (acute,

Focal complications and conservative cost estimates

The most commonly encountered focal complications are osteoarticular (10–70%, mostly joints), genital in both males (6–8%) and females (2–5%), neurological (3–5%), cardiac (1–3%), pulmonary (1–2%) and renal (<1%). Mortality is very low (<1%) and almost exclusively results from cardiac complications [5], [6], [27], [28], [29], [30], [31], [32], [33]. It is noteworthy that in some patients who have undergone even simple surgeries, like cholecystectomy and hernia repair, unexplained protracted

Laboratory diagnosis

The diagnosis of a patient with possible brucellosis requires the combination of several approaches, including medical history, clinical examination, routine haematological and biochemical laboratory tests, radiological investigation and, most importantly, established and newly available Brucella-specific culture, serological and molecular tests, as described in this article.

The routine haematological investigations used in the diagnosis of brucellosis are mainly complete blood count,

Conclusions

Many improvements have been made towards better understanding of the clinical, epidemiological, pathogenetic, diagnostic, therapeutic and other aspects of human brucellosis, a historic zoonotic disease. However, several challenges remain to be addressed: (1) to define specific serological diagnostic and prognostic markers, (2) determine purified, specific and relevant antigenic epitope predictors of each disease stage (e.g. acute, active, relapse, chronic, cure), (3) carry out follow-up studies

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