We searched Medline for relevant studies published from 1997 to 2007 using the term “brucell*” with specific keywords such as “PCR”, “treatment”, “sero*”, “diagnos*”, “clinical”, and “epidemiolog*”. Only English and Spanish language papers were reviewed. Additionally, publications from the authors' personal collections were used.
ReviewHuman brucellosis
Introduction
A renewed scientific interest in human brucellosis has been fuelled by its recent re-emergence and enhanced surveillance in many areas of the world,1 and from its status as a class B bioterrorist agent.2 The disease remains the world's most common bacterial zoonosis, with over half a million new cases annually and prevalence rates in some countries exceeding ten cases per 100 000 population.1 Despite being endemic in many developing countries,1, 3 brucellosis remains underdiagnosed and under-reported.4 Furthermore, since brucellosis is an important cause of veterinary morbidity and mortality, the disease can also cause important economic losses in developing countries.5
Although brucellosis in human beings is rarely fatal, it can be severely debilitating and disabling. Brucellosis is a febrile disease capable of masquerading as a myriad of entities, both infectious and non-infectious. The disease has a tendency towards chronicity and persistence, becoming a granulomatous disease capable of affecting any organ system.6, 7 The timely and accurate diagnosis of human brucellosis continues to challenge clinicians because of its non-specific clinical features, slow growth rate in blood cultures, and the complexity of its serodiagnosis.8, 9, 10
The clinical management of brucellosis is of particular concern because of high initial treatment failure and relapse rates. The availability of the complete genome sequences of the three main human brucellosis pathogens, Brucella melitensis, Brucella suis, and Brucella abortus, and the advancement of genomics and proteomics will enable scientists to better understand the disease's pathogenic mechanisms. Developments in culture and serological methods, and the availability of advanced molecular detection and typing methods have contributed to improved laboratory diagnosis. These molecular methods could serve as important alternatives to culture methods for the confirmation of the disease and may also provide valuable epidemiological tools to trace sources of infection. Some of the newer diagnostic methods are simple, robust, and affordable, and may prove to be essential in endemic areas with limited financial resources and a limited number of laboratory workers.
Section snippets
Pathogenicity and biology of brucellosis
Brucella species are facultative intracellular bacteria that can multiply within phagocytic cells with human beings as end hosts. Brucella may enter the host via ingestion or inhalation, or through conjunctiva or skin abrasions. After infecting the host, the pathogen becomes sequestered within cells of the reticuloendothelial system. The mechanisms by which brucella enters cells and evades intracellular killing and the host immune system are the subject of much research and debate. In depth
Clinical diagnosis
Human brucellosis has a wide spectrum of clinical manifestations, earning it a place alongside syphilis and tuberculosis as one of the “great imitators”.29, 30, 31, 32, 33 The clinical features of brucellosis depend on the stage of the disease, and the organs and systems involved. Brucella has been reported to compromise the central and peripheral nervous system, and the gastrointestinal, hepatobiliary, genitourinary, musculoskeletal, cardiovascular, and integumentary systems. Historically,
Culture
Blood culture is the gold standard in the diagnosis of bacterial infections, including brucellosis (table 3). Although the biphasic Ruiz-Castañeda system (figure 2) is the traditional method for the isolation of Brucella spp from clinical samples,60, 61, 62 it has now largely been replaced by automated culture systems—such as the lysis centrifugation method58, 59—with increased sensitivity and reduced culture times.55, 56, 57, 63
The sensitivity of blood culture depends on several factors,
Agglutination tests
In the absence of culture facilities, the diagnosis of brucellosis traditionally relies on serological testing with a variety of agglutination tests such as the Rose Bengal test, the serum agglutination test, and the antiglobulin or Coombs' test. In general, the Rose Bengal test is used as a screening test, and positive results are confirmed by the serum agglutination test.38, 77 These agglutination tests are based on the reactivity of antibodies against smooth lipopolysaccharide. These
Applications in the diagnosis of brucellosis
PCR is a convenient tool for the diagnosis of human brucellosis that may improve sensitivity compared with culture.95 Several genus-specific PCR systems using primer pairs that target 16S RNA sequences and the genes of different outer membrane proteins have been developed.96, 97, 98, 99, 100, 101 Each of these PCR systems produces a discrete DNA product, whose length is identical for and specific to all Brucella species. Queipo-Ortuno and co-workers102 found 100% sensitivity and 98·3%
Treatment
WHO has not updated its recommended treatment regimens for brucellosis in more than 20 years,128 despite treatment failure and relapse rates ranging from 4·6% to 24% for the oral regimen and 5% to 8% for the oral/parenteral regimen.129, 130 The cause for such high failure rates remains unclear. Since antibiotic resistance can be discounted as a major factor, it would seem logical to assume that patient compliance is an important factor, especially when one considers the length of treatment and
Special considerations for developing countries
Most of the programmes that have been successful in controlling brucellosis took place in developed nations, with developing countries continuing to bear the burden of this disease.65 Notably, most cases of human brucellosis in non-endemic developed countries result from dairy products imported from endemic areas36, 144, 145, 146 or from patients who import the disease.144, 147 Despite the existence of effective vaccines for cattle (S19) and goats (Rev 1), control efforts in economically poor
Conclusions
Developing countries could benefit from the renewed interest in brucellosis shown by the scientific community. Molecular detection methods such as PCR amplification and genotyping will be powerful epidemiological tools for confirmation of the disease and for identification of sources of infection. These methods do not carry the risk of laboratory-acquired infection that culture techniques do. Additionally, rapid point-of-care assays will enable fast and accessible diagnostic capabilities even
Search strategy and selection criteria
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