Review
Human brucellosis

https://doi.org/10.1016/S1473-3099(07)70286-4Get rights and content

Summary

Human brucellosis still presents scientists and clinicians with several challenges, such as the understanding of pathogenic mechanisms of Brucella spp, the identification of markers for disease severity, progression, and treatment response, and the development of improved treatment regimens. Molecular studies have shed new light on the pathogenesis of Brucella spp, and new technologies have permitted the development of diagnostic tools that will be useful in developing countries, where brucellosis is still a very common but often neglected disease. However, further studies are needed to establish optimum treatment regimens and local and international control programmes. This Review summarises current knowledge of the pathogenic mechanisms, new diagnostic advances, therapeutic options, and the situation of developing countries in regard to human 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

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.

References (154)

  • P Andriopoulos et al.

    Acute brucellosis: presentation, diagnosis, and treatment of 144 cases

    Int J Infect Dis

    (2007)
  • JD Ruiz-Mesa et al.

    Rose Bengal test: diagnostic yield and use for the rapid diagnosis of human brucellosis in emergency departments in endemic areas

    Clin Microbiol Infect

    (2005)
  • M Tsolia et al.

    Clinical features, complications and treatment outcome of childhood brucellosis in central Greece

    J Infect

    (2002)
  • MA Yetkin et al.

    Evaluation of the clinical presentations in neurobrucellosis

    Int J Infect Dis

    (2006)
  • A Cascio et al.

    Use of sulesomab in the diagnosis of brucellar spondylitis

    Clin Microbiol Infect

    (2004)
  • I Giannacopoulos et al.

    Transplacentally transmitted congenital brucellosis due to Brucella abortus

    J Infect

    (2002)
  • A Palanduz et al.

    Brucellosis in a mother and her young infant: probable transmission by breast milk

    Int J Infect Dis

    (2000)
  • M Doganay et al.

    Brucellosis due to blood transfusion

    J Hosp Infect

    (2001)
  • B Ruben et al.

    Person-to-person transmission of Brucella melitensis

    Lancet

    (1991)
  • R Ozturk et al.

    The diagnosis of brucellosis by use of BACTEC 9240 blood culture system

    Diagn Microbiol Infect Dis

    (2002)
  • E Navas et al.

    Faster isolation of Brucella spp from blood by isolator compared with BACTEC NR

    Diagn Microbiol Infect Dis

    (1993)
  • M Doganay et al.

    Human brucellosis: an overview

    Int J Infect Dis

    (2003)
  • K Nielsen et al.

    Serological relationship between cattle exposed to Brucella abortus, Yersinia enterocolitica O:9 and Escherichia coli O157:H7

    Vet Microbiol

    (2004)
  • MA Mantecon et al.

    Utility of an immunocapture-agglutination test and an enzyme-linked immunosorbent assay test against cytosolic proteins from Brucella melitensis B115 in the diagnosis and follow-up of human acute brucellosis

    Diagn Microbiol Infect Dis

    (2006)
  • MR Hasanjani-Roushan et al.

    Application of a rapid and simple brucella-specific IgM and IgG antibody test for the serodiagnosis of brucellosis in a hospital in Iran

    Trans R Soc Trop Med Hyg

    (2005)
  • S Alsubaie et al.

    Acute brucellosis in Saudi families: relationship between brucella serology and clinical symptoms

    Int J Infect Dis

    (2005)
  • BJ Bricker

    PCR as a diagnostic tool for brucellosis

    Vet Microbiol

    (2002)
  • J Godfroid et al.

    From the discovery of the Malta fever's agent to the discovery of a marine mammal reservoir, brucellosis has continuously been a re-emerging zoonosis

    Vet Res

    (2005)
  • JD Colmenero Castillo et al.

    Socioeconomic effects of human brucellosis

    Rev Clin Esp

    (1989)
  • G Pappas et al.

    Brucellosis

    N Engl J Med

    (2005)
  • MR Hasanjani Roushan et al.

    Epidemiological features and clinical manifestations in 469 adult patients with brucellosis in Babol, Northern Iran

    Epidemiol Infect

    (2004)
  • JD Colmenero et al.

    Serology, clinical manifestations and treatment of brucellosis in different age groups

    Infection

    (1990)
  • OF Kokoglu et al.

    Clinical and laboratory features of brucellosis in two university hospitals in southeast Turkey

    Trop Doct

    (2006)
  • F Porte et al.

    Role of the Brucella suis lipopolysaccharide O antigen in phagosomal genesis and in inhibition of phagosome-lysosome fusion in murine macrophages

    Infect Immun

    (2003)
  • J Goldstein et al.

    Lipopolysaccharide (LPS) from Brucella abortus is less toxic than that from Escherichia coli, suggesting the possible use of B abortus or LPS from B abortus as a carrier in vaccines

    Infect Immun

    (1992)
  • C Forestier et al.

    Lysosomal accumulation and recycling of lipopolysaccharide to the cell surface of murine macrophages, an in vitro and in vivo study

    J Immunol

    (1999)
  • A Gross et al.

    In vitro Brucella suis infection prevents the programmed cell death of human monocytic cells

    Infect Immun

    (2000)
  • M Tolomeo et al.

    Monocyte and lymphocyte apoptosis resistance in acute and chronic brucellosis and its possible implications in clinical management

    Clin Infect Dis

    (2003)
  • JE Ugalde et al.

    Evaluation of Brucella abortus phosphoglucomutase (pgm) mutant as a new live rough-phenotype vaccine

    Infect Immun

    (2003)
  • C Guzman-Verri et al.

    The two-component system BvrR/BvrS essential for Brucella abortus virulence regulates the expression of outer membrane proteins with counterparts in members of the Rhizobiaceae

    Proc Natl Acad Sci USA

    (2002)
  • D O'Callaghan et al.

    A homologue of the Agrobacterium tumefaciens VirB and Bordetella pertussis Ptl type IV secretion systems is essential for intracellular survival of Brucella suis

    Mol Microbiol

    (1999)
  • J Celli et al.

    Brucella coopts the small GTPase Sar1 for intracellular replication

    Proc Natl Acad Sci USA

    (2005)
  • ML Boschiroli et al.

    The Brucella suis virB operon is induced intracellularly in macrophages

    Proc Natl Acad Sci USA

    (2002)
  • GN Arenas et al.

    Intracellular trafficking of Brucella abortus in J774 macrophages

    Infect Immun

    (2000)
  • J Pizarro-Cerda et al.

    Brucella abortus transits through the autophagic pathway and replicates in the endoplasmic reticulum of nonprofessional phagocytes

    Infect Immun

    (1998)
  • F Porte et al.

    Early acidification of phagosomes containing Brucella suis is essential for intracellular survival in murine macrophages

    Infect Immun

    (1999)
  • BG Mantur et al.

    Protean clinical manifestations and diagnostic challenges of human brucellosis in adults: 16 years' experience in an endemic area

    J Med Microbiol

    (2006)
  • I Giannakopoulos et al.

    Presentation of childhood brucellosis in western Greece

    Jpn J Infect Dis

    (2006)
  • BG Mantur et al.

    Childhood brucellosis—a microbiological, epidemiological and clinical study

    J Trop Pediatr

    (2004)
  • AH Sohn et al.

    Human neurobrucellosis with intracerebral granuloma caused by a marine mammal Brucella spp

    Emerg Infect Dis

    (2003)
  • Cited by (0)

    View full text