Brucellosis: It is not only Malta!

  • Mile Bosilkovski


Brucellosis is caused by one of the ten species of the genus Brucella, of which only several can cause human disease. It is among the most widespread zoonoses in the World. The disease is transmitted to humans by contact with fluids from infected animals or derived food products. The mechanisms by which brucellae manifest their pathogenic features are complex. Lipopolysaccharide (LPS) has a role in evasion of the infected cell and is essential for intracellular survival. Brucellae invade and persist in the host via inhibition of programmed cell death. Despite the high degree of DNA homology within the Brucella genus, molecular typing schemes based on the use of multiple locus variable number of tandem repeats analysis (MLVA) have proven to be able to differentiate unrelated Brucella isolates which could not be differentiated by classical microbiological methods. Due to its high discriminatory power, MLVA has been successfully used for identification of human outbreaks related with a same source of infection, as well as for confirmation of relapse and laboratory acquired infection. Prevention of human brucellosis may be based on prevention of transmission from animal reservoirs to humans and control or eradication of the infection in the reservoir population. Control and prevention programs in animal brucellosis require effective collaboration between all sections of the community and must be properly planned, coordinated and resourced.

In spite of the huge knowledge on the disease until now, many aspects are not yet clarified, like actual taxonomy and the durability and solidness of the immune response after the disease. Also, there is the need of development of better diagnostic techniques and therapeutical options. The production of an effective and acceptable vaccine for use in humans remains as a special challenge in this field.


Chronic Fatigue Syndrome Complement Fixation Test Francisella Tularensis Human Brucellosis Brucella Species 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Al Dahouk S, Nockler K (2011) Implications of laboratory diagnosis on brucellosis therapy. Expert Rev Anti Infect Ther 9:833–845. doi:10.1586/eri.11.55PubMedCrossRefGoogle Scholar
  2. Al Dahouk S, Tomaso H, Nockler K, Neubauer H, Frangoulidis D (2003) Laboratory-based diagnosis of brucellosis—a review of the literature. Part II: serological tests for brucellosis. Clin Lab 49:577–589PubMedGoogle Scholar
  3. Al Dahouk SN, Hagen RM et al (2005a) Human brucellosis in a nonendemic country: a report from Germany, 2002 and 2003. Eur J Clin Microbiol Infect Dis 24:450–456Google Scholar
  4. Al Dahouk SH, Scholz HC et al (2005b) Failure of a short-term antibiotic therapy for human brucellosis using ciprofloxacin. A study on in vitro susceptibility of Brucella strains. Chemotherapy 51:352–356Google Scholar
  5. Al Dahouk SF, Scholz HC et al (2007) Evaluation of Brucella MLVA typing for human brucellosis. J Microbiol Methods 69:137–145PubMedCrossRefGoogle Scholar
  6. Al Dahouk SS, Karges W et al (2010) Differential phenotyping of Brucella species using a newly developed semi-automated metabolic system. BMC Microbiol 10:269. doi: 10.1186/1471-2180-10-269PubMedCentralPubMedCrossRefGoogle Scholar
  7. Al-Hajjaj MS, Al-Kassimi FA, Al-Mobeireek AF, Alzeer AH (2001) Progressive rise of Mycobacterium tuberculosis resistance to rifampicin and streptomycin in Riyadh, Saudi Arabia. Respirology 6:317–322PubMedCrossRefGoogle Scholar
  8. Al-Shamahy HA, Wright SG (1998) Enzyme-linked immunosorbent assay for brucella antigen detection in human sera. J Med Microbiol 47:169–172PubMedCrossRefGoogle Scholar
  9. Araj GF (1999) Human brucellosis: a classical infectious disease with persistent diagnostic challenges. Clin Lab Sci 12:207–212PubMedGoogle Scholar
  10. Araj GF, Kattar MM (2003) Rapid diagnosis of human brucellosis using the bact/alert continuous culture monitoring system. Abstr 103rd Annu Meet Am Soc Microbiol abstract C-200Google Scholar
  11. Ariza J, Pellicer T, Pallares R, Foz A, Gudiol F (1992) Specific antibody profile in human brucellosis. Clin Infect Dis 14:131–140PubMedCrossRefGoogle Scholar
  12. Ariza J, Bosilkovski M, Cascio A, Colmenero JD, Corbel MJ, Falagas ME et al (2007) Perspectives for the treatment of brucellosis in the 21st century: the Ioannina recommendations. PLoS Med 4:e317. doi:10.1371/journal.pmed.0040317PubMedCentralPubMedCrossRefGoogle Scholar
  13. Baldi PC, Miguel SE, Fossati CA, Wallach JC (1996) Serological follow-up of human brucellosis by measuring IgG antibodies to lipopolysaccharide and cytoplasmic proteins of Brucella species. Clin Infect Dis 22:446–455PubMedCrossRefGoogle Scholar
  14. Baldwin CL, Parent M (2002) Fundamentals of host immune response against brucella abortus: what the mouse model has revealed about control of infection. Vet Microbiol 90:367–382PubMedCrossRefGoogle Scholar
  15. Banai M (2010) Insights into the problem of B. Melitensis and rationalizing a vaccination programme in Israel. Prilozi 31:167–180PubMedGoogle Scholar
  16. Barquero-Calvo E, Chaves-Olarte E, Weiss DS, Guzman-Verri C, Chacon-Díaz C, Rucavado A et al (2007) Brucella abortus uses a stealthy strategy to avoid activation of the innate immune system during the onset of infection. PLoS One 2:e631. doi:10.1371/journal.pone.0000631PubMedCentralPubMedCrossRefGoogle Scholar
  17. Bertrand A (1994) Antibiotic treatment of brucellosis. Presse Med 23:1128–1131PubMedGoogle Scholar
  18. Blasco JM (2010) Control and eradication strategies for brucella melitensis infection in sheep and goats. Prilozi 31:145–165PubMedGoogle Scholar
  19. Bosilkovski M, Krteva L, Caparoska S, Dimzova M (2004) Osteoarticular involvement in Brucellosis: study of 196 cases in the Republic of Macedonia. Croat Med J 45:727–733PubMedGoogle Scholar
  20. Bosilkovski M, Krteva L, Dimzova M, Kondova I (2007) Brucellosis in 418 patients from the Balkan Peninsula: exposure-related differences in clinical manifestations, laboratory test results, and therapy outcome. Int J Infect Dis 11:342–347PubMedCrossRefGoogle Scholar
  21. Bosilkovski M, Katerina S, Zaklina S, Ivan V (2010a) The role of Brucellacapt test for follow-up patients with brucellosis. Comp Immunol Microbiol Infect Dis 33:435–442. doi:10.1016/j.cimid.2009.06.001Google Scholar
  22. Bosilkovski M, Krteva L, Dimzova M, Vidinic I, Sopova Z, Spasovska K (2010b) Human brucellosis in Macedonia—10 years of clinical experience in endemic region. Croat Med J 51:327–336Google Scholar
  23. Bricker BJ, Halling SM (1994) Differentiation of Brucella abortus bv. 1, 2, and 4, Brucella melitensis, Brucella ovis, and Brucella suis bv. 1 by PCR. J Clin Microbiol 32:2660–2666PubMedCentralPubMedGoogle Scholar
  24. Bricker BJ, Ewalt DR (2005) Evaluation of the HOOF-Print assay for typing Brucella abortus strains isolated from cattle in the United States: results with four performance criteria. BMC Microbiol 5:37. doi:10.1186/1471-2180-5-37PubMedCentralPubMedCrossRefGoogle Scholar
  25. Bricker BJ, Ewalt DR, Halling SM (2003) Brucella ‘HOOF-Prints’: strain typing by multi-locus analysis of variable number tandem repeats (VNTRs). BMC Microbiol 3:15. doi:10.1186/1471-2180-3-15PubMedCentralPubMedCrossRefGoogle Scholar
  26. Buchanan TM, Sulzer CR, Frix MK, Feldman RA (1974) Brucellosis in the United States, 1960–1972. An abattoir-associated disease. Part II. Diagnostic aspects. Medicine (Baltimore) 53:415–425CrossRefGoogle Scholar
  27. Chevrel J, Riojas A, Lafargues JP, Sarlangue J, Barbier R (2001) Osteoarticular brucellosis and signs of autoimmunity. Arch Pediatr 8:834–837PubMedCrossRefGoogle Scholar
  28. Comerci DJ, Altabe S, de Mendoza D, Ugalde RA (2006) Brucella abortus synthesizes phosphatidylcholine from choline provided by the host. J Bacteriol 188:1929–1934PubMedCentralPubMedCrossRefGoogle Scholar
  29. Corbel MJ (1997) Brucellosis: an overview. Emerg Infect Dis 3:213–221PubMedCentralPubMedCrossRefGoogle Scholar
  30. Cosivi O (1998) Animal brucellosis surveillance and control in the mediterranean and middle east countries. In: The MZCP report on the third workshop on human and animal Brucellosis Epidemiological Surveillance in the MZCP countries. Damascus, Syrian Arab RepublicGoogle Scholar
  31. Cutler SJ, Whatmore AM, Commander NJ (2005) Brucellosis-new aspects of an old disease. J Appl Microbiol 98:1270–1281PubMedCrossRefGoogle Scholar
  32. El-Tras WF, Tayel AA, Eltholth MM, Guitian J (2010) Brucella infection in fresh water fish: evidence for natural infection of Nile catfish, Clarias gariepinus, with Brucella melitensis. Vet Microbiol 141:321–325. doi:10.1016/j.vetmic.2009.09.017PubMedCrossRefGoogle Scholar
  33. Falagas ME, Bliziotis IA (2006) Quinolones for treatment of human brucellosis: critical review of the evidence from microbiological and clinical studies. Antimicrob Agents Chemother 50:22–33PubMedCentralPubMedCrossRefGoogle Scholar
  34. Fiori PL, Mastrandrea S, Rappelli P, Cappuccinelli P (2000) Brucella abortus infection acquired in microbiology laboratories. J Clin Microbiol 38:2005–2006PubMedCentralPubMedGoogle Scholar
  35. Gad El-Rab MO, Kambal AM (1998) Evaluation of a Brucella enzyme immunoassay test (ELISA) in comparison with bacteriological culture and agglutination. J Infect 36:197–201PubMedCrossRefGoogle Scholar
  36. Ganguly R (1984) Brucella: brucellosis. In: Waldman RH, Kluge RM (eds) Infectious diseases. Medical Examination Publishing Co, New York, pp 807–811Google Scholar
  37. Garcia-Yoldi D, Marin CM, de Miguel MJ, Munoz PM, Vizmanos JL, Lopez-Goni I (2006) Multiplex PCR assay for the identification and differentiation of all Brucella species and the vaccine strains Brucella abortus S19 and RB51 and Brucella melitensis Rev1. Clin Chem 52:779–781. doi:10.1373/clinchem.2005.062596PubMedCrossRefGoogle Scholar
  38. Gazapo E, Gonzalez Lahoz J, Subiza JL, Baquero M, Gil J, de la Concha EG (1989) Changes in IgM and IgG antibody concentrations in Brucellosis over time: importance for diagnosis and follow-up. J Infect Dis 159:219–225PubMedCrossRefGoogle Scholar
  39. Ghanem YM, El-Khodery SA, Saad AA, Abdelkader AH, Heybe A, Musse YA (2009) Seroprevalence of camel brucellosis (Camelus dromedarius) in Somaliland. Trop Anim Health Prod 41:1779–1786. doi:10.1007/s11250-009-9377-9PubMedCrossRefGoogle Scholar
  40. Godfroid J, Cloeckaert A, Liautard JP, Kohler S, Fretin D, Walravens K et al (2005) 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 36:313–326PubMedCrossRefGoogle Scholar
  41. Godfroid J, Nielsen K, Saegerman C (2010) Diagnosis of Brucellosis in livestock and wildlife. Croat Med J 51:296–305. doi:10.3325/cmj.2010.51.296PubMedCentralPubMedCrossRefGoogle Scholar
  42. Godfroid J, Scholz HC, Barbier T, Nicolas C, Wattiau P, Fretin D et al (2011) Brucellosis at the animal/ecosystem/human interface at the beginning of the 21st century. Prev Vet Med 102:118–131. doi:10.1016/j.prevetmed.2011.04.007PubMedCrossRefGoogle Scholar
  43. Gomez MC, Nieto JA, Rosa C, Geijo P, Escribano MA, Munoz A et al (2008) Evaluation of seven tests for the diagnosis of human brucellosis in an endemic area. Clin Vaccine Immunol 15:1031–1033PubMedCentralPubMedCrossRefGoogle Scholar
  44. Gorvel JP (2008) Brucella: a Mr “Hide” converted into Dr Jekyll. Microbes Infect 10:1010–1013. doi:10.1016/j.micinf.2008.07.007PubMedCrossRefGoogle Scholar
  45. Gorvel JP, Moreno E (2002) Brucella intracellular life: from invasion to intracellular replication. Vet Microbiol 90:281–297PubMedCrossRefGoogle Scholar
  46. Gotuzzo E (1999) Brucellosis. In: Guerrant RL, Walker DH, Weller PF (eds) Tropical infectious diseases. Principles, pathogens, and practice. Churchill Livingstone, Philadelphia, pp 498–505Google Scholar
  47. Gotuzzo E, Carillo C (2004) Brucella. In: Gorbach SL, Bartlett JG, Blacklow NR (eds) Infectious diseases, 3rd edn. Lippincott Williams & Wilkins, Philadelphia, pp 1837–1845Google Scholar
  48. Gotuzzo E, Carrillo C, Guerra J, Llosa L (1986) An evaluation of diagnostic methods for brucellosis—the value of bone marrow culture. J Infect Dis 153:122–125PubMedCrossRefGoogle Scholar
  49. Issa H, Jamal M (1999) Brucellosis in children in south Jordan. East Mediterr Health J 5:895–902PubMedGoogle Scholar
  50. Jergefa T, Kelay B, Bekana M, Teshale S, Gustafson H, Kindahl H (2009) Epidemiological study of bovine brucellosis in three agro-ecological areas of central Oromiya, Ethiopia. Rev Sci Tech 28:933–943PubMedGoogle Scholar
  51. Kasimova HA, Rentzova MM (1979) Reinfection in brucellosis. Zh Mikrobiol Epidemiol Immunobiol 6:105–109Google Scholar
  52. Kumar A (2010) Brucellosis: need of public health intervention in rural India. Prilozi 31:219–231PubMedGoogle Scholar
  53. Lamontagne J, Beland M, Forest A, Cote-Martin A, Nassif N, Tomaki F et al (2010) Proteomics-based confirmation of protein expression and correction of annotation errors in the Brucella abortus genome. BMC Genomics 11:300. doi:10.1186/1471-2164-11-300PubMedCentralPubMedCrossRefGoogle Scholar
  54. Le Fleche PJ, Denoeud F et al (2006) Evaluation and selection of tandem repeat loci for a Brucella MLVA typing assay. BMC Microbiol 6:9. doi:10.1186/1471-2180-6-9PubMedCentralPubMedCrossRefGoogle Scholar
  55. Lindquist D, Chu MC, Probert WWS (2007) Francisella and Brucella. In: Murray PR, Baron EJO, Jorgensen JH, Landry ML, Pfaller MA (eds) Manual of clinical microbiology, 9th edn. ASM, Washington, pp 824–834Google Scholar
  56. Mantur BG, Amarnath SK, Shinde RS (2007) Review of clinical and laboratory features of human brucellosis. Indian J Med Microbiol 25:188–202PubMedCrossRefGoogle Scholar
  57. Marianelli C, Petrucca A, Pasquali P, Ciuchini F, Papadopoulou S, Cipriani P (2008) Use of MLVA-16 to trace the source of a laboratory-acquired Brucella infection. J Hosp Infect 68:274–276. doi:10.1016/j.jhin.2008.01.003PubMedCrossRefGoogle Scholar
  58. Melzer F, Al Dahouk S, Neubauer H, Mettenleiter TC (2007) Increasing incidence in neighboring EU States. Is brucellosis about to become a travel medicine problem? MMW Fortschr Med 149:46–47PubMedGoogle Scholar
  59. Memish ZA, Almuneef M, Mah MW, Qassem LA, Osoba AO (2002) Comparison of the Brucella standard agglutination test with the ELISA IgG and IgM in patients with Brucella bacteremia. Diagn Microbiol Infect Dis 44:129–132PubMedCrossRefGoogle Scholar
  60. Morelli D (1998) General considerations on the epidemiological surveillance and control of brucellosis. In: The MZCP report on the third workshop on human and animal Brucellosis Epidemiological Surveillance in the MZCP countries. Damascus, Syrian Arab RepublicGoogle Scholar
  61. Moreno E, Moriyon I (2002) Brucella melitensis: a nasty bug with hidden credentials for virulence. Proc Natl Acad Sci U S A 99:1–3PubMedCentralPubMedCrossRefGoogle Scholar
  62. Morgan WJ, MacKinnon DJ, Lawson JR, Cullen GA (1969) The rose bengal plate agglutination test in the diagnosis of brucellosis. Vet Rec 85:636–641PubMedGoogle Scholar
  63. Muma JB, Samui KL, Oloya J, Munyeme M, Skjerve E (2007) Risk factors for brucellosis in indigenous cattle reared in livestock-wildlife interface areas of Zambia. Prev Vet Med 80:306–317PubMedCrossRefGoogle Scholar
  64. Navarro E, Segura JC, Castano MJ, Solera J (2006) Use of real-time quantitative polymerase chain reaction to monitor the evolution of Brucella melitensis DNA load during therapy and post-therapy follow-up in patients with brucellosis. Clin Infect Dis 42:1266–1273PubMedCrossRefGoogle Scholar
  65. Neubauer H (2010) Brucellosis: new demands in a changing world. Prilozi 31:209–217PubMedGoogle Scholar
  66. Nicoletti P (2010) Brucellosis: past, present and future. Prilozi 31:21–32PubMedGoogle Scholar
  67. Nielsen K, Yu WL (2010) Serological diagnosis of brucellosis. Prilozi 31:65–89PubMedGoogle Scholar
  68. Pappas G, Akritidis N, Bosilkovski M, Tsianos E (2005) Brucellosis. N Engl J Med 352:2325–2336PubMedCrossRefGoogle Scholar
  69. Pappas G, Panagopoulou P, Christou L, Akritidis N (2006a) Brucella as a biological weapon. Cell Mol Life Sci 63:2229–2236Google Scholar
  70. Pappas G, Papadimitriou P, Christou L, Akritidis N (2006b) Future trends in human brucellosis treatment. Expert Opin Investig Drugs 15:1141–1149Google Scholar
  71. Pappas G, Papadimitrou PH, Akritidis N, Christou L, Tsianos EV (2006c) The new global map of human brucellosis. Lancet Infect Dis 6:91–99Google Scholar
  72. Payne DJ (1974) Chronic brucellosis. Br Med J 2:221–222PubMedCentralPubMedCrossRefGoogle Scholar
  73. Robinson A (1998) Critical issues in designing and evaluating a surveillance system. In: The MZCP report on the third workshop on human and animal Brucellosis Epidemiological Surveillance in the MZCP countries. Damascus, Syrian Arab RepublicGoogle Scholar
  74. Roushan MR, Amiri MJ, Laly A, Mostafazadeh A, Bijani A (2010) Follow-up standard agglutination and 2-mercaptoethanol tests in 175 clinically cured cases of human brucellosis. Int J Infect Dis 14:e250–e253. doi:10.1016/j.ijid.2009.05.008PubMedCrossRefGoogle Scholar
  75. Simpson WM (1941) Brucellosis. Bull NY Acad Med 17:592–617Google Scholar
  76. Skendros P, Sarantopoulos A, Tselios K, Boura P (2008) Chronic brucellosis patients retain low frequency of CD4+ T-lymphocytes expressing CD25 and CD28 after Escherichia coli LPS stimulation of PHA-cultured PBMCs. Clin Dev Immunol 2008:327346. doi:10.1155/2008/327346PubMedCentralPubMedCrossRefGoogle Scholar
  77. Skendros P, Pappas G, Boura P (2011) Cell-mediated immunity in human brucellosis. Microbes Infect 13:134–142. doi:10.1016/j.micinf.2010PubMedCrossRefGoogle Scholar
  78. Sohn AH, Probert WS, Glaser CA, Gupta N, Bollen AW, Wong JD et al (2003) Human neurobrucellosis with intracerebral granuloma caused by a marine mammal Brucella spp. Emerg Infect Dis 9:485–488PubMedCentralPubMedCrossRefGoogle Scholar
  79. Solera J, Rodriguez-Zapata M, Geijo P, Largo J, Paulino J, Saez L et al (1995) Doxycycline-Rifampin versus Doxycycline-Streptomycin in treatment of human Brucellosis due to Brucella melitensis. GECMEI group. Antimicrob Agents Chemother 39:2061–2067Google Scholar
  80. Stoffregen WC, Olsen SC, Jack Wheeler C, Bricker BJ, Palmer MV, Jensen AE et al (2007) Diagnostic characterization of a feral swine herd enzootically infected with Brucella. J Vet Diagn Invest 19:227–237PubMedCrossRefGoogle Scholar
  81. Verger JM, Grimont F, Grimont PAD, Grayon M (1985) Brucella, a monospecific genus as shown by deoxyribonucleic-acid hybridization. Int J Syst Bacteriol 35:292–295CrossRefGoogle Scholar
  82. Vrioni G, Pappas G, Priavali E, Gartzonika C, Levidiotou S (2008) An eternal microbe: Brucella DNA load persists for years after clinical cure. Clin Infect Dis 46:e131–e136. doi:10.1086/588482PubMedCrossRefGoogle Scholar
  83. World Health Organization (2006) Brucellosis in human and animals. World Health Organization, Geneva, WHO/CDS/EPR/2006.7Google Scholar
  84. Wright SG (2000) Brucellosis. In: Strickland GT (ed) Hunter’s tropical medicine and emerging infectious diseases, 8th edn. Saunders Company, Philadelphia, pp 416–420Google Scholar
  85. Yagupsky P (1999) Detection of Brucellae in blood cultures. J Clin Microbiol 37:3437–3442PubMedCentralPubMedGoogle Scholar
  86. Young EJ (1995) An overview of human brucellosis. Clin Infect Dis 21:283–290PubMedCrossRefGoogle Scholar
  87. Zhan Y, Cheers C (1995) Endogenous interleukin-12 is involved in resistance to brucella abortus infection. Infect Immun 63:1387–1390PubMedCentralPubMedGoogle Scholar
  88. Zhan Y, Liu Z, Cheers C (1996) Tumor necrosis factor alpha and interleukin-12 contribute to resistance to the intracellular bacterium Brucella abortus by different mechanisms. Infect Immun 64:2782–2786PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  1. 1.Faculty of MedicineUniversity Clinic for Infectious Diseases and Febrile Conditions, University “Ss Cyril and Methodius”SkopjeRepublic of Macedonia

Personalised recommendations