国立感染症研究所

 

 The Topic of This Month Vol. 33, No. 7 (No. 389)


 Brucellosis in Japan, April 1999-March 2012
(IASR 33: 183-185, July 2012)

Brucellosis, known as “undulant fever” or “Malta fever”, is a zoonotic disease caused by Brucella  spp.  Brucellosis is a category IV notifiable infectious disease under the Law Concerning Prevention of Infectious Diseases and Medical Care for Patients of Infections (Infectious Diseases Control Law) enforced on April 1, 1999 (http://www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou11/01-04-28.html).  It is designated also as domestic animal infectious disease under the Act on Domestic Animal Infectious Diseases Control.

Brucella  spp. is an aerobic Gram-negative coccobacillus, but the fresh isolate is more like a Gram-negative coccus in shape (Fig. 1).  It has no flagella, does not form spore and is a facultative intracellular parasite.nbsp;nbsp;Species pathogenic to humans are, in descending order of pathogenicity, B. melitensis , B. suis , B. abortus  and B. canis  (Table 1), among which B. melitensis , B. abortus  and B. suis  are livestock pathogens.

On account of their potential use for bioterrorism, B. melitensis , B. suis , B. abortus  and B. canis  are in the list of the group 3 select agents* under Infectious Diseases Control Law in Japan (IASR 28: 185-188, 2007).  B. melitensis , B. suis  and B. abortus  are also in the list of US CDC/USDA's overlap select agents (http://www.cdc.gov/phpr/documents/DSAT_brochure_July2011.pdf).  It is important to note that B. melitensis , B. suis  and B. abortus  are under strict regulation so as to prevent misuse for terrorism not only against humans but also against livestock.

Infection Route and Symptoms: Main route of human infection is ingestion of milk and milk products derived from infected animals, and sometimes ingestion of meat.  Contact with infected animals, their carcasses, aborted fetuses and placentas, as well as, inhalation of bacteria are alternative routes of infection.  Very rarely, infection through sexual contact with infected persons and through breastfeeding may occur (see p. 186 of this issue).  Incubation period is generally 1-3 weeks but can be as long as months.  Clinical symptom includes flu-like symptoms, i.e., general aching, fatigue, chills and sweats, associated with continued, intermittent or irregular fever of variable duration.  However, osteoarticular complications are the most frequent.  Complications of gastrointestinal tract, respiratory tract, central nervous system and cardiovascular system are also known (see p. 187 of this issue).  Endocarditis is the main cause of the death due to brucellosis.  The disease may last for several days, months or even years.  Infection caused by B. canis  is generally mild, and the patients often do not notice the infection.

Incidence: Every year, around 500,000 new patients are reported in the world, mainly from China, India, West Asia, Middle East, Mediterranean Region, Africa and Latin America.  Increase of patients is the current trend; the recent increase of brucellosis caused by B. melitensis  in China is remarkable (see p. 192 of this issue).  In countries that successfully controlled livestock brucellosis, brucellosis is found among those who visited or returned from abroad (see pp. 187 and 193 of this issue), those who consumed imported contaminated milk products, and those in high risk groups, such as, dairy farmers, veterinarians, butcheries, and laboratory technicians.

In Japan, the first brucellosis case was reported in 1933 (see p. 186 of this issue for the situation before 1999).  Since April 1999 when brucellosis became a notifiable disease, 19 brucellosis cases have been reported (Table 2 ).  Among them, seven were due to livestock Brucella  spp. (B. melitensis , 5 cases; B. abortus , 2 cases), which are considered imported cases (Table 2a) as there is no endemic circulation of livestock Brucella  spp. now in Japan (see p. 191 of this issue).  Among recent cases of them, foreigner residents in Japan were found infected after temporary stay in the brucellosis-endemic mother country (see p. 187 of this issue and IASR 33: 101-102, 2012).

Remaining twelve brucellosis cases were due to B. canis  (Table 2b) whose prevalence in dogs in Japan is currently ≈3%.  Diagnosis was based mostly on positive detection of antibody.  Bacteria were successfully isolated from patients in acute phase among employees of a dog breeding facility affected by the brucellosis epidemic (see p. 189 of this issue).

Clinical and Laboratory Diagnosis: Clinical symptom of brucellosis is uncharacteristic and brucellosis is often found among “fever of unknown origin”.  Therefore, if brucellosis is suspected, it is important to ask the patients about possible chance of Brucella  infection, such as, their history of travel to endemic countries, consumption of foods abroad and contact with animals.  As Brucella spp. is notorious for the past history of laboratory infection, physicians should warn the clinical laboratory against the potential danger of the specimens (see p. 187 of this issue).  Notification of brucellosis requires isolation/identification of Brucella  spp. or detection of antibody by in vitro agglutination test (http://www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou11/01-04-28.html).

1) Antibody Test: Brucellosis usually follows chronic course.  Therefore symptomatic cases are usually positive for the antibody.  In addition, on account of intracellular parasitic nature of the bacteria, antibody-positive cases are very often pathogen carriers.  Therefore, the diagnostic value of the serum antibody test is very high.  Usually, the serum antibody test is the tube agglutination test using killed whole bacteria as antigen.  It should be taken into account that antibodies against Francisella tularensis (causative agent of tularemia), Yersinia enterocolitica  and Vibrio cholerae  sometimes show cross-reaction with Brucella  antigen.  The serum test can be conducted in commercial laboratories, whose expense is covered by public medical insurance.

2) Isolation and Identification of Bacteria: Culture for at least 21 days using blood culture bottles, with subculture onto the blood agar twice a week, is recommended.  Bacterial growth is very slow and the colony size is small at most 2 mm after 3 days of culture.  Suspected colonies are further tested for Gram staining and for motility and biochemical characters.  PCR gene amplification is useful for identification.  The target gene for amplification is most frequently a gene encoding cell surface BCSP31 protein, which is conserved in all the Brucella spp.  16S rRNA and IS711 genes are also used as target.  National Institute of Infectious Diseases is conducting differential diagnosis of the above four human pathogen Brucella  spp. using combinatorial-PCR method (http://www.niid.go.jp/niid/images/lab-manual/brucellosis_2012.pdf).

Therapy: As therapy with one antibiotic easily results in therapeutic failure, combination of two or more antibiotics is recommended.  The 1986 WHO Expert Consultation recommends combination of doxycycline (DOXY) and rifampicin (RFP).  However, as RFP increases clearance of DOXY from circulating blood, combination of DOXY and streptomycin (SM) is recommended for treatment of patients with myelitis and other complications.  More recently, combination with gentamycin (GM) whose side effect is lower than SM, i.e., combination of DOXY and GM or that of DOXY, GM and RFP is recommended (http://www.who.int/csr/resources/publications/deliberate/WHO_CDS_EPR_2006_7/en and EJ Young. Brucella species. In: Principles and Practice of Infectious Diseases Seventh edition, Mandell GL, Bennet JE, Dolin R eds, Churchill Livingstone, 2010).  For infants, combination of sulfamethoxazole-trimethoprim (ST) and RFP (or GM) and for pregnant women, combination of ST and RFP are used.

Prevention: For consumer protection, appropriate pasteurization of milk and milk products is the most essential.  From the public health viewpoint, veterinary measures for elimination of carrier animals by vaccination and “test and slaughter” measures are the most effective (see p. 191 of this issue and IASR 16: 127, 1995).  Many countries and regions have successfully reduced human brucellosis by these measures.  No effective vaccine for human use has been developed. 

Additional Comments: B. canis  infection is limited almost to persons who have higher chance of contacting infected dog blood, placenta or aborted pups, i.e., dog breeder, veterinarians and related professions.  As for the livestock brucellosis, Japan has already eradicated them.  However, it is one of the serious zoonotic diseases abroad needing preventive actions against “importation”.  Those who visit brucellosis endemic countries should be aware of the risk of Brucella  infection through ingestion of insufficiently pasteurized milk or milk products and undercooked meat and also through contact with infected animals.


 *Note: Group 3 select agent: Its possession requires notification to and approval by Minister of Health Labour and Welfare as well as a laboratory facility that satisfies the condition required for use of group 3 select agents.  For hospital or other diagnostic laboratories, when they happened to possess a group 3 select agent during their professional practice, they should stop the possession within 10 days; they should destroy the agent by sterilization or transfer the agent to a laboratory, which is authorized to possess the group 3 agents (http://www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou17/03.html).


 

Copyright 1998 National Institute of Infectious Diseases, Japan

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