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1.5.Epidemiology of Brucellosis 1.5.1 Important factors for transmission : Important factors for transmission include:

1. Risk of transmission is affected by the degree of association between potentially infectious and susceptible animals. To become infected, a susceptible animal must come in contact with an infectious animal or discharges that contain a sufficient dose of viable Brucella organisms; 2. Separation in space and time reduces the potential for Relevant aspects of Brucella pathogenesis have been intensively investigated in both cellular and animal models; 3. The risk of B. abortus transmission increases as the number and density of infectious animals in the host population increases. Conversely, the risk is reduced when the number of infectious animals is reduced through reduction in animal crowding, reduction in population size, and vaccination ;

4. The risk of transmission increases as the number of susceptible animals that may associate with infectious animals increases ; 5. The risk of transmission is affected by environmental factors. Outside of its host, the Brucella organisms have limited viability. Discharges remain infectious for longer periods during cold weather. Direct sunlight quickly kills the organism. Scavenging by wildlife reduces the occurrence of infectious tissues, but scavengers may also transport infected tissues ; 6. The risk of transmission is affected by the class of the infectious animals. The available evidence indicates that, risk of B. abortus transmission from bison to cattle is almost certainly confined to contamination by a birth event by adult females. However, limited data exist documenting the presence of B. abortus organisms in bison semen. Therefore, the risk of transmission from bull bison, though logically small, cannot be entirely eliminated based on existing information. Neutered animals are unlikely to transmit the disease ; 7. The risk of transmission may be reduced by vaccination, neutering, and herd management ; 8. Susceptibility varies among species. Some animals also are naturally resistant to infection; 9. Areas where transmission could occur are winter and spring ranges for elk and bison in proximity to the feedground complex. Neither species is in contact with cattle on either the Elk Refuge or the state feedgrounds (WHO 1986)

1.5.2 Routes of Infection Brucella infection may occur by digestive route, inhalation or through nasal mucosa or conjunctiva . After crossing the mucosal barrier, the organisms reach regional lymph nodes, replicate in macrophages, and establish a systemic and persistent infection. A bacteremic phase of infection results in colonization of the spleen, liver, and osteoarticular tissues, and depending on the Brucella species and host, it may also colonize the mammary gland and the reproductive system( Ko et al.2003) . Brucella sp. infection, experimental inoculation is performed mostly through three routes: intraperitoneal, digestive, or nasal (aerosol). The intraperitoneal route of infection is frequently used to establish a persistent infection in the mouse, as it results in a rapid systemic distribution of Brucella sp. and high bacterial loads in the spleen and liver (Enright et al.1990). The digestive tract is the main route of Brucella infection in humans, which is associated with the ingestion of unpasteurized milk and dairy products from infected animals.

Intestinal infection allow the identification of bacterial pathogenic factors that are required to establish infection through the digestive tract . 

Brucellosis may also be acquired by inhalation. The number of organisms required to establish the infection in humans by this route is low, with an estimated infectious dose of 10 to 100 organisms for humans by aerosol . Therefore, Brucella sp. is considered a potential biological warfare agent . infection by the nasal route (aerosol) may be used to evaluate vaccines candidates and therapeutics for human brucellosis . A recent study demonstrated that female immunized with B. melitensis attenuated strain Rev1 followed by aerosol infection with 104 CFU of B. melitensis had a decreased bacterial load in the spleen, suggesting that this animal is a suitable model to evaluate protection during Brucella sp. aerosol infection . Infection by aerosol with B. melitensis or B. abortus resulted in high bacterial load in the spleen, liver, and lungs.

aerosol infection with pathogenic species of Brucella (FAO/WHO ;.1986) 

No histopathological lesions have been described in the lung, but high bacterial loads are recovered from the lungs at early time points during infection, which indicates that Brucella sp. is able to replicate in this organ without eliciting innate immune responses .

Additionally, Brucella sp. infection  may be established due to coinfection through the conjunctiva or oral mucosa. Therefore, it is essential to critically evaluate the results of Brucella sp. aerosol infection . 

An open question in the field is the identity of the Brucella factors that are important for its efficient infection of the respiratory tract (Lang et al.1994). 1.6 Pathogenesis

Brucella spp are facultative intracellular bacteria that have the ability to avoid the killing mechanism and proliferate within the macrophages, similar to other intracellular pathogens. To be a successful infectious agent, Brucella requires four steps: adherence, invasion, establishment, and dissemination within the host

Brucella can infect macrophages. There by indicating direct host cell contact which allows adherence and invasion as well as antibody or complement mediated phagocytises. In the macrophages. Brucella cells survive and multiply, inhibiting phagosome–lysososme fusion. Finally, the accumulated bacteria are disseminated to other host cells ( Ko et al.2003).

Smooth LPS has a role in cell entry and immune evasion of the infected cell. It also alters the capacity of the infected cell to present foreign antigens, preventing the attack and killing the infected cell with the help of the immune system ( Araya et al.1989).

1.7Diagnosis Brucellosis imitates variety of clinical entities. Clinicians practicing must be familiar with this disease and develop a high degree of clinical suspicion based on epidemiological information.Otherwise because of the deceptive nature, the disease may be easily misdiagnosed or diagnosis may be delayed thereby making clinical diagnosis a challenge. 1.7.1 Laboratory diagnosis Diagnostic tools include isolation and identification of Brucellae from clinical samples, detection of antigen, genome, and antibodies. Culture: Blood culture provides definite proof of brucellosis but may not provide a positive result for all patients. Lysis centrifugation and blood clot culture techniques have yielded encouraging results in recent reports in terms of sensitivity and rapidity(Mantur et al 2007). The modern automated blood culture systems have improved the speed of detection. Although bone marrow cultures are considered the gold standard in some studies, results have not been universally reproducible In such cases, bacteremia might also be maintained from other sources of the reticulo-endothelial system. Perhaps, this could be the reason for the discrepancy in the results of blood and bone marrow culture (Shehabi et al 1990). Antigen detection: Antigen detection by enzyme linked immunosorbent assay (ELISA) as an acceptable alternative to blood culture. Although antigen detection methods are potentially useful but have not been validated (Wright 1998). Genome detection Polymerase chain reaction (PCR)has been explored for the rapid detection and confirmation of Brucella. Molecular characterization techniques are very useful tools for differentiating Brucella spp., especially follow-up testing of unusual phenotypic results. Antibody detection: The limitations of a forementioned tools make serology directed against antibody detection the most useful tool. Antibodies usually begin to appear in the blood at the end of the first week of the disease, IgM appearing first followed by IgG. a. Agglutination tests: RBPTis of value as a screening test especially in high risk rural areas where it is not possible to perform SAT. Whenever possible, a serum that gives a positive result should be confirmed by a more specific test. RBPT also plays a great role in the rapid confirmation of neurobrucellosis, arthritis, epididymoorchitis, hydrocele Brucellosis due to Brucella if the neat is positive in cerebrospinal fluid, synovial fluid, testicular fluid /semen and hydrocele fluid respectively. SAT remains the most popular and yet used worldwide diagnostic tool. SAT measures the total quantity of agglutinating antibodies (IgM and IgG), and the quantity of specific IgG is determined by 2-mercaptoethanol (2ME). SAT titres above 1:160 are considered diagnostic in conjunction with a compatible clinical presentation. In endemic areas, a titre of 1:320 as cutoff may make the test more specific. The type of antibody is important, as IgG antibodies are considered a better indicator of active infection and the rapid fall in the level of IgG antibodies is said to be prognostic of successful therapy. The studies have shown persistence of various levels of SAT antibodies in many clinically cured patients. This emphasizes the over diagnosis and diagnostic challenges faced in an area where typhoid, malaria, tuberculosis and rheumatoid arthritis clinically mimic human brucellosis, thereby exposing/ denying patients access to specific therapy. However, study of Mantur et al (2006) reflected importance of the 2ME test for diagnosis in conjunction with the SAT, as well as for follow up. Coombs test that detects incomplete antibodies and immunocapture-agglutination tests have shown similar performances with higher sensitivity and specificity in the diagnosis(Mantur et al 2006). b. ELISA: A comparison with the SAT, ELISA yields higher sensitivity and specificity (Gad El-Rab and Kambal 1998). ELISA is also reported to be the most sensitive test for the diagnosis of neurobrucellosis (Araj 1997). c. Newer rapid assays:

Brucella IgM and IgG lateral flow  (Smits  et al 2003) and latex agglutination assays have been found to be rapid and simple along with high sensitivity and specificity in culture confirmed cases. These tests are ideal for use as field tests in remote areas and as point of care tests in hospitals and health care centres. The brucellosis is very often under diagnosed . Alertness of clinicians and close collaboration with the microbiologist are essential even in endemic areas to correctly diagnose and treat protean human brucellosis. Data sharing between medical and veterinary practitioners is essential for diagnosis and eradicating this infection from public health (Mantur et al 2004).

See also