Brucellosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2] Danitza Lukac Vishal Devarkonda, M.B.B.S[1]

Brucellosis is an ancient zoonotic disease. It is caused by bacteria of the genus Brucella. It is usually acquired by consuming unpasteurized dairy or undercooked meat products. Patients with brucellosis usually present with undulant fever, night sweats and joint pain. Brucellosis can be easily treated with antibiotics. If left untreated, patients with brucellosis may progress to develop focal organ involvement, relapses or chronic brucellosis. Prognosis is good with treatment.

According to some studies, there is evidence that Brucellosis occurred in animals 60 million years ago and 3 million years ago in human beings. In 450 BC, Hippocrates described a disease similar to Brucellosis.^[1]

Brucellosis is a zoonotic disease. Humans could be infected by eating undercook meat or raw dairy products, inhalation of the bacteria and direct contact of bacteria with skin wounds or mucous membranes. Following transmission, white blood cells phagocyte the pathogen and transports it via hematologic or lymphatic route to different organs, specially to those of the reticuloendothelial system. Endotoxic lipopolysaccharide LPS plays an important role in: survival of bacteria inside monocytic cell, supressing phagosome-lysosome fusion and internalizing bacteria into endoplasmic reticulum.^[2][3][4]

Human brucellosis is caused by four Brucellae species: B. abortus, B. canis, B. melitensis, and B. suis.^[5].

Brucellosis must be differentiated from Typhoid fever, Malaria, Tuberculosis, Lymphoma, Dengue, Leptospirosis, Rheumatic disease, Epstein-barr virus, Toxoplasmosis, Cytomegalovirus, and HIV.

Worldwide, the incidence of Brucellosis ranges from a low of 0.01 per 100,000 to high of 200 per 100,000 individuals. Case fatality rate is less than 2% when untreated. Brucellosis most commonly affects men in age group between 20 to 45 years old. Areas currently listed as high risk are the Mediterranean Basin (Portugal, Spain, Southern France, Italy, Greece, Turkey, North Africa), South and Central America, Eastern Europe, Asia, Africa, the Caribbean and the Middle East

Common risk factors in the development of brucellosis are: consuming unpasteurized dairy products or raw meat products, unsafe hunting practices and occupational risks.^[6]

There are no guidelines for screening Brucellosis.^[7][8]

If left untreated, patients with brucellosis may progress to develop focal organal involvement, relapses or chronic brucellosis. Common complications of brucellosis include: granulomatous hepatitis, arthritis, sacroiliitis, meningitis, orchitis, epididymitis uveitis, and endocarditis. The prognosis of brucellosis is good with adequate treatment.^{[9][10][11][12]}

Diagnosis is based on history of potential exposure, presentation consistent with the disease, and supporting laboratory findings.^[13][14][15]

Brucellosis can present with diverse clinical presentation which include systemic flu-like symptoms and symptoms due to focal involvement of organs.^{[16][17][18][19]}

Patients with brucellosis are usually well-appearing. Common physical examination observed include hepatomegaly, splenomegaly and lymphadenopathy.^{[20][21][22][23]}

The diagnosis of brucellosis can be confirmed by either a positive bacterial culture or a positive titre of anti-brucella antibodies on serological testings.^[24][25][26]

There is no specific X-ray, CT or MRI finding associated with Brucellosis.^[27][28][29]

The mainstay of therapy for brucellosis is antimicrobial therapy. The preferred regimen for uncomplicated brucellosis is a combination of Doxycycline and Streptomycin. Rifampicin is the drug of choice for brucellosis in pregnancy. For children less than 8 years of age, the preferred regimen is either Gentamycin or a combination of Trimethoprim-sulfamethoxazole and Streptomycin.^[30]

Brucellosis can be prevented by not consuming unpasteurized dairy products or undercooked meat and having safe occupational practices.^[30]

1. ↑ ^{Jump up to:3.0 3.1} Enfermedades infecciosas: Brucelosis -Diagnóstico de Brucelosis,Guia para el Equipo de Salud. Ministerio de Salud-Argentina. http://www.msal.gob.ar/images/stories/bes/graficos/0000000304cnt-guia-medica-brucelosis.pdf. Accessed on February 2, 2016
2. ↑ ^{Jump up to:4.0 4.1 4.2 4.3} Brucellosis. CDC. http://www.cdc.gov/brucellosis/exposure/index.html.html. Accessed on February 3, 2016 Cite error: Invalid <ref> tag; name “c” defined multiple times with different content Cite error: Invalid <ref>tag; name “c” defined multiple times with different contentCite error: Invalid <ref> tag; name “c” defined multiple times with different content
3. ↑ ^{Jump up to:5.0 5.1 5.2 5.3} Brucellosis. CDC. http://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/brucellosis. Accessed on February 3, 2016 Cite error: Invalid<ref> tag; name “f” defined multiple times with different content Cite error: Invalid <ref> tag; name “f” defined multiple times with different content Cite error: Invalid <ref>tag; name “f” defined multiple times with different content
4. ↑ ^{Jump up to:6.0 6.1} FAO/WHO/OIE Brucellosis in humans and animals. WHO (2006). http://www.who.int/csr/resources/publications/Brucellosis.pdf Accessed on February 3, 2016
5. ↑ ^{Jump up to:9.0 9.1} Brucellosis. CDC. http://www.cdc.gov/brucellosis/treatment/index.html. Accessed on February 5, 2016
6. ↑ ^{Jump up to:10.0 10.1} Brucellosis. CDC. http://www.cdc.gov/brucellosis/prevention/index.html. Accessed on February 5, 2016
7. ↑ ^{Jump up to:14.0 14.1} Brucellosis 2010 Case Definition. CDC. http://wwwn.cdc.gov/nndss/conditions/brucellosis/case-definition/2010/. Accessed on February 2, 2016
8. Jump up↑ Pourbagher A, Pourbagher MA, Savas L, Turunc T, Demiroglu YZ, Erol I; et al. (2006). “Epidemiologic, clinical, and imaging findings in brucellosis patients with osteoarticular involvement.”. AJR Am J Roentgenol. 187 (4): 873–80. PMID 16985128. doi:10.2214/AJR.05.1088.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2] Danitza Lukac Vishal Devarkonda, M.B.B.S[3]

Brucellosis is an ancient disease. According to some studies, there is evidence that Brucellosis occurred in animals 60 million years ago and 3 million years ago in human beings. In 450 BC, Hippocrates described a disease similar to Brucellosis.

Brucellosis is an ancient disease. In 450 BC, Hippocrates described a disease similar to brucellosis. Few of the important events in understanding the nature of disease are:^[1][2][3]

• In 1860, Jeffery Allen Marston, surgical assistant in Royal Academy of Medicine, described brucellosis as “gastric remittent fever”.
• In 1887, Sir David Bruce, Scottish physician, isolated gram negative coccobacilli from spleens of five british soldiers, termed it as micrococcus.
• In 1895, the Danish veterinarian Bernard Lauritz Frederik Bang isolated microorganisms from cattle, termed it as Bacillus abortus
• In 1897, Wright and Smith described brucellosis as a zoonotic disease, after detecting specific antibodies of Brucella melitensis in human and animal serum.
• In 1897, Bernhard Bang and Danish veterinarian isolated Brucella abortus as the agent and the additional name Bang’s disease was assigned. In modern usage “Bang’s disease” is often shortened to just “bangs” when ranchers discuss the disease or vaccine.
• In 1905, Maltese doctor and archaeologist Sir Temi Zammit identified unpasteurized milk as the major source of the pathogen and it has since become known as Malta Fever (or Deni Rqiq locally). In cattle this disease is also known as contagious abortion or infectious abortion.
• The popular name undulant fever originates from the characteristic undulance (or wave-like nature) of the fever which rises and falls over weeks in untreated patients. In the 20th Century, this name, along with “Brucellosis” (after Brucella, named for Dr Bruce), gradually replaced the 19th Century names “Mediterranean fever” and “Malta fever”.
• In 1989, neurologists in Saudi Arabia discovered “Neurobrucellosis”, a neurological involvement in Brucellosis.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Danitza LukacVishal Devarkonda, M.B.B.S[2]

Brucellosis is a zoonotic disease, humans could be infected by eating undercook meat or raw dairy products, inhalation of the bacteria and direct contact of bacteria with skin wounds or mucous membranes. Following transmission, white blood cells phagocyte the pathogen and transports it via hematologic or lymphatic route to different organs, specially to those of the reticuloendothelial system.

Brucellosis is a zoonotic disease, humans could be infected by eating undercook meat or raw dairy products, inhalation of the bacteria and direct contact of bacteria with skin wounds or mucous membranes. Following transmission, white blood cells phagocyte the pathogen and transports it via hematologic or lymphatic route to different organs specially to those of the reticuloendothelial system. Endotoxic lipopolysaccharide LPS, plays an important role in: survival of bacteria inside monocytic cell, supressing phagosome-lysosome fusion and internalizing bacteria into endoplasmic reticulum. The pathophysiology of Brucellosis can be described in the following steps:^{[1][2][3][4][5][6][7][8][9][10][11][12][13]}

According to CDC, humans are generally infected with Brucellosis in one of the following three ways:^[1][14]

Incubation period of brucellosis varies from one to four weeks. But occasionally, it may be as long as several months. 

Following transmission, brucellae is ingested by macrophages and polymorphonuclear cells. On ingestion, they replicate intracellularly inside the lysed cells and disseminate systemically. 

• On transmission, bacteria is actively phagocytosed by neurophilic granulocytes and monocytes.

• On entry into the body, brucellae multiply in the neutrophilic granulocytes and monocytes, initially in lymph nodes, which is followed by systemic hematogenous spread resulting in multiple localizing infection

Brucellosis elicits both humoral and cell-mediated immune responses:^{[1][2][3][4][5][6][7][8][9][15][16]}

• Humoral response has a limited role in protecting host from Brucellae.
• On activation, B-cell produce IgM class antibody, which is followed by IgG antibodies .
• Antibodies promote clearance of extracellular bacteria and facilitate phagocytosis of the Brucellae.

• Tumor necrosis factor α (TNF-α) produces on activation of cell mediated immunity, stimulates T lymphocytes and macrophages, which help in eliminating intracellular brucellae. Virulent brucellae tend to suppress the activity of tumor necrosis factor α (TNF-α) and IFN-gamma.
• Cytokines such as interleukin (IL) 12 promote production of Interferon γ (IFN-γ) responses. IFN-γ, which drives TH1-type responses and stimulates macrophage activation. Cytokines, which include , IL-6, IL-4and IL-10, down-regulate the protective response.

The pathogenesis of brucellosis is complex and not fully understood:^{[1][2][3][4][5][6][7][8][9][17][18][19]}

By avoiding innate immunity, brucella survive with in monocytic cells.

• Endotoxic lipopolysaccharide (LPS), plays a key role in survival of bacteria inside monocytic cell.
• LPS helps in survival of the bacteria inside the monocytic cell, by suppressing phagosome–lysosome fusion, internalizing bacteria into endoplasmic reticulum and inhibiting apoptosis of infected cell.
• Type IV secretion system (VirB) and type III secretion system, that regulates intracellular survival and trafficking has been identified, although type 3 not yet confirmed. Secretion system plays an important role in intracellular transport of the bacteria acid-stable proteins produced by brucella, facilitates the survival in phagosomes
• Cu-Zn superoxide dismutase, produced by brucellae, gives them resistance from reactive oxygen intermediates.
• Two component BvrS/BvrR system, codes for histidine kinase sensor. Histidine kinase sensor plays an important role in controlling the expression of molecular determinants which are necessary for cell invasion.^[20]
• Hemolysins help the bacteria to be realeased from a cell and induce cell necrosis.

There is no known genetic association to Brucellosis.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Danitza Lukac, Vishal Devarkonda, M.B.B.S[2]

Human brucellosis is caused by four Brucellae species: B. abortus, B. canis, B. melitensis, and B. suis.^[1]

• Brucella is a genus of gram-negative bacteria.^[2]They are small (0.5 to 0.7 by 0.6 to 1.5 µm), non-motile and encapsulated coccobacilli.

Brucella species have been found primarily in mammals. ^[3] Brucellla species, with their host and degree of virulence is described below:^[4]

Following tests may be used to differentiate between the different species of brucella.^[5]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Danitza Lukac Vishal Devarkonda, M.B.B.S[2]

Brucellosis must be differentiated from typhoid fever, malaria, tuberculosis, lymphoma, dengue, leptospirosis, rheumatic disease, epstein-barr virus, toxoplasmosis, cytomegalovirus, and HIV.

Brucellosis must be differentiated from typhoid fever, malaria, tuberculosis, lymphoma, Dengue, Leptospirosis, Rheumatic disease, epstein-barr virus, Toxoplasmosis, cytomegalovirus, and HIV.^[1][2][3][4]

A detailed clinical history which includes recent travel history, recent camping or hunting, consumption of unpasteurized milk or raw meat products, and occupational history should be obtained, in order to differentiate brucellosis from other diseases.

Differentiating psittacosis from other diseases

Key;

+, occurs in some cases

++, occurs in many cases,

+++, occurs frequently

Brucellosis must be differentiated from other diseases that cause atypical pneumonia such as Q fever and legionaellosis

Disease	Prominent clinical features	Lab findings	Chest X-ray
Q fever	Q fever is characterized by abrupt onset of fever, myalgia, headache, and other constitutional symptoms. Cough is the most prominent respiratory symptom and it is usually dry.[5] Cough is associated with dyspnea and pleuritic chest pain.	Antibody detection using indirect immunofluorescence (IIF) is the preferred method for diagnosis. PCR can be used if IIF is negative, or very early once disease is suspected. C. burnetii does not grow on ordinary blood cultures, but can be cultivated on special media such as embryonated eggs or cell culture. A two-to-three fold increase in AST and ALT is seen in most patients.
Mycoplasma pneumonia	Mycoplasma pneumonia can be asymptomatic. Headache, nausea, and malaise usually precede the onset of symptoms.[5] Cough is intractable and nonproductive.	Postitve Coombs test Leukocytosis Thrombocytosis
Legionellosis	Legionellosis is characterized by cough that is slightly productive.[5] Constitutional symptoms such as chills, myalgia, and arthralgia. Gastrointestinal symptoms such as diarrhea, nausea, and vomiting.	Labs are nonspecific for diagnosing legionellosis Renal and hepatic dysfunction Thrombocytopenia and leukocytosis Hyponatremia
Chlamydia pneumonia	There are no specific clinical features of chlamydia pneumonia. Symptoms appear gradually. Chlamydia infection is usually associated with upper respiratory tract symptoms (pharyngitis, sinusitis, etc). It might be associated with extrapulmonary maifestations such as meningitis and Guillain-Barre syndrome.[5]	Chlamydia pneumonia is usually associated with normal WBC count. Diagnosed with the presence of antichlamydial antibody (through complement fixation or direct immunofluoroscence) or direct antigen detection.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2] Danitza Lukac Vishal Devarkonda, M.B.B.S[3]

The incidence of brucellosis is estimated to vary from 0.01 to 200 per 100,000 individuals in endemic countries. The case fatality rate of brucellosis is less than 2% when untreated. The majority of disease is reported in Mediterranean basin, South and Central America, Eastern Europe, Asia, Africa, the Caribbean and the Middle East. Patients of age group 20 and 45 years are affected. Men are more affected then women.

Epidemiology and Demographics of Brucellosis include:^{[1][2][3][4][5]}

• The incidence in different endemic countries varies between 0.01 and 200 per 100,000 individuals.
• The low incidence reported in known Brucellosis-endemic areas may reflect low levels of surveillance and reporting.^[3]

• The case fatality rate of brucellosis is less than 2% when untreated.^[4]

Developed countries like the Unites States (0.02-0.09/100,000), Italy (1.40/100,000), Germany (0.03/100,000) and Greece (4.00/100,00) with strict pasteurization laws, animal control/slaughter regulations and brucellosis surveillance programs have reported low incidence of brucellosis.^[6]

Developing countries like Iraq (53.29-268.81/100,000), Iran (0.73-141.60/100,000), Jordon (25.70-130/100,000), Kyrgyzstan (88/100,000) and Mexico (26.60/100,000) due to lack of strict pasteurization laws, animal control/slaughter regulations and brucellosis surveillance programs have reported much higher incidence of brucellosis.^[6]

• Brucellosis most commonly affects individuals 20 and 45 years old.^[5]

• Men are more commonly affected with Brucellosis than women.^[5]

• There is no racial predilection to Brucellosis.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2] Danitza Lukac Vishal Devarkonda, M.B.B.S[3]

Common risk factors in the development of brucellosis include: consuming unpasteurized dairy products or raw meat products, unsafe hunting practices and occupational exposure.

Common risk factors in the development of Brucellosis include:^{[1][2][3][4][5]}

• Living or travelling to brucellosis endemic countries
• Occupational exposure
• Consumption of unpasteurized dairy products or raw meat products
• Hunting

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Danitza Lukac Vishal Devarkonda, M.B.B.S[2]

There are no guidelines for screening brucellosis.^[1][2]

• There are no guidelines for screening brucellosis.^[3]
• However, in some endemic countries, it is recommended to screen family members of patients with brucellosis.^[1][2]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2] Danitza LukacVishal Devarkonda, M.B.B.S[3]

If left untreated, patients with brucellosis may progress to develop focal organ complications, relapses or chronic brucellosis.^[1] Common complications of brucellosis include granulomatous hepatitis, arthritis, sacroiliitis, meningitis, orchitis, epididymitis uveitis, and endocarditis. The prognosis of brucellosis is good with adequate treatment.

If left untreated, patients with brucellosis may progress to develop focal organ involvement, relapses and chronic brucellosis.^[2]

Complications of brucellosis include the following:^{[3][4][5][6][7][8][9][10][11]}

The prognosis of brucellosis is good with treatment. Mortality is less then 1%, usually due to consequence of cardiac involvement or severe neurologic disease.^[13]