written by Francesca Moretto and Valentina De Sario
DEFINITION
Brucellosis, also called undulant fever, undulating fever, or Malta fever, is a zoonosis (infectious disease transmitted from animals to humans) caused by bacteria of the genus Brucella. It is primarily a disease of domestic animals (goats, pigs, cattle, dogs, etc) and humans and has a worldwide distribution, mostly now in developing countries.
Brucellae are Gram-negative coccobacilli; non-spore-forming and non-motile; aerobic, but may need added CO2.
CLASSIFICATION
Three species (B melitensis, B abortus, B suis) are important human pathogens; B canis is of lesser importance.
Species are differentiated by production of urease and H2S, dye sensitivity, cell wall antigens and phage sensitivity. The major species are divided into multiple biovars.
EPIDEMIOLOGY
Brucellosis causes more than 500,000 infections per year worldwide.
The disease is now uncommon in the United States and Britain but common in the Mediterranean and Arabian Gulf regions, Latin America, Africa, and parts of Asia (India).
Incidence rates of 1.2-70 cases per 100,000 people are reported.
Brucella melitensis in sheep and goats represents the most important source of brucellosis in humans.
Human brucellosis carries a low mortality rate ( <5%), mostly secondary to endocarditis.
However, brucellosis can cause chronic debilitating illness with extensive morbidity.
SYMPTOMS
The presentation of brucellosis is characteristically variable. The incubation period is usually from 2 to 4 weeks. The onset may be insidious or abrupt. Subclinical infection is common.
Fever: the most common symptom and sign of brucellosis. It is intermittent in 60% of patients with acute and chronic conditions and undulant in 60% of patients with subacute brucellosis.
Relative bradycardia.
Constitutional symptoms.
Bone and joint symptoms : arthralgias, low back pain, spine and joint pain.
Neuropsychiatric symptoms : headache, depression, fatigue.
Gastrointestinal symptoms.
Neurologic symptoms : weakness, dizziness, unsteadiness of gait, urinary retention.
Respiratory symptoms.
DIAGNOSIS
The diagnosis of brucellosis is primarily dependent on clinical suspicion allied with the taking of an adequate history of possible exposure - including during travel. Presentation can, however, be highly atypical and focal lesions may present decades after exposure.
Unequivocal diagnosis requires isolation of the organism.
Blood culture : method of choice but specimens need to be obtained early in the disease and cultures may need to be incubated for up to four weeks small amount of CO2 produced during growth.
Serology (SAT; EIA) : mainstay of laboratory diagnosis, but the interpretation of results is fraught with difficulties.
Tularemia: cross-reactions with Brucella antigen.
The diagnosis of the chronic brucellosis syndrome, without specific localization, is often very unsatisfactory. When cultures are negative and the results of serologic tests are equivocal a confident diagnosis is often impossible.
DIFFERENTIALS
Due to the non-specific presentation and to the numerous complications of brucellosis in humans,
the differential diagnosis is vast and will not be addressed in detail here.
PATHOGENESIS
The reservoirs of brucellosis are various wild, feral and (particularly) domestic animals. Brucellae frequently invade the mammary gland of infected ruminants. This may allow milk cows, for example, to excrete large numbers of organisms and such milk spread has resulted in extensive outbreaks of brucellosis.
Brucella species differ markedly in their capacity to cause invasive human disease. Brucella melitensis is the most pathogenic; B abortus is associated with less frequent infection and a greater proportion of subclinical cases. The virulence of B suis strains for humans varies but is generally intermediate.
Animal studies suggest that invading brucellae are rapidly phagocytosed by polymorphonuclear leukocytes.
Brucellae are frequently able to survive and multiply in these cells because they inhibit the bactericidal myeloperoxidase- peroxide-halide system by releasing guanosine and adenine, produced by the lipopolysaccharide (LPS; smooth in B melitensis, B abortus, and B suis and rough in B canis).
Moreover, Brucella-infected DCs fail to release tumor necrosis factor alpha (TNF-alpha), a defect involving the bacterial protein Omp25.
TNF alpha
In this way the natural mechanisms of apoptosis that the cell uses to answer to a situation of stress are inhibited, and as well the immune response against infected cells are blocked.
It’s been proved that exogenous TNF-alpha addition to Brucella-infected DCs restores cell maturation and allows them to present antigens; and two avirulent B. suis omp25 mutants, which do not express the Omp25 protein, were able to trigger TNF-alpha production upon DC invasion.
So we can finally have the possibility of an immune response against Brucella: cells infected with these mutants subsequently mature and acquire the ability to present antigens.
This is the way brucella survives inside DCs, through the control of the expression of TNF-alpha (Omp25 protein dependent) that, blocking the immune reaction of the organism against the infected cell through inibition of apoptosis and expression of membrane antigen that allows lymphocytes T to recognise the cell.
This model defines a specific evasion strategy of the bacteria by which they can escape the immune response to chronically infect their host.
After replication in the endoplasmic reticulum, the brucellae are released with the help of hemolysins and induced cell necrosis.
In systemic spread, it is not clear whether the bacteria are transported within neutrophils and macrophages or in the blood stream outside cells but organisms may disseminate widely from regional lymphoid tissue appropriate to the portal of entry and may localize in certain target organs such as lymph nodes, spleen, liver, bone marrow, and (especially in animals) the reproductive organs.
Brucella granuloma
In humans, the tissue lesions produced by Brucella species consist of minute granulomas that are composed of epithelioid cells, polymorphonuclear leukocytes, lymphocytes and some giant cells.
The fact that humans rapidly develop hypersensitivity to brucellar antigens suggests that many of the symptoms of human brucellosis result from the reaction of the host defenses.
A recent research identified a gene, called NRAMP1, which is associated with the susceptibility or resistance of animals to diseases associated with intracellular parasites such as brucellosis. Resistance or susceptibility to ruminant brucellosis is related to specific sequences of bovine NRAMP1. The analysis of said sequences identifies animals who are susceptible or resistant to disease.
Chromosomal location of NRAMP1
Iron is needed for a wide range of metabolic activities in man and is essential for the growth and multiplication of Brucellae. Experimental studies have demonstrated the benefits of iron deficiency in terms of inhibitors of growth rates of bacteria and parasites. This, together with the transient hypoferraemia of acute systemic infection, has sometimes been put forward as an ecological advantage for those individuals who live in a contaminated environment and are continually at risk of infection.
A case-control study has as well provided evidence of higher serum calcium levels in patients with brucellosis. However, prospective studies are needed to investigate the possible role of macrophages and vitamin D metabolites or bone involvement in this hypercalcemia and to ascertain the clinical significance of these higher serum calcium levels.
PATIENT RISK FACTORS
• Raw dairy foods
• Animal-related occupation
• Hunting
• International travel
COMPLICATIONS
Chronic brucellosis may cause complications in only one organ or throughout the body (diffuse brucellosis).
Endocarditis.
Osteoarthritis.
Epididymo-orchitis.
Spontaneous abortion.
Hepatitis.
Central nervous system infections.
TREATMENT
The goal of medical therapy is to control patient symptoms as quickly as possible to prevent complications and relapses.
Multidrug antimicrobial regimens (doxycycline and rifampin from 4 to 6 weeks) are the mainstay of therapy because of high relapse rates reported with monotherapeutic approaches.
doxycycline
rifampin
The role of surgery for patients with brucellosis lies in the treatment of endocarditis or drainage of focal abscesses.
