Brucellosis is a zoonotic infection caused by the bacterial genus Brucella. The bacteria are transmitted from animals to humans by ingestion through infected food products, direct contact with an infected animal, or inhalation of aerosols. The disease is an old one that has been known by various names, including Mediterranean fever, Malta fever, gastric remittent fever, and undulant fever. Humans are accidental hosts, but brucellosis continues to be a major public health concern worldwide and is the most common zoonotic infection. 
Brucella organisms, which are small aerobic intracellular coccobacilli, localize in the reproductive organs of host animals, causing abortions and sterility. They are shed in large numbers in the animal’s urine, milk, placental fluid, and other fluids. To date, 8 species have been identified, named primarily for the source animal or features of infection. Of these, the following 4 have moderate-to-significant human pathogenicity:
Brucella melitensis (from sheep; highest pathogenicity)
Brucella suis (from pigs; high pathogenicity)
Brucella abortus (from cattle; moderate pathogenicity)
Brucella canis (from dogs; moderate pathogenicity)
Although domesticated animals are of particular importance, brucellosis is also found in North American wild animals that exist in herds (eg, bison or elk in North America and wild boar in Germany  ). Humans experience only limited risk from wild animals, mainly because of lack of proximity or intimate contact and infrequent use of milk and meat products from these animals. Concerns have been voiced that interaction of wild animals with domesticated ones may lead to infection of agricultural herds, though supportive evidence is quite limited.
The global burden of human brucellosis remains enormous: The infection causes more than 500,000 infections per year worldwide. The annual number of reported cases in United States (now about 100) has dropped significantly because of aggressive animal vaccination programs and milk pasteurization. Most US cases are now due to the consumption of illegally imported unpasteurized dairy products from Mexico. Approximately 60% of human brucellosis cases in the United States now occur in California and Texas.
Interest in brucellosis has been increasing because of the growing phenomena of international tourism and migration, in addition to the potential use of Brucella as a biologic weapon.  Familiarity with the manifestations of brucellosis and knowledge of the optimal laboratory studies are essential for the recognition of this reemerging zoonosis. B melitensis, B abortus, and B suis have been completely sequenced, and these sequencing data will help improve our understanding of the pathogenesis and the manifestations of this complex disease.
Definitive diagnosis of brucellosis is based on culture, serologic techniques, or both. Clinically, identification to the genus level is sufficient to warrant initiation of therapy. The particular Brucella species involved does not affect the choice of therapeutic agents; however, speciation is necessary for epidemiologic surveillance and requires more detailed biochemical, metabolic, and immunologic testing.
Brucellae are aerobic gram-negative coccobacilli that possess a unique ability to invade both phagocytic and nonphagocytic cells and to survive in the intracellular environment by finding ways to avoid the immune system. This ability helps explain why brucellosis is a systemic disease and can involve almost every organ system.
Brucella can gain entry into the human body through breaks in the skin, mucous membranes, conjunctivae, and respiratory and gastrointestinal (GI) tracts. Sexual transmission has not been convincingly documented. Ingestion usually occurs by way of unpasteurized milk; meat products often have a low bacterial load. In the United States, percutaneous needlestick exposure, conjunctival exposure through eye splash, and inhalation are the most common routes of entry.
Once within the bloodstream, the organisms quickly become intracellular pathogens contained within circulating polymorphonuclear cells (PMNs) and macrophages, making use of numerous mechanisms to avoid or suppress bactericidal responses. Animal data suggest that the lipopolysaccharide (LPS) coat (smooth in B melitensis, B abortus, and B suis; rough in B canis) is likely to play a role in intracellular survival, perhaps because of adenine and guanine monophosphate production, which inhibits phagosomal fusion and oxidative burst activity.
In addition, Brucella species have relatively low virulence, toxicity, and pyrogenicity, making them poor inducers of some inflammatory cytokines, such as tumor necrosis factor (TNF) and interferons. Furthermore, the bacteria do not activate the alternative complement system. Finally, they are thought to inhibit programmed cell death.
After ingestion by phagocytes, about 15-30% of brucellae survive. Susceptibility to intracellular killing differs among species, with B abortus readily killed and B melitensis rarely affected; these differences might explain the differences in pathogenicity and clinical manifestations in human cases of brucellosis. 
Brucellae that survive are transported into the lymphatic system and may replicate there locally; they also may replicate in the kidney, liver, spleen, breast tissue, or joints, causing both localized and systemic infection. Any organ system can be involved (eg, central nervous system [CNS], heart, joints, genitourinary system, pulmonary system, and skin); localization of the process may cause focal symptoms or findings. After replication in the endoplasmic reticulum, the brucellae are released with the help of hemolysins and induced cell necrosis.
Development of cell-mediated immunity is the principal mechanism of recovery. The host response to infection with B abortus is characterized by the development of tissue granulomas indistinguishable from those of sarcoidosis. In contrast, infection with the more virulent species (B melitensis and B suis) more commonly results in visceral microabscesses.
Although Brucella infection is primarily controlled through cell-mediated immunity rather than antibody activity, some immunity to reinfection is provided by serum immunoglobulin (Ig). Initially, IgM levels rise, followed by IgG titers. IgM may remain in the serum in low levels for several months, whereas IgG eventually declines. Persistently elevated IgG titers or second rises in IgG usually indicate chronic or relapsed infection. IgA antibodies are elaborated late and also may persist for very long intervals.
Brucellosis is caused by infection with Brucella species. The traditional classification of these species is based primarily on the preferred hosts (see Table 1, below).
Table 1. Currently Recognized Brucella Species (Open Table in a new window)
|Organism||Animal Reservoir||Geographic Distribution|
|Brucella melitensis||Goats, sheep, camels||Mediterranean, Asia, Latin America, parts of Africa and some southern European countries|
|Brucella abortus||Cows, buffalo, camels, yaks||Worldwide|
|Brucella suis||Pigs (biotype 1-3)||South America, Southeast Asia, United States|
|Brucella ovis||Sheep||No known human cases|
|Brucella neotomae||Rodents||Not known to cause human disease|
|Brucella pinnipediae and Brucella cetaceae||Marine animals, minke whales, dolphins, seals||Case reports describing some human cases (mainly neurobrucellosis)|
Of the 4 Brucella species known to cause disease in humans (B abortus, B melitensis, B canis, B suis), B melitensis is thought to be the most virulent and causes the most severe and acute cases of brucellosis; it is also the most prevalent worldwide. B melitensis may be acquired via exposure to animals or animal products or, in the case of laboratory technicians, to specimens from animals (including humans) whose tissues are operated upon or submitted for culture or pathologic analysis. 
B abortus is more widely distributed throughout the world than B melitensis is, but it is less pathogenic for both animals and humans. It has, however, been the most common cause of brucellosis in North America. This species gives rise to mild-to-moderate sporadic disease that rarely causes complications.
B suis has been the second most common cause of brucellosis in North America. Infection with this species gives rise to a prolonged course of illness, often associated with suppurative destructive lesions.
B canis infection has a disease course that is indistinguishable from that of B abortus infection. It infection has an insidious onset, causes frequent relapses, and does not commonly cause chronic brucellosis.
Although B pinnipediae and B cetaceae typically affect marine animals, they are now known to be capable of causing disease in humans (mainly neurobrucellosis).
Ingestion of unpasteurized goat milk and related dairy products is the main route by which B melitensis is transmitted to humans.
Slaughterhouse workers, primarily those in the kill areas, become inoculated with brucellae through aerosolization of fluids, contamination of skin abrasions, and splashing of mucous membranes. Farmers and shepherds have similar exposure risks, and they also have exposure to aborted animals. Veterinarians are usually infected by inadvertent inoculation of animal vaccines against B abortus and B melitensis. Laboratory workers (microbiologists) are exposed by processing specimens (aerosols) without special precautions.
Occupational exposures tend to be isolated. A large-scale outbreak of the infection should raise suspicion that a biologic weapon has been released, most likely via an infectious aerosol.
United States statistics
Although brucellosis is still a reportable disease, it has become rare as a result of the institution of veterinary control measures (eg, routine screening of domestic livestock and vaccination programs). Currently, fewer than 100 cases are reported annually to the Centers for Disease Control and Prevention (CDC), mostly from California, Florida, Texas, and Virginia. Incidental cases arise as a result of relaxation of surveillance standards or because of the increasing international exchange of foodstuffs and animals that may harbor Brucella organisms.
At present, most human cases of brucellosis in the United States are due to B melitensis. The B abortus and B suis species that have accounted for most brucellosis in North America are less likely to engender clinical disease in humans than B melitensis is. When disease develops in North Americans, it often does so with greater latency to onset and milder manifestations.
Brucellosis causes more than 500,000 infections per year worldwide. Its geographic distribution is limited by effective public and animal health programs, and the prevalence of the disease varies widely from country to country.  Overall, the frequency of brucellosis is higher in more agrarian societies and in places where handling of animal products and dairy products is less stringent.
European Union (EU) data suggest that there is a clear (though nonlinear) association between gross domestic product (GDP) and rates of brucellosis. According to these data, no countries with a GDP above 90% of the mean had an annual incidence of brucellosis higher than 10 cases per million population.
The heaviest disease burden lies in countries of the Mediterranean basin and Arabian Peninsula, and the disease is also common in India, Mexico, and South and Central America. Although some countries (eg, the United Kingdom and Ireland) have effectively controlled brucellosis, new areas of human brucellosis have emerged in areas such as central and southwest Asia.
Because of variable reporting, true estimates in endemic areas are unknown. Incidence rates of 1.2-70 cases per 100,000 people are reported. In very resource-poor countries (such as some African countries) in which brucellosis is endemic, control through animal slaughter is a poor option because of the fragile nature of the food supply.
In a systematic review was commissioned by the World Health Organization (WHO) with the goal of determining a disability weight for clinical manifestations of human brucellosis, the investigators proposed a disability weight of 0.150 for chronic localized brucellosis and 0.190 for acute brucellosis.  These estimates were based on disability weights from the 2004 Global Burden of Disease Study. Further study is required before a consensus can be reached.
Brucellosis in the Mediterranean, chiefly due to B melitensis, has the highest age/sex-related incidence in males in their mid-20s. A report from northern Saudi Arabia found that 60% of cases of brucellosis occurred in individuals aged 13-40 years, whereas 21% occurred in those younger than 13 years, 16% in those aged 40-60 years, and 2.5% in those older than 60 years. 
For unknown reasons, men aged 13-40 years are particularly vulnerable to the manifestation of illness due to B melitensis. Possible explanations include engaging in activities that increase exposure to Brucella organisms (eg, animal husbandry) and less diligent personal hygiene. The predilection is not universal, given that 60% of cases in Jordan occur in individuals younger than 24 years.
Elderly individuals with acute localized brucellosis are particularly likely to manifest destructive localized brucellosis of the spine. 
Brucellosis is generally uncommon in infants. The international literature suggests that brucellosis may be more common in children in developing countries because of lack of pasteurization and working in an agrarian society. Transmission to infants may occur through breastfeeding  or ingestion of raw milk. Prepubertal children account for less than 2% of all cases of neurobrucellosis; fewer than 50 such cases have been described in the peer-reviewed medical literature over the past 50 years.
Worldwide, brucellosis is more common in males than in females. Young adult males predominate in most series of patients with brucellosis compiled in areas of endemic disease. A report from northern Saudi Arabia found a male-to-female ratio of 1.7:1, chiefly individuals aged 13-40 years.  The cases represented in such series are caused chiefly by B melitensis.
Occupational exposure to animals likely plays an important role in the enhanced vulnerability of men to the development of brucellosis. Whether the increased risk manifested by males is additionally influenced by aspects of personal hygiene, immunologic factors, or other circumstances is not known. Food-borne brucellosis is not limited according to age or sex and is found in women and men in equal numbers.
Exposures tend to be primarily occupational; accordingly, no racial predilection has been identified in the United States.
The prognosis is generally excellent. Although initial symptoms of brucellosis may be debilitating, if they are treated appropriately and within the first few months of onset, the disease is easily curable, with a low risk of relapse or chronic disease. However, the prognosis is poor in persons who present with congestive heart failure due to endocarditis, in whom mortality approaches 85%. In some patients, brucellosis can cause chronic debilitating illness with extensive morbidity.
In uncomplicated cases of acute brucellosis, fever, malaise, and many other manifestations improve rapidly with bed rest, whereas sustained physical activity may prolong or worsen the degree of illness. Considerable improvement from the symptoms of the acute phase of illness typically occurs within a few weeks, with or without treatment. In many cases, this is followed by complete remission within 2-6 months. Recovery tends to be more rapid with B abortus infection than with B melitensis or B suis infection.
Overall mortality in recognizably symptomatic acute or chronic cases of brucellosis is very low, certainly less than 5% and probably less than 2%. It is usually the result of the rare instance of Brucella endocarditis or is the result of severe CNS involvement, often as a complication of endocarditis. Postmortem analysis confirms that the burden of acute brucellotic infection is borne by tissues of the lymphoreticular system.
Recurrence of symptoms of acute brucellosis is not uncommon. The recurrent disease may be systemic or localized. In some of these patients, the condition evolves into chronic brucellosis, which may be progressive if untreated. Chronic brucellosis includes systemic and specific localized forms (including various types of neurobrucellosis). These various forms are due to continued infectious disease, for which additional treatment is indicated and effective.
Objective clinical and laboratory evidence for ongoing disease is demonstrable. Patients who do not have such evidence and who complain of occasional mild symptoms similar to those found in acute brucellosis are likely to have psychoneurosis. This complication of acute brucellosis does not usually resolve with anti-brucellosis treatments, although such treatments may exert placebo effects for individual bouts. Psychiatric treatment may be indicated.
The likelihood of recurrence is greater in individuals who are not treated or who are inadequately treated for acute brucellosis. However, recurrence is possible even in properly treated patients who have had acute brucellosis. Addition of oral rifampicin to oral tetracycline may reduce the recurrence risk for patients who are treated with that combined therapy for acute brucellosis.
Chronic brucellosis may continue to trouble patients for as long as 25 years, but such cases are quite rare.
Patient education should include efforts to address the following issues:
The nature of the disease and the routes by which it can be transmitted
The symptoms, complications, and treatment of the disease, as well as the risk of relapse if it is not adequately treated
The potential adverse effects of the medications administered
The need for strict compliance with the antibiotic regimen
In soma case, reassurance concerning recurrent symptoms that are not associated with clinical or laboratory evidence of acute brucellotic disease
The need to avoid potential sources of infection – This may involve avoiding infected animals, using stricter precautions (eg, gloves and mask) when dealing with a potentially infected animal, or avoiding potentially contaminated foods
For farmers and ranchers, immunization of their cattle against the disease as necessary
For laboratory workers, maintenance of the appropriate level of containment
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