central nervous system infections (meningitis, encephalitis), inflammation and infection of the spleen and liver, infection and inflammation of the epididymus and testicles (epididymo-orchitis), arthritis, inflammation of the inner lining of the heart chambers (endocarditis).[2]
Brucellosis[4] is azoonosis spread primarily via ingestion ofunpasteurized milk from infected animals.[5] It is also known asundulant fever,Malta fever, andMediterranean fever.[6]
The bacteria causing this disease,Brucella, are small,Gram-negative, nonmotile, nonspore-forming, rod-shaped (coccobacilli) bacteria. They function asfacultativeintracellular parasites, causingchronic disease, which usually persists for life. Four species infect humans:B. abortus,B. canis,B. melitensis, andB. suis.B. abortus is less virulent thanB. melitensis and is primarily a disease of cattle.B. canis affects dogs.B. melitensis is the most virulent and invasive species; it usually infects goats and occasionally sheep.B. suis is of intermediate virulence and chiefly infects pigs. Symptoms includeprofuse sweating andjoint andmuscle pain. Brucellosis has been recognized in animals and humans since the early 20th century.[7][8]
A graph of the cases of brucellosis in humans in the United States from the years 1993–2010 surveyed by the Centers for Disease Control and Prevention through the National Notifiable Diseases Surveillance System[9]
The symptoms are like those associated with many otherfebrile diseases, but with emphasis on muscular pain and night sweats. The duration of the disease can vary from a few weeks to many months or even years.
This complex is, at least in Portugal, Israel, Syria, Iran, and Jordan, known as Malta fever. During episodes of Malta fever, melitococcemia (presence of brucellae in the blood) can usually be demonstrated using blood culture in tryptose medium or Albini medium. If untreated, the disease can give rise to focalizations[clarification needed] or become chronic. The focalizations of brucellosis usually occur in bones and joints, andosteomyelitis orspondylodiscitis of the lumbar spine, accompanied bysacroiliitis, is very characteristic of this disease.Orchitis is also common in men.
Granuloma andnecrosis in the liver of a guinea pig infected withBrucella suis
Brucellosis in humans is usually associated with consumption of unpasteurized milk and soft cheeses made from the milk of infected animals—often goats—infected withB. melitensis, and with occupational exposure of laboratory workers, veterinarians, and slaughterhouse workers. These infected animals may be healthy and asymptomatic.[12] Some vaccines used in livestock, most notablyB. abortus strain 19, also cause disease in humans if accidentally injected. Brucellosis induces inconstantfevers, miscarriage, sweating, weakness,anemia,headaches,depression, and muscular and bodily pain. The other strains,B. suis andB. canis, cause infection in pigs and dogs, respectively.[13]
Overall findings support that brucellosis poses anoccupational risk togoat farmers with specific areas of concern including weak awareness of diseasetransmission to humans and lack of knowledge on specific safe farm practices such asquarantine practices.[14]
Brucellosis affects both domestic and wildlife species, with the latter serving as significant reservoirs that contribute to disease persistence and transmission. Notably, bison, elk, wild boars, and deer have been identified as carriers, particularly in North America and Europe[15] Humans can contract the disease through direct handling of infected animals, aerosol exposure, or consumption of undercooked game meat.[16] Additionally, the wildlife trade has been implicated in the geographical spread of brucellosis, as the movement and sale of infected animals, particularly in unregulated markets, introduce the bacteria into new ecosystems, increasing disease risks for both humans and animals.[17] Reports from Central Asia and sub-Saharan Africa highlight cases where wildlife trafficking has facilitated brucellosis outbreaks in non-endemic regions.[18]
Transmission through hunting and game meat consumption
Hunters and individuals who consume wild game face an elevated risk of brucellosis exposure due to direct contact with infected animals and inadequate meat preparation. Transmission can occur during field-dressing or handling of infected carcasses, asBrucella bacteria can enter the body through skin abrasions, mucous membranes, or inhalation of aerosolized pathogens.[19] Additionally, the consumption of undercooked or improperly handled wild game meat remains a significant risk factor, particularly in regions where game animals constitute a primary food source. Implementing protective measures, such as the use ofpersonal protective equipment (PPE) during handling and ensuring thorough cooking of game meat, is essential to mitigating the risk of brucellosis transmission within hunting communities.
Demonstration of the agent: blood cultures in tryptose broth, bone marrow cultures. The growth of brucellae is extremely slow (they can take up to two months to grow), and the culture poses a risk to laboratory personnel due to the high infectivity of brucellae.
Demonstration of antibodies against the agent, either with the classic Huddleson, Wright, and/or Bengal Rose reactions, either with ELISA or the 2-mercaptoethanol assay for IgM antibodies associated with chronic disease
Histologic evidence of granulomatous hepatitis on hepatic biopsy
Radiologic alterations in infected vertebrae: the Pedro Pons sign (preferential erosion of the anterosuperior corner of lumbar vertebrae) and marked osteophytosis are suspicious of brucellic spondylitis.
Definite diagnosis of brucellosis requires the isolation of the organism from the blood, body fluids, or tissues, but serological methods may be the only tests available in many settings. Positive blood culture yield ranges between 40 and 70% and is less commonly positive forB. abortus thanB. melitensis orB. suis. Identification of specificantibodies against bacteriallipopolysaccharide and otherantigens can be detected by the standard agglutination test (SAT), rose Bengal, 2-mercaptoethanol (2-ME), antihumanglobulin (Coombs') and indirect enzyme-linked immunosorbent assay (ELISA). SAT is the most commonly usedserology in endemic areas.[21][22] An agglutination titre greater than 1:160 is considered significant in nonendemic areas and greater than 1:320 in endemic areas.[citation needed]
Dipstick assays are new and promising, based on the binding ofBrucella IgM antibodies, and are simple, accurate, and rapid. ELISA typically uses cytoplasmic proteins as antigens. It measures IgM, IgG, and IgA with better sensitivity and specificity than the SAT in most recent comparative studies.[23] The commercial Brucellacapt test, a single-step immunocapture assay for the detection of total anti-Brucella antibodies, is an increasingly used adjunctive test when resources permit.PCR is fast and should be specific. Many varieties of PCR have been developed (e.g., nested PCR, real-time PCR, and PCR-ELISA) and found to have superior specificity and sensitivity in detecting both primary infection and relapse after treatment.[24] Unfortunately, these are not standardized for routine use, and some centres have reported persistent PCR positivity after clinically successful treatment, fuelling the controversy about the existence of prolonged chronic brucellosis.[citation needed]
Other laboratory findings include normal peripheral white cell count, and occasionalleucopenia with relativelymphocytosis. The serum biochemical profiles are commonly normal.[25]
Vaccination is the most effective method for controlling brucellosis in livestock. In cattle, the most common vaccines are Brucella abortus strain 19 and RB51,[26] while for goats and sheep, B. melitensis Rev-1 is used. Other methods include regular serological screening, and the culling of infected animals helps prevent the spread of disease. In many countries, mandatory vaccination programs[27] and test-and-slaughter policies have been shown to significantly reduce brucellosis incidence in livestock populations.[28][29]
Brucellosis is commonly transmitted to humans through the consumption of unpasteurized dairy products, particularly raw milk and cheese. Pasteurization is one of the most effective methods to eliminateBrucella with many countries implementing it while hosting public educational campaigns to discourage the consumption of raw dairy.[30]
Wild animals, including bison, elk, wild boars, and deer, serve as natural reservoirs forBrucella. Spillover infections from wildlife to livestock pose ongoing challenges, particularly in regions with dairy farms.[31] Control measures include restricted feeding areas, selective culling, and experimental wildlife vaccination programs. Hunters and individuals handling game meat are advised to wear protective gloves and cook meat thoroughly to prevent infection.[32]
Brucellosis poses an occupational hazard for veterinarians, farmers, slaughterhouse workers, and laboratory personnel who handle infected animals or biological specimens. Common preventive measures include the use of personal protective equipment (PPE), proper ventilation in slaughterhouses, and adherence to laboratory biosafety protocols.[33] Accidental exposure in laboratory settings can occur through aerosolized bacteria or direct contact with infected samples, necessitating post-exposure antibiotic prophylaxis.[34]
Educational initiatives are essential to reducing brucellosis transmission, particularly in rural communities where unpasteurized dairy products remain widely consumed. Public health campaigns emphasize the importance of basic knowledge of brucellosis disease and transmission, safe food handling, and vaccination compliance.[35]
International disease control efforts and One Health integration
Brucellosis control relies on a One Health approach integrating human, animal, and environmental health. Global organizations, including the World Health Organization (WHO), Food and Agriculture Organization (FAO), World Organisation for Animal Health (WOAH), and United Nations Environment Programme (UNEP),[36] advocate for integrated strategies to manage health threats across humans, animals, plants, and the environment, to prevent prevent future pandemics. Collaborative efforts to identify risk factors enhances outbreak surveillance, livestock vaccination programs, and food safety regulations such as mandatory pasteurization, ensuring a sustainable and comprehensive approach disease management.[37]
The gold standard treatment for adults is dailyintramuscular injections of streptomycin 1 g for 14 days and oraldoxycycline 100 mg twice daily for 45 days (concurrently). Gentamicin 5 mg/kg by intramuscular injection once daily for 7 days is an acceptable substitute when streptomycin is not available or contraindicated.[38] Another widely used regimen is doxycycline plus rifampicin twice daily for at least 6 weeks. This regimen has the advantage of oral administration. A triple therapy of doxycycline, with rifampicin andco-trimoxazole, has been used successfully to treat neurobrucellosis.[39] Doxycycline plus streptomycin regimen (for 2 to 3 weeks) is more effective than doxycycline plus rifampicin regimen (for 6 weeks).[40]
Doxycycline can cross theblood–brain barrier, but requires the addition of two other drugs to prevent relapse.Ciprofloxacin and co-trimoxazole therapy are associated with an unacceptably high rate of relapse. In brucellicendocarditis, surgery is required for an optimal outcome. Even with optimal antibrucellic therapy, relapses still occur in 5 to 10% of patients with Malta fever.[citation needed]
The mortality of the disease in 1909, as recorded in the British Army and Navy stationed in Malta, was 2%. The most frequent cause of death wasendocarditis. Recent advances inantibiotics and surgery have been successful in preventing death due to endocarditis. Prevention of human brucellosis can be achieved by eradication of the disease in animals by vaccination and other veterinary control methods, such as testing herds/flocks and slaughtering animals when infection is present. Currently, no effective vaccine is available for humans. Boiling milk before consumption, or before using it to produce other dairy products, is protective against transmission via ingestion. Changing the traditional food habits of eating raw meat, liver, or bone marrow is necessary, but difficult to implement.[citation needed] Patients who have had brucellosis should probably be excluded indefinitely from donating blood or organs.[citation needed] Exposure of diagnostic laboratory personnel toBrucella organisms remains a problem in both endemic settings and when brucellosis is unknowingly imported by a patient.[41] After appropriate risk assessment, staff with significant exposure should be offered postexposure prophylaxis and followed up serologically for 6 months.[42]
According to a study published in 2002, an estimated 10–13% of farm animals were infected withBrucella species.[43] Annual losses from the disease were calculated at aroundUS$60 million. Since 1932,government agencies have undertaken efforts to contain the disease. As of 2022[update], all cattle aged 3–8 months must receive theBrucella abortus strain 19 vaccine.[44]
Australia is free of cattle brucellosis, although it occurred in the past. Brucellosis of sheep or goats has never been reported. Brucellosis of pigs does occur. Feral pigs are the typical source of human infections.[45][46]
On 19 September 1985, theCanadian government declared its cattle population brucellosis-free. Brucellosis ring testing of milk and cream, and testing of cattle to be slaughtered, ended on 1 April 1999. Monitoring continues through testing at auction markets, through standard disease-reporting procedures, and testing of cattle being qualified for export to countries other than the United States.[47]
An outbreak infecting humans took place inLanzhou in 2019 after the Lanzhou Biopharmaceutical Plant, which was involved in vaccine production, accidentally pumped out the bacteria into the atmosphere in exhaust air due to use of expired disinfectant.[48][49]
According to Georgios Pappas, an infectious-disease specialist and author of a report published in the journalClinical Infectious Diseases,[50] the result was "possibly the largest laboratory accident in the history of infectious diseases." According to Pappas, out of nearly 70,000 people tested, more than 10,000 were seropositive, citing figures compiled by the provincial health authorities in Lanzhou's Gansu province. Pappas also states that Chinese documents show that more than 3,000 people living near the plant applied for compensation, an indication of at least a mild illness.[51]
Until the early 20th century, the disease wasendemic in Malta to the point of it being referred to as "Maltese fever". Since 2005, due to a strict regimen of certification of milk animals and widespread use of pasteurization, the illness has been eradicated from Malta.[52]
Mainland Britain has been free of brucellosis since 1979, although there have been episodic reintroductions since.[55] The last outbreak of brucellosis in Great Britain was in cattle in Cornwall in 2004.[55][56] Northern Ireland was declared officially brucellosis-free in 2015.[55]
Dairy herds in the U.S. are tested at least once a year to be certified brucellosis-free[58] with theBrucella milk ring test.[59] Cows confirmed to be infected are often killed. In the United States,veterinarians are required[citation needed] tovaccinate all young stock, to further reduce the chance ofzoonotic transmission. This vaccination is usually referred to as a "calfhood" vaccination. Most cattle receive a tattoo in one of their ears, serving as proof of their vaccination status. This tattoo also includes the last digit of the year they were born.[60]
The first state–federal cooperative efforts towards eradication of brucellosis caused byB. abortus in the U.S. began in 1934.[citation needed]
Brucellosis was originally imported to North America with non-native domestic cattle (Bos taurus), which transmitted the disease to wildbison (Bison bison) andelk (Cervus canadensis). No records exist of brucellosis in ungulates native to America until the early 19th century.[61]
David Bruce (centre), with members of the Mediterranean Fever Commission (Brucellosis)The lab in which SirThemistocles Zammit and the Mediterranean Fever Commission carried out research about brucellosis from 1904 to 1906 is located within theCastellania inValletta,Malta.
Brucellosis first came to the attention ofBritish medical officers in the 1850s in Malta during theCrimean War, and was referred to as Malta Fever.Jeffery Allen Marston (1831–1911) described his case of the disease in 1861. The causal relationship between organism and disease was first established in 1887 byDavid Bruce.[62][63] Bruce considered the agent spherical and classified it as acoccus.[citation needed]
In 1897,DanishveterinarianBernhard Bang isolated abacillus as the agent of heightened spontaneous abortion in cows, and the name "Bang's disease" was assigned to this condition. Bang considered the organism rod-shaped and classified it as abacillus. At the time, no one knew that this bacillus had anything to do with the causative agent of Malta fever.[64]
Maltese scientist and archaeologistThemistocles Zammit identified unpasteurized goat milk as the major etiologic factor of undulant fever in June 1905.[65]
In the late 1910s, American bacteriologistAlice C. Evans was studying the Bang bacillus and gradually realized that it was virtually indistinguishable from the Bruce coccus.[66] The short-rod versus oblong-round morphologic borderline explained the leveling of the erstwhile bacillus/coccus distinction (that is, these "two" pathogens were not a coccus versus a bacillus but rather were onecoccobacillus).[66] The Bang bacillus was already known to beenzootic in American dairy cattle, which showed itself in the regularity with which herds experienced contagious abortion.[66] Having made the discovery that the bacteria were certainly nearly identical and perhaps totally so, Evans then wondered why Malta fever was not widely diagnosed or reported in the United States.[66] She began to wonder whether many cases of vaguely defined febrile illnesses were in fact caused by the drinking of raw (unpasteurized) milk.[66] During the 1920s, this hypothesis was vindicated. Such illnesses ranged from undiagnosed and untreated gastrointestinal upset to misdiagnosed[66] febrile and painful versions, some even fatal. This advance in bacteriological science sparked extensive changes in the American dairy industry to improvefood safety. The changes included makingpasteurization standard and greatly tightening the standards of cleanliness in milkhouses ondairy farms. The expense prompted delay and skepticism in the industry,[66] but the new hygiene rules eventually became the norm. Although these measures have sometimes struck people as overdone in the decades since, being unhygienic at milking time or in the milkhouse, or drinking raw milk, is not a safe alternative.[citation needed]
In the decades after Evans's work, this genus, which received the nameBrucella in honor of Bruce, was found to contain several species with varying virulence. The name "brucellosis" gradually replaced the 19th-century names Mediterranean fever and Malta fever.[67]
Neurobrucellosis, a neurological involvement in brucellosis, was first described in 1879. In the late 19th century, its symptoms were described in more detail by M. Louis Hughes, a Surgeon-Captain of theRoyal Army Medical Corps stationed in Malta who isolatedbrucella organisms from a patient with meningo-encephalitis.[68] In 1989,neurologists in Saudi Arabia made significant contributions to the medical literature involving neurobrucellosis.[69][70]
These obsolete names have previously been applied to brucellosis:[67][71]
Brucella species had been weaponized by several advanced countries by the mid-20th century. In 1954,B. suis became the first agentweaponized by the United States at itsPine Bluff Arsenal nearPine Bluff, Arkansas.Brucella species survive well in aerosols and resist drying.Brucella and all other remaining biological weapons in the U.S. arsenal were destroyed in 1971–72 when the American offensive biological warfare program was discontinued by order of PresidentRichard Nixon.[72]
The experimental American bacteriological warfare program focused on three agents of theBrucella group:[citation needed]
Agent US was in advanced development by the end ofWorld War II. When theUnited States Air Force (USAF) wanted a biological warfare capability, theChemical Corps offered Agent US in theM114 bomblet, based on the four-pound bursting bomblet developed for spreadinganthrax during World War II. Though the capability was developed, operational testing indicated the weapon was less than desirable, and the USAF designed it as an interim capability until it could eventually be replaced by a more effective biological weapon.[citation needed]
The main drawback of using the M114 with Agent US was that it acted mainly as an incapacitating agent, whereas the USAF administration wanted deadly weapons. The stability of M114 in storage was too low to allow for storing it at forward air bases, and the logistical requirements to neutralize a target were far higher than originally planned. Ultimately, this would have required too much logistical support to be practical in the field.[citation needed]
Agents US and AA had a median infective dose of 500 organisms/person, and for Agent AM, it was 300 organisms/person. The incubation time was believed to be about 2 weeks, with a duration of infection of several months. The lethality estimate was, based on epidemiological information, 1 to 2per cent. Agent AM was believed to be a somewhat more virulent disease, with a fatality rate of 3 per cent being expected.[citation needed]
Species infecting domestic livestock areB. abortus (cattle, bison, and elk),B. canis (dogs),B. melitensis (goats and sheep),B. ovis (sheep), andB. suis (caribou and pigs).Brucella species have also been isolated from several marine mammal species (cetaceans and pinnipeds).[citation needed]
B. abortus is the principal cause of brucellosis in cattle. The bacteria are shed from an infected animal at or around the time of calving orabortion. Once exposed, the likelihood of an animal becoming infected is variable, depending on age, pregnancy status, and other intrinsic factors of the animal, as well as the number of bacteria to which the animal was exposed.[73] The most common clinical signs of cattle infected withB. abortus are high incidences of abortions, arthritic joints, and retainedplacenta.[citation needed]
The causative agent of brucellosis indogs,B. canis, is transmitted to other dogs through breeding and contact with aborted fetuses. Brucellosis can occur in humans who come in contact with infected aborted tissue or semen. The bacteria in dogs normally infect the genitals andlymphatic system, but can also spread to the eyes,kidneys, andintervertebral discs. Brucellosis in the intervertebral disc is one possible cause ofdiscospondylitis. Symptoms of brucellosis in dogs include abortion in female dogs andscrotal inflammation andorchitis in males. Fever is uncommon. Infection of the eye can causeuveitis, and infection of the intervertebral disc can cause pain or weakness. Blood testing of the dogs prior to breeding can prevent the spread of this disease. It is treated with antibiotics, as with humans, but it is difficult to cure.[74]
Brucellosis in cetaceans is caused by the bacteriumB. ceti. First discovered in the aborted fetus of abottlenose dolphin, the structure ofB. ceti is similar toBrucella in land animals.B. ceti is commonly detected in two suborders of cetaceans, theMysticeti andOdontoceti. The Mysticeti include four families ofbaleen whales, filter-feeders, and the Odontoceti include two families of toothed cetaceans ranging from dolphins to sperm whales.B. ceti is believed to transfer from animal to animal through sexual intercourse, maternal feeding, aborted fetuses, placental issues, from mother to fetus, or through fish reservoirs. Brucellosis is a reproductive disease, so it has an extreme negative impact on the population dynamics of a species. This becomes a greater issue when the already low population numbers of cetaceans are taken into consideration.B. ceti has been identified in four of the 14 cetacean families, but the antibodies have been detected in seven of the families. This indicates thatB. ceti is common amongst cetacean families and populations. Only a small percentage of exposed individuals become ill or die. However, particular species apparently are more likely to become infected byB. ceti. The harbor porpoise, striped dolphin, white-sided dolphin, bottlenose dolphin, and common dolphin have the highest frequency of infection amongst odontocetes. In the mysticetes families, the northern minke whale is by far the most infected species. Dolphins and porpoises are more likely to be infected than cetaceans such as whales. Concerning sex and age biases, the infections do not seem influenced by an individual's age or sex. Although fatal to cetaceans,B. ceti has a low infection rate for humans.[75]
The disease in its various strains can infect multiple wildlife species, including elk (Cervus canadensis), bison (Bison bison), African buffalo (Syncerus caffer), European wild boar (Sus scrofa), caribou (Rangifer tarandus), moose (Alces alces), and marine mammals (see section on aquatic wildlife above).[76][77] While some regions use vaccines to prevent the spread of brucellosis between infected and uninfected wildlife populations, no suitable brucellosis vaccine for terrestrial wildlife has been developed.[78] This gap in medicinal knowledge creates more pressure for management practices that reduce spread of the disease.[78]
Wild bison and elk in the greaterYellowstone area are the last remaining reservoir ofB. abortus in the US. The recent transmission of brucellosis from elk back to cattle in Idaho and Wyoming illustrates how the area, as the last remaining reservoir in the United States, may adversely affect the livestock industry. Eliminating brucellosis from this area is a challenge, as many viewpoints exist on how to manage diseased wildlife. However, theWyoming Game and Fish Department has recently begun to protect scavengers (particularlycoyotes andred fox) on elk feedgrounds, because they act as sustainable, no-cost, biological control agents by removing infected elk fetuses quickly.[79]
The National Elk Refuge in Jackson, Wyoming, asserts that the intensity of the winter feeding program affects the spread of brucellosis more than the population size of elk and bison.[76] Since concentrating animals around food plots accelerates spread of the disease, management strategies to reduce herd density and increase dispersion could limit its spread.[76]
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