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Brucellosis
Specialty	Infectious diseases, veterinary medicine

Brucellosis, also called undulant fever, or Malta fever, is a highly contagious zoonosis caused by ingestion of unsterilized milk or meat from infected animals, or close contact with their secretions. Brucella spp. are small, gram-negative, non-motile, non-spore-forming rods, which function as facultative intracellular parasites that cause chronic disease, which usually persists for life. Brucellosis has been recognized in both animals and humans since the 19th century.

History and nomenclature

The disease now called brucellosis, under the name "Mediterranean fever", first came to the attention of British medical officers in Malta during the Crimean War in the 1850s. The causal relationship between organism and disease was first established by Dr. David Bruce in 1887.

In 1897 Danish veterinarian Bernhard Bang 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.

Maltese doctor and archaeologist Sir Temi Zammit identified unpasteurized milk as the major source of the pathogen in 1905, and it has since become known as Malta Fever, or deni rqiq locally. In cattle this disease is also known as contagious abortion and 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, Saudi Arabian neurologists discovered neurobrucellosis, a neurological involvement in brucellosis.

Transmission and incubation

American Bison involved in a brucellosis vaccine study

The disease is transmitted primarily through contaminated or untreated milk (and its derivatives) or through direct contact with infected animals, which may include dogs, pigs, camels and ruminants, primarily sheep, goats, cattle, bison. This also includes contact with their carcasses. Leftovers from parturition are also extremely rich in highly virulent brucellae. Infection may also occur by ingesting contaminated grass, roughage, feed, or water. Once the susceptible animal ingests the organism, the bacterium progresses to the regional lymph nodes where it resides during the incubation period. The incubation period is the time between inoculation (entry into the host) and the appearance of signs and symptoms of the disease, and may range from two weeks to two months and longer in case of brucellosis. After a subsequent brief phase when the bacteria are in the bloodstream, the organisms colonize the uterus, placenta, udder, and/or regional lymph nodes. Although the most common clinical sign of brucellosis in cattle is abortion, no overt clinical signs may be seen with it. The animal is likely to be seronegative shortly after exposure due to the lag time between exposure and seroconversion or clinical disease. Brucellae, along with leptospira, have the unique property of being able to penetrate through intact human skin so infection by mere hand contact with infectious material is likely to occur.

Brucellosis in animals

Species infecting domestic livestock are B. melitensis (goats and sheep), B. suis (pigs, see Swine brucellosis), B. abortus (cattle and bison), B. ovis (sheep), and B. canis (dogs). B. abortus also infects bison and elk in North America and B. suis is endemic in caribou. Brucella species have also been isolated from several marine mammal species (pinnipeds and cetaceans.)

Brucellosis in cattle

The bacterium Brucella abortus is the principal cause of brucellosis in cattle. The bacteria are shed from an infected animal at or around the time of calving or abortion. 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 amount of bacteria to which the animal was exposed. The most common clinical signs of cattle infected with Brucella abortus are high incidences of abortions, arthritic joints and retained after-birth. There are two main causes for spontaneous abortion in animals. The first is due to erythrotol, which can promote infections in the fetus and placenta. Second is due to the lack of anti-Brucella activity in the amniotic fluid. Males can also harbor the bacteria in their reproductive tracts, namely seminal vesicles, ampullae, testicles, and epididymides.

Dairy herds in the USA are tested at least once a year with the Brucella Milk Ring Test (BRT). Cows that are confirmed to be infected are often killed. In the United States, veterinarians are required to vaccinate all young stock, thereby further reducing the chance of zoonotic transmission.

Canada declared their cattle herd brucellosis-free on September 19, 1985. Brucellosis ring testing of milk and cream, as well as testing of slaughter cattle, ended April 1, 1999. Monitoring continues through auction market testing, standard disease reporting mechanisms, and testing of cattle being qualified for export to countries other than the USA.

The first state-federal cooperative efforts towards eradication of brucellosis caused by Brucella abortus in the U.S. began in 1934.

Brucellosis in the Greater Yellowstone area

Wild bison and elk in the Greater Yellowstone Area (GYA) are the last remaining reservoir of Brucella abortus in the U.S. The recent transmission of brucellosis from elk to cattle in Idaho and Wyoming illustrates how brucellosis in wildlife in the GYA may negatively affect cattle. Eliminating brucellosis from this area is a challenge because these animals are on public land and there are many viewpoints involved in the management of these animals.

Brucellosis in dogs

The causative agent of brucellosis in dogs is Brucella canis. It is transmitted to other dogs through breeding and contact with aborted fetuses. Brucellosis can occur in humans that come in contact with infected aborted tissue or semen. The bacteria in dogs normally infect the genitals and lymphatic system, but can also spread to the eye, kidney, and intervertebral disc (causing discospondylitis). Symptoms of brucellosis in dogs include abortion in female dogs and scrotal inflammation and orchitis (inflammation of the testicles) in males. Fever is uncommon. Infection of the eye can cause uveitis, 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.

Brucellosis in humans

Symptoms

Granuloma and necrosis in the liver of a guinea pig infected with Brucella suis

Brucellosis in humans is usually associated with the consumption of unpasteurized milk and soft cheeses made from the milk of infected animals, primarily goats, infected with Brucella melitensis and with occupational exposure of laboratory workers, veterinarians and slaughterhouse workers. Some vaccines used in livestock, most notably B. abortus strain 19, also cause disease in humans if accidentally injected. Brucellosis induces inconstant fevers, sweating, weakness, anaemia, headaches, depression and muscular and bodily pain.

The symptoms are like those associated with many other febrile diseases, but with emphasis on muscular pain and sweating. The duration of the disease can vary from a few weeks to many months or even years. In first stage of the disease, septicaemia occurs and leads to the classic triad of undulant fevers, sweating (often with characteristic smell, likened to wet hay) and migratory arthralgia and myalgia. In blood tests, is characteristic the leukopenia and anaemia, some elevation of AST and ALT and positivity of classic Bengal Rose and Huddleson reactions. This complex is, at least in Portugal, known as the Malta fever. During episodes of Malta fever, melitococcemia (presence of brucellae in blood) can usually be demonstrated by means of blood culture in tryptose medium or Albini medium. If untreated, the disease can give origin to focalizations or become chronic. The focalizations of brucellosis occur usually in bones and joints and spondylodisciitis of lumbar spine accompanied by sacroiliitis is very characteristic of this disease. Orchitis is also frequent in men.

Diagnosis of brucellosis relies on:

1. Demonstration of the agent: blood cultures in tryptose broth, bone marrow cultures. The growth of brucellae is extremely slow (they can take until 2 months to grow) and the culture poses a risk to laboratory personnel due to high infectivity of brucellae.
2. 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
3. Histologic evidence of granulomatous hepatitis (hepatic biopsy)
4. Radiologic alterations in infected vertebrae : the Pedro Pons sign (preferential erosion of antero-superior corner of lumbar vertebrae) and marked osteophytosis are suspicious of brucellic spondylitis.

The disease's sequelae are highly variable and may include granulomatous hepatitis, arthritis, spondylitis, anaemia, leukopenia, thrombocytopenia, meningitis, uveitis, optic neuritis and endocarditis.

Treatment and prevention

Antibiotics like tetracyclins, rifampicin and the aminoglycosides streptomycin and gentamicin are effective against Brucella bacteria. However, the use of more than one antibiotic is needed for several weeks, because the bacteria incubates within cells.

The gold standard treatment for adults is daily intramuscular injections of streptomycin 1 g for 14 days and oral doxycycline 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 difficult to obtain. Another widely used regimen is doxycycline plus rifampin twice daily for at least 6 weeks. This regimen has the advantage of oral administration. A triple therapy of doxycycline, together with rifampin and cotrimoxazole has been used successfully to treat neurobrucellosis. Doxycycline is able to cross the blood-brain barrier, but requires the addition of two other drugs to prevent relapse. Ciprofloxacin and co-trimoxazole therapy is associated with an unacceptably high rate of relapse. In brucellic endocarditis surgery is required for an optimal outcome. Even with optimal antibrucellic therapy relapses still occur in 5-10 percent of patients with Malta fever. The main way of preventing brucellosis is by using fastidious hygiene in producing raw milk products, or by pasteurization of all milk that is to be ingested by human beings, either in its pure form or as a derivate, such as cheese. Experiments have shown that cotrimoxyzol and rifampin are both safe drugs to use in treatment of pregnant women who have Brucellosis.

Biological warfare

In 1954, B. suis became the first agent weaponized by the United States at its Pine Bluff Arsenal in 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 U.S. offensive biological weapons (BW) program was discontinued.

The United States BW program focused on three agents of the Brucella group:

• Porcine Brucellosis (Agent US)
• Bovine Brucellosis (Agent AB)
• Caprine Brucellosis (Agent AM)

Agent US was in advanced development by the end of the Second World War. When the USAF wanted a biological warfare capability, the Chemical Corps offered Agent US in the M114 bomblet, based after the 4-pound bursting bomblet developed for anthrax in the Second World War. Though the capability was developed, operational testing indicated that the weapon was less than desirable, and the USAF termed it an interim capability until replaced by a more effective biological weapon. The main drawbacks of the M114 with Agent US was that it was incapacitating (the USAF wanted "killer" agents), the storage stability was too low to allow for storing at forward air bases, and the logistical requirements to neutralize a target were far higher than originally anticipated, requiring unreasonable logistical air support.

Agents US and AB had a median infective dose of 500 org/person, and AM was 300 org/person. The rate-of-action was believed to be 2 weeks, with a duration of action of several months. The lethality estimate was based on epidemiological information at 1 - 2%. AM was always believed to be a more virulent disease, and a 3% fatality rate was expected.

Historical names

In addition to "Malta Fever" and "undulant fever", the following obsolete names have previously been applied to brucellosis:

• Mediterranean fever
• continued fever
• Cyprus fever
• goat fever
• Gibraltar fever
• Crimean fever
• mountain fever
• Neapolitan fever
• rock fever
• slow fever
• febris melitensis
• febris undulans
• Bruce's septicemia
• melitensis septicemia
• melitococcosis
• Brucelliasis
• Milk Sickness

Popular culture references

• The disease was referred to in the song "Play It All Night Long" by American singer/songwriter Warren Zevon. The song is about a presumably Southern farming family going through hard times: "The cattle all have brucellosis, we'll get through somehow."
• In Flannery O'Connor's short story "The Enduring Chill," the protagonist Asbury is diagnosed with undulant fever. In an act of defiance against what he considers his mother's overbearing ways, he violates a strict rule on her dairy farm by drinking raw milk. The brucellosis he contracts reduces him to an invalid dependent on his mother's care.
• It was also mentioned in All Things Bright and Beautiful, one volume in the memoirs of James Herriot, a Scottish veterinarian who began practice in the 1930s. James Herriot is the pen name of veterinarian James Alfred Wight.
• It was prominently featured in one of the episodes of TV show House entitled "Sex Kills".
• A Brucellosis-like disease called "calpine feaver" was mentioned in Silence of the Goats, an episode of the animated show Weird Years.
• The character Renzi in the Kydd series of novels contracts undulant fever in the book Command.
• Hillary Clinton was offered a fermented milk drink while traveling on a state trip through Mongolia when she was First Lady. When her personal physician found out she had accepted the drink, he ordered her to take a strong course of antibiotics to protect against the risk of brucellosis.

See also

• Swine brucellosis
• Florence Nightingale (She may have suffered from brucellosis in the Crimea.)
• Wildlife disease

External links

• Brucella abortus biovar 1 str. 9-941 (from PATRIC, the PathoSystems Resource Integration Center, a NIAID Bioinformatics Resource Center)
• Brucella melitensis biovar Abortus 2308 (from PATRIC, the PathoSystems Resource Integration Center, a NIAID Bioinformatics Resource Center)
• Prevention about Brucellosis from Center for Disease Control
• Capasso L (2002). "Bacteria in two-millennia-old cheese, and related epizoonoses in Roman populations". J. Infect. 45 (2): 122–7. PMID 12217720. {{cite journal}}: Unknown parameter |month= ignored (help) - re high rate of brucellosis in humans in ancient Pompeii
• Brucellosis factsheet from European Centre for Disease Prevention and Control
• . GPnotebook https://www.gpnotebook.co.uk/simplepage.cfm?ID=53805059. {{cite web}}: Missing or empty |title= (help)
• Brucellosis in Dogs from The Pet Health Library
• Brucella from PATRIC
• Brucella Bioinformatics Portal
• Brucellosis Fact Sheet