Brucellosis

Brucellosis
Classification and external resources
Specialty	Infectious disease
ICD-10	A23
ICD-9-CM	023
DiseasesDB	1716
MedlinePlus	000597
eMedicine	med/248
Patient UK	Brucellosis
MeSH	D002006

Brucellosis, Bang's disease, Crimean fever, Gibraltar fever, Malta fever, Maltese fever, Mediterranean fever, rock fever, or undulant fever, is a highly contagious zoonosis caused by ingestion of unpasteurized milk or undercooked meat from infected animals, or close contact with their secretions.

Brucella species are small, gram-negative, nonmotile, nonspore-forming, rod-shaped (coccobacilli) bacteria. They function as facultative intracellular parasites, causing chronic disease, which usually persists for life. Four species infect humans: B. abortus, B. canis, B. melitensis, and B. suis. B. abortus is less virulent than B. 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 include profuse sweating and joint and muscle pain. Brucellosis has been recognized in animals and humans since the 20th century.

Signs and symptoms

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

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 the 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 (joint and muscle pain). Blood tests characteristically reveal leukopenia and anemia, show some elevation of AST and ALT, and demonstrate positive Bengal Rose and Huddleston reactions.

This complex is, at least in Portugal, Palestine, and Jordan, known as 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 spondylodiscitis of the lumbar spine accompanied by sacroiliitis is very characteristic of this disease. Orchitis is also common 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 up to two 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 on hepatic biopsy
4. 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.

The disease's sequelae are highly variable and may include granulomatous hepatitis, arthritis, spondylitis, anaemia, leukopenia, thrombocytopenia, meningitis, uveitis, optic neuritis, endocarditis, and various neurological disorders collectively known as neurobrucellosis.

Cause

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, miscarriage, sweating, weakness, anaemia, headaches, depression, and muscular and bodily pain. The other strains, B. suis and B. canis, cause infection in pigs and dogs, respectively.

Diagnosis

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 for B. abortus than B. melitensis or B. suis. Identification of specific antibodies against bacterial lipopolysaccharide and other antigens can be detected by the standard agglutination test (SAT), rose Bengal, 2-mercaptoethanol (2-ME), antihuman globulin (Coombs’) and indirect enzymelinked immunosorbent assay (ELISA). SAT is the most commonly used serology in endemic areas. An agglutination titre greater than 1:160 is considered significant in nonendemic areas and greater than 1:320 in endemic areas. Due to the similarity of the O polysaccharide of Brucella to that of various other Gram-negative bacteria (e.g. Francisella tularensis, Escherichia coli, Salmonella urbana, Yersinia enterocolitica, Vibrio cholerae, and Stenotrophomonas maltophilia) the appearance of cross-reactions of class M immunoglobulins may occur. The inability to diagnose B. canis by SAT due to lack of cross-reaction is another drawback. False-negative SAT may be caused by the presence of blocking antibodies (the prozone phenomenon) in the α2-globulin (IgA) and in the α-globulin (IgG) fractions. Dipstick assays are new and promising, based on the binding of Brucella IgM antibodies, and found to be 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. 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, realtime PCR and PCR-ELISA) and found to have superior specificity and sensitivity in detecting both primary infection and relapse after treatment. Unfortunately, these have yet to be 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. Other laboratory findings include normal peripheral white cell count, and occasional leucopenia with relative lymphocytosis. The serum biochemical profiles are commonly normal.

Prevention

Argentina

According to a study published in 2002, an estimated 10-13% of farm animals are infected with Brucella species. Annual losses from the disease were calculated to be around 60 million dollars. Since 1932, government agencies have undertaken efforts to contain the disease. Currently, all cattle of ages 3–8 months is required to be given the Brucella abortus strain 19 vaccine.

Australia

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.

Canada

The Canadian government declared its cattle population to be brucellosis-free on 19 September 1985. The brucellosis ring testing of milk and cream, as well as the testing of cattle to be slaughtered, ended on 1 April 1999. Monitoring continues through testing at auction markets, through standard disease-reporting procedures, and through the testing of cattle being qualified for export to countries other than the United States.

Europe

Disease incidence map of B. melitensis infections in animals in Europe during the first half of 2006

  never reported

  not reported in this period

  confirmed clinical disease

  confirmed infection

  no information

Malta

Until the early 20th century, the disease was endemic in Malta to the point of it being referred to as "Maltese fever". The link between the illness and unpasteurised milk was established by David Bruce and his collaborator. Their discovery is commemorated by a plaque in Maltese and English on the outside of the Sacra Infirmeria, commonly known as the Knights' Hall (the Mediterranean Centre). In this building, Bruce, together with Joseph Caruana Scicluna, confirmed the existence of the microbe of undulant fever in the human spleen in 1887. Today, due to a strict regimen of certification of milk animals and widespread use of pasteurization, the illness has been eradicated from Malta.

Republic of Ireland

Ireland was declared free of brucellosis on 1 July 2009. The disease had troubled the country's farmers and veterinarians for several decades. The Irish government submitted an application to the European Commission, which verified that Ireland had been liberated. Brendan Smith, Ireland's then Minister for Agriculture, Food and the Marine, said the elimination of brucellosis was "a landmark in the history of disease eradication in Ireland". Ireland's Department of Agriculture, Food and the Marine intends to reduce its brucellosis eradication programme now that eradication has been confirmed.

New Zealand

Brucellosis in New Zealand is limited to sheep (B. ovis). The country is free of all other species of Brucella.

United States

Dairy herds in the USA to be certified brucellosis-free are tested at least once a year with the Brucella milk ring test. Cows 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. 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.

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

Brucellosis was originally imported to North America with non-native domestic cattle (Bos taurus), which transmitted the disease to wild bison (Bison bison) and elk (Cervus canadensis). No records exist of brucellosis in ungulates native to America until the early 19th century. Wild bison and elk in the greater Yellowstone area are the last remaining reservoir of B. 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. Purebred bison in the Henry Mountains of southern Utah are free of brucellosis.

Treatment

Antibiotics such as tetracyclines, 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 incubate within cells.

Surveillance using serological tests, as well as tests on milk like the milk ring test, can be used for screening and play an important role in campaigns to eliminate the disease. Also, individual animal testing both for trade and for disease-control purposes is practiced. In endemic areas, vaccination is often used to reduce the incidence of infection. Several vaccines are available that use modified live viruses. The World Organisation for Animal Health Manual of Diagnostic Test and Vaccines for Terrestrial Animals provides detailed guidance on the production of vaccines. As the disease is closer to being eliminated, a test and stamping out program is required to completely eliminate it.

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 seven days is an acceptable substitute when streptomycin is not available or contraindicated. Another widely used regimen is doxycycline plus rifampin twice daily for at least six weeks. This regimen has the advantage of oral administration. A triple therapy of doxycycline, with rifampin and co-trimoxazole, 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 to 10% of patients with Malta fever.

The main way of preventing brucellosis is by using fastidious hygiene in producing raw milk products, or by pasteurizing all milk that is to be ingested by human beings, either in its unaltered form or as a derivate, such as cheese. Co-trimoxazole and rifampin are both safe drugs to use in treatment of pregnant women who have brucellosis.

Prognosis

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 was endocarditis. Recent advances in antibiotics 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 traditional food habits of eating raw meat, liver, or bone marrow is necessary, but difficult to implement. Patients who have had brucellosis should probably be excluded indefinitely from donating blood or organs. Exposure of diagnostic laboratory personnel to Brucella organisms remains a problem in both endemic settings and when brucellosis is unknowingly imported by a patient. After appropriate risk assessment, staff with significant exposure should be offered postexposure prophylaxis and followed up serologically for 6 months. Recently published experience confirms that prolonged and frequent serological follow-up consumes significant resources without yielding much information, and is burdensome for the affected staff, who often fail to comply. The side effects of the usual recommended regimen of rifampicin and doxycycline for 3 weeks also reduce treatment adherence. As no evidence shows treatment with two drugs is superior to monotherapy, British guidelines now recommend doxycycline alone for 3 weeks and a less onerous follow-up protocol.

History

David Bruce (centre), with members of the Mediterranean Fever Commission (Brucellosis).

The lab in which Sir Themistocles Zammit and the Mediterranean Fever Commission carried out research about brucellosis from 1904 to 1906. It is located within the Castellania in Valletta, Malta.

Under the name "Malta fever", the disease now called brucellosis first came to the attention of British medical officers in the 1850s in Malta during the Crimean War. Jeffery Allen Marston (1831-1911) described his own case of the disease in 1861. The causal relationship between organism and disease was first established in 1887 by David Bruce.

In 1897, Danish veterinarian Bernhard Bang isolated B. abortus as the agent, and the additional name "Bang's disease" was assigned.

Maltese doctor and archaeologist Sir Themistocles Zammit earned a knighthood for identifying unpasteurized milk as the major source of the pathogen in 1905, and it has since become known as Malta fever. In cattle, this disease, usually caused by B. abortus, 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 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.

These obsolete names have previously been applied to brucellosis:

3

Biological warfare

Brucella species were weaponized by several advanced countries by the mid-20th century. In 1954, B. suis became the first agent weaponized by the United States at its Pine Bluff Arsenal near Pine 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 President Richard Nixon.

The experimental American bacteriological warfare 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 World War II. When the U.S. Army Air Forces (USAAF) wanted a biological warfare capability, the Chemical Corps offered Agent US in the M114 bomblet, based on the four-pound bursting bomblet developed for spreading anthrax during World War II. Though the capability was developed, operational testing indicated the weapon was less than desirable, and the USAAF designed it as an interim capability until it could replaced by a more effective biological weapon.

The main drawbacks of the M114 with Agent US was that it was an incapacitating agent, whereas the administration of the USAAF wanted deadly weapons. Also, the stability under storage was too low to allow for storing at forward air bases, and the logistical requirements to neutralize a target were far higher than originally planned. This would have required an unreasonable amount of logistical support.

Agents US and AB had a median infective dose of 500 organisms/person, and for Agent AM it was 300 organisms/person. The time-of-incubation was believed to be about two weeks, with a duration of infection of several months. The lethality estimate was based on epidemiological information at 1 to 2%. Agent AM was believed to be a more virulent disease, and a fatality rate of 3% was expected.

Other animals

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

Cattle

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 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 number of bacteria to which the animal was exposed. The most common clinical signs of cattle infected with B. abortus are high incidences of abortions, arthritic joints, and retained placenta.

The two main causes for spontaneous abortion in animals are erythritol, which can promote infections in the fetus and placenta, and 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 epididymes.

Cetaceans

Brucellosis is caused by the bacterium B. ceti. First discovered in the aborted fetus of a bottlenose dolphin, the structure of B. ceti is similar to Brucella in land animals. B. ceti is commonly detected in two suborders of cetaceans, the Mysticeti and Odontoceti. The Mysticeti include four families of baleen whales, filter-feeders, and the Odontoceti include two families of toothed cetaceans ranging from dolphins to sperm whales. B. ceti is believed to be transferred 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 has an extreme negative impact on the population dynamics of a species. This becomes even 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 dedicated in seven of the families. This indicates that B. ceti is common amongst cetacean families and populations. Only a small percentage of exposed individuals become ill or die, yet this disease affects half of cetacean families. However, particular species, it appears, are more likely to become infected by B. ceti. The harbor porpoise, striped dolphin, white-sided dolphin, bottlenose dolphin, and common dolphin have the highest frequency of infection amongst ondontocetes. 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. With regard to sex and age biases, the infections do not seem to be influenced by the age or sex of an individual. Although fatal to cetaceans, B. ceti has a low infection rate for humans.

Dogs

The causative agent of brucellosis in dogs, 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 and lymphatic system, but can also spread to the eyes, kidneys, and intervertebral discs. Brucellosis in the intervertebral disc is one possible cause of discospondylitis. Symptoms of brucellosis in dogs include abortion in female dogs and scrotal inflammation and orchitis 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.

In popular culture

• Brucellosis in cattle is a major plot point in Survivors series 3, episode 5, "Bridgehead" (airdate April 13, 1977).
• At the conclusion of Flannery O'Connor's short story "The Enduring Chill", the main character is diagnosed with undulant fever.

See also

• Andrew Moynihan Victoria Cross recipient who died from Malta fever
• Swine brucellosis
• Wildlife disease

External links

• Brucellosis information from KIT Biomedical research
• Brucellosis subject guide of the University of Navarra
• Fact sheet on Brucellosis from World Organisation for Animal Health
• Brucella genomes and related information at PATRIC, a Bioinformatics Resource Center funded by NIAID
• Prevention about Brucellosis from Centers for Disease Control
• – re high rate of brucellosis in humans in ancient Pompeii
• Brucellosis, factsheet from European Centre for Disease Prevention and Control
• 53805059 at GPnotebook
• Brucellosis in Dogs from The Pet Health Library
• Brucella Bioinformatics Portal
• Brucellosis Fact Sheet
• Special Issue: Brucellosis, Volume 4, 2010, The Open Veterinary Science Journal (ISSN [//www.worldcat.org/search?fq=x0:jrnl&q=n2:1874-3188 1874-3188)]