Tularemia, or rabbit fever, is caused by the infectious bacterial agent Francisella tularensis. The disease is characterized by fever, localized skin or mucous membrane ulceration, regional lymphadenopathy, and occasionally pneumonia. The Gram-negative, non-motile, enveloped coccobacillus exists in two different forms: Francisella tularensis tularensis (Jellison type A) and Francisella tularensis holarctica (Jellison type B). The most common isolate in the United States, the Jellison type A tularemia is more virulent in rabbits and humans than Jellison type B, which is typically found in water, mosquitoes, and aquatic mammals. Type B is more common outside the United States. The bacteria are extremely infectious: 10-50 organisms are enough for transmit the disease and 90-100% of the exposed population will develop symptoms.
History of Tularemia
Evidence of tularemia infection in human populations first surfaced in the late 19th Century in the United States, Norway, Russia and Japan. In the early 20th Century, Japanese physician Hachiro Ohara wrote of a disease that affected rabbits and those who ate rabbits. In Japanese, the disease was called Yato-Byo or rabbit fever. According to reports, Doctor Ohara took blood from an infected rabbit and rubbed it on his wife's skin. A large ulcer appeared and Doctor Ohara's wife developed the characteristic symptoms of tularemia. Further, Doctor Ohara saw the connections between Yato-Byo in Japan and cases of tularemia described by physicians in the United States.
In 1911, George McCoy and Charles Chapin of the US Public Health Service were studying rats and ground squirrels they believed to have been infected with plague. They discovered an entirely separate disease and isolated the bacteria that caused the disease in California ground squirrels. McCoy and Chapin named the bacteria Bacterium tularense after the location, Tulare County, California, where their investigation took place. In 1928, Dr. Edward Francis of the US Health Service linked the causal bacteria agent of deer-fly fever to the bacteria discovered by McCoy and Chapin. The bacteria was renamed Francisella tularensis in Dr. Francis' honor. Further, Francis described seven types of the disease and examined different cases including meningeal, oropharyngeal, and pulmonary forms of tularemia. In addition to insect vectors that facilitated transmission, large waterborne outbreaks occurred in the 1930s and 1940s.
In 1959, the existence of two subspecies of Francisella tularensis were discovered by Russian scientists. The first, type A, isolated in humans and cottontail rabbits in North America, was more virulent. Type B, found primarily in Europe and Asia, was not particularly virulent to humans but causes mass deaths in the water and vole rat populations. A third proposed subspecies Francisella tularensis japonica was not adopted as few differences existed between the Japanese strain and other tularemia bacteria. Scientists differentiated two other subspecies of Francisella tularensis, the mediasiatica found in Central Asia and the novicida associated with the waterborne transmission of tularemia. As of 2007, investigations regarding other possible subspecies with the tularensis 16S rRNA sequence are ongoing.
In 1966-7, a large pneumonic outbreak, the largest recorded outbreak of tularemia, took place in Sweden. More than 2,700 cases of infection from Francisella tularensis type B bacteria were reported during the outbreak. Farm work activities such as the tossing of hay (which were contaminated by dead, diseased voles) during the winter aerosolized the bacteria and facilitated human infection. The outbreak resulted in at least 140 cases of inhalation tularemia. In late summer and early autumn, mosquitoes also rapidly transmitted the disease. Additionally, cat ownership correlated with tularemia spread. Despite the large number of infections, no deaths resulted. In 2000 another outbreak occurred in Sweden where more than 400 cases were reported. Outbreaks have also been reported in Finland, and in 2002, an outbreak of more than 700 cases was reported in Kosovo.
In the United States, tularemia remains endemic. Imported rabbits to Martha's Vineyard for recreational purposes brought the Francisella tularensis bacteria, and an outbreak occurred in 1978. In the summer of 2000, 15 cases of tularemia were reported at Martha's Vineyard, 11 were pneumonic tularemia, and there was one fatality. Landscapers were noted to be especially susceptible to the disease.
History of Tularemia as a Biological Agent
During World War II, the Japanese biological weapons operation Unit 731 expressed interest in tularemia. Ken Alibek, formerly Kanatjan Alibekov, who secretly immigrated to the United States in 1992, revealed information about Soviet experimentation with tularemia as a biological weapons agent prior to World War II. In his 1999 book Biohazard, Alibek reported the possible use of tularemia against German troops shortly before the Battle of Stalingrad. Alibek based his claims on evidence of highly infectious tularemia outbreaks among the soldiers during that time. Some scientists argued that an outbreak from natural causes was the more likely explanation. The former deputy director of the Soviet biological weapons program, Biopreparat, Alibek himself may have been accidentally infected by tularemia bacteria due to a leaky fermentor. In 1982, it was reported that Biopreparat developed a vaccine-resistant strain of tularemia.
Fort Detrick in Maryland, the center of the US biological weapons program, was built in 1942. In the 1950s and 1960s, the United States biological weapons program also developed the potential of using Francisella tularensis bacteria as a biological agent. Volunteers were infected with the bacteria through direct an aerosol delivery system and in the aerosol chamber known at Fort Detrick as the 8 ball, the largest aerosol testing facility in the world. Most of the volunteers were Seventh Day Adventists, army recruits whose religious beliefs did not allow them to participate in combat. The program developed a vaccine that partially protected against the virulent Schu S-4 strain of the tularemia bacteria. The Schu S-4 strain was labeled Agent UL and standardized for use in E120 bursting spherical bomblet. By the 1960s, the US program was able to freeze droplets of tularemia bacteria in a concentrated liquid culture that could be stored up to 3 years at -18 degrees Celsius.
In 1965, near Hawaii, the US biological weapons program tested aerosolized tularemia bacteria on barges populated with monkeys in the deck and in the hold. A military aircraft sprayed a 32 mile line of Agent UL. Over the Pacific, the bacteria were infectious for 60 miles. After a few days of incubation, half the monkeys developed symptoms and most of the sick monkeys died. Since the end of the US biological weapons program, the US Army Research Institute continued to conduct defensive medical research on the Francisella tularensis agent.
A World Health Organization (WHO) expert committee in 1969 estimated that 50 kilograms of Francisella tularensis sprayed in aerosol form over a city of 5 million inhabitants would result in 250,000 incapacitating casualties and 19,000 fatalities. Such an aerosol attack would result in acute symptoms of pleuropneumonic tularemia 3-5 days following the exposure. Tularemia is difficult to diagnose and often under-diagnosed in natural infections. Proper laboratory isolation of the bacterial agent and diagnosis could take weeks. The victims would be incapacitated for a few weeks and relapses would be expected months after the attack. The US Center for Disease Control (CDC) estimated that a tularemia attack would cost society $5.4 million in damages for every 100,000 persons exposed. Vaccinated individuals would only be partially protected. Although inhalation tularemia would be less virulent than inhalation anthrax or plague, tularemia bacteria is distinguished by its superior infectiousness.
Francisella tularensis bacteria can be found in nature and can be purchased for legitimate scientific research purposes. Due to its impressive infectiousness, the Center for Disease Control labels tularemia as a Category A biological weapons agent.
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