Tularemia (also known as rabbit fever, deer fly fever, Ohara's disease, glandular tick disease, Market men's disease, and Francis disease) is a zoonotic disease occurring predominantly in the Northern Hemisphere, caused by the bacterium Francisella tularensis. Tularemia is endemic throughout North America and continental Europe, Russia, China, and Japan, but is rare in the United Kingdom, Africa, and Central and South America. In the United States, the disease is most prevalent in Arkansas, Illinois, Missouri, Oklahoma, Virginia, and Tennessee, although cases have been reported from all states except Hawaii.1, 2
Tularemia is found in natural reservoirs including small mammals such as voles, mice, water rats, squirrels, rabbits, and hares. Naturally acquired human infection occurs through a variety of mechanisms: inoculation into skin or mucous membrane through bites of infected arthropods; handling infectious animal tissues or fluids; direct contact or ingestion of contaminated water, food, or soil; and inhalation of infective aerosols. Tularemia is predominantly a rural disease, infections are usually limited to persons at risk due to occupational or recreational exposure to infected animals or their habitat, including rabbit hunters, trappers, persons exposed to ticks or biting insects, and laboratory technicians working with F. tularensis.1, 2, 3
Tularemia clinical presentations include ulceroglandular, glandular, oculoglandular, oropharyngeal, pneumonic, typhoidal, and septic forms.
There is evidence that tularemia in man may have occurred as early as the nineteenth century in the US, Norway, Russia and Japan, but probably was not recognized as an infectious process. In the early 20th century a Japanese physician named Hachiro Ohara described a disease affecting those who hunted or ate rabbit. The Japanese called it Yato-Byo, meaning rabbit fever, which appeared to be endemic to the Abakuma Mountains.4 He recorded that during certain seasons, dead rabbits were seen in great numbers and human infection resulted from contact with dead or diseased rabbits. He then took some blood from an affected rabbit and rubbed it on his wife's skin. Within days, according to Ohara's report, a large ulcer appeared and she experienced clinical symptoms similar to those of people exposed in nature. Decades later, Ohara recognized that there were clinical differences between the Yato-Byo observed in Japan and the tularemia observed in the United States. 4
In 1910, a Utah physician, RA Pearse, described deer-fly fever. In 1911, George W. McCoy and Charles W. Chapin, from the US Public Health Service, began examining thousands of rats and ground squirrels in order to detect foci of suspected plague infections in San Francisco. Early in the investigation, McCoy noted that they had “encountered an infection with lesions which are readily mistaken for those of plague…It is barely possible that we unknowingly have dealt with more than one disease entity, as no etiological agent has been discovered.” A year later, they isolated the causative organism of this plague-like disease from California ground squirrels and named it Bacterium tularense after Tulare County where the work was performed.1, 4 In addition, McCoy and Chapin developed agglutination and complement fixation tests to aid in the diagnosis. The first bacteriologically confirmed case of human tularemia was reported in Cincinnati in 1914.
Dr. Edward Francis, also from the US Public Health Service, established the cause of deer-fly fever as Bacterium tularense in 1928. Because of his extensive contributions to the knowledge of the bacterium and the disease, the organism was later renamed Francisella tularensis.
During the next decades, a complex epidemiological picture of tularemia emerged, as new vectors, animal reservoirs, degrees of virulence, clinical manifestations, and geographical areas were identified. By 1929, four clinical types were recognized based on Dr. Francis' analysis of 800 cases. Francis added three more clinical types (meningeal, oropharyngeal, and pulmonary) in 1947. Tularemia was recognized as a significant human illness when large water-borne outbreaks occurred in the 1930s and 1940s in Europe and the Soviet Union. In 1959, Russian scientists recognized two subspecies. The first is F. tularensis biovar tularensis (type A), the most common biovar isolated in North America. It can be highly virulent in humans and animals, including its principal reservoir, the cottontail rabbit. The second subspecies is F. tularensis biovar palaearctica (type B), which is thought to be the cause of all human tularemia in Europe and Asia. It is relatively avirulent in humans, but can cause disastrous epizootics in its principal reservoirs, the water rat and vole rat.
Tularemia is widely endemic in Europe and Asia, with the greatest numbers of human cases reported from northern and central Europe, particularly Scandinavian countries, and from countries of the former Soviet Union. One of the largest recorded epidemics of pneumonic tularemia occurred in Sweden from 1966 to 1967. The central and north-central regions of Sweden had been endemic since 1931. The outbreak coincided with a large increase, followed by a sharp, drop in the number of voles in Northern Sweden. It is speculated that the large number of dead voles found in hay barns were the source of the disease.5 There were 2,739 reported cases of tularemia in humans during the 1966-67 epidemic, which is almost half of the total number of cases reported in Sweden from 1931 to 1993. An outbreak of tularemia with more than 400 cases was reported in that country in the summer and autumn of the year 2000. Neighboring Finland has had sporadic epidemics of tularemia since 1939 as well. The year-by-year variation in the incidence of human tularemia appears to be associated with fluctuations in the rabbit and vole populations, which are thought to be the main animal reservoirs. In recent years, the annual number of reported tularemia cases in Finland has ranged from 467 in 1995 to 87 in 1999.
As of February 2002, the Institute of Public Health in the Kosovo region of Yugoslavia, has reported 715 cases of tularemia since the outbreak began on November 1, 2001. One hundred and seventy cases have been laboratory confirmed, while 404 suspected cases were found to be negative. An additional 141 suspected cases remain under laboratory and epidemiological investigation. There have been no deaths to date.
The number of tularemia cases reported in the United States decreased during the latter half of the 20th century; the incidence peaked in 1939, with 2,291 cases. There were 1,368 cases of tularemia reported to the Centers for Disease Control from 1990 through 2000, with Oklahoma, Arkansas, and Missouri reporting the most cases. Approximately 200 to 300 eases are reported each year in the United States.2 In Texas, there were 12 cases of tularemia reported for the 1990-2000 time period.
In 1966, 12 cases occurred on the Pine Ridge and Rosebud Indian Reservations in South Dakota. This was the first of three tick-borne outbreaks of tularemia in this region of the United States. In 1979, 12 cases occurred on the Crow Indian Reservation in Montana. Between May and July of 1984, 20 definite and eight probable cases of tularemia were reported among residents of the adjoining Lower Brule and Crow Creek Indian Reservations in central South Dakota. Tularemia was spread through these two reservations by infected dog ticks. Like the first two epidemics, infection occurred predominantly among children, presumably due to their frequent contact with tick-infested dogs and to their outdoor activities in areas with large numbers of tularemia- infected ticks.6
The import of infected rabbits for sporting and recreation introduced tularemia to Cape Cod and Martha's Vineyard in Massachusetts, where it has been endemic since 1978. During the summer of 2000, fifteen cases of pneumonic tularemia, including one death, were reported in Martha's Vineyard. The infections were probably due to the aerosolization of F. tularensis by lawn mowers and brush cutters, which presumably stirred up the organism from the carcasses of infected animals.7
Tularemia as a biological weapon
The research of tularemia as a biological weapon began around World War II. Japan started an ambitious biological warfare program in occupied Manchuria in 1937, in a laboratory complex known as Unit 731. Studies directed by Japanese General Ishii continued there until 1945, when the complex was destroyed. A post World War II investigation revealed that the Japanese researched numerous organisms and used thousands of prisoners of war as research subjects. Ishii's scientists concentrated their studies on anthrax, but studied several pathogens, including tularemia.1, 3
In the spring of 1942, President Roosevelt and British Prime Minister Winston Churchill announced policies limiting the use of biological weapons only to retaliation, closely paralleling the Geneva Protocol of 1925. But these new policies did not prevent the United States and Great Britain from building arsenals of biological weapons. By 1943, the research center and pilot plant at Camp Dietrick employed over 3,800 military and 100 civilian personnel. During World War II, the United States worked primarily on anthrax and botulism; however, brucellosis, tularemia, and glanders were also studied.
In the 1950s and 1960s, the US military developed weapons that would disseminate F. tularensis aerosols; concurrently, it conducted research to better understand the pathophysiology of tularemia and to develop countermeasures, such as vaccines, antibiotic prophylaxis, and treatment regimens.1, 3 Though tularemia was never used, it became a part of the US military's inventory during the Vietnam War. In 1969, President Nixon ordered the destruction of the US biological stockpile, including F. tularensis; the order was carried out during 1971 and 1972.
In the Soviet Union, Biopreparat was clandestinely established in 1973 by order of Leonid Brezhnev, eventually developing the world's most advanced program for genetically engineered biological weapons. By the late 1980s approximately 60,000 persons were employed in the development and production of biological weapons, including 30,000 Biopreparat employees. The Soviet Union continued weapons production of antibiotic and vaccine resistant strains into the early 1990s. Vaccine-resistant tularemia was developed in 1982.
According to one author, however, the Soviet Union began experimenting with biological weapons years before Biopreparat was established. In 1942, shortly before the Battle of Stalingrad, a large outbreak of tularemia occurred on the German-Soviet front. Many thousands of Soviet and German Wehrmacht troops reportedly contracted the illness. In a recent book, Dr. Kenneth Alibek (aka Kanatjan Alibekov), the former deputy director of Biopreparat and chief scientist of the Soviet offensive biological warfare program, has suggested that the Soviet Red Army used tularemia as a biological weapon during this battle to help stop the advance of the German panzer troops. The Soviet troops also contracted the disease because of what Alibek suspects was a sudden change in wind direction. He bases some of his claims on the high incidence of pneumonic tularemia (reportedly as high as 70%) during this epidemic. Outbreaks of pneumonic tularemia, particularly in low-incidence areas, are considered a warning flag for a possible bioterrorism attack.
Several authors dispute Alibek's speculations. Instead, some suggest that the outbreak was likely due to tularemia foci already in existence in the Rostov region (which had over 14,000 cases of tularemia by 1942) and to the wartime breakdown of public health and hygienic infrastructures.8 Another author points to the fact that crops in the region were abandoned during the war and were probably infested by disease-bearing rodents and other animals. The high incidence of pneumonic tularemia can be explained by the fact that troops likely inhaled tularemia-infected dust from the field hay, which was used as bedding.
In the United States, tularemia was removed from the list of nationally notifiable diseases in 1994, but increased concerns about the potential use of F. tularensis as a biological weapon led to its reinstatement in 2000.
The Working Group on Civilian Biodefense identified in May of 2000 a limited number of agents that, if used as weapons, could cause disease and death in sufficient numbers to cripple a city or region. These agents coincide with the Centers for Disease Control's list of Critical Biological Agents. F. tularensis is included among these pathogens because of the capacity for its mass production and aerosol dissemination and because of its low infectious dose (1 to 10 organisms by aerosol or intradermal route). The overall mortality rate for severe Type A strains has been 5-15%, but in pneumonic or septicemic cases of tularemia without antibiotics treatment the mortality rate has been as high as 30-60%. Although F. tularensis could be used as a weapon in a number of ways, the Working Group believes that an aerosol release would have the greatest adverse medical and public health consequences. A World Health Organization (WHO) expert committee reported in 1970 that 50 kg of virulent F. tularensis dispersed as an aerosol over a population of 5 million could result in an estimated 250,000 incapacitating casualties, including 19,000 deaths.9 Such an attack could result in a large number of temporally clustered patients presenting with similar systemic illnesses and probably produce pneumonia with or without accompanying mucous membrane lesions. The clinical course could progress to respiratory failure, shock, and death if left untreated.
1 Evans ME, Friedlander AM. Tularemia. In: Textbook of Military Medicine. Medical aspects of chemical and biological warfare. Washington, DC. Medical Research Institute of Chemical Defense; 1997:503-512.
2 Anon. Tularemia- United States, 1990-2000. MMWR. March 8, 2001; 51: 181-204.
3 Dennis DT, Inglesby TV, Henderson DA, Bartlett JG, et al. Tularemia as a biological weapon. Medical and public health management [consensus statement]. JAMA. June 6, 2001; 284: 2763-2773.
4 Jewllison WL, editor. Tularemia in North America, 1930-1974. Missoula, Montana: University of Montana Printing Department; 1974.
5 Christenson, B. An outbreak of tularemia in the northern part of central Sweden. Scandinavian Journal of Infectious Diseases. November 1984;16:285-290.
6 Anon. Outbreak of Tick-Borne Tularemia - South Dakota. MMWR. October 26, 1984; 42:601-602.
7 Anon. Tularemia investigation and prevention on Martha's Vineyard. GPPH Rounds. Fall 2001. 1-4.
8 Croddy E, Krcalova S. Tularemia, biological warfare, and the Battle for Stalingrad (1942-1943) [editorial]. Military Medicine. October 2001; 166. Date accessed: March 19, 2002.
9 Health Aspects of Chemical and Biological Weapons. Geneva, Switzerland: World Health Organization; 1970:105-107.
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