Tularemia
Encyclopedia
Tularemia is a serious infectious disease
Infectious disease
Infectious diseases, also known as communicable diseases, contagious diseases or transmissible diseases comprise clinically evident illness resulting from the infection, presence and growth of pathogenic biological agents in an individual host organism...

 caused by the bacterium Francisella tularensis
Francisella tularensis
Francisella tularensis is a pathogenic species of gram-negative bacteria and the causative agent of tularemia or rabbit fever. It is a facultative intracellular bacterium....

. A Gram-negative
Gram-negative
Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...

, nonmotile
Motility
Motility is a biological term which refers to the ability to move spontaneously and actively, consuming energy in the process. Most animals are motile but the term applies to single-celled and simple multicellular organisms, as well as to some mechanisms of fluid flow in multicellular organs, in...

 coccobacillus
Coccobacillus
A coccobacillus is a type of rod-shaped bacteria. The word coccobacillus reflects an intermediate shape between coccus and bacillus . Coccobacilli rods are so short and wide that they resemble cocci. Haemophilus influenzae and Chlamydia trachomatis are coccobacilli...

, the bacterium has several subspecies with varying degrees of virulence
Virulence
Virulence is by MeSH definition the degree of pathogenicity within a group or species of parasites as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. The pathogenicity of an organism - its ability to cause disease - is determined by its...

. The most important of those is F. tularensis tularensis (Type A), which is found in lagomorphs in North America, and is highly virulent in humans and domestic rabbits. F. tularensis palaearctica (Type B) occurs mainly in aquatic rodents (beaver
Beaver
The beaver is a primarily nocturnal, large, semi-aquatic rodent. Castor includes two extant species, North American Beaver and Eurasian Beaver . Beavers are known for building dams, canals, and lodges . They are the second-largest rodent in the world...

s, muskrat
Muskrat
The muskrat , the only species in genus Ondatra, is a medium-sized semi-aquatic rodent native to North America, and introduced in parts of Europe, Asia, and South America. The muskrat is found in wetlands and is a very successful animal over a wide range of climates and habitats...

s) in North America and in hares and small rodents in northern Eurasia. It is less virulent for humans and rabbits. The primary vectors are tick
Tick
Ticks are small arachnids in the order Ixodida, along with mites, constitute the subclass Acarina. Ticks are ectoparasites , living by hematophagy on the blood of mammals, birds, and sometimes reptiles and amphibians...

s and deer flies
Deer fly
Deer flies are flies in the genus Chrysops of the family Tabanidae that can be pests to cattle, horses, and humans. A distinguishing characteristic of a deer fly is patterned gold or green eyes....

, but the disease can also be spread through other arthropod
Arthropod
An arthropod is an invertebrate animal having an exoskeleton , a segmented body, and jointed appendages. Arthropods are members of the phylum Arthropoda , and include the insects, arachnids, crustaceans, and others...

s. The disease is named after Tulare County, California
Tulare County, California
Tulare County is a county located in the Central Valley of the U.S. state of California, south of Fresno. Sequoia National Park is located in the county, as are part of Kings Canyon National Park, in its northeast corner , and part of Mount Whitney, on its eastern border...

.

History

The bacterium was first isolated by GW McCoy of the US Public Health Service plague lab and reported in 1912. Scientists determined tularemia could be dangerous to humans; a human being may catch the infection after contacting an infected animal. The ailment soon became frequent with hunters, cooks and agricultural workers.

Epidemiology

The disease is endemic
Endemic (epidemiology)
In epidemiology, an infection is said to be endemic in a population when that infection is maintained in the population without the need for external inputs. For example, chickenpox is endemic in the UK, but malaria is not...

 in North America, and parts of Europe and Asia. The most common mode of transmission is via arthropod
Arthropod
An arthropod is an invertebrate animal having an exoskeleton , a segmented body, and jointed appendages. Arthropods are members of the phylum Arthropoda , and include the insects, arachnids, crustaceans, and others...

 vectors. Ticks involved include Amblyomma
Amblyomma
Amblyomma is a genus of hard ticks. Some are disease vectors, for example for Rocky Mountain spotted fever in Brazil or ehrlichiosis and anaplasmosis in the USA....

, Dermacentor
Dermacentor
Dermacentor is a genus of hard-bodied ticks.-Species:* Dermacentor abaensis Teng, 1963* Dermacentor albipictus Packard, 1869* Dermacentor andersoni Stiles 1908* Dermacentor asper Arthur, 1960...

, Haemaphysalis
Haemaphysalis
Haemaphysalis is a genus of tick.-Species:* Haemaphysalis aborensis Warburton, 1913* Haemaphysalis aciculifer Warburton 1913* Haemaphysalis aculeata Lavarra, 1904* Haemaphysalis adleri Feldman-Muhsam, 1951...

, and Ixodes
Ixodes
Ixodes is a genus of hard-bodied ticks . It includes important disease vectors of animals and humans . Some ticks in this genus may transmit the pathogenic bacterium Borrelia burgdorferi responsible for causing Lyme disease...

. Rodent
Rodent
Rodentia is an order of mammals also known as rodents, characterised by two continuously growing incisors in the upper and lower jaws which must be kept short by gnawing....

s, rabbits, and hares often serve as reservoir hosts
Natural reservoir
Natural reservoir or nidus, refers to the long-term host of the pathogen of an infectious disease. It is often the case that hosts do not get the disease carried by the pathogen or it is carried as a subclinical infection and so asymptomatic and non-lethal...

, but waterborne infection accounts for 5 to 10% of all tularemia in the US. Tularemia can also be transmitted by biting flies, particularly the deer fly Chrysops discalis. Individual flies can remain infective for 14 days and ticks for over two years. Tularemia may also be spread by direct contact with contaminated animals or material, by ingestion of poorly cooked flesh of infected animals or contaminated water, or by inhalation.

In the United States, although records show that tularemia was never particularly common, incidence rates
Incidence (epidemiology)
Incidence is a measure of the risk of developing some new condition within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during some time period, it is better expressed as a proportion or a rate with a denominator.Incidence proportion is the...

 continued to drop over the course of the 20th century, so between 1990 and 2000, the rate was less than 1 per 1,000,000, meaning the disease is extremely rare in the US today.

Clinical manifestations and microbiological diagnosis

Depending on the site of infection, tularemia has six characteristic clinical syndromes: ulceroglandular (the most common type representing 75% of all forms), glandular, oropharyngeal, pneumonic, oculoglandular, and typhoidal.

The incubation period for tularemia is one to 14 days; most human infections become apparent after three to five days. In most susceptible mammals, the clinical signs include fever, lethargy, anorexia, signs of septicemia, and possibly death. Nonhuman mammals rarely develop the skin lesions seen in people. Subclinical infections are common, and animals often develop specific antibodies to the organism. Fever is moderate or very high, and tularemia bacilli can be isolated from blood cultures at this stage. The face and eyes redden and become inflamed. Inflammation spreads to the lymph nodes, which enlarge and may suppurate (mimicking bubonic plague). Lymph node involvement is accompanied by a high fever. Death occurs in less than 1% if therapy is initiated promptly.

The microbiologist must be informed when tularemia is suspected because F. tularensis requires special media for cultivation such as buffered charcoal and yeast extract (BCYE)
Buffered charcoal yeast extract agar
Buffered charcoal yeast extract agar is a selective growth medium used to culture or grow certain bacteria, particularly the Gram-negative species Legionella pneumophila.It has also been used for the recovery of Acanthamoeba keratitis....

. It cannot be isolated in the routine culture media because of the need for sulfhydryl group donors (such as cysteine). Serological tests (detection of antibodies in the serum of the patients) are available and widely used. Cross reactivity with Brucella
Brucella
Brucella is a genus of Gram-negative bacteria. They are small , non-motile, non-encapsulated coccobacilli, which function as facultative intracellular parasites....

can confuse interpretation of the results, so diagnosis should not rely only on serology. Molecular methods such as PCR are available in reference laboratories.
The bacteria can penetrate into the body through damaged skin and mucous membranes, or through inhalation. Humans are most often infected by tick bite or through handling an infected animal. Ingesting infected water, soil, or food can also cause infection. Tularemia can also be acquired by inhalation; hunters are at a higher risk for this disease because of the potential of inhaling the bacteria during the skinning process. It has been contracted from inhaling particles from an infected rabbit ground up in a lawnmower (see below). Tularemia is not spread directly from person to person.

Francisella tularensis is an intracellular bacterium, meaning it is able to live as a parasite within host cells. It primarily infects macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...

s, a type of white blood cell, thus is able to evade the immune system. The course of disease involves the spread of the organism to multiple organ systems, including the lungs, liver, spleen, and lymphatic system. The course of disease is different depending on the route of exposure. Mortality in untreated (before the antibiotic era) patients has been as high as 50% in the pneumoniac and typhoidal forms of the disease, which however account for less than 10% of cases. Overall mortality was 7% for untreated cases, and the disease responds well to antibiotics, with a fatality rate of about 1%. The exact cause of death is unclear, but it is thought to be a combination of multiple organ system failures.

Treatment and prevention

The drug of choice is streptomycin
Streptomycin
Streptomycin is an antibiotic drug, the first of a class of drugs called aminoglycosides to be discovered, and was the first antibiotic remedy for tuberculosis. It is derived from the actinobacterium Streptomyces griseus. Streptomycin is a bactericidal antibiotic. Streptomycin cannot be given...

. Tularemia may also be treated with gentamicin
Gentamicin
Gentamicin is an aminoglycoside antibiotic, used to treat many types of bacterial infections, particularly those caused by Gram-negative organisms. However, gentamicin is not used for Neisseria gonorrhoeae, Neisseria meningitidis or Legionella pneumophila...

 for ten days, tetracycline-class drugs such as doxycycline
Doxycycline
Doxycycline INN is a member of the tetracycline antibiotics group, and is commonly used to treat a variety of infections. Doxycycline is a semisynthetic tetracycline invented and clinically developed in the early 1960s by Pfizer Inc. and marketed under the brand name Vibramycin. Vibramycin...

 for two to three weeks, chloramphenicol
Chloramphenicol
Chloramphenicol is a bacteriostatic antimicrobial that became available in 1949. It is considered a prototypical broad-spectrum antibiotic, alongside the tetracyclines, and as it is both cheap and easy to manufacture it is frequently found as a drug of choice in the third world.Chloramphenicol is...

 or fluoroquinolones. An attenuated, live vaccine
Vaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...

 is available, but its use is only for high risk groups. Its use as postexposure prophylaxis is not recommended.

Tularemia as a biological weapon

The Centers for Disease Control and Prevention
Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention are a United States federal agency under the Department of Health and Human Services headquartered in Druid Hills, unincorporated DeKalb County, Georgia, in Greater Atlanta...

 regard F. tularensis as a viable biological warfare
Biological warfare
Biological warfare is the use of biological toxins or infectious agents such as bacteria, viruses, and fungi with intent to kill or incapacitate humans, animals or plants as an act of war...

 agent, and it has been included in the biological warfare programs of the United States, Soviet Union and Japan at various times. A former Soviet biological weapons scientist, Kenneth Alibek, has alleged that an outbreak of tularemia among German soldiers shortly before the siege of Stalingrad was due to the release of F. tularensis by Soviet forces. Others who have studied the pathogen "propose that an outbreak resulting from natural causes is more likely". In the US, practical research into using rabbit fever as a biological warfare agent took place in 1954 at Pine Bluff Arsenal
Pine Bluff Arsenal
The Pine Bluff Arsenal is a US Army installation located in Jefferson County, Arkansas, just northwest of the city of Pine Bluff. PBA is one of the six Army installations in the United States that store chemical weapons...

, Arkansas
Arkansas
Arkansas is a state located in the southern region of the United States. Its name is an Algonquian name of the Quapaw Indians. Arkansas shares borders with six states , and its eastern border is largely defined by the Mississippi River...

, an extension of the Camp Detrick program. It was viewed as an attractive agent because:
  • it is easy to aerosolize,
  • it is highly infective; 10-50 bacteria are required to infect,
  • it is nonpersistent and easy to decontaminate (unlike anthrax
    Anthrax
    Anthrax is an acute disease caused by the bacterium Bacillus anthracis. Most forms of the disease are lethal, and it affects both humans and other animals...

    ),
  • it is highly incapacitating to infected persons,
  • it has comparatively low lethality, which is useful where enemy soldiers are in proximity to noncombatants, e.g. civilians.


The Schu S4 strain was standardized as "Agent UL" for use in the United States M143 bursting spherical bomblet
M143 bomblet
The M143 bomblet was a biological cluster bomb sub-munition developed by the United States during the 1960s. The spherical bomblet was the biological version of the Sarin-filled M139 chemical bomblet.-History:...

. It was a lethal biological warfare agent with an anticipated fatality rate of 4060%. The rate-of-action was around three days, with a duration-of-action of one to three weeks (treated) and two to three months (untreated), with frequent relapses. UL was streptomycin resistant. The aerobiological stability of UL was a major concern, being sensitive to sunlight, and losing virulence over time after release. When the 425 strain was standardized as "agent JT" (an incapacitant rather than lethal agent), the Schu S4 strain's symbol was changed again to SR.

Both wet and dry types of F. tularensis (identified by the codes TT and ZZ) were examined during the "Red Cloud" tests, which took place from November 1966 to February 1967 in the Tanana Valley
Tanana Valley
The Tanana Valley is a lowland region in central Alaska in the United States, on the north side of the Alaska Range where the Tanana River emerges from the mountains.-Climate:...

, Alaska.

No vaccine
Vaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...

 is available to the general public. The best way to prevent tularemia infection is to wear rubber gloves when handling or skinning wild lagomorphs and rodents, avoid ingesting uncooked wild game and untreated water sources, wear long-sleeved clothes, and use an insect repellent
Insect repellent
An insect repellent is a substance applied to skin, clothing, or other surfaces which discourages insects from landing or climbing on that surface. There are also insect repellent products available based on sound production, particularly ultrasound...

 to prevent tick bites.

Documented outbreaks

In the summer of 2000, an outbreak of tularemia in Martha's Vineyard
Martha's Vineyard
Martha's Vineyard is an island located south of Cape Cod in Massachusetts, known for being an affluent summer colony....

 resulted in one fatality, and brought the interest of the CDC as a potential investigative ground for aerosolized Francisella tularensis. Over the following summers, Martha's Vineyard was identified as the only place in the world where documented cases of tularemia resulted from lawn mowing.

An outbreak of tularemia occurred in Kosovo
Kosovo
Kosovo is a region in southeastern Europe. Part of the Ottoman Empire for more than five centuries, later the Autonomous Province of Kosovo and Metohija within Serbia...

 in 1999-2000.

In 2004, three researchers at Boston University Medical Center were accidentally infected with F. tularensis, after apparently failing to follow safety procedures.

In 2005, small amounts of F. tularensis were detected in the Mall area of Washington, DC the morning after an antiwar demonstration on September 24, 2005. Biohazard sensors
BioWatch
BioWatch is a United States Federal Government program to detect the release of pathogens into the air as part of a terrorist attack on major American cities. Reportedly operating in Philadelphia, New York City, Washington, DC, San Diego, Boston, Chicago, San Francisco, St...

 were triggered at six locations surrounding the Mall. While thousands of people were potentially exposed, no infections were reported. The detected bacteria likely originated from a natural source, not from a bioterror attempt.

Tularemia is endemic
Endemic (epidemiology)
In epidemiology, an infection is said to be endemic in a population when that infection is maintained in the population without the need for external inputs. For example, chickenpox is endemic in the UK, but malaria is not...

 in the Gori
Gori, Georgia
Gori is a city in eastern Georgia, which serves as the regional capital of Shida Kartli and the centre of the homonymous administrative district. The name is from Georgian gora , that is, "heap", or "hill"...

 region of the Eurasia
Eurasia
Eurasia is a continent or supercontinent comprising the traditional continents of Europe and Asia ; covering about 52,990,000 km2 or about 10.6% of the Earth's surface located primarily in the eastern and northern hemispheres...

n country of Georgia
Georgia (country)
Georgia is a sovereign state in the Caucasus region of Eurasia. Located at the crossroads of Western Asia and Eastern Europe, it is bounded to the west by the Black Sea, to the north by Russia, to the southwest by Turkey, to the south by Armenia, and to the southeast by Azerbaijan. The capital of...

. The last outbreak was in 2006.

In July 2007, an outbreak was reported in the Spanish autonomous region of Castile and León
Castile and León
Castile and León is an autonomous community in north-western Spain. It was so constituted in 1983 and it comprises the historical regions of León and Old Castile...

 and traced to the plague of vole
Vole
A vole is a small rodent resembling a mouse but with a stouter body, a shorter hairy tail, a slightly rounder head, smaller ears and eyes, and differently formed molars . There are approximately 155 species of voles. They are sometimes known as meadow mice or field mice in North America...

s infesting the region. Another outbreak had taken place ten years before in the same area.

In August 2009, a Swedish tourist was bitten by an unidentified insect at Point Grey, Vancouver, BC, Canada. It was not until after return to Sweden that he was diagnosed with tularemia, despite seeking medical treatment in Vancouver.

In Jan 2011, researchers searching for brucellosis among feral hog populations in Texas discovered widespread tularemia infection or evidence of past infection in feral hog populations of at least 2 Texas counties, even though tularemia is not normally associated with pigs at all. Precautions were recommended for those who hunt, dress, or prepare feral hogs. Since feral hogs roam over large distances, there is concern that tularemia may spread or already be present in feral hogs over a very wide geographic area.

In June 2011, in Armenia, Mrgahovit village of Lori Marz two people were infected.

In November 2011, it was reported in Tasmania
Tasmania
Tasmania is an Australian island and state. It is south of the continent, separated by Bass Strait. The state includes the island of Tasmania—the 26th largest island in the world—and the surrounding islands. The state has a population of 507,626 , of whom almost half reside in the greater Hobart...

, Australia and there have been claims that they are a first for the southern hemisphere. However, the causative organism was first isolated from a foot wound in the Northern Territory, Australia and reported back in 2003
.
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