Tularemia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Tularemia is a serious infectious disease caused by the bacterium Francisella tularensis. The disease is endemic in North America, and parts of Europe and Asia. The primary vectors are ticks and deer flies, but the disease can also be spread through other arthropods. Animals such as rabbits, prairie dogs, hares and muskrats serve as reservoir hosts. The disease is named after Tulare County, California.

Franciscella tularensis was first discovered by George Walter McCoy in 1911. The organism was originally named Bacterium tularense, after Tulare county where the causative agent was first discovered. Expounding upon McCoy’s previous research, Dr. Edward Francis furthered global understanding of tularemia, through the discovery of animal reservoirs, vectors, and clinical manifestations. The ailment soon became frequent with hunters, cooks and agricultural workers.^[1] Tularemia was later identified as a potential tool for bio-terrorism.

Tularemia may be classified according the original mode of transmission. The mode of transmission will ultimately dictate the resulting clinical manifestations associated with tularemia infections. There are five common forms of tularemia, they include ulceroglandular, glandular, oculoglandular, oropharyngeal, and pneumonic.^[2]

Francisella tularensis is an extremely infectious bacteria; fewer than ten organisms can cause disease leading to severe illness. The bacteria 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 that it is able to live as a parasite within host cells. It primarily infects macrophages, a type of white blood cell. It is thus able to evade the immune system. The course of disease involves spread of the organism to multiple organ systems, including the lungs, liver, spleen, and lymphatic system.

Francisella is a genus of pathogenic, Gram-negative bacteria.They are small coccobacillary or rod-shaped, non motile organisms, which are also intracellular parasites of macrophages.^[3] Francisella colonies bear a morphological resemblance to those of the genus Brucella.^[4] The bacteria 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 is not spread directly from person to person.

Francisella tularensis is an intracellular bacterium, meaning that it is able to live as a parasite within host cells. It primarily infects macrophages, a type of white blood cell. It is thus able to evade the immune system. The course of disease involves spread of the organism to multiple organ systems, including the lungs, liver, spleen, and lymphatic system.

General symptoms reported within the early stages tularemia often resemble those of other tick-borne diseases. These symptoms include fever, chills, headache, and other non-specific flu like symptoms. Later stages of tularemia may include pneumonic clinical manifestations and ulcers in the epidermal tissue.^[2]

Tularemia has long been a silent disease plaguing the worldwide community. However, it is difficult to quantify the total worldwide incidence since tularemia is rarely reported. North America and Eurasia are commonly referred to as endemic areas. The majority of cases in the United States have been reported in the South-central and Western states. Seasonal distribution of tularemia infection shows a higher incidence between June and September. A higher incidence has also been reported in children under the age of 10 years.

The greatest risk factor for contracting tularemia is the bite of an infected tick. Other risk factors include handling contact with infected animals, contamination of water sources, and potential bio-terrorism. Individuals are at a higher risk of infection during the late spring and summer months. Children and males are at a higher risk of infection.

The disease has a very rapid onset, with headache, fatigue, dizziness, muscle pains, loss of appetite and nausea. 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. Complications may include pneumonia, meningitis, endocarditis, hepatitis, sepsis, or osteomyelitis. The prognosis is usual good for common forms of tularemia. However a high mortality rate is associated with pneumonic and typhoidal variations.[2]

Symptoms associated with tularemia often include non-specific flu like symptoms. As the disease progresses tularemia will differentiate into five more specific variations. Symptoms and clinical manifestations will differentiate according to the type of tularemia infection.

Typically signs of tularemia include a biphasic fever, tachycardia, and changes in blood pressure. Depending on the mode of transmission, tularemia may also cause skin ulcers, eye infection, or swelling of the throat.

There are a variety of lab diagnostic tests used to diagnose tularemia including Gram-stains, bacteria cultures,biochemical,and antibody fluorescence tests. Gram-stains and bacteria cultures are useful in identifying F.tularensis. Unfortunately, these diagnostics offer difficult interpretations with extensive procedures. Antibody fluorescence allows for quick and effective testing. This method is extraordinarily important in diagnosing pneumonic variations of tularemia, as these variations are often associated with a higher mortality rate.

Other diagnostic studies for tularemia include the examination of secretions, fluorescent antibody testing, and immunohistochemical staining. These test demonstrate rapid procedures that provide accurate detection of F. tularensis within a few hours of specimen collection.

The mainstay of therapy for tularemia is antimicrobial therapy. The drug of choice is Streptomycin. Other pharmacologic therapies for tularemia include Gentamicin, Tetracyclines, Chloramphenicol, or Fluoroquinolones.

Tularemia prevention strategies are based on avoiding potentially, infected, tick bites or animal flesh and fecal matter. Avoiding tick bites may be accomplished through limited exposure to endemic areas. However if it is impossible or impractical to avoid these areas, several preventative strategies may be implemented. These strategies are indicated under the Prevention title below. Other prevention strategies include a proper removal of the tick. This process is also outlined below under the title, the best way to remove a tick. Other strategies include daily cleaning, to avoid fecal matter in dust, or proper attire during butchery.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ilan Dock, B.S.

Franciscella tularensis was first discovered by George Walter McCoy in 1911. The organism was originally named Bacterium tularense, after Tulare county where the causative agent was first discovered. Expounding upon McCoy’s previous research, Dr. Edward Francis furthered global understanding of tularemia, through the discovery of animal reservoirs, vectors, and clinical manifestations. The ailment soon became frequent with hunters, cooks and agricultural workers.^[1] Tularemia was later identified as a potential tool for bio-terrorism.

• Tularemia was first documented by George Walter McCoy in 1911 and later isolated in 1912.
• The disease was classified as a severe and fatal with the capability of persisting as a human illness.
• First human case confirmed in Cincinnati in 1914.
• In 1928 Dr. Edward Francis began to identify vectors, animal reservoirs, clinical manifestations associated with tularemia infection.
• In 1959, scientists from Russia discovered two distinct strains of tularemia: type A and type B.
• From 1966 to 1967 an epidemic of tularemia was announced in Sweden.
• Another outbreak of tularemia occurred in Kosovo between the years 1999-2000^[2]

• In summer 2000, an outbreak of tularemia in Martha’s Vineyard resulted in one fatality, and brought the interest of the CDC as a potential investigative ground for aerosol based 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.^[3] The research may prove valuable in preventing bio-terrorism.

• In 2004, three researchers at Boston University Medical Center were accidentally infected with F. tularensis, after apparently failing to follow safety procedures.^[4]

• In 2005, small amounts of F. tularensis were detected in the Mall area of Washington, DC the morning after an anti-war demonstration on September 24, 2005. Bio-hazard sensors were triggered at six locations surrounding the Mall. To this date, no cases of tularemia infection have been reported as a result.^[5]

• In July 2007, an outbreak was reported in the Spanish autonomous region of Castile and León and traced to the plague of voles infesting the region.

• The Centers for Disease Control and Prevention regard F. tularensis as a viable bio-weapon. The disease was used as a weapon by the Russians during World War II. ^[6] Practical research into using Tularemia as a bio-weapon took place at Camp Detrick in the 1950s. It was viewed as an attractive agent because:
  • it is easily condensed into an aerosol form
  • it is highly infectious; fewer than 10 bacteria are required to infect
  • it is non-persistent and easy to decontaminate (unlike anthrax)
  • it is highly incapacitating to infected persons
  • it is rarely lethal, which is useful when enemy soldiers are in close proximity to non-combatants and civilians

• No vaccine is available to the general public.^[7] The best way to prevent tularemia infection is to wear rubber gloves when handling or skinning rodents or lagomorphs (as rabbits), avoid ingesting uncooked wild game and untreated water sources, and wearing long-sleeved clothes and using an insect repellant to prevent tick bites.

• By the late 1950’s the US biological warfare program was focused mostly on tularemia as a biological agent.
• Schu S4 strain was standardized as Agent UL for use in the M143 bursting spherical bomblet.
• It was a lethal, with an anticipated fatality rate of 40 to 60 percent.
• The rate-of-action was around three days, with a duration-of-action of 1 to 3 weeks (treated) and 2 to 3 months (untreated) with frequent relapses. UL was streptomycin resistant.
• Aerobiological stability of UL was a major concern, being sensitive to sun light, and losing virulence over time after release.

• The United States later changed the military symbol for UL to TT (wet-type) and ZZ (dry-type) in an effort to retain security on the identity of military bio-hazards. When the 425 strain was standardized as agent JT (something to incapacitate rather than lethal agent), the Schu S4 strain’s symbol was changed again to SR.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ilan Dock, B.S.

Tularemia may be classified according the original mode of transmission. The mode of transmission will ultimately dictate the resulting clinical manifestations associated with tularemia infections. There are five common forms of tularemia, they include ulceroglandular, glandular, oculoglandular, oropharyngeal, and pneumonic.^[1]

Tularemia clinically manifests in five common forms:

• Ulceroglandular
• Glandular
• Oculoglandular
• Oropharyngeal
• Pneumonic^[1]

The table below represents Tularemia clinical manifestations according to their distinct modes of transmission.

^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Francisella tularensis is an extremely infectious bacteria; fewer than ten organisms can cause disease leading to severe illness. The bacteria penetrate into the body through damaged skin and mucous membranes, or through inhalation. Francisella tularensis is an intracellular bacterium, meaning that it is able to live as a parasite within host cells. It primarily infects macrophages, a type of white blood cell. It is thus able to evade the immune system. The course of disease involves spread of the organism to multiple organ systems, including the lungs, liver, spleen, and lymphatic system.

• Bacteremic phase initiates the spread of disease into reticuloendothelial tissue.
• This evokes an immunological reaction resulting in a flurry of tumor necrosis factor alpha, interleukin-10 and 12, as well as IFN-gamma.
• T-cells become involved as the disease progresses.
• Studies show that T-cells are necessary in stopping the reaction, but not controlling it.
• A successful tularemia infection is the ultimate result of the disease’s ability to survive within macrophage host cells. ^[1]

• Francisella tularensis is one of the most infectious bacteria known; fewer than ten organisms can cause disease leading to severe illness.
• The bacteria 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. ^[2]
• 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.
• Tularemia is not spread directly from person to person.
• Francisella tularensis is an intracellular bacterium, meaning that it is able to live as a parasite within host cells.
• It primarily infects macrophages, a type of white blood cell. It is thus able to evade the immune system.
• The course of disease involves spread of the organism to multiple organ systems, including the lungs, liver, spleen, and lymphatic system. ^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Francisella is a genus of pathogenic, Gram-negative bacteria.They are small coccobacillary or rod-shaped, non motile organisms, which are also facultative intracellular parasites of macrophages.^[1] Strict aerobes, Francisella colonies bear a morphological resemblance to those of the genus Brucella.^[2] The bacteria 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.

Francisella tularensis is an intracellular bacterium, meaning that it is able to live as a parasite within host cells. It primarily infects macrophages, a type of white blood cell. It is thus able to evade the immune system. The course of disease involves spread of the organism to multiple organ systems, including the lungs, liver, spleen, and lymphatic system.

• The type species, F. tularensis, causes the disease tularemia or rabbit fever.^[3] F. novicida and F. philomiragia (previously Yersinia philomiragia) are associated with septicemia and invasive systemic infections.
• It should be noted that the taxonomy of the genus is somewhat uncertain, especially in the case of F. novicida (may be a subspecies of F. tularensis).
• In general, identification of species is accomplished by biochemical profiling or 16S rRNA sequencing.
• F. tularensis is found in widely diverse animal hosts and habitats and can be recovered from contaminated water, soil, and vegetation.
• A variety of small mammals, including voles, mice, water rats, squirrels, rabbits, and hares are natural reservoirs of infection. ^[4]
• They acquire infection through tick, fly, and mosquito bites and by contact with contaminated environments. ^[5]
• Epizootics with sometimes extensive die-offs of animal hosts may herald outbreaks of tularemia in humans.
• Humans can become incidentally infected through diverse environmental exposures: bites by infected arthropods; handling infectious animal tissues or fluids; direct contact with or ingestion of contaminated food, water, or soil; and inhalation of infective aerosols.
• Humans can develop severe and sometimes fatal illness, but do not transmit the disease to others. ^[4]

• Studies conducted on a strain of the Schu S4 genome report a genome size of less than 2 Mbp.
• F. tularensis is composed of a large majority of genes, unique to the species.
• Lesser amount of genes responsible for the encoding of transport and binding.
• There are few matches for genes responsible for gene regulation and energy metabolism between F. tularensis and other documented

• Francisella tularensis is one of the most infectious bacteria known; fewer than ten organisms can cause disease leading to severe illness.
• The bacteria 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.
• Tularemia is not spread directly from person to person.
• Francisella tularensis is an intracellular bacterium, meaning that it is able to live as a parasite within host cells.
• It primarily infects macrophages, a type of white blood cell. It is thus able to evade the immune system.
• The course of disease involves spread of the organism to multiple organ systems, including the lungs, liver, spleen, and lymphatic system.
• The course of disease is similar regardless of the route of exposure. Mortality in untreated (pre-antibiotic-era) patients has been as high as 50% in the pneumonic and typhoidal forms of the disease, which however account for less than 10% of cases.^[6]
• Overall mortality was 7% for untreated cases, and the disease responds well to antibiotics with a fatality rate of about 2%.
• The exact cause of death is unclear, but it is thought be a combination of multiple organ system failures.

it:Francisella tularensis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ilan Dock, B.S.

General symptoms reported within the early stages tularemia often resemble those of other tick-borne diseases. These symptoms include fever, chills, headache, and other non-specific flu like symptoms. Later stages of tularemia may include pneumonic clinical manifestations and ulcers in the epidermal tissue.^[1]

The following table differentiates between variations of tularemia and their associated manifestations. ^[1]

The following table differentiates between general symptoms associated with tularemia and other similarly presenting, tick borne diseases.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Tularemia has long been a silent disease plaguing the worldwide community. However, it is difficult to quantify the total worldwide incidence since tularemia is rarely reported. North America and Eurasia are commonly referred to as endemic areas. The majority of cases in the United States have been reported in the South-central and Western states. Seasonal distribution of tularemia infection shows a higher incidence between June and September. A higher incidence has also been reported in children under the age of 10 years.

• Worldwide incidence of naturally occurring tularemia is unknown.
• It is likely that the disease is greatly under-recognized and under-reported.
• In the U.S., reported cases have dropped sharply from several thousand cases per year prior to 1950 to fewer than 200 cases per year in the 1990’s.
• Between 1985 and 1992, 1409 cases and 20 deaths were reported in the U.S. with a case fatality rate of 1.4%.
• Epidemic in a densely populated area would be expected to result in an abrupt onset of large numbers of acute, nonspecific febrile illness beginning 3–5 days later (incubation range 1–14 days), with pleuropneumonitis developing in a significant proportion of cases during the ensuing days and weeks.^{[1] [2]}.

• Tularemia occurs throughout much of North America and Eurasia.
• In the U.S., human cases have been reported from every state except Hawaii.
• The majority of cases have been reported in South-central and Western states.

• Most U.S. cases occur June–September, when arthropod-borne transmission is most common.
• Cases in winter most commonly occur among hunters and trappers who handle infected animal carcasses.

• The high incidence of tularemia among males and among children aged <10 years might be associated with increased opportunity for exposure to infected ticks or animals, less use of personal protective measures against tick bites, or diagnostic or reporting bias.
• The high incidence among American Indians/Alaska Natives might be associated with their increased risk for exposure; outbreaks of tularemia have been reported on reservations in Montana and South Dakota, where a high prevalence of tularemia infection was found in ticks and dogs.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The greatest risk factor for contracting tularemia is the bite of an infected tick. Other risk factors include handling contact with infected animals, contamination of water sources, and potential bioterrorism. Individuals are at a higher risk of infection during the late spring and summer months. Children and males are at a higher risk of infection.

• In the United States, most persons with tularemia acquire the infection from arthropod bites, particularly tick bites, or from contact with infected mammals, particularly rabbits.
• Outbreaks of tularemia in the United States have been associated with muskrat handling, tick bites, deer-fly bites, and lawn mowing or cutting brush.
• Sporadic cases in the United States have been associated with contaminated drinking water and various laboratory exposures.
• Outbreaks of pneumonic tularemia, particularly in low-incidence areas, should prompt consideration of bioterrorism.^[1]

• In recent years, a seasonal increase in incidence has occurred only in the late spring and summer months, when arthropod bites are most common.

• Tularemia is more common among males than females.
• Tularemia occurs within populations of all ages, however is most common within children.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The disease has a very rapid onset, with headache, fatigue, dizziness, muscle pains, loss of appetite and nausea. 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. Complications may include pneumonia, meningitis, endocarditis, hepatitis, sepsis, or osteomyelitis. The prognosis is usual good for common forms of tularemia. However a high mortality rate is associated with pneumonic and typhoidal variations.[2]

• Infection typically begins with an incubation period of 3 to 6 days.
• Later clinical manifestations of the disease will display themselves in different ways depending on the type of infection. ^[1]

Following an incubation of 3 to 6 days there is a sudden onset of flu-like symptoms including:

• Chills
• Fever
• Headache
• Generalized aches ^[1]

Following the early onset, general symptoms, tularemia will often present itself in a specific form. Specific forms of tularemia and their clinical manifestations may be found below:

• Formation of a skin ulcer near the original site of infection; ulcer may persist for several months.
• Bacteria may travel throughout the body via the lymphatic system.
• Lymph nodes may swell resembling a clinical manifestation commonly associated with the bubonic plague.
• Fatality is less than 3 percent, even when left untreated. ^[1]

• Occurs when eyes are the site of infection.
• Ulcers develop on the conjuctiva, may spread to the lymph nodes. ^[1]

• Soreness in the throat
• Tonsil Enlargement
• Swollen cervical lymph nodes
• Depending on ulceration of the bowel, an infection may persist into an acute fatal disease.

• Pnuemonic disease occurs as a result of an inhalation-based infection.
• May also be the result of a spread of infection associated with other forms of tularemia.
• Pneumonic infection may occur without any obvious signs of infection, however typhoidal infection is associated with a fatality rate of 30-60%.

Due to the inflammation of membranes surrounding central nervous system, liver, and heart, the following complications have been associated with tularemia:

• meningitis
• endocarditis
• hepatitis ^[1]

Other complications include:

• Sepsis
• osteomyelitis

• The prognosis is usually good for the common forms of tularemia.
• Ulceroglandular forms of tularemia usually heal after the course of several months.
• Even when left untreated ulceroglandular and glandular forms of tularemia are rarely fatal.
• Fatal forms of tularemia include pnuemonic and thyphoidal variations, with a mortality rate of 30-60%. ^[1]

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