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Tularemia
Updated: Jan 28, 2010
Introduction
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Background
Soken first described tularemia in 1837 as a febrile illness with generalized lymphadenopathy among people who had eaten infected rabbit meat. McCoy first isolated the causative organism in 1912 following an outbreak of a plaguelike disease among ground squirrels in Tulare County, California. The genus Francisella was named after Edward Francis, whose investigation of the outbreak expanded bacteriologic and epidemiologic understanding of the disease.
Francisella tularensis is one of the most infectious bacteria known, and it can cause illness in humans with exposure to as few as 10-50 organisms. F tularensis is considered a category A agent because of its high infectivity, ease of dissemination, and ability to cause substantial illness and death. Investigation of Francisella tularensis and its use as a biologic weapon began in World War II during the Japanese occupation of Manchuria. F tularensis was weaponized and stockpiled by the United States, until President Nixon terminated the program. As a result, stores maintained by the United States military were destroyed. According to former Soviet expert Dr Ken Alibek, the former Soviet Union produced and maintained strains that were resistant to antibiotics and vaccines.
The World Health Organization (WHO) conducted modeling studies in 1970 for the possible use of F tularensis as a weapon delivered by aerosol release. The WHO estimated that an aerosol dispersal of 50 kg of virulent F tularensis over a metropolitan area with 5 million inhabitants would result in 250,000 incapacitating casualties, including 19,000 fatalities. This dispersal would also result in relapses occurring for many months after the initial exposure and that it might lead to the establishment of enzootic reservoirs of tularemia in wild animals with possible subsequent outbreaks.
Pathophysiology
F tularensis, a facultative, intracellular, aerobic, gram-negative, nonmotile, pleomorphic, and primarily rod-shaped coccobacillus, causes tularemia. It is ubiquitous in the northern hemisphere from 30-71° latitude and is most common in the western south central region of the United States.
F tularensis is an extremely virulent organism. As few as 50 type A organisms would result in disease if inhaled or injected intradermally, whereas oral ingestion would require as many as 108 organisms. Although lagomorphs, rodents, and ticks are the most well-known sources for transmission of the disease to humans, F tularensis has been identified in more than 100 species, including mosquitos. The lagomorphs were historically recognized as the most common source of transmission, hence the name rabbit skinners' disease. However, with decreased rabbit hunting, ticks have now become the most common vector of transmission.
Ticks and deerflies (Chrysops discalis) are common and important vectors. Hard ticks, primarily Amblyomma americanum, Dermacentor andersoni, and Dermacentor variabilis, are also important reservoirs because vertical transmission of their progeny propagates the presence of the organism. A americanum (Lone Star tick) is prevalent in southeast and south central areas of United States, whereas D andersoni (Rocky Mountain wood tick) predominates in the western regions of United States. D variabilis (American dog tick) is widely distributed and found predominantly in the southeastern parts of the United States.
The primary mode of transmission is contact with infected animals or their carcasses, but transmission can follow consumption of inadequately cooked game meats or the bite of a tick or deerfly. Disease can also result from direct contact with or ingestion of contaminated soil, water, or fomites, as well as by inhalation of water aerosols or dust from soil, grains, or contaminated pelts. Person-to-person transmission is rare, but cases have developed in laboratory workers (who should always be notified in advance if tularemia is suspected).
Six clinical forms of tularemia have been identified (see History). Each form is influenced by factors related to the host, organism, and route of transmission. The incubation period depends on the size of the inoculum but generally 1-21 days (usually 2-6 d). A subcutaneous inoculum of 10 organisms is sufficient to induce disease, whereas an inhalational exposure of only 25 organisms may cause disease.
Frequency
United States
Approximately 200 cases of tularemia are reported annually. Ascertaining the true incidence of tularemia is difficult because it is not a reportable condition and is most likely frequently misdiagnosed. A bimodal prevalence occurs with an increased incidence in May to August (associated with tick-borne transmission) and in December to January (associated with hunting). This bimodal prevalence is also associated with an increased incidence in children during the summer months (May to August) and in adults during the winter months (December to January).
International
Tularemia is found around the world, distributed within 30-71° northern latitude, but its incidence is unknown.
Mortality/Morbidity
Untreated, the mortality rate from tularemia is 5-30%, with the highest rate occurring with the typhoidal (systemic) form, particularly when accompanied by tularemia pneumonia. The mortality rate also depends on the strain involved; type A is significantly more virulent and is responsible for almost all reported deaths. The mortality rate is less than 1% with appropriate antibiotic therapy.
Race
No racial predilection is reported.
Sex
Male individuals are more frequently affected than female individuals, despite the lack of biologic affinity. This distribution primarily results from increased exposure to specific activities (eg, hunting and skinning animals) and increased occupational vulnerability among male individuals.
Age
A bimodal prevalence is associated with an increased incidence in children during the summer months (May to August) and increased incidence in adults during the winter months (December to January). This prevalence is most likely related to increased outdoor activities of children during the summer and of adults during hunting season in the winter.
Clinical
History
Six clinical forms of tularemia have been described: ulceroglandular, glandular, oculoglandular, oropharyngeal, pneumonic, typhoidal. These clinical forms are not necessarily distinct entities and may have overlapping features. Children infected with tularemia typically have a clinical presentation similar to that of adults. However, children have been reported to have fever, pharyngitis, hepatosplenomegaly, and constitutional symptoms more often than adults.
- Common to all are the following findings:
- Abrupt onset of fever and chills (typically last for several days, remit for a brief interval, and then recur)
- Headache
- Anorexia
- Malaise and fatigue or prostration
- Myalgias
- Cough
- Vomiting
- Pharyngitis
- Abdominal pain
- Secondary pneumonitis (may occur in 45-83% of patients with the typhoidal form)
- The ulceroglandular form affects as many as 87% of patients (>75% of adults and 44% of children in some series): This form results in the following findings:
- A small, erythematous tender or pruritic papule occurs at site of inoculation usually 2-5 days (with a range of 1-10 d) after cutaneous exposure; the papule enlarges and becomes ulcerated 2-3 days later. Gradually, the tender necrotic base develops with a black eschar, often concomitantly with regional adenopathy.
- Tick-borne tularemia is usually in the groin and lower extremities (50%), the trunk (30%), and the axillae.
- The rabbit-associated form is usually on hands or fingers.
- Ulcers are tender, with raised edges and a jagged floor.
- Examples are shown in the images below.
Ulceroglandular tularemia on the face. Courtesy of Dr Hon Pak.
Ulceroglandular tularemia on an extremity. Courtesy of Dr Hon Pak.
Ulceroglandular type of tularemia on the hand. Courtesy of Dr Hon Pak.
- Lymphadenopathy, lymphadenitis, or both may occur with tender suppurative local enlargement reflecting site of entry.
- The tick-borne form usually involves inguinal or femoral adenopathy.
- The rabbit (animal)-associated form usually involves axillary or epitrochlear adenopathy.
- Systemic adenopathy may occur.
- A small, erythematous tender or pruritic papule occurs at site of inoculation usually 2-5 days (with a range of 1-10 d) after cutaneous exposure; the papule enlarges and becomes ulcerated 2-3 days later. Gradually, the tender necrotic base develops with a black eschar, often concomitantly with regional adenopathy.
- The glandular form accounts for 3-20% of cases and is the second most common form in adults. Tender lymphadenopathy occurs without evidence of local cutaneous lesions.
- The oculoglandular form, which accounts for 0-5% of cases, is secondary to touching or rubbing eyes with contaminated hands. Parinaud oculoglandular syndrome is unilateral conjunctivitis with ipsilateral preauricular adenopathy.
- Unilateral conjunctivitis (with injection and chemosis)
- Lymphadenopathy (most commonly cervical, but preauricular and submandibular also observed)
- Photophobia
- Lacrimation
- Lid edema
- The oropharyngeal form accounts for 0-12% of cases and as many as 23% of cases secondary to ingesting undercooked infected meat or contaminated water. It is the second most common form in children.
- Exudative pharyngitis or tonsillitis (may occasionally develop a membrane resembling diphtheria), and stomatitis
- Abdominal pain, nausea and vomiting
- Cervical lymphadenopathy
- Diarrhea
- GI bleeding (occasionally)
- The pneumonic form accounts for 7-20% of cases and is secondary to inhalation of aerosols of water or dust from soil, grains, or pelts or secondary to hematogenous spread; 30-80% of typhoidal forms and 10-15% of ulceroglandular forms develop pneumonia. The mortality rate can reach 60% if untreated. Inhalational exposure results in the following:
- Cough (nonproductive to minimal sputum production)
- Substernal chest tightness or burning
- Pleuritic chest pain
- Dyspnea
- In rare cases, adult respiratory distress syndrome (ARDS) and death
- The typhoidal, or septicemic, form accounts for 5-30% of cases and results in the following:
- Systemic form of tularemia with no obvious source of entry (may result from any portal of entry)
- Any of the symptoms presented above
- Weight loss
- The absence of an ulcer or lymphadenopathy may hinder immediate diagnosis.
Physical
Physical findings vary according to the mode of transmission and presentation.
- Systemic findings - Fever
- Hepatic findings - Hepatomegaly (tender) with prolonged illness
- Splenic findings - Splenomegaly (tender) with prolonged illness
- Dermal findings
- Rash
- Generalized maculopapular, approximately 20%
- Erythema nodosum (1-13%)
- Erythema multiforme (1-2%)
- Tularemids: These secondary skin eruptions are common, occurring in 3-25% of cases. These exanthems occur on the extremities and face more than on the trunk. They typically appear during the second week of the disease and may occur in any of the clinical forms of tularemia. Papular, macular, pustular, petechial, and papulovesicular exanthems have been described.
- Ulcer
- Begins as small erythematous papule that enlarges and ulcerates after 2-3 days
- Raised edges and jagged floor
- Floor necroses (changing color from yellow to black)
- Tender
- Rash
- Lymphatic findings: Regional lymph nodes may become fluctuant, similar to buboes of plague, and ulcerate and drain spontaneously.
- Ocular findings
- Unilateral injected conjunctivitis
- Lid edema
- Purulent exudate
- Ulcerations or papules on conjunctivae
- Preauricular, submandibular, and/or cervical lymphadenopathy
- Pulmonary findings
- Nonproductive cough
- Rales
- Pleural rub
- Normal pulmonary examination findings (possible)
- Oropharyngeal findings
- Exudative pharyngitis or tonsillitis (may occasionally develop a membrane resembling diphtheria) with ulcers
- Submandibular and cervical lymphadenopathy
Causes
F tularensis, which is a facultative, intracellular, aerobic, gram-negative, nonmotile, pleomorphic, and primarily rod-shaped coccobacillus, is the causative organism of tularemia. This organism is ubiquitous in the northern hemisphere from 30-71° latitude and is most common in the western south central areas of the United States.
- The organism has 2 forms that are serologically identical and that primarily differ in their geographic distribution, fermentation reactions, and virulence.
- Jellison type A (F tularensis biovar tularensis) is generally found in North American rabbits and ticks and causes severe disease in humans. An inoculum of 10 organisms subcutaneously is sufficient to induce disease, while an inhalational exposure of only 25 organisms may cause disease.
- Jellison type B (F tularensis biovar palaearctica) is found primarily in Asian and European rodents and results in a milder form of disease in humans.
- Methods of transmission include inhalational, ingestional, and vector-associated exposure.
- F tularensis has been isolated from more than 100 species of animals, primarily lagomorphs and rodents.
- Tick reservoirs and vectors
- A americanum (Lone Star tick) is prevalent in the southeast and south central regions of United States.
- D andersoni (Rocky Mountain wood tick) predominates in the western areas of the United States.
- D variabilis (American dog tick) is widely distributed.
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References
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Further Reading
Keywords
tularemia, Francisella tularensis, rabbit fever, rabbit skinners' disease, Amblyomma americanum, A americanum, Dermacentor andersoni, D andersoni, Dermacentor variabilis, D variabilis, Chrysops discalis, treatment, symptoms
