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Tularemia is a highly infectious
zoonotic disease caused by several subspecies of the gram- negative
bacterium Francisella tularensis (eTable 291.1).
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Francisella tularensis is a small, aerobic, nonmotile
gram-negative bacterium first identified in 1911 by Dr. Edward Francis,
after an outbreak of plaguelike disease in rodents in Tulare County,
California. Infection has been reported in humans since 1914.2
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In the United States, nearly all human cases of tularemia are
caused by F tularensis subspecies tularensis (Type
A, 66%) or F tularensis subspecies holarctica (Type
B, 34%).3
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Epidemiology
and Pathophysiology
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Mammals provide the primary reservoir for F tularensis, including
ground squirrels, rabbits, hares, voles, muskrats, water rats, and
other rodents.2 Human infection typically occurs
after handling infected animals or after a bite from an arthropod
vector.4 In the United States, biting flies and
ticks are the primary arthropod vectors. In Europe and the former
Soviet Union, ticks and mosquitoes have been reported to transmit
infection.2 Infection can also occur after ingestion
of contaminated food or water or after inhalation of the organism
from decaying animal carcasses, contaminated straw, or other sources.4 There
have been several large waterborne outbreaks of tularemia in Europe
and the former Soviet Union.1 The largest airborne
outbreak of tularemia was reported among farmers in Sweden in the
1960s, attributed to the aerosolization of organisms from rodent-infested
hay.1 There has been no documented person-to-person transmission
of tularemia.4
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Infections with F tularensis are found only
in the northern hemisphere. In the United States cases are reported
from the eastern seaboard, Arkansas, Missouri, Oklahoma, and the central mountain regions. Other endemic
areas include Eurasia, particularly the former Soviet Union, Japan,
and the Scandinavian countries. Tularemia is not a World Health Organization
(WHO) reportable disease. The incidence of disease is believed to
have decreased significantly around the world in the past 50 years,
largely attributed to the decrease in wild rabbits sold in markets
and the introduction of clean water supplies.2
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In the United States, 1939 marked the peak incidence of tularemia,
with 2300 cases reported that year.4 In contrast,
142 cases were reported in the United States in 2000.4 Cases have
been reported in all states except Hawaii, with over 50% of
all cases are reported in Arkansas, Missouri, and Oklahoma.1,3
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There have been two reported outbreaks of pneumonic tularemia
in the United States, both occurring in Martha’s Vineyard
(1978, 2000). The first outbreak was attributed to dogs, shaking
and aerosolizing F tularensis after rolling in
infected animal carcasses. The second was likely caused by brush
cutting over infected animal carcasses, effectively aerosolizing
the bacteria.7
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The groups at highest risk include those who live in rural areas,
farmers, hunters, forestry workers ,and laboratory workers.1 Over 70% of
those infected are male, reflecting their greater participation
in these higher risk activities.3 Human outbreaks
tend to parallel outbreaks among wildlife reservoirs or surges in
the wildlife populations.2 Most infections occur
between May and September, corresponding to times of higher tick
and other arthropod vector activity.3 Cases reported
in the winter months usually occur in hunters and trappers who handle
infected carcasses.
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Clinical Manifestations
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The clinical syndromes associated with F tularensis infection
vary according to the site of entry. The incubation period, from
exposure to initial disease manifestations, is typically 3 to 6 days
but can range from 1 to 14 days depending on the size of the inoculum.1 Most
patients report a prodromal period with the sudden onset of chills,
fever (38–40°C), headache, and generalized aches.3 During
this phase, bacteria are disseminated from the site of entry via
the lymphatic system to regional lymph nodes and the bloodstream.
During this brief bacteremic period, infection can spread to the
spleen, liver, lungs, kidneys, skeletal system, or central nervous
system.3
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Ulceroglandular and glandular tularemia represent 65% of
reported cases of tularemia, occurring more commonly in younger
patients (median age 37 years and 11 years respectively).3 The
patient with ulceroglandular tularemia typically has an ulcer at
the site of bacterial entry and regional lymphadenopathy. Usually, patients
are infected via the bite of an arthropod vector or cuts or abrasions
on their hands when directly handling infected animal carcasses.
A papule develops at the site of bacterial entry that becomes pustular
and eventually ulcerates.3 These ulcers are tender
and can persist for months without proper treatment. Regional lymph
nodes begin to enlarge within several days after the ulcer develops
(Fig. 291-1). Glandular tularemia occurs
via the same disease process as ulceroglandular tularemia, but there
is no ulcer noted.3 Glandular tularemia is reported
more commonly in children, who often present with tender lymphadenopathy
and no history of ulceration or other skin lesion. In some cases,
the ulcer is not recognized before it heals spontaneously and patients
present with lymphadenopathy alone.5 The regional
lymphadenopathy in both ulceroglandular and glandular tularemia
is very tender, with erythema of the overlying skin and eventual
suppuration in some cases (see Fig. 291-2).5,6
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Pneumonic tularemia is caused by the inhalation of as few as
10 F tularensis organisms. Tularemia is highly
pathogenic when inhaled, requiring as few as 10 organisms to cause
clinical disease. Patients most commonly present with a dry or slightly
productive cough, retrosternal chest pain, and constitutional symptoms
consistent with the tularemia prodrome described above,4,5 Patients
may also have purulent sputum, hemoptysis, dyspnea, tachypnea, or
pleuritic chest pain.5 but may also present with
purulent sputum, hemoptysis, dyspnea, tachypnea, or pleuritic chest
pain.5 Most commonly, there will be ill-defined
infiltrates on chest radiographs, although hilar adenopathy and
pleural effusions have also been reported.4 The
difference in virulence between type A tularemia and type B is most pronounced
in pneumonic tularemia. Type A infection leads to fulminant disease,
whereas type B is much milder and frequently presents with only
hilar adenopathy.7
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The other clinical syndromes seen after tularemia infection are
relatively rare. Typhoidal tularemia is tularemia sepsis without
any localizing symptoms (most likely acquired through inhalation). It
is most likely acquired through inhalation. Patients present with
a flulike prodrome, progressing to mental status changes and shock.3 They
may have prominent gastrointestinal symptoms (abdominal pain, diarrhea)
or pulse-temperature dissociation.6 If untreated,
typhoidal tularemia is fatal in 30% to 60% of
cases.
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Oculoglandular tularemia occurs when the conjunctiva are the
initial site of infection, usually following the transfer of bacteria
on a patient’s fingertips from infected tissue to the eye.
Patients present with ulcers and nodules on the conjunctiva, with
associated photophobia, chemosis, and vasculitis.3 Without
treatment, infection spreads to the preauricular lymph nodes. Oropharyngeal
tularemia occurs following ingestion of infected food or water and
is also very rare. Patients present with a sore throat, tonsillar
enlargement, and a yellow white pseudomembrane on physical examination.3 They
may also have associated lymphadenopathy, which is typically unilateral.
After ingestion of infected food or water, patients may also present
with stomatitis alone, although this is very rare.1
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Pneumonic disease is the most likely manifestation expected if
tularemia were utilized as a biologic weapon and should be suspected
in any outbreak of rapidly progressive respiratory disease that
fails to respond to traditional therapy.1
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Routine laboratory evaluations are of limited usefulness in the
diagnosis of tularemia. A complete blood count can be completely
normal, or may have a slightly increased white blood cell count
with increased mononuclear cells.6 Liver function
tests and inflammatory markers such as erythrocyte sedimentation rate
and C-reactive protein are only slightly elevated.6
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Definitive diagnosis of tularemia is complicated by its poor
growth with routine laboratory culture and the exposure risk it
presents to microbiology staff. The organism can be cultured from
lymph node tissues, sputum samples, blood samples, pharyngeal washings, and
fasting gastric aspirates (if inhalational), but the laboratory
should be notified that tularemia is suspected so that workers may
optimize recovery of this technically difficult organism and protect
themselves from accidental inhalation. Cultures should be held for a
minimum of 10 days to allow adequate time for colonies to appear
on routine microbiology agars. Several specific assays, including
pulse field gel electrophoresis for differentiating strains, polymerase-chain-reaction-based
assays, immunohistochemical staining, and direct fluorescent antibody
staining, are available only in select reference and research laboratories
and are not routinely utilized.1
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Diagnosis is usually made by documenting an antibody response
to tularemia infection, which appears 10 to14 days after the onset
of symptoms.2 The most commonly employed agglutination
tests will detect combined immunoglobulin M and immunoglobulin G.6 Tube
agglutination testing for tularemia is considered positive with
a single titer greater than 1:160 or with a 4-fold increase in titers
over the course of the illness. Microagglutination can also be used
and is considered positive with a single titer greater than 1:128.6 Antibody
titers can remain elevated for years following infection, although
the degree of protection from reinfection this provides is unclear.
It is important to note that antibody-based testing would not be
useful during an outbreak of tularemia, given the delay in antibody
production after onset of disease.
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Other disorders that are included in the differential diagnosis
of ulceroglandular tularemia include Staphylococcal or streptococcal skin
infection, cutaneous anthrax, pasteurellosis, sporotrichosis and
blastomycosis. Glandular disease must be differentiated from viral infections
(CMV, HIV, EBV), atypical mycobacteria and lymphoma. Disorders including inhalational
plague, anthrax, mycoplasma, C trachomatis, C Psittaci, Legionellosis,
Q fever, hantavirus, brucellosis, toxoplasmosis, leptospirosis and
SARS may present similarly to pulmonary tularemia. Typhoidal tularemia is
similar to typhoid fever caused by salmonella (eTable
291.2).
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Gentamicin or streptomycin remain the drugs of choice for tularemia
treatment.3 Both are bactericidal against F
tularensis and have been used successfully for decades.
Gentamicin is currently more widely available in the United States
and is the most commonly used therapy for tularemia. Patients are
most often treated with IV/IM gentamicin for 7 to 10 days
with a relatively low rate of relapse if treatment is initiated
in the first week of symptoms.3 There are studies
underway to evaluate once-daily gentamicin regimens for tularemia,
but there are currently no dosing guidelines for once-daily treatment. Gentamicin
is also safe to use during pregnancy for the treatment of tularemia.
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Tetracyclines and chloramphenicol are bacteristatic against F
tularensis and have been used in the past for treatment,
given the ease of oral dosing. These drugs have been associated with
a high rate of treatment failure and relapse and are not recommended
as first-line therapy for tularemia.3 Tetracyclines
are sometimes used to complete therapy, after a short course of
gentamicin, but are rarely used alone. If used, tetracyclines should
be given for at least 10 to 14 days, as the relapse rate may be
lower with prolonged treatment.3
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Fluoroquinolones have been shown to have good in vitro activity
against F tularensis¸ but their effectiveness
against type A tularemia, which is seen more commonly in the United States,
is unclear.4 Although they are not considered first-line
therapy, they could be considered for patients who cannot tolerate
gentamicin or tetracyclines. Most published studies report the successful
use of ciprofloxacin in animal models and outbreak settings, with
very little data available on the other fluoroquinolones.2,8 In an
outbreak in Spain (type B), ciprofloxacin had a lower failure rate
and fewer side effects than oral doxycycline.2 There
have also been small reports published in the United States describing the
successful use of oral ciprofloxacin in children.9F
tularensis is resistant to β-lactam antibiotics,
as well as most macrolides.2
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Postexposure antibiotics are recommended for high-risk laboratory
exposures or biologic attacks, but are not recommended for contacts
of those infected with tularemia or those with lower risk exposures
(tick bites, animal exposure, etc).6 For laboratory
exposures or in a mass casualty situation, the current prophylactic
and treatment regimen recommended by the Centers for Disease Control
and Prevention (CDC) is oral doxycycline or ciprofloxacin.1
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Ulceroglandular and glandular tularemia are rarely fatal, even
without treatment. Early treatment (within 7 days of onset) is associated
with a lower risk of complications and faster healing. If symptoms
have been present for greater than 2 weeks before treatment is initiated,
the risk of lymph node suppuration is much greater (30–40%).1 With
delayed or no treatment, healing of the ulcer can be prolonged.
Pneumonic tularemia has a mortality rate of 30% to 60% if
untreated.6
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Patients hospitalized with tularemia require no isolation beyond
standard precautions as person-to-person transmission has not been
reported with tularemia. Laboratory personnel should be notified
before any potential tularemia specimen is submitted for processing.6
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There are currently no widely available vaccines against tularemia
in the United States. In the United States, a live vaccine strain
(LVS) vaccine has been successfully used in high risk laboratory
workers since the 1960s, with a marked decreased in the incidence
of typhoidal disease in this high-risk group but it is under review
by the Food and Drug Administration (FDA) for general use as its
efficacy and virulence potential have yet to be fully characterized.3
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Water chlorination has virtually eliminated waterborne epidemics
of tularemia in the United States.3 In endemic
areas, the CDC recommends that people wear gloves or other protective equipment
when handling dead animals and that insect bites be minimized. Landscapers
and other such workers should also check the area thoroughly for
any animal carcasses, as brush cutting can aerosolize the organism
from decaying animal tissue.3 Tularemia has been
studied for use as a biologic or bioterrorist weapon, so in an outbreak
of pulmonary tularemia appropriate agencies should be notified.9