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Tularemia
Chapter 8
TULAREMIA
MATTHEW J. HEPBURN, MD
*
; ARTHUR M. FRIEDLANDER, MD
†
;
and
ZYGMUNT F. DEMBEK, P
h
D, MS, MPH
‡
INTRODUCTION
INFECTIOUS AGENT
CLINICAL DISEASE
Epidemiology
Pathogenesis
Clinical Manifestations
Diagnosis
Treatment
PROPHYLAXIS
Postexposure Prophylaxis
Vaccination with Live Vaccine Strain
ISSUES FOR LABORATORY WORKERS
USE OF TULAREMIA AS A BIOLOGICAL WEAPON
SUMMARY
*
Major,MedicalCorps,USArmy;InfectiousDiseasesPhysician,DivisionofMedicine,USArmyMedicalResearchInstituteofInfectiousDiseases,
1425PorterStreet,FortDetrick,Maryland21702
†
Colonel,MedicalCorps,USArmy(Ret);SeniorScientist,DivisionofBacteriology,USArmyMedicalResearchInstituteofInfectiousDiseases,1425
PorterStreet,FortDetrick,Maryland21702;andAdjunctProfessorofMedicine,UniformedServicesUniversityoftheHealthSciences,4301Jones
BridgeRoad,Bethesda,Maryland20814
‡
Lieutenant Colonel, Medical Service Corps, US Army Reserve; Chief, Biodefense Epidemiology and Training & Education Programs, Operational
MedicineDepartment,DivisionofMedicine,USArmyMedicalResearchInstituteofInfectiousDiseases,1425PorterStreet,FortDetrick,Maryland
21702
167
MedicalAspectsofBiologicalWarfare
INTRODUCTION
Francisellatularensis
poses a substantial threat as a bio-
logical weapon, and it is viewed by most experts as a dan-
gerous pathogen if weaponized. Both the United States
and the former Soviet Union developed weaponized
F
tularensis
during the Cold War.
1,2
It is unclear whether
tularemia has ever been used deliberately as a biological
weapon. The Japanese experimented with
Ftularensis
as
a biological weapon, but there is no documentation of its
use in military operations.
3
There is also speculation that
the former Soviet Union used
Ftularensis
as a weapon
against German troops in the Battle of Stalingrad during
World War II.
2
Despite the tularemia outbreak among
soldiers of both armies during this battle, some authors
suggest that natural causes, as opposed to an intentional
release, were responsible for the epidemic.
4
There was
also speculation that
Ftularensis
was used as a biological
weapon by Serbia in the Kosovo conflict, although the
subsequent investigation suggested the observed cases
were not caused by an intentional release.
5,6
Ftularensis
has been included in the list of Centers
for Disease Control and Prevention Category A threat
organisms because of the infectivity with exposure to
low numbers of organisms, the ease of administration,
and the serious consequences of infection.
1
Tularemia’s
effectiveness as a biological weapon includes a nonspe-
cific disease presentation, high morbidity, significant
mortality if untreated, and the limited ability to obtain
a rapid diagnosis. Although tularemia responds to
antibiotics, the use of an antibiotic-resistant strain can
make these countermeasures ineffective.
INFECTIOUS AGENT
Tularemia was named after Tulare County, Califor-
nia, where an epidemic disease outbreak resembling
plague occurred in ground squirrels in 1911. McCoy
and Chapin successfully cultured the causative agent
and named it
Bacteriumtularense
.
7
Wherry and Lamb
subsequently identified the pathogen as the cause of
conjunctival ulcers in a 22-year-old man.
8
Edward
Francis made significant scientific contributions to the
understanding of the disease in the early 20th century,
including naming it “tularemia.”
9
Ftularensis
is an aerobic, gram-negative coccobacilli.
Ftularensis
is not motile, and appears as small (approxi-
mately 0.2–0.5 µm by 0.7–1.0 µm),
10
faintly staining
gram-negative bacteria on Gram’s stain (Figure 8-1).
F
tularensis
was formerly included in the
Pasteurella
and
the
Brucella
genera. Eventually a new genus was cre-
ated, and the name
Francisella
was proposed in tribute
to Edward Francis.
11
A closely related species,
Fran-
cisellaphilomiragia
, has also been described as a human
pathogen.
12,13
F tularensis
is considered to have four
subspecies: (1)
tularensis
, (2)
holarctica
, (3)
mediasiatica,
and
(4)
novicida.
14
Ftularensis
subspecies
tularensis
, also
known as Type A (or biovar A), occurs predominantly
in North America and is the most virulent subspecies
in both animals and humans. This subspecies was
recently divided into A.I. and A.II. subpopulations.
Subpopulation A.I. causes disease in the central United
States, and subpopulation A.II. is found mostly in the
western United States.
15
Ftularensis
subspecies
holarc-
tica
(formerly described as
palearctica
), also known as
Type B (or biovar B), is found in Europe and Asia, but
also occurs in North America.
Ftularensis
subspecies
holarctica
causes a less virulent form of disease than
subspecies
tularensis
, but has been documented to
cause bacteremia in immunocompetent individuals.
16,17
Before antibiotics,
F tularensis
subspecies
tularensis
resulted in 5% to 57% mortality, yet
Ftularensis
sub-
species
holarctica
was rarely fatal.
18
Unlike these other
subspecies,
Fnovicida
rarely causes human disease.
12
F tularensis
subspecies
mediasiatica
has been isolated
in the central Asian republics of the former Soviet
Union, and it appears to be substantially less virulent
in a rabbit model compared to
Ftularensis
subspecies
tularensis
.
19,20
The four subspecies can be distinguished
with biochemical tests and genetic analysis.
Fig. 8-1
. Gram’s stain of
Francisellatularensis
.
Photograph: Courtesy of Dr Larry Stauffer, Oregon State
Public Health Laboratories, Centers for Disease Control and
Prevention, Atlanta, Georgia, Public Health Image Library,
#1904.
168
Tularemia
THE CLINICAL DISEASE
Tularemia is an infection with protean clinical mani-
festations. Healthcare providers need to understand
the range of possible presentations of tularemia to use
diagnostic testing and antibiotic therapy appropriately
for these infections. Most cases of naturally occurring
tularemia are ulceroglandular disease, involving an ul-
cer at the inoculation site and regional lymphadenopa-
thy. Variations of ulceroglandular disease associated
with different inoculation sites include ocular (oculo-
glandular) and oropharyngeal disease. Occasionally
patients with tularemia present with a nonspecific
febrile systemic illness (typhoidal tularemia) without
evidence of a primary inoculation site. Pulmonary
disease from
F tularensis
can occur naturally (pneu-
monic tularemia), but is uncommon and should raise
suspicion of a biological attack, particularly if signifi-
cant numbers of cases are diagnosed. Because of the
threat of this microorganism as a biological weapon,
clusters of cases in a population or geographic area
not accustomed to tularemia outbreaks should trigger
consideration for further investigation.
21
Rotz et al
provide criteria for determining the likelihood that a
tularemia outbreak is caused by intentional use of tu-
laremia as a biological weapon.
21
A tularemia outbreak
in US military personnel deployed to a nonendemic
environment would be one example of an incident
that should be investigated. The investigation should
yield the likely cause of the outbreak, which could be
varied (exposure to infected animals, arthropod-borne,
etc). By determining the cause of tularemia, it may be
possible to implement control measures, such as water
treatment or use of an alternative water supply if the
outbreak is traced to a waterborne source.
an aerosol or contaminated dust.
Various epidemiological categories of tularemia
have been suggested, often dependent on the infective
vector, mode of infection, or occupation of the infected
individuals.
18
Direct Contact
In 1914 a meat cutter with oculoglandular disease,
manifested by conjunctival ulcers and preauricular
lymphadenopathy, had the first microbiologically
proven human tularemia case reported.
8
An early re-
view of tularemia established that a majority of human
cases (368 of 488, or 75%) in North America resulted
from dressing and eating wild rabbits.
9
Other wild
mammals may potentially serve as sources for tula-
remia transmission from direct contact, such as wild
prairie dogs that are captured and sold as pets.
24
Food and Water Ingestion
Tularemia can also be contracted by eating meat
from infected animals
9
or food contaminated by in-
fected animals.
25
Water can also become contaminated
from animals infected with tularemia and cause hu-
man infection. During March through April 1982, 49
cases of oropharyngeal tularemia were identified in
Sansepolcro, Italy.
26
The case distribution in this city
suggested that a water system was the source. The
infected individuals had consumed unchlorinated
water, and a dead rabbit from which
Ftularensis
was
isolated was found nearby.
26
Waterborne transmission
of ulceroglandular tularemia also occurred during a
Spanish outbreak among 19 persons who had contact
with river-caught crayfish.
27
Contaminated water may
have contributed to recent outbreaks of oropharyngeal
tularemia in Turkey
28
and Bulgaria.
25
It is unclear how
Ftularensis
survives in water, but it may be linked to
its ability to survive in certain protozoa species such
as
Acanthamoebacastellanii
.
29
Epidemiology
Ftularensis
subspecies
tularensis
(Type A) is the most
common
Ftularensis
subspecies causing clinical tulare-
mia in North America.
10
Type A was once thought not
to occur in Europe, but a type A strain has recently been
isolated from flea and mite parasites of small rodents
trapped in Slovakia.
22
Ftularensis
subspecies
holarctica
(type B), found throughout the Northern Hemisphere,
is less pathogenic.
1
In the United States an average of
124 tularemia cases per year were reported from 1990
through 2000.
23
Over half of all cases reported came
from Arkansas, Missouri, South Dakota, and Okla-
homa, where the foci of infection are well-established.
Tularemia can be transmitted by direct contact with
infected animals or their tissues, ingestion of under-
cooked infected meat or contaminated water, animal
bites or scratches, arthropod bites, and inhalation of
Mammalian Bites and Arthropod Vectors
Mammalian bites are another source of tularemia
transmission to humans. Instances of human transmis-
sion from the bites or scratch of a cat, coyote, ground
squirrel, and a hog were documented over 80 years ago.
9
In April 2004 a 3-year-old boy from Denver, Colorado,
contracted tularemia from a hamster bite, providing
evidence of disease transmission from these pets.
30
Transmission of tularemia by the bites of ticks and
flies is also well-documented.
10
Dermacentor
species
169
MedicalAspectsofBiologicalWarfare
ticks (dog ticks) are important vectors in areas where
enzootic transmission occurs in North America
31
and
Europe.
32
Ixodes
species ticks may also contribute to
F
tularensis
transmission.
33
In Utah during the summer
of 1971, 28 of 39 tularemia cases were contracted from
deerfly (
Chrysopsdiscalis
) bites.
34
An epidemic of 121
tularemia cases (115 ulceroglandular) in Siberia from
July through August 1941 may have resulted from
transmission of
F tularensis
by mosquitoes, midges
(
Chironomidae
), and small flies (
Similia
).
35
Tularemia in an Unusual Setting
Some tularemia cases have occurred in geographic
areas where the disease has never been reported. An
orienteering contest on an isolated Swedish island in
2000 resulted in two cases of ulceroglandular tulare-
mia.
42
These cases were theorized to have occurred
from contact with migratory birds carrying the micro-
organism. The social disruption caused by war also
has been linked to tularemia outbreaks.
During World
War II, an outbreak of over 100,000 tularemia cases oc-
curred in the former Soviet Union,
4
and outbreaks with
hundreds of cases after the war occurred in Austria
and France.
43
Outbreaks of zoonoses during war since
that time have led to speculation that these epidemics
were purposefully caused. For example, no tularemia
cases had been reported from Kosovo between 1974
and 1999, and tularemia was not previously recognized
endemically or enzootically in the Balkan countries.
5
However, after a decade of warfare, an outbreak of over
900 suspected tularemia cases occurred in Kosovo dur-
ing 1999 and 2000, leading researchers to investigate
claims of use of this agent as a biological weapon by the
Serbs against the Albanian inhabitants of the country.
5,6
The Kosovo outbreak and subsequent investigation
are described in detail in chapter 3, Epidemiology of
Biowarfare and Bioterrorism.
Aerosol Transmission
The largest recorded pneumonic tularemia outbreak
occurred in Sweden during the winter of 1966 through
1967, when 676 cases were reported.
36
Most of the cases
occurred among the farming population, 71% among
adults older than 45 years and 63% among men. The
hundreds of pneumonic cases likely resulted from
contact with hay and dust contaminated by voles
infected with tularemia.
Ftularensis
was later isolated
from the dead rodents found in barns, as well as from
vole feces and hay.
In the summer of 2000, an outbreak of primary
pneumonic tularemia occurred in Martha’s Vineyard,
Massachusetts.
37
Fifteen confirmed tularemia cases were
identified, 11 of which were the pneumonic form of tula-
remia. One 43-year-old man died of primary pneumonic
tularemia. Epidemiological analysis revealed that using
a lawn mower or brush cutter was significantly associ-
ated with illness in the 2 weeks before presentation of
this case.
38
Feldman et al proposed that in Martha’s Vine-
yard,
Ftularensis
was shed in animal excreta, persisted in
the environment, and was transmitted to humans after
mechanical aerosolization by mower or brush cutter
and subsequent inhalation.
38
The strong epidemiological
link with grass cutting adds plausibility to this expla-
nation.
39
A seroprevalence survey conducted in 2001
in Martha’s Vineyard demonstrated that landscapers
were more likely to have antibodies to
Ftularensis
than
nonlandscapers, suggesting an increased occupational
risk for tularemia.
38
The only other previously reported outbreak of
pneumonic tularemia in the United States occurred at
Martha’s Vineyard during the summer of 1978.
40
In a
single week, seven persons who stayed together in a
vacation cottage eventually developed typhoidal tula-
remia. A search for additional cases on the island uncov-
ered six other tularemia cases (five typhoidal and one
ulceroglandular). No confirmed source for the disease
exposure was discovered. Tularemia had been reported
sporadically since the introduction of rabbits to Martha’s
Vineyard in the 1930s,
40
and pneumonic tularemia was
initially reported in Massachusetts in 1947.
41
Laboratory-acquired Tularemia
Soon after the discovery of
Ftularensis
as a pathogen,
cases of laboratory-acquired infection were recognized.
Edward Francis observed that many laboratory per-
sonnel working with the pathogen, including himself,
became infected.
9
Six tularemia cases occurred during
US Public Health Service laboratory investigations of
tularemia outbreaks from 1919 through 1921.
44
Tulare-
mia is the third most commonly acquired laboratory
infection,
45
and recent laboratory-acquired infections
of tularemia emphasize the laboratory hazard that this
organism presents.
46
Because of the extreme infectivity
of this microorganism, investigators of a 2000 outbreak
in Kosovo chose not to culture the organisms from pa-
tients, but instead relied on empirical clinical evidence
of tularemia cases.
Pathogenesis
For infection to occur, bacterial pathogens must tra-
verse the normal skin and mucosal barriers that typi-
cally prevent microorganisms from entering the body.
Breaks in the skin from lacerations or abrasions provide
opportunity for
Ftularensis
transmission and infection.
Arthropod vectors can bypass the skin defenses with
170
Tularemia
a bite, thus inoculating the organism directly into the
host. However, the portal of entry can also be mucous
membranes in the respiratory tract, ocular membranes,
or the gastrointestinal tract.
One of the remarkable attributes of
F tularensis
is
the low infectious dose. As few as 10 organisms can
produce an infection when injected subcutaneously
into human volunteers, and only 10 to 50 organisms
are required when administered to human volunteers
by aerosol.
47,48
Recent investigations have attempted
to elucidate the unique characteristics that allow
F
tularensis
to cause infection at such a low number of
organisms. As an intracellular pathogen,
Ftularensis
has developed the means to survive in the typically
hostile environment inside macrophages by interfer-
ing with multiple aspects of macrophage function.
On initial entry into the macrophage,
Ftularensis
uses
a bacterial acid phosphatase, AcpA, to inhibit the
bactericidal respiratory burst response of the macro-
phage.
49,50
Additionally, both
Ftularensis
Type A and B
can inhibit acidification of the phagosome after entry
into the macrophage, escape from the phagosome,
and reside in the macrophage cytoplasm.
51,52
Another
survival mechanism of
Ftularensis
is the interference
with the normal macrophage response by inhibiting
Toll-like receptor signaling and cytokine secretion,
as demonstrated in experiments with murine macro-
phages and the live vaccine strain (referred to as LVS,
which is subspecies
holarctica
or a Type B strain) of
F
tularensis.
53
An absence of Toll-like receptor signaling
inhibits the typical robust innate immune response
that could eliminate the bacteria. Replication of the
organism in the macrophage begins slowly, but even-
tually large numbers of organisms can be found in a
single macrophage.
52,54,55
Although
F tularensis
may
initially delay apoptosis (programmed cell death) of
the macrophage, the organism eventually induces
apoptosis through mechanisms similar to intrinsic cel-
lular signals.
56
Researchers have identified only some
of the factors required by
Ftularensis
for survival in
macrophages, including
IglC
, a 23-kDa protein that
most likely affects Toll-like receptor-4 signal transduc-
tion,
53,57
and the
MglAB
operon that regulates transcrip-
tion of virulence factors.
58
The MinD protein functions
as a pump for substances containing free radicals such
as hydrogen peroxide, allowing the organism to resist
oxidative killing.
59
The early innate immune response to
F tularensis
involves intracellular killing of the pathogen by the
macrophages and proinflammatory cytokine secre-
tion. Murine experiments have demonstrated the
importance of an effective early cytokine response.
Interferon-g-deficient mice die from sublethal doses of
LVS
60
and tumor necrosis factor-a is at least as impor-
tant as interferon-g for control of
Ftularensis
infection.
61,
62
The host defense within macrophages appears to be
crucial at controlling infection by
Ftularensis
. In human
monocytes/macrophages, LVS strain and
F novicida
induced the processing and release of interleukin
(IL)-1b, an essential component of the inflammatory
immune response.
63
However, killed bacteria did not
induce this response, but did induce the early phases
required for IL-1b, such as mRNA transcription. The
results suggest that only live
Francisella
can escape
from the phagosome, and thus trigger the function of
caspase-1, which converts the precursor of IL-1b to its
active form. In mice deficient in caspase-1 as well as
ASC, an adaptor protein involved in host cell death,
substantially higher bacterial loads were observed, as
well as early mortality, compared to normal mice.
64
Neutrophils perform an important function in limiting
the spread of
F tularensis
after inoculation. Experi-
ments have demonstrated that neutrophils can kill
F
tularensis
,
65
and mice depleted of neutrophils appear
susceptible to infection with
Ftularensis
LVS.
66
The late adaptive immune response to
Ftularensis
requires an intact cell-mediated immune system,
particularly in resolving the initial infection and in
producing long-term immunity.
67
There is no clear
immunodominant epitope on any one
Ftularensis
viru-
lence protein that stimulates the required cell-mediated
response; however, studies have demonstrated that
multiple protein/peptides are required.
68
Vaccination
with
Ftularensis
LVS appears to produce a long-term
memory T-cell response (as measured by lymphocyte
stimulation),
69
but it is unclear what degree of long-
term protection is conferred by this response. Both
CD4
+
and CD8
+
lymphocytes are required for an ef-
fective cell-mediated response to
F tularensis.
60
The
protective memory response is dependent on a robust
proinflammatory cellular response, because admin-
istration of anti-interferon-g and anti-tumor necrosis
factor-a antibodies to previously vaccinated mice
dramatically lowers the lethal infective intradermal
dose of
Ftularensis.
62
This response initially appears 2
to 4 weeks after initial infection,
70-72
and it can remain
detectable for many years.
69,73
The importance of humoral immunity in the defense
against tularemia is not completely understood, but it
appears that the humoral response by itself provides
little or no value in protecting the host.
74
When labo-
ratory workers received a formalin-killed whole-cell
vaccine developed by Foshay et al,
75
a strong humoral
response was elicited but was not protective against
cutaneous
48
or respiratory
47
challenge. The failure of
this vaccine suggested that the formalin inactivation
procedures destroyed some of the essential protec-
tive antigens or that these protective antigens were
171
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