Speaking of Latin American guidelines for the diagnosis of tick-transmitted rickettsiosis

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1
2
Review
3
Syndromic
classification
of
rickettsioses:
an
approach
for
clinical
4
practice
5
Alvaro
A.
Faccini-Martı
´nez
Q1
a
,
Lara
Garcı
´a-Alvarez
b
,
Marylin
Hidalgo
a
,
Jose
´A.
Oteo
b,
*
6
a
Microbiology
Department,
Faculty
of
Sciences,
Pontificia
Universidad
Javeriana,
Bogota
´,
Colombia
7
b
Infectious
Diseases
Department,
Center
of
Rickettsioses
and
Vector-borne
Diseases,
Hospital
San
Pedro-CIBIR,
Logron
˜o,
Spain
8
9
10
1.
Introduction
11
Rickettsioses
Q2
are
zoonotic
infections
caused
by
obligate
12
intracellular
bacteria
of
the
genera
Rickettsia
and
Orientia,
13
belonging
to
the
family
Rickettsiaceae.
1–3
The
lifecycle
of
these
14
microorganisms
is
determined
by
their
survival
in
small
mammals
15
(which
can
act
as
reservoirs
or
as
amplifiers)
and
in
arthropods,
16
such
as
ticks,
fleas,
lice,
and
mites,
which
can
also
act
as
vectors.
In
17
this
regard,
and
with
the
exception
of
Rickettsia
prowazekii,
the
18
human
is
usually
an
accidental
host.
4
19
From
the
first
description
of
R.
prowazekii
as
an
etiological
agent
20
of
epidemic
typhus
in
1916
up
to
the
late
1980s,
eight
further
21
species
were
described
as
causes
of
rickettsioses
around
the
world:
22
Rickettsia
rickettsii,
Rickettsia
typhi,
Rickettsia
conorii
subsp.
conorii,
23
Rickettsia
akari,
Rickettsia
sibirica,
Rickettsia
australis,
Rickettsia
24
conorii
subsp.
israelensis,
and
Orientia
tsutsugamushi.
5
However,
25
with
the
development
and
implementation
of
molecular
biology
in
26
the
1990s,
this
list
has
since
grown
and
more
than
30
species
and
27
subspecies
are
recognized.
Most
of
them
have
been
implicated
as
28
human
pathogens.
6
29Rickettsioses
have
no
pathognomonic
signs,
although
there
are
30signs
and
symptoms
that
are
highly
suggestive,
such
as
the
31presence
of
fever,
rash,
lymphadenopathy,
and
an
eschar
(tache
32noire).
Unfortunately
not
always
and
not
all
rickettsioses
present
33typical
signs
and
symptoms.
In
most
cases
clinical
suspicion
34together
with
a
positive
serology
is
sufficient
to
make
the
diagnosis
35of
rickettsiosis,
although
in
order
to
reach
an
accurate
diagnosis
36and
confirm
the
etiological
agent,
isolation
or
molecular
biology
37assays
are
needed.
38By
definition,
a
syndrome
is
a
set
of
signs
and
symptoms
that
39characterizes
a
disease
with
several
causes
or
etiologies.
7
This
40definition
is
applicable
to
rickettsioses
because
different
species
41can
cause
similar
clinical
presentations.
Therefore,
we
propose
a
42syndromic
classification
for
these
infections
(exanthematic
rick-
43ettsiosis
syndrome
with
a
low
probability
of
inoculation
eschar
and
44rickettsiosis
syndrome
with
a
probability
of
inoculation
eschar
and
45their
variants)
in
order
to
provide
clinicians
with
a
guide
to
the
46suspected
etiological
agent
and
thus
direct
the
diagnosis
taking
the
47clinical
manifestations,
geographic
area,
and
the
possible
vector
48involved
into
account.
We
provide
only
a
brief
description
of
the
49recommended
treatment,
since
the
antibiotic
management
of
50rickettsiosis
is
simple
(doxycycline,
except
where
there
are
51contraindications)
and
remains
the
same
regardless
of
the
species
International
Journal
of
Infectious
Diseases
xxx
(2014)
e1–e14
A
R
T
I
C
L
E
I
N
F
O
Article
history:
Received
28
February
2014
Received
in
revised
form
23
April
2014
Accepted
24
May
2014
Corresponding
Editor:
Eskild
Petersen,
Aarhus,
Denmark
Keywords:
Rickettsioses
Syndrome
Arthropod-borne
diseases
Rickettsia
spp
Rash
Eschar
S
U
M
M
A
R
Y
Rickettsioses
share
common
clinical
manifestations,
such
as
fever,
malaise,
exanthema,
the
presence
or
absence
of
an
inoculation
eschar,
and
lymphadenopathy.
Some
of
these
manifestations
can
be
suggestive
of
certain
species
of
Rickettsia
infection.
Nevertheless
none
of
these
manifestations
are
pathognomonic,
and
direct
diagnostic
methods
to
confirm
the
involved
species
are
always
required.
A
syndrome
is
a
set
of
signs
and
symptoms
that
characterizes
a
disease
with
many
etiologies
or
causes.
This
situation
is
applicable
to
rickettsioses,
where
different
species
can
cause
similar
clinical
presentations.
We
propose
a
syndromic
classification
for
these
diseases:
exanthematic
rickettsiosis
syndrome
with
a
low
probability
of
inoculation
eschar
and
rickettsiosis
syndrome
with
a
probability
of
inoculation
eschar
and
their
variants.
In
doing
so,
we
take
into
account
the
clinical
manifestations,
the
geographic
origin,
and
the
possible
vector
involved,
in
order
to
provide
a
guide
for
physicians
of
the
most
probable
etiological
agent.
ß
2014
The
Authors.
Published
by
Elsevier
Ltd
on
behalf
of
International
Society
for
Infectious
Diseases.
This
is
an
open
access
article
under
the
CC
BY-NC-ND
license
(http://creativecommons.org/licenses/by-
nc-nd/3.0/).
*Corresponding
author.
Tel.:
+34
699607264.
E-mail
address:
jaoteo@riojasalud.es
(J.A.
Oteo).
G
Model
IJID
2029
1–14
Please
cite
this
article
in
press
as:
Faccini-Martı
´nez
AA,
et
al.
Syndromic
classification
of
rickettsioses:
an
approach
for
clinical
practice.
Int
J
Infect
Dis
(2014),
http://dx.doi.org/10.1016/j.ijid.2014.05.025
Contents
lists
available
at
ScienceDirect
International
Journal
of
Infectious
Diseases
jou
r
nal
h
o
mep
ag
e:
w
ww
.elsevier
.co
m
/loc
ate/ijid
http://dx.doi.org/10.1016/j.ijid.2014.05.025
1201-9712/ß
2014
The
Authors.
Published
by
Elsevier
Ltd
on
behalf
of
International
Society
for
Infectious
Diseases.
This
is
an
open
access
article
under
the
CC
BY-NC-ND
license
(http://creativecommons.org/licenses/by-nc-nd/3.0/).

52
involved.
Figure
1
is
a
map
showing
the
distribution
of
the
main
53
human
tick-borne
rickettsioses.
54
2.
Exanthematic
rickettsioses
syndrome
with
a
low
probability
55
of
inoculation
eschar
56
This
is
characterized
by
an
acute
febrile
illness
where
a
rash
is
57
the
predominant
clinical
manifestation
and
the
presence
of
an
58
inoculation
eschar
cannot
be
seen
or
its
presence
is
exceptional.
59
Two
variants
are
proposed
taking
into
account
the
distribution
of
60
the
rash
(Figure
2).
61
2.1.
With
centripetal
rash
distribution
62
This
type
of
rash
is
characteristic
of
the
rickettsioses
caused
by
63
R.
rickettsii.
It
occurs
only
in
3–5%
in
the
first
3
days,
increasing
to
64
60–70%
between
days
7
and
10
of
the
disease.
8
It
usually
starts
on
65
the
wrists
and
ankles
as
small
not
itchy
red
macular
lesions,
with
66
subsequent
extension
to
the
extremities
and
palmoplantar
and
67trunk
involvement.
Maculopapular,
petechial,
or
purpuric
lesions
68can
be
observed
(Figure
3).
9
In
10%
of
cases
we
do
not
observe
rash
69overall
in
African
descent
and
elderly
people
Q3
.
10
In
R.
rickettsii
70infection,
the
presence
of
an
inoculation
eschar
is
an
unusual
71finding
(only
five
cases
reported
in
the
literature
from
1981
to
722012).
11–14
73The
geographical
distribution
of
R.
rickettsii,
the
most
patho-
74genic
species
of
the
tick-borne
rickettsiae,
is
limited
to
the
Western
75Hemisphere
where
its
primary
vectors
are
ticks
of
the
genera
76Dermacentor,
Rhipicephalus,
and
Amblyomma
(Table
1).
15
772.2.
With
centrifugal
rash
distribution
78This
is
typical
of
R.
typhi
and
R.
prowazekii
infections.
The
rash
79usually
starts
on
the
trunk
and
spreads
to
the
extremities
without
80palmoplantar
involvement.
In
both
rickettsioses,
the
exanthema
is
81characterized
by
macular,
maculopapular,
or
petechial
lesions.
27
82The
latter
lesions
and
compromise
of
the
axillary
area
are
more
83frequent
in
R.
prowazekii
infection.
28
Characteristically,
an
Figure
1.
Map
showing
the
distribution
of
the
main
human
tick-borne
rickettsioses.
Syndrome
Type of rash
Epidemiological background
spp
Cent
ripeta
l rash Centrifuga
l ras
h
Exanthemac
rickesioses with low probability of
inocula
on eschar
The Americas
Ticks:
Amblyomma, Derm
acentor
or Rhi
pic
eph
alus genus
R. rickesii
Tro
pical or
sub
tro
pical
area
s
and Med
iterr
anean
Area
Fleas
Popu
la
ons at
risk of p
arasism
by body
li
ce. Flying
squ
irr
els
(USA)
R. typhi R. prowazekii
Rickesia
Figure
2.
Algorithm
for
exanthematic
rickettsioses
and
a
low
probability
of
inoculation
eschar.
A.A.
Faccini-Martı
´nez
et
al.
/
International
Journal
of
Infectious
Diseases
xxx
(2014)
e1–e14
e2
G
Model
IJID
2029
1–14
Please
cite
this
article
in
press
as:
Faccini-Martı
´nez
AA,
et
al.
Syndromic
classification
of
rickettsioses:
an
approach
for
clinical
practice.
Int
J
Infect
Dis
(2014),
http://dx.doi.org/10.1016/j.ijid.2014.05.025

84
inoculation
eschar
does
not
occur.
As
observed
for
R.
rickettsii
85
rickettsioses,
the
rash
is
commonly
missed
on
dark
skin.
In
these
86
cases
it
is
very
important
to
look
for
scratches
secondary
to
lice
87
parasitization
or
antecedents
of
bites
in
the
case
of
fleas.
Also,
in
88
R.
prowazekii
infection,
the
patient
presents
with
confusion
and
89
purpura,
and
gangrene
may
be
observed.
28
90
R.
typhi
has
a
worldwide
distribution
predominantly
in
tropical
91
and
subtropical
areas,
where
its
main
vector
is
the
rat
flea
92
Xenopsylla
cheopis,
followed
by
Ctenocephalides
felis.
29
R.
prowazekii
93
infection
is
related
to
outbreaks
in
populations
at
risk
of
parasitism
94
by
body
lice
(Pediculus
humanus
humanus),
where
poor
hygiene
95
and
overcrowding
are
common
(homeless,
displaced,
refugees,
and
96
imprisoned).
28
However,
in
the
USA
the
eco-epidemiology
of
this
97
disease
is
often
associated
with
the
presence
of
and
contact
with
98
flying
squirrels
(Glaucomys
volans)
and
its
ectoparasites,
in
which
99
an
enzootic
or
wild
cycle
is
described.
30
Significantly,
R.
prowazekii
100
is
the
only
species
of
Rickettsia
able
to
produce
a
latent
infection
101
and
subsequently
manifests
in
a
recrudescent
way
called
‘Brill–
102
Zinsser’
disease,
where
the
presence
of
rash
is
less
common
103
(Table
2).
31
104
3.
Rickettsioses
syndrome
with
a
probability
of
inoculation
105
eschar
106
This
is
characterized
by
an
acute
febrile
illness
with
or
without
107
rash,
where
one
of
the
most
common
signs
is
the
inoculation
108
eschar.
An
eschar
is
defined
as
a
crusty
necrotic
lesion
with
or
109
without
a
surrounding
erythematous
halo,
which
suggests
the
110
location
of
the
vector
bite
(Figure
4).
37
This
is
one
of
the
most
111common
clinical
manifestations
in
different
rickettsioses
associ-
112ated
with
tick
bites
and
in
O.
tsutsugamushi
infections.
38
We
113propose
four
syndrome
variants
taking
into
consideration
other
114associated
signs
(Figure
5
and
Tables
3–6).
1153.1.
Associated
with
a
maculopapular/purpuric
rash
1163.1.1.
Rickettsia
felis
infection
117Since
the
first
reports,
R.
felis
disease
has
been
identified
by
118clinical
manifestations
similar
to
those
caused
by
R.
typhi.
It
119tends
to
manifest
a
generalized
maculopapular
rash
on
the
trunk,
120with
the
difference
that
in
some
cases
it
also
presents
an
121inoculation
eschar
associated
with
regional
lymphadenopathy.
39
122However,
recent
studies
in
Sub-Saharan
Africa
(Kenya
and
123Senegal)
show
that
R.
felis
can
also
cause
an
acute
non-specific
124febrile
illness
without
rash
or
inoculation
eschar.
40
In
Senegal
it
125has
been
proposed
as
the
primary
etiological
agent
of
a
new
126ulcerative-type
disease
termed
‘yaaf’
by
the
authors.
41
Thus,
127R.
felis
is
currently
extremely
common
in
some
African
countries
128(appearing
as
an
eruptive
febrile
illness),
with
evidence
in
129infecting
mosquitoes
(genera
Anopheles
and
Aedes)
and
gorilla
130stools,
suggesting
that
these
mammals
could
be
potential
131reservoirs
Q4
.
42,43
132Human
infection
with
this
Rickettsia
species
has
been
described
133worldwide.
The
prevalence
of
infection
in
the
main
suspected
134vector
(the
cat
flea,
C.
felis)
is
very
high
and
it
has
been
found
all
135around
the
world.
44
R.
felis
is
the
only
species
to
grow
in
vitro,
and
136only
at
low
temperatures
Q5
.
45
Figure
3.
Purpuric
rash
on
a
patient
with
Rickettsia
rickettsii
rickettsiosis.
Courtesy
of
Dr
Rodrigo
Angerami.
Table
1
Exanthematic
rickettsioses
with
a
centripetal
rash
distribution
and
a
low
probability
of
inoculation
eschar
Rickettsia
species
Geographical
distribution
Known
vector
or
possible
vectors
References
R.
rickettsii
America
Canada
Dermacentor
andersoni
16
USA
Dermacentor
variabilis,
D.
andersoni,
Rhipicephalus
sanguineus,
Amblyomma
americanum
12,17,18
Mexico
R.
sanguineus,
Amblyomma
cajennense
sensu
lato
(s.l.)
16,19
Costa
Rica
Haemaphysalis
leporispalustris
20
Panama
A.
cajennense
s.l.
21
Colombia
A.
cajennense
s.l.
22
Brazil
A.
cajennense
s.l.,
Amblyomma
aureolatum,
R.
sanguineus
23–25
Argentina
A.
cajennense
s.l.
26
Table
2
Exanthematic
rickettsioses
with
a
centrifugal
rash
distribution
and
a
low
probability
of
inoculation
eschar
Rickettsia
species
Geographical
distribution
Known
vector
or
possible
vectors
References
R.
typhi
Worldwide
Xenopsylla
cheopis,
Ctenocephalides
felis
29
R.
prowazekii
America
Lice
and
fleas
from
flying
squirrels
(USA)
32–36
USA
(wild
cycle)
Mexico,
Guatemala,
Ecuador,
Bolivia,
Chile,
Argentina,
Peru,
Colombia
Europe
Pediculus
humanus
humanus
France,
Russia
Africa
Algeria,
Burundi
Figure
4.
Eschar
(tache
noire)
on
a
patient
with
Rickettsia
conorii
rickettsiosis.
A.A.
Faccini-Martı
´nez
et
al.
/
International
Journal
of
Infectious
Diseases
xxx
(2014)
e1–e14
e3
G
Model
IJID
2029
1–14
Please
cite
this
article
in
press
as:
Faccini-Martı
´nez
AA,
et
al.
Syndromic
classification
of
rickettsioses:
an
approach
for
clinical
practice.
Int
J
Infect
Dis
(2014),
http://dx.doi.org/10.1016/j.ijid.2014.05.025

137
3.1.2.
Rickettsia
massiliae
infection
138
To
date,
only
four
confirmed
human
cases
of
infection
with
this
139
species
have
been
published;
in
all
cases
an
inoculation
eschar
was
140
observed.
Two
of
them
had
a
maculopapular
rash
(Italy
and
141
France),
46,47
one
was
purpuric
(Argentina),
48
and
the
remaining
142
case
had
no
evidence
of
a
rash
(Italy);
it
is
likely
that
143
warmer
weather
has
an
impact
on
the
epidemiology
of
this
144
rickettsiosis.
47,49
R.
massiliae
usually
infects
ticks
of
the
Rhipice-
145
phalus
sanguineus
complex,
predominantly
in
Europe
50
and
in
the
146
USA,
51
and
it
has
been
identified
recently
in
the
hard
tick
147
Dermacentor
marginatus
in
southern
Hungary.
52
R.
massiliae
has
148
been
involved
in
double
infections
with
R.
conorii
in
R.
sanguineus
149
ticks
(southern
France).
53
150
3.1.3.
Rickettsia
parkeri
infection
151
The
presence
of
this
Rickettsia,
as
with
R.
rickettsii,
is
152
geographically
limited
to
the
Western
Hemisphere.
15
The
clinical
153
manifestations
are
characterized
by
a
maculopapular
rash,
in
some
154
cases
vesiculopapular,
with
palmoplantar
involvement
and,
in
155
more
than
90%
of
cases,
associated
with
single
or
multiple
156
inoculation
eschars
and
the
possibility
of
regional
lymphadenopa-
157
thy.
Hence,
this
is
one
of
the
few
rickettsioses
to
produce
an
eschar
158
in
America.
54–56
The
recognized
vectors
are
Amblyomma
macula-
159
tum
and
Amblyomma
triste.
15
However,
Amblyomma
ovale
has
160
recently
been
proposed
as
an
alternative
vector
of
a
variation
of
161
R.
parkeri
known
as
Rickettsia
sp
Atlantic
rainforest
strain,
given
the
162
findings
in
Colombia
57
and
Brazil,
58
and
this
is
now
recognized
as
a
163
human
pathogen
Q6
.
58
R.
parkeri
has
also
been
detected
in
164
Amblyomma
tigrinum
ticks
in
Cochabamba
(Bolivia)
59
and
in
Ixodes
165
scapularis
from
Louisiana
(USA).
60
166
3.1.4.
Rickettsia
conorii
infection
167
Since
its
first
description
as
a
human
pathogen
in
1910
until
the
168
end
of
the
last
century,
this
was
recognized
as
the
only
causative
169
agent
of
tick-borne
rickettsioses
in
Europe.
50
In
2005,
R.
conorii
was
170
proposed
as
a
complex
with
four
subspecies
based
on
epidemio-
171
logical
and
clinical
differences.
61
The
following
subspecies
were
172
recognized:
R.
conorii
subsp.
conorii,
R.
conorii
subsp.
israelensis,
173
R.
conorii
subsp.
caspia,
and
R.
conorii
subsp.
indica,
all
geographi-
174
cally
restricted
to
the
Eastern
Hemisphere.
R.
conorii
subsp.
conorii
175is
widely
distributed
and
is
the
main
cause
of
exanthematic
176rickettsioses
associated
with
inoculation
eschar
in
Mediterranean
177countries
(European
and
African)
and
in
the
Black
Sea.
38
Clinically,
178patients
present
with
a
maculopapular
or
purpuric
rash
with
179involvement
of
the
palms
of
the
hands
and
soles
of
the
feet
180(Figure
6)
and
the
presence
of
a
single
or
multiple
inoculation
181eschars
(mainly
in
children).
50
For
the
other
subspecies,
the
finding
182of
an
inoculation
eschar
is
less
frequent
and
their
geographical
183distribution
is
more
restricted.
Patients
infected
with
R.
conorii
184subsp.
conorii
usually
have
a
single
eschar
and
a
generalized
185maculopapular
rash
(97%),
and
the
mortality
rate
is
close
to
2.5%.
186For
R.
conorii
subsp.
caspia,
the
symptoms
include
eschar
(23%),
a
187macular
rash
(94%),
and
conjunctivitis;
no
fatal
cases
have
been
188reported.
R.
conorii
subsp.
indica
frequently
presents
a
purpuric
189rash,
however
an
eschar
is
rarely
found
and
no
fatal
forms
have
190been
reported.
Finally,
R.
conorii
subsp.
israelensis
rickettsiosis
has
a
191lesser
presence
of
eschar
than
R.
conorii
subsp.
conorii
and
results
in
192a
mild
to
severe
illness.
38,62
Although
the
main
vector
is
the
brown
193dog
tick
R.
sanguineus,
other
species
belonging
to
the
same
complex
194could
also
act
as
vectors.
50
1953.1.5.
Rickettsia
sibirica
subsp.
sibirica
infection
196This
is
characterized
by
a
benign
evolution
with
a
low
197probability
of
complications.
16
Clinically,
it
presents
a
maculo-
198papular
or
petechial
rash
associated
with
an
inoculation
eschar
199(more
than
95%
of
cases)
and
regional
lymphadenopathy.
63
The
200geographical
distribution
is
limited
to
the
Asiatic
Russia
(Siberia)
201region
and
the
countries
located
in
the
south
of
Russia
202(Kazakhstan,
China,
and
Mongolia),
where
the
main
vectors
are
203ticks
of
the
genus
Dermacentor,
especially
Dermacentor
nut-
204talli.
38,64
In
contrast
to
the
rickettsioses
caused
by
Rickettsia
205heilongjiangensis,
in
Siberia,
cases
of
infection
by
R.
sibirica
subsp.
206sibirica
tend
to
be
more
frequent
in
the
months
of
April
and
207May.
64
2083.1.6.
Rickettsia
heilongjiangensis
infection
209Although
this
species
was
originally
isolated
from
Dermacentor
210silvarum
ticks
in
1982
in
Heilongjiang
Province
(China),
it
was
not
211recognized
as
a
human
pathogen
until
the
late
1990s/early
2122000.
16,65
Cases
often
occur
in
patients
50
years
old
and
during
Maculopapu
lar/pu
rpu
ric
rash
Rickesi
oses wit
h probabilit
y of
inocula
on eschar
R. felis
R. conorii comp
lex
R. sibi
rica subsp
. sibi
ric
a
R. ma
ssili
ae
R. pa
rkeri
R. he
ilongjiange
nsis
R. japon
ica R. aeschlimannii
R. honei O. tsutsug
amushi
R. sibirica
mongolimo
nae
Europe,
Africa and
the
Amer
icas
Ticks
: R.
sanguine
us
comp
lex
Europe, Africa
and Asia
Ticks:
R. sanguine
us
comp
lex
The Amer
ica
s
Ticks
:
Ambly
omma
genus
Europe and
Africa; mai
nly in
Mediterr
anean
and Blac
k Sea
count
ries
Ticks:
R. sanguine
us
comp
lex
Asia
or Southern
Russi
a
Ticks:
Dermacentor
genus
Asi
a
Ticks:
Dermacentor or
Haemaph
ysalis
genus
Asi
a
Ticks
:
Dermacentor,
Haemaph
ysalis
or Ixod
es genu
s
Flind
ers I
sland
s,
Eastern Austral
ia,
Thailand
and
Nepal
Ticks
:
Bothriocroton,
Haemaph
ysalis,
Ixodes or
Rhip
icephal
us
genus
Africa
and
Europe
Ticks
:Hyal
omma
or Rhi
pic
eph
alus
genus
Asian
Pac
ific,
Chile and
Dubai
Tro
mbiculi
d or
chi
ggers
Worldwide
Fleas
Syndrome
Type
of
ras
h
Epidem
iolo
gical
background
Rickesia spp
Figure
5.
Algorithm
for
exanthematic
rickettsioses
with
the
probability
of
an
inoculation
eschar.
A.A.
Faccini-Martı
´nez
et
al.
/
International
Journal
of
Infectious
Diseases
xxx
(2014)
e1–e14
e4
G
Model
IJID
2029
1–14
Please
cite
this
article
in
press
as:
Faccini-Martı
´nez
AA,
et
al.
Syndromic
classification
of
rickettsioses:
an
approach
for
clinical
practice.
Int
J
Infect
Dis
(2014),
http://dx.doi.org/10.1016/j.ijid.2014.05.025

Table
3
Rickettsioses
with
a
probability
of
inoculation
eschar
and
a
maculopapular/purpuric
rash
Rickettsia
species
Geographical
distribution
Known
vector
or
possible
vectors
References
R.
felis
Worldwide
Ctenocephalides
felis
44
R.
massiliae
Confirmed
cases
in
Italy,
France,
and
Argentina
Species
belonging
to
the
Rhipicephalus
sanguineus
complex
46–51
R.
parkeri
America
USA,
Peru
Amblyomma
maculatum,
Ixodes
scapularis
(USA)
(?)
15,60
Brazil
Amblyomma
triste,
Amblyomma
ovale
(Rickettsia
sp
genotype
Atlantic
rainforest)
58
Colombia
A.
ovale
(Rickettsia
sp
genotype
Atlantic
rainforest)
(?)
57
Uruguay,
Argentina
A.
triste
15
Bolivia
Amblyomma
tigrinum
59
R.
conorii
subsp.
conorii
Europe
R.
sanguineus
Mediterranean
countries
(Portugal,
Spain,
France,
Italy,
Malta,
Slovenia,
Croatia,
Albania,
Greece,
Cyprus)
38,50
Countries
around
the
Black
Sea
(Ukraine,
Bulgaria,
Turkey,
Georgia)
Africa
38
Algeria,
Morocco,
Tunisia,
Kenya,
Somalia,
Chad,
Zimbabwe,
South
Africa
R.
conorii
subsp.
israelensis
Europe
50
Portugal,
Italy
Africa
94
Tunisia
Asia
38
Israel
R.
conorii
subsp.
indica
Asia
India
R.
conorii
subsp.
caspia
Europe
Rhipicephalus
pumilio,
R.
sanguineus
38,53
Astrakhan,
Kosovo,
France
Africa
Chad
R.
sibirica
subsp.
sibirica
Asia
Siberia
Dermacentor
nuttalli,
Dermacentor
marginatus,
Dermacentor
silvarum,
Dermacentor
pictus,
Haemaphysalis
concinna
38
Kazakhstan
D.
marginatus
16
China,
Mongolia
D.
nuttalli,
Dermacentor
sinicus,
Dermacentor
auratus,
D.
silvarum,
H.
concinna
63
R.
heilongjiangensis
Asia
China
and
Eastern
Siberia
Haemaphysalis
japonica
douglasi,
H.
concinna,
D.
silvarum
38,67
Japan
H.
concinna
66
R.
japonica
Asia
Japan
Haemaphysalis
flava,
Haemaphysalis
longicornis,
Dermacentor
taiwanensis,
Ixodes
ovatus
16,38
Thailand
Haemaphysalis
hystricis
(R.
japonica-like)
70
Korea
H.
longicornis
95
R.
honei
Oceania
38,74,96
Flinders
Islands
and
Eastern
Australia
(R.
honei
strain
marmionii)
Bothriocroton
hydrosauri,
Ixodes
tasmani,
Haemaphysalis
novaeguineae
Asia
Thailand
Ixodes
granulatus
73
Nepal
Rhipicephalus
haemaphysaloides
(?),
I.
granulatus
(?)
72
R.
aeschlimannii
Africa
Morocco
Hyalomma
marginatum
marginatum
94
Algeria
Hyalomma
marginatum
marginatum,
Hyalomma
aegyptium,
Hyalomma
dromedarii
(?),
Hyalomma
marginatum
rufipes
(?)
94,97
South
Africa
Rhipicephalus
appendiculatus
98
Tunisia
Hyalomma
dromedarii
(?)
77
Europe
Greece
Rhipicephalus
turanicus
(?)
78
O.
tsutsugamushi
Asia
84
Kazakhstan,
Uzbekistan,
Afghanistan,
Pakistan,
India,
Nepal,
Bangladesh,
Myanmar,
Vietnam,
Cambodia,
Sri
Lanka,
Singapore,
Brunei,
Taiwan
Leptotrombidium
deliense
New
Guinea,
Philippines
L.
deliense,
Leptotrombidium
fletcheri
China
L.
deliense,
Leptotrombidium
scutellare,
Leptotrombidium
gaohuensis
Malaysia
L.
deliense,
L.
scutellare,
Leptotrombidium
arenicola,
L.
fletcheri
Indonesia
L.
deliense,
L.
arenicola,
L.
fletcheri
Thailand
L.
deliense,
Leptotrombidium
chiangraiensis,
L.
scutellare,
Leptotrombidium
imphalum
Japan
Leptotrombidium
akamushi,
L.
scutellare,
Leptotrombidium
pallidum
Korea
L.
pallidum,
L.
scutellare,
Neotrombicula
japonica
(?),
Eushoengastia
koreaensis
(?)
84,88
A.A.
Faccini-Martı
´nez
et
al.
/
International
Journal
of
Infectious
Diseases
xxx
(2014)
e1–e14
e5
G
Model
IJID
2029
1–14
Please
cite
this
article
in
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as:
Faccini-Martı
´nez
AA,
et
al.
Syndromic
classification
of
rickettsioses:
an
approach
for
clinical
practice.
Int
J
Infect
Dis
(2014),
http://dx.doi.org/10.1016/j.ijid.2014.05.025

213
the
months
of
June
and
July.
16
Regarding
the
clinical
manifesta-
214
tions,
the
rash
is
maculopapular
and
has
a
mild
appearance,
and
215
this
is
accompanied
by
other
signs
including
an
inoculation
eschar,
216
lymphadenopathy,
and,
in
a
small
proportion,
lymphangitis
and
217
conjunctival
injection.
65
218
In
2010,
the
first
case
of
R.
heilongjiangensis
infection
confirmed
219
by
molecular
tools
was
reported
in
Japan
in
a
35-year-old
man
220
with
rash,
fever,
and
two
lesions
compatible
with
inoculation
221
eschars.
66
Although
Haemaphysalis
japonica
douglasi
and
222
D.
silvarum
are
endemic
in
Eastern
Siberia
and
China,
epidemio-
223
logical
studies
have
determined
Haemaphysalis
concinna
to
be
a
224
possible
vector.
38,67
2253.1.7.
Rickettsia
japonica
infection
226This
rickettsiosis
was
initially
mistaken
for
scrub
typhus
or
227O.
tsutsugamushi
infection.
16
Both
infections
are
characterized
by
228an
acute
febrile
illness
associated
with
a
maculopapular
rash,
229inoculation
eschar,
and
the
possibility
of
a
severe
clinical
picture
230related
with
pulmonary
and
neurological
complications
and
231multiorgan
failure;
both
also
share
a
similar
geographical
232distribution
where
their
vectors
(ticks
and
mites,
respectively)
233are
prevalent.
68
However,
in
the
infection
caused
by
R.
japonica,
the
234presence
of
an
inoculation
eschar
is
more
common
(>90%)
than
in
235scrub
typhus.
On
the
other
hand,
just
one
eschar
that
is
not
236associated
with
lymphadenopathy
is
usually
observed,
and
the
Table
3
(Continued
)
Rickettsia
species
Geographical
distribution
Known
vector
or
possible
vectors
References
Southeastern
Russia
L.
pallidum,
Leptotrombidium
pavlovskyi
84
Arab
Emirates
(Dubai)
Not
determined
92
Oceania
84
Northern
Australia
L.
deliense
America
93
Chile
Not
determined
Table
4
Rickettsioses
with
a
probability
of
inoculation
eschar
and
a
vesicular
rash
Rickettsia
species
Geographical
distribution
Known
vector
or
possible
vectors
References
R.
africae
Africa
East,
West
and
Central
region
Amblyomma
variegatum
16
South
Amblyomma
hebraeum,
Rhipicephalus
(Boophilus)
decoloratus
(?)
16,104
America
15
Caribbean
Islands
A.
variegatum
R.
akari
Worldwide
Liponyssoides
sanguineus
113,115–121,124
Confirmed
cases
in
the
USA,
Mexico,
Ukraine,
Croatia,
Holland,
Turkey,
South
Africa
and
Korea
R.
australis
Oceania
16
Eastern
Australia,
Queensland
(between
the
months
of
June
and
November)
Ixodes
holocyclus,
Ixodes
tasmani,
Ixodes
cornuatus
Table
5
Rickettsioses
with
a
probability
of
inoculation
eschar
and
regional
lymphadenopathy
as
a
main
sign
Rickettsia
species
Geographical
distribution
Known
vector
or
possible
vectors
References
R.
slovaca
Europe
Dermacentor
marginatus,
Dermacentor
reticulatus
50,139
Confirmed
cases
in
Portugal,
Spain,
France,
Italy,
Hungary,
Bulgaria,
Slovakia,
Germany
Candidatus
R.
rioja
Europe
130,131
Confirmed
cases
in
Spain
D.
marginatus
R.
raoultii
Europe
105,132,143–147
Confirmed
case
in
Slovakia
and
suspected
cases
in
Spain,
France,
Poland
D.
marginatus,
D.
reticulatus,
Dermacentor
nuttalli
(Mongolia),
Dermacentor
silvarum
(China)
Rickettsia
sp
strain
364D
(R.
philipii)
America
140–142
USA
(California)
Dermacentor
occidentalis
Table
6
Rickettsioses
with
a
probability
of
inoculation
eschar
and
lymphangitis
Rickettsia
species
Geographical
distribution
Known
vector
or
possible
vectors
References
R.
sibirica
subsp.
mongolitimonae
Europe
France
and
Portugal
Rhipicephalus
pusillus
154,161
Greece
Hyalomma
anatolicum
excavatum
153
Spain
R.
pusillus,
Hyalomma
marginatum
(?)
163,164
Africa
Egypt
and
Algeria
Hyalomma
sp
94
South
Africa
Hyalomma
truncatum
152
A.A.
Faccini-Martı
´nez
et
al.
/
International
Journal
of
Infectious
Diseases
xxx
(2014)
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Model
IJID
2029
1–14
Please
cite
this
article
in
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as:
Faccini-Martı
´nez
AA,
et
al.
Syndromic
classification
of
rickettsioses:
an
approach
for
clinical
practice.
Int
J
Infect
Dis
(2014),
http://dx.doi.org/10.1016/j.ijid.2014.05.025

237
rash
may
progress
to
a
purpuric
appearance.
16
Regarding
the
238
epidemiology,
most
cases
occur
in
Japan
from
April
to
October.
The
239
tick
vectors
recognized
are
Haemaphysalis
flava,
Haemaphysalis
240
longicornis,
Dermacentor
taiwanensis,
and
Ixodes
ovatus.
16,38
Simi-
241
larly,
this
rickettsiosis
has
also
been
described
in
South
Korea
and
242
Thailand.
69,70
243
3.1.8.
Rickettsia
honei
infection
244
This
species
was
first
isolated
in
clinical
samples
from
patients
245
in
the
Flinders
Islands
and
is
now
recognized
as
the
most
frequent
246
species
causing
tick-borne
rickettsioses
in
Australia
after
247
R.
australis.
71
Clinical
manifestations
caused
by
R.
honei
include
248
a
maculopapular
or
purpuric
rash
without
the
presence
of
vesicles
249
and
palmoplantar
involvement.
An
inoculation
eschar
is
seen
in
250
half
of
the
cases.
Other
signs
such
as
lymphadenopathy
and
cough
251
may
occur.
16
This
rickettsiosis
is
more
common
during
the
months
252
of
December
and
January.
16
The
recognized
vectors
in
Australia
are
253
Bothriocroton
hydrosauri,
Haemaphysalis
novaeguineae,
and
Ixodes
254
tasmani.
72
255
Cases
of
human
infection
with
this
species
have
also
been
256
reported
in
Thailand,
where
the
vector
is
Ixodes
granulatus.
73
In
257
Nepal,
the
same
tick
species
has
been
suggested
as
a
possible
258
vector,
together
with
Rhipicephalus
haemaphysaloides,
as
seen
in
a
259
case
published
in
2011.
72
260
In
Eastern
Australia,
during
2003,
a
genetically
related
species
261
of
R.
honei
(marmionii
strain)
was
isolated
in
patients
with
fever
262
and
headache.
Only
a
small
proportion
had
rash
onset
and
an
263
inoculation
eschar.
74
These
cases
occurred
between
February
and
264
June,
in
contrast
to
R.
honei
and
R.
australis
infections.
265
3.1.9.
Rickettsia
aeschlimannii
infection
266
This
Rickettsia
species
was
first
isolated
in
1997
from
Hyalomma
267
marginatum
ticks
in
Morocco;
75
5
years
later,
the
first
human
case
268
was
published
involving
a
patient
in
the
same
country.
76
Up
until
269
2010,
six
more
cases
were
attributed
to
this
rickettsiosis
(South
270
Africa,
Tunisia,
Algeria,
and
Greece)
by
molecular
and
serological
271
methods.
77,78
Most
cases
started
as
an
acute
febrile
illness
272
associated
with
a
maculopapular
rash.
Only
two
patients
273
presented
an
inoculation
eschar.
It
is
remarkable
that
in
the
274
Algerian
cases,
one
patient
had
more
than
one
eschar
and
the
other
275
an
associated
purpuric
rash
component.
79
276
R.
aeschlimannii
has
been
isolated
in
different
species
of
277
anthropophilic
ticks
of
the
genera
Hyalomma
and
Rhipicephalus
278
from
many
countries
of
Africa
and
Europe.
It
is
considered
that
279
infection
with
this
Rickettsia
species
may
have
been
under-
280
diagnosed.
77,80
However,
a
study
from
the
north
of
Spain
281demonstrated
the
absence
of
infection
or
disease
by
R.
aeschlimannii
282in
people
bitten
(even
for
more
than
1
week)
by
H.
marginatum
ticks
283infected
with
this
Rickettsia.
81
2843.1.10.
Orientia
tsutsugamushi
infection
285Previously
included
in
the
genus
Rickettsia,
this
species
was
286reclassified
in
1995
based
on
findings
from
its
cell
wall
and
on
287phylogenetic
analyses
as
a
single
species
belonging
to
the
genus
288Orientia
with
different
related
strains.
82–84
Today,
rickettsiosis
by
289O.
tsutsugamushi
is
an
important
cause
of
acute
febrile
illness
and
is
290endemic
in
the
Asian
Pacific
region,
extending
from
Afghanistan
to
291China,
Korea,
the
South
Pacific
Islands,
and
Northern
Australia.
84
292The
eco-epidemiology
of
this
disease
is
determined
by
humid
293tropical
regions
where
mites
of
the
genus
Leptotrombidium,
known
294as
trombiculids
or
chiggers,
are
reservoirs
of
O.
tsutsugamushi
and
295their
larval
stages
human
vectors
Q7
.
85
Wild
rodents
are
the
main
296hosts
of
these
mites.
86
Endemic
regions
are
characterized
by
rice
297fields,
scrubland,
and
the
presence
of
primary
deforestation.
85,86
298In
Japan,
unlike
infection
caused
by
R.
japonica,
infection
by
299O.
tsutsugamushi
is
usually
more
frequent
in
November.
87
Other
300genera
of
the
Trombiculidae
family,
such
as
Neotrombicula
301(N.
japonica)
and
Eushoengastia
(E.
koreaensis),
have
also
been
302implicated
as
possible
vectors.
88
303The
clinical
manifestations
may
vary
from
mild
to
severe.
Heart
304failure,
acute
renal
failure,
and
central
nervous
system
and
305respiratory
system
compromise,
with
interstitial
pneumonia
and
306acute
respiratory
distress
syndrome
(ARDS)
are
the
most
frequent
307causes
of
complications
and
death.
89–91
The
incubation
period
is
308usually
higher
than
for
other
rickettsioses
(up
to
18–21
days).
68,89
309The
fever
usually
appears
abruptly,
associated
with
headache,
310myalgia,
and
malaise.
A
week
after
the
onset
of
these
symptoms,
a
311maculopapular
rash
with
centrifugal
distribution
may
appear
312(uncommon)
and
an
inoculation
eschar,
which
can
be
single
or
313multiple
(presence
varies
between
7%
and
80%
of
cases),
commonly
314associated
with
regional
lymphadenopathy.
Manifestations
such
315as
non-suppurative
conjunctival
injection
and
hearing
loss
are
316highly
suggestive
of
this
rickettsiosis.
89,91
317Human
cases
of
infection
by
bacteria
of
the
genus
Orientia
318involving
patients
with
a
rash
and
inoculation
eschar
in
Dubai
319(2010)
and
Chile
(2011)
have
been
published.
92,93
These
geo-
320graphical
areas
are
unusual
for
the
occurrence
of
this
disease,
321suggesting
the
presence
of
‘new
species’
of
the
genus
Orientia.
3223.2.
Associated
with
a
vesicular
rash
3233.2.1.
Rickettsia
africae
infection
324This
rickettsiosis,
initially
confused
with
R.
conorii
infection,
325was
described
in
the
1990s
by
Kelly
et
al.,
who
determined
that
it
326was
produced
by
a
new
species
belonging
to
the
spotted
fever
327group
(SFG).
99,100
This
disease
begins
with
an
abrupt
onset
fever,
328headache,
myalgia
(predominantly
in
the
cervical
region),
and
329typically
single
or
multiple
inoculation
eschars
(predominantly
in
330the
extremities),
associated
with
a
vesicular
rash
and
lymphade-
331nopathy
in
half
of
the
cases
(Figure
7).
16
Its
epidemiology
is
332associated
with
the
presence
of
R.
africae
in
Amblyomma
333variegatum
(Eastern,
Western,
and
Central
Africa
and
the
Caribbean
334Islands)
and
Amblyomma
hebraeum
(Southern
Africa)
as
its
335recognized
vectors.
15
However,
R.
africae
has
also
been
detected
336in
other
tick
species,
such
as
Amblyomma
lepidum
and
Hyalomma
337dromedarii
in
northwest
Africa,
93,101,102
Amblyomma
loculosum
in
338New
Caledonia,
103
Rhipicephalus
decoloratus
in
the
Republic
of
339Botswana,
104
and
Hyalomma
aegyptium
in
Turkey.
105
It
is
currently
340recognized
as
the
most
common
rickettsiosis
in
European
and
341American
travelers
returning
from
endemic
areas
of
Africa
and
the
342Caribbean
Islands.
16,106
Figure
8
shows
an
algorithm
for
the
343approach
to
patients
with
rickettsioses
and
a
vesicular
rash.
Figure
6.
Purpuric
rash
affecting
the
soles
of
the
feet
in
a
patient
with
Rickettsia
conorii
rickettsiosis.
A.A.
Faccini-Martı
´nez
et
al.
/
International
Journal
of
Infectious
Diseases
xxx
(2014)
e1–e14
e7
G
Model
IJID
2029
1–14
Please
cite
this
article
in
press
as:
Faccini-Martı
´nez
AA,
et
al.
Syndromic
classification
of
rickettsioses:
an
approach
for
clinical
practice.
Int
J
Infect
Dis
(2014),
http://dx.doi.org/10.1016/j.ijid.2014.05.025

344
3.2.2.
Rickettsia
akari
infection
345
R.
akari
together
with
O.
tsutsugamushi
are
the
rickettsial
agents
346
transmitted
by
mites.
107
The
first
clinical
manifestation
of
this
347
rickettsiosis
is
a
primary
papulovesicular
lesion
at
the
location
of
348
inoculation
at
24–48
h
after
the
bite.
This
primary
lesion
becomes
349
an
eschar,
frequently
associated
with
regional
lymphadenopa-
350
thy.
108
Constitutional
symptoms,
such
as
fever,
headache,
chills,
351
and
myalgia
usually
occur
after
a
week.
109
Characteristically,
a
352
generalized
papulovesicular
rash
appears
between
2
and
3
days
353
after
the
onset
of
these
symptoms.
It
is
usually
distributed
on
the
354
face,
trunk,
and
extremities,
without
compromise
of
the
palms
or
355
soles,
and
it
can
be
associated
with
vesicular
exanthema
on
the
356
palate,
tongue,
mouth,
tonsils,
or
pharynx.
108
The
classic
triad
of
357
this
disease
is
described
as
fever,
papulovesicular
rash,
and
358
inoculation
eschar.
110
The
evolution
of
this
disease
is
usually
359
benign
in
the
absence
of
antibiotic
treatment,
without
associated
360
mortality.
111
In
2008,
two
cases
of
acute
hepatitis
were
described
361
in
patients
infected
with
R.
akari.
112
362
Liponyssoides
sanguineus
(Allodermanyssus
sanguineus)
is
the
363
only
vector
and
reservoir,
and
the
domestic
mouse
(Mus
musculus)
364
is
the
primary
host
of
L.
sanguineus,
113
although
this
mite
has
been
365
found
infesting
wild
and
synanthropic
rodents.
114
The
presence
of
366
R.
akari
has
been
described
in
some
American
countries,
115–117
367
Europe,
118,119
Asia,
120
and
Africa.
121
Thus,
this
disease
could
have
a
368
worldwide
distribution,
taking
into
account
the
cosmopolitan
369
behavior
of
M.
musculus
and
the
vector
mite.
114
It
is
very
likely
that
370
this
rickettsiosis
is
under-diagnosed
or
confused
with
other
371
exanthematic
diseases.
3723.2.3.
Rickettsia
australis
infection
373Unlike
infection
by
R.
honei,
with
which
it
shares
similar
clinical
374features,
in
the
rickettsioses
caused
by
R.
australis
the
presence
of
375an
inoculation
eschar
is
more
frequent
(over
60%
of
cases),
376associated
with
lymphadenopathy.
Characteristically
the
rash
is
377mainly
vesicular
or
maculopapular.
16
It
can
present
as
a
moderate
378to
severe
disease,
with
complications
such
as
renal
failure,
379fulminant
purpura,
myopericarditis,
pneumonia,
splenic
infarct,
380and
vasculitis
associated
with
mortality.
38,122
381Its
distribution
is
restricted
to
the
Australian
territory,
382specifically
to
the
Eastern
region,
where
most
cases
usually
occur
383from
June
to
November.
Ixodes
holocyclus
is
the
main
vector;
69,123
384however
R.
australis
has
also
been
isolated
from
I.
tasmani
385(Southern
and
Western
Australia)
and
from
Ixodes
cornuatus
386(South
Australia).
16
3873.3.
Associated
with
regional
lymphadenopathy
388Two
dominant
signs
characterize
this
syndrome:
an
inoculation
389eschar
and
regional
lymphadenopathy.
In
contrast,
the
occurrence
390of
fever
and
rash
is
rare.
Within
this
clinical
spectrum,
the
main
391syndrome
is
termed
DEBONEL/TIBOLA
(Dermacentor-borne
ne-
392crosis
erythema
lymphadenopathy/tick-borne
lymphadenopathy),
393also
called
SENLAT
(scalp
eschar
and
neck
lymphadenopathy
after
394tick
bite)
by
other
authors
when
the
tick
bite
affects
only
the
scalp.
395DEBONEL/TIBOLA
and
SENLAT
are
produced
by
different
species
of
396Rickettsia.
In
the
case
of
SENLAT,
other
bacteria
such
as
Bartonella
397henselae
have
also
been
involved.
125
The
main
etiological
agent
is
398Rickettsia
slovaca.
126,127
This
Rickettsia
was
first
identified
in
399D.
marginatus
and
Dermacentor
reticulatus
(recognized
vectors)
in
400different
European
countries
(Slovakia,
Switzerland,
France,
401Portugal,
Spain,
Germany,
etc.)
and
was
subsequently
isolated
402(1997)
and
implicated
as
a
human
pathogen
(early
2000)
in
403France
Q8
.
128,129
404Meanwhile,
‘Candidatus
Rickettsia
rioja’
and
Rickettsia
raoultii
405have
also
been
implicated
as
secondary
etiological
agents
in
Spain.
406The
former
was
detected
by
molecular
techniques
in
clinical
407samples
(blood
and
serum
of
patients)
and
in
D.
marginatus
ticks
408removed
from
patients
with
a
diagnosis
of
DEBONEL/TIBOLA
in
409Spain
(half
of
the
cases),
130,131
and
R.
raoultii
was
detected
in
ticks
410of
the
genus
Dermacentor
(mainly
D.
marginatus)
removed
from
411patients
who
developed
the
disease
in
different
regions
of
412Europe.
105,132–134
413DEBONEL/TIBOLA
is
characterized
by
a
benign
evolution
and
a
414short
incubation
period
(average
5
days),
with
a
later
onset
of
a
415meliceric
Q9
exudation
in
the
region
of
the
tick
bite
(>95%
in
the
416scalp),
which
evolves,
within
a
few
days,
into
an
inoculation
eschar
Figure
7.
Vesicular
rash
and
eschar
on
a
patient
with
Rickettsia
africae
rickettsiosis.
Syndrome
Type of
rash
Epidem
iolo
gical ba
ckground
Rickesia spp
Vesicular rash
Rickesioses wit
h probabilit
y of
inocula
on eschar
Africa o
r Ca
ribbean I
sland
s
Ticks
:
Amblyom
ma
genu
s
R. africa
e
Worldwide
Mouse
mite
R. akari
Austra
lia
Ticks: Ixod
es
genu
s
R. au
strali
s
Figure
8.
Algorithm
for
rickettsioses
with
the
probability
of
an
inoculation
eschar
and
a
vesicular
rash.
A.A.
Faccini-Martı
´nez
et
al.
/
International
Journal
of
Infectious
Diseases
xxx
(2014)
e1–e14
e8
G
Model
IJID
2029
1–14
Please
cite
this
article
in
press
as:
Faccini-Martı
´nez
AA,
et
al.
Syndromic
classification
of
rickettsioses:
an
approach
for
clinical
practice.
Int
J
Infect
Dis
(2014),
http://dx.doi.org/10.1016/j.ijid.2014.05.025

417
surrounded
by
erythema
(Figure
9).
The
eschar
is
usually
larger
418
than
in
other
rickettsioses
(up
to
2
cm)
and
is
associated
with
419
painful
regional
lymphadenopathy.
135
When
the
tick
bite
is
out
of
420
the
scalp,
the
erythema
resembles
the
‘erythema
migrans’
of
Lyme
421
disease.
Other
symptoms,
such
as
rash,
facial
edema,
and
fever,
422
occur
in
less
than
20%
of
cases.
135
Notably,
a
third
of
patients
423
develop
persistent
alopecia
where
the
eschar
was
present.
135
424
DEBONEL/TIBOLA/SENLAT
is
currently
the
second
most
prevalent
425
tick-borne
rickettsiosis
in
Europe
after
that
caused
by
R.
conorii,
50
426
with
human
cases
reported
in
France,
Spain,
Hungary,
Slovakia,
427
Bulgaria,
Italy,
Germany,
and
Portugal,
50,136–139
where
it
tends
to
428
affect
mainly
women
and
children.
132,135
A
case
of
this
syndrome
429
caused
by
R.
massiliae
reported
in
Italy
has
recently
been
430
published.
49
Figure
10
shows
an
algorithm
for
diagnosing
this
431
syndrome.
432
There
is
another
Rickettsia
spp
related
with
this
syndrome
in
the
433
USA
–Rickettsia
sp
genotype
364D
(Rickettsia
philipii).
Rickettsia
sp
434
genotype
364D
(R.
philipii)
was
first
isolated
in
1966
in
Derma-
435
centor
occidentalis
ticks
from
Ventura
County,
California
(USA).
140
436
For
a
long
time
it
was
considered
non-pathogenic.
However,
a
case
437
of
infection
in
an
80-year-old
man
in
the
state
of
California
in
438
2008
and
then
three
pediatric
cases
in
2011,
also
in
California,
were
439
confirmed.
141,142
All
cases
had
a
benign
course.
Single
inoculation
440
eschars
associated
with
regional
lymphadenopathy
are
the
main
441
clinical
signs.
A
rash
is
uncommon
and
is
usually
accompanied
by
442
mild
fever,
headache,
myalgia,
arthralgia,
and
malaise.
141,142
443
Currently,
this
new
Rickettsia
sp
should
be
considered
in
the
444
differential
diagnosis
of
the
rickettsioses
that
present
an
eschar
in
445
the
USA,
as
are
those
caused
by
R.
parkeri
and
R.
akari.
55
4463.4.
Associated
with
lymphangitis
447Lymphangitis
is
a
clinical
sign
that
may
be
present
in
several
448rickettsioses.
Half
of
the
cases
of
R.
sibirica
subsp.
mongolitimonae
449infection
present
this
sign
(rope-like
lymphangitis
between
the
450inoculation
eschar
and
lymphadenitis)
(Figure
11).
This
finding
has
451led
to
the
infection
being
termed
lymphangitis-associated
rick-
452ettsiosis
(LAR).
Lymphangitis
is
also
present
in
those
infections
453caused
by
R.
heilongjiangensis
and
R.
africae,
16
although
in
a
lesser
454proportion
than
in
R.
sibirica
mongolitimonae
infection.
50
This
455species
was
first
isolated
in
1991
in
Hyalomma
asiaticum
ticks
from
456inner
Mongolia
(China).
148
Five
years
later,
its
role
as
human
457pathogen
was
confirmed
in
France
and
there
are
26
more
cases
458reported
in
the
literature.
149–162
A
single
eschar
is
present
in
80%
of
459cases
(only
two
cases
with
two
eschars),
151
associated
with
460regional
lymphadenopathy
and
a
maculopapular
rash
affecting
the
461palms
and
soles
(70%
of
cases).
160,162
Although
the
course
of
462disease
is
benign
in
most
cases,
severe
cases
with
septic
shock
160
463and
acute
renal
failure
have
been
reported
Q10
.
153
Ocular
involvement
464(retinal
vasculitis)
has
also
been
described.
156
465Regarding
its
epidemiology,
most
cases
have
occurred
in
466France,
Spain,
and
Portugal.
50
It
has
also
been
reported
from
467Algeria,
151
South
Africa,
152
Greece,
153
and
Egypt.
158
The
tick
468species
involved
as
vectors
are
related
to
ticks
of
the
genus
469Hyalomma,
such
as
H.
truncatum
152
and
H.
anatolicum
excavatum
153
470and
Rhipicephalus
pusillus
in
France,
161
Spain,
163,164
and
471Portugal.
154
4724.
Other
rickettsioses
without
assigned
classification
473Because
of
the
few
cases
described
or
the
not
fiable
Q11
clinical
474features,
some
rickettsioses
have
not
been
assigned
to
any
475proposed
syndrome
in
this
article.
4764.1.
Rickettsia
helvetica
infection
477This
is
also
known
as
the
non-eruptive
rickettsiosis.
1
It
has
been
478reported
only
in
Switzerland,
Sweden,
France,
and
Italy,
where
479most
patients
have
presented
with
isolated
fever
(no
rash
or
480inoculation
eschar).
50
However,
some
cases
in
Sweden
have
481presented
rash,
165
perimyocarditis,
166
and
meningitis.
167
The
482main
vector
is
Ixodes
ricinus.
50
4834.2.
Rickettsia
monacensis
infection
484Two
cases
have
been
reported
from
Spain
(2007)
and
one
from
485Italy
(2012).
168,169
The
Spanish
cases
presented
with
a
febrile
Figure
9.
Big
eschar
and
surrounding
erythema
in
a
patient
with
DEBONEL/TIBOLA
(Rickettsia
slovaca,
Candidatus
Rickettsia
rioja,
and
Rickettsia
raoultii).
Syndrome
Oth
er clini
cal
characteriscs
Epidem
iolo
gical
background
Rickesia sp
p
Reg
ional lymphad
enopath
y
Ricke
sioses with
inocula
on
eschar (>9
5% in scalp)
Europe
Ticks: Dermacentor genu
s
R. slova
ca, Candidatus R. rioja
, R. raouli
California
(USA)
Ticks: D. occidentalis
Rickesia sp genotyp
e 364D
(R. phili
pii
)
Figure
10.
Algorithm
for
rickettsioses
with
predominant
signs
of
eschar
and
lymphadenopathy.
A.A.
Faccini-Martı
´nez
et
al.
/
International
Journal
of
Infectious
Diseases
xxx
(2014)
e1–e14
e9
G
Model
IJID
2029
1–14
Please
cite
this
article
in
press
as:
Faccini-Martı
´nez
AA,
et
al.
Syndromic
classification
of
rickettsioses:
an
approach
for
clinical
practice.
Int
J
Infect
Dis
(2014),
http://dx.doi.org/10.1016/j.ijid.2014.05.025

486
illness
associated
only
with
a
maculopapular
rash.
The
Italian
case
487
presented
with
fever
associated
with
an
inoculation
eschar
and
488
without
rash.
I.
ricinus
is
the
suspected
vector
of
this
rickettsial
489
species.
50
490
4.3.
Candidatus
Rickettsia
kellyi
infection
491
The
only
case
reported
was
confirmed
by
molecular,
histopath-
492
ological,
and
serological
methods.
It
involved
a
child
from
India
493
who
had
a
febrile
illness
associated
with
a
maculopapular
rash
that
494
affected
the
face,
back,
and
limbs,
including
the
palms
of
the
hands
495
and
soles
of
the
feet.
170
The
vector
is
unknown.
496
4.4.
Rickettsia
tamurae
infection
497
Only
one
case
of
R.
tamurae
infection
has
been
reported.
171
This
498
involved
a
Japanese
patient
who
presented
with
an
inflammatory
499
reaction
in
the
popliteal
region
of
his
leg,
secondary
to
the
bite
of
a
500
tick
identified
as
Amblyomma
testudinarium.
It
was
possible
to
501
obtain
molecular
evidence
of
R.
tamurae
in
the
patient’s
blood
and
502
skin
lesions,
and
in
the
tick.
503
5.
Microbiological
diagnosis
504
There
are
several
different
approaches
to
the
diagnosis
of
505
human
rickettsioses.
As
for
other
bacterial
infectious
diseases,
the
506
gold
standard
is
culture.
This
approach
is
difficult
because
it
507
requires
adecuated
Q12
laboratories
and
trained
people,
so
it
is
only
508
performed
in
reference
centers
with
adecuated
biosafety
labora-
509
tories.
However,
the
shell
vial
technique
has
facilitated
the
510
inclusion
of
culture
in
clinical
microbiology
laboratories.
The
511
sample
must
be
processed
quickly
(in
a
few
hours)
or
must
be
512
stored
correctly.
172,173
513
In
recent
years,
molecular
tools
have
been
incorporated
into
the
514
routine
methods
of
a
great
number
of
laboratories.
Molecular
tools
515
such
as
PCR
and
quantitative
PCR
(qPCR)
are
increasingly
used.
The
516
most
common
ones
are
those
that
use
the
amplification
of
different
517
preserved
genes
of
the
genus
Rickettsia
(gltA,
ompA,
ompB,
sca4,
518
htrA,
and
16S
rDNA).
174
This
procedure
allows
a
specific,
sensitive,
Figure
11.
Lymphangitis
and
eschar
on
a
patient
with
lymphangitis-associated
rickettsiosis
(LAR)
(Rickettsia
sibirica
mongolitimonae
infection).
Courtesy
of
Dr
Rita
de
Sousa.
Figure
12.
Algorithm
for
microbiological
diagnosis
of
rickettsioses.
A.A.
Faccini-Martı
´nez
et
al.
/
International
Journal
of
Infectious
Diseases
xxx
(2014)
e1–e14
e10
G
Model
IJID
2029
1–14
Please
cite
this
article
in
press
as:
Faccini-Martı
´nez
AA,
et
al.
Syndromic
classification
of
rickettsioses:
an
approach
for
clinical
practice.
Int
J
Infect
Dis
(2014),
http://dx.doi.org/10.1016/j.ijid.2014.05.025

519
and
rapid
diagnosis
when
samples
(whole
blood,
serum,
520
skin
biopsy,
eschar,
removed
tick,
and
others)
are
processed
521
correctly.
172,173
The
use
of
a
swab
in
cases
where
an
eschar
is
522
present
is
very
useful
for
the
diagnosis
by
PCR
Q13
.
56,175
523
In
most
clinical
microbiology
laboratories,
the
diagnosis
is
524
made
by
the
detection
of
antibodies
measured
using
serological
525
assays.
Immunofluorescence
(IFA)
remains
the
reference
method
526
for
this
approach.
However,
it
is
not
specific
(cross-reactions
527
among
species)
and
is
not
sensitive
in
the
first
days
of
infection.
To
528
obtain
the
diagnosis
it
is
necessary
to
study
two
samples
(acute
529
and
convalescent
sera),
waiting
at
least
2
weeks
between
them.
530
IgG
and
IgM
can
be
studied,
although
the
latter
can
frequently
531
produce
false-positive
results.
To
obtain
an
accurate
diagnosis
it
is
532
necessary
to
observe
seroconversion
(4
titers
folder
Q14
).
In
some
533
reference
laboratories,
cross
absortion
Q15
and
Western
blot
are
534
performed
to
increase
the
specificity.
172,173
Figure
12
shows
an
535
algorithm
useful
for
the
diagnosis.
536
6.
Treatment
of
rickettsioses
537
Since
rickettsioses
are
a
threat
to
human
life,
empirical
538
treatment
must
be
started
when
they
are
suspected.
Physicians
539
should
never
wait
for
laboratory
results.
Doxycycline
is
the
drug
of
540
choice
for
all
of
the
known
rickettsioses,
even
in
children
and
541
pregnant
women
when
the
woman
has
a
severe
infection.
176
For
542
some
rickettsioses
such
as
Mediterranean
spotted
fever,
a
short
543
course
of
doxycycline
has
been
demonstrated
to
be
effective
and
544
safe
(doxycycline
200
mg
twice
daily
for
only
1
day).
177
As
an
545
alternative
to
doxycycline
(allergic
patients,
pregnant
women),
546
macrolides
such
as
azithromycin
or
josamycin
can
be
used.
The
use
547
of
quinolones
is
not
recommended
because
it
has
been
associated
548
with
an
increased
mortality.
178
549
A
review
on
the
prevention
of
tick-borne
diseases
has
recently
550
been
published,
which
provides
useful
information
for
the
551
prevention
and
prophylaxis
of
tick-borne
rickettsioses.
179
552
Table
7
describes
the
duration,
dosage,
and
other
considerations
553
of
the
most
commonly
used
treatments
for
rickettsioses
in
adults,
554
children,
and
pregnant
women
Q16
.
62
555
7.
Conclusions
556
In
the
last
two
decades,
with
the
development
of
new
557
diagnostic
methods,
mainly
based
on
molecular
biology,
the
558
characterization
and
involvement
of
new
species
of
Rickettsia
as
559
etiological
agents
of
human
diseases
worldwide
have
increased
560
considerably.
Clinical
manifestations
combined
with
a
thorough
561
history
(travel,
epidemiological
environment,
and
place
of
resi-
562
dence)
and
knowledge
of
the
distribution
of
rickettsial
agents
and
563
their
vectors
may
help
clinicians
to
correctly
diagnose
a
564
rickettsiosis.
This
is
especially
relevant
when
microbiological
565
identification
of
the
microorganism
is
impossible
(for
example,
due
566to
previous
prescription
of
antimicrobials,
or
if
a
microbiology
567laboratory
or
other
available
techniques
are
missing).
The
aim
of
this
568review
was
to
provide
physicians
with
a
diagnostic
approach,
taking
569into
account
the
common
signs
and
symptoms
of
these
diseases.
570Nevertheless,
to
achieve
a
definitive
diagnosis,
microbiological
571assays
are
needed.
572Of
note,
the
fact
that
one
of
these
clinical
syndromes
is
not
573compatible
with
the
expected
geographical
distribution
may
574suggest
the
emergence
of
a
previously
unknown
species,
new
575species,
or
even
new
clinical
manifestations.
576Finally,
despite
being
outside
of
the
objective
of
this
paper,
we
577would
like
to
emphasize
that
antibiotic
treatment
with
doxycy-
578cline
(including
for
children)
must
be
started
whenever
a
possible
579rickettsiosis
is
suspected,
taking
into
consideration
pregnant
580women
and
allergic
patients.
581Acknowledgements
582We
thank
Dr
Rodrigo
Angerami
and
Dr
Rita
de
Sousa
for
583providing
the
images
corresponding
to
Figures
3
and
11,
584respectively.
585Funding:
None
declared.
586Conflict
of
interest:
None
declared.
587References
588
1.
Renvoise
´A,
Raoult
D.
An
update
on
rickettsiosis.
Med
Mal
Infect
2009;39:
589
71–81.
590
2.
Mansueto
P,
Vitale
G,
Cascio
A,
Seidita
A,
Pepe
I,
Carroccio
A,
et
al.
New
insight
591
into
immunity
and
immunopathology
of
rickettsial
diseases.
Q17
Clin
Dev
Immunol
592
2012;2–26.
593
3.
Merhej
V,
Raoult
D.
Rickettsial
evolution
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the
light
of
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594
Biol
Rev
Camb
Philos
Soc
2011;86:379–405.
595
4.
Olano
JP.
Rickettsial
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Ann
N
Y
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596
5.
Walker
DH,
Fishbein
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Epidemiology
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rickettsial
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Eur
J
Epidemiol
597
1991;7:237–45.
598
6.
Eremeeva
ME.
Molecular
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in
North
America.
599
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Tick
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Dis
2012;3:332–7.
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602
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F.
Rocky
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Dis
2007;7:
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604
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Myers
SA,
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Dermatologic
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605
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Dis
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606
10.
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DJ,
Corey
GR.
Rocky
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607
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608
11.
Walker
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RM,
Valdes-Dapena
M.
The
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eschars
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609
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12.
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M,
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616
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AP,
Hun
L,
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L.
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617
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an
eschar
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Table
7
Treatment
of
rickettsioses;
based
on
Botelho-Nevers
et
al.,
2012
62
Antibiotic
Indications
Dosage
Duration
of
treatment
Doxycycline
(standard
treatment
for
rickettsioses)

Severe
rickettsioses
(including
pregnant
women
and
children),
ideally
intravenous

Adults
or
children
>45
kg

Adults
or
children
>45
kg:
100
mg
twice
a
day

Pregnant
women
(late
trimester):
100
mg
twice
a
day

Children
<45
kg:
2.2
mg/kg
twice
a
day
Continued
for
3
days
after
symptoms
have
resolved
Macrolides
(josamycin,
clarithromycin,
and
azithromycin)

Option
for
not
severe
rickettsioses
in
children
and
pregnant
women

Josamycin:
children
50
mg/kg
twice
a
day,
pregnant
women
1
g/8
h

Clarithromycin
for
children:
15
mg/kg/day
divided
doses

Azithromycin
for
children:
10
mg/kg/day
in
1
dose
Josamycin
5
days,
clarithromycin
7
days,
and
azithromycin
3
days
Chloramphenicol

Alternative
option
in
severe
rickettsioses

Adults
and
pregnant
women
(first
and
second
trimesters):
60–75
mg/kg/day
in
4
divided
doses

Children:
12.5–25
mg/kg
every
6
h
5–10
days
A.A.
Faccini-Martı
´nez
et
al.
/
International
Journal
of
Infectious
Diseases
xxx
(2014)
e1–e14
e11
G
Model
IJID
2029
1–14
Please
cite
this
article
in
press
as:
Faccini-Martı
´nez
AA,
et
al.
Syndromic
classification
of
rickettsioses:
an
approach
for
clinical
practice.
Int
J
Infect
Dis
(2014),
http://dx.doi.org/10.1016/j.ijid.2014.05.025

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M,
Faccini-Martı
´nez
AA,
Valbuena
G.
Rickettsiosis
transmitidas
por
620
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avances
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´gicos,
y
retos
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621
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2013;33:161–78.
622
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Parola
P,
Paddock
CD,
Socolovschi
C,
Labruna
MB,
Mediannikov
O,
Kernif
T,
623
et
al.
Update
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rickettsioses
around
the
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a
geographic
624
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Microbiol
Rev
2013;26:657–702.
625
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L,
Decker
CF.
Rocky
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626
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LJ,
Traeger
MS,
Nicholson
WL,
Paddock
CD,
Blau
DM,
Eremeeva
ME,
627
et
al.
Rocky
Mountain
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from
an
unexpected
tick
vector
in
Arizona.
628
N
Engl
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2005;353:587–94.
629
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ME,
Varela
G.
Estudios
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manchada
en
Mexico,
Papel
del
630
Rhipicephalus
sanguineus
en
la
transmisio
´n
de
la
fiebre
manchada
en
la
631
Republica
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Inst
Salub
Enferm
Trop
1947;8:139–41.
632
20.
Hun
L,
Corte
´s
X,
Taylor
L.
Molecular
characterization
of
Rickettsia
rickettsii
633
isolated
from
human
clinical
samples
and
from
the
rabbit
tick
Haemaphysalis
634
leporispalustris
collected
at
different
geographic
zones
in
Costa
Rica.
Am
J
Trop
635
Med
Hyg
2008;79:899–902.
636
21.
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Rodaniche
E.
Natural
infection
of
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e14
G
Model
IJID
2029
1–14
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cite
this
article
in
press
as:
Faccini-Martı
´nez
AA,
et
al.
Syndromic
classification
of
rickettsioses:
an
approach
for
clinical
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Int
J
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(2014),
http://dx.doi.org/10.1016/j.ijid.2014.05.025