CLINICAL MICROBIOLOGY REVIEWS, Oct. 2005, p. 719–756
Copyright © 2005, American Society for Microbiology. All Rights Reserved.
Vol. 18, No. 4
Tick-Borne Rickettsioses around the World: Emerging Diseases
Challenging Old Concepts
Philippe Parola,1Christopher D. Paddock,2and Didier Raoult1*
Unite ´ des Rickettsies, CNRS UMR 6020, IFR 48, Universite ´ de la Me ´diterrane ´e, Faculte ´ de Me ´decine,
13385 Marseille Cedex 5, France,1and Division of Viral and Rickettsial Diseases, Centers for
Disease Control and Prevention, Mailstop G-32, 1600 Clifton Road, Atlanta, Georgia2
RECENT DEVELOPMENTS AND CONTINUING GAPS IN RICKETTSIOLOGY........................................720
Microbiology and Taxonomy: What Defines a Rickettsia sp.?...........................................................................720
The Genome Era.....................................................................................................................................................722
Pathogenicity of Tick-Borne Rickettsiae..............................................................................................................724
TICK-BORNE RICKETTSIAE IDENTIFIED AS HUMAN PATHOGENS.......................................................725
Pathogens Described Prior to 1984......................................................................................................................725
Rickettsia rickettsii (Rocky Mountain spotted fever).......................................................................................725
“Rickettsia conorii subsp. conorii” (Mediterranean spotted fever) ...............................................................728
“Rickettsia conorii subsp. israelensis” (Israeli spotted fever).........................................................................729
“Rickettsia sibirica subsp. sibirica” (Siberian tick typhus or North Asian tick typhus)............................730
Rickettsia australis (Queensland tick typhus)..................................................................................................730
Emerging Pathogens (1984 to 2004) ....................................................................................................................731
Rickettsia japonica (Japanese or Oriental spotted fever)...............................................................................731
“Rickettsia conorii subsp. caspia” (Astrakhan fever)......................................................................................731
Rickettsia africae (African tick bite fever)........................................................................................................732
Rickettsia honei (Flinders Island spotted fever)..............................................................................................733
“Rickettsia sibirica subsp. mongolitimonae”......................................................................................................733
TICK-BORNE SFG RICKETTSIAE PRESUMPTIVELY ASSOCIATED WITH HUMAN ILLNESSES......738
“Rickettsia conorii subsp. indica” (Indian Tick Typhus)....................................................................................738
RICKETTSIAE ISOLATED FROM OR DETECTED IN TICKS ONLY...........................................................739
NEW APPROACHES TO DIAGNOSIS...................................................................................................................739
Histochemical and Immunohistochemical Methods..........................................................................................745
Molecular Tools ......................................................................................................................................................745
Tick-borne rickettsioses are caused by obligate intracellular
bacteria belonging to the spotted fever group (SFG) of the
genus Rickettsia within the family Rickettsiaceae in the order
Rickettsiales (276). These zoonoses are among the oldest
known vector-borne diseases. In 1899, Edward E. Maxey re-
ported the first clinical description of Rocky Mountain spotted
fever (RMSF), the prototypical tick-borne rickettsiosis (198).
In 1906, Howard T. Ricketts reported the role of the wood tick
in the transmission of the causative agent, subsequently named
Rickettsia rickettsii (283, 284, 365). In 1919, S. Burt Wolbach
provided definitive experimental evidence that R. rickettsii, re-
ferred to as “Dermacentroxenus rickettsii” at that time, was
maintained by ticks and also described the fundamental his-
* Corresponding author. Mailing address: Unite ´ des Rickettsies,
CNRS UMR 6020, IFR 48, Universite ´ de la Me ´diterrane ´e, Faculte ´ de
Me ´decine, 27 Bd. Jean Moulin, 13385 Marseille Cedex 5, France.
Phone: (33) 4 91 32 43 75. Fax: (33) 4 91 32 03 90. E-mail:
topathologic lesions of RMSF (365). For approximately the
next 90 years, R. rickettsii would be the only tick-borne rickett-
sia conclusively associated with disease in humans in the West-
ern Hemisphere. During the 20th century, many other formally
described or incompletely characterized SFG rickettsiae were
detected in North American ticks, including Rickettsia parkeri
in 1939, Rickettsia montanensis (formerly R. montana) in 1963,
and Rickettsia rhipicephali in 1978. However, these rickettsiae
were generally considered nonpathogenic (267, 276).
Distinctions between the occurrences of a single pathogenic
tick-borne rickettsia and the various other nonpathogenic rick-
ettsiae that resided in ticks were also made by investigators
from other continents. In 1910, the first case of Mediterranean
spotted fever (MSF) was reported in Tunis (72). The typical
inoculation eschar was described in 1925 in Marseille (223). In
the 1930s, the roles of the brown dog tick, Rhipicephalus san-
guineus, and the causative agent Rickettsia conorii were de-
scribed (43). For several decades, R. conorii was considered to
be the only agent of tick-borne SFG rickettsioses in Europe
and Africa. In a similar manner, Rickettsia sibirica (in the
former USSR and China) and Rickettsia australis (in Australia)
were generally believed to be the sole tick-borne rickettsial
agents associated with these respective locations (276).
Until relatively recently, the diagnosis of tick-borne SFG
rickettsioses was confirmed almost exclusively by serologic
methods (174, 276). The Weil-Felix test, the oldest but least
specific serological assay for rickettsioses, is still used in many
developing countries. This test is based on the detection of
antibodies to various Proteus antigens that cross-react with
each group of rickettsiae, including the SFG. This assay lacks
sensitivity and specificity and can suggest only possible spotted
fever group rickettsiosis in a patient. Even with the microim-
munofluorescence (MIF) assay, the current reference method
in rickettsial serology, there are wide antigenic cross-reactions
among SFG rickettsiae (276). In this context, when only one
antigen is used (i.e., the agent known to be pathogenic for
humans in the considered location), a positive serologic reac-
tion does not necessarily imply that the patient’s illness was
caused by the rickettsial species used as the antigen in the
assay. Inferences made from the results of relatively nonspe-
cific serologic assays have likely hampered the correct identi-
fication of several novel SFG rickettsioses.
The recognition of multiple distinct tick-borne SFG rickett-
sioses during the last 20 years has been greatly facilitated by
broad use of cell culture systems and the development of
molecular methods for the identification of rickettsiae from
human samples and ticks (267). As a consequence, during 1984
through 2005, 11 additional rickettsial species or subspecies
were identified as emerging agents of tick-borne rickettsioses
throughout the world (267, 276). In 1984, an emerging SFG
rickettsiosis was identified in Japan (183). Its agent was iso-
lated from a patient in 1989 and subsequently named Rickettsia
japonica (342, 343). Thereafter emerging pathogens through-
out the world were described, including “Rickettsia conorii
subsp. caspia” (proposed name) in Astrakhan, Africa, and Ko-
sovo; Rickettsia africae in sub-Saharan Africa and the West
Indies; Rickettsia honei in Flinders Island (Australia), Tasma-
nia, Thailand, and perhaps the United States; Rickettsia slovaca
in Europe; “Rickettsia sibirica subsp. mongolitimonae” (pro-
posed name) in China, Europe, and Africa; “Rickettsia heilong-
janghensis” (proposed name) in China and the Russian Far
East; Rickettsia aeschlimannii in Africa and Europe; “Rickettsia
marmionii” (proposed name) in Australia (N. Unsworth, J.
Stenos, and J. Graves, Abstr. 4th Int. Conf. Rickettsiae Rick-
ettsial Dis., abstr. O-50, 2005), and R. parkeri in the United
States (267). The last rickettsia is probably the best illustration,
as R. parkeri was considered a nonpathogenic rickettsia for
more than 60 years. Furthermore, the pathogenicity of Rick-
ettsia massiliae has been recently demonstrated, 13 years after
its isolation from ticks (349). Other recently described rickett-
siae, including Rickettsia helvetica strains in Europe and Asia,
have been presented as possible pathogens (267).
The last major review on rickettsioses was published in 1997
(276). Since that time, rickettsiology has undergone a signifi-
cant evolution. Some SFG rickettsiae detected or isolated from
ticks only and presented as potential pathogens in 1997 are
now formally described and recognized as emerging patho-
gens. Many previously unrecognized rickettsiae of unknown
pathogenicity have been recently detected in or isolated from
ticks. The use of PCR and sequencing methods for the iden-
tification of SFG rickettsiae in ticks has led to new questions
regarding the geographical distribution of tick-borne rickett-
siae and the tick-rickettsia association. We present here an
overview of the various tick-borne rickettsioses described to
date and focus on some epidemiological circumstances that
have contributed to the emergence of these newly recognized
diseases. We also discuss some of the questions remaining to
be resolved in the future.
RECENT DEVELOPMENTS AND CONTINUING GAPS
Microbiology and Taxonomy: What Defines a Rickettsia sp.?
In recent years, the rickettsial field has undergone a signif-
icant evolution, particularly due to technological advances in
molecular genetics. Wolbach, using a modified Giemsa stain,
was the first to note the intracellular nature of R. rickettsii
(365). In the 1930s and 1940s, Castaneda and Machiavello used
a modified Giemsa stain to describe the tinctorial properties of
rickettsiae. Rickettsiae first appear in reference books of bac-
teriology during the late 1930s (e.g., reference 40a). These
bacteria were described as a group based on filterability, poor
staining with aniline dyes, gram negativity, and staining with
Giemsa or Castaneda stains. Hans Zinsser correctly insisted
that some rickettsia-like forms (e.g., the agent of trench fever)
were not obligatorily intracellular and could be cultivated on
artificial media and therefore did not belong in the genus
Rickettsia (375). However, bacteria of the order Rickettsiales
have long been described simply as short, gram-negative rods
that retained basic fuchsin when stained by the method of
Gimenez, which was described in the mid-1950s (122).
During the last decade, the taxonomy of rickettsiae has un-
dergone extensive reorganization (134, 276). The family Bar-
tonellaceae (including Bartonella quintana, the agent of trench
fever) as well as Coxiella burnetii, the agent of Q fever, were
removed from the order Rickettsiales, which includes now two
families, the Anaplasmataceae and Rickettsiaceae. The classifi-
cation of this order continues to be modified as new data
become available. Currently, all tick-associated rickettsiae
720PAROLA ET AL.CLIN. MICROBIOL. REV.
(with the exception of Rickettsia bellii and Rickettsia canaden-
sis) belong to the spotted fever group of the genus Rickettsia
within the Rickettsiaceae (Fig. 1).
Traditional identification methods used in bacteriology can-
not be routinely applied to rickettsiae because of the strictly
intracellular nature of these organisms. Of the major rickettsial
protein antigens, three high-molecular-mass surface proteins
(OmpA, OmpB, and PS120) contain species-specific epitopes
which provide the basis for rickettsial serotyping using com-
parative MIF techniques. The MIF serotyping was long con-
sidered the reference method for the identification of rickett-
siae (276). Indeed, since the pioneering work of Philip et al. in
1978, two rickettsial strains were considered to have different
serotypes if they exhibited a specificity difference of ?3 (252).
However, with the development of robust molecular ap-
proaches, the use of MIF serotyping as a reference method
should be reconsidered. Even when serotyping by immunoflu-
orescence or monoclonal antibodies is available, the informa-
tion provided by genotypic approaches (discussed below) is
characteristically more objective and definitive.
The comparison of 16S rRNA sequences is not useful for the
taxonomy of rickettsiae because greater than 97% similarity
exists between any two taxa. Several other genes can be used
including gltA, ompA, ompB, and gene D. By use of molecular
tools, one of the difficulties in rickettsiology has been the
determination of a cutoff in the percent divergence among
gene sequences that define a species, subspecies, or strain
within the Rickettsia genus. Recent genetic guidelines for the
classification of rickettsial isolates at the genus, group, and
species levels, using the sequences of five rickettsial genes,
including a 16S rRNA (rrs) gene, gltA, ompA, ompB, and gene
D, have been proposed (104). This work was done using uni-
versally recognized species. According to these guidelines, to
be classified as a new Rickettsia species, an isolate should not
have more than one of the following degrees of nucleotide
similarity, with the most homologous validated species: ?99.8
and ?99.9% for the rrs and gltA genes, respectively, and, when
amplifiable, ?98.8, ?99.2, and ?99.3% for the ompA and
ompB genes and gene D, respectively (104). However, these
guidelines may later be updated by the introduction of addi-
tional genetic or phenotypic characteristics and of new Rick-
FIG. 1. Phylogenetic organization of tick-transmitted rickettsiae based on the comparison of gltA, ompA, ompB, and gene D sequences by using
the parsimony method.
VOL. 18, 2005TICK-BORNE RICKETTSIOSES AROUND THE WORLD 721
The utility of multiple-gene sequencing for taxonomy has
been discussed for the reevaluation of species definitions in
bacteriology. Further, polyphasic taxonomy, which integrates
phenotypic and phylogenetic data, seems to be particularly
useful for rickettsial taxonomy, as demonstrated for other bac-
teria (326, 346). However, experts in the field of rickettsiology
frequently do not agree on defining a species. One example
concerns the closely related rickettsiae of the so-called R.
conorii complex, including R. conorii strain Malish (the agent
of MSF), Israeli spotted fever rickettsia (ISFR), R. conorii
strain Indian (Indian tick typhus rickettsia [ITTR]), and As-
trakhan spotted fever rickettsia (AFR).
In 1978, Philip et al., using mouse MIF serotyping, con-
cluded that R. conorii isolates Malish, Moroccan, and Kenya
belonged to the same serotype as ITTR (252). Using comple-
ment fixation, Bozeman et al. were also unable to distinguish
ITTR from R. conorii isolates (F. M. Bozeman, J. W.
Humphries, J. M. Campbell, and P. L. O’Hara, Symp. Spotted
Fever Group Rickettsiae, p. 7-11, 1960). In contrast, Goldwas-
ser et al. (R. A. Goldwasser, M. A. Klingberg, W. Klingberg, Y.
Steiman, and T. A. Swartz, 12th Int. Congr. Intern. Med., p.
270-275, 1974), using mouse polyclonal antibodies, and Walker
et al. (355), using monoclonal antibodies, observed that ITTR
differed substantially from other R. conorii isolates. Regarding
ISFR and AFR, we reported that PCR-restriction fragment
length polymorphism (RFLP) allowed differentiation of these
rickettsiae (292), and we demonstrated that AFR was different
from ISFR and R. conorii on the basis of sodium dodecyl
sulfate-polyacrylamide gel electrophoresis and pulsed-field gel
electrophoresis profiles (95). In 1995, Walker et al., using se-
rotyping, Western blotting (WB), monoclonal antibody reac-
tivity, and PCR amplification of the tandem repeats within
ompA, concluded that ISFR belonged to the R. conorii species
(352). However, in 1998, Dasch and colleagues differentiated
R. conorii from ISFR by using PCR-RFLP and then proposed
the names “R. sharonii” and “R. caspii” for ISFR and AFR,
respectively (77, 149). However, phylogenetically, these rick-
ettsiae constitute a homogeneous cluster supported by signif-
icant bootstrap values and are distinct from other Rickettsia
species. In 2003, using the combination of genotypic criteria
described above, we demonstrated that ITTR, AFR, and ISFR
were not genetically different enough to be considered new
species but belonged to the R. conorii species (104). Moreover,
these rickettsiae exhibit differentiable serotypes and cause dis-
eases with distinct clinical features in defined geographic loca-
To clarify the situation, we recently considered the report of
the ad hoc committee on reconciliation of approaches to bac-
terial systematics which proposed that bacterial isolates within
a species could be considered distinct subspecies if they were
genetically close but diverged in phenotype (359). Therefore,
we estimated the degrees of genotypic variation among 31
isolates of R. conorii, 1 isolate of ITTR, 2 isolates and 3 tick
amplicons of AFR, and 2 isolates of ISFR by using multilocus
sequence typing (MLST). Also, 16S rRNA and gltA genes, as
well as three membrane-exposed protein-encoding genes,
ompA, ompB, and sca4 (formerly gene D), were incorporated
in MLST. To further characterize the specificities of distinct
MLST types, we incorporated a prototype isolate from each of
these into a multispacer typing (MST) assay, which we have
previously demonstrated to be more discriminant than MLST
at the strain level for R. conorii (see below). Furthermore,
mouse serotypes were obtained for each of these MLST types.
It is important to emphasize that this work was not a pure
sequence-based classification. Among the 39 isolates or tick
amplicons studied, four MLST genotypes were identified: (i)
the Malish type, (ii) the ITTR type, (iii) the AFR type, and (iv)
the ISFR type. Among these four MLST genotypes, the pair-
wise similarity in nucleotide sequence varied from 99.8 to
100%, 99.4 to 100%, 98.2 to 99.8%, 98.4 to 99.8%, and 99.2 to
99.9% for 16S rRNA genes, gltA, ompA, ompB, and sca4,
respectively. Representatives of the four MLST types were also
classified within four types by using MST genotyping as well as
mouse serotyping. By using these results, we proposed to mod-
ify the nomenclature of the R. conorii species through the
creation of the following subspecies: “R. conorii subsp. conorii
subsp. nov.” (type strain Malish, ATCC VR-613), “R. conorii
subspecies indica subsp. nov.” (type strain ATCC VR-597)
(formerly Indian tick typhus rickettsia), “R. conorii subspecies
caspia subsp. nov.” (type strain A-167) (formerly Astrakhan
fever rickettsia), and “R. conorii subspecies israelensis subsp.
nov.” (type strain ISTT CDC1) (formerly Israeli spotted fever
rickettsia) (374). The description of R. conorii has been
emended to accommodate the four subspecies (for detailed
descriptions of the four subspecies, see reference 374 ). The
same approach has been recently proposed for R. sibirica, for
which two subspecies have been proposed, including “R.
sibirica subsp. sibirica” and “R. sibirica subsp. mongolitimonae”
(P. E. Fournier, Y. Zhu, and D. Raoult, Abstr. 4th Int. Conf.
Rickettsiae Rickettsial Dis., abstr. P-180, 2005). Nonetheless,
rickettsial taxonomy remains an evolving and controversial
field; in this context, there is no universal consensus on the
current classification, and some rickettsiologists believe that
there are too many described species of Rickettsia.
The Genome Era
Until 2001, the genome size of rickettsiae, estimated by
using pulsed-field gel electrophoresis, ranged from 1.1 to 1.6
Mb (222). In 2001, the first genome of a tick-transmitted rick-
ettsia (R. conorii strain Seven) was fully sequenced and re-
vealed several unique characteristics among bacterial genomes
(220, 221), including long-palindromic-repeat fragments irreg-
ularly distributed throughout the genome. Further comparison
of the R. conorii genome with that of R. prowazekii (the agent
of epidemic typhus and included in the typhus group of the
genus Rickettsia) provided additional data on the evolution of
rickettsial genomes, the latter appearing to be a subset of the
former (221). Recently, the genomes of R. sibirica, R. rickettsii,
R. akari, R. felis, and R. typhi have been reported (187, 203).
Those of R. bellii, R. massiliae, R. africae, and R. slovaca are
currently being sequenced. These data will provide insights
into the mechanism of rickettsial pathogenicity (282) and will
provide new molecular diagnostic targets and new tools for
phylogenetic and taxonomic studies.
Until recently, there was no formal genotypic method to
describe rickettsiae at the strain level. In 2004, Fournier et al.
tested the hypothesis that the most suitable sequences for
genotyping bacterial strains are those that are found to be most
variable when the genomes of two closely related bacteria are
722PAROLA ET AL.CLIN. MICROBIOL. REV.
aligned (114). Using the nearly perfectly colinear genomes of
R. conorii (a spotted fever group rickettsia) and R. prowazekii
(a typhus group rickettsia), they found that the most variable
sequences at the species level were variable intergenic spacers,
which are significantly more than conserved genes, split genes,
remnant genes, and conserved spacers (P values of ?10?2in
all cases). These spacers were also the most variable at the
strain level. Using a combination of sequences from three
highly variable spacers in a multispacer tool, they identified 27
genotypes among 39 strains of R. conorii subsp. conorii strain
Malish (Seven). Further, this technique, which was named
multispacer typing (MST), appeared to be a valuable tool for
tracing rickettsial isolates from a single source with a difference
in culture history of at least 60 passages. It was also found to be
more discriminatory for strain genotyping than multiple-gene
sequencing (P ? 10?2) (114). The advantages of MST include
high discrimination, reproducibility, simplicity of interpreta-
tion, and ease of incorporation of the data obtained into ac-
cessible databases. MST could be used for tracking isolates
from a wide variety of sources, including isolates from a single
strain with different passage histories, and even be applied to
Ticks belonging to the family Ixodidae, also called “hard”
ticks, can act as vectors, reservoirs, or amplifiers of SFG rick-
ettsiae. These bacteria do not normally infect humans during
their natural cycles between their arthropod and vertebrate
hosts. Ecological characteristics of the tick vectors influence
the epidemiology and clinical aspects of tick-borne diseases
(245). As an example, European Dermacentor species ticks that
bite humans are most active during early spring, autumn, and
occasionally winter and are well known to bite on the scalp.
Because R. slovaca is transmitted by Dermacentor ticks, the
inoculation eschar of R. slovaca infection is characteristically
located on the scalp during these seasons (275). Similarly,
because the principal vectors of RMSF in the United States
(i.e., Dermacentor variabilis and D. andersoni) and MSF in
southern Europe (i.e., Rhipicephalus sanguineus) are most ac-
tive during the late spring and summer, most cases of RMSF
and MSF occur during these months. Further, Rhipicephalus
sanguineus lives in peridomestic environments shared with
dogs (e.g., kennels, yards, and houses) but has a relatively low
affinity for humans. Infection rates of Rhipicephalus sanguineus
with SFG rickettsiae are generally under 10%. Because of
these circumstances, cases of MSF are sporadic and typically
encountered in urban areas. In contrast, Amblyomma he-
braeum (the southern African bont tick), the principal vector of
R. africae in southern Africa, is an aggressive, human-biting
tick and demonstrates high rates of infection with this rickett-
sia (145, 242). Because of these particular characteristics, cases
of African tick bite fever (ATBF) often occur in clusters and
are frequently described among groups of persons who venture
into rural or undeveloped areas on safari or adventure races
(66). More details on biology and behaviors of ticks and their
consequences in tick-borne bacterial diseases have been re-
viewed recently (245).
Questions regarding the specificity of associations among
rickettsiae and a particular tick species are unresolved, in part
because specific characterizations of species and subspecies in
both phyla may lack sensitivity. Consequently, it is difficult to
determine how long a tick species has been associated with a
rickettsial species and if coevolution has occurred. Some rick-
ettsiae, such as R. rickettsii, may be associated with several
different tick vectors from several different genera. This con-
trasts with other rickettsiae, such as R. conorii, which appear to
be associated with only one tick vector (276). Between these
extremes, there are certain rickettsiae which are associated
with several species within the same genus, such as R. africae
and R. slovaca with various Amblyomma spp. and Dermacentor
spp., respectively (245). Finally, there is some evidence to
indicate that some typhus group rickettsiae, particularly Rick-
ettsia prowazekii, may in certain circumstances be associated
with ticks (A. Medina-Sanchez, D. H. Bouyer, C. Mafra, J.
Zavala-Castro, T. Whitworth, V. L. Popov, I. Fernandez-Salas,
and D. H. Walker, Abstr. 4th Int. Conf. Rickettsiae Rickettsial
Dis., abstr. O-53, 2005) (54).
In the 1980s, Burgdorfer et al. showed that ticks infected
with the SFG rickettsia Rickettsia peacockii were refractory to
infection with and maintenance of R. rickettsii (51). Recent
studies of interspecies competition between different rickett-
siae in the same tick, using cohorts of R. montanensis-infected
and R. rhipicephali-infected D. variabilis organisms, have dem-
onstrated similar inhibitory effects between rickettsiae: rickett-
sia-infected ticks exposed to the other rickettsial species by
capillary feeding were incapable of maintaining both rickettsial
species transovarially. It was suggested that rickettsial infection
of tick ovaries may alter the molecular expression of the oo-
cytes and cause interference or blocking of the second infec-
tion (182). The process of rickettsial “interference,” i.e., one
species of SFG rickettsia successfully outcompeting another
for the microenvironment inside the tick, may have profound
implications regarding the distribution and frequency of vari-
ous pathogenic rickettsiae and the specific diseases they cause
(F. M. Bozeman, J. W. Humphries, J. M. Campbell, and P. L.
O’Hara, Symp. Spotted Fever Group Rickettsiae).
The life cycles of most tick-borne rickettsiae are also incom-
pletely known. In natural vertebrate hosts, infections may re-
sult in a rickettsemia that allows noninfected ticks to become
infected and for the natural cycle to be perpetuated. For ex-
ample, R. rickettsii has been isolated from various small mam-
mals, and some, including meadow voles, golden-mantled
ground squirrels, and chipmunks, develop rickettsemias of suf-
ficient magnitude and duration to infect laboratory-reared
ticks. However, other wild and domesticated animals suscep-
tible to infection with R. rickettsii, including dogs, cotton rats,
and wood rats, produce rickettsemias too low or too transiently
to routinely infect ticks (50, 219).
Ticks may also acquire rickettsiae through transovarial pas-
sage (transfer of bacteria from adult female ticks to the sub-
sequent generation of ticks via the eggs). Because ixodid ticks
feed only once at each life stage (245), rickettsiae acquired
during blood meal acquisition from a rickettsemic host or
through tranovarial route can be transmitted to another host
only when the tick has molted to its next developmental stage
and takes its next blood meal. This so-called transstadial pas-
sage (transfer of bacteria from stage to stage) is a necessary
component for the vectorial competence of the ticks. When
rickettsiae are transmitted efficiently both transstadially and
VOL. 18, 2005TICK-BORNE RICKETTSIOSES AROUND THE WORLD 723
transovarially in a tick species, this tick will serve as a reservoir
of the bacteria and the distribution of the rickettsiosis will be
identical to that of its tick host (245). R. slovaca multiplies in
almost all organs and fluids of its tick host, particularly in the
salivary glands and ovaries, which enables transmission of rick-
ettsiae during feeding and transovarially, respectively (279).
Two other methods for acquiring rickettsiae have been re-
ported. Sexual transmission of R. rickettsii from infected males
to noninfected female ticks has been described, but this pro-
cess is unlikely to significantly propagate the infection in tick
lineages, as venereally infected females do not appear to trans-
mit rickettsiae transovarially (307). A second suggested
method of acquisition of rickettsiae by ticks is the process of
cofeeding, which occurs as several ticks feed in proximity on
the host. In this circumstance, direct spread of bacteria from an
infected tick to an uninfected tick may occur during feeding at
closely situated bite sites, as demonstrated with R. rickettsii and
D. andersoni (250).
Although tick-rickettsia relationships were a focus of inter-
est by many pioneering rickettsiologists, most early studies
concentrated on the role of ticks as vectors. Considerably less
attention was directed to the relationships of rickettsiae with
various tick cells, tissues, and organs and with specific physio-
logic processes of acarines. Transovarial transmission of rick-
ettsiae in their recognized vectors has been demonstrated for
several SFG species, including R. rickettsii (307), R. slovaca
(279), R. sibirica (297), R. africae (154), R. helvetica (46), and R.
parkeri (124). In some instances, transovarial transmission of a
particular Rickettsia species may occur in a particular tick but
cannot be sustained for more than one generation (182).
The percentage of infected eggs obtained from females of
the same tick species infected with the same rickettsial strain
may vary for as yet unknown reasons (47, 55). For some rick-
ettsia-tick relationships, such as R. montanensis in D. variabilis
(182), R. slovaca in Dermacentor marginatus (279), and R. mas-
siliae in Rhipicephalus sanguineus group ticks (196), mainte-
nance of rickettsiae via transovarial transmission may reach
100% and have no effect on the reproductive fitness and via-
bility of the tick host. In contrast, transovarial transmission of
R. rickettsii in D. andersoni diminishes survival and reproduc-
tive capacity of tick filial progenies. Recent experiments have
shown that R. rickettsii is lethal for the majority of experimen-
tally and transovarially infected D. andersoni ticks. In one
study, most nymphs infected as larvae by feeding on rickett-
semic guinea pigs died during the molt into adults, and most of
adult female ticks infected as nymphs died prior to feeding.
Rickettsiae were vertically transmitted to 39.0% of offspring,
and significantly fewer larvae developed from infected ticks
(214). The lethal effect of R. rickettsii on its acarine host,
coupled with the competitive interactions among different rick-
ettsiae that inhabit the tick microenvironment, may influence
the low prevalence of ticks infected with R. rickettsii in nature
and affect its enzootic maintenance (214).
Interestingly, basic questions about the tick-rickettsia rela-
tionship remain for MSF, one of the oldest recognized tick-
borne rickettsioses. In this context, we are unaware of any
well-documented demonstration of transovarial transmission
of R. conorii in Rhipicephalus sanguineus. In 1932, Blanc and
Caminopetros demonstrated that larvae, nymphs, and adults
could act as vectors of MSF. Furthermore, over winter, unfed
males and females were shown to be able to transmit the agent
(38). It was also shown that when eggs or larvae obtained from
infected Rhipicephalus sanguineus females were crushed and
inoculated into humans, MSF was obtained. These data sug-
gest that transovarial transmission of the MSF agent occurs in
ticks (38). However, neither the transovarial transmission rate
(the proportion of infected females giving rise to at least one
positive egg or larva) nor the filial infection rate (proportion of
infected eggs or larvae obtained from an infected female),
which would be useful for comparison with infection rates in
nature, is known to our knowledge. It is not known if transo-
varial transmission of R. conorii is maintained from generation
to generation of Rhipicephalus sanguineus. In a similar manner,
the effect of R. conorii on its tick host and potential interactions
with other rickettsiae associated with the same tick species,
such as R. massiliae, are unknown (25).
Female D. andersoni ticks infected with R. rickettsii and in-
cubated at 4°C show a lower mortality rate than infected ticks
at 21°C (214). This discrepancy may be linked with the long-
recognized but poorly explained phenomenon known as reac-
tivation (325). In nature, stress conditions encountered by rick-
ettsiae within the tick include starvation and temperature
shifts. As an example, as ticks enter diapause, weeks to months
may pass until they obtain their next blood meal. In the labo-
ratory, R. rickettsii in D. andersoni ticks loses its virulence for
guinea pigs when the ticks are subjected to physiological stress,
such as low environmental temperature or starvation. How-
ever, subsequent exposure of these same ticks to 37°C for 24 to
48 h or the ascertainment of a blood meal may restore the
original virulence of the bacteria. During tick blood-feeding,
rickettsiae undergo various physiological changes and prolifer-
ate intensively as they reactivate from a dormant avirulent
state to a pathogenic form (47, 325, 363, 364).
The precise molecular mechanisms responsible for the ad-
aptation of rickettsiae to different host conditions and for re-
activation of virulence are unknown. However, the stress ad-
aptation in some gram-negative bacteria, also called the
stringent response, has been shown to be mediated by the
nucleotide guanosine-3,5(bis)pyrophosphate(ppGpp), which is
modulated by spoT genes. Interestingly, annotation of R. cono-
rii genome reveals five spoT paralogs, and environmental stress
conditions are accompanied by a variable spoT1 transcription
in R. conorii (296). This phenomenon could play a role in
adaptation of rickettsiae to ticks and during the process of
reactivation. It has also been hypothesized that changes in
outer surface proteins occur during alternating infection in
ticks and in mammals (296). Further studies of the molecular
dynamics of between rickettsiae and ticks, similar to work on
molecular interactions at the tick ovary-rickettsia interface re-
cently published by Mulenga et al. (210), will be needed to
better understand these processes.
Pathogenicity of Tick-Borne Rickettsiae
Throughout the 20th century, many spotted fever group
rickettsiae were isolated from or detected in ticks. Many of
these rickettsiae were initially characterized as symbionts, en-
dosymbionts, or nonpathogenic bacteria. The rationale for
these characterizations was generally supported by limited
pathogenicity testing in animals and the fact that these rick-
724 PAROLA ET AL.CLIN. MICROBIOL. REV.
ettsiae had been isolated in places where a single, previously
recognized tick-borne rickettsial pathogen already existed. In-
terestingly, the view that multiple and distinct pathogenic rick-
ettsiae may circulate in one or several species of ticks in a given
geographic area is a relatively contemporary concept.
The first component for a rickettsia to be a potential patho-
gen of humans is the likelihood of the bacterium to be trans-
mitted through the tick bite, which generally implies that the
rickettsia can localize to the salivary glands of the tick. Some
SFG rickettsiae, including R. peacockii, produce heavy infec-
tions in the ovaries but do not invade the salivary glands of
their tick hosts, precluding subsequent transmission to poten-
tial vertebrate hosts during blood meal acquisition (215). A
potential pathogen must also be associated with a tick with
some proclivity to bite a human host. In this context, tick-host
specificity is a key component of the epidemiology of tick-
borne diseases. Certain tick species rarely, if ever, bite humans,
and even if these ticks are associated with highly pathogenic
rickettsiae, disease in humans will rarely, if ever, be associated
with these species. However, it may also be possible that tick-
borne rickettsiae that are excreted in tick feces might initiate
infection via abraded skin. For example, viable R. slovaca have
been isolated from the feces of D. marginatus collected in
nature (279). The abundance of a particular tick vector, the
prevalence of the infection within ticks, and the prevalence of
natural hosts of the ticks that come in contact with humans are
other elements that affect the frequency of tick-borne rickett-
sioses that have been discussed elsewhere (245).
When transmitted to a susceptible human host, pathogenic
tick-borne SFG rickettsiae localize and multiply in endothelial
cells of small- to medium-sized blood vessels, causing a vascu-
litis which is responsible for the clinical and laboratory abnor-
malities that occur in tick-borne rickettsioses (276). Molecular
characteristics and the expression of particular rickettsial gene
products likely contribute to differences in pathogenicity
among various species of spotted fever group rickettsiae. The
expression of OmpA by R. rickettsii allows adhesion of and
entry into host endothelial cells by this pathogen (178). Despite
its close phylogenetic placement to R. rickettsii, R. peacockii
(another SFG rickettsia found in D. andersoni) possesses an
ompA gene that contains three premature stop codons and is
unable to express the OmpA protein; this rickettsia is consid-
ered a nonpathogen (18). Also, it has been suggested that the
OmpB plays a role in the adherence to and invasion of host
cells by R. japonica (344).
After phagocytosis and internalization, the phagocytic vac-
uole is rapidly lysed and rickettsiae escape the phagocytic di-
gestion to multiply freely in the host cell cytoplasm and nu-
cleus, the latter a characteristic specific for bacteria in the
spotted fever group of the genus Rickettsia (276). Rickettsiae
can move from cell to cell by actin mobilization (357). Escape
from vacuole is suspected to be mediated by an enzyme, pos-
sibly phospholipase A2 (351). However, the presence of a gene
encoding a phospholipase D has been recently shown, and this
gene may be a key factor for virulence (281). More recently, a
R. conorii surface protein, RickA, was identified in vitro as an
activator of the Arp2/3 complex, which is essential in actin
Many aspects of rickettsial pathogenesis remain unknown.
Animal models have been used to predict the pathogenicity to
humans of other symbionts found in arthropods; however, this
technique is unreliable with the rickettsiae. For example, the
T-type strain of R. rickettsii causes only a mild illness in guinea
pigs but is highly pathogenic in humans. In the past, pathoge-
nicity of various rickettsiae in guinea pigs was considered an
indication of the pathogenicity of the agent in humans; how-
ever, the pathogenic role of a tick-borne rickettsia can only be
determined conclusively by isolating or detecting the organ-
isms from patients with signs of disease. In this context, non-
pathogenic rickettsiae are better characterized as rickettsiae of
unknown pathogenicity until clear evidence exists to show that
the particular bacterium does not cause disease in humans.
In this review, the rickettsiae designated as human patho-
gens have been isolated in cell culture or detected by molecular
methods from blood or tissues from patients with illnesses
clinically compatible with spotted fever rickettsioses. When
cases are documented solely by serologic methods, the patho-
genicity of the rickettsia used as an antigen can only be pre-
sumed, particularly when a limited number of rickettsial anti-
gens are used in the evaluation. Other rickettsiae can be
considered potential pathogens, particularly if they have been
detected in the salivary glands of tick species readily biting
TICK-BORNE RICKETTSIAE IDENTIFIED AS
Pathogens Described Prior to 1984
Rickettsia rickettsii (Rocky Mountain spotted fever). Rocky
Mountain spotted fever was first described as a specific clinical
entity by Maxey in 1899 (284). The role of Dermacentor ticks in
the transmission of the disease was documented in reports by
King (156) and Ricketts (283) in 1906. Ricketts also isolated
the causative organism in guinea pigs and demonstrated that it
circulated between ticks and mammals in nature and that in-
fected ticks could transmit the bacterium transovarially to their
progeny (284, 285). Ricketts, as well as another famous rick-
ettsiologist, von Prowazek, died of typhus, and the agents of
typhus and RMSF were subsequently named Rickettsia
prowazekii and R. rickettsii, respectively, in their honor.
RMSF remains the most severe of all tick-borne rickettsio-
ses. Prior to the discovery of effective antibiotics and appro-
priate supportive therapy, persons with RMSF frequently suc-
cumbed to the infection: from 1873 to 1920, 283 (66%) of 431
reported cases resulted in death (68). RMSF also claimed the
lives of many early investigators, including entomologists and
laboratorians, who worked with R. rickettsii (261). This disease
continues to cause significant mortality in the United States.
Five to 39 deaths were reported annually to public health
authorities during 1983-1998; however, the magnitude of un-
derreporting may be profound, and it is estimated that approx-
imately 400 additional RMSF deaths were not reported during
this same interval (229). Despite its name, RMSF has been
reported throughout most of the continental United States,
except for Maine and Vermont (194).
Although most cases are associated with rural or semirural
areas, autochthonous cases have been described in large urban
centers, including New York City, where rickettsia-infected D.
variabilis were found in parks and vacant lots (302). The dis-
VOL. 18, 2005 TICK-BORNE RICKETTSIOSES AROUND THE WORLD725
ease is most prevalent in the southeastern and midwestern
United States, with the largest number of reported cases orig-
inating from North Carolina, Oklahoma, Tennessee, Arkansas,
South Carolina, Maryland, and Virginia (194, 337). Because of
the seasonal activity associated with the tick vectors of R.
rickettsii, RMSF demonstrates a similar pattern, with a peak in
cases observed during mid-spring through late summer in the
United States. From 1997 through 2002, 3,649 cases of RMSF
were reported to the Centers for Disease Control and Preven-
tion, and approximately 90% of confirmed cases occurred from
April through September. The average annual incidence of
RMSF for this period was 2.2 cases per million persons (67).
Multiple and diverse factors contribute to the incidence
rates of complex zoonoses, including RMSF and other tick-
borne SFG rickettsioses, and annual case counts are generally
subject to wide regional and temporal variabilities. The annual
number of cases of RMSF in the United States, as determined
by passive surveillance, has fluctuated markedly since the be-
ginning of systematic collection of these data in 1920. These
numbers may have been affected by one or more of the fol-
lowing: changes in surveillance affected by improved recogni-
tion and disease reporting, cyclic changes in the transmission
caused by competition or interference with other tick-borne
rickettsiae, diminished tick populations caused by widespread
use of pesticides (particularly dichlorodiphenyltrichloroeth-
ane), and increased human contact with tick-infested habitats
through recreational activities (68). For example, the average
annual incidence of RMSF in the United States fluctuated
from a low of 1.4 cases per million persons in 1998 to a high of
3.8 cases per million in 2002, representing the lowest and
highest incidence rates, respectively, recorded since 1993 (67).
The primary vector of RMSF for most of the United States
is the American dog tick D. variabilis (Fig. 2). This tick inhabits
the Great Plains region, the Atlantic Coast, California, and
southwestern Oregon. It has also been described in southeast-
ern Saskatchewan Province in Canada and as far south as
northern Mexico. Adult and nymphal activity generally begins
in March or April and extends through August or September.
The ticks at immature stages feed almost exclusively on small
rodents. D. andersoni (the Rocky Mountain wood tick) is an
important vector in the Rocky Mountain states and Canada.
The distribution of this tick occurs in the mountainous regions
of the western United States and the southern parts of British
Columbia. Adults feed primarily on large animals such as
horses, cattle, sheep, coyotes, deer, and bear. Immature stages
feed largely on small mammals. The Rocky Mountain wood
tick is most abundant in areas where small rodent share hab-
itats with large wild and domestic animals. This situation was
prevalent in the Bitterroot valley of Western Montana during
early investigations of RMSF, when a large population of Co-
lumbian ground squirrels (Citellus columbianus columbianus)
lived in close association with humans and domestic animals
Other species of ticks found in the United States have been
shown to be naturally infected with R. rickettsii or have been
demonstrated to be potential vectors of the pathogen in the
laboratory. These include Haemaphysalis leporispalustris (the
rabbit tick), Ixodes dentatus, Dermacentor occidentalis, Derma-
centor parumapertus, Amblyomma americanum (the lone star
tick), Rhipicephalus sanguineus, and the soft tick Ornithodoros
parkeri (78, 200, 231, 234, 235). Some of these tick species
seldom bite humans (e.g., H. leporispalustris and D. parumap-
ertus), and for others, contemporary evidence incriminating the
tick as an important vector of RMSF is lacking (e.g., O. parkeri
or A. americanum) (69). It is likely that several tick species are
involved in maintaining and disseminating R. rickettsii in nature
(313). Although ticks serve as a natural reservoir for R. rick-
ettsii, the deleterious effect of this pathogen for all stages of its
acarine host may explain the low prevalence of infected ticks in
nature and may affect its enzootic maintenance (214). Small
mammals, such as chipmunks, voles, ground squirrels, and
rabbits are common blood meal sources for immature ticks of
many species naturally infected with R. rickettsii. Some of these
animals are highly susceptible to rickettsial infection and may
serve as R. rickettsii-amplifying hosts (40, 53).
In Central and South America, natural infections with R.
rickettsii have been identified in Amblyomma cajennense (the
Cayenne tick) specimens collected in Mexico (59), Panama
(84), and Brazil (86) and in Amblyomma aureolatum specimens
in Brazil (303). Considerable evidence accumulated by inves-
tigators in Mexico during the early to mid-1940s convincingly
demonstrated a role of Rhipicephalus sanguineus in the trans-
mission cycle of a severe spotted fever rickettsiosis (presum-
ably RMSF) to humans in several northern and central states
of that country, including Coahuila, Durango, San Luis Potosı ´,
Sinaloa, Sonora, and Veracruz (58, 59, 189). Surprisingly, de-
spite historical data on natural infections in and vector com-
petency of Rhipicephalus sanguineus (235), and a generally
ubiquitous and peridomestic distribution of this tick, similar
studies to conclusively incriminate the brown dog tick as an
important vector of RMSF in other regions of the Western
Hemisphere were absent until 2002-2004, when 15 cases of
RMSF were identified in two rural communities in eastern
Arizona. In both locales, only Rhipicephalus sanguineus ticks
were found in the areas frequented by case patients, typically in
peridomestic settings associated with abundant pet and stray
dogs. Rhipicephalus sanguineus ticks were also found occasion-
ally attached to individuals in the community, most often chil-
dren, and infesting the local dog population. R. rickettsii was
identified by using culture and PCR in ticks collected at case
households (82). It is likely that similar ecologic scenarios exist
in other areas of the Western Hemisphere and that investiga-
tors will subsequently identify other peridomestic cycles of
RMSF that involve Rhipicephalus sanguineus.
FIG. 2. Dermacentor variabilis, the primary vector of Rocky Moun-
tain spotted fever in most of the United States. From left to right,
male, female, nymph, and larva. Bar scale, 1 cm.
726 PAROLA ET AL.CLIN. MICROBIOL. REV.
The mean incubation period of RMSF following tick bite is
7 days (range, 2 to 14 days). Only approximately 60% of pa-
tients recall a tick bite (194, 317), as these bites are generally
painless and the tick may attach in places of the body difficult
to observe, including the scalp, axillae, and inguinal areas
(245). In contrast with most other tick-borne SFG rickettsiae,
R. rickettsii does not generally elicit an eschar at the tick bite
site. The onset of the disease includes high fever and a head-
ache that may be associated with malaise, myalgias, nausea,
vomiting, anorexia, generalized or focal abdominal pain, and
diarrhea. When such nonspecific symptoms dominate the clin-
ical presentation, misdiagnosis and treatment delay can occur.
The rash of RMSF is usually not apparent until the third day
of fever or later and begins as small, irregular, pink macules
that typically appear first on wrists, ankles, and forearms. The
rash may later evolve to papules or petechiae. The character-
istic spotted rash of RMSF is generally observed in persons on
or after the fifth day of illness and heralds progression of the
infection to more severe disease (313, 317). In approximately
10% of patients, the rash may be absent, which may delay
diagnosis and therapy (317).
RMSF may result in various neurological manifestations,
including deafness, convulsions, and hemiplegia. Other mani-
festations of severe disease include pulmonary and renal fail-
ure, myocarditis, and necrosis and gangrene of the fingers,
toes, earlobes, and external genitalia. The case fatality rate of
untreated RMSF is 10 to 25%, depending on patient’s age, and
approximately half of the deaths occur on or before the eighth
day of illness (194). Recently, risk factors for death of 6,388
RMSF-confirmed (81%) and probable RMSF cases reported
during 1981-1998, including 213 deaths (average annual case
fatality rate, 3.3%), were studied. Older patient age, onset-to-
treatment interval of ?5 days, lack of tetracycline treatment,
and chloramphenicol-only treatment remained significantly as-
sociated with fatal outcome (137). Although chloramphenicol
and tetracyclines were considered effective antibiotic therapies
for RMSF, the results of this study indicate that tetracylines
are superior to chloramphenicol for the treatment of this dis-
ease. Doxycycline is currently considered the drug of choice for
nearly all patients with RMSF, including young children (137,
194, 265). Unfortunately some physicians are not aware of this:
among 84 primary care physicians in Mississippi who partici-
pated in a 2002 survey examining the knowledge, attitudes, and
practices regarding diagnosis and treatment of RMSF, only
21% of family practice physicians and only 25% of emergency
medicine physicians correctly identified doxycycline as the an-
tibiotic of choice for treating children with RMSF (224).
RMSF is likely underdiagnosed and underreported in the
United States, particularly in states where physicians are less
aware of the disease (350). Surprisingly few research teams in
the United States currently work with SFG rickettsiae, even
though many questions posed by Ricketts and others in 1909
are still unanswered (350). Early investigators commented on
differences between case fatality rates of RMSF identified
among patients residing in certain areas in the United States
(i.e., 5% in Idaho versus 65 to 80% in the Bitterroot Valley of
Montana) (284, 365). In a similar manner, several contempo-
rary studies have commented on the frequency of antibodies
reactive with R. rickettsii among persons with no history of an
illness of the severity generally associated with RMSF. Using
these data, some have inferred that mild or subclinical infec-
tions with R. rickettsii may occur. For example, serum speci-
mens of 32 (9.1%) of 352 children showed immunoglobulin G
(IgG) titers of ?64 to R. rickettsii antigen when tested by
indirect fluorescent-antibody assay (IFA); however, only 8 of
these children had experienced a febrile illness accompanied
by rash or headache in the previous year, and none had ever
been hospitalized or treated for RMSF (335). Another recent
study identified IgG titers of ?64 to R. rickettsii in the sera of
239 (12%) 1999 children 1 to 17 years of age, collected from
various medical facilities in six southeastern and south-central
states in the United States. These investigators suggested that
at least some of the seroreactivity identified in this study could
be directed against other spotted fever group rickettsiae not
previously considered pathogenic and that most infections with
SFG rickettsia may be relatively mild (192).
More compelling are recent prospective evaluations of indi-
viduals who seroconvert to R. rickettsii following tick bites and
for whom mild or no illness is reported. In two recent studies
involving military personnel exposed to ticks during training
exercises in rural areas, only 20 to 44% of persons with recent
evidence of spotted fever rickettsial infection by IFA or en-
zyme immunoassay tests developed symptoms compatible with
rickettsiosis (e.g., fever, rash, myalgia, or headache), and none
of the 67 individuals from these studies who seroconverted to
R. rickettsii developed an illness severe enough to require hos-
pitalization (199, 370). These findings, particularly viewed in
context with the historically recognized severity of RMSF and
the known cross-reactivity of spotted fever group rickettsial
antigens, strongly suggest that many serologically confirmed
cases of RMSF in the United States represent infections with
spotted fever group rickettsiae other than R. rickettsii.
RMSF has also been identified in several provinces of Can-
ada (201), several states in Mexico (56, 57), and in Panama
(83), Costa Rica (115), Colombia (247), Brazil (86), and Ar-
gentina (286). Outside of the United States, RMSF has been
most extensively described in Brazil, where R. rickettsii has
been associated of with various synonymous diseases termed
“Sa ˜o Paulo exanthematic typhus,” “Minas Gerais exanthe-
matic typhus,” and “Brazilian spotted fever” since the early
1930s (86, 118, 232). A primary vector of R. rickettsii in Brazil
is A. cajennense, a tick that feeds on various medium to large
wild and domesticated animals, including tapirs, capybaras,
horses, and dogs (168). Despite the extensive investigation of
this disease by South American scientists during the years
shortly following its discovery, relatively little attention was
directed to the study of spotted fever in Brazil, and few cases
were identified until the mid-1980s. During the last 20 years, a
resurgence in identified cases, accompanied by increasing in-
terest in rickettsioses by Brazilian investigators and others,
have intensified the study of these diseases in this region (79,
80, 117, 207, 318). Cases of spotted fever have been docu-
mented by serology or immunostaining of tissues in several
states, particularly in the southeast region of the country, in-
cluding Minas Gerais, Sa ˜o Paulo, Rio de Janeiro, and Espirito
Santo (79, 118), where most cases occur between July and
December. Recently, Angerami et al. reported 23 patients with
a confirmed diagnosis of Brazilian spotted fever either by iso-
lation of R. rickettsii from blood or skin (13 patients) or a
fourfold rise in MIF titers (8 patients). They were admitted
VOL. 18, 2005TICK-BORNE RICKETTSIOSES AROUND THE WORLD 727
with fever at the Hospitalas das Clinicas da Unicamp, Sa ˜o
Paulo, Brazil. Relevant clinical features included myalgias
(80%), headache (66%), icterus (52%), exanthema (47%),
consciousness impairment (43%), vomiting (42%), abdominal
pain (38%), respiratory distress (37.5%), acute renal insuffi-
ciency (35.3%), and hypotension and shock (33%). Hemor-
rhagic manifestations, including petechiae and suffusions, were
frequent (69.5%). The case fatality rate was 30% (R. N. An-
gerami, M. R. Resende, S. B. Stuchi Raquel, G. Katz, E.
Nascimento, and L. J. Silva, Abstr. 4th Int. Conf. Rickettsiae
Rickettsial Dis., abstr. P-160, 2005).
The first confirmed cases of spotted fever rickettsiosis in
Argentina were described in 1999. Between November 1993
and March 1994 in Jujuy Province in northwestern Argentina,
six children with fever, rash, and a history of recent tick bite
were evaluated for rickettsial infections. Immunohistochemical
staining of tissues obtained at an autopsy of one fatal case
confirmed a spotted fever group rickettsiosis, and the serum of
another patient convalescing from the illness showed high an-
tibody titers to R. rickettsii when tested by MIF. A. cajennense
ticks were collected from dogs and pets in the area (286). The
recent identification of spotted fever rickettsiosis in Peru (37)
indicates that R. rickettsii or other related rickettsiae are also
endemic in this country (36). The incidence and distribution of
RMSF and other tick-borne rickettsioses in Latin America are
undoubtedly underestimated and await the collaborative ef-
forts of physicians, rickettsiologists, entomologists, and epide-
miologists to characterize the magnitude and public health
impact of these infections in these regions (350).
“Rickettsia conorii subsp. conorii” (Mediterranean spotted
fever). In 1910, the first case of MSF was reported in Tunis
(72). The disease was thereafter also known as “boutonneuse
fever” because of a papular rather than macular rash. The
typical inoculation eschar at the tick bite site, the hallmark of
many SFG rickettsioses, was described in 1925 in Marseille by
Boinet and Pieri (223, 276). In the 1930s, the role of Rhipi-
cephalus sanguineus and the causative agent subsequently
named R. conorii were described (43). As discussed previously,
these isolates may be collectively identified as Rickettsia conorii
subsp. conorii subsp. nov. (104, 374). Three strains of R. conorii
subsp. conorii include (i) Seven or Malish (the most common
strain identified in our laboratory from France, Portugal, and
northern Africa), (ii) Kenyan, and (iii) Moroccan, which is
apparently a unique isolate (D. Raoult, unpublished data).
MSF is endemic in the Mediterranean area, including north-
ern Africa and southern Europe. Cases continue to be identi-
fied in new locations within this region, as some cases were
recently described in Turkey (165). In Italy, approximately
1,000 cases are reported each year (8). MSF is a reportable
disease in Portugal (14), where the annual incidence rate of 9.8
cases per 100,000 persons is the highest of the rates of all
Mediterranean countries (85). As with all rickettsioses, this
rate likely underestimates the true incidence, and some au-
thors suggest that there are seven times more cases than offi-
cially reported (85). Some cases have also been sporadically
reported in northern and central Europe, including Belgium
(172), Switzerland (248), and northern France (312), where
Rhipicephalus sanguineus can be imported with dogs and sur-
vive in peridomestic environments providing acceptable micro-
climatic conditions, including kennels and houses (245). MSF
is also encountered infrequently in sub-Saharan Africa and
around the Black Sea (276). Although an MSF-like disease was
described in Vladivostok in the eastern part of Russia in 1966
(332), no direct evidence of R. conorii infection has been re-
ported there since that time.
In Europe, cases are encountered in late spring and summer,
when the tick vectors are most active. In France, most cases are
diagnosed during July and August, because of increased out-
door activity associated with the peak of activity of immature
ticks that are far smaller than adults and difficult to observe
even when attached to the body (276). Similarly, most samples
submitted for diagnostic evaluation in Portugal at the Center
for Vectors and Infectious Disease Research, National Insti-
tute of Health, are received between July and September (14).
In Croatia, ?80% of cases occur between July and September,
with a peak in August (263).
An increase in the numbers of MSF cases observed in
France, Italy, Spain, and Portugal during the 1970s paralleled
similar increases in RMSF observed in the United States dur-
ing this same decade (188). This increase in incidence was
correlated with higher temperatures and lower rainfall in Spain
and with a decrease in the number of days of frost during the
preceding year in France (121). Although Rhipicephalus san-
guineus adapts well to urban environments, it is relatively host
specific and rarely feeds on people unless its preferred host
(the domestic dog) is not available. For this reason, the inci-
dence of MSF is relatively low in southern France (approxi-
mately 50 cases per year per 100,000 persons), despite the fact
that 5% to 12% of Rhipicephalus sanguineus ticks in the region
are infected with spotted fever group rickettsiae. To our knowl-
edge, a recent report describing 22 Rhipicephalus sanguineus (1
adult and 21 nymphs) attached to an alcoholic homeless man
living with his dog near Marseille (135) was the first documen-
tation of more than one Rhipicephalus sanguineus feeding on a
human host (121). Because this infestation was associated with
the highest summer temperatures noted in France during the
past 50 years in France, it is possible that host-seeking and
feeding behaviors of this tick were altered by unusual climactic
circumstances (245). In this context, it is also likely that other
homeless persons who live and sleep in proximity to Rhipiceph-
alus sanguineus-infested dogs are at increased risk for MSF
(248, 277). Most recently, another unusual case of MSF includ-
ing three inoculation eschars has also been observed in south-
ern France (D. Raoult, unpublished data).
After an asymptomatic incubation of 6 days, the onset of
MSF is abrupt and typical cases present with high fever
(?39°C), flu-like symptoms, a black eschar (tache noire) at the
tick bite site (7, 276) (Fig. 3). In a few cases, the inoculation
occurred through conjunctivae and patients presented with
conjunctivitis. One to 7 days (median, 4 days) following the
onset of fever, a generalized maculopapular rash that often
involves the palms and soles but spares the face develops (Fig.
3). Usually, patients will recover within 10 days without any
sequelae. However, severe forms, including major neurological
manifestations and multiorgan involvement may occur in 5 to
6% of the cases (1, 274). In France, MSF involves mostly males
under 10 years of age or older than 50 years. The mortality rate
is usually estimated around 2.5% among diagnosed cases
(1.50% in the last decade in Portugal, including 2.58% in 1997)
(1, 14). Classic risk factors for severe forms include advanced
728PAROLA ET AL.CLIN. MICROBIOL. REV.
age, immunocompromised situations, chronic alcoholism, glu-
cose-6-phosphate-dehydrogenase deficiency, prior prescription
of an inappropriate antibiotic, and delay of treatment (276). In
1997 in Beja, a southern Portuguese district, the case fatality
rate in hospitalized patients with MSF was 32.3%, the highest
ever obtained there since 1994. Interestingly, when risk factors
for fatal outcome were studied in 105 patients hospitalized
between 1994 and 1998, the risk of dying was significantly
associated with diabetes, vomiting, dehydration, and uremia
(85). Some differences in the severity of MSF in different areas,
even in the same country, such as Catalonia in northern Spain,
have been noted. There, the disease seems to be milder than
elsewhere in the country (102). However, cases in this area
could be caused by rickettsiae different than R. conorii. For
example, a new spotted fever group rickettsial strain (R. mas-
siliae Bar 29) of unknown pathogenicity for humans was iso-
lated there in 1996 from Rhipicephalus sanguineus ticks. We
know now that this rickettsia is pathogenic for humans (349).
We proposed in the last several years a diagnostic score to
help clinicians for the diagnosis of MSF (276). It was recently
presented as an helpful tool even using clinical and epidemi-
ological criteria only, when 62 consecutive charts of patients
with suspected MSF were retrospectively reviewed in Tunisia
“Rickettsia conorii subsp. israelensis” (Israeli spotted fever).
The first cases of rickettsial spotted fever in Israel were re-
ported in the late 1940s (345), and the number of cases in-
creased following the development of new settlements in the
rural areas of this country (276). Clinically, the disease ap-
peared milder and with a shorter duration than classical MSF,
and the typical inoculation eschar was usually lacking. These
preliminary clinical data led some investigators to suspect than
the cause of this rickettsiosis was different from the agent of
MSF. In 1971, the agent of Israeli spotted fever was isolated
from a patient (R. A. Goldwasser, M. A. Klingberg, W. Kling-
berg, Y. Steiman, and T. A. Swartz, Front. Intern. Med., 12th
Int. Congr. Intern. Med., p. 270–275, 1974). Two other anti-
genically identical agents were isolated from Rhipicephalus
sanguineus ticks collected on the dogs of two patients with
serologically documented Israeli spotted fever. These three
isolates were characterized as rickettsiae closely related to but
slightly different from R. conorii isolates obtained from pa-
tients with MSF (R. A. Goldwasser, M. A. Klingberg, W.
Klingberg, Y. Steiman, and T. A. Swartz, Front. Intern. Med.,
12th Int. Congr. Intern. Med., p. 270–275, 1974). This obser-
vation has been confirmed by recent molecular studies (111,
294, 295, 310), and it has been recently proposed that the agent
of Israeli spotted fever constitutes a subspecies of R. conorii
identified as Rickettsia conorii subsp. israelensis subsp. nov.
Israeli spotted fever appears as a typical spotted fever, but
the eschar at the inoculation site is absent in ?90% of cases
and resembles a small pinkish papule rather than a real eschar
(130). Splenomegaly and hepatomegaly are seen in 30 to 35%
of patients. The disease may be acquired even without direct
contact with animals, through exposure to ticks in places fre-
quented by dogs, as demonstrated in three grouped cases in
children (319). Several fatal cases and severe forms have been
described, especially in children and in people with glucose-6-
phosphate dehydrogenase deficiency, and the prevalence of
the disease seems to be increasing (130, 278, 369). Although
asymptomatic infections have been described by seroconver-
sion, the test used was not specific enough to ensure that the
Israeli isolate was definitely the agent provoking the serologic
FIG. 3. Inoculation eschar (top panel) and maculopapular rash
(bottom panel) on a patient with Mediterranean spotted fever.
VOL. 18, 2005 TICK-BORNE RICKETTSIOSES AROUND THE WORLD729
In 1999, R. conorii subsp. israelensis was isolated from three
patients living in semirural areas along the River Tejo in Por-
tugal (12). Of interest was the fact that none of the patients
had traveled away from Portugal during the previous year, and
none reported an eschar. All patients had severe disease, and
two patients died with septic shock and multiorgan failure.
More recently, Sousa et al. reported the clinical data of 44
patients infected with R. conorii subsp. israelensis in Portugal
between 1994 and 2004. Cases were confirmed by isolation of
the rickettsia from blood or by PCR on skin biopsy specimens.
The absence of an eschar was noted for 54% of the patients.
All but two patients presented with a rash. A total of 10
patients died. These clinical characteristics were not statisti-
cally different from those of 44 patients infected with R. conorii
subsp. conorii at the same period (R. Sousa et al., Abstr. 4th
Int. Conf. Rickettsiae Rickettsial Dis., abstr. O-22).
The occurrence of R. conorii subsp. israelensis in Portugal
indicates that the geographic distribution of Israeli spotted
fever is wider than previously appreciated. This was confirmed
more recently when R. conorii subsp. israelensis was detected in
Sicilian Rhipicephalus sanguineus ticks (120).
“Rickettsia sibirica subsp. sibirica” (Siberian tick typhus or
North Asian tick typhus). R. sibirica is the agent of Siberian
tick typhus, a spotted fever group rickettsiosis that was first
described in Primorye in the spring-summer season of 1934 to
1935 by Shmatikov (280). Human isolates obtained in 1946
were used as reference strains for molecular studies many
years later (17). Siberian tick typhus is well documented in the
former USSR, but relatively few descriptions are available in
the English medical literature (280). Active foci of the disease
are widely spread in Asiatic Russia, with more than 80% of the
cases being observed in Altai (Western Siberia) and Krasno-
yarsk regions. The disease is frequently reported during spring
and summer months. Since 1979, a constant increase of the
number of cases has been observed. Between 1979 and 1997,
23,891 cases were recorded (297).
R. sibirica has been found in several species of ticks, and
some of them have been presented as the principal vectors
Siberian tick typhus (297). These include Dermacentor nuttalli
in the mountainous steppe of western and eastern Siberia, D.
marginatus in the steppe and meadow regions of western Si-
beria and northern Kazakhstan, Dermacentor silvarum in forest
shrubs, and Haemaphysalis concinna in swampy tussocks of
some southern and far eastern territories of Siberia (17, 297).
Isolates obtained from these species of ticks, respectively, in
1949, 1959, 1983, and 1986 are available at the Gamaleya
Research Institute of Epidemiology and Microbiology in Mos-
cow (17). These ticks may act as vectors but also reservoirs of
R. sibirica which is maintained in ticks through transstadial and
transovarial transmission, as demonstrated at least for D. nut-
talli. More recently, a rickettsial strain that had been isolated
from Ixodes persulcatus and maintained at the Omsk Research
Institute of Natural Foci Infections was identified as R. sibirica
(S. Shpynov, P. E. Fournier, N. Rudakov, I. Samoilenko, T.
Reshetnikova, V. Yastrebov, M. Schaiman, I. Tarasevich, and
D. Raoult, Abst. 4th Int. Conf. Rickettsiae Rickettsial Dis.,
The incubation period is usually 4 to 7 days following a tick
bite. Clinical features include a high fever associated with an
inoculation eschar that is often accompanied by regional
lymphadenopathy. Severe headache, myalgia, and digestive
disturbances are concomitant symptoms and can last for 6 to 10
days without treatment. The rash, which may be purpuric,
usually occurs 2 to 4 days after the onset of symptoms. Al-
though central neurological involvement may occur, this dis-
ease is usually mild and is seldom associated with severe com-
Infection due to R. sibirica is also prevalent in northern
China, where it is known as North Asian tick typhus (98, 371).
There an isolate was obtained from D. nuttalli in 1974, and
from patients in 1984 when five patients with characteristic
symptoms of spotted fever were seen in Xinjiang, China. D.
nuttalli specimens were attached to four patients, and the last
patient recalled a tick bite (99). About 20 strains of SFG
rickettsiae in China have been identified as R. sibirica from
patients, various species of ticks, rodents (Microtus fortis), and
hedgehogs (99, 372). Recently, a distinct strain of R. sibirica,
currently considered a subspecies (see “Rickettsia sibirica
subsp. mongolotimonae” below), emerged as a pathogen for
humans in Europe and Africa.
Rickettsial strains antigenically identical to R. sibirica have
also been isolated from several species of ticks in Pakistan
(289). However, because only serological methods have been
used to characterize these strains, to our knowledge, there is
no definitive evidence of the prevalence of R. sibirica in Paki-
Rickettsia australis (Queensland tick typhus). Queensland
tick typhus has been clinically recognized since 1946. The first
cases were observed among Australian troops training in the
bush of northern Queensland State in eastern Australia. Rick-
ettsiae were isolated from 2 of 12 infected soldiers (4). Using
serological methods, this agent was found to be a new spotted
fever group rickettsia (256) and was named R. australis in 1950
(249). Thereafter, Queensland tick typhus has been recognized
along the entire eastern coast of Australia east of the Great
Dividing Range (127, 314, 316). In regions south of Queens-
land, cases were recorded in the 1990s in the eastern coastal
region of New South Wales, including its capital, Sydney (93).
Spotted fevers with slight clinical and epidemiological differ-
ences were subsequently reported in Victoria and on Flinders
Island (328). Although these cases were primarily assumed to
be due to R. australis (316), it is now known that a different
pathogenic rickettsia, R. honei, occurs at least in Flinders Is-
land, where it was shown to be responsible for the cases (see
below). To date, R. australis has been definitely isolated only
from patients in Queensland (4, 257).
R. australis has been identified in Ixodes holocyclus, a com-
mon, human-biting tick in Queensland (60). This tick also
feeds on a broad range of vertebrate hosts. It is distributed
primarily in coastal regions but is also prevalent in the rain
forests of Queensland (287). R. australis has also been isolated
from Ixodes tasmani, a species that exists along the coast as well
as in the interior regions of south and western Australia (287).
This tick rarely bites humans but may play a role in the enzo-
otic maintenance of R. australis in small animals (60, 127). An
uncharacterized SFG rickettsia was recently identified in the
hemolymph of an Ixodes cornuatus tick removed from a human
in Victoria (129). This tick is prevalent in south costal New
South Wales, eastern Victoria, and Tasmania (288). A number
of vertebrates, including bush rats, bandicoots, and domestic
730 PAROLA ET AL.CLIN. MICROBIOL. REV.
dogs, are common hosts for all these ticks. In one study, anti-
bodies reactive with R. australis were detected in 54 of 307
bandicoots and rodents trapped in northern Queensland; how-
ever, the precise role of vertebrates as reservoirs of R. australis
is not known (74).
Although Queensland tick typhus is a notifiable disease in
Australia, it is seldom reported. A review on 62 cases of spot-
ted fever recorded in Australia between 1946 and 1989 (16)
indicated that 37 of these cases that originated from Queens-
land and New South Wales could be considered infections due
to R. australis. A total of 78% of the cases occurred between
June and November, and cases from both urban and suburban
areas were reported. Approximately 76% of patients recall an
antecedent tick bite. The disease is characterized by a sudden
onset characterized by fever, headache, and myalgia, followed
within 10 days by maculopapular or vesicular rash. An inocu-
lation eschar is identified in approximately 65% of cases, and
lymphadenopathy is identified in 71% of cases. The disease
ranges from mild to severe, but only two patients with fatal
disease have been described (127, 315).
Emerging Pathogens (1984 to 2004)
Rickettsia japonica (Japanese or Oriental spotted fever). Be-
tween May and July 1984, the Japanese physician Fumihiko
Mahara identified three patients with high fever and rash. All
lived in the same rural area and had collected shoots from
bamboo plantations on the same mountain. For two patients,
an eschar was observed. Scrub typhus, caused by the mite-
borne pathogen Orientia tsutsugamushi, was initially suspected
because of the clinical similarity to the illnesses and because it
is a well-known zoonotic disease in Japan (358). However, the
results of the Weil-Felix test showed positive OX2 serum ag-
glutinins, indicating a possible spotted fever group rickettsiosis,
whereas OXK serum agglutinins (used for the diagnosis of
scrub typhus) were negative (183). Patient sera were then
shown to have antibodies reactive with spotted fever group
rickettsial antigens when tested by immunofluorescence (186,
339). The disease was called Japanese spotted fever. The caus-
ative agent was first isolated from patients in Shikoku in 1985
(340, 341) and was subsequently characterized as a new rick-
ettsia of the spotted fever group and named Rickettsia japonica
Since 1984, approximately 30 to 40 cases have been reported
annually, mainly along the coast of southwestern and central
Japan (184, 185). The disease occurs from April to October.
High-risk areas for acquiring the infection include bamboo
plantations, crop fields, and coastal hills and forests. Japanese
spotted fever has an abrupt onset with headache, high fever (39
to 40°C), and chills. A macular rash appears after two or three
days, all over the body, including the palms and soles. It be-
comes petechial after 3 or four days and disappears in two
weeks. An inoculation eschar was observed in 91% of 34 pa-
tients diagnosed at Mahara Hospital in 1984-1997, and 38% of
the patients recalled a tick bite (184, 185). Severe cases, in-
cluding those of patients with encephalitis, disseminated intra-
vascular coagulopathy, multiorgan failure, and acute respira-
tory distress syndrome, have been reported (9, 158, 159, 161).
In a series of 28 patients hospitalized during 1993-2002, 6
(21%) were classified as severe, including 1 fatality (160, 161).
R. japonica has been detected in or isolated from six species
of ticks in Japan. Of these, Haemaphysalis flava, Haemaphysalis
longicornis, Dermacentor taiwanensis, and Ixodes ovatus com-
monly feed on humans and are considered as the most likely
vectors of the disease (106, 148, 185).
“Rickettsia conorii subsp. caspia” (Astrakhan fever). Since
the 1970s, in Astrakhan, a region of Russia located by the
Caspian Sea, cases of a febrile exanthema have been observed
in patients of rural areas. Prospective surveillance during 1983
through 1988 identified 321 cases of Astrakhan fever. Most
patients were adults (94%), specifically males (61%), and the
cases occurred during summer months (85%, including 43% in
August). The disease was similar to MSF, including fever as-
sociated with a maculopapular rash in 94% of the cases. How-
ever, the presence of a tache noire was reported in only 23% of
the patients. Conjunctivitis was seen in 32% of the cases. No
fatal cases were reported in this series (333). Most of the
patients had dogs and reported having contact with Rhipiceph-
alus sanguineus dog ticks. The Gamaleya Institute for Epide-
miology and Microbiology in Moscow tested sera from patients
with Astrakhan fever using the complement fixation test and
observed the presence of antibodies reactive with R. conorii in
72% of patients (334). These results were also confirmed by
MIF when tested at the Unite ´ des Rickettsies in Marseille (96).
A rickettsial isolate was obtained from a patient with Astra-
khan fever in 1991 (95). In 1992, it was shown that restriction
endonuclease patterns of DNA fragments of rickettsia ampli-
fied from the blood of a patient were identical to those of
rickettsial DNA amplified Rhipicephalus sanguineus ticks col-
lected in Astrakhan and related to those of R. conorii strains
from Israel (88). In 1994, Rhipicephalus pumilio ticks were also
shown to harbor rickettsiae with identical genomic patterns.
This species usually feeds on domesticated and wild mammals,
including rabbits and large rodents, but may occasionally bite
During the summer of 2001, French United Nations troops
in Kosovo collected ticks on asymptomatic soldiers and dogs in
the Morina region. By molecular methods, Rickettsia conorii
subsp. caspia was detected in four Rhipicephalus sanguineus
organisms, including three collected on dogs and one taken
from an asymptomatic soldier. The man with the positive tick
remained asymptomatic (105).
A rickettsial isolate was obtained recently from a patient
from Chad, Africa. The patient presented with fever, dyspnea,
a maculopapular rash, an inoculation eschar on the leg, and
conjunctivitis of the right eye. Five days before the onset of the
symptoms, she had traveled to Lake Chad, where she had
walked into the bush but recalled no tick bite. The 16S rRNA
gene, gltA, and ompA sequences of the isolate, obtained by
inoculating the eschar biopsy specimen in cell culture, were
found to be 99.7%, 99.6%, and 99.5% identical to those of
Rickettsia conorii subsp. caspia, respectively. Based on these
molecular characteristics, the Chad isolate is considered a vari-
ant strain of Rickettsia conorii subsp. caspia (113). Thus, As-
trakhan fever might be a cause of spotted fever in Kosovo and
Chad, and the area of distribution of this rickettsia could be
wider than initially suspected in Astrakhan.
It has been proposed recently that the Astrakhan fever rick-
ettsia actually constitutes several subspecies of R. conorii. R.
VOL. 18, 2005 TICK-BORNE RICKETTSIOSES AROUND THE WORLD731
conorii subsp. caspia subsp. nov. has been proposed as the
name of the agent of Astrakhan spotted fever (374).
Rickettsia africae (African tick bite fever). The etiologic
agent of African tick bite fever was discovered twice. In 1911,
an influenza-like disease named tick bite fever was described in
Mozambique and South Africa (204, 305). Thereafter, there
was debate as to whether these cases were cases of MSF,
described 1 year earlier in Tunisia (see “R. conorii subsp. cono-
rii” above). In the 1930s in South Africa, Pijper described tick
bite fever as a rural disease occurring in people having contact
with cattle ticks, whereas MSF was typically acquired in urban
areas with dog ticks (254, 255). Tick bite fever was a far milder
disease than MSF and was not associated with skin rash. Thus,
Pijper considered tick bite fever to be a distinct disease. He
isolated a rickettsia from a patient and demonstrated that it
was different from R. conorii in cross-protection studies (254,
255). Unfortunately, this isolate was lost and subsequent work-
ers were unable to confirm these findings (119). Erroneously,
MSF and tick bite fever were considered synonyms, and R.
conorii remained the only recognized agent of tick bite fever in
Africa until the 1990s.
In 1990, Kelly et al. isolated rickettsial strains from Ambly-
omma hebraeum ticks in Zimbabwe and demonstrated these
strains to be distinct from R. conorii by MIF typing (155). In
1992, a rickettsia was isolated by shell vial cell culture from a
patient suffering from tick bite fever in Zimbabwe (150). The
rickettsial isolate was found to be distinct from other SFG
rickettsia but indistinguishable from the rickettsial isolates pre-
viously obtained from A. hebraeum and from a strain isolated
from an Amblyomma variegatum specimen collected in Ethio-
pia 20 years earlier (54, 152). Kelly et al. proposed the name
African tick bite fever for the disease and the name Rickettsia
africae for the newly recognized rickettsia causing the disease.
These names were officially adopted when the rickettsia was
definitively characterized (151). This finding confirmed Pijper’s
earlier work and validated the presence of a second tick-trans-
mitted rickettsiosis in Africa approximately 60 years after the
In southern Africa, A. hebraeum, a tick of large ruminants
and wildlife species is a recognized vector and reservoir of R.
africae. Transstadial and transovarial transmission of R. africae
in this tick have been demonstrated (154). Frequent human
cases may be attributed to efficient transovarial transmission of
the agent when larvae, which are small and difficult to notice
when attached to the skin, are involved as vectors. R. africae
has also been detected in A. variegatum throughout west, cen-
tral, and eastern sub-Saharan Africa (181, 242) and in A. lepi-
dum from the Sudan (242). Three uncultivated rickettsiae,
named Rav1, Rav3, and Rav9, detected by PCR from A. var-
iegatum ticks in Niger and Mali, appear to be closely related,
probably variants of R. africae, based on molecular analyses of
the ompA and gltA genes (242).
Infection rates are remarkably high, and as many as 100% of
Amblyomma spp. may be infected with R. africae. Because A.
hebraeum ticks readily bite humans, cases of African tick bite
fever often occur in clusters and patients often present with
multiple inoculation eschars (273). Further, high prevalences
(30 to 80%) of antibodies to spotted fever group rickettsiae
have been shown in persons throughout the continent, includ-
ing children parallel to the distribution of Amblyomma ticks
(145). During the Zimbabwean war of independence in the late
1970s, army medical authorities reported that several thousand
cases of tick typhus occurred in European and African soldiers,
particularly those of urban origin who were deployed to rural
areas and presumptively nonimmune to the infection. Despite
high seroprevalence to R. africae among native Africans, nearly
all acute cases of ATBF described in the literature have oc-
curred in European or American travelers (145, 205, 273).
Recently however, Ndip et al. reported cases of ATBF docu-
mented by serology (26 patients) and molecular techniques
(7 patients) among indigenous patients in Cameroon (212,
Game hunting, traveling to southern Africa, and traveling
during November through April have recently been identified
as independent risk factors of ATBF in travelers (146). Sero-
logical evidence of recent spotted fever group rickettsial infec-
tion was detected in 11% of patients returned to Germany
from southern Africa (144). Further, specific antibodies to R.
africae were detected in 9% of first-time Norwegian travelers
to rural subequatorial Africa (147). Finally, in a prospective
cohort study of 940 Norwegian travelers (mostly short-term) to
rural subequatorial Africa, the incidence rates of African tick
bite fever ranged from 4 to 5% (146).
Between 1983 and 2003, 171 published cases have been
microbiologically confirmed as ATBF. Another 78 cases could,
based on positive (but not species-specific) tests in combina-
tion with typical clinical and epidemiological features, retro-
spectively be classified as probable ATBF (145, 273). The
mean age of these 249 cases was 40 years; most patients (72%)
were male, and most (64%) originated from Europe. Although
cases have been reported from western, central and eastern
Africa, more than 80% of the patients acquired ATBF in South
Africa. Risk areas include wildlife attractions in natural parks,
where the tick vectors are highly prevalent and attack readily
any person who enters their biotope. Up to 74% of travel-
associated cases of African tick bite fever occur in clusters (62,
110). The incubation period ranges from 5 to 7 days, up to 10
(145). In the largest published series, known tick bites or tick
contact were reported in 44% of the patients. Fever occurred
in 88% and clinical signs were generally mild. High prevalence
of multiple inoculation eschars was seen in patients (55%) and
characterizes ATBF from other spotted fever rickettsioses. Es-
chars were predominantly on the lower limbs (62%) presum-
ably because Amblyomma spp. attack from the ground to the
legs and generally bite as soon as possible (Fig. 4). Enlarge-
ment of lymph nodes draining area of the eschar (s) is common
(43%). A rash is seen in 49% of the patient and may be
vesicular (50%). To date no deaths or severe manifestations
have been reported in patients with ATBF. However, differ-
ences in clinical presentation appear between retrospectively
collected cases (including many which were hospitalized and
whose samples were referred to reference labs) (273) and 38
consecutive Norwegian cases (including only 2 hospitalized
cases) (146). When examining consecutive cases, many patients
had mild disease, whereas cases submitted to reference labs
and later presented in a retrospective fashion had more pro-
Recently, ATBF has been identified from locations away
from the African mainland. In 1998, the first case of naturally
acquired R. africae infection in the Western Hemisphere was
732 PAROLA ET AL.CLIN. MICROBIOL. REV.
described for a tick-bitten patient returning from Guadeloupe
Island in the French West Indies (243). R. africae was subse-
quently isolated from A. variegatum ticks collected on cattle,
sheep and goats on Guadeloupe (246). A second human case
was documented in 2001 (273). R. africae may have been in-
troduced into the West Indies from Africa during the 18th or
19th centuries with A. variegatum ticks on cattle shipped from
Senegal to Guadeloupe (19). Over the past 50 years, A. varie-
gatum have propagated and invaded more than 15 islands in
the Caribbean, by livestock movements and migration of birds.
More recently, R. africae was detected from A. variegatum
collected on others islands in the Caribbean including Martin-
ique (237), St. Kitts and Nevis (153) and Antigua (S. A. Thorn-
ton, P. E. Olson, M. Medina, J. Robinson, M. Eremeeva, J. W.
Sumner, T. Parakh, M. L. Lim, and G. A. Dasch, Abstr. 41st
Annu. Meet. Infect. Dis. Soc. Am., p. 40, 2003). Without ef-
fective control measure, great potential exists for A. variegatum
and R. africae to become established on the American main-
land. R. africae has also been recently identified in A. variega-
tum ticks collected on Reunion Island, a French Island in the
Indian Ocean, where ticks where introduced with animals by
humans in the 17th century (238).
Rickettsia honei (Flinders Island spotted fever). Flinders Is-
land spotted fever was described in 1991 by R.S. Stewart, the
only medical doctor among approximately 1,000 inhabitants on
Flinders Island, a small island off the south-east coast of Aus-
tralia near Tasmania. He described 26 cases observed over 12
years of a seasonal, febrile rash illness. The rash was erythem-
atous in the majority of patients and purpuric in two patients
with severe cases associated with thrombocytopenia (328).
Other findings included an inoculation eschar and enlarged
local nodes in 25% and 55% of cases, respectively. Cases oc-
curred in spring and summer, predominantly during December
and January. Incidence was approximately 150 per 100,000
persons. The patients’ sera were initially evaluated by the Weil-
Felix test and subsequently by microimmunofluorescence,
which confirmed that the disease was caused by a SFG rick-
ettsia. At the time of Stewart’s observations, these were con-
sidered to be cases of Queensland tick typhus, although clinical
and epidemiological differences were noted when compared to
cases originating from Queensland. The usual features in
Flinders Island spotted fever were a sudden onset of fever,
headache, arthromyalgias with joint swelling and slight cough.
However, the rash which appeared few days later, was macu-
lopapular and there was no vesiculation, unlike Queensland
tick typhus caused by R. australis. Although most of the re-
ported cases of R. australis occurred during June through No-
vember, and were reported from both urban and suburban
areas, cases in Flinders Island spotted fever occurred predom-
inantly during December through January (328).
In 1992, isolates were obtained from 2 patients with Flinders
Island spotted fever (15). The rickettsia was characterized by
molecular methods and proposed as a new species, R. honei
(16, 327). One patient from whom a rickettsial isolate was
obtained from blood had been bitten by a tick 9 days prior
becoming ill. The tick was identified as Aponomma hydrosauri
(129) a tick that usually bites reptiles. During the same summer
season of 1990, eight people collected the ticks that had bitten
them. Six were I. tasmanii (the main tick that bites humans on
Flinders Island) and 2 were A. hydrosauri. Further, 29/46
(63%) of A. hydrosauri removed from 12 Australian blue-
tongued lizard on Flinders Island were shown to harbor R.
honei by molecular techniques (128, 362). DNA of R. honei has
been detected by PCR in eggs obtained from engorged female
ticks of this species, suggesting transovarial transmission of R.
honei in the acarine host (128).
In addition to Flinders Island, A. hydrosauri is widespread in
south Australia including Victoria area on the Mainland and
Tasmania. It has also been noted in New South Wales (288). In
1995, a similar rickettsiosis emerged in Tasmania, where pa-
tients were found by PCR to be infected with R. honei (70). A.
hydrosauri ticks removed from a Tasmanian were also positive
by PCR, and recent work suggested again that transovarial
transmission may occur in ticks (362). However, the definitive
implication of A. hydrosauri as a vector and possibly reservoir
of R. honei, requires further study.
Interestingly, in 1962 a rickettsia was isolated in Thailand
from pooled larval Ixodes sp. and Rhipicephalus sp. ticks col-
lected on a Rattus rattus specimen, designated Thai tick typhus
rickettsia TT-118 (289); however, this rickettsia has been
shown recently to be a strain of R. honei (327). More recently,
DNA of R. honei has been recently detected in Thai Ixodes
granulatus ticks collected from R. rattus in Thailand in 1974
Finally, a rickettsia closely related to R. honei was detected
by molecular tools in 2 Amblyomma cajennense adult ticks
collected on cattle in south Texas (35). Sequence analysis of
segments of the 17-kDa gene, gltA gene, and the gene encoding
OmpA amplified from these ticks showed the highest degree of
similarity to the Thai tick typhus rickettsia (homologies of 99.5,
99.5, and 100%, respectively). To date, no case of spotted fever
group rickettsioses has been linked to R. honei infection in
Thailand or the United States.
“Rickettsia sibirica subsp. mongolitimonae.” In 1991, a rick-
ettsia was isolated from Hyalomma asiaticum ticks collected in
Inner Mongolia in China. It was antigenically and genotypically
unique among SFG rickettsiae and was named isolate HA-91
FIG. 4. Multiple tick bites on a patient with African tick bite fever
caused by R. africae.
VOL. 18, 2005 TICK-BORNE RICKETTSIOSES AROUND THE WORLD733
(371). In 1996, a genetically indistinguishable isolate was ob-
tained from the blood and the skin of a 63-year-old patient in
southern France. The patient was hospitalized in March (an
atypical month for MSF) with a mild disease characterized by
only a discrete rash and an inoculation eschar involving the
groin. This patient was a resident of Marseille and had no
travel history; however, the patient had collected compost from
a garden where migratory birds were resting (271). The name
“Rickettsia mongolotimonae” was first proposed for the rickett-
sia to refer to the disparate sources of the isolates (i.e., Mon-
golia and La Timone Hospital in Marseille). Using gene se-
quence-based criteria to define Rickettsia species (104), “R.
mongolotimonae” was identified as a member of the R. sibirica
species complex. However, in phylogenetic studies, all strains
of “R. mongolotimonae” group together in clusters separated
from other strains of R. sibirica. In addition, “R. mongolotimo-
nae” exhibits serotypic and ecological differences from other
members of this complex. For these reasons, and in accordance
with Latin nomenclature, this agent is now called “R. sibirica
subsp. mongolitimonae,” and the agent of North Asian tick
typhus called R. sibirica sensu stricto (107) (P. E. Fournier, et
al., Abstr. 4th Int. Conf. Rickettsiae Rickettsial Dis., abstr.
A second human case of infection with R. sibirica subsp.
mongolitimonae was diagnosed in 1998 in an HIV-positive pa-
tient who had gardened in a rural area of Marseille. The
patient presented with fever, headache, an eschar, lymphangi-
tis and painful satellite lymphadenopathy (112). From January
2000 to June 2004, R. sibirica subsp. mongolitimonae infection
has been diagnosed in 7 additional patients. In 3, the bacterium
was cultivated from the inoculation eschar. The other 4 pa-
tients were diagnosed using PCR from the eschar (2 patients)
or blood (2 patients), plus specific Western blot before (2
patients) and after (2 patients) cross-adsorption (CA).
Based on evaluation of these nine cases, R. sibirica subsp.
mongolitimonae infection differs from other tick-borne rickett-
sioses in the Mediterranean area. Specific characteristics in-
clude an incidence from March to early July, the occasional
findings, alone or in combination, of multiple eschars (Fig. 5),
and draining lymph nodes, and a lymphangitis that extends
from the inoculation eschar to the draining node. The unique
clinical features of this new rickettsiosis have led to the mon-
iker lymphangitis-associated rickettsiosis (107).
R. sibirica subsp. mongolitimonae was reported in sub-Sa-
haran Africa in 2001, when it was detected in Hyalomma trun-
catum (242). The first proven human infection with R. sibirica
subsp. mongolitimonae in Africa was reported in a construction
worker, working in South Africa’s Northern Province. The
patient presented with an eschar on his toe, lymphangitis, se-
vere headache, and fever. An eschar biopsy specimen was used
for PCR amplification of the rickettsial OmpA gene which
showed ?99% similarity with the corresponding OmpA gene
fragment of R. sibirica subsp. mongolitimonae (258). More re-
cently, a second African case was documented in a patient
returning to France after a trip in Algeria. She presented with
fever and 2 inoculation eschars. She had been in contact with
camels which are highly parasitized by ticks (107). Thus, lym-
phangitis-associated rickettsiosis should be considered in the
differential diagnosis of tick-borne rickettsioses in Europe, Af-
rica and Asia.
Specific vectors of R. sibirica subsp. mongolitimonae have yet
to be described, particularly in southern France. It has been
hypothesized that French patients may have been bitten by
ticks from migratory birds. The detection of R. sibirica subsp.
mongolitimonae in Hyalomma spp. in Mongolia and Niger sug-
gests a possible association of this rickettsia with ticks of this
genus that are also prevalent in southern France (209). More
arguments for this hypothesis have been provided recently
when two cases of R. sibirica subsp. mongolitimonae have been
documented in Crete, Greece. Indeed, in one patient, this
rickettsia was simultaneously detected on a H. anatolicum ex-
cavatum tick parasitized on him (A. Psaroulaki, A. Ger-
manakis, E. Scoulica, B. Papadopoulos, A. Gikas, and Y.
Tselentis, Abstr. 4th Int. Conf. Rickettsiae Rickettsial Dis.,
abstr. P-207, 2005).
Rickettsia slovaca. R. slovaca was first isolated in 1968 from
Dermacentor marginatus ticks in Czechoslovakia (279). Subse-
quently, it has been detected or isolated from ticks in all Eu-
ropean countries where D. marginatus and D. reticulatus have
been evaluated for rickettsiae, including France, Switzerland,
Slovakia, Ukraine, Yugoslavia, Armenia, and Portugal. Infec-
tion prevalence in ticks varies from 1 to 17% (311). These ticks
are generally common throughout Europe and central Asia,
except for D. marginatus, which has not been identified in
northern Europe. They are active during early spring, autumn,
FIG. 5. Multiples eschars on a patient infected with R. sibirica
734PAROLA ET AL.CLIN. MICROBIOL. REV.
and winter in southern Europe. Adult ticks inhabit forests and
pastures and frequently bite people entering these biotopes,
particularly on the scalp. These ticks may act as vectors but also
reservoirs of R. slovaca, which is maintained in ticks through
transstadial and transovarial transmission (279).
For more than 20 years following its discovery, R. slovaca
was considered a nonpathogenic rickettsia; however, in 1997,
the first documented case of human infection with R. slovaca
was reported, found in a woman who presented with a single
eschar of the scalp and enlarged cervical lymph nodes follow-
ing the bite of a Dermacentor sp. tick in France. This case was
documented by seroconversion and molecular detection of R.
slovaca in the eschar’s biopsy specimen and by isolation of the
bacterium from the tick which had been kept (270). Clinically
similar but undocumented cases had been seen previously in
France, Slovakia, and Hungary, where this clinical syndrome
had been named “TIBOLA” (for tick-borne lymphadenopa-
thy) (Fig. 6).
From January 1996 through April 2000, the role of R. slo-
vaca infection in this syndrome was evaluated in 67 patients
from France and Hungary presenting with tick-borne lymph-
adenopathy (275). A total of 17 cases of R. slovaca infection
were confirmed in this cohort by molecular methods. Infec-
tions were most likely to occur in children and in patients who
were bitten during the colder months of the year. Fever and
rash were uncommon, and sequelae included localized alope-
cia at the bite site and chronic fatigue. During the study period,
R. slovaca infection was shown to represent 19% of the Euro-
pean tick-transmitted rickettsioses documented in the Unite ´
des Rickettsies in Marseille. Cases have also recently been
reported in Bulgaria (163) and Spain (226). Finally, the isola-
tion of R. slovaca from a patient has been recently reported,
providing definitive evidence that R. slovaca is a human patho-
Recently, 22 cases of a similar disease have been reported in
Spain, where the clinical syndrome was called “DEBONEL”
(for Dermacentor-borne necrosis-erythema-lymphadenopathy)
(225). In half of the cases, patients were bitten by ticks iden-
tified as D. marginatus. Cases occurred between October and
April, with a peak in November. The incubation period was
approximately 4 days (range, 1 to 8 days). All patients had an
eschar at the tick bite site (86% of the eschars were on the
scalp) associated with regional painful lymphadenopathy, and
all but one reported a headache. Low-grade fever was present
in 45% of patients. After antibiotic treatment (doxycycline,
except for a child who received josamycin) all patients recov-
ered, but the eschar resulted in alopecia lasting for several
months for several patients. In this series, the infection was not
definitely confirmed to be due to R. slovaca. A weak and late
serological response against this rickettsia was observed in
25% of the cases analyzed. This serological profile had been
previously reported within French and Hungarian patients
(275). R. slovaca was, however, detected by PCR in an en-
gorged D. marginatus female removed from the scalp of one of
the patient. It is also interesting that, in addition to R. slovaca,
another rickettsia of unknown pathogenicity and belonging to
R. massiliae genogroup has been detected from D. marginatus
ticks in Spain (190, 225), as previously in other European
countries. As R. slovaca seems to be involved in most but not
all cases of Dermacentor-borne necrosis-erythema-lymphade-
nopathy or tick-borne lymphadenopathy, one should pay at-
tention to other rickettsiae associated with Dermacentor ticks.
Rickettsia heilongjiangensis. In 1982, a rickettsial isolate
(HLJ-054) was obtained from Dermacentor silvarum ticks col-
lected in Suifenhe in the Heilongjiang Province of China (99).
Between May and July 1992, 12 patients presenting with fever,
headache, rash, eschar, regional lymphadenopathy, and con-
junctivitis following a tick bite in the same area were reported
FIG. 6. Inoculation eschar of the scalp (top panel) and enlarged
cervical lymph nodes (bottom panel) of a patient with tick-borne
lymphadenopathy (R. slovaca infection).
VOL. 18, 2005TICK-BORNE RICKETTSIOSES AROUND THE WORLD 735
to have antibodies against this rickettsial strain. Between May
and June 1996, rickettsial isolates were obtained from seven
patients with clinical manifestations of SFG rickettsiosis in
Suifenhe (99). Serological typing and PCR-RFLP analysis
showed that these isolates were identical to identical to HLJ-
054 (also called “Rickettsia heilongjiangii”), providing the first
direct evidence of the pathogenic role of this rickettsia (368).
Recent genomic analysis allowed a definitive characterization
of this rickettsia (373), which is now called Rickettsia hei-
longjiangensis (104). The most closely related rickettsia is R.
japonica. Until recently, infections caused by R. heilongjangh-
ensis were attributed to R. sibirica (99).
More recently, 13 patients from the Russian Far East were
shown to have been infected by R. heilongjiangensis (206).
Rickettsial DNA (four fragments of three genes) was amplified
from the patients’ skin biopsy specimens and blood samples.
Further, the presence of specific antibodies against R. hei-
longjiangensis was shown when the serum samples of 11 pa-
tients were tested with a panel of rickettsial antigens. All the
patients had a history of tick bite or tick exposure or a stay in
an epidemiologically suspected location. In 12 cases, a macular
or maculopapular rash appeared but was faint in most cases.
Also, 12 patients had eschars. Two patients were shown to have
lymphangitis and regional lymphadenopathy. R. sibirica infec-
tion (Siberian tick typhus) that is endemic in Russia peaks at
the end of April, and the seasonal peak of the newly described
rickettsiosis was at the end of June and July. Further, the
infection due to R. heilongjiangensis seemed to affect younger
people (only one under 45 years) and to be relatively mild and
without any reported deaths (206). The epidemiology of infec-
tions caused by the variant of R. heilongjiangensis remains to be
studied. Recently, the DNA of the same rickettsia was ampli-
fied from Haemaphysalis concinna ticks from Siberia (321) and
from H. concinna and Haemaphysalis japonica douglasi ticks
from Russian Far East (O. Mediannikov, Y. Sildelnikov, L.
Ivanov, E. Mokretsova, P. E. Fournier, I. Tarasevich, and D.
Raoult, Abstr. 4th Int. Conf. Rickettsiae Rickettsial Dis., abstr.
O-52, 2005). The name Far Eastern spotted fever has been
proposed for this emerging infectious disease.
Rickettsia aeschlimannii. R. aeschlimannii was first character-
ized as a new spotted fever group rickettsia following its iso-
lation from Hyalomma marginatum marginatum ticks in Mo-
rocco in 1997 (23). However, genotypically similar organisms
had previously been detected in Hyalomma marginatum rufipes
in Zimbabwe and in H. m. marginatum in Portugal (22). R.
aeschlimannii was also later detected in H. m. rufipes in Niger
and Mali (242). In Europe, R. aeschlimannii has been recently
identified in H. m. marginatum ticks in Croatia (264), from six
tick species in Spain, including H. m. marginatum (101), and
from H. m. marginatum ticks in Cephalonia, the largest Ionian
islands of Greece (A. Psaroulaki, D. Ragiadakou, G. Kouris, B.
Papadopoulos, B. Chaniotis, and Y. Tselentis, Abstr. 4th Int.
Conf. Rickettsiae Rickettsial Dis., abstr. P-208, 2005). This
rickettsia was recently isolated from H. m. marginatum ticks
collected on various mammals and from H. m. rufipes ticks
collected on migratory birds coming from Africa, collected in
Corsica (197). In this work, R. aeschlimannii was shown to be
transstadially and transovarially transmitted in ticks indicating
that Hyalomma ticks may be not only vectors but also reser-
voirs of R. aeschlimannii. As a consequence, the geographic
distribution of R. aeschlimannii in Europe would be at least
that of H. m. marginatum ticks throughout southern Europe
In 2002, the first human infection caused by R. aeschliman-
nii, in a patient returning from Morocco to France, was re-
ported. This patient presented with an inoculation eschar on
his ankle, fever, and a generalized maculopapular rash. MIF
and Western blot assays showed that the patient’s serum re-
acted more intensively with R. aeschlimannii proteins than with
proteins of the other tested SFG rickettsiae. The definitive
diagnosis was obtained using PCR amplification of rickettsial
DNA in the patients’ early serum and sequencing of a frag-
ment of the ompA gene of R. aeschlimannii (272). A second
case, in a patient returning from a hunting and fishing trip in
South Africa, was reported. A Rhipicephalus appendiculatus
tick was attached to his thigh, and an eschar around the at-
tachment site was noted (259). He removed the tick and self-
prescribed doxycycline. No further symptoms developed. A
skin biopsy specimen was, however, taken from the eschar.
Molecular studies of both the biopsy specimen and the tick
allowed the amplification of ompA fragments sharing ?99%
similarity with the ompA of R. aeschlimannii.
Interestingly, for 11 of 144 cases of spotted fever rickettsio-
ses recently reported in Spain, patients presented with multiple
eschars (7). Although all cases were diagnosed as MSF caused
by R. conorii, this diagnosis is doubtful. Rhipicephalus san-
guineus, the vector of R. conorii, has a low affinity to bite
people, and the infection rate by SFG rickettsiae is generally
less than 10%. Thus, the probability of being bitten simulta-
neously by several infected Rhipicephalus sanguineus ticks is
likely to be low (245). Conversely, H. marginatum ticks readily
bite humans, and persons may receive multiple simultaneous
tick bites. For example, from 2001 to 2005, a total of 496 ticks
were removed from people at the Hospital de La Rioja, Spain.
A total of 170 were identified as H. m. marginatum, and 3 of
them (1.8%) were shown to harbor R. aeschlimannii (J. A.
Oteo, A. Portillo, S. Santiba ´n ˜ez, L. Pe ´rez-Martı ´nez, J. R.
Blanco, S. Jime ´nez, V. Ibarra, A. Pe ´rez-Palacios, and M. Sanz,
Abstr. 4th Int. Conf. Rickettsiae Rickettsial Dis., abstr. P-92,
2005). Furthermore, infection rates of H. marginatum may be
high, such as that reported in Croatia (64.7%) (264).
Therapeutic failures with rifampin administration to chil-
dren with MSF have been reported in Catalonia, Spain, al-
though R. conorii, the agent of MSF, is susceptible to rifampin
(28, 290); however, R. aeschlimannii has been shown to be
resistant to rifampin (290). In this context, it is possible that
some cases of tick bite spotted fever acquired in southern
Europe and presenting with several eschars are caused by R.
Rickettsia parkeri. In 1939, R. R. Parker isolated a rickettsia
from Gulf Coast ticks (Amblyomma maculatum) collected
from cows in south Texas (233). Subsequent studies character-
ized this bacterium as a distinct SFG rickettsia, and it was
named Rickettsia parkeri (170). R. parkeri was generally char-
acterized as a nonpathogenic species and received relatively
little attention for the remainder of the 20th century. In 2004,
Paddock et al. reported the first recognized case of infection
with R. parkeri in a human 65 years after the initial isolation of
the rickettsia from ticks (230). It occurred in a 40-year-old man
736PAROLA ET AL.CLIN. MICROBIOL. REV.
living in suburban area in southeast Virginia who presented
with fever, headache, diffuse myalgias and arthralgias, and
multiple eschars on his lower extremities. There was no travel
history, and no arthropod bite was recalled, although the pa-
tient was frequently exposed to ticks and fleas. An erythema-
tous maculopapular rash developed on his trunk and spread to
his extremities, including his palms and soles. The patient was
initially diagnosed with infected arthropod bite and treated
unsuccessfully with a penicillin-class antibiotic. He was subse-
quently diagnosed with rickettsialpox and successfully treated
with doxycycline. R. parkeri was isolated in cell culture from an
eschar biopsy specimen and definitively identified by use of
molecular methods (230).
A remarkable clinical feature was the occurrence of multiple
inoculation eschars. The occurrence of multiple eschars has
been also described for a several other tick-borne rickettsioses,
including African tick bite fever and the rickettsiosis caused by
R. sibirica subsp. mongolotimonae (245), but is generally an
unusual clinical feature of most SFG rickettsial infections. In-
deed, eschars are seldom described for patients with RMSF,
and it has been suggested that rare observations of eschars in
patients with supposed RMSF (76, 354) could be caused by
infection with R. parkeri rather than R. rickettsii (230). A 1994
report describing PCR-restriction fragment length polymor-
phism profiles of several SFG rickettsial stains isolated from
patients presumably infected with R. rickettsii noted close sim-
ilarity of one profile with that of R. parkeri (266). More re-
cently, an analysis of several Western blot profiles of serum
samples from patients presumed to be infected with R. rickettsii
revealed reactivity with a 120-kDa protein of R. parkeri in a
pattern compatible with the profile observed from the index
patient with R. parkeri infection (268). Collectively, these find-
ings suggest that other cases of R. parkeri rickettsiosis were
previously diagnosed as RMSF (230).
The distribution and significance of R. parkeri rickettsiosis
in the Americas await further investigation. In the United
States, A. maculatum ticks are distributed throughout sev-
eral southeastern states that border the Gulf and southern
Atlantic coasts. R. parkeri has been identified in Gulf Coast
ticks collected throughout its range in the United States.
Some clinical, epidemiologic, and serologic evidence suggest-
ing that human infections with R. parkeri have also occurred in
Florida, Mississippi, and South Carolina exists (76, 230). R.
parkeri has also been detected rarely in the lone star tick
(Amblyomma americanum), and a study suggests that this rick-
ettsia may be transovarially and transstadially transmitted in
this widely distributed tick (124). Preliminary studies also sug-
gest that A. cajennense will support the growth and survival of
R. parkeri (303), and a recent investigation has demonstrated
DNA of R. parkeri in Amblyomma triste (formerly A. macula-
tum) ticks collected from humans and animals in Uruguay
(347). These findings, coupled with other reports of eschar-
associated spotted fever rickettsioses in patients following bites
of A. triste in Uruguay (73, 87), suggests that R. parkeri rick-
ettsiosis also occurs in areas of South America. In Uruguay, it
is likely that rickettsiosis caused by R. parkeri has been diag-
nosed as infection with R. conorii based on nonspecific sero-
logic tests (87).
In 1992, a rickettsial agent was isolated from Rhipicephalus
sanguineus ticks collected near Marseille. It was characterized
as a distinct species within the SFG group of rickettsiae and
named R. massiliae (21). In Europe, this rickettsia has been
detected by molecular methods in Rhipicephalus sanguineus in
Greece (11) and Rhipicephalus turanicus in Portugal (13). It
has been also detected in Africa in Rhipicephalus muhsamae,
Rhipicephalus lunulatus, and Rhipicephalus sulcatus in the Cen-
tral African Republic (92) and in Rhipicephalus muhsamae
collected on cattle in Mali (242). In 1996, a variant strain of R.
massiliae (Bar 29) was isolated in Rhipicephalus sanguineus tick
from Catalonia, Spain (26). It was thereafter detected in Swit-
zerland (33). We recently demonstrated transstadial and
transovarial transmission of R. massiliae Bar 29 in ticks of
the R. sanguineus group molecularly identified as Rhipiceph-
alus turanicus, which may also be considered to be reservoirs
R. massiliae exhibits a natural resistance to rifampin in cell
cultures (290). Interestingly, therapeutic failures with rifampin
for the treatment of MSF in children have been reported in
Catalonia, although R. conorii is susceptible to rifampin (28,
290). R. massiliae Bar 29 has been detected in tick saliva,
suggesting that the bacteria could be transmitted through the
tick bite (196). In 2003, among 15 patients of MSF in Catalo-
nia, Spain, eight sera reacted at high titers with only R. conorii
and R. massiliae Bar 29 antigens, and the titers against R.
massiliae Bar 29 were clearly higher than those against R.
conorii, which implied the possible pathogenic role of R. mas-
siliae Bar 29 for humans (61).
The first recognition of infection with R. massiliae in a hu-
man occurred in 2005, 20 years after the isolate was initially
obtained from the patient. A spotted fever rickettsia, pre-
sumed to be R. conorii, was isolated in 1985 from the blood of
a 45-year-old man hospitalized in Palermo, Italy, with fever, a
necrotic eschar, a maculopapular rash involving palms and
soles, and mild hepatomegaly. Treatment with a cephalosporin
antibiotic failed, but he recovered completely after receiving a
tetracycline antibiotic. His antibody titer to R. conorii antigens
rose from 0 to 80 by MIF, and the patient was considered to
have Mediterranean spotted fever caused by R. conorii. The
rickettsial isolate was stored for 2 decades before being iden-
tified as R. massiliae by sequencing of portions of the ompA
and gltA rickettsial genes at the Unite ´ des Rickettsies (349).
“Rickettsia marmionii.” During 2003-2005, six patients from
the states of Queensland, Tasmania, and South Australia, Aus-
tralia, were diagnosed with a SFG rickettsiosis characterized by
fever (all patients), headache (83%), arthralgia (50%), cough
(50%), maculopapular rash (33%), and pharyngitis (33%). An
eschar was observed for only one patient. Genetic analyses of
an isolate obtained from one of the patients showed close
similarity to but distinction from R. honei, with 99.0%, 99.7%,
and 99.6% homology to the 17-kDa antigen, gltA, and 16S
rRNA genes, respectively. Investigators have proposed the
name “R. marmionii” to describe this rickettsia and the term
“Australian spotted fever” to describe the rickettsiosis it
causes. The definitive status of “R. marmionii” as a distinct
species or as a subspecies of R. honei remains to be deter-
mined. Potential vectors include Haemaphysalis novaeguineae
VOL. 18, 2005TICK-BORNE RICKETTSIOSES AROUND THE WORLD737
(N. Unsworth, J. Stenos, and J. Graves, Abstr. 4th Int. Conf.
Rickettsiae Rickettsial Dis., abstr. O-53, 2005).
TICK-BORNE SFG RICKETTSIAE PRESUMPTIVELY
ASSOCIATED WITH HUMAN ILLNESSES
“Rickettsia conorii subsp. indica”
(Indian Tick Typhus)
Indian tick typhus (ITT) is a tick-borne rickettsiosis preva-
lent in India. Although the disease has been clinically recog-
nized at the beginning of the century, the etiologic agent has
never been isolated in patients. However, a SFG rickettsia was
isolated in 1950 from a Rhipicephalus sanguineus tick collected
in India (C. B. Philip, L. E. Hughes, K. N. A. Rao, S. L. Kalra,
Arq. 5th Congr. Int. Microbiol., p. 1–571, 1958). This bacte-
rium, classified as R. conorii, was considered to be the cause of
ITT. However, subsequent serologic studies including cross-
adsorption and MIF serotyping demonstrated significant dif-
ferences in antibody responses of patients of ITT with the ITT
rickettsia and type strains of R. conorii (21, 252). Using mo-
lecular methods, it was recently demonstrated that these rick-
ettsiae are closely related, although their diversity is reflected
in antigenic variation (111, 294, 295). As discussed above, we
have recently proposed that the agent of ITT constitutes a
subspecies of R. conorii different from the agent of MSF des-
ignated Rickettsia conorii subsp. indica subsp. nov.
Indian tick typhus differs from MSF in that the rash is fre-
quently purpuric and an inoculation eschar at the bite site
is rarely identified (143, 211). Cases are documented infre-
quently and generally by using nonspecific serological meth-
ods, such as the Weil-Felix test, which provides indirect evi-
dence of possible rickettsial infection but does not allow a
definitive diagnosis (195, 211). In 2001, MIF, Western blotting,
and cross-absorption assays were used to document the first
serologically confirmed case of severe infection in a returning
traveler caused by “Rickettsia conorii subsp. indica” (241).
More recently, in Kerala, a state at the southernmost tip of
India, seven cases were documented for the first time by MIF.
Patients were laborers working in tea estates and presented
with fever and a generalized maculopapular rash occurring,
involving palms and soles in three patients (330). Recent stud-
ies also suggest that two patients with SFG rickettsioses, in-
cluding one presenting with a rash and an eschar, may have
been infected with “Rickettsia conorii subsp. indica” in Thai-
R. canadensis was first isolated from Haemaphysalis leporis-
palustris ticks removed from rabbits in Ontario, Canada (202).
It was initially considered a member of the typhus group rick-
ettsiae on the basis of antigenic similarities (140). However,
recent molecular studies (104, 293, 295, 310) showed that it
should be representative of a distinct group within the genus
rickettsia, such as R. bellii. The role of R. canadensis as a
human pathogen has not been definitively established. Sero-
logical evidence of human infection has been reported in four
patients presenting with an RMSF-like disease in California
and Texas (39). A role for R. canadensis in acute cerebral
vasculitis was also suspected in a patient from southwestern
Ohio, based on serological studies that included immunoblot
“R. amblyommii” (proposed name), also referred to as
strains 85-1034, WB-8-2, and MOAa, was first isolated from
lone star ticks (A. americanum) collected in Tennessee in 1974
and subsequently identified throughout the range of the lone
star tick (C. Pretzman, D. R. Stothard, D. Ralph, and A.
Fuerst, Proc. 11th Sesquiannu. Meet. Am. Soc. Rickettsiol.
Rickettsial Dis., p. 24, 1994) (49, 52, 361). R. amblyommii has
also been recently detected in A. cajennense and Amblyomma
coelebs ticks collected from the western Amazon forest of Bra-
zil (169). The role of R. amblyommii as an agent of human
disease has been suggested by a study that examined Western
blot profiles of 12 members of a military unit that developed
mild illnesses and antibodies reactive with spotted fever group
rickettsiae following field maneuvers in tick-infested habitats
in Arkansas and Virginia. Investigators determined that five of
these patients exhibited specific profiles of reactivity to major
surface proteins antigens of strain 85-1034, suggesting infec-
tion with this agent [G. A. Dasch, D. J. Kelly, A. L. Richards,
J. L. Sanchez, and C. C. Rives, abstract from Program and
Abstracts of the Joint Annual Meeting of the American Society
of Tropical Medicine and Hygiene and the American Society
of Parasitologists, Am. J. Trop. Med. Hyg. 49(Suppl):220,
1993]. Some investigators have speculated that this rickettsia
may be the agent described as “Rickettsia texiana” (proposed
name) (see below). In some areas of the United States, 40% or
more of A. americanum may be infected with this rickettsia
(125). Because lone star ticks are especially abundant in the
southern and midwestern United States, and because A. ameri-
canum of all three stages readily bite humans, infections with
R. amblyommii could prove to be relatively frequent if this
agent is definitively identified as a human pathogen. Recent
investigations have also identified a spotted fever group rick-
ettsia (strain Aranha) in Amblyomma longirostre ticks collected
from Brazil that shows a very close phylogenetic relationship
with R. amblyommii (167). To our knowledge, no isolate of R.
amblyommii is currently available to the scientific community.
In 1975, Anigstein and Anigstein presented work completed
approximately 30 years earlier that proposed a rickettsial eti-
ology for Bullis fever, a forgotten epidemic which involved
more than 1,000 soldiers participating in field training exercises
at Camp Bullis, Tex., during the spring and summer months of
1942 and 1943 (5). Considerable epidemiologic and entomo-
logic evidence collected during the outbreak implicated an
infectious agent transmitted by the bite of lone star ticks (41).
Because all patients reported a history of tick bites, most no-
tably bites from A. americanum, the disease was also initially
referred to as “Texas tick fever” and “lone star fever.” Clinical
features included fever, chills, orbital and postoccipital head-
ache, weakness, weight loss, and leukopenia. All patients dem-
onstrated enlargement of at least some lymph nodes, and many
had a generalized lymphadenopathy. A maculopapular rash
738 PAROLA ET AL.CLIN. MICROBIOL. REV.
involving the trunk was noted in 10% of cases. The illnesses
varied from a mild febrile syndrome of short duration to severe
disease and included one death (367).
Impression smears made from biopsied lymph nodes stained
by the Machiavello technique showed small intracellular fuch-
sinophilic granule and rods morphologically similar to rickett-
siae (180). Rickettsia-like organisms were also isolated from
blood and lymph nodes of patients and from A. americanum
ticks collected in the area (6). Isolates from humans and ticks,
passaged in chicken embryo culture and in animals, subse-
quently produced clinical features compatible with Bullis fever
when inoculated in human volunteers. The name Rickettsia
texiana was proposed for this agent (5). Because A. america-
num ticks frequently harbor spotted fever group rickettsiae
(125), most notably R. amblyommii, it has been suggested that
R. texiana may have been represented by a strain of this rick-
ettsia; however, no isolate of R. texiana is known to exist today,
precluding analyses by contemporary molecular tools.
Bullis fever vanished in 1947, and the cause of this outbreak
remains enigmatic and controversial. At the time of the out-
break, R. R. Parker and E. A. Steinhaus of the Rocky Moun-
tain Laboratory concluded that no association between the
isolated rickettsia and Bullis fever could be firmly established
based on serological responses in patients and experimentally
infected animals. These investigators suggested that “there
might be pathogens in the local tick population that we have
failed to demonstrate, either because of absence in the partic-
ular ticks tested or that they may not be demonstrable by the
techniques employed” (5). Other tick-borne agents have been
suggested as the etiology of Bullis fever, including Coxiella
burnetii (171) and Ehrlichia chaffeensis (123); however, the
clinical presentation of Bullis fever does not match entirely
with either of these diseases, and its cause remains a mystery.
R. helvetica was first isolated in Ixodes ricinus ticks (the
vector of Lyme borreliosis) in Switzerland in 1979 (24, 46).
Because transstadial and transovarial transmission of this rick-
ettsia has been demonstrated in I. ricinus, this tick represents
both a potential vector and natural reservoir of R. helvetica. R.
helvetica has been identified in I. ricinus ticks in many Euro-
pean countries, including France, Sweden, Slovenia, Portugal,
Italy, and Bulgaria (32, 71, 216, 239, 304). Recently, it has been
shown that the distribution of R. helvetica is not limited to
Europe but extends to Asia. Rickettsiae identical with or
closely related to R. helvetica have been isolated from I. ovatus,
I. persulcatus, and Ixodes monospinosus ticks collected in Japan
For approximately 20 years after its discovery, R. helvetica
was considered a nonpathogenic rickettsia; however, in 1999,
R. helvetica was implicated in fatal perimyocarditis in several
patients in Sweden. Infection was documented by electron
microscopy, PCR, and serology (217). These researchers sub-
sequently reported a controversial association between R. hel-
vetica and sarcoidosis in Sweden (218). However, the validity of
these associations has been questioned by prominent rickett-
siologists (357). As noted by D. H. Walker et al., none of the
sarcoidosis cases had supporting serologic evidence of a SFG
rickettsiosis and results of immunohistochemistry and trans-
mission electron photomicrographs appeared dubious at best
(357). In addition, although histochemical stains were inter-
preted as showing structures consistent with bacteria, the tech-
niques used are known for staining unidentified particles in any
damaged tissues (357).
In 2000, seroconversion to R. helvetica was described for a
French patient with a nonspecific febrile illness (108). In 2003,
serological findings in tick bite patients from Switzerland were
suggestive of acute or past R. helvetica infection (20). More
recently, one patient from France and three from Italy were
also diagnosed using serological criteria that included MIF,
Western blotting, and cross-absorption methods. All four re-
ported tick bites and one developed an eschar (103). Recently,
five cases of SFG rickettsiosis, possibly caused by R. helvetica,
were reported in patients living along the central Thai-Myan-
mar border. Two patients reported a tick bite, one presented
with an eschar, and another patient presented with rash. In-
fection were documented by MIF and Western blot assays
(244). Three more cases, in patients from eastern Thailand
with undifferentiated febrile illnesses, were serologically doc-
umented. Although no vector of R. helvetica has been identi-
fied in Thailand, it is known that I. ovatus, which has been
shown to carry R. helvetica, at least in Japan, is also prevalent
in Thailand (331). Further evidence of R. helvetica infections in
the far East is supported by a recent report of a Japanese
traveler returning from Australia with tick-induced paralysis,
due to I. holocyclus, who subsequently seroconverted to R.
These data suggest that R. helvetica occurs across a much
larger geographical area than previously known and is associ-
ated with Ixodes species ticks. The few patients for whom
serology-based diagnosis exists had relatively mild, self-limited
illnesses associated with headache and myalgias and, less fre-
quently, with a rash and/or an eschar (103). Additional evalu-
ation and isolation of the bacterium from clinical samples are,
however, needed to confirm the pathogenicity of R. helvetica.
RICKETTSIAE ISOLATED FROM OR DETECTED
IN TICKS ONLY
In addition to SFG rickettsiae that are currently recognized
as human pathogens, many other rickettsiae have been de-
tected in or isolated from ticks from several continents (Fig.
7–10). Some of these agents were isolated in culture many
years ago, and others have been detected only recently by using
molecular tools. Other rickettsial genomic fragments detected
from ticks have been deposited in GenBank but have not been
published yet. Rickettsia spp. identified in the literature or by
these searches (by using keywords searches in GenBank (using
“tick” and “rickettsia,” and also “tick” and the tick genera list)
are listed in Table 1.
NEW APPROACHES TO DIAGNOSIS
Generally, the clinical symptoms of tick-borne spotted fever
group rickettsioses begin 4 to 10 days after the bite and typi-
cally include fever, headache, muscle pain, rash, local lymph-
adenopathy, and for most of these diseases, a characteristic
inoculation eschar (tache noire) at the bite site. However,
these signs vary depending on the rickettsial species involved
VOL. 18, 2005 TICK-BORNE RICKETTSIOSES AROUND THE WORLD 739
(Table 2) (276, 358). Common nonspecific laboratory abnor-
malities in rickettsioses include mild leukopenia, anemia, and
thrombocytopenia. Hyponatremia, hypoalbuminemia, and he-
patic and renal abnormalities may also occur (276). The spe-
cific methods for the diagnosis of rickettsioses have been re-
cently reviewed (174).
Serological tests are the most frequently used and widely
available methods for diagnosis. The Weil-Felix test, the oldest
assay, is based on the detection of antibodies to various Proteus
antigens that cross-react with rickettsiae. Although it lacks
specificity and sensitivity, it continues to be used in many
developing countries and in countries with higher level of tech-
nical development (142). For example, the results of Weil-
Felix tests led F. Mahara to suspect a SFG rickettsiosis in
Japan (183). This was the first diagnostic step in the recogni-
tion of R. japonica as a case of disease in this country (183).
MIF is currently being considered as the reference method.
For RMSF, 84.6% to 100% sensitivity and 99.8 to 100% spec-
ificity have been reported, depending on the cutoff chosen (42).
For MSF, MIF sensitivity ranges from 46% (when sampling
day 5 to 9) to 100% (when sampling after day 29) (42). One of
the major limitations of serology is the cross-reactivity that
often exists among antigens of pathogens within the same
genus and occasionally in different genera (245). For example,
it was noted recently that cases of a particular rickettsial in-
fection reported among paleontologists following an expedi-
tion to Mongolia could only be considered as presumptive, as
the diagnosis was supported by an MIF assay using a single
antigen. Indeed, other SFG rickettsiae (pathogenic and of un-
known pathogenicity) are known to occur in that region (177).
To illustrate, when 16 patients with culture-positive or PCR-
documented R. conorii infection and 5 patients with SFG rick-
ettsioses contracted in Mongolia or Siberia were evaluated
solely by MIF, this assay was unable to discriminate between
several antigens tested, including R. conorii, R. rickettsii, R.
africae, R. slovaca, R. sibirica, and R. felis (a flea-borne SFG
rickettsia) (291). MIF remains the reference standard for se-
rological diagnosis of SFG rickettsioses. However, most com-
mercially available MIF assays offer a very limited selection of
antigens (e.g., R. rickettsii in the United States or R. conorii and
R. rickettsii in France). Even national reference centers may
routinely test for only a few other SFG rickettsiae (e.g., R. akari
or R. africae). In this context, it is important to remind the
practicing physician that MIF may be adequate to diagnose the
class of infection (e.g., a spotted fever rickettsiosis) but is likely
to be insufficient to definitively identify the etiologic agent
unless other, more-sophisticated serologic assays are per-
formed or blood or tissue samples can be evaluated by culture-
or PCR-based methods (see below). It is also important to
remind clinicians that collection of acute and convalescent-
phase serum specimens, separated by several weeks, in neces-
sary to confirm disease.
Cross-absorption (CA) techniques and Western blotting
(WB) can be used in reference centers to help to differentiate
rickettsial infections by antibody evaluation (Fig. 11) (174).
For African tick bite fever, the sensitivity of IFA, CA, WB, and
IFA with CA and WB have been estimated at 26%, 83%, 53%,
and 56%, respectively, when 414 patients were tested, includ-
ing 39 cases confirmed by PCR or culture, and 81 considered
positive on the basis of IFA with CA and WB (273). Both
specificity and positive predictive value were 100% for all tech-
FIG. 7. Tick-borne rickettsiae in Africa. Colored symbols indicate
pathogenic rickettsiae. White symbols indicate rickettsiae of possible
pathogenicity and rickettsiae of unknown pathogenicity.
FIG. 8. Tick-borne rickettsiae in the Americas. Colored symbols
indicate pathogenic rickettsiae. White symbols indicate rickettsiae of
possible pathogenicity and rickettsiae of unknown pathogenicity.
740PAROLA ET AL.CLIN. MICROBIOL. REV.
niques. Currently in our laboratory, when cross-reactions are
noted between several rickettsial antigens, the standard pro-
cedure comprises several steps. A rickettsial antigen is consid-
ered to represent the agent of infection when titers of IgG or
IgM antibody against this antigen are at least two serial dilu-
tions higher than titers of IgG or IgM antibody against other
rickettsial antigens. When differences in titers between several
antigens are lower than 2 dilutions, Western blot assays and, if
needed, cross-absorption studies are performed (244).
In this context, serology should be considered as an initial
but not sole method to recognize and diagnose rickettsial dis-
eases, particularly if no rickettsiae have been previously iso-
lated or detected in the considered area. Cautious interpreta-
tion of serologic assays is necessary to avoid misinterpretation
and assignment of a specific etiologic agent, particularly when
novel or “emerging” tick-borne rickettsioses are described
(245). For example, a SFG rickettsioses initially described in
Uruguay in 1990 was observed in three patients who presented
with fever, a small initial maculopapulous lesion on the scalp at
a tick bite site followed by regional lymphadenopathy. MIF
serology using R. conorii as the sole antigen was positive for all
patients, and these infections were presumptively identified as
spotted fever caused by R. conorii (73). During 1993-1994, 23
patients with a previous history of tick bite, including some
with exanthems and inoculation eschars were identified from
rural areas of Canelones County, Uruguay. These patients
were also found to have titers reactive with R. conorii when
tested by MIF; however, R. conorii was again the only antigen
used in the assay (87). Amblyomma triste, a tick commonly
found on dogs with a larval cycle on wild rodents, has been
involved in these cases, and recently, R. parkeri has been iso-
lated from this tick (347). In this context, it is possible that
some or all of these patients were infected with SFG rickettsiae
other than R. conorii, particularly as R. conorii has never been
found in the Western Hemisphere or in Amblyomma species
The need for an effective and versatile serologic assay to
identify a particular rickettsia responsible for infection cannot
be overemphasized. Although other classical and contempo-
rary methods (described below) provide a conclusive etiologic
diagnosis, these techniques may require a clinical specimen
that is not readily available when the patient is initially evalu-
ated for care (e.g., tissue or acute-phase whole blood). A serum
specimen, often collected from the patient days to weeks after
his or her recovery, is the most frequently evaluated and often
the only analyte available to laboratories that perform diag-
nostic tests for tick-borne rickettsioses. Whatever the tech-
nique used, it is important to emphasize that acute- and con-
FIG. 9. Tick-borne rickettsiae in Asia and Australia. Colored sym-
bols indicate pathogenic rickettsiae. White symbols indicate rickettsiae
of possible pathogenicity and rickettsiae of unknown pathogenicity.
FIG. 10. Tick-borne rickettsiae in Europe. Colored symbols indi-
cate pathogenic rickettsiae. White symbols indicate rickettsiae of pos-
sible pathogenicity and rickettsiae of unknown pathogenicity.
VOL. 18, 2005 TICK-BORNE RICKETTSIOSES AROUND THE WORLD741
TABLE 1. SFG rickettsiae of unknown pathogenicity isolated or detected in ticks
Rickettsia sp. or
Confirmed or potential
R. peacockii Dermacentor andersoni United States Transstadially and transovarially transmitted;
the presence of R. peacockii within ovaries
interferes with the ability of R. rickettsii to
infect the ovarian tissues and to be
transovarially transmitted to progeny
Transovarially transmitted in D. variabilis
18, 51, 215, 236,
United States 2, 3, 27, 100,
Represents a distinct ancestral group within
rickettsiae and seems to be one of the most
abundant and broadly distributed rickettsiae
infecting ticks in the United States
Invades both salivary glands and ovaries of the
10, 116, 251, 353
R. rhipicephaliUnited States,
13, 48, 89, 91,
92, 132, 262
R. monacensis Ixodes ricinus Closely related to rickettsiae previously
detected but not isolated in I. ricinus,
including “the Cadiz agent,” IRS3 and IRS4
Previously called strain ATI
Previously called “I-OI”
71, 191, 309, 323
ized, or unculti-
Strains HOT1 and
United States 139, 253
Could be “R. amblyommii”
Strains DnS14 and
Closely related to members of the R. massiliae
group together with R. rhipicephali, R.
aeschlimannii, and R. montanensis
Closely related to R. canadensis
AF45340 Closely related to R. amblyommii
Amblyomma triguttatumBarrow Island,
Ticks were collected off people working on the
aH. Owen, N. Unswarth, J. Stenos, P. Clark, S. Graves, and S. Fenwick, Abstr., 4th Int. Conf. Rickettsiae Rickettsial Dis., abstr. P-200, 2005.
742 PAROLA ET AL.CLIN. MICROBIOL. REV.
TABLE 2. Characteristics of known and potential tick-borne rickettsiae, 2005
potential tick vector(s)
Yr of first
(yr of first clinical
Yr of first
1906 Rocky Mountain spotted
The prototypical and most severe
tick-borne spotted fever rick-
ettsiosis. Case fatality ratio is
20 to 25% in untreated pa-
tients. Peak occurrence during
spring and summer. Eschars
rarely reported. Broadly dis-
tributed in the Western Hemi-
sphere and associated with
several species of tick vectors.
Rhipicephalus sanguineus1932 Mediterranean spotted fever
Disease occurs in urban (66%)
and rural (33%) settings. Rash
occurs in 97%. Cases generally
sporadic. Single eschar. Case
fatality ratio, approximately
Rhipicephalus sanguineus1974 Israeli spotted fever (1940) 1971a
Compared to Mediterranean
spotted fever, eschars are less
frequent. Mild to severe
Disease occurs in predominantly
rural settings. Cases occur
during spring and summer.
Increasing reports of cases.
Cases generally associated with
rash (100%), eschar (77%),
Unknown Siberian tick typhus (1934)1946a
Dermacentor sinicus 1974 North Asian Tick typhus
Ixodes holocyclus, Ixodes
1974 Queensland tick typhus
Disease occurs in predominantly
rural settings. Cases occur
from June to November.
Vesicular rash (100%), eschar
(65%), and lymphadenopathy
(71%). Two fatal cases
Ixodes ovatus, Dermacentor
1996 Oriental or Japanese spotted
Disease occurs in predominantly
rural settings. Agricultural ac-
tivities, bamboo cutting. April
to October. Eschar (91%) and
rash (100%). May be severe.
One fatal case reported.
1992 Astrakhan fever (1970s)1991a
Disease occurs in predominantly
rural settings. Associated with
eschar (23%), maculopapular
rash (94%), and conjunctivitis
Rickettsia africaeAmblyomma hebraeum,
1990African tick bite fever (1934) 1992a
Disease occurs in predominantly
rural settings and is associated
in international travellers
returning from safari, hunting,
camping, or adventure races.
Outbreaks and clustered cases
common (74%). Symptoms
include fever (88%), eschars
(95%) which are often
multiple (54%), maculopapular
(49%) or vesicular (50%) rash,
and lymphadenopathy (43%).
No fatal cases reported.
Continued on following page
VOL. 18, 2005 TICK-BORNE RICKETTSIOSES AROUND THE WORLD 743
potential tick vector(s)
Yr of first
(yr of first clinical
Yr of first
Rickettsia honeiAponomma hydrosauri,
1993Flinders Island spotted fever
Disease occurs in predominantly
rural settings. Peak in Decem-
ber and January. Symptoms
include rash (85%), eschar
(25%), and lymphadenopathy
Few cases described in southern
France between March and
July and South Africa.
Symptoms include eschar
(75%), rash (63%), and
1968 Tick-borne lymphadenopathy
necrosis and lymphade-
Fever and rash rare. Typical
eschar on the scalp with
Dermacentor silvarum1982 Far Eastern spotted fever
Rash, eschar, and lymphadenopa-
thy. No fatal cases reported.
1997 Unnamed (2002)2002b,d
Few cases described in patients
from Morocco and South
Africa. Symptoms include
eschar and maculopapular
Rickettsia parkeriAmblyomma maculatum,
1939Unnamed (2004) 2004a
One case reported in a patient in
the United States. Symptoms
include fever, multiple eschars,
1992Unnamed (2005) 2005a
The strain was obtained from a
blood of a patient from Sicily
in 1985, stored, and defini-
tively identified in 2005.
2003–2005 Australian spotted fever
2003–2005 Between February and June, six
confirmed cases, including one
with escar and two with a
Rhipicephalus sanguineus1950 Indian tick typhus2001b
Compared to Mediterranean
spotted fever, rash usually
purpuric. Eschar rarely found.
Mild to severe.
1967Possible Rocky Mountain spotted
fever-like disease descibed in
California and Texas.
Suspected cause of acute
cerebral vasculitis in Ohio.
1974 Unnamed (1993)1993d
Possible cause of mild spotted
fever rickettsiosis in the United
States. Rickettsiae also recently
identified in Brazilian ticks.
Continued on facing page
744 PAROLA ET AL.CLIN. MICROBIOL. REV.
valescent-phase sera be collected in any case in which
rickettsiosis is suspected.
Although rickettsial isolation in culture remains the most
definitive diagnostic method, this technique is typically per-
formed only in reference laboratories with a P3 safety level and
requires staff capable of maintaining living host cells (animal
mouse models or embryonated eggs) or cell cultures (Vero,
L929, HEL, XTC-2, or MRC5 cells). The centrifugation shell-
vial technique using HEL fibroblasts is an effective application
of this method (348). Isolation of rickettsiae can be performed
routinely in this type of laboratory by using buffy coat prepa-
rations of heparinized or EDTA-anticoagulated whole blood,
skin biopsy specimens, or arthropods. Although this technique
is versatile, approximately one-third of rickettsial isolates may
be lost when passaged to new cells.
Histochemical and Immunohistochemical Methods
Rickettsiae can been detected occasionally in tissue speci-
mens by various histochemical stains, including Giemsa or
Gimenez stains (174); however, immunohistochemical meth-
ods provide superior visualization of SFG rickettsiae when
applied to formalin-fixed, paraffin-embedded tissue specimens
obtained at autopsy or cutaneous biopsy samples (particularly
eschars) (Fig. 12) (82, 228, 230, 300). Similar caution must be
used when interpreting immunohistochemical stains, as most
available assays are SFG specific but not species specific.
PCR and sequencing methods are now used as sensitive and
rapid tools to detect and identify rickettsiae in blood and skin
biopsy specimens throughout the world where these facilities
are available. Primers amplifying sequences of several genes,
including ompA, ompB, gltA, and gene D, have been used
(Table 3) (42, 104, 111, 295, 310). Ticks may also be used as
epidemiological tools to detect the presence of a pathogen in a
specific area, providing insights to and discoveries of rickett-
siae of unknown pathogenicity (245). Recently, we proposed a
PCR assay with increased sensitivity, named “suicide PCR,”
that had been first developed to detect ancient DNA (269).
Thereafter, we have been starting to use it in the diagnosis of
FIG. 11. Western blot assay of an acute MIF-positive serum show-
ing reactivity with the 135- and 115-kDa specific protein antigens of
Rickettsia conorii and Rickettsia africae, respectively. Columns 1, 3, and
5, R. conorii antigens. Columns 2, 4, and 6, R. africae antigens. Columns
1 and 2, untreated sera. Columns 3 and 4, sera absorbed with R. conorii
antigens. Columns 5 and 6, sera absorbed with R. africae antigens.
MW, molecular weight marker. The interpretation is that when ab-
sorption is performed with R. africae, it results in the disappearance of
homologous and heterologous antibodies, but when it is performed
with R. conorii, only homologous antibodies disappeared. This indi-
cates that antibodies are specific for R. africae. Molecular masses are
indicated on the left.
potential tick vector(s)
Yr of first
(yr of first clinical
Yr of first
Rickettsia texianaA. americanum1943 Bullis fever (1942)1943c
Possible agent of an epidemic
which occurred among army
personnel at Camp Bullis,
Texas during 1942–1943.
Ixodes ricinus, Ixodes
Although implicated in
sarcoidosis, the validity of
these associations has been
debated or not accepted by
rickettsiologists. Few cases
documented by serology only
in France and in Thailand.
Rash and eschar seldom occur.
aDocumentation by culture.
bDocumentation by molecular tools.
cDocumentation by animal or human inoculation.
dDocumentation by serology.
VOL. 18, 2005TICK-BORNE RICKETTSIOSES AROUND THE WORLD745
SFG rickettsioses to detect DNA from blood samples, as con-
ventional PCR generally has poor sensitivity for detecting SFG
rickettsiae when applied to blood specimens. Suicide PCR is a
nested PCR using single-use primers targeting a gene never
amplified previously in the laboratory (90, 269). This proce-
dure avoids vertical contamination by amplicons from previous
assays, one of the limitations of extensive use of PCR. There is
no positive control. Because the essential role of positive con-
trols is to validate negative results, the absence of these con-
trols does not impair the interpretation of positive results,
which are validated by appropriate negative controls. All pos-
itive PCR products are sequenced to identify the causative
agent. This technique has been successful with EDTA-blood,
serum, and lymph node specimens in the diagnosis of African
tick bite fever due to R. africae and infection due to R. slovaca
(273, 275). This technique was also applied in our laboratory to
DNA from 103 skin biopsy specimens from patients with con-
firmed rickettsiosis, 109 skin biopsies from patients who pos-
sibly had a rickettsiosis, and from 50 skin biopsy specimens
with patients with no rickettsial diseases. Specificity was 100%.
Sensitivity (68%) was 2.2 times higher than culture and 1.5
times higher than regular PCR (109). This technique requires
validation studies and carefully conducted controls, regardless
of sequencing results, that are usually made in reference lab-
oratories. Other teams have successfully applied nested PCR
to serum and tissue specimens from patients suffering from
severe MSF (175); however, standard nested PCR assays may
be highly subject to contamination and false-positive results.
Early empirical antibiotic therapy should be prescribed in
any suspected tick-transmitted rickettsiosis, before confirma-
tion of the diagnosis (Table 4). More than 50 years after the
introduction of tetracyclines, doxycycline (200 mg per day)
remains the treatment of choice for tick-transmitted rickettsi-
oses (276). Although tetracyclines are contraindicated for gen-
eral use in children less than 9 years of age, doxycycline re-
mains the treatment of choice for all patients, including young
children, with RMSF (137, 194, 265). This recommendation
should be expanded to include other SFG tick-borne rickett-
sioses, several of which may be potentially life-threatening. In
general, the risk of dental staining by doxycycline is negligible
when a single, relatively short (e.g., 5- to 10-day) course of
therapy is administered.
In patients with severe hypersensitivity to tetracyclines, 50 to
75 mg/kg of body weight/day of chloramphenicol can be con-
sidered as an alternate therapy, but its use is limited by side
effects. In general, use of this drug as therapy for rickettsioses
should be considered as empirical treatment of severe cases
only if it is the sole available drug, such as in developing
countries. Josamycin (50 mg/kg/day) has also been used to
treat some patients with certain SFG rickettsioses (276). In
pregnant women with MSF, josamycin can be used at a dose of
3 g per day for 7 days (276). Newer macrolides, such as azithro-
mycin and clarithromycin (63, 308), are also of interest. In a
recent open-label controlled trial, these two drugs were com-
pared in the treatment of children with MSF in Italy. They
were equally tolerated, and no major side effects were ob-
served. All patients recovered, as fever disappeared in less than
7 days in each case. No statistical difference between the times
to defervescence of the drugs was found (63). Azithromycin
seems to be of particular interest, as it is administered once a
day and presents a shorter duration of therapy (3 days, com-
pared to 7 days with clarithromycin). Some fluoroquinolones
may have efficacy against spotted fever rickettsiae, although
these data are largely anecdotal and require careful clinical
evaluation (227, 290, 298, 299).
Many classes of broad-spectrum antibiotics, including peni-
cillins, cephalosporins, and aminoglycosides, are ineffective as
therapies for rickettsial diseases. In vivo animal studies, anec-
dotal clinical experience, and limited evidence from a small
clinical trials suggest that sulfa-containing antimicrobials not
only are ineffective but may actually exacerbate spotted fever
rickettsioses, including RMSF and MSF (131, 133, 299a, 336).
The exact duration of appropriate antibiotic therapy for
SFG rickettsioses is generally related more to clinical response
than a precise number of days; however, for most of these
infections, recommended therapy should continue for at least
3 days after the patient’s fever has abated. A single dose of 200
mg of doxycycline has been shown to be sufficient for MSF
(276), although for patients with severe forms, such as malig-
nant MSF, doxycycline should be administered intravenously
up to 24 h after apyrexia. The use of corticosteroids in severe
forms is controversial (160).
In 1940, R. R. Parker, commenting on the disease-causing
potential of an Amblyomma-associated rickettsia he had iden-
tified a year earlier, wrote, “Final decision as to whether macu-
latum infection is or is not a new disease entity must await
further research” (R. R. Parker, Proc. 3rd Int. Congr. Micro-
biol., p. 390–391, 1940). In the case of R. parkeri, the wait was
65 years. In fact, many of the rickettsiae we now identify as
FIG. 12. Immunohistochemical detection of Rickettsia sibirica
subsp. mongolotimonae (arrows, rickettsiae staining red) in a skin bi-
opsy specimen of an eschar of the patient presented in Fig. 5. Note the
abundant inflammatory infiltrate with necrotic features and vascular
injury in the dermis (polyclonal rabbit anti-R. sibirica subsp. mongoli-
timonae antibody used at a dilution of 1/2,000 with hemalin counter-
stain; original magnification, ?400).
746 PAROLA ET AL.CLIN. MICROBIOL. REV.
human pathogens were first identified in ticks several years or
even decades before a conclusive association with human dis-
ease was demonstrated, including 7 of the 11 species or sub-
species of tick-borne SFG rickettsiae confirmed as pathogens
Various circumstances have contributed to the expansion of
distinct tick-borne rickettsioses recognized during the last de-
cades of the 20th century. Heightened awareness of rickettsial
illnesses, the careful obtaining of histories, and thorough phys-
ical and laboratory examinations by primary physicians have
been crucial factors leading to the discovery of several recently
described tick-borne rickettsial diseases, including Flinders Is-
land spotted fever, Japanese spotted fever, and Astrakhan fe-
ver. Contemporary techniques in molecular biology have
greatly facilitated the description of novel rickettsial agents
and provided new insights into the epidemiology of emerging
rickettsioses on several continents. These include infections
caused by R. sibirica subsp. mongolitimonae, R. slovaca, R.
aeschlimannii, and R. heilongjiangensis. Classical and improved
methods in cell culture methods, coupled with molecular as-
says, have provided critical confirmatory information to in-
criminate various species of Rickettsia, including R. parkeri, as
pathogens of humans. Finally, an increase in the number of
people traveling to foreign countries to participate in recre-
ational activities, including hiking, camping, and hunting, in
nondeveloped or rural areas can result in increased contact
with ticks and tick-borne pathogens endemic to that region.
Increasing reports of imported African tick bite fever among
travelers returning to Europe and the United States from
southern Africa is illustrative of this process.
The recent history of rickettsial diseases is similar in many
ways to that of arboviral diseases, particularly those caused by
flaviviruses. Many newly recognized flaviviral diseases have
been identified only during the last several decades, and vari-
ous other flaviviruses have been isolated or detected from
arthropod hosts and await linkage to human disease. Advances
TABLE 3. Selected DNA primers used for the detection of tick-borne rickettsiae in clinical patient samples or ticks
Primer, sequenceMethodSample Reference(s)
Citrate synthase gene (gltA
RpCS.877p (forward), GGGGACCTGCTCACGGCGGStandard PCRSkin295
RpCS.1258n (reverse), ATTGCAAAAAGTACAGTGAACATicks
Outer membrane protein
A gene ompA (all
species except R.
helvetica, R. australis, R.
bellii, and R. canadensis)
Rr190.70p (forward), ATGGCGAATATTTCTCCAAAA Standard PCRSkin111
Rr190.602n (reverse), AGTGCAGCATTCGCTCCCCCT
Rr190.70p (forward), ATGGCGAATATTTCTCCAAAA
Rr190.70ln (reverse), GTTCCGTTAATGGCAGCATCT
AF1F (forward), CACTCGGTGTTGCTGCA
AF1R (reverse), ATTAGTGCAGCATTCGCTC
AF3F (forward), GGTGGTGGTAACGTAATC
AF3R (reverse), CGTCAGTTATTGTAACGGC
AF2F (forward), GCTGCAGGAGCATTTAGTG
AF2R (reverse), TATCGGCAGGAGCATCAA
AF4F (forward), GGAACAGTTGCAGAAATCAA
AF4R (reverse), CTGCTACATTACTCCCAATA
Outer membrane protein
B gene ompB (all
species except R.
helvetica, R. bellii, and
BG1-21 (forward), GGCAATTAATATCGCTGACGGStandard PCR Skin294
BG2-20 (reverse), GCATCTGCACTAGCACTTTCTicks
Gene D (most rickettsiae)D1F (forward), ATGAGTAAAGACGGTAACCT
D928R (reverse), AAGCTATTGCGTCATCTCCG
Standard PCRSkin 104, 310
gene (all spotted fever
R17122 (forward), CAGAGTGCTATGGAACAAACAAGG Nested PCRSkin 193, 338
R17500 (reverse), CTTGCCATTGCCCATCAGGTTG
TZ15 (forward), TTCTCAATTCGGTAAGGGC
TZ16 (reverse), ATATTGACCAGTGCTATTTC
aNote that primers used for this nested PCR are used only once in the same lab, with no positive control. Other pairs of primers may be designed each time a new
screening is done. They can be selected for other rickettsial genes. These primers are given as examples.
VOL. 18, 2005TICK-BORNE RICKETTSIOSES AROUND THE WORLD747
in viral molecular genetics, phylogenetic studies, genome se-
quencing, computational techniques have recently provided
new tools starting to give some answers on pathogenicity, in-
teractions with vectors, and host and/or vector association
specificity and to resolve taxonomy problems (360).
Efforts to characterize distinct tick-borne rickettsioses are in
progress on many continents for which a single pathogenic
rickettsial species has been previously described, including
Central and South America and Asia. Renewed interest and
collaborative endeavors with new and established investigators
in the tropics, combined with powerful diagnostic methods, will
likely herald the identification of several newly recognized
rickettsial pathogens in these regions and contribute to an
exciting period of discovery in the science of rickettsiology (37,
138, 164, 167, 170, 240, 286, 347). In some Asian countries,
although no SFG rickettsiae have been to date detected from
ticks or people, serosurveys or serology testing of patients with
nonspecified fevers indicates the prevalence of spotted fever
group rickettsioses. For example, in the Central Province of Sri
Lanka, 10 out of 118 clinically investigated patients were re-
cently shown to have IgM antibodies against SFG rickettsiae,
suggestive of an acute SF rickettsiosis (164).
In 2002, rickettsiologist D. H. Walker noted that “old, un-
resolved problems do not receive the attention that new, in-
teresting issues do. For instance, compare the efforts placed on
researching West Nile virus or hantavirus pulmonary syndrome
with the application of medical science to RMSF. . . There is
room for more scientists in rickettsiology, and tools of molec-
ular biology and cell biology allow more to be accomplished”
(350). Myriad applied and basic research questions remain in
TABLE 4. Antibiotic treatments for MSF and RMSF
RickettsiosisPatient cohort Selected antibiotic regimensg
quality of evidenceh
Doxycycline, two oral 200-mg doses separated by a 12-h
Doxycycline, 200 mg single dose or 100 mg twice a day for 2 to
Josamycin, 2 oral doses of 1 g every 8 h for 5 daysc
Ciprofloxacin, 750 mg every 12 h for 7 days
A III81, 298
Doxycycline, 2.2 mg/kg every 12 h for children weighing <99 lb
(45 kg) or adult dosage if >100 lb, for 5 to 10 daysa,b
Clarythromycin, 15/mg/kg/day in two divided doses for 7 days
Azythromicin, 10 mg/kg/day in one dose for 3 days
Josamycin, 50 mg/kg every 12 h for 5 days
A III137, 265
Josamycin, 50 mg/kg every 12 h for 5 daysb,c
Doxycycline, 100 mg every 12 h for 5 to 10 daysa
Doxycycline, 2.2 mg/kg every 12 h for children weighing <99 lb
(45 kg) or adult dosage if >100 lb, for 5 to 10 daysa,d
Chloramphenicol, 12.5 to 25 mg/kg every 6 h for 5 to 10 dayse
A III137, 265
A III 356
Doxycycline, 100 mg every 12 h for 5 to 10 daysf
aOral or intravenous. Intravenous formulation was generally used for patients with vomiting or severe disease. Longer courses of doxycycline treatment may be
warranted for patients with severe disease.
bChloramphenicol could be an alternative if it is the sole available drug for empirical treatment of severe cases, as may be the situation in developing countries (B
cJosamycin is not available in the United States. Based on the results in children and in vitro studies, azythromycin or clarythromycin could represent alternatives
dTetracycline antibiotics are generally contraindicated in children under 8 years because of the dose-dependent risk of staining of permanent teeth; however, these
antibiotics are superior therapy for RMSF, and doxycycline is the drug of choice for therapy of this life-threatening disease in patients of all ages. Shorter treatment
courses may be warranted in some pediatric settings; however, therapy should be continued for at least 48 hours following lysis of fever and evidence of clinical
eAlternate therapy reserved for those patients for whom there is an absolute contraindication for receiving doxycycline. Oral formulation (palmitate) is not available
in the United States. Optimal intravenous dosage is determined by measurement of serum concentrations to achieve peak level particularly in newborns, children ?2
years of age, pregnant women, patients with hepatic disease, or patients receiving therapy for ?5 days. Gray baby syndrome (abdominal distention, pallor, cyanosis,
and vasomotor collapse) has been reported when chloramphenicol is given to neonates. Although it has not been reported in neonates after maternal administration
of chloramphenicol, it is theoretically possible since drug levels reach 30 to 80% of the maternal serum level. Thus, some authorities advise against using
chloramphenicol in women at or near term. New macrolide drugs have not been adequately evaluated as alternate therapies for RMSF.
fTetracycline antibiotics are generally contraindicated during pregnancy because of the risks associated with interference in the development of teeth and long bones
in the fetus. However, because RMSF is a life-threatening illness, and because of the demonstrated superiority of doxycycline as therapy for this infection, this drug
represents the antibiotic of choice.
gCurrent recommended therapies are in bold.
hStrength of recommendation and quality of evidence is used as reported in (reference 157). The author used the letter A to stand for good evidence, B for moderate
evidence, and C for limited evidence to support a recommendation for use. Also by this author, I stood for evidence from ?1 properly randomized controlled trial;
II for evidence from ?1 well-designed clinical trial without randomization or from cohort or case-controlled analytic studies; III for evidence from opinions of respected
authorities, based on clinical experience, descriptive studies, or report of expert committees; and IV for evidence based on in vitro studies or anecdotal case reports
of treatment success in patients with confirmed disease.
748 PAROLA ET AL.CLIN. MICROBIOL. REV.
the study of spotted fever rickettsiae and the diseases that
these agents cause. A sampling of unresolved issues include the
need for reliable, early diagnostic tests; development of sero-
logical assays that discriminate among various SFG rickettsial
infections and provide an agent-specific diagnosis; better char-
acterization of the natural histories of newly recognized SFG
rickettsial pathogens; elucidating the pathogenic mechanisms
(including rickettsial reactivation in the tick, the role and effect
of tick saliva on the early infection, and the identification of
rickettsial virulence genes); and prospective active surveillance
studies that better the magnitude and distribution of various
spotted fever rickettsioses.
There exist many unique tick-associated rickettsiae for
which a role in human disease has yet to be determined. Sev-
eral of these rickettsiae satisfy the first component necessary
for a potential tick-borne pathogen, i.e., they reside in a tick
species with a natural proclivity to bite humans. The combined
efforts of investigators around the world have reduced the
concept of “one continent, one pathogenic tick-borne rickett-
sia” to an anachronism, and subsequent investigations will un-
doubtedly lead to the discovery of new tick-borne rickettsial
diseases in the future.
We are grateful to Pierre-Edouard Fournier for his help in making
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