Rickettsia spp.

, rickettsial-like diseases and

ticks of medical importance: A systematic
review of the literature.
Julian F. Porras-Villamil1, Mario J. Olivera2, Olga P. Fuya-Oviedo3.

Abstract
Background: Several Rickettsia species have been identified that affect humans. The aim
of this study was to conduct a systematic review of published studies on rickettsial 1. Facultad de Medicina, Universidad
diseases and their impact on the medical field to synthesize the fragmented knowledge Nacional de Colombia, Bogotá,
and to inform the current state of this problem. DC, Colombia. CC: 1.019.074.320,
jfporrasv@unal.edu.co,
Methods: A systematic literature review was conducted in Medline, Embase, SciELO and https://orcid.org/0000-0003-
Google Scholar. Articles published in Portuguese, English and Spanish were chosen. 1861-4601.
Eligible studies were case reports and case series that reported outcomes caused by 2. Grupo de Parasitología, Instituto
rickettsial diseases in humans. Patient-level and study-level information were extracted. Nacional de Salud, Bogotá, DC,
Colombia. CC:1.032.380.726,
Results: The literature search yielded 2264 studies; sixty-seven case reports were moliverajr@gmail.com,
included in the systematic review, reporting a total of 99 cases. Of these, 52 patients https://orcid.org/0000-0002-
6885-6353.
were men (55.3%), and the median age was 6.4±23.4 years. The most frequently
3. Grupo de Entomología, Instituto
reported complications were fever, myalgia and skin rashes. The deaths of nineteen Nacional de Salud, Bogotá, DC,
patients were documented (20.8%). Rickettsia species included Rickettsia rickettsii, R. Colombia. CC: 52.099.528,
sibirica mongolitimonae, and R. conorii. https://orcid.org/0000-0003-
3762-0003.
Conclusion:Rickettsial disease, a potentially fatal but treatable disease, should be
considered in all patients presenting with acute febrile illness in endemic areas, in which Corresponding author
it is necessary to quickly diagnose and treat cases adequately to avoid death. Name: Mario Javier Olivera
e-Mail: moliverajr@gmail.com
Keywords: …… Address: Avenida calle 26 No. 51-20
- Zona 6 CAN. Bogotá, D.C.
Institution: National Health Institute

INTRODUCTION (western Montana), described in 1899 in the Medical

Although the first description of Rickettsia was made in
1905 by Doctor Howard Ricketts (1), to whom we owe
the bases and most important principles of rickettsiology
(2-5), the first epidemiological study was performed by
Wilson and Chowning in 1904 in Bitter-Root Valley
Sentinel (6), with the first known case in 1873 (6).
Rickettsias are diverse and can infect a wide array of
organisms (7). They include genera such as Rickettsia,
Orientia and Coxiella (8, 9). The genus Rickettsia is divided
into four groups: the spotted fever group (SFG), the
transition group, the typhus group and the ancestral
group (10). Rickettsias are transmitted by arthropods,

7
and ticks are one of the most important vectors (11, 12).
The distribution and density of the vector determine the
geography and incidence of cases (13).
Clinical symptoms will depend on the species and organ
involvement, but manifestations are unspecific and can
have severe complications (14). Due to the unspecific
manifestations, clinical diagnosis is difficult and requires
serological tests (15). Even so, a good clinical history and
physical exam (i.e., eschars or inoculation sites) as well as
awareness of the epidemiology of the bacteria and its
vectors (16, 17) are crucial. For diagnostic confirmation,
sera from the acute and convalescent phase are needed,
so treatment must be initiated with clinical suspicion
alone. The treatment of choice is doxycycline (16). The
pathogenesis is secondary to the immune response,
which is mediated by T lymphocytes (18).
This review attempts to provide an update to a review
published in 2013 (19). Additionally, we provide a
comment on other rickettsia-like diseases as well as the
importance of ticks in the medical field.
METHODS
Search Strategy
Systematic literature searches were conducted to
identify all published cases or series of patients with
rickettsial diseases. Searches were restricted to articles
published between January 2013 and November 2018. All
searches were conducted in Medline, Embase, Scopus,
SciELO, LILACS and Google Scholar. A secondary search
was carried out by consulting the reference lists of
retrieved studies. The search strategy used was
“’Rickettsia infections’ OR ‘Rickettsia'” AND
“’Outbreaks’ OR ‘Case Reports’ OR ‘Case Series’”. Filters
were applied for publication type (case reports and case
series) and to select studies including human beings only.
The language of the articles was restricted to articles
written in English, Spanish or Portuguese.
Study selection criteria and data collection
The studies were eligible for inclusion if they reported
cases or series of cases of rickettsial diseases and
included at least one patient. We defined studies as a
case report if they described a single case and as a series
of cases if they described more than one patient. Studies
that were not published in English, Spanish or
8 (Insert Vancouver format in this area)
Portuguese were excluded. Two reviewers
independently screened the search results for inclusion
and then extracted all data using a standardized data
extraction form. The discrepancies were resolved
through discussion until consensus was reached.
Information was extracted about the first author,
country, year of publication, genus and species, number
of patients, age, sex, clinical manifestations and the
outcome of death or complete remission.
Data analysis
The data extracted were summarized as the means with
standard deviations for quantitative variables and as
numbers and percentages for qualitative variables, as
appropriate. Comparisons between groups were
performed using the chi-squared test or Fisher’s exact
test, depending on the case. All analyses were
performed using the statistical package Stata, version
13.0 (Stata Corp LP, College Station, TX, USA).
Results
The literature search identified 2264 records. After
removing duplicates and after screening titles and
abstracts, 364 publications met the inclusion criteria and
were eligible. After full-text review and a manual review
of references, 67 publications were included. A PRISMA
flow diagram of study selection is presented in Figure 1.
RESULTS
Of the 67 included studies, all were case reports and
reported a total of 99 cases. The 99 cases included in this
review had an average age of 36.4±23.4 years and
affected 52 men (55.3%) (Supplement 1). The
characteristics of the case reports included are
presented in Supplement 2 through 6. The most
frequently reported clinical manifestations were fever,
myalgia and skin rashes. Other signs and symptoms are
presented in Supplement 7. The deaths of nineteen
patients were documented (20.8%). The number of
reports that included the identification of ticks was 7
(Supplement 8). Most of the reports were published
from the United States of America, followed by Brazil and
Mexico (Supplement 9).
Rickettsia diseases and ticks of medical
importance: A systematic review
RICKETTSIOSIS AROUND THE WORLD
Latin America
In this region of the world, one of the countries with
more published cases due to Rickettsia rickettsii is
Mexico. The cases are generally in the north, although
cases in southern Mexico have been described (20). In
Sonora, cases and fatalities were reported in 2017 (21)
(including pregnant women (22) and children (23)).
Regarding interesting cases, one was apparently
controlled with homeopathic drugs (24). Others include
a case concurrent with appendiceal ectasia (25) and a
coinfection with dengue (26). Rickettsiosis is an
important cause of death and complications (27, 28).
In Panamá, the first case from a wild area was reported
in 2013 (29) as well as two new cases in May 2018 (30).
In Colombia, in a study performed in acute and
convalescent sera that were negative for malaria, it was
found that approximately 3% of them were positive for
rickettsiosis (31).
In a study performed in Perú, 2% of the enrolled patients
had seroconversion to Rickettsia spp. (32).
Brazil is also an important publisher of case reports and
studies. The first report of a case of Brazilian spotted
fever was published in the year 2014 (33). A third patient
with Rickettsia sp. Atlantic forest strain was reported
(34), which has been found in Amblyomma ovale and A.
areolatum (35). In an epidemiological study (carried out
between 2007 and 2015), 1,245 cases with 411 deaths
were confirmed (36), which, alongside other studies
(37), confirms the epidemiological importance of this
disease.
Cases of Rickettsia parkeri have been confirmed in
Argentina (38, 39) and Brazil (33). Autochthonous cases
in which this bacterium has also been confirmed have
been reported in Uruguay (40).
In Argentina, a fatal case by a rickettsia for which the
species could not be determined due to the extremely
fast evolution of the case was reported (41, 42).
Regarding travel medicine, in Brazil, for instance, there
have been previous reports of imported rickettsia, such
as the case from Portugal caused by R. conorii in 2012
(43), and the first report of R. africae from a Brazilian
traveler returning from Africa in 2018 (44).
Julian F. Porras-Villamil, Mario J. Olivera, Olga P. Fuya-Oviedo.
In the Caribbean region, even though other types of
rickettsia such as Rickettsia africae (45) have been
reported, no case of Rickettsia rickettsii has been
reported. There is evidence of other rickettsia (Rickettsia
amblyommii, Cuba)(46).
Asia
In the case of Asia, rickettsial infections are widespread
and occur in many different countries, including South
Korea, India, China, Japan and Sri Lanka.
In India, new cases have been reported since the last
worldwide update, producing a wide array of signs and
symptoms, including macular retinitis (47) purpura
fulminans (48) and multiorgan dysfunction (49), as well
as typical presentations (50).
In Japan, cases of Japanese spotted fever caused by R.
japonica have been reported since 1984 (51). The reports
have been relatively continuous (52), with one of the
most recent in 2014 (53). The youngest case was a 28-
day-old patient (54). Familial clusters have also been
reported (55).
In South Korea, the first isolation of R. monacensis from a
patient was made in the year 2017 (56).
In Israel, a case of purpura fulminans, previously reported
to be secondary to infections by R. rickettsii and R. indica,
has also been reported secondary to R. conorii (57). A
concomitant infection of typhoid fever (Salmonella typhi)
and Rickettsia sp. (SFG) in an Indian migrant was also
reported (58).
In Sri Lanka, a case with widespread subcutaneous
necrosis secondary to R. conorii (59) was reported.
Additionally, a case of purpura fulminans secondary to
Rickettsia conorii has been published (60).
In China, cases caused by R. sibirica BJ90 have been
encountered (61).
Other important rickettsial illnesses, not from the
spotted fever group, have been encountered in
Bangladesh (62).
Africa
On this continent, there are two important rickettsia
species whose distribution is separated by the Sahara
desert: along the Mediterranean, most cases are caused
by Rickettsia conorii (63); on the other hand, in sub-
Saharan Africa, cases are caused by R. africae (64). The
infection can cause complications such as myocarditis, as
exemplified by a case published in Tunisia (65).
Europe
9
As in northern Africa, one of the most important species
causing tick-borne rickettsiosis in Europe is R. conorii,
although its clinical manifestations vary, and it can have
serious consequences. For example, in Portugal, a case
of rickettsial meningitis was reported (risk factor: squirrel
pet) (66). Other cases report multiorgan organ failure
(67). Uncommon routes of transmission include the
conjunctiva (68).
In France, cases in the infant population have been
reported (69). Another infection that has been found is
R. sibirica mongolitimonae (70), which can be transmitted
by Rhipicephalus ticks, for example, Rh. pusillus (71).
Another rising condition, caused by R. slovaca, known as
tick-borne lymphadenitis (TIBOLA), was reported (72);
this condition was also reported in Spain (73). Other
conditions caused by this rickettsia that were not found
in this review are Dermacentor-borne necrosis-erythema-
lymphadenopathy (DEBONEL) (73, 74). Rickettsia slovaca
can be transmitted by Dermacentor marginatus (73).
In Greece, Rickettsia slovaca (75); R.
aeschlimannii (76), which can be transmitted by
Rhipicephalus turanicus (77); and other rickettsia, such as
R. conorii, R. rhipicephalus, and R. sibirica
mongolitimonae, have been reported (78). Additionally,
imported cases, such as R. massiliae (79), are increasing
in importance.
Regarding travel medicine, which requires a high
level of expertise (80), a case secondary to R. conorii was
reported in Belgium (81). Although generally a mild
disease, it can cause respiratory distress syndrome and
hemodynamic instability, as evidenced by a case
reported in Croatia (82), which reported its first fatal case
in the year 2000 (83). Other clinical manifestations of this
infection can be uveitis (84) and rhabdomyolysis that can
lead to renal failure (85). Even so, the most frequent
rickettsial infection is caused by Rickettsia africae. This
infection has been reported in as many as 5% of the
travelers who return from such areas, and such cases
have been reported from the United Kingdom, Belgium
(86), Sweden, Netherlands, Spain, Poland and Slovenia
in patients who returned from South Africa (87-92),
Uganda (93) and Zambia (87); although doxycycline is the
antibiotic of choice, rifampin can be a viable alternative
(94). Another pathogen that can be of importance for
travel medicine could be Rickettsia slovaca (United
Kingdom) (74).
Additionally, the first case from Central Africa
(Cameroon), caused by R. sibirica mongolitimonae, was
10
reported in 2017 in France (95); other previous cases
were reported in South Africa and southern Europe (95).
These reports mean that testing travelers, when there is
reason to suspect rickettsiosis, is important. In Spain, an
imported case of R. parkeri was reported from a traveler
returning from Uruguay (96). Additionally, a patient
coinfected with malaria was reported in the Czech
Republic after he returned from Africa (97). In Belgium,
three cases returning from Morocco caused by R. conorii
were reported in 2016 (98).
Therefore, awareness is of crucial importance, and
physicians must be aware that pathogens other than
endemic ones must be suspected. In Greece, for
example, although only R. conorii and R. typhi are
endemic, R. felis, R. mongolitimonae, and R. slovaca are
also routinely tested. A case of infection by R. slovaca was
described and found because of this screening (99).
Ticks can also be transported alongside the host; for
example, a female patient returned to the United
Kingdom with a tick that could cause tick paralysis—
Ixodes holocyclus (100)
Oceania
International travel presents new challenges regarding
the spread of infectious diseases, especially those
transmitted by vectors. One such event was reported in
Australia in a traveler returning from South Africa (101).
North America
In North America, Rickettsia rickettsii is an important tick-
borne pathogen. Rickettsiosis due to R. rickettsii is
known as a spotted fever due to the presence of
exanthem, although spotless cases have been reported
(102). Atypical and severe manifestations include
polyarthritis (case reported in Oklahoma) (103) and
encephalitis (reported in Kansas) (104). Coinfections are
rare but can be severe and even fatal (105). Children are
at risk of acquiring tick-borne diseases, exemplified by
cases reported in North Carolina (106), Texas (107) and
California (108). Finally, R. parkeri has been identified by
eschar biopsy in Virginia (109). A truly uncommon
complication is transverse myelitis, reported in Illinois
(110).
Regarding travel medicine, cases of African tick bite fever
have also been reported. Cases were reported in
travelers returning from Swaziland (111) and South Africa
(94). Retinitis (112) and uveitis (113) have been reported
in travelers returning from Africa (Uganda and Rwanda)
and India, respectively.
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Rickettsia diseases and ticks of medical
importance: A systematic review
OTHER IMPORTANT RICKETTSIAL-LIKE FEBRILE
ILLNESSES
Genus Anaplasma
The genus Anaplasma, belonging to the
Anaplasmataceae family, is classified, as well as
Rickettsia, as an α-proteobacteria (9, 114). They are
pleomorphic and are found in cytoplasmic inclusion
bodies called morulae (9, 114). This genus includes four
species: three (Anaplasma marginale, A. centrale and A.
ovis) that infect erythrocytes and another (A.
phagocytophilum) that infects granulocytes (115). Of
these species, A. centrale, which is considered to be
limited to Mediterranean countries, is less pathogenic
(116). Anaplasma infects mostly animals, but several
cases in the human population have been reported (117).
This genus is widespread in Latin America
(Supplement 10).
Genus Ehrlichia
Although this bacteria is recognized as a
pathogen of veterinary importance (118), it can also
produce diseases in humans. Two examples are E. ewingii
and E. chaffeensis, which can cause human ehrlichiosis
(119, 120). This genus tends to parasitize circulating
monocytes in infected mammals (except E. ruminantium,
which parasitizes endothelial cells and can produce
encephalitis) (115, 121). Although similar to Anaplasma,
Ehrlichia shows morphological differences (122) and
infects different host cells (Anaplasma infects
granulocytes and Ehrlichia infects monocytes) (118). The
laboratory abnormalities found in patients are similar to
those of other rickettsias (121).
Ehrlichiosis was reported for the first time in
1986; since then, more than 2000 cases have been
reported in the United States alone (123). The main cycle
involves a reservoir of infected white-tailed deer
(Odocoileus virginianus) and the tick vector Amblyomma
americanum. Other vectors include Ixodes pacificus (124),
Ixodes ricinus, Haemaphysalis yeni (125), Amblyomma
testudinarium, A. maculatum and Dermacentor variabilis
(117, 125).
Human monocytic ehrlichiosis can produce a
severe illness, especially in immune-compromised
patients (126). The fatality rate is between 2% and 8%
(117). The clinical manifestations include bleeding and
adult respiratory distress syndrome (127). Symptoms
include fever, headaches, myalgia and arthralgia (123),
Julian F. Porras-Villamil, Mario J. Olivera, Olga P. Fuya-Oviedo.
and rash is present in a low percentage of cases (10%)
(128). Gastrointestinal symptoms are very rare (118).
Genus Neorickettsia
This proteobacteria belongs to the
Anaplasmataceae family. It is one of the only four genera
that comprise this family (along with Anaplasma sp.,
Ehrlichia sp. and Wolbachia sp.) (9). It was discovered in
1950 (129). Diseases caused by this genus can be severe
both in humans and animals (130).
Sennetsu neorickettsiosis is caused by
Neorickettsia sennetsu and resembles infectious
mononucleosis (131, 132); its clinical manifestations are
fever, generalized lymphadenopathy and
hepatosplenomegaly. Its incubation period was found to
be 14 days (133). Epidemiological studies have suggested
that the source of infection comes from eating raw fish
(133). In cell culture, it is resistant to penicillin,
erythromycin, and others, but is sensitive to doxycycline,
ciprofloxacin and rifampicin (134).
As for the host cells that this genus infects, it
changes depending on the species of Neorickettsia: N.
risticii (monocytes, macrophages, enterocytes and mast
cells), N. sennetsu and N. helminthoeca (monocytes and
macrophages) (135).
Genus Neoehrlichia
The first description of this genus occurred in
2004 (136). It is able to infect humans, but little is known
about its pathogenicity (137, 138). In this regard,
Candidatus Neoehrlichia mikurensis has been reported to
cause disease in animals and humans (136). It was first
isolated from wild rats and Ixodes ovatus in Japan (137).
It can be differentiated by molecular analysis (i.e., 16S
rDNA) (137).
Other isolates include Candidatus Ehrlichia
walkerii (Italy) (139), Candidatus Neoehrlichia lotoris
(USA) (140) and a Rattus strain in China (141). It has been
reported in France (142), Germany (143), and other parts
of Europe (136, 144-146). Candidatus Neoehrlichia
mikurensis can cause severe disease in immune-
compromised individuals (144). Reported signs and
symptoms include anemia, hyponatremia and fever
(145). Infection responds to doxycycline. Incriminated
vectors include I. ricinus and I. persulcatus (147);
Dermacentor reticulatus is another candidate (148).
Knowledge about this disease is lacking (147).
11
Importance of Ticks and Ticks found on humans
Ticks are obligate hematophagous parasites of
all land vertebrates (149-153), and they are the second
vector of importance in human public health (154, 155).
They are divided into three main families: Argasidae (soft
ticks), Ixodidae (hard ticks) (156) and Nuttalliellidae
(which is composed of just one species—Nuttalliella
namaqua) (157-160). In recent times, another family, in
this case extinct, called Deinocrotonidae, has been
described (161).
Currently, there are more than 900 accepted
species of ticks, of which it has been estimated that
approximately 10% of those are the ones that affect
humans in an important manner (162, 163). In this regard,
more than 220 species of ticks (including hard and soft
ticks) have been reported to actively or passively
parasitize humans in published literature (163-172). The
implicated genera of soft ticks are Ornithodoros, Argas
and Otobius. On the other hand, the genera of hard ticks
include Amblyomma, Bothriocroton, Ixodes, Nosomma,
Rhipicephalus, Dermacentor, Hyalomma and
Haemaphysalis (163, 173, 174).
The importance of this parasitism lies in the fact
that several of these species of ticks have been positive
for one or several pathogens (164, 167, 175); more
importantly, ticks are the arthropods that transmit the
widest diversity of infectious agents, much more than
any other known vector (162). The factors that allow this
capacity are presented in Supplement 11, and they
generate the perfect vector for different types of
pathogens.
The vectoral capacity of ticks has been
demonstrated since 1893, when the mode of
transmission of the agent of Texas fever (Babesia
bigemina) was described (176); since then, many others
have been found (Supplement 12) (177).
Aggravating the public health situation is the
fact that diagnosis is difficult (178) and treatment
options are limited (179); therefore, the most important
aspect is prevention. In this regard, knowing the risk
factors is crucial; risk factors and protective factors are
found in Supplement 13. Other information can be found
in Supplement 14.
DISCUSSION
This comprehensive systematic review provides
an overview of rickettsial diseases and tick species of
12
public health importance, their distribution and their
effects on human health, which can lead to death. All of
these ticks are capable of transmitting one or more tick-
borne pathogens. Although these events are rare, once
they occur, mortality is high.
Our results show that there are different
rickettsial diseases that can generate important
consequences in human health. These rickettsial
diseases are distributed worldwide and can affect people
in any age range, and there is no difference in the reports
between sexes.
Zoonotic diseases are difficult to control
because of their complicated life cycles, multiple
reservoirs (and therefore multiple transmission cycles),
vectors, and risk factors. In the case of tick-borne
diseases, the cycle involves ticks, vertebrate reservoirs,
the environment and vertebrate hosts (180). Identifying
such diseases and the variants of causative agents
requires molecular analyses, which must be used with
caution (180) because they can be misleading or lead to
errors in interpretation. As ticks usually infest and
parasitize animals, wild or domestic, and the relation or
role of transmission from companion animals to people
has been contextualized in one health study (181, 182),
increasing communication between health providers,
including veterinarians and physicians, is crucial,
especially when cases of unexplained fever occur or
there is a background of traveling to tick-endemic areas
or tick bites (180). It is important to generate rules and
recommendations to ensure minimal risk; to do this,
physicians, and obviously, veterinarians, must know the
life cycles of vectors and agents to know or estimate
risks. Epidemiology must be a crucial element, ticks must
be identified as much as possible, and physicians and
veterinarians must ask for an opinion from experts as
much as necessary.
This is true for rickettsial diseases. This is an
emerging and ever-important public health threat:
national and international travel, climate change, and the
ever-growing interconnectedness of the world mean
that this kind of pathogen alongside other emerging and
re-emerging diseases will affect more patients, with
increasing incidence in endemic regions, and will start to
produce cases in nonendemic areas, creating public
health emergencies (183). Currently, the real
epidemiological aspects and impacts of rickettsial
diseases in endemic regions are well known. We live in a
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Rickettsia diseases and ticks of medical
importance: A systematic review
changing world, and we will probably have to face
threats to health at an increasing frequently.
Diagnosis is not easy, but awareness and
molecular tools can and must be used to clarify the
incidence distribution and burden that this disease has
on health systems around the world (184). Many are the
rickettsial and rickettsial-like pathogens that can produce
disease in humans, much more than those that were
assessed in this systematic review, many of them are
relatively and possibly obscure and uncommon, and
many do not have a species status; therefore, the tools
and the knowledge about the several bacterial and other
kinds of pathogens carried by ticks must be enhanced,
and the vigilance for such cases must be implemented.
The species reported in this review are similar to
those reported in another review (19), but cases
produced by less common or obscure species of
rickettsia (185) were not presented in this review. We
found more commonly assessed rickettsias such as R.
rickettsii, R. conorii, R. africae, R. massiliae, R.
mongolotimae, R. slovaca, and R. aeschlmanii, but we did
not find cases caused by rickettsias associated with soft
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