Emerging Rickettsioses of the Thai-Myanmar Border 
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 Emerging Rickettsioses of the Thai-Myanmar Border

Emerging Rickettsioses of the Thai-Myanmar Border
Human rickettsioses known to occur in Thailand include mainly murine
typhus and scrub typhus.
Emerg Infect Dis 9(5) 2003

Emerging Rickettsioses of the Thai-Myanmar Border

Philippe Parola, R. Scott Miller, Philip McDaniel, Sam R. Telford III,
Jean-Marc Rolain, Chansuda Wongsrichanalai, Didier Raoult
Emerg Infect Dis 9(5), 2003. ? 2003 Centers for Disease Control and Prevention

Posted 06/19/2003
Abstract and Introduction
To investigate the presence of rickettsioses in rural residents of the central
Thai-Myanmar border, we tested the {*filter*} of 46 patients with fever. Four
patients had murine typhus, three patients had scrub typhus, and eight patients
had spotted fever group rickettsioses, including the first case of Rickettsia
felis infection reported in Asia.

Human rickettsioses known to occur in Thailand include mainly murine typhus and
scrub typhus. Murine typhus is caused by Rickettsia typhi and is primarily
maintained by fleas such as Xenopsylla cheopis, with various rodents
reservoirs.[1] Scrub typhus is caused by Orientia tsutsugamushi (formerly named
R. tsutsugamushi), which is transmitted by the bites of the larvae of several
species of trombiculid mites (commonly called "chiggers").[2]

Spotted fever group (SFG) rickettsioses are associated with arthropods, mainly
ticks but mites and fleas as well.[3, 4] In Thailand, few reports of
serologically documented cases of SFG rickettsioses have been published.[5]
Although the specific etiologic agents of these diseases have not been
identified, several SFG rickettsiae have been identified from ticks in
Thailand. Thai tick typhus Rickettsia TT-118 was isolated from a pool of ticks
in the 1970s.[6] Despite its name, its pathogenic role in Thailand is not
known. However, Stenos et al. have suggested that TT-118 is a strain of R.
honei, an emerging pathogen prevalent on Flinders Island, Australia.[7]
Further, a rickettsia identified as R. honei type strain has also been recently
detected by molecular methods in Thai Ixodes granulatus.[8] In addition,
several previously unrecognized rickettsiae of unknown pathogenicity have been
detected from Ixodes and Dermacentor ticks, including species known to bite
humans.[8, 9]

Thailand's Sangkhlaburi District (Kanchanaburi Province) is a major gateway on
the central part of the Thai-Myanmar border where newly arrived migrants from
Myanmar become established as farm or factory laborers. There, the local Thai
people, as well as Karen, Mon, and Burmese migrants, are commonly bitten by
arthropods when working in the fields or at home. Scrub typhus has been
previously reported in the province.[10] Murine typhus was also described as a
cause of fever in refugee camps along the Thai-Myanmar border.[11] However, a
serosurvey undertaken in 1997 suggested that residents of Sangkhlaburi were
commonly exposed not only to the agents of scrub typhus and murine typhus but
also to SFG rickettsiae and agents of human ehrlichioses.[12] Here, we provide
for the first time a more precise indication of rickettsioses in febrile
patients from Sangkhlaburi.

The Study
This study was based at the Armed Forces Research Institute of Medical Sciences
(AFRIMS)-Kwai River Christian Hospital Clinical Center, Sangkhlaburi District,
Kanchanaburi Province, Thailand. (The protocol was approved by the Human
Subjects Research Review Board of the U.S. Army, Ethical Review Committee for
Research in Human Subjects of the Thai Ministry of Public Health, and
Scientific Review Committee of AFRIMS.) Patients were selected from those
enrolled and sampled from June 1999 to February 2002 in an on-going "fever
study," which focuses on the etiology of undifferentiated febrile illnesses
({*filter*}temperature >38C or history of fever within the past 48 h) in local
residents >/=20 years of age. Criteria leading to the suspicion of
rickettsioses included 1) a rash or eschar, 2) arthropod bites or recent
exposure to the jungle, 3) a negative Giemsa-stained malaria smear, and 4)
serum specimens that tested positive by enzyme-linked immunosorbent assay
(ELISA) for SFG-specific immunoglobulin (Ig) M (PanBio, Brisbane, Australia) or
dot-ELISA for total Ig of R. rickettsii or R. typhi (PanBio-INDX, Baltimore,
MD). Serum specimens were sent to the Unit des Rickettsies in Marseille for
specific diagnosis of rickettsioses. Serologic testing was performed by
indirect immunofluorescence (IF) on acute-phase (day 0) and convalescent-phase
(approximately day 21) samples. Serum specimens were tested by using a panel of
13 rickettsial antigens, including SFG rickettsiae (R. conorii Indian, R.
japonica, R. honei, R. helvetica, R. slovaca, AT1 Rickettsia,[13]R. felis, "R.
heilongjiangii") typhus group rickettsiae (R. typhi), Orientia tsutsugamushi
(strain Gilliam, Kato, Karp, and Kawazaki), Anaplasma phagocytophilum,
Ehrlichia chaffeensis, and Coxiella burnetii. The rationale for the antigen
screening panel included the presence of the strains in Asia and results of
previous serosurveys for A. phagocytophilum and E. chaffeensis. The standard
procedure was followed for the use of Western blot and cross-adsorption studies
to complete the IF assay at the Unit des Rickettsies.[14, 15] An
immunofluorescence assay was considered positive for 1) IgG with titers >/=128
and/or IgM titers >/=64 for R. conorii;and 2) for IgG titers >/=64 and/or IgM
titers >/=32 for other rickettsial antigens. When cross-reactions were noted
between several rickettsial antigens, the standard procedure comprised three
steps: 1) A rickettsial antigen was considered to represent the agent of
infection when titers of IgG and/or IgM antibody against this antigen were at
least two serial dilution higher than titers of IgG and/or IgM antibody against
other rickettsial antigens. 2) When the difference in titers between several
antigens was lower than two dilutions, Western blot assays were performed. A
rickettsial antigen was considered to represent the agent of the infection when
acute-phase or convalescent-phase sera reacted only with the specific proteins
of this antigen. 3) When Western blot assays were not diagnostic,
cross-absorption studies were performed: IgG/IgM titers had to be >/=128/32.
Specific diagnosis criteria after cross-absorption studies included a) IF
serologic test results positive for a single antigen or b) a Western blot assay
showing an exclusive reactivity with specific proteins of a sole agent.

From June 1999 to February 2002, 46 patients were selected to be specifically
tested for rickettsioses. These 46 patients were empirically treated by a 7-day
doxycycline regimen (200 mg/d). Rickettsioses were serologically confirmed in
15 (33%) patients by evidence of seroconversion, IgM at significant titers, or
both. Three patients (nos. 1-3) had scrub typhus caused by O. tsutsugamushi.
Serum specimens from patients 1 and 3 provided the highest titers against
Gilliam and Karp strains, and serum from patient 2 had titers against Gilliam
strain only. No further study was conducted to identify the strain responsible
for the disease. Two of these patients had returned from a trip into the
jungle, and the third became sick several days after cutting grass in the
fields. One patient was initially thought to have bacterial meningitis and had
been treated unsuccessfully by a broad-spectrum third-generation cephalosporin
for 3 days before doxycycline was started. Four patients (nos. 4-7) had murine
typhus caused by R. typhi. All had fever and unspecific signs. The patients
recalled no arthropod bite, and none had a rash. Eight cases were SFG
rickettsioses (nos. 8-15). Of the patients with SFG rickettsioses, only one
(no. 9) had fever, eschar, and rash. One patient (no.13) had an eschar at a
tick bite site, and another had a rash (no.15). Others presented with
unspecific signs. Cross-reactions were noted mostly within the SFG rickettsia
antigens. One patient (no. 8) with SFG rickettsioses seroconverted to R. felis,
indicated by high level of antibody titers. Further, although IgG titers were
more than two serial dilutions higher than those for R. typhi, Western blot
assay was performed to confirm IF findings. Two patients (nos. 9 and 10) were
shown to have the highest titers to R. conorii strain Indian. Five patients
(nos. 11-15) had the highest titers to R. helvetica. For patients 4, 9, 10, 13,
and 15, IF results showed differences lower than two dilutions in IgG titers,
IgM titers, or both, between several antigens. Thus, IF assays were completed
by Western blot and with cross-absorption studies for patient 4 (Table). No
cases of infection due to C. burnetii or ehrlichioses were diagnosed in the 46
tested patients.

In this study, we report rickettsioses in Sangkhlaburi, including the first
case of R. felis infection reported in Asia. R. felis is an emerging pathogen
responsible for flea-borne spotted fever. R. felis was likely first detected
(as R. ctenocephali) in European cat fleas (Ctenocephalides felis) in 1918,[16]
then rediscovered in 1990 in the United States.[17]R. felis was then cultivated
and characterized as a unique SFG rickettsia.[18] Its pathogenic role was
recently demonstrated in patients with serologic evidence of infection in
Brazil, France, and Germany. R. felis DNA has also been detected in sera in
Texas, Mexico, Brazil, and Germany.[19] This rickettsia has also been recently
detected in fleas in Brazil, Africa, Spain, and France.[20] Further, during an
entomologic survey, R. felis-like rickettsiae were detected in fleas collected
in Sanghklaburi (P. Parola, unpub. data). These data suggest that R. felis
infection is endemic in Sanghklaburi and perhaps globally.

Murine typhus, a mild disease with nonspecific signs,[21] was found in four of
our patients. Although this disease has a worldwide distribution, it is often
unrecognised, and documented cases are rarely reported. The classic triad of
fever, headache, and skin rash is observed in <15% of cases.[22] For example,
our four patients did not have a rash. Arthralgia, myalgia, and respiratory and
gastrointestinal symptoms (as demonstrated by one of our patients) are
frequent.[21, 22] Regarding disease transmission, although rats and mice are
very common within and around houses in the villages, our patients did not
report contact with rat fleas or a flea bite.

In this study, seven patients with SFG rickettsioses may have been infected by
R. helvetica (five patients) or R. conorii Indian strain (two patients),
according to IF assays completed for some cases by Western blot and
cross-adsorption studies. R. helvetica is an emerging pathogen known to be
prevalent in Europe[23] and Japan.[13] In both areas, R. helvetica is
associated with Ixodes ticks, which are also found in Thailand, although they
have not previously been reported in Sangkhlaburi.[24]R. conorii Indian is
known as an agent of tick-borne rickettsioses prevalent in India, where it is
associated with the dog tick (Rhipicephalus sanguineus),[25] which is found
worldwide. However, an unknown Rickettsia sp. that is cross-reactive with R.
conorii Indian and R. helvetica could also be responsible for the cases
reported here. In particular, we have recently detected, by polymerase chain
reaction, Rickettsia spp. from ticks that have bitten people in the
Sangkhlaburi area, including Dermacentor auratus and Dermacentor sp. larvae.[9]
The pathogenic role of these rickettsiae has yet to be demonstrated.

Scrub typhus is essentially an occupational disease among rural residents in
the Asia-Pacific region.[2] This disease is often underdiagnosed or
misdiagnosed when the classic eschar at the chigger bite sites and the rash are
absent, as reported for two of our three patients.[2] The severity of the
disease varies from asymptomatic to fatal (up to 30%). Delayed or inappropriate
treatment such as with third-generation cephalosporins, as reported for one of
our patients, is associated with a severe outcome. The four major serotypes
studied here have been shown to have sufficient cross-reactivity with antigens
from other strains to be used for serologic diagnostic testing. In our
patients, although the highest titers were obtained by using O. tsutsugamushi
strain Gilliam antigens, other strains that share common epitopes and
cross-react with this strain could be involved.

Patients with rickettsioses may have isolated fever or fever with nonspecific
clinical and laboratory findings. These diseases are easily misdiagnosed
because rash or eschar (the hallmark for rickettsial diseases) is absent, the
diseases are not recognized by local physicians, or the diseases have never
been reported in the area. More studies are needed on tropical rickettsioses,
in particular, molecular detection or rickettsial isolation from patient
samples, complemented by detailed case reports. Studying possible vectors and
animal reservoirs would provide estimates of the degree of zoonotic potential.
Ultimately, such studies will provide the basis for determining prevalence of
rickettsiosis in the tropics and their effects on public health................

Wed, 21 Dec 2005 11:58:53 GMT
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