The Effect of Long-lasting Permethrin Impregnated Socks on Tick Bite in Korea.

BACKGROUND: The risk of tick-borne diseases is decreased by increasing awareness and knowledge through prevention education. The aim of the present study was to evaluate the effect of long-lasting permethrin impregnated (LLPI) socks for tick bites. METHODS: A randomized open label study was conducted to determine the effectiveness of LLPI socks for prevention of tick bites among 367 adults living in a rural area. Participants completed questionnaires at the start of follow-up (July 2014) and at the end of follow-up (December 2014), and tick bites were reported. RESULTS: A total of 332 subjects completed the follow-up survey. The tick bite rate of the two groups was not significantly different (3.6% vs. 3.1%). But the tick bite rate of lower extremities of subjects wearing LLPI socks was significantly lower compared to that of subjects wearing general socks. CONCLUSION: The tick bite rate was not different between the two groups, but the tick bite rate of lower extremities of LLPI was significantly lower than general groups. Further study is needed to investigate the effect of LLPI clothes with larger populations.

A case of Henoch-Schönlein purpura associated with scrub typhus.

BACKGROUND: Henoch-Schönlein purpura (HSP) may be caused by several allergens. However, to date, HSP caused by Orientia tsutsugamushi has not been reported. Here, we report an unusual rash with features of HSP caused by Orientia tsutsugamushi. CASE PRESENTATION: A man visited a tertiary hospital with bilateral symmetrical purpura and fever. He presented with an eschar in the left popliteal fossa and proteinuria. He was diagnosed with tsutsugamushi disease by indirect fluorescent antibody and positive polymerase chain reaction tests. Purpura biopsy demonstrated a feature of leukocytoclastic vasculitis and IgA deposition in dermal vessels, indicative of HSP. CONCLUSIONS: When examining patients with unique rashes, such as in this case, we suggest investigating out-door activities and evidence of mite bites. Furthermore, differential diagnosis of tsutsugamushi disease should be considered when necessary.

Dual Genotype Orientia tsutsugamushi Infection in Patient with Rash and Eschar, Vietnam, 2016.

We report a dual genotype Orientia tsutsugamushi infection in Vietnam in 2016. The patient had fever, rash, and an eschar. The Kawasaki genotype was identified in the eschar specimen and Karp genotype in the whole blood specimen. The genotype co-infection rate for scrub typhus is unknown and should be further evaluated.

A surface antigen of Orientia tsutsugamushi activates human monocyte-derived dendritic cells via nuclear factor-kB & p38 mitogen-activated protein kinase pathways.

BACKGROUND & OBJECTIVES: Scrub typhus is a chigger-borne disease caused by Orientia tsutsugamushi. The immunological reactions to O. tsutsugamushi infection are not completely understood. In this study, we investigated the response of dendritic cells (DCs) to a major 56-kDa scrub typhus antigen Sta56. METHODS: Monocyte-derived human DCs were incubated with different concentrations of recombinant Sta56 and analyzed for maturation based on phagocytic capacity, the ability to induce T-cell proliferation, expression of surface markers, cytokine secretion and activation of toll-like receptor (TLR)-dependent signalling pathways. RESULTS: Treatment of DCs with Sta56 induced cell surface expression of CD80, CD83, CD86 and MHC Class II increased the production of interleukin-12 (IL-12) p40, IL-12 p70 and IL-10 and decreased DC phagocytic capacity. Furthermore, Sta56 increased the ability of DCs to activate T-cell proliferation and interferon-γ secretion. TLR4-specific antibodies neutralized Sta56-elicited effects on DC maturation, suggesting direct interaction between Sta56 and TLR4. Moreover, Sta56 activated nuclear factor (NF)-κB and p38 mitogen-activated protein kinase (MAPK) signalling as evidenced by decrease in Sta56-induced cytokine production and surface marker expression by specific inhibitors helenalin and SB203580, respectively, and increase in IκBα and p38 phosphorylation and NF-κB-DNA binding. INTERPRETATION & CONCLUSIONS: Our results showed that the surface antigen of O. tsutsugamushi activated DCs through interaction with TLR4 and activation of MAPK and NF-κB signalling, suggesting Sta56 as a potential candidate molecule for the development of vaccine against scrub typhus.

Characteristics of Pediatric Scrub Typhus Eschar in South Indian Children.

BACKGROUND: Knowledge of anatomic location of eschar is useful in diagnosing scrub typhus early in children and to initiate appropriate treatment. METHODS: All children younger than 12 years of age admitted with confirmed diagnosis of scrub typhus over a 17-month period were included and the presence of eschar and other characteristics were recorded and analyzed. RESULTS: Of 107 confirmed patients with scrub typhus, 37 (34.6%) presented with eschar. The site of eschar distribution was the face, 2.7%; neck, 5.4%; axilla, 18.9%; trunk, 10.8%; inguinal, 35.1%; and genitalia and buttocks, 27%. Lymphadenopathy was associated with 67.5% of eschars. The presence of eschar did not correlate with severity, complications, or response to therapy. CONCLUSION: Careful examination for eschar in children presenting with fever, particularly in the skin folds of the groin, genitalia, and axillae, can aid in early diagnosis of scrub typhus. Lymphadenopathy should alert the clinician to the possibility of finding an eschar in the drainage area.

ACUTE CHOLECYSTITIS AS AN UNUSUAL PRESENTATION OF SCRUB TYPHUS: A REPORT OF TWO CASES AND REVIEW OF THE LITERATURE.

Scrub typhus rarely presents with acute cholecystitis. We present 2 cases of scrub typhus with cholecystitis. The first patient is a 62 year old female who presented to the hospital with fever and body aches for 1 week and right upper quadrant abdominal pain for 3 days. She gave a history of an insect bite 2 weeks previously. She was diagnosed as having acute cholecystitis and underwent cholecystectomy. She continued with fever post-operatively and physical examination revealed an eschar. She had an immunofluorescence assay (IFA) performed that revealed a high IgM titer for Orientia tsutsugamushi. She was diagnosed as having scrub typhus, treated with doxycycline and she recovered completely. The second patient also presented to the hospital with a 1 week history of fever and upper quadrant abdominal pain. She was diagnosed with having cholecystitis. Her symptoms did not improve with intravenous antibiotics and further investigation revealed elevated titers for O. tsutsugamushi and Leptospira interrogans. She was diagnosed as having a co-infection of scrub typhus and leptospirosis and treated with doxycycline. She recovered completely. Patients from scrub typhus endemic regions who present with acute cholecystitis but do not respond to traditional treatment should be tested for scrub typhus and leptospirosis and should have a careful admission physical examination looking for eschar formation, since scrub typhus may present with acute cholecystitis.

A comparative hospital-based observational study of mono- and co-infections of malaria, dengue virus and scrub typhus causing acute undifferentiated fever.

Positive serology for dengue and/or scrub typhus infection with/without positive malarial smear (designated as mixed or co-infection) is being increasingly observed during epidemics of acute undifferentiated febrile illnesses (AUFIs). We planned to study the clinical and biochemical spectrum of co-infections with Plasmodium sp., dengue virus and scrub typhus and compare these with mono-infection by the same organisms. During the period from December 2012 to December 2013, all cases presenting with AUFIs to a single medical unit of a referral centre in Garhwal region of the north Indian state of Uttarakhand were retrospectively selected and categorised aetiologically as co-infections, malaria, dengue or scrub typhus. The groups thus created were compared in terms of demographic, clinical, biochemical and outcome parameters. The co-infection group (n = 49) was associated with milder clinical manifestations, fewer, milder and non-progressive organ dysfunction, and lesser need for intensive care, mechanical ventilation and dialysis as compared to mono-infections. When co-infections were sub-grouped and compared with the relevant mono-infections, there were differences in certain haematological and biochemical parameters; however, this difference did not translate into differential outcomes. Scrub typhus mono-infection was associated with severe disease in terms of both morbidity and mortality. Malaria, dengue and scrub typhus should be routinely tested in all patients with AUFIs. Co-infections, whether true or due to serological cross-reactivity, appear to be a separate entity so far as presentation and morbidity is concerned. Further insight is needed into the mechanism and identification of the protective infection.

Epidemiology & risk factors of scrub typhus in south India.

BACKGROUND & OBJECTIVES: Scrub typhus is a major public health threat in South and Southeastern Asian countries including India. Understanding local patterns of disease and factors that place individuals at risk is pivotal to future preventive measures against scrub typhus. The primary aim of this study was to identify specific epidemiological and geographical factors associated with an increased risk of developing scrub typhus in this region. METHODS: We mapped 709 patients from Tamil Nadu, Andhra Pradesh and Telangana who were admitted to the Christian Medical College (CMC) Hospital, Vellore, Tamil Nadu, India, for the period 2006-2011, assessed seasonality using monthly counts of scrub typhus cases, and conducted a case-control study among a subset of patients residing in Vellore. RESULTS: The geographic distribution of cases at CMC Hospital clusters around the Tamil Nadu-Andhra Pradesh border. However, distinct hotspots clearly exist distal to this area, near Madurai and the coast in Tamil Nadu, and in the Northeast of Andhra Pradesh. Seasonally, the highest numbers of cases were observed in the cooler months of the year, i.e. September to January. In the case-control analysis, cases were more likely to be agricultural laborers (OR 1.79, 95% CI 1.01 - 3.15), not wear a shirt at home (OR 4.23, 95% CI 1.12 - 16.3), live in houses adjacent to bushes or shrubs (OR 1.95, 95% CI 1.08 - 3.53), and live in a single room home (OR 1.75, 95% CI 1.02 - 3.01). On binary logistic regression, the first three of these variables were statistically significant. INTERPRETATION & CONCLUSIONS: With the growing number of cases detected in India, scrub typhus is fast emerging as a public health threat and further research to protect the population from this deadly infection is essential. Health education campaigns focusing on the agricultural workers of Southern India, especially during the cooler months of the year, can serve as an important public health measure to control infection.

Abundance & distribution of trombiculid mites & Orientia tsutsugamushi, the vectors & pathogen of scrub typhus in rodents & shrews collected from Puducherry & Tamil Nadu, India.

BACKGROUND & OBJECTIVES: Human cases of scrub typhus are reported every year from Puducherry and adjoining areas in southern India. However, information on the presence of causative agent, Orientia tsutsugamushi, and its vectors is lacking. Hence, the objective of the study was to find out the vector as well as pathogen distribution in rodents and shrews present in the scrub typhus-reported areas in southern India. METHODS: Trombiculid mites were collected by combing rats and shrews collected using Sherman traps and identified to species level following standard taxonomical keys. The serum samples of the animals were used for Weil-Felix test and the clots containing blood cells were used for DNA extraction and polymerase chain reaction (PCR). RESULTS: A total of 181 animals comprising four rodent species and one shrew species were collected from 12 villages. High proportion of chiggers was collected from the shrew, Suncus murinus (79.1%) and Rattus rattus (47.6%). A total of 10,491 trombiculid mites belonging to nine species were collected. Leptotrombidium deliense, the known vector of scrub typhus pathogen, was the predominant species (71.0%) and the chigger (L. deliense) index was 41.1 per animal. Of the 50 animals screened for the pathogen, 28 showed agglutination against OX-K in Weil-Felix test indicating the presence of antibodies against O. tsutsugamushi, the causative agent of scrub typhus. PCR carried out with the DNA extracted from blood samples of two of the animals were positive for GroEl gene of O. tsutsugamushi. INTERPRETATION & CONCLUSIONS: L. deliense index was well above the critical limit of chigger load, indicating that all the villages were receptive for high risk of transmission of scrub typhus to human. Pathogen positivity was higher among animals collected from villages recorded for higher chigger indices due to active transmission between the chigger mites and reservoir host animals. The results are suggestive of routine vector/pathogen surveillance at hot spots to initiate timely preventive measures.

Neurological manifestations of scrub typhus.

OBJECTIVE: To evaluate the neurological manifestations of scrub typhus and correlate their clinical, EEG and MRI findings. METHODS: A cross-sectional study over 2 years included patients with scrub typhus diagnosed by solid phase immunochromatographic assay or Weil-Felix test. A detailed clinical evaluation including Glasgow Coma Scale (GCS) was documented. Blood counts, chemistry, ECG, chest radiograph, cerebrospinal fluid (CSF), EEG and cranial MRI were performed. Outcome on discharge and at 1 month were categorised into good and poor based on modified Rankin Scale. RESULTS: Thirty-seven patients with ages ranging between 3 and 71 years were included; 51% of whom were females. All patients had fever and myalgia. Thirty-one (84%) patients had impaired consciousness, and six were deeply comatose (GCS score ≤8). Eight patients presented with status epilepticus. MRI revealed meningeal enhancement in only 1/25 (4%) patient and EEG showed generalised slowing in 6/28 (21.4%). Among 31 patients with altered sensorium, CSF studies were conducted on 28. Nineteen patients had meningoencephalitis and 9 encephalopathy, but no significant differences were observed in clinical, laboratory, EEG and MRI findings. All patients responded within 48 h to doxycycline and had good recovery at 1 month. Patients with low GCS score had significantly more focal neurological deficit (r=0.5; p=0.002), longer hospital stay (r=-0.4; p=0.03) and more disability on discharge (r=-0.4; p=0.01). CONCLUSIONS: Meningoencephalitis/encephalopathy may be seen in two-third of patients with scrub typhus. Scrub typhus should be included in the differential diagnosis of febrile encephalopathy.

Significantly higher cytokine and chemokine levels in patients with Japanese spotted fever than in those with Tsutsugamushi disease.

Tetracyclines are administered to cure Japanese spotted fever (JSF) and tsutsugamushi disease (TD). It is generally said that the clinical course of JSF is worse than that of TD despite antibiotic treatment. The precise mechanism underlying the more severe clinical course of JSF is not fully understood. We therefore examined whether the differential cytokine profile between these two infectious diseases contributes to the difference in clinical severity. The serum concentrations of various cytokines (tumor necrosis factor alpha [TNF-α], interleukin-6 [IL-6], and gamma interferon [IFN-γ]) and chemokines (IL-8, interferon-inducible protein 10 [IP-10], monocyte chemoattractant protein 1 [MCP-1], macrophage inflammatory protein 1α [MIP-1α], MIP-1ß, and eotaxin) were measured in 32 TD and 21 JSF patients. The results showed that serum levels of TNF-α in the acute phases of TD and JSF were significantly increased, with a higher concentration of TNF-α in patients with JSF (mean, 39.9 pg/ml) than in those with TD (mean, 13.8 pg/ml). Comparatively higher levels of other cytokines and chemokines (IL-6, IFN-γ, IL-8, IP-10, MCP-1, MIP-1α, and MIP-1ß) were also observed in the acute phase of JSF. The clinical severity score (3.67 ± 1.71) of JSF patients was higher than that of TD patients (1.47 ± 0.77). Our findings revealed that the cytokine and chemokine levels in the acute phase of JSF were significantly higher than those in the acute phase of TD. The differential cytokine levels may be related to the difference in clinical severity between JSF and TD.

Scrub typhus with sepsis and acute respiratory distress syndrome.

Scrub typhus is a major infectious threat in the Asia-Pacific region. We report an unusual case of scrub typhus in a patient in Singapore who presented with sepsis and acute respiratory distress syndrome but lacked the pathognomonic eschar. The patient recovered after appropriate diagnosis and doxycycline treatment. Rickettsial diseases should be included in the differential diagnosis of febrile illnesses in regions where the diseases are endemic, and absence of eschar should not be the criterion used to rule out scrub typhus.

Eschar in scrub typhus: a valuable clue to the diagnosis.

BACKGROUND: Scrub typhus is an acute febrile illness widely prevalent in the 'tsutsugamushi triangle' region of the world. Clinical features include fever, myalgia, headache, rash, and a pathognomonic eschar. An eschar is formed by the bite of chigger mite that inoculates the causative agent of Scrub typhus Orientia tsutsugamushi. The aim of this study is to determine the most common sites of eschars over the bodies of patients with Scrub typhus. MATERIALS AND METHODS: In a retrospective analysis, we examined a total of 418 patients who presented to Christian Medical College, Vellore between 2009 and 2012 with an acute febrile illness and an eschar on clinical examination and confirmed to have scrub typhus with a positive Scrub typhus IgM ELISA test. We studied the distribution of eschars over the bodies of 418 patients with Scrub typhus. RESULTS: There was a significant difference in the distribution of eschars between males and females with a preponderance of the chest and abdomen (42.3%) among females and the axilla, groin and genitalia (55.8%) in males. Some unusual sites of an eschar were the cheek, ear lobe and dorsum of the feet. CONCLUSION: The eschar is the most useful diagnostic clue in patients with acute febrile illness in areas endemic for Scrub typhus and therefore should be thoroughly examined for its presence especially over the covered areas such as the groin, genitalia, infra-mammary area and axilla.

Scrub typhus in patients reporting with acute febrile illness at a tertiary health care institution in Goa.

BACKGROUND & OBJECTIVES: Scrub typhus is one of the differential diagnoses of haemorrhagic fevers especially if associated with jaundice and/or renal failure. Goa State in the western region of India has been witnessing increased incidence of such fevers, therefore, the present study was undertaken to identify whether scrub typhus is the aetiological agent. METHODS: Adult patients presenting with undiagnosed febrile illness between June 2009 to October 2010, were evaluated. Testing was done using a commercial ELISA kit for specific IgM antibodies against Orientia tsutsugamushi. RESULTS: Of the 44 patients included in the study, 15 (34%) were found to be positive for IGM antibodies against O. tsutsugamushi. The cases were seen mainly in the months between July to November. The common symptoms noted were fever, myalgias, gastrointestinal complaints, followed by breathlessness, rash and jaundice. The pathognomonic features such as eschar and lymphadenopathy were seen only in two patients. Nearly two third of the patients had leukocytosis (67%) and low serum albumin (60%). The most common complication noticed was hepatitis (80%) followed by acute respiratory distress syndrome (ARDS) (60%), thrombocytopenia (40%) and acute renal failure (33%). Five patients died in the course of illness. INTERPRETATION & CONCLUSIONS: Our results showed that scrub typhus should be considered in the differential diagnosis of acute febrile illness associated with gastrointestinal symptoms, rash, myalgia , including those with organ dysfunctions such as hepatorenal syndrome, coagulopathy or ARDS. Empirical treatment with doxycycline or macrolides may be given in cases with strong suspicion of scrub typhus.

OtDUB from the Human Pathogen Orientia tsutsugamushi Modulates Host Membrane Trafficking by Multiple Mechanisms.

Host cell membrane-trafficking pathways are often manipulated by bacterial pathogens to gain cell entry, avoid immune responses, or to obtain nutrients. The 1,369-residue OtDUB protein from the obligate intracellular human pathogen Orientia tsutsugamushi bears a deubiquitylase (DUB) and additional domains. Here we show that OtDUB ectopic expression disrupts membrane trafficking through multiple mechanisms. OtDUB binds directly to the clathrin adaptor-protein (AP) complexes AP-1 and AP-2, and the OtDUB275-675 fragment is sufficient for binding to either complex. To assess the impact of OtDUB interactions with AP-1 and AP-2, we examined trans-Golgi trafficking and endocytosis, respectively. Endocytosis is reduced by two separate OtDUB fragments: one contains the AP-binding domain (OtDUB1-675), and the other does not (OtDUB675-1369). OtDUB1-675 disruption of endocytosis requires its ubiquitin-binding capabilities. OtDUB675-1369 also fragments trans- and cis-Golgi structures. Using a growth-based selection in yeast, we identified viable OtDUB675-1369 point mutants that also no longer caused Golgi defects in human cells. In parallel, we found OtDUB675-1369 binds directly to phosphatidylserine, and this lipid binding is lost in the same mutants. Together these results show that OtDUB contains multiple activities capable of modulating membrane trafficking. We discuss how these activities may contribute to Orientia infections.

Isolation of a novel Orientia species (O. chuto sp. nov.) from a patient infected in Dubai.

In July 2006, an Australian tourist returning from Dubai, in the United Arab Emirates (UAE), developed acute scrub typhus. Her signs and symptoms included fever, myalgia, headache, rash, and eschar. Orientia tsutsugamushi serology demonstrated a 4-fold rise in antibody titers in paired serum collections (1:512 to 1:8,192), with the sera reacting strongest against the Gilliam strain antigen. An Orientia species was isolated by the in vitro culture of the patient's acute blood taken prior to antibiotic treatment. The gene sequencing of the 16S rRNA gene (rrs), partial 56-kDa gene, and the full open reading frame 47-kDa gene was performed, and comparisons of this new Orientia sp. isolate to previously characterized strains demonstrated significant sequence diversity. The closest homology to the rrs sequence of the new Orientia sp. isolate was with three strains of O. tsutsugamushi (Ikeda, Kato, and Karp), with a nucleotide sequence similarity of 98.5%. The closest homology to the 47-kDa gene sequence was with O. tsutsugamushi strain Gilliam, with a nucleotide similarity of 82.3%, while the closest homology to the 56-kDa gene sequence was with O. tsutsugamushi strain TA686, with a nucleotide similarity of 53.1%. The molecular divergence and geographically unique origin lead us to believe that this organism should be considered a novel species. Therefore, we have proposed the name "Orientia chuto," and the prototype strain of this species is strain Dubai, named after the location in which the patient was infected.