Diagnostic markers of acute encephalitis syndrome and COVID-associated multisystem inflammatory syndrome in children from Southern India.

Acute encephalitis syndrome (AES) in children poses a significant public health challenge in India. This study aims to explore the utility of host inflammatory mediators and neurofilament (NfL) levels in distinguishing etiologies, assessing disease severity, and predicting outcomes in AES. We assessed 12 mediators in serum (n = 58) and 11 in cerebrospinal fluid (CSF) (n = 42) from 62 children with AES due to scrub typhus, viral etiologies, and COVID-associated multisystem inflammatory syndrome (MIS-C) in Southern India. Additionally, NfL levels in serum (n = 20) and CSF (n = 18) were examined. Clinical data, including Glasgow coma scale (GCS) and Liverpool outcome scores, were recorded. Examining serum and CSF markers in the three AES etiology groups revealed notable distinctions, with scrub typhus differing significantly from viral and MIS-C causes. Viral causes had elevated serum CCL11 and CCL2 compared with scrub typhus, while MIS-C cases showed higher HGF levels than scrub typhus. However, CSF analysis showed a distinct pattern with the scrub typhus group exhibiting elevated levels of IL-1RA, IL-1ß, and TNF compared with MIS-C, and lower CCL2 levels compared with the viral group. Modeling the characteristic features, we identified that age ≥3 years with serum CCL11 < 180 pg/mL effectively distinguished scrub typhus from other AES causes. Elevated serum CCL11, HGF, and IL-6:IL-10 ratio were associated with poor outcomes (p = 0.038, 0.005, 0.02). Positive CSF and serum NfL correlation, and negative GCS and serum NfL correlation were observed. Median NfL levels were higher in children with abnormal admission GCS and poor outcomes. Measuring immune mediators and brain injury markers in AES provides valuable diagnostic insights, with the potential to facilitate rapid diagnosis and prognosis. The correlation between CSF and serum NfL, along with distinctive serum cytokine profiles across various etiologies, indicates the adequacy of blood samples alone for assessment and monitoring. The association of elevated levels of CCL11, HGF, and an increased IL-6:IL-10 ratio with adverse outcomes suggests promising avenues for therapeutic exploration, warranting further investigation.

Scrub typhus in two COVID-19 patients: a diagnostic dilemma.

The authors describe a case series of co-infection with COVID-19 and scrub typhus in two Indian patients. Clinical features like fever, cough, dyspnea and altered sensorium were common in both patients. Case 1 had lymphopenia, elevated IL-6 and history of hypertension, while case 2 had leukocytosis and an increased liver enzymes. Both patients had hypoalbuminemia and required admission to the intensive care unit; one of them succumbed to acute respiratory distress syndrome further complicated by multiple organ dysfunction syndrome. Seasonal tropical infections in COVID-19 patients in endemic settings may lead to significant morbidity and mortality. Therefore, high clinical suspicion and an early diagnosis for co-infections among COVID-19 patients are essential for better patient management.

Development of a Scrub Typhus Diagnostic Platform Incorporating Cell-Surface Display Technology.

Scrub typhus (ST), also known as tsutsugamushi disease and caused by rickettsia Orientia tsutsugamushi, is an underestimated fatal epidemic in the Asia-Pacific region, resulting in a million human infections each year. ST is easily misdiagnosed as clinical diagnosis is based on non-specific skin eschar and flu-like symptoms. Thus, the lack of accurate, convenient, and low-cost detection methods for ST poses a global health threat. To address this problem, we adopted baculovirus surface-display technology to express three variants of TSA56, the major membrane antigen of O. tsutsugamushi, as well as the passenger domain of ScaC (ScaC-PD), on insect Sf21 cell surfaces rather than biosafety level 3 bacteria in an enzyme-linked immunosorbent assay (ELISA). Recombinant TSA56 and ScaC-PD were all properly expressed and displayed on Sf21 cells. Our cell-based ELISA comprising the four antigen-displaying cell types interacted with monoclonal antibodies as well as serum samples from ST-positive field-caught rats. This cell-based ELISA presented high accuracy (96.3%), sensitivity (98.6%), and specificity (84.6%) when tested against the ST-positive rat sera. Results of a pilot study using human sera were also highly consistent with the results of immunofluorescence analyses. By adopting this approach, we circumvented complex purification and refolding processes required to generate recombinant O. tsutsugamushi antigens and reduced the need for expensive equipment and extensively trained operators. Thus, our system has the potential to become a widely used serological platform for diagnosing ST.

Secreted Wnt antagonists in scrub typhus.

BACKGROUND: The mechanisms that control local and systemic inflammation in scrub typhus have only been partially elucidated. The wingless (Wnt) signaling pathways are emerging as important regulators of inflammation and infection, but have not been investigated in scrub typhus. METHODOLOGY/PRINCIPAL FINDINGS: Plasma levels of secreted Wnt antagonists (i.e. DKK-1, sFRP-3, WIF-1 and SOST) were analyzed in patients with scrub typhus (n = 129), patients with similar febrile illness without O. tsutsugamushi infection (n = 31), febrile infectious disease controls, and in healthy controls (n = 31) from the same area of South India, and were correlated to markers of inflammation, immune and endothelial cell activation as well as for their association with organ specific dysfunction and mortality in these patients. We found i) Levels of SOST and in particular sFRP-3 and WIF-1 were markedly increased and DKK-1 decreased in scrub typhus patients at admission to the hospital compared to healthy controls. ii) In recovering scrub typhus patients, SOST, sFRP-3 and WIF-1 decreased and DKK-1 increased. iii) SOST was positively correlated with markers of monocyte/macrophage and endothelial/vascular activation as well as with renal dysfunction and poor outcome iv) Finally, regulation of Wnt pathways by O. tsutsugamushi in vitro in monocytes and ex vivo in mononuclear cells isolated from patients with scrub typhus, as evaluated by gene expression studies available in public repositories, revealed markedly attenuated canonical Wnt signaling. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that scrub typhus is characterized by attenuated Wnt signaling possibly involving dysregulated levels of several secreted pathway antagonists. The secreted Wnt antagonist SOST was strongly associated with renal dysfunction and poor prognosis in these patients.

Scrub typhus-related hepatotoxicity: The Indian scenario.

In Scrunb Typhus, hepatotoxicity is an important, yet understudied, manifestation. We reviewed studies on scrub typhus, published in the last five years (2014-2019), which evaluated its clinico-epidemiological factors in India, and concentrated on its hepatic involvement. Nine studies were found, and no Indian study exclusively evaluated hepatic dysfunction. Thus, comments from a few international studies were also included. We conclude that liver dysfunction in the form of elevated serum transaminase levels is a common manifestation of scrub typhus, which may herald progress to fulminant hepatic failure.

Follow-up investigation of antibody titers and diagnostic antibody cutoff values in patients with scrub typhus in South Korea.

BACKGROUND: Scrub typhus is a mite-borne infectious disease caused by Orientia tsutsugamushi. Few follow-up studies have assessed antibody titers using serologic tests from various commercial laboratories and the Korea Centers for Disease Control and Prevention (KCDC). METHODS: A prospective study to assess the antibody titers in patients with scrub typhus and seroprevalence in individuals undergoing health checkups was conducted using results of immunofluorescence antibody assays (IFAs) and serologic tests, used by the KCDC and commercial laboratories, respectively. The following tests were performed simultaneously: (i) indirect IFA used by the KCDC to detect immunoglobulin (Ig) M and IgG, (ii) IFA used by a commercial laboratory to detect total Ig, and (iii) antibody tests using two commercially available kits. RESULTS: When the IgM and IgG cutoff values (≥1:16 and ≥1:256, respectively) used in the IFA and the total IgG cutoff values (≥1:40) were used in prospective follow-up investigations, the antibody positivity rates of 102 patients with scrub typhus were 44.1, 35.3, and 57.6%, respectively, within 5 days of symptom onset. Among 91 individuals who recovered from scrub typhus, the follow-up IgM, IgG, and total Ig positivity rates for 13 years were 37.4% (34/91), 22.0% (20/91), and 76.9% (70/91), respectively. Among 216 individuals undergoing health checkups, the seroprevalence of IgM was 4.2% (9/216); no seroprevalence of IgG was observed. CONCLUSIONS: IFAs used by the KCDC and the commercial laboratory and rapid commercial kits could not distinguish between patients who had recovered from scrub typhus and those who are currently infected with O. tsutsugamushi. In South Korea and other countries, where low antibody cutoff values are used, upward adjustments of cutoff values may be necessary.

Diagnostic accuracy of an in-house Scrub Typhus enzyme linked immunoassay for the detection of IgM and IgG antibodies in Laos.

Scrub typhus is a major cause of morbidity and mortality in Southeast Asia. Diagnosis of scrub typhus is difficult due to a lack of accessible validated diagnostic tools. Despite its objectivity, the diagnostic accuracy of ELISA tests is influenced by methodological and patient factors. This study aims to evaluate the performance of a novel in-house ELISA developed in the Mahidol Oxford Tropical Medicine Research Unit (MORU) for anti-scrub typhus group IgM and IgG compared to the "gold standard" reference IFA and PCR, and to determine whether the in-house ELISA can be used as a seroepidemiological screening tool and/or stand-alone test for scrub typhus. A total of 1,976 admission and 1,438 participant follow-up sera collected in the Lao PDR (Laos) were tested with ELISA for IgM and IgG. Samples with an ELISA OD≥0.50 were tested with IFA for IgM and/or IgG. A strong positive relationship was present between ELISA ODs and IFA titers for admission IgM (r2: 0.70, p <0.005) and IgG (r2: 0.76, p<0.005), and for follow-up IgM and IgG (both r2: 0.76, p<0.005) samples. The best compromise between sensitivity and specificity for the ELISA OD cut-off is likely to be between 0.8-1.0 for IgM antibodies and 1.2-1.8 for IgG antibodies. These results demonstrate that the diagnostic accuracy of the MORU in-house scrub typhus group ELISA is comparable to that of IFA, with similar results as reported for the commonly used InBios Scrub Typhus Detect ELISA, validating the use of the in-house ELISA. The optimal ELISA cut-off would depend on the use of the test, and the desired sensitivity and specificity. Further studies are required to authenticate the use of these cut-offs in other endemic regions. This in-house ELISA has the potential to replace the imperfect IFA, which could ultimately reduce the burden of scrub typhus by improving the rate of scrub typhus diagnoses in endemic low-resource areas.

Prediction Rule for Scrub Typhus Meningoencephalitis in Children: Emerging Disease in North India.

OBJECTIVES: To evaluate the proportion of scrub typhus meningoencephalitis among children with acute encephalitis syndrome and to outline its differentiating features. To develop a prediction rule for scrub typhus meningoencephalitis. METHODS: A prospective cohort study was conducted at a tertiary care public hospital in Northern India. Consecutive patients of acute encephalitis syndrome who met our inclusion criteria were enrolled over 2 years. Standardized workup including serum IgM against Orientia tsutsugamushi was performed. Clinical and laboratory features were compared between IgM-positive and IgM-negative patients. The area under the receiver operating characteristic curve of the score derived from "independent predictors" was measured. Sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios were calculated at different cut-offs of the score. RESULTS: Scrub typhus IgM enzyme-linked immunosorbent assay was positive in 66/352 patients (18.8%). Longer duration of fever and prodromal stage along with eschar, hepatomegaly, lymphadenopathy, and pneumonia were significantly more prevalent in scrub typhus meningoencephalitis. However, petechiae were frequent in non-scrub typhus patients. Leucocytosis, lymphocytosis, thrombocytopenia, hypoalbuminemia, and elevated levels of serum bilirubin, serum transaminases, and cerebrospinal fluid protein were associated with scrub typhus meningoencephalitis. Logistic regression revealed fever for >8 days, pneumonia, absence of petechiae, cerebrospinal fluid protein >1000 mg/L, and serum glutamic oxaloacetic transaminase >100 IU/L as independent "predictors" of scrub typhus meningoencephalitis. The area under the receiver operating characteristic curve (95% confidence interval) of the prediction score was 0.832 (0.78-0.89). Score at cutoff ≥1 had 91% sensitivity, 96.1% negative predictive value, and at cutoff ≥4 had 99.7% specificity, 88.9% positive predictive value, 83.1% negative predictive value, 40.3 positive likelihood ratio, 0.88 negative likelihood ratio for identifying scrub typhus meningoencephalitis. CONCLUSION: Prediction score may help physicians in peripheral areas to identify and treat scrub typhus meningoencephalitis, an emerging cause of acute encephalitis syndrome in India.

Evaluation of Recombinant Type-Specific Antigens of Orientia tsutsugamushi Expressed by a Baculovirus-Insect Cell System as Antigens for Indirect Immunofluorescence Assay in the Serological Diagnosis of Scrub Typhus.

Scrub typhus (ST) is a mite-borne rickettsiosis caused by the intracellular bacterium Orientia tsutsugamushi (OTS), which is classified as a biosafety level-3 (BSL-3) pathogen. For serological tests of ST, mouse fibroblast cells infected with the five prevalent serotypes of OTS in Japan are generally used as antigens for indirect immunofluorescence assay (IFA). In this study, Spodoptera frugiperda derived insect cell line (Sf9) cells infected with recombinant type-specific antigen (rTSA)-expressing baculovirus were used for IFA. The paired serum samples of 15 ST patients, 10 rickettsiosis patients, and 10 control individuals were used. IgM and IgG titers determined by the rTSA-based IFA were correlated with those determined by the OTS-infected cell-based IFA (R2 = 0.7319 to 0.7956). Based on the criteria for serological diagnosis, such as a suitable cutoff for single serum samples (IgM ≥ 1:160) and/or a significant increase in IgG titers between paired sera (≥ 4-fold), all 15 ST patients diagnosed as positive with the OTS-infected cell-based IFA were also diagnosed as positive by the rTSA-based IFA, whereas all 10 rickettsiosis patients and 10 control individuals were not. Thus, the rTSAs, which can be prepared in BSL-2 laboratories, are efficacious for the serological diagnosis of ST.

Serum C-reactive protein and procalcitonin values in acute Q fever, scrub typhus, and murine typhus.

BACKGROUND: Although C-reactive protein (CRP) and procalcitonin (PCT) are widely used inflammatory markers for infectious diseases, their role and potential application for rickettsioses were rarely studied. METHODS: A retrospective chart review and serological study were conducted in patients with rickettsioses. The clinical presentations, characteristics, laboratory data, and treatment responses were recorded and their associations with CRP and PCT values were analyzed. RESULTS: A total of 189 cases of rickettsioses, including 115 cases of acute Q fever (60.8%), 55 cases of scrub typhus (29.1%), and 19 cases of murine typhus (10.1%) were investigated. Both CRP and PCT values increased in the acute phase and declined in the convalescent phase. In the acute phase, mean CRP and PCT values were 78.2 ± 63.7 mg/L and 1.05 ± 1.40 ng/mL, respectively. Percentages of patients falling under different cut-off values of CRP and PCT were calculated systematically. Only 10.8% of CRP was > 150 mg/L and 14.2% of PCT was > 2.0 ng/mL. Patients with delayed responses to doxycycline treatment (> 3 days from treatment to defervescence) had significantly higher CRP values (102.7 ± 77.1 vs. 72.2 ± 58.2 mg/L, p = 0.041) and more PCT > 1.0 ng/ml (48.4% vs. 26.0%, p = 0.019) in the acute phase; higher CRP values (19.1 ± 37.4 vs. 3.6 ± 13.1 mg/L, p = 0.049) and more PCT > 0.5 ng/ml (19.2% vs. 1.4%, p = 0.005) in the convalescent phase. Correlation analysis was conducted for patients with acute Q fever. CRP and PCT values were positively correlated to each other, and both markers also had a positive correlation with serum aspartate transaminase values. Both CRP and PCT values and white blood cell counts were positively correlated to the days needed from doxycycline treatment to defervescence. CONCLUSION: CRP and PCT values might be useful in clinical investigations for patients with suspected rickettsioses and in predicting the response to doxycycline treatment for rickettsioses.

Clinical Characteristics and Outcome of Children Hospitalized With Scrub Typhus in an Area of Endemicity.

BACKGROUND: Scrub typhus, caused by Orientia tsutsugamushi, is a major cause of acute febrile illness in children in the rural tropics. METHODS: We recruited 60 febrile pediatric patients with a positive scrub typhus rapid diagnostic test result and 40 healthy controls from Chiang Rai Province in northern Thailand. Diagnosis was confirmed by the detection of (1) O. tsutsugamushi-specific DNA in blood or eschar samples with a polymerase chain reaction assay, (2) a fourfold rise in immunoglobulin M (IgM) titer to ≥1:3200 in paired plasma samples with an indirect immunofluorescence assay (IFA), or (3) a single IgM titer of ≥1:3200 in an acute plasma sample with an IFA. Demographic, clinical, and laboratory data were collected, and patients were followed up for 1 year. RESULTS: Diagnosis was confirmed in 35 (58%) of 60 patients, and all controls tested negative for scrub typhus. Patients with confirmed scrub typhus had clinical symptoms, including fever (35 of 35 [100%]), eschar (21 of 35 [60%]), cough (21 of 35 [60%]), tachypnea (16 of 35 [46%]), lymphadenopathy (15 of 35 [43%]), and headache (14 of 35 [40%]). Only 4 (11%) of 35 patients received appropriate antibiotic treatment for scrub typhus before admission. The median fever-clearance time was 36 hours (interquartile range, 24-53 hours). Complications observed include hepatitis (9 of 35 [26%]), severe thrombocytopenia (7 of 35 [20%]), pneumonitis (5 of 35 [14%]), circulatory shock (4 of 35 [11%]), and acute respiratory distress syndrome (3 of 35 [9%]). Treatment failure, defined by failure to defervesce within 72 hours of antibiotic treatment initiation, was noted in 8 (23%) of 35 patients, and 1 (3%) of the 35 patients died. No evidence of relapse or reinfection was found. CONCLUSION: Pediatric scrub typhus in northern Thailand is often severe and potentially fatal with delays in treatment a likely contributing factor. Additional studies to investigate the bacterial, pharmacologic, and immunologic factors related to treatment outcome along with measures to improve public awareness should be prioritized.

Antinuclear antibodies in infectious diseases.

Introduction: Antinuclear antibody (ANA) tests are widely used for the diagnosis of autoimmune diseases, but ANAs are also commonly found in patients with various infections. This retrospective study aimed to investigate the relationship between infections and ANA status.Methods: Patients that visited the Department of Infectious Diseases at Inha University Hospital between January 2007 and July 2018 were investigated. We analysed their ANA test results and reviewed rheumatic and infectious diagnoses of patients with positive ANA findings.Results: Of the 9,320 patients during the study period, 1,111 underwent ANA testing and 110 tested positive. Seven of the 110 patients were previously diagnosed with ANA-positive disease, and 21 were diagnosed with autoimmune disease during the present study. Of the remaining 82 patients, 43 were confirmed with infectious disease. The most common pathogen was Mycobacterium tuberculosis (n = 10), followed by Treponema pallidum (n = 5), Orientia tsutsugamushi (n = 5), Escherichia coli (n = 5), Bartonella henselae (n = 3), and human immunodeficiency virus (n = 3). Of the 39 patients without a confirmed pathogen, 7 were seropositive for O. tsutsugamushi, B. henselae, or Rickettsia spp. Patients were observed at an average of 24 weeks in our hospital. One patient developed systemic lupus erythematosus after being diagnosed with Epstein-Barr virus-induced infectious mononucleosis, and another patient developed adult-onset Still's disease after being diagnosed with scrub typhus.Conclusion: This study showed that various relationships exist between infections and rheumatic diseases. In particular, several patients with a positive ANA test result were found to have intracellular infections such as mycobacterial infections, syphilis, or scrub typhus.

Human granulocytic anaplasmosis in Kinmen, an offshore island of Taiwan.

BACKGROUND: Human granulocytic anaplasmosis, a tick-borne infection caused by Anaplasma phagocytophilum, has received scant attention, while scrub typhus, a mite-transmitted disease caused by Orientia tsutsugamushi, is the most common rickettsiosis in Taiwan. The clinical presentations of both diseases are characterized by undifferentiated fever, headache and malaise. Moreover, both pathogens have been detected in small mammals that serve as hosts for chiggers and ticks in the wild. The objective of the present study was to investigate whether human granulocytic anaplasmosis occurs in Taiwan. METHODOLOGY/PRINCIPAL FINDINGS: Blood samples from 274 patients suspected of having scrub typhus in Kinmen, an offshore island of Taiwan, in 2011 and 2012 were retrospectively examined by immunofluorescence assays. IgG antibodies reactive with Anaplasma phagocytophilum was found in 31.8% (87/274) of the patients. Paired serology identified 3 patients with human granulocytic anaplasmosis and 8 patients with coinfection with O. tsutsugamushi and A. phagocytophilum. Laboratory tests showed that elevated serum ALT/AST, creatinine, and BUN levels were observed in patients with anaplasmosis and coinfection, but elevated serum CRP levels, thrombocytopenia, and anemia were only observed in coinfected patients. PCR detected A. phagocytophilum 16S rDNA and p44/msp2 in 2 patients. The phylogenetic analysis suggested that the replicons of the 16S rDNA shared high sequence similarity with the reference sequences in the Korea, USA, Japan, and China. The amplicons of p44/msp2 were close to those of the human variants identified in the USA and Japan. CONCLUSIONS: Our findings indicated that A. phagocytophilum infection was prevalent but unrecognized in Taiwan.

Serologic Evidence for Orientia Exposure in the Democratic Republic of Sao Tome and Principe.

Orientia tsutsugamushi is an obligate intracellular bacterium that causes scrub typhus in humans. Formerly thought to be confined to the "tsutsugamushi triangle" within the Asia-Pacific region, scrub typhus was recently identified in the Western Hemisphere. Moreover, a new species of Orientia bacterial genus was isolated from a patient in Dubai. This study investigated Orientia exposure in an African country, the Democratic Republic of Sao Tome and Principe. Two sets of samples were analyzed in the study: 240 dried blood spots (DBSs) collected in 2016 and 863 serum samples from 570 pregnant women in 2003. Antibodies against O. tsutsugamushi were examined by immunofluorescence assay (IFA) and enzyme-linked immunosorbent assay (ELISA). The positive samples were further confirmed by Western blot. The results of IFA showed that 5.8% (14/240) of DBSs and 20.4% (116/570) of the serum samples contained reactive antibodies, whereas IgG ELISA yielded a positive rate of 15.4% (88/570) for the serum samples. These findings provided serologic evidence of potential Orientia exposure even though case of scrub typhus has never been diagnosed in the nation. Further studies are needed to determine the epidemiology and the burden of this neglected tropical disease in Africa.

Quantitative Serodiagnosis of Scrub Typhus Using Surface-Enhanced Raman Scattering-Based Lateral Flow Assay Platforms.

A surface-enhanced Raman scattering-based lateral flow assay (SERS-LFA) technique has been developed for the rapid and accurate diagnosis of scrub typhus. Lateral flow kits for the detection of O. tsutsugamushi IgG (scrub typhus biomarker) were fabricated, and the calibration curve for various standard clinical sera concentrations were obtained by Raman measurements. The clinical sera titer values were determined by fitting the Raman data to the calibration curve. To assess the clinical feasibility of the proposed method, SERS-LFA assays were performed on 40 clinical samples. The results showed good agreement with those of the standard indirect immunofluorescence assay (IFA) method. SERS-LFA has many advantages over IFA including the less sample volume, simpler assay steps, shorter assay time, more systematic quantitative analysis, and longer assay lifetime. As SERS strips can be easily integrated with a miniaturized Raman spectrophotometer, field serodiagnosis is also more feasible.

Marked elevation of serum lipase in scrub typhus without pancreatitis: a report of three cases.

Scrub typhus, a re-emerging acute febrile zoonosis can present as an undifferentiated fever often complicated by potentially fatal systemic involvement. Acute pancreatitis is a rare complication of scrub typhus which can result in a marked elevation of serum lipase. We report three cases of scrub typhus who presented with acute undifferentiated fever, where a marked elevation of serum lipase occurred without any evidence of acute pancreatitis, or other causes of elevated lipase levels. Scrub typhus should be considered as a cause of marked elevation of serum lipase, which can occur in the absence of pancreatitis.

Case Report: Scrub Typhus and Q Fever Coinfection.

A 56-year-old female goat herder had scrub typhus that persisted after receiving doxycycline for 5 days. Her symptoms continued, prompting us to perform further examinations that revealed coinfection of Q fever and scrub typhus via molecular and serological testing. We also isolated Orientia tsutsugamushi using BALB/c mice and L929 cells.

Evaluation of Th1 and Th2 immune response in clinical and sub-clinical scrub typhus infection.

Scrub typhus (ST), caused by a gram negative intracellular bacteria- Orientia tsutsugamushi, is one among the leading causes of febrile illness across Southeast Asia, including India. Clinical presentation can vary from asymptomatic to severely fatal. Th1-cell mediated immunity has been suggested to play an important role against ST infection in animal models. However, human data on protective immunity are limited. The present study was undertaken to identify host immune correlates that could confer protection in individuals that remain clinically asymptomatic/sub-clinical. Serum cytokine profiling and mRNA expression levels of Th1 (TNF-α, IFN-γ, IL-2) and Th2 (IL-10, IL-6, IL-4) cytokines was studied amongst the clinical and sub-clinical infections. It was observed that a Th1/Th2 pattern is not involved in human ST infection irrespective of being a symptomatic or asymptomatic presentation. However, significant difference was observed in IL-10 serum and gene expression levels. This study suggests a possible role of IL-10 in disease phenotypic presentation. Over-production of IL-10 was found to be a significant factor contributing to the severity of the disease whereas a protective immune mechanism might exist with a low level of IL-10 in ST infection.

Indicators of severe prognosis of scrub typhus: prognostic factors of scrub typhus severity.

BACKGROUND: Scrub typhus is an acute disease, characterized by symptoms of fever, which occurs due to infection by Orientia tsutsugamushi. In most cases, patients recover from the disease with appropriate treatment, but serious and fatal complications may occur. The present study examined laboratory findings and tumor necrosis factor-alpha (TNF-α) levels of scrub typhus patients to identify the prognostic predictors of disease severity. METHOD: Patients whose scrub typhus diagnosis was confirmed by elevated indirect fluorescent antibody (IFA) levels and positive polymerase chain reaction (PCR) results were classified according to disease severity into one of three groups; i.e., deceased (n = 7), severe (n = 15), and mild (n = 15) retrospectively registered. Additionally, the usefulness of modified Acute Physiology and Chronic Health Evaluation II (APACHE II) score, C-reactive protein (CRP) level, white blood cell (WBC) count, and TNF-α level as prognostic predictors were examined. RESULT: The mean TNF-α levels of the deceased, severe, and mild groups were 53.5 (range: 7.8-147.8), 26.0 (1.7-64.4), and 8.8 pg/mL (4.6-16.0), respectively. The results of Kruskal-Wallis tests showed statistically significant differences between the deceased and severe groups versus the mild group (p = 0.005). CRP level and Modified APACHE II score also differed significantly among the groups (p = 0.046 and 0.007, respectively); however, WBC count did not (p = 0.196). CONCLUSION: An elevated serum TNF-α level in patients with scrub typhus could predict a severe condition or death and may be useful in predicting patient prognosis.