Association of scrub typhus with the risk of venous thromboembolism and long-term mortality: a population-based cohort study.

BACKGROUND: The existing literature lacks studies examining the epidemiological link between scrub typhus and deep vein thrombosis (DVT) or pulmonary embolism (PE), and the long-term outcomes. The objective of this study is to explore the potential association between scrub typhus and the subsequent risk of venous thromboembolism, and long-term mortality. METHOD: This nationwide cohort study identified 10,121 patients who were newly diagnosed with scrub typhus. Patients with a prior DVT or PE diagnosis before the scrub typhus infection were excluded. A comparison cohort of 101,210 patients was established from the general population using a propensity score matching technique. The cumulative survival HRs for the two cohorts were calculated by the Cox proportional hazards model. RESULT: After adjusting for sex, age, and comorbidities, the scrub typhus group had an adjusted HR (95% CI) of 1.02 (0.80-1.30) for DVT, 1.11 (0.63-1.93) for PE, and 1.16 (1.08-1.25) for mortality compared to the control group. The post hoc subgroup analysis revealed that individuals younger than 55 years with a prior scrub typhus infection had a significantly higher risk of DVT (HR: 1.59; 95% CI: 1.12-2.25) and long-term mortality (HR: 1.75; 95% CI, 1.54-1.99). CONCLUSION: The scrub typhus patients showed a 16% higher risk of long-term mortality. For those in scrub typhus cohort below 55 years of age, the risk of developing DVT was 1.59 times higher, and the risk of mortality was 1.75 times higher. Age acted as an effect modifier influencing the relationship between scrub typhus and risk of new-onset DVT and death.

Orientia tsutsugamushi DNA load and genotypes in blood as a marker of severity.

Scrub typhus is an acute febrile illness caused by Orientia tsutsugamushi and is endemic to many parts of the Asia-Pacific region. We investigated whether the genotype of O. tsutsugamushi or the DNA load would be a useful marker of disease severity in scrub typhus patients. We evaluated the clinical features, genotypes and bacterial DNA load in the blood of 118 patients, including 114 surviving and 4 non-surviving patients, admitted at Chosun University Hospital. Four patients infected with the Pajoo, Yonchon, Youngworl and Boryong genotypes died. In the 114 survivors, 100 Boryong and 2 Taguchi genotypes were identified. The genotypes involved showed significant differences between the surviving and non-surviving patients (p<0.001). The median number of O. tsutsugamushi DNA copies was 78 copies /µL (range 3,960) in surviving patients, whereas 83,800 copies/µL (range 244,600) in the non-surviving patients. We found that the genotype and DNA load in the patient's blood are useful markers of disease severity in scrub typhus.

Outcome Predictors in Scrub Typhus Requiring Ventilator and Vasopressor Support.

BACKGROUND: Age and serum creatinine are known to be predictors of mortality in scrub typhus patients admitted in intensive care unit. This study aimed to explore the factors predicting mortality in patients with scrub typhus requiring both ventilator and vasopressor support in our set up. METHODS: A retrospective analysis of 43 patients with scrub typhus (ELISA IgM positive, optical density ?0.5) admitted in Medical Intensive Care unit of Chitwan Medical College Teaching Hospital between April 2016 to September 2017 was performed considering recovery or death (poor outcome) as outcome measurement. Potential variables (p<0.25) from bivariate analysis were used to perform a multivariate logistic regression analysis (p<0.10) to predict mortality. RESULTS: The mortality rate was 56% (24/43). Acute respiratory distress syndrome and shock were observed in all 43 patients. The median (IQR) duration of ventilation use and vasopressor use was 53(101) hours and 48(79.5) hours, respectively. On bivariate analysis, an independent and statistically significant association of mortality with age in years (p=0.039), number of vasopressor use (p<0.001) and serum creatinine more than 1.4 mg/dl (p=0.012) was observed and on multivariate regression analysis, these variables were also the predictors of mortality (age in years: p=0.011, ?=0.115, OR=1.211, 95% CI=1.027-1.225; number of vasopressor use: p=0.009, ?=3.705, OR=40.647, 95% CI=2.532-652.425; serum creatinine more than 1.4 mg/dl: p=0.046, ?=-2.205, OR=0.110, 95% CI=0.013-0.961) Conclusions: In scrub typhus with ARDS and septic shock, increasing age and serum creatinine, and requiring more than one vasopressor to maintain blood pressure are at increased risk of mortality.

New-onset atrial fibrillation predicting for complicating cardiac adverse outcome in scrub typhus infection.

BACKGROUND: Scrub typhus is a well-known infectious disorder of the Asia-Pacific region. However, adverse cardiac outcomes are an under-recognized complication of scrub typhus infection, and new-onset AF has been reported to be a prognostic factor in other, more common infectious diseases. The present study investigated whether new-onset atrial fibrillation (AF) is significantly associated with 3-month mortality and adverse cardiac complications in scrub typhus infection. METHODS: We examined data from the National Health Information Database (NHID) which covers nearly the entire population of South Korea, from 2006 to 2016. In total, 233 473 patients diagnosed with scrub typhus infection were selected as study participants. New-onset AF, acute heart failure (AHF), ischemic heart disease (IHD), and 3-month mortality were analyzed using a generalized estimating equation model with a Poisson distribution. RESULTS: Of these, 2402 patients (1%) were diagnosed with new-onset AF (87.2% were over 60 years of age, 43.3% were male). Those with new-onset AF were more likely to have underlying cardiovascular disease compared to those without new-onset AF. After being adjusted for demographic factors and comorbidities, those with new-onset AF had a higher incidence risk of concurrent AHF (4.1-fold) and IHD (1.9-fold) compared with those without new-onset AF. In particular, the 3-month mortality was also significantly associated with new-onset AF (1.3-fold), concurrent AHF (2.4-fold), and IHD (13.7-fold). CONCLUSIONS: New-onset AF was significantly associated with 3-month mortality and concurrent AHF and IHD. Therefore, new-onset AF could be a poor prognostic factor for 3-month mortality and cardiac complications in scrub typhus infection.

Mortality due to scrub typhus - report of five cases.

Scrub typhus is largely ignored in India particularly during outbreaks of viral fever. The disease course is often complicated leading to fatalities in the absence of treatment. However, if diagnosed early and a specific treatment is initiated, the cure rate is high. We report here five cases of scrub typhus to highlight the fact that high clinical suspicion for such a deadly disease is an absolute necessity.

Scrub typhus-associated acute kidney injury: A study from a South Indian Tertiary Care Hospital.

Infections including scrub typhus contribute to a significant proportion of community-acquired acute kidney injury (AKI) in the tropics. Scrub typhus infection now requires global attention since disease outbreaks are being reported across continents. We intended to study the clinical profile, renal involvement, and parameters predicting renal involvement in scrub typhus infection. This is a retrospective study. The medical records of all patients who were admitted and treated for scrub typhus infection for a study period of two years (from September 2015 to August 2017) were analyzed, and salient clinical features and laboratory results were collected from the hospital data. Statistical analysis was done from the collected data. Our study had 272 patients including 81 children. Adults constituted 70.96% (n = 193) and the remaining 29.04% (n = 81) were pediatric population. Among adults, females constituted 62.7% (n = 121) and males 37.3% (n = 72). The mean age of the adult population was 45.7 ± 15 years and that of pediatric patients was 8.56 ±5.1 years. 18.7% of adult cases and 3.70% of pediatric cases had AKI. Renal replacement therapy was required in 3.67% of adult cases. Mortality was 4.14% in adults and 1.23% in children. Hypotension, pulmonary involvement, central nervous system involvement, multiorgan dysfunction syndrome, increased total counts, elevated aspartate transaminase levels, and hypoalbuminemia predicted AKI in our adult population. Scrub typhus should be considered as a differential in cases presenting with fever and AKI. Outcomes of scrub typhus infection in terms of mortality seem to be improving in this region.

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.

Clinical profile and outcome of children with scrub typhus from Chennai, South India.

Scrub typhus is an acute febrile illness caused by Orientia tsutsugamushi. We prospectively studied the clinico-laboratory profile and outcome of 358 children aged 1 day to 18 years diagnosed with scrub typhus from Chennai, South India. All children (100%) had fever. Eschar was seen in 67%. All children were treated with oral doxycycline and those with complications were treated with intravenous chloramphenicol/azithromycin. Rapid defervescence (within 48 h) after initiation of doxycline was seen in 306 (85%) and 52 (14.5%) developed complications. Multivariate logistic regression analysis revealed that children who had an elevated aspartate amino transferase (> 120 IU/L) and the presence of thrombocytopenia (platelet count less than 1 lac cells/mm3) at admission had high risk of developing complications. The overall mortality rate in this series was 0.8%. CONCLUSION: Our 4-year study highlights the clinico-laboratory profile of Scrub typhus in children from Chennai, South India. Early recognition and prompt treatment reduces the complication and mortality. What is Known: • Scrub typhus is endemic to tsutsugamushi triangle, a geographical triangle extending from northern Japan in the east to Pakistan and Afghanistan in the west and northern Australia in the south. • There is paucity of data regarding its clinico-laboratory profile in neonates as well as its predictors of outcome. What is New: • Children who had an elevated AST and the presence of thrombocytopenia at admission had high risk of developing complications.

Estimating the burden of scrub typhus: A systematic review.

BACKGROUND: Scrub typhus is a vector-borne zoonotic disease that can be life-threatening. There are no licensed vaccines, or vector control efforts in place. Despite increasing awareness in endemic regions, the public health burden and global distribution of scrub typhus remains poorly known. METHODS: We systematically reviewed all literature from public health records, fever studies and reports available on the Ovid MEDLINE, Embase Classic + Embase and EconLit databases, to estimate the burden of scrub typhus since the year 2000. FINDINGS: In prospective fever studies from Asia, scrub typhus is a leading cause of treatable non-malarial febrile illness. Sero-epidemiological data also suggest that Orientia tsutsugamushi infection is common across Asia, with seroprevalence ranging from 9.3%-27.9% (median 22.2% IQR 18.6-25.7). A substantial apparent rise in minimum disease incidence (median 4.6/100,000/10 years, highest in China with 11.2/100,000/10 years) was reported through passive national surveillance systems in South Korea, Japan, China, and Thailand. Case fatality risks from areas of reduced drug-susceptibility are reported at 12.2% and 13.6% for South India and northern Thailand, respectively. Mortality reports vary widely around a median mortality of 6.0% for untreated and 1.4% for treated scrub typhus. Limited evidence suggests high mortality in complicated scrub typhus with CNS involvement (13.6% mortality), multi-organ dysfunction (24.1%) and high pregnancy miscarriage rates with poor neonatal outcomes. INTERPRETATION: Scrub typhus appears to be a truly neglected tropical disease mainly affecting rural populations, but increasingly also metropolitan areas. Rising minimum incidence rates have been reported over the past 8-10 years from countries with an established surveillance system. A wider distribution of scrub typhus beyond Asia is likely, based on reports from South America and Africa. Unfortunately, the quality and quantity of the available data on scrub typhus epidemiology is currently too limited for any economical, mathematical modeling or mapping approaches.

Scrub Typhus Leading to Acute Encephalitis Syndrome, Assam, India.

To determine the contribution of Orientia tsutsugamushi, the agent of scrub typhus, as a cause of acute encephalitis syndrome (AES) in Assam, India, we conducted a retrospective study of hospital patients with symptoms of AES during 2013-2015. Our findings suggest that O. tsutsugamushi infection leads to AES and the resulting illness and death.

Pattern of Clinical Presentation, Laboratory Findings and Mortality Risk Among Patients of Scrub Typhus in Western Himalayas.

OBJECTIVE: To study the pattern of the clinical presentation, laboratory findings and mortality risk among patients infected by scrub typhus in Western Himalayan region of India. METHODS: We studied all serologically confirmed cases of scrub typhus admitted to our hospital from July 2010 through December 2011. Presence of IgM antibodies to scrub typhus antigens by ELISA was considered as serological confirmation of the diagnosis. We observed the symptoms, signs, laboratory findings, risk factors for death from the time of admission till discharge/death. We performed bivariate and logistic regression analysis to look for independent risk factors for death. RESULTS: Total 253 patients were studied. All patients came from rural areas. More than 2/3rd were women and below 50 years of age each. High grade fever (90%), chills and rigors (68%), conjunctival suffusion (50%), body aches (43%), headache (41%), myalgias (37%), abdominal pain (21%), lymphadenopathy (17%), splenomegaly (17%), cough (16%), altered sensorium (16%), vomiting (15%), hepatomegaly (13%) were main presenting features. Eschar was present in 112 (44%) patients. Transaminitis (49%); and abnormal renal functions (31%) were predominant biochemical abnormalities. All patients were empirically treated with doxycycline/azithromycin. Thirteen (5%) patients died. CONCLUSIONS: In our region, rural women below 50 years of age presenting with high grade fever with or without eschar should be strongly suspected to be having scrub typhus. Renal dysfunction and altered sensorium are significant mortality risk factors (p < 0.05) and need to be identified at early stage to improve the treatment outcomes.

Scrub Typhus in Northeastern Thailand: Eschar Distribution, Abnormal Electrocardiographic Findings, and Predictors of Fatal Outcome.

Scrub typhus is endemic in Thailand. Of the 495 patients with acute undifferentiated fever studied in Maharat Nakhon Ratchasima Hospital, Nakhon Ratchasima, Thailand, from June 1, 2011, to December 31, 2012, 146 patients (29.5%) had confirmed scrub typhus. The majority of cases were male, farmers, with the mean (±standard deviation) age of 54.1 ± 15.2 years. A total of 59 patients (40.4%) had eschar lesion. The commonest sites for an eschar in male patients were the perineum, inguinal, and buttock area; whereas in females, it was the head and neck area. Abnormal electrocardiogram was found in 39 of 79 patients (49.4%) with sinus tachycardia being the most frequent finding (17, 21.5%). A total of 73 patients (50%) had at least one complication. Myocarditis was the cause of complete heart block in a scrub typhus patient, and he fully recovered after receiving intravenous chloramphenicol treatment. The case fatality rate was 6.2% (nine deaths).The independent predictors for fatal outcome were age over 65 years (odds ratio [OR] = 14.49, 95% confidence interval [CI] = 1.26-166.44, P = 0.03), acute kidney injury (OR = 12.75, 95% CI = 1.77-92.07, P = 0.01), and hyperbilirubinemia (OR = 24.82, 95% CI = 2.12-286.61, P = 0.01). Early diagnosis and prompt appropriate treatment can improve the patient's outcome.

Scrub Typhus in a Tertiary Care Hospital in North India.

Scrub typhus, a zoonotic disease caused by the bacterium Orientia tsutsugamushi, has become endemic in many parts of India. We studied the clinical profile of this infection in 228 patients that reported to this tertiary care center from July 2013 to December 2014. The median age of patients was 35 years (interquartile range = 24.5-48.5 years), and 111 were males and 117 females. A high-grade fever occurred in 85%, breathlessness in 42%, jaundice in 32%, abdominal pain in 28%, renal failure in 11%, diarrhea in 10%, rashes in 9%, and seizures in 7%. Common laboratory abnormalities at presentation were a deranged hepatic function in 61%, anemia in 54%, leukopenia in 15%, and thrombocytopenia in 90% of our patients. Acute kidney injury (32%), acute respiratory distress syndrome (ARDS) (25%), and disseminated intravascular coagulation (DIC) (16%) were the commonest complications. A hepatorenal syndrome was seen in 38% and multiple organ dysfunction syndrome (MODS) in 20% patients. The overall case fatality rate was 13.6%. In univariate analysis, ARDS requiring mechanical ventilation, acute kidney injury requiring hemodialysis, hypotension requiring inotropic support, central nervous system dysfunction at presentation, and MODS were inversely associated with survival. Survival was significantly higher in patients that presented with a duration of fever < 10 days compared with those that presented ≥ 12 days (P < 0.05) after onset. In conclusion, scrub typhus has become a leading infectious disease in north India and an important cause of infectious fever. An increasing awareness of this disease coupled with prompt management will go a long way in reducing both morbidity and mortality from this disease.

Scrub typhus in Uttarakhand & adjoining Uttar Pradesh: Seasonality, clinical presentations & predictors of mortality.

BACKGROUND & OBJECTIVES: Scrub typhus is a re-emerging mite-borne rickettsiosis, which continues to be underdiagnosed, with lethal consequences. The present study was conducted to determine the seasonality, clinical presentation and predictors of mortality in patients with scrub typhus at a tertiary care teaching hospital in northern India. METHODS: Scrub typhus was suspected in patients attending the hospital as per the standard case definition and serological evidence was obtained by performing an IgM ELISA. RESULTS: A total of 284 patients with scrub typhus from urban and rural areas were seen, predominantly from July to November. The most common clinical presentation was a bilateral community-acquired pneumonia (CAP), which resembled pneumonia due to atypical pathogens and often progressed to acute respiratory distress syndrome (ARDS). An acute undifferentiated febrile illness (AUFI) or a febrile illness associated with altered sensorium, aseptic meningitis, shock, abdominal pain, gastrointestinal bleeding or jaundice was also seen. Eschars were seen in 17 per cent of patients, and thrombocytopenia, transaminitis and azotaemia were frequent. There were 24 deaths (8.5%) caused predominantly by ARDS and multi-organ dysfunction. The mortality in patients with ARDS was high (37%). ARDS [odds ratio (OR)=38.29, 95% confidence interval (CI): 9.93, 147.71] and acute kidney injury (OR=8.30, 95% CI: 2.21, 31.21) were the major predictors of death. INTERPRETATION & CONCLUSIONS: The present findings indicate that scrub typhus may be considered a cause of CAP, ARDS, AUFI or a febrile illness with multisystem involvement, in Uttarakhand and Uttar Pradesh, especially from July to November. Empiric therapy of CAP may include doxycycline or azithromycin to ensure coverage of underlying unsuspected scrub typhus.

A Systematic Review of Mortality from Untreated Scrub Typhus (Orientia tsutsugamushi).

BACKGROUND: Scrub typhus, a bacterial infection caused by Orientia tsutsugamushi, is increasingly recognized as an important cause of fever in Asia, with an estimated one million infections occurring each year. Limited access to health care and the disease's non-specific symptoms mean that many patients are undiagnosed and untreated, but the mortality from untreated scrub typhus is unknown. This review systematically summarizes the literature on the untreated mortality from scrub typhus and disease outcomes. METHODOLOGY/PRINCIPAL FINDINGS: A literature search was performed to identify patient series containing untreated patients. Patients were included if they were symptomatic and had a clinical or laboratory diagnosis of scrub typhus and excluded if they were treated with antibiotics. The primary outcome was mortality from untreated scrub typhus and secondary outcomes were total days of fever, clinical symptoms, and laboratory results. A total of 76 studies containing 89 patient series and 19,644 patients were included in the final analysis. The median mortality of all patient series was 6.0% with a wide range (min-max) of 0-70%. Many studies used clinical diagnosis alone and had incomplete data on secondary outcomes. Mortality varied by location and increased with age and in patients with myocarditis, delirium, pneumonitis, or signs of hemorrhage, but not according to sex or the presence of an eschar or meningitis. Duration of fever was shown to be long (median 14.4 days Range (9-19)). CONCLUSIONS: Results show that the untreated mortality from scrub typhus appears lower than previously reported estimates. More data are required to clarify mortality according to location and host factors, clinical syndromes including myocarditis and central nervous system disease, and in vulnerable mother-child populations. Increased surveillance and improved access to diagnostic tests are required to accurately estimate the untreated mortality of scrub typhus. This information would facilitate reliable quantification of DALYs and guide empirical treatment strategies.

Increased endothelial and macrophage markers are associated with disease severity and mortality in scrub typhus.

OBJECTIVES: Scrub typhus is endemic in the Asia-Pacific region. Mortality is high even with treatment, and further knowledge of the immune response during this infection is needed. This study was aimed at comparing plasma levels of monocyte/macrophage and endothelial related inflammatory markers in patients and controls in South India and to explore a possible correlation to disease severity and clinical outcome. METHODS: Plasma levels of ALCAM, VCAM-1, sCD163, sCD14, YKL-40 and MIF were measured in scrub typhus patients (n = 129), healthy controls (n = 31) and in infectious disease controls (n = 31), both in the acute phase and after recovery, by enzyme immunoassays. RESULTS: Patients had markedly elevated levels of all mediators in the acute phase, differing from both healthy and infectious disease controls. During follow-up levels of ALCAM, VCAM-1, sCD14 and YKL-40 remained elevated compared to levels in healthy controls. High plasma ALCAM, VCAM-1, sCD163, sCD14, and MIF, and in particular YKL-40 were all associated with disease severity and ALCAM, sCD163, MIF and especially YKL-40, were associated with mortality. CONCLUSIONS: Our findings show that scrub typhus is characterized by elevated levels of monocyte/macrophage and endothelial related markers. These inflammatory markers, and in particular YKL-40, may contribute to disease severity and clinical outcome.

Clinical profile and improving mortality trend of scrub typhus in South India.

BACKGROUND: Scrub typhus, a bacterial zoonosis caused by Orientia tsutsugamushi, may cause multiorgan dysfunction syndrome (MODS) and is associated with significant mortality. This study was undertaken to document the clinical and laboratory manifestations and complications and to study time trends and factors associated with mortality in patients with scrub typhus infection. METHODS: This retrospective study, done at a university teaching hospital, included 623 patients admitted between 2005 and 2010 with scrub typhus. The diagnosis was established by a positive IgM ELISA and/or pathognomonic eschar with PCR confirmation where feasible. The clinical and laboratory profile, course in hospital, and outcome were documented. Factors associated with mortality were analyzed using multivariate logistic regression analysis. RESULTS: The most common presenting symptoms were fever (100%), nausea/vomiting (54%), shortness of breath (49%), headache (46%), cough (38%), and altered sensorium (26%). An eschar was present in 43.5% of patients. Common laboratory findings included elevated transaminases (87%), thrombocytopenia (79%), and leukocytosis (46%). MODS was seen in 34% of patients. The overall case-fatality rate was 9.0%. Features of acute lung injury were observed in 33.7%, and 29.5% required ventilatory support. On multivariate analysis, shock requiring vasoactive agents (relative risk (RR) 10.5, 95% confidence interval (CI) 4.2-25.7, p<0.001), central nervous system (CNS) dysfunction (RR 5.1, 95% CI 2.4-10.7, p<0.001), and renal failure (RR 3.6, 95% CI 1.7-7.5, p=0.001) were independent predictors of mortality. Over 4 years, a decreasing trend was observed in the mortality rate. CONCLUSIONS: Scrub typhus can manifest with potentially life-threatening complications such as lung injury, shock, and meningoencephalitis. MODS occurred in a third of our patients. The overall case-fatality rate was 9%, with shock, renal failure, and CNS associated with a higher mortality.

Cytokine network in scrub typhus: high levels of interleukin-8 are associated with disease severity and mortality.

BACKGROUND: Scrub typhus, caused by Orientia tsutsugamushi, is endemic in the Asia-Pacific region. Mortality is high if untreated, and even with treatment as high as 10-20%, further knowledge of the immune response during scrub typhus is needed. The current study was aimed at comparing plasma levels of a variety of inflammatory mediators in scrub typhus patients and controls in South India in order to map the broader cytokine profile and their relation to disease severity and clinical outcome. METHODOLOGY/PRINCIPAL FINDINGS: We examined plasma levels of several cytokines in scrub typhus patients (n = 129) compared to healthy controls (n = 31) and infectious disease controls (n = 31), both in the acute phase and after recovery, by multiplex technology and enzyme immunoassays. Scrub typhus patients were characterized by marked changes in the cytokine network during the acute phase, differing not only from healthy controls but also from infectious disease controls. While most of the inflammatory markers were raised in scrub typhus, platelet-derived mediators such as RANTES were markedly decreased, probably reflecting enhanced platelet activation. Some of the inflammatory markers, including various chemokines (e.g., interleukin-8, monocyte chemoattractant peptide-1 and macrophage inflammatory protein-1ß) and downstream markers of inflammation (e.g., C-reactive protein and pentraxin-3), were also associated with disease severity and mortality during follow-up, with a particular strong association with interleukin-8. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that scrub typhus is characterized by a certain cytokine profile that includes dysregulated levels of a wide range of mediators, and that this enhanced inflammation could contribute to disease severity and clinical outcome.

Outcome of intravenous azithromycin therapy in patients with complicated scrub typhus compared with that of doxycycline therapy using propensity-matched analysis.

There are no well-matched, controlled studies comparing azithromycin with doxycycline for the treatment of complicated scrub typhus. A retrospective propensity score-matched case-control study was performed for patients who presented with complicated scrub typhus and were treated with doxycycline or azithromycin between 2001 and 2011. Data on comorbidities, clinical manifestations, laboratory studies, treatments, and outcomes were extracted for analysis. The clinical characteristics and outcomes of the azithromycin-treated group (n=73) were compared to those of the doxycycline-treated group (n=108). Of 181 patients, 73 from each group were matched by propensity scores. There were no significant differences in baseline characteristics between the matched groups. The treatment success and survival rates were not significantly different (89% [65/73 patients] versus 96% [70/73 patients] and 96% [70/73 patients] versus 96% [70/73 patients], respectively [P>0.05]). No difference was observed in the time to defervescence or length of hospital stay between the two groups (P>0.05). In complicated scrub typhus patients (n=181), multivariate analysis showed that only APACHE II score was an independent risk factor for mortality (95% confidence interval, 1.11 to 1.56; P<0.001). Our data suggest that outcomes of azithromycin therapy are comparable to those of doxycycline therapy in patients with complicated scrub typhus.