Canonical notch activation in patients with scrub typhus: association with organ dysfunction and poor outcome.

PURPOSE: The mechanisms that control inflammation in scrub typhus are not fully elucidated. The Notch pathways are important regulators of inflammation and infection, but have not been investigated in scrub typhus. METHODS: Plasma levels of the canonical Notch ligand Delta-like protein 1 (DLL1) were measured by enzyme immunoassay and RNA expression of the Notch receptors (NOTCH1, NOTCH2 and NOTCH4) in whole blood was analyzed by real-time PCR in patients with scrub typhus (n = 129), in patients with similar febrile illness without O. tsutsugamushi infection (n = 31) and in healthy controls (n = 31); all from the same area of South India. RESULTS: Our main results were: (i) plasma DLL1 was markedly increased in scrub typhus patients at hospital admission with a significant decrease during recovery. (ii) RNA expression of NOTCH4 was decreased at admission in whole blood. (iii) A similar pattern for DLL1 and NOTCH4 was seen in febrile disease controls. (iv) Admission DLL1 in plasma was associated with disease severity and short-term survival. (vi) Regulation of Notch pathways in O. tsutsugamushi-infected monocytes as evaluated by public repository data revealed enhanced canonical Notch activation with upregulation of DLL1 and downregulation of NOTCH4. CONCLUSION: Our findings suggest that scrub typhus patients are characterized by enhanced canonical Notch activation. Elevated plasma levels of DLL1 were associated with organ dysfunction and poor outcomes in these patients.

Oral Azithromycin Versus Doxycycline in the Treatment of Children With Uncomplicated Scrub Typhus: A Randomized Controlled Trial.

OBJECTIVES: To compare the efficacy of azithromycin versus doxycycline in treatment of children with uncomplicated scrub typhus in terms of percentage of children who attained remission of fever after 72 hours of administration of first dose of the study drug, mean time taken to attain fever defervescence, normalization of laboratory parameters, resolution of hepatosplenomegaly and lymphadenopathy. DESIGN: Interventional, open-labeled randomized controlled trial. STUDY METHODS: Patients admitted with undifferentiated fever in the In-Patient Department (IPD), Department of Paediatrics, All India Institute of Medical Sciences, Bhubaneswar, India, as per the inclusion criteria were randomized and was treated with azithromycin at 10 mg/kg/d in one group and doxycycline at 4.4 mg/kg/d for 5 days in the other group and was assessed based on the primary and secondary objectives. RESULTS: There was no statistically significant difference between the percentage of children who attained remission of fever after 72 hours of administration of azithromycin (98.2%) and doxycycline (96.5%) (P value 0.47) and the average time taken for fever defervescence (azithromycin: 24.53 hours; doxycycline: 25.82 hours; P value 0.36). The odds of attaining fever remission in the doxycycline group as compared with the azithromycin group was 1.01 (95% confidence interval -0.60 to -1.71), which was also statistically not significant. There was less incidence of adverse drug events in the azithromycin group (1.78%) as compared with the doxycycline group (8.6%), which was statistically significant (P value 0.02). CONCLUSION: Azithromycin is equally efficacious in terms of fever defervescence, resolution of clinical signs and laboratory parameters as doxycycline, is safer and better tolerated in children.

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.

Analysis of 262 Children with Scrub Typhus Infection: A Single-Center Experience.

Scrub typhus, a vector-borne rickettsiosis, is the leading treatable cause of non-malarial febrile illness in Asia. The myriad of typical and atypical features poses a clinical conundrum. We aimed to study the clinical and laboratory profile of children with scrub typhus infection diagnosed by IgM ELISA. Data of children < 12 years presenting with undifferentiated fever to the pediatric services of a tertiary teaching institute between January 2012 and December 2018 were retrieved. Children with seropositive IgM ELISA (InBios International Kit, Seattle, WA) for scrub typhus were enrolled in the study. Clinical features, laboratory investigations, treatment received, and the outcome recorded were obtained. Objective evidence of organ dysfunction was taken as severe scrub typhus. In total, 262 children were diagnosed with scrub typhus. The mean age was 5 years, with male preponderance (65%). And, 13 children presented during infancy. Fever was universal, and generalized lymphadenopathy (93.5%) and hepatomegaly (70%) were the common clinical signs. Eschar was identified in 31%, with greater predilection for groin and axilla. Thrombocytopenia was striking in one-third of children. Also, 25 children (9.5%) had severe scrub typhus and 18 required intensive care stay. Elevated aspartate aminotransferase enzyme levels was a predictor of severity ([OR 3.9], P value 0.005) by multivariate analysis. Lymphadenopathy was found significantly associated with eschar (P < 0.005). No mortality was recorded. This 6-year study underscores the varied spectrum of pediatric scrub typhus infection. Zero mortality in our cohort signifies the excellent outcome with judicious first-line antibiotics.

The Characteristics and Clinical Course of Patients with Scrub Typhus and Queensland Tick Typhus Infection Requiring Intensive Care Unit Admission: A 23-year Case Series from Queensland, Tropical Australia.

Scrub typhus and Queensland tick typhus (QTT)-rickettsial infections endemic to tropical Australia-can cause life-threatening disease. This retrospective study examined the clinical course of all patients with laboratory-confirmed scrub typhus or QTT admitted to the intensive care unit (ICU) of a tertiary referral hospital in tropical Australia between 1997 and 2019. Of the 22 patients, 13 had scrub typhus and nine had QTT. The patients' median (interquartile range [IQR]) age was 50 (38-67) years; 14/22 (64%) had no comorbidity. Patients presented a median (IQR) of seven (5-10) days after symptom onset. Median (IQR) Acute Physiology and Chronic Health Evaluation II scores were 13 (9-17) for scrub typhus and 13 (10-15) for QTT cases (P = 0.61). Following hospital admission, the median (IQR) time to ICU admission was five (2-19) hours. The median (IQR, range) length of ICU stay was 4.4 (2.9-15.9, 0.8-33.8) days. Multi-organ support was required in 11/22 (50%), 5/22 (22%) required only vasopressor support, 2/22 (9%) required only invasive ventilation, and 4/22 (18%) were admitted for monitoring. Patients were ventilated using protective lung strategies, and fluid management was conservative. Standard vasopressors were used, indications for renal replacement therapy were conventional, and blood product usage was restrictive; 9/22 (41%) received corticosteroids. One patient with QTT died, and two (8%) additional patients with QTT developed purpura fulminans requiring digital amputation. Death or permanent disability occurred in 3/9 (33%) QTT and 0/13 scrub typhus cases (P = 0.055). Queensland tick typhus and scrub typhus can cause multi-organ failure requiring ICU care in otherwise well individuals. Queensland tick typhus appears to have a more severe clinical phenotype than previously believed.

Haemorrhagic encephalitis in the garb of scrub typhus.

A 19-year-old girl presented with fever, headache, vomiting and drowsiness. She had grade 1 papilloedema and neck rigidity but no focal deficits or seizures. Cerebrospinal fluid analysis revealed lymphocytic pleocytosis, slightly elevated protein and normal glucose. MRI of the brain showed a hyperintense lesion in left ganglio-capsular region on the fluid attenuation inversion recovery sequence with perilesional oedema and mild midline shift. Haemorrhage was seen in the region on susceptibility weighted imaging . The patient was thoroughly investigated for known causes of meningoencephalitis, but the diagnosis of scrub typhus was delayed till the 10th day of illness. She was treated with doxycycline for 2 weeks and had marked improvement, both clinically and radiologically. Literature review has revealed that although meningoencephalitis in scrub typhus is not uncommon, such atypical lesions on brain MRI are a rarity. Serial imaging was performed to document the disease progression and resolution on treatment.

The epidemiology and clinical features of rickettsial diseases in North Queensland, Australia: Implications for patient identification and management.

BACKGROUND: Rickettsial infections are a common cause of hospitalization in tropical settings, although early diagnosis is challenging in the rural locations where these infections are usually seen. METHODS: This retrospective, clinical audit of microbiologically-confirmed cases of scrub typhus or spotted fever group (SFG) rickettsial infection between 1997 and 2016 was performed a tertiary referral hospital in tropical Australia. Clinical, laboratory and radiological findings at presentation were correlated with the patients' subsequent clinical course. RESULTS: There were 135 locally-acquired cases (95 scrub typhus, 37 SFG, 3 undifferentiated). There were nine hospitalizations during the first 5 years of the study period and 81 in the last 5 years (p for trend = 0.003). Eighteen (13%) of the 135 cases required ICU admission, all of whom were adults. A greater proportion of patients with SFG infection required ICU support (8/37 (22%) compared with 10/95 (11%) scrub typhus cases), although this difference did not reach statistical significance (p = 0.10). Three (8%) of the 37 patients with SFG infection had severe disease (1 died, 2 developed permanent disability) versus 0/95 scrub typhus patients (p = 0.02). Adults with a high admission qSOFA score (≥2) had an odds ratio (OR) of 19 (95% CI:4.8-74.5) for subsequent ICU admission (p<0.001); adults with a high NEWS2 score (≥7) had an OR of 14.3 (95% CI:4.5-45.32) for ICU admission (p<0.001). A patient's respiratory rate at presentation had strong prognostic utility: if an adult had an admission respiratory rate <22 breaths/minute, the negative predictive value for subsequent ICU admission was 95% (95% CI 88-99). CONCLUSIONS: In the well-resourced Australian health system outcomes are excellent, but the local burden of rickettsial disease appears to be increasing and the clinical phenotype of SFG infections may be more severe than previously believed. Simple, clinical assessment on admission has prognostic utility and may be used to guide management.

Profile of Pediatric Scrub Typhus in Odisha, India.

OBJECTIVE: To investigate the distribution and clinical profile of scrub typhus infection among children with acute febrile illness in Odisha. METHODS: Children (<15 y) presenting with acute fever (>5 days) in 4 agro-climatic zones from June to November 2017 were evaluated. Patients were screened for malaria, leptospira, dengue, typhoid and scrub typhus. Scrub typhus was confirmed by IgM ELISA and PCR. RESULTS: Out of 413 cases examined, 48.7% were positive for scrub typhus, and 5.5% of them developed systemic complications. Eschar was found in 17.9% of cases. Five days treatment of Doxycycline and/or Azithromycin was clinically effective against scrub typhus. CONCLUSIONS: Our study highlights that scrub typhus is one of the causes of high morbidity in children during rainy months in Odisha.

Clinical Manifestations and Molecular Diagnosis of Scrub Typhus and Murine Typhus, Vietnam, 2015-2017.

Rickettsioses are endemic to Vietnam; however, only a limited number of clinical studies have been performed on these vectorborne bacteria. We conducted a prospective hospital-based study at 2 national referral hospitals in Hanoi to describe the clinical characteristics of scrub typhus and murine typhus in northern Vietnam and to assess the diagnostic applicability of quantitative real-time PCR assays to diagnose rickettsial diseases. We enrolled 302 patients with acute undifferentiated fever and clinically suspected rickettsiosis during March 2015-March 2017. We used a standardized case report form to collect clinical information and laboratory results at the time of admission and during treatment. We confirmed scrub typhus in 103 (34.1%) patients and murine typhus in 12 (3.3%) patients. These results highlight the need for increased emphasis on training for healthcare providers for earlier recognition, prevention, and treatment of rickettsial diseases in Vietnam.

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.

Scrub Typhus and Abnormal Electrocardiography.

This study compared the frequency of abnormal electrocardiogram (ECG) types between scrub typhus patient group and age- and gender-matched health checkup group and their associations with disease severity in scrub typhus patient. Demographic characteristics and ECG and laboratory findings of patients with scrub typhus admitted to Chosun University Hospital, and normal subjects visiting the hospital for health checkup from January 2008 to December 2012 were retrospectively studied. Electrocardiogram abnormalities at admission were observed in 72 of 165 (43.6%) scrub typhus confirmed patients. The following ECG abnormalities were observed: arrhythmic group (31 cases, 18.8%), ischemic change group (25 cases, 15.1%), prolonged QT group (32 cases, 19.4%).Compared with the age and gender-matched health checkup group, ECG abnormalities were more commonly observed in scrub typhus patient group (13.9% versus 43.6%, P < 0.001). In addition, when compared with the normal ECG group, scrub typhus in the abnormal ECG group showed greater disease severity and this phenomenon was particularly prominent in the prolonged QT group. Based on our study prolonged QT observed in approximately 20% of patients with scrub typhus, clinicians should pay additional attention to drugs that affect QT interval.

Characteristics of scrub typhus, murine typhus, and Q fever among elderly patients: Prolonged prothrombin time as a predictor for severity.

BACKGROUND/PURPOSE: The clinical manifestations of scrub typhus, murine typhus and acute Q fever in the elderly are not clear. METHODS: We conducted a retrospective study to identify the characteristics of the elderly aged ≥65 years with a comparison group aged 18-64 years among patients with scrub typhus, murine typhus, or acute Q fever who were serologically confirmed at three hospitals in Taiwan during 2002-2011. RESULTS: Among 441 cases, including 187 cases of scrub typhus, 166 acute Q fever, and 88 murine typhus, 68 (15.4%) cases were elderly patients. The elderly had a higher severe complication rate (10.3% vs. 3.5%, p = 0.022), but did not have a significantly higher mortality rate (1.47% vs. 0.54%, p = 0.396). Compared with those without severe complications, we found the elderly (p = 0.022), dyspnea (p = 0.006), less relative bradycardia (p = 0.004), less febrile illness (p = 0.004), prolonged prothrombin time (PT) (p = 0.002), higher levels of initial C-reactive protein (p = 0.039), blood leukocyte counts (p = 0.01), and lower platelet counts (p = 0.012) are significantly associated with severe complications. Only prolonged prothrombin time was associated with severe complications in multivariate analysis (p = 0.018, CI 95% 0.01-0.66). Among clinical symptoms and laboratory data, multivariate analysis revealed chills was less frequently occurred in the elderly (p = 0.012, 95% confidence interval [CI]: 1.33-9.99). CONCLUSION: The elderly cases with scrub typhus, murine typhus, or acute Q fever would be more likely to have severe complications, for which prothrombin time prolongation is an important predictor for severe complications.

Hemophagocytic lymphohistiocytosis with neurological manifestations in an infant with scrub typhus: a rare fatal occurrence.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of unchecked activation of the immune system leading to phagocytosis of blood cells and proliferation of histiocytes in solid organs. HLH can be primary or secondary to infective, autoimmune and malignant conditions. Scrub typhus is an infective illness caused by Orientia tsutsugamushi, transmitted by mite. The illness ranges from mild fever with rash to severe multisystem illness. Scrub typhus has rarely been associated with secondary HLH. We report an infant with scrub typhus who progressed to develop HLH with central nervous system involvement with fatal outcome.

Case Report: Concurrent Sympatric Scrub Typhus and Japanese Spotted Fever in Japan.

Scrub typhus and Japanese spotted fever-both rickettsial diseases-are endemic and notifiable in Japan and may cause a fatal outcome without prompt treatment. Here we present the first case of a concurrent sympatric infection of both diseases with grade II evidence. A 67-year-old woman, after a single event of potential exposure to the pathogens, presented with a 12-day history of fever, pharyngeal pain, papulo-erythematous rash, and pronounced fatigue. Her erythematous rash was distributed on her trunk and extremities, palms, and soles and eventually progressed to purpura. Fever persisted until doxycycline was administered on day 12. A significant > 4-fold increase in immunoglobulin G and immunoglobulin M titers against multiple serotypes of Orientia tsutsugamushi and Rickettsia japonica were revealed by indirect immunoperoxidase assays. These clinical and serological data, even in the absence of molecular or isolation evidence, provided grade II evidence that this was a concurrent infection of sympatric scrub typhus and Japanese spotted fever.

Dysfunction of Circulating Natural Killer T Cells in Patients With Scrub Typhus.

Background: Human natural killer T (NKT) cells are known to serve as regulatory and/or effector cells in infectious diseases. However, little is known about the role of NKT cells in Orientia tsutsugamushi infection. Accordingly, the objective of this study was to examine the level and function of NKT cells in patients with scrub typhus. Methods: This study included 62 scrub typhus patients and 62 healthy controls (HCs). NKT cell level and function in peripheral blood samples were measured by flow cytometry. Results: Proliferation of NKT cells and their ability to produce interferon-γ and interleukin-4 (IL-4) were significantly lower in scrub typhus patients compared to those in HCs. However, circulating NKT cell levels were comparable between patients and HCs. Expression levels of CD69, programmed death-1 (PD-1), lymphocyte activation gene-3 (LAG-3), and T-cell immunoglobulin domain and mucin domain-containing molecule-3 (TIM-3) were significantly increased in scrub typhus patients. Elevated expression of CD69, PD-1, LAG-3, and TIM-3, impaired proliferation, and decreased IL-4 production by NKT cells were recovered in the remission phase. Conclusions: This study demonstrates that circulating NKT cells are numerically preserved but functionally impaired in scrub typhus patients. In addition, NKT cell dysfunction is recovered in the remission phase.

The reliability of the clinical examination in predicting hemodynamic status in acute febrile illness in a tropical, resource-limited setting.

Introduction: The clinical examination alone is widely considered unreliable when assessing fluid responsiveness in critically ill patients. Little evidence exists on the performance of the clinical examination to predict other hemodynamic derangements or more complex hemodynamic states. Materials and methods: Patients with acute febrile illness were assessed on admission, both clinically and per non-invasive hemodynamic measurement. Correlations between clinical signs and hemodynamics patterns were analyzed, and the predictive capacity of the clinical signs was examined. Results: Seventy-one patients were included; the most common diagnoses were bacterial sepsis, scrub typhus and dengue infection. Correlations between clinical signs and hemodynamic parameters were only statistically significant for Cardiac Index (r=0.75, p-value <0.01), Systemic Vascular Resistance Index (r=0.79, p-value <0.01) and flow time corrected (r=0.44, p-value 0.03). When assessing the predictive accuracy of clinical signs, the model identified only 62% of hemodynamic states correctly, even less if there was more than one hemodynamic abnormality. Discussion: The clinical examination is not reliable to assess a patient's hemodynamic status in acute febrile illness. Fluid responsiveness, cardiodepression and more complex hemodynamic states are particularly easily missed.

Elevated levels of von Willebrand factor and high mobility group box 1 (HMGB1) are associated with disease severity and clinical outcome of scrub typhus.

OBJECTIVES: This study aimed to investigate whether von Willebrand factor (vWF) and high mobility group box 1 (HMGB1) are associated with the severity and clinical outcome of scrub typhus and to seek novel biomarkers for surveillance and prediction of the prognosis of this infection. METHODS: Serum concentrations of vWF and HMGB1 were measured twice by ELISA for scrub typhus patients (n=103), once prior to doxycycline therapy and then on day 7 of doxycycline therapy; concentrations were measured once for healthy controls (n=32). RESULTS: Among the total 103 patients enrolled, 38 had disease complicated by multiple organ dysfunction syndrome (MODS). Serum concentrations of vWF and HMGB1 were significantly higher in all the patients than in the healthy controls, both prior to doxycycline treatment and on day 7 of doxycycline treatment (p<0.01). Furthermore, serum levels of vWF, HMGB1, and creatinine (SCr) in the patients with MODS increased distinctly, while the platelet (PLT) count diminished markedly compared to the levels in patients without MODS (p<0.01). The concentration of vWF was positively correlated with that of HMGB1 (r=0.764, p<0.001) and SCr (r=0.528, p<0.001), but negatively correlated with the PLT count (r=-0.632, p<0.001). Both HMGB1 and vWF were significantly associated with mortality in scrub typhus (area under the curve (AUC)=0.864, p=0.001, and AUC=0.862, p=0.001, respectively). CONCLUSIONS: Elevated levels of vWF and HMGB1 are associated with the severity and clinical outcome of scrub typhus. These represent possible new biomarkers for use in the assessment and prognostic prediction of this infection.

Lateral Flow Rapid Test for Accurate and Early Diagnosis of Scrub Typhus: A Febrile Illness of Historically Military Importance in the Pacific Rim.

Scrub typhus (ST) is an infection caused by Orientia tsutsugamushi. Historically, ST was ranked as the second most important arthropod-borne medical problem only behind malaria during World War II and the Vietnam War. The disease occurs mainly in Southeast Asia and has been shown to emerge and reemerge in new areas, implying the increased risk for U.S. military and civilian personnel deployed to these regions. ST can effectively be treated by doxycycline provided the diagnosis is made early, before the development of severe complications. Scrub Typhus Detect is a lateral flow rapid test based on a mixture of recombinant 56-kDa antigens with broad reactivity. The performance of this prototype product was evaluated against indirect immunofluorescence assay, the serological gold standard. Using 249 prospectively collected samples from Thailand, the sensitivity and specificity for IgM was found to be 100% and 92%, respectively, suggesting a high potential of this product for clinical use. This product will provide a user friendly, rapid, and accurate diagnosis of ST for clinicians to provide timely and accurate treatments of deployed personnel.

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.