Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus.

BACKGROUND: The appropriate antibiotic treatment for severe scrub typhus, a neglected but widespread reemerging zoonotic infection, is unclear. METHODS: In this multicenter, double-blind, randomized, controlled trial, we compared the efficacy of intravenous doxycycline, azithromycin, or a combination of both in treating severe scrub typhus. Patients who were 15 years of age or older with severe scrub typhus with at least one organ involvement were enrolled. The patients were assigned to receive a 7-day course of intravenous doxycycline, azithromycin, or both (combination therapy). The primary outcome was a composite of death from any cause at day 28, persistent complications at day 7, and persistent fever at day 5. RESULTS: Among 794 patients (median age, 48 years) who were included in the modified intention-to-treat analysis, complications included those that were respiratory (in 62%), hepatic (in 54%), cardiovascular (in 42%), renal (in 30%), and neurologic (in 20%). The use of combination therapy resulted in a lower incidence of the composite primary outcome than the use of doxycycline (33% and 47%, respectively), for a risk difference of -13.3 percentage points (95% confidence interval [CI], -21.6 to -5.1; P = 0.002). The incidence with combination therapy was also lower than that with azithromycin (48%), for a risk difference of -14.8 percentage points (95% CI, -23.1 to -6.5; P<0.001). No significant difference was seen between the azithromycin and doxycycline groups (risk difference, 1.5 percentage points; 95% CI, -7.0 to 10.0; P = 0.73). The results in the per-protocol analysis were similar to those in the primary analysis. Adverse events and 28-day mortality were similar in the three groups. CONCLUSIONS: Combination therapy with intravenous doxycycline and azithromycin was a better therapeutic option for the treatment of severe scrub typhus than monotherapy with either drug alone. (Funded by the India Alliance and Wellcome Trust; INTREST Clinical Trials Registry-India number, CTRI/2018/08/015159.).

Coagulation Abnormalities in Severe Scrub Typhus and Their Association with Complications.

AIM: To describe coagulation abnormalities and their association with complications in patients with severe scrub typhus. MATERIALS AND METHODS: A cohort study was conducted among all patients of severe scrub typhus [immunoglobulin M (IgM) positive] who reported to this facility from 1st August 2019 to 31st July 2020 and met our inclusion criteria. We estimated the incidence of severe thrombocytopenia (<50,000/µL) and overt disseminated intravascular coagulation (DIC) (DIC score of ≥5). We determined the association [risk (RR) ratios] of these abnormalities with complications of scrub typhus, namely-septic shock, multiple organ dysfunction syndrome (MODS), and septic shock with MODS. RESULTS: In total, 71 patients were studied with a mean age of 50 ± 15.5 years, of which 45 (63.4%) were females. On presentation, fever 70 (98.5%), myalgias 22 (31.0%), loose stools 13(18.3%), cough, vomiting, headache 11 (15.5%), altered sensorium 10(14.1%), and pain abdomen 9 (12.7%) were main symptoms. On examination, hypotension 31 (43.7%), eschar 25 (35.2%), icterus 17 (23.9%), and rash 16 (22.5%) were noted. The d-dimer (>0.5 µg/mL) levels were increased in all (100%) patients. Thrombocytopenia (91.5%) was the commonest hematological abnormality and 31 (43.6%) of them had severe thrombocytopenia, 25 (35.2%) patients had low fibrinogen levels (<200 mg/dL) and prothrombin time (PT >16.7 seconds) was prolonged in 20 (28.1%). A total of 42 (59.1%) patients developed MODS, 33 (46.4%) developed septic shock, 24 (33.8 %) had MODS with septic shock, 17 (23.9%) developed overt DIC, and eight (11.2%) died. Severe thrombocytopenia (p = -0.028) and overt DIC (p = 0.045) were significantly associated with septic shock development. CONCLUSION: In the patients admitted with severe scrub typhus; thrombocytopenia was the commonest hematological abnormality. The development of septic shock was significantly associated with severe thrombocytopenia and overt DIC.

Is Hyperuricemia a Marker of Severity of Disease in Scrub Typhus?

AIMS: To study association of hyperuricemia with severity of scrub typhus. METHODS: We studied clinical features, laboratory profile, in hospital course and outcome of 92 patients of scrub typhus and association of hyperuricemia with severity of disease. RESULTS: Of total 92 patients in study group, 66 (71.7%) were females and 26(28.3%) were males. Fever (100%), cough (37%), headache (33%), vomiting (31%), altered sensorium (23%), diarrhea (18%), abdominal pain (16%), myalgia (14%), and seizures (3%) were common clinical features. Eschar was present in 23%. Of total 92 patients 34 (37%) patients had hyperuricemia (HU) and 58 patients had normal serum uric acid levels. The patients of scrub typhus with HU had significantly higher presentation with altered sensorium (35.3%). In HU group, mean TLC, mean serum urea and serum creatinine were higher and mean serum albumin and mean HDL cholesterol were lower than patients of scrub typhus without hyperuricemia. These differences between two groups were statistically significant. Neurological dysfunction, severe sepsis, serum creatinine >3.5mg/dL and involvement of at least single organ was significantly higher in HU group. Total 4 patients (4.3%) died and all had HU. CONCLUSION: Hyperuricemia in patients of scrub typhus was associated with severe scrub typhus. The serum uric acid levels should be done in early course of all patients suffering from scrub typhus. The patients showing hyperuricemia should be monitored closely for early recognition of complications and management aggressively.

Heerfordt-Waldenström Syndrome.

Heerfordt's-Waldenström syndrome is a very rare presentation of neurosarcoidosis characterized by parotid gland enlargement, facial palsy, anterior uveitis and fever. World over only few cases of this syndrome have been reported. We present such a case of Heerfordt-Waldenström syndrome.

Predictors of Severity in Scrub Typhus.

AIMS: To study predictors of severity in patients of scrub typhus admitted in a tertiary care hospital. MATERIAL AND METHODS: Total 92 patients of scrub typhus were included in the study. The diagnosis was established by presence of IgM antibodies by Indirect Immunofluorescence Assay (IFA) test which is currently the reference standard for the diagnosis of scrub typhus. The clinical and laboratory profile, course in hospital, and outcome were documented. Factors associated with severe disease were analyzed. OBSERVATIONS: Fever (100%), cough (37%), headache (33%), vomiting (31%), altered sensorium (23%), diarrhea (18%), abdominal pain (16%), myalgia (14%), and seizures (3%) were common clinical features. An eschar was present in 23% of patients. Common laboratory findings included elevated transaminases (61%), thrombocytopenia (39%), and leukocytosis (30%). Severe sepsis was present in 33% patients. Septic shock was present in 4% patients. Presence of one or more organ failure was seen in 34% of patients. The overall case-fatality rate was 4%. Factors significantly associated with organ failure (severe disease) were leucocytosis (p < 0.001), hyperbilirubinemia (p < 0.001), high SGOT levels (p 0.030), hypoalbuminemia (p < 0.001), high urea levels (p < 0.001), and high creatinine levels (p 0.012). Among the criteria used to classify severity of scrub typhus, presence of one or more organ failure was significantly associated with mortality (p 0.004). CONCLUSION: Scrub typhus can manifest with potentially life-threatening complications such as meningoencephalitis, septic shock, ARDS, acute liver failure, acute kidney injury, severe thrombocytopenia. Leukocytosis, hyperbilirubinemia, transaminitis, hypoalbuminemia, and uremia were associated with organ failure and were significantly associated with morbidity and mortality.

Scrub Typhus Presenting as Acute Cerebellitis.

Scrub typhus is known to present with varied presentation including involvement of central nervous system. We present a case who presented with fever and features of isolated cerebellitis. Serum showed IgM antibodies to scrub typhus by ELISA. Patient showed rapid response to doxycycline and dexamethasone.

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.

Molecular epidemiology and genetic diversity of Orientia tsutsugamushi from patients with scrub typhus in 3 regions of India.

Scrub typhus, an acute febrile illness that is widespread in the Asia-Pacific region, is caused by the bacterium Orientia tsutsugamushi, which displays high levels of antigenic variation. We conducted an investigation to identify the circulating genotypes of O. tsutsugamushi in 3 scrub typhus-endemic geographic regions of India: South India, Northern India, and Northeast India. Eschar samples collected during September 2010-August 2012 from patients with scrub typhus were subjected to 56-kDa type-specific PCR and sequencing to identify their genotypes. Kato-like strains predominated (61.5%), especially in the South and Northeast, followed by Karp-like strains (27.7%) and Gilliam and Ikeda strains (2.3% each). Neimeng-65 genotype strains were also observed in the Northeast. Clarifying the genotypic diversity of O. tsutsugamushi in India enhances knowledge of the regional diversity among circulating strains and provides potential resources for future region-specific diagnostic studies and vaccine development.

Approach towards surveillance-based diagnosis of acute respiratory illness in India: Expert recommendations.

BACKGROUND: Emerging infectious diseases, often zoonotic, demand a collaborative "One-Health" surveillance approach due to human activities. The need for standardized diagnostic and surveillance algorithms is emphasized to address the difficulty in clinical differentiation and curb antimicrobial resistance. OBJECTIVE: The present recommendations are comprehensive diagnostic and surveillance algorithm for ARIs, developed by the Indian Council of Medical Research (ICMR), which aims to enhance early detection and treatment with improved surveillance. This algorithm shall be serving as a blueprint for respiratory infections landscape in the country and early detection of surge of respiratory infections in the country. CONTENT: The ICMR has risen up to the threat of emerging and re-emerging infections. Here, we seek to recommend a structured approach for diagnosing respiratory illnesses. The recommendations emphasize the significance of prioritizing respiratory pathogens based on factors such as the frequency of occurrence (seasonal or geographical), disease severity, ease of diagnosis and public health importance. The proposed surveillance-based diagnostic algorithm for ARI relies on a combination of gold-standard conventional methods, innovative serological and molecular techniques, as well as radiological approaches, which collectively contribute to the detection of various causative agents. The diagnostic part of the integrated algorithm can be dealt at the local microbiology laboratory of the healthcare facility with the few positive and negative specimens shipped to linked viral disease research laboratories (VRDLs) and other ICMR designated laboratories for genome characterisation, cluster identification and identification of novel agents.

Rickettsial diseases.

Rickettsiae are a rather diverse collection of organisms with several differences; this prohibits their description as a single homogenous group. Rickettsiae are maintained in nature through a cycle involving reservoir in mammals and arthropod vectors. The public health impact of these on lives or productivity lost is largely unmeasured, but suspected to be quite high worldwide. The diseases caused by Rickettsia and Orientia species are often collectively referred to as rickettsioses. Coxiella burnetii, the agent of Q fever is still frequently categorized as rickettsial disease. New or emerging rickettsial diseases; tickborne lymphadenopathy (TIBOLA) and Dermacentor-borne-necrosis-eschar- lymphadenopathy (DEBONEL) related to Rickettsia slovaca infection have been described. The rickettsial diseases were believed to have disappeared from India are reemerging and recently their presence has been documented in at least eleven states of our country. Many cases of rickettsial diseases go undiagnosed due to lack of diagnostic tools. Greater clinical awareness, a higher index of suspicion, better use of available diagnostic tools would increase the frequency with which rickettsial diseases are diagnosed.

The Evolving Pattern and Outcome of Stroke at Moderate Altitude.

BACKGROUND: The people residing in hills of this Sub-Himalayan region traditionally have a distinct lifestyle involving high level of physical activity. However, increased urbanization in the last two decades has led to changes in lifestyle of people. The present study was an endeavor to document changes in the pattern of stroke in people residing at moderate altitude. AIM: This study was aimed to study the evolving trends in clinical profile, risk factors, and outcome at 3 months in hospitalized patients of stroke in a Tertiary Care Hospital situated at moderate altitude. SETTING AND DESIGN: This prospective, observational study was carried out in a Tertiary Care Hospital, situated at 2000 m mean sea level, from July 2014 to June 2015 in Sub-Himalayan region of India. METHODS: The clinical features and risk factors profile of 235 patients of stroke consecutively admitted in hospital were analyzed, and findings were expressed in percentage. The profile was compared with a study conducted at this institute 15 years back. The outcome of patients at 3 months in terms of modified Rankin Scale >3 (mRS) and Barthel Index <60 (BI) was also studied. RESULTS: The occurrence of stroke as a cause of hospitalization was decreasing. Ischemic stroke was noted in 74%, and 26% had hemorrhagic stroke (HS). There was male predominance (58%), but affliction of females with stroke increased from 34% to 42%. The altered sensorium (P = 0.00) and neurological weakness (P = 0.024) were significantly associated with poor outcome in stroke. The occurrence of hypertension, diabetes mellitus, and coronary artery disease increased but smoking decreased among indoor patients of stroke in the last 15 years. Poor outcome of 203 patients at 3 months follow-up in terms of mRS >3 was 79 (IS-47, HS-32) but in term of BI, 63 (IS-32, HS-31) had poor outcome. Overall HS had poorer outcome. Age >70 years, female sex, altered sensorium, hypertension, and diabetes mellitus, were observed as poor prognostic factors, but the association was significant with advanced age, headache, and altered sensorium. CONCLUSION: The occurrence of stroke decreased among hospitalized patients. Hypertension, diabetes mellitus, and coronary artery disease increased but smoking decreased among patients of stroke.

Development of a real-time PCR assay for the diagnosis of scrub typhus cases in India and evidence of the prevalence of new genotype of O. tsutsugamushi.

A qualitative syber green real-time PCR with primers designed for a truncated portion of the 56kDa major outer membrane antigen gene of Orientia tsutsugamushi was used to diagnose scrub typhus from the blood or serum of suspected patients. Sixty-six blood and/or sera samples from fever cases, either with high index of suspicion for scrub typhus and/or positive by Weil-Felix test (> or = 1:160), were tested with the PCR. Specificity of the PCR was confirmed by end point melt curve analysis and sequencing of the amplicons. A nested PCR for determination of the serotypes of O. tsutsugamushi was performed on to the samples. In real-time PCR strong positive fluorescence was obtained in 73% of the suspected samples. Serotype-specific PCR amplification of some of the positive samples was indicative of the Kuroki type whereas the rest were non-responsive to this test. Sequence analyses of PCR amplicons indicated the presence of new, previously undescribed type of O. tsutsugamushi in this region. This one-step real-time PCR can be used for the detection and confirmation of scrub typhus, when used independently or in conjunction with, the Weil-Felix test, which is still the only available detection test for scrub typhus in most parts of the developing world. Elaborate studies need to be taken up to further evaluate its suitability as specific molecular tool for the diagnosis of scrub typhus and to delineate the prevalent strain types in these regions for a clear epidemiological understanding of this emerging infectious disease.

Neuropsychiatric Manifestations of Scrub Typhus.

Scrub typhus is caused by Orientia tsutsugamushi characterized by focal or disseminated vasculitis and perivasculitis which may involve the lungs, heart, liver, spleen and central nervous system. It was thought to have been eradicated from India. Recently it is being reported from many areas of India. The clinical picture and severity of the symptoms varies widely. The neurological manifestations of scrub typhus are not uncommon but are diverse. Meningoencephalitis is classical manifestation of scrub typhus but cerebellitis, cranial nerve palsies, plexopathy, transverse myelitis, neuroleptic malignant syndrome and Guillan-Barré syndrome are other manifestations reported in literature. The availability of literature on the neurological manifestations of scrub typhus is limited to case reports mainly. This article reviews various neurological manifestations of scrub typhus reported in literature.

Neurological manifestations of scrub typhus in adults.

In order to study the neurological manifestations in adult patients suffering from scrub typhus, 323 patients aged over 18 years, admitted with a positive diagnosis, were screened for neurological dysfunction; 37 patients with symptoms and/or signs suggestive of neurological dysfunction were included in the study. Of these, 31 (84%) patients had altered sensorium, four (11%) had cerebellitis, one (2%) patient had acute transverse myelitis and one (2%) had bilateral papilloedema without focal neurological deficit. Of the 31 patients with altered sensorium, 15 (40%) had meningoencephalitis, three (8%) had seizures, two (5%) had cerebral haemorrhages, one (2%) had a presentation likened to neuroleptic malignant syndrome (NMS) and one (2%) had a 6th nerve palsy with inflammation of the right cavernous sinus. Cerebrospinal fluid (CSF) analysis was abnormal in 23 patients (raised lymphocytes in 68%, raised protein in 80%). All patients improved with anti-rickettsial therapy.

Neurobrucellosis: an often forgotten cause of chronic meningitis.

We report a 26-year-old man of neurobrucellosis who presented with intermittent fever and headache for 2 years, sensori-neural hearing loss with cerebellar ataxia. He responded well to a combination of antimicrobials with significant clinical improvement.

Scrub typhus with visual hallucinations.

The occurrence of psychiatric symptoms in scrub typhus is not commonly reported in literature. We present a case of scrub typhus with visual hallucinations.