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.).

Improving Transplant-free Survival With Low-volume Plasma Exchange to Treat Children With Rodenticide Induced Hepatotoxicity.

Background: In a prior report, no patient with rodenticidal hepatotoxicity who met Kochi criteria (MELD score ≥36 or baseline INR ≥6 with hepatic encephalopathy) (PMID: 26310868) for urgent liver transplantation survived with medical management alone. Plasma exchange (PLEX) may improve survival in these patients. Objectives: We describe our experience with low-volume PLEX (PLEX-LV) in treating rodenticide ingestion induced hepatotoxicity in children. Methods: From prospectively collected database of rodenticidal hepatotoxicity patients managed as in-patient with department of Hepatology from December 2017 to August 2021, we retrospectively studied outcomes in children (≤18 years). Hepatotoxicity was categorized as acute liver injury (ALI, coagulopathy alone) or acute liver failure (ALF, coagulopathy and encephalopathy). Kochi criteria was used to assess need for urgent liver transplantation. The primary study outcome was one-month survival. Results: Of the 110 rodenticidal hepatotoxicity patients, 32 children (females: 56%; age: 16 [4.7-18] years; median, range) constituted the study patients. The study patients presented 4 (1-8) days after poison consumption (impulsive suicidal intent:31, accidental:1). Twenty children (62%) had ALI [MELD: 18 (8-36)] and 12 (38%) had ALF [MELD: 37 (24-45)].All children received standard medical care, including N-acetyl cysteine; ALF patients also received anti-cerebral edema measures. None of the patient families opted for liver transplantation. Seventeen children (ALI: 6, ALF: 11) were treated with PLEX-LV (3 [1-5] sessions, volume of plasma exchanged per session: 26 [13-38] ml/kg body weight) and peri-procedure low dose prednisolone.At 1 month, 28 of the 32 children (87.5%) were alive (4 ALF patients died). Of 10 children who met Kochi listing criteria for urgent liver transplantation, two children were ineligible for PLEX-LV (due to hemodynamic instability) and of the remaining 8 children treated by PLEX-LV, 6 (75%) survived. Conclusions: PLEX-LV shows promise as an effective non-liver transplant treatment in children with rodenticidal hepatotoxicity.

Immunogenicity and safety of homologous and heterologous booster vaccination of ChAdOx1 nCoV-19 (COVISHIELD™) and BBV152 (COVAXIN®): a non-inferiority phase 4, participant and observer-blinded, randomised study.

Background: Primary SARS-CoV-2 vaccination has been shown to wane with time and provide lower protection from disease with new viral variants, prompting the WHO to recommend the administration of booster doses. We determined the safety and immunogenicity of homologous or heterologous boosters with ChAdOx1 nCoV-19 (COVISHIELD™) or BBV152 (COVAXIN®), the two vaccines used widely for primary immunization in India, in participants who had already received two primary doses of these vaccines. Methods: Participants primed with two doses each of COVISHIELD™ or COVAXIN® 12-36 weeks previously, were randomised to receive either COVISHIELD™ or COVAXIN® booster in a 1:1 ratio. The primary outcome was day 28 post-booster anti-spike IgG seropositivity and secondary outcomes were anti-spike IgG levels and assessment of safety and reactogenicity. The results of 90 days intention-to-treat analysis are presented. This trial is registered with ISRCTN (CTRI/2021/08/035648). Findings: In the COVISHIELD™ primed group with 200 participants, the seropositivity 28 days post booster in the heterologous COVAXIN® arm was 99% and non-inferior to the homologous COVISHIELD™ arm, which was also 99% (difference 0%; 95% CI: -2.8% to 2.7%). The geometric mean concentration (GMC) of anti-spike antibodies following heterologous COVAXIN® boost on day 28 was 36,190.78 AU/mL (95% CI: 30,526.64-42,905.88) while the GMC following homologous COVISHIELD™ boost was 97,445.09 AU/mL (82,626.97-114,920.7). In the COVAXIN® primed group with 204 participants, the seropositivity 28 days post booster in the heterologous COVISHIELD™ arm was 100% and non inferior to the homologous COVAXIN® arm which was 96% (difference 4%, 95% CI: 0.2%-7.8%). The GMC following heterologous COVISHIELD™ boost was 241,681.6 AU/mL (95% CI: 201,380.2-290,048.3) compared to homologous COVAXIN® boost, which was 48,473.94 AU/mL (95% CI: 38,529.56-60,984.95). The day 28 geometric mean ratio (GMR) of the anti-spike IgG between the heterologous and homologous boosted arms was 0.42 (95% CI: 0.34-0.52) in the COVISHIELD™ primed group and 5.11 (95% CI: 3.83-6.81) in the COVAXIN® primed group. There were no related serious adverse events reported in any group. Interpretation: Homologous and heterologous boosting with COVISHIELD™ or COVAXIN® in COVISHIELD™ or COVAXIN® primed individuals are immunogenic and safe. A heterologous boost with COVISHIELD™ after COVAXIN® prime offers the best immune response among the four combinations evaluated. Funding: Azim Premji Foundation and Bill and Melinda Gates Foundation.

Prevalence of Hypocortisolemia in Patients with Sepsis or Septic Shock (The HIS Study) Presenting to the Emergency Department.

Background: Cortisol response to stressors (hypothalamic-pituitary-adrenal axis, autonomic nervous system, and immune system) plays a vital role in maintaining stable metabolic homeostasis. This study was done to assess the prevalence of hypocortisolemia in patients presenting to ED with sepsis and/or septic shock. Methods: This prospective observational study was done from July 2020 to April 2021. Serum cortisol levels were measured in patients with sepsis and septic shock, and their clinical and laboratory profile was categorized, coded, and analyzed. Results: Ninety-eight patients were included, of which serum Cortisol <10 µg/dl was noted in 7 (7.2%) patients. The cohort's mean age was 52.9 (SD: 15.3) years with a male predominance (n-61; 62.2%). Most common presenting complaint was fever (n-52; 53.1%), followed by abdominal pain (n-24; 24.5%), and breathing difficulty (n-14; 14.3%). Systolic blood pressure <90 mmHg and tachycardia were seen in 63 patients (64.3%). Assessment of diet and native medication use did not demonstrate a predisposition to hypocortisolemia. The median (IQR) arterial lactate values were lower in the hypocortisolemic group: 2.2 (1.2-2.5) as compared to the non-hypocortisolemic group: 3.7 (2.2-8.0). Patients with septic shock without hypocortisolemia were noted to have a higher mean lactate level (2.6 ± 1.3 Vs 5.4 ± 3.9) and lower platelet counts compared to those with low cortisol levels. Patients with normal cortisol levels (n-38; 38.8%) still had low ACTH values. Conclusion: The prevalence of hypocortisolemia was lower when compared to other Indian studies. Diet and native medication use do not predispose Indians to hypocortisolemia.

Acute management of COVID-19 in the emergency department: An evidence-based review.

Coronavirus disease (COVID-19) has been relentlessly battering the world wave after wave in different countries at different rates and times. Emergency departments (EDs) around the globe have had to constantly adapt to this ever-changing influx of information and recommendations by various national and international health agencies. This review compiles the available evidence on the guidelines for triaging, evaluation, and management of critically ill patients with COVID-19 presenting to the ED and in need of emergency resuscitation. The quintessential components of resuscitation focus on airway, breathing, and circulation with good supportive care as the cornerstone of acute management of critically ill COVID-19 patients. Irrational investigations and therapeutics must be avoided during these times of medical uncertainty and antibiotic stewardship should be diligently followed.

The role and diagnostic accuracy of serology for COVID-19.

BACKGROUND: The role and performance of various serological tests for the diagnosis of COVID-19 are unclear. This study aimed to evaluate the performance of seven commercially available serological assays for SARS-CoV-2 antibodies by testing COVID-19 cases and controls. METHODS: Adult patients with fever for > 5 days, admitted to a tertiary-care teaching hospital in South India, were enrolled prospectively between June and December 2020. SARS-CoV-2 RT-PCR confirmed patients were classified as cases, and patients with febrile illness with laboratory-confirmed alternative diagnosis and healthy participants were controls. All participants were tested with SCoV-2 Detect™ IgM ELISA kit and SCoV-2 Detect™ IgG ELISA kit (InBios International, Seattle, USA) (Inbios), SARS-CoV-2 Total and SARS-CoV-2 IgG (Siemens Healthcare Diagnostics Inc., Tarrytown, USA) (Siemens), Roche Elecsys® Anti-SARS-CoV-2 (Roche Diagnostics, Rotkreuz, Switzerland) (Roche), Abbott SARS-CoV-2 IgG (Abbott Diagnostics, IL, USA) (Abbott), and Liaison® SARS-CoV-2 S1/S2 IgG (DiaSorinS.p.A., Saluggia, Italy) (Liaison). The sensitivities, specificities, positive predictive values (PPV), negative predictive values (NPV), and accuracies were compared. RESULTS: There were 303 participants: 153 cases and 150 controls. ELISA detecting anti-S protein antibody was more sensitive (88.9% for IgG and 86.3% for IgM) than the CLIAs (82.4% for total antibodies and 76.5-85.6% for IgG). Among CLIAs, Roche IgG was most sensitive (85.6%) followed by Abbott (83%) and Liaison (83%). Abbot had the best PPV (88.8%) and was more specific (89.3%) than Liaison (82%) and Roche (82%). Siemens IgG was less sensitive (76.5%) than Siemens Total (82.4%). The specificity of all the serological assays was modest (75-90%). Antibody test positivity increased with the duration of illness reaching 90% after 10 days of illness. When cases were compared against pre-pandemic controls, the IgG gave excellent specificity (98-100%). For seroprevalence studies, InBios IgG had the best accuracy (90.8%) with 88.9% sensitivity and 97.6% specificity. CONCLUSION: The serological assays are important adjuncts for the diagnosis of COVID-19 in patients with persistent symptoms, especially in the second week of illness. The value of serological diagnostic tests is limited in the first week of illness and they provide additional value in seroprevalence studies. The diagnostic accuracy of the ELISA and CLIA platforms were comparable.

Pregnancy-related emergencies: Profile and outcome.

BACKGROUND: National efforts to reduce maternal mortality with respect to community services have primarily focused on upgrading transportation infrastructure and formalizing training for care providers. There is, however, a paucity of baseline data on the profile and outcomes of pregnant women presenting to the Emergency Department (ED) in India. METHODS: This retrospective study enrolled all pregnant women presenting to a large tertiary medical care center in India, between November 2016 and November 2017. RESULTS: There were 696 ED visits by pregnant women during the study period. The mean age was 26.85 (SD: 4.88) years. Pregnant women in the first trimester contributed to 50.8% of all visits, and 54% being multigravida. The most common presenting complaints were bleeding/spotting per vaginum (PV) (38.2%) and abdominal pain (37.6%) followed by fever (21.6%) and vomiting (21.5%). Obstetric causes contributed to 53.2% of the ED visits, while nonobstetric causes amounted to 43.2%. Over a third (39.7%) required hospital admission. Of these patients, 73% delivered in CMC with live births amounting to 62.3% while 3.5% ended in fetal deaths. The miscarriages rate was as high as 28%. More than half (51.1%) of the deliveries were by normal vaginal delivery. There were no maternal deaths during the time of admission. CONCLUSIONS: Our study sheds new light on the profile of emergency visits among pregnant patients and their relationship to the outcome of pregnancy. First trimester visits were most common with complaints of bleeding PV and abdominal pain. This could explain the high rate of miscarriages among this population.

Performance of molecular and serologic tests for the diagnosis of scrub typhus.

Diagnosis of scrub typhus, caused by the bacterium Orientia tsutsugamushi, is challenging because of the overlap of its non-specific symptoms with other infections coupled with the lack of sufficient data on the performance of diagnostic tests. Early diagnosis of scrub typhus is crucial to improve outcomes and this study evaluates the diagnostic performance of various tests. The present study aims at assessing the accuracy of various rapid diagnostic tests, serologic tests, and nucleic acid amplification methods on well-characterized patient samples. Adult patients with acute febrile illness and manifestations suggestive of scrub typhus confirmed by positive PCR in the blood, eschar or tissue were characterized as cases. Patients with acute febrile illness and a confirmed alternate etiology such as culture-confirmed typhoid, smear/PCR positive for malaria, PCR/NS1 antigen positive for dengue, PCR positive for influenza, PCR/MAT positive for leptospirosis, PCR positive for spotted fever were characterized as controls with other infections. The healthy controls consisted of subjects from the same geographic region. We performed the following tests on blood samples for scrub typhus and calculated the sensitivity, specificity, positive predictive value, and negative predictive value: (1) Quantitative real time PCR using 47kDa gene (qPCR); (2) Conventional PCR using 56kDa gene (cPCR); (3) Loop-mediated isothermal amplification assay (LAMP assay); (4) Immunofluorescence assay (IFA); (5) Enzyme-linked immunosorbent assay (ELISA); (6) Weil-Felix test(WF test); and (7) Immunochromatographic Rapid Diagnostic Test (RDT).Among the 316 participants, 158 had confirmed scrub typhus (cases) and 158 were controls. ELISA and RDT detecting Orientia tsutsugamushi specific IgM antibodies had excellent discriminative potential with sensitivities and specificities of 92%, 94% and 92%, 92% respectively. The sensitivity and specificity of IFA were found to be 95% and 74% respectively. IgM serology had a false positivity rate of 8% with other acute febrile illnesses such as dengue, leptospirosis and spotted fever due to the nonspecific binding of the pentavalent IgM. LAMP assay had 91.7% sensitivity and 77.2% specificity while qPCR provided excellent sensitivity (97%) and perfect specificity. In conclusion, ELISA and RDT detecting Orientia tsutsugamushi specific IgM antibodies have excellent sensitivity and specificity while the accuracy of IFA is suboptimal for the diagnosis of scrub typhus. Given its perfect specificity and superior sensitivity, qPCR is preferred for diagnostic confirmation in reference laboratories particularly for diagnosis of early disease with less than 7 days duration. This study provides a comprehensive evaluation of all currently available diagnostic tests for scrub typhus.

Emergencies on the train and railway stations managed at a railway station emergency care center.

BACKGROUND: With the increasing focus on setting up emergency care centers in railway stations across India by the government, there are no baseline data in India, or the world, about the profile of patients presenting with emergencies on the trains and at the railway stations. MATERIALS AND METHODS: This retrospective study included all people who presented with any medical emergency to the Emergency Care Center (ECC), Katpadi Railway Station in South India, between January 2017 and December 2017. Details were obtained from the register maintained by the emergency nurses stationed at the ECC. RESULTS: Among 1076 patients who presented to the ECC during the study period, the mean age was 37 years (standard deviation: 19.01) with two-thirds (66.1%) being males. A quarter (23.4%) were trauma-related and 76.6% were medical emergencies. Sharp force injuries [58.8% (151/252)] was the predominant mode of trauma, while laceration [57.1%] (144/252) was the predominant type of injury sustained. Common nontrauma presenting complaints included fever (27.5%), headache (17.9%), nausea/vomiting (17.9%), and abdominal pain (15%). The maximum number of cases was in the summer months of May-June with heat-related symptoms, while the maximum number of fever cases was recorded during the monsoon season. The majority (905/1076; 84.1%) were able to continue their journey further, and 13.9% required referral to a nearby hospital. During the 1-year study period, 2 patients with trauma and 18 with various medical conditions died at the railway station or at a hospital after resuscitation at the ECC. CONCLUSIONS: Trauma, fever, headache, and vomiting are the most common emergencies among patients traveling by rail and at the railway stations. Establishing well-equipped ECCs across the country to handle trauma and other medical emergencies during travel is part of primary care provided and is the need of the hour.

Profile of patients presenting with seizures as emergencies and immediate noncompliance to antiepileptic medications.

INTRODUCTION: Seizure is a common manifestation of the many neurological conditions faced by primary care physicians. This study aims to determine the prevalence, etiology, and predictors of immediate noncompliance of adult patients presenting with seizures to the department of emergency (ED). MATERIALS AND METHODS: We conducted this study in the ED of CMC, Vellore from November 2015 to February 2016. Retrospective chart review was used to gather specific data regarding these consecutive cases. RESULTS: During the study period, 477 patients presented with seizures. The prevalence of nontrauma seizures in the ED was 2.3% [Figure 1]. The mean age was 41.4 ± 17.25 years. There was a male predominance (63.1%). About 11.7% had active seizures at presentation to the ED and less than a quarter (21.8%) were determined to have status epilepticus. Nearly 41% had new-onset seizures with common etiologies being idiopathic generalized epilepsy (22.6%), metabolic causes (17.9%), acute febrile illnesses (14.42%), and space-occupying lesions (12.3%). Among those with a history of seizures (58.9%), 87.9% were advised regular medications but 58.5% of them were immediately noncompliant. Phenytoin (58.6%), sodium valproate (20.5%), and levetiracetam (18%) were the most commonly used antiepileptics with 23% on multidrug therapy. About 60% were discharged stable from the ED. Univariate analysis showed chronic alcohol consumption (OR: 2.78; 95% CI: 1, 7.7) and female sex (OR: 1.45; 95% CI: 1-2.5) to be predictors of immediate noncompliance to antiepileptics. CONCLUSION: Common etiologies of new-onset seizures in the ED are idiopathic generalized epilepsy, metabolic causes, and acute febrile illnesses. More than half the patients with a known seizure disorder are immediately noncompliant to the advised medications. Knowledge among primary healthcare physicians about the importance of emphasizing compliance will greatly reduce the burden of seizures.

Fatal overdose of iron tablets in adults.

Acute iron toxicity is usually seen in children with accidental ingestion of iron-containing syrups. However, the literature on acute iron toxicity with suicidal intent in adults is scant. We report, the first instance of two adults with fatal ingestion of a single drug overdose with iron tablets from India. Two young adults developed severe gastro-intestinal bleeding and fulminant hepatic failure 48 h after deliberate consumption of large doses of iron tablets. Serum iron levels measured 36 h after ingestion were normal presumably due to the redistribution of iron to the intracellular compartment. Despite aggressive supportive management in medical intensive care unit of a tertiary care hospital, the patients succumbed to the toxic doses of iron.