Oral varespladib for the treatment of snakebite envenoming in India and the USA (BRAVO): a phase II randomised clinical trial.

INTRODUCTION: Snakebite envenoming (SBE) results in over 500 000 deaths or disabling injuries annually. Varespladib methyl, an oral inhibitor of secretory phospholipase A2, is a nearly ubiquitous component of snake venoms. We conducted a phase II clinical trial to assess efficacy and safety of oral varespladib methyl in patients bitten by venomous snakes. METHODS: This double-blind, randomised, placebo-controlled trial enrolled patients in emergency departments in India and the USA. Patients with SBE were randomly assigned (1:1) to receive varespladib methyl or placebo two times per day for 1 week. All patients received standard of care, including antivenom. The primary outcome was change in the composite Snakebite Severity Score (SSS) measuring the severity of envenoming, from baseline to the average composite SSS at 6 and 9 hours. RESULTS: Among 95 patients randomised August 2021 through November 2022, the most common snakebites were from Russell's vipers (n=29), copperheads (n=18) and rattlesnakes (n=14). The SSS improved from baseline to the average at 6 and 9 hours by 1.1 (95% CI, 0.7 to 1.6) in the varespladib group versus 1.5 (95% CI, 1.0 to 2.0) in the placebo group (difference -0.4, 95% CI, -0.8 to 0.1, p=0.13). While key secondary outcomes were not statistically different by treatment group, benefit was seen in the prespecified subgroup initiating study drug within 5 hours of bite (n=37). For this early treatment group, clinically important differences were observed for illness severity over the first week, patient-reported function on days 3 and 7 and complete recovery. No death or treatment emergent serious adverse event occurred. CONCLUSION: For emergency department treatment of snakebites, the addition of varespladib to antivenom did not find evidence of difference for the primary outcome based on the SSS. A potentially promising signal of benefit was observed in patients initiating treatment within 5 hours of snakebite.

A rare case of extensive cutaneous spider angioma in Zieve's syndrome: A case report and review of literature.

Chronic alcoholism is a global public health problem showing increasing trends throughout the world. Alcoholic liver disease is one of the most important causes of mortality worldwide. Cutaneous features are one of the most frequent manifestations of liver disease and can often be a presenting feature. Spider angioma is one of the cutaneous manifestations in liver diseases. More than six spider nevi are considered abnormal. Here we present a case of a gentleman with a history of chronic alcohol intake and diagnosed with Zieve's syndrome, who presented with extensive cutaneous spider angioma.

Corticospinal Tract Involvement in MRI of Neuromelioidosis: Report of Three Cases with a Review of Clinicoradiological Features.

Melioidosis is gram-negative bacterial infection endemic in parts of Australia and Asia with significant morbidity and mortality. It is acquired in wet rainy seasons through occupational and recreational activities. Although central nervous system (CNS) involvement is seen in less than 10%, it can have severe sequelae. MRI (magnetic resonance imaging) findings in reported cases have shown predominant brain stem and frontoparietal involvement. We present three pediatric cases of neuromelioidosis in which corticospinal tract involvement was a characteristic finding.

A simple mortality risk prediction score for viper envenoming in India (VENOMS): A model development and validation study.

BACKGROUND: Snakebite is a neglected problem with a high mortality in India. There are no simple clinical prognostic tools which can predict mortality in viper envenomings. We aimed to develop and validate a mortality-risk prediction score for patients of viper envenoming from Southern India. METHODS: We used clinical predictors from a prospective cohort of 248 patients with syndromic diagnosis of viper envenoming and had a positive 20-minute whole blood clotting test (WBCT 20) from a tertiary-care hospital in Puducherry, India. We applied multivariable logistic regression with backward elimination approach. External validation of this score was done among 140 patients from the same centre and its performance was assessed with concordance statistic and calibration plots. FINDINGS: The final model termed VENOMS from the term "Viper ENvenOming Mortality Score included 7 admission clinical parameters (recorded in the first 48 hours after bite): presence of overt bleeding manifestations, presence of capillary leak syndrome, haemoglobin <10 g/dL, bite to antivenom administration time > 6.5 h, systolic blood pressure < 100 mm Hg, urine output <20 mL/h in 24 h and female gender. The lowest possible VENOMS score of 0 predicted an in-hospital mortality risk of 0.06% while highest score of 12 predicted a mortality of 99.1%. The model had a concordance statistic of 0·86 (95% CI 0·79-0·94) in the validation cohort. Calibration plots indicated good agreement of predicted and observed outcomes. CONCLUSIONS: The VENOMS score is a good predictor of the mortality in viper envenoming in southern India where Russell's viper envenoming burden is high. The score may have potential applications in triaging patients and guiding management after further validation.

The BRAVO Clinical Study Protocol: Oral Varespladib for Inhibition of Secretory Phospholipase A2 in the Treatment of Snakebite Envenoming.

INTRODUCTION: Snakebite is an urgent, unmet global medical need causing significant morbidity and mortality worldwide. Varespladib is a potent inhibitor of venom secretory phospholipase A2 (sPLA2) that can be administered orally via its prodrug, varespladib-methyl. Extensive preclinical data support clinical evaluation of varespladib as a treatment for snakebite envenoming (SBE). The protocol reported here was designed to evaluate varespladib-methyl for SBE from any snake species in multiple geographies. METHODS AND ANALYSIS: BRAVO (Broad-spectrum Rapid Antidote: Varespladib Oral for snakebite) is a multicenter, randomized, double-blind, placebo-controlled, phase 2 study to evaluate the safety, tolerability, and efficacy of oral varespladib-methyl plus standard of care (SoC) vs. SoC plus placebo in patients presenting with acute SBE by any venomous snake species. Male and female patients 5 years of age and older who meet eligibility criteria will be randomly assigned 1:1 to varespladib-methyl or placebo. The primary outcome is the Snakebite Severity Score (SSS) that has been modified for international use. This composite outcome is based on the sum of the pulmonary, cardiovascular, nervous, hematologic, and renal systems components of the updated SSS. ETHICS AND DISSEMINATION: This protocol was submitted to regulatory authorities in India and the US. A Clinical Trial No Objection Certificate from the India Central Drugs Standard Control Organisation, Drug Controller General-India, and a Notice to Proceed from the US Food and Drug Administration have been obtained. The study protocol was approved by properly constituted, valid institutional review boards or ethics committees at each study site. This study is being conducted in compliance with the April 1996 ICH Guidance for Industry GCP E6, the Integrated Addendum to ICH E6 (R2) of November 2016, and the applicable regulations of the country in which the study is conducted. The trial is registered on Clinical trials.gov, NCT#04996264 and Clinical Trials Registry-India, 2021/07/045079 000062.

Prevalence and Risk Factors for Resistant Hypertension: Cross-Sectional Study From a Tertiary Care Referral Hospital in South India.

Background Around 10% patients with hypertension have resistant hypertension (RH). Older age, Black race, obesity, diabetes mellitus (DM) and chronic kidney disease (CKD) are the common risk factors for RH. The present study was done to find out the prevalence and factors associated with RH. Methods This cross-sectional study was done between December 2018 and February 2020. Adult patients registered with the hypertension clinic and on care for more than three months were included in the study. History was noted and blood pressure (BP) was measured using standard precautions. The patients were divided into two groups - resistant and non-resistant hypertension. Chi-square test was done to check the significance of the differences between the two groups. Binary logistic regression was done for the risk factors with a p-value < 0.2 in the Chi-square test. Results A total of 275 patients were included. The mean age was 56 ± 10 years and 61% were females. The mean duration of hypertension was 7 ± 5 years; 77% of patients were overweight or obese. A family history of hypertension was present in 30% and 18% had diabetes mellitus. History suggestive of secondary hypertension was present in 13%. BP was controlled (<130/80 mm of hg) in 145 (53%), uncontrolled in 130 (47%) and resistant hypertension was seen in 31 [(11%) 95% CI 8-16%] patients. Duration of hypertension, obesity, and elevated fasting blood sugar were significantly associated with RH.  Conclusions RH was found in 11% of hypertensive patients. Longer duration of hypertension, obesity, and higher fasting blood glucose were associated with RH.

Immune-mediated Coombs negative intravascular haemolysis in systemic lupus erythematosus (SLE).

A 27-year-old woman presented with a history of excessive hair loss, loss of appetite, loss of weight, amenorrhoea and loss of axillary and pubic hair for 6 months followed by fever and vomiting for 5 months and abdominal pain for 1 month. During the course of her illness, the patient developed intravascular haemolysis as evidenced by a drop in haemoglobin, indirect hyperbilirubinaemia, raised lactate dehydrogenase (LDH) and haemoglobinuria. Examination revealed severe pallor, mild icterus, elevated jugular venous pressure, generalised lymphadenopathy and hyperpigmentation. Investigations revealed severe anaemia, indirect hyperbilirubinaemia, raised LDH and negative Coombs test. Antinuclear antibody and anti-dsDNA, anti-Sm and anti-SS-A/Ro antibodies were positive and complement C3 was low. The patient was diagnosed to have systemic lupus erythematosus and immune-mediated intravascular haemolysis and was treated with prednisolone and hydroxychloroquine. Haemolysis resolved following steroid therapy, and during follow-up, there were no further episodes of haemolysis.

Point-of-care infrared thermal imaging for differentiating venomous snakebites from non-venomous and dry bites.

BACKGROUND: Local envenomation following snakebites is accompanied by thermal changes, which could be visualized using infrared imaging. We explored whether infrared thermal imaging could be used to differentiate venomous snakebites from non-venomous and dry bites. METHODS: We prospectively enrolled adult patients with a history of snakebite in the past 24 hours presenting to the emergency of a teaching hospital in southern India. A standardized clinical evaluation for symptoms and signs of envenomation including 20-minute whole-blood clotting test and prothrombin time was performed to assess envenomation status. Infrared thermal imaging was done at enrolment, 6 hours, and 24 hours later using a smartphone-based device under ambient conditions. Processed infrared thermal images were independently interpreted twice by a reference rater and once by three novice raters. FINDINGS: We studied 89 patients; 60 (67%) of them were male. Median (IQR) time from bite to enrolment was 11 (6.5-15) hours; 21 (24%) patients were enrolled within 6 hours of snakebite. In all, 48 patients had local envenomation with/without systemic envenomation, and 35 patients were classified as non-venomous/dry bites. Envenomation status was unclear in six patients. At enrolment, area of increased temperature around the bite site (Hot spot) was evident on infrared thermal imaging in 45 of the 48 patients with envenomation, while hot spot was evident in only 6 of the 35 patients without envenomation. Presence of hot spot on baseline infrared thermal images had a sensitivity of 93.7% (95% CI 82.8% to 98.7%) and a specificity of 82.9% (66.3% to 93.4%) to differentiate envenomed patients from those without envenomation. Interrater agreement for identifying hot spots was more than substantial (Kappa statistic >0.85), and intrarater agreement was almost perfect (Kappa = 0.93). Paradoxical thermal changes were observed in 14 patients. CONCLUSIONS: Point-of-care infrared thermal imaging could be useful in the early identification of non-venomous and dry snakebites.

Efficacy of Phyllanthus niruri on improving liver functions in patients with alcoholic hepatitis: A double-blind randomized controlled trial.

INTRODUCTION: Phyllanthus niruri, a traditional herbal medicine, was found to be hepatoprotective as evidenced by several preclinical and clinical studies. However, to the best of our knowledge, there are no clinical trials available to date to evaluate its efficacy in alcoholic hepatitis. MATERIALS AND METHODS: The present study is a block randomized, double-blind, parallel-arm placebo-controlled trial that was designed to assess the efficacy of P. niruri on the liver and renal function parameters, total oxidant and antioxidant levels in alcoholic hepatitis patients in comparison to placebo over a 4-week period. Patients were screened by CAGE questionnaire, and those with a confirmed diagnosis of mild-moderate alcoholic hepatitis based on laboratory findings and Maddrey's discriminant function score were randomly allocated to treatment and placebo arms. Clinical assessments were done at baseline, 2 weeks, and 4 weeks. A total of 454 patients were screened and 100 eligible patients were recruited for the study, and 71 were analyzed using the modified intention-to-treat approach. RESULTS: Serum levels of liver and renal function parameters failed to demonstrate significant improvement with P. niruri. However, there was a statistically significant increase in the level of total antioxidants with P. niruri (P = 0.034) with an additional appetite stimulant activity (P = 0.03) in 4 weeks. CONCLUSION: A 4-week administration of P. niruri in mild-moderate alcoholic hepatitis patients showed an improvement in the total antioxidant levels with an appetite stimulant activity compared to a placebo.

Pre-hospital care and its association with clinical outcome of snakebite victims presenting at a tertiary care referral hospital in South India.

Most snakebite victims in low- and middle-income countries continue to seek many forms of first aid therapy before reaching hospital, the commonest being the application of a tourniquet. Our study looked at a prospective cohort of 382 such patients to ascertain the association of pre-hospital care with clinical outcome, and found that 60% developed complications as compared to 36% who had no pre-hospital care (p < 0.001), with 10 fatalities in the former compared to only one in the latter. Pre-hospital care remains very common and definitely increases morbidity and mortality.

Circulating Secretory Phospholipase A2 Activity following Snakebites and Its Relationship with Envenomation Status and Progression of Local Swelling.

We studied whether circulating secretory phospholipase A2 (sPLA2) activity reliably distinguished patients with snakebite envenomation from those with nonvenomous/dry snakebites, and whether patients with progressive local swelling had persistence of circulating sPLA2 activity despite antivenom treatment. We prospectively enrolled adults presenting to the emergency with a history of snakebite in the past 24 hours. We estimated circulating sPLA2 activity at baseline before antivenom administration and after 48 hours in those with envenomation. We enrolled 52 patients with snakebites (mean age 39.3 ± 12.6 years; 35 [67%] men), and 16 patients with infective cellulitis as controls. Thirty patients had local ± systemic envenomation; 15 were classified as dry/nonvenomous bites; and envenomation status was unclear in seven patients. Baseline sPLA2 activity was significantly higher in snakebite patients than that in those with infective cellulitis (4.64 [3.38-5.91] versus 3.38 [1.69-4.01] nmol/minute/mL; P = 0.005). Among patients with snakebites, sPLA2 activity in the highest quartile was significantly associated with envenomation (12 of 27 versus two of 22; P = 0.010). However, median sPLA2 activity did not differ significantly between patients with envenomation and the rest. Baseline sPLA2 activity was significantly associated with the maximum extent of limb swelling (P = 0.031 for trend). In envenomed patients, circulating sPLA2 activity significantly decreased after 48 hours compared with the baseline (5.49 [3.38-8.86] versus 3.38 [2.53-4.64]; P = 0.003) including those with progressive swelling. Although circulating sPLA2 activity was elevated following snakebites, its sensitivity to diagnose envenomation appears to be limited. Administration of more antivenom after systemic manifestations had reversed might not benefit patients with progressive local swelling.

Comparison of two Anti Snake Venom protocols in hemotoxic snake bite: A randomized trial.

The dose of Anti Snake Venom (ASV) in hemotoxic snake bite depends on the amount of venom injected and species of snake. All trials in South East Asia have studied different doses of ASV, wherein the ASV in high dose group itself was lower than the dose that is recommended in Indian National protocol. These studies favored low dose protocol, as there was no difference in mortality and morbidity between the groups. So, this study intended to assess the efficacy of National protocol in reducing morbidity and mortality in hemotoxic snake bite in comparison to current protocol followed in institution. This was an open label randomized trial of 140 hemotoxic snakebite patients. Group A received national protocol: initial dose of 100 ml followed by 100 ml 6th hourly till 20-min Whole Blood Clotting Time (20WBCT) was negative or 300 ml of ASV was given, whichever was earlier. Group B received 70 ml followed by 30 ml every 6th hourly until two consecutive 20WBCT were negative. There was no statistical difference in the amount of ASV required in both the groups. Mortality and acute kidney injury were higher in group A (statistically not significant), probably due to sicker patients in that group. There was no relapse of clotting time abnormality in both the groups. In a significant number of patients (12%), clotting time was persistently prolonged till death. We found that the use of National ASV dosing protocol did not decrease the mortality and morbidity.

Spontaneous intracranial hypotension associated with pachymeningeal enhancement in a patient with systemic lupus erythematosus (SLE): an extremely rare presenting feature.

A 16-years-old girl presented to our institution with history of severe bilateral headache for 5 days associated with vomiting. She also had fever for 2 months without any localising symptoms and skin lesions for 1 month. Examination revealed erythematous rash over bridge of nose and ear lobes, ulcer over hard palate and tenderness of small joints of both hands. Systemic examination was unremarkable except for bilateral papilloedema. Investigations revealed anaemia, leucopenia and elevated erythrocyte sedimentation rate. Cranial imaging revealed diffuse pachymeningeal enhancement with subdural effusion. Lumbar puncture revealed no abnormal findings in cerebrospinal fluid except low opening pressure. Antinuclear antibody was 4+ with anti-Sm antibody positive. She was diagnosed to have spontaneous intracranial hypotension associated with pachymeningeal enhancement secondary to systemic lupus erythematosus. She showed dramatic improvement with steroid and azathioprine therapy. She continues to be asymptomatic after 2 years of follow-up.

Primary Sjogren's syndrome: a great masquerader.

A 41-year-old woman presented with paresthesia and inability to walk for 7 days. She had history of fatigue, polyarthralgia and difficulty in swallowing food for the last 1 year. She became edentulous over the last 5 years and wore dentures for the same. She appeared pale, emaciated and had oral thrush. She had areflexic quadriparesis with weakness more in lower limbs compared with upper limbs. With the initial diagnosis of Guillian-Barre syndrome, she was given five cycles of plasmapheresis following which there was a significant improvement in power. Sjogren's syndrome was suspected based on edentulous state in a middle-aged woman with multisystem involvement. Evaluation with Schirmer's test, parotid scintigraphy and labial minor salivary gland biopsy confirmed the diagnosis. She was treated with steroids following which a dramatic improvement in haemoglobin and total leucocyte count was noted. We report a varied presentation of primary Sjogren's syndrome.

Serum Procalcitonin Concentration and Its Relationship with Local Manifestations after Snakebites.

The local signs and symptoms following snakebites are similar to those of cellulitis caused by bacterial infections. This leads to empirical treatment with antibiotics, which however is not supported by evidence. Procalcitonin (PCT) is a biomarker with good diagnostic accuracy for bacterial infection. We studied serum PCT concentration in 100 patients aged 13 years or more, presenting to the hospital with significant local manifestations (crossing the joint proximal to the bitten wound) within 24 hours after snakebite. The extent and progression of local manifestations were monitored 12 hourly. Baseline PCT measurement was carried out for all patients and measurement was repeated 12 hourly only in those patients with progressive local manifestations. The median interqartile range PCT concentration did not differ significantly by the severity of local manifestation at presentation (Grade 2 = 0.28 [0.26-0.30]; Grade 3 = 0.28 [0.26-0.32]; Grade 4 = 0.27 [0.26-0.32] ng/mL; P = 0.15). Furthermore, we did not observe an increase in PCT concentration on serial estimation in those with progressive local manifestation (0.28, 0.29, and 0.29 ng/mL) over 36 hours. These observations suggest that the local manifestations following snakebites were not caused by bacterial infection.

Angioedema as the presenting feature of systemic lupus erythematosus.

A young female in her early 20s presented with low-grade fever for 1 month, puffiness of face and abdominal distension for 15 days. Evaluation revealed pancytopenia with normocellular marrow, hypocomplementaemia and Coomb's positive haemolytic anaemia. She had angioedema with laryngospasm and worsening facial oedema which had dramatic response to steroids. Further workup lead to a diagnosis of systemic lupus erythematosus with neuropsychiatric involvement. Treatment with pulse steroids and cyclophosphamide resulted in dramatic improvement of her symptoms with no recurrence of angioedema during her follow-up visits.

Primary Intestinal Lymphangiectasia (Waldmann's Disease) Presenting with Chylous Effusions in a 15-Year-Old.

Primary Intestinal Lymphangiectasia (PIL) is a rare disease of unknown aetiology which presents in the paediatric age group with anasarca, diarrhoea, hypoproteinaemia, lymphoedema and chylous effusions. Tuberculosis, filariasis, chest trauma, malignancies and haematological disorders usually contribute to most cases of secondary lymphangiectasia and chylous effusions. We hereby describe a case of PIL presenting with chylous effusions which remained undiagnosed for eight years.

Healthcare Associated Infections in a Resource Limited Setting.

INTRODUCTION: Health Care associated Infections (HAI) are the most common complications affecting the hospitalized patients. HAI are more common in developing and under developed countries. However, there are no systematic surveillance programs in these countries. AIM: To find out the burden, predisposing factors and multidrug resistant organisms causing HAI in a resource limited setting. MATERIALS AND METHODS: This prospective observational study was done at Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER). Patients aged 13 years or more with stay of more than 48 hours in a 16 bedded Medical Intensive Care Unit (MICU) between November 2011 and April 2013 were included in the study. Patients were prospectively followed up till discharge or death for the development of HAI. Device associated HAI like Ventilator Associated Pneumonia (VAP), Catheter Related-Blood Stream Infection (CR-BSI) and Catheter Associated-Urinary Tract Infections (CA-UTI) were studied. Standard laboratory methods were used for identification of microorganisms causing HAI and to test their antibiotic sensitivity. RESULTS: A total of 346 patients were included in the study with median age of 38 years. Common indications for admission to Medical Intensive Care Unit (MICU) were poisoning (31.5%); neurological illness (23.4%) like Guillian-Barre syndrome, tetanus, meningitis, encephalitis; respiratory illness (14.5%) like pneumonia, acute respiratory distress syndrome and tropical infections (7.2%) like malaria, scrub typhus, leptospirosis. Fifty percent (174/346) patients developed one or more HAI with VAP being the most common. The rates of HAI per 1000 device days for VAP, CR-BSI, CA-UTI were 72.56, 3.98 and 12.4, respectively. Acinetobacter baumannii was the most common organism associated with HAI. Multidrug resistance was seen in 74% of the isolates. CONCLUSION: The burden of HAI, especially with MDR organisms, in resource constrained setting like ours is alarming. There is urgent need for infection control and monitoring system to reduce HAI.

Serodiagnosis of Scrub Typhus at a Tertiary Care Hospital from Southern India.

INTRODUCTION: Scrub typhus, a zoonotic disease is one of the most covert emerging and re-emerging Rickettsial infections. There is an upsurge in the incidence of the disease worldwide with ever-changing habitat. Clinical diagnosis of scrub typhus is challenging as the signs and symptoms of scrub typhus are similar to other febrile illnesses. In developing countries, among the various laboratory tests to diagnose scrub typhus, Weil-Felix test is commonly performed despite its low sensitivity. The Immunofluorescence antibody (IFA) test has its limitations in terms of cost and expertise required. The present study was conducted to determine the seropositivity of IgM ELISA for scrub typhus in clinically suspected cases. MATERIALS AND METHODS: Weil-Felix test and IgM ELISA were performed using clinically suspected cases of scrub typhus using commercially available kits. RESULTS: Out of 482 samples tested, 109 were positive by both Weil-Felix test and IgM ELISA. One hundred and sixteen samples which were negative by Weil-Felix test reacted positive by IgM ELISA. Fourteen samples which were positive by Weil-Felix test were negative by ELISA. CONCLUSION: Owing to the limitations of the Weil-Felix test and IFA, commercially available recombinant IgM ELISA which has a good sensitivity and specificity may be an alternative in laboratories with moderate set up.