Objectives: Convalescent plasma (CP) as a passive source of neutralizing antibodies and immunomodulators is a century-old therapeutic option used for the management of viral diseases. We investigated its effectiveness for the treatment of COVID-19. Design: Open-label, parallel-arm, phase II, multicentre, randomized controlled trial. Setting: Thirty-nine public and private hospitals across India. Participants: Hospitalized, moderately ill confirmed COVID-19 patients (PaO2/FiO2: 200-300 or respiratory rate > 24/min and SpO2 ≤ 93% on room air). Intervention: Participants were randomized to either control (best standard of care (BSC)) or intervention (CP + BSC) arm. Two doses of 200 mL CP was transfused 24 hours apart in the intervention arm. Main Outcome Measure: Composite of progression to severe disease (PaO2/FiO2<100) or all-cause mortality at 28 days post-enrolment. Results: Between 22 nd April to 14 th July 2020, 464 participants were enrolled; 235 and 229 in intervention and control arm, respectively. Composite primary outcome was achieved in 44 (18.7%) participants in the intervention arm and 41 (17.9%) in the control arm [aOR: 1.09; 95% CI: 0.67, 1.77]. Mortality was documented in 34 (13.6%) and 31 (14.6%) participants in intervention and control arm, respectively [aOR) 1.06 95% CI: -0.61 to 1.83]. Interpretation: CP was not associated with reduction in mortality or progression to severe COVID-19. This trial has high generalizability and approximates real-life setting of CP therapy in settings with limited laboratory capacity. A priori measurement of neutralizing antibody titres in donors and participants may further clarify the role of CP in management of COVID-19.
Background:A pregnant woman is usually young and in good health until she suffers from some acute injury. Her prognosis will hopefully be better if she receives timely intensive care.Materials and Methods:The aims of this study were to study the indications of medical intensive care unit (MICU) transfers for critically ill pregnant and postpartum females, biochemical and hematological profile, organ failure, ICU interventions, outcome of mother/fetus, APACHE II score and its correlation with mortality.Study Design and Setting:It is a prospective observational study, carried out in the MICU of a tertiary care teaching hospital over a period of 18 months. One hundred and twenty-two pregnant and postpartum females (up to 42 days after delivery) were studied.Results and Conclusion:Maternal age >30 years was associated with high mortality (68.2%). Majority of the females were admitted in the third trimester (50 patients) and postpartum period (41 patients), and mortality was highest in the postpartum period (39%). Increasing parity and gravida was associated with significantly high mortality (59.5%). Acute viral hepatitis E (45 patients) was most common indication for MICU transfer, followed by malaria and pregnancy-induced hypertension. The mortality rate was 30.3%. The most common cause of death was acute viral hepatitis E (24 patients), with hepatic failure (53 patients) being the most common organ failure. Majority of the females (88 patients) were ANC registered. Low Glasgow coma score and high APACHE II score on admission were associated with significantly high mortality (85.2%). Prompt treatment with oseltamivir in H1N1 infection was associated with good maternal and fetal outcomes.
Background To be universally applicable in treatment of severe COVID-19, novel therapies, especially those with little toxicity and low cost, are urgently needed. We report here the use of one such therapeutic combination involving two commonly used nutraceuticals, namely resveratrol and copper in patients with this disease. This study was prompted by pre-clinical reports that sepsis-related cytokine storm and fatality in mice can be prevented by oral administration of small quantities of resveratrol and copper. Since cytokine storm and sepsis are major causes of death in severe COVID-19, we retrospectively analyzed outcomes of patients with this condition who had received resveratrol and copper. Methods & Findings Our analysis comprised of 230 patients with severe COVID-19 requiring inhaled oxygen who were admitted in a single tertiary care hospital in Mumbai between April 1 and May 13 2020. Thirty of these patients received, in addition to standard care, resveratrol and copper at doses of 5.6 mg and 560 ng, respectively, orally, once every 6 hours, until discharge or death. These doses were based on our pre-clinical studies, and were nearly 50 times and 2000 times less, respectively, than those recommended as health supplements. A multivariable-adjusted analysis was used to model the outcome of death in these patients and evaluate factors associated with this event. A binary logistic regression analysis was used, with age, sex, presence of comorbidities and receipt of resveratrol-copper as covariates. Data were updated as of May 30 2020. The number of deaths in resveratrol-copper and standard care only groups were 7/30 (23.3%, 95% CI 8.1%-38.4%) and 89/200 (44.5%, 95% CI 37.6%-51.3%), respectively. In multivariable analysis, age >50 years [odds ratio (OR) 2.558, 95% CI 1.454-4.302, P=0.0011] and female sex (OR 1.939, 95% CI 1.079-3.482, P=0.0267) were significantly associated, while presence of co-morbidities was not significantly associated (OR 0.713, 95% CI 0.405-1.256, P=0.2421) with death. There was a trend towards reduction in death in patients receiving resveratrol-copper (OR 0.413, 95% CI 0.164-1.039, P= 0.0604). Conclusions We provide preliminary results of a novel approach to the treatment of severe COVID-19 using a combination of small amounts of commonly used nutraceuticals, which is non-toxic and inexpensive, and therefore could be widely accessible globally. The nearly two-fold reduction in mortality with resveratrol-copper observed in our study needs to be confirmed in a randomized controlled trial.
Objective : Efficacy and safety of Itolizumab, an immunomodulatory mAb, in treating moderate-to-severe acute respiratory distress syndrome (ARDS) due to cytokine release in COVID-19 patients was evaluated in a multi-centric, open-label, two-arm, controlled, randomized, phase-2 study. Methods : Patients were randomized (2:1) to Arm-A (best supportive care [BSC]+Itolizumab) and Arm-B (BSC). Primary outcome of interest was reduction in mortality 30-days after enrollment. Results : Thirty-six patients were screened, five treated as first-dose-sentinels and rest randomized, while four patients were screen-failures. Two patients in Arm-A discontinued prior to receiving one complete infusion and were replaced. At end of 1-month, there were three deaths in Arm-B, and none in Arm-A (p = 0.0296; 95% CI = −0.3 [−0.61, −0.08]). At end of study, more patients in Arm-A had improved SpO2 without increasing FiO2 (p = 0.0296), improved PaO2 (p = 0.0296), and reduction in IL-6 (43 vs 212 pg/ml; p = 0.0296) and tumor necrotic factor-α (9 vs 39 pg/ml; p = 0.0253) levels. Transient lymphopenia (Arm-A: 11 patients) and infusion reactions (7 patients) were commonly reported treatment-related safety events. Conclusion : Itolizumab is a promising, safe and effective immunomodulatory therapy for treatment of ARDS due to cytokine release in COVID-19 patients, with survival and recovery-benefit.
ObjectiveLarge data on the clinical characteristics and outcome of COVID-19 in the Indian population are scarce. We analysed the factors associated with mortality in a cohort of moderately and severely ill patients with COVID-19 enrolled in a randomised trial on convalescent plasma.DesignSecondary analysis of data from a Phase II, Open Label, Randomized Controlled Trial to Assess the Safety and Efficacy of Convalescent Plasma to Limit COVID-19 Associated Complications in Moderate Disease.Setting39 public and private hospitals across India during the study period from 22 April to 14 July 2020.ParticipantsOf the 464 patients recruited, two were lost to follow-up, nine withdrew consent and two patients did not receive the intervention after randomisation. The cohort of 451 participants with known outcome at 28 days was analysed.Primary outcome measureFactors associated with all-cause mortality at 28 days after enrolment.ResultsThe mean (SD) age was 51±12.4 years; 76.7% were males. Admission Sequential Organ Failure Assessment score was 2.4±1.1. Non-invasive ventilation, invasive ventilation and vasopressor therapy were required in 98.9%, 8.4% and 4.0%, respectively. The 28-day mortality was 14.4%. Median time from symptom onset to hospital admission was similar in survivors (4 days; IQR 3–7) and non-survivors (4 days; IQR 3–6). Patients with two or more comorbidities had 2.25 (95% CI 1.18 to 4.29, p=0.014) times risk of death. When compared with survivors, admission interleukin-6 levels were higher (p<0.001) in non-survivors and increased further on day 3. On multivariable Fine and Gray model, severity of illness (subdistribution HR 1.22, 95% CI 1.11 to 1.35, p<0.001), PaO2/FiO2 ratio <100 (3.47, 1.64–7.37, p=0.001), neutrophil lymphocyte ratio >10 (9.97, 3.65–27.13, p<0.001), D-dimer >1.0 mg/L (2.50, 1.14–5.48, p=0.022), ferritin ≥500 ng/mL (2.67, 1.44–4.96, p=0.002) and lactate dehydrogenase ≥450 IU/L (2.96, 1.60–5.45, p=0.001) were significantly associated with death.ConclusionIn this cohort of moderately and severely ill patients with COVID-19, severity of illness, underlying comorbidities and elevated levels of inflammatory markers were significantly associated with death.Trial registration numberCTRI/2020/04/024775.
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