Predictors of Mortality among Patients Hospitalized with COVID-19 during the First Wave in India: A Multisite Case-Control Study.

Severe acute respiratory syndrome coronavirus 2 disease (COVID-19) has caused more than 6 million deaths globally. Understanding predictors of mortality will help in prioritizing patient care and preventive approaches. This was a multicentric, unmatched, hospital-based case-control study conducted in nine teaching hospitals in India. Cases were microbiologically confirmed COVID-19 patients who died in the hospital during the period of study and controls were microbiologically confirmed COVID-19 patients who were discharged from the same hospital after recovery. Cases were recruited sequentially from March 2020 until December-March 2021. All information regarding cases and controls was extracted retrospectively from the medical records of patients by trained physicians. Univariable and multivariable logistic regression was done to assess the association between various predictor variables and deaths due to COVID-19. A total of 2,431 patients (1,137 cases and 1,294 controls) were included in the study. The mean age of patients was 52.8 years (SD: 16.5 years), and 32.1% were females. Breathlessness was the most common symptom at the time of admission (53.2%). Increasing age (adjusted odds ratio [aOR]: 46-59 years, 3.4 [95% CI: 1.5-7.7]; 60-74 years, 4.1 [95% CI: 1.7-9.5]; and ≥ 75 years, 11.0 [95% CI: 4.0-30.6]); preexisting diabetes mellitus (aOR: 1.9 [95% CI: 1.2-2.9]); malignancy (aOR: 3.1 [95% CI: 1.3-7.8]); pulmonary tuberculosis (aOR: 3.3 [95% CI: 1.2-8.8]); breathlessness at the time of admission (aOR: 2.2 [95% CI: 1.4-3.5]); high quick Sequential Organ Failure Assessment score at the time of admission (aOR: 5.6 [95% CI: 2.7-11.4]); and oxygen saturation < 94% at the time of admission (aOR: 2.5 [95% CI: 1.6-3.9]) were associated with mortality due to COVID-19. These results can be used to prioritize patients who are at increased risk of death and to rationalize therapy to reduce mortality due to COVID-19.

A retrospective study to evaluate the efficacy and safety of SARS-CoV-2 vaccine in patients with advanced genitourinary cancers.

Background: COVID-19 vaccination is one of the pivotal key tools against the ongoing pandemic, but its acceptance relies on efficacy and safety data among various populations, including patients with cancers. However, there is limited data on seroconversion rates, efficacy, and safety of the COVID-19 vaccine in patients with cancer. Breakthrough infections after vaccination have also been reported, which could further strengthen the refusal behavior of specific populations to be immunized. Our objective was to investigate the efficacy and safety of COVID-19 vaccination in real-world patients with advanced genitourinary cancers. Methods and results: A retrospective study of the 738 patients with advanced metastatic genitourinary malignancy was conducted at our genitourinary oncology clinic from October 2020 to September 2021, out of which 462 patients (62.6%) were vaccinated. During the study period, two vaccinated, and six unvaccinated patients tested positive for SARS-CoV-2 (breakthrough infection rate: 0.4% vs. 2.2%, p = 0.027). Vaccine protection against infection was 81.8% (95% CI: 0.04-0.98). One vaccinated and 4 unvaccinated patients were hospitalized due to COVID-19 (0.2% vs. 1.4%, p = 0.048). Vaccine effectiveness in preventing hospitalization was 85.7% (95% CI: 0.02-1.33). Within one month of vaccination, 1.5% of patients (n = 7) had emergency visits, 0.8% (n = 4) were hospitalized for any reason, and of these, 3 (0.6%) experienced a delay in the receipt of their cancer therapy. Conclusion: In our hypothesis-generating data among patients with advanced genitourinary cancers, COVID-19 vaccination was efficacious and safe and was rarely associated with treatment disruptions. These data should help improve the acceptance of the COVID-19 vaccine in the general population and patients with cancer. The vaccine effectiveness in our patients is comparable with existing published data without cancer.

Adverse events following remdesivir administration in moderately ill COVID-19 patients - A retrospective analysis.

Introduction: Remdesivir, an antiviral drug, received an emergency use authorization for treating coronavirus disease 2019 (COVID-19) patients. Though many studies have reported the safety aspects of this antiviral agent, most of them were observed in severely ill COVID-19 patients, making very less data available in the moderately ill patients. The present study was conducted with an objective of finding the adverse events (AEs) associated with remdesivir in moderately ill COVID-19 patients. Methodology: A retrospective observational study was conducted by collecting data of demographic details and details of remdesivir, laboratory investigations, and AEs from the patient medical records from May to July 2021 and analyzed by using the appropriate statistics. Results: Out of the 160 COVID-19 patients, 32 were moderately ill (males: 29, females: 03) and were treated with remdesivir along with steroids and low molecular weight heparin (LMW) heparin. The average number of administered remdesivir doses was 4, with a loading dose of 200 mg and a maintenance dose of 100 mg. A total of 41 AEs were observed out of which 17 were adverse drug reactions (ADRs) (a significant increase in the alanine transaminase (ALT) [P < 0.001]) and 23 AEs (a significant rise in random blood sugars, RBS [one of the AEs] [P = 0.007]). The AEs were more commonly seen in the hypertensive patients. An increased oxygen requirement was a major serious AE observed in four patients. Conclusion: Remdesivir caused a significant increase in the liver enzymes. Increased blood sugar levels were the most common AE and increased oxygen requirement was the major serious AE observed.

A phase III, randomized, open-label study (CONTACT-02) of cabozantinib plus atezolizumab versus second novel hormone therapy in patients with metastatic castration-resistant prostate cancer.

Cabozantinib inhibits multiple receptor tyrosine kinases, including the TAM kinase family, and may enhance response to immune checkpoint inhibitors. One cohort of the ongoing phase Ib COSMIC-021 study (NCT03170960) evaluating cabozantinib plus the PD-L1 inhibitor atezolizumab in men with metastatic castration-resistant prostate cancer (mCRPC) that has progressed in soft tissue on/after enzalutamide and/or abiraterone treatment for metastatic disease has shown promising efficacy. Here, we describe the rationale and design of a phase III trial of cabozantinib plus atezolizumab versus a second novel hormone therapy (NHT) in patients who have previously received an NHT for mCRPC, metastatic castration-sensitive PC or nonmetastatic CRPC and have measurable visceral disease and/or extrapelvic adenopathy - a population with a significant unmet need for treatment options. Trial Registration Clinical Trial Registration: NCT04446117 (ClinicalTrials.gov) Registered on 24 June 2020.

COMMENT: Covid-19: Catalyst for a comprehensive law to combat potential pandemics in India.

Despite the relative decline in communicable diseases, India witnesses hundreds of outbreaks every year. Including the current Covid-19 pandemic, India has suffered through several major pandemics and large-scale epidemics since 1900s. However, the response to most of the epidemics has been inadequate. The Epidemic Diseases Act, enacted in 1897 (EDA 1897), has been in action since and is based on the science and the socio-political environment of the country in the nineteenth century. India has several legal mechanisms to help contain and control the spread of epidemics, but on different platforms. There has been a paradigm shift in the socio-political milieu as well as scientific advancements in the prevention and control of epidemics. The century-old EDA 1897 has not been effective in containing and controlling such epidemics/pandemics, as has been witnessed during the ongoing Covid-19 pandemic. Hence, it needs to be revised to define an appropriate structural scalar chain, provide clear-cut and unambiguous terms/definitions and guidelines, delineate ethics and human rights, determine the duties and responsibilities of the affected population/community, determine the role of the private health sector, and provide for appropriate punitive measures to deter repeated violations.

Can proactive roles played by Community Medicine professionals in times of COVID-19 Pandemic bring the leadership of public health in India in the right hands?

Since the onset of the COVID-19 Pandemic, various public health measures have been in focus, viz. social distancing, hand hygiene, use of masks, screening of patients for COVID-19 symptoms, development of quarantine and isolation facilities, and public health surveillance. Most of these relate to the principles of prevention, early case detection, and primary care. In the ongoing fight against COVID-19, community medicine (CM) professionals are involved at various positions and have been leading from the front in a variety of activities, be it screening, patient care, surveillance, orientation and training of front line workers, community engagement, evidence generation through research, and development of guidelines. However, their engagement in policymaking has still been limited. The government should work more closely with CM professionals in order to stem the tide of COVID-19 or any such public health emergencies in the future by shifting the focus to preventive and promotive interventions. CM professionals should take a more proactive approach in getting involved in policymaking and demonstrate leadership through their actions to lead the national, state, and district-level public health teams through collaboration across disciplines and sectors. This will help bring the leadership of public health in India in the right hands for optimum population health and appropriate and timely health emergency response.

Convalescent plasma therapy in COVID-19 and discharge status: A systematic review.

OBJECTIVE: Covid19 has emerged as a greatest threat of the decade worldwide. At present there is no certain treatment for treating coronavirus diseases, while some antiviral drugs (Remdesivir , Lopinavir and Ritonavir) are under investigation. Many countries including India have adopted the convalescent plasma therapy in the treatment of moderate to severely ill patients. Despite the treatment being given ,there are no such evidences on the utility and efficacy of convalescent plasma. Hence this study tries to find out the impact on the discharge status from hospital of the patients receiving the very therapy. DESIGN: Systematic review and meta analysis. SETTING: An extensive search was made, following PRISMA guidelines on online databases such as Pubmed, Google scholar and Science direct. Studies those fulfilled the inclusion and exclusion criteria ,were included and reviewed and analyzed for a common outcome(discharge status). PARTICIPANTS: A total of 6 eligible studies were analyzed qualitatively and quantitatively which included three case control, two case series and one case report. RESULTS: The overall pooled discharge rate from the above studies was 75.7% after the CP therapy. When analyzed for relative risk , it showed CP therapy having a lower risk of staying in hospital (not getting discharged) when compared to Standard therapy ,overall RR (relative risk) being 0.946. CONCLUSION: Our study shows that there is always a higher rate of discharge and low risk of prolonged hospital stay in those patients who receive plasma therapy. CP therapy being a low cost and easy to administer therapy with very less adverse events, requires more focus on further research as it has a potential to become an ideal effective treatment option for COVID-19.

Early Determinants of Length of Hospital Stay: A Case Control Survival Analysis among COVID-19 Patients admitted in a Tertiary Healthcare Facility of East India.

BACKGROUND: Length of hospital stay (LOS) for a disease is a vital estimate for healthcare logistics planning. The study aimed to illustrate the effect of factors elicited on arrival on LOS of the COVID-19 patients. MATERIALS AND METHODS: It was a retrospective, record based, unmatched, case control study using hospital records of 334 COVID-19 patients admitted in an East Indian tertiary healthcare facility during May to October 2020. Discharge from the hospital (cases/survivors) was considered as an event while death (control/non-survivors) as right censoring in the case-control survival analysis using cox proportional hazard model. RESULTS: Overall, we found the median LOS for the survivors to be 8 days [interquartile range (IQR): 7-10 days] while the same for the non-survivors was 6 days [IQR: 2-11 days]. In the multivariable cox-proportional hazard model; travel distance (>16 km) [adjusted hazard ratio (aHR): 0.69, 95% CI: (0.50-0.95)], mode of transport to the hospital (ambulance) [aHR: 0.62, 95% CI: (0.45-0.85)], breathlessness (yes) [aHR: 0.56, 95% CI: (0.40-0.77)], number of co-morbidities (1-2) [aHR: 0.66, 95% CI: (0.47-0.93)] (≥3) [aHR: 0.16, 95% CI: (0.04-0.65)], COPD/asthma (yes) [ [aHR: 0.11, 95% CI: (0.01-0.79)], DBP (<60/≥90) [aHR: 0.55, 95% CI: (0.35-0.86)] and qSOFA score (≥2) [aHR: 0.33, 95% CI: (0.12-0.92)] were the significant attributes affecting LOS of the COVID-19 patients. CONCLUSION: Factors elicited on arrival were found to be significantly associated with LOS. A scoring system inculcating these factors may be developed to predict LOS of the COVID-19 patients.

Impact of IRS: Four-years of entomological surveillance of the Indian Visceral Leishmaniases elimination programme.

BACKGROUND: In 2005, Bangladesh, India and Nepal agreed to eliminate visceral leishmaniasis (VL) as a public health problem. The approach to this was through improved case detection and treatment, and controlling transmission by the sand fly vector Phlebotomus argentipes, with indoor residual spraying (IRS) of insecticide. Initially, India applied DDT with stirrup pumps for IRS, however, this did not reduce transmission. After 2015 onwards, the pyrethroid alpha-cypermethrin was applied with compression pumps, and entomological surveillance was initiated in 2016. METHODS: Eight sentinel sites were established in the Indian states of Bihar, Jharkhand and West Bengal. IRS coverage was monitored by household survey, quality of insecticide application was measured by HPLC, presence and abundance of the VL vector was monitored by CDC light traps, insecticide resistance was measured with WHO diagnostic assays and case incidence was determined from the VL case register KAMIS. RESULTS: Complete treatment of houses with IRS increased across all sites from 57% in 2016 to 70% of houses in 2019, rising to >80% if partial house IRS coverage is included (except West Bengal). The quality of insecticide application has improved compared to previous studies, average doses of insecticide on filters papers ranged from 1.52 times the target dose of 25mg/m2 alpha-cypermethrin in 2019 to 1.67 times in 2018. Resistance to DDT has continued to increase, but the vector was not resistant to carbamates, organophosphates or pyrethroids. The annual and seasonal abundance of P. argentipes declined between 2016 to 2019 with an overall infection rate of 0.03%. This was associated with a decline in VL incidence for the blocks represented by the sentinel sites from 1.16 per 10,000 population in 2016 to 0.51 per 10,000 in 2019. CONCLUSION: Through effective case detection and management reducing the infection reservoirs for P. argentipes in the human population combined with IRS keeping P. argentipes abundance and infectivity low has reduced VL transmission. This combination of effective case management and vector control has now brought India within reach of the VL elimination targets.

Evaluation of Ivermectin as a Potential Treatment for Mild to Moderate COVID-19: A Double-Blind Randomized Placebo Controlled Trial in Eastern India.

BACKGROUND: There has been a growing interest in ivermectin ever since it was reported to have an in-vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This trial was conducted to test the efficacy of ivermectin in mild and moderate coronavirus disease 19 (COVID-19). METHODS: A double blind, parallel, randomised, placebo-controlled trial conducted among adult COVID-19 patients with mild to moderate disease severity on admission in a COVID dedicated tertiary healthcare of eastern India. Enrolment was done between 1st August and 31st October 2020.  On day 1 and 2 post enrolment, patients in the intervention arm received ivermectin 12 mg while the patients in the non-interventional arm received placebo tablets. RESULTS: About one-fourth (23.6%) of the patients in the intervention arm and one-third (31.6%) in the placebo arm were tested reverse transcriptase polymerase chain reaction (RTPCR) negative for SARS-CoV-2 on 6th day. Although this difference was found to be statistically insignificant [rate ratio (RR): 0.8; 95% confidence interval (CI): 0.4-1.4; p=0.348]. All patients in the ivermectin group were successfully discharged. In comparison the same for the placebo group was observed to be 93%. This difference was found to be statistically significant (RR: 1.1; 95% CI; 1.0-1.2; p=0.045). CONCLUSIONS: Inclusion of ivermectin in treatment regimen of mild to moderate COVID-19 patients could not be said with certainty based on our study results as it had shown only marginal benefit in successful discharge from the hospital with no other observed benefits.

COVID-19 vaccine guidance for patients with cancer participating in oncology clinical trials.

Emerging efficacy data have led to the emergency use authorization or approval of COVID-19 vaccines in several countries worldwide. Most trials of COVID-19 vaccines excluded patients with active malignancies, and thus data on the safety, tolerability and efficacy of the vaccines in patients with cancer are currently limited. Given the risk posed by the COVID-19 pandemic, decisions regarding the use of vaccines against COVID-19 in patients participating in trials of investigational anticancer therapies need to be addressed promptly. Patients should not have to choose between enrolling on oncology clinical trials and receiving a COVID-19 vaccine. Clinical trial sponsors, investigators and treating physicians need operational guidance on COVID-19 vaccination for patients with cancer who are currently enrolled or might seek to enrol in clinical trials. Considering the high morbidity and mortality from COVID-19 in patients with cancer, the benefits of vaccination are likely to far outweigh the risks of vaccine-related adverse events. Herein, we provide operational COVID-19 vaccine guidance for patients participating in oncology clinical trials. In our perspective, continued quality oncological care requires that patients with cancer, including those involved in trials, be prioritized for COVID-19 vaccination, which should not affect trial eligibility.

Epidemiological determinants of COVID-19 infection and mortality: A study among patients presenting with severe acute respiratory illness during the pandemic in Bihar, India.

OBJECTIVES: The study was designed to explore epidemiological characteristics, determinants of COVID-19 infection development and mortality of patients presenting with severe acute respiratory illness (SARI) to a tertiary care health facility of Bihar. METHODS: This was an observational record-based study, longitudinal in design. Data of 281 SARI patients who have attended All India Institute of Medical Sciences, Patna, Bihar, India during 25th April 2020, till 12th July 2020 (16 weeks) were used for the study. RESULTS: Out of 281 study participants, 95 (33.8%) were detected to have COVID-19 and 42 (14.9%) died. Among COVID-positive study subject's death rate was 28.4%. In the multivariable logistic regression analysis; increasing age (adjusted odds ratio [AOR] = 1.02 [1.00-1.03]), gender (males) (AOR = 2.51 [1.27-4.96]), presenting symptom (cough) (AOR = 2.88 [1.46-5.70]), co-morbidity (hypothyroidism) (AOR = 4.59 [1.45-14.56]) and delay between symptom onset and admission (>2 days) (AOR = 2.46 [1.19-5.07]) were significant predictors of COVID-19 infection among study participants adjusted with other co-morbidities (diabetes and hypertension). Similarly, place of residence (outside Patna district) (AOR = 2.38 [1.03-5.50]), co-morbidity (diabetes) (AOR = 3.08 [1.12-8.50]), intensive care unit (ICU) requirement at admission (yes) (AOR = 9.47 [3.98-22.52]) and COVID status (positive) (AOR = 6.33 [2.68-14.96]) were significant predictors of death among the study participants whereas place of residence (outside Patna district) (AOR = 4.04 [1.33-12.28]) and ICU requirement at admission (yes) (AOR = 7.22 [2.54-20.52]) were attributes affecting death of COVID-positive study participants. CONCLUSION: Risk of COVID-19 infection among the study participants was high. Age, gender and co-morbidities increased the risk of infection. COVID-19 infection negatively impacted the treatment outcome of the study participants. Age, co-morbidity and ICU requirement were the other attributes affecting mortality.

Clinical activity of pembrolizumab in metastatic prostate cancer with microsatellite instability high (MSI-H) detected by circulating tumor DNA.

To report a multi-institutional case series of patients with advanced microsatellite instability high (MSI-H) prostate adenocarcinoma identified with clinical cell-free DNA (cfDNA) next-generation sequencing (NGS) testing and treated with immune checkpoint inhibitors. Retrospective analysis of patients with metastatic castration-resistant prostate cancer (mCRPC) and MSI-H tumor detected by a commercially available cfDNA NGS assay Guardant360 (G360, Guardant Health) at eight different Academic Institutions in the USA, from September 2018 to April 2020. From a total of 14 MSI-H metastatic prostate cancer patients at participating centers, nine patients with mCRPC with 56% bone, 33% nodal, 11% liver and 11% soft-tissue metastases and a median PSA of 29.3 ng/dL, were treated with pembrolizumab after 2 lines of therapy for CRPC. The estimated median time on pembrolizumab was 9.9 (95% CI 1.0 to 18.8) months. Four patients (44%) achieved PSA50 after a median of 4 (3-12) weeks after treatment initiation including three patients with >99% PSA decline. Among the patients evaluable for radiographic response (n=5), the response rate was 60% with one complete response and two partial responses. Best response was observed after a median of 3.3 (1.4-7.6) months. At time of cut-off, four patients were still on pembrolizumab while four patients discontinued therapy due to progressive disease and one due to COVID-19 infection. Half of the patients with PSA50 had both MSI-H and pathogenic alterations in BRCA1 and BRCA2 in their G360 assays. The use of liquid biopsy to identify metastatic prostate cancer patients with MSI-H is feasible in clinical practice and may overcome some of the obstacles associated with prostate cancer tumor tissue testing. The robust activity of pembrolizumab in selected patients supports the generalized testing for MSI-H.

COVID-19 and androgen-targeted therapy for prostate cancer patients.

The current pandemic (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global health challenge with active development of antiviral drugs and vaccines seeking to reduce its significant disease burden. Early reports have confirmed that transmembrane serine protease 2 (TMPRSS2) and angiotensin converting enzyme 2 (ACE2) are critical targets of SARS-CoV-2 that facilitate viral entry into host cells. TMPRSS2 and ACE2 are expressed in multiple human tissues beyond the lung including the testes where predisposition to SARS-CoV-2 infection may exist. TMPRSS2 is an androgen-responsive gene and its fusion represents one of the most frequent alterations in prostate cancer. Androgen suppression by androgen deprivation therapy and androgen receptor signaling inhibitors form the foundation of prostate cancer treatment. In this review, we highlight the growing evidence in support of androgen regulation of TMPRSS2 and ACE2 and the potential clinical implications of using androgen suppression to downregulate TMPRSS2 to target SARS-CoV-2. We also discuss the future directions and controversies that need to be addressed in order to establish the viability of targeting TMPRSS2 and/or ACE2 through androgen signaling regulation for COVID-19 treatment, particularly its relevance in the context of prostate cancer management.