Thrombo-inflammation in COVID-19 and Sickle Cell Disease: Two Faces of the Same Coin (preprint)

People with sickle cell disease (SCD) are at greater risk of severe illness and death from respiratory infections, including COVID-19 than people without SCD (Centers for Disease Control and Prevention, USA). Vaso-occlusive crises (VOC) in SCD and severe SARS-CoV-2 infection are both characterized by thrombo-inflammation mediated by endothelial injury, complement activation, inflammatory lipid storm, platelet activation, platelet-leukocyte adhesion, and activation of the coagulation cascade. Notably, lipid mediators, including thromboxane A2, significantly increase in severe COVID-19 and SCD. In addition, the release of thromboxane A2 from endothelial cells and macrophages stimulates platelets to release microvesicles which are harbingers of multicellular adhesion and thrombo-inflammation. Currently, there are limited therapeutic strategies targeting platelet-neutrophil activation and thrombo-inflammation in either SCD or COVID-19 during acute crisis. However, due to many similarities between the pathobiology of thrombo-inflammation in SCD and COVID-19, therapies targeting one disease may likely be effective in the other. Therefore, the preclinical and clinical research spurred by the COVID-19 pandemic, including clinical trials of anti-thrombotic agents, are potentially applicable to VOC. Here, we first outline the parallels between SCD and COVID-19; second, review the role of lipid mediators in the pathogenesis of these diseases and lastly, examine the therapeutic targets and potential treatments for the two diseases.

CovidMis20: COVID-19 Misinformation Detection System on Twitter Tweets using Deep Learning Models (preprint)

Online news and information sources are convenient and accessible ways to learn about current issues. For instance, more than 300 million people engage with posts on Twitter globally, which provides the possibility to disseminate misleading information. There are numerous cases where violent crimes have been committed due to fake news. This research presents the CovidMis20 dataset (COVID-19 Misinformation 2020 dataset), which consists of 1,375,592 tweets collected from February to July 2020. CovidMis20 can be automatically updated to fetch the latest news and is publicly available at: https://github.com/everythingguy/CovidMis20. This research was conducted using Bi-LSTM deep learning and an ensemble CNN+Bi-GRU for fake news detection. The results showed that, with testing accuracy of 92.23% and 90.56%, respectively, the ensemble CNN+Bi-GRU model consistently provided higher accuracy than the Bi-LSTM model.

Community resilience, Corporate Social Responsibility and local economic development: The case of coal mining in India

Corporate social responsibility (CSR) in the mining sector is believed by its proponents to be a critical element of responsible business practice, providing strategic economic advantages while helping to minimize environmental damage. In the midst of the current COVID-19 crisis, this study presents a paradigm for assessing the development of local communities through CSR initiatives by the mining sector. For the purpose of the study, data were gathered from 1209 beneficiaries living in the vicinity of Eastern Coalfield Limited (ECL). According to the findings of the study, CSR initiatives result in enhanced livelihood activities, skills, knowledge, empowerment, and community participation for the community affected by COVID-19. This study has significant implications for academics and corporate executives in the context of India's mandatory CSR laws, as it uses structural equation modelling (SEM) to evaluate the efficacy of CSR initiatives in terms of local community development and to unravel the complexity of the relationship between corporations and society. In addition, community resilience is employed to mediate various CSR initiatives and local community development as an innovative approach to managing the COVID-19 pandemic.

Secondary infections modify the overall course of hospitalized COVID-19 patients: A retrospective study from a network of hospitals across North India (preprint)

IntroductionSARS-CoV-2 infection increases the risk of secondary bacterial and fungal infections and contributes to adverse outcomes. The present study was undertaken to get better insights into the extent of secondary bacterial and fungal infections in Indian hospitalized patients and to assess how these alter the course of COVID-19 so that the control measures can be suggested. MethodsThis is a retrospective, multicentre study where data of all RT-PCR positive COVID-19 patients was accessed from Electronic Health Records (EHR) of a network of 10 hospitals across 5 North Indian states, admitted during the period from March 2020 to July 2021.The data included demographic profile of patients, clinical characteristics, laboratory parameters, treatment modalities, and outcome in those with secondary infections (SIs) and those without SIs. Spectrum of SIS was also studied in detail. ResultsOf 19852 RT-PCR positive SARS-CO2 patients admitted during the study period, 1940 (9.8%) patients developed SIs. Patients with SIs were 8 years older on average (median age 62.6 years versus 54.3 years; P<0.001) than those without SIs. The risk of SIs was significantly (p < 0.001) associated with age, severity of disease at admission, diabetes, ICU admission, and ventilator use. The most common site of infection was urinary tract infection (UTI) (41.7%), followed by blood stream infection (BSI) (30.8%), sputum/BAL/ET fluid (24.8%), and the least was pus/wound discharge (2.6%). As many as 13.4% had infections with more than organism and 34.1% patients had positive cultures from more than one site. Gram negative bacilli (GNB) were the commonest organisms (63.2%), followed by Gram positive cocci (GPC) (19.6%) and fungus (17.3%). Most of the patients with SIs were on multiple antimicrobials - the most commonly used were the BL-BLI for GNBs (76.9%) followed by carbapenems (57.7%), cephalosporins (53.9%) and antibiotics carbapenem resistant entreobacteriace (47.1%). The usage of emperical antibiotics for GPCs was in 58.9% and of antifungals in 56.9% of cases, and substantially more than the results obtained by culture. The average stay in hospital for patients with SIs was twice than those without SIs (median 13 days versus 7 days). The overall mortality in the group with SIs (40.3%) was more than 8 times of that in those without SIs (4.6%). Only 1.2% of SI patients with mild COVID-19 at presentation died, while 17.5% of those with moderate disease and 58.5% of those with severe COVID-19 died (P< 0.001). The mortality was highest in those with BSI (49.8%), closely followed by those with HAP (47.9%), and then UTI and SSTI (29.4% each). The mortality rate where only one microorganism was identified was 37.8% and rose to 56.3% in those with more than one microorganism. The mortality in cases with only one site of infection was 28.8%, which steeply rose to 62.5% in cases with multiple sites of infection. The mortality in diabetic patients with SIs was 45.2% while in non-diabetics it was 34.3% (p < 0.001). ConclusionsSecondary bacterial and fungal infections can complicate the course of almost 10% of COVID-19 hospitalised patients. These patients tend to not only have a much longer stay in hospital, but also a higher requirement for oxygen and ICU care. The mortality in this group rises steeply by as much as 8 times. The group most vulnerable to this complication are those with more severe COVID-19 illness, elderly, and diabetic patients. Varying results in different studies suggest that a region or country specific guideline be developed for appropriate use of antibiotics and antifungals to prevent their overuse in such cases. Judicious empiric use of combination antimicrobials in this set of vulnerable COVID-19 patients can save lives.

Differentials in the characteristics of COVID-19 cases in Wave-1 and Wave-2 admitted to a network of hospitals in North India (preprint)

Second wave of COVID 19 pandemic in India came with unexpected quick speed and intensity, creating an acute shortage of beds, ventilators, and oxygen at the peak of occurrence. This may have been partly caused by emergence of new variant delta. Clinical experience with the cases admitted to hospitals suggested that it is not merely a steep rise in cases but also possibly the case profile is different. This study was taken up to investigate the differentials in the characteristics of the cases admitted in the second wave versus those admitted in the first wave. Records of a total of 14398 cases admitted in the first wave (2020) to our network of hospitals in north India and 5454 cases admitted in the second wave (2021) were retrieved, making it the largest study of this kind in India. Their demographic profile, clinical features, management, and outcome was studied. Age sex distribution of the cases in the second wave was not much different from those admitted in the first wave but the patients with comorbidities and those with greater severity had larger share. Level of inflammatory markers was more adverse. More patients needed oxygen and invasive ventilation. ICU admission rate remained nearly the same. On the positive side, readmissions were lower, and the duration of hospitalization was slightly less. Usage of drugs like remdesivir and IVIG was higher while that of favipiravir and tocilizumab was lower. Steroid and anticoagulant use remained high and almost same during the two waves. More patients had secondary bacterial and fungal infections in Wave 2. Mortality increased by almost 40% in Wave 2, particularly in the younger patients of age less than 45 years. Higher mortality was observed in those admitted in wards, ICU, with or without ventilator support and those who received convalescent plasma. No significant demographic differences in the cases in these two waves, indicates the role of other factors such as delta variant and late admissions in higher severity and more deaths. Comorbidity and higher secondary bacterial and fungal infections may have contributed to increased mortality.

Are Aspirin and Apixaban Sufficient to Prevent Immunothrombosis in COVID-19? (preprint)

Severe COVID-19 disease is associated with respiratory and vascular injury and microvascular immunothrombosis mediated by complement activation, inflammatory lipid storm, platelet activation, platelet-leukocyte adhesion and activation of coagulation cascade. Amongst the inflammatory lipids, thromboxane A2 (TxA2) is a known key mediator of microvascular thrombosis. The levels of TxB2, a stable metabolite of TxA2 are markedly increased in the bronchoalveolar lavage fluid and plasma in severe COVID-19 patients. Low-dose aspirin mitigates the generation of prostanoids including TxA2 by irreversible inactivation of the constitutive enzyme cyclooxygenase (COX)-1. The anti-thrombotic action of aspirin is currently being investigated in outpatient and hospitalized COVID-19 patients in the global RECOVERY and ACTIV-4 clinical trials. Several lines of investigations suggest that COX-2 plays an important and critical role in the immunothrombotic effects mediated by COVID-19. Pharmacologic inhibition of either COX-1 or COX-2 can prevent a plethora of lipid mediators of inflammation that are both pro- and anti-inflammatory in function. Thus, a more definitive approach to prevent immunothrombotic events in COVID-19 will be to directly block the prothrombotic effects of TxA2. Although thromboxane synthase (TS) inhibitors suppress TxA2 formation, accumulation of the substrate PGH2 is known to interact with the platelet and vessel wall TxA2 prostanoid receptor (TPR), thus reducing the antiplatelet effects of TS inhibitors. TPR antagonists block the activity of both TxA2 and PGH2 on platelets and vessels but do not block TxA2 production, which leads to increased generation of 11-dehydro-thromboxane B2, a stable metabolite of TxA2, and a potent agonist of the DP2 (CRTH2) receptor for prostaglandin D2 (PGD2). PGD2/DP2 receptor signaling has been implicated in immune dysregulation in viral infections including COVID-19. Ramatroban, an orally bioavailable, potent, dual TxA2/TP and PGD2/DP2 receptor antagonist, has demonstrated efficacy in a variety of animal models of atherosclerosis, thrombosis and sepsis. Ramatroban has a proven safety profile, having been used in Japan over the past 20 years as a treatment of allergic rhinitis and therefore, merits investigation as a promising antithrombotic and immunomodulator agent for chemoprophylaxis and treatment in COVID-19 patients.

Effectiveness of Convalescent Plasma Therapy in Indian Patients with COVID-19 (preprint)

Background: Convalescent plasma (CP) is being used as a treatment option in hospitalized patients with COVID-19. Till date, there is conflicting evidence on efficacy of CP in reducing COVID-19 related mortality.Objective: to evaluate the effect of CP on 28-day mortality reduction in patients with COVID-19.Methods: We did a multi-center, retrospective case control observational study from 1st May 2020 to 31st August 2020. A total of 1079 adult patients with moderate and severe COVID-19 requiring oxygen, were reviewed. Of these, 694 patients were admitted to ICU. Out of these, 333 were given CP along with best supportive care and remaining 361 received best supportive care only.Results: In the overall group of 1079 patients, mortality in plasma vs no plasma group was statistically not significant (22.4% vs 18.5%; p = 0.125). However, in patients with COVID-19 admitted to ICU, mortality was significantly lower in plasma group (25.5% vs 33.2%; p = 0.026). This benefit of reduced mortality was most seen in age group 60 to 74 years (26.7% vs 43.0%; p = 0.004), driven mostly by females of this age group (23.1% vs 53.5%; p = 0.013). Significant difference in mortality was observed in patients with one comorbidity (22.3% vs 36.5%; p = 0.004). Moreover, patients on ventilator had significantly lower mortality in the plasma arm (37.2% vs 49.3%; p = 0.009); particularly so for patients on invasive mechanical ventilation (63.9% vs 82.9%; p = 0.014).Conclusion: The use of CP reduced mortality in COVID-19 elderly patients admitted in ICU, above 60 years of age, particularly females, those with comorbidities and especially those who required some form of ventilation.Funding Statement: None to declare.Declaration of Interests: None to declare. Ethics Approval Statement: The manuscript has ethical clearance and approval from the ethics committee of the institute . A copy of the approval letter is attached. (Reference number isRS/MSSH/GMRCHS/IEC/IM/20-16).

Exposure to Mycobacteria influences disease progression in COVID-19 patients (preprint)

Background: COVID-19−related deaths are significantly higher in countries with higher quality of life. A strong negative correlation is reported between the BCG index and COVID- 19 mortality. The present study explored if a high Th1immunity due to frequent exposure to strong Th1 antigens like Mycobacteria or Salmonella could be the cause for lesser COVID-19−related deaths in Indian population. Methods: This prospective comparative study was conducted with 3 groups of twenty patients each of mildly symptomatic (A), severely ill (S) Covid patients and healthy volunteers with a Covid Negative report (H).Results: All severely ill patients showed increased leucocyte counts, lymphopenia and raised D-dimer. A gross reversible unresponsiveness of T cells was seen among all patients in S group with absolutely no response even to the mitogen stimulus. Quantiferon TB test value and distribution of test positivity was significantly lower in group S. Three out of 6 survived patients in S group had positive Quantiferon TB test while 2 patients turned positive on repeat test and the sixth patient showed high TH titre on widal test.Conclusion: Altered Th1 immunity associated with frequent community exposure of tuberculosis and typhoid antigen in Indian population might be responsible for its relatively lesser prevalence and mortality following Covid-19.  

Prostaglandin D2 As a Mediator of Lymphopenia and a Therapeutic Target in COVID-19 Disease (preprint)

A characteristic feature of COVID-19 disease is lymphopenia. Lymphopenia occurs early in the clinical course and is a predictor of disease severity and outcomes. The mechanism of lymphopenia in COVID-19 is uncertain. It has been variously attributed to the release of inflammatory cytokines including IL-6 and TNF-a; direct infection of the lymphocytes by the virus; and rapid sequestration of lymphocytes in the tissues. Additionally, we postulate that prostaglandin D2 (PGD2) is a key meditator of lymphopenia in COVID-19. First, SARS-CoV infection is known to stimulate the production of PGD2 in the airways, which inhibits the host dendritic cell response via the DP1 receptor signaling. Second, PGD2 is known to upregulate monocytic myeloid-derived suppressor cells (MDSC) via the DP2 receptor signaling in group 2 innate lymphoid cells (ILC2). We propose targeting PGD2/DP2 signaling using a receptor antagonist such as ramatroban as an immunotherapy for immune dysfunction and lymphopenia in COVID-19 disease.

Risk of Ischemic Stroke in Patients with Covid-19 versus Patients with Influenza (preprint)

Importance: Case series without control groups suggest that Covid-19 may cause ischemic stroke, but whether Covid-19 is associated with a higher risk of ischemic stroke than would be expected from a viral respiratory infection is uncertain. Objective: To compare the rate of ischemic stroke between patients with Covid-19 and patients with influenza, a respiratory viral illness previously linked to stroke. Design: A retrospective cohort study. Setting: Two academic hospitals in New York City. Participants: We included adult patients with emergency department visits or hospitalizations with Covid-19 from March 4, 2020 through May 2, 2020. Our comparison cohort included adult patients with emergency department visits or hospitalizations with influenza A or B from January 1, 2016 through May 31, 2018 (calendar years spanning moderate and severe influenza seasons). Exposures: Covid-19 infection confirmed by evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the nasopharynx by polymerase chain reaction, and laboratory-confirmed influenza A or B. Main Outcomes and Measures: A panel of neurologists adjudicated the primary outcome of acute ischemic stroke and its clinical characteristics, etiological mechanisms, and outcomes. We used logistic regression to compare the proportion of Covid-19 patients with ischemic stroke versus the proportion among patients with influenza. Results: Among 2,132 patients with emergency department visits or hospitalizations with Covid-19, 31 patients (1.5%; 95% confidence interval [CI], 1.0%-2.1%) had an acute ischemic stroke. The median age of patients with stroke was 69 years (interquartile range, 66-78) and 58% were men. Stroke was the reason for hospital presentation in 8 (26%) cases. For our comparison cohort, we identified 1,516 patients with influenza, of whom 0.2% (95% CI, 0.0-0.6%) had an acute ischemic stroke. After adjustment for age, sex, and race, the likelihood of stroke was significantly higher with Covid-19 than with influenza infection (odds ratio, 7.5; 95% CI, 2.3-24.9). Conclusions and Relevance: Approximately 1.5% of patients with emergency department visits or hospitalizations with Covid-19 experienced ischemic stroke, a rate 7.5-fold higher than in patients with influenza. Future studies should investigate the thrombotic mechanisms in Covid-19 in order to determine optimal strategies to prevent disabling complications like ischemic stroke.