Did COVID-19 or COVID-19 vaccines influence the patterns of Dengue in 2021: An exploratory analysis of two observational studies from North India (preprint)

Background Dengue which is endemic in India and has been occurring for decades apparently witnessed a rise in disease burden in 2021 in specific regions of the nation. We aim to explore less studied risk factors of Dengue occurrence and severity in the post-COVID-19 and post-COVID-19 vaccination era. Methods This was an exploratory analysis involving participants from two prior observational studies conducted during the period of Feb 2021-April 2022 in a tertiary hospital in North India. Healthcare workers constituted the majority of study participants. Individuals were stratified into five groups based on COVID-19 infection and timing of vaccination: CovidNoVaccine (CNV), VaccineNoCOVID (VNC), CovidAfterVaccine (CAV), VaccineAfterCOVID (VAC) and NoVaccineNoCovid (NVNC) groups. The occurrence of lab-confirmed Dengue and severe forms of Dengue were the main outcomes of interest. We tried to predict determinants of Dengue occurrence and severity with a particular focus on COVID-19 history and vaccination status. Results A total of 1520 vaccinated individuals and 181 unvaccinated individuals were included. Of these 1701 participants, symptomatic Dengue occurred in 133 (7.8%) and was of 'severe' category in 42 (31.6%). Individuals with a history of COVID-19 in 2020 had 2 times higher odds of developing symptomatic Dengue. The VAC group had 3.6, 2- and 1.9 times higher odds of developing Dengue than the NVNC, VNC, and CAV groups. The severity of dengue was not affected by COVID-19 or COVID-19 vaccination. Conclusions COVID-19 may enhance the risk of developing symptomatic dengue. Future research dealing with long COVID should explore the propensity of COVID-19 victims towards symptomatic forms of other viral illnesses. Individuals receiving the COVID-19 vaccine after recovering from COVID-19 particularly seem to be at greater risk of symptomatic dengue and need long-term watchfulness. Possible mechanisms, such as antibody-mediated enhancement or T-cell dysfunction, should be investigated in COVID-19-recovered and vaccinated individuals. Further large-scale, multicentric, robust studies with a better enrolment of unvaccinated people will help understand the interplay of factors involved in COVID-19 and Dengue.

A prospective observational study on BBV152 coronavirus vaccine use in adolescents and comparison with adults- first real-world safety analysis (preprint)

Background The BBV152 COVID-19 vaccine (COVAXIN) has recently been approved for adolescents. We provide the first real world safety data of COVAXIN use in adolescents and compare this with adults. Methods A prospective observational study is being conducted since January 2022. Enrolled adolescents and adults were contacted telephonically after 14 days of receiving the BBV152 vaccine. Primary outcome was vaccine safety assessed as rates of adverse events following immunization (AEFI). Severity grading of AEFIs was done using the FDA scale. Findings A total of 698 adolescents and 326 adults were enrolled. AEFIs occurred in 36.3% adolescents after first and in 37.9% after second dose. Systemic involvement was seen in 15-17% adolescents. Injection site pain and fever were the common AEFIs. Majority of AEFIs were mild-moderate. Severe and atypical AEFIs were observed in 0.9% and 0.6% adolescents respectively. Majority of AEFIs recovered in 1-2 days. In >2% adolescents, AEFIs were persisting at 14-day follow-up since the second dose. No difference in AEFI incidence and patterns was observed between adolescents and adults. Regression analysis showed females and those with history of allergy to be respectively at 1.5-times and 3-times increased risk of AEFIs among adolescents. Interpretation COVAXIN carries an overall favorable short term safety profile in adolescents. The observed AEFI rates in adolescents are much lower than that reported with mRNA vaccines. Female adolescents and those with history of allergy need watchfulness. With some AEFIs persisting at 14 days, a longer follow-up is recommended to strengthen the safety data of these vaccines. Funding No funding support

Persistent health issues, adverse events of significant concern, and effectiveness of COVID-19 vaccination- findings from a real-world cohort study of healthcare workers in north India (preprint)

Background: There is paucity of real-world data on COVID-19 vaccine effectiveness and safety from cohort designs. The current study aimed to evaluate vaccine performance during second wave in India. It also aimed to determine adverse events of significant concern (AESCs), and to ascertain the effect of vaccination on persistent health issues in individuals post COVID-19. Methods: A cohort study was conducted from July-2021 to December-2021 in a tertiary hospital of north India. The primary outcome was vaccine-effectiveness against COVID-19. Secondary outcomes were AESCs, and persistent health issues in those receiving vaccine. Regression analyses were performed to determine risk factors. Results: In 2760 healthcare workers (HCWs) included, 1033 COVID-19 events were reported. Around 6-17% vaccine effectiveness was observed against COVID-19 occurrence. One dose-recipients were at 1.6-times increased risk of COVID-19. Prior SARS-CoV-2 infection was a strong independent protective factor against COVID-19 (aOR 0.66). Full vaccination reduced moderate-severe COVID-19 by 57%. Those with lung disease were at 2.5-times increased risk of moderate-severe COVID-19. AESCs were observed in 1.3% including one case each of myocarditis and severe hypersensitivity. Individuals with hypothyroidism were at 5-times and those receiving vaccine after recovery from COVID-19 were at 3-times higher risk of persistent health issues. Conclusion: COVID-19 vaccination reduced COVID-19 severity but offered marginal protection against occurrence. Relationship of asthma and hypothyroidism with COVID-19 outcomes necessitates focused research. Independent protection of prior SARS-CoV-2 infection was high and persistent health issues were common in individuals receiving vaccine post COVID-19. Recommendations of vaccinating those recovered from COVID-19 need further studies.

New onset rheumatoid arthritis with refractory hyper-eosinophilia associated with inactivated COVID-19 vaccine (preprint)

COVID-19 vaccines are considered one of the primary strategies for countering the pandemic. While mRNA based and viral vector-based vaccines have been predominantly used, inactivated SARS-CoV-2 vaccines are being manufactured in countries such as China and India. Post approval, rare but serious adverse events such as myocarditis and stroke have been observed with mRNA based and viral vectored COVID-19 vaccines. Inactivated vaccines in general have shown better tolerability in clinical trials. Here we report the first case of new-onset seropositive rheumatoid arthritis (RA) with rheumatoid nodules and refractory reactive eosinophilia within two weeks of receiving an inactivated COVID-19 vaccine (COVAXIN).

Patterns and predictors of COVID-19 occurrence and severity in vaccinated priority groups (preprint)

Background: Varying protection rates have been observed with approved COVID-19 vaccines post-approval, in various real-world studies. However, little data exists on the clinical presentation and risk factors of occurrence and severity of COVID-19 in vaccinated individuals. The aim of the present study is to describe the patterns of presentation of COVID-19 in vaccinated individuals, and to determine the predictors of occurrence of COVID-19 and the predictors of severity in the vaccinated. Methods: : The study is a part of a prospective observational study ongoing since February 2021 in a tertiary teaching and research hospital of northern India. Individuals recruited in this study belong to a high-risk group comprising health care workers and elderly. COVISHIELD, based on ChAdOx1 nCoV-19 platform was the vaccine received by the participants based on policy on allocation.Primary outcomes of the study are the short term and long-term adverse events following immunization (AEFI) with COVID-19 vaccines. Secondary outcomes include the rates of occurrence of COVID-19 and severity of COVID-19. Data on these have been already reported. The clinical presentation, typical and atypical manifestations, time to symptomatic recovery and patterns of post-COVID-19 complaints were analysed in the current study. Logistic regression analysis was performed to predict the risk factors of occurrence of COVID-19 in the vaccinated and the determinants of severe forms of the disease in this group. Findings: 1500 individuals completed at least two month follow up. Of these, 418 developed laboratory confirmed or suspected COVID-19. Fever was the commonest symptom (72%), followed by features of rhinitis (41%) and cough (34%). Nearly 12% individuals had only one symptom or none. Cardiovascular involvement was seen in more than 2% of affected. Time to symptomatic recovery varied from 1-75 days and 11% had post COVID-19 complaints at two month follow up, most common being generalized weakness. Results of regression analysis showed 1.6 times higher odds of contracting the disease in females and young individuals < 40 years of age (P<0.001). Overweight individuals and those receiving only one dose were at 1.4 times and 3 times higher odds of contracting COVID-19 compared to those with normal body mass index and those who were fully vaccinated. Individuals receiving two doses at a gap of < 30 days were at 7 times higher odds of disease acquisition compared to those receiving the second dose at an extended gap of > 60 days (P=0.01).With respect to severity, males and those receiving only one dose each had 3 times higher odds of suffering from moderate to severe COVID-19 compared to females and fully vaccinated. Persons with pre-existing lung disease, such as asthma had 6 times higher odds of suffering from moderate to severe COVID-19 (P=0.024). No association with the occurrence or severity of disease was observed with any other co-morbidity or the use of renin-angiotensin-aldosterone system (RAAS) blockers. Interpretation Sex wise differences exist with respect to occurrence and severity of COVID-19. Two doses of vaccine, compared to one dose provide considerable protection against occurrence as well as severity. Full vaccination with extended dosing interval should be the optimal strategy and should be carried out when the community burden of cases is negligible. Future studies are needed to explore the sex wise differences in the propensity and severity of COVID-19. Further, the risk association of asthma phenotypes with COVID-19 needs to be investigated. Funding: The study received no funding support

Rhino-orbital mucormycosis related to COVID-19- A case series exploring risk factors (preprint)

There has been a surge of rhino-orbital mucormycosis cases in India in the wake of the second wave of the COVID-19 pandemic. It has been widely suggested that dysglycaemia due to diabetes present as a common comorbidity in these COVID-19 patients as well as indiscriminate steroid use has resulted in this surge. Here, we report a series of 13 cases of rhino-orbital mucormycosis in COVID-19 patients admitted at our center between mid-April and early June 2021. Out of the 13, the only common factor was COVID-19 at some time point before diagnosis of mucormycosis or coexistent with it. The cases showed a male preponderance and four of them showed intracranial extension of disease. Eleven of them had received steroids as part of COVID-19 management protocol and twelve of them had pre-existing or newly diagnosed diabetes. We have summarized other probable risk factors being considered such as immunosuppressed state, antiviral and Ayurvedic (Indian traditional) medications, oxygen therapy, with each of which we could not find a link of mucormycosis. We propose that COVID-19 itself through molecular mechanisms predisposes to mucormycosis, with other factors such as dysglycaemia providing a second hit.

The Pathogenetic Dilemma of Post-COVID-19 Mucormycosis in India (preprint)

There has been a surge of mucormycosis cases in India in the wake of the second wave of COVID-19 with more than 14000 cases reported. Mucormycosis in patients of COVID-19 in India is at variance to other countries where Aspergillus, Pneumocystis, and Candida have been reported to be the major secondary fungal pathogens. We discuss the probable causes of the mucormycosis epidemic in India. Whereas dysglycaemia and inappropriate steroid use have been widely suggested as tentative reasons, we explore other biological, iatrogenic, and environmental factors. The likelihood of a two-hit pathogenesis remains strong. We propose that COVID-19 itself provides the predisposition to invasive mucormycosis (first hit), through upregulation of GRP78 and downregulation of spleen tyrosine kinase involved in anti-fungal defense, as also through inhibition of CD8+ T-cell mediated immunity. The other iatrogenic and environmental factors may provide the second hit which may have resulted in the surge.

Hyper-eosinophilic syndrome with myocarditis after inactivated SARS-CoV-2 vaccination: A case study (preprint)

A young man without any co-morbidities presented with persistent periorbital baggy swelling along with itchy swelling over fingers, resting tachycardia and exertional breathlessness following first dose of an inactivated SARS-CoV-2 vaccination (COVAXIN). On investigation, patient had elevated blood eosinophils and myocarditis. He was successfully treated with steroid and supportive treatment.

Occurrence of COVID-19 in priority groups receiving ChAdOx1 nCoV-19 coronavirus vaccine (recombinant): a preliminary analysis from north India (preprint)

Background: In randomized controlled settings, vaccine efficacy close to 70% against symptomatic COVID-19 has been demonstrated by the ChAdOx1 nCoV-19 vaccine which is a recombinant chimpanzee adenovirus based vaccine expressing the SARS-CoV-2 spike protein. Post approval studies are however necessary to validate the findings in the real world.Methods: A prospective observational study is being conducted in a tertiary hospital of north India since 5th February 2021 with the primary objective of determining safety of COVID-19 vaccines and the secondary objective of assessing the rate of occurrence of COVID-19 in vaccinated group. High risk group comprising health care workers, other frontline workers (police, sanitary workers etc) and elderly citizens who were initially focus groups for vaccine roll-out in India, were enrolled in the study. The study included all vaccine recipients who provided consent and were enrolled at the time of receiving the first or second dose of COVISHIELD vaccine, and followed up telephonically.Results: Among 1650 enrolled vaccine recipients, 1500 participants of the study (Female/Male: 472/1028; mean age 38.8 years) completed at least 2 months of follow-up, after the second dose. The common comorbidities in study participants were hypertension (170, 11.3%), diabetes (142, 9.5%), and hypothyroidism (54, 3.6%). Of those who received a single dose of vaccine (n=65), laboratory confirmed SARS-CoV-2 infection was observed in 27 individuals (41.5%) and 3 were suspects. Severity wise, infections were mild in 21 out of 30 (70%) cases, moderate in five (16.7%) and severe in two (6.7%). Of those who received both doses of vaccine (n=1435), 388 were diagnosed as confirmed or suspect cases of SARS-CoV-2 infection. Of these 388, RT-PCR positivity was seen in 271 (18.9%) individuals, 82 (5.7%) were labelled as ‘suspects’ and 35 (2.4%) were RT-PCR negative suspects. Severity wise, majority of SARS-CoV-2 infections were ‘mild’ (331/388, 85.3%), followed by ‘moderate’ (33/388, 8.5%) and ‘severe’ (6/388, 1.5%). 404 out of the 1500 total participants were doctors including consultant/teaching faculty, resident doctors, and those in general practice. Among the 377 doctors who received both doses of vaccine, 160 were diagnosed as confirmed or suspect cases of SARS-CoV-2 infection. Of these, 131 (34.7%), 17 (4.5%) and 12 (3.2%) were laboratory confirmed cases, ‘suspects’ and RT-PCR negative suspects respectively. The infection was asymptomatic, ‘mild’, ‘moderate’ and ‘severe’ in 9 (5.6%), 130 (81.3%), 16 (10%) and 5 (3.1%) respectively. Breakthrough infections occurring at > 14 days after receiving the second dose were seen in 148 doctors who received both doses (39.2%), or 119 doctors (31.6%) if only laboratory confirmed cases were considered. Four deaths occurred in the study participants during the study period, two in partially vaccinated group and two in fully vaccinated group. Two of these participants, both in partially vaccinated group had developed SARS-CoV-2 infection during their follow-up.Conclusion: The disproportionately high occurrence of SARS-CoV-2 infection and COVID-19 in priority vaccinated groups in our study can be explained to some extent by the existence of variants such as the delta which might have escaped the vaccine generated immune protection. Despite the high incidence, the severity of COVID-19 was observed to be low. Since the ongoing study was primarily focused on adverse events following immunization (AEFIs) and enrolled only vaccinated individuals, the secondary outcome results lack a control unvaccinated group. However, the result of this preliminary analysis necessitates vigorous research on the performance of vaccines against variants, optimal timing of vaccination, need for boosters, and also optimal timings of effectiveness studies to guide future vaccination policy.

A prospective observational safety study on ChAdOx1 nCoV- 19 corona virus vaccine (recombinant) use in healthcare workers- first results from India (preprint)

Vaccines are an important public health measure for tiding over the COVID-19 pandemic. Several vaccines have been approved in different countries for emergency use. In India, two vaccines have been currently approved- COVISHIELD (Serum Institute of India (SII)) which is a recombinant simian adenovirus-based vaccine and COVAXIN (Bharat Biotech) which is an inactivated SARS-CoV-2 vaccine. Our current study provides the first post approval safety data on ChAdOx1 nCoV- 19 corona virus vaccine (recombinant) use in healthcare workers in northern India (n=804). Around one half of vaccinees developed adverse events at any time post vaccination with majority of reactions being mild to moderate in severity. AEFIs were seen in 40% participants after first dose and around 16% participants after second dose. This observed reactogenicity is much less compared to 60-88% reactogenicity rate observed with Oxford-AstraZenecas ChAdOx1 vaccine in the UK based population. Individually, fever, injection site pain and headache were the commonly observed AEFIs. Overall, the frequency of systemic events of severity grade 3 was only 0.5% and is much less than the reported rates for other recombinant adenoviral vaccines. The rate of serious AEFIs in our study was only 0.1% (n=1). There was a possibility of this AEFI being an immunization stress related response. No deaths were reported in the vaccinees in our study during the study period. Reactogenicity rate was observed to decrease with age and was higher in females. On the basis of interim findings of this safety study, it may be interpreted that the ChAdOx1 nCoV-19 corona virus vaccine (recombinant) (COVISHIELD, Serum Institute of India) carries a good safety profile overall.

RAAS Blockers and Region-Specific Variations in COVID-19 Outcomes: Findings from a Systematic Review and Meta-Analysis (preprint)

Background: Coronavirus disease 2019 (COVID-19) has evolved as a global crisis with high mortality seen in elderly and people with cardiometabolic diseases. The use of renin angiotensin aldosterone system (RAAS) blockers in these patients is known to enhance the expression of ACE-2, the chief binding receptor of SARS-CoV-2 and may potentially enhance infectivity.Objective: To provide a pooled estimate of the effect of RAAS blocker usage on COVID-19 outcomes.Data Sources: An electronic literature search was performed for published (using MEDLINE/PubMed and Google Scholar) and preprint (using bioRxiv and medRxiv) studies of interest. The last search was conducted on 9th July 2020.Study Selection: Studies reporting data on RAAS blocker use and COVID-19 mortality and severity were included in the review.Data Extraction and Synthesis: Mortality data and severity data including hospitalization, intensive care unit (ICU) admission, invasive ventilation, steroid use and acute kidney injury (AKI) were recorded. Pooled Odds ratio (OR) estimates were reported with 95% CIs and level of heterogeneity (I2).Main Outcomes and Measures: Odds of mortality in users of RAAS blockers with respect to non-users was the primary outcome. Odds of severity, hospitalization, ICU admission, mechanical ventilation, steroid use, and AKI in users with respect to non-users of RAAS blockers were the secondary outcomes.Results: Of 1348 articles identified, 48 published studies were included in the final analysis, with a total of 26432 patients from 31 studies included in mortality analysis and 20127 patients from 23 studies included in severity analysis. Majority of the studies (41.6%) were from China. No increased risk of mortality (Pooled OR 0.91 (0.65-1.26), I2 =89%) or severity (Pooled OR 1.08 (0.79-1.46), I2 =88%) was seen with RAAS blockers. The drug class was protective in hypertension (pooled OR 0.63 (0.46-0.86), I2 =58%). Severity of COVID-19 outcomes was found to be high for Europeans (Pooled OR 2.08 (1.52-2.85), I2 =77%) and US patients (Pooled OR 1.87 (1.62-2.17) in users of RAAS-blockers. A nearly 4 times higher risk of hospitalization, two times higher risk of ICU admission and mechanical ventilation was observed in US patients on RAAS blockers. No net effect on mortality and severity outcomes was seen in Chinese patients. RAAS blocker usage did not have any effect on corticosteroid use and AKI in Chinese patients.Conclusions and Relevance: Use of RAAS blockers is not associated with increased risk of mortality in COVID-19 patients. Reduced mortality is seen in hypertensive patients with COVID-19 and therefore the drugs should be continued in this subset. US and European patients are at higher risk of severe outcomes. Pharmacogenomic differences may explain the ethnicity related variations.Funding Statement: None.Declaration of Interests: None.

RAAS blockers and region-specific variations in COVID-19 outcomes: findings from a systematic review and meta-analysis (preprint)

BackgroundCoronavirus disease 2019 (COVID-19) has evolved as a global crisis with high mortality seen in elderly and people with cardiometabolic diseases. The use of renin angiotensin aldosterone system (RAAS) blockers in these patients is known to enhance the expression of ACE-2, the chief binding receptor of SARS-CoV-2 and may potentially enhance infectivity. ObjectiveTo provide a pooled estimate of the effect of RAAS blocker usage on COVID-19 outcomes. Data SourcesAn electronic literature search was performed for published (using MEDLINE/PubMed and Google Scholar) and preprint (using bioRxiv and medRxiv) studies of interest. The last search was conducted on 9th July 2020. Study SelectionStudies reporting data on RAAS blocker use and COVID-19 mortality and severity were included in the review. Data Extraction and SynthesisMortality data and severity data including hospitalization, intensive care unit (ICU) admission, invasive ventilation, steroid use and acute kidney injury (AKI) were recorded. Pooled Odds ratio (OR) estimates were reported with 95% CIs and level of heterogeneity (I2). Main Outcomes and MeasuresOdds of mortality in users of RAAS blockers with respect to non-users was the primary outcome. Odds of severity, hospitalization, ICU admission, mechanical ventilation, steroid use, and AKI in users with respect to non-users of RAAS blockers were the secondary outcomes. ResultsOf 1348 articles identified, 48 published studies were included in the final analysis, with a total of 26432 patients from 31 studies included in mortality analysis and 20127 patients from 23 studies included in severity analysis. Majority of the studies (41.6%) were from China. No increased risk of mortality (Pooled OR 0.91 (0.65-1.26), I2=89%) or severity (Pooled OR 1.08 (0.79-1.46), I2=88%) was seen with RAAS blockers. The drug class was protective in hypertension (pooled OR 0.63 (0.46-0.86), I2=58%). Severity of COVID-19 outcomes was found to be high for Europeans (Pooled OR 2.08 (1.52-2.85), I2=77%) and US patients (Pooled OR 1.87 (1.62-2.17) in users of RAAS-blockers. A nearly 4 times higher risk of hospitalization, two times higher risk of ICU admission and mechanical ventilation was observed in US patients on RAAS blockers. No net effect on mortality and severity outcomes was seen in Chinese patients. RAAS blocker usage did not have any effect on corticosteroid use and AKI in Chinese patients. Conclusions and RelevanceUse of RAAS blockers is not associated with increased risk of mortality in COVID-19 patients. Reduced mortality is seen in hypertensive patients with COVID-19 and therefore the drugs should be continued in this subset. US and European patients are at higher risk of severe outcomes. Pharmacogenomic differences may explain the ethnicity related variations.

Of Cross-Immunity, Herd Immunity and Country-Specific Plans: Experiences from COVID-19 in India (preprint)

India has witnessed a high number of COVID-19 cases, but mortality has been quite low, and most cases have been asymptomatic or mild. In early April, we had hypothesized a low COVID-19 mortality in India, based on the concept of cross-immunity. The presence of cross-immunity is presumed to lead to a milder course of disease and allow the time necessary for the development of adaptive immunity by the body to eliminate the virus. Evidence supporting our hypothesis has started showing up. Multiple studies have shown the generation of different T cell subsets and B cells responding to epitopes of viral proteins, especially of the spike protein, as a part of adaptive immunity against SARS-CoV-2. Cross-reactive T-cells have been demonstrated in patients who have been previously exposed to endemic coronaviruses. The interplay of cross-immunity and herd immunity is apparent in the COVID-19 scenario in India by the presence of a large number of asymptomatic or mild cases, a low infection-fatality ratio and a generally flat curve of percentage positivity of cases with respect to total testing, both in periods of strict lock-down and step-wise unlocking. It seems that cross-immunity resulted in faster generation of herd immunity. Although the initial restrictive measures such as lockdown prevented the rapid spread of the outbreak, further extension of such measures and overly expensive ones such as enhanced testing in India will result in a huge burden on the health economics as well as the society. Hence, we propose a restructuring of the health services and approach to COVID-19. The restructured health services should move away from indiscriminate testing, isolation and quarantine, and instead, the emphasis should be on improving facilities for testing and management of only critical COVID cases and the replacement of complete lockdowns by the selective isolation and quarantine of the susceptible persons such as the aged and those with co-morbidities. In the process of describing India-specific plans, we emphasize why the development of country-specific plans for tackling epidemics is important, instead of adopting a “one policy fits all” approach.