Explaining the differential severity of COVID-19 between Indians in India and the UK

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a viral infection; while many people experience mild symptoms and recover quickly, others go on to develop severe coronavirus disease (COVID-19) resulting in hospitalisation or death. Many studies have shown that severe COVID-19 is more common in people who are older, overweight, or with existing health conditions. In countries such as the UK and USA, COVID-19 has had a greater impact on ethnic minority populations, including those of Indian ethnicity. One explanation is that the prevalence of these risk factors is higher in Indian populations than in the majority population. In contrast, India has the lowest number of COVID-19 deaths worldwide. This has led to the belief that severe COVID-19 may be less common in people residing in India than in Indian people in other countries. There are several plausible explanations for this; Firstly, people residing in India may have greater environmental exposure to sunlight than Indians residing in other countries, which may result in higher levels of vitamin D.Secondly, people living in India may have greater immunity to COVID-19 resulting from greater exposure to other infections. This is related to socioeconomic status as people living in overcrowded households with poor sanitation may be more likely to contract infections than Indian populations overseas. Thirdly, people residing in India may also be less obese and have fewer pre-existing conditions than Indian people living in higher-income countries. Lower BMI in Indian residents may result from lower calorie intake or higher physical activity - both of which may lower the risk of severe COVID-19.

While it is possible that real biological differences may explain the lower risk of severe COVID-19 in Indian residents, there may be alternative explanations such as differences in the quality of COVID-19 data and age structure of the populations. For example, people living in India may be less likely to visit the hospital with COVID-19 due to stigma around the virus, or they may be more likely to die at home instead of in a medical facility. This means that the cause of death may be less well captured in India than in other countries, and the true number of people with severe COVID-19 may be underestimated. To date, no study has fully answered whether the severity of COVID-19 truly differs between Indian populations in India and in other countries. In this study, we will compare the risk of severe COVID-19 between Indians the UK and India and identify possible explanations. We will conduct two large studies. The first study will use the anonymised medical records of 50400,000 Indians in the UK and interview data from 220,000 people living in urban and rural India. We will first compare the proportion of the population who have ever had severe COVID-19, defined as either going to the hospital for or dying from COVID-19. We will then explore whether differences in the prevalence of severe COVID-19 can be explained by differences in data quality, the age structure of the two populations, or differences in the prevalence of key risk factors. Our study will address the key issue of whether COVID-19 is underestimated in India by firstly interviewing individuals ever admitted to hospital about COVID-19 symptom, and secondly, by interviewing people about deaths of their family members using a method known as a verbal autopsy. The second study will use detailed biological and information collected as part of two studies in India to conduct an in-depth examination of linked between COVID-19 and prior infections or vaccinations, obesity, co-morbidities, and vitamin D. We expect that the impacts of our research will include the development of COVID-19 prevention and management strategies which take into account the specific needs of Indian populations worldwide, and a deeper understanding of factors which lead to the development of severe COVID-19 in people of Indian origin.

Emerging data suggest that Indian residents may be less susceptible to severe COVID-19 than Indians in the diaspora. It remains unclear whether these differences are real or due to data artefact. Hypothesized mechanisms for protection from COVID-19 include lower burden of obesity and cardio-metabolic disease, greater exposure to vitamin D, and cross-immunity from past infections and vaccinations. The aim of this study is to determine whether the risk of severe COVID-19 (defined as COVID-19 related hospitalisation or death) differs between Indian populations in India and the UK and the extent to which this is explained by differences in data quality, age structure, co-morbidities, and cross-immunity. This project will comprise two work packages: The first is an epidemiological study comparing the population prevalence of severe COVID-19 in India and the UK. Using anonymised longitudinal electronic health record data for 400,000 people of Indian ethnicity in the UK, we will quantify the prevalence of severe COVID-19 adjusted for age, sex, and co-morbidities. A parallel analysis will be conducted in India using COVID-19 surveillance and chronic disease registry data from 220,000 people in the extended cohorts of two established studies in the states of Karnataka and Telangana. The second work package will use detailed biomarker and phenotyping data available in a 10,000 person subset of the two Indian cohorts to conduct an in-depth mechanistic study to elucidate hypothesized relationships between COVID-19 severity, environmental (vitamin D levels) and socio-economic factors (cross-immunity from greater exposure to infections and lower rates of obesity and cardiometabolic co-morbidities due to undernutrition). Findings will be used to triangulate evidence on the differential severity of COVID-19 in global Indian populations and translated into recommendations for clinical and policy use targeted at reducing risk of severe COVID-19 in Indian populations worldwide.