ABSTRACT
The extent of gendered COVID-19 impact remains undetermined for the lack of sex-disaggregated data. The prevailing view puts males nearly twice as impacted as females. Globally, access to resources and their usage are gendered- mostly favoring males. Gender gaps widen during natural/man-made calamities and pandemics. Modeling estimates of impact for top 70 countries reporting >300 sex-disaggregated COVID-19 deaths (>80% of total), indicates average mortality sex (male:female) ratio (COVID-MSR) of 1.37{+/-}0.30 (95% confidence interval:1.30-1.44; range:0.85-2.47) against prevalent pre-pandemic MSR of 1.79{+/-}0.41 (1.70-1.89; range:0.93-2.99). Contrary to the prevailing view, widened gender gaps globally increased female mortality by 19.57{+/-}21.16% (14.62%-24.88%; range: -22.46 to +68.50%) causing an estimated 22.03% excess deaths (360 thousand by 30 December 2021). Identification of factors favoring gendered impacts is needed for equitable pandemic management. One-Sentence Summary Missing Females in COVID-19?
ABSTRACT
Biological sex is considered a risk factor for COVID-19. The prevailing view supposes males are about two-fold more impacted than females based on early-stage studies. The observed higher male deaths in COVID-19 are purportedly a result of biological differences that make males more vulnerable to adverse outcomes in infectious diseases. Research and policy paradigms seem to follow a similar line of thought to mitigate COVID-19 impact on populations. The analysis of sex-disaggregated data could help us evaluate the veracity of assertions for a preferred evidence-guided response. The analysis of the sex-disaggregated data available for the top 70 countries contributing about 80% of total deaths (as of 15 September 2021; on average two waves of infections experienced) indicates average Case Sex (Male: Female) ratio (CSR) of 1.09{+/-}0.35 (marginally more male cases) and Death Sex ratio (DSR) of 1.48{+/-} 0.47. Consideration of only laboratory-confirmed cases indicates the mortality sex ratio (MSR) in COVID-19 (MSR-COVID) to be 1.37{+/-}0.30. The prevailing MSR for the same countries was 1.758{+/-}0.409. The relative change in the mortality rate for males as compared to females in COVID-19 (ratio: MSR-COVID/prevailing MSR-PP) was 0.818{+/-}0.261 much lower than anticipated (2 or higher). Overall, over three-fold more countries (51/70) experienced a higher rate of female mortality than male mortality (15/70). Together, it suggests a more disproportionately severe impact of COVID-19 on females than on males, contrary to the prevailing view. Identification and analysis of country-specific factors contributing to differential impact on sexes, whether biological or environmental, seem warranted.
ABSTRACT
Endeavors to identify potentially protective variables for COVID-19 impact on certain populations have remained a priority. Multiple attempts have been made to attribute the reduced COVID-19 impact on populations to their bacillus Calmette-Guerin (BCG) vaccination coverage ignoring the fact that the effect of childhood BCG vaccination wanes within 5 years while most of the COVID-19 cases and deaths have occurred in aged with comorbidities. Since the supposed protection being investigated could come from heterologous trained immunity (TI) conferred by exposure to Mycobacterium spp. (i.e., environmental and BCG), it is argued that the estimates of the prevalence of TI of populations currently available as latent tuberculosis infection (LTBI) prevalence would be a better variable to evaluate such assertions. Indeed, when we analyze the European populations (twenty-four), and erstwhile East and West Germany populations completely disregarding their BCG vaccination coverage, the populations with higher TI prevalence consistently display reduced COVID-19 impact as compared to their lower TI prevalence neighbors. The TI estimates of the populations not the BCG coverage per se, negatively correlated with pandemic phase-matched COVID-19 incidences (r(24): - 0.79 to -0.57; p-value: <0.004), mortality (r(24): -0.63 to -0.45; p-value: <0.03), and interim case fatality rates(i-CFR) data. To decisively arrive at dependable conclusions about the potential protective benefit gained from BCG vaccination in COVID-19, the ongoing/planned randomized controlled trials should consciously consider including measures of TI as - a) all individuals immunized do not respond equally, b)small study groups from higher background TI could fail to indicate any protective effect. O_TEXTBOXSummary BoxO_ST_ABSWhat is already known?C_ST_ABSO_LIPreviously, COVID-19 incidence (SARS-CoV-2 infections) and mortality datasets of disparate populations with regard to phase of pandemic, demographics, medical infrastructure etc. have been modelled to negatively associate with highly transformed BCG vaccination coverage and policy of the countries. C_LIO_LIRecently BCG vaccination has been linked to risk of COVID-19 using vaccinated individuals from disparate populations (different underlying trained immunity) without any estimation of the underlying immune status or attempt to make the confounders for the groups being compared to be equal. C_LIO_LIAbout 8 out of 10 COVID-19 deaths have been in aged >65 years old. C_LIO_LIBCG vaccination is known to provide-cross protection from a number of unrelated diseases. C_LIO_LIBCG vaccination given in childhood protects children from milliary tuberculosis and the conferred protective trained-Immunity correlate or TIC (loosely equals tuberculin positivity) wanes away within 5 years from most in the absence of boosters or rechallenge from environmental Mycobacterium spp. C_LI New FindingsO_LIDisregarding BCG vaccination coverage or policy, the prevailing TIC correlate of populations predict protection from COVID-19 in socially similar European countries, i.e., the countries which are more similar to each other than other parts of the world with regard to various supposed confounders (e.g., exposure, phase of pandemic, health services, social support, food, genetic relatedness etc.). C_LI Recommendations for Policy and PracticeO_LIThe planned and ongoing studies or clinical trials assessing the effectiveness of BCG vaccination in protecting populations against COVID-19 or making them vulnerable to COVID-19 should include TIC correlates information of the participants (both controls and vaccinated) to arrive at dependable conclusions about potential benefit of BCG vaccination in controlling COVID-19 infections and mortality. C_LI C_TEXTBOX
ABSTRACT
A potential protective role of vitamin D serum levels on overall adverse outcomes of SARS-CoV-2 infection or COVID-19 on populations had been suggested previously based upon single-point cross-sectional analysis of 8 April 2020 data from 20 European countries assuming comparable underlying confounding variables for these populations, at an early stage of the current pandemic. Comparative time-series cross-sectional analysis of the COVID-19 data from 12 March (early pre-peak) to 26 July (late post-peak of infections) 2020 was performed to assess the strength of the assertion. The study subjects included 1,829,634 COVID-19 cases (11.11% of total worldwide) and 179,135 associated deaths (27.45 % of total worldwide) on 26 July 2012. Previously suggested cross-sectional study design and methodology could not consistently and significantly (p-value[≥]0.05) support the notion of the potential protective role of the mean serum vitamin D levels of the populations on COVID-19 incidence and mortality. However, the exponential correlative model, as well as alternative simple regression analysis on ln and Log10 transformed COVID-19 data for the time period indicated improved consistently negative covariation with vitamin D levels. Additionally, the later methodology increased the predictive potential for explaining the variability in data [R2 by 1.27-1.96 fold, adjusted-R2 by 1.33-2.47, p-value=0.0457-0.0035, for cases/million; R2 by 1.81-2.67, adjusted-R2 by 2.21-3.74 fold for deaths/million, p-value=0.0049-0.0228). Considering, the established role of vitamin D in immune system functioning randomized well-controlled trials may be suggested to evaluate/assess the potential protective role of vitamin D in reducing the COVID-19 impact on populations.
ABSTRACT
The impact of Zinc (Zn) sufficiency/supplementation on COVID-19 associated mortality and incidence (SARS-CoV-2 infections) remains unknown. During an infection, the levels of free Zn are reduced as part of nutritional immunity to limit the growth and replication of pathogen and the ensuing inflammatory damage. Considering its key role in immune competency and frequently recorded deficiency in large sections of different populations, Zn has been prescribed for both prophylactic and therapeutic purposes in COVID-19 without any corroborating evidence for its protective role. Multiple trials are underway evaluating the effect of Zn supplementation on COVID-19 outcome in patients getting standard of care treatment. However, the trial designs presumably lack the power to identify negative effects of Zn supplementation, especially in the vulnerable groups of elderly and patients with comorbidities (contributing 9 out of 10 deaths; up to >8000-fold higher mortality). In this study, we have analyzed COVID-19 mortality and incidence (case) data from 23 socially similar European populations with comparable confounders (population: 522.47 million; experiencing up to >150 fold difference in death rates) and at the matching stage of the pandemic (12 March - 26 June 2020; 1st wave of COVID-19 incidence and mortality). Our results suggest a positive correlation between populations Zn-sufficiency status and COVID-19 mortality (r(23): 0.7893-0.6849, p-value<0.0003) as well as incidence [r(23):0.8084 to 0.5658; p-value<0.005]. The observed association is contrary to what would be expected if Zn sufficiency was protective in COVID-19. Thus, controlled trials or retrospective analyses of the adverse event patients data should be undertaken to correctly guide the practice of Zn supplementation in COVID-19.
ABSTRACT
Protective variables for COVID-19 are unknown. Trained immunity of the populace as a result of BCG immunization policy implementation and coverage had been suggested to be one of the factors responsible for the differential impact of COVID-19 on different countries. Several trials are underway to evaluate the potential protective role of BCG vaccination in COVID-19. However, the lack of clarity on the use of appropriate controls concerning the measures of trained immunity or the heterologous cell-mediated immunity conferred by BCG vaccination has been a cause of concern leading to more confusion as exemplified by a recently concluded trial in Israel that failed to find any protective correlation with regard to BCG vaccination. Whereas, when we analyze the COVID-19 data of European countries without any regard for BCG vaccination policy but with similar age distribution, comparable confounding variables, and the stage of the pandemic, the prevalence of tuberculin immunoreactivity - a measure of cell-mediated immunity persistence as a result of Mycobacterium spp. (including BCG vaccine) exposure of the populations, is found consistently negatively correlated with COVID-19 infections and mortality per million population, at all the time points evaluated. We propose that on-going and future studies evaluating the effect of BCG vaccination on COVID-19 outcomes may actively consider, if not already, the inclusion of controls for underlying trained immunity and heterologous cell-mediated immunity prevalence that may be pre-existing or resulting from the intervention (e.g., BCG vaccine) in such trials to arrive at more dependable conclusions concerning their potential benefit.
ABSTRACT
Variables responsible for the differential COVID-19 pandemic severity among countries remain undefined. Zinc, a micronutrient required for immunocompetence, is found deficient in populations. We hypothesized the differential COVID-19 severity observed among European countries could be associated with the Zn-deficiency prevalence. The COVID-19 data from different stages of pandemic, i.e., 8 April, 12 and 26 May 2020, were analyzed for covariation with the estimated Zn-deficiency. A significant, relatively stable, but negative correlation of Zn-deficiency with cases per million for the time period [r(20): -0.4930 to -0.5335, p-value: 0.02720 to 0.0154] and a steady improvement of covariation with deaths per million [r(20): -0.4056; p-value: 0.0760 on 26 May 2020] was observed. Considering, Zincs key immunomodulatory role, widespread deficiency along with the self- and prescribed intervention in different target groups, e.g. children, women, elderly, carefully planned dedicated exploratory studies to understand the basis of the observed association are advisable.
ABSTRACT
The reason for the observed country-wise variability in incidence and severity of the COVID-19 outcome remains unknown. Few recent studies have suggested a positive protective correlation of the BCG vaccination policy of the countries with the observed COVID-19 severity. The current study was undertaken to reassess the existing data as of 4th April 2020. The incidence rates (cases per million population), Case Fatality Rates (CFR) and inherently more robust Infection Fatality Rates (IFR) were calculated across countries accounting for about 99% COVID-19 deaths. The initial scrutiny suggested a weaker association with BCG vaccination policy or BCG coverage, so positivity to the Tuberculin Sensitivity Test (TST)/ Interferon Gamma Release Assay (IGRA) as a measure of the potential protective effect of the resident populations exposure to Mycobacterium spp. whether from BCG vaccination or as a result of exposure to environmental mycobacteria was analyzed. The incidence rates (the number of cases per million population) decreased with an increase in % LTBI (TST/IGRA positivity) for the analyzed countries with R2 =0.6343, suggesting an exponentially negative covariation. However, the covariation of CFR estimates that ranged from 0.29% to 12.25 % (average 5.39%) among countries, was tenuous. Interim estimates of IFR (i-IFR), a more dependable measure for such studies, for the best and worst-case scenarios, i.e., i-IFR-l and i-IFR-h, predict on an average 20.57% to 30.15 % COVID-19 fatality rates globally, but individual country estimates display huge variation. Among countries accounting for 92.14% deaths (11 countries; top 20% countries included in current study) the estimate for lowest IFRs (i-IFR-l=4.16 (China) & i-IFR-h=4.61 (China)) and highest IFRs (i-IFR-l=96.39% (UK); & i-IFR-h=96.54% (UK)) displayed huge difference (average for the group: CFR=6.8{+/-}3.6%; i-IFR-l=34.97{+/-}30.55%; & i-IFR-h=44.20{+/-}29.08%). Currently, the worst affected countries Italy (CFR=12.25%; i-IFR-l=42.63%; i-IFR-h=48.69%) and Spain (CFR=9.39%; i- IFR-l=26.85%; i-IFR-h=36.60%) would seemingly cope with COVID-19 better than UK, Netherlands and USA while the countries Germany (CFR=1.40%; i-IFR-l=4.93%; i-IFR-h=17.49%) and Switzerland (CFR=3.01%; i-IFR-l=10.87%; i-IFR-h=16.23%) along with China could fare the best. The rest of the 80% countries (accounting for 6.74% deaths), seemed to have reduced mortality (CFR=2.45{+/-}2.01; i-IFR-l= 30.62{+/-}28.24%; i-IFR-h=40.99{+/-}30.47%) with associated high % LTBI (17.28{+/-}8.87) than top 20% countries. The inherent issues in the data set (e.g., heterogeneity, non- random sampling, different criteria of sampling and reporting, access to health care, genetic composition, underlying co-morbidities, etc) need to be taken into account for making informed decisions.
