key: cord-0910959-1esvgcxp
authors: Singh, S.; Singh, R. K.
title: ASSESSING THE ROLE OF ZINC IN COVID-19 INFECTIONS AND MORTALITY: IS ZINC DEFICIENCY A RISK FACTOR FOR COVID-19?
date: 2020-06-14
journal: nan
DOI: 10.1101/2020.06.12.20105676
sha: 2abfa66e2f00ab40d347bacaf5e969b60793cef5
doc_id: 910959
cord_uid: 1esvgcxp

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, Zinc 's 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.

The world is currently in the middle of a novel coronavirus, i.e., SARS-CoV-2 caused COVID-19 pandemic. The damage from COVID-19 had been significant in terms of morbidity and mortality.

More than 5.67 million people had been infected and over 351 thousand had already died worldwide by 26 May 2020 while more than 1.93 million infections and over 169 thousand deaths were reported from Europe alone [1] . The unprecedented severity of COVID-19 in Europe and North America in contrast to its relatively benign course in the countries of Africa, Asia, South America, and Oceania, had been baffling. Several exploratory studies have been initiated based on assumptions as well as our understanding of coronavirus biology to identify and establish protective interventions [2] [3] [4] . Recently, a protective correlation between Vitamin D serum levels and the cases and the deaths per million from COVID-19 had been indicated in the European countries supposedly having comparable confounding variables and similar health care infrastructure [5, 6] .

The association had been reassuring given the established role of Vitamin D in overall health and the protection offered from acute respiratory tract diseases through an effect on the host's reninangiotensin system comprising ACEs [7, 8] . Identifying such potential protective variables is highly desirable.

Zinc is essential to good health and immunocompetence. Its deficiency is generally associated with a negative impact on overall health, increased susceptibility to disease, and infections [9-12]. In the absence of reliable methods to assess the Zn status of a population, the deficiency or inadequacy in a population is estimated by combining the dietary intake by a population as per FAO's Food Balance Sheet and the estimated prevalence of stunting [10, 11, 13, 14] . Among micronutrients associated with good health, the deficiency of Zinc is quite prevalent ranging from about 5-50 % of the population [13]. Its high prevalence is associated with increased susceptibility to diseases, mental capacity, complications, high morbidity, and mortality in mothers and neonates [9,10]. Given its role in the overall human health and wellbeing, the countries have tried to overcome the problem through fortification of foods [9,10,12,13]. The countries from the high-income group that consumes a more diverse micronutrient-rich diet tend to have Zinc deficiency below 5-10 percent [13, 14] .

Incidentally, these had been the countries also worst affected by COVID-19 [1] .

Given the global prevalence of Zinc deficiency and its role in human health as well as the immunocompetence [9-12], we hypothesized that the incidence of COVID-19 in populations (cases) and the adverse outcomes (deaths) would be directly correlated to Zinc deficiency. The analysis of European countries with comparable underlying confounding variables when performed at different stages of the pandemic was envisioned to provide a more robust indication of the correlation as indicated previously [6] . The primary aim of the current study was to identify any correlation between the prevalence of Zinc deficiency with the adverse outcomes in the European countries.

. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted June 14, 2020. . Additionally, we intended to identify if it affected the number of cases per unit population or crudely the spread of disease. Surprisingly, our analysis of the selected European countries indicated a consistently negative correlation of Zinc deficiency with COVID-19 cases per million population over the time period and indicated an almost significant correlation with the adverse outcome, i.e., death, which seemed improving with the passage of pandemic.

The European countries with seemingly comparable confounding variables were considered for the analysis as done previously [5,6]. The cases and deaths per million population data for COVID-19 from three time-points, i.e., 8 April, 12 May, and 26 May 2020 (Table 1) 

A negative correlation between the Zinc deficiency prevalence estimate for the countries and the reported cases of COVID-19 was consistently observed at all three time-points analyzed that covered pre infections peak, i.e.,8 April 2020, and post infections peak, i.e., 12 and 26 May 2020 (see Table 2 ). The Zinc deficiency of the populations also negatively covaried with adverse outcomes (mortality) per million population and the correlation seemed to better with the passage of the current wave of COVID-19 infections. Refer to Table 2 below for the comparative estimate of the correlation (linear regression) and Figure 1 for the best-fit correlation for the data set (R 2 =0.3936 for cases and R 2 =0.2831 for deaths per million) on 26 May 2020. An exploratory estimation of the correlation for COVID-19 affected countries of the world that had seemingly comparable exposure to disease, population structure, and health care response as on 12th May 2020 (> 30,000 cases and upwards of 15,000 tests performed per million of the population) and accounted for 63.7% of total cases, namely, Spain, UK, Russia, Italy, France, Germany, Belgium, Netherlands, Switzerland, USA, Canada, seemed reassuring. For these eleven countries, the Zn deficiency prevalence was exponentially correlated to cases per million (R 2 = 0.3301) and more strongly to deaths per million (R 2 = 0.4307) suggesting a supposedly robust correlation.

. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted June 14, 2020. . https://doi.org/10.1101/2020.06.12.20105676 doi: medRxiv preprint

Our analysis identified a negative association between the Zinc deficiency prevalence in the European countries and the COVID-19 impact in terms of cases and deaths per million population.

The observed covariation should be evaluated for its biological significance if any by evaluating COVID-19 patient data to allow its potential translation into preventive measures.

In the absence of Zinc storage in the body, its daily intake is required to maintain healthy levels [9, 12] . The recommended daily Zinc intake varies with the age -increasing from 2 mg for newborns to 8 mg for children 9-13 years old. Its recommended intake is 11 mg for >14 years males while 8- Considering the associated adverse effect on immunity, lower level of HDL, low copper levels its upper no-observed-adverse-effect level (NOAEL) and tolerable upper intake limit (UL) have been defined by EFSA as daily intake of 50 mg and 25 mg, respectively [11] . For children and adolescents 1-17 years of age, the recommended UL range is 7-22 mg based upon age and body weight. Zinc deficiency is not considered as a concern as for all the age groups the estimated 97.5 percentile of total Zinc intake is closer to the recommended ULs [11]. In the USA, a 20% reduced no adverse effect upper daily limit for Zinc has been suggested, i.e., >40mg for people older than 18 years while for youngers it is from 4-34 mg depending upon the age and body weight [10].

The estimated Zinc deficiency among the European countries, though low, ranged from 3.1 % (Iceland) to 21.7% (Turkey) based upon their dietary preferences [13] . Countries with a less diverse diet, lower animal protein intake and increased intake of phytate containing diet happen to have a higher prevalence of Zinc deficiency. Generally, the countries with higher Zn deficiency prevalence, e.g., Turkey (21.7%), Slovakia (16.3%), Czechia (11%), Estonia (10.5%), Germany (9%), Hungary (8.4%), Portugal (6.3%), Denmark (6.2%), Norway (6.2%) had reported lesser no of cases per million population as compared to lower Zinc deficiency prevalence countries, e.g., Iceland (3.1), France (3.9), Ireland (4%), UK (4.6%) Switzerland (4.9%) Spain (5.4%), Italy (5.8%). However, the difference in the rate of deaths reported per million population by the above indicated differentially Zinc deficient countries was lesser.

Worldwide estimates indicate lower adverse outcomes from COVID-19 in children, adolescents, and women [1] . The Zinc deficiency in children, adolescents, women, vegetarians, and alcoholics is widespread [10,11]. Among the countries of Europe, the children, adolescents, and women seemed to be relatively less affected [1] . These are the same constituents of the population that tend to have higher Zinc needs and associated physiological deficiency in the body and have a higher . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted June 14, 2020. . https://doi.org/10.1101/2020.06.12.20105676 doi: medRxiv preprint prevalence of Zinc deficiency as compared to the estimated deficiency prevalence in the population [10] [11] [12] [13] [14] . Interestingly, women appear to be more protected from COVID-19 than males in European countries [1] . The COVID-19 associated mortality in women is estimated to be about two-fold lower than that in men. Remarkably, women tend to have a higher prevalence of Zinc deficiency deviating about two fold from that estimated for a population as per surveys performed in low and middleincome countries [14] . The relationship may be coincidental or causal only later studies can reveal.

Elderly people (>60-65 years) in Europe had been affected most by COVID-19. Although there is insufficient data to reliably estimate the Zinc deficiency in the elderly, it is perceived to be quite prevalent in the elderly with less than 50% of daily recommended intake being common [15] .

Despite the lower Zinc levels in elderly, the altered Zn homeostasis (lower intercellular availability), altered interplay with copper and Iron homeostasis, the supposed immunosenescence and Zinc level alteration as a result of fortification, supplementation, and medication [10-12] along with other underlying pathologies could be responsible for the relatively higher mortality in the elderly [1] . It needs to be ascertained whether such a correlation exists.

Carefully designed studies investigating the basis of increased vulnerability of target groups and the elderly could help devise better strategies for future COVID-19 treatment. If the observed correlation is to be believed as having cause and effect relationship, it may be predicted that the inherently or transiently higher Zinc levels resulting from supplementation or medication may be associated with higher COVID-19 infections and mortality in patients. A scrutiny of the COVID-19 patients' data for potential Zinc status alteration, such as resulting from the intake of vitamin C, organic acids, animal protein, phytate content along with Zinc supplementation and the administration of Zn status altering drugs such as Hydroxychloroquine would shed light on the biological significance of the observed covariation of the Zinc deficiency prevalence with COVID-19 cases and mortality in different target populations and its potential preventive role. So, more evidence-gathering follow-up exercises for the closer scrutiny of the COVID-19 patients' medical records, including the micronutrient supplementation and food consumption details is advisable to ascertain the role of Zinc deficiency in COVID-19 pandemic and potentially find an early solution to COVID-19.

.

No specific source of funding was utilized for the current study. However, SS acknowledges the funding support from Banaras Hindu University to his laboratory.

There is no conflict of interest to disclose.

The study complied with the existing ethical standards.

. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted June 14, 2020. . 

. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted June 14, 2020. . https://doi.org/10.1101/2020.06.12.20105676 doi: medRxiv preprint

Draft landscape of COVID-19 candidate vaccines

NOVEL CORONAVIRUS