key: cord-0936765-ud8vz3zu
authors: Raham, T. F.
title: Malaria Endemicity Influence on COVID -19 Mortality: New Evidence Added to BCG and TB Prevalence
date: 2020-09-11
journal: nan
DOI: 10.1101/2020.09.09.20191684
sha: 3fffa74a2c4bb310fa0f7e8cbea5966ccccf912a
doc_id: 936765
cord_uid: ud8vz3zu

Background: Regarding SARS-CoV-2 it is well known that a substantial percentage of adult population cannot get infected if exposed to this novel coronavirus. Several studies give primary indication of the possible role of preexisting immunity whether cross immunity or not. Possible role of latent TB and BCG have been already suggested to create innate cross heterogeneous immunity. Possible role of malaria is suggested in this paper possibly by same mechanism of protection. Material and methods:80 malarious countries are enrolled in this study. Hierarchical multiple regression type of analyses is used for data analyses. TB prevalence/ 100,000 population standardized to BCG coverage rates is taken as direct factor in the test. Malaria incidence /1000 population is considered as intermediate factor and the outcome is COVID-19 mortality/ 1 million (M) population. Results: The results show with robust statistical support that standerized TB prevalence to BCG coverage is significantly associated with reduced COVID-19 mortality and malaria incidence have an additional highly significant effect in reducing COVID-19 mortality. Conclusions: Malaria and standardized TB prevalence are statistical significant factors predicting COVID-19 mortality in negative associations.

Microorganisms infecting mammalian hosts may modulate long lasting protective heterologous cross-immunological reactions once exposed to heterologous agonists in the future 1,2,3 . In 2011, Netea et al proposed the term "trained immunity" to describe this ability of innate immune cells to nonspecifically adapting, protecting and remembering primary stimulation 4 . BCG BCG through attenuated strain of Mycobacterium bovis was used to produce heterogeneous immunity against Mycobacterium tuberculosis , another species within the genus Mycobacterium. BCG was blamed to lead to incomplete and often varying degree of protection against TB disease 5 . On the other hand, studies have been done over the past few decades show that certain adaptations connected with innate immune cells (monocyte/macrophages, NK (Natural Killer) cells are responsible for nonspecific effects of vaccination beyond its target 6,7 .These studies show that Vaccination with BCG induces an improved innate immune response against microorganisms other than Mycobacterium,which include bacteria such as Staphylococcus aureus, fungi such as Candida albicans and viruses such as the yellow fever virus 6,8,9 .

There are evident roles of BCG in reduction of neonatal sepsis and respiratory infection reduction 10,11,12 . Its role in childhood mortality reduction is known since 1927 13,14,15 . Furthermore BCG-vaccination was associated with diminished morbidity and mortality rates associated with malaria , unclassified fever, preventing, sepsis and leprosy 10,11 ,13,16,17,18. In spite of that, many countries discontinue BCG vaccinations or limited its use to high risk groups because great achievements in reduction of TB prevalence rates in these countries. TB Tuberculosis (TB) is one of the major causes of illness and death in many countries and constitute a significant public health problem worldwide. TB disease is one of the top 10 causes of death accounted to estimated 10 million people in 2018 19 .About one-quarter of the world's population has latent TB which leads 5-15% lifetime risk of falling ill with TB 19,20 .

Mycobacterium tuberculosis antigen stimulation without any clinically active disease 21 . The lifetime risk of reactivation of TB is estimated to be around 5-10% 22 .

The WHO recommends tailored latent tuberculosis infection management based on tuberculosis burden and resource availability 23 . Treatment of active disease is by far the major intervention in this regard worldwide, while diagnosis and treatment of LTBI are hindered by the cost implications of testing, lack of a consensus on the tests recommended, and side effects of treatment 24 . Treatment of LTBI in low prevalence (high to upper-middle-income) countries like USA 25 and many Europian countries 26 is feasible (in spite of prolonged adaptive immunological response to Mycobacterium antigen) , as elimination of this reservoir of infection will reduce the burden of TB disease. However, the scenario in high prevalence countries like many countries in Asia and Africa is quite the opposite where, reinfection due to contact with active cases rather than reactivation contributes to a high disease burden 

Malaria infection can be asymptomatic, or, more accurately, "subclinical," because subtle symptoms and chronic health effects may occur but not lead to clinical diagnosis and treatment 30 . In similar way for TB control program , malaria elimination require ( eradicating both clinically symptomatic as well as these "silent" infections 31 Malaria also was founded to clear S. pneumonia much more efficiently in coinfected model 38 

Heterogenous immunological response also exists among different malaria species.

AS far as SARS-CoV-2 is known that a substantial percentage of adult population cannot get infected if exposed to this novel coronavirus 42 . Several studies suggest a possible role of preexisting immunity whether cross immunity or not (antibodies/T cells, etc.) as a factor explaining such diversity 42 .

All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted September 11, 2020. . https://doi.org/10.1101/2020.09.09.20191684 doi: medRxiv preprint Previous studies on latent TB association with reduction of COVID-19 mortality did not give explanation for high mortality in certain countries like south Africa where COVID-19 mortality/M population is 238 at the study time while TB prevalence/1000 population is very high (520). Furthermore these studies do not explain low COVID-19 mortality /M population in countries like in Togo (36), Benin(56) and Mali (53 ) which have relatively low TB prevalence while COVID-19 mortality is (3),(3 ) and (6) respectively.

Our study background hypothesis stands on possible heterogeneous immunity generated by malaria in addition to possible heterogeneous immunity generated by TB. This study will test COVID-19 mortality in malarious countries against malaria incidence and TB prevalence calibrated by BCG coverage to look for statistical associations and significances. Up to our knowledge this is the first work examine the effect of malaria and BCG coverage on COVID-19 mortality . All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted September 11, 2020. Total number of malarious countries and territories enrolled in this study is 80 . All of these countries have current BCG vaccination programs but differ vaccination coverage.

Hierarchical regression of composite -multiple linear model, is used for data analyses. The direct factor of reducing the mortality rates with reference to covid-19 is the standardized TB/100,000 population by BCG vaccination coverage percentage in 2018 through dividing the factor of TB/100,000 population rates by the factor of BCG vaccination coverage in 2018, while the indirect effect that reduce the mortality rates, named as intermediate factor which is "The malaria incidence for 2018/1000 population ".

We investigate the validity of the assumptions of studied model that adopts the results of quantitative measurements. Table No. (1) shows the results of the multiple linear model fitness test resulted from the regression analysis of variance. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted September 11, 2020. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted September 11, 2020. . https://doi.org/10.1101/2020.09.09.20191684 doi: medRxiv preprint meaningful linear regression tested in two tailed alternative statistical hypothesis of studied factor playing effective role for reducing "COVID-19 death /1 M. population" as a function of the previous factor. Slope value estimated indicates that with increasing one unit of the studied factor, a negative influence on unit of the rates function factor occurred, and estimated as (-22.11). This decrement recorded significant influence at P<0.05. Other sources of variations are not included in model, i.e. "Constant term in regression equation" shows that non assignable factors which are not included in regression equation, ought to be informative, since estimation about (127) cases of " COVID-19 Mortality / 1 M." expected initially without effectiveness of the restriction of studied factor.

Back to the results of the table No. (3) , and regarding to composite regression estimate's factors (i.e. the standardized TB/100000 by BCG vaccination coverage 2018 as direct effect, and malaria incidence for 2018/1000 population as indirect effect) results shows a meaningful composite linear regression tested in two tailed alternative statistical hypothesis of studied factor is playing effective role for reducing "Covid-19 death /1 M." rates as a function of the previous factors. Slope value concerning the that the first factor's estimate indicates that with increasing one unit of the studied first factor, a negative influence on unit of the rates function factor would occur, and estimated as (-18.00). The decrement recorded significant influence at P<0.05, while with presence of indirect effect by the second factor, slope value indicates that with increasing one unit of that factor, a negative influence on unit of the rates function factor would occur, and estimated as (-0.331). The decrement recorded has highly significant influence at P<0.01. Ohers source of variations are not included in composite regression model, i.e. "Constant term " ought to be informative, since estimated that about (152) cases of "Covid -19 Mortality / 1 M." expected initially without effectiveness of the restriction of studied factors.

In this study the prevalence of mycobacterium spp. (including BCG vaccine) exposure of the populations is negatively associated with COVID-19 deaths per million populations this supports the three for mentioned studies 27,28 ,29 . TB prevalence standardization for BCG coverage is very important factor regarding studying countries currently implementing BCG programs. Coverage in such studies reflects the degree of benefits added to the factor (latent TB prevalence) the coverage do and that's what we do in this study. Likewise the influence of time duration of cessation of BCG vaccination program is a factor in determining COVID-19 mortality 44 in countries ceased implementing this vaccine and that's what we did in one of our previous studies.

Malaria which possibly induce immunological response similar to TB as we suggest in one way or another is significantly associated with reduction in COVID-19 mortality in this study. This finding is the first to be reported up to our knowledge. This association although needs confirmatory immunological and clinical control studies to establish causation. Furthermore, this finding can explain the variances in COVID-19 mortality among different countries much deeper than TB and BCG alone. BCG vaccination status for countries being of concern earlier before latent TB becomes of concern but previous early studies were conflicting and were criticized because of possible confounding factors. In our study her all countries are implementing national BCG programs but TB countries' prevalence /100,00 population were standardized by BCG coverage rates. Recommendations: Malaria, TB prevalence and BCG coverage rates are possible factors in COVID-19 mortality should looked for deeply for possible causation to current pandemic mortalities.

Ethical permission is not necessary as this study analyzed publically published data and patients were not involved.

There is no conflict of interest. 

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