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On the reduction of COVID-19 associated case fatality rate: reckoning of a physicist

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Abstract

We argue that the human immune system is perfectly equipped to tackle SARS-CoV-2 virus and COVID-19 associated case fatality rate (C.F.R.) can be largely reduced by improving the zinc dietary intake and zinc cellular absorption (via Zn2+ ionophores for the elderly – chloroquine, possibly quinine or clioquinol). Question for the readers: Does the classic anti-malarial Quinine work as a zinc ionophore and/or inhibitor of endosomal acidification (like the chloroquine)?
On the reduction of COVID-19 associated case fatality rate
1
: reckoning of a physicist
Върху намалението на степента на смъртност
2
от COVID-19: мислите на физик
Victor Atanasov
3
/ Виктор Атанасов
Sofia University, Faculty of Physics, 5 blvd J. Bourchier 1164 Sofia, Bulgaria / Софийски Университет,
Физически Факултет, бул. Дж. Баучер 5, 1164 София, България
Abstract/Абстракт
We argue that the human immune system is perfectly equipped to tackle SARS-CoV-2 virus and COVID-19
associated case fatality rate (C.F.R.) can be largely reduced by improving the zinc dietary intake and zinc
cellular absorption (via Zn2+ ionophores for the elderly).
Твърдим, че имунната система на човека е перфектно оборудвана за справяне с вируса SARS-CoV-2 и
COVID-19 свързаната степен на смъртност (С.С.) може значително да се намали чрез подобряване на
приема на цинк чрез диетата и клетъчната абсорбция на цинка (чрез Zn2+ йонофори за възрастните
хора).
Key words: SARS-CoV-2, 2019-nCoV, COVID-19, coronavirus / ключови думи: САРС-КоВ-2, 2019-нКоВ,
КОВИД-19, корона вирус
Date/Дата: 17/03/2020
English lang. text/Текст на англ. език
The Observables associated with COVID-19 include [1]:
1. 80.9% of people will get over the SARS-CoV-2 virus infection (and COVID-19 disease) with mild or no symptoms at all.
2. COVID-19 is mild if present at all in children under 9 years of age (0% C.F.R.).
3. COVID-19 is manifest with progressively increasing C.F.R. as a function of the age ( 10-39y 0.2%; 40-49y 0.4%; 50-59y
1.3%; 60-69y 3.6%; 70-79y 8% and >80y 14.8%).
4. COVID-19 associated C.F.R. is sex dependent with bias towards men. Male’s C.F.R. of 2.8% and is markedly higher than
female’s 1.7%.
5. COVID-19 associated C.F.R. dominates in the retiree occupation group 5.1%.
6. COVID-19 associated C.F.R. increases with the presence of comorbidities: cardiovascular disease 10.5%; diabetes 7.3%;
chronic respiratory disease/ hypertension 6%; cancer 5.6%.
7. Hemoglobin median concentration (in g/L) in ICU
4
care patients is 122, while for non-ICU care patients is 130.5, with little
statistical significance (p=0.2) [2].
The first observable is key to conquering the panic over the present lack of a vaccine and/or a specific virus chemotherapy, that is the
identification (approval) of a small molecule capable of a.) inhibiting the virus replication; b.) achieving therapeutic concentrations in
affected tissues (lung, heart, intestines) in vivo and c.) being non-toxic.
The first observable is a proof that the human immune system is perfectly equipped to tackle the virus, therefore disease C.F.R. is
mainly rooted in its improper functioning.
Naturally, we pose the question: What is the most likely reason for the immune system dysfunction, which leads to non-negligible
COVID-19 associated C.F.R. and is capable of explaining away the rest of the observables as self-evident?
For the purpose of working out an answer to the question, we would raise a hypothesis based on the recommended Chinese treatment
with chloroquine [3,4]. The almost universal anti-viral action of chloroquine (an inhibitor of endosomal acidification) is mainly
associated with inhibiting pH-dependent steps of the viral replication[5].
1
Case Fatality Rate C.F.R. = #deaths/(#deaths + #recovered); 2.3% according to [1].
2
Степен на Смъртност С.С. = #смъртни случаи/(# смъртни случаи + # излекувани); 2.3% според [1].
3
vatanaso@phys.uni-sofia.bg
4
Intensive Care Units (ICU)
However, chloroquine is amongst the few Zn2+ ionophores [6]. Others include zinc pyrithione, zinc dimethyldithiocarbamate (Ziram)
and clioquinol [7]. The latter being a potential alternative to chloroquine. Ionophores are facilitators of ion transport across the cellular
membrane.
Next, it is realized that Zn2+ inhibits coronavirus RNA polymerase activity in cell culture provided it is effectively heralded into the
intracellular milieu, that is zinc ionophores block the replication of the virus [8].
Now we are in position to raise the following hypothesis: Zn-deficit (in all its aspects) is the major cause of the COVID-19 associated
high C.F.R.
Suppose, this is indeed the most likely reason for the immune system dysfunction, than it should be able to explain the rest of the
observables.
Let us begin:
Observables 2, 3 & 5 are exhausted by the statement that COVID-19 is characterized by progressively increasing C.F.R. as a
function of the age and are explained away by Zn-deficiency being age related [9]: The serum Zn concentration is correlated
inversely with age (r=-0.11, p=0.018). Note, the age-dependent deficiency is not necessarily dietary dependent but is rather
an absorption issue.
Zn-deficiency and anemia are gender related [9]: The serum Zn concentration is 77.4 +/- 9.7
microg/dL in men and 79.1 +/- 10.4 microg/dL in women (p= 0.09). Anemia (A) diagnosed by the World Health
Organization criteria is present in 17.3% of men and in 13.5% of women - Amen/Awomen = 1.28, while Covid-19 associated
C.F.R.men/C.F.R.women = 1.65 which is close enough (28%) to explain Observable 4.
Observable 6, that is COVID-19 associated C.F.R. increases with the presence of comorbidities, can be explained away by
the chronic condition induced Zn-deficiency in cancer (5.6% COVID-19 C.F.R.) and diabetes (7.3% COVID-19 C.F.R.)
sufferers. The rest of the relevant comorbidities generally reduce survivability in acute inflammatory instances.
Zn is also the only variable associated with anemia risk [10] and is correlated with hemoglobin concentration [9], that is
hemoglobin concentration can be used to infer Zn-deficiency. The serum Zn concentration is significantly lower in patients
with anemia than in those without anemia. Note, Observable 7 points to complications due to COVID-19 being associated
with hemoglobin concentration being in the lower end (or below) of the range for the average healthy individual, which we
interpret as an indication of Zn-deficiency.
In conclusion, we would like to turn the attention towards the 1+ billion people worldwide, who are Zn-deficient [11] and therefore at
risk with respect to COVID-19 associated complications. The three major causes of Zn- deficiency are 1.) dietary vegeratians at
highest risk; 2.) poor absorption elderly or suffering from acrodermatitis enteropathica; 3.) chronic conditions: alcohol addiction,
cancer, diabetes, ect. The present hypothesis represents a falsifiable statement. If proven correct, improvement in the zinc dietary
intake and zinc cellular absorption (via Zn2+ ionophores for the elderly) can lay the foundation for a doable and strong SARS-CoV-2
viral counter-measure and greatly reduce COVID-19 associated C.F.R., therefore reduce the need for draconian social distancing
which vastly damages world economy.
Текст на български език /Bulgarian lang. text
Наблюдаемите, свързани с COVID-19 включват [1]:
1. 80,9% от хората ще преболедуват SARS-CoV-2 вирусната инфекция (и болестта COVID-19) с лека или никаква
симптоматика.
2. COVID-19 е мека, ако изобщо присъства при деца под 9 години (0% С.С.).
3. COVID-19 се проявява с прогресивно увеличаваща се С.С. като функция на възрастта (10-39г 0,2%; 40-49г 0,4%;
50-59г 1,3%; 60-69г 3,6%; 70-79г 8% и > 80г 14,8%).
4. COVID-19, обвързаната C.С. зависи от пола с уклон към мъжете. Мъжката C.С. от 2,8% и е значително по-висока
от 1,7% при жените.
5. COVID-19, обвързаната C.С. доминира в окупационната група на пенсионерите 5,1%.
6. COVID-19, обвързаната C.С. нараства с наличието на съпътстващи заболявания: сърдечно-съдови 10,5%; диабет
7,3%; хронични респираторни / хипертония 6%; рак 5,6%.
7. Средната концентрация на хемоглобина (в g / L) при пациентите, които се нуждаят от интензивно лечение, е 122,
докато при пациентите, които не се нуждаят от интензивно лечение, е 130,5 с малка статистическа значимост (p =
0,2) [2].
Първото наблюдаемо е от ключово значение за побеждаването на паниката порoдена от липсата на ваксина и/или
специфична вирусна химиотерапия, тоест идентифицирането (и одобрението) на малка молекула, способна да а.) инхибира
репликацията на вируса; б.) постигане терапевтични концентрации в засегнатите тъкани (белите дробове, сърцето, червата)
ин виво и в.) която не е токсична.
Първото наблюдаемо е доказателство, че имунната система на човека е перфектно оборудвана за справяне с вируса,
следователно степента на смъртност от болестта се корени главно в неправилното функциониране на имунната система.
Естествено, ние поставяме въпроса: Коя е най-вероятната причина за дисфункцията на имунната система , и която води до
не-пренебрежима С.С. свързана с COVID-19 и е в състояние да обясни останалата част от наблюдаемите като очевидни?
За да се достигне до отговор на въпроса, излагаме хипотеза на базата на препоръчаното китайско лечение с хлороквин [3,4].
Почти универсалното анти-вирусно действие на хлороквина (инхибитор на ендозомното подкисляване) е свързано главно с
инхибиране на pH-зависимите етапи на вирусната репликация [5].
Хлороквинът обаче е сред малкото Zn2+ йонофори [6]. Други подобни молекули включват цинк пиритион (zinc pyrithione),
цинк диметилдитиокарбамат (zinc dimethyldithiocarbamate (Ziram)) и клиоквинол (clioquinol) [7]. Последният е потенциална
алтернатива на хлороквина. Йонофорите са молекули улесняващи транспортирането на йони през клетъчната мембрана.
По-нататък, показано е, че Zn2+ инхибира активността на коронавирусната РНК полимераза в клетъчна култура, при условие
че е ефективно въведена във вътрешноклетъчната среда, тоест цинковите йонофори блокират репликацията на вируса [8].
Сега сме в състояние да изкажем следната хипотеза: Дефицитът на цинк (във всичките му аспекти) е основната причина за
свързаната със COVID-19 висока степен на смъртност.
Да предположим, че това наистина е най-вероятната причина за дисфункцията на имунната система, тогава трябва да можем
да обясни останалата част от наблюдаемите като очевидни.
Нека започнем:
Наблюдаеми 2, 3 и 5 се изчерпват с твърдението, че COVID-19 се характеризира с прогресивно увеличавaща се C.С.
като функция на възрастта и се обясняват с това, че дефицитът на цинк е свързан с възрастта [9]: Серумната
концентрация на цинк е анти-корелирана с възрастта (r = -0,1, p = 0,02). Забележете, възрастово обусловеният
дефицит на цинк не е непременно свързан с хранителния режим, а е по-скоро въпрос на затруднено усвояване.
Дефицитът на цинк и анемията са свързани с пола [9]: Серумната концентрация на цинк е 77,4 +/- 9,7 microg/dL при
мъжете и 79,1 +/- 10,4 microg/dL при жените (p = 0,09). Анемията (A), диагностицирана по критериите на Световната
здравна организация, е налична при 17,3% от мъжете и при 13,5% от жените, т.е. отношението - A мъже / A жени = 1,28,
докато С,С.мъже/С.С.жени=1,65 свързана с Covid-19, е достатъчно близо (28%), за да се обясни Наблюдаемо 4.
Наблюдаемо 6, което е свързано със увеличаваща се с наличието на придружаващи заболявания С.С. при COVID-19,
може да се обясни със хроничния цинков дефицит на страдащите от рак (5,6% С.С. при COVID-19) и диабет (7,3%
С.С. при COVID-19). Останалите от значимите съпътстващите заболявания са стандартно свързани с редукция на
преживяемостта при остри възпалителни заболявания.
Концентрацията на цинк е и единствената променлива, свързана с риска от анемия [10] и определя концентрацията
на хемоглобин [9], тоест концентрацията на хемоглобин може да се използва за установяване на дефицит на цинк.
Серумната концентрация на цинк е значително по-ниска при пациенти с анемия, отколкото при тези без анемия.
Забележете, Наблюдаемо 7 сочи, че усложненията при COVID-19 се дължат на това, че концентрацията на
хемоглобин при страдащите е в долния край (или под) диапазона за средно статистическия здрав индивид, което ние
интерпретираме като индикация за дефицит на цинк.
В заключение, бихме искали да обърнем внимание на това, че 1+ милиарда души по света, страдат от дефицит на цинк [11] и
следователно са изложени на риск от усложнения, свързани с COVID-19. Трите основни причини за недостиг на цинк са: 1.
хранителен режим - вегетарианци са с най-висок риск; 2.) лоша абсорбция - възрастните хора или страдащите от
акродерматит ентеропатика; 3.) хронични състояния: алкохолна зависимост, рак, диабет и др. Настоящата хипотеза
представлява фалшифицируемо твърдение, т.е. може да бъде подложена на проверка. Ако се окаже правилна, подобряването
на приема на цинк в хранителния режим и клетъчната абсорбция на цинк (чрез Zn2+ йонофори за възрастните хора) може да
постави основата за изпълнимо и силно противодействие на вируса SARS-CoV-2 и значително да намали свързаната с
COVID-19 степен на смъртност, като по този начин доведе до отпадане на нуждата от драконовски мерки за социална
изолация – силно увреждаща световната икономика.
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https://doi.org/10.1038/srep10974
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Chloroquine is a 9-aminoquinoline known since 1934. Apart from its well-known antimalarial effects, the drug has interesting biochemical properties that might be applied against some viral infections. Chloroquine exerts direct antiviral effects, inhibiting pH-dependent steps of the replication of several viruses including members of the flaviviruses, retroviruses, and coronaviruses. Its best-studied effects are those against HIV replication, which are being tested in clinical trials. Moreover, chloroquine has immunomodulatory effects, suppressing the production/release of tumour necrosis factor alpha and interleukin 6, which mediate the inflammatory complications of several viral diseases. We review the available information on the effects of chloroquine on viral infections, raising the question of whether this old drug may experience a revival in the clinical management of viral diseases such as AIDS and severe acute respiratory syndrome, which afflict mankind in the era of globalisation.
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The coronavirus disease 2019 (COVID-19) virus is spreading rapidly, and scientists are endeavoring to discover drugs for its efficacious treatment in China. Chloroquine phosphate, an old drug for treatment of malaria, is shown to have apparent efficacy and acceptable safety against COVID-19 associated pneumonia in multicenter clinical trials conducted in China. The drug is recommended to be included in the next version of the Guidelines for the Prevention, Diagnosis, and Treatment of Pneumonia Caused by COVID-19 issued by the National Health Commission of the People's Republic of China for treatment of COVID-19 infection in larger populations in the future.
Zinc (Zn) is an essential trace element for humans and its deficiency can lead to several clinical problems. This study examined the relationship between the serum zinc concentration and anemia in middle-aged and elderly people. Samples were obtained from 150 men and 303 women who received health checkups over the course of 40 years. The serum concentration of Zn was measured as well as the complete blood count (CBC), alanine aminotransferase (AST), aspartate aminotransferase (ALT), gamma-glutamyl transferase (gamma GT), total cholesterol (TC), high density lipoprotein (HDL-C), triglyceride (TG), creatinine (Cr), uric acid (UA) and fasting plasma glucose (FPG). The serum Zn concentration was 77.4 +/- 9.7 microg/dL in men and 79.1 +/- 10.4 microg/dL in women (p= 0.09). The serum Zn concentration correlated inversely with age (r=-0.11, p=0.018). Anemia diagnosed by the World Health Organization criteria, was present in 17.3% of men and in 13.5% of women. However, more than 80% of the anemia was normocytic (men 86%, women 81%). The serum Zn concentration was significantly lower in those with anemia than in those without anemia. The Hb level correlated with the serum Zn concentration (men r=0.25, p=0.002, women r=0.23, p<0.001). A multiple regression analysis confirmed a low serum Zn concentration to be associated with a low Hb level. In conclusion, this study indicates that the serum Zn concentration decreases with age and that a low Zn concentration is associated with normocytic anemia, thus suggesting that a Zn deficiency may therefore be one of the causes of anemia in elderly people.
Article
Compounds that bind metals such as copper and zinc have many biological activities, including the ability to induce apoptosis in cancer cells. Although some of these compounds have been considered to act as chelators of metals, decreasing their bioavailability, others increase intracellular metal concentrations. We review recent work regarding the recognition of the biological effects of metal ionophores with different structures, particularly with regard to their actions upon cancer cells focusing on dithiocarbamates, pyrithione, and the 8-hydroxyquinoline derivative, clioquinol. We provide a biologically based classification of metal-binding compounds that allows an experimental distinction between chelators and ionophores that can be readily used by biologists, which may lead to further study and classification of metal-binding drugs. Metal ionophores may kill cancer cells by a number of mechanisms, including lysosomal disruption and proteasome inhibition, and likely others. Because some of these compounds have been safely administered to animals and humans, they have the potential to become clinically useful anticancer agents.
Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, the Lancet
  • Chaolin Huang
Chaolin Huang, et.al., Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, the Lancet,395, p497 (2020) https://doi.org/10.1016/ S0140-6736(20)30183-5