COVID-19 – mechanism of action, treatments and improving the data collection

The text below was a part of a global COVID-19 solution challenge. It was rejected by World Health Organisation representatives but may be of interest of other organisations. It was submitted on may 24, 2020 and is based on the information available up to this date.

1. Treatment and prevention.

1.1. Invasion by SARS-CoV-2 and potential drug targets. 

Understanding the timeline and exact mechanism of the virus entry in all susceptible cells is essential to control SARS-CoV-2 and find potential treatments. SARS-CoV-2 enters the respiratory epithelial cells with the help of the cell proteases furin and TMPRSS2 (i), and  the peptidase cathepsin L. The receptor to which the virus attaches to the cell is the angiotensin converting enzyme (ACE2) – a type I membrane protein expressed in lungs, heart, kidneys, and intestines (i). ACE2’s primary role is the maturation of angiotensin (Ang II) – a peptide hormone which controls vasoconstriction and blood pressure. Since ACE2 is the cell receptor of SARS-CoV-2, after the initial induction and replication in the lungs the virus could enter the kidneys and disturb the erythropoietin production which levels are regulated by ACE2 and Ang II. Erythropoietin acts in bone marrow to stimulate the production of mature red blood cells and maintain healthy oxygen levels in our tissues. After the initial invasion in lungs the virus not only interferes with the oxygen supply from the respiratory system but blocks the body’s response to fix the lowering levels of oxygen. This  explains the effect on people with high blood pressure and heart disease which is unusual for the other respiratory viruses –  ACE2 is used as entry together to lungs and kidneys which blocks the oxygen supply of the organism and red blood cell production, and its main function is blocked. One of the ways to control the SARS-CoV-2 entry in the cells and preventing the hijacking of ACE2 is by  the angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) which are taken by the people who suffer from heart disease, diabetes and high blood pressure. The drug’s connection with the COVID-19 outcome is  already investigated but there are mixed results due to the difference among the drugs and timing (i,ii). It is important to understand how long it takes for the virus to move from the respiratory system where it enters the body to the rest of acceptable organs. One of the ways to prevent developing  COVID-19 is to block the virus entry in the cells by inhibiting the proteases which are essential for it (i). Since there are already approved protease inhibitors as drugs it is worth to check their applicability (i).

Additional notes:

* All data show that there death rate in males is much higher than females. Lifestyle and behavior could affect the fatal prognosis but genetics could be another factor. Females generally have higher ACE2 activity and ACE2 gene is located on the X chromosome (i). Since males have only one pair of it and with it may make them more sensitive to ACE2 obstruction. 

** While the main system which is attacked by the virus is the respiratory system it is important to assess the other possible targets of the virus and adjust the treatment accordingly. 

1.2. Other Potential drugs. 

The novel coronavirus belongs to the Coronavirus family some members of which cause common cold (i). This from one side gives natural immunity (i, ii, iii) and partially explains children’s lesser acceptability to the infection (they have cold often), from the other side drugs proven to relieve  common cold symptoms could help with COVID-19. One of these drugs is the little known but widely used in some countries analgin-quinine (i) – a combination of metamizole sodium and quinine. Metamizole sodium blocks prostaglandin synthesis due to inhibition of cyclooxygenase (COX) isoenzymes.  Quinine is known for its antimalarial effect and is already included in clinical tests for COVID-19. As we know sometimes a combination of suitable substances could work better since can be used in lower concentrations and avoid adverse effects.  Analgin-quinine  can have some extra protective features since it may be the reason for the lower death rate in supposedly vulnerable aging populations like  in Bulgaria for example where its use is part of common cold treatment (*the country vaccination schedule includes tuberculosis vaccine as well, see 1.3.). 

Another antimalarial drug artemisinin (i) is worth testing because the African countries have  remarkably low COVID-19 death rate which could be explained with the mass use of antimalarial drugs. There could be another potential benefit from artemisinin since it has proved anti-inflammatory and immunomodulating effect (i).

1.3.  Vaccines. 

Creating new vaccines takes several years. While we can accelerate the molecular biology techniques we can’t change human biology.  Governments and companies are promising fast vaccine development and implementation but that is met with mistrust by the general public. Everyone can access websites like cdc.gov and find out that a new safe vaccine needs years to be created since the adverse effects in humans can show years after the vaccination. The fact that COVID-19 is deadly for the older and people with certain diseases also adds the need of extra precautions.  One of the unusual things about the COVID-19 is that there is a difference in death rate in different countries. The death rate from COVID-19 is significantly lower in the countries with strict tuberculosis vaccination schedules. It could be due cross-immunity and the fact that the vaccine protects against secondary bacterial infections.  Tuberculosis vaccine (BCG) is well tested and will be accepted by the public without hesitation. There are already clinical trials testing the hypothesis, but they may encounter a problem:  seniors who are the main target group have an immune system that has declined and is less able to generate protective immunity after vaccination. Fortunately a recent study shows that could be reversed with a cream (imiquimod, currently used to treat genital warts in humans) on the site of immunization. The detailed explanation of the immunology and the procedure are  explained in recent publications at https://elifesciences.org/articles/52473 and https://www.babraham.ac.uk/news/2020/03/how-boost-immune-response-vaccines-older-people

In addition to the BCG vaccine and is worth to test the potential preventive effect of the current children vaccines. The reason for it is the fact that children and young healthy adults show significant resilience towards the virus and if developed COVID-19 normally is presented with mild symptoms. It has partial explanation with the fact that children are immune thanks to the frequent common colds and the different levels of ACE2 expression but cross-immunity by the vaccines is absolutely possible and testing the vaccines would give an extra way to protect the vulnerable in case BCG is not suitable. Vaccines which protect from respiratory infections and could have similar to the BCG effect: DTaP, Haemophilus influenzae type B and Pneumococcal vaccine.

2. Testing, statistics, death rate and monitoring.

2.1. Testing statistics needs improvement. 

A) People who are tested SARS-CoV-2  positive are put in one category but should be in 3 categories: I – with no symptoms, II –  with mild symptoms and II – with severe symptoms. People from category II and II i.e. tested positive with symptoms are tested again and counted as recovered but it is not clear where in the statistic go the people from category I i.e.  tested positive without symptoms. They haven’t recovered since they never got sick. We need to know exactly how many people were infected without showing any symptoms, how many had mild symptoms and how many severe. 

B) Calculation of the new cases every day aren’t based on constant test rates like X  new cases per 100 or similar. It may show false increase or decrease based on more or less tests per day. Attention to point A above – extra testing of the same patients shouldn’t be put in the new case statistics. 

2.2. What counts as death from COVID-19.

There is a need of clarifying what counts as death from COVID-19. SARS-CoV-2 kills dominantly older people or people with underlying conditions like high blood pressure, hearth problems, diabetes and obesity. Since the coronavirus pandemic is during the time of influenza epidemic in the Northern Hemisphere, and both first attack the respiratory system influenza test and data about how long after the coronavirus positive test people die may help to determine the exact reason for the death.  COVID-19 has a longer  incubation period than flu and that would be helpful in case the person tests positive for both viruses. The possible attack on other systems and organs discussed in point 1.1. could help to diverge COVID-19 from other diseases.  It is important to note that there are reports of people who are counted as  COVID-19 deaths but didn’t test positive for COVID-19 or tested positive for COVID-19 but didn’t show any symptoms of COVID-19 (died from clear alternate causes). This is confirmed in Italy, USA and UK and approved by their government health officials. Must be investigated and fixed. In general the number of deaths as counted now may be overestimated and probably is lower (i, ii).

2.3. Investigating how many people were infected and died since the virus emerged. 

Most of the infected and dead people data (outside China) comes from the end of February and beginning of march. There is a gap  of a few months with limited data about the spread of the virus which is essential for understanding the virus development.  Recent studies show that the virus has spread outside China since December or even in the fall (i, ii, iii). One of the ways to find out how the virus has spread before the mass monitoring is to test for SARS-CoV-2 all saved samples of patients who had flu-like symptoms but were tested negative for influenza virus. Knowing the real timeline of the virus spread could help to improve the consequential measures. Long lockdowns are leading to economic downhill and neglect of other diseases (i, ii, iii, iv, v). If the virus has spread earlier the population has heard immunity and the extending of measures wouldn’t be needed.  

2.4. Standardising the conditions in which asymptomatic people who tested SARS-CoV-2 positive are put in quarantine. 

Since there are a variety of tests from PCR which could detect virus RNA to antibody tests there is a need of clarifying the conditions and tests which clearly state that the person can transmit the virus (i). Antibodies against SARS-CoV-2 mean that the person has been in contact with the virus not that can transmit the virus. PCR tests can detect even one copy of viral RNA but that doesn’t make a person contagious. Putting healthy and non-virus spreading people in quarantine is an unnecessary burden on the administration and medical personnel involved in the pandemic, blocks the economy and interferes people’s lives.

Final note. SARS-CoV-2 is a challenge for humanity which can be defeated by using the whole scientific power in the world. We must be honest that many of the decisions regarding the spread of the virus, and the consequences of COVID-19 weren’t based on science but politics. The mathematical models aren’t reliable because of the initial data unreliability which is discussed in point 2. Unfortunately this is not going to be the last pandemic.  We should be prepared better to fix that and the ones in the future. For it would be useful to create a nexus of thinkers with different scientific backgrounds which could look at the problem from different sides. 

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