China’s Influence on Pathogenesis, Diagnosis and Therapy of Covid-19

Taufiq Muhibbuddin Waly

A patient must undergo x-ray examination for up to 4 times in 4 consecutive days, in order to search for pneumonia. The professors insist that before RT-PCR result is present, then GGO (Ground Glass Opacity) image on CT-Scan is sufficient to establish COVID-19 diagnosis. The presence of thrombocytopenia is even starting to be considered by most Indonesian doctors as part of COVID-19 (even though Indonesia has the highest Dengue infection cases in the world). The presence of cytokine storm in COVID-19 according to Chinese researchers has been accepted by most of the world’s professors.

Is that true? In a situation where most of the world has difficulty in performing the research, then these China’s researches are considered as a sole truth. I will give comments as a second opinion regarding the results of these China’s research. May it be useful.

The target cell of any viruses is the key word to discuss its pathogenesis and pathophysiology. For SARS-CoV-2 virus, 2 types of cells in the respiratory tract are predicted to be the target cells. Namely goblet cells which are located in the upper respiratory tract and the bronchial branches or alveoli cells located in the lungs / lower respiratory tract.

In SARS-CoV-5 alveoli are the target cells. Where the ACE 2 enzyme is considered to facilitate the entry of SARS-CoV-5 to the target cell. Is that also what happens to SARS-CoV-2?

The difference between SARS-CoV-5 and SARS-CoV-2 clinically is that SARS-CoV-5 provides severe clinical symptoms with manifestation of severe shortness breath. Or it matches with the number of destroyed alveoli. Or it is indeed that the alveoli are the target cells of SARS-CoV-5, and ACE 2 is mainly located in alveoli cells. So it can be accepted if ACE 2 is said to facilitate the entry of SARS-CoV-5.

The clinical symptoms of SARS-CoV-2, 95% are mild clinical symptoms such as heat, cough, runny nose, and muscle aches. Only 5% of them provides severe clinical symptom of severe shortness of breath. Because of that it is not possible for alveolus to be the target cell of SARS-CoV-2. The virus can successfully enters the lungs, if the body’s defense mechanism failed to restrain the entry of the virus. And the body mechanism that regulates this is the thick and sticky liquid produced by goblet cells. It is most likely that these goblet cells are the target of SARS-CoV-2. Because the target cell is a goblet cell, the systemic reaction that occurs is mild or absent, not to men. That’s why, severe shortness of breath will be very much unlikely in majority of COVID-19 cases.

The most prominent clinical symptoms are the reaction caused by mucus hypersecretion, which are productive cough and runny nose/sneezing. Because SARS-CoV-2 virus multiply in these goblet cells, many goblet cells are damaged and mucus secretion is greatly reduced.  The stimulation of goblet cells is happening at a rapid rate and massive scale. The same with its destruction, it happens in people with low immunity. That’s what makes the transmission happens very fast and easily. So it’s logical that some people give COVID-19 its nickname as “The King of Rapid Contagious Infection of All Diseases” (further reading on the mechanism of COVID-19 transmission in : http://renungan-tmudwal.com/review-towards-covid-19-mode-of-transmission-an-effort-to-vanquish-world-panic/). After viruses have successfully replicated in goblet cells in the upper respiratory tract through the bronchioles then these viruses will descend into the lungs due to the motion caused by gravity and air pressure difference in the lungs. Systemic symptoms will be more obvious, because blood flow that enters alveoli is more plentiful compared to the blood flow that entersgoblet cells. Fever, muscle aches, fatigue are started to be felt. The cough is still there but the cough will get drier than before while sneezing began to decrease. After the virus enters the lungs, the inflammatory reaction due to the release of cytokines and apoptosis will cause alveoli cells in the lungs to be damaged. Shortness of breath then follow.

Shortness of breath in COPD or chronic asthma with COVID-19 is the main cause of death compared to alveoli cells destruction. Mucous hypersecretion in bronchus and bronchioles causes hypoxia and death. Death may happen even faster before majority of alveolar cells is destroyed. Or the death comes from combination of airways blockage in bronchus, bronchioles and alveolar cells destruction. Just like we already discuss, in the early phase of infection, mucous hypersecretion happen because of the entry of macro and micro droplets into respiratory tract. This situation may cause the finding of greyish thick liquid and whitish liquid in trachea, bronchus, bronchioles or even in lungs after post-mortem biopsy in some COVID-19 patients.

If someone’s immunity is in good shape then since the first time virus enters the goblet cells, the virus would have been quickly destroyed. If there were some that escaped into the lungs, before many alveolar cells were damaged, the virus would have been destroyed beforehand. But if the immune system is low, then the alveolus cells will continue to be destroyed. Their destruction is mainly due to the apoptotic reaction. Or the alveoli cells are programmed to self-destruct. Not because of direct inflammatory reaction.

Viruses that are failed to be destroyed in these people with weak immunity can then enter into blood flow. So then it might be found SARS-CoV-2 virus inside of digestive tract or anal swab. But that virus will not give any meaningful symptoms, because complex immune will not be formed (because of immunocompromised). Natural Killer cells will defeat these viruses easily. If seizure reaction happen in COVID-19 patients, then it will only happen in people with high immunity. It means immune complex has spread into the brain and then be destroyed by macrophage. However, seizure might happen in these individuals but it rarely happens. Because in people with high immunity virus has been destroyed in respiratory tract. In immunocompromised people or elderly, the spread of immune complex to the brain and causing seizure will be very much unlikely. Because of the failure in forming good antibody mechanism. If at one time SARS-CoV-2 was found in CSF, then the explanation will be the same as the finding of SARS-CoV-2 in anal swab.

There is even more bizarre theory. They said that it’s not the target cell that we should search for but it’s the receptors that make virus entry into the cells easier. And they said that receptors from SARS-CoV-2 is ACE 2. Because ACE 2 is located in many organ cells, then SARS-CoV-2 can give various clinical symptoms hence the nickname The Thousand Faces Disease. If this thing is true, then we should find many immune complexes or antibody-virus complex in the blood. That complement increase will trigger macrophage to destroy immune complex by releasing cytokine. There is no report regarding which complement that were released in those COVID-19 researches from China. Without the obvious increase of complement, cytokine storm will be pretty much impossible. What certain is the main cause of death that often be reported is the respiratory failure caused by severe pneumonia. So that it’s logical if target cell for SARS-CoV-2 is located in respiratory tract. In respiratory tract we often find ACE 2. But do ACE 2 has any role in virus entry to the target cells? We don’t know it for sure, because there is no evidence in showing ACE 2 has any role in in the process of virus infiltration to its target cells

Does COVID-19 cause cytokine storm?

The term cytokine storm means various kinds of cytokines come out in large quantities. How many types of cytokines are released that can be confirmed as cytokine storms? There is no literature that have answered that. In my opinion, if more than 5 kinds of cytokines are released and give the effect of severe damage to the organs of the body, only then it can be considered as cytokine storm.

Cytokines are peptides produced by lymphocytes, macrophages, granulocytes and endothelial cells. Especially by macrophages. After goblet cells become infected with a virus, there will be non-specific and specific immune reaction. Non-specific immunity, occurs when the interferon α were released from leukocytes. The interferon will then stimulate Natural Killer cells to kill viruses inside goblet cells, namely by the mechanism of ADCC (Antigen Dependent Cytotoxic Cell). This natural killer cell can also have the ability to kill viruses outside of its target cell (outside of goblet cell). Viruses that are located in throat can be killed by these natural killer cells. Because of that it can be plausible that someone who have good immune system with positive COVID-19 throat swab test can suddenly change into negative result just in the span of 2-3 days. So we don’t have to wait until the next 2 weeks to repeat the throat swab. And there should not be any repeat test if the person has negative throat swab test for the first confirmation test and he doesn’t have any symptoms at all then this person should be put in the clear and need not be isolated. The one that we should search for is the one that spreading it in the first place.

While specific reactions are carried out via cytotoxic T lymphocytes which will kill the virus in goblet cells. Specific reaction by forming antibodies does not occur when the virus is in goblet cells, because blood flow to the goblet cells is not as plentiful as the one that goes into the lungs. After the virus enters the lungs, then specific antibody formation occurs. T-helper 2 lymphocytes will stimulate changes in B lymphocytes into plasma cells. These plasma cells then form antibodies. Antibodies will bind to antigens (SARS-CoV-2) this in turn will create immune complex (antibody-virus complex). The immune complex will stimulate the release of the complement and the complement will stimulate macrophages to release various cytokines that kill the virus in the lungs. Thus, theoretically cytokine storm will occur if there are many immune complexes and the release of complement.

According to the facts in patients with severe symptoms or death due to COVID-19, almost all (95%) are over 65 years old. Or it can be said death happens to people with low immunity. These people are scientifically unable to make various kinds of cytokines in large quantities. Or it might not create a cytokine storm. So saying that the basis for damage to COVID-19 is due to the release of various cytokines such as IL-2, IL-7, granulocyte colony stimulating factor, gamma inducible protein 10 interferon, monocyte chemotactic protein 1, inflammatory protein 1-α macrophages and tumor necrosis factor α (Consider Cytokine Storm Syndrome and Immunosuppression – The Lancet Volume 395, Issue 1029, P1033-1034) is coming into big scrutiny. Cytokine storm can only happen mostly to young people. Because they have strong immunity. Those people are also easily has hypersensitivity reactions due to viruses, bacteria, or foreign objects. Hypersensitivity is theoretically the main cause of cytokine storms, as in dengue infection.

Symptoms of severe illness and death in dengue infection usually occur in young people. That is due to the large number of immune complexes that are formed and spread to almost all of body tissues, various types of complements are formed too in these individuals then cytokine storms will happen. In dengue interleukin infection that comes out are IL-1, IL-2, IL-4, IL-5, IL-12, IL-13, IL-18 and TNF. While the complement that comes out is C1, C2, C3, C4, C5. So some say that the basis for pathogenesis and pathophysiology of dengue infection is hypersensitivity of immune complex / type III hypersensitivity (read: Again Let’s Discuss About DHF Pathogenesis and Pathophysiology, www.dhf-revolutionafankelijkheid.net).

In the Chinese research reports, we also don’t know what kind of complements that rose. So that creates the question for us whether there really is a cytokine storm. Even if there is a cytokine storm almost certainly it happens to young people who are very sensitive (hypersensitive to SARS-CoV-2). But seeing the fact, it rarely happens. Because in young people clinical symptoms that occur are mild. That means no or very little virus escapes from the lungs and enters the blood. If many are released there will be immune complexes and stimulate cytokine storms to destroy the immune complexes. In healthy young people, all viruses have been destroyed in the upper respiratory tract and if there is any that escapes as soon as they reach the lungs they will be destroyed too. Based on what has been written above, the presence of cytokine storms as the cause of severe clinical symptoms in COVID-19 is difficult to accept. Even if we still believe that in severe COVID-19 cases we will found various types of cytokine like what have been written in lancet paper, then the amount of cytokine produced will be low. This in turn will cause that even cytokine storm release various types of cytokine, but the amount will be minimal and cytokine storm will not happen. So various organs damage will not happen.

IMMUNITY PROBLEM IN COVID-19

            Is there any immunity that will be formed after being infected by COVID-19? Based on pathogenesis and pathophysiology that has been explained above, the immunity will only be formed if SARS-CoV-2 successfully enter the lungs. Or someone can get throat inflammation and runny nose for multiple times / get reinfected by COVID-19 for multiple times, but that person will never get the immunity if he hasn’t contract pneumonia yet. Only with getting pneumonia that blood flow will be entering the respiratory tract in large quantity and SARS-CoV-1 will then enter the blood. With that T-memory cell will then start to function.

            Positive throat swab with NK cell and T cytotoxic mechanism will be read as negative. But because T-memory cells are not functioning then COVID-19 can reenter the lower respiratory tract and  the throat swab will be read as positive once more. And people that has been once isolated  because of positive throat swab will then be released after negative throat swab was found. This person will then be reentering isolation room once more after the throat swab resulted in positive again. Or multiple isolation will happen in multiple cases. Because of that the most important thing that we can do is to stop all transmission chains for COVID-19, just like the one that I write in www.renungan-tmudwal.com with the title of “This World is a Big Cluster for COVID-19”.

            Thus, antibody that the body produced will only function as a way to prevent the progression of pneumonia and preventing the virus from run rampant through the whole body. In reality immunocompromised people will be long dead because of pneumonia, before the virus in large quantity spread to the whole body. Or if it can spread then the viral load will be minimum. It will not give any significant reaction in making multiple organs destruction. It will not be able to induce mass organ cells apoptotic mechanism.    

            Conclusion that we can take from the writing above is vaccination and plasmapheresis  from people with COVID-19 immunity are mainly used for preventing lungs destruction that will get worse or preventing the occurence of severe pneumonia. But who are the ones that will get vaccinated?

            Healthy young individuals or people with good immunity will not get any benefit from vaccination. Even if we see sometimes there are young people died because of COVID-19, it’s becaus they were immunocompromised in the first place. Just like hereditary disease, AIDS, cancer, TBC or other chronic diseases like heart disease and diabetes. For Indonesia, the increase of death ratio in young individuals diagnosed with COVID-19 is because there is suspicion of mixed infection from Dengue virus and CoV-2 (this suspicion is plausible because Indonesia is the place of world’s largest Dengue infection). Fear of giving corticosteroid administration in immunosupressive dose is the cause of strong reaction in these mixed infection cases.

            With the basic of the writings such as “Can Dengue Virus Infection Provoke the Occurence of Fulminant Autoimmune Hepatitis and Systemic Lupus Erythemathosus”, “Think of Possible Existence of Dengue Infection Before You Play With Your Surgery Knife”, “Multiple Organs Complication Due to Dengue Virus Infection (Kidney, Heart, and Liver) That was Treated With Heparinization and Hemodialysis”, which all of them can be read in www.dhf-revolutionafankelijkheid.net then Dengue infection that happens in these young individuals is very dangerous. Whereas based on what I have been writen above, COVID-19 is clearly less dangerous to youngsters. Because of that if mixed infection happens, administration of corticosteroid in immunosupressive dose have to be done (“Controversy of Corticosteroid Research in Dengue Infection”). Further discussion about the possibility of mixed infection will be explained in diagnosis section.

With that as the basis, then the vaccination administration in young individuals won’t have any benefit whatsovever. Or if we put cost effectiveness into the picture needless to say it will be unnecessary.

How about vaccination for elderly and other immunocompromised people? Then it will be even more wasteful. Because they don’t have the ability to create immune cells well. Or the stimulation given by vaccination administration will not give the creation of good immune cells. It’ll be different if we talk about plasmapheresis. Plasmapheresis administration by means of giving the plasma from people that already have immunity from COVID-19 infection towards elderly or other immunocompromised people.

When will IgM and IgG appear in COVID-19 sufferer?

            In Dengue infection, after the virus enters into blood stream then IgM will be formed after the 5th day if it’s the primary infection from Dengue virus. Whereas IgG will only appear after more or less the 14th day. In secondary infection or after multiple Dengue infection occur, then IgG will be formed in the 2nd day and IgM in the 5th day. The virus will be detected in day 0 or the 1st day after symptoms appear (positive NS I antigen).

            In COVID-19 infection will not going to happen inside the blood directly. The occurencce of upper respiratory inflammation is not identical with the start of body’s response to produce IgM ad IgG. Only after virus enters the lungs, then the body’s reaction will be triggered to produce immunoglobulin.

            Because of that in primary infection, to find out IgM from COVID-19 it’s logical if it’s done at the minimum of 10th day after symptoms appear. While IgG might appear 15th day after symptoms first occur. It needs to be remembered that IgM in some people might be too low to detect. Sot that in primary infection IgM  (-) and IgG (+) will be found. Or in primary infection only after 15th day it is known that from rapid test IgG will be read as (+). The same happens in secondary infection. If IgM is too low to detect, then in the 10th day after symptoms rapid test will only give IgG postive (without positive IgM). IgM usually will lasts for 3 months, whereas IgG will lasts for years or even through the whole life.

            With what we have learnt so far, then in people with good immunity, it’s possible to find both negative IgM and IgG, no matter if throat swab test was read as positive or having history of positive throat swab. This thing happens because of the occurence of pneumonia in young people with good immunity has never been happening to them. So no matter when we check on them, these young people with good immunity will never give positive IgM and IgG result. Only with the history of positive throat swab test that someone can be indicated to suffer from COVID-19 or was infected by COVID-19. With good immunity, throat swab can change from positive to negative. Because of that throat swab should be done as soon as possible.

            Meanwhile for elderly, other than positive throat swab, IgM and IgG might also be positive. But in people with very low immunity, IgM and IgG will stay negative forever.

            With above information there arise new question, is there actually “carrier” term in COVID-19? Or do people without symptoms can still spread COVID-19?

            In fact, there is no “people without symptom” term in COVID-19 if we are talking about someone who are able to infect other people while not experiencing any symptom themselves. There will always be symptoms in these individuals even only light, for example, tingly sensation in the throat. In people like that if they are talking quite loudly then 3000 droplets will still be expelled. The same thing happen with cough. These people used to be categorized as people without symptom. Even then, it can be in two or three days these people are not infectious anymore to the others. And if it happens then these people can’t be concluded as people without symptom anymore. They will be categorized into healthy individuals. Because all virsuses in their body has been destroyed. People without symptom can’t be interchanged into carrier. Carrier is a condition when viruses and bacterias are available in large quantity in a person’s body and can then infect other people and this condition last for a long time. But these people are not sick nor exhibiting any symptom. So “carrier” term doesn’t have any place in COVID-19. They are either getting sick and then died or getting sick and then recover and then getting sick again, and so on. Everytime people are said to have been recovered, then it means that they are not contagious anymore. Everytime they are categorized as sick then it means they are contagious.

            Based on writing above, then in examination there can be found something like this:

1.      Positive RT-PCR  changed into negative in a short period of time.

2.      Positive RT-PCR  changed into negative in a short period of time and then changed into positive again.

3.      RT PCR (+), IgM (-), IgG (-).

4.      RT PCR (+), IgM (+), IgG (+), at 15th day.

5.      RT PCR (+), IgM (-), IgG (+), at 15th day.

6.      RT PCR (+), IgM(+), IgG (+), at 10th day

7.      RT PCR (+), IgM (-), IgG (+), at 10th day

8.      RT PCR (-), IgG(-), IgM(-).

9.      RT PCR(-), IgG(+), IgM(+).

10.  RT PCR (-), IgM(-), IgG(+).

In order to look for people without symptom to actually spread COVID-19 then it means we have to get positive RT-PCR, no matter what the result of their IgM and IgG.

Because many countries can’t afford to do RT-PCR check then one strategy to search for people without symptom is to perform rapid test. Whereas in that strategy, everybody that has negative rapid test don’t have to continue to perform the next test which is RT-PCR check. And for everybody that has positive rapid test will then continue to RT-PCR test. Even though the one thatwill be contagious is if there will be virus inside of someone’s respiratory system. And the existence of this virus is proven by the positive RT-PCR not by the existence of certain antibody. And it can only be proven by positive RT-PCR result in the end.

Negative rapid test result in some people may result in positive RT-PCR test or he is very potentially able spread COVID-19 to other people. Even though in the strategy of searching people without symptom by using rapid test, everyone that has negative result will not be undergoing RT-PCR test anymore. In reality people without symptom like this are the one that is very dangerously able to spread COVID-19.

In strategy, people with positive rapid test are the ones that will then continuing to undergo RT-PCR examination. Even though it may be possible that in people with positive rapid test, their RT-PCR test may result in negative or they don’t have any potential to spread COVID-19. Or it can be interpreted that these people have immunity against SARS-CoV-2. That’s why it’ll be misleading to suspect people with positive rapid test as people without symptom. On the other hand it should be underlined that positive rapid test can also happen in other Corona virus strains, other than SARS-CoV-2. People that own dog, cat or bird might give positive rapid test. Because in those animals it is often to be found many different strains of Corona virus. The same is true for cow and pig. With it then the result of someone’s rapid test may not be useful to search for people without symptom.

The conclusion from all things above is it is very difficult in searching people without symptoms with rapid test. The possibility of getting people without symptom with positive RT-PCR testbased on positive rapid test in my calculation it’s almost reaching 0%. The positive result in people without symptom will only happens if as soon as we get individuals with positive rapid test we then performing throat swab test immediately. Because positive RT-PCR test can change rapidly into negative in a short time. On the other hand, people with positive rapid test are not undergoing RT-PCR test immediately. Even disastrously, people with positive rapid test and haven’t been through RT-PCR check are being isolated and ostracised by their own community. That’s why chaos ensues everywhere, just like what we have been seeing today. Advice for people with positive rapid test is to not worry if they were experiencing no symptom at all and RT-PCR hasn’t been checked yet.And for government, people with positive rapid test and don’t have any symptom at all, it is advised to stop isolating these people. Meanwhile checking someone with RT-PCR test after negative rapid test is stupidity if we put cost-effectiveness factor into calculation.

With that, in order to search for people without symptom, it’s obvious to do it with RT-PCR. Is this world able to do it? US as the richest country in this world can only perform RT-PCR in 1,11% of its total population (data as of April 19th 2020).

With the inability of nations worldwide to find people without symptom in COVID-19 cases and the uselessness of vaccination, then the problem of COVID-19 seems to last forever.Humanity rejuvenation will keep on happening. Natural selection will keep on happening. Only people with superior immunity that are able to live comfortably in the future.  Superior immunity is not the same as herd immunity. Group immunity because SARS-CoV-2 immunity (herd immunity) will only give minimal effect in fighting out COVID-19 based on pathogenesis and immunity problems just like what has been explained above. Superior immunity usually happen in young individuals with good nutrition and excellent lifestyle. Included in excellent lifestyle is copying Islamic lifestyle in the matter of wudu’, covering own body and fasting. So it’s something absurd for Indians in the midst of COVID-19 pandemic is blaming Muslims. Because in their opinion, the first COVID-19 cases in India happened in tabligh participants. They should also be checking on thousands of Hindus that are bathing in Gangga river. It’s logical for them to copy South Korea’s way of handling COVID-19 infection. South Koreans are not discrediting Christians. Even though the first COVID-19 case in South Korea was started by the infection that run rampant in thousands of Christian followers in Sincheonji in Daegu.

With the total population of 1,3 billion people and reporting COVID-19 cases of only 16.365 and death of 521 people, then Premier Modi’s report is something laughable and should be taken with grain of salt. Moreover just like what we both know together, at least 500 million of Indians are living with income below 2 dollars a day. The world should watch out for 2 countries, China and India, if we really want to win the war against COVID-19.

In the end, there will be only one way to stop this natural selection and save elderly and other immunocompromised people in this world. It is to start “The New Way of Lockdown” at the same time for all countries in all over the world (www.renungan-tmudwal.com-The New Way of Lockdown; The World Is a Big Cluster for COVID-19).

            Note:

1.      To be continued on the matter of COVID-19 diagnosis in other occasion, inshaa Allooh.

2.      Many thanks to Tuswandi Ahmad Waly for his discussion and translation of this writing into English.

Sent to:

1.      WHO

2.      President of United States of America

3.      President of China

4.      Prime Minister of India

5.      President of Indonesia Republic

6.      Organization of Islamic Cooperation (OIC)

7.      Centre for Disease Control and Prevention (CDC)

8.      John Hopkins University

9.      Indonesian Medical Association

10.  Indonesian Society of Internal Medicine

11.  Indonesian Society of Respirology

12.  Indonesian Society of Anaesthesiology and Intensive Care Medicine

13.  Indonesian Pediatric Society

14.  Indonesian Association of Forensic Medicine

15.  Time Magazine

16.  News Week Magazine

17.  The New York Times

18.  Kompas Daily

19.  Republika Daily