Dr. Vijay Yeldani, Head Of Infectious Diseases And Public Health, Share India, On Covid-19 – Myths & Realities
SOME OF YOU MAY REMEMBER THAT I HAVE ADDRESSED ROTARY ON HIV A FEW YEARS PREVIOUSLY. THEN, I SHARED THE EXAMPLE OF THE DECLINE OF THE INCA AND AZTEC POPULATIONS AFTER 1520. AT THAT TIME, AZTEC NUMBERS EXCEEDED 24 MILLION WHILE INCAS EXCEEDED 12 MILLION. AND, YET, THE ESPAGNOLE PREVAILED. NOT BECAUSE THEY BROUGHT WITH THEM FIRE-ARMS BUT BECAUSE THEY BROUGHT SOMETHING DEADLIER: MEASLES, CHICKEN POX AND INFECTIOUS DISEASES AGAINST WHICH THE LOCALS HAD NO IMMUNITY.
Look at what happened over 50 years. Once a few of the elites died, and the infection was more wide-spread, and they had no immunity, it led to socio-economic disruption. Eventually, it led to a complete paralysis of the economy and disintegration of the social fabric. The population of the Aztec fell to less than 4 million and Inca to less than 2 million and never recovered after that. This is known as the demographic collapse. This is the potential of uncontrolled epidemics in population. That is why today, we face Covid-19, and it may kill a few people. However, it has the potential to cause wide-spread collateral damage and socio-economic disruptions that will take longer to recover.
Covid-19 is a new type of corona virus, but corona viruses are something that we have known about for a long time; one-third of common colds are caused by corona viruses. Also, corona viruses are very important pathogens in poultry – the infection, bronchitis viruses of chicken, animal husbandry, the foreseen epidemic, diarrhoea is also caused by the corona virus. So, we know about corona, the reason it is called corona is because of the spike proteins that appear on it, like a crown. That is why it is called corona virus.
In the human population, the first time we saw a major epidemic in terms of corona virus was SARS, 20 years ago, where 10 per cent of infected people died. Fortunately, that epidemic was rapidly brought under control and then 10 years later we saw MERS. 30 per cent of infected people died but again, fortunately, it was brought rapidly under control. By rapidly, I mean within a time frame of a couple of years.
Now Covid-19 has been a different story because unlike SARS and MERS, Covid-19 has a much higher rate of multiplication and transferability in all senses and a high viral burden in initial stages of infection itself. So, how is illness by Covid-19 different than previous epidemics? Although fewer infected people die, ease of transmission and contagiousness is much higher.
Why did the epidemic grow so out of control? What is unique about India as compared to USA vis-à-vis epidemic dynamics? What is the difference between the First wave and Second wave, is there going to be a Third wave? What is the role of the mutations? Will vaccine work against new strains? What is the reason of so many deaths? Why is there lack of oxygen, lack of hospital facilities and trained medical staff? When will things improve and how? What can we do now to address the pandemic in India? A question for the elite and the Government of India: what is the current catastrophe – predictable? Preventable? How and why? Can something like the Covid pandemic happen again with another pathogen, how do we prevent it, what can we do to prevent anything like the Covid pandemic ever happening again?
Some personal observations: I have been taking care of patients in Hyderabad for the past year. I was in Hyderabad when the epidemic hit and I was there until two weeks ago, still taking care of the patients. So, compared to last year here, there has been enormous increase in the number of patients, entire families have come down with Covid at the same time. This is different to what I saw last year with one or two cases per family.
Now, when an entire family comes down at the same time, who is the care-giver? Everyone knows a friend, neighbour or a family member who has become critically-ill or expired. I am seeing a larger number of symptomatic patients as compared to last year, and a larger number of people progressing from mild to severe illness. It’s a much more rapid progression from mild to severe illness – this is called telescoping. A larger proportion of individuals are taking very long to recover from symptomatic illnesses with persistent evaluation of markers of inflammation. There is a very frequent recurrence of symptomatic illness in people a few days after stopping anti-inflammatories. Many individuals have presented after one dose of vaccine and some soon after second dose. The number of people having Post-Acute sequelae SARS-CoV-2 infection (PASC) predominantly chest pain syndrome, rapid heart rate and fatigue. Some people who have recovered suddenly die and the exact cause is uncertain. There is an explosive increase in demand for High-resolution CT Scans and demand for Remdesivir. There is an epidemic of treatment for what I call questionable regimens like Doxy, ivermectin, High dose Vit C, Vit D, Zinc and so on and so forth.
There is an increase in patients at IMC with abnormal lung findings that were not seen last year. What is common with these people with very bad lung findings is that all of them have a history with Doxy, Ivermectin for at least a week or 10 days before they have come to see me. There has been a complete collapse of public hospitals. I am told that some people are being told to go out of the hospital and get their own oxygen from somewhere else and how we will be able to do that is beyond me. And some hospitals have not been providing the one treatment that we know works for which there is inconvertible proof which is Dexamethasone and anticoagulation to patients requiring supplementary oxygen.
So, the key evidence we should look at is what is evidence versus the bunch of stories strung together? What is statistically-adequate study? What are epiphenomena that are something which occur without any causal relation? The importance of correct inference. Now when I was developing antimicrobials for a lab many years ago, I always looked at congruence of evidence to tell me whether or not some molecule is actually going to pan out and become antibiotic that I can actually get a license for. First, preclinical work. Can we show in a laboratory if it works, can we explain in the lab how it works, what is the mechanism? Secondly, do we have any observational clinical data and then finally controlled trials are most important. there are many different kinds of trial. Equivalence trials mean that you can show that your treatment is as good as a gold standard. Unfortunately, for Covid-19 there is no gold standard. At the very least non-inferiority trial shows that the new treatment is almost as good as the existing gold standard, again we don’t have any gold standard for Covid-19. But what we require is the superiority trial which means that your treatment regimen must be much better than anything else. Now remember in Covid-19, 90% of the patients get better on their own, that is the reality. It is only 10% of the people who become very ill and land in hospital and some of them actually die. So, any treatment that you are proposing must be much better which means that that treatment must demonstrate efficacy and benefit to more than 90% who get Covid infections.
What this means is that any kind of trial that is going to show superiority in terms of Covid has to be a very large sample size, thousands of subjects. When everything comes together, the laboratory data, the clinical data, the trial data, then I think we have the ROBUST data set which gives you the correct inference. Let us also remember that Covid-19, as with other viruses in the past, is a warning from nature that environment, animal welfare and humans are integrally linked and there is no way to take one out of the other.
The only evidence that we have of any agent with benefit in Covid-19 is Dexamethasone. The recovery trial gave Dexamethasone to over 2000 patients and there were over 4000 patients who were serving as controls. Dexamethasone reduced deaths by one-third in patients who required a mechanical ventilator, one-fifth in patients who required oxygen but not a mechanical ventilation. There has been no other treatment regimen that has shown this kind of benefit. Unfortunately, all the other treatments that people are trying to push are based on small reports and small trials, none of which are statistically adequate to provide the kind of robust benefit that one needs in public health.
A little bit about coronavirus, the basic biology is very clear, there are many kinds of corona viruses that affect humans and animals, as I quoted before. The spike protein is important for entry into the cell and in humans particularly with Covid-19 the key receptor that is of interest is ACE2 which is found in abundantly in lungs and the entire body and blood vessels. Which is why the major organs impacted are the heart, lungs and also all blood vessels throughout the body, there are other receptors but they are of complementary importance to ACE2 and once the virus enters in the body it starts doing its work. What is interesting about Covid-19 is that it replicates at a phenomenal rate within hours. At this rate, the progeny viruses that are produced are not completely exact duplicates of the original, so, we have what we call genetic heterogamete now. Despite the fact that Covid-19 has a nucleus, the fact that by the time any RNA virus multiplies to billions of particles, you will have a viral quasispecies.
Viral quasispecies is something that Manfred Eigen proposed based on mathematical modelling in the late 1980s. He said viruses are not a simple species because of the enormous amount of heterogeneity of the population, they should be considered as quasi-species. The implication of a quasi-species is that there is an enormous amount of genetic heterogeneity, if you sample only one part of the population, you will not discern the true magnitude of it. What this means is that in Covid-19, it is entirely predictable that over a period of time, we will start to see a lot of variants. The biological properties of these variants will be different from the original properties and we are beginning to see that.
We still think that the vaccines will work for most variants even with lower level of efficiency, however they are still the best tools that we have to prevent viral infections for Covid-19 and therefore the current vaccines should be used as much as possible. It is possible that in the future we will require some different kinds of vaccines and it is also possible that we may require multiple vaccines to keep pace with the changing genetic nature of the Covid-19.
Based on preliminary data we, at Share India, did some epidemic projection doing an SIR model and we projected that with the replication rate approaching RO=3, over one-third of the population of Telangana would be infected by late 2020. At that time everybody thought that our projections were overly pessimistic and not reflected in the data. However, today, there is exclusive increase which tells us that our projections last year were not pessimistic, they were optimistic. We rather projected fewer infections, so, the RO=3 is probably greater than 3. So, what happens? R=1 means that the virus and epidemic will eventually die out. As the RO keeps going up, the slope or the increase in epidemic goes up. With RO=3.44949 the epidemic starts oscillating around the figure. So, there is an initial increase, then a dip and then once again a sudden increase, which is exactly what we have seen. So, as far as I am concerned, this is not a second wave, it is simply the epidemic and the natural history of the epidemic that we are seeing.
Now what happened when people get infected? We need to understand the infection network analysis which is basically anybody who gets infected and goes to the hospital, the patient can infect the healthcare worker, the healthcare worker may infect the patient, and this is how the transmission can go on and on.
With SARS, we saw that one infected person may infect 1 or 2 people but there were certain individuals who had the potential to infect very large number of people, these are super-spreaders. So, what happens is that when you have super spreading, there is an explosive increase in the number of people infected. Particularly when there is a large congregation like a wedding, religious gathering or election campaigns, the probability that you will have some super-spreaders. Why does this happen? Because Covid is spread through air. We spend a lot of time debating whether it is aerosol or airborne, the reality is it is spread through air. The implication of spreading through the air is that to prevent infection, you need fresh and uncontaminated air or a very large volume of air where the virus can be rapidly diluted which means that the most critical prevention is adequate ventilation. And this is one part where we have lost.
What happens when the virus enters the body? The body’s innate immunity and the adaptive immunity combines to get rid of the virus in about 7-10 days and the virus is gone. So, why do people suffer 14 days or more? Once the virus infects the cell, it triggers a series of events that are on-going and do not get switched off even when the virus is not around. The key in this is an inflammosome called NLRP3, which is a bunch of proteins that inside the cell activates a lot of different enzymes that break down a cell and release a substance called Cytokine Storm, recruit other cells, particularly white blood cells, and that further increase of the Cytokine Storm can cause tissue damage and therefore the host’s organs are severely damaged.
Now NLRP3 is part of a very ancient system that developed to deal with unwanted gases, particularly viruses. It is not unique to Covid-19, we see it in a lot of different areas where there is a significant amount of inflammation causing damage to the host body. Why do people some people get ill and some not very ill? It turns out that the NLRP3 system is quite heterogenous in how it works. There is an innate immunity that deals with the virus primarily and these have the ability to control viral infections by activating a lot of intra-cellular systems. But innate responses along with NLRP3 are most potent in terms of clearing out the virus by creating adaptive immunity and response. Now once NLRP3 is activated, it also has to be deactivated so as to prevent severe on-going damage. It turns out in those people who have a good innate response, a strong NLRP3 read for a capacity, they are less symptomatic, they develop immunity, they recover from it. On the other hand, individuals who have innate response but very weak ability to regulate NLRP3, these people have a severe reaction, they don’t develop a protective immunity. So, NLRP3 is key to understanding what Covid-19 does to the body. It is not so much the virus.
Now NLRP3 also activates IL-18 that recruits Macrophages, which are types of white cell very important in defence against the acting agents. They also tend to release very complex chemicals that can also cause a lot tissue damage. So, the best way to see whether the macrophages are activated is to measure the serum feratine, if it’s over 8000 you will know that the macrophages is activated and you will deal with the macrophage activation syndrome causing a lot of chemical release and severe organ damage.
The other thing that happens is that Covid-19 infects all of the blood vessels throughout the body. Once the blood vessels are infected, they are damaged and lot of the fluids inside leaks out of the blood vessel and this is particularly important because once the fluid leaks out of the blood vessel in the lungs, it prevents the lungs from functioning properly and your oxygen levels fall. This is the reason also why we call the multiple-level ground glass opacity, CT scans of lungs infected with Covid. We see dramatic drops in people’s oxygen levels. Once the entire vascular system is damaged, there is a lot of activation on vascular systems which leads to blood clots.
Now, the very interesting question here is, why do some people get sick and some people not get sick? Why is it that 90% people recover and some of the 10% die? To understand that we have to understand what is happening in bats because bats are the ecological niche of a lot of coronaviruses, SARS, MERS, Covid-19. Bats also have other viruses that are lethal like rabies virus and nipah virus. It turns out that in bats, the viral infections don’t activate NLRP3 as much as they do in mammals or humans. However, some human who get infected by these viruses have a severe NLRP3 activated inside the host and due to damage to organs, they die. So, ideally, the agent to be used is the one which can prevent excessive activation of NLRP3. Now, to a certain extent, Dexamethasone does attend the problem. Unfortunately, no anti-viral agents that we have tested today have done better than the host’s own immune system. The innate as well as adaptive immunity reduces the viral load essentially getting rid of more than 95% of the virus in 7-10 days.
There is a new compound that the research foundation has been talking about, that is 2Deoxy glucose, it is not exactly new, we have known about it for couple of decades, initially to combat cancer and it has shown efficacy for other virus especially but also in corona virus that causes acute diarrhoea in pigs. So, mechanistically, this agent will work as anti-viral because it disrupts the intracellular systems but it also dampens the NLRP3 response and therefore it has dual mechanism of action which may be very interesting. However, I would like to see a large clinical trial with thousands of subjects before I am going to accept 2Deoxy glucose as a proven regimen against Covid-19.
How do we prevent Covid from causing trouble in India? As we know that 75% of people still live in rural India. We have to think of options and strategies in area where there are no hospitals, no laboratory and very less healthcare staff. What we need to do is prevent Covid-19 becoming a bigger problem. We need to prevent Covid-19 from overwhelming our hospitals and our already over-stretched medical staff. The way we do that is to try and address Covid-19 in the community. Prevention has two different areas: one is credible information backed by solid evidence that we have to translate into the vernacular to make it easy to understand and then focus of disseminating it in every means possible and today we have lot of social media platforms that can help us. We have to promote vaccine acceptance. The other part is behavioural change, and the key here is ventilation. The most important thing is ventilation because fresh, uncontaminated air will help. This is why your ACs and other things people talk about is irrelevant. I open all the doors and windows no matter how hot it is in India.
If you can’t assure ventilation, the next important thing is masks and it is not necessary to use N95, simple cloth cotton masks will work as effectively, if you can you can double mask, wear all day long, wash and reuse. The other thing is physical distancing to breathe and live, and thereby reducing chances of super spreader. Hand hygiene is very important, sanitation is important and finally vaccination. We need to have a lot more vaccine, we have got to vaccinate over 85% of our population quickly before we have all sorts of variants that are completely immune to our vaccines. So, this is the key.
What we are suggesting here is each outreach worker should be armed with Pancha Astra;
Masks
Hand sanitizers
Oximeter
Dexamethasone [8mg daily]
Rivaroxaban [10mg daily]
Each one should look for the Pancha Guna, which are the signs of Covid because it is not always possible to get testing. Oxygen saturation testing at rest with exertion, look out for weight, Covid is likely to trigger the appearance of diabetes, and blood pressure needs to monitored. We also need to understand that any kind of public campaign needs to be a participatory action at the community level. So, that is why it becomes important to record the illness of the individual, family and society and we need to record the impact of Covid on the society. It is about the collateral damage, impact of livelihood that we are seeing that we will have to deal with for a long time. Also just as important, people who have recovered from acute illness, persistent lingering, severe disability that prevents them from earning their livelihood and we need to understand that support these people.
At MediCiti we have created a low cost Covid unit and we have lots of windows and they are all open. There is a lot of ventilation and fresh air. The patients get oxygen, Dexamethasone and blood thinners. The cost is Rs 1500 a day that includes meals. We need to focus on cost-effective way for care.
ROTARIANS ASK
Shouldn’t we have an epidemiologist heading our Covid drive in India rather than other doctors and do the rains wash away the corona virus which is airborne?
I have no comment on how the Covid response is being led in India, I think each one has their own perspective. Also, I am not sure that the virus being washed away is necessarily true because the rains will not change the amount of virus that is present in the air. So, ventilation is more important. What might help is sunshine.
Recently, we saw on CNN, Dr. Sanjay Gupta saying that it is possible that the virus was created in the lab of Wuhan. Comments.
So, the ecological niche of all the corona viruses that we know of is bats. They are the usual reservoirs of the nature. Now the way this has happened is in the past there has been an intermediary host for SARS it was civet cats and other mammals while for MERS it was camels. We don’t understand exactly what the intermediary host was in Covid-19. So, there is not enough data. People can speculate but I prefer to look at evidence which is that it is not a synthetic virus, it is a natural virus. The question is how did it get into the human population from bats? Is it possible that somebody playing with the virus in a lab inevitably cause the virus to leak into human population? And the concern that CNN has raised, investigation has been led by WHO was inadequate in answering that question, so, that is the status today as I understand.
“Unfortunately, no anti-viral agents that we have tested today have done better than the host’s own immune system. The innate as well as adaptive immunity reduces the viral load essentially getting rid of more than 95% of the virus in 7-10 days.” – Dr. Vijay Yeldani
What are the precautions one should take post recovery from the Covid infections, especially the ones who are in their 30s and 40s without vaccination and 60 plus with vaccination?
Stay on anti-inflammatory until all the symptoms go away and till their blood has normalised. Some take one week, some two, some three months. In every body post-acute sequelae of Covid-19, we need to evaluate them meticulously. Some of them have chest syndromes, some blood clots, some neurologic problems, memory loss, lack of sleep, etc. it is my feeling that a lot of these are persistent activation of NLRP3. And you can measure that, I think some of these people have on-going inflammation of blood vessels and you can measure that by looking at the CRP and also measure in other ways. So, if they have all that then I keep them on anti-inflammatory.
Which vaccine would you prefer?
I would suggest the first available vaccine is the best. Most are equivalent now and remember that the regulatory requirement is that the vaccine is tested at least 50% efficacy than placebo before being approved. Now why do we say one vaccine is 50% effective and another is 65%, or 90% is because a large part of that has to do with the time it was tested, what was the prevalence of the community and what is the magnitude of infections. So, they are not exactly clinically relevant to the extent that people take it out to be. So, the earlier you take the vaccine the better. The beauty of the Moderna, Pfizer platform is that it is easy to modify the antigenic requirements so, it is faster, simpler and cheaper to design the vaccine and produce in large quantities. So, that is the advantage of that platform. We don’t see any clinically significant differences in the vaccines, if they are they are very minute diluted out with the inherent and genetic heterogeneity of the population. Any vaccine will be 85% effective. So, individual differences between vaccines play insignificance.
What is the time frame of the vaccine? We heard that the booster dose will come out, in that case don’t you think the medical management will be far more important?
I think we don’t know how long the immunity will last. At present we will have immunity for 9 months under best circumstances, different people will have different level of immunity. One strategy is not going to work, we need to combine and strategize and focus on saving lives.
On what day should the steroids begin?
Dexamethasone and the dose that we use it really doesn’t not an immuno-suppressive effect and when we use Dexamethasone, we don’t use it in very early part of infection, we use it only and only when people are dropping oxygen levels. I have occasionally them even at times when people have lower oxygen levels and the ferritins are very high because I know by that time the Macrophages have been activated. It is important to understand the difference between anti-inflammatory dose and immune-suppressive dose of Dexamethasone. High dose steroids are immune-suppressive, we don’t need them, remember Covid-19 by itself is a profoundly immune-suppressive infection. I have a prejudice that those patients treated with very high steroids have a higher risk of getting Mucor mycosis or aspergillosis or TB. I think there is no advantage of giving anybody more than 6mg of Dexamethasone a day because then if it has not worked in a day with 6mg, you need to move on to other agents. I think high dose steroids are a mistake and should not be used. We have to be very selective to whom we given Dexamethasone. Is 2deoxy glucose going to be the answer? We will have to see.
We had the most definitive study by ICMR stating that the vaccine will help to minimalize the chances of infection but anecdotally with the rampant spread of virus, what are your thoughts on that?
It raises a lot of questions; how good the entire system was maintaining the cold chain and the efficacy of the vaccine? Even though the vaccine prevents serious illness we know that the vaccine produces but doesn’t eliminate the illness. But we also know that once somebody is vaccinated the chances of transferring that infection is reduced by 50%. So, even one does provide some immunity, optimally we still require two doses of the vaccines. It is an evolving field and this is first time in human history that within one year of discovery of a new pathogen, we have vaccines. Our attempt to control the pandemic by vaccination has questioned our capabilities in logistics, administration, social justice and almost any other facet of organisation.
There are cases where Covishield has created clots in some part of population, so, people with high PLT should they still take it?
It is a small number of people who get these clots and the mechanism appears to be that the vaccine triggers anti-bodies against platelets and that is why the platelets aggregate. Now can you screen people for that kind of people? I am not sure. That is not an area I am very well versed. What you need to do is to keep things in perspective. 15-20% of people with Covid get serious blood clots that kill them, 1% of women who take oral contraceptives get blood clots that kill them, the blood clots caused by vaccines are one in several million. So, it is very very rare. One can actually treat them with blood thinners.
Do you have any advice for people with low immunity to minimise the possibility of catching Covid and for people who have taken 2 shots of vaccines and a period after which the effect wears out and you need to go for a booster does, would that be the same kind or you can shift from one to another?
There seems to merging data about taking heterologous vaccine, there is no downside to it, maybe an upside. This is still evolving. What people can do to prevent? Avoid contact with anybody who is potentially ill, standard precautions, do not take high dose vitamins, it is very dangerous may lead to potential kidney stone problems. Do not take high dose Vitamin D.
