Conversations with an epidemiologist: Plasma therapy

(Over most of April and May, as the Covid-19 pandemic unfolded in India, growing from just a handful of cases to take region after region in its grasp, Dr T Jacob John, India’s foremost virologist, epidemiologist and researcher, spoke daily with Jagdish Rattanani, journalist and editor of Foundation of The Billion Press, to build what we call the COVID-19 diary)

Here, Dr John talks about a possible solution for severely ill patients that he says is right in front of our eyes, the low-hanging fruit of plasma therapy. ICMR might have wanted trials before it recommended the therapy, but really, every qualified doctor is vested with the right to use plasma therapy, says Dr John. And it being a safe treatment, there is nothing to lose from it.

 

Jagdish Rattanani: What are your thoughts on the treatment of COVID patients in India?

Dr Jacob John: This COVID-19 has no vaccine to prevent it, no antiviral to feed its patients. But there is an antiviral right in front of our eyes. It is neutralising antibody in convalescent serum, and it is in the serum of people who are test-positive, antibody-positive. It is antiviral.

Why are we not promoting or practising, popularising, convalescent plasma therapy, I do not know.

JR: Why might it not be practised?

JJ: My suspicion is that there is no evidence that anybody has shown (that it is effective in COVID) . . . but plasma therapy is a conventional therapy for many conditions. All the major hospitals use plasma for many diseases. It uses fresh frozen plasma, from a healthy donor.                                                   

So, when a COVID patient who is a senior citizen or a diabetic has acute respiratory distress syndrome, and is in the ICU or on a ventilator, and you see that one day, no improvement, two days, no improvement, three days, not doing well . . . that’s the time to give convalescent plasma.

JR: OK                                                                                                                      

Dr John: And if you gain enough experience from enough number of people . . . from enough number of doctors . . .  enough meaning, maybe twenty patients whom you do not expect recovery from because you have tried your best for two three days and they are not recovering . . .  If they recover with plasma, if the majority of them recovers – if one or two recover, then it’s no use – that is evidence to try plasma therapy even earlier. Do you understand that method?

There is an antiviral right in front of our eyes. It is neutralising antibody in convalescent serum, and it is in the serum of people who are test-positive, antibody-positive.

JR: Yes. But the only point would be that if it was as seamless as this, then they would have tried it elsewhere in the world. So, maybe there are barriers that we do not know of?

Dr John: If they had tried and failed, that would have been news.

JR: Yes.

Dr John: The Chinese have put in two papers, one on ten patients and one on five patients, and all of them recovered. All of them improved fairly immediately.

JR: OK.

Dr John: So, if doctors are waiting for true evidence, which would be a randomised placebo-controlled study, then that is not going to happen, because nobody is going to do a study right now, in the middle of fighting a war.

JR: Correct.

Dr John: So, what I am saying is, just do it and gain experience.

JR: So, I guess virologists around the world would have thought similarly, obviously, isn’t it so?

Dr John: I am one (a virologist) and I thought about it. I mean, if people had thought about it and didn’t see it as a good idea, then it would have been there in all the news that is coming out.                                                                                   

JR: Yes.

Dr John: But this has not come out. So I am, like, the one putting it in the news.

JR: I got your point.

Dr John: No medical journal will take this in a hurry. It will take a month, a month and a half. But the need (for plasma therapy) is today. We cannot wait for tomorrow.

JR: So, the thing is, once you have an idea you should put it out.

Dr John: You have to put it out. If you have a candle, you don’t put it under your bed, you put it on a candle stand, for others to see.

JR: Yes, absolutely. I want to ask you, is it correct or incorrect that this would require a good study of people who have got COVID and recovered and have antibodies?

Dr John: Yes yes. They are all known (recovered patients); whoever has been tested positive with COVID and has recovered, all over the country, have been registered. There will be 300 or 400 people.

Every major hospital has a plasma extraction machine, called Plasmapheresis Machine. It’s a routine process, every medical college will have it.

JR: So, should they all be called in?

Dr John: Take the younger ones, test their blood for Hepatitis-B, HIV and Hepatitis-C. They are clear. Get their informed consent for their blood plasma. Every major hospital has a plasma extraction machine, called Plasmapheresis Machine. It’s a routine process, every medical college will have it. They use plasma for so many other conditions.                                         

JR: So, how many can be saved by plasma from one recovered patient? Or, how many patients can it be used on?

Dr John: That depends on the antibody level.

JR: OK, and do we have the capacity to measure antibody levels in India?

Dr John: Ah… that is very important, I have been saying that we must have Immunoglobulin G (IgG) antibody testing, which is very simple to create.          

Wherever you have virology labs with this Biosafety Level (BSL-4) facility, like the National Institute of Virology in Pune, Bhopal, and Gwalior. They should get behind this… to create the antigen to capture the antibody.

JR: Which will take time, I guess?

Dr John:  It would take time, it may not be quickly.

Already, they are doing the Immunoglobulin M (IgM) antibody tests, that is called a rapid test.

JR: Right.

Dr John: It is simpler than the rapid test.

But the diagnostic test is different. We are talking about testing for past infection. If you cannot develop the antibody, then the COVID-positive people who have recovered and cleared a particular period of time after full recovery, say, one month, can be considered for plasma donation.

JR: Yes

Dr John: Because, the patient could have virus lurking in the body for a few more days after recovery. So, full recovery and one month’s margin, they are, say, below 15, healthy. Then their convalescent serum is good enough.

JR: OK

Dr John: You can keep a sample and measure antibody eventually. So, plasma from one donor to one patient, or you can divide the plasma into two and give it to two people. No more than that.                  

COVID-positive people who have recovered and cleared a particular period of time after full recovery, say, one month, can be considered for plasma donation.                                

JR: But still it would fall short, I mean, it would still be a difficult effort, would it not?

Dr John: If one person saved, it is one person saved.

JR: I agree, of course.

(A few days later . . .)

JR: The question that comes to my mind is, again, how is it that nobody in Italy, in France, in Germany, in Iran, in America, has thought of this and tried it already? How is that possible? Surely somebody has tried it? I will be amazed if no one has.

Dr John: Well, I have thought about it. The Chinese have thought about it. And the Chinese have given the treatment too. I mentioned those two studies, one on ten and the other on five patients. Whether they have pursued it, I will not know. I have no idea why, that is very low-hanging fruit, and no harm done. That’s why I am saying if there are people on treatment on the ventilator and you are now sure the patient is not going to recover, that’s the kind of patient whom you choose to give this.

That doesn’t do any harm, and this is a very safe treatment. One in a million have some problem. Dr M.S. Seshadri (Retired Professor of Medicine, CMC) and I have written about this in the Hindu.

And the interesting news is that a lot of people are volunteering to donate convalescent plasma.

JR: Yes

Dr John: So that means see one little idea put upfront in the newspapers . . .  it catches on. So, we have shifted the direction of the ship, from going towards randomized, controlled trials to experience-generating by giving a lot of patient plasma therapy and documenting their recovery rate. If the recovery rate is 100 per cent, nobody will argue that it is not effective. If it is 50 per cent, people will argue. So, anyway, a very interesting development in India . . giving the treatment with no trials. Others are, I think, doing trials. Even the United States, I think, is beginning to do some trials.            

To me that is problematic, that is unwise. That's the best word. Unwise. Because we know this plasma it is an antiviral fluid. I can’t call it a drug, and if you have antiviral fluid or access to it, then why don't you use it? I've suggested to an industry that there is a way of purifying the antibodies, the antibodies contained in what is called globulin, gamma globulin. So, you purify the gamma globulin of convalescent people. By that time, you will have antibody titres available. And so you standardize the titre or the quantum of neutralizing antibody in one vial of concentrated hyper-immune coronavirus, even globulin. You have another patient coming in, you take one bottle and shoot, that's it. He may not even go into respiratory failure.        

If there are people on treatment on the ventilator and you are now sure the patient is not going to recover, that’s the kind of patient whom you choose to give this.                                                     

That’s a readymade drug idea.

JR: Okay, trails, can happen later, then?

Dr John: Why do you need trials? Once you know something is good, it's good. I would agree if it was an unsafe procedure. You have to know the risk-benefit ratio of giving an unsafe procedure in a quasi-fatal disease. So, you have to evaluate the risk and benefits of giving an unsafe drug for a serious disease. But if the drug is safe there is no question of this because it is all benefit and virtually no risk.      

JR: Hasn’t WHO mentioned anything about this?

Dr John: This morning I read a piece, ‘WHO is wrong again’ was the title. Their first mistake was to say there was no evidence of person-to-person transmission when there was actually a person-to-person transmission cluster of pneumonia. The second was, the pandemic was not recognized, even when some countries and every continent was infected. They announced a pandemic on 11 March, which in my estimate was four or five weeks late.

Their third error was in saying that the mask does not benefit uninfected people. They said infected people should wear masks to help reduce transmission. Even doctors did not wear masks. So, that really was an unwise recommendation. Today, everybody understands the value of everybody wearing masks.

JR: So, what is the connection to plasma treatment?

Dr John: The latest mistake was WHO saying all recovered people may not have good immunity, that there is no evidence for all the recovered people having good immunity. Implying that a plasma donor may not have immunity. That gives a wrong message. So, I had to counter that by saying all people who recover from the infection must have immunity.

That is a given for all virus infections.

JR: And, therefore, you need to simply extend it to say it will be the same for this virus also.

Dr John: Exactly. However, the robustness and longevity may vary. But the assumption must be that all recovered COVID patients, even if you don't test for antibody, are assumed to be  antibody positive and that is the basis on which people are getting plasma therapy. The

Immunoglobulin E (IgE) antibody test is not yet available.                                                      

So, again, I'm saying that it is unwise for the WHO to say there is no evidence, therefore they assume that people may not have immunity. Okay, you could say that people are likely to have immunity, but the robustness and longevity, the height of the antibody, all these are unknown.

(a few days later)

JR:  Plasma therapy seems to be working?

Dr John: Today, I read the good news that in Max hospital, a fifty-year-old man was on ventilator and not recovering, and was given plasma therapy and showed improvement immediately . . .  dramatic. The second patient got it in Max hospital (in Delhi). Touch wood, the second patient also improved significantly. With that, Kejriwal has made an announcement. A senior ICMR officer called me and said, ‘Please watch television right now, Kejriwal is announcing that plasma therapy is to be the norm.’ Okay, that means Kejriwal is disagreeing with ICMR, which wants a study done before the policy is made.

But giving plasma is any doctor’s right. Once you're registered as a doctor, it's your right to give plasma. That is the line I took in our (Sheshadri and Dr John) article in the Hindustan Times. This is not the time to do a randomized control trial in which it is statistically necessary that half the number of patients not be given plasma therapy. So, I would expect or suspect that our paper emboldened, strengthened, the hands of the people who tried it.

So, that is good news.

JR: Yes. Even in Mumbai, the municipal commissioner has gone on record to say that they are getting many more plasma machines and they will try it out.

Dr John: Okay, they will fight out, right. That's good. Trying out, meaning, you begin with the worst patient. That's what Max hospital did. And, if the first one was a failure, nobody would try it again. We are fortunate that the first one was a success. Therefore, people will try more and more and the study can go on. But there is a problem with the study. The control group that is not going to get plasma . . .  their families will protest. So, I think we have thrown the monkey wrench into the study. But it's all good.

 

This is a consolidated wrap-all ("writethru" in The AP parlance) of daily conversations between Dr. T Jacob John, the eminent virologist and Jagdish Rattanani, Co-founder of The Billion Press, edited and themed for consistency of the subjects discussed. Some of the individual conversations are also listed on this site elsewhere, an endeavour that was abandoned as the conversations became too numerous to be transcribed, edited and reported individually. We believe the conversations capture a wealth of insight into how the Sars-Cov-2 pandemic was managed in the early days (or mismanaged).

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