Here is why the ICMR study that found plasma therapy ineffective on Covid is being questioned

ICMR did not look for presence of neutralising antibodies, which fight off infection, as tests to detect their presence were unavailable when the study was launched in April.

The administration of plasma therapy at the Institute of Liver and Biliary Sciences in New Delhi. | Photo: Manisha Mondal | ThePrint

New Delhi: India may be contemplating removing plasma therapy from its Covid-19 clinical management guidelines, but questions remain on the study conducted by the Indian Council of Medical Research (ICMR), based on which the decision is being taken. 

The ICMR had conducted a trial, called PLACID, involving 464 Covid patients in 39 hospitals across the country, and concluded that plasma therapy was ineffective in reducing Covid-19 mortality. It is the largest convalescent plasma (CP) therapy trial in the world to be completed.

The trial, however, did not look for the presence of neutralising antibodies before transfusing blood plasma of patients who had recovered from Covid. That is because reliable tests for neutralising antibodies were not available in India when the study was launched on 22 April. 

A virus or a bacteria in the body can generate different kinds of antibodies, which fight off the infection, depending on which antigen has triggered their production. 

Antibodies against the SARS-CoV2, for example, can be either against its nuclear protein or against the spike protein. It is only the latter that have a protective effect, and are known as neutralising antibodies (NAb). 

The test for whether NAbs are present or not comes in two steps — first the antibody levels are measured and then in a more complicated process, usually done in a laboratory with BSL (biosafety level)-3 clearance, a test is done to find out whether the antibodies are neutralising or not. It is only recently that some kits have started coming in for the test but they are not 100 per cent accurate.

‘No tests available at start of trial’

The ICMR trial itself admits that when the study was launched, there were no tests available to detect the presence of Covid NAbs. 

“At least 20 mL of the donated plasma was stored at -800C for measurement of SARS-CoV-2 NAb titres, as reliable and approved qualitative and quantitative tests were not available at the time of initiation of the study,” reads the preprint paper on the findings of the PLACID trial site MedRxiv. 

“Commercial qualitative immunoassays for SARS-CoV-2 antibodies on chemiluminescent immunoassay or enzyme-linked immunosorbent assay platforms approved by the ICMR became available halfway through the trial. Once available, sites were encouraged to use them before collection of CP,” it adds. 

After peer review, the paper has now been accepted for publication in the British Medical Journal (BMJ).

Speaking to ThePrint, one of the authors of the study said: “We did a test for NAbs but that was post transfusion. The samples were tested in batches after being sent to the National Institute of Virology in Pune. Initially we had measured the antibody titre and transfused. We chose the donors as per the FDA specifications such as age, lack of comorbidities, time since recovery etc.” 

Asked how the trial came to the conclusion that plasma therapy was ineffective despite the fact that the plasma was not tested for the requisite antibodies, the scientist said: “In many other trials including one in the US with 35,000 patients, NAbs were not checked for before transfusion.”

The ICMR’s findings, without being certain whether the right kind of antibodies had been administered, have not gone down well with many in the scientific community. 

“I am shocked that they published this paper. What kind of publication is this when it is not scientifically sound,” said Dr Ashok Rattan, a microbiologist who retired from AIIMS as an additional professor and currently works for Pathkind Labs. 

“There are tests available now in the country — at least 11 vendors sell them in India — when the presence of NAbs can be found out. Yes, it is expensive but that cannot be a deterrent when this is going to be the basis for taking a policy decision,” he added. “We have known about neutralising antibodies for years and a Chinese study clearly showed that only them and not all antibodies are therapeutic in Covid. To do such a study in 2020 defies logic.”  

The tests Rattan was referring to are the commercial qualitative immunoassays for SARS-CoV-2 antibodies on chemiluminescent immunoassay or enzyme-linked immunosorbent assay platforms mentioned in the preprint paper.

The young patient conundrum

Both Rattan and the ICMR scientist quoted above admit that there is a fundamental problem in conducting a CP trial without specifically checking for NAbs. 

A person who has had a more severe disease is more likely to have neutralising antibodies. But a donor is more likely to be a young and fit person who is most likely to have been asymptomatic when infected, which makes the chances of finding NAbs less. 

“Not everybody produces neutralising antibodies. Only those who have a severe infection produce it,” Dr Rattan explains. “But when you do a trial, it is more likely that your donors would be young people who are more likely to have been asymptomatic. It is proportionately less likely they have NAbs.” 

The study author too accepts that this is an issue. “But we had to design the study based on our realities. This is called pragmatic study design,” said the senior ICMR scientist.

Used on many politicians

Plasma therapy has been approved for “off-label” use by the Drugs Controller General of India (DGCI), which means the hospitals may charge patients for it.

It has been administered on several ministers — among them Satyendra Jain and Manish Sisodia in Delhi and Union Minister Shripad Naik in Goa. All have recovered. 

Both Jain and Sisodia had undergone the process at Max Hospital in Delhi under Dr Sandeep Buddhiraja. The private hospital in fact, according to sources, has conducted over 200-odd CP procedures so far “with very good results”. 

Buddhiraja, however, did not respond to repeated calls and messages from ThePrint specifically on the question of NAbs. 

Dr Anjan Trikha, professor of anaesthesiology, pain and critical care at AIIMS, said: “There are about 5 laboratories in the country including NIV that can check for NAbs. You need a BSL-3 laboratory. Logically, convalescent plasma should work. Theoretically, all doctors should administer it after checking the antibody titre and then the level of neutralising antibodies. However, this may not be possible. during pandemic times in our country.”

He added: “Plasma needs to be administered at the right time of the disease per se. If you ask my experience, I can show you some patients where plasma worked in my opinion but at the same time I can also show you many more patients where it did not. In our institution, plasma has always been administered scrupulously with the consent of the patient with the clarity that it is an experimental therapy.

Trikha also explained the sudden popularity of CP because of its safety profile, especially in the early days when nothing seemed to be working. He said there are three things that clearly work in Covid. “These are oxygen therapy, steroids and heparin.” 

Asked how plasma therapy always seemed to work in celebrities and whether as a special case it is possible that in those cases the NAb assessment is actually done before administration, a senior doctor at a private hospital said: “That, or they would have recovered anyway.”