To Use Or Not To? Indian Doctors Confusion Over Plasma Therapy Worsens After ICMRs Doubts

At Mumbai ’s state-run St George Hospital, a team of doctors overseeing the treatment of former Maharashtra chief minister Devendra Fadnavis , who recently contracted Covid-19 , could not reach a consensus on whether to give him the convalescent plasma therapy or not. While a few doctors felt it was no good, others in the team strongly rooted for it. Fadnavis eventually received two units of plasma, 200 ml each. 

In the same part of the city, doctors from the Bombay Hospital treating Union Minister Ramdas Athawale decided to leave out the plasma therapy completely. While Fadnavis’s symptoms were in the mild to moderate range, Athawale had a moderate to severe form of Covid-19 with persistent fever and oxygen desaturation. “At one point in time, we did discuss if plasma would help but we had seen no benefit from it in the past,” said one of the doctors treating Athawale, on condition of anonymity. 

As the coronavirus pandemic raged through the country, convalescent plasma therapy had brought some hope for the medical fraternity who rely on different, investigational treatments to stop patients’ condition from worsening. The translucent yellow fluid, extracted from the blood of recovered Covid-19 patients, is rich in antibodies. When transfused to patients fighting the infection, the hope is that it will play the role of an antiviral drug. States such as Delhi have set up plasma banks for people to donate plasma after recovery. 

But eight months into the pandemic, plasma therapy remains one of the most fiercely contested treatment approaches. The divide in the medical fraternity has now further deepened with the Indian Council of Medical Research (ICMR ) contemplating dropping it from the national clinical management protocol for Covid-19. While some doctors say they have not seen any benefits from the therapy, others think that shutting off the limited options available to them is counter-productive. The biggest sufferers from this confusion are patients and their relatives, who often run from pillar to post scouting for the scarce blood product. 

The therapy has been widely debated in the US as well. Backed by President Donald Trump , the drug regulator granted emergency use authorization for the treatment but the country’s National Institutes of Health has advised caution over its use. When Trump tested positive for Covid-19, he received an experimental antibody drug on compassionate grounds. 

“We have stopped giving plasma unless the patients or relatives insist,” said Dr. Gautam Bhansali, a consultant physician from Bombay Hospital.

Questionable benefits

“It’s difficult to say what treatment played what role,” Fadnavis told HuffPost India on Tuesday, a day before he was discharged from the hospital. Fadnavis, the BJP’s Bihar election in-charge, said that plasma therapy was a part of the composite treatment administered to him. “At least, I can say that there was no adverse effect of plasma on me. Only my doctors can ascertain how much it helped,” he said. Hospitalised since October 24, he said that the overall treatment regimen had helped him recover faster. 

Fadnavis was transfused with the first unit of plasma on Day 2 of his hospitalization. By then he was already on Remdesivir, another repurposed drug that has received emergency use authorization for Covid-19. A doctor overseeing his treatment said that early transfusion of plasma had ensured that the politician’s condition did not deteriorate. But another doctor on the team said that “plasma transfusion this soon was questionable”.

The ICMR’s discussion on the removal of the therapy from the treatment protocol is based on the findings of its own PLACID trial that was conducted in 39 public and private hospitals across the country from April to July. It enrolled 464 moderately ill patients—235 in the intervention arm who received plasma along with other standard-of-care and 229 in the control arm who received just the standard of care. The findings showed no association of convalescent plasma with ‘reduction in mortality or progression to severe Covid-19’. However, the therapy was associated with a higher resolution of symptoms such as shortness of breath and fatigue on Day 7. The results of the ICMR-funded trial are similar to studies conducted in China and the Netherlands, both of which did not show any mortality benefit.

Dr. Bhansali from Bombay Hospital said that there was no positive or noteworthy development in the 15-odd patients he had treated with plasma. According to him, the treatment also puts patients at the risk of transfusion-related acute lung injury, which may be more devastating. “Why put patients at a new risk unnecessarily, when the benefits from the therapy are nil?” he said.  

The level of antibodies in the donor’s plasma also plays a key role. “Plasma taken from a patient who has recovered from critical Covid-19 symptoms is likely to be beneficial as it will have a high level of antibodies,” said Dr. Bhansali. 

However, tests that measure the level of neutralizing antibodies in the plasma are not available widely. Neutralizing antibodies are the ones that help defend the patient from the disease. 

The PLACID trial, for example, estimated neutralizing antibody titers of the donor and recipient plasma after completion of the trial.  “We generally look for a value of more than 6 or 9 as a cut-off when the antibodies are tested through the commercially available kits that measure binding and not neutralizing antibodies. But that’s not the best way,” said infectious disease specialist Dr. Tanu Singhal from Kokilaben Dhirubhai Ambani Hospital. “The neutralizing antibody titer tests are much better but we don’t have access to those kits,” she said. 

Dr. Singhal too has started using the therapy very selectively. “Patients who don’t respond to corticosteroids or are immunocompromised are likely candidates. We ensure that the baseline antibodies in the recipients are negative before giving plasma”.

Timing is key 

Despite apprehension from the ICMR, Maharashtra, which remains the worst-affected state in India, has decided to throw its weight behind plasma therapy. The state’s medical education department initiated its own trial called PLATINA, which is analyzing the therapy on severe Covid-19 patients. Even the state’s Covid-19 task force has endorsed the therapy. 

“Plasma definitely works. It has to be timed properly,” said Dr. Om Srivastava, a member of the task force who was also a principal investigator for one of the Mumbai sites of the ICMR trial. “No therapy in Covid-19 works at a later stage. We have to intervene at an early stage to arrest the severity or to prevent a cytokine storm that is triggered,” said Dr. Srivastava. He said that there is plenty of anecdotal experience of doctors who have found good results. He has used the therapy in over 70 patients and found it beneficial. 

Then why did the PLACID trial yield such contesting results? “It’s not a simple black-and-white statement to make. What is needed is a restructuring of the trial,” he said. Dr. Srivastava, along with other key members of the task force, are now in the process of registering their own investigator-led study to establish the efficacy of plasma. 

High demand 

Last month, Mumbai-based chartered accountant Ketan Parekh widely circulated an appeal to get plasma for his 65-year-old father battling the coronavirus. Within a day, Parekh received four B+ donors. Two of them qualified for the donation after the tests. “The doctors had tried all the available drugs including Remdesivir and Tocilizumab, but there was no recovery. But 24 hours after the plasma transfusion, my father showed improvement,” said Parekh. “He went off the Continuous Positive Airway Pressure (CPAP) machine, a type of non-invasive ventilator, the very next day,” he added. 

In mid-June, ICMR had allowed such off-label use of plasma under the national treatment protocol. As the demand skyrocketed post-June, appeals on social media asking for donors became common. In absence of a cap on costs, hospitals and blood banks began charging hefty sums for the plasma units. The price for each unit has now been capped at Rs 5,500. 

JB Mantri, joint commissioner, Food and Drug Administration, Maharashtra, said that the state has 111 private and public blood banks equipped with the plasmapheresis machine required for separating the plasma from the blood. Many of these machines were bought with the state government funds under project PLATINA. 

A careful selection of donors and recipients is the key, said Dr. Mohammed Faisal, Maharashtra’s coordinator for the PLATINA trial. Unfazed by the ICMR trial findings, Dr. Faisal said that the PLATINA trial will continue till its logical end. “The trial is a scientific study and we have to complete it. What may be affected is the off-label use of plasma if the ICMR decides to drop the therapy from the treatment protocol,” said Dr. Faisal.  If the permission for off-label use is revoked, patients can get plasma only under a trial. 

Doctors, even those who have not found much promise in the therapy, feel that such a decision will only tie their hands. “Why close down doors when only limited options are available to us for treating patients?” asked pulmonologist Dr. Jalil Parkar from Lilavati Hospital in Bandra. “The clinical acumen of the physician, signs, and symptoms of the patients and the laboratory investigations are key to turn around the progression of the disease with the help of the available drugs and therapies. ICMR should not chain the doctors down,” he said.