Plasma Therapy Ineffective in Reducing COVID Mortality: ICMR Study
Plasma therapy has been approved for off-label use for COVID treatment in India. Will the clinical protocol change?
A multicentric study by the Indian Council of Medical Research (ICMR) has revealed that the use of convalescent plasma therapy in COVID-19 patients does not help in reducing deaths or preventing disease progression.
The researchers aimed to evaluate its effectiveness for coronavirus patients in the largest such randomized controlled trial, even as the therapy has been actively pushed as a treatment option in the country. On August 23, the US Food and Drug Administration also issued an emergency use authorization for plasma therapy as a COVID-19 treatment.
What the ICMR Study Found
The open-label, parallel-arm randomized controlled trial, called PLACID, was conducted in 39 hospitals across India from April 22 to July 14. A total of 464 moderately ill hospitalised patients with COVID-19 were enrolled, of whom 235 were given convalescent plasma along with best of standard care while 229 received only standard care.
"Composite primary outcome was achieved in 44 (18.7 per cent) participants in the intervention arm and 41 (17.9 per cent) in the control arm. Mortality was documented in 34 (13.6 per cent) and 31 (14.6 per cent) participants in intervention and control arm, respectively," the study mentioned.
The study has not been peer-reviewed yet and has been published in the preprint server medRxiv.
Plasma therapy has been approved for ‘off-label’ use by the Drugs Controller General of India under ‘investigational’ therapies.
“This authorization has been paralleled by questionable practices such as calls for donors on social media, and the sale of plasma on the black market with exorbitant price tags in India.”Study authors
As hospitals and family members of patients continue to request plasma donations, and states in the country set up plasma banks to ease the process, does this study - the world’s largest randomized control trial on this treatment so far - warrant a change in the clinical management protocol outlined by the ICMR?
The Problems of Plasma Therapy
Convalescent plasma treatment is an investigational therapy for off-label use in coronavirus infected patients. In this, antibodies from the blood of patients who have recovered from coronavirus are used to treat severely infected COVID-19 patients.
Dr Sumit Ray, a senior consultant of Critical Care Medicine at Holy Family Hospital, told FIT in an earlier interview,
“The theoretical benefit of plasma therapy is in helping boost immunity if not enough is developed in the patient. But, the problem with COVID-19 is not an inadequate immune response, but in severe patients, the immune response goes haywire.”Dr Sumit Ray
Our immune system works in complicated ways, and the issue with COVID is that it is causing patients to have a dysregulated immune response rather than no immune response at all.
“A study from the Netherlands showed that 76 per cent of COVID-19 patients already had antibodies, so what is the point of giving more antibodies through plasma therapy?” asks Dr Ray. “The problem with COVID is not antibodies but a messed up immune response.”
This means that at best, plasma therapy is not getting at the crux of the problem.
At worst? It could have harmful side effects that can prove dangerous.
One of the oft-repeated lines about plasma therapy is that it has been used in other diseases and therefore is safe. “But all diseases are not the same,” says Dr Ray. “Here you are giving plasma (which increases clotting) for a disease which is procoagulant or prone to causing clots.”
Convalescent plasma was used in certain diseases where the immune response was poor or antibodies were not produced. It has a long history (“of a 100 years”, says Dr Ray), especially when there were no antibiotics for certain infections.
“Viral infections rarely have convalescent plasma - Ebola it did not work. The grounds on which it stood is itself very weak.”
Dr Ray explains that the problems are three-fold.
- First - “COVID is primarily a respiratory disease, and plasma treatment can often cause TRALY or transfusion-related acute lung injury. So if there is already lung damage due to COVID, and you give plasma which can cause - in a subset- further lung damage.”
- Second - “Plasma therapy is normally given to increase clotting of the blood but in COVID-19 more clotting is already a problem - a pro-thrombotic state is on and we are giving blood thinners for the same,” says Dr Ray. So giving blood thinners and then plasma seems counter-intuitive for COVID-19 patients.
- Third - “There are adequate antibodies, and so giving plasma is not needed.”
An interim analysis of a randomised controlled trial on convalescent plasma therapy done at AIIMS, Delhi, had found that the treatment does not reduce the risk of death in COVID-19 patients, The Times of India reported.
Dr Neeraj Nischal, associate Professor in the department of medicine at AIIMS, had said that the findings highlight that relatives of the patients should not insist on plasma therapy until and unless the treating doctor considers the patient fit for it and where they may think that the mode of treatment would be beneficial.
"This therapy also carries risks such as inadvertent transfer of blood-borne infections and reactions to serum constituents, including immunological reactions such as serum sickness, that may worsen the clinical condition," Dr Nischal said, according to a PTI report.
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