The ICMR recently revised the guidelines for the usage of convalescent plasma for treating COVID-19, following the Centre's protocol revision. This article covers details on why plasma therapy has been deemed ineffective and how it is further contributing to the problem via the subsequent emergence of viral variants.

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In a pandemic, treating a patient with just the bare minimum is challenging and complicated. The impetus to ‘do something' may push doctors to create recommendations for un-evidenced medicines that are either thought safe or have shown potential in animal trials or theoretical models based on biological pathways. Clinicians mostly think- 'Let's give it our all, even if it doesn't succeed, there would not be much left to lose.’

Several SOS requests have been circulating on social media, desperately looking for plasma treatment. But plasma therapy often takes a toll on an increasingly overburdened healthcare system. A donor must first donate plasma, which must then be checked for antibody strength before being given to a patient. Moreover, plasma therapy's unregulated use could possibly produce new virus strains, which is a major source of concern.

How does plasma therapy produce new virus variants?

SARS-CoV-2 spike protein engages human ACE2 protein1 and is the main antibody target. Using in vitro techniques to identify the mutations discovered by sequencing, indicate that chronic infection with SARS-CoV-2 contributes to viral evolution and decreased susceptibility to neutralising antibodies in an immunosuppressed person treated with convalescent plasma. In vitro, the spike double mutant had a slight reduction in immunity to convalescent plasma while retaining infectivity levels comparable to the wild-type virus.

The spike replacement mutant D796H proved to be the primary cause of the reduced resistance to neutralising antibodies, but it also caused an infectivity deficiency. The spike deletion mutant H69/V70 had two times the infectivity of wild-type SARS-CoV-2, presumably compensating for the D796H mutation's decreased infectivity.

These findings suggest that SARS-CoV-2 is subjected to heavy selection during convalescent plasma therapy, which is linked to the appearance of viral variants with decreased resistance to neutralising antibodies in immunocompromised people.

Convalescent plasma has not been shown to be clinically effective in patients with severe COVID-19, and its use at various levels of infection and disease stays experimental; as such, it is proposed that it be used only in clinical trials with rigorous control of clinical and virological specifications.

The findings suggest that vigilance should be exercised when convalescent plasma therapy is used in patients with combined T and B cell immunosuppression. In these patients, the administered antibodies receive no assistance from cytotoxic T cells, decreasing the likelihood of clearance and potentially increasing the possibility of SARS-CoV-2 escape mutation progression. While additional data are awaited, convalescent plasma administered for clinical need in immunocompromised individuals can ideally be viewed only as part of observational studies conducted in single-occupancy rooms with enhanced infection-control precautions, involving environmental sampling for SARS-CoV-2 and real-time sequencing.

Awareness of viral dynamics and characterising viral evolution in response to various selection pressures in an immunosuppressed person is needed not just for better patient care but also for public health advantage.

The experimental discovery of these viruses' twofold decreased resistance to convalescent plasma containing polyclonal antibodies supports a recurrent evolutionary reaction by SARS-CoV-2 in the presence of antibody therapy during the duration of a chronic infection in an immunocompromised host.

The results of convalescent plasma on virus evolution discovered here are unlikely to be applicable in immunocompetent hosts, where viral diversity is likely to be lower due to improved immune regulation. These findings suggest that infection management strategies may need to be adapted to the requirements of immunocompromised patients.

Plasma therapy's myth- A growing body of evidence arguing against plasma therapy

The researchers behind a Maharashtra state trial for plasma therapy in chronically ill patients with COVID-19 announced in early January 2021 that they had prematurely abandoned the trial after discovering a higher incidence of mortality and clotting in the intervention group. It came after the ICMR conducted a randomised controlled trial of over 450 moderately ill COVID-19 patients, which found that the intervention was ineffective for moderately ill patients.

The ICMR advised against using plasma in moderately to seriously ill patients who had been sick for longer than 10 days, who had immunoglobulin G in their bodies, which is believed to manifest in the body around the same time as neutralising antibodies. This should have put a stop to plasma usage in India, but the only patients on which plasma seems to function are mildly ill, and almost all of these patients improve on their own.

Plasma therapy is still widely practised in areas of India, but there is increasing data against what was once thought to be one of the most effective therapies in the early stages of the pandemic.

Plasma treatment did not reduce mortality of chronically ill patients, according to an Argentinian review presented in the New England Journal of Medicine in November 2020. After an immunocompromised patient was treated thrice with plasma therapy for COVID-19, a review published in December 2020 indicated that the B.1.1.7 mutant first found in the United Kingdom had gained mutations that help it escape human antibodies. After researchers discovered no change in mortality between plasma participants and controls in the more than 10,000 individuals randomised to the study, the UK's RECOVERY trial shut recruitment to its plasma arm in January 2021.