Convalescent plasma for COVID-19: enthusiasm has outweighed the evidence


Hospitalised patients with moderate COVID-19 gain no benefit from convalescent plasma on progression to severe disease or mortality, new research shows.

The findings of an open-label RCT published in the BMJ further weaken any case for any effect of serum containing viral antibodies collected from people recovering from COVID-19 disease, coming on top of previously inconsistent and uncertain evidence.

For example, a Cochrane Systematic Review earlier this year could only conclude there was uncertainty regarding both efficacy and safety of convalescent serum.

The PLACID trial comprised 464 adults admitted to one of 39 tertiary care hospitals in India for treatment of moderately severe COVID-19.

All patients received the best standard of care available and dictated by institutional protocols and guidelines for the management of COVID-19.

The intervention group also received two doses of convalescent plasma (200 mL each, transfused 24 hours apart). Plasma was obtained from mostly young men who had recovered from mild COVID-19 disease. The median titre of neutralising antibody in transfused convalescent plasma was 1:40.

The primary outcome – a composite of progression to severe disease or all cause mortality at 28 days – occurred in 19% of the intervention group and 18% of the control group.

Deaths were reported in 15% of the intervention group and 14% of the controls.

In secondary outcomes, the study found that patients in the intervention group showed some improvement in shortness of breath and fatigue at seven days but no noticeable change in fever or cough.

Other outcomes such as the duration of respiratory support, the proportion of participants receiving invasive ventilation, and the proportion receiving vasopressor support did not differ between the intervention and control groups.

The study found negative conversion of SARS-CoV-2 RNA at day 7 post-enrolment was significantly higher in the intervention group than the control group.

However inflammatory markers such as LDH, ferritin, C-reactive protein and D-dimer were also similar in both groups.

“Additionally, outcomes did not differ between participants receiving convalescent plasma with detectable neutralising antibody titres compared with participants receiving best standard of care alone; or between those receiving convalescent plasma with neutralising antibody titres of 1:80 or higher and those receiving best standard of care alone,” the study said.

They concluded there was no benefit from convalescent plasma being administered within three days of symptom onset in COVID-19.

An accompanying editorial in the BMJ praised the quality of the PLACID trial.

“The PLACID Trial was a rigorous randomised controlled study on a topic of enormous global importance, ethically designed and implemented given the contemporaneous state of scientific knowledge about SARS-CoV-2. With publication of the findings, the bar has been raised for all ongoing and future trials.”

The author, US population health scientist Dr Elizabeth Pathak, agreed the study showed convalescent serum offered no net clinical benefit to COVID-19 patients.

However she made recommendations for any future research on convalescent serum:

  • the potential harms of the non-immune components of convalescent plasma should be rigorously investigated, especially prothrombotic risks
  • only donor plasma with detectable titres of neutralising antibodies should be given to trial participants, to ensure that the potential for benefit exists for all intervention arm patients.
  • double blind designs with sham procedure controls should be the gold standard for future trials. Low risk sham procedures can be ethically acceptable under prescribed conditions.

“The desperation engendered by COVID-19 demands that we strongly resist the urge to succumb to pandemic research exceptionalism,” she said.

“High quality clinical research must be an integral part of a coordinated international response. Low quality research not only wastes scarce resources, it is also inherently unethical.”

Two trials of convalescent are underway in Australia using plasma donations made by recovered Australian COVID-19 patients via Lifeblood.

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