#15,515
For the second time in only a week, a major clinical trial has cast doubt on the effectiveness of a potential treatment for COVID-19. Last Friday, in WHO Solidarity Therapeutics Trial: Remdesivir, HCQ, Lopinar/Ritonavir & Interferon Disappoint, we saw that 4 highly touted drug therapies were found to have `. . . had little or no effect on 28-day mortality or in-hospital course of illness.'
While there have been some criticisms lodged over the design of those trials, particularly from the drug manufacturers, and other (albeit, smaller) clinical trials have shown slightly better results, this was nevertheless a setback for the treatment of COVID-19.
The `other' major therapeutic under investigation has been the use of convalescent plasma, retrieved from COVID survivors, and infused into acutely ill COVID patients. This plasma would theoretically contain enough antibodies to help the recipient fight the infection.
Although often effective, a relatively high percentage of adverse reactions (serum sickness) along with the development of effective antibiotics and drugs, has seen its use decline.Human and animal serum therapy was used extensively during the first half of the 20th century to treat a variety of infectious diseases, including anthrax, scarlet fever, measles, tularemia, diphtheria, rabies and pandemic influenza.
Convalescent plasma could, theoretically, be used as either a treatment for someone already infected, or as a temporary prophylactic, to prevent infection.
Over the past decade we've seen some promising - albeit, mostly anecdotal - results (see 2011's CID Journal: Convalescent Plasma Therapy For Severe H1N1, 2015's Int J Infect Dis: Convalescent Plasma Treatment Of An H7N9 Patient In China), and even some early media reports on Convalescent Plasma treatment of COVID-19 in China.
But when tested under clinical trial conditions, we've seen some high profile failures.
A little over a year ago, the Lancet: Clinical Trial On Use of Convalescent Plasma To Treat Severe Influenza disappointingly found that `High-titre anti-influenza plasma conferred no significant benefit over non-immune plasma' and 2016's NEJM: Evaluation of Convalescent Plasma for Ebola Virus Disease in Guinea, reported no statistically significant improvement in survival over the control group.
Attempts to use convalescent plasma against MERS-CoV, another coronavirus, have also hit obstacles.
A clinical trial NCT02190799 for Anti-MERS-CoV Convalescent Plasma Therapy was attempted in Saudi Arabia, but was never completed due to logistical and technical problems. A 2016 EID Journal report - Feasibility of Using Convalescent Plasma Immunotherapy for MERS-CoV Infection, Saudi Arabia - cited numerous challenges to using this treatment.
Some of those hopes were moderated over the summer, however, when a major Dutch Convalescent Plasma Study For COVID-19 was Halted For Redesign.Despite these past disappointments, convalescent plasma continues to be held out as a promising treatment for COVID-19.
Last July Marion Koopmans, a world renown virologist and head of the Erasmus MC Department of Viroscience - and who also happens to be one of the researchers conducting a clinical trial (see NCT04342182 Convalescent Plasma as Therapy for Covid-19 Severe SARS-CoV-2 Disease (CONCOVID Study) (ConCoVid-19)) - posted the following on her twitter account:
It seems that by the time most of the study group had become sick enough to be hospitalized, they had already developed antibodies against SARS-CoV-2, meaning that giving them convalescent serum was redundant and/or too late to have much effect.
Since then we've seen little hard data on the effectiveness of convalescent plasma, although a number of clinical trials are ongoing.That is, until yesterday's clinical trial research paper in the British Medical Journal (BMJ), which casts further doubt on the effectiveness of this treatment for COVID-19 patients, finding that it ` . . . was not associated with a reduction in progression to severe covid-19 or all cause mortality.'
From the study's summary:
What is already known on this topicAs of October 2020, multiple small case series, one large observational study (>35 000 patients), and three randomised trials have been published on the utility of convalescent plasma to treat coronavirus disease 2019 (covid-19)Although the observational studies suggested clinical benefits in recipients of convalescent plasma, the trials were stopped early and failed to ascertain any mortality benefit from convalescent plasma treatment in patients with covid-19
What this study addsIn settings with limited laboratory capacity, convalescent plasma does not reduce 28 day mortality or progression to severe disease in patients admitted to hospital with moderate covid-19Convalescent plasma treatment was associated with earlier resolution of shortness of breath and fatigue and higher negative conversion of SARS-CoV-2 RNA on day 7 of enrolmentAs a potential treatment for patients with moderate covid-19, convalescent plasma showed limited effectiveness
BMJ 2020; 371 doi: https://doi.org/10.1136/bmj.m3939 (Published 22 October 2020)Cite this as: BMJ 2020;371:m3939
Linked Editorial
Convalescent plasma is ineffective for covid-19
Anup Agarwal, consultant1, Aparna Mukherjee, scientist E1, Gunjan Kumar, scientist C1, Pranab Chatterjee, scientist B1, Tarun Bhatnagar, scientist E2, Pankaj Malhotra, professor3 on behalf of the PLACID Trial Collaborators
Correspondence to: A Mukherjee aparna.sinha.deb@icmr.gov.in
Accepted 12 October 2020
Abstract
Objective To investigate the effectiveness of using convalescent plasma to treat moderate coronavirus disease 2019 (covid-19) in adults in India.
Design Open label, parallel arm, phase II, multicentre, randomised controlled trial.
Setting 39 public and private hospitals across India.
Participants464 adults (≥18 years) admitted to hospital (screened 22 April to 14 July 2020) with confirmed moderate covid-19 (partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO2/FiO2) ratio between 200 mm Hg and 300 mm Hg or a respiratory rate of more than 24/min with oxygen saturation 93% or less on room air): 235 were assigned to convalescent plasma with best standard of care (intervention arm) and 229 to best standard of care only (control arm).
InterventionsParticipants in the intervention arm received two doses of 200 mL convalescent plasma, transfused 24 hours apart. The presence and levels of neutralising antibodies were not measured a priori; stored samples were assayed at the end of the study.
Main outcome measure
Composite of progression to severe disease (PaO2/FiO2 <100 mm Hg) or all cause mortality at 28 days post-enrolment.
ResultsProgression to severe disease or all cause mortality at 28 days after enrolment occurred in 44 (19%) participants in the intervention arm and 41 (18%) in the control arm (risk difference 0.008 (95% confidence interval −0.062 to 0.078); risk ratio 1.04, 95% confidence interval 0.71 to 1.54).
ConclusionConvalescent plasma was not associated with a reduction in progression to severe covid-19 or all cause mortality. This trial has high generalisability and approximates convalescent plasma use in real life settings with limited laboratory capacity. A priori measurement of neutralising antibody titres in donors and participants might further clarify the role of convalescent plasma in the management of covid-19.
Trial registration Clinical Trial Registry of India CTRI/2020/04/024775.
The BMJ editorial, which also raises concerns over the safety of plasma therapy, can be read at:
Convalescent plasma is ineffective for covid-19
BMJ 2020; 371 doi: https://doi.org/10.1136/bmj.m4072
(Published 22 October 2020)Cite this as: BMJ 2020;371:m4072
While it is possible that other clinical trials will show better results, it seems unlikely that convalescent plasma will be the COVID-slayer that some of its more vocal proponents have suggested.
But for now - except for dexamethasone (see JAMA study) - the pharmacological cupboard for COVID-19 remains distressingly bare.It might still have a role if administered very early in one's infection, or as a prophylactic, assuming the safety concerns can be eliminated.
