Updated 20 May, 2021
In less than a year, convalescent plasma, a treatment for COVID-19 patients, has been the subject of four Cochrane reviews. Updated as a living systematic review, the authors have gone from investigating this as an exciting and promising treatment to ‘closing the book’ on it and confirming it has no benefit as a lifesaving treatment for hospitalised patients. We speak to lead author Vanessa Piechotta, from University Hospital Cologne about the review and her experiences.
What is convalescent plasma, is it a new approach? Why was there so much excitement about this treatment option at the start of the pandemic?
Convalescent plasma has been used since the 19th century and has been shown to be an effective treatment for other viral infections, such as SARS (Severe Acute Respiratory Syndrome), Ebola, and influenza. The intervention is based on the ability of our immune system to form antibodies against a virus, when fighting an infection. Individuals who have recovered from their infection carry the virus-specific antibodies in their blood plasma. The hope and hypothesis were that the plasma from recovered people - convalescent plasma - can treat COVID-19 disease through a process called passive immunisation, i.e. by supplying antibodies against the novel coronavirus SARS-CoV-2 from people who have already recovered from COVID-19, to boost the recipient’s immune system, and help clear and render harmless viral particles.
The first version of the review was published in May 2020. At that point there was very little in the way of randomised evidence so you included other study designs, tell us why you included those and would you make the same decision again?
At the inception of our review, convalescent plasma was discussed around the world and the first case reports published suggested a miraculous effect. We decided to include any available evidence (which was not very much at that stage) to provide a rigorous and critical appraisal of the studies being published. We felt it was critical to provide policy makers and the global public with a reliable evidence base for decision-making, and the evidence at that time simply said nothing about the safety or effectiveness of convalescent plasma therapy. Even today, we have little information from randomised controlled trials regarding the safety of convalescent plasma, and large observational studies can provide informative value and important resources to answer this question.
The inclusion of lower-quality evidence, did not bring us any closer to answering our research question, but it provided an important message for health policy. We therefore argue that in certain circumstances it is helpful to include inconclusive studies (or study designs), and would consider the same approach again.
Much has changed since the initial version of the review in terms of our understanding of COVID-19 and of the different treatments available. How has the review changed in light of this?
We reassessed and revised our review questions and methodology for each update in the light of new research findings or hypotheses. As more was known about patient characteristics associated with a higher risk of disease worsening and death, we introduced new subgroups to explore whether some people might benefit more from the intervention than others (e.g. people with pre-existing conditions, or the elderly). We also introduced new intervention-specific subgroups to investigate whether they might affect the outcome (e.g. level of antibody titres in donated plasma, or timing of plasma administration).
Probably, our most important change was to divide the population according to disease severity, as research has shown that response to therapies can depend on the clinical progression of disease, and observed effects are not transferable to all stages; we divided the population into hospitalised patients with or without need of respiratory support, and people with asymptomatic or mild disease.
The review includes added in data from the RECOVERY trial which is a very large multicentre study - it has an interesting design, can you explain what they did in that study and why it was useful for the pandemic?
RECOVERY is a platform or multi-comparison trial with an adaptive design. It investigates drugs and interventions that have either been previously used in other diseases or are newly developed. The adaptive design allows comparisons to be added over time and other treatment arms to be closed if the results are conclusive in terms of (in)efficacy and/or safety. In the context of the COVID-19 pandemic, this study design made a lot of sense, as little to nothing was known about potential treatment candidates for COVID-19. The trial recruited over 40,000 participants and investigated 13 potential treatment options, one of which was convalescent plasma. In about half a year, approx. 11,500 participants were enrolled in the comparison of convalescent plasma. Studies are usually not powered to identify subgroup differences. However, the large scale of the trial allows the investigation of different effects of interventions in specific groups. This is extremely helpful to check whether an intervention works in some groups but not in others. With regard to our research question, data from RECOVERY suggest that there is no difference in the efficacy of convalescent plasma therapy in hospitalised patients who have had symptoms for up to or more than seven days, or in patients with or without detected antibodies before receiving the intervention.
This is the fourth version of the review - so what prompted you to update at different times (and so quickly!)?
Time moves differently during a pandemic. The progress in research that we have seen during the last year is tremendous. Research that normally takes several years or decades is done in a few months.
However, our review updates were not only initiated by new research findings, but also by policy discussions or happenings, e.g. the FDA emergency authorization for convalescent plasma last summer. We closely monitored research and policy developments to identify moments prompting a new update. It was important to have up-to-date results available quickly as huge investments had been made in collecting convalescent plasma all around the world.
There are 77 ongoing randomised controlled trials investigating convalescent plasma. Do you expect to incorporate their results or will this be the final version now that we know that this treatment does not have an effect reducing mortality of COVID-19 patients?
Our review targets different interventions and populations, and so far, we were able to answer one of those – the effectiveness of convalescent plasma for hospitalised patients with COVID-19, or rather the ineffectiveness.
Over the last year, it was discussed that convalescent plasma should be used in the early course of the disease to be effective (e.g. for people with asymptomatic or mild disease, or before their own antibodies are formed), or that certain groups of patients would benefit most from it (e.g. people with an impaired immune system), or that effectiveness depends on the neutralising antibody titre of the transfused plasma.
These hypotheses have been partly introduced after research showed inconclusive or ineffective results, underlining the fascination and continuing hope for the intervention.
To address the existing and emerging presumptions, we will continue to update our review with the aim to resolve those uncertainties. We will then also incorporate results of completed trials of our first answered PICO, even though findings are unlikely to change.
How did you collaborate with your co-authors? What would you advise to other teams working remotely right now?
Our team has regular videoconferences to discuss questions, tasks, and duties, and keeps in touch by email in-between. Because of our global distribution, remote working was an enabler for us rather than a barrier. We have found a set time that suits most of the team on most days (early morning in the UK, after business hours in the evening in Australia), which enabled us to organize meetings at short notice. However, most important, certainly, was that the whole team was fully committed to the project during the last year.
This feels like closure on the topic of convalescent plasma as an effective treatment, but we understand that you remain interested in hyperimmune immunoglobulin treatment for COVID-19 patients?
This isn’t a closure on the topic of convalescent plasma. As mentioned before, there are still some remaining uncertainties around convalescent plasma that need to be addressed. But yes, it is a satisfying feeling to solve at least one of the billion questions that are out there on COVID-19.
We had planned to investigate treatment with hyperimmune immunoglobulins as well in this review, but did not identify any completed studies by the time we “retired” our first PICO (Population, Intervention, Comparison, Outcome question.) First completed studies on hyperimmune immunoglobulins are now being announced. We are thinking about producing a spin-off review and to separate hyperimmune immunoglobulins from the parent review in order to continue the reviews on convalescent plasma and hyperimmune immunoglobulin independently.
How does it feel to have started this process last year at the beginning of the pandemic and to be where you are now?
We are happy that we could contribute to closing the knowledge gap of one highly controversial and fascinating topic discussed around the globe. With the vaccines being finally available, there is now also the option to provide active immunity to the disease. Although, it is unclear if this is a sufficient option for the immune-compromised patient, in which it is still unsure if antibody response will be (sufficiently) elicited. These patients may still rely on passive immunisation options such as convalescent plasma and hyperimmune immunoglobulins. In addition, treatment options for people with COVID-19, no matter the severity, are still limited, and the virus (and its variants) will probably be with us for a while. Safe and effective treatments are needed, and it is unfortunate – but very important to know – that convalescent plasma does not improve outcomes for hospitalised patients.