Monaz: Hello, I'm Monaz Mehta, editor in the Cochrane Editorial and Methods department. Cochrane is producing a series of reviews to help decision makers respond to the COVID-19 pandemic. We're keeping these reviews up to date as new evidence emerges and are now on the fourth version of our living review of convalescent plasma and hyperimmune immunoglobulin for COVID-19 patients, which was published in May 2021. In this podcast, Vanessa Piechotta speaks with one of the lead authors, Claire Iannizzi both from the University Hospital Cologne in Germany about the latest findings.

Vanessa: Hi Claire, first of all, could you give us some background on convalescent plasma and hyperimmune immunoglobulin. What are they and how are they used?

Claire: Hi Vanessa. Convalescent plasma and hyperimmune immunoglobulin come from patients who have recovered from an infection, such as COVID-19, and are given to other patients who develop the infection to try to treat them. They have been used for a variety of viral infections, such as influenza, Severe Acute Respiratory Syndrome, or SARS, and Ebola, where they were shown to reduce the risk of death. 

Vanessa: That's very interesting. How might this treatment help people with COVID-19?

Claire: The hope is that convalescent plasma will treat the disease through a process called passive immunization, which will boost the recipient's immune system and help clear the virus.

Vanessa: That sounds great in theory. Why is it important to review its effectiveness using the living systematic review approach?

Claire: You're right that it sounds great in theory, but that's not always a guarantee that a treatment will work in practice. Any benefit needs to be proven by research and, even though convalescent plasma and hyperimmune immunoglobulin treatment are thought to be generally safe, adverse events can occur, as with any transfusion of blood products. This means that we need to review the available evidence and we're using this living systematic review approach because COVID-19 research is moving quickly and new evidence is emerging all the time.

Vanessa: Thanks Claire, so let's move on to the evidence. What you were looking for and what you found.

Claire: We searched for studies from anywhere in the world, including patients with any severity of COVID-19. We were looking at a variety of patient outcomes, including survival, improvement and worsening of clinical status, quality of life and adverse events. 
For this May 2020 update, there are still no completed studies of hyperimmune immunoglobulin but we now include 13 studies on convalescent plasma, of which 12 are randomised trials and one is an expanded access study investigating side effects. In total, more than 48,000 people took part in the studies, with 41,000 received convalescent plasma, and we divided these into people with asymptomatic or mild disease and those with moderate to severe disease. 

Vanessa: And what do these data tell us about the effects?

Claire: For people with moderate to severe disease, for which we have data from almost 13,000 trial participants, we found that convalescent plasma does not reduce all-cause mortality, at least in the first 28 days after it is given, and that it has little to no impact on improvement or worsening of the patient's condition. 
For those with mild disease, there was only one trial with 160 participants, and so we are very uncertain about the effects on mortality or the development of severe COVID-19 symptoms. 

Vanessa: What about the safety aspects? What could you find out about any unwanted events?

Claire: Our main objective here was to investigate safety in the plasma and the control groups in the randomized trials, but only five trials reported this for approximately 1100 patients, which is too small a number to be certain about the relative safety of convalescent plasma therapy. To overcome this lack of data, we included the expanded access study which contains 20,000 participants and allows us to investigate the incidence of transfusion-related events caused by convalescent plasma transfusion. This shows that around 6% of participants had serious adverse events.  

Vanessa: Overall, how certain are you about these findings and what would be your overall conclusion?

Claire: Unlike the evidence in the earlier versions of the review, we now have high-certainty evidence concerning the ineffectiveness of the treatment for hospitalised individuals with moderate to severe disease, because we could include a much higher number of participants from 12 randomised trials. This allows us to be confident that, overall, convalescent plasma for the treatment of hospitalized individuals does not reduce mortality and has little to no impact on clinical improvement. Coupled with this, we are uncertain about its safety for these patients. 
Turning to the evidence for people with asymptomatic or COVID-19 mild disease, we only have very low- to low-certainty evidence, which makes it hard to draw a conclusion yet.
Most importantly, therefore, we still need randomized evidence in other settings, especially for mild disease and for subgroups such as those with immunodeficiency. Also, we need data on the effectiveness and safety of hyperimmune immunoglobulins. 
The promising note is that some of this evidence may be on the way, with more than 100 ongoing studies, of which 10 are testing hyperimmune immunoglobulins. We are also keeping track of 25 studies that have stopped recruitment but are not yet published and two platform trials that may add a treatment arm of convalescent plasma or hyperimmune immunoglobulin. There are also four studies that published results after we had finished this version of the review.
We are keeping an eye on all of this, to help us to decide what to do next with the review.

Vanessa: Thanks Claire. It sounds as though things are continuing to move forward so, if people would like to read the current review and watch for future update, how can they get hold of it?

Claire: It's available online. If someone goes to the website at Cochrane Library dot com and types 'convalescent plasma' into the search box, they'll see a link to our review near the top of the list.