Lise Estcourt is a consultant in Haematology and Transfusion Medicine at NHS Blood and Transplant (NHSBT), Oxford, UK, and a Senior Clinical Lecturer at the University of Oxford. She is the Director of NHSBT’s Clinical Trials Unit, the Clinical Lead for the National Comparative Audit in Blood Transfusion, Clinical Tutor for NHSBT, and the coordinating editor for Cochrane Haematology. She has authored and co-authored more than 100 papers in peer-reviewed journals.
You are doing a ‘living systematic review’ on the use of convalescent plasma or hyperimmune immunoglobulin in the treatment of patients with COVID-19. What is a living review and what did you want to find with it?
‘Living systematic reviews’ are evidence reviews in which a lot of research is emerging quickly. Living systematic reviews search for evidence monthly and incorporate new, relevant evidence as it becomes available. Living reviews are important so that decision makers such as policymakers can be sure they have the latest evidence when making decisions.
What are the main conclusions of this review so far?
We used evidence from randomised controlled trials (the highest quality evidence) to assess whether convalescent plasma improves outcomes for people hospitalised with COVID‐19. Currently there is not enough evidence to determine whether convalescent plasma affects the risk of dying in hospital or decreases the need for breathing support.
We used evidence from both randomised studies and other study designs to assess whether convalescent plasma causes unwanted effects. There was not enough evidence to determine whether convalescent plasma therapy causes serious unwanted events. None of the studies reported assessed the effects of convalescent plasma on quality of life.
Do you agree that the optimal timing and dosage of convalescent plasma therapy is still unknown?
I agree. We don’t yet know whether convalescent plasma is effective. If it is effective, we don’t know who should receive it, how soon after symptoms start it should be administered or how much they should receive. It is likely that early administration, soon after symptoms start, is going to be more effective because the main way that convalescent plasma is thought to work is by stopping the virus from infecting more of the patient’s cells.
What are the advantages of hyperimmune immunoglobulin over convalescent plasma and what are the differences between them?
Convalescent plasma is plasma derived from a single donor. The amount of antibodies varies significantly between donors. Hyperimmune globulin is a standardised product which is produced by pooling plasma from many different donors. The amount of antibodies present is the same for each ml of hyperimmune globulin. The antibodies are also concentrated in hyperimmune globulin, so it can be given in smaller volumes. Convalescent plasma can be produced much more quickly after the start of a pandemic than hyperimmune globulin, so it can be used to treat patients many months prior to hyperimmune globulin being available as a treatment.
What are the criteria for donating plasma?
The exact criteria for who can donate plasma differs from country to country. People must meet their local requirements for eligibility to donate blood. In addition, they must have recovered from COVID-19; in the UK they must have recovered from COVID-19 at least 28 days prior to donating, however in other EU countries it can be as soon as 14 days after recovery.
The neutralising antibodies titre of the donated plasma must be above a given threshold: what does this mean?
The main mechanism of action of convalescent plasma is thought to be ‘neutralising’ the virus, in other words – stopping the virus infecting cells. This can be assessed in the laboratory by assessing different dilutions of the convalescent plasma and seeing how dilute the plasma can be and still stop the virus infecting cells. So, a neutralising antibody level of 1:100 means you can dilute the plasma 100 times and the antibody can still stop 50% of the cells from being infected. The neutralising antibody titre is therefore a laboratory measure of how effective the plasma is thought to be at stopping the virus. The higher the titre, the more effective the plasma is likely to be.
The use of convalescent plasma or hyperimmune immunoglobulin is useful not only in the acute phase in patients affected by COVID-19, but also as a preventive treatment. Is this correct?
Convalescent plasma and hyperimmune globulin are being used in trials to both treat and prevent infection, whether these treatments work to treat or prevent COVID-19 is currently unknown, but I am eagerly awaiting the results of ongoing trials. Hyperimmune globulin is used to prevent other diseases including varicella zoster infection in immunocompromised patients or pregnant women who have been exposed to the infection.
Administering immunoglobulins increases the level of antibodies that are effective at neutralising the virus. However, would this not reduce the recipient’s ability to develop their own antibody response?
There is currently no evidence that administering immunoglobulins affects a patient’s ability to produce their own antibodies if they already have the SARS-CoV-2 infection.
Do you have any other closing thoughts?
There are two large trials being conducted in the UK that will be able to answer whether convalescent plasma is an effective and safe treatment for individuals admitted to hospital with COVID-19. The RECOVERY trial is assessing the treatment in children and adults who have been admitted to hospital with suspected or confirmed COVID-19. The REMAP-CAP trial is assessing the treatment in adults who have been admitted to intensive care with confirmed COVID-19.