Blood services, <scp>COVID</scp>‐19 and lessons being learnt: the past pandemic is not over, it's not even past

The incidence of COVID-19 has dropped dramatically in many areas of the world, but the epidemic is far from over, echoing William Faulkner's laconic summary of the significance of history, “the past is not dead, it's not even past.”1 The pandemic has exacerbated workforce issues in healthcare, from staffing levels, recruitment and retention to training, that loom over the current crises afflicting many countries.2, 3 Public inquires have been launched to evaluate pandemic responses in the UK4 and by European Commission.5, 6 Perhaps, the national attention will have moved on to other pressing matters by the time the reports of these inquiries reach the airwaves. For some insiders' early views of the pandemic, we can turn to Jeremy Farrar (Director of the Welcome Trust) who has written an insightful and frank account of the high-level policy discussions in the grey area between science and politics7 and to Sarah Gilbert and Cath Green who have published the epic and extraordinary story of the making of the Oxford AstraZeneca Vaccine in less than 12 months.8 Dare we suggest, these accounts are likely to be more enlightening than official reports; they are almost certain to be more entertaining. In the meantime, many health organisations are trying to make sense of what has happened and draw on what lessons they can from the recent history. Clinical, Public Health and Transfusion Services must analyse what has happened, to influence future pandemic policy. Again, these deliberations will take time, particularly with current crises occupying attention. Here we present three papers that examine the COVID-19 pandemic from within blood services, but from different perspectives and provide some thoughts for the future. First, looking at lessons for blood services from the pandemic, Richard Gammon and colleagues from the USA have shown how blood services coped with the pandemic and what lessons can be drawn for future pandemics9 (Box 1). The authors have gathered views of stakeholders on the major challenges faced by blood services in key areas, including maintaining the supply chain, continuing collection and supply of blood, and finally the challenges of supplying and evaluating convalescent plasma for clinical use. Gammon concludes, encouragingly, that the pandemic allowed blood services to refocus on their primary aim, namely, to improve patient outcomes, and, more soberingly, that reflection must continue if we are to improve resilience for the next pandemic. Their paper provides a starting point for discussion for all blood services. Mike Joyner and colleagues from the Mayo clinic have described the huge effort to understand the effect of convalescent plasma under the Expanded Access Programme (EAP) of the FDA and later the Emergency Use Authorisation10 (BOX 2). The paper points out that convalescent plasma will always be the first antibody therapy to be deployed in a new infectious disease; it may even be the first specific therapy for the pathogen. Early evidence of efficacy and safety from powerful randomised trials would seem to be essential. Faced with a tidal wave of requests for individual use of convalescent plasma, the FDA contacted the team at the Mayo to organise the Expanded Access Programme, which became the US Convalescent Plasma Programme (USCPP). The article makes it clear that the FDA did not prescribe a RCT design. Instead, the FDA mandated establishing an EAP which allowed rapid deployment of an experimental therapy when few other therapies were available. It was originally envisaged that the USCPP would be a demonstration project to show CP safety, particularly to consider early adverse events within 4 hours of transfusion and clearly succeeded in this aim. The Mayo clinic team led the collection of real-time data, analysis and weekly Data and Safety monitoring reports. There were substantial contributions from a variety of funders including the Mayo Clinic, the US Biological Advanced Research Defence Agency (BARDA), community funders and crucial support from the US Blood Banking community. The study design allowed simple informed consent for a study protocol approved by a central IRB and therefore, allowed administration of CP with a parallel safety evaluation (against historical data) under a defined bio-regulatory framework. The immediate safety of convalescent plasma was established, and this was undoubtedly very valuable for the whole transfusion medicine community. In September 2020, with over 90 000 units of CP transfused, the FDA issued Emergency Use Authorisation for CP. In all, over 500 000 units of convalescent plasma were transfused. The EAP was clearly conducted under major constraints and the authors have reflected on lessons learnt within the US context of regulation and the diverse systems of medical care, and how this might inform future use of plasma in another pandemic. However, in a future pandemic, we will certainly need to collect and test the safety and efficacy of plasma using RCTs in a wide variety of clinical scenarios, including early treatment and for vulnerable groups of patients, as quickly as possible. Jennie Callum based in Canada and her co-authors take up the challenge of reflecting on the trials and tribulations of providing high-quality evidence for the use of convalescent plasma11 (Box 2). The CONCOR team based in Canada, and collaborators in New York and Brazil, graphically illustrate the complexity of setting up a trial from scratch, during the pandemic. They describe how they were able to overcome the problems of trial design and reaching agreement between the principal investigators and study sites; the need for rapid access to funding for trials and the logistic problems of running the trial in a pandemic. The study enrolled nearly a thousand patients treated within 12 days of their COVID symptoms and concluded that convalescent plasma did not improve the primary outcome of death or intubation in this cohort. You only have to read the details of how the trial was set up in a short space of time to realise what an achievement this was for the team of Physicians, Immunologists and Transfusion Medicine experts, who jointly led the trial. The team rightly conclude that the results of the trial are important in themselves for guiding the use of convalescent plasma and show how convalescent plasma donors may be selected for future trials. If convalescent plasma did provide a clinically significant benefit in this clinical group, then the CONCOR-1 trial had sufficient power to detect about a 30% difference in outcome. The similarly sized REMAP-CAP study and the larger RECOVERY study, also showed no overall benefit of convalescent plasma,12, 13 although further analysis of REMAP-CAP and other RCTs for convalescent plasma showed a signal of benefit for immunocompromised patients and secondary analysis of RECOVERY showed a signal of benefit for seronegative patients.14, 15 AABB have used the living systematic reviews of the use of convalescent plasma to draw up clinical practice guidelines for the appropriate use of convalescent plasma,14 although the use of convalescent plasma for vulnerable patients has not been authorised in many jurisdictions, pending further evidence (BOX 3). The authors of CONCOR-1 concluded that new randomised trials are needed to assess the early use of high-titre convalescent plasma units in immunocompromised patients with COVID-19 who are unable to mount an efficient anti-SARS-CoV-2 antibody response. Indeed, such trials have now started in the UK, Europe and internationally as the COVIC trial and a relaunched REMAP-CAP trial, using very-high titre convalescent plasma for pre-hospital and hospital treatment respectively of immunocompromised patients. The pandemic has clearly illustrated the need the test multiple therapies during a single trial. During a pandemic we have seen many suggestions to repurpose licenced drugs, claims made for efficacy for some medication based on small uncontrolled series and the deployment of specific therapies as the understanding of pathophysiology emerges and/or new therapeutics are developed. It seems likely these considerations would apply in any future pandemic and national and international agencies will surely have to collaborate to develop these platform trials and indeed the recent EU Horizon 2023 funding announcement does call for such proposals.16 It would be disingenuous and perhaps simplistic to summarise these three papers describing responses to such a complex set of challenges in a few sentences. It is evident that the challenges were different for the diverse circumstances faced by each transfusion and health service. Nevertheless, the broad areas for reflection from all three papers would be: first, the need for pandemic plans for all aspects of the work of blood services; second, ensuring the ability to develop, deploy and standardise appropriate testing for donors, blood products and patients; finally, the need for rapid collection and evaluation of convalescent plasma for different groups of patients (see also17). More broadly, the prescient call for comprehensive pandemic planning by infectious disease experts will hopefully be systematically addressed.18 Many blood and health services are still recovering from the aftermath of the pandemic. For now, we are very grateful for the effort of these teams of authors for their thoughtful and honest assessments of different aspects of responses to the pandemic. Further reflections would be welcome. We thank all our authors, reviewers and editors and staff at our publishers and their production teams for their support and hard work to produce the journal. I must also acknowledge and thank the authors, our editorial team and my PA for their comments and corrections.

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