Convalescent plasma for COVID‐19: Back to the future

The global pandemic of the new coronavirus SARS-CoV-2 not only has medical, economic and social but also historical significance. In many parts of the world, the exponential epidemic curve of cases has overwhelmed hospital services. The primary pulmonary viral infection has required supportive care with oxygen and, if needed, mechanical ventilation and clinical teams around the world have successfully cared for hundreds of thousands of severely ill patients. However, there is currently no specific antiviral therapy that is proven to reduce mortality, although many putative antiviral and anti-inflammatory regimes are being tested in large randomised clinical trials. The lack of a specific therapy has caused some sense of hopelessness in clinical staff, trepidation in the wider public and has not made plotting a route out of lockdown any easier. However, the most promising therapy at the moment may be one of the oldest. It is one where transfusion services and hospital blood banks play a direct role in identifying donors, testing, manufacturing and issuing products. It is also one where patients who have had COVID-19 can donate plasma, which can be used as a therapy for new patients who present with the disease. Convalescent plasma treatment, containing polyclonal antibody (Ab), has been used to treat severe viral pneumonia during previous pandemics. In fact, it has been used intermittently for over a century, including patients treated during the era of the Spanish Influenza pandemic in the early 20th century. Although all the studies conducted at that time had significant methodological flaws, and none were randomised, they suggested a reduction in mortality. In the more recent past, convalescent plasma has been used to treat H1N1 influenza and, more relevantly, SARS-CoV infections in 2003, with evidence of some considerable benefit cited in a systematic review, especially if convalescent plasma was given earlier in the course of the disease (within the first 14 days of symptoms). Convalescent plasma has already been used in observational studies of patients with severe COVID-19. However, a systematic review of the evidence has shown that the conclusions about the effectiveness and safety of convalescent plasma in people with COVID-19 that can be drawn from these studies are limited. There have been only eight uncontrolled studies published, including a total of 32 participants. Some of the results reported in these studies are consistent with increased viral clearance and recovery from the disease. In some way, it is remarkable that such a potentially useful treatment has not been rigorously tested to allow definition of evidencebased guidelines for its tactical use in epidemics and for strategic planning for the collection of convalescent plasma to be incorporated into pandemic planning. Lack of evidence for a promising treatment is not unusual, but convalescent plasma has faced the challenge of always being very difficult to collect enough of during a pandemic to provide plasma to treat large number of patients. The other problem has been the lack of a co-ordinated national and international response to allow rapid and timely randomised controlled trials to take place. The present COVID-19 epidemic has already been of such duration and magnitude to allow collection and use of plasma. However, it still takes considerable co-ordination to complete large-scale trials in a short time. A recent report of 5000 patients treated with convalescent plasma in the United States, almost entirely for compassionate use, suggested that convalescent plasma is safe, with no obvious cases of Ab-dependent enhancement of disease. However, without data on control patients, it is impossible to be confident whether convalescent plasma is either safe or effective in the treatment of COVID-19. A more rigorous assessment of the role of convalescent plasma is underway. At the last count, 22 randomised trials around the world had been registered on trial registries. Two living systematic reviews of convalescent plasma will assess the benefits of treating people who have been diagnosed with COVID-19 and the benefits of preventative treatment for people at high risk of getting COVID-19. In the United Kingdom, the Office of Life Sciences, NHS Blood and Transplant (NHSBT) and the Department of Health and Social Care (DHSC) have proposed and planned a new programme to collect high volumes of plasma. The work is funded as a new £20-million project by the DHSC. The strategy is to build up the collection of plasma from convalescent donors to provide enough plasma not only for two large-scale randomised controlled trials to assess the efficacy and safety of convalescent plasma, but also to provide enough plasma to treat hospitalised and/or intensive care patients with COVID-19 if the randomised controlled trials do show efficacy. Within six weeks, NHSBT has set up what is effectively a new production line with workstreams reaching out to potential donors who were admitted to hospital and/or testing positive for COVID-19 and those who had symptoms consistent with the disease. NHSBT has established the collection of over 5000 units a week by rearranging work with existing donor centres, building three new collection centres in London, training over 200 newly-recruited staff by donor centre staff and the core nursing team and defining new manufacturing processes and new methods to evaluate the quantity and quality of anti-SARS-CoV-2 antibodies. These are certainly challenging targets, and we have been faced with high on-session deferral rates as we are plasmapheresing many first-time donors who have recently recovered from serious infection. We are bringing deferral rates down and increasing the proportion of Received: 19 May 2020 Accepted: 20 May 2020