On 23 August 2020, the Food and Drug Administration (FDA) authorised the use of convalescent plasma as a promising new treatment of hospitalised patients with COVID-19.1
This was granted via the emergency use authorisation procedure, which allows the FDA make use of unapproved medical products or unapproved uses for approved products, in an emergency to diagnose, treat or prevent serious or life-threatening diseases or conditions. In the press release, the FDA reported that their decision was based on a review of the science and data gathered over the last few months. But what exactly is convalescent plasma therapy and how robust is the data for its use as a treatment modality for patients with COVID-19?
History of use
Passive antibody administration therapy involves giving plasma or serum that contains antibodies to a particular infection, to an individual in order to help treat the infection. The concept discovered in 1891 by von Behring who used sheep serum containing antibodies against diphtheria toxin to successfully treat a child with the infection. It was later realised that the transferred plasma was not only able to neutralise the pathogen but also provided immunity against subsequent infection and the technique became known as serum therapy. By the 1930s, serum therapy was widely used to successfully treat a range of infections such as pneumonia and meningococcal meningitis.2 However, the introduction of antibiotics in the 1930’s lead to a decline in the use of serum therapy, largely because chemotherapy with antimicrobials was more effective. Additionally, at the time it was difficult to obtain enough sera from convalescing patients for therapeutic purposes because plasma from one donor can only be used to treat a few patients. Nevertheless, today, antibody therapy is used extensively in medicine but in a highly purified form, for example, monoclonal antibodies.
Convalescent plasma therapy (CP) represents the modern-day equivalent of serum therapy. Patients who have previously been infected with a disease develop circulating antibodies to the pathogen and transferring serum from these individuals to a patient with the specific disease, represents an indirect but effective means through which the recipient becomes immune against the specific pathogen.
Efficacy in viral infections
Despite the development of effective antimicrobial and antiviral agents, CP therapy has emerged periodically over the years, especially during outbreaks of infections for which, at the time, there were no effective drug or vaccines available. For example, CP therapy was used to treat patients with the Spanish influenza pneumonia and an analysis in 2006 that included eight studies with 1703 patients, found that patients receiving the treatment may have experienced a clinically important reduction in the risk for death.3 The value of CP therapy has also been evaluated in the context of viral infections such as the SARS-CoV, avian influenza (H5N1) and the 2009 pandemic caused by H1NI (swine flu). A 2015 analysis included 32 studies of coronavirus infections and severe influenza concluded that CP therapy led to 75% reduction in the odds of mortality among treated patients.4 The use of CP therapy has also explored in the treatment of Ebola virus. The first reported use of CP therapy in Ebola virus emerged in 1976. A researcher who accidentally infected himself with the virus, was treated with CP therapy from an Ebola patient and made a full recovery.5 In another study in Sierra Leone, 69 patients infected with Ebola virus were offered CP therapy or standard treatment which included IV fluids, multivitamins, antipyretics, analgesics, antibiotics, anthelmintics and antimalarial drugs. A total of 44 agreed to CP therapy and although one patient dropped out of the study, 31 recovery and 12 succumbed to the disease, giving a case fatality rate of 27.9%. In contrast, for those receiving standard, the case fatality rate was 44%. The authors calculated an odd ratio for survival from CP therapy of 2.3 (95% Cl 0.8–6.5) and concluded that CP therapy was a promising treatment of Ebola in a resource-poor setting.6 The mechanism of action for CP therapy is not fully understood but thought to be related to the presence of the neutralising antibodies which are raised against several of the S proteins present on the surface of coronaviruses, which are involved in receptor recognition, viral receptor attachment and cell entry.7
Convalescent therapy for COVID-19
The increasing death rate and rapid global spread of COVID-19 has resulted in an urgent need to develop either an effective drug or vaccine against the virus. According to the World Health Organization database, there are 2360 current studies looking at treatments and interventions for COVID-19.8 Given its historical success, interested has centred on the use of CP therapy for COVID-19 and it was first used in five critically ill Chinese patients, refractory to steroid and antiviral therapy. All received CP therapy from five different donors and three were discharged from hospital and two remained stable after 37 days.9 In a US-based study that included 25 patients with severe and/or life-threatening COVID-19, a single transfusion of plasma was well tolerated and after 7 days, 36% of patients (9/25) had an improvement in clinical symptoms, whereas after 14 days, 76% (19/25) had improved or been discharged.10 In an effort to summarise the effectiveness of CP therapy in COVID-19, a living Cochrane review (that is, one that is constantly reviewed) has been established. In the most recent review, researchers identified 20 studies with a total of 5443 participants, of whom, 5211 received convalescent plasma. In assessing the efficacy of the intervention, the outcomes considered included all-cause mortality, time to death and an improvement in clinical symptoms, defined in terms of the need for respiratory support.
The analysis revealed a non-significant impact on all of the reported outcomes. For example, all-cause mortality (risk ratio, RR = 0.89, 95% CI 0.61–1.31), time to death (hazard ratio, HR = 0.74, 95% CI 0.30–0.82) and improvement in clinical symptoms at 14 days (RR = 1.85, 95% CI 0.91–3.77). In their conclusion, the authors noted that it was currently uncertain whether convalescent plasma was beneficial for people admitted to hospital with COVID-19.11
Moreover, the Cochrane review also examined any associated adverse effects, which included allergic events such as anaphylaxis, transfusion-associated dyspnoea and transfusion-related acute lung injury. While the review included a small number of studies, the authored noted that there were 98 ongoing studies including 50 randomised controlled trials.
Conclusions
Until an effective vaccine or drug therapy is developed, there remains an urgent need to find effective alternative treatments for patients with COVID-19. Renewed interest in passive immune therapy in the form of convalescent plasma has shown some promise and has been endorsed by the FDA. While the currently available data are limited, it does suggest some benefit although there remains considerably uncertainty. At the time of the Cochrane review, the authors felt that CP therapy was likely to be of benefit since re-infection with COVID-19 was unlikely although a recent case report of re-infection in a patient casts doubt on this assertion.12 Nevertheless, in the absence of effective treatments, CP therapy may offer hope to some of the patients with more severe disease. As more data emerges from on-going studies, both the value and position of CP therapy in the management of those with COVID-19 infection will become much clearer.
References
- FDA News release. FDA issues emergency use authorization for convalescent plasma as potential promising COVID–19 treatment, another achievement in Administration’s fight against pandemic.
www.fda.gov/news-events/press-announcements/fda-issues-emergency-use-authorization-convalescent-plasma-potential-promising-covid-19-treatment - Casadevall A, Scharff MD. Return to the past: the case for antibody-based therapies in infectious diseases. Clin Infect Dis 1995;21(1):150–61.
- Luke TC et al. Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment? Ann Intern Med 2006;145(8):599–609.
- Mateus ALP et al. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral aetiology: a systematic review and exploratory meta-analysis J Infect Dis 2015;211(1):80–90.
- Edmond RT et al. A case of Ebola virus infection Br Med J 1977;2(6086):541–4.
- Sahr F et al. Evaluation of convalescent whole blood for treatment Ebola virus disease in Freetown, Sierra Leone. J Infect 2017;74(3):302–9.
- Du L et al. The spike protein of SARS-Cov – a targer for vaccine and therapeutic development. Nat Rev Microbiol 2009;7:226–36.
- Clinicaltrials.gov. COVID-19 studies.
https://clinicaltrials.gov/ct2/who_table - Shen C et al. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA 2020;323:1582.
- Salazar E et al. Treatment of coronavirus disease 2019 (COVID-19) patients with convalescent plasma Am J Pathol 2020;190:1680–90.
- Piechotta V et al. Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review. Cochrane Database Sys Rev 2020; issue 7. Art No: CD013600.
- To KKW et al. COVID-19 re-infection by a phylogenetically distinct SARS-coronavirus-2 strain confirmed by whole genome sequencing. Clin Infect Dis 2020; ciaa1275, https://doi.org/10.1093/cid/ciaa1275.
