LAUSR

Dear Sir, To date, severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) has infected over 30 million people, resulting in over 900 000 deaths globally and counting. Investigational therapies, including hydroxychloroquine/azithromycin and lopinavir/ritonavir, have been disappointing. Remdesivir shortened median recovery time by 4 days but led to a non-significant decrease in mortality. Nevertheless, remdesivir is unlikely to be available on a large scale in the near future. Thus, immediate interventions to improve COVID-19 mortality represent a public health emergency. COVID-19 convalescent plasma (CCP) is a promising approach, whereby plasma carrying antibodies against SARS-CoV-2 from recently recovered donors is transfused into patients, conferring passive immunity in patients susceptible to having poor outcomes. Passive immunity was first applied in a pandemic during the 1918 influenza outbreak, where recovered patients' sera successfully treated acutely ill patients, reducing fatality from 37% to 16%. The benefit was even more pronounced when convalescent plasma was infused within 4 days of decompensation, reducing the fatality rate from 59% to 19%. In the SARS-CoV-1 epidemic, patients' overall survival improved from 12.5% to 17% when treated with convalescent plasma, with the highest benefit seen when plasma was infused within 14 days of symptom onset. Studies regarding the clinical use of CCP have been inconsistent due to the pressing need for immediate effective treatment during this pandemic. A Cochrane Review by Valk et al highlighted eight studies regarding the use of CCP. Based on the wide spectrum of patients, small total number of treated patients and lack of an ubiquitous endpoint, the authors were unable to draw any concrete conclusions about overall mortality or clinical improvement with regard to CCP use. However, despite various differences, many studies demonstrated some improvement. An early study by Ye et al from Wuhan showed an improvement in chest computed tomography findings post-transfusion of CCP in six patients. It is worth noting that, in this study, only four of the six patients required supplemental oxygen via nasal cannula prior to transfusion (highest need was 5 L/min), and none were intubated. Original data from China showed that only 41% of symptomatic people required supplemental oxygen, of which 6% required mechanical ventilation. Therefore, it is unclear whether those six patients treated with CCP would have progressed to more severe disease or recovered independently. Nonetheless, the Shen et al case series of five critically ill patients from the Shenzhen province highlighted successful extubation of all five patients following CCP infusion. A clinical trial by Li et al noted that patients with severe COVID-19 infection who had CCP added to standard treatment, compared with standard treatment alone, did not demonstrate a statistically significant improvement in both time to clinical improvement and overall mortality. However, this study had a significantly older patient population, as well as a delayed time from symptom onset to administration of CCP. In contrast, a recent clinical trial by Joyner et al demonstrated a mortality benefit between early transfusion of CCP, as well as higher antibody titres. Recently, a propensity score-matched case-control study of 39 patients by Liu et al demonstrated a benefit in both clinical symptoms and overall survival. Despite the uncertainty surrounding CCP, the food and drug administration (FDA) recently announced emergency authorisation use (EUA) for CCP. For COVID-19, the optimal timing and frequency of CCP infusion remains largely unknown. Similarly, the role of CCP in cancer patients, particularly those with haematological malignancies, remains unknown. Here, we describe the outcomes of 17 critically ill patients with COVID-19, including six with haematological malignancies, displaying varying ranges of severe illness and length of infection, who were treated with CCP with marked clinical improvement. Thirteen donors with blood types O, A and B donated two to four CCP units each (200 mL per unit) 18 to 56 days following full recovery from COVID-19. Ten men and seven women between the ages of 24 and 81 years (mean 56) received CCP following informed consent (Data S1). All patients were diagnosed by a reverse transcription polymerase chain reaction (RT-PCR)-based technique with the exception of patients 2, 4, 11 and 13, who were diagnosed using the highly sensitive clustered regularly interspaced short palindromic repeats (CRISPR)based qualitative COVID-19 assay, as detailed in Table S1. Interestingly, these four patients had haematological malignancies and had multiple false negative RT-PCR results prior to the CRISPR diagnosis. Patients 1 and 12 also had haematological malignancies. Most patients had multiple medical comorbidities, and 14 of the 17 patients were treated in the intensive care unit (Table S1). The average time from illness to treatment with convalescent plasma was 12 days (range 4-41) (Table S1). Further patients' characteristics are summarised in Table S1. At the time of CCP infusion, all patients were either mechanically ventilated (six patients), on non-invasive support with high-flow nasal cannula (four patients), on bilevel ventilation (one patient) or on nasal cannula (six patients). Using enzyme-linked immunosorbent assay (ELISA), we were able to determine the Spike protein IgG titres on Received: 13 July 2020 Revised: 2 October 2020 Accepted: 5 October 2020