Introduction

Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory coronavirus 2(SARS-CoV-2), has rapidly spread since its first declaration by the World Health Organization (WHO) as a global pandemic in March 2020 [1]. Until vaccination has started to be rolled out in an increasing number of countries, different modalities of treatment were deployed in an attempt to combat this deadly virus but with limited efficacy so far [2]. Collection and use of convalescent plasma for coronavirus disease-2019 (COVID-19) (CCP) treatment for passive immunotherapy had gained interest worldwide and still is considered as a potentially effective therapeutic option when containing high-titre antibodies and administered early in the course of the infection [3, 4] including against SARS-CoV-2 variants [5]. Transfusion of CCP itself has been conducted either within a framework of clinical trials or on a compassionate basis in patients with active SARS-CoV-2 infection. CCP may also be fractionated into hyperimmune immunoglobulins for treatment of patients or alternatively for prophylaxis in high-risk individuals such as healthcare providers or individuals who have the underlying risk factors, such as an exposure to persons with confirmed COVID-19 infection.

The medical rationale for transfusing CCP is based on historical perspectives that demonstrated the clinical benefit of transfusing convalescent plasma from recovered individuals in respiratory infections caused by other coronaviruses [6] as well as diseases such as Argentine haemorrhagic fever [7]. The advantages of CCP include its almost immediate availability (once safe recovered donors can be identified) as a local resource in all affected countries worldwide, while specific treatments and vaccines are under development and evaluation. The relative ease of access to CCP from recovered donors, and potential for deployment in different settings, including low- and middle-income countries, made it attractive especially in early stages of the pandemic. Soon after the start of the pandemic, recommendations and ‘points to consider’ have therefore been published by the International Society of Blood Transfusion (ISBT) to establish and share at a global level to ensure quality and safety, as well as respect of ethical principles, in the collection and use of CCP [8-11]. An emphasis was given to the fact that CCP transfusion was to be considered as an experimental therapy that, whenever possible, should be evaluated within the scope of controlled clinical studies to maximize the knowledge gained, with optimal monitoring of (1) convalescent donors, (2) CCP characteristics and (3) patients outcomes [9].

In addition, there was recognition of variations and gaps existing at a global level in the practices applied to the collection, testing and preparation of CCP [8, 12]. ISBT initiated a multidisciplinary working group with representation from all six continents with the aim of reviewing existing practices on CCP preparation and use. It was felt that such information would be invaluable not only to document strategies implemented in CCP collection, but also as a tool for better preparedness against future pandemics.

This Vox Sanguinis International Forum aimed to gather information on the practice and challenges of collection of CCP on an international level and to draw lessons learned from establishing a CCP collection programme for blood establishments and hospital-based blood services. This international forum was only intended for institutions that collect CCP. Participants were invited to participate in this international forum on 9 December 2020 and were asked to describe the CCP collection programme in their institutions or countries. Responses were collected up to 17 February 2021. The current document is a summary of the findings that have been collected and analysed for practices in place during the specified timeframe.

Participants

Thirty-eight participants from 34 countries were invited to participate in the international forum. We aimed to cover all WHO regions and include both large national blood suppliers and smaller blood centres. We received 32 responses reflecting practice in 35 centres in 25 countries from around the world (Table 1).

Table 1. Demographics of participating institutions Country, Institution Type of institution Hospital Beds RBCs transfused/year Approximate number of collections/year Americas Argentina Hospital-based BTS/BB 421 587 WB: 600 Brazil Hospital-based BS 510 6000 WB: 5500; Apheresis: 1750 Canada, Héma-Québec National BE - - WB: 220 000; Plateletpheresis: 40 000 Canada, CBS National BS - - WB: 763 319; Plateletpheresis: 11 339 United States, Vitalant Regional blood collector/TS - - RBCs: 87 000; PLT: 25 000 United States, ARC National BE - - WB: 4·4 million; Apheresis: 1·4 million United States, OneBlood Regional BS/BC - - WB: 790 700; Plateletpheresis:48 507 Africa South Africa, SANBS Regional BS/BC - - WB: 900 000; Plateletpheresis: 18 138 South Africa, UCT Regional BS/BC - - WB: 147 684; PLT: 9265 Eastern Mediterranean Region Egypt Hospital-based BS 100 25 000 Data not provided Israel National BE - - WB: 265 000, Plateletpheresis:550 Oman Hospital-based BS 450 18 500 WB: 12 500, Plateletpheresis: on demand Saudi Arabia Hospital-based BS 780 12 000 WB: 12 500; Plateletpheresis: 100 Europe Belgium National BE - - RBCs: 160 000; PLT: 11 000 Finland National BE - - WB: 200 000; Plateletpheresis: 2500 France National BE - - WB: 2·5 million; Apheresis: 440 000 Germany Regional BS/BC - - WB: 5849; Plateletpheresis: 379 Italy National BC - - WB and apheresis: 2 996 264 Norway Hospital-based BS/BC - - WB: ˜175 000; Plateletpheresis: 5000 The Netherlands National BE - - WB: 413 653; Apheresis 313 811 Turkey, BUU Hospital-based BS 900 22 000 WB: 20 000; Plateletpheresis: 1700 Turkey, TRC National BS/BC - - WB: 2 766 581; Apheresis: 42 656 Turkey, AHGH Hospital-based BTS/BB 2129/16 hospitals 44 465 WB: 1080; Apheresis: 5800 United Kingdom National BE - - RBCs: 1·4 million; PLT: 255 000 South-East Asia India, AIIMS Hospital-based BTS/BB 2000 75 000 WB: 80 000; Apheresis: 2000 India, PGIMER Hospital-based BTS/BB 1740 135 685 WB: 57 842 Indonesia National BS/BC - - WB: 3 523 982 Western Pacific Australia National BS/BC - - WB: 690 115; Plateletpheresis 27 024 China, BRCBC, WHBC, SXBC Regional BS/BC - -

BRCBC: WB: 450 000; Plateletpheresis: 68 000

WHBC: WB: 350 000; Plateletpheresis: 70 000

SXBC: WB:32 000; Plateletpheresis: 40 000

Hong Kong, China Regional BS/BC - - WB: ˜215 000; Apheresis: ˜10 000 Singapore, HAS, TTSH National BE (HAS) Hospital-based BTS/BB (TTSH) >1700 15 000 WB: 117 000; Apheresis: 8000 South Korea Hospital-based BTS/BB 2437 50 200 NA AHGH, Acıbadem Health Group Hospitals; AIIMS, All India Institute of Medical Sciences; ARC, American Red Cross; BB, blood bank; BC, blood centre; BE, blood establishment; BRCBC, Beijing Red Cross Blood Center; BS, blood service; BTS, blood transfusion service; BUU, Bursa Uludağ University; CBS, Canadian Blood Services; HAS, Health Sciences Authority; PGIMER, Post Graduate Institute of Medical Education and Research; PLT, platelets; RBC, red blood cell; SANBS, South African National Blood Service; SXBC, Shaanxi Blood Center; TRC, Turkish Red Crescent; TS, transfusion service; TTSH, Tan Tock Seng Hospital; UCT, University of Cape Town; WB, whole blood; WHBC, Wuhan Blood Center. Responses Describe your institution COVID-19 convalescent plasma (CCP) collection programme

Q1: Demographics

The majority of the institutions had apheresis services, including the hospital-based centres. All hospital-based institutions were in hospitals that treated adults and children and had medical and surgical services. These hospitals ranged in size from 100 beds up to ˜2000 beds.

Q2: What type of CCP donation does your institution perform? How many times is a donor allowed to donate CCP by apheresis, and over what time period? Is the frequency different from routine plasma donation by apheresis? If whole blood (WB) is collected, are red blood cells and/or platelets derived from the WB donation used for standard transfusion?

All respondents indicated that CCP is collected in their institution using plasmapheresis (Table 2). The frequency of plasmapheresis was variable between institutions. While 20 respondents indicated that the frequency did not differ from that of routine plasmapheresis, five institutions had CCP collection made at a higher frequency than what is permitted routinely. Two respondents indicated that plasmapheresis was an infrequent procedure in their institutions, only used for specific indications (e.g. collection of plasma for IgA-deficient patients) or was only established for CCP collection.

Table 2. Convalescent plasma donation programmes Country, Institution Intended use of CCP Method of CCP collection Frequency of CCP Plasmapheresis Frequency different from local standard plasmapheresis? Components used from whole blood? Americas Argentina Clinical trials; Compassionate use Plasmapheresis Whole blood Every 2 weeks, maximum 1 l/week, 15 l/year; Maximum 600 ml per session No Yes Brazil Clinical trials; Compassionate use Plasmapheresis

Maximum 4 over 2 months

Shorter inter-donation interval can be allowed in specific circumstances

Maximum 600 ml per session

No NA Canada, Héma-Québec Clinical trials Plasmapheresis Every 6 daysa No NA Canada, CBS Clinical trials Plasmapheresis Every 7 days No NA United States, Vitalant Clinical trials; Compassionate use Plasmapheresis Medical director discretion, up to every 48 h No NA United States, ARC Clinical trials; Compassionate use Plasmapheresis Whole blood Every 7 days, maximum of 8 over 3 months No Yes United States, OneBlood Clinical trials; Compassionate use Plasmapheresis Whole blood Medical director discretion, up to every 48 h No Yes Africa South Africa, SANBS Clinical trials; Compassionate use; Fractionation Plasmapheresis Every 2 weeks, maximum of 24 donations/year No NA South Africa, UCT Clinical trials; Fractionation Plasmapheresis Every 2 weeks, maximum of 24 donations/year Not specified NA Eastern Mediterranean Region Egypt Clinical trials; Fractionation Plasmapheresis Every 2 weeks No NA Israel Clinical trials; Compassionate use PlasmapheresisWhole blood Every 2 weeks, maximum of 6 per 10 days Yes Yes Oman Clinical trials Plasmapheresis Every 7 days, maximum of 4 NA NA Saudi Arabia Clinical trials Plasmapheresis Every 7 days, maximum of 2 Not specified NA Europe Belgium Clinical trials; Compassionate use Plasmapheresis

Maximum 2 l/month, 23/year, and 15 l/year

Maximum 650 ml per session

No NA Finland Clinical trials Plasmapheresis Every 2 weeks, maximum of 5 NA NA France Clinical trials; Compassionate use Plasmapheresis Every 2 weeks, maximum of 24/year No NA Germany Clinical trials; Compassionate use Plasmapheresis Every 2 days (48 h), maximum of 60/year No NA Italy Clinical trials; Compassionate use; Fractionation PlasmapheresisWhole blood

Every 2 weeks, maximum of 12 l/year

600–700 ml per session

No Not specified Norway Clinical trials; Compassionate use PlasmapheresisWhole blood Maximum 4 donations over 4 weeks Yes Yes The Netherlands Clinical trials; Compassionate use; Fractionation Plasmapheresis

Maximum of 26 donations and 25 l/year

Maximum 750 ml per session

No NA Turkey, BUU Compassionate use Plasmapheresis Every 10 days, maximum of 8 in 3 months Yes NA Turkey, TRC Per direction of Ministry of Health Plasmapheresis Every 10 days, maximum of 3 in a month; 1·8 l/month and 8 per 3 months periodb Not specified NA Turkey, AHGH Clinical trials; Compassionate use Plasmapheresis Every 10 days, maximum 3 in a month, maximum 8 per 3 month periodb Not specified NA United Kingdom Clinical trials Plasmapheresis Every 7 days, maximum of 24/year No NA South-East Asia India, AIIMS Clinical trials; Compassionate use Plasmapheresis

Every 2 weeks

Maximum 500 ml per session, 1 l per month

No NA India, PGIMER Clinical trials; Compassionate use Plasmapheresis Every 2 weeks No NA Indonesia Clinical trials Plasmapheresis Every 2 weeks, between 3–6 donations Not specified NA Western Pacific Australia Clinical trials; Fractionation PlasmapheresisWhole blood Every 7 days, up to 12 donations Yes Yes China, BRCBC, WHBC, SXBC Clinical trials; Compassionate use Plasmapheresis Every 2 weeks, maximum of 24 times/year No NA Hong Kong, China Clinical trials; Compassionate use Plasmapheresis Every 2 weeks, maximum of 6 donations No NA Singapore, HAS, TTSH Compassionate use PlasmapheresisWhole blood Every 2 weeksc Yes Yes South Korea Clinical trials Plasmapheresis Every 2 weeks No NA AHGH, Acıbadem Health Group Hospitals; AIIMS, All India Institute of Medical Sciences; ARC, American Red Cross; BRCBC, Beijing Red Cross Blood Center; BUU, Bursa Uludağ University; CBS, Canadian Blood Services; HAS, Health Sciences Authority, NA; not applicable; PGIMER, Post Graduate Institute of Medical Education and Research; SANBS, South African National Blood Service; SXBC, Shaanxi Blood Center; TRC, Turkish Red Crescent; TTSH, Tan Tock Seng Hospital; UCT, University of Cape Town; WHBC, Wuhan Blood Center. a initially allowed for up to 12 weeks after their first donation. Later reduced to up to 6 weeks after resolution of symptoms. b allowed for up to 3 months after recovery. c initially started at allowable frequency as for standard plasmapheresis. Higher frequency is allowed provided donors' serum albumin and globulin levels before each donation was in the reference range.

The majority of the institutions (n = 16) allowed plasmapheresis every 2 weeks, while six allowed every week with variable maximum allowable donations per donor. The highest donation frequency was every 48 h reported by three centres. In Héma-Québec (Canada), CCP collection was initially performed at a frequency identical to that of standard plasmapheresis procedures (every 6 days, up to 12 weeks after first donation) for early CCP donations, but decreased to a maximum of 6 weeks after resolution of symptoms, considering the reported decline in the SARS-CoV-2 antibody titre with time [13-15]. In Singapore, the CCP plasmapheresis was initially conducted at the standard plasmapheresis procedure frequency and was subsequently increased to every 2 weeks to allow more frequent donation.

Eight institutions collected WB and plasmapheresis if the donor/units were found to have anti-SARS-CoV-2 antibodies, and donors meet all other donor eligibility criteria. Considering that these donors fulfilled blood donation qualifications and testing for transfusion-transmitted infections, red blood cells and/or platelet components derived from such donated WB were labelled for clinical use. This decision necessitated approval by the institutional ethics committee in Argentina. Two blood centres in the USA (American Red Cross and OneBlood) applied a minimum deferral period of 14 days from the time of resolution of COVID-19 infection for CCP and WB donation. Plasma components from qualified blood donors were labelled as CCP if they met the necessary levels of anti-SARS-CoV-2 antibodies. In Italy, WB collection from recovered COVID-19 individuals was introduced at later stages of the pandemic, and donors were allowed to donate blood after 10 days of recovery. In Norway, the decision to use derived red blood cells (RBCs) and platelets for standard transfusion was based on the European Center for Disease Prevention and Control and European Blood Alliance guidelines recommending accepting WB donors after 28 days following recovery. The same rule was applied in Australia and Israel. In Singapore, only male blood donors who had made standard WB donation with a history of COVID-19 within 6 months before the donation had their samples tested for SARS-CoV-2 neutralizing antibodies. Based on the antibody level present, a decision was made to label the WB-derived plasma as CCP. Derived RBCs and platelet components were labelled for clinical use. Some respondents indicated that the decision of labelling units as for standard components was made based on a lack of evidence of SARS-CoV-2 transfusion transmission (Norway, Australia).

Q3: Is collected CCP intended for transfusion, prophylaxis, or fractionation purposes? If collected for transfusion, kindly indicate if collected for compassionate-use, trial-use or both?

All respondents indicated that CCP is collected for transfusion purposes, and one also used it for preparation of minipool CoV immunoglobulin (CoVIg). A total of 20 institutions collected CCP for clinical trials and compassionate use. Of these, four institutions had CCP initially collected for use in clinical trials but later was provided on a compassionate basis (India; Hong Kong; China, in Wuhan; Italy; Table 2).

Eight institutions had CCP collected for transfusion in clinical trials only. Three respondents indicated that the CCP had been used in rare cases on a compassionate basis outside a clinical trial setting (Saudi Arabia; Australia; and the UK). A regional institution in the USA had CCP initially provided for use in both compassionate and study protocols, but since the Mayo Clinic investigational new drug trial was completed, CCP was provided as an investigational new drug.

In Brazil, CCP was collected mostly for use within the setting of clinical trials for patients with severe pneumonia, and to a lesser extent, for compassionate use depending on the physician's request. Two institutions collected CCP solely for compassionate use (Singapore; one in Turkey). In the Netherlands, the compassionate use of CCP was offered for immune-compromised hospitalized patients with persistent and/or severe COVID-19 disease. CCP was also collected for clinical trials and as a source plasma for CoVIg production.

Six institutions have been collecting CCP for fractionation purposes. The use of CCP for fractionation was under consideration in Canada, Norway and France at the time of response to this international forum.

Q4: Describe the CCP donor eligibility and recovery criteria used in your institution? Do they need to have a confirmatory test result status of past COVID-19 infection before CCP donation? What type of test?

Laboratory confirmation of COVID-19 infection

The donor eligibility criteria varied dramatically between countries (Table 3). All institutions, except the French and Australian, required proof of a previous COVID-19 infection, either in the form of a positive SARS-CoV-2 polymerase chain reaction (PCR) test (29 respondents) or anti-SARS-CoV-2 antibodies (17 respondents). In France, during the first peak of COVID-19 pandemic, patients with mild clinical symptoms were not systematically tested by SARS-CoV-2 polymerase chain reaction (PCR). The diagnosis of COVID-19 was made presumptively based on patients' symptoms. In Australia, donors had to report that they had a ‘laboratory-confirmed COVID-19 infection’ as per the national guidelines for a confirmed case (tested positive by RNA or cell culture with PCR confirmation or showed evidence of seroconversion). However, donors were not required to provide the diagnostic report when presenting to donate CCP.

Table 3. CCP donor eligibility and testing Country, Institution Confirmatory test of past COVID-19? CCP donor eligibility criteria* Pre-donation SARS-CoV-2 testing Pre-donation anti-SARS-CoV-2 antibody testing SARS-Cov-2 PCR Anti-SARS-Cov-2 Antibody 14 days after resolution of symptoms 14 days after resolution of symptoms + 1 negative PCR 14 days after resolution of symptoms + 2 negative PCR 28 days after resolution symptoms/recovery Americas Argentina Yes No No Yesa No Yesa Yes Yes Brazil Yes No No Yes No No Yes Yes Canada, Héma-Québec Yesb No Yes No No No No No