Accepted Article DR. MARK H YAZER (Orcid ID : 0000-0001-5937-3301) DR. MONICA B. PAGANO (Orcid ID : 0000-0001-5183-6471) PROF. DUCK CHO (Orcid ID : 0000-0001-6861-3282) DR. YULIA LIN (Orcid ID : 0000-0002-5562-9020) Article type : International Forum Corresponding author mail id:- mlozano@clinic.cat Vox Sanguinis International Forum on Hospital Transfusion Services' Response to COVID-19 Mark H. Yazer, Bryon Jackson, Monica Pagano, Naomi Rahimi-Levene, Victoria Peer, José Luis Bueno, Ryan P. Jackson, Hua Shan, Luiz Amorim-Filho, Maria-Esther Lopes, Carla Boquimpani, Ulrik Sprogøe, Mie Topholm Bruun, Kjell Titlestad, Kylie Rushford, Erica M. Wood, Zoe K. McQuilten, Vincenzo de Angelis, Michela Delle Donne, Mike Murphy, Julie Staves, Duck Cho, Fumihiko Nakamura, Akira Hangaishi, Jeannie Callum, Yulia Lin, Mostafa Mogaddam, Ahmad Gharehbaghian, & Miquel Lozano Introduction The novel coronavirus (SARS-Cov-2) that was first reported in Wuhan, China and provokes the COVID- 19 disease has developed into a pandemic with hundreds of thousands of people infected. Many This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/vox.12943 This article is protected by copyright. All rights reserved governments have enforced social isolation protocols on their citizens, which has led to the closure of Accepted Article many large public gatherings in order to limit the spread of the virus. These closures could reasonably be expected to affect blood collections, thereby presaging shortages of blood for transfusion. On the other hand, steps such as the postponement of elective surgeries and other non-urgent transfusions could mitigate against potential shortfalls in the blood supply.[1] The transfusion community has faced epidemics and pandemics before,[2-9] but little has been published about the preparations made by hospital-based transfusion services for handling samples and performing pretransfusion testing on patients who are affected by the disease. A study of the policies and procedures vis-à-vis pre-transfusion testing and the provision of blood products at three Japanese hospitals during the recent Ebola epidemic revealed different approaches to performing pre-transfusion testing on potential recipients and how the blood products were issued.[10] Given the urgent need to develop best practices for conducting pre-transfusion testing and issuing blood products not just during the current novel coronavirus pandemic but also for future pandemics, the time is now propitious to understand how transfusion services in cities with different burdens of this disease are approaching these issues and for the dissemination of different policies and procedures that facilitate the timely provision of blood products to our patients while maintaining a high level of safety for transfusion service staff. Summary of Responses Question 1: Demographics of respondents Responses were received from a total of 12 centers from around the world including Australia, Brazil, Canada, Denmark, Iran, Israel, Italy, Japan, Korea, Spain, UK, and USA. Table 1 demonstrates the demographics of the respondents and the cities in which their institutions were located. All respondents worked in large academic medical centers, although the Brazilian respondent worked at a hospital that only treated hematology oncology patients and the Iranian respondent worked in a private specialty hospital. At the time of survey completion, the absolute number of confirmed coronavirus cases ranged This article is protected by copyright. All rights reserved from a low of 4,831 (Israel) to a high of 386,817 (USA), but accounting for the population of each Accepted Article country, the rate of confirmed cases ranged from 0.01% (Brazil and Japan) to 0.30% (Italy). The rate of coronavirus infections was felt to be increasing in Israel, USA, Canada, Japan, and Brazil, stable in the UK, and Korea, and decreasing in Spain, Denmark, Australia, and Italy. However, the survey responses were received between 31 March, 2020 and 24 April, 2020, so the number of confirmed cases and the respondent’s opinion as to the extent of the spread of coronavirus throughout their country reflected the state of the disease at the time the survey was completed; this number and opinion might have changed in the time between survey completion and the publication of this International Forum. Table 2 presents a short summary of each respondent’s answer to each question. Question 2: Did your hospital blood bank/transfusion service accept samples for pre-transfusion testing (including DAT) from patients who were confirmed or suspected to be infected with novel coronavirus? All of the respondents indicated that their transfusion services accepted samples from patients with confirmed or suspected coronavirus infections. The American, Australian, Iranian, and Japanese respondents indicated that they did not make any changes to the processes of sample procurement and labeling, accepting the sample in the transfusion service, testing, storing, or discarding the sample. For the centers that did institute new policy changes for handling these samples, the Israeli and Korean respondents indicated that the sample label had the word COVID written on it to alert the technologists to implement the enhanced safety measures for handling and testing these samples, and the samples were transported to the transfusion service in clear plastic bags. The Italian respondent indicated that the labeling was performed outside of the patient’s room in a designated safe area. The Spanish respondent indicated all samples that were received at the transfusion service for pre- transfusion testing were assumed to be potentially contaminated with coronavirus and so they were all cleaned with hypochlorite before being processed, and they were also UV irradiated for 30 minutes. Similarly, the Danish respondent indicated that samples from coronavirus patients were cleaned by the phlebotomist before they arrived at the transfusion service. Interestingly, the Italian respondent indicated This article is protected by copyright. All rights reserved that paper requisitions were sealed in plastic bags for 5 days to sanitize them before being archived. At Accepted Article the Brazilian and Canadian respondents’ sites, all samples regardless of the presence of coronavirus were opened behind a plastic shield, while in a similar vein, at the UK respondent’s site, the sample tubes were left for a while to settle after centrifugation so as to reduce the probability of aerosolizing the contents. Also, at the Canadian site, all laboratory staff wore face masks as maintaining appropriate physical distancing is not always possible. All of the respondents indicated that the samples were tested in the usual location in the transfusion service except for the Israeli respondent who indicated that pre-transfusion testing was performed in a biosafety cabinet and the Korean respondent who indicated that the samples were tested in a fume hood. In terms of the personal protective equipment (PPE) that was worn by the transfusion service technologists, the Spanish, American, Brazilian, Danish, Australian, and British respondents indicated that the standard laboratory PPE was worn when testing these samples. The Israeli respondent indicated that double gloves, goggles, an N95 respirator, and a gown was worn when testing samples from known or suspected coronavirus patients, while the Italian respondent indicated that a mask was added to the standard PPE when testing such a sample. At the Korean respondent’s transfusion service, gloves, goggles, and a surgical mask were worn when testing these samples. Once the pre-transfusion testing had been completed, most of the respondents stored these samples in their routine manner, expect at the Israeli respondent’s laboratory where the samples were stored in a separate shelf in a sealed container, and at the Italian respondent’s laboratory where the samples from known or suspected coronavirus patients were kept in a dedicated rack in the same refrigerator as the other samples. The Korean respondent indicated that the samples were returned to the plastic bag into which they were received for storage, and when it was time to dispose of the samples they were sent to their department of microbiology for disinfection and disposal. All of the other respondents indicated that the samples were discarded following their routine protocol. Lastly, as stated above, all of the respondents indicated that their transfusion services accepted samples from known or suspected coronavirus patients. However, the Israeli respondent indicated that This article is protected by copyright. All rights reserved prior to receiving the biosafety cabinet, samples from these patients were not accepted for pre-transfusion Accepted Article testing. Instead, group O RBCs and group AB plasma would have been issued to these patients. All of the patient’s available transfusion and immunohematological history was reviewed prior to issuing blood products, and antigen negative RBCs would have been issued to an alloimmunized recipient. Uncrossmatched RBCs were rarely required in this setting as the biosafety cabinet was available quickly after the need for it arose. Question 3: If a cooler (i.e., a temperature controlled device used for storing blood products outside of the blood bank) of blood products was issued on such a patient how did the transfusion service handle the cooler? The American respondent indicated that blood products were loaded into the cooler in the routine manner for patients with known or suspected coronavirus, while the Australian respondent indicated that RBCs were individually put into bags and then loaded into the cooler. These coolers always remained outside of the patient’s room, thus the cooler did not need to be decontaminated upon its return to the transfusion service. RBCs that were taken into a patient with known or suspected coronavirus’ room but not transfused were discarded if they were returned to the blood bank. The Canadian respondent also issued RBCs in individual plastic bags that had been sealed to indicate if the bag had been opened; at this center, coolers were decontaminated upon return to the transfusion service, which had been the routine practice before this pandemic, and any RBCs that were returned in unopened plastic bags were returned to the inventory; RBCs that were returned in opened bags were discarded. The Australian and Canadian policy of issuing RBCs in individual plastic bags in a cooler were new policies that were implemented during this pandemic. The American and Italian respondents indicated that RBCs that were returned in a cooler were wiped down and restocked. The Canadian, American, and Brazilian respondents indicated that the coolers were also disinfected, with the latter indicating that this was a new policy that had been implemented during this pandemic and that it would become permanently adopted. This article is protected by copyright. All rights reserved The Spanish and British respondents indicated that they did not make any changes to their cooler Accepted Article issuing policy, while the Israeli, Danish, Italian, and Korean respondents indicated that they do not routinely issue coolers to any patient. Question 4: Does your facility have an existing plan to deal with samples from patients with novel pathogens? Many of the respondents indicated that they had a pre-existing plan for handling samples from patients with novel pathogens. For example, the Israeli plan was derived from their experience with the 2003 SARS outbreak, the Korean respondent’s plan was based on their experience with the MERS outbreak, and the Canadian respondent’s plan was based on the Ebola virus outbreak. The Spanish respondent indicated that the hospital had a plan but that it had been dormant before it was reactivated for this pandemic, while the Danish respondent indicated that their pre-existing plan was designed for patients who were contaminated with radiation, chemical or biological agents. Both the American and Italian respondents indicated that they did not have a specific plan for dealing with novel pathogens because standard universal precautions were always being used for all samples. Both the Brazilian and the British respondents indicated that their hospitals did not have a pre-existing plan. Question 5: Was any additional training provided to the staff about the nature of this virus and its infectivity? All of the respondents indicated that some form of training was provided to their transfusion service technologists and/or hospital house staff. The training generally involved education about the proper use of PPE and the application of universal precautions, as well as reminders about the importance of handwashing and frequent surface disinfection. The Israeli and British respondents provided specific education about how to use the biosafety cabinet and about the new policy of not immediately opening the centrifuged samples, respectively. See the individual responses for more details about the specific nature of the training that each respondent provided. This article is protected by copyright. All rights reserved Accepted Article Question 6: How has the utilization of red blood cells, platelets and plasma in your hospital changed since the start of the pandemic? Only the Australian and Korean respondents indicated that the use of RBCs, plasma, and platelets were unchanged from pre-pandemic levels. The other respondents indicated that they had either quantitatively or qualitatively noticed reductions in transfusions at their centers of around 30% for RBCs, 20-47% for platelets, and about 40% for plasma. Not surprisingly, the Brazilian respondent whose hospital exclusively treats hematology oncology patients reported no change in platelet transfusions thus far in the pandemic. Question 7: Does the respondent anticipate blood product shortages as a result of this pandemic? The Israeli, Spanish, Danish, British, and Korean respondents did not expect a blood shortage as a result of this pandemic. Others, such as the Brazilian, Italian and Iranian respondents, expected shortages in the short, medium, and long terms, while the American, Australian, Canadian, and Japanese respondents expected medium term shortages. The Canadian respondent also expects a shortage of plasma fractionation products such as IvIg in the long term. In terms of shortage mitigation strategies, many respondents such as the Israeli, Australian, and Italian respondents indicated that their hospitals had cancelled elective surgeries thereby helping to preserve their blood product inventories. Others, such as the respondents from USA, Brazil, Australia, and Canada held information campaigns to remind clinicians about appropriate transfusion thresholds and transfusing a single RBC unit at a time. The Canadian respondent also indicated that they reminded their clinicians about the appropriate use of pharmaceuticals such as prothrombin complex concentrates, tranexamic acid, and intravenous iron. The British respondent indicated that they reduced their hospital’s blood inventory level by about 30% to reduce wastage. Question 8: Other lessons learned from this pandemic This article is protected by copyright. All rights reserved See the individual responses for more details. In general, the advice from the respondents was to plan Accepted Article ahead of time for how the transfusion service should respond when these events happen. The Spanish and Canadian respondents mentioned their lack of advance preparedness for implementing a convalescent plasma program, while the Brazilian respondents advised having a plan for employee travel to and from the hospital when public transport is unavailable and for dealing with reduced staffing due to illness. The Italian respondent was concerned about having too many people donate blood early in the pandemic when the need for products was low thereby potentially creating waste and making donors ineligible to donate as the pandemic wanes and demand returns to normal. The British respondent suggested keeping the workflow as routine as possible to avoid confusion and errors. Question 9: Will your center offer convalescent plasma (CP)? The Spanish, Canadian, and British respondents indicated that CP will be available in the context of a clinical trial; the multicenter Spanish trial will randomize 278 patients into either the standard of care or standard of care plus CP arms, and primarily use clinical outcomes such as if the patient needs hospitalization and if any supplemental oxygen is required. Patients in the CP arm will receive one unit that will be between 250-300 ml collected by any approved apheresis machine, and the plasma will undergo pathogen inactivation using any approved method. Details of the Canadian and British trials are provided in the response section. The American respondent also plans to offer CP in the context of a clinical trial an also for compassionate use without pathogen inactivation. The Israeli and Brazilian respondents indicated that the Intercept (Cerus) technology will be used for their CP, while the respondents in Denmark, USA, and the UK indicated that the CP will not undergo pathogen inactivation. At the time of survey completion, CP was not available in Australia, Korea, and Japan. Summary Among countries with different levels of people affected by the SAR-Cov 2 pandemic, the hospital blood banks/transfusion departments have reacted differently to the pandemic. A third of the respondents did This article is protected by copyright. All rights reserved not change their policies/procedures for samples received from known or suspected patients while the Accepted Article remainder changed their practice in some way to minimize the exposure to potential contaminated specimens. Interestingly 75% of the respondents reported a decrease in overall blood components utilization due to the changes introduced at the hospitals to treat the COVID-19 patients. Convalescent plasma is also being considered or used in 75% of the responding centers to treat COVID-19 patients. Table legends Table 1. Demographics of the respondents to this International Forum. Table 2. Summary of replies to the questions posed in this International Forum. PPE: Personal protection equipment. BSC: Biosafety cabinet. Guest Editors Dr. Mark H. Yazer University of Pittsburgh University of Tel Aviv University of Southern Denmark Telephone: 1 412 209 7522 Email: yazermh@upmc.edu Dr. Bryon Jackson University of Maryland Telephone: 1 410-328-1612 Email: Bryon.Jackson@som.umaryland.edu This article is protected by copyright. All rights reserved Dr. Monica Pagano Accepted Article University of Washington Telephone: 1 425 387 0491 Email: monibea@uw.edu International Forum Editor Dr. Miquel Lozano University Clínic Hospital. Barcelona. Spain Telephone: +34 932 275 448 E-mail: mlozano@clinic.cat This article is protected by copyright. All rights reserved References: Accepted Article 1 Pagano MB, Hess JR, Tsang HC, et al.: Prepare to adapt: Blood supply and transfusion support during the first 2 weeks of the 2019 Novel Coronavirus (COVID-19) pandemic affecting Washington State. Transfusion in press. 2 Kamp C, Heiden M, Henseler O, et al.: Management of blood supplies during an influenza pandemic. Transfusion 2010; 50: 231-9. 3 Zimrin AB, Hess JR: Planning for pandemic influenza: effect of a pandemic on the supply and demand for blood products in the United States. Transfusion 2007; 47: 1071-9. 4 Zou S: Potential impact of pandemic influenza on blood safety and availability. Transfus Med Rev 2006; 20: 181-9. 5 Abdullah S, Karunamoorthi K: Ebola and blood transfusion: existing challenges and emerging opportunities. European review for medical and pharmacological sciences 2015; 19: 2983-96. 6 Beau F, Lastere S, Mallet HP, et al.: Impact on blood safety of the last arboviruses outbreaks in French Polynesia (2012-2018). Transfus Clin Biol 2020; 27: 4-9. 7 Bierlaire D, Mauguin S, Broult J, et al.: Zika virus and blood transfusion: the experience of French Polynesia. Transfusion 2017; 57: 729-33. 8 Slavov SN, Guaragna Machado RR, Ferreira AR, et al.: Zika virus seroprevalence in blood donors from the Northeastern region of Sao Paulo State, Brazil, between 2015 and 2017. J Infect 2020; 80: 111-5. 9 Dodd RY, Foster GA, Stramer SL: Keeping Blood Transfusion Safe From West Nile Virus: American Red Cross Experience, 2003 to 2012. Transfus Med Rev 2015; 29: 153-61. 10 Sakamoto N, Kosaka A, Imamura A, et al.: Pre-transfusion testing for Ebola virus disease patients in serious communicable infectious diseases hospitals in Tokyo: A cross-sectional study. J Infect Chemother 2019; 25: 489-93. This article is protected by copyright. All rights reserved TABLE 1 1e. Confirmed Accepted Article Novel Coronavirus 1g. Were novel 1.d Approximate 1f. Country Coranavirus Cases 1c. Number of Cases at the time 1a. Country/City 1b. Type of Hospital number of RBCs Population in Increasing, Decreasing or Beds of survey Transfused/Year Millions Stable at the time of completion survey completion ? (Deaths) Academic medical Melbourne, Australia 1639 22190 6553 (67) 25.65 Decreasing center Academic medical Rio de Janeiro, Brazil 100 12604 23830 (1355) 209.50 Increasing center Academic medical Toronto, Canada 1355 10500 42110 (2149) 37.6 Increasing center Odense, Denmark Tertiary hospital 1000 41000 6876 (309) 5.82 Decreasing Academic medical Oxford, England 1185 17000 129044 (17337) 66.50 Stable center Private specialty Tehran, Iran 200 4200 89328 (5650) 83.00 Stable hospital Academic medical Be'er Yaakov, Israel 956 9000 4831 (17) 9.14 Decreasing center Academic medical Udine, Italy 980 16580 181228 (24214) 60.00 Decreasing center Academic medical Tokyo, Japan 749 10000 12429 (328) 125.96 Increasing center Academic medical Seoul, Korea 1989 59838 10674 (236) 51.78 Stable center Madrid, Spain Tertiary hospital 869 13167 117710 (10935) 46.45 Decreasing Academic medical Stanford, United States 969 41000 386817 (10686) 332.64 Increasing center This article is protected by copyright. All rights reserved TABLE 2 9. Are you planning to 2. Did your hospital blood bank/transfusion 5. Was any additional training 7. Do you 2h. Were changes made in testing 2j. Changes made for all 3. Were blood 3l-o. Changes made for 4. Did your facility have an existing 6. Overall blood product use since 8. Describe specific measures use/using convalescent service accept samples from patients confirmed provided to the staff about the anticipate blood Country/City policies/procedures for samples 2i. If yes, what changes? samples or only for known or products dispensed products dispensed/returned in plan to deal with samples from the start of pandemic increasing, to avert or minimize these plasma from COVID-19 or suspected to be infected with novel nature of this virus and its shortages at your from known or suspected patients? suspected cases? in coolers? coolers patients with novel pathogen? decreasing or stable? shortages patients to treat severe coronavirus? infectivity? hospital? Accepted Article Melbourne, Australia Yes No NA NA Yes Cooler remains outside patient room. Products discarded if taken into patient room and not Yes Yes, use of PPE and laboratory disinfection protocols Stable Yes Cancellation of elective surgeries, enforcement of single unit transfusions in forms of the disease? Yes transfused. non-bleeding patients Yes, unspecified training session Rio de Janeiro, Brazil Yes Yes Plastic film used to open tubes All No NA No Decreasing No NA Yes for staff Units placed in individual Maximize use of iv iron, TXA, Addition of splash guard for plastic bags and sealed with a Yes, town hall on risk to lab staff Toronto, Canada Yes Yes All Yes Yes, created in response to Ebola Decreasing Yes epo, PCCs and strict adhesion Yes decapping samples sticker to indicate integrity, from handling COVID samples to strict transfusion triggers coolers disinfected upon return Samples from infected or Yes, e-learning program potentially infected patients were Odense, Denmark Yes Yes Only COVID patients No NA No concerning hand hygiene and Decreasing No NA Yes externally cleaned before arriving infection prevention at transfusion service Cancellation of elective Yes, nature of training not surgeries, adopting more Yes, but not at respondent's Tehran, Iran Yes No NA NA Yes NA Not specified Decreasing Yes specified restrictive transfusion hospital thresholds Labeled as COVID suspected, received in biohazard packages, no Yes, created in response to SARS in Be'er Yaakov, Israel Yes Yes tubing of specimens, sample tested Only COVID patients No NA Yes. Use of new PPE and BSC Stable No NA Yes 2003 in BSC, additional PPE used by staff, samples stored on designated shelf Decrease of non-urgent Surgical mask added to PPE and surgeries and admissions, Udine, Italy Yes Yes samples placed in segregated Only COVID patients No NA No Yes, unspecified online courses Decreasing Yes No use of restrictive transfusion storage triggers Yes, samples are sent to the Yes, general hospital wide Tokyo, Japan Yes No NA NA Yes No National Institute of Infectious Decreasing Yes No current plan No education Diseases Sample bags labeled as possible COVID patient , samples tested in Yes, created in response to MERS in Yes, unspecified hospital wide Seoul, Korea Yes Yes fume hood, stored in labeled bag Only COVID patients No NA Stable No NA No 2015 training and sent to micro for disinfection and disposal Sample tubes underwent Yes, workers trained according to Madrid, Spain Yes Yes hypochlorite wiping and UV light All Not specified NA Yes, but it had been inactive Decreasing No NA Yes their risk assessment. treatment for 30 minutes. Testing delayed after centrifugation Yes, education on testing Oxford, UK Yes Yes Only COVID patients Yes Not specified Yes Decreasing No NA Yes to minimize aerosol droplets procedure changes Yes, assigned lesson and Stanford, United Reinforce good transfusion Yes No NA NA Yes No No corresponding quizzes for lab Decreasing Yes Yes States practices guidelines This article is protected by copyright. All rights reserved