key: cord-287644-ay0vv27m authors: Blackall, Douglas; Wulff, Shephali; Roettger, Timothy; Jacobs, Lauren; Lacasse, Alexandre; Patri, Manokiran; Zinser, Phillip; Pherez, Francisco; Jamkhana, Zafar; Frey, Sharon E.; Smith, Linda; Goel, Ruchika; Katz, Louis title: Rapid Establishment of a COVID‐19 Convalescent Plasma Program in a Regional Healthcare Delivery Network date: 2020-08-04 journal: Transfusion DOI: 10.1111/trf.16026 sha: doc_id: 287644 cord_uid: ay0vv27m BACKGROUND: COVID‐19 convalescent plasma (CCP) represents an appealing approach to the treatment of patients with infections due to SARS‐CoV‐2. We endeavored to quickly establish a sustainable CCP transfusion program for a regional network of healthcare facilities. STUDY DESIGN AND METHODS: A regional collaborative group was activated to address the issues necessary to implementing a CCP transfusion program and making the program sustainable. A wide range of healthcare providers including physicians (critical care, infectious disease, transfusion medicine), nurses, pharmacists, laboratorians, and information technology specialists were required to make the program a success. RESULTS: The CCP implementation team initially consisted of 4 members but quickly grew to a group of nearly 20 participants based on different issues related to program implementation. Overall, 6 major implementation “themes” were addressed: (1) registration of individual hospitals and principle investigators with a national investigational new drug research protocol, (2) collaboration with a regional blood donor center, (3) targeted recruitment of convalesced donors, (4) information technology issues related to all aspects of CCP ordering, distribution, and transfusion, (5) prioritization of patients to receive CCP, and (6) evaluation of CCP products including antibody characteristics and patient response to therapy. CONCLUSION: Within 4 weeks of initiation, CCP was successfully transfused at multiple hospitals in our regional healthcare delivery system. A program infrastructure was established that will make this program sustainable into the future. This approach has broader implications for the success of multi‐institutional programs requiring rapid implementation. SARS-CoV-2 is a novel coronavirus and is the etiologic agent of COVID-19. 1 It is a single-stranded RNA virus that was first identified in Wuhan China in December 2019. Although brought under control locally, the virus proved to be highly communicable with infection declared to have reached pandemic status by the WHO on March 11, 2020. 2 Since that time, the virus has been detected in virtually every country in the world, has caused well over 4 million cases of disease, and is responsible for hundreds of thousands of deaths. 3 The United States has not been immune to the ravages of COVID-19 and now accounts for the highest number of cases and associated fatalities worldwide. 3 A variety of anti-viral agents, and combinations of agents, are under intense evaluation for the treatment of COVID-19. 4 In addition, multiple vaccine candidates are being evaluated. 5 However, no established, evidence-based treatments are available at this time. COVID-19 convalescent plasma (CCP) represents a novel approach to the treatment of COVID-19 patients and has deep historical roots. Passive antibodies obtained from convalesced patients have shown promising results in the treatment of a variety of viral infectious diseases including influenza, measles, and SARS. 6 This strategy is also the basis for hyperimmune globulin therapy (e.g. hepatitis B immune globulin). At the same time, convalescent plasma has not always proven to be a useful adjunct to more conventional therapy, as the recent Ebola virus epidemic in West Africa demonstrated. 7 Without a vaccine or effective medications to ameliorate COVID-19, the establishment of convalescent plasma transfusion programs has taken on greater urgency. To this end, a national investigational new drug (IND) expanded access program (National Clinical Trial Identification This article is protected by copyright. All rights reserved. Number: 04338360), administered by the Mayo Clinic, was initiated in March 2020 to study the effectiveness of CCP in a defined patient population (those with severe or life-threatening COVID-19) and facilitate the provision of CCP to participating institutions. 8 Our regional healthcare delivery network, SSM Health, a major provider of healthcare services in the St. Louis region, became engaged in the rapid establishment of a CCP program for its network hospitals. In this paper, our approach to the implementation of a successful CCP program is described. SSM Health is a comprehensive, not-for-profit health system comprised of 23 hospitals, 300 physician offices, and a variety of other healthcare services. The system spans 4 states (Illinois, Missouri, Oklahoma, and Wisconsin). The St. Louis network of hospitals, heretofore referred to as SSM-STL, includes 7 facilities: 5 community hospitals, a children's hospital, and an academic, university-affiliated hospital. With the exception of the Oklahoma-based hospitals, all other SSM Health facilities use Mississippi Valley Regional Blood Center (MVRBC) as the provider of blood products and related services. Importantly, no hospital has the infrastructure to collect blood products, including CCP. When it became apparent that CCP represented an important therapeutic option for patients with COVID-19, the SSM-STL network became interested in bringing this therapeutic option to its member hospitals in St. Louis. In late March 2020, a core team consisting of the regional directors of pharmacy and laboratory services, the medical director of the regional donor Accepted Article This article is protected by copyright. All rights reserved. center (MVRBC), and a transfusion medicine specialist was convened to initiate program planning. The expressed goals of this group were stated as follows: 1. To have a donor available to MVRBC on the first day that they can accept a donor 2. To infuse a COVID-19 patient within 48 hours of that donation 3. To make as many doses of CCP available to hospital providers as needed Based on these goals, this core team defined 6 program elements that would need to coalesce to meet the goals of the CCP transfusion project and make it sustainable. These program elements included the following: . Convalescent plasma at the children's hospital, if needed, would be undertaken with a patient-specific eIND. Once hospitals were registered, a clinician from each member hospital was identified to serve as principle investigator and that individual was registered with the Mayo site. These individuals were largely infectious disease or critical care physicians. This article is protected by copyright. All rights reserved. Though the transfusion of CCP must be undertaken under an appropriate IND, the collection of CCP and its processing does not differ, in any material way, from the routine collection of blood products. In short, donors of convalescent plasma are required to meet all donor eligibility criteria with the exception that they have positive nucleic acid testing for SARS-CoV-2. In addition, the donor must have been asymptomatic for a period of at least 28 days. The FDA originally made an exception for donors in the 14 to 27 day period of asymptomatic convalescence, but qualification in this time period would require repeat negative molecular testing for SARS-CoV-2. However, this requirement was rescinded on May 1, 2020. Despite this change, MVRBC, in conjunction with the SSM-STL CCP collaborative group, decided to retain the 28-day period of convalescence reasoning that antibody levels would likely be higher in this timeframe. Of note, before CCP is distributed to hospitals by MVRBC, it is assessed for antibody activity using the Abbott Diagnostics SARS-CoV-2 IgG assay. In addition, to implementing a system for qualifying donors (e.g. standard operating procedure changes), the blood center had to validate additional apheresis instruments for the collection of convalescent plasma, assure an adequate supply and availability of apheresis kits, and provide those resources to the St. Louis region for plasma collection (the primary site of operation for MVRBC is Davenport, Iowa). As part of their implementation, the blood center decided that plasma would be collected from eligible donors by apheresis technology rather than through whole blood donation. The benefits of this approach are that (1) up to an 800 mL collection could serve as the source for multiple 200-mL CCP units and (2) donors could be recruited at a more frequent interval for repeat donations. In contrast, only a single CCP unit could be obtained from a whole blood donation, the red cells would likely not be deemed acceptable for Accepted Article transfusion, and the interval between donations would be the standard 56-day temporary deferral. Finally, MVRBC required assistance from their hospital clients to identify eligible convalesced donors in order to successfully launch their CCP collection program. As opposed to making a broad regional appeal for convalescent donors, it became evident that the process could be jump-started by targeting recruitment to patients known to have a positive molecular test for SARS-CoV-2. Fortunately, the SSM-STL network has a regional clinical microbiology facility that implemented a laboratory developed nucleic acid test for SARS-CoV-2. Nearly 200 patients who tested positive were identified. A step-wise process was implemented to connect these potential donation candidates to MVRBC for assessment. First, the potential donor's medical record was interrogated to determine if they were suitable for donation. As an example, patients who were deceased, < 18 or > 80, or currently hospitalized were excluded from immediate consideration. The potential donors were then contacted to determine their interest in donating plasma and their willingness to be contacted by MVRBC to discuss donation. For those who were interested and agreed to contact, an online MVRBC physician referral form was completed. Thereafter, a representative from MVRBC contacted the potential donor, explained the process of donation, and conducted a brief screen to determine suitability. Appropriate donors were then scheduled for donation. This was mostly based on the time at which they would reach the 28-day threshold of convalescence. Additional COVID-19 patients (~100) were identified through an interrogation of the Epic electronic health record, to identify patients who tested positive for the virus in a facility other than the SSM-STL This article is protected by copyright. All rights reserved. centralized microbiology laboratory. These patients were contacted in the same manner described above. Finally, a system was implemented so that hospitalized COVID-19 patients who recovered would be asked about their interest in donating convalescent plasma as part of a routine discharge follow-up call. In sum, this targeted approach to donor recruitment facilitated the identification of over 130 suitable candidates who agreed to be contacted about plasma donation. See Figure 1 for recruitment details and Table 1 Aside from tracking individual units, a robust IT infrastructure would allow for the easy retrieval of program data from the individual hospitals in the SSM-STL network. In addition to the more standard procedural elements described above, unique features were built into the ordering process to meet the needs of the Mayo Clinic IND protocol. These included links to the Mayo consent and the patient registration forms (Figure 2) . Once a patient is registered in the Mayo system, a unique numerical identifier is provided to the principle investigator for the site. The This article is protected by copyright. All rights reserved. inclusion of this number, as a required field in the CCP ordering process, was a critical addition related to blood product billing. Specifically, MVRBC does not charge the ordering hospital for CCP as long as the patient is registered with the Mayo protocol and the patient's unique identifier is provided to the blood center. The cost for the CCP units is borne by the Biomedical Advanced Research and Development Authority (BARDA), a sponsor of this research protocol along with the Food and Drug Administration (FDA). In sum, a robust IT infrastructure has allowed us to closely monitor all aspects of the transfusion process and has provided us with a resource for rapid data extraction. This contrasts with facilities that track CCP using manual downtime procedures. Approximately 2 weeks into the development of our comprehensive, multi-institutional CCP program, it became obvious that, at least early on, the demand for CCP would far outstrip the availability of the product. Because of this, the principle investigators at each site determined that it would be critical for them, as a group, to discuss patients considered to be appropriate for CCP and prioritize patients prior to their registration with the Mayo IND. The Mayo IND provides specific criteria for patient inclusion in the protocol; namely, that they have positive molecular testing for SARS-CoV-2, are an adult (≥ 18 years of age), and have met defined clinical criteria qualifying them as having severe or life-threatening COVID-19. 8 These inclusion criteria were a useful starting point for our clinicians, but it was felt that the additional consideration of significant comorbid conditions and an objective measure of disease severity (SOFA scoring system; Sequential Organ Failure Assessment) would assist in prioritizing patients for CCP. To This article is protected by copyright. All rights reserved. this end, our team of principle investigators developed criteria, approved by the SSM-STL clinical practice group, to rank patients in a tiered prioritization scheme (see Appendix and Reference 9). The overriding ethical principle driving prioritization was maximal survival benefit-that is, with a scarce resource such as CCP, patients most likely to benefit by this therapeutic intervention should have priority in receiving it. Related to this, patient age was not included as a criterion for prioritization though special consideration was given to pregnant patients and healthcare workers. Initially, the principle investigator team met daily to determine the prioritization of patients who were candidates for CCP. After a week of daily meetings, weekly meetings were held as the clinical team developed confidence in the group members' ability to identify appropriate patients and move the process forward successfully (i.e. patient registration, CCP ordering, etc.). The overriding goals of the Mayo IND for CCP are to determine the safety and efficacy of the product in treating severely and critically ill COVID-19 patients while facilitating availability to eligible patients. This aspect of the project is being coordinated through the American Red Cross, but participating hospitals are free to obtain plasma through their local blood supplier (e.g. MVRBC). Unfortunately, because of the likely variability of the antibody content and composition of the plasma products and the almost certain variability of the patients who ultimately receive CCP, a determination of efficacy will be challenging. To gain a better understanding of the utility of CCP, it was reasoned that it would be important to analyze the Accepted Article This article is protected by copyright. All rights reserved. serological characteristics of each unit of CCP transfused along with an evaluation of the recipient. This would provide a more nuanced understanding of efficacy. To this end, serum aliquots from each donor of convalescent plasma will be evaluated through a variety of research assays and a serologic assay that was released by the FDA under emergency use authorization. Research assays include IgG and IgM ELISA assays for antibody to SARS-CoV-2 nucleocapsid antigen, spike proteins (S1 + S2), and spike protein binding domain. The Abbott Diagnostics SARS-CoV-2 IgG assay will also be evaluated at the same time. Most importantly, convalescent serum samples will be assessed in a viral neutralization assay, to determine if a donor's immune response actually has viral neutralizing capability. With Saint Louis University IRB approval, patients receiving CCP will also be evaluated, primarily through electronic medical record review, to determine if the transfusion of convalescent plasm had a beneficial effect, clinically and through laboratory value interrogation. These studies may prove to identify the types of patients who might benefit most by CCP therapy and the CCP donors with the greatest likelihood of having plasma capable of delivering a beneficial therapeutic effect. The timespan from project initiation to the successful transfusion of a unit of CCP was 30 days. The chief reason for the delay in transfusion resided in the fact that we were waiting for our donor pool to reach the 28-day asymptomatic threshold required for donation. All other elements of our comprehensive, multi-institutional CCP program were in place. This article is protected by copyright. All rights reserved. Convalescent plasma has a long history of utilization for patients suffering from a variety of infectious diseases including influenza viruses (more typical influenza A and B as well as H1N1 and H7N9 strains), Ebola virus, and non-SARS-CoV-2 coronavirus infections (SARS and MERS). 6, 7 Early evidence suggests that it may have utility in augmenting severe COVID-19 disease. 10, 11 Although theoretically appealing, all interventions to date have suffered from a lack of rigorous randomized controlled trials that clearly demonstrate clinical efficacy. Most often, the products transfused are not well-characterized with respect to viral neutralization properties and the treated patient populations are heterogeneous. 12 Thus, optimal donors and patients are generally not understood. In addition, even routine plasma transfusions are not without some risk including both infectious and non-infectious adverse effects of transfusion (e.g. transfusionassociated circulatory overload, transfusion-related acute lung injury, and allergic reactions of varying degrees of severity). 12 More specifically, convalescent plasma may be associated with immunologic complications including a blunting of the patient's own immune response and the possibility of antibody-dependent enhancement of disease. [13] [14] [15] Nevertheless, convalescent plasma utilization is more compelling when a disease has no proven therapeutic interventions, such as COVID-19. The current COVID-19 pandemic represents a unique opportunity to put convalescent plasma to the test, as a prophylactic intervention, a disease modulating agent (e.g. to decrease the likelihood of disease progression), and as a therapeutic for severe or life-threatening clinical disease. It is this use which is the basis of the Mayo Clinic IND protocol. Although not a This article is protected by copyright. All rights reserved. randomized controlled study, this protocol provided the infrastructure to initiate a convalescent plasma transfusion program in the SSM-STL network, which is the basis for this report. Our approach is unique in that it is comprehensive, involving all aspects of the transfusion process from donor recruitment to infusion of the plasma product. Further, it includes a research arm that will help to answer important issues regarding the utility of CCP including a definition of the serological characteristics of each unit transfused and a determination of efficacy based on clinical disease manifestations and the evaluation of laboratory parameters. This may provide insight into the patients most likely to benefit from this therapy (i.e. who to transfuse and when to transfuse in the course of their disease). Our CCP program was initiated with a core group of 4 individuals who quickly developed program goals and determined the programmatic elements that would have to be in place to make the program robust and sustainable. The input of a much larger team of individuals, including pharmacy and laboratory staff members, information technology specialists, nurses, and physicians, was required at different points in the program development process. In the end, when CCP became available a fully mature program was already established. We were able to jump-start a convalescent plasma donor pool through the targeted recruitment of appropriate donors. We benefited directly by this approach in creating a sustained supply of CCP. Our approach can serve as a model for others wishing to embark on establishing a CCP program for a multi-hospital system. More than this, though, we hope that our general approach may be of benefit to any organization faced with the need to rapidly establish a complex program requiring the collaboration of a variety of individuals over multiple institutions. It can be done. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2 Coronavirus disease 2019 (COVID-19) situation summary New cases of COVID-19 in world countries Current targeted therapeutics against COVID-19: based on first-line experience in China COVID-19, an emerging coronavirus infection: advances and prospects in designing and developing vaccines, immunotherapeutics, and therapeutics Convalescent plasma: therapeutic hope or hopeless strategy in the SARS-CoV-2 pandemic Evaluation of convalescent plasma for Ebola virus disease in Guinea COVID-19 expanded access program Fair allocation of scarce medical resources in the time of Covid-19 Effectiveness of convalescent plasma therapy in severe COVID-19 patients Treatment of 5 critically ill patients with COVID-19 convalescent plasma COVID-19 convalescent plasma: now is the time for better science Antibody-dependent enhancement of severe dengue disease in humans Current studies of convalescent plasma therapy for COVID-19 may underestimate risk of antibody-dependent enhancement Viral-induced enhanced disease illness The authors acknowledge the outstanding contributions made by regional pharmacy staff for the recruitment of convalescent plasma donors, regional blood bank staff for processing and distributing convalescent plasma, information technology staff for developing the system to manage all aspects of the hospital transfusion process, and the staff at Mississippi Valley Regional Blood Center for rapidly implementing a system to collect convalescent plasma. Most importantly, the authors acknowledge and thank the COVID-19 survivors who donated their convalescent plasma. This article is protected by copyright. All rights reserved. 1) Process of evaluation:  Calculate each patient's priority score using the multi-principle allocation framework. This framework is based on two considerations: 1) saving the most lives and 2) saving the most life-years.  The SOFA (Sequential Organ Failure Assessment) score is used to determine patients' prognoses for hospital survival.  The presence of life-limiting comorbid conditions, as determined by the triage team, is used to characterize patients' longer-term prognosis.  Points are assigned according to the patient's SOFA score (range from 1 to 4 points) (Appendix A, Table 2 ).  These points are added together to produce a total priority score, which ranges from 1 to 8. (Appendix B, Table 1 ). Lower scores indicate a higher likelihood of benefiting from critical care; priority will be given to those with lower scores. 2) Color-coded priority groups. Once a patient's priority score is calculated using the multi-principle scoring system, the patient should be assigned to a color-coded triage priority group, which should be noted clearly in their chart/electronic health record. To avoid marginal differences in scores, the raw score is converted to one of three priority categories. (Appendix B, Table 2 ).  In case of a tie; priority can be assigned on a first-come, first-served basis; by giving heightened priority to pregnant patients; or, the raw score on the patient prioritization score with priority going to the patient with a lower raw score. 4) This prioritization will only occur when the amount of COVID-19 convalescent plasma is not adequate to treat all patients who are candidates for this treatment.Once a sufficient level of convalescent plasma is present, the plasma will be distributed on a first-come, first-served basis. This article is protected by copyright. All rights reserved.