Fung, Mark K

Abstract Background Rho(D) immune globulin (RhIg) is used to reduce RhD alloimmunization in pregnancy. This study describes potential causes for RhD alloimmunization after the development and implementation of RhIg. Study Design and Methods This retrospective descriptive study investigated RhD‐negative patients born in 1965–2005 with anti‐D newly identified during 2018–2022. Transfusion, pregnancy, intravenous drug abuse, and transplantation were considered potential alloimmunization sources. Results There were 1200 study patients (852 females; 348 males) at 30 institutions in 5 countries (USA, Canada, UK, New Zealand, Brazil). Most patients had a single potential source of alloimmunization identified (857/1200, 71%), most commonly pregnancy among females (537/852, 63%) and transfusion among males (180/348, 52%). When multiple potential sources were included, males were more likely than females to have a history of transfusion (235/348 [68%] vs. 149/852 [17%], p < .0001) and confirmed or suspected intravenous drug abuse (100/348 [29%] vs. 138/852 [16%], p < .0001). Among females with a history of pregnancy, 119/718 (17%) had healthcare access issues, 120/718 (17%) had pregnancy in a country where they may not have received RhIg, and 21/718 (3%) refused RhIg. Among patients with a history of transfusion, males were more likely than females to have received RhD‐positive red blood cells or whole blood (143/235 [61%] vs. 30/149 [20%], p < .0001) and/or platelets (84/235 [36%] vs. 19/149 [13%], p < .0001). Discussion Pregnancy was the most frequently identified potential source of RhD alloimmunization among females. Transfusion was most frequent in males. Intravenous drug abuse as a common potential source among patients with RhD alloimmunization merits further study.

Abstract Objectives The red blood cell (RBC) D antigen is highly immunogenic, and anti-D alloimmunization can cause hemolytic transfusion reactions and hemolytic disease of the fetus and newborn. This study examined how RhD-negative patients who required packed RBCs (pRBCs) were handled during the COVID-19 pandemic and whether policies and practices on RhD-positive pRBC allocation to RhD-negative patients changed. Methods The Association for the Advancement of Blood & Biotherapies (AABB) Clinical Hemotherapy Subsection distributed a 17-question survey to physician AABB members to elucidate the impact of the COVID-19 pandemic on the policies and practices governing the provision of RhD-positive pRBCs to RhD-negative patients. Results There were 215 respondents who started the survey, but only 104 answered all the questions. Most institutional policies (130/155 [83.87%]) and personal practices (100/126 [79.37%]) on pRBC selection did not change during the COVID-19 pandemic. The practice of switching back to RhD-negative pRBCs after administration of RhD-positive pRBCs is variable. More than half of respondents (56/104 [53.85%]) reported offering Rh immunoglobulin to any Rh-negative patients who received RhD-positive pRBCs. Conclusions Despite RhD-negative pRBC supply challenges, most institutional policies and personal practices on when to provide RhD-positive pRBCs to RhD-negative patients did not change during the pandemic.

AbstractBackgroundCurrent Association for the Advancement of Blood & Biotherapies (AABB) standards require transfusion services to have a policy on Rh immune globulin (RhIG) immunoprophylaxis for when RhD‐negative patients are exposed to RhD‐positive red cells. This is a survey of AABB‐accredited transfusion services in the United States (US) regarding institutional policies and practices on RhIG immunoprophylaxis after RhD‐negative patients receive RhD‐positive (i.e., RhD‐incompatible) packed red blood cell (pRBC) and platelet transfusions.ResultsApproximately half of the respondents (50.4%, 116/230) have policies on RhIG administration after RhD‐incompatible pRBC and platelet transfusions, while others had policies for only pRBC (13.5%, 31/230) or only platelet (17.8%, 41/230) transfusions, but not both. In contrast, 18.3% (42/230) report that their institution has no written policies on RhIG immunoprophylaxis after RhD‐incompatible transfusions. Most institutions (70.2%, 99/141) do not have policies addressing safety parameters to mitigate the risk of hemolysis associated with the high dose of RhIG required to prevent RhD alloimmunization after RhD‐incompatible pRBC transfusions.DiscussionWith approximately half of US AABB‐accredited institutions report having policies on RhIG immunoprophylaxis after both RhD‐incompatible pRBC and platelet transfusions, some institutions may not be in compliance with AABB standards. Further, most with policies on RhIG immunoprophylaxis after RhD‐incompatible pRBC transfusion do not have written safeguards to mitigate the risk of hemolysis associated with the high dose of RhIG required.ConclusionThis survey underscores the diverse and inadequate institutional policies on RhIG immunoprophylaxis after RhD exposure in Rh‐negative patients via transfusion. This observation identifies an opportunity to improve transfusion safety.

AbstractBackgroundImmunoglobulin (IG) therapy is widely used to treat primary and secondary immune deficiencies and as immunomodulatory agent for various disorders. There is great concern that shortages of IG may rise, potentially affecting medical treatment options.Study Design and MethodsAn international survey was developed to study how intravenous immunoglobulins (IVIGs) are used and managed within hospitals in case of shortages. Study data were collected and managed using REDCap electronic data capture tools hosted by the Biomedical Excellence for Safer Transfusion (BEST) Collaborative. The survey was directed to hospital pharmacists and blood bank transfusion professionals and disseminated through members of the BEST Collaborative network.ResultsSurvey respondents from institutions in the USA, Canada, Europe, Japan, and Australia (n = 13) confirmed that the primary specialties utilizing IG are neurology, hematology, and immunology. More than 60% of respondents reported IG supply shortages, but mitigation strategies were not well developed.DiscussionAs IG is the leading driver in plasma demand, more studies are needed to understand current and future demand for IG from the clinical perspective. Necessity lies in establishing clinical guidance to address shortages.

Context Gene editing–based therapies are currently in development in the areas of oncology, inherited disease, and infectious disease. These potentially life-altering therapies are derived from decades of research in both academic and industry settings that developed technologies rooted in principles and products of nature. However, with such technologic developments come many important considerations, including adverse risks, high cost, and ethical questions. Objective To educate pathologists about gene editing technologies, inform them of potential indications and risks, outline regulatory and practical issues that could affect hospital-based practice and laboratory testing, and advocate that pathologists need to be present at discussions among industry and regulators pertaining to gene editing–based therapies. Design A Gene Editing Workgroup, facilitated by the College of American Pathologists Personalized Health Care Committee and consisting of pathologists of various backgrounds, was convened to develop an educational paper to serve as a stimulus to increase pathologist involvement and inquiry in gene editing therapeutic and diagnostic implementation. Results Through multiple discussions and literature review, the workgroup identified potential gaps in pathologists' knowledge of gene editing. Additional topics that could impact pathology and laboratory medicine were also identified and summarized in order to facilitate pathologists as stakeholders in gene editing therapy administration and monitoring and potential use in diagnostics. Conclusions Gene editing therapy is a complex but potentially transformative area of medicine. This article serves as an introduction to pathologists to assist them in future discussions with colleagues and potentially identify and alter pathology practices that relate to gene editing.

Context.— Ankylosing spondylitis (AS) is an autoimmune disorder with a strong genetic risk, especially with HLA-B27. Clinical testing for HLA-B27 has been used to help diagnose patients with signs and symptoms of AS. Testing methods used by clinical laboratories for HLA-B27 fall into the broad categories of serologic/antibody- or molecular-based methods and have evolved over time. The College of American Pathologists (CAP) offers a proficiency testing survey for HLA-B27. Objective.— To analyze HLA-B27 testing trends and their performance in the past decade, using the proficiency testing survey data submitted to CAP. Design.— We analyzed the HLA-B27 CAP proficiency testing data from 2010 to 2020 for the method used, participant concordance, and error rates. Results from case scenarios to understand evolving scientific data around HLA-B27 risk alleles were also analyzed. Results.— Antibody-based flow cytometry is the most common method, though it has decreased from 60% in 2010 to 52% in 2020, with a corresponding increase in molecular methods. Among the molecular methods, real-time polymerase chain reaction has increased from 2% to 15%. Flow cytometry had the highest error rate (5.33%), and sequence-specific oligonucleotide (0%) is the most accurate (0%). Results of case scenarios demonstrated that most participants understood that allele-level HLA-B27 typing results inform clinical interpretation, for example HLA-B*27:06 is not associated with AS. Conclusions.— These data demonstrated the changing trends for HLA-B27 testing during the past decade. HLA-B27 allelic typing provides a better understanding of AS association. This is possible by testing for the second field with methods like next-generation sequencing.

AbstractBackgroundAlthough the safety and therapeutic efficacy of COVID‐19 convalescent plasma (CCP) has been extensively evaluated, the safety of CCP donation has not been explored in a multi‐institutional context.Study design and methodsNine blood collection organizations (BCOs) participated in a multi‐institutional donor hemovigilance effort to assess the safety of CCP donation. Donor adverse events (DAEs) were defined according to the Standard for Surveillance of Complications Related to Blood Donation, and severity was assessed using the severity grading tool. Multivariate analysis was performed to determine attributes associated with DAE severity.ResultsThe overall DAE rate was 37.7 per 1000 donations. Repeat apheresis and apheresis‐naïve donors experienced adverse event rates of 19.9 and 49.8 per 1000 donations, respectively. Female donors contributed 51.9% of CCP donations with a DAE rate of 49.4 per 1000 donations. The DAE rate for male donors was 27.4 per 1000 donations. Vasovagal reactions accounted for over half of all reported DAEs (51.1%). After adjustment, volume of CCP donated was associated with vasovagal reaction severity (odds ratio [OR] 6.5, 95% confidence interval [CI] 2.5–17.1). Donor age and donation history were also associated with DAE severity. Considerable differences in DAE types and rates were observed across the participating BCOs despite the use of standardized hemovigilance definitions.ConclusionThe safety of CCP donation appears comparable to that of conventional apheresis plasma donation with similar associated risk factors for DAE types and severity.

BACKGROUNDSingle antigen bead (SAB) assays are used to identify human leukocyte antigen (HLA) antibodies in patients with platelet refractoriness due to HLA Class I alloimmunization. Some laboratories use serum pretreatment regimens to eliminate interference from immunoglobulin M antibodies and complement. These modifications may contribute to interlaboratory variability, which is a recognized problem with the SAB assay.STUDY DESIGN AND METHODSFive patientsʼ sera were overnight shipped to 12 laboratories in the United States and internationally. Recipients used their labʼs SAB procedure to identify HLA Class I antibodies. The resultant mean fluorescence intensity (MFI) data were compared by instrumentation, bead lot, and pretreatment regimens. Laboratory‐specific cutoffs for positive antibodies were applied to the results.RESULTSInterlaboratory variability for MFI values appears to be associated with different pretreatment regimens. The coefficient of variation (CV) of MFI from samples pretreated with ethylenediaminetetraacetic acid, dithiothreitol, or heat inactivation (EDHI) were similar, ranging from 14% to 56% (mean, 22%). For samples with no pretreatment, the CVs were significantly higher than EDHI‐treated samples, ranging from 25% to 74% (mean, 39%; 95% confidence interval, 12.10‐21.90; p < 0.0001). An intralaboratory comparison of pretreatment regimens confirmed these findings. Some positive antibody specificities present in EDHI‐treated samples were negative in corresponding samples with no pretreatment when laboratory‐specific cutoffs for positive antibodies were applied.CONCLUSIONOur results show that greater interlaboratory precision can be achieved when samples are pretreated with EDHI as opposed to no pretreatment, likely because these pretreatments eliminate interference from inhibitors. Inhibitors may mask antibodies, leading to missed (or uncalled) specificities when no pretreatment is used.

BACKGROUNDTransfusion‐related acute lung injury (TRALI) is a serious complication of blood transfusion and is among the leading causes of transfusion‐related morbidity and mortality in most developed countries. In the past decade, the pathophysiology of this potentially life‐threatening syndrome has been increasingly elucidated, large cohort studies have identified associated patient conditions and transfusion risk factors, and preventive strategies have been successfully implemented. These new insights provide a rationale for updating the 2004 consensus definition of TRALI.STUDY DESIGN AND METHODSAn international expert panel used the Delphi methodology to develop a redefinition of TRALI by modifying and updating the 2004 definition. Additionally, the panel reviewed issues related to TRALI nomenclature, patient conditions associated with acute respiratory distress syndrome (ARDS) and TRALI, TRALI pathophysiology, and standardization of reporting of TRALI cases.RESULTSIn the redefinition, the term “possible TRALI” has been dropped. The terminology of TRALI Type I (without an ARDS risk factor) and TRALI Type II (with an ARDS risk factor or with mild existing ARDS) is proposed. Cases with an ARDS risk factor that meet ARDS diagnostic criteria and where respiratory deterioration over the 12 hours before transfusion implicates the risk factor as causative should be classified as ARDS. TRALI remains a clinical diagnosis and does not require detection of cognate white blood cell antibodies.CONCLUSIONSClinicians should report all cases of posttransfusion pulmonary edema to the transfusion service so that further investigation can allow for classification of such cases as TRALI (Type I or Type II), ARDS, transfusion‐associated circulatory overload (TACO), or TRALI or TACO cannot distinguish or an alternate diagnosis.