Ebola virus antibody decay-stimulation in a high proportion of survivors.

Neutralizing antibody function provides a foundation for the efficacy of vaccines and therapies1-3. Here, using a robust in vitro Ebola virus (EBOV) pseudo-particle infection assay and a well-defined set of solid-phase assays, we describe a wide spectrum of antibody responses in a cohort of healthy survivors of the Sierra Leone EBOV outbreak of 2013-2016. Pseudo-particle virus-neutralizing antibodies correlated with total anti-EBOV reactivity and neutralizing antibodies against live EBOV. Variant EBOV glycoproteins (1995 and 2014 strains) were similarly neutralized. During longitudinal follow-up, antibody responses fluctuated in a 'decay-stimulation-decay' pattern that suggests de novo restimulation by EBOV antigens after recovery. A pharmacodynamic model of antibody reactivity identified a decay half-life of 77-100 days and a doubling time of 46-86 days in a high proportion of survivors. The highest antibody reactivity was observed around 200 days after an individual had recovered. The model suggests that EBOV antibody reactivity declines over 0.5-2 years after recovery. In a high proportion of healthy survivors, antibody responses undergo rapid restimulation. Vigilant follow-up of survivors and possible elective de novo antigenic stimulation by vaccine immunization should be considered in order to prevent EBOV viral recrudescence in recovering individuals and thereby to mitigate the potential risk of reseeding an outbreak.

Evaluating apheresis platelets at reduced dose as a contingency measure for extreme shortages.

BACKGROUND: The COVID19 pandemic highlights the need for contingency planning in the event of blood shortages. To increase platelet supply, we assessed the operational impact and effect on platelet quality of splitting units prior to storage. STUDY DESIGN AND METHODS: Using production figures, we modeled the impact on unit numbers, platelet counts, and volumes of splitting only apheresis double donations into three units (yielding ⅔ doses), or all standard dose units in half. To assess quality, eight pools of three ABO/Rh-matched apheresis (Trima Accel) double donations in plasma were split to ⅔ and ½ volumes in both Terumo and Fresenius storage bags. These were irradiated and subject to maximal permitted periods of nonagitation (3 × 8 h) before comparing platelet quality markers (including pH, CD62P expression) to Day 9 of storage. RESULTS: Splitting all double donations into three predicted inventory expansion of 23% overall whereas halving all standard dose units clearly doubles stock. In our study, ⅔ and ½ doses contained 153 ± 15 × 109 (~138 ml) and 113 ± 11 × 109 (~102 ml) platelets respectively. Following storage, higher pH was observed in ⅔ than in ½ doses and in Terumo compared to Fresenius bags. The higher pH was reflected in better quality markers, including lower CD62P expression. Despite the differences, on Day 8 (of pH monitoring at expiry) all ⅔ doses and most ½ doses were ≥pH 6.4. CONCLUSION: A strategy to split apheresis platelets in plasma to lower doses is feasible, maintains acceptable platelet quality, and should be considered by blood services in response to extreme shortages.

U.S. cities will not meet blood product resuscitation standards during major mass casualty incidents: Results of a THOR-AABB working party prospective analysis.

BACKGROUND: Mass casualty incidents (MCIs) create an immediate surge in blood product demand. We hypothesize local inventories in major U.S. cities would not meet this demand. STUDY DESIGN AND METHODS: A simulated blast in a large crowd estimated casualty numbers. Ideal resuscitation was defined as equal amounts of red blood cells (RBCs), plasma, platelets, and cryoprecipitate. Inventory was prospectively collected from six major U.S. cities at six time points between January and July 2019. City-wide blood inventories were classified as READY (>1 U/injured survivor), DEFICIENT (<10 U/severely injured survivor), or RISK (between READY and DEFICIENT), before and after resupply from local distribution centers (DC), and features of DEFICIENT cities were identified. RESULTS: The simulated blast resulted in 2218 injured survivors including 95 with severe injuries. Balanced resuscitation would require between 950 and 2218 units each RBC, plasma, platelets and cryoprecipitate. Inventories in 88 hospitals/health systems and 10 DCs were assessed. Of 36 city-wide surveys, RISK inventories included RBCs (n = 16; 44%), plasma (n = 24; 67%), platelets (n = 6; 17%), and cryoprecipitate (n = 22; 61%) while DEFICIENT inventories included platelets (n = 30; 83%) and cryoprecipitate (n = 12; 33%). Resupply shifted most RBC and plasma inventories to READY, but some platelet and cryoprecipitate inventories remained at RISK (n = 24; 67% and n = 12; 33%, respectively) or even DEFICIENT (n = 11; 31% and n = 6; 17%, respectively). Cities with DEFICIENT inventories were smaller (p <.001) with fewer blood products per trauma bed (p <.001). DISCUSSION: In this simulated blast event, blood product demand exceeded local supply in some major U.S. cities. Options for closing this gap should be explored to optimize resuscitation during MCIs.

Transfusion support during mass casualty events.

Transfusion support is an essential element of modern emergency healthcare. Blood services together with hospital transfusion teams are required to prepare for, and respond to, mass casualty events as part of wider healthcare emergency planning. Preparedness is a constant collaborative process that actively identifies and manages potential risks, to prevent such events becoming a 'disaster'. The aim of transfusion support during incidents is to provide sufficient and timely supply of blood components and diagnostic services, whilst maintaining support to other patients not involved in the event.

Temperature mapping in an air ambulance helicopter: Implications for the delivery of pre-hospital transfusion.

BACKGROUND: Pre-hospital blood products, including freeze-dried plasma, are increasingly carried on air ambulance helicopters. The purpose of this study was to map the temperatures within a civilian air ambulance and consider the implications for pre-hospital transfusion. MATERIALS AND METHODS: We conducted a single-site prospective observational study in the United Kingdom. Tinytag temperature data-loggers (Gemini, UK) were secured on to three locations throughout an air ambulance, and one was placed inside an insulated drug-pouch. Temperatures were monitored at 5-min intervals. Data were downloaded monthly and processed using R and MKT software to collate maximum, minimum, and day/night mean kinetic temperatures (MKTs). Blood was transported in Credo ProMed 4 containers (Peli Products, S.L.U) and monitored with QTA data-loggers (Tridentify, Sweden). RESULTS: A total of 344,844 temperature recordings were made on 302 days during a 12-month period from January 2019. The external ambient temperatures varied seasonally from -7.1°C to 31.2°C, whereas internal temperatures ranged from -0.3°C to 60.6°C. The warmest area was alongside the left front-crew position (range 1.9-60.6°C, MKT 24.8°C). The lowest daytime MKT (16.9°C) and range (1.7°C-36.4°C) were recorded next to the patient stretcher. Temperatures ranged from 4.2°C to 40.1°C inside the insulated drugs-pouch, exceeding 25°C on 47 days (15%) and falling below 15°C on 192 days (63%) In contrast, thermally packed blood maintained a range of 2-6°C. CONCLUSION: The temperatures within an air ambulance varied throughout the cabin and often exceeded the external ambient temperature. Appropriately selected thermal protection and monitoring is required for the successful delivery of pre-hospital transfusion, even in a temperate climate.

Effect of parachute delivery on red blood cell (RBC) and plasma quality measures of blood for transfusion.

BACKGROUND: Parachute airdrop offers a rapid transfusion supply option for humanitarian aid and military support. However, its impact on longer-term RBC survival is undocumented. This study aimed to determine post-drop quality of RBCs in concentrates (RCC), and both RBCs and plasma in whole blood (WB) during subsequent storage. STUDY DESIGN AND METHODS: Twenty-two units of leucodepleted RCC in saline, adenine, glucose, mannitol (SAGM) and 22 units of nonclinical issue WB were randomly allocated for air transportation, parachute drop, and subsequent storage (parachute), or simply storage under identical conventional conditions (4 ± 2°C) (control). All blood products were 6-8 days post-donation. Parachute units were packed into Credo Cubes, (Series 4, 16 L) inside a PeliCase (Peli 0350) and rigged as parachute delivery packs. Packs underwent a 4-h tactical flight (C130 aircraft), then parachuted from 250 to 400 ft before ground recovery. The units were sampled aseptically before and after airdrop at weekly intervals. A range of assays quantified the RBC storage lesion and coagulation parameters. RESULTS: Blood units were maintained at 2-6°C and recovered intact after recorded ground impacts of 341-1038 m s-2 . All units showed a classical RBC storage lesion and increased RBC microparticles during 42 days of storage. Fibrinogen and clotting factors decreased in WB during storage. Nevertheless, no significant difference was observed between Control and Parachute groups. Air transportation and parachute delivery onto land did not adversely affect, or shorten, the shelf life of fresh RBCs or WB. DISCUSSION: Appropriately packaged aerial delivery by parachute can be successfully used for blood supply.

Civilian walking blood bank emergency preparedness plan.

BACKGROUND: The current global pandemic has created unprecedented challenges in the blood supply network. Given the recent shortages, there must be a civilian plan for massively bleeding patients when there are no blood products on the shelf. Recognizing that the time to death in bleeding patients is less than 2 h, timely resupply from unaffected locations is not possible. One solution is to transfuse emergency untested whole blood (EUWB), similar to the extensive military experience fine-tuned over the last 19 years. While this concept is anathema in current civilian transfusion practice, it seems prudent to have a vetted plan in place. METHODS AND MATERIALS: During the early stages of the 2020 global pandemic, a multidisciplinary and international group of clinicians with broad experience in transfusion medicine communicated routinely. The result is a planning document that provides both background information and a high-level guide on how to emergently deliver EUWB for patients who would otherwise die of hemorrhage. RESULTS AND CONCLUSIONS: Similar plans have been utilized in remote locations, both on the battlefield and in civilian practice. The proposed recommendations are designed to provide high-level guidance for experienced blood bankers, transfusion experts, clinicians, and health authorities. Like with all emergency preparedness, it is always better to have a well-thought-out and trained plan in place, rather than trying to develop a hasty plan in the midst of a disaster. We need to prevent the potential for empty shelves and bleeding patients dying for lack of blood.

Re-introducing whole blood for transfusion: considerations for blood providers.

Whole blood is the original blood preparation but disappeared from the blood bank inventories in the 1980s following the advent of component therapy. In the early 2000s, both military and civilian practice called for changes in the transfusion support for massive haemorrhage. The 'clear fluid' policy was abandoned and replaced by early balanced transfusion of platelets, plasma and red cells. Whole blood is an attractive alternative to multi-component therapy, which offers reduced hemodilution, lower donor exposure and simplified logistics. However, the potential for wider re-introduction of whole blood requires re-evaluation of haemolysins, storage conditions and shelf-life, the need for leucocyte depletion/ pathogen reduction and inventory management for blood providers. This review addresses these questions and calls for research to define the optimal whole blood product and the indications for its use.

London 2017: Lessons learned in transfusion emergency planning.

BACKGROUND AND OBJECTIVES: Hospitals prepare for emergencies, but the impact on transfusion staff is rarely discussed. We describe the transfusion response to four major incidents (MIs) during a 6-month period. Three events were due to terrorist attacks, and the fourth was the Grenfell Tower fire. The aim of this paper was to share the practical lessons identified. METHODS: This was a retrospective review of four MIs in 2017 using patient administration systems, MI documentation and post-incident debriefs. Blood issue, usage and adverse events during the four activation periods were identified using the Laboratory Information Management System (TelePath). RESULTS: Thirty-four patients were admitted (18 P1, 4 P2, 11 P3 and 1 dead). Forty-five blood samples were received: 24 related to nine MI P1 patients. Four P1s received blood components, three with trauma and one with burns, and 35 components were issued. Total components used were six red blood cells (RBC), six fresh frozen plasma (FFP) and two cryoprecipitate pools. Early lessons identified included sample labelling errors (4/24). Errors resolved following the deployment of transfusion staff within the emergency department. Components were over-ordered, leading to time-expiry wastage of platelets. Careful staff management ensured continuity of transfusion services beyond the immediate response period. Debriefing sessions provided staff with support and enabled lessons to be shared. CONCLUSIONS: Transfusion teams were involved in repeated incidents. The demand for blood was minimal. Workload was related to sample handling rather than component issue. A shared situational awareness would improve stock management. A laboratory debriefing system offered valuable feedback for service improvement, staff training and support.

Triage tool for the rationing of blood for massively bleeding patients during a severe national blood shortage: guidance from the National Blood Transfusion Committee.

The emerging COVID-19 pandemic has overwhelmed healthcare resources worldwide, and for transfusion services this could potentially result in rapid imbalance between supply and demand due to a severe shortage of blood donors. This may result in insufficient blood components to meet every patient's needs resulting in difficult decisions about which patients with major bleeding do and do not receive active transfusion support. This document, which was prepared on behalf of the National Blood Transfusion Committee in England, provides a framework and triage tool to guide the allocation of blood for patients with massive haemorrhage during severe blood shortage. Its goal is to provide blood transfusions in an ethical, fair, and transparent way to ensure that the greatest number of life years are saved. It is based on an evidence- and ethics-based Canadian framework, and would become operational where demand for blood greatly exceeds supply, and where all measures to manage supply and demand have been exhausted. The guidance complements existing national shortage plans for red cells and platelets.

Emergency preparedness, resilience and response guidance for UK hospital transfusion teams.

OBJECTIVES: To present Emergency Preparedness, Resilience and Response (EPRR) guidance for Hospital Transfusion Teams on behalf of the National Blood Transfusion Committee emergency planning working group. BACKGROUND: The Civil Contingencies Act 2004 requires healthcare organisations to demonstrate that they can deal with major incidents while maintaining critical services. Recent mass casualty events and the use of transfusion-based resuscitation have highlighted the evolving role of the Hospital Transfusion Team. METHODS: This multi-disciplinary advice is informed by recent global and national experience, the 2018 NHS England clinical guidelines for Major Incidents, and stakeholder workshops. GUIDANCE: Transfusion staff should be familiar with local EPRR plans including casualty type and numbers. Staff should be exercised as part of wider Trust preparation, with documented roles and responsibilities. Transfusion support should be proactive and include blood issue, regulatory compliance and sample handling. Robust LIMS-compatible emergency identification systems are essential to minimise errors. Emergency stock management requires rapid assessment of existing stock and estimated demand before re-ordering. Initial demand should be based on 2 to 4 red blood cells (RBC) per patient admitted. Patients with significant haemorrhage may require further red cells and early haemostatic support. Where "universal" components are demanded, they should be gender appropriate. Senior staff should lead the response, log and communicate key decisions, and prepare for post-incident recovery. CONCLUSIONS: Transfusion teams have an important role in ensuring continuity of transfusion support. Teams should develop their EPRR plans based on local plans and national guidance. Emergency preparedness should include post-incident debriefing for ongoing staff support and future service improvement.

Investigation of the quality of stored red blood cells after simulated air drop in the maritime environment.

BACKGROUND: Maritime medical capability may be compromised by blood resupply. Air-dropped red blood cells (RBCs) is a possible mitigation factor. This study set out to evaluate RBC storage variables after a simulated parachute air drop into the sea, as limited data exist. STUDY DESIGN AND METHODS: The air load construction for the air drop of blood was subject to static drop assessment to simulate a worst-case parachute drop scenario. One control and two test Golden Hour shipping containers were each packaged with 10 RBC units. The control box was not dropped; Test Boxes 1 and 2 were further reinforced with waterproof boxes and underwent a simulated air drop on Day 7 or Day 8 postdonation, respectively. One day after the drop and once a week thereafter until Day 43 of storage, RBCs from each box were sampled and tested for full blood counts, hemolysis, adenosine triphosphate, 2,3-diphosphoglycerate, pH, extracellular potassium, glucose, lactate, deformability, and RBC microvesicles. RESULTS: The packaging configuration completed the air drop with no water ingress or physical damage. All units met UK specifications for volume, hemoglobin, and hemolysis. There were no significant differences for any of the variables studied between RBCs in the control box compared to RBCs in Test Boxes 1 and 2 combined over storage. CONCLUSION: The test proved that the packaging solution and the impact of a maritime air drop as performed in this study, on Day 7 or Day 8 postdonation, did not affect the in vitro quality of RBCs in SAGM over storage for 35 days.

Detection, characterization, and enrollment of donors of Ebola convalescent plasma in Sierra Leone.

BACKGROUND: Passive therapy with convalescent plasma provides an early opportunity to intervene in Ebola virus disease (EVD). Methods for field screening and selection of potential donors and quantifying plasma antibody are needed. STUDY DESIGN AND METHODS: Recombinant Ebola virus glycoprotein (EBOV GP) was formatted into immunoglobulin G-capture, competitive, and double-antigen bridging enzyme immunoassays (EIAs). EVD survivors in Freetown, Sierra Leone, were recruited as potential plasma donors and assessed locally using sera alone and/or paired sera and oral fluids (ORFs). Uninfected controls comprised unexposed Gambians and communities in Western Area, Sierra Leone. Antibody neutralization in selected sera was measured retrospectively in a pseudotype virus assay. RESULTS: A total of 115 potential donors were considered for enrollment: 110 plasma samples were concordantly reactive in the three EIAs; three were concordantly unreactive and two were reactive in two of three EIAs (98.2% agreement; 95% confidence interval [CI], 93.9%-99.8%). In 88 donors with paired ORF and plasma, G-capture EIA reactivity correlated well in the two analytes (R2 = 0.795). Plasma and ORF from 44 Gambians were unreactive. ORF samples from 338 of 339 unexposed Western Area community controls were unreactive (specificity, 99.7%; 95% CI, 98.4%-99.7%); ORF samples from 113 of 116 Kerry Town EVD survivors were reactive (sensitivity, 97.4%; 95% CI, 92.5%-99.5%). Strong reactivity in G-capture and/or competitive EIAs identified donors with high plasma EBOV GP antibody levels in the double-antigen bridging assay, correlating with high levels of neutralizing antibody. CONCLUSIONS: In-field testing can qualify convalescent donors for providing high-titer antibody.

A paired comparison of thawed and liquid plasma.

BACKGROUND: To make plasma readily available to treat major hemorrhage, some centers are internationally using either thawed plasma (TP) or "never-frozen" liquid plasma (LP). Despite the routine use of both, there are limited data comparing the two. The hemostatic properties of LP were evaluated and compared to TP in a paired study. STUDY DESIGN AND METHODS: Two ABO-matched plasma units were pooled and split to produce 1 unit for LP and 1 unit for TP. Samples of TP and LP, stored at 2 to 6°C, were tested for a range of coagulation factors, thrombin generation, and rotational thromboelastometry. An additional 119 units of LP were collected and analyzed for markers of contact activation (S-2302 cleavage) and cellular content. RESULTS: LP and TP were compared, up to 7 days of storage, with results showing no difference in the rate of change over time for any variable measured. When compared to Day 5, LP on Day 7 showed no difference for any factors measured; however, on Day 11 Factor (F)II, FV, FVII, and protein S (activity) were lower. Analysis of 119 LP units showed that 26 of 119 (22%) exhibited cold-induced contact activation by Day 28. CONCLUSION: LP and TP were comparable in terms of hemostatic variables up to 7 days of storage. Decreasing coagulation factor activity along with an increased activation risk during storage of LP needs to be balanced against availability to supply and clinical need when considering using LP with more than 7 days of storage.

Group O low titre only emergency donor panels for small combat teams.

INTRODUCTION: Military elements increasingly operate in small teams in remote areas with no immediate blood product support. Planners and operators may endorse collection of fresh whole blood from pretested donors in emergency situations. The biggest risk of transfusion is the accidental use of ABO incompatible blood which can be fatal. The risk may be mitigated by using only group O LOw (OLO) titre donors with plasma containing low levels of the naturally occurring antibody to group A and B red cells. This paper reviews the ABO blood group distribution in potential blood donors from a high readiness UK medical regiment and explores the feasibility of using only group OLO donors in small teams. METHODS: A retrospective review of routine volunteer blood donor samples was undertaken at 6 monthly intervals during a 2-year period. Personnel were tested in groups when available during training to create multiple donor panels to simulate small teams. RESULTS: 206 donation samples were collected from 157 potential donors. All donors were acceptable based on the lifestyle questionnaire, serology and microbiology screen. Of the 206 samples reviewed, 85 (41%) were group O (D pos and D neg). 14 group O (16.5%) were shown to have high titre of anti-A or B. Therefore, 71, that is, 34% overall were suitable as OLO donors. The donor panel size varied from 15 to 44. The absolute number of OLO donors in each panel ranged from 4 to 17 and the number of O neg donors was 0-3. CONCLUSION: A third of samples were suitable as OLO donors; however, there were insufficient 'universal' donors within smaller subgroups (<10). In this situation, we recommend the careful use of both group O and group A donors or the use of a buddy-buddy blood group matrix.

Mass casualty events: blood transfusion emergency preparedness across the continuum of care.

Transfusion support is a key enabler to the response to mass casualty events (MCEs). Transfusion demand and capability planning should be an integrated part of the medical planning process for emergency system preparedness. Historical reviews have recently supported demand planning for MCEs and mass gatherings; however, computer modeling offers greater insights for resource management. The challenge remains balancing demand and supply especially the demand for universal components such as group O red blood cells. The current prehospital and hospital capability has benefited from investment in the management of massive hemorrhage. The management of massive hemorrhage should address both hemorrhage control and hemostatic support. Labile blood components cannot be stockpiled and a large surge in demand is a challenge for transfusion providers. The use of blood components may need to be triaged and demand managed. Two contrasting models of transfusion planning for MCEs are described. Both illustrate an integrated approach to preparedness where blood transfusion services work closely with health care providers and the donor community. Preparedness includes appropriate stock management and resupply from other centers. However, the introduction of alternative transfusion products, transfusion triage, and the greater use of an emergency donor panel to provide whole blood may permit greater resilience.

NATO Blood Panel perspectives on changes to military prehospital resuscitation policies: current and future practice.

The North Atlantic Treaty Organization (NATO) Blood Panel exists to promote interoperability of transfusion practice between NATO partners. However, it has served as an important forum for the development of prehospital transfusion and transfusion in the austere environment. There are synergies with the trauma hemostasis and oxygen research community especially in the areas of innovation and research. Four presentations are summarized together with a review of some scientific principles. The past decade has already seen significant changes in early transfusion support. Sometimes practice has preceded the evidence and has stretched regulatory and logistic constraints. Ethical and philosophical issues are also important and require us to question "should we" and not just "could we." The challenge for the combined communities is to continue to optimize transfusion support underpinned by evidence-based excellence.

A proposed field emergency donor panel questionnaire and triage tool.

BACKGROUND: The provision of transfusion support to isolated military or civilian projects may require the use of an emergency donor panel (EDP) for immediate warm fresh whole blood (WFWB). The aim of this short discussion article is to raise and resolve some of the practical aspects for the nonspecialist faced with the emergency collection of WFWB whole blood in the austere medical environment (AME). METHODS AND RESULTS: A proposed field EDP questionnaire and triage tool (QTT) is presented. It is designed for the hostile, remote, or austere environment that falls outside normal regulated supply of cold-stored blood products or removed from trained blood collection personnel, where collection may fall to an isolated medical provider. The tool has been drafted based on review of existing guidelines and consultation with practitioners. It serves as a point of reference for local guidelines and has yet to be validated. CONCLUSIONS: The use of the EDP is associated with risk; however, it remains the simplest method of providing rapid transfusion support. The best way to manage the risk is to brief and prescreen blood donors before deployment. An abbreviated donor QTT can be an aide to decision making at the time of donation. The tool should be tailored to requirements and underpinned by policy and training.