Biovigilance Update - Winter 2015

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WINTER 2015

IN THIS ISSUE

Meta-Analysis Shows Effectiveness of Low-Risk TRALI Donor Strategies »

FDA Approves First US Pathogen Inactivation System for Plasma and Platelets »

Experts Outline Regulatory Considerations for Changes in MSM Donation Deferral Criteria »

Platelet Dose per Transfusion Is Strongest Predictor of Adverse
Events »

Support Resources for NHSN Hemovigilance Module »

Case Report: TRALI Associated With Pooled Immune Globulin Transfusion »

Alloimmunization Associated With Chronic Pain and Other Symptoms in SCD Patients »

ISBT, AABB and the International Haemovigilance Network Publish Internationally Harmonized Definitions for Donor Hemovigilance »

Advisory Committee on Blood and Tissue Safety and Availability to Meet April 7-8 »

Database Links 50 Years of Data on Scandinavian Donations and Transfusions »

AIDS Research Pioneer Shares Perspective on History of Human Retrovirus Research »

Study Shows Persistence of West Nile Virus RNA in Whole Blood »

TOP NEWS

Meta-Analysis Shows Effectiveness of Low-Risk TRALI Donor Strategies

A recent study on the effects of donor strategies aimed at lowering the risk of transfusion-related acute lung injury, or TRALI, found that these strategies significantly reduce the onset of TRALI. M. Müller et al. performed a meta-analysis of studies on the effect of low-risk strategies for plasma-containing blood products on antibody-mediated TRALI and mortality. The researchers analyzed studies from MEDLINE and the Cochrane Library published between Jan. 1, 1995 and Jan. 1, 2013. The low-risk strategies included donor deferrals based on antibody screening, history of pregnancy or transfusion, sex (deferral of all female donors) and screening either all donors or those previously alloexposed for antibodies to human leukocyte antigen and/or human neutrophil antigen. Evidence from the 10 studies ultimately included in the analysis shows a significant reduction in TRALI risk in general populations and in those prone to develop TRALI.


RECIPIENT HEMOVIGILANCE

FDA Approves First US Pathogen Inactivation System for Plasma and Platelets

The Food and Drug Administration in December approved the first pathogen reduction system for plasma and for single donor platelets authorized for use in the United States.

The FDA’s approval of Cerus Corporation’s Intercept Blood System for plasma is expected to make transfusions safer for recipients. Blood establishments will be able to treat plasma derived from whole blood or by apheresis and decrease the risk of transfusion-transmitted infections, or TTI. “Plasma represents the component of greatest infectious disease risk due to its volume and thus highest burden of pathogens,” said Susan L. Stramer, PhD, American Red Cross vice president for Scientific Affairs and chair of AABB’s Transfusion Transmitted Diseases committee. “This decision will give hospitals options for a wider range of products, including those that will further reduce the risk of TTIs, especially for those for which testing is not in place.” Stramer added, “This decision paves the way for inactivation to be in place in the U.S. as has been available throughout the rest of the world.” The system has been used in Europe for more than 10 years.

The FDA also approved the Intercept Blood System to treat single donor apheresis platelets to reduce pathogens — such as gram-negative and gram-positive bacteria, HIV, the hepatitis B and C viruses and West Nile virus (WNV). In addition, the system decreases the number of T cells to a level that lowers the risk of transfusion-associated graft-versus-host disease.

The system reduces numerous bacterial and viral pathogens by exposing plasma or platelets to ultraviolet light and a chemical called amotosalen. While there is evidence that Intercept reduces numerous bacterial and viral pathogens, no available pathogen inactivation system has been shown to eliminate all of them. Some agents, including human parvovirus B19 and bacterial spores, have proven resistant to the process.

The FDA recently granted Investigational Device Exemption status to the system for two studies, one on reducing the risk of transfusion transmission of the chikungunya and dengue viruses and another in which researchers are preparing Ebola convalescent plasma to treat those infected with Ebola virus disease. To increase U.S. preparedness for Ebola, researchers are creating a stockpile of convalescent plasma that has been treated with Intercept.


Experts Outline Regulatory Considerations for Changes in MSM Donation Deferral Criteria

Transfusion recipient safety should be the highest priority for national regulatory authorities, or NRAs, considering changes to blood donation deferral policies for men who have sex with men (MSM), according to an international group of regulatory experts in a 2014 report in “Vox Sanguinis.” When considering a less restrictive donor deferral policy, authorities should assess scientific data, local epidemiology, societal concerns and stakeholder input as part of the overall decision-making process. In particular, the authors make several recommendations regarding scientific considerations. NRAs should take into account risk-mitigating steps that could be implemented to accompany a change in criteria. They also should consider and evaluate scientific data from other countries that have moved from an indefinite to a time-based deferral for MSM “indicating that there has been no increase in risk… and no observed increase in the frequency of pathogen transmissions based on sound haemovigilance monitoring.” The experts also suggest that NRAs consider evidence that the current policy does not effectively reduce the risk of TTIs and study evidence that revised donor selection criteria would not be likely to increase the risk of TTIs. Lastly, they should consider evidence that changes to the current policy are unlikely to increase the risk of inadvertent release of infectious units from quarantine. As part of the overall decision process, the authors recommend further studies to assess the effects of potential policy changes, to validate accompanying candidate risk mitigation strategies and to monitor safety outcomes related to policy changes. Finally, jurisdictions should assess hemovigilance data on the risk of TTI in donors with an emphasis on monitoring adherence to donor selection criteria.


Platelet Dose per Transfusion Is Strongest Predictor of Adverse Events

The dose of prophylactic platelet transfusions was the most important predictor of transfusion-related adverse events, or TRAEs, in patients with hypoproliferative thrombocytopenia resulting from chemotherapy or hematopoietic stem cell transplantation. The findings come from a post hoc secondary analysis of data from the Platelet Dose, or PLADO, study in the January issue of “Transfusion.” The risk of any TRAE was one and a half times greater for patients who received high-dose compared with medium-dose prophylactic platelet transfusions (odds ratio = 1.50). However, the risk of TRAEs was similar for patients who received medium- or small-dose transfusions.

In the randomized controlled PLADO study, researchers examined the effect of prophylactic platelet dose on bleeding in patients, who were randomized to receive high-dose (4.4 x 1011 platelets/m2 body surface area), medium-dose (2.2 x 1011 platelets/m2) or low-dose (1.1 x 1011 platelets/m2) transfusions. In this analysis, the researchers examined whether the risk of TRAE varied based on platelet characteristics, such as dose and ABO matching status; source, ABO matching status and storage duration; and other factors. The analysis included 5,034 transfusions in 1,102 patients. Platelet dose was found to be a significant predictor of any TRAE versus no TRAE; of fever; and of chills or rigors. In addition, there was a trend toward increasing risk of more serious TRAEs with increasing dose, though it did not reach statistical significance. The authors noted that “some of the increased risk of high dose platelets may be related to the increased volume of plasma per transfusion.” Platelet source (apheresis or whole blood), storage duration and ABO matching status were not significantly associated with TRAE risk.


Support Resources for NHSN Hemovigilance Module

Officials at the Center for Disease Control and Prevention’s National Healthcare Safety Network remind network users to send all questions regarding the Hemovigilance Module — including technical issues and requests for support — to nhsn@cdc.gov and to include “Biovigilance” in the subject line. A professional from the Biovigilance Component team will respond to all questions within one business day. Questions related to the AABB Center for Patient Safety (PSO) should be directed to hemovigilance@aabb.org.


Case Report: TRALI Associated With Pooled Immune Globulin Transfusion

Though very rare, TRALI can occur after transfusion of pooled intravenous immune globulin, or IVIG. Quest et al. document such a case in the December issue of “Transfusion.” The case involved a 77-year-old woman, who had been receiving monthly prophylactic IVIG transfusions for common variable immune deficiency for more than 15 years. She had a history of transfusion reactions to two IVIG products and was known to have anti-Immunoglobulin A antibodies. She received a transfusion of a product she had been receiving without reaction since 2011. During this transfusion, she developed dyspnea and hypertension and had to be intubated and transferred to intensive care. Chest radiographs and contrast chest CT following transfusion revealed “bilateral hazy ground-glass opacifications within the context of previously documented lung changes.” She was found to be group B D+ with a negative antibody screen and a negative direct antiglobulin test.

After 24 hours, the patient was extubated; after 8 days, she was released from the hospital. The authors stated that the patient had not received this lot number of product previously. Following the reaction, she received twelve subsequent transfusions of the same product from different lots without event. In the discussion, the authors noted that increased use of pooled fractionated female donor plasma to produce IVIG “can be expected to produce products with an increased probability of having multiple alloreactive antibodies at lower titers, which individually may have a low likelihood of resulting in immune activation, but may act in synergy to result in TRALI in individuals with multiple cognate antigens.”


Alloimmunization Associated With Chronic Pain and Other Symptoms in SCD Patients

A study posted in “Transfusion” Early View suggests that alloimmunization may be associated with a number of complications of sickle cell disease, or SCD, including chronic pain, avascular necrosis, end-organ damage and red blood cell autoantibodies. Alloimmunized patients also had poorer survival rates. Marilyn J. Telen, MD, Wellcome professor of medicine at Duke University, and colleagues reviewed data on antigen phenotype and alloimmunization, and analyzed clinical and medical histories including transfusion history and disease severity, for 319 patients enrolled in a larger institutional review study of clinical outcome-modifying genes in adults with SCD. Patients, who ranged in age from 18 to 84 years, were considered to be alloimmunized if their serum contained at least one antibody to an antigen not found in their own red blood cells.

The researchers found an overall alloimmunization rate of 27 percent, with 99 percent of subjects self-identified as African American. In addition, a history of transfusion and a hemoglobin diagnosis were associated with alloimmunization. Although alloimmunization was not associated with frequency of vasoocclusive episodes, it was strongly associated with chronic pain, as well as being significantly associated with avascular necrosis of the hip or shoulder. The authors noted that although the data show an association between alloimmunization and chronic pain, at this point they can only speculate as to causation. They suggest that immune system activation may play a role in both.


DONOR HEMOVIGILANCE

ISBT, AABB and the International Haemovigilance Network Publish Internationally Harmonized Definitions for Donor Hemovigilance

The International Society of Blood Transfusion, or ISBT, in collaboration with AABB and the International Haemovigilance Network, released a revised classification system with updated definitions for complications related to blood donation. Working groups from the three organizations revised definitions from the 2008 ISBT standard, which were considered too general and required information that was difficult to obtain in many places. The full rationale for the revision is available.

The revision had four goals: to simplify definitions so they can be applied consistently by many countries; to provide minimal requirements for international comparison that meet the needs of a basic surveillance system; to suggest additional attributes that can be collected nationally when feasible; and to align definitions with those from AABB’s Donor Hemovigilance Program so they can be entered into an adapted version of the Donor Hemovigilance Analysis and Reporting Tool, or DonorHART, software and used for comparison purposes. Knowledge Based Systems Inc. recently updated DonorHART to reflect the revisions. Blood donor complications include adverse reactions and events such as hematoma, arterial puncture, generalized vasovagal symptoms and allergic reactions. Those who are interested in joining the AABB United States Donor Hemovigilance Program may direct inquires to hemovigilance@aabb.org.


BIOVIGILANCE

Advisory Committee on Blood and Tissue Safety and Availability to Meet April 7-8

The HHS Advisory Committee on Blood and Tissue Safety and Availability announced plans in a “Federal Register” notice to meet April 7-8 in Rockville, Md. The meeting will focus on the tracking and traceability of tissue recovered from deceased donors, with an emphasis on relevant federal and state regulations. Additional information is available on the ACBTSA website.


Database Links 50 Years of Data on Scandinavian Donations and Transfusions

Researchers succeeded in tracing 96 percent of transfusions to their respective donations in a new database of more than 3.6 million blood donors with almost 50 years of follow-up. This database — the Scandinavian Donations and Transfusions database 2, or SCANDAT2 — links national registry data from Sweden and Denmark that links with data from all current blood bank and transfusion medicine clinic local blood donation and transfusion databases. The findings are published in the January issue of “Transfusion.” The researchers reformatted records to fit a common data structure and cleaned, pseudonymized and linked records with official registers. In Sweden, the registers include population registers, the Cancer Register, In-and Out-patient Registers, Medical Birth Register and Cause of Death Register. In Denmark, the registers include the Civil Registration System, the Danish Cancer Registry, Hospital Discharge Register and Cause of Death Register. The database allows users to link blood components, donations, transfusions and individuals, making it possible to track donation date and type; component type and manufacturing date; and recipient identification and date of transfusion. The database also includes information on donation erythrocyte antigens and antibodies. The researchers note that “the primary purpose of SCANDAT2 is to provide a versatile tool with high statistical resolution for the assessment of threats to the blood supply, including possible donation-associated risks, risks of transfusion-transmitted disease, and transfusion safety in a more general sense.”

The researchers found that more than 1.6 million individuals made at least one donation; more than 2.1 million received at least one transfusion; and 113,086 fell into both groups. When compared with official data from both countries, the total number of donations and transfusions in the database varied less than 3 percent in Sweden and less than 2 percent in Denmark.


TRANSFUSION-TRANSMITTED INFECTIONS

AIDS Research Pioneer Shares Perspective on History of Human Retrovirus Research

Robert C. Gallo, MD, co-discoverer of HIV and a member of the team that pioneered the development of the HIV blood test, recounts his experiences researching human retroviruses in a January “Transfusion” article. At a time when science held a bias against the idea of cancer-causing retroviruses, Gallo’s early work on the HTLV-I retrovirus — which causes adult T-cell leukemia — led to his ultimate recognition that a retrovirus was responsible for AIDS. “Readers are extremely fortunate to have access to the Gallo commentary, which documents the history of retrovirus discovery and testing and provides insights into the persistent problems still encountered in the battle to prevent AIDS from transfusions and other causes,” states Paul M. Ness, MD, editor of “Transfusion.”

Gallo’s commentary describes how early discoveries of leukemia-causing viruses in animals and technological advances, such as the development of reverse transcriptase assays and the discovery of the IL-2 molecule, enabled him to isolate the first human retrovirus. This research, in turn, was instrumental to his 1982 proposal that a human retrovirus, originally called HTLV-III, was responsible for AIDS. Gallo describes the path from discovering HIV to verifying that it causes AIDS, including the development of the HIV blood test now in routine use in donor screening and patient diagnosis. Gallo also suggests future directions for AIDS research and treatments that ultimately could lead to a vaccine to prevent and eliminate HIV infection.


Study Shows Persistence of West Nile Virus RNA in Whole Blood

M.C. Lanteri and colleagues confirmed the presence of WNV RNA in blood donors’ red blood cell compartment three months after the donors had tested positive for WNV. In a study published in “Transfusion,” the researchers recorded demographic and symptom information from 54 WNV-infected individuals identified through routine donor screenings. They collected the subjects’ blood samples throughout the following year and tested them for WNV immunoglobulin and immunoglobulin antibodies and for WNV RNA using real-time reverse transcription polymerase chain reaction techniques. Then they compared viral load in plasma with viral load in whole blood over time. They also looked for correlations between viral load and donor blood group and between viral load and clinical outcome. While none of the donors had WNV RNA in their plasma after three weeks, 42 percent had substantial levels in their whole blood after two months, and some for as long as three months. In addition, donors with the highest initial plasma levels of WNV RNA exhibited the highest levels in their whole blood for the next three months. Finally, donors with type A blood showed higher levels of viral load in whole blood than did donors with type O blood. The results were suggestive of, but not conclusive for, an association between whole blood levels of WNV RNA and WNV symptomatology. According to the authors, screening whole blood — as opposed to plasma — could improve screening sensitivity and consequently reduce WNV transfusion transmission, which could be particularly helpful for marrow and organ transplant recipients.