Assessing Emerging Infectious Threats to Blood Safety for the Blood Disorders Community

Sean R. Trimble, MPH, Christopher S. Parker, PhD, Althea M. Grant, PhD, J. Michael Soucie, PhD, Nimia Reyes, MD
Abstract: Technologic advances in diagnostic testing, vaccinations, pathogen inactivation, and vigilant donor screening have greatly reduced the risk of transmitting pathogens through blood transfusion. Nevertheless, transfusion-related infections and fatalities continue to be reported, and emerging pathogens continue to become an increasing threat to the blood supply. This threat is even greater to patients with blood disorders, who are heavily transfused and rely on safe blood products. This article describes some of the emerging and re-emerging transfusion-transmitted pathogens that have increased in incidence in the U.S. in recent years. Peer-reviewed articles and agency websites were the sources of information. The article focuses on the treatment of hereditary blood disorders including hemophilia and thalassemia, and hereditary bone marrow failure. A coordinated approach to addressing blood safety and continued development of sensitive diagnostic testing are necessary to reduce risk in an increasingly globalized society.
(Am J Prev Med 2010;38(4S):S468 S474) Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine

Introduction
lood disorders are most often hereditary and can be categorized as bleeding disorders, clotting disorders, or hemoglobinopathies. The clinical severity of these disorders can vary widely, ranging from asymptomatic to severe or even fatal manifestations. Patients with blood disorders often rely heavily on blood products as a form of treatment. Over the past 20 years, improvements in the management of blood banking, informed consent questionnaires, and pathogen inactivation have made the blood supply safer.1 However, the risk for transmission of known pathogens such as HIV, hepatitis B, hepatitis C, and HTLV-1 persists due to the window period between infection and detection.1 The incidence of new or emerging threats to the blood supply has also been steadily increasing. These emerging pathogens pose serious risks, as many are resistant to pathogen inactivation and have an extended incubation period. According to the IOM,2 an emerging infectious disease is defned as one whose incidence in humans has increased within the past 2 decades or threatens to increase
From the Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, CDC, Atlanta, Georgia Address correspondence and reprint requests to: Sean R. Trimble, MPH, CDC, Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, CDC, 1600 Clifton Road, MS-E64, Atlanta GA 30333. E-mail: STrimble@cdc.gov. 0749-3797/00/$17.00 doi: 10.1016/j.amepre.2009.12.019

in the near future. The American Association of Blood Banks (AABB) Transfusion-Transmitted Diseases Committee has identifed 69 agents that are known or suspected to be transfusion-transmitted and for which there is currently no implemented intervention in the U.S. or Canada.2 In this list, agents such as Babesia, dengue virus, and variant Creutzfeldt-Jakob disease (vCJD) are a high threat. In addition, interventions are in place for some agents on this list that continue to be labeled as high threat because either implementation of donor screening was recent or gaps in the intervention render it inadequate. Regional testing for these pathogens and the inability to detect window-period infections are examples of these gaps. The current paper describes these previous and emerging threats to blood safety and provides a historical overview of blood safety activities in the U.S. Additionally, emerging pathogens are described, as well as key steps to improving blood safety in the future; blood disorders of hereditary etiology are highlighted.

Background and Context

More than 3 centuries ago, when efforts were frst made to replace blood in humans because of severe anemia or blood loss, the most important clinical complication was the tendency for the blood to clot. This problem resulted in blood replacement being done infrequently until 1914, when citrate anticoagulant was introduced, making

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transfusion an important means of supportive therapy.3 The demand increased considerably for blood and blood components during and after World War II. This demand was the driving force in the growth and development of blood banks, transfusion services, and other blood and laboratory support services. The frst reported case of post-transfusion hepatitis (PTH) in the U.S. was in 1943.4 The risk for contracting this disease was acknowledged and in the following decades decreased markedly through a mandate for an all-voluntary blood donor system, implementation of blood donation screening, and advances in molecular biology techniques that enabled a better understanding of transfusion-transmitted viral etiologies. Currently, the most substantial risks from blood transfusion are non-infectious complications (e.g., transfusionrelated acute lung injury [TRALI]), bacterial contamination of platelets, and acute hemolytic transfusion reaction. Nevertheless, transfusion transmission of viruses can still occur when a donor presents for donation in the incubation phase of an illness. These transfusion-transmitted viruses, as well as emerging infections such as babesiosis and West Nile virus, require the development of proactive strategies and vigilant recipient surveillance. The development of diagnostic tests for these emerging pathogens continues to be an obstacle for blood safety. Until the challenge of developing these diagnostic tests is met, patients with blood disorders who rely on blood products must be monitored thoroughly and used as sentinels for blood safety outbreaks.

Infectious Threats to Blood Safety

Infectious pathogens have been the main focus of the effort to ensure the safety of blood and transfusions for the past half century. During this time, the risk of transmission by transfusion has been greatly reduced for many pathogens, and surveillance of blood recipients has brought attention to emerging pathogens capable of transmission by transfusion. Variables such as disease window periods (the time between infection with a pathogen and diagnostic detection of the infection); migrant populations; and blood product type are important to consider in assessing these threats to people with blood disorders. These patients encompass a broad clinical spectrum, requiring various blood products or none at all for treatment.

a potentially fatal risk.5 One study6 reported that one transfusion-associated sepsis death occurs for every 1 million transfused platelet units, and one for every 10 million red cell units. The sources of bacterial contamination of blood are not always easy to identify. Contamination can come from the skin flora of the donors arm, nonsterile blood containers, or even the environment where the donor is giving blood. Contamination can also occur when the donor possesses an asymptomatic bacteremia. The results of one study7 showed that the majority of deaths associated with platelet or red blood cell transfusion were caused by gram-negative organisms. Bacterial pathogens pose the greatest threat to individuals receiving platelets. The storage conditions of 20C 24C for platelets are ideal for the growth of certain bacteria, particularly coagulase-negative Staphylococcus, which accounts for 25% of cases. As of 2004, culture surveillance suggests that contamination occurred in 1 of every 2000 units of platelet concentrate and apheresis-collected platelets.8 Patients receiving red blood cells are at risk as well. In one case, an autologous blood donor developed bacteremia after receiving his own blood that had been stored for 41 days.9 The most common agent of contamination for red blood cells is Yersinia enterocolitica, followed by Pseudomonas spp. and Serratia spp.10 Although progress has been made in reducing bacterial contamination associated with transfusion, the number of cases has not dropped sharply in the past 25 years, as it has for viral pathogens.11 Bacterial contamination continues to be an issue where every source of contamination needs to be addressed continually. Continued vigilance in sterile phlebotomy, enhanced bacterial detection methods, and continued development of pathogen inactivation techniques are needed to address these persistent threats.

Viral Pathogens
Human immunodeciency virus. Human immunodefciency virus is an infectious agent that garnered the nations attention regarding the need for blood safety. Its effective transmissive properties pointed to the need to screen donors, screen donor blood, and institute inactivation regimens. Since the initiation of HIV testing for all donated blood in 1985, there have been numerous advances in the current system of ensuring HIV does not enter the blood supply and is not transfused to patients. The CDC has several national surveillance programs in place to monitor the safety of the blood supply and identify potential outbreaks of HIV. Today, HIV as an infectious agent serves more as a reminder for the need for vigilance than as an eminent threat to actual supply. In order to further retard the transmission of HIV, vigilance should be extended beyond the blood supply to address

Bacterial Pathogens
Bacterial contamination of blood products was the frst acknowledged infectious threat to the blood supply. Although sterile collection systems appear to have led to a reduction in bacterial contamination, it continues to pose
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proper sterilization of equipment and supplies that come into contact with infected blood and are then used on other patients. Hepatitis A virus. The transmission of hepatitis through blood products has been a major focus of blood safety in previous decades. Presently, hepatitis A virus (HAV) is not commonly transmitted by blood transfusion. It is estimated12 that there is one transmission of HAV through blood transfusion for every 1 million units. In addition, a retrospective study13 of heavily transfused thalassemia patients indicated that these patients were at no greater risk than children that had not been transfused. Until the mid-1990s, there had been outbreaks of HAV associated with factor VIII (FVIII) anti-hemophilic concentrate in Europe and South Africa, but none in the U.S.14 19 In 1995, two cases of acute hepatitis A were reported in which both patients received the same lot of a particular brand of FVIII concentrate.14 Later that year, another case of acute hepatitis A was reported in an individual that had been exposed to factor IX (F IX) concentrate. The U.S. Advisory Committee on Immunization Practices recommends20 that susceptible people with bleeding disorders who receive clotting factor be given the hepatitis A vaccine, a measure that has helped to prevent hepatitis. Other advances, such as FVIII and F IX concentrates made from recombinant technology, have also helped to prevent transmission of HAV. Timely identifcation and investigation of future cases related to blood products depend on vigilant recipient surveillance. Hepatitis B virus. Universal vaccinations for healthcare workers and children, screening of donors, viral inactivation technologies, and an all-volunteer blood donor supply are among the factors that have helped to reduce hepatitis B virus (HBV) infections in the U.S. However, the prolonged window period of this infection and the lack of sensitivity of anti-HBc assays contribute to the persistent risk of transmission. In 2003, of the 7381 cases of acute hepatitis B reported, 49 were initially reported as transfusion-related, with ten being confrmed by the CDC as being associated with blood products and one being associated with a single infected donor.21 Despite continuous advances in blood donation screening, hepatitis B infection still poses a strong threat of transfusion-transmitted viral infection. Increasing the sensitivity of diagnostic tests that can detect infection within this window period is of upmost importance. Several automated testing platforms have made HBV nucleic acid testing (NAT) feasible and could possibly narrow the window period. Hepatitis C virus. Hepatitis C virus (HCV) was frst discovered in the 1980s and was known as non-A, non-B hepatitis. Despite the absence of a vaccine for HCV, anti-

body screening and NAT have helped to reduce the overall risk of PTH related to HCV. Current estimated risk per unit of blood is one in 1,600,000 for HCV.8,2224 The cost of screening the blood donor population for HCV is offset by the reduction in healthcare costs achieved by prevention.25 Hepatitis E virus. Hepatitis E virus (HEV) is an enterically transmitted, self-limiting, acute viral hepatitis that is usually endemic in Asia, Africa, and Central and South America.26 It belongs to the Calicivirus family and is a non-enveloped RNA virus. Characterization at the molecular level has shown27 that cases in countries where the virus is hyperendemic tend to belong to genotypes 1 and 2, whereas sporadic cases in developed countries belong to genotypes 3 and 4. The long incubation phase of HEV makes the donation of HEV-infected blood very possible. Two case reports of transfusion-transmitted HEV have come from a study in Japan,28 one discovered through retrospective testing of four dialysis patients, and the other in a patient who had undergone open heart surgery and later presented with acute hepatitis. The HEV-positive blood donor was an asymptomatic resident of Japan, where HEV has not been considered endemic. Another study in western Europe27 shows seroprevalence rates for donors not exceeding 3%, whereas in countries where HEV is endemic, such as China, it is as high as 16%. This study showed that although the number of hemodialysis patients was small, the prevalence of anti-HEV antibodies is very high in these patients.1 A near miss possible transfusion transmission of HEV was described in Hong Kong.27,28 The donor presented with symptoms and elevated liver enzymes 1 week after donation but was able to inform the transfusion service before the products were used. Hepatitis E virus should be considered an emerging threat to blood safety. The lack of transfusion-transmitted cases in the U.S. should not prevent a coordinated and concerted effort to address this pathogen in the context of blood safety. Cytomegalovirus. Transfusion-transmitted cytomegalovirus (CMV) poses the largest risk for immunocompromised patients that are receiving stem cell or solid organ transplantation. However, CMV can also be transmitted readily by whole blood with a 30% 60% incidence.29 Although blood component therapy is now the gold standard for treatment, CMV continues to be a threat through transmission by red blood cell transfusion. The use of screened blood for transfusion has become the standard of treatment and has helped to reduce the incidence of infection from transfusion. However, maintaining a supply of screened blood is expensive and diffcult. Attention has also been given to the designation of
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CMV-safe blood products that have been leukocytereduced and to their effcacy in comparison to CMVnegative blood. A 1995 study30 comparing fltered leukocyte-reduced and CMV-negative blood products concluded that fltration is just as effective in preventing transfusion-acquired CMV. However, another study31 disputed the reliability of this conclusion, based on concerns about the testing power of the earlier study. More studies are needed to assess other variables that may be relevant regarding the effcacy of the CMV-safe blood, as well as which clinical cases should be given frst priority for receiving these products. West Nile virus. West Nile virus (WNV) is a member of the family of Flaviviridae and is transmitted through the bite of infected mosquitoes. Prior to 1999, there were no known cases of WNV in the western hemisphere. However, that year saw the virus introduced to areas of North America where the virus is non-endemic. Transmission of WNV through blood transfusion was frst reported in 2002.32,33 What followed was the rapid implementation of a nationwide screening of blood donations for WNV.34,35 Because of these effective screening policies, risk for transfusion transmission of WNV has been greatly reduced. Nevertheless, tests do yield a percentage of false positives, and transfusion transmission of WNV can still occur. Continued vigilance is required by both donors and recipients to ensure the continued reduction of these risks. Parvovirus B19. Parvovirus B19 is a ubiquitous DNA virus infecting up to 50% of people by the age of 15 years.36 Most people have only a mild rash as a child with no long-term complications from the infection. However, the infection can produce a multitude of symptoms depending on the immune function and hematologic status of the host. Parvovirus B19 infection causes acute arthralgias in 10% of children and up to 50% of adults, most often in women.36 It has also been linked to red cell aplasia in immunocompromised hosts.37 Following the infection, some patients may develop a chronic arthritis that is clinically similar to rheumatoid arthritis.38 Parvovirus B19 has been proposed as a causative agent for rheumatoid arthritis by some authors on the basis of a reported association with this syndrome in some studies.39 41 One study42 reported fluctuating levels of anti-parvovirus IgM in conjunction with disease flare-ups in children with juvenile rheumatoid arthritis. Hemophilia patients often experience spontaneous bleeding into joints, leading to severe, crippling arthritis over time. The treatment of joint bleeds involves the intravenous infusion of concentrates of factor VIII or IX. The relatively high prevalence of Parvovirus B19 infection in the general population combined with the large
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number of blood donations used in the manufacture of plasma-derived factor concentrates virtually assures some contamination. This prevalence, combined with its small size, which makes fltration diffcult, and its resistance to inactivation by available viracidal processes, has led to the transmission of Parvovirus B19 by plasmaderived factor replacement products used to treat hemophilia.43 45 Although use of plasma-derived factor has been greatly reduced, Parvovirus B19 has been found in recombinant (nonplasma-derived) factor VIII products as well, most likely introduced by the albumin used as a stabilizer.46 Continued surveillance and studies are warranted to reduce the risk of Parvovirus B19 being spread by blood products.

Other Emerging Pathogens

Trypanosoma cruzi. Trypanosoma cruzi is the parasitic agent of Chagas disease and is endemic to parts of Latin America. However, the immigration from these countries requires that it be recognized as an emerging threat in the U.S. There have been at least seven cases of transmission of T. cruzi through transfusion in the U.S. and Canada. One seroprevalence study47 suggested that 1 in 7500 9000 blood donors are seropositive in areas of the U.S. with large migrant populations. Some patients carry a chronic, life-long infection with approximately 60% of donors in the U.S. remaining polymerase chain reaction (PCR)positive for the parasite many years after frst infection. In one case of transfusion-transmitted T. cruzi, the implicated donor was from Bolivia and had not been to the country where it is endemic in 17 years while showing no noteworthy symptoms of Chagas disease.48 The extended duration of asymptomatic parasitemia and the continued increase in immigration from Latin American countries has heightened awareness for the risks of transmitting this pathogen. Currently, blood donations are screened for T. cruzi. However, attention must be paid to this pathogen as the asymptomatic period is of considerable length. Babesia spp. Babesia spp., the agent of babesiosis infection, is endemic to parts of the upper midwestern and northeastern U.S. The black-legged ticks of the Ixodes genus serve as the primary vectors for this disease, with the white-footed mouse serving as the primary reservoir host. The intracellular nature and extended asymptomatic parasitemia of this organism make it an ideal agent to be transmitted by blood transfusion. The ability of Babesia to survive and remain viable in blood storage conditions for longer than 3 weeks also complicates intervention efforts. One study49 determined that the risk of acquiring Babesia microti from a unit of red blood cells is 1 in 601. A

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later study50 reported the risk to be 1 in 1800. The threat of infection is relevant to those with hereditary blood disorders who receive red blood cells through transfusion, such as those with thalassemia and hereditary bone marrow failure syndromes. However, it is of particular concern for thalassemia patients, many of whom are splenectomized, making them predisposed to severe infection. Currently, there is no assay that is capable of detecting all Babesia spp. in the U.S. The tests used to identify the various Babesia spp. are the immunofluorescent assay, which is not automated, and an enzyme-linked immunosorbant assay that is still in the developmental phases. The limited geographic distribution of specifc species of the pathogen, along with return on research and development costs, contributes to the lack of manufacturers trying to develop an assay that would be benefcial across the U.S. Variant Cruetzfeld-Jakob disease. Variant CruetzfeldJakob disease (vCJD) is caused by a prion protein and is the agent of bovine spongiform encephalopathy. To date, there have been no cases of transmission of vCJD by blood products in the U.S. However, in a recent case in the United Kingdom (UK) in a person with hemophilia, factor VIII concentrate was the implicated source of infection.51 As a result, patients who received blood products between 1980 and 2001 were notifed that they are at increased risk of vCJD. Guidance was also issued to these patients on how to limit further transmission of this disease. This case has raised concern among the blood disorders community worldwide. Animal studies52,53 have shown that prion diseases can be transmitted by blood during the incubation phase and during the clinical manifestations. The fact that vCJD can also be manifested asymptomatically reinforces the need for vCJD surveillance in the UK and a strong prevention strategy in the U.S. Currently, the only way to confrm a diagnosis of vCJD in humans is to perform a postmortem brain biopsy. This emerging infection should continue to remain a surveillance priority as there is no specifc or sensitive screening test for vCJD available.

such as hemophilia. This system screens for the bloodborne pathogens HAV, HBV, HCV, and HIV, and documents potential risk factors for infectious disease for patients who have received blood products used to treat bleeding episodes. The TDC serves a complementary role, helping further detect these pathogens, which can also be transmitted through blood transfusions. Thalassemia patients are at greater risk for these transmissions as many are required to receive therapeutic transfusions on a frequent basis as a treatment for severe anemia. Informed consent is obtained for participants at the respective centers. Serum specimens and clinical data are collected at the time of enrollment and during each annual visit. In addition, a specimen repository has been established at the CDC to facilitate rapid investigation of emerging bloodborne agents. These surveillance systems and biospecimen repositories can provide an infrastructure that could be expanded in order to help people with other conditions and increase the likelihood that a new or emerging threat to the safety of blood could be identifed. No fnancial disclosures were reported by the authors of this paper.

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The CDC has primary responsibility for surveillance of infectious disease threats to the blood supply. Two surveillance systems that the CDC currently uses to monitor blood product safety for persons with blood disorders are the Universal Data Collection (UDC) Project and the Thalassemia Data and Blood Specimen Collection (TDC). The UDC Project is an established, blood-safety monitoring system for people with bleeding disorders

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