Transfusion- and Transplantation-Transmitted Infections

Revised June 25, 2020

Revised March 29, 2021

Transfusion-Associated Infections

Beeson reported the first cases of transfusion-associated hepatitis in 1943, describing seven patients who developed illness 1 to 4 months after having received a red blood cell (RBC) or plasma transfusion. Later identified as transfusion-transmitted hepatitis B virus (HBV), the advent of the acquired immunodeficiency syndrome (AIDS) epidemic in the 1980s followed by recognition of transfusion transmission of hepatitis C virus (HCV) in the 1990s and, most recently, reports of transfusion-transmitted West Nile virus (WNV) and Zika virus (ZIKV) infections in the 21st century have continued to draw attention to the safety of the blood supply, particularly the potential risk from emerging infectious agents.

Although infections with the human immunodeficiency virus (HIV), HBV, HCV, WNV, and ZIKV have been the most publicized, a wide spectrum of other organisms, including viruses, bacteria, parasites, and prions, have been transmitted by transfusion ( Table 304.1 ). Of these, transfusion transmission of bacterial infections is most common and earliest recognized in the history of transfusion, now is most often associated with platelet transfusions, and infrequently results in sepsis and death. Recognition of the threat of Trypanosoma cruzi transmission via transfusion and the availability of suitable testing have led to screening for this pathogen, which is the cause of Chagas disease. In addition to WNV, mosquito-borne pathogens, such as dengue virus, chikungunya virus, and most recently, ZIKV, have shown potential for transfusion transmission, although the burden of disease is unknown. Tick-borne agents also are recognized to pose an increasing risk to transfusion safety, including transmission of babesiosis and, most recently, anaplasmosis and ehrlichiosis. Transmission of variant Creutzfeldt-Jakob disease (vCJD) via transfusion has occurred in the United Kingdom.

An ongoing dilemma of the blood-banking community is a mandate to ensure a maximally safe blood supply while giving consideration to the cost of such measures. The current questions for screening donors that have been adopted by most blood banks are presented in Fig. 304.1 , and the laboratory screening measures currently in place are listed in Table 304.2 . As of 2014, pathogens or diseases screened solely through donor interview include malaria and vCJD. Real or perceived threats to the blood supply occur regularly, as emerging or reemerging infectious diseases raise concern over potential transmission. A previously published review summarizes potential blood supply risks from pathogens, the majority of which are not screened for with laboratory testing.

Pathogen reduction technology (PRT) is now available to reduce the need to develop screening measures for new infectious threats. In December 2014, the US Food and Drug Administration (FDA) approved a PRT method for plasma and apheresis platelets that uses chemicals activated by ultraviolet light to inactivate nucleic acid material comprising DNA and RNA. However, there is no approved method for treatment of RBCs. Although this technology is likely to reduce the risk of transmitted infections of viruses, bacteria, and parasites, it will not likely eliminate it, because there are organisms occurring in high titers or that have structures (e.g., non–lipid-enveloped viruses, bacterial spores, prions) that resist or are not affected by the inactivation mechanism.

Scope of Blood Transfusion

According to estimates from the World Health Organization (WHO), more than 112 million units of blood were collected in 2013. Less than half of donated blood is collected in developing and transitional countries, which are home to about 80% of the world's population. Of the 156 countries providing data to WHO for 2013, 13 were not able to screen all of their donated blood for one or more of the four infections (HIV, HBV, HCV, and syphilis) that are most widely recognized to be transmitted through blood and are recommended by WHO to be screened at donation. A total of 126 countries have national guidelines on the appropriate clinical use of blood, and 70 countries have a national hemovigilance system to monitor adverse events associated with transfusion.

Surveys to determine blood product use in the United States, led by the National Heart and Lung Institute (now called the National Heart, Lung, and Blood Institute), began in 1971. In the United States, surveys have reported the frequency of blood collection and utilization since the late 1980s, most recently through the National Blood Collection and Utilization Survey (NBCUS), which has been conducted biannually since 1998. In the 2017 NBCUS report, reflecting data collected in 2015, there were nearly 11 million whole-blood and 3.7 million apheresis collections, with approximately 19 million blood components transfused. In 2015, 11.33 million whole-blood and RBC units, 2.7 million units of plasma, 1.8 million units of apheresis platelets, 0.17 million units of whole-blood–derived platelets (measured in apheresis equivalent units), and 1.2 million units of cryoprecipitate were given. The number of RBC transfusions has continued to decline since 2008, perhaps reflecting the growing adoption of more aggressive hospital blood management practices. The number of transfused platelets has remained approximately the same, but transfusion of apheresis platelets has continued to increase, while the amount of whole-blood–derived or pooled platelets has continued to decline. In addition to contributions from the voluntary donor pool, plasma units also are collected annually from paid donors and are used to prepare immune globulin, albumin, and various other plasma-derived products. By 1987, the cost of collecting, processing, and transfusing patients exceeded $3 billion; since then, costs have increased steadily with the addition of new screening tests and the implementation of leukoreduction. In 2015, the mean price paid by a hospital was $217 for a unit of leukocyte-reduced RBCs, $60 for fresh-frozen plasma, and $537 for apheresis platelets, so current costs are likely to exceed $4 billion annually.

It has been estimated that the annual likelihood of an individual's receiving a transfusion increases dramatically with age; in 2015, the transfusion rate in the US population was 35.3 units per 1000 people. Because of concern about contracting an infectious disease, there has been historic interest in autologous and donor-directed blood donation. However, donor-directed units, usually given by family members for a specific patient, have been shown to have higher rates of various infectious agents. There has been movement away from donor-directed donation and toward building a dedicated, voluntary repeat donor population. Viral infections are much less common among repeat donors compared with first-time whole-blood donors, and they may be even less common among donors associated with apheresis collection.

A majority of, but not all, blood components transfused in the United States are leukoreduced, a modification that is performed to filter out the majority of white blood cells. Leukoreduction is performed to reduce nonhemolytic transfusion reactions, but it may also reduce the risk for infectious disease transmission through removal of infected white blood cells, particularly for cell-associated agents.

In 2015, only about 0.42% of the donated allogeneic blood supply was discarded on testing, usually because of detection of a potentially transmissible infection. This reflects a continued steady decline in units discarded owing to testing, perhaps indicating improved accuracy of screening tests and retention of repeat donors. The incidence of viral markers in donated units was increased among volunteers who donated after September 11, 2001, primarily owing to a large cohort of first-time and infrequent repeat donors.

Bloodborne Pathogens

Transfusion-associated transmission risk has persisted for HIV, HBV, and HCV for two distinct reasons: (1) the incomplete sensitivity of the available screening tests, and (2) the “window” period, which is defined as the period between acute infection (and potential infectivity) and the point at which serologic tests can reliably detect infection.

The development and implementation of routine nucleic acid amplification testing (NAAT) has transformed blood bank screening for viral pathogens. NAAT can detect viral RNA after the first 10 to 14 days of infection, narrowing the window period by 7 to 10 days for HIV and by 50 to 60 days for HCV compared with serology. NAAT for blood donor screening, in addition to HIV, HBV, and HCV, is now additionally required for WNV and ZIKV, and is voluntarily performed by plasma manufacturers in pools for parvovirus B19.

With introduction of NAAT, the risk of acquiring HIV or HCV per unit of blood transfused has plummeted from approximately 1 per 500,000 for HIV and 1 per 100,000 for HCV before NAAT to a current rate of 1 per 2 million for both viruses. Detected cases are so unusual that the incidence can only be estimated statistically. As remarkable as this advance is, a small window period remains, meaning that the risk for receiving one of these viruses in a unit of blood is not zero. Four cases of HIV transmission and many more cases of HCV transmission through transfusion have been recognized and reported to public health authorities since NAAT was implemented; the modeling data estimate more cases than the number reported, so some cases likely go unrecognized.

The advent of NAAT also has had a substantial impact on the choice of serologic tests. In addition to sensitivity, blood bankers seek optimal specificity: False-positive or indeterminate test results exclude otherwise appropriate donors from subsequent donations and create anxiety due to incorrect diagnosis of infection. The introduction of an extremely sensitive test such as NAAT allows blood banks to focus on the specificity of other screening tests, thereby limiting the number of persons potentially excluded from the donor pool because of misleading test results. Although sensitivity varies little between the second- and third-generation antibody tests, the third-generation assay has superior specificity, decreasing the proportion of persons with indeterminate antibody tests for HCV. HBV NAAT has been adopted for blood donor screening.