In 2009 the AABB's Transfusion-Transmitted Diseases Committee made up of volunteer members with expertise in infectious disease, including representation from the Food and Drug Administration, Centers for Disease Control and Prevention, the US Department of Defense, the American Society of Hematology, and the Association of Public Health Laboratories, convened to publish a supplement to the journal Transfusion on the threat of emerging infectious diseases (EIDs).87 They prioritized specific agents into categories: red agents had the highest priority, followed by orange and yellow. White agents have not yet been given a priority status. The prioritization was based on several features of the organism including scientific/epidemiological evidence regarding blood safety, public perception and/or regulatory concern regarding blood safety, and public concern regarding the disease agent. Curious readers are directed to the reference for further understanding of the classification system.87
Red agents include human variant Creutzfeldt-Jacob disease, dengue viruses, and Babesia species. Orange agents include Chikungunya virus, St Louis encephalitis virus, Leishmania species, Plasmonium species, and Trypanosoma cruzi. Yellow agents include chronic wasting disease prions, human herpes virus 8, HIV variants, human parvovirus B19, influenza A virus subtype H5N1, simian foamy virus, Borrelia burgdorferi, and hepatitis A virus. White agents include hepatitis E and Anaplasma phagocytophilum.87
Bacterial contamination of blood components can be asymptomatic or induce sepsis with a high mortality. It occurs in random donor-pooled platelets (5-30 in 10000 units) and apheresis platelets (0.5-23 in 10000 units) stored at room temperature, PRBCs (0.25 in 10000 units) stored at 39.2°F (4°C), and, rarely, in FFP or cryoprecipitate contaminated during thawing in water baths.88,89 Bacterial contamination of platelet products is acknowledged as the most frequent infectious risk from transfusion, occurring in approximately 1 of 2000 to 3000 platelet units, and is considered one of the most common causes of death from transfusion (along with TRALI and clerical errors resulting in ABO mismatch) with mortality rates ranging from 1:20000 to 1:85000 donor exposures.88
Although bacterial contamination rate estimates vary, they are generally approximately 0.2% to 0.3%.89,90 Clinically recognized septic reactions have been reported at a rate of 1:2500 to 1:11400 for whole-blood–derived platelet concentrate pools and 1:15400 for apheresis platelets. Symptoms occurred after 17% to 42% of contaminated platelet transfusions, with a 17% mortality rate.90 The incidence of severe septic episodes has not been clearly established but is probably approximately 200 per million platelet units transfused (50% sensitivity).28,91 Given the 5-day storage life and the persistent risk of platelet shortage, in September 2005 the Food and Drug Administration (FDA) approved the use of 7-day apheresis platelets under the surveillance program PASSPORT to determine the safety of extending the storage life. The study was discontinued early after 2 true positive cultures were detected in 2571 day-8 platelets (778/million).92 However, after discontinuation, a group was convened to conduct a risk assessment. Based on their modeling, overall recipient risk may not have been improved by withdrawal of 7-day apheresis platelets, given the platelet pools that would have replaced them (surrogate-tested whole-blood platelets vs culture-tested apheresis or whole-blood platelets) and risk of delaying a TRALI risk reduction strategy, which could not be implemented without the additional platelet stores provided by the use of 7-day apheresis platelets.93
Bacteria can enter the blood bag during venipuncture as a result of inadequate skin preparation; during component preparation, transient bacteremia concurrent with the blood donation, or a break in technique during pooling or sealing; or through disruption of container integrity. Bacterial proliferation occurs more rapidly in platelet concentrates stored for up to 5 days at room temperature than in red cells refrigerated for up to 42 days.
The clinical response may include fever, rigors, skin flushing, abdominal cramps, myalgia, DIC, renal failure, cardiovascular collapse, and cardiac arrest; reactions may be immediate or delayed by several hours. This may be clinically indistinguishable from a febrile nonhemolytic transfusion reaction (FNHTR). If this picture presents, blood samples must be sent to rule out incompatible transfusion, and simultaneously the blood unit must be sent for culture. Patient evaluation includes blood culture; treatment includes stopping the transfusion, supportive measures for developing shock, and broad-spectrum antibiotics.
Gram-negative bacteria, including? Pseudomonas, Yersinia, Enterobacter, and Flavobacterium, are organisms commonly associated with a contaminated unit of refrigerated blood. In contrast, platelet concentrates contaminated with Bacillus, Escherichia coli, Klebsiella, Staphylococcus aureus, Staphylococcus epidermidis, Serratia marcescens, and Streptococcus account for 85% of fatal reactions.90,94 Bacterial contamination may be masked clinically by concomitant antibiotic administration.
Screening for syphilis was mandated in 1958, but the last reported case of transfusion-related disease was in 1966. Any risk of transmission is reduced by sensitivity to most penicillin or cephalosporin antibiotics. Treponema pallidum is not currently a threat to the US blood supply.
The risk for infection by HIV and hepatitis C viruses is extremely rare in the United States (<1 case per 2 million units transfused) after implementation of nucleic acid testing (NAT) in 1999.95,96 Contrast this blood safety record to the risk of morbidity or mortality in people with indications for transfusion for which blood products are withheld, and HIV or HCV should not affect transfusion decisions. However, a rare but real risk exists, so inappropriate transfusion should be avoided.
The HAV, a nonenveloped RNA virus in the Picornaviridae family, is transmitted predominantly through the fecal–oral route. Because acute HAV infection is generally symptomatic, infected prospective donors are typically eliminated before donation.
The HBV is a DNA virus in the Hepadnaviridae family. The infective virion is known as the Dane particle and has surface and core components: HBsAg and hepatitis B core antigen (HBcAg). Among blood donors, the prevalence of new HBV infections declined from 1.97 per 100000 person years to 1.27 between 1998 and 2001. Most current HBV transfusion transmission cases correspond to blood donations by asymptomatic donors during acute infections before HBsAg appearance and therefore detection (a "window period" of 37-87 days). With current screening, the risk of HBV transmission per unit is approximately 1:205000 units, with likely reduction in risk with the introduction of NAT testing.95,96
The HCV is an RNA virus in the Flaviviridae family that has 6 genotypes. In the United States, genotypes 1, 2, and 3 cause 75%, 10%, and 10% of infections, respectively, and have similar replication and transmission rates and natural history. The risk of HCV transmission by transfusion declined after the introduction of serologic testing for HCV antibody in May 1990, and NAT testing for the HCV viral genome in 1999 reduced the test-negative window period to 40 days. Combined NAT and serologic testing reduced the risk from an estimated 1:276000 units to 1:1 935000 units.
Originally called the delta agent, hepatitis D virus is a defective RNA-containing passenger virus that requires HBV to act as a "helper" for assembly of envelope proteins. Screening for hepatitis B therefore helps prevent transfusion-associated hepatitis D.
The hepatitis E virus (HEV) is an RNA calicivirus associated with fecally contaminated water supplies, which usually causes a self-limited illness; it is not a known transfusion-related pathogen.
Human Immunodeficiency Virus-1
The Centers for Disease Control and Prevention (CDC) report 9352 AIDS cases in the United States linked to transfusion through December 31, 2001, including 41 adults or adolescents and 2 children who received blood from HIV-seronegative donors. In addition, during the 1980s, 4799 hemophiliacs and other patients with coagulation deficiencies acquired AIDS as a result of therapy with plasma derivatives.
Among 37 million donations screened for HIV-1 RNA by NAT between 1999 and 2002, only 12 were NAT positive and antibody negative.96 The risk with plasma derivatives, such as coagulation factor concentrates and albumin and immunoglobulin preparations, can be expected to be even lower because of additional viral inactivation processes, including heat (pasteurization), physicochemical processes (SD treatment), and nanofiltration, that have been implemented since the mid-1980s; since then, no new HIV infections have been attributed to manufactured blood products.
Human Immunodeficiency Virus-2
Human immunodeficiency virus-2, a retrovirus linked more closely to the simian immunodeficiency virus than to HIV-l, was recognized initially in West Africa. In 1998, the CDC reported 79 cases of HIV-2 infection in the United States, mostly in natives of West African countries. Transmissibility of HIV-2 appears to be lower, the course of infection milder, and the interval between infection and AIDS longer than that associated with HIV-1, presenting a lower risk for HIV-2 transmission by transfusion.
Human T-Cell Lymphotropic Virus-I and -II
HTLV-I and -II are closely related retroviruses in the Oncovirinae group. In contrast with HIV, HTLV is rarely present in cell-free plasma and shows little active replication in infected humans. HTLV is found around the globe, with endemic foci in southern Japan, the Caribbean, South America, and the Middle East. A sensitive HTLV-I/II combination assay was introduced in 1998, and the threat of acquiring HTLV infection from screened blood is currently minimal.
Human herpesviruses (HHVs) are enveloped, structurally complex, double-stranded DNA viruses that cause common infectious diseases, usually associated with lifelong carrier states and the possibility of recurrent reactivation infections. However, the common alpha herpesviruses, herpes simplex and varicella zoster, are not linked to transfusion-transmitted infections.
CMV, a beta herpesvirus (HHV-5), can infect a wide range of cell types, primarily leukocytes; cell-depleted blood components (plasma, cryoprecipitate) do not transmit CMV. In immunocompetent people, this community-acquired infection is either asymptomatic or associated with a mild, self-limited infectious mononucleosis-like syndrome. However, latent virus persists permanently intracellularly, allowing lifelong potential for reactivation of infections or viral transmission by transfusion of cellular blood products or transplanted donor organs.
In immunosuppressed patients, CMV infection leads to morbid and occasionally lethal pneumonitis, hepatitis, gastroenteritis, retinitis, and other inflammatory conditions requiring treatment with ganciclovir and other antiviral agents. Primary infection in pregnancy may be associated with severe fetal malformations and congenital infections complicated by jaundice, hepatosplenomegaly, microencephaly, and thrombocytopenia with significant mortality. Screening for CMV status is essential for neonates, bone marrow transplant recipients, and transplant recipients. A CMV-seronegative transplant recipient is not denied an organ from a seropositive donor but is treated prophylactically and tested for infection. If leukoreduced blood components are not available, transfusion from CMV seropositive donors is avoided to reduce viral load.
At least 50% of blood donors have antibodies against CMV, thereby indicating previous CMV infection. CMV infection develops in 2% of CMV-seronegative transplant recipients given CMV-seronegative blood, compared with 30% to 60% historically seen after infusion of CMV-unscreened blood components.66 Additional safety is conferred by prestorage leukocyte reduction and apheresis platelet collection.
Epstein-Barr virus (EBV), a gamma herpesvirus (HHV-4), causes infectious mononucleosis and is closely associated with Burkitt lymphoma, nasopharyngeal carcinoma, and posttransplantation lymphoproliferative disease. More than 90% of the adult population has evidence of previous exposure, and virus-specific cytotoxic T lymphocytes lyse EBV-infected B lymphocytes, so transfusion-transmitted EBV infection is rare in both immunocompetent and immunosuppressed recipients.
Patients with sickle cell anemia, thalassemia, and other conditions associated with shortened red blood cell survival are at risk for developing acute aplastic or hypoplastic anemia after infection. Others at risk for aplasia after parvovirus infection include immunodeficient patients, HIV-infected patients, solid-organ transplant recipients, and children with malignancies. Persistent parvovirus infection may cause severe chronic anemia in immunocompromised patients. Acute parvovirus infection during pregnancy may result in fetal loss, neurologic abnormalities, and congenital infection. Red blood cell aplasia and chronic anemia caused by parvovirus infection often respond to infusion with immunoglobulin preparations.
Parvovirus can be expected to be present in 1:20000 to 1:50000 blood donors or a higher incidence during epidemic periods. Reactive antibodies may be present in the donor or the recipient, and only 3 cases of transfusion-related transmission have been reported. Pooled plasma products theoretically pose a greater threat, and factor VIII concentrates demonstrated a 40% risk of parvovirus infection.97 The pasteurization process inactivates virus in albumin-based products.
West Nile virus (WNV) is a member of the Flaviviridae family, the genus Flavivirus, and the Japanese encephalitis virus serocomplex that includes Japanese encephalitis virus and St Louis encephalitis virus. Viruses in this complex are arthropod-borne viruses, or arboviruses (ie, transmitted by mosquitoes and other arthropod vectors), with the potential to cause meningoencephalitis. WNV was first isolated in 1937 in the West Nile district of northern Uganda and derives its name from that region. The natural life cycle of the virus includes female mosquitoes as vectors, with birds serving as the primary vertebrate hosts. Humans are incidental hosts, with transmission occurring through bites of infected mosquitoes. Peak transmission occurs in the late summer and early fall.
Since 1999 there have been sporadic outbreaks in the United States, with more than 4000 cases—277 attributed to a 2002 epidemic. In 2002, 23 cases of transfusion (any blood component) or transplant-related transmission were reported; 12 patients developed meningoencephalitis and more severe outcomes were seen in immunocompromised patients.98
Currently, donors are asked about fevers or exposure to endemic areas, and recommendations exclude donors with suspected or confirmed diagnosis of WNV within 120 days of donation. Since June 2003 NAT was instituted on pooled donor samples, and 800 of 6 million US blood donations were WNV NAT positive. Despite this, 6 cases of transfusion-transmitted WNV infection occurred in susceptible individuals.99 The risk of WNV infection depends on the immune status of the recipient, the presence of donor antibodies, and the rate of endemic disease prevalence.
Dengue virus was prioritized in the red category based on scientific/epidemiological evidence regarding blood safety, specifically related to the asymptomatic viremia that poses a significant transfusion risk.87 It is a mosquito-borne disease. Asia, Oceania, Africa, Australia, and the Americas contain at-risk populations. Transmission through blood transfusion has been documented. The clinical disease most commonly is limited to dengue fever with fever and rash, conjunctivitis, myalgia, nausea/vomiting, and prostration. Other more severe forms including dengue hemorrhagic fever and dengue shock syndrome are more rare and occur primarily in children. The mortality in this group is high, 10% to 20%. There is currently no FDA-licensed screening test.87
Lyme Disease and Other Tick-Borne Illnesses
Borrelia burgdorferi, the agent responsible for Lyme disease, is transmitted to humans by deer tick bites. Spirochetemia probably occurs after infection and may be present in asymptomatic individuals, but again, only rarely documented transfusion-related transmissions have been reported for this or other tick-borne pathogens: Babesia species (babesiosis) and Rickettsia rickettsii (Rocky Mountain spotted fever).
Malaria in the United States is typically limited to travelers, military personnel, and immigrants from endemic countries. Prevention of transfusion-transmitted malaria relies on deferral of blood donors immigrating or returning from malaria-endemic regions; there are no available screening tests. Approximately 3 transfusion-associated malaria cases occur per year in the United States, with a reported incidence of 0 to 0.2 cases per million units.
Babesia was placed in the red category based on scientific/epidemiologic evidence regarding blood safety.87 Babesiosis is a malaria-like zoonosis in which humans are infected incidentally, usually through the bite of an infected tick. Blood transfusion has been documented. Babesia infections are usually asymptomatic or cause mild flu-like symptoms but can be fatal in the immunocompromised. Endemic throughout the United States, more than 40 cases of cellular transfusion-transmitted babesiosis have occurred since 1980. A history of babesiosis precludes blood donation, but no screening test is available.
Toxoplasmosis is caused by the intracellular protozoal parasite Toxoplasma gondii, whose usual host is the domestic cat. Transmission is via cats or from undercooked pork, goat, lamb, beef, or wild game. There is evidence of infection in 20% to 25% of the US population, but transfusion-associated disease has only been described in immunocompromised patients.
Chagas was assigned category orange with primary concern with public perception and/or regulatory concern regarding blood safety.87
The flagellate protozoan parasite Trypanosoma cruzi causes Chagas disease. The disorder is widespread in South America, but T. cruzi is also found in North and Central America. Infection is not endemic in the United States, but it is considered emergent in the United States and Canada based on increased immigration. Routes of infection include exposure to feces from infected vectors (largely insects), blood transfusion and organ transplantation, and congenital transmission and breast-feeding. Severe complications include myocarditis, meningoencephalitis, cardiomyopathy, megacolon, or achalasia. Transfusion-associated cases of Chagas disease are more common in immunocompromised patients. In North America, testing is available but is not required by the FDA, and even testing of donors with risk factors or those from endemic areas has not been implemented.87
Human Variant Creutzfeldt-Jakob Disease
Human variant Creutzfeldt-Jakob disease (vCJD) is a prion disease given red priority based on public perception and/or regulatory concern regarding blood safety.87 Exposure is through consumption of bovine spongiform encephalopathy–infected neural beef products. Current to October 2008, 206 cases and 203 deaths had occurred in the United Kingdom or secondary to UK beef products. Blood transmissibility of the disease has been documented and a potentially long incubation period increases the theoretical possibility of transfusion-related transmission. The likelihood of clinical disease after transmission is hypothesized to be high, with mortality estimated to be 100% for those who are symptomatic. There are no screening tests available and there is no treatment. Screening questions that eliminate US donors with UK travel history, leukoreduction, and filtration methods may reduce prion content in US blood stores.87
New molecular assays, such as NAT, can enhance safety but at a high cost compared with the serologic screening that was effective for virtually negating the HBV, HIV, and HCV risk of transfusion. The advent of newer infectious agents, such as vCJD, WNV, severe acute respiratory syndrome (SARS), and potentially Avian influenza A (H5N1) virus, may lead to the deferral of increasing numbers of potential blood donors, with implications for blood supply.
The discussion of infectious agents is mostly based on North American data, but additional challenges exist for ensuring a safe blood supply in developing countries. With global travel and immigration, proactive and collaborative surveillance on an international level is essential to protect any country's blood supply.100