Transfusion Medicine

Pediatr Clin N Am 49 (2002) 1211 – 1238

Transfusion medicine for the pediatrician Keith C. Quirolo, MDa,b,* a

Department of Clinical Laboratory Medicine, University of California, San Francisco, Moffitt-Long Hospital, 505 Parnassus Avenue, San Francisco, CA 94143-0100, USA b Department of Hematology, Children’s Hospital and Research Center at Oakland, 747 52nd Street, Oakland, CA 94609, USA

Over the past few years, major changes in transfusion medicine have improved the safety of the supply of blood, particularly in the areas of infectious disease testing (Fig. 1) and processing. Since about 1990, blood banking has been regulated as a manufacturing process similar to the manufacture of pharmaceuticals [1]. This has led to more uniform blood products with more predictable outcomes. Recommendations have been made for universal leukoreduction [2], more uniform collection of blood products [3], pathogen inactivation of blood products [4], and a quest for a ‘‘zero risk’’ blood product. These new practices and regulations have made blood banking more complex, resulting in the acquisition of many local blood banks by the two major blood suppliers: Blood Systems Inc. and the American Red Cross.

Screening for infectious disease Currently, all blood donations are screened for HIVantigen, antibodies to HIV-1 and HIV-2, human T lymphotrophic virus (HTLV I-II), hepatitis B surface antigen (HBsAg), hepatitis B core antigen (HBC), hepatitis C (HCV), and syphilis. Nucleic acid testing (NAT) [5], used under an investigative new drug license from the US Food and Drug Administration (FDA), uses a transcription-mediated amplification [6] to test for HIVand hepatitis C but not hepatitis B. There are algorithms to define positive screening tests. In addition to laboratory testing, a donor questionnaire is used to decrease the likelihood of transmission of malaria, HIV, and sexually transmitted viral infections, as well as to identify other conditions or travel history that would indicate that a donor’s blood is high-risk for disease transmission. The list of potential blood-borne pathogens is long (Box 1). Not all blood-borne viruses * Department of Clinical Laboratory Medicine, University of California, San Francisco, MoffittLong Hospital, 505 Parnassus Avenue, San Francisco, CA 94143-0100, USA. E-mail address: [email protected] 0031-3955/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 0 3 1 - 3 9 5 5 ( 0 2 ) 0 0 0 9 0 - 1

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Fig. 1. Declining risk of viral infection in blood products. (From Busch MP. Closing the windows on viral transmission by blood transfusion. In: Stramer SL, editor. Blood safety in the new millennium. Bethesda (MD): American Association of Blood Banks; 2001. p. 33 – 54; with permission.)

are pathogenic, though: hepatitis G and the TTV and SEN viruses have been found not to cause disease [7].

Viral pathogens/NAT testing Once an individual has become infected with a viral pathogen, there is a window of time (Fig. 2) during which the viral load is too low, or is intermittently too low, to be detected by pooled sample NAT. Recipients of donated blood products are at highest risk for infection during this window phase. Because NAT testing is so sensitive and there are so few instances of virally infected products, only mathematical models based on research data can predict the risk of infection from a single transfusion. The problem of detecting risk during the window phase has recently been reviewed [8]. Another concern is the risk that an individual unit may be improperly tested or has a variant strain of pathogen that the highly sensitive and specific NAT will not detect. Currently, NAT testing is performed in minipools (MP) of 16 or 24 units. If an MP test is positive, the individual donations in that pool can be further tested to detect the infected unit or source of a false positive. During the window phase before the ramp-up of viral replication, sample dilution may cause MP testing to be inaccurate. A low level of virus that would be missed with MP testing could be detected with individual unit testing (ID); however, ID is prohibitively expensive, time-consuming, and identifies few additional positive units. HIV NAT testing has increased detection of HIV-infected units and significantly shortened the window phase. Mathematical modeling of HIV-infected products predicts that ID NAT rather than MP testing would result in an increased

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Box 1. Transmissible pathogens Viruses Enveloped

Retroviral agents: HIV-1, HIV-2, HTLV I-II Herpes Virus: CMV, HHV-6, HHV-8, EBV Hepatitis Virus: HBV, HBC Non-enveloped Hepatitis Virus: HAV Other Virus: Parvovirus B-19 Bacteria Streptococcus viridans Gram Positive Staphylococcus Enterococcus ssp. epidermidis Staphylococcus aureus Bacillus cereus Coagulase negative Staphylococcus Gram Negative Yersinia enterocolitica Pseudomonas Salmonella enteritidis fluorescence Serratia marcescens Citrobacter freundii Escherichia coli Enterobacter cloacae Flavobacterium spp. Coliforms Klebsiella pneumoniae Protozoa Plasmodium spp. Trypanosoma cruzi Babesia microti Toxoplasma gondii Leishmania donovani Ehrlichia chaffeensis Spirochete Borrelia burgdorferi Treponema pallidum Rickettsia Rickettsia rickettsii Prions vCJD Not all of these pathogens have been proven to be transfusion transmitted and some are not pathogenic.

detection of 3 viral positive units per 10 million units tested (6 units with MP versus 9 units with ID). During the first year of MP NAT testing, four cases of HIV would have been missed with antigen testing, a detection rate of 5.2 per 10 million units. From a cost-effectiveness perspective, the current cost per case detected with HIV p24 antigen testing is $40 million per case [9]; with MP NAT testing the cost per case of HIV is $1.7 million, and with ID testing the cost would be $2.7 million per case. HIV p24 testing will probably be discontinued when NAT testing becomes the FDA standard, because any antigen-positive product should be detectible by NAT. Current studies are in the process of defining the infective dose of virus; in the case of HIV, this could be less than 100 genome equivalents per ml (gEq/ml). Currently with MP NAT, the risk of contracting HIV from a single unit

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Fig. 2. Illustration of the window phase and the ramp-up phase of viral replication. The window phase is the period after initial infection before virus can be consistently detected to the beginning of the ramp-up phase. The ramp-up phase is the period from detection to the peak of viral load. (From Busch MP. Closing the windows on viral transmission by blood transfusion. In: Stramer SL, editor. Blood safety in the new millennium. Bethesda (MD): American Association of Blood Banks; 2001. p. 33 – 54; with permission.)

transfusion is between 1:1,930,000 [10] and 1:3,500,925 [11]. In 1996, the risk was 1:676,000 [12] with HIV p24 antigen testing as the standard. HCV NAT testing has had a huge impact on the transmission of HCV via blood products. HCV has a very long window phase (Fig. 3) with a very high viral titer before antibody can be detected in the serum. The average period of infectivity before antibody detection is between 41 and 61 days. Alanine aminotransferase has been used as a marker for HCV in the past because it is elevated weeks before the antibody can be detected The doubling time for HCV is only 17 hours (HIV doubling time is 21.5 hours); therefore, the ramp-up after the window phase is rapid. The viral load is very high when detection becomes possible. This high viral titer ramp-up also makes the difference between MP and ID detection less dramatic because the slope from the window phase to the plateau is so steep. A troublesome feature of HCV is that there are periods during the window phase when the viral RNA increases to levels intermittently detectable by NAT. It is not known what risk these intermittent increases pose to recipients. Determining the infectivity during the window phase of HCV and other infective agents is an active and important area of study in blood safety. During the first year of NAT testing there were 42 positive units detected that would have

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Fig. 3. Window phase dynamics for HIV, HVC, and HBV primary infection. 0, initial infection; dt, doubling time. (From Busch MP. Closing the windows on viral transmission by blood transfusion. In: Stramer SL, editor. Blood safety in the new millennium. Bethesda (MD): American Association of Blood Banks; 2001. p. 33 – 54; with permission.)

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been missed with antibody screening, a detection rate of 40.3 per 10 million units. Currently, the risk of HCV from a single transfusion is 1:260,000 to1:543,000 [10], compared with a risk of 1:103,000 in 1996 [12]. HBV NAT testing is less sensitive for HBV because HBV has a long doubling time (2.8 days), a slow increase in viremia, and a high rate of infectivity (10 HBV DNA gEq in chimpanzees causes infection) [8]. The level of HBV DNA during this long window phase is low and not consistently identified by NAT testing. HBV may be infective 40 days before the detection of HBsAg. For these reasons, the effectiveness of NAT testing for HBV is less dramatic than for HCV and HIV. The risk of infection from a single transfusion in 1999 was 1:138,700; the risk in 1996 was 1:63,000. There are two new developments in HBV testing. The first is a more sensitive HBsAg assay that is claimed to be equivalent to NAT. The second development concerns recent studies that have shown infectivity in donors who are HbsAgnegative and anti-HBc –positive. These studies are from Japan, where HBV is endemic and point to a source of infectivity not previously appreciated. The new HBsAg testing may place HBV NAT in question; the actual risk of infection by HbsAg-negative and anti-HBc – positive has to be evaluated in this country [13]. HTLV I/HTLV II HTLV screening began in the United States in 1988. Because of the high degree of cross-reactivity between these two viruses, it was soon discovered that donors thought to be infected with HTLV I were actually infected with HTLV II. HTLV I is a retrovirus associated with adult T cell leukemia [14], tropical spastic paraparesis/HTLV I– associated myelopathy [15], and uveitis [16]. In addition, there is increased incidence of infections and immune-mediated disease in persons harboring this virus, indicating a mild to moderate immune-deficient state. Testing is effective in detecting infected donors [12]. The combined donor prevalence in 1991 was 0.05% [17]. In a recent review of the Retrovirus Epidemiology Donors Study, 1,817,502 donors were evaluated; 201 donors tested positive for HTLV I, while 513 tested positive for HTLV II [18]. The incidence of seroconversion to HTLV I or HTLV II in blood recipients is low. There are more data on donors who have tested positive for these viruses [19] than recipients. Very few donors had clinical evidence of infection.

Bacterial contamination of blood products Bacterial sepsis from contaminated blood products is the second leading cause of transfusion-related death (Fig. 4) in the United States today, behind transfusion errors. Between 1990 and 1998, there were 277 reported transfusion-related deaths, 17% of which were due to bacterial contamination. The fact that patients

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Fig. 4. Risk of bacterial contamination relative to the risk of other, more familiar pathogens. Bacterial contamination estimates for red blood cells and platelets are based on the BaCon study (unpublished data). (Adapted from Busch MP. Closing the windows on viral transmission by blood transfusion. In: Stramer SL, editor. Blood safety in the new millennium. Bethesda (MD): American Association of Blood Banks; 2001. p. 33 – 54; with permission.)

receiving blood transfusions are likely to have complex medical conditions and are frequently immune suppressed contributes to the morbidity of transfusionrelated sepsis. The culture positive rate for red blood cells is as high as 0.2%. The reported incidence of platelet contamination for single-donor apheresis platelet products is much lower, on the order of 0.006% to 0.02%, and 0.02% to 0.5% of individual units in platelet concentrates. The incidence of platelet contamination has varied among studies (Table 1). There are three major studies of bacterial contamination in blood products: the French BACTHEM study [20], the United Kingdom SHOT study [21,22], and the United States BaCon study (unpublished data). There has been a recent review of the detection of bacterial contamination in cellular blood products [23]; however, there are currently no standards for detection of bacterial contamination of products other than visual inspection. Bacteria can contaminate blood products in several ways. The most common is inadequate decontamination of the skin before venous puncture. McDonald et al Table 1 Comparison of numbers of bacterially contaminated platelet products by study

Single donor platelets

Platelet concentrate (% per unit)

Study

% Contaminated (n)

Products

Ness et al [29] French BACTHEM [34] Yomitovian et al [39] Liu et al [33] Chiu et al [31]

0.006% 0.003% 0% 0.053% 0.046%

30,197 282,848 2476 26,210 21,503

(2) (9) (14) (10)

Platelet concentrates are more frequently contaminated but are diluted before administration. Single donor platelets have a greater volume with higher numbers of bacteria per unit administered and are more frequently implicated in sepsis.

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[24] reported on several skin preparations and found that the standard American Association of Blood Banks was only 83.2% effective in removing bacteria from the venipuncture site on donors. Because of the large bore needles used to collect blood products, skin plugs are sometimes found in collection bags [25]. Skin bacteria are the most common contaminants, but as can be seen from the studies cited below, they do not carry the highest morbidity. Transient bacteremia [26] caused by dental procedures, endoscopy, and even chewing gum is short-lived but is nevertheless a potential source of blood product contamination. Red cell products After processing, which can include leukoreduction, red blood cells are kept at 4° C for the 42 days of their storage life; this temperature slows the multiplication of bacteria. Leukoreduction can reduce intracellular bacteria [27] in the product, including Yersinia enterocolitica [28] a potential cause of sepsis. The only bacterial screening test performed on red blood cell products is for Treponema palladium and is a screen for sexual behavior, not infection risk. T palladium is viable for 92 hours in stored red blood cell products. Published reports from the BACTHEM and SHOT studies document the bacterial contamination of red blood cells. The BACTHEM study covered the years 1996 to 1998. During that time, 158 suspected cases of transfusiontransmitted infection were reported, but only 41 met the criteria to be included as events in the study. All of the patients who became septic had severe underlying disease. The majority of the episodes occurred in older adults, but there was one death in a pediatric patient. Sepsis correlated with the bacterial contaminant rather than the type of blood product received. All deaths were associated with gram-negative sepsis. Although Y enterocolitica is frequently believed to be associated with red blood cell sepsis, it was less common than Acinetobacter, Klebsiella, and Escherichia coli as a cause of sepsis in this study. The SHOT study reviewed all cases of morbidity from transfusion from 1996 to 1998. Only 3% of the morbidity was infectious; the types of bacteria implicated in sepsis were similar to the BACTHEM study. The single death from bacterial contamination of red blood cells was due to Y enterocolitica. Y enterocolitica is a more common contaminant of red blood cells in the United States than in the United Kingdom or France. The Centers for Disease Control reported 21 cases of Y enterocolitica sepsis in 1997; there were 11 cases between 1985 and 1991 and 10 cases between 1991 and 1996. It was not noted whether these cases were from leukocyte-reduced units; however, it is believed that leukocytes continue to ingest bacteria following collection and that early leukodepletion may decrease this protective effect. The optimum time for leukoreduction has not been determined. Red cells can be visually screened before administration for color changes and clotting. If present, cultures of the unit should be obtained and the unit should be discarded or quarantined. All febrile transfusion reactions, including fevers

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within 24 hours of a transfusion, should be considered as possible septic events and treated as such. Most symptoms of infection will occur within 6 hours. Hospital blood banks should hold blood bags for 24 hours after a transfusion for culture in the event of fever in the recipient. Platelet products There have been numerous reports of infectious complications from platelet transfusions. Ness et al [29] reported the incidence of platelet contamination to be 1:4300 units. In the BACTHEM study, the risk of infection from a blood product was 3 times higher for platelet products, 5.5 times higher for apheresis platelet products, and 12 times higher for pooled platelet products. In addition, mortality for apheresis platelet products was 7 times higher than with red blood cell products. Over the past several years, there has been a dramatic increase in the use of platelet obtained by apheresis in transfusions. Some studies have demonstrated a decrease in the incidence of infectious complications with the use of apheresis [29], while others have not [20,30]. The bacteria found in contaminated platelet products are predominantly skin flora; more severe episodes of sepsis are usually caused by gram-negative organisms. In the Ness study, there were four deaths, three from skin flora and one from E coli. This is similar to other studies [31]. Platelet products have a storage life of 5 days. This figure would be even shorter if 24 to 48 hours were used to culture all products and follow up positive cultures. Platelets, like red blood cells, can be visually examined before transfusion for signs of contamination such as discoloration, aggregation, and swirling (cloudiness) [32]. As with red blood cell transfusions, all fevers that develop within 24 hours should be treated as a potential septic event. Platelet bags should be retained by the blood bank for 24 hours in the event of fever. New methods to detect bacterial contamination Several studies have evaluated the use of culture and gram stain to identify bacterially contaminated platelet products [33]. These studies have been cumbersome and time-consuming, although some have been successful in decreasing contaminated products. Few studies have evaluated red blood cell products. Currently, there are no methods in common practice to detect bacterial contamination of blood products. Red blood cells Red cells have a storage life of 42 days; in the future, this period may extend to 63 or 70 days [34,35]. This allows ample time for bacterial surveillance by culture. There have been two recent reports of surveillance by culture using special bags attached to the collection system currently used for red blood cell collection. Bruneau et al [36] focused on the contamination resulting from skin flora introduced in the first 15 ml and second 15 ml of blood collected and found

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that 2.2% of samples collected were positive for skin flora (first 30 ml of donation). Diversion of only the first aliquot would reduce the risk of contaminating the unit to 0.06%. No plasma tested positive, and no unit testing positive in the second aliquot was a true positive. A study by de Korte et al [37] examined a system for collecting an aliquot from the entire donation for bacterial culture; it was reported that 0.34% of the units tested had a bacterial contaminant. Platelets Platelets are much more likely than red blood cells to cause bacterial sepsis, because they are stored at 20° to 24° C and potentially have a higher bacterial load. There have been many studies of methods for determining bacterial contamination of platelets, including antibiotic-labeled probes [38], visual inspection , pH and glucose testing [32], and the use of gram stain and culture [39]. Most of these tests are laborious and time-intensive, possibly taking longer than the 5-day storage life of the product. A system similar to the red blood cell culture methods that will use a specially designed collection system and use oxygen consumption as a marker for bacterial growth will be marketed soon. One abstract reported using bacterial cultures on the second day of storage to extend the storage life of platelets safely to 7 days [40].

Emerging pathogens With the advent of comprehensive donor screening, NAT testing, and perhaps universal leukoreduction, blood transfusion is safer than it was only a decade ago. Pathogens like HIV, HCV, and HBV are a persistent but vanishing risk of transfusion. Infections once considered low risk have become more significant (Table 2). For these low-risk pathogens there are no approved screening tests. The blood supply is protected by accurate history taking and deferral at the time of donation and in some cases by the apparent low virulence of the organism. Human herpes virus There are eight human herpes virus (HHV) species, four of which are of importance in transfusion medicine. Cytomegalovirus (CMV) is the most common. Two of the HHVs have been implicated in oncogenesis: Epstein-Barr virus (EBV), which has been documented to be transmitted via blood transfusion, and human herpes virus-8 (HHV-8), which has not. Two other HHVs that infect mononuclear cells are HHV-6 and HHV-7. HHV-6 infects leukocytes, natural killer cells, and monocytes, and is the causative agent for roseola. HHV-7 infects the same cell lines as human herpes virus-6 and has been associated with viral rashes. All of these viruses are lymphotrophic, and their transmission could be reduced by leukocyte filtration.

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Table 2 Emerging pathogens and their relationship to leukocytes and transmission Pathogen Viral CMV EBV HHV-8 HHV-6/HHV-7 Protozoa Trypanosoma Plasmodium Tick-borne Babesiosis Ehrlichioses Borrelia Rickettsia Prion vCJD

Vector

Leukocyte associated

Documented transmission

Human Human Human Human

Yes Yes Yes Yes

Yes Yes Yes No

Insect Mosquito

Yes No

Yes Yes

Deer tick Deer tick Deer tick Wood tick

No Yes Yes Yes

Yes No No One case

Bovine/Human

Yes

No

Emerging pathogens may become more important sources of blood product contamination as screening eliminates other risks. With the exception of CMV, blood products are not routinely tested for these potential pathogens. Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV, human herpes virus; vCJD, variant Creutzfeldt-Jakob disease.

CMV CMV is a common virus that infects approximately 40% of blood donors, though there is a geographic variation. In the immunocompentent person the viral infection is not severe, but the virus remains latent in mononuclear cells for an indefinite period. Immunocompentent individuals are infected with CMV but do not develop CMV disease. CMV disease is characterized by retinitis, gastroenteritis, and interstitial pneumonitis, which can be fatal in the seronegative immunocompromised host. Seronegative immodeficient individuals at risk of developing CMV disease as a result of a CMV-positive transfusion include: the fetus, premature infants less than 1200 g, recipients of allogeneic stem cell transplants, solid organ recipients, and individuals with HIV. In the mid-1980s, bedside leukofiltration was used in an attempt to reduce the incidence of CMV disease in at-risk patients. There have been numerous studies and reviews regarding the safety and equivalence of leukoreduced blood products to seronegative products. As prestorage leukofiltration and apheresis platelet collection became more common, research showed that a three-log reduction in leukocytes could render products statistically as safe as CMV-negative products [41]. CMV studies were complicated by the seasonal variation in the detection of CMV DNA in seropositive individuals. In addition, detection of CMV DNA may or may not equate with infective virus, and seronegative individuals can have detectible levels of CMV DNA. There is a long history of use of leukoreduced blood products being considered ‘‘CMV safe.’’ The Institute for Clinical Evaluative Sciences in

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Ontario recently published a consensus statement [42] on the use of leukoreduced products as CMV safe. A second reviewer (Box 2) [43] did not recommend use of leukoreduced products as equivalent to CMV-negative blood products under all circumstances. It would seem prudent to transfuse CMV-negative, leukoreduced blood products to seronegative patients in particularly high-risk situations such as in utero surgery, expectant mothers, very low birth weight infants, recipients of T cell – depleted stem cells during transplant, and autologous transplant recipients. Studies comparing leukoreduced with leukoreduced CMV-negative blood products will make clinical decision-making easier. EBV It has been demonstrated that EBV is transmitted by transfusion [44] to immunocompromised patients. This virus is the etiologic factor in posttransplant lymphoproliferative disorder, Burkitt’s lymphoma, Hodgkin’s disease, and nasopharyngeal carcinoma. Currently, there is no screening test for the presence of EBV in blood products. Theoretically, leukoreduction could decrease the risk of transmission, but transmission during active viremia would not be prevented. Defining the at-risk recipients, the infective dose of virus, and the effectiveness of leukoreduction are active areas of research. HHV-8 HHV-8 was discovered in 1994 as the etiologic agent of Kaposi sarcoma in HIV-infected individuals. It has also been implicated as an agent in multicentric Castelman’s disease and primary effusion lymphoma. Research has shown that HHV-8 is transmitted by renal transplantation to seronegative recipients [45]. A recent report from France [46] reveals that HHV-8 is primarily transmitted by sexual contact. Protozoan Protozoal infection transmitted by blood transfusion is rarely documented [47]. There is some evidence that leukoreduction reduces the numbers of some protozoan organisms in blood products [48]. Plasmodium spp (malaria) Infection by this protozoal pathogen is the most common and important in transfusion medicine. There are four species of Plasmodium that infect humans: P falciparum, P vivax, P malariae, and P ovle. There have been approximately 3000 transfusion-transmitted cases reported worldwide since 1911 [49]. In a recent review of cases [50] in the United States, there were 93 cases of malaria transmitted by transfusion over a period of 30 years. In the United States 54% of the cases were caused by P falciparum and P vivax. Of the remaining, 2% were

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Box 2. Indications for the use of CMV-‘‘safe’’ cellular blood products

Category A: populations in whom the use of CMV-‘‘safe’’ cellular blood products has been proven to reduce the incidence and morbidity of CMV infection using controlled trials 

Low birth weight infants born to seronegative mothers Seronegative recipients of seronegative donor bone marrow (allogeneic)  Seronegative recipients of autologous bone marrow transplants 

Category B: populations at high risk of significant morbidity as the result of transfusion-acquired CMV infection, but the incidence of transfusion-acquired CMV infection in these populations has not been clearly documented or the benefit of using CMV-‘‘safe’’ cellular blood products has not been proven 

Seronegative pregnant women requiring antepartum transfusion or intrauterine blood transfusions and seropositive women requiring intrauterine blood transfusions in the second semester  Low birth weight infants born to seronegative or seropositive mothers or other seronegative immunosuppressed patients requiring granulocyte transfusions  Seronegative recipients of seronegative donor lungs and livers and possibly other organs excluding heart and kidney recipients  Seronegative HIV-infected and AIDS patients and children born to HIV-infected mothers Category C: populations who may be at higher risk of transfusion-acquired CMV infection or morbidity, but in whom the incidence or morbidity of transfusion-acquired CMV infection is low or poorly documented 

Low birth weight infants born to seropositive mothers Infants with birth weights >1500 grams born to seronegative mothers  Neonates receiving ECMO (extracorporeal membrane oxygenation) and other neonates requiring extensive transfusion support (i.e. exchange transfusion, cardiovascular surgery)  Seronegative recipients of seronegative donor kidneys and hearts  Seronegative patients with malignant disease receiving chemotherapy 

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Seronegative patients with hematologic or genetic disorders requiring repetitive transferors in who bone marrow transplantation may be a future therapeutic option  Seronegative patients experiencing major trauma or splenectomy Category D: populations in which the incidence and morbidity associated with transfusion-acquired CMV is low, and the use of CMV-‘‘safe’’ cellular blood products is not indicated 

Infants with birth weights >1,500 grams born to seropositive mothers  Other seronegative immunocompentent patients  Seropositive transfusion recipients (excluding neonates) Although leukoreduced red blood cell products are statistically as safe as CMV-negative products, some patients would benefit from CMV-negative products when available. (Adapted from Preciosities JK. The cytomegalovirus-‘‘safe’’ blood product: is leukoreduction equivalent to antibody screening? Transfus Med Rev 2000;14:126; with permission.)

unidentified and 3% were mixed; the rest were caused by P malariae and P ovale. Of the donors identified, 75% were infective at the time of donation, and 60% were foreign born; of the cases since 1994, 62% would have been deferred by the existing donation criteria. There were three cases between 1996 and 1998; two of these cases were fatal. Trypanososma cruzi (Chagas’ disease) Trypanososma cruzi is endemic in Mexico, Central America, and South America, where it is transmitted by a diatomite insect during a blood meal. In the United States, the infection is a current threat to the blood supply of California, Arizona, New Mexico, Texas, and other states with a large immigrant population. In Los Angeles, the seroprevalence in donors has been estimated to be between 1 in 500 and 1 in 7500. In some areas of Texas, the seroprevalence is 1 in 7700. In Miami, the prevalence is 1 in 9500 [51]. Other areas of the country report transfusion-transmitted T cruzi, as well; there have been only five reported cases of T cruzi transmission by blood transfusion in North America, compared with a 13% to 49% transmission rate in Brazil. Transfusion to an immune deficient host (four of the reported North American cases) causes fulminant disease. The diagnosis can be made by serology, PCR, and microscopy.

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Tick-borne infections Transfusion-transmitted tick-borne infections are at least as rare as protozoal infections. These infections tend to be seasonal and have geographic distributions. History of transfusion should be kept in mind when there seems to be no other risk factor for a tick-transmitted disease. Babesiosis microti (Human babesiosis) Babesiosis microti was first recognized as a human pathogen in 1969. This intracellular parasite is endemic in the northeastern and midwestern United States with cases also reported in California and Washington. The parasite is transmitted to humans and deer by the tick Ixodes scapularis. The reservoir for this pathogen is a species of white footed mouse. Because of transmission by a tick vector, blood-borne infection is seasonal. There have been approximately 25 cases reported in the past 20 years. The parasite can survive in refrigerated red blood cells for as long as 21 days. Ehrlichioses spp. (Ehrlichiosis) There are five species of Ehrlichioses. E chaffeensis causes human monocytic ehrlichiosis (HME). E ewingii and another unidentified species resembling the two animal species (E equi and E phagocytophila) cause human granulocytic ehrlichiosis (HEG). HME was first described in 1986 and HGE in 1994. HME occurs in the south central United States; HGE occurs in the northeastern and midwestern states. The HGE parasite is transmitted by Ixodes scapularis and I pacificus. E chaffeensis is transmitted by Ambylomma americanum. These parasites infect humans and are found in the cellular elements of blood. There is the potential of transmission by transfusion, though there are no reported cases. Borrelia burgdorferi (Lyme disease) Lyme disease was first described in 1977 and is the most common tick-borne disease in the continental United States. Ninety percent of the cases are reported in 10 states in the mid-Atlantic, northeastern, and upper midwestern regions of the United States. The signs and symptoms of this disease are well known by pediatricians. Even with widespread and frequent diagnosis, this spirochete has never been implicated in a transfusion-related infection. Rickettsia rickettsii (Rocky Mountain spotted fever) Rickettsia rickettsii has been known for over a century and is endemic in most of the continental United States. Rocky Mountain spotted fever is transmitted by the American dog tick (Dermacentor variabilis) and the Rocky Mountain wood tick (Dermacentor andersoni). There has been one case of transfusion-transmitted Rocky Mountain spotted fever [52].

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Table 3 Comparison between variant and classical Creutzfeldt-Jakob disease Clinical presentation

vCJD

CJD

Age of onset Mean age at death Psychiatric and sensory symptoms EEG changes Duration of illness Neuropathologic features

Early 30 years Frequent early in the course of the disease Absence of EEG changes 14 months Florid prion protein plaques surrounded by spongiform changes Abnormal prion protein detectable in lymphoid tissue

Late 67 years Appear later in the course of the disease Diagnostic EEG changes 4 months Florid plaques uncommon

Immunohistochemistry

Abnormal prion protein not detected in lymphoid tissue

Abbreviations: CJD, Creutzfeldt-Jakob disease; EEG, electroencephalogram; vCJD, variant Creutzfeldt-Jakob disease.

Prions (Creutzfeldt-Jakob disease) Prions and prion-related disease have recently been reviewed [53] and discussed [54] in the medical literature. The emergence of variant CreutzfeldtJakob disease (vCJD) has dramatically altered donor recruitment. The differences between vCJD and classic CJD can be seen in Table 3. Screening tests to distinguish between the two isoforms [55] are under investigation, but a test for routine blood donor screening is unlikely to be available for some time. No cases of vCJD have been associated with transfusion and there is some debate as to whether transfusion-transmitted infections are possible. There is an animal model [56] showing transmission by transfusion is possible. Currently, the only method of reducing the possibility of transmission is by donor history [2]. The disease has a long latency period, and transmission by transfusion may be rare. In Europe, one of the goals of universal leukocyte filtration has been to decrease the transmission of vCJD.

Transfusion-mediated immune modulation The first well-documented immune effect of transfusion was reported in 1973 by Opeiz et al [57] and showed increased survival of renal allografts in patients who had received allogeneic blood transfusions before transplantation. Since this report, there have been numerous studies and reports of the immune effects of transfusion [58]. Microchimerism has been detected decades following transfusion of whole blood and other products containing viable leukocytes [59]. Transfusion-related graft versus host disease has been reported in immunocompetent patients following transfusion for surgery [60]. Thalassemic children who were transfused at a younger age have a decreased incidence of alloimmunization throughout their life [61]. There have been studies to evaluate the effect of transfusion on the recurrence of cancer [62] and the incidence of infection

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following surgery [63]. These effects are frequently cited by proponents of universal leukocyte reduction as reasons for its institution for all cellular blood products. It should be noted that the immunomodulatory effects of blood products appear to be inherent in the leukocyte fraction of transfused products, both at the cellular level and the cytokine level. Most studies and effects are seen only with nonleukocyte-reduced products. Controversy concerning the immunomodulatory effects of nonleukoreduced red blood cells continues. This is most strikingly represented in the report of a conference held in March 2000 in Washington, DC, in which experts claimed both immunomodulatory effects of blood transfusion and disclaimed the same effects. Vamvakas and Blajchman [64] published a review of the studies of surgical infection and cancer recurrence one year later. They felt that the immunomodulatory effects of blood transfusion are small and could not be conclusively documented for infection or cancer recurrence with the studies done to date. Patients who may benefit from leukoreduction to prevent possible immunomodulatory effects are candidates for renal transplant, immunosuppressed patients requiring intensive platelet support, premature infants, and chronically transfused patients.

Transfusion-related acute lung injury In August 2001, a letter circulated by the US Department of Health and Human Services warned about the possibility of transfusion-related acute lung injury (TRALI) in transfused patients [65]. There have been 45 reported fatalities since 1992. TRALI is thought to be responsible for 13% of all transfusion fatalities, making it the third leading cause of transfusion-related death. Most deaths have been associated with the administration of fresh frozen plasma, but TRALI has also been reported with all blood products containing plasma. First reported in 1951 [66], TRALI was not widely recognized as a common complication of transfusion until 1985, when Popvsky and Moore [67] published a report that described 36 patients with TRALI complications. Initially, it was theorized that donor human leukocyte antigen (HLA) and neutrophil antibodies alone were responsible for this pulmonary syndrome. This was probably not the sole etiology, because 1% to 2% of blood donors have HLA antibodies in their serum, and TRALI is relatively rare. The prevalence in adult transfusions of packed red blood cells is 1 in 2000; for platelets it is 3 in 1000 units of concentrate [68]. Clinically, TRALI is similar to acute respiratory distress syndrome. The patient receives a transfusion of a product containing plasma, be it platelets, whole blood, packed red blood cells, fresh frozen plasma, cryoprecipitate, or intravenous gamma globulin (IVIG) [69]. Within 6 hours, but usually sooner, the patient develops a fever ( > 1° C), tachypnea, and dyspnea. Hypotension has also been reported. A chest radiograph is consistent with pulmonary edema; the findings can progress from scattered interstitial infiltrates to complete ‘‘white-out.’’ The mortality can be as high as 10%. If aggressive respiratory support is instituted

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immediately, the patient usually improves within 72 hours. Occasionally, oxygen administration is all that is required. Diuretics are not indicated because the etiology is microvascular injury without pulmonary edema. The differential diagnosis for this constellation of symptoms is: circulatory overload, sepsis, anaphylactic transfusion reaction, and immediate hemolytic transfusion reaction. Circulatory overload is most common in infants in whom there has been an error in calculation of blood requirement, and usually occurs within hours; it is usually not accompanied by fever and typically presents signs of cardiac enlargement on chest radiograph. Anaphylactic transfusion reactions usually occur within minutes of receiving a small amount of blood product; these reactions include bronchospasm, laryngeal edema, wheezing, hypotension, and urticaria. Bacterial sepsis from a blood component can occur rapidly in an immune compromised patient but may occur many hours later in an immunocompetent patient. The manifestation of sepsis is protean and includes fever, hypotension, and respiratory distress. Pulmonary findings are infrequent. Immediate transfusion reactions can begin with fever, respiratory distress, and hypotension. Renal involvement and a disseminated intravascular coagulopathy are common; pulmonary infiltrates are uncommon. A workup for a hemolytic transfusion reaction will show a positive direct antiglobulin test and will usually reveal a discrepancy in the blood type of the patient and the product. If TRALI is due to the infusion of the plasma component of the product, washing could eliminate this risk; however, only red blood cells easily lend themselves to washing. The use of products with a shorter storage life has been advocated because older products have increased lipid and cytokine concentrations. Lipid receptor antagonists and calcium channel blockers have also been used, but more trials are needed to prove their efficacy. Fortunately, like acute respiratory distress syndrome, TRALI is not common in pediatric patients but needs to be considered when evaluating a child or adolescent with a transfusion reaction that includes pulmonary symptoms.

Leukoreduction Leukoreduction was first proposed as a goal for the blood industry in 1995 by the FDA. In January 2001, Guidance for Industry [70] was released, arguing in favor of universal leukocyte reduction. In addition, this document set forth industry standards for quality assurance, quality monitoring, registration, and production licensure. The FDA argument accepted most of the reasoning in favor of leukoreduction: transfusion-associated immunomodulation, bacterial overgrowth, viral reactivation, reperfusion injury, red blood cell and platelet storage lesions, and a reduction in the risk of vCJD. The FDA was not convinced that leukoreduction was protective against transfusion-associated graft versus host disease. It is recommended that all leukocyte reduction occurs at the time of storage [71]. There are numerous problems with bedside leukoreduction, including rare episodes of severe hypotension, lack of quality monitoring for the actual log

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reduction of leukocytes, and no quality control for the procedure itself. In addition, leukocytes in stored products undergo necrosis and release cytokines and other degradation materials that are not well removed by leukoreduction and can cause febrile nonhemolytic transfusion reactions. Currently, leukocyte filtration following collection removes 99.9% of all leukocytes (Table 4) to a final concentration of 5  106 leukocytes per unit for red blood cell products; 85% of the initial product must be retained during this process. In Guidance for Industry, the FDA noted that in the future it would require leukocyte-reduced products to have a final concentration of 1  106 leukocytes. There are strong arguments for and against universal leukoreduction. Universal is the key word stressed in all arguments. There is little debate that leukoreduction benefits some patients and that leukoreduced blood products have a greater safety profile with few side effects. In all likelihood, universal leukoreduction will eventually be the standard of care in the United States, because the only downside of leukoreduction is the cost. In January 2001, the US Department of Health and Human Resources Advisory Committee on Blood Safety and Availability made recommendations for leukoreduction [72]. These recommendations and the recommendations of the University Health Consortium are presented in Boxes 3 and 4.

Pathogen inactivation Pathogen inactivation has been a goal of blood banking since the 1940s, when the pasteurization of albumin was used to prevent jaundice following its infusion. For stable products such as albumin, there have been advances since the 1980s,

Table 4 Relationship between the numbers of leukocytes in blood products relative to the reduction to their reduction by filtration     

109 108 106 – 7 106 – 8 107

Leukocyte count of Whole blood blood products Packed red blood cells Frozen/washed red blood cells Apheresis platelets Platelet concentrate (from whole blood )

1 1 1 1 1

Log of leukocyte reduction

Log reduction

Percent leukocyte Residual removal leukocyte count

1 2 3 4

90% 99% 99.9% 99.99%

log logs logs logs

1 1 1 1

   

108 107 106 105

With today’s technology, it may not be possible to achieve the log reductions recommended by the FDA (apheresis platelets are reduced at time of collection). From Preciosities JK. The cytomegalovirus-‘‘safe’’ blood product: is leukoreduction equivalent to antibody screening. Transfusion Medicine Reviews 2000;14:126; with permission.

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Box 3. Recommendations for leukoreduction of blood products

Technology Assessment Group Clinical Practice Advancement Center University HealthSystem Consortium Indications for Use of Leukoreduced Components Decrease alloimmunization during platelet long-term support Reduction of risk of cytomegalovirus infection . Prevention of febrile non-hemolytic transfusion reactions . Decrease the incidence of HLA alloimmunization in nonhepatic solid-organ transplantation . .

Non-indications for Use of Leukoreduced Components Prevention of reactivation of endogenous viral infections Prevention of immunomodulatory effects of transfusion . Reduction of length of hospital stay . Prevention of transfusion-associated GVHD or TRALI . Prevention of bacterial sepsis . Prevention of transmission of cell associated known or unknown infectious agents . Prevention of vCJD . .

Administrative . .

Prestorage leukoreduction is recommended Use of leukoreduction to maintain a single inventory of products is not justified

Policy Universal leukoreduction is not justified – For benefit-to-risk reasons – For benefit-to-cost reasons . Universal Leukoreduction is not justified to align United States policy with the policy of other nations . The FDA should not mandate universal leukoreduction on the basis of current scientific and medical evidence .

Adapted from Ratko TA, Cummings HA, Obermann HA. Evidence-based recommendations for the use of WBC-reduced cellular blood components. Transfusion 2001; with permission.

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Box 4. Universal leukoreduction advisory committee on blood safety and availability January 2001

1. Universal leukoreduction should be implemented as soon as feasible. 2. With regard to universal leukoreduction, the Advisory Committee is concerned about the availability of blood and the resources necessary to implement universal leukoreduction. For these reasons, the Advisory Committee recommends that the actions of the Department of Health and Human Resources should strive to a. Minimize the impact on supply b. Ensure adequate funding for this effort c. Issue a regulation to implement universal leukoreduction that addresses these concerns, and d. Report to the Advisory Committee on a regular basis the progress toward these goals. 3. Given the unresolved scientific issues in the field, the Advisory Committee supports continuing research on the effectiveness of leukoreduction. 4. In the above resolutions, the word ‘‘leukoreduction’’ is intended to mean prestorage leukoreduction, and the resolutions refer to non-leukocyte cellular blood components. Source for these recommendations can be found at www.dhhs.gov/bloodsafety. The Advisory Committee to the Food and drug Administration has recommended Universal Leukoreduction be implemented as soon as possible for the national blood supply

such as solvent/detergent processing to nanofiltration methods, in the processes used to create a safer product. This article does not explore the methods used for the purification of nonlabile blood products, because an excellent review of this topic has recently been published [73]. Experiments in pathogen inactivation have used porphyrins, phenothiazines (methylene blue), cyanines, psoralens (Helinx), and other compounds such as riboflavin, ethylene imines (Inactine), and frangible anchor-linked effector compounds (FRALEs) to inactivate viruses, bacteria, and leukocytes. A recent review explores all of the recent studies of pathogen inactivation [10]. Currently, the most promising methods of pathogen inactivation are psoralens, ethylene imines, and riboflavin.

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Psoralens Psoralens are naturally occurring compounds that were used to treat psoriasis in the 1970s through oral ingestion followed by ultraviolet light exposure. The chemistry and toxicity of these compounds was investigated at that time. Psoralens are planar, aromatic compounds that intercalate with bases in nucleic acids and, when exposed to ultraviolet light (UVA 320– 400 nm), form covalent additions (called adducts) to the pyrimidine bases. They can form either mono- or diadducts, and in either case block nucleic acid replication. These compounds can be used in a dose that will overwhelm the repair mechanisms of bacteria, viruses [74], or leukocytes [75], and halt replication and therefore infectivity or function. Neither red blood cells nor platelets require replication to function, nor are they affected by psoralens. FRALEs FRALEs (S-303) are unique compounds that irreversibly cross-link nucleic acids without the use of light. They are used to inactivate pathogens in red blood cell products. FRALEs are reported to decompose after pathogen inactivation. They have been tested against common viral and bacterial pathogens and have been proven to be very effective. Ethylene imine Ethylene imine is a unique, low molecular weight, water-soluble imine that crosses cell membranes. The active compound is known as PEN110; the process of pathogen inactivation is known as the INACTINEÔ process. This compound does not require light for activation and is effective in low concentrations. The process of inactivation is complex. The blood product is incubated for 24 hours at 23° C, then washed 12 times with an instrument (Hemonetics) designed specifically for this process. The finished product is a unit of washed, leukoreduced, pathogen-free product in a standard preservation solution (AS-3). Riboflavin Riboflavin (vitamin B2) is a water-soluble coenzyme that participates in oxidation reduction reactions. This vitamin is ingested in the diet and is rapidly taken up by cells to participate in metabolic processes. This vitamin/pathogen inactivator has only been used in platelets. It is activated by visible light and cross-links nucleic acids. The latest research on this compound has been performed in the Netherlands. Pathogen inactivation holds great promise for the future of transfusion medicine and blood banking. Like all new medical procedures and pharmaceuticals, the actual risks and benefits of these components and procedures will take years to determine. The cost of these procedures could be significant.

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Red blood cell storage, substitutes, stealth cells Prolonging red blood cell storage In 1961, Simon et al [76] demonstrated that adenine could be added to red blood cells to prolong their survival. In 1977, Zuck et al [77] demonstrated that this was a viable method of preservation, convincing the FDA to approve adenine for red blood cell storage. With the removal of plasma and the use of additive solutions (AS-1, AS-3, and CPDA-1, CPDA-2 or CPDA-3), the storage life of blood is currently 42 days. Even with these additive solutions, there continues to be a storage lesion shorting the life of preserved red blood cells. The storage lesion has been recently reviewed [49]. Recent developments will eventually have an impact on the preservation and storage of red blood cell concentrates. With new apheresis collection devices it will be possible to collect leukoreduced products in combinations ready for transfusion with limited, if any, component processing. These devices can collect two units of red blood cells; a unit of red blood cells, platelets, and plasma; or combinations of these components. In addition, because they are apheresis products, the volume, hematocrit, leukocyte count, and platelet count can be predetermined by the collection machine [78]. Removing leukocytes and creating a uniform product will have a positive impact on red blood cell storage. Two recent reports by Hess and colleagues [34,35] show that the 42-day storage limit may be extended to 63 or 70 days. Red blood cell substitutes A substitute for blood has been an elusive goal [79] since the 1970s, when free hemoglobin was used as a red blood cell substitute. Since that time, hemoglobinbased substitutes and perfluorocarbon-based red blood cell substitutes have been investigated. In 1986, a study of a perfluorocarbon emulsion showed that it was not an effective substitute for blood products [80]. In 1991, the Center for Biologics Evaluation and Research published strict guidelines [81] for the production, use, and efficacy of hemoglobin-based blood substitutes. The only hemoglobin-based red blood cell substitute currently in clinical use is being applied in veterinary medicine. All of these substitutes are marketed as ‘‘bridges’’ to be used for stabilization until red blood cell products are available. In the past, the safety and availability of donated blood products has been a driving force for the development of these products. As the availability and safety of blood products improves, there may be less demand for these potentially expensive synthetic products. ‘‘Stealth’’ red blood cells In 1996, the attachment of polyethylene glycol (PEG) to red blood cells was accomplished [82]. Since that time there have been several groups working with

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PEG in various forms to coat red blood cells, making their antigens unavailable for immune interaction when transfused. In early testing, treated cells did not react with commercially available antibodies against the Rh antigens (D, C, c, E, e), Kell antigen, or Duffy or Kidd antigens. Some studies have indicated a shortened survival for PEG-treated red blood cells, and preliminary indications are that PEG itself may be immunogenic. A recent report of human red blood cells treated with PEG showed that PEG did not activate complement but actually enhanced interactions with ABO-mismatched sera leading to complement activation and cell lysis [83].

Summary In the next decade, many of the methodologies and research reviewed in this article will become clinical practice, making the transfusion of blood products safer and more universally available than they are today. NAT will be standard and will surely be performed on each unit of product, PCR testing for pathogens will evolve, and the pathophysiology and immunology of transfusion-related events such as TRALI and immunomodulation will be elucidated. New methods of preservation and early detection of contamination will extend the life of blood products. Red blood cell antigens may be attenuated, making safe products available to more patients. Clinical vigilance at the bedside and in the blood bank will remain key areas for transfusion safety. As I have told many a resident and patient, blood is not saline; there are and will remain risks inherent in this commonly used medical therapy.

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