Transfusion-Transmitted Diseases

Blood transfusion has been and continues to be a possible source of disease transmission. A myriad of agents can potentially be transmitted through blood transfusions, including bacteria, viruses, and parasites. Of these, bacteria are the most commonly transmitted.

Viral agents that are capable of being transmitted through blood transfusion include the following:

• Human immunodeficiency virus (HIV)
• Hepatitis viruses
• West Nile virus (WNV)
• Cytomegalovirus (CMV)
• Human T-cell lymphotrophic viruses (HTLVs)
• Parvovirus B19

Protozoal organisms that can be passed on through transfusion include species of the genus Plasmodium, which cause malaria.

Prions, which cause Creutzfeldt-Jakob disease, are also transmissible through transfusion; they cannot be destroyed using current techniques for inactivating pathogens in the blood supply.

In 2009, the American Association of Blood Banks (AABB) published a detailed description of 68 infectious agents capable of being transmitted by blood transfusion and prioritizing emerging infectious diseases for which there was not yet an implemented intervention. Since that time the list has been continuously expanded and updated as new agents emerge. ^{[1, 2]}

Despite the potential for disease transmission through transfused blood, the safety of the blood supply in the United States continues to improve and, in fact, is the greatest that it has ever been. As the known threats come under control, however, new challenges will continue to arrive. Careful donor selection, vigilant screening, lookback programs, inactivation of pathogens, and continuous efforts to develop new techniques for screening and inactivation will be required to make blood products, and thus blood transfusions, continually safe.

Bacteria or, for that matter, any infective agent that potentially evades the sterility of the transfusion loop can come from the donor's blood or skin or from a contaminated environment. As previously stated, however, bacteria are most common infective agents to be transmitted through blood transfusion, a fact supported by extensive data that have been derived from studies such as the following:

• French Haemovigilance Bacthem study - From France; regarding determinants of transfusion-associated bacterial contamination ^[3]

• US Assessment of the Frequency of Blood Component Bacterial Contamination Associated with Transfusion Reaction (BaCon) study - From the United States; regarding transfusion-transmitted bacterial contamination in the US from 1998 through 2000 ^[4]

• United Kingdom Serious Hazard of Transfusion (SHOT) program - From the United Kingdom; data collection in the UK and Ireland regarding deaths or major complications of transfusion of blood or its components ^[5]

The incidence of bacterial transmission depends on the blood product and also on the definition of the cases.

The estimated residual risk of contamination of blood products with bacterial agents is 1 in 5,000 for platelets and 1 in 30,000 for red blood cells. ^{[4, 6]} The higher incidence of bacterial transmission via platelets has been attributed to the difference in storage temperatures. Also important is the duration of storage, which has a direct correlation with the likelihood of bacterial contamination. ^{[7, 8, 9]}

A meta-analysis of 22 studies of bacterial contamination rate estimates for apheresis (AP), platelet-rich plasma (PRP), and buffy coat (BC) collection methods found an overall mean contamination rate of 0.51 per 1000 components (95% confidence index [CI], 0.38-0.67).  Lower contamination rates were reported for AP (0.23, 95% CI: 0.18-0.28) and PRP (0.38; 95% CI, 0.15-0.70) components compared with BC (1.12; 95% CI, 0.51-1.96). ^[10]

An important concept in the evaluation of data regarding transfusion-transmitted bacterial infections (TTBIs) is the definition of a case. The Bacthem study provided widely accepted criteria based on the separation of cases into possible, probable, and definite contamination. These are defined as follows ^[3] :

• Possible contamination - The blood culture from a recipient grows a bacterial pathogen, with documentation of no other apparent source, but there is failure to isolate the same bacteria from the donor blood product, either because the culture is negative or it could not be done

• Probable contamination - The blood culture from the recipient is negative or could not be done, but there is definite bacterial growth in the donor blood product.

• Definite contamination - The blood culture from the recipient and the donor blood product grow the same bacteria.

Another intriguing dimension to TTBI is the fact that bacterial contamination in the blood product will not necessarily lead to clinical disease in the recipient. Likely causes of this discrepancy include the following:

• Insufficient bacterial inocula that may result in a positive culture from the donor product or the recipient but that is not sufficient to produce clinical signs and symptoms

• Infectivity and virulence of the bacteria under consideration

• Contamination of the blood during testing procedures

Microbiologic spectrum of transfusion-transmitted bacterial contamination

A multitude of microorganisms have been isolated from contaminated blood products. There is also a wide variation in the species of bacteria that are reported from different parts of the world. Some of these organisms and species include the following:

• The Bacthem study, ^[3] BaCon study, ^[4] and SHOT program ^[5] found a similar range of microorganisms; isolates from the Bacthem study included Yersinia, Proteus, Pseudomonas, Escherichia, Klebsiella, Acinetobacter, and Serratia, while among gram-positive organisms, Propionibacterium, Staphylococcus, Bacillus, and Enterococcus were isolated

• The Japanese Red Cross reported Propionibacterium acnes as the most common bacterial contaminant ^[11]

• Blood banks in Holland reported coagulase-negative staphylococci to be the most common bacteria isolated ^[12]

• Some investigators have reported Yersinia enterocolitica as the most common isolate in TTBI; this organism is capable of growing and multiplying at low temperatures, which may increase its chances of survival during storage of blood products ^[13]

Clinical features of TTBI

Although TTBI can produce a wide variety of clinical manifestations (including death), fever (> 102º F, or a > 3.6º F increase from the pretransfusion baseline), rigors, tachycardia, or an increase in heart rate by more than 40 beats per minute from the baseline and a fall of systolic blood pressure of greater than 30 mm Hg are highly suggestive of the condition. Chills and fever are the most commonly reported symptoms. Other clues include backache, abdominal pain, vomiting, and hypothermia. ^{[3, 4]}

As soon as TTBI is suspected, the following course of action should be taken:

• Stop the transfusion

• Aggressively hydrate and resuscitate the patient

• Make sure the signs and symptoms are not due to a mismatched blood product resulting from a clerical error, and make the blood bank aware of the possibility of an infection; the blood product should be sent for a culture and Gram stain in an attempt to confirm TTBI and to isolate bacteria

• Repeat the type and cross-match, and also collect blood for a Coombs test and bacterial culture from the recipient

• Start the patient on empiric parenteral antibiotics until isolation of an agent is available to help in narrowing down the antibiotic coverage

In order to prevent an infective incident, strict sterile precautions and donor screening are required. ^{[14, 15, 16, 17, 18, 19]} Recommended measures include the following:

• Donors who are febrile and likely infected should be deferred

• Chlorhexidine or iodine should be used to properly disinfect the venipuncture site

• The initial aliquot of donor blood should be discarded to prevent contamination with the skin flora.

• Attempt to identify bacterial contamination by laboratory methods

• Bactericidally treat the donated blood

The above-mentioned lab testing for contamination is especially important for platelet products. Identification can be done by culture method or nonculture methods, including Gram staining and metabolic screening for markers of contamination. A negative culture for 24-48 hours before the product is released for transfusion is highly recommended.

Human immunodeficiency virus

The human immunodeficiency virus (HIV), a member of the Lentivirus family of retroviruses, is the causative agent of acquired immunodeficiency syndrome (AIDS). In the United States, more than 1.2 million people are living with HIV, and 1 in 8 of them don't know they are infected. Individuals who engage in male-male sexual behavior accounted for 82% (26,375) of HIV diagnoses in men and 67% of all diagnoses in 2015. ^[20] Less than 1% of HIV cases are attributed to blood or blood product transfusions.

The risk of transmission of HIV through blood products is as follows ^{[21, 22, 23]}

• United States - 1 in 2 million units (2,135,000)
• Canada - 1 in 7.8-10 million units 
• Parts of Europe - 1 in 1 million to 1 in 5 million units

With the 2002-2003 licensure of HIV minipool nucleic acid testing (MP-NAT), HIV-1 p24 antigen testing has been eliminated as a blood donor screening test. This is because the window period reduction that is achieved with the antigen test is only 6 days, compared with a window period reduction of approximately 11 days with NAT.

MP-NAT detects viral ribonucleic acid (RNA) rather than the p24 protein; because the viral RNA appears in blood before p24, an infection can be detected earlier, and the window period is therefore reduced. Furthermore, all p24-antigen–positive, anti-HIV–negative donors are positive in HIV MP-NAT. ^{[24, 25, 26]} HIV-positive individuals are permanently deferred from blood donations.

Hepatitis B virus

The hepatitis B virus (HBV), a member of the Hepadnaviridae family, is capable of withstanding extreme temperatures and humidity. The viral genome consists of partially double-stranded, circular deoxyribonucleic acid (DNA) containing 3.2 kilobase (kb) pairs that encodes 4 overlapping, open reading frames.

Hepatitis B is a worldwide healthcare problem, especially in developing areas. An estimated one third of the global population has been infected with HBV. Approximately 300 million people are lifelong carriers, although annually, only 2% spontaneously seroconvert. In the United States, 300,000 cases of acute HBV disease are reported annually to the Centers for Disease Control and Prevention (CDC). ^[27]

HBV is transmitted hematogenously and sexually. The outcome of this infection results from a complicated viral-host interaction that produces an acute symptomatic disease, an asymptomatic disease, or a chronic carrier state. Later consequences include cirrhosis and the development of hepatocellular carcinoma (HCC). The residual risk of transmission of HBV is estimated to be close to 1 in 270,000 units in the United States and 1 in 70,000 to 1,000,000 units in various parts of Europe. ^[28]

Hepatitis B surface antigen (HBsAg) detection is a routine in many parts of the world. However, some chronic carriers have such a low viral load that screening by HBsAg may not be able to detect the infection in the donor. To overcome this obstacle, many blood banks in several countries also attempt to detect antibody against the hepatitis B core antigen (anti-HBcAg or anti-HBc). ^{[29, 30]} The core antibody develops early in the course of the infection and remains positive even in patients with low-level viremia.

Hepatitis B poses another problem in some chronically infected people in whom HBV DNA is present in the blood products, but also in whom HBsAg is not detectable and anti-HBc is also equivocal. NAT has tremendous potential in this area of transfusion medicine. ^{[23, 31, 32]} Hepatitis B–positive donors are permanently deferred from giving blood.

Hepatitis A and E viruses

The hepatitis A virus (HAV) is a single-stranded RNA enterovirus and a member of the Picornaviridae family. In humans, viral replication depends on hepatocyte uptake and synthesis, and assembly occurs exclusively in liver cells. The common method of HAV transmission is via the fecal-oral route, but the infection may also rarely be transmitted through blood transfusion. ^{[33, 34]}

The hepatitis E virus (HEV) is classified in the Caliciviridae family and has many similarities with HAV. The common mode of transmission is also fecal-oral, but HEV may also be transfusion transmitted. ^{[35, 36]}  HEV can occur with transfusion of RBCs, platelet concentrate, fresh frozen plasma, and pooled granulocytes. ^[1]

Both of these nonenveloped viruses are not inactivated by the methods used in the production of blood components subjected to plasma fractionation and processed by solvent and detergent methods alone. ^{[33, 34, 35, 36]}

Hepatitis C virus

The hepatitis C virus (HCV) is a spherical, enveloped, single-stranded RNA virus belonging to the Flaviviridae family. The World Health Organization (WHO) estimates that 170 million individuals worldwide are infected with HCV, with a wide variation in the prevalence of the disease. For example, in 2000, Frank et al reported that Egypt had the highest number of reported HCV infections, largely attributed to the use of contaminated, parenteral, antischistosomal therapy. ^[37] This led to a mean 22% prevalence of HCV antibodies in persons living in Egypt. According to the CDC, an estimated 1.8% of the US population is positive for HCV antibodies. ^{[25, 29, 38]}

HCV is predominantly transmitted via percutaneous exposure to infected blood. In developed countries, most new HCV infections are related to intravenous (IV) drug abuse and are found because of intensive screening and lookback programs.

Blood transfusion was a major risk for acute HCV infection in the past, with more than 10% of transfusion recipients acquiring the infection in some studies. ^[28] The screening of blood donors by donor history and elevated serum alanine aminotransferase (ALT) caused a striking reduction of non-A, non-B posttransfusion hepatitis, even before HCV was identified. The subsequent initiation of donor screening for anti-HCV antibodies in 1990 nearly eliminated the risk of posttransfusion acute HCV infection, ^[28]  decreasing the risk to less than 1 case in 103,000 transfused units. ^{[21, 22, 23, 38]}

Detection of HCV infection by MP-NAT is the standard of care in the United States for the detection of the viral RNA. The HCV MP-NAT has reduced the window period for the detection of infection by 80-90% when compared with HCV testing by detection of antibodies. ^[24]

The use of the polymerase chain reaction (PCR) assay has further reduced the risk of acquiring HCV from blood transfusions, to 1 in 230,000 donations. The newer assays have decreased the window period after infection to 1-2 weeks. Hepatitis C–positive donors are permanently deferred from blood donations.

West Nile virus

The West Nile virus (WNV), a flavivirus, is transmitted by mosquito bite. The organism has the potential of being transmitted through blood. The infection is usually asymptomatic and goes undetected but it may cause meningoencephalitis, especially in individuals who are older and who have depressed immunity, with a mortality rate of about 2.6%. In 2002,  about 9858 cases of WNV infection were reported to the CDC. ^{[39, 40]}

WNV has 2 important properties compared with HCV, which is also a flavivirus. First, the transmission of WNV is seasonal, unlike HCV transmission, and second, even though a low-level viremia may exist for several months in the presence of immunoglobulin M (IgM), transmission occurs from donors who are acutely infected. ^{[41, 42, 43]}

The current strategy to break the chain of WNV transmission via blood is NAT. An intriguing situation is the high risk of residual transmission in some early-phase viremic patients. Thus, NAT is used on individual donor samples (ie, individual donation nucleic acid testing [ID-NAT], instead of pool testing [ie, MP-NAT]) to detect these low-level viremic patients. This is especially useful to interdict transmission in the high-incidence season. For donors who are detected as positive for WNV infection, the US Food and Drug Administration (FDA) recommends deferral for at least 120 days. ^{[44, 45, 46, 47]}

Arboviruses

Like West Nile virus, mosquito-borne dengue viruses (DENV), chikungunya virus (CHIKV), and zika virus (ZIKV) have the potential to be transmitted through blood. 

Zika virus

As of April 2016, no blood transfusion-transmitted cases of Zika virus infection had been confirmed in Puerto Rico or the continential US, however, Zika virus was detected retrospectively in 2.8% of asymptomatic blood donors during 2013–2014. In 2018, the FDA recommended testing all donations collected in the US and its territories with a licensed NAT, or collecting and preparing blood components (eg, platelets, plasma) using pathogen reduction technology (PRT) with an FDA-approved pathogen reduction device. ^[48]

Dengue virus and chikungunya virus

Both dengue virus (DENV) and chikungunya virus (CHIKV) pose a risk to the safe transfusion of blood components, including plasma. During a 2012 outbreak of DENV in Brazil, 42 DENV-positive units were transfused into 35 recipients. ^[49] Fryk et al reported that methylene blue and light illumination at 630 nm for pathogen inactivation resulted in at least a 4.46-log reduction in all DENV serotypes and CHIKV infectious virus, suggesting it may be an effective option for managing the risk of transfusion transmission. ^[50]

Cytomegalovirus

The transmission of cytomegalovirus (CMV), which belongs to the herpes group of viruses, is well documented throughout the literature. The organism's transmission is prevented by transfusing leukocyte-depleted blood products, which is consistent with the fact that CMV is a leukocyte-associated pathogen. The organism is a major concern when transfusing immunocompromised hosts. For that reason, all immunocompromised patients are given CMV-seronegative or leukocyte-depleted blood products. ^{[51, 52, 53, 54]}

Human T-cell lymphotrophic virus

Human T-cell lymphotrophic virus–1 (HTLV-1) and HTLV-2 have been shown to be transmitted by blood transfusion. The residual risk of transmission is 1 in 3 million in the United States. Infection with these retroviruses may result in HTLV-related myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia/lymphoma. Various laboratories test for the presence of these agents by different serologic or nucleic acid–based tests, including enzyme immunoassay (EIA) and PCR assay. ^{[55, 56, 57, 58]}

Parvovirus B19

Parvovirus is a nonenveloped virus that is usually transmitted by the respiratory route and that eventually infects hematopoietic cells. The virus is also transmitted vertically from mother to child and via blood products. Transmission by blood products is common because the virus does not have a lipid envelope, rendering inactivation methods (eg, using methylene blue or the solvent-detergent method) ineffective. ^[59]

The spectrum of clinical results of parvovirus infection depends mainly on the immune status of the recipient. The parvovirus may cause bone marrow failure in immunocompromised patients and patients with sickle cell disease. In the immunocompromised host, the disease is self-limited, without subsequent complications.

As stated, pregnant women can transmit the virus vertically to the fetus, leading to fetal hydrops (heart failure). ^{[60, 61]} This is of importance considering the fact that many pregnant women receive RhoGAM (anti-D immunoglobulin; Ortho-Clinical Diagnostics, Inc, Raritan, NJ) to prevent sensitization by fetal antigens. PCR assay–based tests are being developed to counteract this problem. ^[62]

Other viruses

Hepatitis G virus (HGV) and transfusion-transmitted virus (TTV) also have been shown to be transmissible via blood. The clinical impact of their transmission on a larger scale has still to be deciphered. ^{[63, 64]}

Malaria

Malaria is endemic in many tropical and subtropical regions of the world. Over 300 million people worldwide are infected, with 1 million fatalities annually. ^[65] The known causative agents are the following 5 species of Plasmodium:

• P falciparum
• P malariae
• P ovale
• P vivax
• P knowlesi

Malaria is spread mainly through mosquito bites, but cases of transfusion-transmitted malaria have been reported. The risk of spread depends on the prevalence of the disease. For example, in Benin, where malaria is highly endemic, one third of screened blood donors were found to have P falciparum trophozoites, making them capable of transmitting the disease through blood donation. ^[66]

In areas with a low prevalence of malaria, donors who are recent travelers or who are immigrants from endemic areas are potential sources for transmission of the infection. ^{[66, 67, 68]} The FDA recommends that donors with a history of malaria be deferred for 3 years after becoming asymptomatic. Provided that donors are asymptomatic, travelers to endemic areas are deferred for 1 year after they return to the United States.

Trypanosoma cruzi

Trypanosoma cruzi is the causative agent of Chagas Disease (American Trypanosomiasis), which is generally spread by the bite of the reduviid bug. The illness has an acute and a chronic form. The acute form principally affects children in endemic areas, including Central and South America and parts of Mexico, and manifests as fever, lymphadenopathy, and hepatosplenomegaly. In severe cases, myocarditis and encephalitis may occur. The disease may take a more indolent course, however, and after a latency period of decades, patients can present with serious end-organ damage such as chagasic cardiomyopathy and megaesophagus. ^{[69, 70, 71]}

Individuals from endemic areas may become chronic carriers of the T cruzi parasite and are responsible for transmission of T cruzi through blood transfusion. Such cases are well known in high-prevalence areas. Seroprevalence in the United States ranges from 0.12-0.20%, but only 7 cases have been reported to be transmitted by blood. Serologic testing and deferral of positive donors is a policy in endemic countries, and an enzyme-linked immunosorbent assay (ELISA)–based screening test has been instituted in the United States as well. ^{[69, 71]}

Babesia microti

Babesia microti is an intraerythrocytic protozoan parasite that produces a malarialike illness and is the principal cause of human babesiosis in the United States. The majority of the cases have been reported from the Northeast. The common mode of transmission is via an Ixodes tick bite, but B microti can also be acquired via the transfusion of infected blood. In a study by Herwaldt et al, which included data from over 31 years, most transfusion-related cases were associated with red blood cell components. ^[72] The cases occurred in all 4 seasons. Babesiosis should be suspected, particularly in cases of posttransfusion hemolytic anemia.

The clinical spectrum of B microti infection ranges from asymptomatic infection to severe disease with massive parasitemias that cause hemolytic anemia, thrombocytopenia, shock, and death. The risk of severe infection is particularly high in patients who have HIV infection, have had a splenectomy, or are immunosuppressed. Because B microti is intraerythrocytic, leukoreduction does not reduce the transmission risk.

Leishmania donovani

L donovani belongs to a group of intracellular parasites. The common mode of transmission is a bite by sandflies of the genus Phlebotomus. Cases of transmission by transfusion of blood products have been reported in highly endemic areas. For this reason, people returning to the United States from war zones in Iraq were deferred from donations for 1 year. ^[73]

Two forms of Creutzfeldt-Jakob disease (CJD) have been reported in the literature; namely, classical CJD and variant CJD (vCJD). The latter, vCJD, is a form of human bovine spongiform encephalopathy (BSE) that is transmissible through consumption of infected tissues or potentially via blood transfusions. Initially, there was evidence of vCJD transmission through blood transfusion in animal studies, and cases in which the prion disease resulted from the administration of blood products were reported from high-prevalence areas in Europe. No new transfusion-related cases of vCJD have occurred since 2003, but concerns about the safety of blood products remain. ^[74]  

An interesting fact to note is that people who have had transfusion-transmitted vCJD did not receive leukocyte-depleted blood. The prolonged asymptomatic phase and carrier states present a unique challenge with respect to prion disease in the context of transfusion medicine. In order to counteract this problem, donor deferral becomes critical. Donors in high-prevalence countries in Europe are deferred permanently if they themselves received blood products after 1980. ^{[75, 76, 77, 78, 79]}

The FDA has the vital role of ensuring that the 3.5 million patients who receive a blood transfusion each year are protected by layers of overlapping safeguards.

Blood donor screening

Donors are informed about the potential disease transmission risks from blood donors and are required to answer questions about factors that may have a bearing on the safety of their blood. For example, donors with a history of intravenous drug abuse are routinely deferred. Moreover, since November 1999, the FDA has requested that the blood industry defer potential donors who have lived in European countries with reported or suspected cases of BSE and those who might be carriers of the BSE agent.

Questionnaire

Donor screening is primarily performed using a questionnaire. The American Association of Blood Banks came out with version 1.3 of the donor questionnaire, which has been approved by the FDA. The information below is not all-inclusive; responses are yes or no, unless otherwise indicated. ^[80]

Are you

• Feeling healthy and well today?
• Currently taking an antibiotic?
• Currently taking any other medication for an infection?

Please read the Medication Deferral List.

• Are you now taking or have you ever taken any medications on the Medication Deferral List?
• Have you read the educational materials?

In the past 48 hours

• Have you taken aspirin or anything that has aspirin in it?

In the past 6 weeks

• Female donors: Have you been pregnant or are you pregnant now?

In the past 8 weeks have you

• Donated blood, platelets, or plasma?
• Had any vaccinations or other shots?
• Had contact with someone who had a smallpox vaccination?

In the past 16 weeks

• Have you donated a double unit of red cells using an apheresis machine?

In the past 12 months have you

• Had a blood transfusion?
• Had a transplantation such as organ, tissue, or bone marrow?
• Had a graft such as bone or skin?
• Come into contact with someone else’s blood?
• Had an accidental needle-stick?
• Had sexual contact with anyone who has HIV/AIDS or has had a positive test for the HIV/AIDS virus?
• Had sexual contact with a prostitute or anyone else who takes money or drugs or other payment for sex?
• Had sexual contact with anyone who has ever used needles to take drugs or steroids, or anything notprescribed by their doctor?
• Had sexual contact with anyone who has hemophilia or has used clotting factor concentrates?
• Female donors: Had sexual contact with a male who has ever had sexual contact with another male? (Males: Check "I am male.")
• Had sexual contact with a person who has hepatitis?
• Lived with a person who has hepatitis?
• Had a tattoo?
• Had ear or body piercing?
• Had or been treated for syphilis or gonorrhea?
• Been in juvenile detention, lockup, jail, or prison for more than 72 hours?

In the past 3 years have you

• Been outside the United States or Canada?

From 1980 through 1996,

• Did you spend time that adds up to 3 months or more in the United Kingdom?
• Were you a member of the US military, a civilian military employee, or a dependent of a member of the US military?

From 1980 to the present, did you

• Spend time that adds up to 5 years or more in Europe?
• Receive a blood transfusion in the United Kingdom or France?

From 1977 to the present, have you

• Received money, drugs, or other payment for sex?
• Male donors: had sexual contact with another male, even once? (Females: Check "I am female.")

Have you EVER

• Had a positive test for the HIV/AIDS virus?
• Used needles to take drugs, steroids, or anything notprescribed by your doctor?
• Used clotting factor concentrates?
• Had hepatitis?
• Had malaria?
• Had Chagas' disease?
• Had babesiosis?
• Received a dura mater (or brain covering) graft?
• Had any type of cancer, including leukemia?
• Had any problems with your heart or lungs?
• Had a bleeding condition or a blood disease?
• Had sexual contact with anyone who was born in or lived in Africa?
• Been in Africa?
• Have any of your relatives had Creutzfeldt-Jakob disease (CJD)?

Deferral due to medication use

The FDA has provided guidelines for the deferral of patients who are using some medications. Specific medications and the deferral period for them are as follows:

• Finasteride and isotretinoin - 1 month from last dose (the rationale behind deferral is the risk to the fetus if the blood is transfused to a pregnant women)

• Dutasteride - 6 months from last dose (the rationale behind deferral is the risk to the fetus if the blood is transfused to a pregnant women)

• Acitretin - 3 years from last dose (the rationale behind deferral is the risk to the fetus if the blood is transfused to a pregnant women)

• Etretinate - Permanent deferral (the rationale behind deferral is the risk to the fetus if the blood is transfused to a pregnant women)

• Growth hormone from human pituitary glands - Permanent deferral (due to the risk of CJD)

• Prior use of bovine insulin - Permanent deferral (due to the risk of CJD)

• Hepatitis B immunoglobulin - Deferral for 12 months (the rationale is that this immunoglobulin is used in cases of exposure to hepatitis B, and since the administration does not prevent the development of hepatitis B infection in all cases, a waiting period of 12 months is recommended before the donor can be screened and deemed fit for donation again.)

• Clopidogrel - Cannot donate platelets until 14 days after last dose

Screening of donated blood

After donation, each unit of donated blood undergoes a series of tests for the following:

• HBV and HCV
• HIV-1 and HIV-2
• HTLV-1 and HTLV-2
• Syphilis
• T cruzi

Note: Apheresis platelets are also tested for bacterial contamination.

Donor deferral lists

Blood establishments must keep current a list of deferred donors to make sure that they do not collect blood that would be a health risk.

Quarantine

Donated blood must be quarantined until it is tested and shown to be free of infectious agents.

A very important case scenario in transfusion medicine is lookback. Lookback programs are designed to identify and notify recipients who may have received blood products from a previously negative, screened donor who has now become positive for an infectious agent. (This situation is especially of concern with transfusion-transmitted HCV infections.) Lookback programs represent an attempt to reduce further blood-borne transmission of the infectious agent and to provide a chance for the infected recipients to seek medical attention.

Canada organized a huge lookback program to identify over 100,000 individuals who received blood products in the 1980s. Of the recipients involved in the lookback program, 50,000 tested positive for HCV. It is estimated that about half of these newly diagnosed cases were due to infected blood. ^{[81, 82]}

As per FDA guidelines, once a blood bank identifies an HCV-positive donor, it must do the following ^[83] :

• Perform a confirmatory test after a positive screen to confirm the diagnosis
• Quarantine/destroy the blood products, if any, from the newly diagnosed, HCV-positive donor
• Inform the hospitals where the patient has donated blood previously

The informed hospitals must look up their records and identify the patients who received blood products from that particular donor. Once the recipients are identified, the current attending physician or the physician who initially ordered the blood product must be made aware. The informed physician has the responsibility to follow up with the recipients and notify them.

A desirable inactivation method would interfere the least with the function of blood products and yet be effective against infectious agents. Some of these methods are described below.

Solvent-detergent method

The solvent-detergent method is used to disrupt membranes of lipid-enveloped viruses without affecting the majority of plasma proteins, except protein S, antitrypsin, and antiplasmin. Hence, the method is effective in destroying HIV, HTLV, Epstein-Barr virus (EBV), HBV, and HCV. It is not effective against HAV and parvovirus; consequently, the blood product is tested for these 2 agents if the solvent-detergent method is used.

Once the blood product is prepared, the solvent-detergent chemicals must be removed by extraction, using oils and chromatography. This method can be employed in the preparation of coagulation factors. ^{[84, 85]}

Loss of protein S, antitrypsin, and antiplasmin may occur during processes involving the removal of residual solvent detergent. This has been concerning in patients with hyperfibrinolysis, which occurs, for example, during the reperfusion stage of liver transplantation. Clustered deaths in such patients in the United States were the reason that the solvent-detergent method fell out of favor in North America. This technique is still widely used in Europe, however, where alternative methods are employed to remove residual solvent detergent in order to minimize the loss of these 3 proteins. ^[86]

Methylene blue

Methylene blue is a dye that combines with cellular elements. Once it is exposed to light, the dye becomes active and disrupts the wall to which it is attached. This method has been used extensively in Europe to inactivate viruses. Limitations of the methylene blue technique include ineffectiveness against intracellular pathogens and likely interaction with coagulation factors. The loss of fibrinogen content is estimated to be around 20%, raising issues of efficacy when the treated product is used for plasma exchange in thrombotic thrombocytopenic purpura. ^{[87, 88]}

Methylene blue also gives a tinge to the treated units; recipients who receive a lot of such treated blood products may develop skin discoloration. Filters that can remove the dye before transfusion have become available in some countries, thus avoiding this problem. ^[89]

Note: Neither the solvent-detergent method nor the methylene blue method is capable of inactivating prions, the putative cause of vCJD. Accordingly, the selection of donors from areas in which vCJD has not been reported is the only method currently available for preventing the spread of this infection via the transfusion of blood products.

Synthetic psoralen

Amotosalen is a synthetic psoralen that acts after exposure to ultraviolet (UV) light to form cross-links in nucleic acid chains and stop the multiplication of pathogens. This method inactivates almost all of the currently screened agents (eg, HIV, HAV, T cruzi, gram-negative rods), including enveloped and nonenveloped viruses, bacteria, and protozoa. The drawback to synthetic psoralen is a reduction in platelet activity, thus requiring more frequent platelet transfusions. ^{[90, 91, 92, 93, 94]}

Riboflavin

Riboflavin (vitamin B2) can inactivate pathogens in platelets and plasma and is approved for this use in Europe. Riboflavin binds to DNA and RNA to create cross-links when photoactivated. It appears to be effective in inactivating HIV and WNV, as well as some bacteria and protozoa. Pathogen inactivation via riboflavin and UV-light treatment processes result from irreversible, photochemically induced damage to nucleic acids.

Chemicals used in the solvent-detergent, methylene blue, and amotosalen methods are removed from the blood product after treatment; usually, the loss of efficacy of the product is attributable to these final steps. Riboflavin, however, is a natural product that does not need to be removed from the blood product and for this reason may better allow the blood to retain its coagulant and anticoagulant properties.

There were concerns in the past about the effect of several preparation agents on the stability of proteins in blood products, particularly fresh frozen plasma. Studies have since shown, however, that fresh frozen plasma units treated with riboflavin can maintain coagulant and anticoagulant in vitro protein activity at -30°C for up to 2 years. ^[95]

Leukodepletion

Some infectious agents reside within leukocytes, and hence, their transmission can be interrupted if the blood product is depleted of these cells. CMV is the major pathogen that can be transmitted through leukocytes and cause significant mortality and morbidity in transplant recipients and immunocompromised cancer patients.

Even though filtration of the blood to remove leukocytes has been used extensively, filtered red blood cell units from CMV-positive donors are believed to be the primary source of transfusion-transmitted CMV in some studies. This has raised the issue of whether leukocyte-depleted blood products are as good as CMV-seronegative products. ^[96] A Canadian consensus panel on this issue stated that it could not definitely say whether either of these 2 methods is better than the other or even whether they are equivalent. ^[97] Additional data on this issue may clarify the answer in future. ^{[97, 98]}