Infectivity of Blood

For the past 20 years, transfusion-induced hepatitis and AIDS were dominant concerns regarding allogeneic blood administration. These infectious risks are now rare ( Table 47-10 ). Human error, emerging infections, and sepsis have become dominant concerns (see "Transfusion Reactions") (see Table 47-7 ). The summary of Busch and associates^[110] provides definitive information on this topic.

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One of the major reasons for the decrease in blood-borne infections has been the use of nucleic acid technology (NAT). The changes in blood transfusion testing can be appreciated when comparing tests used in 1998 ( Table 47-11 ) with those used in 2004 ( Table 47-12 ). The use of NAT testing has decreased the window of infectivity (i.e., time from being infected to a positive test result), which is a major reason for the decrease in infectivity with hepatitis and human immunodeficiency virus (HIV). Better donor screening and restrictive donor eligibility also have helped. The near-elimination of transfusion-transmitted hepatitis and HIV has made the exact incidence difficult to determine. However, emerging infectious risks, including West Nile virus, Chagas' disease, malaria, and even variant Creutzfeldt-Jakob disease (vCJD) are of increasing concern ( Table 47-13 ). Because hepatitis and AIDS have been dominant concerns for years, their history is discussed in the following sections.

Hepatitis

When blood transfusions became a reality in the 1940s, viral hepatitis was recognized as a major complication. In the past 10 years, the incidence of viral hepatitis has dramatically decreased. Nevertheless, when it occurs, it is very serious. Classically, icteric hepatitis develops 50 to 180 days after a blood transfusion and has a variable clinical course, ranging from asymptomatic to fatal. However,

TABLE 47-11 -- Infectious disease testing for blood transfusions, 1998

1. Discontinue serum alanine aminotransferase testing

2. Hepatitis C antibody testing

3. Antibody to hepatitis B core antigen

4. Human immunodeficiency virus (HIV) type 1

5. HIV-2

6. HIV Ag (p24 antigen)

7. Human T-cell lymphotropic virus (HTLV) types 1 and 2

8. Serologic test for syphilis

Adapted from Infectious disease testing for blood transfusions. NIH Consensus Development Panel on Infectious Disease Testing for Blood transfusions. JAMA 274:1374–1379, 1995.

TABLE 47-12 -- Tests used for detecting infectious agents in all units of blood, 2004

Virus	RNA Minipool	Antibody To
Human immunodeficiency virus (HIV)	Nucleic acid technology	HIV-1, HIV-2
Hepatitis C virus (HCV)	Nucleic acid technology	HCV
Hepatitis B virus (HBV)		HCV
Human T-cell lymphotropic virus (HTLV)		HTLV-1, HTLV-2
West Nile virus	Nucleic acid technology

two to five anicteric cases occur for every case of overt icteric hepatitis. Generally, the diagnosis of acute anicteric post-transfusion hepatitis is made with the observation, between 14 and 180 days after transfusion, of two consecutive elevations (at least 14 days apart) of the recipient's alanine aminotransferase level. Other possible causative factors, such as congestive heart failure, alcohol, and certain drugs that can mimic or simulate viral hepatitis, must be considered. Both transaminase elevations must be at least two standard deviations above the geometric mean value for healthy persons.

Serologic requirements for the diagnosis of hepatitis B include the de novo appearance of hepatitis B surface antigen or hepatitis B surface or core antibody. Hepatitis A antibody seroconversion is considered evidence for hepatitis A infection. However, 90% of post-transfusion hepatitis is caused by the hepatitis C virus. Less than one third of these patients develop jaundice.^[111] To determine their ultimate fate, Tong and colleagues^[112] monitored 131 patients with chronic post-transfusion hepatitis C for several years and found the following incidence of signs, symptoms, and conditions:

1. Fatigue (67%)
2. Hepatomegaly (67%)
3. Chronic hepatitis (23%)
4. Chronic active hepatitis (51%)
5. Hepatocellular carcinoma (11%)

1. Complications of cirrhosis (8 patients)
2. Hepatocellular carcinoma (11 patients)
3. Chronic active hepatitis-pneumonia (1 patient)

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Before 1983 to 1985, the overall incidence of post-transfusion hepatitis ranged from a low of 3% to a high of 19%, depending on the institution and the location (e.g., donors from large cities have a higher incidence of the hepatitis virus). In most areas, the incidence of hepatitis has ranged from 3% to 10%. Since 1985, the incidence of post-transfusion hepatitis has decreased, probably for three reasons. The first is improved donor screening. In 1984, donors who were in a high-risk category for AIDS were requested not to donate blood on a volunteer basis. Second, in 1985, all donor blood was tested for antibodies to HIV (see "Acquired Immunodeficiency Syndrome"). Third, a specific test for hepatitis C was developed. Specifically, molecular techniques were used to derive clones from the genome of hepatitis C. The derived proteins from these clones were used to develop an enzyme-linked immunosorbent assay to detect antibodies to hepatitis C. NAT testing is now being used, which makes post-transfusion hepatitis so uncommon that its actual incidence is difficult to determine (see Table 47-10 and Table 47-12 ).^[110] Despite the effectiveness of this test, donor infectivity is important as a screening device. The demographics of infectivity among donors are variable, and HIV infection is especially common in intravenous drug users.^[112] Many blood components, such as FFP and platelet concentrates, also transmit hepatitis at an incidence equal to that of whole blood and PRBCs.

Acquired Immunodeficiency Syndrome

AIDS is characterized by severe depression of cellular immunity. Clinically, opportunistic infections or Kaposi sarcoma appears, progressing to debility and death. The pattern of transmission is similar to that of hepatitis B. HIV is most frequently transmitted by intimate homosexual contact and intravenous drug abuse, but whole blood, plasma, blood cellular products, or clotting factors also can transmit the virus.^[113] Several measures have been recommended to decrease the chances that donor blood will be infected with HIV. Blood banks have instituted procedures to discourage members of high-risk groups from donating blood. Designated donors and surrogate testing were recommended.^{[114] [115] [116]} Despite these measures, there were hundreds of cases of transfusion-transmitted HIV. In March 1985, all donor blood was tested for the presence of antibodies to HIV-1. It is a major health care advance or even miracle that HIV is only rarely transmitted by blood transfusions except in some developing countries^[1] (see Table 47-10 ).

Human T-Cell Lymphotropic Virus Type 1

Human T-cell lymphotropic virus type 1 (HTLV-1) can be transmitted by blood transfusions and has been causally associated with adult T-cell leukemia and progressive myelopathy. Cohen and coworkers^[116] found that there is a very small risk of HTLV-1 infection from transfused blood and blood products that have been screened for antibodies to HIV, but that risk is nearly 10-fold higher than risk of HIV infections. The estimated risk is about 1 in 641,000 (see Table 47-10 ). Even though there is no firm association between transfusion and leukemia or myelopathy, the decision was made to test all donor blood for antibodies to HTLV-1 (see Table 47-12 ).

West Nile Virus

The West Nile virus (WNV) is a mosquito-borne flavivirus that is transmitted among birds, and humans are incidental hosts. Since it was first recognized in New York, it has spread to most of the United States. In 2003, 4156 WNV cases (with 284 deaths) were reported for the year 2002 to the Centers for Disease Control and Prevention.^[117] Twenty-three patients (i.e., blood recipients) received the WNV through transfusions (i.e., leukocyte-reduced and non-leukocyte-reduced cells), and seven died. The exact causes of death were not clear. Potential infection from WNV has become a major problem in blood transfusions, for which NAT testing may be extremely valuable, as with hepatitis and HIV (see Table 47-13 ).

Cytomegalovirus

Asymptomatic chronic infection with cytomegalovirus (CMV) is so common in healthy adults that this agent can almost be viewed as normal flora. CMV survives best within cells and is thought to exist in latent form in the leukocytes of many people with antibodies indicative of earlier infection. CMV causes a heterophil antibody-negative response that closely resembles infectious mononucleosis in many respects. An infectious mononucleosis-like syndrome that can occur 1 to 2 months after open heart surgery is known as the post-perfusion syndrome or post-transfusion mononucleosis. The evidence for transmission of CMV is most convincing when the recipient changes from a seronegative state before transfusion to a seropositive state accompanied by the mononucleosis-like illness several weeks after transfusion.

Transfusion-transmitted CMV can cause significant clinical problems in certain patient populations, such as premature neonates, allograft recipients, and patients who have had their spleens removed.^[118] To prevent infection in high-risk populations, use of leukocyte-depleted blood, use of frozen deglycerolized RBCs, and screening of donors for the absence of antibody to CMV have been sometimes recommended (see "Leukoreduction of Blood Transfusions" and "Acquired Immunodeficiency Syndrome"). The risk of seroconversion is about 0.14% overall, or 0.38% per unit of seropositive donor blood.^[119] Wilhelm and associates^[120] concluded that it is not necessary to provide blood products from CMV-seronegative donors for most patients who receive blood transfusions. They continue to use CMV-seronegative blood to prevent CMV infection in preterm and newborn babies. Whether CMV-negative blood should be used for other immunocompromised patients and pregnant women has not been resolved.

Other Transfusion-Associated Infectious Diseases

Although many other infectious diseases can theoretically be transmitted by blood transfusion, only a few are of real concern. They include Yersinia enterocolitica infection, syphilis, malaria, Chagas' disease, vCJD, B19 parvovirus, severe adult respiratory syndrome (SARS), and "new" virus, which represents a diverse group of agents isolated from donors transmitted to patients but with no associated disease^[110] (see Table 47-13 ).

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During the late 1980s, Tripple and colleagues^[121] described seven cases of fatal transfusion-associated Y. enterocolitica sepsis. These investigators also reviewed the literature and found 26 cases of gram-negative bacterial sepsis with whole blood or PRBCs. Y. enterocolitica is a bacterium that can cause mostly mild gastrointestinal problems. However, in severe cases, sepsis and death can occur. Unfortunately, storage of blood at 4°C in phosphate buffer enhances its growth. Aber^[122] suggested that the donor screening process include assessment as to whether gastrointestinal problems occurred within 4 weeks of donation and that the storage time be minimized. More specific recommendations were not provided, although some were suggested by Grossman and coworkers.^[123]

Post-transfusion syphilis is unlikely because the infective agent cannot survive during storage at 1°C to 6°C. The only blood products that have the potential to transmit syphilis are those stored at room temperature. Platelet concentrates are the blood component most likely to be implicated because they commonly are stored at room temperature.

Post-transfusion malaria has never been a significant cause of blood recipient morbidity. Nevertheless, malaria can occur, especially if blood donors at risk of harboring parasites are not excluded. Consequently, blood banks thoroughly question donors for history of travel or migration from areas where malaria is endemic.

Several other diseases have been reported to be transmitted by blood transfusion, including herpesvirus infections, infectious mononucleosis (i.e., Epstein-Barr virus), toxoplasmosis, trypanosomiasis, leishmaniasis, brucellosis, typhus, filariasis, measles, salmonellosis, and Colorado tick fever.

Like malaria, several infectious agents are feared as possibly transmitting disease to patients through blood transfusions for which there are no blood testing methods ( Table 47-14 ). Without a specific test, donor screening with increasingly restrictive criteria are used. For example, in 2003 in the United States, donors with suspected SARS or who traveled to certain countries in Southeast Asia would not be accepted. Even though there are no cases of vCJD infections from blood transfusions, the virus can be

TABLE 47-14 -- Downregulated immune functions after allogeneic blood transfusions

• Reduced response in mixed lymphocyte culture

• Decreased cytokine production

• Decreased response to mitogens (substance that stimulates mitosis and lymphocyte transformation) or soluble antigens in vivo or in vitro

• Increased suppressor cell number or function

• Decreased natural killer cell activity

• Decreased monocyte function

• Decreased cell-mediated cytotoxicity against certain target cells

• Enhanced production of soluble mediators and anti-idiotypic antibodies, suppressive or mixed lymphocyte response

transmitted by blood in animal models, and stringent donor policies based on travel and residence in England or other countries in Europe are in place.^[110] Do these increasingly restrictive donor policies increase the risk of an inadequate blood supply^[124] (see "Synthetic Oxygen-Carrying Substances")?