Roger Y. Dodd1 & Susan L. Stramer2
1American Red Cross, Jerome H. Holland Laboratory for the Biomedical Sciences, Rockville, Maryland, USA
2American Red Cross, Scientific Support Office, Gaithersburg, Maryland, USA
Introduction
Transmission of infectious agents by blood transfusion has been a recognized risk since the identification of transmission and an introduced intervention for syphilis in the 1940s [1]. In particular, in the late 1960s, viral hepatitis was recognized among more than 10% of blood recipients [2]. Since that time, however, there have been continuous advances to the point at which the risk from posttransfusion hepatitis ranges from one infection per 350 000 units transfused for hepatitis B virus (HBV) to one infection per 1.15 million units transfused for hepatitis C virus (HCV) [3–5]. However, many other infections have been found to be transmitted via this route, with HIV being the most notable; the risk of infection with this virus has been reduced to less than one in 1.5 million units transfused [5]. This chapter describes posttransfusion infection and its recognition, details the means that are used to prevent or minimize the risk of such transmission and outlines those infectious agents known to be transmitted by this route. Emerging infections are discussed in Chapter 16 and the problem of bacterial contamination of blood components is reviewed in Chapter 14.
Transmission of infections by blood transfusion
A number of conditions must be met in order for a disease to be transmitted by blood transfusion [6]:
· an asymptomatic phase during which the agent is present in the bloodstream;
· ability of the agent to survive during the collection, processing and storage of the donation;
· infectivity via the intravenous route;
· a susceptible patient population;
· development of the disease in at least some infected recipients.
The infections discussed in this chapter are all well recognized as offering risk to transfusion recipients and all are subject to some measures to reduce such risk, but it must be recognized that, to date, no intervention is completely effective. In cases where testing has been implemented, risks are currently extremely low and it is clear that any residual risk is attributable to collection of blood during the so-called early window period after exposure, when the infectious agent may circulate but be undetectable by current methods. Testing has reduced this window period to a few days, reducing residual risk by many orders or magnitude [7,8]. Another threat is the development of new strains or mutations that lead to agents that escape detection, but in most cases key agents are subject to multiple redundant tests, generally avoiding this problem. This also reduces the risk attributable to laboratory failures (which are themselves very rare). In cases where the principal intervention is a donor question, it is self-evident that a donor's failure to answer the questions correctly may lead to the collection of an infectious unit. It is also not generally possible to craft a question that is completely effective in segregating all those who are infected with a given organism while assuring that there is not an undue loss of donors.
Transfusion-transmitted infections: detection and management
Clinicians responsible for the care of transfused patients should be alert to the possibility of transfusion-transmitted disease or infection, even though this is now a rare event. Unfortunately, recognition of most transfusion-transmitted infections is not easy, for one or more of the following reasons [6]:
· Many transfusion-transmitted infections (TTIs) are asymptomatic.
· If disease symptoms occur, they tend to be nonspecific (fever, flu-like illness).
· The incubation period may be prolonged, in some cases extending out to months or even years.
· The patient's underlying disease may mask or modulate evidence of other infections.
· There may be pre-existing risk factors for, or infection with, the disease agent that is thought to have been transfusion transmitted.
· Exotic infections may be transmitted by transfusion; they may be unexpected, unfamiliar or hard to recognize or diagnose.
Effective investigation of a potential TTI is relatively complex, time consuming and does not always lead to a definitive conclusion. Nevertheless, care should be taken to avoid inappropriate designation of the source of an infection temporally linked to transfusion. The following activities may contribute to the proper investigation of a suspected TTI:
· clinical diagnosis of the transfusion-associated disease;
· use of serological and/or nucleic acid testing to diagnose the disease definitively and to identify the infecting agent.
· Investigation of the patient's pretransfusion blood samples to establish the absence of infection prior to transfusion.
· Investigation of the patient's risk history to eliminate the possibility of alternate routes of infection.
· Investigation of all implicated blood donors for evidence of current or recent infection with the relevant agent; this will require the cooperation of the blood provider.
· Comparison of the agent isolated from the patient with that isolated from the donor by nucleic acid sequencing.
· Alert, or consult with, infectious disease specialists and/or public health agencies as appropriate.
· Early reporting of cases to the blood provider is critical and is usually required, so that other blood components from the implicated donor can be identified and recovered.
This chapter is concerned with those infections known to be transmitted by transfusion, the individual agents responsible and the diseases that they cause. However, it is worth noting that the presentation of a disease in a transfused patient may offer some clues. A patient may react very rapidly (e.g. even during administration) to the transfusion of a blood component that is contaminated with significant levels of bacteria; this topic is discussed in Chapter 14.
Viruses
Early manifestations (a few days to three weeks) are not common and if they occur they most likely reflect transmission of a virus that causes acute infection, such as West Nile virus or even dengue virus [9,10]. Such an event is most likely to be associated with a known outbreak of the disease in question [11]. The most common symptoms are likely to be fever and headache, muscle pain, malaise, possibly with more severe manifestations typical of the virus itself [9]. In the case of the B19 parvovirus, infection may result in red cell aplasia or even an aplastic crisis in addition to viral syndromes [12]. Interestingly, infection with HIV can also result in an early acute viral syndrome, although the manifestations of AIDS are not likely to occur until many years after infection.
Hepatitis was, for many years, the most common infectious complication of transfusion, but is now very infrequent. HBV and HCV infections are usually asymptomatic initially and if there is any clinically apparent disease, it will not occur until several months after transfusion [2]. Transfusion-transmitted hepatitis A virus (HAV) is rare, but occasional cases have been reported, as is also the case for hepatitis E virus (HEV). These agents tend to have a shorter incubation period and generally cause an acute, rather than chronic, form of hepatitis [13].
As with hepatitis viruses, transfusion transmission of retroviruses is also extremely rare. As pointed out above, there may be an acute viral syndrome shortly after infection with HIV-1, but there is no such early response to infection with HTLV-1 or -2. In the absence of treatment, HIV infection almost invariably will lead to the eventual development of AIDS many years after the original infection, but only a minority of those infected with HTLV will develop symptomatic disease (tropical spastic paraparesis or adult T-cell leukaemia).
Thus, detection of transfusion-transmitted retroviral infection, or indeed hepatitis virus infection, is almost entirely dependent on laboratory testing. However, because most blood collection organizations actively trace recipients of prior donations from repeat donors who are newly found to be infected with these viruses, transfusion services may be notified that an earlier blood component may be infectious and are asked to identify and test the affected recipients. This approach has been responsible for the detection of essentially all confirmed transfusion transmissions of HIV and HCV in the USA since 1999, when nucleic acid testing of all blood donors was implemented.
Parasites
A number of protozoan parasites are transmissible by transfusion, most notably Plasmodium spp. (the agents of malaria), Babesia spp. and Trypanosoma cruzi (the agent of Chagas disease) [13]. Malaria and babesia infection may present with typical flu-like symptoms a few weeks to a few months after transfusion and may progress to the typical manifestations of the disease. Asplenic patients are at particular risk of disease from babesia infection. In many cases, posttransfusion infection with these agents may be detected by examination of blood smears. Posttransfusion babesia infection is not uncommon in the USA, particularly in areas where the parasite is endemic, but is rare elsewhere in the world [14,15]. In the USA, transfusion-transmitted babesia may be mistaken for malaria. Posttransfusion T. cruzi infection may occur in Latin America, where the parasite is endemic (although control programmes are reducing the threat), but is also recognized in areas where there is significant immigration from endemic areas [16]. Transfusion-transmitted T. cruzi may be asymptomatic but can result in severe or fulminant disease in immune compromised patients. The incubation period for acute infection ranges from 20 to 40 days; fever that is unresponsive to antibiotics is the most common symptom, followed by lymphadenopathy and splenomegaly. The parasite may be detectable in blood films in some cases.
Prions
It is now clear from experience in the UK that the prion that causes variant Creutzfeldt–Jakob disease (vCJD) may be transmitted by transfusion and four such transmissions have been clearly documented (Chapter 15). There is, as yet, no evidence for transmission of other prions. Detection of transfusion transmission of the vCJD prion was dependent upon a carefully designed surveillance programme and such an event is not likely to be observed in routine clinical practice, as the incubation period is in excess of several years [13, 17].
Interventions to minimize the impact of transfusion-transmitted infection
A variety of methods and processes are used to control TTIs. In general, they involve: the identification of appropriate donor populations and the selection of safe donors; testing blood donations for markers of infection or infectivity; treatment of the donation and, in some circumstances, treatment of the blood recipient. Many of these interventions are required by laws and regulations and/or by voluntary standards [18,19].
Donor populations are selected implicitly by location of collection sites and by voluntary nonremuneration policies and explicitly by avoidance of collection from a variety of institutions (particularly prisons). Asking presenting donors questions relating to medical, travel and behavioural histories is used to assess donor suitability. These questions are intended to identify those at higher risk of certain infections. Typically, donors are asked about [18]:
· a history of selected diseases or infections, such as viral hepatitis, HIV/AIDS, selected parasitic diseases;
· intimate or family exposure to specific infectious diseases;
· exposure to blood or body fluids through illicit injection or routine transfusion;
· receipt of potentially infectious vaccines or therapeutic agents;
· behavioural risk factors, particularly involving male–male sex or payment or exchange of drugs for sex;
· travel to locations or areas offering risk of exposure to (for example) malaria or the vCJD prion.
Depending upon the responses to these questions, the presenting donor will be temporarily or permanently deferred from donation and the deferral will be recorded so that the risk may be identified should the donor try to present again during the time of deferral. The efficacy of these measures to select safer donors can be evaluated by comparing the prevalence and incidence of positive TTI test results among donors, with those seen in the general population. In the USA, studies suggest that donor prevalence rates for key TTIs are some 6- to 20-fold lower than those for the general population, while incidence rates may be 4- to 20-fold lower than community rates [20]. Testing each donation for markers of infection or infectivity using serologic and/or nucleic acid tests is a critical step in assuring safety from infections where such tests are available and suitable; this aspect is covered in Chapter 20.
To some extent, routine postcollection processing of blood components may impact their infectivity. There is some evidence that infectivity for some agents may vary by component, with infectivity for malaria and babesia being found primarily (but not exclusively) in red cell concentrates [13]. Conversely, infectivity for T. cruzi seems to be confined to platelet concentrates [16]. The infectivity titre for some agents (most notably HTLV-1) clearly declines with product storage, although this is not considered to be a safety measure in its own right. However, leucocyte reduction of blood components clearly reduces the risk of transmission of CMV and probably that of other cell-associated viruses including HTLV [13]. Most promising, of course, is the application of formal pathogen reduction methods, which are currently available in many countries for the treatment of platelet concentrates and plasma for transfusion [6]. Methods for whole blood and for red cell concentrates remain under development.
Transfusion-transmitted infectious agents
Viruses
Hepatitis A virus (HAV)
HAV is a small (27–32-nm diameter) nonenveloped virus with a single strand of positive sense RNA, 7.5 kb in length, in the family Picornaviridae, genus Hepatovirus. The primary transmission route is faecal-oral, sometimes through food or water or close personal contact. Single-source outbreaks are not uncommon. The incidence of infection in the general population tends to be relatively low at less than 7 per 100 000 annually, although seroprevalence rates are 29 to 34% in the USA [13]. The incubation period is 10 to 50 days, with a mode of one month. The course of disease is almost always acute, typically with anorexia, relatively mild fever, fatigue, vomiting, leading to typical hepatitis with varying degrees of transaminase elevation and icterus. Overall, the disease tends not to be severe with fulminant or fatal cases infrequent – usually much less than 1%. There is a 7- to 14-day period of viremia prior to the appearance of symptoms and, during this time, blood is likely to be infectious via transfusion. Tests for IgG and IgM antibodies and for viral RNA are available. A handful of transfusion-transmitted HAV cases have been reported, some with secondary transmission [13]. Testing of whole blood donations is not warranted because transmission is so rare, but plasma for further manufacture is tested for HAV RNA by pooled NAT. Blood donors are usually asked to notify the collection site if they become sick shortly after donation and such postdonation information has led to the identification and recovery of at least some potentially infectious units.
Hepatitis B virus (HBV)
HBV is a small enveloped spherical virus 42 to 47 nm in diameter, with a partially double-stranded, circular DNA genome 3.2 kb in length with overlapping reading frames, in the family Hepadnaviridae, genus Hepadnavirus. Transmission routes are primarily sexual, parenteral and perinatal. An unusual feature of HBV infection is the overproduction of viral coat material that can circulate at high concentrations. This is termed hepatitis B surface antigen (HBsAg); its presence is indicative of active infection (acute or chronic) and it is the primary analyte for blood donor screening. Antibodies to HBsAg (anti-HBs) are generally indicative of past infection, but antibodies to the inner core of the virus (anti-HBc) appear earlier and may also indicate some risk of infectivity. IgM anti-HBc in combination with HBsAg are markers of infection within the last 6 months [21]. Detectable HBV DNA in the plasma is associated with varying levels of infectivity, depending upon the phase of the infection; the early window phase when DNA is the only detectable marker appears to be the most infectious. The estimated incidence of infection in the USA is approximately 12 per 100 000 whereas the prevalence is 4 to 5% [22]. Since the introduction of an effective vaccine in the USA, the incidence has decreased by 80%. The global burden of chronic HBV infection is as high as 400 million individuals. The incubation period from exposure to infection is from one week to six months. While many infections are asymptomatic, the range of disease manifestations is extensive, from mild acute symptoms to life-threatening or fatal fulminant cases. Symptoms are generally similar to those described for HAV infection. Chronic infection results more frequently from infection early in life and chronic disease may lead to cirrhosis and/or liver cancer. Diagnostic tests include serum transaminase measurement and detection of HBV antibodies, particularly IgM anti-HBc. Nucleic acid testing may also be of value.
The risk of transfusion transmission varies widely, but in the USA has been estimated as approximately one case per 350 000 units transfused [3,4]. However, the number of confirmed reported cases is considerably less than would be anticipated from this figure. The major interventions to reduce the risk of transmission include donor questioning for a history of viral hepatitis, close contact with a case and risk behaviours for sexual and parenteral exposure. Donations are tested for markers of HBV infection; most important is the use of sensitive immunoassays for HBsAg. In addition, in some countries donors are tested for anti-HBc, which identifies a small number of additional infectious donations. Such testing is not practical in areas with a high prevalence of HBV infection. Increasingly, donors are also being tested for HBV DNA, using triplex tests that are also designed to detect HIV and HCV RNA. However, the incremental impact of such testing on HBV safety appears to be limited if performed in mini-pools [4].
Hepatitis D virus (HDV) is a very small RNA virus that only infects those with on-going HBV infection. HDV coinfection increases the severity of disease in those with chronic hepatitis B [13]. Because HDV is dependent on HBV for replication, measures to prevent HBV transmission are also effective against HDV.
Hepatitis C virus (HCV)
HCV is a small, enveloped spherical (55–65 nm in diameter) virus with a single positive strand of RNA, 9.6 kb in length, in the family Flaviviridae, genus Hepacivirus. The transmission route is primarily parenteral. The incidence of new infections in the USA is estimated at approximately 6 per 100 000 annually and the prevalence is 1.3 to 1.9% [22]. Most infections are chronic and lifelong; around 20% of infections may resolve. The incubation period is typically 4 to 12 weeks, with an extended range of 2 to 24 weeks. Most infections are asymptomatic, but when symptoms occur they include fever, fatigue, loss of appetite and abdominal pain among others. Chronic disease may lead to cirrhosis and, in some cases, liver cancer after many years. The incidence has declined significantly over recent years. Although the virus was not specifically identified until 1989, it was recognized as the predominant causative agent of posttransfusion hepatitis [2]. The development, progressive improvement and universal implementation of tests for anti-HCV in donors have profoundly reduced the impact of this virus on blood safety, with a further significant improvement attributable to the implementation of testing for HCV RNA [23]. Nucleic acid testing has reduced the infectious window period from around 70 days to about 7 days [8]. In the USA, the current risk of transmission of HCV by transfusion is 1 per 1 150 000 units [5]. Fewer cases of posttransfusion HCV infection are observed than would be predicted from this figure. Diagnostic tools include serum transaminase testing, antibody and RNA detection.
Interventions to reduce the transmission of HCV by transfusion include questioning donors about a history of viral hepatitis, exposure to a case or risk behaviours involving parenteral exposure to blood. All donations are tested for antibodies to HCV and, in some cases, also to the core antigen of the virus. Nucleic acid testing for HCV has been in place in a number of countries since the late 1990s and has been instrumental in decreasing the residual risk.
Hepatitis E virus (HEV)
HEV is a small, nonenveloped icosahedral (30–34 nm in diameter) virus with a single, positive strand of RNA, 7.2 kb in length, in the family Hepeviridae, genus Hepevirus. The transmission routes are primarily faecal-oral, often waterborne, but apparently also foodborne, with cases attributable to consumption of raw or undercooked pork [13]. There are four genotypes representing a single serotype; the genotypes have varying geographic distribution and pathogenicity for humans. HEV1 and HEV2 are restricted to humans and transmitted via contaminated water in developing countries and HEV3 and HEV4 infect humans as well as pigs and other mammals; HEV3 and HEV4 are of lower human pathogenicity and are responsible for the localized sporadic, mostly foodborne, HEV cases worldwide. Incidence data are not readily available, but prevalence rates of 20 to 40% are found in endemic regions. However, similar rates have been observed in the USA and other nonendemic regions: it is likely that these high rates are attributable to serotypes of low human pathogenicity. The incubation period is usually 3 to 8 weeks and infection may result in a wide spectrum of disease from unapparent to fulminant, with apparently increased severity in pregnant women [13]. Transfusion transmission has been noted rarely in nonendemic areas and with some frequency in endemic areas, such as Hokkaido in Japan [13]. Nucleic acid testing of presenting donors has been implemented as a preventative measure in some areas of concern, but there seems to be little justification for widespread application of this intervention.
Human immunodeficiency virus (HIV)
HIV is an enveloped, more or less spherical (106–183 nm in diameter) virus, with two linear, positive sense strands of RNA, 9.2 kb in length, in the family Retroviridae, genus Lentivirus. There are two major species, HIV-1 and HIV-2, although HIV-2 is much less common and less virulent than HIV-1. HIV-1 has multiple distinct clades [13]. The predominant transmission routes are sexual, perinatal and parenteral. Prevalence and incidence rates vary widely, with prevalence and incidence rates as high as 20% and 1–2% in parts of sub-Saharan Africa. Prevalence in the USA is estimated at about 0.4% and incidence rates are about 16 per 100 000 annually [24]. Rates in Western Europe and other highly developed countries are generally somewhat lower. The incubation period to the acute retroviral syndrome averages about 21 days, but may range from 5 to 70 days. It is now known that HIV RNA becomes detectable around 9 days after infection using current NAT assays. Sensitive tests for antibodies to HIV will become positive about 3 weeks after infection [8]. These periods represent the window periods for nucleic acid and antibody testing. Most infections are asymptomatic and the acute retroviral syndrome, when it occurs, tends to be relatively mild, with a short (a week or two) period of fever, fatigue and possibly lymphadenopathy and rash. Typically, patients recover and are asymptomatic for many years thereafter, until the symptoms of full-blown AIDS emerge. Diagnosis of infection may be based upon tests for antibodies to HIV and/or the presence of HIV RNA in the plasma. Currently the risk of transmission of HIV by transfusion has been estimated as approximately 1 case per 1 500 000 units [5]. Again, however, transfusion-transmitted HIV infections are not recognized as frequently as this risk estimate would suggest. It is of interest to note that two of the five transmission events noted in the USA since 1999 have involved infection from a transfusable plasma unit, but not from the accompanying red cell concentrate, suggesting that the sensitivity of nucleic acid testing is approaching the infectious dose of HIV offered by a red cell concentrate [4].
While the AIDS epidemic has been a medical and human disaster, it stimulated the current stringent approach to blood safety and continuous quality improvement. All donors are directly asked about a history of AIDS-related symptoms and about possible exposure to infection. Questions about behavioural risk are asked and individuals acknowledging such risk are permanently or temporarily deferred. Some of the questions, particularly those relating to male-to-male sexual activity, have been challenged as discriminatory, particularly when accompanied by permanent deferral. Nevertheless, the rights of the patient to receive safe blood also have to be recognized and policies differ from one country to another, but almost always involve some period of deferral for those considered to be at increased risk of HIV infection. All donations are, at a minimum, tested for antibodies to HIV and, in many areas, also for HIV RNA. Testing for the HIV p24 antigen may be performed as an alternative to testing for RNA, but this approach offers lesser sensitivity [23].
Human T-lymphotropic viruses 1 and 2 (HTLV-1 and -2)
HTLV is an enveloped, spherical (150–200 nm in diameter) virus, with two linear, positive-sense, single strands of RNA, 8.5 kb in length, in the family Retroviridae, genus Deltaretrovirus. There are two different viruses, HTLV-1 and HTLV-2, and at least two additional variants have been described [13]. The primary routes of transmission are sexual and perinatal (via breast milk) and parenteral transmission (particularly via injecting drug use) has been widely documented, especially for HTLV-2. Prevalence rates vary widely, but tend to be very low in developed Western countries. There are pockets of high prevalence in Japan, the Caribbean and Africa (HTLV-1) and among some native populations in the Americas (HTLV-2). Infection is most often asymptomatic; for HTLV-1, there is a lifetime risk of a few percent for the eventual development of adult T-cell leukaemia/lymphoma or tropical spastic paraperesis, but only the latter has ever been associated with transfusion. Less is known about disease associations for HTLV-2. Transfusion transmission of these viruses has been recognized for many years. In the USA and a number of other countries, donations are tested for antibodies to HTLV-1 and -2, using a single combination test. There is no evidence of residual transmission although it may be estimated that there is a risk of one transmission per several million units [7]. Leucocyte reduction seems to eliminate the risk of transmission, which also declines during refrigerated storage of red cell components.
Cytomegalovirus (human CMV, HHV-5)
CMV is an enveloped, spherical beta herpesvirus 200 to 300 nm in diameter, with a double-stranded DNA genome of 235 kb pairs, in the family Herpesviridae, genus Cytomegalovirus. Seroprevalence rates vary by age and location but are on the order of 30 to 40% among blood donors in the USA and Western Europe [13]. There are no good measures of incidence rates, but the presence of antibodies to CMV implies that the virus is present, albeit often in a latent form. The normal transmission route is by contact, droplets or body fluid exposure, but it is also transmissible from mother to fetus and by blood transfusion and organ transplant. In general, healthy individuals are asymptomatic or show only mild symptoms (fever, lymphadenopathy, mononucleosis-like disease), but vulnerable individuals, including the fetus, low birth-weight infants, transplant patients and those with severe immune deficiencies may suffer serious or fatal disease, including pneumonia, multiorgan disease, etc. Infection during pregnancy may have profound effects on the fetus including developmental problems. TTI is typically recognized one to two months posttransfusion. There are two primary interventions to reduce or eliminate posttransfusion CMV infection: leucocyte reduction and/or the use of seronegative blood components for those at risk. Studies have suggested that both methods have similar efficacy in reducing risk but that breakthrough infections may still be seen [25]. There are a number of explanations for such breakthrough cases, including failure of testing or leucocyte reduction, the presence of extracellular virus in early infection and the possibility that at least some hospital-acquired infections may be mistaken for transfusion transmissions. Lastly, reactivation of latent CMV infection triggered by transfusion probably accounts for most reported cases of transfusion-transmitted CMV [26].
Other human herpesviruses
Two other human herpesviruses, Epstein–Barr virus (EBV) and human herpes virus-8 (HHV-8) are known to be transmissible by transfusion [13]. EBV is an almost ubiquitous virus, associated with mononucleosis, and in some locations, especially in Africa, Burkitt's lymphoma and nasopharyngeal carcinoma in Asia. Evidence is increasing for its role in the causation of lymphoproliferative disease among transfused immunocompromised patients, but other than leucocyte reduction, there is little in the way of an intervention, at least in the absence of pathogen reduction. HHV-8 is the causative agent of Kaposi's sarcoma and there is evidence for its transmissibility by transfusion, at least in parts of Africa, where it is endemic. To date, however, there does not appear to be any evidence for transfusion-transmitted HHV-8 disease; reductions in viral loads are most likely the result of leucocyte reduction [13].
West Nile virus (WNV)
WNV is an enveloped, spherical (40–60 nm in diameter) virus with a linear, single strand of positive-sense RNA, 11 kb in length, in the family Flaviviridae, genus Flavivirus (Japanese encephalitis complex). The primary transmission route is via (mainly culicine) mosquitoes and the amplifying hosts are primarily birds. Humans are accidental, dead-end hosts, although the virus is readily transmitted via blood transfusion [11]. At the peak of the new epidemic, which emerged in the USA in 1999, several hundred thousand individuals were naturally infected each year; the largest WNV outbreaks ever recorded worldwide occurred in the USA in 2002 and again in 2003 but the number of cases have declined and appear to have reached a stable number until a resurgence in 2012. The virus is endemic in parts of Africa, the Middle East and parts of Southern Europe where smaller outbreaks frequently occur. Infection results in a range of outcomes from asymptomatic, through flu-like symptoms occurring in approximately 25% of infected individuals. Symptoms include headache, weakness, new rash, fever muscle joint and eye pain, and is referred to as West Nile fever [9]. A more severe neurologic disease involving meningoencephalitis, with outcomes sometimes leading to death, occurs in between 1 in 150 and 1 in 200 infected individuals [9]. The incubation period is 2 to 14 days with a period of early viremia of about 7 to 10 days during which the blood of the patient may be infectious; low levels of viremia may be detectable for a longer time. In the USA, cases occur mainly between April and October. In 2002, there was a report of 23 well-characterized transfusion-transmitted cases of WNV infections and within less than a year, universal donor screening for WNV RNA by pooled nucleic acid testing was implemented [27]. Experience showed that such testing was insufficiently sensitive to detect all infectious donations so measures were established to perform single donation testing in areas and times with a high incidence of WNV activity [28]. Outside the USA, there has not been widespread testing, but donor deferral based upon travel to endemic areas has been implemented in some countries. Testing has been implemented in parts of Europe in response to a number of discrete outbreaks.
Other arboviruses
WNV illustrated two somewhat unexpected facts: the ability of arthropod-borne viruses (arboviruses) to establish huge, unprecedented outbreaks in previously unaffected areas and efficient transmission of an acute infection via blood transfusion. Accordingly, unexpected intense outbreaks of infection with chikungunya virus (an alphavirus transmitted by Aedes spp. mosquitoes) resulted in specific measures designed to prevent transfusion transmission in some affected areas; however, although explosive outbreaks occurred, transfusion transmission was never documented [6, 13]. In contrast, three clusters of transfusion transmission of dengue virus have been reported from Hong Kong, Singapore and Puerto Rico [13]. Donor testing has been implemented in Puerto Rico and may be considered elsewhere in the future, particularly in countries in which this virus is not endemic but outbreaks may occur [10].
Human B19 parvovirus (B19V)
B19V is a small, nonenveloped, icosahedral (23–26 nm in diameter) virus with a linear, negative-sense, single strand of DNA, 5.6 kb in length, in the family Parvoviridae, genus Erythrovirus. The primary transmission routes are respiratory and transplacental [13]. The virus is transmitted by blood transfusion and, at least in the past, via some plasma-derived products. Levels of viraemia during acute infection can be extremely high, sometimes exceeding 1012DNA copies per mL. The virus is ubiquitous, often causing seasonal outbreaks of mild disease, particularly among children. Seroprevalence rates are around 50% in adults and incidence rates can be 1.5%. Most infections are asymptomatic, but the virus causes erythema infectiosum (fifth disease) in children and occasional arthropathy in adults. Of particular concern is transient aplastic crisis in patients with shortened red cell survival or haemolytic anaemias; in some cases there may be pure red cell aplasia or pancytopenia. Infection in pregnant women may result in hydrops fetalis. Symptomatic infection from transfusion transmission is extremely rare. Nevertheless, in some countries (such as Germany and Japan), donor blood is routinely screened for viral DNA or by haemagglutination to eliminate the transfusion of components with high titres of virus. Currently, plasma for further manufacture is tested in pools for B19 DNA in order to minimize the levels of virus in manufacturing pools. Such testing is becoming available through rapid, high throughput procedures and this may lead to expansion of routine blood donation testing.
Bacteria
Currently, the major blood safety risk from bacteria results from contamination of components and subsequent outgrowth, resulting in septic reactions in the patient. This is discussed in Chapter 14. However, a small number of bacterial species may be transmitted from donor to recipient by blood, leading to infection and the development of disease. The best-known (but least-frequent) example of this is syphilis, although there has been no reported case in the literature since 1960. The rarity of such transmission is likely to be due to a combination of factors, including donor selection and testing and to the fragility of Treponema pallidum (the infectious spirochete) in stored components, along with the frequent use of antibiotics among patients. Recently, there has been concern about the potential for transmission of Q fever (caused by the small bacterium Coxiella burnetii) as a result of large, focused outbreaks of human infection in the Netherlands [13]. The infection resulted from human exposure to airborne bacteria associated with intensive goat farming. Investigations demonstrated bacteraemia in some patients and a small amount of suggestive evidence for rare transfusion transmission. In times and in areas of concern, donations were tested for C. burnetii by PCR. Veterinary public health measures have, however, essentially eliminated the outbreaks. Other tickborne rickettsia-like bacteria have engendered some concern, but to date there have been several reports of transfusion transmission of Anaplasma phagocytophilum [13]. There has been no evidence of transmission of Borrelia burgdorferi (the agent of Lyme disease) by this route [13].
Parasitic diseases
Malaria
Human malaria is caused by intraerythrocytic protozoan parasites of the genus Plasmodium, namely P. falciparum, P. vivax, P. ovale and P. malariae; recently, some cases have also been attributed to the primate parasite, P. knowlesi[13]. The parasites are transmitted by anophelene mosquitoes. The parasites may be present in the circulation during a prolonged asymptomatic period and are readily transmitted by blood transfusion. Such transmission is thought to be quite common in the endemic areas in the tropics, but is also a significant risk in nonendemic countries, as a result of collection of blood from donors infected as a result of travel from endemic areas. Disease symptoms include periodic fever, rigors and chills, headache, myalgias, arthralgias, splenomegaly and haemolytic anaemia. Although the typical incubation period is usually a few weeks, this period may be extended in blood recipients and recognition and diagnosis may not be easy. In general, the most severe forms of the disease are attributable to P. falciparum. Diagnosis may be achieved through microscopic inspection of blood smears and serological testing; research-level nucleic acid tests are also available. In nonendemic countries, transfusion-transmitted malaria is controlled by questioning donors about a history of malaria and of travel from, or residence in, malarious areas. Policies differ somewhat, but in general casual travel by residents of nonendemic countries is not a major risk, provided that such travellers are deferred for a few months. On the other hand, those who have resided for long periods in malarious areas may be partially immune and can be infectious for a number of years. Many donors are deferred for travel histories, with a negative impact on blood availability, and in some European countries and in Australia deferred donors may be tested for antibodies to Plasmodium spp.; if nonreactive they are permitted to donate after a shortened deferral period [29].
Babesiosis
Babesia is also an intraerythrocytic protozoan parasite and the causative agent of babesiosis; a variety of species may be found throughout the world [13, 15]. Babesia spp. are transmitted by ticks and primarily affect mammals, with humans as an accidental host. Babesiosis has symptoms similar to those of malaria, but the disease is more severe in the elderly and those patients without a functioning spleen. Transfusion-transmitted babesiosis may be confused with malaria, as the characteristic ‘Maltese cross’ appearance of the parasite in red cells is quite infrequent. B. microti is most often associated with human disease and with transmission by transfusion, which is most often seen in the USA, with a recent report detailing 162 cases since 1979 [14]. Few cases have been reported from any other countries. The disease is generally treatable, but, nevertheless, transfusion-transmitted cases have a significant fatality rate. At the time of writing, there has been no effective intervention available, as donor questioning regarding tick bite or clinical disease is insensitive and licensed donation tests are not available. Infection may be diagnosed by serologic and nucleic acid tests, or by examination of blood films.
Chagas disease
Chagas disease is caused by the protozoan parasite Trypanosoma cruzi, which infects numerous mammalian hosts [13]. It is transmitted to humans by reduviid bugs, generally as a result of exposure to the parasites in the bug's faecal material, which may be rubbed into mucous membranes, or the site of a bite from the bug itself. The parasite is endemic in the Americas, generally between latitudes 40 N and 40 S. Most human infections occur in rural or underdeveloped areas of Latin America where there are more opportunities for interactions between humans and the vector insects, which tend to colonize substandard housing. The parasite often infects infants and children and infection may be lifelong. Infected individuals may be asymptomatic over periods of many years and their blood can transmit the infection via transfusion. Transplacental infection may also occur, sometimes across more than one generation. Population movements have introduced the infection into nonendemic countries, especially the USA, Canada and Spain. Initial symptoms after infection may involve localized swelling and mild fever. Over the longer term, hepatomegaly and cardiac or gastrointestinal symptoms may emerge. Fulminant disease may occur in immunocompromised patients, particularly in the case of transfusion transmission. Diagnosis may be achieved through the use of serological tests, although infections are occasionally recognized on examination of blood films. Prevention of transfusion transmission relies primarily upon blood donor testing for antibodies to T. cruzi. Such testing is widespread in Latin America and was implemented in the USA in 2007. Subsequent evaluation of the testing programme in the USA suggested that selective testing was effective and, currently, blood donors are tested only once and if nonreactive subsequent donations are accepted without any testing. In other countries, notably Canada and Spain, presenting donors are asked about prolonged travel, residence or birth in Chagas-endemic countries and whether their mothers or grandmothers were born in such an area. If so, the donors are tested for T. cruzi antibodies and may donate if such tests are nonreactive. The number of transfusion-transmitted cases is limited and has been described primarily from platelets [16].
Prions
Variant Creutzfeldt–Jakob disease (vCJD) (see Chapter 15)
Variant CJD is the human form of bovine spongiform encephalopathy (BSE, mad cow disease), transmitted to humans through ingestion of tissues from infected cattle [13]. The disease was first recognized as a distinct entity in 1996. Although similar to classic CJD, vCJD occurs primarily among younger individuals, presents with psychiatric symptoms and generally has a longer course from diagnosis to death. The pathology typically involves unusual, florid plaques in the brain. About 220 cases have occurred, mostly in Great Britain. The frequency of reported cases has been declining over the past 5 or more years. Careful review of surveillance data has shown that there have been four instances of transmission of the vCJD agent by transfusion. Three such cases resulted in the development of vCJD in the recipient and the fourth occurred in an individual who died of underlying disease but was found to harbour the agent in the spleen and at least one lymph node [17]. One other possible case of transmission has been reported, attributed to receipt of Factor VIII concentrates. Although these events are infrequent, they do reflect a high transmission rate among exposed recipients. Because of concern about such transmissions, a number of preventative measures had been implemented well before the recognition of any transmissions. In the USA, such measures included permanent deferral from donation of individuals judged at risk of exposure to BSE by virtue of residence or prolonged cumulative travel to the UK and Western Europe and similar measures were taken elsewhere. In the UK, universal leucocyte reduction of blood components was implemented, domestic plasma was eliminated for transfusion or fractionation and there have been considerable efforts to reduce the overall use of donor blood. There has been a prolonged effort to develop pre mortem tests for infection with vCJD, but at the time or writing, no such test was available. To date, there has been no evidence that the classic form of CJD is transmissible by transfusion [13].
Key points
1. A number of pathogens, including viruses, bacteria, protozoan parasites and one prion are known to be transmitted by transfusion.
2. Measures are in place to control such transmission, including blood donor selection, deferral, laboratory testing and component treatment.
3. These measures have reduced the incidence of key TTIs to very low levels, usually less than one case per million components transfused.
4. TTIs are difficult to detect and diagnose.
5. Careful studies involving the patient and all implicated donors are necessary in order to confirm that an infection is attributable to transfusion.
6. TTI should be appropriately reported to blood providers and other agencies, as required by regulation or practice.
References
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13. AABB: Emerging Infectious Diseases Fact Sheets. http://www.aabb.org/resources/bct/eid/Pages/eidpostpub.aspx.
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17. Hewitt PE, Llewelyn CA, Mackenzie J & Will RG. Creutzfeldt–Jakob disease and blood transfusion: results of the UK transfusion medicine epidemiological review study. Vox Sanguinis 2006; 91: 221–230.
18. Eder A & Bianco C (eds). Screening Blood Donors. Bethesda, MD: AABB Press; 2007, pp. 1–287.
19. AABB. Standards for Blood Banks and Transfusion Services, 27th edn. Bethesda, MD: AABB Press; 2011, pp. 1–118.
20. Dodd RY. Current estimates of transfusion safety worldwide. Dev Biol (Basel) 2005; 120: 3–10.
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Further reading
Alter HJ & Klein HG. The hazards of blood transfusion in historical perspective. Blood 2008; 112: 2617–2626.
Barbara JAJ, Regan FAM & Contreras MC (eds). Transfusion Microbiology. Cambridge: Cambridge University Press; 2008, pp. 1–390.
Bern C, Kjos S, Yabsley MJ & Montgomery SP. Trypanosoma cruzi and Chagas' disease in the United States. Clin Microbiol Rev 2011; 24: 655–681.
Busch MP. Transfusion-transmitted viral infections: building bridges to transfusion medicine to reduce risks and understand epidemiology and pathogenesis. Transfusion 2006; 46: 1624–1640.
Perkins HA & Busch MP. Transfusion-associated infections: 50 years of relentless challenges and remarkable progress. Transfusion 2010; 50: 2080–2099.
Petersen LR & Hayes EB. Westward Ho? The spread of West Nile virus. New Engl J Med 2004; 351: 2257–2259.