Mollison’s Blood Transfusion in Clinical Medicine - part 9 pdf

The first reported case of transfusion-associated AIDS (TAA) turned out to be an 18-month-old infant with severe combined immunodeficiency who had been transfused repeatedly at birth and had received a unit of platelets from a donor who subsequently developed AIDS (Amman et al. 1983). By 1984, 38 cases of AIDS had been reported in patients with no risk factors other than a history of transfusion. Nineteen of the patients were adults who, during the previous 5 years, had received blood components derived from unpooled donations. In those cases in which all the donors could be followed up, an individual in a ‘high- risk’ group could always be identified (Curran et al. 1984). An expanded study of 194 patients showed that in most cases the high-risk donor was anti-HIV positive, and in those few cases in which the high-risk donor lacked anti-HIV, another donor tested positive (Peterman et al. 1985). A total of 157 525 cases of AIDS was reported in the USA by the end of 1990, and 5371 (3.4%) of these were attributed to the transfusion of blood or blood components. The median incubation period, estimated as the time from expos- ure by transfusion to diagnosis of AIDS, has been estimated to be 34 months in adults and 22 months in children (Peterman 1987), although later estimates indicated a longer period with a median of 7–8 years for adults and 3–5 years for children (Rogers 1992). In total, 50% of untreated subjects infected with HIV by transfusion will develop AIDS within 7 years compared with 33% of subjects infected by other routes (Ward et al. 1989). Following the first reports, the number of cases of TAA in the USA increased rapidly. By the end of 1991, out of a total of 206 392 cases of AIDS, there were 6060 adults and 472 infants or children who had acquired the disease by transfusion of blood or blood products, representing 3% and 13.6% of the total cases in adults and children respectively (CDC 1992). The risk of transmission of HIV by blood transfusion is now trivial in countries without major heterosexual spread and in which donor education, encouragement of self-exclusion and screening for HIV antibodies have been established since 1985. In these countries, the risk of transmission of HIV is almost solely attributable to donations given during the window period (see below). In western Europe, HIV prevalence among blood donors has declined progressively since the onset of systematic testing and, according to the European Centre for Epidemiologic Monitoring of AIDS, approximated 1.3 positives per 100 000 donations in 2002 (www.eurohiv.org). Since 1995, the prevalence has remained relatively constant in Belgium, Scandinavia, Ireland, the Netherlands and the UK, has decreased regularly in France and Spain, but has remained above 2 per 100 000 in Italy, Greece and Portugal (Hamers and Downs 2004). In Eastern Europe, prevalence has increased markedly since 1995, now exceeding 30 per 100 000 in 2002. The highest levels are reported in the Ukraine (93), Estonia (54) followed by Azerbaijan, Georgia and the Russian Federation. Because HIV is both cell associated and present in plasma, all blood components are potentially infectious (Curran 1985). The viral load has been estimated at between 1.5 × 10 4 tissue culture infective doses in a 250-ml unit of blood from an asymptomatic donor, to 1.75 × 10 6 from a unit drawn from a symptomatic person (Ho et al. 1989). The relative importance of the viral strain, concurrent infection by other blood-borne agents, cellular receptors for HIV and other genetic and acquired host factors, both for infection and for clinical course of HIV in transfusion recipients, has received a great deal of attention, but is still an area of intense research (Vicenzi et al. 1997; Keoshkerian et al. 2003; Zaunders et al. 2004). Follow-up studies have shown that 90–95% of patients receiving blood or blood components from anti-HIV-positive donors have become infected (Ward et al. 1987; Donegan et al. 1990b). The virus is well preserved in refrigerated and frozen blood; however, components that are washed, leucoreduced or cold stored for several weeks, procedures that diminish the number of viable leucocytes or the amount of virus, reduce the likelihood of transfusion transmission (Donegan et al. 1990a). Neither donor status nor recipient characteristics affect the likelihood of HIV transmission (Busch et al. 1990a). However, when AIDS developed in the donor shortly after donation, the period of asymptomatic infection in the recipient was also shortened (Ward et al. 1989). Albumin pre- parations, immunoglobulins, antithrombin III and hepatitis B vaccine have not been associated with HIV infection (Desmyter 1986; Melbye 1986; Morgenthaler 1989; Cuthbertson 1991). Furthermore, when HIV is added to plasma and the plasma is then fractionated by the cold-ethanol process, HIV does not appear in the Ig fraction (Morgenthaler 1989). CHAPTER 16 720 TAA in infants, and AIDS in infants and children in general, has a shorter incubation period than in adults and many of the clinical manifestations of the disease are different (Rogers 1992). Infants born to anti-HIV- positive mothers who become infected perinatally and infants transfused during the first years of life have the shortest median incubation period (less than 5 years), and usually develop AIDS in the first year of life. The increased susceptibility of infants to AIDS may be related to their immature immune system and to the larger viral load relative to body size. Children likely to develop TAA are those who are likely to be transfused: premature infants and children with haemophilia, thalassaemia and sickle cell anaemia. In the USA, of 2734 children with AIDS, 250 (9.1%) were transfusion associated and 138 (5.0% of the total) occurred in children with coagulation factor deficiencies (CDC 1991). In much of Asia and Africa, the transmission of HIV by blood transfusion is still an important source of infection. Reasons for an alarmingly high rate of transmission, reported to be up to 10% of all cases, include: (1) the high demands for blood for inpatients with severe anaemia and haemorrhage, mainly in obstetrics, gynaecology and paediatrics; (2) the prevalence of HIV infection amongst the donor population, which can be as high as 20%; (3) the fact that HIV infection is not confined to a minority of the population who can be requested to refrain from blood donation; and (4) the inability of many laboratories to test for HIV or to perform and control the tests properly. The patient groups at greatest risk of acquiring HIV-1 or -2 by blood transfusion in tropical Africa are children with malaria and anaemia, patients with sickle cell anaemia (120 000 infants with sickle cell disease are born each year in Africa), anaemic antenatal patients, women with severe obstetric haemorrhage and trauma victims (Fleming 1990). Transfusion-associated AIDS and haemophilia To December 1996, 4674 cases of AIDS were reported in patients with haemophilia, accounting for less than 1% of the 581 429 AIDS cases reported in adults and children. Of the 7629 cases of AIDS reported in children under the age of 13 years, 373 (5%) were recipients of blood or tissue and 231 (3%) were haemophiliacs (Centers for Disease Control and Prevention 1997). All but 39 of these infections occurred prior to testing blood and plasma donors for HIV. Studies of patient cohorts and specimens in serum repositories revealed that more than 90% of severe haemophiliacs (subjects with less than 1% factor VIII activity) treated with factor VIII concentrate had been infected prior to 1984 (Evatt et al. 1985). In a study of a 16-centre cohort of haemophiliacs in the USA and Europe, infections first appeared in 1978, peaked in October 1982 and declined to an estimated four infections per 100 person-years by July 1984 (Kroner et al. 1994). For patients who were high-dose recipients, peak risk appeared even earlier, indicating that the majority of patients with haemophilia were infected before the disease was widely recognized and long before it was attributed to transfusion. The risk was related to each patient’s mean annual dose of clotting factor concentrate. As clotting factor concentrates are prescribed on the basis of patient weight or plasma volume, older patients with severe disease generally received more concentrate, had more ‘donor expos- ures’ and seroconverted sooner than did children and patients with milder disease. When corrected for dose and severity of disease, the association between age and early seroconversion disappears. The cumulative incidence of infection was 96% for high-dose recipients, 92% for moderate-dose recipients and 56% for low-dose recipients. Subjects who received only single- donor products (plasma and/or cryoprecipitate) had the lowest cumulative incidence of infection, 16% (Kroner et al. 1994). This experience is consistent with other reports (Andes et al. 1988; Gjerset et al. 1991). These startling numbers underscore the potential public health risks of using transfusion products manufactured from pools of plasma drawn from 20 000 donors or more. Although AIDS was first reported in three haemophiliacs in 1982, studies of serum samples stored from as far back as 1968 have shown that the first cases of the development of anti-HIV in haemophiliacs occurred in 1978 in the USA and in 1981 in the UK (Evatt et al. 1983; Machin et al. 1985; Ragni et al. 1986). Plasma for preparing the implicated clotting factor concentrates may have been collected a year prior to that. The prevalence of HIV seropositivity and of AIDS varies from one haemophilia centre to another depending on the source, volume and type of concentrate used. In a study of 13 haemophilia centres in western Europe, Canada and Australia involving INFECTIOUS AGENTS TRANSMITTED BY TRANSFUSION 721 2370 patients with haemophilia A and 434 patients with haemophilia B, the overall incidence of anti- HIV was 53.6% (CDC 1987a). The percentage of haemophiliacs infected with HIV in different countries has varied from 4% to more than 60%, with the higher rates in those countries using mainly concentrates from plasma imported from the USA. Some batches of factor VIII concentrate from European plasma have also transmitted HIV (Madhok and Forbes 1990). A clear correlation was also found between the severity of haemophilia and HIV seropositivity (Melbye 1986; UK Haemophilia Centre 1986). Haemophiliacs treated before 1985 with cryoprecipitate alone have shown a low risk of HIV infection (Ragni et al. 1986; UK Haemophilia Centre 1986). Patients with haemophilia B fared somewhat better (Evatt et al. 1984; Mannucci et al. 1985; Ragni et al. 1986; UK Haemophilia Centre 1986). The difference may be due partly to the uneven partitioning of HIV in infected plasma during fractionation, with HIV sepa- rating preferentially in the cryoprecipitate fraction (Aronson 1979; Morgenthaler 1989; Madhok and Forbes 1990). The source of plasma used for fractionation is also partly responsible for this difference. In many countries all the factor IX is prepared locally, whereas at least part of the factor VIII is imported from the USA. Approximately 70% of patients in the USA with haemophilia A and 35% with haemophilia B developed HIV antibodies before the introduction of methods for viral inactivation in blood products (CDC 1987b). In a multicentre study of haemophiliacs treated in the UK between 1980 and 1984, 896 (44%) of 2025 patients with haemophilia A were positive for anti-HIV; 20 (6%) of 324 patients with haemophilia B and 11 (5%) of 215 patients with von Willebrand’s disease were seropositive. Although a large number of severe haemophiliacs in the UK were treated up to 1983 with unheated factor VIII concentrate imported from the USA, the incidence of anti-HIV in haemophiliacs in the UK is much lower than in countries such as Germany, Spain and the USA, where the frequency of anti-HIV ranges between 68% and 94% (Kitchen et al. 1984; 1985). On the other hand, in Groningen, in the Netherlands, only 1 out of 18 severe haemophiliacs treated with commercial factor VIII concentrates between 1978 and 1983 developed HIV antibodies (van der Meer et al. 1986). There has been no transmission of HBV, HCV or HIV by US-licensed plasma derivatives since the introduction of effective virus inactivation procedures (Tabor 1999). Prevention of transfusion-transmitted HIV infection Reducing the residual risk The reduction in risk of transfusion-transmitted HIV over the past 15 years has been dramatic and reassuring. Nevertheless, enormous public concern persists. As in almost no other area, blood safety, and specifically the possibility of HIV transmission, provokes emotions and measures to further reduce risks that defy the conventional cost–benefit calculus. Actions to reduced residual risk fall into three general categories: (1) measures that can be introduced by blood collection facilities, such as improved donor screening, testing, education and exclusion techniques; (2) enlightened transfusion practice, such as judicious use of allogeneic blood components, appropriate use of autologous blood, and alternatives to transfusion (see Chapter 17); and (3) measures that depend on the development of new technologies, such as viral inactivation of cellular components and safe substitutes for blood. Donor demographics have proved effective at identi- fying and excluding donors at high risk for infection and transmission of HIV (Busch et al. 1991a). Donors with high-risk profiles include men who have had sexual contact with other men since 1977, intravenous drug users, residents of high prevalence regions, prisoners, prostitutes, haemophiliacs who have received ‘unsafe’ clotting factor concentrates and the sexual partners of people in all of these groups. The year 1977 was chosen as the point of reference, because the first clinical cases of AIDS in the USA were diagnosed retro- spectively as far back as 1978 (Jaffe et al. 1985). The rate of seropositivity has been higher in paid plasma donors than in volunteers. Seven HIV positives were found out of 35 000 plasma donors attending centres located outside high prevalence areas (Stramer et al. 1989). Measures to exclude such subjects from blood donor rolls are among the most important means of preventing the spread of AIDS by transfusion. Nevertheless, predonation medical screening and donor education are not infallible (Leitman et al. 1989). Between 1% and 2% of donors do not report CHAPTER 16 722 risks that would disqualify them from blood donation, and donation incentives such as complimentary labor- atory testing increases this rate (Glynn et al. 2001). In a study of blood donors found positive for hepatitis C antibody, 42% admitted to intravenous drug use on subsequent questioning, despite denying such use on predonation screening (Conry-Cantilena et al. 1996). In an anonymous mail survey of 50 162 volunteer allogeneic blood donors, 1.9% of the 34 726 respondents reported one or more risk factors that should have led to their deferral at the time of their last donation (Williams et al. 1997). Refinements in blood donor screening techniques, such as the use of illustrated risk- related activities, expansion of the screening question- naire and interactive computer-based screening, have been proposed, but data supporting the effectiveness of such measures are lacking (Mayo et al. 1991). How- ever, the reasons why some volunteer blood donors appear to disregard certain screening criteria are un- known and may have more to do with donor psycho- logy than with inadequate screening and education. Donors who are confirmed positive for HIV should be counselled and referred to specialized centres for follow-up. Counselling should be performed by spe- cially trained staff. Appropriate interventions will not only help the donor to obtain long-term supportive care and to prevent further spread, but will also aid transfusion services to understand which groups of the population are HIV seropositive and still come forward to donate (Lefrere et al. 1992). Donor education and selection methods can then be modified accordingly. Self-exclusion (‘self-deferral’) of donors Retrospective analysis indicates that the risk of con- tracting AIDS from the transfusion of blood and blood components (other than products of plasma fractionation) prior to focused screening and testing was far higher than the one infection per million units transfused that had been estimated during the 1983–1985 interval. The risk of HIV transmission from transfusion in San Francisco has been calculated from its first appearance in 1978 to rise exponentially to a peak risk of approximately 1.1% per unit transfused in 1983 (Busch et al. 1991a). A retrospective study of heavily transfused patients with leukaemia in New York City revealed an overall risk between 0.02% and 0.11% per component transfused (Minamoto et al. 1988). The major blood collectors published a Joint Statement of Recommendations in January 1983 (American Association of Blood Banks et al. 1983), and the Public Health Service published recommendations in March 1983 (CDC 1983) that proposed such measures as public education, self-deferral for donors engaging in high-risk activity and confidential unit exclusion procedures (Pindyck et al. 1984, 1985). These measures proved unusually effective. An estimated 90% of men in high-risk cat-egories self deferred. By 1984, the risk in San Francisco had dropped to less than 0.2% per unit. Screening with anti-HIV-1 in 1985 reduced the risk to about 1 in 40 000 units (Busch et al. 1991a). Routine screening tests for HIV in blood donors In most countries, screening tests for anti-HIV by the enzyme immunoassay (EIA) format are now com- pulsory for all blood donations. If reactive (‘repeat reactive’), additional tests for HIV using independent methods are used to confirm the diagnosis of HIV infection (Stramer et al. 2004). The current algorithm in the USA requires that anti-HIV-1/2 repeat reactive specimens be further tested with the HIV-1 Western blot (see below) and a specific anti-HIV-2 EIA. Early ELISA assays using disrupted purified virus were plagued by false-positive reactions. Current generation screening assays, using recombinant and synthetic antigens, have reduced false reactives dramatically while increasing test sensitivity for both the predominant and the variant viral strains (Busch and Alter 1995). Less than 10% of reactive assays confirm positive using this strategy. Western blot is notoriously subjective and complicated by non-viral bands (Kleinman et al. 1998). Alternative strategies use a second EIA or a NAT assay of HIV RNA. Approximately 25.6 million donations were screened by the American National Red Cross from September 1999 to 30 June 2003, resulting in 17 090 HIV repeat reactive blood donations (Stramer et al. 2004). Only 4.8% of these donors (818) were Western blot positive and approximately 90% (759) of those also tested positive by NAT. Follow-up testing of the remaining 10% demonstrated that almost all of these donors represent Western blot false-positive results. Although some antibodies to core and other antigens of HIV-1 and HIV-2 crossreact (Sazama et al. 1992), currently available tests are designed to detect both anti-HIV-1 and anti-HIV-2. Such combined INFECTIOUS AGENTS TRANSMITTED BY TRANSFUSION 723 assays are available as antiglobulin ELISAs and as sandwich ELISAs and are routinely used in several countries. Seroconversion in infection with HIV-1 is detected earlier in these combined assays than by anti-HIV-1 assays (Gallarda et al. 1994; Fiebig et al. 2003). Most of the combined assays have been found to be less sensitive for the detection of anti-HIV-2 than most anti-HIV-2 specific tests (Christiansen et al. 1996). Some samples with anti-HIV are repeatedly positive in some, but negative in other screening assays. If only one screening test is used, such samples may give false- negative results (Hancock et al. 1993). One cause of such false negatives is that antibodies against subtype O, a variant found predominantly in West Africa, are not recognized in all screening assays (Loussert-Ajaka et al. 1994; Schable et al. 1994). At present group O prevalence is low in the USA and in western Europe (Sullivan et al. 2000). False-negative reactions have also been found to be due to contamination with glove powder, inhibition by serum proteins, haemoglobin and certain anticoagulants (Sazama 1995). Currently available ELISAs for HIV-1 antibodies detect HIV-1 subtype group 0. Soon after the dis- covery of an assay for HIV-Ab, transmission of HIV by blood from seronegative donors had been recognized (Esteban et al. 1985; Raevsky et al. 1986; Ward et al. 1988; Cohen and Munoz 1989). Studies reported detection of HIV-1 p24 antigen in analyses of stored blood specimens from plasma donors as early as 1986, and confirmed cases of HIV-Ag-positive, Ab-negative blood in primary HIV infection were reported by 1988 (Allain et al. 1986; Clark et al. 1991; Irani et al. 1991). The utility of this test as a screening assay was not so obvious. Antigen tests are positive for only part of the initial antibody-negative viraemic phase. In some subjects antigen can be detected as early as 2 weeks after infection, persisting for between 3 weeks and 3 months, and is no longer detectable when anti-p24 appears in the serum, although it may reappear inter- mittently during the asymptomatic phase (Allain et al. 1986; Fiebig et al. 2003). Later, antigen may reappear with a loss of anti-p24. A prospective study of 515 494 units donated at 13 blood centres in the USA failed to detect a single instance of Ag-positive/Ab-negative donated blood. A retrospective analysis of 200 000 repository specimens and prospective studies of blood donors in Europe confirmed these findings (Backer et al. 1987; Busch et al. 1990a). However, after three anti-HIV seroconversions followed transfusion of p24 antigen-positive units, testing of donated blood for p24 antigen was mandated in the USA in 1996 (Busch and Alter 1995). Mathematical models predicted that universal antigen screening would detect eight additional potentially infectious units per year. In fact it took 5 years before eight antigen-positive/antibody-negative units were interdicted (Kleinman et al. 1997; Kleinman and Busch 2000). Because of this limited usefulness and troubling frequency of false positives, HIV p24 antigen screening was not adopted widely outside of the USA. With the adoption of universal NAT for HIV in the USA in 1999 and its licensure in 2002, HIV-Ag screening was rendered unnecessary (Busch et al. 2000). Confirmatory tests: they do not always confirm The Western blot is the most widely used additional or ‘confirmatory’ test for HIV. The criteria for the interpretation of Western blot results have been re- evaluated several times because of greater sensitivity and specificity of screening assays and Western blot reagents, better insight into the serological patterns of HIV infection, experience with patterns of non-specific reactivity in low- and high-risk populations and knowledge of the serological basis of non-specificity (Sayre et al. 1996). Samples are now considered to be WB positive demonstrate reaction with the gp41 and gp120/160 env bands or with either of these bands and the p24 gag band. The earlier requirement for a reaction with a third gene product (e.g. p31 or p66 pol bands) has been abandoned and reactivity with more than one env antigen alone is enough for confirmation (O’Gorman et al. 1991). If there is reactivity with only one band, the result of the Western blot is considered to be indeterminate. The absence of reactivity in the Western blot indicates that the donor has not developed anti-HIV (Dodd 1991). In the original Western blot assay, viral lysate was used as a source of antigen. In the newer assays, recombinant or synthetic viral antigens are applied. These assays have been found to be both more sensitive and specific than the original WB (Soriano et al. 1994). Nevertheless, the assay is still relatively subjective and beset by indeterminate and false-positive results when compared with NAT as the ‘gold standard’ or when investigated with sequential sampling follow-up (Kleinman et al. 1998; Mahe et al. 2002; Stramer 2004). CHAPTER 16 724 Detection of HIV DNA and HIV RNA Donations during the window period constitute the predominant risk for HIV transmission through transfusion (Busch et al. 2000). A more sensitive and specific alternative to testing for p24 antigen is NAT for HIV DNA in PBMC (Ou et al. 1988) or HIV-1 RNA in plasma by reverse transcription PCR or a similar amplification assay (Henrard et al. 1992). All blood in the USA, Japan and most European countries is tested by NAT in pools of 16–90 specimens. Ultrasensitive assays can detect fewer than 10 genomic copies/ml (Busch et al. 2000). However, tests have been optimized for HIV subtype B and may lack sensitivity when applied to non-B subtypes (Triques et al. 1999). Single-donor assays are inevitable, but await the development of fully automated combination (HIV/ HCV/HBV) assays. Current risk of transmission of HIV by blood transfusion Although the various measures outlined above have dramatically reduced the risk of TAA-AIDS, a small residual risk remains (Delwart et al. 2004; Phelps et al. 2004). Most of this risk results from ‘window period’ donations. Before the introduction of HIV-Ag and NAT, prospective studies estimated this risk at about one infection in 60 000 units (Busch et al. 1991b; Nelson et al. 1992). Subsequent estimates rely on models based on calculations of HIV incidence and window period. In the USA, residual risk has been calculated as 1 per 2 135 000 repeat donors (Dodd et al. 2002). The incidence rate is approximately two times greater among first-time donors. In most European countries where the prevalence of HIV in blood donors is lower than in the USA, the residual risk is probably lower still. However, in countries with a high percentage of infected subjects and where HIV is spread mainly by heterosexual intercourse, the risk of transmission of HIV by blood transfusion is still considerable. Human T-cell leukaemia viruses types I and II The human T-cell leukaemia virus type I (HTLV-I), the first human retrovirus to be described, was isolated from cultured cells from a patient with an aggressive variant of Mycosis fungoides and from a patient with Sézary syndrome (Poiesz et al. 1980; Gallo et al. 1981). The virus has subsequently been shown to be identical to the adult T-cell leukaemia virus (Yoshida et al. 1982; Watanabe et al. 1984). HTLV-I is the causative agent of adult T-cell leukaemia (ATL) and is associated with a chronic demyelinating neurological disease called tropical spastic paraperesis (TSP), known in Japan as HTLV-associated myelopathy (HAM) (Vernant et al. 1987; Roman and Osame 1988). HTLV- seropositive individuals appear to have a 0.25% life- time risk of developing TSP, compared with a 2–5% risk of developing ATL (Kaplan et al. 1990). The virus is also associated with lung infections, cancer of other organs, monoclonal gammopathy, renal failure, infection with Strongyloides stercoralis, intractable non-specific dermatomycosis, lymphadenitis and uveitis. These effects may be due to the immunodeficiency induced by HTLV-I infection (Takatsuki 1996). The association of HTLV-I with Mycosis fungoides is controversial, as no HTLV-related DNA sequences could be detected in patients with this disease (Bazarbachi et al. 1993; Vallejo et al. 1995). In Japan, only 2.5% of HTLV-I carriers develop ATL (Takatsuki 1996). HTLV-I and -II belong to the oncovirus subtype of the retrovirus family and are able to induce polyclonal proliferation of T lymphocytes in vitro and in vivo. Like the lentiviruses HIV-1 and -2, these viruses are lymphotropic and neurotropic, and have the essential structural genes gag (group antigen), pol (reverse tran- scriptase) and env (envelope) in addition to regulatory genes. In HTLV-I, the gag gene codes for the structural proteins p55/24/19; pol codes for a protein of approximately 100 kDa, and env codes for glycoproteins gp61/46/21. In HTLV-II the structural proteins are similar to those in HTLV-I with a high degree of crossreactivity; gag encodes the polypeptides p53/24/19; pol a protein of approximately 100 kDa; and env codes for the glycoproteins gp61/46/21. Areas endemic for HTLV have been found, particularly in south-west Japan, with prevalence as high as 15% (Maeda et al. 1984), in the Caribbean with a 1–8% prevalence (Clark et al. 1985), in regions of Central and South America and in parts of sub- Saharan Africa (Gessain et al. 1986; Vrielink and Reesink 2004). Populations in these areas show different prevalence rates for anti-HTLV-I, as do emigrants from these regions (Sandler et al. 1991; Vrielink and INFECTIOUS AGENTS TRANSMITTED BY TRANSFUSION 725 Reesink 2004). It has been estimated that more than 1 million Japanese people are healthy carriers of HTLV-I. Carriers of HTLV have also been found in the USA, especially in Florida and states on the Pacific, and in France, UK, the Netherlands and many other countries. The prevalence in blood donors has been reported to be one in 6250 in the USA (CDC 1990), about one in 30 000 in France (Pillonel et al. 1996), one in 45 000 in the Netherlands (Zaaijer et al. 1994) and one in 20 000 in London (Brennan 1992). HTLV-II, the second human retrovirus to be dis- covered, has a 65% nucleotide sequence identity with HTLV-I and a significant serological crossreactivity (Hjelle 1991). However, HTLV-II antibodies are not detected by all HTLV-I assays. The distinction between HTLV-I and -II can be made by DNA PCR (Reesink et al. 1994), and in the recently developed WB assays in which specific HTLV-I and -II recombinant antigens are used. The relative prevalence of the two viruses in blood donors in the USA was found to be about equal (Glynn et al. 2000), but in many other countries HTLV-I predominates in blood donors. There is a high prevalence of HTLV-II among i.v. drug users and their sexual contacts in the USA and other countries (Vrielink and Reesink 2004). A large proportion of HTLV-II-positive subjects in the USA were Hispanics and American Indians (Hjelle et al. 1990a; Sandler et al. 1991). HTLV-II has been found to be associated with a HAM-like neurological disease (Hjelle et al. 1992; Murphy et al. 1997). Although the virus was first found in a patient with hairy cell leukaemia (Kalyanaraman et al. 1982) and subsequently in other T-cell malignancies, no viral RNA could be detected in the malignant cells (Manns and Blattner 1991). Transmission of human T-cell leukaemia virus HTLV is mainly transmitted by sexual contact, by the sharing of infected needles and from mother to child, particularly by breast-feeding (Kajiyama et al. 1986). If infected mothers refrain from breast-feeding, transmission of HTLV to their infants is prevented in 80% of cases (Hino et al. 1996). Infection of infants is also prevented when the milk is freeze-thawed or heated at 56°C for 30 min (Ando et al. 1986; Hino et al. 1987). Transmission from mother to fetus has been demonstrated by culture studies of cord blood lymphocytes in 2 out of 40 cord blood samples from HTLV-I-positive mothers (Satow et al. 1991). Human T-cell leukaemia virus and blood transfusion HTLV-I has been transmitted by cellular components, but not by cell-free plasma or plasma derivatives (Okochi 1985). However, HTLV-RNA is detectable in plasma from infected subjects. The lack of infectivity of HTLV-positive plasma may be explained by the presence of neutralizing antibodies, the fact that it is integrated in viral DNA and the requirement of cell– cell interactions for infectivity (Rios et al. 1996). Antibodies are usually first detectable 14–30 days after transfusion, although the interval may be as long as 98 days (Inaba et al. 1989; Gout et al. 1990). Of 85 recipients of anti-HTLV-I-positive cell concentrates in Japan, 53 (62%) developed antibodies 3–6 weeks after transfusion: IgM antibodies were present only in the early stages, whereas IgG antibodies persisted at high titre throughout the period of follow-up (Sato and Okochi 1986). Storage of blood appears to decrease the risk of transmission of HTLV. This may explain the lower rate of transmission reported in USA transfusion recipients, whose blood may have been stored for a longer period than the units in Japan and the Caribbean (Donegan et al. 1994). Antibodies became detectable in 79.2% of recipients of blood stored for 1–5 days, but in only 55% of recipients of blood stored 11–16 days (Okochi 1989). Recipients of HTLV-I-infected concentrates may develop HAM (Gout et al. 1990; Araujo and Hall 2004). It has been estimated that 2–8% of subjects infected with HTLV-I by blood transfusion will even- tually develop HAM (Murphy et al. 1997; Araujo and Hall 2004). ATL developed in two immunosuppressed patients who had received multiple transfusions 6 and 11 years earlier (Chen et al. 1989). HTLV-II has also been transmitted by blood transfusion (Hjelle et al. 1990b). Screening tests for human T-cell leukaemia virus antibodies For the detection of HTLV antibodies, ELISAs are used as well as gelatin particle assays. In the ELISAs for the detection of anti-HTLV-I, viral lysate has been used. Although there is considerable (65%) crossreactivity CHAPTER 16 726 between HTLV-I and -II, the sensitivity of anti-HTLV- I assays for detecting anti-HTLV-II was found to be only 55–91% (Wiktor et al. 1991; Cossen et al. 1992). As infection with HTLV-II is probably associated with HAM and as many HTLV-positive donors (more than 50% in the USA) are HTLV-II positive, tests designed to detect both antibodies are now used (US Food and Drug Administration 1998). In these ELISAs, recombinant proteins, including HTLV-I and -II-specific ones, have been added to lysate or are used exclusively (Hartley et al. 1991). The sensitivity of such assays has been claimed to be 100% (Vrielink et al. 1996a). In Japan, an agglutination test in which gelatin particles are coated with HTLV-I-antigens has been developed and used extensively. The sensitivity of the commercially available agglutination test Serodia HTLV-I has been claimed to be 100% for detecting anti-HTLV-I; all of 12 anti-HTLV-II-containing sera gave positive reactions (Vrielink et al. 1996a). An ELISA for the combined detection of anti-HIV-1 and -2 and anti-HTLV-I and -II in which synthetic peptides of all four viruses are used, has been developed (McAlpine et al. 1992). In a study 242 samples from anti-HIV-1/-2 or HTLV-I/-II panels, two HTLV- II-positive samples and two very weak anti-HIV-1- positive samples were negative. The specificity of the test was slightly less than that of specific assays (Flanagan et al. 1995). Despite the improved specificity of anti-HTLV-I/-II screening tests, many repeatedly positive reactions that cannot be confirmed are still found and all repeatedly reactive samples must therefore be tested in confirmatory assays. Human T-cell leukaemia virus confirmatory assays Confirmatory testing for HTLV-I/-II continues to be challenging, primarily because of a dearth of licensed reagents. Western blot and radioimmunoprecipitation assays (RIPAs) are used (Anderson et al. 1989; Hartley et al. 1990). For a positive reaction, antibody reactivity with both a gag (p19 and/or p24) and an env protein (gp46 and/or gp68) are required (WHO 1990). All other reaction patterns were considered to be indeterminate. As the sensitivity of the Western blot in detecting antibodies against env proteins was low, many indeterminate results had to be checked in RIPA, a much more elaborate assay (Lillehoj et al. 1990; Lal et al. 1992). A report on the transmission of HTLV-I by blood from a donor with an indeterminate pattern in the WB and RIPA (p19 and gp68 reactivity) to four out of six recipients, confirmed by PCR, demonstrated the insufficient sensitivity of these original confirmation assays (Donegan et al. 1992). A modified WB has been developed in which both shared (r21e) and specific (rgp46 I and rgp46 II ) HTLV-I and -II recombinant env proteins are used (Lillehoj et al. 1990; Lal et al. 1992). For a positive reaction in this modified Western blot, a reaction with at least one gag protein (p19 and/or p24) and with env r21e as well as rgp46 I or rgp46 II is required. All other patterns are indeterminate. This Western blot, in which a reaction with HTLV-I or -II can be distinguished, has been found to be more sensitive and specific than the original Western blot. Instead of 66, only two positive samples required confirmation by RIPA and none of 158 indeterminate samples (original Western blot) reacted (Brodine et al. 1993). A recombinant immunoblot assay (RIBA) in which the same antigens are applied gave similar results (Vrielink et al. 1996b). NAT has not been licensed for confirmatory testing. Cytomegalovirus Characteristics of the virus and of cytomegalovirus infection Cytomegalovirus (CMV) is a large, enveloped, double- stranded DNA, beta herpes virus that is cell associated, but may also be found free in plasma and other body fluids (Drew et al. 2003). CMV has a direct cytopathic effect on infected cells. The result may lead to neu- tropenia, some depression of cellular immunity and inversion of T-cell subset ratios, with a consequent increase in susceptibility to bacterial, fungal and protozoa infections in immunosuppressed patients (Grumet 1984; Landolfo et al. 2003). CMV infection causes parenchymal damage, such as retinitis, pneu- monitis, gastroenteritis and encephalitis, and can result in substantial morbidity and mortality. CMV can cause primary acute clinical and subclinical infections. Chronic subclinical infections may occur in which the virus is shed in saliva and urine. CMV remains latent in a large proportion of infected subjects. The presence of anti-CMV does not guarantee immunity. As with HIV and HCV infection, specific antibody is a marker of potential infectivity although INFECTIOUS AGENTS TRANSMITTED BY TRANSFUSION 727 only in the case of CMV, a relatively small proportion of seropositive subjects seem to be infectious (Drew et al. 2003). CMV antibody-positive subjects may infect others through sexual contact, breast-feeding, transplacental transmission or transfusion (Tegtmeier 1986). In subjects with antibody, CMV infection may be reactivated, or the subject may become re-infected with exogenous strains of CMV. Primary CMV infection is generally more severe than is re-infection (co-infection with a different strain) or reactivation. In view of the difficulty of distinguish- ing between reactivation and re-infection, the term recurrent infection has been coined to embrace both. However, when necessary to distinguish between the two, donor viral DNA can be distinguished from recipient viral DNA by restriction enzyme analysis (Glazer et al. 1979; Chou 1990). In practice, the diagnosis of recurrent infection is limited to demonstrating a four- fold increase in antibody titre or the presence of IgM anti-CMV. In immunosuppressed patients, serological tests cannot be relied upon for a diagnosis of CMV partly because the patients may not make antibody and partly because any anti-CMV detected may have been derived from transfused blood. Viral culture is impractical because the virus grows slowly in vitro. On the other hand, immunofluorescence techniques to detect viral antigen using monoclonal antibodies on biopsies or bronchial washings provide results within hours (Griffiths 1984). Prevalence of anti-CMV The frequency of subjects with anti-CMV varies widely in different populations. Seroprevalence is lower (30–80%) in developed than in developing countries, where the figure may reach 100% (Krech 1973; Preiksaitis 1991). The prevalence of anti-CMV corre- lates with age and socioeconomic status (Lamberson 1985; Tegtmeier 1986). The frequency of anti-CMV- positive donors may vary widely within a given coun- try, for example 25% in southern California and 70% in Nashville, Tennessee (Grumet 1984; Tegtmeier 1986). Transmission of cytomegalovirus by transfusion The transmission of CMV by blood transfusion was first reported in the 1960s (Kaariainen et al. 1966; Paloheimo et al. 1968; Klemola et al. 1969). CMV is now known as one of the infectious agents most frequently transmitted by transfusion. The pathogenesis of transfusion-transmitted CMV infection is not clearly understood. In most cases CMV appears to be transmitted in a latent, particulate state only by cellular blood components, and the virus reactivates from donor leucocytes after transfusion. Host as well as donor factors are involved in CMV infection (Tegtmeier 1989; Preiksaitis 1991). CMV has been isolated from the mononuclear and polymorpho- nuclear cells of patients with acute infections. The specific cell type responsible for carrying the virus has not been identified, although mononuclear cells are the favourite candidates as hosts of CMV in latent infection. Fresh blood appears more likely than stored blood to transmit CMV infection, although no con- trolled studies document this impression (Tegtmeier 1986). Some 3–12% of units have the potential to transmit CMV (Adler 1984), although most authors have reported a carrier rate of 1% or less (Tegtmeier 1986; Drew et al. 2003). The discrepancy may be related to the frequency of donor testing and the sensitivity and specificity of the assay used. Primary infection rates depend on the number of transfusions, age of blood, time of year and immunocompetence of the recipient (Tegtmeier 1989; Preiksaitis et al. 1988; Preiksaitis 2000). Donors with IgM anti-CMV appear to be more likely than others to transmit CMV (Lamberson et al. 1984). One large study found that only 0.5% of antibody-positive donors have detectable CMV DNA in their leucocytes (Roback et al. 2003). At present, no rapid, easy way to identify infectious subjects exists. Viral excretion in urine is a good index of infectivity, but blood donors would probably rebel at this screening strategy. Virus can also be cultured from saliva, and PCR-based assays are available for the detection of viral genome in peripheral blood. Detection of pp65 antigen in leucocytes (pp65 antigenaemia) is considered the ‘gold standard’ among diagnostic tools for diagnosing CMV infection and initiating antiviral therapy. Both CMV DNA and immediate early-messenger RNA detection have been compared with pp65 antigenaemia, but none of them showed advantages in terms of earlier diagnosis and better prognosis. PCR’s major advantage is its semi- automation compared with the immunofluorescence employed for pp65 antigenaemia. Isolation of CMV by culture is reliable for the diagnosis of active CHAPTER 16 728 infection, but is less sensitive and requires more time for viral detection. Transfusion-transmitted cytomegalovirus infection in immunocompetent subjects Before the era of universal (or near universal) leuco- reduction, some 30% of anti-CMV-negative recipients undergoing cardiac surgery involving transfusion developed infection, as confirmed by virus isolation or the development of anti-CMV. In addition, some anti- CMV-positive patients developed recurrent infection. In almost all cases, the infection is asymptomatic. Of patients who develop a primary or recurrent CMV infection following transfusion, fewer than 10% develop a mononucleosis-like syndrome. This syndrome, originally termed the post-perfusion syndrome, but now referred to as the post-transfusion syndrome, appears 3–6 weeks after transfusion. Common fea- tures include fever, exanthema, hepatosplenomegaly, enlargement of lymph nodes and the presence in peripheral blood of atypical lymphocytes resembling those found in infectious mononucleosis (Foster 1966). Recovery is usually complete. The development of atypical lymphocytes due to post-transfusion CMV infection should be distinguished from the development of atypical lymphocytes 1 week after transfusion as a response to allogeneic lymphocytes. Consequences of transfusion in patients with impaired immunity During the past decade, major advances have been achieved regarding the management of CMV infection through thedevelopment of new diagnostictechniques for the detection of the virus and through the perform- ance of prospective clinical trials of antiviral agents (Meijer et al. 2003). Nevertheless, in immunosuppressed patients, or in fetuses and premature infants with an immature immune system, CMV infections, particularly primary infections, still cause severe disease that can be fatal. 1 The fetus in utero. Following maternal primary CMV infection, the fetus becomes infected in 30–40% of cases. Approximately 5–10% of infected infants develop sequelae such as mental retardation, hearing loss or chorioretinitis (Stagno et al. 1986). 2 Premature infants. The risk of serious CMV infection is high when the infant’s birthweight is less than about 1300 g and when the mother is anti-CMV negative. In two large prospective studies, 25–30% of infants with these risk factors, transfused with a total of 50 ml or more of blood, some of which was anti- CMV positive, acquired CMV infection, and 25% of these infants died. Infants transfused with anti-CMV- negative blood did not develop CMV infection (0 out of 90) (Yeager et al. 1981; Adler et al. 1983). A lower incidence of CMV infection (7–9%) has been reported from two other centres: in infants weighing less than 1500 g born to anti-CMV-negative mothers and transfused with blood, some of which was anti-CMV positive (Smith et al. 1984; Tegtmeier 1984). All reports agree that clinically significant CMV infection in newborn infants develops only when the infant is premature and of low birthweight, when the mother lacks anti-CMV and when anti-CMV-positive blood is transfused (Tegtmeier 1986). 3 Bone marrow transplant recipients frequently develop primary or recurrent CMV infections that may prove fatal (Tegtmeier 1986). Blood transfusion represents the main risk factor for CMV acquisition in CMV-negative patients receiving bone marrow from a CMV-negative donor. In a prospective randomized trial of 97 anti-CMV-negative patients, 57 received anti-CMV-negative marrow: 32 out of the 57 received anti-CMV-negative blood components and only one of these developed a CMV infection; of the 25 who received blood components unscreened for anti-CMV, eight developed CMV infection. Among the 40 recipients of anti-CMV-positive bone marrow, the rate of CMV infection was no lower in those who received only anti-CMV-negative blood components (Bowden et al. 1986). Granulocyte concentrates, which contain large numbers of leucocytes that can harbour CMV, reportedly carry the greatest risk of transmitting CMV infection (Winston et al. 1980; Hersman et al. 1982). However, when only two prophylactic transfusions were given, the risk appeared to be no higher in those who received granulocytes than in those who did not (Vij et al. 2003). 4 Renal transplant recipients are at high risk of primary or recurrent CMV infection; the main source of infection lies in the transplanted kidney (Tegtmeier 1986). In anti-CMV-negative recipients of a kidney from an anti-CMV-negative donor, blood transfusion plays a significant role in CMV transmission (Rubin et al. 1985). 5 Heart and heart–lung transplant recipients may INFECTIOUS AGENTS TRANSMITTED BY TRANSFUSION 729 [...]... al ( 198 4) Intrauterine parvovirus infection in pregnancy and hydrops fetalis Lancet ii: 1033–1034 Bruce-Chwatt LJ ( 197 2) Blood transfusion and tropical disease Trop Dis Bull 69: 825 754 Bruce-Chwatt LJ ( 197 4) Transfusion malaria Bull WHO 50: 337 Bruce-Chwatt LJ ( 198 2) Transfusion malaria revisited Trop Dis Bull 79: 827–840 Bruce-Chwatt LJ ( 198 5) Transfusion associated parasitic infections In: Infection,... et al 198 3) Alternatively viral DNA can be detected by PCR (Salimans et al 198 9; McOmish et al 199 3) HPV B 19 has been detected by PCR in solvent–detergent-treated clotting factor concentrates (Lefrere et al 199 4), in heat-treated factor VIII and IX concentrates and in IVIG (McOmish et al 199 3; Santagostino et al 199 4) and in clotting factor concentrates prepared by different purification and inactivation... Busch MP, Korelitz SH, Kleinman SR et al ( 199 5) Declining value of alanine aminotransferase in screening of blood donors to prevent posttransfusion hepatitis B and C virus infection Transfusion 35: 90 3 91 0 Busch MP, Kleinman SH, Jackson B et al (2000) Committee report Nucleic acid amplification testing of blood donors for transfusion- transmitted infectious diseases: Report of the Interorganizational Task... cases in the following 4 years (Westphal 199 1b) In Canada, only three cases of transfusion- transmitted malaria were reported between 199 4 and 199 9, a rate of 0.67 cases per million donations (Slinger et al 2001) The rate of transfusiontransmitted malaria in the USA since 199 2 has fluctuated from 0.18 to 0.6 per million units transfused (Mungai et al 2001) In many malarious areas where reporting is inefficient,... instituted by the USA Department of Defense in 199 1 and again in 2003 for service personnel stationed in endemic areas in Iraq Deferral for diagnosed infection is indefinite Cases of possible transmission of kala-azar by transfusion in India, China, Brazil and four European countries have been reported (Chung et al 194 8; Cummins et al 199 5; Singh et al 199 6) Subjects with a history of visceral leishmaniasis... References Aach RD, Stevens CE, Hollinger FB et al ( 199 1) Hepatitis C virus infection in post -transfusion hepatitis An analysis with first- and second-generation assays N Engl J Med 325: 1325–13 29 Ablashi DV, Salahuddin SZ, Josephs SF et al ( 198 7) HBLV (or HHV-6) in human cell lines (Letter) Nature (Lond) 3 29: 207 Adler SP ( 198 4) International forum: Transfusion transmitted CMV infections Vox Sang 46: 387–414... donations indicate that the probability of recording a case of vCJD in this population in the absence of transfusion- transmitted infection ranges between about 1 in 15 000 and 1 in 30 000 (Llewelyn et al 2004) A case of preclinical vCJD has been reported in a patient who died from a non-neurological disorder 5 years after receiving a blood transfusion from a donor who subsequently developed vCJD: In 199 9,... cepacia, septicaemia or wound infection developed several days or weeks after transfusion 742 (Goldman and Blajchman 199 1) However, atypical presentations have been well documented in prospective studies and suggest that clinical syndromes are under-reported (Yomtovian et al 199 3) Investigations following the suspected transfusion of injected blood Any blood remaining in the container should be cultured... infection through blood transfusion Indian J Pathol Microbiol 46: 367–370 Christiansen CB, Jessen TE, Nielsen C et al ( 199 6) False negative anti-HIV-1/HIV-2 ELISAs in acute HIV-2 infection Vox Sang 70: 144–147 Chung H-L, Chow H-K, Lu J-P ( 194 8) The first two cases of transfusion kala-azar Chinese Med J 66: 325–326 Clark J, Saxinger C, Gibbs WN ( 198 5) Seroepidemiologic studies of human T-cell leukemia/lymphoma... (Gerber et al 196 9) Post -transfusion infectious mononucleosis is seen only rarely in anti-EBV-negative immunocompetent patients and usually occurs when only a single unit of blood or blood component, obtained from the donor during the incubation phase is given within 4 days of collection When more than 1 unit is transfused, one 731 CHAPTER 16 of the units is almost certain to contain anti-EBV In the reported . one in 6250 in the USA (CDC 199 0), about one in 30 000 in France (Pillonel et al. 199 6), one in 45 000 in the Netherlands (Zaaijer et al. 199 4) and one in 20 000 in London (Brennan 199 2). HTLV-II,. Screening with anti-HIV-1 in 198 5 reduced the risk to about 1 in 40 000 units (Busch et al. 199 1a). Routine screening tests for HIV in blood donors In most countries, screening tests for anti-HIV. anti-HIV-1 and -2 and anti-HTLV-I and -II in which synthetic peptides of all four viruses are used, has been developed (McAlpine et al. 199 2). In a study 242 samples from anti-HIV-1 /-2 or HTLV-I/-II

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