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Current Opinion in Hematology:
Transfusion medicine

Risks of transfusion-transmitted infections: 2003

Pomper, Gregory J.a; Wu, YanYunb; Snyder, Edward L.b

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aDepartment of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, and bDepartment of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut, USA

Correspondence to Edward L. Snyder, Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06510, USA

Tel: 203-688-2441; fax: 203-688-2748; e-mail: edward.snyder@yale.edu

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Abstract

Purpose of review: While the risks of transfusion-transmitted human immunodeficiency virus, hepatitis C virus, and human T-cell leukemia virus I/II continue to decrease, additional threats to transfusion safety are posed by emerging “new” infectious diseases.

Recent findings: Following the introduction of nucleic acid testing for human immunodeficiency virus and hepatitis C virus, the American Red Cross estimates the risk of transfusion-transmitted human immunodeficiency virus to be 1:1,215,000 (per unit transfused) and 1:1,935,000 for transfusion-transmitted hepatitis C virus. Hepatitis B virus nucleic acid testing has not been implemented, and the risk of transfusion-transmitted hepatitis B virus in the United States remains relatively high at an estimated 1:205,000. The risk of transfusion-transmitted human T-cell leukemia virus I/II is 1:2,993,000, based on Red Cross estimates. Nucleic acid testing for West Nile virus began in the United States in 2003 under an investigational new drug program. No approved laboratory tests are available to screen the blood for Chagas disease, malaria, severe acute respiratory syndrome, or variant Creutzfeldt-Jakob disease.

Summary: Prevention of these potential transfusion-transmitted infections is addressed by deferring potential donors whose personal behaviors or travel histories place them at risk.

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Introduction

Abbreviations:CMV Cytomegalovirus, FDA Food and Drug Administration, HBV hepatitis B virus, HCV hepatitis C virus, HHV human herpes virus, HIV human immunodeficiency virus, HTLV human T-cell leukemia virus, NAT nucleic acid testing, SARS severe acute respiratory syndrome, TT transfusion-transmitted, WNV West Nile virus

As the number of newly recognized transfusion-transmitted (TT) infectious diseases increases, blood services have expanded donor deferral practices and improved methods for detecting infectious agents in donated blood [1]. The following review summarizes certain recent advances in transfusion safety and alerts readers to issues of transfusion safety posed by the increasing number of emerging “new” infections.

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Human immunodeficiency virus 1/2

The public's fear and awareness of the potential for HIV transmission through blood transfusion, evidenced during the AIDS epidemic in the 1980s, has been a major driving force for improvement of blood safety. The risk of HIV transmission through blood products has decreased dramatically, owing to more stringent donor history screening as well as continuous improvement of donor testing, including tests for anti-HIV1/2 and HIV p24 antigen. Albeit rare, cases of transfusion-transmitted (TT) human immunodeficiency virus (HIV) continue to be reported due to the existence of window periods. A window period for any TT agent is defined as the period of time that a donor is potentially infectious but still displays negative serological test results. With newly developed polymerase chain reaction (PCR) –based nucleic acid testing (NAT), further risk reduction has been achieved. According to a recent publication by Dodd et al. based on data from the American Red Cross, the estimated risk of TT-HIV is now 1:2,135,000 (per unit transfused) with a window period of 11 days after implementation of NAT. This risk is compared with an estimated risk of TT-HIV of 1:1,468,000 with a window period of 16 days using p24 antigen testing, but without NAT [2••]. Currently, NAT is assayed either as a mini-pool (about 14–16 donors per pool) NAT (MPNAT), already in wide use by many blood centers, or as single-donor NAT (SDNAT). SDNAT has a detection sensitivity of less than 50 copies/mL and is associated with higher cost. Even though cost-effective analysis does not favor the replacement of p24 antigen testing by NAT [3•], many blood centers, including the American Red Cross, have implemented NAT and discontinued p24 antigen testing, following the Food and Drug Administration's (FDA) licensure of an HIV-NAT assay.

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Hepatitis C virus

In 1990, after research finally linked the hepatitis C virus (HCV) to most of the cases of what was then called non-A, non-B hepatitis, donor testing with anti-HCV was implemented. This resulted in significant reduction in the incidence of TT-HCV. However, because of the slower doubling time of HCV, the window period was about 70 days, and the residual TT-HCV risk was 1:276,000 [2••]. With newly developed PCR-based NAT (NAT/MPNAT/SDNAT), the window period has been reduced to 10 days. In addition, the TT-HCV risk is now estimated to be 1:1,935,000 [2••]. The FDA has recently licensed a test coupling HCV-NAT with HIV-NAT, which has been adopted by many blood centers, including the American Red Cross. A less efficient assay for HCV tests for the HCV core antigen. It is less sensitive than HCV-NAT and may have up to an additional 2- to 5-day delay in detection of HCV compared with HCV-MPNAT or HCV-SDNAT. The level of HCV core antigen can fluctuate during the initial infection, thus making HCV-NAT testing a more desirable choice for blood donor screening [4•].

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Hepatitis B virus

Currently in the United States, prevention of TT-HBV relies on donor testing for HBsAg, anti-HBc, as well as donor history screening. The most recent report estimated that the risk of TT-HBV is 1:205,000 with an estimated window period of 59 days [2••]. NAT testing for HBV has been developed but has not been implemented for donor testing in the United States or Europe. A recent publication, Biswas et al. reported that the window period can be reduced by 25 to 36 days using SDNAT, reduced by 9 to 11 days using MPNAT, and reduced by 2 to 9 days using a new and more sensitive HBsAg assay [5•].

An additional challenge in TT-HBV detection relates to the transient nature of HBsAg. A common finding of a positive anti-HBc, but negative HBsAg, makes it difficult to interpret the likelihood of donor infectivity and to decide on donor reentry. Roth et al. recently reported that by using NAT with a sensitivity of 1000 copies/mL they found six HBV-NAT–positive donors who were HbsAg negative among 3.6 million samples drawn between 1997 and 2000, and four of the six were anti-HBc-positive [6]. In line with this finding, data from the REDS study showed that 0.84% of 4,885,732 donations from 1991 to 1995 were anti-HBc-positive and negative for all other donor tests [7•]. Using a new and more sensitive anti-HBc assay to test the available 5121 repository specimens, they found only 65% were positive for the new anti-HBc test, implying a decreased false-positive rate. Among those, the specimens with negative or low-level anti-HBs were also tested by an HBV-NAT. They found four were HBV-NAT positive [7•]. There is still disagreement as to whether HBV-NAT will be cost effective to further reduce the risk of TT-HBV.

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Human T-cell leukemia virus I/II

Current donor testing for human T-cell leukemia virus (HTLV) is serologically based and designed to detect anti-HTLV I/II. According to the recent report from the American Red Cross, for reasons not clear at this time, the risk for TT-HTLV has decreased dramatically from 1:514,000 in 1998–1999 to 1:2,993,000 in 2000–2001 with the same 51-day window period [2••]. Even though it is still controversial, evidence exists that leukoreduction may decrease the incidence of TT-HTLV [8,9].

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Non B–Non C hepatitis

Currently, there are no donor tests for hepatitis other than hepatitis B and C. Hepatitis A and E do not have a chronic phase. Thus, infected donors may transmit the virus(es) through blood components only during the acute viremic phase. There are rare reports of posttransfusion hepatitis A, which has an estimated risk of as low as 1 in 1,000,000 components [10]. A study by Arankalle et al. reported possible HEV transmission by blood components in recipients from asymptomatic donors with positive HEV-NAT [11]. It is still not clear if HGV and TT virus, two newly identified viruses, cause TT disease [12].

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Parvovirus B19

Immunosuppressed patients, such as transplant recipients or persons with chronic hemolytic diseases such as sickle cell disease, are at particular risk for parvovirus B19 infection. Even though the prevalence of B19 viremia may be as high as 0.025% among donors, according to results of NAT testing [13,14], there have been only rare reports of B19 infection attributable to blood transfusion. As opposed to cellular blood components, B19 transmission is more commonly reported following the use of plasma-derived products, such as clotting factor concentrates in hemophilia patients [15]. Currently, there is no mandatory donor testing for B19, although many efforts are made to inactivate or remove B19 in plasma-derived products using nanofiltration or heat inactivation [16,17].

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Human herpes virus-8

Human herpes virus–8 (HHV-8) is associated with Kaposi sarcoma and multicentric Castleman disease. Although not clear, it is generally considered possible that HHV-8 can be transmitted by blood products. A recent French study showed that HHV-8 seroprevalence in volunteer blood donors is about 3.2% [18]. Analysis of seroprevalence among different groups, including patients who received multiple transfusions, showed that HHV-8 transmission appeared to be mainly through sexual routes, not blood transfusion. It is of interest to note, however, the high prevalence rates in multiply transfused sickle cell patients, in kidney transplant patients, but not in multiply transfused thalassemia patients. Again, questions remain as to whether the use of leukoreduced blood component is associated with reduced HHV-8 infection.

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Syphilis

Syphilis is caused by the Treponema pallidum spirochete. Transmission is possible through sexual contact with an infected individual as well as through transfusion of blood and components. Blood donor testing for syphilis was established in 1938 and has been required by federal regulation since 1958 [19•]. Serological assays include nontreponemal (VDRL, RPR, and ART) and treponemal assays (FTA-ABS, TPI, and TPHA). In 1990, the FDA cleared an automated treponemal-based test for T. pallidum. This resulted in significant increases in donor reactive rates and increased donor deferrals. This increase occurred because antibodies to T. pallidum remain detectable for a lifetime, while the prior assays used nontreponemal capture antigens, and these latter tests do not remain positive if the potential donor had been successfully treated. The FDA issued a final rule in December 2001 that contained a requirement to test blood donations for syphilis serology [20]. The FDA, despite concerns that testing is no longer productive, has retained a very conservative approach and issued a Draft Guidance for Industry containing revised recommendations for donor and product management based on screening tests for syphilis [19•]. Due to this governmental approach, even though no cases of TT syphilis have been reported since 1968 [19•], syphilis testing will remain a requirement for blood donor screening for the foreseeable future. A review of syphilis testing of blood donors was published several years ago, but is still relevant [21].

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Cytomegalovirus

Transmission of cytomegalovirus (CMV) by blood transfusion is well known. Since CMV is a major cause of post bone marrow transplantation mortality, prevention of CMV, rather than treatment alone, is a major goal. The main preventative approach has been serological testing for CMV. In 1995, Bowden et al. [22] published data that use of third-generation leukocyte-reduction filters prepared under current Good Manufacturing Practice guidelines containing <5 × 10E6 leukocytes/unit transfused could provide blood that was considered CMV safe. While controversy about this report still exists, due to the fact that all of the CMV infections occurred in the filter group (test group), general acceptance by the blood bank and transplant community was achieved [23]. However, some specialists still feel that CMV-seronegative allogeneic transplant recipients receiving a CMV-seronegative stem cell transplant should receive only CMV-seronegative blood components. This philosophy was supported by a recent paper by Nichols et al. [24•] that purported to show that CMV-seronegative blood components were superior to leukoreduced components (especially red blood cells) for prevention of TT-CMV. However, the study has been criticized for its “before vs after” design. A prospective randomization approach would likely be a better scheme. This latter approach would be less susceptible to coincident changes in CMV infectivity unrelated to transfusion. Of note, the authors of the Nichols et al. report have stated that despite their publication, they still use leukoreduced blood products as equivalent to CMV-seronegative products. In summary, most experts believe that leukoreduced components using 4–5 log leukoreduction filters under current Good Manufacturing Practice conditions are CMV safe and can be used in lieu of CMV seronegative blood components or if CMV-seronegative blood components are unavailable. Two related articles on the use of leukoreduced blood components and an editorial have recently been published and may be of interest to the reader [25–27].

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Malaria

There is no FDA-approved laboratory test to screen donated blood for malaria in the United States. TT malaria is prevented by exclusion of potentially infected donors. Blood donors are excluded at the time of donation based on a history of travel to endemic areas or symptoms of infection. Donor deferral based on a travel history to an endemic area appears to be an effective approach to the prevention of TT malaria. An average of 2 to 3 cases of TT malaria, or one case per 4,000,000 donated units, occurs annually in the United States [28].

Travelers who visit malaria-endemic areas are deferred for 1 year after return to the United States, and those who immigrate to the United States from malaria-endemic areas are deferred from blood donation for 3 years. Deferral criteria are based on statistics collected by the Centers for Disease Control [29]. Of US travelers to malaria-endemic regions, 97% will develop the disease within 1 year, whereas 99% of immigrants to the US from endemic areas will develop the disease within 3 years. Additionally, asymptomatic parasitemia may occur in immigrant populations from endemic areas for decades and may, in part, explain the continued low-grade incidence of TT malaria [30].

Patients who develop malaria in the United States are overwhelmingly likely to have acquired the parasite while visiting an endemic area. Similarly, TT malaria is usually traced to a donor who acquired the infection while outside the United States. A majority of these donors meet current deferral criteria and reveal the importance of obtaining accurate predonation information. As additional epidemiological information accrues, it is likely that malaria donation screening requirements will be modified to further improve the exclusion of plasmodium species from the blood supply.

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Chagas disease (American trypanosomiasis)

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi, and the parasite is transmitted by the Reduviidae family of insects. These “true bugs” ingest the parasite when taking a blood meal from an infected mammal and pass the infectious trypomastigotes in their feces. The infection is not transmitted by the bite, such as with malaria, but rather by contamination of the bite wound or mucus membrane with infectious organisms.

There is no approved laboratory test to screen donated blood for Chagas disease in the United States. Chagas disease in the United States is usually imported by a person infected while in an endemic area, and autochthonous transmission has only been reported in five cases [31]. Transmission has been reported through organ transplantation in which the organ donor was an emigrant from Central America [32].

Those who immigrate to the United States from endemic areas may be chronic, asymptomatic carriers of the parasite, and reports of the disease are likely to increase in this country. In Los Angeles, the seroprevalence of blood donors was 1:7500, based on a history of residence in an endemic area and a positive test result for T. cruzi antibody [33]. Despite the rates reported in the study, investigations of recipients of the blood revealed no seroconversions.

Infection with T. cruzi causes an acute illness in 1% of cases but may be more pronounced or even fatal in immunocompromised recipients. Acute infections have nonspecific symptoms. Once the acute phase has passed, most individuals enter a chronic phase of intermittent parasitemia, and after decades with the infection, clinical Chagas disease manifestations such as the megasyndromes (cardiomegaly, megacolon, megaesophagus) can appear. Some early infections need sensitive PCR testing for diagnosis, especially in immunocompromised recipients in whom antibody titers may not increase significantly. The disease should be considered and tested for in selected patients experiencing an acute illness a few days following a blood transfusion. Medications are available to treat an acute infection, but there are no medications or immunizations available to prevent or treat chronic parasitemia. In endemic regions, parasite reduction has been performed on donated blood using gentian violet or other chemicals; however, exposure to these agents poses additional risks [34].

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Babesiosis

A review of recent journal articles pertaining to TT babesiosis and other tick-born diseases appears elsewhere in this issue.

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Transmissible spongiform encephalopathies

In 1996, variant Creutzfeldt-Jacob disease (vCJD) was recognized as an emerging epidemic in the United Kingdom. vCJD is caused by a prion linked to bovine spongiform encephalopathy and has been traced to the outbreak of bovine spongiform encephalopathy in the United Kingdom that peaked at almost 1000 new bovine cases per week in 1993. In contrast to classic CJD, vCJD presents in younger patients with a median age at death of 28 years compared with 68 years for classic CJD. The incubation period for vCJD is estimated to be greater than a decade. vCJD has been shown to reside in the human lymphatic system, a property not described in classic CJD.

There has not been a reported human case of TT vCJD, but there have been reports of prion disease transmission via blood in animal models [35]. Whether vCJD can be transmitted through blood transfusion in humans remains unknown. To protect the blood supply from theoretical contamination, the US government and other blood regulatory agencies have responded to the possible risk by instituting more stringent donor screening criteria. In the United States, blood donors are now deferred if they have spent more than 3 months in the United Kingdom between 1980 and 1996, are affiliated with the United States military and have spent more than 6 months in Northern European countries between these years, have lived more than 5 years cumulatively in Europe, or have received a blood transfusion while in the United Kingdom. Additional deferral criteria include persons who have been exposed to medications produced from bovine sources such as insulin or other hormones, are related to a person who has contracted CJD, or have received a dura mater tissue graft.

Classic CJD has been a concern for blood collection agencies for many years despite the absence of any reported case of transfusion transmission. Classic CJD generally presents as sporadic cases without a known cause that are presumed to be the result of spontaneous prion generation, as familial disease with known mutations, or as iatrogenic disease. Classic CJD has been iatrogenically transmitted via dura mater, pituitary hormone, corneal transplantation, or the use of contaminated neurosurgical instruments [36].

The study of this rare disease poses difficulty in the accumulation of epidemiological data, and intense public pressures have assisted in the creation of collaborative research efforts that maximize the information gained from each case. The National CJD Surveillance Unit in the United Kingdom has compiled data from virtually every case of CJD in the United Kingdom. Fortunately, current information and research have not demonstrated transfusion transmissibility in humans, and the risk remains only theoretical.

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West Nile virus

The blood collection community has responded to the 2003 seasonal increase in West Nile virus (WNV) infections by introducing NAT for the viral genome. Although the testing is being performed only regionally and under investigational new drug restrictions, some positive test results have already been reported in volunteer blood donors [37]. Because WNV is so widespread in distribution, it is likely that formal FDA approval of test methods will occur in the near future.

WNV is a seasonal infection transmitted by mosquitoes, and the disease first emerged in the United States in 1999. During the first year of the outbreak, 62 cases were reported, and the number steadily increased to 4156 reported cases, including 284 deaths, in 2002. As the virus spread across the continental United States, human cases of WNV have been reported in every state except Oregon, Nevada, Utah, Arizona, Hawaii, and Alaska. Furthermore, data from blood donor samples collected during 2002 have shown that the virus may be present in as many as 1:1000 donors in endemic areas. Some European communities have responded to the WNV epidemic in the United States by deferring for 1 month any donor who has traveled to North America.

WNV is a flavivirus and is endemic among avian species (>100 species identified), but it has also been found in common animals such as cats, horses, squirrels, and rabbits. Although the virus is not spread by human-to-human contact, the mosquito vector and numerous available host species suggest that the virus will continue to spread and remain a risk to the blood supply. Transmission by transfusion and by organ transplantation is known to occur [38•].

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Severe acute respiratory syndrome

In contrast to WNV, the severe acute respiratory syndrome (SARS) virus is spread by close person-to-person contact, and it is believed to be caused by a virus similar to the coronavirus that causes the common cold. The virus can be aerosolized, and respiratory mucosal secretions facilitate disease spread through direct contact with the patient or through contact with contaminated clothing or other objects. SARS first appeared in Guangdong province of China in November 2002, and the World Health Organization began receiving reports and monitoring the outbreak by February 2003. SARS spread to family members and healthcare workers in contact with affected patients. Spread to other countries was linked to airline travel, often by healthcare workers who had recently been in contact with SARS patients.

SARS is thought to be caused by a new coronavirus and/or possibly a paramyxovirus cofactor. Coronaviruses are known for their frequent rate of mutation, and both coronaviruses and paramyxoviruses are composed of lipid-enveloped, single-stranded RNA. The pathogenesis of SARS remains unclear at this time.

It is unknown whether SARS can be transmitted through blood, but the SARS virus has been isolated from the blood of an infected individual. Given the contagious nature of the virus, TT SARS could occur if blood was collected during a viremic phase of the infection. To address this potential risk, the FDA issued a guidance for blood collection facilities recommending deferral of at-risk donors [39]. Blood donors are deferred for at least 14 days after a possible exposure to SARS, and in cases of suspected SARS, donors are deferred for at least 28 days after symptom resolution and completion of therapy. Furthermore, donors are deferred for a history of travel to or residence in a SARS-affected community.

The SARS epidemic has been reportedly contained through classic quarantine and isolation approaches. As the medical community learns more about the virus and disease, blood donation requirements and product testing will invariably be modified in accordance with the new information.

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Orthopoxviruses (smallpox, vaccinia, and monkeypox)

Smallpox has been described in human populations since antiquity, but the last reported naturally occurring case was described in 1977 in Somalia. Since that time, smallpox has not recurred in human populations. But recently, concern over the purposeful reintroduction of the disease as an agent of bioterrorism has increased public awareness of the disease. There have been no reported cases of human transfusion transmission of any orthopoxvirus, and there are currently no FDA-approved laboratory tests to screen donated blood for orthopoxviruses in the US.

Smallpox is caused by the variola virus and is transmitted by direct contact with infected bodily fluids, contaminated objects such as clothing or bedding, or more rarely, aerosolization. Before the characteristic rash appears, there is a 1- to 2-week, noninfectious incubation period followed by several days of prodromal fever and malaise. The patient is infectious at the onset of prodromal symptoms until the rash has formed scabs and until the scabs have spontaneously detached, and, during this time, transfusion transmission is hypothesized. Because smallpox research has occurred primarily in the relatively distant past, accurate data regarding viremia using modern viral detection methods is limited, although new research is ongoing.

In addition, people who receive a smallpox vaccine, which uses the vaccinia virus, may also transmit this poxvirus to others during specific time periods. The vaccine is administered as a live virus percutaneous inoculum to the skin. A pustule and scab form at the vaccine site, and the virus may be transmitted through contact with the vaccine site until the scab detaches. Vaccinia viremia has been described in the older literature in both primary infected individuals and smallpox vaccine recipients [40,41]. The current understanding of smallpox, vaccinia, and the smallpox vaccine has been integrated into a new government regulatory guidance regarding blood donor deferral [42]. Recipients of a smallpox vaccine or persons forming any pustules after contact with a vaccine recipient are deferred for at least 3 weeks after vaccination or longer, until the vaccine scab separates spontaneously. Furthermore, any vaccine recipient or person in contact with a vaccine recipient is deferred for 2 to 3 months if any complications from the vaccine or exposure have occurred. Since the route of infection can influence the severity [41], it is possible that vaccinia infection transmitted intravenously would result in a different or more severe infection than when acquired percutaneously, and moreover, the infection would likely be more severe in the immunocompromised or critical patient.

Human monkeypox is a zoonotic smallpox-like disease caused by an orthopoxvirus in which human transmissibility is too low to sustain the spread in susceptible populations. In the United States, there have been no reported deaths due to monkeypox virus, but the fatality rate has been reported as high as 10% in Africa. However, the higher African fatality rate may in part reflect fewer healthcare resources available in the affected areas. Several mammalian species may serve as a reservoir for the infection, and the recent outbreak in the United States has been attributed to housing imported African squirrels, rats, and mice with prairie dogs. The outbreak was limited to persons coming in close contact with the infected animals and was also limited by the naturally lower transmissibility of this orthopoxvirus. There have been no specific blood donor deferral recommendations due to monkeypox, but since the smallpox vaccine has been employed to protect those with occupational or other risk, the vaccine recommendations apply to those individuals, too. Blood donors who are potentially at risk are screened through the general health questions about feeling well and temperature measurements taken at the time of donation.

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Chlamydia pneumoniae

Chlamydia pneumoniae infection has been associated with abdominal aortic aneurysm and ischemic heart disease and has been detected in atheromatous vascular tissue. C. pneumoniae is a common cause of atypical respiratory infections, but asymptomatic infections also occur. There are seasonal and geographic variations in the infectious outbreaks of C. pneumoniae, and clusters of infections can be periodic with several years between epidemics. The microbe circulates in peripheral blood mononuclear cells, and these cells have been postulated as one mechanism of systemic transportation of the microbe from infected pulmonary sites.

More recent studies have examined the presence of the pathogen in blood donors and the possibility of transfusion transmitted infection. In one study, evidence of the microbe was detected either by PCR or fluorescence microscopy in 9% of healthy blood donors in the United States [43]. This study also suggested a broad seasonal variation in the infection with as many as 28% of donors testing positive during some months. Additionally, one Scandinavian study reported 46% of healthy donors testing positive for the microbe. However, clear evidence of TT infection has not yet been described [44], although transmission appears likely based on the gathering evidence. Clinical investigations of transfusion transmission may be limited by the numerous variations in the infectious outbreaks that would require higher numbers of study subjects during implicated seasons. Furthermore, as the microbe resides within mononuclear cells, leukoreduction of blood products may decrease the levels of the pathogen below infectious levels.

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References and recommended reading

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Papers of particular interest, published within the annual period review, have been highlighted as:

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• Of special interest

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•• Of outstanding interest

1. Code of Federal Regulations: Additional standards for human blood and blood products—suitability of donor. Title 21 CFR, 640.3.

2.•• Dodd RY, Notari EP, Stramer SL: Current prevalence and incidence of infectious disease markers and estimated window-period risk in the American Red Cross blood donor population. Transfusion 2002, 42:975–979. Comprehensive analysis of a consolidated database on blood donations between 1995 and 2001 from the American Red Cross presented current information on estimated risks and window periods for TTD, including HIV, HBV, HCV, HTLV, with comparison of pre- and post-NAT testing.

3.• Jackson BR, Busch MP, Stramer SL, et al.: The cost-effectiveness of NAT for HIV, HCV, and HBV in whole-blood donations. Transfusion 2003, 43:721–729. Cost-effective analysis of NAT testing for HIV, HCV, and HBV using Markov decision model with updated disease incidence information from 2001 American Red Cross donation data and with window period data from REDS.

4.• Nubling CM, Unger G, Chudy M, et al.: Sensitivity of HCV core antigen and HCV RNA detection in the early infection phase. Transfusion 2002, 42:1037–1045. Comparison of new HCV core antigen testing and HCV NAT in terms of sensitivity and their effects on window periods.

5. Biswas R, Tabor E, Hsia CC, et al.: Comparative sensitivity of HBV NATs and HBsAg) assays for detection of acute HBV infection. Transfusion 2003, 43:788–798. Comparison of HBsAg antigen testing and HBV NAT in terms of sensitivity and their effects on window periods.

6. Roth WK, Weber M, Petersen D, et al.: NAT for HBV and anti-HBc testing increase blood safety. Transfusion 2002, 42:869–875.

7.• Kleinman SH, Kuhns MC, Todd DS, et al.: Frequency of HBV DNA detection in US blood donors testing positive for the presence of anti-HBc: implications for transfusion transmission and donor screening. Transfusion (Paris) 2003, 43:696–704. Comparison of new anti-HBc testing and HBV NAT in terms of sensitivity and their effects on window periods.

8. Pennington J, Taylor GP, Sutherland J, et al.: Persistence of HTLV-I in blood components after leukocyte depletion. Blood 2002, 100:677–681.

9. Wenz B, Ortolano GA: Leukocyte reduction and HTLV-I: is the glass half empty or half full? Blood 2003, 101:370.

10. Dodd R: Adverse consequences of blood transfusion: quantitative risk estimates. In Blood Supply Risks, Perceptions and Prospects for the Future. Edited by Nance SJ. Bethesda: American Association of Blood Banks; 1994:1–24.

11. Arankalle VA, Chobe LP: Retrospective analysis of blood transfusion recipients: evidence for post-transfusion hepatitis E. Vox Sang 2000, 79:72–74.

12. Allain JP, Thomas I, Sauleda S: Nucleic acid testing for emerging viral infections. Transfus Med 2002, 12:275–283.

13. Hitzler WE, Runkel S: Prevalence of human parvovirus B19 in blood donors as determined by a haemagglutination assay and verified by the polymerase chain reaction. Vox Sang 2002, 82:18–23.

14. Koenigbauer UF, Eastlund T, Day JW: Clinical illness due to parvovirus B19 infection after infusion of solvent/detergent-treated pooled plasma. Transfusion 2000, 40:1203–1206.

15. Gaboulaud V, Parquet A, Tahiri C, et al.: Prevalence of IgG antibodies to human parvovirus B19 in haemophilia children treated with recombinant factor (F)VIII only or with at least one plasma-derived FVIII or FIX concentrate: results from the French haemophilia cohort. Br J Haematol 2002, 116:383–389.

16. Omar A, Kempf C: Removal of neutralized model parvoviruses and enteroviruses in human IgG solutions by nanofiltration. Transfusion 2002, 42:1005–1010.

17. Blumel J, Schmidt I, Effenberger W, et al.: Parvovirus B19 transmission by heat-treated clotting factor concentrates. Transfusion 2002, 42:1473–1481.

18. Challine D, Rondot-Thoraval F, Sarah T, et al.: Seroprevalence of human herpes virus 8 antibody in populations at high or low risk of transfusion, graft, or sexual transmission of viruses. Transfusion 2001, 41:1120–1125.

19.• US Department of Health and Human Services, Food and Drug Administration/Center for Biologics Evaluation and Research: Draft Guidance for Industry containing revised recommendations for donor and product management based on screening tests for syphilis. June 2003. Available at: http://www.fda.gov/cber/guidelines.htm. Accessed August 6, 2003. A useful review of the FDA policy on syphilis testing of blood donors.

20. Code of Federal Regulations: General Biological Products Standards-Test Requirements. Title 21 CFR, 610.40(i).

21. Cable RG: Evaluation of syphilis testing of blood donors. Transfus Med Rev 1996, 10:296–302.

22. Bowden RA, Slichter S, Sayers M, et al.: A comparison of filtered leukocyte-reduced and cytomegalovirus (CMV) seronegative blood products for the prevention of transfusion associated CMV infection after marrow transplant. Blood 1995, 86:3598–3603.

23. Centers for Disease Control and Prevention: IDSA, ASBMT: Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. Biol Blood Marrow Transplant 2000, 6:665–666.

24.• Nichols WG, Price TH, Gooley T, et al.: Transfusion-transmitted cytomegalovirus infection after receipt of leukoreduced blood products. Blood 2003, 101:4195–4200. Analysis the effect of leukoreduction on CMV transmission based on the incidence rates of CMV conversion in two time periods, both with a mixed use of CMV seronegative and CMV-safe leukoreduced blood transfusion but with a change in terms of ratio of the two.

25. Hebert PC, Fergusson D, Blajchman MA, et al.: Clinical outcomes following institution of the Canadian universal leukoreduction program for red blood cell transfusions. JAMA 2003, 289:1941–1949.

26. Fergusson D, Herbert PC, Lee SK, et al.: Clinical outcomes following institution of universal leukoreduction of blood transfusions for premature infants. JAMA 2003, 289:1950–1956.

27. Corwin HL: AuBuchon JP: Is leukoreduction of blood components for everyone? JAMA 2003, 289:1993–1995.

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Keywords:

transfusion transmitted diseases; blood safety; donor testing; nucleic acid testing

© 2003 Lippincott Williams & Wilkins, Inc.

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