Current concepts in transfusion transmitted diseases

During the 1950s, 25% of recipients of four or more whole blood transfusions in New York City, USA, developed jaundice, and this was accepted as a ‘fact of life’. At that time, the only transfusion transmitted infectious diseases (TTID) of importance were syphilis and ‘serum hepatitis’, later recognized as hepatitis B. Syphilis screening was introduced in the 1940s and the first assays for hepatitis B surface antigen in the early 1970s. In the early 1980s, the tragedy of AIDS brought serious consequences for blood recipients but also brought attention and resources to the prevention of TTID, resulting in the introduction of additional screening tests in the U.S. and in several other countries [1]. As new screening tests, donor screening procedures and quality systems were developed, they were cumulatively added to the list of donor eligibility and blood processing requirements. Obsolete procedures were removed only under exceptional circumstances. Gradually, multiple layers of safety became part of regulatory requirements including in addition to testing and quality systems, more extensive donor history questionnaires in which donors are asked about potential exposure to transmissible agents (e.g. history of risk behaviours, travel); deferral files listing donors who were deferred because of travel, risk behaviour or reactive screening tests results; quarantine of untested and unsuitable components, kept separately to avoid inappropriate release for transfusion. It should be noted that donor history questions [2] and deferral files [3] have lower sensitivity and poorer predictive value than donor screening tests. In addition, requirements for donor notification and counselling after positive test results were instituted under the presumption that knowledge about their positive results would discourage positive donors from returning to donate. Also, the movement towards volunteer, non-remunerated donations as opposed to replacement donations (made by donors referred by a patient to ensure admission to a hospital) or paid donations was intensified. Donor screening procedures introduced in the last several decades have focused on established TTIDs. Table 1 includes a list of donor screening tests implemented in the US with the year of implementation. Several tests were replaced by subsequent generations in later years as technology improved. Only ALT (alaninoaminotransferase) and HIV-1 p24 Ag were abandoned after newer, more sensitive and specific tests became available. Most other assays were retained because of concerns about the potential for increased risk to transfusion recipients if they were removed. For instance, syphilis transmission by transfusion has not been reported in over 50 years. Incidence and prevalence have been substantially reduced in the general population, Treponema pallidum does not survive the conditions currently used for storage of blood and components, the disease is clearly recognizable and effective therapy is available. However, syphilis screening tests have been applied since the 1940s, and regulators and recipient advocacy groups are afraid that transmission, even if a rare event, may occur if the test is abandoned. It should be noted that there are no screening assays applicable to blood donors for a number of TTID, and preventive measures are based on donor history questions and travel deferrals. Among the most important are malaria, babesiosis and variant Creutzfeldt–Jakob disease (vCJD). Many emerging infections have the potential for transmission by transfusion. A Supplement to the journal Transfusion prepared by the Transfusion Transmitted Diseases Committee of AABB and published in August, 2009 has a detailed review of 68 diseases that could be a source of TTID. The issue is posted on the public side of the AABB website [4]. The Supplement also has an excellent discussion of conditions required for a disease to behave as a TTID and defines priorities that should be the focus of concern. Essentially, infections with an asymptomatic blood-borne phase have the potential for transmission by transfusion, whether the infectious phase is prolonged as is the case for hepatitis B virus (HBV) or HIV, or short, as in the case of West Nile virus (WNV) or dengue virus (DENV), because the donor feels well at the time of donation. Other characteristics that are necessary for transmission of an infectious disease agent by transfusion are ability to survive in stored blood or components, and ability to cause infection by the intravenous route. The frequency with which an infection is transmitted to blood recipients depends directly upon the length of the asymptomatic blood-borne period, how often blood is donated during this period, and the immune status of the recipient population. Susceptibility of recipients and manifestation of disease are other important elements that complete the picture of TTID. As mentioned above, many TTID transmissions occur because prospective donors are feeling well during the asymptomatic period of infection. Thus, the efficacy of blood donor screening tests relies not only on the ability to recognize an individual infected by a TTID but also on the length of the ‘window’ period, i.e. the period between infection and the ability of assays to detect it. Window period detection depends mostly on assay sensitivity. Table 2 lists the substantial progress made over the years in shortening the average window period of assays for HIV-1/2. Most of the reported transmissions of HIV after screening tests were implemented occurred as consequence of transfusion of blood components collected from donors who were in the window period at the time of donation [5]. The selection of appropriate assays and the algorithms used for screening receive careful attention from those involved in the collection and processing of blood for transfusion into recipients. Among the factors considered for the selection are sensitivity, specificity, positive and negative predictive values. The epidemiology and the geography of the agents are also critical. Serological assays for antibodies detect antibodies against the infectious agent generated by the immune system of the infected individual. Serological assays for antigens use specific antibodies to detect constituents of the infectious agent (e.g. HBsAg and HIV-1 p24 Ag). Molecular assays (nucleic acid amplification tests or NAT) detect the nucleic acid sequences, RNA or DNA of the infectious agent through a process of amplification that takes place in a test tube. Serological assays for antibodies are effective for detection of antibodies in infected individuals in a population, or prevalent cases. Molecular assays are effective for the detection of recent infections, or incident cases. Serological assays for antigens would theoretically help detection of incident cases. Unfortunately, they are not as sensitive as molecular tests. In some instances, like detection of parasitic infections, serological tests are more effective because the few parasites present in a component may be sufficient to transmit infection but may be missed in the small specimen used for testing (Poisson distribution). While there is correlation between prevalence and transfusion transmission, not all individuals positive on a serological test are able to transmit infection. Molecular assays, on the other hand, are in general more sensitive and are more effective for the detection of recent infections in a population, or incident cases. Essentially, the yield of individuals who are positive on NAT and negative on the corresponding serological assay is higher among populations in which an infection is having a high rate of spread. Serological screening for HIV is highly effective for the detection of infected individuals in populations with high prevalence of infection. In these situations, the NAT yield maybe rather small when compared with that of serological assays. However, in situations where the infection is spreading rapidly, even the less sensitive serological assay for HIV-1 p24 Ag can contribute significantly to blood safety [6]. Similarly, NAT can also be quite effective [7] because it becomes positive earlier than serological tests. Decisions about implementation of screening assays for TTIDs of concern in the geographical area where blood is collected are usually made by policymakers and regulatory authorities, based on the prevalence and incidence of disease. Under certain circumstances, these decisions have been made for political reasons in the absence of sufficient information showing the expected contribution of the assay in terms of blood safety. This was the case with the implementation of screening for HIV-1 p24 antigen in the United States in the mid-1990s. No individuals positive for the antigen and negative for antibodies to HIV-1 were found in the screening of over 500 000 donors [8]. Despite this finding, the U.S. Food and Drug Administration recommended test implementation to show to the public that everything possible was being done to ensure the safety of the blood supply. The test produced no significant yield and was abandoned after implementation of NAT for HIV-1. While serological assays are extremely useful tools for prevention of transmission of infections like HIV, HBV and HCV by transfusion, they are not useful for arboviruses like West Nile Virus because most transmissions occur in the early stages of infection, prior to the appearance of antibodies. Viraemia declines and gradually disappears as antibody titres increase. This would also be true for other arboviral infections like dengue or Chikungunya. Test selection must also consider regional epidemiology. TTIDs like HIV, HBV, HCV and Syphilis are worldwide concerns. Other agents like Trypanosoma cruzi, Babesia spp., HTLV-I, Q Fever, affect donors in more restricted geographical areas and donor screening when appropriate, is applied locally, frequently under a ‘selective’ screening protocol, i.e. only donors at risk are screened. Examples are antibodies to T. cruzi for prospective donors born in endemic areas (Spain) [9] or on the first time they donate after test availability (U.S.) [10], one time screening for HTLV-I/II in certain EU countries and screening of individuals coming from areas affected by Q Fever in The Netherlands. It should be noted that improvements in technology have brought sensitivity of newer generation serological assays for antibodies and combined assays for both antigens and for antibodies to HIV, HBV and HCV closer to that of NAT. In some instances, like the detection of parasitic infections, serological tests are more effective than NAT because the few parasites present in a unit of component may be sufficient to transmit infection but, as mentioned before, may not be present in the small specimen obtained for testing. This has been another approach to increase effectiveness of serological screening. For instance, some countries in Latin America have required the use of two different assays for HIV or for antibodies to T. cruzi in order to increase the sensitivity of donor screening tests. The US has used in the past a second FDA licensed serological assay before notifying donors that they are infected with HTLV-I/II [11]. Unfortunately, one of the tests is not anymore manufactured. There is hope that a new assay will be submitted for licensure by another manufacturer in the near future. Another example is the use of an assay for antibodies to the core antigen of HBV (HBcAb) in addition to the serological assay for HBsAg. This is the practice in North America, an area with relatively low prevalence for HBV, but is not common practice in European countries or in Asia. HBcAb was initially adopted in the 1980s in the US as a correlate of HIV infection and non-A, non-B Hepatitis. The use of HBcAb is very difficult in high prevalence areas because a large segment of the population has been exposed to HBV and is positive in the assay, with great impact in blood availability. Often, resources for the implementation of NAT are not available in these areas; thus, screening relies more frequently on high sensitivity of serological assays for HBsAg. The more recent introduction of sensitive NAT assays for HBV became an additional tool for the prevention of transmission of HBV and in a certain way diminished the contribution of HBcAb to blood safety [12]. Ideally, a combination of serological tests and NAT brings the highest degree of safety to blood products for transfusion. Unfortunately, NAT implementation is not feasible in every environment. Despite public demand for the unattainable ‘zero risk’, investments in transfusion safety need to be balanced with available resources and other healthcare priorities. Thus, choices need to be made. Many areas of the world have attempted to introduce NAT for HIV, HCV and also for HBV and have not yet succeeded because of a series of obstacles that include costs, assay complexity (the technology is very different from ELISA), the requirement for collection of separate specimens, and the issues of contamination of negative specimens with amplified products from positive specimens (resolved in most commercial assays). Homebrew assays have been developed and validated by the plasma fractionation industry in the nineties and some have been licensed by North-American and European regulatory bodies. However, the issues of high development and implementation costs and patent royalties remain as obstacles. Many of the currently available assays have excellent sensitivity, specificity, positive and negative predictive value for the detection of TTID recognized as significant. However, technology evolves faster than biological knowledge, and agents with questionable relevance for transfusion recipients are detected in a proportion of blood donors otherwise negative for HIV, HBV, HCV and HTLV. Among these are Hepatitis G or GVBC and SEN V [13]. More recently, concerns have been raised about HHV-8, a herpes virus associated with Kaposi’s Sarcoma [14] and XMRV, a gamma retrovirus detected in individuals with prostate cancer, in some cohorts of patients with chronic fatigue syndrome and in some blood donors [15]. At this time, definitive association of these diseases with transfusion has not been established. Despite public demand for unattainable ‘zero risk’, investments in transfusion safety also need to be balanced with other healthcare priorities appropriate for each environment. However, we cannot continue to add screening assays for every newly recognized pathogen transmissible by transfusion. Hopefully, in the foreseeable future, safe and effective pathogen inactivation technologies will allow us to limit the number of screening assays needed to ensure the safety of the blood supply. Obviously, the practice of adding screening tests for every newly recognized pathogen transmissible by transfusion is not feasible. This concern became even clearer after the recent publication of a comprehensive list of relevant emerging infectious agents [3]. Hopefully, in the foreseeable future, safe and effective pathogen inactivation technologies (PI) will allow us to limit screening assays to the most relevant needed to ensure the safety of the blood supply [16]. Pathogen inactivation has been applied successfully to proteins derived from human plasma as for instance albumin, IVIg, Factor VIII, alpha-1 anti-trypsin, etc. Unfortunately, the methods of inactivation used for proteins (solvent detergent, heat, nanofiltration, etc.) are not compatible with cellular components. It should be noted that even after the introduction of PI, regulatory agencies require, and advisory bodies like the World Health Organization recommend for the manufacture of derivatives the exclusive use of plasma that tested negative for HIV, HBC and HCV in screening tests [17]. Many scientific, regulatory and economic hurdles will have to be overcome before pathogen inactivation processes for cellular components of blood become widely accepted [18]. In addition, the availability of safe and effective pathogen inactivation processes will not eliminate the need for screening of cellular blood components for the most relevant transfusion transmitted diseases using serological and molecular tests. Essentially, many of the current testing strategies are here to stay, at least for the foreseeable future. The author is a full time employee of America‘s Blood Centers, an association of U.S. and Canadian Blood Centers. The article and presentation do not mention or promote any specific commercial product. There are no potential conflicts of interest to declare.

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