B19: benign or not? (2011)

For many years, transfusion medicine has had an uneasy relationship with parvovirus B19. We know that it causes disease and, in some cases, severe disease. We know it is present in blood and in plasma products, that it can circulate at extraordinarily high titers, and that it infects recipients. Manufacturers of pooled plasma products have implemented testing measures to limit the levels of B19 in manufacturing pools but, for the most part, blood collectors have been comfortable in letting this testing occur as an in-process step and managing it so that the testing occurs after the release of labile products. In general, the rationale has been that the number of reported clinically significant outcomes attributable to transfusion-transmitted B19 is minuscule and that accessible tools for real-time donor testing are not logistically accessible. Further, even when a “B19-safe” product is made available, it sees little use. It has generally been thought that only those components with a high titer of B19 virus are likely to be infectious and that the presence of IgG antibodies signifies the absence of B19 infectivity via transfusion. Three articles in this issue of TRANSFUSION give some pause for thought on these issues. All are linked by the observation of detectable low levels of circulating B19 DNA in the presence of IgG antibodies. Not a unique observation, but what is unexpected is the clear linkage of some samples of this type to transmission and recognized disease, as reported in the article by Satake and colleagues,1 who investigated eight cases of posttransfusion B19 disease identified through a remarkably effective voluntary hemovigilance system, in association with a repository of samples of prior donations. In four of the cases, complete sequence identity was demonstrated between the B19 from the patient sample and that from the implicated donation. Three of these cases were attributable to donations that had both IgG and IgM antibodies, and with DNA levels of 1.8 × 105, 3.0 × 105, and 5.1 × 103 IU/mL. Even more remarkably, the potential cause of one probable case appeared to be a washed red blood cell (RBC) from a donation containing only 6.8 × 103 IU/mL B19 DNA. The patients in this study suffered a number of different outcomes, including prolonged RBC aplasia, fever, erythema, and even pancytopenia in one of the probable cases. While none of these was life-threatening, not all were benign and aplasia is regarded as a significant problem. The authors of this article concluded that the outcome of transfusion-transmitted B19 infection was more a function of the immune status of the patient than of the viral titer in the transfused product. They did, however, note that the presence of IgM antibodies to B19 in the donor appeared to be a risk factor for transmission.1 This study does, at first sight, seem to be at variance with a recent publication by Kleinman and colleagues2 who failed to demonstrate any evidence of transmission of B19 from low-titer donations. However, it must be remembered that the observations of Satake and colleagues were based on clinically reported disease from 10 years of observation representing approximately 1 million patient-recipients per year. The absence of any cases associated with high titers of B19 may be attributed to the fact that, in Japan, donations are screened for B19, using an insensitive method. On the other hand, Kleinman and coworkers2 looked for evidence of infection in the recipients of only 12,592 donations, of which 105 had detectable B19 DNA. One recipient of a high-titer (>1010 IU/mL) unit may have demonstrated an anamnestic antibody response, but was asymptomatic. Yu and coworkers3 found that 14 of 869 blood recipients were B19 DNA positive, but only one demonstrated transfusion-transmitted infection and was again, a recipient of a high load (5 × 1010 IU) of B19 in a unit of RBCs. Hourfar and colleagues4 found no infection among 16 recipients of components with less than 105 viral genes/mL, but 9 of 18 recipients of products with higher titers. A study from China evaluated 3957 blood donors for B19 DNA using real-time polymerase chain reaction and found 23 (0.58%) to have detectable DNA, all of relatively low titer (2.5 × 102-6.4 × 104 copies/mL), with 61% of them having IgG antibody, but none having IgM.5 There are no data about infectivity and the data do not appear to be materially different from those published elsewhere in the world. The absence of higher-titer DNA-positive samples is not surprising, given the relatively small sample size and the infrequency of high-titer samples found in other studies. Lee and colleagues6 provide additional information about low-level B19 infection. Of note is a finding that some 88% of B19-positive donors still had detectable viral DNA when they returned to donate at least 6 months later. It is thus likely that such viral persistence is the norm, rather than the exception. This study also showed that, during the IgM-positive, high-titer phase of infection, there was a significant, albeit weak, association between the virus and the RBCs, resulting in greater detection of DNA in whole blood or RBCs than in the plasma. Such an association was not seen in later phases of infection, characterized by low viral titers and the presence of IgG antibodies. The difference is curious and not well explained, although the authors hypothesized that, during early infection, virus may be associated with, or even internal to, RBCs and/or that IgG antibodies inhibit the binding.6 What is also curious is that, although the common RBC P antigen (or globoside) is known to be the receptor for B19, the binding is so weak. In this context, it should perhaps be noted that pH had to be adjusted to a nonphysiologic value of 5.6 to optimize the hemagglutination test that has been used in Japan for B19 donor screening. Absent the data from Satake and colleagues,1 these latter two articles would probably not provoke much concern. However, the clear demonstration of a small number of clinically apparent transmissions of B19V from low-titer, IgG-positive donations raises the ante. Additionally, automated duplex nucleic acid test procedures for B19V DNA and HAV RNA are in development and offer the potential of moving such testing away from manufacturing and into the realm of real-time donation screening. Should this donor testing be adopted, and if so, do we need to reconsider the sensitivity cutoff to be used? Satake and colleagues point out that such decisions are not in fact easy: in their study the adverse outcomes of infection were extremely infrequent and most symptoms spontaneously resolved. These authors imply that only the recognition of more serious outcomes should prompt changes in current policies. They also question the cost-effectiveness of such measures. Even if the cost of testing were to be absorbed into the economics of provision of plasma for further manufacture, the newly recognized need to detect low-titer samples would have a significant impact on blood availability. It should also be noted that other national hemovigilance programs do not appear to have reported any serious outcomes attributable to B19 infection. With respect to decision-making on donor testing for B19, it is difficult to challenge the conclusions by Satake and colleagues,1 namely, that observed outcomes of transfusion-transmitted B19 infection are infrequent and self-limiting and that immediate action is not warranted absent observation of more serious consequences. None.