Evidence Against a Direct Role Played by Transfusion-Transmitted Virus Infection in Causing Hepatic or Hematologic Manifestations

To the Editor:

Transfusion-transmitted virus (TTV) is a newly described nonenveloped, single-stranded DNA virus, recently detected with high prevalence in Japanese patients with fulminant hepatitis and chronic liver disease of unknown origin.1 Having a high buoyant density (1.26 g/mL) and a single-stranded DNA genome of at least 3,700 bases,2 TTV resembles the Parvoviridae. It could be argued that, in analogy to Parvovirus B19, which has a remarkable tropism for human erythroid progenitor cells, TTV-infected hosts may have hematologic manifestations, including anemia, leukopenia, or thrombocytopenia.3 However, whether TTV has any role in causing hepatic and/or hematologic diseases remains an unsettled issue. Here we report the results of searching for TTV DNA in fasting serum samples collected from 250 subjects, belonging to the following four categories: patients with chronic liver disease (N = 49), patients with coagulopathy (N = 34), intravenous drug users (N = 50), and nonremunerated blood donors (N = 117).

TTV DNA sequences, determined by polymerase chain reaction (PCR),4 were detected in 4 of 117 (3.4%) healthy blood donors and 15 of 133 (11.3%) patients (P = .019). The prevalence of TTV DNA seropositivity was similar in the three groups of patients, being 4 of 34 (11.8%) in patients with coagulopathy, 5 of 50 (10.0%) in intravenous drug users, and 6 of 49 (12.2%) in patients with chronic liver disease (P = .935). There were no significant differences between TTV DNA⁺ and TTV DNA⁻ subjects with regard to age (41.7 ± 17.8v 39.1 ± 14.1 years, mean ± SD; P = .535) and gender distribution (male/female ratio 13/6 v 78/153;P = .846).

The rate of positivity for serum markers of infection by known or presumed hepatotropic viruses in TTV DNA positive subjects is presented in Table 1. Serum markers for hepatotropic viruses were present in 16 of 19 TTV DNA⁺ patients. Twelve of 19 TTV DNA⁺ subjects were anti-HCV antibody⁺, in comparison with 90 of 231 TTV DNA⁻ (P = .039). In nonremunerated, regular blood donors, which are selected for being at low risk for infections by parenterally transmitted viruses, TTV DNA was found in one HGV RNA positive subject and in one subject with evidence of previous exposure to HAV.

Table 2 shows the relationship between TTV DNA seropositivity and abnormal serum alanine aminotransferase (ALT) concentrations. Although TTV DNA⁺ subjects had more commonly ALT >1.5-fold the upper limit of the normal reference range than TTV DNA⁻ patients (P = .010), none of the seven TTV DNA⁺, anti-HCV⁻ subjects had abnormal ALT. Hemoglobin values, leukocyte count, and platelet count were similar in TTV DNA⁺ and TTV DNA⁻subjects; moreover, none of TTV DNA⁺ subjects had hemoglobin level <110 g/L, leukocyte count <4.0 × 10⁹/L, or platelet count <50 × 10⁹/L.

This report confirms that TTV infection has a worldwide distribution and a surprisingly high prevalence, both in healthy volunteer blood donors and in groups traditionally considered at risk for parenterally transmitted viral infections. However, it also casts doubts that prospective screening of blood donors for TTV will ever be indicated, at least for the purpose of avoiding posttransfusion hepatitis. In fact, none of TTV-infected blood donors had alanine aminotransferases above normal limits. Moreover, although among subjects belonging to groups at risk the presence of TTV DNA is accompanied by abnormal alanine aminotransferase in approximately 40% of cases, this might be entirely due to the frequent coexistence, in these populations, of infection by HCV, an agent routinely tested for by blood banks. Finally, none of the TTV-infected subjects had anemia, leukopenia, or thrombocytopenia.

The risk for viral transmission by transfusion has been reduced dramatically through improved techniques for selecting and testing blood donors.5 Initiatives to further improve the safety of the blood supply, including more stringent donor qualifications, additional testing for infectious disease markers, viral inactivation processes, and refinement of transfusion decisions are possible. However, because the risk for viral transmission by allogeneic transfusion is already low, additional measures will have a predictably limited yield and poor cost-effectiveness.6 Although efforts to improve the safety of blood supply will continue, to minimize the risks of transmitting by blood transfusion the next (yet undiscovered) agent, we will have no other choice than a judicious use of blood and blood components.