Changes In CD8+57+ T Lymphocyte Expansions After Autologous Hematopoietic Stem Cell Transplantation Correlate With Changes in Torquetenovirus Viremia

Although we rely on the total lymphocyte and CD4+ absolute counts to assess the degree of cell-mediated immune deficiency in hematopoietic stem cell transplant (HSCT) recipients, these patients frequently develop opportunistic infections after these parameters have returned to normality. In fact, we lack easy-to-use functional markers that could help decide how long preemptive antimicrobial prophylaxis should be continued. Recently, attention is being paid to memory-like CD8+57+ T lymphocytes, which undergo oligoclonal expansions in AIDS (1) and cancer (2) patients and in lymphopenia-induced proliferation after high-dose chemotherapy (3). Torquetenovirus (TTV) is a nonenveloped virus with a small single-stranded circular DNA genome, classified into the floating genus Anellovirus (4). Chronic TTV viremia is extraordinarily common, being present in approximately 90% of the general population worldwide, regardless of age and health conditions. Although the life cycle of TTV is still poorly understood, the virus is believed to replicate in bone marrow cells and activated peripheral blood mononuclear cells (5, 6). Data have demonstrated particularly high TTV loads in adults with autoimmune rheumatic diseases and children with severe acute respiratory diseases (4, 7). However, the disease potential of TTV remains to be established. The behavior and significance, if any, of TTV in different hematological settings are also unknown (8, 9). In 1999, Kanda et al. (10) reported a high prevalence of TTV in HSCT recipients, but no work has investigated how TTV viremia behaves after HSCT. Nineteen consecutive multiple myeloma patients undergoing tandem autologous HSCT with high-dose melphalan (14 patients treated with 100 mg/m2; 5 patients with 200 mg/m2) were enrolled after written informed consent was obtained and followed for 100 days after reinfusion. All patients received at least one leucodepleted and irradiated platelet concentrate before day 10. The patients were analyzed for serum TTV presence and load with a universal real-time PCR targeting the viral untranslated region. All patients tested TTV positive before transplantation. Figure 1 shows that by day 40 average TTV viremia was still unchanged, but by day 70 it was approximately 2 log higher than at baseline and by day 100 it had grown a little further. Percent circulating CD8+57+ T lymphocytes were already significantly increased relative to baseline by day 40, and peaked by day 100. Statistical analysis showed that, despite an initial slight asynchrony, TTV viremia and percent CD8+57+ T lymphocyte changes correlated (Fig. 1). The correlation was reinforced by the observation that the kinetics of the two parameters were similar in patients undergoing the first or second HSCT, and that in patients who could be followed longer because rehospitalized for a second HSCT, both variables had returned to baseline values (data not shown). Subgroup analysis showed no difference between patients receiving different melphalan doses.FIGURE 1.: Changes of percent CD8+57+ T lymphocytes and plasma titer of TTV in 19 multiple myeloma patients undergoing tandem HSCT. Pearson's correlation coefficient between the two variables was r=0.449 (P=0.001) and, when measured at baseline and at day 100 it was r=0.667 (P<0.001).At the top of our knowledge, although CD8+57+ T lymphocyte expansions have been already associated with both multiple myeloma and cytomegalovirus reactivactions (11, 12), this is the first demonstration of a temporal correlation between the size of a widespread chronic viremia and circulating CD8+57+ T lymphocytes. It is tempting to speculate that TTV viremia might be exploited to obtain a functional assessment of the immune status in HSCT recipients. Maggi Fabrizio Ricci Valentina Bendinelli Mauro Ceccherini Nelli Luca Virology Unit Azienda Ospedaliera Universitaria Pisana Pisa, Italy Focosi Daniele Papineschi Federico Petrini Mario Division of Hematology Azienda Ospedaliera Universitaria Santa Chiara Pisa, Italy Paumgardhen Elena Ghimenti Massimo Division of Laboratory Analysis University of Pisa, Italy