Relationships Between Late Viral Infections and Immune Reconstitution after Hematopoietic Stem Cell Transplantation.
Authors: Asano-Mori Yuki , Kanda Yoshinobu , Oshima Kumi , Nanya Yasuhito , Kumano Keiki , Asai Takashi , Hangaishi Akira , Takahashi Tsuyoshi , Imai Yoichi , Kurokawa Mineo 
Published: April 2020

Abstract
Late occurrence of viral infections beyond day 100 after hematopoietic stem cell transplantation (HSCT) was widely recognized to depend on the profound immune suppression due to severe chronic GVHD and its treatment. However, there have been few reports clarifying the direct relationships between the development of late viral infections and immune reconstitution after HSCT. To evaluate the correlation of the immune recovery with the occurrence of late cytomegalovirus (CMV) or varicella-zoster virus (VZV) infections, we retrospectively analyzed the records of 60 Japanese adult patients who underwent allogeneic HSCT for the first time from April, 2002 to February, 2007 at the University of Tokyo Hospital, and survived longer than 180 days after HSCT. Absolute lymphocyte subset counts (CD3+ T cells, CD3−CD19+ B cells, CD3+CD4+ helper T cells, CD4+CD45RO+ memory T cells, CD4+CD45RA+ naïve T cells, CD3+CD8+ cytotoxic T cells, CD3−CD56+ natural killer cells), absolute monocyte counts, serum IgG, IgA, and IgM levels were measured at 3 and 6 months after HSCT. As a prophylaxis against late CMV disease, risk-adopted preemptive therapy with ganciclovir was performed by monitoring CMV antigenemia beyond day 100 after HSCT. For late VZV disease, oral administration of acyclovir at 200 mg/day was principally continued until the end of immunosuppressive therapy and at least one year after HSCT in 52 patients, whereas valacyclovir at 500 mg/day three times a week was administered until one year after HSCT in eight patients. Two out of 60 patients have already developed CMV disease within 100 days after HSCT. Thirteen of the remaining 58 patients developed late CMV infection defined as 10 or more CMV-Ag positive cells per two slides at a median of 125 days (101 to 546 days) after HSCT. CD3+ T cells less than 400x106/L (P=0.003), CD3+CD4+ T cells less than 200 x106/L (P=0.013), CD4+CD45RO+ T cells less than 100x106/L (P&lt;0.001), CD4+CD45RA+ T cells less than 50x106/L (P&lt;0.001), and CD3+CD8+ T cells less than 400x106/L (P=0.005) at 3 months after HSCT were associated with a high incidence of late CMV infections. Of these, six patients developed high-grade CMV antigenemia with 50 or more positive cells, for which CD4+CD45RO+ T cells less than 100x106/L (P=0.043) was the only significant risk factor. Nine of the 58 patients developed late CMV disease (retinitis in 7 and colitis in 2) at a median of 160 days (114 to 215 days) after HSCT. CD3+CD4+cell less than 300 x106/L (P=0.047) and CD4+CD45RA+ less than 50 x106/L (P=0.043) were identified as risk factors for the CMV disease, and CD3+CD4+cell counts were less than 300x106/L in all of the nine patients (median of 75 x106/L, range 12 to 273 x106/L). None developed VZV disease within 100 days after HSCT, while eleven of the 60 patients developed late VZV disease later on, a median of 481 days (149 to 1034 days) after HSCT. CD4/CD8 ratio less than 0.4 at 3 months after HSCT was the only significant risk factor for late VZV disease (P=0.043), whereas the absolute CD3+CD4+ cell count was similar and CD3+CD8+ cell count was rather higher in patients who developed VZV disease compared to those who did not. Among 35 patients who received anti-VZV prophylaxis at least 6 months after HSCT and discontinued thereafter, nine developed late VZV disease after day 180, in all of whom CD4/CD8 ratio at 6 months was less than 0.5 (median 0.18, range 0.11 to 0.42). Two patients showed cutaneous dissemination at day 481 and day 571 after HSCT, whose CD4/CD8 ratio was 0.16 or 0.22 at 3 months, and 0.25 or 0.17 at 6 month after HSCT, respectively. These finding suggested that the development of late CMV infection and disease was associated with a low CD3+CD4+ T cell count, whereas late VZV disease tended to occur in patients with a low CD4/CD8 ratio. Patients with enough CD3+CD8+ cells but with insufficient CD3+CD4+ cells, probably due to the resumed immunosuppressants, might be at highest risk for VZV disease.