Torque Teno Viruses Infection Associated with Suboptimal Hematological Recovery of Severe Aplastic Anemia

Introduction Infections remain the major cause of death in severe aplastic anemia (SAA) and delay the recovery of hematological profiles of patients receiving anti-thymocyte globulin (ATG)-based immunosuppressive therapy. Due to the immunocompromised state after ATG, infections in SAA patients can be occult and with distinct etiological characteristics. Viruses, in particular the Torque Teno Viruses (TTVs) (De Vlaminck I, et al. Cell 2013), take advantage of a reduction of immunocompetence whereas their influence on hematopoiesis is not yet understood. Metagenomic next-generation sequencing (mNGS) enables the detection of most known pathogens in a single test. It shows higher performance than routine microbiological tests in detecting viral infections. Here we report the findings of plasma mNGS in SAA patients and the impact on their hematological profiles. Methods Plasma mNGS data of SAA patients enrolled in a registry study (ChiCTR2100045895) from March 2021 to July 2024 were analyzed. For those with a decline of hematological indices and concomitant infections of TTVs, hematological parameters before and after clinical interventions were compared. Response is defined as an increase of platelet count by 20×109/L or of hemoglobin (Hb) level by 1.5 g/dL within 8 weeks, independent of transfusions. Results A total of 136 samples from 85 SAA patients were analyzed: 32 taken before ATG and 104 taken after ATG, for signs of infections, mostly fever (87 samples from 38 patients) or for a decline of hematological indices after response to ATG (49 samples from 23 patients). Pathogens with the highest incidence in post ATG samples were TTVs, significantly higher than their counterparts in samples before ATG (44% vs 22%, p=0.04). The median time to TTVs infection post ATG was 18.7 weeks. In samples specially tested for decline of hematological indices, TTVs infection occurred with an extremely higher rate (77%) than any other pathogens including Cytomegalovirus (29%). Platelet and Hb level decreased by an average of 19×109/L and 0.5 g/dl respectively after TTVs infection, compared with their best records within 8 weeks before infection. Based on the close interplay between TTV loads and immunocompetence (De Vlaminck I, et al. Cell 2013), 14 patients were given intravenous immunoglobulin (IVIG) at a dose of 0.4 g/kg/d for 5 consecutive days. The cumulative overall response rate to IVIG was 37% at 4 weeks and 63% at 8 weeks after treatment. The median time to response was 5.4 [95% CI: 3.0~7.9] weeks. Cumulative platelet response rate was 26% at 4 weeks and 47 % at 8 weeks, with an average increase of platelet count by 34×109/L and 52×109/L respectively in patients with response. Cumulative erythroid response rate was 29% at 4 weeks and 44% at 8 weeks, with an average increase of Hb level by 2.7 g/dl and 3.2 g/dl respectively in patients with response. For 5 patients including 3 without response to IVIG, cyclosporine dosage was reduced to alleviate immunosuppression: overall response rate was 40% at 8 weeks，with 1 erythroid response and 1 platelet response. Conclusions TTVs infection might be associated with a decline of hematological indices in SAA patients after response to ATG. IVIG and downregulation of cyclosporine dosage could be beneficial to hematological recovery.