Serious infection risk and immune recovery after double-unit cord blood transplantation without antithymocyte globulin

Abstract

Factors contributing to infection risk after cord blood transplantation (CBT) include the use of anti-thymocyte globulin (ATG), prolonged neutropenia, and failure to transfer immunity. In the present study, we investigated the potential of double-unit CBT without ATG to reduce the risk of infection and evaluated the nature of serious infections in the first year after CBT using this approach. Seventy-two predominantly adult patients underwent CBT for hematologic malignancies; of these, 52 patients received myeloablative conditioning, and 20 received nonmyeloablative conditioning. The peak incidences of bacterial infections (32%), fungal infections (14%), and bacterial/fungal pneumonias (10%) occurred in the first 30 days posttransplantation. Three such infections contributed to early mortality. The peak incidence of viral infections was 31-60 days posttransplantation, affecting 30% of patients. Cytomegalovirus (CMV) was the most common viral infection. CMV infections occurring before day 120 (n = 23) had no relationship with graft-versus-host disease (GVHD), whereas CMV infections occurring after day 120 (n = 5), along with all cases of Epstein-Barr virus viremia (n = 5) and adenoviral enteritis (n = 2), occurred exclusively in the context of GVHD therapy or corticosteroid use for another indication. Viral infections had the highest lethality: 2 were a direct cause of death, and 3 contributed to death. Patients exhibited steady immune recovery, achieving a median CD3(+)4(+) T cell count >200 cells/μL by day 120 post-CBT, and no infection-related deaths occurred after day 120. Our results suggest that double-unit CBT without ATG is associated with prompt T cell recovery, and, unlike in CBT incorporating ATG, infection is rarely a primary cause of death. However, CBT without ATG is associated with a significant risk of GVHD, and serious infections remain a challenge, especially in the setting of GVHD. New strategies are needed to further reduce infectious complications after CBT; these will require earlier neutrophil recovery and more effective prevention of GVHD, ideally without the profound T cell depletion associated with ATG therapy.

Figure 1. Incidence of serious infections by type and time period in the first year post-transplant: there was a marked decrease after day 60 although a low but persistent viral infection risk persisted during the first post-transplant year

Pneumonias due to a specific organism, or diagnosed as due to a specific infection type (based on the clinical presentation, course, and response to therapy) are included under the bacterial, fungal and viral categories. The category of “Pneumonias” had no organism identified, responded to combined anti-bacterial and anti-fungal therapy, but a specific infection category could not be determined. The fall in patient number is due to lack of complete follow-up or patient death.

Figure 2

Cumulative incidence of first infection by etiology: bacterial and fungal infections had an earlier onset than viral infections.

Figure 3

Type and number of bacterial infections: serious bacterial infections markedly decreased after day 30.

Figure 4. Type and number of viral infections: serious viral infections markedly decreased after day 60

Notably, however, the incidence remained stable during time periods day 61-1 year (see Figure 1), although mortality from viral infections was limited to the first 120 days.

Figure 5. ALC recovery (5A), CD3+4+ T-cell recovery (5B), CD3+8+ T-cell recovery (5C), and PHA response (5D) after double unit CBT: median ALC counts were within the normal range by day 60, the median CD3+4+ T-lymphocyte counts were over 200, and PHA responses at 80% the LLN by day 120 post-transplant, respectively

The dotted lines (---) represent the normal ranges. The boxes represent the interquartile range, and the solid lines within the boxes represent the median value. The closed circles (•) represent outlier values > 1.5 the interquartile range.

Figure 6

The median ALC recovery (6A), CD3+4+ T-cell recovery (6B), CD3+8+ T-cell recovery (6C), and PHA response (6D) after double unit CBT according to age: progressive immune recovery is seen in both adult and pediatric patients.