Prolonged immune deficiency following allogeneic stem cell transplantation: risk factors and complications in adult patients

Abstract

Summary. To evaluate the long-term immune reconstitution after allogeneic haematopoietic stem cell transplantation (SCT), we prospectively screened standard immune parameters in a series of 105 patients, at a median time of 15 months after SCT. Analysing lymphoid phenotypes, in vitro immune functions and immunoglobulin levels, we found that, more than 1 year post SCT, cellular and humoral immunity was still altered in a significant number of patients. CD41 T cells were , 200/ml in one third of patients, and the CD4/CD8 ratio was still reversed in 78% of patients. Almost all patients showed positive T-cell responses against mitogens, but antigen-specific proliferation assays identified 20% to 80% of non-responders. B-cell counts were reconstituted in 61% of the patients, but levels of total immunoglobulins were still low in 59%. In multivariate analyses, human leucocyte antigen (HLA) disparity between donor and recipient and chronic graft-versus-host disease were the leading causes affecting immune reconstitution. Interestingly, cytomegalovirus (CMV) infections were strongly associated with normal CD81 T-cell counts. Studying the impact of impaired immune reconstitution on the rate of infections occurring in the 6 years following screening, we identified three parameters (low B-cell count, inverted CD4/CD8 ratio, and negative response to tetanus toxin) as significant risk factors for developing such late infections.

Risk factors for fatal infectious complications developing late after allogeneic stem cell transplantation

“…41 Furthermore, use of a mismatched or unrelated stem cell donor was an independent risk factor, showing that immunologic incompatibilities between donor and recipient influence immune reconstitution for a long time after HSCT. This finding is supported by other results showing delayed recovery of CD3 þ , CD4 þ and CD8 þ cell numbers as well as decreased T-cell proliferative responses 31,42 in patients with non-sibling donors.…”

“…This fits with previously published data. 1,2,30,31 In our single center study, the cumulative incidences of different types of infection were 1.6% for viral, 1.5% for bacterial, 1.3% for fungal infections and 0.15% for Pneumocystis jirovecii pneumonia. Although directly comparable data are lacking, extrapolation of results from other studies indicates a similar pattern.…”

“…[38][39][40] However, it was somewhat surprising when correcting for severe chronic GVHD that acute GVHD remained a strong predictive factor as regards late fatal infection, since Maury et al 31 have shown that patients with acute GVHD not followed by chronic GVHD have near normal immune reconstitution with only slightly lowered CD8 þ levels late after transplantation. 31 One explanation for increased susceptibility to infection could be a persistent immune defect after high doses of steroids. 41 Furthermore, use of a mismatched or unrelated stem cell donor was an independent risk factor, showing that immunologic incompatibilities between donor and recipient influence immune reconstitution for a long time after HSCT.…”

“…Both acute and severe chronic GVHD were independent risk factors for late death caused by infections. The immune defects associated with chronic GVHD include delayed immune reconstitution of all lymphocytic subsets (B, T and NK cells) 31,35 and impaired thymic and splenic function. 36,37 These defects in combination with the ongoing immunosuppressive treatment in 80% of the patients could therefore explain the increased risk for developing a late fatal infection.…”

Early reconstitution of effector memory CD4+ CMV-specific T cells protects against CMV reactivation following allogeneic SCT

“…The cellular immune response is impaired for many months post-HSCT and contributes to serious morbidity and mortality from infectious complications. 1 In particular, CMV seropositivity remains an important risk factor for transplant-related mortality after sibling donor and matched unrelated donor haematopoietic stem cell recipients, 2,3 particularly in the setting of T-cell-depleted conditioning regimens. The development of effective T-cell immunity is important for the control of CMV infection and disease.…”