Immune monitoring and risk of infection in pediatric liver transplantation: a prospective study

Abstract

Background: Immune monitoring has been proposed to optimize immunosuppressive therapy in liver recipients. This study aims to describe immunological changes following liver transplantation in pediatric recipients and to identify immune markers associated with post-transplant complications.

Methods: The immunological status of 95 pediatric liver recipients was prospectively assessed before transplantation and at 1, 3, 6, 9 and 12 months post-transplantation. Serum immunoglobulins (Ig) were measured by nephelometry and immunophenotype was evaluated by flow cytometry. T, B and NK lymphocyte counts were adjusted for age using standard reference ranges.

Results: Graft rejection, post-transplant lymphoproliferative disorder and autoimmune hepatitis was diagnosed in 6%, 2% and 0% patients, respectively. Early infections affected 43% patients, while late infections occurred in 17%, 24%, 10% and 9% recipients at each follow-up interval. Baseline immune dysregulation primarily involved the cellular compartment, with 78% recipients showing lymphopenia. Lymphocyte subpopulation scores improved following liver transplantation, with CD4⁺ score normalizing by month 1 and CD8⁺, CD19⁺ and NK scores by month 6. First-month IgG hypogammaglobulinemia, observed in 20% recipients, resolved completely at month 12. First-month T-cell lymphopenia (CD3⁺ hazard ratio [HR] 2.48, p=0.005; CD8⁺ HR 2.38, p=0.008) and hypogammaglobulinemia (IgG HR 2.18, p=0.036; IgA HR 2.40, p=0.011; IgM HR 2.61, p=0.006) were associated with higher risk of late infections. In multivariate analysis, only CD3⁺ T-cell lymphopenia remained a significant predictor (HR 2.13, p=0.030).

Conclusions: Baseline immune dysregulation resolved within the first months post-transplantation. Early infections were unrelated to immune markers, while late infections were associated with CD3⁺ T-cell lymphopenia and hypogammaglobulinemia.

Keywords: cellular immunity; flow cytometry; humoral immunity; immune monitoring; liver transplantation.

Figure 1

Flowchart for the inclusion of the pediatric liver transplanted patient cohort (n=95).

Figure 2

Percentage of (A) infected pediatric liver recipients and (B) distribution of infection types (viral, bacterial, or fungal) across each follow-up period: from transplantation (Tx) to 1 month post-transplantation (1M), 1M to 3M, 3M to 6M, 6M to 9M and 9M to 12M.

Figure 3

Evolution of (A) immunoglobulin G (IgG), (B) IgA and (C) IgM serum levels in a cohort of pediatric liver recipients grouped by age ranges across each follow-up period: pre-transplantation (Pre-Tx) and 1, 3, 6, 9 and 12 months post-transplantation (1M, 3M, 6M, 9M and 12M, respectively).

Figure 4

Evolution of each lymphocyte subpopulation score in a cohort of pediatric liver recipients across each follow-up period: pre-transplantation (Pre-Tx) and 1, 3, 6, 9 and 12 months post-transplantation (1M, 3M, 6M, 9M and 12M, respectively). Studied subsets included (A) total lymphocytes, (B) CD3⁺ T lymphocytes, (C) CD3⁺CD4⁺ T lymphocytes, (D) CD3⁺CD8⁺ T lymphocytes, (E) CD19⁺ B lymphocytes and (F) CD3^-CD16⁺CD56⁺ NK lymphocytes. Scores were calculated by substracting the median of the age-specific normal range from the absolute number of lymphocytes in the subpopulation. Dashed lines mark the normal range, defined as scores between -0.5 and 0.5. Horizontal lines represent statistically significant differences between the median scores of two distinct follow-up periods.

Figure 5

Effect of the presence of (A) T CD3⁺ T lymphopenia, (B) CD4⁺ T lymphopenia or (C) CD8⁺ T lymphopenia on late infection risk. Global p-values were obtained at 1 month post-transplantation by Kaplan-Meier analysis.