Long-term follow-up in common variable immunodeficiency: the pediatric-onset and adult-onset landscape

Abstract

Introduction: The primary aim of this study is to investigate the evolution of the clinical and laboratory characteristics during the time in a longitudinal cohort of pediatric-onset and adult-onset Common Variable Immunodeficiency (CVID) patients in order to identify early predictive features of the disease and immune dysregulation complications.

Methods: This is a retrospective-prospective monocentric longitudinal study spanning from 1984 to the end of 2021. The data of pediatric-onset vs. adult-onset patients have been compared for immunological features and for infectious and non-infectious complications assessed at diagnosis and follow-up.

Results: Seventy-three CVID patients have been enrolled, with a mean of 10.0 years (SD ± 8.17) of prospective follow-up. At diagnosis, infections were observed in 89.0% of patients and immune dysregulation in 42.5% of patients. At diagnosis, 38.6% of pediatric-onset and 20.7% of adult-onset patients presented with only infections. Polyclonal lymphoid proliferation (62.1%) and autoimmunity (51.7%) were more prevalent in the adult-onset than in the pediatric-onset group (polyclonal lymphoid proliferation 52.3% and autoimmunity 31.8%, respectively). Enteropathy was present in 9.1% of pediatric-onset and 17.2% of adult-onset patients. The prevalence of polyclonal lymphoid proliferation increased during follow-up more in pediatric-onset patients (diagnosis 52.3%-follow-up 72.7%) than in adult-onset patients (diagnosis 62.1%-follow-up 72.7%). The cumulative risk to develop immune dysregulation increases according to the time of disease and the time of diagnostic delay. At the same age, pediatric-onset patients have roughly double the risk of having a complication due to immune dysregulation than adult-onset patients, and it increases with diagnostic delay. The analysis of lymphocyte subsets in the pediatric-onset group showed that CD21 low B cells at diagnosis may be a reliable prognostic marker for the development of immune dysregulation during follow-up, as the ROC curve analysis showed (AUC = 0.796). In the adult-onset group, the percentage of transitional B cells measured at diagnosis showed a significant accuracy (ROC AUC = 0.625) in identifying patients at risk of developing immune dysregulation.

Discussion: The longitudinal evaluation of lymphocyte subsets combined with clinical phenotype can improve the prediction of lymphoid proliferation and allow experts to achieve early detection and better management of such complex disorder.

Keywords: CD21low B cells; autoimmunity; common variable immunodeficiency (CVID); cytopenia; immune dysregulation; inborn errors of immunity; lymphoid proliferation.

Figure 1

Demographic distribution of age and sex of the whole CVID cohort.

Figure 2

CVID complications of the whole cohort. The comparison between manifestations at diagnosis (full colored) and follow-up (colorful stripped) is shown if significate: **p < 0.001; *p < 0.05.

Figure 3

The patients’ year of birth has been plotted with the time of diagnostic delay. The correlation index (R²) is also shown.

Figure 4

Distribution of B, T and NK cell subsets, switched memory B cells, CD21 low B cells, and transitional B cells at diagnosis and follow up in the pediatric-onset group.

Figure 5

Distribution of B, T and NK cell subsets, switched memory B cells, CD21low B cells, and transitional B cells at diagnosis and follow up in the adult-onset group.

Figure 6

Distribution of patients according to Chapel et al clinical phenotypes (7) at diagnosis and follow-up in the pediatric-onset and adult-onset groups.

Figure 7

Prevalence of complications of immune dysregulation at diagnosis and at follow-up in the pediatric-onset (A) and adult-onset patients (B).

Figure 8

Prevalence of autoimmune cytopenias at diagnosis and at follow up in the pediatric-onset and adult-onset groups.

Figure 9

Cumulative risk curves of developing immune dysregulation observed in the pediatric-onset group (green line) and the adult-onset group (blue line) according to age at diagnosis of CVID (A) and time of CVID follow-up (B).

Figure 10

ROC curve analysis to predict immune dysregulation at follow-up of switched memory B cells (%), CD21low cells (%), and transitional B cells (%) measured at diagnosis in the pediatric-onset group. Details of the area under the curve (AUC) on the graph.

Figure 11

ROC curve analysis to predict the presence of immune dysregulation of switched memory B cells (%), CD21low cells (%), and the transitional B cells (%) measured at follow-up in the pediatric-onset group (A) and adult-onset (B) group.