Idiopathic CD4 lymphocytopenia: clinical and immunologic characteristics and follow-up of 40 patients

Abstract

Idiopathic CD4 T lymphocytopenia (ICL) is a rare and severe condition with limited available data. We conducted a French multicenter study to analyze the clinical and immunologic characteristics of a cohort of patients with ICL according to the Centers for Disease Control criteria.We recruited 40 patients (24 female) of mean age 44.2 ± 12.2 (19-70) years. Patients underwent T-lymphocyte phenotyping and lymphoproliferation assay at diagnosis, and experiments related to thymic function and interferon (IFN)-γ release by natural killer (NK) cell were performed. Mean follow-up was 6.9 ± 6.7 (0.14-24.3) years. Infectious, autoimmune, and neoplastic events were recorded, as were outcomes of interleukin 2 therapy.In all, 25 patients had opportunistic infections (12 with human papillomavirus infection), 14 had autoimmune symptoms, 5 had malignancies, and 8 had mild or no symptoms. At the time of diagnosis, the mean cell counts were as follows: mean CD4 cell count: 127/mm (range, 4-294); mean CD8: 236/mm (range, 1-1293); mean CD19: 113/mm (range, 3-547); and mean NK cell count: 122/mm (range, 5-416). Most patients had deficiency in CD8, CD19, and/or NK cells. Cytotoxic function of NK cells was normal, and patients with infections had a significantly lower NK cell count than those without (p = 0.01). Patients with autoimmune manifestations had increased CD8 T-cell count. Proliferation of thymic precursors, as assessed by T-cell rearrangement excision circles, was increased. Six patients died (15%). CD4 T-cell count <150/mm and NK cell count <100/mm were predictors of death.In conclusion, ICL is a heterogeneous disorder often associated with deficiencies in CD8, CD19, and/or NK cells. Long-term prognosis may be related to initial CD4 and NK cell deficiency.

FIGURE 1

Biological heterogeneity of patients with idiopathic CD4 lymphocytopenia (ICL) at diagnosis and clinical manifestations during follow-up. A. Classification of patients with ICL by main clinical manifestations (n = 40); (B) lymphocyte subpopulation deficiencies (n = 37); and (C) clinical manifestation according to subpopulation-associated cell deficiency. CD19, CD8, and NK cell counts were available for only 37 patients at diagnosis.

FIGURE 2

Descriptive analysis of lymphocyte populations and subpopulations. Positive correlations of CD4 (A1), CD8 (A2), CD19 (A3), and CD3-CD16+CD56+ NK (A4) counts and lymphocyte count. Negative correlations of CD45RO+ memory (B1) and HLA-DR+ –activated (B2) residual CD4 lymphocytes and CD4 lymphocytopenia severity. Dashed lines represent normal values ± 2 SDs. Abbreviations: R2 = goodness-of-fit of linear regression, p = probability that slope is null.

FIGURE 3

A. T-lymphocyte proliferation induced by mitogens (PHA, CD3, CD3+CD28, CD3+IL-2, PWD). B. T-lymphocyte proliferation induced by antigens (CMV, candidin, tuberculin, streptococcal enzyme). A positive test result is defined as both thymidine incorporation (cpm) above threshold (dashed line) and a positive stimulation index (SI). Positive and negative SIs are represented by black (positive) and open (negative) dots. Abbreviations: CMV = cytomegalovirus, cpm = count per minute, PHA = phytohemagglutinin, PWD = pokeweed.

FIGURE 4

Survival in 40 patients with ICL by lymphocyte subpopulation counts. Kaplan-Meier survival curves by (A) initial NK cell count and (B) combined CD4 T-lymphocyte and NK cell count.

FIGURE 5

T-cell rearrangement excision circles (TRECs) in patients with ICL and healthy control individuals. Quantification of (A) sjTRECs/10⁵ naive T cells and (B) sj/βTREC ratio in patients with ICL and healthy controls. Abbreviations: R² = Spearman correlation, p = associated probability.

FIGURE 6

IFN-γ production by NK cells from patients with ICL and healthy control individuals. Peripheral blood mononuclear cells were collected from ICL patients and healthy donors to determine the proportion of IFN-γ–producing NK cells after overnight treatment with IL-12 and IL-18. Samples were gated on CD3-CD56+ NK cells. Horizontal bars indicate the mean.