Idiopathic CD4+ lymphocytopenia: natural history and prognostic factors

Abstract

Idiopathic CD4(+) lymphocytopenia (ICL) is a rare non-HIV-related syndrome with unclear natural history and prognosis. This prospective natural history cohort study describes the clinical course, CD4 T lymphocyte kinetics, outcome, and prognostic factors of ICL. Thirty-nine patients (17 men, 22 women) 25 to 85 years old with ICL were evaluated between 1992 and 2006, and 36 were followed for a median of 49.5 months. Cryptococcal and nontuberculous mycobacterial infections were the major presenting opportunistic infections. Seven patients presented with no infection. In 32, CD4 T-cell counts remained less than 300/mm(3) throughout the study period and in 7 normalized after an average of 31 months. Overall, 15 (41.6%) developed an opportunistic infection in follow-up, 5 (13.8%) of which were "AIDS-defining clinical conditions," and 4 (11.1%) developed autoimmune diseases. Seven patients died, 4 from ICL-related opportunistic infections, within 42 months after diagnosis. Immunologic analyses revealed increased activation and turnover in CD4 but not CD8 T lymphocytes. CD8 T lymphocytopenia (< 180/mm(3)) and the degree of CD4 T cell activation (measured by HLA-DR expression) at presentation were associated with adverse outcome (opportunistic infection-related death; P = .003 and .02, respectively).

Trial registration: ClinicalTrials.gov NCT00001319.

Figure 1

Immunologic investigation of ICL patients. The percentage of HLA-DR⁺ (A), Ki-67⁺ (C), and Foxp3⁺ (D) expression within CD4 T lymphocytes is higher in 21 ICL patients compared with 10 controls. Naive (E) and CD127 ⁺ (F) cells are lower in CD4 T lymphocytes of ICL patients compared with controls. There is no difference in HLA-DR⁺ (A), Ki-67⁺ (C), and CD127⁺ (F) expression within the CD8T lymphocyte subset in ICL patients and controls. Naive (E) cells are lower in CD8 T lymphocytes of ICL patients compared with controls. Finally, there is a negative correlation between expression of HLA-DR on CD4 T cells and the CD4 T-cell count in 28 ICL patients (B). Horizontal lines represent median values.

Figure 2

Kaplan-Meier curve for the occurrence of “AIDS-defining clinical conditions” during follow-up. Five “AIDS-defining” opportunistic infections occurred during the follow-up of 36 patients with ICL within the first 24 months of follow-up. Bottom line represents the number of ICL patients still on follow-up at 12-month intervals. Vertical lines represent the time at which patients were censored (end of follow-up or occurrence of an “AIDS-defining clinical condition”). MAC indicates M avium complex; EBVLPD, Epstein-Barr virus lymphoproliferative disease; PCP, P jirovecii pneumonia; PML, progressive multifocal leucoencephalopathy.

Figure 3

Kaplan-Meier curves of patients with low and high CD8 T-cell counts at diagnosis (< 180/mm³ or > 180/mm³, respectively). (A) All-cause survival. (B) Opportunistic infection (AIDS-defining illness)–related survival. The P value for the exact log rank test is also provided. Bottom lines represent the number of ICL patients still in follow-up at 12-month intervals. Vertical lines represent the time at which patients were censored: (A) at end of follow-up and (B) at end of follow-up or non-ICL death. In Figure 1A, one patient with high CD8 T-cell count died of a nonopportunistic infection after 96 months (at 114 months).

Figure 4

CD4 T-cell counts from 39 ICL subjects during follow-up. Individual CD4 trajectories are shown for 5 subjects whose median CD4 T-cell count among those with at least 2 years of follow-up and 4 measurements was the minimum, maximum, or an innerquartile trajectory. The average individual trend fitted from the linear mixed model is also shown (bold solid line). The slope (SD) of the estimated trend is 0.66/mm³ per month (95% confidence interval, −0.20-1.54).