Reappraisal of Idiopathic CD4 Lymphocytopenia at 30 Years

Abstract

Background: Idiopathic CD4 lymphocytopenia (ICL) is a clinical syndrome that is defined by CD4 lymphopenia of less than 300 cells per cubic millimeter in the absence of any primary or acquired cause of immunodeficiency. Some 30 years after its original identification, ICL has remained a disease of obscure cause, with limited evidence with respect to its prognosis or management, despite diagnostic and therapeutic innovations.

Methods: We evaluated the clinical, genetic, immunologic, and prognostic characteristics of 108 patients who were enrolled during an 11-year period. We performed whole-exome and targeted gene sequencing to identify genetic causes of lymphopenia. We also performed longitudinal linear mixed-model analyses of T-cell count trajectories and evaluated predictors of clinical events, the response to immunization against coronavirus disease 2019 (Covid-19), and mortality.

Results: After the exclusion of patients with genetic and acquired causes of CD4 lymphopenia, the study population included 91 patients with ICL during 374 person-years of follow-up. The median CD4+ T-cell count among the patients was 80 cells per cubic millimeter. The most prevalent opportunistic infections were diseases related to human papillomavirus (in 29%), cryptococcosis (in 24%), molluscum contagiosum (in 9%), and nontuberculous mycobacterial diseases (in 5%). A reduced CD4 count (<100 cells per cubic millimeter), as compared with a CD4 count of 101 to 300 cells, was associated with a higher risk of opportunistic infection (odds ratio, 5.3; 95% confidence interval [CI], 2.8 to 10.7) and invasive cancer (odds ratio, 2.1; 95% CI, 1.1 to 4.3) and a lower risk of autoimmunity (odds ratio, 0.5; 95% CI, 0.2 to 0.9). The risk of death was similar to that in the age- and sex-adjusted general population, but the prevalence of cancer was higher.

Conclusions: Among the study patients, ICL continued to be associated with increased susceptibility to viral, encapsulated fungal, and mycobacterial diseases, as well as with a reduced response to novel antigens and an increased risk of cancer. (Funded by the National Institute of Allergy and Infectious Diseases and the National Cancer Institute; ClinicalTrials.gov number, NCT00867269.).

Figure 1.. Distribution of CD4, CD8, and NK Cell Counts in Patients with Opportunistic Infections, Cancers, and Autoimmune Diseases.

Shown are the median absolute numbers of CD4+ and CD8+ T cells and natural killer (NK) cells in the study patients, according to the presence or absence of opportunistic infection of clinical significance (Panel A), cancer (Panel B), and autoimmune disease (Panel C) (upper panels). The red dashed lines show the cutoffs for the lowest third, middle third, and highest third of the values. In each graph, the horizontal black bar indicates the median value, and the dashed black bars indicate the interquartile range. The lower panels show log-transformed odds ratios for opportunistic infection, cancer, or autoimmune disease among the study patients in the lowest third and middle third of values as compared with the highest third after adjustment for age and sex. Data points in red indicate the odds ratios in which the 95% confidence intervals (represented by error bars) exclude the null value of 1, indicating a significant increase or decrease in the risk of the specified outcome.

Figure 2.. Absolute Values and Trajectories of CD4 and CD8 Counts during Follow-up.

In the upper panels, shown are absolute numbers of CD4+ T cells (Panel A) and CD8+ T cells (Panel B) for all the study patients during 11 years of follow-up. In the lower panels, shown are the longitudinal trajectories of CD4+ T cells (Panel C) and CD8+ T cells (Panel D) over time as evaluated by linear mixed models for longitudinal data.