More Details of Rare Immune Disease Idiopathic CD4 Lymphocytopenia Discovered

National Institutes of Health researchers shared new details about idiopathic CD4 lymphocytopenia (ICL), a rare immune deficiency that leaves people vulnerable to infectious diseases, autoimmune diseases and cancers. Findings were published this week in New England Journal of Medicine.

ICL is a condition marked by too few CD4+ T-cells and has limited therapeutic options.

The clinical definition of ICL is a CD4+ T-cell count of less than 300 cells per cubic millimeter (mm³) of blood for at least 6 weeks, in the absence of any disease or therapy associated with reduced white blood cells.

Unlike HIV, a virus that suppresses the immune system if left untreated, there is no evidence that ICL is transmitted from person to person. It has no known cause.

Researchers evaluated the clinical, genetic, immunologic, and prognostic characteristics of 108 patients enrolled over 11 years and performed whole-exome and targeted gene sequencing to identify genetic causes of lymphopenia. They conducted longitudinal linear mixed-model analyses of T-cell count trajectories and evaluated predictors of clinical events, the response to immunization against COVID-19, and mortality.

Patients with genetic and acquired causes of CD4 lymphopenia were excluded.

Ninety-one patients with ICL were analyzed. Over 374 person-years of follow-up, results showed:

• Median CD4+ T-cell count was 80 cells per cubic millimeter
• The most prevalent opportunistic infections were diseases related to human papillomavirus (29%), cryptococcosis (24%), molluscum contagiosum (9%), and nontuberculous mycobacterial diseases (5%).
• A reduced CD4 count (<100 cells per cubic millimeter), as compared with a CD4 count of 101 to 300 cells, was linked with a higher risk of opportunistic infection (odds ratio [OR], 5.3; 95% CI, 2.8-10.7) and invasive cancer (OR, 2.1; 95% CI, 1.1-4.3) and a lower risk of autoimmunity (OR, 0.5; 95% CI, 0.2-0.9).
• The risk of death was similar to that in the age- and sex-adjusted general population, but cancer prevalence was higher.

Patients with the most severe cases of ICL had the highest risk of acquiring or developing several of the diseases associated with this immune deficiency.

Participants with CD4+ T-cell counts below 100 cells per mm³ had a more than 5-fold higher risk of opportunistic infections than those with CD4+ T-cell counts above 100 cells. Cancer risk was also higher in individuals with the lowest CD4+ T-cell counts, but the risk of autoimmune disease was lower.

“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,” researchers concluded.

The higher cancer prevalence "supports primary and secondary cancer preventive strategies in ICL management," they wrote.

Reference

Lisco A, Ortega-Villa A, Mystakelis H, et al. Reappraisal of idiopathic CD4 lymphocytopenia at 30 Years. N Engl J Med. 2023;388(18):1680-1691. doi:0.1056/NEJMoa2202348.