Reappraisal of Idiopathic CD4 Lymphocytopenia at 30 Years.

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-exorne and targeted gene sequencing to identify genetic causes of Iymphopenia. We also performed longitudinal linear mixed-model analyses of T-cell count tra-Jectories 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 lymphoat penia, 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°6), cryptococcosis (in 2490), molluscum contagiosum On 996), and nontuberculous mycobacterial diseases (in 5°/o). A re-duced 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 ICI], 2.8 to 10.7) and invasive cancer Codds 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 sexadjusted 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 In fectious Diseases and the National Cancer Institute; ClinicalTrials.gov number, NCT00867269). [ABSTRACT FROM AUTHOR]