From the Laboratory of Immunoregulation (A.L., H.M., M.V.A., E.L., M.M., G.R., V.S., I.S.), Biostatistics Research Branch, Division of Clinical Research (A.M.O.-V.), Centralized Sequencing Program, Division of Intramural Research (M.A.W., M.S.), and the Laboratory of Clinical Immunology and Microbiology (A.F.F.), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, the Clinical Monitoring Research Program Directorate (A.M.), Leidos Biomedical Research (J.H.), and the Clinical Research Directorate (S.K.), Frederick National Laboratory for Cancer Research, Frederick, and the Division of Allergy and Immunology, Department of Pediatrics, Johns Hopkins University, Baltimore (J.W.L.) - all in Maryland.
N Engl J Med. 2023 May 4;388(18):1680-1691. doi: 10.1056/NEJMoa2202348.
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.
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.
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.
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.).
特发性 CD4 淋巴细胞减少症（ICL）是一种临床综合征，其定义为在没有任何原发性或获得性免疫缺陷原因的情况下，每立方毫米少于 300 个 CD4 淋巴细胞。在最初发现后的 30 年里，尽管在诊断和治疗方面取得了创新，但 ICL 仍然是一种病因不明的疾病，其预后或治疗方法的证据有限。
我们评估了在 11 年期间入组的 108 名患者的临床、遗传、免疫和预后特征。我们进行了全外显子组和靶向基因测序，以确定淋巴细胞减少的遗传原因。我们还对 T 细胞计数轨迹进行了纵向线性混合模型分析，并评估了临床事件、对 2019 年冠状病毒病（COVID-19）疫苗接种的反应以及死亡率的预测因素。
在排除了 CD4 淋巴细胞减少的遗传和获得性原因后，研究人群包括在 374 人年的随访期间患有 ICL 的 91 名患者。患者的中位 CD4+T 细胞计数为 80 个细胞/立方毫米。最常见的机会性感染是与人类乳头瘤病毒（29%）、隐球菌病（24%）、传染性软疣（9%）和非结核分枝杆菌病（5%）相关的疾病。与 CD4 计数为 101 至 300 个细胞相比，CD4 计数<100 个细胞/立方毫米与机会性感染（比值比，5.3；95%置信区间[CI]，2.8 至 10.7）和侵袭性癌症（比值比，2.1；95%CI，1.1 至 4.3）的风险增加以及自身免疫（比值比，0.5；95%CI，0.2 至 0.9）的风险降低相关。死亡风险与年龄和性别调整后的一般人群相似，但癌症患病率更高。
在研究患者中，ICL 仍然与病毒、囊包真菌和分枝杆菌疾病的易感性增加、对新型抗原的反应降低以及癌症风险增加有关。（由美国国家过敏和传染病研究所和美国国家癌症研究所资助；ClinicalTrials.gov 编号，NCT00867269）。
