National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Leidos Biomedical Research, Inc, Frederick, Maryland, USA.
Clin Infect Dis. 2023 Feb 8;76(3):e561-e570. doi: 10.1093/cid/ciac717.
People with HIV and mycobacterial infections can develop immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral therapy (ART). Severe mycobacterial IRIS has an overlapping clinical phenotype with hemophagocytic lymphohistiocytosis (HLH). We evaluated the pathophysiologic similarities between mycobacterial IRIS and HLH to identify clinical and immune predictors of mycobacterial IRIS severity.
HLH criteria were applied to a longitudinal cohort of 80 patients with HIV (CD4 <100 cells/µL) and mycobacterial infections. Participants were subdivided into IRIS meeting HLH criteria (HLH-IRIS), IRIS without HLH (IRIS), and those without IRIS (non-IRIS). Clinical outcomes were evaluated by regression analyses. Soluble biomarkers and T-cell subsets were assessed at baseline and IRIS-equivalent time points.
HLH-IRIS patients required corticosteroids more frequently (OR: 21.5; 95%CI: 5.6-114.8) and for longer duration (21.2; 95%CI: 10.7-31.7 weeks) than those not meeting HLH criteria. Utilizing decision tree analyses, hemoglobin <9.2 g/dL was the best predictor of HLH-IRIS before ART, whereas ferritin, CXCL9 and sCD25 were most diagnostic for HLH at IRIS onset. At the IRIS timepoint, but not baseline, HLH-IRIS patients had lower regulatory and higher activated T cells along with greater production of IFNγ-IL-18 axis biomarkers compared with both IRIS and non-IRIS groups. Principal component analysis corroborated the distinct clustering of HLH-IRIS patients.
Severe mycobacterial IRIS and HLH have an overlapping pathogenesis involving IFNγ and unopposed T-cell activation causing severe inflammatory disease clinically distinguished by hyperferritinemia (hyperferritinemic IRIS [FIRIS]). Hemoglobin, ferritin, CXCL9, and sCD25 identify high-risk patients and may improve risk stratification and therapeutic strategies for mycobacterial IRIS.
在开始抗逆转录病毒治疗（ART）后，HIV 感染者和分枝杆菌感染者可能会出现免疫重建炎症综合征（IRIS）。严重分枝杆菌 IRIS 与噬血细胞性淋巴组织细胞增生症（HLH）具有重叠的临床表型。我们评估了分枝杆菌 IRIS 和 HLH 的病理生理相似性，以确定分枝杆菌 IRIS 严重程度的临床和免疫预测指标。
HLH 标准适用于 80 名 HIV（CD4<100 个/μL）和分枝杆菌感染患者的纵向队列。参与者被分为符合 HLH 标准的 IRIS（HLH-IRIS）、不符合 HLH 标准的 IRIS（IRIS）和无 IRIS 的患者（非 IRIS）。通过回归分析评估临床结局。在基线和 IRIS 等效时间点评估可溶性生物标志物和 T 细胞亚群。
HLH-IRIS 患者更频繁（比值比：21.5；95%置信区间：5.6-114.8）和更长时间（21.2；95%置信区间：10.7-31.7 周）需要使用皮质类固醇。在 ART 之前，血红蛋白<9.2 g/dL 是预测 HLH-IRIS 的最佳指标，而 ferritin、CXCL9 和 sCD25 在 IRIS 发病时对 HLH 的诊断最具诊断价值。在 IRIS 时间点，但不在基线时，与 IRIS 和非 IRIS 组相比，HLH-IRIS 患者的调节性 T 细胞更低，激活性 T 细胞更高，IFNγ-IL-18 轴生物标志物的产生更多。主成分分析证实了 HLH-IRIS 患者的明显聚类。
严重分枝杆菌 IRIS 和 HLH 的发病机制重叠，涉及 IFNγ 和未被抑制的 T 细胞激活，导致临床上以高 ferritinemia（高 ferritinemic IRIS [FIRIS]）为特征的严重炎症性疾病。血红蛋白、ferritin、CXCL9 和 sCD25 可识别高危患者，并可能改善分枝杆菌 IRIS 的风险分层和治疗策略。
