艾滋病毒相关的隐球菌脑膜炎（HIV-CM）患者在经过CM的最佳治疗后，即使脑脊液（CSF）真菌培养为阴性，仍有持续的颅内炎症，这可能对中枢神经系统造成毁灭性影响。然而，对于经过最佳抗真菌治疗仍具有持续性颅内炎症的明确治疗策略尚未确定。我们确定了14例持续颅内炎症的HIV-CM患者，并进行了一项为期24周的前瞻性干预研究。所有参与者在28天的周期中的第1至21天内口服依托利麦德（25毫克）。随访持续24周，包括基线和第4、8、12和24周的访问。主要终点是依托利麦德治疗后临床表现、常规CSF参数和MRI结果的变化。对CSF细胞因子水平的变化进行了探索性分析。对至少接受一次依托利麦德的患者进行了安全性和疗效分析。在14名参与者中，11名患者完成了24周的随访。依托利麦德治疗后观察到快速的临床缓解。临床表现（发热、头痛、意识改变）在第4周完全逆转，并在随访期内保持稳定。在第4周观察到CSF白细胞（WBC）计数显著降低（P=0.009）。CSF中的中位蛋白质浓度从基线的1.4(0.7-3.2) g/L降低到第4周的0.9(0.6-1.4) g/L（P=0.004）。CSF中的中位白蛋白浓度从基线的79.2(48.4-149.8) mg/L降低到第4周的55.3(38.3-89.0) mg/L（P=0.011）。CSF中的WBC计数、蛋白水平和白蛋白水平保持稳定，并接近正常范围至第24周。在每次访问中，免疫球蛋白G、颅内压力（ICP）或氯离子浓度均未发生明显变化。脑MRI显示多发病变在治疗后吸收。随访24周期间，肿瘤坏死因子α、粒细胞集落刺激因子、白细胞介素（IL）-6和IL-17A的水平显著降低。两名（14.3％）患者出现轻度皮疹，自行缓解。未观察到依托利麦德相关的严重不良事件。依托利麦德显著改善HIV-CM患者持续颅内炎症，并且耐受性良好，未观察到严重的不良事件。需要进行额外的随机对照研究以进一步验证这一发现。 ©2023年作者

Patients with human immunodeficiency virus-associated cryptococcal meningitis (HIV-CM) have persistent intracranial inflammation despite negative cerebrospinal fluid (CSF) fungal cultures after optimal treatment for CM, which could be devastating for the central nervous system. However, a definitive treatment strategy for persistent intracranial inflammation despite optimal antifungal therapies is undefined.We identified 14 HIV-CM patients with persistent intracranial inflammation and conducted a 24-week, prospective, interventional study. All participants received lenalidomide (25 mg, p.o.) on days 1 to 21 of a 28-day cycle. Follow-up lasted for 24 weeks with visits at baseline and weeks 4, 8, 12, and 24. The primary endpoint was the change in clinical manifestations, routine CSF parameters, and MRI findings after lenalidomide treatment. An exploratory analysis was made on changes in cytokine levels in CSF. Safety and efficacy analyses were undertaken in patients who received at least one dose of lenalidomide.Of 14 participants, 11 patients completed the 24 weeks of follow-up. Rapid clinical remission following lenalidomide therapy was observed. Clinical manifestations (fever, headache, altered mentation) were reversed fully by week-4 and remained stable during follow-up. A significant reduction in white blood cell (WBC) count in CSF was noted occurred at week-4 (P = 0.009). The median protein concentration in CSF decreased from 1.4 (0.7-3.2) g/L at baseline to 0.9 (0.6-1.4) at week-4 (P = 0.004). The median albumin concentration in CSF decreased from 79.2 (48.4-149.8) mg/L at baseline to 55.3 (38.3-89.0) mg/L at week-4 (P = 0.011). The WBC count, protein level, and albumin level in CSF remained stable and approached a normal range through week-24. There was no significant change in immunoglobulin-G, intracranial pressure (ICP), or chloride-ion concentration at each visit. Brain MRI demonstrated multiple lesions to be absorbed post-therapy. Levels of tumor necrosis factor-α granulocyte colony stimulating factor, interleukin (IL)-6, and IL-17A decreased significantly during 24-week follow-up. Two (14.3%) patients had mild skin rash, which resolved spontaneously. Lenalidomide-related serious adverse events were not observed.Lenalidomide could improve persistent intracranial inflammation in HIV-CM patients significantly and was well tolerated without serious adverse events observed. And the additional randomized controlled study is required to further validate the finding.© 2023. The Author(s).