白细胞介素-18结合蛋白对特发性肺纤维化预后的临床意义

doi:10.3877/cma.j.issn.1674-6902.2025.05.008

目的

分析支气管肺泡灌洗液(bronchoalveolar lavage fluid, BALF)和血清白细胞介素-18结合蛋白(interleukin-18 binding protein, IL-18BP)对特发性肺纤维化(idiopathic pulmonary fibrosis, IPF)预后的临床意义。

方法

前瞻性选择2019年1月至2023年12月我院收治的IPF患者87例为对象，接受抗纤维化治疗，采用酶联免疫吸附试验法检测BALF和血清IL-18BP水平。根据IPF患者预后情况分组，治疗后生存为对照组52例，救治无效死亡者为观察组35例。

结果

87例患者血清IL-18BP水平3.40(0.67，120.64)ng/ml，BALF IL-18BP水平为3.12( 0.06，72.97)ng/ml。中位随访36个月，死亡35例(40.23%)，1年内病情急性加重27例(31.03%)。观察组血清IL-18BP 12.04(5.05，33.14)ng/ml和BALF IL-18BP 2.53(1.15，4.44)ng/ml高于对照组IL-18BP 2.55(1.82，3.40)ng/ml和BALF IL-18BP 3.65(1.66，6.25)ng/ml(P<0.05)。Spearman秩相关性分析显示，血清IL-18BP与BALF IL-18BP水平正相关(r＝0.215，P＝0.020)。急性加重者血清IL-18BP 56.12(22.99，124.37)ng/ml高于无急性加重者4.92(2.39，11.85)ng/ml(Z＝－4.787，P<0.001)。血清IL-18BP水平预测IPF相关预后受试者工作特征(receiver operating characteristic, ROC)曲线下面积(area under the curve, AUC)0.864，截断值5.10 ng/ml(P<0.05)。多因素COX风险回归分析显示，血清IL-18BP高水平是影响IPF预后的危险因素(P<0.05)。Kaplan-Meier曲线分析显示，血清IL-18BP低水平(<5.10 ng/ml)54例中生存47例(87.04%)，高水平(≥5.10 ng/ml)33例中生存5例(15.15%)，中位OS分别为34、26个月(χ²＝47.795，P<0.001)。Spearman秩相关性分析显示，血清IL-18BP水平与一氧化碳弥散量(diffusing capacity of the lung for carbon monoxide, DLCO)%呈负相关(r＝－0.193，P＝0.037)。

结论

高血清IL-18BP水平与IPF预后不良有关，血清IL-18BP可为IPF早期风险分层标志物。

关键词: 特发性肺纤维化, 白细胞介素-18结合蛋白, 支气管肺泡灌洗液, 预后

Objective

To analyze the clinical significance of bronchoalveolar lavage fluid (BALF) and serum interleukin-18 binding protein (IL-18BP) in predicting the prognosis of idiopathic pulmonary fibrosis (IPF).

Methods

Eighty-seven IPF patients admitted to our hospital between January 2019 and December 2023 were prospectively enrolled. All received antifibrotic therapy. Serum and BALF IL-18BP levels were measured using enzyme-linked immunosorbent assay (ELISA). The patients were grouped according to their survival status. 52 surviving cases were assigned to the control group, and 35 deceased cases were assigned to the observation group.

Results

The median serum IL-18BP level across all 87 patients was 3.40 (IQR: 0.67, 120.64) ng/ml, and the median BALF IL-18BP level was 3.12 (IQR: 0.06, 72.97) ng/ml. During a median follow-up of 36 months, 35 patients (40.23%) died. 27 cases (31.03%) experienced acute exacerbation within one year. The observation group had significantly higher serum IL-18BP levels [12.04 (5.05, 33.14)ng/ml] and significantly lower BALF IL-18BP levels [2.53 (1.15, 4.44) ng/ml] compared to the control group [serum: 2.55 (1.82, 3.40) ng/ml, BALF: 3.65 (1.66, 6.25) ng/ml] (P<0.05). Spearman rank correlation analysis revealed a positive correlation between serum and BALF IL-18BP levels (r=0.215, P=0.020). Serum IL-18BP levels were significantly higher in AE patients [56.12 (22.99, 124.37) ng/ml] compared to non-AE patients [4.92(2.39, 11.85) ng/ml] (Z=-4.787, P<0.001). Receiver operating characteristic (ROC) curve analysis showed serum IL-18BP predicted IPF-related death with an area under the curve (AUC) of 0.864, and an optimal cutoff value of 5.10 ng/ml (P<0.05). Multivariate Cox proportional hazards regression analysis identified high serum IL-18BP level as an independent risk factor for poor IPF prognosis (P<0.05). Kaplan-Meier curve analysis showed that among 54 cases with low serum IL-18BP level (<5.10 ng/ml), 47 cases (87.04%) survived, and among 33 cases with high serum IL-18bp level (≥5.10 ng/ml), 5 cases (15.15%) survived. The median OS was 34 and 26 months respectively (χ²=47.795, P<0.001). Spearman rank correlation analysis showed a negative correlation between serum IL-18BP levels and diffusing capacity of the lung for carbon monoxide (DLCO)% predicted (r=-0.193, P=0.037).

Conclusion

High serum IL-18BP levels are associated with a significantly increased risk of poor prognosis in IPF. Serum IL-18BP may serve as a biomarker for early risk stratification in IPF.

Key words: Idiopathic pulmonary fibrosis, Interleukin-18 binding protein, Bronchoalveolar lavage fluid, Prognosis

表1 两组IPF患者临床资料结果比较

临床资料	观察组(n＝35)	对照组(n＝52)	t/χ²/Z	P值
吸烟史[n(%)]			1.767	0.413
从未	9(25.71)	13(25.0)
现在	22(62.86)	29(55.77)
既往	3(8.57)	10(19.23)
吸烟指数[M(M₂₅，M₇₅)]	20.00(1.25，37.50)	20.00(0.00，34.00)	－0.016	0.916
病史[n(%)]
糖尿病	21(40.38)	10(28.57)	1.273	0.259
高血压	20(38.46)	14(40.0)	0.021	0.885
冠心病	14(26.92)	8(22.86)	0.183	0.669
哮喘	0(0.0)	1(2.86)	－	0.402
抗纤维化药物[n(%)]
吡非尼酮	17(48.57)	34(65.38)	2.438	0.118
尼达尼布	7(20.0)	13(25.0)	0.295	0.587
其他用药[n(%)]
乙酰半胱氨酸片	11(31.43)	19(36.54)	0.242	0.623
质子泵抑制剂	7(20.0)	14(26.92)	0.548	0.459
肺功能指标
FVC%[%，(±s)]	79.81±16.87	88.08±17.00	2.232	0.028
FEV₁%[%，(±s)]	93.71±19.26	98.65±20.66	1.123	0.264
DLCO%[%，(±s)]	71.63±20.39	81.98±21.25	2.264	0.026
炎症指标
白细胞计数[×10⁹/L，M(M₂₅，M₇₅)]	7.67(6.35，9.67)	6.68(5.09，9.18)	－1.446	0.148
C反应蛋白[mg/L，M(M₂₅，M₇₅)]	8.10(1.90，34.30)	3.15(1.00，12.98)	－1.558	0.119
红细胞沉降率[mm/1 h，M(M₂₅，M₇₅)]	25.00(10.00，37.00)	17.00(10.00，28.00)	－1.668	0.095

表1 两组IPF患者临床资料结果比较

临床资料	观察组(n＝35)	对照组(n＝52)	t/χ²/Z	P值
吸烟史[n(%)]			1.767	0.413
从未	9(25.71)	13(25.0)
现在	22(62.86)	29(55.77)
既往	3(8.57)	10(19.23)
吸烟指数[M(M₂₅，M₇₅)]	20.00(1.25，37.50)	20.00(0.00，34.00)	－0.016	0.916
病史[n(%)]
糖尿病	21(40.38)	10(28.57)	1.273	0.259
高血压	20(38.46)	14(40.0)	0.021	0.885
冠心病	14(26.92)	8(22.86)	0.183	0.669
哮喘	0(0.0)	1(2.86)	－	0.402
抗纤维化药物[n(%)]
吡非尼酮	17(48.57)	34(65.38)	2.438	0.118
尼达尼布	7(20.0)	13(25.0)	0.295	0.587
其他用药[n(%)]
乙酰半胱氨酸片	11(31.43)	19(36.54)	0.242	0.623
质子泵抑制剂	7(20.0)	14(26.92)	0.548	0.459
肺功能指标
FVC%[%，(±s)]	79.81±16.87	88.08±17.00	2.232	0.028
FEV₁%[%，(±s)]	93.71±19.26	98.65±20.66	1.123	0.264
DLCO%[%，(±s)]	71.63±20.39	81.98±21.25	2.264	0.026
炎症指标
白细胞计数[×10⁹/L，M(M₂₅，M₇₅)]	7.67(6.35，9.67)	6.68(5.09，9.18)	－1.446	0.148
C反应蛋白[mg/L，M(M₂₅，M₇₅)]	8.10(1.90，34.30)	3.15(1.00，12.98)	－1.558	0.119
红细胞沉降率[mm/1 h，M(M₂₅，M₇₅)]	25.00(10.00，37.00)	17.00(10.00，28.00)	－1.668	0.095

图1 IPF患者肺部CT影像学表现。图A为胸廓对称，双肺多发斑片、条索、网格影，胸膜下为著，病灶内见支气管牵拉扩张。双侧肺门及纵隔淋巴结增多，部分增大，双侧胸膜增厚；图B为胸廓对称，双肺见多发磨玻璃、网状影及蜂窝状影，以双肺下叶为主，病灶分布在双肺下叶基底段及肺野外周带胸膜下，见少许支气管牵拉扩张；纵隔内淋巴结增多、增大，双侧胸膜增厚

图2 IPF患者血清IL-18BP与肺功能相关性散点。图A为血清IL-18BP与DLCO%相关性；图B为血清IL-18BP与FVC%相关性；图C为血清IL-18BP与FEV₁%相关性注：FEV₁为1秒用力呼气容积；FVC为用力肺活量；DLCO为一氧化碳弥散量；IL-18BP为白细胞介素-18结合蛋白

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Clinical significance of interleukin-18 binding protein in the prognosis of idiopathic pulmonary fibrosis

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Clinical significance of interleukin-18 binding protein in the prognosis of idiopathic pulmonary fibrosis