呼吸道过敏原特异性IgE累积水平与重度哮喘奥马珠单抗治疗反应性的关系

doi:10.3877/cma.j.issn.1674-6902.2023.05.004

目的

分析呼吸道过敏原特异性免疫球蛋白E(sIgE)累积水平与重度哮喘奥马珠单抗治疗反应性的关系。

方法

选择2020年10月至2022年6月我院收治的经奥马珠单抗治疗重度哮喘患者106例，根据国际疾病分类，过敏性哮喘57例，非过敏性哮喘40例和混合型哮喘9例。采用标准经验过敏诊断(过敏记忆、皮肤点刺试验、传统途径的总IgE和过敏原sIgE测定)、血液嗜酸性粒细胞计数、Phadiatop™测试对呼吸道过敏原sIgE累积水平。34例过敏性哮喘患者经奥马珠单抗治疗12个月，评估临床疗效。

结果

在过敏性和混合性严重哮喘患者中，通过Phadiatop™测试确定的呼吸道过敏原sIgE累积水平高于非过敏性哮喘患者(P<0.001)。区分过敏性哮喘和非过敏性哮喘的受试者工作特征曲线下面积为0.891±0.038，最佳临界值0.24 kAU/L。Phadiatop™测试≥0.24 kAU/L为阳性，过敏记忆＋Phadiatop™测试阳性诊断过敏性哮喘的患病率为84.21%(48/57)，高于过敏记忆＋sIgE阳性(56.14%，32/57)，P＝0.001。34例经奥马珠单抗治疗过敏性哮喘患者中，8例症状控制良好，Phadiatop™测试≥1.55 kAU/L可良好预测奥马珠单抗治疗反应，最佳灵敏度和特异性分别为100.0%和76.90%。

结论

Phadiatop™测试优于TIgE水平的测量和用于识别重度过敏性哮喘患者的过敏诊断经典假设驱动方法，可提高IgE靶向哮喘治疗的临床疗效。

关键词: 重度哮喘, 奥马珠单抗, Phadiatop?测试, 呼吸道过敏原特异性免疫球蛋白E累积水平

Objective

To evaluate the relationship between the cumulative level of respiratory allergen specific immunoglobulin E (sIgE) and the reactivity of omalizumab in severe asthma.

Methods

All of 106 0patients with severe asthma who received omalizumab in our hospital from October 2020 to June 2022 were retrospectively included. According to the International Classification of Diseases, there were 57 cases of allergic asthma, 40 cases of non-allergic asthma and 9 cases of mixed asthma. Standard empirical allergy diagnosis (anaphylaxis memory, skin prick test, total IgE and allergen sIgE determination by traditional route), blood eosinophilic count, Phadiatop™ test for measurement of respiratory allergen sIgE accumulation levels were performed. 34 patients with allergic asthma were treated with omalizumab for 12 months to evaluate the clinical efficacy.

Results

Accumulative levels of respiratory allergen sIgE determined by Phadiatop™ testing were significantly higher in patients with allergic and mixed severe asthma than in patients with non-allergic asthma (P<0.001). The area under the subject operating characteristic curve to distinguish allergic asthma from non-allergic asthma was calculated as 0.891±0.038, and the optimal cutoff value was 0.24 kAU/L. Phadiatop™ test ≥0.24 kAU/L was regarded as positive, and the prevalence of allergic asthma diagnosed by positive anaphylactic memory+ Phadiatop™ test was 84.21% (48/57), slightly higher than that diagnosed by positive anaphylactic memory + sIgE (56.14%, 32/57), P=0.001. Among 34 patients with allergic asthma who received omalizumab treatment, 8 patients had good symptom control. Phadiatop™ test ≥1.55 kAU/L could predict omalizumab treatment response well, and the optimal sensitivity and specificity were 100.0% and 76.90%, respectively.

Conclusion

The Phadiatop™ test appears to outperform the measurement of TIgE levels and the classical hypothesis-driven approach to allergy diagnosis used to identify patients with severe allergic asthma, and may improve the clinical efficacy of IGE-targeted asthma therapy.

Key words: Severe asthma, Omalizumab, Phadiatop? test, Cumulative levels of respiratory allergen specific immunoglobulin E

表1 重度哮喘患者基线资料比较

临床特征	过敏性哮喘(n＝57)	非过敏性哮喘(n＝40)	混合型哮喘(n＝9)	χ²/F/H	P值
性别(男/女)	19/38	7/33	3/6	3.142	0.208
年龄(岁)	38.93±14.36	34.63±13.57	43.22±15.34	1.842	0.164
吸烟指数(包年)	7.95(0.0，24.79)	2.65(0.0，20.25)	7.50(1.0，9.60)	1.021	0.600
体质量(kg)	66.89±14.60	62.83±14.23	75.11±24.80	2.483	0.088
体质量指数(kg/m²)	26.73±6.02	25.05±5.61	28.84±8.80	1.741	0.181
TIgE水平(IU/ml)	201.29(101.82，431.19)	93.10(19.64，314.29)	186.79(45.94，278.57)	5.373	0.068
过敏原sIgE累积水平(kAU/L)	1.11(0.41，2.67)	0.03(0.01，0.12)	1.06(0.11，3.40)	43.287	0.000
氧饱和度(%)	95.16±2.99	94.43±2.36	93.11±2.32	2.553	0.083
症状VAS(mm)
咳嗽	53.0(28.0，72.0)	50.0(24.0，70.50)	55.0(25.0，78.0)	0.676	0.713
呼吸困难	74.0(44.0，87.0)	70.0(49.0，80.0)	70.0(27.0，80.0)	0.270	0.874
咳痰	25.0(3.0，50.0)	19.0(0.0，24.0)	19.0(0.0，22.0)	3.799	0.150
浓痰	12.0(0.0，53.0)	10.0(0.0，39.50)	10.0(0.0，16.0)	1.744	0.418
淋巴细胞(×10⁹/L)	10.77(9.26，12.98)	11.74(9.19，15.10)	9.11(8.79，10.35)	5.289	0.071
中性粒细胞(×10⁹/L)	7.89(5.84，10.84)	8.71(5.48，11.19)	6.02(5.41，9.20)	2.392	0.302
嗜酸性粒细胞(×10⁹/L)	0.36(0.13，0.81)	0.17(0.03，0.42)^a	0.51(0.16，0.81)^b	10.372	0.006
CRP　(mg/L)	8.50(1.0，23.10)	10.95(2.60，36.0)	24.0(13.40，138.10)^ab	6.623	0.036

表1 重度哮喘患者基线资料比较

临床特征	过敏性哮喘(n＝57)	非过敏性哮喘(n＝40)	混合型哮喘(n＝9)	χ²/F/H	P值
性别(男/女)	19/38	7/33	3/6	3.142	0.208
年龄(岁)	38.93±14.36	34.63±13.57	43.22±15.34	1.842	0.164
吸烟指数(包年)	7.95(0.0，24.79)	2.65(0.0，20.25)	7.50(1.0，9.60)	1.021	0.600
体质量(kg)	66.89±14.60	62.83±14.23	75.11±24.80	2.483	0.088
体质量指数(kg/m²)	26.73±6.02	25.05±5.61	28.84±8.80	1.741	0.181
TIgE水平(IU/ml)	201.29(101.82，431.19)	93.10(19.64，314.29)	186.79(45.94，278.57)	5.373	0.068
过敏原sIgE累积水平(kAU/L)	1.11(0.41，2.67)	0.03(0.01，0.12)	1.06(0.11，3.40)	43.287	0.000
氧饱和度(%)	95.16±2.99	94.43±2.36	93.11±2.32	2.553	0.083
症状VAS(mm)
咳嗽	53.0(28.0，72.0)	50.0(24.0，70.50)	55.0(25.0，78.0)	0.676	0.713
呼吸困难	74.0(44.0，87.0)	70.0(49.0，80.0)	70.0(27.0，80.0)	0.270	0.874
咳痰	25.0(3.0，50.0)	19.0(0.0，24.0)	19.0(0.0，22.0)	3.799	0.150
浓痰	12.0(0.0，53.0)	10.0(0.0，39.50)	10.0(0.0，16.0)	1.744	0.418
淋巴细胞(×10⁹/L)	10.77(9.26，12.98)	11.74(9.19，15.10)	9.11(8.79，10.35)	5.289	0.071
中性粒细胞(×10⁹/L)	7.89(5.84，10.84)	8.71(5.48，11.19)	6.02(5.41，9.20)	2.392	0.302
嗜酸性粒细胞(×10⁹/L)	0.36(0.13，0.81)	0.17(0.03，0.42)^a	0.51(0.16，0.81)^b	10.372	0.006
CRP　(mg/L)	8.50(1.0，23.10)	10.95(2.60，36.0)	24.0(13.40，138.10)^ab	6.623	0.036

图1 根据Phadiatop™测试的过敏原sIgE累积水平表征过敏性哮喘ROC曲线

表2 重度哮喘不同表型Phadiatop™测试结果和标准诊断方法的关系

标准诊断方法	TIgE水平(IU/ml)			过敏原sIgE累积水平(kAU/L)
标准诊断方法	数值	Z值	P值	数值	Z值	P值
皮肤点刺试验		－1.501	0.133		－3.841	0.000
阴性(n＝39)	155.94(20.36，374.57)			0.08(0.01，0.84)
阳性(n＝47)	198.25(105.68，348.85)			0.97(0.34，2.63)
sIgE阳性		－1.140	0.254		－3.295	0.001
阴性(n＝9)	170.51(21.45，381.06)			0.10(0.01，0.94)
阳性(n＝32)	202.46(93.60，477.23)			1.09(0.28，3.40)

表2 重度哮喘不同表型Phadiatop™测试结果和标准诊断方法的关系

标准诊断方法	TIgE水平(IU/ml)			过敏原sIgE累积水平(kAU/L)
标准诊断方法	数值	Z值	P值	数值	Z值	P值
皮肤点刺试验		－1.501	0.133		－3.841	0.000
阴性(n＝39)	155.94(20.36，374.57)			0.08(0.01，0.84)
阳性(n＝47)	198.25(105.68，348.85)			0.97(0.34，2.63)
sIgE阳性		－1.140	0.254		－3.295	0.001
阴性(n＝9)	170.51(21.45，381.06)			0.10(0.01，0.94)
阳性(n＝32)	202.46(93.60，477.23)			1.09(0.28，3.40)

表3 不同Phadiatop™结果的重度过敏性哮喘患者基线特征和疗效比较

临床特征	<0.24 kAU/L(n＝10)	≥0.24 kAU/L(n＝24)	χ²/F/H	P值
性别(男/女)	1/9	8/16	－	0.225^a
年龄(岁)	41.0±8.49	39.33±16.17	0.308	0.761
吸烟指数(包年)	15.56(0.0，28.50)	1.18(0.0，22.13)	－0.731	0.465
体重(kg)	69.0±14.70	69.88±15.24	0.155	0.878
体重指数(kg/m²)	28.62±5.46	27.0±6.77	0.670	0.508
TIgE水平(IU/ml)	49.63(21.12，132.56)	323.31(144.38，685.78)	－3.326	0.001
氧饱和度(%)	96.20±2.39	94.50±3.22	1.501	0.143
症状VAS(mm)
咳嗽	44.0(9.0，68.0)	60.50(37.50，73.0)	－0.700	0.484
呼吸困难	59.50(0.0，89.0)	73.50(47.0，88.0)	－0.607	0.544
咳痰	21.50(0.0，50.0)	23.0(3.0，50.50)	－0.342	0.733
浓痰	19.50(0.0，43.0)	3.0(0.0，47.50)	－0.136	0.892
淋巴细胞(×10⁹/L)	9.59(8.57，12.90)	11.67(9.85，13.75)	－1.247	0.212
中性粒细胞(×10⁹/L)	6.56(5.43，10.29)	8.42(7.01，10.94)	－1.058	0.290
嗜酸性粒细胞(×10⁹/L)	0.38(0.15，0.85)	0.37(0.18，0.71)	－0.132	0.895
CRP(mg/L)	3.15(0.60，23.10)	10.05(1.35，22.95)	－0.682	0.495
FEV₁/FVC	0.68(0.50，0.72)	0.65(0.51，0.71)	－0.436	0.633
治疗结局
12个月时ACT	16.90±2.88	18.79±1.98	2.213	0.034
12个月时AQLQ	106.40±50.09	151.17±70.36	1.822	0.078
12个月内哮喘加重[n(%)]	6(60.0)	5(20.83)	4.948	0.026
12个月时FEV₁/FVC	0.71(0.66，0.74)	0.83(0.78，0.88)	－3.803	0.000
4个月时服用全身皮质激素[n(%)]	5(50.0)	3(12.50)	5.517	0.019
12个月时服用全身皮质激素[n(%)]	2(20.0)	3(12.50)	0.317	0.574

表3 不同Phadiatop™结果的重度过敏性哮喘患者基线特征和疗效比较

临床特征	<0.24 kAU/L(n＝10)	≥0.24 kAU/L(n＝24)	χ²/F/H	P值
性别(男/女)	1/9	8/16	－	0.225^a
年龄(岁)	41.0±8.49	39.33±16.17	0.308	0.761
吸烟指数(包年)	15.56(0.0，28.50)	1.18(0.0，22.13)	－0.731	0.465
体重(kg)	69.0±14.70	69.88±15.24	0.155	0.878
体重指数(kg/m²)	28.62±5.46	27.0±6.77	0.670	0.508
TIgE水平(IU/ml)	49.63(21.12，132.56)	323.31(144.38，685.78)	－3.326	0.001
氧饱和度(%)	96.20±2.39	94.50±3.22	1.501	0.143
症状VAS(mm)
咳嗽	44.0(9.0，68.0)	60.50(37.50，73.0)	－0.700	0.484
呼吸困难	59.50(0.0，89.0)	73.50(47.0，88.0)	－0.607	0.544
咳痰	21.50(0.0，50.0)	23.0(3.0，50.50)	－0.342	0.733
浓痰	19.50(0.0，43.0)	3.0(0.0，47.50)	－0.136	0.892
淋巴细胞(×10⁹/L)	9.59(8.57，12.90)	11.67(9.85，13.75)	－1.247	0.212
中性粒细胞(×10⁹/L)	6.56(5.43，10.29)	8.42(7.01，10.94)	－1.058	0.290
嗜酸性粒细胞(×10⁹/L)	0.38(0.15，0.85)	0.37(0.18，0.71)	－0.132	0.895
CRP(mg/L)	3.15(0.60，23.10)	10.05(1.35，22.95)	－0.682	0.495
FEV₁/FVC	0.68(0.50，0.72)	0.65(0.51，0.71)	－0.436	0.633
治疗结局
12个月时ACT	16.90±2.88	18.79±1.98	2.213	0.034
12个月时AQLQ	106.40±50.09	151.17±70.36	1.822	0.078
12个月内哮喘加重[n(%)]	6(60.0)	5(20.83)	4.948	0.026
12个月时FEV₁/FVC	0.71(0.66，0.74)	0.83(0.78，0.88)	－3.803	0.000
4个月时服用全身皮质激素[n(%)]	5(50.0)	3(12.50)	5.517	0.019
12个月时服用全身皮质激素[n(%)]	2(20.0)	3(12.50)	0.317	0.574

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Correaltion between cumulative specific IgE for respiratory allergens and the efficacy of Omalizumab for severe asthma

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Correaltion between cumulative specific IgE for respiratory allergens and the efficacy of Omalizumab for severe asthma