儿童肝炎伴发粒细胞减少的临床特征及其进展为再生障碍性贫血的危险因素分析

曹丽丽; 闫建国; 董漪; 朱世殊; 徐志强; 王福川; 王璞; 李爱芹; 王丽旻; 张敏

doi:10.3969/j.issn.1001-5256.2021.07.025

儿童肝炎伴发粒细胞减少的临床特征及其进展为再生障碍性贫血的危险因素分析

DOI: 10.3969/j.issn.1001-5256.2021.07.025

解放军总医院第五医学中心肝病医学部肝病科，北京 100039

基金项目:

首都临床特色应用研究 (Z181100001718030)

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。

作者贡献声明：曹丽丽负责课题设计，资料分析，撰写论文；王福川负责数据整理和统计学分析；闫建国、王璞、李爱芹、王丽旻参与收集分析数据；朱世殊、徐志强负责整理、分析文献；董漪负责修改论文；张敏负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
张敏，gcmw2001@163.com

中图分类号: R575
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出版历程
- 收稿日期: 2020-11-18
- 录用日期: 2021-03-08
- 出版日期: 2021-07-20

Clinical features of children with hepatitis and granulocytopenia and risk factors for progression to aplastic anemia

Department of Liver Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China

Research funding:

Project on the Application of Clinical Characteristics in the Capital (Z181100001718030)

摘要

摘要: 目的总结儿童肝炎伴发粒细胞减少的发生率和临床特征，分析其进展为再生障碍性贫血(AA)的危险因素。方法回顾性选取2014年7月—2020年3月解放军总医院第五医学中心肝病医学部肝病科因肝功异常住院的≤18岁患儿2944例，统计病程中新发血象中性粒细胞减少(＜1.5×10⁹/L)患儿的临床特点及病情转归，分析其进展为AA的危险因素。正态分布的计量资料2组间比较采用t检验；非正态分布的计量资料2组间比较采用Wilcoxon秩和检验。计数资料2组间比较采用χ²检验。危险因素采用logistic回归分析。结果 2944例以肝功能异常入院的儿童中38例为肝炎伴发粒细胞减少，发生率为1.3%。68.4%(26/38)为药物性肝损伤、2.6%(1/38)为自身免疫性肝炎、28.9%(11/38)为不明原因肝损伤。血液异常表现为粒细胞减少症21.1%(8/38)，粒细胞减少+三系下降47.4%(18/38)，粒细胞缺乏症7.9%(3/38)，粒细胞缺乏+三系下降23.7%(9/38)。骨髓细胞学检查，14例(36.8%)诊断为肝炎相关再生障碍性贫血(HAAA)，24例(63.2%)为非HAAA。HAAA组与非HAAA组的CD4⁺(8.5% vs 17%，P=0.008)、CD4⁺/CD8⁺(0.17 vs 0.47，P=0.015)比较差异均有统计学意义。进一步多因素logistic回归分析发现CD4⁺下降为HAAA发生的危险因素(OR=0.009, 95%CI: 0~0.838，P＜0.05)。38例患儿均常规保肝、降酶、退黄治疗。14例HAAA患儿中6例免疫抑制剂治疗，7例异基因骨髓移植，血象逐渐恢复，1例因重型AA死亡；24例非HAAA患儿中23例经治疗血象逐渐恢复正常，1例因急性肝衰竭死亡。结论儿童肝炎伴发粒细胞减少需警惕AA，尤以药物性或不明原因多见，其中CD4⁺下降可作为AA的预测因子。
- 肝炎 /
- 粒细胞缺乏 /
- 中性粒细胞减少 /
- 贫血, 再生障碍性 /
- 儿童 /
- 危险因素
Abstract: Objective To investigate the incidence rate and clinical features of children with hepatitis and granulocytopenia and the risk factors for progression to aplastic anemia (AA). Methods A retrospective analysis was performed for 2944 children, aged ≤18 years, who were hospitalized due to abnormal liver function in Pediatric Liver Diseases Treatment and Research Center, The Fifth Medical Center of Chinese PLA General Hospital, from July 2014 to March 2020. Clinical features and prognosis were analyzed for children with new-onset neutropenia (< 1.5×10⁹/L) during the course of the disease, and the risk factors for progression to AA were analyzed. The t-test was used for comparison of normally distributed continuous data between groups, and the Wilcoxon rank-sum test was used for comparison of non-normally distributed continuous data between groups; the chi-square test was used for comparison of categorical data between groups. A logistic regression analysis was used to investigate risk factors. Results Among the 2944 children admitted due to abnormal liver function, 38 had hepatitis with granulocytopenia, with an incidence rate of 1.3%. Among these 38 children, 68.4% (26/38) had drug-induced liver injury, 2.6% (1/38) had autoimmune hepatitis, and 28.9% (11/38) had unexplained liver injury; as for blood abnormalities, 21.1% (8/38) had granulocytopenia, 47.4% (18/38) had granulocytopenia and reductions in three lines of blood cells, 7.9% (3/38) had agranulocytosis, and 23.7% (9/38) had agranulocytosis and reductions in three lines of blood cells. Bone marrow cytology showed that among the 38 children, 14 (36.8%) were diagnosed with hepatitis-associated AA (HAAA) and 24 (63.2%) were diagnosed with non-HAAA. In order to analyze the risk factors for HAAA, there were significant differences in CD4⁺ (8.5% vs 17%, P=0.008) and CD4⁺/CD8⁺ ratio (0.17 vs 0.47, P=0.015) between the HAAA group and the non-HAAA group. Further multivariate logistic regression analysis showed that the reduction in CD4⁺ was a risk factor for HAAA (β=-4.757, P < 0.05). All 38 children were given routine liver-protecting, transaminase-lowering, and jaundice clearance treatment. Among the 14 children with HAAA, 6 had gradual recovery of hemogram after immunosuppressant therapy, 7 had gradual recovery of hemogram after allogeneic hematopoietic stem cell transplantation, and 1 died due to severe AA; among the 24 children with non-HAAA, 23 had hemogram gradually returning to normal after treatment, and 1 died of acute liver failure. Conclusion AA should be taken seriously for children with hepatitis and granulocytopenia, especially for those with drug-induced or unexplained liver injury, and the reduction in CD4⁺ may be used as a predictive factor for AA.
- Hepatitis /
- Agranulocytosis /
- Neutropenia /
- Anemia, Aplastic /
- Children /
- Risk Factors

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表 1 38例肝炎患儿发生血象异常的类型及分布特点

项目	粒细胞减少症(n=8)	粒细胞缺乏症(n=3)	粒细胞减少+ 三系下降(n=18)	粒细胞缺乏+ 三系下降(n=9)	总计
病因(例)
药物	6	1	14	5	26
不明原因	2	2	3	4	11
自身免疫性肝炎	0	0	1	0	1
发生时间(d)	19.0(6.5~55.5)	105.0(27~140)	42.0(28~73)	30.0(27.5~63.5)
发病时期(例)
极期	2	0	6	2	10
恢复期	6	3	12	7	28
HAAA(例)	0	0	5	9	14
骨穿结果(例)
增生减低	1	1	7	8	17
增生活跃	6	2	9	1	18
未做	1	0	2	0	3

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表 2 38例肝炎患儿粒细胞减少时生化、血象及免疫学指标与肝炎发病时的比较

指标	肝炎发病时	发生粒细胞减少时	统计值	P值
ALT(U/L)	1 141.00(644.58~1 482.13)	206.00(65.25~592.75)	Z=4.805	＜0.001
AST(U/L)	1 005.00(714.63~1 489.28)	185.00(72.00~735.50)	Z=4.473	＜0.001
TBil(μmol/L)	199.35(115.85~270.48)	66.75(26.75~205.33)	Z=3.719	＜0.001
DBil(μmol/L)	148.85(76.75~211.88)	52.50(18.30~170.40)	Z=2.587	0.010
PTA(%)	65.17±17.02	93.3±26.98	t=6.635	＜0.001
WBC(×10⁹/L)	5.10±2.85	3.03±1.61	t=5.802	＜0.001
NEUT(×10⁹/L)	3.19±2.52	1.69±1.37	t=5.047	＜0.001
RBC(×10¹²/L)	4.46±0.57	3.88±0.72	t=5.377	＜0.001
Hb(g/L)	126.66±16.15	114.24±18.54	t=5.591	＜0.001
PLT(×10⁹/L)	204.00±113.23	128.37±113.16	t=4.490	＜0.001
T淋巴细胞(%)	69.89±14.33	68.29±17.26	t=0.951	0.348
CD4⁺(%)	18.50±14.08	19.39±15.22	t=1.384	0.175
CD8⁺(%)	44.16±18.04	43.05±19.04	t=0.773	0.445
CD4⁺/CD8⁺	0.28(0.15~0.73)	0.35(0.15~0.80)	Z=0.918	0.359

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表 3 38例肝炎伴发粒细胞减少患儿的治疗及预后

项目	粒细胞减少症	粒细胞缺乏症	粒细胞减少+三系下降	粒细胞缺乏+三系下降	总计
常规治疗(例)	5	1	12	3	21
激素和/或丙种球蛋白治疗(例)	3	2	6	6	17
HAAA治疗(例)
ATG序贯CsA	0	0	1	0	1
CsA	0	0	3	2	5
allo-HSCT	0	0	2	5	7
转归(例)
恢复	7	3	18	8	36
死亡	1	0	0	1	2

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表 4 儿童肝炎伴发粒细胞减少发生AA的单因素分析

因素	HAAA组(n=14)	非HAAA组(n=24)	统计值	P值
男性[例(%)]	11(78.6)	13(54.2)	χ2=2.263	1.132
年龄(岁)	9.8(5.7~11.2)	10.8(9.5~13.5)	Z=1.181	0.238
BMI(kg/m²)	18.80±2.01	16.96±3.11	t=1.965	0.057
病因(药物)[例(%)]	7(50.0)	19(79.2)	χ2=3.481	0.062
皮疹[例(%)]	2(14.3)	6(25.0)	χ2=0.684	0.365
感染[例(%)]	8(57.1)	12(50.0)	χ2=0.181	0.671
激素[例(%)]	7(50.0)	10(41.7)	χ²=0.248	0.618
ALT(U/L)	1 218.5(730.0~1 668.0)	796.0(422.0~1 471.0)	Z=1.210	0.226
AST(U/L)	1 082.9(337.0~1 328.0)	971.0(669.0~1 590.0)	Z=0.393	0.694
TBil(μmol/L)	263.8(156.0~308.0)	241.6(163.6~354.3)	Z=0.030	0.976
WBC(×10⁹/L)	5.22(2.50~6.70)	4.67(2.88~6.15)	Z=0.303	0.762
NEUT(×10⁹/L)	3.17(1.51~4.51)	2.34(1.48~3.82)	Z=0.832	0.405
T淋巴细胞百分比(%)	67.5(53.5~80.5)	73.0(63.0~81.0)	Z=1.014	0.310
CD4⁺(%)	8.5(6.5~14.5)	17.0(10.0~43.0)	Z=2.638	0.008
CD8⁺(%)	47.5(35.5~60.0)	33.0(25.0~60.0)	Z=1.499	0.134
CD4⁺/CD8⁺	0.17(0.15~0.35)	0.47(0.18~1.44)	Z=2.422	0.015

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