儿童噬血细胞性淋巴组织细胞增生症175例临床特征及预后分析

doi:10.12372/jcp.2022.21e1321

摘要/Abstract

摘要：

目的探讨噬血细胞性淋巴组织细胞增生症（HLH）的临床特征及预后因素。方法回顾分析2015年1月至2020年10月收治的175例HLH患儿的临床资料,比较存活组和死亡组的临床特征,采用log-rank检验及COX比例风险回归模型进行生存分析。结果 175例HLH患儿中男91例、女84例,中位年龄2.0（1.0~8.0）岁,以婴幼儿期起病最常见（54.3%）。原发性HLH 9例,继发性HLH 166例。继发性HLH中以感染相关性HLH最常见（66.9%）。临床以发热、脾大为突出表现,血清乳酸脱氢酶（LDH）升高最为显著。与存活组相比,死亡组患儿白细胞计数和血红蛋白较低,活化部分凝血活酶时间、凝血酶原时间较长,纤维蛋白原（FIB）较低,中枢神经系统受累率较高,差异均有统计学意义（P<0.05）。中枢神经系统受累、FIB≤1.5 g/L是影响患儿总生存期的独立危险因素（P<0.05）。结论 HLH多见于婴幼儿,临床表现以发热最多见,血清LDH大多异常升高。中枢神经系统受累及FIB水平对初诊HLH患儿疗效评估及预后判断具有重要意义。

关键词: 噬血细胞性淋巴组织细胞增生症, 临床特征, 预后

Abstract:

Objective To investigate the clinical characteristics and prognostic factors of hemophagocytic lymphohistosis (HLH). Methods The clinical data of 175 children with HLH admitted from January 2015 to October 2020 were retrospectively analyzed. Clinical manifestations of the patients of HLH in the survival group and the deceased group were compared. Log-rank test and COX proportional riskregression model were used for survival analysis. Results Among the 175 cases, 91 were male and 84 were female, with a median age of 2.0 (1.0-8.0) years, and the most common onset age was in infancy (54.3%). There were 9 cases of primary HLH and 166 cases of secondary HLH. Infection-associated HLH was the commonest in secondary HLH (66.9% of them were EBV infection). The clinical manifestations were persistent fever (99.4%) and splenomegaly (72%). Laboratory examination showed that elevated serum LDH was the most significant (97.1%), followed by serum ferritin≥500μg/L (85.1%). Compared with the surviving group, children in the deceased group had lower WBC, lower HB, longer APTT, longer PT, lower FIB, higher central nervous system involvement, all with statistically significant differences (P<0.05). Central nervous system involvement and fibrinogen≤1.5g/L were independent prognostic factors of OS. Conclusions HLH is most often seen in infants, and the commonest clinical manifestation is fever with abnormally elevated serum LDH. Central nervous system involvement and FIB levels are important for the assessment of the outcome and prognosis of children with HLH.

Key words: Hemophagocytic lymphohistiocytosis, Clinical feature, Prognosis

毛舒婷, 王欣, 刘玉峰. 儿童噬血细胞性淋巴组织细胞增生症175例临床特征及预后分析[J]. 临床儿科杂志, 2022, 40(2): 123-128.

MAO Shuting, WANG Xin, LIU Yufeng. Clinical features and prognosis of 175 children with hemophagocytic lymphohistiocytosis[J]. Journal of Clinical Pediatrics, 2022, 40(2): 123-128.

图/表 4

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9例原发性HLH患儿临床资料分析"

例号	性别	年龄/岁	突变基因	突变碱基位点	治疗和疾病转归	OS/月
1	女	1	STXBP2-Exon11 STXBP2-Exon14	c.953C>T (p.Thr318Met) c.1214G>A(p.Arg405Gln)	确诊后给予HLH-2004方案化疗达CR,8个月后非亲缘造血干细胞移植,移植后发生肝静脉窦闭塞综合征	43
2	男	8	PRF1-Exon2 PRF1-Exon2	c.503G>A(p.Ser168Asn) c.65delC(p.Pro22ArgfsX29)	患儿霍奇金淋巴瘤（HL）,混合细胞型。家族性HLH诊断明确后给予HLH-1994方案化疗达PR,后采用HL方案化疗,2个月后因发热伴抽搐,考虑疾病复发,采用 HLH-94 方案再次诱导,后因脓毒性休克、多脏器衰竭死亡	3
3	男	7	UNC13D-Exon31 UNC13D-Exon13	c.G2986A:p.G996R c.1055+1G>A	确诊后给予HLH-2004方案化疗达CR,6个月后骨髓细胞学检查提示淋巴瘤样细胞占5%,7个月后行非亲缘造血干细胞移植	68
4	男	13	PRF1-Exon2	c.503G>A(p.Ser168Asn)	确诊后给予“糖皮质激素、人免疫球蛋白”等治疗,2个月后病情反复,予以口服“环孢素、泼尼松”治疗,3个月后给予HLH-2004方案治疗, 7个月后死于疾病进展	7
5	女	1	RAB27A-Exon3 RAB27A-Exon5	c.121delA(p.Thr41GlnfsTer44) c.272delA(p.Asp91ValfsTer11)	确诊后给予HLH-2004方案化疗未达部分缓解（PR）,9个月后死于疾病进展	9
6	男	3	LYST-Exon46 LYST-Exon38	c.10526G>A(p.Arg3509Gln) c.9162+11G>A	确诊后给予HLH-2004方案化疗达CR,5周后复发,继续HLH-2004方案化疗,2个月后出现CNS-HLH,5个月后再次复发,家属拒绝行造血干细胞移植,继续按HLH-2004方案化疗达CR	60
7	女	1	UNC13D-Exon10	c.766C>T(p.Arg256Ter)	确诊后给予HLH-2004方案化疗达CR,17个月后患真菌性肺炎,死于感染	17
8	女	1	UNC13D-Exon 10	c.766C>T(p.R256*)	确诊后给予HLH-2004方案治疗,2个月后因直肠阴道瘘感染死亡	2
9	女	4	UNC13D- Exon27	c.2588G>A（p.Gly863Asp）	确诊后给予HLH-2004方案化疗达CR	24

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临床特征	存活组 (n=110)	死亡组 (n=65)	统计量	P
性别(男/女,n)	56/54	35/30	χ²=0.141	0.707
年龄[M(P₂₅~P₇₅)]/岁	2.0(1.0~7.3)	2.0(1.0~12.0)	Z=1.83	0.068
发热[n(%)]	110(100.0)	64(98.5)	-	0.833¹⁾
皮疹[n(%)]	19(17.3)	11(16.9)	χ²=0.00	0.953
肝大[n(%)]	80(72.7)	49(75.4)	χ²=0.15	0.700
脾大[n(%)]	75(68.2)	51(78.5)	χ²=2.14	0.143
淋巴结肿大[n(%)]	58(52.7)	29(44.6)	χ²=1.08	0.300
WBC[M(P₂₅~P₇₅)]×10⁹·L^-1	2.8(1.6~6.2)	2.1(1.4~3.7)	Z=2.25	0.025
HB[M(P₂₅~P₇₅)]/g·L^-1	88.2(78.0~103.9)	83.0(68.0~95.8)	Z=2.02	0.044
PLT [M(P₂₅~P₇₅)]×10⁹·L^-1	62.0(27.5~110.5)	42.0(20.0~68.0)	Z=1.53	0.125
APTT[M(P₂₅~P₇₅)]/s	37.2(33.3~43.2)	40.3(34.5~49.8)	Z=2.33	0.020
PT[M(P₂₅~P₇₅)]/s	11.7(10.8~13.4)	13.1(11.6~16.9)	Z=4.09	<0.001
FIB[M(P₂₅~P₇₅)]/g·L^-1	1.5(1.2~1.9)	0.9(0.7~1.4)	Z=4.33	<0.001
铁蛋白[M(P₂₅~P₇₅)]/μg·L^-1	1 802.3(1 157.5~5 265.9)	1 608.8(824.9~2 606.8)	Z=1.39	0.165
ALT[M(P₂₅~P₇₅)]/U·L^-1	83.0(39.0~210.3)	59.0(31.5~188.3)	Z=1.05	0.292
AST[M(P₂₅~P₇₅)]/U·L^-1	161.0(72.8~288.8)	119.5(56.5~381.0)	Z=0.13	0.899
ALB[M(P₂₅~P₇₅)]/g·L^-1	32.6(27.5~35.3)	29.0(26.7~34.2)	Z=1.24	0.214
LDH[M(P₂₅~P₇₅)]/U·L^-1	978.0(557.5~1554.8)	945.0(533.0~2338.0)	Z=1.06	0.288
TG[M(P₂₅~P₇₅)]/mmol·L^-1	2.9(1.9~4.0)	2.7(2.0~4.9)	Z=1.28	0.200
CD4⁺/CD8⁺[M(P₂₅~P₇₅)]	0.9(0.5~1.6)	1.2(0.6~1.9)	Z=1.38	0.168
中枢神经系统受累[n(%)]	7(6.4)	13(20.0)	χ²=7.51	0.006

因素	分组	中位生存时间 (M±SE)	χ²值	P
性别	男	42.4±3.4	0.02	0.891
性别	女	41.9±3.4	0.02	0.891
年龄	<3岁	41.1±3.0	0.26	0.609
年龄	≥3岁	41.5±3.7	0.26	0.609
EBV感染	有	45.1±3.6	0.68	0.410
EBV感染	无	41.3±3.3	0.68	0.410
肿瘤相关 HLH	有	30.6±7.0	0.70	0.404
肿瘤相关 HLH	无	43.6±2.6	0.70	0.404
淋巴结肿大	有	43.6±3.2	0.98	0.322
淋巴结肿大	无	40.4±3.5	0.98	0.322
皮疹	有	40.6±5.4	0.01	0.908
皮疹	无	42.9±2.7	0.01	0.908
肝大	有	40.7±2.7	0.22	0.637
肝大	无	44.6±4.7	0.22	0.637
脾大	有	39.4±2.8	1.48	0.223
脾大	无	48.7±4.4	1.48	0.223
肺炎	有	45.9±3.3	1.50	0.221
肺炎	无	38.8±3.4	1.50	0.221
CNS受累	有	16.9±4.6	8.77	0.003
CNS受累	无	45.5±2.5	8.77	0.003
ANC	<1.0×10⁹/L	41.1±3.2	1.09	0.297
ANC	≥1.0×10⁹/L	45.6±3.8	1.09	0.297
HB水平	<90 g/L	38.3±3.1	2.29	0.130
HB水平	≥90 g/L	47.0±3.7	2.29	0.130
PLT计数	<50×10⁹/ L	37.4±3.5	5.73	0.017
PLT计数	≥50×10⁹/ L	49.2±2.4	5.73	0.017
ALT水平	>200 U/ L	45.2±4.8	1.12	0.731
ALT水平	≤200 U/ L	42.5±2.8	1.12	0.731
LDH水平	≥2 000 U/L	35.4±5.2	3.67	0.055
LDH水平	<2 000 U/L	45.3±2.7	3.67	0.055
ALB水平	<30 g/L	36.6±3.6	3.48	0.062
ALB水平	≥30 g/L	46.7±3.2	3.48	0.062
铁蛋白水平	≥500 μg/L	44.5±2.6	2.02	0.155
铁蛋白水平	<500 μg/L	23.5±4.2	2.02	0.155
FIB水平	≤1.5 g/L	34.1±3.2	20.15	<0.001
FIB水平	>1.5 g/L	56.7±3.1	20.15	<0.001
TG水平	≥3.0 mmol/L	41.1±3.3	0.18	0.670
TG水平	<3.0 mmol/L	42.0±3.3	0.18	0.670

因素	回归系数	标准误	Waldχ²值	HR(95%CI)	P
CNS受累	0.66	0.32	4.39	1.93(1.04~3.60)	0.036
FIB≤1.5 g/L	1.19	0.34	12.10	3.29(1.68~6.44)	0.001