血红素加氧酶1在儿童继发性噬血细胞综合征诊断及预后判断中的价值研究

doi:10.12114/j.issn.1007-9572.2019.00.209

摘要/Abstract

摘要： 背景　噬血细胞综合征（HPS）是一种病情严重、病死率较高的增殖性疾病，缺乏特异性的诊断指标，造成部分患儿诊断与治疗不及时，危及生命。血红素加氧酶1（HO-1）是近年来发现的有可能成为一种新的更为特异性的指标，但国内外关于此类的报道较少，寻找更多的循证医学证据，进一步确定其诊断价值显得尤为重要。目的　探讨血清HO-1水平在HPS的诊断及预后判断中的价值。方法　选取2015年9月—2017年9月郑州大学第一附属医院儿科病房收治的86例继发性HPS患儿（HPS组）及排除HPS诊断的66例感染患儿（感染组），以同期门诊体检的79例健康儿童为对照组。收集受试者性别、年龄、病因、实验室检查；HPS组、感染组与对照组就诊当日及HPS组患儿治疗前、治疗后2周、4周、8周采用酶联免疫吸附试验（ELISA）法检测血清HO-1水平，HPS组、感染组与对照组就诊当日采用实时荧光定量聚合酶链式反应（real-time PCR）检测HO-1 mRNA表达水平。HPS组患儿随访1年，根据预后分为生存63例，死亡23例。采用受试者工作特征（ROC）曲线分析血清HO-1和铁蛋白对HPS的诊断价值，比较不同预后HPS患儿临床指标的差异。结果　HPS组患儿白细胞计数（WBC）、血红蛋白（Hb）、血小板计数（PLT）、自然杀伤（NK）细胞百分比、纤维蛋白原（FIB）低于感染组，C反应蛋白（CRP）、乳酸脱氢酶（LDH）、铁蛋白水平高于感染组（P<0.05）。对照组、感染组、HPS组血清HO-1、HO-1 mRNA表达水平比较，差异均有统计学意义（P<0.05）；其中感染组、HPS组血清HO-1、HO-1 mRNA表达水平高于对照组，HPS组血清HO-1、HO-1 mRNA表达水平高于感染组（P<0.05）。HPS患儿治疗前、治疗后2周、4周、8周血清HO-1水平比较，差异有统计学意义（P<0.05）。HPS患儿血清HO-1水平与铁蛋白呈正相关（rs=0.661，P<0.001）。血清HO-1诊断HPS的ROC曲线下面积大于铁蛋白（Z=1.68，P=0.046）；血清HO-1联合铁蛋白诊断HPS的ROC曲线下面积大于血清HO-1和铁蛋白（Z=1.81，P=0.035；Z=1.98，P=0.023）。死亡HPS患儿CRP、LDH、铁蛋白、HO-1水平较生存HPS患儿升高，PLT较生存HPS患儿降低（P<0.05）。结论　HPS患儿血清HO-1水平明显高于其他感染患儿，与血清铁蛋白水平高度相关，联合检测血清HO-1和铁蛋白水平更具有诊断价值，可能作为儿童HPS早期诊断及预后判断的一个新的分子标志物。

关键词: 淋巴组织细胞增多症, 嗜血细胞性；血红素加氧酶1；预后；诊断；灵敏度；特异度

Abstract: Background　Hemophagocytic syndrome（HPS） is a kind of serious proliferative disease with high mortality.It can be life-threatening to some children with delayed diagnosis and treatment due to lack of specific diagnostic markers.Heme oxygenase-1（HO-1） is a recently discovered indicator that may be used as a novel diagnostic marker for HPS with higher specificity.However，studies about it are few，so it is important to carry out more evidence-based studies to verify its diagnostic value.Objective　To investigate the diagnostic and prognostic values of serum HO-1 in HPS.Methods　Between September 2015 and September 2017，231 cases from the First Affiliated Hospital of Zhengzhou University were enrolled，including 86 with secondary HPS（HPS group），and 66 infection without HPS（infection group） from pediatric ward，and 70 healthy physical examinees from outpatient department（control group）． Data about sex，age，etiology and laboratory results of all participants，serum HO-1 levels detected with ELISA in HPS group on the admission day，and before treatment，at the end of the 2nd，4th，8th weeks of treatment，and in other two groups on the admission day，and serum HO-1 mRNA levels detected with real-time PCR in all groups on the admission day were collected.Children in HPS group were given a one-year follow-up，during which 63 survived，and 23 died.ROC analysis was performed to investigate the diagnostic values of serum HO-1，ferritin，and the combination of the two in HPS.Outcomes of HPS children were compared by clinical markers.Results　HPS group showed lower average white blood cell count（WBC），hemoglobin（Hb），platelet count（PLT），natural killer（NK）cell percentage and fibrinogen（FIB） levels，and higher average C-reactive protein（CRP），lactate dehydrogenase（LDH） and ferritin levels compared with the infection group（P<0.05）． Serum HO-1 and HO-1 mRNA expression levels differed significantly across the groups（P<0.05）． In particular，they were the highest in HPS group，followed by infection group，and control group（P<0.05）． Serum HO-1 levels of HPS children before treatment，at the end of 2nd，4th，8th weeks of treatment were significantly different（P<0.05）． Serum HO-1 level was positively correlated with ferritin in HPS children（rs=0.661，P<0.001）． For the diagnosis of HPS，serum HO-1 level had a greater AUC than ferritin（Z=1.68，P=0.046）． But the AUC of the combination of the two was greater than that of serum HO-1 or ferritin（Z=1.81，P=0.035；Z=1.98，P=0.023）． The survived HPS children showed much lower average levels of CRP，LDH，ferritin and HO-1 but much higher average PLT level compared with those decreased（P<0.05）． Conclusion　Serum HO-1 level in children with HPS is significantly higher than that of those with other infections，which is closely correlated with serum ferritin level.And the combination of the two showed a higher diagnostic value in HPS，which may serve as a new molecular diagnostic and prognostic marker for HPS in children.

Key words: Lymphohistiocytosis, hemophagocytic；Heme oxygenase-1；Prognosis；Diagnosis；Sensitivity；Specificity

王颖超,李壮壮,朱桂英,等. 血红素加氧酶1在儿童继发性噬血细胞综合征诊断及预后判断中的价值研究[J]. 中国全科医学, 2019, 22(32): 3944-3949. DOI: 10.12114/j.issn.1007-9572.2019.00.209.
WANG Yingchao,LI Zhuangzhuang,ZHU Guiying, et al. Diagnostic and Prognostic Values of Heme Oxygenase-1 in Secondary Phagocytic Syndrome in Children　[J]. Chinese General Practice, 2019, 22(32): 3944-3949. DOI: 10.12114/j.issn.1007-9572.2019.00.209.

参考文献

［1］AL-SAMKARI H，BERLINER N.Hemophagocytic lymphohistiocytosis［J］．Annu Rev Pathol，2018，13：27-49．DOI：10.1146/annurev-pathol-020117-043625.
［2］ESPINOZA J A，GONZALEZ P A，KALERGIS A M.Modulation of antiviral immunity by heme oxygenase-1［J］．Am J Pathol，2017，187（3）：487-493．DOI：10.1016/j.ajpath.2016.11.011.
［3］HENTER J I，HORNE A，ARICó M，et al．HLH-2004：diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis［J］．Pediatr Blood Cancer，2007，48（2）：124-131．DOI：10.1002/pbc.21039.
［4］蔡国龙，严静，邱海波.中国严重脓毒症/脓毒性休克治疗指南（2014）：规范与实践［J］．中华内科杂志，2015，54（6）：484-485．DOI：10.3760/cma.j.issn.0578-1426.2015.06.
CAI G L，YAN J，QIU H B.The standardization of diagnosis and treatment of severe sepsis/septic shock and its practice［J］．Chinese Journal of Internal Medicine，2015，54（6）：484-485．DOI：10.3760/cma.j.issn.0578-1426.2015.06.
［5］林立，李昌崇.“儿童社区获得性肺炎管理指南（2013修订）”解读［J］．中华妇幼临床医学杂志（电子版），2014，10（6）：728-732．DOI：10.3877/cma.j.issn.1673-5250.2014.06.006.
LIN L，LI C C.Interpretation of“guidelines for the management of community-acquired pneumonia in children（revised 2013）”［J］．Chinese Journal of Obstetrics & Gynecology and Pediatrics（Electronic Edition），2014，10（6）：728-732．DOI：10.3877/cma.j.issn.1673-5250.2014.06.006.
［6］郭霞，高举.传染性单核细胞增多症的诊断与治疗［J］．国际输血及血液学杂志，2012，35（4）：308-310．DOI：10.3760/cma.j.issn.1673-419X.2012.04.005.
GUO X，GAO J.Diagnosis and treatment of infectious mononucleosis［J］．International Journal of Blood Transfusion and Hematology，2012，35（4）：308-310．DOI：10.3760/cma.j.issn.1673-419X.2012.04.005.
［7］JANKA G E.Familial and acquired hemophagocytic lymphohistiocytosis［J］．Annu Rev Med，2012，63：233-246．DOI：10.1146/annurev-med-041610-134208.
［8］SEPULVEDA F E，DE SAINT BASILE G.Hemophagocytic syndrome：primary forms and predisposing conditions［J］．Curr Opin Immunol，2017，49：20-26．DOI：10.1016/j.coi.2017.08.004.
［9］周永海，夏芳琴，金江兵，等.儿童恙虫病致继发性噬血细胞综合征一例并文献复习［J］.中国全科医学，2015，18（17）：2114-2116.DOI：10.3969/j.issn.1007-9572.2015.17.032.
ZHOU Y H，XIA F Q，JIN H B，et al.Scrub typhus-associated hemophagocytic syndrome in children：a case report and literatures review［J］.Chinese General Practice，2015，18（17）：2114-2116.DOI：10.3969/j.issn.1007-9572.2015.17.032.
［10］LI J，WANG Q，ZHENG W J，et al．Hemophagocytic lymphohistiocytosis：clinical analysis of 103 adult patients［J］.Medicine（Baltimore），2014，93（2）：100-105．DOI：10.1097/MD.0000000000000022.
［11］KIRINO Y，TAKENO M，IWASAKI M，et al．Increased serum HO-1 in hemophagocytic syndrome and adult-onset Still's disease：use in the differential diagnosis of hyperferritinemia［J］．Arthritis Res Ther，2005，7（3）：R616-624．DOI：10.1186/ar1721.
［12］KIM K S，ZHANG D L，KOVTUNOVYCH G，et al．Infused wild-type macrophages reside and self-renew in the liver to rescue the hemolysis and anemia of Hmox1-deficient mice［J］．Blood Adv，2018，2（20）：2732-2743．DOI：10.1182/bloodadvances.2018019737.
［13］MIYAZAKI T，KIRINO Y，TAKENO M，et al．Serum HO-1 is useful to make differential diagnosis of secondary hemophagocytic syndrome from other similar hematological conditions［J］．Int J Hematol，2010，91（2）：229-237．DOI：10.1007/s12185-010-0495-y.
［14］王宇，李硕，闫丽娟，等．血清HO-1水平在获得性噬血细胞综合征中的临床意义探讨［J］．临床和实验医学杂志，2013，12（20）：1609-1611．DOI：10.3969/j.issn.1671-4695.2013.20.001.
WANG Y，LI S，YAN L J，et al．Discussion about the clinical significance of the levels of serum HO-1 in hemophagocytic syndrome［J］．Journal of Clinical and Experimental Medicine，2013，12（20）：1609-1611．DOI：10.3969/j.issn.1671-4695.2013.20.001.
［15］GROM A A.Natural killer cell dysfunction：a common pathway in systemic-onset juvenile rheumatoid arthritis，macrophage activation syndrome，and hemophagocytic lymphohistiocytosis?［J］．Arthritis Rheum，2004，50（3）：689-698．DOI：10.1002/art.20198.
［16］YAMASHITA S，FURUKAWA N E，MATSUNAGA T，et al．
Extremely high serum ferritin：an instrumental marker of masquerading adult-onset Still's disease with hemophagocytic syndrome［J］．Am J Case Rep，2017，18：1296-1301.

[1]	施晓琦, 罗南都, 黄娇娇, 杜作晨, 黄佩, 曹秀丽, 陈艳, 何志旭. 天冬氨酸氨基转移酶/丙氨酸氨基转移酶与儿童噬血细胞性淋巴组织细胞增生症预后的相关性研究[J]. 中国全科医学, 2023, 26(30): 3801-3808.
[2]	陈春江. Castleman病相关性嗜血细胞综合征一例报道并文献复习[J]. 中国全科医学, 2020, 23(14): 1804-1807.
[3]	周永海，夏芳琴，金江兵，留佩宁. 儿童恙虫病致继发性噬血细胞综合征一例并文献复习[J]. 中国全科医学, 2015, 18(17): 2114-2116.