中国当代儿科杂志  2017, Vol. 19 Issue (4): 484-489   PDF    
儿童中性粒细胞减少症研究进展
冯建华, 钱燕     
温州医科大学附属第一医院儿童血液肿瘤科, 浙江 温州 325000
摘要: 中性粒细胞是参与宿主抗感染过程的一种重要的免疫细胞。中性粒细胞减少症是表现为外周血循环中成熟中性粒细胞绝对值减少的一组疾病,通常伴随细菌感染风险的增加。根据病因及发病机制可分为先天性和后天获得性。本文综述近期儿童中性粒细胞减少症病因学研究现状及进展。深入了解中性粒细胞减少症的病因,有助于提高中性粒细胞减少症的诊治水平。
关键词中性粒细胞减少症     感染     粒细胞集落刺激因子     儿童    
Advances in research on childhood neutropenia
FENG Jian-Hua, QIAN Yan     
Department of Pediatric Hematology/Oncology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
Abstract: Neutrophils, an important type of human immune cells, are involved in host defense against infections. Neutropenia refers to a group of diseases manifesting as a reduction in the absolute value of mature neutrophils and is often accompanied by an increased risk of bacterial infection. According to etiology and pathogenesis, neutropenia is classified into congenital and acquired neutropenia. This article reviews the current research status and advances in the etiology of neutropenia in children. A deep understanding of the etiology of neutropenia helps to improve the diagnosis and treatment of this disease.
Key words: Neutropenia     Infection     Granulocyte colony-stimulating factor     Child    

中性粒细胞或多形核细胞作为一种重要的免疫细胞,主要通过吞噬作用参与宿主的抗感染作用。中性粒细胞抗感染功能的正常发挥需要骨髓产生并输送合适数量的中性粒细胞至外周血循环[1]。中性粒细胞减少症是由于外周血中性粒细胞绝对计数(absolute neutrophil count, ANC)低于相应年龄的正常低限而出现的一组综合征。新生儿ANC的正常低限为6.0×109/L,生后2周~1岁其低限为1.0×109/L,≥l岁其低限为1.5×109/L。根据ANC减少程度可将中性粒细胞减少分为轻度(1.0×109/L≤ANC < 1.5×109/L)、中度(0.5×109/L≤ANC < 1.0×109/L)和重度(ANC < 0.5×109/L)。引起中性粒细胞减少的机制主要包括粒细胞生成减少、无效增殖(骨髓粒细胞向外周血转运障碍)、破坏过多及假性粒细胞减少(边缘池扣留增加)等4大类。此外,根据病程长短或是否遗传可将中性粒细胞减少症分为急性和慢性或先天遗传性和后天获得性。儿童常见急性暂时性中性粒细胞减少症,而慢性中性粒细胞减少症则相对少见。本文就近年来中性粒细胞减少症病因学研究现状和进展进行文献复习。

1 先天性中性粒细胞减少症

先天性中性粒细胞减少症病因可涉及中性粒细胞各个不同发育或成熟阶段,发生罕见,但可导致反复感染和慢性病程。

1.1 重型先天性中性粒细胞减少症

重型先天性中性粒细胞减少症(severe congenital neutropenia, SCN)由瑞典医师Kostmann于1956年首次报道,又称Kostmann综合征[2]。中性粒细胞常小于0.2×109/L。发病率约为12/100万,无性别差异。多数呈常染色体隐性遗传,也可呈常染色体显性遗传、X连锁隐性遗传或自发突变[3-4]。目前发现有20多种突变基因参与发病,其中最常见的突变基因为中性粒细胞弹性蛋白酶基因(ELANE)和HS-1相关蛋白X基因(HAX1)[4-5]。基因突变可使骨髓粒细胞成熟阻滞在早幼粒/中幼粒阶段、或增殖能力减低及凋亡增加。例如,引发Wiskott-Aldrich综合征(Wiskott Aldrich syndrome, WAS)或称湿疹、血小板减少伴免疫缺陷综合征的WAS基因为“功能丧失”突变,而WAS基因的“功能获得”突变可诱导增加肌动蛋白多聚化,干扰细胞分裂、增殖并加速细胞凋亡[6],从而引起X-连锁隐性遗传性粒细胞减少。患儿表现为出生后不久发生严重细菌感染,包括脐炎、中耳炎、肺炎、尿路感染、败血症以及皮肤和肝脓肿等。最常见的感染病原体包括葡萄球菌、链球菌、革兰氏阴性杆菌和真菌等。在引进粒细胞集落刺激因子(granulocyte colony-stimulating factor, G-CSF)之前,SCN患儿生后1年内死于严重细菌感染的风险高达50%;而应用G-CSF后,SCN患儿长期生存率可达95%[7]。G-CSF通过改善粒细胞成熟障碍、增加中性粒细胞数量,从而降低感染风险。由于重组人G-CSF经皮下注射时,半衰期仅为3.5 h,故需每日给药,不仅降低治疗依从性,而且增加感染机会。最近报道pegfilgrastim(PEGF),即长效的聚乙二醇化非格司亭(filgrastim),其长期应用可在不增加用药成本的情况下,增加中性粒细胞数量,减少感染率,同时改善生活质量[8]

12%的SCN幸存者可出现G-CSF受体基因(CSF3R)突变,50%可出现包括单倍体7在内的细胞遗传学改变。发生遗传信息改变的患者存在向恶性疾病如骨髓增生异常综合征(myelodysplastic syndrome, MDS)或急性髓系白血病(acute myeloid leukemia, AML)转化的风险。根据国际重症慢性中性粒细胞减少症登记处(SCNIR)、法国重症慢性中性粒细胞减少症登记处(SCNFR)和瑞典群体的报告,启动G-CSF治疗15年后,SCN的MDS/AML累计转化率分别为22%、8.1%和31%[7, 9-10]。此外,根据意大利中性粒细胞减少症登记处(INR)的报告,启动G-CSF治疗4年后的MDS累计转化率为6%[11]。异基因造血干细胞移植是这些患者唯一的治愈手段,指征包括对中/低剂量G-CSF(每日剂量≤5 μg/kg)失去反应、反复发生难以控制的感染以及出现MDS/AML转化[12]。早期研究认为恶性疾病转化时接受造血干细胞移植的患者预后不良[13]。然而,近期一项纳入136例SCN患者的大样本回顾性临床研究发现造血干细胞移植时存在MDS/急性白血病的转化并不影响总体生存率[14]

1.2 慢性良性中性粒细胞减少症

慢性良性中性粒细胞减少症(chronic benign neutropenia, CBN)的ANC约为0.2~0.5×109/L,为4岁以下儿童除感染外最常见的中性粒细胞减少原因,90%见于婴儿,无感染、炎症或恶性疾病的证据,呈良性病程,预后与中性粒细胞减少程度无关[15-16]。CBN患儿骨髓象可正常,或髓系前体细胞增多并出现晚期成熟停滞;少数患者血清中存在抗中性粒细胞抗体。发病机制尚不清楚。有学者推测此病可能呈常染色体显性遗传模式[17]。约95%的CBN患儿在诊断2年内可出现自发缓解,G-CSF仅推荐应用于反复发生感染的患儿[16]

1.3 周期性中性粒细胞减少症

周期性中性粒细胞减少症(cyclic neutropenia, CyN)发病率约为0.5~1/100万。通常于生后1年内发病,表现为周期性发作中性粒细胞减少伴反复感染,包括咽喉炎、牙龈炎、牙周炎等,偶可发生严重感染,如肺炎、中耳乳突炎、皮肤和皮下组织的细菌感染,可伴血小板、单核细胞和网织红细胞计数的周期性变化。发作呈规律性,发作间隔为21 d(14~35 d),低谷期持续3~6 d。发作间期中性粒细胞计数正常,亦无临床表现[18]。CyN呈常染色体显性遗传,主要与19号染色体的ELANE基因突变有关,该基因突变可加速中性粒细胞前体细胞凋亡,导致中性粒细胞减少[19]。通常认为CyN不会发展成白血病,但最近Klimiankou等报道两例存在获得性CSF3R基因突变的CyN患儿,其中一例发生AML[20]。CSF3R基因突变常见于SCN患者,存在该基因突变的SCN患者白血病转化风险增加[21-22]。但该基因突变与CyN患儿白血病发病风险之间的关系尚不明确,常规监测CSF3R基因突变的临床获益仍待观察。大多数患儿可应用低剂量G-CSF(每天2~3 μg/kg)增加中性粒细胞计数、降低感染风险以及减轻感染症状[23]。目前推荐使ANC维持在0.5×109/L以上即可。

1.4 Shwachman-Diamond综合征

Shwachman-Diamond综合征(Shwachman-Diamond syndrome, SDS)的发病率约为0.5~1/100万,男性多见,通常于婴儿期起病,除中性粒细胞减少外,胰腺外分泌功能衰竭(脂肪泄、营养吸收不良)为该病特异性的临床表现,其他临床表现包括矮小、发育停滞、自身免疫性疾病、骨骼发育异常以及血液系统受累,如贫血、HbF水平升高、血小板减少、中性粒细胞化学趋化功能受损以及骨髓衰竭等[24]。SDS幸存者的恶性疾病(MDS或AML)转化风险超过30%[25]。SDS呈常染色体隐性遗传,主要与Shwachman-Bodian-Diamond综合征基因(SBDS)突变有关[26]。最近研究发现,该基因突变的白细胞中存在雷帕霉素靶蛋白(mTOR)和信号转导子与转录激活子3(STAT3)通路激活[27]。由于STAT3参与调节中性粒细胞生存和诱导白血病或淋巴瘤发生,而STAT3活化受mTOR调控,因此mTOR在细胞生长和肿瘤发生中发挥重要作用。靶向mTOR/STAT3通路也许是SDS新的治疗思路。SDS患儿如出现胰腺外分泌功能衰竭可予肠溶性胰酶替代治疗,出现骨髓衰竭可应用环孢素A,间断或持续性中性粒细胞减少( < 0.5×109/L)可给予G-CSF治疗。

1.5 WHIM综合征

WHIM综合征为一种可导致严重中性粒细胞减少的罕见病,临床表现可归纳为“WHIM”4个字母:人乳头状瘤病毒所导致的疣(Warts),低丙种球蛋白血症(hypogammaglobulinemia),反复细菌感染(infections)和骨髓中性粒细胞滞留(myelokathexis)。由于反复感染和肿瘤易感性,患者生存期缩短。据一项纳入60例WHIM综合征病例的文献报道,幸存者在40岁时的恶性肿瘤发生风险接近30%[28]。WHIM综合征呈常染色体显性遗传,与趋化因子受体CXCR4基因突变有关,该基因突变截断了CXCR4羧基末端,使CXCR4负性调控通路受阻,导致CXCR4信号活性及其对骨髓中性粒细胞的促黏附功能增强,从而干扰骨髓成熟中性粒细胞向外周血释放(无效髓系造血),最终引起外周血中性粒细胞减少和成熟中性粒细胞存留在骨髓而凋亡[29-30]。G-CSF可增加外周血中性粒细胞数量,输注丙种球蛋白可改善低丙种球蛋白血症。此外,普乐沙福(plerixafor)作为CXCR4的拮抗剂,近期一项Ⅰ期临床研究证实其长期(6个月)、低剂量(0.01~0.02 mg/kg)应用对于增加WHIM成人患者的外周血白细胞计数是安全、有效的[31]

1.6 网状发育不全

网状发育不全为一种罕见的重症联合免疫缺陷病,髓系和淋巴系细胞均发育受阻,而红细胞和血小板产生正常;临床表现包括先天性粒细胞重度减少、外周血T淋巴细胞缺乏以及感音性耳聋;患者通常在婴儿早期因严重细菌感染死亡[32-33]。网状发育不全呈常染色体隐性遗传,与腺苷酸激酶2基因(AK2)突变有关,该基因突变可引起细胞内AMP/ADP(腺苷单磷酸/腺苷二磷酸)比例增加以及线粒体膜电位暂时性升高,导致细胞能量耗竭和氧化应激,从而影响造血干细胞及前体细胞正常发育[34]。抗氧化可能是网状发育不全患儿的一种潜在的治疗手段,G-CSF无助于患者中性粒细胞计数改善,造血干细胞移植或可用于治愈此病[35]

1.7 先天性角化不良

先天性角化不良(dyskeratosis congenita, DKC)为一种罕见的端粒功能障碍性疾病。除表现为特征性的皮肤黏膜三联征(指/趾甲角化不良,口腔黏膜白斑和皮肤网状色素沉着),还表现为进行性骨髓衰竭、肺部纤维化和恶性肿瘤易感性;中性粒细胞轻度减少,感染少见[36]。目前已经发现12种端粒或端粒酶相关的基因突变参与发病,以X连锁隐性遗传性DKC1基因突变最常见[37-39]。雄激素有助于改善其造血功能[40]。造血干细胞移植或可治愈进行性骨髓衰竭,但此病患者对于移植前预处理的耐受性较差,常面临致死性移植相关副作用[41]

2 获得性中性粒细胞减少症

获得性中性粒细胞减少症的原因为外周血中性粒细胞破坏或消耗增加导致其生存期缩短。骨髓象正常或存在晚幼粒/杆状核细胞成熟停滞。感染风险较先天性中性粒细胞减少症低。

2.1 感染相关性中性粒细胞减少症

中性粒细胞减少常发生于季节转换期间,可能与环境中存在的优势病毒感染有关[42],包括水痘病毒、麻疹病毒、风疹病毒、甲型和乙型肝炎病毒、流感病毒、呼吸道合胞病毒、巨细胞病毒、EB病毒、B19病毒、腺病毒、人疱疹病毒6型和柯萨奇病毒等。病毒感染可通过直接作用或诱导产生抗中性粒细胞抗体引起中性粒细胞生成减少及破坏增加[43]。急性暂时性中性粒细胞减少通常始于感染发生的前几天,直至病毒血症结束。治疗措施包括隔离及防治继发细菌感染。可使用G-CSF改善中性粒细胞计数。

2.2 药物相关性中性粒细胞减少症

多种药物可引起中性粒细胞减少,主要机制为药物引起的剂量依赖性髓系细胞直接抑制,可见于细胞毒药物、吩噻嗪类、半合成青霉素类、非甾体类、氨基比林衍生物、巴比妥类、金制剂、磺胺类和抗甲状腺药物等[44]。通常于药物使用2~3个月内出现,并持续至停药后10 d左右。此外,抗生素、降血糖药、抗组胺药和降压药等也可引起特质性中性粒细胞减少,可能与相关药物的活化代谢产物介导免疫反应有关[45]。还有部分药物(保泰松、氯磺丙脲等)作为半抗原进入体内与白细胞蛋白结合形成全抗原,诱导机体产生自身抗体,导致中性粒细胞破坏[46]。少数情况下,特定的遗传易感性也参与发病。例如,人类白细胞抗原-28基因(HLA-28)携带增加氯氮平诱导的中性粒细胞减少症发病风险,而HLA-B35携带可避免发病[47]。治疗包括停用相关药物,应用G-CSF可加速中性粒细胞数量恢复。

2.3 免疫性中性粒细胞减少症

免疫性中性粒细胞减少症与抗中性粒细胞特异性抗体导致中性粒细胞破坏有关[48]。中性粒细胞表面抗原分两类:一类为中性粒细胞与其他细胞共有的抗原,如HLA等,另一类为中性粒细胞特有的抗原。目前共鉴定出10种人类粒细胞抗原(human granulocyte antigen,HNA),其中HNA-1(FcγIIIb受体)是中性粒细胞膜表面免疫原性最强的糖蛋白[49]

特发性自身免疫性中性粒细胞减少症(primary autoimmune neutropenia, PAIN)主要见于3~8个月婴儿,平均诊断年龄为7~9个月,ANC为0~0.15×109/L,表现为反复发作的轻度皮疹和上呼吸道感染,但感染程度较SCN所致感染轻,甚至无临床症状[50-51]。诊断金标准为检测到抗HNA抗体,但Audrain等[52]研究发现,在临床高度疑似PAIN的患者中,约40%不能检测到抗中性粒细胞抗体,可能与自身抗体水平低或HNA型别覆盖不全有关。

PAIN骨髓象可正常,或增生活跃伴或不伴有粒细胞发育停滞在较成熟阶段。PAIN预后良好,意大利中性粒细胞减少症登记处(INR)报道,89%的PAIN患者的中性粒细胞计数可在数月至几年内自行恢复[53]。患者发生严重感染的风险极低,因此不推荐预防性使用抗生素。此外,有学者认为静脉用丙种球蛋白、糖皮质激素、环孢素或抗CD20抗体治疗无效[54]。如存在严重感染,可应用G-CSF,起始剂量为每日1~2 μg/kg,并根据中性粒细胞计数和感染控制情况调整剂量[54-55]

继发性自身免疫性中性粒细胞减少症(secondary autoimmune neutropenia, SAIN)或称为与其他自身免疫性疾病相关的自身免疫性中性粒细胞减少症。与PAIN的最大区别在于发病年龄较大以及罕见自行缓解[56]。最常见的相关疾病包括风湿性疾病、自身免疫性淋巴增殖综合征以及Evans综合征等[55, 57]。G-CSF可降低感染风险,尤其是ANC减少至1×109/L以下的。对于单用G-CSF治疗失败的患者,推荐使用免疫抑制治疗[55]

同族免疫性新生儿中性粒细胞减少症是由胎-母白细胞抗原型别不合引起,例如HNA-1a阴性表型母亲孕期接触HNA-1a阳性表型胎儿来源的中性粒细胞,则产生针对胎儿中性粒细胞的同种抗体,并经胎盘转运至胎儿体内导致胎儿/新生儿发生中性粒细胞破坏,表现出中度至重度中性粒细胞减少。除HNA-1a外,其他不合的HNA抗原型别如HNA-1b、1c、2a、3a、4a、4b和5a也均有相应病例报道[58-61]。此病为自限性,通常不需干预。若患儿出现严重感染包括反复细菌感染或败血症,应行骨髓检查。若存在髓系早期成熟停滞,可予G-CSF治疗[16]

3 结语

中性粒细胞减少是儿科常见的就诊原因,深入认识其病因有助于改进及完善当前治疗手段,从而减少感染风险或克隆演化风险。此外,为有助于病因揭示和治疗,中性粒细胞减少症患儿应在专业儿童血液中心进行全面诊断和监测随访。

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