普通变异性免疫缺陷症临床诊疗思维
Clinical Diagnosis and Treatment Thinking of Common Variable Immunodeficiency
DOI: 10.12677/ACM.2023.1361350, PDF, HTML, XML, 下载: 178  浏览: 249 
作者: 谢卓君:暨南大学第一临床医学院,广东 广州;肖小敏*:暨南大学附属第一医院产科,广东 广州
关键词: 普通变异性免疫缺陷症临床表现治疗Common Variable Immunodeficiency Clinical Manifestations Therapy
摘要: 普通变异性免疫缺陷症(CVID)是一种以低免疫球蛋白血症、反复细菌感染为主要特征的异质性免疫缺陷综合征,临床罕见,易于漏诊、误诊。大量研究表明,不同的免疫和遗传缺陷参与了CVID的发病机制。然而,在大多数情况下,这种疾病的遗传背景仍未查明。本文对普通变异性免疫缺陷症的临床表现、发病机制、诊断和治疗进行归纳、总结,为该病的早期诊断、早期治疗提供依据,以减低误诊、漏诊率。
Abstract: Common variable immunodeficiency (CVID) is a rarely encountered heterogeneous immunodefi-ciency syndrome characterized mainly by low immuneglobulinemia and repeated bacterial infec-tions, easily to be missed and misdiagnosed. Numerous studies demonstrated that different immu-nological and genetic defects are involved in the pathogenesis of CVID. However, in most cases, the genetic background of the disease remains unidentified. This review aims to discuss different as-pects of CVID including clinical manifestations, pathogenesis, diagnosis and management of the disease and provide basis for early diagnosis and treatment of the disease, so as to reduce the rate of misdiagnosis and missed diagnosis.
文章引用:谢卓君, 肖小敏. 普通变异性免疫缺陷症临床诊疗思维[J]. 临床医学进展, 2023, 13(6): 9648-9654. https://doi.org/10.12677/ACM.2023.1361350

1. 引言

普通变异性免疫缺陷症(common variable immunodeficiency, CVID)是一种以不同程度的低免疫球蛋白血症、反复细菌感染和B淋巴细胞向记忆B细胞和浆细胞转化功能缺陷为特征的异质性免疫缺陷综合征,由Sanford [1] 等于1954年首次提出。据估计,CVID国外发病率为1:50,000~1:25,000,性别之间无明显差异,在我国目前还没有大样本的数据证明其发病率,根据所报道的文献来看,国内的发病情况相对罕见。CVID的罕见性和临床异质性导致了其诊断和治疗方面的困难。除了复发性和严重感染外,CVID患者还容易出现自身免疫性和炎症性并发症 [2] ,患肿瘤的风险增加 [3] 。并且由于缺乏特异性抗体反应,CVID患者的实验室检查(如抗核抗体、直接Coomb试验和抗血小板抗体)可能呈阴性 [4] ,在诊断时易忽略导致漏诊、误诊或延迟诊断。本文对CVID的临床表现、发病机制、诊断、治疗进行综述,以提高对这一异质性疾病的认识,促进早期诊断和适当管理。

2. CVID临床表现

普通变异性免疫缺陷症为罕见病,国内对此研究甚少,中文期刊检索到的文献几乎均为个案报道 [5] [6] [7] [8] ,并且各个案例患者的首发症状各有不同,文献数量较少,临床表现各异。其中龚胜兰等 [9] 2020年发表在《南方医科大学学报》上的文献曾回顾性的分析了四川大学华西医院的一共13例普通变异性免疫缺陷症的患者,其主要的临床表现为感染,其中10例患者表现为反复的呼吸道感染。新近一篇关于CVID的报道 [10] ,一例新型STAT3基因突变所致的10月龄CVID患儿,却并未表现出反复的呼吸系统感染,而是以慢性腹泻为主要的临床表现。Gathman [11] 等曾回顾性地分析了欧洲免疫缺陷协会数据库收集的28个医疗中心2212例CVID患者的资料发现,CVID的临床表现主要包括:肺炎、自身免疫性疾病、脾大、支气管扩张、肉芽肿性炎、肠病、实体肿瘤、脑炎或脑膜炎、淋巴瘤。同时,Janssen [12] 等对51项研究共8521例患者进行系统性地荟萃分析,确定了270项CVID诊断前后的临床表现,由此观之,CVID的临床表现变异性高,笔者查阅相关文献总结CVID的临床表现(见表1):

Table 1. Clinical manifestations of CVID

表1. CVID的临床表现

CVID是一种异质性疾病,以反复细菌感染、自身免疫性疾病、非恶性淋巴细胞增生为主 [13] [14] ,呼吸道感染是最常见的临床表现,Zainaldain [15] 等人所报告的系统性荟萃分析是卫生系统第一次对CVID的感染进行系统评价,研究结果表明了呼吸道感染是最常见的感染性并发症,肺炎的患病率为67.7%,其次为上呼吸道感染,发病率为59%;根Jolles [16] 的研究,90%的CVID患者会出现反复的细菌性呼吸道感染,最常见的诊断是肺炎(超过70%的患者);同时,在伊朗患者中,最常诊断的也为肺炎 (31.9%) [17] 。肺炎链球菌、嗜血杆菌、卡他莫拉菌、脑膜炎奈瑟菌和葡萄球菌是引起CVID的细菌感染的主要病原体群 [18] 。胃肠道感染表现为慢性或急性腹泻 [19] ,蓝氏贾第鞭毛虫、空肠弯曲杆菌和沙门氏菌是最常见的病原体。约10%的严重病例可能引起营养吸收不良和体重减轻 [20] ,但CVID患者的幽门螺杆菌(Hp)感染率与普通人相当。然而,感染Hp的CVID患者更容易发生胃炎、胃异型增生和胃癌 [21] 。非感染性胃肠道疾病发生在10%至12%的CVID患者中,例如克罗恩病、溃疡性结肠炎、乳糜泻、结节性淋巴组织增生 [22] 。有研究表明,高达30%的CVID患者会经历自身免疫过程。CVID中的自身免疫最常表现为自身免疫性血细胞减少症,见于4%~20%的患者,如免疫性血小板减少性紫癜(ITP)、自身免疫性溶血性贫血(AIHA)和自身免疫性中性粒细胞减少症(AIN),CVID患者自身免疫过程的另一个特征是在肺部 [23] 、胃肠道 [22] 、肝脏 [24] 或其他器官中存在肉芽肿浸润 [4] [25] 。但I型糖尿病、甲状腺功能减退等常见的自身免疫性疾病的发生率在CVID患者中并没有增多。CVID患者发生各种恶性肿瘤的发病率为1.5%~20.7%,发生实体或血液恶性肿瘤的风险增加10倍,淋巴瘤患者通常在童年时期发病,而胃癌则出现在成年后期,尤其是生命的第四个十年。CVID患者中最常见的恶性肿瘤类型是非霍奇金淋巴瘤,其次是胃、乳腺、膀胱和子宫颈的上皮肿瘤 [26] [27] 。CVID肝脏受累的患病率从5%到79%不等,结节性再生性增生(NRH)是CVID中最常见的肝脏受累形式,NRH患者可表现出门静脉高压、脾肿大、腹水、静脉曲张和肝合成功能障碍。值得注意的是,NRH可能与肉芽肿的形成有关,强调肝脏NRH可能是免疫驱动所引起 [28] 。CVID合并自身免疫性肝炎 [28] 、肝肉芽肿病、原发性胆汁性胆管炎和原发性硬化性胆管炎在临床中也可见 [29] 。

由于CVID临床表现各异,涉及到呼吸系统、消化系统、血液系统、自身免疫系统等,从而容易导致漏诊、误诊。因此,对于反复出现呼吸系统、消化系统感染症状,并合并低免疫球蛋白血症,出现非特异性临床表现、累积多系统的患者要考虑到CVID的可能。

3. CVID发病机制

目前关于CVID的发病机制仍不明确,主要有以下几点:1) B细胞缺乏或B细胞功能障碍导致抗体产生减少 [30] [31] ;2) T细胞功能缺陷导致T细胞对B细胞辅助不足 [32] ;3) 遗传变异 [33] ;4) 自身免疫失调 [34] (包括体液免疫、细胞免疫);5) 表观遗传调控异常 [35] ,(例如致病性核因子kappa b亚基1 (NF-κB1)是美国和欧洲CVID同源群中最常见的缺陷 [36] [37] ,也包括组蛋白和染色质修饰、DNA甲基化与去甲基化 [38] 等);6) 单基因的缺陷 [39] (例如STAT3基因、IKAROS、诱导型T细胞共刺激因子(ICOS)、IKAROS转录因子等)。

4. CVID诊断

CVID具有广泛的表型,一般来说,低丙种球蛋白血症和反复感染是诊断CVID的标志 [40] ,CVID的诊断标准由欧洲免疫缺陷学会(ESID)于1999年提出 [41] ,并在随后几年里根据实验室检查发现和临床症状重新定义,目前CVID诊断的多采用最新ESID标准 [42] 为(见表2):

Table 2. ESID criteria (2014)

表2. ESID标准(2014年)

上述四项内容中,满足ABC或ABD可拟诊为CVID,应静脉输注免疫球蛋白/皮下注射免疫球蛋白进行替代治疗,若仅符合A标准、AB或AC或AD但不符合B标准的患者则被称为疑似CVID,其中一些患者可能需要静脉输注免疫球蛋白/皮下注射免疫球蛋白治疗。除了ESID诊断标准,2013年,Ameratunga等人提出了一套CVID的替代诊断标准 [43] 。2016年,Bonilla等人发表了关于CVID的国际共识文件 [44] 。3项诊断标准均要求血清IgG水平较低,但低IgG的定义各不相同,这反映了认可IgG生成受损是CVID的基本特征的一致性,但对所需损伤程度存在分歧。除此之外,对于年龄、IgM缺乏、IgA缺乏、额外的实验室检查、组织学表现、基因检测的要求不同 [45] 。标准之间的这些差异突出了目前在CVID诊断共识方面存在的挑战。

5. CVID治疗

CVID的标准治疗是免疫球蛋白替代疗法,通过静脉滴注或皮下注射的途径 [46] ,指南建议免疫球蛋白替代疗法的起始剂量为0.4~0.6 g/kg体重,每个月输注1次 [47] ,免疫球蛋白的使用可以大大减少患者细菌感染的数量,降低自身免疫性细胞减少的频率,从而显著改变CVID的临床病程,延长CVID患者的寿命 [48] 。但是,免疫球蛋白并不能预防或改善大多数炎症和自身免疫性疾病 [49] 。在针对某些患者合并呼吸系统、消化系统感染等相关症状时,单纯的免疫球蛋白并不能发挥良好的作用,仍需要在急性期使用抗生素,或在慢性期进行预防 [49] ,抗生素种类的选择应根据患者的临床药敏试验来确定,选择相对敏感的药物可以尽早控制感染,使病情得到更大程度的好转;在针对其他并发症例如肉芽肿性疾病、淋巴瘤或癌症的发展时,还需要考虑额外使用皮质类固醇激素或免疫调节剂 [13] 。

临床工作中,遇到反复发生以咳嗽、腹泻为主的症状,且抗感染治疗效果较差时,需要高度怀疑并非单纯的呼吸系统相关疾病,应该警惕CVID的可能性,并注意和其他疾病相鉴别,避免漏诊或仅诊断为低免疫球蛋白血症而停止进一步的病因探讨,以致患者不能得到及时、正确的诊断及治疗。CVID缺乏特异性的症状,具有异质性的临床表现和免疫学特征,临床医生对此病认识度不够,难以早期发现,易漏诊、误诊,从而延误病情,导致治疗效果不佳,花费较多,医疗资源的浪费,所以我们应该加强对CVID的认识。

综上,CVID患者常表现为反复的感染,也可并发自身免疫性疾病、呼吸系统疾病、消化系统疾病、肉芽肿性疾病及恶性肿瘤等,由于临床医生认识不足,常因漏诊、误诊导致延误诊断。因此,强化对本病的认识有助于早期诊断和治疗,改善预后,节约医疗资源。

NOTES

*通讯作者。

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