Abstract
Drug induced hypersensitivity syndrome (DIHS) is often manifested as severe systemic drug trans-reactions characterized by acute and extensive skin lesions (mostly measles-like rash), fever, enlargement of lymph nodes, multiple organ involvement (hepatitis, nephritis, and pneumonia), eosinophilia and mononucleosis,within 2-6 weeks of the application of sensitizing drugs. In the early stage of the lesion, macular papules or erythema multiforme were common, and in severe cases, exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis were also common. Most of them deve-loped after taking allergic drugs for 2-6 weeks (average: 3 weeks). Symptoms persisted after discontinuation of allergic drugs. It takes more than one month to alleviate, which may endanger life in severe cases. Documents report that the most common drugs causing DIHS are phenytoin sodium, carbamazepine and phenobarbital aromatic drugs. However, it was reported that phenobarbital sodium was the most common anticonvulsant among allergenic drugs in children, followed by antipyretics, analgesics and antibio-tics, which may be related to the spectrum of childhood diseases and the particularity of the drug. Lamotrigine has been reported to cause DIHS in adults in China, but less in children. In order to improve the understanding of clinical diagnosis and treatment of DIHS in children, reduce misdiagnosis, missed diagnosis, and untimely treatment, and prevent the aggravation of the disease, we studied the case of a 4-year-old 7-month-old girl who presented with systemic erythematous papules, fever, hepatosplenomegaly, marked increase of white blood cells, marked decrease of anemia and platelets, abnormal liver function and coagulation routine after taking lamotrigine for one month due to epilepsy seizures. Now, accor-ding to the DIHS diagnostic criteria established by Registration of Severe Cutaneous Adverse Reactions Drug Review Group in 2007, plasma exchange was immediately given to replace the toxic metabolites in hemorrhagic plasma, and methylprednisolone was given intravenously for three days. At the same time, after symptomatic supportive treatments, such as loratadine and albumin, the condition gradually improved without recurrence. Through a case report of Drug reaction with eosinophilia and systemic symptoms in a child caused by lamotrigine, we can strengthen our understanding and improve the level of diagnosis and treatment of drug hypersensitivity syndrome in children. Lamotrigine can cause DIHS in children, which is very dangerous. Early diagnosis and early withdrawal of allergenic drugs, plasma exchange and glucocorticoid therapy are the key to treatment.
Keywords: Drug-induced hypersensitivity syndrome, Lamotrigine, Human herpes virus 6
药物超敏反应综合征(drug induced hypersensitivity syndrome,DIHS)为应用致敏药物2~6周内,主要以急性广泛的皮损(最多见的为麻疹样皮疹)伴发热、淋巴结增大、多脏器受累(肝炎、肾炎、肺炎)和嗜酸性粒细胞增多及单核细胞增多等血液学异常为特征的严重全身性药物反应[1]。在国内拉莫三嗪引起成人DISH有报道,但引起儿童过敏的报道较少,重庆儿童医院报道22例DIHS住院患儿中,有3例为拉莫三嗪引起[2],因此,为了提高对儿童DIHS临床诊治的认识,减少误诊、漏诊,及时治疗,防止病情加重,现将苏州大学附属儿童医院近期1例儿童典型拉莫三嗪致DIHS报道如下。
1. 病例资料
患儿,女,4岁7个月。因皮疹10 d,间断发热7 d为主诉入院。患儿10 d前面部、耳后出现红色散在斑丘疹,有明显痒感,起疹前 1 个月因癫痫发作予加用口服拉莫三嗪,起疹后即自行停药,未予特殊处理。7 d前出现发热,最高温度38.5 ℃,热前无寒战,热极无抽搐,无咳嗽咳痰,无气促喘息,无腹胀腹泻,遂就诊于当地医院,予“林可霉素、地塞米松、头孢克洛”治疗2 d,患儿仍有发热,且皮疹无明显消退,遂来苏州大学附属儿童医院,查血常规:白细胞17.98×109/L,C-反应蛋白(C-reactive protein,CRP)4.13 mg/L,血红蛋白131 g/L,中性粒细胞百分比50.5%,予“头孢美唑、炎琥宁”治疗4 d,期间患儿体温平稳2 d后又发热,且皮疹加重,蔓延至全身,部分融合成片,痒感加重,无破溃,予“甲泼尼龙”补液1 d,皮疹较前减少。复查血常规:白细胞 44.84×109/L,CRP 0.75 mg/L,血红蛋白111 g/L,中性粒细胞20.3%。胸腹部CT:右下肺絮片影,右侧少量胸腔积液,肝脾增大,门静脉增宽,胆囊窝积液,疑“脓毒血症?”收入苏州大学附属儿童医院重症监护病房。既往史:患儿2016年5月确诊“癫痫”, 2017年5月开始口服“左乙拉西坦(1.5 mL,每日2次)、丙戊酸钠(0.25 mg,每日2次)”,入院前1个月加用“拉莫三嗪”(具体剂量不详)。
入院查体:面部浮肿,全身可见散在红色斑丘疹,部分融合成片,部分压之褪色,有痒感,双侧颈部可及数枚蚕豆大小淋巴结,腹软,肝肋下3 cm,脾肋下2 cm,质韧,未及异常包块,四肢肌张力正常,病理反射未引出(图1)。辅助检查:血白细胞 23.75×109/L,CRP 0.99 mg/L,嗜酸性粒细胞4.5%,血红蛋白86 g/L,血小板18×109/L,淋巴细胞百分比61%;凝血常规:D-二聚体630 μg/L, 活化部分凝血激酶时间(activated partial thromboplastin time,APTT)36.1 s,凝血酶原时间(prothombin time,PT)15.8 s,纤维蛋白原1.46 g/L;肝功能谷丙转氨酶77.9 U/L,白蛋白32.5 g/L;铁蛋白224.7 μg/L;自身抗体初筛阴性;胸腹部CT:右下肺絮片影,右侧少量胸腔积液,肝脾增大,门静脉增宽,胆囊窝积液。入院初步诊断:多形红斑。治疗经过:复方甘草酸苷保肝,查凝血常规:D-二聚体710 μg/L,APTT>180 s,PT 18 s,纤维蛋白原1.25 g/L;肝功能谷丙转氨酶35.5 U/L,白蛋白21 g/L,口服氯雷他定,外涂药物,血小板输注等对症支持,入院第2天加用丙种球蛋白(2 g/kg)支持,次日病情加重,皮疹明显增多,颜面部水肿加重,仍有发热,最高温度39 ℃,复查胸腹部CT:两肺感染,右侧肺门、纵膈、双侧腋窝及颌下淋巴结肿大,右侧胸腔积液,左侧局部胸膜反应,肝脾肿大;头颅CT未见明显异常,鼻窦CT示副鼻窦炎及腺样体肥大;心脏彩超:双侧冠状动脉无扩张,加用头孢曲松抗感染,白蛋白(5 g/次,每日3次)纠正低蛋白血症;复查血常规:白细胞52.13×109/L,CRP 8.03 mg/L,血红蛋白100 g/L,血小板75×109/L,骨髓涂片提示感染伴嗜酸细胞增多征象,修订诊断为“药物超敏反应综合征”,行血浆置换,甲泼尼龙15 mg/(kg·d)冲击, 3 d后减为7.5 mg/(kg·d),白蛋白减量为(5 g/次,每日2次), 并加用维生素C(每日1 g), 1周后患儿眼睑、颜面浮肿减轻,全身皮疹明显消退,肝肋下一横指,脾肋下一横指,血象、凝血功能及肝功能恢复正常(图2)。9 d后转入苏州大学附属儿童医院肾脏免疫科,仍有咳嗽,转入后次日改为注射用哌拉西林钠他唑巴坦钠及阿奇霉素联合抗感染,异甘草酸镁(10 mL,每日1次)保肝,甲泼尼龙(30 mg/次,每日1次)改为口服醋酸泼尼松片(5 mg/次,每日3次), 住院16 d肝肾功能、血红蛋白、血小板及凝血常规恢复正常,好转出院。
1.
散在红色斑丘疹,部分融合成片,部分压之褪色
Scattered red macular papules, partially fused into patches, partially pressed to fade
2.
治疗后浮肿减轻,皮疹明显消退
After treatment, edema was alleviated and rash subsided markedly
2. 讨论
DIHS皮损早期多见为斑丘疹或多形性红斑,严重时也表现为剥脱性皮炎、Stevens-Johnson综合征、中毒性表皮坏死松解症等。多在服用过敏药物2~6周后(平均3周)发病,症状于停用致敏药物后仍持续发展和迁延,多经过1个月以上才能缓解。DIHS严重时可能危及生命,主要死因是重症肝炎[3]。引发DIHS最为常见的药物是苯妥英钠、卡马西平和苯巴比妥类芳香族抗癫痫药,但有报道引起儿童致敏药物中以抗惊厥药苯巴比妥钠最常见,其次是解热镇痛药物和抗生素,可能与儿童疾病谱及用药特殊性有关[2]。另外,人疱疹病毒6型(human herpes virus 6,HHV6)感染[4]、遗传因素也是其主要发病原因。
目前沿用的DIHS诊断标准为2007年欧洲严重不良反应登记处药物评议小组制定:(1)使用某种特定药物之后出现迟发型红斑并迅速发展;(2)停用该药后,临床表现持续超过2周;(3)出现体温>38 ℃的发热;(4)明显的肝功能异常,或其他内脏损害(肾、肺、心):(5)外周血白细胞 >11× 109/L,或异形淋巴细胞>5%,或嗜酸性粒细胞计数>1.5×109/L;(6)淋巴结增大(直径>2 mm);(7)HHV6 再激活(+)。所有7项都存在诊断为DIHS,而存在前面5项则诊断为非典型DIHS[5]。
本例中患儿口服拉莫三嗪1个月后面部、耳后出现红色散在斑丘疹,有明显痒感,3 d后出现发热,入院前最高温度38.5 ℃,予抗生素治疗,随即出现体温最高达39 ℃,双侧颈部可及肿大淋巴结,肝脾肿大,且肝功能异常(谷丙转氨酶77.9 U/L),外周血白细胞52.13×109/L,CRP 8.03 mg/L,血红蛋白100 g/L,血小板75×109/L,;胸腹部CT示右下肺絮片影,右侧少量胸腔积液,肝脾肿大,门静脉增宽,胆囊窝积液,未检测HHV6,但本例符合诊断标准前6项,故可诊断。本例外周血嗜酸性粒细胞增多,Skowron等[6]报道皮肤嗜酸性粒细胞浸润在DIHS中更显著。对于DIHS,嗜酸粒细胞增多是诊断标准,80%的患者均有嗜酸性粒细胞增多[7]。嗜酸性粒细胞是参与宿主防御寄生虫、细菌、病毒和过敏反应的循环粒细胞,嗜酸性粒细胞也参与多种炎症反应,并可调节先天性和适应性免疫。生理情况下皮肤、肝脏和肺脏中不存在嗜酸性粒细胞,而发生超敏反应时,嗜酸性粒细胞在血液、皮肤和器官中均增加[8]。血小板减少不是DIHS诊断标准,但本例中患儿出现明显血小板降低,未见出血点,考虑与HHV6病毒感染有关,既往有报道该病毒可引起血小板减少性紫癜[9]。
DIHS的治疗首先是快速诊断并且避免致敏药物的再摄入,停用或更换以及慎用结构类似的可疑药物:首选糖皮质激素,人们对糖皮质激素的应用一直存有争议,糖皮质激素可使HHV6再激活,有引起病毒感染扩散的危险[10],通常选用甲泼尼龙或地塞米松,起始剂量可根据所引起的药物不同、患儿基础情况以及年龄等因素来综合决定;其次可选用血浆置换及双重膜血浆过滤分离,适用于有免疫功能低下或重症感染而不宜采用大剂量糖皮质激素治疗者,大剂量静脉注射人免疫球蛋白,早期足量地系统使用,仍是目前最为有效的手段,可迅速缓解临床症状及改善实验室指标,但也存在争议。本例患儿确诊DIHS后立即予血浆置换出血浆中的药物毒性代谢产物,并予15 mg/(kg·d)甲泼尼龙静脉冲击3 d,后减半量,同时给予氯雷他定、复方甘草酸苷及白蛋白等对症支持治疗后,病情逐渐好转,未出现病情反复。抗癫痫药拉莫三嗪引起的过敏反应较多发,故应密切观察患儿的反应,若出现皮疹、发热及内脏器官受累等临床表现,需警惕发生DIHS 的可能,尽早停用可疑药品并积极对症治疗。
(本文编辑:刘淑萍)
Funding Statement
国家自然科学基金（81771626）; 江苏省妇幼健康重点人才项目（FRC201731）; 苏州市科技发展计划项目（SS201428）
the National Natural Science Foundation of China(81771626); Maternal and Child Health Key Talents Project in Jiangsu Province(FRC201731); Suzhou Science and Technology Development Plan Project(SS201428)
References
- 1.Chen CB, Abe R, Pan RY, et al. An updated review of the molecular mechanisms in drug hypersensitivity. J Immunol Res. 2018;2018:6431694. doi: 10.1155/2018/6431694. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.刘 聪, 许 红梅, 谭 利平, et al. 儿童药物超敏反应综合征22例临床分析. 临床儿科杂志. 2017;35(7):522–524. [Google Scholar]
- 3.万 学峰, 王 珊珊, 陈 永琴. 别嘌醇致药物超敏反应综合征1例. 临床皮肤科杂志. 2010;39(2):131. [Google Scholar]
- 4.Hagiya H, Iwamuro M, Tanaka T, et al. Reactivation of human herpes virus-6 in the renal tissue of a patient with drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms (DIHS/DRESS) Intern Med. 2016;55(13):1769–1774. doi: 10.2169/internalmedicine.55.6287. [DOI] [PubMed] [Google Scholar]
- 5.Kardaun SH, Sidoroff A, Valeyrie-Allanore L, et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol. 2007;156(3):609–611. doi: 10.1111/j.1365-2133.2006.07704.x. [DOI] [PubMed] [Google Scholar]
- 6.Skowron F, Bensaid B, Balme B, et al. Comparative histological analysis of drug-induced maculopapular exan-thema and DRESS. J Eur Acad Dermatol Venereol. 2016;30(12):2085–2090. doi: 10.1111/jdv.13832. [DOI] [PubMed] [Google Scholar]
- 7.Cacoub P, Musette P, Descamps V, et al. The DRESS syndrome: a literature review. Am J Med. 2011;124(7):588–597. doi: 10.1016/j.amjmed.2011.01.017. [DOI] [PubMed] [Google Scholar]
- 8.Musette P, Janela B. New insights into drug reaction with eosinophilia and systemic symptoms pathophysiology. Front Med (Lausanne) 2017;4:179. doi: 10.3389/fmed.2017.00179. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.董 学君, 刘 忠民, 施 长根, et al. 人类疱疹病毒6、7、8型感染与特发性血小板减少性紫癜相关性研究. 医学研究通讯. 2004;33(9):45–46. [Google Scholar]
- 10.石 平荣, 李 凯, 段 逸群, et al. 药物超敏反应综合征发病机制及治疗的研究进展. 国际皮肤性病学杂志. 2006;32(2):117–120. [Google Scholar]