慢性肉芽肿病中远期随访和感染预防性药物的效果分析

目的 探讨慢性肉芽肿病（CGD）患儿使用人重组IFN-γ（rhIFN-γ）、复方磺胺甲噁唑联合用药的疗效和安全性。方法 对2004年1月至2011年12月复旦大学附属儿科医院诊断的CGD患儿进行随访研究，包括感染部位、感染病原体、非感染性炎症反应和药物治疗等。比较联合使用rhIFN-γ和复方磺胺甲噁唑以及单用复方磺胺甲噁唑治疗前后的感染发生频率，分析感染预防性用药的有效性和安全性。结果 29例CGD患儿纳入本研究，平均发病和诊断年龄分别为2.5月龄和2.4岁，人均随访时间为2.9年。①每年人均感染发生频率为1.28，其中严重感染和非严重感染发生频率分别为0.48和0.80。肺部和淋巴结感染是诊断前（49和26例次）和随访期间（26和37例次）最常见的感染部位，分枝杆菌是导致本组患儿感染（34/61例次）和死亡（3/4例）的主要原因。②21例联合用药，8例因出现rhIFN-γ不良反应或自行停药而单用复方磺胺甲噁唑。联合用药组总感染和严重感染每年人均发生频率均较治疗前明显降低（总感染：1.986 vs 1.098，P=0.002；严重感染：1.290 vs 0.452，P=0.001），以肺部感染最明显（0.758 vs 0.275，P=0.004）。单用复方磺胺甲噁唑组总感染、严重感染每年人均感染发生频率较使用前差异均无统计学意义。联合用药组较单用复方磺胺甲噁唑组总感染和非严重感染每年人均发生频率明显降低（总感染：1.098 vs 1.823，P=0.015；非严重感染：0.646 vs 1.248，P=0.047），而严重感染每年人均发生频率差异无统计学意义（0.452 vs 0.576，P=0.254）。③14/29例（48.3%）使用rhIFN-γ治疗后出现不良反应，以发热为主要表现（12/29例），未发现致命性不良反应。结论 分枝杆菌是导致本组CGD患儿感染和死亡的主要原因。rhIFN-γ、复方磺胺甲噁唑联合治疗方案可明显降低CGD患儿感染发生频率，rhIFN-γ是CGD患儿安全有效的治疗药物。

Moderate- and long-term follow up of chronic granulomatous disease and efficacy of preventive drugs

Objective To describe the clinical features of pediatric chronic granulomatous disease (CGD) and incidence of infection after treatment program (combine rhIFN-γ and TMP-SMX). Methods The follow-up study of clinical features, including the site of infection, the pathogen of infection, noninfectious inflammatory response and drug treatment, etc., was performed in CGD patients diagnosed in Children′s Hospital of Fudan University from January 2004 to December 2011. The incidence of infection calculated as per patient-year was compared between patients who received combination treatment program or separated TMP-SMX treatment. The clinical efficacy and safety of rhIFN-γ treatment were analyzed. Results A total of 29 cases were recruited into the study. The mean age of onset and diagnosis was 2.5 months and 2.4 years respectively. Mean duration of per follow-up patient was 2.9 years. ① The incidence of all infections, severe infections and non-severe infections was 1.8, 0.48 and 0.80 per patient-year. Lung infection and lymphadenitis were the most frequent manifestations both prior to diagnosis (49 and 26) and during follow-up (26 and 37). Mycobacteria species was the leading cause of infection (34/61) and death (3/4) in our cohort. ② Combined treatment program was used in 21 cases while separated TMP-SMX treatment was performed in 8 cases because of drug adverse reaction or self-withdrawal. After combined treatment, the incidence of total and severe infection was significantly lower than that prior to treatment(total infection: 1.986 vs 1.098, P=0.002; severe infection:1.290 vs 0.452, P=0.001）, the most remarkable to the lung (0.758 vs 0.275, P=0.004), the incidence of infection did not significantly differ from separated TMP-SMX treatment. The incidence of total and non-severe infection in combined treatment program was significant lower than that in separated TMP-SMX treatment (total infection: 1.098 vs 1.823, P=0.015; non-serious infection: 0.646 vs 1.248, P=0.047), serious infection had no significant difference (0.452 vs 0.576, P=0.254). ③ 14/29（48.3%）cases reported an adverse event after the use of rhIFN-γ, the commonest was fever (12/29). There was no life-threatening rhIFN-γ-related adverse events. Conclusions Combined treatment program significantly reduced the incidence of infection. The use of rhIFN-γ in patients with CGD appeared to be effective and safe. Mycobacteria species was the first cause of infection and death in our cohort.