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Abstract：
Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on the effects of population-based newborn screening for SCID that was initiated in 2008 and expanded during 2010-18.
We analysed transplantation-related data from children with SCID treated at 34 PIDTC sites in the USA and Canada, using the calendar time intervals 1982-89, 1990-99, 2000-09, and 2010-18. Categorical variables were compared by χ2 test and continuous outcomes by the Kruskal-Wallis test. Overall survival was estimated by the Kaplan-Meier method. A multivariable analysis using Cox proportional hazards regression models examined risk factors for HCT outcomes, including the variables of time interval of HCT, infection status and age at HCT, trigger for diagnosis, SCID type and genotype, race and ethnicity of the patient, non-HLA-matched sibling donor type, graft type, GVHD prophylaxis, and conditioning intensity.
For 902 children with confirmed SCID, 5-year overall survival remained unchanged at 72%-73% for 28 years until 2010-18, when it increased to 87% (95% CI 82·1-90·6; n=268; p=0·0005). For children identified as having SCID by newborn screening since 2010, 5-year overall survival was 92·5% (95% CI 85·8-96·1), better than that of children identified by clinical illness or family history in the same interval (79·9% [69·5-87·0] and 85·4% [71·8-92·8], respectively [p=0·043]). Multivariable analysis demonstrated that the factors of active infection (hazard ratio [HR] 2·41, 95% CI 1·56-3·72; p<0·0001), age 3·5 months or older at HCT (2·12, 1·38-3·24; p=0·001), Black or African-American race (2·33, 1·56-3·46; p<0·0001), and certain SCID genotypes to be associated with lower overall survival during all time intervals. Moreover, after adjusting for several factors in this multivariable analysis, HCT after 2010 no longer conveyed a survival advantage over earlier time intervals studied (HR 0·73, 95% CI 0·43-1·26; p=0·097). This indicated that younger age and freedom from infections at HCT, both directly driven by newborn screening, were the main drivers for recent improvement in overall survival.
Population-based newborn screening has facilitated the identification of infants with SCID early in life, in turn leading to prompt HCT while avoiding infections. Public health programmes worldwide can benefit from this definitive demonstration of the value of newborn screening for SCID.
National Institute of Allergy and Infectious Diseases, Office of Rare Diseases Research, and National Center for Advancing Translational Sciences.
We analysed transplantation-related data from children with SCID treated at 34 PIDTC sites in the USA and Canada, using the calendar time intervals 1982-89, 1990-99, 2000-09, and 2010-18. Categorical variables were compared by χ2 test and continuous outcomes by the Kruskal-Wallis test. Overall survival was estimated by the Kaplan-Meier method. A multivariable analysis using Cox proportional hazards regression models examined risk factors for HCT outcomes, including the variables of time interval of HCT, infection status and age at HCT, trigger for diagnosis, SCID type and genotype, race and ethnicity of the patient, non-HLA-matched sibling donor type, graft type, GVHD prophylaxis, and conditioning intensity.
For 902 children with confirmed SCID, 5-year overall survival remained unchanged at 72%-73% for 28 years until 2010-18, when it increased to 87% (95% CI 82·1-90·6; n=268; p=0·0005). For children identified as having SCID by newborn screening since 2010, 5-year overall survival was 92·5% (95% CI 85·8-96·1), better than that of children identified by clinical illness or family history in the same interval (79·9% [69·5-87·0] and 85·4% [71·8-92·8], respectively [p=0·043]). Multivariable analysis demonstrated that the factors of active infection (hazard ratio [HR] 2·41, 95% CI 1·56-3·72; p<0·0001), age 3·5 months or older at HCT (2·12, 1·38-3·24; p=0·001), Black or African-American race (2·33, 1·56-3·46; p<0·0001), and certain SCID genotypes to be associated with lower overall survival during all time intervals. Moreover, after adjusting for several factors in this multivariable analysis, HCT after 2010 no longer conveyed a survival advantage over earlier time intervals studied (HR 0·73, 95% CI 0·43-1·26; p=0·097). This indicated that younger age and freedom from infections at HCT, both directly driven by newborn screening, were the main drivers for recent improvement in overall survival.
Population-based newborn screening has facilitated the identification of infants with SCID early in life, in turn leading to prompt HCT while avoiding infections. Public health programmes worldwide can benefit from this definitive demonstration of the value of newborn screening for SCID.
National Institute of Allergy and Infectious Diseases, Office of Rare Diseases Research, and National Center for Advancing Translational Sciences.
摘要：
背景：除非建立持久的适应性免疫，否则严重的联合免疫缺陷（SCID）是致命的，最常见的是通过异基因造血细胞移植（HCT）。初级免疫缺陷治疗联盟（PIDTC）探讨了近四十年来影响SCID患者生存的因素。重点关注2008年启动并在2010-18年期间扩大的基于人群的SCID新生儿筛查的效果.
方法：我们分析了在美国和加拿大34个PIDTC点接受SCID治疗的儿童移植相关数据，使用日历时间间隔1982-89、1990-99、2000-09和2010-18。通过χ2检验比较分类变量，通过Kruskal-Wallis检验比较连续结果。通过Kaplan-Meier方法估计总生存期。使用Cox比例风险回归模型的多变量分析检查了HCT结果的危险因素，包括HCT的时间间隔变量，HCT的感染状况和年龄，触发诊断，SCID类型和基因型，患者的种族和种族，非HLA匹配的同胞供体类型，移植物类型,GVHD预防,和调理强度。
结果：对于902名患有SCID的儿童，5年总生存率保持在72％-73％，持续28年，直到2010-18年增加到87％（95％CI82·1-90·6；n=268；p=0·0005）。对于自2010年以来通过新生儿筛查确定患有SCID的儿童，5年总生存率为92·5％（95％CI85·8-96·1），优于相同间隔内通过临床疾病或家族史确定的儿童（79·9％[69·5-87·0]和85·4％[71·8-92·8]，分别为[p=0·043])。多变量分析表明，活动性感染的因素（危险比[HR]2·41，95％CI1·56-3·72；p<0·0001），HCT年龄3·5个月或以上（2·12，1·38-3·24；p=0·001），黑人或非裔美国人种族（2·33，1·56-3·46；p<0·0001），某些SCID基因型在所有时间间隔内与较低的总生存率相关。此外，在多变量分析中调整了几个因素后，2010年后的HCT不再比研究的早期时间间隔具有生存优势（HR0·73，95％CI0·43-1·26；p=0·097）。这表明HCT的年龄较小，没有感染，都是由新生儿筛查直接驱动的，是近期总体生存率改善的主要驱动因素。
结论：基于人群的新生儿筛查促进了SCID早期婴儿的识别，反过来导致提示HCT，同时避免感染。全世界的公共卫生计划都可以从这一明确证明SCID新生儿筛查的价值中受益。
背景：国家过敏和传染病研究所，罕见疾病研究办公室,和国家促进转化科学中心。
方法：我们分析了在美国和加拿大34个PIDTC点接受SCID治疗的儿童移植相关数据，使用日历时间间隔1982-89、1990-99、2000-09和2010-18。通过χ2检验比较分类变量，通过Kruskal-Wallis检验比较连续结果。通过Kaplan-Meier方法估计总生存期。使用Cox比例风险回归模型的多变量分析检查了HCT结果的危险因素，包括HCT的时间间隔变量，HCT的感染状况和年龄，触发诊断，SCID类型和基因型，患者的种族和种族，非HLA匹配的同胞供体类型，移植物类型,GVHD预防,和调理强度。
结果：对于902名患有SCID的儿童，5年总生存率保持在72％-73％，持续28年，直到2010-18年增加到87％（95％CI82·1-90·6；n=268；p=0·0005）。对于自2010年以来通过新生儿筛查确定患有SCID的儿童，5年总生存率为92·5％（95％CI85·8-96·1），优于相同间隔内通过临床疾病或家族史确定的儿童（79·9％[69·5-87·0]和85·4％[71·8-92·8]，分别为[p=0·043])。多变量分析表明，活动性感染的因素（危险比[HR]2·41，95％CI1·56-3·72；p<0·0001），HCT年龄3·5个月或以上（2·12，1·38-3·24；p=0·001），黑人或非裔美国人种族（2·33，1·56-3·46；p<0·0001），某些SCID基因型在所有时间间隔内与较低的总生存率相关。此外，在多变量分析中调整了几个因素后，2010年后的HCT不再比研究的早期时间间隔具有生存优势（HR0·73，95％CI0·43-1·26；p=0·097）。这表明HCT的年龄较小，没有感染，都是由新生儿筛查直接驱动的，是近期总体生存率改善的主要驱动因素。
结论：基于人群的新生儿筛查促进了SCID早期婴儿的识别，反过来导致提示HCT，同时避免感染。全世界的公共卫生计划都可以从这一明确证明SCID新生儿筛查的价值中受益。
背景：国家过敏和传染病研究所，罕见疾病研究办公室,和国家促进转化科学中心。
