美国弗雷德哈钦森癌症研究中心Monica S Thakar团队研究了新生儿筛查对重度联合免疫缺陷患者造血细胞移植后存活的影响。2023年6月20日出版的《柳叶刀》杂志发表了这项成果。
重度联合免疫缺陷（SCID）是致命的，除非建立持久的适应性免疫，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合会（PIDTC）探讨了近四十年来影响SCID患者生存的因素，重点关注2008年开始并在2010-2018年扩大的基于人群的新生儿SCID筛查的影响。
研究组分析了在美国和加拿大34个PIDTC治疗点接受SCID治疗儿童的移植相关数据，使用的日历时间间隔为1982-89、1990-99、2000-09和2010-18。分类变量通过χ2检验进行比较，连续结果通过Kruskal-Wallis检验进行比较。
采用Kaplan-Meier方法估算总生存率。使用Cox比例风险回归模型进行的多变量分析检查了HCT结果的风险因素，包括HCT的时间间隔、感染状态和HCT时的年龄、诊断触发因素、SCID类型和基因型、患者的种族和民族、HLA不匹配的兄弟姐妹供体类型、移植物类型、GVHD预防和条件强度等变量。
对于902名确诊SCID的儿童，5年总生存率在28年内保持在72%-73%不变，直到2010-18年，总生存率增至87%（n=268；p=0.0005）。自2010年以来，通过新生儿筛查确定为SCID的儿童，5年总生存率为92.5%，优于同一区间内通过临床疾病或家族史确定的儿童（分别为79.9%和85.4%）。
多变量分析表明，活动性感染（危险比[HR]为2.41；p＜0.0001）、HCT年龄3.5个月或以上（2.12；p＝0.001）、黑人或非裔美国人种族（2.33；p＜0.001）和某些SCID基因型在所有时间段内与较低的总生存率相关。此外，在对该多变量分析中的几个因素进行校正后，2010年后的HCT与早期研究的时间间隔相比不再具有生存优势（HR 0.73；p=0.097）。这表明，新生儿筛查直接推动了HCT的年轻化和免于感染，是最近总体生存率提高的主要驱动因素。
研究结果表明，基于人群的新生儿筛查有助于在婴儿早期识别SCID，从而在避免感染的同时及时进行HCT。世界各地的公共卫生计划可受益于新生儿筛查SCID价值。
附：英文原文
Title: Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium
Author: Monica S Thakar, Brent R Logan, Jennifer M Puck, Elizabeth A Dunn, Rebecca H Buckley, Morton J Cowan, Richard J OReilly, Neena Kapoor, Lisa Forbes Satter, Sung-Yun Pai, Jennifer Heimall, Sharat Chandra, Christen L Ebens, Deepak Chellapandian, Olatundun Williams, Lauri M Burroughs, Blachy Davila Saldana, Ahmad Rayes, Lisa M Madden, Shanmuganathan Chandrakasan, Jeffrey J Bednarski, Kenneth B DeSantes, Geoffrey D E Cuvelier, Pierre Teira, Alfred P Gillio, Hesham Eissa, Alan P Knutsen, Frederick D Goldman, Victor M Aquino, Evan B Shereck, Theodore B Moore, Emi H Caywood, Mark T Vander Lugt, Jacob Rozmus, Larisa Broglie, Lolie C Yu, Ami J Shah, Jeffrey R Andolina, Xuerong Liu, Roberta E Parrott, Jasmeen Dara, Susan Prockop, Caridad A Martinez, Malika Kapadia, Soma C Jyonouchi, Kathleen E Sullivan, Jack J Bleesing, Sonali Chaudhury, Aleksandra Petrovic, Michael D Keller, Troy C Quigg, Suhag Parikh, Shalini Shenoy, Christine Seroogy, Tamar Rubin, Hélène Decaluwe, John M Routes
Issue&Volume: 2023-06-20
Abstract:
Background
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.
Methods
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.
Findings
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.
Interpretation
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.
DOI: 10.1016/S0140-6736(23)00731-6
Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00731-6/fulltext
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