Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth
Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth
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DOI：
10.1542/peds.107.1.1
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发表时间：
2001-01-01
期刊：
影响因子：
8
通讯作者：
Splaingard, ML
中科院分区：
文献类型：
--
作者：
Farrell, PM;Kosorok, MR;Splaingard, ML
Objective.尽管囊性纤维化在常染色体隐性遗传病中相对频繁，并且汗液测试可用，但囊性纤维化（CF）在儿童早期很难诊断，延误可能导致严重营养不良，肺部疾病甚至死亡。威斯康星州CF新生儿筛查项目是一项随机临床试验，旨在评估通过筛查进行早期诊断的获益和风险。此外，还测定了CF的发生率，并通过比较16个人口统计学变量来评估我们的随机化方法的有效性。1985年至1991年，免疫反应性胰蛋白酶原分析应用于干新生儿血液标本，以识别CF风险，并于1991年至1994年结合基于DNA的Delta F508突变检测。当650 341名新生儿的血液样本到达威斯康星州筛查实验室时，他们被随机分组。这创建了2组-早期诊断，筛选队列和标准诊断或对照组。为了避免选择偏差，我们设计了一种独特的破盲方法和监测程序来完全识别对照受试者。由于营养结果指标的序贯分析显示，1996年筛选的患者生长明显更好，我们加速了揭盲，并在1998年4月前完全确定了对照组。在该队列的每个成员均入选并评估至少1年并完成全面监测计划后，我们对包括所有无胎粪性肠梗阻的CF患者的人体测量评估指标进行了另一项统计分析。经典CF的发生率为1：4189，即本试验中诊断为汗液氯化物大于60 mEq/L的患者。通过纳入随机化期间出生的其他CF患者，包括2例尸检诊断患者和8例可能患者，我们计算出最大发生率为1：3938（95%置信区间：3402-4611）。虽然在DF 508基因型和胰腺功能不全患者的比例方面存在组间差异，但通过分析16个人口统计学变量证明了随机化计划的有效性，并在调整多重比较后发现无显著差异。关注无胎粪性肠梗阻的患者，我们发现筛选患者的平均+/-标准差诊断年龄（13 +- 37周）与标准诊断组（100 +/- 117周）有显著差异。在筛查组中，诊断时营养状况的人体测量指标显著较高，包括身长/身高、体重和头围。在13年的研究中，尽管对照组有类似的营养治疗和固有的更好的胰腺状态，但营养结果分析显示，早期诊断与生长显著相关。最令人印象深刻的是，筛查组在整个儿童期体重和身高数据低于第10百分位数的患者比例要低得多。尽管筛选组胰腺功能不全患者比例较高，但在13年随访评价期间，其生长指数显著优于对照组，因此，这项早期CF诊断的随机临床试验必须被解释为明确阳性。当通过揭盲检测到的对照组4岁之前的身高和体重数据纳入分析时，我们的结论没有改变。此外，所有受试者4岁后的生长结果比较显示持续存在显著差异。因此，选择偏倚作为一种潜在的解释已经被排除。此外，结果表明，严重营养不良持续延迟诊断CF后，追赶可能是不可能的。我们的结论是，早期诊断CF通过新生儿筛查结合积极的营养治疗可以导致显着增强长期的营养状况。
Objective. Despite its relative frequency among autosomal recessive diseases and the availability of the sweat test, cystic fibrosis (CF) has been difficult to diagnose in early childhood, and delays can lead to severe malnutrition, lung disease, or even death. The Wisconsin CF Neonatal Screening Project was designed as a randomized clinical trial to assess the benefits and risks of early diagnosis through screening. In addition, the incidence of CF was determined, and the validity of our randomization method assessed by comparing 16 demographic variables.Methodology. Immunoreactive trypsinogen analysis was applied to dried newborn blood specimens for recognition of CF risk from 1985 to 1991 and was coupled to DNA-based detection of the Delta F508 mutation from 1991 to 1994. Randomization of 650 341 newborns occurred when their blood specimens reached the Wisconsin screening laboratory. This created 2 groups-an early diagnosis, screened cohort and a standard diagnosis or control group. To avoid selection bias, we devised a unique unblinding method with a surveillance program to completely identify the control subjects. Because sequential analysis of nutritional outcome measures revealed significantly better growth in screened patients during 1996, we accelerated the unblinding and completely identified the control group by April 1998. Having each member of this cohort enrolled and evaluated for at least 1 year and having completed a comprehensive surveillance program, we performed another statistical analysis of anthropometric evaluated indices that includes all CF patients without meconium ileus.Results. The incidence of classical CF, ie, patients diagnosed in this trial with a sweat chloride of 60 mEq/L greater, was 1: 4189. By incorporating other CF patients born during the randomization period, including 2 autopsy diagnosed patients and 8 probable patients, we calculate a maximum incidence of 1:3938 (95% confidence interval: 3402-4611). Although there were group differences in the proportion of patients with DF508 genotypes and with pancreatic insufficiency, validity of the randomization plan was demonstrated by analyzing 16 demographic variables and finding no significant difference after adjustment for multiple comparisons. Focusing on patients without meconium ileus, we found a marked difference in the mean +/- standard deviation age of diagnosis for screened patients (13 +- 37 weeks), compared with the standard diagnosis group (100 +/- 117). Anthropometric indices of nutritional status were significantly higher at diagnosis in the screened group, including length/height, weight, and head circumference. During 13 years of study, despite similar nutritional therapy and the inherently better pancreatic status of the control group, analysis of nutritional outcomes revealed significantly greater growth associated with early diagnosis. Most impressively, the screened group had a much lower proportion of patients with weight and height data below the 10th percentile throughout childhood.Conclusions. Although the screened group had a higher proportion of patients with pancreatic insufficiency, their growth indices were significantly better than those of the control group during the 13-year follow-up evaluation and, therefore, this randomized clinical trial of early CF diagnosis must be interpreted as unequivocally positive. Our conclusions did not change when the height and weight data before 4 years of age for the controls detected by unblinding were included in the analysis. Also, comparison of growth outcomes after 4 years of age in all subjects showed persistence of the significant differences. Therefore, selection bias has been eliminated as a potential explanation. In addition, the results show that severe malnutrition persists after delayed diagnosis of CF and that catch-up may not be possible. We conclude that early diagnosis of CF through neonatal screening combined with aggressive nutritional therapy can result in significantly enhanced long-term nutritional status.