Shapiro Adam J, Josephson Maureen, Rosenfeld Margaret, Yilmaz Ozge, Davis Stephanie D, Polineni Deepika, Guadagno Elena, Leigh Margaret W, Lavergne Valery
1 Division of Pediatric Respiratory Medicine, Montreal Children's Hospital, McGill University Health Centre Research Institute, Montreal, Quebec, Canada.
2 Division of Pediatric Pulmonology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania.
Ann Am Thorac Soc. 2017 Jul;14(7):1184-1196. doi: 10.1513/AnnalsATS.201701-062SR.
Primary ciliary dyskinesia (PCD) is a rare disorder causing chronic otosinopulmonary disease, generally diagnosed through evaluation of respiratory ciliary ultrastructure and/or genetic testing. Nasal nitric oxide (nNO) measurement is used as a PCD screening test because patients with PCD have low nNO levels, but its value as a diagnostic test remains unknown.
To perform a systematic review to assess the utility of nNO measurement (index test) as a diagnostic tool compared with the reference standard of electron microscopy (EM) evaluation of ciliary defects and/or detection of biallelic mutations in PCD genes.
Ten databases were searched for reference sources from database inception through July 29, 2016.
Study inclusion was limited to publications with rigorous nNO index testing, reference standard diagnostic testing with EM and/or genetics, and calculable diagnostic accuracy information for cooperative patients (generally >5 yr old) with high suspicion of PCD.
Meta-analysis provided a summary estimate for sensitivity and specificity and a hierarchical summary receiver operating characteristic curve. The Quality Assessment of Diagnostic Accuracy Studies-2 tool was used to assess study quality, and Grading of Recommendations Assessment, Development, and Evaluation was used to assess the certainty of evidence. In 12 study populations (1,344 patients comprising 514 with PCD and 830 without PCD), using a reference standard of EM alone or EM and/or genetic testing, summary sensitivity was 97.6% (92.7-99.2) and specificity was 96.0% (87.9-98.7), with a positive likelihood ratio of 24.3 (7.6-76.9), a negative likelihood ratio of 0.03 (0.01-0.08), and a diagnostic odds ratio of 956.8 (141.2-6481.5) for nNO measurements. After studies using EM alone as the reference standard were excluded, the seven studies using an extended reference standard of EM and/or genetic testing showed a summary sensitivity of nNO measurements of 96.3% (88.7-98.9) and specificity of 96.4% (85.1-99.2), with a positive likelihood ratio of 26.5 (5.9-119.1), a negative likelihood ratio of 0.04 (0.01-0.12), and a diagnostic odds ratio of 699.3 (67.4-7256.0). Certainty of the evidence was graded as moderate.
nNO is a sensitive and specific test for PCD in cooperative patients (generally >5 yr old) with high clinical suspicion for this disease. With a moderate level of evidence, this meta-analysis confirms that nNO testing using velum closure maneuvers has diagnostic accuracy similar to EM and/or genetic testing for PCD when cystic fibrosis is ruled out. Thus, low nNO values accompanied by an appropriate clinical phenotype could be used as a diagnostic PCD test, though EM and/or genetics will continue to provide confirmatory information.
原发性纤毛运动障碍（PCD）是一种导致慢性耳肺疾病的罕见病症，通常通过评估呼吸道纤毛超微结构和/或基因检测来诊断。鼻一氧化氮（nNO）测量被用作PCD筛查试验，因为PCD患者的nNO水平较低，但其作为诊断试验的价值尚不清楚。
进行一项系统评价，以评估与通过电子显微镜（EM）评估纤毛缺陷和/或检测PCD基因双等位基因突变的参考标准相比，nNO测量（指标试验）作为诊断工具的效用。
检索了10个数据库，以获取从数据库建立至2016年7月29日的参考文献。
纳入研究仅限于具有严格nNO指标检测、采用EM和/或遗传学进行参考标准诊断检测以及可计算出高度怀疑PCD的合作患者（一般>5岁）诊断准确性信息的出版物。
荟萃分析提供了敏感性和特异性的汇总估计值以及分层汇总接受者操作特征曲线。使用诊断准确性研究质量评估-2工具评估研究质量，并使用推荐分级评估、制定和评价工具评估证据确定性。在12个研究人群（1344例患者，包括514例PCD患者和830例非PCD患者）中，采用单独EM或EM与/或基因检测作为参考标准，nNO测量的汇总敏感性为97.6%（92.7 - 99.2），特异性为96.0%（87.9 - 98.7），阳性似然比为24.3（7.6 - 76.9），阴性似然比为0.03（0.01 - 0.08），诊断比值比为956.8（141.2 - 6481.5）。在排除仅使用EM作为参考标准的研究后，使用EM和/或基因检测扩展参考标准的7项研究显示，nNO测量汇总敏感性为96.3%（88.7 - 98.9），特异性为96.4%（85.1 - 99.2），阳性似然比为26.5（5.9 - 119.1），阴性似然比为0.04（0.01 - 0.12），诊断比值比为699.3（67.4 - 7256.0）。证据确定性等级为中等质量。
对于临床高度怀疑患有PCD的合作患者（一般>5岁），nNO是一种敏感且特异的检测方法。本荟萃分析以中等证据水平证实，如果排除囊性纤维化，则采用软腭闭合动作进行的nNO检测对于PCD的诊断准确性与EM和/或基因检测相似。因此，伴有适当临床表型的低nNO值可作为PCD诊断试验，不过EM和/或遗传学检测仍将提供确诊信息。
