Accuracy of Nasal Nitric Oxide Measurement as a Diagnostic Test for Primary Ciliary Dyskinesia. A Systematic Review and Meta-analysis

Abstract

Rationale: 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.

Objectives: 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.

Data sources: Ten databases were searched for reference sources from database inception through July 29, 2016.

Data extraction: 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.

Synthesis: 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.

Conclusions: 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.

Keywords: Kartagener syndrome; nitric oxide; primary ciliary dyskinesia.

Figure 1.

Summary of evidence search and selection. nNO = nasal nitric oxide; NO = nitric oxide; PCD = primary ciliary dyskinesia.

Figure 2.

Assessment of validity of individual studies with Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 tool for the 12 included studies. The QUADAS-2 tool is designed to assess the quality of primary diagnostic accuracy studies and consists of four key domains evaluating the methods used in regard to patient selection, index test, reference standard, and flow of patients through the study, as well as timing of the index test and reference standard. The results presented show several studies with high risk of bias with regard to the index test domain, especially in case–control studies.

Figure 3.

Forest plot (in ascending order of nasal nitric oxide cutoff value in nanoliters per minute). CI = confidence interval; FN = false negative; FP = false positive; TN = true negative; TP = true positive.

Figure 4.

Hierarchical summary receiver operating characteristic curve (HSROC) for the 12 included studies.

Figure 5.

Assessment of validity of individual studies with Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 tool for the seven included studies comparing nasal nitric oxide to an extended reference standard of electron microscopy and/or genetics. The QUADAS-2 tool is designed to assess the quality of primary diagnostic accuracy studies and consists of four key domains evaluating the methods used with regard to patient selection, index test, reference standard, and flow of patients through the study, as well as timing of the index test and reference standard. The results presented show that the 7 selected studies were at lower risk of bias and concern regarding applicability than the initial 12 analyzed studies presented in Figure 2.

Figure 6.

Hierarchical summary receiver operating characteristic curve (HSROC) for the seven studies comparing nasal nitric oxide to an extended reference standard of electron microscopy and/or genetics.