Nasal nitric oxide measurement demonstrated high diagnostic accuracy for primary ciliary dyskinesia but should be used as part of a multimodal diagnostic pathway rather than a stand-alone test, according to a review by Eric Gerardus Haarman of Amsterdam University Medical Center, and colleagues.
Primary ciliary dyskinesia (PCD) is a rare genetic disorder of motile cilia associated with impaired mucociliary clearance and progressive airway disease. Diagnosis relies on integrating clinical features with functional testing, ultrastructural analysis, and genetic evaluation, with nasal nitric oxide (nNO) used as a first-line assessment tool.
The review synthesized evidence from systematic reviews, prospective referral cohorts, and guideline-supported analyses evaluating nNO against reference standards such as transmission electron microscopy and genetic testing.
Across 12 studies including 1,344 patients, nNO demonstrated a sensitivity of 98% and specificity of 96%. When limited to studies using combined reference standards, sensitivity and specificity were both 96%.
In referral populations reflecting clinical practice, diagnostic performance was lower. Studies included in European Respiratory Society guidance reported sensitivity ranging from 90% to 100% and specificity from 80% to 97%, depending on measurement technique.
A multicenter study using a cutoff of 77 nL/min showed sensitivity of 99% and specificity of 100% in case-control cohorts, but specificity decreased to 75% in referral cohorts.
Similarly, pooled data from five cohorts in the joint European Respiratory Society–American Thoracic Society guideline showed sensitivity of 93% and specificity of 88%. Using the 77 nL/min cutoff, sensitivity was 94% and specificity was 83%.
Subgroup analyses demonstrated reduced diagnostic performance in patients with preserved ciliary ultrastructure. In a cohort of 301 patients, sensitivity decreased from 95% in patients with abnormal ultrastructure to 85% in those with normal ultrastructure using the standard cutoff. Increasing the cutoff to approximately 108 nL/min improved sensitivity to 89% but reduced specificity to 78%.
The review also reported that some patients with confirmed PCD had nNO values within the normal range, including those with variants in genes such as DNAH11, RSPH1, and FOXJ1. In addition, 9 of 16 patients classified as probable PCD had nNO values within the normal range.
Test performance was influenced by technical and clinical factors. Chemiluminescence devices remain the reference standard, while electrochemical devices provide a more accessible alternative. Measurements are affected by sampling technique, patient cooperation, ambient nitric oxide levels, and infection status. Respiratory tract infections can reduce nNO values by 70% to 80%, potentially overlapping with values seen in PCD.
Age also affects interpretation, with guideline-recommended cutoffs ranging from 30 nL/min in younger children to 77 nL/min in patients aged 5 years or older using velum-closure techniques.
The review emphasized that variability across genetic subtypes, age groups, and clinical contexts limits the reliability of nNO as a universal diagnostic marker and supports its use alongside complementary testing.
The researchers noted that PCD represents a heterogeneous spectrum of motile ciliopathies, limiting the ability of any single biomarker to perform consistently across all patients.
Disclosures: The authors reported no conflicts of interest.
Source: Pediatric Pulmonology