Nitric oxide in primary ciliary dyskinesia

Abstract

Nitric oxide is continually synthesised in the respiratory epithelium and is upregulated in response to infection or inflammation. Primary ciliary dyskinesia (PCD) is characterised by recurrent sinopulmonary infections due to impaired mucociliary clearance. Despite chronic infections, nasal nitric oxide in such patients is markedly reduced and is used as a screening test for this condition. These low levels were first described .15 yrs ago but the underlying mechanisms have yet to be fully elucidated. We review epithelial nitric oxide synthesis, release and measurement in the upper airways with particular reference to PCD. The key hypotheses that have been proposed to explain the low nitric oxide levels in this condition are explored and the potential benefits of augmenting airway nitric oxide levels are considered. Further work in these patients clarifying both whether the respiratory epithelium is able to biosynthesise normal levels of nitric oxide and the role played by abnormalities in the anatomy of the paranasal sinuses is essential. While nitric oxide augmentation is unlikely to be beneficial in common PCD phenotypes, it has potential in the treatment of secondary dyskinesias and may also improve treatment of bacterial infections, particularly where biofilms are implicated.

Standardizing Nasal Nitric Oxide Measurement as a Test for Primary Ciliary Dyskinesia

“…For the confirmed PCD group with defined ultrastructural defects in the ciliary axonemes, the mean nNO level (20.0 nl/ min) is less than 10% of the mean nNO measurement for healthy control subjects (304.6 nl/min) with minimal overlap. Previous reports in smaller subsets show a similar magnitude of difference between PCD and healthy control subjects (7)(8)(9)(10)(11)(12). The cutoff value defined in this study (77 nl/min) is slightly lower than what was identified in our earlier study that examined a smaller patient population (7).…”

“…The nNO values in some of the patients with CF, however, did overlap with PCD values, which has been described in other studies (7)(8)(9)11). Therefore, CF must be excluded by a quantitative pilocarpine iontophoresis sweat test or CFTR genotype testing in all individuals with nNO measurements below the cutoff values.…”

“…The American Thoracic Society (ATS), in cooperation with the European Respiratory Society (ERS), has published guidelines for nNO measurements, which recommend obtaining levels while the patient performs trained velum closure or exhales against resistance or other techniques to decrease dilution from the lower airways (15). Although several studies have demonstrated that nNO levels are significantly lower in PCD than those measured in healthy control subjects, these investigations had several limitations, including small numbers of PCD-affected subjects and few disease control subjects, and each of these single-site studies has used a different NO analyzer with different sampling flow rate and methodology, which restricts side-by-side comparisons to assess reproducibility at multiple sites with different operators (7)(8)(9)(10)(11)(12)(13). Further standardization is needed for its use as a test to support the clinical diagnosis of PCD.…”

“…An alternative, reproducible, and cost-effective test would help direct appropriate individuals to further testing and potentially lead to earlier therapy. Studies have suggested that nasal nitric oxide (nNO) measurement could be a useful test for PCD (7)(8)(9)(10)(11)(12).…”

Diagnostic Methods in Primary Ciliary Dyskinesia

“…Whilst the reason for reduced nNO remains elusive [27], measurement became widely established as a screening test [11,17,19,[28][29][30][31]. A recent meta-A c c e p t e d M a n u s c r i p t analysis of 11 studies comparing nNO during a velum closure breath hold reported a mean nNO output of 19 nl/min (SD 18.6) in PCD (n=478) and 265 nl/min (SD 118.9) in healthy controls (n=338) [32].…”