Tidal Breathing Nasal Nitric Oxide Measurement as a Test for Primary Ciliary Dyskinesia in Young Children

Margaret W Leigh; Adam J Shapiro; Kunal K Chawla; Milan J Hazucha; David E Brown; Feng-Chang Lin; Li Jiang; Johnny L Carson; Stephanie D Davis; Sharon D Dell; Scott D Sagel; Margaret Rosenfeld; Carlos Milla; Kelli M Sullivan; Maimoona A Zariwala; Thomas W Ferkol; Michael R Knowles; Genetic Disorders of Mucociliary Clearance Consortium

doi:10.1183/13993003.01540-2025

Tidal Breathing Nasal Nitric Oxide Measurement as a Test for Primary Ciliary Dyskinesia in Young Children

Eur Respir J. 2026 Jan 29:2501540. doi: 10.1183/13993003.01540-2025. Online ahead of print.

Authors

Margaret W Leigh^{1

2}, Adam J Shapiro³, Kunal K Chawla⁴, Milan J Hazucha^{4

5}, David E Brown⁶, Feng-Chang Lin⁷, Li Jiang⁷, Johnny L Carson^{1

4}, Stephanie D Davis^{1

8}, Sharon D Dell^{9

10}, Scott D Sagel¹¹, Margaret Rosenfeld¹², Carlos Milla¹³, Kelli M Sullivan¹, Maimoona A Zariwala^{1

2}, Thomas W Ferkol^{14

2

15}, Michael R Knowles^{2

4}; Genetic Disorders of Mucociliary Clearance Consortium

Affiliations

¹ Department of Pediatrics, UNC School of Medicine, Chapel Hill, NC, USA.
² Marsico Lung Institute, University of North Carolina, Chapel Hill, North Carolina.
³ Department of Pediatrics, McGill University Health Centre Research Institute, Montreal, Canada.
⁴ Department of Medicine, UNC School of Medicine, Chapel Hill, NC, USA.
⁵ Center for Environmental Medicine, Asthma and Lung Biology, UNC School of Medicine, Chapel Hill, NC, USA.
⁶ Department of Pediatrics, University of South Carolina, Columbia, SC, USA.
⁷ Department of Biostatistics, University of North Carolina at Chapel Hill, NC, USA.
⁸ Department of Pediatrics, Indiana University, Indianapolis, IN, USA.
⁹ Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children and Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
¹⁰ Department of Pediatrics, University of British Columbia.
¹¹ Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA.
¹² Center for Respiratory Biology and Therapeutics, Seattle Children's Research Institute, Seattle, WA, USA.
¹³ Department of Pediatrics, Stanford University, Palo Alto, CA, USA.
¹⁴ Department of Pediatrics, UNC School of Medicine, Chapel Hill, NC, USA thomas_ferkol@med.unc.edu.
¹⁵ Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, USA.

PMID: 41611251
DOI: 10.1183/13993003.01540-2025

Abstract

Rationale: Nasal nitric oxide (nNO) measurement during velum closure is a useful test for primary ciliary dyskinesia (PCD) but not feasible in young children. Measurement during tidal breathing is an alternative approach.

Objectives: To define a protocol with age-specific cut-off values for nNO measurements during tidal breathing and evaluate as an adjunctive test for PCD.

Methods: A standardized method for nNO measurement during tidal breathing was developed and tested at University of North Carolina in children under 6-years with PCD, asthma, cystic fibrosis, and healty controls. Normative curves were generated as a function of age and generalized estimating equations were used to define age-specific cut-off values. The protocol was subsequently validated in 107 children undergoing evaluation for PCD at eight additional sites.

Results: In healthy controls, tidal breathing nNO values increased from birth to age 6-years, but remained low for children with PCD. With sensitivity set at 0.98, cut-off values of nNO increased from 13.9 nL·min^-1 at 2-months to 47.7 nL·min^-1 at 5-years of age. Receiver operating characteristic curves had high areas for nNO cut-offs under each curve, ranging from 0.98 to 0.99 across the ages represented in the study. Validation testing at participating sites showed tidal breathing nNO accurately identified 93% of the 60 children under 6 years with PCD confirmed by ultrastructural ciliary analysis or genetic testing, with high specificity.

Conclusion: Tidal breathing nNO measurement is a useful adjunctive test to distinguish young children with PCD from healthy controls as young as 2-months using age-specific cut-off nNO values.