Diagnostic Value of Nasal Nitric Oxide Measured with Non-Velum Closure Techniques for Children with Primary Ciliary Dyskinesia

doi:10.1016/j.jpeds.2011.03.007

The Journal of Pediatrics

Volume 159, Issue 3, September 2011, Pages 420-424

https://doi.org/10.1016/j.jpeds.2011.03.007 Get rights and content

Objectives

Nasal nitric oxide (nNO) is a reliable non-invasive screening test for primary ciliary dyskinesia (PCD), but the recommended technique, exhalation against resistance (ER), requires cooperation limiting its use in young children. Our objectives were to determine whether easier non-velum closure techniques have the ability to discriminate PCD and longitudinal reproducibility.

Study design

We conducted a case-control study evaluating 5 breathing techniques (ER, breath hold, tidal breathing mouth open, tidal breathing mouth closed, and humming) for measuring nNO in patients with PCD compared with control subjects (cystic fibrosis [CF], non-PCD non-CF bronchiectasis, and healthy). A subgroup repeated measurements 1 month later. Sensitivity, specificity, and intraclass correlation coefficient of each nNO technique were determined.

Results

We tested 85 children (20 PCD, 32 CF, 14 broncheoctasis, and 19 healthy), aged 5 to 18 years (mean age, 11.5 years); 52% of children were male. All breathing techniques discriminated patients with PCD from control subjects with high specificity (>90%), 100% sensitivity, and intraclass correlation coefficient >0.8. nNO output cutoff values for diagnosing PCD varied with techniques (ER, 59 nL/min; breath hold, 61 nL/min; tidal breathing mouth open, 37 nL/min; tidal breathing mouth closed, 30 nL/min; humming, 41 nL/min).

Conclusion

Non-velum closure techniques are reproducible and valid to discriminate PCD; however, they generally yield lower values than ER.

Section snippets

Methods

This study was designed as a case-control diagnostic test validation study with longitudinal follow-up (for assessment of longitudinal reliability) in a subsample. The study was approved by the SickKids Research ethics board, and written informed consent and assent was obtained from each participating child, parent, or both, as appropriate.

Subjects with PCD, cystic fibrosis (CF), and non-PCD non-CF bronchiectasis (BE) aged 5 to 18 years were recruited from the outpatient clinics at the Hospital

Results

The 85 participating study subjects (Table I) had a mean age of 11.5 years (range, 5 to 18 years), and all were able to comply with all 5 breathing techniques. Within the PCD group, 8 subjects (40%) had situs inversus totalis, 2 subjects (10%) had situs ambiguous, and 10 subjects (50%) had situs solitus; 18 subjects (90%) reported a history of neonatal respiratory distress, 18 subjects (90%) reported recurrent otitis media, and 15 subjects (75%) had bronchiectasis detected on computed

Discussion

The results of this study show that all the breathing techniques tested were reproducible and valid to discriminate PCD from disease and healthy controls in subjects older than 5 years. We also demonstrated that different cutoff values are required for each breathing technique to achieve optimum sensitivity and specificity as a screening test for PCD.

Earlier studies have used multiple breathing techniques to measure nNO in healthy control subjects,¹²^,13 showing, similar to our data, lower

References (12)

G.L. Piacentini et al.
Nasal nitric oxide for early diagnosis of primary ciliary dyskinesia: practical issues in children
Respir Med
(2008)
J.O. Lundberg et al.
Primarily nasal origin of exhaled nitric oxide and absence in Kartagener’s syndrome
Eur Respir J
(1994)
ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005
Am J Respir Crit Care Med
(2005)
A. Bush et al.
Primary ciliary dyskinesia: current state of the art
Arch Dis Child
(2007)
A. Bush et al.
Primary ciliary dyskinesia: diagnosis and standards of care
Eur Respir J
(1998)
E. Weitzberg et al.
Humming greatly increases nasal nitric oxide
Am J Respir Crit Care Med
(2002)

There are more references available in the full text version of this article.

Cited by (56)

Primary Ciliary Dyskinesia
2016, Clinics in Chest Medicine
Diagnostic Methods in Primary Ciliary Dyskinesia
2016, Paediatric Respiratory Reviews
Citation Excerpt :
Although measurement is recommended during a velum closure breath-hold [33], tidal breathing produces a reasonable alternative if breath-hold cannot be achieved e.g. young children [32]. Tidal breathing measurements are lower in both PCD and controls [31,32,34,35,39,40] and are less discriminatory than measures during a velum-closure breath-hold. In summary, nNO provides an excellent screening test for PCD, and we now need standardisation of methods of analysis and reporting.
Diagnosing primary ciliary dyskinesia is difficult. With no reference standard, a combination of tests is needed; most tests require expensive equipment and specialist scientists. We review the advances in diagnostic testing over the past hundred years, with emphasis on recent advances. We particularly focus on use of high-speed video analysis, transmission electron microscopy, nasal nitric oxide and genetic testing. We discuss the international efforts that are in place to advance the evidence base for diagnostic tests.
Establishing normative nasal nitric oxide values in infants
2015, Respiratory Medicine
Citation Excerpt :
More recently, the measurement of nasal nitric oxide (nNO) has been shown to be useful for PCD screening, as PCD patients are observed to have nNO levels that are only 10–20% of normal, healthy controls [5,6]. Nasal NO values are detectable in neonates within hours of being born and measurements are relatively easy to obtain, reproducible, and noninvasive [7–9]. Several nNO sampling methods exist whereby a small sampling cannula is placed just into the naris and the amount of nNO being produced by the nasal sinuses is analyzed [10].
Primary ciliary dyskinesia (PCD), a disease of impaired respiratory cilia motility, is often difficult to diagnose. Recent studies show low nasal nitric oxide (nNO) is closely linked to PCD, allowing the use of nNO measurement for PCD assessments. Nasal NO cutoff values for PCD are stratified by age, given nNO levels normally increase with age. However, normative values for nNO have not been established for infants less than 1 year old. In this study, we aim to establish normative values for nNO in infants and determine their utility in guiding infant PCD assessment.
We obtained 42 nNO values from infants less than 1 year old without a history of PCD or recurrent sinopulmonary disease. Using regression analysis, we estimated the mean age-adjusted nNO values and established a 95% prediction interval (PI) for normal nNO. Using these findings, we were able to show 14 of 15 infant PCD patients had abnormally low nNO with values below the 95% PI.
In this study we determined a regression model that best fits normative nNO values for infants less than 1 year old. This model identified the majority of PCD infants as having abnormally low nNO. These findings suggest nNO measurement can help guide PCD assessment in infants, and perhaps other pulmonary diseases with a link to low nNO. With early assessments, earlier clinical intervention may be possible to slow disease progression and help reduce pulmonary morbidity.
Device comparison study to measure nasal nitric oxide in relation to primary ciliary dyskinesia
2024, Journal of Breath Research
Research Progress of Experimental and Numerical Study on Nitric Oxide Distributions in Nasal Cavity
2023, Yiyong Shengwu Lixue/Journal of Medical Biomechanics
Role of Nasal Nitric Oxide in Primary Ciliary Dyskinesia and Other Respiratory Conditions in Children
2023, International Journal of Molecular Sciences

View all citing articles on Scopus

: Funded by a grant from the Pediatric Consultants Group of The Hospital for Sick Children, Toronto, Canada. The authors declare no conflicts of interest.

View full text

Original ArticleDiagnostic Value of Nasal Nitric Oxide Measured with Non-Velum Closure Techniques for Children with Primary Ciliary Dyskinesia

Objectives

Study design

Results

Conclusion

Section snippets

Methods

Results

Discussion

Respir Med

Primarily nasal origin of exhaled nitric oxide and absence in Kartagener’s syndrome

Eur Respir J

ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005

Am J Respir Crit Care Med

Primary ciliary dyskinesia: current state of the art

Arch Dis Child

Primary ciliary dyskinesia: diagnosis and standards of care

Eur Respir J

Humming greatly increases nasal nitric oxide

Am J Respir Crit Care Med

Original Article
Diagnostic Value of Nasal Nitric Oxide Measured with Non-Velum Closure Techniques for Children with Primary Ciliary Dyskinesia