Limitations of Nasal Nitric Oxide Testing in Primary Ciliary Dyskinesia

Shapiro, Adam J.; Davis, Stephanie D.; Leigh, Margaret W.; Knowles, Michael R.; Lavergne, Valéry; Ferkol, Thomas

doi:10.1164/rccm.202003-0835le

Cited by 34 publications

(28 citation statements)

References 5 publications

(8 reference statements)

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“…With our finding of 15% of discordant diagnostic outcomes, we can confirm the already previously discussed theoretical differences between the ERS and the ATS algorithms [ 8 , 10 , 11 ], based on data from a real-life setting. The five cases (patients 15–19) that were only diagnosed based on reduced nNO according to the ATS algorithm support the doubts that nNO as sole investigation can diagnose PCD [ 2 , 10 , 28 – 30 ]. nNO has a sensitivity and specificity of >95% compared with TEM or genetic testing when performed in children >5 years old with cystic fibrosis excluded [ 7 , 18 , 30 ].…”

Section: Discussionmentioning

confidence: 73%

“…The five cases (patients 15–19) that were only diagnosed based on reduced nNO according to the ATS algorithm support the doubts that nNO as sole investigation can diagnose PCD [ 2 , 10 , 28 – 30 ]. nNO has a sensitivity and specificity of >95% compared with TEM or genetic testing when performed in children >5 years old with cystic fibrosis excluded [ 7 , 18 , 30 ]. However, a considerable risk for false negative [ 5 , 10 , 17 ] and false positive results [ 10 , 17 , 30 , 31 ] remains.…”

Section: Discussionmentioning

confidence: 73%

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Diagnosis of primary ciliary dyskinesia: discrepancy according to different algorithms

et al. 2021

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BackgroundDiagnosis of primary ciliary dyskinesia (PCD) is challenging since there is no gold standard test. The European Respiratory (ERS) and American Thoracic (ATS) Societies developed evidence-based diagnostic guidelines with considerable differences.ObjectiveWe aimed to compare the algorithms published by the ERS and the ATS with each other and with our own PCD-UNIBE algorithm in a clinical setting. Our algorithm is similar to the ERS algorithm with additional immunofluorescence staining. Agreement (Cohen's κ) and concordance between the three algorithms were assessed in patients with suspicion of PCD referred to our diagnostic centre.ResultsIn 46 out of 54 patients (85%) the final diagnosis was concordant between all three algorithms (30 PCD negative, 16 PCD positive). In eight patients (15%) PCD diagnosis differed between the algorithms. Five patients (9%) were diagnosed as PCD only by the ATS, one (2%) only by the ERS and PCD-UNIBE, one (2%) only by the ATS and PCD-UNIBE, and one (2%) only by the PCD-UNIBE algorithm. Agreement was substantial between the ERS and the ATS (κ=0.72, 95% CI 0.53–0.92) and the ATS and the PCD-UNIBE (κ=0.73, 95% CI 0.53–0.92) and almost perfect between the ERS and the PCD-UNIBE algorithms (κ=0.92, 95% CI 0.80–1.00).ConclusionThe different diagnostic algorithms lead to a contradictory diagnosis in a considerable proportion of patients. Thus, an updated, internationally harmonised and standardised PCD diagnostic algorithm is needed to improve diagnostics for these discordant cases.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 73%

Diagnosis of primary ciliary dyskinesia: discrepancy according to different algorithms

et al. 2021

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“…The nNO in our cohort was both feasible and useful in supporting the clinical diagnosis of PCD. Nonetheless, caution should be exercised using nNO as the final standalone test to diagnose PCD, due to possible false-positive results as exemplified in recent reports [ 37 , 38 ] as well as in the current study. This is particularly true when evaluating children <5 years in whom low nNO values are nonspecific.…”

Section: Discussionmentioning

confidence: 78%

Whole-exome sequencing accuracy in the diagnosis of primary ciliary dyskinesia

et al. 2020

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The diagnosis of Primary Ciliary Dyskinesia (PCD) relies on clinical features and sophisticated studies. The detection of bi-allelic disease-causing variants confirms the diagnosis. However, a standardised genetic panel is not widely available and new disease-causing genes are continuously identified.To assess the accuracy of untargeted whole-exome sequencing (WES) as a diagnostic tool for PCD, patients with symptoms highly suggestive of PCD were consecutively included. Patients underwent measurement of nasal nitric oxide (nNO) levels, ciliary transmission electron microscopy analysis (TEM) and WES. A confirmed PCD diagnosis in symptomatic patients was defined as a recognised ciliary ultrastructural defect on TEM and/or two pathogenic variants in a known PCD-causing gene.Forty-eight patients (46% male) were enrolled, with a median age of 10.0 years (range 1.0–37 years). In 36 patients (75%) a diagnosis of PCD was confirmed, of which 14 (39%) patients had normal TEM. A standalone untargeted WES had a diagnostic yield of 94%, identifying bi-allelic variants in eleven known PCD causing genes in 34 subjects. A nNO<77 nL·min was nonspecific when including patients younger than 5 years (area under the ROC curve (AUC) 0.75 (95%CI, 0.60–0.90)). Consecutive WES considerably improved the diagnostic accuracy of nNO in young children (AUC 0.97 (95%CI, 0.93–1). Finally, WES established an alternative diagnosis in four patients.In patients with clinically suspected PCD and low nNO levels, WES is a simple, beneficial and accurate next step to confirm the diagnosis of PCD or suggest an alternative diagnosis, especially in preschool-aged children in whom nNO is less specific.

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“…Around 5–10% of PCD cases have nNO values above the established cut-off of 77 nL/min, specifically those associated with mutations in radial spoke or central apparatus proteins [ 23 , 24 ]. These include cases due to genetic variants in RSPH1 , which are associated with normal ciliary ultrastructure by TEM and nNO values of 100 to 300 nL/min [ 18 ] ( Table 1 ).…”

Section: Pcd Diagnostic Testingmentioning

confidence: 99%

Progress in Diagnosing Primary Ciliary Dyskinesia: The North American Perspective

2021

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Primary Ciliary Dyskinesia (PCD) is a rare, under-recognized disease that affects respiratory ciliary function, resulting in chronic oto-sino-pulmonary disease. The PCD clinical phenotype overlaps with other common respiratory conditions and no single diagnostic test detects all forms of PCD. In 2018, PCD experts collaborated with the American Thoracic Society (ATS) to create a clinical diagnostic guideline for patients across North America, specifically considering the local resources and limitations for PCD diagnosis in the United States and Canada. Nasal nitric oxide (nNO) testing is recommended for first-line testing in patients ≥5 years old with a compatible clinical phenotype; however, all low nNO values require confirmation with genetic testing or ciliary electron micrograph (EM) analysis. Furthermore, these guidelines recognize that not all North American patients have access to nNO testing and isolated genetic testing is appropriate in cases with strong clinical PCD phenotypes. For unresolved diagnostic cases, referral to a PCD Foundation accredited center is recommended. The purpose of this narrative review is to provide insight on the North American PCD diagnostic process, to enhance the understanding of and adherence to current guidelines, and to promote collaboration with diagnostic pathways used outside of North America.

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Limitations of Nasal Nitric Oxide Testing in Primary Ciliary Dyskinesia

Abstract: Increased echocardiographic pulmonary pressure in HIVinfected and-uninfected individuals in the veterans aging cohort study.

Cited by 34 publications

References 5 publications

Diagnosis of primary ciliary dyskinesia: discrepancy according to different algorithms

Diagnosis of primary ciliary dyskinesia: discrepancy according to different algorithms

Whole-exome sequencing accuracy in the diagnosis of primary ciliary dyskinesia

Progress in Diagnosing Primary Ciliary Dyskinesia: The North American Perspective

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