Browsing by Subject "Primary ciliary dyskinesia"

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    Accuracy of Nasal Nitric Oxide Measurement as a Diagnostic Test for Primary Ciliary Dyskinesia. A Systematic Review and Meta-analysis
    (American Thoracic Society, 2017-07) Shapiro, Adam J.; Josephson, Maureen; Rosenfeld, Margaret; Yilmaz, Ozge; Davis, Stephanie D.; Polineni, Deepika; Guadagno, Elena; Leigh, Margaret W.; Lavergne, Valery; Pediatrics, School of Medicine
    RATIONALE: Primary ciliary dyskinesia (PCD) is a rare disorder causing chronic otosinopulmonary disease, generally diagnosed through evaluation of respiratory ciliary ultrastructure and/or genetic testing. Nasal nitric oxide (nNO) measurement is used as a PCD screening test because patients with PCD have low nNO levels, but its value as a diagnostic test remains unknown. OBJECTIVES: To perform a systematic review to assess the utility of nNO measurement (index test) as a diagnostic tool compared with the reference standard of electron microscopy (EM) evaluation of ciliary defects and/or detection of biallelic mutations in PCD genes. DATA SOURCES: Ten databases were searched for reference sources from database inception through July 29, 2016. DATA EXTRACTION: Study inclusion was limited to publications with rigorous nNO index testing, reference standard diagnostic testing with EM and/or genetics, and calculable diagnostic accuracy information for cooperative patients (generally >5 yr old) with high suspicion of PCD. SYNTHESIS: Meta-analysis provided a summary estimate for sensitivity and specificity and a hierarchical summary receiver operating characteristic curve. The Quality Assessment of Diagnostic Accuracy Studies-2 tool was used to assess study quality, and Grading of Recommendations Assessment, Development, and Evaluation was used to assess the certainty of evidence. In 12 study populations (1,344 patients comprising 514 with PCD and 830 without PCD), using a reference standard of EM alone or EM and/or genetic testing, summary sensitivity was 97.6% (92.7-99.2) and specificity was 96.0% (87.9-98.7), with a positive likelihood ratio of 24.3 (7.6-76.9), a negative likelihood ratio of 0.03 (0.01-0.08), and a diagnostic odds ratio of 956.8 (141.2-6481.5) for nNO measurements. After studies using EM alone as the reference standard were excluded, the seven studies using an extended reference standard of EM and/or genetic testing showed a summary sensitivity of nNO measurements of 96.3% (88.7-98.9) and specificity of 96.4% (85.1-99.2), with a positive likelihood ratio of 26.5 (5.9-119.1), a negative likelihood ratio of 0.04 (0.01-0.12), and a diagnostic odds ratio of 699.3 (67.4-7256.0). Certainty of the evidence was graded as moderate. CONCLUSIONS: nNO is a sensitive and specific test for PCD in cooperative patients (generally >5 yr old) with high clinical suspicion for this disease. With a moderate level of evidence, this meta-analysis confirms that nNO testing using velum closure maneuvers has diagnostic accuracy similar to EM and/or genetic testing for PCD when cystic fibrosis is ruled out. Thus, low nNO values accompanied by an appropriate clinical phenotype could be used as a diagnostic PCD test, though EM and/or genetics will continue to provide confirmatory information.
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    Antigen stasis and airway nitrosative stress in human primary ciliary dyskinesia
    (American Physiological Society, 2024) Gaston, Benjamin; Smith, Laura A.; Davis, Michael D.; Saunders, Jessica; Daniels, Ivana; Horani, Amjad; Brody, Steven L.; Giddings, Olivia; Zhao, Yi; Marozkina, Nadzeya; Pediatrics, School of Medicine
    Nasal nitric oxide (nNO) is low in most patients with primary ciliary dyskinesia (PCD). Decreased ciliary motion could lead to antigen stasis, increasing oxidant production and NO oxidation in the airways. This could both decrease gas phase NO and increase nitrosative stress. We studied primary airway epithelial cells from healthy controls (HCs) and patients with PCD with several different genotypes. We measured antigen clearance in fenestrated membranes exposed apically to the fluorescently labeled antigen Dermatophagoides pteronyssinus (Derp1-f). We immunoblotted for 3-nitrotyrosine (3-NT) and for oxidative response enzymes. We measured headspace NO above primary airway cells without and with a PCD-causing genotype. We measured nNO and exhaled breath condensate (EBC) H2O2 in vivo. Apical Derp1-f was cleared from HC better than from PCD cells. DUOX1 expression was lower in HC than in PCD cells at baseline and after 24-h Derp1-f exposure. HC cells had less 3-NT and NO3- than PCD cells. However, NO consumption by HC cells was less than that by PCD cells; NO loss was prevented by superoxide dismutase (SOD) and by apocynin. nNO was higher in HCs than in patients with PCD. EBC H2O2 was lower in HC than in patients with PCD. The PCD airway epithelium does not optimally clear antigens and is subject to oxidative and nitrosative stress. Oxidation associated with antigen stasis could represent a therapeutic target in PCD, one with convenient monitoring biomarkers. NEW & NOTEWORTHY: The PCD airway epithelium does not optimally clear antigens, and antigen exposure can lead to NO oxidation and nitrosative stress. Oxidation caused by antigen stasis could represent a therapeutic target in PCD, and there are convenient monitoring biomarkers.
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    Respiratory Distress in the Newborn with Primary Ciliary Dyskinesia
    (MDPI, 2021-02-18) Machogu, Evans; Gaston, Benjamin; Pediatrics, School of Medicine
    Primary ciliary dyskinesia (PCD) is inherited in a predominantly autosomal recessive manner with over 45 currently identified causative genes. It is a clinically heterogeneous disorder that results in a chronic wet cough and drainage from the paranasal sinuses, chronic otitis media with hearing impairment as well as male infertility. Approximately 50% of patients have situs inversus totalis. Prior to the development of chronic oto-sino-pulmonary symptoms, neonatal respiratory distress occurs in more than 80% of patients as a result of impaired mucociliary clearance and mucus impaction causing atelectasis and lobar collapse. Diagnosis is often delayed due to overlapping symptoms with other causes of neonatal respiratory distress. A work up for PCD should be initiated in the newborn with compatible clinical features, especially those with respiratory distress, consistent radiographic findings or persistent oxygen requirement and/or organ laterality defects.