Role of Nasal Nitric Oxide in Primary Ciliary Dyskinesia and Other Respiratory Conditions in Children.

Nitric oxide (NO) is produced within the airways and released with exhalation. Nasal NO (nNO) can be measured in a non-invasive way, with different devices and techniques according to the age and cooperation of the patients. Here, we conducted a narrative review of the literature to examine the relationship between nNO and some respiratory diseases with a particular focus on primary ciliary dyskinesia (PCD). A total of 115 papers were assessed, and 50 were eventually included in the review. nNO in PCD is low (below 77 nL/min), and its measurement has a clear diagnostic value when evaluated in a clinically suggestive phenotype. Many studies have evaluated the role of NO as a molecular mediator as well as the association between nNO values and genotype or ciliary function. As far as other respiratory diseases are concerned, nNO is low in chronic rhinosinusitis and cystic fibrosis, while increased values have been found in allergic rhinitis. Nonetheless, the role in the diagnosis and prognosis of these conditions has not been fully clarified.

The RSPH4A Gene in Primary Ciliary Dyskinesia.

The radial spoke head protein 4 homolog A (RSPH4A) gene is one of more than 50 genes that cause Primary ciliary dyskinesia (PCD), a rare genetic ciliopathy. Genetic mutations in the RSPH4A gene alter an important protein structure involved in ciliary pathogenesis. Radial spoke proteins, such as RSPH4A, have been conserved across multiple species. In humans, ciliary function deficiency caused by RSPH4A pathogenic variants results in a clinical phenotype characterized by recurrent oto-sino-pulmonary infections. More than 30 pathogenic RSPH4A genetic variants have been associated with PCD. In Puerto Rican Hispanics, a founder mutation (RSPH4A (c.921+3_921+6delAAGT (intronic)) has been described. The spectrum of the RSPH4A PCD phenotype does not include laterality defects, which results in a challenging diagnosis. PCD diagnostic tools can combine transmission electron microscopy (TEM), nasal nitric oxide (nNO), High-Speed Video microscopy Analysis (HSVA), and immunofluorescence. The purpose of this review article is to provide a comprehensive overview of current knowledge about the RSPH4A gene in PCD, ranging from basic science to human clinical phenotype.

Application of fractional exhaled nitric oxide and nasal nitric oxide in control evaluation of bronchial asthma and diagnosis of allergic rhinitis in children. / 口鼻呼出气一氧化氮检测在儿童支气管哮喘控制评估及过敏性鼻炎诊断中的应用.

OBJECTIVES: To study the association of fractional exhaled nitric oxide (FeNO) and nasal nitric oxide (nNO) with asthma control and their value in the diagnosis of allergic rhinitis in children. METHODS: A total of 186 children aged 5-12 years, who attended the outpatient service of the Department of Respiration, Shanghai Children's Hospital due to bronchial asthma and/or allergic rhinitis or who underwent physical examination, were enrolled as subjects, with 52 children in the asthma group, 60 children in the asthma+allergic rhinitis group, 36 children in the allergic rhinitis group, and 38 children in the control group. FeNO, nNO, and pulmonary function were compared between groups. RESULTS: The asthma+allergic rhinitis, asthma, and allergic rhinitis groups had a significantly higher level of FeNO than the control group (P<0.05). The asthma+allergic rhinitis and allergic rhinitis groups had a significantly higher level of nNO than the asthma and control groups (P<0.05). The uncontrolled asthma and partially controlled asthma groups had significantly higher levels of FeNO and nNO than the completely controlled asthma group (P<0.05). The receiver operating characteristic (ROC) curve analysis showed that nNO had an area under the ROC curve of 0.91, with a sensitivity of 80.0% and a specificity of 89.5% in the diagnosis of allergic rhinitis in children with asthma (P<0.05). CONCLUSIONS: The combined measurement of nNO and FeNO can be used to evaluate the control of asthma, and the measurement of nNO can help with the diagnosis of allergic rhinitis in children with bronchial asthma.

Nasal nitric oxide in relation to asthma characteristics in a longitudinal asthma cohort study.

OBJECTIVE: Cross-sectional studies report relations between low nasal nitric oxide (nNO) and poor asthma control and between low nNO and chronic rhinosinusitis (CRS). In our cohort study, we studied if changes in nNO related to changes in asthma control, symptoms of CRS, or asthma or rhinitis medication. METHODS: A total of 196 subjects with predominantly mild to moderate asthma, aged 10-35 years, performed nNO measurements at both baseline and follow-up after a median of 43 (range 23-65) months. Asthma control, CRS symptoms, and medication, were questionnaire-assessed at both timepoints. IgE sensitisation against aeroallergens was quantified at baseline. RESULTS: There was an increase in nNO between baseline and follow-up (764 ± 269 ppb vs. 855 ± 288 ppb, p < 0.001). When adjusted for covariates, a larger increase in nNO was found in subjects sensitised to perennial aeroallergens than those not sensitised (92 (16-167) ppb), as well as in subjects with daily use of inhaled corticosteroids (ICS) at baseline but not at follow-up than those on ICS daily at both timepoints (146 (51-242) ppb). In the same model, subjects using nasal steroids daily at both timepoints had decreased nNO compared with those without such treatment at both timepoints (-185 (-321-(-48)) ppb). No relations between changes in nNO levels and changes in asthma control or symptoms of CRS were found. CONCLUSION: Longitudinal changes in nNO were not related to changes in asthma control, but were related to changes in asthma or rhinitis medication.

The Clinical Significance of Nasal Nitric Oxide Concentrations in Preschool Children with Nasal Inflammatory Disease.

BACKGROUND: Allergic rhinitis is an allergic inflammation of the nasal airways, and chronic rhinosinusitis is an inflammation of the paranasal sinuses. It can be induced by infection, allergy, or autoimmune problems. Diagnosis of these two diseases is made primarily based on clinical symptoms, allergen test, and imaging. The allergen test is invasive and expensive. The imaging test is harmful to children. Measurement of nasal nitric oxide (NNO) was noninvasive, without radiation, and inexpensive. This study was to evaluate the clinical significance of NNO in preschool children with nasal inflammatory diseases. METHODS: A total of 55 cases of allergic rhinitis, including 35 mild cases and 20 moderate to severe cases, and 33 cases of chronic rhinosinusitis, including 18 mild cases and 15 moderate to severe cases were selected as the experimental group. Fifty healthy preschool children were chosen as the control group. The levels of NNO in all children were measured. The differences in the levels of NNO among allergic rhinitis, chronic rhinosinusitis, and the control group were compared. The levels of NNO in the control group were also analyzed. RESULTS: The levels of NNO were significantly higher in preschool children with allergic rhinitis than in the control group, and the differences were significant. However, the levels of NNO in preschool children with chronic rhinosinusitis were lower than in the control group. In the control group, the levels of NNO were not significantly different between genders, and no significant correlation between NNO levels and the children's height was found. CONCLUSION: As a noninvasive method for detecting nasal inflammatory diseases, measuring the levels of NNO had a high clinical significance in preschool children.

Predictive and Diagnostic Value of Nasal Nitric Oxide in Eosinophilic Chronic Rhinosinusitis with Nasal Polyps.

BACKGROUND: A hallmark of eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP) is mucosal eosinophil-predominant inflammation. Nasal nitric oxide (nNO) is a known biomarker of eosinophilic inflammation in the upper airway. However, the utility of nNO measurement in the upper airway remains controversial. The present study aimed to compare the use of other clinical parameters with nNO to prediagnose patients with eCRSwNP from Central China. METHODS: From June 2019 to December 2019, 70 patients with CRSwNP undergoing endoscopic sinus surgery and 30 healthy subjects were enrolled. nNO measurements were performed in all of these subjects. Computed tomography scans, full blood count with differential analysis, and determination of total immunoglobulin E (total IgE) and plasma cytokines were performed before surgery. Receiver operating characteristic curves and logistic regression analysis were used to assess the predictive potential of the clinical parameters. RESULTS: We recruited 24 patients with eCRSwNP and 46 with noneosinophilic CRSwNP (non-eCRSwNP). In patients with eCRSwNP, nNO levels were significantly higher than those in patients with non-eCRSwNP (p < 0.0001). Blood eosinophil percentages and counts, total IgE, and CT-derived ethmoid sinus and maxillary sinus ratio (E/M ratio) were all significantly higher compared with those in patients with non-eCRSwNP (p < 0.05). To diagnose eCRSwNP, the highest area under the curve (0.803) was determined for nNO. At a cutoff of >329 parts per billion (ppb), the sensitivity was 83.30% and the specificity was 71.70%. However, the levels of plasma cytokines Th1/Th2 were not significantly different between the histological types of CRSwNP (p > 0.05). CONCLUSION: Measurement of nNO is useful for the early diagnosis of eCRSwNP.

The Pattern of Sensitization Influences Exhaled and Nasal Nitric Oxide Levels in Young Adults.

Nitric oxide (NO) from upper (nasal NO, nNO) or lower airways (fractional exhaled NO, FeNO) is considered a surrogate marker for Th2-type inflammation, which is influenced by atopy. The aim of this study was to analyze nNO and FeNO in regard to qualitative and quantitative aspects of sensitization. We evaluated 244 non-smoking young adults. All of them were first-year students recruited for a longitudinal study. An inhalation allergy screening tool was used for atopy definition (specific immunoglobulin E (sIgE) to sx1 ≥ 0.35 kU/L), and also sIgE response to three inhalant perennial allergens, house dust mite (HDM, d1), cat (e1), and dog (e5), was determined in the non-pollen season. With respect to sx1, 100 subjects could be classified as atopic. Sensitization to one, two, or three perennial allergens could be demonstrated in 46, 10, and 16 students, respectively. The subjects with positive IgE response to sx1, but not sensitized to HDM, cat, and/or dog, had FeNO levels comparable to those of non-atopic subjects (13.5 vs. 13.0 ppb, respectively; p = 0.485). These levels were significantly lower compared to atopic subjects being sensitized to any perennial allergen (19.0 ppb; p = 0.0003). After grouping the atopic subjects for perennial sensitization patterns, significantly higher FeNO could be detected in subjects with poly-sensitization (n = 26; 26.0 ppb) compared to the mono-sensitized ones (n = 46; 18.0 ppb; p = 0.023). Regarding nNO, no differences could be observed. Applying a two-way ANOVA, we could reveal a significant correlation of specific HDM-IgE CAP-class with FeNO (p < 0.0001) and nNO levels (p = 0.007). Finally, a significant relationship was found between nNO and FeNO for the whole cohort (p < 0.0001). In summary, our findings support the argument that atopy and perennial sensitization should be considered for the interpretation of NO.

Nasal Nitric Oxide in Primary Immunodeficiency and Primary Ciliary Dyskinesia: Helping to Distinguish Between Clinically Similar Diseases.

PURPOSE: Primary ciliary dyskinesia (PCD) is a rare disorder of the mucociliary clearance leading to recurrent upper and lower respiratory tract infections. PCD is difficult to clinically distinguish from other entities leading to recurrent oto-sino-pulmonary infections, including primary immunodeficiency (PID). Nasal nitric oxide (nNO) is a sensitive and specific diagnostic test for PCD, but it has not been thoroughly examined in PID. Past publications have suggested an overlap in nNO levels among subjects with PCD and PID. We sought to determine if nNO measurements among patients diagnosed with PID would fall significantly above the established PCD diagnostic cutoff value of 77 nL/min. METHODS: Children > 5 years old and adults with definitive PID or PCD diagnoses were recruited from outpatient subspecialty clinics. Participants underwent nNO testing by standardized protocol using a chemiluminescence analyzer and completed a questionnaire concerning their chronic oto-sino-pulmonary symptoms, including key clinical criteria specific to diagnosed PCD (neonatal respiratory distress at term birth, year-round cough or nasal congestion starting before 6 months of age, any organ laterality defect). RESULTS: Participants included 32 patients with PID, 27 patients with PCD, and 19 healthy controls. Median nNO was 228.9.1 nL/min in the PID group, 19.7 nL/min in the PCD group, and 269.4 in the healthy controls (p < 0.0001). Subjects with PCD were significantly more likely to report key clinical criteria specific to PCD, but approximately 25% of PID subjects also reported at least 1 of these key clinical criteria (mainly year-round cough or nasal congestion). CONCLUSIONS: While key clinical criteria associated with PCD often overlap with the symptoms reported in PID, nNO measurement by chemiluminescence technology allows for effective discrimination between PID and PCD.

Nasal nitric oxide in relation to psychiatric status of patients with empty nose syndrome.

BACKGROUND: Although cases of empty nose syndrome (ENS) are not very common, the suffering that ENS causes patient is immense and could be very difficult to imagine. Nasal nitric oxide (nNO) is an airway disease biomarker, and its levels increase after endoscopic sinus surgery. The trend of nNO levels in ENS before and after surgical treatment remains unknown. This study aimed to evaluate the role of nNO in ENS. METHODS: Patients with ENS who received surgical implantation and with chronic hypertrophic rhinitis (CHR) who underwent turbinoplasty and completed at least 1 year of follow-up were prospectively enrolled. nNO measurements and subjective assessments [SinoNasal Outcome Test (SNOT)-22, Beck Depression Inventory (BDI)-II, and Beck Anxiety Inventory (BAI)] were performed preoperatively and at 3, 6, and 12 months postoperatively. RESULTS: We enrolled 19 ENS and 12 CHR patients. nNO levels were significantly lower in the ENS than in the CHR patients before surgical treatment (p < 0.001). nNO levels in the ENS patients significantly increased 3 months after implantation and remained plateaued (p = 0.015). BDI-II and BAI scores significantly improved after surgical treatment for the ENS patients but not for the CHR patients; changes in nNO levels correlated well with improvements in BDI-II and BAI scores (p = 0.025 and 0.035, respectively). CONCLUSIONS: nNO significantly increased at third month after surgical treatment and remained plateaued in ENS patients. This increase correlated with improvements in BDI-II and BAI scores. Therefore, nNO may be important in assessing the psychiatric status of empty nose syndrome.

Proof of Concept: Very Rapid Tidal Breathing Nasal Nitric Oxide Sampling Discriminates Primary Ciliary Dyskinesia from Healthy Subjects.

INTRODUCTION: Nasal nitric oxide (nNO) is extremely low in individuals with primary ciliary dyskinesia (PCD) and is recommended as part of early workup. We investigated whether tidal breathing sampling for a few seconds was as discriminative between PCD and healthy controls (HC) as conventional tidal breathing sampling (cTB-nNO) for 20-30 s. METHODS: We performed very rapid sampling of tidal breathing (vrTB-nNO) for 2, 4 and 6 s, respectively. Vacuum sampling with applied negative pressure (vrTB-nNOvac; negative pressure was applied by pinching the sampling tube) for < 2 s resulted in enhanced suction of nasal air during measurement. Feasibility, success rate, discriminatory capacity, repeatability and agreement were assessed for all four sampling modalities. RESULTS: We included 13 patients with PCD, median (IQR) age of 21.8 (12.2-27.7) years and 17 HC, 25.3 (14.5-33.4) years. Measurements were highly feasible (96.7% success rate). Measured NO values with vrTB-nNO modalities differed significantly from TB-nNO measurements (HC: p < 0.001, PCD: p < 0.05). All modalities showed excellent discrimination. The vacuum method gave remarkably high values of nNO in both groups (1865 vs. 86 ppb), but retained excellent discrimination. vrTB-nNO4sec, vrTB-nNO6sec and vrTB-nNOvac showed identical specificity to cTB-nNO (all: 1.0, 95% CI 0.77-1.0). CONCLUSION: vrTB-nNO sampling requires only a few seconds of probe-in-nose time, is feasible, and provides excellent discrimination between PCD and HC. Rapid TB-nNO sampling needs standardisation and further investigations in infants, young children and patients referred for PCD workup.

Measurement of fractional exhaled nitric oxide and nasal nitric oxide in male patients with obstructive sleep apnea.

OBJECTIVE: Airway inflammation plays an important role in obstructive sleep apnea (OSA); exhaled nitric oxide is regarded as a noninvasive marker of airway inflammation. The aim of this study was to evaluate fractional exhaled nitric oxide (FeNO) and nasal nitric oxide (nNO) in patients with OSA. METHODS: Seventy-five patients with OSA and 30 health controls were enrolled in this study. FeNO and nNO were measured before and after sleep. Nasal lavage was performed in 31 non-smoking individuals immediately after NO measurement in the morning. The sample of nasal lavage was taken for cell classification and analyzing interleukin 6 (IL-6) and interleukin 8 (IL-8). RESULTS: Both FeNO and nNO were significantly higher in OSA (before sleep FeNO 21.08 ± 8.79 ppb vs.16.90 ± 6.86 ppb, p = 0.022; after sleep FeNO 25.57 ± 15.58 ppb vs.18.07 ± 6.25 ppb, p = 0.003; before sleep nNO 487.03 ± 115.83 ppb vs. 413.37 ± 73.10 ppb, p = 0.001; after sleep nNO 550.07 ± 130.24 ppb vs. 460.43 ± 109.77 ppb, p < 0.001). Furthermore, in non-smoking OSA, nNO levels were positively correlated with apnea hypopnea index (AHI) and average decrease of pulse arterial oxygen saturation (SpO2); after sleep, nNO was also positively associated to recording time with SpO2 < 90% and negatively associated to minimum SpO2. Both before and after sleep nNO levels were positively correlated with the percentage of neutrophils in nasal lavage (r = 0.528, p = 0.014; r = 0.702, p < 0.001, respectively). Additionally, before sleep nNO was also positively associated with IL-6 (r = 0.586, p = 0.005) and IL-8 (r = 0.520, p = 0.016) concentration. CONCLUSION: This study sustains the presence of airway inflammation in OSA patients with the increase of FeNO and nNO. The data suggests nNO might have greater value than FeNO since it positively correlated with OSA severity, and nNO is a potential bio-marker of nasal inflammation in non-smoking OSA patients.

Methodological Implications and Repeatability of Nasal Nitric Oxide: Relevance for Challenge Studies.

There is an interest in assessing changes in nasal NO (nNO) levels as an effect marker of upper airways. In this study, we examined methodologic influences on short and long term repeatability of nNO levels assessed by a portable electrochemical analyzer. Nine atopic and eighteen healthy subjects were exposed for 4 h to ethyl acrylate concentration of 0.05 ppm (sham) and mean concentrations of 5 ppm (either constant 5 ppm or variable 0 to 10 ppm). Sampling of nNO was performed by using passive aspiration during both breath-holding (634 ppb) or calm tidal breathing (364 ppb, p < 0.0001). The intra-session (between-session) repeatability in terms of coefficient of variation was 16.4% (18.5%) using the tidal-breathing and 8.6% (13.0%) using the breath-holding method, respectively. Atopic subjects demonstrated a significant increase in nNO (breath-holding mean 16%, tidal-breathing mean 32%) after applying a constant ethyl acrylate concentration (5 ppm). Our findings suggest that the less elaborate tidal-breathing method might be sufficient to detect significant changes at a group level. Given a lower coefficient of variation of breath-holding we assume there is an advantage of that approach at an individual level. Further research is needed to validate the usefulness of nNO in the evaluation of irritative, non-allergic responses.

Reduced nasal nitric oxide levels in patients with eosinophilic chronic rhinosinusitis.

BACKGROUND: In Eosinophilic chronic rhinosinusitis (ECRS), it is difficult to estimate the refractoriness and recurrence risk for each patient. Fraction of exhaled nitric oxide (FeNO) is known as a biomarker of eosinophilic inflammation in lower airway. It has been reported that nasal NO has some crucial functions in the upper and lower airways. However, in upper airway, paranasal sinuses, the usefulness of NO measurement remains controversial. The purpose of this study is to identify the usefulness of nasal NO measurement in ECRS and the involvement of nasal NO in the pathogenesis of ECRS. METHODS: We compared the nasal NO levels of ECRS, non-ECRS, and normal control groups. Correlation between nasal NO levels and clinical findings were observed. Then, we compared nasal NO levels before and after endoscopic sinus surgery (ESS). We also examine whether nasal NO levels might discriminate ECRS by the receiver operating characteristic (ROC) curve analysis. RESULTS: Nasal NO levels were significantly decreased in ECRS compared to the other two groups. Moreover, nasal NO levels in ECRS significantly and negatively correlated with eosinophil levels and CT score. However, they did not correlate with the nasal polyp score. Nasal NO levels were not upregulated soon after opening the sinus ostium by ESS. The ROC curves for nasal NO levels were used to discriminate all CRS patients and ECRS patients from normal controls. CONCLUSIONS: Nasal NO may be useful as a marker of ECRS severity and low nasal NO levels in ECRS may contribute to its pathogenesis.

Olfactory dysfunction is worse in primary ciliary dyskinesia compared with other causes of chronic sinusitis in children.

Cilia have multiple functions including olfaction. We hypothesised that olfactory function could be impaired in primary ciliary dyskinesia (PCD). Olfaction, nasal nitric oxide (nNO) and sinus CT were assessed in patients with PCD and non-PCD sinus disease, and healthy controls (no CT scan). PCD and non-PCD patients had similar severity of sinus disease. Despite this, defective olfaction was more common in patients with PCD (P<0.0001) and more severe in patients with PCD with major Transmission Electron Microscopy (TEM) abnormalities. Only in classical PCD did olfaction inversely correlate with sinusitis and nNO. We speculate that defective olfaction in PCD is primary in nature.

Inflammatory Biomarkers During Bacterial Acute Rhinosinusitis.

PURPOSE OF REVIEW: Diagnosis of bacterial acute rhinosinusitis is difficult. Several attempts have been made to clarify the diagnostic criteria. Inflammatory biomarkers are easily obtainable variables that could shed light on both the pathophysiology and diagnosis of bacterial acute rhinosinusitis. The purpose of this review article is to assess literature concerning the course of inflammatory biomarkers during acute rhinosinusitis and the use of inflammatory biomarkers in diagnosing bacterial acute rhinosinusitis. RECENT FINDINGS: We included C-reactive protein, erythrocyte sedimentation rate, white blood cell counts, procalcitonin, and nasal nitric oxide in this review and found that especially elevated C-reactive protein and erythrocyte sedimentation rate are related to a higher probability of a bacterial cause of acute rhinosinusitis. Still, normal levels of these two biomarkers are quite common as well, or the levels can be heightened even during viral respiratory infection without suspicion of bacterial involvement. Elevated levels of C-reactive protein or erythrocyte sedimentation rate support diagnosis of bacterial acute rhinosinusitis, but due to a lack of sensitivity, they should not be used to screen patients for bacterial acute rhinosinusitis.

Nasal nitric oxide in sleep-disordered breathing in children.

BACKGROUND: Inflammation plays a role in the pathogenesis and consequences of sleep-disordered breathing (SDB). The nasal mucosa and paranasal sinuses produce high levels of nitric oxide (NO). In asthma, exhaled NO is a marker of airway inflammation. There is only limited information whether nasal NO (nNO) accompanies also chronic upper airway obstruction, specifically, SDB. The objective of this study was to investigate nNO levels in children with SDB in comparison to healthy non-snoring children. METHODS: Nasal NO was measured in children who underwent overnight polysomnographic studies due to habitual snoring and suspected SDB and in healthy non-snoring controls. RESULTS: One hundred and eleven children participated in the study: 28 with obstructive sleep apnea (OSA), 60 with primary snoring (PS), and 23 controls. Nasal NO levels were significantly higher in children with OSA and PS compared to controls (867.4 ± 371.5, 902.0 ± 330.9, 644.1 ± 166.5 ppb, respectively, p = 0.047). No difference was observed between children with OSA and PS. No correlations were found between nNO levels and any of the PSG variables, nor with age, BMI percentile or tonsils size. CONCLUSIONS: Compared to healthy controls, nNO is increased in children with SDB, but it is not correlated with disease severity. This is probably due to the local mechanical processes and snoring.

Comparison of Nasal Nitric Oxide Levels between the Inferior Turbinate Surface the Middle Meatus in Patients with Symptomatic Allergic Rhinitis.

BACKGROUND: Because of the anatomical complexity and the high output of the human nose, it has been unclear whether nasal nitric oxide (NO) serves as a reliable marker of allergic rhinitis (AR). We examined whether nasal NO levels in the inferior turbinate (IT) surface and the middle meatus (MM) differ in symptomatic AR patients. METHODS: We measured fractional exhaled NO (FeNO) and nasal NO in normal subjects (n = 50) and AR patients with mild symptoms (n = 16) or moderate or severe symptoms (n = 27). Nasal NO measurements were obtained using an electrochemical analyzer connected to a catheter and an air-suction pump (flow rate 50 mL/ sec). RESULTS: Compared to the normal subjects, the AR patients showed significantly higher nasal FeNO and nasal NO levels in the IT area. No significant difference in the MM area was observed among the three groups. The MM area showed higher NO levels than the IT area in all three groups. The ratio of nasal NO levels of the MM area to the IT area (MM/IT ratio) was significantly lower in the AR groups. The moderate/severe AR patients showed significantly higher nasal NO in the IT area (104.4 vs. 66.2 ppb) and lower MM/IT ratios than those in the mild AR patients. The analysis of nasal brushing cells revealed significantly higher eosinophil cationic protein and nitrotyrosine levels in the AR groups. CONCLUSIONS: Nasal NO assessment in the IT area directly reflects persistent eosinophilic inflammation and may be a valid marker to estimate the severity of AR.

The utility of nasal nitric oxide in the diagnostic evaluation of primary ciliary dyskinesia.

BACKGROUND: There is no gold-standard test for primary ciliary dyskinesia (PCD), rather American Thoracic Society guidelines recommend starting with nasal nitric oxide (nNO) in children ≥5 years old and confirming the diagnosis with genetic testing or ciliary biopsy with transmission electron microscopy (TEM). These guidelines have not been studied in a clinical setting. We present a case series describing the PCD diagnostic process at our pediatric PCD center. METHODS: Diagnostic data from 131 patients undergoing PCD consultation were reviewed. RESULTS: In all participants ≥ 5 years old and who completed nNO using resistor methodology, the first diagnostic test performed was nNO in 77% (73/95), genetic testing in 14% (13/95), and TEM in <1% (9/95). nNO was the only diagnostic test performed in 75% (55/73) of participants who completed nNO first. Seventy-five percent (55/73) had a single above the cutoff nNO value and PCD was determined to be unlikely in 91% (50/55) without performing additional confirmatory testing. Eleven percent (8/73) had multiple below the cutoff nNO values, with 38% (3/8) being diagnosed with PCD by confirmatory testing and 50% (4/8) with negative confirmatory testing, but being managed as PCD. The genetic testing positivity rate was 50% in participants who completed nNO first and 8% when genetic testing was completed first. CONCLUSION: nNO is useful in three situations: an initial above the cutoff nNO value makes PCD unlikely and prevents additional confirmatory testing, repetitively below the cutoff nNO values without positive confirmatory testing suggests a probable PCD diagnosis and the yield of genetic testing is higher when nNO is performed first.

Elexacaftor/tezacaftor/ivacaftor improves nasal nitric oxide in patients with cystic fibrosis.

BACKGROUND: In health, nitric oxide (NO) shows high concentrations in the upper airways, while nasal NO (nNO) is significantly lower in patients with sinonasal inflammation, such as people with cystic fibrosis (PwCF). In PwCF treated with elexacaftor/tezacaftor/ivacaftor (ETI; PwCF-ETI), clinical improvement of sinonasal symptoms and inflammation was observed. We therefore hypothesised that ETI may increase nNO in PwCF. METHODS: 25 PwCF-ETI underwent nNO measurement at baseline and after 3 to 24 months of ETI treatment. NNO was measured using velum closure (VC) techniques in cooperative patients and tidal breathing (TB) for all patients. As controls, 7 CF patients not eligible for ETI (PwCF-non ETI) and 32 healthy controls (HC) were also repeatedly investigated. RESULTS: In PwCF-ETI, sinonasal symptoms, lung function parameters and sweat chloride levels improved from baseline to follow-up whereas there was no change in PwCF-non ETI and HC. NNO increased from a median (IQR) value at baseline to follow-up from 348.2 (274.4) ppb to 779.6 (364.7) ppb for VC (P < 0.001) and from 198.2 (107.0) ppb to 408.3 (236.1) ppb for TB (P < 0.001). At follow-up, PwCF-ETI reached nNO values in the normal range. In PwCF-non ETI as well as HC, nNO did not change between baseline and follow-up. CONCLUSIONS: In PwCF-ETI, the nNO values significantly increased after several months of ETI treatment in comparison to baseline and reached values in the normal range. This suggests that nNO is a potential non-invasive biomarker to examine sinonasal inflammatory disease in PwCF and supports the observation of clinical improvement in these patients.