Nasal Nitric Oxide in Children: History
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Iva Mrkić Kobal
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Mirjana Turkalj
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Davor Plavec

Nasal nitric oxide (nNO) is a gas synthesized by the inducible and constitutive NO synthase (NOS) enzyme in the airway cells of the nasal mucosa. Like lung nitric oxide, it is thought to be associated with airway inflammation in various respiratory diseases in children. 

  • nasal nitric oxide
  • children
  • allergic rhinitis
  • chronic rhinosinusitis
  • primary ciliary dyskinesia

1. Nasal Nitric Oxide Role in Upper Airways

Since the identification of NO in exhaled air in 1991, extensive research has unveiled its pivotal role in the respiratory system [1]. The primary origin of intrinsic NO production within the human airway has been identified as paranasal cavities [2][3]. There are three distinct variants of NOS in the human body: neuronal, endothelial, and inducible. All three distinct variants found in the respiratory system contribute to the regulation of respiratory physiology [4]. Neuronal and endothelial NOS are considered constitutive forms, while inducible NOS was initially observed in alveolar macrophages but is now known to exist in various cell types such as alveolar cells type 2, lung fibroblasts, mastocytes, endothelial cells, and neutrophils. NO’s fundamental effects encompass neurotransmission, bronchodilation (reducing airway resistance), surfactant production, mucus secretion, and stimulation of ciliary motility, and it has an anti-inflammatory role. In the upper airway, it acts as a vasodilator and smooth muscle relaxant, stimulates mucus production, and aids in mucociliary clearance by regulating ciliary beat frequency. Furthermore, NO exhibits direct antimicrobial activity against both bacteria and viruses [5][6]. Certain research findings indicate that the body’s internal production of NO may trigger heightened activity in the submucosal glands of the respiratory system, resulting in an augmentation of mucus production [7]. Reduced NO synthesis is evident in conditions such as primary ciliary dyskinesia (PCD) and cystic fibrosis (CF), where mucociliary clearance is impaired [8].
It remains unclear whether the decreased NO levels detected in chronic rhinosinusitis result from reduced NO production by the paranasal sinuses or from hindered NO diffusion in the nasal cavity due to sinus ostia obstruction [9].

2. Nasal Nitric Oxide in Allergic Rhinitis

Allergic rhinitis is an atopic disease characterized by a Th-2 inflammatory response. As it represents the prevalent allergic upper respiratory condition in both children and adults, immediate efforts were made to establish a connection between nNO levels and allergic inflammation in these patients. [10]. The data prior to the year 2000 were controversial because several studies claimed that nNO could be used to predict allergic rhinitis [11][12][13], whereas others, in contradiction, claimed that nNO levels in allergic rhinitis were not significantly different from those in healthy subjects [14][15]. The controversial nature of these results may be attributed to several factors, including swelling of the nasal mucosa and the blockage of sinus ostia, which can impede the distribution of nNO into the nasal cavity. Furthermore, the administration of therapeutic interventions aimed at symptom control, the timing of measurements in relation to allergen exposure, and the techniques employed for nNO measurement can all contribute to the observed discrepancies [16]. It has been demonstrated that the choice of measurement technique and the type of analyzer employed can significantly influence nNO values. Both the type of analyzer (chemiluminescence vs. electrochemical) and the aspiration rate during sampling, as well as the specific sampling technique used, can impact nNO levels. Chemiluminescence analyzers utilize exhalation against resistance and the breath-holding technique, whereas electrochemical analyzers employ the tidal breathing technique. These different approaches have been found to have varying degrees of reproducibility in measuring nNO values, with electrochemical analysis being less extensively studied and exhibiting lower reproducibility [17].
In 2021, Wang et al. conducted a meta-analysis of nNO levels and their clinical utility in children with allergic rhinitis, which revealed significantly elevated nNO levels compared with healthy controls [16]. Cutoff values to distinguish between AR and healthy controls were 169.4 and 161.4 nl/min in two different studies by Nesic et al. and Wen et al., respectively, with sensitivity of 83% and 100% and specificity of 80 and 94.4% [12][18].
Wang et al. also compared the influence of different types of nNO analyzers, nNO sampling methods, sampling flow rates, presence of coexisting asthma, and rhinitis symptoms, and found no evidence of differences between subgroups. The three entities that were found to undermine the differentiation of children with allergic rhinitis based on nNO values are nasal polyps, sinusitis, and marked ostial obstruction.
Hong and Parisi et al. demonstrated that nNO levels can also serve as a noninvasive assessment of clinical effectiveness in managing allergic rhinitis in children. They demonstrated a significant reduction in symptoms and nNO values of allergic rhinitis after treatment according to the guidelines of ARIA (nNO (91.4 ± 56.7 vs. 72.9 ± 52.4; p < 0.05)) and after treatment with sublingual allergen-specific immunotherapy (nNO (1035.2 ± 956.08 vs. 139.2 ± 59.01; p < 0.05)) [19][20]. In the study by Antosova et al., the data for treatment with H1 antihistamines alone were not reviewed. Only the combination treatment of antihistamines and nasal corticosteroids significantly decreased nNO levels in patients with allergic rhinitis [21].
In their study focusing on house dust mite-triggered allergic rhinitis, Sutiratanachai et al. observed that nNO levels could be used to discern the degree of rhinitis severity. Specifically, children with severe allergic rhinitis exhibited markedly elevated nNO levels compared to their counterparts with moderate rhinitis. Fraction of exhaled NO (FeNO) levels were not changed as a function of severity of allergic rhinitis [22].
In seasonal allergic rhinitis, nNO levels are significantly elevated during and after pollen exposure, suggesting increased activity of inducible NOS during pollen exposure. The nNO levels in allergy patients were also higher during the year than in the control group [14]. In contrast to the study conducted by Sutiratanachai et al. [22], Antosova et al. did not categorize patients based on the severity of their condition. This omission suggests that individuals who are dealing with substantial mucosal swelling and nasal discharge might display reduced nNO levels, even in the presence of pronounced inflammation [21].
When examining clusters of seasonal allergic rhinitis in children, Malizia et al. found significantly different nNO values between the different clusters. Cluster I had intermediate nNO values, a lower percentage of neutrophils, low IL-5 and IL-17, high IFN-y, and IL-23 responses. Cluster 2 exhibited elevated nNO levels, an increased ocular symptom score, and a heightened IL-5 response. Cluster 3 had a neutrophil response, predominantly Th1/Th17 with significantly higher levels of IL-23, IFN-y, and IL-17 compared to other clusters which had lower nNO levels. This makes nNO a potential biomarker for endotyping allergic rhinitis [23].

3. Nasal Nitric Oxide in Chronic Rhinosinusitis

Because the upper respiratory tract is the main source of nNO and the paranasal sinuses are the main site of nNO production [2][3], it has also been the subject of numerous studies in chronic rhinosinusitis. Chronic rhinosinusitis in children is a condition defined by a duration of at least 90 days with two or more symptoms of purulent rhinitis, nasal obstruction, facial pressure/pain, and either endoscopic evidence of mucosal edema, purulent discharge, or nasal polyposis and/or computed tomography (CT) imaging of changes in mucosa or/and in the sinuses and/or ostiomeatal complex. It is divided into two distinct entities: chronic rhinosinusitis with and without nasal polyposis [24].
Studies of nNO in chronic rhinosinusitis are mostly performed in adults [25][26][27], although there are studies in children [28].
In all studies, nNO levels were consistently decreased in chronic rhinosinusitis, especially in cases with nasal polyps [29]. Individuals with chronic rhinosinusitis and nasal polyposis demonstrate significantly lower nNO levels compared to both individuals with chronic rhinosinusitis but no nasal polyposis and healthy individuals [30].
The conclusion from the various studies is that inflammation of the nasal mucosa, especially in association with polyps, prevents the flow of nNO from the sinuses into the nasal cavities, resulting in a decrease in nNO levels [25][26][27][29]. An alternative hypothesis for the reduced nNO levels in chronic rhinosinusitis patients could be a disruption in the expression of NOS-2 synthase within the ciliary epithelial cells of the mucosa lining the paranasal sinuses [31][32].
Since nNO plays a role in airway defense, this may lead to an additional increase in the risk for recurrent infections [33].
Response to treatment of chronic rhinosinusitis is also difficult to assess. Assessing the response to therapy can involve symptom scores, endoscopic observations, and parallel measures such as saccharin clearance, as repeated use of CT examinations may not be feasible. nNO has also been shown to be a useful tool to monitor chronic rhinosinusitis response to therapy. In the study conducted by Ragab et al., they found that initial absolute nNO values exhibited an inverse correlation with changes in CT scans (Kendall’s tau-b correlation coefficient: −0.483, p < 0.001). Conversely, the percentage increase in nNO following both medical intervention and surgical intervention showed correlations with changes in symptom scores (Kendal’s tau-b correlation coefficient: −0.298, p < 0.001), saccharin clearance duration (Kendal’s tau-b correlation coefficient: −0.676, p < 0.001), endoscopic observations (Kendal’s tau-b correlation coefficient: −0.368, p < 0.001), polyp grades (Kendal’s tau-b correlation coefficient: −0.209, p < 0.05), and surgical scores (Kendal’s tau-b correlation coefficient: 0.291, p < 0.01) [27]. Absolute nNO values changed according to groups: in medically treated group the absolute nNO values increased from 724 ± 486 ppb to 1137 ± 547 ppb (p < 0.001), and in the surgically treated group they increased from 773 ± 426 ppb to 1129 ± 496 ppb (p < 0.001) at sixth months follow up [34].

This entry is adapted from the peer-reviewed paper 10.3390/children10101671

References

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