Is Nasal Nitric Oxide Measurement an Useful Diagnostic Tool in Respiratory Diseases?

Primary ciliary dyskinesia (PCD) is an autosomal recessive disease resulting in impaired mucociliary clearance associated with respiratory distress in term neonates, chronic otosino-pulmonary disease, male infertility, and organ laterality defects in ~50% of cases (20). This syndrome was initially recognized based on the triad of chronic sinusitis, bronchiectasis, and situs inversus (Kartagener syndrome) and Afzelius later recognized that these patients had “immotile” cilia and defective ciliary ultrastructure (21).

nNO is markedly reduced in this condition, with a diagnostic potential, being highly feasible, painless, noninvasive, rapid, and relatively inexpensive (22). nNO levels in patients with PCD are quite low (<77 nl/min), relative to normal values (range 125 to 867 nl/min; mean, 287 nl/min) (19). In the metaanalysis of 1,344 patients comprising 514 with PCD and 830 without PCD, diagnostic nNO cutoff values ranged from 16.8 to 100 nl/min, with a median cutoff at 76.9 nl/min (22).

It is critical to recognize that low nNO levels are also seen in some patients with cystic fibrosis (CF), even though nNO level in CF is not as low as in primary ciliary dyskinesia. Therefore, CF needs to be ruled out by sweat testing or CFTR genetic studies if nNO is low (21). However, in some cases, normal nNO levels do not rule out PCD, and patients with highly compatible PCD clinical phenotypes but normal nNO levels should be subjected to further testing (22).

Allergic rhinitis (AR), the most common allergic disease in both adult and pediatric population, is characterized by sneezing, itching, nasal congestion, and rhinorrhea following an exposure of allergens (5). Due to the chronic and recurrent inflammatory process in the sinonasal complex, nNO level is supposed to be significantly higher. Unfortunately, the detection of nNO as a marker in allergic rhinitis is still not validated for routine clinical use (18). Several studies have been performed to define the cut off value of nNO in allergic rhinitis patients. In the meta analysis of Wang et al., including 10 original studies with 561 AR patients, 327 healthy controls, and 123 NAR patients, the authors found that nNO in AR was significantly higher than in the healthy controls or NAR patients (5). Similar results were published by Chen et al, examined 55 cases of preschool children with AR. The levels of nNO were significantly higher in children with allergic rhinitis compared to the control group (23). The similar cut – off value (169.4 and 161.4 nl/min, respectively) was reported by two studies of Nesic et al. and Wen et al. (24, 25). The study of Antosova et al. confirmed the increase of nNO in allergic subjects during the pollen season and also out of it (18). However, some studies did not report a statistically significant difference of nNO levels in AR patients compared with the healthy controls. The probable cause is the swelling of nasal mucosa, leading to occluded sinus ostia and the blockage of NO distribution to the nasal cavity. For the same reason, nNO could not detect AR patients concomitant with nasal polyps, sinusitis, or marked ostial obstruction (5). The values of nNO in allergic rhinitis patients are also affected by medication. In the study of Antosova et al., the antiinflammatory treatment by the combination of antihistamines and nasal corticosteroids led to the significant decrease of nNO and this effect was more significant for women (18). Intranasal steroids therapy significantly reduces NO production by blocking the transcription of the iNO-synthase gene (26).

However, other studies failed to show the effect of nasal corticosteroid treatment on nNO levels (27, 28). This conflicting result is likely caused by diffusion impairment, extensive mucus production, mucosal swelling, impaired communication with sinuses, or occlusion of the nostril and application of decongestants (29). There are also studies documenting the elevation of nNO levels after corticosteroid treatment in participants with chronic inflammation and nasal polyps (18), which is probably caused by the reduction of swelling, opening ostiomeatal complex, and the release of nNO from maxillary ostia (30).

Liu et al. compared nNO values in patients with allergic rhinitis (AR) and nonallergic rhinitis (NAR) and the impact of sinus inflammation. Patients with allergic rhinitis without sinus inflammation showed the highest nNO levels and patients with non-allergic rhinitis with sinus inflammation had the lowest nNO levels (31).

As we see, the variable obstruction of ostiomeatal ostia and the medication have a significant impact on the nNO levels.

Chronic rhinosinusitis is an inflammatory disease of the nose and paranasal sinuses defined by the presence of at least two out of four cardinal symptoms (i.e., facial pain/pressure, hyposmia/anosmia, nasal drainage, and nasal obstruction) for at least 12 consecutive weeks, in addition to objective evidence (32).

Despite the absence of reference values, lower nNO levels were observed in case of the chronic rhinosinusitis with nasal polyps (CRSwNP) and also without them (CRSsNP). CRSwNP patients exhibit significantly lower nNO values as compared to both CRSsNP and healthy subjects (33). In patients with CRSsNP were documented decreased nNP values with respect to the healthy subjects (26). It is uncertain whether the low NO levels detected in chronic rhinosinusitis result from a reduced maxillary NO production or are rather mainly due to an obstruction of sinus ostia (34). However, restoring patency of sinus ostia by endoscopic surgery has shown to be associated with a rapid increase in nNO levels (35). Hence, the low nNO levels can be explained through the nasal obstruction resulting from mucosal swelling (36). Another reason is the damage of the NO-producing sinus mucosa by an increased synthesis of cytotoxic agents in chronic inflammation (37). The reduced expression of the inducible isoform of NO synthase (iNO-synthase) caused by some inflammatory cytokines (IL-4, IL-6, and TGF-β) has been found in the sinus mucosa of chronic rhinosinusitis patients (37). An increased arginase activity was confirmed in patients with chronic rhinosinusitis, that may decrease NO levels by means of reduced availability of L-arginine, the main NO precursor (38). Adult patients with CRSwNP have high levels of iNOS in the nasal epithelium due to inflammation of nasal and paranasal cavities, they exhibit reduced levels of nNO in comparison with subjects affected by uncomplicated allergic rhinitis (39). Lower nNO levels in patients with paranasal sinus inflammatory diseases are caused by mechanical obstruction of the draining ostia and by the negative pressure within the sinuses, resulting in a reduced transit of NO from sinuses to the nasal lumen, despite the increased NO synthesis due to inflammation.

Chronic cough is defined as a cough that lasts for eight weeks or longer (40). Most common causes of chronic cough are asthma, gastroesophageal reflux disease, and upper airway cough syndrome (previously known as postnasal drip syndrome), collectively known as ‘diagnostic triad of chronic cough’ (40).

Manisalco et al. studied the FeNO and nNO in patients with chronic cough, classified to four cathegories (cough variant asthma (CVA), non-asthmatic eosinophillic bronchitis (NAEB), gastrooesophageal reflux disease (GERD), and upper airway cough syndrome (UACS). FeNO value was significantly higher in CVA and NAEB compared to GERD and UACS. However, no differences were found in nNO levels among the four groups and also in comparison with control groups (41). The explanation can be a continuous NO gas exchange between nasal cavity and the sinuses. The high NO levels in paranasal sinuses could easily blunt slight alteration of NO (42).

Similarly, in the study of Kim et al., the levels of nNO were not elevated in patients with UACS compared with other causes. UACS is not a single disease entity, this term refers to a variety of diseases, such as allergic rhinitis, nonallergic rhinitis, nonallergic rhinitis with eosinophilia, and bacterial sinusitis (43).

Among UACS patients, the concentrations of nNO in patients with sinusitis were significantly lower than in those without sinusitis. Furthermore, the levels of nNO in sinusitis were much lower than those in non-UACS; thus, the measurement of nNO discriminated sinusitis from non-sinusitis causes in patients with prolonged cough (43).

The most important characteristic of obstructive sleep apnea (OSA) is repeated pharyngeal collapses during sleep. Local inflammation at nose, pharynx, and larynx aggravates upper airway narrowing and increases the risk of OSA (9). The most important mechanisms of upper airway inflammation in OSA is hypoxia-reflexogen-induced inflammatory cytokine release (44). The study of Zhang et al. observed the positive correlation between nNO and the percentage of neutrophils, IL-6, IL-8 in nasal lavage, which indicates that nNO is a marker of the severity of OSA (9).

According to the same study, both FeNO and nNO levels were significantly higher in OSA patients than in the controls (9). Moreover, FeNO and nNO are increased after sleep in OSA patients, while nNO is also slightly increased after sleep in the healthy group. The levels of nNO before and after sleep were closely related with sleep apnea severity (9). Compared to the healthy controls, nNO is also increased in children with sleep-disordered breathing, but it is not correlated with disease severity. This is probably due to the local mechanical processes and snoring (45).

Smoking and OSA have opposite effects on FeNO and nNO level, so the concentration of FeNO and nNO in smoking OSA were close to the normal range (9).

In adenoid hypertrophy (AH), clinical utility of nasal nitric oxide is still critically questioned and remains to be established. Chladkova et al. studied the adenoid hypertrophy as a factor that influences nNO values in children with PCD. The results show that nNO of patients with AH is less than in the healthy controls and decrease with its grade (46). This result was confirmed by Rybnikar et al. in the study of 48 non allergic patients. According to this study, nNO and FeNO were reduced in nonallergic children with obstructive adenoids and the median of nNO decreased with the increasing grade of adenoids. Following adenoidectomy, nNO level increased (47). As we see, adenoid hypertrophy can potentially cause a false positive result of the test for PCD (47). Bugova et al. studied nNO in 60 children with adenoid hypertrophy. The value of nNO in younger children was significantly lower. Children with confirmed bacterial nasopharyngeal colonization had significantly higher measured values of nNO (48).