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Exhaled nitric oxide analysis and applications

Exhaled nitric oxide analysis and applications
Literature review current through: Aug 2023.
This topic last updated: Mar 07, 2023.

INTRODUCTION — Nitric oxide (NO) is a gaseous molecule initially considered to have a health-related role only in the context of its formation from the combustion of fossil fuels and its contribution to air pollution. However, this view has been greatly modified since the 1987 discovery that the free radical NO is the previously uncharacterized endothelial-derived relaxing factor. It is now clear that NO plays an important role in most human organ systems.

Within the respiratory system, NO regulates vascular and bronchial tone (promoting dilation of both vessels and airways), facilitates the coordinated beating of ciliated epithelial cells, and acts as an important neurotransmitter for non-adrenergic, non-cholinergic neurons that run in the bronchial wall [1-8]. This molecule can be detected in exhaled gas as the fractional exhaled NO (FENO), which varies in health and disease.

The biology of NO, techniques available for measuring this gas in exhaled breath, and potential uses of these measurements in clinical practice will be reviewed here. The therapeutic use of inhaled NO is discussed separately. (See "Inhaled nitric oxide in adults: Biology and indications for use" and "Acute respiratory distress syndrome: Investigational or ineffective therapies in adults" and "Primary lung graft dysfunction", section on 'Treatment'.)

FORMATION OF NO — In biological systems, nitric oxide (NO) is formed by the action of one of the isoforms of the enzyme nitric oxide synthase (NOS). Three such isoforms have been identified and are termed type I or neuronal cell NOS (nNOS), type II or inducible NOS (iNOS), and type III or endothelial cell NOS (eNOS) (table 1) [9,10]. Although these enzymes are distinct proteins encoded by genes on disparate chromosomes, all three catalyze the adduction of the guanidino nitrogen of the amino acid arginine to molecular oxygen, yielding NO and water (figure 1) [11].

Regulation of NOS — While the three isoforms of NOS catalyze the same reaction, regulation of the activity of these isozymes occurs through distinct processes. Both nNOS and eNOS are usually constitutively active and produce low amounts of NO, with output varying with changes in the intracellular calcium concentration. In contrast, iNOS binds calcium so avidly that its function is not influenced by calcium fluxes within the physiologic range. While not constitutively active in most settings, iNOS is constitutively expressed in the airway epithelium of normal and asthmatic subjects [12,13]. iNOS also has the capacity to generate large quantities of NO when transcriptionally upregulated by inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, interleukin 1 (IL-1)-beta, interferon (IFN)-gamma, IL-4, and IL-13 [9,10,14]. In vitro evidence suggests that this upregulation can be abolished by glucocorticoids in vitro [15] and in vivo [12].

Location of NOS — The cellular location of the various NOS isoforms in the respiratory system has been investigated using immunohistochemical and DNA hybridization techniques. In the human lung, nNOS localizes to airway epithelium and likely to the submucosal nerves [16,17], iNOS has been documented in airway epithelial cells [12], and eNOS exists in the vascular endothelium [18].

The observation that iNOS is inducible by inflammatory cytokines and is inhibited by glucocorticoids provides circumstantial evidence that iNOS activity within airway epithelial cells is the source of the increased NO encountered in asthma.

Source of exhaled NO — The precise anatomic source of exhaled NO was not initially clear, because nitric oxide is formed by multiple mechanisms and in various types of cells. Early studies suggested that the NO in orally exhaled air was likely to represent contamination with NO derived from the sinuses, as the nasal sinuses contain very high levels of NO (>1000 ppb) [19-21]. However, subsequent studies using bronchoscopic techniques to isolate the lower airway from nasal gas have demonstrated that the concentrations of NO in gas derived exclusively from the lower airway are comparable to those obtained in the orally exhaled breath [22-24]. Thus, it is now accepted that the majority of exhaled NO originates from the lower airways. Mathematical models using simultaneous high resolution recordings of FENO and flow rate suggest that the majority of NO is excreted from the larger central airways and that central airway NO derives in large part from airway epithelial cells [25,26].

EFFECT OF NO IN THE AIRWAY — The exhaled air of asthmatic individuals contains higher levels of nitric oxide (NO) than healthy non-smoking individuals [27,28], but the exact role of NO in asthma is less clear and likely multifaceted. Some studies suggest that increased NO relaxes bronchial smooth muscle leading to bronchodilatation and inhibits pro-inflammatory signaling events [29,30], while others suggest it contributes to airway inflammation and injury through formation of toxic reactive nitrogen species (RNS) [31].

NO is highly reactive and once produced it can rapidly lead to the formation of several nitric oxide related end products with differing downstream effects [23,32]. Increased production of NO or RNS may increase nitration of tyrosine residues in proteins or decrease nitrosylation of thiol residues on proteins, which in turn decreases the bronchodilating S-nitrosothiols (SNO) [23,32]. A model of NO dynamics derived from allergen challenge studies in humans demonstrates that NO may have harmful effects through formation of peroxynitrite (one of the reactive nitrogen species), but may also have an antioxidant role by consuming reactive oxygen species during the immediate asthmatic response [23]. Ultimately, the functional role of NO, as with any molecule, depends on both its concentration and association with other biomolecules and proteins [24].

MEASUREMENT OF EXHALED NO — Chemiluminescence analysis allows determination of nitric oxide (NO) concentration in the gas phase by the reaction of NO in the sample with ozone to produce nitrogen dioxide in an excited state [33]. As nitrogen dioxide moves to a relaxed state, light is emitted in a stoichiometric relationship with the amount of NO present in the gas sample. Most initial studies reported in the literature used ozone-chemiluminescence to measure exhaled NO concentrations, and this technology was used in the first US Food and Drug Administration (FDA) approved devices [34]. Subsequently, devices based on other technologies, including hand held devices utilizing electrochemical methods, have also been approved [35,36] and are more commonly used in clinical settings. Chemiluminescence methods are still the gold standard and are more commonly used in research settings.

Standardized methods for measuring exhaled NO were jointly developed by the American Thoracic Society (ATS) and the European Respiratory society (ERS) in 1999 and revised in 2005 [37,38]. The guidelines recommend the use of the term FENO (the fractional exhaled NO concentration) to describe the level of NO in exhaled breath. FENO is expressed in parts per billion which is equivalent to nanoliters per liter. Further technical standards have been published by the ERS [36].

Exhaled NO can be measured online, while the subject exhales directly into the analyzer, or offline, by collection of exhaled air in an NO-impervious container and later measurement. Important technical factors include exclusion of nasal NO, use of proper procedures for online or offline measurement, adherence to optimal expiratory flow rates, and monitoring ambient NO levels [36-38]. Key features of the technique are reviewed here.

Online measurements – For online measurements obtained while the subject exhales at a constant flow directly into the analyzer, the mean FENO value over a three-second plateau is recorded, not the early peak. In order to achieve an appropriate plateau, the duration of exhalation must be sufficient (at least four seconds for children <12 years and more than six seconds for children ≥12 years and adults) [37].

Offline measurements – Specifications include using an apparatus to collect exhaled air without loss of NO; depleting the inspiratory air of NO prior to inhalation; and maintaining an expiratory flow rate of 0.350 L/second (range 0.315 to 0.385 L/second) throughout exhalation. Sometimes the first 150 to 250 mL of exhaled air is discarded but the optimal volume is not known and this step requires special valves. As with on-line measurements, the actual flow rate should be recorded with the test results.

Exclusion of nasal NO – Exclusion of nasal NO is important as these levels are high relative to lower respiratory tract levels [37]. In general, a nose clip is not used as this may allow nasal NO to accumulate and leak into the posterior pharynx. On the other hand, if the patient is not able to avoid nasal inspiration, a nose clip may be used. After inserting the mouthpiece, the patient inhales through the mouth to total lung capacity and immediately exhales completely to avoid breath holding. In addition, having the subject maintain a positive mouthpiece pressure of about 10 cm H2O (but not above 20 cm H2O) during exhalation helps to close the velopharyngeal opening and further minimize nasal NO leakage.

Expiratory flow rate – Exhaled NO levels are dependent on the expiratory flow rate [39], so a constant exhalation rate of 0.050 L/second is preferred for online measurements and a rate of 0.35 L/second for offline measurements (as noted above) [37]. Acceptable methods to achieve a constant flow rate include a visual display of the target flow rate while the patient exhales against a fixed resistance, use of a dynamic resistor, and operator controlled flow rates [37]. In any case, the flow rate should be recorded with the test results.

The ambient NO level should be recorded at the time of testing, as this level can also influence the test results.

CLINICAL USE OF FENO IN ASTHMA — A large body of research has examined the potential role of FENO as a noninvasive biomarker in asthma. It has been hoped that using FENO, rather than just symptoms or airflow limitation, would help in asthma diagnosis, characterization of asthma in individual patients (eg, eosinophilic or noneosinophilic), guidance regarding selection and adjustment of asthma therapy, and advancement of our understanding of the effects of medications on airway inflammation [40-51].

Interpretation of exhaled NO in asthma — Initial studies of FENO in asthma used reference ranges to define normal and abnormal values. However, it is difficult to determine appropriate reference ranges as healthy individuals sometimes fall outside the “normal” range and individuals with asthma occasionally fall within the range [52-56].

Suggested cut-points for FENO interpretation – Rather than develop reference ranges based on the varied combinations of individual characteristics, a simpler method of using cut-points has been proposed in the American Thoracic Society Clinical Practice Guideline for interpretation of FENO [40,57], as follows:

A FENO less than 25 ppb in adults and less than 20 ppb in children younger than12 years of age implies the absence of eosinophilic airway inflammation.

A FENO greater than 50 ppb in adults or greater than 35 ppb in children suggests eosinophilic airway inflammation.

Values of FENO between 25 and 50 ppb in adults (20 to 35 ppb in children) should be interpreted cautiously with reference to the clinical situation.

A rising FENO with a greater than 20 percent change and more than 25 ppb (20 ppb in children) from a previously stable level suggests increasing eosinophilic airway inflammation, but there are wide inter-individual differences.

A decrease in FENO greater than 20 percent for values over 50 ppb or more than 10 ppb for values less than 50 ppb may be clinically important.

Once the clinical setting is taken into consideration, certain patterns begin to emerge. FENO levels above 50 ppb correlate with glucocorticoid responsiveness [58], while levels below 25 ppb may predict a lack of responsiveness to addition of inhaled glucocorticoids [59]. In a glucocorticoid naive individual with symptoms, FENO levels above 20 to 25 ppb may support the presence of asthma, while lower levels are less likely to be associated with eosinophilic airway inflammation or respond to addition of inhaled glucocorticoids [60-62].

Other factors that affect FENO – Several factors other than asthmatic inflammation, such as age, sex, height, atopy, and cigarette smoking, affect FENO values to a variable extent (table 2) [53,63,64]. The two main factors that need to be taken into consideration when interpreting FENO measurements are smoking (associated with lower FENO levels) and atopy (associated with higher FENO levels). There are no specific guidelines, however, regarding the exact adjustments to use.

Diagnosis and characterization of asthma — While FENO levels correlate with the presence of asthma and with eosinophilic airway inflammation and increase with exposure to asthma triggers, the exact role of FENO measurement in the diagnosis of asthma has not been defined [65,66]. The Global Initiative for Asthma advises against the use of FENO for the diagnosis of asthma, as it may not be elevated in noneosinophilic asthma and may be elevated in diseases other than asthma, such as eosinophilic bronchitis or allergic rhinitis [66]. The following observations have been reported:

Patients with asthma have higher concentrations of nitric oxide (NO) in their exhaled air than do nonasthmatic subjects [67,68]. In addition, exhaled NO levels rise in association with acute airway inflammation, sputum eosinophilia, viral upper respiratory infections, and other clinical parameters associated with deteriorating asthma control [68-73].

Inhalation of inflammatory stimuli, including allergens, plicatic acid (the etiologic agent of Western red cedar asthma), isocyanates, and hyperventilation of cold-dry air, increases FENO [74-78].

Levels of FENO correlate with bronchial reactivity, the number of eosinophils in induced sputum in patients with stable asthma not using glucocorticoids, and the percentage of eosinophils in bronchoalveolar lavage [79,80]. Intermediate or high FENO values are associated with asthma, wheeze, and asthma exacerbations [81].

Ongoing research should provide guidance on whether characterization of asthma phenotypes by assessment of biomarkers (eg, FENO, sputum or blood eosinophilia) will improve asthma management.

As a guide to therapy — National and international guidelines suggest using FENO levels, in addition to other assessments (eg, clinical care, questionnaires) to guide initiation and adjustment of asthma controller therapy [40,57,66]. However, usual clinical care without FENO measurement is also reasonable. Of note, guidelines caution that FENO should not be used to decide against inhaled glucocorticoid therapy in patients with a diagnosis of asthma or suspected diagnosis of asthma [66].

Predicting response to inhaled glucocorticoids – FENO levels generally predict which patients will respond to inhaled glucocorticoid therapy [42,48,82,83], but systematic reviews have found mixed evidence regarding the use of FENO to guide asthma therapy [84-88]. As an example, a systematic review (16 studies) compared trials of asthma therapy guided by FENO with those in which guidance was based on standard measures (symptoms with or without spirometry/peak flow) [87]. The analysis found that asthma management based on FENO was associated with reduced odds ratio for asthma exacerbations in adults 0.60 (95% CI 0.43-0.84) and children 0.58 (95% CI 0.45-0.75), but did not improve measures of asthma control or lung function. The review noted heterogeneity between studies in the definition of asthma exacerbations, algorithms for adjustment of medication, and cut-off values for increasing or decreasing therapy. An earlier meta-analysis noted that the rate of exacerbations was significantly reduced in a FENO-based asthma management algorithm compared with a clinically-based algorithm [14].

For centers in which FENO levels are incorporated into asthma management, the interpretation of FENO levels should consider the context in which the measurement is being obtained (eg, presence/absence of symptoms, use of glucocorticoids, change from prior values, cigarette smoking, viral infection), as described in the table (table 3) [40,57] and above. (See 'Interpretation of exhaled NO in asthma' above.)

Based on the ATS guidelines, some common clinical scenarios where FENO is helpful in the clinic include the following [40,57]:

Low FENO (<25 ppb) in adult asthmatics with persistent symptoms suggests other etiologies for these symptoms and a lower likelihood of benefit from adding or increasing inhaled glucocorticoids.

High FENO (>50 ppb) in adult asthmatics even with atypical symptoms suggests glucocorticoid responsiveness.

High FENO (>50 ppb) can help identify poor adherence or uncontrolled inflammation in asthma patients with otherwise seemingly “controlled” asthma.

In children, the cut-points for FENO are slightly different: a low FENO value is <20 ppb, and an elevated FENO value that would predict responsiveness to inhaled glucocorticoids is >35 ppb.

Although we have included established cutoff values for ease of clinical use, different cutoffs have been found useful in different populations, with the usual diagnostic tradeoffs between sensitivity and specificity [67]. Overzealous use of specific cutoff values without additional context may lead to suboptimal clinical decision-making [57].

Predicting response to biologic agents – FENO has been used in a number of clinical trials of biologic therapies for asthma to evaluate the presence of Type 2 inflammation [89-91]. In one trial of omalizumab for severe asthma, a FENO ≥19.5 ppb was associated with a greater reduction in exacerbation frequency [89], although FENO levels were not predictive of a response in a separate trial [91]. In a trial of dupilumab versus placebo, baseline FENO levels ≥50 ppb or ≥25 to <50 ppb predicted a better response to dupilumab in reducing asthma exacerbations than that achieved in patients with a FENO <25 ppb [92]. (See "Treatment of severe asthma in adolescents and adults", section on 'Persistently uncontrolled asthma'.)

Use in clinical research — Exhaled nitric oxide has an important role in clinical research and will likely help in expanding our understanding of asthma, such as the factors responsible for asthma exacerbations [81] and the sites and mechanisms of action of medications for asthma [93]. In addition, it is used to characterize the asthma phenotype of subjects in clinical trials [50]. As an example of how FENO levels might improve our understanding of asthma therapy, FENO levels, which are thought to reflect airway inflammation mediated by interleukin (IL)-4 and IL-13, appear to be a good marker for response to inhaled glucocorticoids, lebrikizumab (anti-IL-13), and omalizumab (anti-IgE), consistent with IL-4 and IL-13 mediating the effects of these agents [89,93,94]. On the other hand, FENO levels do not correlate with responses to mepolizumab (anti-IL-5), which is thought to affect systemic (rather than local airway) eosinophil production and mobilization [95]. (See "Investigational agents for asthma", section on 'Biologic agents'.)

USE IN OTHER RESPIRATORY DISEASES — Diseases other than asthma are associated with altered levels of exhaled nitric oxide (NO) [96]. The role of measuring the fractional exhaled NO (FENO) in these diseases is not established, although with further study FENO may be useful as a screening test in chronic cough due to nonasthmatic eosinophilic bronchitis.

Bronchiectasis and cystic fibrosis — Children with cystic fibrosis (CF) have lower FENO levels than appropriately matched controls [97,98]. This may be due to elevated arginase activity; arginase competes for L-arginine, the substrate of nitric oxide synthesis [99]. In contrast, one study found that patients with non-CF bronchiectasis had elevated levels of FENO, and these levels were correlated with the degree of abnormality apparent on chest CT [100]. Whether this discrepancy relates to disease activity, especially coexistent infection, is not yet clear.

Interstitial lung disease and sarcoidosis — A few studies have assessed exhaled NO values in interstitial lung disease related to scleroderma and sarcoidosis. In general, the differences in values are within the range of variability of the test. In a study of patients with scleroderma, a higher exhaled NO was noted among patients with interstitial lung disease (ILD) compared with those without ILD [101], while the opposite was found in another study [102].

Variable results have also been reported in sarcoidosis. In a study of 52 patients with sarcoidosis, the mean FENO value was 6.8 ppb, which is substantially less than the cut-point of 25 ppb used to denote asthma inflammation [103]. A separate study found a mean FENO of 6.7 ppb among patients with sarcoidosis compared with 5.17 ppb in healthy controls [104]. However, the FENO values did not correlate with disease activity [104].

Chronic obstructive pulmonary disease — FENO levels are minimally elevated in stable COPD, but may increase with more severe disease and during exacerbations [105-108]. Current smokers have approximately 70 percent lower levels of FENO [63]. In patients with COPD, FENO levels may be useful in establishing the presence of reversible airflow obstruction and determining glucocorticoid responsiveness, although this has not been assessed in large randomized trials [109].

Cough variant asthma — FENO has moderate diagnostic accuracy in predicting a diagnosis of cough variant asthma (CVA) in patients with chronic cough. In a systematic review of 13 studies (2019 patients), the optimal cut-off range for FENO was 30 to 40 ppb (although lower values were noted in two studies), and the summary area under the curve was 0.87 (95% CI, 0.83-0.89) [110]. Specificity was higher and more consistent than sensitivity (0.85 [95% CI 0.81-0.88] and 0.72 [95% CI 0.61-0.81], respectively), although heterogeneity among studies was high. The interstudy variability was attributed, at least in part, to differences in the diagnostic criteria for CVA, the type of device used to measure FENO, and variability in the requirement for a normal or near normal chest radiograph prior to study entry.

The same review assessed the ability of FENO to identify patients with CVA OR nonasthmatic eosinophilic bronchitis. Among five studies (529 patients), the sensitivity and specificity were 0.72 (95% CI 0.61-0.81) and 0.85 (95% CI 0.81-0.88) [110].

Nonasthmatic eosinophilic bronchitis — In patients with nonasthmatic eosinophilic bronchitis (NAEB), sputum eosinophils and FENO are increased in a range similar to patients with asthma [111]. In a systematic review of four studies (390 patients) in patients with chronic cough due to NAEB, optimal FENO cut-off levels were 22.5 to 31.7 ppb [110]. The estimated sensitivity was 0.72 (95% CI 0.62-0.80) and estimated specificity was 0.83 (95% CI 0.73-0.90). Thus, FENO is more useful to confirm NAEB, than to exclude it. (See "Causes and epidemiology of subacute and chronic cough in adults", section on 'Nonasthmatic eosinophilic bronchitis'.)

Upper respiratory infections — In one study of patients without underlying pulmonary disease, viral upper respiratory infections resulted in increased FENO [112]. These levels were dramatically reduced when rechecked three weeks later.

Pulmonary hypertension — NO is well-recognized as a pathophysiologic mediator in pulmonary arterial hypertension (PAH) [113,114]. In addition to vasodilation, NO regulates endothelial cell proliferation and angiogenesis, and maintains overall vascular health [115]. Interestingly, patients with PAH have low FENO values [115]. Individuals with PAH also have a lower than normal concentration of NO reaction products in the bronchoalveolar lavage fluid, which is inversely related to the degree of pulmonary hypertension [116]. Replacement of NO seems to work well in treating this disease, although PAH is a far more complex issue than the simple lack of a vasodilator [114,117]. (See "Inhaled nitric oxide in adults: Biology and indications for use".)

Therapies that target other steps in the NO pathway have revolutionized the treatment of PAH, including the widely-used phosphodiesterase type 5 (PDE5) inhibitors, which prevent the breakdown of the NO effector molecule 3’, 5’-cyclic guanosine monophosphate (cGMP), thus prolonging NO effects on tissues [117,118]. FENO seems to also have a prognostic significance, with improved survival in patients who have a rise in FENO level with therapy (calcium channel blockers, epoprostenol, treprostinil) compared to those who do not [119]. Thus, the low FENO levels in patients with PAH and the improvement with effective therapies suggest it may be a promising biomarker for this disease. More studies are needed to determine whether serial monitoring of FENO levels are clinically useful in evaluating the response (or lack of it) to medical therapy in PAH [47].

Primary ciliary dysfunction — Nasal NO is very low or absent in patients with primary ciliary dysfunction (PCD). The use of nasal NO to screen for PCD in patients with a clinical suspicion of PCD is discussed separately. (See "Primary ciliary dyskinesia (immotile-cilia syndrome)", section on 'Nasal nitric oxide'.)

Other conditions — In addition to pulmonary hypertension, other conditions associated with low FENO levels include hypothermia, and bronchopulmonary dysplasia, as well as the use of alcohol, tobacco, caffeine, and other drugs (table 3) [18,63,120-125].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pulmonary function testing".)

SUMMARY AND RECOMMENDATIONS

Role of nitric oxide in lungs – Within the respiratory system, nitric oxide (NO) regulates vascular and bronchial tone (promoting dilation of both vessels and airways), facilitates the coordinated beating of ciliated epithelial cells, and acts as an important neurotransmitter for non-adrenergic, non-cholinergic neurons. (See 'Formation of NO' above and 'Effect of NO in the airway' above.)

Measurement of exhaled NO – NO can be detected in exhaled gas by chemiluminescence and other technologies. The level of exhaled NO is expressed as the fractional exhaled NO (FENO) in parts per billion (ppb), which is equivalent to nanoliters per liter. Accurate measurement depends upon factors such as the rate of exhalation (generally 0.05 L/sec for online measurement, 0.35 L/second for offline measurement), ambient value of NO, and the accuracy of the device. (See 'Measurement of exhaled NO' above.)

Measurement of FENO is noninvasive, can be performed repeatedly, and can be used in children and patients with severe airflow obstruction where other techniques are difficult or not possible to perform. FENO may also be more sensitive in detecting eosinophilic airway inflammation than other noninvasive tests. (See 'Clinical use of FENO in asthma' above.)

FENO as biomarker – Patients with asthma generally have high levels of FENO in their exhaled breath that returns to normal after treatment with glucocorticoids. It is believed that eosinophilic inflammation in the airways stimulates airway epithelial cells to produce NO, thus making FENO a potentially useful marker to monitor airway inflammation in asthma. (See 'Formation of NO' above and 'Clinical use of FENO in asthma' above.)

A number of factors other than asthma and eosinophilic inflammation affect FENO levels, such as atopy, age, sex, height, smoking status, and medications. (See 'Interpretation of exhaled NO in asthma' above.)

Interpretation of FENO – The use of the following cut-points, rather than normative values, is suggested for the interpretation of FENO levels in asthma. (See 'Interpretation of exhaled NO in asthma' above.)

A FENO less than 25 ppb in adults and less than 20 ppb in children younger than 12 years of age implies noneosinophilic airway inflammation or the absence of airway inflammation.

A FENO greater than 50 ppb in adults or greater than 35 ppb in children suggests eosinophilic airway inflammation.

Values of FENO between 25 and 50 ppb in adults (20 to 35 ppb in children) should be interpreted cautiously with reference to the clinical situation (eg, symptomatic, on or off therapy, current smoking).

A rising FENO with a greater than 20 percent change and more than 25 ppb (20 ppb in children) from a previously stable level suggests increasing eosinophilic airway inflammation, but there are wide inter-individual differences.

A decrease in FENO greater than 20 percent for values over 50 ppb or more than 10 ppb for values less than 50 ppb may be clinically important.

FENO in other respiratory diseases – Several other diseases are associated with altered levels of exhaled NO: low levels of FENO have been noted in cystic fibrosis, current smoking, pulmonary hypertension, hypothermia, primary ciliary dyskinesia, and bronchopulmonary dysplasia. Elevated FENO has been noted in atopy, nonasthmatic eosinophilic bronchitis, COPD exacerbations, noncystic fibrosis bronchiectasis, and viral upper respiratory infections. (See 'Use in other respiratory diseases' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Aaron Deykin, MD, and Anthony Massaro, MD who contributed to earlier versions of this topic review.

  1. Belvisi MG, Ward JK, Mitchell JA, Barnes PJ. Nitric oxide as a neurotransmitter in human airways. Arch Int Pharmacodyn Ther 1995; 329:97.
  2. Jain B, Rubinstein I, Robbins RA, et al. Modulation of airway epithelial cell ciliary beat frequency by nitric oxide. Biochem Biophys Res Commun 1993; 191:83.
  3. Belvisi MG, Stretton CD, Yacoub M, Barnes PJ. Nitric oxide is the endogenous neurotransmitter of bronchodilator nerves in humans. Eur J Pharmacol 1992; 210:221.
  4. Blitzer ML, Loh E, Roddy MA, et al. Endothelium-derived nitric oxide regulates systemic and pulmonary vascular resistance during acute hypoxia in humans. J Am Coll Cardiol 1996; 28:591.
  5. Combes X, Mazmanian M, Gourlain H, Hervé P. Effect of 48 hours of nitric oxide inhalation on pulmonary vasoreactivity in rats. Am J Respir Crit Care Med 1997; 156:473.
  6. Mélot C, Vermeulen F, Maggiorini M, et al. Site of pulmonary vasodilation by inhaled nitric oxide in microembolic lung injury. Am J Respir Crit Care Med 1997; 156:75.
  7. Buga GM, Ignarro LJ. Electrical field stimulation causes endothelium-dependent and nitric oxide-mediated relaxation of pulmonary artery. Am J Physiol 1992; 262:H973.
  8. Que LG, Yang Z, Stamler JS, et al. S-nitrosoglutathione reductase: an important regulator in human asthma. Am J Respir Crit Care Med 2009; 180:226.
  9. Marletta MA. Nitric oxide synthase: aspects concerning structure and catalysis. Cell 1994; 78:927.
  10. Nathan C, Xie QW. Nitric oxide synthases: roles, tolls, and controls. Cell 1994; 78:915.
  11. Gaston B, Drazen JM, Loscalzo J, Stamler JS. The biology of nitrogen oxides in the airways. Am J Respir Crit Care Med 1994; 149:538.
  12. Guo FH, De Raeve HR, Rice TW, et al. Continuous nitric oxide synthesis by inducible nitric oxide synthase in normal human airway epithelium in vivo. Proc Natl Acad Sci U S A 1995; 92:7809.
  13. Guo FH, Uetani K, Haque SJ, et al. Interferon gamma and interleukin 4 stimulate prolonged expression of inducible nitric oxide synthase in human airway epithelium through synthesis of soluble mediators. J Clin Invest 1997; 100:829.
  14. Donohue JF, Jain N. Exhaled nitric oxide to predict corticosteroid responsiveness and reduce asthma exacerbation rates. Respir Med 2013; 107:943.
  15. Radomski MW, Palmer RM, Moncada S. Glucocorticoids inhibit the expression of an inducible, but not the constitutive, nitric oxide synthase in vascular endothelial cells. Proc Natl Acad Sci U S A 1990; 87:10043.
  16. Asano K, Chee CB, Gaston B, et al. Constitutive and inducible nitric oxide synthase gene expression, regulation, and activity in human lung epithelial cells. Proc Natl Acad Sci U S A 1994; 91:10089.
  17. Kobzik L, Bredt DS, Lowenstein CJ, et al. Nitric oxide synthase in human and rat lung: immunocytochemical and histochemical localization. Am J Respir Cell Mol Biol 1993; 9:371.
  18. Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995; 333:214.
  19. Lundberg JO, Weitzberg E, Nordvall SL, et al. Primarily nasal origin of exhaled nitric oxide and absence in Kartagener's syndrome. Eur Respir J 1994; 7:1501.
  20. Lundberg JO, Weitzberg E, Rinder J, et al. Calcium-independent and steroid-resistant nitric oxide synthase activity in human paranasal sinus mucosa. Eur Respir J 1996; 9:1344.
  21. Lundberg JO, Rinder J, Weitzberg F, et al. Heavy physical exercise decreases nitric oxide levels in the nasal airways in humans. Acta Physiol Scand 1997; 159:51.
  22. Massaro AF, Mehta S, Lilly CM, et al. Elevated nitric oxide concentrations in isolated lower airway gas of asthmatic subjects. Am J Respir Crit Care Med 1996; 153:1510.
  23. Dweik RA, Comhair SA, Gaston B, et al. NO chemical events in the human airway during the immediate and late antigen-induced asthmatic response. Proc Natl Acad Sci U S A 2001; 98:2622.
  24. Dweik RA, et al. Nitric oxide production in the lungs and its regulation by oxygen. In: Disease Markers in Exhaled Breath: basic mechanisms and clinical applications (NATO Science Series), Marczin N, Yacoub MH (Eds), IOS press, Amsterdam, Netherlands 2002. p.11-17.
  25. Hyde RW, Geigel EJ, Olszowka AJ, et al. Determination of production of nitric oxide by lower airways of humans--theory. J Appl Physiol (1985) 1997; 82:1290.
  26. Paraskakis E, Brindicci C, Fleming L, et al. Measurement of bronchial and alveolar nitric oxide production in normal children and children with asthma. Am J Respir Crit Care Med 2006; 174:260.
  27. Persson MG, Zetterström O, Agrenius V, et al. Single-breath nitric oxide measurements in asthmatic patients and smokers. Lancet 1994; 343:146.
  28. Kharitonov SA, Yates D, Robbins RA, et al. Increased nitric oxide in exhaled air of asthmatic patients. Lancet 1994; 343:133.
  29. Sanders SP. Nitric oxide in asthma. Pathogenic, therapeutic, or diagnostic? Am J Respir Cell Mol Biol 1999; 21:147.
  30. Raychaudhuri B, Dweik R, Connors MJ, et al. Nitric oxide blocks nuclear factor-kappaB activation in alveolar macrophages. Am J Respir Cell Mol Biol 1999; 21:311.
  31. van der Vliet A, Eiserich JP, Shigenaga MK, Cross CE. Reactive nitrogen species and tyrosine nitration in the respiratory tract: epiphenomena or a pathobiologic mechanism of disease? Am J Respir Crit Care Med 1999; 160:1.
  32. Ghosh S, Erzurum SC. Nitric oxide metabolism in asthma pathophysiology. Biochim Biophys Acta 2011; 1810:1008.
  33. Gustafsson LE, Leone AM, Persson MG, et al. Endogenous nitric oxide is present in the exhaled air of rabbits, guinea pigs and humans. Biochem Biophys Res Commun 1991; 181:852.
  34. Silkoff PE, Carlson M, Bourke T, et al. The Aerocrine exhaled nitric oxide monitoring system NIOX is cleared by the US Food and Drug Administration for monitoring therapy in asthma. J Allergy Clin Immunol 2004; 114:1241.
  35. Gill M, Graff GR, Adler AJ, Dweik RA. Validation study of fractional exhaled nitric oxide measurements using a handheld monitoring device. J Asthma 2006; 43:731.
  36. Horváth I, Barnes PJ, Loukides S, et al. A European Respiratory Society technical standard: exhaled biomarkers in lung disease. Eur Respir J 2017; 49.
  37. American Thoracic Society, European Respiratory Society. ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med 2005; 171:912.
  38. Baraldi E, Carrá S, Dario C, et al. Effect of natural grass pollen exposure on exhaled nitric oxide in asthmatic children. Am J Respir Crit Care Med 1999; 159:262.
  39. Silkoff PE, McClean PA, Slutsky AS, et al. Marked flow-dependence of exhaled nitric oxide using a new technique to exclude nasal nitric oxide. Am J Respir Crit Care Med 1997; 155:260.
  40. Dweik RA, Boggs PB, Erzurum SC, et al. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med 2011; 184:602.
  41. Berkman N, Avital A, Breuer R, et al. Exhaled nitric oxide in the diagnosis of asthma: comparison with bronchial provocation tests. Thorax 2005; 60:383.
  42. Pijnenburg MW, Hofhuis W, Hop WC, De Jongste JC. Exhaled nitric oxide predicts asthma relapse in children with clinical asthma remission. Thorax 2005; 60:215.
  43. Michils A, Baldassarre S, Van Muylem A. Exhaled nitric oxide and asthma control: a longitudinal study in unselected patients. Eur Respir J 2008; 31:539.
  44. Pavord ID, Shaw D. The use of exhaled nitric oxide in the management of asthma. J Asthma 2008; 45:523.
  45. Sivan Y, Gadish T, Fireman E, Soferman R. The use of exhaled nitric oxide in the diagnosis of asthma in school children. J Pediatr 2009; 155:211.
  46. Guida G, Rolla G, Badiu I, et al. Determinants of exhaled nitric oxide in chronic rhinosinusitis. Chest 2010; 137:658.
  47. Barnes PJ, Dweik RA, Gelb AF, et al. Exhaled nitric oxide in pulmonary diseases: a comprehensive review. Chest 2010; 138:682.
  48. Sippel JM, Holden WE, Tilles SA, et al. Exhaled nitric oxide levels correlate with measures of disease control in asthma. J Allergy Clin Immunol 2000; 106:645.
  49. Bates CA, Silkoff PE. Exhaled nitric oxide in asthma: from bench to bedside. J Allergy Clin Immunol 2003; 111:256.
  50. Szefler SJ, Wenzel S, Brown R, et al. Asthma outcomes: biomarkers. J Allergy Clin Immunol 2012; 129:S9.
  51. Agency for Healthcare Research and Quality: Effective Healthcare Program. The clinical utility of fractional exhaled nitric oxide (FeNO) in asthma management. https://effectivehealthcare.ahrq.gov/sites/default/files/evidence-summary-cer-197-fractional-exhaled-nitric-oxide_0.pdf (Accessed on January 05, 2018).
  52. Smith AD, Cowan JO, Taylor DR. Exhaled nitric oxide levels in asthma: Personal best versus reference values. J Allergy Clin Immunol 2009; 124:714.
  53. Travers J, Marsh S, Aldington S, et al. Reference ranges for exhaled nitric oxide derived from a random community survey of adults. Am J Respir Crit Care Med 2007; 176:238.
  54. Michils A, Louis R, Peché R, et al. Exhaled nitric oxide as a marker of asthma control in smoking patients. Eur Respir J 2009; 33:1295.
  55. Scott M, Raza A, Karmaus W, et al. Influence of atopy and asthma on exhaled nitric oxide in an unselected birth cohort study. Thorax 2010; 65:258.
  56. Gelb AF, George SC, Camacho F, et al. Increased nitric oxide concentrations in the small airway of older normal subjects. Chest 2011; 139:368.
  57. Khatri SB, Iaccarino JM, Barochia A, et al. Use of Fractional Exhaled Nitric Oxide to Guide the Treatment of Asthma: An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med 2021; 204:e97.
  58. Smith AD, Cowan JO, Brassett KP, et al. Exhaled nitric oxide: a predictor of steroid response. Am J Respir Crit Care Med 2005; 172:453.
  59. Smith AD, Cowan JO, Brassett KP, et al. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med 2005; 352:2163.
  60. Smith AD, Cowan JO, Filsell S, et al. Diagnosing asthma: comparisons between exhaled nitric oxide measurements and conventional tests. Am J Respir Crit Care Med 2004; 169:473.
  61. Berry MA, Shaw DE, Green RH, et al. The use of exhaled nitric oxide concentration to identify eosinophilic airway inflammation: an observational study in adults with asthma. Clin Exp Allergy 2005; 35:1175.
  62. Dupont LJ, Demedts MG, Verleden GM. Prospective evaluation of the validity of exhaled nitric oxide for the diagnosis of asthma. Chest 2003; 123:751.
  63. Olin AC, Rosengren A, Thelle DS, et al. Height, age, and atopy are associated with fraction of exhaled nitric oxide in a large adult general population sample. Chest 2006; 130:1319.
  64. Collaro AJ, Chang AB, Marchant JM, et al. Developing Fractional Exhaled Nitric Oxide Predicted and Upper Limit of Normal Values for a Disadvantaged Population. Chest 2023; 163:624.
  65. Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC), Cloutier MM, Baptist AP, et al. 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol 2020; 146:1217.
  66. Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention. www.ginasthma.org (Accessed on August 10, 2022).
  67. Wang Z, Pianosi PT, Keogh KA, et al. The Diagnostic Accuracy of Fractional Exhaled Nitric Oxide Testing in Asthma: A Systematic Review and Meta-analyses. Mayo Clin Proc 2018; 93:191.
  68. Massaro AF, Gaston B, Kita D, et al. Expired nitric oxide levels during treatment of acute asthma. Am J Respir Crit Care Med 1995; 152:800.
  69. Strunk RC, Szefler SJ, Phillips BR, et al. Relationship of exhaled nitric oxide to clinical and inflammatory markers of persistent asthma in children. J Allergy Clin Immunol 2003; 112:883.
  70. Kharitonov SA, Yates DH, Barnes PJ. Inhaled glucocorticoids decrease nitric oxide in exhaled air of asthmatic patients. Am J Respir Crit Care Med 1996; 153:454.
  71. Sandrini A, Ferreira IM, Gutierrez C, et al. Effect of montelukast on exhaled nitric oxide and nonvolatile markers of inflammation in mild asthma. Chest 2003; 124:1334.
  72. Tsujino I, Nishimura M, Kamachi A, et al. Exhaled nitric oxide--is it really a good marker of airway inflammation in bronchial asthma? Respiration 2000; 67:645.
  73. Dweik RA, Sorkness RL, Wenzel S, et al. Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma. Am J Respir Crit Care Med 2010; 181:1033.
  74. Kharitonov SA, O'Connor BJ, Evans DJ, Barnes PJ. Allergen-induced late asthmatic reactions are associated with elevation of exhaled nitric oxide. Am J Respir Crit Care Med 1995; 151:1894.
  75. Deykin A, Halpern O, Massaro AF, et al. Expired nitric oxide after bronchoprovocation and repeated spirometry in patients with asthma. Am J Respir Crit Care Med 1998; 157:769.
  76. Obata H, Dittrick M, Chan H, Chan-Yeung M. Sputum eosinophils and exhaled nitric oxide during late asthmatic reaction in patients with western red cedar asthma. Eur Respir J 1999; 13:489.
  77. Ferrazzoni S, Scarpa MC, Guarnieri G, et al. Exhaled nitric oxide and breath condensate ph in asthmatic reactions induced by isocyanates. Chest 2009; 136:155.
  78. Jackson DJ, Virnig CM, Gangnon RE, et al. Fractional exhaled nitric oxide measurements are most closely associated with allergic sensitization in school-age children. J Allergy Clin Immunol 2009; 124:949.
  79. Jatakanon A, Lim S, Kharitonov SA, et al. Correlation between exhaled nitric oxide, sputum eosinophils, and methacholine responsiveness in patients with mild asthma. Thorax 1998; 53:91.
  80. Warke TJ, Fitch PS, Brown V, et al. Exhaled nitric oxide correlates with airway eosinophils in childhood asthma. Thorax 2002; 57:383.
  81. Malinovschi A, Fonseca JA, Jacinto T, et al. Exhaled nitric oxide levels and blood eosinophil counts independently associate with wheeze and asthma events in National Health and Nutrition Examination Survey subjects. J Allergy Clin Immunol 2013; 132:821.
  82. Jones SL, Kittelson J, Cowan JO, et al. The predictive value of exhaled nitric oxide measurements in assessing changes in asthma control. Am J Respir Crit Care Med 2001; 164:738.
  83. Cowan DC, Taylor DR, Peterson LE, et al. Biomarker-based asthma phenotypes of corticosteroid response. J Allergy Clin Immunol 2015; 135:877.
  84. Szefler SJ, Mitchell H, Sorkness CA, et al. Management of asthma based on exhaled nitric oxide in addition to guideline-based treatment for inner-city adolescents and young adults: a randomised controlled trial. Lancet 2008; 372:1065.
  85. Calhoun WJ, Ameredes BT, King TS, et al. Comparison of physician-, biomarker-, and symptom-based strategies for adjustment of inhaled corticosteroid therapy in adults with asthma: the BASALT randomized controlled trial. JAMA 2012; 308:987.
  86. Essat M, Harnan S, Gomersall T, et al. Fractional exhaled nitric oxide for the management of asthma in adults: a systematic review. Eur Respir J 2016; 47:751.
  87. Petsky HL, Cates CJ, Kew KM, Chang AB. Tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils): a systematic review and meta-analysis. Thorax 2018; 73:1110.
  88. Agency for Healthcare Reseach and Quality (AHQR). The Clinical Utility of Fractional Exhaled Nitric Oxide (FeNO) in Asthma Management. https://effectivehealthcare.ahrq.gov/products/asthma-nitric-oxide/research (Accessed on February 16, 2022).
  89. Hanania NA, Wenzel S, Rosén K, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med 2013; 187:804.
  90. Menzies-Gow A, Mansur AH, Brightling CE. Clinical utility of fractional exhaled nitric oxide in severe asthma management. Eur Respir J 2020; 55.
  91. Casale TB, Luskin AT, Busse W, et al. Omalizumab Effectiveness by Biomarker Status in Patients with Asthma: Evidence From PROSPERO, A Prospective Real-World Study. J Allergy Clin Immunol Pract 2019; 7:156.
  92. Castro M, Corren J, Pavord ID, et al. Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma. N Engl J Med 2018; 378:2486.
  93. Pavord ID, Bafadhel M. Exhaled nitric oxide and blood eosinophilia: independent markers of preventable risk. J Allergy Clin Immunol 2013; 132:828.
  94. Noonan M, Korenblat P, Mosesova S, et al. Dose-ranging study of lebrikizumab in asthmatic patients not receiving inhaled steroids. J Allergy Clin Immunol 2013; 132:567.
  95. Nair P, Kjarsgaard M, Armstrong S, et al. Nitric oxide in exhaled breath is poorly correlated to sputum eosinophils in patients with prednisone-dependent asthma. J Allergy Clin Immunol 2010; 126:404.
  96. Kharitonov SA, Barnes PJ. Exhaled markers of pulmonary disease. Am J Respir Crit Care Med 2001; 163:1693.
  97. Grasemann H, Michler E, Wallot M, Ratjen F. Decreased concentration of exhaled nitric oxide (NO) in patients with cystic fibrosis. Pediatr Pulmonol 1997; 24:173.
  98. Ojoo JC, Mulrennan SA, Kastelik JA, et al. Exhaled breath condensate pH and exhaled nitric oxide in allergic asthma and in cystic fibrosis. Thorax 2005; 60:22.
  99. Grasemann H, Schwiertz R, Matthiesen S, et al. Increased arginase activity in cystic fibrosis airways. Am J Respir Crit Care Med 2005; 172:1523.
  100. Kharitonov SA, Wells AU, O'Connor BJ, et al. Elevated levels of exhaled nitric oxide in bronchiectasis. Am J Respir Crit Care Med 1995; 151:1889.
  101. Tiev KP, Coste J, Ziani M, et al. Diagnostic value of exhaled nitric oxide to detect interstitial lung disease in systemic sclerosis. Sarcoidosis Vasc Diffuse Lung Dis 2009; 26:32.
  102. Malerba M, Radaeli A, Ragnoli B, et al. Exhaled nitric oxide levels in systemic sclerosis with and without pulmonary involvement. Chest 2007; 132:575.
  103. Wilsher ML, Fergusson W, Milne D, Wells AU. Exhaled nitric oxide in sarcoidosis. Thorax 2005; 60:967.
  104. Ziora D, Kaluska K, Kozielski J. An increase in exhaled nitric oxide is not associated with activity in pulmonary sarcoidosis. Eur Respir J 2004; 24:609.
  105. Maziak W, Loukides S, Culpitt S, et al. Exhaled nitric oxide in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157:998.
  106. Rutgers SR, van der Mark TW, Coers W, et al. Markers of nitric oxide metabolism in sputum and exhaled air are not increased in chronic obstructive pulmonary disease. Thorax 1999; 54:576.
  107. Ansarin K, Chatkin JM, Ferreira IM, et al. Exhaled nitric oxide in chronic obstructive pulmonary disease: relationship to pulmonary function. Eur Respir J 2001; 17:934.
  108. Brindicci C, Ito K, Resta O, et al. Exhaled nitric oxide from lung periphery is increased in COPD. Eur Respir J 2005; 26:52.
  109. Papi A, Romagnoli M, Baraldo S, et al. Partial reversibility of airflow limitation and increased exhaled NO and sputum eosinophilia in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000; 162:1773.
  110. Song WJ, Kim HJ, Shim JS, et al. Diagnostic accuracy of fractional exhaled nitric oxide measurement in predicting cough-variant asthma and eosinophilic bronchitis in adults with chronic cough: A systematic review and meta-analysis. J Allergy Clin Immunol 2017; 140:701.
  111. Oh MJ, Lee JY, Lee BJ, Choi DC. Exhaled nitric oxide measurement is useful for the exclusion of nonasthmatic eosinophilic bronchitis in patients with chronic cough. Chest 2008; 134:990.
  112. Kharitonov SA, Yates D, Barnes PJ. Increased nitric oxide in exhaled air of normal human subjects with upper respiratory tract infections. Eur Respir J 1995; 8:295.
  113. Archer S, Rich S. Primary pulmonary hypertension: a vascular biology and translational research "Work in progress". Circulation 2000; 102:2781.
  114. Dweik RA. Pulmonary hypertension and the search for the selective pulmonary vasodilator. Lancet 2002; 360:886.
  115. Kaneko FT, Arroliga AC, Dweik RA, et al. Biochemical reaction products of nitric oxide as quantitative markers of primary pulmonary hypertension. Am J Respir Crit Care Med 1998; 158:917.
  116. Dweik RA. The lung in the balance: arginine, methylated arginines, and nitric oxide. Am J Physiol Lung Cell Mol Physiol 2007; 292:L15.
  117. Ozkan M, Dweik RA, Laskowski D, et al. High levels of nitric oxide in individuals with pulmonary hypertension receiving epoprostenol therapy. Lung 2001; 179:233.
  118. Girgis RE, Frost AE, Hill NS, et al. Selective endothelin A receptor antagonism with sitaxsentan for pulmonary arterial hypertension associated with connective tissue disease. Ann Rheum Dis 2007; 66:1467.
  119. Machado RF, Londhe Nerkar MV, Dweik RA, et al. Nitric oxide and pulmonary arterial pressures in pulmonary hypertension. Free Radic Biol Med 2004; 37:1010.
  120. Girgis RE, Champion HC, Diette GB, et al. Decreased exhaled nitric oxide in pulmonary arterial hypertension: response to bosentan therapy. Am J Respir Crit Care Med 2005; 172:352.
  121. Corbelli R, Bringolf-Isler B, Amacher A, et al. Nasal nitric oxide measurements to screen children for primary ciliary dyskinesia. Chest 2004; 126:1054.
  122. Kharitonov SA, Robbins RA, Yates D, et al. Acute and chronic effects of cigarette smoking on exhaled nitric oxide. Am J Respir Crit Care Med 1995; 152:609.
  123. Bruce C, Yates DH, Thomas PS. Caffeine decreases exhaled nitric oxide. Thorax 2002; 57:361.
  124. Baraldi E, Bonetto G, Zacchello F, Filippone M. Low exhaled nitric oxide in school-age children with bronchopulmonary dysplasia and airflow limitation. Am J Respir Crit Care Med 2005; 171:68.
  125. Afshar M, Poole JA, Cao G, et al. Exhaled Nitric Oxide Levels Among Adults With Excessive Alcohol Consumption. Chest 2016; 150:196.
Topic 542 Version 32.0

References

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