Investigating Fractional Exhaled Nitric Oxide in Chronic Obstructive Pulmonary Disease (COPD) and Asthma-COPD Overlap (ACO): A Scoping Review

Figures & data

Table 1. Themes, research questions, and the number of studies those were able to answer the related questions.

No.	Theme title	Research questions	Number of studies (%)
1	Factors modifying FENO Measurement	Which factors have been demonstrated to modify the level of FENO in COPD patients?	24 (63.15)
2	FENO in COPD or in COPD compared with Healthy Subjects	Does the FENO level increase in patients with COPD and is there an optimal cut-off value that may be useful in COPD versus healthy subjects?	18 (47.36)
3	FENO and Asthma-COPD Overlap (ACO)	Are there differences in FENO levels between patients with asthma COPD overlap (ACO), i.e., with asthma features and patients with COPD-only?	7 (18.42)
4	FENO and disease severity and/or progression	Are FENO values associated with disease severity and/or disease progression in patients with COPD?	22 (57.89)
5	FENO and Inflammatory Biomarkers	Are FENO values associated with changes in the level of inflammatory biomarkers such as blood/sputum eosinophils and/or IgE in patients with COPD?	12 (31.57)
6	FENO and Treatment Response	Whether increased or decreased FENO level has an influence on treatment response, especially ICS/GCS therapy with or without inhaled bronchodilators in patients with COPD.	8 (21.05)

F_ENO: fractional exhaled nitric oxide; COPD: chronic obstructive pulmonary disease; ACO: asthma-COPD overlap; IgE: immunoglobulin E; ICS: inhaled corticosteroid; GCS: glucocorticoid.

Figure 1. PRISMA flow diagram.

Table 2. Factors modifying fractional exhaled nitric oxide measurement^a.

References	Decreased	Increased	No effect/association	Comments
Bhowmik et al. (41)	Smoking	Cold weather/viral infection, exacerbation	ICS/LABA	Current COPD smokers versus ex-smokers Increased FENO in cold weather (October to December) could be due to viral infections.
Liu et al. (48)	–	–	Smoking, GCS	Smoking was reported in both COPD and healthy subjects; FENO
de Laurentiis et al. (42)	Smoking	–	–	Current COPD smokers versus ex–smokers, FENO50
Kunisaki et al. (50)	ICS	–	–	ICS therapy to COPD patients was prescribed for 4 weeks, FENO50
Roy et al. (44)	Smoking, Sex (female)	–	–	COPD smoker versus COPD ex-smoker, COPD women versus COPD men, FENO50
Dummer et al. (49)	GCS	–	–	Oral prednisone was prescribed for 3 weeks. Current smokers were excluded; FENO50
Antus et al. (39)	Smoking, GCS	–	Sex (male or female)	Exacerbated COPD smokers versus ex-smokers Systemic (IV or oral) corticosteroids were prescribed in all exacerbated patients in the hospital. Tend to have decreased FENO50 with GCS therapy at discharge.
Lehouck et al. (43)	Smoking	–	ICS, Age	Current smokers in both COPD patients and healthy controls. Prescribed ICS (39% of COPD patients) among different GOLD stages (I-IV); FENO50
Tilemann et al. (45)	Smoking	–	–	Current COPD smokers versus non-smokers (never smokers and ex-smokers), FENO50
Rouhos et al. (57)	Sodium bicarbonate	–	–	Both COPD and healthy subjects whom were prescribed sodium bicarbonate to rinse their mouth; FENO50
Bazeghi et al. (40)	Smoking	–	–	Current COPD smokers versus ex-smokers, FENO50
Akamatsu et al. (54)	ICS/LABA	–	–	ICS was prescribed twice daily for 12 weeks; FENO50
Antus et al. (52)	–	–	GCS, LABA, LAMA	Exacerbated COPD patients were prescribed systemic (IV or oral) corticosteroids and bronchodilators during hospital stay. No difference between low (<27 ppb) and high FENO50 (≥ 27 ppb) regarding GCS and bronchodilator therapy.
Xia et al. (58)	–	Smoking, exacerbation	–	Current COPD smoker versus non-smoker Exacerbation effect was considered in mixed group of subjects including healthy, stable COPD, asthma and non-asthma; FENO50
Rawy et al. (59)	Age	–	–	Negative association between FENO50 and age
Ishiura et al. (74)	–	–	ICS/LABA	ACO patients were prescribed ICS/LABA for 12 weeks; FENO50
Santini et al. (46)	Smoking	–	ICS	COPD current smokers versus COPD ex-smokers No difference in FENO50 values between COPD patients on ICS therapy and those not on ICS therapy.
Logotheti et al. (51)	ICS	Older age, exacerbation	–	COPD patients were prescribed an inhaled corticosteroid (ICS) for maintenance treatment. Older COPD patients (69 ± 6 years) versus younger patients (66 ± 7 years). A significant increase in exacerbations during previous year in COPD patients with elevated FENO50 levels.
Amer et al. (72)	–	Bronchodilator	–	FENO50 was measured before and 15 minutes after short inhaled bronchodilator therapy.
Ji et al. (55)	ICS/LABA	–	–	ACO patients were prescribed ICS/LABA for maintenance treatment; FENO50
Huang et al. (56)	6MWT (exercise)	–	–	FENO50 was measured after exercise test in COPD patients.
Kobayashi et al. (53)	–	–	ICS	ACO patients with prescribed ICS versus non-ACO with prescribed ICS, FENO50
Feng et al. (3)	ICS	–	–	COPD patients were prescribed ICS, 3 times per day for 6 months. FENO50 was measured before and after ICS therapy.
Zhao et al. (71)	–	–	Bronchodilator	FENO50 was measured before and 15 minutes after inhaled short-acting bronchodilator.

F_ENO: fractional exhaled nitric oxide; ICS: inhaled corticosteroid; LABA: long-acting beta agonist; GCS: glucocorticosteroid; COPD: chronic obstructive pulmonary disease; IV: intravenous; ppb: parts per billion; GOLD: Global Initiative for Chronic Obstructive Lung Disease; ACO: asthma-COPD overlap; 6MWT: 6-minute walk test.

^a– = Not mentioned, for expressing the F_ENO, the exhalation flow rate (if indicated) was given as a subscript in mL·s⁻¹. For instance, a flow rate of 50 mL·s⁻¹ was written F_ENO50. If there was no direct or indirect evidence regarding the flow rate (mL·s⁻¹), we only used F_ENO.

Table 3. Fractional exhaled nitric oxide in COPD or in COPD compared with healthy and in ACO compared with COPD subjects^a.

COPD compared with healthy
References	InCOPD or compared with healthy^b	Optimal cut-off value^c	Comments
Foschino Barbaro et al. (61)	Increase	–	COPD patients compared with healthy control subjects and reversible COPD compared with non-reversible COPD, FENO45
Liu et al. (48)	Increase	–	COPD patients compared with healthy subjects, FENO
de Laurentiis et al. (42)	Increase	–	COPD patients compared with healthy subjects: Not significant baseline mean level of FENO50 but significant FENO50 mean coefficient of variability (CoV).
Beg et al. (60)	Increase	–	COPD patients compared with healthy subjects, FENO50
Lehouck et al. (43)	–	–	COPD patients compared with age-matched healthy control subjects, FENO50
Tilemann et al. (45)	Decrease	–	COPD patients compared with subjects with no airway obstruction, FENO50
Rouhos et al. (57)	Increase	–	COPD patients compared with healthy subjects, FENO50
Bazeghi et al. (40)	–	–	COPD patients only (severe emphysema, chronic bronchitis, frequent exacerbations, low body mass), FENO50
Donohue et al. (28)	Increase	–	COPD patients with different phenotypes, especially those with concomitant asthmas, FENO50
Xia et al. (58)	Increase	–	COPD patients compared with healthy subjects and also exacerbated COPD compared with stable COPD. No association in FENO50 levels between stable COPD and healthy subjects
Durmaz et al. (63)^f	–	–	COPD patients at admission (exacerbation) or before discharge, FnNO5
Santini et al. (46)	Increase	–	COPD ex-smoker compared with healthy ex-smoker, FENO50
Arif et al. (62)	–	–	COPD patients, FENO50
Alcazar-Navarrete et al. (25)	Increase	–	COPD patients compared with non-smoker healthy controls, FENO50
Logotheti et al. (51)	Increase	–	COPD patients with GOLD stages (ABCD), FENO50
Ji et al. (55)	Increase	–	ACO patients compared with healthy subjects, both before and after treatment (ICS/LABA), FENO50
Huang et al. (56)	Increase	–	COPD patients compared with healthy subjects, FENO50
Feng et al. (3)	Increase	–	ACO patients compared with healthy subjects, FENO50
ACO compared with COPD
References	In ACO compared with COPD^d	Optimal cut-off value^e	Comments
Tamada et al. (27)	Increase	–	Higher FENO50 values in COPD with asthma-like airway inflammation (ACO) among COPD patients
Alcazar-Navarrete et al. (25)	Increase	19 ppb	Higher FENO50 values in ACO patients than those with other COPD phenotypes
Chen et al. (4)	Increase	22.5 ppb	Higher levels of FENO50 in ACO group than COPD group
Goto et al. (65)	Increase	–	Higher levels of FENO50 in ACO than those with COPD alone
Kobayashi et al. (53)	Increase	23 ppb	Higher FENO50 levels in ACO than non-ACO (among COPD patients).
Deng et al. (64)	Increase	29 ppb	Higher levels of FENO50 in ACO than COPD patients
Cosío et al. (67)	Increase	–	Higher levels of FENO50 in ACO than COPD patients

F_ENO: fractional exhaled nitric oxide; COPD: chronic obstructive pulmonary disease; ACO: asthma-COPD overlap; F_nNO: fractional concentration of nasally aspirated/exhaled nitric oxide; CoV: coefficient of variability; FEV1: forced expiratory volume in one second; ICS: inhaled corticosteroid; LABA: long-acting beta agonist; ppb: parts per billion; GOLD: Global Initiative for Chronic Obstructive Lung Disease

^aFor expressing the F_ENO, the exhalation flow rate (if indicated) was given as a subscript in mL·s⁻¹. For instance, a flow rate of 50 mL·s⁻¹ was written F_ENO50. If there was no direct or indirect evidence regarding the flow rate (mL·s⁻¹), we only used F_ENO.

^b In COPD compared with healthy: – = no difference/change.

^cOptimal cutoff value: – = not mentioned.

^dACO definition is different among the studies using major and minor criteria (25, 65) or either Global Initiative for Asthma (GINA)/Global Initiative for Chronic Obstructive Lung Diseases (GOLD) joint document 2014 (64) or 2015 (updated document) (53) or positive bronchodilator test and history of asthma (4) or history of asthma and smoking (≥ 20 pack-years) and chronic airflow limitation or diagnosed COPD and elevated blood eosinophil count (67) or high levels of fractional exhaled nitric oxide (F_ENO50 > 35 ppb) or immunoglobulin E (IgE ≥173 IU/mL) in diagnosed COPD (27). Details are available in the Supplementary file (Table S1).

^eOptimal cutoff value: – = not mentioned.

^fThe flow rate of the nasally exhaled/aspirated nitric oxide (F_nNO) was given as a subscript in mL·s⁻¹ (F_nNO5).

Table 4. Fractional exhaled nitric oxide and disease severity and/or progression^a.

References	Association			Comments^b
	Disease severity		Disease progression
	GOLD	Exacerbations	Pulmonary Function Tests
Bhowmik et al. (41)	–	N	N	No association between FENO and FEV1, FVC or exacerbation frequency
de Laurentiis et al. (42)	–	Y	N	No association between FENO50 and FEV1; exacerbation rate was significantly associated with FENO50
Kunisaki et al. (50)	–	–	N	No association between FENO50 and FEV1 or FVC
Beg et al. (60)	–	–	Y	Negative association between FENO50 and FEV1/FVC ratio
Dummer et al. (49)	–	–	N	No association between FENO50 and FEV1
Antus et al. (39)	–	–	Y/N	Positive association between FENO50 levels at admission (acute exacerbation) and the post-treatment increase in FEV1 and FEV1% predicted No association with FVC
Lehouck et al. (43)	N	–	N	No association between FENO50 and GOLD stages (I–IV) No association with FEV1
Akamatsu et al. (54)	–	–	N	No association between FENO50 and changes in FEV1 as well as other pulmonary physiological parameters
Antus et al. (52)	–	Y	–	Association between low FENO50 level and more exacerbations (increased number of exacerbation per patient-year) during the follow-up
Donohue et al. (28)	N	–	–	No association between FENO50 levels and GOLD stages (I–IV)
Xia et al. (58)	–	Y	N	Association between elevated FENO50 and acute exacerbations (compared with stable COPD) No association with FEV1 and FEV1/FVC
Tamada et al. (27)	N	–	N	No association between high and low FENO50 levels with GOLD stages (I–IV) No association between low (≤ 35 ppb) and high FENO50 (> 35 ppb) levels with pulmonary function tests (FVC, FEV1, and FEV1/FVC)
Rawy et al. (59)	–	–	N	No association between FENO50 and FEV1/FVC
Durmaz et al. (63)^c	–	N	–	No association between FnNO5 level at presentation or before discharge and exacerbated patients
Arif et al. (62)	N	–	–	No association between FENO50 and GOLD stages (I–IV)
Alcazar-Navarrete et al. (25)	N	–	–	No association between FENO50 and GOLD 2011 (ABCD)
Logotheti et al. (51)	Y	Y	–	Association between FENO50 and GOLD 2011 (ABCD). Association with the increase in a number of exacerbations
Chen et al. (4)	N	–	–	No association between FENO50 and GOLD stages (I–IV)
Ji et al. (55)	–	–	N	No association between FENO50 and FEV1% predicted in ACO
Huang et al. (56)	–	–	N	No association between FENO50 and FEV1% predicted or the FEV1 change secondary to 6MWT
Feng et al. (3)	–	–	Y	Negative association between FENO50 levels with FEV1% predicted and FEV1/FVC in ACO patients
Deng et al. (64)	–	–	N	No association between FENO50 with FEV1% predicted and FEV1/FVC in COPD and ACO

GOLD: Global Initiative for Chronic Obstructive Lung Disease; F_ENO: fractional exhaled nitric oxide; FEV1: forced expiratory volume in first second; FVC: forced vital capacity; COPD: chronic obstructive pulmonary disease; F_nNO: fractional concentration of nasally aspirated/exhaled nitric oxide; 6MWT: 6-minute walk test; ACO: asthma-COPD overlap.

^aDisease severity and progression: Y = Yes, N = No, – = Not mentioned, for expressing the F_ENO, the exhalation flow rate (if indicated) was given as a subscript in mL·s⁻¹. For instance, a flow rate of 50 mL·s⁻¹ was written F_ENO50. If there was no direct or indirect evidence regarding the flow rate (mL·s⁻¹), we only used F_ENO.

^bSubjects are COPD patients unless stated otherwise

^cThe flow rate of the nasally exhaled/aspirated nitric oxide (F_nNO) was given as a subscript in mL·s⁻¹ (F_nNO5).

Table 5. Fractional exhaled nitric oxide and inflammatory biomarkers^a.

References	Association			Optimal cut-off value	Comments^d
	Sputum eosinophils^b	Blood eosinophil^c	Serum IgE
Foschino Barbaro et al. (61)	Y	–	–	–	COPD patients with airway reversibility, FENO45
Roy et al. (44)	Y	–	–	–	Regardless of percentage differential or cell count, FENO50
Dummer et al. (49)	Y	–	–	–	Off-steroid FENO50 and sputum eosinophil percentage
Tilemann et al. (45)	–	Y	Y	–	Mixed group of patients (COPD, asthma, and patient with partial reversibility), FENO50
Soter et al. (70)	Y	–	–	19 ppb	Regardless of percentage/number. Both at exacerbation and discharge, FENO50
Rawy et al. (59)	Y	Y	–	–	Positive association, blood and sputum eosinophil percentage, FENO50
Chou et al. (68)	Y	–	Y	23.5 ppb	Patients with sputum eosinophilia compared with those without sputum eosinophilia, FENO50
Ji et al. (55)	Y	–	Y	–	Pre- and post-treatment (ICS/LABA) FENO50 levels with sputum eosinophils and serum total IgE.
Feng et al. (3)	Y	–	Y	–	ACO patients, FENO50
Cosío et al. (67)	–	N	–	–	Patients with elevated blood eosinophil compared with those without elevated blood eosinophil, FENO50
Gao et al. (69)	Y	N	–	17.5 ppb	Patients with elevated eosinophils either in sputum or in blood compared with those without elevated sputum/blood eosinophils, FENO50
Zhao et al. (71)	N	–	–	–	Before and after bronchodilator inhalation, FENO50

F_ENO: fractional exhaled nitric oxide; IgE: immunoglobulin E; COPD: chronic obstructive lung disease; ppb: parts per billion; ICS: inhaled corticosteroid; LABA: long-acting beta agonist; ACO: asthma-COPD overlap.

^aY = Yes, N = NO, – = Not mentioned, for expressing the F_ENO, the exhalation flow rate (if indicated) was given as a subscript in mL·s⁻¹. For instance, a flow rate of 50 mL·s⁻¹ was written F_ENO50. If there was no direct or indirect evidence regarding the flow rate (mL·s⁻¹), we only used F_ENO.

^bSputum eosinophilia/elevated sputum eosinophils defined as sputum eosinophil count ≥2.5% (69) or ≥3% (70) or >3% (68) or no definition (3, 44, 45, 49, 55, 59, 61, 67, 71).

^cElevated blood eosinophils defined as blood eosinophil count ≥1% (69) or ≥200 eosinophils·μL⁻¹ (67) or no definition (45, 59).

^dSubjects/patients are COPD unless stated otherwise.

Table 6. Fractional exhaled nitric oxide and treatment response^a.

References	Treatment response influence/association^b	Optimal cut-off value	Comments^c
Kunisaki et al. (50)	Y	–	Higher baseline FENO50 levels in ICS responder than non-responders
Dummer et al. (49)	Y	50 ppb	Significant improvement in FEV1 from the lowest to the highest FENO50 tertile using oral glucocorticoid
Antus et al. (39)	Y	26.8 ppb	Higher increase in FEV1 and FEV1% predicted at discharge in the exacerbated patients with FENO50 > 26.8 ppb by administrating systemic (IV or orally) glucocorticoids and bronchodilators
Akamatsu et al. (54)	Y	35 ppb	Higher increase in FEV1 in patients with FENO50 >35 ppb and atopy by adding ICS/LABA
Soter et al. (70)	Y	26.8 ppb	Higher increase in FEV1 at admission in exacerbated patients with FENO50 >26.8 ppb by administrating systemic (IV or orally) glucocorticoids and bronchodilators
Amer et al. (72)	N	–	No association between FENO50 and change in FEV1 after bronchodilator therapy
Feng et al. (3)	Y	–	Association between FENO50 and ICS therapy (for 6 months) in ACO. Lower FENO50 in mild and moderate than severe and extremely severe ACO^d
Zhao et al. (71)	N	–	No association between the FENO50 and change in FEV1 after bronchodilator therapy

F_ENO: fractional exhaled nitric oxide; ICS: inhaled corticosteroid; ppb: parts per billion; FEV1: forced expiratory volume in first second; COPD: chronic obstructive pulmonary disease; IV: intravenous, ACO: asthma-COPD overlap; GINA: Global Initiative for Asthma; GOLD: Global Initiative for Chronic Obstructive Lung Disease.

^a Treatment response influence/association: Y = Yes, N = No, Optimal cut-off value: – = Not mentioned, for expressing the F_ENO, the exhalation flow rate (if indicated) was given as a subscript in mL·s⁻¹. For instance, a flow rate of 50 mL·s⁻¹ was written F_ENO50. If there was no direct or indirect evidence regarding the flow rate (mL·s⁻¹), we only used F_ENO.

^bTreatment response was defined as an increase in FEV1 ≥ 200mL (50) or >200mL (54) or >12% and >200 mL (39, 70). Treatment response was not defined in three studies (3, 71, 72).

^c Subjects/patients are COPD unless stated otherwise

^dACO and its severity was defined as GINA-GOLD joint document 2014 (8) and GOLD 2011 stages (ABCD) (73), respectively.

Bhowmik A, Seemungal TA, Donaldson GC, Wedzicha JA. Effects of exacerbations and seasonality on exhaled nitric oxide in copd. Eur Respir J. 2005;26(6):1009–1015.

 PubMed Web of Science ®Google Scholar

Liu J, Sandrini A, Thurston MC, Yates DH, Thomas PS. Nitric oxide and exhaled breath nitrite/nitrates in chronic obstructive pulmonary disease patients. Respiration. 2007;74(6):617–623.

 PubMed Web of Science ®Google Scholar

de Laurentiis G, Maniscalco M, Cianciulli F, Stanziola A, Marsico S, Lundberg JO, Weitzberg E, Sofia M. Exhaled nitric oxide monitoring in copd using a portable analyzer. Pulm Pharmacol Ther. 2008;21(4):689–693.

 PubMed Web of Science ®Google Scholar

Kunisaki KM, Rice KL, Janoff EN, Rector TS, Niewoehner DE. Exhaled nitric oxide, systemic inflammation, and the spirometric response to inhaled fluticasone propionate in severe chronic obstructive pulmonary disease: a prospective study. Ther Adv Respir Dis. 2008;2(2):55–64.

 PubMedGoogle Scholar

Roy K, Smith J, Kolsum U, Borrill Z, Vestbo J, Singh D. Copd phenotype description using principal components analysis. Respir Res. 2009;10:41.

 PubMed Web of Science ®Google Scholar

Dummer JF, Epton MJ, Cowan JO, Cook JM, Condliffe R, Landhuis CE, Smith AD, Taylor DR. Predicting corticosteroid response in chronic obstructive pulmonary disease using exhaled nitric oxide. Am J Respir Crit Care Med. 2009;180(9):846–852.

 PubMed Web of Science ®Google Scholar

Antus B, Barta I, Horvath I, Csiszer E. Relationship between exhaled nitric oxide and treatment response in copd patients with exacerbations. Respirology. 2010;15(3):472–477.

 PubMed Web of Science ®Google Scholar

Lehouck A, Carremans C, De Bent K, Decramer M, Janssens W. Alveolar and bronchial exhaled nitric oxide in chronic obstructive pulmonary disease. Respir Med. 2010;104(7):1020–1026.

 PubMed Web of Science ®Google Scholar

Tilemann L, Gindner L, Meyer F, Szecsenyi J, Schneider A. Differences in local and systemic inflammatory markers in patients with obstructive airways disease. Prim Care Respir J. 2011;20(4):407–414.

 PubMedGoogle Scholar

Rouhos A, Kainu A, Piirila P, Sarna S, Lindqvist A, Karjalainen J, Sovijarvi AR. Repeatability of exhaled nitric oxide measurements in patients with copd. Clin Physiol Funct Imaging. 2011;31(1):26–31.

 PubMed Web of Science ®Google Scholar

Bazeghi N, Gerds TA, Budtz-Jorgensen E, Hove J, Vestbo J. Exhaled nitric oxide measure using multiple flows in clinically relevant subgroups of copd. Respir Med. 2011;105(9):1338–1344.

 PubMed Web of Science ®Google Scholar

Akamatsu K, Matsunaga K, Sugiura H, Koarai A, Hirano T, Minakata Y, Ichinose M. Improvement of airflow limitation by fluticasone propionate/salmeterol in chronic obstructive pulmonary disease: What is the specific marker? Front Pharmacol. 2011;2:36.

 PubMed Web of Science ®Google Scholar

Antus B, Barta I. Relationship between exhaled nitric oxide and the frequency of severe acute exacerbation of copd: 3-year follow-up. Acta Physiol Hung. 2013;100(4):469–477.

 PubMed Web of Science ®Google Scholar

Xia Q, Pan P, Wang Z, Lu R, Hu C. Fractional exhaled nitric oxide in bronchial inflammatory lung diseases. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2014;39(4):365–370.

 PubMedGoogle Scholar

Rawy AM, Mansour AI. Fraction of exhaled nitric oxide measurement as a biomarker in asthma and copd compared with local and systemic inflammatory markers. Egypt J Chest Dis Tuberc. 2015;64(1):13–20.

 Web of Science ®Google Scholar

Ishiura Y, Fujimura M, Shiba Y, Ohkura N, Hara J, Kasahara K. A comparison of the efficacy of once-daily fluticasone furoate/vilanterole with twice-daily fluticasone propionate/salmeterol in asthma-copd overlap syndrome. Pulm Pharmacol Ther. 2015;35:28–33.

 PubMed Web of Science ®Google Scholar

Santini G, Mores N, Shohreh R, Valente S, Dabrowska M, Trove A, Zini G, Cattani P, Fuso L, Mautone A, et al. Exhaled and non-exhaled non-invasive markers for assessment of respiratory inflammation in patients with stable copd and healthy smokers. J Breath Res. 2016;10(1):017102.

 PubMed Web of Science ®Google Scholar

Logotheti H, Pourzitaki C, Tsaousi G, Aidoni Z, Vekrakou A, Ekaterini A, Gourgoulianis K. The role of exhaled nitric oxide in patients with chronic obstructive pulmonary disease undergoing laparotomy surgery – the noxious study. Nitric Oxide. 2016;61:62–68.

 PubMed Web of Science ®Google Scholar

Amer M, Cowan J, Gray A, Brockway B, Dummer J. Effect of inhaled β2-Agonist on Exhaled Nitric Oxide in Chronic Obstructive Pulmonary Disease. PLoS One. 2016;11(6):e0157019.

 PubMed Web of Science ®Google Scholar

Ji Z, Pan X, Ji F, Ni DT, Shang Y, Bai C. Fractional exhaled nitric oxide detection in treatment of asthma-chronic obstructive pulmonary disease overlap syndrome [Chinese]. Acad J Second Military Med Univ. 2016;37(10):1250–1255.

 Google Scholar

Huang SY, Chou PC, Wang TY, Lo YL, Joa WC, Chen LF, Sheng TF, Chung KF, Wang CH, Kuo HP. Exercise-induced changes in exhaled no differentiates asthma with or without fixed airway obstruction from copd with dynamic hyperinflation. Medicine (Baltimore). 2016;95(15):e3400.

 PubMed Web of Science ®Google Scholar

Kobayashi S, Hanagama M, Yamanda S, Ishida M, Yanai M. Inflammatory biomarkers in asthma-copd overlap syndrome. Int J Chron Obstruct Pulmon Dis. 2016;11:2117–2123.

 PubMed Web of Science ®Google Scholar

Feng JX, Lin Y, Lin J, He SS, Chen MF, Wu XM, Xu YZ. Relationship between fractional exhaled nitric oxide level and efficacy of inhaled corticosteroid in asthma-COPD overlap syndrome patients with different disease severity. J Korean Med Sci. 2017;32(3):439–447.

 PubMed Web of Science ®Google Scholar

Zhao H, Li R, Lv Y, Dong H, Yao L, Wu Y, Xiao G, Cai S. Albuterol inhalation increases feno level in steroid-naive asthmatics but not copd patients with reversibility. Clin Respir J. 2017;11(3):328–336.

 PubMed Web of Science ®Google Scholar

Foschino Barbaro MP, Carpagnano GE, Spanevello A, Cagnazzo MG, Barnes PJ. Inflammation, oxidative stress and systemic effects in mild chronic obstructive pulmonary disease. Int J Immunopathol Pharmacol. 2007;20(4):753–763.

 PubMed Web of Science ®Google Scholar

Beg MF, Alzoghaibi MA, Abba AA, Habib SS. Exhaled nitric oxide in stable chronic obstructive pulmonary disease. Ann Thorac Med. 2009;4(2):65–70.

 PubMed Web of Science ®Google Scholar

Donohue JF, Herje N, Crater G, Rickard K. Characterization of airway inflammation in patients with copd using fractional exhaled nitric oxide levels: a pilot study. Int J Chron Obstruct Pulmon Dis. 2014;9:745–751.

 PubMed Web of Science ®Google Scholar

Durmaz D, Goksu E, Kilic T, Ozbudak O, Eray O. The role of nitric oxide in predicting revisit of patients with exacerbated chronic obstructive pulmonary disease. J Emerg Med. 2015;48(2):247–253.

 PubMed Web of Science ®Google Scholar

Arif AA, Mitchell C. Use of exhaled nitric oxide as a biomarker in diagnosis and management of chronic obstructive pulmonary disease. J Prim Care Community Health. 2016;7(2):102–106.

 PubMed Web of Science ®Google Scholar

Alcazar-Navarrete B, Romero-Palacios PJ, Ruiz-Sancho A, Ruiz-Rodriguez O. Diagnostic performance of the measurement of nitric oxide in exhaled air in the diagnosis of copd phenotypes. Nitric Oxide. 2016;54:67–72.

 PubMed Web of Science ®Google Scholar

Tamada T, Sugiura H, Takahashi T, Matsunaga K, Kimura K, Katsumata U, Takekoshi D, Kikuchi T, Ohta K, Ichinose M. Biomarker-based detection of asthma-copd overlap syndrome in copd populations. Int J Chron Obstruct Pulmon Dis. 2015;10:2169–2176.

 PubMed Web of Science ®Google Scholar

Chen FJ, Huang XY, Liu YL, Lin GP, Xie CM. Importance of fractional exhaled nitric oxide in the differentiation of asthma-COPD overlap syndrome, asthma, and COPD. Int J Chron Obstruct Pulmon Dis. 2016;11:2385–2390.

 PubMed Web of Science ®Google Scholar

Goto T, Camargo CJ, Hasegawa K. Fractional exhaled nitric oxide levels in asthma-copd overlap syndrome: analysis of the national health and nutrition examination survey, 2007–2012. Int J Chron Obstruct Pulmon Dis. 2016;11:2149–2155.

 PubMed Web of Science ®Google Scholar

Deng DD, Zhou AY, Shuang QC, Chen P. The value of fractionated exhaled nitric oxide in the diagnosis of asthma-chronic obstructive pulmonary disease overlap syndrome. Chung-Hua Chieh Ho Ho Hu Hsi Tsa Chih – Chinese J Tuberculosis Respiratory Diseases. 2017;40(2):98–101.

 Google Scholar

Cosio BG, Perez de Llano L, Lopez Vina A, Torrego A, Lopez-Campos JL, Soriano JB, Martinez Moragon E, Izquierdo JL, Bobolea I, Callejas J, et al. Th-2 signature in chronic airway diseases: towards the extinction of asthma-copd overlap syndrome? Eur Respir J. 2017;49(5):pii: 1602397

 Google Scholar

Soter S, Barta I, Antus B. Predicting sputum eosinophilia in exacerbations of copd using exhaled nitric oxide. Inflammation. 2013;36(5):1178–1185.

 PubMed Web of Science ®Google Scholar

Chou KT, Su KC, Huang SF, Hsiao YH, Tseng CM, Su VY, Hung SC, Perng DW. Exhaled nitric oxide predicts eosinophilic airway inflammation in copd. Lung. 2014;192(4):499–504.

 PubMed Web of Science ®Google Scholar

Gao J, Zhang M, Zhou L, Yang X, Wu H, Zhang J, Wu F. Correlation between fractional exhaled nitric oxide and sputum eosinophilia in exacerbations of copd. Int J Chron Obstruct Pulmon Dis. 2017;12:1287–1293.

 PubMed Web of Science ®Google Scholar

Hanania NA, Wittman R, Kesten S, Chapman KR. GINA-GOLD Diagnosis of diseases of chronic airflow limitation: Asthma, COPD and asthma-COPD overlap syndrome (ACOS). 2014. Chest. 1994;105.

 PubMedGoogle Scholar

Osterberg L, Blaschke T. From the Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD). 2011. N Engl J Med. 2005;353.

 Google Scholar