Identifying the predictive value of fractional exhaled nitric oxide (FeNO) for uncontrolled asthma in 3–7-year-old Thai children

Introduction

Asthma, a chronic inflammatory disorder of the airways, poses substantial impact on patients’ quality of life, necessitating effective control as a principal objective in its management. The Global Initiative for Asthma (GINA) 2022 guidelines (1) underscore the importance of evaluating control levels through clinical and spirometry data to assess airway obstruction. However, spirometry presents challenges in young children, particularly those under 6 years of age.

Nitric oxide (NO), produced from the respiratory epithelium as a byproduct of eosinophilia inflammation and L-arginine oxidation, serves as a biological mediator implicated in airway inflammation (2-4). The measurement of fractional exhaled nitric oxide (FeNO) has emerged as a novel tool for monitoring NO in exhaled breath. It is useful assessing airway inflammation and, when combined with clinical assessments, predicting future risk (5,6). Elevated FeNO values are predominantly associated with eosinophilic airway inflammation and type 2 asthma inflammation (7,8). This non-invasive, simple tool is particularly advantageous for use in children as young as 3 to 4 years old (9).

The American Thoracic Society (ATS) (3) and the European Respiratory Society (ERS) (10), in 2005 recommended reference FeNO values for both children and adults. However, FeNO values are influenced by various factors such as age, gender, race, height, and atopy (11). Research in Thailand conducted by Suksawat et al. on healthy children indicated that mean FeNO values in the 6–10 years age group are lower than in older children and lower than the values reported in other countries (12). Consequently, a single FeNO cutoff value may not accurately identify uncontrolled asthma across diverse populations. Uncontrolled asthma is associated with increased exacerbations and a higher degree of airway inflammation. Identifying a correlation between uncontrolled asthma and FeNO values could enhance management strategies. Therefore, this study aims to evaluate FeNO values in relation to asthma control levels in Thai children aged 3 to 7 years, aiming to identify an optimal cutoff point and associated factors influencing FeNO levels, thereby contributing to tailored management approaches. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-383/rc).

Methods

Study design

A cross-sectional study was conducted at the pediatric tertiary care center of the Naresuan University Hospital in Phitsanulok, Thailand, from April 1, 2023 to July 31, 2023. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and approved by the Naresuan University Institutional Review Board (No. P3-0001/2566). Informed consent was obtained from all participants and their parents.

Subjects

This study was conducted on asthmatic Thai children who visited the outpatient and inpatient departments at Naresuan University Hospital. Inclusion criteria were asthmatic patients aged 3 to 7 years, capable of following FeNO measurement instructions. Children diagnosed with coronavirus disease 2019 (COVID-19) infection, those experiencing difficulty breathing, or those unable to perform the FeNO measurement were excluded from the study. A minimal sample size for estimating population mean was 44 subjects.

Study procedure

All participants underwent comprehensive history taking, including underlying diseases, respiratory symptoms, and current medication use. Screening for COVID-19 infection was conducted for those suspected of having the infection. The patients were categorized according to the level of asthma control as outlined in the GINA 2022 guidelines (1)—well controlled, partly controlled, and uncontrolled—based on symptoms experienced in the preceding four weeks according to the following criteria: (I) daytime asthma symptoms more than twice per week; (II) nocturnal awakenings due to asthma; (III) use of short-acting beta-agonist (SABA) relievers for symptoms more than twice per week; and (IV) any activity limitation due to asthma. Absence of these symptoms indicated well-controlled asthma, the presence of 1–2 symptoms indicated partly controlled asthma, and 3–4 symptoms indicated uncontrolled asthma.

Demographic and anthropometric data were collected from each participant. The FeNO level was measured using electrochemical sensor of the NObreath^® device. A single technician, who explained and supervised the procedure, conducted the FeNO test. Participants were instructed to exhale into the mouthpiece for 10 seconds. The test was terminated if the participant failed to complete it more than 10 times, experienced difficulty breathing, or refused to continue. Healthcare providers closely monitored the patients during and after the FeNO test.

Statistical analysis

Quantitative variables were expressed as mean and standard deviation (SD), while qualitative variables were presented as percentages. Comparisons among variables and levels of asthma control were conducted using the Chi-squared test and analysis of variance (ANOVA). The FeNO levels across different groups were compared using the Kruskal-Wallis test. The association between factors and FeNO levels was analyzed using a generalized linear mixed model. The diagnostic capability of FeNO levels for identifying uncontrolled asthma was assessed through receiver operating characteristic (ROC) curve analysis, with the optimal FeNO level cutoff determined by the Youden index. A P value of less than 0.05 was considered statistically significant for all tests. Data analyses were carried out using STATA software, version 12.0 (StataCorp., College Station, TX, USA).

Results

A total of 130 participants underwent FeNO measurement at Naresuan University Hospital, of which 22 were excluded due to inability to perform the test. Consequently, 108 participants successfully completed the FeNO measurement, comprising 72 males (66.7%) and 72 individuals (66.7%) with underlying diseases. According to the GINA 2022 guideline, asthma control was categorized as follows: 59 participants (54.6%) were well controlled, 34 (31.5%) were partly controlled, and 15 (13.9%) were uncontrolled. The mean ages for each group were 6.1±1.1, 5.8±1.2, and 6.4±1.4 years for the well-controlled, partly controlled, and uncontrolled group, respectively. Most of the patients had a normal nutritional status, as shown in Table 1.

Allergic rhinitis emerged as the most common underlying disease, predominantly presenting as an uncontrolled symptom in an uncontrolled group. The well controlled asthma group exhibited a higher rate of asymptomatic individuals compared to the others. Clinically significant respiratory symptoms were observed in the partly controlled and uncontrolled groups, with a statistically significant difference (P<0.001). Inhaled corticosteroid (ICS), either alone in varying doses or combined with long-acting beta agonists, were commonly used in the well-controlled and partly controlled groups than in the uncontrolled group (P<0.001).

The mean FeNO values for the well-controlled, partly, and uncontrolled asthma groups were 8.8±7.9, 8.6±6.6, and 14.7±10.8 ppb, respectively, with the uncontrolled group showing significantly higher values than the other groups (P=0.03). Excluding factors that might affect the FeNO values, such as uncontrolled allergic rhinitis, resulted in a decrease in the mean FeNO value for the well-controlled asthma group and an increase for the partly controlled asthma group, although these changes were not statistically significant (P=0.053). In terms of ICS usage, the mean FeNO values for the well-controlled, partly controlled, and uncontrolled asthma groups were 8.5±7.8, 8.6±6.7, and 19.2±12.1 ppb, respectively, with a statistical significance (P=0.01), as shown in Table 2.

The area under the ROC curve for FeNO levels in detecting uncontrolled asthma was 0.672 (95% CI: 0.518–0.826), as illustrated in Figure 1. The optimal cutoff point for FeNO values was identified as equal to greater than 15 ppb, yielding a sensitivity of 46.7%, specificity of 86.0%, positive predictive value (PPV) of 35.0%, negative predictive value (NPV) of 90.9%, and an accuracy of 80.6% (Table 3). The low FeNO values ranged from 1 to 7 ppb, whereas high FeNO values were ≥15 ppb, showing a significant distinction (P=0.01), as shown in Table 4.

Figure 1 Area under the ROC curve for FeNO levels in detecting GINA-defined uncontrolled asthma. AUC, area under the curve; CI, confidence interval; ROC, receiver operating characteristic; FeNO, fractional exhaled nitric oxide; GINA, Global Initiative for Asthma.

Factors associated with an increase in FeNO levels included uncontrolled allergic rhinitis [incident rate ratio (IRR) 1.29, P=0.002], compliance below 80% (IRR 1.31, P=0.04), symptoms at the time of measurement (IRR 1.13, P=0.046), and uncontrolled asthma (IRR 1.67, P<0.001), all of which were statistically significant. Conversely, second-hand smoking exposure (IRR 0.78, P=0.001), use of corticosteroids (IRR 0.87, P=0.045), and use of ICS with long-acting beta agonists (IRR 0.82, P=0.003) were factors that significantly reduced FeNO values. Whereas pet exposure, family history of asthma and environment did not show correlation with FeNO value. Multivariate analysis revealed that uncontrolled allergic rhinitis, poor compliance, and uncontrolled asthma had a stronger correlation with increased FeNO values, as shown in Table 5.

Discussion

The FeNO test has recently become more widely used in assessing asthma control. Evaluating the level of asthma control is crucial for adjusting future risk management strategies. Our study demonstrated a significant correlation between uncontrolled asthma and higher FeNO levels, aligning with the findings of Songnuy et al. (13), while showing discordance with other previous studies (11,14,15). However, our results indicated that FeNO values were not effective in distinguishing between partly controlled and well controlled asthma, showing no significant difference in mean FeNO values. This could be attributed to factors such as uncontrolled allergic rhinitis observed in the well-controlled asthma group. After excluding this factor, FeNO values appeared slightly lower in well controlled compared to partly controlled and uncontrolled asthma, albeit not significantly. Nevertheless, FeNO testing can be useful in evaluating uncontrolled asthma.

Several studies in Asia (16-18) reported higher FeNO values across well-controlled asthma groups than those found in our study. Similar findings were observed in previous research on Thai children over 7 years old (19), suggesting that differences in age and ethnicity may influence FeNO values, with younger children exhibiting lower FeNO values due to different expiratory flow rates and reduced NO synthase activity (20,21). In this study, we were unable to compare mean FeNO values between children receiving ICS and those not receiving ICS due to the small sample size of the non-ICS group, which precluded a clear distinction of FeNO values.

The ATS recommends using FeNO cutoff points in clinical management rather than relying solely on reference values (3). However, these cutoff points vary across different guidelines (6). Our study investigated a FeNO cutoff point of ≥15 ppb for predicting uncontrolled asthma in children aged 3–7, showing high specificity (86.0%) and accuracy (80.6%) but low sensitivity (ROC =0.67). Similarly, another study in children aged 6–11 years identified an optimal FeNO cutoff point of 19 ppb (sensitivity 69%, specificity 59%; ROC =0.58) (22). These findings, along with a previous study in Thailand reporting a higher optimal cutoff point of 31 ppb in children over 7 years old (23), highlight the potential benefit of age-specific FeNO cutoff points for asthma management in children.

Our study supports the use of a FeNO cutoff point to reliably rule out well-controlled asthma. Conversely, low FeNO values (1–7 ppb) may indicate good asthma control. However, FeNO measurements should always be interpreted in conjunction with clinical symptoms to guide asthma treatment decisions. For instance, symptomatic asthma with high FeNO levels might suggest the need for increased ICS dosage, whereas low FeNO values in asymptomatic patients could potentially warrant ICS dose reduction (3,8,24).

FeNO levels are influenced by various factors (17,25). Our study found correlations between FeNO values and uncontrolled allergic rhinitis, symptoms at onset, smoking exposure, compliance, and the use of ICS. Matsunaga et al. also demonstrated the effect of allergic rhinitis, showing higher FeNO values in patients with both asthma and rhinitis compared to those with asthma alone (20), due to the eosinophilic airway inflammation in uncontrolled allergic rhinitis leading to increase NO synthesis (26). In contrast, second-hand smoke exposure was associated with lower FeNO values, consistent with previous studies (20,27), as smoking may downregulate NO synthase and reduce exhaled NO levels (27,28). Our findings also corroborate the correlation of FeNO values with the use of corticosteroids, especially ICS combined with long-acting beta-agonists (LABA) and good compliance, similar to Yin et al.’s study (29). However, the effect of varying ICS doses on FeNO values was not established. Utilizing FeNO testing can aid in optimizing management by interpreting the response to corticosteroids and adherence (30), suggesting the importance of considering these factors before interpreting FeNO values.

Limitation

This study has limitations, including a small sample size of children with uncontrolled asthma and the absence of symptom duration recording before FeNO measurement. The accuracy of FeNO testing should ideally be assessed before initiating systemic steroid treatment or new treatments, although pre-test restrictions were not feasible. For future research, we recommend longitudinal FeNO measurements before and after treatment to accurately evaluate FeNO’s utility in adjusting management strategies.

Conclusions

This study has demonstrated a significant correlation between FeNO values and uncontrolled asthma. A cutoff point of FeNO equal to greater than 15 ppb was identified as optimal for predicting uncontrolled asthma in Thai children aged 3 to 7 years. Factors associated with FeNO values included uncontrolled allergic rhinitis, symptoms at onset, exposure to smoking, adherence to treatment, and the use of ICS. The application of FeNO testing should be combined with the assessment of clinical symptoms and consideration of these associated factors for a comprehensive evaluation.

Acknowledgments

We would like to thank Ms. Daisy Jimenez Gonzales from the International Relations Section, Faculty of Medicine, Naresuan University for revising and editing the manuscript.

Funding: This study was supported by the Faculty of Medicine, Naresuan University, Phitsanulok, Thailand.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-383/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-383/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-383/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-383/coif). All authors report that this study was supported by the Faculty of Medicine, Naresuan University, Phitsanulok, Thailand. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and approved by the Naresuan University Institutional Review Board (No. P3-0001/2566). Informed consent was obtained from all participants and their parents.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention [Internet]. 2022 [cited 2022 Oct 17]. Available online: https://ginasthma.org/gina-reports/
2. Hoyte FCL, Gross LM, Katial RK. Exhaled Nitric Oxide: An Update. Immunol Allergy Clin North Am 2018;38:573-85. [Crossref] [PubMed]
3. 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;184:602-15. [Crossref] [PubMed]
4. Ricciardolo FL, Sorbello V, Ciprandi G. A pathophysiological approach for FeNO: A biomarker for asthma. Allergol Immunopathol (Madr) 2015;43:609-16. [Crossref] [PubMed]
5. Pijnenburg MW, De Jongste JC. Exhaled nitric oxide in childhood asthma: a review. Clin Exp Allergy 2008;38:246-59. [Crossref] [PubMed]
6. Loewenthal L, Menzies-Gow A. FeNO in Asthma. Semin Respir Crit Care Med 2022;43:635-45. [Crossref] [PubMed]
7. Escamilla-Gil JM, Fernandez-Nieto M, Acevedo N. Understanding the Cellular Sources of the Fractional Exhaled Nitric Oxide (FeNO) and Its Role as a Biomarker of Type 2 Inflammation in Asthma. Biomed Res Int 2022;2022:5753524. [Crossref] [PubMed]
8. Murugesan N, Saxena D, Dileep A, et al. Update on the Role of FeNO in Asthma Management. Diagnostics (Basel) 2023;13:1428. [Crossref] [PubMed]
9. Hanson JR, De Lurgio SA, Williams DD, et al. Office-based exhaled nitric oxide measurement in children 4 years of age and older. Ann Allergy Asthma Immunol 2013;111:358-63. [Crossref] [PubMed]
10. American Thoracic 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;171:912-30. [Crossref] [PubMed]
11. Thomas B, Chay OM, Allen JC Jr, et al. Concordance between bronchial hyperresponsiveness, fractional exhaled nitric oxide, and asthma control in children. Pediatr Pulmonol 2016;51:1004-9. [Crossref] [PubMed]
12. Suksawat Y, Pacharn P, Jirapongsananuruk O, et al. Determination of fractional exhaled nitric oxide (FENO) reference values in healthy Thai population. Asian Pac J Allergy Immunol 2017; [PubMed]
13. Songnuy T, Petchuay P, Chutiyon W, et al. Correlation between fractional exhaled nitric oxide level and clinical outcomes among childhood asthmatic patients: community hospital-based perspective. Heliyon 2021;7:e06925. [Crossref] [PubMed]
14. Meena RK, Raj D, Lodha R, et al. Fractional Exhaled Nitric Oxide for Identification of Uncontrolled Asthma in Children. Indian Pediatr 2016;53:307-10. [Crossref] [PubMed]
15. Waibel V, Ulmer H, Horak E. Assessing asthma control: symptom scores, GINA levels of asthma control, lung function, and exhaled nitric oxide. Pediatr Pulmonol 2012;47:113-8. [Crossref] [PubMed]
16. Nguyen Nhu V, Le An P, Chavannes NH. Combination of Fractional Exhaled Nitric Oxide (FeNO) Level and Asthma Control Test (ATC) in Detecting GINA-Defined Asthma Control in Treated Asthmatic Patients in Vietnam. Can Respir J 2020;2020:5735128. [Crossref] [PubMed]
17. Jang YY, Ahn JY. Evaluation of Fractional Exhaled Nitric Oxide in Pediatric Asthma and Allergic Rhinitis. Children (Basel) 2020;8:3. [Crossref] [PubMed]
18. Nguyen VN, Chavannes NH. Correlation between fractional exhaled nitric oxide and Asthma Control Test score and spirometry parameters in on-treatment-asthmatics in Ho Chi Minh City. J Thorac Dis 2020;12:2197-209. [Crossref] [PubMed]
19. Visitsunthorn N, Prottasan P, Jirapongsananuruk O, et al. Is fractional exhaled nitric oxide (FeNO) associated with asthma control in children? Asian Pac J Allergy Immunol 2014;32:218-25. [PubMed]
20. Matsunaga K, Hirano T, Akamatsu K, et al. Exhaled nitric oxide cutoff values for asthma diagnosis according to rhinitis and smoking status in Japanese subjects. Allergol Int 2011;60:331-7. [Crossref] [PubMed]
21. Buchvald F, Baraldi E, Carraro S, et al. Measurements of exhaled nitric oxide in healthy subjects age 4 to 17 years. J Allergy Clin Immunol 2005;115:1130-6. [Crossref] [PubMed]
22. Yavuz ST, Civelek E, Sahiner UM, et al. Identifying uncontrolled asthma in children with the childhood asthma control test or exhaled nitric oxide measurement. Ann Allergy Asthma Immunol 2012;109:36-40. [Crossref] [PubMed]
23. Visitsunthorn N, Mahawichit N, Maneechotesuwan K. Association between levels of fractional exhaled nitric oxide and asthma exacerbations in Thai children. Respirology 2017;22:71-7. [Crossref] [PubMed]
24. Au-Doung PLW, Chan JCH, Kui OYH, et al. Objective monitoring tools for improved management of childhood asthma. Respir Res 2024;25:194. [Crossref] [PubMed]
25. Rao DR, Phipatanakul W. An Overview of Fractional Exhaled Nitric Oxide and Children with Asthma. Expert Rev Clin Immunol 2016;12:521-30. [Crossref] [PubMed]
26. Czubaj-Kowal M, Nowicki GJ, Kurzawa R, et al. Factors Influencing the Concentration of Exhaled Nitric Oxide (FeNO) in School Children Aged 8-9-Years-Old in Krakow, with High FeNO Values ≥ 20 ppb. Medicina (Kaunas) 2022;58:146. [Crossref] [PubMed]
27. Bobrowska-Korzeniowska M, Stelmach I, Brzozowska A, et al. The effect of passive smoking on exhaled nitric oxide in asthmatic children. Nitric Oxide 2019;86:48-53. [Crossref] [PubMed]
28. Hoyt JC, Robbins RA, Habib M, et al. Cigarette smoke decreases inducible nitric oxide synthase in lung epithelial cells. Exp Lung Res 2003;29:17-28. [Crossref] [PubMed]
29. Yin SS, Liu H, Gao X. Elevated fractional exhaled nitric oxide (FeNO) is a clinical indicator of uncontrolled asthma in children receiving inhaled corticosteroids. Int J Clin Pharmacol Ther 2017;55:66-77. [Crossref] [PubMed]
30. Marckmann M, Hermansen MN, Hansen KS, et al. Assessment of adherence to asthma controllers in children and adolescents. Pediatr Allergy Immunol 2020;31:930-7. [Crossref] [PubMed]