Further Fine-Tuning of the Interpretation of FeNO Measurement in Asthma

Measurement of FeNO has been extensively studied over the past 3 decades. The method is noninvasive and easy to perform, which has enabled the generation of a lot of research data. This, in turn, has facilitated the identification of several individual factors that influence FeNO. Early on, it was identified that bronchoconstriction leads to a reduced FeNO, and subsequent bronchodilation normalizes FeNO.1de Gouw H.W. Hendriks J. Woltman A.M. Twiss I.M. Sterk P.J. Exhaled nitric oxide (NO) is reduced shortly after bronchoconstriction to direct and indirect stimuli in asthma.Am J Respir Crit Care Med. 1998; 158: 315-319Crossref PubMed Google Scholar,2Ho L.P. Wood F.T. Robson A. Innes J.A. Greening A.P. The current single exhalation method of measuring exhales nitric oxide is affected by airway calibre.Eur Respir J. 2000; 15: 1009-1013Crossref PubMed Scopus (54) Google Scholar In this issue of The Journal of Allergy and Clinical Immunology (JACI): In Practice, Michils et al3Michils A. Akset M. Haccuria A. Perez-Bogerd S. Malinovschi A. Van Muylem A. The impact of airway obstruction on FENO values in asthma patients.J Allergy Clin Immunol Pract. 2024; 12: 111-117Abstract Full Text Full Text PDF Google Scholar report on the independent effect of reduced lung function on FeNO in a relatively large real-life sample of patients with asthma, and suggest a way to correct for this effect in the clinic. It has often been stated that the consideration of individual factors affecting FeNO constitutes a problem. However, although not generally recognized, this is true for basically all biomarkers. For example, male sex, obesity, and cigarette smoking are all associated with higher blood eosinophil counts in healthy individuals.4Amaral R. Jacinto T. Malinovschi A. Janson C. Price D. Fonseca J.A. et al.The influence of individual characteristics and non-respiratory diseases on blood eosinophil count.Clin Transl Allergy. 2021; 11: e12036Crossref Scopus (3) Google Scholar Thus, individual factors affecting biomarkers should be identified and possibly rectified. FeNO depends on the NO-producing airway mucosal surface area.5Pedroletti C. Hogman M. Merilainen P. Nordvall L.S. Hedlin G. Alving K. Nitric oxide airway diffusing capacity and mucosal concentration in asthmatic schoolchildren.Pediatr Res. 2003; 54: 496-501Crossref PubMed Scopus (39) Google Scholar This area is affected by age (or rather, body height) in growing children, height in adults, and sex, because men have larger airways than women independent of height.6Harris E.A. Hunter M.E. Seelye E.R. Vedder M. Whitlock R.M. Prediction of the physiological dead-space in resting normal subjects.Clin Sci Mol Med. 1973; 45: 375-386PubMed Google Scholar Thus, the commonly recognized determinants for FeNO are age, height, and sex. Michils et al3Michils A. Akset M. Haccuria A. Perez-Bogerd S. Malinovschi A. Van Muylem A. The impact of airway obstruction on FENO values in asthma patients.J Allergy Clin Immunol Pract. 2024; 12: 111-117Abstract Full Text Full Text PDF Google Scholar shed new light on another determinant, airway caliber, which also may influence the NO-producing airway mucosal surface area. The authors were able to show that reduced airway caliber, in terms of reduced prebronchodilator FEV1, is independently associated with reduced FeNO. The relationship between lung function and FeNO is complex, because an increase in FeNO is also associated with reduced lung function, and vice versa.7Tsolakis N. Jacinto T. Janson C. Borres M. Malinovschi A. Alving K. Relationship between longitudinal changes in type-2 inflammation, immunoglobulin E sensitization, and clinical outcomes in young asthmatics.Clin Transl Allergy. 2021; 11: e12066Crossref Scopus (3) Google Scholar That is, a negative correlation is commonly seen, which is congruent with the idea that more inflammation will cause a reduction in lung function. This was also shown by Michils et al3Michils A. Akset M. Haccuria A. Perez-Bogerd S. Malinovschi A. Van Muylem A. The impact of airway obstruction on FENO values in asthma patients.J Allergy Clin Immunol Pract. 2024; 12: 111-117Abstract Full Text Full Text PDF Google Scholar in their study. By analyzing intraindividual changes over time, a significant negative correlation was shown for a change in FeNO and change in FEV1, at least in the two middle quartiles (according to the initial FEV1) of the included patients with asthma, with an average FEV1 % predicted of 74% to 87%. Moreover, the cross-sectional analysis revealed a significant positive association between FeNO and lung function. Thus, a reduced FeNO was seen with reduced prebronchodilator FEV1. The latter was probably driven by patients in the fourth quartile with an average FEV1 % predicted of 55%, that is, with more severe bronchoconstriction. This effect was independent of age, sex, blood eosinophil count, and inhaled corticosteroid use, which supports the view that a reduction in FeNO owing to a more marked reduction in airway caliber is not related to airway inflammation, but rather to a change in the NO-producing airway mucosal surface area. Thus, reduced lung function may lead to the underestimation of FeNO. One way to minimize the effect of reduced lung function on FeNO in the clinic may be to measure FeNO after bronchodilation. Unfortunately, Michils et al3Michils A. Akset M. Haccuria A. Perez-Bogerd S. Malinovschi A. Van Muylem A. The impact of airway obstruction on FENO values in asthma patients.J Allergy Clin Immunol Pract. 2024; 12: 111-117Abstract Full Text Full Text PDF Google Scholar did not report on the association between postbronchodilator FEV1 and FeNO, because that information was lacking in this real-life sample. It is clear that regular bronchodilator tests may not be feasible, especially not within primary care. Furthermore, an irreversible reduction in lung function may be present in some patients with asthma. As an alternative, the authors suggest introducing a correction factor: for every 10% unit reduction in FEV1 % predicted, FeNO should be adjusted with the addition of 4 parts per billion. If applied, we believe that such a correction should be done together with the individualization of FeNO cutoffs based on age, height, and sex. Reference equations with these three factors have recently been preliminarily reported to increase the sensitivity of FeNO to rule out type 2 inflammation.8Amaral R, Jacinto T, Malinovschi A, Janson C, Sousa-Pinto B, Olin A, et al. Development and validation of novel individualized FeNO cut-offs. Paper presented at: 2023 ERS International Congress, September 10-13; Milan, Italy.Google Scholar It is hoped that adding lung function as a factor will increase the explanatory value of the reference equations. Biomarkers are affected by individual factors, and these should be identified and possibly rectified. The understanding of factors influencing FeNO, and how to deal with them in the clinic, has been furthered by Michils et al3Michils A. Akset M. Haccuria A. Perez-Bogerd S. Malinovschi A. Van Muylem A. The impact of airway obstruction on FENO values in asthma patients.J Allergy Clin Immunol Pract. 2024; 12: 111-117Abstract Full Text Full Text PDF Google Scholar in this issue of JACI: In Practice. The Impact of Airway Obstruction on Feno Values in Asthma PatientsThe Journal of Allergy and Clinical Immunology: In PracticeVol. 12Issue 1PreviewExhaled nitric oxide (Feno) is used as a marker of type-2 airway inflammation in asthma management. Studies with airway challenges demonstrated that a reduction in airway caliber decreases Feno levels. Full-Text PDF