FENO is a simple non-invasive test and can be easily measured in pediatric office practice. FENO measurements decrease in a dose dependent fashion in response to treatment with inhaled corticosteroids (ICS) [3,4]. FENO has been shown to correlate with the degree of airway hyper-responsiveness, and the numbers of eosinophils in induced sputum [5]. Few studies have evaluated the relationship between asthma control as per Global Initiative for Asthama (GINA) guidelines and FENO measurements [6-8]. Data are limited from India on the utility of FENO in management of childhood asthma [9]. We prospectively evaluated the utility of FENO in identification of uncontrolled asthma in selected Indian children with asthma. The secondary objective was to identify cut-off value of FENO for determining asthma control.

This cross-sectional study was carried out in the Pediatric Chest Clinic of a tertiary-care hospital in Northern India over 19 months. Children aged between 5-15 years with physician-diagnosed asthma, on treatment with a regular follow up of at least 12 months, were enrolled in the study after obtaining informed consent from parents. Children not able to perform spirometry and those with acute exacerbation of asthma (any severity) were excluded from the study.

Details of history and physical examination were recorded in a structured form. FENO was measured by using NIOX Mino (Aerocrine AB, Solna, Sweden) portable machine using standard guidelines [2]. Spirometry was performed using portable spirometer (Superspiro MK2 Micro Medical Ltd, UK) as per American Thoracic Society (ATS) guidelines [10]. Asthma control was assessed as per GINA guidelines [1]. The study was approved by the Institutional ethics committee of our institute.

A total of 207 children with asthma were enrolled in the study. Median (IQR) FENO was 14 (10, 23) ppb. Minimum FENO was 5 ppb (<5 value was considered equal to 5 ppb) and maximum FENO value was 110 ppb. Seventy-one (34.3%) children had an FENO value of 20 ppb or above. Based on the GINA guidelines, out of 207 study participants, 156 (75%) had uncontrolled or partly controlled asthma. Fifty-one (25%) participants were assessed to have controlled asthma. Median (IQR) FENO in children with controlled asthma was 16 (11, 23) ppb as compared to 13 (11, 25) ppb for uncontrolled asthma (P=0.26) (Fig 1). The area under the curve was 0.448, suggesting poor discriminatory value of FENO for control of asthma (Fig. 2). Table I shows sensitivity and specificity of various cut-off values of FENO (15 ppb, 20 ppb, 25 ppb, 30 ppb) for identification of uncontrolled asthma. None of the cut-off values had a good discriminatory value to identify asthma control. We compared the characteristics of children with controlled and uncontrolled asthma (Table II). The groups did not differ in terms of baseline variables (age, sex, family history of asthma or allergy). Uncontrolled children had poorer lung function and were more likely to be using higher doses of inhaled corticosteroids (Table II).

TABLE I	Different Cut-offs of FENO for Assessment of Uncontrolled Asthma

TABLE II  Comparison of Characteristics of Children with Controlled and Uncontrolled Asthma 

Fig. 1 Box-plot graph showing the distribution of FENO values in children with controlled and uncontrolled asthma.

Fig. 2 ROC curve at different cut off values of FENO.

In this cross-sectional study on 207 children, we observed that FENO has a poor discriminatory power to differentiate between controlled and uncontrolled/partly controlled asthma as assessed by GINA guidelines. Earlier studies have evaluated the utility of FENO measurements in assessing asthma control, and there is evidence in support [11-15] as well as against [16-19] agreement of FENO with different measures of asthma control.

GINA guidelines assess control over the preceding four weeks. On the other hand, FENO measurement is a reflection of inflammation on the day of assessment. There is a possibility that a measure of control which takes into account the previous four weeks, and FENO measurement which assesses inflammation on the day of assessment, may not show good agreement, as shown by our study.

Corticosteroids (either inhaled or systemic) are known to bring down FENO levels. A recent study of two distinct populations (United States and Spain) showed that the correlation between asthma control (as defined by Asthma Control Test [ACT]) and FENO was only observed for the Spain site in ICS-naive patients [16]. They concluded that lack of correlation of ACT with FENO probably reflects the heterogeneity of asthma patients who have varied asthma severity and treatment regimens. A longitudinal study in unselected asthmatic patients by Michils, et al. [20] showed that FENO was a useful marker of asthma control for those patients treated with low doses of ICS but not for patients on high-to-medium ICS. They suggested that changes in FENO values, rather than absolute cut-off points (i.e. personalized FENO profiles), may be more useful. This suggests that ICS doses might have to be taken into account when using FENO to assess asthma control.

The present study has certain limitations. Various factors/comorbidities affecting FENO measurements including atopy, allergic rhinitis, eczema, sleep-disordered breathing, and allergen exposure were not measured and adjusted for in the analysis. The shorter exhalation used for FENO measurements of younger children (5-8 years) may also have caused bias.

To summarize, FENO measurement does not seem to have good discriminatory value in assessment of controlled and uncontrolled asthma in children between 5-15 years of age on treatment for asthma. Monitoring of children with asthma should routinely include standard asthma control tools and spirometry. Measurement of FENO may give useful information regarding airway inflammation but cannot be used as a surrogate for asthma control.

Contributors: RKM: study design, data collection, analysis and manuscript writing, DR: data analysis and manuscript writing, RL: study design, analysis and manuscript writing; SKK: study design, data analysis, and manuscript writing. He will act as guarantor for the study.

Funding: M/s Aerocrine provided material for carrying out this research. M/s Aerocrine did not have any role in study design, data collection, data analysis or manuscript writing; Competing interests: None stated.