Correlation of fractional exhalation of nitric oxide values with asthma control test score and spirometric parameters in steroid naïve asthmatic children at 6–8 weeks follow up

ABSTRACT

Context:

In pediatric asthma, it is critical to have a reliable airway inflammation marker that may be used to assess its severity and prognosis. Fractional exhalation of nitric oxide (FeNO) is a non-invasive objective method can be utilized as a supplemental tool if proven to correlate with clinical parameters.

Aims:

To study the correlation between FeNO, and asthma control test (ACT) scores and spirometry data in steroid naive asthmatic children 6–18 years at visit one and after 6–8 weeks follow-up.

Settings and Design:

This was observational follow-up study conducted among steroid naïve asthmatics attending the Outpatient Department.

Materials and Methods:

At baseline visit, they were classified as well controlled, not well controlled, and poorly controlled as per ACT, FeNO and Spirometry done as per standard technique. After 6–8 weeks of follow-up, all the above parameters were repeated.

Statistical Analysis Used:

Pearson correlation coefficient/Kendall’s tau 2 of 10 analysis was used for the association of two related variables. P <0.05 was considered statistically significant.

Results:

Among 56 enrolled, mean FeNO at visit 1 was 41.8 ± 33.26, which decreased to 20.26 ± 14.57 at visit 2. Changes in mean FeNO values between both visits and ΔACT scores (P = −0.001) and change in forced expiratory volume in 1 sec (ΔFEV1) were statistically significant (P = 0.001). A decrease in FeNO values from baseline was accompanied by significant increase in ACT scores and an improvement in FEV1.

Conclusion:

The FeNO values correlated inversely with the ACT scores as well as FEV1 proving its scope for incorporating it in the clinical setting for monitoring asthma treatment.

Introduction

Asthma is a heterogenous disease affecting around 7.9%[1] of Indian children. Asthma control test (ACT) has shown to be a reliable test valid for categorizing the control of asthma symptoms. Spirometry provides objective measurements of lung function to assess the severity, and treatment response. Yet ACT scores are subjective and few children have difficulty performing spirometry. Since the essence of asthma is chronic airway inflammation, it is particularly important to seek objective airway inflammation indicators. In this study, we investigate the correlation between fractional exhalation of nitric oxide (FeNO) values, asthma control scores and spirometry parameters aiming to elucidate their relationship and potential implications in management.

Subjects and Methods

Study design

Prospective observational 6–8 weeks follow-up study was chosen to evaluate both the baseline value as well as the effect of treatment initiation on parameters including FeNO, ACT as well as spirometric values.

Study setting

Pediatric pulmonology and general pediatric outpatient set up between December 2022 and February 2024.

Inclusion criteria

Children above 6 years till 18 years of age, who have been diagnosed with asthma and are “steroid naïve,” defined as not on oral/inhaled corticosteroids (ICS) for past 4 weeks, were included in the study.

Exclusion criteria

Those with history of upper respiratory tract infection 3 weeks before recruitment/immunodeficiency, history of smoking in parents were excluded. Those who do not give consent/assent, did not report for follow-up, were unable to perform FeNO/spirometry were also excluded.

Sample size calculation

A sample off 56 were enrolled, based on regression method with sample correlation coefficient of 0.70 and population correlation coefficient of 0.85 with power of 80% and alpha error of 5%.[2]

Statistical methods used

All statistical analysis were performed using the Statistical Package for the Social Sciences (SPSS), version 17 was developed by (SPSS Inc, Chicago, Illinois, United States) for Microsoft windows. Descriptive statistics were presented as numbers and percentages The data were expressed as mean and standard deviation. For within the group comparison paired t-test/Wilcoxon singed ranks test. Chi-square test was used for comparison between two attributes. Pearson correlation coefficient/Kendall’s tau 2 of 10 analysis was used to examine the association of two related variables. Two-sided P < 0.05 was considered statistically significant.

Methodology

The Ethics committee approval was obtained prior to the start of the study. We included 56 children who completed both visits after excluding 38 children due to varied reasons as depicted in Figure 1. Through a pre structured proforma, clinicodemographic data and examination findings were recorded, FeNO, ACT, Spirometry were done as per standard technique.[2,3] Childhood ACT score were used in children less than 12 years. ACT were used in children more than 12 years and they were classified as well controlled (20–25), not well controlled (16–19) and poorly controlled (<15) accordingly. FeNO values of more than 35 and 50 were defined as high in children less than 12 years and more than 12 years respectively. After evaluation they were treated as per standard practice. During follow-up visit, within a window period of 6–8 weeks, recording of exacerbation details, examination, treatment, compliance, ACT scoring, FeNO and spirometry were repeated and data analysis was done.

Figure 1.

Study flowchart. The recruitment process of the study as a study flowchart. A total of 38 children were excluded from the study for the reasons mentioned in the flow chart. Five subjects were lost to follow up and a total of 56 subjects who completed both visits were included

Results

Final analysis included 56 steroid naïve asthmatic children with male predominance (70%). Family history was present in about 30%, Asthma with allergic rhinitis (AR) was present in 48% of them. Majority of them presented to us with cough as their presenting symptom (86%) and all of them were started on either ICS alone or ICS + long-acting beta-agonist (LABA).

The mean ACT scores prior to therapy was 18.7 ± 1.58 with 75% having score between 16 and 19 (not well controlled). In my study nobody was in poorly controlled category during the time of enrolment as we did enroll cases during an acute exacerbation. On visit two, after starting treatment all my study population went into category of well controlled as per age-appropriate ACT scores. Mean ACT at visit two increased to 23.3 ± 1.318. Delta change between both visits (visit 2 and visit 1) was 4.49 ± 0.27. This delta changes before and after treatment was statistically significant with P value of 0.000 [Table 1].

Table 1.

Changes in asthma parameters between two visits

	Mean±SD			P
	Baseline visit	Visit 2	Δ change (v2−v1)
ACT	18.77±1.58	23.26±1.313	4.49±0.27	0.000
FENO	41.8±33.26	20.26±14.57	−21.54±18.69	0.000
Spirometry indices
FEV1	84.5±14.44	93.5±11.67	9±2.77	0.000
FVC	91±16.435	96.8±10.997	5.804±13.394	0.002
FEF25-75	75.82±20.39	85.05±13.413	9.232±22.327	0.003

The changes of asthma clinical parameters and ACT scores between both visits. As ACT score increases towards better asthma control FeNO values decreases significantly (P=−0.000). Likewise, as spirometric values increase FeNO values also decreases significantly (P=−0.000). ACT=Asthma control test, FeNO=Fractional exhalation of nitric oxide, FEV1=Forced expiratory volume in 1 s, FVC=Forced vital capacity, FEF=Forced expiratory flow, SD=Standard deviation

Mean forced expiratory volume in 1 sec (FEV1) at baseline visit one and at visit two was 84.5 ± 14.44 and 93.54 ± 11.6, respectively. At baseline visit around 28.6% of my study population had moderate to severe asthma as per FEV1 values, which post treatment at 6 to 8 week follow-up had reduced to a mere 11%. This delta change between two visits was statistically significant (P = −0.000) Similar reduction in other spirometry values including forced vital capacity (FVC), forced expiratory flow (FeF) 25%–75% was observed between baseline and follow up visit. Delta changes being significant with P values 0.002 and 0.003 for changes in FVC, FeF 25%–75% between both visits, respectively [Table 1].

Mean FeNO at visit one was 41.8 ± 33.26 that decreased to 20.26 ± 14.57 at visit 2. Change of FeNo between both visits in our study was −21.54 ± 18.69, which was statistically significant (P = 0.000) [Table 1].

Analytical comparison between FeNO and ACT score between both visits showed that decrease in FeNO values from baseline was accompanied by significant increase in ACT scores as well (P = 0.001) and vice versa. Thus, our study shows that better asthma control as reflected by an increase in ACT scores results in decrease in FeNO value.

Out of 48 patients who had increase in FEV1 score in second visit, FENO decreased in 89.5%, which is statistically significant. This states that significant decrease in FeNO leads to improvement in lung function. Around 7% of my study population had abnormal FEV1/FVC at baseline visit and in all of them FeNO values were in the intermediate to high range though this was not statistically significant. On visit two after treatment as with decrease in FeNO values FEV1/FVC ratio improved but was not statistically significant. At baseline visit, nine had abnormal FVC of which 78% had intermediate to high FeNO. At visit two, 53 had normal FVC out of which 70% had normal FeNO (P = −0.943) [Table 1].

In my study, 30 children (53.5%) had abnormal FeF 25%–75%, among that 70% had intermediate to high FeNO. FeF 25%–75% remained abnormal in only 16 (28.5%) children during the second visit. Among them 50% continued to have intermediate to high FeNo, which was not statistically significant. 30% of my study population had family history of atopy, allergy, asthma. Among them 88.3% had FENO value in intermediate to high level. This association was statistically significant (P = −0.002).

Though not our primary study objective we compared FeNO values with history of AR associated with asthma (A + AR) and found that it was not statistically significant (P = −0.123).

Discussion

Change of FeNO between both visits in our study was −21.54 ± 18.69 which was statistically significant. In a study done by Papakosta et al. there was significant reduction in FeNO values from baseline to visit two (P < 0.000) and in the same study children, who had received ICS showed decrease in FeNO values.[2]

Many studies have proposed FeNO as a biomarker to help diagnose and track the severity of asthma in children.[2,4] Recent study showed high FeNO value in children have been shown to indicate more likely corticosteroid dependent inflammation. In our study to 64% had intermediate to high FeNo which after ICS came down to 29%.[5]

The study done by Wandalsen et al. in 2015 started that in addition to the more conventional clinical tools including history, physical examination, and lung function test, non-invasive FeNO technique is a useful tool for tracking airway inflammation and evaluating the efficacy of corticosteroid therapy in asthmatic patients.[5]

Some studies have suggested that FeNO may be used for tapering ICS and can be used as indicator of drug compliance and monitoring adherence.[6,7] In a study published in Indian journal of medical research,[8,9] the baseline ACT for newly diagnosed asthmatic children was 18.78 ± 3.68. After initiation of therapy mean value significantly improved to 22.53 ± 2.81 at end of 6 weeks. Similar results had been observed, significant improvement of asthma symptom score from baseline and follow-up with ICS.[2,3]

In my study, Mean FEV1 at baseline visit and at second visit was 84.5 ± 14.44 and 93.54 ± 11.6. At baseline around 28.6% of my study population had moderate to severe asthma as per FEV1 values which post treatment at 6 to 8 week follow-up had reduced to a mere 11% like a Randomized control trial published in journal of allergy and clinical immunology.[9]

Study published in Respiratory research[10] showed that children who are on ICS + LABA, lung function showed a significant improvement in terms of symptoms as well as FEV1 values. Analytical comparison between FeNO and ACT score between both visits showed that decrease in FeNO values from baseline was accompanied by significant increase in ACT scores as well (P = 0.001) and vice versa. Thus, our study shows that better asthma control as reflected by an increase in ACT scores results in decrease in FeNO value and hence FeNO could be incorporated with the routine clinical monitoring in childhood asthma.

Study done in Greece on “ACT score and correlation with FeNO and FEV1”[2] showed that between both visits there was negative correlation between ACT scores and FeNO. In a study published in Allergy rhinal[11] in subjects greater than 15 years, similar negative correlation was found between ACT and FeNo values. This study concluded that along with clinical assessment in every individual FeNO should also be assessed. However there have been reports, where correlation between ACT and FeNO values have not been proven conclusively.[12,13,14]

Similar study done on relationship of ACT with pulmonary function and exhaled nitric oxide published in Ann Allergy Asthma Immunol[15] showed weak correlation between ACT and FeNO (r = −0.310). This study was done on 105 asthmatics. There has been varied results and no uniform consensus in relation between FeNo values and ACT. Studies state that the lack of agreement may be partially the result of inhaled corticosteroid treatment.

As mentioned by studies done by Kanniess et al., Kharitonov et al., Jones et al. and Beck-Ripp et al. inhaled corticosteroid has a quick, potent, dose -dependent effect on airway inflammation which can complicate any analysis attempting to link relation between FeNO and clinical expression of asthma.[16,17,18,19] Out of 48 patients who had increase in FEV1 score in second visit, FENO decreased in 89.5%, which is statistically significant. This states that significant decrease in FeNO leads to improvement in lung function.

Around 7% of my study population had abnormal FEV1/FVC at baseline visit and in all of them FeNO values were in the intermediate to high range though this was not statistically significant. On visit two after treatment as with decrease in FeNO values FEV1/FVC ratio improved but was not statistically significant.

In my study, 30 children (53.5%) had abnormal FeF 25%–75%. Among that 70% had intermediate to high FeNO. FeF 25%–75% remained abnormal in only 16 (28.5%) children during the second visit. Among them 50% continued to have intermediate to high FeNo, which was not statistically significant.

In a study done by Xie et al. in China on correlation between FeNo and lung function parameters, weak negative correlation was seen between FeNO and FEV1/FVC (P = 0.042).[20] Few similar studies have stated that significant correlation was seen between FeNO and lung function parameters such as FEV1, FEV1/FVC, FEF 25%–75%[5,6] Study done by Al Ghobain Mo et al. found a strong inverse relationship between FeNO and FEV1%.[21]

Study done by Kasteleyn et al. has mentioned that in comparison with patients with high FeNo levels those with lower FeNO levels showed better FEV1, FEV1/FVC values as in our study.[22] But there has been disputable association between FeNO and spirometry data as in study done in 2018 in Brazil[23] showed that the FeNO values did not have significant association with FEV1 values.

There are similar articles where FeNO did not correlate exactly with spirometry values.[5] In our study Δ change in FeNO correlated with Δ change in FEV1 whereas FeF 25%–75%, FEV1/FVC between baseline and second visit was not statistically significant. In a study done and published in Journal of Thoracic Medicine,[7] FeNO significantly correlated with spirometry parameters including FEV1, FEV1/FVC, FeF 25%–75% but did not correlate with FVC. Most recent study done in 2023 on correlation between FeNO and spirometry in patients with asthma,[19] significant inverse relation was noted in terms of mean FEV1/FVC and FEV1 values.

30% of my study population had family history of atopy, allergy, asthma. Among them 88.3% had FeNO value in intermediate to high level. This association was statistically significant (P = −0.002). Several studies have indeed explored the association between FeNO level and positive family history of asthma.

The study was conducted on Chinese children with Asthma and Allergy[24] have found that individual with family history of asthma tend to have higher FeNO values compared to those without such a history. Though not our primary study objective we compared FeNO values with history of AR associated with Asthma (A + AR). Out of 56 of my study population, 27 had AR along with asthma of which 74% had intermediate to high FeNO which was not statistically significant.

Study done by Xie et al. has stated that compared to children with Asthma alone, children with rhinitis had a considerably higher FeNO levels which was statistically significant.[20] This study was done on 100 asthmatic children. There are some conflicting data of FeNO in a study done by Kim et al. where subjects were divided into three groups - AR alone (AR), Asthma alone, AR with Asthma (A + AR). In this study compared to AR group, asthma group had higher FeNO levels.[8]

Another study done by De bot et al. elevated FeNO was seen more in children with AR than in asthma + AR.[25] Further research with well-defined subgroups and large sample size will shed light on these challenges. In a study published in European Respiratory Journal[26] showed that FeNO may be used to identify people, who have asthma that is challenging to treat and who are susceptible to appropriate dose of corticosteroid therapy.

Conclusion

As ACT score increases toward better asthma control, FeNO values decreases significantly. As FEV1 values increases indicating a decrease in the severity of asthma, FeNO values also decreases significantly.

FeNO along with ACT and FEV1 improved significantly after starting treatment with ICS in correct dose and good compliance in steroid naïve asthmatic children. Hence FeNO values are comparable to ACT and FEV1 in monitoring the response to treatment with ICS in asthmatic child.

Thus, FeNO can be incorporated as a routine tool in clinical practice along with ACT and spirometry, to scrutinize the compliance to ICS therapy and to monitor control of asthma in children.

Limitations

Further large-scale studies with longer term follow up of variation in FeNO values along with asthma clinical symptoms are needed to provide a better comprehensive view in this regard.

It was not feasible for us to record other inflammatory markers in childhood asthma, such as Ig E levels, Eosinophil counts etc., due to invasive nature of these test along with FENO recordings to prove its direct implication

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.