INTRODUCTION
Asthma is a chronic inflammatory disorder of the respiratory system, characterized by airway hyper-responsiveness, which in turn leads to recurrent episodes of wheezing, breathlessness, chest tightness and cough, in particular at night or early morning.[1
The immediate objective of asthma treatment is to achieve and maintain control of symptoms. The asthma control test (ACT) scoring, levels of fractional exhaled nitric oxide (FeNO), and spirometry can adequately assess severity and symptom control in asthmatics. FeNO is a reliable, noninvasive and reproducible test for discerning airway inflammation in patients of asthma that correlates with disease activity. The role of FeNO as a predictor of asthma exacerbations is uncertain.[2
The study aimed to assess and compare the ability of FeNO, spirometry, and ACT in predicting future exacerbations of asthma and their correlation with each other.
MATERIALS AND METHODS
The study population consisted of patients with asthma, aged 18–65 years, from the outpatient and inpatient departments of Respiratory Medicine, Kasturba Medical College, Manipal. Asthma was diagnosed based on GINA guidelines.[1
We collected the demographic and clinical data of patients such as age, sex, clinical diagnosis, duration of asthma, corticosteroid use, comorbidities, blood parameters such as hemoglobin, total leukocyte count, differential cell counts, and absolute eosinophil count.
All patients underwent FeNO and spirometry. Spirometry and FeNO were performed as per the American Thoracic Society (ATS) guidelines.[3 4
We followed the patients for 4 months and captured the details of the worsening of symptoms and unplanned hospitalizations. The data were extracted either from history or by reviewing hospital records of the patient.
Statistics
Anticipating at least 30% of asthma patients to go for one or more physician visits in 4 months, and assuming a sensitivity of 70% for the tests, with a 95% confidence, a sample size of 154 asthma patients was estimated. The data were analyzed using SPSS software version 25.0 (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY, USA: IBM Corp.). Test of normality was done using the Shapiro–Wilk test. Significant values concerning multiple parameters indicated skewed distribution. Thus, Mann–Whitney U test for the binary outcomes was used for the assessment of FeNO, spirometry, ACT in patients with and without exacerbations. Spearman's correlation coefficient was used to analyze correlations between FeNO, spirometry, ACT, and number of exacerbations.
RESULTS
Our study population comprised of 154 patients. The mean age of the population was 44 years, ranging from 18 to 65 years. The population size included 154 patients with 67 male (43.5%) and 87 female (56.5%) [Table 1 ].
Table 1: Baseline data for 154 patients
Most of the patients were poorly controlled asthma with a mean ACT score of 14.8. 81 (52.6%) patients were on inhaled steroids (ICS) whereas 73 (47.4%) patients were not on ICS [Figure 1 ]. Fifty-eight (37.7%) patients had allergic rhinitis as comorbidity.
Figure 1: Population distribution with respect to history of treatment with ICS
At the end of 4 months of follow-up, 43 (38.7%) patients had exacerbations. When we compared the age of the subjects to FeNO, FEV1%, and ACT score using Spearman's correlation coefficient (r = −0.20, −0.30, and −0.19, respectively) we found a significant negative correlation with all the three parameters (P < 0.05). On comparison of the gender groups, we found that FeNO was higher in males when compared to females but not statistically significant (P = 0.67).
We found that the FeNO levels median (interquartile range [IQR]) were lower in patients with exacerbations (22 [15–61]) compared to patients without exacerbations (25 [15–43]), but this difference was not statistically significant (P = 0.7) [Table 2 ]. We also observed that there was a statistically significant difference in FEV1% values when we compared the patients having exacerbations in whom median (IQR) FEV1% predicted was 68 (55–79) in comparison with those without exacerbations who had a median (IQR) FEV1% predicted of 75 (65–88) (P = 0.013). ACT scores in patients with exacerbations were significantly lower, with a median (IQR) of 12 (10–16), while patients without exacerbations had a median (IQR) of 16 (14–18), the difference being statistically significant (P = 0.003).
Table 2: Comparison of the variables between the presence and absence of the exacerbation using Mann-Whitney U -test
We observed a poor positive correlation of FEV1% with FeNO, which was not statistically significant (correlation coefficient 0.031). There was a poor negative correlation of ACT with FeNO, which was statistically significant (correlation coefficient −0.167). The duration of asthma showed no correlation with FeNO, FEV1%, and ACT [Figure 2 ]. FeNO showed a fair positive correlation with absolute eosinophil count (correlation coefficient 0.247) [Figure 3 ]. There was no significant correlation between AEC to either FEV1% or ACT score.
Figure 2: Scatterplot showing the correlations between FeNO, FEV1%, ACT score as measured by Spearman's correlation coefficient. Significant correlation between FeNO and ACT score: Correlation co-efficient = 0.167 (P = 0.038). FEV1 = Forced expiratory volume in the first second, FeNO = Fraction of exhaled nitric oxide, ppb = parts per billion, ACT score = Asthma control test score
Figure 3: Scatterplot showing correlation between FeNO and AEC. Correlation co-efficient = 0.247 (P = 0.002). FeNO = Fraction of exhaled nitric oxide, ppb = parts per billion, AEC = Absolute eosinophil count
The difference in FeNO, ACT, and FEV1 values in patients with and without allergic rhinitis was not statistically significant.
In our study, we found a statistically significant difference in FeNO, FEV1%, and ACT score in between populations receiving ICS and not on ICS. Levels of FeNO were lower in patients on ICS (median [IQR], 22 [14–38]) when compared to patients who were not on ICS (30 [17–58]) (P = 0.050). FEV1% was lower in patients on ICS (median 69, IQR 57–82) in comparison to (median 78, IQR 68–90) those who were not on ICS (P = 0.003). The ACT score was lower in the population on ICS [median (IQR), 14 (12–16)] than those who were not on ICS [median (IQR), 16 (14–18)] (P < 0.001) [Table 3 ].
Table 3: Comparison of fraction of exhaled nitric oxide, forced expiratory volume in the one second, and asthma control test score scores with the use of steroid using Mann-Whitney U-test
DISCUSSION
Our study showed that FeNO to be less useful in predicting exacerbations of asthma compared to FEV1% and ACT scores. Lung function and asthma control assessment tests proved independent predictors of asthma exacerbations as per prior studies.[5 6 7
The FeNO level, in our study, did not predict exacerbations of asthma. The result was in concordance with other studies.[8 9 et al . found that FeNO was not useful either independently or in combination with symptom scores in predicting exacerbations in asthmatic children.[10 et al . demonstrated that FeNO can predict future exacerbations irrespective of the past exacerbation history.[11 12
The utility of a single baseline FeNO is unestablished. Single baseline FeNO level as well as FEV1% were not related to asthma outcomes at the end of 3 months, as per a meta-analysis of seven randomized control trials in children by Fielding et al .[13
In this study, ACT score correlated negatively with FeNO, in contrast to a previous study by Menzies et al .[14
We observed a negative correlation between the percentage of predicted FeNO level and FEV1%, but it was not statistically significant. This finding is in agreement with the study by Mogensen et al ., where they found elevated FeNO and blood eosinophils were associated with poorer lung functions but not increase in asthma exacerbations.[15 et al . found that FeNO did not correlate with spirometry measurements.[16 17
Kavitha et al . showed that FeNO negatively correlated with FEV1% and ACT score.[18 19
A study by Shrestha et al . showed that IgE correlated well with FeNO and AEC, but the correlation between FeNO and AEC was weak and FeNO was more sensitive as well as specific compared to IgE and AEC to identify asthma and atopy.[20
FeNO level increased with the advancement of age, according to the present study. The previous studies have shown inconsistency in the variation of FeNO with age. A few studies had shown an increase in FeNO with age.[21 22 23
The study showed that the FeNO level was higher in male compared to female, but this difference was not statistically significant. This is in agreement with a prior study, which suggests FeNO is higher in male compared to the female population.[21 et al ., age and height were determining factors, but FeNO was independent of gender.[22
Low FeNO level, FEV1%, ACT score were noted in the subset of patients on ICS. Corticosteroids suppress inflammation and consequently reduce the levels of FeNO. This result is in agreement with previous studies that have stated the usefulness of FeNO in predicting steroid responsiveness.[24 25
FeNO was higher in patients with allergic rhinitis, though statistically not significant. This finding is in agreement with the studies by Ciprandi et al . and Kumarand Gupta.[26 27 28
Our study had certain limitations. A control group was absent. The follow-up period was short, i.e., for 3 months. There was the nonuniformity of treatment of patients, especially corticosteroids, which might have affected the measured values, such as FeNO. Even though we stressed on the inhaler technique and compliance with the given treatment during the follow-up, we could not ascertain it completely and may have a bearing on the outcome. We measured the parameters such as FeNO, FEV1%, and ACT score at the baseline only. A serial recording of FeNO may be required to see if the FeNO level was influenced by exacerbations or vice versa. As the assessment of the three study parameters were not done before the initiation of treatment, this may lead to bias. For example, FeNO could be lesser in patients treated already with corticosteroids.
Larger prospective cohort studies may be needed to ascertain the prognostic value of serial FeNO levels in predicting the loss of asthma control. The cost-effectiveness of serial FeNO measurements also needs to be taken into consideration. We need studies to establish a reference value of FeNO in adult nonsmoker Indian population.
CONCLUSIONS
In our study, FEV1% and ACT score could predict exacerbations of asthma whereas FeNO could not. FeNO level correlated inversely with ACT score, i.e., symptom control. FeNO level, as well as ACT score, decreased with inhaled corticosteroid usage. There was no significant correlation between FeNO level and airflow limitation. FeNO level linearly correlated with absolute eosinophil count.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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