Demographic characteristics of the subjects
Altogether, 100 subjects were analyzed in this study (Table 1). The average age at registration was 58.5 ± 12.2 years; 58% of the patients were male (n = 58) and 61% were atopic (n = 61); 12 (12%) of the subjects were current smokers and 51 (51%) were ex-smokers; 37 subjects (37%) used daily oral corticosteroids (OCS). The median FeNO at baseline (VE) was 27.5 ppb (range, 17.0–47.5 ppb). During the 3-year follow-up period, 59 subjects (59%) experienced at least one exacerbation, and the median number of exacerbation events was 1.5 (interquartile range, 0–4).
Annual changes in FeNO
We used FeNO values at 25 ppb and 50 ppb as thresholds indicating low and high levels of FeNO based on the ATS guidelines8. As shown in Figure 2, 24% of the subjects had FeNO levels of 50 ppb or greater at baseline (VE); 50% of them still had FeNO level of at least 50 ppb after 1 year (V1), and 75% of them had sustained FeNO level of at least 50 ppb after 2 years (V2). On the other hand, 47% of the subjects had FeNO levels less than 25 ppb at baseline. Approximately 85% of them still had FeNO levels lower than 25 ppb after 1 year, and 82% of them had FeNO less than 25 ppb after 2 years.
We classified the subjects into three groups according to FeNO values at VE, V1, and V2: (1) the sustained high group (≥50 ppb at all three visits), (2) the sustained low group (<25 ppb at all three visits), and (3) the intermediate group, which did not meet any of the two aforementioned criteria. Nine (9%) subjects were classified into the sustained high group, 33 (33%) into the sustained low group, and 58 (58%), intermediate group. After 3 years (V3), 88% of the sustained high group had FeNO ≥50 ppb and 83% of the sustained low group had FeNO <25 ppb (Figure 2).
As shown in Table 1, the use of regular OCS was frequent in the sustained high group, and the prevalence of sinusitis was low in the sustained low group. During the follow-up period, exacerbation events were more frequent in the sustained high group than in the sustained low group (median number of exacerbation events, 3 vs. 0, p = 0.01, Figure 3).
Analysis of the intermediate group
We calculated the individual coefficients of variation (CV) of FeNO levels from VE to V3 for subjects in the intermediate group (median, 0.335; range, 0.200–0.520) and classified them into two groups (high CV and low CV intermediate groups, n = 29 each) based on the median value. Table 2 shows the clinical characteristics of the two groups. There were no significant differences in age, body mass index, or pulmonary function test results between the two groups. The asthma control test score, asthma quality of life questionnaire score, and score for sinusitis (Lund–Mackay score) also did not differ between the two groups. The smoking and depression scores (Self-Rating Depression Scale) were significantly higher in the high CV intermediate group than in the latter. The daily dose of ICS tended to be higher in the high CV intermediate group, although this did not reach statistical significance. Moreover, exacerbation-free survival was shorter in the high CV intermediate group than in the low CV intermediate group (Figure 4). The Kaplan–Meier curve for exacerbation-free survival of the high CV intermediate group was similar to that of the sustained high group, and the Kaplan–Meier curve of the low CV intermediate group was similar to that of the sustained low group (p = 0.03, log-rank test among the four groups) (Figure 4). When subjects in the high CV intermediate group were classified into two groups based on the pattern of FeNO variation by cluster analysis (Figure 5), there was no difference in exacerbation-free survival among the clustered groups; most of the subjects in the high CV intermediate group experienced their first exacerbation within 1 year (Figure 6).
In the intermediate group, the multivariate Cox proportional hazards model showed that the CV of FeNO was a significant and independent risk factor for the early onset of the first exacerbation event (Table 3). Furthermore, the multivariate Poisson regression model showed that blood eosinophil count and CV of FeNO were significantly associated with exacerbation frequency during the follow-up period (Table 3).
Table 3. Factors associated with exacerbations in the intermediate group
Exacerbation-free survival
|
Variable
|
Hazard ratio (95% CI)
|
P-value
|
CV of FeNO
|
6.01 (1.09-29.29)
|
0.04
|
Exacerbation frequency
|
Variable
|
Rate ratio (95% CI)
|
P-value
|
CV of FeNO
|
7.76 (2.32-26.15)
|
0.001
|
CV, coefficient of variation; FeNO, fractional exhaled nitric oxide.
The hazard ratio was derived from the multivariate Cox proportional hazards model, and the rate ratio was derived from the multivariate Poisson regression model. Both models were adjusted for age, sex, body mass index, pack-years, blood eosinophil count, and FeNO at baseline.