This Asthma Clinical Research Network protocol prospectively evaluated biomarkers and characteristics associated with ICS response and additionally, determined whether a short term response or lack of response to ICS predicted longer term asthma control. With regard to biomarkers and characteristics as predictors of ICS response, only the response to a short acting β2-agonist (albuterol), low percentage 0.6) predicted FEV1, and FEV1/FVC ratio had a strong (r ≥ ± 0.6) correlation with response. Of potential importance was the observation that a short term non-response to ICS, 6 weeks with ≤ 5% FEV1 improvement, indicated that these individuals may not need ICS in their treatment program. That is, whether they were maintained on or taken off ICS, asthma control and other secondary outcomes of response were maintained and similar. It is important to note that of the 33 poor short term ICS responders, 17 were maintained on ICS long term and 3 of these improved their FEV1 to the responder range after four additional months on ICS. The long term ICS improvement in FEV1 for these three subjects (16, 14.5, and 12.3%) did not necessarily coincide with the baseline maximal β2-agonist reversibility (21.6, 3.0, and 11.7%, respectively). For the subjects with a short-term ICS response in FEV1, defined as improvement > 5%, who were subsequently taken off ICS, their asthma control worsened compared to subjects maintained on ICS (p=0.007). Secondary response outcomes had similar findings.
Although the prior Asthma Clinical Research Network study retrospectively demonstrated that albuterol response, FEV1
/FVC, FeNO, sputum eosinophils, and shorter duration of asthma diagnosis predicted ICS response as to FEV1
or bronchial hyperresponsiveness (7
), the present prospective study only showed the albuterol response, % predicted FEV1
, and FEV1
/FVC as strong predictive biomarkers. The inclusion and exclusion criteria were similar between the studies as well as the baseline lung function and bronchial hyperresponsiveness. For the present study compared to the prior study: the baseline FEV1
was 73 vs 74% predicted and PC20
0.75 vs 0.52 mg/ml, respectively. However, the biomarkers appeared different between the present study and the prior report. The FeNO was slightly lower in the present study, 13 vs 16 ppb, respectively. The present study had a higher percentage of subjects with an asthma diagnosis greater than 15 years, 71 vs 64%, and sputum eosinophils, 1.5 vs 1.0%, respectively. A similar β2
-agonist response was seen between studies, 21 vs 20%. Thus, besides the important difference between prospective and retrospective study analyses, some differences in baseline biomarkers could also have added to the differing study results.
Other investigators have suggested that FeNO and sputum eosinophils are markers of corticosteroid response. Little and colleagues (14
) reported that elevated levels of FeNO and sputum eosinophils before treatment were predictors of improvement in FEV1
with a course of oral corticosteroids. Smith and colleagues reported in 52 patients presenting with undiagnosed respiratory symptoms (27 asthmatic diagnoses) that the FeNO tertile of > 47 ppb predicted the greatest ICS response for all endpoints that they measured (15
). For the 27 asthmatic subjects the FeNO >47 ppb resulted in a 14.8 ± 6.4% increase in FEV1
after four weeks of ICS (fluticasone 500 mcg/d) therapy. In subjects with an FeNO 15-47 ppb, improvement in FEV1
was only 7.3 ± 4.7% and if < 15 ppb, the improvement was 2.2 ± 4.9%. Our study, using different methodology for FeNO measurement, did not demonstrate a significant correlation between FeNO and ICS improvement in FEV1
. However, as with most reported studies, we had very few individuals with FeNO > 47 ppb. With respect to sputum eosinophils, Pavord and colleagues (16
) demonstrated a significant positive correlation between sputum eosinophils and the improvement in PC20
with ICS treatment. Bacci and colleagues also demonstrated that improvement with ICS occurred in subjects with eosinophils > 3% for FEV1
, BHR, and symptoms (17
). However, long term asthma control was not determined in either study. We also found a significant correlation between sputum eosinophils and FEV1
improvement with ICS (p=0.04), but the correlation was weak r=0.17. Additionally, at the present time, induced sputum is not a practical clinical test (18
Szefler and colleagues in children 6-17 years of age defined response to an ICS, fluticasone propionate, as an improvement of > 7.5% (19
). Only 40% of these asthmatic subjects were responders to the ICS. Those that did respond had greater allergic inflammation (increased IgE, circulatory eosinophils, serum eosinophils cationic protein), increased FeNO, lower lung function, and decreased PC20
. We also found the lower FEV1
relationship to exist in adults. Those subjects who were responders to ICS over the six week trial had a lower starting FEV1
(68% predicted) compared to the non-responders 77% predicted. Thus, airway caliber may play a role indicating ICS responsiveness to some extent, but not totally since when low FEV1
was combined with maximum albuterol reversibility in a regression model, the low FEV1
was no longer a predictor of ICS response.
Deykin and colleagues demonstrated that the change in the percentage of induced sputum eosinophils during the first two weeks after ICS cessation was a useful predictor of subsequent deterioration of asthma control (20
). Neither FeNO nor methacholine PC20
were robust for being able to predict stability or deterioration upon ICS withdrawal. Of interest, it was estimated that 48% of subjects with mild-to-moderate asthma could discontinue ICS therapy without an increased risk of asthma deterioration over a period of at least 14 weeks. Either the prior ICS eliminated the inflammatory process or these subjects were poor responders to begin with. When prospective monitoring of either FeNO (21
) or sputum eosinophils (22
) have been used as reference points to guide ICS dosing strategies, both have been found to be superior to standard care in maintaining control while minimizing ICS dosing burden over time. However, these trials answered different questions than posed by the ACRN study.
Since it appears that predictive biomarkers and characteristics can give varying results, our observation suggests an intriguing possibility that the use of a simple short term ICS trial (six weeks) based upon FEV1 change appears to be a good indicator of longer term asthma control in our study population. Of the short-term non-responders to ICS, it did not matter whether they were maintained on or removed from this medication with regard to their long-term asthma control and other secondary outcome measures. Conversely, for short term responders, long term asthma control and secondary outcome measures were maintained with the continued use of ICS compared to removing this agent from the therapeutic regimen. Although the ICS induced change in PC20 to methacholine had some predictive value, these results were not as strong as for FEV1. Additionally, BHR testing is not as practical for office practice use as is spirometry.
The duration of both the short term (six week) and long term (four month) trials can be critiqued for their relatively short time intervals. We elected a 6-week short term interval as our prior study (7
) demonstrated that if a subject did not respond with regard to FEV1
in six weeks, progressive increases in ICS dosing over the next 15 weeks did not produce a further change in the results. Furthermore, Szefler and colleagues analyzed eight randomized, double-blind, placebo controlled clinical trials of at least 8-weeks duration and determined that the best observed effect with ICS occurred within three to four weeks for peak expiratory flow, asthma symptoms, supplemental albuterol use and FEV1
). As to long term asthma control, no study has addressed the issue of the length of time ICS are needed to be used to determine maximal benefit. However, for good to total asthma control, Bateman and colleagues demonstrated that even when the dose of fluticasone-salmeterol combination was increased to 500/50 mcg for one year and a two-week oral corticosteroid burst was added, approximately 30% of asthmatic subjects still were not well controlled depending on severity at enrollment (8
In summary, the short term response to ICS leading to FEV1 improvement appears to predict long term asthma control. With this relatively simple office procedure, spirometry, a determination of response can guide decision making in those patients who are ICS naïve or have been off ICS for a period of time, as to the continued use of ICS or elimination of it from the therapeutic regimen. However, it must be stressed that these results need to be confirmed in larger, longer term studies. If these follow-up studies, indeed, validate the results of our study, different therapeutic strategies would need to be established for the ICS non-responders.
Clinical Implications: The decision to use long term inhaled steroids could be based on a short term trial. Different therapeutic strategies would need to be established for non-responders.