As observed in The additional online file, there was a scarcity of information particularly for biomarkers at different exacerbation levels. It is also unclear to us whether any of the variables that changed with exacerbation severity are causally-related. Hence, longitudinal studies and/or less restrictive eligibility criteria would be needed to address all these questions. One difficulty in tackling such problems is the enormous amount of time and expense involved in implementing such studies. In addition, the current methods for data analysis in clinical studies have limitations imposed by the assessment of the reduction in frequency or total suppression of exacerbation episodes (i.e. rare event or "non-event").