It could be argued that a weakness of the work of Klein et al14 is that it is totally devoid of any mechanistic insights. This is true, but, perhaps paradoxically, it may be an advantage of their biomarker. Of course, measuring specific cytokines may give mechanistic insights of great importance, but if you measure the wrong cytokine, you will be misled (clinically and in randomized controlled trials). Thus, measuring a signal well downstream in the inflammatory pathway, such as a pulmonary hot spot, while telling us nothing about pathobiology, also is much less vulnerable to erroneous assumptions than measuring the upstream inflammatory cascade. Yet again, this underscores that the only really essential ability required is that of asking the right question. In this case, the question is, does the finding of a pulmonary hot spot correlate with a CF infective exacerbation in a clinically useful way.