In a recent paper on the INPULSIS trials, two duplicate 1-year randomised controlled trials evaluating nintedanib in the treatment of idiopathic pulmonary fibrosis (IPF) [1], we provided the methodological explanation for the apparent inconsistent results arising from the two different definitions of exacerbations used in those studies [2]. These trials reported vastly different findings in their pooled analysis [1]. Indeed, the risk of an investigator-reported acute exacerbation was lower by 36% with nintedanib compared with placebo but not statistically significant (p=0.08), while, after adjudication according to a complex definition involving multiple criteria, the risk was lower by 68% and statistically significant (p=0.001). We explained that such differences in risk reductions and in statistical significance are simply the result of including outcome events that are not actual exacerbations, leading to the phenomenon of treatment effect dilution and false nonsignificant effects [2]. The correct risk reduction of 68% based on the accurate adjudicated events is diluted to a less impressive and now nonsignificant risk reduction of 36% when "false" events were added in the same proportion to both groups.

Treatment of multidrug-resistant (MDR) tuberculosis (TB) (defined as resistance to at least isoniazid and rifampicin, two core first-line drugs for TB treatment) and extensively drug-resistant (XDR)-TB (defined as resistance to isoniazid and rifampicin plus any fluoroquinolone and at least one of the injectable drugs amikacin, capreomycin or kanamycin) are a challenge for both clinicians and public health specialists [1–5]. Treatment outcomes of difficult-to-treat MDR-TB cases (e.g. those with an extensive resistance pattern) are still unsatisfactory, adverse events frequent and severe, and the necessary drugs expensive [6].

In 2014, two landmark clinical trials (ASCEND and INPULSIS) were published demonstrating, for the first time, a treatment benefit for patients with idiopathic pulmonary fibrosis (IPF). Both pirfenidone and nintedanib were shown to have a clear therapeutic benefit in slowing the relentless disease progression evident in IPF patients. The results of these studies have had a major impact upon management of IPF patients worldwide, with subsequent changes made to international guidelines, which now recommend in favour of antifibrotic therapy. However, this is not the whole story: there are many unanswered questions with regard to the real-world treatment benefit and use of antifibrotic therapy. In this issue of the European Respiratory Journal, Noble et al. [1] present the pooled data of the three multinational, phase 3, placebo-controlled trials of pirfenidone in IPF patients, the ASCEND, and CAPACITY 004 and 006 studies. Examining the combined patient population reveals important insights about specific subgroups along with broader inferences that are only possible through pooled analysis.

The concepts of susceptibility and vulnerability are intertwined because vulnerability is sometimes a consequence of being susceptible. Women are more likely to be susceptible to chronic obstructive pulmonary disease (COPD) than men [1]. As many women continue to smoke during pregnancy, the impact of tobacco in women can begin before birth [2], because maternal smoking during pregnancy may increase the risk of childhood respiratory diseases [3] and reduce lung function [2]. Indeed, this susceptibility starts before women become smokers. For example, women with specific genotype variants are at a significantly increased risk of becoming heavy smokers [4], while those women with the haplotype TAS2R38 (proline-alanine-valine) have a genetic propensity to experience heightened bitter taste perception and an increased preference for menthol cigarettes [5]. Recent findings of the Global Youth Tobacco survey on adolescents aged 13–15 years showed that young girls smoke as much as young boys [6]. The early onset of smoking may have a greater deleterious impact on lung function among girls [7] because their lungs are smaller than those of males. Accordingly, the same exposure to a given number of cigarettes smoked can lead to more deleterious effects in women [8]. In this regard, once young females become smokers, addiction may be reinforced by both nicotine and the sensory and social contexts of smoking. Motivations associated with gender can provoke women to have different cues for smoking compared with males [9]; therefore, women are more vulnerable to the social context of smoking and can easily become involved in the nicotine addictive process, along with consequent disease risks.