In retrospect, 2014 will be seen as the year in which idiopathic pulmonary fibrosis (IPF) therapies came of age. Treatment effects reported previously were inconclusive with regard to both pirfenidone (two positive studies [1, 2] and a negative study [2]) and nintedanib (a single phase II study in which trends were marginal due to under-powering [3]). The ASCEND pirfenidone trial [4] and the two INPULSIS nintedanib trials [5] ended uncertainty. The two agents appear remarkably similar in both tolerability and efficacy, with a 50% reduction in forced vital capacity (FVC) decline. Whither now? No biomarker data exist to indicate that either agent might be more efficacious in individual patients. Initially, the routine use of these therapies is likely to be sequential, with one agent replaced by the other when side-effects are problematic or treatment failure is evident, however this is defined. In the longer term, combinations of pirfenidone and nintedanib appear attractive in principle, based both on the possibility of synergy in a disease in which there is a multiplicity of coactivated pathways, and also on precedence in other lung diseases including asthma, chronic obstructive pulmonary disease, lung cancer and pulmonary artery hypertension [6]. However, the road to combination regimens in IPF is likely to have many twists and turns. Two particular problems need to be addressed, even supposing that additive or synergistic benefits exist (something that has yet to be established). Tolerability issues are important, as both agents give rise to significant gastrointestinal side-effects. It should also be understood from the outset that demonstrating efficacy will not be straightforward. Intense multinational activity was needed to show treatment benefits against placebo arms characterised by FVC declines approximating 220 mL·year^–1. The treatment advances of 2014 sound the death knell of placebo-controlled evaluation in IPF: it seems inevitable that combination regimens will be compared with monotherapy. The rate of FVC decline of approximately 110 mL·year^–1 in patients receiving either pirfenidone or nintedanib will pose major challenges with regard to powering future trials [6]. The current issue of the European Respiratory Journal (ERJ) features two studies that are highly relevant to tolerability and study design issues.

Multidrug-resistant tuberculosis (MDR-TB) is a serious obstacle to TB control [1]. The disproportionately negative outcomes among patients with drug resistance reflect a strong global need to develop new anti-TB drugs [2, 3]. Delamanid is a novel anti-TB agent that has recently been approved for the management of MDR-TB patients [4]. Treatment of MDR-TB patients with delamanid in combination with an optimised background regimen for 2 months significantly improved 2-month sputum culture conversion (SCC) by ~50%, in comparison to treatment with placebo plus an optimised background regimen [5]. Additionally, compared to ≤2 months of treatment, ≥6 months of treatment with delamanid plus an optimised background regimen was associated with higher favourable treatment outcomes (55.0% versus 74.5%) and significantly lower mortality (8.3% versus 1.0%, p<0.001) [6]. While early SCC is recognised as a biomarker in the development of anti-TB drugs [7–9], the impact of early SCC on long-term mortality in MDR-TB patients has only been assessed in retrospective cohort analyses [10–13]. Using updated prospective data from the delamanid development programme, we assessed the association between 2-month SCC and mortality in MDR-TB patients and expanded a previous analysis on the impact of long-term treatment with delamanid on mortality.

We thank M. Miravitlles and C. Llor for their comments. While we do, of course, agree with their statement that it is impossible to detect bacteria when no sample is obtained, this issue is addressed in our study by the subgroup analysis, which examines only those patients with sputum samples tested for bacteria. This group demonstrates identical findings to our main cohort: that C-reactive protein (CRP) levels and body temperature are strongly associated with viral detection (either alone or with bacteria) but not with bacterial detection alone, and suggests that the findings in the main cohort are not due to a lack of sputum samples. We would also like to point out that it is similarly impossible to detect viruses if one does not test for them and of the studies referenced by M. Miravitlles and C. Llor as demonstrating an association between CRP level, sputum purulence and bacterial detection [1–5], none has tested for respiratory viruses apart from that by Daniels et al. [5] and this was not in a standard manner. Interestingly, another study referenced by the authors [6] did systematically test patients with exacerbations for both viruses and bacteria, and demonstrated that although infective exacerbations were associated with sputum purulence compared with those where no pathogen was detected, it found no difference in sputum purulence between exacerbations with viral or bacterial detection. It is also notable that in the randomised, placebo-controlled trial of doxycycline by Daniels et al. [5], although there was a weak association between CRP levels >50 mg·L^–1 and a favourable response to antibiotics, there was no demonstrable association between antibiotic response and bacterial detection. Viruses were not tested for in a meaningful way in this study but only by serology for selected viruses, and patients with fever were excluded, which would be likely to exclude many patients with viruses. No analysis was conducted to examine the association between the small number of viruses detected by serology and CRP, sputum purulence or response to antibiotics. Therefore, the place of viral detection within this evidence base is uncertain and any conclusion about associations between bacterial detection, sputum purulence, CRP levels and response to antibiotics must acknowledge this uncertainty.

Formerly regarded as a rare disease, bronchiectasis is now increasingly recognised and a renewed interest in the condition is stimulating drug development and clinical research. Bronchiectasis represents the final common pathway of a number of infectious, genetic, autoimmune, developmental and allergic disorders and is highly heterogeneous in its aetiology, impact and prognosis.

The goals of therapy should be: to improve airway mucus clearance through physiotherapy with or without adjunctive therapies; to suppress, eradicate and prevent airway bacterial colonisation; to reduce airway inflammation; and to improve physical functioning and quality of life.

Fortunately, an increasing body of evidence supports interventions in bronchiectasis. The field has benefited greatly from the introduction of evidence-based guidelines in some European countries and randomised controlled trials have now demonstrated the benefit of long-term macrolide therapy, with accumulating evidence for inhaled therapies, physiotherapy and pulmonary rehabilitation.

This review provides a critical update on the management of bronchiectasis focussing on emerging evidence and recent randomised controlled trials.