DNase alone had negative effects on pleural infection, and this may be a clue about the mechanism of action. In MIST2, the need for surgical intervention was increased with DNase alone, and in parallel, there was a nonsignificant trend toward increased fever in the DNase-alone group.2 This is in contrast to the result seen with combination tPA and DNase in which there was a statistically significant reduction in the need for surgery and a statistically significant reduction in the odds of fever by day 3 compared with placebo. Although these were secondary outcome measures and should, therefore, be treated with some caution, one possible explanation for this result is that DNase alone liberated bacteria (eg, from biofilms), but in the absence of an agent to improve pleural drainage (ie, a fibrinolytic), this resulted in increased systemic sepsis. The effect of DNase alone on neutrophil extracellular traps would also be a reasonable potential mechanism. Within the MIST2 study,2 we specified that surgical intervention should occur in response to both ongoing pleural collection and markers of systemic sepsis after treatment (eg, raised inflammatory markers and fever), and this might explain the negative effects of DNase alone on the surgical outcome. We agree that further translational work is now required to elucidate the interactions of tPA, DNase, and the pleural infection microenvironment, which create the significant clinical results seen in MIST2.