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John P. Corcoran, MD; Najib M. Rahman, DPhil
Author and Funding Information

From the Oxford Centre for Respiratory Medicine (Drs Corcoran and Rahman), Oxford University Hospitals; Oxford Respiratory Trials Unit (Drs Corcoran and Rahman), University of Oxford; and NIHR Oxford Biomedical Research Centre (Dr Rahman).

CORRESPONDENCE TO: Najib M. Rahman, DPhil, Oxford Respiratory Trials Unit, Oxford University Hospitals, Old Rd, Oxford, OX3 7LE, England; e-mail: najib.rahman@ndm.ox.ac.uk


FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST the following conflicts of interest: Dr Rahman was the corresponding author for the Multicenter Intrapleural Sepsis Trial 2 (MIST2) study and is the current clinical director of the Oxford Respiratory Trials Unit, which received an unrestricted educational grant from Roche UK to the University of Oxford for the conduct of the MIST2 study. Dr Corcoran has reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(2):e71-e72. doi:10.1378/chest.14-1007
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Published online
To the Editor:

We would like to thank Dr Ntelios for his letter regarding the point/counterpoint editorial discussion on the treatment in pleural infection.1 Dr Ntelios discusses the potential mechanisms of combined intrapleural fibrinolytics and deoxyribonuclease (DNase) therapy in improving drainage in pleural infection and the potential causes of DNase monotherapy in increasing the need for surgical referral.

The second Multicenter Intrapleural Sepsis Trial (MIST2) study results demonstrated efficacy for improving radiographically measured pleural drainage with the combination of intrapleural tissue plasminogen activator (tPA) and DNase, whereas the agents given alone had no significant effect over placebo for the primary outcome measure.2 In the first MIST study, fibrinolytics alone were shown to have no significant effect over placebo.3 We assume that this is related to a combination of septation disruption and a DNase effect that could be related to either viscosity changes or treatment of intrapleural biofilms, although the exact mechanism is unclear.

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.

References

Corcoran JP, Rahman NM. Point: should fibrinolytics be routinely administered intrapleurally for management of a complicated parapneumonic effusion? Yes. Chest. 2014;145(1):14-17. [CrossRef] [PubMed]
 
Rahman NM, Maskell NA, West A, et al. Intrapleural use of tissue plasminogen activator and DNase in pleural infection. N Engl J Med. 2011;365(6):518-526. [CrossRef] [PubMed]
 
Maskell NA, Davies CW, Nunn AJ, et al; First Multicenter Intrapleural Sepsis Trial (MIST1) Group. U.K. Controlled trial of intrapleural streptokinase for pleural infection. N Engl J Med. 2005;352(9):865-874. [CrossRef] [PubMed]
 

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References

Corcoran JP, Rahman NM. Point: should fibrinolytics be routinely administered intrapleurally for management of a complicated parapneumonic effusion? Yes. Chest. 2014;145(1):14-17. [CrossRef] [PubMed]
 
Rahman NM, Maskell NA, West A, et al. Intrapleural use of tissue plasminogen activator and DNase in pleural infection. N Engl J Med. 2011;365(6):518-526. [CrossRef] [PubMed]
 
Maskell NA, Davies CW, Nunn AJ, et al; First Multicenter Intrapleural Sepsis Trial (MIST1) Group. U.K. Controlled trial of intrapleural streptokinase for pleural infection. N Engl J Med. 2005;352(9):865-874. [CrossRef] [PubMed]
 
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