Pleural infection
Randomisation to one of two arms in a 1:1 ratio, utilising sealed envelope randomisation software: 1. Intrapleural Enzyme Therapy (or IET) – this involves giving six doses of IET therapy (DNase and alteplase) through a chest tube. 2. Keyhole surgery to drain infected fluid – known as Video Assisted Thoracoscopic Surgery (VATS). Both treatments are established and used routinely in hospitals every day; follow-up activity for both arms will follow standard of care.
All patients will initially be treated with chest drain insertion for up to 24 hours, and only those with residual pleural collections will be randomised (MIST-3 demonstrated that with an identical recruitment strategy, 15% of patients required no further treatment), hence this will enrich the population for those who stand to benefit most from intervention. Pleural infection will be diagnosed on BTS guideline criteria. 1. Aged 18 years or above. 2. Clinical presentation compatible with pleural infection plus, pleural fluid requiring drainage which is: 2.1. Purulent OR 2.2. Culture positive OR 2.3. Acidic (pH <7.2) OR* 2.4. Pleural contrast enhancement on CT or septation on ultrasound 3. Fail initial (12 to 24 hours) drainage treatment, defined as clinically significant residual pleural collection on chest imaging (chest radiograph, ultrasound, or CT) 4. Clinical Frailty Score ≤6** 5. Participant is willing and able to give informed consent for participation in the trial. *In the absence of pleural fluid pH measurement access or concern over accuracy – a PF LDH >1000, glucose <2.0mmol/L may be adequate alternatives particularly in the presence of other radiological features such as septations on thoracic ultrasound or pleural contrast enhancement on CT (if done). ** Patients will be included if they are potentially fit for surgical intervention, using deliberately broad criteria to minimise selection bias. Only those who are clearly unfit for surgery (pre-morbid Clinical Frailty Scale >6) will be excluded. Patients with significant comorbidities (e.g., renal or cardiac failure) will remain eligible. Participants randomised to surgery who are later deemed unfit will still be analysed in the intention-to-treat population, consistent with the previous feasibility trial.
1. Has previously received an intrapleural fibrinolytic and/or DNase for this episode of pleural infection 2. Has previously received large volume saline flushes akin to irrigation for this episode of pleural infection* 3. Has a known sensitivity to tPA or DNase. 4. Has had a previous pneumonectomy on the side of the infection. 5. Coincidental major bleed within the last 7 days. 6. Clinically significant renal or hepatic impairment in the view of the recruiting clinician e.g. CKD 5 on dialysis or advanced cirrhosis. 7. Participant with life expectancy of less than 3 months due to other disease (for example, known malignancy with poor prognosis). 8. Female participant of childbearing age who is pregnant, lactating or planning pregnancy during the trial. 9. Scheduled elective surgery (i.e. not for this episode of pleural infection) or other procedures requiring general anaesthesia within 30 days of prospective enrolment. 10. Significant irreversible coagulopathy that in the local investigator's opinion would prevent the participant from safely receiving IET. 11. Participation in another interventional clinical trial for pleural infection. * Standard intrapleural saline flush regimens to maintain tube patency (e.g. 20 ml qds / 30 ml tds) are permitted