Annals of the American Thoracic Society

Rationale: Intrapleural tissue plasminogen activator (tPA)/deoxyribonuclease (DNase) therapy for pleural infection given at the time of diagnosis has been shown to significantly improve radiological outcomes. Published cases are limited to only a single randomized controlled trial and a few case reports.

Objectives: Multinational observation series to evaluate the pragmatic “real-life” application of tPA/DNase treatment for pleural infection in a large cohort of unselected patients.

Methods: All patients from eight centers who received intrapleural tPA/DNase for pleural infection between January 2010 and September 2013 were included. Measured outcomes included treatment success at 30 days, volume of pleural fluid drained, improvement in radiographic pleural opacity and inflammatory markers, need for surgery, and adverse events.

Measurements and Main Results: Of 107 patients treated, the majority (92.3%) were successfully managed without the need for surgical intervention. No patients died as a result of pleural infection. Most patients (84%) received tPA/DNase more than 24 hours after failing to respond to initial conservative management with antibiotics and thoracostomy. tPA/DNase increased fluid drained from a median of 250 ml (interquartile range [IQR], 100–654) in the 24 hours preceding commencement of intrapleural therapy to 2,475 ml (IQR 1,800–3,585) in the 72 hours following treatment initiation (P < 0.05). We observed a corresponding clearance of pleural opacity on chest radiographs from a median of 35% (IQR 25–31) to 14% (7–28) of the hemithorax (P < 0.001), as well as significant reduction in C-reactive protein (P < 0.05). Pain necessitating escalation of analgesia occurred in 19.6% patients, and nonfatal bleeding occurred in 1.8%.

Conclusions: This large series of patients who received intrapleural tPA/DNase therapy provides important evidence that the treatment is effective and safe, especially as a “rescue therapy” in patients who do not initially respond to antibiotics and thoracostomy drainage.

Pleural infection is associated with a high morbidity and mortality (1). Prompt drainage is fundamental to treatment; however, pus is often loculated and thick, making drainage difficult. Surgical drainage is often necessary to evacuate infected material. Various fibrinolytic agents have been used in an effort to improve drainage of infected pleural fluid, but with mixed results (28).

A recent multicenter randomized controlled trial showed that combination intrapleural therapy with tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) improved drainage of infected effusions and reduced both the need for surgical intervention and the length of hospital stay (9). Despite the fact that only 48 patients in the trial received tPA/DNase (9), these results have attracted strong interest, and many units worldwide have started employing this treatment.

The majority (>70%) of patients with pleural infection can be managed successfully with chest tube drainage and systemic antibiotics alone (8, 9). In the above-mentioned randomized trial (9), patients in the tPA/DNase arm received the intrapleural treatment immediately following intercostal catheter (ICC) insertion. The effectiveness of this treatment in patients for whom conventional therapy fails is not known.

In this observational series, we aimed to validate the pragmatic, “real-life” application of tPA/DNase treatment for pleural infection in a large cohort of unselected patients from centers in three countries. We describe the clinical, laboratory, and radiological outcomes of patients undergoing tPA/DNase therapy, especially in those who did not improve with conventional treatment. We hypothesized that intrapleural tPA/DNase therapy is effective and safe and represents a viable alternative to surgical management.

Eight respiratory centers from Australia, New Zealand, and the United Kingdom contributed data. Consecutive patients who received intrapleural tPA/DNase therapy for pleural infection between January 2010 and September 2013 were prospectively recorded in all centers, and relevant data were extracted retrospectively. The study was approved by the institutional review boards of each center (Table 1).

Table 1. Involved centers, patient numbers, and ethics approvals

CenterNo. of PatientsEthics Approval
Australia  
 Sir Charles Gairdner Hospital422012/024, Sir Charles Gairdner Group Human Research Committee
 Tweed Heads District Hospital3North NSW Local Health District Regional Ethics Committee
 The Prince Charles Hospital2HREC/12/2PCU/95 Prince Charles Hospital Human Regional Ethics Committee Metro North Health Service District
New Zealand  
 Dunedin Hospital7CEN/12EXP/030, Central Regional Ethics Committee, Wellington
 Wellington Hospital6
 Middlemore Hospital4
United Kingdom  
 Greater Glasgow & Clyde30NHS Greater Glasgow and Clyde Regional Ethics Committee
  Gartnavel General Hospital  
  Glasgow Royal Infirmary Southern General Hospital  
  Victoria Infirmary  
 Southmead Hospital13NHS North Bristol Regional Ethics Committee

Pleural infection was defined, in line with previous studies (8), to include both complicated parapneumonic effusion (fluid pH ≤7.2 in a patient with clinical evidence of infection, such as fever, elevated leukocyte and/or C-reactive protein [CRP]) and empyema (macroscopic pus and/or presence of bacteria on pleural fluid Gram stain or culture). Suitability and timing of intrapleural tPA/DNase therapy following chest tube insertion were determined by the attending physicians. tPA (10 mg) and DNase (5 mg) (each in 50 ml of 0.9% NaCl) were instilled intrapleurally twice daily up to a maximum of six doses as employed in the second Multicenter Intrapleural Sepsis Trial (MIST2) (9). The protocol was as follows. First, tPA was instilled via the ICC, followed by a 10- to 25-ml flush of 0.9% saline. The ICC was clamped for 40–60 minutes before unclamping and allowing free drainage for 40–60 minutes. This procedure was then repeated with DNase. In one center (30 patients), an abridged protocol of simultaneous instillation of both drugs (at the same dose) was employed. tPA and DNase were instilled immediately after each other via the ICC, followed by saline flush. The drain was then clamped for 40–60 minutes before being put on free drainage. In either protocol, the drugs were instilled twice daily for a maximum of six doses.

Hospital notes were interrogated for patient demographics, treatment details (e.g., timing to therapy), and outcomes, including volume of fluid drained, adverse events, length of hospital stay, need for surgery, and mortality. Laboratory data—in particular, blood inflammatory marker levels (e.g., CRP), pleural fluid biochemistry, and microbiologic cultures—were recorded. The area of pleural opacity, expressed as the percentage of the ipsilateral hemithorax occupied by effusion, was quantified on digital chest radiographs (CXR) by one investigator (a respiratory physician or radiologist) at each site using a validated method (9). The change in area between the CXR obtained prior to the first treatment dose and the one taken at 72 hours following the first dose was recorded.

Patients were defined as having had successful treatment if they survived to hospital discharge and avoided the need for surgical intervention for their pleural infection in the 30 days after the first treatment dose.

The following were the measured outcomes:

1.

Treatment success (composite outcome as described above);

2.

Death from any cause up to 90 days;

3.

Number of patients referred for thoracic surgery, and reasons, up to 30 days from the first dose of tPA/DNase;

4.

Length of stay from first dose of tPA/DNase to hospital discharge or death;

5.

Volume of pleural fluid drained;

6.

Area of pleural opacity on CXR (as described above);

7.

Blood CRP levels; and

8.

Adverse events, including (a) significant pleural bleeding, defined as a decrease in hematocrit causing hemodynamic instability or requiring blood transfusion; and (b) significant pain requiring escalation of analgesia or cessation of intrapleural therapy.

Statistical analyses were performed using SigmaPlot 11.0 (Systat Software, San Jose, CA). Unless otherwise stated, results were expressed as mean (SD) if normally distributed and as median (interquartile range [IQR]) if not. The Wilcoxon rank-sum test was used to compare the pre- and posttreatment CXR area of pleural opacity. Multiple group comparisons were performed using analysis of variance on ranks, followed by Dunn’s post hoc test. Significance was defined as P < 0.05.

A total of 107 patients (74 males; mean (SD) age, 55.7 years (19.1)) received intrapleural tPA/DNase treatment (Table 2). Most patients (n = 97, 90.6%) developed a pleural infection following community-acquired pneumonia. Associated medical comorbidities were present in most (76.6%, 82/107) patients (Table 3). Seven patients had an indwelling pleural catheter and associated pleural infection.

Table 2. Patient demographics, pleural infections, and treatment characteristics

Demographics and CharacteristicsPatient Data
Patient characteristics 
 Mean age (SD), yr55.7 (19.1)
 Males, n74 (69%)
 Cause of pleural infection 
  Community-acquired pneumonia97 (90.6%)
  IPC-associated infection7 (6.5%)
  Infection of chronic effusion3 (2.8%)
Pleural effusion characteristics 
 Ultrasonographic evidence of loculation93 (87%)
 Visibly purulent pleural fluid49 (46%)
 Positive pleural fluid culture35 (33%)
 Mean pleural fluid pH (SD)6.97 (0.3)
 Median LDH expressed as fold increase over serum LDH ULN (IQR)4.1 (1.7–13.1)
 Median protein pleura/serum ratio (IQR)0.66 (0.6–0.72)
Treatment characteristics 
 Days from drain insertion to first tPA/DNase dose 
 Median days (IQR)2 (1–4)
 Patients who received intrapleural treatment 
  24 h after ICC insertion90 (84%)
  48 h after ICC insertion69 (65%)

Definition of abbreviations: ICC = intercostal catheter, IPC = indwelling pleural catheter, LDH = lactate dehydrogenase, ULN = upper limit of normal

Table 3. All comorbidities

Comorbiditiesn%
Respiratory  
 Chronic obstructive pulmonary disease109.3%
 Asthma65.6%
 Chronic pleural effusion32.8%
 Recent pulmonary embolism32.8%
 Bronchiectasis21.9%
 Other32.8%
Cardiovascular  
 Hypertension1917.8%
 Atrial fibrillation1312.1%
 Diabetes mellitus109.3%
 Ischemic heart disease87.5%
 Hypercholesterolemia21.9%
 Congestive cardiac failure32.8%
Hepatic and renal  
 Hepatitis B or C1211.2%
 Liver cirrhosis21.9%
 Chronic renal failure5 (3 on dialysis)4.7%
Neurological  
 Stroke109.3%
 Epilepsy54.7%
 Cerebral palsy21.9%
 Multiple sclerosis21.9%
 Head injury10.9%
 Other43.7%
Concurrent malignancy  
 Thoracic malignancy109.3%
 Squamous carcinoma of the mouth21.9%
 Gastric adenocarcinoma10.9%
 Prostate cancer10.9%
 Past malignancy32.8%
Recent surgery32.8%
 Esophageal surgery10.9%
 Ruptured appendix10.9%
 Right hemicolectomy10.9%
Other  
 Psychiatric illness109.3%
 Excessive alcohol/intravenous drug use1110.3%
 Gastroesophageal reflux disease/ulcer76.5%
 Autoimmune disorders76.5%
 Gout21.9%

In all cases, the pleural fluid pH was ≤7.2, with a mean (SD) of 6.97 (0.3). The median pleural fluid lactate dehydrogenase (LDH) level was 1,725 U/L (IQR, 855–4,985), which was a median of 4.1 (IQR, 1.7–13.1) times the upper limit of normal for serum LDH. The effusions were visibly purulent in 45.8% (49/107) and 32.7% (35/107) yielded one or more microbes on pleural fluid culture (including 10 Streptococcus milleri, five Staphylococcus aureus, four S. pneumoniae, four S. epidermidis, and four Pseudomonas aeruginosa). Bedside pleural ultrasound was performed on all patients, and 86.9% (93/107) showed evidence of pleural loculations (Table 2). The median serum CRP at time of first tPA/DNase dose was 190 mg/L (IQR, 126–279).

The median time from catheter insertion to first fibrinolytic dose was 2 days (IQR, 1–4). Most patients (84%) received the first tPA/DNase dose >24 hours following thoracostomy. Twenty-five patients (23%) did not receive the full six doses of tPA/DNase, with the commonest reason being complete drainage of effusion with fewer than six doses (Table 4).

Table 4. Incomplete treatments and adverse events

Outcomesn (%)
Incomplete therapy25 (23%)
 Complete drainage of effusion with <6 doses17
 Progressed to surgery2
 Severe increased pain4*
 Secondary to bronchopulmonary fistula1
 Pleural bleeding1
Adverse effects 
 Pain requiring escalation of analgesia21 (19.6%)
 Pleural bleeding2 (1.8%)

*Of the four patients who developed severe pain, two ceased therapy after one dose and the remainder stopped treatment after five doses.

Treatment Outcomes

Treatment with tPA/DNase was effective, and 92.3% of patients were successfully treated without surgery. Eight patients required surgery despite intrapleural therapy. Three patients died between 20 and 30 days after intrapleural therapy. In all three cases, sepsis due to pleural infection had been controlled, but the patients died due to their underlying comorbidities (end-stage renal failure and malignancy). Using the composite endpoint of survival and discharge from the hospital without need for surgical intervention at 30 days, 89.7% (96/107) of patients had a completely successful recovery with intrapleural tPA/DNase treatment.

The survival rates at 30 and 90 days were 97.8% and 91.2%, respectively. The median (IQR) hospital stay from first intrapleural treatment dose was 10 days (6–17).

The eight patients whose treatment course progressed to surgery were all discharged and alive 90 days following the first treatment dose. In all cases, the indication for surgery was failure to respond to treatment with persistent clinical and laboratory evidence of active infection. Six of these patients had completed six doses of intrapleural therapy. The median time from first fibrinolytic dose to surgery was 3 days (IQR 3–4.75). Six patients underwent video-assisted thoracoscopic surgery (VATS) decortication, one had minithoracotomy and rib resection, and another had rib resection and stoma formation. Hospital stay was longer in those who needed surgery (median, 18.5 days; IQR, 13.8–31.8), as compared with the patients who did not need surgery (median, 10 days; IQR, 6–17) (P > 0.1). No significant differences were observed between those successfully treated with tPA/DNase and those in whom treatment failed with regard to age, pleural fluid biochemistry, amount of effusion, and inflammatory markers.

Fluid Drainage

Intrapleural tPA/DNase increased the volume of pleural fluid drained from a median of 250 ml (IQR, 100–645) in the 24 hours preceding tPA/DNase treatment to a median of 1,300 ml (IQR, 735–1,980) at 24 hours following the first dose of tPA/DNase (P < 0.05). The median total amount of fluid drained was 2,475 ml (IQR, 1,800–3,585) in the first 72 hours of therapy (P < 0.05) (Figure 1). Most patients (75%) were successfully managed with small-bore chest tubes (≤16 French).

Radiographic Clearance

Intrapleural tPA/DNase reduced the pleural opacity on CXR from a median of 35% (IQR, 23–51) of the hemithorax to a median of 14% (IQR, 7–28) (P < 0.001) (Figure 2).

Infection Parameters

All successfully treated patients had resolution of sepsis with a clinically significant reduction in CRP of 40% from the pretreatment baseline by day 5 from initiation of tPA/DNase (Figure 3). A transient rise in CRP in the first 24 hours of treatment was observed in 16 patients (14.9%), after which CRP decreased.

Adverse events

There were two cases (1.8%) of nonfatal pleural bleeding requiring red blood cell transfusion (Table 4). One occurred following the first dose and the other following the fifth dose of treatment. Both patients had underlying bleeding risks. One was on renal replacement therapy for end-stage renal failure and had been diagnosed concurrently with pulmonary embolism, for which he was receiving unfractionated heparin. The other patient had chronic liver disease with increased prothrombin time and had had a difficult chest tube insertion requiring multiple attempts. Both patients remained hemodynamically stable and were managed conservatively with interruption of intrapleural therapy and transfusion. One died 19 days after treatment with recurrent sepsis and dialysis being ceased. The other was discharged without complications and remained alive at 24 months. There were no episodes of hemoptysis or gastrointestinal bleeding in our cohort.

Chest pain requiring initiation or escalation of opioid analgesia occurred in 21 patients (19.6%), all within the first 24 hours of intrapleural therapy. In four patients, the pain was severe and therapy was terminated early; surgery was avoided in all four of them.

This international collective experience provides the largest data set confirming the efficacy and safety of intrapleural tPA/DNase therapy for pleural infection. It further establishes the role of this treatment even in patients who have failed to respond to initial conventional therapy with antibiotics and chest tube drainage. In this unselected cohort, treatment successfully led to avoidance of the need for surgery (at 30 days) in 92.3% of the patients. Clinical and laboratory evidence of resolution of sepsis was paralleled by an increase in the amount of pleural fluid drained and a decrease in the size of radiographic pleural effusion. This study helps establish the role of tPA/DNase therapy as an effective alternative to surgery for pleural infection.

An alarming number of reports have confirmed the rising incidence of pleural infection worldwide (10, 11), particularly in the older population. The keystones of pleural infection management are control of sepsis and evacuation of infected pleural fluid. Standard care with antibiotics and chest tube drainage has been reported to fail in ∼30% of patients in large clinical trials (8, 9). In these patients, surgery is the only established means by which to clear the infected pleural material. Mortality due to pleural infection is high in adults (10–20%) (1) and is skewed toward older patients, who have an increased likelihood of comorbidities precluding surgical management. For this reason, research efforts have been focused on uncovering effective, minimally invasive intrapleural treatments.

Infected pleural fluid is difficult to drain for two reasons: the fluid is loculated by septations and often has high viscosity. In two recent randomized trials, fibrinolytics, used alone, were reported to have failed to improve clinical outcomes (need for surgical rescue and/or mortality) compared to placebo (8, 9). Efforts have thus turned to targeting fluid viscosity. The thickness of pleural pus is believed to arise from DNA liberated by degranulated leukocytes. DNase, which effectively fragments free uncoiled DNA in pus, has been used for decades to enhance sputum clearance in patients with cystic fibrosis. DNase, when applied to pleural pus ex vivo, has been found to potently enhance drainage (12).

The combined use of fibrinolytics and DNase has been shown to have synergistic actions in an animal model of empyema (13), as well as subsequently in the MIST2 study (9), whereas individual agents alone appear to be ineffective or worse than placebo. In MIST2, 196 patients were randomized to combined intrapleural treatment with tPA and DNase, tPA alone, DNase alone, or neither. Combined intrapleural tPA/DNase therapy significantly improved radiographic clearance compared to all other groups and reduced surgical referrals and hospital stays. The results from the 48 patients treated with tPA and DNase showed that 96% were successfully treated without surgery.

Our study builds on previous evidence. Our large cohort adds weight to the results from the 48 patients treated in MIST2, confirming the treatment’s efficacy and safety. Our baseline data confirmed that the study group had significant pleural infection, as evidenced by the low pH and high LDH, and a high percentage had frank pus and presence of loculations. tPA/DNase was effective despite significant pleural infection, and the predefined cure was achieved in 89.7% without the need for thoracic surgery. This result is particularly important, as 76.6% of the patients had at least one comorbidity and up to 15% had major life-limiting diseases (e.g., cancer or end-stage renal failure)—patients who were otherwise not suitable for surgery.

tPA/DNase allows successful treatment with minimally invasive procedures. Treatment was successfully delivered via small-bore chest drains (≤16-French) in the majority (75%) of patients. Small-bore drains have been shown to produce significantly less pain than larger ones (14, 15). This, together with the avoidance of surgery (and its risks and complications), makes tPA/DNase an attractive treatment.

The optimal place of tPA/DNase in the treatment algorithm for pleural infection remains to be established. In MIST2, patients were treated with the trial medications immediately after randomization. In contrast, our population consisted mainly of patients who did not improve despite initial standard therapy; 84% received tPA/DNase >24 hours after thoracostomy. In these patients, tPA/DNase served as a “rescue therapy” following failure of conservative management. Given that standard therapy is effective in 70–80% of patients (8, 9), it would be reasonable to reserve tPA/DNase as a rescue therapy for patients who show no significant improvement with antibiotics and chest tube drainage.

The clinical outcome data were also associated with improvements in other parameters. Intrapleural tPA/DNase promoted a significant volume of drainage (up to 2.5 L). Despite increasing recognition that fibrinolytics can potentially stimulate excess reactive pleural fluid, increased drain output in our patients was paralleled by improved radiographic appearances. This suggests that the combination treatment was able to break down loculations and allow free drainage of otherwise noncontiguous fluid pockets. It is also possible that this consistent production of large volumes of fluid serves to lavage the infected cavity and clear infection. Importantly, treatment with tPA/DNase was also associated with reduction of systemic infection markers.

Our study offers strong reassurance regarding the safety of tPA/DNase, even in patients with considerable comorbidity, thus supporting the use of tPA/DNase. The treatment was well tolerated, with <20% of patients requiring escalation of baseline analgesia.

Hemorrhagic fluid is a common observation after intrapleural administration of fibrinolytics for any indication. However, significant pleural bleeding occurred in only two of 107 patients. Both of these patients had underlying risks for bleeding and required blood transfusion following persistent, large-volume drainage of hemorrhagic fluid in association with a reduction in hemoglobin and/or hematocrit. Neither patient demonstrated hemodynamic instability. As the incidence of serious complications from tPA/DNase appears to be low, long-term multicenter collaborations are needed to adequately document potential complications of this therapy. Bronchopleural fistula is another contraindication to intrapleural tPA/DNase use. Treatment was terminated in one patient when an unsuspected fistula was uncovered.

Future research is needed. The optimal role of tPA/DNase in the treatment algorithm for pleural infection remains to be determined. VATS remains the preferred treatment for pleural infection in many centers, and direct comparison of VATS with intrapleural tPA/DNase is a current topic of interest. Likewise, identifying predictors of tPA/DNase therapy failure may aid in early selection of patients for surgical intervention. The dosing regimen for intrapleural tPA/DNase used in MIST2 and in our cohort was empirically based on early case reports. Given the very high success rates in both studies, it is likely that future studies may target simplifying and/or reducing the doses and/or frequency of administration in addition to assessing the health economics of the treatment. To date, the regimen has been applied only to adults. Considerable interest has been shown in the pediatric community. The Canadian-based Intrapleural DNase and Tissue Plasminogen Activator Pediatric Empyema randomized trial is currently underway to assess the treatment’s efficacy and safety in this population. Furthermore, fibrinolytics have been used in patients with peritonitis undergoing chronic ambulatory peritoneal dialysis (16, 17).

The mechanistic actions of tPA/DNase have not yet been clearly established. Intense pleural inflammation is thought to create an imbalance between fibrinolytic (e.g., tPA) and profibrotic (e.g., plasminogen activator inhibitor 1) mediators in the pleural space, favoring fibrin deposition and loculation of pleural effusions (18). In vitro and animal studies suggest that intrapleural tPA lyses pleural adhesions by activation of plasmin, enhancing drainage (13). It has been speculated that the drugs may offer additional benefits beyond lysing adhesions and thinning pus, including breaking down biofilms. Whether the drugs have direct effects on bacterial clearance and interactions with antimicrobials remains to be seen.

This study has limitations. It was a retrospective observational study, and the potential for selection bias remains. We have not collected comparative data from other patients with pleural infection not requiring tPA/DNase. However, any potential bias would have been addressed by the original randomized placebo-controlled study (MIST2). The main objective of the present study was to expand on the safety profile and further validate the effectiveness of the treatment in a larger cohort in a pragmatic, “real-world” clinical environment. The majority (91%) of treated patients had pleural infections associated with community-acquired pneumonia, as would be expected. This limits inferring the effectiveness of tPA/DNase in patients with nursing home–acquired or hospital-acquired pleural infection. Owing to the retrospective nature of the study, there were no predefined criteria for progression to surgery, and all treatment decisions were made by the attending physicians, which may have led to heterogeneity in management. However, this approach allowed us to validate the effectiveness of the tPA/DNase in “real-life” settings.

In summary, this large, open-label study adds to the existing evidence that intrapleural tPA/DNase is effective and safe, even as a rescue therapy. It presents an attractive minimally invasive alternative to surgery.

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Correspondence and requests for reprints should be addressed to Y. C. Gary Lee, Ph.D., FRACP, FRCP, Centre for Asthma, Allergy & Respiratory Research, School of Medicine & Pharmacology, University of Western Australia, 533 Harry Perkins Building, QE II Medical Centre, Perth, WA 6009, Australia. E-mail:

Funding: Y.C.G.L. is a National Health and Medical Research Council (NHMRC) Career Development Fellow and receives project grant funding from the NHMRC, New South Wales Dust Disease Board, Sir Charles Gairdner Research Advisory Committee, LIWA Westcare Grants, and the Cancer Council of Western Australia.

Author Contributions: Y.C.G.L.: guarantor; F.P., N. Popowicz, Y.C.G.L.: conception and design; F.P., N. Pitman, R.B., N.A.S., B.B., R.N., A.J.B., C.A.W.: center coordinators; F.P., N. Pitman, R.B., N. Popowicz, N.A.S., B.B., R.N., A.J.B., C.A.W., R.M., B.C.-K., K.G.B., N.A.M., Y.C.G.L.: data collection and patient care; F.P., Y.C.G.L.: statistical analyses; F.P., N. Pitman, R.B., N.A.S., B.B., R.K., A.J.B., N. Popowicz, C.A.W., N.M., Y.C.G.L.: manuscript drafting; F.P., N. Pitman, R.B., N. Popowicz, N.A.S., B.B., R.N., A.J.B., C.A.W., R.M., B.C.-K., K.G.B., N.A.M., Y.C.G.L.: manuscript revision and final approval.

Author disclosures are available with the text of this article at www.atsjournals.org

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