International Lung Symposium on Pleural Diseases, Manila 2019. Common pleural infections by Dr. Gary Lee

1. Professor, University of Western Australia
Director, Pleural Services, Sir Charles Gairdner Hospital
Head, Pleural Medicine Unit, Institute for Respiratory Health
NHMRC/MRFF Next Generation Practitioner Fellow
Y C Gary Lee
MBChB PhD FCCP FRCP FRACP
Pleural Infection
Diagnosis & Management 2019

2. HIPPOCRATES
460-377 BC
Mayno G. The healing hand.
Harvard University Press, 1975
Courtesy Dr Tschop, Switzerland
Pleural infection is a centuries old problem
Hippocratic Succussion:
Shake the patient by the
shoulders to identify sound of
fluid
The Sign of Damp Earth:
Covering thorax of the empyema
patient in mud. Identify the rib
space that dried first, as best site
for drainage of empyema

3. *
*
*
*
*
*
***
*
Rising incidences of pleural infection
reported worldwide
Lisboa, Waterer & Lee. Respirology 2011

4. USA national data: 1996-2008; N=157,094
Grijalva et al. Thorax 2011
>65 yr
40-64 yr
18-39 yr
<18 yr
Rising incidence mainly in the elderly

5. CASE 1
M/38. Married man. Previously well
Upper respiratory tract infection 3 weeks ago
Worsened cough, fever,
mild chest pain 1 wk
Presented to ED. Febrile.
CXR performed.
CURB-65 score = 0.
Diagnosis: Pneumonia
Oral antibiotics. Sent home.
CXR: Feb 12

6. CXR: Feb 12 CXR: Feb 14
Symptoms worsened next 48 hours. Presented again to ED.
Febrile. CRP >450 mg/L. Hemodynamically stable.
CURB-65 score still 0. CXR performed.

7. CASE 1
Febrile. Unwell at bedside.
Patient and family understandably anxious.
‘Is this serious? Life-threatening?’
What would your answer be?
A) He is likely to make a full recovery with the right
treatment.
B) This is a serious condition. Up to 20% adults will die.
C) He needs urgent surgery to have a chance.



8. Pleural Effusion is a significant
prognostic factor in pneumonia

9. Pleural effusions at first emergency department encounter
predict worse clinical outcomes in pneumonia patients
NC Dean, PP Griffith, J Sorensen, L McCauley,
BE Jones and Y C Gary Lee
CHEST 2016; 149:1509-15

10. Adult ED patients (24 month)
n = 458,837
Community Acquired Pneumonia
1st presentation n = 4771
Pleural Effusion:
NO
n = 4081 (85%)
Median age: 68 yrs;
46% male
Predictors of Effusion
(p<0.001):
• Age (OR=1.15)
• BNP (OR=1.20)
• Higher Elixhauser
score (OR=1.13)
Pleural Effusion:
YES
n = 690 (15%)
5.0% 14.0% p = 0.001Mortality
After severity adjustment, 30-day mortality remains
greater in patients with effusion(s) (OR 2.6; p<0.001)

11. Prognostic Score of Mortality
Adults: ~ 20% mortality by 3 months
RAPID score - a validated prognostic guide
developed: MIST-1 (n=454); validated: MIST-2 (n=196)
Rahman et al Chest 2013
- Renal impairment
- Age (esp >70) * * Most important
- Pus ^ ^ Non-purulent worse
- Inpatient (hospital) acquired
- Diet: Low albumin level

12. What does RAPID teach us?
RAPID = CRUMBLING score
- Renal impairment
- Age (esp >70)
- Pus
- Inpatient (hospital) acquired
- Diet: Low albumin level
Pleural infection is a marker of frailty
Patients die from comorbidity; rarely from sepsis
Surgery not likely to reduce mortality significantly

13. CASE 1: CT Thorax
Multi-loculated pleural effusion confirmed on CT.

14. CASE 1: CT Thorax
Parenchymal consolidation in most lobes. Widespread
nodular infective changes; perhaps early cavitation.
Working diagnosis: Staphylococcus pneumonia / empyema

15. Pleural Fluid pH Measurement
pH <7.2; fibrin +
Empyema
‘Simple’ effusion
Complicated effusion
Pneumonia No effusion
pH >7.2
Pus and fibrin
++
Pleural fluid pH often
used to define pleural
infection
Low pH predicts need
of pleural fluid
drainage
We show that pleural
pH accuracy critically
depends on collection

16. PLEURAL FLUID: Laboratory Tests
Tests routinely request
• Protein and LDH
• Differential cell count
• pH and/or glucose
• Culture [infection]
• Cytology [malignancy]
Tests only when indicated
• NTproBNP
• ADA
• Flow Cytometry [lymphoma]
• Chylomicron; TGL [chylous]
• Amylase [pancreas/esophagus]
• Transferrin [dural-pleural]

17. Method
No additives (control)
>analyzed at 0, 1, 4 + 24hr
0.2ml lidocaine
0.4ml lidocaine
1.0ml lidocaine
1ml air
0.2ml heparin
0hr 24hr
Rahman N et al. Am J Respir Crit Care Med 2008

18. Oxford
Pleural
Unit
pH increased by air
Air
-0.1
0
0.1
0.2
0.3
ChangeinpH
p<0.001
Mean 0.08
SD 0.05
Rahman N et al. AJRCCM 2008

19. Oxford
Pleural
Unit
pH decreased by lidocaine
-0.8
-0.6
-0.4
-0.2
0
Volume of lidocaine (ml)
ChangeinpH
p<0.001 p<0.001 p<0.001
Mean -0.16
SD 0.09
Mean -0.26
SD 0.11
Mean -0.45
SD 0.13
0.2 0.4 1.0
Rahman N et al. AJRCCM 2008

20. Oxford
Pleural
Unit
pH decreased by delay in analysis
ChangeinpH
-0.5
-0.4
-0.3
-0.2
-0.1
0
0.1
0.2
0.3
0.4
0.5
Time (hours)
1 4 24
p=0.001p=0.178
ChangeinpH
ChangeinpH
Mean 0.02
SD 0.03
Mean 0.04
SD 0.05 Mean 0.13
SD 0.09
p=0.024

21. 0
2
4
6
8
10
12
14
Control 24 hr
[Glucose](mmol/L)
0
2
4
6
8
10
12
14
Control Air
0
2
4
6
8
10
12
14
Control Lidocaine
[Glucose](mmol/L)
Pleural fluid glucose level
not affected by
air, lidocaine
or delay in analysis

22. Increasing bacterial capture with
Blood Culture Bottles
Sensitivity same 2 vs 5 vs 10mL injected in culture bottles
Anaerobic vial captures most bacteria
Ferrer A.
Eur J Clin Micro
Infect Dis 1999
Menzies S.
Thorax 2011
n=245 n=71
Sterile container only 64% 38%
Sterile container +
Blood culture bottles
92% 59%

23. Mesothelial Layer
PLEURALSPACE
BACTERIA
BACTERIA
If you are the bacteria,
where in the pleural cavity will you live?
Bacterial culture of pleural fluid notoriously low yield.
Are we looking at the wrong place?

24. A Pilot Feasibility Study in Establishing the Role of
Ultrasound-Guided Pleural Biopsies in Pleural Infection
(The AUDIO Study) Psallidas I et al. CHEST (in press)
U/S guided biopsy (n=20) at time of chest tube provided
high yield of bacterial culture:
Blood (10%) vs Fluid (20%) vs Pleural Biopsy (45%)
75% of pts with +ve
pleural Bx were already
on antibiotics
• Bx still worthwhile on
antibiotics
• Antibiotics regime for
pleural infection needs
optimization

25. Empyema Bacteriology Community Hospital
Strep milleri 31% 4%
Strep pneumoniae 14% 5%
Enterobacteriacea 13% 15%
Anaerobes 12% 11%
Staphylococci 10% 13%
Enterococci 1% 15%
MRSA 1% 36%
Distinguish Community- vs Hospital-Acquired Pleural
Infection. Bacteriology and choice of antibiotics are different.
Geographic differences in bacteriology common.
Need to know your local data.

26. Pleural Infection: Treatment Principles
Light RW & Lee YCG. Textbook of Pleural Disease, 3rd ed
Evacuate infected
pleural fluid
Eradicate infection
• Chest tube
• Fibrinolytics/DNase
• Surgery
• Broad-spectrum
antibiotics

27. Mayno G. The healing hand. Harvard University Press, 1975
Courtesy Dr Tschop, Switzerland
‘if empyema does not rupture,
death follows’
HIPPOCRATES
460-377 BC

28. Question
How big is the chest drain you use?
eg 16 Fr

29. What is catheter bore?
Chest tube size indicates EXTERNAL diameter
• 1 French gauge =1/3mm
ie 6Fr = 2 mm
12Fr = 4 mm
24Fr = 8 mm
But INTERNAL diameters vary depending on
thickness of catheter wall
eg 12Fr Cook has ID 2.54mm or 8.4Fr
Courtesy of Dr Helen Ward

30. Park JK et al. AJR 1993; 160: 165-9
12 Fr
18 Fr
6 Fr
External diameter
Internal diameter

31. Chest Tube Size NOT affect Clinical Outcome
31 (22%)54 (20%)Gram stain +ve
125 (90%)215 (78%)Purulent
139275Number
Large boreSmall bore* Not randomized
Rahman N et al. Chest 2010
p=0.70 Small Bore Large Bore
Surgery 40 (15%) 23 (17%)
No Surgery 233 115
Total 273 138

32. CASE 1
Initial improvement with chest tube drainage:
Fever settled. CRP started to fall. Fluid: S aureus.
CXR: Feb 14 CXR: Feb 16
But after initial improvement, CRP plateaued ~200.
Still residual loculations esp in fissure and mediastinal

33. CASE 1
What would you do?
(A) Surgery
(B) Intrapleural fibrinolytics (urokinase or tPA)
(C) Combined intrapleural tPA+DNase therapy
(D) Perserve with antibiotics and tube drainage

34. VATS as first line: Randomized trials
Adult
Empyema
Wait et al (n=19)
Chest 1997
Bilgin et al (n=70)
ANZ J Surg 2006
VATS vs Drain + SK VATS vs Drain
Mortality No difference
(1 vs 1)
No difference
(0 vs 1)
Costs No difference Not examined
Hospital Stay VATS (8.7 d)
Drain (12.8 d)
VATS (8.3 d)
Drains (12.8 d)

35. Combination intrapleural therapy
Fibrinolytics + DNase
is effective, esp in the ~20% patients with
persistent infection despite antibiotics + tube

36. 52 centres: n=430 pleural infection
StreptokinasePlacebo

37. SK has no benefit over placebo in
avoiding death or surgery
Placebo SK
Surgery 32
(15%)
32
(16%)
Death 30
(14%)
32
(16%)
Change practice
worldwide

39. tPA
lysis of pleural adhesions*
DNase
decreased viscosity+
The mechanism of action of tPA and DNase
Synergistic effect to
improve pleural fluid drainage
* Zhu Z, et al. Chest. 2006
+ Simpson G, et al. Chest. 2000
Maskell et al. N Engl J Med. 2005

40. Multi-Centre Intrapleural Sepsis Trial-2
Pleural Infection
DNase Placebo
Endpoints: Surgery? Alive?
Radiograph outcome?
tPA DNase + tPA

41. MIST-2: New Engl J Med 2011
• N=193
• 60% male
• Age 59 (19)
• tPA + DNAse
significantly superior

42. Surgical referral
Arm
Requiring
Surgery
OR 95% CI
Placebo 15.7 % n/a n/a n/a
tPA 6.2 % 0.30 0.07 to 1.25 p = 0.10
DNase 39.1 % 3.56 1.30 to 9.75 p = 0.01
tPA +
DNase
4.2 % 0.17 0.03 to 0.87 p = 0.03
tPA DNase therapy also significantly reduced
hospital stay (6.7 days vs placebo)

43. Contemporary Questions of tPA DNase
use in Pleural Infection:
Does it work in ‘real life’?
What patients to use on?
Safety profile?

44. Hospital Total = 107
Sir Charles Gairdner Hospital WA 42
Tweed Heads Hospital NSW 3
Prince Charles Hospital Qld 2
Wellington Hospital NZ 6
Dunedin Hospital NZ 7
Middlemore hospital NZ 4
Southmead Hospital UK 13
Greater Glasgow & Clyde UK 30
Sick patients (n=107) who failed antibiotics + drain: many
would have been sent to surgery

45. Regime
• tPA (alteplase) 10mg intrapleural via chest tube
• Clamp tube 45 min; then open to free drainage 45 min
• DNase 5mg intrapleural instillation
• Clamp tube 45 min; then open to free drainage 45 min
• Twice daily instillations
• Daily assessment with CXR and blood inflammatory
markers – stop instillations if fluid cleared
• Usually no more than 6 doses

46. -24 hrs +24 hrs +72 hrs
0
1000
2000
3000
4000
5000
6000
7000
*
*
*
*p<0.05, ANOVA-on-ranks, Dunn's method
Duration following treatment
CumulativePleuralFluidVolume(mL)
24hrs pre 24hrs post 72 hr post
Median (mL)
IQR
250 1300 2475
100-645 735-1980 1800-3585
Outcomes: Increased fluid drainage

47. Pre- Post-
0
10
20
30
40
50
60
70
80
90
100
***p<0.001, Mann-Whitney rank sum tests
***
Treatment
RatioofEffusiontoHemithorax
Outcomes: Reduction in effusion size
Pre-treatment Post
Med 34.8 % 13.7 %
IQR 23-51 7-29

48. Day 1 Day 2 Day 3 Day 4 Day 5
0
20
40
60
80
100
*p<0.05, ANOVA-on-ranks, Dunn's method
*
*
*
*
106
206
306
CRP(%changefromdayoftreatment)
Outcomes: Reduction of CRP

49. CASE 1
3 days of tPA DNase therapy. Much improved.
Resolution of collections. Remains afebrile.
Pre- tPA DNase Discharge
Discharged. Back to work the following day.
Continued antibiotics for further two weeks.

51. Intrapleural tPA consistently and
potently stimulated production of
large volume of hemorrhagic
exudative pleural fluid
Can occasionally be associated with
- slow drop in Hb requiring transfusion
- which stops when tPA ceased
- rarely causes hemodynamic collapse
FAQs: Safety (Short Term)

53. ADAPT Alteplase Dose Assessment for Pleural infection Therapy
Systematic dose de-escalation series to establish the lowest
effective intrapleural tPA dose
Piccolo F et al. Annals Am Thorac Soc 2014
n=107 Open label showing 10mg tPA/DNase effective
Popowicz N et al. Annals Am Thorac Soc 2017
n=61 5mg tPA/DNase effective (success rate 90+%)
Popowicz N et al.
n=55 2.5mg tPA/DNase in analysis

54. tPA 5mg / DNase 5mg twice daily
Radiographic
Resolution
Increased
Drainage
Reduced
CRP

55. FAQs: Safety (Short Term)
• Pain is common
Requires escalation of analgesia
- Piccolo et al: 21/107 (19%)
- Jantz et al: 8/55 (15%)
• Usually with first dose; rare after
• Mechanism unclear
• Recommend prophylactic analgesia

56. FAQs on tPA DNase
Piccolo, Popowicz, Wong, Lee. J Thorac Dis 2015
Use other fibrinolytics?
tPA used with original study (proven); widely available
slightly more expensive (but few pts)
Other fibrinolytics – probably work but unproven
Drain size - No evidence for need of large bore drains

57. FAQs on Practical Tips
Always need 6 doses? - No, assess daily
Mix the drugs for instillation? - Unknown, being tested
Should tPA / DNase be started at diagnosis? -
- Rahman et al: Used for all pt at diagnosis, showed
efficacy but also reduction in LOS
- Piccolo et al: Used as ‘rescue therapy’ (>80% after 24 hr)
- No difference in efficacy
What is the long term consequences?

58. Many of the components in infected
pleural cavity can be two way swords

59. Is Inflammation During Pleural
Infection always beneficial?

60. Community Acquired Pneumonia (n=3612):
633 had inhaled steroid
• Fewer parapneumonic effusions [OR 0.42]
• Smaller effusions
• Lower inflammatory indices in pleural fluid
Can parapneumonic effusions be a result of over-
exaggerated inflammatory responses?
Role of steroid?

61. 60 children (4.7 yrs): Pneumonia + Parapneumonic effusion
• Dexamethasone (0.25mg/kg q 6 hr) vs placebo
DXM group: shorter median time to recovery 109 vs 177 hrs
(p=0.037)
Benefits more with simple
than complicated effusion
(2.8 vs 0.5 days shorter)
Safe except for transient
hyperglycemia

62. Is adhesion good or bad in pleural
infection?

63. Conventional Teaching:
Adhesions prohibit
drainage and are Villains
Adhesions in Empyema: Hero or Villain?
Adhesions may be the body’s
effort to wall off infection and
prevent pleural spread and
systemic sepsis (similar to
lung/liver abscess)?

64. Sir William Osler (1849-1919)
- Father of Modern Medicine
- 100th anniversary of his death
- Developed empyema
‘empyema needs a surgeon and 3 inches
of cold steel instead of the fool of a
physician’…
- Most literature: ‘died from empyema’
Gregory P, Rahman N, Lee YCG. Postgrad Med J (invited review)
• Underwent rib resection + surgical drainage
• Died Day 5 post-op from massive pleural haemorrhage
• Empyema did not kill Sir Osler… Surgery did!
In 2019: he would be treated with tPA DNase, likely not
needed surgery and survived the empyema…

65. One more important point
Provide that infection settles, residual pleural
opacities will resolve with time.
Surgery is unnecessary to clear residual pleural
collections when patient clinically improved.

66. Pleural infection is like lung infection,
residual changes will settle with time provided the
infection is controlled
29/M Pneumonia.
Fever and CRP  with ab
but significant residual
consolidation RUL
What would you do?
Send to lobectomy because CXR
not improved?
Reassured him that CXR changes
will settle with time
Would be a crime to send this patient to lobectomy!

67. 18/F pleural infection
post-appendicectomy
Loculated. 2x chest drain
Fever & CRP  with ab
but residual collection
Radiographic changes resolve with time
What would you do?
Send to surgery because CXR not
improved?
Reassured her that CXR changes
will settle with time

68. I removed all the drains and
sent her home on antibiotics
Radiographic changes resolve with time
TREAT THE PATIENT, NOT THE X-RAY!

69. Translational Research in Pleural Infection and Beyond
Y C Gary Lee, Steven Idell & Geogious Stathopoulos
CHEST 2016 Dec; 150: 1361-1370
Francesco Piccolo, Natalia Popowicz, Donny Wong,
Yun Chor Gary Lee J Thorac Dis 2015; 7: 999-1008

70. Calvin Sidhu
Deirdre Fitzgerald
Tara Hannon
Sally Lansley
Hui Min Cheah
Natalia Popowicz
Rajesh Thomas
Cathy Read
Deirdre Fitzgerald
Carolyn McIntyre
Amber Louw
Natalia Popowicz
Edward Fysh
Emily Jeffery
PLEURAL MEDICINE UNIT
Funding NHMRC; MRFF; Cancer Council WA; Cancer Australia;
NSW Dust Diseases Board; SCGH; WA Cancer & Palliative Network

71. THE PLEURAL MEDICINE UNIT
Sir Charles Gairdner Hospital,
Harry Perkins Institute of Medical Research, Perth, Australia
gary.lee@uwa.edu.au
pleura.com.au