International Lung Symposium on Pleural Diseases, Manila 2019. Uncommon causes of pleural effusions 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
MRFF Practitioner Fellow
Y C Gary Lee
MBChB PhD FCCP FRCP FRACP
Difficult / Uncommon
Pleural Effusion Management

2. • Pleural effusion: 3000 / million population each yr
• Annual incidence of pleural effusions in USA
CONGESTIVE HEART FAILURE 500,000
PNEUMONIA 300,000
MALIGNANT EFFUSION 200,000
PULMONARY EMBOLISM 150,000
UNDIAGNOSED (?VIRAL) 100,000
POST-CABG 50,000
CIRRHOSIS WITH ASCITES 50,000
GASTROINTESTINAL DISEASE 25,000
CONNECTIVE TISSUE DISEASE 6,000
TUBERCULOSIS 3,000
Pleural Effusions

3. RWLight.Pleuraldiseases4thed60+ causes
of pleural
effusions

4. Other (Less Common) Causes
pleural effusions are not just LVF,
infection and cancer!

5. Tuberculous Pleural Effusion

6. TB Pleural Effusion
• Rising incidence (eg AIDS; immunosuppressants)
Overall ~ 1 in 30 patients with TB
TB patients with HIV (38% in one series from S. Africa)
• Geographical variations in incidence:
USA ~3000 cases/yr; Endemic areas: commonest exudates
Textbook of Pleural Disease 3rd ed; Light RW and Lee YCG
• TB Effusions often difficult to diagnose
Diagnosis often delayed in non-endemic areas because of
lack of clinical suspicion
Over-diagnosis common in endemic regions

7. TB Pleural Effusion: Etiology
Rupture of peripheral loci of mycobacteria in the lung
(often undetectable) ► pleural cavity
• Actual bacterial load is usually very small
• Bacteria need not be viable: culture often –ve
Mycobacterial protein elicits a type IV (delayed)
hypersensitivity reaction in pleura
• Caseating granulomata characteristic
• Diffuse involvement of the pleura
Hypersensitivity inflammatory reaction
• ↑ vascular permeability; exudative effusions

8. • Symptoms non-specific: Constitutional, Cough, SOB
• Often no known TB contact: reactivated latent infection
• Up to 50% have no detectable TB elsewhere
• Size: most small to moderate; 5% are massive effusions
• Occur in any age group/origin (next slide)
TB Pleuritis: diagnostic challenge
Typical Pleural Fluid characteristics:
• Exudative: Protein often high (eg >50g/L)
• Lymphocytic predominant: >50% WBC in 95% pts
• Few mesothelial cells in fluid: Generalized pleuritis
‘covered’ the mesothelium, minimizing shedding

9. TB Pleural Effusion: Presentation
1993-2001
CDC notified cases
Pleural Only Cases*
N=6,458 (M:F = 2:1)
Age Group n %
0-15 120 1.9
16-24 676 10.5
25-44 2,211 34.2
45-64 1,466 22.7
65+ 1,983 30.7
Origin
US-born 4,175 65
Foreign-born 2,240 35

10. Diagnosis often based on caseating
granuloma in pleural tissue
Most patients diagnosed with TB effusions do not have
microbiologic confirmation
• Closed (Blind) pleural biopsy
Abram needle or Cope’s needle
• Thoracoscopic biopsy
• Image-guided biopsy (especially CT)

11. Diacon AH et al. Eur Respir J 2003
• Randomized study of diagnosis of TB pleuritis:
pleuroscopy biopsy vs closed Abram biopsy
• Pleuroscopy sensitivity 100%
Abram biopsy 79%
Indication: Diagnosis of TB Pleuritis
As the pleura is diffusely involved, blind biopsy often is
adequate to detect granuloma
Should be used in initial workup in endemic areas

12. • Adenosine Deaminase (ADA)
• Polymerase Chain Reaction (PCR)
• Interferon- (IFN)
• ‘ELISPOT’ or Quantiferon test
TB Effusion: Search for a diagnostic marker
Routine workup of effusion in many countries
• An enzyme present in lymphocytes; Activity in vitro
related to proliferation / differentiation
• ADA unit: Enzymatic activity to produce 1 mol of
ammonia/min from adenosine at standard assay conditions

13. Valdes L et al. Eur Respir J 1996
False positives:
• Empyema
• Rheumatologic
• Other lymphocytic
e.g. lymphoma,
malignant, chylothorax
etc.
• Limiting ADA testing to lymphocytic effusions
can easily avoid most of the false +ve

14. ADA for TB pleural effusions
Applies  Pediatrics Mishra et al. Arch Dis Child 2006
 Immunosuppressed
Renal transplant Chung JH et al. Yonsei Med J 2004
HIV/AIDS patients Riantawan P et al. Chest 1999
Meta-analysis (63 studies):
Sensitivity 92%; Specificity 90%
Positive likelihood ratio: 9.0
Negative likelihood ratio: 0.1
Diagnostic odds ratio: 110.1
Liang Q-L Respir Med 2008

15. ADA for TB pleural effusions
Negative Predictive Values
• 99% (n=410 lymph effusions)
Castro D et al. ERJ 2003
• 94% (endemic area)
Chen ML et al. Clin Chim Acta 2004
• post-test prob 0.4% (non-endemic)
Greco et al. IJTLD 2004
Very valuable test to rule out TB in lymphocytic
effusions esp in non-endemic countries (avoid bx)

16. TB pleural effusion: Natural Course
• Most TB effusions spontaneously resolve within
2-4 months [historic data, Finnish Armed Forces 1939-45]
• ~10% develop pleural thickening - usually mild
with no functional sequalae
• Pleural fibrosis is not reduced by
⸱ drainage of effusion ⸱ corticosteroids
So why do we treat TB pleuritis?

17. TB pleural effusion: Natural Course
• Mycobacteria enters the pleura via other organs
(usually the lung)
• TB pleuritis usually heals with / without treatment,
but untreated patients high risk (~60%) of
developing active TB elsewhere (usually lung)
within a few years of the pleural effusion

18. Treatment
• Standard TB Treatment according to local
resistance pattern
• Use of high dose oral corticosteroid controversial
- improve fluid drainage; improve symptoms
- no difference to long-term outcome
- steroid side effects
- risk of Kaposi’s sarcoma in HIV +ve
• Drainage of effusion if symptomatic
- Pleurodesis not indicated as fluid should settle

19. TB Effusion: Differential Diagnosis
Granulomatous inflammation of the pleura
TB (95%)
Rheumatoid pleuritis; Fungal; Drug; Sarcoidosis
Lymphocytic pleural effusions
Rheumatoid pleuritis
Malignant effusions (including lymphoma)
Post-CABG
Lymphatic disruption
(Yellow Nail Sx; Chylothorax; LAM)

20. pleural effusions are not just
heart failure, infection, cancer
or TB!

21. Rheumatoid Pleuritis
• ~40% of RA patients have pleural disease at autopsy
• ~20% pleuritic pain; 5% clinically evident pleural disease
• Usually with severe arthritis and subcutaneous nodules
• M>F; mean age 51
• Dx of exclusion Pleural EffusionsPleural Effusions
• Uncommon 2-3%
• Usually small; resolve spontaneously
• 25% bilateral, no predilection for side
• Fluid analysis does not differentiate:
Exudative;  pH & glucose,  LDH
• Pleural fluid Rheum Factor not useful
• ADA may be elevated in RA
Pleural fluid cytology

22. Spectrum of pleural diseases in RA
• Rheumatoid pleuritis/effusions
• Pleural thickening/fibrosis (can progress), trapped lung
• Pleural rheumatoid nodules (can necrotize/rupture)
• Infection: Common bacterial pathogens, TB, fungal
• Chylothorax / Pseudochylothorax
• Drug-related effusions: MTX, sulfasalazine, etc
• Pneumothorax; Bronchopleural fistula
• Transudates: Cardiac/liver failure, hypoalbuminemia
• Amyloidosis

23.  Pale, thickened, granular
appearance of parietal pleura
 Non-specific fibrotic or
granulomatous changes (can be
necrotizing)
 Multinucleated giant cells
 Fibrin accumulation
 Loss of mesothelial cell
covering
 Pleural RA nodules rare
Yokosuka et al. 2013
Cibas &Ducatman. 2013

24. Rheumatoid pleural disease management
• 50% RA effusions resolve in 4 wks without specific Rx
• If unresolved: pleural thickening, progressive pleural
fibrosis, trapped lung, restrictive defects
• Treatment of pleuritis/effusions not well-established
Treatment Options
NSAIDs Repeated Thoracentesis
Corticosteroids (oral vs Intrapleural) Pleurodesis
Cytotoxic drugs Surgery
IVIg

25. Empyema or chylous effusion?
(chylothorax; pseudochylothorax)
 All turbid
Investigate pleural effusions: Look and Smell

26. FAQ
Empyema or chylous effusion?
 Neutrophilic vs lymphocytic
 Centrifuge

27. Chylothorax Pseudochylothorax
Biochemistry Triglyceride Cholesterol
Fluid color Creamy Creamy
Features Chylomicrons Cholesterol crystal
Light RW & Lee YCG.
In: Murray & Nadel’s Textbook of Respiratory Diseases, 5th ed, 2010
If chylous; then need to separate

28. Pseudochylothorax
• TB and Rheumatoid pleuritis most common causes
• Conventional textbooks all said pseudochylothorax only
occurs with very thickened pleura
• Now disproved, at least in RA-related Pseudochylothorax
• Wrightson et al CHEST 2009

29. Pleural Amyloidosis
• Protein folding disorders:
insoluble B-rich fibrils into organs
• Refractory effusions: usually in AL (6-18%)
• 60% transudative, often unilateral
• Dx: Biopsy with amyloid infiltration on Apple green
birefringence/Congo red stain

30. Pleural Amyloidosis

31. Pleural Amyloidosis
Prognosis
• Typically presents late and refractory effusion
• Prognosis if untreated 1.6 months if pleural involvement

32. Drug related effusion
Bilateral eosinophilic effusions
presumed related to clozapine
Bx usually non-specific inflammation +/- granuloma
Dx by exclusion; re-challenge rarely advisable

33. Pulmonary emboli related effusion
Pleural effusion in 48% of pts with CTPA proven PE
Effusions are inevitably small. If large, consider
alternative causes
Yap E et al Respirology 2008

34. IgG4-Related Disease
• Systemic, immune-mediated disease
- Characterised by
- raised serum IgG4
- tissue infiltration by IgG4+ plasma cells
• Relatively new disease
- 1961 - “Autoimmune pancreatitis”
- 2001 - Association with IgG4 established
- 2003 - Extra-pancreatic manifestations recognized

35. Pleuro-Pulmonary Disease - Diverse
Presentations
 Thickening of bronchovascular bundle -
characteristic finding
- Obliterative arteritis
- Nodules/pseudo-tumours
- Ground glass opacity
- ILD/Fibrosis
- Pleural thickening/effusions ~5%

36. Pathophysiology
- Unclear
- Affects older
males
Stone. NEJM 2012

37. Diagnosis
• Requires high index of suspicion
- Clinical features & raised serum IgG4
(>1.35 g/L) are suggestive
• Histopathology essential for diagnosis
- Lymphoplasmacytic infiltration:
- >10 IgG4+ cells per HPF
- >40% IgG+ plasma cells are IgG4
- Fibrosis with storiform features
- Obliterative phlebitis

38. IgG4 Disease Management
• Most cases respond to steroids
- Prednisolone (0.6mg/kg/day x 2-4wks)
- Maintenance 2.5-5mg/day for up to 3yrs
• Steroid-sparing therapy (AZA, MMF, Mtx)
• Reports of response to rituximab
• Monitor IgG4 levels & for end-organ damage
- IgG4 remains elevated in 63%
• 25-50% relapse, chronic disease
• Future malignancy risk

39. What is the diagnosis
Intercostal artery bleed
What should we do next?
a) Urgent thoracotomy/VATS
b) Intercostal artery embolisation
c) CT angiogram

40. • Resuscitated
IV fluids and blood transfusions
Chest drain inserted – drained 100ml blood/15 min
• Remained hypotensive & hemodynamically
unstable
Case 5

41. Intercostal Artery Bleeding
• Highest risk posteriorly
- vessels are not protected by
rib flange till angle of rib
- increased vessel tortuosity
Carney et al. Chest 1979
Fox et al. Radiology 2003
• Avoid the first 10 cm of
the ICA
• Avoid choosing pleural
puncture sites at the
posterior medial aspects

42. Intercostal Artery Bleeding
Specific Management
• External pressure over intercostal space
• Suture around the rib medial to pleural entry site
• Thoracic surgery is often required (especially if large
residual clots that need evacuation)
• ICA embolisation is an alternative option if available

43. Points to Ponder
• > 60 causes of pleural effusions
• Most effusions given one diagnosis and assumed to
arise from a single etiology. Too simplistic?
• Disease-specific markers now can help decode co-
existing diseases and contributing etiologies

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