Pleural Effusion evaluation and differential diagnosis

1. Pleural Effusion
S. A. Saleemi

2. PLEURAL EFFUSION
•Fluid production exceeds absorption.
•Fluid is formed in the parietal pleura and absorbed in
parietal pleural lymphatics.
•Lymphatics have the capacity to absorb 20 times more
than what is Produced.
•Fluid can also enter the pleural cavity from interstitial
spaces of lung through visceral pleura.
•Peritoneal fluid can enter the pleural cavity via
diaphragm pores.

4. Mechanism of Pleural effusions
increased hydrostatic pressure(LVF)
decreased oncotic pressure in microcirculation
(hypoalbuminemia)
decrease in pleural pressure (atelectasis)
increased permeability of microcirculation
( pneumonia)
impaired lymphatic drainage from pleural space
(malignancy)
movement of fluid from abdomen to pleural
space ( cirrhosis)

5. In health, the volume of pleural fluid in
humans is small (<1 ml), forming a film
about 10 micro thick between the visceral
and parietal pleural surfaces.

6. Normal composition of pleural fluid
Volume
Cells/mm³
%mesothelial cells
%monocytes
%lymphocytes
%granulocytes
% eosinophils
Protein
%albumin
Glucose
LDH
0.1-0.2 ml/kg
1000-5000
3-70%
30-70%
2-30%
~ 10%
0%
1-2 gm/dl
50-70%
~plasma level
<50% plasma level

7. Differentiation between transudate and exudate
parameter
transudate exudate
Total protein
<30 g/l
>30 g/l
Pleural-serum
protein ratio
<0.5
>0.5
LDH
<200 u/l
>200 u/l
Pleural-serum
LDH ratio
<0.6
>0.6
cholestrol
<45mg/dl
>45 mg/dl
Bilirubin pleural- <0.6
serum ration
>0.6

8. Light Criteria
1- Pleural fluid protein-to-serum protein
ratio more than 0.5
2- Pleural fluid LDH-to-serum LDH
ratio more than 0.6
3-Pleural fluid LDH level greater than
two third the upper limit of normal
serum level

9. Modified 1997 (NO SERUM LEVELS)
(by Haffner)
1-Pl. fluid protein more than 2.9g/dl(29g/L
2- Pl. fluid LDH more than 66% of upper limit
of normal serum reference range
3- Pl. fluid cholestrol more than 45 mg/dl

10. Serum-effusion albumin gradient (SAG)
In general Light’s criteria occasionally
misidentify a transudative effusion as an
exudative effusion as in cardiac failure
with diuretic therapy
Clinically if a patient should have a
transudative effusion, but meets Light’s
criteria for an exudative effusion, measure
serum - pleural fluid albumin gradient
Serum- effusion albumin gradient of more
than 1.2 g/dl is used to diagnose presence
of transudate effusion.

11. Causes of transudative pleural effusions
Very common causes
– Left ventricular failure
– Liver cirrhosis
– Hypoalbuminaemia
– Peritoneal dialysis
Less common causes
– Hypothyroidism
– Nephrotic syndrome
– Mitral stenosis
– Pulmonary embolism
Rare causes
– Constrictive percarditis
– Urinothorax
– Superior vena cava obstruction
– Ovarian hyperstimulation
– Meigs’ syndrome

12. Causes of exudative pleural effusions
Common causes
– Malignancy
– Parapneumonic effusions
Less common causes
– Pulmonary infarction
– Rheumatoid arthritis
– Autoimmune diseases
– Benign asbestos effusion
– Pancreatitis
– Post-myocardial infarction syndrome
Rare causes
– Yellow nail symdrome
– Drug (see box1 )
– Fungal infections

13. Drugs known to cause pleural effusions
Over 100 reported cases globally
– Amiodarone
– Nitrofurantoin
– Phenytoin
– Methotrexate
20-100 reported cases globally
– Carbamazepine
– Procainamide
– Propylthiorucil
– Penicillamine
– GCSF
– Cyclophosphamide
– Bromocriptine
* pneumotox.com (2001)

14. Approximate annual incidence of various
types of pleural effusions in the USA
Etiology
Congestive heart failure
Other causes
Pneumonia
Malignant disease
Pulmonary embolism
Cirrhosis with ascites
Gastrointestinal disease
Collagen vascular disease
Tuberculosis
Asbestos pleuritis
Mesothelioma
TOTAL
Number
500,000
Percentage
Percentage
of noncardiac
effusions
37.5
63.6
400,000
200,000
150,000
50,000
25,000
6,000
2,500
2,000
1,500
100.0
48.0
24.0
18.0
6.0
3.0
0.7
0.3
0.25
0.2
100.0

15. Frequency distribution of
noncardiac effusions
Authors
Number
Neoplastic
%
Infectious
%
Various
%
Idiopathic
%
Storey et al.
115
56
6
16
22
Hirsch et al.
295
39
31
9
21
194
46
33.5
12
20
646
34.5
26.5
15
12.5
250
34
39
18
9
42
29
14
15
Lamy et al.
Engel,
Loddenkemper, 1500
TOTAL

16. Useful Tests in the Evaluation of Pleural
Effusions
Test
Abnormal Values
Frequently Associated
Condition
Red blood cells, per
mm3
>100.000
Malignancy, trauma,
pulmonary embolism
White blood cells, per
mm3
>10.000
Pyogenic infection
neutorphils, %
>50
Acute pleuritis
lymphocytes, %
>90
Tuberculosis,
malignancy, lymphoma
eosinophilia, %
>10
Asbestos effusion,
hydro-pneumothorax,
resolving infection
mesothelial cells
absent
Tuberculosis

17. Cont:Glucose, mg/dl
<40
Empyema, TB,
malignancy, rheumatoid
arthritis
pH
<7.20
Esophageal rupture,
empyema, TB,
malignancy, rheumatoid
arthritis
Amylase, PF/S
>1
Pancreatitis,
esophageal rupture
Bacteriologic
Positive
Etiology of effusion
Cytology
Positive
Diagnostic of malignancy

18. Pleural fluid eosinophilia (>10%)
Usually due to air or blood in the pleural space
Consider drug reactions
– Dantrolene, bromocriptine, nitrofurantoin
Frequent with asbestos pleural effusion
Rarely paragonimiasis or Churg-Strauss
syndrome
– also low glucose and pH
Frequently no diagnosis obtained

19. Appearance of pleural fluid
Fluid
Suspected disease
Putrid odour
Anaerobic empyema
Food particles
Oesophageal rupture
Bile stained
Cholothorax (biliary
fistula)
Milky
Chylothorax/pseudoch
ylo- thorax
“Anchovy sauce” like
fluid
Ruptured amoebic
abscess

20. Pleural infections

21. Pleural infection was first described by
Hippocrates in 500BC.
Open thoracic drainage was the only
treatment for this disorder until the 19th
century when closed chest tube drainage
was first described.
open surgical drainage was associated
with a mortality rate of up to 70%.

22. Characteristics of parapneumonic pleural
effusions
Stages
Macroscopic
appearance
Pleural fluid
characteristics
Comments
Simple
parapneumonic
Clear fluid
pH >7.2
LDH <1000 IU/l
Glucose >2.2 mmol/L
No organism on
culture or Gram stain
Will usually resolve
with antibiotics alone
Perform chest tube
drainage for symptom
relief if required
Complicated
parapneumonic
Clear fluid or
cloudy/turbid
pH <7.2
LDH >1000 IU/l
Glucose <2.2 mmol/l
May be positive Gram
stain/culture
Requires chest tube
drainage
Empyema
Frank pus
May be positive Gram
stain/culture
Requires chest tube
drainage
No additional
biochemical tests
necessary on pleural
fluid (do not measure
pH)

23. Classification of and Therapies for
Parapneumonic Effusion and Empyema
Appearance and
Studies
Class
Type
1
Insignificant pleural
effusion (<10 mm
thick) on decubitus
radiograph)
Thoracentesis not
indicated
2
Typical parapneumonicpH >7.2
pleural effusion
(>10 mm thick)
Glucose >40 mg/dL
Radiologic
Appearance
Gram stain and culture
negative
Treatment
Antibiotics alone

24. Classification of and Therapies for
Parapneumonic Effusion and Empyema (cont.)
Appearance and
Studies
Radiologic
Appearance
Class
Type
Treatment
3
Bordeline
complicated
pleural effusion
ph 7.0-7.2 and/or
No loculations
LDH >1000IU/L and
Glucose >40 mg/dL
Gram stain and culture
negative
Antibiotics and
repetition
4
Simple complicated pleural
effusion
ph<7.0 and/or
Not loculated,
Glucose <40 mg/dL nonpurulent
and/or
Gram stain culture
positive
Tube thoracostomy
and antibiotics or
serial thoracentesis

25. Classification of and Therapies for
Parapneumonic Effusion and Empyema (cont;)
Appearance and
Radiologic
Class
Type
Studies
Appearance
Treatment
5
Complex complicated pH<7.0 and/or
Multiloculated
Tube thoracostomy a
pleural effusion Glucose <40 mg/dL nonpurulent
& thrombolytic agent
and/or
In rare instances
Gram stain or culture
surgical intervention
positive
6
Simple empyema
Frank pus
7
Complex empyema Frank pus
Single loculation or
Tube thoracostomy
with or without
decortication
Multiple locules
Tube thoracostomy &
thrombolytic agents
Often thoracoscopy
or decortication

26. Septation
Loculation

27. Resolution of pleural effusion
Disease
Incidence%
Therapy
Resolution time
Parapneumonic
9-66
Antibiotics
2-8 weeks
Tubeculosis
3-23
No therapy
2-4 months
Anti-TB treatment
1-2 months
Post CABG
40-90
Self limiting
8 weeks(6w-20m)
RA
4-7
NSAID, Prednisone
3-4m(1m-5y)
SLE
16-37
Steroids
1-6w
PE
10-50
Heparin
3-7d
PCIS
40-68
NSAID, Steroids
1w-4m
Sarcoidosis
0-7.5
Self limiting,steroids
1-3m
Chest 119(5), 2001

28. Resolution of pleural effusion by time interval
<2 months
2-6 months
6m-1year
Benign persistent
Parapneumonic
CHF
Acute pancreatitis
PCIS
Post CABG
PE
SLE
Sarcoidosis
Traumatic chylothorax
Uremic effusion
TB
PCIS
Post CABG
RA
sarcoidosis
RA
Benign
asbestosis
Trapped lung
Lymphangiectasia
Noonan’s syndrome
LAM
Yellow nail syndrome
Chest 119(5), 2001

29. Resolution of parapneumonic pleural effusion
organism
Incidence%
Therapy
Resolution time
(Range)
S pneumoniae
30-60
B-lactams,
macrolides
4-8 weeks
M pneumoniae
4-20
Macrolide,
tetracyclines
2-3 weeks
L pneumoniae
12-35
Macrolides
3-4 weeks
Adenovirus
2-18
Self limiting
2-3 weeks
Chest 119(5), 2001

30. Tuberculous pleural effusion
AFB stain positive in only 10-20%
AFB culture positive 25-50%
Diagnostic yield increases to 90% with
addition of pleural biopsy histology and
biopsy cultures for AFB

31. Pleural fluid markers for
tuberculosis
Adenosine Deaminase (ADA)
Gamma interferon
PCR for DNA of M. tuberculosis

32. Pleural fluid ADA
T-lymphocyte enzyme
Patients with TB have levels above 45 IU/L
unless they are immunologically suppressed
High levels also seen with empyema and
rheumatoid pleuritis
Specificity increased if combined with PF
lymph/poly ratio greater than 3
Pleural fluid ADA helpful in areas of high TB
prevelance
Fluid ADA levels not useful in HIV patients with
TB

33. Pleural fluid gamma interferon
Produced by lymphocytes
Lymphocytes specifically sensitized to PPD produce
gamma interferon when incubated with PPD
PF levels above 140pg/ml are very suggestive of TB
Elevated whether or not the patient is
immunosuppressed
Is more expensive than ADA

34. PCR for the diagnosis of
tuberculous pleuritis
With PCR one can identify the presence of
DNA from M. tuberculosis in the pleural fluid
Study from spain on 107 pleural fluids
– PCR positive in 17/21 with TB
– PCR positive in only two others and they probably
had TB
– PCR was not superior to an ADA level >45
Querol JM et al. Am J Respir Crit Care Med 1995;152:1977

35. Diagnosis of tuberculous pleuritis
If pleural fluid ADA >70 units - diagnostic
If pleural fluid gamma interferon is high diagnostic
Granulomas on pleural biopsy - diagnostic
If lymphocytic effusion and positive PPD,
treat for TB pleuritis if pleural fluid ADA is
above 40

36. Pleural effusions in HIV infection
A pleural effusion is seen in 7–27% of
hospitalised patients with HIV
Leading causes are
Kaposi sarcoma
parapneumonic effusion
Tuberculosis
Lymphoma
pneumocystic carinii pneumonia

37. Chylothorax and Psudochylothorax

38. Fluid Triglyceride >110 mg /dl - Diagnostic
Presence of Chylomicron - Diagnostic
Fluid Triglyceride 50-110 mg/dl – probable
Fluid Triglyceride <50 mg/dl – Not chylothorax

39. Laboratory differentiation of chylothorax and
pseudothorax
Pseudochylothorax
Chylothorax
<0.56 mol/l
(50mg/dl)
>1.24 mmol/l
(110 mg/dl)
Cholesterol
>5.18 mmol/l
(200 mg/dl)
>5.18 mmol/l
(200 mg/dl)
Cholesterol
crystals
Often present
Absent
Absent
Present
Feature
Triglycerides
Chylomicrons

40. Causes of chylothorax and pseudochylothorax
Chylothorax
–
–
–
Neoplasm: lymphoma, metastatic carcinoma
Trauma: operative, penetrating injuries
Miscelaneous: tuberculosis, sarcoidosis,
lymphangioleiomyomatosis, cirrhosis, obstruction of
central veins, amyloidosis
Pseudochylothorax
–
–
–
Tuberculosis
Rheumatoid arthritis
Poorly treated empyema

41. Malignant pleural effusion

42. Malignant pleural effusion

43. Pleural fluid cytology
Very useful test
1st specimen positive in 60% and if three
specimens submitted, may be positive in >80%
Very effective with adenocarcinoma
Less effective with lymphoma, squamous cell
carcinoma, mesothelioma or Hodgkin’s disease
cytology much better than needle biopsy in most
series looking at malignant effusions
– in one series of patients with malignancy, pleural
biopsy positive in only 20/118 (17%) with negative
cytology
– rarely is needle biopsy indicated

44. Sensitivity of pleural fluid cytology in malignant pleural
effusion
Reference
No.of patients
No. caused by
malignancy
% diagnosed
by cytology
Salyer et al10
271
95
72.6
Prakash et al12
414
162
57.6
Nance et al11
385
109
71.0
Hirsch39
300
117
53.8
Total:
1370
371
61.6

45. Malignant pleural effusion
Observation
Observation is recommended if the patient is asymptomatic or there is
no recurrence of symptoms after initial thoracentesis. [C]
Therapeutic pleural aspiration
Repeat pleural aspiration is recommended for the
palliation of breathlessness in patients with a very short life
expectancy. [C]
Caution should be taken if removing more than 1.5 L
on a single occasion. [C]
The recurrence rate at 1 month after pleural
aspiration alone is close to 100%. [B]
Intercostal tube drainage without pleurodesis is not
recommended because of a high recurrence rate. [B]

46. Success rates of commonly used pleurodesis agents
Chemical
agent
Talc
Total
Successful
patients (n)
(%)
165
dose
93
2.5-10g
Doxycycline 60
72
500mg
tetracycline
359
67
500mg
Bleomycin
199
54
15-250 units

48. Rheumatoid arthritis associated
pleural effusions

49. • Suspected cases should have a pleural fluid pH,
glucose and complement measured.
• Rheumatoid arthritis is unlikely to be the cause of an
effusion if the glucose level in the fluid is above
1.6 mmol/l (29 mg/dl).

50. Frequency of low glucose values in pleural effusions
Entity
Frequency (%)
Rheumatoid
Arthritis
Empyema
85
Malignant
effusion
30
Tuberculous
20
Lupus
20
80

51. SLE associated pleural
effusion

52. The presence of LE cells in pleural fluid
is diagnostic of SLE.
The pleural fluid ANA level should not
be measured as it mirrors serum levels
and is therefore unhelpful.

53. Hepatic hydrothorax

54. Pleural effusion associated with liver
cirrhosis
Mostly associated with ascites
Can occur without ascites
Diagnostic tap of both pleural effusion and
ascites
Difficult to treat
Pleurodesis usually unsuccessful

55. MANAGEMENT OF PERSISTENT
UNDIAGNOSED PLEURAL EFFUSION
• In persistently undiagnosed effusions the possibility
of pulmonary embolism and tuberculosis should be
reconsidered since these disorders are amenable to
specific treatment.
• Undiagnosed pleural malignancy proves to be the
cause of many “undiagnosed” effusions with sustained
observation.

56. Pleural Effusion Pearls
Presence of transudate effusion indicates the existence
of systemic disease.
Exudative effusion is caused by a local pleural process.
Spontaneous bacterial empyema can complicate
hepatic hydrothorax.
TB and malignancy are the two commonest causes of
unexplained exudative effusion.
TB effusion is caused with equal frequency by primary
& reactivated TB
Hemothorax if HCT > 20%

57. Pleural Effusion Pearls
Massive pleural effusions are most
commonly due to malignancy. [B]
The majority of malignant effusions are
symptomatic. [C]
Very low glucose in the absence of infection
is highly suggestive of RA

58. Thank you