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Note: Tables and figures
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Introduction
Nearly one third of the global population i.e. two
billion people are infected with Mycobacteria
tuberculosis and at risk of developing the disease. More
than eight million people develop active TB and about
two million die every year. More than 90% of global TB
cases and deaths occur in the developing world mainly
Asia and Africa.
In Myanmar(Formerly Burma), it is one of the major
public health problems and recent estimates suggest that
1.66% of the population become infected with
tuberculosis every year, out of which about 80000 people
progress to develop tuberculosis. According to the
"Annual Hospital Statistical Report, Ministry of
Health”, it is the 8th single leading cause of morbidity
by trend, 1998 - 2003 and the 2nd single leading cause
of mortality by sex treated in hospitals, 2003 (Ministry
of Health, 2003).
Tuberculosis is a disease with protean manifestations.
The clinical presentation of TB can mimic several
diseases and can be a diagnostic problem even in endemic
areas. Virulence and load of the infecting
mycobacterium, the immune status of the host, the organ
system involved, all influences the clinical
manifestations of tuberculosis. Pleural effusion is one
of the common complications of primary tuberculosis or
in conjunction with pulmonary infiltrate typical of post
primary tuberculosis (Seibert, Haynes, Middleton, &
Bass, 1991). Ferrer JS et al (1996) pointed out that
28.7% of pleural effusions (113 patients out of 394
patients) are due to tuberculosis among Spanish
patients.
The inner surface of the chest wall and the surface of
the lungs are covered by the parietal and visceral
pleural, respectively, with a potential space of 10-24
µm between the 2 pleural surfaces. This space is
normally filled with approximately 1 ml of fluid,
representing the balance between (1) hydrostatic and
oncotic forces in the visceral and parietal pleural
vessels and (2) extensive lymphatic drainage. Pleural
effusions result from disruption of this balance. Large
amounts of fluid can accumulate in the pleural space
under pathologic conditions. The parietal pleura have
sensory innervation and small apertures that aid in the
absorption of particles and fluid.
The diagnosis of tuberculosis pleural effusion (TPE) can
be difficult to make because of the low positivity of
the various diagnostic tests. Lymphocytic exudates seen
in TB pleural effusion also can occur in other disease
such as malignancy, collagen vascular disease and
lymphoma. A definitive diagnosis of TPE requires the
presence of granulomas in pleural tissue or a stained
AFB or positive culture from the pleural tissue or
pleural fluid.
The physical signs of the presence of pleural effusions
may identify patients who require further diagnostic
procedures. A met analysis addressed the diagnostic
accuracy of the physical examination for pleural
effusion using CXR or computed tomography (CT) scan as
the reference standard (Wong, Holroyd-Leduc, & Straus,
2009). To achieve this objective, the authors identified
310 potential studies, totaling 934 patients, met the
inclusion criteria. Of the 8 physical examination
maneuvers evaluated in the included studies, the
presence of dullness to conventional percussion (summary
positive likelihood ratio-LR-8.7) and asymmetric chest
expansion (positive LR 8.1) argued convincingly for the
diagnosis of pleural effusion. In contrast, the absence
of reduce tactile vocal fremitus reduced the probability
of pleural effusion (negative LR 0.21). These signs
should guide performance of the clinical examination for
detecting pleural effusion (Ocak, 2010).
Many patients are asymptomatic on the discovery of a
pleural effusion. Pleuritic chest pain indicates
inflammation of the parietal pleura (because the
visceral pleura are not innervated and thus not
sensitive to pain). Other symptoms include dry,
nonproductive cough and dyspnea. Constitutional symptoms
are almost always present. Physical examination findings
that can reveal the presence of an effusion are reduced
tactile fremitus, stony dull note on percussion, and
diminished or absent breath sounds on auscultation. TB
pleural effusion is usually unilateral and is small to
moderate in size although massive effusion can also
occur. Bilateral effusion is rare. The pleural fluid is
exudative and lymphocyte rich.
T-cell interferon-gamma release assays (IGRAs) have
emerged as attractive for the diagnosis of latent
tuberculosis. One prospective study has recently
compared the diagnostic performance of four different
IGRAs using pleural fluid mononuclear cells with that of
unstimulated IFN-γ concentrations in pleural fluid, in
63 patients from a high TB/HIV burden setting (Dheda et
al., 2009). All IGRAs, performed poorly because, at
best, they missed 15% of TB cases and incorrectly
diagnosed a further 20%. In contrast, unstimulated IFN-γ
levels >0.31 IU/mL had 97% sensitivity and 100% specifi
city for identifying TB pleuritis. Currently, there is
little convincing evidence to support the use of IGRAs
against other available markers of TB such as IFN-γ or
adenosine deaminase (Ocak, 2010).
Few studies have examined the role of positron-emission
tomography (using 18-fl uorodeoxyglucose) combined with
CT (PET-CT) in the investigation of pleural diseases. In
one series, 83 patients with undiagnosed effusions
and/or pleural thickening after routine clinical
investigations (including blind pleural biopsy)
underwent a PET-CT scan before a thoracoscopic or open
surgical biopsy (Orki et al., 2009). The final
histopathological diagnoses were malignant disease in 44
patients (including 25 mesotheliomas) and benign pleural
conditions in the remaining 39 patients (30 chronic
pleuritis and 9 tuberculosis). The operating
characteristics of PET-CT for identifying malignant
pleurisy were: sensitivity 100%, specificity 94%,
positive LR 19.5 and negative LR 0.01.
Evaluation of exudative pleural effusion usually
includes thorough history, complete clinical
examination, appropriate blood tests, radiographs,
studies of pleural fluid and needle biopsy of pleura
using Abram's pleural biopsy needle or Cope's biopsy
needle. However following these procedures some patients
still have undiagnosed condition and the clinical
management of these cases is controversial. The initial
step of the investigation is the distinction between
transudates and exudates, as this gives an indication of
the pathophysiologic mechanisms, the differential
diagnosis and the need for further investigations.
Because of their high sensitivity in identifying
exudates, the criteria proposed by Light et al (1972)
have become the standard method for making the
distinction. The classic work of Light and colleagues
demonstrated that 99% of pleural effusions could be
classified into two general categories: transudative or
exudative .A basic difference is that transudates, in
general, reflect a systemic perturbation, whereas
exudates usually signify underlying local (pleuropulmonary)
disease. The 'Light' criteria include a pleural fluid to
serum protein ratio greater than 0.5, a pleural fluid to
serum LDH ratio greater than 0.6 and a pleural LDH
concentration more than two thirds normal upper limit
for serum. If any one of these critical values is
exceeded, the effusion is exudates. The original study
of Light and colleagues had a diagnostic sensitivity of
99% and specificity of 98% for exudates.
In this study we report our experience with 108 patients
with confirmed diagnosis of TPE and discuss the clinical
features, radiological findings, biochemical,
cytological and microbiological analysis of pleural
fluid, hematological and biochemical profiles of serum
and positivity rates of microbiological procedure and
blind pleural biopsy in these patients. We also analyzed
the likelihood ratios of some of the important
presenting features in this study.
Patients and methods
Patients: This study was a hospital based
descriptive cross sectional study performed at the
Department of Respiratory Medicine, Rangoon General
Hospital (RGH), Myanmar (Formerly Burma) from January
2004 through January 2005. We did not perform any
sampling procedure. All patients with pleural effusion,
having positive AFB in pleural fluid (smear or culture)
or positive histology of tuberculosis in pleural biopsy
were included except those with following exclusion
criteria.
Exclusion criteria
1. Renal insufficiency and/or liver insufficiency:
Patients may present faulty high values of pleural fluid
Adenosine deaminase level.
2. Multiple pathology of pleural effusion: Patients with
more than one etiology of pleural effusion.
3. Patient’s refusal
Written informed consent was obtained from patient.
Before requesting consent, the individual was explained
in an understandable language about the aims of the
study, the methods of conduct, expected duration of
subject participation, benefits, foreseeable rights or
discomfort, the extent of confidentiality, extent of
investigators responsibility, provision of medical
services, the right to refuse to participate and
withdraw from the study without affecting further
medical care.
Detailed history, thorough physical examination,
radiological findings, haematological and biochemical
findings were recorded in the proforma. Pleural
aspiration and biopsy was performed on all patients
after obtaining the written consent. At least two pieces
of pleural tissue were taken and one piece of each
sample of pleural tissue was cultured for mycobacteria
and the rest was sent for histological examination.
Macroscopic findings, cytological, microbiological and
biochemical analysis of pleural fluid were performed in
all patients.
History taking: Patients name, age, sex, race, ID
number, marital status, occupation, body weight,
address, date of admission and discharge were recorded.
Symptoms such as the history of fever, cough, sputum,
haemoptysis, dyspnoea, chest pain, weight loss, loss of
appetite and night sweats were recorded and analyzed.
The past history of TB, TB contact, diabetes mellitus,
hypertension and frequent chest infection were also
enquired. Personal and social history such as history of
drinking, smoking and income were recorded. Family
history also was noted.
Physical examinations: Patient's general
conditions such as cachexia, body weight,
breathlessness, and fever were noted. Physical signs
such as cervical or scalene lymph node enlargement,
clubbing, erythema nodosum, phlyctanugular
conjunctivitis, SVC obstruction were also recorded.
Thorough respiratory system examination was done to find
out features of collapse, consolidation and pleural
effusion.
Radiological examinations: CXR (PA) view
was taken in every patient and lateral view was taken,
if necessary. The amount of fluid, the side involved,
hilar and/or mediastinum lymphadenopathy, parenchymal
involvement, cavitation and any other radiographic
abnormalities were noted.
Serum haematological profiles: Full blood
count and ESR were done in every patient.
Serum biochemical profiles: Plasma total and
differential protein and LDH were taken in every patient
to calculate the ratio fulfilling 'light' criteria.
Pleural fluid aspiration
Macroscopic appearance of pleural fluid:
Macroscopic appearance of pleural aspirates was
recorded.
Cytology, cell types and cell counts: Differential white
cell counts of pleural fluid were recorded and
calculated as percentage. The actual number of cells was
not counted.
Microbiology of pleural fluid:
Ziehl-Neelsen staining and AFB culture were done. AFB
culture was performed on Lowenstein Jensen medium in all
patients. Gram stain, aerobic and an aerobic culture of
pleural fluid were performed only on patients suspected
of pneumonia.
Biochemistry of pleural fluid:
Determination of pleural fluid total protein
concentration (g/l), LDH(U/L), total cholesterol (mmol/l)
and sugar (mmol/l) were performed . To differentiate
transudate from exudate, the ratio of pleural fluid and
serum protein ; the ratio of pleural fluid and serum LDH
were calculated. Pleural fluid Adenosine deaminase level
was measures by Giusti and Galanti method.
Pleural biopsy: All patients were
subjected to thoracentesis and closed pleural biopsy
using Abram's needle after obtaining a written consent.
At least two samples were taken, one was sent for
histological examination the other was for tissue AFB
culture. If no definite tissue diagnosis was obtained
after 3rd pleural biopsy, he or she was classified as
undiagnosed and excluded from the study unless pleural
fluid AFB was detected. Biopsy procedure was usually
done at 8th or 9th ICS at posterior axillary line.
Statistical Analysis: All the background
clinical data were recorded in standardized proforma.
Record files were constructed in the Microsoft Excel
software. The final data file in the form of record file
in Microsoft Excel was exported as data base file and it
was opened in the SPSS 16.0 for Windows software.
Descriptive statistics including mean with SD, median,
minimum and maximum values were calculated. Correlations
of regression Coefficients (finding of r value) and P-
value were calculated among pleural fluid biochemical
finding were tabulated. The correlation matrix of
multiple regressions among independent variables of
pleural fluid all TB patients were created as multiple
small scattered diagrams with regression line.
Results
A total of 108 patients, 74 males and 34 females were
included in this research. Their mean age was 42.60 ±
16.34 (range 12-81 years). The commonest one was age
between thirty one and forty.
The
positivity of microbiological procedures is shown in
table 1.
All patients had positive
histology of granulomas in pleural biopsy tissue
examination. Ninety one patients (84.3 %) of TPE were
diagnosed as TB by histology on first biopsy procedure.
Fifteen (13.8) and two (1.9 %) of patients needed second
and third session of procedures respectively.
Figure 2 and 3 and 4 show
the clinical symptoms and signs of patients with TPE.
Haemoptysis was present in only 7.4% and all had
associated pulmonary parenchymal lesions on CXR.
Table 2 shows sides of
chest involved in patients with TB pleural effusion.
Associated radiological
pulmonary parenchymal lesions were noted in twenty eight
patients (25.9 %). Out of 108 patients with TPE, seven
patients revealed blood stained pleural fluid (6.48%).
The rest had straw color aspirates.
Table 4 shows the biochemical and hematological profiles
of serum and pleural fluid in all patients.
Besides, Table 5 and figure 6 represent the correlation
among independent biochemical variables. Linear
correlation is noted between age and pleural fluid
glucose level (P=.01), pleural fluid protein and serum
protein (P=.005), pleural fluid LDH and serum LDH
(P=.000) and pleural fluid glucose and pleural fluid
cholesterol (P.002).There are no associations among
other biochemical profiles of TPE.
The
likelihood ratio (LR) of some of the presenting symptoms
and signs were calculated. The presence of pleural rub
(positive likelihood ratio LR 3.9) and breathlessness
(positive likelihood ratio LR 0.9) for blood stained
pleural fluid were noted. Clubbing of the fingers for
pulmonary crackles and for cervical lymphadenopathy were
(negative LR 1.02) and (negative LR 1.0) respectively.
The LR of chest pain for pleural rub was 1.3. The LR of
breathlessness (positive LR 0.95) and pulmonary crackles
(positive LR 2.08) for haemoptysis were also calculated.
Discussion & Conclusion
Common presentation of tuberculous pleural effusion
were fever, breathlessness, cough, night sweat, loss of
appetite, weight loss and chest pain. Cough was mainly
unproductive. Haemoptysis was rare and if present, was
associated with parenchymal lesion. Generally clinical
symptoms and physical signs do not positively help for
definitive diagnosis of TPE.
According to the likelihood ratio calculation, pleural
rub is the important physical signs for blood stained
pleural fluid and pulmonary crackles is valuable for
haemoptysis. These signs should guide in clinical
teaching.
Diagnostic pleural aspiration and pleural biopsy could
be performed by a single session of procedure. Results
of cytological and microbiological examination as well
as pleural biopsy could be obtained within 3 to 5 days
but AFB culture took one months to produce results and
it did not influence the diagnosis as well as treatment
of the patient in this study. In patients with non
informative pleural fluid and pleural biopsy
examinations, the procedure needed to be repeated.
Smear examination of pleural fluid using Ziehl-Neelson
stain had a very low positivity rate i.e. 0.9 % of cases
in this study and so was the positive culture of AFB
from the fluid i.e. 5.6 % of patients. Mycobacteria can
be cultured from pleural tissue but the time required
and the positivity rate was still unsatisfactory to be
of value in routine clinical management. Pleural biopsy
culture was positive in 1.9 % in the present study. This
may reflect the paucibacillary status of pleural fluid
which results at least partly from immunologic
mechanism.
The positivity rate of microbiological tests in this
study was consistent with another study from 105
patients in which pleural fluid AFB staining, pleural
fluid AFB culture and pleural biopsy AFB culture were
positive in 0 %, 5 % and 2 % respectively (Mihmanli &
Ozseker, 2004). But the positivity rate was higher in
the study by Valdes L et al (1998) which showed a
positive smear of pleural fluid was 5.5 % and positive
culture was 36.6 % of patients. Pleural biopsy tissue
culture also was high at 56.4 %. The low positivity rate
in the present study supports that the basic mechanism
of TPE is immunologic.
The positivity rate of first session of pleural biopsy
was 84.3 % of TPE in this study. The second and third
biopsy sessions were needed in fifteen patients and two
patients respectively. Repeat performance of pleural
biopsy is obviously an inconvenience to the patients and
also consumes a certain amount of medical resources.
Closed pleural biopsy is a fairly blind procedure
rendering it into a diagnostic procedure with less than
desired positivity rate. However pleural biopsy will be
useful as an ultimate procedure in cases with diagnostic
problem as it is a procedure which can give a definitive
tissue diagnosis. Pleuroscopy resolves the diagnostic
problem but the procedure requires more material
resources and expertise.
Although a number of tests have been proposed to
differentiate pleural fluid transudates from exudates,
the tests first proposed by Light et al have become the
criterion standards. The fluid is considered exudates if
any of the following apply:
• Ratio of pleural fluid to serum protein greater than 0.5
• Ratio of pleural fluid to serum lactate dehydrogenase (LDH)
greater than 0.6
• Pleural fluid LDH greater than two thirds of the upper limits of
normal serum value
In our study, the nature of TPE was that of an exudates
which is easily demonstrable by measuring protein and
LDH in serum and pleural fluid, applying the Light
criteria. According to a meta-analysis by Heffner J,
Brown L, Barbieri C et al (1997), exudative pleural
effusions meet at least one of the following criteria:
• Pleural fluid protein >2.9 g/dL (29 g/L)
• Pleural fluid cholesterol >45 mg/dL (1.16 mmol/L)
• Pleural fluid LDH >60 percent of upper limit for serum
In our study mean pleural fluid protein +/- SD was 49.15
+/- 12.2 and mean pleural fluid cholesterol +/- SD was
2.27 +/- 0.64 which is consistent with the meta-
analysis data to support exudates. Mean pleural fluid
LDH was 726.7 which is above 60% of the upper limit for
serum and also consistent with the data of
meta-analysis. The normal value for serum LDH is 70-250
IU/L.
Leers MP, Kleinveld HA and Scharnhorst V (2007) stated
that pleural fluid cholesterol concentration for correct
classification of more pleural effusions than achieved
by the use of Light criteria. They also pointed out that
combination of cholesterol and LDH had the highest
discriminatory potential and the added advantage that no
patient plasma is needed for correct classification. In
our study, these findings as well as Light criteria are
supported.
Light RW et al (2002) also found that pleural fluid
glucose level below 60 mg/dl (3.3 mmol.l) suggests
malignant effusion, TPE or lupus pleuritis. In our study
mean pleural fluid glucose concentration was 4.49 mmol/l
which is not very low compared to the finding of Light
et al (2002).
Main type of pleural fluid leucocyte in tuberculous
pleural effusion was lymphocyte. Neutrophil count in
pleural fluid of tuberculous effusion was low. In a
study by Burgess LJ et al (1995), pleural fluid
lymphocyte / neutrophil ratio 0.75 or greater was used
as a combined parameter for diagnostic confirmation, the
sensitivity, the specificity; positive predictive value
(PPV), negative predictive value (NPV) and efficiency
for the identification of TB were increased. In our
study lymphocyte counts were significantly higher than
other studies to such an extent that many cases reached
infinity in ratio (e.g. 100 polymorph: 0 neutrophil).
Statistically it is inapplicable to include them in
calculating sensitivity and specificity. Cell counting
in pleural fluid depends on the method of counting and
needs a standardization to be of use in calculating such
important measures as sensitivity and specificity. Cell
counting in the present study was done manually and
counting by machine is more reliable to get accurate
result. There was no significant change of peripheral
blood differential white cell count. ESR which reflects
inflammatory state in general was raised in most cases.
It has no diagnostic value for any specific disease.
In this study the best cutoff level of ADA activity was
tested at 42.5 IU/L when sensitivity was 87% and
specificity was 89%. Several studies have suggested that
an elevated pleural fluid ADA level predict TPE with
sensitivity of 90 to100 % and specificity of 89 to 100%
when the Giusti method is used (Roth, 1999).
We noticed that there were significant linear
correlation between age and pleural fluid glucose level,
pleural fluid protein and serum protein, pleural fluid
LDH and serum LDH and pleural fluid glucose and pleural
fluid cholesterol. There are no associations among other
biochemical profiles of TPE. It is suggested that
pleural fluid levels of protein and LDH are partially
depends on their plasma values and need measuring the
plasma levels at the same time to get more accurate
result. The reason of significant correlation between
pleural fluid glucose level and age and pleural fluid
glucose level and pleural fluid cholesterol is unclear.
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