05 Arijitd Medicine Review

REVIEW OF LITERATURE

I

n the approach in the diagnosis of pleural effusion the first step is to determine whether the effusion is a transudate or exudates (Light et al

1995 & Sahn 1988). An extensive diagnosis work–up is needed in cases with exudative effusion to determine the aetiology [Light et aI 1972]. Till the time of Paddok [1940] who used the P H , specific gravity and pleural fluid protein to divide the exudates from transudates. It becomes the standard parameter to divide the pleural fluid as exudates and transudates by a pleural fluid protein concentration of greater than and less than 3.0 gm/dl respectively till 1972. Light and coworkers [1972] demonstrated that misclassifications of 10% cases were made using the parameter of pleural fluid protein of3.0 gl/dl alone. Anatomy of Pleura: The pleura is the serous membrane that covers the lung parenchyma, the mediastinum, diaphragm and the rib cages. This is divided into visceral and parietal pleura. The visceral pleura covers the points of contact with wall, diaphragm mediastinum and the interlobar tissues. The parietal pleura line the inside of the thoracic cavity. In accordance with the intrathoracic surfaces it is divided into the costal, mediastinal and diaphragmatic pleura the visceral and parietal pleura meet at the lung root. At the pulmonary hilus the mediastinal pleura is swept laterally onto the root of the lung. Posterior to the lung root the pleura are carried downward as a thin double fold called the pulmonary ligament [Light et al, 1995]. A film of fluid is normally present between the parietal and the visceral pleura. This thin layer of fluid acts as a lubricant and allows the visceral pleura covering the lung to slide along the parietal pleura lining the thoracic cavity during respiratory movements. A potential space present between two layers of pleura is designated the pleural space. The mediastinum separates the right from the left pleural space in humans.

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Development of Pleura and Pleural Space: The body cavity in the embryo, the coelomic cavity is a U– shaped system with the thick bend cephalad. The cephalad portion becomes pericardium and communicates bilaterally with the pleural canals, which in turn communicates with peritoneal canals. As the embryo develops, the coelomic cavity becomes divided into the pericardium, the pleural cavities and the peritoneal cavities through the development of the sets of partition – (1)

The septum transversum which serves as an early, partial diaphragm.

(2)

Pleuropericardial membrane which divides the pericardial and pleural cavities and

(3)

Pleuroperitoneal membranes which unites with the septum transversum to complete the partition between each pleura and peritoneal cavities. This newly formed pleural cavity fully lined by a mesothelial membranes, the pleura. When the primordial bronchial buds first appear they and the

trachea lie in a median mass of mesenchyme, cranial and dorsal to the peritoneal cavity. The mass of the mesenchymal tissue is the future mediastinum and separates the two pleura cavities. As the growing primordial lung buds bulge into the right and left pleural cavity. They carry with them a covering of the living mesothelium, which becomes the visceral pleura. As the separate lobes evolve they retain the mesothelial covering. This becomes the visceral pleura and the living mesothelium of the pleural cavity becomes the parietal pleura [Light et al 1995]. Nerve Supply of Pleura: The parietal pleura are supplied by the somatic nerves. These are: (1)

Inter costal nerves, supply the costal pleura and parietal pleura and peripheral part of the diaphragmatic pleura.

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(2)

5

Phrenic nerve supplies the mediastinal and central portion of the diaphragmatic pleura. These somatic nerves are pain sensitive and innervates the part of the pleura supplies by inter costal nerve is referred to the adjacent chest wall and the pleura supplied by the phrenic nerve referred to ipsilateral shoulder. The visceral pleura are supplied by autonomic nerves, so it is

not pain sensitive [Singh 1993]. Blood Supply of Pleura: The parietal pleura receives its blood supply from the systemic capillaries. Small branches of the inter costal arteries supply the costal pleura whereas mediastinal pleura is supplied principally by the pericardiophrenic artery. The diaphragmatic pleura are supplied by the superior phrenic and musculophrenic arteries. The veins drain mostly into the azygos and internal thoracic veins. The visceral pleura are supplied mainly by the branches of the bronchial artery which divides into a network of much dilated capillaries [Hayek 1960; Harris et al 1977]. Lymphatic Drainage: The lymphatic vessels of the costal pleura drain ventrally toward the nodes along the internal thoracic artery and dorsally toward the internal inter costal lymph nodes near the heads of the ribs. The lymphatics of the mediastinal pleura pass to the tracheobronchial and mediastinal nodes, where as the lymphatics of the diaphragmatic pleura pass to the parasternal, middle phrenic and posterior mediastinal nodes [Bernauddin et al 1980]. The lymphatics of the visceral pleura drain sub–pleurally into interlober vessels then to hilar nodes [Burke et al 1966]. Microanatomy of the Pleura: The microstructure of the pleura consists of a single layer of mesothelial cells, without basement membranes. A layer of compressed

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6

connective tissue which may be up to 100mm thick separate it from the adipose tissue of the chest wall [Parietal pleura] and alveoli [visceral pleura]. Blood vessels, lymphatics and nerves are distributed in the substance of pleura [Sheldon et al I981]. Applied Anatomy: Normal visceral pleura glides smoothly over the parietal pleura during respiration and does not produce any appreciable auscultalory sound. But if the pleura is inflamed a friction sound is produced. The sound gradually disappears if fluid accumulates in the pleural cavities due to any cause. If a massive amount of fluid collects in this pleural cavity, the heart and mediastinum are displaced toward the opposite side and the lung gradually collapse. Entry of air into the pleural cavities due to any cause may also results in collapse of the lung due to contraction of the elastic tissue of the lung, which is normally prevented by negative intra pleural pressure. Physiological Aspects of Pleura: The pleura transmit the force generated by the respiratory muscles to the lung. During normal respiration there is a pressure negative to atmosphere, [about 5mm Hg et FRC] within the pleural space. This would tend to suck the capillary fluid and gas from surrounding tissue into the space. A hydrostatic pressure difference exist between the parietal pleural capillaries supplied by the systemic arterial vessels [about 30mm Hg] and visceral pleural capillaries supplied by the pulmonary arterial vessels [about 11 mm Hg]. Plasma oncotic pressure is the same in both sets of capillaries [about 35mm Hg], while plural osmotic pressure is only about 6mm Hg, since little protein is able to escape from the adjacent healthy capillaries. Thus there is a net force driving fluid from parietal capillaries to pleural space [–5–30–6 + 35 = –6mm Hg] and similarly a force driving pleural fluid into visceral capillaries and lymphatics [–5–11–6 + 35 = + 13 mmHg]. This results in a

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7

regular transfer of low protein fluid parietal pleura to visceral pleura, the driving force being approximately 19mmHg. The pleural fluid is in a dynamic state between 30 – 75% of the water being turned over every hour. This is accelerated by increased lung movements, as in exercise. Protein and particles are turned over much less rapidly, being absorbed by lymphatics only [Leckie et al 1965]. Stomata leading to lymphatics have been demonstrated over the lower mediastinal, chest wall, and diaphragmatic pleura [Leak et al 1978]. These together with the valves of the lymphatics ensue transport of protein and particulate containing

fluid

from the pleural space. Any disease which

cause

inflammatory or neoplastic changes in the parietal pleura is likely to decrease protein re–absorption and therefore alters the fluid hydrodynamics in such a way to increase the size if the effusion. The pleural space is lubricated by a thin layer of fluid and this is probably in concert with the more efficient surface active phospholipid i.e. surfactant [Hills et al 1982]. Pleural Effusion: Definition:

Pleural effusion is the accumulation of serous fluid in the

pleural space [Edward et al, 1995]. Pleural fluid is an ultra filtrate of plasma & usually there is less than 10ml of fluid in each pleural cavity (Black LF et al 1972). Mechanism of Pleural Effusion: Pleural fluid is in a dynamic state [Seaton et al, 1993]. Normal pleural fluid turnover in the pleural space is about 1–2 lit / day. Two factors prevent the accumulation of fluid in pleural cavity under physiological circumstances [Bensons, 1996]. (1)

Hydrostatic gradient between the capillaries of parietal and visceral pleural.

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(2)

8

Lymphatic system absorbing fluid and proteins in the pleural space. The factor that alters the equilibrium between the formation and

absorption pleural fluid results in pleural effusion. The factors that alter the equilibrium are [a] an imbalance between the hydrostatic and oncotic pressure in the pleural capillaries, [b] alteration in the permeability in the pleural capillaries, [c] impaired lymphatic drainage and [d] abnormal sites of entry [Bensons, 1996]. As a result of the factors altering the dynamics of pleural fluid formation the pleural effusion fluid can be either a transudate or an exudate. Exudate and Transudates: The gross appearance of the fluid may be helpful although most transudates & exudates are clear, may be straw coloured, odorless & non viscous, blood stained; turbid milky may suggest the particular cause (Jay S J et al 1985). The first step in the evaluation of pleural effusion is to differentiate the exudate and transudates [Light et al, 1972]. If the pleural effusion fluid is transudate usually no further diagnostic work up is needed & on the other hand an extensive diagnostic investigation of pleural fluid is needed in case of exudate. A rough of differentiation between transudate and exudate is there but the differences are not sharp. The differentiation between exudates & transudate was based on the cell count the presence or absence of clots in the fluid & specific gravity Paddock F K (1940). Characteristics Macroscopic appearance Colour Clot on standing Specific gravity Chemical analysis–protein Microscopic examination

Exudates

Transudate

Amber coloured, Turbid > 1018 >3g% Plenty of pus cells,

Pale straw coloured, Clear <1015 <3g% Occasional or no pus cells,

Mostly lymphocytes

Few mesothelial cells.

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9

For many years pleural fluid protein level of more than 3g% was used frequently to separate exudates from transudates [Carr et al, 1958]. However Light and his colleagues [1972] found 18% of total misclassification rate when the pleural fluid protein concentration of more than 3g% was used. The works done by Light, Macgregor, Luchsinger and Ball [1972] showed that simultaneously obtained pleural fluid and serum protein and LDH values correctly classify 99% of cases into exudates or transudates. Light criteria includes: (1)

Pleural fluid protein divided by serum protein greater than 0.5.

(2)

Pleural fluid LDH divided by serum LDH greater than 0.6.

(3)

Pleural fluid LDH greater than two– thirds the upper limit of normal for the serum LDH. Exudates meet one or more of the criteria but the transudates

meet none [Light 1995]. Causes, of Pleural Effusion: (1)

Transudative Pleural Effusion: (i)

(ii)

Increased hydrostatic pressure: (a)

Congestive cardiac failure.

(b)

Constrictive pericarditis.

(c)

Pericardial effusion.

(d)

Constrictive cardiomyopathy.

(e)

Massive pulmonary embolism.

Decreased capillary oncotic pressure: (a)

Cirrhosis of Liver

(b)

Nephrotic syndrome.

(c)

Malnutrition.

(d)

Protein losing enteritis.

(e)

Small bowel disease.

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(iii)

(iv)

(2)

Transmission from peritoneum: (a)

Any cause of ascites.

(b)

Peritoneal dialysis.

Increased capillary permeability: (a)

Small pulmonary emboli.

(b)

Myxoedema.

Exudative Pleural Effusion: (i)

(ii)

(iii)

(iv)

Neoplasms: (a)

Mesothelioma.

(b)

Pleural sarcoma.

(c)

Lymphoma.

(d)

Metastases.

Infections: (a)

Pneumonia, abscess.

(b)

Tuberculosis.

(c)

Fungal and actinomycotic disease.

(d)

Subphrenic abscess.

(e)

Hepatic amoebiasis.

Immune disorders: (a)

Post– myocardial infarct/cardiotomy syndrome

(b)

Rheumatoid disease.

(c)

Systemic lupus erythematosus.

(d)

Wegener's granulomatosis

(e)

Rheumatic fever.

Abdominal diseases: (a)

Pancreatitis.

(b)

Uremia.

(c)

Other causes ofperitoneal exudates.

10

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(v)

Pulmonary embolism and infarction

(vi)

Other causes: (a)

Sarcoidosis.

(b)

Drug reaction.

(c)

Radiation therapy.

(d)

Asbestos exposure.

(e)

Recurrent poly serositis.

(f)

Yellow nail syndrome.

(g)

Oesophageal perforation

11

Clinical Features of Pleural Effusion: The effects of accumulation of fluid in the pleural spaces depends on the cause and the amount of fluid. Small effusion are symptom– less and even a large effusion if they accumulate very slowly may cause little or no discomfort to the patients. The presence of moderate to large amount of pleural fluid produces symptoms and characteristic change on physical examination [Seaton et al 1993]. Symptoms: The commonest symptom of pleural effusion is breathlessness [Edward et al 1995]. Localized pleuritic chest pain is associated in the early part of the pleurisy and subsides when pleural effusion occurs. Dry, non– productive cough is frequently present. A dull aching chest pain with effusion is suggestive of malignancy [Light 1995]. Physical Examination: Inspection: Pleural effusion can increase the relative size of the hemithorax on the same side of effusion. The intercostal spaces may be bulged or indrawn depending on the intra pleural pressure. The intercostal space may be retracted, if intrapleural pressure is decreased, during the inspiration.

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Movement of the hemithorax with respiration may be reduced on the side of effusion. Palpation: Apex beat or trachea may be shifted to the opposite side depending on the size of the effusion[Munro et al 1995]. Tactile vocal fremitus is either diminished or absent in areas of the chest where pleural fluid separates the lung from chest wall. Percussion: The percussion note over the pleural effusion can be dull or stony dull, The dullness is maximum at the lung bases where the thickness of the fluid is greatest. Shifting of dullness to percussion is a definite indication of presence of the free fluid in the pleural cavity. Auscultation: Auscultation over the pleural fluid characteristically reveals decreased or absent breath sounds, Occasionally breath sounds may be accentuated near the superior border of the fluid for which bronchial breath sounds or aegophony can be heard, This phenomenon has been attributed to increased conductance of breath sounds through the partially atelectatic lung beneath the fluid, Pleural rub may be audible in some cases in early part of the pleurisy with pleural effusion. Radiology: The fluid accumulates in the most dependent parts of the thoracic cavity due to the effect of gravity as fluid is more dense than the lung, The fluid will increase the density which is radiologically evident when an X– ray beam is passed through the fluid. Typical radiological appearance of moderate sized effusion [~1000 ml]: In Postero–anterior Projection: 

Lateral costophrenic angle is obliterated.



Density of the fluid is higher laterally curves gently downward and medially with smooth meniscus shaped upper border to terminate at the mediastinum.

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In Lateral Projection: 

The upper surface of the fluid density is semicircular high anteriorly and posteriorly. Curving smoothly downward to its lowest part in the midway between the sternum and posterior chest wall (Fraser et al 1999).

Minimal effusion [~500 ml]: In Lateral Projection: 

Fluid accumulation may be localized in the space between the lung base and diaphragm and some times may spilled to obliterate the posterior costophrenic angle.

1n Lateral Decubitus Projection: 

Free fluid is seen as a homogeneous density with a straight horizontal superior border between the dependent chest wall and lower border of the lung. The distance is usually < 10 mm.

Massive effusion: The entire hemithorax is opacified and mediastinal shadow may be shifted to the opposite side [Light 19951]. Atypical effusion: The typical arrangement of fluid in the pleural space depends upon underlying lung free of disease and therefore having uniform elastic recoil. If the lung underlying the effusion is diseased, the elastic recoil of the diseased portion is frequently different from that of remainder of the lung, and fluid accumulates most where the elastic recoil is greatest. The effusion may be loculated or fissural sometimes subpulmonic(Fleischner et al 1963). Ultrasound can detect very minimal amount of fluid in the pleural cavity. CT, MRI can detect the presence of fluid as well as pleural or parenchymal pathology.

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Laboratory tests in differential diagnosis of transudates and exudates: The accumulation of clinically detectable quantities of pleural fluid is distinctly abnormal. A diagnostic thoracentesis should be attempted whenever the thickness of pleural fluid on decubitus radiograph is greater than 10mm [Light 1995] and the information available from the examination of pleural fluid is invaluable in the management of the patient. (1)

Gross Examination: Transudates are usually clear, straw coloured, non–viscid and

odorless. Exudates may be hemorrhagic or turbid but also may be straw coloured. If a turbid fluid becomes clear on centrifuge, it is probably due to increased cell number and if remain unchanged probably it is due to high lipid content [Light 1995]. A bloody viscous pleural fluid may be due to malignant mesothelioma or pyothorax of long standing duration. (2)

Microscopic Examination:

Red blood cells: Hemorrhagic effusion is usually associated with exudates but about 15% transudates also may have a hemorrhagic pleural fluid [Light 1973]. While Blood Cell Counl: Most transudates usually have a WBC count < 1,000/cm 3 . Whereas the exudates have a WBC count above 1,000/cm 3 [Light 1972] Parapneumonic effusion have a WBC count > 10,000/cm in the pleural fluid [Light 1973]. Neutrophils: They are predominantly present in acute inflammatory exudates. Transudates usually do not have neutrophils in their pleural fluid [Light 1995]. Eosinophils: Pleural fluid Eosinophilia is due to either air or blood in pleural space, Parasitic infestations & traumatic hemothorax [Spriggs et al, 1968].

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Eosinophilia in pleural effusion is usually due to malignancy or tuberculosis. Transudates usually do not have eosinophilia. Lvmphocvtes: Mostly present in exudative pleural effusion and approximately one third of transudates have lymphocytes in their pleural fluid [Light 1973]. Mesothelial cells: Transudates usually have a higher number of mesothelial cells. Though other pleural exudates may have mesothelial cells in their fluid, tubercular exudates do not have a mesothelial cell more than five [Light 1995]. (3)

Specific Gravity: Specific gravity gr measured with a hydrometer was used to separate

the transudates and exudates in the past [Paddok 1940]. A specific gravity of 1.015 correspond to a protein content of 3.o g/dl and this value was used to separate the exudates and transudate [Paddok, 1941]. A specific gravity below 1.015 is associated with transudative effusion and above with an exudative effusion. (4)

Protein: Most of the transudates have a low pleural fluid protein content

and the exudates a higher protein content [Carr et al 1958]. Pleural fluid protein content of 3.0 g/dl is used to classify the transudates and exudates. A transudative effusion usually have pleural fluid protein content of less than 3.0 gm/dl and exudates have a value greater than 3.0 g/dl. A pleural fluid protein to serum protein ratio of less than 0.5 is associated with transudative effusions and a ratio greater than 0.5 is associated with exudative pleural effusions [Light et al 1972]. However an erroneous classification of 8% of transudate and 11 % of exudates occurred. (5)

Lactic Acid Dehydrogenase: Raised lactic acid dehydrogenase [LDH] levels are characteristic

of all inflammatory causes of pleural effusion [Kirkeby and Prydz, 1959]. So the exudative pleural effusions have a higher LDH and transudate have a low

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16

LDH level in pleural fluid. An LDH level of greater than upper two thirds of that of the normal serum level or greater than 200 IU is associated with an exudates pleural effusion. [Light et al, 1972] and the transudates have an LDH level less than that. A pleural fluid LDH to serum LDH ration of greater than 0.6 is associated with an exudative effusion and a ratio less than 0.6 indicates a transudative effusion [Light et al 1972]. (6)

Cholesterol: Cholesterol in the pleural fluid arises from the degeneration of

red blood cells and white blood cells [Hamm et al 1991]. A pleural fluid cholesterol concentration of 60 mg/dl is used to differentiate the exudates and transudates [Hamm et al, 1987]. An exudative pleural effusion has a pleural fluid cholesterol concentration greater than 60 mgldl and the transudates has a ratio of pleural fluid to serum cholesterol of 0.3 is also used to differentiate the exudates and the transudates. An exudate has a ratio greater than 0.3 and the transudates has a ratio less than 0.3. [Valdes et al 1991]. (7)

Bilirubin: Meisel et al [1990] used the parameter of Pleural fluid to serum

bilirubin of.6 to classify pleural transudates and exudates. Transudative pleural fluids have a pleural fluid to serum bilirubin ratio of < 0.6 and in the exudates the ratio is > 0.6. However Burgess et al [1995] recorded a total misclassification of 25% with the pleural fluid to serum bilirubin ratio of 0.6. (8)

Albumin: In 1990 Roth et al assessed the diagnostic value of serum–

effusion albumin gradient (ie. The difference between Serum albumin & Pleural fluid albumin) with a cut off value of 1.2gm/dcl. A SEAG value of more than 1.2gm/dl is indicative of transudates & SEAG less than 1.2gm/dcl is indicative of exudates.

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Roth et al in a series of 59 patients used the serum effusion albumin gradient for the classification of pleural effusions with a cut of value of 1.2gm/dls, all the transudates & 39 of the 41 exudates were classified correctly with a sensitivity & specificity of 87 & 92 % respectively. Mutinas M et al in his study obtained the sensitivity of only 63% & specificity of 81% with the serum effusion albumin gradient of 1.2 g/dl. K.B. Gupta et al studied a total of 60 patients of pleural effusion of diverse etiology (ie, 12 transudates & 48 exudates) were evaluated for SEAG & results were compared with Light’s criteria to distinguish between transudates & exudates. The cut off value of 1.2g/dl albumin gradient was able to differentiate transudate & exudate with sensitivity & specificity of 100% only misclassification rate of 2% that too in exudates & 0% in transudates. M C Dhar et al studied a total of 50 patients of pleural effusion of diverse etiology (ie. 15 transudates & 35 exudates) the serum–effusion albumin gradient & Light’s criteria were compared. Light’s criteria correctly identified all the exudates but misdiagnosed 2 of the 5 transudates (cases of heart failure). By using albumin gradient of 1.2g/dl or less all the patient were correctly diagnosed. Sensitivity for identifying exudates was 100% with Light’s criteria but for transudates it was 87%. The corresponding sensitivity for identifying exudates & transudates with albumin gradient was 100% (Dhar et al 2000). (9)

Glucose: Glenger and Wiggers [1957] from their study suggested the

estimations of pleural fluid glucose level in diagnosis of tuberculosis and malignancies. They suggested a value of 30mg% or less should be diagnostic of tuberculosis, the value between 30–60mg% should be treated as

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18

tuberculosis unless proved otherwise and value above 60mg% as malignant diseases or other causes of pleural effusion. Calnan et al [1951] also supported with the findings from their study that a value of pleural fluid glucose level below 60% is strongly suggestive of tuberculous origin of the fluid and value above 100mg% indicate the fluid is probably non tuberculous origin. However Carr and Power [1960] reported that pleural effusion with rheumatoid pleurisy had a pleural fluid glucose level varying from 5– 7mg%. Light et al [1973] also showed that in pleural effusion due to malignancy, frequently the glucose level below is encountered. (10)

Alkaline Phosphatase: Lubber [1963] reported that pleural effusion due to neoplastic

diseases have a high alkaline phosphatase level in their pleural fluid. Seth et al also reported that the alkaline phosphatase level is higher in neoplastic diseases than tuberculosis, however without any statistical significance. Morel et al [1991] in a computer aided discrimination analysis found that the measurement of alkaline phosphatase level in pleural fluid may differentiate the tubercular from the neoplastic exudates. Feldstein [1963] in his study found no utility of pleural fluid alkaline phosphatase estimation. Out of extensive causes of pleural effusion some of the common causes in relation to the plan of study are reviewed. Tubercular Pleural Effusion: In many areas of the world, tuberculosis remains the most common cause of pleural effusion in the absence of demonstrable pulmonary disease (Valdes et al 1996). Pleural involvement with tuberculosis is a common manifestation of primary infection with direct extension from a sub pleural focus. A large number of cases of pleural effusion in tuberculosis is probably due to delayed hypersensitivity reaction involving the pleura (Allen

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19

JC et al 1968 & Yamanotoz S et al 1976) & most of the pleural fluid cultures are negative for tubercle bacilli (Bueno CE et al 1990). Occasionally tubercular empyema occurs due to rupture of caseous or lung cavity (Berger HW et al 1973). Although tuberculosis is considered a chronic illness, tubercular pleuritis most commonly manifest as acute illness. Most of the patients have nonproductive cough, pleuritic chest pain and are febrile. Sometimes the onset is less acute with mild chest pain, low grade fever, non– productive cough, weight less and easy fatiguability (Moudgil H et al). The patients with tuberculuos pleurities are younger than patients with parenchymal tuberculosis and patients with pleural effusion secondary to reactivation tend to be older than those with post primary pleural effusion(Aho K et al 1968). Pleural effusion secondary to tuberculuos pleurisy are almost always unilateral and usually small to moderate in size. About one third of patients have radiologically demonstrable active parenchymal disease (Valdes et al 1998). Laboratory Investigation: Blood: ESR is elevated and most of the patients do not have Leukocytosis. Sputum: Zhiel Neelsen stain of sputum for acid fast bacilli in most of the patients is

negative.

Diagnostic Thoracentesis and Pleural Fluid Analysis: Pleural fluid is usually exudate and straw coloured and on microscopic examination reveals predominance of lymphocytes. Centrifuged deposit of pleural fluid may show presence of acid fast bacilli after Zheil– Neelsen stain. AFB can sometimes be cultured in Lowenstein–Zensen media or newer rapid BACTEC system. Mesothelial cells usually not raised above 5% in tubercular pleural effusion (Spriggs et al 1968).

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Tuberculin Test: (Light R W, Pleural disease 4 th edition) It is helpful in diagnosing primary tubercular infection in younger patients under 5 years. Tuberculin positivity in general population is very high and may only indicate prior BCG vaccination or harmless non progressive primary infection. It does not either help to establish or discard the diagnosis of tuberculosis in adult. Though in some instance like tuberculosis of peripheral lymph nodes [cervical] shows strong tuberculin positivity and pleural tuberculosis a positive tuberculin test. A negative tuberculin test virtually excludes the diagnosis of tuberculosis except in some special situations like 

Acute viral infection (e.g., Measles)



Immuno–suppressed persons (e.g., AIDS or Corticosteroids)



Women in third trimester (pregnancy)



Moribund / Cachectic patients.



Early part of tubercular pleurisy and pleural effusion due to sequestration lymphocytes at the local sites.

Pleural Biopsy: Pleural biopsy has its greater utility in establishing the diagnosis of tubercular pleuritis, pleural effusion. Demonstration of granuloma in the biopsy specimen is suggestive of tuberculosis in 95% of cases where caseous necrosis, presence of AFB need not be demonstrated (Light R W 1998). Malignant Pleural Effusion: Malignant diseases involving the pleural are leading causes of Pleural effusion (Sprigg A I et al 1968). Carcinoma of the lung, breast, and lymphoma accounts for approximately 15% of malignant pleural effusions. Other tumour that cause malignant pleural effusion are ovarian carcinoma,

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21

primary tumour of pleura [mesothelioma] and other small number of cases are caused by sarcoma, malignant melanoma (Anderson et al 1974). Malignant disease can directly or indirectly results in pleural effusion & direct pleural metastasis of malignant tumor increases the permeability of the pleural surfaces. Decreased clearance of fluid from the pleural space due to the obstruction of lymphatics in the parietal pleural or metastatic involvement of mediastinal lymph nodes causing obstruction to the draining lymphatics from parietal pleural, are other mechanisms of production of malignant pleural effusion (Light R W 1997). Pleural effusion may be an indirect result of malignancy due to hypo albuminemia, post obstruction pneumonitis,

pulmonary

embolism,

post

radiation

therapy

or

chemotherapeutic agents [e.g. Methotrexate, cyclophosphamide]. Pleural effusion which is sometimes the first manifestation of malignant disease is usually massive and difficulty in breathing is an early prominent symptom (Chernow B et al 1977). Diagnostic Thoracentesis and Pleural Fluid Analysis: Pleural fluid may be serous or blood stained (Jarvi O H et al 1972). Red blood cell count greater than 1 lakh mm usually suggest malignant pleural disease. Pleural fluid LDH, cholesterol, alkaline phosphates, carcino– embryonic antigens are raised (Light R W et al 1972, Ordonez N G et al 1999, Light R W 1973). Pleural fluid glucose is low. Cytological examination of pleural fluid may demonstrate malignant cells in 60 – 80% of cases (Bueno C E et al 1980). Pleural Biopsy: A needle biopsy of pleura may be of considerable value in the diagnosis of the cause of the malignant pleural effusion.The incidence of positive pleural biopsy ranges from 39 – 75% (Salyer W R et al 1975, First A V et al).

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Parapneumonic Effusion: Pleural effusion associated with bacterial pneumonia lung abscess or bronchiectasis are a para pneumonic effusion (Ligt R W et al 1973). 40% of bacterial pneumonia are associated with parapneumonic effusion (Light R W 1980). Pleural effusion in pneumonia results from inflammation of pleura over an area of parenchymal infection and as a result there is leakage of fluids, proteins into the pleural space (Andrews N E et al 1962). Parapneumonic effusion is commonly associated with streptococcus, staphylococcus

and

anaerobic

gram–negative

bacteria.

. Laboratory Investigations: Blood: There is a definite leukocytosis with polymorphonuclear cells raised than lymphocytes. ESR is raised. Pleural Fluid Analysis: It shows the characteristics of an exudate where plenty of polymorphs predominates. Pleural fluid P H is reduced not more than 7.2, LDH < 1000 IU/lit, glucose level low (Light R W 1980). Pleural Biopsy: It only shows non– specific changes in the pleura in majority of cases. Pleural Effusion in Other Infections: Viral infection is common cause of exudative pleural effusion. This is due to increased permeability of pleural capillaries. About 20% with mycoplasma pneumonia have pleural effusion (Fine N L et al 1970). Pleural effusion is occasionally seen in patients with fungal infections like

 REVI E W OF LI TERATUR E 

23

aspergillosis, cryptococcosis, coccidioidomycosis and others. Most cases of pulmonary actinomycosis and about 25% of nocardiasis (Bates M et al 1957, Present C A et al 1974) have pleural effusion. About 35% of patients with amoebic liver abscess develop pleural effusion (Le Rowx B T et al 1969). It results from subphrenic inflammation and sometimes direct rupture into the pleural cavity results in typical' anchovy –sauce' like effusion. Diagnosis can be made by demonstrating the offending organism in the pleural fluid, detecting specific antigens or rising titer of the specific antibodies in pleural fluid. Pleural biopsy is nonspecific. Empyema: Accumulation of pus in the pleural cavity is called empyema. The excess of white cells denotes active intrapleural infection. Empyema usually follows a pulmonary infection in the form of pneumonia, lung abscess or bronchiectasis but may occur after septicemia, thoracic surgery, penetrating chest wound or following transdiaphragmatic extension from a subphrenic or hepatic abscess. Tubercular empyema can result when the caseous material enters the pleural cavity from a superficial lung cavity, paratracheal gland or paravertebral abscess resulting from pott's spine(Weese et al 1973). Infection in the pleural space result in inflammatory exudate with pus cell and organisms and gradually involves the production of fibrinous adhesion between visceral and parietal pleural may cause loculation of the fluid. The pus in the pleural space is often under considerable pressure and if the condition is inadequately treated there may be rupture into a bronchus producing broncho pleural fistula or through an intercostal space producing empyema necessitates. Aerobic gram positive organism like streptococcus pneumoniae, staph. aureus, S. Pyogenes are the most common organism which produce empyema. E. coli is the most common gram negative organism and bacteriod,

 REVI E W OF LI TERATUR E 

24

peptostreptococcus are commonly isolated anaerobic organisms. Other uncommon organism which can produce empyema are M. Tuberculosis, fungi, parasites(Alfogeme et al 1993). Empyema produced by aerobic organisms usually produces an acute illness and anaerobic organism produces a sub– acute illness. Laboratory Investigation: ESR

is

usually

raised

and

there

is

polymorphonuclear

leukocytosis which is more marked with empyema produced by anaerobic organisms. Pleural Fluid Analysis: Pleural fluid is frankly purulent with low P H , low glucose and raised LDH level. Gram stain or Zhiel – Neelsen stain may demonstrate the offending agent. Pleural fluid culture most commonly isolate the aerobic organisms accounting for about 53% cases and remaining are mixed aerobes – 25% and anaerobes – 22%, Pleural Biopsy: Pleural biopsy specimen shows the structure of a pyogenic membrane with polymorphonuclear leukocytes infiltration in case of acute empyema. Hydrothorax: Passive transudation of fluid into pleural cavity is called hydrothroax. This occurs as result of three basic mechanisms – (1)

Systemic venous hypertension.

(2)

Pulmonary venous hypertension

(3)

Reduced plasma oncotic pressure – Rarely transudation can be as a result of direct leakage of fluid from the interstitial space of the lung. In ascites right sided pleural effusion can occur because of direct passage

 REVI E W OF LI TERATUR E 

25

of ascitic fluid across the diaphragm through small defective pores. Congestive heart failure is the commonest cause of transudative pleural effusion which occurs in about 60 – 70% symptomatic congestive heart failure patients (Glazier J B et al). The elevated systemic as well as pulmonary venous pressure increase the escape of fluid into pleural space and decreased lymphatic clearance of pleural fleid. Most of the pleural effusion in CHF are bilateral, roughly of equal volume in both sides. Unilateral effusion most common in right side. Pleural fluid is a transudate. Diuretics usually change the characteristic of pleural fluid. Biopsy is nonspecific. Effusion disappears with successful treatment of heart failure. Pleural effusion occurs occasionally as a complication of hepatic cirrhosis with ascites in 5% of cases (Lieberman F L et al 1966 & Lieberman 1970). Right sided effusion is more common. Hypoalbuminaemia is a major contributory factor in development of pleural effusion. In some ascitic fluid pass directly into the pleural space either through the defects in the diaphragm or via lymphatics, Pleural fluid is a transudate and the protein level is slightly higher than the ascitic protein, It can be sometimes blood tinged and pleural biopsy is nonspecific(Lieberman F L et al 1966 & Lieberman 1970). Pleural Effusion in Collagen Vascular Disease: Pleural effusion is quiet common in patients with rheumatoid arthritis, systemic lupus erythematosus, drug induced lupus etc. Other collagen vascular diseases, which can produce pleural effusion are Wegener's granulomatosis,

Churg–strauss

syndrome,

Sjogren's

syndrome,

familial

mediterranean fever etc. Rheumatoid Disease: Rheumatoid disease are occasionally complicated by exudative

 REVI E W OF LI TERATUR E 

26

pleural effusion that characteristically have low pleural fluid glucose level. They occur in about 3 % of patients with active rheumatoid disease and are more common in man than woman. Although pleural effusion usually unilateral, but they can be bilateral in 20% cases. Pleural fluid is exudative and may appear turbid due to presence of cholesterol crystals or high cholesterol level [chyliform effusion], low pleural fluid glucose of less than 45mg/dl, high LDH level of >700 IU/L and high rheumatoid factor titers. Cellular elements are mostly polymorphs. Pleural biopsy has a limited role in the diagnosis of rheumatoid pleural disease although the specimen may show rheumatoid nodule diagnostic of rheumatoid pleurisy (Walker W C et al 1967 & Horler A R et al 1959). Systemic Lupus Erythematosus: Pleural involvement is common in SLE. Approximately 50% of patients have pleurisy and majority of them have pleural effusion at some stage of the disease. Effusion is usually small. Most patients are female. Many drugs like hydralazine, procainamide, isoniazid, phenytion, chlorpromazine are associated with lupus like syndrome. Some patients with SLE may have nephrotic syndrome and may have hypoproteinemia and pleural effusion. Pleural fluid shows ploymorpho nuclear leukocytosis, low pleural fluid glucose, raised LDH and have characteristics of exudate. Estimation of anti nuclear antibody is suggestive (>1:320). Demonstration of LE. Cells in pleural fluid is diagnostic. Pleural biopsy is useful if combined with immunofluorescence techniques (Winslow WA et al 1958 & Alarcon Segovia Dete 1961). Pleural Effusion due to Pulmonary Embolism: Pulmonary embolism as a cause of pleural effusion is commonly overlooked. Pleural effusion occurs in 30–50% of patients with pulmonary embolism (Fedullo P F et al 2000). Patients usually presents with pleuritic

 REVI E W OF LI TERATUR E 

27

chest pain and dyspnoea out of proportion to the amount of effusion. Pleural effusion may occur due to: (1)

Obstruction of the pulmonary vasculature leading to systemic venous congestion or

(2)

Increased permeability of pleural capillaries due to release of inflammatory mediators from the platelet rich thrombi and a minor role is played by ischemia of the visceral pleura which may contribute to the increased capillary permeability. (Bynum L J et al 1976)

Laboratory Investigations: Pleural fluid analysis or pleural biopsy does not help in diagnosis except to exclude other causes of pleural effusions. In 24% of patients pleural fluid is transudative and exudative in the remaining. Sometimes can be blood tinged. Diagnosis is suggested by Lung–scan or pulmonary arteriography. SERUM AND PLEURAL FLUID PROTEIN: Serum Protein and Serum Albumin: The term protein is derived from "proteios" which means holding first place. As the name indicate these group of compound is the most important of cell components present abundantly in cytoplasm and the cell walls. Chemistry: Proteins are high molecular weight polypeptides. They contains C, H, 0 & N. In some proteins small amount of sulphur or phosphorus also present. Proteins are large molecules and can be splitted into smaller units by hydrolysis which are the amino acids. The simplest form of protein structure is a long polypeptide chain containing an N–terminal amino acid with a carboxylic group. This is the primary structure of protein and this with conformational change into three dimensional form and combination of two or more polypeptides produces secondary, tertiary and quaternary structure of

 REVI E W OF LI TERATUR E 

28

protein. About 3/4 th of the body solids are proteins which includes structural proteins, enzymes, genes, protein that transport oxygen, muscle proteins that cause contraction. Classification: Depending on the overall shape and physical characteristics proteins are divided into: (1)

Globular proteins

(2)

Fibrous proteins.

(3)

Conjugated proteins.

Globular Proteins: They have a globular or elliptical shape, in general soluble in water or salt solution. Some of the important globular proteins are albumin, globulin, fibrinogen, hemoglobin and cytochromes. They constitute most of the plasma proteins and cellular enzymes. Fibrous Protein: They are highly complex and fibrillar proteins. Major types of fibrous proteins are collagen, elastin, keratin, actin and myosin. These fibrillar proteins have got the properties capable of stretching and recoil to their natural length also has a tendency to creep. Conjugated Proteins: Many proteins are combined as conjugated proteins with nonproteins substances. Conjugated proteins are – 

Nucleo proteins: Contains highly basic amino acids and nucleic acids.



Proteoglycans: Contains large amount of glycosamino glycans.



Lipoproteins: Contains lipid with proteins.



Chromoproteins: Composed of coloring agents.



Phosphoproteins: Contains phosphorus.

 REVI E W OF LI TERATUR E 



29

Metalloproteins: Contains metallic ions which constitutes many enzymes.

Digestion and Absorption: The endogenous secretion of 25 gm/day of digestive enzymes and another 30 gm/ day of desquamated G I epithelium adds significantly to the average dietary intake of about 70 gm/ day of protein. Protein digestion first takes place in the lumen by the gastric and pancreatic enzymes [proteases]. These enzymes are activated by the brush border enteropeptidases. Then the oligopeptidases of the brush border cause digestion. The products of these reactions are absorbed as di or tri– peptides as well as amino acids and are often Na+–coupled. Further hydrolysis of these absorbed peptides occurs in the cytoplasm of the enterocytes. Amino acids leave the cells by carriers in the basolateral membranes moving down the concentration gradient. Once the amino acids are entered the cells they are conjugated and stored in the form of proteins which can be decomposed again by the intra cellular enzymes into amino acids released into blood. Liver, kidney, intestinal mucosal cells participate mostly in storage function and maintains a dynamic equilibrium between the plasma amino acids and the tissue proteins. Storage of protein in each cell types has an upper limit above which the excess amino acids are degraded and utilized for energy production or stored as fat. Degradation of protein and amino acids occur by deamination which ultimately produces urea and excreted in urine. Degradation can also occur through transamination reaction in which the proteins will be converted into intermediary substrates for carbohydrate or fat synthesis. Plasma Proteins: Three major types of protein are presented in plasma. They are — (a)

Albumin

 REVI E W OF LI TERATUR E 

(b)

Globulin

(c)

Fibrinogen

30

The level of certain plasma protein are also increased during acute inflammatory states or secondary to certain types of tissues damage and are known as acute phase reactants. Most of the plasma proteins are synthesised in liver on the membrane bound plyribosomes, however gamma globulins are synthesised in plasma cells certain other plasma proteins are also synthesised in other sides like endothelial cells. Most of the plasma proteins are glycoprotiens except the albumin which does not contain sugar residues, and exhibits polymorphism which can be demonstrated by electrophoresis. Albumin: Major plasma portent comprising 60% of total plasma proteins 40% remains in the plasma and 60% in extra cellular space normal. Amount of albumin is 4.5 gm/dl. Liver produces about 12gms albumins per days representing about 25% of total hepatic protein synthesis and half of all of its secreted proteins. Plasma albumin is thought to be responsible for 70–80% of the colloid osmotic pressure that prevents escape of fluid from the intra vascular space to extravascular space if colloid osmotic pressure is reduced markedly than the systemic hydrostatic pressure than the fluid will escape from the intra vascular space to extra vascular space. Serum or plasma albumin level may be increased in dehydration, shock, hemoconcentration, and administration of large quantities of dirutics albumin. Albumin levels decreased in malnutrition, nephrotic syndrome, chronic liver disease, neoplastic disease, leukemia etc. Globulin:

 REVI E W OF LI TERATUR E 

31

Second major constituent of plasma proteins consisting about 2.5 gm/dl. 60–80% of the globulins are synthesised in liver and remaining by the lymphoid and other reticulo endothelial cells which are mostly immunoglobulins that constitute the antibodies. Types: (1)

Alpha globulins

(2)

Beta globulins

(3)

Gamma globulins

Fibrinogen: It is a high molecular weight protein occurring in quantities of 100–700 mg/dl. Fibrinogen is found in liver and diseases of the liver may decrease the plasma level of fibrinogen. Because of the larger molecular size very little fibrinogen normally leaks into the interstitial spaces and since it is an essential factor for coagulation process, interstitial fluids coagulate poorly. When the permeability of the capillaries increased pathologically fibrinogen level may be raised and coagulation can occur much the same way that the whole blood and plasma clots. The extrinsic and intrinsic path ways of clotting ultimately leads to formation of fibrin from fibrinogen and fibrin clots. The fibrin clot ultimately will be lysed by plasmin and various fragments of fibrin called fibrin degradation products are released and can be detected in some diseases. Pleural Fluid Protein & Albumin: Normally pleural fluid contains about 1.5 g/dl of protein [Agostoni, 1972]. This amount of protein account for osmotic pressure of 8 cm of water in the pleural fluid favouring absorption of fluid through the capillaries. The pleural fluid protein are similar to that of the corresponding

 REVI E W OF LI TERATUR E 

32

serum except in that the low molecular weight proteins such as albumin are present in greater quantities in the intrapleural fluids Protein. Normally pleural fluids contains about 3.5 to 4.5 gm/dl of albumin. (Light RW et al 1990) Protein content gradually diminished in normal pleural fluid as the age increases due to the increase in the systemic vascular pressure [Broaddus et al 1991]. Pleural Fluid Protein in Transudates and Exudates: Transudative pleural effusions are the result of systemic, pulmonary venous hypertension, reduced plasma oncotic pressure and to lesser extent due to leakage of fluid from interstitial space of lung [Broaddus et al 1985]. Because the pleural membranes are not effected in these conditions the change in the pleural fluid content is less.

Pleural fluid are

classically divided into transudates and exudates by specific gravity, protein content and cell count [Paddok 1940]. Specific gravity of 1.0 15 correspondence to a protein concentration of 3 g/dl in the pleural fluid. Transudates have a specific gravity of less than 1.015 and a protein concentration less than 3 g/ dl in the pleural fluid whereas an exudate have higher values than that. Pleural fluid to serum protein ratio is less than 0.5 in transudates and greater in exudates. Congestive heart failure is the most common cause of pleural effusion [Mofel et al], which accounts for 58% of all transudative pleural effusions. In most of the transudative pleural effusions [84%] due to congestive heart failure the pleural fluid protein concentration are below 3g/dl [Carr and Power 1958] and the pleural fluid to serum protein ratio is less than 0.5 [Light et al 1972]. The pleural fluid protein level may be raised with use of diuretics in treating congestive heart failure. Shinto and Light [1990] in their study on 15 patients one had developed characteristics of exudates when only protein was measured. Pleural effusions may also be associated with

 REVI E W OF LI TERATUR E 

33

hepatic cirrhosis and ascites. The pleural fluid in this condition originates in the peritoneal space and escapes across the diaphragm to enter into the pleural space [Johnston and Loo 1964]. In ascites with pleural effusion the pleural fluid protein is higher than the ascitic fluid protein [Lieberman et al 1966] but still does not cross the transudative level. Hypoproteinemia with resultant reduced plasma oncotic pressure and increased hydrostatic pressure due to salt and water overload are that factors leading to pleural effusion in nephrotic syndrome. Cavina and Vichi [1958] found radiological evidence of pleural effusions in 21 % of nephrotics. Pulmonary emboli were demonstrated in 22% of nephrotics in one study [Liach et al 1975], which may account for pleural effusion and the protein content of the pleural fluid was in the transudative range [less than 3 gl/dl]. Continuous ambulatory peritoneal dialysis [CAPD] can result in pleural effusion due to the movement of the dialysate from peritoneal to pleural space, which is being used increasingly for treating the chronic renal failure [CRF] patients. In a Japanese study 16% of patients on CAPD was reporetd to have pleural effusions. The pleural fluid protein was typically intermediate between that of the dialysate and serum which was less than 1.0g/dl. Pleural effusions occurring as a result of superior venacaval obstruction have a protein level about 1.2–2.2 gl/dl [Dhande et a11983]. Tuberculosis is the most common cause of exudative pleural effusion (86%) found in a study from Rwanda (Balungwanayo et al 1993). They usually produce unilateral small to moderate size pleural effusion. Pleural fluid is frequently above 5gm/dl in tubercular effusions [Berger et al 1973; Bueno et al 1990; Chan et al 1991]. Malignancies in various ways effect the pleura and results in pleural effusions. The pleural fluid is characteristically exudative (Light et al 1972), Pleural fluid to serum protein ratio is more than 0.5 in 20% of

 REVI E W OF LI TERATUR E 

34

malignant pleural effusion cases [Chernow et al 1977, Light et al 1972]. Pleural fluid may attain a very high protein level in malignant pleural effusion [Leckie et al 1965]. In a study by Ram et al (1995] protein level in malignant pleural effusion was upto 5.7 gm/dl. In another study by Seth et al [1986] pleural fluid protein found to be raised up to 8.4 gm/dl. Parapneumonic effusions mostly have a pleural fluid protein in the exudative range [Light et al 1980]. The protein level usually ranges between 3.4 – 5.3 gm/dl with a mean value of 4.2 glm/l [Van de Water 1970]. Serum LDH: Lactate Dehydrogenase: Lactate dehydrogenase (LDH) is a ubiquitous enzyme present in both plants and animals. It catalyses the reaction between pyruvate and lactate and vice versa, dependent on the abundance of either. As it can also dehydrogenate hydroxybutyrate, it is occasionally called Hydroxybutyrate Dehydrogenase

(HBD).

LDH

requires

NAD+

(Nicotinamide

adenine

dinucleotide) as a hydrogen acceptor. Enzyme Isoforms: Every enzyme is a tetramer of four subunits, where subunits are either H or M (based on their electrophoretic properties.) There are, therefore, five LDH isotypes: 

LDH–1 (4H) – in the heart



LDH–2 (3H1M) – in the reticuloendothelial system



LDH–3 (2H2M) – in the lungs



LDH–4 (1H3M) – in the kidneys



LDH–5 (4M) – in the liver and striated muscle Usually LDH–2 is the predominant form in the serum: if an

LDH–1 level is higher than the LDH–2 level (a "flipped pattern"), myocardial

 REVI E W OF LI TERATUR E 

35

infarction is suggested. This method has been largely superseded by the use of Troponin I or T measurement. Hemolysis: In medicine, LDH is often used as a marker of tissue breakdown. As LDH is abundant in red blood cells, it can function as a marker for hemolysis. A blood sample that has been handled incorrectly can show false– positively high levels of LDH due to erythrocyte damage. Tissue Turnover: Other uses are assessment of tissue breakdown in general; this is possible when there are no other indicators of hemolysis. It is used to follow– up cancer patients, as cancer cells have a high rate of turnover, with destroyed cells leading to an elevated LDH activity. Exudates and Transudates: Measuring LDH in pleural effusion (or pericardial fluid) can help in the distinction between exudates (actively secreted fluid, e.g. due to inflammation) or transudates (passively secreted fluid, due to a high hydrostatic pressure or a low oncotic pressure). LDH is elevated (>200 U/l) in an exsudate and low in a transudate. In empyema, the LDH levels generally exceed 1000 U/l. Meningitis and Encephalitis: The enzyme is also found in cerebrospinal fluid where high levels of lactate dehydrogenase in cerebrospinal fluid are often associated with bacterial meningitis. High levels of the enzyme can also be found in cases of viral meningitis, generally indicating the presence of encephalitis and poor prognosis. PEURAL FLUID LACTIC ACID DEHYDROGENASE:

 REVI E W OF LI TERATUR E 

36

Pleural fluid LDH Level is used to separate transudates from exudates. Most patients who meet the criteria for exudative pleural effusions with LDH but not with protein levels have either parapneumonic effusions or malignant pleural disease. Although initial reports suggested that the pleural fluid LDH level was increased only in patients with malignant pleural disease (Wroblewski F et al, 1958), subsequent reports demonstrated that the pleural fluid LDH was elevated in most exudative effusions regard–less of origin, and therefore, this determination is of no use in the differential diagnosis of exudative pleural effusions (Light et al, 1972). Nevertheless, every time a thoracentesis performed, a pleural fluid LDH level is measured. This is because the level of the pleural fluid LDH is a reliable indicator of the degree of pleural inflammation; the higher the LDH, the more inflamed the pleural surfaces. Serial measurement of the pleural fluid LDH levels is informative when one is dealing with a patient with an undiagnosed pleural effusion. If with repeated thoracenteses the pleural fluid LDH level becomes progressively higher, the degree of inflammation in the pleural space is increasing and one should be aggressive in pursuing a diagnosis. Alternatively, if the pleural fluid LDH level decreases with time, the process is resolving and one need not be as aggressive in the approach to the patient. Wroblewski and Wrobleswski [1958] first reported that the malignant neoplastic cells in tissues cultures contributed to increased amount of LDH in the medium. They found that the pleural effusion fluids that contain malignant cells had higher valves of LDH and simultaneously Well and Sung [1962] supported the above findings & suggested that raised LDH levels in pleural fluid is characteristic of malignant effusions. Kirkeby and Prydz [1959] suggested that raised pleural LDH level may be characteristic of all inflammatory exudates. Chandrasekhar and his colleagues [1969] conduded that absolute values of LDH in pleural fluid

 REVI E W OF LI TERATUR E 

37

served better than the pleural– fluid protein level in differentiating exudates form transudates. The study by Light et al [1972] showed that most of the exudates [71 %] had pleural LDH concentration above 200U/L where as none of the transudates had a values higher that that. It was also observed that only 2% of the transudates had a pleural fluid to serum LDH ratio more than 0.5. Whereas 86% of exudates exceeded this value. Using various combination of parameters pleural– fluids to serum protein ratio, pleural fluid LDH level and pleural fluid to serum protein ratio, pleural fluid found that the combination of pleural–fluid to serum protein ratio of greater than 0.5, pleural–fluid LDH level greater than 200U/L and pleural–fluid to serum LDH ratio greater than 200U/L and pleural–fluid to serum ration greater than 0.6 was most suitable to differentiate the transudates from exudates. It appears that combination of all these parameters will be more helpful in differentiation. When bloody pleural fluid is obtained, one might wonder whether the LDH measurement would be useful because red blood ceils contain large amounts of LDH. The presence of blood in the pleural fluid, however, usually does not adversely affect the measurement of the LDH. In one study, LDH isoenzyme analysis was performed on 12 pleural fluids that had contained more than 100,000 erythrocytes per mm3. In only one effusion was the LDH–1 percentage–wise more than 5% above that in the serum, and the total pleural fluid LDH in that effusion was only 107(Light RW et al, 1973). Although the total pleural fluid LDH level is not useful in distinguishing among various exudative pleural effusions, one might suppose that LDH isoenzymes have limited value in the differentiation.three studies have shown that LDH isoenzyme have limited vale in the differential diagnosis of exudative pleural effusions (Ligt RW et al, 1973, Raabo E et al ; 1966, Lossos IS et al ; 1999). All benign effusions with elevated pleural fluid LDH levels and most malignant effusions are characterized by a higher

 REVI E W OF LI TERATUR E 

38

percentage of LDH–4 and LDH–5 in the pleural fluid than in the corresponding serum (Ligt RW et al, 1973). The increased amounts of LDH–4 and LDH–5 are thought to arise from the inflammatory white blood cells in the pleural effusion (Ligt RW et al, 1973). Approximately one third of malignant pleural effusions have a different pleural fluid LDH isoenzyme pattern that is characterized by large amounts (>35%) of LDH–2 and less LDH–4 and LDH–5. None of 31 benign exudates in one series had more than 35% LDH–2 (Ligt RW et al, 1973). No relationship exists between the histologic type of the malignant pleural disease and the pleural fluid LDH– isoenzyme pattern (Ligt RW et al, 1973). At present, the only situation in which we obtain LDH isoenzyme analysis of pleural fluid is when there is a bloody pleural effusion in a patient who clinically is though to have a transudative pleural effusion. If the LDH is in the exudative range and the protein is in the transudative range, the demonstration that the majority of the pleural LDH is LDH–1 indicates that the increase in the LDH is due to the blood. SERUM–EFFUSION ALBUMIN GRADIENT (SEAG): In 1990 Roth et al assessed the diagnostic value of serum– effusion albumin gradient (i.e. The difference between Serum albumin & Pleural fluid albumin) with a cut off value of 1.2gm/dl. A SEAG value of more than 1.2gm/dl is indicative of transudates & SEAG less than 1.2gm/dcl is indicative of exudates. Roth et al in a series of 59 patients used the serum effusion albumin gradient for the classification of pleural effusions with a cut of value of 1.2gm/dls, all the transudates & 39 of the 41 exudates were classified correctly with a sensitivity & specificity of 87 & 92 % respectively. Mutinas M et al in his study obtained the sensitivity of only 63% & specificity of 81% with the serum effusion albumin gradient of 1.2 g/dl.

 REVI E W OF LI TERATUR E 

39

E Razi et al studied 89 effusion samples taken from patients with pleural effusions. Based on clinical & various laboratory parameters 47 were transudates & 42 were exudates. Based on serum–effusion albumin gradient with a cut off value of 1.2 g/dl, 4 patients with transudates & three with exudates, were misclassified which gives an overall accuracy of 91.5%, with sensitivity of 91.5% & specificity of 92.86% (Feyez et al 1998). Burges et al 1995 in there 393 cases of established diagnosis of pleural effusion ie (270 exudates & 123 transudates) were compared with Light’s criteria and Roth’s SEAG at a cut off value of 1.2g/dl. Using the criteria of Light 93% effusions were correctly classified, yielding a sensitivity & specificity of 94% and 83%. The SEAG at a cut off value of 1.2g/dl yielding the following results: accuracy 91%, sensitivity 87% & specificity 92% (Burges et al, 1995). K.B. Gupta et al studied a total of 60 patients of pleural effusion of diverse etiology (ie, 12 transudates & 48 exudates) were evaluated for SEAG & results were compared with Light’s criteria to distinguish between transudates & exudates. The cut off value of 1.2g/dl albumin gradient was able to differentiate transudate & exudate with sensitivity & specificity of 100% only misclassification rate of 2% that too in exudates & 0% in transudates. M C Dhar et al studied a total of 50 patients of pleural effusion of diverse etiology (ie. 15 transudates & 35 exudates) the serum–effusion albumin gradient & Light’s criteria were compared. Light’s criteria correctly identified all the exudates but misdiagnosed 2 of the 5 transudates (cases of heart failure). By using albumin gradient of 1.2g/dl or less all the patient were correctly diagnosed. Sensitivity for identifying exudates was 100% with Light’s criteria but for transudates it was 87%. The corresponding sensitivity for identifying exudates & transudates with albumin gradient was 100% (Dhar et al 2000). Differentiation between exudative and transudative pleural effusion:

 REVI E W OF LI TERATUR E 

40

Clinicians for years have searched for some diagnostic means by which the cases of pleural effusion could be definitely identified as to etiology. Various test upon the fluid removed has been proposed. Some have used the serology or pleural fluid protein level, others the cellular morphology or glucose levels of the pleural fluid. Nearly all investigators have come to conclusion that the only definitive diagnosis finding is the present of neoplastic cells or the causative organism in the fluid removed [Barber et al 1957]. Landouzy et al (1884) arrived at an etiological diagnosis of plural effusion by demonstrating tubercle bacilli in plural fluid by guinea pig inoculation. In 1895 Roentgen had discovered X–ray & good X–ray picture of the chest could be obtained in 1930 and this enhanced the diagnostic yield of pleural fluid. (Fraser et al 1999) For more than a century diagnostics thoracocentesis remain the only popular method of investigation which was first discovered by Bowditch et al (1852) and if done carefully chemical, bacteriological, cytological study should help to arrive at an diognosis in 75% cases (Collins et al 1987). In the past transudate were separated from exudates by specific gravity, the cell count and the presence or absence of clotting of the fluid [Paddock, 1940]. However, if was soon found that it is often difficult to classify a given fluid on the basis of the above tests. Paddock [1940] in his study of 836 pleural effusion found that 10% of all effusions are caused by congestive heart failure. Cirrhosis and nephrosis had a specific gravity greater than 1.016 where as 10% of the pleural effusion secondary to tuberculosis and more than 40% of those caused by malignancy had specific gravity less than 1.016. He found that the protein level in the pleural fluid no more helpful than specific gravity in differentiating exudates from transudates. In a subsequent report in 1941, he

 REVI E W OF LI TERATUR E 

41

stated that the measurement of specific gravity less accurate by commonly used hydrometer when used to measure specific gravity of serous effusions. Leuallen and Carr [1955] reported that pleural effusions caused by neoplasm and tuberculosis had a specific gravity less than 1.016 and that caused by congestive heart failure had a specific gravity greater than 1. 016. They suggested that the use of protein level of fluid might better differentiate the transudates from exudates. Luetscher [1941] found that it was impossible to draw any dividing line between transudate and exudates form total protein content without encountering frequent exceptions. He suggested that the pleural fluid protein to serum protein ratio of 0.5 was more discriminating than any protein concentrations. But some exceptions still observed. Carr and Power [1985] reported that only 16% of pleural effusion caused by congestive heart failure had pleural fluid protein of more than 3.0gm/dl and none of the tubercular pleural effusion fluid had a value less than 3.0 g/dl. In a study by Light et al [1972] showed that erroneous classification of 8% of transudate and 10% of exudates occurred when a pleural protein level of 3.0g/dl % was used as cut off value between transudates and exudates. Pleural –fluid protein to serum –protein ration of 0.5 served better to differentiate the transudates from exudates. But still 10% of exudates were misclassified. Wroblewski and Wrobleswski [1958] first reported that the malignant neoplastic cells in tissues contributed to increased amount of LDH in the medium. They found that the pleural effusion fluids that contain malignant cells had higher values of LDH & this was supported by Seru Well & Sung [1962]. Kirkeby and Prydz [1959] suggested that raised pleural LDH level may be characteristic of all inflammatory exudates. Chandrasekhar and his colleagues [1969] concluded that absolute values of LDH in pleural fluid

 REVI E W OF LI TERATUR E 

42

served better than the pleural– fluid protein level in differentiating exudates form transudates. The study by Light et al [1972] showed that most of the exudates [71 %] had pleural LDH concentration above 200 U/L where as none of the transudates had a values higher that that. It was also observed that only 2% of the transudates had a pleural fluid to serum LDH ratio more than 0.5. Whereas 86% of exudates exceeded this value. Using various combination of parameters of pleural fluids to serum protein ration of.5, pleural–fluid LDH level greater than 0.6U/L ill and pleural–fluid to serum LDH ratio greater than 200U/L and pleural–fluid to serum ration greater than 0.6 was most suitable to differentiate the transudates from exudates. It appears that combination of all these parameters will be more helpful in differentiation. Ferguson

in

1966

first

reported

cholesterol

crystals

in

rheumatoid pleural effusions. Lillington et al [1971] and Naylor [1990] also reported high cholesterol level with or without cholesterol crystals in the pleural–fluid in pleural effusion due to rheumatoid pleurisy. Hamm [1987] reported that cholesterol estimation in the pleural fluid may help in differential diagnosis of pleural effusion. In a subsequent report in 1990, Hamm and his associates found that pre–defined criteria of protein and LDH led to 11 – 15% misclassification of pleural effusion. He found that the exudates either malignant or inflammatory had a pleural–fluid cholesterol value below that level and Suggested that the use of pleural–fluid cholesterol measurement, which is easy and cheaper, would help to differentiate the transudate form exudates. Valdes and his colleagues [1991] reported that when Light’s three criteria was used, the sensitivity and specificity was 94.6% and 78.4% respectively. Whereas pleural–fluid cholesterol level of 55mg/dl taken as the threshold had a sensitivity and specificity of 91% and 100% respectively in differentiating the transudates form exudates. Pleural fluid to serum

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cholesterol ratio of.3 had a sensitivity of 92.5% and specificity of 87.6%. He suggested the determination of pleural–fluid cholesterol; pleural–fluid to serum cholesterol ration should be included in the routine clinical and laboratory analysis of pleural fluid to distinguish the exudates form transudates. Romero et al [1993] and Burgess et al [1995] found contradictory results. They found that cholesterol level in pleural fluid and the ratio of pleural fluid to serum cholesterol had lower sensitivity and specificity. Meisel et al [1990] form their study concluded that pleural fluid to serum bilirubin ratio of.6 separated the transudates from exudates – The study by Berger et al [1955] and Hoffener et al [1997] however concluded that the use of pleural fluid to serum bilirubin ratio of 0.6 has a low sensitivity and specificity of 81 % and 61 % only with diagnostic accuracy of 75%. Calnan et al [1951] also reported that a glucose level under 60mg% appear to be strongly suggestive of tubercular effusion and a level above 100mg% probably of nontubercular origin. Barber et al [1957]. Summarized their findings that pleural fluid glucose level of 26mg% or lower are suggestive of tuberculosis and levels above 60mg% were suspicious of non–tubercular etiology. Although pleural fluid glucose levels are valuable tool, but they should not be relied upon as sole diagnostic criteria. Currently, the criteria proposed by Light et al 1972 is the standard method for this discrimination. However in recent years several reports indicated that this criteria misclassified a number of effusions and that was why several parameters such as pleural fluid cholesterol level & pleural fluid to serum cholesterol ratio, plural fluid to serum bilirubin and pleural fluid to serum cholinesterase ratio (Pachon EG) et at 1996 have been proposed

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in segregating the transudates from exudates than those of Light’s criteria is therefore insignificant, if not dubious. One of the explanations put forward for the poor specificity of Light’s criteria leading to significant errors in the classification of transudate is the effect of previous diuretic therapy on chemical (Anne et al) composition of effusion fluids. Pillay et al reported increase in protein content from 15–29 gm/dl after diuretic therapy & this was confirmed by Chakko et al . This problem of high protein transudates is more common in the evaluation of Ascitic fluid too, which has led to the development of Serum– ascitis albumin gradient with a cut off value of 1.1 gm/dcl (<1.1gm/dcl for exudates & >1.1gms/dcl for transudates) and is now universally accepted (Pare P et al & Rector WG et al). In 1990 Roth et al assessed the diagnostic value of serum– effusion albumin gradient with a cut off value of 1.2gm/dcl (<1.2gm/dcl for exudates & >1.2gms/dcl for transudates) & found that this gradient was significantly higher in transudative than exudative pleural effusion. Roth et al in a series of 59 patients used the serum effusion albumin gradient for the classification of pleural effusions with a cut of value of 1.2gm/dl, all the transudates & 39 of the 41 exudates were classified correctly with a sensitivity & specificity of 87 & 92 % respectively. Mutinas M et al in his study obtained the sensitivity of only 63% & specificity of 81% with the serum effusion albumin gradient of 1.2 g/dl. E Razi et al studied 89 effusion samples taken from patients with pleural effusions. Based on clinical & various laboratory parameters 47 were transudates & 42 were exudates. Based on serum–effusion albumin gradient with a cut off value of 1.2 g/dl, 4 patients with transudates & three

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with exudates, were misclassified which gives an overall accuracy of 91.5%, with sensitivity of 91.5% & specificity of 92.86% (Feyez et al 1998). Burges et al 1995 in there 393 cases of established diagnosis of pleural effusion i.e. (270 exudates & 123 transudates) were compared with Light’s criteria and Roth’s SEAG at a cut off value of 1.2g/dl. Using the criteria of Light 93% effusions were correctly classified, yielding a sensitivity & specificity of 94% and 83%. The SEAG at a cut off value of 1.2g/dl yielding the following results: accuracy 91%, sensitivity 87% & specificity 92% (Burges et al, 1995). K.B. Gupta et al studied a total of 60 patients of pleural effusion of diverse etiology (ie, 12 transudates & 48 exudates) were evaluated for SEAG & results were compared with Light’s criteria to distinguish between transudates & exudates. The cut off value of 1.2g/dl albumin gradient was able to differentiate transudate & exudate with sensitivity & specificity of 100% only misclassification rate of 2% that too in exudates & 0% in transudates. M C Dhar et al studied a total of 50 patients of pleural effusion of diverse etiology (ie. 15 transudates & 35 exudates) the serum–effusion albumin gradient & Light’s criteria were compared. Light’s criteria correctly identified all the exudates but misdiagnosed 2 of the 5 transudates (cases of heart failure). By using albumin gradient of 1.2g/dl or less all the patient were correctly diagnosed. Sensitivity for identifying exudates was 100% with Light’s criteria but for transudates it was 87%. The corresponding sensitivity for identifying exudates & transudates with albumin gradient was 100% (Dhar et al 2000). However, with the battery of test present to differentiate the transudates from exudates it is found that the some of the effusions are misclassified. Gracia & Padilla; 1996 after analysis of different studies concluded that a method to differentiate perfectly the transudates & exudates is not yet available, of course, the histopathological of pleural tissue is the final single diagnosis fate, level the biopsy itself is increased technique with

usu

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all its hazards specially in experienced hand. We remain same simple inexpensive, easy test or test to differentiate transudates & exudates.