Pleural

Effusion

: Pathophysiology

Hamid Sahebjami,

HE PLEURA is a serous membrane of mesodermal origin composed of a layer of connective tissue covered by squamous epithelium. The pleural cavity is only a potential space, since under normal conditions the visceral pleura and parietal pleura are in apposition, separated only by a small quantity of lubricating fluid. The visceral pleura receives its blood supply from both bronchial and pulmonary artery branches, whereas the parietal pleura is supplied by the systemic circulation only. The visceral pleura is drained by the pulmonary veins, and the parietal pleura is drained by intercostal and bronchial veins. Lymphatic drainage of the visceral pleura is toward the hilar nodes, and that of the parietal pleura is toward the mediastinal glands. The visceral pleura is supplied by autonomic nerve fibers and is devoid of pain fibers; the parietal pleura is innervated by phrenic, intercostal, and spinal nerves. The intrapleural pressure is mostly subatmospheric, and it varies at different levels of the pleural cavity.” At any given point in the respiratory cycle, the pressure gradient between the apex and the base of the thorax is about 7.5 cm H,O. In erect man, the intrapleural pressure gradient is approximately 0.2 cm H,O per centimeter of vertical descent2* Pleural fluid is being formed and absorbed constantly. In normal man, transudation and absorption of fluid within the pleural cavity follow the Starling law of capillary exchange and depend on a combination of hydrostatic pressure, colloid osmotic pressure, and tissue forces, the last not yet having been measured. Since hydrostatic pressure is significantly greater in parietal pleural capillaries, which Hamid Sahebjami, M.D.: Associate Professor of Medicine, Pulmonary Disease Division, Veterans Adminirtration Hospital, Cincinnafi, Ohio. Robert G. Loudon, M.D., Ch.B.: Professor of Medicine, Director, Pulmonary Disease Division, University of Cincinnati College of Medicine, Cincinnati, Ohio. Reprint requests should be addressed to Hamid Sahebjami. M.D., Pulmonary Disease Division. Veterans Adminisrration Hospital, 3200 Vine Street. Cincinnati, Ohio 45220. 0 1977 by Grune & Stratton, Inc. ISSN: 0037-198X. in Roentgenology,

Vol. XII. No. 4 (October).

Features

M.D., and Robert G. Loudon. M.B., Ch.B.

T

Seminars

and Clinical

1977

arise from the systemic circulation, in the state of health the Starling forces favor filtration of fluid from the systemic capillaries in the parietal pleura and absorption of fluid by the pulmonary capillaries in the visceral pleura. This is an oversimplification, since other factors such as tissue pressure, permeability of the mesothelial layer, and lymphatic pressure should also be taken into consideration. In health, the protein content of pleural fluid is low (about 100 mg/lOO ml), which allows normal movement of the fluid.47 When protein concentration in the fluid rises to about 1 g/l00 ml, the reabsorptive effect of colloid osmotic pressure of visceral pleural capillaries is reduced to a negligible level, so that the only route for fluid absorption is via lymphatics by bulk flo~.~ MECHANISMS

OF FLUID ACCUMULATION

Abnormal fluid accumulation in the pleural cavity occurs as a result of one or more of the following mechanisms: (1) an increase in hydrostatic pressure in the systemic circulation (congestive heart failure, constrictive pericarditis); (2) a decrease in colloid osmotic pressure of plasma (nephrotic syndrome, hypoalbuminemia of any cause); (3) an increase in pleura1 capillary permeability (inflammation, malignancy); (4) an increase in lymphatic pressure (hepatic hydrothorax, lymphatic obstruction caused by tumor, inflammation, or parasites). CHARACTERISTICS

OF PLEURAL

FLUID

The first step in characterizing pleural fluid is to determine whether it is a transudate or an exudate. This distinction is very important in the further diagnostic approach to pleural effusions. Transudates are frequently bilateral and are due to hydrodynamic imbalance of forces maintaining capillary blood pressure, without involvement of pleural surfaces. Exudates, in contrast, result from such pathologic processes as inflammation, malignancy, or infection involving pleural surfaces. Conventionally, pleural fluid containing protein of 3 g/100 ml or more and specific gravity of 1.016 or more has been classed as an exudate 269

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rather than a transudate.35 However, if these criteria are used, a significant number of effusions will be misclassified. In one series, 8% of exudates and 15% of transudates were misclassified.23 In 1971 Light and associates” reported a new set of criteria that have proved to be more sensitive: (1) a ratio of pleural fluid to serum protein of 0.5 or more, (2) a pleural fluid lactate dehydrogenase (LDH) content of 200 IU or more, (3) a ratio of pleural fluid to serum LDH of 0.6 or more, and (4) a pleural fluid red blood cell count of 100,000 cells/mm3 or more. Using these criteria, exudative pleural fluids will be diagnosed accurately in more than 70% of patients if any one of these criteria is present and in more than 90% if two or more of these criteria are found. GROSS APPEARANCE

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LOUDON

thoracic duct by surgical or other trauma, malignant involvement of the thoracic duct or left subclavian vein, compression by tuberculous mediastinal lymph glands, filariasis, lymphangioma of the thoracic duct, thrombosis of the left subclavian vein, nephrosis, or cirrhosis.35 The presence of frank pus is diagnostic of empyema. Lesser degrees of infection lead to a cloudy effusion. Silky sheen and shimmering effusions contain cholesterol crystals in suspension.15 Almost all such fluids are found in longstanding untreated cases of pleurisy, usually due to tuberculosis.35 Odor. A foul-smelling effusion is diagnostic of anaerobic infection, usually associated with infection of the underlying lung.

OF THE ASPIRATE

Observations made on the gross appearance of pleural effusions can be of significant diagnostic value. Volume. Massive pleural effusion (occupying the entire hemithorax) is the result of malignant disease in 67% of cases, most commonly lung or breast carcinoma.3o Cirrhosis of the liver (67% right-sided), congestive heart failure, empyema, and tuberculosis account for the remainder.30 Color. Exudates vary from straw to amber in color, but are usually yellowish and cloudy, and they clot on standing. Transudates are paler and less liable to clot on standing. The presence of blood in a pleural effusion has a significant diagnostic value. A hemorrhagic effusion should be distinguished from a bloody tap, in which there is progressive loss of red color as aspiration proceeds. Bloody fluid is attributable to malignant tumor in 65% of patients, half of whom have lung cancer. The remaining nonmalignant causes include pulmonary infarction, infection (including tuberculosis), trauma, leukemia, cirrhosis of the liver, and rarely congestive heart failure and chronic hemodialysis. l6 In these situations the blood usually does not form clots. The presence of pure blood in an aspirate is evidence of bleeding directly into the pleural space (e.g., in chest injury). Chylous or milky fluid is usually more evident if the patient has had a meal before aspiration. It is usually the result of an injury to the

PLEURAL

FLUID EXAMINATION

Although the gross appearance of a pleural effusion gives clues to certain diagnostic possibilities, further chemical and cytologic investigations are necessary. Protein. Measurement of protein content of pleural effusion is essential in distinguishing between transudate and exudate. Beyond this, protein studies have no diagnostic value. Protein electrophoresis of pleural fluid has revealed a wide variety of immunoglobulins, but no correlation between the different patterns and clinical diagnosis has been established.42 Lactate dehydrogenase (LDH). Elevation of LDH in pleural fluid is nonspecific, as it is in other body fluids; it has no etiologic or prognostic significance.’ LDH isoenzymes have also been measured and found to be of no specific diagnostic value.27 Glucose. A low glucose level relative to its level in serum is observed in four conditions: tuberculosis, rheumatoid arthritis, empyema, and malignant tumor. A glucose level below 20 mg/ 100 ml is highly suggestive of rheumatoid arthritis.” In tuberculous pleural effusions, the glucose concentration may reach a very low level and make the differential diagnosis from rheumatoid arthritis difficult. It has been suggested that in this situation a flat pleural fluid glucose tolerance curve is specific for rheumatoid pleural effusion, indicating defective transport,” although a recent study suggests that the barrier to

PLEURAL

EFFUSION

transport of glucose is a nonspecific phenomenon.6 In 15% of malignant pleural effusions the glucose concentration is low.’ The primary tumor is usually bronchogenic, ovarian, or breast cancer. There is no relationship between the low glucose content and the cell type of these tumors. The only apparent correlation is with the presence of a large effusion. The mechanism responsible for low pleural fluid glucose concentration has not been established. A high content of free cells associated with thickened pleural membranesL7 and decreased pleural circulation interfering with the diffusion of glucose” has been postulated as the means for lowering glucose content. In empyema, the presence of a large number of leukocytes that utilize glucose is probably responsible for the low glucose concentration. Amylase. In about 15% of patients with acute pancreatitis there is associated pleural effusion containing high amylase concentrations. This can be detected long after the serum amylase has returned to a normal level. Amylase values in the range of 500-2000 units indicate that the amylase in pleural fluid is not bloodborne but reaches the pleural cavity by other routes. In rare cases of extraordinarily high titers, in the range of 20,000 to 50,000 units, an almost free communication between the pancreas and the pleural space may be assumed.r8 Pleural effusion containing high amylase concentrations has also been reported in association with esophageal rupture.26 In such cases the electrophoretic pattern suggests that saliva is the source of the amylase elevation.43 There is a fair amount of amylaselike substances in normal lungs. High serum amylase levels have been observed in pneumonia and lung cancer, particularly adenocarcinoma.13 Therefore a high amylase level may be found in pleural fluid complicating pneumonia and bronchogenic carcinoma. Cells. The value of cell counts in distinguishing transudates from exudates has already been mentioned. Predominance of neutrophils favors bacterial infection. After treatment of pyogenic pleural effusion, a pleomorphic picture emerges, with varying numbers of neutrophils, lymphocytes, and mesothelial cells. Therefore the cytologic pictures in a patient with tubercu-

271

lous effusion and a patient with postempyemic lymphocytosis may be identical, except for the presence of basophilic mesothelial cells in the latter. Pleural effusion with a cell count of 50% or more lymphocytes is arbitrarily called lymphocytic, and 73% of patients with such fluid have tuberculosis or lymphoma. Mature lymphocytes, few neutrophils, and an absence of basophilic mesothelial cells favor tuberculosis.46 Conversely, abnormal lymphocytes and basophilic mesothelial cells favor lymphoma. Congestive heart failure and pulmonary infarction are found in 15% of patients with lymphocytic effusion; infectious mononucleosis (atypical lymphocytes may be present), systemic lupus erythematosus, and cirrhosis of the liver account for the rest.50 In pleural with effusion associated sarcoidosis, lymphocytes may predominate.34 Normal lymphocytes are capable of being transformed into primitive blast cells when stimulated with phytohemagglutinins. In rare instances of chronic lymphocytic leukemia associated with lymphocytic pleural effusion, the lymphocytes fail to transform after stimulation.41 This may prove to be of diagnostic value. Eosinophilic pleural effusion is identified by an eosinophil count of 10% or more. The fluid is often blood-tinged or frankly bloody. Blood eosinophilia is not uncommonly associated, but it is usually less striking than the pleural fluid eosinophilia.3 When they coexist, hypersensitivity states (14%) are suggested.3 On the other hand, pleural fluid eosinophilia in the absence of blood eosinophilia points to pulmonary infection (24%), trauma (16%), malignant tumor (6%), pulmonary infarction and congestive heart failure (5%) cirrhosis of the liver (4%), and miscellaneous causes (3%).4 In a significant number of eosinophilic pleural effusions (28%), the etiology remains unexplained. It may be concluded that pleural eosinophilia argues strongly against tuberculosis, fungal infections, and malignant tumor. The presence of foreign substances in the pleural space (such as proteins, air, oil, iodine, egg albumin, chalk, or even saline) may provoke accumulation of eosinophilic fluid.45 In pleural effusion due to multiple myeloma, a large number of plasma cells and a protein electrophoretic pattern showing a sharp-spiked

272

peak in gamma globulins have been reported.3Y In such cases pleural biopsy may help in diagnosis. Exfoliative cytology. In about half of the patients with malignant pleural effusion, cytologic study of the fluid may be positive for malignant cells. Most often the tumor is adenocarcinoma or one of the lymphomaleukemia group.33 False positive cytology for tumor has been reported in 3%5% of patients with pleural effusion. It is usually difficult to distinguish the normally shed mesothelial cells from the malignant cells of mesotheliomas. Cultures. Bacteriologic study of the fluid for both aerobic and anaerobic organisms is an essential part of the diagnostic workup. Routine bacterial cultures of the fluid are more reliable guides to the etiology of the infection than are sputum cultures, in which multiple organisms are frequently present. In tuberculous pleural effusion, cultures for acid-fast bacilli are positive in less than 30% of cases.14 The diagnostic yield is improved by multiple cultures of large volumes of fluid and by inoculation into guinea pigs.44 Pleural biopsy provides histologic evidence of tuberculosis in 50?&80% of cases.2 Culture of the biopsy specimen may yield positive results in 76% of cases.24 Culture and histologic results combined will detect over 95% of cases. Any fungal infection that causes pneumonic consolidation or abscess may cause pleural effusion as well. Fungal culture is necessary to establish the diagnosis. Parasitic involvement of the pleura is a rare cause of pleural fluid. Pleuropulmonary involvement with Entamoeba histolytica is a complication of amebic liver abscess. The pleural effusion is usually bloody or brownish red and may contain amebae, cytolized liver tissue, and particles of liver parenchyma.” Hydatid disease due to Echinococcus granulosus is rarely complicated by pleural effusion. If pleural involvement occurs, hooklets and scolices may be found in the fluid.36 Complement. In systemic lupus erythematosus and rheumatoid arthritis, the mean values for whole hemolytic complement and its three components (Clq, Ca, and C,) in the pleural fluid may be very low. 2o In some of these patients, anticomplementary activity has been found in the fluid. This suggests that the complement de-

SAHEBJAMI

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LOUDON

pletion may be the result of immunologic inactivation. In pyogenic and tuberculous pleural effusions, complement levels are relatively high, which may help differentiate them from those of systemic lupus erythematosus and rheumatoid arthritis. Rheumatoid factor, RA cell. Polymorphonuclear leukocytes with cytoplasmic inclusion bodies, also called ragocytes, have been found in rheumatoid pleural fluid.“’ But the specific term RA ceil should be reserved for ragocytes that release rheumatoid factor on disintegration or those in which specific gammaglobulin-containing phagosomes can be demonstrated by immunofluorescence studies.‘” Ragocytes can also be found in pleural fluid of other etiology, such as lymphoma and histoplasmosis. Rheumatoid factor is associated with rheumatoid arthritis, but it can also be found in the sera and pleural fuid of patients with a wide variety of nonrheumatoid diseases, such as bacterial pneumonia, carcinoma and tuberculosis.“” LE ceils. In lupus pleural effusions, LE cells may be found in association with LE cells in the serum. The presence of LE cells in pleural fluid is highly specific. Acid mucopolysaccharide (AMP) and hyaluronic acid (HA). Pleural fluid concentrations of AMP greater than 120 mg/ml and of HA above 0.8 mg/ml are highly indicative of mesothelioma.“7*4R Lower values of either are not helpful in differential diagnosis. CLINICAL

FEATURES

Pleural effusion is a manifestation of disease rather than a disease in its own right; the clinical features of the effusion may therefore be separated into those of the effusion itself and those of the underlying diseaseprocess. A patient with fluid in his chest may be aware of a heavy or tight feeling. He may be conscious of a gurgling sensation on changing posture. He may be short of breath because of the reduction in intrathoracic volume associatedwith the effusion, because of secondary lung collapse, or because of underlying lung disease. Pain is more likely to precede pleural effusion than to accompany it. With pleural effusion, especially that resulting from pleural inflammation, there is likely to be a period of time prior to exudation of fluid when inflamed visceral and parietal pleura rub against one another, causing the typical

PLEURAL

273

EFFUSION

sharp pleuritic pain that is exacerbated by normal breathing, deep breathing or coughing. The sensitive parietal pleura usually localizes pleuritic pain quite accurately, although pain originating in the diapragmatic pleura may be referred to the shoulder. As more fluid appears, it tends to separate the visceral from the parietal pleura and prevent the two from rubbing against one another, except perhaps when certain postures are assumed. It has been claimed that cough may result from pleural disease, but the evidence for this is not clear; cough is more likely to result from underlying lung involvement. Cough, sputum, hemoptysis, or wheeze may point to an underlying lung condition; pulmonary edema suggests other causes. Constitutional symptoms such as weight loss, fever, or lassitude suggest underlying malignancy or infection and may help establish a time scale for the patient’s illness. Physical examination may also be helpful, not only in establishing the presence of an effusion but also in suggesting or demonstrating underlying conditions. Dullness to percussion and absence of breath sounds and vocal fremitus are the characteristic findings of pleural effusion. If the effusion is large enough to cause mediastinal shift, this may also be detectable by physical examination. On the other hand, a small effusion visible roentgenographically may be undetectable on physical examination. Associated disease (pneumonia, heart failure, cancer of the lung) may produce its own physical findings. A DIAGNOSTIC

APPROACH

The most important element in the diagnostic approach to a patient with pleural effusion is taking a careful history and conducting a complete physical examination. This will yield information not only about the presence of the pleural effusion itself but also about its underlying cause. Findings that may be encountered have already been mentioned. It is not intended to expand on this subject here, as one could include with justification a large part of what is known about physical diagnosis. The chest roentgenogram is obviously the most important single item in the diagnosis of pleural effusion. The roentgen manifestations are described in more detail elsewhere in this Seminar. Estimates of the volume of pleural fluid necessary before it can be detected on the erect film have varied from 250 to 600 ml. In

1931, Rigler suggested use of the lateral decubitus film in the diagnosis of pleural effusion.3s Although he did not state the minimum volume that could be detected with this additional view, it is generally believed to be in the range of 50-100 ml. Moskowitz and associates, in describing the results of cadaver experiments, indicated that on a properly exposed radiograph 5 ml of pleural fluid could be detected.32 Light and George found that by taking both lateral decubitus films in addition to PA and left lateral films, pleural effusion could be detected in almost 50% of patients after abdominal surgery, a yield much higher than previous estimates.28 Skin testing and laboratory studies of various sorts are often the next steps taken toward reaching a diagnosis in a patient with pleural effusion. The tuberculin and sputum examination for mycobacteria, fungi, and bacteria may provide a diagnosis, as may cytologic examination of sputum. Other procedures may be needed, and these may involve virtually any body system, particularly if metastatic malignant disease of the pleura is a likely cause of the effusion. But the specific approach that is adopted in almost every case is that of thoracentesis and pleural biopsy. THORACENTESIS

AND PLEURAL

BIOPSY

The characteristics of pleural fluid and the ways in which they can be helpful in diagnosis have already been described. Biopsy of the parietal pleura, using one of the special pleural biopsy needles such as the Cope or Abrams needle, can provide additional diagnostic information. Pleural biopsy is a relatively simple procedure that is associated with a very low complication rate if certain precautions are taken. It can be undertaken with safety only if an adequate amount of pleural fluid is present; so if biopsy is planned, it should be done before the fluid is evacuated. Some physicians routinely perform a pleural biopsy with the first thoracentesis; others prefer to do a diagnostic tap to distinguish between transudate and exudate and remove only a small amount of fluid. If an exudate is present, a biopsy can be performed during a second thoracentesis. If pleural biopsy is to be performed, any bleeding tendency should first be ruled out. Usually three bites of pleura are taken, one to the left, one to the right, and one downward, but none upward, as the intercostal bundle runs just

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SAHEBJAMI

under each rib. After satisfactory biopsy specimens have been obtained, the remaining fluid may be withdrawn, completely or in part. If pleural disease is suspected, it is often useful to allow 100-200 ml of air to enter the pleural space and provide a small pneumothorax to outline the pleural surfaces on subsequent roentgenograms or fluoroscopy. It is also helpful to leave about 100 ml of pleural fluid to allow the pleural space to be mapped out by positioning the patient in various ways, using the air and fluid as contrast media. Thoracentesis and pleural biopsy are both relatively free from complications if performed with care. Thoracentesis may be complicated by traumatic pneumothorax, air embolism, or bleeding, either from the lung or from an intercostal vessel. If a large amount of fluid is removed rapidly, it is possible for the patient to develop unilateral pulmonary edema in the suddenly expanded lung. Another complication that may occur from rapid removal of a large volume of fluid is mediastinal shift, with attendant discomfort to the patient and possibly with interference to cardiovascular phenomena. It is not uncommon for patients to develop vasovagal symptoms during thoracentesis. The reason for this is not always clear and may vary from incident to incident. At one time “pleural shock” was regarded as an appropriate term to describe this event. It is not clear whether the symptoms are reflex in origin, caused by minor degrees of air embolism, or are associated with some other mechanism, such as shifting of great vessels or alteration in pressure relationships within the thorax. Infection can be introduced into the pleural space if imperfect techniques are used or if an infected lung is punctured by the thoracentesis needle. Implantation of tumor at the site of thoracentesis has been reported but is very rare. The complications encountered with pleural biopsy are also rare. Bleeding is more likely to be a problem than with thoracentesis alone, and in patients with a bleeding tendency or with

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LOUDON

azotemia this risk is increased; deaths have been reported from bleeding. Many of the other complications associated with thoracentesis, other than those due to the sudden removal of a large volume of fluid, apply also to pleural biopsy. Several reviews concerning the reliability of pleural biopsy and cytologic examination have been published. Von Hoff and LiVolsi reviewed 272 biopsies from the pleura; 95% of the specimens contained identifiable pleural tissue.4g Overall, in 133 of the 272 patients a diagnosis was established. Granulomatous disease was diagnosed with 57% accuracy and malignancy with 48% accuracy. False negatives were common, because of the small size of the pleural biopsy, but false positives were very rare. Salyer and associates4” reviewed information from 271 patients. They compared pleural needle biopsy and pleural fluid cytopathology in the diagnosis of neoplastic disease of the pleura. Of 95 cases of malignant disease, 53 were diagnosed on needle biopsy, 69 on cytopathology, and 86 of the 95 (90%) by one or the other means. The same authors quoted ten reported series in which a range of 40%56% positive diagnoses was obtained by needle biopsy; they quoted eight reported studies with a range of 33%72% positive diagnoses on cytologic examination of pleural fluid. Newer diagnostic approaches that have been applied to pleural effusion include reflected ultrasound2’ and electrical impedance.“’ Methods such as these may at some time in the future be found to be heIpful diagnostically, but at the present time they do not compete with the simple chest x-ray. Impedance methods may perhaps become useful in patient monitoring, for example during peritoneal dialysis or other situations where fluid is likely to accumulate or disappear rapidly. Ultrasound may be of value in loculated effusions. Computerized axial tomography may also provide information about pleural effusions, but at the moment this will be a byproduct rather than a primary application for that method.

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glucose Am Rev Chest

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4. Campbell GD, Webb WR: Eosinophilic pleural effusion. A review with the presentation of seven new cases. Am Rev Respir Dis 90:194201, 1964 5. Carr DT, Mayne JG: Pleurisy with effusion in rheumatoid arthritis, with reference to the low concentration of glucose in pleural fluid. Am Rev Respir Dis 85:345-350, 1962

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EFFUSION

6. Chandrasekhar AJ, Moisan T: The significance of a flat pleural fluid glucose tolerance curve. Clin Res 24:550A, 1976 (abstract) 7. Chandrasekhar AJ, Palatao A, Dubin A, et al: Pleural fluid lactic acid dehydrogenase activity and protein content. Value in diagnosis. Arch Intern Mcd 123:48-50, 1969 8. Courtice FC, Simmonds WJ: Absorption from lungs. J Physiol 109:103~116, 1949 9. Delahaye RP, Pannier R, Laaban J, et al: Les aspect radiologiques des localisations thoraciques de I’amebiase: 17 observations metropolitaines. J Radio] Electrol Med Nucl 48:173-182, 1967 IO. Denniston JC, Baker LE: Measurement of pleural effusion by electrical impedance. J Appl Physiol 38:851-857, 1975 I I. Dodson WH, Hollingsworth JW: Pleural effusion in rheumatoid arthritis. Impaired transport of glucose. N Engl J Med 275:1337-1342, 1966 12. Durieu H: MCcanismes de la rCgulation du taux du glycose dans les ipanchements pleuroux. Acta Tuberc Pneumol Belg 45:205%238, 1954 13. Ende N: Amylase activity in body fluids. Cancer 14:110%1114, 1961 14. Falk A: Tuberculous pleurisy with effusion: Diagnosis and results of chemotherapy. Postgrad Med 38:631-635, 1965 15. Ferguson GC: Cholesterol pleural effusion in rheumatoid lung disease. Thorax 21:577-582, 1966 16. Galen MA, Steinberg SM. Lowrie EG, et al: Hemorrhagic pleural effusion in patients undergoing chronic hemodialysis. Ann Intern Med 82:359-361, 1975 17. Glenert J: Sugar levels in pleural effusions of different etiologies. Acta Tuberc Stand 42~222-227, 1962 18. Goldman M, Goldman G, Fleischner FG: Pleural fluid amylase in acute pancreatitis. N Engl J Med 266:715-716, 1962 19. Hollander JL, McCarthy DJ, Rawson AJ: The “RA cell”, “ragocyte”, or “inclusion body cell”. Bull Rheum Dis 16:382-383, 1965 20. Hunder GG, McDullie FC, Hepper NCG: Pleural fluid complement in systemic lupus erythematosus and rheumatoid arthritis. Ann Intern Med 76:357-363, 1972 21. Joyner CR, Herman RJ, Reid JM: Reflected ultrasound in the detection and localization of pleural effusion. JAMA 200:399-402, 1967 22. Krueger JJ, Bain T, Patterson JL Jr: Elevation gradient of intrathoracic pressure. J Appl Physiol 16:465-468, 196 I 23. Leuallen EC, Carr DT: Pleural effusion. A statistical study of 436 patients. N Engl J Med 252:79-83, 1955 24. Levine H, Metzger W, Lacera D, et al: Diagnosis of tuherculous pleurisy by culture of pleura1 biopsy specimen. Arch Intern Med 126:269-271, 1970 25. Levine H, Szanto M, Griehle HG, et al: Rheumatoid factor in nonrheumatoid pleura1 effusions. Ann Intern Med 69:487-492, 1968 26. Levine PH, Kelley ML Jr: Spontaneous perforation of esophagus simulating acute pancreatitis. JAMA 191:343-345, 1965 27. Light RW, Ball WC Jr: Lactate dehydrogenase isoenzymes in pleural effusions. Am Rev Respir Dis 108:660-664, 1973 28. Light RW, George RB: Incidence and significance of

275 pleural effusion after abdominal surgery. Chest 69:621-625, 1976 29. Light RW, Macgregor MI, Luchsinger PC, et al: Pleural effusions: The diagnostic separation of transudates and exudates. Ann Intern Med 77:507-513, 1972 30. Maher GC, Berger HW: Massive pleural effusion: Malignant and nonmalignant causes in 46 patients. Am Rev Respir Dis 105:458-460, 1972 3 I. Mandl MA, Watson JI, Henderson JA, et al: Pleural fluid in rheumatoid pleuritis. Patient summary with histopathologic studies. Arch Intern Med 124:373-376, 1969 32. Moskowitz H, Platt RT, Schachar R, et al: Roentgen visualization of minute pleural effusion. An experimental study to determine the minimum amount of pleural fluid visible on a radiograph. Radiology 109:33-35, 1973 33. Naylor B, Schmidt RW: The case for exfoliative cytology of serous effusions. Lancet 1:71 I-712, 1964 34. Nelson DG, Loudon RG: Sarcoidosis with pleural involvement. Am Rev Respir Dis 108:647-651, 1973 35. Paddock FK: Diagnostic significance of serous fluids indisease. N Engl J Med 223:1010-1015, 1940 36. Rakower J, Milwidsky H: Hydatid pleural disease. Amer Rev Respir Dis 90:623-631, 1964 37. Rasmussen KN, Faber V: Hyaluronic acid in 247 pleura1 fluids. Stand J Respir Dis 48:366-371, 1967 38. Rigler LG: Roentgen diagnosis of small pleural effusions: A new roentgenographic position. JAMA 96:104-108, 1931 39. Safa AM, Van Ordstrand HS: Pleural effusion due to multiple myeloma. Chest 64:246-248, 1973 40. Salyer WR, Eggleston JC, Erozan YS: Efficacy of pleural needle biopsy and pleural fluid cytopathology in the diagnosis of malignant neoplasm involving the pleura. Chest 67:536-539, 1975 41. Schrek R, Rabinowitz Y: Effects of phytohemagglutinin on rat and normal and leukemic human blood cells. Proc Sot Exp Biol Med 113:191~194, 1963 42. Shallenberger DW, Daniel TM: Quantitative determination of several pleural fluid proteins. Am Rev Respir Dis 106:121~122, 1972 43. Sherr HP, Light RW, Merson MH, et al: Origin of pleural fluid amylase in esophageal rupture. Ann Intern Med 76:985-986, 1972 44. Sibley JC: Study of 200 cases of tuberculous pleurisy with effusion. Am Rev Tuberc 62:314323, 1950 45. Spriggs AI: Cytology of Effusions in the Pleural, Pericardial and Peritoneal Cavities. New York, Grune & Stratton, 1957 46. Spriggs AI, Boddington MM: Absence of mesothelial cells from tuberculous pleural effusions. Thorax 15:169-171, 1960 47. Stewart PB: The rate of formation and lymphatic removal of fluid in pleural e&ions. J Clin Invest 42:258-262, 1963 48. Thompson ME, Bromherg PA, Amenta JS: Acid mucopolysaccharide determination. A useful adjunct for the diagnosis of malignant mesothelioma with effusion. Am J Clin Pathol52:335-339, 1969 49. Von Hoff DD, LiVolsi V: Diagnostic reliability of needle biopsy of the parietal pleura. A review of 272 biopsies. Am J Clin Pathol64:200-203, 1975 50. Yam LT: Diagnostic significance of lymphocytes in pleural effusions. Ann Intern Med 66:972-982, 1967