Pleural effusion

Pleural Effusion WILLIAM Vr STEAD J O H N M. SPROUL

TABLE

PLEURAL

STRUCTURE

DETECTION

.

OF PLEURAL

OF

.

CONTENTS

.

.

.

.

EFFUSION

.

.

.

.

.

. . . . .

4 9

QUALITATIVE AND QUANTITATIVE EXA~IINATION OF PLEURAL F L U m

.

.

PLEURAL BIOPSY

.

.

.

.

.

.

HYDROTHORAX

.

.

.

.

.

.

TUBERCULOUS

.

.

. .

. .

.

PLEURISY ~VITH EFFUSION

SPECIFIC DIAGNOSTIC AIDS .

.

.

.

.

.

.

.

.

.

.

.

16

.

28

. . . . . .

.

.

23

.

.

THERAPEUTIC CONSIDERATIONS OF NEOPLASTIC DISEASE

31 37

43

is Professor of Medicine, Marquette University School of Medicine, Chief, Medical Chest Service, ]~Iilwaukee County General ttospital, and Medical Director, /~Iuirdale Sanatorium for Tuberculosis, Milwaukee. Dr. Stead received his M.D. degree from Emory University School of .Medicine and secured experience in care of patients, teaching and research at the Veterans Administration ttospital, Minneapolis, Fitzsimons Army tIospital, the University of Florida and Milwaukee County General ttospital, ttis major fields of research interest are tuberculosis and pulmonary emphysema.

received his .XI.D. degree from Northwestern University .Xiedlcal School and served his residency in internal medicine at the Veterans Administration Research tIospital and Wesley Memorial tfospital in Chicago. Dr. Sproul completed a Fellowsblp in chest disease at Milwaukee County General tIospltal in 1963 and is presently on the staff at Mulrdale Sanatorium as well as being Instructor in Medicine at .Xiarquette University School of .Medicine.

DISEASES W H I C H AFFECT the serous membranes that line any of the major body cavities may be expected to produce rather similar entities, although anatomically localized. Unique to the pleural surface is its indirect exposure to the external environment via its contiguity with the lung and hence its vulnerability to assault by the spectrum of air-borne infections. A second feature unique to the pleura among serous linings is the negative pressure to which its free surface is subjected. The ease with which diagnostic information may be obtained during pleural involvement makes an understanding of the pleural space and its lining of general interest to physicians. Diagnosis is often slmplifled, with little risk to the patient, following examination of either pleural fluid, pleura or both. The large volume of associated effusion which usually accompanies either passive or active pleural involvement allows free investigation of this representa-

tlve extracellular body fluid. It is of value to know the necessary steps to be taken which may assist in categorization of the underlying disease. Of equal importance is an understanding, as far as possible, of the mechanism by which pleural fluid accumulates. Although the pathophysiology of pleural fluid formation in certain diseases is incompletely understood, newer technics and extended interest are rapidly being applied to this problem. PLEURAL STRUCTURE

Von Hayek (1) describes the visceral pleura as being attached to the limiting membrane of the lung, except in interlobar areas, where it rests on connective tissue which is associated with blood vessels and bronchi. He describes three layers: a superficial epithelium, an intermediate layer of collagen and elastic fibers and subpleural interstitial vascular tissue. Tile last-mentioned layer is continuous with the septal interstitial tissue of the lung. The largest lymphatic vessels are adjacent to the limiting membrane, and small collections of lymphocytes are present at intercellular junctions. The parietal pleura, which covers the diaphragm, mediastinum and chest wall, is similar in structure, but superficial and deep connective tissue layers are distinguishable. The subpleural connective tissue is alternatively termed endothoracic fascia. Cell processes connect across intercellular mesothelial clefts, and occasional wandering cells are present. Collagenous tissue comprises the deep connective tissue layer of the pleura over the pericardium, whereas that over the diaphragm is nearly all elastic tissue. The blood supply to the visceral pleura--that covering the lung--and greater part of the diaphragmatic parietal pleura is from the pulmonary artery. The bronchial artery supplies the mediastinal, interlobar and a portion of the diaphragmatic pleura. The remaining parietal pleura is supplied by the intercostal arteries. The anatomy of the lymphatic system of the pleural surfaces is most important. Although Simer (2) acknowledges the work of others who have shown that some of the visceral pleural lymphatic vessels surround the periphery of an entire lung or lobe and drain superficially to the tracheobronchial lymph nodes, his own investigation indicates that the usual flow of lymph from

the visceral pleura is via the small lymphatics within interlobular connective tissue which communicate with the deep l)anphatic vessels within the lung. The lymphatic collecting ducts of the costal parietal pleura are located immediately above and below the ribs and drain either ventrally to parasternal trunks and sternal lymph nodes or dorsally to paravertebral trunks and upper mediastinal lymph nodes. Mediastinal pleural lymphatic vessels proceed cephalad to upper mediastinal and tracheobronchial lymph nodes. Some lymph from the caudal parietal pleura drains to infradlaphragmatic nodes. Lymphatic vessels of the pleuraI diaphraganatic surface intercommunicate with subperitoneal vessels of the undersurface of the diaphragm. CAPILLARY ULTRASTRUGTURE Pleural components must account for production of fluidwhich exceeds their resorptive capacity, if effusion is to become manifest. The lymphatic vessels have long been known to function as a drainage system for the body, and pleural lymphatics serve this role. Elaboration of fluid is provided by the network of pleural capillaries. Recent electron-microscopic studies allow formulation of a general concept of the fine structure of the capillary. Fawcett (3) states that prior to the era of electron microscopy, the capillary was conceived as a closed tube, with its walls composed of polygonal squamous cells joined together by intercellular cement and lined by an endocapillary layer of adsorbed protein. Although the capillary was acknowledged by several investigators to have a basement membrane, this concept was generally denied. Pericytes, or Rouget cells, were noted to surround the capillary in some areas, but their function was uncertain. The intercellular cement was thought to be elaborated by the squamous cells and to function as an uhrafilter which allowed the passage of crystallolds. Blood colloids were thought to be impermeable for the most part. Pores approximately 45 A in diameter were believed to be present between the endothelial cells to account for molecular passage across the capillary wall. Fawcett further notes that electron-microscoplc studies since 1952 indicate that there is a very narrow space between endothelial cells and that it probably contains a much thinner layer

of extracellular material than that seen by light microscopy. Secondly, pores of the size mentioned above have not been found within the intercellular substance. Although accumulated evidence to date tends not to support the earlier concept of permeability, a more plausible concept has not been formulated. Fawcett lists two of the major contributions of electron microscopy regarding the capillary as revealing (1) its diversity and (2) greater inherent activity of the endothelial cell. Three types of capillary have been defined. The first is the muscle type, in which short endothelial microvilli and pseudopods project into the lumen in contrast to the previous concept of a relatively smooth endothelial surface. Interdigitated margins are formed at adjacent cell junctures in lieu of a very prominent layer of intercellular cement, and "attachment bands," although not apparent in mammalian capillaries, apparently represent condensation of opposing cell membranes. Numerous vesicular invaginations of the plasma membrane of the endothelial cell are present, some of which appear closed beneath the surface. These vesicles may represent a process termed pinocytosis, which refers to cytoplasmic englalfment of fluid, and could be involved in the transfer of fluid through a cell. The basement membrane, termed basement lamina by electron microscopists, is a continuous layer 30-50 m/~ in thickness on the outer surface of the capillary. This layer is presumed to be a chief factor in capillary permeability. The primary feature of the other two types of capillary is a greater proportion of attenuated surface area. Fenestrated visceral capillaries are present in many of the endocrine glands, gastric and intestinal mucosa and in the kidney. The attenuated areas in the capillaries of the kidney consist of circular fenestrations 50-100 m/x in diameter, which are apparently separated only by the basement lamina from the extraluminal space. The third type of capillary is the hepatic sinusold, which probably contains actual intercellular gaps and has an insufficient or absent basement lamina. LYMPHATIC ULTRASTRUCTURE These variations of capillary structure have been mentioned to bring attention to the fact that regional physiology is at least a partial function of capillary variability. Because pleural capil-

laries have not been investigated per se, the extent to which their structure influences permeability of the pleural vessels can only be inferred. Lymphatic endothelium is generally similar to that of blood capillaries of either muscle or subcutaneous tissue. CasleySmith and Florey (4) noted that the chief differences between lymphatic endothelium and capillary endothellum were that in the former, (1) adhesion plates at intercellular junctions were less conspicuous or often not seen; (2) gaps as large as 1,5002,000 A were present between plasma membranes of adjacent cells, and particularly in the (mouse) diaphragan appeared open; and (3) the basement membrane often appeared to be interrupted or absent in many places beneath the endothelium. CAPILLARYAND LYMPHATIC PHYSIOLOGY Mayerson (5) has published data in reference to differences in regional permeability which suggest that there are two pore sizes in capillaries, the smaller permitting passage of molecules of less than 250,000 molecular weight and the larger of the two permitting passage of molecules of at least 400,000 molecular weight. Cervical, intestinal and hepatic capillaries were found to have a decreasing percentage of small pore area and an increasing percentage of large pore area respectively. Large molecules, i.e., colloids, are considered to filter through the capillary. The capillary wall is relatively more permeable to albumin (MW 70,000) than to globulin (MW 250,000) and more pervious to globulin than to fibrinogen (MW 450,000). fll-lipoprotein (MW 1,300,000) permeates less readily than al-lipoprotein (MW 200,000). The capillary system leaks albumin 1.6 times as readily as it does globulin. Red blood cells, microfilariae and pneumococci are all large particles which are known to cross the capillary endothelium without affecting it. Again, Mayerson et al. have confirmed an extravascular-lymphatlc circulation of 50% or more of the total circulating plasma protein per 94 hours in man. In addition to molecular size and capillary pressure gradients as factors which affect permeability, temperature, pH, calcium content, oxygen saturation and structural differences in the venular from the arteriolar capillary have been invoked. Tile protein concentration of the serum tends to be a relatively constant factor

among these variables, although the absolute level is significant. Lymph is qualitatively similar to plasma, but it contains quantitatively fewer constituents. Similarly, the fluid of pleural effusion resembles plasma. Although it is technically not lymph, its composition is similar to that of plasma and lymph. Such molecules as enz)wnes may thus be present within the fluid, and discovery of these may offer considerable help in clinical diagnosis. Fluid within the pleural space is not static. This is appreciated from clinical observation of quantitative, often rapid, fluctuations as the course of a disease proceeds. Particles within serous cavities are returned to the circulation almost solely by the lymphatic vessels. The costal parietal and lower mediastinal pleura constitutes the main absorptive route within the thorax. Anesthesia and immobilization depress absorption, as do pneumothorax and pneumoperitoneum. Diaphrag-matie paralysis in animals initially causes delayed absorption, which returns to supernormal at the end of some time. The necessity for either active or passive motion is evident elsewhere in that practically no gradient for lymph flow exists in tissue at rest. The variation in the flow of lymph in active and inactive musculature is an example. Stretching of parietal pleura and subsequent separation of mesothelial cells probably facilitate absorption. The elastic network is thinned over the intercostal spaces and other junctional areas. The capacity for maximal rate of absorption is not known. Indications are that the maximal absorptive rate for the rabbit may be 10% i)f the plasma volume per hour and for the rat 25% per hour. A recent study of 15 patients with pleural effusions from various causes indicated that about 20~b of the plasma volume (assuming a 70-kg. body weight) was formed and absorbed per day (6). Finally, the lymph must have some propulsive mechanism for its return to the intravaseular compartment. Although lower vertebrates possess lymph hearts for this purpose, mammals do not. Mechanisms which have been postulated include that whereby intermuscular ampullary dilatations of the lymphatic vascular system fill and empty with alteration of muscular tonus, and some authors have thought that the cisterna chyli similarly empties on expiration. Mayerson (7) offers a plausible theory. If it may be assumed that the smallest lymphatics are freely permeable to molecules moving in either direction and that compression

of these vessels forces fluid in all directions, some fluid will be directed centrally and prevented from retrograde flow by the lymphatic valves. Once the lymph attains the larger vessels, it is retained. The reason for this is that the walls of the larger lymphatics limit the passage of molecules of molecular weight greater than 2,000. The response of the lymphatic vascular system to injury is an increased flow of lymph coincident with a rise in tissue pressure. Regeneration of lymphatics lags behind that of blood vessels, although it readily occurs. I n summary, there are several points to be emphasized regarding the mechanism for pleural fluid formation. The first is that there are basic regional differences in capillary structure, but this information relative to pleural blood vessels is incomplete. Other meaningful concepts are that capillary permeability is a multifactorial phenomenon, that pleural fluid is dynamic and that pleural lymphatics comprise the resorptive route whereby particles such as cells and proteins are returned to the blood vascular system. DETECTION OF PLEURAL EFFUSION

Careful physical examination of a patient in whom pleural effusion is suspected is essential for subsequent correlation with more definitive data. An intrathoracic lesion may primarily involve the lung or involve the pleura and leave the lung relatively intact. Extensive involvement of both lung and pleura may be present. In the majority of cases in which separation of pulmonary and pleural disease exists, differentiation is possible. "Pleurisy" is a common term which is often incorrectly used by the laity. An a c c u r a t e description of the pain which often accompanies pleurisy assists in differential diagnosis. Localized chest pain which occurs with a deep breath, cough or sneeze is a frequent initial complaint when the pleura is inflamed. Referral of pain to the shoulder suggests diaphragmatic involvement. If pain is absent, other nonspecifie systemic complaints such as lassitude, anorexia or fever may indicate the need for further investigation. The patient who has pleural effusion plus pain is frequently observed lying on the affected side. The rate of breathing may

be accelerated either because pain is accentuated by greater expansion of the chest (larger tidal volume, slower rate of breathing) or because the compliance of the lung is reduced by large volumes of pleural effusion. The thoracic wall moves less well on the affected side than on the uninvolved side, and with severe degrees of effusion the intercostal spaces may bulge. The point of maximal cardiac impulse may be shifted from its normal position. It may not be detectable if the effusion is on the left side and is large enough to displace the heart to the right beneath the sternum. Trail (8) has described the sternomastoid sign in physical diagnosis of mediastinal displacement. It consists of tension of the sternocleidomastoid muscle on the side of displacement. An example of its usefulness follows: An effusion which is coexistent with ipsilateral atelectasis of a lobe of the lung might be properly attributed to the atelectasls if a nondisplaced cardiac apical pulsation and a tense sternocleidomastold muscle were the physical findings. The classic physical findings of pleural effusion are diminished or absent fremitus, flatness to percussion and distant or absent breath sounds over the effusion. Other useful signs include tracheal displacement (detected above the suprasternal notch), a feeling of underlying resistance by the pleximeter finger, tympany just above tile fluid level and a tendency for flatness to be more prominent over the posterolateral rather than anterior portion of the chest. Grocco's sign is dullness to percussion posteriorly over a triangular area at the base of the normal lung. This was formerly attributed to shift of the medlastinal contents but is now believed to result from interference with resonance of the normal hemithorax by the contralateral effusion. Mediastinal shift has rarely been demonstrated in conjunction with this sign. Bronchial breath sounds and egophony are frequently present just above the effusion. Not infrequently, these findings may be present over the effusion itself. Bernstein and White (9) attempted to determine whether compression of underlying lung might explain this latter phenomenon. In 17 patients who had these unusual findings on physical examination in conjunction with pleural effusion from either cardiac decompensation or carcinoma, they demonstrated that the fluid was under positive pressure throughout the breathing cycle. Normal controls had 10

the classic physical signs and normal pressure relationships. (Readings taken at two levels 10 cm. apart were equal, which reaffirmed the expected equal distribution of pressure in a fluid medium.) According to these authors, an effusion of high consistency would be more likely to produce the unusual findings of bronchial breathing and bronchophony than a watery fluid of equal height. If there is no fluid detectable in the early phase of pleuritls, a pleural rub may be heard at the site of involvement. Other physical signs ordinarily attributable to the presence of fluid may not be present if the effusion is small or loculated. If air is present with a pleural effusion, it may be possible to detect a succussion splash. This is a splashing sound within a hemlthorax that may be obtained by shaking a seated patient while the examiner auscults the chest. It is diagnostic of pneumohydrothorax and has most often been demonstrated in cases of bronchopleural fistula.

ROENTGENOGRAPHICTECtINIC Roentgenographlc examination of the chest is certainly the most productive of the laboratory means in the diagnosis of pleural effusion. However, the sensitivity of a posteroanterior teleroentgenogram regarding detection of fluid is generally insufficient when the volume of fluid is 300 cc. or less. Other maneuvers may increase the efficiency of radiographic application. Fluoroscopy is useful t o demonstrate mediastinal mobility. Motion of the medlastinum or lateral contiguous structures when a patient performs sudden insplratory or expiratory maneuvers is ordinarily pathologic. Other phenomena, such as change in shape of a localized mass during inspiration and expiration (which usually indicates a fluid mass) or demonstrable shifting of shadows with change in position, may be easily seen fluoroscopically but can be recorded on film as well. Free pleural fluid is characteristically of uniform radiographic density and presents a concave-upwards superior border, which extends higher at the lateral thoracic wall and is best seen in the costophrenie sinuses posteriorly or posterolaterally on the standard posteroanterior chest roentgenogram. Small lateral effusions may require oblique views for visualization. Small free effusions, in particular, are best 11

demonstrated by radiographic projection in a lateral decubitus with the suspected side of involvement in the dependent position. This technic is also useful for the demonstration of infrapulmonary effusions. These effusions are present between the lung and diaphragm and often masquerade as diaphragm. Assumption of the supine position will produce haziness on the roentgenogram over one hemlthorax and allow visualization of the diaphragm in its normal position. It is of interest that the fluid resumes its original position when the upright position is again assumed. Felson (10) recommends that films in the recumbent position be taken o[ most patients who have an apparent elevation of one or both hemidiaphragm(s). Another useful clue he offers is that ttle apex of subpulmonary effusion is often located more laterally on the posteroanterior chest film than would be that of a normal hemidiaphragm. On the left side, the gas bubble of the stomach may be located more inferiorly than normally beneath the apparent diaphragm, i.e., the subpulmonary effusion. Oral administration of carbonated water (soft drink) may help in this regard. If the shadow between the accentuated stomach bubble and apparent upper diaphragmatic border widens on inspiration, the elevation of the hemidiaphragxn may be due to infrapulmonary effusion. The bubble tends to approach this border if the elevation is due to ascites. Occasionally, fat and muscle may overlap tile parietal pleura and simulate pleural involvement. In addition to a film of the chest in the lateral recumbent position, which may aid in differentiation, the linear shadow of fat and muscle is characterlstieaIly bilateral and has a wavy outline. Bizarre shadows are frequently produeecl when fluid collects in certain areas (Fig. 1). Paramediastinal collections may simulate cardiac enlargement. If such fluid collects posteriorly, it presents as a unilateral widening which parallels the vertebral column. An effective method of demonstrating paramediastinal effusion is use of an overpenetrated film, which will separate the shadows. Occasionally, ipsilateral anterior and posterior paramediastlnal effusions may occur; an overpenetrated film may be used to demonstrate this. Felson et al. (1 I) postulate that those portions of lung which exhibit a greater tendency toward atelectasis create localized areas of increased negative pressure, which promote accumulation of fluid. The 12

o~

c~

o ~f

~4 C~ 0~ h~

0~

Q

! o~ 13

presence of adhesions and either structural variation in development of a normal fissure or an accessory interlobar fissure may explain an unusual loculated effusion when encapsulated interlobar effusions are present. An interfissural accumulation of fluid must be in tangential position to the penetrating x-rays if it is to be distinctly marginated on the roentgenogram. Thus, fluid in the lesser fissure often presents as a distinct linear opacity, whereas an accumulation of fluid in a long oblique (major) fissure presents as only a diffusely increased opacity, at best, when visualized in the posteroanterior projection. Radiographic examination of a patient in lordotic position may identify fluid in a major fissure. The presence of pleural thickening in some place other than that in question may be a useful clue when difficulty is encountered in distinguishing between a localized collection of fluid and intrapulmonary disease. Circular or oval shadows in the minor fissure may simulate a tumor (Fig. 2). Remedial measures which lead to compensation of congestive heart failure, e.g., will cause the fluid to disappear, as will perforation into a bronchus. The term "vanishing tumor" has been applied to these roentgcno~aphic lesions. An interlobar fissure may calcify following an effusion. Loculated fluid in the medial aspect of the right major fissure may simulate consolidation or collapse of the middle lobe or atelectasis of the lower lobe. It presents as a triangular shadow which borders the heart. Lordotic or lateral views will assist in differentiation. An

air bronchogram, if present, indicates intrapulmonary disease. Roentgenographic diagnosis of plcural effusion tends to be very specific if the aforementioned procedures are properly applied. Other less frequently used, but no less valuable, procedures include larninagraphy, tilting the patient from a vertical position, either posteriorly or toward the affected side if a posteroanterior projection is made, and, on occasion, injection of air into the pleural space to demonstrate a nodular pleura or a shift of diseased lung. Occasionally, cysts or benign tumors may be differentiated from interlobar effusion only with difficulty. An echinococcal cyst has even been present within a fissure. If distinction between pleural thickening and effusion cannot be made indirectly, exploratory aspiration should be performed. 14

Fio. 2.--Schematlc representation of effusions limited to the interlobar fissure. A, effusion in the Hght horizontal interlobar fissure; B, effusion in the lateral segment of the tight horizontal interlobar fissure; C, effusion in the right oblique interlobar fissure. The shadow in the dorsoventral roentgenogram does not always have a sharp linear border; D, effusion in the right oblique interlobar fissure. The effusion shows an hourglass form; E, effusion in the upper segment of the right oblique interlobar fissure; F, large effusion in the upper segment of the left interlobar fissure; G, effusion in the upper segment of the right oblique interlobar fissure, extending into the horizontal interlobar fissure. The same dorsoventral aspect may also be produced by an effusion in the upper segment of the oblique ]nterlobar fissure (punctated line iu the lateral projection). (Reproduced with permission from Schlnz, H. R., Baensch, W. E., Ftiedl, E., and Uehlinger, E.: Lefirbucfi der RSntgendiagnostlk [5th ed.; Stuttgart: Georg Thieme Verlag, 1952.])

15

QUALITATIVE AND QUANTITATIVE EXAMINATION OF PLEURAL FLUID

Once having established that pleural effusion exists, the clinician's interest revolves primarily around the incidence of pleural effusion encountered with a given disease state and around diagnostic measures which will aid in attainment of a specific diagnosis. The frequency of disease encompassed in an individual experience influences the frequency of pleural effusion observed in a given patient population by any one person or group of persons. Therefore, some difficulty is encountered when one tries to state an over-all causal incidence. This variation in experience is reflected in the wide range of causation in case reports. From 1950 to 1952, 436 cases of pleural effusion observed at the Mayo Clinic were categorically subdivided. Of this series, more than 50% were due to neoplasia, 10% to congestive heart failure, 8% to infection of some type, 12% to miscellaneous causes and 17% were indeterminate (12). Certain qualifying factors were not considered. Age, for example, bears a relationship to causation in that neoplasia is more frequently associated with pleural effusion in later years. The chief concern of the managing physician in reference to pleural effusion, as in any other disease state, is to provide the patient with optimum care. This therapeutic provision may occasionally have to be made in the absence of a specific diagnosis. As many as 40% of pleural effusions may not be diagnosable even after application of the many technics.

TRANSUDATE

VS. EXUDATE

Fluid within the pleural space has been classically divided into two categories--transudate and exudate. Transudative fluid is conceived as an ultrafiltrate of serum, and its components are present according to the Donnan equilibrium equation. Such fluid arbitrarily has a specific gravity of <1.015, a protein concentration of <3.0 Gin./100 ml. and contains few cells. If the specific gravity of the fluid is >1.015, the protein concentration is >3.0 Gin./100 ml. and the fluid contains 100-10,000 white blood cells per cubic millimeter of fluid, it is termed an exudate. The presence of exudative fluid presupposes compromise of the 16

integrity of the capillary network and subsequent alteration of permeability. Exudative fluid accompanies inflammatory disease of the pleura in contrast to diseases such as congestive heart failure, nephritis and hepatic cirrhosis, which are not believed to include primary pathologic change of the pleural vessels and are generally associated with transudates. The mechanism of formation of fluid in many diseases is not yet known. APPEARANCE M a n y aspects of the pleural fluid have been examined. Not all are useful. The first quality of the fluid to be noticed following aspiration is its appearance. Although transudates and exudates are not distinguishable by appearance, an estimate of light transmission or color may be useful in that a grossly purulent effusion, i.e., empyema, will be cloudy or opaque. Fluid which contains cells may be translucent, however, and is termed "purulent pleural effusion" by Ungerleider (12). Chylous fluid refers to its resemblance to chyle which contains visible fat globules. This appearance is best described as milky. By use of Sudan I I I stain, this characteristic may be further resolved; fat globules are stained orange. Ether extraction may also be used to differentiate chylothorax from other effusions. The presence of cholesterol crystals in an effusion imparts a characteristic sheen to it. Cholesterol may also exist in high concentration in the noncrystalline form. Cholesterol crystals, if present, are readily identifiable during microscopic examination of the fluid. In the cases reported by Leuallen and Carr (13), the presence or absence of gross blood in an effusion was of little diagnostic value. Of those fluids which contained blood, only 62% were due to neoplasm, while 45~b of nonbloody fluids were due to neoplasm. Other causes of hemorrhagic effusion include pulmonary infarction, congestive heart failure, pancreatitis, tuberculosis, hepatic cirrhosis and ovarian fibromas. The degree to which blood discolors an effusion is dependent, to some extent, on the degree of hemorrhage. A reddish tinge only may be imparted to the fluid, or the fluid may exist as nearly pure blood. Determination of the hematoerit of the fluid will differentiate hemothorax (pure blood) from other bloody effusions. Reddlsh-tinged 17

fluid is associated with a red blood cell count of at least 5,000 cells per cubic millimeter. A traumatic aspiration, although initially or terminally productive of bloody fluid, should not produce continuously bloody fluid. The appearance of the fluid does not determine a specific cause of an effusion. It does assist in channeling further diagnostic effort, however. For instance, in a case of chylous effusion, one presumes either obstruction or rupture of a major lymphatic vessel--namely the thoracic duct. Interruption of the duct may occur following traumatic injury to the thorax or after surgical manipulation; obstruction may be associated with tumorous or inflammatory disease such as Hodgkin's disease, tuberculosis or histoplasmosls.

SPECIFIC GRA~qTY The value of ordinary hydrometric determination of specific gravity has been questioned. Ungerleider states that the determination of specific gravity is a relatively inaccurate measure because of the effect of the temperature at which it is determined. The standard hydrometer is corrected to a temperature of 15.5 ~ C., which, he states, may affect the determination as much as 0.010 when allowance is made for the difference of temperature between body and room. In 1941, Paddock (14) undertook to determine whether a relationship existed between the specific gravity and protein content of human transudatlve and exudatire effusions and found a linear correlation. The relationship between the specific gravity and the concentration of protein of biologic fluids is close but not quite linear. However, the correlation between the specific gravity of effusions and various diseases is not as good. Occasional effusions in patients with congestive heart failure, e.g., contain a high content of protein and have a high specific gravity. Paddock listed possible explanations which might account for the disparity. Resorption of fluid with concentration of unabsorbed protein, which might occur following diuresis in a patient with congestive heart failure, protein breakdown after a period of time and hypoalbumlnemia were considered. An effusion in a patient with hypoalbuminemla may contain a high concen{ration of protein. 18

Twenty-eight per cent of 32 patients in the series from the Mayo Clinic (13) who had pleural effusion in association with congestive heart failure had fluid with a specific gravity >1.016. The specific gravity of the effusion of 137 patients with tuberculosis was <1.016 in 27%. In the same study, 29 of 30 fluids which resulted from tuberculosis or carcinoma had a concentration of protein >3.0 Gin./100 ml., but 2 of 8 effusions due to congestive heart failure also had a concentration of protein >3.0 Gm./100 ml. The authors concluded that the concentration of protein was more specific in the differentiation of a transudate from an exudate. Determination of the specific gravity is a procedure which may be rapidly executed at the bedside. Some authors have stated that formation of a clot is unique to exudates; this is not confirmed. Consideration has been given to whether or not clotting affects the specific gravity. Paddock found this to be an insignificant factor in either transudates, when clotting occurred, or exudates. An abnormal lipid content has not been found to affect the specific gravity, although fat prolongs the clotting time of lymph, which ordinarily clots less readily than does plasma. In the dog, the concentration of fibrinogen and prothrombln in thoracic-duct lymph is about one half that of plasma. Because platelets are absent from lymph, the clotting mechanism is believed to be initiated by the activation of thromboplastin precursors.

DIFFERENTIAL CELL COUNT Leuallen and Carr state that the determination of a total and differential cell count is of no value in determination of a specific cause of pleural effusion. Some general associations exist, which may assist in differential diagnosis, particularly if other data are available. A predominance of polymorphonuclear leukocytes is associated with bacterial pneumonias, pulmonary infarction, the early phase of tuberculous effusion and reactive pleuritls to disease below the diaphragm. Tuberculous effusion is more often associated with lymphocytosis, which may equal 90% of cells. Sulavik and Katz (15) state that about 75% of tuberculous pleural effusions contain more than 1,000 white blood cells per cubic millimeter with a predominance of lymphocytes. These au19

thors also note that tile ratio of polymorphonuclear leukocytes to lymphocytes in pleural effusion associated with rheumatoid arthritis was from 1:1 to 4:6 in those cases they reviewed, and that polymorphonuclear leukocytes never occur alone in this type of effusion. Other effusions which contain a prevalence of lymphocytes include that in association with infectious mononucleosis, when it occurs, and that affiliated with neoplastic disease. The effusion which results from congestive heart failure is reported to contain significant leukocytosls in 10% of cases. A distinct difficulty that often arises in detection of this type of effusion is recognition of coincident pulmonary infarction. Pulmonary infarction may be suggested by the presence of red blood ceils in the pleural fluid. There is sufficient overlap, however, in the many disease entities to render a total cell count, even with differential enumeration, of little value in diagnosis. EOSINOPHILIA Of some interest is the discover), of eosinophilia in a pleural effusion. It may be determined by either a differential or chamber count. MacMurray et al. (16) defined eosinophilia as being present if the eosinophils comprised > 5 ~ of white blood cells. Some authors require >50% eosinophils in the fluid in the absence of significant eosinophilia in the blood. In those diseases known to be associated with eosinophilla in the pleural fluid, no factor has yet been shown to be common to all. These effusions tend to be transient and benign. MaeMurray and his associates reported the first case of Hodgkin's disease in association with eoslnophille effusion; as many as 60~b of cells were eosinophils. These authors further mention that tuberculosis is frequently associated with eoslnophilic effusion, usually as a late manifestation of the disease, and that eosinophils have ranged as high as 80~b. However, in the review by Clurran and Williams (17), experience of French authors is cited that indicates eosinophilic fluids are sterile. Nor are other authors convinced of any relation of eosinophilia in the pleural fluid to tuberculosis, stating that it is rare or nonexistent. Histoplasmosis, coccidioidomycosis and convalescent bacterial pneumonia have been reported in conjunction with eosinophillc pleural fluid. Eosinophils may appear 20

in pleural effusion following pneumothorax or pulmonary infarction and range as high as 9 0 ~ of cells in the latter disease. Asthma has been frequently described in association with eosinophilic pleural fluid, but peripheral eosinophilla is often present as well. Less commonly associated conditions which may bear a relationship to eosinophilic pleural fluid include carcinoma, viral infections, congestive heart failure and sarcoidosis. (The last-named is itself rarely associated with pleural effusion.) Because there is such a diversity of disease associated with pleural-fluid eosinophilia, the value of this finding when the disease is known, i.e., secondary pleural-ftuld eoslnophilia, is limited. Idiopathic pleural effusion with eoslnophilia, i.e., primary pleural-fluid eosinophilia, is a relatively benign phenomenon and is not associated with nearly the incidence of subsequent tuberculosis as is pleural effusion when eoslnophilia is absent and for which no cause is known. Among the concepts which have been derived to explain the eosinophilic response are a hypersensitivity phenomenon, a relation to adrenocortical steroids whereby the eosinophilia occurs following a stressful situation as a rebound reaction and a plausible hypothesis which relates eosinophilia of the pleural fluid to the presence of a stimulating substance in the red blood cell. In the cases reviewed by MacMurray, red blood cell concentrations were high in about two thirds of the eosinophilic effusions. Chapman has demonstrated that intraperltoneal injection of either autogenous or heterogenous blood into mice promotes first a polymorphonuclear, then a lymphocytic and finally an eoslnophilic response. An eosinophil-stimulating substance has been found in association with the stroma of the red blood cell and may be either a protein or protein-linked carbohydrate (18), but there is little evidence thus far that this material functions in a hypersensitivity reaction.

PROTEIN Previous reference to the protein in pleural effusions has been to total protein concentration. In an effort to refine the value of the determination of protein, Luetscher (19) electrophoretically separated five protein fractions from plasma and pleural effusions in various diseases. It was apparent from this determination that 21

the major protein fractions were present in both fluids and that they had somewhat similar compositions. The fraction of albumin tended to be greater in effusions than in corresponding plasma. No evidence of selective secretion of any one protein fraction into the effusion was detected when this was investigated in cases of lobar pneumonia. The findings in effusions of neoplastic origin were highly variable and were influenced by hemorrhage. The suggestion was made that the ratio of total protein in the fluid to that in the plasma might permit more accurate differentiation of the types of effusion. Routine electrophoretic determination of pleural fluid protein is not an established practice. The clinical significance of mucoprotein in pleural fluid was evaluated in a study of 72 patients, and the conclusion from this study was that it did not have diagnostic significance (20). A recent investigation was undertaken by Feldstein et al. (21) to determine calcium~ phosphorus, alkaline phosphatase and protein concentrations in effusion fluid in man. Five patients were studied; and of 71 samples of fluid, 39 were pleural. Proportionately, for low values of protein:serum protein concentration in effusions, high values of calcium:serum calcium concentration were present. The effect of protein on calcium concentration was less marked than expected, although the average calcium concentration was within the expected range. The theory of Stewart and Burgen that allows for a greater passage of albumin, which binds more calcium than globulin, through a heteroporous serous membrane was mentioned in relation to the relatively high calcium concentration. The findings of Luetscher previously mentioned tend to support this concept. There was no apparent relation between phosphorus and calcium or phosphorus and protein. These investigators were not able to detect any significant difference in the effusion fluid:serum protein concentration ratio in neoplastic disease when contrasted with nonneoplastic disease; i.e., mean values for serum protein and protein of the effusion did not differ significantly in tile two diseases. Although the alkaline phosphatase level rose as the protein level increased in the effusions, the correlation was poor in those cases in which this enzymatic reaction was determined. The level of alkaline phosphatase did not facilitate diagnosis of neoplastic disease. 22

PLEURAL BIOPSY

The technic of needle biopsy of the parietal pleura has been an invaluable addition to the diagnostic armamentarlum of the physician who is called on to diagnose diseases of the chest. Its use is now routine in the evaluation of pleural effusions of unknown cause. The several small fragments, 3-4 ram. in greatest dimension, obtained from a single biopsy site are often sufficient to permit a specific diagnosis. Although the use of pleural biopsy in diagnosis was not new in 1954, Sutliff et al. (22) reported the histopathologic findings of 21 patients subjected to pleural biopsy. Resection of 3-4 inches of rib was performed under local anesthesia. To the best of their knowledge, the pleural space was free of fluid, and biopsy was not performed if tuberculosis was evident. A specific diagnosis was obtained in 20 of the 21 cases. Tuberculous pleurisy was diagnosed in 17 patients, carcinoma in 3 patients and North American blastomycosls in 1 patient. Acidfast bacilli were demonstrated by culture in 6 of 9 specimens and only by stain in 2 specimens. Three needle-type instruments are now in general use. These are the Vim-Silverman needle, well known to gastroenterologists and others who perform liver biopsies, the Cope needle and the Abrams needle. The last two are similar, and each resembles a needle with a hooked end and cutting cannula. The Vim-Silverman needle consists of two leaf-spring blades and an outer sheath. A full-thickness core of tissue is ordinarily obtained when the pleura is blopsied with this needle. It represents an advantage over the Cope or the Abrams needle if the pleura is thickened. Donohoe et al. (23) reported their experience with the use of the Vim-Silverman needle in 45 cases of undiagnosed pleurisy with effusion. Granulomatous pleurltis was diagnosed from a pleural specimen obtained by needle biopsy in 12 of 23 patients whose disease was diagnosed clinically as tuberculous pleurisy with effusion and from whom adequate specimens were obtained. A satisfactory specimen was obtained by needle biopsy from 19 of the 23 patients. The disease in 19 of these patients was ultimately diagnosed as tuberculous pleuritis after open surgical biopsy. Neoplasia was diagnosed four times from specimens of tissue which were obtained from 8 of 11 patients in whom a neoplasm pre23

sumably accounted for the pleural effusion. A histologic diagnosis of malignancy with pleural involvement was eventually obtained in 10 of these 11 patients. No organisms were evident after acidfast, PAS or Grldley stain was applied in any of 14 needle-blopsy specimens which were diagnosed as granulomatous pleurltis. Open surgical biopsy in this series was utilized only after three specimens were obtained by needle aspiration and did not suffice for diagnosis. Levine and Cugell (24) state that the use of the Vim-Silverman needle fails to produce an adequate specimen in 10-40% of attempted pleural biopsies. They report their experience with 150 patients in whom the Cope needle, first described in 1958, was used. They excluded from their series patients whose effusions were associated with congestive heart failure, hepatic cirrhosis, nephrosls, pneumonia, trauma or connective tissue diseases, and those patients with pleural effusions containing less than 2.5 Gm./ 100 ml. of protein. They obtained a pleural specimen in all but 4 of 202 samples. Failure to obtain pleura occurred only in those patients who did not have an effusion. A specific diagaaosis was obtained of 70 patients, 57 of these after the first attempt at biopsy. Eighty-three per cent of 38 patients with proved tuberculous effusion had a corroborative tissue specimen, as did 75% of 28 patients with proved carcinomatous effusion. Although the sections were not routinely stained for acid-fast bacilli, this was recommended. Cope and Bernhardt (25) have recently reported over 200 patients in whom the Cope needle has been used to obtain tissue for hlstopathologic examination. Other serous membranes besides the pleura which were subjected to this procedure were pericardium, peritoneum and synovlum. More than 120 patients with undiagnosed pleural effusion or pleural thickening were examined. A specific diagnosis was obtained by biopsy in 25% of the patients. Thirty patients with pleural thickening were safely biopsled when pleural fluid was absent. They recommend that 1-2 fragments of tissue be submitted to the bacteriologic laboratory for culture of acld-fast bacilli and fungi, even though the yle!d has been poor when Ziehl-Neelsen and auramine-rhodamine fluorescent stain have been applied. 24

INDICATIONS AND CONTRAINDICATIONS A candidate for pleural biopsy is a patient with p]eural effusion for which the cause is not apparent through use of other routine diagnostic measures. Some authors have recommended that biopsy be performed at the tlme of initial thoraccntesis. Although very few complicationsfollowneedle biopsyof the pleura, tllis approach seems unnecessarily aggressive. Among the few patients to be denied the procedure are those with a known bleeding diathesis. The presence of a hemorrhagic disorder can best be determined by questioning and careful review of other routine laboratory data. Cope (25) has not encountered bleeding complications when the prothrombln time has been as low as 40~ of the control value. Known prolongationof either bleeding or clotting time is a contraindication. Occasionally, it is difl:icu]t to determinewhether a rocntgenographlcdensityrepresents pleura] effusionor pleural thickening. Although inability to recover fluid by needle aspiration is not a contraindicationto biopsy, the chances of obtaining a satisfactoryspecimen of pleura are somewhat less. The rationale for biopsy in the absence of effusionis that no harm wi]l eventuate should the needle penetrate the lung at a site of pleural thickeningbecause of adhesive obliteration of the pleural space at that point. A complication might ensue should the needle not be placed at an obliterated site. ~Vhether or not specific pathologic material may be obtained in a given condition depends on the nature of the disease. Recovery of material is facilitated when a disease diffuselyinvolves the pleura, as is usually the case in tuberculous p]eurltis. Neoplastic involvementmay consist of widelyscattercd ]eslons, which lessens the opportunity for achieving a specific diagnosis by a single biopsy. The proportionate yield of diagaaostic material to repeated biopsy in various diseases is not known. Recovery of diagnostic material may perhaps be augmented when biopsy is performed opposite an observable lesion or over a painful area, if present. One of the advantages of needle biopsy over surgical biopsy is the short time in which tissue may be obtained. As little time as needle biopsy takes, it should be performed as early as possible in the course of active disease. If three attempts have been made at needle biopsy of the pleura, and either inadequate 9

.

25

material is obtained or nonspeeific pleuritis has been the only pathologic finding, open surgical biopsy should be considered. Some authors recommend (26) that frozen-sectlon examination be applied to tissue obtained by a closed intercostal approach and, if negative, full thoracotomy be performed. Failure to proceed with thoracotomy will preclude diagaaosls in some cases.

COMPLICATIONS The complications of needle biopsy of the pleura include pneumothorax, hemorrhage, infection and, rarely, metastasis of tumor. Levine and Cugell (24) encountered 2 cases of pneumothorax with 1 fatality, 1 case of hemothorax and 4 episodes of persistent air space in their series of 150 patients. Attention should be given to the proper technic of needle biopsy. When either the Cope or the Abrams instrument is used, the hook is directed inferiorly and kept close to the superior leading edge of the subjacent rib. Injury to the intercostal vessels which course the underside of the rib may thus be avoided. Prevention of pneumothorax is not ahvays possible, but it may be obviated if the patient is asked to hold his breath during the biopsy. If the Cope needle is used, the patient should expire prior to interchange of curet and needle. This latter maneuver lessens the intrapleural negative pressure. Advantages of the Abrams needle are that it represents a closed system and provides a slightly larger piece of tissue than do other needles. A roentgenogram of the chest is recorded within a few hours following the biopsy to alert the physician if air is present within the pleural space. A prebiopsy film is necessary for comparison purposes. During the time of follow-up observation, Levine and Cugell were not aware of the presence of tumor in the needle track of any of their patients. CAsv. REPOgT.--A ten-year-old white boy was admitted to a private hospital on 10/4/63, 2 days after fever was noted. He did not admit other symptoms. A film of the chest on admission was interpreted by the radiologist to reveal a pneumonic infiltrate and effusion at the left base. Antibiotic and oxygen therapy were administered for 4 days. His maximum temperature during this time was 105~ F. Thoraeentesis was performed 6 days after admission. An "occasional pus cell" was reportedly present in the pleural fluid. Eseheriehia coli and coagulasepositive Staphylococcus albus were cultured from the fluid. The PPD26

i'J i]i

Fto. 3.--Case report. A, posteroanterior roentgenogram of the chest.

Note pleural effusion in left hemithorax; B, hlgh-powered view of pleural specimen removed by needle biopsy. Note granulomas.

27

tuberculin tcst was posltivc, and 1 week following admission the patient was transferred to Mulrdale Sanatorium. On admission to lkIuirdale, the patient was noted to be thin, pale and irritable. His respiratory rate was 20 per minute, and his temperature was 99.2* F. The left hemithorax was dull to percussion anteriorly and posteriorly from the base to the axilla, and breath sounds were decreased over the area of dullness. Induration from intermediate PPD was 15 X 20 ram. The sedimentation rate was 55 ram. per hour. Initiation of isonlazid and para-aminosalicylic acid was begun on 10/14/63. Aspiration and needle biopsy of the pleura of the left chest were performed on 10/16/63. The fluid was straw colored but slightly cloudy. No organisms were identified by Gram stain. Ninety-one per cent of the white blood cells were mononuclear. The protein concentration of the fluid was 4.85 Gin./100 nal. Caseating granulomas and acidfast bacilli were present in the biopsy specimen. Cultures of 3 gastric specimens and the pleural fluid for acld-fast bacilli were negative at the end of 8 weeks (Fig. 3). HYDROTHORAX

~'[EIGS' SYNDROI~IE Several of the diseases associated with pleural effusion do not include primary pleural inflammation, as do most of those which will be mentioned. The complex of an ovarian tumor (either fibroma, thecoma, granulosa-cell or Brenner), ascites, hydrothorax and the stipulation that cure must follow resection of the tumor comprise Meigs' syndrome. Other nonfibromatous benign tumors, e.g., ovarian cysts, uterine leiomyomas and teratomas, are associated with ascltes and hydrothorax. Because of the predominant association of fibrornas with these effusions, regardless of the relatively infrequent occurrence of fibromas in contrast to epithelial and teratomatous tumors, this (arbitrary) definition is made. Of interest is the occasional occurrence of hydrothorax in malignant ovarian disease with or without carcinomatous cells in the pleural fluid which improves after resection of the tumor. The protein concentration of ascitic and pleural fluid is usually quite low. Again, the exact mechanism of this phenomenon is not understood, but in vitro cultures of flbromatous tumors indicate that a considerable quantity of fluid per unit of tumor mass may be formed. These tumors are edematous and contain areas of 28

pressure necrosis when examined by light microscopy. Whether or not different mechanisms exist for the formation of fluid by fibromatous and nonfibromatous tumors is not known. Remedial measures include surgical removal of the tumor if it is benign and consideration of either hysterectomy and bilateral salpingooophorectomy or radiation therapy if it is malignant (27). CONGESTIVE HEART FAILURE The most common condition associated with hydrothorax, i.e., transudative pleural effusion, is congestive heart failure. In 1957, Race r al. (28) undertook a study to determine whether unilateral effusion in this condition was in fact more frequent on the right side, as often stated. Two hundred and ninety autopsied cases were reviewed and accepted, after certain criteria were applied. Obliteration of a pleural space by pleural symphysis was reason for rejection of that case from the study, as was hydrothorax of less than 250 ml. The latter criterion was applied to eliminate accumulations of fluid which might have occurred only terminally. Right, left and bilateral effusions were present in 8.3%, S.8% and 87.9% of patients respectively. Of partlcular interest was the occurrence of pulmonary infarction in 60 of the 290 patients. In only 2 of 11 patients who had either right or left pleural effusion was the infarction contralaterally located. Thirty-four of 54 patients who had pneumonia and bilateral hydrothorax also had bilateral pneumonia. Because the separation of (predominantly) right from left hydrothorax was very narrow, these authors were not able to correlate their data with theoretic considerations of others in regard to mechanisms. Many factors have been given consideration in reference to the pathogcnesis of hydrothorax in congestive heart failure. These include diminished return of venous blood to the heart by obstructlon from right atrial dilatatlon, dilatation of a branch of the pulmonary artery or traction from the right heart (all of which were believed to compromise the diameter of the azygous vein), and compression of the right or left pulmonary vein by the respective auricle, lymphatic insufficiency, increased negativity of the intrapleural pressure and an effect by hypoxla on capillary permeability. Inflammatory reaction as a universal pathogenetic 29

factor probably cannot be implied because the effusion is a transudate in most instances. SLxty-one per cent of the 290 patients in the aforementioned series had pulmonary edema. This low percentage does not suggest a restrictive relationship between pulmonary edema and hydrothorax. No one factor was wholly involved in this series of pleural effusion associated with congestive heart failure. Other authors have concluded from clinical, radiologic and postmortem studies that a combination of factors favors the right pleural cavity when pleural effusion occurs with congestive heart failure. Both a greater frequency of formation of fluid in the right pleural cavity and, when both sides develop effusion, a greater quantity of fluid on the right side are implied by "favors." The therapeutic approach to this type of effusion is directed at relief of congestive heart failure. Disappearance of a loculated collection of fluid, or "phantom tumor," during serial roentgenographic examination of the chest is evidence of therapeutic effectiveness, as is disappearance of a nonloculated effusion. CIRRItOSIS OF T H E

LIVER

Perhaps related to the hydrothorax which occurs with fibromatous tumors of the ovary is that associated with cirrhosis of the liver. Ascites appears to be an invariable accompaniment of pleural effusion with cirrhosis, so that the primary reason for fluid in the chest is more closely related to those factors which influence the development of ascites. Portal hypertension, hypoalbuminemia and perhaps those factors relative to inadequate metabolic degradation of certain hormones by an insufficient liver are potentially significant. The intercommunication of peritoneal and pleural diaphrag-matic lymphatic vessels may be a critical factor. The ultimate route of the dlaphrag-rnatic lymphatics is chiefly via the right lymphatic duct to the right subclavian vein. Experimental obstruction of this pathway has resuited in pleural effusion in animals, which presumably results from an abnormally elevated intralymphatlc pressure distal to the site of the obstruction. Whether or not previous inflammatory disease which may have involved the lymphatic system of the pleura must be postulated in each instance is not known. Clinical 30

characteristics of this type of pleural effusion include the findings of a transudate, a unilateral location which sometimes favors the right pleural cavity and evidence of cirrhosis of the liver, ascites and hypoalbuminemia. Red blood cells are frequently found in the effusion. TUBERCULOUS PLEURISY WITH EFFUSION

Roper and Waring (29) covered the historic aspects of tuberculous pleural effusion in a report in 1955. They mention that although the roentgenogram was not discovered until 1895, it was even later--in the 1920's--that an appreciation and use of this technic were realized. Their report is a 5-year follow-up study of 141 military personnel who had acute, primary, serofibrinous pleurisy with effusion without evidence of pre-existent tuberculosis. All patients were tuberculin positive, and roentgenograms of the chest recorded prior to the onset of effusion were available in all cases. Because no therapy was available at the time of initial illness, none was given. Ninety-two of 141 patients subsequently developed tuberculosis in some form. Those patients under 25 years of age were more prone to develop reactivation, which occurred in almost every form in nearly all parts of the body. Slightly more than half of the 92 patients developed pulmonary involvement only. Other manifestations were pulmonary involvement with effusion, pleural effusion only and extrathoracic tuberculosis with pleural effusion or with pleural effusion and pulmonary involvement. The last (triad) was least common. Tuberculosis became evident within 3 )'ears in 81 of the 92 patients. These authors concluded that pleurisy with effusion was part of a generalized infectious process and that it was apparently due to perforation of a subpleural tubercle, although the possibility of lymphohematogenic spread of tuberculosis with effusion as a first manifestation was not excluded. PATHOGENESIS

Stead et al. (30) reviewed the pathogenesis of tuberculous effusion in 1955. They noted Paterson's discovery in 1917 that only tuberculln-sensitized guinea pigs developed pleural effusion when 31

they were subsequently challenged with an intrapleural inoculation of tubercle bacilli. Their report is of the operative findings in 15 tuberculous patients and in 9 nontuberculous patients. A caseous tuberculous focus in the lung was conti~maous with diseased pleura in 12 of the patients with tuberculosis. In all 15 tuberculous cases, typical caseous tubercles were identified in the pathologic sections. In 12 of the 15 cases, acid-fast bacilli were observed in caseous material from small pockets within the fibrous peel. These and other data led these authors to ratify an explanation by Le Damany of tuberculous pleurisy with effusion which appeared in 1903 and stated that rupture of a peripheral pulmonary lesion into the intrapleural space in the postprimary phase of tuberculosis excited an exudative response by the pleura. "Postprimary phase" refers to the fact that the tuberculin test is positive in those patients who have an effusion which is attributed to tuberculosis. The tendency for tuberculosis to become evident within a 5-year period, particularly in younger persons, lends credence to the concept that tuberculous pleurisy with effusion is part of the primary infection (Figs. 4 and 5). Although enlargement of hilar lymph nodes or a segxnental lesion is not infrequently present, the primary tuberculous lesion may not be evident--particularly at the time the patient is seen. The fact that the effusion tends to resorb spontaneously within 2--4 months and to leave no underlying evidence o/ pulmonary disease suggests that routine roentgenographic technics are not sufficiently sensitive to permit detection o/ the very early tuberculous focus. Planigraphy has been successfully employed in the demonstration of a primary focus of insuffieient density to appear on a standard radiograph. The residual primary lesion is generally not identified unless calcium has been deposited, and this takes many months. Thus, it would be unusual for a patient infected with Mycobacterium tuberculosis, who becomes sensitized to tuberculoprotein within 3-7 weeks thereafter and develops subsequent pleural effusion, usually within 7 months, to manifest objective evidence of pulmonary disease unless progressive primary tuberculosis were evident from its inception. These observations partly account for the apparent paradox of either contralateral or bilateral tuberculous effusion and subsequent unilateral pulmonary tuberculosis. Tuberculous infection 32

4 FxG. 4.--Diagram of formation and course of tuberculous pleural effusion. Tuberculous pleurisy is most often associated with progressive expansion of tuberculous nodules in the periphery of the lung (1). A caseous area may break through the visceral pleura and give rise to a pleural exudate (2). This commonly resolves spontaneously, as do the pulmonary lesions, but tlny tuberculous focl are seeded throughout the body via the blood stream. Those bacilli in the pulmonary apices survive and lie dormant for many years (3). The principal danger of primary tuberculous effusion is that the dormant apical focl may reactivate in later years (4).

of the pulmonary parenchyma affects both lungs similarly. Systemic dissemination of tubercle bacilli and apical pulmonary seeding occur via a lymphohematogenic route. T h e risk of dissemination is perhaps accentuated once viable organisms reach the pleural space because of the multiplicity of lymphatic vessels which is then involved. Subcutaneous tuberculous abscesses and tuberculosis of the bone have both been attributed to necrosis of lymph nodes which drain the pleura and are in contiguity with the affected area. According to Ungerleider (12), when the sediment from 100-500 ml. of centrifuged pleural fluid is cultured for M. tuberculosis, growth occurs in 70% of cultures of effusions from young people with primary tuberculous pleurisy. However, 33

o

o

~.'~< <<~ ]

:"

-', ' < ' - 7

:-,r*,

, ),

~.~,',~,~,d",, ~

~ ~-:,~:." <

""

",;i

,,. , , : c < , ~ , / : . . i,

;o'~,,~

~-~

.

:, ~,

~<.:.+.,

~,;~it ~ . ~ 4 > i L , ~ c t

>~,~?~~ ,+

~

t - . , N +,

I ~ .o

~:.

~ 0 ",,z4 " ~ 9

':~

X'),='~.-i:.,.,:'i:~..:~i - - , . , - . ~ , ~ l l

"~ ~ '~

...~

34

others report much less success when recovery of M. tuberculosis by culture is attempted. Some authors admit that their technics were somewhat inadequate. IN CHILDHOOD A group of 202 consecutive cases of tuberculous pleural effusion in clfildhood which were observed at Bellevue Hospital from 1930 to 1956 was reported in 1958 by Lincoln et al. (31). Only 5 of 176 patients who did not have tuberculous complications had visible calcification of the primary lesion at the time of the pleurisy. This finding further supports the concept that tuberculous effusion develops relatively early following the initial infection. Of particular note in this study was the fact that only 25.6% of children less than 4 )'ears of age developed pleurisy. (Those less than 4 years of age comprised 65% of the group.) The highest percentage of effusions occurred in children 5 through 9 years of age. M. tuberculosis was recovered elther by culture or after gfllnea pig inoculation from 17.7% of 136 patients from whom pleural fluid was obtained. Pleural thickening was evident for at least 5 years in more than half of the 176 patients. Other complications were contraction of a hemithorax, seollosls, empyema, meningitis and peritonitis. Following pleurisy with effusion, 5.7% of patients developed chronic pulmonary tuberculosis within 6 months to 10.4 )'ears (58% of patients were followed to beyond 16 )'ears of age). This is in striking contrast to the incidence of chronic pulmonary tuberculosis after tuberculous effusion occurs in an adult. The conclusions which were drawn from this study were that pleurisy which accompanies primary tuberculosis in children does not increase the risk of later development of pulmonary tuberculosis and that the increased morbidity of children 5-13 years of age can be attributed to the greater incidence of chronic pulmonary tuberculosis with advancing age. The incidence of pleural effusion in children who are over 5 years of age and who have uncomplicated primary tuberculosls has been estimated from other studies as about 7 ~ of such cases.

35

SEQUELAE Data have been obtained by several investigatorswho utilized differential bronchospirometry to evaluate the effect of pleural disease on pulmonary function. Oxygen uptake within the involved hcmithorax is more scvcrcly impaired than the rcsting minute ventilation of that same side. Gaensler et al. (32) determined that whereas the mean minute ventilation by the hmg of the involved side comprised 3 3 ~ of the total ventilation in a series of 127 patients which they reported, mean oxygen uptake was only 19% of the total uptake. Thirty-five per cent of patients had lungs which contributed less than 10% of the total oxygen uptake. The disproportionate ratio was believed to result from a decrease of the cross-sectlonal area (and increase of the pulmonat3' vascular resistance) of the vascular bed of the confined lung, which promotes a shunt of the cardiac output to the opposite side, although the restriction is not enough to significantly reduce ventilation. A very practical obsetn,ation which they note is that the extent of lung involvement is all too frequently underestimated by the physician who observes only a thin margin of pleural thickening at the lateral aspect of a roentgenogram of the chest when, in fact, the pleural thickening entraps the whole lung. Pulmonary function studies of children seem to contradict the findings in adults. Filler and Porter (33) reported the results of such studies in 40 children, 10 of whom were investigated by bronchospirometrlc technic. Measurements which they obtained included lung volume, maximum breathing capacity, minute ventilation, arterial oxygen saturation, carbon dioxide tension at rest and exercise, vital capacity and functional residual Capacity. Eight of the 40 children received a combined course of antituberculous and cortlcosterold therapy, 25 of the children received antituberculous chemotherapy only and 7 children received no treatment. Because no significant impairment of the ventilorespiratory function of the lungs was evident from this study, the authors questioned the rationale for adjunctive therapy, i.e., corticosteroids, in the management of tuberculous pleural effusion. Although serial determinations of vital capacity and maximum breathing capacity increased more rapidly than could be expected from growth when these were determined in the acute and con36

valescent phase of the illness, there was no difference in the sterold-treated group. Although the authors of some series conclude that resorption of pleural fluid occurs within 2-14 days after initiation of corticosteroid therapy, the question of whether or not concomitant antituberculous and corticosteroid medication should be administered to children with the hope that adhesive pleural disease may be diminished or abolished by shortening tile duration of effusion is not resolved at this time. Repeated aspiration of pleural fluid is another therapeutic approach which has been used. An evaluation of this procedure by Large and Levick (34), who performed repeated aspirations (usually on successive days) in 33 of 52 soldiers who were 17-24 years of age and who had primary tuberculous effusion, indicated that there was no significant difference in the degree of pleural opacity when this was used as a parameter of effectiveness. They did note subjective improvement in some patients--particularly when the effusion was large--after aspirating as completely as possible. SPECIFIC DIAGNOSTIC AIDS

BACTERIOLOGY Certain diseases have a tendency toward reactions of one type or another which have a narrower range of diagnostic possibilities than those findings previously mentioned. RecoveIT of an organism by culture from either pleural fluid or the pleura itself is highly specific when diagnosis of infectious disease is required. An absolute diagnosis of an effusion which is secondary to tuberculosis, for instance, is permitted only after M. tuberculosis tlas been cultured from whatever material has been submitted. Some bacteriologic problems referable to this disease have been mentioned. Documentation in the literature of recovery of pathogens in other infectious diseases is scant. This may be because of improper processing of specimens, exertion of insufficient effort or other technical or unknown reasons. A large series of 35 patients with blastomycosis was reported in 1959 (35). "Pleural reactions" were recorded in 11 of 27 patients who had pulmonary involvement. The presence of pleural effusion was confirmed in 2 pa37

+i" + + . . . . . . . .9

. " I +.+

h

0

z~ o.'~

+1~

~.

P 0

"~

..~

=~ o~o

4~

~

f

IIi +~ ~'~ 6 9

0

!~

Q

~e

.: + .

O

8 38

tients. No mention was made of bacteriologic examination of the fluid. One patient had bilateral pleural effusion and developed millary pulmonary lesions 3 days after the fluid was detected. A report of another large series of 40 patients who had blastomycosis does not include pleural effusion among the physical findings. Pleural effusions which are secondary to bacterial infection are more likely to be identified when culture is attempted from less than grossly empyemlc fluid. CYTOLOGY Cytologic examination of the sediment from centrifuged pleural fluid may be diagnostic. The primary concern is whether or not malignant cells are present. Differentiation of malignant cells from mesothelial cells--particularly if the latter are atyplcal--is sometimes difficult. Fluid which stands for a long time will cause the cells to develop atypical features. In a case of infectious mononucleosis with bilateral pleural effusion which was reported in 1954, an overwhelming predominance of lymphocytes was noted in the effusion, but the cytologic characteristics of the lymphocytes were not noted. Further investigation is neccessary to determine whether these cells contain the same changes as those in the peripheral blood in that disease. The finding of tile "L.E. cell" in a pleural effusion, according to Katz (36), is specific for the diagnosis of systemic lupus erythematosus, even though the presence of this cell in the peripheral blood is a false-positive finding in several other diseases. The Sternberg-Reed cell Ires been identified in pleural effusion which occurs in conjunction with Hodgkin's disease (see Fig. 6, A) and, likewise, the lymphosarcoma cell has been identified in lymphosarcoma (37) (see Fig. 6, B). ENZYMOLOGY Enzymologic examination of the pleural fluid has value. Numerous reports document the frequency of the pulmonary complications of pancreatitis, including pleural effusion. Most reports have not generally included the use of roentgenograms of the chest recorded in various positions in an effort to document the 39

effusion, which leaves the true incidence of pleural effusion in association with this disease in doubt. Six of 135 cases of acute pancreatitis were noted by Coffey (38) to include pleural effusion. The number of those patients whose chests were x-rayed is not mentioned. Other reports of the incidenee of pleural effusion with pancreatitis range from 2.5% to 40~b. Determination of the pleural-fluid amylase should be requested when fluid is withdrawn from the chest of any patient with pleural effusion of unknown cause--particularly if abdominal symptoms are present. Peculiar characteristics of pancreatitic effusions are predominantly left-slded involvement, although bilateral and right-sided involvement occur; high determinations of amylase activity ranging from an average of 500-2,000 units, but as high as 53,000 units; and a tendency for the pleural-fluid amylase to be higher than corresponding serum amylase and to remain elevated even after serum amylase has returned to normal. An elevation of pleural-fluid amylase may be the only clue to the diagnosis of pancreatitis after the latter has subsided. Some authors agree that the lack of amylase activity in effusions which result from diseases other than pancreatitis supports a statistically sig'nifieant relationship of an elevated amylase titer to pancreatitis. However, neoplastic seeding of the pleura by adenocarcinoma of the lung and ovary has resulted in increased titers of starch-splitting activity (39). Carcinoma of the parotid gland and colon have rarely yielded elevations of amylase activity when the tumor itself has been analyzed. The mechanism whereby pleural effusion attains such high amylase titers is disputed. The close structural relation of the body and tail of the pancreas to the left hemidiaphragm and predominance of left-sided effusion suggest a direct relationship. Extensive peripancreatic necrosis with hemorrhage and abscess formation may directly involve the diaphragm and extend to the pleural cavity but is not required for amylase to reach the pleural cavity. Previous mention of the communication between pleural and peritoneal diaphragmatic lymphatics will be recalled. The lymphatic system may suffer sufficient chemical damage so that it allows passage of enzymes which are absorbed from the peritoneal cavity. An actual fistula has not been demonstrated anatomically and, in fact, when a pancreatic pseudocyst is associated 40

with effusion, its contents may be hemorrhagic or chocolate colored, while the pleural effusion is straw colored. Passage of enzymes from blood to pleural effusion does not seem likely because of a usually greater effusion-amylase value than that of the serum; and when the amylase titer of a pseudocyst has been determined, it has been higher than that of the effusion. The titer decreases in both the effusion and blood after extirpation of the cyst. This last possibility has not been excluded, however. Determination of lactic dehydrogenase activity of pleural fluid is a useful measure and bears a definite relation to neoplastic disease. Tissue cultures of malignant cells are known to contribute lactic dehydrogenase activity to extracellular fluid. The particular value of this determination is that activity tends to be higher in effusions of malignant origin than in simultaneously analyzed serum. The level of lactic dehydrogenase activity of the serum in patients with nonmalignant pleural effusions and those with malignant tumor and pleural effusion but without known tumor cells in the effusion is greater than that of the effusion. Other extrinsic factors, i.e., previous therapy, hemolysis and the presence of other cellular components, may affect enzyme activity.

CHEMISTRY Pleural involvcment occurs with scleroderma, polyarterltis nodosa, dermatomyosltis, and systcmlc lupus erythematosus and, not infrequently, with rheumatoid arthritls--somctimes as an isolated finding in this diseasc. Effusion in rheumatoid arthritis is morc often unilateral and tends to occur in middle-aged men. This sex incidence contrasts with that of rheumatoid arthritis in gcncral. The fluid tcnds to rcsolve, although it may recur on either the same or the opposite side. The most unusual finding in pleural effusion which is secondary to rheumatoid arthritis is its low glucose concentration. Concentrations in the presence of active disease have ranged as low as 5 rag. of glucose per 100 ml. Tuberculous effusions present the greatest differential diag-aostic problem. Some authors have stated that conccntrations of pleuralfluid glucosc less than 30 mg./100 ml. should be considered diagnostic of tuberculous effusion. Pleural biopsy is less likely to be diagnostic of rheumatoid arthritis than tuberculosis. However, 41

Sf

_r-'%

~,~..~.-

"

s -4. ~-:~,'~'~

.

,~_~

~

\\

~,.,

J

f

~

~' 9

t~b. ~

'

Fio. 7.--Cholesterol crystals in pleural fluid.

42

~..~..~,.~ ~'~"~ ~",'

.~" ~ ~ " ~ r

the finding of a very low concentration of pleural-fluid glucose in the absence of bacteriologic or pathologic evidence of tuberculosis is most suggestive of rheumatoid arthritis. Resolution of an effusion has occurred not infrequently without other therapy than repeated thoracentesis. Administration of corticosteroids is more likely to benefit the symptoms related to joints than to effect resolution of pleural fuid, but decortication has been successfully used for pleural effusion. Quite infrequently, cholesterol crystals are present in pleural effusion (Fig. 7). The consensus of most authors is that most of these effusions are associated with tuberculous infection, which may be either active or inactive. Peculiarities of a cholesterolcontaining effusion are its lack of associated symptoms, its frequently unilateral, loculated occurrence in the presence of otherwise markedly thickened pleura and its prolonged course. Fifteen years may be required for the evolution of cholesterol-containing pleural effusion. The fluid itself may be clear or may contain large amounts of lipids without cholesterol crystals. The concentration of cholesterol has ranged from 145--4,500 mg./100 ml. The pathogenesis Of cholesterol-containing effusion is not known. No consistent alteration of metabolism of cholesterol--namely as reflected in the peripheral blood--is apparent, nor is there evidence for local synthesis by tissue when this has been studied by isotopic tracer technic. Metabolic alteration of breakdown products of the tubercle bacillus and release of cholesterol from degenerating white or red blood cells have been postulated, but high concentrations of cholesterol are present in nonsanguineous, nonpurulent fluids. The cholestcrol-solubilizing activity of pleural effusions varies, and some alteration of either an a- or p-solubilizing globulin may be responsible. THERAPEUTIC CONSIDERATIONS OF NEOPLASTIC DISEASE

SURGICAL Although effusions within the pleural space which are known to be associated with neoplastic disease may prompt a fatalistic attitude from the managing physician, accepted therapeutic procedures are available and are of value in selected cases. It is acknowl43

edged that therapeutic endeavors against malignant disease within the pleural space and its confines cannot change the ultimate prognosis, which remains that of the primary disease and its response to therapy. The first reported case of decortlcation for metastatic tumor was that of a patient operated on for uncontrollable effusion in 1945. Beattie (40) has noted that the disadvantages of pleural fluid are that it occupies space and may produce a tension effusion and that deposition of fibrin on the visceral pleura may produce entrapment of a lung which could necessitate decortication--particularly after fibroblasts have invaded the area. The experience he reports is that gained from approximately 50 patients subjected to partial pleurectomy. Parietal pleural implants of malignant tumor are usually present with these effusions, although pleural effusions which occur with neoplasia may also follow lymphatic obstruction by tumor or inflammatory reaction to tumor elsewhere. Patients who were considered eligible for decorticatlon were those with a lung that remained atelectatlc following aspiration of the fluid and who did not have demonstrable obstruction of the ainvay. If, during surgery, fibrinous deposits were noted to enclose the lung, standard decortieatlon was the procedure of choice. Beattie has found that neither removal of diaphragTnatic pleura nor dissection of mediastinal pleura from the pericardium is necessary, although certain cases require pericardiectomy. There was no recurrence of effusion during the follow-up period. Three operative deaths occurred. It was noted by Jensik et al. (41) that 40% of their patients with carcinoma of the breast who had "pleural pulmonary complications" died from pulmonary insufficiency. The indication which they used in the selection of 50 patients for pleurectomy with or without decortication was rapid reaccumulation of fluid in conjunction with dyspnea and the requirement of frequent thoracentesis. Decortication was performed in 15 patients and carried a higher mortality rate and shorter survival time. Recurrent effusion was encountered in 4 ~ of their cases. They state that an optimal patient should have unilateral effusion and carcinoma of the breast as the primary tumor, should require two or more aspirations of fluid per week, should show subjective improvement after thoracentesls and should not have prominent 44

extension of metastatic deposits elsewhere. Five of 18 of their patients who had primary tumor within the breast survived longer than 24 months. Using an intercostal tube and suction for several days, other surgeons have achieved obliteration of the pleural space and prevented reaccumulation of fluid. Other diseases for which decortication has been used include tuberculous effusion and empyema, hemothorax (with or without pleural calcific deposits), acute, subacute and chronic empyema and chylothorax. Haupt et al. (42) utilized talc poudrage in 19 patients who had pleural effusion associated with malignant disease and achieved relief of dyspnea and prevention of recurrence of effusion in all of them for as long as 26 months postoperatively. In this procedure, sterile talc is applied to the pleural surface, and this is followed by intercostal suction for 48-72 hours. Knowledge of the dense adhesion-forming properties of talc within the pleural space was gained from early work with dogs. CHEMICAL

The final category of useful therapeutic adjuncts for pleural effusion associated with neoplastic disease is that of the cytotoxlc agents--both chemical and radioactive. Nitrogen mustard is the most often used chemical agent. Radioactive zinc, iodine, phosphorus and gold have all been used for treatment of intracavitary malignant disease. A 30-60% response to these measures has been variously estimated. Among the early reports is that of Kent and Moses (43) who administered carrier-free I T M in weak, basic sodium sulfite solution to all but 3 of 19 patients. These last 3 patients received either Au xgs or I13X-alubumin as it became available. Reaccumulation of fluid was prevented in 8 patients, even though total cellular damage was superficial and complete nodular destruction by the relatively low-dose radiation was not evident in the pathologic specimens. Ilal-albumin persisted significantly longer within the pleural space than did carrier-free I ~at. Intrapleural nitrogen mustard is most effective when it is used against effusions which derive from either carcinoma of the breast or ovary. An advantage of nitrogen mustard over radioactive gold 45

is t h a t it does not present a r a d i a t i o n h a z a r d to the a t t e n d i n g personnel. R a d i o a c t i v e gold is fixed by the p l e u r a a n d the m e d i a s t i n u m a n d m a y p r o d u c e depression of the bone m a r r o w some 6 weeks after i n t r a p l e u r a l injection. Use of either nitrogen m u s t a r d or radioisotopes seems to p r o d u c e a b o u t the same t h e r a p e u t i c result. F o r m a t i o n of dense scar tissue accounts for obliteration of the pleural space w h e n these agents are used. REFERENCES

1. Von Hayek, H.: The Human Lung, translated by V. E. Krahl (New York: Hafner Publishing Co., Inc., 1960). 2. Simer, P. H.: Drainage of pleural lymphatics, Anat. Rec. 113:269, 1952. 3. Fawcett, D. W.: Comparative Observations on the Fine Structure of Blood Capillaries, in Orbison, J. L., and Smith, D. E. (eds.) : The Peripheral Blood Vessels (Baltimore: The Williams & Wilklns Company, 1963). 4. Casley-Smith, J. R., and Florey, H. W.: The structure of normal small lymphatics, Quart. J. Exper. Physiol. 46:101, 1961. 5. Mayerson, H . S., et al.: Regional differences in capillary permeability, Am. J. Physiol. 198: 155, 1960. 6. Stewart, P. B.: The rate of formation and lymphatic removal of fluid in pleural effusions, J. Clin. Invest. 42 : 258, 1963. 7. Mayerson, H. S.: The lymphatic system with particular reference to the kidney, Surg., Gynec. & Obst. 116 : 259, 1963. 8. Trail, R. R. : The significance of pleurisy and pleural effusion in differential diagnosis, Brit. M. J. 1:98, 1943. 9. Bernsteln, A., and White, F. Z.: Unusual findings in pleural effusion: Intrathoraeic and manometric studies, Ann. Int. Med. 37: 733, 1952. 10. Felson, B.: Fundamentals of Ghest Roentgenography (Philadelphia: W. B. Saunders Company, 1960). 11. Felson, B., et al.: Some basic principles in the diagnosis of chest diseases, Radiology 74 : 740, 1959. 12. Ungerlelder, J. T.: The diagnostic significance of pleural effusion, Dis. Chest 32:83, 1957. 13. Leuallen, E. C., and Cart, D. T.: Pleural effusion, New England J. Med. 252 : 79, 1955. 14. Paddock, F. K.: The relationship between the specific gravity and the protein content in human serous effusions, Am. J. M. Sc. 201:569, 1941. 15. Sulavik, S., and Katz, S.: Pleural l~ffusion (Springfield, Ill.: Charles C Thomas, Publisher, 1963 ). 16. MacMurray, F. G., Katz, S., and Zimmerman, M. J.: Pleural fluid eoslnophilia, New England J. Med. 243 : 330, 1950. 46

17. Curran, W. S., and Williams, A. W.: Eosinophilic pleural effusion, Arch. Int. l~fed. 111:809, 1953. 18. Chapman, J. S.: Effect of solvents on eosinophilic stimulating substance of erythrocyte stroma, Proc. Soc. Exper. Biol. & l~Ied. 108:566, 1961. 19. Luetscher, J. A., Jr.: Electrophoretic analysis of the protein of plasma and serous effusions, J. Clin. Invest. 20 : 99, 1941. 20. Taipale, E., and Hokkanen, E.: The mucoprotein levels of the ascitic and pleural fluids and their clinical significance, Acta rned. scandinav. 155:113, 1955. 21. Feldsteln, A. M., Samachson, J., and Spencer, U.: Levels of calcium, phosphorus, alkaline phosphatase and protein in effusion fluid and serum in man, Am. J. Med. 35 : 530, 1963. 22. Sutliff, W. D., Hughes, F. A., and Rice, lkl. L.: Pleural biopsy, Dis. Chest 26:551, 1954. 23. Donohoe, R. F., Katz, S., and l~fatthews, M. J.: Aspiration biopsy of the parietal pleura, Am. J. Med. 22 : 883, 1957. 24. Levlne, H., and Cugell, D.: Blunt-end needle biopsy of pleura and rib, Arch. Int. Med. 109:516, 1962. 25. Cope, C., and Bernhardt, H.: Hook-needle biopsy of pleura, pericardium, peritoneum and synovium, Am. J. Med. 35:189, 1963. 26. Donohoe, R. F., Katz, S., and l~Iatthews, 1~I. J.: Pleural biopsy as an aid in the etiologic diagnosis of pleural effusion: Review of the literature and report of 132 biopsies, Ann. Int. ikfed. 48:344, 1958. 27. l~feigs, J. V.: Pelvic tumors other than fibromas of the ovary with ascites and hydrothorax, Obst. & Gynec. 3:471, 1954. 28. Race, G. A., Scheifley, C. M., and Edwards, J. E.: Hydrothorax in congestive heart failure, Am. J. l~Ied. 22 : 83, 1957. 29. Roper, W. l~I., and Waring, J. J.: Primary serofibrinous pleural effusion in military personnel, Am. Rev. Resp. Dis. 71:616, 1955. 30. Stead, W. W., Eichenholz, A., and Stauss, H. K.: Operative and pathologic findings in twenty-four patients with syndrome of idiopathic pleurisy with effusion, presumably tuberculous, Am. Rev. Resp. Dis. 71:473, 1955. 31. Lincoln, E. M., Davies, P. A., and Bovornkitti, S.: Tuberculous pleurisy with effusion in children, Am. Rev. Resp. Dis. 77:271, 1958. 32. Gaensler, E. A., Watson, T. R., Jr., and Patton, W. E.: Bronchosplrometry; results of 1,089 examinations, J. Lab. & Clin. Med. 41:436, 1953. 33. Filler, J., and Porter, M.: Physiologic studies of the sequelae of tuberculous pleural effusion in children treated with antlmlcroblal drugs and prednlsone, Am. Rev. Resp. Dis. 88: 181, 1963. 34. Large, S. E., and Levlck, R. K.: Aspiratio~n in the treatment of primary tuberculous pleural effusion, Brit. M. J. 1 : 1512, 1958. 35. Abernathy, R. S.: Clinical manifestations of pulmonary blastomycosls, Ann. Int. Med. 51:707, 1959. 47

36. Katz, S.: Some infrequently emphasized causes of pleural effusion, GP 18:138, 1958. 37. Scheerer, P. P.: Personal communication. 38. Coffey, J. R.: Unusual features of acute pancreatic disease, Ann. Surg. 135:715, 1952. 39. Ende, N.: Studies of amylase activity in pleural effusions and ascites, Cancer 13 : 283, 1960. 40. Beattie, E. J.: The treatment of malignant pleural effusions by partial pleurectomy, S. Clin. North America 43:99, 1963. 41. Jensik, R., et al.: Pleurectomy in the treatment of pleural effusion due to metastatic malignancy, J. Thoracic & Cardiovas. Surg. 46 : 322, 1963. 42. Haupt, J. G., et al.: Treatment of malignant pleural effusions by talc poudrage, J.A.M.A. 172:918, 1960. 43. Kent, E . M., and /',foses, C.: Radioactive isotopes in the palliative management of carcinomatosls of the pleura, J. Thoracic Surg. 22:503, 1951.

48