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Tuberculous Pleural Effusion
TUBERCULOUS PLEURAL EFFUSION'*' CAPTAIN DANIEL
J. FELDMAN
AND LT. COLONEL HOWARD
P.
LEWIS
MEDICAL CORPS, ARMY OF THE UNITED STATES
THE so-called "idiopathic" pleural effusion, when it occurs in the younger age groups, has long been considered to be largely tuberculous in origin. Pleural effusion is also recognized as an early sign of malignant invasion of the pleura, as a complication of pneumonia, rheumatic fever, renal disease, cardiac failure or inflammatory disease below the diaphragm. In these latter conditions the cause of the effusion is usually apparent, but it is in that group in which the effusion is the paramount disorder that tuberculosis is dominant. Often the significance of spontaneous pleural effusion is not given the serious consideration it deserves. Figures vary as to the percentage of pleural effusions that are tuberculous, but it is generally conceded that 80 per cent or more of them have this etiology. For this reason a pleural effusion cannot be dismissed lightly when the cause is not obvious, even though the effusion may be small and transient. The frequent inability to isolate the tubercle bacillus from pleural fluid and the common failure to find visible foci of tuberculosis in the lungs by x-ray often lead the observer to believe that an effusion is not tuberculous or, if it is, that it holds minimal future significance for the patient. Numerous studies have demonstrated, however, that tubercle bacilli frequently are not recovered from the fluid of tuberculous effusions. For this reason a bacteriologically sterile fluid still carries the same import as one that is positive. Active caseous tuberculosis can exist in the lung and be directly responsible for the onset of effusion, and yet the fluid may remain sterile. These facts demonstrate the importance of following up these patients in the years after the occurrence of their initial effusion. Tuberculous pleural effusion is generally thought to occur through a number of different mechanisms. Extrapulmonary lesions with direct invasion of the pleura, such as tuberculosis of the spine with abscess of the mediastinum, or caseous tuberculosis of mediastinal lymph nodes are not often responsible, but they should always be sought for. An effusion may be the result of pleural tuberculosis or active tuberculosis of the lung in the subpleural region. Direct invasion of the pleura from the lung can result from the liquefaction of an underlying tuberculous focus, which either extends to and directly involves the pleura or ruptures through to the pleural space. From the Medical Service, Rhoads General Hospital, Utica, New York. * The antistreptolysin and cold agglutinin titers and the classification of the streptococci obtained from the throat cultures were performed by Dr. Colin MacLeod, Professor of Bacteriology, New York University College of Medicine.
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Tubercle bacilli from an active focus in the outer portion of the lung may be carried to the pleura by the lymphatic flow, which in this region moves toward the pleura and the hilum. They may also be transported to the pleura by hematogenous dissemination from a pulmonary or extrapulmonary lesion. Hematogenous spread from a distant area usually results in bilateral pleural effusion, although unilateral effusions often occur by this route. The pleural exudate is the direct result of a tuberculosis of the pleura. For this reason tubercle bacilli may be recovered from such fluids more consistently than from the types which follow. Tuberculous foci in the immediate subpleural area can provoke exudation by the phenomenon of "collateral edema" in the same manner that edema of subcutaneous tissue occurs over the region of a deepseated infection. In this instance the pleura reacts with an inflammatory exudate which ordinarily is sterile to all bacteriological study, since no local tuberculosis of the pleura exists. Allergic sensitivity of the pleural membranes to the tuberculoprotein undoubtedly plays an important role in certain individuals who have become sensitized to it as a result of prior infection. How much this phenomenon contributes to the reaction observed in the various modes of infection is not entirely known, but there is little doubt of its influence and importance. Most tuberculous effusions are thought to be associated with the post-primary stage of the disease and, therefore, are important warnings of the presence of active tuberculosis in the lungs or in the extrapulmonary tissues. The focus responsible for the pleural reaction may lie in the lung, in caseous mediastinal nodes or in regions remote from the thorax. Extrapulmonary sources of infection, from whence spread can be accomplished by hematogenous or lymphatic routes, must always be looked for when pulmonary disease is not obviously apparent. Lesions in the lung which provoke pleural effusion are usually . exudative or caseous and are seldom productive. Consequently, the effusion has a grave significance as concerns the future prospect for active parenchymal disease. We became interested in this subject when we observed the relatively high proportion of pleural effusions in troops who were returned to this country because of medical diseases of the chest. If these cases were all tuberculous, the incidence of pleural tuberculosis in relation to the total number of tuberculous patients was inordinately high. This finding caused us to wonder if some other cause might be responsible. The severe pleural thickening and fibrosis, as well as the chronic nature of many of these cases, seemed to contradict previous experience. Subsequent observation impressed us with the importance of this condition as a cause of prolonged disability and prompted us to investigate the cases that reached this hospital to determine whether they were tuberculous or whether other factors such as streptococcal disease, virus infections of the lungs or simple pneumonias might be
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responsible. The study was encouraged and the protocol for the scheme of investigation was worked out by Col. Hermann L. Blumgart, at that time the Consultant in Medicine for the Second Service Command. METHODS OF STUDY
In the investigation of these cases, the following selected procedures were carried out: 1. Patients were given careful historical and physical appraisals with searching, continuous clinical observation. 2. The sputum was examined for tubercle bacilli by smears, cultures and guinea pig inoculations. 3. The fasting gastric content was examined for tubercle bacilli. 4. A thorough examination of all obtainable pleural fluid was made by the usual methods, including culture and guinea pig inoculation. S. Serial x-ray examinations of the chest were given during the period of observation. 6. There were weekly estimations of the sedimentation rate by the Wintrobe-Landsberg method. Normal values for males are 2 to 9 mm. in one hour and for females, 2 to 20 mm. in one hour. 7. Antistreptolysin titers were determined serially in a selected group. S. The cold agglutinin titer in the blood was determined in a selected number of cases. 9. Throat cultures were taken to ascertain the possible correlation between the pathogens so obtained and the pleural pathology. 10. Tuberculin tests were made on all patients. CLINICAL OBSERVATIONS
Fifty-nine patients with pleural effusion, admitted to this hospital between November 1943 and July 1945, were included in the group. The great majority of the patients had served in the European Theater, but cases were received from the Pacific and the continental United States. Many of the patients arrived in the resolving stage of the disease with only residual pleural exudate or pleural thickening of variable intensity. The results of pleural fluid studies, clinical findings and laboratory and x-ray examinations were available in the overseas records accompanying almost all the patients. A considerable number of acute cases in troops stationed nearby were also available for study. All the male patients were kept in one ward, whose personnel were specially trained in their duties. The clinical observation, all of which was carried out by the authors, was extremely minute and continuous. Fifty-six of the patients were males and three were females. The ages varied from 20 to 47 years, but only five of the entire group were over 30 years of age. In thirty-nine patients the effusion was right-sidep. in eighteen left-sided and in two bilateral. The presence
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of fluid in the pleural space was ascertained by characteristic x-ray findings and thoracentesis in all patients. No fluid could be obtained from two patients because they were seen late in the course of the disease, but the x-ray and physical findings were so characteristic that they were included in the series. Twenty-one of the patients had pleural fluid present at the time of their hospitalization at Rhoads General Hospital. Symptoms.-The illness began in three rather characteristic ways. For thirty-four of the patients the onset was insidious, with mild prodromal complaints. For sixteen of the patients the onset was acute and followed a period of prodromal symptoms over various periods of time. Nine of the patients had acute fulminating onsets with no significant prodromal symptoms. The first group exhibited a slow, progressive onset with general malaise, chronic cough, easy fatigability, the subjective sensation of fever and weight loss. After a period of time ranging from several weeks to months, dyspnea and pleuritic chest pain were generally noted, and eventually hospitalization resulted. In the second group, the onset of symptoms was similar to that described above but instead of a slow progression of complaints, a sudden increase in the severity of symptoms occurred accompanied by marked malaise,' chilliness or chills, chest pain, cough, fever and considerable dyspnea. In the last group the onset was abrupt and severe with chills, high fever, marked malaise or prostration, cough and chest pain. Dyspnea usually ensued after several days of illness. The general appearance was that of a severe, acute, pulmonary infection. Fever was noted in all cases. The height varied roughly with the severity, rising to as high as 105° F. in the more acute types. The febrile curve was irregular and variations of 3° to 4° within twentyfour hours were not uncommon. The high fevers would gradually drop over a period of seven to ten days in most instances, but a lowgrade fever, particularly in the afternoon, would persist for weeks or months. After the temperature became normal, an afternoon rise was often observed if the patient became too active. In the patients whose onset was insidious, high fevers were not frequent, but a low-grade, irregular fever with a pronounced tendency toward afternoon elevation was observed. The general appearance of the patients at the time of their admission to a hospital varied. Those in whom the onset was sudden and severe, were acutely ill. The clinical picture resembled an acute pneumonia, and an early diagnosis of atypical or lobar pneumonia was often made. Physical examination at that time frequently suggested consolidation in the involved side. The effusions were very often minimal at this time and x-ray studies did not clearly demonstrate their presence. Although in many instances it was recognized that pleural fluid probably existed, there was uncertainty as to whether or not. an under-
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lying consolidation was present as the primary cause of the illness. Penicillin and sulfonamide therapy was often instituted without benefit. Within a week of their admission most patients had developed a characteristic massive pleural effusion. Marked dyspnea was outstanding at this time. It was often necessary to remove fluid frequently in order to relieve respiratory embarrassment. During the period of high fever and acute illness the fluid tended to reaccumulate rapidly. In a few of the acute cases transient, mild splenomegaly was found during the active stage. One patient exhibited transient generalized lymphadenopathy as well. In those patients whose onset was insidious, the clinical features were far less striking. The appearance was that of chronically ill patients. Unequivocal signs of pleural effusion were usually present at the time of admission. Dyspnea at rest and respiratory embarrassment were far less common than in the acute group, even when a large pleural effusion was present. This was undoubtedly due to the slow accumulation of the fluid which allowed adequate time for compensatory shifting of the mediastinum and emphysema of the unaffected lung tissue. With prolonged bed rest and supportive therapy the acute symptoms disappeared and were replaced by complaints of easy fatigability, exertional dyspnea and failure to regain lost weight. These symptoms closely paralleled the period during which a low-grade fever was present, and were definitely increased with any activity. The last symptom to disappear was the easy fatigability, and this showed a great tendency to recur with any more than the mildest activity even months after the acute phase had ended. Chest pain on deep breathing, coughing or sudden movement persisted for excessively long periods of time. In two cases with insidious onset, the patients developed fresh plcural effusions on the opposite side after the original ones had been absorbed. In both of these patients there was x-ray evidence of hilar enlargement and suggestive parenchymal infiltration. In seven cases the effusion reappeared on the same side after clinical and x-ray study had indicated complete absorption of the exudate and its replacement by thickened pleura. \Vith these recurrences there was a resurgence of symptoms, and the entire picture as described above repeated itself. In onc patient a massive ascites developed after a pleural effusion had disappeared, leaving a thickened pleura of significant degree. The abdominal fluid revealed tubercle bacilli on culture. In another patient a subpectoral eold abscess appeared and pointed just to the right of the sternum after a left pleural effusion had been completely absorbed. Evidence by x-ray of marked mediastinal widening appeared in this case as the effusion disappeared. Material aspirated from the abscess had the characteristics of tuberculous pus, but it was sterile to smear and culture. Early follow-ups have determined that at least two of the patients who were discharged from the service after prolonged hospitalization had recurrences of pleural effusion. In both instances a moderate amount of residual thickening of the pleura was present at the time of discharge, but laboratory and clinical studies failed to reveal any signs of activity.
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LABORATORY OBSERVATIONS
Blood counts on the patients studied at this hospital were within normal limits. Total and differential counts failed to reveal any constant variation, regardless of the phase of the illness. Occasionally a slight or moderate leukocytosis, with a normal differential count, was present very early in the disease, but this was transitory and not correlated with the clinical course. Serial blood counts during the convalescent phase of the illness were normal. No information of the activity of the disease was obtained by blood count studies. The sedimentation rate was significantly elevated in fifty-five patients. In three the rate was normal upon arrival at this hospital, and no record of the test having been performed previously was available. Two patients had normal rates throughout. One of these two patients had a recurrence of the effusion on the opposite side, the other had tubercle bacilli in the gastric content and subsequently developed a parenchymal infiltrate. The most marked elevations in the sedimentation rate were seen early in the disease, and the rise tended to persist in varying degrees for long periods of time, closely paralleling the clinical course regardless of its severity. Frequently, abnormal sedimentation rates persisted after all symptoms had disappeared and the exudate had been completely absorbed. This was most marked in those patients who exhibited persistent pleural thickening. Upon resumption of mild activity, an elevation of the sedimentation rate often reappeared and warned of the recurrence of clinical symptoms. A rising rate seemed to indicate an exacerbation of the activity of the disease. Skin tests with purified protein derivative (PPD) injected intracutaneously were performed in fifty-seven patients, fifty-six of whom showed positive reactions to either the 0.00002 mg. or 0.005 mg. dose. Two of the patients with positive reactions had negative reactions prior to the onset of their pleural effusion. No clinical correlation was noted between the degree of sensitivity to purified protein derivative and the severity of the disease. Throat cultures were made in thirty-six cases to determine the possible relation between the organism so obtained and the primary disease. The organisms obtained varied considerably. A great majority were green-producing streptococci, and in some cases hemolytic streptococci were recovered. No significant correlation of these findings to the clinical condition was observed. The titer of cold agglutinins was determined in twenty-three patients. Whenever possible blood specimens were, obtained early in the onset of disease, and subsequent check examinations were made at intervals. No significant increase in titer was noted either at the onset or during the course of the illness in any patient. No important change in titer was seen in those cases in whom serial examinations were made. Antistreptolysin titers of the blood were obtained in twenty-three
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cases. Titers were determined in some of the pleural fluids and these were found to be essentially the same as those in the blood. Serial determinations were done in those cases seen at the onset, in those in whom severe exacerbations had occurred and in patients in a relatively stable phase of the disease. No persistent elevations of the antistreptolysin titer were found. A few relatively high figures appeared in isolated specimens, but subsequent samples from the same patient showed normal levels after short intervals. Such incidental high values, therefore, were not considered significant. Pleural fluid studies were performed in fifty-seven cases. The greater number of these fluids were originally studied overseas prior to the return of the patient to the United States. We examined the pleural .fluid of twenty-one patients. In general the fluids were pale yellow to amber in color and were relatively clear or moderately hazy. No markedly cloudy, purulent or grossly bloody fluids were encountered. Specific gravities were all over 1.015. The protein levels varied between 3.5 and 6 mg. per 100 cc. with albumin-globulin ratios similar to that in the blood. The fluid in a number of cases showed a marked tendency toward spontaneous coagulation in the test tube shortly after it had been withdrawn. This phenomenon generally appeared after the effusion had been present for several weeks or more, but in some instances it was observed within the first week. Large, stringy fibrin precipitates without complete coagulation were also seen, usually presaging the complete coagulation of later samples. Because of this difficulty, samples of pleural fluid for cytological examination are now collected in a tube containing potassium oxalate. Cell counts of the pleural fluid varied considerably, the total counts ranging from 100 to 2000-3000. Differential study showed a great preponderance of the lymphocyte series, 80 to 100 per cent of the cells falling in this group. In only six patients polymorphonuclear leukocytes made up 40 to 50 per cent or more of the total cell count in the pleural fluid initially, but later preponderant lymphocytosis appeared. No relationship between the total or differential cell counts and the presence of tubercle bacilli in the fluid was noted. Cultures and smears of the fluid for pyogenic organisms were negative in all instances. Smears of the centrifuged sediment failed to reveal tubercle bacilli in all cases. Repeated culture of the centrifugate of large amounts of fluid on Petragnani's medium and inoculation of the same into several guinea pigs was done whenever possible. Where onl~' a small amount of fluid could be obtained, the entire amount was cultured and injected into guinea pigs. Cultures were observed for eight weeks before they were considered negative. Guinea pigs were tuberculin tested prior to their use and were sacrificed after at least eight weeks. Such procedures were carried out repeatedly in the same patient when multiple aspirations were done. Not infrequently only one fluid specimen would be found positive by one of these methods
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out of several specimens from the same patient. Of the twenty-one caSes so studied five, or 23 per cent, were positive for tubercle bacilli. In three patients the organism was isolated both by culture and in the guinea pig, in one by culture only and in another by guinea pig inoculation. A personal communication received from a military general laboratory in the European Theater of Operations, from an area where most of our patients had been evacuated, indicated that less than 25 per cent of the pleural fluids examined by guinea pig inoculation revealed the presence of tubercle bacilli. Sputum examinations for tubercle bacilli were done on all of the patients. Earlier in the investigation these were twenty-four hour concentrates which were examined by direct smear. The results were so uniformly negative that a more intensive search was made in the cases studied later. In these the seventy-two hour pooled sputum was examined by smear, culture and guinea pig inoculation'. One positive sputum was found in the entire group and this was positive by culture. Gastric secretion secured from fasting stomachs was collected for three days and studied similarly. Four patients were found to have tubercle bacilli in their gastric contents. In the positive cases the organisms were found either by culture or in the guinea pigs. In one of the four the smear was positive as well. ' ROENTGENOLOGIC OBSERVATIONS
Chest roentgenograms of each patient were taken serially throughout the period of observation. Aside from the characteristic findings of pleural effusion, the changes preceding and following the acute phase were of the greatest interest. A notable thickening of the pleural membranes was observed in nearly all cases in which the fluid had not been evacuated and was allowed to absorb. When air had been introduced and the effusion was not subsequently removed, chronic localized areas of hydropneumothorax persisted, often for months. The initial pleural thickening, often as much as 4 cm. in thickness, had an appearance similar to that of a fibrinous coagulum. Extraordinarily slow absorption of these plaques took place and it is of interest to note that in many of these patients the sedimentation rate remained elevated during most of the time required for their organization. Those patients whose fluid, when aspirated, developed a coagulum or a firm clot exhibited a high incidence of what was apparently a sudden and spontaneous clotting of the whole fluid mass in the pleural space. In several this solid mass extended from the topmost portion of the apex to the base and varied from 2 cm. to as much as 4 cm. in thickness. Organization and absorption of these coagulums was exceedingly slow and almost always resulted in a fibroth6rax. In fifty-two of the cases studied there was x-ray evidence of pleural thickening to a significant degree. Complete, uncomplicated resolution occurred in only, five of these patients during the period of our observation.
Fig. 39 (Case I).-Illustrates massive coagulation of pleural effusion. Three hundred cc. of fluid were secured after numerous thoracic punctures. The fluid removed coagulated spontaneously.
Fig. 40 (Case I) .-Chronic pleural change still remaining three months later. Patient underwent acute febrile relapse one month prior. No fluid obtainable at this time. 253
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The great majority of the films showed no evidence of parenchymal disease. Seven of the patients exhibited exudative parenchymal lesions by x-ray which varied in size from about 0.5 cm. to areas occupying about one-fifth of the involved lobe. They varied from small, flocculent, ill-defined shadows to dense-appeariqg, well-established parenchymal lesions. No relationship was noted between the lung containing the parenchymal lesion and the side 011 which the pleural effusion developed. In six of these cases the lesions were found in the upper third of the lung field, and in one the disease was basilar. In four cases the parenchymal infiltrate was present for some time before the de-
•
Fig. 41 (Case II).-Parenchymal infiltrate, left second and third inters paces allteriorly. First noted three and one-half months after onset of left pleural effusion. No clinical symptoms at this time.
velopment of the effusion. In one case it appeared during the existence of the effusion and in two was first noted after the effusion had been absorbed and the lung had been clear by x-ray for several months. Only two of the patients studied had discernible calcified areas. Tubercle bacilli were isolated in five of these patients from the sputum or gastric contents and in one from the pleural fluid. The diagnosis of atypical pneumonia had been made in most of the patients in whom a significant parenchymal infiltration preceded the development of the effusion. In many others the hazy density at the base, combined with the mild atelectatic changes in the adjacent lung and the common hilar swelling on the affected side were thought to
Fig. 42 (Case III).-Early left pleural effusion with associated infiltrates in upper and lower portions of left lung and accompanying left hilar enlargement. A diagnosis of atypical pneumonia was made at this time.
Fig. 43 (Case Ill).-Three and one-half months later. Residual changes from left pleural effusion. No fluid obtainable. Patient asymptomatic. Note changes in hilum and upper portion of left lung. . 255
Fig. 44 (Case IiI) .-Relapse with high fever, hemoptysis and severe systemic manifestations fifteen days later. Note paramediastinal collection associated with a new right-sided effusion. Tubercle bacilli cultured from gastric secretion at this time. Pleural fluid sterile.
Fig. 45 (Case Ill) .-Residual changes, both lungs, one month later. Patient asymptomatic. Sedimentation rate high. 256
Fig. 46 (Case IV).-Marked hilar swelling associated with pneumOnItiS, left lower chest and early pleural effusion, right. Admission diagnosis, atypical pneumonia.
Fig. 47 (Case IV).-One month later. Right pleural effusion. Patient acutely ill and febrile at this time. Tubercle bacilli recovered from pleural fluid by culture at this time. 257
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be due to pneumonia. The subsequent effusion was often believed to be a postpneumonic exudate. In a number of patients the early clinical picture and roentgenologic findings were not incompatible with those seen in primary atypical pneumonia, and it is easy to understand why such a diagnosis would seem tenable. Enlargement of the hilar lymph nodes was seen frequently. This enlargement was usually present in the early phases of the disease and was often transitory, persisting for a period of several weeks and then gradually disappearing. In a small number of cases the hilar enlarge-
Fig. 48 (Case IV) .-One month later. Residual changes of right pleural effusion. Small amount of pleural fluid obtainable. Gastric contents positive for tubercle bacilli by culture, and pleural fluid positive by guinea pig inoculation. Between figures 47 and 48, 2400 cc. of fluid removed. Note persistence of lesions in left lung and hilum.
ment was marked and was accompanied by perihilar edema. The latter finding was much more persistent and was seen principally in those patients in whom parenchymal lesions were found by x-ray. In the films of those patients in whom parenchymal disease was noted prior to the development of fluid, the hilar component was striking and was greater on the side affected. PLAN OF TREATMENT
The treatment of these cases was carried out according to the principles laid down by TB MED 71 of the Medical Department, United
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States Army. In the acute cases a sufficient amount of fluid was withdrawn (300 cc.) for diagnosis at necessary intervals. The effusion was not otherwise disturbed unless pressure effects required withdrawal of some of the exudate. The effusion was given the opportunity to absorb, but if after eight weeks it failed to exhibit any significant tendency to do so, it was then evacuated as completely as possible. No air replacement was employed, but in a few instances a small amount of air was introduced in order to facilitate the study of the character of the underlying pulmonary tissue. We have been impressed by the fact that, even with this relatively short delay in the evacuation of the fluid, in many instances chronic thickening of the pleural membranes or spontaneous coagulation of the whole exudate took place in that length of time. COMMENT
The results of this study substantiate the opinion that pleural effusion which occurs in younger persons, in whom no other readily determinable .cause for it exists, can be considered tuberculous until clear proof to the contrary is found. While it is true that only a small part of our total patients were proved to have tuberculosis by recovery of the organism, nevertheless the marked similarity of all these cases has convinced us that all were tuberculous. The prolonged and intimate observation which we were able to give each patient made it possible to eliminate many uncertainties in diagnosis. Tuberculous pleural effusion is in every way as important a manifestation of active tuberculous disease as visible tuberculosis of the lungs or other organs. It carries with it the same implications as to future spread and disability as does active tuberculosis anywhere in the body. Tuberculous pleural effusion demands the same care as active parenchymal disease, for active pulmonary tuberculosis may be the undedying cause of the effusion and may make its appearance at some future date after the effusion has resolved. The incidence of frank pulmonary tuberculosis following pleural effusion is high, the figures of various authors ranging from 17 to 50 per cent. The first five years, and particularly the first year, following the development of a pleural exudate are important in respect to the subsequent appearance of active tuberculosis. The manner of onset of this disease can justifiably give rise to the belief that it is a condition resulting from pulmonary lesions other than tuberculosis. The presence of an obvious inflammatory change in the lungs prior to the development of the effusion does not establish a nontuberculous etiology, as we have demonstrated. In our patients the determination of the antistreptolysin and the cold agglutinin titers and the negative bacteriological studies for pyogenic organisms in the fluids would seem to eliminate to a large extent any cause other than tuberculosis. All our patients who exhibited a pulmonary infil-
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trate, either prior to or coincident with the effusion, had considerable enlargement of the hilar lymph nodes. Hilar enlargement is not ordinarily a feature of the various specific and nonspecific types of pneumonitis, and this finding is a valuable one in suggesting a tuberculous etiology. The hilar enlargements seen in this region have not appeared to be malignant. The sedimentation rate was valuable in determining the activity of the disease. It frequently suggested the presence of an active lesion in a patient who, by clinical appraisal, would be adjudged to have an inactive lesion. This has always been useful in judging the patient's response to physical activity. In a number of patients a rise in the sedimentation rate was the first warning of reactivation of the process. An increase in the sedimentation rate has been observed in patients who have been convalescent and completely free of symptoms for as long as two or three months. Laboratory examination must be intensive and repeated if the maximum number of positive results are to be obtained. In our experience the examination of the three-day gastric specimens was the most satisfactory method for securing tubercle bacilli. Direct smear examination, culture on appropriate media and guinea pig inoculation should be performed on the pleural fluid, the pooled seventy-two hour sputum and the gastric secretions in all cases. Reliance on anyone test has been shown to be unreliable. The enormous thickening of the pleura seen in many of the patients has been unusual. The fibrin content of a number of the fluids has been high. Instances of spontaneous coagulation of the whole exudate with the formation of a solid, "jelled" mass extending from apex to base was most common when this phenomenon was observed. Numerous patients also developed thick coatings of what were interpreted to be fibrinous deposits on the pleural surfaces. These changes were by far most common in old cases in which the fluid was not evacuated. Fibrothorax with the subsequent development of diaphragmatic fixation and probable fibrosis of the underlying lung usually resulted. This group, as gauged by the sedimentation rate and the clinical response, exhibited an abnormally long period of activity of the disease. There is a considerable difference of opinion as to the proper treatment of a tuberculous pleural effusion. There are those who advocate that only the fluid necessary for diagnosis be withdrawn and that the patient be permitted to absorb the remainder. Others believe that if absorption of the fluid does not occur within a reasonable time, all fluid should be evacuated in order to prevent severe fibrosis of the pleura and consequent injury to the underlying lung. Still another group holds the opinion that the fluid should be evacuated as soon as the acute febrile phase and the period of rapid reaccumulation has ended. According to this group the fluid should be completely withdrawn and replaced by an equal or nearly equal volume of air in
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order to maintain a pneumothorax and to splint the mediastinum. Any reaccumulation of the fluid is removed. It4' is clear that any patient with an underlying active pulmonary . tuberculosis, whose effusion is allowed to resolve of its own accord, is exposed to the serious risk of adherence of the pleural surfaces, making the future employment of artificial pneumothorax impossible . . This leaves available to the patient only the formidable procedures of thoracoplasty or extrapleural pneumolysis in case an advancing, uncontrollable parenchymal lesion appears. Failure to evacuate an effusion of any considerable size tends also to prolong inordinately the patient's convalescence. It would seem advisable, in view of the foregoing, that after the febrile period has passed and reasonable stability in the effusion has occurred, which is ordinarily a period of two to three weeks, the fluid should be evacuated completely in successive stages if necessary, depending upon the size of the effusion. By this procedure the coagulation of large effusions can be prevented and the marked fibrinous deposits on the pleural surface can be avoided. Since the complete removal of fluid results in approximation of the pleural surfaces and thereby fosters their adherence, it would seem desirable that a pneumothorax of at least 200 to 300 cc. be induced initially. Adequate x-ray observation of the underlying lung may then be made and, if necessary,collapse therapy may be continued. If proper aseptic technic is employed in all thoracic punctures, there is no reason to anticipate complication by secondary infection or undue changes from the introduction of air into the pleural space. REFERENCES
1. 2. . 3. 4. 5.
Ornstein, G. G. and Ulmar, D.: Quart. Bull. Seaview Hosp., 4:269, 1939. Schl,lman, c.: Quart. Bull. Seaview Hosp., 7:69, 1941 . Pagel, W.: Tubercle, April, 1943, p. 68. TB MED 71, Medical Deparmlent, U. S. Army, July, 1944. Miller, O. O. in Goldberg: Clinical Tuberculosis, Vol. 11, 4th ed~ Philadelphia; F. H. Davis Co., 1944. 6. Norris, G. W. and Landis, H. R. M.: Diseases of the Chest and the Principles of Physical Diagnosis. Philadelphia, W. B. Saunders Co., 1938.
J. FELDMAN
AND LT. COLONEL HOWARD
P.
LEWIS
MEDICAL CORPS, ARMY OF THE UNITED STATES
THE so-called "idiopathic" pleural effusion, when it occurs in the younger age groups, has long been considered to be largely tuberculous in origin. Pleural effusion is also recognized as an early sign of malignant invasion of the pleura, as a complication of pneumonia, rheumatic fever, renal disease, cardiac failure or inflammatory disease below the diaphragm. In these latter conditions the cause of the effusion is usually apparent, but it is in that group in which the effusion is the paramount disorder that tuberculosis is dominant. Often the significance of spontaneous pleural effusion is not given the serious consideration it deserves. Figures vary as to the percentage of pleural effusions that are tuberculous, but it is generally conceded that 80 per cent or more of them have this etiology. For this reason a pleural effusion cannot be dismissed lightly when the cause is not obvious, even though the effusion may be small and transient. The frequent inability to isolate the tubercle bacillus from pleural fluid and the common failure to find visible foci of tuberculosis in the lungs by x-ray often lead the observer to believe that an effusion is not tuberculous or, if it is, that it holds minimal future significance for the patient. Numerous studies have demonstrated, however, that tubercle bacilli frequently are not recovered from the fluid of tuberculous effusions. For this reason a bacteriologically sterile fluid still carries the same import as one that is positive. Active caseous tuberculosis can exist in the lung and be directly responsible for the onset of effusion, and yet the fluid may remain sterile. These facts demonstrate the importance of following up these patients in the years after the occurrence of their initial effusion. Tuberculous pleural effusion is generally thought to occur through a number of different mechanisms. Extrapulmonary lesions with direct invasion of the pleura, such as tuberculosis of the spine with abscess of the mediastinum, or caseous tuberculosis of mediastinal lymph nodes are not often responsible, but they should always be sought for. An effusion may be the result of pleural tuberculosis or active tuberculosis of the lung in the subpleural region. Direct invasion of the pleura from the lung can result from the liquefaction of an underlying tuberculous focus, which either extends to and directly involves the pleura or ruptures through to the pleural space. From the Medical Service, Rhoads General Hospital, Utica, New York. * The antistreptolysin and cold agglutinin titers and the classification of the streptococci obtained from the throat cultures were performed by Dr. Colin MacLeod, Professor of Bacteriology, New York University College of Medicine.
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Tubercle bacilli from an active focus in the outer portion of the lung may be carried to the pleura by the lymphatic flow, which in this region moves toward the pleura and the hilum. They may also be transported to the pleura by hematogenous dissemination from a pulmonary or extrapulmonary lesion. Hematogenous spread from a distant area usually results in bilateral pleural effusion, although unilateral effusions often occur by this route. The pleural exudate is the direct result of a tuberculosis of the pleura. For this reason tubercle bacilli may be recovered from such fluids more consistently than from the types which follow. Tuberculous foci in the immediate subpleural area can provoke exudation by the phenomenon of "collateral edema" in the same manner that edema of subcutaneous tissue occurs over the region of a deepseated infection. In this instance the pleura reacts with an inflammatory exudate which ordinarily is sterile to all bacteriological study, since no local tuberculosis of the pleura exists. Allergic sensitivity of the pleural membranes to the tuberculoprotein undoubtedly plays an important role in certain individuals who have become sensitized to it as a result of prior infection. How much this phenomenon contributes to the reaction observed in the various modes of infection is not entirely known, but there is little doubt of its influence and importance. Most tuberculous effusions are thought to be associated with the post-primary stage of the disease and, therefore, are important warnings of the presence of active tuberculosis in the lungs or in the extrapulmonary tissues. The focus responsible for the pleural reaction may lie in the lung, in caseous mediastinal nodes or in regions remote from the thorax. Extrapulmonary sources of infection, from whence spread can be accomplished by hematogenous or lymphatic routes, must always be looked for when pulmonary disease is not obviously apparent. Lesions in the lung which provoke pleural effusion are usually . exudative or caseous and are seldom productive. Consequently, the effusion has a grave significance as concerns the future prospect for active parenchymal disease. We became interested in this subject when we observed the relatively high proportion of pleural effusions in troops who were returned to this country because of medical diseases of the chest. If these cases were all tuberculous, the incidence of pleural tuberculosis in relation to the total number of tuberculous patients was inordinately high. This finding caused us to wonder if some other cause might be responsible. The severe pleural thickening and fibrosis, as well as the chronic nature of many of these cases, seemed to contradict previous experience. Subsequent observation impressed us with the importance of this condition as a cause of prolonged disability and prompted us to investigate the cases that reached this hospital to determine whether they were tuberculous or whether other factors such as streptococcal disease, virus infections of the lungs or simple pneumonias might be
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responsible. The study was encouraged and the protocol for the scheme of investigation was worked out by Col. Hermann L. Blumgart, at that time the Consultant in Medicine for the Second Service Command. METHODS OF STUDY
In the investigation of these cases, the following selected procedures were carried out: 1. Patients were given careful historical and physical appraisals with searching, continuous clinical observation. 2. The sputum was examined for tubercle bacilli by smears, cultures and guinea pig inoculations. 3. The fasting gastric content was examined for tubercle bacilli. 4. A thorough examination of all obtainable pleural fluid was made by the usual methods, including culture and guinea pig inoculation. S. Serial x-ray examinations of the chest were given during the period of observation. 6. There were weekly estimations of the sedimentation rate by the Wintrobe-Landsberg method. Normal values for males are 2 to 9 mm. in one hour and for females, 2 to 20 mm. in one hour. 7. Antistreptolysin titers were determined serially in a selected group. S. The cold agglutinin titer in the blood was determined in a selected number of cases. 9. Throat cultures were taken to ascertain the possible correlation between the pathogens so obtained and the pleural pathology. 10. Tuberculin tests were made on all patients. CLINICAL OBSERVATIONS
Fifty-nine patients with pleural effusion, admitted to this hospital between November 1943 and July 1945, were included in the group. The great majority of the patients had served in the European Theater, but cases were received from the Pacific and the continental United States. Many of the patients arrived in the resolving stage of the disease with only residual pleural exudate or pleural thickening of variable intensity. The results of pleural fluid studies, clinical findings and laboratory and x-ray examinations were available in the overseas records accompanying almost all the patients. A considerable number of acute cases in troops stationed nearby were also available for study. All the male patients were kept in one ward, whose personnel were specially trained in their duties. The clinical observation, all of which was carried out by the authors, was extremely minute and continuous. Fifty-six of the patients were males and three were females. The ages varied from 20 to 47 years, but only five of the entire group were over 30 years of age. In thirty-nine patients the effusion was right-sidep. in eighteen left-sided and in two bilateral. The presence
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of fluid in the pleural space was ascertained by characteristic x-ray findings and thoracentesis in all patients. No fluid could be obtained from two patients because they were seen late in the course of the disease, but the x-ray and physical findings were so characteristic that they were included in the series. Twenty-one of the patients had pleural fluid present at the time of their hospitalization at Rhoads General Hospital. Symptoms.-The illness began in three rather characteristic ways. For thirty-four of the patients the onset was insidious, with mild prodromal complaints. For sixteen of the patients the onset was acute and followed a period of prodromal symptoms over various periods of time. Nine of the patients had acute fulminating onsets with no significant prodromal symptoms. The first group exhibited a slow, progressive onset with general malaise, chronic cough, easy fatigability, the subjective sensation of fever and weight loss. After a period of time ranging from several weeks to months, dyspnea and pleuritic chest pain were generally noted, and eventually hospitalization resulted. In the second group, the onset of symptoms was similar to that described above but instead of a slow progression of complaints, a sudden increase in the severity of symptoms occurred accompanied by marked malaise,' chilliness or chills, chest pain, cough, fever and considerable dyspnea. In the last group the onset was abrupt and severe with chills, high fever, marked malaise or prostration, cough and chest pain. Dyspnea usually ensued after several days of illness. The general appearance was that of a severe, acute, pulmonary infection. Fever was noted in all cases. The height varied roughly with the severity, rising to as high as 105° F. in the more acute types. The febrile curve was irregular and variations of 3° to 4° within twentyfour hours were not uncommon. The high fevers would gradually drop over a period of seven to ten days in most instances, but a lowgrade fever, particularly in the afternoon, would persist for weeks or months. After the temperature became normal, an afternoon rise was often observed if the patient became too active. In the patients whose onset was insidious, high fevers were not frequent, but a low-grade, irregular fever with a pronounced tendency toward afternoon elevation was observed. The general appearance of the patients at the time of their admission to a hospital varied. Those in whom the onset was sudden and severe, were acutely ill. The clinical picture resembled an acute pneumonia, and an early diagnosis of atypical or lobar pneumonia was often made. Physical examination at that time frequently suggested consolidation in the involved side. The effusions were very often minimal at this time and x-ray studies did not clearly demonstrate their presence. Although in many instances it was recognized that pleural fluid probably existed, there was uncertainty as to whether or not. an under-
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lying consolidation was present as the primary cause of the illness. Penicillin and sulfonamide therapy was often instituted without benefit. Within a week of their admission most patients had developed a characteristic massive pleural effusion. Marked dyspnea was outstanding at this time. It was often necessary to remove fluid frequently in order to relieve respiratory embarrassment. During the period of high fever and acute illness the fluid tended to reaccumulate rapidly. In a few of the acute cases transient, mild splenomegaly was found during the active stage. One patient exhibited transient generalized lymphadenopathy as well. In those patients whose onset was insidious, the clinical features were far less striking. The appearance was that of chronically ill patients. Unequivocal signs of pleural effusion were usually present at the time of admission. Dyspnea at rest and respiratory embarrassment were far less common than in the acute group, even when a large pleural effusion was present. This was undoubtedly due to the slow accumulation of the fluid which allowed adequate time for compensatory shifting of the mediastinum and emphysema of the unaffected lung tissue. With prolonged bed rest and supportive therapy the acute symptoms disappeared and were replaced by complaints of easy fatigability, exertional dyspnea and failure to regain lost weight. These symptoms closely paralleled the period during which a low-grade fever was present, and were definitely increased with any activity. The last symptom to disappear was the easy fatigability, and this showed a great tendency to recur with any more than the mildest activity even months after the acute phase had ended. Chest pain on deep breathing, coughing or sudden movement persisted for excessively long periods of time. In two cases with insidious onset, the patients developed fresh plcural effusions on the opposite side after the original ones had been absorbed. In both of these patients there was x-ray evidence of hilar enlargement and suggestive parenchymal infiltration. In seven cases the effusion reappeared on the same side after clinical and x-ray study had indicated complete absorption of the exudate and its replacement by thickened pleura. \Vith these recurrences there was a resurgence of symptoms, and the entire picture as described above repeated itself. In onc patient a massive ascites developed after a pleural effusion had disappeared, leaving a thickened pleura of significant degree. The abdominal fluid revealed tubercle bacilli on culture. In another patient a subpectoral eold abscess appeared and pointed just to the right of the sternum after a left pleural effusion had been completely absorbed. Evidence by x-ray of marked mediastinal widening appeared in this case as the effusion disappeared. Material aspirated from the abscess had the characteristics of tuberculous pus, but it was sterile to smear and culture. Early follow-ups have determined that at least two of the patients who were discharged from the service after prolonged hospitalization had recurrences of pleural effusion. In both instances a moderate amount of residual thickening of the pleura was present at the time of discharge, but laboratory and clinical studies failed to reveal any signs of activity.
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LABORATORY OBSERVATIONS
Blood counts on the patients studied at this hospital were within normal limits. Total and differential counts failed to reveal any constant variation, regardless of the phase of the illness. Occasionally a slight or moderate leukocytosis, with a normal differential count, was present very early in the disease, but this was transitory and not correlated with the clinical course. Serial blood counts during the convalescent phase of the illness were normal. No information of the activity of the disease was obtained by blood count studies. The sedimentation rate was significantly elevated in fifty-five patients. In three the rate was normal upon arrival at this hospital, and no record of the test having been performed previously was available. Two patients had normal rates throughout. One of these two patients had a recurrence of the effusion on the opposite side, the other had tubercle bacilli in the gastric content and subsequently developed a parenchymal infiltrate. The most marked elevations in the sedimentation rate were seen early in the disease, and the rise tended to persist in varying degrees for long periods of time, closely paralleling the clinical course regardless of its severity. Frequently, abnormal sedimentation rates persisted after all symptoms had disappeared and the exudate had been completely absorbed. This was most marked in those patients who exhibited persistent pleural thickening. Upon resumption of mild activity, an elevation of the sedimentation rate often reappeared and warned of the recurrence of clinical symptoms. A rising rate seemed to indicate an exacerbation of the activity of the disease. Skin tests with purified protein derivative (PPD) injected intracutaneously were performed in fifty-seven patients, fifty-six of whom showed positive reactions to either the 0.00002 mg. or 0.005 mg. dose. Two of the patients with positive reactions had negative reactions prior to the onset of their pleural effusion. No clinical correlation was noted between the degree of sensitivity to purified protein derivative and the severity of the disease. Throat cultures were made in thirty-six cases to determine the possible relation between the organism so obtained and the primary disease. The organisms obtained varied considerably. A great majority were green-producing streptococci, and in some cases hemolytic streptococci were recovered. No significant correlation of these findings to the clinical condition was observed. The titer of cold agglutinins was determined in twenty-three patients. Whenever possible blood specimens were, obtained early in the onset of disease, and subsequent check examinations were made at intervals. No significant increase in titer was noted either at the onset or during the course of the illness in any patient. No important change in titer was seen in those cases in whom serial examinations were made. Antistreptolysin titers of the blood were obtained in twenty-three
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cases. Titers were determined in some of the pleural fluids and these were found to be essentially the same as those in the blood. Serial determinations were done in those cases seen at the onset, in those in whom severe exacerbations had occurred and in patients in a relatively stable phase of the disease. No persistent elevations of the antistreptolysin titer were found. A few relatively high figures appeared in isolated specimens, but subsequent samples from the same patient showed normal levels after short intervals. Such incidental high values, therefore, were not considered significant. Pleural fluid studies were performed in fifty-seven cases. The greater number of these fluids were originally studied overseas prior to the return of the patient to the United States. We examined the pleural .fluid of twenty-one patients. In general the fluids were pale yellow to amber in color and were relatively clear or moderately hazy. No markedly cloudy, purulent or grossly bloody fluids were encountered. Specific gravities were all over 1.015. The protein levels varied between 3.5 and 6 mg. per 100 cc. with albumin-globulin ratios similar to that in the blood. The fluid in a number of cases showed a marked tendency toward spontaneous coagulation in the test tube shortly after it had been withdrawn. This phenomenon generally appeared after the effusion had been present for several weeks or more, but in some instances it was observed within the first week. Large, stringy fibrin precipitates without complete coagulation were also seen, usually presaging the complete coagulation of later samples. Because of this difficulty, samples of pleural fluid for cytological examination are now collected in a tube containing potassium oxalate. Cell counts of the pleural fluid varied considerably, the total counts ranging from 100 to 2000-3000. Differential study showed a great preponderance of the lymphocyte series, 80 to 100 per cent of the cells falling in this group. In only six patients polymorphonuclear leukocytes made up 40 to 50 per cent or more of the total cell count in the pleural fluid initially, but later preponderant lymphocytosis appeared. No relationship between the total or differential cell counts and the presence of tubercle bacilli in the fluid was noted. Cultures and smears of the fluid for pyogenic organisms were negative in all instances. Smears of the centrifuged sediment failed to reveal tubercle bacilli in all cases. Repeated culture of the centrifugate of large amounts of fluid on Petragnani's medium and inoculation of the same into several guinea pigs was done whenever possible. Where onl~' a small amount of fluid could be obtained, the entire amount was cultured and injected into guinea pigs. Cultures were observed for eight weeks before they were considered negative. Guinea pigs were tuberculin tested prior to their use and were sacrificed after at least eight weeks. Such procedures were carried out repeatedly in the same patient when multiple aspirations were done. Not infrequently only one fluid specimen would be found positive by one of these methods
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out of several specimens from the same patient. Of the twenty-one caSes so studied five, or 23 per cent, were positive for tubercle bacilli. In three patients the organism was isolated both by culture and in the guinea pig, in one by culture only and in another by guinea pig inoculation. A personal communication received from a military general laboratory in the European Theater of Operations, from an area where most of our patients had been evacuated, indicated that less than 25 per cent of the pleural fluids examined by guinea pig inoculation revealed the presence of tubercle bacilli. Sputum examinations for tubercle bacilli were done on all of the patients. Earlier in the investigation these were twenty-four hour concentrates which were examined by direct smear. The results were so uniformly negative that a more intensive search was made in the cases studied later. In these the seventy-two hour pooled sputum was examined by smear, culture and guinea pig inoculation'. One positive sputum was found in the entire group and this was positive by culture. Gastric secretion secured from fasting stomachs was collected for three days and studied similarly. Four patients were found to have tubercle bacilli in their gastric contents. In the positive cases the organisms were found either by culture or in the guinea pigs. In one of the four the smear was positive as well. ' ROENTGENOLOGIC OBSERVATIONS
Chest roentgenograms of each patient were taken serially throughout the period of observation. Aside from the characteristic findings of pleural effusion, the changes preceding and following the acute phase were of the greatest interest. A notable thickening of the pleural membranes was observed in nearly all cases in which the fluid had not been evacuated and was allowed to absorb. When air had been introduced and the effusion was not subsequently removed, chronic localized areas of hydropneumothorax persisted, often for months. The initial pleural thickening, often as much as 4 cm. in thickness, had an appearance similar to that of a fibrinous coagulum. Extraordinarily slow absorption of these plaques took place and it is of interest to note that in many of these patients the sedimentation rate remained elevated during most of the time required for their organization. Those patients whose fluid, when aspirated, developed a coagulum or a firm clot exhibited a high incidence of what was apparently a sudden and spontaneous clotting of the whole fluid mass in the pleural space. In several this solid mass extended from the topmost portion of the apex to the base and varied from 2 cm. to as much as 4 cm. in thickness. Organization and absorption of these coagulums was exceedingly slow and almost always resulted in a fibroth6rax. In fifty-two of the cases studied there was x-ray evidence of pleural thickening to a significant degree. Complete, uncomplicated resolution occurred in only, five of these patients during the period of our observation.
Fig. 39 (Case I).-Illustrates massive coagulation of pleural effusion. Three hundred cc. of fluid were secured after numerous thoracic punctures. The fluid removed coagulated spontaneously.
Fig. 40 (Case I) .-Chronic pleural change still remaining three months later. Patient underwent acute febrile relapse one month prior. No fluid obtainable at this time. 253
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The great majority of the films showed no evidence of parenchymal disease. Seven of the patients exhibited exudative parenchymal lesions by x-ray which varied in size from about 0.5 cm. to areas occupying about one-fifth of the involved lobe. They varied from small, flocculent, ill-defined shadows to dense-appeariqg, well-established parenchymal lesions. No relationship was noted between the lung containing the parenchymal lesion and the side 011 which the pleural effusion developed. In six of these cases the lesions were found in the upper third of the lung field, and in one the disease was basilar. In four cases the parenchymal infiltrate was present for some time before the de-
•
Fig. 41 (Case II).-Parenchymal infiltrate, left second and third inters paces allteriorly. First noted three and one-half months after onset of left pleural effusion. No clinical symptoms at this time.
velopment of the effusion. In one case it appeared during the existence of the effusion and in two was first noted after the effusion had been absorbed and the lung had been clear by x-ray for several months. Only two of the patients studied had discernible calcified areas. Tubercle bacilli were isolated in five of these patients from the sputum or gastric contents and in one from the pleural fluid. The diagnosis of atypical pneumonia had been made in most of the patients in whom a significant parenchymal infiltration preceded the development of the effusion. In many others the hazy density at the base, combined with the mild atelectatic changes in the adjacent lung and the common hilar swelling on the affected side were thought to
Fig. 42 (Case III).-Early left pleural effusion with associated infiltrates in upper and lower portions of left lung and accompanying left hilar enlargement. A diagnosis of atypical pneumonia was made at this time.
Fig. 43 (Case Ill).-Three and one-half months later. Residual changes from left pleural effusion. No fluid obtainable. Patient asymptomatic. Note changes in hilum and upper portion of left lung. . 255
Fig. 44 (Case IiI) .-Relapse with high fever, hemoptysis and severe systemic manifestations fifteen days later. Note paramediastinal collection associated with a new right-sided effusion. Tubercle bacilli cultured from gastric secretion at this time. Pleural fluid sterile.
Fig. 45 (Case Ill) .-Residual changes, both lungs, one month later. Patient asymptomatic. Sedimentation rate high. 256
Fig. 46 (Case IV).-Marked hilar swelling associated with pneumOnItiS, left lower chest and early pleural effusion, right. Admission diagnosis, atypical pneumonia.
Fig. 47 (Case IV).-One month later. Right pleural effusion. Patient acutely ill and febrile at this time. Tubercle bacilli recovered from pleural fluid by culture at this time. 257
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be due to pneumonia. The subsequent effusion was often believed to be a postpneumonic exudate. In a number of patients the early clinical picture and roentgenologic findings were not incompatible with those seen in primary atypical pneumonia, and it is easy to understand why such a diagnosis would seem tenable. Enlargement of the hilar lymph nodes was seen frequently. This enlargement was usually present in the early phases of the disease and was often transitory, persisting for a period of several weeks and then gradually disappearing. In a small number of cases the hilar enlarge-
Fig. 48 (Case IV) .-One month later. Residual changes of right pleural effusion. Small amount of pleural fluid obtainable. Gastric contents positive for tubercle bacilli by culture, and pleural fluid positive by guinea pig inoculation. Between figures 47 and 48, 2400 cc. of fluid removed. Note persistence of lesions in left lung and hilum.
ment was marked and was accompanied by perihilar edema. The latter finding was much more persistent and was seen principally in those patients in whom parenchymal lesions were found by x-ray. In the films of those patients in whom parenchymal disease was noted prior to the development of fluid, the hilar component was striking and was greater on the side affected. PLAN OF TREATMENT
The treatment of these cases was carried out according to the principles laid down by TB MED 71 of the Medical Department, United
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States Army. In the acute cases a sufficient amount of fluid was withdrawn (300 cc.) for diagnosis at necessary intervals. The effusion was not otherwise disturbed unless pressure effects required withdrawal of some of the exudate. The effusion was given the opportunity to absorb, but if after eight weeks it failed to exhibit any significant tendency to do so, it was then evacuated as completely as possible. No air replacement was employed, but in a few instances a small amount of air was introduced in order to facilitate the study of the character of the underlying pulmonary tissue. We have been impressed by the fact that, even with this relatively short delay in the evacuation of the fluid, in many instances chronic thickening of the pleural membranes or spontaneous coagulation of the whole exudate took place in that length of time. COMMENT
The results of this study substantiate the opinion that pleural effusion which occurs in younger persons, in whom no other readily determinable .cause for it exists, can be considered tuberculous until clear proof to the contrary is found. While it is true that only a small part of our total patients were proved to have tuberculosis by recovery of the organism, nevertheless the marked similarity of all these cases has convinced us that all were tuberculous. The prolonged and intimate observation which we were able to give each patient made it possible to eliminate many uncertainties in diagnosis. Tuberculous pleural effusion is in every way as important a manifestation of active tuberculous disease as visible tuberculosis of the lungs or other organs. It carries with it the same implications as to future spread and disability as does active tuberculosis anywhere in the body. Tuberculous pleural effusion demands the same care as active parenchymal disease, for active pulmonary tuberculosis may be the undedying cause of the effusion and may make its appearance at some future date after the effusion has resolved. The incidence of frank pulmonary tuberculosis following pleural effusion is high, the figures of various authors ranging from 17 to 50 per cent. The first five years, and particularly the first year, following the development of a pleural exudate are important in respect to the subsequent appearance of active tuberculosis. The manner of onset of this disease can justifiably give rise to the belief that it is a condition resulting from pulmonary lesions other than tuberculosis. The presence of an obvious inflammatory change in the lungs prior to the development of the effusion does not establish a nontuberculous etiology, as we have demonstrated. In our patients the determination of the antistreptolysin and the cold agglutinin titers and the negative bacteriological studies for pyogenic organisms in the fluids would seem to eliminate to a large extent any cause other than tuberculosis. All our patients who exhibited a pulmonary infil-
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trate, either prior to or coincident with the effusion, had considerable enlargement of the hilar lymph nodes. Hilar enlargement is not ordinarily a feature of the various specific and nonspecific types of pneumonitis, and this finding is a valuable one in suggesting a tuberculous etiology. The hilar enlargements seen in this region have not appeared to be malignant. The sedimentation rate was valuable in determining the activity of the disease. It frequently suggested the presence of an active lesion in a patient who, by clinical appraisal, would be adjudged to have an inactive lesion. This has always been useful in judging the patient's response to physical activity. In a number of patients a rise in the sedimentation rate was the first warning of reactivation of the process. An increase in the sedimentation rate has been observed in patients who have been convalescent and completely free of symptoms for as long as two or three months. Laboratory examination must be intensive and repeated if the maximum number of positive results are to be obtained. In our experience the examination of the three-day gastric specimens was the most satisfactory method for securing tubercle bacilli. Direct smear examination, culture on appropriate media and guinea pig inoculation should be performed on the pleural fluid, the pooled seventy-two hour sputum and the gastric secretions in all cases. Reliance on anyone test has been shown to be unreliable. The enormous thickening of the pleura seen in many of the patients has been unusual. The fibrin content of a number of the fluids has been high. Instances of spontaneous coagulation of the whole exudate with the formation of a solid, "jelled" mass extending from apex to base was most common when this phenomenon was observed. Numerous patients also developed thick coatings of what were interpreted to be fibrinous deposits on the pleural surfaces. These changes were by far most common in old cases in which the fluid was not evacuated. Fibrothorax with the subsequent development of diaphragmatic fixation and probable fibrosis of the underlying lung usually resulted. This group, as gauged by the sedimentation rate and the clinical response, exhibited an abnormally long period of activity of the disease. There is a considerable difference of opinion as to the proper treatment of a tuberculous pleural effusion. There are those who advocate that only the fluid necessary for diagnosis be withdrawn and that the patient be permitted to absorb the remainder. Others believe that if absorption of the fluid does not occur within a reasonable time, all fluid should be evacuated in order to prevent severe fibrosis of the pleura and consequent injury to the underlying lung. Still another group holds the opinion that the fluid should be evacuated as soon as the acute febrile phase and the period of rapid reaccumulation has ended. According to this group the fluid should be completely withdrawn and replaced by an equal or nearly equal volume of air in
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order to maintain a pneumothorax and to splint the mediastinum. Any reaccumulation of the fluid is removed. It4' is clear that any patient with an underlying active pulmonary . tuberculosis, whose effusion is allowed to resolve of its own accord, is exposed to the serious risk of adherence of the pleural surfaces, making the future employment of artificial pneumothorax impossible . . This leaves available to the patient only the formidable procedures of thoracoplasty or extrapleural pneumolysis in case an advancing, uncontrollable parenchymal lesion appears. Failure to evacuate an effusion of any considerable size tends also to prolong inordinately the patient's convalescence. It would seem advisable, in view of the foregoing, that after the febrile period has passed and reasonable stability in the effusion has occurred, which is ordinarily a period of two to three weeks, the fluid should be evacuated completely in successive stages if necessary, depending upon the size of the effusion. By this procedure the coagulation of large effusions can be prevented and the marked fibrinous deposits on the pleural surface can be avoided. Since the complete removal of fluid results in approximation of the pleural surfaces and thereby fosters their adherence, it would seem desirable that a pneumothorax of at least 200 to 300 cc. be induced initially. Adequate x-ray observation of the underlying lung may then be made and, if necessary,collapse therapy may be continued. If proper aseptic technic is employed in all thoracic punctures, there is no reason to anticipate complication by secondary infection or undue changes from the introduction of air into the pleural space. REFERENCES
1. 2. . 3. 4. 5.
Ornstein, G. G. and Ulmar, D.: Quart. Bull. Seaview Hosp., 4:269, 1939. Schl,lman, c.: Quart. Bull. Seaview Hosp., 7:69, 1941 . Pagel, W.: Tubercle, April, 1943, p. 68. TB MED 71, Medical Deparmlent, U. S. Army, July, 1944. Miller, O. O. in Goldberg: Clinical Tuberculosis, Vol. 11, 4th ed~ Philadelphia; F. H. Davis Co., 1944. 6. Norris, G. W. and Landis, H. R. M.: Diseases of the Chest and the Principles of Physical Diagnosis. Philadelphia, W. B. Saunders Co., 1938.