Tuberculous Pleurisy

CRITICAL REVIEW Tuberculous Pleurisy* Herbert W. Berger, M.D., F.C.C.P.,oo and Ervido Me;ia, M.D.t

The average age of patients with tuberculous pleurisy is increasing and the disease is now commonly seen in middle and old age. Abrupt onset occurs in two-thirds of cases and may resemble acute bacterial pneumonia. The temperature may not be elevated above normal in occasional patients when they are first examined. Initial intermediate strength tuberculin or tine tests are negative in almost one-third of patients but upon repeat of these tests or performance of second strength tests a positive reaction is invariably obtained. The pleural effusion is usually unilateral, most commonly less than one-half the volume of the hemithorax but may involve the entire hemithorax, and is associated with active pulmonary lesions in slightly more than one-third of the cases. Pleural fluid lymphocytosis of 95-100 percent is found in most cases but is a nonspecific finding. Serosanguinous fluid is rarely present. Pleural fluid protein is almost invariably above 3 gml 100 ml and LDR levels are usually elevated. The frequency of diminished pleural fluid glucose has been overemphasized in the previous literature. Less than one-fifth of patients have values below 50 mgll00 ml but none has had a level less than 30 mgll 00 ml in our series of cases. Pleural biopsy histologic examination and pleural biopsy culture for tuberculous organisms are each positive in more tban two-thirds of patients. Pleural fluid culture demonstrates tubercle bacilli less frequently than biopsy culture and sputum or gastric cultures are usually negative unless pulmonary lesions are present. Treatment for two years with isoniazid and ethambutol or with isoniazid and para-aminosalicylic acid produces excellent· results and development of new pulmonary lesions, recurrence of pleural effusion, or a need for pleural decortication are very rare.

Although tuberculous pleurisy initially is a selflimited disease, 65 percent of untreated patients develop active pulmonary or extrapulmonary tuberculosis within five years of its occurrence.! After adequate therapy these complications are rarely seen. Pneumonia, pulmonary infarction, malignancy of the pleura, systemic lupus erythe-

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• From the Department of Medicine, Mount Sinai Hospital St'rvices-City Hospital Center at Elmhurst, Elmhurst, New York, and the ~Iount Sinai School of l\ledicine of the City University of New York, New York City. o ·Chief, Pulmonary Disease Service, Mount Sinai Hospital Services-City Hospital Center at Elmhurst; Associate Professor of Clinical Medicine, Mount Sinai School of Medicine of the City University of New York. tResident in l\ledicine, Mount Sinai Hospital Services-City Hmpital Center at Elmhurst. Repri/lt requests: Dr. Berger, City Hospital Center at Elmhurst, 79-01 Broacltcay, Elmhurst, New York 11373

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matosus, and subdiaphragmatic conditions, as well as other diseases, can easily be confused with tuberculous pleurisy. The differences in prognosis and treatment require that a proved diagnosis be made whenever possible. The following is a review of tuberculous pleurisy based upon a survey of the medical literature and upon our experience with 49 patients seen at the Mount Sinai Hospital Services-City Hospital Center at Elmhurst between July, 1964 and June, 1970. In 42 patients the diagnosis of tuberculous pleurisy was established by biopsy of the pleura or other tissue showing caseating or noncaseating epithelioid granulomas and! or culture of pleural fluid, pleural biopsy tissue, sputum, or gastric contents demonstrating typical tubercle bacilli. An additional seven CHEST, VOL. 63, NO.1, JANUARY, 1973

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patients with strongly positive tuberculin skin tests, predominance of lymphocytes in the pleural fluid, and no evidence of a diagnosis other than tuberculous pleurisy, but with biopsies and cultures negative for tuberculosis are included in this report as presumptive cases of tuberculous pleurisy. Seven other cases were eliminated from the study because of lack of certainty about the correct diagnosis. PATHOGENFSIS Tuberculous pleurisy denotes inflammatory disease of the pleura due to Mycobacterium tuberculosis. Usually an unexplained pleural effusion first suggests the diagnosis; however, a pleural effusion is not always clinically recognized. The disease is thought to result from rupture of a subpleural caseous focus in the lung into the pleural space. 2.3 The pulmonary focus has been frequently recognized when performing open pleural biopsy.2 Hypersensitivity to the tubercle bacillus also plays an important role in determining the occurrence and amount of pleural effusion. Tuberculous pleurisy most commonly occurs three to seven months following the primary infection, but may be seen at any time in the natural course of tuberculosis. 4 Although it is the most common type of extrapulmonary tuberculosis, tuberculous pleurisy occurs much less frequently than pulmonary tuberculosis.

100° F at the time of admission to the hospital. The temperature was between 100° and 103°F in 31 patients, and was 103.1 ° to 104.6°F in nine patients. It was thought that a previously elevated temperature had returned to normal by the time of admission in several of the afebrile patients. Thus a normal temperature, although uncommon, does not rule out a diagnosis of tuberculous pleurisy. Tuberculous pleurisy may coexist with other diseases as noted in two of our patients, one with malignancy of the pleura and another with congestive heart failure. Three patients in our series had tuberculous peritonitis and one had tuberculous epididymitis in addition to tuberculous pleurisy. Sibley5 reported hematogenous spread of tuberculosis in 18.5 percent of his cases particularly in those with bilateral pleural effusions. The hemoglobin content and peripheral white blood cell count are usually near normal in tuberculous pleurisy. Only two patients had a hemoglobin determination below 10 gm/l00 ml and three patients had a white blood cell count above 12,000/ cu mm in our series. Levine et al 6 state that tuberculous pleurisy should be suspected when pleural pain appears prior to cough, the cough is not productive of purulent material, the pleural fluid is clear, and the peripheral white blood count is not increased.

CLINICAL FEATURFS

Previously, tuberculous pleurisy was found almost exclusively in young adults. The average age in Sibley's5 series of cases was 25 years. Twenty of our 49 patients were more than 35 years old, including seven more than 70 years of age. The increasing age of patients with tuberculous pleurisy creates diagnostic difficulties since malignancy, congestive heart failure, pneumonia, and pulmonary infarction are common problems in older patients. The onset may be either abrupt or insidious. In 31 patients (63 percent) the disease began abruptly, often mimicking acute pneumonia. Levine et al 6 noted acute onset in two-thirds of their patients and found that older patients more frequently had an insidious onset. Forty-six of our patients had cough and 38 had chest pain. The cough was usually nonproductive, particularly when active pulmonary lesions were not present; the chest pain was usually pleuritic. Night sweats, chilliness, dyspnea, weakness, and weight loss were common complaints, but occurred less frequently than cough and chest pain. A pleural friction rub was heard in onlv five patients. All but seven patients had a temperature above CHEST, VOL. 63, NO.1, JANUARY, 1973

TUBERCULIN TFSTS

Although it was formerly observed that almost all patients with active tuberculosis have positive intermediate strength tuberculin skin tests, more recent reports stress the frequent occurrence of negative results. 7 •8 Eleven out of 36 patients had negative purified protein derivative (PPD) intermediate and two out of six patients had negative tine tests when first studied (31 percent), but all had positive reactions when re-evaluated with the above tests or with second strength PPD tests. Falk9 stated that tuberculous pleurisy can be excluded if the tuberculin test is negative after six to eight weeks. Mechanisms explaining the temporary negative results include testing before tuberculin sensitivity has developed, transient hyposensitization due to outpouring of a large volume of pleural fluid, adsorption of tuberculin onto the glass syringe, and errors in performance and interpretation of the tests. 7 •8 • IO It should be emphasized that a negative initial intermediate strength tuberculin test is not uncommon and should not result in the diagnosis of tuberculous pleurisy being discarded. However. if frequently repeated properly performed intermediate and second strength tests are nonreactive

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after two months, tuberculous pleurisy is an extremely unlikely diagnosis. ROENTGENOGRAPffiC FINDINGS

In our cases the pleural effusion occurred on the right side in 28 patients, on the left in 19, and bilaterally in two patients. Sibley5 also noted a greater frequency of right-sided effusions, but had 10 percent bilateral effusions in his series. The effusion occupied less than one-half the hemithorax in 39 of our patients. Two patients had effusions which completely filled the hemithorax and are included in a group of massive pleural effusions not due to malignancy. 11 In untreated patients the side or size of the effusion had no bearing on the incidence of complications and development of subsequent pulmonary tuberculosis. 5 In a classic case of tuberculous pleurisy pulmonary parenchymal lesions cannot be recognized on routine chest roentgenograms but develop in 53 percent of untreated patients within five years. 1 Eighteen of our patients (37 percent) had coexisting active pulmonary and pleural tuberculosis. In six of these patients previous chest roentgenograms were available showing the pulmonary lesions prior to development of the effusion. The pulmonary disease varied from minimal to far advanced and was either unilateral or bilateral. The pleural effusion always occurred on the side of a parenchymal infiltration in those patients with both pulmonary and pleural disease. Combined pulmonary and pleural tuberculosis occurred in nine patients more than 35 years old, a higher incidence of older aged patients than in the group as a whole. Fifteen percent of Sibley's5 cases had pulmonary lesions preceding the pleural effusion. PLEURAL FLUID

The pleural fluid white blood cell count was between 1,000 and 6,000/ cu mm in 23 out of 41 patients. Twenty-eight out of 42 patients (67 percent) showed values of more than 95 percent lymphocytes and only five patients (12 percent) had less than 50 percent lymphocytes on the initial determination. The finding of 95 to 100 percent lymphocytes is not specific for tuberculosis, but is also frequently seen in carcinoma, lymphoma, and in chronic effusions of many causes. 12 As is well known, serial pleural fluid differential white blood cell counts may show progression from a predominance of polymorphonuclear cells in early cases to a predominance of lymphocytes as seen in two patients. 10 None of our patients had pleural fluid eosinophilia, which is usually defined as more than

5-10 percent eosinophils in the pleural fluid. This confirms the impression that pleural eosinophilia is rare in tuberculous pleurisy.13 Serosanguinous fluid was found in only two instances, both attributable to a traumatic thoracentesis. Others have found blood-stained pleural fluid in from 1.5 to 9 percent of their cases. 5.6.14 Serosanguinous pleural fluid suggests a diagnosis of malignancy, pulmonary infarction, trauma, or pneumothorax, rather than tuberculosis. We did not observe cholesterol crystals as reported in longstanding effusions. 10 The pleural fluid protein concentration was less than 3 gm/l00 ml in only one patient, and greater than 5 gm/l00 ml in 34 patients (77 percent). Carr and Power 15 found that 100 percent of tuberculous fluids were exudates in their study of 20 patients. Elevated lactic acid dehydrogenase (LDH) levels in the pleural fluid were found in 27 out of 35 patients (77 percent) as has been previously noted. 16 PLEURAL FLUID GLUCOSE

Earlier reports mention the frequency of diminished glucose concentration in tuberculous effusions. Calnan et aP1 found a glucose concentration less than 60 mg/l00 ml in 13 out of 25 cases including seven with less than 30 mg/l00 ml. Gelenger and Wiggers l8 reported values below 39.5 mg/l00 ml in ten cases, with an average value of 15.7 mg/l00 ml. They stated that a pleural glucose concentration of 30 mg/l00 ml or less was diagnostic of tuberculosis and that the diagnosis of tuberculosis was unlikely if the value was above 60 mg/l00 ml. Barber et aP9 found glucose concentrations between 10 and 48 mg/l00 ml in 70 cases of tuberculous pleurisy. The results in our study are significantly different from those above. Only three patients out of 43 initially had pleural fluid glucose concentrations of less than 50 mg/l00 rnl on thoracentesis. Three other patients had pleural fluid concentrations of less than 50 mg/l00 ml on followup thoracentesis. Seven patients had values between 51 and 60 mg/l00 ml. In no patient was the pleural fluid glucose concentration less than 30 mg/ 100 ml. Thus, glucose concentrations between 30 and 60 mg/l00 ml were seen in 13 patients (30 percent) and between 30 and 50 mg/l00 ml in six patients (14 percent), but values below 30 mg/l00 ml were not observed. We have found pleural fluid glucose concentrations less than 30 mg/l00 ml in malignancy, rheumatoid arthritis, and empyema. 20 We did not regularly examine for mesothelial cells which are said to be absent or scarce in tuberculous effusions. 21 CHEST, VOL. 63, NO.1, JANUARY, 1973

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TUBERCULOUS PLEURISY PLEURAL BIOPSY FINDINGS

Results of needle pleural biopsy have been reported positive in 50-SO percent of cases of tuberculous pleurisy.22'24 Usually a biopsy demonstrating either caseating or noncaseating epithelioid granulomas is accepted as tuberculous although only identification of acid-fast bacilli or culture of tubercle bacilli from the specimen is completely diagnostic. 25 We used the Abrams needle in all but a few early cases and found it to give more satisfactory results than the Vim-Silverman needle. The Cope needle also has been used successfully by some groupS.6 The biopsies were performed by a large number of different medical and chest residents after minimal instruction. No pleural tissue was obtained in one patient. We attempted to perform a pleural biopsy only when pleural fluid was present. Recently biopsies have been performed with the Abrams needle in the absence of pleural fluid. 24 Results of pleural biopsies were positive in 29 out of 42 patients (69 percent). Caseating epithelioid granulomas were seen in 18 cases, noucaseating granulomas in 11, and acid-fast bacilli in 6 cases. Findings in repeat biopsies were positive in three patients out of seven whose initial biopsies showed nonspecific results. Pleural biopsy findings in the three patients who had tuberculous peritonitis were negative as has been noted previously.26 Mestitz et al 23 found that the chances of obtaining positive results in a pleural biopsy were uninfluenced by the size or white blood count of the pleural effusion, presence of parenchymal lung shadows, antituberculosis chemotherapy, or the duration of symptoms. We did not perform any open pleural biopsies. Arrington et al 27 felt that failure to find granulomatous pleuritis after open pleural biopsy virtually excluded tuberculosis. On follow-up tuberculosis did not develop in any of their untreated positive tuberculin reactors who had nonspecific open pleural biopsies. Internal mammary lymph node biopsy has also been reported to be useful in obtaining a diagnosis of tuberculous pleurisy.28.29 Tubercle bacilli were cultured from pleural biopsy tissue using Dubos liquid medium in 11 out of 17 patients (65 percent), including four with negative pleural biopsies. Positive pleural biopsy cultures have been reported in 55 to 80 percent of cases.22.24.30 Liquid culture medium is superior to solid medium. 30 PLEURAL FLUID CULTIJRE

Cultures of the pleural fluid revealed tubercle bacilli in 11 out of 45 cases (24 percent) including CHEST, VOL. 63, NO.1, JANUARY, 1973

three with negative results of biopsies. Sibley5 reported positive cultures in 70 percent of his cases, although in most other series positive results are found in less than 30 percent of cases. 9 The percentage of positive cultures has been increased by centrifuging large volumes of pleural fluid (100500 ml ), performing multiple cultures, and by inoculation into guinea pigs. S•19 Our recent results with Dubos liquid medium have been superior to those obtained previously with Lowenstein-Jensen medium. Twelve patients out of 40 (30 percent) demonstrated tubercle bacilli in their sputum or gastric contents; ten of these patients had visible pulmonary lesions on their chest roentgenograms. One of the two patients with no pulmonary lesions and positive cultures had a massive pleural effusion and the other coexisting carcinoma of the lung. Tubercle bacilli have been cultured from the sputum or gastric contents in from zero to 32 percent of cases. 14.27 Thus, failure to find granulomas on needle pleural biopsy does not exclude a diagnosis of tuberculosis and repeat biopsies should be performed. Culture of the pleural biopsy specimen is as useful a diagnostic tool as histologic examination and may be positive when microscopy is negative. The triad of pleural biopsy histologic examination, pleural biopsy culture, and pleural fluid culture for tuberculosis should be performed on all patients with pleural effusions since only one of these examinations may be positive. Gastric and sputum cultures infrequently yield tubercle bacilli unless visible pulmonary tuberculosis coexists with the pleurisy. TREATMENT

We treated our patients 24 months with a twodrug regimen, isoniazid (INH), para-aminosalicylic acid (PAS), at the beginning of the study, and I~H­ ethambutol since 1967 with equally good res"lts. (Doses: INH 300 mg daily, PAS 12 gm d:ti1v, ethambutol 15 mg/kg daily). The PAS or ethambutol therapy was usually discontinued after 12 to 18 months. We did not employ either a three-drug or one-drug regimen initially in any patients. The pleural effusion partially or completely cleared within a few weeks to several months. Response to therapy was not necessarily dramatic. The pulmonary lesions, when present, resolved more slowly than the pleural effusions. Only one patient who discontinued his drugs prematurely had a spread of coexisting pulmonary lesions. No patients without pulmonary lesions subsequently developed pulmonary tuberculosis and there was no recurrence of

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pleural effusion once resolution had started. We did not keep our patients on bed rest for more than a few days, make a consistent effort to aspirate the pleural fluid completely, administer steroids, breathing exercises, or perform pleural decortication in our treatment program. Complete aspiration of pleural fluid and the use of steroids have not resulted in significant longterm benefits. Fever in all but three patients subsided within one to three weeks after chemotherapy was started, and never lasted more than 30 days in contrast to the fairly frequent occurrence of prolonged fever after treatment of pulmonary and miliary tuberculosis. 31 REFERENCES

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Roper WH, Warin!1: 11: Primary serofibrinous pleural effusion in military personnel. Am Rev Tuberc 71 :616635, 1955 Stead WW, Eichenholz A, Stauss H-K: Operative and patholo!1:ic findin!1:s in twenty-four patients with syndrome of idiopathic pleurisy with effusion, presumably tuberculous. Am Rev Tuberc 71 :473-502, 195.5 Abrams WB, Small MJ: Current concepts of tuberculous pleurisy with effusion as derived from pleural biopsy studies. Scand J Resp Dis 38:60-65, 1960 Wallgren A: The time-table of tuberculosis. Tubercle 29:245-251, 1948 Sibley JC: A shldy of 200 cases of hibercliious pleurisy with effusion. Am Rev Tuberc 62:314-323, 1950 Levine H, Szanto PB, CU!1:e11 DW: Tuberculous pleurisy an acute illness. Arch Intern Med 122:329-332, 1968 Kent DC, Schwartz R: Active pulmonary hlbereulosis with negative hlberculin skin reactions. Am Rev Resp Dis 95:411-418 1967 Holden M, Dubin MR, Diamond PH: Frequency of negative intermediate-strength hlberculin sensitivity in patients with active tuberculosis. N Engl J ~fcd 28.5: 1.5061509, 1971 Falk A: Tuberculous pleurisy with effusion: diagnosis and results of chemotherapy. Postgrad Med 38:631-635, 1965 Wier JA: Tuberculous pleurisy with effusion. III Clinical Tuberculosis; Essentials of Diagnosis and Treatment (Pfuetze KH, Radner DB, eds). Springfield, Ill, C C Thomas, 1966 ~faher GG, Ber!1:er HW: Massive pleural effusion malignant and nonmalignant causes in 46 patients. Am Rev Resp Dis 10.5:458-460, 1972 Yam LT: Diagnostic si!1:nificance of Iynlphocytes in pleural effusions. Ann Intern ~led 66:972-982, 1967 Bower G: Eosinophilic pleural effusion: a condition with

multiple causes. Am Rev Resp Dis 95:746-751,1967 14 Poppius H, Kokkola K: Diagnosis and differential diagnosis in tuberculous pleurisy. Scand J Resp Dis (Suppl) 63:105-110,1968 1.5 Carr DT, Power ~fH: Clinical value of measurements of concentration of protein in pleural fluid. N Engl J ~fed 2.59:926-927, 1958 16 Raabo E, Rasmussen KN, Terkildsen TC: A shldy of the isoenzymes of lactic dehydrogenase in pleural effusions. Scand J Resp Dis 47:150-156,1966 17 Calnan WL, Winfield BJO, Crowley ~fF, et aI: Diagnostic value of the glucose content of serous pleural effusions. Br Med J 1: 1239-1240, 1951 18 Gelenger SM, Wiggers RF: Relationship of the pleural fluid sugar to pulmonary tuberculosis. Dis Chest 1.5:32.5328, 1949 19 Barber LM, Mazzadi L, Deakins DD, et al: Glucose level in pleural f1jid as a diagnostic aid. Dis Chest 31 :680-687, 1957 20 Berger HW, Maher G: Decreased !1:lucose concentration in malignant pleural effusions. Am Rev Resp Dis 103:427429, 1971 21 Spriggs AI, Boddington M1\1: Absence of mesothelial cells from tuberculous pleural effusions. Thorax 15:169-171, 1960 22 Scharer L, McClement JH: Isolation of tubercle bacilli from needle biopsy specimens of parietal pleura. Am Rev Resp Dis 97 :466-468, 1968 23 Mestitz P, Purves MJ, Po))ard AC: Pleural biopsy in the diagnosis of pleural effusion a report of 200 cases. Lancet 2:1349-1353,1958 24 Scerbo J, Keltz H, Stone DJ: A prospective study of closed pleural biopsies. JAMA 218:377-380,1971 25 Richert JH, Wier JA, Salyer JM, et al: The reliability of tissue diagnosis of pleurisy: a preliminary report. Ann Intern Med 52:320-325, 1960 26 Levine H: Needle biopsy diagnosis of tuberculous peritonitis. Am Rev Resp Dis 97 :889-894, 1968 27 Arrington CW, Hawkins JA, Richert JH, et al: ~fanage­ ment of undiagnosed pleural effusions in positive tuberculin reactors. Am Rev Resp Dis 93:587-593,1966 28 Conklin EF, Yeoh CB, Jones JM: Internal-mammarylymph-node biopsy as a diagnostic aid in pleural effusion. N Engl J!\fed 271:1346-1348,1964 29 Burke HE, Wilson JAS: A new method for establishin!1: the diagnosis of pleural disease-parasternal lymph node biopsy. Am Rev Resp Dis 93:201-208, 1966 30 Levine H, Metzger W, Lacera D, et al: Diagnosis of tuberculous pleurisy by culture of pleural biopsy specimen. Arch Intern Med 126:269-271, 1970 31 Berger HW, Rosenbaum I: Prolonged fever in patients treated for tuberculosis. Am Rev Resp Dis 97:140-143, 1968

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