Corticosteroids in the Treatment Tuberculous Pleurisy* A Double-blind, Study Placebo-controlled, Cheng-Huei Lee, M.D., F.C.C.P; Wen-Jye Ray-Shee Lan, M.D., F.C.C.P; Ying-Huang and Ying-Chieh Chiang, M.D., Randomized Wang, M.D., Tsai, M.D., double-blind, randomized study of the role of corticosteroids in the treatment of tuberculous pleurisy was performed in 40 patients. All patients received adequate antituberculosis chemotherapy (isoniazid, 300 mg/ day; rifampin, 450 mg/day; ethambutol, 20 mg/kg/day) for more than nine months. They were randomly assigned to take prednisolone 0.75 mg/kg/day orally or placebo for the initial treatment, which was tapered gradually for the next two to three months. Twenty-one were treated with steroids and 19 were given a placebo. The two groups were identical with regard to age, sex, duration from onset of symptoms to diagnosis, and initial amount of pleural effusion. The mean duration from symptoms (fever, chest pain, dyspnea) uberculous pleurisy bined regimen therapy since the of the published has been treated with are such combination therapy improvement and absorption ever, its routine application in general ‘ Most that most 1960s when the treatment of tuberculosis had not been fully developed. With the modern multi-drug regimen, extrapulmonary as well as pulmonary tuberculosis can determine the of tuberculous benefits to to role of corticosteroids pleurisy. Whether modern patients is unknown. tions, we conducted trolled, randomized in: 1) relief of pleural effusion, No our On this study therapy in to these the basis of these observadouble-blind, placebo-conto see the effects of steroids clinical symptoms, and 3) prevention without 2) absorption of of pleural adhe- sions. Hospital, Manuscript Department Taipei, ofChest Taiwan, Republic Medicine, Chang Gung Memorial of China. received April 25; accepted Reprint requests: Dr Lee, 199 Tim Hwa BOG 10591 Road, Taipei, 1256 Downloaded From: http://journal.publications.chestnet.org/ on 09/09/2014 elsewhere had and were had who admitted the onset denied for of pleural a past further history evaluation. Taiwan inflammation. Patients with other pulmonary dis- or conditions which contraindicated the use of corticosteroids, like diabetes, peptic ulcer and hypertension were also excluded. Alipatients received pleural biopsy and diagnostic thoracocentesis (less than 50 ml) on the first day ofhospitalization. Those who were eligible for the study prednisolone placebo with were plus randomly assigned antituberculosis antituberculosis drugs to drugs (placebo treatment (steroid group). with group) The or antituber- culosis regimen included isoniazid, 300 mg/day; rifampin 450 mg/ day; and ethambutol, 20 mg/kg/day for the initial three months, and isoniazid and rifampin for the subsequent six to nine months. Prednisolone was initially. The showed improvement administered dosage was in an tapered and oral gradually was dose once diminished of 0.75 mg/kg/day chest radiograph two-thirds if any the by of the following conditions existed: 1) the effusion was right-sided and the fluid level was only one intercostal space higher than that of the left hemidiaphragm; 2) the effusion was left-sided and the fluid level was at the same height disappearance of pleural as the right hemidiaphragm; 3) complete effusion. Dosage of prednisolone was then diminished week day chest the May 16. North METHODS who eases the the AND 45 years tuberculosis granulomatous Standard *From age treatment of pulmonary either well-controlled knowledge, in the treatment corticosteroids add antimicrobial effusion under Other etiologies of pleural effusion such as congestive heart failure, pneumonia, malignancy and others were excluded through diagnostic testing, The diagnosis of tuberculous pleurisy was confirmed on the basis of pleural biopsy, reported as tuberculosis or chronic rapid clinical fluid. ‘ Howwith tubercu- bus pleurisy remains controversial. In addition, reported clinical trials were performed in the be eradicated more study has been undertaken, MATERIALS All patients agreement causes more of pleural to patients to relief was 2.4 days in the steroid-treated group, and 9.2 days in the placebo group (p<O.O5). Complete reabsorption of pleural effusion occurred an average of 54.5 days in the steroid-treated group and 123.2 days in the placebo group (p<O.Ol). The development of residual pleural thickening was not influenced by the administration of corticosteroids. No serious side effects were noted during the treatment in either group. We conclude that the administration of corticosteroids, in conjunction with antituberculosis chemotherapy, will resolve the clinical symptoms more quickly and hasten the absorption of pleural effusion in patients with tuberculous pleurisy. (Chest 1988; 94:1256-59) a corn- of corticosteroids-antirnicrobial middle half of this century. articles F.C.C.P; F.C.C.P; F.C.C.P A prospective, T of by 5 mg chest per of admission hospitalization pleural during opacity discontinued. and for all patients. roentgenogram monthly until posterioanterior on period. the persisted days 4 and After lateral patient 7 and then discharge, out-patient without Corticosteroids films Each follow-up any change were was every chest visits. for in Tuberculous taken on evaluated week films by during were Patients more Pleurisy taken whose than (Lee three et a!) Table 1-Clinical Characteristks and 19 Patients Steroids of 21 Patients Receiving Receiving Placebo months were erized amount Treatme Characteristic nt Group small (less one third effusion than and one two of one thirds (n = 21) (n = 19) the subjective symptoms were period. Statistical comparisons subjects) 12 12 9 7 18-44 18-45 28.4 28.9 Student’s t-test, Whitney U test Side chi-square (years) Range Mean time from onset 20.6 15.4 Small 9 5 Moderate 9 9 Large 3 5 symptoms Initial amount to diagnosis (days) of pleural differences between effu- the two groups are statistically than were and throughout made exact with test the unpaired and Mann- patients were entered into this study from October, 1983 to June, 1987. During the period, one patient developed renal cell carcinoma and four did not return for follow-up visits. Thus, 40 patients were eligible for final analysis, 21 in the steroid group and sions The (more of corticosteroids recorded Fisher’s (between large RESULTS Forty-five of effects carefully test, and The considered moderate hemithorax), hemithorax). abnormity. was hemithorax), of one or comput- of the presentation two of one sonography nature at initial third thirds chest the Placebo Female Mean with Steroid Male Age evaluated to determine of pleural study Sex (No. further tomography nonsignifi- 19 in the placebo The characteristics group. (sex, time age, cant. mean of the 40 randomized from onset of subjects symptoms to tthY DAY 350 14 P0.0l 13 300 12 p 11 < oo5 250 10 9.2 9 8 7 () ‘SO S 123.2 100 4 3 2.4 _____ 2 SO - 54.5 II, 0 .5 0 SThR()ID GR. (N:21) 1. The average sions: 2.4 days (steroid respectively. FIGURE duration group) of disappearance and 9.2 days PLACEBO STEID CR FIGURE 2. The duration for an average of 54.5 group) respectively. of disappearance days (steroid group) CHEST Downloaded From: http://journal.publications.chestnet.org/ on 09/09/2014 PLNE0 (P1=21) (N=19) of pleural effu(placebo group), c. GR (14=19) of clinical symptoms was and 123.2 days (placebo I 94 I 6 I DECEMBER, 1988 1257 diagnosis and shown in Table between the Clinical initial amount 1 . There were two of pleural no significant multidrug and signs, pain and dyspnea subsided (range, 1 to 7) in the steroid was placebo significant statistically old-fashioned antituberculosis regimen results of this study demonstrate that groups. symptoms 1 to 75) in the effusion) are differences an group including fever, benefits in average of 2.4 days and 9. 2 days (range, pleural The effusion. rapidity group (Fig 1). The (p<O. 05). Roentgenologic evidence of clearing field, with visualization of the diaphragm of ent of the (15.8 21 patients percent) ofthe treated with 19 patients (4.8 steroids and treated with rapidity differ- five Study Aspin and Smith 2-Studies on in three Administration demonstrated investigators tion Mathur 50 49 Menons* complained than two finding effusion of sustained months. in this absorption corticosteroids chemotherapy, adhesion in study is between were the by concomitant Tuberculous 66 Mathur et al7 300 SM 1 g/d Corticosteroids mg/d ACTH 20 mgIkg/d 300 SM 1 gtiw 300 SM 1 g/d INH 200 SM 1 g/d Damany and Grewal and Shahs* Dixits* 25 102 Prednisone 0.5 mg/d Prednisone 30 mg/d mg/d Intrapleural mg/d Intrapleural et alt 40 INH: isoniazid; SM: streptomycin; *Controlled study; tdouble-blind, 1258 Downloaded From: http://journal.publications.chestnet.org/ on 09/09/2014 acid; RM: 125-250 hydrocortisone mg 25 mg/d 15 mg/d or po Intrapleural hydrocortisone 125 mg or PAS 13 g/d triamquinolone 20 mg/d INH 300 SM 1 g/d INH 300 SM 1 g/d INH 300 SM 1 g/d EMB PAS: p-amino-salicylic randomized study. po 1 g/d INH study po SM RM Present po mgfkg/d hydrocortisone mg/d Intrapleural mg/d Triamcinolone mg/d Intrapleural hydrocortisone rifampin; 300 mg)d 450 125-250 24 mg/d hydrocortisone prednisolone Lee or 20 mg/d mg/kg/d INH INH 40 units/d prednisone INH300mg/d 102 added to the clearance of administration prednisolone Tanietal6 the the Pleurisy regimen INH INH 26 et al patient even pain for more 1 by statistical analysis. Data from other usually indicated benefits in the preven- ofpleural Anti-TB 6 et al dyspnea Figure receiving ously (Table 3). While the incidence of pleural adhesions seems lower in the group receiving steroids than placebo (4.8 vs 15.8 percent), a significant difference was not PAS 0.5 Paley and of the pleural fluid was much more rapid. Disappearance ofpleural effusion was achieved in a mean of54.5 days and 123.2 days in the two groups, respectively. This is in agreement with the observations reported previ- ofCortkosteroids 30 et al2 One chest two groups. When updated antimicrobial placebo. No. ofcases O’Hara* pain in the steroid group. (14/21) of the patients The most striking difference in pleural percent) previous studies regarding the role of in the treatment of tuberculous pleuconducted in the 1950s and 1960s with an Table days. pleuritic from were chest exert absorption corticosteroids were free from complaints within two days after treatment. The same fact was also noted by Paley et al,3 Mathur and colleagues, and Tani et al.6 Conversely, half (9/19) of the patients in the placebo group suffered from acute symptoms for more than DISCUSSION risy ofreliefoffever, still and the lung and costo- There was no demonstrable statistical difference between the two groups (p = 0.27). Only one patient developed transient moon face, lower limb edema and epigastralgia after administration ofprednisolone. These side effects subsided after tapering of the steroid dosage. Reports corticosteroids reflief was well demonstrated shows that two thirds group (Fig 2). The was significantly between the two groups (p<0.01). Pleural adhesions were noted in one corticosteroids symptomatic 2). The modern difference phrenic angle, occurred at an average of 54.5 days (range, 6 to 365) in the steroid-treated group. This was in contrast to an average of 123. 2 days (range, 7 to 395) in the placebo-treated of pleural effusion absorption chemotherapy, chest (Table with po mg po 100 mg or 20 mg/d Prednisolone 0.75 mg/d mgfkg/d po 20 mg/kg/d EMB: ethambutol. Corticosteroids in Tubercutous Pleurisy (Lee at a!) Table 3-Outcome ofCorticosteroid Therapy in Tuberculous Pleurisy Advantages Study Aspin and Clinical Fluid Pleural improvement absorption adhesion Transient moon + + + Paleyeta1 + + + + + + No + + + Transient et al et a16 Mathur et al Damany and Grewal and Shah8 Dixit’ et al Lee side effect moon a few cases) effect + + + No side + + + No side effect + + ? No side effect + + + + Rebound phenomenon(1) moon ?: not ofcorticosteroidst be due to the small In the study corticosteroids ening in the improvement one patient developed genologic initiated. oped them mentioned; edema, (Table 3). The disparity number ofpatients of Tani decreased et the al,6 the amount in our group pleural thickening, improvement Another three may possibly in this study. administration of pleural receiving ceased 12 days after in the placebo thickening any further the of thick- steroids, to show who roent- treatment groups was devel- within six months. None of improvement on chest roent- Transient side served in only edema, mated and after rebound symptoms developed, corticosteroids effects one epigastralgia. tapering phenomena were noted it is not are added altered by or not. of corticosteroids patient the causing These dose “moon were face, symptoms were of prednisolone. of pleural effusions in this series. and ob“ leg elimNo ofpleural adhesions was not influenced of however. mine the in the long-term study effect management face(1) this small to deter- ofsuch combination of tuberculous pleurisy. therapy Prof Robert REFERENCES J, 1 Aspin Br O’Hara J Tuberc 2 Smith H. Steroid-treated 1958; MHD, effusions Pediatrics 3 Paley Matsaniotis with 1959; 79:307-14 Mathur KS, 5 Menon reference Mais EL, Prasad adrenal JS. effusion. Steroid SA, pleural R, Mathur pleural NK. effusions. of tuberculous to Gittens oftuberculous in tuberculous pleural pleural corticosteroids. 22: 1074-87 MihalyJI in the treatment 4 N. Treatment particular 1958; SS, tuberculous 52:81-3 Lupini Am Rev Tuberc Intrapleural Tubercle therapy B. Prednisone effusions. hydrocortisone 1960; in tuberculous 41:358-62 effusion. Tubercle 1964; 45:17-20 6 Tani P Poppius H, tuberculous pleurisy Scand 44:303-09 1964; 7 Mathur KS, pleural in the light JS, Sapru Mathur effusion with local KT J chemotherapy. KS, regilflens tuberculous in Indian Dixit with and pleural Cortisone ofa Med RP A without effusion. therapy follow-up for exudative study. RP Treatment instillation Treatment triamcinolone 9 Grewal J. Makipaja Acta Tuberc of tuberculous of hydrocortisone. of pleural addition to Assoc 1968; Dis effusion usual with and antituberculosis 51:391-93 comparative study corticosteroids J Indian Med of therapeutic in the treatment of Assoc 1969; 52:514- 16 10 American berculosis 1986; Thoracic Society. infection in adults Treatment and children. of tuberculosis Am Rev and Respir tuDis 134:355-63 CHEST Downloaded From: http://journal.publications.chestnet.org/ on 09/09/2014 in is necessary ACKNOWLEDGMENT: The authors wish to thank F Heimberger for his careful review ofthis manuscript. without by corticosteroids Further Chest 1965; 47:83-7 8 Damany SJ, Shah clinical In conclusion, the results of the present study suggest that adrenal corticosteroids still play some role in the treatment of tuberculous pleurisy. Given together with modern antituberculosis chemotherapy, they exert benefit in the more rapid relief of clinical symptoms and absorption of pleural effusion. The occurrence administration series, genograms after a two-year follow-up. In contrast, those patients who did not develop pleural thickening showed a persistent, gradual decrease in pleural effusion until resorption was complete, though it may be prolonged. This implies that once pleural adhesion or thickening has treatment, whether moon N: no benefit. initial two to six months, though no further was noted a year after treatment. The pleural showed face(3) Epigastralgia, transient + : beneficial; face Transient N + face(l) ? ( Tani (cases) phenomenon(1) phenomenon(1) + + Menon5 effects Rebound Rebound ? Smithetal Mathur O’Hara’ Side I 94 I 6 I DECEMBER, 1988 1259