Development of Pleural Effusion in Patients During Anti- Tuberculous Chemotherapy : Analysis of Twenty-Nine Cases with Review of Literature

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1 ORIGINAL ARTICLE Development of Pleural Effusion in Patients During Anti- Tuberculous Chemotherapy : Analysis of Twenty-Nine Cases with Review of Literature Rakesh C. Gupta, Ramakant Dixit, S.D. Purohit and Anil Saxena 1 Department of Chest Diseases and Tuberculosis, J.L.N. Medical College, Ajmer and Government Medical College 1, Kota ABSTRACT Twenty-nine cases of tuberculosis developing pleural effusion (PE) during antituberculous chemotherapy (ATT) were analysed for clinical presentation and management outcome. Sixteen (55%) patients had pulmonary tuberculosis alone while rest had associated or isolated extrapulmonary tuberculosis. Thirteen (44.8%) patients developed PE during the 5th-8th week of chemotherapy and nine (31%) during 9th-12th week. Eighteen (62%) patients were on either HRZE or HRE while five (17.2%) were on SHRZ regimen before developing PE. All cases had exudative PE. Pleural fluid centrifuge was smear positive for AFB in two (6.8%) cases and culture positive for Mycobacterium tuberculosis in four (13.7%) cases. Pleural biopsy sections were negative for either AFB or tuberculous histology in 15 out of the 24 biopsies done. Twenty-four (82.7%) patients showed good response on the same ATT without modification. Development of PE during successful ATT seems to be an extension of paradoxical events having an immunological basis, which does not necessarily require any modification in chemotherapy. Key words: Pleural effusion, Antituberculous chemotherapy. [Indian J Chest Dis Allied Sci 2000; 42: ] INTRODUCTION Tuberculosis is the most common cause of pleural effusion (PE) in our country but development of PE during successful antituberculous chemotherapy (ATT) is uncommon. Tuberculous pleurisy is self limiting and, therefore, is considered as an example of protective immunity while active pulmonary tuberculosis on the other hand is less likely to heal spontaneously and therefore is associated with non protective immune reactions and immunopathology 1. Pleural T cells from tubercular pleuritis patients show phenotypic signs of activation in vivo and produce a variety of cytokines in situ. The pleural cells seem most active in cell mediated immune functions while peripheral lung cells are rather hyporesponsive and bronchoalveolar lavage-t cells probably occupy an intermediate position 2. Paradoxical events during antituberculous chemotherapy such as persistent fever, newly developing and enlarging lymph nodes, choroid or brain tubercles and even acute respiratory distress syndrome which bears an immunological basis have been reported 3. Development of PE during successful ATT seems to be just another paradoxical reaction which is mediated by Correspondence: Dr Rakesh C. Gupta, Associate Professor and Head, Department of TB and Respiratory Diseases, TB Hospital, Jaipur Road, Ajmer (Rajasthan); Tele. : , Extn 525, Telefax :

2 162 PE During Anti-Tuberculous Chemotherapy R. C. Gupta et al various cytokines. Although there are sporadic reports of development of PE during ATT 4-12, to our knowledge this is the largest number of patients being reported to date. MATERIAL AND METHODS This is a 13-year-prospective study of patients of tuberculosis who developed PE during course of ATT. All the 29 patients were evaluated by detailed clinical history, physical examination and skiagram of the chest. Extent and site of tuberculosis at the outset, sputum status, antituberculous regimen and time of development of PE after starting the ATT were recorded. Thoracocentesis was done in all cases and pleural fluid was subjected to routine biochemical investigation (i.e., pleural fluid sugar, protein, LDH, chloride and cells), pleural fluid smear and/or culture for acid-fast bacilli etc. Pleural biopsy was attempted in all patients who consented and subjected to histopathological examination and demonstration of AFB. All these patients were assessed carefully during the course of chemotherapy in terms of response, adverse drug reactions and pleuritic chest pain. RESULTS Twenty-nine patients developed PE during ATT. There were 19 (65.5%) male patients with an average age of 31.8 years (range years). Among the 10 (34.4%) female patients, the average age was 26.3 years (range years). Pulmonary tuberculosis (PTB) alone was the primary disease in 16 (55%) patients, followed by cervical lymphadenopathy in three (10.3%). Tuberculosis of lumbar spine with para vertebral abscess, miliary tubercul@sis, tubercular meningitis, right sided PE, PTB with left sided PE, bilateral PE, Koch's abdomen, Koch's abdomen with PTB, ascites and cold abscess neck with Eale's disease was initial diagnosis in one patient (3.4%) each. Fourteen (48.2%) patients had sputum smears positive for acid-fast bacilli (AFB) while two patients had positive sputum culture for M. tuberculosis with a negative smear on initial examination. In one case each, AFB was confirmed in CSF, ascitic fluid and pus on either smear or culture examination. Tuberculous granuloma was visualised on histopathological examination in all the three cases of cervical lymphadenopathy (Table 1). Thirteen (44.8%) patients developed PE between 5th-8th week of starting ATT, nine (31%) between 9th-12th week, five (17.2%) between 13th-24th week while in two (6.8%) patients PE developed within four weeks of starting ATT. 4 Nine (31%) patients were on rifampicin (R), isoniazid (H), pyrazinamide (Z) and ethambutol (E) followed by HRE regimen, five (17.2%) were on SHRZ and SHRZE regimen and one patient was on SHRZ along with cirpofloxacin regimen before they developed PE. Pleural effusion was exudative in all cases. It was right sided in 17 (58.6%), left sided in seven (24.1%) and bilateral in five (17.2%) patients. It was predominantly lymphocytic in character in 25 (86.2%) cases. Pleural fluid smear was positive for AFB in two (6.8%) and culture was positive for M. tuberculosis in four (13.7%) patients where the initial smear examination was negative. Histopathological examination of the pleural biopsy sections was suggestive of tuberculosis in seven (29.1%) patients, AFB in one and both AFB as well as tuberculous histology in one patient out of 24 cases in whom the procedure was attempted. It was negative for either AFB or tuberculous histology in 15 (62.5%) cases. Twenty-four (82.7%) patients showed good response to the same ATT without interruption, of them 17 (58.6%) recovered at nine months, three (10.3%) patients each at six and 12 months; and one patient (3.4%) at eight months of ATT. This variation in duration of chemotherapy was largely due to extent and site of underlying tuberculous disease. Four (13.7%) patients were lost during follow up but till last visit they were responding favourably.

3 2000; Vol. 42 The Indian Journal of Chest Diseases & Allied Sciences 163 Table 1. Details of patients developing pleura] effusion during A TT Chemotherapy S. Ini- Age Primary Sputum status/ Time of Regimen Side Pleural Pleural Remarks with No. tial and disease HPE or other dev. of given fluid biopsy total treatment sex biological PE after AFB details and outfluid starting (smear/ come ATT culture) (in weeks) 1. AC 32M PTB Smear+ve 8 HRZE Rt -ve Tubercul- Good recovery ous histo- with 2 HRZE/ logy 4 HR 2. MD 48M PTB Smear-ve but 6 HRE Rt -ve - Good recovery culture +ve with 9 HRE 3. PS 28F Cervical HPE of LN+ve 3 HRE Rt Smear - Tubercul- Good recovery LN +ve ous histo- with 2 HRE/ logy 7HR 4. RD 32F PTB Smear+ve 8 SHRZ Lt -ve - Good recovery with 2 1 / 2 SHRZ/ 4HR 5. BL 21F PTB Smear+ve 5 HRZE Rt -ve - Lost at 3 months (2 HRZE/1HR) 6. LA 27M PTB with Smear+ve 9 HRZE Lt -ve Tubercul- Lost at 3 months Koch's ous histoabdomen logy and +ve for AFB 7. SK 24F Ascites Ascitic fluid 13 2HRE/1HR Rt -ve -ve Good recovery culture +ve with 2 HRE/. 7 HR 8. RM 38M PTB Smear+ve 12 SHRZ Lt -ve -ve Good recovery with 3 SHRZ/ 5 HR 9. VK 17M PTB Smear+ve 10 HRE Rt -ve - Lost at 5 months 10. ZH 34M B/LPE Smear-ve,and 4 HRZE Lt Culture Tubercul- Good recovery culture -ve +ve ous histo- with 2 HRZE/ logy 4 HR 11. IM 18M Eale's dis.. Smear-ve and 6 SHRZ + B/L -ve +ve for Good recovery with cold culture-ve steroid AFB with 2 SHRZ/ abscess 7 HR neck MT +ve 12. HN 23M Koch's Smear -ve 8 HRE Rt -ve Tubercuous Good recovery abdomen histology with 9 HRE 13. RS 24M PTB Smear+ve 5 SHRZE Rt -ve -ve Good recovery with 2 SHRZE/ 7 HR 14. GS 33F Cervical HPE of 19 HRE Lt -ve -ve Good recovery LN LN+ve with 6 HRE/ 3 HE 15. HK 23F PTB Smear +ve 12 1 / 2 SHRZE/ Rt Smear -ve MDR case, 2 SHE +ve sputum +ve after 5 months of diagnosis Cont...

4 164 PE During Anti-Tuberculous Chemotherapy R.C. Gupta et al Table 1. (Continued) S. Ini- Age Primary Sputum status/ Time of Regimen Side Pleural Pleural Remarks with No. tial and disease HPE or other dev. of given fluid biopsy total treatment sex biological PE after AFB details and outfluid starting (smear/ come ATT culture) (in weeks) 16. RJ 27M Cervical HPE of 10 HRE Rt -ve -ve Good recovery LN LN+ve with 2 HRE/7HR 17. HG 24M PTB Smear+ve 7 SHRZE Lt -ve -ve Good recovery with 2 SHRZE/ 7HR 18. RC 19M PE(Rt) Smear-ve 24 HRE B/L Culture Tubercu- Good recovery +ve lous histo- with 1 HRE/ logy 11 HE 19. QI 23M PTB Smear+ve 5 SHRZ Rt Culture -ve Good recovery +ve with 2SHRZ/ 7HR 20. RM 41M TBM CSF smear 12 SHRZ + B/L -ve -ve Good recovery +ve steroid with 3 SHRZ/ 9 HRE 21. SK 17F Miliary Smear-ve 8 SHRZE Rt -ve -ve Lost after 4 mon- TB ths (2 SHRZE/ 2 HRE 22. RK 33F PTB Smear-ve and 17 HRE Rt -ve Tubercul- Good recovery culture + ve ous histo- with 3 HRE/ logy 6 HR 23. GK 55M PTB Smear+ve 6 HRZE Rt -ve -ve Good recovery with 2 HRZE/ 7HR 24. SP 24F Potts Pus smear 9 SHRZ + Lt -ve -ve Good recovery spine -ve and Ciprox. with 2 SHRZ with PVA culture +ve criprox./10 HR 25. LM 29M PTB Smear+ve 5 HRZE Rt -ve -ve Good recovery with 2 HRE/7HR 26. RT 28F PTB Smear+ve 13 HRZE Rt Culture Tubercul- Good recovery +ve ous histo- with 2 HRZE/ logy 7HR 27. MK 53M PTB Smear+ve 11 HRZE Rt -ve -ve Good recovery with 2 HRZE/ 2HR/5HE 28. TP 45M PTB with Smear-ve 8 SHRZE B/L -ve -ve Good recovery PE (Lt) with 2 SHRZE/ 3 HR/4HR 29. SK 28M PTB Smear-ve 9 HRZE B/L -ve - Good recovery with 2 HRZE/ 7HR PTB : Pulmonary tuberculosis, PE : Pleural effusion, LN : Lymphadenopathy, B/L: Bilateral, TBM : Tubercular meningitis, PVA : Paravertebral abscess, HPE : Histopathological examination, MT : Mantoux, CSF : Cerebrospinal fluid, S. : Streptomycin, H : Isoniazid, R : Rifampicin, E : Ethambutol, Z : Pyrazinamide, Rt: Right, Lt: Left, Ciprox.: Ciprofloxacin.

5 2000; Vol. 42 The Indian Journal of Chest Diseases & Allied Sciences 165 DISCUSSION Pleural effusion developed during ATT was first reported by Trocme 4 in In most of the reported cases, PE developed between three to eight weeks of starting ATT Pleural effusion in tuberculosis occurs on an immunologic basis when a subpleural focus of M. tuberculosis grows and ruptures into the pleural space 13. Tuberculin protein or the live bacillus interacts with sensitized 'T' lymphocytes with liberation of lymphokines, which may alter the permeability of the pulmonary vasculature and affect activity of the mononuclear phagocytes and pleural fibroblasts. Other mechanisms for tuberculous pleuritis are rupture of caseous foci in lymphnodes, ribs or vertebral column in the pleural space or by hematogenous dissemination 14,15. Patients with tuberculous PE tend to have higher levels of tuberculous antigen and specific antituberculous antibodies in their pleural fluid 14, Recently, hypersensitivity reaction to isoniazid has also been implicated in development of PE during ATT. Isoniazid is known to be associated with lupus pleuritis causing chest pain, fever and arthritis 19. The development of PE during ATT could be due to either INH-induced pneumonia's or INH induced lupus pleuritis 8,9. During active pulmonary tuberculosis, signs of both immune depression and immune activation are concomitantly present 2. It has been observed that mycobacterial products induce the production of tumour necrosis factor-alpha (TNFα) which is involved in the expression of many of the local and systemic toxicities evident in tuberculosis. Kaplan et al 20 have recently shown that cytokines in newly diagnosed tuberculosis patients falls with ATT, except TNF, which increases to a maximum at 7-14 days. This temporary rise in TNF is associated with a transitory clinical deterioration. Interleukin-2 (IL-2) is also known to cause development of pulmonary infiltrates and PE 21. The possible mechanism of development of PE during ATT seems to have an immunological basis (see flow diagram for the suggested mechanism). The Successful chemotherapy Rapid mycobacterial killing Release of mycobacterial products Production of TNF-Alpha, IL-2,IL-6 and IL-8 Local inflammation i Necrotising/ caseous reaction Expansion/ rupture of subpleural focus Pleuritis/ pleural effusion Figure. Flow diagram of possible mechanism of development of pleural effusion during successful antituberculous chemotherapy. possibility of a local hypersensitivityinflammatory reaction to tuberculoprotein is further supported by the negative pleural biospy for tuberculous pathology in 15 cases and negative pleural fluid smear and/or culture for M. tuberculosis in 23 (79.3%) cases in our study. Most cases developed PE early in the course of ATT (within eight weeks) and effusion subsided spontaneously on the same treatment. However, Al-Majed reported six patients who developed massive PE with respiratory distress requiring therapeutic aspiration and oral corticosteroids 9. Endo et al 12 reported a case where recovery occurred after stopping all drugs and adding steroids. Similar to as reported in the literature 4-12,15 (51.7%) of our patients developed PE within eight weeks of starting ATT but none of them required withdrawal of ATT or addition of oral corticosteroid or a therapeutic aspiration. We agree with Matthay et al 5 that development of tuberculous pleuritis or effusion during the early stages of chemotherapy does not imply failure of the current therapeutic regimen and no change in therapy is indicated unless there are other reasons, like progressive paraenchymal infiltrates or an unfavourable bacteriological response. Eighty-two percent of our patients

6 166 PE During Anti-Tuberculous Chemotherapy R.C. Gupta et al showed good response to the same chemotherapy during which they developed the PE while the remaining were lost to follow up except one who was subsequently diagnosed as a case of MDR tuberculosis. The regimens were not modified or altered and no relapse was observed at six months of treatment. Thus, there is no need to change the drugs or increase the duration of chemotherapy when pleural effusion occurs during ATT. ACKNOWLEDGEMENTS The authors are grateful to Dr Kamal Sood, Dr Archana Sood and Dr Neeraj Nagpal, Faculty Members of PGI, Chandigarh, for their active involvement in this project during 1986 to REFERENCES 1. Tsuyuguchi I. Regulation of human immune response in tuberculosis. Infect Agent Dis 1996; 5 : Vanham G, Toossi Z, Hirsch CS, et al. Examining a paradox in the pathogenesis of human pulmonary tuberculosis: Immune activation and suppression/anergy. Tubercle Lung Dis 1997; 78 : Onwubalili JK, Scott GM, Smith H. Acute respiratory distress related to chemotherapy of advanced pulmonary tuberculosis : A study of two cases and review of the literature. Quart J Med 1986; 59 : Trocme P. Sur certains 'epanchements pleureux survenus au cours d'um traitement par la streptomycine. Rev Tuberc(Paris) 1950; 14 : 570 (Cited from Ref. 2). 5. Matthay RA, Neff TA, Iseman MD. Tuberculous pleural effusion developing during chemo therapy for pulmonary tuberculosis. Am Rev Respir Disl97A; 109 : Vachharajani SD, Rastogi DS. Pleural effusion while on antitubercular therapy for pulmonary tuberculosis. Indian J Tuberc 1976; 23 : Vilaseca J, Lopez Vivancos J, Arnau J, Guardia J. Contralateral pleural effusion during chemotherapy for tuberculous pleurisy. Tubercle 1984; 65 : Baldev Raj, Chawla RK, Chopra RK, Gupta KB, Kumar P. Development of contralateral pleural effusion during tuberculosis chemotherapy. Indian J Tuberc 1987; 34 : Al-Majed SA. Study of paradoxical response to chemotherapy in tuberculous pleural effusion. Respir Med 1996; 90 : Dasgupta UK. Development of pleural effusion during chemotherapy for pulmonary tuberculosis. Indian] Tuberc 1911; 44 : Hiraoka K, Nagata N, Kawajiri T, et al. Paradoxical pleural response to antituberculous chemotherapy and isoniazid-induced lupus : Review and report of two cases. Respiration 1998; 65 : Endo T, Saito T, Nakayama M, et al. A case of isoniazid-induced pneumonitis. Nihon Kokyuki Gakkai Zasshi 1998; 36: Sahn SA. Diseases of the pleural and pleural space. In : Baum GL, Crapo JD, Celli BR, Karlinsky JB, ed Textbook of Pulmonary Diseases; 6th edn. Philadelphia : Lippincott-Raven; 1998 : Light RW. Tuberculous pleural effusion. In : Retford DC, ed Pleural Diseases; 3rd edn. Baltimore : Williams and Wilkins; 1995 : Johnston RF, Dovanareky JH. Pleural diseases. In : Fishman AP, ed Pulmonary Diseases and Disorders;Vo\. 2, 5th edn. New York: McGraw- Hill Book Company; 1980: Baig MME, Pettengell KE, Simgee AE, et al. Diagnosis of tuberculosis by detection of mycobacterial antigens in pleural effusion and ascites. S Afr Med J 1986; 69: Yew WW, Chan CY, Kwan SY, etal. Diagnosis of tuberculous pleural effusion by the detection of tuberculostearic acid in pleural aspirates. Chest 1991; 100 : Van Vooren JP, Farber CM, De Bruyen J, Yernault JC. Antimycobacterial antibodies in pleural effusions. Chestl990; 97 : Antony VB. Drug induced pleural disease. Clin Chest Med 1998; 19 : Kaplan G, Freedman VH. The role of cytokines in the immune response to tuberculosis. Res Immunol 1996; 147 : Light RW. Pleural effusion due to drug reactions. In : Retford DC, ed Pleural Diseases; 3rd edn. Baltimore : Williams and Wilkins; 1995 :