Role of steroids in Tuberculosis | Jindal Chest Clinic

Presentation on "Role of steroids in Tuberculosis"

1. ROLE OF STEROIDS IN TUBERCULOSIS

2. Historical Background Landmark MRC trial of streptomycin in PTB published in the year 1948 Incidentally, in same year Philip Hench and colleagues discovered the anti-inflammatory properties of cortisone (also received Nobel Prize) This inspired early attempts to use corticosteroids for treatment of TB despite a lack of empirical evidence Rather, data from animals actually suggested that use of corticosteroids might worsen the disease* *D’Arcy-Hart P, Rees RJ. Enhancing effect of cortisone on tuberculosis in the mouse. Lancet 1950

3. Historical Background Soon, reports of reactivation and dissemination of TB in humans following steroid use started appearing in literature. The advent of combination chemotherapy dramatically improved the outcomes in pulmonary TB to such an extent that corticosteroids were almost abandoned as an adjunct in pulmonary TB

4. Historical Background However some investigators demonstrated that clinical outcomes in certain forms of extrapulmonary TB (particularly meningitis) could potentially be improved by concurrent use of antimycobacterial agents and corticosteroids. Also, common occurrence of adverse outcomes such as death, neurological disability, and fibrotic sequelae such as pleural fibrosis/ loculations , constrictive pericarditis , and strictures of hollow viscera despite ATT has kept alive the possibility of steroids as an adjunctive treatment

5. Mechanism of action 1. MMP-9/VEGF inhibition Matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) play an important role in the disruption of the bloodbrain barrier in TBM* Corticosteroids significantly reduce the CSF levels of MMP-9 in patients with TBM* Corticosteroids also inhibit Mycobacterium tuberculosis induced production of VEGF in vitro** *Green JA et al PLoS One 2009 **van der Flier M et al Pediatr Infect Dis J 2004

6. Mechanism of action The role of MMP 9 in the pathogenesis of pulmonary tuberculosis similarly linked to disruption of lung extracellular matrix, leading to early dissemination of Myobacterium tuberculosis. Also, MMP 9 implicated in macrophage recruitment in granuloma formation in pulmonary tuberculosis. Taylor JL et al Infect Immun 2006

7. Mechanism of action 2. Decreases side effects Treatment-limiting severe adverse events that necessitated a change in ATT less common in corticosteroid arm (p=0.02), and such changes were independently associated with death on multivariable analysis* Hence steroids may improve outcomes by reducing frequency of adverse events that necessitate a change in ATT dose or regimen eg severe hepatitis * Thwaites et al. NEJM 2004

8. Mechanism of action 3. Genetic variation at the LTA4H gene affects the development of mycobacterial pathogenesis Corticosteroids could affect outcomes through interruption of mycobacterial pathogenesis mechanisms, rather than acting only by suppressing the immune response* In Vietnamese TBM study steroids only reduced mortality in patients who were LTA4H major allele homozygous with the hyperinflammatory phenotype** Steroids seemed to be detrimental in those with a hypoinflammatory phenotype *Tobin et al. Cell 2010 **Tobin et al. Cell 2012

9. CNS TB Largest RCT was conducted by Thwaites et al in Vietnam published in NEJM 2004

10. Methods 618 patients enrolled, 545 randomized 271 = ATT + Placebo 274 = ATT + Dexa HIV negative tratment naïve: 3 mon HRZS + 6 mon HRZ In HIV+: 3 mon HRZE + 6 mon HRZ In retreatment cases: 3 mon HRZES + 6 mon HRZ 1 Outcome = Death/Severe disability at 9 months 2 outcomes = Coma clearance time, Fever clearance time, time to relapase , presence of residual deficits Baseline – More HIV+ in placebo arm (16.1 vs 19.9%)

11. Long term outcomes 5 year Follow-up study published in 2011

12. Results 2-year survival tended to be higher in dexa arm (0.63 versus 0.55; p = 0.07) 5-year survival rates were similar (0.54 versus 0.51, p = 0.51) in both groups In patients with grade 1 TBM, but not with grade 2 or grade 3 TBM, the benefit of dexamethasone treatment tended to persist over time (five-year survival probabilities 0.69 versus 0.55, p = 0.07) but there was no conclusive evidence of treatment effect heterogeneity by TBM grade (p = 0.36) The dexa group had a similar proportion of severely disabled patients among survivors at five years as the placebo group (17/128, 13.2% vs. 17/116, 14.7%: p = 0.32)

13. Seven studies with1140 participants in total Only one study gave subgroup analysis of HIV+ vs Neg Overall, corticosteroids reduced the risk of death (RR 0.78, 95% CI 0.67 to 0.91; 1140 participants, 7 trials). Data on disabling residual neurological deficit from three trials showed that corticosteroids reduce the risk of death or disabling residual neurological deficit (RR 0.82, 95%CI 0.70 to 0.97; 720 participants, 3 trials). Adverse events included gastrointestinal bleeding, bacterial and fungal infections and hyperglycaemia , but they were mild and treatable.

14. Conclusion Corticosteroids should be routinely used in HIV-negative people with TBM reduce death and disabling residual neurological deficit amongst survivors. However, not enough evidence to support or refute a similar conclusion for those who are HIV positive

15. Dosage and duration

16. Tuberculous Pericarditis - CCP First RCT on TB pericarditis with CCP from Transkei, South Africa published in Lancet 1987

17. Methods 143 patients with active tuberculous constrictive pericarditis without significant pericardial effusion all received the same daily 6-month antituberculosis regimen of streptomycin, isoniazid , rifampicin , and pyrazinamide for 14 weeks followed by isoniazid and rifampicin . They were randomly allocated to receive in addition either prednisolone or placebo for the first 11 weeks Tab. Prednisolone 60 mg/day orally Day 1-28; 30 mg/day orally Day 29-56; 15 mg/day orally Day 57-70; 5 mg/day orally Day 71-77

18. Results Improvement was significantly more rapid in the prednisolone group - Faster rate of fall in the mean pulse rate and faster rate at which jugular venous pressure and level of physical activity became normal. During follow-up, 2 (4%) of the 53 prednisolone and 7 (11%) of the 61 placebo patients died from pericarditis , and 11 (21%) and 18 (30%), respectively, required pericardiectomy By 24 months 50 (94%) prednisolone and 52 (85%) placebo patients had a favourable status. 3 patients (1 prednisolone , 2 placebo) were normally active but were classified as not having achieved a favourable status

19. Tuberculous pericardial effusion

20. 240 patients with active tuberculous pericardial effusion received a 4-drug daily antituberculosis regimen for 6 months (2HRZS + 4HR). Those willing were randomly allocated to open pericardial biopsy and complete drainage of pericardial fluid on admission or no intervention All patients were randomly allocated to prednisolone or matching placebo for the first 11 weeks, on a double-blind basis

21. Results Complete open drainage on admission abolished the need for pericardiocentesis (p < 0.01) but did not influence the need for pericardiectomy for subsequent constriction or the risk of death. Among patients who did not have open drainage on admission, 2 (3%) of 76 given prednisolone compared with 10 (14%) of 74 given placebo died (p < 0.05) 6 patients in steroid group (8%) vs 9 controls (12%) required pericardiectomy (p = ns) 7 (9%) and 17 (23%) repeat pericardiocentesis (p < 0.05), and 3 (4%) and 7 (9%) open surgical drainage

22. 10 year combined follow-up

23. Results

24. TB Pericarditis in HIV Double blind RCT of 58 HIV seropositive patients aged 18–55 years with tuberculous pericardial effusion from Harare, Zimbabwe Received 4 drug ATT (HRZE) + placebo/steroids and follow-up for 18 mon Significantly lower deaths in steroid group (5 vs 10 deaths, p = 0.004) Significant Resolution of JVP, hepatomegaly and improvement in physical activity No difference in rate of resolution of effusion (echo/CT) Hakim et al, Heart, 2000

25. Results Steroids improve survival and reduce the need for pericardiectomy in both effusive and constrictive tubercular pericarditis but the number of RCTs is small Survival benefit also seen in HIV positive patients

26. Tubercular Pleural Effusion Most tubercular pleural effusions resolve spontaneously even without specific ATT in 2-4 months.* However, the resolution is often incomplete leaving behind loculated collections and considerable pleural thickening. It is believed that corticosteroids might reduce fibrotic sequelae and hasten resolution of pleural effusion as well as clinical symptoms. But this view is controversial and not evidence based Light RW. Pleural Diseases. Fifth Edition

27. 6 RCTs with 663 particpiants were analysed 1 study confined to HIV+ve patients

28. Results No evidence of any effect of corticosteroids on death from any cause (194 participants, 1 trial), respiratory function (191 participants, 2 trials), residual pleural fluid at eight weeks (399 participants, 4 trials), or pleural adhesions (123 participants, 2 trials) Steroid use was associated with less residual pleural fluid at four weeks ( RR 0.76 , 95% CI 0.62 to 0.94; 394 participants, 3 trials) and reduced pleural thickening ( RR 0.69 , 95% CI 0.51 to 0.94; 309 participants, 4 trials) However in studies which reported less pleural thickening and PFT was done, no significant difference found in PFT

29. In HIV+ve faster clinical as well as radiological improvement seen with steroids. However, it was also associated with a significantly increased risk of Kaposi’s sarcoma and a non-significant but higher risk of recurrent TB.

30. Conclusion As of now, there is not enough evidence to suggest use of steroids in Tubercular pleural effusions

31. TB Peritonitis Intense inflammation followed by post-Inflammatory fibrotic process in abdominal TB results in adhesions and subsequent intestinal obstruction Adjunctive steroids may offer benefit by minimizing inflammation and preventing the postinflammatory fibrosis and strictures However no RCTs available FM Sanai . Systematic review: tuberculous peritonitis Aliment Pharmacol Ther 2005

32. TB peritonitis Several small prospective and retrospective studies showed mild to moderate benefit – symptomatic relief and reduced need for laparotomy Retrospective study by Alrajhi et al in Saudi Arabia* n=35 (ATT = 26, ATT + steroid = 9) Steroid dose 0.5 to 1 mg/kg prednisolone (tapering) Mean duration 6.6 weeks (range 4 to 9 weeks) Method of diagnosis: Fluid or biopsy positive for AFB smear/culture Tubercles on laparoscopy with HPE s/o TB * Alrajhi et al Clin Infectious Diseases 1998

33. Results

34. Conclusion No RCTs available Few trials with small number of patients show possible benefit Hence as of now not enough evidence to recommend routine use

35. ARDS No RCTs Retrospective study* of 90 TB with acute respiratory failure patients who received mechanical ventilation Patients were divided into 2 groups based on radiology: 1.TB Pneumonia 2. Miliary TB Steroids given at Prednisolone or equivalent 1mg/kg/day *Kim et al ERS 2008

36. Endobronchial TB Prospective randomised trial of 34 patients* ATT vs ATT + Steroids given and followed up every 2 months for 1 year No significant difference in healing rate and sequelae on clinical/radiological/ bronchoscopic findings and Lung function Testing. *Park IW, et al. Respirology 1997

37. IRIS Results from the recovering immune system driving inflammatory reaction against tubercular antigens. More common in HIV+ Two types: Paradoxical response Unmasking response CDC Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, July 2013

38. Unmasking IRIS Sub-clinical undiagnosed TB who are started on ART TB becomes unmasked and present with an accelerated course - consolidation, rapidly progressive infiltrates, ARDS, lymphadenopathy , etc Treatment= ATT+/- steroids (if life threatening) CDC Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, July 2013

39. Paradoxical IRIS Occurs in patients diagnosed with TB and startred on ATT  Initially improve clinically But when ART started  Develop IRIS (15.7 %) Risk factors = Low CD4 count <100/ ul , disseminated TB, Early starting of ART (< 2 months) Fever, enlarging lymph nodes, effusions, splenomegaly , etc May be rarely life threatening ( eg tamponade / stridor due to LN compressing airway) Minor symptoms managed with NSAIDs, may require steroids if severe symptoms or life threatening complications ART delayed till at least 8 weeks CDC Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, July 2013

40. Steroids in IRIS Recent RCT from South Africa (2010) with 110 participants with HIV-TB-IRIS* Prednisolone 1.5 mg/kg/day for 2 weeks followed by 0.75 mg/kg/day for 2 weeks vs Placebo Those with life threatening manifestations exculded * Meintjes G et al. AIDS 2011

41. Steroids in IRIS Steroids resulted in a significant reduction of days hospitalized plus outpatient therapeutic procedures Significantly greater improvements in symptoms, Karnofsky score, and quality of life (MOS-HIV) in the prednisone versus the placebo arm Infections on study medication occurred in more participants in prednisone than placebo arm (27 vs 17 respectively; p=0.05), but there was no difference in severe infections (2 vs 4 respectively; p=0.40) Overall 10% were drug resistant TB * Meintjes G et al. AIDS 2011

42. Conclusion May be used for faster resolution of symptoms in IRIS However, drug resistance must also be ruled out before starting steroids More RCTs required, esp in patients with severe IRIS

43. Meta analysis of 41 trials which compared ATT+steroids vs ATT alone between 1955-2012 Steroid dose, duration and type variable Non-RCTs also included (Only 18/41 double blind RCTs) Pulm TB = 18 TBM = 9 Pericardial TB = 6 Pleural TB = 7 Abdominal TB = 1

44. Pulmonary TB Only 4/18 were >1990 Only 7/18 blinded Only 5/18 had Rif containing regimens Most relied on Sputum microscopy/culture However in 4/18 unclear how diagnosis was made In 2/18 diagnosis was based upon MTx + Radiology

45. PTB – overall results

46. PTB – Rif containing regimens Only one trial reported mortality in Rif era – this trial included only HIV patients Both overall and in Rif containing regimens – No statistically significant difference in mortality

47. TBM 9/41 trials were TBM (2 nd largest group) Only 4/9 were blinded 6/9 in Rif containing regimens 2/9 included required CSF microbiological diagnosis (culture/smear/PCR) Rest diagnosed based on clinical/radiological/CSF picture Culture/smear positivity between 20-73% in remaining studies Only mortality as outcome was considered as “event”

48. TBM Overall Rif containing Steroid No steroid Steroid No steroid Risk ratio of 0.85 in both overall and Rif containing regimens (barely significant)

49. TB Pericarditis 6/41 studies were in pericarditis 4/6 Rif containing regimens Only one study ( Lepper and Spies, 1963) had almost all cases culture confirmed Rest relied on clinical/radiological/pericardial fluid analysis 38-73% histology or culture confirmed cases in those trials

50. Steroid No steroid TB Pericarditis - Results Overall Rif containing Risk ratio of 0.61 in Rif containing regimens (barely significant) Steroid No steroid

51. TB Pleural effusion 7/41 in pleural effusion 6/7 used Rif containing regimens 4/7 had culture/biopsy confirmed TB In one study therapeutic aspiration done only in control group but not steroid group

52. TB Pleuritis – Results Overall Rif containing Steroid No steroid Steroid No steroid Statistically Non-significant

53. TB Peritonitis Singh et al 1969, n = 47, non- randomised trial ATT + Prednisone 30 mg/day for 3 months, then tapered (total 4 months) vs ATT only Isoniazid and streptomycin; after 3 months streptomycin replaced with PAS Tuberculosis confirmed by AFB smear However no deaths in either arms in the study – hence did not affect the meta-analysis

54. Authors’ conclusions ? ?

55. Criticism 1. Most of the mortality and hence the reducton in mortality was from the TBM and pericarditis studies (607/761 ~ 80%). Hence results weighted in favour of steroids because of results in these 2 groups 2. Overall no statistically significant difference found. Barely significant difference only in TBM, and TB pericarditis groups. Hence incorrect to conclude benefit across all groups

56. Criticism 3. Mechanism of death in TBM, Pericarditis and Pulm TB entirely different. Hence logic of using steroids in all organ groups and combining the studies questionable 4. Only mortality was used as outcome measure across all groups. Morbidity outcomes not measured. Recent trials show hardly any mortality in TB other than CNS/pericardial TB

57. Criticism 5. Most of the studies ( esp Pulm TB) are in pre- rifampin era No mortality in non-HIV PulmTB studies in multidrug era 6. Many trials non-blinded, non-RCT and done before modern, stringent guidelines 7. Steroid dose/duration/type highly variable 8. Sub-group analysis of HIV not available in many trials 9. Transkei trial ( pericarditis ) 10yr follow-up data not included

58. Summary Evidence based Indications 1. TBM 2. Adrenal insufficiency 3. IRIS 4. Pericarditis No evidence to support use Pulmonary TB ARDS Pleural effusion Endobronchial TB TB Peritonitis

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