Recent Advances in the Diagnosis and Treatment of Tuberculous Pericarditis

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1 Recent Advances in the Diagnosis and Treatment of Tuberculous Pericarditis Bongani M Mayosi FACULTY OF HEALTH SCIENCES GROOTE SCHUUR HOSPITAL AND UNIVERSITY OF CAPE TOWN

2 Figure 1 Apical four chamber view of a two dimensional echocardiogram of a patient with tuberculous pericardial effusion showing multiple fibrin strands as linear or band like structures crossing the pericardial space or protruding from the epicardium or parietal pericardium and exudates. LA, left atrium; LV, left ventricle; Per eff, pericardial effusion; RA, right atrium; RV, right ventricle. George, S et al. Heart 2004;90: Copyright 2004 BMJ Publishing Group Ltd.

3 Relative risk (95%CI) of death for individuals treated with adjuvant prednisolone or placebo. Ntsekhe M et al. QJM 2003;96: Association of Physicians 2003; all rights reserved

4 Relative risk (95%CI) of pericardiectomy for pericardial constriction in individuals treated with adjuvant prednisolone or placebo. Ntsekhe M et al. QJM 2003;96: Association of Physicians 2003; all rights reserved

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6 The Investigation of the Management of Pericarditis Registry IMPI was born in 2004 (Named after the Zulu Warriors who vanquished the armies of Queen Victoria)

7 Contemporary Use of Adjunctive Steroids in TB Pericarditis Number of participants Cameroon Gauteng W Cape KZN E Cape Nigeria No adjunctive corticosteroids Adjunctive steroids Wiysonge C et al. Int J Cardiol 2008; 124:

8 Impact of HIV infection: Mortality %.75 26% 40% Survival time (days) Clinical HIV Overall No clinical HIV Mayosi BM et al. S Afr Med J 2008; 98:36-40

9 Impact of HIV infection: Mortality s s s s c s 1970s 1980s 1990s 2004c Mayosi BM et al. S Afr Med J 2008; 98:36-40

10 Impact of HIV infection: Constriction Died within 3 months 37 No clinical assessment available (telephonic followup) Consented to HIV test Clinical No Clinical HIV HIV seropositive HIV seronegative HIV (42) (79) (33) (34) Constrictive pericarditis seen in 6 months 2/42 (5%) 13/79 (16%) 0 9/34 (26%) Ntsekhe M et al. PLoS ONE 2008; 3:e2253

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12 60 ml pericardial fluid sent for measurement of: 1. ADA 2. LDH 3. Cell counts 4. Smear microscopy 5. Liquid culture 6. Xpert MTB/RIF

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14 Definite TB: - Fluid (pericardial or non-pericardial) culture-positive - Granulomatous inflammation on the pericardial tissue histology Probable TB: - Symptomatic but not meeting the criteria for definite - Started on empirical anti-tb treatment in the absence of an alternative diagnosis Non-TB: - No microbiological evidence of TB - Alternative diagnosis available, and not started on anti-tb treatment

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16 Accuracy of Xpert MTB/RIF and ADA (Definite TB versus Non-TB) - Sub-optimal sensitivity of Xpert - ADA relatively low specificity

17 Accuracy of unstimulated IFN-γ (Definite TB versus Non-TB) - uifn has excellent sensitivity and specificity - Just under 1/10 positive results will be a false positive - Just over 1/50 negative results will be false negative Assuming a pre-test probability of 49% (seen in the parent study at Cape Town GSH)

18 Key findings: diagnosis of TB pericarditis Due to low bacillary load in the pericardium, methods that rely on direct detection of TB bacilli will always have a limited sensitivity uifnγ offers superior accuracy for the diagnosis of microbiologically confirmed TBP compared to the new Xpert MTB/RIF test and the established ADA assay; Xpert MTB/RIF could confirm a TB diagnosis (and allow for drug susceptibility testing) in two thirds of patients with suspected TBP; PF Xpert MTB/RIF, when combined with either ADA or uifnγ, offers >97% sensitivity and specificity for TBP diagnosis.

19 The Investigation of the Management of Pericarditis Trial The IMPI Trial

20 Background Tuberculous (TB) pericarditis affects a million people per year. The case fatality rate is 26% despite anti-tb treatment. Hypotheses: Anti-inflammatory effect of Steroids may reduce morbidity (i.e., cardiac tamponade and constrictive pericarditis) and mortality in TB pericarditis. Immunotherapy with Mycobacterium indicus pranii (Mw), a non-pathogenic environmental organism, may enhance cure of TB. However, the effectiveness and safety of Steroids and Mw in TB pericarditis are uncertain.

21 IMPI Trial: Primary Objectives To assess the effect of Prednisolone and Mw in definite or probable TB pericardial effusion on: (1) The composite outcome of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis; (2) The incidence of opportunistic infection and malignancy.

22 IMPI Trial: Study Design PATIENTS WITH DEFINITE OR PROBABLE TUBERCULOUS PERICARDIAL EFFUSION RANDOMIZATION PREDNISOLONE X 6 weeks PLACEBO X 6 weeks M. w X 5 Doses Placebo X 5 Doses M. w X 5 Doses Placebo X 5 Doses Follow-up data at hospital discharge, at weeks 2, 4 and 6, and months 3, 6 and thereafter 6 monthly for 2 years, and annually up to 4 years

23 IMPI Trial Interventions Prednisolone or placebo 120 mg/day in 1st wk, followed by 90 mg/day in 2nd wk, 60 mg/day in 3 rd wk, 30 mg/day in 4 th wk, 15 mg/day in 5 th wk, and 5 mg/day in 6 th wk. M. w injection or placebo 5 doses of 0.1 ml intradermal injection at enrolment, then 2 wks, 4 wks, 6 wks, and 3 mo.

24 International Coordinating Center Population Health Research Institute HHS and McMaster University, Hamilton, Canada Sponsors: Canadian Institutes for Health Research, Cadila Pharma, South African Medical Research Council, Lily and Ernst Hausmann Trust IMPI: Organization 19 centres, 8 countries African Coordinating Center University of Cape Town South Africa

25 IMPI Trial: Target Population Inclusion Criteria Age 18 years Pericardial effusion on echocardiography Evidence of definite or probable TB pericarditis Within 1 week of starting of anti-tb treatment Exclusion Criteria Presence of an alternative cause of pericardial disease Pregnancy Use of corticosteroids in the previous month Allergy to the M. w

26 IMPI Trial: Baseline Characteristics Characteristics Prednisolone Placebo N Age in yrs Female % HIV positive % Centesis done % Definite TB % Probable TBP % Non-TB cause % On anti-retrovirals %

27 Effect of Prednisolone on Outcomes Prednisolone Placebo Hazard Ratio (95% CI) P N(%) N(%) Primary efficacy outcome 168 ( 23.8) 170 (24.5 ) 0.95 ( ) 0.66 Death Tamponade Constriction Hospitalization 133 ( 18.8) 115 (16.6 ) 1.15 ( ) ( 3.1 ) 28 ( 4.0 ) 0.77 ( ) ( 4.4 ) 54 ( 7.8 ) 0.56 ( ) ( 20.7) 175 (25.2 ) 0.79 ( ) 0.04 Opportunistic infection Malignancy AE, Not Hospitalized Injection side effect 78 ( 11.0) 68 ( 9.8 ) 1.16 ( ) ( 1.8 ) 4 ( 0.6 ) 3.27 ( ) ( 24.2) 149 (21.5 ) 1.15 ( ) ( 19.8) 137 (19.7 ) 0.98 ( ) Prednisolone Better Placebo Better

28 Effect of M. indicus pranii on Outcomes Mycobacterium Placebo Hazard Ratio (95% CI) P N(%) N(%) Primary efficacy outcome 156 ( 25.0) 152 (24.3 ) 1.03 ( ) 0.81 Death Tamponade Constriction Hospitalization 119 ( 19.0) 111 (17.8 ) 1.07 ( ) ( 3.5 ) 22 ( 3.5 ) 0.99 ( ) ( 5.8 ) 37 ( 5.9 ) 0.97 ( ) ( 24.3) 141 (22.6 ) 1.09 ( ) 0.46 Opportunistic infection Malignancy AE, Not Hospitalized Injection side effect 75 ( 12.0) 61 ( 9.8 ) 1.25 ( ) ( 1.8 ) 3 ( 0.5 ) 3.69 ( ) ( 23.7) 149 (23.8 ) 1.00 ( ) ( 41.4) 18 ( 2.9 ) 18.51( ) < Mycbacterium Better Placebo Better

29 IMPI Prednisolone: Time To Constriction

30 IMPI: Time To Malignancy

31 4. The beneficial effects of prednisolone on constriction and hospitalization were similar in HIV-positive and HIV-negative patients. IMPI Trial: Conclusions In those with definite or probable TB pericardial effusion: 1. Prednisolone for 6 weeks and M.w for three months had no significant effect on the combined outcome of death from all causes, cardiac tamponade requiring pericardiocentesis or constrictive pericarditis. 2. Both therapies were associated with an increased risk of HIVassociated malignancy. 3. However, use of prednisolone reduced the incidence of constrictive pericarditis and hospitalization.

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33 Kaplan Meier Estimates of the Time to the Primary Efficacy Outcome, According to Treatment Group. Mayosi BM et al. N Engl J Med 2014;371:

34 Fig. 4 EBioMedicine , DOI: ( /j.ebiom ) Copyright 2015 The Authors Terms and Conditions

35 Fig. 2 EBioMedicine , DOI: ( /j.ebiom ) Copyright 2015 The Authors Terms and Conditions

36 Fig. 3 EBioMedicine , DOI: ( /j.ebiom ) Copyright 2015 The Authors Terms and Conditions

37 Fig. 4 EBioMedicine , DOI: ( /j.ebiom ) Copyright 2015 The Authors Terms and Conditions

38 Fig. 5 EBioMedicine , DOI: ( /j.ebiom ) Copyright 2015 The Authors Terms and Conditions

39 Fig. 6 EBioMedicine , DOI: ( /j.ebiom ) Copyright 2015 The Authors Terms and Conditions

40 Conclusion There was no significant difference between isoniazid pericardial fluid and plasma concentrations, and isoniazid peak concentrations were above MIC. The concentrations of rifampicin and ethambutol in pericardial were low and < MICs of M tuberculosis The ph in pericardial fluid was alkaline, which would mean that pyrazinamide effect would be compromised A new regimen that overcomes these limitations is needed for the treatment of TB pericarditis.

41 The 2nd Investigation of the Management of Pericarditis Trial (IMPI-2) A Trial of Complete Percutaneous Pericardial Drainage Facilitated by Intrapericardial Alteplase Compared to Conventional Pericardiocentesis When Indicated in Adults with Large Pericardial Effusion due to Tuberculous and Non-tuberculous Pericarditis