ROLE OF STEROIDS IN TUBERCULOSIS

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ROLE OF STEROIDS IN TUBERCULOSIS
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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

DArcy-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

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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

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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
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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
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Mechanism of action

• 2. Decreases side effects
• Treatment-limiting severe adverse events that
  necessitated a change in ATT less common in
  corticosteroid arm (p0.02), 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
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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
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CNS TB

• Largest RCT was conducted by Thwaites et al in
  Vietnam published in NEJM 2004

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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
• 10 Outcome Death/Severe disability at 9 months
• 20 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)

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Long term outcomes

• 5 year Follow-up study published in 2011

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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)

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• 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, 95CI 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.

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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

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Dosage and duration
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Tuberculous Pericarditis - CCP

• First RCT on TB pericarditis with CCP from
  Transkei, South Africa published in Lancet 1987

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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

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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

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Tuberculous pericardial effusion
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• 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

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Results

• Complete open drainage on admission abolished the
  need for pericardiocentesis (p lt 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 lt 0.05)
• 6 patients in steroid group (8) vs 9 controls
  (12) required pericardiectomy (p ns)
• 7 (9) and 17 (23) repeat pericardiocentesis (p
  lt 0.05), and 3 (4) and 7 (9) open surgical
  drainage

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10 year combined follow-up
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Results
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TB Pericarditis in HIV

• Double blind RCT of 58 HIV seropositive patients
  aged 1855 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
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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

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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
31

• 6 RCTs with 663 particpiants were analysed
• 1 study confined to HIVve patients

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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 ?uid at eight weeks
  (399 participants, 4 trials), or pleural
  adhesions (123 participants, 2 trials)
• Steroid use was associated with less residual
  pleural ?uid 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

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• In HIVve faster clinical as well as radiological
  improvement seen with steroids.
• However, it was also associated with a
  significantly increased risk of Kaposis sarcoma
  and a non-significant but higher risk of
  recurrent TB.

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Conclusion

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

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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
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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
• n35 (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
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Results
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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

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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
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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
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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
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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
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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 lt100/ul,
  disseminated TB, Early starting of ART (lt 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
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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 Get al. AIDS 2011
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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 p0.05), but there was no
  difference in severe infections (2 vs 4
  respectively p0.40)
• Overall 10 were drug resistant TB

Meintjes Get al. AIDS 2011
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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

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• Meta analysis of 41 trials which compared
  ATTsteroids 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

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Pulmonary TB

• Only 4/18 were gt1990
• 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

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PTB overall results
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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

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TBM

• 9/41 trials were TBM (2nd 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

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TBM

• Overall
• Rif containing

Steroid No steroid
Steroid No steroid
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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

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TB Pericarditis - Results

• Overall
• Rif containing

Steroid No steroid
Steroid No steroid
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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

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TB Pleuritis Results

• Overall
• Rif containing

Steroid No steroid
Steroid No steroid
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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

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Authors conclusions
?
?
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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

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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

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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

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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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