cns tuberculosis: an update · tb meningitis. arnold rich. 1893-1968. bull john hopkins hosp....
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Guy ThwaitesDirector, Oxford University Clinical Research Unit
Wellcome Trust Africa Asia ProgrammeViet Nam
CNS tuberculosis: an update
@Thwaitesguy @oucru_vietnam
TB meningitis
Arnold Rich1893-1968
Bull John Hopkins Hosp. 1933;52:5-37.
Bacteraemia ↑Inflammation
DEATH(25%)
↑bacteria
TB meningitis: pathology• Basal meningitis• Hydrocephalus• Infarcts• Tuberculomas
Time from start of treatment (days)
3002001000
Prop
ortio
n aliv
e
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
.0
HIV negative
HIV positive
Log rank P<0.001
Why study TB meningitis?545 adults with TBMConservative estimate: 100,000 cases each year
TBM is a medical emergency
Treatment before the onset of coma is the greatest benefit a physician
can give a patient with TBM
The problem: rapid diagnosisClinical algorithms CSF ZN stain, microscopy, culture
GeneXpertCan we get to this?
Is a ZN stain/culture of the CSF useful?
Modern confirmation of the method• 132 consecutive adults
with TBM• AFB seen in CSF of 77
(58%)• AFB seen or cultured in 94
(71%)
J Clin Microbiol. 2004 Jan;42(1):378-9.
1 2 3 4 5
Volume of CSF examined (mls)
0
25
50
75
100
M.tb
isola
ted f
rom
CSF
(%)
40
5762
80 78
0-1.9 2.0-3.9 4-5.9 6-7.9 >8
Odds ratio CI P-value
Duration of symptoms (days) 1.05 1.00-1.10 0.050
Volume of CSF (ml) 1.36 1.06-1.75 0.017CSF neutrophils (% of white cell count)
1.03 1.01-1.05 0.008
CSF lactate (mmol/liter) 1.42 1.16-1.73 0.001CSF/blood glucose ratio 0.03 0.02-0.62 0.023
Predictors of positive bacteriology
Lancet Infect Dis. 2018 Jan;18(1):68-75
• 129 HIV infected adults, suspected TBM• 23 definite/probable TBM• Sensitivity:
Ultra: 70% (47-87)Xpert: 43% (23-66)Culture: 43% (22-66)
• Likelihood of positive test ++ if >6mls CSF tested
A randomised diagnostic study comparingson of GeneXpert Ultra MTB/RIF and GeneXpert MTB/RIF for the diagnosis of tuberculous meningitis
Ultra Xpert ZN smear MGIT culture
Reference standard: definite, probable and possible TBMPositive tests 25/53* 21/53 77/108 45/94Sensitivity (95% CI) 47·2%
(34·4-60·3%)
39·6%
(27·6-53·1%)
71·3%
(62·5-79.0%)
47·9%
(38·0-57·9%)Specificity (95% CI) 100%
(92·0-100%)
100%
(92·6-100%)
100%
(96·1-100%)
100%
(95·6-100%)Reference standard: definite and probable TBMPositive tests 25/43 21/43 77/88 45/75Sensitivity (95% CI) 58·1%
43·3-71·6%
48·8%
34·6-63·2%
87·5%
79·0-92·9%
60·0%
48·7-70·3%Specificity (95% CI) 100%
93·4-100%
100%
93·8-100%
100%
96·8-100%
100%
96·4-100%
Ultra Xpert
HIV negative HIV positive HIV negative HIV positiveReference standard: definite and probable TBMPositive tests 14/29 9/11 8/27 10/12Sensitivity (95% CI)
48·3%31·4-65·6%
81·8%52·3-94·9%
29·6%15·9-48·5%
83·3%55·2-95·3%
TBM management
Enhance bacterial killing
Control intra-cerebral inflammation
INTENSIVE CARE
Intra-cerebral drug penetration
INH
PZARifampicinETHSM
Blood-brain barrier
New agentse.g. bedaquilinedelaminid
?
LevofloxacinMoxifloxacin
Lancet Infect Dis. 2013 Jan;13(1):27-35.
60 Indonesian Adults. Oral rifampicin (450mg) vs IV 600mg for 1st 2 weeks
N Engl J Med. Jan 2016;374:124-134.
817 Vietnamese adults. Standard regimen vs rifampicin 15mg/kg + levofloxacin (1g/day)For 1st 2 months
PK/PD analysis from the trial
• No relationship between rifampicin exposure and outcome
• Strong independent relationship between isoniazid exposure and survival
• 38 deaths; 28 were fast metabolisers
Rifampicin PK Standard therapy Intensified therapy Day 14 CMAX plasma (mg/L) 10.6 (2.8-21.6) 18.2 (0.9-41.8)Day 14 AUC0-24 plasma (h∙mg/L) 48.2 (18.2-93.8) 82.5 (8.7-161.0)Day 14 CMAX CSF (μg/L) 189.3 (64.9-566.6) 330.8 (35.1-828.8)Day 14 AUC0-24 CSF (h∙mg/L) 3.5 (1.2-9.6) 6.0 (0.7-15.1)
Controlling intracerebral inflammation: adjunctive dexamethasone
N Engl J Med. 2004;351(17):1741-51
545 Vietnamese adults. 6-8 week dexamethasone vs placebo
How does dexamethasone save lives?
Infarcts
Hydrocephalus
Thwaites et al. Lancet Neurol. 2007Simmons et al. J Immunol. 2007
Green J et al. PLOS One. 2009
LTA4H Genotype determines survival and dexamethasone responsiveness
CC genotype (LTA4H low) CT genotype TT genotype
Survival in 182 HIV uninfected Vietnamese adults with TBM treated with or withoutAdjunctive dexamethasone
Dex Dex
Dex
Cell. 2012; 148, 434–446
Homozygotes
P<0.001
Heterozygotes
J Infect Dis. 2017 Apr 1; 215(7): 1020–1028.
All patients(n=764)
HIV-uninfected(n=439)
HIV-infected(n=325)
TTCT
CC
Will more directed, ‘intelligent’ host-directed therapies improve outcome?
- Aspirin- Thalidomide- Anti-TNF biologicals- Interferon-gamma- Developing list of ‘rational’ candidates
Sir John Vane FRSNobel Acceptance1982
Aspirin
J Neurol Sci. 2010 Jun 15;293(1-2):12-7. 2010.
P=0.03 P=0.18
J Child Neurol. 2011 Aug;26(8):956-62 J Neurol Sci. 2010 Jun 15;293(1-2):12-7
Mechanism of action
↑Resolvins↑Protectins↑Maresins↑Lipoxins
Hypotheses
Low dose aspirin (<200mg/day)
Inhibits TXA2 ↓ infarcts
↑ survivalHigh dose aspirin (>600mg/day)
Anti-inflammatoryPro-resolving
↓ inflammation
Randomised double blind placebo-controlled trial of aspirin 81mg or 1000mg for TBM
Elife. 2018 Feb 27;7. pii: e33478.
Safety (ITT population)
Placebo 81mg 1000mg Placebo 81mg 1000mg Placebo 81mg 1000mg
Cerebral bleed Any GI bleed Either
ITT, PP and Planned sub-group analysis Placebo vs aspirin 81mg
Note: P-value for interaction between diagnostic criteria and outcome. P=0.01
ITT, PP, and Planned sub-group analysisPlacebo vs 1000mg aspirin
Efficacy in those with definite TBM
P=0.03
New infarcts by day 60 Deaths by day 60 Deaths or infarcts
Dose-dependent impact of aspirin on CSF inflammatory mediators
Lancet Infect Dis. 2018 Jan 23. pii: S1473-3099.
Distinct TBM metabolome
CSF tryptophan concentrations predicts survival and are controlled by 11 genetic loci
Critical care and TBM
Sodium/hyponatraemia
Glucose/diabetes
Temperature
Mechanical VentilationNutrition Rehabilitation
Current and future clinical research priorities
Prevention• Vaccine: Adult/HIV-infected
Diagnosis• High sensitivity; resistance detection
Treatment• PK optimised regimens; old and new drugs• Can we improve upon corticosteroids?• Precision/personalised anti-inflammatory therapy?• Evidence-based critical care
OUCRU Vietnam TB group
Nguyen Thuy Thuong ThuongLalli Ramakrishnan
Jes DalliReinout van Crevel and friends in Bandung
Raph Hamers, Darma Imran and friends in Jakarata