PediatricTBMeningitis

AlexKay,MD
CaliforniaDepartmentofPublicHealth
ManyFacesofTB
April20th,2016

1
2
 Epidemiology
Pediatric
PediatricTBandTBmeningitis
TB and TB meningitis
(TBM)aresentineleventsas
markers of recent TB
markersofrecentTB
transmission
PPDConversion
I II III Disseminated(TBM)
Infecction

PrimaryPulmonary

0 1 2 3 4 5 6 7 8
Months
3
Maraisetal.Thenaturalhistoryofchildhoodtuberculosis.Int JTuberc LungDis.2004;8;392402
 Risk of TBM
RiskofTBM

A
AgeatInfection
I f i Ri k f Di
RiskofDisease
<1year Pulmonarydisease3040%
TBMormiliary disease1020%

12
1 2years
years Pulmonarydisease10
Pulmonary disease 1020%
20%
TBMormiliary disease25%

2yearsadult Pulmonary disease5%

TBMormiliary disease0.5%

Maraisetal.Thenaturalhistoryofchildhoodtuberculosis.Int JTuberc LungDis.2004;8;3924024

5
 TheEpidemiology,Clinical
The Epidemiology Clinical
CharacteristicsandOutcomesof
PediatricCentralNervousSystem
TB in California from 19932011
TBinCaliforniafrom1993 2011
 AlexDuqueSilva,MD
Al D Sil MD
PediatricInfectiousDiseasesClinician
ContraCostaCountyHealthDepartment

PennanBarry,MD,MPH
ChiefSurveillanceandEpidemiologySection
p gy
CaliforniaDepartmentofPublicHealth
Tuberculosis Control Branch
TuberculosisControlBranch

7
 Objectives
1. IdentifyriskfactorsforpediatricCNSTBand
deathfromTB

2. Determinehowclinicalanddemographic
factors impact outcome following CNS TB
factorsimpactoutcomefollowingCNSTB

3. Examinetheeffectoftimetotreatmenton
clinicaloutcomeandstageatpresentation

8
 Pediatric CNS TB
PediatricCNSTB
Ratesofclinicalmorbidity(4050%)and
mortality(1025%)inUSpediatricseries
li (10 25%) i US di i i
Largestseriesarefromresourcelimitedsettings
b hi hl
buthighlyvariable
i bl
Pooroutcomesassociatedwith
Youngage
Advancedclinicalstageatpresentation
Advanced clinical stage at presentation

Doerr C.etal.ClinicalandpublichealthaspectsofTBmeningitisinchildren.Jpeds;1995.
p p g p ;
Yaramis A.etal.CentralNervousSystemTuberculosisinChildren:Areviewof2016cases.Pediatrics1998.
vanWellG.etal.TwentyYearsofPediatricTuberculousMeningitis:Aretrospectivecohortstudyinthe
WesternCapeofSouthAfrica.Pediatrics;2009. 9
 Pediatric CNS TB in California
PediatricCNSTBinCalifornia
Increase 10%

PediiatricCNSTTB/PediatriicNonCNSSTB
14
proportion
proportionof
of 9%
8% 14
pediatricCNS
diseasein 7%
6% 14
Californiain2011 19
8
5% 13

4% 12 11
19 15 6
Promptedthis
Prompted this 3% 6 7 5
12 8 8
largeU.S. 2%
populationbased 1% 7
2

studyofpediatric 0%
CNSTB
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
10
 Factors For CNS Tuberculosis1
RiskFactorsForCNSTuberculosis
Risk
RegistryData

6, 93 pediatric T
6,193pediatricTB 5,993Casesof
casesinCalifornia NonCNSTB
TBregistrydata
TBRegistry1993 analysis
200CasesofCNS
2011
TB

1) Identifydemographicandclinicalfactorsassociated
Identify demographic and clinical factors associated
withpediatricCNSTB
2) IdentifyfeaturesassociatedwithdeathfromTB
1DuqueSilva,Aetal.RiskFactorsForCentralNervousSystemTuberculosis.

Pediatrics;2015. 11
 Demographics
Demographic CNSTB NonCNSTB Multivariate
Factors n(%)
( ) n(%)
( ) OR ((95%CI))
Age 04y 144(72) 2615(44) 2.6(1.64.2)

Ethnicity 150(75) 3787(63) 2.5(1.06.3)

Hispanic
U.S.birth^ 164(82) 3482(58) 1.9(1.32.9)
^76%ofUSbornchildrenwithCNSTBin2010
76% of US born children with CNS TB in 20102011
2011hadat
had at
leastoneforeignbornparent

DuqueSilva,Aetal.RiskFactorsForCentralNervousSystemTuberculosis.Pediatrics;2015. 12
 ClinicalCharacteristics
Clinical CNSTB NonCNSTB Multivariate
Characteristics N(%)
( ) N(%)
( ) OR(95%CI)
( )

TSTPositive 105(61)
( ) 5322(93)
( ) 0.1(0.10.2)
( )

CulturePositive 118(59)
( ) 1978(33)
( )
78 %ofculturesfromCSFand22%fromnonCSF

DuqueSilva,Aetal.RiskFactorsForCentralNervousSystemTuberculosis.Pediatrics;2015.
13
 Factors Associated with Death
FactorsAssociatedwithDeath
Died (N=32) Survived (N= Multivariate
N (%)
N(%) 6142) N(%) OR (95% CI)
OR(95%CI)
CNS TB 9(28) 191(3) 3.8(1.49.9)
Culture
Culture
25(78) 2056(34) 6.2(2.217.3)
Positive
Factors AssociatedwithSurvival
Associated with Survival
TSTPositive 8(25) 5418(88) 0.1(0.040.02)

Age,gender,ethnicity,countryoforigin,susceptibilities
andreceiptofDOTwerenotassociatedwithdeath

DuqueSilva,Aetal.RiskFactorsForCentralNervousSystemTuberculosis.Pediatrics;2015. 14
 Summary
Pediatric
PediatricCNSTBcasesweremorelikely<5
CNS TB cases were more likely <5
years,U.S. bornandHispanic

AFBculturepositiveandTSTnegativeresults
wereassociatedwithbothCNSTBanddeath
i d i h b h CNS TB d d h

CNSTBhada4.5%vs.0.4%mortalityfornon
CNSTB
15
 PediatricCNSTBChartReview
TBregistrydatalackinformationabout
1. Clinicalpresentation2.Outcome3.Time
totreatment
ChartReview
151(76%)
92(61%)with 79(86%)cases
cases
200Casesof
200 Cases of complete
complete with complete
withcomplete
reviewed
CNSTB outcome date
&18LHJ
information information
visited

Timeto
Clinical Outcome
Treatment
Features Analysis
y
A l i
Analysis

16
CNS TB Cli i l F t
CNSTBClinicalFeatures

04
0 4yrs
yrs

518yrs

17
 Presenting symptoms by age
Presentingsymptomsbyage
04yrs 5 18yrs
100
90
80
70
60
% 50
40
30
20
10
0

18
 Severity at Presentation
SeverityatPresentation
Total
MMRCI(50vs.16%) MMRCIII(31vs.3%)
MMRC N (%) 100

Stage I 30(26)
% 50
StageII 59(51)

StageIII 26(23) 0
I II III
*MMRC=ModifiedMedicalResearchCouncil
19
 CSFParameters
InitialLP N(%)
Normal 8(6)
Abnormal 125(94)
CSF Parameters
WBC10cells/l 115(92)
Lymphocytes>50% 67(63) Protein (70
vs.50%))
Glucose<40mg/dl 86(66)

Protein>100mg/dl 85(64)
Trend(p=0.09)fornormalCSFfromanEVDvsLP
(p )
Marais,Setal.TuberculousMeningitis;auniformcasedefinitionforuseinclinicalresearch.LancetInfectious
Disease,2010. 20
 ImagingFeatures
Neuroimaging N(%)
(MRI CT
(MRIorCTscan)
)
Normal 18(14)
Normal(24vs.10%)
Normal (24 vs 10%)
Basilar 75(58)
enhancement
Hydrocephalus 85(66)

I f t
Infarct 50 (39)
50(39) Hydrocephalus(78
vs.35%)
Focallesion 32(25) Infarct(47vs.19%)
Infarct (47 vs. 19%)
Marais,Setal.TuberculousMeningitis;auniformcasedefinitionforuseinclinicalresearch.LancetInfectious
Disease,2010. 21
 ClinicalFeatures
Siteofdisease N(%)
CNSTBonlyy 90(69)
( )
Disseminated 39(30)
Other 1(0.8)
CNSOnly(86vs.63%)
CNS Only (86 vs 63%)
CultureforMtb
Positive 88(58)
Negative 63(41)
Susceptibilityresults
DisseminatedTB(37
Pansusceptible
ibl 69(78)
69 ( 8) vs.8%)
INHresistance 4(4) Culture+(64vs.44%)
MDR 3 (3)
3(3) Pansusceptible(86vs.
p (
PZAmonoresistance 10(11) 53%)
22
 Treatment
N(%)
IInitialTBregimen
iti l TB i
3drugs(notEMB) 79(56)
4 CNS drugs
4CNS 62 (44)
62(44)
Steroids
4drugs50vs.30%
Yes 106(70) Surgery57vs.21%
g y
No 45(30)
Surgery
EVD/VP h t
EVD/VPshunt 70(46)
70 (46)
Tuberculoma biopsy 7(5)

23
Predictorsofgoodvs.
Predictors of good vs.
poor outcome
pooroutcome
Measuring posttreatment
Measuringpost treatmentoutcomes
outcomes
Sixdeficitareasassessed
Hearing
Hearing,Vision,Language,Ambulation,Development,
Vision Language Ambulation Development
Focalneurologicdeficits
Developedastandardizedprotocolforclassifyingdeficits
Caseswithinformationon4areasincludedforoutcome
analysis
Determinationofoutcomes
Determination of outcomes
Good:Normal(nodeficits)ormild(1areaabnl)clinical
sequelae
Poor:Moderate(2areasabnl)/Severeclinicalsequelae(3
areasabnl orcompletedeficitin1)ordeath

25
 Pediatric CNS TB Outcomes
PediatricCNSTBOutcomes

Goodoutcome=40% Pooroutcome=60%

Mild
Mild Moderate SSevere
Normal clinical clinical clinical Death
20.7% sequelae sequelae sequelae 13%
19.6% 13% 33.7%

N=37 N=55

0 20 40 60 80 100
%
N = 92
N=92
26
 Clinical Severity Score
ClinicalSeverityScore
ClinicalSeverity
Clinical Severity Good
Good Poor
Poor Adjusted for
Adjustedfor
Score* Outcome Outcome Age
PRR^ (95%CI)
( )
Stage I 13(39) 2(5) Ref
Stage II 17 (52)
17(52) 23 (52)
23(52) 1.2 (0.991.5)
1.2(0.99 1.5)

StageIII 3(9) 19(43) 1.4(1.11.9)

*MMRC=ModifiedMedicalResearchCouncil
^PRR=PrevalenceRateRatio

28
 ClinicalParameters
CSFAnalysis Neuroimaging
IncreasedProtein
I dP t i Infarction
I f ti
*PRR1.2(1.031.4) *PRR1.2(1.041.3)

Multivariate
Cli i l S
ClinicalSeverity
it A
Age
MMRCIIorIII PRR 1.4(1.2 1.7)
PRR 1.2(1.03 1.5)

*Ageadjusted 29
Nodifferencedetectedingoodvs.
poor outcome for:
pooroutcomefor:
ClinicalSymptoms
y p
MTb culturepositive
Susceptibilities
Clinicalcasedefinition:definitevs.probablevs.possible
Numberofdrugsinregimen
Steroiduse
Durationoftherapy
Surgical treatment
Surgicaltreatment

30
 Impactoftimetotreatmenton
outcome?
2
1

TB Post
Symptom 1st medical
treatment treatment
onset encounter
started outcomes

1. DateofTBtreatment Dateofsymptomonset
2. DateofTBTreatment Dateof1st medical
encounter
31
 TimetoTreatment
Good Poor Adjustedfor
Age PRR
Outcome Outcome
1.Sx OnsetTBRx
median(days) 16 15 n/a
<10days
d 8(22)
( ) 8(17)
( )
10days 28(78) 39(83) 1.04(0.91.2)
2.1stMedical
EncounterTBRx
median(days) 11 11 n/a
<7days
7d 11 (31)
11(31) 12 (27)
12(27)
7days 24(69) 32(73) 1.01(0.91.2)
Noassociationbetweentimefromsymptomonsettopresentation
No association between time from symptom onset to presentation
andtheclinicalstageatpresentation
32
 1.Earlydiagnosisremainscriticalforagoodoutcome
2.Noclearlinearrelationshipbetweentimetotreatmentand
outcomeinthisanalysis
SymptomOnset
Good Outcome
GoodOutcome
1st MedicalEvaluation
nicalSttage
IIIIIII

Treatment
TBBMClin

PoorOutcome

Time 33
 SourceCaseIdentified
N=58(38%)
Contact
Contact SourceCase
Source Case
Investigation Investigation
40% 57%

61% Poor Outcome

61%PoorOutcome 76% Poor Outcome
76%PoorOutcome
Source Parent52% Foreign
g
casefound Relative40% Born
inhome Other8% 78%
95%
34
 Limitations
Nopre
No preexisting
existingvalidatedoutcomescale
validated outcome scale
Limitedaccesstoprehospitalizationrecords
Differenceingroupthathadoutcomesavailable
ff h h d l bl
Smallnumberslimited:
Powertodetectdifferencesbetween
outcomegroups
Abilitytoadjustforconfoundingvariables

35
 Summary
Almost2/3ofpediatricCNSTBcasesinCaliforniahad
poorclinicaloutcomes

Ageandseverityofdiseaseatpresentationare
g y p
associatedwithpooroutcomebutarenoteasily
amenabletointervention

OutcomesarebetterinStage1diseasebutrecognition
ofearlynonspecificCNSTBsymptomsischallengingin
younginfantsandwithanincreasinglyraredisease

36
 Clinical Interventions For CNS TB
ClinicalInterventionsForCNSTB
Think
ThinkCNSTBfornon
CNS TB for nonspecific
specificsymptomssuch
symptoms such
asfeverandvomitinginayounginfantwith
TB exposure or who is high risk for exposure
TBexposureorwhoishighriskforexposure
Treatempiricallybasedonimagingfindings,
CSF parameters and the absence of another
CSFparametersandtheabsenceofanother
etiology
RemembersteroidsforCNSTBtreatmentand
R b id f CNS TB d
thatTSTisonlypositiveinabout50%ofCNS
TBcases
TB
37
 Public health focus on TB prevention
PublichealthfocusonTBprevention
Prioritizerapid contactinvestigationsinvolving
children with appropriate treatment
childrenwithappropriatetreatment
EmphasizeLTBIriskassessment/testing/
treatment for adult caregivers (Cocooning)
treatmentforadultcaregivers(Cocooning)
EmphasizeroutineTBriskassessmentsin
infants (2 weeks 6 mo 1 yr annually)
infants(2weeks,6mo,1yr,annually)
ConsiderBCGincommunitieswithhighratesof
recent TB transmission or for infants with
recentTBtransmissionorforinfantswith
extendedtraveltohighTBincidencecountries

38
 Acknowledgements
AlexDuque

Alex DuqueSilva
CDPH
Silva,MD
MD Thank You!
ThankYou!
PennanBarry,MD,MPH
VarshaNimbal,MPH
JenniferFlood,MD,MPH
AmitChitnis,MD,MPH
, ,
NehaShah,MD,MPH
JaniceWastenhouse,MPH
Saul Kanowitz
SaulKanowitz
GiselaSchecterMD,MPH

InfectiousDiseasesDepartmentat
CHRCO
39