Multidrug-resistant tuberculosis in children - …. Tuberculosis Epidemiology Diagnostics Treatment Vaccinology Immunology. ... Relationship between HIV and tuberculosis in children

Childhood Tuberculosis

Launch of the Centre for International Child Health

29th January 2016

James Seddon

Clinical Lecturer

Imperial College London

Introduction

• Paediatric tuberculosis fascinating topic• Quite a challenging field to work in• Exciting times

• More funding• More research• More interest

• Opportunity • Advance field• Make a significant difference to some of the most vulnerable and

marginalised children

Why is paediatric tuberculosis important?

Donald PR. Curr Opin Pulm Med 2002

Tuberculosis

Epidemiology

Diagnostics

Treatment

Vaccinology

Immunology

Tuberculosis

Epidemiology

Diagnostics

Treatment

Vaccinology

Immunology

Tameris et al. Lancet 2013; 381: 1021–28

Kaufmann et a. Lancet Respir Med 2014; 2: 301-320.

Tuberculosis

Epidemiology

Diagnostics

Treatment

Vaccinology

Immunology

Child with symptoms

Identification of host response to organism

Identification of organism

Phenotypic identification of

organism

Genotypic identification of

organism

Making a diagnosis

Phenotypic identification or

resistance

Genotypic identification of

resistance

The impact of Bacillus Calmette–Guérin

vaccination on tuberculin skin test responses in

children is age-dependent: evidence to be

considered when screening children for

tuberculosis infection

NIKS study team. Thorax. Under review

Anderson et al. NEJM 2014; 370: 1712-1723

Child with symptoms

Identification of host response to organism

Identification of organism

Phenotypic identification of

organism

Genotypic identification of

organism

Making a diagnosis

Phenotypic identification or

resistance

Genotypic identification of

resistance

Boehme et al. N Engl J Med 2010; 363: 1005-1015

Smear status

Smearpositive

Smearnegative Xpert MTB/RIF

GeneXpertpositive

GeneXpertnegative

Culture

Culturepositive

Culturenegative

Tuberculosis

Epidemiology

Diagnostics

Treatment

Vaccinology

Immunology

Why understanding the epidemiology important?

• Who, where, when• Targeting resources• Discrepancies• Sentinel event• Market assessment• Advocacy

Challenges

• Few cases confirmed• Difficult to obtain specimens• Paucibacillary disease• Limited laboratory capability• Greatest challenge in youngest

children

• Under-reporting• Previously only sputum smear-

positive cases reported• Private sector frequently not

reported

All children with TB

Children who are diagnosed

with TB

Children with TB who are reported to

WHO

Children with TB who present to health services

Dodd et al. Lancet Glob Health 2014; 2: e453-459

0

25

50

75

AFR AMR EMR EUR SEA WPR GLOBAL

WHO region

% o

f inc

iden

t MD

R−T

B in

chi

ldre

n

MDR type

DS

FQR

SLR

XDR

0

25

50

75

100

AFR AMR EMR EUR SEA WPR GLOBAL

WHO region

% o

f in

ciden

t T

B in

child

ren

DR type

S

INH

RIF

MDR

DST S INH RIF MDR FQR SLR XDR

Disease 753,096 40,289 6,156 18,603 2,566 2,731 1,988

Infection 57,305,870 3,088,543 452,635 1,413,608 201,005 228,580 167,223

Burden of drug-resistant tuberculosis

Dodd et al. In prep

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●

●

●

●

●

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●

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●

●

0.01

0.10

1.00

0 10 20 30

Months on ART

Incid

ence r

ate

ra

tio (

log s

ca

le)

First author, Year

●

●

●

●

●

●

●

●

●

●

Auld, 2014

Bakeera−Kitaka, 2011

Braitstein, 2009

Brennan, 2014

Crook, 2016

Curtis, 2012

De Beaudrap, 2013

Edmonds, 2009

Li, 2013

Walters, 2014

Author/Year

Berggren Palme, 2001

Bhat, 1993

Chintu, 1993

Chintu, 1995

Luo, 1994

Mukadi, 1997

Rose, 2012

Yassin, 2011

RE summary

HIV in

TB

(n/N)

47 / 377

36 / 96

88 / 237

42 / 61

67 / 110

31 / 160

18 / 33

14 / 141

OR [95 % CI]

HIV in

controls

(n/N)

2 / 122

18 / 134

26 / 242

15 / 160

16 / 167

0 / 161

22 / 93

3 / 153

7.9 [ 4.5 −13.7]

1.0 5.0 20.0 100.0

Odds Ratio (log scale)

Relationship between HIV and tuberculosis in children

Dodd et al. In prep

0 10000 20000 30000 40000 50000 60000 70000 80000

AFR

AMR

EMR

EUR

SEA

WPR

DeathsinchildrenduetoTB

Ontx(HIV-)

Offtx(HIV-)

Ontx(HIV+)

Offtx(HIV+)

Mortality in children due to tuberculosis

Child TB mortality

(absolute numbers)

0 to 524

524 to 1,978

1,978 to 6,080

6,080 to 18,080

18,080 to 42,332

No data

Dodd et al. In prep

Tuberculosis

Epidemiology

Diagnostics

Treatment

Vaccinology

Immunology

Treatment of MDR-TB disease

Treatment of MDR-TB infection

Treatment of DS-TB disease

Treatment of DR-TB

infection

Treatment of TB Meningitis

New Drugs

Children < 5 years

(aged 1-5 years TST positive or < 12 months regardless of TST)with known MDR-TB adult contact in the household

N=988 households

Randomise (1:1)

INTERVENTION ARM

Treatment Phase:6 months daily dosing of

levofloxacin

Follow-up phase:18 months post-treatment

CONTROL ARM

Treatment Phase:6 months daily dosing of

placebo

Follow-up phase:18 months post-treatment

Harare

Bulawayo

Ndole

Lusaka

Mbale

KampalaHo Chi Minh City

SURE

Tuberculosis

Epidemiology

Diagnostics

Treatment

Vaccinology

Immunology

Conclusions

• Childhood TB big problem globally• Important problem in the UK

• After a long period of little investigation lots of work now being done on paediatric TB

• Lots being done at Imperial

Questions?