Paediatric Tuberculosis: Management Challenges

Paediatric tuberculosis:

management challenges Steve Graham Centre for International Child Health University of Melbourne Department of Paediatrics Royal Children’s Hospital Melbourne Child Lung Health International Union Against Tuberculosis and Lung Disease Paris Chairman, Child TB subgroup Stop TB Partnership, WHO

Childhood TB and TB control • Traditional public health approach: Case-finding and effective treatment of infectious TB cases will prevent childhood TB • Therefore, child TB historically afforded a low priority by NTPs • But - this disregards the impact of TB on childhood morbidity and mortality - child TB reflects recent TB control - infected children become adults with disease

Putting child TB on the global public health agenda Child TB subgroup of Stop TB Partnership formed 2003 …opportunities provided by expanding global TB control strategy WHO Stop TB Symposium, Global Lung Health Conference 2011 "Meeting the unmet needs of women and children for TB prevention, diagnosis and care: expanding our horizons“

Children an integral part of the post-2015 Global TB control strategy “towards elimination” …opportunities provided by renewed focus on child survival post-2015 TB being considered in the context of child survival: important cause or comorbidity in children with pneumonia, malnutrition, HIV and meningitis

“Know your epidemic�

need for better data

Child TB is common wherever TB is common – but how common?

Estimated TB incidence rates, 2011 Global Tuberculosis Report 2012

“best estimates” of 490 000 cases of TB in children per year = 6% of the global burden the assumption that the ratio of notified to incident cases at global level in 2011 was the same in children as for adults is not necessarily correct and likely to lead to under-estimates 64,000 deaths but TB-related deaths in children are often attributed to HIV or pneumonia or malnutrition

Reported: range 1%-40%

Important factors: Incidence of TB Demographics - age Effectiveness of case-finding and management Prevalence of risk factors in children

BCG coverage

Donald PR. Curr Opin Pulm Med 2002

Limitations of child TB data Reported burden of child TB ranges from 2% to 40%

Under-recognition Recent prevalence survey in Laos: Culture-positive TB was 606 per 100,000 Only 78 children treated for TB in 2012 i.e. <5 per 100,000 children

Under-reporting Recent study from Java, Indonesia: Only 1.6% of 4,821 TB cases in children were registered with NTP Lestari T, et al BMC Public Health 2011

â&#x20AC;&#x153;Diagnosis is difficultâ&#x20AC;?

the most critical step

Incidence by age when TB was first diagnosed Average annual case rate (per 100,000)

400

Diagnostic challenges

300

200

100

0 0

5

10

15

20

25

30

35

Age (years) Comstock GW, et al. Am J Epidemiol 1974;99:131-8

40

Clinical challenges are the diagnostic challenges • Young age • Acute severe pneumonia • HIV-infected • Malnourished • MDR TB

Recommended approach to diagnose TB in children WHO Guidance for NTP on management of TB in children 2006

1. Careful history includes history of TB contact symptoms suggestive of TB

2. Clinical examination includes growth assessment

3. Tuberculin skin test 4. Bacteriological confirmation whenever possible 5. Investigations relevant for suspected PTB or suspected EPTB 6. HIV testing

Recommended approach to diagnose TB in children 1. Careful history includes history of TB contact symptoms suggestive of TB

2. Clinical examination includes growth assessment

Note that TST and culture are often unavailable. Neither is required for a decision to treat for TB in most cases.

CXR is an important tool for diagnosis of TB in children

Sputum should be collected for 3. Tuberculin skin test smear microscopy if available 4. Bacteriological confirmation possible as whenever in older children 5. Investigations relevant for suspected PTB or suspected EPTB 6. HIV testing routine

Published diagnostic studies in children versus adults Test

Publications Adults

Children

> 6000

140

Fluorescence Microscopy (FM)

299

1

LED-FM

33

0

MODS

31

2

BACTEC 960

49

0

Fully automated BACTEC

13

0

Line Probe assays

113

1

LAMP

13

0

Automated NAAT (Xpert)

32

?

Fine needle aspiration

Published diagnostic studies in children versus adults Test

Publications Adults

Children

> 6000

140

Fluorescence Microscopy (FM)

299

1

LED-FM

33

0

MODS

31

2

BACTEC 960

49

0

Fully automated BACTEC

13

0

Line Probe assays

113

1

LAMP

13

0

Automated NAAT (Xpert)

32

9

Fine needle aspiration

Expert opinion to Xpert 16 studies in children to date â&#x20AC;&#x201C; published and unpublished

Sensitivity 66% compared to culture Specificity >98% compared to culture Time to diagnosis < 2 days Yield from induced sputum higher than from gastric aspirate

Aim is to support diagnosis and management by health workers at primary and secondary care levels where most cases present - when and how to treat and when to refer

Treatment needs specific to children

Revised dosages for children up to 30 kgs:

Rifampicin Isoniazid Pyrazinamide Ethambutol

15 (10-20) mg/kg/day 10 (10-15) mg/kg/day 35 (30-40) mg/kg/day 20 (15-25) mg/kg/day

The new revised dosages in children < 2 years resulted in higher blood levels for all three first-line drugs Thee S et al, AAC 2011

Survey of NTPs and current recommendations

Dec 2011-Feb 2012

12 use 2006 dosage guidelines and 19 use 2010 dosage guidelines Many still will not use ethambutol in young children Obstacles to implementation relate to awaiting update of guidelines, need for training, that available FDCs do not match dosage guidelines, the need for change not accepted by local experts, and quantity of pills required is increased Preventive therapy not implemented and shortages and stock outs of H100 Detjen A, et al Pub Health Action 2012

Revised National Guideline on Management of Tuberculosis in Children, 2012, Myanmar

Informal consultation on the development of new paediatric fixed-dose formulations 5 May 2012, Stellenbosch, South Africa • New additions and preferably dispersable or crushable – RHZ 75/50/150 – RH 75/50

• Revise range for isoniazid to 7-15 mg/kg • Cut-off for children 25 kg • Retain following products and add that prefer dispersible or crushable – H 50 & H 100 tablet – E 100 tablet – Z 150 tablet

Suggested weight band table when using the most widely available FDC WHO Guidance child TB 2nd edition 2013

Weight bands 4-6kg 7-10kg 11-14kg 15-19 kg 20-24kg 25 kg+

Numbers of tablets Intensive Phase Continuation Phase RHZ RH 60/30/150 60/30 1 1 2 2 3 3 4 4 5 5 Go to adult dosages and preparations

Challenges for contact screening and preventive therapy

Risk of TB disease following infection by age

Studies of child contacts in Asian countries Study

Location

No. of child contacts

Proportion with TB infection

Proportion with TB disease

Andrew et al

India

398 790 142

39 % 24 %

5.5 %

Narain et al

India

Kumar et al

India

NR

3 %*

Singh et al

India

281 151 153

34 %* 27 % 69 %

3 %*

Rathi et al

Pakistan

Salazar et al

Philippines

Tornee et al

Thailand

47 % 31 %

NR

Lao PDR

500 148

Nguyen et al

Okada et al

Cambodia

217

24 %*

9 %*

NR

NR

3% NR

* Data only for < 5 years; NR: not recorded From Triasih R et al, J Trop Med 2011

WHO symptom based screening Children in close contact with a case of sputum smear-positive TB

More than 5 years

Less than 5 years

Well

Symptomatic

Preventive therapy

If becomes symptomatic

Symptomatic

Evaluate for TB disease

Well

No treatment

If becomes symptomatic

Note that contact screening has two important roles 1. Active case-finding 2. Preventive therapy for at-risk contacts without TB

The outcome of symptom based screening in Indonesian children 269 All child contacts 108 Children < 5 yrs

161 Children > 5 yrs

71 well

37 symptomatic

61 symptomatic

100 well

0

9

12

0

TB DISEASE AT BASELINE

0

0

+2

2

TB DISEASE AT FOLLOW UP Triasih R, Graham SM. Unpublished data

The outcome of symptom based screening in Indonesian children 269 All child contacts

IPT

No IPT

108 Children < 5 yrs

161 Children > 5 yrs

71 well

37 symptomatic

61 symptomatic

100 well

0

9

12

0

TB DISEASE AT BASELINE

0

0

+2

TB DISEASE AT FOLLOW UP

2

Addressing the policy-practice gap

The challenge is to bridge the wide policy-practice gap Political will is increasing â&#x20AC;&#x201C; especially at NTP level Tools/training are needed to support implementation beyond the tertiary care level Need to engage the broader child health sector Contact screening: universally recommended, rarely implemented

Roadmap for Childhood TB 

Document writing and coordination led by the Child TB Subgroup of Stop TB Partnership



Discusses engagement and responsibilities of policy makers, health workers and advocates at all levels



Emphasizes broad-based approach and engagement of entire maternal and child health community



Launch October 1st - Washington

From guidelines to implementation: addressing the policy-practice gap Issue

Response

Understanding child TB epidemiology

Training NTP data

The challenge of diagnosis Clinical approach Perceptions and misperceptions

Training Operational research

Contact screening and management Understanding of rationale Challenges for implementation

Training Operational research

NTP management issues for children differ from adults Classification of cases Drug dosages

Training NTP data

“ There are many contributions which the pediatrician can make to a TB control program.

First the negativism about tuberculosis so prevalent in pediatrics must be overcome…”

Edith Lincoln, 1961

Donald PR. Edith Lincoln, an American Pioneer of Childhood Tuberculosis. Pediatr Infect Dis J 2013