EPIDEMIOLOGY OF TUBERCULOSIS AND the IMPACT ON CHILDREN

EPIDEMIOLOGY OF TUBERCULOSIS AND the IMPACT ON CHILDREN Anneke C. Hesseling Professor in Paediatrics and Child Health Director: Desmond Tutu TB center Stellenbosch University 11 September 11 th International Childhood TB Course Goudini South Africa

Statement TB transmission to young children only occurs in the household

Answer False TB transmission in the household is important in young children < 5 years. However, in up to 40% in children < 5 years with TB, there is no known TB contact

WHO Global TB report, 2015

WHO Global TB report, 2015

60% India, Brazil, Russian Federation, South Africa Estimated > 1 000 000 children exposed to MDR-TB annually

Key transitions in tuberculosis Susceptible Exposed Infected Diseased Infectious Sick Accessed care Recognized Don Enarson, The Union Each transition has a measurable probability Probability varies with the situation = childhood TB Diagnosed Treated Completed Cured Mortality

WHO Global TB report, 2015

Global TB emergency: DOTS programme launched TB declared a global emergency in 1993 Targets for TB control first formulated at 44 th World Health Assembly 1991 Initial performance targets:ed to 2005) Detect 70% of new smear+ cases Successfully treat 85% of cases

1995-2008: 15 years DOTS/Stop TB Strategy 36 million patients cured in 1995-2008 Up to 7 million deaths averted, compared to non-dots treatment Case fatality rate halved from 7.6% to 4% Cure rate at its highest ever (87%) But TB incidence declining much more slowly than predicted

HIGH-BURDEN COUNTRY 1. Overall TB burden (absolute number of incident TB cases) 2. TB/HIV (absolute number of incident TB cases among people living with HIV) 3. MDR-TB (absolute number of incident MDR- TB cases)

Contribution of HBC 22 countries responsible for ~80% of TB morbidity and mortality worldwide 22 HBCs: Afghanistan, Bangladesh, Brazil, Cambodia, China, the Democratic Republic of the Congo, Ethiopia, India, Indonesia, Kenya, Mozambique, Myanmar, Nigeria, Pakistan, the Philippines, the Russian Federation, South Africa, Thailand, Uganda, Tanzania, Viet Nam, Zimbabwe 8 of 22 HBCs are in Africa Other countries not HBC due to smaller population but high incidence reflects TB burden

SOUTH AFRICAN CONTEXT WHO high burden TB country - all 3 criteria Estimated 454 000 (95% CI: 294 000-649 000) incident TB cases in 2015 Estimated incidence of 834/100 000 (95% CI: 539-1190/100 000) HIV prevalence of 57% amongst all notified TB cases in 2015. >10% in children < 15 years TB is the 4 th leading cause of death in children between 1 and 14 years of age, and is reported to currently account for 3.6% of all childhood deaths in SA WHO Global Tuberculosis Report 2016 http://www.who.int/tb/publications/global_report /en/

80000 70000 60000 50000 40000 30000 20000 10000 0 Children in ETR by age band and Children as a proportion of adults 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 <2 years 2-4 years 5-9 years 10-14 years Children as a proportion of adults 14% 13% 13% 12% 12% 11% 11% 10%

Relationship GNP & TB incidence The lower the Gross National Income, the higher TB incidence

TB deaths in England and Wales

Age standardised prevalence of M.tb infection in children (Mantoux test done n=25 048, read n= 22 563) 30 Comparison of crude Vs indirect age-standardised TB infection prevalence measures (TST>=15mm) by ZAMSTAR community 25 TB infection prevalence 20 15 10 5 0 allacedene Delft Nyanga Mbekweni Kayamandi Harare Phillipi Site C Chipata George Kanyama Chipukulusu Chawama Chifubu himwemwe Maramba Dambwa nsa Central Makululu Pemba Ndeke Senema Ngungu Shampande

Annual risk of TB infection (ARI) Zambia: 2.8% South Africa: 4.2% Shanaube, PLOS One, 2010

HISTORICAL PUBLIC HEALTH APPROACH TO TB CONTROL Proper identification and treatment of infectious cases will also prevent childhood TB Child TB historically afforded low priority by NTP Diagnostic challenges Usually not infectious Limited resources Lack of recording and reporting Disregard: morbidity and mortality

A deterioration in the control of TB thus immediately hurts the youngest generation Rieder, 1997

RELEVANCE OF TB IN CHILDREN 1. Indication of epidemic control: failure of health systems 2. Recent transmission: DS, DR-TB 3. Unique spectrum and severity of disease especially in young 4. Childhood TB as sentinel event

Key transitions in tuberculosis Susceptible Exposed Infected Diseased Infectious Sick Accessed care Recognized Don Enarson, The Union Each transition has a measurable probability Probability varies with the situation = childhood TB Diagnosed Treated Completed Cured Mortality

RISK OF PROGRESSION IN CHILDREN Young age 43% of infants (children < 1year) 25% of children aged one to five years 15% of adolescents Recent infection (1-2 years) children with close contact Malnutrition HIV Marais et al. Int J Tuberc Lung Dis. 2004

Children reflect TB transmission including MDR-TB Drug resistant pattern in children with DST 60 18,0% 50 12,8% 15,1% 15,4% 14,4% 16,0% 14,0% 40 12,0% 30 20 10 0 8,9% 7,7% 6,9% 7,1% 6,7% 5,1% 5,9% 5,6% 1,4% 1,8% 0,7% 0,0% 2003-2005 2005-2007 2007-2009 2009-2011 10,0% 8,0% 6,0% 4,0% 2,0% 0,0% Any DR INH mono-r RMP mono-r** MDR-TB %Any DR %INH mono-r %RMP mono-r** %MDR-TB Schaaf, IJTLD and in progress

AGE RELATED RISK OF TUBERCULOSIS Marais et al. Int J Tuberc Lung Dis. 2004

NON-SEVERE TB SEVERE TB (INCLUDING DISSEMINATED)

HIV antenatal maternal prevalence, South Africa: 1990-2012 >50% TB infected South African Department of Health, 2011

Increasing incidence of TB, Cape Town, South Africa HIV prevalence in general population: 3-4%: 20-39y 25%: 20-39y Lawn SD et al. CID 2006

EMERGENCE OF MATERNAL TB HIV-infected mothers have 10-fold increase in TB TB 3 rd leading cause of death: women 15-44 years age Maternal TB/HIV increased risk of postpartum mortality by 2-3 fold and probability of infant death by 2-6 fold Maternal death airr 2.2 p=0.006 Infant death airr = 3.4 p=0.02 Gupta. Clin Infect Dis 2007, WHO fact sheet, 2009

WHAT IS THE GLOBAL BURDEN OF TB IN CHILDREN? Direct incidence estimates unavailable WHO estimates build on paediatric notifications, with adjustment for incomplete surveillance by the same factor as adult notifications. Notification: < 15 years (0-4 years and 5-14 years)

Estimated total TB cases in children < 15 years 1 000 000 (10% global burden) Childhood cases notified 360 000 TB deaths 136 000 (81 000 HIV-) 13.6% case fatality rate TB infections 6.6 million MDR-TB estimates 30-50 0000 MDR-TB infection 500 000 WHO 2015 Global TB report www.who.int

South African Population Pyramid (2010 StatsSA Estimate) 80+ 70-74 60-64 50-54 40-44 30-34 20-24 10-14 0-4 15% 10% 5% 0% 5% 10% 15%

Where are the missing TB cases?

Incomplete registration of hospital-managed TB in children in South Africa Clinical factors Not registered n=101 (37.8%) Registered n=166 (62.2% p-value Disseminated TB 29 (28.7) 27 (16.3) 0.015* Miliary TB 12 (11.9) 16 (9.6) 0.562 TB Meningitis 22 (21.8) 13 (7.8) 0.001* Deaths prior to referral 10 (9.9) 0 (0.0) <0.001* Type of consultation Outpatient 16 (15.9) 41 (24.7) 0.087 Inpatient 85 (84.2) 125 (75.3) Admission (days) 16 (5, 29) 3 (9, 20) 0.052 Du Preez, PHA, 2012

Findings in Zambian children at autopsy, Lusaka Teaching Hospital Bates et al, BMC Medicine, 2016

WHO 2014 Global TB report www.who.int

Key transitions in tuberculosis Susceptible Exposed Infected Diseased Infectious Sick Accessed care Recognized Don Enarson, The Union Each transition has a measurable probability Probability varies with the situation = childhood TB Diagnosed Treated Completed Cured Mortality

Key Transitions in TB Who gets Infected? Close Casual Intermediate From Rieder Epidemiologic Basis of Tuberculosis Control

Percent infected Key Transitions in Tuberculosis 40 35 30 25 20 Who Gets Infected? Close 15 10 5 0 Casual Close Casual Smear + Smear - Tuberculous Infection Among Children by Type of Contact and Bacteriologic Status of Index Case, British Columbia and Saskatchewan, 1966-1971 Grzybowski S, et al. Bull Int Union Tuberc 1975;50:90-106

Percent infected 70 60 50 Key Transitions in TB S+/C+ Who Gets Infected? S-/C+ 40 30 20 10 0 Bedfordshire 1948-1952 S+/C+ Rotterdam 1967-1969 S+/C+ S-/C- S-/C- S-/C+ S-/C+ S-/C- Saskatchewan 1966-1971 Shaw JB, Am Rev Tuberc 1954;69:724-32 Grzybowski S, et al. Bull Int Union Tuberc 1975;50:90-106 Van Geuns HA, Bull Int Union Tuberc 1975;50:107-21

TB AFFECTS FAMILIES AND HOUSEHOLDS

TB CONTROL STRATEGIES FOR CHILDREN Improved adult TB control (also MDR-TB) Early diagnosis and appropriate treatment Contact management and IPT HIV prevention and treatment Vaccination

25 Early ART reduces TB in 1 st year of life by >3 fold (per 100 patient years) 20 15 10 ART Early Deferred 5 0 The CHER Trial: Violari et al. N Engl J Med 2008; 359: 2233-44

Summary: key principles Childhood TB is a sentinel epidemiological event TB in children is an indicator of ongoing (recent) transmission: DS and DR-TB TB burden in children varies by in-country TB incidence Children may be exposed in and outside of the household Improved surveillance of TB in children important; diagnosis, recording and reporting: informs epidemic control and planning of services