Ethics in Pediatrics

Ethics in Pediatrics Jeffrey R. Starke, MD December 02, 2016 Medical Consultant Meeting December 02, 2016 San Antonio, TX EXCELLENCE EXPERTISE INNOVATION Jeffrey R. Starke, MD, has the following disclosures to make: Member of a data safety monitoring board for Otsuka Pharmaceuticals concerning pediatric trials of Delamanid. 1

Childhood Tuberculosis in 2016 Ethics and Reality Jeffrey R. Starke, M.D. Professor of Pediatrics Baylor College of Medicine Disclosures Dr. Starke is a member of a Data Safety Monitoring Board for Otsuka Pharmaceuticals concerning pediatric trials of delamanid. This will not be discussed during this talk. Dr. Starke will not discuss off-label use of drugs or diagnostic tests during this talk. 2

Tuberculosis is a social disease with medical implications THE GREAT PARADOX OF TUBERCULOSIS A CAUTIONARY TALE By the use of drugs and BCG vaccines, we can cure tuberculosis disease prevent progression of tuberculosis infection into disease prevent a significant proportion of lifethreatening childhood tuberculosis [by BCG vaccination] Yet, tuberculosis is AGAIN the #1 infectious disease killer of humans, and our inability to control it is our biggest public health failure. 3

When I started in TB [1983] 23,846 cases of TB in the U.S. Tine and multipuncture skin tests predominated Only solid media for mycobacterial culture 9-12 months of daily isoniazid was the only treatment for TB infection Treatment for TB disease was 9-12 months of isoniazid and rifampin with streptomycin given IM for the first 2-3 months Pyrazinamide was not used Ethambutol discouraged in children [possible ocular toxicity] The link between TB and HIV was unrecognized WHO 2016 Global TB Report 10.4 million new cases: 5.9 million in men, 3.5 million in women, 1.0 million in children This is an increase from 2014, accounted for mostly by new surveillance and survey data from India Only 6.1 million cases were detected and notified, a gap of 4.3 million cases The gap is caused by underreporting of TB cases in countries with large unregulated private sectors, and under-diagnosis in countries with major barriers to accessing care 4

The Basic Conundrum of Childhood Tuberculosis There has been a circular argument concerning childhood tuberculosis. Some have said that without evidence of underdiagnosis of tuberculosis in children there is no justification for allotting additional resources for diagnosis, treatment and prevention. However, the resources to adequately determine the burden of childhood tuberculosis [the evidence] have not been made available. Why Are Obtaining Accurate Measures of Childhood TB So Important? Allocation of resources within an NTP Allocation of resources along the health care spectrum: community workers and programs, clinics, hospitals Awareness among pediatric providers Recognition of the issue among child survival experts and planners MDG 4 and 5 Approaching and interesting funders for both grants and programs Attracting the attention of researchers Protect the human rights of children and families 5

HOW IS TUBERCULOSIS DIAGNOSED? Adults Mycobacterial-based diagnosis positive sputum AFB smear - 60% - 75% positive sputum culture - 90% positive tuberculin skin test - 80% [HIV < 50%] Children positive sputum or gastric AFB smear - < 10% positive Xpert 10% - 20% positive sputum or gastric culture - 10% - 40% positive tuberculin skin test - 50% - 80% DIAGNOSIS OF TUBERCULOSIS IN CHILDREN Even in developed countries, the gold standard for the diagnosis of tuberculosis in children is the triad of: 1. a positive TST 2. an abnormal CXR and/or physical exam 3. a history of recent contact to an infectious adult case of TB 6

The Implication of Using Sputum Microscopy The decision to rely on sputum microscopy for the diagnosis of tuberculosis in high burden countries ensured the exclusion of children from tuberculosis control. This is what happens when vulnerable groups are not represented when policy decisions are made. GLOBAL ESTIMATES OF CHILDHOOD TUBERCULOSIS WHO, 2012: 460,000 annual cases, 64,000 deaths in non-hiv-infected children [no estimate for HIVinfected] Only 36% of estimated cases are actually reported Jenkins et al 2014: Modeling study estimate 999,792 cases Dodd et al 2014, 2016: Modeling study estimates in 22 high burden countries: 650,977 cases; 7,591,759 children annually infected; 53,234,854 total infected children, 100 MILLION GLOBALLY WHO, 2015: 1 million annual cases, 210,000 deaths 7

CASE NOTIFICATIONS OF CHILDHOOD TUBERCULOSIS IN SELECTED HIGH-BURDEN COUNTRIES - 2011 Total New < 15 smear + < 15 smear - Per cent of Country Cases N [%] N [%] Total Cases Afghanistan 26,853 669 [28] 1,753 [72] 9.0 Brazil 71,337 692 [36] 1,243 [64] 2.7 China 865,059 1,378 [25] 4,165 [75] 0.6 India 1,211,441 12,985 [26] 36,673 [74] 4.1 Pakistan 255,094 3,895 [22] 14,142 [78] 7.1 South Africa 325,321 3,404 [10] 32,080 [90] 10.9 Viet Nam 98,462 95 -------? Zimbabwe 36,960 326 [11] 2,635 [89] 8.0 Total 2,890,527 23,444 92,691 4.0 Jenkins, et al. Mortality among children diagnosed with tuberculosis: a systemic review and meta-analysis. Lancet Infect Dis, in press. Reviewed the literature in the pre- and postchemotherapy eras to estimate mortality rates Pre-chemotherapy Pooled case fatality rate was 21.9% Rate was 43.6% in children under age 5 years versus 14.9% in older children Post-chemotherapy Pooled case fatality rate was 0.9% Rate was 1.9% in children under age 5 years Case fatality rate in HIV-infected children prior to widespread use of ARV was 14.3% compared with 3.4% when ARV was given 8

Table: Estimated Tuberculosis Morbidity and Mortality in Children 0 14 years of age by WHO Region 2015 Children 0 14 years of age Region Estimated morbidity Estimated mortality % Mortality [CFR] % of deaths occurring in HIVinfected children % Child contacts < 5 years of age given preventive therapy [Est.] Africa 287,000 97,500 34 35 5 The Americas 26,000 2,370 9 8 67 Eastern Mediterranean 75,000 10,810 14 3 12 Europe 25,000 568 2 8 42 South East Asia 406,000 90,000 22 7 2 Western Pacific 138,000 8,570 6 < 1 13 Total 957,000 209,818 22 Source: World Health Organization Global Tuberculosis Report 2016 CFR case fatality ratio 9

ECONOMIC AND SOCIAL BURDEN OF TUBERCULOSIS FOR CHILDREN Direct treatment costs Inpatient or institutional treatment Lost earnings of the family Redirecting resources from other needs Withdrawal from school Stigmatization and discrimination Creation of orphans Tuberculosis Orphans 10

Some Issues for Foreign Children and Families Language barriers Lack of transportation Lack of health insurance immigrants [not refugees] Lack of access to a medical home Understanding the difficult concept of TB infection Minimal or no orientation to prevention Medication distribution pharmacies, refills Distrust of government agencies Stigma of tuberculosis New TB Tests Are Not Applied to Children (as of 2013) Test # of published studies in children FNA 140 Fluorescent microscopy 1 LED-FM 0 MODS 7 Line-probe assays 1 LAMP 0 GeneXpert 3 11

TB Studies on Adults & Children - 2013 Modality Adult Studies * Pedi Studies * Ratio adult to pedi Year of 1 st publication Culture: 400 38 362 11x 1967 Solid Culture: 248 13 235 19x 1966 Liquid MODS 37 7 30 5x 2000 PPD/TST 6399 2031 4368 3x 1907 IGRA 344 87 257 4x 1999 Xpert 7 1 6 7x 2010 PCR, all 1831 187 1644 10x 1990 *: PubMed Queries 12

A Fundamental Question Much of the attention for HIV and malaria has focused on children, but this has not happened for tuberculosis: Why not? 13

SOME REASONS WHY CHILDHOOD TUBERCULOSIS HAS BEEN NEGLECTED Inadequate data Difficulty confirming the diagnosis Children are rarely contagious [public health dead end ] Perception from TB policy makers that treating adults is enough Government programs fail to address children Lack of family centered contact tracing Perceived lack of scientific study and scrutiny Misplaced faith in the BCG vaccines Lack of industry support Inadequate advocacy by pediatricians Some Special Problems for Childhood TB Lack of accurate diagnostic tests Lack of pediatric dosing forms of medications Dispersible pediatric dosage forms developed using U.S. funding but will not be available in the U.S. as FDA approval not being sought Prevention of childhood TB depends on well-functioning local health departments that can rapidly investigate the contacts of new cases Federal funding cuts have made these investigations be delayed or not occur at all, which will lead to more childhood TB cases 14

Availability of Tuberculosis Medications to Children RCT data are very difficult to obtain for children due to lack of funding and small case loads at single centers Childhood TB experts generally accept that if it works in adults, it will work in children However, children may need fewer drugs and shorter durations than adults PK data are essential in several age groups Bedaquiline: U.S. approval, no pk data for children [orphan status] Delamanid: European approval, de-escalated age pk data being determined for children TRANSITIONS IN TUBERCULOSIS Susceptible Exposed Infected Prevent Infection Prevent Disease Diseased Sick Diagnosed Register, Record, Report Treated Cured 15

Childhood TB Control Strategies in the U.S. Never used a BCG vaccine Slow, steady decline [~5%/Yr] until the mid-1980s when it recurred with a vengeance Strategy of universal periodic testing [TST] for TB infection began in the late 1950s [when INH became available] and continued until the 1990s Universal testing replaced with screening for risk factors and testing for risk Heavy use of INH treatment for TB exposure and LTBI Specific recording and reporting of childhood TB cases each case is a sentinel event Why is treating tuberculosis infection an essential part of getting to zero? TB infections are not latent but are active Vulnerable patients progress rapidly to life-threatening forms of TB: young children, immunocompromised persons, elderly In some cases, can treat TB infection before the person becomes immunocompromised Prevention of future cases = less transmission in the future to vulnerable persons BCG vaccine prevents many but not all cases of lifethreatening TB in children and adults Treating MDR-TB infection may be safer and more effective than treating MDR-TB disease Contact investigation: the most bang for the buck high risk, high rate, motivation to treat, drug susceptibilities known, DOT and DOPT 16

Childhood TB in the U.S. Effect of Immigration Lobato and Hopewell. ARRCCM 1998; 158:1871 Children living in a household that had a visitor from a high prevalence country were 2.4 times more likely to have LTBI Winston and Menzies. Pediatrics 2012; 130:e1425 31% of children diagnosed with TB in the U.S. in 2008 2010 were foreign-born [61% for all ages] Among U.S.-born children with TB, 66% had a foreign-born parent [over 3 times the U.S. average] Only 25% of U.S.-born children with TB did not have an international connection Foreign-born children in the U.S. are not treated for LTBI prior to immigration, are less likely to have health insurance and a medical home, more likely to not be in school 1800 1600 1400 1200 1000 Tuberculosis Cases in Children 0-14 Years of Age, 1980-2014 United States 800 600 400 2014-460 cases 200 0 1980 1985 1990 1995 2000 2005 2010 17

How Have We Lowered Childhood TB Rates in the U.S.? Family-centered contact investigation Use of the best available diagnostic modalities Screening and treating high risk children and adolescents Adequate funding of TB control programs How Do We Find Children With Tuberculosis Disease? 1. Contact Investigation Active Case-finding 50 % of cases in Houston Milder disease, rarely need microbiologic confirmation 2. Ill Children Passive Case-Finding More severe disease, harder to treat No source case, more difficult to diagnose Broader differential diagnosis, esp. immunocompromise 3. Screening high risk children Low yield, nonspecific findings in chest radiograph and physical examination because of other, more common, causes 18

How Do We Find Children With Tuberculosis Infection? 1. Contact Investigation Highest yield, higher accuracy [positive predictive value] of diagnostic tests Recently infected, highest risk of rapid progression Higher adherence to therapy parents understand 2. Associate Investigation A window into high risk households 3. Screening high risk children and adolescents Low infection rates; worse PPV for tests of infection Questionnaires: length of travel as a risk factor Questionnaires: foreign-born parents -? Real risk? Less acceptance of therapy Medical homes and school-based testing Hsu KHK: Contact investigation: A practical approach to tuberculosis eradication. AJPH 53;1751, 1963. 19

What Does Family Centered Contact Tracing Do? Identifies recently exposed and infected children 1) Opportunity to prevent establishment of infection 2) Prevent infection from progressing to disease 3) Detect early disease easier to treat & cure 4) Prevent dissemination, hospitalization Only opportunity to determine drug susceptibility for: 1) 50% to 70% of children with disease 2) 100% of children with infection Some Results from Contact Tracing Studies Triasih et al. J Trop Med 2012 DOI:10.1055/2012/301808 20

ADVERSE EFFECTS IN CHILDREN OF NOT PERFORMING CONTACT TRACING Missed cases Misdiagnosis tuberculosis not recognized Diagnose cases later increased morbidity and mortality Missed drug resistance [need source case culture and drug susceptibility results] Missed prevention treating exposed or infected children Graham and Triasih. More evidence to support screening of child contacts of tuberculosis cases: If not now, then when? Clin Infect Dis 2013 We already have the policy, the evidence and the tools we need to implement [contact tracing]; even the political will is beginning to emerge. It will not be easy, but this recent study [in Uganda] further highlights the consequences and missed opportunities of continued neglect. 21

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Houston High School Study Lindsay Hatzenbuehler, Andrea Cruz, Jeffrey Starke Educate 9-10 th graders at 2 public high schools in Houston, screen for risk factors, test those with risk factors via IGRAs Provide short-course therapy with 12 weekly doses of INH/rifapentine (3HP) for IGRA+ children at school Houston High School Study Lindsay Hatzenbuehler, Andrea Cruz, Jeffrey Starke Piloted at a magnet high school for health sciences Then rolled out at low-income school Phlebotomy school students and TCH nurses volunteered for blood draws Manufacturers of QuantiFERON (Qiagen) and T.SPOTTB (Oxford) donated test kits Under programmatic conditions, only 1 IGRA would be used Collaborator ran assays in his lab TSTs not performed 23

Variable Houston High School Study Lindsay Hatzenbuehler, Andrea Cruz, Jeffrey Starke Risk Factors & IGRA Results IGRA positive (n = 16) IGRA negative (n = 399) p-value Student birth in a high-risk country 5 (31%) 106 (27%) 0.71 Student travel to a high-risk country in past year 7 (44%) 44 (11%) 0.001 Contact with TB disease 2 (13%) 4 (1%) 0.02 Household adult birth in a high-risk country 16 (100%)** 394 (99%)** 0.99 Take-Home Messages Adolescents understood their risk They agreed to testing, even with a test requiring venipuncture They and their parents were adherent with therapy They discussed it with others in their community 24

Childhood TB: Lessons From a Low Burden Environment Prevention of TB in children requires a system with central coordination and community activity Linking a child to a source case improves the accuracy of diagnosis and effectiveness of treatment Analysis of childhood tuberculosis is a window into the effectiveness of TB control yellow canaries Most childhood TB can be prevented with very little cost but better organization and emphasis Migrating children are at high risk and have difficulty accessing central and community services Young children with tuberculosis are rarely infectious to others Main Challenges to TB Elimination in the U.S. Political commitment As cases continue to decrease, seems less of a priority to general public and policymakers Resources at risk U-shaped Curve of Concern Loss of expertise and experience Clinical [nurses and MDs], laboratory, program Drug and biologic shortages because of lack of market Regulatory requirements (FDA) limit access to larger global market, e.g. child-friendly formulations Concentration of remaining cases and outbreaks in more difficult-to-reach populations Foreign-born, homeless, etc. ***How to address the large pool of persons with latent tuberculosis infection (LTBI) <10 thousand TB cases; up to 13 million persons with LTBI 25

The Old Approach to Childhood Tuberculosis Childhood TB has been relegated to National TB Control Programs, many of which have not had pediatric-specific guidelines or content in their educational and instructional materials Children are identified only when they become sick, when TB is advanced and more difficult to manage Because of the under-reporting of childhood TB, the disease has not been considered in discussions of child survival and the Millennium Development Goals Childhood contacts of cases are rarely identified and given preventive therapy in the highest burden settings Insanity is doing the same thing over and over again and expecting a different result! Albert Einstein A New Approach We need to decentralize care to people and organizations that will take the science of childhood tuberculosis and make it effective practice. Children and adolescents must be included in the three pillars of public health: Scientific and operational research Policy Development Implementation of appropriate clinical practices Science Guidelines Policy Practice 26

Childhood Tuberculosis: What Will Be The Tipping Point? In his 2000 book, The Tipping Point, Malcolm Gladwell described the three basic elements of social epidemics that lead to fundamental change the tipping point how trends are often driven by a handful of exceptional people [The Law of the Few] how to make a contagious message memorable [The Stickiness Factor] the central importance of environment in changing behaviors [The Power of Context] Tipping Point #1: The Law of the Few We need to identify connectors people and organizations that will take science and make it effective practice eg. the WHO for 35 years has recommended that asymptomatic children who live in households with a case of tuberculosis receive 6 months of INH. This simply is not done! Science Guidelines Policy Practice Never doubt that a small group of thoughtful, committed, citizens can change the world. Indeed, it is the only thing that ever has. Margaret Mead 27

Tipping Point #2: The Stickiness Factor We need more effective messages We need to tell patient and family stories We need to market childhood tuberculosis to funders, scientists, clinicians and policy-makers Little things matter Tipping Point #3: The Power of Context All public health is local: local data and need always trump global data and policies Childhood tuberculosis should be linked with other perceived pressing needs HIV, malnutrition, vaccination, MCH The most expensive case of a disease will be the last one Reichman s U-shaped curve of concern 28

So, are we at the Tipping Point for childhood tuberculosis? 29

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WHO End TB Strategy 31

Ten Truths About Childhood Tuberculosis 1. Adequate TB control for children requires a robust public health system. 2. We can prevent most childhood TB with simple, inexpensive measures. 3. Childhood TB can be found earlier when it is easier to treat. 4. Finding and treating adults with TB is not sufficient for controlling childhood TB. 5. BCG vaccines alone cannot control childhood TB. Ten Truths About Childhood Tuberculosis 6. Some tests, like chest xray, are more important for children than adults. 7. Many adult TB cases arise from infection that occurred in childhood. 8. Childhood TB is a window into the effectiveness of tuberculosis control. 9. Almost all children with TB are treated with medications designed for adults. 10. Childhood TB is a neglected disease in most of the world. 32

CHILDHOOD TUBERCULOSIS: THE HIDDEN EPIDEMIC Donald Int J Tuberc Lung Dis 2004; 8:627 The time has come for the hidden epidemic of childhood tuberculosis to emerge from the shadow of adult tuberculosis and be seen as a neglected child health problem of considerable proportions in precisely those communities that do not have the resources to deal with it adequately. 33