Current Issues and Controversies in Child and Adolescent Tuberculosis Jeffrey R. Starke, M.D. Professor of Pediatrics Baylor College of Medicine [With great thanks to Andrea Cruz, M.D.] Disclosures Dr. Starke is a member of a Data Safety Monitoring Board for pediatric studies of delamanid for Otsuka Pharmaceuticals. ESTIMATES OF CHILDHOOD TUBERCULOSIS WHO, 2013: 530,000 annual cases, 74,000 deaths in non-hiv-infected children [no estimate for HIVinfected] Actual notifications to WHO were 301,233 Jenkins et al 2014: Modeling study estimate 999,792 cases Dodd et al 2014: Modeling study estimates in 22 high burden countries: 650,977 cases; 7,591,759 children annually infected; 53,234,854 total infected children WHO, 2015: 1 million annual cases, 140,000 deaths www.tbcontrollers.org/nstc/ 1
Tuberculosis Cases in Children 0-14 Years of Age, 1980-2014 United States 1800 1600 1400 1200 1000 800 600 400 200 0 1980 1985 1990 1995 2000 2005 2010 2014-460 cases Why Did TB in Children Resurge in the United States? 1. HIV/AIDS mostly HIV-uninfected children who got TB infection from HIV-infected adults with pulmonary TB 2. Congregate Settings schools, churches 3. Immigration Prior to 2009, no testing for children < 15 yrs of age; now looking only for TB disease, not infection 4. Poor Tuberculosis Control declined budgets, loss of expertise, lack of emphasis on prevention Some Aspects of TB Control for Children - Low Burden Countries Elimination of background noise TB as a collection of outbreaks Value of contact tracing Value of reverse contact tracing [ Associate Investigation ] Identifying less common modes and locations of transmission Effectiveness of treating TB infection Infectiousness of children with pulmonary TB www.tbcontrollers.org/nstc/ 2
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 and continued until the 1990s 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 Some Trends in Childhood TB in the U.S. - 2016 Declining disease rates need to shift attention from disease to infection Shift to foreign families language and cultural barriers, lack of medical home and insurance Lack of access to new technologies rapid diagnostics, dispersible drugs Loss of public resources disproportionately affects children Loss of interest/research CDC, granting agencies Less expertise for managing childhood TB 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 www.tbcontrollers.org/nstc/ 3
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 Emerging Infections Network [EIN] Survey Conducted in late 2015 On-line 14-question survey of pediatric infectious disease experts in North America asking about diagnosis and treatment if LTBI 197/323 [61%] eligible members participated 75% of respondents had > 5 years experience Most worked in university medical centers Results submitted for publication EIN Survey of Pediatric Infectious Disease Specialists - 2015 www.tbcontrollers.org/nstc/ 4
TRANSITIONS IN TUBERCULOSIS Susceptible Exposed Infected Prevent Infection Prevent Disease Diseased Sick Diagnosed Register, Record, Report Treated Cured Hsu KHK: Contact investigation: A practical approach to tuberculosis eradication. AJPH 53;1751, 1963. 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 www.tbcontrollers.org/nstc/ 5
How Do We Find Children With Tuberculosis Disease? 1. Contact Investigation 50 % of cases in Houston Milder disease, rarely need microbiologic confirmation 2. Ill Children 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 Microbiologic Confirmation of Tuberculosis Disease in Children Microbiologic confirmation from any specimen using any technique is rarely above 40% for clinically suspected disease Intensive sampling of several sources using several techniques on one day tends to give higher yields than less intensive sampling over several days e.g 3 early morning gastric aspirates Sputum induction is generally superior to gastric aspiration New techniques slow to become available e.g. Xpert MTB/RIF in children s hospitals Treatment of Tuberculosis Disease in Children If it works in adults, it will work in children However, shorter and less intense regimens also may work in children For new drugs and regimens, pk, safety and tolerability data are key Will new drugs be available for children in the U.S., e.g. bedaquiline? Why aren t dispersible drug formulations going to be available in the U.S.? [TB Alliance] www.tbcontrollers.org/nstc/ 6
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 ASSOCIATE INVESTIGATION [ Reverse Contact Tracing ] Identification and evaluation of close contacts of children and adolescents with LTBI or TB disease can be considered a form of targeted testing Index Case Source Case yield of finding cases of tuberculosis may be low yield of finding LTBI is 30% to 40% in the U.S. effective only if index child with LTBI was tested because of risk www.tbcontrollers.org/nstc/ 7
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 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 www.tbcontrollers.org/nstc/ 8
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 How Do We Test For Tuberculosis Infection In Children? Tuberculin skin test vs. IGRAs How important is age for use of IGRAs? Should we ever do both a TST and an IGRA? Is one IGRA better than the other? Are there false positive IGRA tests? What strategies work best for BCG-vaccinated children? What do we do for immunocompromised children? Can rates of indeterminate/invalid results be lowered? www.tbcontrollers.org/nstc/ 9
BCG vaccinated? No Age <5 yrs? Yes No Yes Likely to return for TST reading? TST preferred Yes No Either TST or IGRA acceptable Negative TST Positive TST Testing complete Testing complete unless criteria A* unless criteria B** met, then IGRA are met, then IGRA IGRA preferred Negative result Testing complete unless criteria A* met, then IGRA Positive result Testing complete unless criteria B** are met, then IGRA Negative result testing complete Negative result testing complete Indeterminate Repeat IGRA Positive result testing complete Positive result testing complete *Criteria A 1) High clinical suspicion for TB disease and/or 2) High risk for infection, progression or poor outcome **Criteria B 1) Additional evidence needed to ensure adherence and/or 2) child healthy and at low risk and/or 3) NTM suspected IGRAs IN CHILDREN SOME CLINICAL ISSUES BCG-vaccinated child Strategy 1: TST: if negative, no more testing; if positive, follow with an IGRA Strategy 2: Do only the IGRA Note: If TB exposure, child should be considered infected if either test is positive Child about to be immune compromised No TB risk factor: do either a TST or an IGRA TB risk factor: do both a TST and an IGRA and evaluate and treat if either test result is positive [RISK and BENEFIT] Ongoing Issues with IGRAs in Children Age: Strong consensus on their use in children > 5 years, developing consensus for ages 3-4 years. Many experts do IGRAs in children down to 2 years of age, some even lower. Problem: Sensitivity data are from children with severe TB disease, mostly in Africa, many malnourished and with helminthic infection: skews data toward lower sensitivity Low-grade false positive results: Should there be a 5-10-15 rule for IGRAs based on epidemiology? Indeterminate/Invalid Results: rates vary from 2% to 31%, are higher in younger children and immune compromised patients Boosting: Does a previous TST alter subsequent IGRA results? Choice: Is one IGRA better than the other for children? www.tbcontrollers.org/nstc/ 10
EIN Survey of Pediatric Infectious Disease Specialists - 2015 31% of 182 children had indeterminates Associated with: Inpatient status (OR 8.7, 4 22) Not associated with: Age, medical comorbidities Conclusion: Indeterminates may be due to modifiable factors external to the patient, such as specimen handling Pediatr Infect Dis J 2014;33:220 Is there a TST size cut-off above which children simply should be treated for LTBI without confirmatory IGRA? Note: Tiered testing is not recommended by CDC under routine operational conditions Recommendation: pick 1 screening test and stick to it Difficult when children are referred in whom testing was not indicated Clin Pediatr 2014;53(12):1196 www.tbcontrollers.org/nstc/ 11
130 children not identified via contact investigations referred for + TSTs in whom IGRAs were obtained; 32% IGRA + TST <15mm: 21% IGRA +; TST 15mm: 47% IGRA+ TST 20mm: 42% IGRA + [OR 2, 0.8-5] Clin Pediatr 2014;53(12):1196 EIN Survey of Pediatric Infectious Disease Specialists - 2015 EIN Survey of Pediatric Infectious Disease Specialists - 2015 www.tbcontrollers.org/nstc/ 12
How Do We Treat Children With Tuberculosis Infection Established therapies include: Isoniazid for 9 months Isoniazid for 6 months Rifampin for 4 months Isoniazid and rifampin for 3 months Isoniazid and rifapentine once weekly for 12 weeks [under directly observed therapy] 289 children treated for LTBI with 9H, 2007-2010 33% identified during contact investigations 63% foreign-born Univariate: poor adherence associated with Foreign birth (OR 1.9, 1.1-3.8) Self-administered therapy (11.6, 5.7-23.6) Identification of LTBI outside of investigation (7.7, 2.9-20.1) Multivariate: completion of therapy associated with Receipt of DOPT (7.2, 3.8-13.8) Pediatr Infect Dis J 2012;31(2):193 Cruz and Starke. Increasing adherence for latent tuberculosis infection therapy with health department-administered therapy. PIDJ 2012; 31:193. www.tbcontrollers.org/nstc/ 13
404 treated for LTBI; 80% 9H, 20% 4R Completion rates: 4R/self-meds vs 9 H/DOPT: OR 0.6, 0.2-1.7 4R/self-meds vs 9 H/self-meds: OR 7.9, 2.7-32.2 *Cost consequences: RIF more expensive than INH But, cost of DOPT is substantial, and DOPT not available for all children Adverse events: (none serious) 4R: 3% 9H: 6% Int J Tuberc Lung Dis 2014;18(9):1057 Cruz and Starke. Safety, adherence and efficacy of twice-weekly therapy for childhood tuberculosis exposure or infection. IJTLD 2013; 17:169. Treatment was twice weekly DOT: INH 20-30 mg/kg or RIF 15-20 mg/kg Treatment was by the same health workers who treated the source case 855 children had household exposure: 62 had conversion of TST from negative to positive; no child developed TB disease Villarino et al. JAMA Pediatr 2015; doi:10:1001/jamapediatrics.2014.3158 Part of a larger trial of ~7,800 patients Included children ages 2 to 17 years 905 children evaluable for effectiveness 12 weekly doses of 3HP vs. 9 months daily doses of INH Completion rates: 3HP 88% 9INH 91% Development of TB: 3HP 0/471 9INH 3/434 No child experienced hepatotoxicity, Grade 4 adverse event Grade 3 Adverse Effect: 3HP 3 of 539 9INH 1 of 493 Conclusion: 3HP was at least as effective, safe and had a higher completion rate than 9 months of INH www.tbcontrollers.org/nstc/ 14
Safety and Adherence for 12 Weekly Doses of Isoniazid and Rifapentine for Pediatric Tuberculosis Infection Cruz and Starke. Accepted by PIDJ, 2016. Rifapentine: dosed by weight in 150 mg increments up to 900 mg maximum Isoniazid: 15 mg/kg up to 900 mg maximum All doses via DOT by the health department Patients in clinic at DX, 6 weeks and 12 weeks No routine lab work, only for symptoms 80 children 2-19 years: 23 were 5-11; 2 < 5 years 79/80 completed therapy AEs: only one - an 11 yr old girl with abdominal pain, AST/ALT = 146/99, quickly resolved; therapy with 4R completed **A 16 year old girl [contact to a case] developed AFB smear + pulmonary TB 7 months after completion great concern that she cheeked her 3HP. EIN Survey of Pediatric Infectious Disease Specialists - 2015 ARE YOUNG CHILDREN WITH TUBERCULOSIS EVER CONTAGIOUS? Difficult to answer in the community Orphanages caretaker with TB led to transmission; a child with TB did not Schools only 2 reported epidemics caused by children <13 years old Children s Hospitals rare case reports of transmission, all with special circumstances; none has been patient - to - patient www.tbcontrollers.org/nstc/ 15
Methods From January, 2003 to December, 2009, all children at TCH with suspected TB were admitted to a private room Negative pressure rooms were used only if the child had characteristics of infectious TB [cavity, extensive apical infiltrate, sputum production, intubation], if a caregiver was ill or had an abnormal chest radiograph, or if there were delays in obtaining a chest radiograph for a caregiver Chest radiographs were obtained ASAP at TCH at the hospital s expense for up to 3 caregivers per patient. Children and caregivers were confined to the patient s room until all the chest radiographs were cleared by a radiologist Other visitors were not allowed unless they could show proof of a negative chest radiograph performed elsewhere within the past 2 weeks. Results During the 7 year study period, 153 children suspected by the treating physician of having TB disease were admitted to TCH Ultimately, 59 (39%) had confirmed TB; 2 additional children were treated for 2 months before an alternative diagnosis was established 5 children had miliary TB [of which 3 were intubated], 1 had cavitary TB and 1 adolescent had extensive apical disease; 5 of these 7 patients were AFB sputum smear positive Diagnoses in the 94 children found not to have TB included: CAP [42],malignancy [9],parapneumonic effusion [9], NTM disease [8], CF with NTM [6], pyogenic lung abscess [6], viral pneumonitis [5], other [9] Results Caregivers 254 chest radiographs were obtained [mean 1.7 per child] Among the 59 children ultimately diagnosed with TB, 10/59 families [16.9%] and 9/110 caregivers [9.1% or 9,100 per 100,000] had abnormal chest radiographs and each caregiver was confirmed to have pulmonary TB Of the 10 caregivers with TB, 4 were fathers, 3 were mothers, 2 were grandmothers and 1 was an aunt Overall rate of abnormal caregiver chest radiographs was 8% of families and 12/254 [5%] of caregivers Health Care Workers No TST conversions among those who cared for TB patients www.tbcontrollers.org/nstc/ 16
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 www.tbcontrollers.org/nstc/ 17