Pediatric TB Updates, Tools, and Adorable Faces

Transcription

1 Pediatric TB Updates, Tools, and Adorable Faces Andrea T. Cruz, MD, MPH Baylor College of Medicine Santa Fe, New Mexico November 6, 2018

2 Disclosures I am on the data safety monitoring board for a trial of TB preventive therapy for children with multidrug resistant TB infection being conducted in South Africa. The photographs of my kids are presented with the permission of their families

3 Objectives Revisions in TB infection guidelines Tests of infection Treatment options Routes of administration of therapy Self administered Health department supported Source case investigations

4 Scenario #1 2yo previously healthy boy emigrating from Guatemala No known TB contacts, BCG status unknown, normal CXR Has no scar on deltoid 10 20% of BCG recipients do not have a scar TST: 10mm Caveat: the TST is always 10mm. What do you do? Does it change based on BCG status? On TST induration? On age? On other factors?

5 Testing for Infection

6 Comparison of TST & IGRAs Characteristic TST IGRA Antigens studied Many ESAT-6, CFP-10, (TB-7.7) Cross-reactivity with BCG Yes Unlikely Cross-reactivity with NTM Yes Less Likely Estimated sensitivity, TB in 75-90% 75-95% immunocompetent adults Estimated specificity, TB in 70-95% % immunocompetent adults Distinguish between TB infection No No and TB disease Boosting Yes No Patient visits required Two One

7 Newest Generation QuantiFERON Differences 3 rd generation 4 th generation Name QuantiFERON Gold QuantiFERON-Plus # of tubes 3 4 CD4 detection Yes: ESAT-6, CFP-10, TB 7.7 Yes: ESAT-6, CFP-10 CD8 detection No Yes: 6 MHC class I peptides Sensitivity 89-96% 91-96% Specificity 98-99% 98-99% Goal: improved sensitivity, especially in PLHIV or persons with recent infection; fewer indeterminate results (unclear if actually meets these goals)

8 What is a Positive TST? 5 mm 10 mm 15 mm HIV infected Contact to a TB case Child in whom you suspect TB disease Children < 4 years of age Children exposed to high risk adults Immigrants from highprevalence regions Children with diabetes or other immunocompromising conditions 2018 Red Book Anyone, even without risk factors

9 TST Advantages First used in 1907 We know a LOT about the dynamics and limitations Availability: Lab? What lab? Can be done whenever and wherever You need a kid (with an arm) and a tuberculin needle and syringe Don t need to draw blood You get an interpretable response No borderline or indeterminate results Cost: Tuberculin solution is cheap! Important for families and public health departments

10 TST Disadvantages: Interpretation Up to 20% of children don t return for TST interpretation But > 20% of parents are upset when a blood draw fails Sliding scale is confusing Red Book Table (3.82) is not There are issues with variation in TST induration measurement Come on how hard is it to measure a bump on an arm?

11 How hard can it be? We even skin test cows. So are we seriously saying that a toddler is more unruly than a 1,500 lb dairy cow? (Kids are not little adults; or really little bovines)

12 TST Disadvantages: False positives False positives BCG vaccine But vaccine used in those countries because they have a lot more TB, so threshold for treating kids from these countries is low CDC doesn t alter threshold for interpretation based on BCG status Nontuberculous species I know other people s children (and patients) eat soil But not my kids. Definitely not my kids. But kids do well with TB meds; it s ok to over treat some

13 TST: Cost Some argue that TST costs are > IGRA costs when include indirect costs of testing IGRA costs often reimbursed by insurance companies In TX, costs about $90/test for QuantiFERONs But. many of my kids and their families are uninsured So is the same cost model applicable for all families? WHO: IGRAs not recommended in low and middle income countries

14 Cost of QuantiFERON at commercial labs So, yes, the family has to return for testing, but even then it may still be cheaper for them test/infectious disease testing/tb blood test cost quest Very reputable website (not fake news)

15 LCA: method of differentiating between discordant results when there exists no reference standard Evaluated performance of TST, QFT, and TSPOT in US and foreign born HIV uninfected and infected children and adults Dichotomized ages as < 5 and 5 years of age Thorax 11/2018

16 Pediatrics

17 TST/IGRA Summary Data Foreign-born, 5 yrs TST had roughly same performance as coin flip for predicting LTBI Both QFT and TSPOT had high PPVs Foreign-born, < 5 yrs LTBI prevalence by LCA was 4% For TST 10mm as positive, PPV was 10% Almost all + TST results were false positives

18 2015 vs 2018 Red Book: IGRAs Recommendation Age* 5 years 2 years Preferred test for BCG recipients Yes Unchanged Use in immunocompromised children Cautiously Unchanged *States that some experts use down to 1 year of age

19 There continue to be roles for both tests IGRAs when TSTs: TSTs are ambiguously read (the ubiquitous non integer positive TST) You suspect TB disease and the TST is 0mm Immunocompromised kids Families need more convincing prior to treatment TSTs when IGRAs: IGRAs are borderline or indeterminate You suspect TB disease and the IGRA is negative or uninterpretable Immunocompromised kids

20 TB Infection Regimens

21 Infection Regimens We select regimens based on safety, tolerability, efficacy We know TB therapy is effective if taken as suggested However, completion rates abysmal with the traditionally-used 9 months of INH (9H): ~ 50% Completion inversely associated with duration of therapy Pediatric emphasis historically has been on 9H

22 905 children (2-17-yrs-old) from US, Canada, Brazil, China, Spain Pediatric cohort nested within PREVENT RCT Variable 3HP 9INH p= Progression to disease 0% 0.74% 0.11 Treatment completion 88.1% 80.9% Discontinuation due to AE 0.6% 0.2% 0.63 Drug related hepatotoxicity 0% 0% JAMA Pediatr 2015;169(3):247

23 Pediatrics 2018;141(2):e HP vs 4RIF vs 9H, retrospective, non-randomized, Shift in study period in diagnosis, treatment: Diagnosed by TST alone: 65% 45% Treated with INH: 60% 8% Completion not associated with race/ethnicity or test of infection Completion frequencies: Regimen % completion OR (CI) 9H (given by families) 53% REF 9H (given by DOT) 89% 7.1 ( ) 4RIF (given by families) 84% 4.6 ( ) 4RIF (given by DOT) 97% 30.6 ( ) 3HP (given by DOT) 97% 27.4 ( )

24 4RIF vs 9H, nonrandomized, retrospective study Drug toxicity all dermatologic (1.5% in RIF, 0.7% in INH, non-signif) No known treatment failures Completion higher with RIF (84% vs 69%, p<0.0001) Completion rates higher when: IGRA used for diagnosis Children identified in contact tracing Shorter regimens used Pediatr Infect Dis J 2018;37(3):224

25 2015 vs 2018 Red Book: LTBI Regimens Recommendation Preferred regimen INH No specific preference (this is order in Red Book): 3HP* 4RIF 9H RIF role Limited: Expanded INH intolerance INH resistance in source case isolate 3HP Use in 12 years Use in 2 years *States that some experts think 3HP is the preferred regimen

26 Pediatrics

27 Rifampin Dosing Dosing initially used for RIF was in adults who weighed far less than TB patients do today Resulted in a 60-70% dose reduction Children metabolize many TB drugs faster than adults Need higher mg/kg dose to achieve target serum concentration (8 μg/ml) Recognition that there is substantial between-child variation in metabolism of certain TB drugs

28 2015 vs 2018 Red Book: RIF dosing (mg/kg/day) Recommendation Standard treatment TB meningitis Non meningitic TB, infants, toddlers Exceed adult maximum (600mg) No Yes

29 Routes of Administration

30 Scenario #2 8yo referred to see you for + IGRA performed after child did not complete 9 INH following a positive TST Pediatrician restarted INH You delve into barriers family faces: Cannot afford rifampin 9 months is a LONG time Family unclear on rationale for therapy What do you do now? Change regimen? Change way we give it?

31 Routes of administration Self administered therapy (SAT) Family fills prescription, administers medication to child Enhanced SAT (ESAT) Health department drops off meds, family administers them Video directly observed therapy (vdot) Health department drops off meds periodically, family uses app to securely send video of child taking meds Traditional (in person) directly observed therapy (DOPT) Health department drops off meds, watches family administer them

32 Pros and cons of the options Route Pros Cons SAT Low cost (to system) High cost (to family) ~50% of children will complete therapy ESAT vdot DOPT Removes barrier of finding pharmacy, paying for prescription Intermediate in cost between SAT, DOT Convenience for families Lower cost than DOPT Allows for closest monitoring of highrisk children Does not address barrier of family giving the medication Assumes a degree of tech savviness Need IT infrastructure for secured data portal Acceptability to some families Cost

33 Monitoring while on therapy May have to see in clinic less frequently if on DOPT (or video DOPT) Few children need baseline or serial LFTs. Exceptions: Obesity Existing liver disease or comorbid medical conditions Receipt of other hepatically metabolized medications Low threshold for stopping meds and checking LFTs were the child to have any GI symptoms Importance of anticipatory guidance

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35 Lean: promethazine + codeine + Sprite +/ Jolly Ranchers Pediatrics Dro: hydroponically grown marijuana

36 Teens, Substance Use & Abuse Drug Prevalence of use Ethanol 28 41% of high school seniors 6 million teens binge drink Marijuana 40% use, 23% used in last month Cocaine 6.8% Heroin 2.9% Inhalants 11.4% Methamphetamines 3.8% Prescription Stimulants 1.7 3% Prescription Sedatives % Prescription Opioids 4 12% J Adolesc Health 2012;51:6;; Can J Psychiatry 2012;57:745

37 My philosophy Our families face a lot of barriers to receiving care Financial Health literacy Transportation Linguistic Blaming families for not completing therapy is a cop out Instead, recognizing that there are things we as providers can do to make completion of therapy easier, we need to be asking how can we make things easier for our families

38 Source Case Investigations

39 How much contact is enough? A. Mother with cavitary disease, child sleeps in same bedroom B. Grandfather who visited once for Thanksgiving, holding his newborn granddaughter C. ICU nurse who cared for a premature baby while baby was intubated D. Respiratory therapist who helped transport a diabetic adolescent with cavitary disease during a 1 hour ambulance ride

40 The conundrum of the exposed young child Risk of progression from infection to disease is high Age at Primary Infection (year) No Disease (%) Pulmonary TB (%) CNS or Miliary Disease (%) < < 0.5 > < 0.5 We have mixed faith in the value of tests of infection for the youngest, most vulnerable children

41 Defining household contact This should not be a rigid definition Grandmother who cares for the child each day while parents are at work? Aunt who lives across the street and watches the baby frequently?

42 Establishing when contact was broken Try to triangulate information from index case and child s caregivers Err on the side of caution and assume a later date of breaking contact Explain potentially life threatening consequences of missed prevention opportunities Also explain to parents how well young children tolerate TB medications Try to link to other events: has your child been around X since Halloween?

43 Some of our Houston data Treated over 750 children for TB exposure, health departments Over 99% of families agreed to start therapy Over 99% of children who started window prophylaxis completed therapy Incredibly well tolerated Received treatment for weeks

44 Exposed children Approximately 5% of children with an initial 0mm TST converted TST conversion: Associated with a parent being the source case Not associated with smear status or being a household contact What does this mean? Proxies we often use for risk of being contagious are not great These factors donʼt help us risk stratify which young children would receive most benefit from window prophylaxis

45 Opportunities for improvement Better ways to assess exposure Historical variables Newer diagnostic modalities Optimizing window prophylaxis Expansion of video DOT

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47 Cough aerosols are a better proxy of contact acquisition of infection than smear positivity Measure concentrations of viable bacteria in colony forming units (CFUs) Contacts of persons with high CFU cases had larger IGRA results than contacts of cases with lower CFUs IGRA conversion less associated with smear positivity in cases Suggests possibility of using cough generated aerosols to target preventive strategies PLoS One; e published ahead of print 10/29/18

48 Optimizing window prophylaxis Switch to rifampin? Keeping on INH, then changing to a shorter regimen only if the 2 nd TST is positive? Do we change plan based on how long we suspect a child will be on medication? Household contact vs not Persistently positive smear status in source case The youngest children

49 Pediatrics

50 Conclusions New recommendations exist for TB infection diagnosis and treatment Most non TB providers continue to rely upon the TST and 9 months of INH, despite acknowledged poor specificity and completion rates, respectively Likely reflects reduced awareness, not resistance to change Publication of new guidelines alone will not immediately change practice Feel comfortable nudging providers be an agent of change