Predicting Progression to Tuberculosis Disease in Young Children. Amina Ahmed, MD Levine Children s Hospital March 2, 2018

Transcription

1 Predicting Progression to Tuberculosis Disease in Young Children Amina Ahmed, MD Levine Children s Hospital March 2, 2018

2 Children Are Our Future Diagnosis and treatment of latent tuberculosis infection (LTBI) in children is critical for prevention of tuberculosis (TB) Risk of progression to TB is higher in young children with untreated LTBI Diagnosis and treatment of LTBI in children is paramount to TB elimination efforts Children with LTBI, especially those immigrating from high TB burden countries, are reservoirs for future cases of TB

3 Risk of Disease Following Primary Infection Age < 1 year 1-2 years Pulmonary TB Disseminated TB/ TB meningitis No Disease 30-40% 10-20% 50% 10-20% 2-5 % 75-80% 2-5 years 5% 0-5% 95% 5-10 years > 10 years 2% < 0-5% 98% 10-20% < 0-5% 80-90% 3 Lancet Infect Dis 2008; 8:

4 TST versus IGRAs: Estimates of Performance Sensitivity ( %) Specificity (%) Adult and Pediatric Studies TST 89 (63-100) 85 (22-100) QFT 83 (56-93) 99 (99-100) T-Spot 90 (50-100) 88 (85-100) Pediatric Studies TST 80 (70-90) 85 (63-100) QFT 83 (75-92) 91 (78-100) T-Spot 84 (63-100) 94 (87-100) 4 Ann Intern Med 2008; 149: ; IJTLD 2011; 15: MMWR 2010; 59 (RR-5): 1-25

5 What Do We Know? Sensitivity TST and IGRA equivalent Some studies suggest higher sensitivity of TST Specificity IGRAs likely have higher specificity, especially in BCG-vaccinated No gold standard for LTBI Neither test is highly predictive of disease 5

6 Which Test Do We Use? For children > 5 years of age, either TST or IGRA BCG vaccinated- IGRA preferred For children < 5 years of age, TST preferred Sensitivity deemed more important than specificity Younger children more likely to be closer to BCG vaccination We may be overdiagnosing and overtreating LTBI in children 6

7 What Are We Afraid Of in Young Children? Lack of data Lack of longitudinal data on IGRAs informing predictive value Operational issues Rates of indeterminate results for IGRAs are higher in young children Discordant results (TST+/IGRA-) Is TST more sensitive or IGRA more specific? Which is more predictive of disease? 8

8 Cinq-o-phobia!! Fear of under-diagnosing children < 5 years of age with LTBI Results in believing the positive test even when you know better Probably results in overtreatment

9 Where Do We Go from Here? An accurate test for the identification LTBI in children could support more focused programmatic delivery of preventive treatment to at risk children No gold standard for LTBI Neither test highly predictive of disease We need longitudinal studies informing predictive value 10

10 1. California Department of Public Health 2. Denver Health and Hospitals Authority 3. Duke University and Carolinas HealthCare, NC; Vanderbilt University, TN 4. Emory University 5. Hawaii Department of Health 6. Seattle-King County Health Department 7. Maricopa County Health Department 8. Maryland Department of Health 9. University of Florida 10. University of North Texas Health Science Center

11 TBESC Prospective cohort study All age groups Comparison of TST, Quantiferon Gold In Tube (QFT IT) and T Spot in those at high risk for LTBI or progression to TB Agreement between TST and the 2 IGRAs Ability to predict progression to disease

12 TBESC: Inclusion Criteria Close contact with pulmonary TB FB from high risk country or travel (30 days) to high risk country in the last 5 years FB from medium risk country, in US for 5 years Belonging to local population with prevalence of LTBI 25% HIV positive

13 TBESC Follow-Up Any positive test, treated or untreated Every 6 months for 24 months Symptoms or signs of TB; diagnosis of TB Adverse effects if on treatment Registry match every 6 months Negative tests Registry match every 6 months

14 Characteristic All Participants Age (Years) < N (%) N % N % N (%) N (%) (35.7) 1484 (39.2) Race/ethnicity American Indian/Alaska native 14 (0.4) 2 (0.9) (0.2) 6 (0.4) Asian 1284 (33.4) 100 (43.7) 288 (40.1) 402 (29.7) 494 (33.3) Black/African American 825 (21.8) 36 (15.7) 139 (19.3) 313 (23.2) 337 (22.7) White/Caucasian 206 (5.4) 8 (3.5) 36 (5.0) 89 (6.6) 73 (4.9) Native Hawaiian/Pacific Islander 74 (2.0) 2 (0.9) 5 ( (2.4) 34 (2.3) Hispanic/Latino 309 (8.2) 10 (4.4) 38 (5.3) 123 (9.1) 138 (9.3) Other 1125 (29.7) 61 (31.4) 216 (30.0) 406 (30.0) 431 (29.0) Foreign-born 3471 (91.7) 208 (90.8) 667 (92.8) 1229 (90.9) 1367 (92.1) Contact 406 (10.7) 23 (10.0) 69 (9.6) 156 (11.5) 158 (10.6) BCG Vaccination 2485 (65.7) 155 (67.7) 477 (66.3) 873 (64.6) 980 (66.0)

15 Single Test Prevalence TST QFT T Spot N No. Positive % N No. Positive % N No. Positive % All Age (y) <

16 Single Test Prevalence, All Patients TST QFT T Spot < 2 2 to 4 5 to 9 10 to 14 Age

17 LTBI PREVALENCE (%) Single Test Prevalence, USB, Contacts TST QFT TSPOT (US) < AGE GROUP

18 LTBI PREVALENCE (%) Single Test Prevalence, FB, Non-contacts TST QFT TSPOT (US) < AGE GROUP

19 Concordance and Agreement between TST and QFT All < Concordance (%) Concordance (%) Concordance (%) Concordance (%) Concordance (%) All k Origin of birth US-born Foreign-born Contact status Yes USB FB No

20 Incident Cases By Age/Risk and Treatment Age Risk Factors Test Results (TST/QFT/TSpot) Treatment for LTBI Interval to Diagnosis Diagnosis 12 years Foreign-born, high risk country +++ Not offered 11 months Abnormal CXR; culture confirmed 7 months Close Contact --- Window prophylaxis 11 weeks Abnormal CXR; culture confirmed 7 months Close Contact -+- Yes- ongoing 11 weeks Abnormal CXR; culture confirmed 14 years Foreign-born, high risk country +++ Yes-completed 20 months Abnormal CXR; culture confirmed

21 Incident Cases Incident Cases Total Patients Completed Treatment Percent Progression Triple Positive Triple Negative TST QFT T Spot TST+/QFT TST+/QFT TST-/QFT TST-/QFT- 1 2, TST+/TSpot TST+/TSpot TST-/TSpot TST-/TSpot

22 Incidence in Treated and Untreated Patients Incident Cases No. Patients Personyears Incidence Rate (IR) Incidence Rate Ratio (CI) TST (0.22, 3.57) 2.44 (0.34, 17.31) TST (1.17, 1.47) QFT (1.19, 11.43) (2.62, 242.5) QFT (0.02, 1.04) T Spot (0.86, 13.76) (1.68, 85.09) T Spot (0.07, 1.15) 26

23 Incidence in Untreated Patients Incident Cases No. Patients Personyears Incidence Rate (IR) Incidence Rate Ratio (CI) TST+ TST- QFT+ QFT- T Spot+ T Spot , (0.10, 4.86) 1.85 (0.16, 20.38) (0.09, 1.48) (1.73, 27.65) (4.09, ) (0.09, 38.49) (0.76, 38.49) (1.61, ) (0.31, 5.01) 28

24 Incidence in Untreated Patients Incident Cases No. Patients Person-years Incidence Rate (IR) TST+/QFT (0.64, 32.08) TST+/QFT TST-/QFT (2.07, 104.5) TST-/QFT (0.03, 1.34) TST+/TSpot (0.14, ) TST+/TSpot TST-/TSpot TST-/TSpot (0.10, 1.52) 29

25 What Have We learned? Predictive value of all tests are low Progression rates and IRs for both TSTs and IGRAs are low Highest IR is for children < 2 years of age who were contacts Progression rates, IR and IRR higher for IGRAs than for TSTs Of 681 TST+/QFT- patients, 0 developed disease over 2 years 555 of these were untreated 65 of these were < 2 years of age

26 Performance of TST and IGRAs Based on Incident Cases Sensitivity (%) Specificity (%) PPV (%) NPV (%) TST QFT T Spot

27 Latent Class Analysis Latent class analysis is a statistical technique to find underlying but unmeasurable groups within a study population Requires measurement of binary indicators believed to be related to underlying classes For this study: Latent classes are LTBI and No LTBI Indicators are the three tests (TST, QFT, T-Spot)

28 Latent Class Analysis Updated for 820 children, FB, HIV-, < 5 years of age. LTBI Prevalence 1.3% ( ) Sensitivity (%) Specificity (%) PPV (%) NPV (%) TST 82.0 ( ) 71.9 ( ) 3.6 ( ) 99.7 ( ) QFT 80.4 ( ) 98.5 ( ) 40.3 ( ) 99.7 ( ) T Spot 74.1 ( ) 99.7 ( ) 76.6 ( ) 99.6 ( ) 34

29 What Does This Mean? Prevalence of 1.3%= 13 children in a cohort of 1000 with LTBI For every 1000 FB children tested for LTBI based on TST 305/316 (96.5%) who test positive will not have LTBI 2/13 (15%) will be missed For every 1000 FB children diagnosed with LTBI based on QFT 15/25 (60%) will not have LTBI 3/13 (23%) will be missed 35

30 Conclusions Almost 1000 children < 5 years of age followed for 2 years Majority were FB and BCG vaccinated Predictive value of IGRAs appears higher than for TSTs Performance of IGRAs Sensitivity of IGRAs similar to TST PPV of TST is very low NPV of all tests is high

31 Which Test to Use in Young Children? A high proportion of young children tested for LTBI are BCG vaccinated Discordant results most common in this population With TST we are likely over-diagnosing and overtreating Use of IGRAs may allow for more accurate testing and appropriate use of resources Tradition TSTs have a long standing history of being reliable in predicting disease But..in current era, TSTs are difficult to administer, difficult to read

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33 Acknowledgements CDC Dolly Katz Pei-Jean Feng Rose Punnoose Duke Site Jason Stout, MD Protocol team Katya Salcedo, MPH James Gaensbauer, MD Renuka Khurana, MD Randall Reves, MD

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35 Rates of Indeterminate QFT Results Age (Years) All n (%) Foreign-born n (%) US-born n (%) <2 2 (1.8) 2 (1.9) (0.3) 1 (0.3) (0.6) 5 (0.7) (0.1) 1 (0.1) (0.7) 9 (0.5) 1 (0.6) (0.7) 22 (0.6 6 (0.9)

36 Variation in Mitogen Values By Age

37 Prevalent Cases No. Cases No. Patients Percent All <

38 Incident Disease Across Risk Factors Age (Years) Contacts Non-contacts Foreign-born US-born Cases No. Patients IR Cases No. Patients IR Cases No. Patients IR Cases No. Patients IR < , , , ,