1. Whole-Genome Sequencing; It’s Not Just For Epis
Leslie Henry, BSN, RN, PHN
Nurse Consultant
Tuberculosis Control Branch
California Dept. of Public Health

2. How Can PHNs and TB Program Managers Use WGS?
Combined with clinical and epidemiologic data, WGS can help:
Confirm or refute that a genotype cluster is an outbreak
Confirm transmission hypotheses
Inform decisions on where to focus public health action
Identify cases not likely to be part of outbreak

3. Beginnings of an Outbreak
Hispanic male
Smear + pulmonary TB
Very long IP

4. Suspected Outbreak Identified May 2015
3 sputum smear positive, cavitary cases with family and social epi links diagnosed within 2.5 months in early 2015
Suspected outbreak identified by local health department and reported to CDPH
All 3 shared the same, rare genotype

5. More Outbreak Cases Identified Through Genotyping
Search CDC’s TB Genotyping Info Management System for other cases with this genotype
3 additional recent cases with this rare genotype found but no known epi links
1 resided in County A; 2 resided in counties neighboring County A
2 adult white males
1 Hispanic adolescent male
Epi links quickly found through interviews and record searches

6. More cases identified 6/2015 – 8/2016 County A identifies 5 new cases
2 new possible exposure sites identified

7. Genotyping Analysis This genotype is rare in CA and the US
No CA cases with this genotype between
All CA cases in this cluster from 2014 – present are in 3 neighboring counties
Findings consistent with a likely outbreak

8. Number of TB Outbreak Cases in California, 2010-2017 YTD (N=11)*
*As of 2/27/2017, there are no suspected outbreak cases

9. Epidemiologic Links
11 (100%) of case-patients had definite, probable, or possible epi links to other cases
4 case-patients epi linked after genotype identified
Complex and overlapping family, church, band, work, and social networks
Many outbreak case-patients and their contacts have been exposed to multiple cases
Contacts have increased risk of infection
Increases challenge in attributing transmission to specific people, places, and times
Whole-genome sequencing by CDC might further elucidate transmission links 14

10. Red boxes indicate smear pos and/or cavitary CXR
WGS Results
Red boxes indicate smear pos and/or cavitary CXR
Case 10
5/2016
Case 4
3/2015
MRCA se
Case 1
4/2014
Case 8
7/2015
Case 3
2/2015
Case 2
2/2015
Case 11
8/2016
Case 5
5/2015
Case 6
5/2015
Case 9
3/2016

11. WGS results and likely transmission links for GXXXXX - Provisional Data1 2
Case 10
Rx Start: 4/2016
IP: NA (x-pulm TB only; not infectious)
Spec Coll Date: 3/2016
US entry ~ 1/2015
No epi links
MRCA
Not an outbreak case
Case 4
Rx Start: 3/2015
IP: 9/2014-3/2015
Spec Coll Date: 3/2015
Unnamed social contact to Case 3 in summer 2013
Case 2
Rx Start: 2/2015
IP: 9/2014-2/2015
Spec Coll Date: 1/2015
Organ transplant 9/2014 rec’d from donor w/ social contact with Case 3
Case 1
Rx Start: 4/2014
IP: NA (sputum smear/cx neg)
Spec Coll Date: 4/2014
Possible social contact to Case 3
Organ donor (TB 2)
Social contact of Case 3
TST converter 3/2012
died 9/2014
= Definite transmission link
= Probable transmission link
= Possible transmission link
= More infectious TB case (sputum smear positive and/or cavitary TB
IP = infectious period dates
Spec Coll = specimen collection
Case 3
Rx Start: 2/2015
IP: 1/2012-2/2015
Spec Coll Date: 3/2015
Case 8
Rx Start: 7/2015
IP: 9/2014-7/2015
Spec Coll Date: 7/2015
Work contact of Case 3:
Coworker of Cases 3, 11
Case 11
Rx Start: 8/2016
IP: 6/2015-8/2016
Spec Coll Date: 8/2016
IGRA: pos 11/2014
Coworker of Cases 3, 8; named contact to Case 8. 1
Case 9
Rx Start: 2/2016
IP: 11/2014-2/2016
Spec Coll Date: 2/2016
Church/music band link to Cases 3, 5 1 3
Case 6
Rx Start: 5/2015
IP: 8/2014-5/2015
Spec Coll Date: 5/2015
Friend, named contact to Case 3;
cousin of Case 5
Case 5
IP: 12/2014-5/2015
Cousin of Case 6; church/ music band link to Cases 3, 9
Case 7
Rx Start: 6/2015
IP: NA (pleural TB, sputum smear/cx negative, clinical case)
Friend, named contact to Case 6

12. Four Primary Findings and Public Health Implications

13. Finding 1: WGS results are consistent with a large, multijurisdictional outbreak

14. Finding 1: Public Health Implications
Local health department initiated TB outbreak investigation and response activities in May 2015 with epidemiologic, field investigation, and fiscal support from the CDPH TB Control Branch
Intensified activities should be sustained until recent transmission interrupted
Local health department reported the outbreak to CDPH
CDPH reported the outbreak to CDC as it meets CDC’s definition of a large TB outbreak
CDC performed whole-genome sequencing as that is standard practice for all incident large TB outbreaks in the U.S.
CDPH and CDC are monitoring the outbreak to help assess when recent transmission has been interrupted

15. Finding 2: Case 3 is the most likely source case for the majority of the outbreak cases

16. Finding 2: Public Health Implications
The best window of opportunity to find and prevent TB among contacts to Case 3 is closing soon since this case’s infectious period ended two years ago in February 2015
Identify and evaluate high priority contacts who were exposed to the outbreak cases, including contacts to the sputum smear positive cases in 2016

17. Finding 3: Case 2 acquired TB from a lung transplant and is an outbreak case. The deceased lung donor for Case 2 was infected by Case 3 prior to the donor’s death.

18. Finding 3: Public Health Implications
This is an unusual event and was reported as such to the many providers, organizations, healthcare facilities, and public health departments involved in investigating transplant-derived infectious diseases
Other patients who received organs from the same deceased donor who infected Case 2 were notified and evaluated for TB; one patient was presumptively treated for LTBI
Manuscript describing the unusual circumstances of this transmission event and potential interventions has been written and will be submitted to CDC for consideration to publish in the MMWR

19. Finding 4: Case 10 is probably not linked to this outbreak

20. Finding 4: Public Health Implications
Case 10 can be excluded from further investigation unless emerging findings later contradict this conclusion

21. Whole-Genome Sequencing Observations
Along with clinical and epi data, these WGS results helped focus limited resources by confirming:
This is a large multicounty outbreak
a single patient with hyperinfectious TB was the likely source case for the majority of outbreak cases
The highest priority exposure sites
Case 10 was unlikely to be part of outbreak

22. Tuberculosis Control Branch Outbreak Response Team TB Outbreak Duty Officer

23. Leslie Henry, BSN, RN, PHN leslie.henry@cdph.ca.gov 510-620-3040
Thank you!
Leslie Henry, BSN, RN, PHN