1. Using Whole Genome Sequencing Analysis in California
CTCA 2019 Educational Conference
Martin Cilnis MPH, MS
Epidemiologist, Outbreak Prevention and Control Section
Tuberculosis Control Branch, Division of Communicable Disease Control
Center for Infectious Diseases, California Department of Public Health

2. I have no conflicts of interest to declare.

3. Objectives
How are WGS analyses used by the California TB Control Branch (TBCB)?
How does the TBCB communicate WGS analysis to local TB programs?
When should local health departments request WGS analysis to improve TB outbreak and cluster investigations?
How can local health departments request WGS analysis?
How can TBCB outbreak response team help with requesting WGS analysis?

4. How are WGS analyses used by the California TB Control Branch (TBCB)?
Assess potential outbreaks and recent transmission events

5. How do TB Cases Occur in California?
Reactivation of remote infection. Cases not from importation or recent transmission
80%
Importation
TB within 6 months of
arrival in US 6%
2,000
TB cases/yr
Recent Transmission
RT recipient
14%

6. How Does TBCB Learn About Outbreaks?
Genotype cluster alerts generated by the CDC TB Genotyping Information Management System (TB GIMS)
CDC surveillance of large outbreaks
Genotype watch list in TB GIMS
Notifications from local health departments
Media

7. TB Genotype Cluster Alerts in CA, 2011-2018

8. Steps of a TB Genotype Cluster Investigation
TBCB Outbreak Response Team assesses genotype, clinical, and epi data
+WGS analysis since 2018
Prioritize genotype clusters
Reassess,
Reprioritize
Higher priority
Lower or no priority
Notify local health departments
Monitor genotype
Investigation
Implement interventions

9. WGS performed for 41 potential outbreaks
Impact of WGS Analysis on TB Outbreak Confirmation, California, 2013 – 2016
WGS performed for 41 potential outbreaks
Molecular, clinical, and epidemiologic data analyzed
26 (63%) outbreaks confirmed
15 (37%) outbreaks refuted

10. Genotype cluster alert for a medium TB morbidity county
Example of How “Real-Time” WGS Helped Assess A Genotype Cluster For Transmission
Genotype cluster alert for a medium TB morbidity county

11. TBCB’s Initial Assessment of the Genotype Cluster
Genotype cluster alert received for County A in 2019
County A
Reports TB cases per year
Never had a TB genotype cluster alert
Genotype data
County A reported 9 of the 14 (64%) patients in the cluster from 2003 to 2018
5 patients were reported in 2 other counties (2013 to 2018)
3 County A patients were reported within the past 2 years

12. TBCB’s Initial Assessment of the Genotype Cluster, continued
Demographic and epi data
County A patients were US-born Hispanic or Mexico-born
No epi links indicated among the TB patients
Clinical data
One recent case in County A cases had smear positive pulmonary TB
Most had less infectious TB disease (sputum smear negative and non-cavitary CXR)
2 of the recent patients were still on TB treatment
Initial TBCB assessment: higher priority cluster
WGS analysis was done for isolates from 3 TB patients from 2018

13. WGS Analysis of the Isolates from the 2018 Patients
Isolates from County A patients
The isolates from County A patients are 11 SNPs apart (a large difference!)
The isolate from a 2018 patient from another county is at least 9 SNPs from the County A isolates (a large difference!)
WGS analysis is pending for isolates from 2 County A patients from 2015, 2017
The WGS analysis indicates that none of these patients were in a recent chain of transmission with each other.
Isolate from a patient from another CA county

14. Current Status of the Genotype Cluster Assessment
WGS analysis suggested that the 2018 patients were not in a chain of recent transmission
The priority level was provisionally decreased from high to low (i.e., limited or no recent transmission)
CA TBCB outbreak team will:
Reassess likelihood of recent transmission when pending WGS analysis becomes available
Notify County A of the genotype cluster alert
Provide County A the assessment of the cluster, WGS analysis
Provide any recommendations for follow-up

15. Summary
Outbreaks and other recent transmission events remain important barriers to TB elimination
Combined analysis of clinical, epidemiologic, and WGS data can help focus TB investigations by:
More precisely identify outbreaks and outbreak cases
Avoid unnecessary investigations of clusters with cases not linked by recent transmission
All TB isolates submitted for genotyping are sequenced
Turn-around time for WGS analysis of isolates from 2018 and later is now fast!
Request WGS analysis through TBCB Outbreak Response Team

16. When Should Local Health Departments Request WGS Analysis?
Consider if WGS analysis could help:
Confirm or refute that a genotype cluster is an outbreak
Determine if transmission can be refuted between recent cases in a genotype cluster
Confirm transmission hypotheses
Determine which cases are due to recent versus remote transmission in large multi-year outbreaks
Inform other decisions about where to focus public health action

17. How Can Local Health Departments Request WGS Analysis?
Determine transmission-related questions WGS analysis might help answer
Decide which TB isolates require WGS analysis
TBCB can provide consultation about isolate selection, including whether to include isolates from TB patients outside of the county
Contact the TBCB Outbreak Response Team and provide a list of isolates and reason for request
Note: Isolates genotyped prior to 2018 have to be cultured and sequenced and analyzed (slower turn-around time)

18. TBCB Outbreak Response Team
Provide outbreak-related support and consultation to local health departments
Conduct statewide TB outbreak surveillance and reporting
Please report TB outbreaks, even if only suspected, to the TBCB Outbreak Response Team

19. Outbreak Support and Consultation Services Available to Local TB Programs
Investigation planning and prioritization
Tracking of outbreak-associated genotypes
Field assistance to conduct interviews, locate contacts, and refer patients to care
Data collection and analysis
Fiscal resources
Facilitation of interjurisdictional communication
Staff training
Access to specialized laboratory services
Tools tailored to specific outbreaks/exposure settings
Technical assistance with media communications
Medical and nursing case management consultation

20. Acknowledgments
Local Public Health TB Programs
Local Public Health Laboratories
CDC Division of TB Elimination, Molecular Epi Activity team
California TB Control Branch
Contact Info,
TBCB Outbreak Prevention and Control Section
Tambi Shaw, Chief, ,
Martin Cilnis, Epidemiologist, ,
TBCB Main Phone Line:

21. Extra Slides

22. Current CDPH Surveillance Definition for a Confirmed TB Outbreak
≥ 4 TB cases occurring in California
Definite epidemiologic links indicating all 4 cases are part of the same chain of transmission
Matching TB genotypes*
Case 1 and Case 4 counted within three years of each other
*Exception: a pediatric case less than 5 years of age without genotype results can be included as one of the 4 cases

23. Investigation of TB Genotype Cluster Alerts, 2017
Assess genotype data with clinical and epi data (25 clusters)
Prioritize genotype clusters
Higher priority
Lower or no priority
12 (48%) clusters
13 (52%) clusters
5 (42%) outbreaks
3 (23%) not an outbreak, no or limited transmission
2 (17%) suspected outbreaks
2 (17%) lab error/cross-contamination