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

I have no conflicts of interest to declare.

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?

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

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 2015-2017 6% 2,000 TB cases/yr Recent Transmission RT recipient 2014-2016 14%

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

TB Genotype Cluster Alerts in CA, 2011-2018

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

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

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

TBCB’s Initial Assessment of the Genotype Cluster Genotype cluster alert received for County A in 2019 County A Reports 10-20 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

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

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

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

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

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

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)

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

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

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, 510-620-3016, Tambi.Shaw@cdph.ca.gov Martin Cilnis, Epidemiologist, 510-620-3015, Martin.Cilnis@cdph.ca.gov TBCB Main Phone Line: 510-620-3000

Extra Slides

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

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