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

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

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

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

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

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

Genotyping Analysis This genotype is rare in CA and the US No CA cases with this genotype between 2010 -2013 All CA cases in this cluster from 2014 – present are in 3 neighboring counties Findings consistent with a likely outbreak

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

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

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

WGS results and likely transmission links for GXXXXX - Provisional Data 1 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: 2012-2013 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

Four Primary Findings and Public Health Implications

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

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

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

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

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.

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

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

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

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

Tuberculosis Control Branch Outbreak Response Team TB Outbreak Duty Officer 510-620-3000 http://cdph.ca.gov/programs/tb

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