HEPATITIS A: PULLING A MOLECULAR RABBIT FROM SAN DIEGOS HAT Tracy - - PDF document

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6/28/2019 1 HEPATITIS A: PULLING A MOLECULAR RABBIT FROM SAN DIEGOS HAT Tracy Basler June 28, 2019 PUBLIC HEALTH SERVICES 1 6/28/2019 SAN DIEGO COUNTY HEPATITIS A OBJECTIVES Participants will be able to: Describe the

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6/28/2019 1

1

HEPATITIS A: PULLING A MOLECULAR RABBIT FROM SAN DIEGO’S HAT

Tracy Basler June 28, 2019

PUBLIC HEALTH SERVICES

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6/28/2019 2 SAN DIEGO COUNTY – HEPATITIS A OBJECTIVES

  • Participants will be able to:
  • Describe the strategies and tactics used by San Diego County to combat

the Hepatitis A outbreak.

  • Discuss how Next Generation Sequencing (NGS) technologies aided in

characterizing the Hepatitis A virus outbreak and provided cluster detection.

SAN DIEGO COUNTY – HEPATITIS A SAN DIEGO COUNTY IS…

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6/28/2019 3 SAN DIEGO COUNTY – HEPATITIS A SAN DIEGO HAS…

  • 3.3 million residents
  • 18 federally recognized

Indian reservations

  • 16 naval and military

installations

  • 18 municipalities; 36

unincorporated towns

  • 42 school districts
  • 21 hospitals

SAN DIEGO COUNTY – HEPATITIS A OUTLINE

  • Hepatitis A Background
  • Hepatitis A in San Diego
  • Public Health Response
  • Laboratory Response
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6/28/2019 4 SAN DIEGO COUNTY – HEPATITIS A

  • Hepatitis A Background
  • Hepatitis A in San Diego
  • Public Health Response
  • Laboratory Response

SAN DIEGO COUNTY – HEPATITIS A OVERVIEW

  • Hepatitis A can be easily spread from person to

person

  • Can cause liver disease lasting a few weeks to a

serious illness lasting several months

  • Can cause death in some cases
  • Average incubation period for the Hepatitis A

virus is 28 days (range:15-50 days)

  • Hepatitis A virus can live outside the body for

months, depending on the environmental conditions

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6/28/2019 5 WHAT ARE THE SYMPTOMS OF HEPATITIS A? SAN DIEGO COUNTY – HEPATITIS A WHO IS AT RISK FOR HEPATITIS A?

  • Travelers to certain countries
  • Men who have sex with men
  • Injection and non-injection drug users
  • Persons with clotting factor disorders
  • Persons with chronic liver disease
  • Persons experiencing homelessness &/or those with unstable living conditions
  • Household members, and other close personal contacts with high or intermediate

Hepatitis A occurrences

  • Persons with close ongoing contact with persons experiencing homelessness

and/or illicit drug users or their environment via employment or volunteer activities (during this outbreak)

SAN DIEGO COUNTY – HEPATITIS A

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6/28/2019 6 SAN DIEGO COUNTY – HEPATITIS A

  • Hepatitis A Background
  • Hepatitis A in San Diego
  • Public Health Response
  • Laboratory Response

SAN DIEGO COUNTY – HEPATITIS A

  • Reportable in California within one working day of

identification by laboratory & provider (CCR Title 17 Sections 2500, 2505)

  • Surveillance noted increase in cases above

baseline in early March 2017

  • 11/16 to 2/17: 7- 9 cases expected, 19 cases

reported

  • Health alert on outbreak on March 10, 2017
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6/28/2019 7 SAN DIEGO COUNTY – HEPATITIS A

  • 592 confirmed outbreak cases from 11/22/16 –

10/18/18

  • 407 (68%) hospitalizations, 20 (3.4%) deaths
  • 404 (68%) male (14 MSM), 188 (32%) female
  • Age range 5-87 (median 43.0)
  • Suspected Exposure Type
  • 201 (34%) homeless and illicit drug use
  • 91(15%) homeless only
  • 79 (13%) illicit drug use only
  • 167 (28%) neither
  • 54 (9%) unknown

5 10 15 20 25 30 35 40

11/6/16 12/4/16 1/1/17 1/29/17 2/26/17 3/26/17 4/23/17 5/21/17 6/18/17 7/16/17 8/13/17 9/10/17 10/8/17 11/5/17 12/3/17 12/31/17 1/28/18 2/25/18 3/25/18 4/22/18 5/20/18 6/24/18 7/22/18 8/19/18 9/16/18 10/14/18

Confirmed and Probable Cases Reported 10/13/17 State Emergency Declared 3/8/17 Outbreak Determined 9/1/17 Public Health Emergency Declared 1/23/18 Public Health Emergency Undeclared 10/18/18 Outbreak Declared Over

| 2017

Onset Week

Data as of 10/18/18

2016 | 2018 N = 6 N = 571 N = 15

Outbreak-associated Hepatitis A Cases by Onset Week San Diego County Residents, 11/1/2016 – 10/18/2018*, N = 592

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6/28/2019 8

HEPATITIS A, SAN DIEGO

. *Year to date as of 05/31/2019. New CSTE case definition effective 01/01/2019 may affect case numbers and trends. Prepared by County of San Diego, Health & Human Services Agency, Public Health Services, Epidemiology & Immunization Services, 05/31/2019

100 200 300 400 500 600 700 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Hepatitis A Cases, San Diego County 1994 – 2019*

Vaccine introduced Routine vaccination for children in high‐incidence states (including California) Routine vaccination for all U.S. children

5 10 15 20 25 30 35 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 *2019 Rate per 100,000 Rate of HAV Infection by Age, San Diego County 1996‐2019* 0‐14 years 15‐24 years 25‐44 years 45‐64 years 65+ years

*Year to date as of 05/31/2019. New CSTE case definition effective 01/01/2019 may affect case numbers and trends. Prepared by County of San Diego, Health & Human Services Agency, Public Health Services, Epidemiology & Immunization Services, 05/31/2019

SAN DIEGO COUNTY – HEPATITIS A

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6/28/2019 9 OUTBREAK SUMMARY

Cases (% of 592) Dark urine 413 (70%) Jaundice 394 (67%) Sex (male) 404 (68%) Age (years) Minimum Median Maximum 5 43 87 Hospitalized 407 (69%) Died 20 (3.4%) Homelessness

17% 37% 15%

Illicit drug use

n = 538

Data as of 10/18/18

SAN DIEGO COUNTY – HEPATITIS A

SAN DIEGO COUNTY – HEPATITIS A

  • Hepatitis A Background
  • Hepatitis A in San Diego
  • Public Health Response
  • Laboratory Response
  • Summary
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6/28/2019 10 PUBLIC HEALTH INTERVENTIONS

  • Vaccinate
  • Sanitize/hygiene
  • Educate

~203,858 vaccinations ~85% targeting risk groups

  • Handwashing

stations

  • Street sanitation
  • Hygiene kits
  • Food inspections
  • Presentations
  • Outreach
  • Posters
  • 2-1-1 San Diego Calls

SAN DIEGO COUNTY – HEPATITIS A

Mass Vaccination at St. Vincent de Paul 4/10/17

SAN DIEGO COUNTY – HEPATITIS A

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6/28/2019 11

Mobile Vaccination in Rosecrans Parking Lot 5/15/17 with outreach workers from Family Health Centers San Diego

SAN DIEGO COUNTY – HEPATITIS A

“Foot team” in downtown San Diego 6/8/17 with volunteers from Friend to Friend, Episcopal Community Services Photo credit: County of San Diego

SAN DIEGO COUNTY – HEPATITIS A

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6/28/2019 12

Source: COSD. Downloaded 10/19/18 from:

https://www.sandiegocounty.gov/content/dam/sdc/hhsa/programs/phs/Epidemiology/HepA_ZipCodes.pdf

SAN DIEGO COUNTY – HEPATITIS A

Source: COSD. Downloaded 10/19/18 from:

https://www.sandiegocounty.gov/content/dam/sdc/hhsa/programs/phs/Epidemiology/HepA_ZipCodes.pdf

SAN DIEGO COUNTY – HEPATITIS A

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6/28/2019 13

PHS staff member with “Hepatitis A prevention kits” for distribution to raise awareness among homeless about hepatitis. They contain water, non-alcohol hand sanitizer, cleaning wipes, clinic location information, and plastic bags.

SAN DIEGO COUNTY – HEPATITIS A

Handwashing station being installed in downtown San Diego on 9/2 (Photo: San Diego Union Tribune)

SAN DIEGO COUNTY – HEPATITIS A

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6/28/2019 14

City contractor cleaning a street in downtown San Diego

  • n 9/11/2017 (Photo: San Diego Union Tribune)

SAN DIEGO COUNTY – HEPATITIS A

Photo of “tent city” set up in September 2017 by the City of San Diego January 2018 Photo credit: San Diego Union Tribune Interior photo of one of three homeless tents set up by the City of San Diego January 2018 Photo credit: San Diego Union Tribune

SAN DIEGO COUNTY – HEPATITIS A

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6/28/2019 15

SAN DIEGO COUNTY – HEPATITIS A

  • Hepatitis A Background
  • Hepatitis A in San Diego
  • Public Health Response
  • Laboratory Response

SAN DIEGO COUNTY – HEPATITIS A LABORATORY APPROACH

  • Phase 1
  • Acquire funding and equipment
  • Phase 2
  • Laboratory assay implementation
  • Phase 3
  • Analysis and Genotyping
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6/28/2019 16 SAN DIEGO COUNTY – HEPATITIS A LABORATORY TIMELINE

March 2017 First specimen sent to CDC for genotyping by Sanger sequencing May 2017 Research sequencing methods to perform testing in- house August 2017 Order MiSeq instrument and research screening methods to perform testing in- house September 1, 2017 Emergency Outbreak Declared by San Diego County Health Officer October 2017 Begin testing specimens in- house by NAAT screening method. MiSeq Installed. November 2017 Molecular scientist hired January 2018 Begin testing specimens in- house for genotyping by NGS method using GHOST January 23, 2018 Emergency Declaration Ended October 18, 2018 Outbreak Declared Over

Phase 1 Phase 2 Phase 3

SAN DIEGO COUNTY – HEPATITIS A

  • Training
  • PCR screening
  • Sequencing
  • Instrumentation
  • Purchasing NGS equipment
  • IT and Bioinformatics
  • Software and networking approvals

through County IT

  • Novice experience in bioinformatics
  • Staffing
  • Capacity strained due to high volume
  • f Zika specimens
  • Shipping specimens to the CDC and

California Department of Public Health (CDPH)- Viral and Rickettsial Disease Laboratory (VRDL)

  • Implementing PCR screening assay
  • Implementing NGS methods

LABORATORY CHALLENGES

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6/28/2019 17 SAN DIEGO COUNTY – HEPATITIS A NAAT SCREENING TEST

  • Determined a need to confirm by molecular methods in addition to

serology methods with a short TAT

  • No commercial PCR assays available.
  • Attended AMD Day September 25-26, 2017
  • TaqMan assay for Hepatitis A screening in different matrices such as

food, water, and clinical samples. (N. Jothikumar et al. 2005. Development

and Evaluation of a Broadly Reactive TaqMan Assay for Rapid Detection of Hepatitis A Virus. Appl. Environ. Micro. Vol. 71 No.6)

  • Began reporting results October 30, 2017

SAN DIEGO COUNTY – HEPATITIS A WGS VS TARGETED SEQUENCING?

  • Initially started with Whole Genome Sequencing of Hepatitis A (C. Chiapponi et al. 2014. Isolation and

Genomic Sequence of Hepatitis A Virus from Mixed Frozen Berries in Italy. Food Environ. Virol. 2014 Sep; 6(3):202-6)

  • WGS assay produced non-uniform genome coverage, and low sensitivity prompting a

move to targeted NGS approach

  • Developed targeted NGS assay with help from CDPH Viral and Rickettsial Disease

Laboratory and CDC

  • Improved sensitivity and coverage in the region of interest
  • Geneious software purchased to align reads and generate phylogenetic trees
  • January 2018- GHOST HAV protocol available and adopted for sequencing
  • Processed 480 HAV specimen through the GHOST assay
  • Analyzed using GHOST portal and Geneious Software
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6/28/2019 18 SAN DIEGO COUNTY – HEPATITIS A

GLOBAL HEPATITIS OUTBREAK SURVEILLANCE TECHNOLOGY

  • Why GHOST?
  • Efficient, straightforward Next Generation Sequencing method for

Hepatitis A and C

  • Allows for partnered surveillance efforts with the CDC
  • Data analysis tools

Specimen Received HAV Screening Negative Report Positive GHOST NGS Assay Data Analysis Report

SAN DIEGO COUNTY – HEPATITIS A

cDNA Synthesis Verification and Purification Index NAAT Quantification and Library Pooling MiSeq Sequencing

Geneious Analysis Sub-Cluster Identification

GHOST NGS Assay Data Analysis

Hepatitis A Specimen Workflow

GHOST Portal Genotype

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6/28/2019 19 SAN DIEGO COUNTY – HEPATITIS A

VP1-P2B Region used for Genotyping analysis 5’-UTR Region used for PCR screening Expanded view of the viral proteins used in HAV assays provided by Nainan et al 2006 Nucleotide diversity of the genome provided by Nainan et al., 2014

Hepatitis A – M14707

SAN DIEGO COUNTY – HEPATITIS A STRAIN DIVERSITY

(n= 3) (n= 1) (n= 2) (n= 1) (n= 1) (n= 1) (n= 4) (n= 3) (n= 1) (n= 324) (n= 34) (n= 2) (n= 33) (n= 2) (n= 1) (n= 1) (n= 1) (n= 1) (n= 1) CA_Cluster_A CA_Cluster_B (n= 2) (n= 2) (n= 8) (n= 1) (n= 1) A17CA300 A17CA79 A17CA232 CA_Cluster_D (n= 1) (n= 1) (n= 1) (n= 1) (n= 1) (n= 1)

Total Specimen = 464

IA - Non-

Outbreak

IB - Outbreak

(n= 6) (n= 10) (n= 1) (n= 3) (n= 3) (n= 1) (n= 1) (n= 1) (n= 1)

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6/28/2019 20 SAN DIEGO COUNTY – HEPATITIS A STRAIN DIVERSITY

(n= 3) (n= 2) (n= 1) (n= 1) (n= 1) (n= 4) (n= 3) (n= 1) (n= 1) (n= 1) (n= 1) (n= 1) (n= 1) (n= 1) (n= 1) (n= 1)

IA - Non-

Outbreak

(n= 3) (n= 1) (n= 1) (n= 1) (n= 1) (n= 1)

SAN DIEGO COUNTY – HEPATITIS A STRAIN DIVERSITY

(n= 324) (n= 34) (n= 2) (n= 33) (n= 2) (n= 1) (n= 1) (n= 2) (n= 2) (n= 8) (n= 1) (n= 1) (n= 1)

IB - Outbreak

(n= 6) (n= 10) (n= 1) (n= 3) CA_Cluster_A CA_Cluster_B A17CA300 A17CA79 A17CA232 CA_Cluster_D

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6/28/2019 21 SAN DIEGO COUNTY – HEPATITIS A

HAV TRANSMISSION NETWORK

IB- CA Cluster A IB- CA Cluster D IB- CA Cluster B IB- A17CA300 IB- A17CA232 IB- A17CA79

SAN DIEGO COUNTY – HEPATITIS A SUCCESS!

  • San Diego County successfully built the capacity to respond to the local Hepatitis A
  • utbreak and can quickly respond in the future.
  • Laboratory + Epidemiology + Public Health Response teams
  • NAAT Screening and sequencing were valuable tools in the laboratory’s ability to

respond to the outbreak and implement NGS capabilities in our lab.

  • The collaborative partnerships developed over the course of responding to the
  • utbreak were invaluable to the laboratory’s success.
  • Outbreak Over!
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6/28/2019 22 HEPATITIS A – UNITED STATES

Source: CDC. Downloaded 6/17/19 from: https://www.cdc.gov/hepatitis/outbreaks/2017March-HepatitisA.htm

State-Reported Hepatitis A Outbreak Cases as of June 14, 2019

Cases = 20,133 Hospitalizations = 11,595 (56%) Deaths = 191

HEPATITIS A – UNITED STATES

State Case Total Hospitalizations n (%) Deaths Outbreak Start Date Data Current Through Total 20133 11595 (58%) 191 States with an ongoing outbreak Alabama 77 36 (47%) NR 9/1/2018 6/12/2019 Arizona 374 295 (79%) 2 11/1/2018 6/13/2019 Arkansas 343 NR (NR) NR 2/7/2018 6/7/2019 Colorado 71 44 (62%) 10/1/2018 6/12/2019 Florida 1876 1353 (72%) 21 1/1/2018 5/31/2019 Georgia 416 280 (67%) 1 6/1/2018 6/7/2019 Illinois 90 55(61%) 9/1/2018 6/12/2019 Indiana 1581 851 (54%) 4 11/1/2017 6/14/2019 Kentucky 4695 2267 (48%) 58 8/1/2017 6/1/2019 Louisiana 281 169 (60%) 1 1/1/2018 6/14/2019 Massachusetts 360 296 (82%) 5 4/1/2018 6/7/2019 Michigan 916 735 (80%) 28 8/1/2016 6/12/2019 Missouri 314 158 (50%) 2 9/1/2017 6/11/2019 New Hampshire 130 79 (61%) 1 11/1/2018 6/11/2019 New Mexico 124 99 (80%) 2 11/8/2018 6/13/2019 North Carolina 79 56 (71%) 1 1/1/2018 5/31/2019 Ohio 3039 1821 (60%) 10 1/1/2018 6/10/2019 South Carolina 133 101 (76%) 1 11/1/2018 6/7/2019 Tennessee 1647 992 (60%) 9 12/1/2017 6/7/2019 Virginia 70 43 (61%) 1/1/2019 6/13/2019 West Virginia 2528 1249 (49%) 21 3/19/2018 6/7/2019 States with a declared end to their outbreak California 708 464 (66%) 21 11/1/2016 4/11/2018 Utah 281 152 (54%) 3 5/8/2017 2/12/2019

Source: CDC. Downloaded 6/17/19 from: https://www.cdc.gov/hepatitis/outbreaks/2017March-HepatitisA.htm

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6/28/2019 23 Thank you!

On May 17, 2016, the County of San Diego Health and Human Services Agency Division

  • f Public Health Services received accreditation from the Public Health Accreditation Board.
  • CDC
  • Suma Ramachandran, Ph.D.
  • Yury Khudyakov, Ph.D.
  • California Department of Public Health-

Viral & Rickettsial Disease Laboratory

  • Jill Hacker, Ph.D.
  • Will Probert, Ph.D.
  • Michigan Department of Health & Human

Services

  • Marty Soehnlen, Ph.D.
  • County of Alameda, CA
  • Mark Pandori, Ph.D.
  • San Diego County SDPHL
  • Wilma Wooten, MD, MPH – Health Officer &

Director of Public Health Services

  • Eric McDonald, MD, MPH, FACEP –

Medical Director

  • Brett Austin, MA, MPH – Laboratory Director
  • Syreeta Steele, Ph.D. – Assistant Laboratory

Director

  • Jovan Shepherd – Public Health

Microbiologist

  • Sarah Stous, MPH – Epidemiologist I

SAN DIEGO COUNTY – HEPATITIS A QUESTIONS?

Contact information Tracy.Basler@sdcounty.ca.gov

On May 17, 2016, the County of San Diego Health and Human Services Agency Division

  • f Public Health Services received accreditation from the Public Health Accreditation Board.