Tuberculosis Cluster Investigations Using Genotyping Data

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Tuberculosis Cluster Investigations Using
Genotyping Data
Frank Romano, MPH CDC Public Health Advisor
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Historical Perspective

• 1989 ACET CDC Publishes A Strategic Plan for
  the Elimination of TB in the US
• Predicted incidence rate of 3.5 per 100,000 by
  2000
• Predicted the elimination of TB by 2010

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History (cont.)

• Late 1980s early 1990s Few states
  performing TB genotyping using IS6110 RFLP
• Jan. 1990August 1993 Strain W
• MDR Strain
• 357 cases reported in NYC prisons and hospitals
• HIV seropositive population
• 80 mortality (Duration 46 weeks)

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• April 1996 CDC establishes the National
  Tuberculosis Genotyping and Surveillance Network
  (NTGSN)
• 19962000 NTGSN conducts population-based study
  to determine the frequency of specific strains
  geographically using IS6110 RFLP and
  Spoligotyping
• 2001 Results of study published

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Use Genotype Results to Better Understand

• spread of related strains in communities
• geographic mobility of related strains
• relatedness of strains in persons at high risk
  for tuberculosis
• capacity of local TB controllers to identify
  patients involved in outbreaks and to provide a
  database of DNA fingerprints for tuberculosis
  control activities

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CDC TB Genotyping Program

• January 2004, the CDC Tuberculosis Genotyping
  Program was initiated to enable rapid genotyping
  of isolates from every patient in the USA with
  culture-positive tuberculosis (TB)
• The Federal Tuberculosis Task Force recommended
  nationwide TB genotyping in response to the
  Institute of Medicine report, Ending Neglect
• The TB Genotyping Program contracts with
  laboratories that provide results within 10
  working days using two PCR-based genotyping tests

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PCR Based Testing

• Polymerase chain reaction (PCR)
• Only a small amount of culture is needed for
  PCR-based genotyping, and the PCR test can be
  completed in 1day
• because the PCR tests are batched, the actual
  turn-around time from receipt of a specimen to
  reporting the results can be longer

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CDC TB Genotyping Program

• Goal Provide nationwide rapid
  genotyping tests
• Two CDC-funded laboratories perform genotyping
  for one isolate from every culture-positive TB
  case in the US
• CDC funded TB programs submit isolates to
  regional genotyping labs
• Genotyping labs report results within 10 days

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CDC TB Genotyping Program Genotyping Laboratory
Assignments
LAB
LAB
Assigned to California Lab
Assigned to Michigan Lab
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CDC Genotyping Program Laboratory Methods

• Two tiered testing to maximize discriminatory
  power
• PCR
• MIRU Variable number tandem repeats of
  mycobacterial
  
• interspersed repetitive
  units
• Spoligotyping Spacer oligonucleotide typing
• IS6110-based RFLP
• Done only for isolates that match by both PCR
  tests
• At request of CDC grantee

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Comparison of Testing Methods

• IS6110RFLP- (Restriction Fragment Length
  Polymorphism)
• Considered most discriminatory test worldwide
• DisadvantagesCost, time, need for specialized
  training lab
  equipment
• Spoligotype- (Spacer Oligonucleotide Typing)
• Lower Specificity than RFLP
• Lower cost, rapid results
• MIRU- (Variable number tandem repeats of
  mycobacterial
  
• interspersed repetitive
  units)
• Lower Specificity than RFLP
• Lower cost, rapid results

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Tuberculosis Genotyping Guide

• National TB Controllers Association
• Centers for Disease Control and Prevention

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(No Transcript)
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Value of Genotyping

• Identify and prevent transmission
• Enhance contact investigations
• Identify nontraditional settings of transmission
• Facilitate identification of clusters and
  outbreaks
• Improve clinical management
• More readily identify false-positive cultures
• Help distinguish between relapse and reinfection

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Value of Genotyping (II)

• Enhance surveillance
• Evaluate prevalence of M. tuberculosis genotypes
• Monitor trends in recent transmission
• Evaluate prevention activities
• Completeness of contact investigations
• Progress toward TB elimination

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CDC TB Genotyping Program

• All programs with CDC Cooperative Agreements are
  eligible (64)
• Program options
• Selective genotyping
• Universal genotyping
• Universal genotyping for subregion

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TB Genotyping Programs
NYC
D.C.
SD
Universal Selective Mixed Not enrolled
Aug 04
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TB Genotyping Programs
NYC
D.C.
SD
Universal Selective Mixed Not enrolled
June 06
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CDC National TB Genotyping Program Update

• As of May 1, 2006, 15,573 isolates have been
  submitted nationally
• 439 isolates submitted from Ohio as of 7/19/2006
• Ohio has 44 clusters (range 2 - 13 patients) as
  of 7/19/2006
• Sharing genotype pattern data across
  jurisdictions (Quarterly Reports from CDC)

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Ohios Role
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County Genotyping Report
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County Cluster Report
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Genotyping Results

• Interpreting genotyping results and epidemiologic
  data
• When to initiate a cluster investigation,
  initiate (expand) an outbreak investigation, or
  do nothing
• Epi-link a characteristic that 2 or more TB
  patients share that explains where and when TB
  could have been transmitted between them

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Interpreting Results

• Matching genotype vs. non-matching genotype
• Epi-linked vs. non-epi-linked
• Involved in same recent chain of transmission vs.
  not involved

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Matching Genotypes

• False-positive culture?
• Suspected false-positives are a priority
• need to stop treatment for falsely diagnosed
  patients as soon as possible

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False-Positive Cultures

• Clinical Picture
• Health care provider or clinical lab is
  suspicious
• patient had only 1 positive culture out of 1 or
  multiple specimens collected
• patient asymptomatic for TB
• patients chest radiograph not consistent with TB
• patient has another confirmed diagnosis to
  explain symptoms

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False-Positive Cultures

• Laboratory
• specimens were processed in the same laboratory
  on the same day
• isolates were collected in the same hospital or
  clinic within 3 days
• PCR genotyping pattern matches the laboratory
  control strains (H37rv or H37ra) or laboratory
  proficiency specimens

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False-Positive Cultures

• False-positive result confirmed
• identify which patients actually have TB and
  which patients were misdiagnosed
• alert the health care providers so they can
  correctly diagnose and treat the misdiagnosed
  patients
• alert the laboratory so the cause of the
  false-positive culture can be determined and
  corrected

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Matching Genotypes

• Patients Epi-linked prior to genotyping
• Interpretation
• probably involved in same chain of recent
  transmission
• RFLP confirmation or cluster investigation not
  needed
• may determine that an outbreak investigation is
  needed

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Outbreak Investigations

• An increase in the expected number of cases
• Transmission continues despite adequate control
  efforts by the TB program
• The contact investigation has grown to a size
  that requires additional outside help

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Cluster OH_009

• 11 Hamilton County cases 1 Kentucky case
• CDC currently assisting with investigation in
  Indiana

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3
1
4
2
1
12
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1
3
2
3
Number of isolates as of 06/30/2006 n 55 IN
61.8 of isolates (Note 1 case in Florida
matches on spoligotype and is missing MIRU but is
linked epidemiologically)
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Matching Genotypes

• Patients have possible epi-links
• are there 3 people in the cluster?
• are there high-risk people in the cluster?
• If yes, request RFLP for confirmation
• if RFLP does not confirm match, no further
  investigation needed
• if RFLP confirms match, consider doing a cluster
  investigation

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High-risk Patients

• live in congregate settings
• are infected with HIV or have other
  immunocompromising conditions
• are children
• have cavitation on chest radiographs
• have MDR TB
• are homeless

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Cluster Investigations

• Should only be done when needed
• can be labor intensive
• detailed cluster investigation protocols and data
  collection forms are available from CDC
• review information previously collected to
  determine if additional information is needed
• may need to interview patients again

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Prioritizing Cluster Investigations

1. suspected false positive culture
2. cluster of 3 high-risk persons w/ possible
   epi-links
3. cluster of 2 high-risk persons w/ possible
   epi-links
4. cluster of 3 low-risk persons w/ possible
   epi-links
5. cluster of 2 low-risk persons w/ possible
   epi-links
6. cluster of high-risk persons with no epi-links
7. cluster of low-risk persons with no epi-links

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Matching Genotypes

• Patients have no epi-links identified, but are
  involved in same chain of recent transmission
• Interpretation Failure to identify known
  epi-links due to -
• inadequate contact investigation
• transmission from casual contact

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Matching Genotypes

• Patients not epi-linked and not involved in same
  chain of recent transmission
• Interpretation Matching genotypes with no recent
  transmission due to -
• transmission of endemic strain
• large outbreak in the past
• false positive culture(s)
• laboratory error

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Non-matching Genotypes

• Patients epi-linked and involved in same chain of
  recent transmission
• Interpretation non-matching genotypes with no
  recent transmission due to -
• genotypes that changed slightly over time
• co-infection with gt1 strain of M. tb
• laboratory error

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Non-matching Genotypes

• Patients epi-linked and not involved in same
  chain of recent transmission
• Interpretation
• misleading epi-links identified

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Non-matching Genotypes

• Patients not epi-linked
• Interpretation
• no evidence of recent transmission

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Large Clusters

• As clusters grow in size, it becomes easier to
• identify epi-links
• identify an endemic strain

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Deciding What To Do

• Making the correct decision depends upon having
  complete and accurate data from a variety of
  sources
• patient interviews
• contact investigations
• laboratory results
• medical records

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Questions????
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Definitions Selective Genotyping The process of
submitting only selected high priority M
tuberculosis isolates for genotyping Universal
Genotyping The process of submitting all M
tuberculosis isolates for genotyping
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Definitions Genotype The designation that
results from one or more of the three genotyping
techniques used for M tuberculosis
Spoligotyping, MIRU analysis, and IS6110-based
RFLP Genotyping Also referred to as DNA
fingerprinting. A laboratory approach that
provides a description of the genetic makeup and
relatedness of M. tuberculosis isolates Cluster
A genotyping cluster is two or more M
tuberculosis isolates that share matching
genotypes An epidemiologic cluster is two or
more persons with TB who share epidemiologic links
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ODH Genotyping Contacts

• Frank Romano, MPH
• Public Health Advisor
• [phone]
• Frank.Romano_at_odh.ohio.gov

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Laboratory Contact Person

• Kevin Sohner, B.S.
• Ohio Dept. of Health Laboratories
• Special Microbiology Section
• 8995 E. Main St., Bldg. 22
• Reynoldsburg, OH 43068
• phone [phone]
• fax [phone]
• e-mail ksohner_at_odh.ohio.gov

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CDC WebBoard and Contact Information

• NTCA/CDC TB Genotyping Working Group
• Tom Navin, MD at TNavin_at_cdc.gov
• Guide, application instructions and updates
• for CDC TB Genotyping Program
• http//web-tb.forum.cdc.gov
• Guide (printed copy)
• Alan Schley at ASchley_at_cdc.gov