Application of molecular epidemiologic methods to infectious disease surveillance

Infectious disease epidemiological problems addressed by molecular biology techniques 2016  Tracking strains across time and geography  Distinguishing endemic from epidemic disease occ

National Institute of Infectious Disease

Infectious disease epidemiological problems addressed by

molecular biology techniques (2016)

 Tracking strains across time and geography

 Distinguishing endemic from epidemic disease occurrence

 Stratification of data to refine study designs

 Distinguishing pathovars vs commensal flora or saprophytes

 Identifying new modes of transmission

 Studying microorganisms associated with healthcare or institutional infections

 Characterizing population distribution and determinants of distribution of parasitic organisms

 Identifying genetic basis for disease transmission

 Validating microdiversity genotyping methods applied to epidemiology

 Virus quasispecies population structure analysis

 Identifying direction and chain of transmission

 Identifying hidden social networks and transmission links

 Analyzing microbiomes to study non-infectious disease epidemiology

 A continuous and systematic process of collection,

analysis interpretation and dissemination of descriptive information for monitoring health problems.

 This information ideally is linked to specific actions in the decision-making process

General functions of surveillance:

 Measures disease burden

 Facilitates initiation of outbreak investigations

 Generates hypotheses concerning risk factors and provides a source of cases to test these hypotheses

 Guides prevention, control or treatment strategies

 Evaluates effects of interventions and confirms findings from outbreak investigations that lead to control measures

 Provides public health officials with information (and the ability to anticipate future health service demands) required to make policy decisions and allocate resources appropriately

Types of surveillance systems

• Passive, provider-based

• Passive, laboratory-based

• Active, provider or laboratory-based

• Sentinel: provider, hospital, or laboratory

Choice of surveillance system

• Depends on the question that needs to be addressed by the surveillance system:

 Completeness (sensitivity or % cases identified), specificity

Infectious disease surveillance timeline (Lipkin WI Nat Rev Micro 2013)

Function of surveillance in molecular epidemiology

 Helps to validate new strain typing tests

 Provides reference for pattern analysis

 Identifies outbreaks not previously recognized

 Provides opportunity to perform type of analysis not possible to do by

conventional methods

 Monitors clonal group distribution over time and place

 Identifies new modes and reservoir of transmission

 Identifies clones that may have distinct biologic properties responsible for their predominance in a community

 Identifies new pathogens or variants of recognized pathogens—provides

evidence for a causal relationship

Validation of new typing methods—premises that need to

be considered

What is the specific public health question to be answered?

 Geographical target population for surveillance?

 Global

 National

 State or Local

 Duration of the surveillance system?

 Outbreaks/epidemics in a discrete time period

 e.g., influenza, SARS,

 Long-term (hospital, national, global)

 MRSA, Salmonella, Shigella, E coli O157;H7, HIV, etc.

Choice of strain typing tests for surveillance depends on its purpose

 Targets that evolve slowly

 Metabolic enzymes (housekeeping gene products)

 Ribosomal RNA sequences

 Targets that evolve rapidly

 Outer membrane protein genes

 Other genes whose products undergo selection pressure

 Elements that undergo rearrangement

 Intergenic sequences

Selection and use of molecular typing method for surveillance

Does a validated typing method exist?

 MLST for Neisseria meningitidis

PFGE for Streptococcus pneumoniae

IS6110 typing for tuberculosis

 A validated method may not exist or feasibly implemented.

 New methods require epidemiological validation.

Surveillance with genotyping capacity provides a reference for pattern analysis

 PFGE analysis: Tenover’s criteria can be satisfied if a reference pattern exists

 Sequence-based methods: Constructing trees based on nucleic sequences and identifying a sequence to root the other sequences

Providing reference for pattern analysis

 PFGE analysis: Tenover’s criteria can be satisfied if

a reference PFGE pattern exists

 Sequence-based tests: Constructing trees based

on nucleic sequences—which sequence to root the other sequences

Identifying outbreaks not previously recognized.

 Examples:

 Salmonellosis in Pennsylvania

 Identification of a new clonal group E coli ST69 during a local

UTI surveillance study

 Drug-resistant pneumococcal meningitis in Salvador, Brazil

 Salmonellosis and E coli O157:H7 infections in Minnesota

1995

Surveillance for E coli 0157:H7 infections, Minnesota:

Surveillance for E coli 0157:H7 infections, Minnesota:

Are strains identified during surveillance related according to their typing patterns?

Surveillance for E coli 0157:H7 infections, Minnesota:

Genotyping pathogens for surveillance provides opportunity to perform type of analysis/research not possible to do by conventional methods

 Redefine cases according to strain type to conduct a case-control study

 Make stochastic inferences based on sample size smaller than what would be required for a conventional epidemiologic study.

 Identify new biologic tests (e.g., diagnostic) that may not have

been considered otherwise.

Monitoring clonal group distribution over time and place

 Uropathogenic E coli ST69 over 6 years at UC Berkeley

 Global spread of ST131 E coli

 International spread of drug-resistant pneumococcus,

Salmonella, M tuberculosis, HIV

 Spread of CA-MRSA

 Introduction of enterovirus 71 in China in 2008

 Serotype replacement after vaccine introduction (19A Pneumococcus)

Changes in incidence of invasive pneumococcal disease, USA, since introduction of PCV7 in 2000

Hospital-based surveillance before and after the introduction of Hib

conjugate vaccines, Salvador, Brazil, 1996-2000 (Ko et al, Clin Infect Dis 2000)

 In the one-year period following Hib immunization, 29

cases of H influenzae meningitis were identified vs 308

cases in the previous 3½ year period.

 However, 5 (16%) of the 29 cases were due to H

influenzae type a, whereas only 2 (0.7%) of the 308 cases

during the pre-vaccine period were due to this serotype

Tipo a Tipo b

1996 1997 1998 1999 2000

Date of hospitalization

Campanha de Vacina

C USA

Pre Post

SP

PFGE Typing of H influenzae Type a isolates

from Salvador and other cities in Brazil

Identifying new modes and reservoir of

transmission examples

 UTI as a possible foodborne disease

 Produce as new vehicles of transmission of Salmonella

and E coli O157:H7

 Bats as a reservoir of SARS-coronavirus

 Camel as a reservoir of MERS-coronavirus

Surveillance: providing evidence for causality

 Outbreaks or epidemics of a disease recognized by a conventional surveillance system can be used to show causal relationship of a detected organism with the disease

 Clusters of a disease unrecognized as an outbreak can be unmasked by

genotyping methods to provide new information that can be used to find a causal relationship

 Sporadic illnesses (e.g., bloody diarrhea) may be unmasked as parts of an

epidemic by molecular biology tools Once shown as an outbreak, the same methods can be used to show a causal relationship

 Lipkin WI The changing face of pathogen

discovery and surveillance Nat Rev Microbiol 2013;11:133-141.