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Influenza Sentinel Site Surveillance Training Addis Ababa, Ethiopia: February, 2010. Council of State and Territorial Epidemiologists. United States Centers for Disease Control and Prevention. Part 1: Background and Objectives. Outline. Background Purpose of the Training Guiding Principles - PowerPoint PPT Presentation
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Influenza Sentinel Site Surveillance TrainingAddis Ababa, Ethiopia: February, 2010
Council of State and Territorial Epidemiologists
United States Centers for Disease Control and Prevention
Part 1: Background and Objectives
Outline
BackgroundPurpose of the TrainingGuiding PrinciplesObjectives of sentinel surveillanceTopics covered in the guidance
Global Burden of Respiratory Infections
Influenza: 3 – 5 million cases of severe illness 250,000 – 500,000 deaths
Lower Respiratory Infections: Leading cause of death in low-income countries 3rd leading cause worldwide
Need for Improved Surveillance
Historically, influenza surveillance data collection: Virologic data for vaccine selection Limited epidemiologic data Lacked international standards
Remaining gaps in understanding: Epidemiology, burden of disease Social factors, clinical risk factors Climatic factors
Global Surveillance for Influenza
WHO Global Influenza Surveillance Network (GISN) International, laboratory-based (NICs) surveillance
network Provides virus strain information to select seasonal
vaccine• National Influenza Centres (NICs)
Laboratories designated by national Ministries of Health and recognized by WHO to participate in GISN
131 NICs, in 102 countries (as of Feb. 4, 2010)
Pandemic H1N1 (2009)
Timely virologic and epidemiologic monitoring at national level:o Track progression of pandemico Track impact of pandemico Convey an accurate perspective on severity and risk to
populationo Prioritize country-specific risk groups for intervention
resources
Seasonal Influenza Preparedness
Pandemic Monitoring
Relatedness of Seasonal and Influenza Pandemic Preparedness
Surveillance Needs During a Pandemic
Is the situation changing?o Total amount of ILI, proportion of outpatient ILI due to influenzao Laboratory data to look at proportion of subtypes circulating in the
communityo Systematic sampling of viruses by age
How severe is the disease and is it changing?o SARI hospitalizationso Deaths (and ICU admissions) from sentinel hospitalso Clinical picture of hospitalized cases
Is the virus changing?o Drug resistance, drift and shift from laboratorieso Comparison of viruses from less and more severe cases
Why is Monitoring the Severity/Virulence of a Pandemic Important?
Inform how aggressively we think about interventions, for example: School closures Stopping public gatherings Vaccination priorities Antivirals priorities
Mitigation, gain time to procure vaccine
Role of Sentinel Surveillance in Broader Monitoring Systems
Reporting of qualitative indicators
Aggregate reporting of laboratory-confirmed cases
Aggregate reporting of syndromes ILI/SARI/Mortality
Embedded sentinel sites to efficiently monitor oVirus characteristicsoSeverity and change in severityoRisk factors for severe illnessoHospital impact
Routine Value of Sentinel Surveillance
Routinely produce useful epidemiologic and virologic datao Identify priority groups for intervention (severe outcomes)oAccurately characterize circulating virusesoMonitor seasonality to prepare for influenza seasonoCompare provinces, countries and regionsoEstimate burden of disease
Establish standards for surveillance reporting, collection and analysis
Provide a platform for the study of influenza and other respiratory pathogens
Guiding Principles: Short and Long Term Value
Integration into national systemsStandard case definitions for comparisons (ILI,
SARI)Efficiently monitor pandemic severity, high risk
groups, and impact Ongoing surveillance of influenza and other
pathogensHigh quality data in limited amounts
Seasonal Surveillance Pandemic Monitoring
Virologic Objectives
• Monitoring changes in virus• Monitor antiviral susceptibility• Monitor known markers of virulence• Strain surveillance, by age, for the
development of new vaccines• Strain surveillance, by severity, to
assess virologic risk factors for severe disease
• Detect novel viruses
• Monitoring changes in virus• Monitor antiviral susceptibility• Monitor known markers of
virulence• Strain surveillance, by age, for the
development of new vaccines• Strain surveillance, by severity, to
assess virologic risk factors for severe disease
• Detect novel viruses
Epidemiologic Objectives
• Identify priority groups for intervention--risk factors for severe outcomes.
• Monitor the intensity of influenza season in relation to baselines
• Estimate burden of disease• Monitor the timing/ seasonality of
influenza to inform seasonal planning
• Provide a platform for surveillance that includes additional pathogens
• Identify priority groups for intervention--risk factors for severe outcomes.
• Monitor the intensity of influenza season in relation to baselines
• Estimate burden of disease • Inform timely public risk
communication messages• Monitor treatment practices• Support rapid investigations• Be useful in the long term
Topics Covered in Training
Toolkit to establish a few high quality sentinel IP/OP sites
Criteria for selecting sentinel SARI and ILI sitesMethods to avoid bias in the selection of cases for
testingEpidemiologic data collection formsProcedures for laboratory specimensReport templates for weekly and annual data
summariesTechniques for routine monitoring of the surveillance
systemPandemic support functions
Part 2: Case Definitions
Goal of Pathogen-based Surveillance: Global Burden of Influenza
DeathsDeaths
HospitalizedSARI CasesHospitalizedSARI Cases
Mild Disease, Not Medically-Attended Mild Disease, Not Medically-Attended
Medically-Attended Outpatient Cases
Medically-Attended Outpatient Cases
ILI Surveillance
SARI Surveillance
Pathogen-based surveillance
Household Surveys/ Serum
Surveys
SARI Surveillance
Should be priority/minimum basic influenza surveillance for countries with limited resources
Recommend adding this measure in countries with existing outpatient surveillance
SARI Case Definition > 5 Years Old
Any person requiring hospitalization* and presenting with manifestations of acute lower respiratory infection with: sudden onset of fever (> 38 ºC) and cough or sore throat and shortness of breath, or difficulty breathing with or without
clinical or radiographic findings of pneumonia, or any person who died of an unexplained respiratory illness.
* hospitalization may not be a required in some sites (i.e. remote from hospitals). Time requirement for onset of illness may vary.
SARI Case Definition < 5 Years Old
IMCI case definition for pneumonia:Any child aged 2 months to 5 years with cough or
difficulty breathing and: Breathing faster than 40 breaths / minute (ages 1 – 5 years) Breathing faster than 50 breaths / minute (ages 2 – 12
months)
*Note that infants less than 2 months of age with fast breathing of 60 breaths or more per minute should be referred for serious bacterial infection.
SARI Case Definition < 5 Years Old
IMCI case definition for severe pneumonia:
Any child aged 2 months to 5 years with cough or difficulty breathing and any of the following: Unable to drink or breastfeed, or Vomits everything, or Convulsions, or Lethargic or unconscious, or Chest indrawing or stridor in a calm child
ILI Case Definition
A person with:osudden onset of fever >38°C, and ocough or sore throat in the absence of other
diagnosis
ILI SARI
Strengths • Less resource intensive as a case definition than SARI.
•Captures hospitalized component of influenza.
•Will capture cases with exacerbations of chronic conditions, not just those with pneumonia.
Weaknesses •Fever requirement may overlook persons without fever, such as elderly and immune-compromised.
• Not ideal if being used to monitor viral respiratory pathogens other than influenza.
•Will overlook those that do not present with fever.
•Will overlook those that do not seek care at a hospital.
•Fever requirement makes it more specific, less sensitive
Considerations When Using the SARI Case Definition
Fever requirement: may exclude elderly and immunocompromised
Option: do not include fever, or require a measured fever May detect non-influenza viral pathogens Will increase resource demands Should record presence or absence of measured fever on the
swab form for comparison to other countries Ensure consistent application of case definitions across all
sites
Experiences with SARI Surveillance
Early data from Member States in 5 WHO regions suggests routine surveillance for SARI will….
…achieve virologic objectives of seasonal influenza surveillance (pct. positive similar to ILI during influenza season)
…provide epidemiologic and virologic data on severe influenza infections
…provide a basis for monitoring severe respiratory disease during a pandemic
…serve as a platform for assessing burden of multiple viral respiratory pathogens
Prioritizing the Focus of the Surveillance System
Simple ModelBudget: Low, no existing surveillanceSurveillance for: SARI as a minimum standard
Epidemiologic data collection (i.e., denominator data = total number of SARI or ILI seen)
Virologic testing Small number of well-run sentinel sites preferred to large
number of poorly-run sites.
Prioritizing the Focus of the Surveillance System
Intermediate ModelBudget: MediumSurveillance for: SARI and outpatient ILI
Virologic testing Epidemiologic data collection (i.e. denominator data)
Prioritizing the Focus of the Surveillance System
Advanced ModelBudget: HighSurveillance for: SARI and ILI surveillance
Virologic testing Epidemiologic data collection (i.e. denominator data) Multiple pathogens, possibly reduce fever requirement in
inpatient setting as well
Part 3: Mechanics of Sentinel Surveillance
Outline
Sentinel site selectionCase sampling strategiesEpidemiologic data collection and forms
Selection of Sentinel Sites
What is sentinel surveillance?
One or more designated health care facilities that routinely collect epidemiologic information and laboratory specimens from patients presenting an illness consistent with a specified case definition
The system provides an efficient way to obtain high-quality data on relatively common conditions from a manageable number of locations
Why Sentinel Surveillance?
For monitoring/ identification of: Identify target groups:
For antiviral use and timing That might have greatest impact on transmission
Strains to include in vaccine Appropriate management practices Hospital staffing and procurement needs
Key Attributes of Sentinel Sites
Efficient data collectionHigh quality data Limited number of well-chosen sites
“A few high quality data are better than a lot of bad data”
The Efficiency of Sentinel Sites
Systematic testing of inpatient and outpatient (SARI and ILI) cases
Representation of viruses by age and severity Efficient collection of demographic and epidemiologic data
that is linked to virologic data Can yield measures of disease burden Valuable seasonally as well as in a pandemic Can support efforts to monitor surge on hospitals
ILI Sentinel Surveillance
SARI Sentinel Surveillance
Strengths • Not a “new” system that must be created in a pandemic.
• Can be used to monitor progression of pandemic when other testing shifts to focus on only severe cases.
• Can be compared to meaningful baselines in many places to provide a measure of the relative magnitude of ILI consultations as compared to previous seasons.
• Efficient way to monitor severity and clinical characteristics of severe cases, and their change over time
• Monitor the progression and impact of a pandemic by focusing on an important outcome with a standard case definition.
• Will inform understanding of viruses that cause severe disease
• Timely feedback of results to clinicians can inform treatment practices.
• Sentinel hospitals can be used to estimate burden of severe disease.
• Sentinel hospitals can be used to monitor the impact of a pandemic on health care resources.
Weaknesses • Does not capture severe illness, which is needed to inform priority groups for intervention
• Not an easy or highest priority entity to collect epidemiologic data on
• No viruses from severe cases• Not ideal for monitoring if a
pandemic is becoming worse.
• Baselines are less well established at this point in time.
• It is a change from traditional practices to initiate systematic testing in hospitalized setting
• Sentinel sites are limited in their ability to characterize geographic spread.
Ideal Characteristics of Sentinel Sites
Feasibility People that are motivated to run the system Political willingness for a site to participate Sufficient staffing and laboratory capacity to maintain sampling
and testing during healthcare surge Efficient data management and transmission capability
Ideal Characteristics of Sentinel Sites
Patient representativeness All ages Wide range of medical conditions
For SARI surveillance, general or community hospitals are preferable to specialty care hospitals
For ILI surveillance, general outpatient clinics are often appropriate
Ideal Characteristics of Sentinel Sites
Quantifiable population denominatoro Facilitates estimates of burden of diseaseo Requires understanding of population served by the
sentinel site
Large referral hospitals may underestimate community incidence and require extra staff Difficult to test a large proportion of all SARI cases
identified If calculating rates, may be difficult to assess the total
population served by the surveillance site
Placement of Sentinel Sites
Population representativeness Ethnicity Socioeconomics
Climatic representativeness Climate affects virus activity (transmission and viability in
environment)
Example: Influenza Sentinel Site Selection in Cote d’Ivoire
Selection originally based on locations with confirmed AI and high poultry density/activity
Other considerations: Health centers/hospitals that
provide care to both adults and children
Availability of staff Availability of a cold chain Status of the health
center/hospital; public, private, religious
Availability of financial and material resources for setting-up & monitoring
Example: SARI sentinel sites in South Africa, 2009
Chris Hani Baragwanath
Agincort
Edendale
Example: SARI Sentinel Surveillance in South Africa, 2009
Example: Sentinel Site Selection in Ukraine
Integration into National Clinical Reporting Systems
Ideally, sentinel sites could be integrated: Adopt standard case definitions Establish smaller number of sentinel sites within
the broader universal reporting system Assure high-quality data at these sites through more
intensive training and oversight Systematic laboratory testing only at sentinels Broader clinical reporting provides valuable indicator
of geographic spread within a country
Integration into National Clinical Reporting Systems
ILI/SARICase-based epi data collection, laboratory testing
ILI/SARI Syndrome Reporting
ILI/SARI Syndrome Reporting
ILI/SARI Syndrome Reporting
ILI/SARI Syndrome Reporting
ILI/SARI Syndrome Reporting
ILI/SARI Syndrome Reporting
ILI/SARICase-based epi data collection, laboratory testing
ILI/SARICase-based epi data collection, laboratory testing
Selection of SARI Cases
It is preferable to collect data and specimens from all or most SARI cases from a few facilities rather
than a small sample of SARI cases from multiple facilities
Logistically feasible Less bias If not possible, an unbiased sampling protocol should be
established
Selection of ILI Cases
Large number of cases at outpatient sentinel sites is likely
Total number of ILI cases seen is very important to collect
Collect specimens and case-based epidemiologic data from only a sample of ILI cases
Select cases for laboratory testing in as unbiased a manner as logistically possible
Sampling Methods for Respiratory Specimen and Case-based Epidemiologic Data Collection
Select all cases for testing
Select every xth case for testing
Select all cases on certain days of the week for testing
Select the first x cases on a certain day of the week
Selecting All Cases For Testing
Minimizes bias
Requires the most resources
May not be feasible in many settings
More feasible for sentinel surveillance focused on hospitalized cases (SARI)
Selecting Every Xth Case For Testing
Less likely to be biased than methods that only select cases on the same day or at the same time
Fewer resources than sampling all cases
Frequently used for hospital-based (SARI) surveillance
Selecting All Cases On Certain Days Of The Week For Testing
Does introduces biaso Patient volume and mix is not the same every day of the weeko Day(s) of the week should be alternated
Reduces logistical challenges of transport to laboratory
Selecting the First X Cases On a Certain Day of the Week
Can introduce bias by day-of-week or time-of-day
Commonly used for ILI surveillance where General Practitioners (GP’s) require convenience sampling models
Consider local health seeking behaviors
Not desirable for burden estimation of for SARI surveillance
SARI ILI
Feasibility Desirability Feasibility Desirability
Selecting all cases 2 3 1 3
Selecting every xth case 3 3 2 3
Selecting all cases on certain days of the week
3 1-2 2 2
Selecting the first x cases on certain days of the week
3 1 3 2
1 = least feasible/desirable; 3 = most feasible/desirable
Epidemiologic Data Collection
Data Collection Tools
Forms filled out by designated sentinel site staff
At a minimum, collect data 4 weeks before and after typical peak months
Assign each patient a unique identification number to link epidemiologic and laboratory data Recorded on data collection form,
swab forms, and laboratory specimen
Minimal Data Elements
Unique identification numberPatient demographicsMinimal clinical information including relevant dates
of onset and clinical symptomsPre-existing medical conditions (for SARI only)Vaccine and antiviral use
Case-Based Data Collection Forms: SARI Swab Form
For all SARI cases tested for influenzao Should be completed as soon as possible after identification
Send one copy to laboratory with the specimen, one to the national surveillance centre, keep original at the sentinel site
Case-Based Data Collection Forms: Outpatient Swab Form
For all ILI cases tested for influenza
Complete as soon as possible after selection for laboratory testing
Send one copy to laboratory with the specimen, one to the national surveillance centre, keep original at the sentinel site
SARI Weekly Aggregate Data Form
ID number of sentinel site, and focal pointNew SARI cases during weekNew inpatients during weekNumber of SARI cases selected for influenza
testingNumber of SARI deaths during the week
Ages: 0-4, 5-14, 15-29, 30-64, 65+, Total
SARI Weekly Aggregate Data Form
ILI Weekly Aggregate Data Form
ID number of sentinel site, and focal pointDay(s) of week surveillance was undertakenNew ILI cases during weekNew outpatients during weekNumber of ILI cases selected for influenza
testing
Ages: 0-4, 5-14, 15-29, 30-64, 65+, Total
Unique Identification Numbers
Important for linkage between laboratory and epidemiologic information
Numbers should be standardized throughout the country
Assigned when SARI or Outpatient Swab forms are filled out
Same number used on any forms or specimens for each patient
Identification Number Example
001 / 09 / 1 / 0001Sentinel
SiteYear SARI or
ILICase
Number
Example: 1 = SARI 2 = ILI
Part 4: Roles and Responsibilities Within the Sentinel Surveillance
System
Sentinel Surveillance Structure
Countries implementing a sentinel surveillance system should have:
•Sentinel sites with a designated focal point
•National surveillance centre that coordinates the epidemiologic data collection and analyses
•National Influenza Centre / laboratory that oversees virologic aspects of the surveillance system and laboratory quality
WHO / Regional Offices
Regional Surveillance Platform
CountriesData
Summary Reports
WHO Global Platforms (FluNet and FLU-ID)
Sentinel Site Focal Point
Adhere to case definitionsAdhere to unbiased
systematic sampling strategies
Collect respiratory specimens
Package, store, and transport specimens
Assign unique ID number to specimens and forms
All data forms are filled out completely and accurately
Manage and transmit epidemiologic data
Track daily number of SARI and ILI cases, and number selected for laboratory testing
Assure timeliness of data reporting and specimen collection and transport
Report SARI laboratory test results to the clinician
Ensures that staff at the site carry out the following:
National Surveillance Centre
Organizational entity assigned to coordinate influenza surveillance in a country
Should have a national surveillance focal point who is responsible for implementation and coordination of the national influenza sentinel site surveillance system
May be located in different agencies or institutes in different countries
National Surveillance Centre Focal Point
Assist MOH with selection of sentinel sitesAssist with decisions about ILI and SARI sampling
and epidemiologic data collectionAssure that sites have data collection forms and
reporting mechanismsAssure that the data is analyzed correctlyDisseminate the weekly and annual flu reportReport data into the regional and global platformsRoutinely monitor the sentinel surveillance system
Responsibilities:
National Influenza Centre (NIC)
Recognized by WHO
Participates in regional influenza network and GISN
An up-to-date list of NICS can be found at: http://www.who.int/csr/disease/influenza/centres/en/index.html
NIC Routine Responsibilities
Provide technical support and guidance to sentinel sitesReceive, register, and store specimens from SARI and ILI
casesPerform analyses on seasonal virusesPerform subtyping of non-seasonal viruses, minimally
Influenza A(H5N1) Pandemic influenza A(H1N1) 2009
Archive and store original specimens at least one yearShare samples with WHO CCsConduct antiviral susceptibility testing (where possible)Maintain linkage between site and laboratory ID numbers
NIC Responsibilities: Data Analysis and Reporting
Communicate results of confirmatory testsConsolidate and analyze national laboratory dataReport weekly national surveillance data into
regional and global surveillance platformsDevelop national diagnostic standards and assays,
provide training, and organize quality assurance programs (where possible)
SentinelSites
INHP ( Epi Surv, MoH)
DGS (Gen. Dir, MoH)
IPCI (NIC)
Partners: WHO, CDC, UNICEF…
SentinelSite
SentinelSite
Example: Surveillance System Organization in Cote D’Ivoire
CABINET (Minister)
UkraineUkraine GeorgiaGeorgia
Sentinel site focal point submits data forms
Regional surveillance coordinator enters data and verifies accuracy and completeness
Regional laboratories test specimens
NIC provides confirmatory testing and ensures functioning of the system
Smaller population and geographic area
Sentinel sites send samples and data forms to NIC within national public health agency
National Center for Disease Control and Public Health monitors operation of the system
Examples of Surveillance System Organization
Notification of Novel Influenza Viruses through the IHR Mechanism
Immediate notification to WHO through the IHR mechanism: Human infection with influenza A other than seasonal subtypes
Any combination of H2, or H4-H16 with any of the N1-N9 subtypes
Includes avian influenza subtypes A(H5N1), A(H9N2), and A(H7N7)
Human infections of Influenza A viruses that grow poorly in cell culture or react poorly with standard WHO reagents in HAI assays
May have same subtype as seasonal viruses, but be of animal origin (such as pandemic (H1N1) 2009)
Participating in WHO External Quality Assessment Project for the Detection of Influenza A Viruses by PCR
To improve global laboratory capacity for influenza diagnosis
To monitor quality and standards of performance of NICs around the world
Requirements: Laboratories test a panel of simulated H1, H3, H5 specimens
twice per year Each laboratory receives performance report
Part 5: Data Reports and Analysis
Outline
Measures of BurdenWeekly ReportsAnnual ReportsReporting Outside the Country/Publications
Measures of Burden
Incidence rate o Number of influenza cases per 100,000 population per time unito Allows for estimate of age-specific burden of disease o International standard for reportingo Incidence of influenza consultations also valuable to monitor
seasonal intensity over time
Proportion of SARI and ILI at sentinel sites that is caused by laboratory-confirmed influenzao Minimal standard
Example: The Netherlands
General practitioners Collect specimens and data from a random sample of persons
meeting ILI case definition Each maintains list of 2,500 patients, which can be used for
denominator data
Incidence rate Calculated per 100,000 per week
Minimal Analyses and Reports
Generate weekly, at least 4 weeks prior and following typical peak months
Disseminate to all relevant governmental partners, sentinel sites, and the public
Virologic surveillance conducted outside flu season may be reported less frequently
Weekly SARI Data
During the previous week:Number of new cases at each sentinel siteNumber of total new hospital admissions at each
sentinel siteNumber of SARI cases selected for influenza
testing % testing positive By influenza type and subtype
Number of inpatient deaths due to SARINumber of sentinel SARI sites reporting
Results for all sites stratified by the age groups: 0-4, 5-14, 15-29, 30-64, 65+
Example: SARI Surveillance Weekly Report (South Africa)
Report comes out weeklyPosted on website:
http://www.nicd.ac.za/Includes graph and table
portraying virological data By epidemiological week By sentinel site
Weekly Outpatient Data
During the previous week:Number of new ILI cases reported Number of total outpatients seen at ILI sentinel siteNumber of ILI cases selected for influenza testing
Percent of tested ILI positive for influenza By influenza type and subtype
Additional Data to Report
If available, report: Weekly consultation rates for ILI, or
SARI Antiviral resistance testing results
http://www.cdc.gov/flu/weekly/
• Data on geographical spread (map)
• Level of detail will depend on number and location of sentinel sites
Annual Analyses and Reports
Annual Analyses
SARI, ILI, and confirmed influenza cases by age and month
Underlying medical conditions of SARI patientsNumber and percent of positive influenza
cases who received vaccination in the current season.
Number and percent of positive influenza cases exposed to antivirals 14 days before onset of symptoms
Incidence rates
All AnalysesAll Analyses Optional StratificationsOptional Stratifications
0-4 years5-14 years15-64 years>65 years
0-12 months15-2930-64>75 yearsAdditional age
categories that inform vaccination policy
Standard Age Stratification
Assessment of Seasonality
Establish the baseline rate of influenza in a region/ country
Inform the timing of vaccination and treatment
Example: Using Data in the UK
Yearly guidance issued to doctors about when antiviral agents should be prescribed
Recommendations are based off of surveillance data and are triggered when:o GP consultation rates rise above 30 consultations per 100,000
populationo Community-based influenza surveillance is above baseline
Reporting and Publication
Regional and Global Reporting for Seasonal Influenza
Flu Season (4 weeks before and after typical peak influenza months): epidemiologic and virologic data should be reported regionally
Non-flu season: only virologic data
Can be used for a regularly published bulletin
Example: EuroFlu Weekly Electronic Bulletin
Detailed epidemiologic and virologic data for each country and Europe as a whole. Presented with: Maps Tables Graphs Pie charts
National level reporting mechanism is important
Example: EuroFlu as a Basis for Synthesizing Regional Information
Reports for Posting/Publication
Public posting of routine analysis and data should be national surveillance system goal.
Peer-reviewed publication is also important. May include: Routine analyses Special studies
Informs international influenza control effortsCreates advocates for influenza interventions
Part 6: System Monitoring
Outline
Suggested Quality IndicatorsTimelinessCompletenessValidity
Timeliness Indicators
Expected dates of data reporting from sentinel site to next administrative level compared to actual dates
Some examples are time elapsed from: Specimen collection to arrival at the laboratory Laboratory receipt of specimens to laboratory
processing and testing Laboratory confirmation results to inclusion of results in
Weekly Influenza Reports Laboratory confirmation results for individual SARI
cases to notification of the sentinel site focal point Laboratory results for individual SARI cases by the
sentinel site focal point to notification of the patient’s doctor
Quantification of Timeliness Indicators
Percent of time site achieves targets for specific time intervals
e.g. 90% of specimens received at the laboratory within 48 hours of specimen collection
Percent of samples tested within a target time framee.g. 90% of tested specimens have results within 1 week
Percent of sites achieving time targets or time lag averagese.g. 90% of sentinel sites package and transport 90% of specimens within 48 hours of collection
Percent of time that doctors receive laboratory results for SARI cases within 48 hours of confirmatory test completion
Completeness
Percentage of swab forms received from each site with complete data
Percentage of total expected swab forms that are received
Percentage of total expected cases that have specimens submitted to the laboratory
Validity: Data Audits
Ensures Validity by determining the following:oCase definitions are understood and adhered tooCases are counted appropriately (no duplicates)oReported cases meet the case definitionoUniform sampling procedures are being followedo Laboratory equipment and staff are sufficientoData values are being recorded correctly (can be
compared to gold-standard of chart-review)o Sentinel sites and doctors are receiving timely feedback
and SARI test results
Validity: Compare to Expected Results
Number of cases reported each month at siteNumber of specimens submitted each month at each
sitePercent of specimens positive for influenza each
month at each siteNumber and percent of SARI and ILI cases tested
Does something look out of the ordinary?
Comprehensive System Evaluations
Conduct in addition to routine monitoringWhen to conduct
At start-up At regular intervals If aberrations in expected results are observed
Part 7: Additional Uses of the System and
Surveillance Data
Outline
Estimating disease burden
Establishing baselines and thresholds
Pandemic detection, planning, and monitoring
Overview
Make decisions about health resource allocation
Identification of risk groups for targeted intervention
Monitoring of the impact of intervention programs, including vaccination
Estimating Disease Burden
Estimates of Disease Burden
Disease burden = amount and impact of influenza in the population represented by a sentinel site(s)Basic measures
o Incidence rates of hospitalized SARI caused by laboratory-confirmed influenza
o Estimates of excess mortalityo Direct costs of medical care and treatmento Indirect costs due to lost time from employment or costs
incurred by family members of a sick person
Importance of Disease Burden
Assist policy makers Decisions about allocation of
resources by putting influenza in perspective relative to other diseases
Judge cost-benefit ratio of interventions
Stimulate or target future surveillance activities
Estimating Catchment Area
Sources of population denominator data:Patient lists from sentinel physiciansWell circumscribed municipalities of medium
size where sentinel sites capture a large portion of admissions/outpatients
Health Utilization Survey can be used if: Well-defined community Site does not receive a large proportion of cases
from distant areas See guidance document for more details
Establishing Baselines and Thresholds
Baseline Incidence
Baseline = level of influenza activity typically seen outside the seasonal epidemic
Rise above baseline indicates start of seasonal epidemic
Serves as an objective threshold for public health action
Occasionally influenza activity does not exceed the baseline threshold
Pandemic Detection, Planning, and Monitoring
Sentinel Surveillance Supports Public Health Response
Establishes infrastructure for: Prioritizing investigation of severe respiratory illness cases Creating clinical specimen collection and transport network Building expertise in confirmatory testing for human and novel
influenza viruses Strengthening relationships between laboratory, epidemiologic,
and clinical personnel
Sentinel Systems and Early Warning
Sentinel systems are generally not adequate for detection of unusual events or outbreaks early in their
course
The Role of the Sentinel System in Monitoring a Pandemic
Monitoring the course of a pandemic will use existing routine influenza surveillance data describing: Location of the virus Trend in cases Severity of pandemic Changes in virulence
Part 8:Laboratory Specimen Processing
Outline
Specimen collectionSpecimen storage and packagingSpecimen testingShipment of specimens
Specimen Collection
Collecting Respiratory Specimens
For direct detection of antigens or nucleic acids, and for virus isolation (culture)o Take no more than 7 days after onset of symptomso Ideally take within 3 dayso Preferably before antiviral therapy
Record time from illness onset to specimen collection
Give patient verbal explanation of reason for specimen collection and how it will be collected
Specimen Tube Labeling
Patient unique identifier
Specimen date
Type of specimen in the tube
Hazard label
Upper Respiratory Specimens
Best for virus isolation and PCR Nasopharyngeal (NP) swab Nasopharyngeal aspirates or washes Nasal wash
Alternatively, collect both Nasal swab Throat swab Combine in single vial of VTM
Materials Required
Personal protective equipmentSwabsTongue depressorsPlastic vials, such as cryovials, containing 2-3
ml of virus transport medium (VTM) stored at 4°C (supplied by the NIC)
Serum collection: collection tubes, alcohol, gauze, non-heparin treated needles
Alcohol and/or bleachPackaging materials for transport in country
Specimen Storage and Packaging
Specimen Storage
Place in VTM immediatelyStore at 4°C, up to 24 hoursFor immunoflourescence:
Refrigerate and process within 1-2 hours
For virus isolation: Refrigerate and inoculate into cell cultures as soon as
possible
If not processed within 48-72 hours, freeze at or below -70°C
Specimen Storage
Specimens may be divided into aliquotsFreeze-thaw cycles should be minimizedDo not store in a household freezer (-20°C)
with a “defrost” cycle Keeping sample on ice up to a week is better than
allowing freeze-thaw cyclesBlood may be stored at room temperature
overnight or incubated at 56°C for 30 minutes Remove serum and store at 4°C up to a week or
put into long term storage at -20°C
Preparation of VTM
Add 10g veal infusion broth and 2g bovine albumin fraction V to 400 ml sterile distilled water
Add 0.8 ml gentamicin sulfate solution (50 mg/ml) and 3.2 ml amphotericin B (250 μg/ml)
Sterilize by filtration
Store unopened for up to one year
Packaging
3 layers of packagingCompliance with P650
requirements for infectious substances in UN 3373 category B
1st layer Watertight specimen tube
(no more than 500mL) Absorbent material
2nd layer Watertight container (zip-
loc or hard plastic)3rd layer
Rigid outer packaging
Packaging
May need to include ice packs or dry ice
Example: P650 packaging system in combination with Safetybag
Specimen Testing
Specimen Processing
BSL-2 laboratoryClass II microbiological safety cabinet for
procedures that may give rise to infectious aerosols
Seasonal influenza: disposable gloves and gownSuspect avian influenza / severe respiratory
pathogens: BSL-2 laboratory with BSL-3 practices, or BSL-3 laboratory
Non-molecular Influenza Detection and Subtyping
Viral isolation Eggs Cell culture Followed by HAI assay using WHO reagent kit
Immunofluorescence assay Initial screen to select specimens for viral
isolation Low sensitivity Requires living cells
ELISA Low sensitivity
1918 influenza virions.CDC/ Dr. Terrence Tumpey
Influenza Detection and Subtyping by RT-PCR
Higher sensitivityIncreased biosafety
Uses low amounts of virus Viral isolation can be performed on known subtypes
Cost effectiveRapid
Can provide results in 24 hours
RT-PCR is Recommended for Confirmatory Testing and to Select Specimens for Virus Isolation
Real-time RT-PCR preferred
Assays can be developed locally or obtained commercially Primers and probes must be validated at least once a year
Can be performed in BSL-2 laboratory o Reduces chances that isolation of a novel virus (a BSL-3
practice) will be attempted in BSL-2 conditions
Virus Isolation
Performed after confirmation of type and subtype
Cell or egg culture Cell line: Madin-Darby canine
kidney
Results in 2-10 daysFollowed by HAI, RT-PCR,
or IFAMing Wang, et al. Food Markets with Birds as a Source of Avian Influenza. Emerg Inf Dis Vol. 12, No. 11. Nov 2006
Principles for Viral Isolation
BSL-2 laboratories test for: Seasonal influenza A(H1N1) Seasonal influenza A(H3N2) Influenza B Other respiratory viruses (RSV, adenovirus)
BSL-3 laboratories test for: Influenza A, subtype not identified Influenza A, subtype identified as not being
Human seasonal A(H1N1) or Human seasonal A(H3N2)
Testing Algorithm for SARI and ILI
Test one of duplicate specimens by (real time) RT-PCR: type A/B
Isolate virus on cell culture or eggs
Perform lineage identification or influenza A subtyping
Ship an aliquot of to a WHO CC for further virus identification and strain characterisation
Subtyping for H1, H1v, and H3 by RT-
PCR
A+
BSL2: Ship aliquot of specimen to a WHO CC
BSL 3: isolate virus on cell culture of eggs from early specimens, and a sample of future specimens
Test for other respiratory viral pathogens
B +Influenza -
H1+ or H3+
H1v
Seasonal Influenza Serology
TestingUse reagents from WHO
CDC test kitConduct HAI assay on
paired sera (if available) Positive: 4-fold rise in
antibody titerCollect convalescent serum
14 days – 4 weeks after symptom onset
Other considerationsImportant for
retrospective analysis of outbreaks
Avian influenza A(H5N1) Serology
TestingVirus neutralization
assayBSL-3 laboratory with
BSL-3 standardsPositive: 4-fold or greater
rise in neutralization antibody titer
Paired serum samples
Other considerationsSingle serum samples can
be useful for detecting antibodies
Used for: Confirmation when
respiratory specimen testing and virus isolation are inconclusive
Retrospective analysis of outbreaks
WHO kits and protocols for real time RT-PCR detection of pandemic (H1N1) 2009
In response to the pandemic, WHO CC at CDC has developed and distributed kits for real-time RT-PCR detection of pandemic (H1N1) 2009.
Shipment of Specimens
Shipment of Specimens to WHO Collaborating Center
Logistical support: WHO Global Shipment Project Covers 2-3 shipments of seasonal viruses per season Covers novel viruses as necessary Uses World Courier Shipment initiated by completing booking form Requires export permit (standing permit recommended)
Shipment Regulations
International regulations for air shipment Technical Instructions for the Safe Transport of Dangerous
Goods by Air Dangerous Goods Regulations (DGR) may add further
restrictions
Shipping personnel IATA-certified training available to NIC staff Certificate valid for 12 months Encouraged, but not required for personnel shipping
seasonal influenza pathogens
Shipping Specimens on Ice
For fresh isolates Use ice packs Use insulated vials Delivery within 48 hours or refrigerate at 4°C
For frozen isolates Ship on dry ice
Include swab form and itemized list of contents between secondary and outer packaging
Specimens for WHO CC or WHO H5 Reference Laboratories
Forward to WHO CC for virus strain characterization and vaccine strain selection:
Representative seasonal viruses from SARI and ILI cases
A(H3N2) A(H1N1) Influenza B
At beginning, peak and near end of season
Dispatch immediately to WHO CC and/or WHO H5 Reference Laboratory: The first specimens found to be positive for H1N1vLow-reacting virusesSpecimens with influenza A viruses for which subtype was not identifiedSpecimens with avian influenza or other novel virusesInclude swab form and list of contents