# Presentation: 261769

## Influenza 2005:  The Laboratory’s Role in Pandemic Preparedness & Response

**Pete A. Shult, Ph.D**.
- Director,
-   Communicable Disease Division
-   & Emergency Laboratory Response
- shult@mail.slh.wisc.edu

**Carol Kirk**
- Laboratory Network Coordinator
- cjk@mail.slh.wisc.edu

- Wisconsin State Laboratory of Hygiene
- December 6, 2005

## Agenda

- Overview of Influenza Antigenic Characteristics
- Overview of Laboratory Diagnostic Methods
- Surveillance for New Strains of Influenza Viruses
- Current Pandemic Concerns
- Pandemic Preparedness Activities
- The Laboratory’s Role in Pandemic Preparedness & Response

## Influenza:  Resources

**CDC home page for influenza**
- _[http://www.cdc.gov/flu](http://www.cdc.gov/flu)_
- _[http://www.cdc.gov/flu/weekly/fluactivity.htm](http://www.cdc.gov/flu/weekly/fluactivity.htm)_
- U.S. web site for pandemic flu & U.S. Pandemic Flu Plan and Preparedness Planning
- 	_[http://pandemicflu.gov/](http://pandemicflu.gov/)_
- W.H.O. home page for influenza (including avian influenza)
- 	_[http://www.who.int/csr/disease/influenza/en/](http://www.who.int/csr/disease/influenza/en/)__	__	_

- Promed (Program for Monitoring Emerging Diseases, International Society for Infectious)
- 	_[http://www.promedmail.org](http://www.promedmail.org/)_
- U.S. Food & Drug Administration (FDA)
-  “Cautions in Using Rapid Flu Tests”
- 		_[http://www.fda.gov/cdrh/oivd/tips/rapidflu.html](http://www.fda.gov/cdrh/oivd/tips/rapidflu.html)_
- Review of Performance Characteristics of Rapid Tests:
- 	Uyeki TM.* Influenza diagnosis and treatment in children: a review of studies on clinically useful tests and antiviral treatment for influenza.****  ***Pediatr Infect Dis J 2003; 22:164-77***.***

- Influenza:  Resources

*Public Health Guidance for Community-Level Preparedness and Response to Severe Acute respiratory Syndrome (SARS),*Version 2.3; July 20 2004
- _[http://www.cdc.gov/ncidod/sars/guidance](http://www.cdc.gov/ncidod/sars/guidance)_
*Biosafety in Microbiological and Biomedical Laboratories (BMBL), 4**th** ed*
- _[http://www.cdc.gov/od/ohs/biosfty/bmbl4/bmbl4toc.htm](http://www.cdc.gov/od/ohs/biosfty/bmbl4/bmbl4toc.htm)_

- Influenza:  Safety

## Overview of Influenza Antigenic Characteristics

## 	Influenza – The Virus

- Family:	Orthomyxoviridae
- Genera:	3 Influenzavirus Types
- 			 - **A & B** & C
- - _Type B_ influenza viruses only infect humans.
- - _Type A_ influenza viruses infect humans & birds & other mammals.
- _Influenza A_ Subtypes:
- 	Human - **H****1****N****1****, H****3****N****2**, **H****1****N****2, **H**2**N**2**
- 	Birds - H**1** to H**16**, N**1** to N**9**
- 	Bird →Human -  H**5**N**1**, H**9**N**2** ,H**7**N**7**, H**7**N**2**, H**7**N**3**

## Influenza: Nomenclature

- A/Fujian/411/2002 (H3N2)-like
- Strains:	A/California/7/2004 (H3N2)-like
- (2005-6)	A/New Caledonia/20/99 (H1N1)-like
- 			B/Shanghai/361/2002-like

**Original Lab ID #**

**Type**

**Subtype**
**(****Influenza A Viruses Only)**

**Location of Original Isolation**

**Year of Initial Isolation**

## InfluenzaAntigenic Change- A Hallmark

_**Antigenic Drift**_
- Process of _gradual and continuous change_ in HA and NA glycoproteins
- Accumulation of point mutations in the genes during viral replication
- Occurs with _both_ influenza A and B, leading to new *viral strains*
- Allows for repeated infections over a lifetime
- Responsible for annual epidemic

## Annual Epidemic (Interpandemic) Influenza, Wisconsin, 1996 - 2005

## Influenza  

**Seek Care**** **

**~10%-20% Infected (29-59 million)**

**~50% Symptomatic (15-30 million)**

**Treat at Home**

**Death**
**~36,000**

**U.S. population ~290 million**

- Influenza
*Annual Impact*

**Hospitalized>200,000**

- 1

**Notes:**
Each year ~10-20% of the US population becomes infected with influenza virus
Most, but not all of those infected will be symptomatic.
Of those that are symptomatic, most will treat at home but some will seek healthcare.
Of those that seek healthcare, some will require hospitalization and a subset of both the outpatients and the hospitalized patients will be tested for influenza.
Some of the people with influenza virus infection will die.

## InfluenzaAntigenic Change- A Hallmark

_**Antigenic Shift**_
- Process(es) whereby existing surface HA and/or NA proteins are replaced by HA and NA proteins that are *significantly different (novel)*.
- Occurs _only_ with influenza A and leads to a new *viral subtype*
- An abrupt change, infrequent and unpredictable
- Can result in a *pandemic influenza*

## What is Pandemic Influenza?

- Results from a ***novel subtype ***of influenza A virus to which the overall population possess no immunity
- Occurrence in multiple or widespread geographic areas worldwide; locally explosive epidemics
- Associated with unusually high rates of morbidity and mortality
- Extremely rapid global spread
- Multiple waves of disease

##     Timeline of Emergence of 

- Influenza Viruses in Humans

**1918**

**1957**

**1968**

**1977**

**1997**

**1998/9**

**2003**

**H1**

**H1**

**B**

**H2**

**H7**

**H5**

**H5**

**H9**

**Spanish**
**Influenza**

**Asian**
**Influenza**

**Russian**
**Influenza**

**Avian**
**Influenza**

**Hong Kong**
**Influenza**

**H3**

## Generation of Pandemic Influenza Subtypes

*Current Models*

**Direct Transmission**

## Overview of Laboratory Diagnostic Methods

## Laboratory Diagnosis of Influenza

| Test
Method | Time to Results | Comments |
| --- | --- | --- |
| Culture | 1-10 days | Still gold standard(?), requires expertise, provides virus for studies |
| Molecular
(RT-PCR) | 2-4 hours | Becoming gold standard(?), requires expertise & expensive equipment |
| Antigen Detection (IF) | 2-4 hours | Requires reading expertise & IF microscope |
| Serology | >2 weeks | Retrospective, requires paired sera |
| Antigen Detection (Rapid EIA-like) | 15-30 minutes | Widely available, requires little expertise |

## Laboratory Diagnosis of Influenza Rapid EIA-Like Tests

| Test | CLIA Status | Antigen Detected |
| --- | --- | --- |
| Clearview Flu A/B | Non-Waived | A & B |
| Directigen Flu A | Non-waived | A |
| Directigen Flu A & B | Non-waived | A & B |
| Directigen EZ Flu A + B | Non-waived | A & B |
| Flu OIA | Non-waived | A / B |
| Flu OIA A/B | Non-waived | A & B |
| NOW Flu A and NOW Flu B | Waived/Non-waived | A & B |
| BinaxNOW Influenza A & B | Waived | A & B |

## Laboratory Diagnosis of Influenza Rapid EIA-Like Tests (continued)

| Test | CLIA Status | Antigen Detected |
| --- | --- | --- |
| QuickVue Influenza | Waived | A / B |
| QuickVue Influenza A + B | Waived | A & B |
| SAS Influenza A and Influenza B | Non-Waived | A & B |
| Xpect Flu A & B | Non-waived | A & B |
| ZstatFlu | Waived | A / B |

## Rapid Influenza Tests

- Advantages
- Rapid turn-around time
- “Stat” testing possible
- Rapid outbreak identification
- Cost-effective (?)
- Wide-spread testing possible
- Less expertise required
- Optimize antibiotic and antiviral usage

- Concerns
- Performance Characteristics:
- Poor PVP early & late season
- Poor test sensitivity→Impact on PVN
- Biosafety issues
- Supplies of test kits
- Loss of isolates for further characterization
- Loss of surveillance data

## Rapid Tests:  Optimizing Use

- Educate clinicians on predictive values & limitations of test results
- Confirm early, late and out-of-season positives
- Confirm peak-season negatives, if applicable
- Recognize the value of negative results.
- Use prevalence indicators to decide:
- When to test
- When to qualify result
- When to confirm results

## Rapid Tests: Biosafety Concerns in an Age of Emerging Diseases 

- Reasons for Concern:  SARS, avian influenza, influenza A (H2N2)
- Addressing the Concerns:
- Enhance communication with ID Drs., Infection Control
- _Need_ patient travel history
- Perform risk assessment
- Consider strategies to enhance biosafety
- Use BSC, additional PPE, isolated testing area
- Need for a new model for biosafety in the laboratory?
- Universal  (“Standard”) precautions for blood in the 80’s
- Enhanced precautions for suspect EIDs in the 2000’s?

## Wisconsin Influenza Rapid Testing Sites Identified in 2004-2005

## Rapid Influenza TestingReported by Wisconsin Test Sites

## Surveillance for New Strains of Influenza Viruses

## Objectives of Influenza Surveillance

- Determine _when_ influenza viruses are circulating*
- Determine _where _influenza viruses are circulating*
- Determine _how much_ influenza activity is occurring (intensity and impact)
- Identify the _types & strains_ of circulating influenza viruses*
- Detect unusual events
- Infection by unusual viruses*
- Unusual syndromes caused by influenza viruses
- Unusually large/severe outbreaks of influenza
- Increased mortality
- Optimize use of vaccines & antivirals*
- *Laboratory contributions

## WHO Global Surveillance System for Human Influenza 

- Source:  Status of Human Health Preparedness & Response, Meeting on Avian & Human Pandemic Influenza, WHO, Nov 7-9, 2005

## U.S. Influenza Surveillance Weekly Updates at http://www.cdc.gov/flu/weekly.htm

- U.S. Influenza Surveillance Weekly Updates at _[http://www.cdc.gov/flu/weekly.htm](http://www.cdc.gov/flu/weekly.htm)_

**CDC**

**Laboratories**

**Sentinel Providers**

**State and Territorial **
**Epidemiologists**

**Vital Statistics**
**Registrars**

**Other**

**Public Health**
**Officials**

**Physicians**

**Media**

**Public**

**Health Departments**

**Pediatric **
**Hospitalization**

**Pediatric Mortality**

## Influenza Surveillance in Wisconsin

**WDPH**

**Laboratories**

**Sentinel Providers**

**Other**

**Public Health**
**Officials**

**Clinicians**

**Media**

**Public**

**Institutional/Outbreak Reports **

**Pediatric Mortality**

- WDPH = Wisconsin Division of Public Health

## Statewide Laboratory-Based Influenza Surveillance in Wisconsin

- Statewide _Laboratory-Based_ Influenza Surveillance in Wisconsin

**WSLH**

**Sentinel Submitters**

**Virology Laboratories**

**Rapid Test Sites**

**Public Health**
**Epidemiologists**

**Clinicians**

**Laboratories**

- WSLH = Wisconsin State Laboratory of Hygiene

## Elements of Laboratory-Based Surveillance

- Selected patient samples and viral isolates for testing at State Laboratory
- Weekly reports of number & types of specimens tested and test results
- Communication/information about unusual occurrences, current status of influenza activity
- Education for clinicians and test sites of implications of prevalence, use and interpretation of tests

## Recommendations to Enhance Laboratory-Based Surveillance

- Develop algorithms for use of PCR for surveillance by state public health laboratories
- Incorporate rapid test sites as key partners
- Incorporate molecular sites in influenza surveillance
- Provide public health testing protocols
- Provide clinical testing data
- Refer samples for test verification, confirmatory testing & subytping and repositories
- Expand influenza surveillance to year-round

## Current Pandemic Concerns

## Direct Interspecies Transmission of Avian Viruses to Humans Exposed to Infected Poultry

- 1997: 18 cases of respiratory illness caused by HP avian H5N1; 6 deaths – Hong Kong
- 1998/9: 7 cases of respiratory illness caused by H9N2; no deaths – China, HK
- 2003: 2 additional HP H5N1 cases; 1 death – China, HK
- 2003: >80 cases of infection by HP H7N7 avian viruses; 1death – The Netherlands
- 2004: 2 cases of infection by HP H7N3; no deaths – British Columbia
- 2004-2005:  Additional cases of H5N1 in Southeast Asia

## 2004-2005:  H5N1 in Southeast Asia

## July-October, 2005:  H5N1 in Birds

- Source: Food and Agriculture Organization, World Health Organization

## Human H5N1 Cases Reported to WHO Through November 17, 2005

| Country | H5N1 Cases | Deaths | Case Fatality |
| --- | --- | --- | --- |
| Cambodia | 4 | 4 | 100% |
| Thailand | 21 | 13 | 62% |
| Indonesia | 11 | 7 | 64% |
| Vietnam | 92 | 42 | 46% |
| China | 2 | 1 | 50% |
| Total | 130 | 67 | 52% |

## Avian (H5N1) Influenza Situation Update – November 18, 2005

- Expansion of geographic and host range via wild birds
- Continuing large outbreaks in domestic fowl
- In human isolates so far, _all genes of avian origin_
- Viral resistance to adamantanes; sensitive to oseltamivir
- Continued evolution of pathogenicity & antigenicity
**No evidence of sustained human-to-human transmission!**

## AVIAN  INFLUENZA  (H5N1)The Recipe For a Human Pandemic

**   **Emergence of a _novel subtype_ of influenza
- An immunologically naïve population
-    Replication in humans → disease
-    Efficient human-to-human transmission

## An Influenza Pandemic Will be Unlike A Bioterrorism Event or A Natural Disaster

**Inevitable yet unpredictable **
**	****	****	****	****vs. imminent, overdue???**
***Widespread, not focused like a bioterrorism event***
***Will be a  ***_***global ***_***event***
***Will affect entire national infrastructure rapidly***
- Effect will be relatively prolonged, weeks to months, occurring in waves
- May have unique age predilection

## PANDEMIC INFLUENZA Risk Communication

**Walking the fine line between**
*** “******appropriately sounding the alarm”***** **
**and “*****causing panic”***

## The Arrival of Avian Flu in the U.S.???

- Article from _Orlando Sun Times_,
- “Beloved Duck at Theme Park                                 Succumbs to Mystery Flu”

## Pandemic Preparedness Activities:  An International Priority

## Pandemic Preparedness Activities:A National Priority

- National Strategy for Pandemic Influenza

- National Pandemic
- Influenza Plan

## Pandemic Preparedness Activities: A State Priority

## W.H.O. Framework  for Pandemic Planning

| Interpandemic period |  |
| --- | --- |
| Phase 1 | No new influenza virus subtypes have been detected in humans.  An influenza virus subtype that has caused human infection may be present in animals.  If present in animals, the risk of human infection or disease is considered to be low.  |
| Phase 2 | No new influenza virus subtypes have been detected in humans.  However, a circulating animal influenza virus subtype poses a substantial risk of human disease. |
| Pandemic alert period |  |
| Phase 3 | Human infection(s) with a new subtype, but no human-to-human spread, or at most rare instances of spread to a close contact. |
| Phase 4 | Small cluster(s) with limited human-to-human transmission but spread is highly localized, suggesting that the virus is not well adapted to humans. |
| Phase 5 | Larger cluster(s) but human-to-human spread still localized, suggesting that the virus is becoming increasingly better adapted to humans, but may not yet be fully transmissible (substantial pandemic risk). |

## W.H.O. Framework  for Pandemic Planning (continued)

| Pandemic period |  |
| --- | --- |
| Phase 6 | Pandemic phase:  increased and sustained transmission in general population. |
| Postpandemic period
Return to interpandemic period. |  |

## The Laboratory’s Role in Pandemic Preparedness & Response

## Pandemic Influenza Preparedness & Response

## Interpandemic/Pandemic Alert Influenza: Laboratory Responsibilities

- Perform diagnostic testing
- Support surveillance activities
- Seasonal influenza
- Novel influenza subtypes
- Participate in pandemic planning and exercises
- Develop/review pandemic response plans and checklists
- Educate clinicians and laboratorians

## Pandemic Influenza Period: The Laboratory’s Responsibilities

- _Clinical Laboratories_
- Perform diagnostic testing for influenza (stat)
- Maintain other diagnostic services
- Support surveillance activities
- Continue clinician education
- Other?

- _Public Health Laboratories_
- Maintain surveillance activities
- Conduct special studies with CDC
- Maintain reference testing for influenza
- Maintain emergency response for other outbreaks (e.g., foodborne)
- Continue education of clinicians & laboratorians
- Share data/information in “real-time”
- Maintain other diagnostic services?
- Other?

## Pandemic Influenza Period: The Impact on the Laboratory

- Staff shortages
- Supply shortages
_**Very high**_ demand for diagnostic testing
- Continued need for routine (non-pandemic) work
- Disruptions of medical community
- Severe disruptions of community infrastructure
- High visibility likely for laboratory

## Pandemic Influenza Period: Plan Now!

**Issues & Options**
**Staffing Shortages:**
- “Continuity of Operations” Plan
- Cross-train
- Surge testing laboratories
- Temporary employment agencies
- Prioritize testing (influenza AND non-influenza)
- Identify other staff capabilities
**Supply Shortages:**
- Stockpiles
- Multiple vendors

## Pandemic Influenza Period: Plan Now!

**Issues & Options**
**Biosafety:**
- Risk assessment (specimen collection, testing processes)
- Enhanced biosafety, e.g., PPE, sequestering work, barriers
**Protocols:**
- Notification of changes to testing capabilities & schedules
- Clinical diagnosis vs. testing
- Specimen management
- Specimen referral to public health laboratory
- Employee health
- Alternate transport options

## Pandemic Influenza Period: Plan Now!

**Issues & Options**
**Training/Education:**
- Cross-train staff
- Accelerated training protocol
- Clinician training
**Communications:**
- Integration of laboratory planning with institutional plans
- Institutional prioritization
- Real-time information-sharing from PHLs to sentinel laboratories

## Pandemic Influenza Period: Plan Now!

- Develop/Review your “Continuity of Operations” Plan
- Develop checklist(s)
- Exercise
- Support surveillance for earliest detection
- Integrate plans with:
- institutional plans
- community plans
- regional & statewide plans
- other laboratories’ plans
- Public health laboratories must accept responsibility for leadership in laboratory planning & response

## THE LRN FOR BIOTERRORISM

***PUBLIC HEALTH***
***EMERGENCIES***