PREPARING FOR AN INFLUENZA PANDEMIC: FOCUS ON LOCAL PREPAREDNESS

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PREPARING FOR AN INFLUENZA PANDEMIC FOCUS ON
LOCAL PREPAREDNESS

• David Jay Weber, M.D., M.P.H.
• Professor of Medicine, Pediatrics Epidemiology
• Medical Director, Hospital Epidemiology and
  Occupational Health
• University of North Carolina at Chapel Hill

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INFLUENZA PRIMER
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Influenza Disease Burden to U.S. Societyin an
Average Year
Deaths 25,000 - 72,000
Hospitalizations 114,000 - 257,500
Physician visits 25 million
Infections and illnesses 50 - 60 million
Thompson WW et al. JAMA. 2003289179-86. Couch
RB. Ann Intern Med. 2000133992-8. Patriarca PA.
JAMA. 199928275-7. ACIP. MMWR.
200453(RR06)1-40.
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INFLUENZA BIOLOGY IMPACT

• Single-stranded, enveloped, RNA virus
  (orthomyxoviridae)
• Influenza A
• Potentially severe illness epidemic and
  pandemics
• Rapidly changing
• Hemagluttinin (HA) 16 types neuraminidase (NA) 9
  types
• Influenza B
• Usually less severe illness may cause epidemics
• More uniform
• Influenza C
• Usually mild or asymptomatic illness

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INFLUENZA BIOLOGY IMPACT

• Impact
• 25-50 million people contract influenza annually
  (attack rate of 10-20)
• 226,000 hospitalizations per year
• 36,000 deaths per year
• Cost 1 to 3 billion dollars per year
• Causes respiratory tract disease
• Sudden onset
• More severe pneumonia during pregnancy
• No carrier state (but inapparent illness may
  occur)

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Influenza Activity Can Peak From December
Through May
Month of peak influenza activity during influenza
seasons in the United States, 19762002
11
6
4
3
1
1
www.cdc.gov/nip/publications/pink/flu.pdf.
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Structure of the Influenza Virus
Hemagglutinin (HA) 16 types in influenza A
Neuraminidase (NA) 9 types in influenza A
M2
Nucleoprotein (NP) ssRNAhighly mutable 8
segments-allows reassortment during double
infection
M1
Polymerase (P) Proteins
Adapted from Hayden FG et al. Clin Virol.
1997911-42.
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Viral Nomenclature
Type of Nuclear Material
Hemagglutinin
Neuraminidase
A / Sydney / 184 / 93 (H3N2)
Virus subtype
Virus type
Geographic origin
Year of isolation
Strain number
CDC. Atkinson W, et al. Chapter 13 Influenza.
In Epidemiology and Prevention of
Vaccine-Preventable Diseases, 4th ed. Department
of Health and Human Services, Public Health
Service, 1998, 220
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Antigenic Drift
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Antigenic Shift
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Hampson AW, Mackenzie JS. MJA 2006185S39-43
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De Clercq E. Nature Rev 200651015-25
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INFLUENA PANDEMICS IN THE 20th CENTURY
HHS Pandemic Influenza Plan, October 2005
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INFLUENZA, UK, 1918-1919
Taubenberger JK, Morens DM. EID 2006126-22
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INFLUENZA AND PNUEMONIA MORTALITY, US, 1911-17
VS 1918
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AVIAN INFLUENZA
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PANDEMIC INFLUENZA PLANNING CHALLENGES

• Widespread
• Simultaneous appearance in multiple
  states/locales
• Long duration (gt2 years)
• Surge capacity Medications, ventilators,
  hospital beds, personnel
• Personnel Exhaustion, concerns about infection
• Providing adequate antivirals including
  distribution/allocation
• Vaccine development and distribution/allocation
• Maintaining quarantine

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CHARACTERISTICS OF AN INFLUENZA PANDEMIC

• The ability of the virus to spread worldwide
• The fact that many people may be asymptomatic
  while infectious
• Simultaneous outbreaks throughout the US,
  limiting the ability of an jurisdiction to
  provide assistance to other areas
• Enormous demands on the healthcare system
• Delays and shortages in the availability of
  vaccines and antivirals
• Potential disruption of national and community
  infrastructures including transportation,
  commerce, utilities and public safety due to
  illness and death among workers and their families

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WHO, 10 THINGS WE NEED TO KNOW ABOUT PANDEMIC
INFLUENZA

• Pandemic influenza is different from avian
  influenza
• Influenza pandemics are recurring events
• The world may be on the brink of another pandemic
• All countries will be affected
• Widespread illness will occur
• Medical supplies will be inadequate
• Large number of deaths will occur
• Economic and social disruption will be great
• Every country must be prepared
• WHO will alert the world when the pandemic threat
  increases

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AVIAN INFLUENZA EPIDEMIOLOGY
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Current Influenza A/H3N2 is Partly Derived from
the 1918 Virus
Taubenberger et al, Nature, Oct 2005
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Fauci AS. EID 20061273-77
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AVIAN INFLUENZA EPIDEMIOLOGY

• Carried by many wild birds may infect domestic
  poultry
• Highly pathogenic subtypes H5, H7
• May survive in environment (esp. when temp low)
  bird feces gt35 days
• Management
• Culling of infected poultry proper disposal of
  carcasses
• Restrictions on movement of live poultry
• Human infections
• N5N1, H2N2, N7N3, N7N7, H9N2

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AVIAN INFLUENZA EPIDEMIOLOGY

• Animals infected with H5N1
• Pigs serology/culture in china (ProMed)
• Cats experimental infection (Kuiken. Science,
  2004 9/02)
• Cats (domestic) multiple reports worldwide
• Tigers (zoo) Singapore
• Stone marten Germany
• Dog

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AVIAN INFLUENZA EPIDEMIOLOGY

• Major risk for human infection contact with
  infected poultry
• Human-to-human cases reported
• Requires close contact, inefficient transmission
• Mechanisms for improved transmissibility
• Reassortment
• Adaptive mutation

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AVIAN INFLUENZACLINICAL FEATURES

• Incubation period 2-8 days (range, up to 17
  days)
• Aggressive course (rapid clinical deterioration)
• High fever
• Influenza-like symptoms (cough, chest pain, SOB)
  may have bloody sputum
• GI symptoms vomiting, watery diarrhea (no blood)
• Rare encephalitis, no respiratory symptoms

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AVIAN INFLUENZAPROPHYLAXIS AND TREATMENT

• Treatment
• Current H5N1 Amantadine and Rimantadine resistant
• Neuraminidase inhibitors
• Oseltamivir (Tamiflu)
• Zanamivir (Inhaled)
• Resistance described (Vietnam)
• Likely would also work for chemoprophylaxis
• For influenza clinical activity only if given in
  first 48 hours

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HUMAN DISEASES DUE TO H5N1 SNAPSHOT, WHO, 12
JANUARY 2007

• 266 cases (159 deaths)
• N5H1 strains now present in multiple countries
• Virus spreading beyond the original geographic
  (Asia) region to India subcontinent, Europe, and
  North Africa
• Not all countries have reported human cases
• 150 million birds culled (cost gt10 billion)

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HUMAN DISEASES DUE TO H5N1, WHO, 2003 2007 (12
Jan. 2007)

• 266 cases (159 deaths)
• N5H1 strains now present in multiple countries
• Virus spreading beyond the original geographic
  (Asia) region to India subcontinent, Europe, and
  North Africa

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CUMULATIVE NUMBER OF HUMAN CASES OF AVIAN
INFLUENZA (H5N1 ), WHO 12 Jan 2007
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FACTORS LEADING TO CONCERN OF AN H5N1 INFLUENZA
PANDEMIC

• Avian H5N1 is widespread and endemic in Asia with
  spread to Russia, North Africa, Middle East and
  Europe
• Avian H5N1 is becoming more deadly in a growing
  number of bird and mammals species
• Wild birds and domestic ducks may be
  asymptomatically infected
• The virus is able to transmit directly from birds
  to some mammals (e.g., zoo tigers, cats, dogs)
  and in some circumstances to people
• Sporadic spread directly from animals to humans
  suspected human-to-human transmission in rare
  instances
• Genetic studies demonstrated ongoing evolution of
  H5N1

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WHO PANDEMIC SCALE
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AVIAN INFLUENA PREPAREDNESS
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PANDEMIC INFLUENZA IMPACT, US
HHS Pandemic Influenza Plan, October 2005
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AVIAN INFLUENZA IMPACT, NC

• Number of cases 1,856,296
• Hospitalizations 65,637
• Deaths 14,987
• Assumptions strain 3x more lethal than 1968-69
  Hong Kong influenza
• Source USA Today, 11 October 2005

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PANDEMIC PREPAREDNESSGENERAL PREPAREDNESS

• Isolation and quarantine
• Border control
• Social distancing
• Hospital infection control
• Vaccines
• Antivirals
• Personal protection

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PANDEMIC PREPAREDNESSHOME PREPAREDNESS

• 2 weeks of food supplies
• Bottled water, canned meats, fish, fruits,
  vegetables, dry cereal, protein and fruit bars,
  beans, soup, and infant formula
• Medical supplies
• 2 weeks of prescription medications
• Nonprescription medications fever and pain
  relievers
• Plan for child care, pet care, elder care,
  transportation
• Miscellaneous
• Batteries, manual can opener, radio, flashlights,
  alcohol hand rubs, pet supplies, tissue and
  toilet paper

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FluSurg Model FOR Hospitals, CDC Assumptions

• UNC Hospitals (catchment area 320,000)
• 80 ICU beds (minimum, does not include PACU, step
  down units)
• 628 non-ICU beds (minimum, does not include
  non-licensed beds)
• Ventilators 112
• Model
• Duration of outbreak 8 weeks
• Attack rate 25
• Need for intensive care 15 Need for
  ventilators 7.5
• Length of stay, hospital 5 d length of stay,
  ICU 10 d

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UNC Catchment 320,000
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NATIONAL PROBLEMS(Not Under Control of Hospital)

• General issues
• Lack of surge capacity (ICU beds, ventilators,
  floor beds)
• Nursing shortage
• Just in time delivery of goods
• Response to avian influenza
• Inadequate supply of PPE
• Inadequate supply of antivirals
• Lack of effective vaccine for avian influenza
• Public hysteria

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VACCINE BY THE NUMBERS

• 40 million estimated number of deaths worldwide
  for 1918 pandemic
• 6.2 billion worlds population
• 300 million doses worldwide capacity for
  trivalent influenza vaccine
• 900 million doses worldwide capacity for
  monovalent vaccine (issues include yield,
  adjuvant, process used, antigen content
• 1 or 2 doses?
• /- 2 years expected duration of pandemic
• /- 6 months time from recognition of pandemic
  till vaccine available
• 9 countries number of countries with vaccine
  capacity (70 in EU)
• 3-5 million doses/week (15 ?g) current capacity
  of US manufacturers

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Generalized Influenza Vaccine Global Production
Timetable (NH - Representative Year)
Egg supply organization
Egg supply for production
Seed lots
Monovalent batches
Formulation
Filling / Packaging
Packaging documentation
Ref Member State Release
Pharmaceutical file
MA
Clinical trial
Vaccine Delivery
WHO meeting D0 mid Feb
D0
Reagent availabilityEnd of May
Mid May
July/August
D0 - 6 months
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Moscona, A. N Engl J Med 20053531363-1373
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OSELTAMIVIR EFFICACY
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Tamiflu (oseltamivir phosphate) Seasonal
Prophylaxis in a Vaccinated Frail Elderly
Population Results
of patients with laboratory-confirmed clinical
influenza
Data on file (Ref. 155-027). Hoffmann-La Roche
Inc.
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OSELTAMIVIR IMPACT ON LOWER RESIRATORY TRACT
COMPLICATIONS (LRTC)

• Analysis of prospective data from patients
  enrolled in 10 placebo controlled trials (N3564)
• Results confirmed influenza (oseltamivir vs
  placebo)
• Reduced overall antibiotic use 14.0 vs 19.1
  (plt0.001)
• Reduced LRTCs-associated antibiotic use 4.6 vs
  10.3 (plt0.001)
• Reduced LRTCs leading to antibiotics in high risk
  patients 12.2 vs 18.5 (p0.02)
• Reduce overall hospitalizations 1.0 vs 1.7
  (p0.02)
• Unconfirmed influenza No difference in
  incidence of LRTC, overall antibiotic use or
  hospitalizations

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EFFICACY OF OSELTAMIVIR IN A MOUSE MODEL
(A/Vietnam/1203/04 H5N1)
Yen H-L, et al. JID 2005192665
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Proposed Priority Target Groups
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LOCAL PREPAREDNESS
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LESSONS FROM SARS
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Time-line NC Confirmed SARS Case, 2003

• 5/15-18 Visited Toronto
• 5/19-23 Worked at UNC
• 5/24 Developed fever (did not work)
• 5/27, 5/28, 6/1, 6/3 Visited LMD (free standing
  clinic)
• 5/30 Doxycycline begun for suspected RMSF
• 6/2 Respiratory symptoms
• 6/3 CXR with infiltrate SARS suspected, health
  department notified

• 6/3, 6/9 Serum collected sent to CDC
• 6/9 Seroconversion to SARS-CoV
• 2 workplace contacts investigated for atypical
  pneumonia
• 6/13 Contact 1 diagnosed with mycoplasma 6/13
• 6/13 Contact 2 dies with pneumonia/ARDS

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SARS in Toronto, 2003
Orange County mans travel dates
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LESSONS FROM SARS

• Need to nestle response to a highly communicable
  disease in hospital disaster plan
• Solution Revised disaster plan
• Concern about being labeled SARS hospital
• Work with NC State Health Department
• Must manage worker and public concern (i.e.,
  provide public relations use local/state health
  departments)
• Improved communication within hospital and with
  health departments
• Inadequate supplies of PPE
• 3 months PPE stockpiled by hospital (being
  increased to 6 months)

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LESSONS FROM SARS

• Inadequate outpatient facilities to handle highly
  communicable diseases
• Solution New ID clinic (all rooms meet CDC
  airborne isolation requirements)
• Need to screen for travel to endemic area at
  entry to hospital or clinic
• Message on phone while awaiting operator, signs
  at hospital entry
• Need for UNC Health Care System to have its own
  diagnostic laboratory capacity (i.e., not rely on
  CDC)
• PCR developed for SARS-coV

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LESSONS FROM SARS

• Need for State policy on transport of patients
  with highly communicable diseases
• Solution Ongoing discussions with State Health
  Department
• Must manage worker exhaustion
• Solution enforced rest periods
• Inability of workers to adhere exactly to
  guidelines for placing and removing PPE
• Solution PPE monitor

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LOCAL PREPAREDNESS
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FEDERAL AND STATE LOCAL PREPAREDNESS

• HHS pandemic influenza plan
• Stockpile ventilators and other equipment in
  Strategic National Stockpile
• Widely available accurate rapid diagnostic tests
• Assist communities with surge mortuary services
• Provide psychosocial support to responders

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UNC HOSPITAL PREPAREDNESS

• Surveillance
• Influenza like activity (ILI) in NC sentinel
  sites, UNC ED
• Laboratory tests for influenza (number and
  frequency positive)
• Diagnosis (detection)
• Rapid testing available for influenza A B, and
  RSV (24/7)
• Ability to develop PCR for avian strains
• Graded response (i.e., hierarchy of response
  depending on threat)
• Hospital response plan
• Modeled on SARS response plan

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RESPIRATORY VIRUS SURVEILLANCE, UNC HOSPITALS
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UNC HOSPITAL PREPAREDNESS

• Cooperation with county and state public health
  authorities
• State response plan
• Communication pathways established (PHE network,
  SPICE, others)
• Nestle influenza response in disaster planning
• Hospital disaster plan
• Frequent drills
• Incident command system
• Access to senior administrators
• Ad Hoc Committee for vaccine distribution
  (reports to MSEC)
• Ethics Committee to assist if there are limited
  supplies/beds

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UNC HOSPITAL PREPAREDNESS

• Minimizing exposure
• Universal respiratory hygiene (signs in
  clinics/ED, method to provide persons with
  symptoms of URI tissues, mask, education)
• Droplet precautions for persons with URI until
  diagnosis rules out need for isolation
• Adequate PPE supplies
• 3-6 month stockpile of PPE (especially N95
  respirators)
• Training and institution of special airborne
  isolation
• Components N95 respiratory, airborne isolation
  room (negative pressure, direct out exhausted
  air), eye protection

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UNC HOSPITAL PREPAREDNESS

• Ability to rapidly train large numbers of
  healthcare workers in use of N95
• Use train the trainers approach
• Multiple screeners available (NX)
• Plan for evaluating ill employees with URI
  symptoms
• Fever plus symptoms Relieve from duty, care per
  LMD
• Symptoms (work in PICU, NICU, BMTU) Rapid RSV
  and influenza testing (positive test exclusion
  from these units)
• Symptoms without fever allowed to work while
  wearing mask

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UNC HOSPITAL PREPAREDNESSSURG CAPACITY

• Outpatient
• Infectious disease clinic 8 clinic rooms, all
  meet airborne isolation requirements
• Use of Family Practice Center for outpatient
  evaluations
• Inpatient
• Many airborne isolation beds available at UNC
  gt75 (Adult ICU 13, Ped/Neonatal ICU 8, Adult
  floor 48, Peds floor 9)
• Use of unlicensed beds (e.g., PACU)
• Use of medical/nursing students allied faculty
  (e.g., SPH)
• Plan for flexible shifting of personnel and
  locations to meet demand

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UNC HOSPITAL PREPAREDNESSMAINTAINING ADEQUATE
STAFFING

• Incentive pay (UNC-CH will provide 1.5 salary)
• Preferential access to antivirals and vaccines
• Overnight accommodations (e.g., Carolina Inn,
  Franklin Hotel)
• Free parking (UNC-CH)
• Use of UNC-CH personnel (e.g., security)
• Day care under discussion
• Coverage for illness under workers compensation
  administrative leave

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ISSUES FOR UNIVERSITIES

• When to close university
• How to manage students who cannot go home
• How to provide remote learning
• Refund tuition and/or room and board?
• How to manage students with known or suspected
  pandemic influenza
• Medical care (inpatient and outpatient)
• Housing (same dorm or sick dorm)
• Provision of food and essential services for
  students
• Travel to endemic areas Faculty, students

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