P1254325861tPeVG

1
Seasonal and Pandemic Influenza Changing
Epidemiology and Awareness
Tina Q. Tan, M.D., FAAP Associate Professor of
Pediatrics Feinberg School of Medicine,
Northwestern University Infectious Diseases
Attending, Childrens Memorial Hospital
2
Influenza

• Annual epidemics during winter months with 10
  20 of population becoming ill every year
• Caused by both influenza A and B viruses
• Highest rates of infections in children but
  highest rates of serious illness and death in
  persons 65 years, children lt 5 years, pregnant
  women, and persons of any age with underlying
  medical conditions
• Complications each year are responsible for
• gt 200,000 excess hospitalizations - about half
  in persons lt 65 years
• 35,000 50,000 excess deaths - 90 in the
  elderly
• billions of dollars in health care work loss
  costs
• Recommendations for vaccination
• Prioritize reducing serious morbidity mortality
• Also permissive encouraging anyone who wishes
  to avoid influenza also to be immunized

JAMA 20042921333-1340 MMWR 2006 55
(RR-10)1-58 MMWR 2005541-57
3
Kuby J. Chapter 21 Immune response to infectious
diseases. In Immunology, 2nd ed. W.H. Freeman
and Co., New York, 1991, 487
4
Antigenic Drift A Modest Change

• Point mutations in HA and/or NA genes of both
  influenza A and B viruses
• Influenza B viruses undergo antigenic drift less
  rapidly than influenza A viruses
• Amino acid substitutions in HA, NA, 0.5-1/year
• Sequential changes accumulate over years in
  response to immunological pressure
• Drift variants with HA mutations at antigenic
  sites exhibit reduced susceptibility to
  pre-existing antibodies in population
• Rapid spread and symptomatic infection

5
Schematic of Antigenic Drift in Hemagglutinin
Monomer Antibody-Binding Sites in the HA1 Subunit
NEJM 2004350218-220
6
Influenza Vaccine Strains, 2006-2007
Influenza A H1N1 New Caledonia/20/1999-like
Influenza A H3N2 Wisconsin/67/2005-like or
A/Hiroshima/52/2005 (antigenically equivalent)
Influenza B Malaysian/2506/2004-like or
Ohio/1/2005 (antigenically equivalent)
7
Transmission of Influenza

• Community at Large
• Persons at increased risk of complications
• Community-dwelling elderly
• Social contacts of 1, 2, and 3 cases

• Family Members of School Children
• Working adults (parents)
• Younger siblings
• Other contacts

3
2
More School Children Infected
1
Index Case Immunologically Naïve Schoolchild
Elveback LR et al. Am J Epidemiol.
1976103152-165.
8
Infection Rates Vary by Age
Median Influenza Infection Rates 500 Influenza
A/H2N2 Epidemics
Attack Rate (per 100 persons)
Median Infection Rate ()
Elveback LR et al. Am J Epidemiol.
1976103152-165.
9
Influenza Clinical Signs and Symptoms

• Influenza viruses are spread from person to
  person by droplets or by direct contact with
  articles contaminated with nasopharyngeal
  secretions via coughing and sneezing.

• Incubation period 1 to 4 days (average 2 days)

• Adults can be infectious from day before
  symptoms begin through 5 days after illness
  onset. While children can be infectious for 10
  days and shed virus for several days before
  their illness onset.

- Severely immunocompromised persons can shed
virus for weeks to months

• Uncomplicated influenza characterized by abrupt
  onset of fever, myalgia, headache, chills,
  malaise, dry cough, sore throat and rhinitis.

- Symptoms typically resolve after 3 to 7 days,
however cough and malaise can persist for gt 2
weeks
10
Influenza Complications in Adult Population

• Primary influenza viral pneumonia
• Secondary bacterial pneumonia may be
  necrotizing
• Exacerbation of underlying pulmonary or cardiac
  disease
• Guillain-Barre syndrome
• Encephalitis
• Transverse myelitis
• Toxic Shock Syndrome
• Myositis
• Myocarditis
• Pericarditis

11
Presentation of Clinical Influenza Differs by
Age Group
Sign/Symptom Children Adults Elderly
Cough (nonproductive)
Fever
Myalgia
Headache
Malaise
Sore throat
Rhinitis/nasal congestion
Abdominal pain/diarrhea
Nausea/vomiting
Highest positive predictive value (PPV)
Lowest PPV No predictive value
Monto AS et al. Arch Intern Med.
20001603243-3247 Cox NJ, Subbarao K. Lancet.
19993541277-1282.
12
Pediatric Influenza Infection Annual Incidence

• Regional studies show 15 to 42 of children
  infected annually1 with 1 requiring
  hospitalization
• 13.8 to 16 million respiratory illnesses in
  persons lt20 years of age1
• Highest attack ratesschool-aged children1
• Children shed influenza virus longer ( 10 days)
  and at higher titers than adults1
• Children lt 2 years of age at highest risk for
  influenza complications and have hospitalization
  rates that approach that of elderly adults 65
  years.

Sources 1AAP. Pediatrics 20021101246-1252
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Complications of Pediatric Influenza Infection

• Death (3.8/100,000 children infected)1
• Acute Otitis Media1
• Bronchiolitis/laryngotracheobronchitis1
• Febrile seizures1,2
• Myocarditis/pericarditis2
• Encephalitis and encephalopathy2
• Reye syndrome2
• Myositis2
• Transverse myelitis2
• Bacterial pneumonia including necrotizing
  pneumonia3
• Dehydration with severe hypotension3
• Respiratory failure3

Sources 1AAP. Pediatrics 20021101246-1252 2CDC
. MMWR 2003 RR-81-363MMWR 200352(49)1197-1202
.
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Populations at High Risk for Severe Disease and
Complications With Influenza

• Persons 50 years of age
• Pregnant women
• Children aged 6 to 59 months
• Healthcare workers
• Persons of any age with chronic disorders of
  the pulmonary or cardiovascular systems
• Persons of any age with chronic metabolic
  diseases (including DM), renal dysfunction,
  hemoglobinopathies, or immunosuppression
• Children and adolescents receiving long-term
  aspirin therapy at risk for developing Reye
  syndrome after wild-type influenza infection
• Persons who live with or care for persons at
  high risk and who can transmit influenza to
  those at high-risk

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Major Changes in Routine Pediatric Influenza
Vaccine Recommendations

• All healthy children aged 6 to 59 months and
  their household contacts and out of home
  caregivers should be vaccinated annually
  against influenza
• All children aged 6 months to lt 9 years who
  have NOT BEEN previously vaccinated at any
  time with either trivalent inactivated or
  live, attenuated influenza vaccine should
  receive 2 doses of vaccine

16
Trivalent Inactivated Influenza Vaccine

• Formalin-inactivated whole virus vaccine first
  used in WW II
• Modern refinements to decrease adverse reactions
• zonal gradient centrifugation (removes
  reactogenic contaminants
• split product vaccine (treated with solvents)
• Contains 2 type A strains (H1N1 and H3N2) and 1
  type B strain

• Given as intramuscular injection beginning in
  fall before influenza season starts to any
  persons 6 months of age.

• For children 6 months to 9 years who have
  never received influenza vaccine, two doses,
  separated by at least 1 month are
  recommended. Older children and those previously
  vaccinated need only one dose.

• Contraindication hives or anaphylaxis to egg
  or egg products

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Trivalent Cold-Adapted Influenza Vaccine

• Live, attenuated, cold-adapted and
  temperature-sensitive vaccine against both
  influenza A and influenza B
• Induces both local and systemic Ab as well as
  cellular immune response
• Nasal replication for 1-14 days but no
  significant transmission documented to date

• Administered as a 0.25 cc (1/2 dose) into each
  nostril for total of 0.5cc children lt 9
  years of age should receive 2 doses separated by
  6 weeks. Recommended for healthy persons 5
  to 49 years of age.

• Contraindicated in individuals 5-17 years of
  age receiving aspirin or aspirin containing
  therapy and in any person with known or
  suspected immune deficiency hives or anaphylaxis
  to egg or egg products

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Comparing TIV and CAIV-T
Category TIV CAIV-T
Administration Intramuscular Serum antibodies Intranasal Mucosal immunity
Frequency of administration Annually Annually
Formulation Inactivated Live attenuated
Efficacy children Efficacy adults lt65 y 5090 7090 7090 7090
Safety (side effects) Sore arm Runny nose
Growth medium Chick embryos Chick cells
Indication Any person gt6 mo 5 49 yrs (healthy)
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TIV Prevents Influenza Illness

• Children protection varies from 5090
• Healthy working adults 7090 effective if
  vaccine is a good antigenic match
• Elderly nursing home population prevents
• death in 80 of persons
• hospitalization or pneumonia in almost 60
• confirmed influenza illness in 3040

CDC. MMWR Morb Mortal Wkly Rep.
200352(RR-8)1-34.
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Numbers of Persons Covered by Current Influenza
Vaccine Recommendations 2006-2007
Children 6 to 23 months 6.0 million Healthy
children 24 to 59 months 10.6
million Persons 2-64 years with high risk
condition 44.0 million
Pregnant women 4.0
million Healthy persons 50 to 64 years
33.0 million Nursing home residents
2.0 million Persons 65 years
37.2 million Healthy household contacts
94.8 million Health care workers lt 65 years
7.0 million
Total 218.1 million (72.7)
Total US population 300 million
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Influenza Vaccination Coverage Rates Among Adult
Target Population Groups
Population Group Influenza
vaccination rates
All aged 50-64 yrs
36.8 (35.4-38.2)
All aged 65 yrs
65.5 (64.1-66.9)
Persons with high risk conditions
Aged 18-64 yrs
34.2 (32.5-35.9)
Aged 18-49 yrs
24.2 (22.1-26.4)
Aged 50-64 yrs
46.3 (43.7-49.0)
Pregnant women
12.8 (9.0-17.9)
Healthcare workers
40.1 (37.5-42.7)
Household contacts of high risk pts
Aged 18-49 yrs
14.9 13.4-16.6)
Aged 50-64 yrs
38.4 (33.6-43.5)
NHIS, United States, 2003
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Influenza Immunization Rates for High-Risk
Populations by Age
Immunized
Children with asthma adults with high-risk
conditions such as asthma and/or pulmonary and
cardiovascular disorders includes all persons
65 and older irrespective of health condition
Sources 1Kramarz P. Vaccine 2000182288-94
2CDC. MMWR 200352(RR-8)1-36.
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Many Barriers to Influenza Immunization

• Inadequate access to vaccination1
• Racial/socioeconomic status2
• Low reimbursement1,3
• Misconception about severity of disease1,3
• Concern for vaccine safety1,3
• Contraindications1
• Missed opportunities1
• Indifference

1. Gershon AA et al. Clin Infect Dis.
199725782-786.2. Medicare Current Beneficiary
Survey, 1996. 3. Fedson DS. JAMA.
19942721133-1137.
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Antiviral Drugs for Influenza Prophylaxis and
Treatment

• Drug Approval Age
• M2 Inhibitors (A only)
• Amantadine Prophylaxis ?1 y
• (Symmetrel) Treatment ? 1 y
• Rimantadine Treatment Adults
• (Flumadine) Prophylaxis Children, adults
• Neuraminidase Inhibitors (A and B)
• Zanamivir Treatment ?7 y
• (Relenza)
• Oseltamivir Treatment ?1 y
• (Tamiflu) Prophylaxis ?13 y

CDC. MMWR Morb Mortal Wkly Rep.
200352(RR-8)1-34.
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Anti-viral Resistance in Influenza Viruses

• Viral resistance to adamantanes can emerge
  rapidly during treatment because a single
  point mutation at amino acid positions 26,
  27, 30, 31, or 34 on the M2 protein can confer
  cross resistance to both amantadine or
  rimantadine
• Drug resistant viruses can emerge in about 1/3
  of patients when either amantadine or
  rimantadine is used for therapy and replace
  susceptible strains within 2-3 days of starting
  therapy
• Frequency of transmission of resistant viruses
  from person to person is unknown

NEJM 2006354785-788 www.cdc.gov/flu/professiona
ls/treatment/antiviral.htm
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Anti-viral Resistance in Influenza Viruses

• Dramatic increase in resistance in US has been
  linked to global spread of viruses with a
  specific mutation that occurred in absence of
  sustained selective drug pressure
• This increase in resistance has also been seen
  worldwide among both the H3N2 and H1N1
  influenza A viruses and is associated with a
  serine to asparagine change in residue 31 of
  the M2 ion channel protein
• Development of resistance to oseltamivir occurs
  much less frequently and only one clinical
  isolate has demonstrated decreased
  susceptibility to zanamivir

NEJM 2006354785-788 www.cdc.gov/flu/professiona
ls/treatment/antiviral.htm www.who.int/csr/diseas
e/influenza/recommendationfinal.pdf
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Incidence of M2-Inhibitor Resistance Among Human
Influenza A (H3N2) Viruses in the US
Time period of isolates tested
Resistance
1992-1995 991

0.8 1996-1997 508

0.4 1998-1999 510

2.2 2000-2001 283

1.4 2002
290
1.4 2003
174
1.7 2004
466
1.9 Oct 04-Mar 05 636
14.5 Oct
Dec 05 209
92.3
NEJM 2006354785-788
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Updated Recommendations for Use of Antiviral
Agents in the Treatment of Influenza

• Amantadine and rimantadine should NOT be used
  for the treatment or chemoprophylaxis of
  influenza A in the US because of widespread
  resistance of influenza virus to these
  medications. At this time only oseltamivir or
  zanamivir should be used when indicated

29
Avian Influenza A Virus
H5N1 Influenza A Virus
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Antigenic Shift A Profound Change

• Gene segment reassortment during coinfection with
  animal and human strains (most favored
  hypothesis)
• Facilitated by species susceptible to both avian
  and human strains (i.e. pigs)
• Sudden appearance of novel antigenic composition
  of Influenza A strain and absence of population
  immunity results in
• Rapid transmission up to one billion infected
• High attack rates
• Susceptibility of all/most age groups (age cohort
  effect)
• Rapid global (pandemic) spread
• High morbidity and mortality up to 500 million
  requiring hospital care and 7.5 million deaths
  (may be as high as 150 million)

31
1918 Spanish Flu Pandemic
32
Antigenic Shifts in Influenza A Pandemics
Year Circulation Virus Vernacular
Estimated (Years) Type Term U.S.
Mortality 1889 H2N2 High 1901 12 H3N8 Mod
erate 1918 29 H1N1 Spanish, Swine gt500,000 194
6 11 H1N1 A prime Low 1957 39 H2N2 Asian 86,000
1968 Present H3N2 Hong Kong 34,000 1977 Present H
1N1 Russian Negligible
Adapted from Kilbourne ED. Influenza, Plenum, NY,
1987.
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Modes of Transmission of Influenza Pandemics
Pandemic Transmission
Population Most affected
Spanish Flu Avian Influenza Virus
Unusually high mortality in
healthy persons 15 to 34 years of age
transmitted from birds to humans, then human to
human
1918
Asian Flu Human/Animal Viruses
Young children and elderly
1957
Hong Kong Flu Human/Animal Viruses
Infants/Adults over age 65
1968
H5N1 Avian Flu Avian Influenza Virus
Most severe illness in
healthy young adults
Emerged 1997
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Avian Influenza (Bird Flu)

• Influenza A (H5N1) strain

• This is a disease of birds that started in
  chickens, ducks, fighting cocks and other
  birds in 10 Asian countries (China, Vietnam,
  Thailand with highest rate of infected
  animals). Virus has since expanded to multiple
  areas of world along avian migratory routes.
  Disease also seen in pigs less likely host
• Causes severe systemic disease in poultry

• H5N1 can mutate rapidly and has a propensity
  to acquire genes from viruses infecting
  other species. It causes severe disease in
  humans transmitted by saliva or feces of
  infected birds (visiting live poultry
  market, cleaning, defeathering or living with
  poultry in home setting).

• Symptoms fever, sore throat, cough, and in
  fatal cases severe respiratory distress
  due to pneumonia (of bacterial etiology) and
  multiorgan failure

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Avian Influenza (Bird Flu)

• Several cases of healthcare worker becoming
  infected with H5N1after caring for patient
  with disease, however, risk of transmission is
  felt to be low

• Limited data about disease in pediatrics and in
  pregnant women. Most of pediatric cases have
  been fairly mild. Only one case in pregnant woman
  who died from disease

• Since 1/1/04, 272 people have been infected and
  166 (61) have died. Humanhuman
  transmission has been confirmed but is rare.

• Organism resistant to Amantidine and
  Rimantidine
• Several cases of H5N1 disease in humans have
  been found to be resistant to Oseltamivir but
  were susceptible to Zanamivir

• Human vaccine in development Phase I clinical
  trials have begun in US and a completed in
  other countries there are multiple companies
  that are producing the vaccine

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Clinical Features of Avian Influenza Cases

• Median age 17.2 years (range 2 to 58 years)

• Incubation period 2 to 8 days all patients
  contracted disease from direct handling or
  expose to sick poultry (including handling
  fighting cocks, playing with poultry
  especially ducks, consumption of duck blood
  or undercooked poultry) usually during week
  before onset of illness

- Feeding of raw infected chickens to tigers and
leopards in zoos in Thailand have resulted in
animals becoming ill and dying with
transmission to uninfected animals

• Median time between onset of illness and
  hospitalization 5.8 days (range 1 to 8 days)

• Most common clinical signs/symptoms fever
  38.5ºC, cough, dyspnea, myalgias, malaise,
  sore throat, diarrhea, rhinorrhea, increased work
  of breathing, crackles

NEJM 20043501179-1188 NEJM 20053531374-1385
37
Chest Radiograph Findings of Avian Influenza Virus
Panel A Admission CXR Panel B CXR 24 hours
later
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Clinical Features of Avian Influenza Cases

• Most common laboratory abnormalities
  leukopenia (median total WBC count 2100/mm3),
  lymphopenia, thrombocytopenia (median platelet
  count 75,000/mm3), elevated transaminases, BUN
  and creatinine

- Increased risk of death associated with
leukopenia, lymphopenia and thrombocytopenia at
the time of hospital admission

• Chest radiograph findings extensive bilateral
  infiltrates, lobar and focal consolidation
  which progressively worsen throughout illness.
  Median time from onset of illness to ARDS is 6
  days (range 4 to 13 days)

- Multiorgan failure with renal dysfunction,
pulmonary hemorrhage, cardiac dilatation and
supraventricular tachyarrhythmias common in
severe cases

NEJM 20043501179-1188 NEJM 20053531374-1385
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Clinical Features of Avian Influenza Cases

• Mortality rate 52 - highest rates seen in
  infants and young children may be as high
  as 90.

- Death occurs an average of 9-10 days after
onset of illness most common cause is
progressive respiratory failure

• Diagnosis isolation of virus in culture or
  identification of virus by RT- PCR from nasal
  and throat swabs (throat swabs better specimen)

- Virus can be detected early as early as 2-3
days after illness onset due in part to very high
viral loads at least 10 times as high as
patients with human influenza A.

• Treatment aggressive supportive ICU care,
  oseltamivir

- broad-spectrum antibiotics and corticosteroids
have also been used effects unknown
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Investigational Anti-Influenza Agents
Novel neuraminidase inhibitors
- Peramivir (PO and IV) - A-315675
Long-acting topical neuraminidase
inhibitors Conjugated sialidase Hemagglutinin
inhibitors Small interfering RNA Polymerase
inhibitors Protease inhibitors
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Key Factors to Influenza Pandemic Readiness and
Control

• Surveillance need to be able to detect an
  outbreak rapidly at the source so it can be
  contained
• Authority must be in place to impose and
  enforce a quarantine at the first sign of
  human to human transmission
• Antiviral drugs and vaccines must be available
• Hospitals must be in a state of readiness to
  accommodate and treat majority of severely
  ill patients

At this point in time, the world is NOT READY to
handle a pandemic in any of the above areas
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Surveillance

• Currently, the surveillance systems worldwide
  in all countries are not adequate, especially
  in developing countries

• ALL COUNTRIES need to understand that if
  something happens anywhere in the world, with
  regards to an outbreak of pandemic influenza,
  THE ENTIRE WORLD IS AT RISK

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Authority for Enforcing Quarantine

• WHO has plan that calls for an immediate
  quarantine, freezing all traffic in and out
  of an infected area

- Also involves closing of all schools,
businesses and planned public gatherings

• Currently these measures can only be
  implemented by the various National
  goverments but require the active cooperation
  of the public

- In many developing countries, enforcement will
be left to military

• Worldwide, man power will be the major problem

44
Antiviral drugs and Vaccines

• Of currently available drugs only Oseltamivir
  (Tamiflu-PO) and Zanamivir (Relenza-inhaled)
  are effecive at preventing viral replication
• Most effective use will be in outbreak setting
  using ring of prophylaxis strategy
• WHO recommends that countries stockpile enough
  of these drugs to cover 10 of the population
  US needs 20-30 million courses, currently
  US has 2.3 million courses. US on long list of
  countries waiting to get more drug. Another
  major problem are individual citizens who are
  trying to stockpile drug.
• Several vaccines have been developed but
  vaccine is against strain of H5N1 that is not
  pandemic producing strain level of protection
  unknown
• Vaccine against pandemic strain can only be
  produced when strain emerges will need to
  produce enough vaccine in 6 months time to
  protect at least 300 million people here in US
• Current vaccine production capability is
  inadequate to accomplish this

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Readiness of Hospitals

• Place where at least 80 of the cases will
  present in US this is about 2 million or
  more persons
• Currently we are woefully under prepared we
  are unable to cope with patients presenting
  during a regular influenza season, during a
  pandemic this will be at least 100 times worst
• Example during pandemic, there may be 100s of
  1000s of patients that will need ventilatory
  support. The US has about 105,000
  ventilators with 75,000 in use at any given time
• All hospital pandemic plans that are in place
  are grossly insufficient much worse in
  developing countries

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Pandemic Planning Assumptions
Event Moderate pandemic
Severe pandemic
Illness 90 million
(30) 90 million
(30) Outpatient care 45 million
(50) 45 million
(50) Hospitalization
865,000
9,900,000 ICU care
128,750
1,485,000 Mechanical ventilation
64,875 745,500 Death
209,000
1,903,000
http//www.hhs.gov/pandemicflu/plan/part1.html
47
Increasing Pediatric and Adult Influenza
Immunization Rates Summary

• Influenza is a disease that continues to cause a
  lot of morbidity and a fair amount of mortality
  each year
• Influenza vaccine is an effective way of
  protecting the population against disease
• Immunization rates of high risk groups in the
  pediatric and adult populations are fairly low
• ACIP, AAP and AAFP now recommend the routine use
  of vaccine in children under 5 years of age
• More effective practice strategies and
  interventions must be used to achieve higher
  immunization rates in high risk groups
• The continued emergence of avian influenza virus
  as a serious public health threat to humans bears
  close monitoring as this may be the next
  influenza pandemic producing virus
• Vaccines against avian influenza virus (H5N1)
  are currently in development but effective
  vaccine can only be produced once pandemic strain
  emerges