The influence of influenza

1
The influence of influenza
Janice K. Louie, MD, MPH California Department of
Public Health
2
Influenza virus
Influenza type
Hemagglutinin subtype
Year of isolation
A/California/7/04 (H3N2)
Geographic source
Isolate number
Neuraminidase subtype
3
Hemagglutinin Subtypes of Influenza A Virus
Subtype Human Swine Horse Bird H1 H2 H3 H4 H5 H6 H
7 H8 H9 H10 H11 H12 H13 H14 H15 H16
Adapted from Levine AJ. Viruses. 1992165, with
permission.
4
Neuraminidase Subtypes of Influenza A Virus
Subtype Human Swine Horse Bird N1 N2 N3 N4 N5 N6 N
7 N8 N9
Adapted from Levine AJ. Viruses. 1992165, with
permission.
5
Influenza Antigenic Changes

• Structure of hemagglutinin (H) and neuraminidase
  (N) periodically change
• Drift Minor change, same subtype
• Point mutations in gene May result in
  epidemic
• Shift Major change, new subtype
• Exchange of gene segment
• May result in pandemic

6
Mechanisms of Influenza Virus Antigenic Shift
15 HAs 9 NAs
Non-human virus
Human virus
Reassortant virus
7
Occurrence of Influenza Pandemics and Epidemics
Incidence of clinically manifest influenza Mean
level of population antibody vs A HxNx Mean level
of population antibody vs A HyNy
Pandemic
Pandemic
Interpandemic Period
Epidemic
Epidemic
Disease Incidence
Mean Population Antibody Level
Epidemic
1
2
3
4
5
6
7
8
9
10
11
12
Time in Years
Introduction of hypothetical A HxNx virus
Significant minor variation A HxNx may occur at
any of these points. Epidemics may or may not
be associated with such variations
Introduction of hypothetical A HyNy major (new
subtype) variant A HxNx disappears
Mandell, Douglas and Bennetts Principles and
Practice of Infectious Diseases, 5th ed.
20001829. Modified from Kilbourne ED. Influenza.
1987274, with permission.
8
Seasonal Influenza
9
Impact of Influenza-US

• 82 million infected annually
• 36,000 (range 8000-68,000) excess deaths per
  year
• 226,000 (range 55,000-431,000) excess
  hospitalizations per year
• Kills as many or more people than breast cancer
  and three times as many as HIV
• Higher mortality during seasons when influenza
  type A (H3N2) viruses predominate
• 90 of influenza-related deaths occur among
  persons gt65 years

Prevention and control of influenza
recommendations of the Advisory Committee on
Immunization Practices (ACIP), 2008. MMWR Recomm
Rep. 2008 Aug 857(RR-7)1-60.
10
Influenza-associated Hospitalizations
11
(No Transcript)
12
The Burden of Pediatric Influenza High
Infection Rates

• Children have higher rates of infection than
  adults
• 40 of preschool children can be involved in an
  epidemic
• 30 of school children can be involved in an
  epidemic
• Children can be the primary vector in the family

Neuzil KM, et al. N Engl J Med. 2000342225.
13
Influenza Epidemic in the Community
National Institute of Allergy and Infectious
Diseases, 12/97.
14
Onset of Influenza A
-1
0
1
2
3
4
5
6
7
8
23
Days After Inoculation
100
Temp F
99
97
Illness
Headache, Malaise, Myalgia
Nasal Obstruction and Discharge,Throat Pain,
Cough
Adapted from Mandell GL, Bennett JE, Dolin R,
eds. Mandell, Douglas and Bennetts
Principlesand Practice of Infectious Disease.
5th ed. 20001831.
15
Signs and Symptoms of Influenza
Type of Symptoms Children lt5 yrs Adults Elderly Re
spiratory ? Rhinitis ? Nonproductive cough ?
Nasal obstruction ? Sore throat ? Sore
throat Constitutional or ? Fever ? Rapid onset ?
Fever gt99.0F systemic ? Vomiting of
symptoms ? Lassitude ? Diarrhea ? Fever, usually
gt100F ? Confusion ? Chills/sweats ?
Headache ? Myalgia ? Potentially severe,
persistent malaise ? Substernal soreness,
photophobia and ocular problems
16
Laboratory Diagnosis

• Commercial rapid tests (ELISA)
• Direct fluorescent antibody (DFA)
• Viral culture
• Polymerase chain reaction (PCR)
• Serology (HIA and neut)

17
Sensitivity of Rapid Antigen Detection Tests
Using cell culture as the gold standard Monto
et al, Antiviral Res 2002(55)227-278.
18
Influenza Routes of Transmission

• Poorly characterized
• Common large droplets (sneezing, coughing,
  contact with saliva)
• Probably common contact
• Direct
• Fomite
• Rare airborne

19
Infection Control in Hospitals

• Droplet Precautions (surgical mask-within 3 feet)
• Contact Precautions (gloves, gown)
• Eye protection
• Standard Precautions (hand hygiene)

20
Influenza Vaccine
Content Updated yearly to protect
against anticipated strains, consists of type A
(2) and type B (1) Process Grown in
embryonated chicken eggs and formalin
inactivated Record 170 million doses available
for 2008-09 season
21
Timetable for interpandemic vaccine production
22
2009-2010 Northern Hemisphere Influenza Vaccine
Recommendations

• A/Brisbane/59/2007 (H1N1)-like virus
• A/Brisbane/10/2007 (H3N2)-like virus
• B/Brisbane/60/2008-like virus

23
The global circulation of seasonal influenza A
(H3N2) viruses. Russell CA et al. Science. 2008
Apr 18320(5874)340-6
24
Prevention and control of influenza
recommendations of the Advisory Committee on
Immunization Practices (ACIP), 2008. MMWR Recomm
Rep. 2008 Aug 857(RR-7)1-60.
25
Prevention and control of influenza
recommendations of the Advisory Committee on
Immunization Practices (ACIP), 2008. MMWR Recomm
Rep. 2008 Aug 857(RR-7)1-60.
26
(No Transcript)
27

• Randomized blinded trial of 340 healthy women
  vaccinated in the 3rd trimester
• Mothers and infants followed for 24 weeks after
  birth
• Results showed
• - lower risk of laboratory-confirmed influenza
  in infants by 63
• - lower risk of any febrile respiratory illness
  in infants (20) and mothers (36)

28

• Elderly persons have diminished immune response
• Most studies of elderly have been observational
  and varied greatly in conclusions
• Advantages of this study
• - Large dataset 18 HMO cohorts and 713,872
  person-seasons
• - Over 10 flu seasons, including mismatch years
• - Multiple sites (MN, WI, WA, NYC)
• - Multiple attempts to control for bias
• Conclusions influenza vaccination reduced the
  risk of hospitalization by 27 and death by 48

29
Move to Universal Vaccination

• Recognition of suboptimal vaccine effectiveness
  among groups at highest risk for influenza
  complications (e.g. elderly, persons with chronic
  illness)
• Potential for reducing community transmission
  through vaccinating school children and healthy
  adults if high coverage can be achieved
• Better understanding of health and economic
  impact of influenza among older children and
  adults
• Lessened concerns about vaccine supply
• Increased concern about an influenza
  pandemic-need to lean how to vaccinate an entire
  population against influenza.
• Belief that current low coverage for most
  recommended groups might be improved by a simple
  universal recommendation

30
Proposed ACIP Timeframe

• 2007-08 Expand recommendations to include all
  school age children (5-18 year olds)
• 2010-2011 Expand recommendations to include
  household contacts and caregivers of school-aged
  children
• 2012-2013 Expand to universal vaccination

31
Antivirals Adamantanes and Neuraminidase
Inhibitors
NA inhibitors
HA blockers
32
Adamantanes

• Inexpensive
• Amantadine 0.60/pill
• Rimantidine 2.20/pill
• Not effective against influenza B
• Resistance due to a single point S31N
  substitution in the M2 protein
• gt90 of currently circulating influenza A/H3
• Usefulness for monotherapy of seasonal influenza
  now unclear

33
(No Transcript)
34
Treatment with Neuraminidase Inhibitors

• Oseltamivir 75 mg bid x 5 days
• Zanamivir (gt7 yrs)10 mg inhaled bid
• Evidence for effectiveness based on studies of
  outpatients with uncomplicated influenza
• If treatment begun within 48 hours of onset of
  symptoms, reduction in symptoms by 1 day
• Inconsistent data, but likely reduces viral
  shedding

MMWR July 13, 2007 / 56(RR06)1-54
35
(No Transcript)
36
Oseltamivir Treatment Benefits Retrospective
Cohort Studies

• Reduction in risk of otitis media
• Reduction in development of pneumonia.
• Reduction in secondary use of antibiotic therapy.
• Reduction in risk of hospitalization.
• Decreased length of stay.
• Reductions in severity of outbreak due to
  laboratory-confirmed influenza in older residents
  of long term care facilities when given
  oseltamivir with 48 hours of onset. Treated
  patients were significantly less likely to
• Be prescribed antibiotics.
• Hospitalized
• Fatal outcome

Nordstrom et al, Curr Med Res Opin 2005 21(5)
71. Lee et al, Antiviral Therapy 12 501. Barr
et al, Curr Med Res Opin 2007 23(3) 523.
Orzeck et al, Clin Ther 2007 29 (10)
2246. Blumentals et al, Curr Med Res Opin
200723(12) 2961. Bowles et al, J Am Geriatr
Soc 200750 (4) 608.
37
Toronto Invasive Bacterial NetworkProspective
Cohort Study

• Significant reduction in mortality in highly
  vaccinated population (71) of adults and
  children with laboratory confirmed influenza
  (odds ratio 0.21, CI 0.06-0.80). Benefit seen
  even when oseltamivir started gt48 hr after onset.
• Significant reduction in mortality in small
  number of adults admitted to ICU for
  laboratory-confirmed influenza (none treated
  within 48 hours of onset)

McGeer et al, Clin Infect Dis 2007451568, ICAAC
2007.
38
(No Transcript)
39
Moscona, A. Global transmission of
oseltamivir-resistant influenza. N Engl J Med.
2009 Mar 5360(10)953-6. Epub 2009 Mar 2
40
(No Transcript)
41
Swine influenza 2009
42
Typical influenza illness-like in 2
childrenCalifornia

• CDPH notified April 14, 2009
• Case Patient A, San Diego county. March 30, 2009
• Previously healthy 10 year old boy with fever,
  cough, vomiting x 1 week
• No exposure to pigs
• Mother and brother had respiratory illness
  preceding case patient
• Flew to Dallas, Texas on April 3rd while febrile
• Case Patient B, Imperial county. March 28, 2009
• Previously healthy 9 year old girl with fever to
  104F and cough x 1 week
• No direct exposure to pigs
• Attended state fair where pigs exhibited but
  never saw pigs
• Traveled to Mexicali, Mexico 2 weeks prior
• 13 year old brother and 13 year old cousin with
  respiratory symptoms

43
Typical influenza-like illness in 2
childrenCalifornia

• Cases occurred 80 miles apart
• Samples collected by different people at
  different times
• Samples never went through the same lab
• Both cases positive for influenza A by PCR but
  untypeable for human H1 or H3
• Reference testing at CDC swine flu A/H1N1

44
Early Confirmed Cases of SIV
No known epidemiologic link between the Texas and
California cases
Case Patient A Flew to Dallas, Texas
Number of Confirmed Cases
45
Mexicali
46
(No Transcript)
47
April 24, 2009
48
(No Transcript)
49
WHO Definition of a Pandemic

• Isolation from humans of an influenza A virus
  with a novel hemagglutinin or a novel
  hemagglutinin and neuraminidase gene, and
  susceptibility (lack of antibody) to this novel
  virus in a large proportion of the population.
• Demonstrated ability of the virus to replicate
  and cause disease.
• Efficient transmission from person-to-person.

50
WHO Pandemic Influenza stages
51
Swine influenza in swine

• Swine influenza first identified in 1930
• Endemic in pig herds throughout the world
• Herd level seroprevalence 50-90
• Cause respiratory symptoms (cough, runny nose,
  lethargy, decreased feeding)
• Secondary bacterial infections common
• Herds often vaccinated

52
Human Swine influenza-US (2005- 2008)

• 11 human cases identified since 2005 by CDC
• Median age 10 years (range 16 mo-48 yrs)
• Four with underlying illness (asthma,
  immunosuppression, excema)
• Mild upper respiratory illness common (diarrhea
  in 30 four hospitalized and two adults required
  mechanical ventilation
• 9 had direct or indirect pig exposure at
  farms/fairs
• All had genetically similar viruses commonly
  circulating in pigs
• All triple reassortant viruses

53
Human Swine Influenza

• Literature review interspecies transmission
  well documented
• Recent review of 37 human civilian cases from
  1976 through 2006
• Median age 24.5 years
• 22 (61) reported direct pig exposure (2- lab
  workers)
• Case fatality rate 6/17 35
• All had pneumonia
• Underlying illnesses leukemia (1), Hodgkins
  (1), pregnant (1),
• Known swine exposure in 22/36 (61)
• 5/14 unexposed- family cluster exposed to person
  with direct exposure
• Person-to-person spread documented, though most
  dead-end transmissions

Myers KP et al Clin Infect Dis 20074 1084-88
54
(No Transcript)
55
Serosurveys of Occupationally-Exposed Persons

• 17 swine farmers, 11 vets (Myers et al, CID
  2006)
• 23 swine farmers (Olsen EID 2002)
• 7 vets, 135 abbatoir workers vs 0.4 general
  population (Schnurrenberger ARRD 1970)

56
Non-occupational Exposures

• Petting zoos
• Agricultural fairs
• Animal markets

57
Current Swine Influenza Outbreak-US

• Mostly mild influenza-like illness
• Person-to-person transmission
• Triple re-assortant strain not seen before in US
• hemagluttanin gene classical North American
  swine
• neuraminidase (2) and matrix (M) genes Eurasian
  swine
• polymerase genes of avian and human origin
• US, Mexico and other strains identical
• Resistant to adamantane drugs mostly sensitive
  to neuraminidase inhibitors

58
(No Transcript)
59
Spring/Summer 2009 Summary09/09/09

• Total Cases Reported 43,771 (April 25-July 23,
  2009)
• Total Hospitalizations Reported 9,079 (53 SLTT
  affected)
• Total Deaths Reported 593 (43 SLTT affected)

60
(No Transcript)
61
(No Transcript)
62
(No Transcript)
63
(No Transcript)
64
(No Transcript)
65
Underlying conditions among those hospitalized
and those who have died from H1N1 compared to the
general populationDeath and Hospitalization Case
Series Spring/Summer 2009
66
(No Transcript)
67
(No Transcript)
68
Laboratory Diagnosis

• Commercial rapid tests (ELISA)
• Direct fluorescent antibody (DFA)
• Viral culture
• Polymerase chain reaction (PCR)
• Serology (HIA and neut)

69
Pandemic Influenza Vaccine

• Grown in embryonated chicken eggs and
  formalin-inactivated
• Five manufacturers in US
• CSL
• Novartis (/- adjuvant)
• Sanofi
• GlaxoSmithKline
• Medimmune
• Small safety trials ongoing
• Pandemic influenza vaccine campaign will be
  concurrent with seasonal influenza vaccine
  campaign
• 120 million doses seasonal
• 190 million doses H1N1

70
Pandemic Influenza Vaccine

• Priority groups include
• Children 6 months- 24 years of age (100 million)
• All pregnant women (4 million)
• Health care and emergency services personnel (10
  million)
• All persons aged 25-64 years with medical
  conditions associated with higher risk of severe
  influenza (34 million)
• All household contacts of children younger than 6
  months of age (4 million)

71
(No Transcript)
72
Antiviral resistance
WHO 21 sporadic cases of oseltamivir resistance
with H275Y mutation. Of these, 12-post-exposure
prophylaxis, 4- long term oseltamivir treatment
in immunosuppressed cases. Two cases never
recieved Tamiflu.
73
Current Pandemic (H1N1) Recommendations

• Monitor for influenza-like illness (fever
  gt100.0F PLUS cough and/or sore throat)
• In the absence of reliable point-of-care tests,
  diagnosis of influenza relies on the astute
  clinician.
• Patients with high risk for complications or who
  are hospitalized should be treated with a
  neuraminidase inhibitor.
• All ACIP risk factors, including
  immunosuppression, neuromuscular disease, obesity
• Start treatment ASAP, mortality benefit even if
  started gt48 hours from onset.
• Use double dose if severely ill or obese.

74
Current Pandemic (H1N1) Recommendations

• If hospitalized for influenza like illness, admit
  to respiratory isolation
• Collect respiratory specimen for PCR and
  subtyping
• For persistent symptoms or clinical
  deterioration, retest. If PCR still positive-gt
  resistance testing
• Immunosuppressed patients- consider isolation
  until PCR negative

75
Infection Control in Hospitals

• Airborne Isolation in negative pressure room
• Fit-tested N95 respirator
• Contact Precautions (gloves, gown)
• Eye protection
• Standard Precautions (hand hygiene)

76
Respiratory Etiquette
77
Current Challenges

• Limited resources
• Who gets tested?
• Who gets antivirals?
• Who uses N95 masks? (and are they needed?)
• Lack of information about characteristics of this
  novel virus
• Who is at risk for complications?
• Who is at risk for development of antiviral
  resistance?
• How can we stop the virus if it mutates into a
  more deadly strain?
• Seasonal influenza vaccine provides no
  cross-protection
• Limited global vaccine manufacturing capacity
• Overwhelming logistics of mass vaccination
• Repercussions from failed swine flu vaccine
  campaign in 1976

78
Extra slides
79
(No Transcript)
80
Live Attenuated Influenza Vaccine (FluMist)
www.flumist.com/
81
LAIV vs TIV efficacy age 24-59 months2004-05
season
Overall culture confirmed
Matched and mismatched strains
Belshe RB et al. N Engl J Med. 2007 Feb
15356(7)685-96
82
LAIV versus TIV adults

• 2004-05 (mismatch- H3 and some B)
• Healthy adults age 18-46 yrs in community (year
  1) TIV more effective than LAIV (77 vs 57),
  mostly due to poor efficacy for B (but study
  underpowered to analyze specific efficacy by
  type)
• 2005-06 (match with predominant H3 strain some B
  mismatch)
• Healthy adults age 18-46 yrs in community (year
  2)
• Similary efficacy between TIV and LAIV (16 vs
  8), but low activity and attack rates makes
  comparison difficult

Ohmit SE et al, N Engl J Med. 2006 Dec
14355(24)2513-22, Ohmit SE et al, J Infect
Dis. 2008 Aug 1198(3)312-7.
83

• Three season study
• Over 1 million military recruits aged 17-49 years
• Highly vaccinated population followed for
  encounters for pneumonia and influenza
• Variable rates of vaccination with LAIV in some
  seasons
• Vaccination with TIV was associated with fewer
  medical encounters (including hospitalizations)
  compared with LAIV or no immunization.
• Among vaccine-naiive, LAIV efficacy more robust
  and comparable with TIV.
• Conclusions preexisting vaccine immunity
  important to LAIV efficacy