…and in flew enza - new jersey immunization...
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…and In Flew EnzaThe Never Ending Story
Peter N. Wenger, MD
Division of Pediatric Infectious Diseases
Department of Pediatrics
Saint Peter’s University Hospital
“I had a little bird.His name was Enza.
I opened the window,and in flew Enza.”
A popular chant during the 1918 influenza epidemic
Emergency Hospital, 1918 Influenza
Pandemic, Camp Funston, Kansas
Courtesy of the National Museum of Health and Medicine, AFIOP, Washington, D.C., Image NCP 1603
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Influenza
Acute febrile respiratory disease– Abrupt onset of fever, malaise, and myalgia followed by
respiratory symptoms– Duration: 5-7 days– Respiratory (droplet and droplet nuclei) and contact transmission– Incubation Period: 1-4 days, average: 2 days
– Adults shed virus typically from 1 day before through 5 days after onset of symptoms
– Children shed normally more and longer than adults, with a range from 6 days before to 14 days after onset of symptoms
Yearly cycles– Temperate climates: Late fall through winter
Influenza Sign/Symptom Children Adults Elderly
Cough (nonproductive) ++ ++++ +++
Fever +++ +++ +
Myalgia + + +
Headache ++ ++ +
Malaise + + +++
Sore throat + ++ +
Rhinitis/nasal congestion ++ ++ +
Abdominal pain/diarrhea + – +
Nausea/vomiting ++ – +
++++ Most frequent sign/symptom; + Least frequent; – Infrequent
Monto AS et al. Arch Intern Med. 2000;160:3243-47. Cox NJ et al. Lancet. 1999;354:1277-82.
Clinical Manifestations by Age Group
Influenza Complications
Loughlin J et al. Pharmocoeconomics. 2003;21:273-283. Treanor JJ. Influenza virus. In: Mandell GL, Bennett
JE, Dolin R, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 5th ed.
Philadelphia, PA: Churchill Livingstone; 2000:1823-1849. ACIP. MMWR 2004;53 (RR06):1-40.
Complications Children Adults
Frequent complications
Sinusitis, bronchitis, bronchiolitis, pneumonia, croup, acute otitis media
Primary viral pneumonia, secondary bacterial pneumonia, sinusitis, bronchitis
Rare complications
Encephalopathy, myositis, rhabdomyolysis, myocarditis, pericarditis, Reye syndrome, sepsis-like syndrome
Myositis, rhabdomyolysis, myocarditis, pericarditis
Exacerbations of underlying disease
Cardiovascular, diabetes, asthma, cystic fibrosis
Cardiovascular, diabetes, asthma, COPD
Influenza Surveillance Systems United States
Centers for Disease Control and Prevention (CDC)
World Health organization (WHO) collaborating laboratories
National Respiratory and Enteric Virus Surveillance System (NREVSS)
US Outpatient Influenza Surveillance Network (ILINet)
Outpatient visits for influenza-like illness (ILI)
Biosense surveillance system
Includes ED visits due to ILI
122 Cities Mortality Reporting System
Influenza-Associated Pediatric Mortality Reporting System
National Notifiable Disease Surveillance System (NNDSS)
Novel influenza A
CDC. MMWR. Influenza Activity-US and Worldwide, June 13-September 25 2010.59(39); 1270-73. October 8, 2010.
Deaths* (1976-2007)3,349 (’86-’87)-48,614 (’03-’04)
Average = 23,6079.0 per 100,000 persons
(range, 1.4-16.7)
Hospitalizations*117,000 – 816,000
Infections and illnesses50-60 million
Physician visits~25 million
Thompson WW et al. JAMA. 2003;289:179-186; Thompson WW et al. JAMA. 2004;292:1333-1340;
Couch RB. Ann Intern Med. 2000;133:992-998; Patriarca PA. JAMA. 1999;282:75-77; ACIP. MMWR.
2004;53(RR06):1-40.
Influenza Disease Burden in the US in an Average Year
* CDC. Estimates of deaths associated with seasonal influenza, US. 1976-2007. MMWR August 27, 2010;59(33):1057-62.
Estimates of Death Associated with Seasonal Influenza, United States, 1976-2007*
Age-specfic estimates
<19 years of age
Estimated annual average: 124 (range, 57 [1981-82] to 197 [1977-78])
Rate: 0.2 deaths per 100,000 (range, 0.1-0.3)
19-64 years of age
Estimated annual average: 2,385 (range, 504 [1981-82] to 4,752 [2003-04])
Rate: 1.5 per 100,000 persons (range, 0.4-3.1)
≥65 years of age
Estimated annual average: 21,098 (range, 2,344 [1986-87] to 43,727 [2004-05]
Rate: 66.1 per 100,000 persons (range, 8.0 – 121.1)
89.4% of influenza-associated mortality
*CDC. Estimates of deaths associated with seasonal influenza, US. 1976-2007. MMWR August 27, 2010;59(33):1057-62.
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Virology
Family Orthomyxoviridae
• Segmented RNA virus
Three distinct types
• Influenza A
• Influenza B
• Influenza C
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Anatomy of the Influenza Virus
Polymerase (P) Proteins
Hemagglutinin (HA)
Neuraminidase (NA)
M2
Nucleoprotein (NP)
M1
Adapted from: Hayden FG et al. Clin Virol. 1997:911-42.
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Virology
Envelope glycoproteins
Hemagglutinin (H or HA)
Viral attachment to host cells
Cleaved by host cell proteases
16 highly divergent, antigenically distinct HAs in Influenza A
H1-3 have caused epidemic and pandemic activity in man since 1900
H1-16 may be found in avian spp
Anti-HA antibody protects against infection and disease in homologous virus
Some degree of protection vs strains demonstrating drift within a subtype
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Virology
Envelope glycoproteins
Neuraminidase (N or NA)
Cleaves sialic acid from viral and host cell membranes
Prevents virus-virus aggregation
Prevents virus-host cell surface retention
Nine antigenically distinct NAs identified in Influenza A
N1-2 have caused epidemic and pandemic activity in man since 1900
N1-9 may be been found in avian spp
Anti-NA antibodies reduces efficient virus release from host cells
Does not prevent infection
Decreased severity of illness
Decreased viral shedding
22Cox NJ, Subbarao K. Lancet. 1999;354:1277–82.
Shift
Major change, new subtype
Exchange of gene segments
Occurs in A subtypes only
May cause pandemic
Example: H3N2 replaced
H2N2 in 1968
Drift
Minor change, within subtype
Gradual accumulation of amino
acid changes in HA and/or NA
Occurs in A and B subtypes
May cause epidemic
Example: drifted A/H3N2/Fujian
circulated vs. A/H3N2/Panama
(vaccine strain) in 2003/04
Occurs infrequently
Occurs continuously
Antigenic Shift & Drift
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Animal StrainCurrent Circulating Human Strain
Co-infect cells
Reassortment Leading to Pandemic Strain
PB1PB2PAHA
NA
NP
M
NS
PB1PB2PAHA
NA
NP
M
NS
Animal Strain HA and NA
PB1PB2PAHANANPMNS
Antigenic Shift
From HumanStrain
New Pandemic Strain
Avian Influenza
Do not usually infect humans, but human infection has occurred
Illness in humans ranges from mild to severe
Associated with contact with infected birds
Saliva, mucous and feces
Person-to-person transmission is rare
Limited, inefficient and not sustained
Three types of avian influenza known to infect humans
H5, H7 and H9
Swine Influenza
4 variant virus infections (influenza A H3N2v) reported by CDC the week of August 7, 2016
Exposure to pigs at state fairs the week preceding onset of illness
Ohio (2), Michigan (2)
Respiratory, contact, or possibly fomite transmission
Illness similar to seasonal flu
Hospitalization and death may occur
CDC recommends that people at high risk for serious flu complications avoid pigs and swine barns at fairs
Influenza ImmunizationHistory
Pandemics consistent with influenza described since the 16th century
Influenza virus first isolated in 1933
Development of vaccine followed quickly
Military
Commercial vaccine approved in the US in 1945
Ability to produce millions of doses annually
Grow large quantities of virus in eggs
Elucidation of the physical properties of the virus
Development of the principles of chemical deactivation
Influenza ImmunizationHistory
1970’s
Subviron or split virus preparations
Solvent (ether or a detergent) used to dissolve viral lipid envelop
Less reactogenic than whole cell preparations
Monovalent, bivalent, trivalent, quadrivalent, and pentavalent preparations
Since 1978
Trivalent vaccines: A(H1N1), A(H3N2), B virus
2003 – approval of live, attenuated influenza vaccine (LAIV)
Mimics wild type infection
Broader, longer lasting protection
Same components as the inactivated vaccine
Inactivated Vaccine Live Attenuated
Influenza Vaccine (LAIV)
FDA-approved Since 1960s Since 2003
Route of administration
Intramuscular Intranasal
Immunity Primarily humoral Mucosal and humoral
VirusSplit-virus or subunit inactivated virus (HA)
Cold-adapted, temperature-sensitive, live attenuated virus
Growth Medium Chick embryos Chick embryos
Indication Persons 6 monthsHealthy persons 2–49
years
Ruben FL. Clin Infect Dis. 2004;38:689-91. cdc.gov/nip/publications/pink/flu.pdf.
Currently Available Influenza Vaccines
Changes in Influenza Vaccine Nomenclature
TIV is now IIV3 (Inactivated Influenza Vaccine Trivalent)avvines
Standard and high-dose
High-dose formulation: approved for those > 65 years of age
ccIIV3 (cell culture IIV3)
Small amount of egg protein
approved for those > 18 years of age
RIV3 (Recombinant Influenza Vaccine)
No egg protein
approved for those > 18 years if age
IIV4 (Inactivated Influenza Vaccine Quadrivalent)
intramuscular and intradermal administration
intradermal: approved for those 18 through 64 years of age
LAIV4 (Live Attenuated Influenza Vaccine Quadrivalent)
Only form of the live attenuated vaccine
Healthy people 2 through 49 years of age
2014-15 season – preferred vaccine for ages 2 – 8 years
2016-2017 Influenza Vaccine
Contains:
A/California/7/2009(H1N1)pdm09-like virus
A/Hong Kong/4801/2014(H3N2)-like virus
B/Phuket/3073/2013-like virus (B/Yamagata lineage)
B/Brisbane/60/2008-like virus (B/Victoria lineage)
Vaccine Virus Selection Process
At least 6 months to produce large quantities of vaccine
some manufacturers begin growing one or more vaccine viruses in January based on a best guess
142 national influenza centers in 113 countries
established in 1948
year-round surveillance
study influenza disease trends
send influenza viruses to the 5 World Health Organization (WHO) Collaborating Centers for Reference and Research on Influenza
Atlanta, Georgia, USA (CDC)
London, UK (National Institute for Medical Research)
Melbourne, Australia (Victoria Infectious Diseases Reference Laboratory)
Tokyo, Japan (National Institutes for Infectious Diseases)
Beijing, China (National Institute for Viral Disease Control and Prevention)
WHO recommends specific viruses for inclusion in the upcoming season’s vaccines
Bi-annual meetings
February – Northern Hemisphere
September – Southern Hemisphere
Individual countries make final decision for vaccines licensed in their country
USA: USFDA
Selection Criteria
Surveillance data
circulating viruses
Forecasts
predictions for upcoming seasons
Availability of a good vaccine virus candidate
similarity to predicted circulating strains
ability to grow in select pathogen-free chicken eggs or canine kidney cells
Vaccine viruses must be tested and available in time to allow for full-scale production
Adjusted Vaccine Effectiveness Estimates, 2005-2015
Influenza
Season
Study
Site(s)
No. of
Patients
Adjusted
Overall VE (%)
95%
CI
2004-05 WI 762 10 -36, 40
2005-06 WI 346 21 -52, 59
2006-07 WI 871 52 22, 70
2007-08 WI 1914 37 22,49
2009-10 WI, MI, NY, TN 6757 56 23, 75
2010-11 WI, MI, NY, TN 4757 60 53, 66
2011-12 WI, MI, PA, TX,
WA
4771 47 36, 56
2012-13 WI, MI, PA, TX,
WA
6452 49 43, 55
2013-14 WI, MI, PA, TX,
WA
5990 51 43, 58
2014-15 WI, MI, PA, TX,
WA
4913 23 7, 29
http://www.cdc.gov/flu/professional/vaccination/effectiveness-studies.htmhttp
Preliminary Influenza Vaccine Effectiveness, United States, 2015 – 2016 Season
Overall vaccine effectiveness (VE) – 59%
H1N1pdm09 – 51%
All influenza B viruses – 76%
B/Yamagata lineage of B viruses – 79%
http://www.cdc.gov/media/releases/2016/flu-vaccine-60-percent.html
Advisory Committee on
Immunization (ACIP)
Recommendation
February 24, 2010
• Advisory Committee on Immunization Practices (ACIP)
Universal immunization for all persons ≥6 months of age
• Published in the MMWR
August 6, 2010
Volume 59; RR-08
ACIP Votes Down Use Of LAIV
For 2016-17 Flu Season Recommend annual flu vaccination with
either IIV or RIV for all >6 months
Poor or relatively lower effectiveness of LAIV from 2013 through 2016
• Preliminary data on the effectiveness of flu vaccine among children, 2 years through 17 years during the 2015-16 season vs any flu virus
LAIV: 3% (-49%-37%)
IIV: 63% (52%-72%)
Special Considerations
Vaccination in Children, 6 months through 8 years of age
• In those who have previously received >2 doses of tri- or quadrivalent vaccine need 1 dose this season
Previous doses do not have to be given in the same or consecutive seasons
• For those who received <1 dose of vaccine need 2 doses of vaccine, separated by at least 4 weeks, this season
Contraindications and
Precautions All vaccines should be administered in settings in
which personnel and equipment for rapid recognition and treatment of anaphylaxis are available
Contraindications• Severe allergic reaction to any component of the vaccine
or to a previous dose of influenza vaccine
Precautions• Moderate or severe acute illness with or without fever
Give asap on recovery
• History of Guillian-Barrè Syndrome within 6 weeks of vaccine administration Generally do not give if not at high risk for complications
Egg Allergy
History of egg allergy and experienced only hives after exposed• No contraindication
IIV or RIV3 (in those > 18 years of age)• No data on use of LAIV
Observe for > 30 minutes for signs of reaction
History of reactions to eggs including angioedema, respiratory distress, lightheadedness, or recurrent emesis or required epinephrine or another emergency medical intervention• RIV3 if meet criteria• If RIV3 is not available or doesn’t meet criteria then give IIV by physician
with experience in the recognition and treatment of severe allergic reactions
• Observe for > 30 minutes for reaction
Suspicion of egg allergy secondary to previous allergy testing but no known exposure to eggs• RIV3 if meets criteria• If RIV3 is not available or doesn’t meet criteria then consultation with a
physician with expertise in the management of allergic conditions should be obtained before vaccination
http://www.cdc.gov/flu/fluvaxview/nifs-estimates-nov2015.htm
Impact of Influenza in Healthcare Personnel (HCP)
HCP are often involved in hospital-acquired influenza outbreaks– Many HCP continue to work while ill, exposing both co-
workers and patients
Mean excess hospital costs associated with a case of hospital-acquired influenza - $7500– Mortality: 6%-8%
Large-scale HCP absenteeism during outbreaks compromises patient safety
Improved HCP vaccination rates associated with decreased hospital-acquired influenza in both acute care and long-term care facilities
Indirect Benefits of Influenza Vaccination of Healthcare Personnel with TIV
Mortality of residents was significantly reduced (10% vs 17%)
in nursing homes where the staff was vaccinated (SV)
compared to facilities where they were not (S0)
Potter J et al. J Inf Dis. 1997;175:1-6.
Vaccine groups
SV (n=490)
SO (n=561)(P=0.0009)
To
tal
pati
en
t m
ort
ality
(%
)
Time in days
0 20 40 60 80 100 120 140
0
10
20
Influenza Vaccination in Healthcare Personnel (HCP)
Since 1986
Healthcare infection Control Practices Committee (HICPAC) and the Advisory Committee on Immunization Practices (ACIP)
Recommends all healthcare personnel receive annual influenza vaccination
Healthy People 2020 target of 90% of HCP receive influenza vaccination
http://www.cdc.gov/flu/fluvaxview/hcp-icp-nov2015.htm
http://www.cdc.gov/flu/fluvaxview/hcp-icp-nov2015.htm
http://www.cdc.gov/flu/fluvaxview/hcp-icp-nov2015.htm
http://www.cdc.gov/flu/fluvaxview/hcp-icp-nov2015.htm
Professional Societies Recommending Annual Influenza Vaccination for Healthcare Personnel
American Academy of Family Physicians (AAFP)
American College of Physicians (ACP)
American Medical Directors Association (AMDA)
American Public Health Association (APHA)
Infectious Disease Society of America (IDSA)
National Foundation for Infectious Diseases (NFID)
Society for Healthcare Epidemiology of America (SHEA)
American Academy of Pediatrics (AAP)
American Hospital Association (AHA)
American Pharmacists Association (APhA)
Association of Professionals in Infection Control and Epidemiology, Inc. (APIC)
National Business Group on Health
National Patient Safety Foundation (NPSF)
Anti-Influenza Medications
Neuraminidase inhibitors
Recommended for use in the US by USFDA during the 2015-16 influenza season
Anti-viral resistance to neuraminidase inhibitors is currently low this season
Oseltamivir (Tamiflu®)
Oral
Influenza A and B
Treatment in any age
Prophylaxis in those >3 months of age
Adverse events
Nausea and vomiting
Post-marketing reports include:
Serious skin reactions
Sporadic transient neuropsychiatric events: self-injury and delirium
Anti-Influenza Medications
Neuraminidase Inhibitors
Zanamivir (Relenza®)
Inhalation
Influenza A and B
Treatment in those > 7 years of age
Not recommended for those with underlying respiratory disease (e.g., asthma, COPD)
Prophylaxis in those > 5 years of age
Not recommended for those with underlying respiratory disease (e.g., asthma, COPD)
Adverse reactions
Allergic reactions
Oropharyngeal or facial edema
Diarrhea, nausea, sinusitis, bronchitis, cough, headache, dizziness, URT infections
Anti-Influenza Medications
Neuraminidase inhibitors
Peramivir (Rapivab®)
Intravenous
Influenza A and B
Treatment in those > 18 years of age
Not recommended for prophylaxis
Adverse reactions
Diarrhea
Post-marketing reports include:
Serious skin reactions
Transient neuropsychiatric events: self-injury and delirium
Anti-Influenza Medications
Recommendations for influenza antiviral treatment
As early as possible for the following with confirmed or suspected influenza:
Hospitalized patients
Patients with severe, complicated, or progressive disease
Patients at higher risk of complications
High Risk Factors for Complications from Influenza Infection
Children < 2 years of age
Adults > 65 years of age
Persons with immunosuppression, including ttat caused by medications or by HIV infection
Pregnant women or those in within 2 weeks of delivery
Persons < 19 years of age and receiving long-term aspirin therapy
American Indians/Alaskan Natives
Morbidly obese (BMI > 40)
Residents of nursing homes and other chronic care facilities
High Risk Factors for Complications from Influenza Infection
Those with the following conditions:
Chronic pulmonary conditions, including asthma
Cardiopulmonary conditions except isolated hypertension
Renal, hepatic, and hematological (including sickle cell disease) conditions
Metabolic conditions including diabetes mellitus
Neurologic and neurodevelopmental conditions
Disorders of the brain, spinal cord, peripheral nerves, and muscle
Cerebral palsy, epilepsy, stroke, intellectual disability, moderate to severe developmental delay, muscular dystrophy, spinal cord injury
“There’s nothing more
predictable about flu
than it’s unpredictability”Arnold MontoEpidemiologist
University of Michigan School of Public Health
