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Aniruddha Chatterjee, MD

Influenza Virus
Acute respiratory illness caused by infection with influenza viruses Family Orthomyxoviridae Types - Influenza A, B & C viruses Influenza A & B viruses - most commonly cause human disease

Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrison's principles of internal medicine, 17th edition,. New York: McGraw-Hill Medical Publishing Division, 2008:749.

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Influenza A Virus
NA HA
PB1 M1 M2

PA

PB2

RNA NP

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Cox R.J et al., Scandinavian Journal of Immunology 2003; 59: 115

Components of Influenza Virus


Hemagglutinin (H or HA)
Site by which virus binds to sialic acid cell receptors Allows virus to adhere to epithelial cells in respiratory tract Immune responses to H antigen are major determinants of protection against infection

Neuraminidase (N or NA)
Degrades the receptor Allows release of newly formed viruses from infected cell Immune responses to N antigen limit viral spread & contribute to reduction of infection

M1 protein
Matrix protein which forms the viral capsid Stabilization of lipid envelope and in virus assembly

M2 protein channel
Functioning as an ionchannel (energy regulators)

Ribonucleoprotein
RNA (genetic code) Nucleoprotein (NP)

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Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrison's principles of internal medicine, 17th edition,. New York: McGraw-Hill Medical Publishing Division, 2008:749.

Types of Influenza Virus


Influenza A Host Range Humans Swine Equine Avian Influenza B Humans only Influenza C Human Swine

Epidemiology
Clinical Features

Antigenic Shift Antigenic Drift


May cause large pandemics with significant mortality in young persons

Antigenic Drift only

Antigenic Drift

Severe disease Mild disease generally confined to without older adults or seasonality person at high risk

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Mandell: Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7th ed.

Influenza Virus Transmission

Mainly Airborne Aerosols (Coughs & Sneezes). Through direct contact : Animate or Inanimate. Incubation Period 18 72 h
Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrison's principles of internal medicine, 17th edition,. New York: McGraw-Hill Medical Publishing Division, 2008:749.

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Natural Hosts of Influenza Viruses

(H1-H15) Haemagglutinin Subtypes


Neuraminidase Subtypes (N1-N9)

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Nicholson K. G. Influenza. Lancet 2003; 362: 173345

Epidemiology
Influenza outbreaks recorded virtually every year Global pandemics have occurred at variable intervals Most extensive & severe outbreaks caused by influenza A viruses Pandemics provide most dramatic evidence of impact of influenza A
Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrison's principles of internal medicine, 17th edition,. New York: McGraw-Hill Medical Publishing Division, 2008:749.

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Influenza : Adverse Imapct

Important cause of Morbidity & Mortality in:


Elderly. Children aged < 2 years. People with underlying chronic medical conditions:
Chronic cardiac & pulmonary diseases. Hyperreactive Airway Disease, Cystic Fibrosis. Nephrotic Syndrome , Immunodeficiency states. Pregnancy!

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Zuccotti et al. Expert Opin. Biol. Ther. 2011; 11 (1): 89-98

Influenza : Burden
As per World Health Organization : 3-5 million cases of severe influenza illness annually in industrialized countries, resulting in:

Zuccotti et al. Expert Opin. Biol. Ther. 2011; 11 (1): 89-98

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Situation Update in India Dec 2010

Laboratory confirmed cases 46,142 Confirmed death 2,728

http://mohfw-h1n1.nic.in

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Influenza Pandemics
1918 1957 1968 1977 2009

Spanish Severe Asian Severe Pandemic Pandemic H1N1 H2N2 50 million dead 2 million dead

Hong kong Moderate Pandemic H3N2 1 million dead

Mild Pandemic

Pandemic Novel H1N1 18449 dead

Since 1977, viruses of H1N1, H3N2 have circulated outbreaks of varying severity

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Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrison's principles of internal medicine, 17th edition,. New York: McGraw-Hill Medical Publishing Division, 2008:749.

Influenza A Epidemics
Begin abruptly, peak over 2- to 3-week period. Generally last for 23 months & subside rapidly. Temperate zones - during winter months . Tropics - throughout the year. Children with febrile respiratory illnesses, Influenza-like illnesses among adults. Hospital admissions - pneumonia, worsening of CHF & exacerbations of chronic pulmonary disease.
Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrison's principles of internal medicine, 17th edition,. New York: McGraw-Hill Medical Publishing Division, 2008:749.

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Influenza B Outbreaks
Less extensive Less severe disease Less variation in subtypes Most frequently seen in schools and military camps

Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrison's principles of internal medicine, 17th edition,. New York: McGraw-Hill Medical Publishing Division, 2008:749.

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Influenza

Clinical Manifestations

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Clinical Manifestations
Abrupt onset of systemic symptoms: Complications most frequently in:
Headache, feverishness, chills, myalgia, or malaise, cough & sore throat. Elderly>64 years. Chronic underlying medical disorders. Pregnancy , more so in 2nd or 3rd trimester. Children <2 years old

Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrison's principles of internal medicine, 17th edition,. New York: McGraw-Hill Medical Publishing Division, 2008:749.

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Complications Pulmonary Complications:


Extrapulmonary complications:
Reyes syndrome Myositis, Rhabdomyolysis Encephalitis Guillain-Barre syndrome

Pneumonia (secondary bacterial pneumonia). ARDS.

Post Influenza Depression

Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrison's principles of internal medicine, 17th edition,. New York: McGraw-Hill Medical Publishing Division, 2008:749.

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Influenza : Prevention
Three time tested methods:
Avoid the Source. Remove the source. Strengthen your defences.

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Preventive Steps to Stop Spread

Cover nose & mouth during cough or sneeze. Wash hands often with soap and water. If soap and water not available, use alcohol-based hand rub. Avoid touching eyes, nose & mouth. Try to avoid close contact with sick people. If sick with flulike illness :

While sick, limit contact with others as much as possible.


http://www.cdc.gov/flu/protect/preventing.htm

Stay home for at least 24 hours after fever is gone except to get medical care or for other necessities.

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Prevention of Influenza

Most effective strategy for preventing influenza and its complications is : Annual Vaccination

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Prevention of Influenza
Vaccines

Inactivated Influenza Vaccine (TIV)


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Live-attenuated Influenza Vaccine (LAIV)

Comparison of TIV with LAIV


Factor Route of administration Type of vaccine No. of virus strains Vaccine virus strains updated Frequency of administration Approved age Interval between 2 doses recommended for children aged 6 mos8 yrs who are receiving influenza vaccine for the first time Can be given to persons with medical risk factors for influenza-related complications Can be given to children with asthma or children aged 24 yrs with wheezing in the past yr Can be administered to family members or close contacts of immunosuppressed persons requiring a protected environment (e.g., hematopoietic stem cell transplant recipient) If not administered simultaneously, can be administered within 4 weeks of another live vaccine TIV Intramuscular/ deep subcutaneous Killed virus 3 (2 influenza A, 1 influenza B) Annually Annually Persons aged 6 months 4 wks LAIV Intranasal spray Live virus 3 (2 influenza A, 1 influenza B Annually Annually Persons aged 249 yrs 4 wks

Yes Yes Yes

No No No

Yes

Prudent to space 4 wks apart

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CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2009;58[No. RR-8]

Historical Development in Influenza Vaccination

Whole virus vaccine (1945)

Split virus vaccine (1964)

Subunit vaccine (1976)

Wood JM, Williams MJ. Textbook of Influenza 1998; pg no 317-323.

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Subunit vs Split Vaccines


Jenning et al.1:
Significantly less local reactions with Subunit vaccine compared to Split vaccine

Review & meta-analysis of literature by Beyer et al.2:


Subunit vaccines showed a significant lower frequency of local and systemic reactions than split and whole vaccines
1. Jenning R. et al., Vaccine 1984; 2: 75-80 2. Beyer et al., Clin. Drug Invest. 1998 Jan; 15 (1): 1-12

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Basic concept of Influenza vaccination

Current vaccine trivalent preparation Influenza A (H1N1), Influenza A (H3N2), Influenza B viruses Protection is achieved Blymphocytes (antiHA and anti-NA antibodies). Specific immunity persists from 6 to 12 months

Vaccination
Serum antibodies peak between 2 & 4 months after vaccination but fall quickly

Vaccination can begin as soon as vaccine is available


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Mandell: Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7th ed.

Influenza Vaccine
Clinical Efficacy

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Benefits of Influenza Vaccination

43% reduction in absenteeism from work. 25% reduction in frequency of upper respiratory tract illness. Considerable cost savings. Reduction in mortality in those with chronic illnesses.
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Szucs T, J Antimicrobial Chemotherapy, 1999, 44: 11-15

Benefits of Influenza Vaccination in Healthy Adults & Children

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Nichol KL. The efficacy, effectiveness and cost-effectiveness of inactivated influenza virus vaccines. Vaccine 2003; 21:17691775.

Benefits of Influenza Vaccination in Elderly

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Nichol KL. The efficacy, effectiveness and cost-effectiveness of inactivated influenza virus vaccines. Vaccine 2003; 21:17691775.

Benefits of Influenza vaccine Elderly Persons

Effectiveness in hospitalizations & mortality


Outcome Hospitalizations for Respiratory Conditions Pneumonia & Influenza Mortality Pneumonia & Influenza All Cause
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Vu T, et al. Vaccine 2002; 20: 1831.

Effectiveness

30% (25% - 35%) 33% (27% - 38%)

47% (25% - 62%) 50% (45% - 56%)


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Immunogenicity in Healthy Adults, Elderly

Vaccine is Immunogenic in Healthy Adults & Elderly. Seroprotection rates for all 3 virus strains:
Healthy adults - 80 90% Elderly - > 70%

Mean fold increase [geometric mean of the intra-individual fold increases in HI titre (GMT)] for all 3 virus strains
Healthy adults > 10 Elderly > 6

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Zuccotti et al., Influvac, a trivalent inactivated subunit vaccine. Expert Opin. Biol. Ther 2011; 11 (1): 89:98

Benefits of Influenza Vaccination - Stroke

Two casecontrol studies involving:


90 and 370 patients with stroke
Influenza vaccination in previous year associated with ~50% reduction in odds of stroke
Grau AJ, Urbanek C, Palm F Nat Rev Neurol. 2010 Dec;6(12):681-94. Epub 2010 Nov 9.

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Benefits of Influenza Vaccination Cardiac Diseases

Significant reduction in risk of hospitalization:


Cerebrovascular disease, Cardiac disease or Pneumonia

Guidelines recommendation:
Coronary or other atherosclerotic vascular disease should be immunized with inactivated influenza vaccine
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Grau AJ, Urbanek C, Palm F Nat Rev Neurol. 2010 Dec;6(12):681-94. Epub 2010 Nov 9.

Benefits of Influenza Vaccination - VTE

Case-control study involving 1,454 adults Protective effect of vaccination was similar for deep venous thrombosis and pulmonary embolism Conclusion of the study:
Influenza vaccination associated with reduced risk of VTE
Thromb Haemost. 2009 Dec;102(6):1259-64.

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Benefits of Influenza Vaccination -Type 1 Diabetes

Immunogenicity and reactogenicity in type I diabetes (9 30 years, n=53) Met CPMP requirement one month postvaccination:
High Seroprotection rates (>95%) for strains A/H1N1 and A/H3N2 Seroprotection of 70% in subunit vaccine for strain B Safe & adequately immunogenic against 3 influenza vaccine strains
Zuccotti et al., Long-lasting immunogenicity of a virosomal vaccine in older children and young adults with type I diabetes mellitus. Vaccine 2009 Aug 27;27(39):5357-62 Committee on Proprietary Medicinal Products (CPMP)

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Effectiveness of Vaccine in Children


Influenza-like Infections in children participating in a mass vaccination programme compared with control communities

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Ghendon YZ, Kaira AN, Elshina GA, The effect of mass influenza immunization in children on the morbidity of the unvaccinated elderly, Epidemiol Infect, 2006;134:718

Safety in Asthmatic Patients

Cochrane review of 9 trials (aged 2 years or older):


No significant increase in asthma exacerbations immediately after vaccination

Vaccination in asthmatic children is recommended Randomized double-blind placebo-controlled trial in 696 asthmatic children aged 6-18 yrs
Moderate beneficial effect on quality of life
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Bueving HJ Influenza vaccination in asthmatic children: effects on quality of life and symptoms. Eur Respir J. 2004; 24 (6): 925:931 Cates CJ, Jefferson TO, Bara AI, Rowe BH. Vaccines for preventing influenza in people with asthma (Cochrane review). Cochrane Database Syst Rev. 2004;(2):CD000364.

Comparison between Influenza Vaccines

Randomized, three-arm, parallel group, multi-centre trial in 386 elderly subjects Immunogenicity & Safety of 3 vaccines:
Split Viron Vaccine MF59-adjuvanted subunit influenza vaccine Virosomal subunit influenza vaccine

Conclusion:

All have similar immunogenicity Virosomal subunit and Split Viron vaccines- less reactogenic than MF59-adjuvanted vaccine in elderly. Adjuvanted Vaccine not cleared for use in children and in pregnancy.
De Bruijn et al. Antibody induction by virosomal, MF59-adjuvanted, or conventional influenza vaccines in the elderly. Vaccine 2007; 26: 119-127.

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Influenza Vaccine : Which Strains?

How does WHO determine which strains are put into influenza vaccine?
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WHO Global Influenza Surveillance Network


Make Recommendation on Influenza Vaccine Twice Annually
Antigenic & Genetic analyses WHO Collaborating Centres Serological Studies Diagnostic reagents Vaccine Strains Potency testing reagents National Licensing Agencies

Isolation of representative strains from clinical samples

National Influenza Centres

Disease and Epidemiological Data


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Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrison's principles of internal medicine, 17th edition,. New York: McGraw-Hill Medical Publishing Division, 2008:749.

Composition for 2011-2012 - WHO

an A/California/7/2009 (H1N1)-like virus 15 g HA/dose an A/Perth/16/2009 (H3N2)-like virus - 15 g HA/dose a B/Brisbane/60/2008-like virus - 15 g HA/dose

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Flu Vaccine Indications

Person aged > 65 years All children between 6 months to 8 years. Children age between 8 years to 18 years who receive long-term aspirin containing medications Adult and children with:
Chronic disorders such as HAD (Asthma), COPD, heart, renal, diabetes and people with immunodeficiencies.
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Flu Vaccine in Pregnant Women

Flu vaccine may be considered from 2nd trimester of pregnancy. Administration of vaccine is recommended, irrespective of their stage of pregnancy in:
Pregnant women with medical conditions that increase risk of complications from influenza.

The American College of Obstetricians & Gynecologists and the American Academy of Family Physicians
Recommend routine vaccination of all pregnant women.
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Flu Vaccine Dosage & Administration

Adults and Children from 36 months: 0.5 mL. Children from 6 to 35 months: 0.25 mL/0.5 mL limited clinical trial data. Children not previously vaccinated: 2nd dose given after 4 weeks interval. Route of administration: Intramuscular or deep subcutaneous injection.
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Influenza
Treatment

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Influenza treatment:
Antiviral drugs

Antiviral drugs to treat influenza:


M2-channel inhibitors
Amantadine Rimantadine

Neuraminidase inhibitors
Zanamivir (inhalation) Oseltamivir

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Mandell: Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7th ed.

Influenza treatment:
Antiviral drugs

Opportunity to impact viral replication with antiviral agents is limited Drug resistance
Limits use of antiviral agents

Effective use requires early initiation of therapy:


Greatest effect seen when therapy started in the first 24 h

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Mandell: Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7th ed.

Influenza

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Is all general population at risk for flu?

Influenza viruses cause disease among persons in all age groups . Rates of infection are highest among children.

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http://www.cdc.gov/flu/about/qa/misconceptions.htm. Accessed 09 August 2011 CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2009;58[No. RR-8]

I never get sick, I don't need a flu shot


Are you Really sure?

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Why

need it?

Some persons can be infected with flu virus but have no symptoms. May pass on flu to someone else before you know you are sick, as well as while you are sick. It's worth considering for flu vaccine, even if you're young and healthy. Cost-Effectiveness:
Reduces health care, societal, productivity losses & absenteeism associated with flu illness.
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http://www.cdc.gov/flu/about/qa/misconceptions.htm. Accessed 09 August 2011 CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2009;58[No. RR-8]

Can the seasonal flu vaccine provide protection even if the vaccine is not a good match?

Antibodies created through vaccination with one strain of influenza viruses will often offer protection against related strains of influenza viruses. So even though circulating influenza viruses may drift or change from the time the vaccine composition is recommended, the vaccine may cross-protect against circulating viruses. The influenza vaccine contains three virus strains; so the vaccine would still protect against the other two viruses. This is particularly important in people at high risk for serious flurelated complications and for close contacts of high risk people.
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Is there a need for general population to get vaccinated?


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http://www.cdc.gov/flu/about/qa/misconceptions.htm. Accessed 09 August 2011

disease. Influenza Is a Highly infectious

Flu has Significant morbidity and mortality. Vaccination decreases transmission of flu from caregivers and household contacts to persons at high risk.

CDC recommends:

Annual vaccination - all persons aged 6 months Children aged 6 months till 8 years to get 2 doses to provide adequate protection during first season.

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CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2009;58[No. RR-8]

Unexpected Benefits
Reduction in Streptococcus Pnemoniae cases. Reduction in Otitis Media. Benefit to Grandparents!

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What kind of flu vaccines are there ?


There are two influenza vaccines:
The flu shot is an inactivated vaccine (containing killed virus) given with a needle and injected into the muscle. Nasal-spray flu vaccine (LAIV for Live Attenuated Influenza Vaccine).
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Can we use LAIV?


Not recommended for children below 2 years Side effects in kids. Not for use in pregnancy. No data about vaccine uptake in Indian scenario.

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Can a flu shot give you the flu?

TIV contains inactivated viruses.


Cannot cause flu

France EK et al.
No increase in clinically important medically attended events during 2 weeks after inactivated influenza vaccination children aged <18 years.
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http://www.cdc.gov/flu/about/qa/misconceptions.htm. Accessed 09 August 2011 France EK, Glanz JM, Xu S, et al. Safety of the trivalent inactivated influenza vaccine among children: a population-based study. Arch Pediatr Adolesc Med 2004;158:10316

Why?

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http://www.cdc.gov/flu/about/qa/misconceptions.htm. Accessed 09 August 2011

Reasons
Exposed to one of influenza viruses in vaccine shortly before getting vaccinated. Ill from non-flu viruses. Weakened immune systems
Flu vaccine can still help prevent complications.
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http://www.cdc.gov/flu/about/qa/misconceptions.htm. Accessed 09 August 2011

There will be side effects...


Some individuals do not feel well after getting the seasonal flu shot. Most commom and mild side effect of seasonal flu shots is soreness at the site. Rare symptoms - fever, muscle pain & feelings of discomfort or weakness. DO NOT USE IN PATIENTS ALLERGIC TO EGGS!!
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http://www.cdc.gov/flu/about/qa/misconceptions.htm. Accessed 09 August 2011

Northern or Southern ?
Year round surveillance. Strains specific for Northern or Southern Hemisphere. Tropics as in India have 2 spikes of Flu season. No data yet.
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Why do we need to get vaccinated every year?

Influenza viruses continually undergo antigenic drift changes. Specific immunity persists from 6 to 12 months.

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CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2009;58[No. RR-8]

If strains are same as last year

Do we still need to give the shot this

year?

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Euro surveillance , Volume 16, Issue 7, 17 February 2011. Surveillance and outbreak reports EFFECTIVENESS OF TRIVALENT SEASONAL AND MONOVALENT INFLUENZA A (H1N1) 2009. VACCINES IN POPULATION WITH MAJOR CHRONIC CONDITIONS OF NAVARRE, SPAIN: 2010/11. MID-SEASON ANALYSIS.

It's too late to get the vaccine this season


Everyone 6 months or more of age. Flu epidemics

Should get flu vaccine as soon as vaccines are available.


Occur in winter months in Northern hemisphere (India follows WHO recommendation).

Protective antibody titres by 2 weeks postvaccination


90% of subjects.
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CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2009;58[No. RR-8]

Infant got only one dose last year


Such children NEED two shots this year , one to two months apart for proper immunity

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How much to use in kids ?

0.25ml or 0.5ml ?

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Flu vaccine in high-risk children

TIV - recommended for high-risk children from 6 months of age. Effective in children at high risk of complications of flu including :
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Asthma & other chronic respiratory diseases, impaired immune response & cystic fibrosis.
Giezeman K. European Paediatrics, 2010;4: 2-8

What if Im pregnant or breastfeeding ?


Vaccination of pregnant women protects women and newborns. Flu Shot in Pregnancy prevents severe ILI in infants by 91%
The American College of Obstetricians and Gynecologists and the American Academy of Family Physicians: Recommend routine vaccination of all pregnant women.

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Giezeman K. European Paediatrics, 2010;4: 2-8

CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2009;58[No. RR-8]

Does immunity wane before end of season if vaccinated against seasonal flu early in season?

Flu vaccination provides protection against influenza strains through one influenza season. 90% of subjects have protective antibody titers by 2 weeks postvaccination. Vaccination can begin as soon as vaccine is available.
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http://www.cdc.gov/flu/about/qa/misconceptions.htm. Accessed 09 August 2011

There's nothing I can do to prevent the flu


Try to avoid close contact with sick people. Avoid touching eyes, nose & mouth. Wash hands - soap and water or use alcohol-based hand rub. Seasonal influenza vaccine provides best protection available from seasonal flu.
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http://www.cdc.gov/flu/about/qa/misconceptions.htm. Accessed 09 August 2011

Is the stomach flu really the flu?

Loosely used term to describe illnesses with nausea, vomiting or diarrhea.


Caused by many different viruses, bacteria or food poisoning. Rarely main symptoms of influenza.

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http://www.cdc.gov/flu/about/qa/misconceptions.htm. Accessed 09 August 2011

Conclusion
Influenza vaccination:
Overall considered best way to prevent infection & related complications Proved to be substantially efficacious in all studies:
Seroprotection rates met CPMP serological criteria for immunogenicity in all age group

Efficacy & safety in all target populations have been demonstrated by several studies & post-marketing surveillance.

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Please, please WASH hands with soap & water. And do a favor to your family and patients: And if sick with ILI, take rest till fever has gone!
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