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Influenza

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  • 1. Influenza Dr.T.V.Rao MD
  • 2. Influenza Virus belong to Myxovirus
    • Enveloped RNA virus
    • Absorb to mucoprotein receptors
    • Many viruses are included in this group
    • Influenza
    • Mumps
    • Measles.
    • Newcastle disease
    • Parainluenza virus
  • 3. Myxovirus
    • Classified into
    • 1 Influenza virus
    • 2 Parainluenza virus
    • A Mumps virus
    • B Parainluenza virus
    • C Measles virus
    • D Rspiratory syncitical virus
  • 4. INFLUENZA
    • Cause of the infection of the Respiratory tract.
    • Occurs as
    • Sporadic
    • Epidemic
    • Pandemic
    • Major pandemic in 1918 – 1919
  • 5. Published Pandemic Mortality Estimates for Selected Countries (Johnson NPAS & Mueller J. Bulletin of the History of Medicine (2002) 76:105-15) ( 1918: 28% of current global population . http://birdfluexposed.com/resources/NIALL105.pdf ) USA: 675,000 Bangl./ India/ Pak.: 18.5 million Nigeria: 455,000 Egypt: 139,000 Guatemala: 49,000 Afghan.: 320,000 Indonesia: 1.5 million Philip.: 94,000 Japan: 388,000 Brazil: 180,000 South Africa: 300,000 Kenya: 150,000 Global Total: 50 – 100 million (WHO: 40 million +) Russia/USSR: 450,000 Spain: 257,000 Canada: 50,000 Chile: 35,000 Australia: 15,000, in 1919 only British isles: 249,000
  • 6. Scientific contributions
    • Shoppe ( 1931 ) Isolated the Swine influenza
    • 1933 Smith, Andrews, Laidlaw identifies Etiological agent
    • Land mark in advances of Medical virology
    • 1935 Burnet developed chick embryo techniques
    • 1941 McClelland and Hare influenza virus tests showing agglutination of fowl erythrocytes
  • 7. WHO defines Influenza
    • Influenza is a viral infection that affects mainly the nose, throat, bronchi and, occasionally, lungs. Infection usually lasts for about a week, and is characterized by sudden onset of high fever, aching muscles, headache and severe malaise, non-productive cough, sore throat and rhinitis.
  • 8. Spread of Influenza
    • The virus is transmitted easily from person to person via droplets and small particles produced when infected people cough or sneeze.
    • Most infected people recover within one to two weeks without requiring medical treatment. However, in the very young, the elderly, and those with other serious medical conditions.
  • 9. Origin of Pandemics Influenza Migratory water birds H 1-16 N 1-9 Domestic pig Domestic birds (All human flu pandemics come from bird flu by 1 of 2 mechanisms)
  • 10. H16 XXXXXX (type A)
  • 11. Current incidence of Influenza
  • 12. Pandemics and Pandemic Threats of the 20 th Century
    • 1918-19 “Spanish flu” H1N1
    • 1957 “Asian flu” H2N2
    • 1968 “Hong Kong flu” H3N2
    • 1976 “Swine flu” episode H1N1
    • 1977 “Russian flu” H1N1
    • 1997 “Bird flu” in HK H5N1
    • 1999 “Bird flu” in HK H9N2
    • 2003 “Bird flu” in Netherlands H7N7
    • 2004 “Bird flu” in SE Asia H5N1
  • 13. Classification of Influenza virus
    • What are A B C
    • Classification on the basis of
    • Ribonucleoprotein Antigen and Matrix
  • 14. Reservoirs of Virus
    • Virus harbored as Asymptomatic infection
    • All isolates from Non human hosts harbor type A virus
    • Types B and C are exclusively common to Humans, Not identified in animals or birds
    • Plays a great role in emerging pandemics
  • 15. Influenza Virus
    • Virus are spherical in shape
    • Size is 80 -120 nm
    • Pleomorphism is common with variant forms
  • 16. Viral structure
    • Virus contains RNP in Helical symmetry
    • A negative sense Single stranded RNA genome is segmented into 8 segments
  • 17. Viral structure
    • The nucelocapsid is surrounded by an envelope with inner membrane protein layer and outer lipid
    • From the envelop there are projections of two types
    • 1 Hemagglutinins
    • 2 Neuraminidase
  • 18. Resistance of Virus
    • Inactivated by heating at 50 0 c for 30 mt
    • Survive for 1 week at 0 – 4 0 c for 1 week
    • Virus preserved at – 70 0 c
    • Survive in the blankets for 2 weeks
    • Ether, formaldehyde, Phenol destroy the virus
  • 19. Prominent Characters of the Virus
    • Hemagglutination Important character, when mixed with Fowl erythrocytes virus absorbed onto mucoprotein receptors on the cell surface
    • Links other cells produce Hemagglutination
    • Elution Detachment of virus from cell surface resisting Hemagglutination is called elution.
    • Caused by enzyme neuraminidase
    • Act on cell receptor splits off N – Acetylneuraminiase
  • 20. Hemagglutination defines the nature of the Virus
  • 21. Hemagglutination
    • Act with red cells of
    • different species
    • Type A and B – RBC’s of Fowl, Human and guinea pigs
    • Type C only RBC’s of Fowl at 40 c
    • Hemagglutination titer - Highest titer of virus with fixed quantity of RBC
    • Hemagglutination Inhibition titers convient way of measuring quantity o antibodies to virus.
  • 22. Antigenic Structure Influenza virus
    • Contains
    • Internal antigens
    • Surface antigens
    • Internal RNP antigen – Ribonucleic protein
    • It is a soluble antigen
    • Can be detected , complex fixation test and Immuno precipitation tests..
    • Anti RNP antibodies develop after natural infection, but not by killed vaccines
  • 23. Surface Antigens
    • V antigens of virus present on surface
    • V antigens are two types
    • Hemagglutinins
    • Neuraminidases
    • Hemagglutinins are of two polypeptides
    • HA 1 and HA 2
  • 24. Heamagglutination
    • Haemagglutinnins responsible for
    • Hemagglutination and Hem adsorption
    • Allows to absorb to mucoproteins on respiratory epithelium
    • Antihemagglutinin antibodies are produced following infection or Immunization
  • 25. Types of Haemagglutinnins
    • Hemagglutination is strain specific
    • Great variation
    • H A there are 15 subtypes H 1 to H15 in avian influenza
    • But only 4 variants in humans
  • 26. Neuraminidases
    • Neuraminidase are glycoprotein's
    • Destroys cell receptors by hydrolysis cleavage
    • Anti neuraminidase antibodies are produced following infection and immunization
    • Not protective as Antihemagglutinin antibodies
    • Helps to inhibit the release and spread of progeny
    • Strain specific exhibit variation, There are nine different subtypes N 1 – N9.
  • 27. Antigenic Variation
    • Unique feature of this virus lies with antigenic variation.
    • High in type A virus
    • Less in type B virus
    • Not in type C virus
    • RNP and Matrix proteins are stable
    • Hemagglutination and Neuraminidase are independ of the variations.
  • 28. Influenza prominent Antigenic Changes
    • Antigenic Shift
      • major change, new subtype
      • caused by exchange of gene segments
      • may result in pandemic
    • Example of antigenic shift
      • H2N2 virus circulated in 1957-1967
      • H3N2 virus appeared in 1968 and completely replaced H2N2 virus
  • 29. Influenza Antigenic Changes
    • Antigenic Drift
      • minor change, same subtype
      • caused by point mutations in gene
      • may result in epidemic
    • Example of antigenic drift
      • in 2002-2003, A/Panama/2007/99 (H3N2) virus was dominant
      • A/Fujian/411/2002 (H3N2) appeared in late 2003 and caused widespread illness in 2003-2004
  • 30. Antigenic Variations
  • 31. Antigenic Drift
    • Antigenic Drift
    • Gradual sequential change in antigenic structure
    • At regular intervals
    • New antigens react with
    • Antisera to the precursor virus strains
    • Occurs due to mutation and selection due to the presence of antibodies to previous infection.
  • 32. Antigenic Shift
    • It is abrupt and Drastic
    • Discontinuous variation in structure in antigens
    • Results in novel virus and unrelated to previous strains causing infections
    • Involves – Hemagglutinins, Neuraminidase or both
    • Subtypes depends only on antigenic shifts, occurs on Hemagglutinins
  • 33. Antigenic shift initiates Pandemics
  • 34. Mechanism of Antigenic Shift
  • 35. Terminology by WHO
    • Ao A1 A2 ( Asian ) A2 ( H K )
    • Ho H1 H2 H3
    • Designated on the Basis of
    • Type, Place of Origin, Serial Number,
    • Year of isolation – Followed by Antigenic subtypes of H and NA
    • A /Hong Kong / 1/68 ( H3 N2 )
  • 36. Host Range
    • Experimented in Animals
    • Spread through respiratory shredding
    • Respiratory disease in Ferrets
    • Intranasal passage in Mice
    • Infect the amniotic cavity of Allantioic and Amniotic fluids
    • Virus can be grown in primary monkey kidney and in continuous cell lines
  • 37. Pathogenesis
    • Infects the respiratory tract
    • Even 3 or few viral particles can infect
    • Neuraminidase facilitates infection reducing the viscosity of Mucous
    • Ciliated cells are infected in the Respiratory tract - site of viral infection
    • When superficial layers are damaged exposes the basal layers
    • And exposure of the basal layer causes the bacterial infections.
  • 38. Infection of cell in Influenza virus
  • 39.
    • Modes of Person-to-Person Transmission:
    • Large droplets from coughing, sneezing, & talking, to other’s eyes, nose, or mouth;
    • Contact : direct (hand-to-hand) & indirect (hand-to-surface-to-hand – less common?);
    • ? Airborne / aerosol / droplet
    Courtesy of CDC
  • 40. Pathogenesis – Viral Pneumonia
    • Thickening of the Alveolar cells
    • Intestinal infiltration with leucocytes with capillary thrombosis of Leucocytic exudates
    • Hyaline membrane is formed occupying alveolar ducts and alveoli
    • In late stages infiltration with Macrophages
  • 41. Clinical features
    • Incubation 1 to 3 days
    • Present with mild cold lead to fulminating rapidly fatal Pneumonia
    • Can abruptly present with head ache malign
    • Can also present with abdominal pain with type B in children
    • Bacteria superinfect
  • 42. Viral Pneumonia is Leading cause of Death
  • 43. Complications of Influenza
    • Bacterial super infections
    • Cardiac complications
    • Congestive heart failure
    • Myocarditis
    • Neurological involvement
    • Encephalitis
    • Type B virus can produce Reye’s syndrome
    • Degenerative changes in the Brain and Liver
    • Gastric flu with type B virus
  • 44. Complication in Influenza
    • Pneumonia
      • secondary bacterial
      • primary influenza viral
    • Reye’s syndrome
    • Myocarditis
    • Death 0.5-1 per 1,000 cases
  • 45. Influenza Diagnosis
    • Clinical and epidemiological characteristics
    • Isolation of influenza virus from clinical specimen (e.g., nasopharynx, throat, sputum)
    • Significant rise in influenza IgG by serologic assay
    • Direct antigen testing for type A virus
  • 46. Isolation of Virus
    • In the first 2 -3 days from gargle samples
    • Specimens inoculated into eggs, and Monkey kidney cells.
    • Eggs are inoculated into Amniotic and Allantoic cavity Grows at 37 0 C in 3 days
    • The virus causes Hemagglutination of Guinea pig and Fowl erythrocytes at 37 0 C
    • Type A and B agglutinate guinea pig and fowl red cells
    • Type C Hem agglutinates only Fowl cells
    • Cytopathic effects on Monkey Kidney and Continuous cell lines
    • RNA detection by RT – PCR
    • Immuno florescence – surface of Nasopharyngeal cells
  • 47. Serology
    • Compliment fixation test
    • Heamagglutination Inhibition testing
    • Testing on paired sera
    • Detection of Hemagglutination Inhibition testing
    • Radial immunodiffusion
  • 48. Immunity
    • After infection immunity lasts 1 to 2 years
    • Immunity lasts short duration due antigenic variants infecting at intervals.
    • Antibodies produced locally are effective IgA immunoglobulin.
    • Anti Hemagglutinins and Antinerumanidase are effective in prevention of infection.
  • 49. Original Antigenic sin
    • Repeated infections with different antigens varies will produce different antibodies
    • The antibodies produced in the first instance of infection continues to be produces even with variants.
  • 50. Epidemiology
    • Virus enters through respiratory route
    • In 3 – 4 days majority manifest
    • Many are subclinical infections
    • Type A produce pandemics
    • Type B sporadic cases, epidemics
    • Dangerous in the Temperate regions
    • Higher mortality in aged and patients with existing cardiopulmonary involvement
  • 51. WHO records the Pandemics
    • Probable in
    • 1173, 1889, 1918-1919
    • Major pandemic in 1918- 1919
    • 200 million affected
    • 20 million infected in India
    • 10 million dead in India
  • 52. Circulating Seasonal Influenza A Sub-Types from Pandemics of the 20 th Century 1920 1940 1960 1980 2000 H1N1 Seasonal Flu H1N1 Seasonal Flu H2N2 H3N2 Seasonal Flu 1918/19 1957/58 1968/69 40-100 million deaths ~2 million deaths ~1 million deaths 4 pandemics since 1889, with 11 to 39 years (average ~30 years) between each = ~3.3% annual risk of pandemic onset (but likely higher now)
  • 53. Camp Funston, Kansas, March 1918: Sadly, the comparatively benign first wave was not at all predictive of what was to come
  • 54.  
  • 55. Major recent Major Pandemics 1957 Asian flu H2 N2 1968 Hong Kong H3 N2 1977 China ( Red flu )
  • 56. What is Bird Flu
    • Avian Influenza in Animals
    • Only birds get infected
    • Less common Pigs
    • Avian influenza is species specific
    • Less common in Humans
    • Can spread from poultry to Humans can produce sever disease
  • 57. BIRD FLU
    • Birds, just like people, get the flu. Bird flu viruses infect birds, including chickens, other poultry and wild birds such as ducks. Most bird flu viruses can only infect other birds. However, bird flu can pose health risks to people.
  • 58. Bird flu can spread from Birds to Humans
    • The first case of a bird flu virus infecting a person directly, H5N1, was in Hong Kong in 1997. Since then, the bird flu virus has spread to birds in countries in Asia, Africa and Europe
  • 59. New strain Hon Kong H5 N1 strain
    • Originated in Hong Kong
    • 18 confirmed 6 dead
    • Can spread from Chicken to Humans
    • Wild aquatic birds spread.
  • 60. Wild Birds Migrate and spread the Disease Globally
  • 61. How Pandemics are Produced
    • Wild aquatic birds carry full repetoire of genes of Influenza virus strains.
    • Birds shed the viruses abundantly in feces
    • Which can contaminated the Rivers, and ponds
  • 62. Cycle of Events on spread
    • Wild Birds to Ducks to Pigs as they are susceptible to infection by both Human and Avian influenza.
    • Recombination takes place in Pigs,
    • Such Hybrid strains may lead to Human infections with potential pandemics.
  • 63. Role of Migratory Birds
    • Migratory birds can introduce low pathogenic H5 and H7 viruses to poultry flocks which can mutate to the highly pathogenic form.
    • Now known some migratory birds are spreading the infection
  • 64. What will happen with H5 N1
    • H5 N1 can spread and cause severe disease
    • Some have crossed the Poultry and produced severe disease and Deaths.
    • Rapid detoriation of patients and high fatality.
    • Severe Viral pneumonia multigrain failure are common
  • 65. Culling is the early option in control of Influenza
  • 66.  
  • 67.
    • WHO, May 2006:
    • “ In patients with
    • confirmed or
    • strongly suspected
    • H5N1 infection,
    • clinicians should
    • administer Oseltamivir
    • treatment as soon as
    • possible ( strong recommendation , very low quality
    • evidence ).” (Evidence = seasonal flu clinical trials in
    • humans & H5N1 animal data).
    • “ clinicians might administer a combination of
    • neuraminidase inhibitor & M2 inhibitor ” (weak
    • recommendation, very low quality evidence).”
    • ( Resistance to Tami flu is a concern.)
  • 68. Tamiflu! (oral) Ralenza (inhaled) (Older drugs) (Viral resistance to these is more common) (Injectable Peramivir has completed phase-1 trials)
  • 69. Prevention
    • WHO monitors the events on Influenza
    • Identifies the subtypes circulating all over the world.
    • Vaccine
    • Cocktail vaccine contains one or two types of A and type B virus of the previous winter months.
    • May contain upto 10 billion viral particles
  • 70. Influenza Vaccines
    • Inactivated subunit (TIV) vaccine
      • intramuscular
      • trivalent
      • split virus and subunit types
      • duration of immunity 1 year or less
    • Live attenuated vaccine (LAIV)
      • intranasal
      • trivalent
      • duration of immunity at least 1 year
  • 71. Recombinant vaccines
    • Growth from old established strains is retained
    • Surface antigens of New virus are incorporated.
  • 72. Composition of the 2008-2009 Influenza Vaccine*
    • A/Brisbane/59/2007 (H1N1)
    • A/Brisbane/10/2007 (H3N2)
    • B/Florida/4/2006
    *manufacturers may use strains that are antigenically identical to the selected strains
  • 73. Inactivated Influenza Vaccines Available in 2007-2008 *vaccines approved for children younger than 4 years +all multi-dose vials contain thimerosal as a preservative 0.5 mL 0.5 mL 0.25 mL Age-dependent Dose > 36 mos Single dose vial* > 36 mos Single dose syringe* 6-35 mos Single dose syringe* > 6 mos Multi-dose vial* + Fluzone (sanofi pasteur) Age Package Vaccine
  • 74. Inactivated Influenza Vaccines Available in 2007-2008 +all multi-dose vials contain thimerosal as a preservative > 18 yrs 0.5 mL Single dose syringe Afluria (CSL) > 18 yrs 0.5 mL Multi-dose vial + > 18 yrs 0.5 mL Multi-dose vial + FluLaval (GSK) > 18 yrs 0.5 mL Single dose syringe Fluarix (GSK) 0.5 mL Dose > 4 yrs Multi-dose vial + Fluvirin (Novartis) Age Package Vaccine
  • 75. Inactivated Influenza Vaccine Efficacy
    • 70%-90% effective among healthy persons younger than 65 years of age
    • 30%-40% effective among frail elderly persons
    • 50%-60% effective in preventing hospitalization
    • 80% effective in preventing death
  • 76. HIV Infection and Inactivated Influenza Vaccine
    • Persons with HIV at increased risk of complications of influenza
    • TIV induces protective antibody titers in many HIV infected persons
    • TIV will benefit many HIV-infected persons
    • Do not administer LAIV to persons with HIV infection
  • 77. Influenza Vaccine Recommendations
    • Healthcare providers, including home care*
    • Employees of long-term care facilities
    • Household contacts of high-risk persons
    *LAIV should not be administered to healthcare workers who have contact with severely immunosuppressed persons who require hospitalization and care in a protective environment
  • 78. Indication to Vaccinate
    • To all high risk groups
    • 1 Elderly,
    • 2 Chronic heart and Lung disease patients,
    • 3 Asthmatic patients
    • 4 Metabolic and, renal disease patients.
    • 5 HIV patients.
  • 79. Inactivated Influenza Vaccine Contraindications and Precautions
    • Severe allergic reaction to a vaccine component (e.g., egg) or following a prior dose of vaccine
    • Moderate or severe acute illness
    • History of Guillian Barre’ syndrome within 6 weeks following a previous dose of TIV (precaution)
  • 80. Emerging trends in Vaccines
    • A live attenuated Cold adopted temperature sensitive used as nasal spray on major trails.
  • 81. Created for benefit of Medical and Paramedical workers in Developing world Dr.T.V.Rao MD Email [email_address]