Dr.T.V.Rao MD 2 Myxovirus• Classified into 1 Influenza virus 2 Parainluenza virus A Mumps virus B Parainluenza virus C Measles virus D Respiratory syncytial virus
Dr.T.V.Rao MD 3 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
Dr.T.V.Rao MD 4 Historically Speaking• Influenza can be traced as far back as 400 BC• In Hippocrates‟ Of the Epidemics, he describes a cough outbreak that occurred in 412 BC in modern- day Turkey at the turn of the autumn season
Dr.T.V.Rao MD 5 Early Recognized Pandemics• The first recognized pandemic occurred in July and August of 1510 when an outbreak of “gasping oppression” appeared nearly everywhere at once. It was described as a “„gasping oppression‟ with cough, fever, and a sensation of constriction of the heart and lungs”, leaving an impression strong enough for people to write of it decades later (Morens et al, 2010). At least seven contemporary and near-contemporary reports exist of the 1510 pandemic (Morens, North & Taubenberger, 2010).
Dr.T.V.Rao MD 6 1918 Spanish Flu A great Memorable Event• Mortality was greater than the 4-year “Black Death” Bubonic Plague• Mortality rate was 2.5%, other epidemics had been 0.1%• Unusually, most deaths associated with young, healthy adults• Researchers isolated a wide selection of bacteria – virus for influenza unknown • Years later, H1NI strain found responsible for infection • However, bacteria responsible for the severe secondary complications of pneumonia causing death
Dr.T.V.Rao MD 7 Circulating Seasonal Influenza A Sub-Types from Pandemics of the 20th Century 1918/19 1957/58 1968/69 40-100 million deaths ~2 million deaths ~1 million deaths H3N2 Seasonal Flu H2N2 H1N1 Seasonal Flu H1N1 Seasonal Flu 1920 1940 1960 1980 20004 pandemics since 1889, with 11 to 39 years (average ~30 years) between each = ~3.3% annual risk of pandemic onset (but likely higher now)
Camp Funston, Kansas, March 1918: Sadly, the comparatively Dr.T.V.Rao MD 8benign first wave was not at all predictive of what was to come
Dr.T.V.Rao MD 9 INFLUENZA• Cause of the infection of the Respiratory tract.• Occurs as Sporadic Epidemic PandemicMajor pandemic in 1918 – 1919
Dr.T.V.Rao MD 10 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
Dr.T.V.Rao MD 11 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.
Dr.T.V.Rao MD 12 Spread of Influenza• The virus is transmitted easily from person to person via droplets and small particles produced when infected people cough or sneeze.
Dr.T.V.Rao MD 13Most recover few Suffer • 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.
Dr.T.V.Rao MD 14 Origin of Pandemics Influenza (All human flu pandemics come from bird flu by 1 of 2 mechanisms)Migratory water birds H 1-16 Domestic pig N 1-9 Domestic birds
Dr.T.V.Rao MD 15 Where do “new” HA and NA come from?• >13 types HA• 9 types NA • all circulate in birds• pigs • avian and human
Dr.T.V.Rao MD 16Where do “new” HA and NA come from?
Dr.T.V.Rao MD 17Current incidence of Influenza
Dr.T.V.Rao MD 18Pandemics and Pandemic Threats of the 20th 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
Dr.T.V.Rao MD 19 Structure of Virion HA - hemagglutinin NA - neuraminidase helical nucelocapsid (RNA plus 100 n m NP protein) lipid bilayer membrane polymerase complexInfluenza virions are SMALL. The average eukaryotic cell diameter is 10,000 nm (10 microns), which is 100 times bigger than the influenza virion diameter. M1 protein http://www.med.sc.edu:85/pptvir2002/INFLUENZA-2002.ppt
Dr.T.V.Rao MD 20 Influenza Virus• Virus are spherical in shape• Size is 80 -120 nm• Pleomorphism is common with variant forms
Dr.T.V.Rao MD 21Viral structure A negative sense Single stranded RNA genome is segmented into 8 segments
Dr.T.V.Rao MD 22 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 Hem agglutinins• 2 Neuraminidase
Dr.T.V.Rao MD 23 Resistance of Virus• Inactivated by heating at 500c for 30 mt• Survive for 1 week at 0 – 40c for 1 week• Virus preserved at – 700c• Survive in the blankets for 2 weeks• Ether, formaldehyde, Phenol destroy the virus
Dr.T.V.Rao MD 24 Prominent Characters of the Virus• Haemagglutination Important character, when mixed with Fowl erythrocytes virus absorbed onto mucoprotein receptors on the cell surface Links other cells produce Haemagglutination• Elution Detachment of virus from cell surface resisting Haemagglutination is called elution. Caused by enzyme neuraminidase Act on cell receptor splits off N – Acetylneuraminiase
Dr.T.V.Rao MD 25Haemagglutination defines the nature of the Virus
Dr.T.V.Rao MD 26 HN terminology• H refers to Haemagglutinnins types and each is given a number H1, H2 etc,• Neuraminidase is designated N and different forms are available as well e.g. H5N1 (avian) and H1N1.• Different combinations of H and N glycoproteins give rise to different strains
Dr.T.V.Rao MD 27 Haemagglutination• 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 40c• Haemagglutination titer - Highest titer of virus with fixed quantity of RBC• Haemagglutination Inhibition titers convenient way of measuring quantity o antibodies to virus.
Dr.T.V.Rao MD 28 Types of Haemagglutinnins• Haemagglutination is strain specific• Great variation• H A there are 15 subtypes H 1 to H15 in avian influenza• But only 4 variants in humans
Dr.T.V.Rao MD 29 Neuraminidases• Neuraminidase are glycoproteins• 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.
Dr.T.V.Rao MD 30 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• Haemagglutination and Neuraminidase are independent of the variations.
Dr.T.V.Rao MD 31 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
Dr.T.V.Rao MD 32 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
Dr.T.V.Rao MD 35 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 – Haemagglutinnins, Neuraminidase or both• Subtypes depends only on antigenic shifts, occurs on Haemagglutinnins
Dr.T.V.Rao MD 37 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 )
Dr.T.V.Rao MD 38 Host Range• Experimented in Animals• Spread through respiratory shredding• Respiratory disease in Ferrets• Intranasal passage in Mice• Infect the amniotic cavity of Allantois and Amniotic fluids• Virus can be grown in primary monkey kidney and in continuous cell lines
Dr.T.V.Rao MD 40 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.
Dr.T.V.Rao MD 41 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
Dr.T.V.Rao MD 42 TRANSMISSION• AEROSOL • 100,000 TO 1,000,000 VIRIONS PER DROPLET• 18-72 HR INCUBATION• SHEDDING
Dr.T.V.Rao MD 44 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
Dr.T.V.Rao MD 45 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
Dr.T.V.Rao MD 47 CLINICAL FINDINGS• SEVERITY • VERY YOUNG • ELDERLY • IMMUNO- COMPROMISED • HEART OR LUNG DISEASE
Dr.T.V.Rao MD 48 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
Dr.T.V.Rao MD 49Viral Pneumonia is Leading cause of Death
Dr.T.V.Rao MD 50 Complication in Influenza• Pneumonia • secondary bacterial • primary influenza viral• Reye‟s syndrome• Myocarditis• Death 0.5-1 per 1,000 cases
Dr.T.V.Rao MD 51 Immunity in Influenza• 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.
Dr.T.V.Rao MD 52 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
Dr.T.V.Rao MD 54 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.
Dr.T.V.Rao MD 55 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
Dr.T.V.Rao MD 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.
Dr.T.V.Rao MD 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
Dr.T.V.Rao MD 59Wild Birds Migrate and spread the Disease Globally
Dr.T.V.Rao MD 60 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
Dr.T.V.Rao MD 61Be familiar with Importance of Throat Swab in Diagnosis
Dr.T.V.Rao MD 62 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 370 C in 3 days• The virus causes Haemagglutination of Guinea pig and Fowl erythrocytes at 370 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
Dr.T.V.Rao MD 64 SWINE FLU 2009• Swine influenza (also called H1N1 flu, swine flu, hog flu, and pig flu) is an infection by any one of several types of swine influenza virus. Swine influenza virus (SIV) is any strain of the influenza family of viruses that is endemic in pigs
Dr.T.V.Rao MD 65 2009 H1N1 Flu• H1N1 (sometimes called “swine flu”) is a new influenza virus causing illness in people. This new virus was first detected in people in the United States in April 2009. This virus is spreading from person-to-person worldwide, probably in much the same way that regular seasonal influenza viruses spread. On June 11, 2009, the World Health Organization (WHO) declared that a pandemic of 2009 H1N1 flu was underway.
Dr.T.V.Rao MD 69 Pigs infect Humans• Pigs can pass mutated viruses back to humans, and these can be passed from human to human. Transmission among humans is thought to occur in the same way as with seasonal flu.
Dr.T.V.Rao MD 70 (Injectable Peramivir has completed phase-1 trials) Tamiflu! (oral) Ralenza (inhaled) (Older drugs)(Viral resistance to these is more common)
Dr.T.V.Rao MD 71 Chemotherapy• Tamiflu (oseltamivir) – inhibits the neuraminidase and thus prevents the spread of the virus in the body• Tamiflu can therefore be used to reduce the length of illness and its transmission within a household• Resistance of H1N1 strain to oseltamivir has been reported at 25%
Dr.T.V.Rao MD 72 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.
Dr.T.V.Rao MD 73 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
Dr.T.V.Rao MD 74 Influenza Vaccine Recommendations• Healthcare providers, including home care*• Employees of long- term care facilities• Household contacts of high-risk be administered to healthcare workers who have *LAIV should not persons contact with severely immunosuppressed persons who require hospitalization and care in a protective environment
Dr.T.V.Rao MD 75Indication to Vaccinate Patents ?• 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.
Dr.T.V.Rao MD 76 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)
Dr.T.V.Rao MD 77Emerging trends in Vaccines• A live attenuated Cold adopted temperature sensitive used as nasal spray on major trails.
Dr.T.V.Rao MD 78 Newer Vaccines are available• The 2011-2012 vaccine will protect against an influenza A H3N2 virus, an influenza B virus and the H1N1 virus that emerged in 2009 to cause a pandemic. Everyone 6 months of age and older should get a flu vaccine as soon as the 2011-2012 vaccines are available.
Dr.T.V.Rao MD 79HIV 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
Dr.T.V.Rao MD 80Prevention is the Best option • Covering your nose and mouth with a tissue when you cough or sneeze. Throw the tissue in the trash after you use
Dr.T.V.Rao MD 81 Hand washing a Top priority• Washing yourhands often withsoap and water,especially afteryou cough orsneeze. You canalso use alcohol-based handcleaners.
Dr.T.V.Rao MD 82Influenza is a Global ConcernBe Familiar with Facts
Dr.T.V.Rao MD 83Major References• WHO current issues on Influenza• CDC Literature on facts, and prevention
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