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INFLUENZA

VIRUS

II MBBS

Common Properties
myxo- mucous tropic
orthomyxovirus = influenza
• (-) polarity ssRNA
• enveloped viruses
• encapsidates RNA polymerase
• causes worldwide disease
• responsible for > 10% work/school absence
• acute infections and diseases
• known since 1500’s

Orthomyxovirus: Classification

Three types
• Influenza A - highly variable
- infects humans, birds, pigs, horses,
seals
- most prevalent human virus
- cause of most human epidemics
• Influenza B - infects only animals
• Influenza C - infects human and
swine
- antigenic stable, only mild illness

Structure of Virus
 Spherical, 80-120nm in diameter but
pleomorphism is common
 Nucleocapsid – helical symmetry
 Genome – 8 segmented RNA
(ribonucleoprotein - RNP)
 Envelope –
5. Inner membrane protein layer – “M” protein,
2 components: M1 & M2
6. Outer lipid layer – 2 types of spikes:
Hemagglutinin(HA) & Neuraminidase(NA).

Ribonucleoprotein (RNP) Ag .HA & NA . Includes: .M protein Ag • Surface/ External Ags – Strain specific Ags Composed of 2 virus coded proteins : . Antigenic Structure  Influenza virus Ags – 2 types: • Internal Ags – Type specific Ags.

type specific . Internal Antigens  Ribonucleoprotein . does not exhibit any significant antigenic variation  M protein .found free in infected tissues .Stable. B & C .Used to classify into types A.

Hemagglutinin  Glycoprotein – made up of 2 polypeptides HA1 & HA2.Surface Antigens . . named H1 to H16 have been identified.  Responsible for hemagglutination & hemadsorption  Adsorbs to mucoprotein receptor on RBCs as well as on epithelial cells  Capable of great variation  16 HA subtypes.

N1 to N9.Surface Antigens .  Antigenic variation  9 subtypes. .Neuraminidase  Glycoprotein enzyme  Destroys sialic acid (neuraminic acid) receptors on cell surface during exit  Promotes the release & spread of progeny virions  Also helps in the penetration of the mucus layers in the respiratory tract.

Antigenic shift . Properties of Influenza virus  Hemagglutination  Hemadsorption  Antigenic variation – Antigenic drift .

the virus is adsorbed onto the mucoprotein receptors on the cell surface – clumping of cells occurs – known as Hemagglutination (brought about by HA)  After some time. the virus detaches itself from the cell surface by the action of Neuraminidase (NA) enzyme – reversal of hemagglutination – known as Elution. . Hemagglutination  When mixed with a suspension of fowl erythrocytes.

guinea pig & some other species Type C – fowl only.  Occurs with in a wide range of temp. Hemagglutination  Virus particles which have eluted from RBCs can still agglutinate fresh RBCs. at 4°C .  RBCs that have been acted on by the virus are not susceptible to agglutination by the same strain – due to destruction of specific cell receptors by initial contact with the virus. 0°C to 37°C  Can agglutinate RBCs of different species Type A & B – fowl. human.

Application of Hemagglutination  Detection & titration of the influenza virus in egg & other culture fluids. .  Hemagglutination titre – highestdilution of virus suspension that produces agglutination of a fixed quantity of RBCs.  Can also be used for the titration of inactivated influenza virus.

Hemagglutination Inhibition  A convenient method for the detection and quantitation of antibody to the virus  Disadvantage – certain substances in serum can also cause non specific inhibition of HA .

. hence RBCs are adsorbed onto the surface of such cells. Hemadsorption  A technique employed for the identification of growth of influenza virus in cell cultures.  The plasma membrane of tissue culture cells in which the viruses are multiplying contain HA.

Antigenic shift . undergo independent antigenic variations  Two types – Antigenic drift . none in type C. HA & NA. Antigenic Variation  Unique feature of influenza virus  Important in the epidemiology of disease  Highest variability in Influenza type A.  Both surface/ external Ags.

Antigenic drift  Gradual sequential change in antigenic structure occurring at regular intervals. though different from the previous Ags. So the pre existing Abs will provide only partial protection  Occurs due to mutation & selection  Results in sporadic outbreaks & limited epidemics .  HA and NA accumulate mutations  New Ags. are yet related to them.

 New variants can spread widely in population causing major epidemics or pandemics. discontinuous variation in antigenic structure  ‘New’ NA or HA proteins .Results in a new virus strain antigenically unrelated to the predecessor strain  Pre-existing Abs do not protect. Antigenic Shift  An abrupt. . drastic.

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No viremia involved .Spread to URT aided by NA activity . Pathogenesis  Portal of entry .direct contact with aerosols (105 to 106 virions/ droplet)  Person to person transmission .sneezing .Initial replication in nasal passage cells .hands on contaminated surfaces  Incubation period – 18 to 72 hrs  Movement to target organ inside host .airborne droplets .

Pathogenesis  Neuraminidase – dilution of mucus film lining respiratory epithelium – exposure of cell surface receptors  Entry of virus in to the epithelial cells via HA – virus adsorption. destroyed nearly after 3 days  Cell death occurs due to .effects of Interferons .  Chief target cells – Ciliated cells.action of cytotoxic T cells .direct effects of virus on the cell .

Decreased ciliary clearance 3. viremia is rare . Pathogenesis  All this results in: 2. Exposure of basal cells in trachea & bronchi 4. Increased risk of bacterial invasion 5. However.

NORMAL TRACHEAL MUCOSA 3 DAYS POST-INFECTION 7 DAYS POST-INFECTION .

myalgia. Reduce virus production 3. fatigue. Symptoms of influenza – fever. Recovery from disease  Interferons: 2. malaise  Cell mediated immunity – viral clearance  Repair of respiratory epithelium .

Interferon Time course of virus production will vary from virus to virus .

Interferon .

Interferon antiviral state antiviral state antiviral state antiviral state .

Interferon antiviral state antiviral state antiviral state antiviral state .

Interferon antiviral state antiviral state antiviral state antiviral state .

BACK TO INFLUENZA .

prevents initiation of infection  Abs to NA .slows the spread of virus * usually develops short term immunity due to frequent antigenic variations.protects against re-infection . Protection / Immunity  Main source – humoral immunity  IgA & IgG .IgG less efficient but lasts longer  Abs to HA .can neutralize the virus (blocks binding) . .

photophobia . Symptoms  Fever  Headache  Myalgia  Dry Cough  Rhinitis  Ocular symptoms .

Clinical Findings  SEVERITY Very Young Elderly Immuno-compromised Heart OR Lung disease .

H. stridor. influenzae . aureus . pneumoniae . Pulmonary Complications  Croup (Acute laryngotracheobronchitis) in young children – cough.S. difficulty breathing  Primary influenza virus pneumonia  Secondary bacterial infections .S.

> in children. > with type B)  Cardiac complications  Recent studies report encephalopathy  2002/2003 season studies of patients younger than 21 yrs in Michigan . Non-pulmonary Complications  Myositis (rare.8 cases (2 deaths)  Liver and CNS  Reye’s syndrome  Peripheral nervous system  Guillian-Barré syndrome .

Isolation of the virus 6. Demonstration of virus Ag 5. Serology . Diagnosis  Provisional diagnosis – clinical picture + knowledge of influenza outbreak  Laboratory Diagnosis: 4.

highly sensitive . rapid diagnosis  RT-PCR: for viral RNA. Demonstration of virus Ag  Immunofluorescence – for virus Ag on the surface of the nasopharyngeal cells. Laboratory Diagnosis 1.

test the amniotic & allantoic fluid for hemagglutination at RT & 4°C. . B & C . Isolation of Virus  Best during the first 2-3 days of illness  Specimen – throat gargles. . 2.identification & typing of isolate by CFT with antisera to types A. should be treated with antibiotics to destroy bacteria  Methods of isolation • Amniotic cavity of 11 –13 days old chick embryos: incubate at 35°C for 3 days.subtyping by HI test.

fowl or guinea pig erythrocytes . 2. .growth is detected & identified by hemadsorption with human O group.incubate at 33°C in roller drums .primary monkey kidney cell culture. other continuous cell cultures like baboon kidney .rapid results by demonstration of viral Ag in infected cell cultures by IF. Isolation of Virus  Methods of isolation • Tissue culture .

.convenient & sensitive test .detection of Abs to RNP Ag.highest dilution of serum that inhibits hemagglutination is its HI titre. HA & NA. Serology  Examination of paired sera to demonstrate rise in titre of Abs. • Radial Immunodiffusion – useful screening test . HI . B & C as Abs are formed only during infection 2. • CFT with RNP Ags of types A.

formulated with the types & strains of influenza predicted to be a major problem. grown in chick embryo . Prophylaxis  Yearly vaccine .inactivated virus.“cold adapted” live attenuated virus (Flu-mist) . has 2 strains of type A & 1 of type B.HA & NA subunit .  Current vaccine – multivalent . .short lived protection  New vaccines .

 Travellers & general population who wish to be vaccinated. .elderly >65 years .children 6-59 months .people with underlying diseases  Women in 2nd or 3rd trimester of pregnancy during influenza season  Persons who are clinically or sub clinically infected and can transmit to high risk individuals. Who should receive vaccine?  Health care workers  High risk individuals .

Treatment  Antibiotics – to control 2 bacterial infections  Antiviral drugs can be given after exposure 3. Zanamivir (Relenza)/ Oseltamivir (Tamiflu) – Type A & B  Other treatment – rest. Rimantadine / Amantadine – Type A 4. liquid. anti febrile agents (no aspirin to ages 6 mths to 18 years) .

Influenza A Pandemics .

where do “new” HA and NA come from?  16 types HA  9 types NA  all circulate in birds  pigs  avian and human .

Where do “new” HA and NA come from? .

Where do “new” HA and NA come from .can ‘new’ bird flu directly infect humans? Bird flu H5N1? .

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This form is characterized by sudden onset. and rapid death.ranging from mild illness to a highly contagious and rapidly fatal disease resulting in severe epidemics. severe illness. The latter is known as “highly pathogenic avian influenza”. with a mortality that can approach 100%. Avian Influenza  Avian influenza is an infectious disease of birds caused by type A strains of the influenza virus. .  Wide spectrum of symptoms in birds .

when the H5N1 strain caused severe respiratory disease in 18 humans. of whom 6 died. all outbreaks of the highly pathogenic form have been caused by influenza A viruses of subtypes H5 and H7. The first documented infection of humans with an avian influenza virus occurred in Hong Kong in 1997.  Avian influenza viruses do not normally infect species other than birds and pigs. Avian Influenza  To date. .

 The most recent cause for alarm occurred in January 2004. which began in the Netherlands in February 2003. caused the death of one veterinarian two months later. when laboratory tests confirmed the presence of H5N1 avian influenza virus in human cases of severe respiratory disease in the northern part of Viet Nam. Avian Influenza  An outbreak of highly pathogenic H7N7 avian influenza. . and mild illness in 83 other humans.

the great influenza pandemic of 1918–1919. .  In the 20th century. which caused an estimated 40 to 50 million deaths worldwide. Avian Influenza  Based on historical patterns. three to four times each century when new virus subtypes emerge and are readily transmitted from person to person. on average. influenza pandemics can be expected to occur. was followed by pandemics in 1957–1958 and 1968–1969.

why do we not have influenza B pandemics?  so far no shifts have been recorded  no animal reservoir known .

H5N1 – in birds  Avian H5N1 has spread to humans  So far human cases in Asia and Africa  256 cases (12-1-03 through 10-16-06)  151 (59%) fatal  Have been a few instances where may have spread human-to-human  So far no sustained spread in humans AND  Surveillance continues .

SURVEILLANCE CDC/Katherine Lord .