Dr.T.V.

Rao MD

INFLUENZA
Dr.T.V.Rao MD

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Myxovirus
Classified into
1 Influenza virus 2 Parainluenza virus A Mumps virus B Parainluenza virus C Measles virus
D Respiratory syncytial virus

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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

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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 modernday Turkey at the turn of the autumn season

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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).

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Mortality was greater than the 4-year Black

1918 Spanish Flu A great Memorable Event

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
complications of pneumonia causing death

Years later, H1NI strain found responsible for infection However, bacteria responsible for the severe secondary

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Circulating Seasonal Influenza A Sub-Types from Pandemics of the 20th Century

1918/19 40-100 million deaths

1957/58 ~2 million deaths

1968/69 ~1 million deaths

H3N2 Seasonal Flu H2N2 H1N1 Seasonal Flu

1920 1940 1960

H1N1 Seasonal Flu

1980 2000

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)

Dr.T.V.Rao MD 8 Camp Funston, Kansas, March 1918: Sadly, the comparatively benign first wave was not at all predictive of what was to come

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INFLUENZA
Cause of the

infection of the Respiratory tract. Occurs as Sporadic Epidemic Pandemic Major pandemic in 1918 1919

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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

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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.

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Spread of Influenza
The virus is

transmitted easily from person to person via droplets and small particles produced when infected people cough or sneeze.

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Most 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.

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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

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Where do new HA and NA come from?

>13 types HA
9 types NA all circulate in birds

pigs avian and human

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Where do new HA and NA come from?

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Current incidence of Influenza

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Pandemics 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

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Structure of Virion
HA - hemagglutinin NA - neuraminidase

100 n m

helical nucelocapsid (RNA plus NP protein) lipid bilayer membrane polymerase complex

Influenza 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

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Influenza Virus
Virus are

spherical in shape Size is 80 -120 nm Pleomorphism is common with variant forms

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Viral structure
A negative sense Single stranded RNA genome is segmented into 8 segments

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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

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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

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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

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Haemagglutination defines the nature of the Virus

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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

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Haemagglutination
Act with red cells of

different species Type A and B RBCs of Fowl, Human and guinea pigs Type C only RBCs 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.

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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

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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.

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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.

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Antigenic Shift

Influenza prominent Antigenic Changes

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

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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

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Antigenic Variations

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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

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Antigenic shift initiates Pandemics

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Terminology by WHO
Ao
Ho

A1 A2 ( Asian ) A2 ( H K ) 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 )

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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

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Life cycle of the flu virus

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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.

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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

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TRANSMISSION
AEROSOL 100,000 TO 1,000,000 VIRIONS PER DROPLET
18-72 HR

INCUBATION
SHEDDING

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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

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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

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SYMPTOMS
FEVER HEADACHE MYALGIA COUGH RHINITIS OCULAR SYMPTOMS

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CLINICAL FINDINGS
SEVERITY VERY YOUNG ELDERLY IMMUNOCOMPROMISED HEART OR LUNG DISEASE

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Complications of Influenza
Bacterial super infections

Cardiac complications
Congestive heart failure Myocarditis

Neurological involvement
Encephalitis Type B virus can produce Reyes syndrome

Degenerative changes in the Brain and Liver

Gastric flu with type B virus

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Viral Pneumonia is Leading cause of Death

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Complication in Influenza
Pneumonia secondary bacterial primary influenza viral Reyes syndrome Myocarditis Death 0.5-1 per 1,000 cases

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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.

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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

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RECENT MAJOR PANDEMICS

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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.

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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

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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.

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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

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Wild Birds Migrate and spread the Disease Globally

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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

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Be familiar with Importance of Throat Swab in Diagnosis

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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

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Serology
Compliment fixation

test Haemagglutination Inhibition testing Testing on paired sera Detection of Haemagglutination Inhibition testing Radial Immunodiffusion

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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

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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.

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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.

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(Injectable Peramivir has completed phase-1 trials) Tamiflu! (oral)

Ralenza (inhaled) (Older drugs) (Viral resistance to these is more common)

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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%

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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.

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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

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Influenza Vaccine Recommendations

Healthcare

providers, including home care* Employees of longterm care facilities Household contacts *LAIV should not persons of high-risk be administered to healthcare workers who have
contact with severely immunosuppressed persons who require hospitalization and care in a protective environment

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Indication 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.

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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)

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Emerging trends in Vaccines

A live

attenuated Cold adopted temperature sensitive used as nasal spray on major trails.

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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.

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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

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Prevention 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

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Hand washing a Top priority

Washing your

hands often with soap and water, especially after you cough or sneeze. You can also use alcoholbased hand cleaners.

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Influenza is a Global Concern

Be Familiar with Facts

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Major References
WHO current issues on Influenza

CDC Literature on facts, and prevention

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Programme Created by Dr.T.V.Rao

MD for e learning resources for Medical and Paramedical Students in the Developing World
Email

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