Influenza Viruses

Sponsored by:The Gerald Brennan Medical Corporation

A proud consumer of Tamiflu® (oseltamivir phosphate)

October 30, 2009

AgendaInfluenza overviewDiagnosis and testingTreatmentVaccination

Influenza overviewWhat is influenza?What is the difference between Human and

Swine influenza?What is special about H1N1?What constitutes a pandemic?What have we seen with Pandemics of the past?What have we seen with past seasonal influenza?What have we seen with H1N1 so far?What can we expect for the fall?

What is influenza?•ssRNA virus 50-200 nm in diameter of the order of Mononegavirales and of the family Orthomyxoviridae

•There are 3 immunological types: Influenza type A, type B and type C

•Type A is the most virulent human pathogen and is responsible for all pandemics

•Type A can be further broken down into subtypes based on it’s surface proteins: Hemagglutinin and Neuraminidase

•There are 16 Hemagglutinins (H1-H16)•There are 9 Neuraminidases (N1-N9)•There are also Nucleocapsid proteins (NP) that coat the RNA strands and Matrix proteins that line the inner side of the viral envelope

What is influenza?•Influenza virus first binds to the host cells glycoprotein receptors via HA, where it is then adsorbed into the cell via endocytosis•The nucleocapsids are then released by the virus and these are taken to the nucleus where transcription of the viral mRNA occurs•The mRNA is then translated into viral proteins by the host machinery, but it is also replicated with the help of viral RNA polymerase•These materials are then combined in the cytoplasm and new virion particles are assembled and then released via exocytosis, allowing for new cells to become infected

What is the difference between Human and Swine influenza?Typically, Influenza type A is species specific,

but all have the potential to cross the species barrier

Reassortment is the theory that allows for a virus to cross the species barrier

What is the difference between Human and Swine influenza?In this example, a pig is infected simultaneously with both an avian and a human influenza virus. The “mixing” of the avian and human viral proteins results in the new subtype H3N2 (the pandemic virus of 1968)

What is special about H1N1?By itself, there is nothing special about H1N1

It is not a “super virus”It is not much more virulent than other Type A

influenza But it has been affecting more young people though

It is the result of a reassortment and is new to the human population

Because the human population has no immunity, as they would to most seasonal influenza, more people are susceptible

Once immunity has built up in the population at large, further outbreaks will be more limited

What constitutes a pandemic?

What have we seen with Pandemics of the past?1918 Spanish FluH1N120-40 Million deaths>500 Million people infected

What have we seen with Pandemics of the past?1957 Asian FluH2N21-4 Million Deaths

What have we seen with Pandemics of the past?1968 Hong Kong FluH3N21-4 Million Deaths

What have we seen with past seasonal influenza: 2005-06Canada (Sept 1-Aug 31) Manitoba (July 1 – June

30)Total cases = 6590

Type A = 4028 Type B = 2562

Hospitalizations = n/aDeaths = n/aPediatric Hospitalizations

>2 years: 144 >2 years: 230

Pediatric Mortality Type A: 3 Type B: 2

Total cases = 88Type A = 63Type B = 25


>2 years: 14>2 years: 16

Pediatric MortalityType A: 0Type B: 0



Type A = 6051 Type B = 972


>2 years: 183 >2 years: 187








Type A = 5356 Type B = 3765


>2 years: 231 >2 years: 239






What have we seen with past seasonal influenza: 2008-09 (prior to April 09 when H1N1 appeared)Canada (Sept 1-Aug 31) Manitoba (July 1 – June


Type A = 5588 Type B = 3612


>2 years: 185 >2 years: 225






What have we seen with H1N1 so far: 2008-09 Canada (Sept 1-Aug 31) Manitoba (July 1 – June


Type A = 19464Type B = 3902

Hospitalizations = 1454Deaths = 72Pediatric Hospitalizations

Total = 737Pediatric Mortality

Type A: 4Type B: 0

Total cases = 1119 (440 peds)Type A = 1082Type B = 37


Total = 81PICU = 12

Pediatric MortalityType A: 1

What have we seen with H1N1 so far: 2009-10Canada (Sept 1-Aug 31) Manitoba (July 1 – June


Type A = 2816Type B = 2


Total = 52Pediatric Mortality

Type A: 0Type B: 0

Total cases = 94 (27 peds)Type A = 94Type B = 0


Total = n/aPICU = 1

Pediatric MortalityType A: 0

What have we seen with H1N1 so far?

Worldwide: 182,166 Cases & 1799 Deaths (current to Aug 13, 2009)

WHO Africa1469 Cases3 Deaths

WHO Americas105,882 Cases1579 Deaths

WHO Eastern Mediterranean2532 Cases8 Deaths

WHO Europe> 32,000 Cases53 Deaths

WHO South-East Asia13,172 Cases106 Deaths

WHO Western Pacific27,111 Cases50 Deaths

What have we seen with H1N1 so far? (current to Aug 13, 2009)

Per PHAC:Median Age

All Cases = 18 yoHospitalizations =

25 yoICU = 40 yoDeaths = 51 yo


Per PHAC:Aboriginal Status

All Cases = 12.5%Hospitalizations =

16.5%ICU = 14.5%Deaths = 11.4%


Per PHAC:Female (Pregnancy)

All Cases = 51.9% (4.1%)

Hospitalizations = 51.4% (22.4%)

ICU = 56.7% (15.7%)

Deaths = 60% (33.3%)


Per PHAC:Underlying Medical

ConditionsAll Cases = 36.4%Hospitalizations =

54.2%ICU = 65.3%Deaths = 75.5%

What can we expect for the fall?No one knows for sureWe can postulate based

on past experience with H1N1 in 1918

The first wave hit in the spring and was about ¼ to 1/3 the size of the second wave, which hit in the fall

We have just started the second wave

What can we expect for the fall?

What should we be doing?Influenza virus is spread to person to person by

droplets released into the air when an infected person coughs or sneezesTravels about 1 meter (3 feet)Virus enters through the eyes, nose or throat

Can also be picked up from contaminated objectsSurvives 24-48 hours on hard, non-porous surfacesSurvives 8-12 hours on cloth, paper and tissueSurvives 5 minutes on handsLoves cold, dry climates

Which is why we have winter outbreaks

What should we be doing?Once infected, symptoms develop within 1-7

daysAn infected person can be contagious for 24

hours prior to the onset of symptoms and for up to 7 days afterwards

It is possible to spread it to others without being sick, but the actual viral load is very low. This is why vaccination will be important for people living with high risk individuals!!!

What should we be doing?Signs and symptoms include:

FeverSore throatCoughRunny noseSore muscles and jointsHeadacheProstration (feeling like you have no energy)

What should we be doing?Because H1N1 will be so difficult to

distinguish from other respiratory viruses, we need to be vigilantIdentify and treat patients with H1N1Reduce the spread/Protect other patients

Hand washing Respiratory precautions/Droplet precautions Housekeeping Cohorting Diverting (avoidance strategies)

Protect ourselves

Diagnosis and TestingHow can we diagnose H1N1?What testing is available?

How can we diagnose H1N1?Clinical

ILI (Influenza-like Illness) Fever > 38 C AND Cough AND one or more of:

Sore throat Arthralgia Myalgia Prostration

*** Cough may not be prominent in young children *** Children < 5 years may also present with GI symptoms

LaboratoryNasal swab or throat swab

Sent to Cadham for viral culture and PCRRapid Influenza A test (30 min) not available to us at this

timeThere is presently no available antibody test to verify if

someone has had H1N1 already

TreatmentWhat treatment is available for H1N1?What are the adverse effects from these

treatments?Who should be treated and why?

What treatment is available for H1N1?There are two antiviral drugs:

Oseltamivir (Tamiflu)Zanamivir (Relenza)Canada has a stockpile of 55 million doses (both

drugs)They are neuraminidase inhibitors

Prevent viral enzymes from cleaving sialic acid thereby preventing virion release from infected cells, thus reducing infection with the host organism

Translation: it stops the virus from spreading to other cells and shortens the severity of disease by about 60%

What are the adverse effects from these treatments?The drug is “activated” by the liver, so

beware of patients with liver dysfunctionThe drug is cleared by the kidney, so may

need to go to once daily dosing in moderate-severe renal dysfunction

Major side-effects in the clinical trials of children age 1-12 (>1000 pts) were:Nausea and vomiting (15%)Diarrhea (9%)Abdominal pain (4%)

Who should be treated and why?PHAC has stated that treatment should be

limited to:Severe disease (hospitalized/ICU) patientsHigh risk patients (as per the WHO):

Patients with underlying medical conditions All pregnant women All children under the age of 5 years Aboriginal peoples

Who should be treated and why?Treatment, if initiated promptly, has been

shown to dramatically reduce the burden of illnessWithin 12 hours of onset of illness is bestWithin 48 hours of onset of illness is likely

helpful Not considered beneficial if initiated after 48 hours,

except in cases of severe illness (i.e., requiring hospitalization)

VaccinationArepanrix H1N1 vaccine was approved for use

in Canada this month as a means of decreasing the burden of illness expected from the second wave of H1N1

0.5 cc of vaccine is injected into the deltoid muscle and antibodies to the H1N1 virus are formed within 10-14 days

The formed antibodies allow the body’s immune system to protect it from H1N1, resulting in either no disease or very mild illness

Vaccination preparationH1N1 is grown inside hens eggs. After

14(ish) days, the virus is extracted and then killed by exposing it first to intense ultraviolet radiation, and then to formaldehyde

This results in a neutralization of the virus without altering it’s antigenic properties (the antigens are what allow your body to develop antibodies against the virus)

The killed virus is then cleaned and centrifuged in order to concentrate it

Vaccination preparationEach dose of vaccine contains:

3.75 mcg of killed H1N1 virus5 mcg of thimerosol (Mercury based

preservative)An adjuvant containing:

11.86 mg of DL-alpha-tocopherol 10.69 mg of Squalene 4.86 mg of Polysorbate 80


Thimerosol: People are concerned about this because of the

mercury content Although it has been a part of vaccine for decades,

and has been proven safe, there are many people who still believe that it is the cause of Autism

For what it’s worth, Canada regulates the content of mercury acceptable for human consumption to <0.5 ppm (1 mg/kg)

This vaccine contains 5 ppm (10 x greater), but the actual total dose is 2.5 mcg of Mercury

For comparison, the dose of Mercury in a 75 gram serving of canned tuna is 37.5 mcg


Adjuvant These are extra ingredients used to “boost” the immune

reaction to the vaccine, allowing the manufacturer to produce more usable vaccine with less killed virus per dose

Tocopherols are naturally occurring antioxidants that prevent the oxidation of unsaturated fatty acids. Vitamin E is a tocopherol. It is used to keep the squalene from breaking down

Squalene is a naturally occurring organic compound found in shark liver oil and vegetable oils. It is what stimulates the immune system

Polysorbate 80 is an emulsifier, which means that is allows the oily squalene to become suspended with watery vaccine. It is used mostly in ice-cream

Vaccination EfficacyInitial studies done in Canada showed that the

vaccine was very efficacious and safeAlthough the number of test subjects was low in

Canada, using this information along with studies done in other parts of the world where this vaccine, or similar vaccines, had been used, Health Canada was able to ensure a safe means of preventing H1N1

Additionally, unlike most seasonal influenza that changes frequently, H1N1 has not modified much so far, which will make the vaccine that much more effective when compared to typical seasonal flu shots

Vaccination EfficacyH1N1 vaccine (15 mcg/dose)

Adjuvanted H1N1 (3.75 mcg/dose)

Seroprotection = 93.9 %Refers to the ability of

vaccinated people who have no antibodies to develop antibodies above a threshold titer of 1:40

Seroconversion = 84.8 %Refers to the ability of

vaccinated people who have antibodies to increase the number of antibodies by a factor of 4 or more

Seroprotection = 100 %Refers to the ability of

vaccinated people who have no antibodies to develop antibodies above a threshold titer of 1:40

Seroconversion = 96.7 %Refers to the ability of

vaccinated people who have antibodies to increase the number of antibodies by a factor of 4 or more

ConclusionsWe have no innate immunity

H1N1 is not a super virus

Because this virus hasn’t been seen for many years, persons living today have no antibody “memory” for this virus, which is why so many more people have and will get sick

For seasonal flu, even though it differs somewhat from season to season, most of us have some immunity – which is why healthy adolescents and adults don’t usually get sick

In of itself, H1N1 is not more virulent than regular seasonal flu

More people are getting sick because fewer people are immune to it

Because so many more people are becoming ill, there are increases in hospitalizations and deaths

ConclusionsThe second wave will be worse

It is hard to predict who will get severe disease

We have to assume that the pattern of this pandemic will follow the one from 1918 (as it has so far), which means that we will see 3-4 times more sick people

This will likely result in 3-4 times the number of admissions to hospital and in the number of deaths

Usually, with seasonal influenza, the very young and the very old get sick and have severe disease

With the lack of immunity, we are seeing otherwise healthy individuals who have gotten gravely ill 2/3 of all cases were healthy

people ½ of hospitalizations were

“healthy” ¼ of all deaths were in people

who had no underlying medical conditions

ConclusionsSimple precautions decrease the spread

Vaccination is safe and effective

Hand washingCoughing into your

sleeveStaying home when you

are sick or at least until you are

without fever for at least 24 hours

The more people who are vaccinated, the fewer people who are going to get sick and the less disruption to the lives of Canadians (not to mention Emergency physicians)

There are many outrageous claims, but none are supported by credible or reproducible evidence

The risks of contracting H1N1 and having a severe illness are much greater than the risk of serious adverse effects from the vaccine

My advice:If you get sick:

Stay home, get plenty of rest, drink lots of fluids, eat properly and for God’s sake stop coughing on me…

If you feel very short of breath or find it difficult to breath, seek the assessment of a physician or nurse-practitioner

If you haven’t gotten sick:Get the vaccination, especially if you have risk

factors or live/work with people who do?Wash your hands, get plenty of sleep, exercise

and eat right

Questions?

Thanks for reading!!!

Documents

Influenza Viruses