1. “This is scary and we don’t know…”
“We don’t know the timing of the next pandemic, how severe it will be. We don’t know what drugs will work. We don’t have a vaccine. Yet we are telling everyone to prepare for a pandemic. It’s tricky…This is scary and we don’t know…that’s the message.”
Dick Thompson
World Health Organization
December 2005

2. INFLUENZA - the name
Influenza is Italian for "influence", Latin: influentia. It used to be thought that the disease was caused by a bad influence from the heavens.

3. Flu sometimes is confused with the common cold
Flu sometimes is confused with the common cold. However, the flu is caused by influenza virus, and is a much more severe disease than the common cold, which is caused by a different type of virus. Influenza is a more severe viral infection of the respiratory tract that shows the additional symptoms to those of the common cold (rapidly rising fever, chills, and body and muscle aches).

5. INFLUENZA

6. Influenza is an acute systemic viral disease.
Has very serious complications.
Caused by influenza virus.

7. Classification \Family is Orthomyxoviridae
Influenza family which is subdivided into 3 genera: A, B, and C, based on antigenic differences in the nucleoprotein (NP) and matrix (M) protein.
2. Influenza A viruses are further characterized by antigenic differences associated with the Haemagglutinin (HA) and Neuraminidase (N) glycoproteins; there are at least 15 subtypes of H and 9 subtypes of N proteins in influenza A virus.
3. All subtypes have been described in birds and some of them have been found in mammals.

8. Type A Type B Type C Humans Humans Swine Birds Horses Seals Humans
Because of A’s ability to infect numerous carriers, it is the most dangerous subtype, and will be focus of presentation.
Dangerous outbreaks are often the result of genetic reassortment, which relies on cross infection of one host with more than one strain of the virus, followed by transmission from one species to humans. This can’t happen with B, so there are less outbreaks.
Humans
Swine

9. Virus characteristics
Virion is nm in diameter), enveloped, spherical to slightly pleomorphic in shape.
Underline the envelope is the Matrix ( M1 & M2)
2. Genome consists of 8 segments of ss RNA in A& B and 7 segments in C
3. The envelope contains 2 glycoproteins: H (hemagglutinin), and N (neuraminidase)
4. associated with the genome is nucleoprotein (NP)

11. ORTHOMYXOVIRUSES HA - hemagglutinin NA - neuraminidase
M1 protein
helical nucleocapsid (RNA plus
NP protein)
HA - hemagglutinin
polymerase complex
lipid bilayer membrane
NA - neuraminidase
Type A, B, C : NP, M1 protein
Sub-types: HA or NA protein

12. Influenza virus A/Beijing/32/92 (H3N2) Hemagglutinin Neuraminidase
Influenza type A viruses have a major name from the 2 surface proteins – H & N – and strain numbers from where the subtype is first discovered
Neuraminidase
A/Beijing/32/92 (H3N2)
Virus type
Geographic origin
Strain number
Year of Isolation
Virus subtype

13. Influenza A is classified into subtypes based on HA & NA

14. DISEASE Influenza A virus cause Influenza B virus cause
worldwide epidemics (pandemic)
major outbreaks of influenza
occurs virtually every year.
Influenza B virus cause

15. Nomenclature A/equine/Prague/1/56(H7N7) A/fowl/Hong Kong/1/98(H5N1)
A/equine/Saskatoon/1/90(H3N8)
Serotype of
HA and N
group
year
species
Isolate number
location
A/equine/Prague/1/56(H7N7)
A/fowl/Hong Kong/1/98(H5N1)
A/swine/Lincoln/1/86(H1N1)

16. Seasonal (human) Influenza ( H1N1)
Endemic
Strain varies slightly year to year
Avian Influenza (H5N1)
May be reservoir for completely new strains in humans
Can be Highly Pathogenic Avian Influenza (HPAI)
Pandemic Influenza (H1N1)
Global epidemic of new influenza A subtype in humans
Instructor: This slide is review if Modules 1 and 2 have already been completed. You may skip this slide or cover only briefly.
Seasonal Influenza is human influenza. It is endemic worldwide and is seen at regular intervals annually. The same hemagglutinin type circulates around the globe year after year, mutating slightly as it goes. The result of these mutations is that over time, susceptibility is renewed because of changes in the surface proteins of the virus that allow it to evade the immunity built up by previous influenza infections. The season in which it occurs may be different in temperate climates, where it is a winter-time disease, and tropical climates where transmission probably occurs year round but is largely unstudied.
Avian influenza is a disease of birds that can occasionally infect humans when there is significant exposure. Avian influenza viruses are thought to be the reservoir for new types of influenza viruses in humans that cause pandemics when they acquire the ability to circulate in humans. The factors that must be present to enable the virus to do this are unknown.
Pandemic Influenza is a global epidemic of a new influenza A virus subtype that passes easily from person to person and causes severe disease. The emergence of a new human influenza A virus subtype occurs either through genetic reassortment or direct poultry to human transmission from an avian species with a virus that has acquired the ability to spread easily from human-to-human.

17. ANTIGENIC CHANGES
Influenza viruses especially type A show changes in antigenicity of hemagglutinin (H) and neuraminidase (N) proteins.
Antigenic shifts:
major changes based on the reassortment of RNA segments. It occurs only with influenza A.
Other theories of antigenic shift includes:
Recirculation of existing subtypes
Gradual adaptation of animal viruses to human transmission
Antigenic drifts:
minor changes based on mutations in the RNA genome.

18. Animal viruses (aquatic birds, chicken, swine) are the source of RNA segments that encode antigenic shift variants.
Because influenza B virus is only a human virus, there is no animal source of new RNA segments. Influenza B virus shows only antigenic drift, but not shift.

19. Antigenic Variation Due to:- A. genome is segmented
Can infect wild range of different species.
It is RNA virus ( mutation more common).
Two forms

20. 1. Antigenic shift Major change. Occurs in influenza A only.
Result in a new subtype.
Associated with pandemic

21. Mechanism
Co-infection with 2 different subtypes usually avian and human occurs in pigs ( mixing vessel) .(same cell 2 subtypes)
Genetic reassortment occurs ( swapping of the genes) results in development of a new subtype

22. Reassortment

23. Pigs Serve As Mixing Vessels for reassortants
Pig cells contain receptors for both human and avian viruses.
Aquatic birds
and domestic Pigs Human
Poultry (Human virus)
(Avian virus)
Human
(reassortant
virus)

24. A / PHILIPPINES / 82 (H3N2) A group antigen of influenza A
Philippines / 82 location and year the virus isolated
H3N2 Hemagglutinin and Neuraminidase types
H1N1 and H3N2 strains of influenza A are the most common types at this time and are the strains included in the current vaccine.

25. Past Antigenic Shifts
1918 H1N1 “Spanish Influenza” million deaths
1957 H2N2 “Asian Flu” 1-2 million deaths
1968 H3N2 “Hong Kong Flu” 700,000 deaths
1977 H1N1 Re-emergence No pandemic
At least 15 HA subtypes and 9 NA subtypes occur in nature. Up until 1997, only viruses of H1, H2, and H3 are known to infect and cause disease in humans.

26. 2. Antigenic drift Minor change. Occurs in influenza A & B
Occurs between epidemics.
Results in seasonal localized outbreaks.

27. Mechanism
Due to cumulative point mutations in the HA gene

29. Transmission
Airborne – droplets – esp. crowded populations in enclosed spaces
Direct contact – virus may persist on object for hours to days – esp. in cool, dry areas
Incubation – 1 – 3 days
Communicable – 1-2 days before onset of symptoms and 4-5 days after onset
Possibly up to 21 days in < 12 y.o. or adults w/ avian

30. Influenza spread
Influenza is spread by droplet, especially from coughing and sneezing
Courtesy of Centers for Disease Control and Prevention

31. Clinical Features Incubation period 24 – 48 hours
Sudden onset of fever with chills , myalgias, headache, dry cough, photophobia, sore throat
Diarrhoea and vomiting may occur
Resolve spontaneously in 4 – 7 days. although cough and malaise can persist for >2 weeks. Influenza B is similar to A, but influenza C is usually subclinical or milder in nature.

32. Complications Tend to occur in the young, elderly, pregnants
persons with chronic cardio-pulmonary diseases.
Persons with chronic diseases :DM,renal,liver
Immunocompromized patients

33. COMPLICATIONS Tracheobronchitis and bronchiolitis Croup
Primary viral pneumonia
Secondary bacterial pneumonia
usually occurs late in the course of disease, after a period of improvement has been observed for the acute disease. S. aureus is most commonly involved although S. pneumoniae and H. influenzae may be found.
Myositis and myoglobinuria

34. Myocarditis and pericaditis
Reye's syndrome
Reye's syndrome is characterized by encephalopathy and fatty liver degeneration. It occurs in children with viral infection and are taken aspirin to reduce fever. The disease had been associated with several viruses; such as influenza A and B, Coxsackie B5, echovirus, HSV, VZV, CMV and adenovirus.
Myocarditis and pericaditis

35. LABORATORY DIAGNOSIS Virus Isolation
Specimens :Throat swabs, Nasopharyngeal aspirate (NPA) and nasal washings may be used for virus isolation.. Influenza viruses isolated from embryonated eggs or tissue culture can be identified by serological or molecular methods.
Rapid Diagnosis by Immunoflurescence (Antigen detetection)
cells from pathological specimens may be examined for the presence of influenza A and B antigens by indirect immunofluorescence.
Nucleic acid detection using PCR ( same specimen as above)

36. Serology
Demonstration of a rise in serum antibody to the infecting virus

37. TREATMENT Amantidine The only effective against influenza A.
Act at the level of virus uncoating inhibit M2 protein.
Both therapeutic and prophylactic effects.
Significantly reduces the duration of fever (51 hours as opposed to 74 hours) and illness.
70% protection against influenza A when given prophylactically.
Rimantadine is an amantadine derivative but not as effective as amantadine and less toxic.

38. Neuraminidase inhibitors
- zanamivir (given by inhalation)
- oseltamivir (orally)
Used for influenza A and B including pandemic H1N1
Used for treatment and prophylaxis
To be maximally effective the drugs must be administered very early in the disease.

39. Anti-viral drugs: General background
Amantadine
Rimantadine
Zanamivir
Oseltamivir
Type of Influenza virus infection indicated for use
Influenza A
Influenza B
Administration
oral
oral inhalation
Ages approved for treatment of flu
1 year
14 year
7 years
18 years
Ages approved for prevention of flu
not approved

40. PREVENTION Vaccine Protection lasts only 6 months
Yearly boosters are recommended
Should be given to people
Older than 65 years
With chronic respiratory diseases
With chronic cardiovascular diseases.
Immunity to Influenza
Antibody against hemagglutinin (H) is the most important component in the protection against influenza viruses.

41. Influenza Vaccines
Though existing vaccines are continually being rendered obsolete as viruses undergo antigenic drift and shift.
Yet controlled trials of influenza vaccines indicate that a moderate degree of protection (50-80%) is attainable.

42. 1) Inactivated influenza vaccines
Is a trivalent vaccine containing (H1N1 ,H3N2 and B )
Vaccines are either whole virus (WV) vaccine which contains intact, inactivated virus
or subvirion (SV) vaccine:
contain purified HA and NA glycoproteins. .

43. 2) Live influenza vaccines:
The only feasible strategy to develop a live-virus vaccine is to devise a way to transfer defined attenuating genes from an attenuated master donor virus to each new epidemic or pandemic isolate.
A cold-adapted influenza virus (able to grow at 25C but not at 37C) introduced intranasally should replicate in the nasopharynx but not in the lower respiratory tract, its multiplication stimulate the local production of IgA.
( Flumist)

44. Good luck

45. AVIAN INFLUENZA Avian influenza A viruses usually do not infect humans
Rare cases of human infection with avian influenza viruses have been reported since 1997 with avian influenza A (H5N1) viruses
All strains of the infecting virus were totally avian in origin and there was no evidence of reassortment.
Infection in humans are thought to have resulted from direct contact with infected poultry or contaminated surfaces.
To date, human infections with avian influenza A viruses have not resulted in sustained human-to-human transmission.

47. PICORNAVIRUSES

48. PICORNAVIRUSES
Small (20 – 30 nm) non–enveloped viruses, with icosahedral nucleocapsid and ssRNA genome with positive polarity.
Includes two groups:
Enteroviruses
Enteroviruses include poliovirus, coxsackieviruses, echovirus and hepatitis A virus.
replicate optimally at 37 ºC
Enteroviruses are stable under acid conditions (pH 3 – 5)
Rhinoviruses
Rhinoviruses grow better at 33 ºC in accordance with the lower temperature of the nose.
Rhinoviruses are acid – labile.

49. RHINOVIRUSES

50. RHINOVIRUSES
Common cold accounts for 1/3 to 1/2 of all acute respiratory infections in humans.
Rhinoviruses are responsible for 50% of common colds, coronaviruses for 10%, adenoviruses, enteroviruses, RSV, influenza, parainfluenza can also cause common cold symptoms indistinguishable form those caused by rhinoviruses and coronaviruses.
Common cold is a self-limited illness.
More than 100 serologic types of rhinoviruses (No vaccine)

51. TRANSMISSION Directly from person to person via respiratory droplets
Indirectly in which droplets are deposited on the hands or on a surface such as table and then transported by fingers to the nose or eyes.
An individual may suffer 2 to 5 episodes of colds per year. The primary site of rhinovirus infection is in the nasal epithelium. Rhinoviruses rarely cause lower respiratory infection.

52. CLINICAL FINDINGS Incubation period: 2 – 4 days Sneezing
Nasal discharge
Nasal obstruction
Sore throat
Cough
Headache
Lasts for 1 week

53. COMPLICATIONS Acute bacterial sinusitis Acute bacterial otitis media
The major causes are Pneumococcus, Hemophilus influenza, Moraxella, and Staphylococci.
Acute bacterial otitis media
mainly a problem in children
Asthma attacks in children
Exacerbation of chronic bronchitis

54. LABORATORY DIAGNOSIS
Usually, common cold does not require laboratory investigation
Cell culture isolation from nasal secretion

55. TREATMENT Cold treatments recommended include the following:
Antihistamines
Nonsteroidal antinflammatory drugs
Decongestants (vasoconstrictors)
Cough suppressants (narcotics)

56. CORONAVIRUSES 

57. CORONAVIRUSES
The group was so named because of the crown-like projections on its surface.
At present, at least 10 species are recognized, of which human coronavirus is one. The other viruses are found in animals.

58. PROPERTIES ssRNA enveloped viruses of pleomorphic morphology
60 to 220nm in diameter.
Positive stranded RNA; helical symmetry
Three antigenic molecules are found in the virions i.e. nucleocapsid, surface projection and transmembrane proteins. The main antigenic determinants reside on the surface projections.
Human coronavirus strains fall into serological groups, which are named OC43, and 229E.

59. EPIDEMIOLOGY
Human coronavirus infections occur during the winter and early spring.
High infection rates during the year are caused by either 229E or OC43 group viruses. This pattern is observed throughout the world.
Human coronaviruses are responsible for % of all common colds.

60. DIAGNOSIS AND TREATMENT
Laboratory diagnosis is not attempted.
Coronaviruses have fastidious growth requirement in cell culture.
No antiviral drugs against coronaviruses are available.

61. OTHER CAUSES OF COMMON COLD SYNDROME
Coxsackievirus
Herpangina (severe sore throat with vesiculoulcerative lesions)
Pleurisy
common cold syndrome
Adenovirus
Pharyngitis
Bronchitis
pneumonia (types 3, 4, 7 and 21)
Influenza C

62. Definition of Terms Seasonal (human) Influenza Avian Influenza
Endemic
Strain varies slightly year to year
Avian Influenza
May be reservoir for completely new strains in humans
Can be Highly Pathogenic Avian Influenza (HPAI)
Pandemic Influenza
Global epidemic of new influenza A subtype in humans
Instructor: This slide is review if Modules 1 and 2 have already been completed. You may skip this slide or cover only briefly.
Seasonal Influenza is human influenza. It is endemic worldwide and is seen at regular intervals annually. The same hemagglutinin type circulates around the globe year after year, mutating slightly as it goes. The result of these mutations is that over time, susceptibility is renewed because of changes in the surface proteins of the virus that allow it to evade the immunity built up by previous influenza infections. The season in which it occurs may be different in temperate climates, where it is a winter-time disease, and tropical climates where transmission probably occurs year round but is largely unstudied.
Avian influenza is a disease of birds that can occasionally infect humans when there is significant exposure. Avian influenza viruses are thought to be the reservoir for new types of influenza viruses in humans that cause pandemics when they acquire the ability to circulate in humans. The factors that must be present to enable the virus to do this are unknown.
Pandemic Influenza is a global epidemic of a new influenza A virus subtype that passes easily from person to person and causes severe disease. The emergence of a new human influenza A virus subtype occurs either through genetic reassortment or direct poultry to human transmission from an avian species with a virus that has acquired the ability to spread easily from human-to-human.

63. Three Types of Influenza
Seasonal influenza refers to the periodic outbreaks of respiratory illness in the fall and winter.
Avian influenza - also known as the bird flu - is caused by virus that infects wild birds and domestic poultry. Two types: Low pathogenic avian influenza virus (H5 and H7) and highly pathogenic avian or bird influenza of the H5N1 strain.
Pandemic influenza refers to a worldwide outbreak of influenza among people when a new strain of the virus emerges that has the ability to infect humans and to spread from person to person.

64. What is seasonal flu? Contagious, respiratory illness
Affects 5-20% of population each year
Kills approximately 36,000 every year
Can be prevented with a vaccine

65. Bird or Avian Flu – H5N1 A powerful virus Spread by migratory birds
Transmitted from birds to humans and other mammals
Kills 60% of its victims
It continues to change
-Why are we so concerned about pandemic flu now?
-First, the last one was almost 40 years ago, in 1968, so we are due.
-Second, there is a potential candidate out there that has the potential to be extremely deadly if it becomes a pandemic.
-You have probably heard of H5N1, the bird flu or avian flu.
-Avian flu occurs naturally in birds.
-Since 1996, we have seen an increase in the number of H5N1 cases that have spread from bird to human.
-Flu viruses are very smart and mutate in order to survive.
-If the H5N1 mutates into a virus that can spread from human-to-human, we are likely to have a deadly pandemic on our hands.

66. H5N1 Transmission Bird  Human Human  Human
Handling live diseased birds
Preparing dead diseased birds
Eating undercooked poultry
Human  Human
Rare
2004 Thailand
2006 Indonesia
Takes a large inoculum, not very contagious
Case contacts, HCW’s rare seroconversion – can’t exclude separate poultry exposure
For seasonal flu, human to human transmission occurs from coughing/sneezing/talking via droplets, also hand to hand
Courtesy of Dr. Steve Lawrence 66

67. What is Pandemic Influenza?
An influenza pandemic occurs when a new influenza virus appears against which the human population has no immunity, resulting in several, simultaneous epidemics worldwide with enormous numbers of deaths and illness.
-A virus to which people have little or no immunity.
-It spreads easily and quickly from person to person.
-It causes serious illness and even death.
-This picture shows a mail carrier in Seattle during the 1918 pandemic.

68. How Influenza Can Spread Between People
Influenza is thought to be primarily spread through large droplets (droplet transmission) that directly contact the nose, mouth or eyes.
Droplets are produced when infected people cough, sneeze or talk, sending the relatively large infectious droplets and very small sprays (aerosols) into the nearby air and into contact with other people.
Large droplets can only travel a limited range; therefore, people should limit close contact (within 6 feet) with others when possible.