1. INFLUENZA VIRUS INFLUENZA VIRUS CDC WEBSITE

2. Swine Influenza A (H1N1) Infection in Two Children --- Southern California, March--April 2009
On April 17, 2009, CDC determined that two cases of febrile respiratory illness occurring in children who resided in adjacent counties in southern California were caused by infection with a swine influenza A (H1N1) virus. The viruses from the two cases are closely related genetically, resistant to amantadine and rimantadine, and contain a unique combination of gene segments that previously has not been reported among swine or human influenza viruses in the United States or elsewhere. Neither child had contact with pigs; the source of the infection is unknown. Investigations to identify the source of infection and to determine whether additional persons have been ill from infection with similar swine influenza viruses are ongoing. Although this is not a new subtype of influenza A in humans, concern exists that this new strain of swine influenza A (H1N1) is substantially different from human influenza A (H1N1) viruses, that a large proportion of the population might be susceptible to infection, and that the seasonal influenza vaccine H1N1 strain might not provide protection. The lack of known exposure to pigs in the two cases increases the possibility that human-to-human transmission of this new influenza virus has occurred. Clinicians should consider animal as well as seasonal influenza virus infections in their differential diagnosis of patients who have febrile respiratory illness and who 1) live in San Diego and Imperial counties or 2) traveled to these counties or were in contact with ill persons from these counties in the 7 days preceding their illness onset, or 3) had recent exposure to pigs.
Editorial Note (
In the past, CDC has received reports of approximately one human swine influenza virus infection every 1--2 years in the United States (2,3). However, during December January 2009, 12 cases of human infection with swine influenza were reported; five of these 12 cases occurred in patients who had direct exposure to pigs, six in patients reported being near pigs, and the exposure in one case was unknown (1,4,5). In the United States, novel influenza A virus infections in humans, including swine influenza infections, have been nationally notifiable conditions since The recent increased reporting might be, in part, a result of increased influenza testing capabilities in public health laboratories, but genetic changes in swine influenza viruses and other factors also might be a factor (1,4,5). Although the vast majority of human infections with animal influenza viruses do not result in human-to-human transmission (2,3), each case should be fully investigated to be certain that such viruses are not spreading among humans and to limit further exposure of humans to infected animals, if infected animals are identified. Such investigations should include close collaboration between state and local public health officials with animal health officials.

3. ‘FLU’
True influenza
influenza virus A or influenza virus B
(or influenza virus C infections - much milder)
Febrile respiratory disease with systemic symptoms caused by a variety of other organisms often inaccurately called ‘flu’

4. South Carolina 1996-1997 DHEC bulletin
malathia influenzae per le stelle
no virus
CULTURE
RESULTS
influenza A
influenza B
SEASONAL INFLUENZA

5. THE IMPACT OF INFLUENZA PANDEMICS
Deaths:
figures have been revised upwards in recent years, so this is higher than will find in older books.
Remember US population in 1918 about 1/3 of what it is now ~100,000,000, current ~300,000,000

6. THE IMPACT OF INFLUENZA
In the US, , on average:
36,000 deaths per year
226,000 hospitalizations per year
Figures have tended to increase recently - in part due to aging of population?

7. ORTHOMYXOVIRUSES pleomorphic influenza types A,B,C
febrile, respiratory illness with systemic symptoms

8. ORTHOMYXOVIRUSES type A, B, C : NP, 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

9. TRANSMISSION AEROSOL SURFACES 18-72 HR INCUBATION SHEDDING
100,000 TO 1,000,000 VIRIONS PER DROPLET
SURFACES
- VIRUS CAN SURVIVE APPROX 2 TO 8 HRS
18-72 HR INCUBATION
SHEDDING :
One study showed that influenza virus can survive on environmental surfaces and can infect a person for up to 2-8 hours after being deposited on the surface. To reduce the chance of spread of the novel influenza A (H1N1) virus, disinfect commonly-touched hard surfaces in the workplace, such as work stations, counter tops, door knobs, and bathroom surfaces by wiping them down with a household disinfectant according to directions on the product label.

10. RECOVERY INTERFERON - SIDE EFFECTS INCLUDE:
FEVER, MYALGIA, FATIGUE, MALAISE
CELL-MEDIATED IMMUNE RESPONSE
TISSUE REPAIR
CAN TAKE SOME TIME

11. An immunological diversion
INTERFERON

12. INTERFERON
time course of virus production will vary from virus to virus

13. INTERFERON

14. INTERFERON
antiviral state

15. INTERFERON
antiviral state

16. INTERFERON
antiviral state

17. TYPES OF INTERFERON TYPE I
Interferon-alpha (leukocyte interferon, about 20 related proteins)
- leukocytes, etc
Interferon-beta (fibroblast interferon)
- fibroblasts, epithelial cells, etc
TYPE II
Interferon-gamma (immune interferon)
- certain activated T-cells, NK cells

18. INDUCTION OF INTERFERON
interferon-alpha and interferon-beta
induced by
viral infection (especially RNA viruses)
double stranded RNA
certain bacterial components
- strong anti-viral properties
interferon-gamma
- antigens, mitogenic stimulation of lymphocytes

19. INTERFERON induces variety of proteins in target cells
many consequences, not all fully understood

20. INTERFERON-ALPHA AND INTERFERON-BETA

21. interferon-alpha, interferon-beta
interferon receptor
induction of
2’5’oligo A synthase
induction of
ribonuclease L
induction of
protein kinase R (PKR)
2’5’oligo A
activated
2’5’oligo A synthase
activated
ribonuclease L
activated
protein kinase R
ATP
ATP
phosphorylated initiation factor (eIF-2)
2’5’oligo A
mRNA degraded
inhibition of protein synthesis

22. interferon-alpha, interferon-beta
interferon receptor
induction of
2’5’oligo A synthase
induction of
ribonuclease L
induction of
protein kinase R (PKR)
ds RNA
ds RNA
2’5’oligo A
activated
2’5’oligo A synthase
activated
ribonuclease L
activated
protein kinase R
ATP
ATP
phosphorylated initiation factor (eIF-2)
2’5’oligo A
mRNA degraded
inhibition of protein synthesis

23. interferons
only made when needed

24. OTHER EFFECTS OF INTERFERONS
ALL TYPES
INCREASE MHC I EXPRESSION
CYTOTOXIC T-CELLS
ACTIVATE NK CELLS
CAN KILL VIRALLY INFECTED CELLS

25. OTHER EFFECTS OF INTERFERONS
INTERFERON-GAMMA
INCREASES MHC II EXPRESSION ON APC
HELPER T-CELLS
INCREASES ANTIVIRAL POTENTIAL OF MACROPHAGES
INTRINSIC
EXTRINSIC

26. THERAPEUTIC USES OF INTERFERONS
ANTI-VIRAL
e.g. interferon-alpha is currently approved for certain cases of acute and chronic HCV and chronic HBV
MACROPHAGE ACTIVATION
interferon-gamma has been tried for e.g. lepromatous leprosy, leishmaniasis, toxoplasmosis
ANTI-TUMOR
have been used in e.g. melanoma, Kaposi’s sarcoma, CML
MULTIPLE SCLEROSIS
interferon-beta

27. Viral response to host immune system
Viruses may :
block interferon binding
inhibit function of interferon-induced proteins
interfere with MHC I or MHC II expression
inhibit NK function
block complement activation
inhibit apoptosis
etc!

28. SIDE EFFECTS OF INTERFERONS
FEVER
MALAISE
FATIGUE
MUSCLE PAINS

29. BACK TO INFLUENZA

30. SYMPTOMS FEVER HEADACHE MYALGIA COUGH RHINITIS OCULAR SYMPTOMS
GI tract symptoms not typically seen
but common with 2009 H1N1 influenza (‘swine flu’)
vomiting, diarrhea

31. INTERFERON
time course of virus production will vary from virus to virus

32. PROTECTION AGAINST RE-INFECTION
IgG and IgA
IgG less efficient but lasts longer
antibodies to both HA and NA important
antibody to HA more important (can neutralize)

33. CLINICAL FINDINGS SEVERITY VERY YOUNG ELDERLY IMMUNO-COMPROMISED
HEART OR LUNG DISEASE

34. PULMONARY COMPLICATIONS
CROUP (YOUNG CHILDREN)
PRIMARY INFLUENZA VIRUS PNEUMONIA
SECONDARY BACTERIAL INFECTION
Streptococcus pneumoniae
Staphlyococcus aureus
Hemophilus influenzae

35. NON-PULMONARY COMPLICATIONS
myositis (rare, > in children, > with type B)
cardiac complications
encephalopathy
2002/2003 season studies of patients younger than 21 yrs in Michigan - 8 cases (2 deaths)
liver and CNS
Reye’s syndrome
peripheral nervous system
Guillian-Barré syndrome

36. Reye’s syndrome liver - fatty deposits brain - edema
vomiting, lethargy, coma
risk factors
youth
certain viral infections (influenza, chicken pox)
aspirin

37. Guillian-Barré syndrome
peripheral nervous system involved
autoimmune
cases per year US
most recover fully
may follow infectious disease
Campylobacter jejuni one of most common risk factors
may be associated with some viral infections
1976/77 swine flu vaccine
35,000,000 doses
354 cases of GBS (approx 1-2 additional cases per 100,000 vaccinated)
28 GBS-associated deaths
recent infuenza vaccines much lower risk
risk from vaccination much lower than risk from infection
About two-thirds of people who develop GBS symptoms do so several days or weeks after they have been sick with a diarrheal or respiratory illness. Infection with the bacterium Campylobacter jejuni is one of the most common risk factors for GBS. People can also develop GBS after having the flu or other infections (such as cytomegalovirus and Epstein Barr virus). On very rare occasions, they may develop GBS in the days or weeks following receiving a vaccination.

38. MORTALITY MAJOR CAUSES OF INFLUENZA VIRUS- ASSOCIATED DEATH
SEASONAL INFLUENZA
MORTALITY
MAJOR CAUSES OF INFLUENZA VIRUS- ASSOCIATED DEATH
BACTERIAL PNEUMONIA
CARDIAC FAILURE
90% OF DEATHS IN THOSE OVER 65 YEARS OF AGE

39. DIAGNOSIS ISOLATION SEROLOGY PCR RAPID TESTS
NOSE, THROAT SWAB
GROW IN TISSUE CULTURE OR EGGS
SEROLOGY
PCR
RAPID TESTS
provisional - clinical picture + outbreak
Rapid tests - signifcance in ascertaining whether the infection is influenza and which type it is since now have therapeutic agents (some of which are type specific)
- signifcance in differential diagnosis - eg if need to determine if Flu v. SARS
- advent of rapid easy tests may increase diagnosis - may realise that flu involved in more illnesses than realised (eg enhanced surveillance of patients <21 at low risk for complications who were admitted to hospital for a variety of symptoms revealed that more severe morbitity and mortality assoc with influenza that was realised -2003).

40. HA protein - attachment, fusion
membrane S
host enzymes
inside of virion
=antibody

41. NA protein - neuraminidase
membrane
inside of virion
=antibody

42. ANTIGENIC DRIFT HA and NA accumulate mutations
RNA virus
immune response no longer protects fully
sporadic outbreaks, limited epidemics

43. ANTIGENIC SHIFT “new” HA or NA proteins
pre-existing antibodies do not protect
may get pandemics

44. where do “new” HA and NA come from?
~16 types HA
~9 types NA
all circulate in birds
pigs
can be infected by avian and human influenza viruses

45. Where do “new” HA and NA come from?

46. Where do “new” HA and NA come from 2009 PANDEMIC H1N1?

47. Where do “new” HA and NA come from - can ‘new’ bird flu directly infect humans?
Current “Bird flu” H5N1?
1918 influenza

48. H5N1 – in birds Avian H5N1 has spread to humans
So far human cases in Asia and Africa
442 cases ( through )
262 (59%) fatal
Have been a few instances where may have spread human-to-human
So far no sustained spread in humans
Surveillance continues

49. 2009 NOVEL H1N1 PANDEMIC
first novel H1N1 patient in the United States confirmed by laboratory testing at CDC on April 15, 2009.
Quickly determined that the virus was spreading from person-to-person.
By June 3, 2009, all 50 states in the United States and the District of Columbia and Puerto Rico were reporting cases of novel H1N1 infection.

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

51. SURVEILLANCE

52. % typed cases
influenza season

53. actual percentage of deaths
CDC:

54. VACCINE ‘BEST GUESS’ OF MAIN ANTIGENIC TYPES
CURRENTLY SEASONAL VACCINE TRIVALENT
type A - H1N1
type A - H3N2
type B
each year choose which strain of each subtype is the best to use for optimal protection
the trivalent vaccine for seasonal influenza has:
A/Brisbane/59/2007 (H1N1)-like
A/Brisbane/10/2007 (H3N2)-like
B/Brisbane/60/2008

55. VACCINE inactivated (trivalent inactivated influenza vaccine, TIV)
egg grown
some formulations licensed for children
reassortant, trivalent live vaccine (live attenuated vaccine, LAIV)
for healthy non-pregnant persons (those not at risk for complications from influenza infection) ages 2-49 years
(not approved for children under 5yrs with a history of recurrent wheezing)

56. usual timing – 2009 rather different
CDC

57. http://www. cdc. gov/flu/professionals/acip/flu_vax_adults0910

58. http://www. cdc. gov/flu/professionals/acip/flu_vax_children0910

59. PREVENTION - DRUGS
ZANAMIVIR (NA)
types A and B
OSELTAMIVIR (NA)
RIMANTADINE (M2)
type A only
AMANTADINE (M2)
2005 to present: high levels of resistance of influenza A viruses to amantidine and rimantidine, so these drugs not recommended until resistance drops
have been reports of some strains being oseltamivir resistant
pandemic 2009 H1N1 is sensitive
surveillance and rapid diagnosis techniques important in determining optimal drug treatment

60. TREATMENT - DRUGS ZANAMIVIR (NA) OSELTAMIVIR (NA) RIMANTADINE (M2)
types A and B, needs to be given early
OSELTAMIVIR (NA)
(some resistant strains but resistant strains currently still sensitive to zanamivir)
RIMANTADINE (M2)
type A only, needs to be given early
currently resistance problems so not recommended
AMANTADINE (M2) –

61. NA protein - neuraminidase. . . . . . . . . . . . . . . . . . .

62. OTHER TREATMENT
REST, LIQUIDS, ANTI-FEBRILE AGENTS (NO ASPIRIN FOR AGES 6MTHS-18YRS)
BE AWARE OF COMPLICATIONS AND TREAT APPROPRIATELY

63. severity of illness
animal reservoir
human pandemics
human epidemics
antigenic changes
segmented genome
amantadine, rimantidine
zanamivir,
oseltamivir
surface glycoproteins
TYPE A
++++
yes
shift, drift
(sensitive)
sensitive 2
TYPE B ++ no
yes
drift
no effect
sensitive 2
TYPE C + no
no (sporadic)
drift
yes
no effect
(1)

64. seasonal
pandemic
Outbreaks follow predictable seasonal patterns; occurs annually, usually in winter, in temperate climates
Usually some immunity built up from previous exposure
Healthy adults usually not at risk for serious complications; the very young, the elderly and those with certain underlying health conditions at increased risk for serious complications
Health systems can usually meet public and patient needs
Vaccine developed based on known flu strains and available for annual flu season
Adequate supplies of antivirals are usually available
Average U.S. deaths approximately 36,000/yr
Symptoms: fever, cough, runny nose, muscle pain. Deaths often caused by complications, such as pneumonia.
Generally causes modest impact on society (e.g., some school closing, encouragement of people who are sick to stay home)
Manageable impact on domestic and world economy
Occurs rarely (a few times a century)
No previous exposure; little or no pre-existing immunity
Healthy people may be at increased risk for serious complications
Health systems may be overwhelmed
Vaccine probably would not be available in the early stages of a pandemic
Effective antivirals may be in limited supply
Number of deaths could be quite high (e.g., U.S death toll approximately 675,000)
Symptoms may be more severe and complications more frequent
May cause major impact on society (e.g. widespread restrictions on travel, closings of schools and businesses, cancellation of large public gatherings)
Potential for severe impact on domestic and world economy

65. Swine Influenza A (H1N1) Infection in Two Children --- Southern California, March--April 2009
On April 17, 2009, CDC determined that two cases of febrile respiratory illness occurring in children who resided in adjacent counties in southern California were caused by infection with a swine influenza A (H1N1) virus. The viruses from the two cases are closely related genetically, resistant to amantadine and rimantadine, and contain a unique combination of gene segments that previously has not been reported among swine or human influenza viruses in the United States or elsewhere. Neither child had contact with pigs; the source of the infection is unknown. Investigations to identify the source of infection and to determine whether additional persons have been ill from infection with similar swine influenza viruses are ongoing. Although this is not a new subtype of influenza A in humans, concern exists that this new strain of swine influenza A (H1N1) is substantially different from human influenza A (H1N1) viruses, that a large proportion of the population might be susceptible to infection, and that the seasonal influenza vaccine H1N1 strain might not provide protection. The lack of known exposure to pigs in the two cases increases the possibility that human-to-human transmission of this new influenza virus has occurred. Clinicians should consider animal as well as seasonal influenza virus infections in their differential diagnosis of patients who have febrile respiratory illness and who 1) live in San Diego and Imperial counties or 2) traveled to these counties or were in contact with ill persons from these counties in the 7 days preceding their illness onset, or 3) had recent exposure to pigs.
Editorial Note (
In the past, CDC has received reports of approximately one human swine influenza virus infection every 1--2 years in the United States (2,3). However, during December January 2009, 12 cases of human infection with swine influenza were reported; five of these 12 cases occurred in patients who had direct exposure to pigs, six in patients reported being near pigs, and the exposure in one case was unknown (1,4,5). In the United States, novel influenza A virus infections in humans, including swine influenza infections, have been nationally notifiable conditions since The recent increased reporting might be, in part, a result of increased influenza testing capabilities in public health laboratories, but genetic changes in swine influenza viruses and other factors also might be a factor (1,4,5). Although the vast majority of human infections with animal influenza viruses do not result in human-to-human transmission (2,3), each case should be fully investigated to be certain that such viruses are not spreading among humans and to limit further exposure of humans to infected animals, if infected animals are identified. Such investigations should include close collaboration between state and local public health officials with animal health officials.

66. the end

67. SEASONAL INFLUENZA

68. Novel Influenza A Virus – Jan 24th 2009 (week 3)
One case of human infection with a novel influenza A virus was reported by the South Dakota Department of Health during week 3. The person was infected with a swine influenza A (H1N1) virus, and an investigation is currently underway to determine the source of illness. Although human infection with swine influenza is uncommon, sporadic cases have occurred in many years, usually among people in direct contact with ill pigs or who have been in places where pigs may have been present (e.g. agricultural fairs or farms). The sporadic cases of human infections with swine influenza viruses identified in recent years have not resulted in sustained human-to-human transmission or community outbreaks. Nonetheless, when cases are identified, CDC recommends thorough investigations to evaluate the extent of the outbreak and possible human to human transmission, as transmission patterns may change with changes in swine influenza viruses.
(This was a regular swine flu virus, not the pandemic strain)

69. Public health response – 2009
April 15, 2009
The first novel H1N1 patient in the US was confirmed by laboratory testing at CDC.
April 17, 2009
The second patient was confirmed.
It was quickly determined that the virus was spreading from person-to-person.
April 22, 2009
CDC activated its Emergency Operations Center to better coordinate the public health response
April 26, 2009
The US Government declared a public health emergency and actively implemented the nation’s pandemic response plan

70. 06-19-2009 http://www.cdc.gov/h1n1flu/update.htm - downloaded 6/22/09
The first novel H1N1 patient in the United States was confirmed by laboratory testing at CDC on April 15, The second patient was confirmed on April 17, It was quickly determined that the virus was spreading from person-to-person. On April 22, CDC activated its Emergency Operations Center to better coordinate the public health response. On April 26, 2009, the United States Government declared a public health emergency and has been actively and aggressively implementing the nation’s pandemic response plan.
Since the outbreak was first detected, an increasing number of U.S. states have reported cases of novel H1N1 influenza with associated hospitalizations and deaths. By June 3, 2009, all 50 states in the United States and the District of Columbia and Puerto Rico were reporting cases of novel H1N1 infection.
June 19th While nationwide U.S. influenza surveillance systems indicate that overall influenza activity is decreasing in the country at this time, novel H1N1 outbreaks are ongoing in parts of the U.S., in some cases with intense activity. CDC is continuing to watch the situation carefully, to support the public health response and to gather information about this virus and its characteristics. The Southern Hemisphere is just beginning its influenza season and the experience there may provide valuable clues about what may occur in the Northern Hemisphere this fall and winter.
- downloaded 6/22/09

71. CDC site – for 2007
Influenza-Associated Pediatric Hospitalizations:
Laboratory-confirmed influenza-associated pediatric hospitalizations are monitored in two population-based surveillance networks: the Emerging Infections Program (EIP) and the New Vaccine Surveillance Network (NVSN). EIP estimated rates of hospitalization for influenza will be reported every two weeks beginning October 26, NVSN estimated rates of hospitalization for influenza will be reported every two weeks, beginning November 30, 2007.

72. Influenza - USA SEASONAL INFLUENZA
Estimated rates of influenza-associated hospitalizations and deaths varied substantially by age group in studies conducted during different influenza epidemics.
During , estimated average rates of influenza-associated pulmonary and circulatory deaths per 100,000 persons were:
among persons aged years
7.5 among persons aged years
98.3 among persons aged 65 years and older.

73. Novel H1N1 U.S. Hospitalization Rate per 100,000 Population, By Age Group (07-31-09)
                                                                                                                                                

74. 2009 PANDEMIC INFLUENZA Danger signs in all patients
Worldwide, the majority of patients infected with the pandemic virus continue to experience mild symptoms and recover fully within a week, even in the absence of any medical treatment.
In addition to the enhanced risk documented in pregnant women, groups at increased risk of severe or fatal illness include people with underlying medical conditions, most notably chronic lung disease (including asthma), cardiovascular disease, diabetes, and immunosuppression. Some preliminary studies suggest that obesity, and especially extreme obesity, may be a risk factor for more severe disease.
Within this largely reassuring picture, a small number of otherwise healthy people, usually under the age of 50 years, experience very rapid progression to severe and often fatal illness, characterized by severe pneumonia that destroys the lung tissue, and the failure of multiple organs. No factors that can predict this pattern of severe disease have yet been identified, though studies are under way.
As progression can be very rapid, medical attention should be sought when any of the following danger signs appear in a person with confirmed or suspected H1N1 infection:
shortness of breath, either during physical activity or while resting
difficulty in breathing
turning blue
bloody or colored sputum
chest pain
altered mental status
high fever that persists beyond 3 days
low blood pressure
In children, danger signs include fast or difficult breathing, lack of alertness, difficulty in waking up, and little or no desire to play.
2009 PANDEMIC INFLUENZA
, downloaded