Transcript INFLUENZA

INFLUENZA VIRUS
INFLUENZA VIRUS
CDC WEBSITE
http://www.cdc.gov/ncidod/diseases/flu/fluinfo.htm
1
•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.
•http://www.cdc.gov/mmwr/preview/mmwrhtml/mm58d0421a1.htm
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‘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’
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South Carolina 1996-1997 DHEC bulletin
malathia influenzae per le stelle
no virus
CULTURE
RESULTS
influenza A
influenza B
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http://www.state.sc.us/dhec/LAB/labbu017.htm
SEASONAL INFLUENZA
THE IMPACT OF INFLUENZA
PANDEMICS
Deaths:
1918-19 Spanish flu
>675,000 US
>50,000,000 world
1957-58 Asian flu
70,000 US
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THE IMPACT OF INFLUENZA
• In the US, 1990-1999, on average:
• 36,000 deaths per year
• 226,000 hospitalizations per year
http://www.cdc.gov/flu/professionals/acip/clinical.htm
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ORTHOMYXOVIRUSES
• pleomorphic
• influenza types A,B,C
• febrile, respiratory
illness with systemic
symptoms
http://www.uct.ac.za/depts/mmi/stannard/fluvirus.html
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ORTHOMYXOVIRUSES
HA - hemagglutinin
NA - neuraminidase
helical nucleocapsid (RNA plus
NP protein)
lipid bilayer membrane
polymerase complex
M1 protein
type A, B, C : NP, M1 protein
sub-types: HA or NA protein
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TRANSMISSION
• AEROSOL
– 100,000 TO 1,000,000
VIRIONS PER DROPLET
• SURFACES
- VIRUS CAN SURVIVE
APPROX 2 TO 8 HRS
• 18-72 HR INCUBATION
• SHEDDING
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RECOVERY
• INTERFERON - SIDE EFFECTS
INCLUDE:
– FEVER, MYALGIA, FATIGUE, MALAISE
• CELL-MEDIATED IMMUNE RESPONSE
• TISSUE REPAIR
– CAN TAKE SOME TIME
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An immunological diversion
INTERFERON
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INTERFERON
time course of virus production will vary from virus to virus
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INTERFERON
13
INTERFERON
antiviral state
antiviral state
antiviral state
antiviral state
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INTERFERON
antiviral state
antiviral state
antiviral state
antiviral state
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INTERFERON
antiviral state
antiviral state
antiviral state
antiviral state
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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
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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
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INTERFERON
• induces variety of proteins in target cells
• many consequences, not all fully
understood
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INTERFERON-ALPHA AND
INTERFERON-BETA
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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
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interferon-alpha, interferon-beta
interferon receptor
induction of
2’5’oligo A synthase
ds RNA
induction of
ribonuclease L
2’5’oligo A
activated
2’5’oligo A synthase
activated
ribonuclease L
induction of
protein kinase R (PKR)
ds RNA
activated
protein kinase R
ATP
ATP
phosphorylated initiation
factor (eIF-2)
2’5’oligo A
mRNA degraded
inhibition of protein synthesis
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interferons
• only made when needed
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OTHER EFFECTS OF
INTERFERONS
• ALL TYPES
– INCREASE MHC I EXPRESSION
• CYTOTOXIC T-CELLS
– ACTIVATE NK CELLS
• CAN KILL VIRALLY INFECTED CELLS
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OTHER EFFECTS OF
INTERFERONS
• INTERFERON-GAMMA
– INCREASES MHC II EXPRESSION ON APC
• HELPER T-CELLS
– INCREASES ANTIVIRAL POTENTIAL OF
MACROPHAGES
• INTRINSIC
• EXTRINSIC
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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
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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!
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SIDE EFFECTS OF
INTERFERONS
•
•
•
•
FEVER
MALAISE
FATIGUE
MUSCLE PAINS
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BACK TO INFLUENZA
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SYMPTOMS
•
•
•
•
•
•
•
FEVER
HEADACHE
MYALGIA
COUGH
RHINITIS
OCULAR SYMPTOMS
GI tract symptoms not typically seen
– but common with 2009 H1N1 influenza (‘swine
flu’)
• vomiting, diarrhea
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INTERFERON
time course of virus production will vary from virus to virus
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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)
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CLINICAL FINDINGS
• SEVERITY
– VERY YOUNG
– ELDERLY
– IMMUNOCOMPROMISED
– HEART OR LUNG
DISEASE
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PULMONARY
COMPLICATIONS
• CROUP (YOUNG CHILDREN)
• PRIMARY INFLUENZA VIRUS
PNEUMONIA
• SECONDARY BACTERIAL INFECTION
– Streptococcus pneumoniae
– Staphlyococcus aureus
– Hemophilus influenzae
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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
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Reye’s syndrome
•
•
•
•
liver - fatty deposits
brain - edema
vomiting, lethargy, coma
risk factors
– youth
– certain viral infections (influenza, chicken
pox)
– aspirin
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Guillian-Barré syndrome
•
•
•
•
•
peripheral nervous system involved
autoimmune
3000-6000 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
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SEASONAL INFLUENZA
MORTALITY
• MAJOR CAUSES OF INFLUENZA
VIRUS- ASSOCIATED DEATH
– BACTERIAL PNEUMONIA
– CARDIAC FAILURE
• 90% OF DEATHS IN THOSE OVER 65
YEARS OF AGE
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DIAGNOSIS
• ISOLATION
– NOSE, THROAT SWAB
– GROW IN TISSUE CULTURE OR EGGS
•
•
•
•
SEROLOGY
PCR
RAPID TESTS
provisional - clinical picture + outbreak
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HA protein - attachment, fusion
membrane
S
S
inside of virion
host enzymes
S
S
=antibody
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NA protein - neuraminidase
membrane
inside of virion
=antibody
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ANTIGENIC DRIFT
• HA and NA accumulate mutations
– RNA virus
• immune response no longer protects
fully
• sporadic outbreaks, limited epidemics
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ANTIGENIC SHIFT
• “new” HA or NA proteins
• pre-existing antibodies do not protect
• may get pandemics
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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
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Where do “new” HA and NA come from?
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Where do “new” HA and NA come from
2009 PANDEMIC H1N1?
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Where do “new” HA and NA come from
- can ‘new’ bird flu directly infect humans?
Current “Bird flu” H5N1?
1918 influenza
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H5N1 – in birds
• Avian H5N1 has spread to humans
• So far human cases in Asia and Africa
– 442 cases (12-1-03 through 09-24-09)
– 262 (59%) fatal
• Have been a few instances where may have
spread human-to-human
• So far no sustained spread in humans
• Surveillance continues
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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.
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http://www.cdc.gov/h1n1flu/update.htm
why do we not have influenza
B pandemics?
• so far no shifts
have been
recorded
• no animal
reservoir
known
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SURVEILLANCE
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http://www.csiro.au/science/AIatAAHL.html
% typed cases
80
A - HI
A - H3
B
70
60
50
40
30
20
10
0
05/06
06/07
07/08
influenza season
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actual percentage of deaths
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CDC: http://www.cdc.gov/flu/weekly/
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 2009-2010 trivalent vaccine for seasonal influenza
has:
A/Brisbane/59/2007 (H1N1)-like
A/Brisbane/10/2007 (H3N2)-like
B/Brisbane/60/2008
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VACCINE
• inactivated (trivalent inactivated influenza
vaccine, TIV)
– egg grown
– some formulations licensed for children
• reassortant, trivalent live vaccine (live attenuated
vaccine, LAIV)
– egg grown
– 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)
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usual timing – 2009
rather different
CDC
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•http://www.cdc.gov/flu/professionals/acip/flu_vax_adults0910.htm#box2
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•http://www.cdc.gov/flu/professionals/acip/flu_vax_children0910.htm#box1
PREVENTION - DRUGS
•
ZANAMIVIR
(NA)
• types A and B
•
OSELTAMIVIR
(NA)
• types A and B
•
RIMANTADINE
(M2)
• type A only
•
AMANTADINE
(M2)
• type A only
•
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
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TREATMENT - DRUGS
• ZANAMIVIR (NA)
• types A and B, needs to be given early
• OSELTAMIVIR (NA)
• types A and B, needs to be given early
• (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) –
• type A only, needs to be given early
• currently resistance problems so not recommended
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NA protein - neuraminidase
.
.
.
.
.
. . .
.
.
..
...
.
.
.
.
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OTHER TREATMENT
• REST, LIQUIDS, ANTI-FEBRILE
AGENTS (NO ASPIRIN FOR AGES
6MTHS-18YRS)
• BE AWARE OF COMPLICATIONS AND
TREAT APPROPRIATELY
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severity of illness
animal reservoir
human pandemics
human epidemics
antigenic changes
segmented genome
amantadine, rimantidine
zanamivir,
oseltamivir
surface glycoproteins
TYPE A
TYPE B
TYPE C
++++
yes
yes
yes
shift, drift
yes
(sensitive)
sensitive
(sensitive)
2
++
no
no
yes
drift
yes
no effect
sensitive
sensitive
2
+
no
no
no (sporadic)
drift
yes
no effect
(1)
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seasonal
pandemic
•
Outbreaks follow predictable seasonal patterns;
occurs annually, usually in winter, in temperate
climates
•
Occurs rarely (a few times a century)
•
Usually some immunity built up from previous
exposure
•
No previous exposure; little or no pre-existing
immunity
•
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
•
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
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
•
•
•
•
•
•
•
•
•
•
•
Number of deaths could be quite high (e.g.,
U.S. 1918 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
64
www.pandemicflu.gov/season_or_pandemic.html
•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.
•http://www.cdc.gov/mmwr/preview/mmwrhtml/mm58d0421a1.htm
65
the end...............
66
SEASONAL INFLUENZA
http://www.cdc.gov/flu/professionals/acip/clinical.htm#signs
67
•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)
68
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 personto-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
•http://www.cdc.gov/h1n1flu/background.htm
69
06-19-2009
•
•
•
The first novel H1N1 patient in the United States was confirmed by laboratory
testing at CDC on April 15, 2009. The second patient was confirmed on April 17,
2009. It was quickly determined that the virus was spreading from person-toperson. 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 2009. 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.
70
http://www.cdc.gov/h1n1flu/update.htm - downloaded 6/22/09
71
SEASONAL INFLUENZA
Influenza - USA
•Estimated rates of influenza-associated
hospitalizations and deaths varied substantially by age
group in studies conducted during different influenza
epidemics.
•During 1990--1999, estimated average rates of
influenza-associated pulmonary and circulatory deaths
per 100,000 persons were:
•0.4--0.6 among persons aged 0--49 years
•7.5 among persons aged 50--64 years
•98.3 among persons aged 65 years and older.
http://www.cdc.gov/flu/professionals/acip/clinical.htm#signs
72
Novel H1N1 U.S. Hospitalization Rate per 100,000
Population, By Age Group (07-31-09)
http://www.cdc.gov/h1n1flu/surveillanceqa.htm
73
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.
2009 PANDEMIC INFLUENZA
•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.
74
•http://www.who.int/csr/disease/swineflu/notes/h1n1_pregnancy_20090731/en/index.html , downloaded 7-31-09