Transcript Influenza 1999

Influenza
• “probably the most under-rated major
pathogen in the developed world…”
• John Barlett, Update in Infectious
Diseases
– Annals of Internal Medicine August 1999
Case 1
• 38 year-old man
presented February
• 2-day history of fever,
chills, cough, sore
throat, nasal
congestion, muscle
aches, headache,
fatigue
• Did not receive flu
vaccine
“Influenza-like illness”
• Recent, acute onset
• Fever or feverishness
• Respiratory (cough, sore throat,
coryza) and systemic (malaise,
headache, myalgias) components
Influenza in Healthy, Young and
Middle-aged, Unvaccinated Adults
Symptom
Labconfirmed
flu
(n=2470)
No labLikelihoo
confirmed
d Ratio
flu (n=1274)
Fever(>37.8)
68%
40%
1.7
Feverishness
90%
89%
1.0
Cough
93%
80%
1.2
Nasal congestion
91%
81%
1.1
Sore throat
84%
84%
1.0
Headache
91%
89%
1.0
Myalgia
94%
94%
1.0
Monto et al. Arch Intern Med 2000; 160: 3243.
Recognizing influenza in
hospitalized patients?
Influenza Bacteria
(n=65)
(n=93)
Atypical
fever
75
77
67
cough
78
73
83
CXR “pneum”
25
54
60
CXR “clear”
38
16
10
WBC < 12,000
78
40
55
(n=89)
Dowell et al. JID 1996; 174:456.
Influenza in a Fully-Immunized
Veteran COPD Population
Symptom
LabNo labLikelihood
confirmed confirmed Ratio
flu (n=107) flu (n=279)
Fever(>100)
50
44
1.1
Chills
68
57
1.2
Cough
93
92
1.0
Nasal
congestion
84
90
.93
Sore throat
62
56
1.1
Headache
72
65
1.1
Myalgia
84
64
1.3
Neuzil et al. CID 2003; 36: 169.
Accuracy of Clinical
Diagnosis
• Diagnosis from clinical signs and
symptoms is of limited accuracy
• Maintain a high index of suspicion
during the right time of year
• Other co-circulating respiratory
pathogens: Adeno; RSV;
Parainfluenza; Rhino; Strep;
Chlamydia; Mycoplasma
Seasonal Occurrence of Influenza, RSV
and Parainfluenza Viruses, United
States,1996-99
35
30
positive
% respiratory specimens
40
25
20
15
10
5
0
7/96
1/97
7/9
7
Influenza
1/98
RSV
7/98
Para 3
1/9
9
7/99
Should I perform a
diagnostic test?
• Utility of test in individual patient depends
on quality of sample, timing of sample,
turn-around time of test
• Collecting specimens still critical because it
provides information about circulating
influenza types
• BMC: Antigen testing +/- reflex PCR
[Antigen testing Sensitivity (40 - 90%)
Specificity (90 - 99%).]
• Typing is done at state labs
How and who should be
tested?
• Nasopharyngeal swabs or washes on
patients
• Immunocompetent adults at high risk for
complications who present within 5 days of
illness.
• Immunocompromised adults with acute
febrile illness regardless of time of onset
• Recently hospitalized adults with fever and
respiratory symptoms regardless of time
of onset.
Virology of Influenza A
and B
• Orthomyxoviridae
• Enveloped negative stranded RNA
viruses
• Four genera are included in this family
– Influenza A and B (human pathogens)
– Influenza C
– Thogotovirus (sometimes called Influenza
D).
Influenza A Viruses
 Subtyped
based on surface glycoproteins:
• 16 hemagglutinins (HA) and
9 neuraminidases (NA)
• current human subtypes:
H1N1, H3N2, H1N2
 Segmented genome
HA
NA
Antigenic Drift
• H1, H2, H3 / N1 and N2
• Antigenic drift:
– Both A and B
– Individual point mutations
Antigenic Shift
• Influenza A only
• Sudden appearance of
a virus with a
completely novel HA or
HA and NA.
• This occurs when a
strain of Influenza A
that usually infects
bird or other mammals
crosses over to cause
human infection.
• May result in
emergence of
pandemic strains
• Asia appears to be a
fertile ground for such
shifts.
Mechanisms of Influenza Virus Antigenic “Shift”
15 HAs
9 NAs
Non-human
virus
Human
virus
Reassortant
virus
Pandemic Influenza
• Emergence & spread of “novel”
influenza A virus
– HA (or HA/NA) derived from animal viruses
– Sustained and efficient human-human
transmission
• Near simultaneous global outbreak
• Elevated rates illness & death
The Great Influenza of
1918
• First wave less pathogenic (AprilMay), possibly beginning in Kansas and
spreading by military travel
throughout the world
• Second wave (July-Nov) much more
lethal; hemorrhagic pneumonia in
young adults
• Between 20-100 million deaths
worldwide
Barry J. The Great Influenza –
Viking
Press, 2004
Mortality Comparisons
# DEATHS
World War II
50 million
1918 Flu Epidemic
20-100 million
World War I
15 million
Ebola
1000- 2000
SARS
774
Infectious Disease Mortality,
United States - 20th Century
Armstrong, et al. JAMA 1999;281:61-66.
Pathogenesis of 1918
Influenza
• Hemagglutinin (HA) antigen the key
determinant of virulence in a mouse
model
• Massive inflammation in lungs with
cytokine “storm” and neutrophil influx
• Might immunomodulatory therapy be
a useful adjunct to appropriate
antivirals?
Timeline of Emergence of
Influenza A Viruses in Humans
Avian
Influenza
Russian
Influenza
Asian
Influenza
Spanish
Influenza
H1
1918
H9
H5
H7
H7
H5
H1
H3
H2
Hong Kong
Influenza
1957 1968 1977
2009 pandemic
H1
1997 2003 2009
1998/9
2009 Pandemic Influenza A
(H1N1)
H7N9 Virus
• Avian influenza, first reported from
China April 1, 2013
• Over 130 infections detected. Most
subjects exposure to poultry.
Reported 44 deaths.
• No evidence of sustained human to
human transmission
• If virus acquires ability for sustained
human to human transmission, then
high potential for a pandemic
Should I use antivirals?
• Amantadine and rimantadine: effective
against influenza A viruses
• Neuraminidase inhibitors: oseltamivir
(oral), zanamivir (inhaled); effective
against influenza A and B viruses
• Differ in terms of pharmacokinetics, side
effects, routes of administration, cost
Antivirals
• Neuraminidase inhibitors: Inteferes with viral
release from infected cell.
– Ostelamivir: 75 mg BID; $55; Approved for prophylaxis.
Can use higher doses
– Zanamivir: Inhalation 10 mg BID; $45
Contraindicated in people with asthma or other chronic
respiratory conditions
DURATION: Generally 5 days but can be longer in ill patients.
Antivirals
• Amantadine and rimantadine: Inteferes
with M2 protein function
– Amantadine: 100 mg BID; $2 (Neuro sideeffects)
– Rimantadine: 100 mg BID; $2; Approved for
prophylaxis.
– Associated with CNS toxicity
– Because of wide resistance, these drugs
should not be used for treatment other than
special circumstances
Antiviral Resistance
• Resistance to all drugs have been
described.
• Generally single point mutations lead to
resistance
• CDC website provides information about %
circulating variants with resistance
• Durnig 2012 – 2013 season, resistance to
Tamiflu was observed in less than 1% of
isolates.
Adverse Effects
• Ostemlavir
– Nausea and vomiting
– Mild abdominal pain
– Dosing must be modified for renal insufficiency
• Zanamavir
– Broncospasm
– Not recommended to be used with ventilation
tubing
Treatment in hospitalized
with severe disease
• Confirmed or Suspected disease
– Therapy should be initiated prior to
diagnostic test results
– With high clinical suspicion therapy
should not be stopped even if diagnostic
test is negative
– For patients with severe disease therapy
should be instituted even if they present
after 48 hours
Proportion with symptoms
Oseltamivir Reduces Time to
Alleviation of All Symptoms
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Days 0
Placebo
End of treatment
Oseltamivir
1
2
3
4
5
6
7
Treanor et al. JAMA 2000; 283: 1016.
Treatment
• Treatment best if initiated early
• Duration of illness is reduced and return to
usual activities is earlier
• Treatment reduces virus shedding
• None of the treatments has been shown to
prevent serious influenza-related
complications (bacterial pneumonia or
exacerbation of chronic disease)
Clinical Case 2
• 43yo man with CML,
chronic phase, on
interferon
• 2-week history of
sore throat, cough,
fever/chills/
myalgias/headache,
dizziness, weight loss
• ?atypical pneumonia
• Rx: azithromycin
• (in addition to
trimeth-sulfa and
PCN VK)
Clinical Case 2
• Returned 12 days
later: worsening
dyspnea, dry cough
• PE: cyanosis,
bilateral crackles
lower lung fields
• Hypoxic
• BAL: Influenza A,
Staph. Aureus
• Blood culture + S.
aureus
Complications of Influenza
• Secondary bacterial infection
(Streptococcus or Staph. Aureus)
• Myositis
• CNS
– Guillan Barre, transverse myelitis,
aseptic meningitis
• Cardiac
– Myocarditis, pericarditis, MI
Influenza Vaccine
• Each year, vaccine formulation
depends on the circulating strains.
• Since 1980s vaccine have been
trivalent although quadrivalent may
be standard at some point
• Current vaccines consist of a H1N1,
H3N2 and influenza B
Who Should be Immunized?
Persons at High Risk for Complications
• All persons aged 6 months or older
• All people including pregnant women can receive
the inactivated influenza vaccine (IIV)
• Healthy, nonpregnant person age 2 – 49 without
high risk medical conditions can receive either
intranasally administered live, attenuated
influenza vaccine (LAIV) (FluMist) or IIV.
• Health care workers who care for severely
immunocompromised persons should receive
IIV.
Efficacy of Inactivated
Influenza Vaccine
• Healthy children and adults: 70-90% in
preventing culture-confirmed influenza
• Elderly: 30-70% in preventing
hospitalization for pneumonia and influenza
• Frail elderly: 30-40% in preventing illness;
50-60% in preventing hospitalization; 80%
in preventing death
MMWR 2003;52: 1-36.
Vaccine Efficacy 2012 - 2013
• Overall effectiveness 56%
• Against H3N2 – 47%
– Only 9% for individuals 65 or older
• Against Flu B 67%
Influenza Vaccine Effectiveness:
Hospitalizations per 1000 65+
40
30
20
10
0
P&I
Acute resp
Vax
CHF
Unvax
Nichol et al. N Engl J Med 1994; 331: 778
Special Target Populations
• Healthcare workers
• Household members (including children) of persons
in high-risk groups
• Employees of chronic-care facilities, assisted
living facilities or persons who provide home care
to persons in high-risk groups
• Household and close contacts of young children (<
2 years)
MMWR 2003;52: 1-36.
Who Should Not be Immunized?
• LAIV and TIV are grown in embroyonated hens’
eggs. Therefore vaccine should not be given to
those with anaphylactic hypersensitivity to eggs or
other components of the influenza vaccine.
(Newer vaccine formulations are now available that
are egg free. Flucelvax and FluBlok)
• Persons with acute febrile illness should not be
vaccinated until their symptoms have abated
MMWR 2003;52: 1-36.
Which vaccine should I
recommend/administer?
LAIV
TIV
Route
Nasal spray
Injection
Virus
Live, attenuated
Killed
Antigens
A/H3N2, A/H1N1, B
A/H3N2, A/H1N1, B
FDA use
Healthy 2-49yrs
All > 6 mos
Schedule
Annual
Annual
Side
effects
Nasal congestion,
Sore arm
sore throat
Potential advantages of live
vaccine?
• Broad mucosal and systemic immune
response
• Ease of administration
• Intranasal route of administration
Potential disadvantages?
• Expense
• Limited viral replication and potential
for transmission (rare)
• After vaccination, antigen and PCR
tests can be positive
• Less experience
• Storage requirements
Live versus Dead
• Multiple head to head randomized
controlled trials.
– RCT in ~5000 subjects no difference
– RCT 2004/05 season in ~1300 subjects, both
vaccine similar efficacy against A but IIV
better than LAIV against B
– RCT 2007/08 season in ~2000 subjects, IIV
was more effective (72%) versus LAIV (29%)
– Surveillance study 2004 – 07 IIV associated
with lower healthcare associated visits
compared to LAIV.
Efficacy differences likely depend on year
(circulating strains) and patient characteristics
Clinical Case 3
• 56 yo man 14
days s/p
autologous
pbsct for
multiple
myeloma
• Fever, hypoxia,
respiratory
failure
Case 3
• Prescribed imipenem, tobramycin,
levofloxacin, metronidazole
• “This will cover his pulmonary
pathogen for sure”
• BAL: FA and culture positive for
influenza A virus
Nosocomial Influenza
• Outbreaks in long-term care facilities,
acute care hospitals and specialized units
well-documented in medical literature
• Testing is important
• Focus on:
– Reducing reservoirs of infection (vaccinations,
keeping ill staff and visitors out of the
hospital)
– Infection control principles
– Antivirals when needed
Effectiveness of Flu Vaccine in
Health Care Workers
• Randomized, double-blind, controlled trial
over 3 consecutive years from 1992-1995
• 264 healthy health care professionals
(75% resident physicians)
• Main outcome measure: Serologically
defined influenza infection, days of febrile
respiratory illness, days absent from work
Wilde et al. JAMA. 1999; 281: 908.
Influenza Infection During Annual
Epidemics 1992-1995
Year of
Study
Flu Vaccine
Control
1992-1993
2/52 (3.9%)
14/50 (28%)
1993-1994
0/51 (0%)
4/52 (7.1%)
1994-1995
1/77 (1.3%)
7/77 (9.1%)
Total
1992-1995
3/180
(1.7%)
25/179
(13.9%)
Influenza Vaccination of HCW in
Long-Term-Care Hospitals
• 1059 residents in 12 geriatric longterm-care hospitals in Glasgow
• Hospitals randomized for their HCWs
to be routinely offered either flu vax
or no vax
• Primary outcome: patient mortality
Potter et al. JID 1997; 175: 4.
Total Patient Mortality in LongTerm Care Hospitals
0.2
0.15
Patients Vaccinated
0.1
Patients Not Vaccinated
0.05
0
0
20
40
60
80
100
120
140
Potter et al. JID 1997; 175: 4.
Total Patient Mortality in LongTerm Care Hospitals
0.2
Staff Not Vaccinated
0.15
0.1
Staff Vaccinated
0.05
0
0
20
40
60
80
100
120
140
Potter et al. JID 1997; 175: 4.
Summary
Influenza is a major cause of morbidity,
mortality and lost productivity worldwide.
Influenza vaccine can reduce influenza and
its complications in individuals, and may
affect the spread of influenza in
populations.
Health care workers need to get the
influenza vaccine!
Avian Influenza
• Several recent outbreaks, including:
– 1997 (H5N1) in Hong Kong; 18 human
cases and 6 deaths; 20 million chickens
culled
– 2003 (H7N7) in Holland; 83 cases and 1
death; 30 million chickens killed (JID
2004;190:2088-95)
– 2004 (H7N3) in Canada (18 farms in BC);
2 humans to date; 19 million chickens
killed
– 2003/2005 (H5N1) in > 8 Asian countries
H5N1 Cases & Mortality
Through April 05, 2005*
(*more since)
Country
H5N1
Cases
Deaths
Case
Fatality
Thailand
17
12
71%
Vietnam
60
35
58%
Cambodia
1
1
100%
Total
79
49
62%
Avian Influenza Poultry Outbreaks,
Asia, 2003-04
2005 H5N1 Avian Influenza
• Continued evolution, with host range
expansion to mammals (pigs, cats,
tigers)
• Potentiated by large, densely
populated poultry farms; minimal
human to human spread so far
• Viral pneumonia and lymphopenia in
children and young adults
• Over 100 million poultry killed in Asia
Transmission of Avian Influenza
• Direct contact with infected birds or their
secretions
• Possible contacts with fomites (eg,
contaminated equipment, clothing, etc.)
• Human-human rare to date; rare
healthcare worker transmission (HK),
unlike SARS
How quickly will the next
Influenza pandemic spread?
• Larger, denser population
• Increase in international travelers
since 1918
• Experience with SARS:
Between Feb 21 – June 10,
31 countries involved
Comparisons of 1918 and
2005
• Similarities
– Likely new virus strain emerging
– ARDS in previously healthy young
adults
– High mortality
• Differences
– Better surveillance mechanisms
– Antibiotics for secondary infections
– Anti-influenza drugs and vaccines
H5N1 Vaccine Strategies
• Currently, manufacturers would need
6-10 months minimum to produce
vaccine
• Major hurdles are political and
economic, not scientific
• Some companies/governments are
testing small batches in 2005
• NIH, Japanese, and French are
beginning programs to test and
stockpile vaccines
• Avian vaccines also under study
Influenza
Type
A
B
Gene
Segments
8
7
Hosts
wide
humans
Structure
NA,HA
M2
NA,HA
Epi
shift & drift
pandemics
drift
epidemics
NA
M2
HA