Transcript Document

Influenza Update
Eliane Haron, M.D.
Influenza Viruses
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Orthomyxoviruses
Enveloped, RNA viruses
Estimated to measure 80-120 nm in
diameter
Subtypes A, B and C
• Mainly A and B cause significant infection in
humans.
• Subtype C can cause mild infection without
seasonality
Influenza – Surface Glycoproteins
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Hemaglutinin
• Sialic acid receptor-binding molecule, which
binds to sialic acid residues present on the
surface of respiratory epithelial cells.
• Mediates entry of the virus into the target cell
• 16 types H1-H16
• Mainly H1, H2, H3 cause disease in humans
Influenza- Surface Glycoproteins
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Neuraminidase
• Responsible for cleavage of the newlyformed virions from the host cell.
• Inhibition of this protein halts viral
replication.
• 9 types N1-N9
• Mostly N1 and N2 are involved in
human infections
Current circulating virus
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Since 1977, AH1N1 and A/H3N2 have
circulated along with influenza B viruses
In 2001-2002 a novel reassortment strain
A/H1N2 appeared but did not cause
extensive outbreaks
In 2004-2005, influenza A isolates were
mostly A/H3N2
Influenza - Transmission
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Usually transmitted by direct contact and inhalation of large
infectious droplets produced during coughing and sneezing
Hands and other objects can get contaminated with
infected respiratory secretions, and subsequent contact
with mucosal surfaces can transmit the virus
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Close contact needed (<3 feet)
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Droplet precautions in hospitalized patients
• For 5 days in normal hosts
• For the duration of illness in immunocompromised patients
Clinical Manifestations
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Uncomplicated Influenza
• Abrupt onset of fever, HA, myalgias, malaise
along with respiratory symptoms particularly
cough and sore throat.
• Illness usually improves/resolves in 3-7 days
• Occasional post infectious asthenia
Clinical Manifestations
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Complications
• Primary Influenza Pneumonia
• Secondary Bacterial Pneumonia
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Strep. pneumoniae; Staph aureus
Exacerbation of fever and respiratory symptoms after
initial improvement of influenza symptoms
• Other complications
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Myositis,
CNS involvement: encephalitis, transverse myelitis,
aseptic meningitis, Guillan-Barre’ syndrome.
Myocarditis and pericarditis (rare).
Influenza- Diagnosis
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Clinical Diagnosis
• Clinical diagnosis is straightforward during a flu epidemic
• In sporadic cases, symptoms can be indistinguishable from
other acute respiratory infections
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Laboratory Diagnosis
• Viral cultures of respiratory secretions (nasal washes, sputum,
throat swab, BAL)
• Rapid detection tests (EIA, IF, PCR)
• Serologic tests
Influenza- Treatment
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Adamantanes (Amantadine/Rimantadine)
• Inhibition of viral uncoating inside the host cell due to
interaction with the M2 protein of susceptible viruses
• Active against Influenza A,
• No activity against Influenza B
• Both drugs have shown a decrease in clinical symptoms
and a reduction in the levels and duration of viral
shedding
• Need to be started within 48 hours of symptoms
• Resistant isolates can develop
Influenza- Treatment
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Amantadine
• Dose:
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100mg PO q12hs x 5days for rx acute infection
100mg PO q12hs x 10 days post exposure, 2-4 wks
post vaccine
• Excreted unaltered in urine
• Needs dose correction in renal insufficiency
• CNS side effects such as insomnia, dizziness,
difficulty concentrating, seizures
• Main use: Treatment and prophylaxis
Influenza- Treatment
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Rimantadine
• Dose:
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100mgPO q12hs x 7 days for rx acute infection
• Less than 15% excreted unchanged in urine
• Dose should be decreases by half in ESRD,
hepatic insufficiency and in elderly patients
• Considerably less CNS side effects than
amantadine
Influenza- Treatment
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Neuraminidase Inhibitors:
• Zanamivir and Olseltamivir
• Active against Influenza A and B viruses
• Must be given within 48hs of development of
symptoms
• Mechanism of action: mimic the natural
substrate, fitting into the neuraminidase site of
the virus
• Halts viral replication by impeding release of
new formed virions.
Mechanism of Action of Neuraminidase Inhibitors
Moscona, A. N Engl J Med 2005;353:1363-1373
Influenza- Treatment
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Zanamivir
• Dose: two 5mg inhalations twice daily x 5 days
• Powder for inhalation
• Highly concentrated in respiratory tract when
inhaled
• No bio-availability
• Only 5%-15% of the drug is absorbed and
excreted in the urine
• Side effects: mainly bronchospasm, cough
Influenza- Treatment
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Oseltamivir
• Dose:
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75mg PO q 12hs x 5 days for Rx
75 mg PO daily for prophylaxis
• Good oral bioavailability (capsule or
suspension)
• Mainly excreted in the urine
• Needs dose correction for renal insufficiency
• Side Effects: nausea, vomiting, diarrhea
Influenza - Prevention
Influenza Vaccine
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2005-2006 vaccine strains
• A/NewCaledonia/20/99 (H1N1)
• A/California/7/2004(H3N2)
• B/Shanghai/361/2002
Coverage 2004-2005 Season
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Children 6-23 months old: 48.4%
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Adults ≥ 65 years old: 62.7%
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Non-priority adults: 8.8%
(2003-2004: 17.8%)
Centers for Disease Control and Prevention, MMWR, 2005.
Priority Groups For Influenza
Vaccination, 2005-2006
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Children 6-23 months of age
Adults >50 years
Persons 2-64 years of age with underlying
chronic medical conditions
Women who will be pregnant during
influenza season
Priority Groups For Influenza
Vaccination, 2005-2006
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Residents and staff of nursing homes and
long-term care facilities
Children 6 months-18 years of age on
chronic aspirin therapy
Healthcare workers with direct, face-to-face
patient contact
Household contacts and out-of-home
caregivers of persons in a high-risk group
Inactivated Influenza Vaccine
Recommendations
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Persons with the following chronic illnesses
should be considered for inactivated
influenza vaccine:
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pulmonary (e.g., asthma, COPD)
cardiovascular (e.g., CHF)
metabolic (e.g., diabetes)
renal dysfunction
hemoglobinopathy
immunosuppression, including HIV infection
New Chronic Disease Risk Group
(2005-2006)
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Conditions (e.g. cognitive dysfunction, spinal cord
injuries, seizure disorders or other neuromuscular
disorders) that can:
• Compromise respiratory function
• Compromise the handling of respiratory
secretions
• Increase the risk of aspiration
Live Attenuated
Influenza Vaccine
Approved by FDA June 2003
Live Attenuated Influenza Vaccine
(LAIV) Indications
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Healthy* persons 5–49 years of age
• Household contacts of persons at increased risk
of complications of influenza
• Health care workers
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Persons who do not have medical conditions that increase
their risk of complications of influenza
LAIV
Persons Who Should not be Vaccinated
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Children <5 years of age*
Persons >50 years of age*
Persons with underlying medical
conditions*
Pregnant women*
Persons immunosuppressed from disease
(including HIV) or drugs*
*These persons should receive inactivated
influenza vaccine
LAIV
Persons Who Should not be Vaccinated
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Children or adolescents receiving long-term
therapy with aspirin or other salicylates*
Severe (anaphylactic) allergy to egg or other
vaccine components
History of Guillain-Barre´ syndrome
*These persons should receive inactivated
influenza vaccine
Avian Influenza
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Caused by Influenza A viruses
Can affect domestic poultry and wild
birds
Migratory birds are considered the
natural reservoir of influenza viruses
Avian Influenza
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Two forms of infection in birds
• Low Pathogenicity
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Mild disease, ruffled feathers, drop in egg production
Can go undetected
• High Pathogenicity
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Dramatic bird disease affecting multiple organs
Spreads rapidly through poultry flocks
High mortality, usually within 48 hours
Implications of Avian Influenza in Human
Health
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Direct Infection
• Virus crosses from birds to humans, causing severe
disease in humans
• Birds shed large amounts of virus in their feces
• Caused by direct contact with poultry or objects/surfaces
contaminated with poultry feces
• Exposure during slaughter, de-feathering, butchering
and preparing for cooking most likely
• No evidence of transmission through cooked foods
Implications of Avian Influenza in Human
Health
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Transformation of the virus into a form that is
highly infectious to humans and can spread easily
from person to person
• Adaptive mutation
• Reassortment
• Will trigger a pandemic given lack of immunity of the
population
The Two Mechanisms whereby Pandemic Influenza Originates
Belshe, R. B. N Engl J Med 2005;353:2209-2211
Avian Influenza A(H5N1) in Humans
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Affects younger population; very high mortality
Incubation may be longer (up to 8 days)
Clinical presentation includes high fever, and an influenza-like
illness with lower tract respiratory symptoms, pleuritic chest pain,
diarrhea, vomiting, abdominal pain, bleeding from gums and nose
CXR with diffuse, patchy, multi-focal infiltrates
Progression to respiratory failure and ARDS requiring ventilatory
support
Labs: leukopenia, lymphopenia, thrombocytopenia, elevated LFTs,
renal function tests
Virologic diagnosis:
• Viral cultures or viral RNA in pharyngeal samples (rather than nasal).
• Viral loads higher than A(H1N1) or A(H3N2) viruses
• Commercial rapid antigen tests less sensitive in detecting A(H5N1)
Proposed Mechanism of the Cytokine Storm Evoked by Influenzavirus
Osterholm, M. T. N Engl J Med 2005;352:1839-1842
Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO
29 November 2005
Indonesia
Date of
onset
Viet Nam
Thailand
Cambodia
China
Total
cases
deaths
cases
deaths
cases
deaths
cases
deaths
cases
deaths
cases
deaths
26.12.0310.03.04
0
0
23
16
12
8
0
0
0
0
35
24
19.07.0408.10.04
0
0
4
4
5
4
0
0
0
0
9
8
16.12.04to date
12
7
66
22
4
1
4
4
3
2
89
36
Total
12
7
93
42
21
13
4
4
3
2
133
68
Belshe, R. B. N Engl J Med 2005;353:2209-2211
Pandemic Risk
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Three conditions need to be met
• New influenza virus sub-type emerges
• Can infect and cause serious illness in humans
• It spreads easily and in a sustainable fashion
among humans
Current alert status (WHO)
Pandemic Risk
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Causes for concern
• Current outbreak is the largest and most severe outbreak of
avian influenza on record, with many countries simultaneously
affected
• Expanding geographic distribution, making more human
populations at risk
• Current virus more lethal in experimental conditions to mice
and ferrets when compared with A(H1N5) viruses from 1997
and early 2004
• A(H5N1) virus transmission to felids has occurred by feeding
chickens to leopards and tigers in zoos in Thailand
• Behavior of the virus in its natural reservoir, waterfowl, may be
changing
Treatment and prevention
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Antiviral agents
• Adamantanes
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Recent A(H5N1) isolates are highly resistant to these
drugs
• Neuraminidase inhibitors - early treatment
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Oseltamivir:
• likely higher doses, for a longer duration are needed
• High level resistance, resulting from the substitution of
a single amino acid in the N1 neuraminidase has been
detected in up to 16% of children with influenza
A(H1N1) and recently in several patients with A(H5N1)
infection treated with oseltamivir
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Zanamivir: Active in vitro, but has not been studied
in cases of human influenza A(H5N1)
Treatment and prevention
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No specific vaccine is currently available
Production cannot start until the new virus has
emerged, because the vaccine needs to closely
match the pandemic virus
Earlier H5 vaccines were poorly immunogenic and
required two doses to generate neutralizing
antibody response
Pandemic Warning Signal
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Most important warning signal:
• Clusters of A(H5N1) influenza cases closely
related in time and place are detected,
suggesting that human-to-human transmission
is taking place.
Bibliography
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www.cdc.gov
www.who.org
www.uptodate.com
Treanor John. Influenza Virus. Principles and Practice of
Infectious Diseases. Mandell/Bennett/Dolin. Fifth Edition.
Sanford, Jay P. Influenza: Considerations on Pandemics.
Advances in Internal Medicine Vol.15, 1969
Prevention and control of Influenza. MMWR July 29, 2005/
54(RR08);1-40
Osterholm,M. Preparing for the next pandemic. NEJM
May5,2005
Bibliography
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Moscona, A. Neuraminidase Inhibitors for Influenza. NEJM,
Sept29,2005
WHO writing committee. Avian influenza A infections in
humans. NEJM, Sept29,2005
Avian Influenza Symposium. CDC, November 3,2004
Uyeki T. Public Health Impact of Avian Influenza. CDC,
November 3, 2004
Belshe R. The origins of pandemic influenza. NEJM,
Nov.24,2005
Stöhr, K. Avian Influenza and Pandemics. NEJM, January
27,2005
Meltzer M. Emerging Infectious Diseases 1999;5:659-671