Influenza Update

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Influenza Update

• Eliane Haron, M.D.

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Influenza Viruses

• 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

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Influenza Surface Glycoproteins

• 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

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Influenza- Surface Glycoproteins

• Neuraminidase
• Responsible for cleavage of the newly-formed
  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

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Current circulating virus

• 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

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Influenza - Transmission

• 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
• Close contact needed (lt3 feet)
• Droplet precautions in hospitalized patients
• For 5 days in normal hosts
• For the duration of illness in immunocompromised
  patients

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Clinical Manifestations

• 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

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Clinical Manifestations

• Complications
• Primary Influenza Pneumonia
• Secondary Bacterial Pneumonia
• Strep. pneumoniae Staph aureus
• Exacerbation of fever and respiratory symptoms
  after initial improvement of influenza symptoms
• Other complications
• Myositis,
• CNS involvement encephalitis, transverse
  myelitis, aseptic meningitis, Guillan-Barre
  syndrome.
• Myocarditis and pericarditis (rare).

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Influenza- Diagnosis

• Clinical Diagnosis
• Clinical diagnosis is straightforward during a
  flu epidemic
• In sporadic cases, symptoms can be
  indistinguishable from other acute respiratory
  infections
• Laboratory Diagnosis
• Viral cultures of respiratory secretions (nasal
  washes, sputum, throat swab, BAL)
• Rapid detection tests (EIA, IF, PCR)
• Serologic tests

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Influenza- Treatment

• 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

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Influenza- Treatment

• Amantadine
• Dose
• 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

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Influenza- Treatment

• Rimantadine
• Dose
• 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

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Influenza- Treatment

• 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.

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Mechanism of Action of Neuraminidase Inhibitors
Moscona, A. N Engl J Med 20053531363-1373
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Influenza- Treatment

• 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

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Influenza- Treatment

• Oseltamivir
• Dose
• 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

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Influenza - Prevention
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Influenza Vaccine

• 2005-2006 vaccine strains
• A/NewCaledonia/20/99 (H1N1)
• A/California/7/2004(H3N2)
• B/Shanghai/361/2002

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Coverage 2004-2005 Season

• Children 6-23 months old 48.4
• Adults 65 years old 62.7
• Non-priority adults 8.8 (2003-2004 17.8)
• Centers for Disease Control and Prevention,
  MMWR, 2005.

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Priority Groups For Influenza Vaccination,
2005-2006

• Children 6-23 months of age
• Adults gt50 years
• Persons 2-64 years of age with underlying chronic
  medical conditions
• Women who will be pregnant during influenza
  season

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Priority Groups For Influenza Vaccination,
2005-2006

• 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

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Inactivated Influenza VaccineRecommendations

• Persons with the following chronic illnesses
  should be considered for inactivated influenza
  vaccine
• pulmonary (e.g., asthma, COPD)
• cardiovascular (e.g., CHF)
• metabolic (e.g., diabetes)
• renal dysfunction
• hemoglobinopathy
• immunosuppression, including HIV infection

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New Chronic Disease Risk Group (2005-2006)

• 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

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Live Attenuated Influenza Vaccine
Approved by FDA June 2003
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Live Attenuated Influenza Vaccine (LAIV)
Indications

• Healthy persons 549 years of age
• Household contacts of persons at increased risk
  of complications of influenza
• Health care workers

• Persons who do not have medical conditions
  that increase their risk of complications of
  influenza

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LAIV Persons Who Should not be Vaccinated

• Children lt5 years of age
• Persons gt50 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

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LAIVPersons Who Should not be Vaccinated

• 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
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Avian Influenza

• Caused by Influenza A viruses
• Can affect domestic poultry and wild birds
• Migratory birds are considered the natural
  reservoir of influenza viruses

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Avian Influenza

• Two forms of infection in birds
• Low Pathogenicity
• Mild disease, ruffled feathers, drop in egg
  production
• Can go undetected
• High Pathogenicity
• Dramatic bird disease affecting multiple organs
• Spreads rapidly through poultry flocks
• High mortality, usually within 48 hours

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Implications of Avian Influenza in Human Health

• 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

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Implications of Avian Influenza in Human Health

• 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

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The Two Mechanisms whereby Pandemic Influenza
Originates
Belshe, R. B. N Engl J Med 20053532209-2211
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Avian Influenza A(H5N1) in Humans

• 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)

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Proposed Mechanism of the Cytokine Storm Evoked
by Influenzavirus
Osterholm, M. T. N Engl J Med 20053521839-1842
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Cumulative Number of Confirmed Human Cases of
Avian Influenza A/(H5N1) Reported to WHO 29
November 2005
Date of onset Indonesia Indonesia Viet Nam Viet Nam Thailand Thailand Cambodia Cambodia China China Total Total
Date of onset cases deaths cases deaths cases deaths cases deaths cases deaths cases deaths
26.12.03-10.03.04 0 0 23 16 12 8 0 0 0 0 35 24
19.07.04-08.10.04 0 0 4 4 5 4 0 0 0 0 9 8
16.12.04- to 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


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Belshe, R. B. N Engl J Med 20053532209-2211
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Pandemic Risk

• 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

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Current alert status (WHO)
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Pandemic Risk

• 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

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Treatment and prevention

• Antiviral agents
• Adamantanes
• Recent A(H5N1) isolates are highly resistant to
  these drugs
• Neuraminidase inhibitors - early treatment
• 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
• Zanamivir Active in vitro, but has not been
  studied in cases of human influenza A(H5N1)

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Treatment and prevention

• 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

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Pandemic Warning Signal

• 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.

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Bibliography

• 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

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Bibliography

• 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
  19995659-671