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Influenza Update. Eliane Haron, M.D. 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 update

Influenza Update

Eliane Haron, M.D.

influenza viruses
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
influenza surface glycoproteins
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
influenza surface glycoproteins1
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
current circulating virus
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
influenza transmission
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 (<3 feet)
  • Droplet precautions in hospitalized patients
    • For 5 days in normal hosts
    • For the duration of illness in immunocompromised patients
clinical manifestations
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
clinical manifestations1
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).
influenza diagnosis
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
influenza treatment
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
influenza treatment1
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
influenza treatment2
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
influenza treatment3
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.

Mechanism of Action of Neuraminidase Inhibitors

Moscona, A. N Engl J Med 2005;353:1363-1373

influenza treatment4
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
influenza treatment5
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
influenza vaccine
Influenza Vaccine
  • 2005-2006 vaccine strains
    • A/NewCaledonia/20/99 (H1N1)
    • A/California/7/2004(H3N2)
    • B/Shanghai/361/2002
coverage 2004 2005 season
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.

priority groups for influenza vaccination 2005 2006
Priority Groups For Influenza Vaccination, 2005-2006
  • 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 20061
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
inactivated influenza vaccine recommendations
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
new chronic disease risk group 2005 2006
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
live attenuated influenza vaccine
Live Attenuated Influenza Vaccine

Approved by FDA June 2003

live attenuated influenza vaccine laiv indications
Live Attenuated Influenza Vaccine (LAIV) Indications
  • Healthy* persons 5–49 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

laiv persons who should not be vaccinated
LAIVPersons Who Should not be Vaccinated
  • 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 vaccinated1
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

avian influenza
Avian Influenza
  • Caused by Influenza A viruses
  • Can affect domestic poultry and wild birds
  • Migratory birds are considered the natural reservoir of influenza viruses
avian influenza1
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
implications of avian influenza in human health
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
implications of avian influenza in human health1
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

The Two Mechanisms whereby Pandemic Influenza Originates

Belshe, R. B. N Engl J Med 2005;353:2209-2211

avian influenza a h5n1 in humans
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)

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

pandemic risk
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
pandemic risk1
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
treatment and prevention
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)
treatment and prevention1
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
pandemic warning signal
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.
  • 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
  • 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