INFLUENZA VIRUS

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INFLUENZA VIRUS
2002

• INFLUENZA VIRUS
• CDC WEBSITE
• http//www.cdc.gov/ncidod/diseases/flu/fluinfo.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 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
http//www.state.sc.us/dhec/LAB/labbu017.htm
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THE IMPACT OF INFLUENZAPANDEMICS
Deaths
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THE IMPACT OF INFLUENZA

• 1972-1994 (19 influenza seasons)
• gt20,000 US deaths in 11 seasons
• gt40,000 US deaths in 6 of these
• many more hospitalizations (110,000 per year)

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THE IMPACT OF INFLUENZA

• recently some increase in morbidity and mortality
  - possible factors?
• more elderly people
• CF patients live longer
• more high risk neonates
• more immunosuppressed patients

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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.h
tml
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ORTHOMYXOVIRUSES
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
• 18-72 HR INCUBATION
• SHEDDING

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NORMAL TRACHEAL MUCOSA
3 DAYS POST-INFECTION
7 DAYS POST-INFECTION
Lycke and Norrby Textbook of Medical Virology 1983
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• DECREASED CLEARANCE
• RISK BACTERIAL INFECTION
• VIREMIA RARE

Lycke and Norrby Textbook of Medical Virology 1983
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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
timecourse of virus production will vary from
virus to virus
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INTERFERON
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INTERFERON
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INTERFERON
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INTERFERON
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INTERFERON
THE VIRUSES ARE COMING!
PAUL REVERE http//www.mfa.org/collections/one_hou
r/6.htm
http//www.paulreverehouse.org/midnight.html
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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
• - viral infection (especially RNA viruses),
  double stranded RNA, certain bacterial components
• - strong anti-viral properties
• interferon-gamma
• - antigens, mitogenic stimulation lymphocytes

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INTERFERON

• induce various 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 25oligo A synthase
induction of a protein kinase
induction of ribonuclease L
ds RNA
ds RNA
25oligo A
activated ribonuclease L
activated protein kinase
activated 25oligo A synthase
ATP
ATP
phosphorylated initiation factor (eIF-2)
25oligo 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, Kaposis
  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
• inhibit NK function
• interfere with MHC I or MHC II expression
• 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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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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SYMPTOMS

• FEVER
• HEADACHE
• MYALGIA
• COUGH
• RHINITIS
• OCULAR SYMPTOMS

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CLINICAL FINDINGS

• SEVERITY
• VERY YOUNG
• ELDERLY
• IMMUNO-COMPROMISED
• 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, gt in children, gt with type B)
• cardiac complications
• recent studies report encephalopathy
• studies of patients lt21 yrs in Michigan - 8 cases
  seen last season
• liver and CNS
• Reye syndrome
• peripheral nervous system
• Guillian-Barré syndrome

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Reyes syndrome

• liver - fatty deposits
• brain - edema
• vomiting, lethargy, coma
• risk factors
• youth
• certain viral infections (influenza, chicken pox)
• aspirin

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NON-PULMONARY COMPLICATIONS

• myositis (rare, gt in children, gt in type B)
• cardiac complications
• encephalopathy
• liver and CNS
• Reyes syndrome
• peripheral nervous system
• Guillian-Barré syndrome

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Guillian-Barré syndrome

• 1976/77 swine flu vaccine
• 35,000,000 doses
• 354 cases of GBS
• 28 GBS-associated deaths
• recent vaccines much lower risk

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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
• TISSUE CULTURE OR EGGS
• SEROLOGY
• RAPID TESTS
• provisional - clinical picture outbreak

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HA protein - attachment, fusion
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NA protein - neuraminidase
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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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INFLUENZA A PANDEMICS
Ryan et al., in Sherris Medical Microbiology
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where do new HA and NA come from?

• 13 types HA
• 9 types NA
• all circulate in birds
• pigs
• avian and human

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where do new HA and NA come from?
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why do we not have influenza B pandemics?

• so far no shifts have been recorded
• no animal reservoir known

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SURVEILLANCE
CDC/Katherine Lord
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actual percentage of deaths
(CDC MMWR 2003 / Vol. 52 / No. RR-8)
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VACCINE

• BEST GUESS OF MAIN ANTIGENIC TYPES
• CURRENTLY
• type A - H1N1
• type A - H3N2
• type B
• each year choose which variant of each subtype is
  the best to use for optimal protection

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VACCINE

• inactivated
• egg grown
• sub-unit vaccine for children
• reassortant live vaccine approved 2003
• for healthy persons (those not at risk for
  complications from influenza infection) ages 5-49
  years

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CDC
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RECOMMENDATIONS
Persons at High Risk for Influenza-Related
Complications 65 years residents of
nursing homes and other chronic-care facilities
adults/children who have chronic pulmonary or
cardiovascular disorders, including asthma
adults/children who have required regular medical
follow-up or hospitalization during the last year
because of chronic metabolic diseases (including
diabetes mellitus), renal dysfunction,
hemoglobinopathies, or immunosuppression
(including immunosuppression caused by
medications)
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RECOMMENDATIONS
Persons at High Risk for Influenza-Related
Complications children and teenagers (6 mths
to 18 yrs) receiving long-term aspirin therapy -
might be at risk for developing Reye syndrome
after influenza women who will be in the 2nd
or 3rd trimester of pregnancy during the
influenza season.
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RECOMMENDATIONS
Persons aged 50-64 years increased prevalence
of high-risk conditions from public health
point of view, easier to target by age than by
high-risk condition (which may not have been
discovered)
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RECOMMENDATIONS
Persons Who Can Transmit Influenza to Those at
High Risk Persons who are clinically or
subclinically infected can transmit influenza
virus to persons at high risk for complications
from influenza.
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RECOMMENDATIONS
physicians, nurses, and other personnel in
both hospital and outpatient-care settings
employees of nursing homes and chronic-care
facilities who have contact with patients or
residents employees of assisted living and
other residences for persons in high-risk
groups persons who provide home care to
persons in high-risk groups household members
(including children) of persons in high-risk
groups.
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RECOMMENDATIONS
Children from 0-23 mths are at increased risk for
hospitalization from influenza, vaccination is
encouraged for their household contacts and
out-of-home caretakers, particularly for contacts
of children aged 05 months because influenza
vaccines have not been approved for use among
children aged lt6 months.
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RECOMMENDATIONS

• others, including travellers and the general
  population may wish to be vaccinated

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PREVENTION - DRUGS

• RIMANTADINE (M2)
• type A only
• AMANTADINE (M2)
• type A only
• ZANAMIVIR (NA)
• types A and B, not yet approved for prevention
• OSELTAMIVIR (NA)
• types A and B

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TREATMENT - DRUGS

• RIMANTADINE (M2)
• type A only, needs to be given early
• AMANTADINE (M2)
• type A only, needs to be given early
• ZANAMIVIR (NA)
• types A and B, needs to be given early
• OSELTAMIVIR (NA)
• types A and B, needs to be given early

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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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TYPE A yes yes yes shift,
drift yes sensitive sensitive 2
severity of illness animal reservoir human
pandemics human epidemics antigenic
changes segmented genome amantadine,
rimantidine zanamivir surface glycoproteins
TYPE B no no yes drift yes no
effect sensitive 2
TYPE C no no no (sporadic) drift yes no
effect (1)
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END
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live vaccine development
adapted from Treanor JJ Infect. Med. 15714
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