2002

INFLUENZA VIRUS

INFLUENZA VIRUS CDC WEBSITE http://www.cdc.gov/ncidod/diseases/flu/fluinfo.htm

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
2

South Carolina 1996-1997 DHEC bulletin

malathia influenzae per le stelle

no virus

CULTURE RESULTS

influenza A influenza B

3
http://www.state.sc.us/dhec/LAB/labbu017.htm

THE IMPACT OF INFLUENZA PANDEMICS

Deaths:

1918-19 Spanish flu 500,000 US 20,000,000 world 1957-58 Asian flu 70,000 US

1968-69 Hong Kong 34,000 US flu

THE IMPACT OF INFLUENZA

1972-1994 (19 influenza seasons)
>20,000 US deaths in 11 seasons >40,000 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

ORTHOMYXOVIRUSES
pleomorphic influenza types A,B,C febrile, respiratory illness with systemic symptoms
http://www.uct.ac.za/depts/mmi/stannard/fluvirus.html

ORTHOMYXOVIRUSES
HA - hemagglutinin NA - neuraminidase

helical nucleocapsid (RNA plus NP protein)

lipid bilayer membrane

polymerase complex

M1 protein

type A, B, C : NP, M1 protein sub-types: HA or NA protein

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
Lycke and Norrby Textbook of Medical Virology 1983

7 DAYS POST-INFECTION
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 DECREASED CLEARANCE RISK BACTERIAL INFECTION VIREMIA RARE

11
Lycke and Norrby Textbook of Medical Virology 1983

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

antiviral state

antiviral state

antiviral state

antiviral state

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INTERFERON

antiviral state

antiviral state

antiviral state

antiviral state

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INTERFERON

antiviral state

antiviral state

antiviral state

antiviral state

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INTERFERON
THE VIRUSES ARE COMING!

PAUL REVERE
http://www.mfa.org/collections/one_hour/6.htm

19

http://www.paulreverehouse.org/midnight.html

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

ds RNA

induction of ribonuclease L
25oligo A

induction of a protein kinase

ds RNA

activated 25oligo A synthase

ATP 25oligo A

activated ribonuclease L

activated protein kinase

ATP phosphorylated initiation factor (eIF-2)

mRNA degraded

inhibition of protein synthesis 24

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 IMMUNOCOMPROMISED 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, > in children, > with type B) cardiac complications recent studies report encephalopathy
studies of patients <21 yrs in Michigan - 8 cases seen last season

liver and CNS

Reye syndrome

peripheral nervous system

Guillian-Barr 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, > in children, > in type B) cardiac complications encephalopathy liver and CNS
Reyes syndrome

peripheral nervous system

Guillian-Barr syndrome
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Guillian-Barr 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

S S

cell enzymes

acid pH

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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

50
CDC/Katherine Lord

actual percentage of deaths

(CDC MMWR 2003 / Vol. 52 / No. RR-8)

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100 90 80 70 60 50 40 30 20 10 0 99/00 00/01 01/02 02/03

H1N1 H3N2 B

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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 55

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 <6 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
type A only

(M2)
(M2) (NA)

AMANTADINE
type A only

ZANAMIVIR

types A and B, not yet approved for prevention

OSELTAMIVIR
types A and B

(NA)
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TREATMENT - DRUGS
RIMANTADINE
AMANTADINE ZANAMIVIR

(M2)
(M2) (NA)

type A only, needs to be given early

type A only, needs to be given early

types A and B, needs to be given early

OSELTAMIVIR

(NA)
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types A and B, needs to be given early

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 severity of illness animal reservoir human pandemics human epidemics antigenic changes segmented genome amantadine, rimantidine zanamivir surface glycoproteins ++++ yes yes yes shift, drift yes sensitive sensitive 2

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. 15:714

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