1

INFLUENZA VIRUS

INFLUENZA VIRUSCDC WEBSITEhttp://www.cdc.gov/ncidod/diseases/flu/fluinfo.htm

2002

2

‘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’

3

South Carolina 1996-1997 DHEC bulletin

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

no virus

influenza A

influenza B

CULTURE RESULTS

malathia influenzae per le stelle

4

1918-19 Spanish flu 500,000 US20,000,000 world

1957-58 Asian flu 70,000 US

1968-69 Hong Kongflu

34,000 US

THE IMPACT OF INFLUENZAPANDEMICS

Deaths:

5

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)

6

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

7

ORTHOMYXOVIRUSES

http://www.uct.ac.za/depts/mmi/stannard/fluvirus.html

• pleomorphic• influenza types A,B,C• febrile, respiratory

illness with systemic symptoms

8

ORTHOMYXOVIRUSES

M1 protein

helical nucleocapsid (RNA plus NP protein)

HA - hemagglutinin

polymerase complex

lipid bilayer membrane

NA - neuraminidase

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

9

TRANSMISSION

• AEROSOL– 100,000 TO

1,000,000 VIRIONS PER DROPLET

• 18-72 HR INCUBATION

• SHEDDING

10

NORMAL TRACHEAL MUCOSA

3 DAYS POST-INFECTION 7 DAYS POST-INFECTION

Lycke and Norrby Textbook of Medical Virology 1983

11

• DECREASED CLEARANCE

• RISK BACTERIAL INFECTION

• VIREMIA RARE

Lycke and Norrby Textbook of Medical Virology 1983

12

RECOVERY

• INTERFERON - SIDE EFFECTS INCLUDE:– FEVER, MYALGIA, FATIGUE, MALAISE

• CELL-MEDIATED IMMUNE RESPONSE

• TISSUE REPAIR– CAN TAKE SOME TIME

13

An immunological diversion

INTERFERON

14

INTERFERON

timecourse of virus production will vary from virus to virus

15

INTERFERON

16

INTERFERON

antiviral stateantiviral state

antiviral state

antiviral state

17

INTERFERON

antiviral stateantiviral state

antiviral state

antiviral state

18

INTERFERON

antiviral stateantiviral state

antiviral state

antiviral state

19

INTERFERONTHE VIRUSES ARE COMING!

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

PAUL REVEREhttp://www.mfa.org/collections/one_hour/6.htm

20

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

21

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

22

INTERFERON

• induce various proteins in target cells

• many consequences, not all fully understood

23

INTERFERON-ALPHA AND INTERFERON-BETA

24

interferon-alpha, interferon-beta

interferon receptor

induction of 2’5’oligo A synthase

induction of aprotein kinase

2’5’oligo A

induction of ribonuclease L

activated ribonuclease L

ATP

ds RNA ds RNA

activatedprotein kinase

activated2’5’oligo A synthase

ATP

2’5’oligo A

mRNA degraded

phosphorylated initiation factor (eIF-2)

inhibition of protein synthesis

25

interferons

• only made when needed

26

OTHER EFFECTS OF INTERFERONS

• ALL TYPES– INCREASE MHC I EXPRESSION

• CYTOTOXIC T-CELLS– ACTIVATE NK CELLS

• CAN KILL VIRALLY INFECTED CELLS

27

OTHER EFFECTS OF INTERFERONS

• INTERFERON-GAMMA– INCREASES MHC II EXPRESSION ON APC

• HELPER T-CELLS– INCREASES ANTIVIRAL POTENTIAL OF

MACROPHAGES • INTRINSIC• EXTRINSIC

28

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, Kaposi’s sarcoma, CML

• MULTIPLE SCLEROSIS– interferon-beta

29

Viral response to host immune system

Viruses may :block interferon bindinginhibit function of interferon-induced proteinsinhibit NK functioninterfere with MHC I or MHC II expressionblock complement activationinhibit apoptosisetc!

30

SIDE EFFECTS OF INTERFERONS

• FEVER• MALAISE• FATIGUE• MUSCLE PAINS

31

BACK TO INFLUENZA

32

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)

33

SYMPTOMS

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

34

CLINICAL FINDINGS

• SEVERITY– VERY YOUNG– ELDERLY– IMMUNO-

COMPROMISED– HEART OR LUNG

DISEASE

35

PULMONARY COMPLICATIONS

• CROUP (YOUNG CHILDREN)• PRIMARY INFLUENZA VIRUS

PNEUMONIA• SECONDARY BACTERIAL

INFECTION– Streptococcus pneumoniae– Staphlyococcus aureus– Hemophilus influenzae

36

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-Barré syndrome

37

Reye’s syndrome

• liver - fatty deposits• brain - edema• vomiting, lethargy, coma• risk factors

– youth– certain viral infections (influenza, chicken pox)– aspirin

38

NON-PULMONARY COMPLICATIONS

• myositis (rare, > in children, > in type B)• cardiac complications• encephalopathy• liver and CNS

– Reye’s syndrome• peripheral nervous system

– Guillian-Barré syndrome

39

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

40

MORTALITY

• MAJOR CAUSES OF INFLUENZA VIRUS- ASSOCIATED DEATH– BACTERIAL PNEUMONIA– CARDIAC FAILURE

• 90% OF DEATHS IN THOSE OVER 65 YEARS OF AGE

41

DIAGNOSIS

• ISOLATION– NOSE, THROAT SWAB– TISSUE CULTURE OR EGGS

• SEROLOGY• RAPID TESTS • provisional - clinical picture + outbreak

42

S S

S S

S S

cell enzymes

acid pH

HA protein - attachment, fusion

43

NA protein - neuraminidase

44

ANTIGENIC DRIFT

• HA and NA accumulate mutations– RNA virus

• immune response no longer protects fully

• sporadic outbreaks, limited epidemics

45

ANTIGENIC SHIFT

• “new” HA or NA proteins

• pre-existing antibodies do not protect

• may get pandemics

46

INFLUENZA A PANDEMICS

Ryan et al., in Sherris Medical Microbiology

47

where do “new” HA and NA come from?

• 13 types HA• 9 types NA

– all circulate in birds• pigs

– avian and human

48

where do “new” HA and NA come from?

49

why do we not have influenza B pandemics?

• so far no shifts have been recorded

• no animal reservoir known

50

SURVEILLANCE

CDC/Katherine Lord

51

actual percentage of deaths

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

520

102030405060708090

100

99/00 00/01 01/02 02/03

H1N1H3N2B

53

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

54

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

55

CDC

56

RECOMMENDATIONSPersons 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)

57

RECOMMENDATIONSPersons 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.

58

RECOMMENDATIONSPersons 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)

59

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.

60

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.

61

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 0–5 months because influenza vaccines have not been approved for use among children aged <6 months.

62

RECOMMENDATIONS

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

63

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

64

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

65

NA protein - neuraminidase

.. ..

. . .. .

. .

....

..

..

66

OTHER TREATMENT

• REST, LIQUIDS, ANTI-FEBRILE AGENTS (NO ASPIRIN FOR AGES 6MTHS-18YRS)

• BE AWARE OF COMPLICATIONS AND TREAT APPROPRIATELY

67

TYPE A

++++yesyesyesshift, driftyessensitivesensitive2

severity of illnessanimal reservoirhuman pandemicshuman epidemicsantigenic changessegmented genomeamantadine, rimantidinezanamivirsurface glycoproteins

TYPE B

++nonoyesdriftyesno effectsensitive2

TYPE C

+nonono (sporadic)driftyesno effect

(1)

68

END

69

live vaccine development

adapted fromTreanor JJ Infect. Med. 15:714

70