NEW INFLUENZA VIRUS H 1 N 1 (H 1 N 1 v) ΕΠΙΔΗΜΙΟΛΟΓΙΑ ΚΑΙ ΠΑΘΟΓΕΝΕΣΗ. Άγγελος Πεφάνης, ΓΝΝΘΑ «Η Σωτηρία»

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1 NEW INFLUENZA VIRUS H 1 N 1 (H 1 N 1 v) ΕΠΙΔΗΜΙΟΛΟΓΙΑ ΚΑΙ ΠΑΘΟΓΕΝΕΣΗ Άγγελος Πεφάνης, ΓΝΝΘΑ «Η Σωτηρία»

2 Ιοί γρίππης Ορθομυξοϊοί RNA (8 διαφορετικά τμήματα, καθένα από τα οποία κωδικοποιεί διαφορετική πρωτεΐνη π.χ. συγκολλητίνη, νευραμινιδάση) Γενετική μεταβλητότητα 3 τύποι ιού (γενετικός ανασυνδυασμός) Οι ιοί γρίππης Α βρίσκονται στα ζώα (πτηνά, χοίρους, άλογα,)

3 Clinically Relevant Influenza Viruses Type A Type B Type C Potentially severe illness Epidemics and pandemics Rapidly changing Usually less severe illness Epidemics More uniform Usually mild or asymptomatic illness Minimal public health impact Centers for Disease Control and Prevention. Influenza Prevention and Control. Influenza. Available at:

4 Influenza Surface Proteins Neuraminidase Hemagglutinin RNA M 2 protein (only on type A)

5 15 αντιγονικοί τύποι Η 9 αντιγονικοί τύποι Ν H1N1 H2N2 H3N2 H5N1

6 Ονοματολογία ιού της γρίπης

7 Antigenic Drift (Διολίσθηση) RNA Hemagglutinin Neuraminidase Antibodies Sialic acid

8 Antigenic Shift (παρέκκλιση ή μετατροπή)

9 Mechanisms of Antigenic Shift DIRECT 15 HAs 9 NAs Non-human virus Human virus Reassortant virus

10 Εμφάνιση νέων υπότυπων του ιού της γρίπης παθογόνων για τον άνθρωπο

11 Antibody recognition of a highly conserved influenza virus epitope. CR6261 Fab Ekiert DC, et al.science 2009;324(5924):246 51

12 Pathology of Influenza Infection A. Binding to Sialic Acid B. Entering Cell C. Replication D. Release From Cell

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14 Δράσεις της Νευραμινιδάσης (ΝΑ) NA cleaves newly formed virus particles from the host cell membrane. NA prevents newly released virus particles from aggregating to each other, preventing clumping that would reduce dissemination. NA promotes viral penetration of sialic acidrich mucin that bathes and protects respiratory epithelium through which the virus must spread and replicate.

15 Ιογενείς λοιμώξεις του αναπνευστικού ΕΠΙΔΗΜΙΟΛΟΓΙΑ ΠΟΣΟ ΣΥΧΝΕΣ ΕΊΝΑΙ ;

16 Ιογενείς λοιμώξεις του αναπνευστικού ΣΥΧΝΟΤΗΤΑ ΕΜΦΑΝΙΣΗΣ ΚΟΙΝΟΤΗΤΑΣ: Ενήλικες: 10 30% <3ετων: 60% ΝΟΣΟΚΟΜΕΙΑΚΕΣ 1 6%

17 Επιδημίες γρίπης 1. Έναρξη με κρούσματα παιδικής ηλικίας 2. Αύξηση νοσοκομειακών εισαγωγών με πνευμονία 3. Εύκρατα κλίματα Οκτώβριος Απρίλιος: Β. Ημισφαίριο Μάιος Σεπτέμβριος: Ν. Ημισφαίριο Τροπικά κλίματα: Επιδημία όλους τους μήνες (;)

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20 Προηγούμενες αντιγονικές μετατροπές (Shifts) 1918 H1N1 Ισπανική Γρίπη εκατ. θάνατοι 1957 H2N2 Ασιατική 1 2 εκατ. θάνατοι 1968 H3N2 Hong Kong γρίπη θάνατοι 1976 H1N1 γρίπη των χοίρων Όχι πανδημία 1997 H5N1 γρίπη των πουλερικών πρόληψη πανδημίας

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23 Emergency hospital during 1918 influenza epidemic, Camp Funston, Kansas"

24 2005: Νέαπανδημίαγρίπης; INFLUENZA Avian Τύπος A H5N1 Νόσος στα εκτροφεία για πουλερικά πάπιες στη Κίνα και στη ΝΑ Ασία. Νόσος στα κατοικίδια ορνιθώνων Νόσος και αποικισμός σε αποδημητικά πουλιά Μετάδοση στον άνθρωπο και σε άλλα ζώα, από τα πτηνά Μετάδοση από άνθρωπο σε άνθρωπο (NEJM 2004) Κλινική εικόνα μήνιγγοεγκεφαλίτιδας (NEJM 2005)

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28 Εξέλιξη των ιών της γρίπης

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32 Προέλευση πανδημικών στελεχών Pandemic influenza may originate through at least two mechanisms: Reassortment between an animal influenza virus and a human influenza virus that yields a new virus, and Direct spread and adaptation of a virus from animals to humans. Belshe RB. NEJM ;21:2209

33 Παγκόσμια διασπορά των ιών της γρίπης Worldwide dissemination of influenza A (H3N2) viruses based on analysis of approximately 13,000 human influenza strains from 6 continents during supports the idea that there was continuous circulation of H3N2 viruses in East and Southeast Asia, and that seed variants from that region spread worldwide via Europe and North America.

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35 Ταχεία διασπορά του ιού Such dissemination can be quite rapid and has important implications for vaccines; for example, when the A/Sidney/5/97 virus emerged, it was first detected in June/July, after the Northern hemisphere recommendations had been made. Unfortunately, the part of the world that may be the source of antigenically drifted influenza strains largely comprises countries where there is a need for greater surveillance.

36 Νοσηρότητα A number of studies have demonstrated that the greatest morbidity, as measured by hospitalizations, is observed at the extremes of age, revealing a U shaped curve for hospitalizations

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38 Πώς αρχίσαμε Βέρα Κρούζ 15 και 17/4: Καλιφόρνια 24 4: WHO Swine Flu 27 4: PPAlert Phase : Phase 5

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43 Intensity

44 Geographic spread

45 Παθογένεια

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47 Πρόσφατες Μελέτες (2009) Παθογένεια

48 Munster VJ, et al. Science. 2009;325:481 3 In a ferret pathogenesis and transmission model The H1N1v influenza virus was found to be more pathogenic than a seasonal A(H1N1) virus, With more extensive virus replication occurring in the respiratory tract.

49 Munster VJ, et al. Science. 2009;325:481 3 Replication of seasonal A(H1N1) virus was confined to the nasal cavity, but the H1N1v virus also replicated in the trachea, bronchi, and bronchioles. Virus shedding was more abundant from the upper respiratory tract for H1N1v virus as compared with seasonal virus, and Transmission via aerosol or respiratory droplets was equally efficient.

50 Maines TR, et al. Science. 2009;325: In contrast to seasonal influenza H1N1 virus, H1N1v viruses caused: increased morbidity, replicated to higher titers in lung tissue, and were recovered from the intestinal tract of intranasally inoculated ferrets.

51 Protective role for protease activated receptor 2 (PAR 2), against influenza virus pathogenesis via an IFN gamma dependent pathway. Khoufache K, et al. J Immunol. 2009;182:

52 Khoufache K, et al. J Immunol. 2009;182: In vitro, stimulation of PAR(2) on epithelial cells inhibited influenza virus type A (IAV) replication through the production of IFN γ. In vivo, stimulation of PAR(2) using specific agonists protected mice from IAV induced ALI and death.

53 Khoufache K, et al. J Immunol. 2009;182: This effect correlated: with an increased clearance of IAV in the lungs associated with increased IFN gamma production and a decreased presence of neutrophils and RANTES release in bronchoalveolar fluids.

54 PB1 F2 protein A viral factor (PB1 F2 protein) that drives an exuberant inflammatory response with subsequent respiratory tract damage, and is associated with a predisposition to bacterial super infection. The PB1 gene segment of the H1N1 swine origin influenza virus pandemic strain codes for a truncated PB1 F2 protein which terminates after 11 amino acids, but could acquire the full length form by mutation or reassortment. This fact, perhaps somewhat reduce the odds of bacterial pneumonia complicating H1N1. J. McCullers. ICAAC 2009

55 PB1 F2 protein Disruption of PB1 F2 expression in several backgrounds, or expression of the PB1 F2 from the1918 pandemic strain or a 1956 H1N1 strain, had no effect on viral lung load in mice. Alternate mechanisms besides alterations to replication are likely responsible for the enhanced virulence in mammalian hosts attributed to PB1 F2 in previous studies. McAuley JL, et al. J Virol Oct 14. [Epub ahead of print]

56 Comparative Pathogenesis of an Avian H5N2 and a Swine H1N1 Influenza Virus in Pigs Avian virus Swine virus Bronchi De Vleeschauwer A, et al. PLoS ONE 2009;4(8): e6662.

57 Comparative Pathogenesis of an Avian H5N2 and a Swine H1N1 Influenza Virus in Pigs Avian virus Swine virus Bronchioles De Vleeschauwer A, et al. PLoS ONE 2009;4(8): e6662.

58 Perez Padilla R, et al. NEJM 2009;361:680 9.

59 Gram positive cocci with use of Lillie Twort Gram stain of lung tissue MMWR Vol. 58 / September 29, 2009

60 Immunohistochemical staining of multiple S. pneumoniae MMWR Vol. 58 / September 29, 2009

61 Ευχαριστώ Αθήνα 4/11/2009