Influenza. Mercy Family Practice SC Kevin P Rosteing MS MSMI 1500 Heritage Rd Ste A De Pere WI mfprac.com

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1 Influenza Mercy Family Practice SC Kevin P Rosteing MS MSMI 1500 Heritage Rd Ste A De Pere WI mfprac.com

2 Size: Metric System Meter, average height human 1.7 m = 5'7 ; 1.0 m = 3.28 feet

3 Size: Millimeter 1 Millimeter, 10^-3

4 Size: Microns 7 Microns, 7 x10^-6

5 Size: Nanometer 80 Nanometers, 80 x 10^-9

6 Influenza Virus Electron Micrography & Diagram showing H:N proteins

7 Influenza: Transmission Spread by a sneeze, or hand to mouth contact

8 Influenza: Highly Contagious Sneeze, can travel 15 feet or more Carries 40,000 droplets (25% rate) Each droplet carries 390 of virions Potential inoculum: 3.9 x10^6 virions Duration: 5 minutes on hand; 2 days on plastic or metal Deaths: 30,000 to 48,000 per year in the US

9 Influenza: History Spanish Flu Pandemic: 1918, H1N1 500 million infected million deaths: 15% mortality rate In WWI Spain remained neutral Death of King Alfonso XIII

10 Influenza Pandemics Year Name Type Mortality Spanish Flu H1N1 75 x10^ Asian Flu H2N2 2.5 x10^6; 69,800 in US Hong Kong Flu H3N2 1 x10^ Russian Flu H1N1 Small < 23 yo 2008 Bird Flu, Asia H5N1 379 (59% fatality) Swine Flu, Mexico H1N1 284, subtypes Mutation occurs once every 30 years

11 Bird Flu Cases, Asia Initial cases: SE Asia

12 Influenza: Vectors 2013 in: Shanghai (24), Jiangsu (16), Zhejiang (15)

13 Vectors: Chickens & Pigs Bird Flu H5N1; Avian Flu H7N9 & H2N2; Swine Flu H1N1

14 Influenza: Seasonal Outbreak

15 Influenza: Symptoms & Signs Rapid course: Incubation period 4-7 days, Hospitalization 4 days, Death 7 days Feverishness & Chills Cough & Phlegm production Dyspnea (SOB) Fatigue & Prostrate: hit by a Mack Truck VS: Temp 102 P 100 RR 20 BP 110/70 mmhg Lungs: Consolidation, Wheezing, Rhonchi Labs: WBC, Lymphocytes, Platelets, Creatinine, LFT, pos Nasal swab Influenza A/B

16 Influenza: Case Hx

17 Influenza: Cases Characteristic Patient 1 Patient 2 Patient 3 Age Comorbitities Hepatitis B Hepatitis B, Obesity COPD, HTN Chickens Yes Yes No Viral typing H7N9 H7N9 H7N9 Septic Shock No No No ARDS Yes Yes Yes ATN No Yes No Encephalopathy No Yes Yes Rhabdomyolysis Yes Yes No Resp Assist Ventilator Ventilator O2 Mask Treatment Ab, Tamiflu, Amantadine Ab,Tamiflu Ab, Tamiflu Outcome Died (day 6) Died (day 19) Died (day 6) Ref: Gao, NEJM, 2013, 368 (20), p 1888

18 Influenza: ARDS

19 Influenza: ARDS

20 DNA

21 DNA vs RNA

22 DNA Replication

23 RNA Translation

24 Influenza Replication Error once every 10,000 nucleotides

25 Influenza Budding

26 Influenza: Recombination

27 Influenza: Treatment Vaccination: primary prevention Less 50% of the population gets vaccinated 2009: 78 million doses to 77 countries Effectiveness: 62% based on meta-analysis H1N1,H5N1 with adjuvant, inactivated Influenza A & B, in 2013, 3 subtypes: H1N1,H3N2,H5N1 Incubated in hen eggs Takes about 5-9 months Alternatives: Trasdermal, Nasal, Cell Culture Anti-viral: oseltamivir (Tamiflu); resistant H1N Start <48 hours from onset of fever

28 Influenza: Vaccination TLR=Toll-Like Receptor APC=Antigen (Ag) Presenting Cell HLA=Human Leukocyte Antigen TCR=T-Cell antigen Receptor CTL= Cytotoxic T Lymphocyte T-Helper B-cells, Plasma cells, B-Memory cells Immune globulin (Ig-M, Ig-G)

29 T-Cell-B-cell Interaction Ig-M, immediate response in less than 4 days Ig-G, takes up to 4 weeks, lasts 4 months

30 T-Cell and B-Cell

31 Influenza Vaccine Two types: Trivalent inactivated and Nasal attenuated Each vaccine is grown in hen's eggs Duration: 5 months to manufacture 1976 Swine Flu and Guillian Barre Syndrome Fluzone (Aventis Pasteur), Fluvirin (Evans), and Fluarix (GlaxoSmithKline), intramuscular injection LAIV (FluMist; MedImmune), intranasal spray

32 Vaccination Timeline

33 Vaccine Trivalence Season H1N1 H3N2 B-Strain A/ California/ 7/2009 A/ Perth/ 16/2009 B/ Brisbane/ 60/ A/ California/ 7/2009 A/ Perth/ 16/2009 B/ Brisbane/ 60/ A/ California/ 7/2009 pdm09 A/ Victoria/ 361/ 2011 B/ Wisconsin/ 1/ 2010, B/ Brisbane/ 60/ A/ California/ 7/2009 pdm09 A/ Victoria/ 361/ 2011 variant B/ Massachusetts/ 2/ 2012, B/ Brisbane/ 60/ A/ California/ 7/2009 pdm09 A/ Texas/ 50/ 2012 B/Massachusetts/ 2/ 2012

34 Influenza Vaccine Indications Children ages 6 to 59 months Pregnant women Adults older than 50 years of age Asthma & COPD CAD, CHF, cardiac disease Diabetes mellitus Blood dyscrasias Renal insufficiency Immunosuppression (including HIV) Aspiration risk, compromised airway Nursing Homes and Assisted Living Facilities health care workers household contacts of persons at high risk

35 Influenza Vaccine Contraindications Trivalent inactive virus (Injection) Egg Allergy Prior allergic reaction Prior Guillian Barre syndrome Live attenuated virus (Nasal) Children younger than 5 years Children or adolescents taking aspirin Adults older than 50 Immunocompromised persons Adults with chronic heart, lung, or kidney disease Adults with Diabetes Mellitus Pregnant women

36 Vaccine: is there a better way? Cell Culture: $20 to $80 per dose Production time drops from 20 (5 mo) to 10 weeks (2.5 mo) Available on short notice during any season Maintained in aseptic environment (avoids bacterial contamination in eggs) Might provide broader immunity to influenza variants such as H3N2 Safe for individuals with allergy to eggs

37 Vaccine Production

38 Influenza A Antivirals M2 Channel Inhibitors; Amantadine (Symmetrel) & rimantadine (Flumadine)

39 Influenza A&B Antivirals Neuraminidase Inhibitors (NAI): oseltamivir (Tamiflu) & zanamivir (Relenza)

40 References 1918 Flu Pandemic, Wikipedia, www [ accessed 4/25/2014. Anonymous, Pandemic Influenza Vaccine Manufacturing Process and Timeline-WHO, Saturday, 8, August, 2009, www [ influenza- vaccinemanufacturing- process- and- timeline- who], accessed 5/4/2014. Breesee, Joseph, Epidemic Influenza Responding to the Expected but Unpredictable, NEJM, 2/14/2013, 368(7), pp Fineberg, Harvey, Pandemic Preparedness and Response Lessons from the H1N1 Influenza of 2009, 4/3/14, NEJM, 370 (14), pp Gao, R, et al, Human Infection with a Novel Avian-Origin Influenza A (H7N9) Virus, 5/16/13, NEJM, 368 (20), pp Glezen, WP, Cell-Culture-Derived Influenza Vaccine Production, , Lancet, Vol 377 (9767), pp Influenza Pandemic, Wikipedia, www [ accessed 4/25/2014.

41 References Madsen, John, Utilization of Single-Use Technology for Production of Virus-Like Particle (VLP)-based Influenza Vaccines, Novavax, Inc, www [ download/ file/ anaheim_dispo_conf_9_08.pdf], accessed 5/4/2014. Qun Li, et al, Epidemiology of Human Infections withavian Influenza A(H7N9) Virus in China, 2/6/14, NEJM, 370 (6), pp Sanchez, TMC, Development of an in Vitro Mimic of the In Vivo Deposition of Virus-Containing Particulate Matter onto the Bronchial Epithelium, Thesis Paper, Simon Fraser University, Summer Szymczakiewicz-Multanowska, et al, A New Mammalian Cell Culture-Derived Influenza Vaccine is as Safe as, and Immunogenically Non-Inferior to, an Egg-Based Influenza Vaccine, International Journal of Infectious Diseases, Vol 12 ( Supp 1), pp e155-e155. White, Jason, Influenza, Medical Ecology, www [ accessed 4/27/2014. Waldman, SA, et al, Pharmacology and Therapeutics: Principles to Practice, First Edition, Chapter 91, Vaccines, 2009 by Saunders, an imprint of Elsevier Inc., pp