Influenza, novel H1N1 (swine flu), H5N1 (avian influenza) and Occupational Infection

1. Influenza, novel H1N1 (swine flu), H5N1 (avian influenza) and Occupational Infection Stephen Born MD, MPH University of California, San Francisco Division of Occupational and Environmental Medicine

2. Influenza • “An acute viral disease of the respiratory tract characterized by fever, headache, myalgia, prostration, coryza, sore throat and cough. Cough is often severe and protracted, but other manifestations are usually self-limited, with recovery in 2-7 days.” • From Control of Communicable Diseases Manual 17th edition

3. Influenza IS IT A COLD OR THE FLU? (Adapted from the CDC)

4. nH1N1 Symptoms • Broad clinical spectrum from mild upper respiratory tract illness with or without fever to acute respiratory distress syndrome (ARDS) • Some patients present with gastro-intestinal symptoms of vomiting or diarrhea • Many with severe illness have underlying diseases such as asthma. Obstructive airways disease, diabetes, immunodeficinecy cardiovascular disease, renal failure, malignancy and morbid obesity. Also, pregnant women, especially 3rd trimester (13 fold increased risk of hospitalization). • See PMID 19790188

5. Influenza A Nomenclature Influenza type Year of isolation Hemagglutinin subtype A/Sydney/5/97 (H3N2) Geographic source Isolate number Neuraminidase subtype

6. What name for the current Pandemic Influenza? • The World Health Organization has struggled mightily to avoid the ethnic monikers given the Spanish, Hong Kong and Asian flus, instructing its representatives to shift from “swine flu” to “H1N1” to “A (H1N1) S-O.I.V.” (the last four initials stand for “swine-origin influenza virus”) to, recently, “Pandemic (H1N1) 2009.” • http://www.nytimes.com/2009/05/01/health/01name.html • IOM refers to nH1N1 • Aka H1N1v

7. What Influenza? What Name? • A/California/7/2009 (H1N1) virus • According to WHO update 65 dated 11 September 2009 • Pandemic (H1N1) 2009 influenza virus continues to be the predominant circulating virus of influenza, both in the northern and southern hemisphere. All…viruses analyzed to date have been antigenically and genetically similar to A/California/7/2009-like pandemic H1N1 virus

9. nH1N1 • On August 24, the President’s Council of Advisors on Science and Technology said that H1N1 could infect up to half the U.S. population, result in the hospitalization of 1.8 million people, and cause 30,000 to 90,000 deaths in addition to the 30,000 to 40,000 deaths from a typical flu season.

11. Influenza • Hemagglutinin (HA) spike • Governs virus binding and entry into cells • 15 Subtypes, H1 to H15 • In pandemics, a novel subtype arises • Only H1, H2, and H3 have circulated in humans in the past century • All 15 HA subtypes are found in free-flying birds • WHO Avian influenza: assessing the pandemic threat

12. Influenza • Neuraminidase (NA) governs the release of the newly formed virus from infected cells • There are 9 subtypes, N1 to N9 • Immunity to NA subtype reduces the amount of virus released from a cell, resulting in less severe disease • All 9 types found in free-flying birds • Only N1 & N2 in stable human lineages • WHO Avian influenza: assessing the pandemic threat

13. Influenza • Influenza A • Virus mutates rapidly • Infects pigs, horses, sea mammals and birds • Large number of subtypes/huge pool of genetic diversity • Only Influenza A known to cause pandemics • Many genetic replication errors due to lack of a proof reading mechanism • Constant small changes result in antigenic drift • WHO Avian influenza: assessing the pandemic threat

14. Influenza • Influenza B and C • Essentially human viruses • Influenza B causes sporadic outbreaks of severe respiratory disease • Nomenclature • B/Shanghai/361/2002 • Also prone to mutation • Influenza C causes no or very mild symptoms • Few mutations • WHO Avian influenza: assessing the pandemic threat

15. Influenza • Antigenic Changes • Drift • Same subtype, minor changes often involving point mutations • Shift • New subtype, major changes, may involve genetic recombination between different viruses • Likely responsible for pandemics • Pigs often thought of as the crucible for genetic recombination since they may be infected with both human and avian types of viruses

18. Improvements on Nature • Concentrated animal feeding operations (CSFOs) • During the later stages of the 1918 pandemic, farmers noted that their pigs were getting sick and called the disease “hog flu.” • Generally milder than human disease • One 2007 study showed that CAFO workers were 50 times more likely and their spouses were 25 times more likely to have elevated H1N1 antibodies

20. Avian Influenza • Avian influenza viruses are excreted in feces and secretions • Wild birds contaminate ponds/lakes • Domestic foul become infected • Chicken coops often above pig pens or pigs may be fed bird carcasses • China is often thought of as a major area of risk for genetic recombination since pigs, chickens, ducks and humans often live in close proximity • WHO Avian influenza: assessing the pandemic threat

21. Influenza • Instances of Avian Influenza in Humans • N5H1, Hong Kong 1997 • 18 people hospitalized/6 died • 1.5 million chickens killed to stop outbreak • H9N2, China and Hong Kong 1999 • 2 children infected • H7N2, Virginia 2002 • One person had serologic evidence of infection • H5N1 China and Hong Kong 2003 • Ongoing worldwide • Many, many other sporadic examples

22. Influenza • Since 2003 62 countries/territories have experienced outbreaks of HPAI H5N1 • FAO AIDE News May 2009 • Jumped species to tigers in Thailand with 147 out of 418 captive tigers developing severe symptoms after being fed chicken carcasses in October 2004 • WHO Avian influenza: assessing the pandemic threat

23. Influenza • H5N1 • Inefficient human to human transmission

24. HPAI H5N1 • H5N1 affects the young, in the prime of life, similar to the 1918 pandemic strain • H5N1 causes viral pneumonia, like the 1918 strain, without evidence of bacterial pneumonia • Why has H5N1 not shown sustained human to human transmission? • Is it only a matter of time? • Is there something that is preventing reassortment? • NEJM January 27, 2005 Editorial

25. Mortality Associated with Influenza Pandemics and Selected Seasonal Epidemic Events, 1918-2009 Morens D et al. N Engl J Med 2009;361:225-229

26. Genetic Relationships among Human and Relevant Swine Influenza Viruses, 1918-2009 Morens D et al. N Engl J Med 2009;361:225-229

27. Influenza • Three prerequisites for a pandemic: • A novel virus subtype • The general population will have little or no immunity • The virus must be able to replicate in humans and cause serious disease • The new virus must be efficiently transmitted from one human to another • The first two conditions have been met by the H5N1 avian strain but have been met by nH1N1 • WHO Avian influenza: assessing the pandemic threat

28. Influenza • The 1918 “Spanish Flu” pandemic (H1N1) killed about 40-50 million people worldwide in less than one year, with 500,000 US deaths—2.5% estimated case fatality rate • The young and healthy were especially affected • First wave simultaneously in Europe and USA in March 1918—Spring and Summer • Second wave in August—ten fold increase in fatality rate • Some reports of being “healthy” in the morning, dead by night • The total military deaths in WW1 were 8.3 million over 4 years • WHO Avian influenza: assessing the pandemic threat

29. Pandemic Influenza • 1957-1958 H2N2 “Asian Flu” caused 70,000 US deaths • 1968-1969 H3N2 “Hong Kong Flu” caused 34,000 US deaths • Relatively mild, only 11 years after the previous pandemic with the same N2 subtype which may have conferred some protection • One constant feature: A rapid surge in cases with exponential increases in a matter of weeks • A severe pathogenic pandemic influenza is likely to overwhelm ED and hospital bed capacity • WHO Avian influenza: assessing the pandemic threat

31. Influenza • Vaccine development • Usually produced in fertilized chicken eggs • (H5N1 kills chicken embryos) • Modified seed viruses are in development using recombinant genetic technology to remove lethal genes • Process of producing vaccine using this technology takes months—pandemic basically over when vaccine was available in quantity in 1957 and 1968 • A few companies are developing cell culture production techniques • WHO Avian influenza: assessing the pandemic threat

32. Seasonal Influenza Vaccine • The vaccines to be used in the 2009-2010 influenza season in the U.S. contain the following: • an A/Brisbane/59/2007 (H1N1)-like virus; * • an A/Brisbane/10/2007 (H3N2)-like virus; ** • a B/Brisbane/60/2008-like virus. • *A/Brisbane/59/2007 is a current vaccine virus; A/South Dakota/6/2007 (an A/Brisbane/59/2007-like virus) is a current vaccine virus used in live attenuated vaccines.**A/Brisbane/10/2007 and A/Uruguay/716/2007 (an A/Brisbane/10/2007-like virus) are current vaccine viruses. • http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Post-MarketActivities/LotReleases/ucm162050.htm

33. nH1N1 Vaccine • Two recent studies of vaccines derived from the A/California/7/2009 (H1N1) virus • A single 15 microgram dose of the 2009 H1N1 vaccine was immunogenic in adults, with mild to moderate vaccine-associated reactions. PMID: 19745216 • A single 7.5 microgram dose of the MF59-adjuvanted vaccine was effective. PMID: 19745215

34. Live Attenuated Influenza Vaccine • Aka FluMist • Derived from a live influenza A and B virus strains modified by cold adaptation creating a Master Donor Virus • Cold adapted • Temperature Sensitive • Attenuated • The MDV is updated annually with hemagglutinin (HA) and neuraminidase (NA) genes from contemporary flu viruses • See: PMID 19453395

35. LAIV • Replicates primarily in the ciliated epithelial cells of the nasopharyngeal mucosa to induce immune responses. • Does not replicate well in warmer temperatures found in the lower airways and lung • In adults, studied in ages 18-64. Studies evaluated the effectiveness in preventing any febrile illness. Post hoc analysis in adults 50-64 years old failed to show effectiveness. As a result, not approved for use in adults >50 in the United States. • See: PMID 19453395

36. LAIV • Cross protection among antigenically distinct viruses within the same subtype may be induced by LAIV • See PMID 19768402 • LAIV may work better in populations that have not received multiple influenza vaccinations • See PMID 19464536

37. Influenza • Antiviral Drugs • “M2 inhibitors” including amantadine and rimantadine are ineffective against H5N1 and nH1N1, but work against seasonal H1N1 • Neuraminidase inhibitors include oseltamivir and zanamivir are effective against nH1N1 with sporadic resistance • Better safety profile • More expensive • Negligible capacity for surge production • Resistance does develop (summer camps)

39. Influenza • Short incubation-1 to 3 days • Individuals infectious before symptoms develop • Transmitted by person-to-person contact, fomites and droplets >10 microns • Probable transmission by droplet nuclei, <5 microns (airborne) • Disease may not present with full clinical symptoms, but can be spread by the affected person

41. DHS Office of Biotechnology Activities Notice of Proposed Changes September 22, 2009 • Designation of human H2N2 viruses that circulated from 1957-8, the fully reconstructed 1918-1919 H1N1 and HPAI H5N1 as Risk Group 3 agents. • Requires enhanced biosafety practices, including uses of powered air purifying respiratiors and other PPE • Recombinant work using any genes/segments from the above strains will require BSL 3 enhanced containment • Federal Register/Voll 74, No. 182/Tuesday September 22, 2009/Notices

42. ACIP Recommends Five Groups as Priority Targets for H1N1 Vaccination • The CDC’s Advisory Committee on Immunization Practices (ACIP) has recommended which U.S. population groups should be targeted to receive H1N1 influenza vaccine when it becomes available. People over 65 have the lowest priority. • The 15-member ACIP says these five groups should be targeted: • pregnant women; • household contacts of infants under 6 months; • healthcare and emergency-services workers; • young people between 6 months and 24 years of age; • and nonelderly adults with underlying risk conditions, such as diabetes and chronic lung disease.

43. J. Cohen Science 325, 1328-1329 (2009) Published by AAAS

44. CDC Recommended Respiratory Protection Occupational (non-health care) • No novel H1N1 in community: Facemask/respirator not recommendedFacemask • Novel H1N1 in community: Facemask/respirator not recommended but could be considered under certain circumstances Occupational (health care) • Caring for persons with known, probable or suspected novel H1N1 or influenza-like illness: Respirator. • Use respirator and consider temporary reassignment for employees at high risk. http://www.cdc.gov/h1n1flu/masks.htm

45. PUSHBACK! • Much disagreement with CDC and OSHA guidelines • Who needs a respirator when surgical masks are cheaper and are thought by some to be equally effective against droplet spread? • Examples: CCSF DPH and SFGH ID

46. Institute of Medicine Report 9/1/09 • (1) Healthcare workers who are in close contact with individuals with nH1N1 or ILI should use fit tested N95 respirators • (2) Increase research on Influenza transmission and personal respiratory protection • Investigate relative importance of aerosol vs airborne transmission See: http://www.nap.edu/catalog/12748.html

47. Influenza Transmission changes with Humidity and Temperature • Cold and Dry conditions favor in the guinea pig host model • PMID: 17953482 PMCID: PMC2034399 • Same PI hypothesizes that transmission of influenza virus in temperate zones is predominantly by aerosol, in the tropics by contact— • Also hypothesize that current summertime transmission in North America is by contact.

48. I had a little bird, Its name was Enza. I opened the window, And in-flu-enza.

49. Indications for Hand Hygiene • When hands are visibly dirty, contaminated, or soiled, wash with non-antimicrobial or antimicrobial soap and water. • If hands are not visibly soiled, use an alcohol-based handrub for routinely decontaminating hands. Guideline for Hand Hygiene in Health-care Settings. MMWR 2002; vol. 51, no. RR-16.

50. Efficacy of Hand Hygiene Preparations in Killing Bacteria Better Good Best Antimicrobial soap Plain Soap Alcohol-based handrub