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ABCs of Influenza and Pandemics Photo: Cynthia Goldsmith, CDC 1 Learning Objectives • Describe the characteristics of influenza virus infection in humans • Understand different types of influenza viruses and how they can infect humans and animals • Describe the ways that influenza viruses can change or mutate 2 Learning Objectives • Describe the epidemiology of influenza, and contrast seasonal (or human) influenza with avian and pandemic influenza • Understand the recent history of avian influenza virus infections in humans • Describe the epidemiology and clinical characteristics of influenza A (H5N1) in humans 3 Outline • Fundamentals of influenza viruses • Human infection with seasonal influenza: characteristics, diagnosis, and control • Avian influenza viruses and zoonotic infection • Human infection with H5N1 viruses • Pandemic influenza 4 Fundamentals of Influenza Viruses 5 Definitions of Terms • Seasonal influenza: Influenza that occurs every year with gradual variations in the previous year’s virus surface proteins (antigenic drift) • Avian Influenza: a disease of birds that occasionally jumps species and infects humans. Ultimately is the source of new influenza A viruses in humans that can lead to pandemics • Pandemic influenza: a worldwide surge in human influenza cases caused by the introduction of a new type A virus surface protein (antigenic shift) 6 Pandemic Avian http://www.pandemicflu.gov/ Seasonal http://www.cdc.gov/flu/weekly/ TIMEasia, February 9, 2004 7 Seasonal Influenza Preparedness Pandemic Influenza Preparedness 8 Influenza Viruses • Illness caused by infection of the respiratory tract with influenza virus • Negative singlestranded RNA virus • 8 gene segments code for 11 proteins This file has been released into the public domain by the copyright holder, http://en.wikipedia.org/wiki/Influenza_virus 9 Influenza Viruses • Classified into types A, B, and C • Types A and B cause significant disease worldwide • Types B and C limited to humans • Type A viruses More virulent Wild waterfowl reservoir Affect many species Photo: Cynthia Goldsmith, CDC 10 Influenza A Viruses Categorized by subtype • Classified according to two surface proteins • Hemagglutinin (HA) – 16 known subtypes Site of attachment to host cells Antibody to HA is protective • Neuraminidase (NA) – 9 known subtypes Helps release virions from cells Antibody to NA can help modify disease severity Hemagglutinin This image is in the public domain in the United States 11 Nomenclature Virus type Strain number Virus subtype A /Duck/ Hunan/ 795 / 2002 (H5N1) Optional: Type of Animal Place virus isolated Year isolated 12 Influenza Types/Influenza A Subtypes Circulating in Tropical Country X, January 2006 through June 2007 45 40 35 30 25 20 15 10 5 H1N1 B Month and Year H3N2 07 6/ 07 5/ 07 4/ 07 3/ 07 2/ 07 1/ 6 /0 6 12 /0 6 11 /0 10 06 9/ 06 8/ 06 7/ 06 6/ 06 5/ 06 4/ 06 3/ 06 2/ 06 0 1/ % ILI testing Positive for Influenza Positive(%) 13 Influenza A HA and NA Subtypes H1 H2 H3 H4 H5 H6 H7 H8 H9 H10 H11 H12 H13 H14 H15 H16 N1 N2 Other Animals Other Animals Other Animals Other Animals N3 N4 N5 N6 N7 N8 N9 Other Animals Other Animals 14 Review Question 1 Which influenza virus type affects humans, pigs, and birds: A, B, or C? Answer: Influenza A viruses can infect multiple species including humans pigs and birds. 15 Influenza Virus Infection in Humans U.S. Centers for Disease Control and Prevention 16 Importance of Influenza • Global burden largely unknown • Data from temperate climates • 3-5 million severe cases/year • 300,000 - 500,000 deaths/year http://www.cdc.gov/flu/about/disease/us_flu-related_deaths.htm 17 Transmission • Influenza is an acute respiratory disease • • • Signs and symptoms reflect respiratory route Fever, cough, headache, muscle aches Sometimes lower respiratory • Transmission of influenza viruses • • • Person-to-person through droplets from coughing or sneezing Transmission from objects (fomites) possible Infectious 1 day before and up to 5 days after becoming sick U.S. Centers for Disease Control and Prevention 18 Communicability • • • • Viral shedding can begin 1 day before symptom onset Peak shedding first 3 days of illness Subsides usually by 5-7th day in adults Infants, children and the immunosuppressed may shed virus longer U.S. Centers for Disease Control and Prevention 19 Seasonality Incubation period • • • Time from exposure to onset of symptoms Average 2 days (range = 1-4 days) Peak shedding first 3 days of illness Seasonality • In temperate zones, increases in winter months • • Driven by mutations and viral preference for cold, dry weather conditions In tropical zones, circulates year-round • • Fall-winter and rainy season increase has been observed More international data are needed 20 Human Influenza Clinical Diagnosis • Clinical symptoms nonspecific • Symptoms overlap with many • • pathogens Couple with laboratory data to verify diagnosis Even during peak seasonal influenza activity, only about 30% specimens tested for influenza are positive in the United States U.S. Centers for Disease Control and Prevention 21 Clinical Illness, Human Influenza • • Abrupt onset Fever, chills, body aches, sore throat, non-productive cough, runny nose, headache. U.S. Centers for Disease Control and Prevention • GI symptoms and muscle inflammation more common in young children 22 Human Influenza Complications • Sinus and ear infections • Viral and bacterial pneumonia • Myocarditis and Pericarditis • Myositis • Encephalopathy and encephalitis • Febrile seizures • Worsening of underlying chronic conditions • Sepsis-like syndrome in infants U.S. Centers for Disease Control and Prevention 23 Individuals at Increased Risk for Hospitalizations and Death • • • • • Adults>65 years Adults and children with chronic medical conditions Neruomuscular dysfunction Heart disease Asthma Chronic lung disease Liver disease Diabetes Immune compromised U.S. Centers for Disease Control and Prevention Pregnant women Nursing home residents Children on long-term aspirin therapy 24 Laboratory Testing for Influenza • Rapid diagnostic tests • Can provide results <30 minutes ~ 70+% sensitive, 90+% specific • Serology Must used paired serum samples >2 week delay for results Viral culture “Gold standard” Results take 2-7 days Influenza isolates for yearly vaccine development • RT-PCR Most sensitive Becoming more widely available • Immunofluorescence Requires intact cells and laboratory skill/experience 25 Influenza Surveillance in the U.S.: What Are We Trying to Measure? U.S. population ~300 million 1 Lab Tested ~5%-20% Infected (15-60 million) Hospitalized >200,000 Seek Care Death ~36,000 ~50% Symptomatic (15-30 million) Treat at Home 26 Influenza Vaccination • • • • • Best way to prevent influenza Developed from 3 circulating strains (2 Type A and 1 Type B strain) Seasonal “flu shot” only works for 3 influenza subtypes and will not work on pandemic strains Inactivated, intramuscular vaccine injection for persons 6 months and older Live, intranasal spray vaccine for healthy non-pregnant persons (2 – 49 years old) U.S. Centers for Disease Control and Prevention 27 The Two Classes of Influenza Antiviral Medications • Can be used for both prevention and for treatment • Adamantanes Rimantadine and Amantadine Only for Type A viruses Currently not recommended for use due to resistance among circulating influenza A viruses • Neuraminidase inhibitors Oseltamivir (Tamiflu®) and Zanamivir (Relenza®) Type A and B viruses Emergence of global resistance to Oseltamivir in influenza 28 A (H1N1) viruses in 2007-08 Infection Control Measures for Seasonal, Avian, and Pandemic Influenza • • Mostly in healthcare settings and nursing homes Standard precautions For example, gloves, hand washing and cough etiquette • Transmission-based precautions For example, contact, droplet and sometimes droplet nuclei precautions • U.S. Centers for Disease Control and Prevention Annual influenza vaccination of all healthcare workers 29 Non-Pharmaceutical Interventions • Social distancing • Personal protective measures (e.g., masks) • Travel screening and restriction • Public health communication campaigns This image is in the public domain of the United States http://en.wikipedia.org/wiki/Respirator 30 Review Question 2 After an adult is infected with an influenza virus, during what time period are they most likely to shed virus? Answer: Peak shedding occurs during the first 3 days of illness. (Shedding can occur up to one day before illness and usually declines within 5-7 days) 31 Review Question 3 During the 2009-2009 influenza season, what class(es) of antivirals is recommended by the CDC for treatment of Influenza A (H1N1) virus infection or suspected exposure? A. Oseltamivir B. Zanamivir C. Oseltamivir and rimantadine D. Both B and C E. None Answer: D 32 Avian Influenza This image has been released to the public domain of the United States http://en.wikipedia.org/wiki/Chicken 33 H5N1 Epizootic – 2003-2008 • • Since December 2003 >60 countries have reported H5N1 among domestic poultry or wild birds Current outbreaks in many countries Expanded from Asia to the Middle East, Europe, and Africa Largest epizootic of avian influenza ever described Over 200 million birds died or destroyed Photo: Tim Uyeki, CDC 34 Cause for Concern • Avian influenza can have a large impact on poultry • Can cause morbidity/mortality in poultry • Significant economic impact • Rarely, avian influenza A virus infection can cause illness in humans • Highly pathogenic avian influenza A viruses could be a source of the next pandemic influenza virus strain 35 Avian Influenza Viruses • • • • • Type A influenza Endemic in birds May be low pathogenic or high pathogenic H5, H7 subtypes can be highly pathogenic and cause serious disease or death in wild birds; often cause death in poultry Virus in saliva and feces of wild birds and poultry can be directly transmitted to humans and other animals This image has been released into the public domain by the copyright holder, http://en.wikipedia.org/wiki/Waterfowl 36 Avian Influenza Virus Pathogenicity • • • Low pathogenic AI (LPAI) viruses Most common influenza virus infection in birds Causes mild clinical and unapparent infections May be any subtype (H1 to H16) Highly pathogenic AI (HPAI) viruses Some H5 or H7 virus strains to date Causes severe illness in poultry and often death LPAI H5 or H7 virus subtypes can mutate into HPAI H5 or H7 virus subtypes Usually no symptoms or mild symptoms in wild birds Determined by molecular and pathogenicity criteria 37 Highly Pathogenic Avian Influenza A (H5N1) Virus • Currently spreading through Asia, Africa, Europe, Middle East • Can be highly lethal to domestic poultry and other animal species • Occasional human cases but no sustained human-tohuman transmission • Virus of greatest concern for pandemic potential, but other influenza viruses in animals also of concern *As of September 2008 38 Influenza A (H5N1) viruses in Other Animals H5N1 viruses can infect other animals: • • • • • Pigs (China, Vietnam) Dogs Domestic cats; has infected civet cats Tigers, leopards (Thailand, China) Tiger-to-tiger transmission (Thailand) These images have been released into the public domain by the copyright holders, http://commons.wikimedia.org/wiki/Category:Felis_silvestris_catus http://en.wikipedia.org/wiki/Image:Sow_with_piglet.jpg 39 Avian Influenza Virus Infections • Usually do not jump species Wild bird strains do not usually infect domestic poultry • Usually do not infect people • Humans can become infected with avian influenza viruses Usually through close exposure to infected domestic poultry 40 Transmission Across Species Wild Water Fowl Influenza A subtypes circulate in wild birds which can then infect domestic birds. Domestic Birds Wild birds are the natural reservoir for Influenza A strains and are the source for viruses infecting other species. 41 Review Question 4 What is the natural reservoir for avian influenza A (H5N1) viruses, and how can humans be infected with H5N1 virus? Answer: The natural reservoir for all avian influenza viruses are wild aquatic birds. Currently, humans are chiefly infected by exposure to infected poultry. 42 Human Infection with H5N1 Virus 43 H5N1 in Humans: Clinical Features • Case fatality proportion: 63% • Median age: 18 years • Previously healthy children, young adults • Incubation period: 2-7 days • Fever, cough, shortness of breath, diarrhea • Pneumonia, acute respiratory disease syndrome, multi-organ failure World Health Organization. New England J Medicine 2008;358:261-73. *WHO WER;26:249-260 44 H5N1 Clinical Illness • Very severe with high mortality • Has primarily affected children and young adults • Severe pneumonia is common • Incubation period may be longer than for seasonal • • influenza Duration of infectious period likely longer than seasonal influenza, particularly among adults Multi-organ dysfunction is common 45 Avian Influenza in Humans Year Subtype Location Cases Deaths 1996 H7N7 United Kingdom 1 0 1997 H5N1 Hong Kong 18 6 1998 H9N2 China 6 0 1999 H9N2 Hong Kong 2 0 2002 H7N2 United States 1 0 2003 H7N2 United States 1 0 2003 H9N2 Hong Kong 1 0 2003 H5N1 Hong Kong 2 1 2003 H7N7 The Netherlands 89 1 2004 H7N3 Canada 2 0 2007 H7N2 United Kingdom 4 0 2003-08 H5N1 Worldwide 412 256 46 (March 23, 2009) Worldwide H5N1 Outbreak in Birds: 2003 - 2008 47 Source: WHO Worldwide H5N1 Outbreak in Humans: 2003 - 2008 48 Source: WHO Human H5N1 Epidemiology • Direct and close contact with sick or dead poultry Slaughtering or cleaning poultry Visiting a live poultry market • No evidence of sustained person-to-person spread • Limited probable person-to-person spread1 1 World Health Organization. New England J Medicine 2008;358:261-73. 49 Possible Mechanisms of International Spread • Legal poultry business • Illegal bird trade • Migrating birds • Humans (contaminated objects) • Untreated fertilizer This image has been released into the public domain by the copyright holder. http://commons.wikimedia.org/wiki/Image:Industrial-Chicken-Coop.JPG 50 The Possibility of a Pandemic 51 What is Pandemic Influenza? • Pandemic: epidemic spreading around the world affecting hundreds of thousands of people, across many countries • Flu pandemic: global epidemic of new influenza A virus subtype that: Passes easily from person to person Causes severe disease • Essentially no pre-existing immunity; everybody at risk 52 Influenza Viruses Characterized by ability to change: • Continually (antigenic drift) → yearly epidemics • Drastically (antigenic shift) → rare pandemics U.S. Centers for Disease Control and Prevention 53 Antigenic “Drift” Minor antigenic changes to the hemagglutinin protein • • • • • Point mutation in viral RNA Continuous process during viral replication Cause of seasonal epidemics Immunity may be limited to a specific strain Vaccine strains must be updated each year 54 Antigenic “Shift” Major antigenic changes leading to emergence of a new human influenza A virus subtype through: • Genetic reassortment (human and animal viruses) • Direct animal (poultry) to human transmission A pandemic can occur if: • Efficient and sustained virus transmission occurs among humans (sustained person-to-person spread) 55 Drift and Shift, Illustrated This image has been released into the public domain by the copyright holder. http://en.wikipedia.org/wiki/Influenza 56 Re-assortment and Direct Transmission Non-human virus Human virus Reassortant virus 57 Requirements for an Influenza Pandemic Virus • A new influenza A subtype virus emerges that can infect humans AND • Causes serious illness AND • Spreads easily from human-to-human in a sustained manner 58 Pandemic Influenza • Timing unpredictable • High illness rates across age groups • Increased mortality Higher proportion deaths in younger persons 59 Estimated Mortality from Previous Influenza Pandemics • 1918-19 (H1N1) >500,000 deaths US 20 -100 million worldwide • 1957-58 (H2N2) 70,000 excess deaths US • 1968-69 (H3N2) 34,000 excess deaths US US National Archives at College Park, MD. Record number 165-WW-269B-25 60 Why worry? Total deaths in 1918-1919 estimated to be 20-100 million worldwide. U.S. Deaths = 550,000-675,000 U.S. Life Expectancy 1900-1960 70 65 Age 60 55 50 45 40 35 1900 1918 Source: CDC Pandemic Influenza Update, May, 2006; http://www.immunize.org/pandemic/panflu506.pdf Date 1960 61 U.S. Impact Estimates for the Next Influenza Pandemic Deaths: 89-207,000 Hospitalizations: 314-733,000 Outpatient care: 18-42 m Total infected: 43-100 m .03-.07% .1-.3% 6-15% 15-35% Health related economic impact Estimated: $71 to $166 billion Meltzer M, et al. Emerging Infectious Diseases 1999;5:659-671 62 Geographic spread: 1918-19 06/18 ? 03/18 04/18 06/18 05/18 ? 01/19 06/18 JVT – IVW, Lisbon C.W. Potter, Textbook of Influenza, 1998 63 Seasonal Epidemics vs. Pandemics • • • • Human Influenza A public health problem each year Usually some immunity built up from previous exposures to the same subtype Infants and elderly most at risk Result of Antigenic Drift Influenza Pandemics • • • • Appear in the human population rarely and unpredictably Human population lacks immunity to a new influenza A virus subtype All age groups, including healthy young adults, may be at increased risk for serious complications Result of Antigenic Shift 64 Timeline of New Influenza A Subtype Virus Infections in Humans Avian Influenza H9 H7 H5 H3 H2 H1 H1 1915 1925 1935 1945 1955 1965 1975 1985 1995 1918 1957 1968 1977 Spanish Influenza H1N1 Asian Influenza H2N2 Hong Kong Influenza H3N2 Emergence of H1N1 2005 65 Concerns about Pandemic Influenza • Rapid global spread (morbidity and mortality) • Shortages and delays – vaccines and antiviral medications • Increased burden on hospitals and outpatient care systems • Disruption of national and community infrastructures 66 Review Question 4 Match each term to the statement that it best fits • Seasonal Flu • Occurred 3 times in the 20th century • Avian Flu • Pandemic Flu • Outbreaks result from antigenic drift • Usually does not infect people 67 Potential Strategies to Decrease the Impact of a Pandemic • Prevent or delay introduction, slow spread • Decrease illness and death Vaccine when available Antiviral treatment and isolation for people with illness Non-pharmaceutical interventions Unprepared Impact Prepared Weeks 68 WHO Phases of a Pandemic http://www.who.int/csr/disease/avian_influenza/phase/en/index.html 69 WHO Phases of a Pandemic Inter-pandemic Period Phase 1: No new Influenza virus subtypes in humans Phase 2: No new virus subtypes in humans; animal subtype poses a risk of human disease 70 WHO Phases of a Pandemic Pandemic Alert Period Phase 3: Human infection with novel virus; no or very limited human-to-human spread Phase 4: Small, localized clusters of human-tohuman spread Phase 5: Larger clusters, still localized; virus adapting to humans 71 WHO Phases of a Pandemic Pandemic Period Phase 6: Increased and sustained transmission in the general population. Post Pandemic Period Recovery phase 72 Influenza Pandemic Viruses A new influenza A subtype virus can infect humans AND Causes serious illness AND Spreads easily from human-to-human in a sustained manner The first two prerequisites have been met, but not the last 73 Summary • Seasonal influenza differs slightly each year Disease often mild but may have serious complications • Avian influenza viruses may experience antigenic shift and infect humans Current concern over influenza A (H5N1) virus • Pandemic requirements for H5N1 virus have not been met Virus does not transmit easily between humans, no sustained transmission 74 Glossary Virus A small, infectious agent consisting of a core of genetic material (DNA or RNA) surrounded by a shell of protein. A virus needs a living cell [a host] to reproduce. Viral shedding Multiplication of a virus in an infected person with subsequent release of the virus from that infected person, such that others who come into contact with the person may become infected. A state of being contagious. Epidemiology The branch of medicine that deals with the study of the causes, distribution, and control of disease in populations. 75 Glossary Seasonal Influenza Refers to annual influenza epidemics occurring during winter among people living in temperate climates; caused by circulating strains of human influenza A and B viruses that have minor antigenic changes each season and are transmitted from person-to-person. Pandemic Influenza A global epidemic causing widespread morbidity and mortality among a high proportion of people, caused by the emergence of a novel influenza A subtype virus among people that is spread from person-to-person in a sustained manner. 76 Glossary Antigenic Drift A process of small changes in the genetic material of human influenza A and B viruses, called point mutations, that occur during the normal virus replication process and result in changes to the surface proteins producing new strains; causes seasonal influenza epidemics Antigenic Shift Refers to human infection by novel influenza A viruses (not circulating among people) with a new hemagglutinin subtype virus, and may also include infection with both a new hemagglutinin and a new neuraminidase protein. Can result from direct transmission from an animal influenza A virus, or through genetic reassortment between human and animal influenza A viruses; the new virus has pandemic potential among humans. 77 Glossary Highly Pathogenic Avian Influenza (HPAI) Virus Kind of avian influenza viruses (H5 or H7 subtypes) that usually causes high mortality among domestic poultry and other bird species. Can be transmitted to other kinds of animals and rarely to humans resulting in a range of symptoms including severe illness and death. Low Pathogenic Avian Influenza (LPAI) Virus Kind of avian influenza viruses that infect many wild bird species and poultry. Can evolve into highly pathogenic viruses. Can cause rare human infection that is usually clinically mild. 78 References and Resources • • • Cécile Viboud, et al. Emerg Infect Dis [serial on the Internet]. 2006 Apr. Available from http://www.cdc.gov/ncidod/EID/vol12no04/05-0695-G2.htm Writing Committee of the Second World Health Organization (WHO) Consultation on Clinical Aspects of Human Infection with Avian Influenza A (H5N1) Virus. Update on Avian Influenza A (H5N1) Virus Infection in Humans. N Engl J Med. 2008;358;261-73. Ungchusak K, et al. Probable Person-to-Person Transmission of Avian Influenza A (H5N1) N Engl J Med 2005;352:333340. 79 References and Resources • • • Tiensin T, et al. Highly Pathogenic Avian Influenza H5N1, Thailand, 2004. EID;2005;11(11):1664-72. http://www.cdc.gov/ncidod/eid/vol11no11/05-0608.htm World Health Organization. Epidemic and Pandemic Alert and Response. 2006. http://www.who.int/csr/en/ Center for Food Security and Public Health. Iowa State University: http://www.cfsph.iastate.edu/ 80