Module1 ABCs of Influenza and Pandemics Joshua A

Module-1 ABCs of Influenza and Pandemics Joshua A. Mott. MA, EMT-P, Ph. D Influenza Division, CDC 1

Learning Objectives • Describe the characteristics of influenza 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 outbreaks in humans • Describe the epidemiology and clinical characteristics of influenza A (H 5 N 1) in humans 3

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Seasonal Influenza Preparedness Pandemic Influenza Preparedness 5

Influenza Viruses • Illness caused by infection with an influenza virus • Negative singlestranded RNA virus • 8 gene segments code for 10 proteins 6

Influenza Viruses • Classified into types A, B, and C • Only Types A and B cause significant disease C Goldsmith, CDC • Types B and C limited to humans • Type A viruses • More virulent • Affect many species 7

Influenza A Viruses • Influenza A viruses categorized by subtype • Classified according to two surface proteins • Hemagglutinin (H) – 16 known – Site of attachment to host cells – Antibody to HA is protective • Neuraminidase (N) – 9 known – Helps release virions from cells – Antibody to NA can help modify disease severity N H 8

Nomenclature Virus type Strain number Virus subtype A / Sydney / 05 / 97 (H 3 N 2) Place virus isolated Year isolated 9

Influenza Infection in Humans 10

Key Characteristics Influenza is a respiratory infection Transmission of influenza viruses – person-to-person transmission through close contact – Primarily through contact with respiratory droplets – Transmission from objects (fomites) possible 11

Shedding – Viral shedding can begin 1 day before symptom onset – Peak shedding first 3 days of illness – Correlates with temperature – Subsides usually by 5 -7 th day in adults – can be longer in children – Infants, children and the immunocompromised may shed the virus longer 12

Key Characteristics Incubation period – Time from exposure to onset of symptoms – 1 to 4 days (average = 2 -3 days) Seasonality – In temperate zones, sharp peaks in winter months – In tropical zones, circulates year-round with seasonal increases. • A fall-winter seasonal increase, and secondary rainy season increase has been observed in some tropical countries. – More international data is needed 13

Clinical Illness, Human Influenza • Abrupt onset • Fever and constitutional symptoms: body aches, headaches, fatigue • Cough, rhinnitis, sore throat • GI symptoms and myositis more common in young children • Sepsis-like syndrome in infants • Complications: sinus and ear infections, viral and bacterial pneumonia, myocarditis, pericarditis, encephalopathy/encephalitis, febrile seizures, worsening underlying chronic conditions 14

Human Influenza - Clinical Diagnosis • Clinical symptoms non-specific – Symptoms overlap with many pathogens – Coupling with laboratory data to verify diagnosis – Even at peak seasonal influenza season, about 30% specimens tested for influenza are positive in the United States 15

Laboratory Testing for Influenza • Viral culture – Gold standard but results take 7+ days usually – Influenza isolates for yearly vaccine development • RT-PCR – Most sensitive – Becoming more widely available • Immunofluorescence – Requires intact cells and laboratory skill/experience • Point-of-care rapid diagnositc tests – Can provide results <30 minutes – Generally 70+% sensitive, 90+% specific • Serology − Must used paired serum samples − >2 week delay for results 16

Individuals at Increased Risk for Hospitalizations and Death • Elderly > 65 years • Young Infants • Persons with chronic medical conditions – Heart or lung disease, including asthma – Metabolic disease, including diabetes – HIV/AIDs, other immunosuppression – Conditions that can compromise respiratory function or the handling of respiratory secretions • Pregnant women • Nursing home residents • Children on long-term aspirin therapy 17

600 100 500 400 80 300 60 200 40 100 20 Deaths Per 100, 000 Person Years Hospitalizations Per 100, 000 Person Years Influenza-Associated Hospitalizations, United States Deaths By Age Group 0 0 0 - 4 Yrs 5 - 49 Yrs 50 - 64 Yrs 65+ Yrs Age Group *Thompson WW, JAMA, 2004 18

Vaccination • Influenza vaccine is the best prevention for seasonal influenza. • Inactivated viruses in the vaccine developed from three circulating strains (generally 2 Type A and 1 Type B strain) – Therefore, seasonal “flu shot” only works for 3 influenza subtypes and will not work on pandemic strains. • Inactivated, injectable vaccine for persons 6 months and older • Live, intranasal spray vaccine for healthy nonpregnant persons 5 -49 years 19

Influenza Antiviral Medications • Can be used for both prevention and for treatment • Two classes – Adamantanes – rimantadine and amantadine • Currently not recommended for use due to resistance among circulating influenza A viruses – Neuraminidae inhibitors • Oseltamivir and zanamivir 20

Infection control measures • use of droplet precautions (masks, gowning, gloves) • isolating or cohorting influenza patients • limiting exposures • having ill workers stay home • screening and limiting visitors • annually vaccinating all healthcare workers 21

Non-Pharmaceutical Interventions • Voluntary isolation of sick people • Voluntary quarantine of healthy contacts • School closures • Social distancing 22

Avian Influenza 23

Cause for Concern • Avian influenza can have a large impact on poultry – Can cause high mortality – Significant economic impact • Rarely, avian influenza can cause illness in humans • Avian influenza viruses can serve as source of next pandemic strain 24

Influenza A HA and NA Subtypes H 1 H 2 H 3 H 4 H 5 H 6 H 7 H 8 H 9 H 10 H 11 H 12 H 13 H 14 H 15 H 16 N 1 N 2 Other Animals N 3 N 4 N 5 N 6 N 7 N 8 N 9 Other Animals 25

Avian Influenza • Type A influenza • Endemic in birds • H 5, H 7 subtypes can 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 26

Avian Influenza • Low pathogenic AI (LPAI) – Most common influenza infection in birds – Causes mild clinical and unapparent infections – May be any subtype (H 1 to H 15) • Highly pathogenic AI (HPAI) – Some H 5 or H 7 subtypes – Causes severe illness in poultry and often death – LPAI H 5 or H 7 subtypes can mutate into HPAI H 5 or H 7 subtypes 27

Avian Influenza Viruses • Usually do not jump species – Each “subtype” infects a specific set of animals – Wild bird strains do not usually infect domestic poultry • Usually do not infect people • Humans can become infected with avian influenza viruses – Usually through exposure to infected domestic poultry that have become infected with wild bird avian viruses 28

Avian influenza 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. 29

H 5 N 1 Avian Influenza • Currently spreading through Asia, Africa, Europe, Middle East • Can be highly lethal to domestic poultry and other animal species • Occasional human cases but no efficient human-to-human transmission • Virus of greatest concern for pandemic potential, but other influenza viruses in animals also of concern *As of March 8, 2007 30

H 5 N 1 Epizootic – 2003 -2006 • Since December 2003, – >50 countries have reported H 5 N 1 among domestic poultry and wild birds – Current outbreaks in a 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 31

H 5 N 1 Clinical Features • Case fatality ratio: 60% • Median age: 20 years (range 3 mos-75 yrs)* • Previously healthy children, young adults • Incubation: 2 -7 days • Fever, cough, shortness of breath, diarrhea • Pneumonia, acute respiratory disease syndrome, multi-organ failure 32 Beigel JH, et al. NEJM 2005; 353: 1374 -85 *WHO WER; 26: 249 -260

Clinical illness with H 5 N 1 compared with typical human influenza illness • More severe illness in younger persons • Primary viral pneumonia appears to be more common and with rapid onset • Incubation period may be longer • Duration of infectious period likely longer, particularly among adults 33

Avian Influenza in Humans (July 17, 2007) Year 1996 1997 1998 Subtype H 7 N 7 H 5 N 1 H 9 N 2 Location United Kingdom Hong Kong China Cases 1 18 6 Deaths 0 6 0 1999 2002 2003 2004 2003 -07 H 9 N 2 H 7 N 2 H 9 N 2 H 5 N 1 H 7 N 7 H 7 N 3 H 5 N 1 Hong Kong United States Hong Kong The Netherlands Canada Worldwide 2 0 1 0 1 0 2 1 89 1 2 0 318 192 * As of March 21, 2007 34

Worldwide H 5 N 1 Outbreak in Humans: 2003 - 2007 35 Source: WHO

Human H 5 N 1 Epidemiology • Primarily avian-to-human transmission • No evidence of sustained person-toperson spread • Limited probable person-to-person spread 1 1 N Engl J Med 2005; 352: 333 -340 36

H 5 N 1 Possible Travel Routes • Legal poultry business • Illegal bird trade • Untreated fertilizer • Migrating birds • Humans (contaminated objects) 37

What is Pandemic Influenza? • Pandemic: epidemic spreading around the world affecting hundreds of thousands of people, across many countries • Flu pandemics: global influenza epidemics of newly emerged strain of influenza that – passes easily from person to person – causes severe disease • Essentially no pre-existing immunity; every body at risk 38

Influenza Viruses • Characterized by ability to change Continually → yearly epidemics ‒ Drastically → sporadic pandemics ‒ 39

Antigenic “drift” Minor antigenic changes to the hemagglutinin protein • Point mutation in viral RNA • Continuous process • Cause of seasonal epidemics • Immunity may be limited to an individual strain • Vaccine strains must be updated each year 40

Antigenic “shift” Major antigenic changes leading to emergence of a new human influenza A virus subtype (e. g. new HA 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) 41

Re-assortment and Direct Transmission CT E R I D Non-human virus Human virus Reassortant virus 42

Seasonal Epidemics vs. Pandemics Human Influenza Pandemics – A public health problem each year – Appear in the human population rarely and unpredictably – Usually some immunity built up from previous exposures to the same subtype – Human population lacks any immunity – Infants and elderly most at risk – All age groups, including healthy young adults, may be at increased risk for serious complications – Result of Antigenic Drift – Result of Antigenic Shift 43

Pandemic Influenza • • • Timing unpredictable High illness rates across age groups Increased mortality – Higher proportion deaths in younger persons 44

Estimated Mortality from Influenza Pandemics • 1918 -19 (H 1 N 1) • • • 1957 -58 (H 2 N 2) • • >500, 000 deaths US 20 -100 million worldwide 70, 000 deaths US 1968 -69 (H 3 N 2) • 34, 000 deaths US 45

Timeline of Influenza Pandemics Avian Influenza H 2 H 1 1915 1925 1918 Spanish Influenza H 1 N 1 1935 1945 1957 Asian Influenza H 2 N 2 H 9 H 7 H 5 H 3 1965 1975 1985 1995 2005 1968 Hong Kong Influenza H 3 N 2 46

Why Worry? • Total deaths in 1918 -1919 estimated to be 20 -50 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 1960 1918 Date 47

Geographic spread: 1918 -19 06/18 ? 03/18 04/18 06/18 05/18 ? 01/19 06/18 C. W. Potter, Textbook of Influenza, 1998 JVT – IVW, Lisbon 48

U. S. Impact Estimates for the Next Influenza Pandemic Deaths: 89 -207, 000 Hospitalizations: 314 -733, 000 . 03 -. 07%. 1 -. 3% Outpatient care: 18 -42 m Total infected: 43 -100 m 6 -15% 15 -35% Health related economic impact Estimated: $71 to $166 billion Meltzer M, et al. Emerging Infectious Diseases 1999; 5: 659 -671 49

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 50

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 51 Weeks

WHO Stages of a Pandemic • Inter-pandemic period • Pandemic alert period • Pandemic period • Post pandemic period 52

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 53

WHO Phases of a Pandemic Alert Period Phase 3: Human infection with novel virus; no instances of human-to-human spread Phase 4: Small, localized clusters of human-to-human spread Phase 5: Larger clusters, still localized; virus adapting to humans 54

WHO Phases of a Pandemic Period Phase 6: Increased and sustained transmission in the general population. Post Pandemic Period Recovery phase 55

Efforts by Governments and Others to Address H 5 N 1 Limit Animal Infections • Improving farming practices to reduce contact between wild and domestic birds • Culling sick/exposed farms animals to limit further spread • Vaccinating poultry to limit infection/transmission Limit Human Infections • Using protective gear when working with sick animals & humans • Isolating and treating human cases • Conducting public awareness campaigns Coordinate Preparedness and Response • Preparedness planning, interagency/donor coordination • Stockpiling medicines, protective gear, animal vaccines, etc. 56

Influenza Pandemic Viruses A new influenza A subtype can infect humans AND Causes serious illness AND Spreads easily from human-to-human The first two prerequisites have been met, but not the last – Each new human infection is an opportunity for 57 the virus to change

Summary • Influenza is a serious human health concern each year • Influenza virus strains evolve rapidly and can develop into a novel virus with pandemic potential • Influenza pandemics have caused high morbidity and mortality in the past 58

Summary • H 5 N 1 Avian Influenza is currently spreading through birds with occasional cases among humans • While there is evidence of rare human-tohuman transmission, sustained transmission has not occurred • If H 5 N 1 virus obtains the ability to easily transmit from person-to-person, a pandemic may result 59

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. 60

Glossary Seasonal Influenza Expected rise in influenza occurrence among humans living in temperate climates; occurs during the winter season with strains of influenza that have minor changes from season to season. Pandemic An epidemic occurring over a wide geographic area and affecting a large proportion of the population. Antigenic Drift A process of small changes in the genetic material of a virus, called point mutations, that occur during the normal virus replication process. 61

Glossary Antigenic Shift A process of major changes in the genetic material of a virus; for influenza, the H and N proteins change altogether, resulting in a new strain of virus. Highly Pathogenic Avian Influenza (HPAI) Influenza infection in poultry that causes severe illness and often death. Can be transmitted to humans resulting in severe illness or death. Low Pathogenic Avian Influenza (LPAI) The most common influenza infection in birds; causes mild clinical and unapparent infections. 62

References and Resources • Cécile Viboud, et al. Emerg Infect Dis [serial on the Internet]. 2006 Apr. Available from http: //www. cdc. gov/ncidod/EID/vol 12 no 04/05 -0695 G 2. htm • The Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H 5. Avian Influenza A (H 5 N 1) infection in humans. N Engl J Med. 2005 Sep 29; 353(13): 1374 -85. • Ungchusak K, et al. Probable Person-to-Person Transmission of Avian Influenza A (H 5 N 1) N Engl J Med 2005; 352: 333 -340. 63

References and Resources • Tiensin T, et al. Highly Pathogenic Avian Influenza H 5 N 1, Thailand, 2004. EID; 2005; 11(11): 1664 -72. http: //www. cdc. gov/ncidod/eid/vol 11 no 11/050608. 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/ 64