Pandemic Influenza Serhat Ünal MD. Hacettepe University, Faculty of Medicine Department of Medicine Section of Infectious Diseases
Neuraminidase Hemagglutinin RNA M2 protein (only on type A) Influenza Surface Proteins
Influenza Is Recurrent • Explosive outbreaks • Last 5 to 8 weeks1 each autumn/winter • Rapid spread of infection • Unpredictableoutbreaks • Timing (November to April in Northern hemisphere) • Intensity varies • Worldwide geographic distribution 1. Cox NJ, et al. Infect Dis Clin North Am. 1998;12:29.
Everyone Is at Risk 100 million people infected every year in Northern Hemisphere* 1:10 adults 1:3 children 10,000-40,000 deaths in the USA *In North America, Europe, and Japan. ESWI. Available at: http//www.eswi.org/library/bulletins/0499-4.html. CDC. MMWR. 2001;50(RR-04)1-46.
Influenza-Related Deaths in Context Risk RangeRisk of Dying in a Year 10-2- 10-3 from smoking 10 cigarettes a day from natural causes, age 40 years 10-3- 10-4 of influenza in a road accident 10-4- 10-5 of leukemia from homicide 10-5- 10-6 in a rail accident 10-6 by lightning strike Calman KC. BMJ. 1996;313:799-802.
Annual Burden of Influenza Individuals feel awful, “knocked flat” Increased work absenteeism Increased primary care visits Increased hospitalizations Lost productivity Impaired work performance Excess mortality Disruption of family and social life
Adults with influenza1 Rapid symptom onset Confined to bed 3 to 7 days Reduced activity 10 to 13 days Young adults with influenza2 Airway dysfunction/hyper-reactivity May persist for weeks after infection Influenza Affects Healthy Adults The majority of people affected by influenza are adults, most of whom are “healthy” 1. Vital and Health Statistics for CDC NCHS. Current estimates from the National Health Interview Survey, 1994. Series 10, No. 193. 2. Glezen WP, et al. J Infect Dis. 1987;155:1119-1126.
Influenza knocks people flat. They experience: 5 to 7 days of acute illness 10 to 13 days of reduced activity Persistent cough and malaise Risk of complications Personal Burden of Influenza Vital and Health Statistics for CDC NCHS. Current estimates from the National Health Interview Survey, 1994. Series 10, No. 193.
Influenza-Related Complications • Most complications occur in otherwise healthy persons1 • Bronchitis, pneumonia • Sinusitis • Exacerbation of underlying disease • 60%-80% of patients with complications receive antibiotics1,2 • Antibiotics prescribed for 30%-45% of patients presenting with influenza or ILI1,2 High risk Healthy 38% 62% 1. Meier CR, et al. Eur J Clin Microbiol Infect Dis. 2000;19:834-842. 2. Monto AS, et al. 9th International Congress on Infectious Diseases. April 2000; Buenos Aires, Argentina.
Increased Antibiotic Prescribing During Influenza Outbreak Total N=141,293 Complications No complications 100 80 60 % of Study PopulationReceiving Antibiotics 40 20 0 65 65 1-14 15-64 1-14 15-64 Age (y) Age (y) Meier CR, et al. Eur J Clin Microbiol Infect Dis. 2000;19:834-842.
Influenza Adds to the Health Care Burden • Annual 30% to 50% increase in primary care consultations1 • 100% to 170% increase in hospitalizations2,3 • The majority hospitalized are • <65 years old3 • Not in high-risk groups3 1. Barker WH, Mullooly JP. Am J Epidemiol. 1980;112:798-811. 2. Perrotta DM, et al.Am J Epidemiol. 1985;122:468-476. 3. Glezen WP, et al. J Infect Dis. 1987;155:1119-1126.
Economic Costs of Influenza Outbreak • Total annual costs of influenza are estimated at more than $14.6 billion in the USA • 10%: Direct costs of increased medical care • 90%: Indirect costs (lost productivity, employee absenteeism) American Lung Association. Fact sheet – Influenza. Available at http://www.lungusa.org/diseases/influenza_factsheet.html.
Influenza Epidemic in the Community • Virus easily transmitted in confined environments • School children key disseminators in family and community • Epidemic starts in school children and spreads to preschoolers and adults National Institute of Allergy and Infectious Diseases, USA, 12/97.
Mortality From Influenza Epidemics • 10,000 deaths per epidemic are common in the USA1 • Recent epidemics caused 20,000 - 40,000 deaths in the USA2 • Up to 870 deaths per 100,000 in patients with cardiovascular or pulmonary conditions3* *Northern Hemisphere data. 1. Piedra PA. Semin Respir Infect. 1995;10:216. 2. MMWR. 2001;50(RR-4):4. 3. Aymard M. ESWI Influenza Bulletin. April 1999.
Options for Influenza Management • Prevention • Vaccination is the cornerstone of influenza management • Chemoprophylaxis with antiviral agents • Treatment • Antiviral agents such as Tamiflu® (oseltamivir) • reduce severity and duration of influenza symptoms • help prevent serious secondary complications such as bronchitis and pneumonia
Influenza Vaccination • Important control measure • Recommended for elderly and high-risk groups of all ages • Efficacy depends on match with circulating strains and patient’s age and immune status MMWR. 2001;50(RR-4):5,8.
Content Updated yearly to protect againstanticipated strains, consists of type A (2) and type B (1) Process Grown in embryonated chicken eggs and formalin inactivated Inactivated Influenza Virus Vaccine MMWR. 2001;50:5.
Influenza Virus Vaccine • Efficacy • Varies with age and immunocompetence • Depends on match between projected vs actual strains • Children/teens • Stimulates high HA-inhibition antibody titers • Prevents infection • Elderly • Produces lower HA-inhibition antibody titers • May not eliminate URTI susceptibility • May reduce LRTI morbidity/mortality URTI = upper respiratory tract infection; LRTI = lower respiratory tract infection. MMWR. 2001;50:5-6.
Efficacy of the Influenza Vaccine • Most effective (70%-90%) in preventing illness in persons aged <65 years • 30%-70% in preventing P/I hospitalization in elderly not in chronic care facility • 30%-40% in preventing illness in frail elderly • 50%-60% in preventing P/I hospitalization in nursing home elderly • 80% in preventing death in nursing home elderly P/I = pneumonia and influenza. MMWR. 2001;50:5-6.
Therapeutic Goals • Relieve symptoms • Improve function • Prevent complications • Reduce transmission
Pathology of Influenza Infection A. Hemagglutinin binds to sialic acid B. Virus is engulfed into cell D. Neuraminidase facilitates release from cell C. RNA replicates virus in nucleus
Neuraminidase Hemagglutinin RNA M2 protein (only on type A) Influenza Surface Proteins
Clinically Relevant Influenza Viruses Type A Potentially severe illness Epidemics and pandemics Rapidly changing Type B Usually less severe illness Epidemics More uniform Type C Usually mild or asymptomatic illness Minimal public health impact Centers for Disease Control and Prevention. Influenza Prevention and Control. Influenza. Available at: http://www.cdc.gov/ncidod/diseases/flu/fluinfo.htm.
Naming Influenza Viruses A/Sydney/5/93 (H1N1) Neuraminidase Strain Sequence No. Type Origin Yr Isolated Hemagglutinin B/Beijing/184/93
Antigenic Drift RNA Hemagglutinin Neuraminidase Antibodies Sialic acid
Antigenic Shift – Influenza Type A Novel strain results (may lead to pandemic) New HA or NA subtype reassorts directly into current virus or to humans via avian hosts
Occurrence of Influenza Pandemics and Epidemics Incidence of clinically manifest influenza Mean level of population antibody vs A HxNx Mean level of population antibody vs A HyNy Pandemic Pandemic Interpandemic Period Epidemic Epidemic Disease Incidence Mean Population Antibody Level Epidemic 1 2 3 4 5 6 7 8 9 10 11 12 Time in Years Introduction of hypothetical A HyNy major (new subtype) variant A HxNx disappears Introduction of hypothetical A HxNx virus Significant minor variation A HxNx may occur at any of these points. Epidemics may or may not be associated with suchvariations Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases, 5th ed. 2000:1829. Modified from Kilbourne ED. Influenza. 1987:274, with permission.
What is a Pandemic? • Pan + demos = Whole + people • Epidemic occurring over a very wide area, crossing international boundaries and affecting a large number of people • Modern pandemics= Fast and explosive • Preview: SARS
Pandemics occur every 10 to 40 years3 Affect up to 50% of population worldwide3 Novel virus for human population Huge death toll 1997 “chicken flu” in Hong Kong – reminder of pandemic threat (H5N1) Influenza Pandemics Mortality associated with 20th century pandemics1,2 1918-19 “Spanish flu” 30 million deaths A(H1N1) worldwide 1957-58 “Asian flu” 1 million deaths A(H2N2) worldwide 1968-69 “Hong-Kong 800,000 deaths flu” worldwide A(H3N2) 1. WHO Report on Global Surveillance of Epidemic-prone Infectious Disease. Influenza. Available at: http://www.who.int/emc-documents/surveil…scsrisr2001.html/Influenza/Influenza.htm. 2. Oxford JS. Rev Med Virol. 2000;10(2):119-133. 3. Oxford JS, Lambkin R. Drug Discov Today. 1998;3:448-456.
Influenza Type A (H1N1) • Cause of 1918-1919 pandemic (swine) • Antigenic drift and subsequent epidemics • Disappeared in 1957 with appearance of H2N2 virus • Reappeared as the “Russian flu” in 1977 • Immunity in persons born before 1950 CDC. Influenza Prevention and Control. Available at: http://www.cdc.gov/ncidod/diseases/flu/fluinfo.htm.
Influenza Type A (H3N2) • Cause of 1968-1969 pandemic • Most severe morbidity and mortality of currently circulating influenza viruses (within past 30 years) • US mortality over 30 yrs: 400,000 CDC. Influenza Prevention and Control. Available at: http://www.cdc.gov/ncidod/diseases/flu/fluinfo.htm.
Fast and Explosive 30.000/day passenger flights only in the USA
A preview of a pandemic: SARS • 2002 November;severe pneumonia with unknown etiology in China • 2003 March;cases in Hong Kong, Vietnam, Kanada • When it was finally controlled, 8098 cases, 774 deaths (in 6 months!) • Most of the cases and deaths were health care workers
Requirements for a Pandemic • New influenza virus subtype • Transmission to humans • Severe infections in humans • Efficient transmission from human to human
Influenza Type A (H5N1) • First appeared in humans in Hong Kong, 1997 • Primarily associated with avian species • Fatal epidemic among Hong Kong poultry in 1997 • 18 total confirmed cases, with 6 deaths Lee Y, Mak KH, Saw TA. Public Health and Epidemiology Bulletin. 1999;8:1-8.
Half MeasureA bundle of live chickens gets a quick squirt of disinfectant on its way into the poultry section of the Long Bien market in Hanoi, Vietnam. At "wet" markets like this one, where chickens and ducks are sold and slaughtered on the spot, flu viruses can spread among the live birds and infect customers. The perfunctory spray is unlikely to do much good against a virus that lives in the birds' lungs and intestines. In any case, vendors headed into the market the day this picture was taken often bypassed the disinfection station..
Heavy TollPham Van Oanh, a lotus farmer in Vietnam's Mekong Delta, lost his wife and 13-year-old daugher to bird flu last January. They fell ill after eating infected chicken prepared by his brother-in-law, who stands in the doorway behind him. A portrait of his wife rests on the table in Oanh's hut, which overlooks a canal 30 minutes by water from the nearest village. His daughter, he says, used to pilot the boat carrying the lotus seed harvest to town. "She was the master sailor," he recalls sadly.
Ducks in DetentionFarmers and animal health workers in Thailand corral ducks to be tested for the H5N1 bird flu virus. Deadly to chickens and people, the virus can also infect ducks, yet the birds remain healthy as they are herded through the rice fields to fatten on leftover grains. "These gypsy ducks or wandering ducks are spreading H5N1 around South Vietnam and parts of Thailand and, of course, China," says flu expert Malik Peiris. This flock will spend eight days waiting for the results of the blood tests; only if they are free of the virus will their owner be allowed to move them to new paddies. Such measures have helped control the spread of avian flu in Thailand. .
October 2005 Manyas 2000 turkeys died in one night
wild birds in Thailand magpies in Korea crows in Japan single heron and peregrine falcon in Hong Kong In the spring 2005, an outbreak was detected in bar-headed geese at Qinghai Lake in western China,
Reported Cases of HPAI in Wild Birds in Turkey 2006 Sporrow in Karabük Pigeon, sporrows İn Erzincan Wild duck İn Ankara Sporrow İn Yozgat Wild duck İn Bitlis Wild duck İn Karaman Cormorant, swan, pigeon in Aydın Major migration routes for wild migratory birds in Turkey
Current WHO Phase Of Pandemic Alert November 2005 “Experts at WHO and elsewhere believe that the world is now closer to another influenza pandemic than at any time since 1968, when the last of the previous century's three pandemics occurred”
www.who.int • What strategic actions are recommended by WHO? • In August 2005, WHO sent all countries a document outlining recommended strategic actions for responding to the avian influenza pandemic threat. Recommended actions aim to strengthen national preparedness, reduce opportunities for a pandemic virus to emerge, improve the early warning system, delay initial international spread, and accelerate vaccine development • Is the world adequately prepared? • No. Despite an advance warning that has lasted almost two years, the world is ill-prepared to defend itself during a pandemic. WHO has urged all countries to develop preparedness plans, but only around 40 have done so. WHO has further urged countries with adequate resources to stockpile antiviral drugs nationally for use at the start of a pandemic. Around 30 countries are purchasing large quantities of these drugs, but the manufacturer has no capacity to fill these orders immediately. On present trends, most developing countries will have no access to vaccines and antiviral drugs throughout the duration of a pandemic.