UPDATE ON INFLUENZA IN A YEAR OF VACCINE SHORTAGE

1. UPDATE ON INFLUENZA IN A YEAR OF VACCINE SHORTAGE Brian Goldstein, M.D., M.B.A. Andrew Kaplan, M.D. Melissa Miller, Ph.D David Jay Weber, M.D., M.P.H.

2. THE INFLUENZA VACCINE SHORTAGE Manufacturers and estimated production Chiron � Fluvirin (inactivated): 50 million doses Aventis � Fluzone (inactivated): 58 million doses Medimmune - FluMist (live attenuated): ~2.5 million doses Chiron will not be shipping any vaccine due to contamination (Serratia) No shortage of pediatric doses (Aventis only manufacturer)

3. INFLUENZA:EPIDEMIOLOGY AND VIROLOGY Andrew Kaplan, M.D. Associate Professor Departments of Medicine and Microbiology & Immunology

4. Influenza Disease Burden to U.S. Societyin an Average Year Influenza Disease Burden to U.S. Society in an Average Year� A recent study by Thompson et al concluded that the number of influenza-related deaths has increased significantly in the past 2 decades [Thompson 2003]. The number of pneumonia and influenza deaths rose by 83% from the 1976-1977 through 1997-1998 influenza seasons. For the 1990-1991 through 1998-1999 seasons, the greatest average numbers of deaths were associated with influenza A (H3N2) viruses, followed by influenza B, and influenza A (H1N1). Influenza viruses were associated with annual averages of 8,097 underlying pneumonia and influenza deaths, 36,155 underlying respiratory and circulatory deaths, and 51,203 all-cause deaths. The authors attributed the increase in influenza-related deaths during the past 2 decades at least partially to the aging of the population. They noted that people aged 85 years of age and older are 32 times more likely to die from an influenza-associated underlying pneumonia and influenza death than people between 65 and 69 years old. Because it is a highly contagious, acute respiratory disease, influenza is responsible for an average of 50 to 60 million infections annually, resulting in 25 million health care visits [Couch 2000]. An estimated 114,000 to 142,000 excess hospitalizations occur each year secondary to influenza [ACIP 2004], although others suggest it may be over 0.25 million [Couch 2000]. The annual direct medical costs of influenza are estimated at between $1 and $3 billion [Patriarca 1999]. Economic losses are likely higher: $3 to $5 billion [Patriarca 1999]. Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289:179-186. Couch RB. Influenza: prospects for control. Ann Intern Med. 2000;133:992-998. Advisory Committee on Immunization Practices. Prevention and control of influenza. MMWR. 2004;53(RR06):1-40. Patriarca PA. New options for prevention and control of influenza. JAMA. 1999;282:75-77.Influenza Disease Burden to U.S. Society in an Average Year� A recent study by Thompson et al concluded that the number of influenza-related deaths has increased significantly in the past 2 decades [Thompson 2003]. The number of pneumonia and influenza deaths rose by 83% from the 1976-1977 through 1997-1998 influenza seasons. For the 1990-1991 through 1998-1999 seasons, the greatest average numbers of deaths were associated with influenza A (H3N2) viruses, followed by influenza B, and influenza A (H1N1). Influenza viruses were associated with annual averages of 8,097 underlying pneumonia and influenza deaths, 36,155 underlying respiratory and circulatory deaths, and 51,203 all-cause deaths. The authors attributed the increase in influenza-related deaths during the past 2 decades at least partially to the aging of the population. They noted that people aged 85 years of age and older are 32 times more likely to die from an influenza-associated underlying pneumonia and influenza death than people between 65 and 69 years old. Because it is a highly contagious, acute respiratory disease, influenza is responsible for an average of 50 to 60 million infections annually, resulting in 25 million health care visits [Couch 2000]. An estimated 114,000 to 142,000 excess hospitalizations occur each year secondary to influenza [ACIP 2004], although others suggest it may be over 0.25 million [Couch 2000]. The annual direct medical costs of influenza are estimated at between $1 and $3 billion [Patriarca 1999]. Economic losses are likely higher: $3 to $5 billion [Patriarca 1999]. Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289:179-186. Couch RB. Influenza: prospects for control. Ann Intern Med. 2000;133:992-998. Advisory Committee on Immunization Practices. Prevention and control of influenza. MMWR. 2004;53(RR06):1-40. Patriarca PA. New options for prevention and control of influenza. JAMA. 1999;282:75-77.

5. INFLUENZA: BIOLOGY & IMPACT Single-stranded, enveloped, RNA virus (orthomyxoviridae family) Influenza A Potentially severe illness; epidemic and pandemics Rapidly changing Influenza B Usually less severe illness; may cause epidemics More uniform Influenza C Usually mild or asymptomatic illness

6. INFLUENZA: BIOLOGY & IMPACT Impact 25-50 million people contract influenza annually representing and attack rate of 10-20%. ~115,000 hospitalizations per year ~35,000 (20,000 � 40,000) deaths per year Causes respiratory tract disease Sudden onset More severe pneumonia during pregnancy No carrier state (but inapparent illness may occur)

7. INFLUENZA: EPIDEMIOLOGY Geographic distribution � global Reservoir: Humans, swine, birds Incubation - 1 to 5 days; usually 2 days Transmission Droplet (airborne?) route Direct contact Communicability 1 to 2 days before onset of symptoms to 4 to 5 days post-onset Attack rates: Up to 60%

8. Influenza Activity Can Peak From December Through May Influenza Activity Can Peak From December Through May� The occurrence of influenza infection is recognized to be highly seasonal. The CDC monitors the incidence of influenza throughout the U.S. each year with epidemics usually appearing during the winter months. For the last several decades (1976-2002), the majority of cases were reported during the fall and winter months, with peak incidence typically appearing in February, followed by January. Influenza epidemic peaks can vary (regional differences, etc.). � www.cdc.gov/nip/publications/pink/flu.pdf Influenza Activity Can Peak From December Through May� The occurrence of influenza infection is recognized to be highly seasonal. The CDC monitors the incidence of influenza throughout the U.S. each year with epidemics usually appearing during the winter months. For the last several decades (1976-2002), the majority of cases were reported during the fall and winter months, with peak incidence typically appearing in February, followed by January. Influenza epidemic peaks can vary (regional differences, etc.). � www.cdc.gov/nip/publications/pink/flu.pdf

9. Structure of the Influenza Virus Structure of the Influenza Virus Influenza is a single-stranded, helically shaped RNA virus of the orthomyxoviridae family. Three types of influenza virus have been classified (A, B, and C) based on antigenic differences. The glycoprotein hemagglutinin (HA) is the principal antigen on the surface of the influenza virus and is cleaved by proteases in host epithelial cells. HA undergoes proteolytic cleavage to HA1 and HA2 moieties. HA1 facilitates viral entry into cell principal viral neutralization epitopes. HA2 is important in viral attachment and entry into host cells - fusion activity. The enzyme neuraminidase (NA), also on the influenza virus surface, cleaves sialic acid residues from the host cell receptor for the virus, freeing virus particles and enabling them to spread through secretions. NA also plays a secondary role in viral neutralization. The M2 envelope protein is an ion channel through which hydrogen ions pass to acidify the endosomes, facilitating viral uncoating. Note that the M2 proteins of influenza A and B viruses differ. Within each nucleocapsid is a single segment of RNA that is associated with the viral nucleoprotein (NP), with 3 polymerase proteins (PP) bound to 1 end. These internal viral proteins are important targets for cytotoxic T lymphocytes. Two nonstructural proteins (PB and PA) are also found within the nucleocapsid; they participate in viral replication. � Hayden FG, Palese P. Clinical Virology. 1997: 911-942. Structure of the Influenza Virus Influenza is a single-stranded, helically shaped RNA virus of the orthomyxoviridae family. Three types of influenza virus have been classified (A, B, and C) based on antigenic differences. The glycoprotein hemagglutinin (HA) is the principal antigen on the surface of the influenza virus and is cleaved by proteases in host epithelial cells. HA undergoes proteolytic cleavage to HA1 and HA2 moieties. HA1 facilitates viral entry into cell principal viral neutralization epitopes. HA2 is important in viral attachment and entry into host cells - fusion activity. The enzyme neuraminidase (NA), also on the influenza virus surface, cleaves sialic acid residues from the host cell receptor for the virus, freeing virus particles and enabling them to spread through secretions. NA also plays a secondary role in viral neutralization. The M2 envelope protein is an ion channel through which hydrogen ions pass to acidify the endosomes, facilitating viral uncoating. Note that the M2 proteins of influenza A and B viruses differ. Within each nucleocapsid is a single segment of RNA that is associated with the viral nucleoprotein (NP), with 3 polymerase proteins (PP) bound to 1 end. These internal viral proteins are important targets for cytotoxic T lymphocytes. Two nonstructural proteins (PB and PA) are also found within the nucleocapsid; they participate in viral replication. � Hayden FG, Palese P. Clinical Virology. 1997: 911-942.

11. Viral Nomenclature

13. Occurrence of Influenza Pandemics and Epidemics Here�s how cycles of antigenic shifts and antigenic drifts translate into cycles of epidemics and pandemics. A new virus (shown here as Type A HxNx) is introduced to a population that has no antibodies against it.17 The result is widespread infection throughout the world, or a pandemic. After widespread exposure to the virus, however, antibody formation increases. Increased immunity applies evolutionary pressures to the virus, which can respond with the formation of variant strains, ie, antigenic drift. If these slightly different strains have the �right� degree of transmissibility, they can cause repeated epidemics, each of which increases the level of immunity among the population. After about 10 years, the population as a whole develops widespread immunity to the virus. Once again, selection pressures make the environment especially ripe for the spread of an entirely new virus, perhaps one introduced by genetic reassortment or antigenic shift. This new virus (shown here as Type A HyNy) spreads through a population that has no immunologic protection against it. Once again, the result is pandemic infection.17Here�s how cycles of antigenic shifts and antigenic drifts translate into cycles of epidemics and pandemics. A new virus (shown here as Type A HxNx) is introduced to a population that has no antibodies against it.17 The result is widespread infection throughout the world, or a pandemic. After widespread exposure to the virus, however, antibody formation increases. Increased immunity applies evolutionary pressures to the virus, which can respond with the formation of variant strains, ie, antigenic drift. If these slightly different strains have the �right� degree of transmissibility, they can cause repeated epidemics, each of which increases the level of immunity among the population. After about 10 years, the population as a whole develops widespread immunity to the virus. Once again, selection pressures make the environment especially ripe for the spread of an entirely new virus, perhaps one introduced by genetic reassortment or antigenic shift. This new virus (shown here as Type A HyNy) spreads through a population that has no immunologic protection against it. Once again, the result is pandemic infection.17

14. Antigenic Change - Drift

15. Antigenic Change - Shift

16. Antigenic Change - Shift

17. Antigenic Change - Shift Shift - major change from previous to new viral subtype1 Viral reassortment between two viral subtypes May occur in humans & animals (water fowl, pigs, etc.) Occurs in type A viruses No longer suppressed by previous antibody Selected as predominant virus Results in pandemics in 10 to 40 year cycles Depends on virulence & transmissibility of virus Example: H2N2 to H3N2

18. Historical Pandemics Spanish flu (1918-19) was caused by H1N1. Twenty million deaths worldwide (~600,000 in the U.S.) Asian flu (1957) resulted in 70,000 deaths in the U.S. and was caused by H2N2. Hong Kong flu (1968) was caused by H3N2 and killed 30,000 people in the U.S. The Asian and Hong Kong pandemics were associated with attack rates of up to 50%. In 1977, the H1N1 subtype reappeared with the Russian flu pandemic. Spanish/Asian/Hong Kong --603,000 EXCESS deaths Interpandemic years (1957-90)--600,800 EXCESS deaths (normal is 20,000-400,000 EXCESS deaths annually) Spanish - MOST severe; fatality and pneumonia in 20-40 yrs; ~50% of population were infected; decreased life expectancy in US by 12 yrs Asian - >50% of illness in school-aged children Hong Kong - highest outbreaks in children; but more �across the board� Russian - some do not consider �true� pandemic b/c almost exclusively in people < 20 yrs--but 50% attack rateSpanish/Asian/Hong Kong --603,000 EXCESS deaths Interpandemic years (1957-90)--600,800 EXCESS deaths (normal is 20,000-400,000 EXCESS deaths annually) Spanish - MOST severe; fatality and pneumonia in 20-40 yrs; ~50% of population were infected; decreased life expectancy in US by 12 yrs Asian - >50% of illness in school-aged children Hong Kong - highest outbreaks in children; but more �across the board� Russian - some do not consider �true� pandemic b/c almost exclusively in people < 20 yrs--but 50% attack rate

20. Projected Health Impact of the Next Pandemic on the U.S. Estimated Averages Deaths . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89,000 - 207,000 Hospitalizations . . . . . . . . . . . . . . . . . . . . . . . . . .. . 314,00 - 734,000 Outpatient Clinic Visits . . . . . . . . . . �18 - 42 million Sick at Home . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 � 47 million

21. Percentage of Visits for Influenza-like Illness,Sentinel Providers, 2003-04 Here we see a graph of the percentage of ambulatory physician visits for influenza-like illness from CDC�s Sentinel Physician network. If the percentage rises above 2.5% of all visits, we deem it indicative of an influenza outbreak. You see the early and high peak for 2003 in red, with over 7% of all physician visits in weeks 50 to 52 accounted for by influenza-like illness, and a similar, but later peak for 1999 in green. As we saw on the previous graph, the relatively less severe outbreak in 2002 in purple peaked in late January and February.Here we see a graph of the percentage of ambulatory physician visits for influenza-like illness from CDC�s Sentinel Physician network. If the percentage rises above 2.5% of all visits, we deem it indicative of an influenza outbreak. You see the early and high peak for 2003 in red, with over 7% of all physician visits in weeks 50 to 52 accounted for by influenza-like illness, and a similar, but later peak for 1999 in green. As we saw on the previous graph, the relatively less severe outbreak in 2002 in purple peaked in late January and February.

22. INFLUENZA; 2003-04 Characteristics of 2003-04 influenza season Early onset influenza activity Reports of severe illness, especially in children Predominant circulation of A (H3N2) strain antigenically different from the influenza (H3N2) vaccine strain Given the concerns about influenza vaccine effectiveness with a drifted strain dominating this past season, CDC studied vaccine effectiveness against influenza-like illness in health care workers in Colorado. We could not demonstrate vaccine effectiveness, possibly because of relatively small sample size. A case-cohort study in Colorado, evaluating vaccine effectiveness against lab confirmed influenza, suggests the vaccine is effective, ranging between 16% and 63%. A French case-cohort study, conducted annually, this year estimated 61% vaccine effectiveness against influenza-like illness. CDC is conducting a case-control study, also in Colorado, and those data are expected to be analyzed and published by June.Given the concerns about influenza vaccine effectiveness with a drifted strain dominating this past season, CDC studied vaccine effectiveness against influenza-like illness in health care workers in Colorado. We could not demonstrate vaccine effectiveness, possibly because of relatively small sample size. A case-cohort study in Colorado, evaluating vaccine effectiveness against lab confirmed influenza, suggests the vaccine is effective, ranging between 16% and 63%. A French case-cohort study, conducted annually, this year estimated 61% vaccine effectiveness against influenza-like illness. CDC is conducting a case-control study, also in Colorado, and those data are expected to be analyzed and published by June.

23. Pathogenesis of Influenza Pathogenesis of Influenza� Influenza can be transmitted via 3 routes: Large particle aerosols (droplets). Small particle aerosols (droplet nuclei). Direct contact with contaminated surfaces. Following transmission, influenza virus can infect both the upper and lower airways. Influenza is thought to spread primarily by small particle aerosols or airborne transmission and may thus be more likely to infect the lower respiratory tract than some other respiratory viruses, like rhinovirus, that tend to be transmitted largely by direct contact followed by self-inoculation. Sneezing, coughing, and even talking can produce droplets of varying sizes, which can lead to spread of virus. If influenza virus is not neutralized by mucosal antibodies, an assault on the respiratory epithelium occurs. Invasion of the respiratory epithelium leads to cellular dysfunction, viral replication, and further spread of virus. The release of inflammatory mediators subsequently leads to manifestations of systemic illness. Bridges CB, Kuehnert MJ, Hall CB. Transmission of influenza: Implications for control in health care settings. Clin Infect Dis. 2003;37:1094-101. Heikkinen T, Jarvinen A. The common cold. Lancet. 2003;361:51-9. Pathogenesis of Influenza� Influenza can be transmitted via 3 routes: Large particle aerosols (droplets). Small particle aerosols (droplet nuclei). Direct contact with contaminated surfaces. Following transmission, influenza virus can infect both the upper and lower airways. Influenza is thought to spread primarily by small particle aerosols or airborne transmission and may thus be more likely to infect the lower respiratory tract than some other respiratory viruses, like rhinovirus, that tend to be transmitted largely by direct contact followed by self-inoculation. Sneezing, coughing, and even talking can produce droplets of varying sizes, which can lead to spread of virus. If influenza virus is not neutralized by mucosal antibodies, an assault on the respiratory epithelium occurs. Invasion of the respiratory epithelium leads to cellular dysfunction, viral replication, and further spread of virus. The release of inflammatory mediators subsequently leads to manifestations of systemic illness. Bridges CB, Kuehnert MJ, Hall CB. Transmission of influenza: Implications for control in health care settings. Clin Infect Dis. 2003;37:1094-101. Heikkinen T, Jarvinen A. The common cold. Lancet. 2003;361:51-9.

24. Disease Manifested

25. Sudden onset of symptoms, persist for 7+ days Incubation period: 1-4 days, average 2 days Infectious period of wild type virus: Adults shed virus typically from 1 day before through 5 days after onset of symptoms Children shed higher titers for a longer duration than adults Clinical Features of Influenza Clinical Features of Influenza� Influenza is characterized by the sudden onset of symptoms after an incubation period of 1 to 4 days (average 2 days). Patients will shed the virus from approximately 1 day prior to the appearance of symptoms. Shedding of virus continues for about 4 to 5 days after symptoms appear, but may occur for a longer period in children. Children may be infectious for more than 10 days, and young children may shed virus for less than 6 days prior to appearance of symptoms. Frank c.s. cultured various respiratory viruses weekly or biweekly and during acute respiratory illness as part of the Houston Family Study. Influenza A was proven in 41 children and Influenza B in 14. Influenza A cultures were positive from 6 days prior to onset of symptoms through day 14 after onset of symptoms. 3 Children produced positive cultures in week 2 after onset of symptoms (a 10% shedding frequency early in week 2). Influenza B cultures were positive from the day of onset of symptoms though day 14 after onset of symptoms (shedding frequency of 45% early in week 2 and 23% later that week) [Frank 1981]. While most symptoms last for only 3 or 4 days, some symptoms, such as cough and malaise, may persist for a week or longer. Type A and type B influenza infections manifest similar symptoms, which makes it difficult to distinguish between the 2 types. The placebo group in the Hayden c.s. study on oseltamivir (n=13 healthy adults 18-40) mean duration of shedding was 107 h (83-131) [Hayden FG 1999]. Advisory Committee on Immunization Practices (ACIP). Prevention and control of influenza. MMWR. 2004;53(RR06):1-40. Kavet J. A perspective on the significance of pandemic influenza. Am J Public Health. 1977;67:1063-70. Frank AL, Taber LH, Wells CR et al. Patterns of shedding myxoviruses and paramyxoviruses in children. J Infect Dis 1981;144:433-41. Hayden FG, Treanor JJ, Scott Fritz R et al. Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza. JAMA 1999;282:1240-6. Clinical Features of Influenza� Influenza is characterized by the sudden onset of symptoms after an incubation period of 1 to 4 days (average 2 days). Patients will shed the virus from approximately 1 day prior to the appearance of symptoms. Shedding of virus continues for about 4 to 5 days after symptoms appear, but may occur for a longer period in children. Children may be infectious for more than 10 days, and young children may shed virus for less than 6 days prior to appearance of symptoms. Frank c.s. cultured various respiratory viruses weekly or biweekly and during acute respiratory illness as part of the Houston Family Study. Influenza A was proven in 41 children and Influenza B in 14. Influenza A cultures were positive from 6 days prior to onset of symptoms through day 14 after onset of symptoms. 3 Children produced positive cultures in week 2 after onset of symptoms (a 10% shedding frequency early in week 2). Influenza B cultures were positive from the day of onset of symptoms though day 14 after onset of symptoms (shedding frequency of 45% early in week 2 and 23% later that week) [Frank 1981]. While most symptoms last for only 3 or 4 days, some symptoms, such as cough and malaise, may persist for a week or longer. Type A and type B influenza infections manifest similar symptoms, which makes it difficult to distinguish between the 2 types. The placebo group in the Hayden c.s. study on oseltamivir (n=13 healthy adults 18-40) mean duration of shedding was 107 h (83-131) [Hayden FG 1999]. Advisory Committee on Immunization Practices (ACIP). Prevention and control of influenza. MMWR. 2004;53(RR06):1-40. Kavet J. A perspective on the significance of pandemic influenza. Am J Public Health. 1977;67:1063-70. Frank AL, Taber LH, Wells CR et al. Patterns of shedding myxoviruses and paramyxoviruses in children. J Infect Dis 1981;144:433-41. Hayden FG, Treanor JJ, Scott Fritz R et al. Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza. JAMA 1999;282:1240-6.

26. Age-Specific Influenza Infection Rates Age-Specific Influenza Infection Rates Results from the Houston family Study, 1976-84. The graph shows age-specific influenza infection rates, acute respiratory illness and lower respiratory tract infection. Glezen WP, Taber LH, Frank AL et al. Influenza virus infections in infants. Pediatr Infect Dis J 1997;16:1065-8.Age-Specific Influenza Infection Rates Results from the Houston family Study, 1976-84. The graph shows age-specific influenza infection rates, acute respiratory illness and lower respiratory tract infection. Glezen WP, Taber LH, Frank AL et al. Influenza virus infections in infants. Pediatr Infect Dis J 1997;16:1065-8.

27. Clinical Manifestations by Age Group Clinical Manifestations by Age Group In general, influenza may include these symptoms [http://www.cdc.gov/flu/protect/sick.htm; http://www.cdc.gov/nip/flu_or_flulike.htm]: High fever Headache Tiredness/weakness (can be extreme) Nonproductive cough Sore throat Runny nose Body or muscle aches Diarrhea and vomiting also can occur, but are more common in children Common physical signs of influenza infection include the appearance of being ill, skin that is hot and moist to the touch, flushed face, hyperemic mucus membranes, and clear nasal discharge [Cox 1999]. This slide identifies the symptoms that occur most or least frequently in persons of varying age with influenza and, therefore, that have the more or less value in diagnosing influenza infection in specific age groups. Monto et al reported that, in patients aged 12 years and older, the best multivariate predictors of influenza during confirmed community influenza outbreaks are cough and fever, with a significant positive predictive value of 79% (P<.001) [Monto 2000]. In children, gastrointestinal symptoms such as nausea, vomiting, abdominal pain, and diarrhea are frequently observed [Cox 1999]. Febrile convulsions are the initial sign of influenza infection in many children [Cox 1999]. Adults and adolescents may have abrupt onset of fever and chills with headache, sore throat, myalgia, malaise, anorexia, and a dry cough [Cox 1999]. Elderly patients may not develop a low-grade fever, thereby its absence does not rule out the flu. However, shortness of breath is a common presenting symptoms in elderly persons [Cox 1999]. www.cdc.gov/flu/protect/sick.htm www.cdc.gov/nip/flu_or_flulike.htm Monto AS, Gravenstein S, Elliott M, et al. Clinical signs and symptoms predicting influenza infection Arch Intern Med. 2000;160:3243-3247. Cox NJ, Subbarao K. Influenza. Lancet. 1999;354:1277-1282. Clinical Manifestations by Age Group In general, influenza may include these symptoms [http://www.cdc.gov/flu/protect/sick.htm; http://www.cdc.gov/nip/flu_or_flulike.htm]: High fever Headache Tiredness/weakness (can be extreme) Nonproductive cough Sore throat Runny nose Body or muscle aches Diarrhea and vomiting also can occur, but are more common in children Common physical signs of influenza infection include the appearance of being ill, skin that is hot and moist to the touch, flushed face, hyperemic mucus membranes, and clear nasal discharge [Cox 1999]. This slide identifies the symptoms that occur most or least frequently in persons of varying age with influenza and, therefore, that have the more or less value in diagnosing influenza infection in specific age groups. Monto et al reported that, in patients aged 12 years and older, the best multivariate predictors of influenza during confirmed community influenza outbreaks are cough and fever, with a significant positive predictive value of 79% (P<.001) [Monto 2000]. In children, gastrointestinal symptoms such as nausea, vomiting, abdominal pain, and diarrhea are frequently observed [Cox 1999]. Febrile convulsions are the initial sign of influenza infection in many children [Cox 1999]. Adults and adolescents may have abrupt onset of fever and chills with headache, sore throat, myalgia, malaise, anorexia, and a dry cough [Cox 1999]. Elderly patients may not develop a low-grade fever, thereby its absence does not rule out the flu. However, shortness of breath is a common presenting symptoms in elderly persons [Cox 1999]. www.cdc.gov/flu/protect/sick.htm www.cdc.gov/nip/flu_or_flulike.htm Monto AS, Gravenstein S, Elliott M, et al. Clinical signs and symptoms predicting influenza infection Arch Intern Med. 2000;160:3243-3247. Cox NJ, Subbarao K. Influenza. Lancet. 1999;354:1277-1282.

28. Influenza Manifestations & Complications Influenza Manifestations & Complications Loughlin J, Napalkov P, Wegmueller Y et al. A study of influenza and influenza-related complications among children in a large US health insurance plan database. Pharmacoeconomics 2003;21:273-83. Treanor JJ. Influenza virus. In: mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennetts Principles and Practice of Infectious Diseases. 5th ed. Philadelphia, PA: Churchill Livingstone; 2000:1823-49. ACIP. MMWR 2004;53(RR06):1-40.Influenza Manifestations & Complications Loughlin J, Napalkov P, Wegmueller Y et al. A study of influenza and influenza-related complications among children in a large US health insurance plan database. Pharmacoeconomics 2003;21:273-83. Treanor JJ. Influenza virus. In: mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennetts Principles and Practice of Infectious Diseases. 5th ed. Philadelphia, PA: Churchill Livingstone; 2000:1823-49. ACIP. MMWR 2004;53(RR06):1-40.

29. Increased risk of influenza complications among: Children <2 years Children and adolescents receiving long-term aspirin therapy Children and adults with chronic conditions Chronic pulmonary, metabolic, or CV disorders Renal dysfunction Hemoglobinopathies Immunosuppression, including HIV infection Pregnant women Residents of chronic care facilities Persons ?65 years old Patient Groups at Risk for Complications Patient Groups at Risk for Complications� Per the CDC, persons at highest risk for influenza complications includes: Adults aged 65 years and older. Adults and children who are residents of nursing homes or other chronic care facilities because of chronic medical conditions. Adults and children with chronic pulmonary or cardiovascular disorders, including asthma. Adults and children with chronic metabolic disorders, including diabetes mellitus, renal dysfunction, and hemoglobinopathies, or immunosuppression (from medications or HIV infection). Women who will be in the second or third trimester of pregnancy during the influenza season because of the increased incidence of cardiopulmonary complications among pregnant women. Children/adolescents (6 months to 18 years) who are receiving chronic aspirin therapy and therefore are at risk for developed Reye�s syndrome following influenza infection. Children aged 6 months to 23 months because they are at increased risk for influenza-related hospitalization. These groups of patients are the primary targets to receive influenza immunization each year. Note that in the 2004 recommendations, healthy children 6 to 23 months of age are added as a group recommended for influenza vaccination. � Advisory Committee on Immunization Practices (ACIP). Prevention and control of influenza. MMWR. 2004;53(RR06):1-40. Patient Groups at Risk for Complications� Per the CDC, persons at highest risk for influenza complications includes: Adults aged 65 years and older. Adults and children who are residents of nursing homes or other chronic care facilities because of chronic medical conditions. Adults and children with chronic pulmonary or cardiovascular disorders, including asthma. Adults and children with chronic metabolic disorders, including diabetes mellitus, renal dysfunction, and hemoglobinopathies, or immunosuppression (from medications or HIV infection). Women who will be in the second or third trimester of pregnancy during the influenza season because of the increased incidence of cardiopulmonary complications among pregnant women. Children/adolescents (6 months to 18 years) who are receiving chronic aspirin therapy and therefore are at risk for developed Reye�s syndrome following influenza infection. Children aged 6 months to 23 months because they are at increased risk for influenza-related hospitalization. These groups of patients are the primary targets to receive influenza immunization each year. Note that in the 2004 recommendations, healthy children 6 to 23 months of age are added as a group recommended for influenza vaccination. � Advisory Committee on Immunization Practices (ACIP). Prevention and control of influenza. MMWR. 2004;53(RR06):1-40.

30. Complications Pulmonary: Primary influenza viral pneumonia Secondary bacterial pneumonia Croup Asthma, COPD,* bronchitis, cystic fibrosis exacerbation Increased severity of influenza in HIV patients * Chronic obstructive pulmonary disease Non-Pulmonary: Myositis Cardiac complications Toxic shock syndrome Guillain-Barr� syndrome Transverse myelitis Encephalitis Reye syndrome

31. Mortality - USA Increased mortality due to influenza itself pneumonia exacerbation of cardiopulmonary & chronic diseases 90% of deaths occur in persons > 65; mortality rate 0.5-1.0/1,000 cases Average flu season - 20,000 deaths Case fatality rate - 30% in nursing home outbreaks Deaths increasing due to increased elderly & at risk population

32. Hospitalization - USA

33. Hospitalization - USA

34. DIAGNOSIS OF VIRAL INFLUENZA Melissa Miller, Ph.D. Assistant Professor of Pathology and Laboratory Medicine

35. Influenza Diagnostic Testing Rapid Antigen (EIA) Sensitivity: 60-80% Specificity: 90% Culture (Shell Vial) Sensitivity: 70-80% Specificity: 100%

36. Influenza Diagnostic Testing Specimen Collection NP aspirates and NP swabs Transport immediately to the Microbiology Lab NP aspirates should be transported on ice Specimens may be transported in Viral Transport Media Lower respiratory samples can only be tested by: Viral Culture Real-time RT-PCR

37. Influenza Diagnostic Testing Rapid Antigen (EIA) NP aspirates and swabs only Detects Influenza A/B nucleoproteins 1 hour TAT, batched on the hour Viral Culture (Shell Vial) Upper and lower respiratory specimens Detects Influenza A/B, Parainfluenza 1/2/3, Adenovirus and RSV 24-72 hour TAT Real-time RT-PCR Upper and lower respiratory specimens Detects Influenza A matrix gene Influenza B validation in progress 24 hour TAT

38. Influenza Diagnostic Testing Rapid Antigen $116 for both antigens (A and B) Reimbursement: $32 Viral Culture $122 for negative culture Reimbursement: $23 $233 for positive culture Reimbursement: $46 Real-time RT-PCR $75 for Influenza A Reimbursement: $35

39. Molecular Detection of Influenza A Real-time RT-PCR assay Analytic sensitivity: 48 copies/reaction (2400 copies/ml) Analytic specificity: no cross-reaction with other respiratory pathogens (viral, bacterial and fungal) or normal flora

40. Molecular Detection of Influenza A Retrospective validation (n=96) Upper and lower respiratory sites Prospective validation (n=102) NP aspirates and swabs Rapid antigen, shell vial culture and PCR

41. Molecular Detection of Influenza A Gold Standard = Real time RT-PCR Rapid Antigen Sensitivity: 75%, Specificity 100% Shell Vial Culture Sensitivity: 86%, Specificity 99%

42. Rapid Antigen Outpatients 24h/7d: 1h TAT Real-time RT-PCR Inpatients and early in the season Negative rapid antigens upon request 24 hour TAT (M-F) One run on the weekend (if epidemic conditions warrant) Respiratory Viral Cultures Negative rapid antigens upon request Order when identification of other respiratory viruses is important 24-72 h TAT (M-F), Set up once on the weekend Influenza Testing Algorithm

43. If you desire a more sensitive method to back-up negative rapid antigen tests: Order a �Specimen in Lab� test and type in the comment line one of the following: Viral culture- upper respiratory Influenza A PCR There is a 72 hour limit for our add-on policy. We will notify you through UNC P&A Newsletter and a numbered memo when Influenza B PCR is available. Remember: FluMist may cause �positive� results for up to 21 days post-vaccination! Influenza Testing Algorithm

44. INFLUENZA VACCINES David J. Weber, M.D., M.P.H. William A. Rutala, Ph.D., M.P.H. Hospital Epidemiology

47. ADULT VACCINE INDICATIONS

49. INFLUENZA VACCINE: 2004-5 1. A/Fujian/411/2002 (H3N2) � like {New} OR 1. A/Wyoming/3/2003 (H3N2) {New} 2. A/New Caledonia/20/99 (H1N1) - like 3. B/Shanghai/361/2002 � like OR 3. B/Jilin/20/2003 or B/Jiangsu/10/2003

50. Vaccine Efficacy

51. INFLUENZA VACCINE EFFECTIVENESS, 2003-04 Colorado study, children 6-23 mo VE = 25% (ILI) and 49% (P & I) CDC study, persons 50-64 years VE (High risk) = 38% (95% CI, 5-59%) VE (not high risk) = 52% (95% CI, 31-66%) VE (all) = 47% (95% CI, 30-60%) Children�s Hospital, Denver, HCWs VE = 0.03 to 0.14 (not significant) ILI = influenza like illness P & I = pneumonia and influenza Given the concerns about influenza vaccine effectiveness with a drifted strain dominating this past season, CDC studied vaccine effectiveness against influenza-like illness in health care workers in Colorado. We could not demonstrate vaccine effectiveness, possibly because of relatively small sample size. A case-cohort study in Colorado, evaluating vaccine effectiveness against lab confirmed influenza, suggests the vaccine is effective, ranging between 16% and 63%. A French case-cohort study, conducted annually, this year estimated 61% vaccine effectiveness against influenza-like illness. CDC is conducting a case-control study, also in Colorado, and those data are expected to be analyzed and published by June.Given the concerns about influenza vaccine effectiveness with a drifted strain dominating this past season, CDC studied vaccine effectiveness against influenza-like illness in health care workers in Colorado. We could not demonstrate vaccine effectiveness, possibly because of relatively small sample size. A case-cohort study in Colorado, evaluating vaccine effectiveness against lab confirmed influenza, suggests the vaccine is effective, ranging between 16% and 63%. A French case-cohort study, conducted annually, this year estimated 61% vaccine effectiveness against influenza-like illness. CDC is conducting a case-control study, also in Colorado, and those data are expected to be analyzed and published by June.

52. INFLUENZA VACCINE SHORTAGE:A FAILURE OF PUBLIC HEALTH

54. AVAILABLE INFLUENZA VACCINES

55. AVAILABLE INFLUENZA VACCINES

56. Potential benefits Improved immunogenicity and vaccine efficacy Improved protection against drifted, antigenically different strains Improved patient acceptance, which would reduce barriers to vaccination Why a Live, Attenuated Vaccine? Rationale for FluMist�

57. Pivotal Efficacy Trial in Children: Year 1(1996-97) Pivotal Efficacy Trial in Children: Year 1 (1996-97)� No difference in demographics (age, gender, race, day-care use, household makeup) was observed between the LAIV and placebo treatment groups. Slight preponderance of females (52%). Majority were Caucasian (85%). Mean age 42 months. By the end of Year 1 (April 1997), 3,009 illnesses led to viral culture assessment. A total of 71 subjects had influenza A (H3N2) and 44 subjects had influenza B; no subject had wild-type influenza A (H1N1). These findings paralleled observations in the communities in general during the 1996-1997 influenza season. Overall influenza attack rate in the placebo group was 18%. Specifically, cases of influenza occurred in 14 subjects in the LAIV treatment group (7 type A, 7 type B) and in 95 placebo-treated subjects (64 Type A, 37 Type B). As shown in the slide, FluMist? was efficacious when given as a single dose or as 2 doses. For Type A, 87% efficacy (95% CI 47-97) following a single dose vs. 96% with 2 doses (95% CI 90-99) For Type B, 91% efficacy (95% CI 46-99) following a single dose vs. 91% with 2 doses (95% CI 78-96) For both types combined, 89% efficacy (95% CI 65-96) following a single dose vs. 94% with 2 doses (95% CI 88-97) Major reason for wide confidence interval for 1 dose regimen is the lower number of cases studied (288 vs. 1,314) Another key finding of the study was that children receiving LAIV had significantly fewer episodes of febrile otitis media (30% less) compared with placebo recipients (95% CI 18-45; P<0.001). Belshe RB, Mendelman PM, Treanor J, et al. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine in children. N Engl J Med. 1998;338:1405-1412. Pivotal Efficacy Trial in Children: Year 1 (1996-97)� No difference in demographics (age, gender, race, day-care use, household makeup) was observed between the LAIV and placebo treatment groups. Slight preponderance of females (52%). Majority were Caucasian (85%). Mean age 42 months. By the end of Year 1 (April 1997), 3,009 illnesses led to viral culture assessment. A total of 71 subjects had influenza A (H3N2) and 44 subjects had influenza B; no subject had wild-type influenza A (H1N1). These findings paralleled observations in the communities in general during the 1996-1997 influenza season. Overall influenza attack rate in the placebo group was 18%. Specifically, cases of influenza occurred in 14 subjects in the LAIV treatment group (7 type A, 7 type B) and in 95 placebo-treated subjects (64 Type A, 37 Type B). As shown in the slide, FluMist? was efficacious when given as a single dose or as 2 doses. For Type A, 87% efficacy (95% CI 47-97) following a single dose vs. 96% with 2 doses (95% CI 90-99) For Type B, 91% efficacy (95% CI 46-99) following a single dose vs. 91% with 2 doses (95% CI 78-96) For both types combined, 89% efficacy (95% CI 65-96) following a single dose vs. 94% with 2 doses (95% CI 88-97) Major reason for wide confidence interval for 1 dose regimen is the lower number of cases studied (288 vs. 1,314) Another key finding of the study was that children receiving LAIV had significantly fewer episodes of febrile otitis media (30% less) compared with placebo recipients (95% CI 18-45; P<0.001). Belshe RB, Mendelman PM, Treanor J, et al. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine in children. N Engl J Med. 1998;338:1405-1412.

58. INFLUENZA VACCINE: INDICATIONS Healthcare providers Persons >65 years of age Residents of extended care facilities of any age Adults and children with chronic cardio-respiratory illnesses Adults and children with chronic metabolic disorders, immune deficiencies, or immunosuppression Children (6 mo�18 yr) receiving aspirin (risk for Reye syndrome) Out-of-home caregivers and household contacts of children <6 mo Women who will be pregnant during influenza season Children aged 6-23 months People who want to avoid influenza

59. INFLUENZA VACCINE: INDICATIONS2003-04 DUE TO VACCINE SHORTAGE Healthcare providers who provide direct patient care Persons >65 years of age Residents of extended care facilities of any age Adults and children with chronic cardio-respiratory illnesses Adults and children with chronic metabolic disorders, immune deficiencies, or immunosuppression Children (6 mo�18 yr) receiving aspirin (risk for Reye syndrome) Out-of-home caregivers and household contacts of children <6 mo Women who will be pregnant during influenza season Children aged 6-23 months Prohibition from providing vaccine to non-priority groups (NC Reg)

60. Indirect Benefits of Influenza Vaccination of Health Care Workers Indirect Benefits of Influenza Vaccination of Health Care Workers In the 1994-95 season, the effects of vaccination of healthcare workers on morbidity and mortality of the patient population was studied in a randomized, controlled study in Glasgow. N = 1059 patients in 12 geriatric medical long-term care facilities; 653 (61%) of 1078 healthcare workers were vaccinated Vaccination of healthcare workers was associated with a reduction in total patient mortality from 17% to 10% (odds ratio 0.56; 95% CI 0.40, 0.80). ILI odds ratio was 0.57 (95% CI 0.34, 0.94). Vaccination of residents was not associated with significant effects on mortality; odds ratio 1.15 (95% CI 0.81, 1.64). Potter J, Stott DJ, Elder RAG et al. Influenza vaccination of health care workers in long-term-care Hospitals reduces the mortality of elderly patients. J Infect Dis 1997;175:1-6.Indirect Benefits of Influenza Vaccination of Health Care Workers In the 1994-95 season, the effects of vaccination of healthcare workers on morbidity and mortality of the patient population was studied in a randomized, controlled study in Glasgow. N = 1059 patients in 12 geriatric medical long-term care facilities; 653 (61%) of 1078 healthcare workers were vaccinated Vaccination of healthcare workers was associated with a reduction in total patient mortality from 17% to 10% (odds ratio 0.56; 95% CI 0.40, 0.80). ILI odds ratio was 0.57 (95% CI 0.34, 0.94). Vaccination of residents was not associated with significant effects on mortality; odds ratio 1.15 (95% CI 0.81, 1.64). Potter J, Stott DJ, Elder RAG et al. Influenza vaccination of health care workers in long-term-care Hospitals reduces the mortality of elderly patients. J Infect Dis 1997;175:1-6.

61. Indirect Benefits of Influenza Vaccination of Health Care Workers 20 long-term care facilities, stratified cluster randomization staff influenza vaccination or not Resident mortality odds ratio 0.58 (95% CI 0.40, 0.84) p=0.014 Indirect Benefits of Influenza Vaccination of Health Care Workers 20 long-term care facilities in UK (44-105 patients). Randomly offered vaccine or not. All deaths were recorded over 6 months in winter of 1996/97. Random sample of 50% of patients selected for virological surveillance combined with nasal and throat swabs every 2 weeks during the epidemic period. Swabs tested by tissue culture and PCR for influenza A and B. Influenza uptake in healthcare workers was 50.9% in hospitals in which they were routinely offered vaccine, compared with 4.9% in those in which they were not. Uncorrected rates of mortality are given in the slide. Mortality of residents (n =102/749) in �vaccine hospitals� was 13.6% Mortality of residents (n=154/688) in �no vaccine hospitals� was 22.4% At necropsy, PCR was positive in 0 of 17 patients from vaccine hospitals and 6 of 30 from no vaccine hospitals (p=0.055). Vaccination of healthcare workers was associated with a substantial decrease in mortality among LTCF residents. Virological surveillance showed no associated decrease in non-fatal influenza infection in patients. Carman WF, Elder AG, McAulay K et al. Effects of influenza vaccination of healthcare workers on mortality of elderly people in long-term care: a randomised controlled trial. Lancet 2000;355:93-7. Indirect Benefits of Influenza Vaccination of Health Care Workers 20 long-term care facilities in UK (44-105 patients). Randomly offered vaccine or not. All deaths were recorded over 6 months in winter of 1996/97. Random sample of 50% of patients selected for virological surveillance combined with nasal and throat swabs every 2 weeks during the epidemic period. Swabs tested by tissue culture and PCR for influenza A and B. Influenza uptake in healthcare workers was 50.9% in hospitals in which they were routinely offered vaccine, compared with 4.9% in those in which they were not. Uncorrected rates of mortality are given in the slide. Mortality of residents (n =102/749) in �vaccine hospitals� was 13.6% Mortality of residents (n=154/688) in �no vaccine hospitals� was 22.4% At necropsy, PCR was positive in 0 of 17 patients from vaccine hospitals and 6 of 30 from no vaccine hospitals (p=0.055). Vaccination of healthcare workers was associated with a substantial decrease in mortality among LTCF residents. Virological surveillance showed no associated decrease in non-fatal influenza infection in patients. Carman WF, Elder AG, McAulay K et al. Effects of influenza vaccination of healthcare workers on mortality of elderly people in long-term care: a randomised controlled trial. Lancet 2000;355:93-7.

62. INFLUENZA VACCINE (Inactivated):CONTRAINIDATIONS Hypersensitivity to eggs or vaccine components Acute febrile illness (postpone vaccine) Active neurologic disorder characterized by changing neurologic findings. Previous Guillain-Barre or other neurologic illnesses related to previously administered vaccine Pregnancy or breastfeeding NOT a contraindication

63. Adverse Reactions

64. INFLUENZA VACCINE (Live):CONTRAINIDATIONS <5 years or >50 years of age Reactive airway disease Chronic medical conditions Children receiving aspirin Pregnant women Hypersensitivity to eggs Persons with contact with severely immunocompromised persons in the next 7 days

65. PROVIDING VACCINES Patient name and identification number Vaccine Dose, Site, Route of Administration Date given Manufacturer Lot number Name, title & address of person providing vaccine Date next dose due Informed consent

66. ANTIVIRAL PROPHYLAXIS AND THERAPY

68. INFLUENZA: ANTIVIRAL THERAPIES Amantadine: Influenza A Treatment and prophylaxis; dose adjust in renal failure Rimantadine: Influenza A Treatment and prophylaxis; dose adjust in renal and hepatic failure Oseltamivir {Tamiflu}: Influenza A & B Treatment and prophylaxis (PEP � 7 days; Seasonal � 42 days); dose adjust in renal failure Zanamivir {Relenza}: Influenza A & B Treatment only *Must begin therapy within 2 days of onset of illness

69. INFLUENZA: ANTIVIRAL THERAPIES Amantadine Treatment and prophylaxis Age 1-9: 5 mg/kg (max 150 mg) in 2 divided doses Age 10-12: 100 mg 2x/day Age 13-64: 100 mg 2x/day Age >65: <100 mg/day Dose adjust in renal failure Rimantadine Treatment Age 13-64: 100 mg 2x/day Age >65: 100 mg/day Prophylaxis Age 1-9: 5 mg/kg (max 150 mg) in 2 divided doses Age 10-12: 100 mg 2x/day Age 13-64: 100 mg 2x/day Age >65: 100 mg/day Dose adjust in renal and hepatic failure

70. INFLUENZA: ANTIVIRAL THERAPIES Zanamavir Treatment only Age >7: 10 mg 2x/day Oseltamivir Treatment Age 1-12: Weight based Age >13: 75 mg 2x/day Prophylaxis Age >13: 75 mg/day x 7 d (PEP) Age >13: 75 mg/day x 42 d (seasonal) Dose adjust in renal failure

71. INFLUENZA - ANTIVIRAL THERAPIES:TOXICITIES Amantadine and rimantadine CNS (anxiety, insomnia, seizures, hallucinations), GI CNS toxicity greater in patients on amantadine Resistance develops in 10%-30% during treatment course Teratogenic and embryogenic in animals Zanamivir Brochospasm (avoid in asthmatics) Oseltamivir GI (nausea and/or vomiting ~5-10%)

72. OSELTAMIVIR: EFFICACY

73. Tamiflu� (oseltamivir phosphate) � Seasonal Prophylaxis in a Vaccinated Frail Elderly Population Results This is one of the first placebo-controlled studies to report successful prophylaxis with a neuraminidase inhibitor in frail elderly people living in residential housing for seniors.3 Tamiflu� (oseltamivir phosphate) 75 mg once-daily treatment for 42 days reduced the incidence of laboratory-confirmed clinical influenza from 4.4% (12/272) for the placebo group to 0.4% (1/276) for the Tamiflu group (a difference of 92%). This is one of the first placebo-controlled studies to report successful prophylaxis with a neuraminidase inhibitor in frail elderly people living in residential housing for seniors.3 Tamiflu� (oseltamivir phosphate) 75 mg once-daily treatment for 42 days reduced the incidence of laboratory-confirmed clinical influenza from 4.4% (12/272) for the placebo group to 0.4% (1/276) for the Tamiflu group (a difference of 92%).

74. OSELTAMIVIR: IMPACT ON LOWER RESIRATORY TRACT COMPLICATIONS (LRTC) Analysis of prospective data from patients enrolled in 10 placebo controlled trials (N=3564) Results � confirmed influenza (oseltamivir vs placebo) Reduced overall antibiotic use: 14.0% vs 19.1% (p<0.001) Reduced LRTCs-associated antibiotic use: 4.6% vs 10.3% (p<0.001) Reduced LRTCs leading to antibiotics in high risk patients: 12.2% vs 18.5% (p=0.02) Reduce overall hospitalizations: 1.0 vs 1.7% (p=0.02) Unconfirmed influenza: No difference in incidence of LRTC, overall antibiotic use or hospitalizations

77. ANTIVIRALS: CDC RECOMMENDATIONS Use amatadine or rimantadine for chemoprophylaxis and oseltamivir or zanamivir for treatment Use antiviral for treating all persons with a life-threatening influenza-related illness Use antiviral for all persons at high risk for serious complications of influenza who are within the first 2 days of illness

78. ANTIVIRALS FOR CHEMOPROPHYLAXIS: CDC RECOMMENDATIONS Community outbreak (usual duration 6-8 weeks) Persons at high risk of serious complications Persons at high risk of serious complications following vaccination until immunity develops (2 weeks for adults, 6 weeks for first time pediatric vaccinees) Persons who are not expected to mount a sufficient immune response due to immunosuppression Healthcare workers with direct patient care responsibilities unable to obtain vaccine

79. CONTROL OF INFLUENZA IN HEALTHCARE FACILITIES

80. INFLUENZA IN HEALTHCARE FACILITIES More than 25 outbreaks described in literature in acute care hospitals Infected staff may initiate outbreak or aid in propagation HCW infection may lead to absenteeism and disruption of health care Attack rates in HCWs have ranged from 25% to 80% More than 15 outbreaks described in literature in extended care facilities Important morbidity and mortality among residents may result High rates of immunization (>60%) among staff may lead to decreased attack rate in residents

83. UNIVERSAL RESPIRATORY HYGIENE Applies to all patients with symptoms of upper respiratory tract infection (e.g., cough, runny nose) Includes the following: Cover mouth/nose when coughing (use tissues) Perform hand hygiene Sit >3 feet apart from other patients Implementation Bag provided to all symptomatic patients at ED triage or clinic check in that includes tissues, hand cleanser, and mask Signs in ED and all clinics in English and Spanish describing universal respiratory hygiene

84. INFLUENZA: HICPAC RECOMMENDATIONS, 2004 Vaccinate per ACIP high risk groups in acute-care settings (IA) Vaccinate per ACIP residents of ECFs (IA) Place patients with influenza in private room (IB) Wear a mask with 3 feet of a patient with influenza (IB) Practice hand hygiene (IA) Use rapid tests on patients with suspected influenza (IB) Use antiviral as prophylaxis to all patients without illness during an outbreak for a minimum of 2 weeks (IA) Do not allow contact between persons at risk for influenza and patients or personnel taking antiviral prophylaxis during and for 2 days after therapy discontinued (IB)

85. INFLUENZA: HICPAC RECOMMENDATIONS - OHS, 2004 Provide influenza vaccine to HCWs (IA) Offer antiviral prophylaxis to unvaccinated HCWs during an outbreak (IA) Consider antiviral prophylaxis to all HCWs, regardless of vaccination status, if outbreak caused by variant of influenza not well matched to vaccine (1B) Furlough employees with influenza (IB)

86. UNC GUIDELINES: HCWs WITH POTENTIAL RESPIRATORY INFECTIONS Febrile HCWs: Excluded on sick leave Non-febrile HCWs Rapid testing for RSV and influenza A and B performed on employees with respiratory symptoms who work in stem-cell transplant unit, neonatal ICU, pediatric ICU If positive, excluded from above units If negative, may continue to work using a mask and practicing hand hygiene Allowed to work using a mask and practicing hand hygiene Post-exposure prophylaxis may be offered if unvaccinated (osteltamivir 75 mg PO Qd x 2 weeks)

87. New Reporting Requirement:Pediatric Influenza Deaths All deaths occurring in children (<18 years of age) that are associated with laboratory-confirmed cases of influenza. Report to the Orange County Health Department (919-245-2400) and Hospital Epidemiology (919-966-1636) within 24 hours.

88. AVIAN INFLUENZA

89. February 2003: Re-emergence of human H5N1 disease

91. Clinical features of 10 patients with H5N1 disease in Vietnam 2004 Key features: Incubation period � 2-4 days Definite poultry exposure - 9/10 No pre-existing medical conditions Age 5-24 years Fever, Short of breath, Sputum Diarrhoea � 7 / 10 NO URI symptoms (sore throat, runny nose) Hien et al NEJM 2004; 350: 1179

92. Clinical features: 10 patients with H5N1 disease in Vietnam 2004 Key features on admission Low WBC: 10/10 (1.7-3) (normal 4-11) Lymphopenia: 10/10 (0.26-1.1) (N 1.5-4) Thrombocytopenia Elevated liver enzymes Outcome: 8 died; 1 recovering; 1 recovered

93. THANK YOU FOR ATTENDING!