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Saturday, May 29, 2010
INFLUENZA
                            Jaime A. Santos




Saturday, May 29, 2010
Influenza

                                     • commonly called “the
                                       flu”
                                     • a contagious respiratory
                                       illness caused by
                                       influenza viruses
                                     • Infection with influenza
                                       viruses can result in
                                       illness ranging from mild
                                       to severe with life-
                                       threatening
                                       complications



Saturday, May 29, 2010
Saturday, May 29, 2010
1918 Spanish flu pandemic: 20 to 50 million people may have died worldwide

Saturday, May 29, 2010
Saturday, May 29, 2010
Viral Titers Peak Early




Saturday, May 29, 2010
“Flu” symptoms

                                          Fever/ chills
                                          Headache
                                          Nasal congestion
                                          Sore throat
                                          Dry cough
                                          Myalgia/ body aches
                                          GI symptoms
                                          Malaise/ tiredness



Saturday, May 29, 2010
Influenza - Clinical Signs and Symptoms


                         • incubation period for influenza is 1--4 days,
                           with an average of 2 days
                         • Adults - infectious from the day before
                           symptoms begin through approximately 5 days
                           after onset
                         • Children - infectious for > 10 days, and young
                           children can shed virus for < 6 days before
                           their illness onset
                         • immunocompromised persons can shed virus
                           for weeks or months


Saturday, May 29, 2010
Influenza - Clinical Signs and Symptoms

                         • resolves after a limited number of days for
                           the majority of persons, although cough
                           and malaise can persist for >2 weeks
                         • young children can have initial symptoms
                           mimicking bacterial sepsis with high fevers
                            – < 20% of children hospitalized with
                              influenza can have febrile seizures




Saturday, May 29, 2010
Influenza - Clinical Signs and Symptoms


                         • Influenza infection has also been associated with
                                    encephalopathy
                                    transverse myelitis
                                    Reye syndrome
                                    myositis
                                    myocarditis
                                    pericarditis




Saturday, May 29, 2010
Influenza - Hospitalization and Deaths
                         • Population at risk for complications,
                           hospitalizations, & deaths:> 65 years old
                           – young children
                           – persons of any age with certain
                             underlying health conditions:
                             cardiovascular and pulmonary
                             (including asthma), metabolic e.g. DM,
                             Hgbpathies, immunosuppression
                           – receiving long term ASA


Saturday, May 29, 2010
“U” Shaped Epidemic Curve of Influenza During the
                         Interpandemic Period

                                                      Visits/100
                                                      ARD Hospitalizations/10,000
                                                      P&I Mortality/100,000




                         Rate




                                                    Age group

Saturday, May 29, 2010
“U” Shaped Epidemic Curve of Influenza During the
                         Interpandemic Period

                              120                               Visits/100
                                                                ARD Hospitalizations/10,000
                                                                P&I Mortality/100,000
                              100

                               80
                         Rate 60

                               40

                               20

                                0
                                    <5   5–9   10–14   15-19   20-24   25-34   35-44   45-54   55-64   > 64

                                                               Age group

Saturday, May 29, 2010
“U” Shaped Epidemic Curve of Influenza During the
                         Interpandemic Period

                              120                               Visits/100
                                                                ARD Hospitalizations/10,000
                                                                P&I Mortality/100,000
                              100

                               80
                         Rate 60

                               40

                               20

                                0
                                    <5   5–9   10–14   15-19   20-24   25-34   35-44   45-54   55-64   > 64

                                                               Age group

Saturday, May 29, 2010
“U” Shaped Epidemic Curve of Influenza During the
                         Interpandemic Period

                              120                               Visits/100
                                                                ARD Hospitalizations/10,000
                                                                P&I Mortality/100,000
                              100

                               80
                         Rate 60

                               40

                               20

                                0
                                    <5   5–9   10–14   15-19   20-24   25-34   35-44   45-54   55-64   > 64

                                                               Age group

Saturday, May 29, 2010
“U” Shaped Epidemic Curve of Influenza During the
                         Interpandemic Period

                              120                               Visits/100
                                                                ARD Hospitalizations/10,000
                                                                P&I Mortality/100,000
                              100

                               80
                         Rate 60

                               40

                               20

                                0
                                    <5   5–9   10–14   15-19   20-24   25-34   35-44   45-54   55-64   > 64

                                                               Age group

Saturday, May 29, 2010
Influenza Responsible for
                         Substantial Disease
                                                                                   Deaths
                                                                                   36,0001
                              Hospitalizations
                                 114,0002



                                                          Physician visits
                                                            25 million3

                                                     Infections and illnesses
                                                          50–60 million3
                                                      Direct medical costs
                                                          $1-$3 billion4
                                  1. Thompson WW et al. JAMA. 2003;289:179-186.
                                  2. CDC. MMWR Recomm Rep. 2003;58(RR-8):1-34.
                                  3. Couch RB. Ann Intern Med. 2000;133:992-998.
                                  4. Patriarca PA. JAMA. 1999;282:75-77.



Saturday, May 29, 2010
Seasonal

                                    • In colder countries flu
                                      is largely seen during
                                      colder months and
                                      they vaccinate prior
                                      to this season (e.g.
                                      October)
                                    • In tropical countries
                                      flu is seen all year
                                      round




Saturday, May 29, 2010
Flu Season in the Philippines
                         Southern Hemisphere Pattern
                         Cumulative Data: RITM Influenza Surveillance Data Feb. 1998 – Oct. 2004




                                                                                                   B
                                                                                                   A




Saturday, May 29, 2010
Flu Season in the Philippines
                         Southern Hemisphere Pattern
                         Cumulative Data: RITM Influenza Surveillance Data Feb. 1998 – Oct. 2004


                         80



                         70



                         60



                         50
                                                                                                                           B
                                                                                                                           A

                         40



                         30



                         20



                         10



                          0
                              Jan   Feb      Mar      Apr      May      Jun      Jul      Aug      Sep   Oct   Nov   Dec




Saturday, May 29, 2010
Influenza virus types

                         • Three : Influenza A, B, and C
                         • Influenza types A or B viruses cause
                           epidemics; influenza A may cause
                           pandemics
                         • Getting a flu shot can prevent illness from
                           types A and B influenza but not from type C
                         • Influenza type C causes mild respiratory
                           illness ; not thought to cause epidemics




Saturday, May 29, 2010
Influenza Virus: Segmented genome




Saturday, May 29, 2010
Influenza A virus divided into subtypes based on HA and N
                         proteins on surface

                                                           • 15 HA, 9 N
                                                           • Nomenclature based
                                                             on: site of origin
                                                                  isolate number
                                                                  year of isolation
                                                                  subtype
                                                           Example:
                                                           influenzaA/
                                                              Johannesburg/33/94
                                                              (H3N2)




Saturday, May 29, 2010
Drift or shift

                         • “Antigenic drift" - small changes in
                           the virus that happen continually
                           (influenza A and B)
                         • “Antigenic shift” - abrupt, major
                           change in the influenza A viruses,
                           resulting in new H &/or new H and
                           N proteins that infect humans
                           (influenza A only)



Saturday, May 29, 2010
Influenza subtypes in humans

                         • current subtypes of influenza A viruses
                           found in people are A(H1N1) and A(H3N2)
                         • Influenza B virus is not divided into
                           subtypes
                         • Influenza A(H1N1), A(H3N2), and influenza
                           B strains are included in each year's
                           influenza vaccine
                         • Protection is serotype specific



Saturday, May 29, 2010
Saturday, May 29, 2010
Domestic pig:
                         Domestic poultry
                                                 Mixing vessel



                         Migratory water birds




Saturday, May 29, 2010
Domestic pig:
                         Domestic poultry
                                                 Mixing vessel



                         Migratory water birds




Saturday, May 29, 2010
Avian Influenza
                          • Caused by 15 subtypes of
                            influenza A virus subtype
                            of avian influenza
                          • Low pathogenicity avian
                            influenza (LPAI)
                          • Highly pathogenic avian
                            influenza (HPAI)
                             – First recognized in Italy in
                               1878
                             – Extremely contagious in
                               birds
                             – Rapidly fatal, high
                               mortality (almost 100%
                               in a few days)




Saturday, May 29, 2010
Avian Influenza Infections in Humans
                         Confirmed instances of avian influenza viruses infecting humans since 1997


                         • 1997: Hong Kong, avian influenza A (H5N1)
                         • 1999: Hong Kong, avian influenza A(H9N2)
                         • 2003: 2 cases of avian influenza A (H5N1)
                         • 2003:H9N2 infection was confirmed in a child
                           in Hong Kong
                         • 2003: Avian influenza A (H7N7) infections
                           among poultry workers / families in the
                           Netherlands (> 80 cases )




Saturday, May 29, 2010
Characteristics of Avian Influenza Infections in
                         Humans
                         • reported symptoms of avian influenza :
                           typical influenza-like symptoms (e.g.,
                           fever, cough, sore throat and muscle aches)
                           to eye infections, pneumonia, acute
                           respiratory distress, viral pneumonia, and
                           other severe and life-threatening
                           complications
                         • It is believed that most cases of H5N1
                           infection in humans have resulted from
                           contact with infected poultry or
                           contaminated surfaces
                                                               CDC


Saturday, May 29, 2010
Current Avian Flu (H5N1) Strain


                         – genetically sequenced: all bird origin
                         – antiviral resistance to amantadine and
                           rimantadine
                         – oseltamavir and zanamivir should still be
                           effective




Saturday, May 29, 2010
Avian Influenza (Bird Flu) Outbreak
                         Why H5N1 is of particular concern

                         • H5N1 mutates and acquires genes rapidly from
                           other species
                         • Documented to cause severe disease in humans
                         • avian influenza virus could change so that it could
                           infect humans and could spread easily from
                           person to person
                         • no immune protection against them in the human
                           population
                         • If an avian virus were able to infect people and
                           gain the ability to spread easily from person to
                           person, an “influenza pandemic” could begin



Saturday, May 29, 2010
FLU PANDEMICS: THEN AND NOW

                             1918                       Year                     2005
                         WHAT HAPPENED                                    WHAT COULD HAPPEN


                            1.8 billion          World Population               7 billion


                           Troop ships,           Primary mode of
                                                   transportation                 Jets
                             railroad

                                               Time for virus to circle
                            4 months                 the globe                  4 days


                          Gauze masks,         Preventive measures             Vaccines
                          disinfectants

                            Bed rest,               Treatments            Some antiviral drugs
                             aspirin

                           20+ million            Estimated dead              60 million?
                                                                                         Janet Englund, MD
                                                                                         PIDSP Feb. 2005




Saturday, May 29, 2010
Treatment of Influenza
                         • Antiviral Medications:
                           – antiviral drugs:
                             adamantanes: amantadine,
                             rimantadine
                             neuraminidase inhibitors: zanamivir,
                             oseltamivir

                           – Antiviral treatment lasts for 3-5
                             days and must be started within the
                             first 2 days of illness.

Saturday, May 29, 2010
Antiviral treatment and prophylaxis

                          • amantadine [4.4-8.8 mg/kg/day, not to
                            exceed 150 mg/day] can be given for 3-5
                            days; for treatment of influenza A
                          • oseltamivir [2 mg/kg/dose BID] can be
                            given for 5 days for treatment of influenza
                            A and B.
                            Its use for treatment and prophylaxis of
                            household contacts has been effective for
                            children > 12 years old




Saturday, May 29, 2010
Saturday, May 29, 2010
Do I Need A
                         Flu Shot?




Saturday, May 29, 2010
Target Groups For Vaccination

                         1. Those with increased risk of complications:
                         • Persons age 50 yrs old and above
                         • Children from 6 to 23 months old
                         • Adults and children with the following risk
                           factors:
                            – Chronic cardiovascular disease (e.g. congestive
                              heart failure, Hypertensive cardiovascular
                              disease, valvular heart disease, rheumatic
                              heart disease, stroke)
                            – Chronic lung disease (e.g COPD, asthma,
                              bronchiectasis, malignancies, chronic PTB)


Saturday, May 29, 2010
• Chronic metabolic disease (diabetes mellitus)
                         • Chronic renal dysfunction
                         • Hemoglobinopathies
                         • Immunosuppressed (e.g.HIV, malignancies,
                           immunosuppressive drugs, radiation therapy,
                           transplant patients)
                         • Children and adolescents who are receiving long-
                           term aspirin therapy
                         • Residents of nursing homes and other chronic
                           care facilities
                         • Pregnant women on their 2nd or 3rd trimester
                           who have not received their flu vaccine within the
                           last 12 months.



Saturday, May 29, 2010
Target Groups For Vaccination

                         2. Those who can transmit the disease to others

                          • Health care workers and other personnel
                            of out patient care settings, hospitals, nursing
                            homes, and chronic care facilities.
                          • Household contacts (including children) and
                            caregivers of person at high risk.




Saturday, May 29, 2010
When Should You Give the Flu Shot?
                         Highlights Influenza Consensus – Flu TWG Oct. 2004



                          • Data from the five-year epidemiologic data
                            (February 1998 – September 2003) shows
                            increased influenza activity June to November.
                          • Vaccination should be given once a year
                            preferrably from February to June
                          • The Southern Hemisphere vaccine which is made
                            available starting February of each year is
                            recommended to cover the expected increase in
                            influenza activity from June to November.




Saturday, May 29, 2010
Vaccine dosage by age group
                          Age                    Dose                  No. doses   Route


                          6 – 35 mos             0.25 ml               1 or 2*     IM


                          3 – 8 yrs              0.5 ml                1 or 2*     IM


                          = or > 9               0.5 ml                1           IM
                          yrs

                          * 2 if receiving vaccine for 1st time, 1 month apart

Saturday, May 29, 2010
38



Saturday, May 29, 2010
Thank You!


                                      38



Saturday, May 29, 2010

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Influenza

  • 2. INFLUENZA Jaime A. Santos Saturday, May 29, 2010
  • 3. Influenza • commonly called “the flu” • a contagious respiratory illness caused by influenza viruses • Infection with influenza viruses can result in illness ranging from mild to severe with life- threatening complications Saturday, May 29, 2010
  • 5. 1918 Spanish flu pandemic: 20 to 50 million people may have died worldwide Saturday, May 29, 2010
  • 7. Viral Titers Peak Early Saturday, May 29, 2010
  • 8. “Flu” symptoms Fever/ chills Headache Nasal congestion Sore throat Dry cough Myalgia/ body aches GI symptoms Malaise/ tiredness Saturday, May 29, 2010
  • 9. Influenza - Clinical Signs and Symptoms • incubation period for influenza is 1--4 days, with an average of 2 days • Adults - infectious from the day before symptoms begin through approximately 5 days after onset • Children - infectious for > 10 days, and young children can shed virus for < 6 days before their illness onset • immunocompromised persons can shed virus for weeks or months Saturday, May 29, 2010
  • 10. Influenza - Clinical Signs and Symptoms • resolves after a limited number of days for the majority of persons, although cough and malaise can persist for >2 weeks • young children can have initial symptoms mimicking bacterial sepsis with high fevers – < 20% of children hospitalized with influenza can have febrile seizures Saturday, May 29, 2010
  • 11. Influenza - Clinical Signs and Symptoms • Influenza infection has also been associated with encephalopathy transverse myelitis Reye syndrome myositis myocarditis pericarditis Saturday, May 29, 2010
  • 12. Influenza - Hospitalization and Deaths • Population at risk for complications, hospitalizations, & deaths:> 65 years old – young children – persons of any age with certain underlying health conditions: cardiovascular and pulmonary (including asthma), metabolic e.g. DM, Hgbpathies, immunosuppression – receiving long term ASA Saturday, May 29, 2010
  • 13. “U” Shaped Epidemic Curve of Influenza During the Interpandemic Period Visits/100 ARD Hospitalizations/10,000 P&I Mortality/100,000 Rate Age group Saturday, May 29, 2010
  • 14. “U” Shaped Epidemic Curve of Influenza During the Interpandemic Period 120 Visits/100 ARD Hospitalizations/10,000 P&I Mortality/100,000 100 80 Rate 60 40 20 0 <5 5–9 10–14 15-19 20-24 25-34 35-44 45-54 55-64 > 64 Age group Saturday, May 29, 2010
  • 15. “U” Shaped Epidemic Curve of Influenza During the Interpandemic Period 120 Visits/100 ARD Hospitalizations/10,000 P&I Mortality/100,000 100 80 Rate 60 40 20 0 <5 5–9 10–14 15-19 20-24 25-34 35-44 45-54 55-64 > 64 Age group Saturday, May 29, 2010
  • 16. “U” Shaped Epidemic Curve of Influenza During the Interpandemic Period 120 Visits/100 ARD Hospitalizations/10,000 P&I Mortality/100,000 100 80 Rate 60 40 20 0 <5 5–9 10–14 15-19 20-24 25-34 35-44 45-54 55-64 > 64 Age group Saturday, May 29, 2010
  • 17. “U” Shaped Epidemic Curve of Influenza During the Interpandemic Period 120 Visits/100 ARD Hospitalizations/10,000 P&I Mortality/100,000 100 80 Rate 60 40 20 0 <5 5–9 10–14 15-19 20-24 25-34 35-44 45-54 55-64 > 64 Age group Saturday, May 29, 2010
  • 18. Influenza Responsible for Substantial Disease Deaths 36,0001 Hospitalizations 114,0002 Physician visits 25 million3 Infections and illnesses 50–60 million3 Direct medical costs $1-$3 billion4 1. Thompson WW et al. JAMA. 2003;289:179-186. 2. CDC. MMWR Recomm Rep. 2003;58(RR-8):1-34. 3. Couch RB. Ann Intern Med. 2000;133:992-998. 4. Patriarca PA. JAMA. 1999;282:75-77. Saturday, May 29, 2010
  • 19. Seasonal • In colder countries flu is largely seen during colder months and they vaccinate prior to this season (e.g. October) • In tropical countries flu is seen all year round Saturday, May 29, 2010
  • 20. Flu Season in the Philippines Southern Hemisphere Pattern Cumulative Data: RITM Influenza Surveillance Data Feb. 1998 – Oct. 2004 B A Saturday, May 29, 2010
  • 21. Flu Season in the Philippines Southern Hemisphere Pattern Cumulative Data: RITM Influenza Surveillance Data Feb. 1998 – Oct. 2004 80 70 60 50 B A 40 30 20 10 0 Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Saturday, May 29, 2010
  • 22. Influenza virus types • Three : Influenza A, B, and C • Influenza types A or B viruses cause epidemics; influenza A may cause pandemics • Getting a flu shot can prevent illness from types A and B influenza but not from type C • Influenza type C causes mild respiratory illness ; not thought to cause epidemics Saturday, May 29, 2010
  • 23. Influenza Virus: Segmented genome Saturday, May 29, 2010
  • 24. Influenza A virus divided into subtypes based on HA and N proteins on surface • 15 HA, 9 N • Nomenclature based on: site of origin isolate number year of isolation subtype Example: influenzaA/ Johannesburg/33/94 (H3N2) Saturday, May 29, 2010
  • 25. Drift or shift • “Antigenic drift" - small changes in the virus that happen continually (influenza A and B) • “Antigenic shift” - abrupt, major change in the influenza A viruses, resulting in new H &/or new H and N proteins that infect humans (influenza A only) Saturday, May 29, 2010
  • 26. Influenza subtypes in humans • current subtypes of influenza A viruses found in people are A(H1N1) and A(H3N2) • Influenza B virus is not divided into subtypes • Influenza A(H1N1), A(H3N2), and influenza B strains are included in each year's influenza vaccine • Protection is serotype specific Saturday, May 29, 2010
  • 28. Domestic pig: Domestic poultry Mixing vessel Migratory water birds Saturday, May 29, 2010
  • 29. Domestic pig: Domestic poultry Mixing vessel Migratory water birds Saturday, May 29, 2010
  • 30. Avian Influenza • Caused by 15 subtypes of influenza A virus subtype of avian influenza • Low pathogenicity avian influenza (LPAI) • Highly pathogenic avian influenza (HPAI) – First recognized in Italy in 1878 – Extremely contagious in birds – Rapidly fatal, high mortality (almost 100% in a few days) Saturday, May 29, 2010
  • 31. Avian Influenza Infections in Humans Confirmed instances of avian influenza viruses infecting humans since 1997 • 1997: Hong Kong, avian influenza A (H5N1) • 1999: Hong Kong, avian influenza A(H9N2) • 2003: 2 cases of avian influenza A (H5N1) • 2003:H9N2 infection was confirmed in a child in Hong Kong • 2003: Avian influenza A (H7N7) infections among poultry workers / families in the Netherlands (> 80 cases ) Saturday, May 29, 2010
  • 32. Characteristics of Avian Influenza Infections in Humans • reported symptoms of avian influenza : typical influenza-like symptoms (e.g., fever, cough, sore throat and muscle aches) to eye infections, pneumonia, acute respiratory distress, viral pneumonia, and other severe and life-threatening complications • It is believed that most cases of H5N1 infection in humans have resulted from contact with infected poultry or contaminated surfaces CDC Saturday, May 29, 2010
  • 33. Current Avian Flu (H5N1) Strain – genetically sequenced: all bird origin – antiviral resistance to amantadine and rimantadine – oseltamavir and zanamivir should still be effective Saturday, May 29, 2010
  • 34. Avian Influenza (Bird Flu) Outbreak Why H5N1 is of particular concern • H5N1 mutates and acquires genes rapidly from other species • Documented to cause severe disease in humans • avian influenza virus could change so that it could infect humans and could spread easily from person to person • no immune protection against them in the human population • If an avian virus were able to infect people and gain the ability to spread easily from person to person, an “influenza pandemic” could begin Saturday, May 29, 2010
  • 35. FLU PANDEMICS: THEN AND NOW 1918 Year 2005 WHAT HAPPENED WHAT COULD HAPPEN 1.8 billion World Population 7 billion Troop ships, Primary mode of transportation Jets railroad Time for virus to circle 4 months the globe 4 days Gauze masks, Preventive measures Vaccines disinfectants Bed rest, Treatments Some antiviral drugs aspirin 20+ million Estimated dead 60 million? Janet Englund, MD PIDSP Feb. 2005 Saturday, May 29, 2010
  • 36. Treatment of Influenza • Antiviral Medications: – antiviral drugs: adamantanes: amantadine, rimantadine neuraminidase inhibitors: zanamivir, oseltamivir – Antiviral treatment lasts for 3-5 days and must be started within the first 2 days of illness. Saturday, May 29, 2010
  • 37. Antiviral treatment and prophylaxis • amantadine [4.4-8.8 mg/kg/day, not to exceed 150 mg/day] can be given for 3-5 days; for treatment of influenza A • oseltamivir [2 mg/kg/dose BID] can be given for 5 days for treatment of influenza A and B. Its use for treatment and prophylaxis of household contacts has been effective for children > 12 years old Saturday, May 29, 2010
  • 39. Do I Need A Flu Shot? Saturday, May 29, 2010
  • 40. Target Groups For Vaccination 1. Those with increased risk of complications: • Persons age 50 yrs old and above • Children from 6 to 23 months old • Adults and children with the following risk factors: – Chronic cardiovascular disease (e.g. congestive heart failure, Hypertensive cardiovascular disease, valvular heart disease, rheumatic heart disease, stroke) – Chronic lung disease (e.g COPD, asthma, bronchiectasis, malignancies, chronic PTB) Saturday, May 29, 2010
  • 41. • Chronic metabolic disease (diabetes mellitus) • Chronic renal dysfunction • Hemoglobinopathies • Immunosuppressed (e.g.HIV, malignancies, immunosuppressive drugs, radiation therapy, transplant patients) • Children and adolescents who are receiving long- term aspirin therapy • Residents of nursing homes and other chronic care facilities • Pregnant women on their 2nd or 3rd trimester who have not received their flu vaccine within the last 12 months. Saturday, May 29, 2010
  • 42. Target Groups For Vaccination 2. Those who can transmit the disease to others • Health care workers and other personnel of out patient care settings, hospitals, nursing homes, and chronic care facilities. • Household contacts (including children) and caregivers of person at high risk. Saturday, May 29, 2010
  • 43. When Should You Give the Flu Shot? Highlights Influenza Consensus – Flu TWG Oct. 2004 • Data from the five-year epidemiologic data (February 1998 – September 2003) shows increased influenza activity June to November. • Vaccination should be given once a year preferrably from February to June • The Southern Hemisphere vaccine which is made available starting February of each year is recommended to cover the expected increase in influenza activity from June to November. Saturday, May 29, 2010
  • 44. Vaccine dosage by age group Age Dose No. doses Route 6 – 35 mos 0.25 ml 1 or 2* IM 3 – 8 yrs 0.5 ml 1 or 2* IM = or > 9 0.5 ml 1 IM yrs * 2 if receiving vaccine for 1st time, 1 month apart Saturday, May 29, 2010
  • 46. Thank You! 38 Saturday, May 29, 2010