Influenza from wikipedia

Influenza Including H1N1, H3N2 & H5N1

Compiled from Wikipedia using Book Creator Dated July 29, 2017, 10:00PM. Abu Dhabi, UAE

Influenza Including H1N1, H3N2 & H5N1

Contents 1

Influenza

1

1.1

Signs and symptoms

1.2

Virology

1

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2

1.2.1

Types of virus

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2

1.2.2

Structure, properties, and subtype nomenclature . . . . . . . . . . . . . . . . . . . . . . .

3

1.2.3

Replication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4

Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4

1.3.1

Transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4

1.3.2

Pathophysiology

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5

Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6

1.4.1

Vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6

1.4.2

Infection control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6

Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7

1.5.1

Antivirals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7

1.6

Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7

1.7

Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8

1.7.1

Seasonal variations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8

1.7.2

Epidemic and pandemic spread

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9

1.8.1

Etymology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9

1.8.2

Pandemics

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9

Society and culture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11

1.3

1.4

1.5

1.8

1.9

History

1.10 Research

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11

1.11 Other animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12

1.11.1 Bird flu . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12

1.11.2 Swine flu . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13

1.12 References

2

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13

1.13 Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23

1.14 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23

''Influenza A virus’'

24

2.1

Variants and subtypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

24

2.2

Annual flu . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

25

i

ii

CONTENTS 2.2.1

3

FI6 antibody . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

25

2.3

Structure and genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

25

2.4

Multiplicity Reactivation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

26

2.5

Human influenza virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

26

2.5.1

Evolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

28

2.6

Other animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

28

2.7

See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

30

2.8

Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

30

2.9

Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33

2.10 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33

''Influenzavirus B''

34

3.1

Morphology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

34

3.2

Genome structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

34

3.3

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

34

3.3.1

Sources and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

34

External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

35

3.4 4

5

''Influenzavirus C''

36

4.1

Influenza C virus

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

36

4.2

Structure and Variation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

36

4.3

Identification

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

37

4.4

Vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

37

4.5

References

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

37

4.6

Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

38

4.7

External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

38

Influenza A virus subtype H1N1

39

5.1

Swine influenza . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

39

5.2

Notable incidents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

39

5.2.1

Spanish flu . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

39

5.2.2

Fort Dix outbreak . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

40

5.2.3

Russian flu . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

40

5.2.4

2009 A(H1N1) pandemic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

40

5.2.5

2015 India outbreak . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

41

5.2.6

2017 Maldives outbreak . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

41

5.2.7

2017 Myanmar outbreak . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

42

5.3

In pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

42

5.4

Additional images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

42

5.5

Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

42

5.6

External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

44

5.6.1

44

Nontechnical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CONTENTS 5.6.2 6

Technical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

44

1918 flu pandemic

46

6.1

History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

46

6.1.1

Hypotheses about source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

46

6.1.2

Spread . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

47

Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

47

6.2.1

Around the globe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

47

6.2.2

Patterns of fatality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

48

6.2.3

Deadly second wave . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

49

6.2.4

Devastated communities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

49

6.2.5

Less-affected areas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

49

6.2.6

Aspirin poisoning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

50

6.2.7

End of the pandemic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

50

6.3

Legacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

50

6.4

Spanish flu research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

51

6.5

In popular culture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

52

6.6

Gallery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

52

6.7

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

54

6.7.1

Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

54

6.7.2

Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

56

6.7.3

Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

58

External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

59

6.2

6.8 7

iii

2009 flu pandemic

60

7.1

History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

60

7.2

Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

60

7.3

Signs and symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

61

7.3.1

Severe cases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

61

7.3.2

Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

61

7.4

Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

62

7.5

Cause . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

62

7.5.1

Transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63

Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63

7.6.1

Public health response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63

7.6.2

Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

64

7.6.3

Accusations of conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

64

7.6.4

Infection control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

65

Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

67

7.7.1

Side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

67

7.7.2

Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

67

7.7.3

Effectiveness of antivirals questioned . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

67

7.6

7.7

iv

CONTENTS 7.8

Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

68

7.8.1

Mexico . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

68

7.8.2

United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

68

7.8.3

Data reporting and accuracy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

68

7.8.4

Followup . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

69

Comparisons to other pandemics and epidemics . . . . . . . . . . . . . . . . . . . . . . . . . . .

69

7.10 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

70

7.11 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

70

7.12 Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

78

7.13 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

78

7.13.1 Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

78

7.13.2 North America . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

79

7.9

8

9

Influenza A virus subtype H2N2

80

8.1

Russian flu . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

80

8.2

Asian flu . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

80

8.3

Test kits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

80

8.4

Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

81

8.5

Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

81

8.6

External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

81

Influenza A virus subtype H3N2

82

9.1

Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

82

9.2

Seasonal H3N2 flu . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

82

9.3

Swine flu . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

82

9.4

Flu spread, by season . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

83

9.4.1

Hong Kong Flu (1968–1969) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

83

9.4.2

Fujian flu (2003–2004) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

83

9.4.3

2004–2005 flu season . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

84

9.4.4

2005–2006 flu season . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

84

9.4.5

2006–2007 flu season . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

84

9.4.6

2007–2008 flu season . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

84

9.4.7

2008–2009 flu season . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

84

9.4.8

2009–2010 flu season . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

85

9.4.9

2010–2011 flu season

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

85

9.4.10 2011–2012 flu season

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

85

9.4.11 2012–2013 flu season

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

85

9.4.12 2014–2015 flu season

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

85

9.4.13 2015–2016 flu season

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

86

9.4.14 2016–2017 flu season

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

86

9.5

See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

86

9.6

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

86

CONTENTS

v

9.7

Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

87

9.8

External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

87

10 1968 flu pandemic

88

10.1 The 1968–1969 pandemic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

88

10.2 Clinical data

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

88

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

88

10.4 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

89

10.5 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

89

10.6 Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

89

10.7 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

89

10.3 Virology

11 Influenza A virus subtype H5N1

90

11.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

90

11.2 Signs and symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

91

11.2.1 In birds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

91

11.3 Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

91

11.3.1 Terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

92

11.3.2 Genetic structure and related subtypes . . . . . . . . . . . . . . . . . . . . . . . . . . . .

93

11.3.3 Low pathogenic H5N1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

93

11.3.4 High mutation rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

94

11.4 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

94

11.4.1 Vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

94

11.4.2 Public health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

94

11.5 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

95

11.6 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

95

11.6.1 Contagiousness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

95

11.6.2 Virulence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

96

11.6.3 Transmission and host range . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

96

11.6.4 H5N1 transmission studies in ferrets (2011) . . . . . . . . . . . . . . . . . . . . . . . . .

97

11.7 Society and culture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

97

11.8 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

97

11.9 Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

97

11.10References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

97

11.11External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 12 Avian influenza 12.1 History

102

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

12.2 Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 12.3 Subtypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 12.4 Spread

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

12.4.1 Village poultry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

vi

CONTENTS 12.5 H5N1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 12.5.1 Controversial Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 12.6 H7N9 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 12.7 In domestic animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 12.7.1 Birds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 12.7.2 Seals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 12.7.3 Cats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 12.8 Global impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 12.8.1 Stigma

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106

12.8.2 Indonesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 12.8.3 Economic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 12.9 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 12.9.1 For village poultry farmers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 12.9.2 Culling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 12.9.3 People-poultry relations

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

12.10See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 12.11References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 12.12Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 12.13External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 13 Inuenza A virus subtype H7N7

112

13.1 Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 13.2 Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 13.3 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 14 Zoonosis

114

14.1 History

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

14.2 Causes

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

14.2.1 Contamination of food or water supply . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 14.2.2 Farming, ranching and animal husbandry 14.2.3 Wild animal attacks

. . . . . . . . . . . . . . . . . . . . . . . . . . 115

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

14.2.4 Insect vectors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 14.2.5 Pets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 14.2.6 Exhibition

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

14.2.7 Hunting and bushmeat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 14.2.8 Zoophilia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 14.2.9 Secondary transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 14.3 Lists of diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 14.4 Use in vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 14.5 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 14.6 References 14.7 Bibliography

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

CONTENTS

vii

14.8 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 15 Influenza A virus subtype H1N2

118

15.1 History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 15.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 15.3 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 16 Influenza A virus subtype H9N2

119

16.1 Infection in birds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 16.2 Transmission from chicken to human . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 16.3 Antigenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 16.4 Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 16.5 Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 16.6 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 17 Influenza A virus subtype H7N2

121

17.1 Sources and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 17.2 Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122 17.3 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122 18 Influenza A virus subtype H7N3

123

18.1 Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 18.2 Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 18.3 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 19 Influenza A virus subtype H10N7

124

19.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 19.2 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 20 Influenza A virus subtype H7N9

125

20.1 H7N9 virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 20.2 Human cases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 20.2.1 Reported cases in 2013 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 20.2.2 Reported cases in 2014 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 20.2.3 Reported cases in 2015 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 20.2.4 Reported cases in late 2016 and 2017 (5th epidemic) . . . . . . . . . . . . . . . . . . . . 127 20.3 Symptoms and treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 20.4 Transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 20.4.1 Human to human transfer of virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 20.5 Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 20.6 Age/gender distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 20.7 Vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 20.8 Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 20.8.1 Efforts to prevent spread of disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

viii

CONTENTS 20.9 International response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 20.10See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 20.11References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 20.12Text and image sources, contributors, and licenses . . . . . . . . . . . . . . . . . . . . . . . . . . 136 20.12.1 Text . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 20.12.2 Images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144 20.12.3 Content license . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148

Chapter 1

Influenza Not to be confused with Haemophilus influenzae.

hibitor oseltamivir, among others, have been used to treat influenza.[1] Their benefits in those who are otherwise healthy do not appear to be greater than their risks.[7] “Flu” and “Grippe” redirect here. For other uses, see Flu No benefit has been found in those with other health (disambiguation) and Grippe (disambiguation). problems.[7][8] Influenza spreads around the world in a yearly outbreak, resulting in about three to five million cases of severe illness and about 250,000 to 500,000 deaths.[1] In the Northern and Southern parts of the world, outbreaks occur mainly in winter while in areas around the equator outbreaks may occur at any time of the year.[1] Death occurs mostly in the young, the old and those with other health problems.[1] Larger outbreaks known as pandemics are less frequent.[2] In the 20th century, three influenza pandemics occurred: Spanish influenza in 1918 (~50 million deaths), Asian influenza in 1957 (two million deaths), and Hong Kong influenza in 1968 (one million deaths).[9] The World Health Organization declared an outbreak of a new type of influenza A/H1N1 to be a pandemic in June 2009.[10] Influenza may also affect other animals, including pigs, horses and birds.[11]

Influenza, commonly known as “the flu", is an infectious disease caused by an influenza virus.[1] Symptoms can be mild to severe.[4] The most common symptoms include: a high fever, runny nose, sore throat, muscle pains, headache, coughing, and feeling tired. These symptoms typically begin two days after exposure to the virus and most last less than a week. The cough, however, may last for more than two weeks.[1] In children, there may be nausea and vomiting, but these are not common in adults.

Nausea and vomiting occur more commonly in the unrelated infection gastroenteritis, which is sometimes inaccurately referred to as “stomach flu” or “24-hour flu”.[5] Complications of influenza may include viral pneumonia, secondary bacterial pneumonia, sinus infections, and worsening of previous health problems such as asthma or heart failure.[4][2] Three types of influenza viruses affect people, called Type A, Type B, and Type C.[2] Usually, the virus is spread through the air from coughs or sneezes.[1] This is believed to occur mostly over relatively short distances.[6] It can also be spread by touching surfaces contaminated by the virus and then touching the mouth or eyes.[4][6] A person may be infectious to others both before and during the time they are showing symptoms.[4] The infection may be confirmed by testing the throat, sputum, or nose for the virus. A number of rapid tests are available; however, people may still have the infection if the results are negative. A type of polymerase chain reaction that detects the virus’s RNA is more accurate.[2]

1.1 Signs and symptoms Symptoms of

Influenza Central - Headache Systemic - Fever (usually high)

Nasopharynx - Runny or stuffy nose - Sore throat - Aches

Frequent hand washing reduces the risk of infection Muscular Respiratory because the virus is inactivated by soap.[3] Wearing a - (Extreme) - Coughing [3] surgical mask is also useful. Yearly vaccinations against tiredness influenza are recommended by the World Health Organization for those at high risk. The vaccine is usually effecGastric Joints tive against three or four types of influenza.[1] It is usu- Vomiting - Aches ally well tolerated. A vaccine made for one year may not be useful in the following year, since the virus evolves rapidly. Antiviral drugs such as the neuraminidase in- Symptoms of influenza,[13] with fever and cough the most common symptoms.[12]

1

2

CHAPTER 1. INFLUENZA

Approximately 33% of people with influenza are absence of a local outbreak, treatment may be justified asymptomatic.[14] in the elderly during the influenza season as long as the [25] Symptoms of influenza can start quite suddenly one to prevalence is over 15%. two days after infection. Usually the first symptoms are chills or a chilly sensation, but fever is also common early in the infection, with body temperatures ranging from 38 to 39 °C (approximately 100 to 103 °F).[15] Many people are so ill that they are confined to bed for several days, with aches and pains throughout their bodies, which are worse in their backs and legs.[16] Symptoms of influenza may include: • • • • •

The available laboratory tests for influenza continue to improve. The United States Centers for Disease Control and Prevention (CDC) maintains an up-to-date summary of available laboratory tests.[26] According to the CDC, rapid diagnostic tests have a sensitivity of 50– 75% and specificity of 90–95% when compared with viral culture.[27] These tests may be especially useful during the influenza season (prevalence=25%) but in the absence of a local outbreak, or peri-influenza season [25] Fever and extreme coldness (chills shivering, shak- (prevalence=10% ). ing (rigor)) Occasionally, influenza can cause severe illness including primary viral pneumonia or secondary bacteCough rial pneumonia.[28][29] The obvious symptom is trouble breathing. In addition, if a child (or presumably an adult) Nasal congestion seems to be getting better and then relapses with a high Vomiting fever, that is a danger sign since this relapse can be bacterial pneumonia.[30] Runny nose

• Sneezing • Body aches, especially joints and throat • Fatigue

1.2 Virology 1.2.1 Types of virus

• Headache • Irritated, watering eyes • Reddened eyes, skin (especially face), mouth, throat and nose • Petechial rash[17] • In children, gastrointestinal symptoms such as diarrhea and abdominal pain,[18][19] (may be severe in children with influenza B)[20] It can be difficult to distinguish between the common cold and influenza in the early stages of these infections.[21] Influenza is a mixture of symptoms of common cold and pneumonia, body ache, headache, and fatigue. Diarrhea is not normally a symptom of influenza in adults,[12] although it has been seen in some human cases of the H5N1 “bird flu”[22] and can be a symptom in children.[18] The symptoms most reliably seen in influenza are shown in the adjacent table.[12] Since antiviral drugs are effective in treating influenza if given early (see treatment section, below), it can be important to identify cases early. Of the symptoms listed above, the combinations of fever with cough, sore throat and/or nasal congestion can improve diagnostic accuracy.[23] Two decision analysis studies[24][25] suggest that during local outbreaks of influenza, the prevalence will be over 70%,[25] and thus patients with any of these combinations of symptoms may be treated with neuraminidase inhibitors without testing. Even in the

Structure of the influenza virion. The hemagglutinin (HA) and neuraminidase (NA) proteins are shown on the surface of the particle. The viral RNAs that make up the genome are shown as red coils inside the particle and bound to ribonuclearproteins (RNP).

In virus classification influenza viruses are RNA viruses that make up three of the five genera of the family Orthomyxoviridae:[31] • Influenzavirus A • Influenzavirus B • Influenzavirus C These viruses are only distantly related to the human parainfluenza viruses, which are RNA viruses belonging

1.2. VIROLOGY

3

to the paramyxovirus family that are a common cause of respiratory infections in children such as croup,[32] but can also cause a disease similar to influenza in adults.[33] A fourth family of influenza viruses has been proposed - influenza D.[34][35][36][37][38][39][40] The type species for this family is Bovine Influenza D virus which was first isolated in 2012.

Influenzavirus A This genus has one species, influenza A virus. Wild aquatic birds are the natural hosts for a large variety of influenza A. Occasionally, viruses are transmitted to other species and may then cause devastating outbreaks in domestic poultry or give rise to human influenza pandemics.[41] The type A viruses are the most virulent human pathogens among the three influenza types and cause the severest disease. The influenza A virus can be subdivided into different serotypes based on the antibody response to these viruses.[42] The serotypes that have been confirmed in humans, ordered by the number of known human pandemic deaths, are:

Type of nuclear material

Hemagglutinin

A/Fujian/411/2002 (H3N2) Virus type

• H3N2, which caused Hong Kong Flu in 1968 • H5N1, which caused Bird Flu in 2004 • H7N7, which has unusual zoonotic potential[43] • H1N2, endemic in humans, pigs and birds • H9N2 • H7N2 • H7N3 • H10N7 • H7N9 Influenzavirus B This genus has one species, influenza B virus. Influenza B almost exclusively infects humans[42] and is less common than influenza A. The only other animals known to be susceptible to influenza B infection are the seal[44] and the ferret.[45] This type of influenza mutates at a rate 2–3 times slower than type A[46] and consequently is less genetically diverse, with only one influenza B serotype.[42] As a result of this lack of antigenic diversity, a degree of immunity to influenza B is usually acquired at an early age. However, influenza B mutates enough that lasting immunity is not possible.[47] This reduced rate of antigenic change, combined with its limited host range (inhibiting cross species antigenic shift), ensures that pandemics of influenza B do not occur.[48]

Geographic origin

Strain number

Year of isolation

Virus subtype

Influenza virus nomenclature (for a Fujian flu virus)

Influenzavirus C This genus has one species, influenza C virus, which infects humans, dogs and pigs, sometimes causing both severe illness and local epidemics.[49][50] However, influenza C is less common than the other types and usually only causes mild disease in children.[51][52]

• H1N1, which caused Spanish Flu in 1918, and 1.2.2 Swine Flu in 2009 • H2N2, which caused Asian Flu in 1957

Neuraminidase

Structure, properties, and subtype nomenclature

Influenzaviruses A, B and C are very similar in overall structure.[53] The virus particle is 80–120 nanometers in diameter and usually roughly spherical, although filamentous forms can occur.[54][55] These filamentous forms are more common in influenza C, which can form cordlike structures up to 500 micrometers long on the surfaces of infected cells.[56] However, despite these varied shapes, the viral particles of all influenza viruses are similar in composition.[56] These are made of a viral envelope containing two main types of glycoproteins, wrapped around a central core. The central core contains the viral RNA genome and other viral proteins that package and protect this RNA. RNA tends to be single stranded but in special cases it is double.[55] Unusually for a virus, its genome is not a single piece of nucleic acid; instead, it contains seven or eight pieces of segmented negative-sense RNA, each piece of RNA containing either one or two genes, which code for a gene product (protein).[56] For example, the influenza A genome contains 11 genes on eight pieces of RNA, encoding for 11 proteins: hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), M1, M2, NS1, NS2 (NEP: nuclear export protein), PA, PB1 (polymerase basic 1), PB1-F2 and PB2.[57] Hemagglutinin (HA) and neuraminidase (NA) are the two large glycoproteins on the outside of the viral particles. HA is a lectin that mediates binding of the virus to target cells and entry of the viral genome into the target cell, while NA is involved in the release of progeny virus from infected cells, by cleaving sugars that bind the mature viral particles.[58] Thus, these proteins are targets for antiviral drugs.[59] Furthermore, they are antigens to

4

CHAPTER 1. INFLUENZA

which antibodies can be raised. Influenza A viruses are classified into subtypes based on antibody responses to HA and NA. These different types of HA and NA form the basis of the H and N distinctions in, for example, H5N1.[60] There are 16 H and 9 N subtypes known, but only H 1, 2 and 3, and N 1 and 2 are commonly found in humans.[61]

1.2.3

Replication

Host cell invasion and replication by the influenza virus. The steps in this process are discussed in the text.

[62]

Viruses can replicate only in living cells. Influenza infection and replication is a multi-step process: First, the virus has to bind to and enter the cell, then deliver its genome to a site where it can produce new copies of viral proteins and RNA, assemble these components into new viral particles, and, last, exit the host cell.[56] Influenza viruses bind through hemagglutinin onto sialic acid sugars on the surfaces of epithelial cells, typically in the nose, throat, and lungs of mammals, and intestines of birds (Stage 1 in infection figure).[63] After the hemagglutinin is cleaved by a protease, the cell imports the virus by endocytosis.[64] The intracellular details are still being elucidated. It is known that virions converge to the microtubule organizing center, interact with acidic endosomes and finally enter the target endosomes for genome release.[65] Once inside the cell, the acidic conditions in the endosome cause two events to happen: First, part of the hemagglutinin protein fuses the viral envelope with the vacuole’s membrane, then the M2 ion channel allows protons to move through the viral envelope and acidify the core of the virus, which causes the core to disassemble and release the viral RNA and core proteins.[56] The viral RNA (vRNA) molecules, accessory proteins and RNAdependent RNA polymerase are then released into the cytoplasm (Stage 2).[66] The M2 ion channel is blocked

by amantadine drugs, preventing infection.[67] These core proteins and vRNA form a complex that is transported into the cell nucleus, where the RNAdependent RNA polymerase begins transcribing complementary positive-sense vRNA (Steps 3a and b).[68] The vRNA either is exported into the cytoplasm and translated (step 4) or remains in the nucleus. Newly synthesized viral proteins are either secreted through the Golgi apparatus onto the cell surface (in the case of neuraminidase and hemagglutinin, step 5b) or transported back into the nucleus to bind vRNA and form new viral genome particles (step 5a). Other viral proteins have multiple actions in the host cell, including degrading cellular mRNA and using the released nucleotides for vRNA synthesis and also inhibiting translation of hostcell mRNAs.[69] Negative-sense vRNAs that form the genomes of future viruses, RNA-dependent RNA polymerase, and other viral proteins are assembled into a virion. Hemagglutinin and neuraminidase molecules cluster into a bulge in the cell membrane. The vRNA and viral core proteins leave the nucleus and enter this membrane protrusion (step 6).

The mature virus buds off from the cell in a sphere of host phospholipid membrane, acquiring hemagglutinin and neuraminidase with this membrane coat (step 7).[70] As before, the viruses adhere to the cell through hemagglutinin; the mature viruses detach once their neuraminidase has cleaved sialic acid residues from the host cell.[63] After the release of new influenza viruses, the host cell dies.

Because of the absence of RNA proofreading enzymes, the RNA-dependent RNA polymerase that copies the viral genome makes an error roughly every 10 thousand nucleotides, which is the approximate length of the influenza vRNA. Hence, the majority of newly manufactured influenza viruses are mutants; this causes antigenic drift, which is a slow change in the antigens on the viral surface over time.[71] The separation of the genome into eight separate segments of vRNA allows mixing or reassortment of vRNAs if more than one type of influenza virus infects a single cell. The resulting rapid change in viral genetics produces antigenic shifts, which are sudden changes from one antigen to another. These sudden large changes allow the virus to infect new host species and quickly overcome protective immunity.[60] This is important in the emergence of pandemics, as discussed below in the section on Epidemiology.

1.3 Mechanism 1.3.1 Transmission When an infected person sneezes or coughs more than half a million virus particles can be spread to those close by.[72] In otherwise healthy adults, influenza virus shedding (the time during which a person might be infectious

1.3. MECHANISM

5

to another person) increases sharply one-half to one day after infection, peaks on day 2 and persists for an average total duration of 5 days—but can persist as long as 9 days.[73] In those who develop symptoms from experimental infection (only 67% of healthy experimentally infected individuals), symptoms and viral shedding show a similar pattern, but with viral shedding preceding illness by one day.[73] Children are much more infectious than adults and shed virus from just before they develop symptoms until two weeks after infection.[74] In immunocompromised people, viral shedding can continue for longer than two weeks.[75] Influenza can be spread in three main ways:[76][77] by direct transmission (when an infected person sneezes mucus directly into the eyes, nose or mouth of another person); the airborne route (when someone inhales the aerosols produced by an infected person coughing, sneezing or spitting) and through hand-to-eye, hand-to-nose, or handto-mouth transmission, either from contaminated surfaces or from direct personal contact such as a handshake.

The relative importance of these three modes of transmission is unclear, and they may all contribute to the spread of the virus.[6] In the airborne route, the droplets that are small enough for people to inhale are 0.5 to 5 µm in diameter and inhaling just one droplet might be enough to cause an infection.[76] Although a single sneeze releases up to 40,000 droplets,[78] most of these droplets are quite large and will quickly settle out of the air.[76] How long influenza survives in airborne droplets seems to be influenced by the levels of humidity and UV radiation, with low humidity and a lack of sunlight in winter aiding its survival.[76]

The different sites of infection (shown in red) of seasonal H1N1 versus avian H5N1. This influences their lethality and ability to spread.

For instance, part of the process that allows influenza viruses to invade cells is the cleavage of the viral hemagglutinin protein by any one of several human proteases.[64] In mild and avirulent viruses, the structure of the hemagglutinin means that it can only be cleaved by proteases found in the throat and lungs, so these viruses cannot infect other tissues. However, in highly virulent strains, such as H5N1, the hemagglutinin can be cleaved by a wide variety of proteases, allowing the virus to spread throughout the body.[83] The viral hemagglutinin protein is responsible for determining both which species a strain can infect and where in the human respiratory tract a strain of influenza will bind.[84] Strains that are easily transmitted between people have hemagglutinin proteins that bind to receptors in the upper part of the respiratory tract, such as in the nose, throat and mouth. In contrast, the highly lethal H5N1 strain binds to receptors that are mostly found deep in the lungs.[85] This difference in the site of infection may be part of the reason why the H5N1 strain causes severe viral pneumonia in the lungs, but is not easily transmitted by people coughing and sneezing.[86][87]

As the influenza virus can persist outside of the body, it can also be transmitted by contaminated surfaces such as banknotes,[79] doorknobs, light switches and other household items.[16] The length of time the virus will persist on a surface varies, with the virus surviving for one to two days on hard, non-porous surfaces such as plastic or metal, for about fifteen minutes from dry paper tissues, and only five minutes on skin.[80] However, if the virus is present in mucus, this can protect it for longer periods (up to 17 days on banknotes).[76][79] Avian influenza viruses can survive indefinitely when frozen.[81] They are inacti- Common symptoms of the flu such as fever, headaches, vated by heating to 56 °C (133 °F) for a minimum of 60 and fatigue are the result of the huge amounts of proinflammatory cytokines and chemokines (such as interferon minutes, as well as by acids (at pH <2).[81] or tumor necrosis factor) produced from influenzainfected cells.[21][88] In contrast to the rhinovirus that causes the common cold, influenza does cause tissue dam1.3.2 Pathophysiology age, so symptoms are not entirely due to the inflammatory response.[89] This massive immune response might proThe mechanisms by which influenza infection causes duce a life-threatening cytokine storm. This effect has symptoms in humans have been studied intensively. One been proposed to be the cause of the unusual lethalof the mechanisms is believed to be the inhibition of ity of both the H5N1 avian influenza,[90] and the 1918 adrenocorticotropic hormone (ACTH) resulting in low- pandemic strain.[91][92] However, another possibility is ered cortisol levels.[82] Knowing which genes are carried that these large amounts of cytokines are just a result of by a particular strain can help predict how well it will in- the massive levels of viral replication produced by these fect humans and how severe this infection will be (that is, strains, and the immune response does not itself conpredict the strain’s pathophysiology).[50][83] tribute to the disease.[93]

6

CHAPTER 1. INFLUENZA

1.4 Prevention 1.4.1

vaccine is supposed to prevent, as the vaccine takes about two weeks to become effective.[108]

Vaccination

Vaccines can cause the immune system to react as if the body were actually being infected, and general infection symptoms (many cold and flu symptoms are just general Main article: Influenza vaccine The influenza vaccine is recommended by the World infection symptoms) can appear, though these symptoms are usually not as severe or long-lasting as influenza. The most dangerous adverse effect is a severe allergic reaction to either the virus material itself or residues from the hen eggs used to grow the influenza; however, these reactions are extremely rare.[109] The cost-effectiveness of seasonal influenza vaccination has been widely evaluated for different groups and in different settings.[110] It has generally been found to be a cost-effective intervention, especially in children[111] and the elderly,[112] however the results of economic evaluations of influenza vaccination have often been found to be dependent on key assumptions.[113][114] Giving an influenza vaccination

1.4.2 Infection control Health Organization and United States Centers for Disease Control and Prevention for high-risk groups, such as children, the elderly, health care workers, and people who have chronic illnesses such as asthma, diabetes, heart disease, or are immuno-compromised among others.[94][95] In healthy adults it is modestly effective in decreasing the amount of influenza-like symptoms in a population.[96] Evidence is supportive of a decreased rate of influenza in children over the age of two.[97] In those with chronic obstructive pulmonary disease vaccination reduces exacerbations,[98] it is not clear if it reduces asthma exacerbations.[99] Evidence supports a lower rate of influenza-like illness in many groups who are immunocompromised such as those with: HIV/AIDS, cancer, and post organ transplant.[100] In those at high risk immunization may reduce the risk of heart disease.[101] Whether immunizing health care workers affects patient outcomes is controversial with some reviews finding insufficient evidence[102][103] and others finding tentative evidence.[104][105] Due to the high mutation rate of the virus, a particular influenza vaccine usually confers protection for no more than a few years. Every year, the World Health Organization predicts which strains of the virus are most likely to be circulating in the next year (see Historical annual reformulations of the influenza vaccine), allowing pharmaceutical companies to develop vaccines that will provide the best immunity against these strains.[106] The vaccine is reformulated each season for a few specific flu strains but does not include all the strains active in the world during that season. It takes about six months for the manufacturers to formulate and produce the millions of doses required to deal with the seasonal epidemics; occasionally, a new or overlooked strain becomes prominent during that time.[107] It is also possible to get infected just before vaccination and get sick with the strain that the

Further information: Influenza prevention Reasonably effective ways to reduce the transmission of influenza include good personal health and hygiene habits such as: not touching your eyes, nose or mouth;[115] frequent hand washing (with soap and water, or with alcoholbased hand rubs);[116] covering coughs and sneezes; avoiding close contact with sick people; and staying home yourself if you are sick. Avoiding spitting is also recommended.[117] Although face masks might help prevent transmission when caring for the sick,[118][119] there is mixed evidence on beneficial effects in the community.[117][120] Smoking raises the risk of contracting influenza, as well as producing more severe disease symptoms.[121][122] Since influenza spreads through both aerosols and contact with contaminated surfaces, surface sanitizing may help prevent some infections.[123] Alcohol is an effective sanitizer against influenza viruses, while quaternary ammonium compounds can be used with alcohol so that the sanitizing effect lasts for longer.[124] In hospitals, quaternary ammonium compounds and bleach are used to sanitize rooms or equipment that have been occupied by patients with influenza symptoms.[124] At home, this can be done effectively with a diluted chlorine bleach.[125] Social distancing strategies used during past pandemics, such as closing schools, churches and theaters, slowed the spread of the virus but did not have a large effect on the overall death rate.[126][127] It is uncertain if reducing public gatherings, by for example closing schools and workplaces, will reduce transmission since people with influenza may just be moved from one area to another; such measures would also be difficult to enforce and might be unpopular.[117] When small numbers of

1.6. PROGNOSIS

7

people are infected, isolating the sick might reduce the H3N2 has increased to 91% in 2005.[134] This high level risk of transmission.[117] of resistance may be due to the easy availability of amantadines as part of over-the-counter cold remedies in countries such as China and Russia,[135] and their use to prevent outbreaks of influenza in farmed poultry.[136][137] 1.5 Treatment The CDC recommended against using M2 inhibitors during the 2005–06 influenza season due to high levels of Main article: Influenza treatment drug resistance.[138] People with the flu are advised to get plenty of rest, drink plenty of liquids, avoid using alcohol and tobacco and, if necessary, take medications such as acetaminophen (paracetamol) to relieve the fever and muscle aches associated with the flu.[128] Children and teenagers with flu symptoms (particularly fever) should avoid taking aspirin during an influenza infection (especially influenza type B), because doing so can lead to Reye’s syndrome, a rare but potentially fatal disease of the liver.[129] Since influenza is caused by a virus, antibiotics have no effect on the infection; unless prescribed for secondary infections such as bacterial pneumonia. Antiviral medication may be effective, if given early, but some strains of influenza can show resistance to the standard antiviral drugs and there is concern about the quality of the research.[130]

1.6 Prognosis Influenza’s effects are much more severe and last longer than those of the common cold. Most people will recover completely in about one to two weeks, but others will develop life-threatening complications (such as pneumonia). Thus, influenza can be deadly, especially for the weak, young and old, or chronically ill.[60] People with a weak immune system, such as people with advanced HIV infection or transplant patients (whose immune systems are medically suppressed to prevent transplant organ rejection), suffer from particularly severe disease.[139] Pregnant women and young children are also at a high risk for complications.[140]

The flu can worsen chronic health problems. People with emphysema, chronic bronchitis or asthma may experiThe two classes of antiviral drugs used against influenza ence shortness of breath while they have the flu, and inof coronary heart disease or are neuraminidase inhibitors (oseltamivir and zanamivir) fluenza may cause worsening [141] congestive heart failure.

Smoking is another risk facand M2 protein inhibitors (adamantane derivatives). tor associated with more serious disease and increased mortality from influenza.[142] Neuraminidase inhibitors According to the World Health Organization: “Every

1.5.1

Antivirals

Overall the benefits of neuraminidase inhibitors in those who are otherwise healthy do not appear to be greater than the risks.[7] There does not appear to be any benefit in those with other health problems.[7] In those believed to have the flu, they decreased the length of time symptoms were present by slightly less than a day but did not appear to affect the risk of complications such as needing hospitalization or pneumonia.[8] Previous to 2013 the benefits were unclear as the manufacturer (Roche) refused to release trial data for independent analysis.[131] Increasingly prevalent resistance to neuraminidase inhibitors has led to researchers to seek alternative antiviral drugs with different mechanisms of action.[132] M2 inhibitors The antiviral drugs amantadine and rimantadine inhibit a viral ion channel (M2 protein), thus inhibiting replication of the influenza A virus.[67] These drugs are sometimes effective against influenza A if given early in the infection but are ineffective against influenza B viruses, which lack the M2 drug target.[133] Measured resistance to amantadine and rimantadine in American isolates of

winter, tens of millions of people get the flu. Most are only ill and out of work for a week, yet the elderly are at a higher risk of death from the illness. We know the worldwide death toll exceeds a few hundred thousand people a year, but even in developed countries the numbers are uncertain, because medical authorities don't usually verify who actually died of influenza and who died of a flu-like illness.”[143] Even healthy people can be affected, and serious problems from influenza can happen at any age. People over 65 years old, pregnant women, very young children and people of any age with chronic medical conditions are more likely to get complications from influenza, such as pneumonia, bronchitis, sinus, and ear infections.[144] In some cases, an autoimmune response to an influenza infection may contribute to the development of Guillain– Barré syndrome.[145] However, as many other infections can increase the risk of this disease, influenza may only be an important cause during epidemics.[145][146] This syndrome has been believed to also be a rare side effect of influenza vaccines. One review gives an incidence of about one case per million vaccinations.[147] Getting infected by influenza itself increases both the risk of death (up to 1 in 10,000) and increases the risk of developing GBS to

8

CHAPTER 1. INFLUENZA

a much higher level than the highest level of suspected mans and birds.[156] vaccine involvement (approx. 10 times higher by recent An alternative hypothesis to explain seasonality in inestimates).[148][149] fluenza infections is an effect of vitamin D levels on immunity to the virus.[157] This idea was first proposed by Robert Edgar Hope-Simpson in 1965.[158] He proposed 1.7 Epidemiology that the cause of influenza epidemics during winter may be connected to seasonal fluctuations of vitamin D, which is produced in the skin under the influence of solar (or ar1.7.1 Seasonal variations tificial) UV radiation. This could explain why influenza occurs mostly in winter and during the tropical rainy seaFurther information: Flu season Influenza reaches peak prevalence in winter, and because son, when people stay indoors, away from the sun, and their vitamin D levels fall.

1.7.2 Epidemic and pandemic spread Further information: Flu pandemic

Seasonal risk areas for influenza: November–April (blue), April– November (red), and year-round (yellow).

the Northern and Southern Hemispheres have winter at different times of the year, there are actually two different flu seasons each year. This is why the World Health Organization (assisted by the National Influenza Centers) makes recommendations for two different vaccine formulations every year; one for the Northern, and one for the Southern Hemisphere.[106] A long-standing puzzle has been why outbreaks of the flu occur seasonally rather than uniformly throughout the year. One possible explanation is that, because people are indoors more often during the winter, they are in close contact more often, and this promotes transmission from person to person. Increased travel due to the Northern Hemisphere winter holiday season may also play a role.[150] Another factor is that cold temperatures lead to drier air, which may dehydrate mucus, preventing the body from effectively expelling virus particles.

The virus also survives longer on surfaces at colder temperatures and aerosol transmission of the virus is highest in cold environments (less than 5 °C) with low relative humidity.[151] The lower air humidity in winter seems to be the main cause of seasonal influenza transmission in temperate regions.[152][153] However, seasonal changes in infection rates also occur in tropical regions, and in some countries these peaks of infection are seen mainly during the rainy season.[154] Seasonal changes in contact rates from school terms, which are a major factor in other childhood diseases such as measles and pertussis, may also play a role in the flu.

A combination of these small seasonal effects may be amplified by dynamical resonance with the endogenous disease cycles.[155] H5N1 exhibits seasonality in both hu-

As influenza is caused by a variety of species and strains of viruses, in any given year some strains can die out while others create epidemics, while yet another strain can cause a pandemic. Typically, in a year’s normal two flu seasons (one per hemisphere), there are between three and five million cases of severe illness and around 500,000 deaths worldwide,[159] which by some definitions is a yearly influenza epidemic.[160] Although the incidence of influenza can vary widely between years, approximately 36,000 deaths and more than 200,000 hospitalizations are directly associated with influenza every year in the United States.[161][162] One method of calculating influenza mortality produced an estimate of 41,400 average deaths per year in the United States between 1979 and 2001.[163] Different methods in 2010 by the Centers for Disease Control and Prevention (CDC) reported a range from a low of about 3,300 deaths to a high of 49,000 per year.[164] Roughly three times per century, a pandemic occurs, which infects a large proportion of the world’s population and can kill tens of millions of people (see pandemics section). One study estimated that if a strain with similar virulence to the 1918 influenza emerged today, it could kill between 50 and 80 million people.[165] New influenza viruses are constantly evolving by mutation or by reassortment.[42] Mutations can cause small changes in the hemagglutinin and neuraminidase antigens on the surface of the virus. This is called antigenic drift, which slowly creates an increasing variety of strains until one evolves that can infect people who are immune to the preexisting strains. This new variant then replaces the older strains as it rapidly sweeps through the human population, often causing an epidemic.[166] However, since the strains produced by drift will still be reasonably similar to the older strains, some people will still be immune to them. In contrast, when influenza viruses reassort, they acquire completely new antigens—for example by reassortment between avian strains and human strains; this is called antigenic shift. If a human influenza virus is pro-

1.8. HISTORY

9

highly pathogenic avian strain

human strain

dividuals (the basic reproduction number for influenza is generally around 1.4). However, the generation time for influenza is extremely short: the time from a person becoming infected to when he infects the next person is only two days. The short generation time means that influenza epidemics generally peak at around 2 months and burn out after 3 months: the decision to intervene in an influenza epidemic therefore has to be taken early, and the decision is therefore often made on the back of incomplete data. Another problem is that individuals become infectious before they become symptomatic, which means that putting people in quarantine after they become ill is not an effective public health intervention.[169] For the average person, viral shedding tends to peak on day two whereas symptoms peak on day three.[14]

1.8 History new highly pathogenic human strain

Antigenic shift, or reassortment, can result in novel and highly pathogenic strains of human influenza

duced that has entirely new antigens, everybody will be susceptible, and the novel influenza will spread uncontrollably, causing a pandemic.[167] In contrast to this model of pandemics based on antigenic drift and shift, an alternative approach has been proposed where the periodic pandemics are produced by interactions of a fixed set of viral strains with a human population with a constantly changing set of immunities to different viral strains.[168]

See also: Timeline of influenza

1.8.1 Etymology The word Influenza comes from the Italian language meaning “influence” and refers to the cause of the disease; initially, this ascribed illness to unfavorable astrological influences.[170] Changes in medical thought led to its modification to influenza del freddo, meaning “influence of the cold”. The word influenza was first used in English to refer to the disease we know today in 1703 by J. Hugger of the University of Edinburgh in his thesis De Catarrho epidemio, vel Influenza, prout in India occidentali sese ostendit.[171] Archaic terms for influenza include epidemic catarrh, grippe (from the French, first used by Molyneaux in 1694 [172] ), sweating sickness, and Spanish fever (particularly for the 1918 flu pandemic strain).[173]

1.8.2 Pandemics Further information: Influenza pandemic, Spanish flu, and Hong Kong flu The symptoms of human influenza were clearly described by Hippocrates roughly 2,400 years ago.[175][176] Although the virus seems to have caused epidemics throughout human history, historical data on influenza are difficult to interpret, because the symptoms can be similar to those of other respiratory diseases.[177][178] The The generation time for influenza (the time from one infection to disease may have spread from Europe to the Americas the next) is very short (only 2 days). This explains why influenza as early as the European colonization of the Americas; epidemics start and finish in a short time scale of only a few since almost the entire indigenous population of the Anmonths.[169] tilles was killed by an epidemic resembling influenza that out in 1493, after the arrival of Christopher ColumFrom a public health point of view, flu epidemics spread broke [179][180] bus. rapidly and are very difficult to control. Most influenza virus strains are not very infectious and each infected in- The first convincing record of an influenza pandemic was dividual will only go on to infect one or two other in- of an outbreak in 1580, which began in Russia and spread

10

CHAPTER 1. INFLUENZA most striking of the complications was hemorrhage from mucous membranes, especially from the nose, stomach, and intestine. Bleeding from the ears and petechial hemorrhages in the skin also occurred.”[181] The majority of deaths were from bacterial pneumonia, a secondary infection caused by influenza, but the virus also killed people directly, causing massive hemorrhages and edema in the lung.[183]

The difference between the influenza mortality age distributions of the 1918 epidemic and normal epidemics. Deaths per 100,000 persons in each age group, United States, for the interpandemic years 1911–1917 (dashed line) and the pandemic year 1918 (solid line).[174]

The 1918 flu pandemic was truly global, spreading even to the Arctic and remote Pacific islands. The unusually severe disease killed between two and twenty percent of those infected, as opposed to the more usual flu epidemic mortality rate of 0.1%.[174][181] Another unusual feature of this pandemic was that it mostly killed young adults, with 99% of pandemic influenza deaths occurring in people under 65, and more than half in young adults 20 to 40 years old.[184] This is unusual since influenza is normally most deadly to the very young (under age 2) and the very old (over age 70). The total mortality of the 1918–1919 pandemic is not known, but it is estimated that 2.5% to 5% of the world’s population was killed. As many as 25 million may have been killed in the first 25 weeks; in contrast, HIV/AIDS has killed 25 million in its first 25 years.[181] Later flu pandemics were not so devastating. They included the 1957 Asian Flu (type A, H2N2 strain) and the 1968 Hong Kong Flu (type A, H3N2 strain), but even these smaller outbreaks killed millions of people. In later pandemics antibiotics were available to control secondary infections and this may have helped reduce mortality compared to the Spanish Flu of 1918.[174]

to Europe via Africa. In Rome, over 8,000 people were killed, and several Spanish cities were almost wiped out.

Pandemics continued sporadically throughout the 17th and 18th centuries, with the pandemic of 1830–1833 being particularly widespread; it infected approximately a quarter of the people exposed.[178]

The first influenza virus to be isolated was from poultry, when in 1901 the agent causing a disease called “fowl plague” was passed through Chamberland filters, which have pores that are too small for bacteria to pass through.[189] The etiological cause of influenza, the Orthomyxoviridae family of viruses, was first discovered in pigs by Richard Shope in 1931.[190] This discovery was shortly followed by the isolation of the virus from humans by a group headed by Patrick Laidlaw at the Medical Research Council of the United Kingdom in 1933.[191] However, it was not until Wendell Stanley first crystallized tobacco mosaic virus in 1935 that the non-cellular nature of viruses was appreciated.

The most famous and lethal outbreak was the 1918 flu pandemic (Spanish flu pandemic) (type A influenza, H1N1 subtype), which lasted from 1918 to 1919. It is not known exactly how many it killed, but estimates range from 50 to 100 million people.[174][181][182] This pandemic has been described as “the greatest medical holocaust in history” and may have killed as many people as the Black Death.[178] This huge death toll was caused by an extremely high infection rate of up to 50% and the extreme severity of the symptoms, suspected to be caused by cytokine storms.[182] Symptoms in 1918 were so unusual that initially influenza was misdiagnosed as dengue, cholera, or typhoid. One observer wrote, “One of the

The main types of influenza viruses in humans. Solid squares show the appearance of a new strain, causing recurring influenza pandemics. Broken lines indicate uncertain strain identifications.[192]

Thermal imaging camera and screen, photographed in an airport terminal in Greece during the 2009 flu pandemic. Thermal imaging can detect elevated body temperature, one of the signs of swine flu.

1.10. RESEARCH The first significant step towards preventing influenza was the development in 1944 of a killed-virus vaccine for influenza by Thomas Francis, Jr. This built on work by Australian Frank Macfarlane Burnet, who showed that the virus lost virulence when it was cultured in fertilized hen’s eggs.[193] Application of this observation by Francis allowed his group of researchers at the University of Michigan to develop the first influenza vaccine, with support from the U.S. Army.[194] The Army was deeply involved in this research due to its experience of influenza in World War I, when thousands of troops were killed by the virus in a matter of months.[181] In comparison to vaccines, the development of anti-influenza drugs has been slower, with amantadine being licensed in 1966 and, almost thirty years later, the next class of drugs (the neuraminidase inhibitors) being developed.[61]

11 In an assessment of the 2009 H1N1 pandemic on selected countries in the Southern Hemisphere, data suggest that all countries experienced some time-limited and/or geographically isolated socio/economic effects and a temporary decrease in tourism most likely due to fear of 2009 H1N1 disease. It is still too early to determine whether the H1N1 pandemic has caused any long-term economic impacts.[201]

1.10 Research Further information: Influenza research Research on influenza includes studies on molecular vi-

1.9 Society and culture Further information: Social impact of H5N1 Influenza produces direct costs due to lost productivity and associated medical treatment, as well as indirect costs of preventative measures. In the United States, influenza is responsible for a total cost of over $10 billion per year, while it has been estimated that a future pandemic could cause hundreds of billions of dollars in direct and indirect costs.[195] However, the economic impacts of past pandemics have not been intensively studied, and some authors have suggested that the Spanish influenza actually had a positive long-term effect on per-capita income growth, despite a large reduction in the working population and severe short-term depressive effects.[196] Other studies have attempted to predict the costs of a pandemic as serious as the 1918 Spanish flu on the U.S. economy, where 30% of all workers became ill, and 2.5% were killed. A 30% sickness rate and a three-week length of illness would decrease the gross domestic product by 5%.

Additional costs would come from medical treatment of Dr. Terrence Tumpey examining a laboratory-grown reconstruc18 million to 45 million people, and total economic costs tion of the 1918 Spanish flu virus in a biosafety level 3 environwould be approximately $700 billion.[197] ment.

Preventative costs are also high. Governments worldwide have spent billions of U.S. dollars preparing and planning for a potential H5N1 avian influenza pandemic, with costs associated with purchasing drugs and vaccines as well as developing disaster drills and strategies for improved border controls.[198] On 1 November 2005, United States President George W. Bush unveiled the National Strategy to Safeguard Against the Danger of Pandemic Influenza[195] backed by a request to Congress for $7.1 billion to begin implementing the plan.[199] Internationally, on 18 January 2006, donor nations pledged US$2 billion to combat bird flu at the two-day International Pledging Conference on Avian and Human Influenza held in China.[200]

rology, how the virus produces disease (pathogenesis), host immune responses, viral genomics, and how the virus spreads (epidemiology). These studies help in developing influenza countermeasures; for example, a better understanding of the body’s immune system response helps vaccine development, and a detailed picture of how influenza invades cells aids the development of antiviral drugs. One important basic research program is the Influenza Genome Sequencing Project, which is creating a library of influenza sequences; this library should help clarify which factors make one strain more lethal than another, which genes most affect immunogenicity, and how the virus evolves over time.[202]

12 Research into new vaccines is particularly important, as current vaccines are very slow and expensive to produce and must be reformulated every year. The sequencing of the influenza genome and recombinant DNA technology may accelerate the generation of new vaccine strains by allowing scientists to substitute new antigens into a previously developed vaccine strain.[203] New technologies are also being developed to grow viruses in cell culture, which promises higher yields, less cost, better quality and surge capacity.[204] Research on a universal influenza A vaccine, targeted against the external domain of the transmembrane viral M2 protein (M2e), is being done at the University of Ghent by Walter Fiers, Xavier Saelens and their team[205][206][207] and has now successfully concluded Phase I clinical trials. There has been some research success towards a “universal flu vaccine” that produces antibodies against proteins on the viral coat which mutate less rapidly, and thus a single shot could potentially provide longer-lasting protection.[208][209][210]

CHAPTER 1. INFLUENZA as well-studied as human infection, but an outbreak of influenza in harbor seals caused approximately 500 seal deaths off the New England coast in 1979–1980.[213] However, outbreaks in pigs are common and do not cause severe mortality.[47] Vaccines have also been developed to protect poultry from avian influenza. These vaccines can be effective against multiple strains and are used either as part of a preventative strategy, or combined with culling in attempts to eradicate outbreaks.[214]

1.11.1 Bird flu Flu symptoms in birds are variable and can be unspecific.[215] The symptoms following infection with low-pathogenicity avian influenza may be as mild as ruffled feathers, a small reduction in egg production, or weight loss combined with minor respiratory disease.[216] Since these mild symptoms can make diagnosis in the field difficult, tracking the spread of avian influenza requires laboratory testing of samples from infected birds.

Some strains such as Asian H9N2 are highly virulent to poultry and may cause more extreme symptoms and significant mortality.[217] In its most highly pathogenic form, influenza in chickens and turkeys produces a sudden appearance of severe symptoms and almost 100% mortality within two days.[218] As the virus spreads rapidly in the crowded conditions seen in the intensive farming of chickens and turkeys, these outbreaks can cause large economic losses to poultry farmers.

A number of biologics, therapeutic vaccines and immunobiologics are also being investigated for treatment of infection caused by viruses. Therapeutic biologics are designed to activate the immune response to virus or antigens. Typically, biologics do not target metabolic pathways like anti-viral drugs, but stimulate immune cells such as lymphocytes, macrophages, and/or antigen presenting cells, in an effort to drive an immune response towards a cytotoxic effect against the virus. Influenza models, such as murine influenza, are convenient models to test the effects of prophylactic and therapeutic biologics.

For example, Lymphocyte T-Cell Immune Modulator in- An avian-adapted, highly pathogenic strain of H5N1 hibits viral growth in the murine model of influenza.[211] (called HPAI A(H5N1), for “highly pathogenic avian influenza virus of type A of subtype H5N1”) causes H5N1 flu, commonly known as “avian influenza” or simply “bird flu”, and is endemic in many bird populations, especially 1.11 Other animals in Southeast Asia. This Asian lineage strain of HPAI A(H5N1) is spreading globally. It is epizootic (an epiFurther information: Influenzavirus A, H5N1, and demic in non-humans) and panzootic (a disease affectTransmission and infection of H5N1 ing animals of many species, especially over a wide area), killing tens of millions of birds and spurring the culling Influenza infects many animal species, and transfer of of hundreds of millions of other birds in an attempt to viral strains between species can occur. Birds are control its spread. Most references in the media to “bird most references to H5N1 are about this specific thought to be the main animal reservoirs of influenza flu” and [219][220] strain.

[212] viruses.

Sixteen forms of hemagglutinin and nine forms of neuraminidase have been identified. All known subtypes (HxNy) are found in birds, but many subtypes are endemic in humans, dogs, horses, and pigs; populations of camels, ferrets, cats, seals, mink, and whales also show evidence of prior infection or exposure to influenza.[47] Variants of flu virus are sometimes named according to the species the strain is endemic in or adapted to. The main variants named using this convention are: bird flu, human flu, swine flu, horse flu and dog flu. (Cat flu generally refers to feline viral rhinotracheitis or feline calicivirus and not infection from an influenza virus.) In pigs, horses and dogs, influenza symptoms are similar to humans, with cough, fever and loss of appetite.[47] The frequency of animal diseases are not

At present, HPAI A(H5N1) is an avian disease, and there is no evidence suggesting efficient human-to-human transmission of HPAI A(H5N1). In almost all cases, those infected have had extensive physical contact with infected birds.[221] In the future, H5N1 may mutate or reassort into a strain capable of efficient human-to-human transmission. The exact changes that are required for this to happen are not well understood.[222] However, due to the high lethality and virulence of H5N1, its endemic presence, and its large and increasing biological host reservoir, the H5N1 virus was the world’s pandemic threat in the 2006–07 flu season, and billions of dollars are being raised and spent researching H5N1 and preparing for a potential influenza pandemic.[198]

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[197] Poland G (2006). “Vaccines against avian influenza—a race against time” (PDF). N Engl J Med. 354 (13): 1411– [185] Valleron AJ, Cori A, Valtat S, Meurisse S, Carrat 3. PMID 16571885. doi:10.1056/NEJMe068047.

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1.14. EXTERNAL LINKS

1.13 Further reading 1.14 External links • Influenza at DMOZ • Seasonal Influenza at the Centre for Health Protection in Hong Kong • Info on influenza at CDC • Fact Sheet Overview of influenza at World Health Organization

23

Chapter 2

''Influenza A virus’' Influenza A virus causes influenza in birds and some mammals, and is the only species of influenza virus A. Influenza virus A is a genus of the Orthomyxoviridae family of viruses. Strains of all subtypes of influenza A virus have been isolated from wild birds, although disease is uncommon. Some isolates of influenza A virus cause severe disease both in domestic poultry and, rarely, in humans.[1] Occasionally, viruses are transmitted from wild aquatic birds to domestic poultry, and this may cause an outbreak or give rise to human influenza pandemics.[2][3]

Different influenza viruses encode for different hemagglutinin and neuraminidase proteins. For example, the H5N1 virus designates an influenza A subtype that has a type 5 hemagglutinin (H) protein and a type 1 neuraminidase (N) protein. There are 18 known types of hemagglutinin and 11 known types of neuraminidase, so, in theory, 198 different combinations of these proteins are possible.[4][5] Some variants are identified and named according to the isolate they resemble, thus are presumed to share lineage (example Fujian flu virus-like); according to their typical host (example human flu virus); according to their subtype (example H3N2); and according to their deadliness (example LP, low pathogenic). So a flu from a virus similar to the isolate A/Fujian/411/2002(H3N2) is called Fujian flu, human flu, and H3N2 flu.

Influenza A viruses are negative-sense, single-stranded, segmented RNA viruses. The several subtypes are labeled according to an H number (for the type of hemagglutinin) and an N number (for the type of neuraminidase). There are 18 different known H antigens (H1 to H18) and 11 different known N antigens (N1 to N11).[4][5] H17 was isolated from fruit bats in 2012.[6][7] Variants are sometimes named according to the species H18N11 was discovered in a Peruvian bat in 2013.[5] (host) in which the strain is endemic or to which it is Each virus subtype has mutated into a variety of strains adapted. The main variants named using this convention with differing pathogenic profiles; some are pathogenic to are: one species but not others, some are pathogenic to multiple species.

• Bird flu A filtered and purified influenza A vaccine for humans has been developed, and many countries have stockpiled • Human flu it to allow a quick administration to the population in the event of an avian influenza pandemic. Avian influenza is • Swine influenza sometimes called avian flu, and colloquially, bird flu. In 2011, researchers reported the discovery of an antibody • Equine influenza effective against all types of the influenza A virus.[8] • Canine influenza

2.1 Variants and subtypes

Variants have also sometimes been named according to their deadliness in poultry, especially chickens:

Influenza type A viruses are categorized into subtypes based on the type of two proteins on the surface of the viral envelope:

• Low pathogenic avian influenza (LPAI) • Highly pathogenic avian influenza (HPAI), also called deadly flu or death flu

H = hemagglutinin, a protein that causes red blood cells to agglutinate.

N = neuraminidase, an enzyme that cleaves the glycosidic bonds of the monosaccharide, neuraminic acid

Most known strains are extinct strains. For example, the annual flu subtype H3N2 no longer contains the strain that caused the Hong Kong flu.

24

2.3. STRUCTURE AND GENETICS

25

2.2 Annual flu

only H 1, 2 and 3, and N 1 and 2 are commonly found in humans.[19]

Main article: Flu season

The central core of a virion contains the viral genome and other viral proteins that package and protect the genetic material. Unlike the genomes of most organisms (including humans, animals, plants, and bacteria) which are made up of double-stranded DNA, many viral genomes are made up of a different, single-stranded nucleic acid called RNA. Unusually for a virus, though, the influenza type A virus genome is not a single piece of RNA; instead, it consists of segmented pieces of negative-sense RNA, each piece containing either one or two genes which code for a gene product (protein).[16] The term negative-sense RNA just implies that the RNA genome cannot be translated into protein directly; it must first be transcribed to positive-sense RNA before it can be translated into protein products. The segmented nature of the genome allows for the exchange of entire genes between different viral strains.[16]

The annual flu (also called “seasonal flu” or “human flu”) in the U.S. “results in approximately 36,000 deaths and more than 200,000 hospitalizations each year. In addition to this human toll, influenza is annually responsible for a total cost of over $10 billion in the U.S.”[9] The annually updated, trivalent influenza vaccine consists of hemagglutinin (HA) surface glycoprotein components from influenza H3N2, H1N1, and B influenza viruses.[10] Measured resistance to the standard antiviral drugs amantadine and rimantadine in H3N2 has increased from 1% in 1994 to 12% in 2003 to 91% in 2005.

“Contemporary human H3N2 influenza viruses are now endemic in pigs in southern China and can reassort with avian H5N1 viruses in this intermediate host.”[11]

2.2.1

FI6 antibody

FI6, an antibody that targets the hemagglutinin protein, was discovered in 2011. FI6 is the only known antibody effective against all 16 subtypes of the influenza A virus.[12][13][14]

2.3 Structure and genetics See also: H5N1 genetic structure Influenza type A viruses are very similar in structure to influenza viruses types B and C. The virus particle (also called the virion) is 80–120 nanometers in diameter and usually roughly spherical, although some rare filamentous forms can occur.[15] According to researchers, there are more filamentous particles in clinical isolates, whereas laboratory strains consist of more spherical virions.[16] Despite these varied shapes, the virions of all influenza type A viruses are similar in composition. They are all made up of a viral envelope containing two main types of proteins, wrapped around a central core.[16] The two large proteins found on the outside of viral particles are hemagglutinin (HA) and neuraminidase (NA).

HA is a protein that mediates binding of the virion to target cells and entry of the viral genome into the target cell, while NA is involved in the release of progeny virions from infected cells.[17] These proteins are usually the targets for antiviral drugs.[18] Furthermore, they are also the antigen proteins to which a host’s antibodies can bind and trigger an immune response. Influenza type A viruses are categorized into subtypes based on the type of these two proteins on the surface of the viral envelope. There are 16 subtypes of HA and 9 subtypes of NA known, but

The entire Influenza A virus genome is 13,588 bases long and is contained on eight RNA segments that code for 11 proteins:[16] • Segment 1 encodes RNA polymerase subunit (PB2).

• Segment 2 encodes RNA polymerase subunit (PB1) and the PB1-F2 protein, which induces cell death, by using different reading frames from the same RNA segment.

• Segment 3 encodes RNA polymerase subunit (PA); an alternate form of this polymerase can sometimes be made with a change to the reading frame.

• Segment 4 encodes for HA (hemagglutinin). About 500 molecules of hemagglutinin are needed to make one virion. HA determines the extent and severity of a viral infection in a host organism.

• Segment 5 encodes NP, which is a nucleoprotein.

• Segment 6 encodes NA (neuraminidase). About 100 molecules of neuraminidase are needed to make one virion.

• Segment 7 encodes two matrix proteins (M1 and M2) by using different reading frames from the same RNA segment. About 3000 matrix protein molecules are needed to make one virion.

• Segment 8 encodes two distinct non-structural proteins (NS1 and NEP) by using different reading frames from the same RNA segment.

The RNA segments of the viral genome have complementary base sequences at the terminal ends, allowing them to bond to each other with hydrogen bonds.[17] After transcription from negative-sense to positive-sense RNA takes place, the positive-sense RNA strands are capped

26

CHAPTER 2. ''INFLUENZA A VIRUS’'

on the 5’ end by a process called cap snatching. This involves the viral protein NS1 binding to the host cell’s early messenger RNA transcripts. A second viral protein, PA, cleaves the cap from the host’s RNA. The short cap is then added to the influenza positive-sense RNA strands, allowing it to be processed by ribosomes and translated into its protein products.[16] The positive-sense RNA strands also serve for synthesis of negative-sense RNA strands for new virions.[16] The RNA synthesis takes place in the cell nucleus, while the synthesis of proteins takes place in the cytoplasm.

Once the viral proteins are assembled into virions, the assembled virions leave the nucleus and migrate towards the cell membrane.[20] The host cell membrane has patches of viral transmembrane proteins (HA, NA, and M2) and an underlying layer of the M1 protein which assist the assembled virions to budding through the membrane, releasing finished enveloped viruses into the extracellular fluid.[20]

2.4 Multiplicity Reactivation Influenza virus is able to undergo multiplicity reactivation after inactivation by UV radiation,[21][22] or by ionizing radiation.[23] If any of the eight RNA strands that make up the genome contains damage that prevents replication or expression of an essential gene, the virus is not viable when it alone infects a cell (a single infection). However, when two or more damaged viruses infect the same cell (multiple infection), viable progeny viruses can be produced provided each of the eight genomic segments is present in at least one undamaged copy. That is, multiplicity reactivation can occur.

residue) position 627 in the PB2 protein encoded by the PB2 RNA gene. Until H5N1, all known avian influenza viruses had a Glu at position 627, while all human influenza viruses had a lysine.

HA: (hemagglutinin): Avian influenza HA binds alpha 2–3 sialic acid receptors, while human influenza HA binds alpha 2–6 sialic acid receptors. Swine influenza viruses have the ability to bind both types of sialic acid receptors.

“About 52 key genetic changes distinguish avian influenza strains from those that spread easily among people, according to researchers in Taiwan, who analyzed the genes of more than 400 A type flu viruses.”[27] “How many mutations would make an avian virus capable of infecting humans efficiently, or how many mutations would render an influenza virus a pandemic strain, is difficult to predict. We have examined sequences from the 1918 strain, which is the only pandemic influenza virus that could be entirely derived from avian strains. Of the 52 speciesassociated positions, 16 have residues typical for human strains; the others remained as avian signatures. The result supports the hypothesis that the 1918 pandemic virus is more closely related to the avian influenza A virus than are other human influenza viruses.”[28]

Human flu symptoms usually include fever, cough, sore throat, muscle aches, conjunctivitis and, in severe cases, severe breathing problems and pneumonia that may be fatal. The severity of the infection will depend in large part on the state of the infected person’s immune system and if the victim has been exposed to the strain before, Upon infection, influenza virus induces a host re- and is therefore partially immune. sponse involving increased production of reactive oxy- Highly pathogenic H5N1 avian influenza in a human is gen species, and this can damage the virus genome.[24] If, far worse, killing 50% of humans who catch it. In one under natural conditions, virus survival is ordinarily vul- case, a boy with H5N1 experienced diarrhea followed nerable to the challenge of oxidative damage, then mul- rapidly by a coma without developing respiratory or flutiplicity reactivation is likely selectively advantageous as like symptoms.[29] a kind of genomic repair process. It has been suggested The influenza A virus subtypes that have been confirmed that multiplicity reactivation involving segmented RNA in humans, ordered by the number of known human pangenomes may be similar to the earliest evolved form of demic deaths, are: sexual interaction in the RNA world that likely preceded the DNA world.[25] (Also see RNA world hypothesis.)

• H1N1 caused "Spanish flu" and the 2009 swine flu outbreak

2.5 Human influenza virus

• H2N2 caused "Asian flu" in the late 1950s

“Human influenza virus” usually refers to those subtypes that spread widely among humans. H1N1, H1N2, and H3N2 are the only known influenza A virus subtypes currently circulating among humans.[26]

• H3N2 caused "Hong Kong flu" in the late 1960s

Genetic factors in distinguishing between “human flu viruses” and “avian influenza viruses” include:

• H7N7 has unusual zoonotic potential

PB2: (RNA polymerase): Amino acid (or

• H5N1 considered a global influenza pandemic threat through its spread in the mid-2000s

• H1N2 is currently endemic in humans and pigs • H9N2, H7N2, H7N3, H5N2, and H10N7.

2.5. HUMAN INFLUENZA VIRUS H1N1

27 H5N1 is the world’s major influenza pandemic threat.

Main article: Influenza A virus subtype H1N1

H1N1 is currently pandemic in both human and pig populations. A variant of H1N1 was responsible for the Spanish flu pandemic that killed some 50 million to 100 million people worldwide over about a year in 1918 and 1919.[30] Another variant was named a pandemic threat in the 2009 flu pandemic. Controversy arose in October, 2005, after the H1N1 genome was published in the journal, Science, because of fears that this information could be used for bioterrorism.

H2N2 Main article: Influenza A virus subtype H2N2

The Asian flu, a pandemic outbreak of H2N2 avian influenza, originated in China in 1957, spread worldwide that same year during which a influenza vaccine was developed, lasted until 1958 and caused between one and four million deaths.

H3N2 Main article: Influenza A virus subtype H3N2

“When he compared the 1918 virus with today’s human flu viruses, Dr. Taubenberger noticed that it had alterations in just 25 to 30 of the virus’s 4,400 amino acids. Those few changes turned a bird virus into a killer that could spread from person to person.”[34] H7N7 Main article: Influenza A virus subtype H7N7

H7N7 has unusual zoonotic potential. In 2003 in Netherlands, 89 people were confirmed to have H7N7 influenza virus infection following an outbreak in poultry on several farms. One death was recorded.

H7N9 Main article: Influenza A virus subtype H7N9

On 2 April 2013, the Centre for Health Protection (CHP) of the Department of Health of Hong Kong confirmed four more cases in Jiangsu province in addition to the three cases initially reported on 31 March 2013.[35] H1N2

H3N2 is currently endemic in both human and pig populations. It evolved from H2N2 by antigenic shift and caused the Hong Kong flu pandemic of 1968 and 1969 that killed up to 750,000.[31] “An early-onset, severe form of influenza A H3N2 made headlines when it claimed the lives of several children in the United States in late 2003.”[32] The dominant strain of annual flu in January 2006 was H3N2. Measured resistance to the standard antiviral drugs amantadine and rimantadine in H3N2 increased from 1% in 1994 to 12% in 2003 to 91% in 2005.[33]

Main article: Influenza A virus subtype H1N2

H1N2 is currently endemic in both human and pig populations. The new H1N2 strain appears to have resulted from the reassortment of the genes of the currently circulating influenza H1N1 and H3N2 subtypes. The hemagglutinin protein of the H1N2 virus is similar to that of the currently circulating H1N1 viruses, and the neuraminidase protein is similar to that of the current H3N2 viruses.

H9N2

"[C]ontemporary human H3N2 influenza viruses are now endemic in pigs in southern China and can reassort with avian H5N1 viruses in this intermediate host.”[11] H5N1 Main article: Influenza A virus subtype H5N1

Main article: Influenza A virus subtype H9N2

Low pathogenic avian influenza A (H9N2) infection was confirmed in 1999, in China and Hong Kong in two children, and in 2003 in Hong Kong in one child. All three fully recovered.[36]

28

CHAPTER 2. ''INFLUENZA A VIRUS’'

H7N2 Main article: Influenza A virus subtype H7N2

One person in New York in 2003 and one person in Virginia in 2002 were found to have serologic evidence of infection with H7N2.

Both fully recovered.[36] H7N3 Main article: Influenza A virus subtype H7N3

In North America, the presence of avian influenza strain H7N3 was confirmed at several poultry farms in British Columbia in February 2004. As of April 2004, 18 farms had been quarantined to halt the spread of the virus.

Two cases of humans with avian influenza have been confirmed in that region. “Symptoms included conjunctivitis and mild influenza-like illness.”[37] Both fully recovered.

H5N2 Main article: Influenza A virus subtype H5N2

Japan’s Health Ministry said January 2006 that poultry farm workers in Ibaraki prefecture may have been exposed to H5N2 in 2005.[38] The H5N2 antibody titers of paired sera of 13 subjects increased fourfold or more.[39] H10N7 Main article: Influenza A virus subtype H10N7

In 2004 in Egypt, H10N7 was reported for the first time in humans. It caused illness in two infants in Egypt. One child’s father was a poultry merchant.[40]

2.5.1

Evolution

H1N1 viruses and reassorted H2N2 and H3N2 viruses. The latter are composed of key genes from the 1918 virus, updated by subsequently incorporated avian influenza genes that code for novel surface proteins, making the 1918 virus indeed the “mother” of all pandemics.”[41] Researchers from the National Institutes of Health used data from the Influenza Genome Sequencing Project and concluded that during the ten-year period examined, most of the time the hemagglutinin gene in H3N2 showed no significant excess of mutations in the antigenic regions while an increasing variety of strains accumulated. This resulted in one of the variants eventually achieving higher fitness, becoming dominant, and in a brief interval of rapid evolution, rapidly sweeping through the population and eliminating most other variants.[42] In the short-term evolution of influenza A virus, a 2006 study found that stochastic, or random, processes are key factors.[43] Influenza A virus HA antigenic evolution appears to be characterized more by punctuated, sporadic jumps as opposed to a constant rate of antigenic change.[44] Using phylogenetic analysis of 413 complete genomes of human influenza A viruses that were collected throughout the state of New York, the authors of Nelson et al. 2006 were able to show that genetic diversity, and not antigenic drift, shaped the short-term evolution of influenza A via random migration and reassortment.

The evolution of these viruses is dominated more by the random importation of genetically different viral strains from other geographic locations and less by natural selection. Within a given season, adaptive evolution is infrequent and had an overall weak effect as evidenced from the data gathered from the 413 genomes. Phylogenetic analysis revealed the different strains were derived from newly imported genetic material as opposed to isolates that had been circulating in New York in previous seasons. Therefore, the gene flow in and out of this population, and not natural selection, was more important in the short term.

2.6 Other animals See H5N1 for the current epizootic (an epidemic in nonhumans) and panzootic (a disease affecting animals of many species especially over a wide area) of H5N1 influenza

Taubenberger says: “All influenza A pandemics since [the Spanish flu pandemic], and indeed almost all cases of influenza A worldwide (excepting human infections from avian viruses such as H5N1 and H7N7), have been caused by descendants of the 1918 virus, including “drifted”

Avian influenza Main article: Avian influenza Fowl act as natural asymptomatic carriers of influenza A viruses. Prior to the current H5N1 epizootic, strains

2.6. OTHER ANIMALS

29

of influenza A virus had been demonstrated to be transmitted from wild fowl to only birds, pigs, horses, seals, whales and humans; and only between humans and pigs and between humans and domestic fowl; and not other pathways such as domestic fowl to horse.[45]

into the pig population and caused widespread disease among pigs. Most recently, H3N8 viruses from horses have crossed over and caused outbreaks in dogs.”[51]

H5N1 has been shown to be transmitted to tigers, leopards, and domestic cats that were fed uncooked domestic fowl (chickens) with the virus. H3N8 viruses from horses have crossed over and caused outbreaks in dogs. Laboratory mice have been infected successfully with a variety of avian flu genotypes.[46]

2004: In North America, the presence of avian influenza strain H7N3 was confirmed at several poultry farms in British Columbia in February 2004. As of April 2004, 18 farms had been quarantined to halt the spread of the virus.[37]

2000: “In California, poultry producers kept their knowledge of a recent H6N2 avian influenza outbreak to themWild aquatic birds are the natural hosts for a large variety selves due to their fear of public rejection of poultry prodof influenza A viruses. Occasionally, viruses are trans- ucts; meanwhile, the disease spread across the western mitted from these birds to other species and may then United States and has since become endemic.”[52] cause devastating outbreaks in domestic poultry or give 2003: In Netherlands H7N7 influenza virus infection rise to human influenza pandemics.[2][3] broke out in poultry on several farms.[53]

Influenza A viruses spread in the air and in manure, and survives longer in cold weather. It can also be transmitted by contaminated feed, water, equipment and clothing; however, there is no evidence the virus can survive in well-cooked meat. Symptoms in animals vary, but virulent strains can cause death within a few days.

2005: Tens of millions of birds died of H5N1 influenza and hundreds of millions of birds were culled to protect humans from H5N1. H5N1 is endemic in birds in southeast Asia and represents a long-term pandemic threat.

2006: H5N1 spreads across the globe, killing hundreds of millions of birds and over 100 people, and causing a significant H5N1 impact from both actual deaths and pre“Highly pathogenic avian influenza virus is on every dicted possible deaths. top ten list available for potential agricultural bioweapon agents”.[47] Swine flu Avian influenza viruses that the OIE and others test for to control poultry disease include: H5N1, H7N2, H1N7, Main article: Swine influenza H7N3, H13N6, H5N9, H11N6, H3N8, H9N2, H5N2, H4N8, H10N7, H2N2, H8N4, H14N5, H6N5, H12N5 and others.

Swine influenza (or “pig influenza”) refers to a subset of Orthomyxoviridae that create inKnown outbreaks of highly pathogenic flu in poultry fluenza and are endemic in pigs. The species 1959–2003[48] of Orthomyxoviridae that can cause flu in pigs are influenza A virus and influenza C virus, but not all genotypes of these two species infect *Outbreaks with significant spread to numerous farms, resulting pigs. The known subtypes of influenza A virus in great economic losses. Most other outbreaks involved little or that create influenza and are endemic in pigs no spread from the initially infected farms. are H1N1, H1N2, H3N1 and H3N2.

1979: “More than 400 harbor seals, most of them immature, died along the New England coast between December 1979 and October 1980 of acute pneumo- Horse flu nia associated with influenza virus, A/Seal/Mass/1/180 Main article: Equine influenza (H7N7).”[49] 1995: "[V]accinated birds can develop asymptomatic infections that allow virus to spread, mutate, and recombine (ProMED-mail, 2004j). Intensive surveillance is required to detect these “silent epidemics” in time to curtail them. In Mexico, for example, mass vaccination of chickens against epidemic H5N2 influenza in 1995 has had to continue in order to control a persistent and evolving virus (Lee et al., 2004).”[50]

Horse flu (or “equine influenza”) refers to varieties of influenza A virus that affect horses.

Horse flu viruses were only isolated in 1956.

The two main types of virus are called equine1 (H7N7), which commonly affects horse heart muscle, and equine-2 (H3N8), which is usually more severe.

1997: “Influenza A viruses normally seen in one species sometimes can cross over and cause illness in another Dog flu species. For example, until 1997, only H1N1 viruses circulated widely in the U.S. pig population. However, Main article: Canine influenza in 1997, H3N2 viruses from humans were introduced

30

CHAPTER 2. ''INFLUENZA A VIRUS’' Dog flu (or “canine influenza”) refers to varieties of influenza A virus that affect dogs. The equine influenza virus H3N8 was found to infect and kill – with respiratory illness – greyhound race dogs at a Florida racetrack in January 2004.

H3N8 Main article: Influenza A virus subtype H3N8 H3N8 is now endemic in birds, horses and dogs.

2.7 See also • FI6 (antibody) • Influenza vaccine • Veterinary virology

2.8 Notes [1] “Avian influenza (" bird flu”) — Fact sheet”. WHO. [2] Klenk, Hans-Dieter; Matrosovich, Mikhail; Stech, Jürgen (2008). “Avian Influenza: Molecular Mechanisms of Pathogenesis and Host Range”. In Mettenleiter, Thomas C.; Sobrino, Francisco. Animal Viruses: Molecular Biology. Caister Academic Press. ISBN 978-1-904455-22-6.

[8] Gallagher, James (29 July 2011). "'Super antibody' fights off flu”. BBC News. Retrieved 29 July 2011.

[9] whitehouse.gov Archived 9 January 2009 at the Wayback Machine. National Strategy for Pandemic Influenza — Introduction — “Although remarkable advances have been made in science and medicine during the past century, we are constantly reminded that we live in a universe of microbes – viruses, bacteria, protozoa and fungi that are forever changing and adapting themselves to the human host and the defenses that humans create. Influenza viruses are notable for their resilience and adaptability. While science has been able to develop highly effective vaccines and treatments for many infectious diseases that threaten public health, acquiring these tools is an ongoing challenge with the influenza virus. Changes in the genetic makeup of the virus require us to develop new vaccines on an annual basis and forecast which strains are likely to predominate. As a result, and despite annual vaccinations, the U.S. faces a burden of influenza that results in approximately 36,000 deaths and more than 200,000 hospitalizations each year. In addition to this human toll, influenza is annually responsible for a total cost of over $10 billion in the U.S. A pandemic, or worldwide outbreak of a new influenza virus, could dwarf this impact by overwhelming our health and medical capabilities, potentially resulting in hundreds of thousands of deaths, millions of hospitalizations, and hundreds of billions of dollars in direct and indirect costs. This Strategy will guide our preparedness and response activities to mitigate that impact.”

[6] “Unique new flu virus found in bats”. NHS Choices. 1 March 2012. Retrieved 16 May 2012.

[10] Daum LT, Shaw MW, Klimov AI, Canas LC, Macias EA, Niemeyer D, Chambers JP, Renthal R, Shrestha SK, Acharya RP, Huzdar SP, Rimal N, Myint KS, Gould P (August 2005). “Influenza A (H3N2) outbreak, Nepal”.

Emerging Infect. Dis. 11 (8): 1186–91. PMC 3320503 . PMID 16102305. doi:10.3201/eid1108.050302.

“The 2003–2004 influenza season was severe in terms of its impact on illness because of widespread circulation of antigenically distinct influenza A (H3N2) Fujian-like viruses. These viruses first appeared late during the 2002– 2003 influenza season and continued to persist as the dominant circulating strain throughout the subsequent 2003– 2004 influenza season, replacing the A/Panama/2007/99like H3N2 viruses (1). Of the 172 H3N2 viruses genetically characterized by the Department of Defense in 2003–2004, only one isolate (from Thailand) belonged to the A/Panama-like lineage. In February 2003, the World Health Organization (WHO) changed the H3N2 component for the 2004–2005 influenza vaccine to afford protection against the widespread emergence of Fujian-like viruses (2). The annually updated trivalent vaccine consists of hemagglutinin (HA) surface glycoprotein components from influenza H3N2, H1N1, and B viruses.”

[7] Tong S, Li Y, Rivailler P, Conrardy C, Castillo DA, Chen LM, Recuenco S, Ellison JA, Davis CT, York IA, Turmelle AS, Moran D, Rogers S, Shi M, Tao Y, Weil MR, Tang K, Rowe LA, Sammons S, Xu X, Frace M, Lindblade KA, Cox NJ, Anderson LJ, Rupprecht CE, Donis RO (2012). “A distinct lineage of influenza A virus from bats”. Proc. Natl. Acad. Sci. U.S.A. 109 (11): 4269–74. PMC 3306675 . PMID 22371588. doi:10.1073/pnas.1116200109.

[11] Mahmoud 2005, p. 126 “H5N1 virus is now endemic in poultry in Asia (Table 2-1) and has gained an entrenched ecological niche from which to present a long-term pandemic threat to humans. At present, these viruses are poorly transmitted from poultry to humans, and there is no conclusive evidence of humanto-human transmission. However, continued, extensive exposure of the human population to H5N1 viruses increases the likelihood that the viruses will acquire the nec-

[3] Kawaoka Y, ed. (2006). Influenza Virology: Current Topics. Caister Academic Press. ISBN 1-904455-06-9.

[4] “Influenza Type A Viruses and Subtypes”. Centers for Disease Control and Prevention. 2 April 2013. Retrieved 13 June 2013.

[5] Tong S, Zhu X, Li Y, Shi M, Zhang J, Bourgeois M, Yang H, Chen X, Recuenco S, Gomez J, Chen LM, Johnson A, Tao Y, Dreyfus C, Yu W, McBride R, Carney PJ, Gilbert AT, Chang J, Guo Z, Davis CT, Paulson JC, Stevens J, Rupprecht CE, Holmes EC, Wilson IA, Donis RO (October 2013). “New World Bats Harbor Diverse Influenza A Viruses”. PLoS Pathogens. 9 (10): e1003657. PMC 3794996 . PMID 24130481. doi:10.1371/journal.ppat.1003657.

2.8. NOTES

essary characteristics for efficient human-to-human transmission through genetic mutation or reassortment with a prevailing human influenza A virus. Furthermore, contemporary human H3N2 influenza viruses are now endemic in pigs in southern China (Peiris et al., 2001) and can reassort with avian H5N1 viruses in this 'intermediate host.' Therefore, it is imperative that outbreaks of H5N1 disease in poultry in Asia are rapidly and sustainably controlled. The seasonality of the disease in poultry, together with the control measures already implemented, are likely to reduce temporarily the frequency of H5N1 influenza outbreaks and the probability of human infection.”

[12] Gallagher, James (29 July 2011). "'Super antibody' fights off flu” – via www.bbc.co.uk.

[13] “Scientists hail the prospect of a universal vaccine for flu”.

29 July 2011.

[14] Chan, Amanda L. (28 July 2011). “Universal Flu Vaccine On The Horizon: Researchers Find 'Super Antibody'" – via Huff Post.

[15] Lamb, R.A & Choppin, P.W. The gene structure and replication of influenza virus. Annu. Rev. Biochem. 52, 467–506 (1985) [16] Bouvier NM, Palese P (2008).

“The biology of influenza viruses”.

Vaccine.

26 Suppl 4: D49–53.

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PMID 19230160. doi:10.1016/j.vaccine.2008.07.039.

[17] Suzuki Y (2005). “Sialobiology of influenza: molecular mechanism of host range variation of influenza viruses”.

Biol. Pharm. Bull. 28 (3): 399–408. PMID 15744059. doi:10.1248/bpb.28.399.

[18] Wilson JC, von Itzstein M (2003). “Recent strategies in the search for new anti-influenza therapies”. Curr Drug Targets. 4 (5): 389–408. PMID 12816348. doi:10.2174/1389450033491019.

[19] Lynch JP, Walsh EE (2007). “Influenza: evolving strategies in treatment and prevention”. Semin Respir Crit Care Med. 28 (2): 144–58. PMID 17458769. doi:10.1055/s2007-976487.

[20] Smith AE, Helenius A (2004). “How viruses enter animal cells”. Science. 304 (5668): 237–42. PMID 15073366. doi:10.1126/science.1094823.

[21] Barry RD (August 1961). “The multiplication of influenza virus. II. Multiplicity reactivation of ultraviolet irradiated virus”. Virology. 14 (4): 398–405. PMID 13687359. doi:10.1016/0042-6822(61)90330-0.

[22] Henle W, Liu OC (October 1951). “Studies on host-virus interactions in the chick embryo-influenza virus system.

VI. Evidence for multiplicity reactivation of inactivated virus”. J. Exp. Med. 94 (4): 305–22. PMC 2136114 .

PMID 14888814. doi:10.1084/jem.94.4.305.

[23] Gilker JC, Pavilanis V, Ghys R (June 1967). “Multiplicity reactivation in gamma irradiated influenza viruses”.

PMID 6066111.

Nature.

214 (5094): 1235–7. doi:10.1038/2141235a0.

31

[24] Peterhans E (May 1997). “Oxidants and antioxidants in viral diseases: disease mechanisms and metabolic regulation”. J. Nutr. 127 (5 Suppl): 962S–965S. PMID 9164274.

[25] Bernstein H, Byerly HC, Hopf FA, Michod RE (October 1984). “Origin of sex”. J. Theor. Biol. 110 (3): 323–51.

PMID 6209512. doi:10.1016/S0022-5193(84)80178-2.

[26] CDC Key Facts About Avian Influenza (Bird Flu) and Avian Influenza A (H5N1) Virus [27] Bloomberg News article Scientists Move Closer to Understanding Flu Virus Evolution published 28 August 2006 [28] Chen GW, Chang SC, Mok CK, Lo YL, Kung YN, Huang JH, Shih YH, Wang JY, Chiang C, Chen CJ, Shih SR (September 2006). “Genomic signatures of human versus avian influenza A viruses”. Emerging Infect. Dis. 12 (9): 1353–60. PMC 3294750 . PMID 17073083. doi:10.3201/eid1209.060276.

[29] de Jong MD, Bach VC, Phan TQ, Vo MH, Tran TT, Nguyen BH, Beld M, Le TP, Truong HK, Nguyen VV, Tran TH, Do QH, Farrar J (February 2005). “Fatal avian influenza A (H5N1) in a child presenting with diarrhea followed by coma”. N. Engl. J. Med. 352 (7): 686–91.

PMID 15716562. doi:10.1056/NEJMoa044307.

[30] Mahmoud 2005, p. 7 [31] Detailed chart of its evolution here at PDF called Ecology and Evolution of the Flu [32] Mahmoud 2005, p. 115 “There is particular pressure to recognize and heed the lessons of past influenza pandemics in the shadow of the worrisome 2003–2004 flu season. An early-onset, severe form of influenza A H3N2 made headlines when it claimed the lives of several children in the United States in late 2003. As a result, stronger than usual demand for annual flu inactivated vaccine outstripped the vaccine supply, of which 10 to 20 percent typically goes unused. Because statistics on pediatric flu deaths had not been collected previously, it is unknown if the 2003–2004 season witnessed a significant change in mortality patterns.”

[33] Reason Archived 26 October 2006 at the Wayback Machine. New York Times This Season’s Flu Virus Is Resistant to 2 Standard Drugs By Altman Published: 15 January 2006 [34] New York Times Published: 8 November 2005 — Hazard in Hunt for New Flu: Looking for Bugs in All the Wrong Places [35] Schnirring, Lisa (2 April 2013). “China reports 4 more H7N9 infections”. CIDRAP News.

[36] CDC Avian Influenza Infection in Humans [37] Tweed SA, Skowronski DM, David ST, Larder A, Petric M, Lees W, Li Y, Katz J, Krajden M, Tellier R, Halpert C, Hirst M, Astell C, Lawrence D, Mak A (December 2004). “Human illness from avian influenza H7N3, British Columbia”. Emerging Infect. Dis. 10 (12): 2196–9. PMC 3323407 . PMID 15663860. doi:10.3201/eid1012.040961.

32

CHAPTER 2. ''INFLUENZA A VIRUS’'

[38] CBS News article Dozens In Japan May Have Mild Bird Flu January 2006.

current vaccination strategies are adequate against a 1918like virus (Tumpey et al., 2004).”

[39] Ogata T, Yamazaki Y, Okabe N, Nakamura Y, Tashiro M, Nagata N, Itamura S, Yasui Y, Nakashima K, Doi M, Izumi Y, Fujieda T, Yamato S, Kawada Y (July 2008).

“Human H5N2 Avian Influenza Infection in Japan and the Factors Associated with High H5N2-Neutralizing Antibody Titer” (PDF). J Epidemiol. 18 (4): 160–6. PMID 18603824. doi:10.2188/jea.JE2007446.

[47] Mahmoud 2005, p. 285 “As of October 2001, the potential for use of infectious agents, such as anthrax, as weapons has been firmly established. It has been suggested that attacks on a nation’s agriculture might be a preferred form of terrorism or economic disruption that would not have the attendant stigma of infecting and causing disease in humans. Highly pathogenic avian influenza virus is on every top ten list available for potential agricultural bioweapon agents, generally following foot and mouth disease virus and Newcastle disease virus at or near the top of the list. Rapid detection techniques for bioweapon agents are a critical need for the first-responder community, on a par with vaccine and antiviral development in preventing spread of disease.”

[40] niaid.nih.gov Timeline of Human Flu Pandemics [41] Taubenberger JK, Morens DM (January 2006). “1918 Influenza: the mother of all pandemics”. Emerging Infect.

Dis. 12 (1): 15–22. PMC 3291398 . PMID 16494711. doi:10.3201/eid1201.050979. Archived from the original on 1 October 2009.

[42] Science Daily article New Study Has Important Implications For Flu Surveillance published 27 October 2006 [43] Nelson MI, Simonsen L, Viboud C, Miller MA, Taylor J, George KS, Griesemer SB, Ghedin E, Ghedi E, Sengamalay NA, Spiro DJ, Volkov I, Grenfell BT, Lipman DJ, Taubenberger JK, Holmes EC (2006).

“Stochastic processes are key determinants of shortterm evolution in influenza a virus”. PLoS Pathog. 2 (12): e125. PMC 1665651 . PMID 17140286. doi:10.1371/journal.ppat.0020125.

[44] Smith DJ, Lapedes AS, de Jong JC, Bestebroer TM, Rimmelzwaan GF, Osterhaus AD, Fouchier RA (July 2004).

“Mapping the Antigenic and Genetic Evolution of Influenza Virus”. Science. 305 (5682): 371–376. PMID 15218094. doi:10.1126/science.1097211.

[45] Mahmoud 2005, p. 30 [46] Mahmoud 2005, p. 82 “Interestingly, recombinant influenza viruses containing the 1918 HA and NA and up to three additional genes derived from the 1918 virus (the other genes being derived from the A/WSN/33 virus) were all highly virulent in mice (Tumpey et al., 2004). Furthermore, expression microarray analysis performed on whole lung tissue of mice infected with the 1918 HA/ NA recombinant showed increased upregulation of genes involved in apoptosis, tissue injury, and oxidative damage (Kash et al., 2004). These findings were unusual because the viruses with the 1918 genes had not been adapted to mice. The completion of the sequence of the entire genome of the 1918 virus and the reconstruction and characterization of viruses with 1918 genes under appropriate biosafety conditions will shed more light on these findings and should allow a definitive examination of this explanation. Antigenic analysis of recombinant viruses possessing the 1918 HA and NA by hemagglutination inhibition tests using ferret and chicken antisera suggested a close relationship with the A/swine/Iowa/30 virus and H1N1 viruses isolated in the 1930s (Tumpey et al., 2004), further supporting data of Shope from the 1930s (Shope, 1936). Interestingly, when mice were immunized with different H1N1 virus strains, challenge studies using the 1918-like viruses revealed partial protection by this treatment, suggesting that

[48] “Avian influenza A(H5N1)- update 31: Situation (poultry) in Asia: need for a long-term response, comparison with previous outbreaks”. Epidemic and Pandemic Alert and Response (EPR). WHO. 2004.

Known outbreaks of highly pathogenic flu in poultry 1959–2003.

[49] Geraci JR, St Aubin DJ, Barker IK, Webster RG, Hinshaw VS, Bean WJ, Ruhnke HL, Prescott JH, Early G, Baker AS, Madoff S, Schooley RT (February 1982). “Mass mortality of harbor seals: pneumonia associated with influenza A virus”. Science. 215 (4536): 1129–31. PMID 7063847. doi:10.1126/science.7063847. More than 400 harbor seals, most of them immature, died along the New England coast between December 1979 and October 1980 of acute pneumonia associated with influenza virus, A/Seal/Mass/1/180 (H7N7). The virus has avian characteristics, replicates principally in mammals, and causes mild respiratory disease in experimentally infected seals.

Concurrent infection with a previously undescribed mycoplasma or adverse environmental conditions may have triggered the epizootic. The similarities between this epizootic and other seal mortalities in the past suggest that these events may be linked by common biological and environmental factors.

[50] Mahmoud 2005, p. 15 “Unlike most other affected countries, Indonesia also instituted mass vaccination of healthy domestic birds against H5N1, followed by routine vaccination (China has a similar policy; other Asian countries are considering it [ProMED-mail, 2004j]) (Soebandrio, 2004). This is a risky strategy, because vaccinated birds can develop asymptomatic infections that allow virus to spread, mutate, and recombine (ProMED-mail, 2004j). Intensive surveillance is required to detect these “silent epidemics” in time to curtail them. In Mexico, for example, mass vaccination of chickens against epidemic H5N2 influenza in 1995 has had to continue in order to control a persistent and evolving virus (Lee et al., 2004).”

[51] CDC Centers for Disease Control and Prevention — Transmission of Influenza A Viruses Between Animals and People [52] Mahmoud 2005, p. 27

2.10. EXTERNAL LINKS

[53] BBC News Early bird flu warning for Dutch — 6 November 2005

2.9 Further reading Official sources Further information: H5N1

• Avian influenza and Influenza Pandemics from the Centers for Disease Control and Prevention • Avian influenza FAQ from the World Health Organization • Avian influenza information from the Food and Agriculture Organization • U.S. Government’s avian influenza information website • European Centre for Disease Prevention and Control (ECDC) Stockholm, Sweden

33 • Mahmoud 2005, p. 285 “Highly pathogenic avian influenza virus is on every top ten list available for potential agricultural bioweapon agents” • Mahmoud, Adel A. F; Institute of Medicine; Knobler, Stacey; Mack, Alison (2005). The Threat of Pandemic Influenza: Are We Ready?: Workshop Summary. Washington, D.C: National Academies Press. ISBN 0-309-09504-2.

• 'The Threat of Bird Flu': HealthPolitics.com • Is a Global Flu Pandemic Imminent? from Infection Control Today.

• Bird Flu is a Real Pandemic Threat to Humans by Leonard Crane, author of Ninth Day of Creation.

• Links to Bird Flu pictures (Hardin MD/Univ of Iowa) • Yoshihiro Kawaoka (2006). Influenza Virology: Current Topics. Caister Academic Pr. ISBN 1904455-06-9.

• Francisco Sobrino; Thomas Mettenleiter (2008).

Animal Viruses: Molecular Biology. Caister Academic Pr. ISBN 1-904455-22-0.

General information Further information: Flu

• “The Bird Flu and You” Full-color poster provided by the Center for Technology and National Security Policy at the National Defense University, in collaboration with the National Security Health Policy Center • Influenza Report 2006 Online book. Research level quality information. Highly recommended.

• Special issue on avian flu from Nature • Nature Reports: Homepage: Avian Flu • Beigel JH, Farrar J, Han AM, Hayden FG, Hyer R, de Jong MD, Lochindarat S, Nguyen TK, Nguyen TH, Tran TH, Nicoll A, Touch S, Yuen KY (September 2005). “Avian influenza A (H5N1) infection in humans”. N. Engl. J. Med. 353 (13): 1374–85. PMID 16192482. doi:10.1056/NEJMra052211.

• Pandemic Influenza: Domestic Preparedness Efforts Congressional Research Service Report on Pandemic Preparedness.

• A guide to bird flu and its symptoms from BBC Health • A Variety of Avian Flu Images and Pictures

2.10 External links • Influenza Research Database – Database of influenza genomic sequences and related information.

• Health-EU portal European Union response to influenza

Chapter 3

''Influenzavirus B'' Influenzavirus B is a genus in the virus family sidated, each segment in a separate nucleocapsid, and the Orthomyxoviridae. The only species in this genus is called nucleocapsids are surrounded by one envelope.[10] Influenza B virus.

Influenza B viruses are only known to infect humans and seals,[1] giving them influenza.

This limited 3.3 References host and range is apparently responsible for the lack of Influenzavirus B-caused influenza pandemics 3.3.1 Sources and notes in contrast with those caused by the morphologically similar Influenzavirus A as both mutate by both [1] Osterhaus AD, Rimmelzwaan GF, Martina BE, Bestebroer TM, Fouchier RA (2000). “Influenza B virus in antigenic drift and reassortment.[2][3][4] Currently there seals”. Science. 288 (5468): 1051–3. PMID 10807575. are two co-circulating lineages of the Influenza B doi:10.1126/science.288.5468.1051. virus based on the antigenic properties of the surface glycoprotein hemagglutinin. The lineages are [2] Hay AJ, Gregory V, Douglas AR, Lin YP (2001). termed B/Yamagata/16/88-like and B/Victoria/2/87-like “The evolution of human influenza viruses”.

Phiviruses.[5] The quadrivalent influenza vaccine licensed by los. Trans. R. Soc. Lond., B, Biol. Sci. 356 the CDC is currently designed to protect against both co(1416): 1861–70. PMC 1088562 . PMID 11779385. circulating lineages and has been shown to have greater doi:10.1098/rstb.2001.0999. effectiveness in prevention of influenza caused by in[3] Matsuzaki Y, Sugawara K, Takashita E, Muraki Y, Hongo fluenza B virus than the previous trivalent vaccine.[6] Further diminishing the impact of this virus “in human, influenza B viruses evolve slower than A viruses and faster than C viruses".[7] Influenzavirus B mutates at a rate 2 to 3 times slower than type A.[8] It is currently accepted that influenza B viruses cause significant morbidity and mortality worldwide, and significantly impacts adolescents and schoolchildren.[9]

3.1 Morphology The Influenza B virus capsid is enveloped while its virion consists of an envelope, a matrix protein, a nucleoprotein complex, a nucleocapsid, and a polymerase complex. It is sometimes spherical and sometimes filamentous. Its 500 or so surface projections are made of hemagglutinin and neuraminidase.[10]

3.2 Genome structure The Influenza B virus genome is 14548 nucleotides long and consists of eight segments of linear negative-sense, single-stranded RNA. The multipartite genome is encap34

S, Katsushima N, Mizuta K, Nishimura H (2004). “Genetic diversity of influenza B virus: the frequent reassortment and cocirculation of the genetically distinct reassortant viruses in a community”. J. Med. Virol. 74 (1): 132– 40. PMID 15258979. doi:10.1002/jmv.20156.

[4] Lindstrom SE, Hiromoto Y, Nishimura H, Saito T, Nerome R, Nerome K (1999). “Comparative Analysis of Evolutionary Mechanisms of the Hemagglutinin and Three Internal Protein Genes of Influenza B Virus: Multiple Cocirculating Lineages and Frequent Reassortment of the NP, M, and NS Genes”. J. Virol. 73 (5): 4413–26.

PMC 104222 . PMID 10196339.

[5] Klimov, Alexander I.; Garten, Rebecca; Russell, Colin; Barr, Ian G.; Besselaar, Terry G.; Daniels, Rod; Engelhardt, Othmar G.; Grohmann, Gary; Itamura, Shigeyuki; Kelso, Anne; McCauley, John; Odagiri, Takato; Smith, Derek; Tashiro, Masato; Xu, Xiyan; Webby, Richard; Wang, Dayan; Ye, Zhiping; Yuelong, Shu; Zhang, Wenqing; Cox, Nancy (October 2012). “WHO recommendations for the viruses to be used in the 2012 Southern Hemisphere Influenza Vaccine: Epidemiology, antigenic and genetic characteristics of influenza A(H1N1)pdm09, A(H3N2) and B influenza viruses collected from February to September 2011”. Vaccine. 30 (45): 6461–6471.

PMID 22917957. doi:10.1016/j.vaccine.2012.07.089.

[6] Moa, Aye M.; Chughtai, Abrar A.; Muscatello, David J.; Turner, Robin M.; MacIntyre, C. Raina (July

3.4. EXTERNAL LINKS

2016). “Immunogenicity and safety of inactivated quadrivalent influenza vaccine in adults: A systematic review and meta-analysis of randomised controlled trials”. Vaccine. 34 (35): 4092–4102. PMID 27381642. doi:10.1016/j.vaccine.2016.06.064.

[7] Yamashita M, Krystal M, Fitch WM, Palese P (1988).

“Influenza B virus evolution: co-circulating lineages and comparison of evolutionary pattern with those of influenza A and C viruses”. Virology. 163 (1): 112–22.

PMID 3267218. doi:10.1016/0042-6822(88)90238-3.

[8] Nobusawa E, Sato K (April 2006). “Comparison of the Mutation Rates of Human Influenza A and B Viruses”.

J Virol. 80 (7): 3675–8. PMC 1440390 . PMID 16537638. doi:10.1128/JVI.80.7.3675-3678.2006.

[9] van de Sandt, Carolien E; Bodewes, Rogier; Rimmelzwaan, Guus F; de Vries, Rory D (September 2015).

“Influenza B viruses: not to be discounted”. Future Microbiology. 10 (9): 1447–1465. doi:10.2217/fmb.15.65.

[10] Büchen-Osmond, C. (Ed) (2006). “ICTVdB Virus Description—00.046.0.04. Influenzavirus B”. ICTVdB— The Universal Virus Database, version 4. Columbia University, New York, USA. Retrieved 2007-09-15.

3.4 External links • Influenza Research Database Database of influenza genomic sequences and related information.

• Viralzone: Influenzavirus B • Biere B, Bauer B, Schweiger B (2010).

“Differentiation of influenza B virus lineages Yamagata and Victoria by real-time PCR”. J. Clin.

Microbiol. 48 (4): 1425–7. PMC 2849545 .

PMID 20107085. doi:10.1128/JCM.02116-09.

35

Chapter 4

''Influenzavirus C'' Influenza virus C is a genus in the virus family dren between five and ten years old have already proOrthomyxoviridae, which includes those viruses which duced antibodies for influenza virus C.[8] As with all incause influenza. fluenza viruses, type C affects individuals of all ages, but is most severe in young children, the elderly and individThe species in this genus is called Influenza C virus. In[4][9] Young chil[1] uals with underlying health problems. fluenza C viruses are known to infect humans and pigs. dren have less prior exposure and have not developed Flu due to the type C species is rare compared to types the antibodies and the elderly have less effective imA or B, but can be severe and can cause local epidemics. mune systems.[4] Influenza virus infections have one of Subtype C has 7 RNA segments and encodes 9 proteins, the highest preventable mortalities in many countries of while types A and B have 8 RNA segments and encode the world.[9] at least 10 proteins.

4.1 Influenza C virus Influenza viruses are members of the family Orthomyxoviridae.[2] Influenza viruses A, B and C represent the three antigenic types of influenza viruses.[3] Of the three antigenic types, influenza virus A is the most severe, influenza virus B is less severe but can still cause outbreaks, and influenza virus C is usually only associated with minor symptoms.[4] Influenza virus A can infect a variety of animals as well as humans and its natural host or reservoir is birds whereas influenza viruses B and C do not have animal reservoirs.[4][5] Influenza virus C is not as easily isolated so less information is known of this type, but studies show that it occurs worldwide.[6] This virus may be spread from person to person through respiratory droplets or by fomites (non-living material) due to its ability to survive on surfaces for short durations.[4] Influenza viruses have a relatively short incubation period (lapse of time from exposure to pathogen to the appearance of symptoms) of 18–72 hours and infect the epithelial cells of the respiratory tract.[4] Influenza virus C tends to cause mild upper respiratory infections.[7] Cold-like symptoms are associated with the virus including fever (38-40ᵒC), dry cough, rhinorrhea (nasal discharge), headache, muscle pain, and achiness.[4][8] The virus may lead to more severe infections such as bronchitis and pneumonia.[7] After an individual becomes infected, the immune system develops antibodies against that infectious agent. This is the body’s main source of protection.[4] Most chil-

4.2 Structure and Variation Influenza viruses, like all viruses in the Orthomyxoviridae family, are enveloped RNA viruses with single stranded genomes.[2] The antigens, matrix protein (M1) and nucleoprotein (NP), are used to determine if an influenza virus is type A, B, or C.[4] The M1 protein is required for virus assembly and NP functions in transcription and replication.[10][11] These viruses also contain proteins on the surface of the cell membrane called glycoproteins.

Type A and B have two glycoproteins: hemagglutinin (HA) and neuraminidase (NA). Type C has only one glycoprotein: hemagglutinin-esterase fusion (HEF).[4][12] These glycoproteins allow for attachment and fusion of viral and cellular membranes. Fusion of these membranes allows the viral proteins and genome to be released into the host cell, which then causes the infection.[13] Type C is the only influenza virus to express the enzyme esterase. This enzyme is similar to the enzyme neuraminidase produced by type A and B in that they both function in destroying the host cell receptors.[7] Glycoproteins may undergo mutations (antigenic drift) or reassortment in which a new HA or NA is produced (antigenic shift). Influenza virus C is only capable of antigenic drift whereas type A undergo antigenic shift, as well. When either of these processes occur, the antibodies formed by the immune system no longer protect against these altered glycoproteins. Because of this, viruses continually cause infections.[4]

36

4.5. REFERENCES

4.3 Identification Influenza virus C is different from type A and B in its growth requirements. Because of this it is not isolated and identified as frequently. Diagnosis is by virus isolation, serology, and other tests.[8] Hemagglutination inhibition (HI) is one method of serology that detects antibodies for diagnostic purposes.[6] Western blot (immunoblot assay) and enzyme-linked immunosorbent assay (ELISA) are two other methods used to detect proteins (or antigens) in serum. In each of these techniques, the antibodies for the protein of interest are added and the presence of the specific protein is indicated by a color change.[14] ELISA was shown to have higher sensitivity to the HEF than the HI test.[5] Because only influenza virus C produces esterase, In Situ Esterase Assays provide a quick and inexpensive method of detecting just type C.[7] If more individuals were tested for influenza virus C as well as the other two types, infections not previously associated with type C may be recognized.[7]

4.4 Vaccination Effective and safe vaccines have been developed for influenza viruses.[15] The Center for Disease Control and Prevention (CDC) and the World Health Organization (WHO) are constantly surveying the wild population of viruses. In doing this, they are able to predict which virus strains might cause the most harm each year during flu season. The strains expected to be most harmful are put into the vaccine for that year’s flu vaccine. These vaccines are more commonly known as “flu shots”.[4]

37

4.5 References [1] Guo Y.; Jin F.; Wang P.; Wang M.; Zhu J.M. (1983).

“Isolation of Influenza C Virus from Pigs and Experimental Infection of Pigs with Influenza C Virus”. Journal of General Virology. 64: 177–82. PMID 6296296. doi:10.1099/0022-1317-64-1-177.

[2] Pattison; McMullin; Bradbury; Alexander (2008). Poultry Diseases (6th ed.). Elsevier. p. 317. ISBN 978-0-702028625.

[3] “Seasonal Influenza (Flu)” Centers for Disease Control and Prevention. March 22, 2012. http://www.cdc.gov/ flu/about/viruses/types.htm [4] Margaret Hunt. “Microbiology and Immunology On-line” University of South Carolina School of Medicine. 2009. http://pathmicro.med.sc.edu/mhunt/flu.htm [5] World Health Organization (2006). “Review of latest available evidence on potential transmission of avian influenza (H5H1) through water and sewage and ways to reduce the risks to human health” (PDF).

[6] Manuguerra JC, Hannoun C, Sáenz Mdel C, Villar E, Cabezas JA (1994). “Sero-epidemiological survey of influenza C virus infection in Spain”. Eur. J. Epidemiol. 10 (1): 91–4. PMID 7957798.

[7] Wagaman, Spence & O'Callaghan 1989 [8] Matsuzaki Y, Katsushima N, Nagai Y, Shoji M, Itagaki T, Sakamoto M, Kitaoka S, Mizuta K, Nishimura H (2006).

“Clinical features of influenza C virus infection in children”. J. Infect. Dis. 193 (9): 1229–35. PMID 16586359. doi:10.1086/502973.

[9] Ballada D, Biasio LR, Cascio G, D'Alessandro D, Donatelli I, Fara GM, Pozzi T, Profeta ML, Squarcione S, Riccò D (1994). “Attitudes and behavior of health care personnel regarding influenza vaccination”. Eur. J. Epidemiol. 10 (1): 63–8. PMID 7957793.

Vaccines can use living strains that have been made less harmful or inactive strains. Both forms work by exposing the body to the viral strains within the vac- [10] Ali A, Avalos RT, Ponimaskin E, Nayak DP (2000). cine. As a result, the immune system develops antibodies “Influenza virus assembly: effect of influenza virus glycoproteins on the membrane association of M1 protein”. providing protection from these strains.[3] Studies show that the vaccines containing less harmful forms of living J. Virol. 74 (18): 8709–19. PMC 116382 . PMID strains are more effective in providing immunity.[16] It 10954572. is recommended that all individuals be vaccinated each year, especially health care providers and individuals with [11] Portela A, Digard P (2002). “The influenza virus nucleoprotein: a multifunctional RNA-binding protein pivotal chronic illness, in order to prevent infection from into virus replication”. J. Gen. Virol. 83 (Pt 4): 723–34.

[9][16] Influenza virus vaccines have benfluenza viruses.

PMID 11907320. doi:10.1099/0022-1317-83-4-723. eficial implications to an individual’s health.[16] Because influenza virus A has an animal reservoir that [12] Gao Q, Brydon EW, Palese P (2008). “A sevensegmented influenza A virus expressing the influenza contains all the known subtypes and it can undergo antiJ. Virol.

82 (13): C virus glycoprotein HEF”. genic shift, this type of influenza virus is capable of pro6419–26.

PMC 2447078 .

PMID 18448539.

[5] ducing pandemics. Influenza viruses A and B also cause doi:10.1128/JVI.00514-08. seasonal epidemics every year due to their ability to anti[3] genic shift. Influenza virus C does not have this capa- [13] Weissenhorn W, Dessen A, Calder LJ, Harrison SC, Skebility and it is not thought to be a significant concern hel JJ, Wiley DC (1999). “Structural basis for membrane for human health.[5] Therefore, there are no vaccinations fusion by enveloped viruses”. Mol. Membr. Biol. 16 (1): against influenza virus C.[4] 3–9. PMID 10332732.

38

[14] Nelson, DL; Cox, MM (2013). Principles of Biochemistry (6th ed.). p. 179. ISBN 978-1-4292-3414-6.

[15] Belshe RB, Mendelman PM, Treanor J, King J, Gruber WC, Piedra P, Bernstein DI, Hayden FG, Kotloff K, Zangwill K, Iacuzio D, Wolff M (1998). “The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children”. N. Engl.

PMID 9580647.

J. Med. 338 (20): 1405–12. doi:10.1056/NEJM199805143382002.

[16] Belshe RB, Gruber WC (2001). “Safety, efficacy and effectiveness of cold-adapted, live, attenuated, trivalent, intranasal influenza vaccine in adults and children”. Philos. Trans. R. Soc. Lond., B, Biol. Sci. 356 (1416): 1947–51. PMC 1088573 . PMID 11779396. doi:10.1098/rstb.2001.0982.

4.6 Further reading • Wagaman PC, Spence HA, O'Callaghan RJ (May 1989). “Detection of influenza C virus by using an in situ esterase assay”. J. Clin. Microbiol. 27 (5): 832–6. PMC 267439 . PMID 2745694.

• ICTVdB database for Influenza virus C

4.7 External links • Influenza Research Database Database of influenza genomic sequences and related information.

• Viralzone: Influenza virus C

CHAPTER 4. ''INFLUENZAVIRUS C''

Chapter 5

Influenza A virus subtype H1N1 For the H1N1/09 virus strain responsible for the 2009 flu Swine influenza virus is common throughout pig populapandemic, see Pandemic H1N1/09 virus. For the 1918 tions worldwide. Transmission of the virus from pigs to influenza A(H1N1) pandemic, see 1918 flu pandemic. humans is not common and does not always lead to human influenza, often resulting only in the production of antiInfluenza A (H1N1) virus is the subtype of influenza A bodies in the blood. If transmission does cause human influenza, it is called zoonotic swine flu or a variant virus. virus that was the most common cause of human influenza (flu) in 2009, and is associated with the 1918 outbreak People with regular exposure to pigs are at increased risk of swine flu infection. The meat of an infected animal known as the Spanish Flu. poses no risk of infection when properly cooked.

It is an orthomyxovirus that contains the glycoproteins haemagglutinin and neuraminidase. For this reason, they Pigs experimentally infected with the strain of swine flu are described as H1N1, H1N2 etc. depending on the type that caused the human pandemic of 2009–10 showed of H or N antigens they express with metabolic synergy. clinical signs of flu within four days, and the virus spread [5] Haemagglutinin causes red blood cells to clump together to other uninfected pigs housed with the infected ones. and binds the virus to the infected cell. Neuraminidase During the mid-20th century, identification of influenza are a type of glycoside hydrolase enzyme which help to subtypes became possible, allowing accurate diagnosis of move the virus particles through the infected cell and as- transmission to humans. Since then, only 50 such transsist in budding from the host cells.[1] missions have been confirmed. These strains of swine flu Some strains of H1N1 are endemic in humans and cause rarely pass from human to human. Symptoms of zoonotic swine flu in humans are similar to those of influenza and a small fraction of all influenza-like illness and a small fraction of all seasonal influenza. H1N1 strains caused of influenza-like illness in general, namely chills, fever, sore throat, muscle pains, severe headache, coughing, a small percentage of all human flu infections in 2004– [2] 2005. Other strains of H1N1 are endemic in pigs (swine weakness, and general discomfort. The recommended time of isolation is about five days. influenza) and in birds (avian influenza).

In June 2009, the World Health Organization (WHO) declared the new strain of swine-origin H1N1 as a 5.2 Notable incidents pandemic. This strain is often called swine flu by the public media. This novel virus spread worldwide and had caused about 17,000 deaths by the start of 2010. On Au- 5.2.1 Spanish flu gust 10, 2010, the World Health Organization declared the H1N1 influenza pandemic over, saying worldwide flu Main article: 1918 flu pandemic activity had returned to typical seasonal patterns.[3] The Spanish flu, also known as la grippe, La Gripe Española, or La Pesadilla, was an unusually severe and deadly strain of swine influenza, a viral infectious disease, 5.1 Swine influenza that killed some 50 to 100 million people worldwide over Swine influenza (swine flu or pig flu) is a respiratory dis- about a year in 1918 and 1919. It is thought to be one of ease that occurs in pigs that is caused by the Influenza A the deadliest pandemics in human history. virus. Influenza viruses that are normally found in swine are known as swine influenza viruses (SIVs). The known SIV strains include influenza C and the subtypes of influenza A known as H1N1, H1N2, H3N1, H3N2 and H2N3. Pigs can also become infected with the H4N6 and H9N2 subtypes.[4]

The 1918 flu caused an unusual number of deaths, possibly due to it causing a cytokine storm in the body.[6][7] (The current H5N1 bird flu, also an Influenza A virus, has a similar effect.)[8] The Spanish flu virus infected lung cells, leading to overstimulation of the immune system via release of cytokines into the lung tissue. This leads to

39

40

CHAPTER 5. INFLUENZA A VIRUS SUBTYPE H1N1

extensive leukocyte migration towards the lungs, causing destruction of lung tissue and secretion of liquid into the organ. This makes it difficult for the patient to breathe.

In contrast to other pandemics, which mostly kill the old and the very young, the 1918 pandemic killed unusual numbers of young adults, which may have been due to their healthy immune systems mounting a too-strong and damaging response to the infection.[9] The term “Spanish” flu was coined because Spain was at the time the only European country where the press were printing reports of the outbreak, which had killed thousands in the armies fighting World War I. Other countries suppressed the news in order to protect morale.[10]

5.2.2

Fort Dix outbreak

Main article: 1976 swine flu outbreak In 1976, a novel swine influenza A (H1N1) caused severe respiratory illness in 13 soldiers with 1 death at Fort Dix, New Jersey. The virus was detected only from January 19 to February 9 and did not spread beyond Fort Dix.[11] Retrospective serologic testing subsequently demonstrated that up to 230 soldiers had been infected with the novel virus, which was an H1N1 strain. The cause of the outbreak is still unknown and no exposure to pigs was identified.[12] Illustration of influenza antigenic shift

5.2.3

Russian flu

The 1977–1978 Russian flu epidemic was caused by strain Influenza A/USSR/90/77 (H1N1). It infected mostly children and young adults under 23 because a similar strain was prevalent in 1947–57, causing most adults to have substantial immunity. Because of a striking similarity in the viral RNA of both strains – one which is unlikely to appear in nature due to antigenic drift – it was speculated that the later outbreak was due to a laboratory incident in Russia or Northern China, though this was denied by scientists in those countries.[13][14][15] The virus was included in the 1978–1979 influenza vaccine.[16][17][18][19] See also 1889–1890 flu pandemic for the earlier Russian flu pandemic caused either by H3N8 or H2N2

5.2.4

2009 A(H1N1) pandemic

can swine influenza, North American avian influenza, human influenza, and swine influenza virus typically found in Asia and Europe – “an unusually mongrelised mix of genetic sequences.”[20] This new strain appears to be a result of reassortment of human influenza and swine influenza viruses, in all four different strains of subtype H1N1.

Preliminary genetic characterization found that the hemagglutinin (HA) gene was similar to that of swine flu viruses present in U.S. pigs since 1999, but the neuraminidase (NA) and matrix protein (M) genes resembled versions present in European swine flu isolates.

The six genes from American swine flu are themselves mixtures of swine flu, bird flu, and human flu viruses.[21] While viruses with this genetic makeup had not previously been found to be circulating in humans or pigs, there is no formal national surveillance system to determine what viruses are circulating in pigs in the U.S.[22]

In April 2009, an outbreak of influenza-like illness (ILI) occurred in the United States and then in Mexico; the Main article: Pandemic H1N1/09 virus CDC reported seven cases of novel A/H1N1 influenza.

By April 24 it became clear that the outbreak of ILI in In the 2009 flu pandemic, the virus isolated from patients Mexico and the confirmed cases of novel influenza A in in the United States was found to be made up of genetic the southwest US were related and WHO issued a health elements from four different flu viruses – North Ameri- advisory on the outbreak of “influenza-like illness in the

5.2. NOTABLE INCIDENTS United States and Mexico”.[23] The disease then spread very rapidly, with the number of confirmed cases rising to 2,099 by May 7, despite aggressive measures taken by the Mexican government to curb the spread of the disease.[24] The outbreak had been predicted a year earlier by noticing the increasing number of replikins, a type of peptide, found in the virus.[25] On June 11, 2009, the WHO declared an H1N1 pandemic, moving the alert level to phase 6, marking the first global pandemic since the 1968 Hong Kong flu.[26] On October 25, 2009, U.S. President Barack Obama officially declared H1N1 a national emergency[27] Despite President Obama’s concern, a Fairleigh Dickinson University PublicMind poll found in October 2009 that an overwhelming majority of New Jerseyans (74%) were not very worried or not at all worried about contracting the H1N1 flu virus.[28] However, the President’s declaration caused many U.S. employers to take actions to help stem the spread of the swine flu and to accommodate employees and / or workflow which may be impacted by an outbreak.[29] A study conducted in coordination with the University of Michigan Health Service — scheduled for publication in the December 2009 American Journal of Roentgenology — warned that H1N1 flu can cause pulmonary embolism, surmised as a leading cause of death in this pandemic.

The study authors suggest physician evaluation via contrast enhanced CT scans for the presence of pulmonary emboli when caring for patients diagnosed with respiratory complications from a “severe” case of the H1N1 flu.[30] However pulmonary embolism is not the only embolic manifestation of H1N1 infection. H1N1 may induce a number of embolic events such as myocardial infarction, bilateral massive DVT, arterial thrombus of infrarenal aorta, thrombosis of right external Iliac vein and common femoral vein or cerebral gas embolism. The type of embolic events caused by H1N1 infection are summarized in a recently published review by Dimitroulis Ioannis et al.[31] The March 21, 2010 worldwide update, by the U.N.'s World Health Organization (WHO), states that “213 countries and overseas territories/communities have reported laboratory confirmed cases of pandemic influenza H1N1 2009, including at least 16,931 deaths.”[32] As of May 30, 2010, worldwide update by World Health Organization(WHO) more than 214 countries and overseas territories or communities have reported laboratory confirmed cases of pandemic influenza H1N1 2009, including over 18,138 deaths.[33] The research team of Andrew Miller MD showed pregnant patients are at increased risk.[34] It has been suggested that pregnant women and certain populations such as native North Americans have a greater likelihood of developing a T helper type 2 response to H1N1 influenza which may be responsible for the systemic inflammatory response syndrome that causes pulmonary edema and death.[35]

41 On 26 April 2011, an H1N1 pandemic preparedness alert was issued by the World Health Organization for the Americas.[36] In August 2011, according to the U.S. Geological Survey and the CDC, northern sea otters off the coast of Washington state were infected with the same version of the H1N1 flu virus that caused the 2009 pandemic and “may be a newly identified animal host of influenza viruses”.[37] In May 2013, seventeen people died during an H1N1 outbreak in Venezuela, and a further 250 were infected.[38] As of early January 2014, Texas health officials have confirmed at least thirty-three H1N1 deaths and widespread outbreak during the 2013/2014 flu season,[39] while twenty-one more deaths have been reported across the US. Nine people have been reported dead from an outbreak in several Canadian cities,[40] and Mexico reports outbreaks resulting in at least one death.[41] Spanish health authorities have confirmed 35 H1N1 cases in the Aragon region, 18 of whom are in intensive care.[42] On March 17, 2014, three cases were confirmed with a possible fourth awaiting results occurring at the Centre for Addiction and Mental Health in Toronto, Ontario, Canada.[43]

5.2.5 2015 India outbreak Main article: 2015 Indian swine flu outbreak Swine flu was reported in India in early 2015. The disease affected more than 31,000 people and claimed over 1,900 lives.[44]

5.2.6 2017 Maldives outbreak Maldives reported Swine flu in early 2017. [45] 501 people were tested for the disease; 185 (37%) of those tested were positive for the disease. 4 people from these 185 died due to this disease. [46] Total number of people who passed away due to this disease is so far unknown. Patient zero was never identified.[47] Schools were closed for a week due to the disease, but were ordered by the Ministry of Education to open after the holidays even though the disease was not fully under control. [48] After widespread rumors about Saudi Arabia going to purchase an entire atoll from Maldives, Saudi Arabian embassy in Maldives issued a statement against the rumors. [49] [50] However the trip of the Saudi monarch was going forward until it was cancelled later due to the H1N1 outbreak in Maldives. [51]

42

5.2.7

CHAPTER 5. INFLUENZA A VIRUS SUBTYPE H1N1

2017 Myanmar outbreak

5.4 Additional images

Myanmar reported H1N1 in late July 2017. As of 27 July 2017, 30 confirmed cases and 6 people had died[52] . The Ministry of Health and Sports of Myanmar sent official request to WHO to provide help to control the virus; and also mentioned that government would be seeking international assistance, including from the UN, China and the United States[53]

•

This colorized transmission electron micrograph shows H1N1 influenza virus particles. Surface proteins on the virus particles are shown in black

5.3 In pregnancy

•

This colorized transmission electron micrograph shows H1N1 influenza virus particles.

Pregnant women who contract the H1N1 infection are at a greater risk of developing complications because of hormonal changes, physical changes and changes to their immune system to accommodate the growing fetus.[54] For this reason the Center for Disease Control and Prevention recommends that those who are pregnant to get vaccinated to prevent the influenza virus. The vaccination should not be taken by people who have had a severe allergic reaction to the influenza vaccination. Additionally those who are moderately to severely ill, with or without a fever should wait until they recover before taking the vaccination.[55] Pregnant women who become infected with the influenza are advised to contact their doctor immediately. Influenza can be treated using antiviral medication, which are available by prescription. Oseltamivir (trade name Tamiflu) and zanamivir (Relenza) are two neuraminidase inhibitors (antiviral medications) currently recommended.

It has been shown that they are most effective when taken within two days of becoming sick.[56] Since October 1, 2008, the CDC has tested 1,146 seasonal influenza A (H1N1) viruses for resistance against oseltamivir and zanamivir. It was found that 99.6% of the samples were resistant to oseltamivir while none were resistant to zanamivir. In 853 samples of 2009 Influenza A (H1N1) virus only 4% showed resistance to oseltamivir, while none of 376 samples showed resistance to zanamivir.[57] A study conducted in Japan during the 2009 H1N1 pandemic concluded that infants exposed to either oseltamivir or zanamivir had no short term adverse effects.[58] Both amantadine and rimantadine have been found to be teratogenic and embryotoxic (malformations and toxic effects on the embryo) when given at high doses in animal studies.[59]

5.5 Notes [1] Boon, Lim (23 September 2011).

“Influenza A H1N1 2009 (Swine Flu) and Pregnancy”. The Journal of Obstetrics and Gynecology. 61 (4): 386–393. doi:10.1007/s13224-011-0055-2.

[2] “Influenza Summary Update 20, 2004–2005 Season”.

FluView: A Weekly Influenza Surveillance Report. Centers for Disease Control and Prevention.

[3] Roos R (10 August 2010). “WHO says H1N1 pandemic is over”. CIDRAP. Center for Infectious Disease Research and Policy, University of Minnesota.

[4] Dhama, Kuldeep. “Swine Flu is back again”. Pakistan Journal of Biological Science. 15 (21): 1001–1009. doi:10.3923/pjbs.2012.1001.1009.

[5] “Humans May Give Swine Flu To Pigs In New Twist To Pandemic”. Sciencedaily.com. 2009-07-10. Retrieved 2010-10-16.

[6] Kobasa D, Jones SM, Shinya K, et al.

(January 2007). “Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus”.

Nature. 445 (7125): 319–23. PMID 17230189. doi:10.1038/nature05495.

[7] Kash JC, Tumpey TM, Proll SC, et al. (October 2006).

“Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus”. Nature. 443 (7111): 578–81. PMC 2615558 . PMID 17006449. doi:10.1038/nature05181.

5.5. NOTES

[8] Cheung CY, Poon LL, Lau AS, et al. (December 2002). “Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease?".

Lancet. 360 (9348): 1831–7. PMID 12480361. doi:10.1016/S0140-6736(02)11772-7.

[9] Palese P (December 2004). “Influenza: old and new threats”. Nat. Med. 10 (12 Suppl): S82–7. PMID 15577936. doi:10.1038/nm1141.

[10] Barry, John M. (2004). The Great Influenza: The Epic Story of the Greatest Plague in History. Viking Penguin.

ISBN 0-670-89473-7.

[11] Gaydos JC, Top FH, Hodder RA, Russell PK (January 2006). “Swine influenza a outbreak, Fort Dix, New Jersey, 1976”. Emerging Infect. Dis. 12 (1): 23–8. PMID 16494712. doi:10.3201/eid1201.050965.

[12] “Pandemic H1N1 2009 Influenza”. CIDRAP. Center for Infectious Disease Research & Policy, University of Minnesota. Retrieved 2011-07-30.

[13] “1977 Russian Flu Pandemic”. GlobalSecurity.org. Retrieved 22 December 2011.

[14] “Origin of current influenza H1N1 virus”. virology blog.

2 March 2009. Retrieved 22 December 2011.

[15] “New Strain May Edge Out Seasonal Flu Bugs”. NPR. 4 May 2009. Retrieved 22 December 2011.

[16] “Interactive health timeline box 1977: Russian flu scare".

CNN. Archived from the original on March 22, 2007.

[17] “Invasion from the Steppes”. Time magazine. February 20, 1978.

[18] “Pandemic Influenza: Recent Pandemic Flu Scares”.

Global Security.

[19] “Russian flu confirmed in Alaska”. State of Alaska Epidemiology Bulletin (9). April 21, 1978.

[20] “Deadly new flu virus in US and Mexico may go pandemic”. New Scientist. 2009-04-26. Retrieved 2009-0426.

[21] Susan Watts (2009-04-25). “Experts concerned about potential flu pandemic”. BBC. [22] Centers for Disease Control and Prevention (CDC) (April 2009). “Swine influenza A (H1N1) infection in two children—Southern California, March–April 2009”.

MMWR Morb. Mortal. Wkly. Rep. 58 (15): 400–2.

PMID 19390508.

[23] “Influenza-like illness in the United States and Mexico”.

Disease Outbreak News. World Health Organization.

2009-04-24. Retrieved 2010-10-16.

[24] “Influenza A(H1N1) — update 19”. Disease Outbreak News. World Health Organization. 2009-05-07. Retrieved 2010-10-16.

43

[25] “Efforts To Quickly Develop Swine Flu Vaccine”. Science Daily. June 4, 2009. Retrieved December 28, 2016.

One company, Replikins, actually predicted over a year ago that significant outbreaks of the H1N1 flu virus would occur within 6-12 months.

[26] Blippitt (2009-06-11). “H1N1 Pandemic – It’s Official”.

N/A. [27] “Obama declares swine flu a national emergency”. The Daily Herald. 2009. Retrieved 2009-10-26.

[28] http://publicmind.fdu.edu/h1n1/release.pdf [29] “The Arrival of H1N1 Influenza: Legal Considerations and Practical Suggestions for Employers”. The National Law Review. Davis Wright Tremaine, LLP. 2009-11-02.

Retrieved 2011-11-03.

[30] Mollura DJ, Asnis DS, Crupi RS, et al. (December 2009).

“Imaging Findings in a Fatal Case of Pandemic SwineOrigin Influenza A (H1N1)". AJR Am J Roentgenol.

193 (6): 1500–3. PMC 2788497 . PMID 19933640. doi:10.2214/AJR.09.3365.

[31] Dimitroulis I, Katsaras M, Toumbis (October 2010).

“H1N1 infection and embolic events. A multifaceted disease”. Pneumon. 29 (3): 7–13.</ [32] “Situation updates – Pandemic (H1N1) 2009”. World Health Organization. Retrieved 2010-10-16.

[33] “Pandemic (H1N1) 2009 – update 103”. Disease Outbreak News. World Health Organization. 2010-06-04.

Retrieved 2010-10-16.

[34] “H1N1 Pandemic Flu Hits Pregnant Women Hard”. Businessweek.com. 2010-05-24. Retrieved 2010-10-16.

[35] McAlister VC (October 2009). “H1N1-related SIRS?".

CMAJ. 181 (9): 616–7. PMC 2764762 . PMID 19858268. doi:10.1503/cmaj.109-2028.

[36] “WHO Issues H1N1 Pandemic Alert”. Recombinomics.

April 26, 2011.

[37] Rogall, Gail Moede (2014-04-08). “Sea Otters Can Get the Flu, Too”. U.S. Department of the Interior, U.S. Geological Survey. Retrieved 11 April 2014.

[38] “H1N1 flu outbreak kills 17 in Venezuela: media”.

Reuters. 27 May 2013.

[39] “North Texas confirmed 20 flu deaths - Xinhua - English.news.cn”.

[40] CBC News http://www.cbc.ca/news/canada/edmonton/ 9-deaths-caused-by-h1n1-flu-in-alberta-update-1.

2488037. Missing or empty |title= (help) [41] “Un muerto en Coahuila por influenza AH1N1”.

[42] EFE (12 January 2014). “Aumentan a 35 los hospitalizados por gripe A en Aragón”.

[43] The Star. Toronto http://www.thestar.com/news/gta/ 2014/03/21/three_cases_of_h1n1_reported_at_camh. html. Missing or empty |title= (help)

44

CHAPTER 5. INFLUENZA A VIRUS SUBTYPE H1N1

[44] “Swine Flu Toll Inches Towards 1,900; Number of Cases Cross 31,000”.

• Centers For Disease Control and Prevention H1N1 Flu (Swine Flu).

[45] “Makeshift flu clinics swamped as H1N1 cases rise to 82 - Maldives Independent”.

• Consultant Magazine H1N1 (Swine Flu) Center

[46] “Breaking: Swine flu gai Ithuru meehaku maruve, ithuru bayaku positive vejje - Mihaaru”.

[47] “H1N1 death toll rises to three - Maldives Independent”.

[48] “Schools to open after flu outbreak - Maldives Independent”.

[49] Diplomat, Ankit Panda, The. “Will Saudi Arabia Purchase an Entire Atoll From the Maldives?".

[50] “Maldives dismisses claims Saudi Arabia buying atoll”. 11 March 2017.

[51] “PressTV-Saudi king cancels Maldives trip, citing swine flu”.

[52] http://www.reuters.com/article/ us-myanmar-h1n-idUSKBN1AC1XZ [53] https://www.irrawaddy.com/news/burma/ myanmar-asks-help-fight-h1n1-virus.html [54] Boon, Lim (September 23, 2011). “Influenza A H1N1 2009 (Swine Flu) and Pregnancy”. The Journal of Obstetrics and Gynecology of India. 61 (4): 389–393. doi:10.1007/s13224-011-0055-2.

[55] “Key Facts about Seasonal Flu Vaccine”. Centers for Disease Control and Prevention. 2013. Retrieved 31 January 2014.

[56] “What You Should Know About Flu Antiviral Drugs”.

Centers for Disease Control and Prevention. Retrieved 31 January 2014.

[57] “2008-2009 Influenza Season Week 32 ending August 15, 2009”. Centers for Disease Control and Prevention. Retrieved 31 January 2014.

[58] Saito, S; Minakami, H; Nakai, A; Unno, N; Kubo, T; Yoshimura, Y (Aug 2013). “Outcomes of infants exposed to oseltamivir or zanamivir in utero during pandemic (H1N1) 2009.”. American Journal of Obstetrics and Gynecology. 209 (2): 130.e1–9. PMID 23583838. doi:10.1016/j.ajog.2013.04.007.

[59] “Pandemic OBGYN”. Sarasota Memorial Health Care System. Retrieved 31 January 2014.

5.6 External links • European Commission – Public Health EU Coordination on Pandemic (H1N1) 2009.

• Health-EU Portal EU work to prepare a global response to influenza A(H1N1).

• Influenza Research Database Database of influenza genomic sequences and related information.

• Pandemic Influenza: A Guide to Recent Institute of Medicine Studies and Workshops A collection of research papers and summaries of workshops by the Institute of Medicine on major policy issues related to pandemic influenza and other infectious disease threats.

• H1N1 Flu, 2009: Hearings before the Committee on Homeland Security and Governmental Affairs, United States Senate, of the One Hundred Eleventh Congress, First Session: April 29, 2009, Coordinating the Federal Response; September 21, 2009, Protecting Our Community: Field Hearing in Hartford, CT; October 21, 2009, Monitoring the Nation’s Response; November 17, 2009, Getting the Vaccine to Where It is Most Needed.

5.6.1 Nontechnical • Shreeve, J. (29 January 2006). “Why Revive a Deadly Flu Virus?". New York Times. Six-page human-interest story on the recreation of the deadly 1918 H1N1 flu virus • “1918 flu virus’s secrets revealed”. BBC News. 28 September 2006. Results from analyzing a recreated strain.

• Noymer, A. (September 2005). “Some information on TB and the 1918 flu”. Data from Noymer A, Garenne M (2000). “The 1918 influenza epidemic’s effects on sex differentials in mortality in the United States”. Popul Dev Rev. 26 (3): 565–81. PMC 2740912 . PMID 19530360. doi:10.1111/j.17284457.2000.00565.x.

• Oral history by 1918 pandemic survivor

5.6.2 Technical • Ludwig S, Haustein A, Kaleta EF, Scholtissek C (July 1994). “Recent influenza A (H1N1) infections of pigs and turkeys in northern Europe”.

Virology. 202 (1): 281–6. PMID 8009840. doi:10.1006/viro.1994.1344.

• Centers for Disease Control (CDC) (February 1987). “Influenza A(H1N1) associated with mild illness in a nursing home–Maine”. MMWR Morb.

Mortal. Wkly. Rep. 36 (4): 57–9. PMID 3100930.

• Lederberg J (February 2001). “H1N1-influenza as Lazarus: Genomic resurrection from the tomb of an unknown”. Proc. Natl. Acad. Sci. U.S.A. 98 (5): 2115–6. PMC 33382 . PMID 11226198. doi:10.1073/pnas.051000798.

5.6. EXTERNAL LINKS • H1N1 Registry (ESICM – European Society of Intensive Care Medicine)

45

Chapter 6

1918 flu pandemic weaker immune systems of children and middle-aged adults resulted in fewer deaths among those groups.[11] More recent investigations, mainly based on original medical reports from the period of the pandemic,[12][13] found that the viral infection itself was not more aggressive than any previous influenza, but that the special circumstances (malnourishment, overcrowded medical camps and hospitals, poor hygiene) promoted bacterial superinfection that killed most of the victims typically after a somewhat prolonged death bed.[14][15] Historical and epidemiological data are inadequate to identify the pandemic’s geographic origin.[2] It was implicated in the outbreak of encephalitis lethargica in the 1920s.[16]

Soldiers from Fort Riley, Kansas, ill with Spanish influenza at a hospital ward at Camp Funston.

The 1918 flu pandemic (January 1918 – December 1920) was an unusually deadly influenza pandemic, the first of the two pandemics Involving H1N1 influenza virus.[1] It infected 500 million people around the world,[2] including remote Pacific islands and the Arctic, and resulted in the deaths of 50 to 100 million (three to five percent of the world’s population[3] ), making it one of the deadliest natural disasters in human history.[4][5][6] Disease had already greatly limited life expectancy in the early 20th century. A considerable spike occurred at the time of the pandemic, specifically the year 1918. Life expectancy in the United States alone dropped by about 12 years.[7][8][9][10] Most influenza outbreaks disproportionately kill juvenile, elderly, or already weakened patients; in contrast, the 1918 pandemic predominantly killed previously healthy young adults.

There are several possible explanations for the high mortality rate of the 1918 influenza pandemic. Some research suggests that the specific variant of the virus had an unusually aggressive nature. One group of researchers recovered the original virus from the bodies of frozen victims, and found that transfection in animals caused a rapid progressive respiratory failure and death through a cytokine storm (overreaction of the body’s immune system). It was then postulated that the strong immune reactions of young adults ravaged the body, whereas the

To maintain morale, wartime censors minimized early reports of illness and mortality in Germany, the United Kingdom, France, and the United States.[17][18] However, papers were free to report the epidemic’s effects in neutral Spain (such as the grave illness of King Alfonso XIII).[19] This reporting dichotomy created a false impression of Spain as especially hard hit,[20] thereby giving rise to the pandemic’s nickname, Spanish Flu.[21] In Spain, a different nickname was adopted, the Naples Soldier (Soldado de Nápoles), which came from a musical operetta (zarzuela) titled La canción del olvido (The Song of Forgetting), which premiered in Madrid during the first epidemic wave. Federico Romero, one of the librettists, quipped that the play’s most popular musical number, Naples Soldier, was as catchy as the flu.[22]

6.1 History 6.1.1 Hypotheses about source The site of the very first confirmed outbreak was at Camp Funston, Fort Riley, Kansas, then a military training facility preparing American troops for involvement in World War I. The first victim diagnosed with the new strain of flu on Monday, March 11, 1918, was mess cook Private Albert Gitchell.[23][24] Historian Alfred W. Crosby recorded that the flu originated in Kansas,[25] and popular writer John Barry echoed Crosby in describing Haskell County,

46

6.2. MORTALITY Kansas, as the point of origin.[26]

47 the disease.[38]

In contrast, investigative work in 1999 by a British team led by virologist John Oxford[27] of St Bartholomew’s Hospital and the Royal London Hospital identified the major troop staging and hospital camp in Étaples, France, as being the center of the 1918 flu pandemic. These researchers postulated that a significant precursor virus, harbored in birds, mutated to pigs that were kept near the front.[28]

In the United States, the disease was first observed in Haskell County, Kansas, in January 1918, prompting local doctor Loring Miner to warn the U.S. Public Health Service’s academic journal. On 4 March 1918, company cook Albert Gitchell reported sick at Fort Riley, Kansas.

By noon on 11 March 1918, over 100 soldiers were in the hospital.[39] Within days, 522 men at the camp had reported sick.[40] By 11 March 1918, the virus had reached [41] meaEarlier hypotheses of the epidemic’s origin have varied. Queens, New York. Failure to take preventative [5] sures in March/April was later criticised.

[29][30] Some hypothesized the flu originated in East Asia.

Dr. C. Hannoun, leading expert of the 1918 flu for the In August 1918, a more virulent strain appeared simulInstitut Pasteur, asserted the former virus was likely to taneously in Brest, France; in Freetown, Sierra Leone; have come from China, mutating in the United States near and in the U.S. in Boston, Massachusetts. The Spanish Boston and spreading to Brest, France, Europe’s battle- flu also spread through Ireland, carried there by returnfields, Europe, and the world using Allied soldiers and ing Irish soldiers. The Allies of World War I came to sailors as main spreaders.[31] He considered several other call it the Spanish flu, primarily because the pandemic rehypotheses of origin, such as Spain, Kansas, and Brest, ceived greater press attention after it moved from France as being possible, but not likely. to Spain in November 1918. Spain was not involved in [42] Political scientist Andrew Price-Smith published data the war and had not imposed wartime censorship. from the Austrian archives suggesting the influenza had earlier origins, beginning in Austria in the spring of 1917.[32]

6.2 Mortality

In 2014, historian Mark Humphries of Canada’s Memorial University of Newfoundland stated that newly 6.2.1 unearthed records confirmed that one of the side stories of the war, the mobilization of 96,000 Chinese laborers to work behind the British and French lines on World War I’s western front, might have been the source of the pandemic. In the report, Humphries found archival evidence that a respiratory illness that struck northern China in November 1917 was identified a year later by Chinese health officials as identical to the Spanish flu.[33][34] However, a report published in 2016 in the Journal of the Chinese Medical Association found no evidence that the 1918 virus was imported to Europe from Chinese and Southeast Asian soldiers and workers. In fact, it found evidence that the virus had been circulating in the European armies for months and potentially years before the 1918 pandemic.[35]

6.1.2

Spread

When an infected person sneezes or coughs, more than half a million virus particles can be spread to those close by.[36] The close quarters and massive troop movements of World War I hastened the pandemic, and probably both increased transmission and augmented mutation; the war may also have increased the lethality of the virus.

Some speculate the soldiers’ immune systems were weakened by malnourishment, as well as the stresses of combat and chemical attacks, increasing their susceptibility.[37]

Around the globe

The difference between the influenza mortality age-distributions of the 1918 epidemic and normal epidemics – deaths per 100,000 persons in each age group, United States, for the interpandemic years 1911–1917 (dashed line) and the pandemic year 1918 (solid line)[43]

The global mortality rate from the 1918/1919 pandemic is not known, but an estimated 10% to 20% of those who were infected died. With about a third of the world population infected, this case-fatality ratio means 3% to 6% of the entire global population died.[2] Influenza may have killed as many as 25 million people in its first 25 weeks.

Older estimates say it killed 40–50 million people,[4] while current estimates say 50–100 million people world[45] A large factor in the worldwide occurrence of this flu was wide were killed. increased travel. Modern transportation systems made it This pandemic has been described as “the greatest medieasier for soldiers, sailors, and civilian travelers to spread cal holocaust in history” and may have killed more people

48

CHAPTER 6. 1918 FLU PANDEMIC lung.[64] The unusually severe disease killed up to 20% of those infected, as opposed to the usual flu epidemic mortality rate of 0.1%.[2][45]

6.2.2 Patterns of fatality

Three pandemic waves: weekly combined influenza and pneumonia mortality, United Kingdom, 1918–1919[44]

than the Black Death.[46] It is said that this flu killed more people in 24 weeks than AIDS killed in 24 years, and more in a year than the Black Death killed in a century.[11] The disease killed in every corner of the globe. As many as 17 million died in India, about 5% of the population.[47] The death toll in India’s British-ruled districts alone was 13.88 million.[48] In Japan, of the 23 million people who were affected, 390,000 died.[49] In the Dutch East Indies (now Indonesia), 1.5 million were assumed to have died among 30 million inhabitants.[50] In Tahiti 13% of the population died during only a month. Similarly, in Samoa 22% of the population of 38,000 died within two months.[51] In the U.S., about 28% of the population became infected, and 500,000 to 675,000 died.[52] Native American tribes were particularly hard hit. In the Four Corners area alone, 3,293 deaths were registered among Native Americans.[53] Entire village communities perished in Alaska.[54] In Canada 50,000 died.[55] In Brazil 300,000 died, including president Rodrigues Alves.[56] In Britain, as many as 250,000 died; in France, more than 400,000.[57] In West Africa an influenza epidemic killed at least 100,000 people in Ghana.[58] Tafari Makonnen (the future Haile Selassie, Emperor of Ethiopia) was one of the first Ethiopians who contracted influenza but survived,[59][60] although many of his family’s subjects did not; estimates for the fatalities in the capital city, Addis Ababa, range from 5,000 to 10,000, or higher.[61] In British Somaliland one official estimated that 7% of the native population died.[62] This huge death toll was caused by an extremely high infection rate of up to 50% and the extreme severity of the symptoms, suspected to be caused by cytokine storms.[4] Symptoms in 1918 were so unusual that initially influenza was misdiagnosed as dengue, cholera, or typhoid. One observer wrote, “One of the most striking of the complications was hemorrhage from mucous membranes, especially from the nose, stomach, and intestine. Bleeding from the ears and petechial hemorrhages in the skin also occurred”.[45] The majority of deaths were from bacterial pneumonia,[63][64] a common secondary infection associated with influenza, but the virus also killed people directly, by causing massive hemorrhages and edema in the

An unusual feature of this pandemic was that it mostly killed young adults. In 1918–1919, 99% of pandemic influenza deaths in the US occurred in people under 65, and nearly half in young adults 20 to 40 years old. In 1920 the mortality rate among people under 65 had decreased sixfold to half the mortality rate of people over 65, but still 92% of deaths occurred in people under 65.[65] This is noteworthy, since influenza is normally most deadly to weak individuals, such as infants (under age two), the very old (over age 70), and the immunocompromised. In 1918, older adults may have had partial protection caused by exposure to the 1889–1890 flu pandemic, known as the Russian flu.[66] According to historian John M. Barry, the most vulnerable of all – “those most likely, of the most likely”, to die – were pregnant women. He reported that in thirteen studies of hospitalized women in the pandemic, the death rate ranged from 23% to 71%.[67] Of the pregnant women who survived childbirth, over onequarter (26%) lost the child.[68] Another oddity was that the outbreak was widespread in the summer and autumn (in the Northern Hemisphere); influenza is usually worse in winter.[69] Modern analysis has shown the virus to be particularly deadly because it triggers a cytokine storm, which ravages the stronger immune system of young adults.[26] In fast-progressing cases, mortality was primarily from pneumonia, by virus-induced pulmonary consolidation.

Slower-progressing cases featured secondary bacterial pneumonias, and there may have been neural involvement that led to mental disorders in some cases. Some deaths resulted from malnourishment.

A study – conducted by He et al. – used a mechanistic modelling approach to study the three waves of the 1918 influenza pandemic. They tried to study the factors that underlie variability in temporal patterns, and the patterns of mortality and morbidity. Their analysis suggests that temporal variations in transmission rate provide the best explanation and the variation in transmission required to generate these three waves is within biologically plausible values.[70] Another study by He et al. used a simple epidemic model, to incorporate three factors including: school opening and closing, temperature changes over the course of the outbreak, and human behavioral changes in response to the outbreak to infer the cause of the three waves of the 1918 influenza pandemic. Their modelling results showed that all three factors are important but human behavioral responses showed the largest effects.[71]

6.2. MORTALITY

6.2.3

49

Deadly second wave

American Expeditionary Force victims of the flu pandemic at U.S. Army Camp Hospital no. 45 in Aix-les-Bains, France, in 1918

A chart of deaths in major cities, showing a peak in the autumn of 1918.

the health-care workers could not tend the sick nor the gravediggers bury the dead because they too were ill.

The second wave of the 1918 pandemic was much dead- Mass graves were dug by steam shovel and bodies buried lier than the first. The first wave had resembled typical flu without coffins in many places.[77] epidemics; those most at risk were the sick and elderly, while younger, healthier people recovered easily. But in Several Pacific island territories were particularly hardAugust, when the second wave began in France, Sierra hit. The pandemic reached them from New Zealand, Leone and the United States,[72] the virus had mutated to which was too slow to implement measures to prevent ships carrying the flu from leaving its ports. From New a much deadlier form.

Zealand, the flu reached Tonga (killing 8% of the popuThis increased severity has been attributed to the circum- lation), Nauru (16%) and Fiji (5%, 9,000 people).[78] stances of the First World War.[73] In civilian life, natural selection favours a mild strain. Those who get very ill Worst affected was German Samoa, today the indepenstay home, and those mildly ill continue with their lives, dent state of Samoa, which had been occupied by New preferentially spreading the mild strain. In the trenches, Zealand in 1914. A crippling 90% of the population natural selection was reversed. Soldiers with a mild strain was infected; 30% of adult men, 22% of adult women stayed where they were, while the severely ill were sent and 10% of children died. By contrast, the flu was kept Governor John Maron crowded trains to crowded field hospitals, spreading away from American Samoa when [78] tin Poyer imposed a blockade.

In New Zealand itthe deadlier virus. The second wave began and the flu self, 8,573 deaths were attributed to the 1918 pandemic quickly spread around the world again. Consequently, influenza, resulting in a total population fatality rate of during modern pandemics health officials pay attention [79] 0.74%.

In Ireland, the Spanish Flu accounted for 10% when the virus reaches places with social upheaval (lookof the total deaths in 1918 which can be seen as quite [74] ing for deadlier strains of the virus). detrimental considering World War 1 was still occurring.

The fact that most of those who recovered from firstwave infections were now immune showed that it must have been the same strain of flu. This was most dramat- 6.2.5 Less-affected areas ically illustrated in Copenhagen, which escaped with a combined mortality rate of just 0.29% (0.02% in the first In Japan, 257,363 deaths were attributed to influenza wave and 0.27% in the second wave) because of exposure by July 1919, giving an estimated 0.425% mortality to the less-lethal first wave.[75] On the rest of the popula- rate, much lower than nearly all other Asian countries tion it was far more deadly now; the most vulnerable peo- for which data are available. The Japanese government ple were those like the soldiers in the trenches – young severely restricted maritime travel to and from the home previously healthy adults.[76] islands when the pandemic struck.

In the Pacific, American Samoa[80] and the French colony of New Caledonia[81] also succeeded in preventing even a 6.2.4 Devastated communities single death from influenza through effective quarantines.

[82] Even in areas where mortality was low, so many were in- In Australia, nearly 12,000 perished. capacitated that much of everyday life was hampered. By the end of the pandemic, the isolated island of Marajó, Some communities closed all stores or required cus- in Brazil’s Amazon River Delta had not reported an tomers to leave orders outside. There were reports that outbreak.[83]

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6.2.6

CHAPTER 6. 1918 FLU PANDEMIC

Aspirin poisoning

pathogenic viruses to become less lethal with time, as the hosts of more dangerous strains tend to die out[26] (see In a 2009 paper published in the journal Clinical Infec- also “Deadly Second Wave”, above). tious Diseases, Karen Starko proposed that aspirin poisoning had contributed substantially to the fatalities. She based this on the reported symptoms in those dying from 6.3 Legacy the flu, as reported in the post mortem reports still available, and also the timing of the big “death spike” in OctoSee also: List of 1918 flu pandemic cases ber 1918 which happened right after the Surgeon General Academic Andrew Price-Smith has made the argument of the United States Army, and the Journal of the American Medical Association both recommended very large doses of 8.0–31.2 g of aspirin per day.[84] Starko also suggests that the wave of aspirin poisonings was due to a "perfect storm" of events: Bayer's patent on aspirin expired, so that many companies rushed in to make a profit and greatly increased the supply; this coincided with the flu pandemic; and the symptoms of aspirin poisoning were not known at the time.[84] As an explanation for the universally high mortality rate, this hypothesis was questioned in a letter to the journal published in April 2010 by Andrew Noymer and Daisy Carreon of the University of California, Irvine, and Niall Johnson of the Australian Commission on Safety and Quality in Health Care. They questioned this universal applicability given the high mortality rate in countries such as India, where there was little or no access to aspirin at the time.[85] They concluded that “the salicylate [aspirin] poisoning hypothesis [was] difficult to sustain as the primary explanation for the unusual virulence of the 1918–1919 influenza pandemic”.[85]

American Red Cross nurses tend to flu patients in temporary wards set up inside Oakland Municipal Auditorium, 1918.

that the virus helped tip the balance of power in the later days of the war towards the Allied cause. He provides data that the viral waves hit the Central Powers beBut they overlooked that inexpensive aspirin had be- fore they hit the Allied powers, and that both morbidity come available in India and other places after October and mortality in Germany and Austria were considerably 1918, when the Bayer patent expired. In responding, higher than in Britain and France.[32] Starko pointed to anecdotal evidence of aspirin overprescription in India and argued that even if aspirin over- In the United States, Britain and other countries, despite prescription had not contributed to the high Indian mor- the relatively high morbidity and mortality rates that retality rate, it could still have been a major factor for sulted from the epidemic in 1918–1919, the Spanish flu other high rates in areas where other exacerbating factors began to fade from public awareness over the decades until the arrival of news about bird flu and other pandemics present in India played less of a role.[86] in the 1990s and 2000s.[87] This has led some historians to label the Spanish flu a “forgotten pandemic”.[25]

6.2.7

End of the pandemic

Various theories of why the Spanish flu was “forgotten” include the rapid pace of the pandemic, which killed most of its victims in the United States, for example, within a period of less than nine months, resulting in limited media coverage. The general population was familiar with patterns of pandemic disease in the late 19th and early 20th centuries: typhoid, yellow fever, diphtheria, and cholera all occurred near the same time. These outbreaks probably lessened the significance of the influenza pandemic for the public.[88] In some areas, the flu was not reported on, the only mention being that of advertisements for medicines claiming to cure it.[89]

After the lethal second wave struck in late 1918, new cases dropped abruptly – almost to nothing after the peak in the second wave.[11] In Philadelphia, for example, 4,597 people died in the week ending 16 October, but by 11 November, influenza had almost disappeared from the city. One explanation for the rapid decline of the lethality of the disease is that doctors simply got better at preventing and treating the pneumonia that developed after the victims had contracted the virus, although John Barry stated in his book that researchers have found no evidence to support this.[26] In addition, the outbreak coincided with the deaths and Another theory holds that the 1918 virus mutated ex- media focus on the First World War.[90] Another explatremely rapidly to a less lethal strain. This is a common nation involves the age group affected by the disease. occurrence with influenza viruses: there is a tendency for The majority of fatalities, from both the war and the epi-

6.4. SPANISH FLU RESEARCH

51

demic, were among young adults. The deaths caused by the flu may have been overlooked due to the large numbers of deaths of young men in the war or as a result of injuries. When people read the obituaries, they saw the war or postwar deaths and the deaths from the influenza side by side. Particularly in Europe, where the war’s toll was extremely high, the flu may not have had a great, separate, psychological impact, or may have seemed a mere extension of the war’s tragedies.[65] The duration of the pandemic and the war could have also played a role. The disease would usually only affect a certain area for a month before leaving, while the war, which An electron micrograph showing recreated 1918 influenza virimost had initially expected to end quickly, had lasted for ons. four years by the time the pandemic struck. This left little time for the disease to have a significant impact on the economy.

Regarding global economic effects, many businesses in the entertainment and service industries suffered losses in revenue, while the health care industry reported profit gains.[91] Historian Nancy Bristow has argued that the pandemic, when combined with the increasing number of women attending college, contributed to the success of women in the field of nursing. This was due in part to the failure of medical doctors, who were predominantly men, to contain and prevent the illness. Nursing staff, who were predominantly women, felt more inclined to celebrate the success of their patient care and less inclined to identify the spread of the disease with their own work.[92] In Spain, sources from the period explicitly linked the Spanish flu to the cultural figure of Don Juan. The nickname for the flu, the “Naples Soldier”, was adopted from Federico Romero and Guillermo Fernández Shaw's operetta, The Song of Forgetting (La canción del olvido), the protagonist of which is a stock Don Juan type. Davis has argued the Spanish flu–Don Juan connection served a cognitive function, allowing Spaniards to make sense of their epidemic experience by interpreting it through a familiar template, namely the Don Juan story.[93]

6.4 Spanish flu research

Centers for Disease Control and Prevention as Dr. Terrence Tumpey examines a reconstructed version of the 1918 flu.

Others have disagreed,[97] and more recent research has suggested the strain may have originated in a nonhuman, mammalian species.[98] An estimated date for its appearance in mammalian hosts has been put at the period 1882–1913.[99] This ancestor virus diverged about 1913– 1915 into two clades (or biological groups), which gave rise to the classical swine and human H1N1 influenza lineages. The last common ancestor of human strains dates to between February 1917 and April 1918. Because pigs are more readily infected with avian influenza viruses than are humans, they were suggested as the original recipients of the virus, passing the virus to humans sometime between 1913 and 1918.

Main article: Spanish flu research The origin of the Spanish flu pandemic, and the relationship between the near-simultaneous outbreaks in humans and swine, have been controversial. One hypothesis is that the virus strain originated at Fort Riley, Kansas, in viruses in poultry and swine which the fort bred for food; the soldiers were then sent from Fort Riley around the world, where they spread the disease.[94] Similarities between a reconstruction of the virus and avian viruses, combined with the human pandemic preceding the first reports of influenza in swine, led researchers to conclude the influenza virus jumped directly from birds to humans, and swine caught the disease from humans.[95][96] An effort to recreate the 1918 flu strain (a subtype of

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CHAPTER 6. 1918 FLU PANDEMIC

avian strain H1N1) was a collaboration among the Armed Forces Institute of Pathology, the USDA ARS Southeast Poultry Research Laboratory and Mount Sinai School of Medicine in New York City. The effort resulted in the announcement (on 5 October 2005) that the group had successfully determined the virus’s genetic sequence, using historic tissue samples recovered by pathologist Johan Hultin from a female flu victim buried in the Alaskan permafrost and samples preserved from American soldiers.[100]

6.5 In popular culture

On 18 January 2007, Kobasa et al. (2007) reported that monkeys (Macaca fascicularis) infected with the recreated flu strain exhibited classic symptoms of the 1918 pandemic, and died from a cytokine storm[101] —an overreaction of the immune system. This may explain why the 1918 flu had its surprising effect on younger, healthier people, as a person with a stronger immune system would potentially have a stronger overreaction.[102]

In season four of British drama Upstairs, Downstairs, Hazel Bellamy dies of Spanish flu in 1918, after her husband James Bellamy survives injuries in the “Great War” (World War I). Her funeral takes place on 11 November, the day the war ends.

The 1995 film Outbreak,[109] the 2011 film Contagion and the 2013 film World War Z make reference to the pandemic.[110] The television show Resurrection uses the pandemic, in the episode “Afflictions” that aired on November 2, 2014, as the explanation for why many of the Returned were getting sick and disappearing.

In season two of British drama Downton Abbey, Lavinia Swire dies of the Spanish flu in April 1919, after her fiancé Matthew Crawley recovers from injuries and temOn 16 September 2008, the body of British politician porary paralysis from the Great War. and diplomat Sir Mark Sykes was exhumed to study the Twentieth-century fiction includes at least three novels RNA of the flu virus in efforts to understand the ge- with the flu pandemic as a major theme: Katherine Anne netic structure of modern H5N1 bird flu. Sykes had been Porter’s Pale Horse, Pale Rider, Thomas Mullen’s The buried in 1919 in a lead coffin which scientists hoped had Last Town on Earth, and Thomas Wolfe’s Look Homehelped preserve the virus.[103] However, the coffin was ward, Angel. found to be split because of the weight of soil over it, and In the one-act play 1918 by Horton Foote (part of his the cadaver was badly decomposed. Nonetheless, samOrphans’ Home Cycle (1979)), the presence and threat of ples of lung and brain tissue were taken through the split, the flu (and the tragedy it ultimately causes) is a major with the coffin remaining in situ in the grave during this element of the plot. The play was made into a film of [104] process. the same title, released in 1985, which was subsequently In December 2008, research by Yoshihiro Kawaoka of edited for broadcast by PBS as the last part of the ministhe University of Wisconsin linked the presence of three eries “The Story of A Marriage”. specific genes (termed PA, PB1, and PB2) and a nucleoprotein derived from 1918 flu samples to the ability of the flu virus to invade the lungs and cause pneumonia.

6.6 Gallery The combination triggered similar symptoms in animal [105] testing.

In June 2010, a team at the Mount Sinai School of Medicine reported the 2009 flu pandemic vaccine provided some cross-protection against the 1918 flu pandemic strain.[106] One of the few things known for certain about the influenza in 1918 and for some years after was that it was, out of the laboratory, exclusively a disease of human beings.[107]

•

Two American Red Cross nurses demonstrating treatment practices during the influenza pandemic of 1918.

•

Albertan farmers wearing masks to protect themselves from the flu.

In 2013, the AIR Worldwide Research and Modeling Group “characterized the historic 1918 pandemic and estimated the effects of a similar pandemic occurring today using the AIR Pandemic Flu Model”. In the model, “a modern day “Spanish flu” event would result in additional life insurance losses of between USD 15.3–27.8 billion in the United States alone” with 188,000–337,000 deaths in the United States.[108]

6.6. GALLERY

•

53

Policemen wearing masks provided by the American Red Cross in Seattle, 1918

•

• •

•

•

1919 Tokyo, Japan

Japanese poster in 1919

A street car conductor in Seattle in 1918 refusing to allow passengers aboard who are not wearing masks

•

Demonstration at the Red Cross Emergency Ambulance Station in Washington, D.C., during the influenza pandemic of 1918

•

Cavalry memorial on the hill Lueg, memory of the Bernese cavalrymen victims of the 1918 flu pandemic; Emmental, Bern, Switzerland

•

The Spanish flu as the Naples Soldier (Spain, 1918)

Red Cross workers remove a flu victim in St. Louis, Missouri (1918)

Influenza ward at Walter Reed Hospital during the Spanish flu pandemic of 1918–1919

•

Burying flu victims, North River, Canada (1918)

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CHAPTER 6. 1918 FLU PANDEMIC

[15] Morens, David M; Fauci, Anthony S. (2007). “The 1918 influenza pandemic: insights for the 21st century”.

Journal of Infectious Diseases. 195 (7): 1018–1028. doi:10.1086/511989.

[16] Vilensky, Foley & Gilman 2007.

[17] Valentine 2006.

•

Spanish biologists and the flu microbe (Spain, 1918)

[18] Anderson, Susan (29 August 2006). “Analysis of Spanish flu cases in 1918–1920 suggests transfusions might help in bird flu pandemic”. American College of Physicians.

Retrieved 2 October 2011.

[19] Porras-Gallo & Davis 2014.

[20] Barry 2004, p. 171.

6.7 References 6.7.1

[21] Galvin 2007.

Notes

[22] Davis 2013, pp. 103–104 cited María Encina Cortizo

[1] “La Grippe Espagnole de 1918” (in French). Institut Pasteur. Archived from the original on 17 November 2015.

[23] 'The so-called “Spanish” flu' by JACKIE ROSENHEK | November 2005

[2] Taubenberger & Morens 2006.

[24] ‘A Doughboy’s War: Letters Home’ pg.42, by Thomas Lindholtz

[3] “Historical Estimates of World Population”. Retrieved 29 March 2013.

[25] Crosby 2003.

[26] Barry 2004b.

[4] Patterson & Pyle 1991.

[27] “EU Research Profile on Dr. John Oxford”. Archived from the original on 12 May 2009. Retrieved 9 May 2009.

[5] Billings 1997.

[6] Johnson & Mueller 2002.

[7] “The Nation’s Health”. www.flu.gov. U.S. Department of Health & Human Services. Archived from the original on 2016-10-26. Retrieved 2016-03-31.

[8] “Life Expectancy”. Our World in Data. Retrieved 201603-31.

[9] “Life expectancy in the USA, 1900–98”. mog.berkeley.edu. Retrieved 2016-03-31.

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[10] “The Influenza Epidemic of 1918”.

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[11] Barry 2004.

[12] MacCallum, W.G. (1919). “Pathology of the pneumonia following influenza”.

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[13] Hirsch, Edwin F.; McKinney, Marion (1919). “An epidemic of pneumococcus broncho-pneumonia” (PDF).

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[14] Brundage, John F.; Shanks, G. Dennis (2007). “What Really Happened during the 1918 Influenza Pandemic?

The Importance of Bacterial Secondary Infections”. Journal of Infectious Diseases. 196 (11): 1717–1718. doi:10.1086/522355.

[28] Connor, Steve, “Flu epidemic traced to Great War transit camp”, The Guardian (UK), Saturday, 8 January 2000.

Accessed 2009-05-09. Archived 11 May 2009.

[29] 1918 killer flu secrets revealed. BBC News. 5 February 2004.

[30] Erkoreka A (2009). “Origins of the Spanish Influenza pandemic (1918–1920) and its relation to the First World War.”. J Mol Genet Med (Review). 3 (2): 190–4. PMC 2805838 . PMID 20076789.

[31] Hannoun, Claude, “La Grippe”, Ed Techniques EMC (Encyclopédie Médico-Chirurgicale), Maladies infectieuses, 8-069-A-10, 1993. Documents de la Conférence de l'Institut Pasteur : La Grippe Espagnole de 1918.

[32] Price-Smith 2008.

[33] Humphries 2014.

[34] Vergano, Dan (January 24, 2014). “1918 Flu Pandemic That Killed 50 Million Originated in China, Historians Say”. National Geographic. Retrieved November 4, 2016.

[35] http://www.jcma-online.com/article/S1726-4901% 2815%2900261-0/pdf [36] Sherman, Irwin W. (2007). Twelve diseases that changed our world. Washington, DC: ASM Press. p. 161. ISBN 978-1-55581-466-3.

[37] Ewald 1994.

6.7. REFERENCES

55

[38] Film: We Heard the Bells: The Influenza of 1918 (2010).

U.S. Department of Health and Human Services, Center for Medicare and Medicaid Services. 2010. Retrieved 20 February 2012.

[63] “Bacterial Pneumonia Caused Most Deaths in 1918 Influenza Pandemic”. National Institutes of Health.

[39] “Influenza 1918”. American Experience. Retrieved 17 January 2012.

[65] Simonsen et al. 1998.

[40] Avian Bird Flu. 1918 Flu (Spanish flu epidemic).

[41] Spanish flu strikes during World War I, Timelines of great Epidemics, xtimeline.com Archived 14 January 2010 at the Wayback Machine.

[64] Taubenberger et al. 2001, pp. 1829–1839.

[66] Hanssen, Olav. Undersøkelser over influenzaens optræden specielt i Bergen 1918–1922. Bg. 1923. 66 s. ill.

(Haukeland sykehus. Med.avd.Arb. 2) (Klaus Hanssens fond. Skr. 3)

[43] Taubenberger & Morens 2006, pp. 15–22.

[67] Payne, Matthew S.; Bayatibojakhi, Sara (2014).

“Exploring Preterm Birth as a Polymicrobial Disease: An Overview of the Uterine Microbiome”. Frontiers in Immunology. 5: 595. ISSN 1664-3224. PMC 4245917 . PMID 25505898. doi:10.3389/fimmu.2014.00595.

[44] CDC 2009.

[68] Barry 2004, p. 239.

[45] Knobler 2005.

[69] Key Facts about Swine Influenza accessed 22:45 GMT-6 30 April 2009. Archived 4 May 2009.

[42] Channel 4 – News – Spanish flu facts.

[46] Potter 2006.

[47] Flu experts warn of need for pandemic plansBritish Medical Journal.

[48] Chandra, Kuljanin & Wray 2012.

[49] “Spanish Influenza in Japanese Armed Forces, 1918– 1920”. Centers for Disease Control and Prevention (CDC).

[50] Historical research report from University of Indonesia, School of History, as reported in Emmy Fitri. Looking Through Indonesia’s History For Answers to Swine Flu Archived 2 November 2009 at the Wayback Machine..

The Jakarta Globe. 28 October 2009 edition.

[51] Kohn 2007.

[52] The Great Pandemic: The United States in 1918–1919, U.S. Department of Health & Human Services.

[70] He et al. 2011.

[71] He et al. 2013.

[72] UK Parliament – http://www.parliament. the-stationery-office.com/pa/ld200506/ldselect/ ldsctech/88/88.pdf. Accessed 2009-05-06. Archived 8 May 2009.

[73] Gladwell 1997, p. 55.

[74] Gladwell 1997, p. 63.

[75] Fogarty International Center. “Summer Flu Outbreak of 1918 May Have Provided Partial Protection Against Lethal Fall Pandemic”. Fic.nih.gov. Retrieved 2012-0519.

[76] Gladwell 1997, p. 56.

[53] “Flu Epidemic Hit Utah Hard in 1918, 1919”. 28 March 1995. Retrieved 7 July 2012.

[77] Fortune article " Viruses of Mass Destruction" written 1 November 2004. accessed 01:12 GMT+1 30 April 2009

[54] “The Great Pandemic of 1918: State by State”. Archived from the original on 6 May 2009. Retrieved 4 May 2009.

[78] Denoon 2004.

[55] “A deadly virus rages throughout Canada at the end of the First World War”. CBC History.

[56] “A gripe espanhola no Brasil – Elísio Augusto de Medeiros e Silva, empresário, escritor e membro da AEILIJ” (in Portuguese). Jornal de Hoje. Retrieved 22 January 2014.

[57] The “bird flu” that killed 40 million. BBC News. 19 October 2005.

[58] Hays 1998.

[59] Harold Marcus, Haile Sellassie I: The formative years, 1892–1936 (Trenton: Red Sea Press, 1996), pp. 36f

[79] Rice 2005, p. 221.

[80] “Influenza of 1918 (Spanish Flu) and the US Navy”. history.navy.mil. Archived from the original on 11 January 2015. Retrieved 14 May 2009.

[81] World Health Organization Writing Group (2006).

“Nonpharmaceutical interventions for pandemic influenza, international measures” (PDF). Centers for Disease Control and Prevention (CDC) Emerging Infectious Diseases (EID) Journal. 12 (1): 189.

[82] Anne Grant, History House, Portland. Influenza Pandemic 1919. Portland Victoria

[60] Pankhurst 1991, pp. 48f.

[83] Ryan, Jeffrey, ed. Pandemic influenza: emergency planning and community preparedness. Boca Raton : CRC Press, 2009. P. 24

[61] Pankhurst 1991, p. 63.

[84] Starko 2009.

[62] Pankhurst 1991, pp. 51ff.

[85] Noymer, Carreon & Johnson 2010.

56

[86] Starko 2010.

[87] Honigsbaum 2008.

[88] Morrissey 1986.

[89] Benedict & Braithwaite 2000, p. 38.

[90] Crosby 2003, pp. 320–322.

[91] Garrett 2007.

[92] Lindley, Robin, The Forgotten American Pandemic: Historian Dr. Nancy K. Bristow on the Influenza Epidemic of 1918 [93] Davis 2013, pp. 103–136.

[94] “Open Collections Program: Contagion, Spanish Influenza in North America, 1918–191”. Retrieved 22 November 2016.

CHAPTER 6. 1918 FLU PANDEMIC

6.7.2 Bibliography • Antonovics, J.; Hood, M. E.; Baker, C. H. (2006). “Molecular virology: was the 1918 flu avian in origin?". Nature. 440 (7088): E9, E10.

Bibcode:2006Natur.440E...9A. PMID 16641950. doi:10.1038/nature04824.

• Barry, John M. (2004). The Great Influenza: The Epic Story of the Greatest Plague in History. Viking Penguin. ISBN 978-0-670-89473-4.

• Barry, John M. (2004b). “The site of origin of the 1918 influenza pandemic and its public health implications”. Journal of Translational Medicine.

2 (3): 3. PMC 340389 . PMID 14733617. doi:10.1186/1479-5876-2-3. Archived from the original on 4 May 2009.

[95] Sometimes a virus contains both avian-adapted genes and human-adapted genes. Both the H2N2 and H3N2 pandemic strains contained avian flu virus RNA segments.

“While the pandemic human influenza viruses of 1957 (H2N2) and 1968 (H3N2) clearly arose through reassortment between human and avian viruses, the influenza virus causing the 'Spanish flu' in 1918 appears to be entirely derived from an avian source (Belshe 2005).” (from Chapter Two: Avian Influenza by Timm C. Harder and Ortrud Werner, an excellent free on-line book called Influenza Report 2006 which is a medical textbook that provides a comprehensive overview of epidemic and pandemic influenza.)

• Benedict, Michael Les; Braithwaite, Max (2000).

“The Year of the Killer Flu”. In the Face of Disaster: True Stories of Canadian Heroes from the Archives of Maclean’s. New York, N.Y: Viking. p. 38. ISBN 978-0-670-88883-2.

[96] Taubenberger et al. 2005.

• “1918 Influenza: the Mother of All Pandemics”.

Archived from the original on 1 October 2009. Retrieved 2 September 2009.

[97] Antonovics, Hood & Baker 2006.

[98] Vana & Westover 2008.

[99] dos Reis, Hay & Goldstein 2009.

[100] Center for Disease Control: Researchers Reconstruct 1918 Pandemic Influenza Virus; Effort Designed to Advance Preparedness Retrieved on 2 September 2009 [101] Kobasa & et al. 2007.

[102] USA Today: Research on monkeys finds resurrected 1918 flu killed by turning the body against itself Retrieved on 14 August 2008.

[103] BBC News: Body exhumed in fight against flu Retrieved on 16 September 2008.

[104] BBC Four documentary. In Search of Spanish Flu [105] Fox 2008.

[106] Fox 2010.

[107] Crosby 1976, p. 295.

[108] Madhav 2013.

[109] “Outbreak – Daily Script” (PDF). p. 94.

[110] “World War Z Quotes – 'Every human being we save is one less zombie to fight.'". Retrieved 22 November 2016.

• Billings, Molly (1997). “The 1918 Influenza Pandemic”. Virology at Stanford University. Archived from the original on 4 May 2009. Retrieved 1 May 2009.

• Bristow, Nancy K. American Pandemic: The Lost Worlds of the 1918 Influenza Epidemic (OUP, 2012)

• Chandra, S.; Kuljanin, G.; Wray, J. (2012).

“Mortality From the Influenza Pandemic of 1918– 1919: The Case of India”. Demography. 49 (3): 857–865. PMID 22661303. doi:10.1007/s13524012-0116-x.

• Collier, Richard (1974). The Plague of the Spanish Lady – The Influenza Pandemic of 1918–19.

Atheneum. ISBN 978-0-689-10592-0.

• Crosby, Alfred W. (1976). Epidemic and Peace, 1918. Westport, Ct: Greenwood Press. ISBN 9780-8371-8376-3.

• Crosby, Alfred W. (2003). America’s Forgotten Pandemic: The Influenza of 1918 (2nd ed.). Cambridge University Press. ISBN 978-0-521-54175-6.

• Davis, Ryan A. (2013). The Spanish Flu: Narrative and Cultural Identity in Spain, 1918. Palgrave Macmillan. ISBN 978-1-137-33921-8.

• Denoon, Donald (2004). “New Economic Orders: Land, Labour and Dependency”. In Denoon, Donald. The Cambridge History of the Pacific Islanders.

CUP. p. 247. ISBN 978-0-521-00354-4.

6.7. REFERENCES • dos Reis, M.; Hay, A. J.; Goldstein, R. A. (2009), “Using Non-Homogeneous Models of Nucleotide Substitution to Identify Host Shift Events: Application to the Origin of the 1918 'Spanish' Influenza Pandemic Virus”, Journal of Molecular Evolution, 69 (4): 333–345, PMC 2772961 , PMID 19787384, doi:10.1007/s00239-009-9282-x • Ewald, Paul W. (1994). Evolution of infectious disease. OUP. ISBN 978-0-19-506058-4.

• Fox, Maggie (29 December 2008). “Researchers unlock secrets of 1918 flu pandemic”. Reuters. Retrieved 2 September 2009.

• Fox, Maggie (16 June 2010). “Swine flu shot protects against 1918 flu: study”. Reuters.

• Galvin, John (31 July 2007). “Spanish Flu Pandemic: 1918”. Popular Mechanics. Retrieved 2 October 2011.

• Garrett, T. A. (2007). Economic Effects of the 1918 Influenza Pandemic: Implications for a Modern-day Pandemic (PDF).

• Gladwell, Malcolm (29 September 1997). “The Dead Zone”. New Yorker.

• Hays, J. N. (1998). The Burdens of Disease: Epidemics and Human Response in Western History. p.

274. ISBN 978-0-8135-2528-0.

• He, Dai Hai; Dushoff, Jonathan; Day, Troy; Ma, Junling; Earn, David J. D. (2011). “Mechanistic modelling of the three waves of the 1918 influenza pandemic”. Theoretical Ecology. 4 (2): 283–288.

ISSN 1874-1738. doi:10.1007/s12080-011-01233.

• He, Dai Hai; Dushoff, Jonathan; Day, Troy; Ma, Junling; Earn, David J. D. (2013). “Inferring the causes of the three waves of the 1918 influenza pandemic in England and Wales”. Proceedings of the Royal Society of London B: Biological Sciences. 280 (1766): 20131345. ISSN 0962-8452. PMC 3730600 . PMID 23843396. doi:10.1098/rspb.2013.1345.

• Honigsbaum, Mark (2008). Living with Enza: The Forgotten Story of Britain and the Great Flu Pandemic of 1918. Palgrave Macmillan. ISBN 978-0230-21774-4.

• Humphries, Mark Osborne (2014). “Paths of Infection: The First World War and the Origins of the 1918 Influenza Pandemic” (PDF). War in History.

21 (1): 55–81. doi:10.1177/0968344513504525.

• Johnson, Niall P.; Mueller, J. (2002). “Updating the accounts: global mortality of the 1918– 1920 “Spanish” influenza pandemic”. Bull Hist

57 Med. 76 (1): 105–115. doi:10.1353/bhm.2002.0022.

PMID 11875246.

• Knobler, S.; Mack, A.; Mahmoud, A.; et al. (eds.).

“1: The Story of Influenza”. The Threat of Pandemic Influenza: Are We Ready? Workshop Summary (2005). Washington, D.C.: The National Academies Press. pp. 60–61.

• Kobasa, Darwyn; Jones, Steven M.; Shinya, Kyoko; Kash, John C.; Copps, John; Ebihara, Hideki; Hatta, Yasuko; Kim, Jin Hyun; Halfmann, Peter; Hatta, Masato; Feldmann, Friederike; Alimonti, Judie B.; Fernando, Lisa; Li, Yan; Katze, Michael G.; Feldmann, Heinz; Kawaoka, Yoshihiro (2007). “Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus”. Nature. 445 (7125): 319–323.

Bibcode:2007Natur.445..319K. PMID 17230189. doi:10.1038/nature05495.

• Kohn, George C. (2007). Encyclopedia of plague and pestilence: from ancient times to the present (3rd ed.). Infobase Publishing. p. 363. ISBN 978-08160-6935-4.

• Madhav, Nita (21 February 2013). Markey, Molly J., ed. “Modeling a Modern-Day Spanish Flu Pandemic”. AIR’s Research and Modeling Group. Retrieved 5 August 2014.

• Morrisey, Carla R. (1986). “The Influenza Epidemic of 1918”. Navy Medicine. 77 (3): 11–17.

• Noymer, Andrew; Carreon, Daisy; Johnson, Niall (2010). “Questioning the salicylates and influenza pandemic mortality hypothesis in 1918–1919”.

Clinical Infectious Diseases. 50 (8): 1203. PMID 20233050. doi:10.1086/651472.

• Pankhurst, Richard (1991). An Introduction to the Medical History of Ethiopia. Trenton: Red Sea Press. ISBN 978-0-932415-45-5.

• Patterson, K. D.; Pyle, G. F. (1991). “The geography and mortality of the 1918 influenza pandemic”.

Bull Hist Med. 65 (1): 4–21. PMID 2021692.

• Phillips, Howard (2010). “The re-appearing shadow of 1918: trends in the historiography of the 1918– 19 influenza pandemic”. Can Bull Med Hist. 21 (1): 121–134. PMID 15202430.

• Porras-Gallo, Maria; Davis, Ryan A., eds. (2014).

“The Spanish Influenza Pandemic of 1918–1919: Perspectives from the Iberian Peninsula and the Americas”. Rochester Studies in Medical History.

30. University of Rochester Press. ISBN 978-158046-496-3.

58 • Potter, C. W. (October 2006). “A History of Influenza”. J Appl Microbiol. 91 (4): 572– 579.

PMID 11576290. doi:10.1046/j.13652672.2001.01492.x.

• Price-Smith, Andrew T. (2008). Contagion and Chaos. Cambridge, MA: MIT Press. ISBN 9780-262-66203-1.

CHAPTER 6. 1918 FLU PANDEMIC • Vana, G.; Westover, K. M. (2008). “Origin of the 1918 Spanish influenza virus: a comparative genomic analysis”. Molecular Phylogenetics and Evolution. 47 (3): 1100–1110. PMID 18353690. doi:10.1016/j.ympev.2008.02.003.

• Vilensky, J. A.; Foley, P.; Gilman, S. (2007).

“Children and encephalitis lethargica: a historical”.

Pediatr Neurol. 37 (2): 79–84. PMID 17675021. doi:10.1016/j.pediatrneurol.2007.04.012.

• Rice, Geoffrey W. (2005). Black November; the 1918 Influenza Pandemic in New Zealand (2nd ed.). University of Canterbury Press. ISBN 9786.7.3 1-877257-35-3.

• Simonsen, L.; Clarke, M.; Schonberger, L.; Arden, N.; Cox, N.; Fukuda, K. (1998). “Pandemic versus Epidemic Influenza Mortality: A Pattern of Changing Age Distribution”. The Journal of Infectious Diseases. 178 (1): 53–60. JSTOR 30114117.

PMID 9652423. doi:10.1086/515616.

• Starko, Karen M. (2009). “Salicylates and Pandemic Influenza Mortality, 1918–1919, Pharmacology, Pathology, and Historic Evidence”. Clinical Infectious Diseases. 49 (9): 1405–1410.

PMID 19788357. doi:10.1086/606060. (summary

by Infectious Diseases Society of America and ScienceDaily, October 3, 2009) • Starko, Karen M. (2010). “Reply to Noymer et al.”.

Clinical Infectious Diseases. 50 (8): 1203–1204. doi:10.1086/651473.

• Taubenberger, J.; Reid, A.; Janczewski, T.; Fanning, T. (2001). “Integrating historical, clinical and molecular genetic data in order to explain the origin and virulence of the 1918 Spanish influenza virus”.

Philos Trans R Soc Lond B Biol Sci. 356 (1416): 1829–1839. PMC 1088558 . PMID 11779381. doi:10.1098/rstb.2001.1020.

• Taubenberger, J.; Reid, A.; Lourens, R. M.; Wang, R.; Jin, G.; Fanning, T. G. (2005). “Characterization of the 1918 influenza virus polymerase genes”. Nature. 437 (7060): 889–893.

Bibcode:2005Natur.437..889T. PMID 16208372. doi:10.1038/nature04230.

• Taubenberger, Jeffery K.; Morens, David M. (2006). “1918 Influenza: the mother of all pandemics”. Emerging Infectious Diseases. Centers for Disease Control and Prevention. 12 (1): 15–22. PMC 3291398 . PMID 16494711. doi:10.3201/eid1201.050979. Archived from the original on 1 October 2009. Retrieved 28 September 2009.

• Valentine, Vikki (20 February 2006). “Origins of the 1918 Pandemic: The Case for France”. NPR. Retrieved 2 October 2011.

Further reading

• Beiner, Guy (2006). “Out in the Cold and Back: New-Found Interest in the Great Flu”. Cultural and Social History. 3 (4): 496–505.

• Duncan, Kirsty (2003). Hunting the 1918 flu: one scientist’s search for a killer virus (illustrated ed.).

University of Toronto Press. ISBN 978-0-80208748-5.

• Humphries, Mark Osborne. The Last Plague: Spanish Influenza and the Politics of Public Health in Canada (University of Toronto Press; 29013) examines the public-policy impact of the 1918 epidemic, which killed 50,000 Canadians.

• Johnson, Niall (2006). Britain and the 1918–19 Influenza Pandemic: A Dark Epilogue. London and New York: Routledge. ISBN 0-415-36560-0.

• Johnson, Niall (2003). “Measuring a pandemic: Mortality, demography and geography”. Popolazione e Storia: 31–52.

• Johnson, Niall (2003). “Scottish 'flu – The Scottish mortality experience of the “Spanish flu”.

Scottish Historical Review. 83 (2): 216–226. doi:10.3366/shr.2004.83.2.216.

• Kolata, Gina (1999). Flu: The Story of the Great Influenza Pandemic of 1918 and the Search for the Virus That Caused It. New York: Farrar, Straus and Giroux. ISBN 0-374-15706-5.

• Little, Jean (2007). If I Die Before I Wake: The Flu Epidemic Diary of Fiona Macgregor, Toronto, Ontario, 1918. Dear Canada. Markham, Ont.: Scholastic Canada. ISBN 978-0-439-98837-7.

• Noymer, Andrew; Michel Garenne (2000). “The 1918 Influenza Epidemic’s Effects on Sex Differentials in Mortality in the United States”. Population and Development Review. 26 (3): 565–581. PMC 2740912 . PMID 19530360. doi:10.1111/j.17284457.2000.00565.x.

• Oxford JS, Sefton A, Jackson R, Innes W, Daniels RS, Johnson NP (2002). “World War I may have allowed the emergence of “Spanish” influenza”. The

6.8. EXTERNAL LINKS Lancet infectious diseases. 2 (2): 111–4. PMID 11901642. doi:10.1016/S1473-3099(02)00185-8.

• Oxford JS, Sefton A, Jackson R, Johnson NP, Daniels RS (1999). “Who’s that lady?". Nat. Med. 5 (12): 1351–2.

PMID 10581070. doi:10.1038/70913.

• Pettit, Dorothy; Janice Bailie (2008). A Cruel Wind: Pandemic Flu in America, 1918–1920.

Murfreesboro, TN: Timberlane Books. ISBN 9780-9715428-2-2.

• Phillips, Howard; Killingray, David, eds. (2003).

The Spanish Flu Pandemic of 1918: New Perspectives. London and New York: Routledge.

59 • The 1918 Influenza Pandemic in New Zealand – includes recorded recollections of people who lived through it • PBS – recovery of flu samples from Alaskan flu victims • An Avian Connection as a Catalyst to the 1918– 1919 Influenza Pandemic • Fluwiki.com Annotated links to articles, books and scientific research on the 1918 influenza pandemic • Alaska Science Forum – Permafrost Preserves Clues to Deadly 1918 Flu • Pathology of Influenza in France, 1920 Report

• Rice, Geoffrey W.; Edwina Palmer (1993). “Pandemic Influenza in Japan, 1918–1919: Mortality Patterns and Official Responses”. Journal of Japanese Studies. 19 (2): 389–420. JSTOR 132645. doi:10.2307/132645.

• Yesterday’s News blog 1918 newspaper account on impact of flu on Minneapolis

• Tumpey TM, García-Sastre A, Mikulasova A, et al. (2002). “Existing antivirals are effective against influenza viruses with genes from the 1918 pandemic virus”. Proc. Natl.

Acad.

Sci. U.S.A. 99 (21): 13849–54.

Bibcode:2002PNAS...9913849T. PMC 129786 .

PMID 12368467. doi:10.1073/pnas.212519699.

• Spanish Influenza in North America, 1918–1919

• “Study uncovers a lethal secret of 1918 influenza virus” University of Wisconsin – Madison, 17 January 2007

• 1918 Influenza Virus and memory B-cells – Exposure to virus generates lifelong immune response.

• Influenza Research Database – Database of influenza genomic sequences and related information.

• Spanish Flu with rare pictures from Otis Historical Archives

6.8 External links • Nature “Web Focus” on 1918 flu, including new research • Influenza Pandemic on stanford.edu • The Great Pandemic: The U.S. in 1918–1919. US Dept. of HHS • The American Influenza Epidemic of 1918–1919: A Digital Encyclopedia Largest digital collection of newspapers, archival manuscripts and interpretive essays exploring the impact of the epidemic on 50 U.S. cities (Univ. of Michigan).

• Little evidence for New York City quarantine in 1918 pandemic. 27 Nov 2007 (CIDRAP News) • Flu by Eileen A. Lynch. The devastating effect of the Spanish flu in the city of Philadelphia, PA, USA • Dialog: An Interview with Dr. Jeffery Taubenberger on Reconstructing the Spanish Flu • The Deadly Virus – The Influenza Epidemic of 1918 US National Archives and Records Administration – pictures and records of the time

• “No Ordinary Flu” a comic book of the 1918 flu pandemic published by Seattle & King County Public Health • “Influenza 1918” The American Experience (PBS) • “Closing in on a Killer: Scientists Unlock Clues to the Spanish Influenza Virus” An online exhibit from the National Museum of Health and Medicine.

• Sources for the study of the 1918 influenza pandemic in Sheffield, UK Produced by Sheffield City Council’s Libraries and Archives • Booknotes interview with Gina Kolata on Flu: The Story of the Great Influenza Pandemic of 1918 and the Search for the Virus That Caused It, 27 February 2000.

Chapter 7

2009 flu pandemic The 2009 flu pandemic or swine flu was an influenza pandemic, and the second of the two pandemics involving H1N1 influenza virus (the first of them being the 1918 flu pandemic), albeit in a new version. First described in April 2009, the virus appeared to be a new strain of H1N1 which resulted when a previous triple reassortment of bird, swine and human flu viruses further combined with a Eurasian pig flu virus,[2] leading to the term "swine flu".[3] Unlike most strains of influenza, H1N1 does not disproportionately infect adults older than 60 years; this was an unusual and characteristic feature of the H1N1 pandemic.[4] Even in the case of previously very healthy people, a small percentage will develop pneumonia or acute respiratory distress syndrome (ARDS). This manifests itself as increased breathing difficulty and typically occurs 3–6 days after initial onset of flu symptoms.[5][6] The pneumonia caused by flu can be either direct viral pneumonia or a secondary bacterial pneumonia. In fact, a November 2009 New England Journal of Medicine article recommends that flu patients whose chest X-ray indicates pneumonia receive both antivirals and antibiotics.[7] In particular, it is a warning sign if a child (and presumably an adult) seems to be getting better and then relapses with high fever, as this relapse may be bacterial pneumonia.[8]

7.1 History

flu virus cannot be spread by eating pork or pork products;[12][13] similar to other influenza viruses, it is typically contracted by person to person transmission through respiratory droplets.[14] Symptoms usually last 4– 6 days.[15] Antivirals (oseltamivir or zanamivir) were recommended for those with more severe symptoms or those in an at-risk group.[16] The pandemic began to taper off in November 2009,[17] and by May 2010, the number of cases was in steep decline.[18][19][20][21] On 10 August 2010, the DirectorGeneral of the WHO, Margaret Chan, announced the end of the H1N1 pandemic,[22] and announced that the H1N1 influenza event has moved into the post-pandemic period.[23] According to the latest WHO statistics (as of July 2010), the virus has killed more than 18,000 people since it appeared in April 2009, however they state that the total mortality (including deaths unconfirmed or unreported) from the H1N1 strain is “unquestionably higher”.[18][24] Critics claimed the WHO had exaggerated the danger, spreading “fear and confusion” rather than “immediate information”.[25] The WHO began an investigation to determine[26] whether it had “frightened people unnecessarily”.[27] A flu follow-up study done in September 2010, found that “the risk of most serious complications was not elevated in adults or children.”[28] In an 5 August 2011 PLoS ONE article, researchers estimated that the 2009 H1N1 global infection rate was 11% to 21%, lower than what was previously expected.[29] However, by 2012, research showed that as many as 579,000 people could have been killed by the disease, as only those fatalities confirmed by laboratory testing were included in the original number, and meant that many of those without access to health facilities went uncounted. The majority of these deaths occurred in Africa and Southeast Asia. Experts, including the WHO, have agreed that an estimated 284,500 people were killed by the disease, much higher than the initial death toll.[30][31]

Initially called an “outbreak”, widespread H1N1 infection was first recognized in the state of Veracruz, Mexico, with evidence that the virus had been present for months before it was officially called an “epidemic”.[9] The Mexican government closed most of Mexico City's public and private facilities in an attempt to contain the spread of the virus; however, it continued to spread globally, and clinics in some areas were overwhelmed by infected people. In late April the World Health Organization (WHO) declared its first ever “public health emergency of inter- 7.2 Classification national concern,” or PHEIC,[10] and in June the WHO and the U.S. CDC stopped counting cases and declared Further information: Pandemic H1N1/09 virus § the outbreak a pandemic.[11] Nomenclature Despite being informally called “swine flu”, the H1N1 60

7.3. SIGNS AND SYMPTOMS The initial outbreak was called the “H1N1 influenza”, or “Swine Flu” by American media. It is called the pandemic H1N1/09 virus by the WHO,[32] while the U.S. Centers for Disease Control and Prevention refer to it as “novel influenza A (H1N1)" or “2009 H1N1 flu”.[33] In the Netherlands, it was originally called “Pig Flu”, but is now called “New Influenza A (H1N1)" by the national health institute, although the media and general population use the name “Mexican Flu”. South Korea and Israel briefly considered calling it the “Mexican virus”.[34] Later, the South Korean press used “SI”, short for “swine influenza”. Taiwan suggested the names “H1N1 flu” or “new flu”, which most local media adopted.[35] The World Organization for Animal Health proposed the name “North American influenza”.[36] The European Commission adopted the term “novel flu virus”.[37]

61

7.3.1 Severe cases The World Health Organization reports that the clinical picture in severe cases is strikingly different from the disease pattern seen during epidemics of seasonal influenza.

While people with certain underlying medical conditions are known to be at increased risk, many severe cases occur in previously healthy people. In severe cases, patients generally begin to deteriorate around three to five days after symptom onset. Deterioration is rapid, with many patients progressing to respiratory failure within 24 hours, requiring immediate admission to an intensive care unit.

Upon admission, most patients need immediate respiratory support with mechanical ventilation.[45] Research later indicated that the severe flu effects in healthy young and middle-aged adults are caused by an excessive immune response.[46]

7.3.2 Complications

7.3 Signs and symptoms Main article: Influenza § Signs and symptoms The symptoms of H1N1 flu are similar to those of other influenzas, and may include fever, cough (typically a “dry cough”), headache, muscle or joint pain, sore throat, chills, fatigue, and runny nose. Diarrhea, vomiting, and neurological problems have also been reported in some cases.[38][39] People at higher risk of serious complications include those aged over 65, children younger than 5, children with neurodevelopmental conditions, pregnant women (especially during the third trimester),[5][40] and those of any age with underlying medical conditions, such as asthma, diabetes, obesity, heart disease, or a weakened immune system (e.g., taking immunosuppressive medications or infected with HIV).[41] More than 70% of hospitalizations in the U.S. have been people with such underlying conditions, according to the CDC.[42]

Most complications have occurred among previously healthy individuals, with obesity and respiratory disease as the strongest risk factors. Pulmonary complications are common. Primary influenza pneumonia occurs most commonly in adults and may progress rapidly to acute lung injury requiring mechanical ventilation. Secondary bacterial infection is more common in children. Staphylococcus aureus, including methicillinresistant strains, is an important cause of secondary bacterial pneumonia with a high mortality rate; streptococcus pneumoniae is the second most important cause of secondary bacterial pneumonia for children and primary for adults. Neuromuscular and cardiac complications are unusual but may occur.[47] A United Kingdom investigation of risk factors for hospitalisation and poor outcome with pandemic A/H1N1 influenza looked at 631 patients from 55 hospitals admitted with confirmed infection from May through September 2009. 13% were admitted to a high dependency or intensive care unit and 5% died; 36% were aged <16 years and 5% were aged ≥65 years. Non-white and pregnant patients were over-represented. 45% of patients had at least one underlying condition, mainly asthma, and 13% received antiviral drugs before admission. Of 349 with documented chest x-rays on admission, 29% had evidence of pneumonia, but bacterial co-infection was uncommon. Multivariate analyses showed that physicianrecorded obesity on admission and pulmonary conditions other than asthma or chronic obstructive pulmonary disease (COPD) were associated with a severe outcome, as were radiologically confirmed pneumonia and a raised Creactive protein (CRP) level (≥100 mg/l). 59% of all inhospital deaths occurred in previously healthy people.[48]

In September 2009, the CDC reported that the H1N1 flu “seems to be taking a heavier toll among chronically ill children than the seasonal flu usually does.”[8] Through 8 August 2009, the CDC had received 36 reports of paediatric deaths with associated influenza symptoms and laboratory-confirmed pandemic H1N1 from state and local health authorities within the United States, with 22 of these children having neurodevelopmental conditions such as cerebral palsy, muscular dystrophy, or developmental delays.[43] “Children with nerve and muscle problems may be at especially high risk for complications because they cannot cough hard enough to clear their airways”.[8] From 26 April 2009, to 13 February 2010, the CDC had received reports of the deaths of 277 chil- Fulminant (sudden-onset) myocarditis has been linked to dren with laboratory-confirmed 2009 influenza A (H1N1) infection with H1N1, with at least four cases of myocardiwithin the United States.[44] tis confirmed in patients also infected with A/H1N1.

62 Three out of the four cases of H1N1-associated myocarditis were classified as fulminant, and one of the patients died.[49] Also, there appears to be a link between severe A/H1N1 influenza infection and pulmonary embolism. In one report, five out of 14 patients admitted to the intensive care unit with severe A/H1N1 infection were found to have pulmonary emboli.[50] An article published in JAMA in September 2010[51] challenged previous reports and stated that children infected in the 2009 flu pandemic were no more likely to be hospitalised with complications or get pneumonia than those who catch seasonal strains. Researchers found that about 1.5% of children with the H1N1 swine flu strain were hospitalised within 30 days, compared with 3.7% of those sick with a seasonal strain of H1N1 and 3.1% with an H3N2 virus.[28]

7.4 Diagnosis Confirmed diagnosis of pandemic H1N1 flu requires testing of a nasopharyngeal, nasal or oropharyngeal tissue swab from the patient.[52] Real-time RT-PCR is the recommended test as others are unable to differentiate between pandemic H1N1 and regular seasonal flu.[52] However, most people with flu symptoms do not need a test for pandemic H1N1 flu specifically, because the test results usually do not affect the recommended course of treatment.[53] The U.S. CDC recommend testing only for people who are hospitalized with suspected flu, pregnant women and people with weakened immune systems.[53] For the mere diagnosis of influenza and not pandemic H1N1 flu specifically, more widely available tests include rapid influenza diagnostic tests (RIDT), which yield results in about 30 minutes, and direct and indirect immunofluorescence assays (DFA and IFA), which take 2–4 hours.[54] Due to the high rate of RIDT false negatives, the CDC advises that patients with illnesses compatible with novel influenza A (H1N1) virus infection but with negative RIDT results should be treated empirically based on the level of clinical suspicion, underlying medical conditions, severity of illness and risk for complications, and if a more definitive determination of infection with influenza virus is required, testing with rRT-PCR or virus isolation should be performed.[55] Rhonda Medows of the Georgia Department of Community Health states that the rapid tests are incorrect anywhere from 30% to 90% of the time and warns doctors in her state not to use them because they are wrong so often.[56] The use of RIDTs has also been questioned by researcher Paul Schreckenberger of the Loyola University Health System, who suggests that rapid tests may actually pose a dangerous public health risk.[57] Nikki Shindo of the WHO has expressed regret at reports of treatment being delayed by waiting for H1N1 test results and suggests, "[D]octors should not wait for the laboratory confirmation but make diagnosis based on clinical and epidemiological back-

CHAPTER 7. 2009 FLU PANDEMIC grounds and start treatment early”.[58] On 22 June 2010, the CDC announced a new test called the “CDC Influenza 2009 A (H1N1)pdm Real-Time RTPCR Panel (IVD)". It uses a molecular biology technique to detect influenza A viruses and specifically the 2009 H1N1 virus. The new test will replace the previous real-time RT-PCR diagnostic test used during the 2009 H1N1 pandemic, which received an emergency use authorization from the U.S. Food and Drug Administration in April 2009. Tests results are available in four hours and are 96% accurate.[59]

7.5 Cause Main article: Pandemic H1N1/09 virus The virus was found to be a novel strain of influenza for which extant vaccines against seasonal flu provided little protection. A study at the U.S. Centers for Disease Control and Prevention published in May 2009 found that children had no preexisting immunity to the new strain but that adults, particularly those older than 60, had some degree of immunity. Children showed no cross-reactive antibody reaction to the new strain, adults aged 18 to 60 had 6–9%, and older adults 33%.[60][61] While it has been thought that these findings suggest the partial immunity in older adults may be due to previous exposure to similar seasonal influenza viruses, a November 2009 study of a rural unvaccinated population in China found only a 0.3% cross-reactive antibody reaction to the H1N1 strain, suggesting that previous vaccinations for seasonal flu and not exposure may have resulted in the immunity found in the older U.S. population.[62] It has been determined that the strain contains genes from five different flu viruses: North American swine influenza, North American avian influenza, human influenza and two swine influenza viruses typically found in Asia and Europe. Further analysis has shown that several proteins of the virus are most similar to strains that cause mild symptoms in humans, leading virologist Wendy Barclay to suggest on 1 May 2009, that the initial indications are that the virus was unlikely to cause severe symptoms for most people.[63] The virus is currently less lethal than previous pandemic strains and kills about 0.01–0.03% of those infected; the 1918 influenza was about one hundred times more lethal and had a case fatality rate of 2–3%.[64] By 14 November 2009, the virus had infected one in six Americans with 200,000 hospitalisations and 10,000 deaths – as many hospitalizations and fewer deaths than in an average flu season overall, but with much higher risk for those under 50. With deaths of 1,100 children and 7,500 adults 18 to 64, these figures “are much higher than in a usual flu season”.[65] In June 2010, scientists from Hong Kong reported discov-

7.6. PREVENTION ery of a new swine flu virus which is a hybrid of the pandemic H1N1 virus and viruses previously found in pigs. It is the first report of a reassortment of the pandemic virus, which in humans has been slow to evolve. Nancy Cox, head of the influenza division at the U.S. Centers for Disease Control and Prevention, has said, “This particular paper is extremely interesting because it demonstrates for the first time what we had worried about at the very onset of the pandemic, and that is that this particular virus, when introduced into pigs, could reassort with the resident viruses in pigs and we would have new gene constellations. And bingo, here we are.” Pigs have been termed the mixing vessel of flu because they can be infected both by avian flu viruses, which rarely directly infect people, and by human viruses. When pigs become simultaneously infected with more than one virus, the viruses can swap genes, producing new variants which can pass to humans and sometimes spread amongst them.[66] “Unlike the situation with birds and humans, we have a situation with pigs and humans where there’s a two-way street of exchange of viruses. With pigs it’s very much a two-way street”.[67]

7.5.1

63 In the UK, the NHS recommended vaccine priority go to people over six months old who were clinically at risk for seasonal flu, pregnant women and households of people with compromised immunity.[75] Although it was initially thought that two injections would be required, clinical trials showed that the new vaccine protected adults “with only one dose instead of two”, and so the limited vaccine supplies would go twice as far as had been predicted.[76][77] Health officials worldwide were also concerned because the virus was new and could easily mutate and become more virulent, even though most flu symptoms were mild and lasted only a few days without treatment. Officials also urged communities, businesses and individuals to make contingency plans for possible school closures, multiple employee absences for illness, surges of patients in hospitals and other effects of potentially widespread outbreaks.[78] In February 2010, the CDC’s Advisory Committee on Immunization Practices voted for “universal” flu vaccination in the U.S. to include all people over six months of age. The 2010–2011 vaccine will protect against the 2009 H1N1 pandemic virus and two other flu viruses.[79]

Transmission

Spread of the H1N1 virus is thought to occur in the same 7.6.1 Public health response way that seasonal flu spreads. Flu viruses are spread mainly from person to person through coughing or sneez- See also: 2009 flu pandemic by country ing by people with influenza. Sometimes people may be- On 27 April 2009, the European Union health commiscome infected by touching something – such as a surface or object – with flu viruses on it and then touching their face. “Avoid touching your eyes, nose or mouth. Germs spread this way”.[12] The basic reproduction number (the average number of other individuals whom each infected individual will infect, in a population which has no immunity to the disease) for the 2009 novel H1N1 is estimated to be 1.75.[68] A December 2009 study found that the transmissibility of the H1N1 influenza virus in households is lower than that seen in past pandemics. Most transmissions occur soon 50 000+ confirmed cases before or after the onset of symptoms.[69] 5,000+ confirmed cases 500+ confirmed cases

The H1N1 virus has been transmitted to animals, includ50+ confirmed cases ing swine, turkeys, ferrets, household cats, at least one 5+ confirmed cases [70][71][72][73] dog and a cheetah.

1+ confirmed cases

7.6 Prevention See also: Influenza prevention, 2009 flu pandemic vaccine, and Influenza vaccine § 2009-2010 Northern Hemisphere winter season The H1N1 vaccine was initially in short supply and in the U.S., the CDC recommended that initial doses should go to priority groups such as pregnant women, people who live with or care for babies under six months old, children six months to four years old and health-care workers.[74]

sioner advised Europeans to postpone nonessential travel to the United States or Mexico. This followed the discovery of the first confirmed case in Spain.[80] On 6 May 2009, the Public Health Agency of Canada announced that their National Microbiology Laboratory (NML) had mapped the genetic code of the swine flu virus, the first time that had been done.[81] In the U.K., the National Health Service launched a website, the National Pandemic Flu Service,[82] allowing patients to self-assess and get an authorisation number for antiviral medication. The system was expected to reduce the burden on general practitioners.[75]

64 U.S. officials observed that six years of concern about H5N1 avian flu did much to prepare for the current H1N1 flu outbreak, noting that after H5N1 emerged in Asia, ultimately killing about 60% of the few hundred people infected by it over the years, many countries took steps to try to prevent any similar crisis from spreading further.[83] The CDC and other U.S. governmental agencies[84] used the summer lull to take stock of the United States’ response to H1N1 flu and attempt to patch any gaps in the public health safety net before flu season started in early autumn.[85] Preparations included planning a second influenza vaccination program in addition to that for seasonal influenza, and improving coordination between federal, state and local governments and private health providers.[85] On 24 October 2009, U.S. President Obama declared swine flu a national emergency, giving Secretary of Health and Human Services Kathleen Sebelius authority to grant waivers to requesting hospitals from usual federal requirements.[86]

CHAPTER 7. 2009 FLU PANDEMIC cine administration demonstrated the shortcomings of the world’s capacity for vaccine-production, as well as problems with international distribution. Some manufacturers and wealthy countries had concerns regarding liability and regulations, as well as the logistics of transporting, storing, and administering vaccines to be donated to poorer countries.[87]

7.6.3 Accusations of conflict of interest

In January 2010, Wolfgang Wodarg, a German deputy who trained as a physician and now chairs the health committee at the Council of Europe, claimed major firms had organised a “campaign of panic” to put pressure on the World Health Organisation (WHO) to declare a “false pandemic” to sell vaccines. Wodarg said the WHO’s “false pandemic” flu campaign is “one of the greatest medicine scandals of the century”. He said that the “false pandemic” campaign began in May 2009 in Mexico City, when a hundred or so “normal” reported influenza cases 7.6.2 Vaccines were declared to be the beginning of a threatening new pandemic, although he said there was little scientific evMain article: 2009 flu pandemic vaccine idence for this. Nevertheless, he argued that the WHO, By 19 November 2009, doses of vaccine had been ad“in cooperation with some big pharmaceutical companies and their scientists, re-defined pandemics”, removing the statement that “an enormous amount of people have contracted the illness or died” from its existing definition and replacing it by stating simply that there has to be a virus, spreading beyond borders and to which people have no immunity.[88]

Barack Obama, then-president of the United States, being vaccinated against H1N1 flu on 20 December 2009.

The WHO responded by stating that they take their duty to provide independent advice seriously and guarded against interference from outside interests. Announcing a review of the WHO’s actions, spokeswoman Fadela Chaib stated: “Criticism is part of an outbreak cycle. We expect and indeed welcome criticism and the chance to discuss it”.[89][90] In March 2010, the Council of Europe launched an enquiry into “the influence of the pharmaceutical companies on the global swine flu campaign”, and a preliminary report is in preparation.[91]

ministered in over 16 countries. A 2009 review by the U.S. National Institutes of Health (NIH) concluded that On 12 April 2010, Keiji Fukuda, the WHO’s top inthe 2009 H1N1 vaccine has a safety profile similar to that fluenza expert, stated that the system leading to the decof seasonal vaccine. laration of a pandemic led to confusion about H1N1 cirIn 2011, a study from the US Flu Vaccine Effectiveness culating around the world, and he expressed concern that Network estimated the overall effectiveness of all pan- there was a failure to communicate in regard to uncerdemic H1N1 vaccines at 56%. A CDC study released tainties about the new virus, which turned out to be not as 28 Jan 2013, estimated that the Pandemic H1N1 vaccine deadly as feared. WHO Director-General Margaret Chan saved roughly 300 lives and prevented about 1 million ill- has appointed 29 flu experts from outside the organization nesses in the US. The study concluded that had the vac- to conduct a review of WHO’s handling of the H1N1 flu cination program started 2 weeks earlier, close to 60% pandemic. She has told them, “We want a frank, criticredible and independent review of our more cases could have been prevented. The study was cal, transparent, [92] performance”. based on an effectiveness in preventing cases, hospitalizations, and deaths of 62% for all subgroups except people over 65, for whom the effectiveness was estimated at 43%. The effectiveness was based on European and Asian studies and expert opinion.[3] The delay in vac-

In June 2010, Fiona Godlee, editor-in-chief of the BMJ, published an editorial which criticised the WHO, saying that an investigation had disclosed that some of the experts advising WHO on the pandemic had financial

7.6. PREVENTION ties with drug companies which were producing antivirals and vaccines.[93] Margaret Chan, Director-General of the WHO, replied stating, “Without question, the BMJ feature and editorial will leave many readers with the impression that WHO’s decision to declare a pandemic was at least partially influenced by a desire to boost the profits of the pharmaceutical industry. The bottom line, however, is that decisions to raise the level of pandemic alert were based on clearly defined virological and epidemiological criteria. It is hard to bend these criteria, no matter what the motive”.[92]

7.6.4

Infection control

Travel precautions

65 the effect of the virus. They did not recommend closing borders or restricting travel.[94] On 26 April 2009, the Chinese government announced that visitors returning from flu-affected areas who experienced flu-like symptoms within two weeks would be quarantined.[95] U.S. airlines had made no major changes as of the beginning of June 2009, but continued standing practices which include looking for passengers with symptoms of flu, measles or other infections, and relying on in-flight air filters to ensure that aircraft were sanitised.[96] Masks were not generally provided by airlines and the CDC did not recommend that airline crews wear them.[96] Some non-U.S. airlines, mostly Asian, including Singapore Airlines, China Eastern Airlines, China Southern Airlines, Cathay Pacific and Aeromexico, took measures such as stepping up cabin cleaning, installing state-of-the-art air filters and allowing in-flight staff to wear face masks.[96] According to studies conducted in Australia and Japan, screening individuals for influenza symptoms at airports during the 2009 H1N1 outbreak was not an effective method of infection control.[97][98]

Schools

Flu inspection on a flight arriving in China

U.S. government officials have been especially concerned about schools because the H1N1 flu virus appears to disproportionately affect young and school-age people, between six months and 24 years of age.[99] The H1N1 outbreak led to numerous precautionary school closures in some areas. Rather than closing schools, the CDC recommended that students and school workers with flu symptoms should stay home for either seven days total, or until 24 hours after symptoms subsided, whichever was longer.[100] The CDC also recommended that colleges should consider suspending fall 2009 classes if the virus began to cause severe illness in a significantly larger share of students than the previous spring. They also urged schools to suspend rules, such as penalties for late papers or missed classes or requirements for a doctor’s note, to enforce “self-isolation” and prevent students from venturing out while ill;[101] schools were advised to set aside a room for people developing flu-like symptoms while they waited to go home and to have ill students or staff and those caring for them use face masks.[102]

In California, school districts and universities were on alert and worked with health officials to launch education campaigns. Many planned to stockpile medical supplies and discuss worst-case scenarios, including plans to provide lessons and meals for low-income children in case elementary and secondary schools closed.[103] University Thermal imaging camera and screen, photographed in an airport of California campuses stockpiled supplies, from paper terminal in Greece. Thermal imaging can detect elevated body masks and hand sanitizer to food and water.[103] To help temperature, one of the signs of swine flu. prepare for contingencies, University of Maryland School of Medicine professor of pediatrics James C. King Jr. On 7 May 2009, the WHO stated that containment was suggested that every county should create an “influenza not feasible and that countries should focus on mitigating action team” to be run by the local health department,

66

CHAPTER 7. 2009 FLU PANDEMIC

parents and school administrators.[104] By 28 October 2009, about 600 schools in the United States had been temporarily closed, affecting over 126,000 students in 19 states.[105]

disagreement about the value of wearing facial masks, some experts fearing that masks may give people a false sense of security and should not replace other standard precautions.[111] Masks may benefit people in close contact with infected persons, but it is unknown whether they prevent H1N1 flu infection.[111] Yukihiro Nishiyama, Workplace professor of virology at Nagoya University's School of Medicine, commented that the masks are “better than Fearing a worst-case scenario, the U.S. Department nothing, but it’s hard to completely block out an airborne of Health and Human Services (HHS), the Cen- virus since it can easily slip through the gaps”.[112] ters for Disease Control and Prevention and the Department of Homeland Security (DHS) developed up- According to mask manufacturer 3M, masks will filter dated guidance[106] and a video for employers to use out particles in industrial settings, but “there are no eslimits for biological agents such as as they developed plans to respond to the H1N1 out- tablished exposure [111] swine flu virus”.

However, despite the lack of evibreak. The guidance suggested that employers condence of effectiveness, the use of such masks is comsider and communicate their objectives, such as reduc[112][113] mon in Asia.

They are particularly popular in ing transmission among staff, protecting people who are Japan, where cleanliness and hygiene are highly valued at increased risk of influenza-related complications from and where etiquette obligates those who are sick to wear becoming infected, maintaining business operations, and [112] masks to avoid spreading disease. minimising adverse effects on other entities in their supply chains.[106] The CDC estimated that as much as 40% of the workforce might be unable to work at the peak of the pandemic due to the need for many healthy adults to stay home and care for an ill family member,[107] and advised that individuals should have steps in place should a workplace close down or a situation arise that requires working from home.[108] The CDC further advised that persons in the workplace should stay home sick for seven days after getting the flu, or 24 hours after symptoms end, whichever is longer.[100]

Quarantine

During the height of the fear of a pandemic, some countries initiated or threatened to initiate quarantines of foreign visitors suspected of having or being in contact with others who may have been infected. In May 2009, the Chinese government confined 21 U.S. students and three teachers to their hotel rooms.[114] As a result, the US State Department issued a travel alert about China’s anti-flu measures and warned travellers against travelling to China [115] In Hong Kong, an entire hotel was quarantined In the UK, the Health and Safety Executive (HSE) also if ill.

[116] [109] with 240 guests; Australia ordered a cruise ship with issued general guidance for employers.

2,000 passengers to stay at sea because of a swine flu threat.[117] Egyptian Muslims who went on the annual Facial masks pilgrimage to Mecca risked being quarantined upon their return.[118] Russia and Taiwan said they would quarantine visitors with fevers who come from areas where the flu was present.[119] Japan quarantined 47 airline passengers in a hotel for a week in mid-May,[120] then in mid-June India suggested pre-screening “outbound” passengers from countries thought to have a high rate of infection.[121] Pigs and food safety Main article: 2009 flu pandemic actions concerning pigs

Mexico City Metro

The U.S. CDC does not recommend use of face masks or respirators in non-health care settings, such as schools, workplaces, or public places, with a few exceptions: people who are ill with the virus when around other people, and people who are at risk for severe illness while caring for someone with the flu.[110] There has been some

The pandemic virus is a type of swine influenza, derived originally from a strain which lived in pigs, and this origin gave rise to the common name of “swine flu”. This term is widely used by mass media. The virus has been found in American hogs,[122] and Canadian[123] as well as in hogs in Northern Ireland, Argentina, and Norway.[124] Leading health agencies and the United States Secretary of Agriculture have stressed that eating properly cooked pork or other food products derived from pigs will not cause flu.[125][126] Nevertheless, on 27 April, Azerbaijan

7.7. TREATMENT imposed a ban on the importation of animal husbandry products from the entire Americas.[127] The Indonesian government also halted the importation of pigs and initiated the examination of 9 million pigs in Indonesia.[128] The Egyptian government ordered the slaughter of all pigs in Egypt on 29 April 2009.[129]

67 addition, a British report found that people often failed to complete a full course of the drug or took the medication when not needed.[137]

7.7.1 Side effects

Both medications have known side effects, including lightheadedness, chills, nausea, vomiting, loss of appetite 7.7 Treatment and trouble breathing. Children were reported to be at increased risk of self-injury and confusion after taking Further information: Influenza treatment oseltamivir.[130] The WHO warn against buying antiviral medications from online sources, and estimate that half A number of methods have been recommended to the drugs sold by online pharmacies without a physical [138] help ease symptoms, including adequate liquid intake address are counterfeit. and rest.[130] Over-the-counter pain medications such as acetaminophen and ibuprofen do not kill the virus; however, they may be useful to reduce symptoms.[131] Aspirin 7.7.2 Resistance and other salicylate products should not be used by people under 16 with any flu-type symptoms because of the In December 2012, 2010, the World Health Organization (WHO) reported 314 samples of the 2009 pandemic risk of developing Reye’s Syndrome.[132] H1N1 flu tested worldwide have shown resistance to If the fever is mild and there are no other complica- oseltamivir (Tamiflu).[139] This is not totally unexpected tions, fever medication is not recommended.[131] Most as 99.6% of the seasonal H1N1 flu strains tested have depeople recover without medical attention, although those veloped resistance to oseltamivir.[140] No circulating flu with pre-existing or underlying medical conditions are has yet shown any resistance to zanamivir (Relenza), the more prone to complications and may benefit from fur- other available anti-viral.[141] ther treatments.[133] People in at-risk groups should be treated with antivirals (oseltamivir or zanamivir) as soon as possible when they first experience flu symptoms. The at-risk groups include pregnant and post partum women, children under two years old, and people with underlying conditions such as respiratory problems.[16] People who are not in an at-risk group who have persistent or rapidly worsening symptoms should also be treated with antivirals.

People who have developed pneumonia should be given both antivirals and antibiotics, as in many severe cases of H1N1-caused illness, bacterial infection develops.[58] Antivirals are most useful if given within 48 hours of the start of symptoms and may improve outcomes in hospitalised patients.[134] In those beyond 48 hours who are moderately or severely ill, antivirals may still be beneficial.[14] If oseltamivir (Tamiflu) is unavailable or cannot be used, zanamivir (Relenza) is recommended as a substitute.[16][135] Peramivir is an experimental antiviral drug approved for hospitalised patients in cases where the other available methods of treatment are ineffective or unavailable.[136]

7.7.3 Effectiveness of antivirals questioned

On 8 December 2009, the Cochrane Collaboration, which reviews medical evidence, announced in a review published in BMJ that it had reversed its previous findings that the antiviral drugs oseltamivir (Tamiflu) and zanamivir (Relenza) can ward off pneumonia and other serious conditions linked to influenza. They reported that an analysis of 20 studies showed oseltamivir offered mild benefits for healthy adults if taken within 24 hours of onset of symptoms, but found no clear evidence it prevented lower respiratory tract infections or other complications of influenza.[142][143] Their published finding relates only to its use in healthy adults with influenza; they say nothing about its use in patients judged to be at high risk of complications (pregnant women, children under five and those with underlying medical conditions), and uncertainty over its role in reducing complications in healthy adults may still leave it as a useful drug for reducing the duration of symptoms. The drugs might eventually be To help avoid shortages of these drugs, the U.S. CDC demonstrated to be effective against flu-related complicaCollaboration concluded recommended oseltamivir treatment primarily for peo- tions; in general, the Cochrane [143][144] “Paucity of good data”. ple hospitalised with pandemic flu; people at risk of serious flu complications due to underlying medical con- Some specific results from the BMJ article include: “The ditions; and patients at risk of serious flu complications. efficacy of oral oseltamivir against symptomatic laboraThe CDC warned that the indiscriminate use of antivi- tory confirmed influenza was 61% (risk ratio 0.39, 95% ral medications to prevent and treat influenza could ease confidence interval 0.18 to 0.85) at 75 mg daily ... The rethe way for drug-resistant strains to emerge, which would maining evidence suggests oseltamivir did not reduce inmake the fight against the pandemic that much harder. In fluenza related lower respiratory tract complications (risk

68

CHAPTER 7. 2009 FLU PANDEMIC

ratio 0.55, 95% confidence interval 0.22 to 1.35)".[143] Notice especially the wide range for this second result.

was of a toddler from Mexico City who was visiting family in Brownsville, Texas, before being air-lifted to Houston for treatment.[153]

7.8 Epidemiology 7.8.3 Data reporting and accuracy Further information: 2009 flu pandemic timeline, 2009 flu pandemic tables, and 2009 flu pandemic by country While it is not known precisely where or when the virus originated,[146][147] analyses in scientific journals have suggested that the H1N1 strain responsible for the 2009 outbreak first evolved in September 2008 and circulated amongst humans for several months before being formally recognised and identified as a novel strain of influenza.[146][148]

7.8.1

Mexico

Further information: 2009 flu pandemic in Mexico The virus was first reported in two U.S. children in March 2009, but health officials have reported that it apparently infected people as early as January 2009 in Mexico.[149] The outbreak was first detected in Mexico City on 18 March 2009;[150] immediately after the outbreak was officially announced, Mexico notified the U.S. and World Health Organization, and within days of the outbreak Mexico City was “effectively shut down”.[151] Some countries cancelled flights to Mexico while others halted trade. Calls to close the border to contain the spread were rejected.[151] Mexico already had hundreds of non-lethal cases before the outbreak was officially discovered, and was therefore in the midst of a “silent epidemic”. As a result, Mexico was reporting only the most serious cases which showed more severe signs different from those of normal flu, possibly leading to a skewed initial estimate of the case fatality rate.[150]

7.8.2

United States

See also: GISAID, National Influenza Centers, Disease surveillance, and Clinical surveillance Influenza surveillance information “answers the questions of where, when, and what influenza viruses are circulating. It can be used to determine if influenza activity is increasing or decreasing, but cannot be used to ascertain how many people have become ill with influenza”.[154] For example, as of late June 2009, influenza surveillance information showed the U.S. had nearly 28,000 laboratory-confirmed cases including 3,065 hospitalisations and 127 deaths; but mathematical modelling showed an estimated 1 million Americans currently had the 2009 pandemic flu, according to Lyn Finelli, a flu surveillance official with the CDC.[155] Estimating deaths from influenza is also a complicated process. In 2005, influenza only appeared on the death certificates of 1,812 people in the US. The average annual US death toll from flu is, however, estimated to be 36,000.[156] The CDC explains:[157] "[I]nfluenza is infrequently listed on death certificates of people who die from flu-related complications” and hence, “Only counting deaths where influenza was included on a death certificate would be a gross underestimation of influenza’s true impact”.

Influenza surveillance information on the 2009 H1N1 flu pandemic is available, but almost no studies attempted to estimate the total number of deaths attributable to H1N1 flu. Two studies were carried out by the CDC; the later of them estimated that between 7,070 and 13,930 deaths were attributable to H1N1 flu from April to 14 November 2009.[158] During the same period, 1642 deaths were officially confirmed as caused by H1N1 flu.[159][160] The WHO state that total mortality (including deaths unconfirmed or unreported) from H1N1 flu is “unquestionably higher” than their own confirmed death statistics.[161]

Further information: 2009 flu pandemic in the United The initial outbreak received a week of near-constant media attention. Epidemiologists cautioned that the numStates ber of cases reported in the early days of an outbreak can be very inaccurate and deceptive, due to several The new strain was first identified by the CDC in two chil- causes, among them selection bias, media bias and incordren, neither of whom had been in contact with pigs. The rect reporting by governments. Inaccuracies could also first case, from San Diego County, California, was con- be caused by authorities in different countries looking at firmed from clinical specimens (nasopharyngeal swab) differing population groups. Furthermore, countries with examined by the CDC on 14 April 2009. A second case, poor health care systems and older laboratory facilities from nearby Imperial County, California, was confirmed may take longer to identify or report cases.[162] "[E]ven in on 17 April. The patient in the first confirmed case had developed countries the [numbers of flu deaths] are unflu symptoms including fever and cough on clinical exam- certain, because medical authorities don't usually verify ination on 30 March, and the second on 28 March.[152] who actually died of influenza and who died of a flu-like The first confirmed H1N1/09 pandemic flu death, which illness”.[163] Joseph S. Bresee (the CDC flu division’s epioccurred at Texas Children’s Hospital in Houston, Texas, demiology chief) and Michael Osterholm (director of the

7.9. COMPARISONS TO OTHER PANDEMICS AND EPIDEMICS

69

Center for Infectious Disease Research and Policy) have pointed out that millions of people have had H1N1 flu, usually in a mild form, so the numbers of laboratoryconfirmed cases were actually meaningless, and in July 2009, the WHO stopped keeping count of individual cases and focused more on major outbreaks.[164]

deaths ranged from about 5,000 to about 52,000, with an average of about 25,000. While the 36,000 number is often cited, it’s important to note that during that decade, influenza A (H3N2) was the predominant virus during most of the seasons, and H3N2 influenza viruses are typically associated with higher death rates. CDC believes that the range of deaths over the past 31 years (~3,000 to ~49,000) is a more accurate representation of the unpredictability 7.8.4 Followup and variability of flu-associated deaths.[170] The annual toll from seasonal influenza in the US is more accurately A Wisconsin study published in the Journal of the Ameri- estimated at 3000–49,000 deaths per year. So the H1N1 can Medical Association in September 2010, reported that pandemic estimated mortality of 8,870 to 18,300, places findings showed that the 2009 H1N1 flu was no more it in the mid-range of estimates.[171] severe than the seasonal flu. “The risk of most serious The 2009 pandemic caused hospitals around the councomplications was not elevated in adults or children”, try to make significant preparations in terms of hospithe study’s authors wrote. “Children were disproportiontal surge capacities, especially within the emergency deately affected by 2009 H1N1 infection, but the perceived partment and among vulnerable populations. In many severity of symptoms and risk of serious outcomes were cases, hospitals were relatively successful in making sure not increased.” Children infected in the 2009 H1N1 flu that those patients most severely affected by the influenza pandemic were no more likely to be hospitalized with strain were able to be seen, treated, and discharged in an complications or get pneumonia than those who catch efficient manner. A proper case-study of the preparation, seasonal strains. About 1.5% of children with the H1N1 planning, mitigation, and response efforts during the Fall swine flu strain were hospitalized within 30 days, comof 2009 is that of the Children’s Hospital of Philadelpared with 3.7% of those sick with a seasonal strain of phia (CHOP). For example, CHOP took several steps H1N1 and 3.1% with an H3N2 virus.[165] to increase the emergency department (ED) surge capacCDC illness and death estimates from April 2009 to April ity response abilities through careful planning and mit2010, in the US are as follows: igation efforts. To increase ED capacity and response, CHOP used portions of the main lobby area as an ED • CDC estimates that between 43 million and 89 mil- waiting room; several of the region’s hospital-based outlion cases of 2009 H1N1 occurred between April patient facilities were in use during evening and week2009 and 10 April 2010. The mid-level in this range end hours for non-emergency cases; the ED’s 24-hour is about 61 million people infected with 2009 H1N1. short-stay unit was utilized to care for ED patients in a longer-term capacity; non-board certified physicians (in • CDC estimates that between about 195,000 and pediatric emergency medicine) and inpatient-unit med403,000 H1N1-related hospitalizations occurred ical nurses were utilized for ED patient care; hospital between April 2009 and 10 April 2010. The mid- units normally utilized for other medical or therapeutic level in this range is about 274,000 2009 H1N1- purposes were transformed into ED patient rooms; and rooms normally used for only one patient were expanded related hospitalizations. to at least a capacity of 2[172] • CDC estimates that between about 8,870 and 18,300 2009 H1N1-related deaths occurred between April 2009 and 10 April 2010. The mid-level in this range is about 12,470 2009 H1N1-related 7.9 Comparisons to other pandeaths.[166][167][168]

demics and epidemics

It is often stated that about 36,000 die from the seasonal flu in the U.S. each year,[169] and this is frequently understood as an indication that the H1N1 strain was not as severe as seasonal influenza. The 36,000 estimate was presented in a 2003 study by CDC scientists published in the Journal of the American Medical Association but only refers to a period from 1990–91 through 1998–99. During those years, the number of estimated deaths ranged from 17,000 to 52,000, with an average of about 36,000. The JAMA study also looked at seasonal influenza-associated deaths over a 23-year period, from 1976–77 and 1998–99. During that period, estimates of respiratory and circulatory influenza-associated

Annual influenza epidemics are estimated to affect 5– 15% of the global population. Although most cases are mild, these epidemics still cause severe illness in 3–5 million people and 250,000–500,000 deaths worldwide.[173] On average 41,400 people die of influenza-related illnesses each year in the United States, based on data collected between 1979 and 2001.[174] In industrialised countries, severe illness and deaths occur mainly in the high-risk populations of infants, the elderly and chronically ill patients,[173] although the H1N1 flu outbreak (like the 1918 Spanish flu) differs in its tendency to affect younger, healthier people.[175]

70 In addition to these annual epidemics, Influenza A virus strains caused three global pandemics during the 20th century: the Spanish flu in 1918, Asian flu in 1957, and Hong Kong flu in 1968–69. These virus strains had undergone major genetic changes for which the population did not possess significant immunity.[176] Recent genetic analysis has revealed that three-quarters, or six out of the eight genetic segments, of the 2009 flu pandemic strain arose from the North American swine flu strains circulating since 1998, when a new strain was first identified on a factory farm in North Carolina, and which was the first-ever reported triple-hybrid flu virus.[177] The 1918 flu epidemic began with a wave of mild cases in the spring, followed by more deadly waves in the autumn, eventually killing hundreds of thousands in the United States and 50–100 million worldwide.[178] The great majority of deaths in the 1918 flu pandemic were the result of secondary bacterial pneumonia. The influenza virus damaged the lining of the bronchial tubes and lungs of victims, allowing common bacteria from the nose and throat to infect their lungs. Subsequent pandemics have had many fewer fatalities due to the development of antibiotic medicines which can treat pneumonia.[179] [1] Not necessarily pandemic, but included for comparison purposes.

[2] The ratio of confirmed deaths to total deaths due to pandemic H1N1/09 flu is unknown. For the difficulties in estimating the ratio, see "Data reporting and accuracy"; for some modelling estimates see below.

The influenza virus has also caused several pandemic threats over the past century, including the pseudopandemic of 1947 (thought of as mild because although globally distributed, it caused relatively few deaths),[176] the 1976 swine flu outbreak and the 1977 Russian flu, all caused by the H1N1 subtype.[176] The world has been at an increased level of alert since the SARS epidemic in Southeast Asia (caused by the SARS coronavirus).[190] The level of preparedness was further increased and sustained with the advent of the H5N1 bird flu outbreaks because of H5N1’s high fatality rate, although the strains currently prevalent have limited human-to-human transmission (anthroponotic) capability, or epidemicity.[191] People who contracted flu before 1957 appeared to have some immunity to H1N1 flu. Daniel Jernigan, head of flu epidemiology for the U.S. CDC, has stated: “Tests on blood serum from older people showed that they had antibodies that attacked the new virus ... That does not mean that everyone over 52 is immune, since Americans and Mexicans older than that have died of the new flu”.[192] In June 2012, a model based study was published finding that the number of deaths related to the H1N1 influenza may have been fifteen times higher than the reported laboratory confirmed deaths. According to their findings, 80% of the respiratory and cardiovascular deaths were

CHAPTER 7. 2009 FLU PANDEMIC in people younger than 65 years and 51% occurred in southeast Asia and Africa. The researchers believe that a disproportionate number of pandemic deaths might have occurred in these regions and that their research suggests that efforts to prevent future influenza pandemics needs to effectively target these regions.[193] A WHO supported 2013 study estimated that the 2009 global pandemic respiratory mortality was ~10-fold higher than the World Health Organization’s laboratoryconfirmed mortality count (18.631). Although the pandemic mortality estimate was similar in magnitude to that of seasonal influenza, a marked shift toward mortality among persons <65 y of age occurred, so that many more life-years were lost. Between 123,000 and 203,000 pandemic respiratory deaths were estimated globally for the last 9 mo of 2009. The majority (62%–85%) were attributed to persons under 65 y of age. The burden varied greatly among countries. There was an almost 20-fold higher mortality in some countries in the Americas than in Europe. The model attributed 148,000–249,000 respiratory deaths to influenza in an average pre-pandemic season, with only 19% in persons <65 y.[194]

7.10 See also • 2009 flu deaths by region • Health crisis • Public health emergency (United States)

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7.12 Further reading

CHAPTER 7. 2009 FLU PANDEMIC doi:10.1038/nbt0609-510.

2011.

Retrieved 14 April

• Centers for Disease Control and Prevention (CDC) (October 2009). “Introduction and transmission of 2009 pandemic influenza A (H1N1) Virus—Kenya, June–July 2009”. Morbidity and Mortality Weekly Report. Centers for Disease Control and Prevention (CDC). 58 (41): 1143–6. PMID 19847148.

Archived from the original on 13 May 2011. Retrieved 14 April 2011.

7.13 External links • Influenza: H1N1 at DMOZ • Pandemic (H1N1) 2009 at the World Health Organization (WHO) • International Society for Infectious Diseases PROMED-mail news updates • H1N1 Flu Resource Centre of The Lancet • Novel H1N1 Influenza (Swine Flu) Overview from CIDRAP • Influenza Research Database – Database of influenza genomic sequences and related information.

• CDC 2009 H1N1 Influenza Vaccine Supply Status • The H1N1 Pandemic and Global Health Security, Dean Julio Frenk, 2009-09-17 • What the Tamiflu saga tells us about drug trials and big pharma Guardian, 2014

• Cannell, JJ; Zasloff, M; Garland, CF; Scragg, R; 7.13.1 Europe Giovannucci, E (25 February 2008). “On the epidemiology of influenza”. Virology Journal. 5 • Health-EU Portal EU response to influenza (1): 29. PMC 2279112 . PMID 18298852. doi:10.1186/1743-422X-5-29. Retrieved 14 April • 2009 influenza A (H1N1) pandemic. European 2011.

Centre for Disease Prevention and Control (ECDC).

• MacPhail, Theresa (2014). The Viral Network.

Ithaca, London: Cornell University Press. ISBN 978-0-8014-7983-0.

• Smith, GJ; et al. (25 June 2009). “Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic”. Nature. 459 (7250): 1122–1125.

Bibcode:2009Natur.459.1122S. PMID 19516283. doi:10.1038/nature08182.

• Soundararajan, V; et al.

(June 2009).

“Extrapolating from sequence—the 2009 H1N1 'swine' influenza virus” (PDF). Nature Biotechnology. 27 (6): 510–513. PMID 19513050.

• Summaries of the pandemic. European Centre for Disease Prevention and Control (ECDC).

• European Commission – Public Health EU coordination on Pandemic (H1N1) 2009.

• UK National Pandemic Flu Service • Official UK government information on swine flu from Directgov • Human/Swine A/H1N1 Influenza Origins and Evolution – Analysis of genetic data for the origin and evolution of swine flu virus.

7.13. EXTERNAL LINKS

7.13.2

North America

• Health Canada flu portal • Pan-American Health Organization (PAHO) Swine Influenza portal • H1N1 Influenza (Flu) portal at the US Centers for Disease Control (CDC) • US Government swine, avian and pandemic flu portal • Medical Encyclopedia Medline Plus: Swine Flu • Swine Flu Outbreak, Influenza Virus Resource – Sequences and related resources (GenBank, NCBI)

79

Chapter 8

Influenza A virus subtype H2N2 “H2N2” redirects here. For the chemical compound neuraminidase proteins in the virus) of type A influenza, with the formula H2 N2 , see Diazene. and an influenza vaccine was developed in 1957 to contain its outbreak.

H2N2 is a subtype of the influenza A virus. H2N2 has mutated into various strains including the Asian flu strain (now extinct in the wild), H3N2, and various strains found in birds. It is also suspected of causing a human pandemic in 1889.[1][2] The geographic spreading of the 1889 Russian flu have been studied and published.[3]

8.1 Russian flu

The Asian flu strain later evolved via antigenic shift into H3N2, which caused a milder pandemic from 1968 to 1969.[10] Both the H2N2 and H3N2 pandemic strains contained avian influenza virus RNA segments. “While the pandemic human influenza viruses of 1957 (H2N2) and 1968 (H3N2) clearly arose through reassortment between human and avian viruses, the influenza virus causing the 'Spanish flu' in 1918 appears to be entirely derived from an avian source (Belshe 2005).”[11]

For the 1977–78 Russian flu, see Influenza A virus subtype H1N1 § Russian flu.

8.3 Test kits Some researchers have asserted that the 1889–1890 flu pandemic (also known as Russian flu) was caused by the influenzavirus A virus subtype H2N2. More recent research has suggested H3N8 as a more likely cause. It is the earliest flu pandemic for which detailed records are available.[4] “The 1889 pandemic, known as the Russian Flu, began in Russia and spread rapidly throughout Europe. It reached North America in December 1889 and spread to Latin America and Asia in February 1890.

About 1 million people died in this pandemic.”[5]

8.2 Asian flu The category 2 Asian flu pandemic outbreak of influenza A virus originated in China in early 1956, and lasted until 1958. Some authors believe it originated from a mutation in wild ducks combining with a pre-existing human strain.[6] Other authors are less certain.[7] The virus was first identified in Guizhou.[8] It spread to Singapore in February 1957,[9] reached Hong Kong by April, and the US by June. The death toll in the US was about 69,800.[6] Estimates of worldwide deaths caused by this pandemic varies widely depending on source, ranging from one to four million, with WHO settling on “about two million”.

Asian flu was of the H2N2 subtype (a notation that refers to the configuration of the hemagglutinin and

From October 2004 to February 2005, approximately 3,700 test kits of the 1957 H2N2 virus were accidentally spread around the world from the College of American Pathologists (CAP). CAP assists laboratories in accuracy by providing unidentified samples of viruses; private contractor Meridian Bioscience in Cincinnati, U.S., chose the 1957 strand instead of one of the less deadly avian influenza virus subtypes. “CAP spokesman Dr. Jared Schwartz said Meridian knew what the virus was but believed it was safe. In selecting it, the company had determined that the virus was classified as a biosafety level 2 (BSL-2) agent, which meant it could legally be used in the kits. [...] Before the problem came to light, the CDC had made a recommendation that the H2N2 virus be reclassified as a BSL-3 agent, Gerberding said. She promised to speed up the reclassification. The CDC determines the classifications in collaboration with the National Institutes

80

8.5. FURTHER READING

81

of Health. In BSL-3 labs, agents are handled with equip- [13] “Flu.org”. ment designed to prevent any airborne contamination and resulting respiratory exposure.”[12] The 1957 H2N2 virus [14] “Page Not Found”. is considered deadly and the U.S. government called for the vials containing the strain to be destroyed.

"CDC officials reported on 21 April that 99% of the samples had already been destroyed. News reports on 25 April said the last samples outside the United States had been destroyed at the American University of Beirut in Lebanon, after they were found at the Beirut airport. Earlier reports said H2N2 samples were sent to 3,747 labs under CAP auspices and to about another 2,700 labs certified by other organizations. All but about 75 labs that received the CAP samples were in the United States.”[13] “In the United States, there is no government regulation over the 1957 flu strain. In fact, federal officials at the CDC do not even know how many U.S. laboratories keep this deadly strain in their viral libraries.”[14]

8.4 Bibliography [1] Sdstate.edu [2] “pilva.com”.

[3] Alexis Madrigal (April 26, 2010). “1889 Pandemic Didn’t Need Planes to Circle Globe in 4 Months”. Wired Science. External link in |publisher= (help) [4] “Encarta on influenza”. Archived from the original on 2009-11-01.

[5] CIDRAP article Pandemic Influenza Last updated 16 Jun 2011 [6] Greene Jeffrey. Moline, Karen. [2006] (2006) The Bird Flu Pandemic. ISBN 0-312-36056-8.

[7] Belshe Robert. [2005] (2005) The Origins of Pandemic Influenza. New England Journal of Medicine 353:22092211.

[8] Goldsmith, Connie. [2007] (2007) Influenza: The Next Pandemic? 21st century publishing. ISBN 0-7613-94575 [9] Bud, Robert (January 2007). “Germ Warfare”. History Today. Vol. 57 no. 1. Retrieved 20 February 2017.

[10] Starling, Arthur. [2006] (2006) Plague, SARS, and the Story of Medicine in Hong Kong. HK University Press.

ISBN 962-209-805-3 [11] Chapter Two : Avian Influenza by Timm C. Harder and Ortrud Werner from free on-line Book called Influenza Report 2006 which is a medical textbook that provides a comprehensive overview of epidemic and pandemic influenza.

[12] Roos, Robert (Apr 13, 2005). “Vendor thought H2N2 virus was safe, officials say”. Center for Infectious Disease Research and Policy.

8.5 Further reading • Pandemic preparedness: lessons learnt from H2N2 and H9N2 candidate vaccines • Interim CDC-NIH Recommendation for Raising the Biosafety Level for Laboratory Work Involving Noncontemporary Human Influenza Viruses • New Scientist: Bird Flu • Pandemic-causing 'Asian flu' accidentally released • Persistence of Q strain of H2N2 influenza virus in avian species: antigenic, biological and genetic analysis of avian and human H2N2 viruses

8.6 External links • Influenza Research Database Database of influenza sequences and related information.

Chapter 9

Influenza A virus subtype H3N2 Influenza A virus subtype H3N2 (A/H3N2) is a subtype of viruses that causes influenza (flu). H3N2 Viruses can infect birds and mammals. In birds, humans, and pigs, the virus has mutated into many strains. H3N2 is increasingly abundant in seasonal influenza, which kills an estimated 36,000 people in the United States each year.

strains of H3N2 appeared in East and Southeast Asian countries about six to 9 months earlier than anywhere else. The strains generally reached Australia and New Zealand next, followed by North America and Europe.

The new variants typically reached South America after an additional six to 9 months, the group reported.[2]

9.1 Classification

9.3 Swine flu

H3N2 is a subtype of the viral genus Influenzavirus A, Main article: Swine influenza which is an important cause of human influenza. Its name A 2007 study reported: “In swine, three influenza A derives from the forms of the two kinds of proteins on the surface of its coat, hemagglutinin (H) and neuraminidase (N). By reassortment, H3N2 exchanges genes for internal proteins with other influenza subtypes.

9.2 Seasonal H3N2 flu Seasonal influenza kills an estimated 36,000 people in the United States each year. Flu vaccines are based on predicting which “mutants” of H1N1, H3N2, H1N2, and influenza B will proliferate in the next season. Separate vaccines are developed for the Northern and Southern Hemispheres in preparation for their annual epidemics.

In the tropics, influenza shows no clear seasonality. In the past ten years, H3N2 has tended to dominate in prevalence over H1N1, H1N2, and influenza B. Measured resistance to the standard antiviral drugs amantadine and rimantadine in H3N2 has increased from 1% in 1994 to 12% in 2003 to 91% in 2005.[1] Seasonal H3N2 flu is a human flu from H3N2 that is slightly different from one of last year’s flu season H3N2 variants. Seasonal influenza viruses flow out of overlapping epidemics in East and Southeast Asia, then trickle around the globe before dying off. Identifying the source of the viruses allows global health officials to better predict which viruses are most likely to cause the most disease over the next year. An analysis of 13,000 samples of influenza A/H3N2 virus that were collected across six continents from 2002 to 2007 by the WHO’s Global Influenza Surveillance Network showed the newly emerging

Pigs can harbor influenza viruses adapted to humans and others that are adapted to birds, allowing the viruses to exchange genes and create a pandemic strain.

virus subtypes (H1N1, H3N2, and H1N2) are circulating throughout the world. In the United States, the classic H1N1 subtype was exclusively prevalent among swine populations before 1998; however, since late August 1998, H3N2 subtypes have been isolated from pigs.

Most H3N2 virus isolates are triple reassortants, containing genes from human (HA, NA, and PB1), swine (NS, NP, and M), and avian (PB2 and PA) lineages. Present vaccination strategies for SIV control and prevention in swine farms typically include the use of one of several bivalent SIV vaccines commercially available in the United States. Of the 97 recent H3N2 isolates examined, only 41 had strong serologic cross-reactions with antiserum to three commercial SIV vaccines. Since the protective ability of influenza vaccines depends primarily on the closeness of the match between the vaccine virus and the epi-

82

9.4. FLU SPREAD, BY SEASON demic virus, the presence of nonreactive H3N2 SIV variants suggests current commercial vaccines might not effectively protect pigs from infection with a majority of H3N2 viruses.”[3] Avian influenza virus H3N2 is endemic in pigs in China, and has been detected in pigs in Vietnam, contributing to the emergence of new variant strains. Pigs can carry human influenza viruses, which can combine (i.e. exchange homologous genome subunits by genetic reassortment) with H5N1, passing genes and mutating into a form which can pass easily among humans. H3N2 evolved from H2N2 by antigenic shift and caused the Hong Kong Flu pandemic of 1968 and 1969 that killed up to 750,000 humans. The dominant strain of annual flu in humans in January 2006 was H3N2. Measured resistance to the standard antiviral drugs amantadine and rimantadine in H3N2 in humans had increased to 91% by 2005. In August 2004, researchers in China found H5N1 in pigs.[4]

9.4 Flu spread, by season 9.4.1

Hong Kong Flu (1968–1969)

83 genes from avian influenza viruses. The new subtypes arose in pigs coinfected with avian and human viruses and were soon transferred to humans. Swine were considered the original “intermediate host” for influenza, because they supported reassortment of divergent subtypes.

However, other hosts appear capable of similar coinfection (e.g., many poultry species), and direct transmission of avian viruses to humans is possible. H1N1 may have been transmitted directly from birds to humans (Belshe 2005).[10] The Hong Kong flu strain shared internal genes and the neuraminidase with the 1957 Asian flu (H2N2). Accumulated antibodies to the neuraminidase or internal proteins may have resulted in much fewer casualties than most pandemics. However, cross-immunity within and between subtypes of influenza is poorly understood.

The Hong Kong flu was the first known outbreak of the H3N2 strain, though there is serologic evidence of H3N? infections in the late 19th century. The first record of the outbreak in Hong Kong appeared on 13 July 1968 in an area with a density of about 500 people per acre in an urban setting. The outbreak reached maximum intensity in two weeks, lasting six weeks in total. The virus was isolated in Queen Mary Hospital. Flu symptoms lasted four to five days.[8]

Main article: Hong Kong flu The Hong Kong Flu was a category 2 flu pandemic By July 1968, extensive outbreaks were reported in Vietnam and Singapore. By September 1968, it reached India, the Philippines, northern Australia and Europe.

That same month, the virus entered California from returning Vietnam War troops. It reached Japan, Africa and South America in 1969.[8]

“Three strains of Hong Kong influenza virus isolated from humans were compared with a strain isolated from a calf for their ability to cause disease in calves. One of the human strains. A/Aichi/2/68, was detected for five days in a calf, but all three failed to cause signs of disease. Strain A/cal/Duschanbe/55/71 could be detected for seven days and caused an influenza-like illness in calves.”[11]

9.4.2 Fujian flu (2003–2004) Main article: Fujian flu The influenza viruses that caused Hong Kong flu (magnified Fujian flu refers to flu caused by either a Fujian human flu strain of the H3N2 subtype or a Fujian bird flu strain of about 100,000 times) the H5N1 subtype of the Influenza A virus. These strains caused by a strain of H3N2 descended from H2N2 by are named after Fujian province in China. antigenic shift, in which genes from multiple subtypes A/Fujian (H3N2) human flu (from reassorted to form a new virus. This pandemic of A/Fujian/411/2002(H3N2)-like flu virus strains) 1968 and 1969 killed an estimated one million people caused an unusually severe 2003–2004 flu season. This worldwide.[5][6][7] The pandemic infected an estimated was due to a reassortment event that caused a minor 500,000 Hong Kong residents, 15% of the population, clade to provide a haemagglutinin gene that later became with a low death rate.[8] In the United States, about part of the dominant strain in the 2002–2003 flu season.

33,800 people died.[9] A/Fujian (H3N2) was made part of the trivalent influenza Both the H2N2 and H3N2 pandemic flu strains contained vaccine for the 2004–2005 flu season.

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CHAPTER 9. INFLUENZA A VIRUS SUBTYPE H3N2

9.4.6 2007–2008 flu season The composition of influenza virus vaccines for use in the 2007–2008 Northern Hemisphere influenza season recommended by the World Health Organization on 14 February 2007[14] was: • an A/Solomon Islands/3/2006 (H1N1)-like virus • an A/Wisconsin/67/2005 (H3N2)-like virus (A/Wisconsin/67/2005 (H3N2) and A/Hiroshima/52/2005 were used at the time) Diagram of influenza virus nomenclature

9.4.3

2004–2005 flu season

9.4.4

2005–2006 flu season

• a B/Malaysia/2506/2004-like virus[15][16]

“A/H3N2 has become the predominant flu subtype in the United States, and the record over the past 25 years The 2004–05 trivalent influenza vaccine for the United shows that seasons dominated by H3N2 tend to be worse than those dominated by type A/H1N1 or type B.” States contained: Many H3N2 viruses making people ill in this 2007– 2008 flu season differ from the strains in the vaccine • an A/New Caledonia/20/99 (H1N1)-like virus and may not be well covered by the vaccine strains.

“The CDC has analyzed 250 viruses this season to de• an A/Fujian/411/2002 (H3N2)-like virus termine how well they match up with the vaccine, the report says. Of 65 H3N2 isolates, 53 (81%) were char• a B/Shanghai/361/2002-like virus.[12] acterized as A/Brisbane/10/2007-like, a variant that has evolved [notably] from the H3N2 strain in the vaccine— A/Wisconsin/67/2005.”[17] The vaccines produced for the 2005–2006 season used:

9.4.7 2008–2009 flu season

The composition of virus vaccines for use in the 2008– 2009 Northern Hemisphere influenza season recommended by the World Health Organization on February • an A/California/7/2004-like(H3N2) (or the anti14, 2008[18] was: genically equivalent strain A/New York/55/2004) • an A/New Caledonia/20/1999-like(H1N1)

• a B/Jiangsu/10/2003-like viruses

• an A/Brisbane/59/2007 (H1N1)-like virus • an A/Brisbane/10/2007 (H3N2)-like virus

9.4.5

2006–2007 flu season

• a B/Florida/4/2006-like virus (B/Florida/4/2006 and B/Brisbane/3/2007 (a B/Florida/4/2006-like virus) were used at the time)[19][20]

The 2006–2007 influenza vaccine composition recommended by the World Health Organization on 15 February 2006 and the US FDA’s Vaccines and Related BiologAs of May 30, 2009: “CDC has antigenically charical Products Advisory Committee on 17 February 2006 acterized 1,567 seasonal human influenza viruses [947 used: influenza A (H1), 162 influenza A (H3) and 458 influenza B viruses] collected by U.S. laboratories since • an A/New Caledonia/20/99 (H1N1)-like virus October 1, 2008, and 84 novel influenza A (H1N1) viruses. All 947 influenza seasonal A (H1) viruses are • an A/Wisconsin/67/2005 (H3N2)-like virus related to the influenza A (H1N1) component of the (A/Wisconsin/67/2005 and A/Hiroshima/52/2005 2008–09 influenza vaccine (A/Brisbane/59/2007). All strains) 162 influenza A (H3N2) viruses are related to the A (H3N2) vaccine component (A/Brisbane/10/2007). All • a B/Malaysia/2506/2004-like virus from 84 novel influenza A (H1N1) viruses are related to the B/Malaysia/2506/2004 and B/Ohio/1/2005 strains A/California/07/2009 (H1N1) reference virus selected which are of B/Victoria/2/87 lineage[13]

by WHO as a potential candidate for novel influenza A

9.4. FLU SPREAD, BY SEASON (H1N1) vaccine. Influenza B viruses currently circulating can be divided into two distinct lineages represented by the B/Yamagata/16/88 and B/Victoria/02/87 viruses. Sixty-one influenza B viruses tested belong to the B/Yamagata lineage and are related to the vaccine strain (B/Florida/04/2006). The remaining 397 viruses belong to the B/Victoria lineage and are not related to the vaccine strain.”[21]

9.4.8

2009–2010 flu season

The vaccines produced for the 2009–2010 season used: • an A/Brisbane/59/2007(H1N1)-like virus • an A/Brisbane/10/2007 (H3N2)-like virus • a B/Brisbane 60/2008-like antigens[22]

85 So far this season, most (91%) of the influenza viruses that have been analyzed at CDC are like the viruses included in the 2012–2013 influenza vaccine.

In January 2013, influenza activity continued to increase in the United States and most of the country is now experiencing high levels of influenza-like-illness (ILI), according to CDC’s latest FluView report. Reports of influenzalike-illness (ILI) are nearing what have been peak levels during moderately severe seasons, and CDC continues to recommend influenza vaccination and antiviral drug treatment when appropriate at this time.

On January 9, 2013, the Boston Government declared Public Health Emergency for H3N2 Flu Epidemic.[28] One factor that may indicate increased severity this season is that the predominant circulating type of influenza virus is Influenza A (H3N2) viruses, which account for about 76 percent of the viruses reported. Typically, H3N2 seasons have been more severe, with higher numbers of hospitalizations and deaths.[29]

A separate vaccine was available for pandemic H1N1 influenza using the A/California/7/2009-like pandemic H1N1 strain.[23] 9.4.12

9.4.9

2014–2015 flu season

2010–2011 flu season

The vaccines produced for the 2010–2011 season used: • an A/California/7/2009-like (pandemic H1N1) • an A/Perth/16/2009-like (H3N2)-like virus • a B/Brisbane/60/2008-like antigens[24]

9.4.10

2011–2012 flu season

The vaccines produced for the 2011–2012 season used: • an A/California/07/2009 (H1N1)-like virus • an A/Victoria/210/2009 (an A/Perth/16/2009-like strain) (H3N2)-like virus • a B/Brisbane/60/2008-like virus[25]

9.4.11

2012–2013 flu season A man wearing a procedure mask prior to taking his octogenarian

The vaccines produced for the Northern Hemisphere father home on Christmas 2014.

2012–2013 season used: • an A/California/07/2009 (H1N1)-like virus • an A/Victoria/361/2011 (H3N2)-like virus • a B/Massachusetts/2/2012-like virus,[26] which replaced B/Wisconsin/1/2010-like virus[27]

The vaccines produced for the Northern Hemisphere 2014–2015 season used: • A/California/7/2009 (H1N1)pdm09-like virus • A/Texas/50/2012 (H3N2)-like virus

86

CHAPTER 9. INFLUENZA A VIRUS SUBTYPE H3N2

9.6 References

• B/Massachusetts/2/2012-like virus,[30] Quadrivalent vaccines include a B/Brisbane/60/2008-like virus.[31] The CDC announced that drift variants of the A (H3N2) virus strain from the 2012–2013 potentially foretold a severe flu season for 2014–2015.[32][33]

9.4.13

2015–2016 flu season

The vaccines produced for the Northern Hemisphere 2015-2016 season used: • A/California/7/2009 (H1N1)pdm09-like virus • A/Switzerland/9715293/2013 (H3N2)-like virus • B/Phuket/3073/2013-like virus.

B/Yamagata lineage virus)

(This is a

The “Split Virion” vaccine distributed in 2016 contained the following strains of inactivated virus: • A/California/7/2009 (H1N1)pdm09 - like strain (A/California/7/2009, NYMC X-179A)

[1] Ronald Ban This Season’s Flu Virus Is Resistant to 2 Standard Drugs. New York Times. January 15, 2006 [2] CIDRAP article Study: New seasonal flu strains launch from Asia published 16 April 2008 [3] René Gramer, Marie; Hoon Lee, Jee; Ki Choi, Young; Goyal, Sagar M.; Soo Joo, Han (2007). “Serologic and genetic characterization of North American H3N2 swine influenza A viruses”. Canadian Journal of Veterinary Research. 71 (3): 201–206. PMC 1899866 . PMID 17695595.

[4] WHO (28 October 2005). “H5N1 avian influenza: timeline” (PDF). Archived from the original (PDF) on 27 July 2011.

[5] Paul, William E. Fundamental Immunology. p. 1273.

[6] “World health group issues alert Mexican president tries to isolate those with swine flu”. Associated Press. April 25, 2009. Retrieved 2009-04-26.

[7] Mandel, Michael (April 26, 2009). “No need to panic ... yet Ontario officials are worried swine flu could be pandemic, killing thousands”. Toronto Sun. Retrieved 200904-26.

• A/Hong Kong/4801/2014 (H3N2) - like strain (A/Hong Kong/4801/2014, NYMC X-263B)

[8] Starling, Arthur (2006). Plague, SARS, and the Story of Medicine in Hong Kong. HK University Press. p. 55.

ISBN 962-209-805-3.

• B/Brisbane/60/2008 like (B/Brisbane/60/2008, wild type)[34]

[9] U.S. Department of Health and Human Services, http:// www.pandemicflu.gov/general/historicaloverview.html

9.4.14

strain

2016–2017 flu season

• A/California/7/2009 (H1N1)pdm09-like virus, • A/Hong Kong/4801/2014 (H3N2)-like virus • B/Brisbane/60/2008-like virus (B/Victoria lineage) Quadrivalent influenza vaccine adds: • B/phuket/3073/2013-like strain

9.5 See also • 2009 H1N1 influenza outbreak • Bird flu • Dog flu • Horse flu • Human flu • Swine flu

[10] Chapter Two : Avian Influenza by Timm C. Harder and Ortrud Werner from excellent free on-line book Influenza Report 2006 [11] J Infect Dis. 1977 Apr;135(4):678-80. article Strains of Hong Kong influenza virus in calves [12] CDC article Update: Influenza Activity — United States and Worldwide, 2003–04 Season, and Composition of the 2004–05 Influenza Vaccine published 2 July 2004 [13] CDC fluwatch B/Victoria/2/87 lineage [14] “14 February 2007: WHO information meeting (Morning)".

[15] Recommended composition of influenza virus vaccines for use in the 2007–2008 northern hemisphere influenza season. WHO [16] WHO — Recommended composition of influenza virus vaccines for use in the 2007–2008 influenza season (PDF) [17] CIDRAP article Flu widespread in 44 states, CDC reports published 15 February 2008 [18] “14 February 2008: Information meeting (Morning)".

[19] “WHO website recommendation for 2008–2009 season”.

[20] WHO — Recommended composition of influenza virus vaccines for use in the 2008–2009 influenza season (PDF)

9.8. EXTERNAL LINKS

[21] CDC article “2008–2009 Influenza Season Week 21 ending May 30, 2009” published May 30, 2009 [22] “Recommended composition of influenza virus vaccines for use in the 2009–2010 influenza season”.

[23] “Weekly U.S. Influenza Surveillance Report - Seasonal Influenza (Flu) - CDC”.

[24] “Weekly U.S. Influenza Surveillance Report - Seasonal Influenza (Flu) - CDC”.

[25] “U S Food and Drug Administration Home Page”.

[26] “WHO recommends new B strain for next season’s flu vaccine”. Center for infectious Disease Research and Policy.

21 Feb 2013. Retrieved 2 October 2013.

[27] “Recommended composition of influenza virus vaccines for use in the 2013 southern hemisphere influenza season”.

World Health Organization. 20 Sep 2012. Retrieved 8 December 2012.

[28] “Mayor declares flu emergency in Boston”. Boston Herald. 9 Jan 2013. Retrieved 10 January 2013.

[29] “Flu Activity Picks Up Nationwide CDC recommends vaccination and antiviral treatment against influenza”.

January 4, 2013. Retrieved January 8, 2013.

[30] “What You Should Know for the 2014-2015 Influenza Season”. Center for Infectious Disease Research and Policy. Retrieved 30 December 2014.

[31] “WHO - Recommended composition of influenza virus vaccines for use in the 2014-2015 northern hemisphere influenza season”.

[32] “CDC Press Releases”.

[33] “Dr Mark Dowell urges flu shots despite mutated h3n2 strain”. 2014/12/08. Check date values in: |date= (help) [34] “Inactivated Influenza Vaccine (Split Virion) BP - Summary of Product Characteristics (SPC) - (eMC)".

9.7 Further reading • Graphic showing H3N2 mutations, amino acid by amino acid, among 207 isolates completely sequenced by the Influenza Genome Sequencing Project.

• Influenza A (H3N2) Outbreak, Nepal • Hot topic – Fujian-like strain A influenza • New Scientist: Bird Flu

9.8 External links • Influenza Research Database Database of influenza sequences and related information.

87

Chapter 10

1968 flu pandemic The 1968 flu pandemic was a category 2 flu pandemic Fewer people died during this pandemic than the two prewhose outbreak in 1968 and 1969 killed an estimated vious pandemics for various reasons:[8] one million people worldwide.[1][2][3] It was caused by an H3N2 strain of the influenza A virus, descended from 1. some immunity against the N2 flu virus may have H2N2 through antigenic shift, a genetic process in which been retained in populations struck by the Asian Flu genes from multiple subtypes reassorted to form a new strains which had been circulating since 1957; virus. Because it originated in Hong Kong, the pandemic 2. the pandemic did not gain momentum until near the is also referred to as Hong Kong flu. winter school holidays, thus limiting the infection spreading;

10.1 The 1968–1969 pandemic

3. improved medical care gave vital support to the very ill;

The first record of the outbreak in Hong Kong appeared 4. the availability of antibiotics that were more effecon 13 July 1968. By the end of July 1968, extensive tive against secondary bacterial infections. outbreaks were reported in Vietnam and Singapore. Despite the fatality of the 1957 Asian Flu in China, little improvement had been made regarding the handling of such epidemics. The Times newspaper was actually the 10.2 Clinical data first source to sound alarm regarding this new possible Flu symptoms lasted 4 to 5 days (some symptoms lasted pandemic. up to 2 weeks).[4] Those over the age of 65 were most

By September 1968, the flu reached India, the likely to die.

Philippines, northern Australia and Europe.

That same month, the virus entered California from returning Vietnam War troops but did not become widespread in the United States until December 1968. It would 10.3 Virology reach Japan, Africa and South America by 1969.[4] The outbreak in Hong Kong, where density is about 500 The Hong Kong flu was the first known outbreak of the people per acre, reached maximum intensity in 2 weeks, H3N2 strain, though there is serologic evidence of H3N1 lasting 6 months in total from July to December 1968, infections in the late 19th century. The virus was isolated however worldwide deaths from this virus peaked much in Queen Mary Hospital. later, in December 1968 and January 1969. By that In the 1968 pandemic vaccine became available one time, public health warnings[5] and virus descriptions[6] month after the outbreaks peaked in the US. were issued in the scientific and medical journals.

Both the H2N2 and H3N2 pandemic flu strains contained In comparison to other pandemics, the Hong Kong genes from avian influenza viruses. The new subtypes flu yielded a low death rate, with a case-fatality ra- arose in pigs coinfected with avian and human viruses tio below 0.5% making it a category 2 disease on the and were soon transferred to humans. Swine were conPandemic Severity Index. The pandemic infected an sidered the original “intermediate host” for influenza, beestimated 500,000 Hong Kong residents, 15% of the cause they supported reassortment of divergent subtypes. population.[4] In the United States, approximately 33,800 However, other hosts appear capable of similar coinfecpeople died,[7] including conjoined twins Daisy and Vio- tion (e.g., many poultry species), and direct transmission let Hilton in January 1969. of avian viruses to humans is possible. H1N1 may have The same virus returned the following years: a year later, been transmitted directly from birds to humans (Belshe in late 1969 and early 1970, and in 1972.

2005).[9] 88

10.6. FURTHER READING

89

[5] Jones, F. Avery (1968), “Winter Epidemics”, British Medical Journal, 1968 (4): 327, doi:10.1136/bmj.4.5626.327-c.

[6] Coleman, Marion T.; Dowdle, Walter R.; Pereira, Helio G.; Schild, Geoffrey C.; Chang, W. K. (1968), “The Hong Kong/68 Influenza A2 Variant”, The Lancet, 292 (7583): 1384–1386, doi:10.1016/S0140-6736(68)92683-4.

[7] “Pandemics and Pandemic Threats since 1900”. U.S. Department of Health and Human Services. Archived from the original on 2009-03-31.

[8] http://www.globalsecurity.org/security/ops/hsc-scen-3_ pandemic-1968.htm [9] Chapter Two : Avian Influenza by Timm C. Harder and Ortrud Werner from excellent free on-line Book called Influenza Report 2006 which is a medical textbook that provides a comprehensive overview of epidemic and pandemic influenza.

The influenza viruses that caused the Hong Kong flu. (magnified approximately 100,000 times)

The Hong Kong flu strain shared internal genes and the neuraminidase with the 1957 Asian Flu (H2N2). Accumulated antibodies to the neuraminidase or internal proteins may have resulted in much fewer casualties than most pandemics. However, cross-immunity within and between subtypes of influenza is poorly understood.

“Three strains of Hong Kong influenza virus isolated from humans were compared with a strain isolated from a calf for their ability to cause disease in calves. One of the human strains. A/Aichi/2/68, was detected for five days in a calf, but all three failed to cause signs of disease. Strain A/cal/Duschanbe/55/71 could be detected for seven days and caused an influenza-like illness in calves.”[10]

10.4 See also • Influenza vaccine • Influenza A virus subtype H3N2

10.5 References [1] Paul, William E. Fundamental Immunology. p. 1273.

[2] “World health group issues alert Mexican president tries to isolate those with swine flu”. Associated Press. April 25, 2009. Retrieved 2009-04-26.

[3] Mandel, Michael (April 26, 2009). “No need to panic ... yet Ontario officials are worried swine flu could be pandemic, killing thousands”. Toronto Sun. Retrieved 200904-26.

[4] Starling, Arthur (2006). Plague, SARS, and the Story of Medicine in Hong Kong. HK University Press. p. 55.

ISBN 962-209-805-3.

[10] Campbell, Charles H.; Easterday, Bernard C.; Webster, Robert G. (1977), “Strains of Hong Kong Influenza Virus in Calves”, Journal of Infectious Diseases, 135 (4): 678– 680, PMID 853249, doi:10.2307/30107903.

10.6 Further reading • Blakely, Debra E. (2006), Mass Mediated Disease: A Case Study Analysis of Three Flu Pandemics and Public Health Policy, Lanham: Lexington Books, pp. 148–196, ISBN 0-7391-1387-9.

10.7 External links • Influenza Research Database – Database of influenza genomic sequences and related information.

Chapter 11

Influenza A virus subtype H5N1 Influenza A virus subtype H5N1, also known as A(H5N1) or simply H5N1, is a subtype of the influenza A virus which can cause illness in humans and many other animal species.[1] A bird-adapted strain of H5N1, called HPAI A(H5N1) for highly pathogenic avian influenza virus of type A of subtype H5N1, is the highly pathogenic causative agent of H5N1 flu, commonly known as avian influenza ("bird flu"). It is enzootic (maintained in the population) in many bird populations, especially in Southeast Asia. One strain of HPAI A(H5N1) is spreading globally after first appearing in Asia. It is epizootic (an epidemic in nonhumans) and panzootic (affecting animals of many species, especially over a wide area), killing tens of millions of birds and spurring the culling of hundreds of millions of others to stem its spread. Many references to “bird flu” and H5N1 in the popular media refer to this strain.[2] According to the World Health Organization and United Nations Food and Agriculture Organization, H5N1 pathogenicity is gradually continuing to rise in endemic areas, but the avian influenza disease situation in farmed birds is being held in check by vaccination, and so far there is “no evidence of sustained human-to-human transmission” of the virus.[3] Eleven outbreaks of H5N1 were reported worldwide in June 2008 in five countries (China, Egypt, Indonesia, Pakistan and Vietnam) compared to 65 outbreaks in June 2006 and 55 in June 2007. The global HPAI situation significantly improved in the first half of 2008, but the FAO reports that imperfect disease surveillance systems mean that occurrence of the virus remains underestimated and underreported.[4] In July 2013 the WHO announced a total of 630 confirmed human cases which resulted in the deaths of 375 people since 2003.[5] Several H5N1 vaccines have been developed and approved, and stockpiled by a number of countries, including the United States (in its National Stockpile),[6][7] Britain, France, Canada, and Australia, for use in an emergency.[8] Research has shown that a highly contagious strain of H5N1, one that might allow airborne transmission between mammals, can be reached in only a few mutations, raising concerns about a pandemic and bioterrorism.[9]

11.1 Overview HPAI A(H5N1) is considered an avian disease, although there is some evidence of limited human-to-human transmission of the virus.[10] A risk factor for contracting the virus is handling of infected poultry, but transmission of the virus from infected birds to humans has been characterized as inefficient.[11] Still, around 60% of humans known to have been infected with the current Asian strain of HPAI A(H5N1) have died from it, and H5N1 may mutate or reassort into a strain capable of efficient human-to-human transmission. In 2003, world-renowned virologist Robert G. Webster published an article titled “The world is teetering on the edge of a pandemic that could kill a large fraction of the human population” in American Scientist. He called for adequate resources to fight what he sees as a major world threat to possibly billions of lives.[12] On September 29, 2005, David Nabarro, the newly appointed Senior United Nations System Coordinator for Avian and Human Influenza, warned the world that an outbreak of avian influenza could kill anywhere between 5 million and 150 million people.[13] Experts have identified key events (creating new clades, infecting new species, spreading to new areas) marking the progression of an avian flu virus towards becoming pandemic, and many of those key events have occurred more rapidly than expected.

Due to the high lethality and virulence of HPAI A(H5N1), its endemic presence, its increasingly large host reservoir, and its significant ongoing mutations, the H5N1 virus has recently been regarded to be the world’s largest current pandemic threat, and billions of dollars are being spent researching H5N1 and preparing for a potential influenza pandemic.[14] At least 12 companies and 17 governments are developing prepandemic influenza vaccines in 28 different clinical trials that, if successful, could turn a deadly pandemic infection into a nondeadly one. Full-scale production of a vaccine that could prevent any illness at all from the strain would require at least three months after the virus’s emergence to begin, but it is hoped that vaccine production could increase until one billion doses were produced by one year after the initial identification of the virus.[15] H5N1 may cause more than one influenza pandemic,

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11.3. GENETICS as it is expected to continue mutating in birds regardless of whether humans develop herd immunity to a future pandemic strain.[16] Influenza pandemics from its genetic offspring may include influenza A virus subtypes other than H5N1.[17] While genetic analysis of the H5N1 virus shows that influenza pandemics from its genetic offspring can easily be far more lethal than the Spanish flu pandemic,[18] planning for a future influenza pandemic is based on what can be done and there is no higher Pandemic Severity Index level than a Category 5 pandemic which, roughly speaking, is any pandemic as bad as the Spanish flu or worse; and for which all intervention measures are to be used.[19]

91 60% of cases classified as H5N1 resulted in death. However, there is some evidence the actual mortality rate of avian flu could be much lower, as there may be many people with milder symptoms who do not seek treatment and are not counted.[24][25]

In one case, a boy with H5N1 experienced diarrhea followed rapidly by a coma without developing respiratory or flu-like symptoms.[26] There have been studies of the levels of cytokines in humans infected by the H5N1 flu virus. Of particular concern is elevated levels of tumor necrosis factor-alpha, a protein associated with tissue destruction at sites of infection and increased production of other cytokines. Flu virus-induced increases in the level of cytokines is also associated with flu symptoms, including fever, chills, vomiting and headache. Tissue damage associated with pathogenic flu virus infection can 11.2 Signs and symptoms ultimately result in death.[12] The inflammatory cascade triggered by H5N1 has been called a 'cytokine storm' by Further information: Influenza some, because of what seems to be a positive feedback In general, humans who catch a humanized influenza A process of damage to the body resulting from immune system stimulation. H5N1 induces higher levels of cytokines than the more common flu virus types.[27]

11.2.1 In birds Clinical signs of H5N1 in birds range from mild - decrease in egg production, nasal discharge, coughing and sneezing - to severe, including loss of coordination, energy, and appetite; soft-shelled or misshapen eggs; purple discoloration of the wattles, head, eyelids, combs, and hocks; and diarrhea. Sometimes the first noticeable sign is sudden death.[21] The different sites of infection (shown in red) of seasonal H1N1 versus avian H5N1 influences their lethality and ability to spread.[20]

virus (a human flu virus of type A) usually have symptoms that include fever, cough, sore throat, muscle aches, conjunctivitis, and, in severe cases, breathing problems and pneumonia that may be fatal.[21] The severity of the infection depends in large part on the state of the infected persons’ immune systems and whether they had been exposed to the strain before (in which case they would be partially immune). No one knows if these or other symptoms will be the symptoms of a humanized H5N1 flu.

The avian influenza hemagglutinin binds alpha 2-3 sialic acid receptors, while human influenza hemagglutinins bind alpha 2-6 sialic acid receptors.[22] This means when the H5N1 strain infects humans, it will replicate in the lower respiratory tract, and consequently will cause viral pneumonia.[23] There is as yet no human form of H5N1, so all humans who have caught it so far have caught avian H5N1.

11.3 Genetics Further information: Influenzavirus A and H5N1 genetic structure The first known strain of HPAI A(H5N1) (called A/chicken/Scotland/59) killed two flocks of chickens in Scotland in 1959, but that strain was very different from the current highly pathogenic strain of H5N1. The dominant strain of HPAI A(H5N1) in 2004 evolved from 1999 to 2002 creating the Z genotype.[28] It has also been called “Asian lineage HPAI A(H5N1)".

Asian lineage HPAI A(H5N1) is divided into two antigenic clades. “Clade 1 includes human and bird isolates from Vietnam, Thailand, and Cambodia and bird isolates from Laos and Malaysia. Clade 2 viruses were first identified in bird isolates from China, Indonesia, Japan, and South Korea before spreading westward to the Middle East, Europe, and Africa. The clade 2 viruses have been primarily responsible for human H5N1 infecThe reported mortality rate of highly pathogenic H5N1 tions that have occurred during late 2005 and 2006, acavian influenza in a human is high; WHO data indicate cording to WHO. Genetic analysis has identified six sub-

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CHAPTER 11. INFLUENZA A VIRUS SUBTYPE H5N1 clade, with 9 isolates, is V2. The remaining 22 isolates all fall into a third, clearly distinct clade, labeled EMA, which comprises samples from Europe, the Middle East, and Africa. Trees for the other 7 segments display a similar topology, with clades V1, V2, and EMA clearly separated in each case. Analyses of all available complete influenza (H5N1) genomes and of 589 HA sequences placed the EMA clade as distinct from the major clades circulating in People’s Republic of China, Indonesia, and Southeast Asia.”[31]

11.3.1 Terminology H5N1 isolates are identified like this actual HPAI A(H5N1) example, A/chicken/NakornPatom/Thailand/CU-K2/04(H5N1): • A stands for the genus of influenza (A, B or C).

• chicken is the animal species the isolate was found in (note: human isolates lack this component term and are thus identified as human isolates by default) • Nakorn-Patom/Thailand is the place this specific virus was isolated

The H in H5N1 stands for "hemagglutinin", as depicted in this molecular model

clades of clade 2, three of which have a distinct geographic distribution and have been implicated in human infections: Map • Subclade 1, Indonesia

• CU-K2 is the laboratory reference number that identifies it from other influenza viruses isolated at the same place and year • 04 represents the year of isolation 2004 • H5 stands for the fifth of several known types of the protein hemagglutinin.

• N1 stands for the first of several known types of the protein neuraminidase.

Other examples include: A/duck/Hong • Subclade 2, Europe, Middle East, and Africa (called Kong/308/78(H5N3), A/avian/NY/01(H5N2), EMA) A/chicken/Mexico/31381-3/94(H5N2), and A/shoveler/Egypt/03(H5N2).[32] • Subclade 3, China”[16][29][30] A 2007 study focused on the EMA subclade has shed further light on the EMA mutations. “The 36 new isolates reported here greatly expand the amount of wholegenome sequence data available from recent avian influenza (H5N1) isolates. Before our project, GenBank contained only 5 other complete genomes from Europe for the 2004–2006 period, and it contained no whole genomes from the Middle East or northern Africa. Our analysis showed several new findings. First, all European, Middle Eastern, and African samples fall into a clade that is distinct from other contemporary Asian clades, all of which share common ancestry with the original 1997 Hong Kong strain. Phylogenetic trees built on each of the 8 segments show a consistent picture of 3 lineages, as illustrated by the HA tree shown in Figure 1. Two of the clades contain exclusively Vietnamese isolates; the smaller of these, with 5 isolates, we label V1; the larger

As with other avian flu viruses, H5N1 has strains called “highly pathogenic” (HP) and “low-pathogenic” (LP).

Avian influenza viruses that cause HPAI are highly virulent, and mortality rates in infected flocks often approach 100%. LPAI viruses have negligible virulence, but these viruses can serve as progenitors to HPAI viruses. The current strain of H5N1 responsible for the deaths of birds across the world is an HPAI strain; all other current strains of H5N1, including a North American strain that causes no disease at all in any species, are LPAI strains. All HPAI strains identified to date have involved H5 and H7 subtypes. The distinction concerns pathogenicity in poultry, not humans. Normally, a highly pathogenic avian virus is not highly pathogenic to either humans or nonpoultry birds. This current deadly strain of H5N1 is unusual in being deadly to so many species, including some, like domestic cats, never previously susceptible to any influenza virus.[33]

11.3. GENETICS

11.3.2

Genetic structure and related subtypes

93 • H2N2, which caused “Asian flu” • H3N2, which caused “Hong Kong flu” and currently causes seasonal human flu • H5N1, ("bird flu"), which is noted for having a strain (Asian-lineage HPAI H5N1) that kills over half the humans it infects, infecting and killing species that were never known to suffer from influenza viruses before (e.g. cats), being unable to be stopped by culling all involved poultry - some think due to being endemic in wild birds, and causing billions of dollars to be spent in flu pandemic preparation and preventiveness • H7N7, which has unusual zoonotic potential and killed one person • H1N2, which is currently endemic in humans and pigs and causes seasonal human flu • H9N2, which has infected three people • H7N2, which has infected two people • H7N3, which has infected two people • H10N7, which has infected two people

The N in H5N1 stands for "Neuraminidase", the protein depicted in this ribbon diagram.

H5N1 is a subtype of the species Influenza A virus of the Influenzavirus A genus of the Orthomyxoviridae family.

Like all other influenza A subtypes, the H5N1 subtype is an RNA virus. It has a segmented genome of eight negative sense, single-strands of RNA, abbreviated as PB2, PB1, PA, HA, NP, NA, MP and NS.

• H7N9, which as of Feb 2014 has infected 309 people, and lead to 70 deaths

11.3.3 Low pathogenic H5N1

Low pathogenic avian influenza H5N1 (LPAI H5N1) also called “North American” H5N1 commonly occurs in wild birds. In most cases, it causes minor sickness or no noticeable signs of disease in birds. It is not known to afHA codes for hemagglutinin, an antigenic glycoprotein fect humans at all. The only concern about it is that it is found on the surface of the influenza viruses and is re- possible for it to be transmitted to poultry and in poultry sponsible for binding the virus to the cell that is be- mutate into a highly pathogenic strain. ing infected. NA codes for neuraminidase, an antigenic glycosylated enzyme found on the surface of the • 1966 LPAI H5N1 influenza viruses. It facilitates the release of progeny A/Turkey/Ontario/6613/1966(H5N1) was deviruses from infected cells.[34] The hemagglutinin (HA) tected in a flock of infected turkeys in Ontario, and neuraminidase (NA) RNA strands specify the strucCanada[35][36] ture of proteins that are most medically relevant as targets for antiviral drugs and antibodies. HA and NA are also • 1975 – LPAI H5N1 was detected in a wild mallard used as the basis for the naming of the different subtypes duck and a wild blue goose in Wisconsin. of influenza A viruses. This is where the H and N come from in H5N1.

• 1981 and 1985 – LPAI H5N1 was detected in ducks by the University of Minnesota conducting a samInfluenza A viruses are significant for their potential for pling procedure in which sentinel ducks were mondisease and death in humans and other animals. Influenza itored in cages placed in the wild for a short period A virus subtypes that have been confirmed in humans, in of time. order of the number of known human pandemic deaths that they have caused, include: • H1N1, which caused the 1918 flu pandemic (“Spanish flu”) and currently is causing seasonal human flu and the 2009 flu pandemic ("swine flu")

• 1983 – LPAI H5N1 was detected in ring-billed gulls in Pennsylvania.

• 1986 - LPAI H5N1 was detected in a wild mallard duck in Ohio.

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• 2005 - LPAI H5N1 was detected in ducks in Manitoba, Canada.

Both the H2N2 and H3N2 pandemic strains contained avian influenza virus RNA segments. “While the pandemic human influenza viruses of 1957 (H2N2) and 1968 • 2008 - LPAI H5N1 was detected in ducks in New (H3N2) clearly arose through reassortment between huZealand. man and avian viruses, the influenza virus causing the 'Spanish flu' in 1918 appears to be entirely derived from • 2009 - LPAI H5N1 was detected in commercial an avian source”.[42] poultry in British Columbia.[37] “In the past, there was no requirement for reporting or tracking LPAI H5 or H7 detections in wild birds so states and universities tested wild bird samples independently of USDA. Because of this, the above list of previous detections might not be all inclusive of past LPAI H5N1 detections. However, the World Organization for Animal Health (OIE) recently changed its requirement of reporting detections of avian influenza. Effective in 2006, all confirmed LPAI H5 and H7 AI subtypes must be reported to the OIE because of their potential to mutate into highly pathogenic strains. Therefore, USDA now tracks these detections in wild birds, backyard flocks, commercial flocks and live bird markets.”[38]

11.3.4

High mutation rate

Influenza viruses have a relatively high mutation rate that is characteristic of RNA viruses. The segmentation of its genome facilitates genetic recombination by segment reassortment in hosts infected with two different influenza viruses at the same time.[39][40] A previously uncontagious strain may then be able to pass between humans, one of several possible paths to a pandemic.

The ability of various influenza strains to show speciesselectivity is largely due to variation in the hemagglutinin genes. Genetic mutations in the hemagglutinin gene that cause single amino acid substitutions can significantly alter the ability of viral hemagglutinin proteins to bind to receptors on the surface of host cells. Such mutations in avian H5N1 viruses can change virus strains from being inefficient at infecting human cells to being as efficient in causing human infections as more common human influenza virus types.[41] This doesn't mean that one amino acid substitution can cause a pandemic, but it does mean that one amino acid substitution can cause an avian flu virus that is not pathogenic in humans to become pathogenic in humans.

11.4 Prevention 11.4.1 Vaccine There are several H5N1 vaccines for several of the avian H5N1 varieties, but the continual mutation of H5N1 renders them of limited use to date: while vaccines can sometimes provide cross-protection against related flu strains, the best protection would be from a vaccine specifically produced for any future pandemic flu virus strain. Dr. Daniel Lucey, co-director of the Biohazardous Threats and Emerging Diseases graduate program at Georgetown University has made this point, “There is no H5N1 pandemic so there can be no pandemic vaccine".[43] However, “pre-pandemic vaccines” have been created; are being refined and tested; and do have some promise both in furthering research and preparedness for the next pandemic.[44][45][46] Vaccine manufacturing companies are being encouraged to increase capacity so that if a pandemic vaccine is needed, facilities will be available for rapid production of large amounts of a vaccine specific to a new pandemic strain.

11.4.2 Public health Further information: Influenza pandemic “The United States is collaborating closely with eight international organizations, including the World Health Organization (WHO), the Food and Agriculture Organization of the United Nations (FAO), the World Organization for Animal Health (OIE), and 88 foreign governments to address the situation through planning, greater monitoring, and full transparency in reporting and investigating avian influenza occurrences. The United States and these international partners have led global efforts to encourage countries to heighten surveillance for outbreaks in poultry and significant numbers of deaths in migratory birds and to rapidly introduce containment measures. The U.S. Agency for International Development (USAID) and the U.S. Department of State, the U.S. Department of Health and Human Services (HHS), and Agriculture (USDA) are coordinating future international response measures on behalf of the White House with departments and agencies across the federal government”.[47]

Influenza A virus subtype H3N2 is endemic in pigs in China, and has been detected in pigs in Vietnam, increasing fears of the emergence of new variant strains.

The dominant strain of annual flu virus in January 2006 was H3N2, which is now resistant to the standard antiviral drugs amantadine and rimantadine. The possibility of H5N1 and H3N2 exchanging genes through reassortment is a major concern. If a reassortment in H5N1 occurs, it might remain an H5N1 subtype, or it could shift subtypes, as H2N2 did when it evolved into the Hong Kong Flu strain of H3N2.

Together steps are being taken to “minimize the risk of

11.6. EPIDEMIOLOGY

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further spread in animal populations”, “reduce the risk of scientist announced that studies had confirmed cases of human infections”, and “further support pandemic plan- H5N1 strains resistant to Tamiflu and Amantadine.[55] ning and preparedness”.[47] Tamiflu-resistant strains have also appeared in the EU, [56][57] Ongoing detailed mutually coordinated onsite surveil- which remain sensitive to Relenza. lance and analysis of human and animal H5N1 avian flu outbreaks are being conducted and reported by the USGS National Wildlife Health Center, the Centers for Disease 11.6 Epidemiology Control and Prevention, the World Health Organization, the European Commission, and others.[48] Further information: Transmission and infection of H5N1 and Global spread of H5N1

11.5 Treatment Further information: Flu research

The earliest infections of humans by H5N1 coincided with an epizootic (an epidemic in nonhumans) of H5N1 influenza in Hong Kong’s poultry population in 1997.

This panzootic (a disease affecting animals of many species, especially over a wide area) outbreak was stopped by the killing of the entire domestic poultry population within the territory. However, the disease has continued to spread; outbreaks were reported in Asia again in 2003. On December 21, 2009 the WHO announced a total of 447 cases which resulted in the deaths of 263.[21][58]

There is no highly effective treatment for H5N1 flu, but oseltamivir (commercially marketed by Roche as Tamiflu), can sometimes inhibit the influenza virus from spreading inside the user’s body. This drug has become a focus for some governments and organizations trying to prepare for a possible H5N1 pandemic.[49] On April 20, 2006, Roche AG announced that a stockpile of three million treatment courses of Tamiflu are waiting at the disposal of the World Health Organization to be used in case of a flu pandemic; separately Roche donated two million 11.6.1 courses to the WHO for use in developing nations that may be affected by such a pandemic but lack the ability to purchase large quantities of the drug.[50]

Contagiousness

However, WHO expert Hassan al-Bushra has said: “Even now, we remain unsure about Tamiflu’s real effectiveness. As for a vaccine, work cannot start on it until the emergence of a new virus, and we predict it would take six to nine months to develop it. For the moment, we cannot by any means count on a potential vaccine to prevent the spread of a contagious influenza virus, whose various precedents in the past 90 years have been highly pathogenic”.[51] Animal and lab studies suggest that Relenza (zanamivir), which is in the same class of drugs as Tamiflu, may also be effective against H5N1. In a study performed on mice in 2000, “zanamivir was shown to be efficacious in treating avian influenza viruses H9N2, H6N1, and H5N1 transmissible to mammals”.[52] In addition, mice studies suggest the combination of zanamivir, celecoxib and mesalazine looks promising producing a 50% survival rate compared to no survival in the placebo arm.[53] While no one knows if zanamivir will be useful or not on a yet to exist pandemic strain of H5N1, it might be useful to stockpile zanamivir as well as oseltamivir in the event of an H5N1 influenza pandemic. Neither oseltamivir nor zanamivir can currently be manufactured in quantities that would be meaningful once efficient human transmission starts.[54] In September, 2006, a WHO

Highly pathogenic H5N1 Countries with humans, poultry and wild birds killed by H5N1.

Countries with poultry or wild birds killed by H5N1 and has reported human cases of H5N1 Countries with poultry or wild birds killed by H5N1.

H5N1 is easily transmissible between birds, facilitating a potential global spread of H5N1. While H5N1 undergoes mutation and reassortment, creating variations which can infect species not previously known to carry the virus, not all of these variant forms can infect humans. H5N1 as an avian virus preferentially binds to a type of galactose receptors that populate the avian respiratory tract from the nose to the lungs and are virtually absent in humans, occurring only in and around the alveoli, structures deep in the lungs where oxygen is passed to the blood. Therefore, the virus is not easily expelled by coughing and sneezing, the usual route of transmission.[22][23][59] H5N1 is mainly spread by domestic poultry, both through the movements of infected birds and poultry products

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and through the use of infected poultry manure as fertilizer or feed. Humans with H5N1 have typically caught it from chickens, which were in turn infected by other poultry or waterfowl. Migrating waterfowl (wild ducks, geese and swans) carry H5N1, often without becoming sick.[60][61] Many species of birds and mammals can be infected with HPAI A(H5N1), but the role of animals other than poultry and waterfowl as disease-spreading hosts is unknown.[62] According to a report by the World Health Organization, H5N1 may be spread indirectly. The report stated the virus may sometimes stick to surfaces or get kicked up in fertilizer dust to infect people.[63]

11.6.2

Virulence

H5N1 has mutated into a variety of strains with differing pathogenic profiles, some pathogenic to one species but not others, some pathogenic to multiple species. Each specific known genetic variation is traceable to a virus isolate of a specific case of infection. Through antigenic drift, H5N1 has mutated into dozens of highly pathogenic varieties divided into genetic clades which are known from specific isolates, but all currently belonging to genotype Z of avian influenza virus H5N1, now the dominant genotype.[40][39] H5N1 isolates found in Hong Kong in 1997 and 2001 were not consistently transmitted efficiently among birds and did not cause significant disease in these animals. In 2002, new isolates of H5N1 were appearing within the bird population of Hong Kong.

These new isolates caused acute disease, including severe neurological dysfunction and death in ducks. This was the first reported case of lethal influenza virus infection in wild aquatic birds since 1961.[64] Genotype Z emerged in 2002 through reassortment from earlier highly pathogenic genotypes of H5N1[2] that first infected birds in China in 1996, and first infected humans in Hong Kong in 1997.[39][40][65] Genotype Z is endemic in birds in Southeast Asia, has created at least two clades that can infect humans, and is spreading across the globe in bird populations. Mutations occurring within this genotype are increasing their pathogenicity.[66] Birds are also able to shed the virus for longer periods of time before their death, increasing the transmissibility of the virus.

11.6.3

Transmission and host range

Infected birds transmit H5N1 through their saliva, nasal secretions, feces and blood. Other animals may become infected with the virus through direct contact with these bodily fluids or through contact with surfaces contaminated with them. H5N1 remains infectious after over 30 days at 0 °C ( 32.0 °F) (over one month at freezing temperature) or 6 days at 37 °C ( 98.6 °F) (one week at human body temperature); at ordinary temperatures it lasts in the environment for weeks. In Arctic temperatures, it

Transmission electron micrograph (TEM) of negatively stained Influenza A virus particles (small and white) attached to host cells (large and irregular) (late passage). (Source: Dr. Erskine Palmer, Centers for Disease Control and Prevention Public Health Image Library)

does not degrade at all.

Because migratory birds are among the carriers of the highly pathogenic H5N1 virus, it is spreading to all parts of the world. H5N1 is different from all previously known highly pathogenic avian flu viruses in its ability to be spread by animals other than poultry.

In October 2004, researchers discovered H5N1 is far more dangerous than was previously believed. Waterfowl were revealed to be directly spreading this highly pathogenic strain to chickens, crows, pigeons, and other birds, and the virus was increasing its ability to infect mammals, as well. From this point on, avian flu experts increasingly referred to containment as a strategy that can delay, but not ultimately prevent, a future avian flu pandemic.

“Since 1997, studies of influenza A (H5N1) indicate that these viruses continue to evolve, with changes in antigenicity and internal gene constellations; an expanded host range in avian species and the ability to infect felids; enhanced pathogenicity in experimentally infected mice and ferrets, in which they cause systemic infections; and increased environmental stability.”[67] The New York Times, in an article on transmission of H5N1 through smuggled birds, reports Wade Hagemeijer of Wetlands International stating, “We believe it is spread by both bird migration and trade, but that trade, particularly illegal trade, is more important”.[68] On September 27, 2007 researchers reported the H5N1 bird flu virus can also pass through a pregnant woman’s placenta to infect the fetus. They also found evidence of what doctors had long suspected — the virus not only affects the lungs, but also passes throughout the body into the gastrointestinal tract, the brain, liver, and blood cells.[69] In May 2013, North Korea confirmed a H5N1 bird flu

11.8. SEE ALSO

97

outbreak that forced authorities to kill over 160,000 been spent and over 200 million birds have been killed to ducks in Pyongyang.[70] try to contain H5N1.[14][80][81][82][83][84][85][86][87] People have reacted by buying less chicken, causing poultry sales and prices to fall.[88] Many individuals have 11.6.4 H5N1 transmission studies in fer- stockpiled supplies for a possible flu pandemic. Interrets (2011) national health officials and other experts have pointed out that many unknown questions still hover around the Novel, contagious strains of H5N1 were created by Ron disease.[89] Fouchier of the Erasmus Medical Center in Rotterdam, Dr. David Nabarro, Chief Avian Flu Coordinator for the the Netherlands, who first presented his work to the pubUnited Nations, and former Chief of Crisis Response for lic at an influenza conference in Malta in September the World Health Organization has described himself as 2011.[71] Three mutations were introduced into the H5N1 “quite scared” about H5N1’s potential impact on humans. virus genome, and the virus was then passed from the Nabarro has been accused of being alarmist before, and noses of infected ferrets to the noses of uninfected ones, on his first day in his role for the United Nations, he prowhich was repeated 10 times.[72] After these 10 passages claimed the avian flu could kill 150 million people. In an the H5N1 virus had acquired the ability of transmission interview with the International Herald Tribune, Nabarro between ferrets via aerosols or respiratory droplets. compares avian flu to AIDS in Africa, warning that unAfter Fouchier offered an article describing this work to derestimations led to inappropriate focus for research and the leading academic journal Science, the US National intervention.[90] Science Advisory Board for Biosecurity (NSABB) recommended against publication of the full details of the study, and the one submitted to Nature by Yoshihiro 11.8 See also Kawaoka of the University of Wisconsin describing related work. However, after additional consultations at • Antigenic shift the World Health Organization and by the NSABB, the NSABB reversed its position and recommended publi• Fujian flu cation of revised versions of the two papers.[73] How• H5N1 clinical trials ever, then the Dutch government declared that this type of manuscripts required Fouchier to apply for an export • Influenza research permit in the light of EU directive 428/2009 on dual [notes 1] use goods.

After much controversy surrounding the • International Conference on Emerging Infectious publishing of his research, Fouchier complied (under forDiseases mal protest) with Dutch government demands to obtain a • National Influenza Centers special permit[74] for submitting his manuscript, and his research appeared in a special issue of the journal Science • Swine influenza devoted to H5N1.[75][76][77] The papers by Fouchier and Kawaoka conclude that it is entirely possible that a natural • Zoonosis chain of mutations could lead to an H5N1 virus acquiring the capability of airborne transmission between mam• Avian influenza virus mals, and that a H5N1 influenza pandemic would not be • Influenzavirus A impossible.[78] In May 2013, it was reported that scientists at the Harbin Veterinary Research Institute in Harbin, China had created H5N1 strains which passed between guinea pigs.[79]

• H7N9

11.9 Notes 11.7 Society and culture Main article: Social impact of H5N1 H5N1 has had a significant effect on human society, especially the financial, political, social, and personal responses to both actual and predicted deaths in birds, humans, and other animals. Billions of U.S. dollars are being raised and spent to research H5N1 and prepare for a potential avian influenza pandemic. Over $10 billion have

[1] The World Intellectual Property Organization (WIPO) lists strategic goods with prohibited goods or goods that require a special permit for import and export without which the carrier faces pecuniary punishment or up to 5 years’ imprisonment.

11.10 References [1] International Committee on Taxonomy of Viruses (2002).

“46.0.1. Influenzavirus A”. Retrieved 2006-04-17.

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[2] Li KS, Guan Y, Wang J, Smith GJ, Xu KM, Duan L, Rahardjo AP, Puthavathana P, Buranathai C, Nguyen TD, Estoepangestie AT, Chaisingh A, Auewarakul P, Long HT, Hanh NT, Webby RJ, Poon LL, Chen H, Shortridge KF, Yuen KY, Webster RG, Peiris JS (2004). “Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia”. Nature. 430 (6996): 209– 213. PMID 15241415. doi:10.1038/nature02746.

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[7] Availability of a new recombinant H5N1 vaccine virus, June 2010, World Health Organization; Availability of a new recombinant H5N1 vaccine virus, May 2009, World Health Organization.

[8] UK to buy bird flu vaccine stock, BBC, February 4, 2009.

[9] “Fears of bioterrorism or an accidental release”.

February 2012.

16

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[12] Webster, R. G. and Walker, E. J. (2003). “The world is teetering on the edge of a pandemic that could kill a large fraction of the human population”. American Scientist. 91 (2): 122. doi:10.1511/2003.2.122.

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[15] Science and Development Network article Pandemic flu: fighting an enemy that is yet to exist published May 3, 2006.

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[17] CDC Archived 20091001000000 at WebCite ARTICLE 1918 Influenza: the Mother of All Pandemics by Jeffery K. Taubenberger published January 2006 [18] Informaworld article Why is the world so poorly prepared for a pandemic of hypervirulent avian influenza? published December 2006 [19] Roos, Robert; Lisa Schnirring (February 1, 2007). “HHS ties pandemic mitigation advice to severity”. University of Minnesota Center for Infectious Disease Research and Policy (CIDRAP). Retrieved 2007-02-03.

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[47] United States Agency for International Development (2006). “Avian Influenza Response: Key Actions to Date”. Archived from the original on 2006-04-17. Retrieved 2006-04-18.

[48] United States Department of Health and Human Services (2002). “Pandemicflu.gov Monitoring outbreaks”. Retrieved 2006-04-18.

[49] Medline Plus (2006-01-12). “Oseltamivir (Systemic)".

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[50] Associated Press, “Tamiflu is Set Aside for WHO,” The Wall Street Journal, April 20, 2006, page D6.

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[79] Chinese Scientists Create New Mutant Bird-Flu Virus, Wired, May 2, 2013 [80] State.gov Archived 2006-09-14 at the Wayback Machine.

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11.11. EXTERNAL LINKS

[82] MSNBC US AID [83] “BMO Financial Group”. .bmo.com. Retrieved 2010-0405.

[84] “Council on Foreign Relations”. Cfr.org. Retrieved 201004-05.

101 • Official outbreak reports by country • Official outbreak reports by week • Chart of outbreaks by country European Union

[85] Reuters article Vietnam to unveil advanced plan to fight bird flu published on April 28, 2006

• Health-EU Portal EU response to Avian Influenza.

[86] Poultry sector suffers despite absence of bird flu Archived March 30, 2006, at the Wayback Machine.

• Avian influenza - Q & A’s factsheet from European Centre for Disease Prevention and Control

[87] Barber, Tony (2006-02-13). “Italy imposes controls after bird flu discovery”. FT.com. Retrieved 2012-08-19.

[88] India eNews article Pakistani poultry industry demands 10-year tax holiday published May 7, 2006 says “Pakistani poultry farmers have sought a 10-year tax exemption to support their dwindling business after the detection of the H5N1 strain of bird flu triggered a fall in demand and prices, a poultry trader said.”

[89] International Institute for Sustainable Development (IISD) Scientific Seminar on Avian Influenza, the Environment and Migratory Birds on 10–11 April 2006 published 14 April 2006.

[90] Donald G. McNeil Jr. (March 28, 2006). “The response to bird flu: Too much or not enough? UN expert stands by his dire warnings”. International Herald Tribune.

11.11 External links • Influenza Research Database – Database of influenza genomic sequences and related information.

• WHO World Health Organization • WHO’s Avian Flu Facts Sheet for 2006 • Epidemic and Pandemic Alert and Response Guide to WHO’s H5N1 pages • Avian Influenza Resources (updated) - tracks human cases and deaths • National Influenza Pandemic Plans • WHO Collaborating Centres and Reference Laboratories Centers, names, locations, and phone numbers • FAO Avian Influenza portal Information resources, animations, videos, photos • FAO Food and Agriculture Organisation - Biweekly Avian Influenza Maps - tracks animal cases and deaths • FAO Bird Flu disease card • FAO Socio-Economic impact of AI Projects, Information resources • OIE World Organisation for Animal Health - tracks animal cases and deaths

United Kingdom • Exotic Animal Disease Generic Contingency Plan — DEFRA generic contingency plan for controlling and eradicating an outbreak of an exotic animal disease. PDF hosted by BBC (a government entity).

• UK Influenza Pandemic Contingency Plan by the National Health Service - a government entity. PDF hosted by BBC • UK Department of Health United States • Center for Infectious Disease Research and Policy Avian Influenza (Bird Flu): Implications for Human Disease - An overview of Avian Influenza • PandemicFlu.Gov U.S. Government’s avian flu information site • USAID U.S. Agency for International Development - Avian Influenza Response • CDC, Centers for Disease Control and Prevention - responsible agency for avian influenza in humans in US - Facts About Avian Influenza (Bird Flu) and Avian Influenza A (H5N1) Virus • USGS - NWHC National Wildlife Health Center responsible agency for avian influenza in animals in US • Wildlife Disease Information Node A part of the National Biological Information Infrastructure and partner of the NWHC, this agency collects and distributes news and information about wildlife diseases such as avian influenza and coordinates collaborative information sharing efforts.

• HHS U.S. Department of Health & Human Services's Pandemic Influenza Plan

Chapter 12

Avian influenza For the H5N1 subtype of Avian influenza, see Influenza Anhui (14), Guangdong (14), Shanghai (2), Fujian (2) A virus subtype H5N1. and Hunan (1). Similar sudden increases in the number of human cases of H7N9 have occurred in previous years [14] Avian influenza — known informally as avian flu or during December and January. bird flu — refers to "influenza caused by viruses adapted to birds.”[1][2][3][4][5][6][7] The type with the greatest risk is highly pathogenic avian influenza (HPAI).

12.1 History

“Bird flu” is a phrase similar to "swine flu,” "dog flu,” "horse flu,” or "human flu" in that it refers to an illness caused by any of many different strains of influenza viruses that have adapted to a specific host. Out of the three types of influenza viruses (A, B, and C), influenza A virus is a zoonotic infection with a natural reservoir almost entirely in birds.[8] Avian influenza, for most purposes, refers to the influenza A virus.

The most widely quoted date for the beginning of recorded history of avian influenza (initially known as fowl plague) was in 1878 when it was differentiated from other diseases that caused high mortality rates in birds.[15] Fowl plague, however, also included Newcastle disease until as recently as the 1950s. Between 1959 and 1995, there were 15 recorded occasions of the emergence of HPAI viruses in poultry, but losses were minimal. BeThough influenza A is adapted to birds, it can also stably tween 1996 and 2008 however, HPAI outbreaks in pouladapt and sustain person-to person transmission.[8] Re- try have occurred at least 11 times and 4 of these outcent influenza research into the genes of the Spanish flu breaks have involved millions of birds.[15] virus shows it to have genes adapted from both human and avian strains. Pigs can also be infected with human, avian, In the 1990s, the world’s poultry population grew 76% and swine influenza viruses, allow for mixtures of genes in developing countries and 23% in developed counto the increased prevalence of avian (reassortment) to create a new virus, which can cause an tries, contributing [16] influenza.

Before the 1990s, HPAI caused high morantigenic shift to a new influenza A virus subtype which tality in poultry, but infections were sporadic and con[8] most people have little to no immune protection. tained. Outbreaks have become more common due to Avian influenza strains are divided into two types based the high density and frequent movement of flocks from on their pathogenicity: high pathogenicity (HP) or low intensive poultry production. pathogenicity (LP).[9] The most well-known HPAI strain, H5N1, appeared in China in 1996, and also has low Influenza A/H5N1 was first isolated from a goose in infections were first reported in pathogenic strains found in North America.[9][10] Com- China in 1996. Human [10] 1997 in Hong Kong.

Since 2003, more than 700 hupanion birds in captivity are unlikely to contract the virus man cases of Asian HPAI H5N1 have been reported to and there has been no report of a companion bird with WHO, primarily from 15 countries in Asia, Africa, the avian influenza since 2003. Pigeons do not contract or the Pacific, Europe, and the Middle East, though over 60 [11][12][13] spread the virus. countries have been affected.[10][15] In the approximate four years from early 2013 to early 2017, 916 lab-confirmed human cases of H7N9 were reported to the World Health Organization (WHO).[14] 12.2 Genetics On 9 January 2017, the National Health and Family Planning Commission of China reported to WHO 106 cases Genetic factors in distinguishing between "human flu of H7N9 which occurred from late November through viruses” and “avian flu viruses” include: late December, including 35 deaths, 2 potential cases of human-to-human transmission, and 80 of these 106 perPB2: (RNA polymerase): Amino acid (or sons stating that they have visited live poultry markets. residue) position 627 in the PB2 protein enThe cases are reported from Jiangsu (52), Zhejiang (21), coded by the PB2 RNA gene. Until H5N1, all 102

12.4. SPREAD known avian influenza viruses had a Glu at position 627, while all human influenza viruses had a Lys. HA: (hemagglutinin): Avian influenza HA viruses bind alpha 2-3 sialic acid receptors, while human influenza HA viruses bind alpha 2-6 sialic acid receptors. Swine influenza viruses have the ability to bind both types of sialic acid receptors. Hemagglutinin is the major antigen of the virus against which neutralizing antibodies are produced, and influenza virus epidemics are associated with changes in its antigenic structure. This was originally derived from pigs, and should technically be referred to as “pig flu”.[17]

103

12.4 Spread Avian influenza is most often spread by contact between infected and healthy birds, though can also be spread indirectly through contaminated equipment.[22] The virus is found in secretions from the nostrils, mouth, and eyes of infected birds as well as their droppings. HPAI infection is spread to people often through direct contact with infected poultry, such as during slaughter or plucking.[22] Though the virus can spread through airborne secretions, the disease itself is not an airborne disease. Highly pathogenic strains spread quickly among flocks and can destroy a flock within 28 hours; the less pathogenic strains may affect egg production but are much less deadly.

Although it is possible for humans to contract the avian influenza virus from birds, human-to-human contact is much more difficult without prolonged contact. However, public health officials are concerned that strains of avian flu may mutate to become easily transmissible be12.3 Subtypes tween humans.[20] Some strains of avian influenza are present in the intestinal tract of large numbers of shore There are many subtypes of avian influenza viruses, but birds and water birds, but these strains rarely cause huonly some strains of five subtypes have been known man infection.[23] to infect humans: H5N1, H7N3, H7N7, H7N9, and H9N2.[18] At least one person, an elderly woman in Five manmade ecosystems have contributed to modern Jiangxi Province, China, died of pneumonia in Decem- avian influenza virus ecology: integrated indoor commerber 2013 from the H10N8 strain, the first human fatality cial poultry, range-raised commercial poultry, live poultry markets, backyard and hobby flocks, and bird colconfirmed to be caused by that strain.[19] lection and trading systems including cockfighting. InMost human cases of the avian flu are a result of either door commercial poultry has had the largest impact on handling dead infected birds or from contact with infected the spread of HPAI, with the increase in HPAI outbreaks fluids. It can also be spread through contaminated sur- largely the result of increased commercial production faces and droppings. While most wild birds mainly have since the 1990s.[16] only a mild form of the H5N1 strain, once domesticated birds such as chickens or turkeys are infected, it can become much more deadly because the birds are often in close contact. There is currently a large threat of this in Asia with infected poultry due to low hygiene conditions and close quarters. Although it is easy for humans to contract the infection from birds, human-to-human transmis- 12.4.1 Village poultry sion is more difficult without prolonged contact. However, public health officials are concerned that strains of avian flu may mutate to become easily transmissible be- In the early days of the HPAI H5N1 pandemic, village poultry and their owners were frequently implitween humans.[20] cated in disease transmission.[16] Village poultry, also Spreading of H5N1 from Asia to Europe is much more known as backyard and hobby flocks, are small flocks likely caused by both legal and illegal poultry trades than raised under extensive conditions and often allowed free dispersing through wild bird migrations, being that in re- range between multiple households. However, research cent studies, there were no secondary rises in infection has shown that these flocks pose less of a threat than in Asia when wild birds migrate south again from their intensively raised commercial poultry with homogenous breeding grounds. Instead, the infection patterns fol- genetic stock and poor biosecurity.[16] Backyard and villowed transportation such as railroads, roads, and coun- lage poultry also do not travel great distances compared try borders, suggesting poultry trade as being much more to transport of intensively raised poultry and contribute likely. While there have been strains of avian flu to ex- less to the spread of HPAI.[24] This initial implication of ist in the United States, such as Texas in 2004, they have Asian poultry farmers as one broad category presented been extinguished and have not been known to infect hu- challenges to prevention recommendations as commermans. cial strategies did not necessarily apply to backyard poultry flocks.

Examples of avian influenza A virus strains:[21]

104

12.5 H5N1 Further information: Influenza A virus subtype H5N1 and Transmission and infection of H5N1

CHAPTER 12. AVIAN INFLUENZA patients in February 2017 which rendered it more deadly to chickens, inasmuch as it could infect every organ; the risk to humans was not increased, however.[30]

12.5.1 Controversial Research The highly pathogenic influenza A virus subtype H5N1 is an emerging avian influenza virus that is causing global concern as a potential pandemic threat. It is often referred to simply as “bird flu” or “avian influenza”, even though it is only one of many subtypes.

A study published in 2012 in Science Magazine reported on research findings that allowed for the airborne transmission of H5N1 in laboratory ferrets. The study identified the 5 mutations necessary for the virus to become airborne and immediately spiked controversy over the ethical implications of making such potentially dangerous information available to the general public. The study was allowed to remain available in its entirety, though it remains a controversial topic within the scientific community.

H5N1 has killed millions of poultry in a growing number of countries throughout Asia, Europe, and Africa. Health experts are concerned that the coexistence of human flu viruses and avian flu viruses (especially H5N1) will provide an opportunity for genetic material to be exchanged between species-specific viruses, possibly creating a new virulent influenza strain that is easily transmissible and The study in question, however, created airborne H5N1 lethal to humans. The mortality rate for humans with via amino acid substitutions that largely mitigated the devastating effects of the disease. This fact was underH5N1 is 60%. scored by the 0% fatality rate among the ferrets infected Since first human H5N1 outbreak occurred in 1997, there via airborne transmission, as well as the fundamental bihas been an increasing number of HPAI H5N1 bird-toology underlying the substitutions. Flu viruses attach to human transmissions, leading to clinically severe and fahost cells via the hemagluttinin proteins on their envelope. tal human infections. Because a significant species barThese hemagluttinin proteins bind to sialic acid receptors rier exists between birds and humans, the virus does not on host cells, which can fall into two categories. The sialic easily spread to humans, however some cases of infection acid receptors can be either 2,3 or 2,6-linked, with the are being researched to discern whether human-to-human species of origin largely deciding receptor preference. In [25] transmission is occurring. More research is necessary influenzas of avian origin 2,3-linkage is preferred, vs. into understand the pathogenesis and epidemiology of the fluenzas of human origin in which 2,6-linkage is preferH5N1 virus in humans. Exposure routes and other disable. 2,3-linked SA receptors in humans are found preease transmission characteristics, such as genetic and imdominantly in the lower respiratory tract, a fact that is the munological factors that may increase the likelihood of primary foundation for the deadliness of avian influen[26] infection, are not clearly understood. zas in humans, and also the key to their lack of airborne The first known transmission of H5N1 to a human oc- transmission. In the study that created an airborne avian curred in Hong Kong in 1997, when there was an out- influenza among ferrets it was necessary to switch the rebreak of 18 human cases; 6 deaths were confirmed. ceptor preference of the host cells to those of 2,6-linkage, None of the infected people worked with poultry. Af- found predominantly in humans’ upper respiratory tract, ter culling all of the poultry in the area, no more cases in order to create an infection that could shed aerosolized were diagnosed.[23] In 2006, the first human-to-human virus particles. Such an infection, however, must occur in transmission likely occurred when 7 members of a fam- the upper respiratory tract of humans, thus fundamentally ily in Sumatra became infected after contact with a family undercutting the fatal trajectory of the disease.[31] member who had worked with infected poultry.[27] Although millions of birds have become infected with the virus since its discovery, 359 people have died from the 12.6 H7N9 H5N1 in twelve countries according to World Health Organization reports as of August 10, 2012.[28] Further information: Influenza A virus subtype H7N9 As an example, the H5N1 outbreak in Thailand caused massive economic losses, especially among poultry work- Influenza A virus subtype H7N9 is a novel avian influenza ers. Infected birds were culled and slaughtered. The virus first reported to have infected humans in 2013 in public lost confidence with the poultry products, thus de- China.[32] Most of the reported cases of human infeccreasing the consumption of chicken products. This also tion have resulted in severe respiratory illness.[33] In the elicited a ban from importing countries. There were, month following the report of the first case, more than however, factors which aggravated the spread of the virus, 100 people had been infected, an unusually high rate for including bird migration, cool temperature (increases a new infection; a fifth of those patients had died, a fifth virus survival) and several festivals at that time.[29] had recovered, and the rest remained critically ill.[34] The A mutation in the virus was discovered in two Guangdong World Health Organization (WHO) has identified H7N9

12.7. IN DOMESTIC ANIMALS

105

as "...an unusually dangerous virus for humans.”[35] As 12.7 In domestic animals of June 30, 133 cases have been reported, resulting in the deaths of 43.

Several domestic species have been infected with and Research regarding background and transmission is shown symptoms of H5N1 viral infection, including cats, [44] ongoing.[36] It has been established that many of the hu- dogs, ferrets, pigs, and birds. man cases of H7N9 appear to have a link to live bird markets.[37] As of July 2013, there had been no evidence of sustained human-to-human transmission, however a 12.7.1 Birds study group headed by one of the world’s leading experts on avian flu reported that several instances of human-to- Attempts are made in the United States to minimize the human infection were suspected.[38] It has been reported presence of HPAI in poultry through routine surveillance that H7N9 virus does not kill poultry, which will make of poultry flocks in commercial poultry operations. Desurveillance much more difficult. Researchers have com- tection of a HPAI virus may result in immediate culling of mented on the unusual prevalence of older males among the flock. Less pathogenic viruses are controlled by vacciH7N9-infected patients.[39] While several environmental, nation, which is done primarily in turkey flocks (ATCvet behavioral, and biological explanations for this pattern codes: QI01AA23 (WHO) for the inactivated fowl vacfor the inactivated turkey comhave been proposed,[40] as yet, the reason is unknown.[41] cine, QI01CL01 (WHO) [45] bination vaccine).

Currently no vaccine exists, but the use of influenza antiviral drugs known as neuraminidase inhibitors in cases of early infection may be effective.[42]

12.7.2 Seals

The number of cases detected after April fell abruptly.

The decrease in the number of new human H7N9 cases may have resulted from containment measures taken by Chinese authorities, including closing live bird markets, or from a change in seasons, or possibly a combination of both factors. Studies indicate that avian influenza viruses have a seasonal pattern, thus it is thought that infections may pick up again when the weather turns cooler in China.[43]

A recent strain of the virus is able to infect the lungs of seals.[46]

12.7.3 Cats

Avian influenza in cats can show a variety of symptoms and usually lead to death. Cats are able to get infected by either consuming an infected bird or by contracting the In the four years from early 2013 to early 2017, 916 virus from another infected cat. lab-confirmed human cases of H7N9 were reported to WHO.[14] On 9 January 2017, the National Health and Family Planning Commission of China reported to WHO 106 cases which occurred from late November through December.

29, 2016. The cases are reported from Jiangsu (52), Zhejiang (21), Anhui (14), Guangdong (14), Shanghai (2), Fujian (2) and Hunan (1). 80 of these 106 persons have visited live poultry markets. Of these cases, there have been 35 deaths. In two of the 106 cases, human-tohuman transmission could not be ruled out.[14] Affected prefectures in Jiangsu province closed live poultry markets in late December 2016, whereas Zhejiang, Guangdong and Anhui provinces went the route of strengthening live poultry market regulations. Travellers to affected regions are recommended to avoid poultry farms, live bird markets, and surfaces which appear to be contaminated with poultry feces. Similar sudden increases in the number of human cases of H7H9 have occurred in previous years during December and January.[14]

12.8 Global impact In 2005, the formation of the International Partnership on Avian and Pandemic Influenza was announced in order to elevate the importance of avian flu, coordinate efforts, and improve disease reporting and surveillance in order to better respond to future pandemics. New networks of laboratories have emerged to detect and respond to avian flu, such as the Crisis Management Center for Animal Health, the Global Avian Influenza Network for Surveillance, OFFLU, and the Global Early Warning System for major animal diseases. After the 2003 outbreak, WHO member states have also recognized the need for more transparent and equitable sharing of vaccines and other benefits from these networks.[47] Cooperative measures created in response to HPAI have served as a basis for programs related to other emerging and re-emerging infectious diseases.

HPAI control has also been used for political ends. In Indonesia, negotiations with global response networks were used to recentralize power and funding to the Ministry of Health.[48] In Vietnam policymakers, with the support of the Food and Agriculture Organization of the United Nations (FAO), used HPAI control to accelerate

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the industrialization of livestock production for export by proposing to increase the portion of large-scale commercial farms and reducing the number of poultry keepers from 8 to 2 million by 2010.[49]

istry of Health, already weak due to the decentralized nature the government, was experiencing further leakage of funding to state and non-state agencies due to global health interventions. By reasserting control over public health issues and funding by setting itself up as the sole Indonesian representative to the WHO, the Ministry of Health made itself a key player in the management of fu12.8.1 Stigma ture international funds relating vaccine production and Backyard poultry production was viewed as “traditional renegotiated benefits from global surveillance networks.

Asian” agricultural practices that contrasted with modern commercial poultry production and seen as a threat to biosecurity. Backyard production appeared to hold 12.8.3 Economic greater risk than commercial production due to lack of biosecurity and close contact with humans, though HPAI Approximately 20% of the protein consumed in develspread in intensively raised flocks was greater due to high oping countries come from poultry.[16] In the wake of the density rearing and genetic homogeneity.[16][50] Asian H5N1 pandemic, millions of poultry were killed. In Vietculture itself was blamed as the reason why certain in- nam alone, over 50 million domestic birds were killed due terventions, such as those that only looked at placed- to HPAI infection and control attempts.[52] A 2005 report based interventions, would fail without looking for a mul- by the FAO totaled economic losses in South East Asia tifaceted solutions.[49] around US$10 billion.[52] This had the greatest impact on small scale commercial and backyard producers relative to total assets compared to industrial chains which 12.8.2 Indonesia primarily experience temporary decreases in exports and loss of consumer confidence. Some governments did proPress accounts of avian flu in Indonesia were seen by vide compensation for culled poultry, it was often far bepoultry farmers as conflating suspected cases while the low market value (close to 30% of market value in Vietpublic did see the accounts as informative, though many nam), while others such as Cambodia provide no combecame de-sensitized to the idea of impending dan- pensation to farmers at all. ger or only temporarily changed their poultry-related As poultry serves as a source of food security and liqbehavior.[51] Rumors also circulated in Java in 2006. uid assets, the most vulnerable populations were poor These tended to focus on bird flu being linked to big busismall scale farmers.[49] The loss of birds due to HPAI and nesses in order to drive small farmers out of the market by culling in Vietnam led to an average loss of 2.3 months of exaggerating the danger of avian influenza, avian flu beproduction and US$69–108 for households where many ing introduced by foreigners to force Indonesians to purhave an income of $2 a day or less.[52] The loss of food sechase imported chicken and keep Indonesian chicken off curity for vulnerable households can be seen in the stuntthe world market, and the government using avian flu as ing of children under 5 in Egypt.[16] Women are another a ploy to attract funds from wealthy countries. Such rupopulation at risk as in most regions of the world, small mors reflected concerns about big businesses, globalizaflocks are tended to by women.[53] Widespread culling tion, and a distrust of the national government in a counalso resulted in the decreased enrollment of girls in school try where “the amount of decentralization here is breathin Turkey.[16] taking” according to Steven Bjorge, a WHO epidemiologist in Jakarta in 2006.[51] In the context a decentralized national government that the public did not completely trust, Indonesian Health Minister Siti Fadilah Supari announced in December 2006 that her government would no longer be sharing samples of H5N1 collected from Indonesian patients.

This decision came as a shock to the international community as it disrupted the Global Influenza Surveillance Network (GISN) coordinated by the WHO for managing seasonal and pandemic influenza. GISN is based on countries sharing virus specimens freely with the WHO which assesses and eventually sends these samples to pharmaceutical companies in order to produce vaccines that are sold back to these countries.[48] Though this was initially seen as an attempt to protect national sovereignty at all costs, it was instead used for a domestic political struggle. Prior to Indonesia’s dispute with the GISN, the Min-

12.9 Prevention People who do not regularly come into contact with birds are not at high risk for contracting avian influenza. Those at high risk include poultry farm workers, animal control workers, wildlife biologists, and ornithologists who handle live birds.[20] Organizations with high-risk workers should have an avian influenza response plan in place before any cases have been discovered. Biosecurity of poultry flocks is also important for prevention. Flocks should be isolated from outside birds, especially wild birds, and their waste; vehicles used around the flock should be regularly disinfected and not shared between farms; and birds from slaughter channels should not be returned to the farm.[54]

12.9. PREVENTION With proper infection control and use of personal protective equipment (PPE), the chance for infection is low.

Protecting the eyes, nose, mouth, and hands is important for prevention because these are the most common ways for the virus to enter the body. Appropriate personal protective equipment includes aprons or coveralls, gloves, boots or boot covers, and a head cover or hair cover. Disposable PPE is recommended. An N-95 respirator and unvented/indirectly vented safety goggles are also part of appropriate PPE. A powered air purifying respirator (PAPR) with hood or helmet and face shield is also an option.[23]

107 Recommendations also involve restructuring commercial markets to improve biosecurity against avian influenza.

Poultry production zoning is used to limit poultry farming to specific areas outside of urban environments while live poultry markets improve biosecurity by limiting the number of traders holding licenses and subjecting producers and traders to more stringent inspections. These recommendations in combination with requirements to fence and house all poultry, and limit free ranging flocks will eventually lead to fewer small commercial producers and backyard producers, costing livelihoods as they are unable to meet the conditions needed to participate.[49]

Proper reporting of an isolated case can help to prevent spread. The Centers for Disease Control and Prevention (US) recommendation is that if a worker develops symptoms within 10 days of working with infected poultry or potentially contaminated materials, they should seek care and notify their employer, who should notify public health officials.[23]

A summary of reports to the World Organisation for Animal Health in 2005 and 2010 suggest that surveillance and under-reporting in developed and developing countries is still a challenge.[16] Often, donor support can focus on HPAI control alone, while similar diseases such as Newcastle disease, acute fowl cholera, infectious laryngotracheitis, and infectious bursal disease still affect poulFor future avian influenza threats, the WHO suggests a 3 try populations. When HPAI tests come back negative, a lack of funded testing for differential diagnoses can leave phase, 5 part plan.[55] farmers wondering what killed their birds.

• Phase: Pre-pandemic • Reduce opportunities for human infection • Strengthen the early warning system • Phase: Emergence of a pandemic virus • Contain or delay spread at the source

Since traditional production systems require little investment and serve as a safety net for lower income households, prevention and treatment can been seen as less cost effective than letting a few birds die.[49][52] Effective control not only requires prior agreements to be made with relevant government agencies, such as seen with Indonesia, they must also not unduly threaten food security.[48]

• Phase: Pandemic declared and spreading internationally 12.9.2

Culling

• Reduce morbidity, mortality, and social disCulling is used in order to decrease the threat of avian inruption fluenza transmission by killing potentially infected birds.

• Conduct research to guide response measures The FAO manual on HPAI control recommends a zoning strategy which begins with the identification of an inVaccines for poultry have been formulated against sev- fected area (IA) where sick or dead birds have tested poseral of the avian H5N1 influenza varieties. Control mea- itive. All poultry in this zone are culled while the area 1 sures for HPAI encourage mass vaccinations of poultry to 5 km from the outer boundary of the IA is considered though The World Health Organization has compiled a the restricted area (RA) placed under strict surveillance. list of known clinical trials of pandemic influenza proto- 2 to 10 km from the RA is the control area (CA) that type vaccines, including those against H5N1.[56] In some serves as a buffer zone in case of spread. Culling is not countries still at high risk for HPAI spread, there is com- recommended beyond the IA unless there is evidence of pulsory strategic vaccination though vaccine supply short- spread.[24] The manual, however, also provides examples ages remain a problem.[16] of how control was carried out between 2004 and 2005 to contain H5N1 where all poultry was to be stamped out in a 3 km radius beyond the infected point and beyond 12.9.1 For village poultry farmers that a 5 km radius where all fowl was to be vaccinated.

Initial response to H5N1, a one size fits all recommenda- This culling method was indiscriminate as a large proportion was used for all poultry production systems, though tion of the poultry inside these areas were small backyard measures for intensively raised birds were not necessarily flocks which did not travel great enough distances to carry human effort and appropriate for extensively raised birds. When looking infection to adjacent villages without [24] Between 2004 and may have not been infected at all. at village poultry, it was first assumed that the household 2005, over 100 million chickens were culled in Asia to was the unit and that flocks did not make contact with [57] contain H5N1. other flocks, though more effective measures came into use when the epidemiological unit was the village.[16]

The risk of mass culling of birds and the resulting eco-

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nomic impact led farmers who were reluctant to report sick poultry. The culls often preempted actual lab testing for H5N1 as avian flu policy justified sacrificing poultry as a safeguard against HPAI spread.[50] In response to these policies, farmers in Vietnam between 2003 and 2004 became more and more unwilling to surrender apparently healthy birds to authorities and stole poultry destined for culls as it stripped poultry of their biosocial and economic worth. By the end of 2005, the government implemented a new policy that targeted high-risk flock in the immediate vicinity of infected farms and instituted voluntary culling with compensation in the case of a local outbreak.[50]

poultry.[49][58] Farmers, pointed to wind and environmental pollution as reasons poultry would get sick. NSCAI recommendations also would disrupt longstanding livestock production practices as gates impede sales by restricting assessment of birds by appearance and offend customers by limiting outside human contact. Instead of incorporating local knowledge into recommendations, cultural barriers were used as scapegoats for failed interventions. Prevention and control methods have been more effective when also considering the social, political, and ecological agents in play.[49]

Not only did culling result in severe economic impacts especially for small scale farmers, culling itself may be an ineffective preventative measure. In the short-term, mass culling achieves it goals of limiting the immediate spread of HPAI, it has been found to impede the evolution of host resistance which is important for the longterm success of HPAI control. Mass culling also selects for elevated influenza virulence and results in the greater mortality of birds overall.[57] Effective culling strategies must be selective as well as considerate of economic impacts to optimize epidemiological control and minimize economic and agricultural destruction.

12.10 See also

12.9.3

People-poultry relations

Prevention and control programs must take into account local understandings of people-poultry relations. In the past, programs that have focused on singular, place-based understandings of disease transmission have been ineffective. In the case of Northern Vietnam, health workers saw poultry as commodities with an environment that was under the control of people. Poultry existed in the context of farms, markets, slaughterhouses, and roads while humans were indirectly the primary transmitters of avian flu, placing the burden of disease control on people. However, farmers saw their free ranging poultry in an environment dominated by nonhuman forces that they could not exert control over. There were a host of nonhuman actors such as wild birds and weather patterns whose relationships with the poultry fostered the disease and absolved farmers of complete responsibility for disease control.[49] Attempts at singular, place-based controls sought to teach farmers to identify areas where their behavior could change without looking at poultry behaviors. Behavior recommendations by Vietnam’s National Steering Committee for Avian Influenza Control and Prevention (NSCAI) were drawn from the FAO Principles of Biosecurity.[49] These included restrictions from entering areas where poultry are kept by erecting barriers to segregate poultry from non-human contact, limits on human movement of poultry and poultry-related products ideally to transporters, and recommendations for farmers to wash hands and footwear before and after contact with

• H7N9 • Global spread of H5N1 • H5N1 • Health crisis • Influenza • Influenzavirus A • Influenza pandemic • Influenza Genome Sequencing Project • Influenza research • Influenza vaccine • International Partnership on Avian and Pandemic Influenza • OIE/FAO Network of Expertise on Avian Influenza • Pandemic Preparedness and Response Act • Subtypes of Influenza A virus • Transmission and infection of H5N1

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Food and Agriculture Organisation.

[53] Bagnol, B. (2012). Advocate gender issues: A sustainable way to control Newcastle Disease in village chickens. INFPD Good Practices of Family Poultry Production Note No 03.

[54] “CDC - NIOSH Publications and Products - Protecting Poultry Workers from Avian Influenza (Bird Flu) (2008128)". www.cdc.gov. Retrieved 2015-07-31.

[55] “Responding to the avian influenza pandemic threat: Recommended strategic actions”. World Health Organization. 2005.

[56] “Research and development”. WHO. [57] Shim, E.; Galvani, A. P. (2009).

“Evolutionary repercussions of avian culling on host resistance and influenza virulence”.

PLoS ONE. 4 (5): e5503. doi:10.1371/journal.pone.0005503.

[58] “Transmission of Influenza Viruses from Animals to People”. Centers for Disease Control and Prevention. 19 Aug 2014.

12.12 Sources • Orent, Wendy (2006) The Science of Avian Flu, Answers to Nine Frequently Asked Questions (Discover Magazine. Health & Medicine. February 20, 2006.

59-61) • Haugan, Salomon (2012) Avian Influenza: Etiology, Pathogenesis and Interventions (Nova Science Publishers, Inc.) ISBN 978-1607418467

12.13 External links International

12.13. EXTERNAL LINKS United Nations System Coordinator for Avian and Human Influenza (UNSIC) • Avian Influenza and the Pandemic Threat World Health Organisation (WHO)

111 • Species Profile- Avian Influenza (Orthomyxoviridae Influenza Type A, subtype H5N1), National Invasive Species Information Center, United States National Agricultural Library. Lists general information and resources for Avian Influenza.

• The United Nation’s World Health Organization’s Avian Flu Facts Sheet for 2006

• Strategic Health Communication for Avian and Pandemic Influenza Prevention Johns Hopkins Bloomberg School of Public Health Center for Communication Programs Global Program on Avian and Pandemic Influenza.

• In-depth analysis of bird flu Symptoms & in-depth analysis on avian flu

• Avian Influenza: Critical Program Issues Global Health Technical Brief on Avian Influenza.

• WHO Avian influenza resource

Food and Agriculture Organization of the UN (FAO) • FAO Avian Influenza portal Information resources, animations, videos, photos • FAO Bird Flu disease card World Organisation for Animal Health (OIE) • Current status of HPAI worldwide at OIE. WAHID Interface – OIE World Animal Health Information Database • Disease card • Avian influenza resource By Dr. Nati Elkin – Atlases, vaccines and information.

United States • PandemicFlu.Gov U.S. Government avian and pandemic flu information • CIDRAP Avian Flu Overview “Avian Influenza (Bird Flu): Agricultural and Wildlife Considerations” • US Avian Influenza Response U.S. Agency for International Development (USAID) • Avian influenza research and recommendations National Institute for Occupational Safety and Health • Influenza Research Database Database of influenza sequences and related information.

• Wildlife Disease Information Node A part of the National Biological Information Infrastructure and partner of the NWHC, this agency collects and distributes news and information about wildlife diseases such as avian influenza and coordinates collaborative information sharing efforts.

• Avian Influenza information AVMA – The American Veterinary Medical Association.

• NIOSH Alert: Protecting Poultry Workers from Avian Influenza (Bird Flu) CDC/NIOSH recommendations for poultry workers Europe • Health-EU Portal EU response to Avian Influenza.

• Avian Influenza: Prevention and Control Proceedings of the Frontis workshop on Avian Influenza: Prevention and Control, Wageningen, The Netherlands • Avian Influenza: Questions & Answers European Centre for Disease Prevention and Control – Official website • FluTrop: Avian Influenza Research in Tropical Countries French Agricultural Research Center for Developing Countries (CIRAD), Avian Influenza website

Chapter 13

Influenza A virus subtype H7N7 H7N7 is a subtype of Influenza A virus, a genus of Orthomyxovirus, the viruses responsible for influenza.

Highly pathogenic strains (HPAI) and low pathogenic strains (LPAI) exist. H7N7 can infect humans, birds, pigs, seals, and horses in the wild; and has infected mice in laboratory studies. This unusual zoonotic potential represents a pandemic threat.

mortality in one shed and a reduction in egg production recorded two weeks before a large number of deaths on 2 June that led to the diagnosis of HP H7N7 on 4 June.[6]

In 2003, 89 people in the Netherlands were confirmed to have been infected by H7N7 following an outbreak in poultry on approximately 255 farms. One death was recorded - a veterinarian who had been testing chickens for the virus - and all infected flocks were culled. Most affected people had mild symptoms including conjunctivitis.[1][2] Antibodies were found in over half of 500 people tested according to the final official report by the Dutch government:

In August 2013, high pathogenic (HP) H7N7 was found in markets in Wenzhou, Zhejiang province in China when testing for H7N9.[8]

In October 2009, high pathogenic (HP) H7N7 was confirmed on a farm in Almoguera, Guadalajara, Spain.

Hong Kong announced that it would suspend the import of poultry from Spain.[7]

In July 2015, high pathogenic (HP) H7N7 was confirmed on a poultry farm in Lancashire, England.[9]

13.1 Sources

As at least 50% of the people exposed to infected poultry had H7 antibodies detectable with the modified assay, it was estimated that avian influenza A/H7N7 virus infection occurred in at least 1000, and perhaps as many as 2000 people. The seroprevalence of H7 antibodies in people without contact with infected poultry, but with close household contact to an infected poultry worker, was 59%.

This suggests that the population at risk for avian influenza was not limited to those with direct contact to infected poultry, and that person to person transmission may have occurred on a large scale.[3] Final analysis of Dutch avian influenza outbreaks reveals much higher levels of transmission to humans than previously thought.[4]

[1] “Early bird flu warning for Dutch”. Panorama. BBC News. 6 November 2005. Retrieved 25 May 2015.

In August 2006, low pathogenic (LP) H7N7 was found during routine testing at a poultry farm in Voorthuizen in the central Netherlands. As a precautionary measure, 25,000 chickens were culled from Voorthuizen and surrounding farms.[5]

[5] “Mild form of H7N7 bird flu found in Netherlands”.

Xinhua News Agency. 10 August 2006. Retrieved 25 May 2015.

[2] “CDC - NIOSH Publications and Products - Protecting Poultry Workers from Avian Influenza (Bird Flu) (2008128)". www.cdc.gov. Retrieved 2015-07-30.

[3] Bosman A, Mulder YM, de Leeuw JRJ, Meijer A, Du Ry van Beest Holle M, Kamst RA, van der Velden PG, Conyn-van Spaendonck MAE, Koopmans MPG, Ruijten MWMM (20 December 2004). “Avian Flu Epidemic 2003: Public health consequences. Executive summary”.

Rijksinstituut voor Volksgezondheid en Milieu. REFID 630940004. Retrieved 25 May 2015.

[4] Bosman A, Meijer A, Koopmans M (6 January 2005).

“Final analysis of Netherlands avian influenza outbreaks reveals much higher levels of transmission to humans than previously thought”. Eurosurveillance. 10 (12): 2616.

Retrieved 25 May 2015.

In June 2008, high pathogenic (HP) H7N7 was confirmed on a 25,000-bird laying unit at Shenington, England; probably derived from a pre-existing low pathogenic variety. Farmers Guardian reported a 2.5 per cent increased 112

[6] “Poultry farmers’ avian flu warning”. Farmers Guardian.

20 June 2008. Archived from the original on 2 October 2009. Retrieved 25 May 2015.

[7] Sahuquillo, María R. (15 October 2009). “El virus de gripe aviar de Guadalajara es el H7N7”. El País (in Spanish). Madrid. EFE. Retrieved 25 May 2015.

13.3. EXTERNAL LINKS

[8] Sample, Ian (21 August 2013). “New H7N7 bird flu strain discovered that could pose threat to humans”. The Guardian. London. Retrieved 25 May 2015.

[9] Press Association (13 July 2015). “Bird flu confirmed on Lancashire farm”. The Guardian. London. Retrieved 13 July 2015.

13.2 Further reading • Du Ry van Beest Holle M, Meijer A, Koopmans M, de Jager CM (1 December 2005).

“Outbreak report: Human-to-human transmission of avian influenza A/H7N7, The Netherlands, 2003”. Eurosurveillance. 10 (12): 584.

• “2. How the Virus Spread from Poultry to People and Pigs”. Highly Pathogenic Avian Influenza Virus HPAI H7N7 - 2003 Epidemic in Europe. Pig Disease Information Centre U.K. 2010. Retrieved 25 May 2015.

• Suarez, David; Schultz Cherry, Stacey; Perdue, Michael; Swayne, David (23 September 2000).

Comparison of Four H7n7 Avian Influenza Viruses Associated with Infection and Disease in Humans.

Options for the Control of Influenza Conference.

Agricultural Research Service, USDA. Publication #111993. Retrieved 25 May 2015. Abstract only.

• “Avian influenza in the Netherlands”. Global Alert and Response, World Health Organization. 24 April 2003. Retrieved 25 May 2015.

• Fouchier RA, Schneeberger PM, Rozendaal FW, et al. (February 2004). “Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome”. Proceedings of the National Academy of Sciences of the United States of America. 101 (5): 1356–61. PMC 337057 . PMID 14745020. doi:10.1073/pnas.0308352100. Retrieved 25 May 2015.

13.3 External links • Influenza Research Database—Database of influenza genomic sequences and related information

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Chapter 14

Zoonosis “Zoonotic” redirects here. For the television episode, tion and expansion of epidemics depend on frequent consee Zoonotic (Law & Order: Criminal Intent). tact with other individuals who have not yet developed an adequate immune response. To persist in such a popZoonoses (/ˌzoʊ.əˈnoʊsᵻs/, plural -/ˈnoʊsiːz/, also spelled ulation, a pathogen either had to be a chronic infection, zoönoses; singular zoonosis (or zoönosis); from Greek: staying present and potentially infectious in the infected ζῷον zoon “animal” and νόσος nosos “sickness”) are host for long periods, or it had to have other additional infectious diseases of animals (usually vertebrates) that species as reservoir where it can maintain itself until further susceptible hosts are contacted and infected. In fact, can naturally be transmitted to humans.[1][2] for many 'human' diseases, the human is actually better Major modern diseases such as Ebola virus disease and viewed as an accidental or incidental victim and a deadsalmonellosis are zoonoses. HIV was a zoonotic disease end host. Examples include rabies, anthrax, tularemia transmitted to humans in the early part of the 20th cen- and West Nile virus. Thus, much of human exposure to tury, though it has now evolved to a separate human- infectious disease has been zoonotic. only disease. Most strains of influenza that infect humans are human diseases, although many strains of swine and Many modern diseases, even epidemic diseases, started bird flu are zoonoses; these viruses occasionally recom- out as zoonotic diseases. It is hard to establish with cerbine with human strains of the flu and can cause pan- tainty which diseases jumped from other animals to hudemics such as the 1918 Spanish flu or the 2009 swine mans, but there is increasing evidence from DNA and flu. Taenia solium infection is one of the neglected tropi- RNA sequencing, that measles, smallpox, influenza, HIV, cal diseases with public health and veterinary concern in and diphtheria came to humans this way. Various forms of the common cold and tuberculosis also are adaptations endemic regions.[3] Zoonoses can be caused by a range of strains originating in other species. of disease pathogens such as viruses, bacteria, fungi and parasites; of 1,415 pathogens known to infect humans, Zoonoses are of interest because they are often previ61% were zoonotic.[4] Most human diseases originated ously unrecognized diseases or have increased virulence in animals; however, only diseases that routinely involve in populations lacking immunity. The West Nile virus animal to human transmission, like rabies, are considered appeared in the United States in 1999 in the New York direct zoonosis.[5] City area, and moved through the country in the summuch distress. Bubonic plague is Zoonoses have different modes of transmission. In di- mer of 2002, causing [8] a zoonotic disease, as are salmonellosis, Rocky Mounrect zoonosis the disease is directly transmitted from antain spotted fever, and Lyme disease. imals to humans through media such as air (influenza) or through bites and saliva (rabies).[6] In contrast, transmission can also occur via an intermediate species (referred to as a vector), which carry the disease pathogen without getting infected. When humans infect animals, it is called reverse zoonosis or anthroponosis.[7]

A major factor contributing to the appearance of new zoonotic pathogens in human populations is increased contact between humans and wildlife.[9] This can be caused either by encroachment of human activity into wilderness areas or by movement of wild animals into areas of human activity. An example of this is the outbreak of Nipah virus in peninsular Malaysia in 1999, when intensive pig farming began on the habitat of in14.1 History fected fruit bats. Unidentified infection of the pigs amplified the force of infection, eventually transmitting the [10] During most of human prehistory groups of hunter- virus to farmers and causing 105 human deaths. gatherers were probably very small. Such groups proba- Similarly, in recent times avian influenza and West Nile bly made contact with other such bands only rarely. Such virus have spilled over into human populations probably isolation would have caused epidemic diseases to be re- due to interactions between the carrier host and domestic stricted to any given local population, because propaga114

14.2. CAUSES animals. Highly mobile animals such as bats and birds may present a greater risk of zoonotic transmission than other animals due to the ease with which they can move into areas of human habitation.

Because they depend on the human host for part of their life-cycle, diseases such as African schistosomiasis, river blindness, and elephantiasis are not defined as zoonotic, even though they may depend on transmission by insects or other vectors.

14.2 Causes

115 can be spread from infected sheep by food or water contaminated with feces or wool. Bird flu is common in chickens. While rare in humans, the main public health worry is that a strain of bird flu will recombine with a human flu virus and cause a pandemic like the 1918 Spanish flu. In 2017, free range chickens in the UK were temporarily ordered to remain inside due to the threat of bird flu.[17] Cattle are an important reservoir of cryptosporidiosis[18] and mainly affects the immunocompromised.

14.2.3 Wild animal attacks

Zoonotic transmission can occur in any context in which • Rabies there is companionistic (pets), economic (farming, etc.), predatory (hunting, butchering or consuming wild game) or research contact with or consumption of animals, ani14.2.4 Insect vectors mal products, or animal derivatives (vaccines, etc.).

• African sleeping sickness

14.2.1

Contamination of food or water supply

The most significant zoonotic pathogens causing foodborne diseases are Escherichia coli O157:H7, Campylobacter, Caliciviridae, and Salmonella.[11][12][13] In 2006, a conference held in Berlin was focusing on the issue of zoonotic pathogen effects on food safety, urging governments to intervene, and the public to be vigilant towards the risks of catching food-borne diseases from farm-to-dining table.[14] Many food outbreaks can be linked to zoonotic pathogens. Many different types of food can be contaminated that have an animal origin. Some common foods linked to zoonotic contaminations include eggs, seafood, meat, dairy, and even some vegetables.[15] Food outbreaks should be handled in preparedness plans to prevent widespread outbreaks and to efficiently and effectively contain outbreaks.

14.2.2

• Dirofilariasis • Eastern equine encephalitis • Japanese encephalitis • Saint Louis encephalitis • Tularemia • West Nile fever • Western equine encephalitis • Venezuelan equine encephalitis • Zika fever

14.2.5 Pets Farming, ranching and animal husbandry Pets can transmit a number of diseases. Dogs and cats are

Contact with farm animals can lead to disease in farmers or others that come into contact with infected animals. Glanders primarily affects those who work closely with horses and donkeys. Close contact with cattle can lead to cutaneous anthrax infection, whereas inhalation anthrax infection is more common for workers in slaughterhouses, tanneries and wool mills.[16] Close contact with sheep who have recently given birth can lead to clamydiosis, or enzootic abortion, in pregnant women, as well as an increased risk of Q fever, toxoplasmosis, and listeriosis in pregnant or the otherwise immunocompromised. Echinococcosis is caused by a tapeworm which

routinely vaccinated against rabies. Pets can also transmit ringworm and Giardia, which are endemic in both animal and human populations. Toxoplasmosis is a common infection of cats; in humans it is a mild disease although it can be dangerous to pregnant women.[19] Dirofilariasis is caused by Dirofilaria immitis through mosquitoes infected by mammals like dogs and cats. Cat-scratch disease is caused by Bartonella henselae and Bartonella quintana from fleas which are endemic in cats. Toxocariasis is infection of humans of any of species of roundworm, including species specific to the dog (Toxocara canis) or the cat (Toxocara cati). Cryptosporidiosis can be spread to humans from pet lizards, such as the leopard gecko.

116

14.2.6

CHAPTER 14. ZOONOSIS

Exhibition

Outbreaks of zoonoses have been traced to human interaction with and exposure to animals at fairs, petting zoos, and other settings. In 2005, the Centers for Disease Control and Prevention (CDC) issued an updated list of recommendations for preventing zoonosis transmission in public settings.[20] The recommendations, developed in conjunction with the National Association of State Public Health Veterinarians, include educational responsibilities of venue operators, limiting public and animal contact, and animal care and management.

14.2.7

Hunting and bushmeat

• HIV

14.2.8

Zoophilia

Further information: Zoophilia and health § Zoonoses acquired via sexual contact

14.2.9

Secondary transmission

• Ebola and Marburg

14.3 Lists of diseases 14.4 Use in vaccines The first vaccine against smallpox by Edward Jenner in 1800 was by infection of a zoonotic bovine virus which caused a disease called cowpox. Jenner had noticed that milkmaids were resistant to smallpox. Milkmaids contracted a milder version of the disease from infected cows that conferred cross immunity to the human disease. Jenner abstracted an infectious preparation of 'cowpox' and subsequently used it to inoculate persons against smallpox. As a result, smallpox has been eradicated globally, and mass vaccination against this disease ceased in 1981.

14.5 See also • Conservation medicine • Cross-species transmission • Emerging infectious disease • Foodborne illness • Wildlife disease

• Veterinary medicine • List of zoonotic primate viruses

14.6 References [1] WHO. “Zoonoses”. Retrieved 18 December 2014.

[2] The Merriam-Webster Dictionary. “Zoonosis”. Retrieved 18 December 2014.

[3] Coral-Almeida, Marco; Gabriël, Sarah; Abatih, Emmanuel Nji; Praet, Nicolas; Benitez, Washington; Dorny, Pierre (2015-07-06). “Taenia solium Human Cysticercosis: A Systematic Review of Sero-epidemiological Data from Endemic Zones around the World”. PLOS Neglected Tropical Diseases. 9 (7): e0003919. ISSN 1935-2735. PMC 4493064 . PMID 26147942. doi:10.1371/journal.pntd.0003919.

[4] Taylor LH, Latham SM, Woolhouse ME (2001). “Risk factors for human disease emergence”. Philosophical Transactions of the Royal Society B: Biological Sciences.

356 (1411): 983–989. PMC 1088493 . PMID 11516376. doi:10.1098/rstb.2001.0888.

[5] Marx PA, Apetrei C, Drucker E (October 2004). “AIDS as a zoonosis? Confusion over the origin of the virus and the origin of the epidemics”. Journal of medical primatology. 33 (5–6): 220–6. PMID 15525322. doi:10.1111/j.1600-0684.2004.00078.x.

[6] “Zoonosis”. Medical Dictionary. Retrieved 30 January 2013.

[7] Messenger AM, Barnes AN, Gray GC (2014). “Reverse zoonotic disease transmission (zooanthroponosis): a systematic review of seldom-documented human biological threats to animals”.

PLoS ONE. 9 (2): e89055.

PMC 3938448 .

PMID 24586500. doi:10.1371/journal.pone.0089055. Retrieved 18 December 2014.

[8] Meerburg BG, Singleton GR, Kijlstra A (2009). “Rodentborne diseases and their risks for public health”. Crit Rev Microbiol. 35 (3): 221–70. PMID 19548807. doi:10.1080/10408410902989837.

[9] Daszak P, Cunningham AA, Hyatt AD (2001). “Anthropogenic environmental change and the emergence of infectious diseases in wildlife”. Acta tropica. 78 (2): 103–116. PMID 11230820. doi:10.1016/S0001706X(00)00179-0.

[10] Field H, Young P, Yob JM, Mills J, Hall L, Mackenzie J (2001). “The natural history of Hendra and Nipah viruses”. Microbes and infection / Institut Pasteur.

3 (4): 307–314. PMID 11334748. doi:10.1016/S12864579(01)01384-3.

[11] Humphrey T, O'Brien S, Madsen M (2007). “Campylobacters as zoonotic pathogens: A food production perspective”. International Journal of Food MicroPMID 17368847. biology.

117 (3): 237–257. doi:10.1016/j.ijfoodmicro.2007.01.006.

14.8. EXTERNAL LINKS

[12] Cloeckaert A (2006). “Introduction: emerging antimicrobial resistance mechanisms in the zoonotic foodborne pathogens Salmonella and Campylobacter”. Microbes and Infection. 8 (7): 1889–1890. PMID 16714136. doi:10.1016/j.micinf.2005.12.024.

[13] Frederick, A. Murphy (1999). “The Threat Posed by the Global Emergence of Livestock, Food-borne, and Zoonotic Pathogens”. Annals of the New York Academy of Sciences. 894: 20–7. PMID 10681965. doi:10.1111/j.1749-6632.1999.tb08039.x.

[14] Med-Vet-Net. “Priority Setting for Foodborne and Zoonotic Pathogens” (PDF). Retrieved 5 April 2008.

[15] “Investigating Foodborne Outbreaks” (PDF). Centers for Disease Control and Prevention. 15 September 2011. Retrieved 5 June 2013.

117 • H. Krauss, A. Weber, M. Appel, B. Enders, A. v. Graevenitz, H. D. Isenberg, H. G. Schiefer, W. Slenczka, H. Zahner: Zoonoses. Infectious Diseases Transmissible from Animals to Humans. 3rd Edition, 456 pages. ASM Press. American Society for Microbiology, Washington, D.C., 2003. ISBN 155581-236-8.

• Jorge Guerra González (2010), Infection Risk and Limitation of Fundamental Rights by Animal-ToHuman Transplantations. EU, Spanish and German Law with Special Consideration of English Law (in German), Hamburg: Verlag Dr. Kovac, ISBN 9783-8300-4712-4 • David Quammen (2013). Spillover: Animal Infections and the Next Human Pandemic. ISBN 978-0393-34661-9.

[16] “Inhalation Anthrax”. www.cdc.gov. Retrieved 2017-0326.

[17] “Avian flu: Poultry to be allowed outside under new rules”.

BBC News. 2017-02-28. Retrieved 2017-03-26.

[18] Lassen, Brian; Ståhl, Marie; Enemark, Heidi L (201406-05). “Cryptosporidiosis – an occupational risk and a disregarded disease in Estonia”. Acta Veterinaria Scandinavica. 56 (1): 36. ISSN 0044-605X. PMC 4089559 .

PMID 24902957. doi:10.1186/1751-0147-56-36.

[19] Prevention, CDC - Centers for Disease Control and.

“Toxoplasmosis - General Information - Pregnant Women”. www.cdc.gov. Retrieved 2017-04-01.

[20] Centers for Disease Control and Prevention (2005).

“Compendium of Measures To Prevent Disease Associated with Animals in Public Settings, 2005: National Association of State Public Health Veterinarians, Inc. (NASPHV)" (PDF). MMWR. 54 (RR–4): inclusive page numbers. Retrieved 28 December 2008.

[21] Information in this table is largely compiled from: World Health Organization. “Zoonoses and the Human-AnimalEcosystems Interface”. Retrieved 21 December 2014.

[22] http://www.who.int/zoonoses/diseases/haemorrhagic_ fevers/en/ [23] Clark, Laura. “How Armadillos Can Spread Leprosy”.

Smithsonianmag.com. Smithsonian.com. Retrieved 16 April 2017.

[24] Shute, Nancy. “Leprosy From An Armadillo? That’s An Unlikely Peccadillo”. NPR.org. National Public Radio.

Retrieved 16 April 2017.

14.7 Bibliography • Bardosh, K. One Health: Science, Politics and Zoonotic Disease in Africa. 2016. Routledge; London, UK. ISBN 978-1-138-96148-7.

14.8 External links • AVMA Collections: Zoonosis Updates • WHO tropical diseases and zoonoses • Detection and Forensic Analysis of Wildlife and Zoonotic Disease • Publications in Zoonotics and Wildlife Disease

Chapter 15

Influenza A virus subtype H1N2 H1N2 is a subtype of the species Influenza A virus (some- December 2011.[2] times called bird flu virus). It is currently endemic in both human and pig populations.

H1N1, H1N2, and H3N2 are the only known Influenza A virus subtypes currently circulating among humans.

15.2 References

The virus does not cause more severe illness than other influenza viruses, and no unusual increases in influenza activity have been associated with it.

15.1 History Between December 1988 and March 1989, 19 influenza H1N2 virus isolates were identified in 6 cities in China, but the virus did not spread further.[1]

This article incorporates public domain material from the Centers for Disease Control and Prevention document “Questions and Answers About Influenza A(H1N2) Viruses”.

•

This article incorporates public domain material from the Centers for Disease Control and Prevention document “2001-02 INFLUENZA SEASON SUMMARY”.

[1] Guo, YJ; Xu, XY; Cox, NJ (1992). “Human influenza A (H1N2) viruses isolated from China”. The Journal of general virology. 73 (2): 383–7. PMID 1538194. doi:10.1099/0022-1317-73-2-383

A(H1N2) was identified during the 2001–02 flu season (northern hemisphere) in Canada, the U.S., Ireland, Latvia, France, Romania, Oman, India, Malaysia, and Singapore with earliest documented outbreak of the virus occurring in India on May 31, 2001.

[2] “Infant In Minn. Develops H1N2, Unique Type Of H1N1”. WCCO. Retrieved 9 January 2013.

On February 6, 2002, the World Health Organization (WHO) in Geneva and the Public Health Laboratory Service (PHLS) in the United Kingdom reported the identification influenza A(H1N2) virus from humans in the UK, Israel, and Egypt.

• Choi YK, Goyal SM, Farnham MW, Joo HS (August 2002). “Phylogenetic analysis of H1N2 isolates of influenza A virus from pigs in the United States”.

Virus Res. 87 (2): 173–9. PMID 12191781. doi:10.1016/S0168-1702(02)00053-9.

The 2001–02 Influenza A(H1N2) Wisconsin strain appears to have resulted from the reassortment of the genes of the currently circulating influenza A(H1N1) and A(H3N2) subtypes.

Because the hemagglutinin protein of the virus is similar to that of the currently circulating A(H1N1) viruses and the neuraminidase protein is similar to that of the current A(H3N2) viruses, the seasonal flu vaccine should provide good protection against influenza virus as well as protection against the currently circulating seasonal A(H1N1), A(H3N2), and B viruses.

•

• CDC. “Information on Avian Influenza”.

15.3 External links

Between December 2010 and January 2011, there have been cases in China, but the virus is spreading further.

19 people have died, while tens of thousands are currently sick.

New case of H1N2 was found on a Minnesota baby in 118

• Influenza Research Database Database of influenza genomic sequences and related information.

Chapter 16

Influenza A virus subtype H9N2 H9N2 is a subtype of the species Influenza A virus (bird ventilation is poor, leading to severe respiratory disease flu virus).[1][2] and death.[5] Over the years the H9N2 influenza strain caused illness in several children aged nine months to 5 years in Hong Kong with the latest occurring in December 2009.[3][4]

16.3 Antigenicity

16.1 Infection in birds H9N2 is the most common subtype of influenza viruses in Chinese chickens and thus causes great economic loss for the poultry industry, even under the long-term vaccination programs. Recent human infections with avian influenza virus revealed that H9N2 is the gene donor for H7N9 and H10N8 viruses that are infecting humans too.

The crucial role of H9N2 viruses due to the wide host range, adaptation to both poultry and mammals and extensive gene reassortment. In China, which is regarded as an epicenter of avian influenza viruses, the H9N2 virus has been detected in multiple avian species, including chicken, duck, quail, pheasant, partridge, pigeon, silky chicken, chukar and egret.[5] Epidemiological and genetic studies revealed that the hemagglutinin (HA) gene of the H9N2 influenza viruses could be divided into Eurasian avian and American avian lineages. The Eurasian avian lineage involved three distinct lineages, including A/chicken/Beijing/1/94-like (BJ/94-like), A/quail/Hong Kong/G1/97-like (G1-like), and A/duck/Hong Kong/Y439/97 (Y439-like).[5]

16.2 Transmission from chicken to human The H9N2 influenza virus can be transmitted by air droplet, dust, feed, or water. Chickens usually seemed to be healthy after the infection but some of them do show depression and ruffled feathers. The virus replicates itself in the trachea. It makes chickens more susceptible to secondary infections, especially Escherichia coli infections with a mortality rate of at least 10%. Also, the trachea or bronchi are easily embolized by mucus when the

Localization of amino acids related to the antigenicity of H9N2 influenza virus on the three-dimensional map of A/Swine/Hong Kong/9/98. PDB ID is 1JSD. All positions are shown with H9 numbering

H9N2 viruses isolated from chickens in China showed antigenic drift that evolved into distinct antigenic groups.

This antigenic drift may have led to immunization failure and may explain the current prevalence of the H9N2 influenza virus in China. The identification of amino acids in H9 antigenic sites revealed different distribution of antigenic areas among other subtypes. Multiple amino acid positions in HA protein related to the antigenicity of H9N2 viruses were identified, most of which located in the distal head of the HA trimer. H9N2 influenza virus has been recognized to reassort with multiple other subtypes, including H6N1, H6N2, and H5N1 viruses. Moreover, H7N9 influenza viruses continued to reassort with circulating H9N2 viruses, resulting in multiple genotypes of H7N9 viruses. The contribution of H9N2 genes, especially ribonucleoprotein (RNP) genes, to the infection

119

120 in human needs to be determined.[5]

16.4 Sources [1] Guan Y, Shortridge KF, Krauss S, Webster RG (August 1999). “Molecular characterization of H9N2 influenza viruses: were they the donors of the “internal” genes of H5N1 viruses in Hong Kong?". Proc. Natl. Acad.

Sci. U.S.A. 96 (16): 9363–7. PMC 17788 . PMID 10430948. doi:10.1073/pnas.96.16.9363.

[2] NAID NIH [3] Influenza A (H9N2) infection in a 5-year-old boy [4] HK girl infected with rare but mild A/H9N2 flu virus [5] H9N2 influenza virus in China: a cause of concern

16.5 Further reading • Butt AM, Siddique S, Idrees M, Tong Y (November 2010). “Avian influenza A (H9N2): computational molecular analysis and phylogenetic characterization of viral surface proteins isolated between 1997 and 2009 from the human population”. BMC Virology. 7 (1): 319. PMC 2994543 . PMID 21078137. doi:10.1186/1743-422X-7-319. Our findings support the continuous evolution of avian H9N2 viruses towards human as host and are in favor of effective surveillance and better characterization studies to address the issue.

• Li C, Yu K, Tian G, et al.

(September 2005). “Evolution of H9N2 influenza viruses from domestic poultry in Mainland China”. Virology. 340 (1): 70–83. PMID 16026813. doi:10.1016/j.virol.2005.06.025. Our findings suggest that urgent attention should be paid to the control of H9N2 influenza viruses in animals and to the human’s influenza pandemic preparedness.

• Centers for Disease Control and Prevention (CDC) - Influenza A(H9N2) infections in Hong Kong published April 8, 1999.

• Uyeki TM, Chong YH, Katz JM, et al. (February 2002). “Lack of evidence for human-to-human transmission of avian influenza A (H9N2) viruses in Hong Kong, China 1999”. Emerging Infect. Dis. 8 (2): 154–9. PMC 2732440 . PMID 11897066. doi:10.3201/eid0802.010148.

• People’s Daily Online - Hong Kong reports human case of H9N2 published March 20, 2007.

• Xinhua News Agency - HK girl infected with rare but mild A/H9N2 flu virus published December 23, 2009.

CHAPTER 16. INFLUENZA A VIRUS SUBTYPE H9N2

16.6 External links • Influenza Research Database Database of influenza genomic sequences and related information.

Chapter 17

Influenza A virus subtype H7N2 H7N2 is a subtype of the species Influenza A virus. This subtype is one of several sometimes called bird flu virus.

H7N2 is considered a low pathogenicity avian influenza (LPAI) virus. [1] With this in mind, H5 & H7 influenza viruses can re-assort into the Highly Pathogenic variant if conditions are favorable.

at a poultry farm near Corwen, in Wales from tests on chickens that died from H7N2. The owners of the Conwy farm bought 15 Rhode Island Red chickens two weeks prior but all died from H7N2. The 32 other poultry at the site were slaughtered. A one kilometer exclusion zone was put in force around the property in which birds and A CDC study following outbreaks of H7N2 in commer- bird products cannot be moved and bird gathering can only take place under licence. Nine people who were ascial poultry farms in western Virginia in 2002 concluded: sociated with the infected or dead poultry and reported flu-like symptoms were tested. Four tested positive for An important factor contributing to rapid early evidence of infection from H7N2 and were successfully spread of AI virus infection among commertreated for mild flu.[7] In early June it was discovered that cial poultry farms during this outbreak was disthe virus had spread to a poultry farm 70 miles (113 km) posal of dead birds via rendering off-farm. Beaway near St. Helens in north-west England. All the poulcause of the highly infectious nature of AI virus try at the farm were slaughtered and a 1 km exclusion zone and the devastating economic impact of outimposed.[8] breaks, poultry farmers should consider carIn December 2016, an outbreak of low pathogenic avian cass disposal techniques that do not require offinfluenza H7N2 occurred in a feline population in the farm movement, such as burial, composting, or [2] New York City Animal Care Center (ACC) shelters after incineration. testing by the University of Wisconsin-Madison School of Veterinary Medicine and confirmed by USDA’s NaOne person in Virginia, United States in 2002, one person tional Veterinary Diagnostic Services Laboratory.[9] Over in New York, United States, in 2003, and one person in 100 cats were found to be infected and subsequently quarNew York, United States, in 2016[3] were found to have antined, but only one human, a veterinarian involved serologic evidence of infection from H7N2; all fully re- in obtaining respiratory specimens, was found to be incovered. fected. The veterinarian had a brief illness with mild An analysis of the New York 2003 case concluded that symptoms and recovered completely. All other humans the H7N2 virus responsible could be evolving toward the exposed to the infected cats tested negative.[3] same strong sugar-binding properties of the three worldwide viral pandemics in 1918, 1957 and 1968. (Human flus and bird flus differ in the molecules they are good 17.1 Sources and notes at binding with because mammals and birds differ in the molecules on the cell surface to be bound with. Humans [1] CDC: Influenza Type A Viruses have very few cells with the bird sugar on its cell surface.)

A study with ferrets showed that this H7N2 strain could [2] flu research be passed from mammal to mammal.[4][5] In February 2004, an outbreak of low pathogenic avian influenza (LPAI) A (H7N2) was reported on 2 chicken farms in Delaware and in four live bird markets in New Jersey supplied by the same farms. In March 2004, surveillance samples from a flock of chickens in Maryland tested positive for LPAI H7N2. It is likely that this was the same strain.[6] On 24 May 2007, an outbreak of H7N2 was confirmed 121

[3] NYC DOHMH 2016 Health Alert #52: Update on Avian Influenza A H7N2 Infection in Cats in NYC Shelters [4] timesonline article Scientists identify second H7 strain of bird flu that could cause pandemic published May 27, 2008 [5] Evolution of flu strains points to higher risk of pandemic: study [6] CDC: Information on Avian Influenza

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[7] BBC article “Bird flu case confirmed at farm” May 24, 2007 [8] Scotsman News article Mild bird flu virus spreads to northwest England June 8, 2007 [9] NYC DOHMH 2016 Veterinary Advisory # 1: Influenza A, H7N2 Identified in Cats from Animal Care Centers of New York City Facility in Manhattan

17.2 Further reading • Research Update on H7n2 Avian Influenza Virus in Turkeys and Chickens • Epidemiology of an H7N2 Avian Influenza Outbreak in Broilers in Pennsylvania in November 2001- January 2002 • Avian influenza H7N2 in Wales and the Northwest of England • North Wales bird flu outbreak ends

17.3 External links • Influenza Research Database Database of influenza sequences and related information.

• CDC avian flu information

CHAPTER 17. INFLUENZA A VIRUS SUBTYPE H7N2

Chapter 18

Influenza A virus subtype H7N3 H7N3 is a subtype of the species Influenza A virus (sometimes called bird flu virus).

In North America, the presence of H7N3 was confirmed at several poultry farms in British Columbia in February 2004; flocks were culled to halt the spread of the virus. Two humans, both poultry workers, were infected and had symptoms including conjunctivitis and mild influenza-like illness. Both fully recovered and were treated with oseltamivir.[1] In 1963, H7N3 was first found in Britain, in turkeys.[2] For the first time since 1979, H7N3 was found in the UK in April 2006. It infected birds and one poultry worker (whose only symptom was conjunctivitis) in a Norfolk, England Witford Lodge Farm. Oseltamivir was used for prevention and 35,000 chickens were culled.[3] In 2005, H7N3 was detected in migratory bird droppings in Taiwan.[4]

[6] http://www.marketwatch.com/story/ mexico-bird-flu-contained-to-10-farms-2012-06-30

• CDC detailed analysis • CDC - Novel Avian Influenza H7N3 Strain Outbreak, British Columbia

18.2 Further reading • Comparative Pathobiology of Low and High Pathogenicity H7N3 Chilean Avian Influenza Viruses in Chickens

18.3 External links

On September 27, 2007, another outbreak of H7N3 was detected in a poultry operation in Saskatchewan, Canada.

The Canadian Food Inspection Agency has announced the euthanization of the flock, and the disinfection of all building, materials and equipment in contact with the birds or their droppings.[5] In June, 2012, an outbreak was found on about 10 farms in Jalisco, Mexico. Of the over 6 million birds checked, 1.7 million were found to be sick. The area primarily produces layers and supplies eggs. The virus is not transmitted from hens to their eggs.[6]

18.1 Sources [1] “CDC - NIOSH Publications and Products - Protecting Poultry Workers from Avian Influenza (Bird Flu) (2008128)". www.cdc.gov. Retrieved 2015-07-30.

[2] Washington.edu [3] Medical News Today article Norfolk Poultry Worker Contracts H7N3 Bird Flu Strain, UK published April 28, 2006 [4] Washington.edu [5] Canada Food Inspection Agency - News Release

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• Influenza Research Database Database of influenza sequences and related information.

Chapter 19

Influenza A virus subtype H10N7 H10N7 is a subtype of the species Influenza A virus (sometimes called bird flu virus). In 2004 in Egypt, H10N7 was reported for the first time in humans.[1] It caused illness in two one-year-old infants, residents of Ismaillia, Egypt; one child’s father a poultry merchant.[2] The first reported H10N7 outbreak in the US occurred in Minnesota on two turkey farms in 1979 and on a third in 1980. “The clinical signs ranged from severe, with a mortality rate as high as 31%, to subclinical. Antigenically indistinguishable viruses were isolated from healthy mallards on a pond adjacent to the turkey farms”.[3]

19.1 References [1] Wright PF, Neumann G, Kawaoka Y (2013). “41Orthomyxoviruses”. In Knipe DM, Howley PM. Fields Virology. 1 (6th ed.). Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins. p. 1201. ISBN 978-1-4511-0563-6.

[2] “EID Weekly Updates - Emerging and Reemerging Infectious Diseases, Region of the Americas”. Pan American Health Organization. 2004-05-07. Retrieved 2007-1020.

[3] Karunakaran D, Hinshaw V, Poss P, Newman J, Halvorson D (1983). “Influenza A outbreaks in Minnesota turkeys due to subtype H10N7 and possible transmission by waterfowl”. Avian Dis. American Association of Avian Pathologists, Inc. 27 (2): 357–66. JSTOR 1590162. PMID 6870718. doi:10.2307/1590162.

19.2 External links • Influenza Research Database Database of influenza sequences and related information.

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Chapter 20

Influenza A virus subtype H7N9 H7N9 is a bird flu strain of the species Influenza virus A (avian influenza virus or bird flu virus). Avian influenza A H7 viruses normally circulate amongst avian populations with some variants known to occasionally infect humans. An H7N9 virus was first reported to have infected humans in March 2013, in China.[2] Cases continued to be reported throughout April and then dropped to only a few cases during the summer months. At the closing of the year, 144 cases had been reported of which 46 had died.[3][4][5] It is known that influenza tends to strike during the winter months, and the second wave, which began in October, was fanned by a surge in poultry production timed for Chinese New Year feasts that began at the end of January. January 2014 brought a spike in reports of illness with 96 confirmed reports of disease and 19 deaths.[6][7] As of April 11, 2014, the outbreak’s overall total was 419, including 7 in Hong Kong, and the unofficial number of deaths was 127.[8][9][10] A 5th epidemic of the H7N9 virus began in October 2016 in China. The epidemic is the largest since the first epidemic in 2013 and accounts for about one-third of human cases ever reported.[11][12] The cumulative total of laboratory-confirmed cases since the first epidemic is 1,223. About 40 percent have died.[13] The CDC estimates that the H7N9 virus has the greatest potential compared with other influenza A viruses to cause a pandemic, although the risk is low because like other type A viruses, it is not easily transmitted between people in its current form.[12] The World Health Organization (WHO) has identified H7N9 as "...an unusually dangerous virus for humans.”[14] Most of the cases resulted in severe respiratory illness, with a mortality rate of roughly 30 percent.[15] [16] Researchers have commented on the unusual prevalence of older males among H7N9-infected patients.[17] While several environmental, behavioral, and biological explanations for this pattern have been proposed,[18] the reason remains unknown.[19] It has been established that many of the human cases of H7N9 appear to have a link to live bird markets.[20] As of January 2014, there has been no evidence of sustained human-to-human transmission,[5] however a study group headed by one of the world’s leading experts on avian flu reported that several instances of human-to-human infec-

tion are suspected.[21] H7N9 virus does not kill poultry, which makes surveillance much more difficult. Chinese scientists announced the development of a vaccine on October 26, 2013, but said that H7N9 had not spread far enough to merit widespread vaccination.[22][23] Research regarding background and transmission is ongoing.[24]

20.1 H7N9 virus Influenza A viruses are divided into subtypes based on two proteins on the surface of the virus: hemagglutinin (HA) and neuraminidase (NA). The avian influenza A(H7N9) virus designation of H7N9 identifies it as having HA of the H7 subtype and NA of the N9 subtype.[25] Avian influenza A H7 viruses are a group of influenza viruses that normally circulate among birds. H7 influenza infections in humans are uncommon, but have been confirmed worldwide in people who have direct contact with infected birds. Most infections have been mild involving only conjunctivitis and mild upper respiratory symptoms.[24][26] The avian influenza A(H7N9) virus is a subgroup among this larger group of H7 viruses. Although some H7 viruses (e.g. H7N2, H7N3 and H7N7) have occasionally been found to infect humans, H7N9 has previously been isolated only in birds, with outbreaks reported in the Netherlands, Japan, and the United States.

Until the 2013 outbreak in China, no human infections with H7N9 viruses have ever been reported.[24][26] Genetic characterisation of avian influenza A(H7N9) shows that the H7N9 virus that infects human beings resulted from the recombination of genes between several parent viruses noted in poultry and wild birds in Asia.[27] It is most closely related to sequences found in samples from ducks in Zhejiang province in 2011.[28] Evidence so far suggests that the new H7N9 virus might have evolved from at least four origins. It is hypothesized that the gene that codes for HA has its origin in ducks and the gene that codes for NA has its origin with ducks and probably also wild birds. Six internal genes originated with at least two H9N2 chicken viruses. The HA genes were circulating in the East Asian flyway in both wild birds and ducks, while the NA genes were introduced from European lineages

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and transferred to ducks in China by wild birds through and March 15, 2013).[33] On April 2, the CHP confirmed migration along the East Asian flyway.[28][29] four more cases in Jiangsu province, all considered in critical condition in hospitals in Nanjing, Suzhou, and Wuxi.

Dr. Keiji Fukuda, WHO’s assistant director-general for In a statement, the CHP said that no epidemiologic links health security and environment, remarked at a Toronto had been found between the four patients and so far no interview that “I think we are genuinely in new territory other H7N9 infections have been identified in 167 of their here in which the situation of having something that is low [34] close contacts. path in birds (yet) appears to be so pathogenic in people...

And then to have those genetic changes ... I simply don't know what that combination is going to lead to.” “Almost everything you can imagine is possible. And then what’s likely to happen are the things which you can't imagine,” he also remarked.[30] According to the deputy director of CDC’s influenza division, the genetic makeup of H7N9 is “disturbingly different” from that of the H5N1 virus that has infected more than 600 people over the past 10 years and killed more than half of them. “The thing that’s different between them is the H5 virus still maintains a lot of the avian or bird flu characteristics, whereas this H7N9 shows some adaptation to mammals. And that’s what makes it different and concerning for us. It still has a ways to go before it becomes like a human virus, but the fact is, it’s somewhere in that middle ground between purely avian and purely human.”[31] In August 2013, it was announced that scientists plan to create mutant forms of the virus so they can gauge the risk of it becoming a lethal human pandemic. The genetic modification work will result in highly transmissible and deadly forms of H7N9, and is being carried out in several high security laboratories around the world.[32]

20.2 Human cases 20.2.1

Reported cases in 2013

Influenza A virus subtype H7N9 - Total reported cases

On March 31, 2013, the Centre for Health Protection (CHP) of the Department of Health of Hong Kong and the Chinese National Health and Family Planning Commission notified the World Health Organization of three confirmed human cases of influenza A (H7N9) in Shanghai and Anhui (illness onset between February 19

The first reported death associated with H7N9 was an 87year-old man who died on March 4. A second man, aged 27, died on March 10.[33][35] On April 3, Chinese authorities reported another death, bringing the number to three.[36] On April 4, the number of reported cases was 14, with 5 deaths. The two victims were a 48-year-old man and a 52-year-old woman, both from Shanghai.[37] On April 5, a farmer, aged 64, living in Huzhou (Zhejiang province), died, raising the death toll to 6.[38] On April 6, the Chinese Ministry of Health reported 18 positive cases, death toll still at 6.[39][40] Two days later, positive cases rose to 24 and one death case from Shanghai brought the death toll to 7.[41] On April 9, the Chinese National Health and Family Planning Commission announced “an additional three laboratory-confirmed cases of human infection with influenza A(H7N9) virus.”[42] The new patients “are two patients from Jiangsu – an 85-year-old man who became ill on 28 March 2013” and a “25-year-old pregnant woman who became ill on 30 March 2013” and “a 64year-old man from Shanghai who became ill on 1 April 2013, and died on 7 April 2013”.[42] As of April 9, a “total of 24 cases have been laboratory confirmed with influenza A(H7N9) virus in China, including seven deaths, 14 severe cases and three mild cases.”[42] In Jiangsu, more than “600 close contacts of the confirmed cases are being closely monitored.”[42] In an update on April 11, Xinhua reported 38 identified cases and 10 deaths.[43] According to the WHO, of the 28 patients who had survived their infections, 19 illnesses were severe and 9 were mild. The WHO said they were monitoring 760 close contacts and so far had no evidence of ongoing human-to-human transmission.[44] On April 13, a seven-year-old girl from Beijing was the first confirmed case of H7N9 bird flu outside eastern China.[45] On April 14, Xinhua Chinese state media reported two human cases in central Henan just west of the area where the disease had been centered. Totals included 61 infected and 13 dead.[46][47] On April 14, Chinese officials also reported the first asymptomatic case in Beijing. A health department notice suggested that a 4-year-old boy had no clinical symptoms and was tested during surveillance of high-risk groups.[48] On April 17, a total of 82 cases had been confirmed, with 17 deaths.[49] On April 18, China reported 87 confirmed cases.[50] On April 20, there were 96 confirmed cases, of which 18 were fatal.[51] The next day, confirmed cases rose to 102 and fatal cases to 20.[52][53] On April 22, there were 104 cases with 21 deaths.[54] On April 23, 3 more

20.2. HUMAN CASES cases were reported in an update from the WHO. All of the newly reported cases were in older men from eastern China. Two cases came from the Zhejiang province and the third was from the Anhui province. Total cases count reached 108 with 22 deaths.[55]

127 On December 31, Taiwan’s CDC released a press statement indicating that an 86-year-old man from Jiangsu Province, China, who was visiting Taiwan, became ill and tested positive for H7N9 flu. This is the second case in Taiwan, the first being in April.[74]

On April 24, a case was confirmed by the Taiwanese Government, marking the first case outside mainland 20.2.2 China.[56][57] On April 25, the National Health and Family Planning Commission said that a total of 109 H7N9 cases had been reported within mainland China, including 23 deaths.[14] However, Anne Kelso, director of the WHO Collaborating Centre for Reference and Research on Influenza, VIDRL, Australia, reported that researchers had seen a “dramatic slowdown” in human cases in Shanghai after the city’s live poultry markets were closed on April 6.[14] The following day cases in mainland China rose to 118.[58]

Reported cases in 2014

On January 21, 2014, it was reported that a 31-year-old thoracic surgeon had died four days previously, the first medical professional to die from H7N9 flu. There was no evidence that he had been in contact with live poultry recently. Yuen Kwok-yung, a University of Hong Kong microbiologist, said, “If the diagnosis is confirmed and no [bird] exposure history is elicited, this does point slightly more to the possibility that H7N9 may be more transmissible between humans than H5N1”.[75]

On January 28 it was reported by the Chinese Center for Disease Control and Prevention that the virus had killed 20 people in China in 2014, with the total number of human infections at 102. That compares with 144 confirmed cases, including 46 deaths, in the whole of 2013.

At the end of January more than half of 2014 cases had been in Zhejiang, with another 24 in Guangdong, and eight in Shanghai. The director of the Chinese National Influenza Center, Shu Yuelong, said a large-scale H7N9 epidemic still remains unlikely because the virus has not yet mutated in such a way that would allow person to per[76] On May 7, Hong Kong’s Centre for Health Protec- son transmission. tion reported that there were 130 confirmed cases of On February 13, 2014, it was reported that a 67-yearH7N9 avian flu in mainland China following the hospi- old female tourist from China had been diagnosed with talization of a 79-year-old woman from China’s Jiangxi having the H7N9 virus while visiting Malaysia.[1][77] province,[66] bringing the count to 131 cases.[67] On April 28, four provinces, Zhejiang, Shandong, Jiangxi and Fujian, reported new cases, raising the total number of cases in mainland China to 125 with 24 deaths.[59][60] On May 2, there were 127 confirmed cases in mainland China,[61] of which 27 were fatal,[62] and including the case in Taiwan there were a total of 128 cases worldwide.[63] On May 6, in a weekly update, China’s Ministry of Health announced there were 129 confirmed cases in mainland China with 31 deaths,[64] for a total of 130 cases worldwide.[65]

The Ministry of Health of People’s Republic of China reported on July 10 that in the month of June, there was only 1 confirmed case, and there were a total of 132 confirmed cases in Mainland China as of June 30, 2013 (43 fatal, 85 patient recovery cases).[68] Though there is a slow increase in the number of cases, China recently warned that the transmission of H7N9 virus might be active again by autumn and winter seasons.[69][70]

20.2.3 Reported cases in 2015 In January 2015, A Canadian visitor to China was diagnosed with H7N9 after she returned home to British Columbia. After returning to Canada on January 12, she felt ill on January 14.[78]

In June 2015, 15 cases of H7N9 infection were reported [79] In August, Guangdong province confirmed its first case of in China.

H7N9 bird flu, a 51-year-old woman in critical condition after having been admitted to a hospital on August 3.[71] As of November 1, 2013, China reported to the WHO that “rare and sporadic human infections with H7N9” have been reported with “the total number of cases reported to 137, including 45 deaths” in China.[72] The CDC and U.S. government H7N9 preparedness efforts have continued over the summer and are “continuing to watch this situation closely”.[72]

20.2.4 Reported cases in late 2016 and 2017 (5th epidemic)

Beginning in October 2016 China began experiencing a 5th epidemic of H7N9, the largest since the first epidemic in 2013.[11][12] For the 5th epidemic, the WHO reported 460 human infections as of early March 2017, which accounts for about one-third of cases ever reported since As of December 14, 2013, two cases of H7N9 were re- this strain of influenza virus first appeared in 2013.[80][13] ported in Hong Kong. Hong Kong reported its first death The cumulative total of laboratory-confirmed cases since from H7N9 on 26 December 2013.[73] the first epidemic is 1,223. About 40 percent have died.[81] As of May 23, 2017, the World Health Organiza-

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tion reported another 23 human infections, which brings parakeets which then shed the virus into their environthe total number to 688 infections.[82] ment. This finding implies that these birds may potentially serve as intermediate hosts with the ability to facilitate transmission and dissemination of H7N9.[84]

20.3 Symptoms and treatment According to the World Health Organization, symptoms include fever, cough, and shortness of breath, which may progress to severe pneumonia.[24][42] The virus can also overload the immune system, causing what is known as a cytokine storm. Blood poisoning and organ failure are also possible.[16] In an article in the The New England Journal of Medicine, doctors reported that most of the patients with confirmed cases of H7N9 virus infection were critically ill and that approximately 20% had died of acute respiratory distress syndrome (ARDS) or multiorgan failure.[15] Antigenic and genome sequencing suggests that H7N9 is sensitive to neuraminidase inhibitors, such as oseltamivir and zanamivir.[26][42] The use of these neuraminidase inhibitors in cases of early infection may be effective,[26] although the benefits of oseltamivir treatment have been questioned.[83]

20.4 Transmission

Live poultry market in Xining, China.

Information released in 2014 indicated that 75% of those that came down with H7N9 influenza had previously been exposed to domestic poultry.[84] In April, 2013, the World Health Organization (WHO) said H7N9 was “unlikely” to become a pandemic[85] and that there was no evidence of human-to-human transmission.[42][86][86] In late July, 2013, however, Chinese scientists found evidence that person-to-person transmission was possible, but would not transmit easily.[87] In April 2013, it was also reported that the virus had been found only in chickens, ducks, and pigeons at live poultry markets and that no migratory birds had tested positive for the virus, easing concerns about that route of transmission.[14] However, later investigation demonstrated that H7N9 may infect wild songbirds and caged

At an April 26 news conference, the WHO assistant director-general for health stated, “This is an unusually dangerous virus for humans. We think this virus is more easily transmitted from poultry to humans than H5N1.”[14] Furthermore, there is great concern because unlike the H5N1 viral form, H7N9 does not cause visible disease in poultry, which makes surveillance, prevention, and control of the virus in poultry extremely difficult.[20] On April 30, it was announced that the Ministry of Agriculture of the People’s Republic of China had asked the Director General of the World Organisation for Animal Health (OIE) to send OIE experts to assess the situation and provide advice. According to the information and data collected, it was confirmed that many of the human cases of H7N9 appeared to have a link with live bird markets, but to that date no human cases or animal infections of H7N9 had been detected on poultry farms. The OIE experts made the hypothesis that people could be infected through exposure to infected birds in markets or to a contaminated environment such as live poultry markets where the virus is present. They believe that live bird markets may play a key role in human and animal infections with H7N9 and that, even if the overall level of infection is relatively low (having not been detected yet in poultry farms), live bird markets provide an environment for amplification and maintenance of the H7N9 virus.[20] The OIE mission also confirmed that currently infection with H7N9 does not cause visible disease in poultry and therefore veterinary services must be especially involved in preventing its further spread. According to the April 30 report, there is no evidence to suggest that the consumption of poultry or eggs could transmit the virus to humans. More assessment is needed to know whether poultry vaccination could be considered as a control option for H7N9. It will also be important to verify whether the H7N9 virus is transmissible from humans to animals because if established, it could be a potential channel for the global spread of the virus.[20] The number of cases detected after April fell abruptly.

The decrease in the number of new human H7N9 cases may have resulted from containment measures taken by Chinese authorities, including closing live bird markets, or from a change in seasons, or a possibly a combination of both factors. Studies indicate that avian influenza viruses have a seasonal pattern, much like human seasonal influenza viruses. If this is the case, H7N9 infections – in birds and people – may pick up again when the weather turns cooler in China. Limited person-to-person spread of bird flu is thought to have occurred rarely in the past, most notably with avian influenza A (H5N1). According to the US CDC, based on previous experience, some limited human-to-human spread of this H7N9 virus would

20.6. AGE/GENDER DISTRIBUTION not be surprising if the virus reemerges in the fall.[88] Furthermore, according to the WHO, since migratory birds were first implicated in H7N9 transmission, the possibility that the virus may spread into other regions or countries with colder weather cannot be excluded, given the widespread bird migratory patterns.[89]

129 cases sharply declined and the mortality rate remained at about 20%.[91]

In early May it was reported that testing of more than 20,000 Chinese who had influenza-like illnesses in March and April turned up only six cases of H7N9 infection.

“We did not find evidence of widespread mild disease, suggesting that the reported cases reflect the true distribution of infection and not a surveillance artifact,” the 20.4.1 Human to human transfer of virus researchers wrote. The study suggests that the reported mortality rate is accurate, however the researchers noted In a study published in July, 2013, an international team several limitations of the study, including that the testing led by Yoshihiro Kawaoka, one of the world’s leading ex- was carried out in city hospitals only and therefore may perts on avian flu, reported that while avian flu viruses not have detected cases in rural areas.[92] typically lack the ability to transfer through respiratory droplets, studies using ferrets, who like humans infect one another through coughing and sneezing, showed that one of the H7N9 strains isolated from humans can trans20.6 Age/gender distribution mit through respiratory droplets. Kawaoka says, “H7N9 viruses combine several features of pandemic influenza viruses, that is their ability to bind to and replicate in Researchers have commented on the unusual prevalence human cells and the ability to transmit via respiratory of older males among H7N9-infected patients.[17][93] droplets.” Further, because several instances of human- Two-thirds of persons who are ill from H7N9 are 50 to-human infection are suspected, Kawaoka states that “If years of age or older, which is an older age curve than H7N9 viruses acquire the ability to transmit efficiently that for H5N1. In addition, two-thirds of persons ill from person to person, a worldwide outbreak is almost from H7N9 are male.[18] Possible reasons for the prevacertain since humans lack protective immune responses lence of older males among H7N9-infected patients include: a difference in exposure between males and feto these types of viruses.”[21] males due to gender-associated practices; biological difOn August 6, 2013, the British Medical Journal released ferences between males and females; and the differences the results of epidemiological investigations conducted in healthcare-seeking behavior and healthcare access beafter a family cluster of two patients were infected with tween males and females.[17] Both the median age and avian H7N9 in March 2013 and later died in April and male to female relationship appear to have remained staMay. A 60-year-old man became infected after an exble: The February 2014, WHO report stated "...37 cases, posure to poultry and his daughter, who had not been the median age was 60 years, ranging from 5-84 years, exposed to poultry but had cared for her ill father, bewith a male to female ratio of 3.6:1.” [10] came infected as well. Genome sequence and analyses of phylogenetic trees showed that both viruses were al- Dr. Yuzo Arima and his colleagues at WHO report most genetically identical. Forty-three close contacts of “While poultry exposure appears to be a common risk the infected patients did not become ill and they all tested factor, the age distribution among reported cases also negative for haemagglutination inhibition antibodies spe- raises the question why so few young adults (i.e. those cific for avian H7N9. It was concluded that the infec- of working age exposed to poultry as vendors/LBM [live tion of the daughter probably resulted from close contact bird market] workers/breeders/transporters) have been with her father during unprotected exposure, suggesting reported. This not only suggests greater exposure among that the virus was able to transmit from person to person. elderly men but also a possible greater biological susceptiHowever, the researchers consider that the transmissibil- bility to more severe outcomes.”[17] Danuta M. Skowronski, MD, of the British Columbia Centre for Disease ity of the virus remains limited and non-sustainable.[90] Control and three colleagues put forward the hypothesis that older Chinese men have more lifetime exposure to H7 avian flu viruses and thus have immune responses 20.5 Mortality which are weakly cross-reactive but not protective. This immune phenomenon is called antibody-dependent enIn the month following the report of the first case, more hancement (ADE), and is perhaps best known in cases than 100 people had been infected, an unusually high rate of Dengue fever when a person who has previously been for a new infection; a fifth of those patients had died, a infected with one serotype of Dengue fever becomes fifth had recovered, and the rest remained critically ill.[16] infected many months or years later with a different Keiji Fukuda, the World Health Organization's (WHO) serotype. It is thought to occur when weakly crossassistant director-general for health, security and the en- reactive antibodies form bridging complexes to facilivironment, identified H7N9 as "...an unusually dangerous tate uptake and replication of related but non-identical virus for humans.”[14] By early May the number of new variants.[18][19]

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20.7 Vaccine

a pandemic, adjuvants may be used as part of a “dosesparing strategy”.[98]

Although China has been praised for its quick response,[2] some experts believe that there would be great difficulty providing adequate supplies of a vaccine if the virus were to develop into a pandemic. According to an article in the Journal of the American Medical Association (JAMA) in May 2013, “Even with additional vaccine manufacturing capacity . . . the global public health community remains woefully underprepared for an effective vaccine response to a pandemic...There is no reason to believe that a yet-to-be-developed pandemic A(H7N9) vaccine will perform any better than existing seasonal vaccines or the A(H1N1)pdm09 vaccines [about 60% to 70% effectiveness], particularly with regard to vaccine efficacy in persons older than 65 years.”[94]

In response to a request from the CDC and Biomedical Advanced Research and Development Authority (BARDA), and after the H7N9 flu virus gene sequences were made available through the Global Initiative on Sharing All Influenza Data (GISAID), the J. Craig Venter Institute (JCVI), and Synthetic Genomics Vaccines, Inc. (SGVI) began working with Novartis to synthesize the genes of the new viral strain and supplied these synthesized genes to the CDC.[99]

On October 26, 2013, Chinese scientists announced that they had successfully produced an H7N9 vaccine, the first influenza vaccine to be developed entirely in China.[22] It was developed jointly by researchers from Zhejiang University, Hong Kong University, the Chinese Center for Disease Control and Prevention, China’s National Institute for Food and Drug Control, and the Chinese Academy of Medical Sciences. Chinese National Influenza Center director Shu Yuelong said the vaccine passed tests on ferrets and had been approved for humans, but H7N9 has not spread far enough to merit widespread vaccination. The vaccine was developed from a throat swab of an infected patient taken April 3.[23]

20.8 Reactions The scientific community has praised China for its transparency and rapid response to the outbreak of H7N9.[100] In an editorial on April 24, 2013, the journal Nature said “China deserves credit for its rapid response to the outbreaks of H7N9 avian influenza, and its early openness in the reporting and sharing of data.”[2] This, in spite of initial worries by Chinese scientists and officials that they might lose credit for their work in isolating and sequencing the novel H7N9 virus, after learning that pharmaceutical company Novartis and the J. Craig Venter Institute had used their sequences to develop US-funded H7N9 vaccine without offering to collaborate with the Chinese team, according to Nature.[101] They believed, the usage of their data was initially not handled in the spirit of the GISAID sharing mechanism, which requires scientists who use the sequences to credit and propose collaboration with those who deposited the data in GISAID. Nature cited a Chinese official who concluded that this situation was quickly mitigated once communication channels were opened and the parties agreed to collaborate, thanks to GISAID president Peter Bogner.[102][103]

On November 12, 2013, US scientists at Novavax, Inc. announced their successful clinical testing of an H7N9 vaccine in the New England Journal of Medicine. They had previously described the development, manufacture, and efficacy in mice of an A/Anhui/1/13 (H7N9) viruslike particle (VLP) vaccine produced in insect cells with the use of recombinant baculovirus. The vaccine combined the HA and neuraminidase (NA) of A/Anhui/1/13 with the matrix 1 protein (M1) of A/Indonesia/5/05. The study enrolled 284 adults (≥18 years of age) in a random- Despite concerns that vaccination of poultry against the ized, observer-blinded, placebo-controlled clinical trial H5N1 avian influenza virus over the last decade might of this vaccine.[95] have made it harder for Chinese veterinary technicians to The Centers for Disease Control and Prevention (CDC) spot the recent spread of the H7N9 virus, China’s Agribegan sequencing and development of a vaccine as rou- culture Ministry defended its policy of large-scale vaccitine procedure for any new transgenic virus.[96] The CDC nation of poultry against the earlier bird flu strain, saying with its efforts now to identify and vaccine manufacturers are developing a candidate that it was not interfering [104] the emerging H7N9 virus. virus to be used in vaccine manufacturing if there is widespread transmission.[24][97] On September 18, 2013, NIH announced that researchers have begun testing an investigational H7N9 influenza vaccine in humans. Two Phase II trials are collecting data about the safety of the vaccine, immune system responses to different vaccine dosages, both with and without adjuvants. Healthy adults 19 to 64 years of age will be enrolled in the two studies. The inactivated vaccine was made with H7N9 virus that was isolated in Shanghai, China. Adjuvants are being tested with the vaccine to determine if an adequate immune response can be produced. In addition, during

On April 15, 2013, the RIWI Corporation, led by researcher Neil Seeman of the University of Toronto released data on 7,016 Chinese “fresh” (i.e. non-panel based) Internet users – with a 24.08% response rate – over 20 hours. The level of contagion awareness was 31% in Beijing, 38% in Hangzhou, 33% in Nanjing, 40% in Shanghai, 52% in Ürümqi, and 28% in Zhengzhou (Chi Square; P = 0.05). The result far exceeds that of other internet surveys, suggesting an intense relevancy of interest and sense of urgency related to the current disease outbreak in the minds of average Chinese citizens.[105]

20.10. SEE ALSO

20.8.1

131

Efforts to prevent spread of disease On April 10, 2013, the Public Health Agency of Canada

In April 2013, Shanghai’s health ministry ordered culling of birds after pigeon samples collected at the Huhuai wholesale agricultural products market in Songjiang District of Shanghai showed H7N9[38][106] On April 4, 2013, Shanghai authorities closed a live-poultry-trading zone and began slaughtering all birds. Poultry trading areas in two other areas of the Minhang district were also closed.[107] On April 6, 2013, all Shanghai live poultry markets closed temporarily in response to the H7N9 found in the pigeon samples.[24][38][108] The same day, Hangzhou also closed its live poultry markets.[108] After gene sequence analysis, the national avian flu reference laboratory concluded that the strain of the H7N9 virus found on pigeons was highly congenic with those found on persons infected with H7N9 virus, the ministry said.[106] On April 22, 2013, Forbes quoted Chinese state media reporting $2.7 billion in poultry industry losses.[54] When January 2014 brought a dramatic increase in reports of disease, the Chinese government responded by halting live poultry trading in three cities in Zhejiang province where 49 cases and 12 deaths had been reported.

In addition, live poultry trading in Shanghai was halted for three months. In Hong Kong, authorities reacted to the discovery of H7N9 in live chickens from the province of Guangdong by suspending imports of fresh poultry from mainland China for 21 days, culling 20,000 chickens, and other measures in an effort to control the spread of the virus.[109] On February 18, it was announced that they would extend the ban for four months. The health minister also said that they plan to prevent diseased birds from entering the market by setting up a facility where imported poultry can be quarantined to ensure they are disease-free.[110]

(PHAC) and the Canadian Food Inspection Agency (CFIA) spelled out bio-safety guidance for handling the H7N9 virus.[114] They stated that work with live cultures must be conducted in biosafety level 3 (BSL-3) containment. They also said that studies growing H7N9 virus should not be done in labs that culture human influenza viruses and that personnel should not have contact with susceptible animals for 5 days after handling H7N9 samples.[115] Malaysia Malaysia announced that it would temporarily ban Chinese chicken imports.[116] Vietnam Vietnam announced that it would temporarily ban Chinese poultry imports.[35][117] Singapore All hospitals were informed to remain vigilant, and to notify Singapore’s Ministry of Health (MOH) immediately of any suspected cases of avian influenza in individuals who have recently returned from affected areas in China.[111] MOH advised returning travellers from affected areas in China (Shanghai, Anhui, Jiangsu, and Zhejiang) to look out for signs and symptoms of respiratory illness, such as fever and cough, and seek early medical attention if they are ill with such symptoms.[111] MOH also advised individuals to inform their doctors of their travel history, should they develop these symptoms after returning to Singapore.[111]

20.9 International response The WHO does not advise against travel to China at this point in time, as there is no evidence of human-to-human transmission of the virus.[111] United States On April 9, 2013, the Centers for Disease Control and Prevention (CDC) activated its Emergency Operations Center (EOC) in Atlanta at Level II, the second-highest level of alert.[112] Activation was prompted because the novel H7N9 avian influenza virus has never been seen before in animals or humans and because reports from China have linked it to severe human disease. EOC activation will “ensure that internal connections are developed and maintained and that CDC staff are kept informed and up to date with regard to the changing situation.”[113] Canada

20.10 See also • Antigenic shift • Influenza A virus subtype H5N1 • Influenza research • Zoonosis

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[104] Bradsher, Kieth (April 12, 2013). “China Defends Vaccination of Poultry as Flu Spreads”. New York Times. Hong Kong. Retrieved April 30, 2013.

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135

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CHAPTER 20. INFLUENZA A VIRUS SUBTYPE H7N9

20.12 Text and image sources, contributors, and licenses 20.12.1

Text

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Dickman, Rich Farmbrough, FuzzyBunny, Arcadian, Alansohn, ABCD, Ketiltrout, Kolbasz, Bdelisle, Peregrine Fisher, Nick, WAS 4.250, Betacommand, RDBrown, G716, JohnM4402, Thijs!bot, OhanaUnited, Tracer9999, Laughingyet, Plr4ever, Wieno, Fimbriata, Alexbot, Addbot, AkhtaBot, Yobot, Ptbotgourou, Viralzone, AnomieBOT, Citation bot, Plumpurple, Rootmarm, Capricorn42, GrouchoBot, Frosted14, January2009, Philippe Le Mercier, DrilBot, Tim1357, Teflotax, Dcirovic, Brycehughes, ChrisGualtieri, GoShow, Monkbot, L0st H0r!z0ns, Octoberwoodland, Magic links bot and Anonymous: 22 • Influenza A virus subtype H1N1 Source: https://en.wikipedia.org/wiki/Influenza_A_virus_subtype_H1N1?oldid=792633689 Contributors: Heron, Bth, Rickyrab, Jose Icaza, Collabi, Ixfd64, Ellywa, Ahoerstemeier, WeißNix, Darkwind, Kwekubo, Timc, Tpbradbury, BobDrzyzgula, Lumos3, Globe199, Dale Arnett, Jredmond, Nurg, Cyrius, Enochlau, Centrx, Giftlite, Zigger, Ddama, Eequor, Matt Crypto, OldakQuill, SarekOfVulcan, Beland, OverlordQ, Neutrality, Joyous!, N328KF, Discospinster, Rich Farmbrough, Sladen, Kndiaye, Bender235, Shanes, Art LaPella, Unsungzeros, Cmdrjameson, Storm Rider, Alansohn, Rray, Keenan Pepper, Ncdoyle, BanyanTree, Prianis, Amorymeltzer, Alfvaen, Geraldshields11, Woohookitty, Halcatalyst, Mandarax, Rjwilmsi, Bubba73, Brighterorange, FlaBot, Wikidgood, Chobot, Bgwhite, Scoo, YurikBot, Phantomsteve, Ericyu, Seahcj, Adjensen, Rsrikanth05, Rupert Clayton, Krakatoa, Moe Epsilon, RUL3R, WAS 4.250, Varaaki, Allens, Katieh5584, Tim1965, SmackBot, Ashenai, Person man345, McGeddon, SmartGuy Old, Ohnoitsjamie, Wuffyz, LinguistAtLarge, RDBrown, Thumperward, Salvor, TheFeds, Eusebeus, Martixer, Frap, Snowmanradio, Eduardoferreira, Yateenp, Cybercobra, G716, Electprogeny, TiCPU, JohnM4402, Lambiam, Goodnightmush, Chrisch, BillFlis, Mrfeek, Korovioff, General Eisenhower, Kencf0618, Joseph Solis in Australia, Che Sohal, Mere Mortal, Igoldste, Wwallacee, Fvasconcellos, Ozga, Balloonman, Eric Martz, Ibanix, Michael C Price, Quibik, DumbBOT, JamesAM, Epbr123, Hervegirod, Marek69, Esbullin, Nick Number, DPdH, Oreo Priest, Seaphoto, TimVickers, KKong, Smartse, Baseballdude, JAnDbot, Ericoides, Pyisoeyz, OhanaUnited, Xeno, MastCell, Avicennasis, Ciar, Wdflake, Tracer9999, Gandydancer, Arjun01, Wowaconia, Kateshortforbob, Ombudswiki, Shaiks4, Thirdright, RockMFR, J.delanoy, CFCF, Terrek, Maurice Carbonaro, Mamyles, RandMC, Janus Shadowsong, Touisiau, Mikael Häggström, Hoffmansk, In Transit, Barley55, SriMesh, 2help, Juliancolton, Ja 62, Izno, Tkgd2007, Halmstad, VolkovBot, Butwhatdoiknow, Gunnar Guðvarðarson, Quentonamos, TXiKiBoT, AlexRampaul, Anna Lincoln, Una Smith, Martin451, PawełS, Noformation, Ilyushka88, Randomblink, Falcon8765, Turgan, Kavri, Sjefen6, Naughtyzzz, Doc James, Symane, Xakzen, SieBot, Tresiden, Yintan, LeadSongDog, Flyer22 Reborn, KoshVorlon, Realm of Shadows, WikiLaurent, Pinkadelica, Montydad5000, ClueBot, Drewiki, Eugene chan, The Thing That Should Not Be, Gaia Octavia Agrippa, R000t, NPIC, Reignofgold, Uncle Milty, Rprpr, Carusus, Awickert, Excirial, Alexbot, Jusdafax, OpinionPerson, SpikeToronto, Aurora2698, Razorflame, Elizium23, SchreiberBike, Netanel h, Leonard22, Subash.chandran007, Burner0718, Qwfp, SoxBot III, XLinkBot, Dthomsen8, Sakura Cartelet, Avoided, Facts707, NellieBly, Spoonkymonkey, Monfornot, Antewolf, D.M. from Ukraine, Addbot, Yoenit, Landon1980, Binary TSO, Dr.MS SanFrancisco, Cst17, MrOllie, Download, SoSaysChappy, LaaknorBot, Glane23, Green Squares, Blaylockjam10, 5 albert square, F Notebook, LarryJeff, Tide rolls, Krukouski, Webwizard, Legobot, Yobot, Otm77, Supersubadam g, Ged Sparrowhawk, Ptbotgourou, Librsh, Nguyengiap84~enwiki, N3hima, Ajh16, QueenCake, Laurenlt, Tancee, Ninja200640, Starbois, AnomieBOT, Felipe P, ThaddeusB, Jim1138, Ipatrol, Materialscientist, Hldavids, Citation bot, OllieFury, Cmscritic, LovesMacs, Quebec99, Xqbot, Anativecantonesespeaker, Predecess, Rootmarm, AH-64 Longbow, Ryomaandres, Pontificalibus, Anna Frodesiak, Locos epraix, Rdawg466, Coretheapple, ‫المصرى الحر‬, Mouagip, Anonymous from the 21st century, Jwyndelts, GrouchoBot, Gfarmer4, GainLine, Moby-Dick3000, Žiedas, Spongefrog, Mtownene, Cortamears, FrescoBot, Nicolas Perrault III, Pepper, Nageh, Bringbackwyners, S73v3n, HaniballCartho, Knee427, Alboran, Illiterate:TSR, NuclearWizard, Citation bot 1, Kevinherrmann, Tim10fifty, Tunneltunnel, Javert, Ypna, I dream of horses, Xepto, Elockid, Campeck2009, Tom.Reding, Cerevisae, Brad Polard, Irshaad15, ArizonaNestea, Eoeoeoeo, Yannick.sealth, Qqqq0, December21st2012Freak, Wiki1236, ActivExpression, Lightlowemon, Bella541, Aseidlernyc, Sagan666, Teamabby, Capt. James T. Kirk, Fakemailalh, Edwardhau, Draguvi, Diannaa, Abernathy123, Suffusion of Yellow, Accuracy-searcher, Tbhotch, Brianboone, Stephers8194, Alex Ji LT-21, SUCKISSTAPLES, DARTH SIDIOUS 2, RjwilmsiBot, Beyond My Ken, Salvio giuliano, DASHBot, Immunize, Sophie, GoingBatty, Dcirovic, K6ka, Pbfy0, AvicBot, JSquish, Susfele, Shuipzv3, Big Bosses, Zezen, Mattidor123, Wayne Slam, Halkaide.m, Thine Antique Pen, Suturestudyreview, L Kensington, Donner60, LibertyOrDeath, 91177info, FeatherPluma, Morgis, Bb3bb3bb, ClueBot NG, Satan6969, Jack Greenmaven, Akashaaaaa, Jsones618, Jo Wright WB, Lemonpartyhard, Delusion23, Pedia07, NickHenry1, JumperCables18, Bobnob1234, Ronpedia, DBigXray, BG19bot, Rt davies, Joydeep, BattyBot, Tutelary, Smasongarrison, Cyberbot II, Ushau97, GoShow, Lugia2453, Navleshgenetics, Hannahlikestoeditwiki, Lkranenka, Ugog Nizdast, Quenhitran, Watercao, Ioannisd, Monkbot, Abbymalby, Jos343535367, Prisaud, Mayngo8, Rikblok, Colombo Eagle, Justin23384, Julietdeltalima, Drknowitall956, YesPretense, Harsha.rayasam, Vsakshi, 1h4v3451gn, My Chemistry romantic, Onz123, Entranced98, GreenC bot, Bender the Bot, Octoberwoodland, Zcarstvnz, Chrystian Anaya and Anonymous: 498 • 1918 flu pandemic Source: https://en.wikipedia.org/wiki/1918_flu_pandemic?oldid=791763985 Contributors: AxelBoldt, Bryan Derksen, Malcolm Farmer, Danny, Rmhermen, William Avery, GrahamN, Mintguy, Rickyrab, Stevertigo, Nealmcb, Infrogmation, Alan Peakall, Ezra Wax, Llywrch, Dominus, Nixdorf, Karada, CesarB, Egil, Card~enwiki, Ahoerstemeier, Arwel Parry, JWSchmidt, Darkwind, LittleDan, Alex756, Rl, Jengod, Emperorbma, RodC, Wikiborg, Lou Sander, Fuzheado, Haukurth, Tpbradbury, Jason M, Jerzy, Flockmeal, Phil Boswell, Gentgeen, Dale Arnett, Greudin, Yelyos, Meelar, Auric, Mervyn, Hadal, Profoss, Aetheling, Isopropyl, Diberri, Giftlite, MPF, Andy, Akadruid, ShaunMacPherson, Inter, Tom harrison, Zigger, Everyking, Dratman, Alison, Xinoph, Mboverload, Prosfilaes, Eequor, Gregb, Jackol, Stevietheman, Utcursch, Pgan002, Mendel, Knutux, Sonjaaa, Antandrus, Beland, Onco p53, MisfitToys, Jossi, MacGyverMagic, Rdsmith4, DragonflySixtyseven, Balcer, Tothebarricades.tk, Bodnotbod, Kuralyov, Icairns, PeR, Neutrality, Ukexpat, McCart42, Trilobite, Demiurge, Squash, Lacrimosus, DmitryKo, SYSS Mouse, Mike Rosoft, PZFUN, Rfl, Venu62, Discospinster, Rich Farmbrough, Guanabot, Andicat, Vsmith, Westendgirl, LeeHunter, SpookyMulder, SamEV, Bender235, ESkog, CanisRufus, Dnwq, Simonfairfax, Shanes, Hurricane111, John Vandenberg, BrokenSegue, Viriditas, ZayZayEM, Zarateman, Ziggurat, Rishiboy, DCEdwards1966, Krellis, Nsaa, Knucmo2, Ranveig, Mrzaius, Alansohn, JYolkowski, Terrycojones, Anthony Appleyard, PMLF, DanielLC, Guy Harris, 119, Alyeska, Axl, Ferrierd, Mailer diablo, Avenue, Wtmitchell, BanyanTree, Nwhyte, Suruena, Ubermonkey, Evil Monkey, Amorymeltzer, Grenavitar, Mikeo, Geraldshields11, Outlanderssc, Djsasso, CINCABF, Mahanga, Richard Arthur Norton (1958- ), OwenX, Woohookitty, Shreevatsa, LOL, Ritz, LoopZilla, BillC, Pol098, Before My Ken, Lincher, Ardfern, Burgher, Kelisi, Wikiklrsc, Damicatz, Wayward, MarcoTolo, Dysepsion, Tslocum, Sherpajohn, RichardWeiss, Neiltupper, Graham87, WBardwin, NCdave, Magister Mathematicae, BD2412, Mikeheth, Kbdank71, Canderson7, Rjwilmsi, Markkawika, Koavf, Dabisu, Iseespots, Alaney2k, Lugnad, BlueMoonlet, Wipfeln, Vegaswikian, UriBudnik, Boccobrock, Brighterorange, Yug, Fred Bradstadt, Leithp, FlaBot, SchuminWeb, KarlFrei, GünniX, Catsmeat, Takometer, BjKa, Pinkville, Fresheneesz, Srleffler, Valentinian, Mstroeck, King of Hearts, Chobot, DVdm, Bgwhite, Gwernol, Cornellrockey, Ravenswing, The Rambling Man, TexasAndroid, Brandmeister (old), JarrahTree, RussBot, Jtkiefer, Zigamorph, Wikispork, GusF, IanManka, Stephenb, CambridgeBayWeather, Eleassar, Varnav, Brooza, Cleon169, NawlinWiki, Dysmorodrepanis~enwiki, Wiki alf, Bruguiea, Grafen, Czyrko, ExRat, Rupert Clayton, Rjensen, Toya, LiamE, Retired username, Waqas1987, Grafikm fr, Threepwood89, Ejl, DocWilson, Private Butcher, Typer 525, Wknight94, Cmskog, Metallion, Randommouse, WAS 4.250, FF2010, 21655, Lt-wiki-bot, Pb30, Wsiegmund, GraemeL, JoanneB, SyntaxPC, T. Anthony, Curpsbot-unicodify, Bluezy, Andrew73, Jeff Silvers, Groyolo, Jwmcglone, Resolute, SG, David Straub, A bit iffy, SmackBot, Neuroghost, MattieTK, Espresso Addict, Schyler, Masonpatriot, Skeezix1000, The Monster, Roosh4, Unyoyega, Pgk, C.Fred, Verne Equinox, Delldot, RockRockOn, Kintetsubuffalo, Codey, Actricalian, Mihail ioniu~enwiki,

20.12. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES

139

Emcee2k, Siebren, Gilliam, R.M. Brady, JQJ, Hmains, The Gnome, Skizzik, Dhall10067, Dark jedi requiem, Durova, Izehar, Dycotiles, Keegan, Dr bab, Jon513, Salvor, MalafayaBot, Aridd, Illori, Bkehoe, Hgrosser, Scwlong, Can't sleep, clown will eat me, Shalom Yechiel, Hatchetfish, Jennica, Leftism, TheKMan, Rrburke, Nunocordeiro, Blicarea, Parent5446, Addshore, Greenshed, Grover cleveland, Calbaer, Mitrius, Cybercobra, TGC55, Artie p, RandomP, Bmgoau, G716, Weregerbil, Suetsumuhana, Parrot of Doom, Kukini, Rockpocket, Ceoil, Ohconfucius, JohnM4402, Nishkid64, Cberejik, John, Microchip08, Gobonobo, Sir Nicholas de Mimsy-Porpington, Nishment, Skellious, Babygrand1, A. Parrot, JHunterJ, Mr Stephen, Interlingua, RHB, PSUMark2006, Vashtihorvat, Theseus Athens, Levineps, WilliamJE, Aznmastermind5, Clarityfiend, Foxylibrarian, Missionary, Joseph Solis in Australia, Twas Now, Alextesar, CapitalR, Courcelles, Tawkerbot2, Vitriden, JForget, Deon, Unionhawk, Jibal, Charvex, FlyingToaster, Lazulilasher, Evilgohan2, Moltimert, Tokalon73, Themightyquill, Cydebot, Peripitus, BruceWiley, Ozmanuk, Zghortaman, UncleBubba, Gogo Dodo, Crowish, ST47, A Softer Answer, Beatpoet, Agne27, Cnhardman, Pascal.Tesson, Soetermans, Odie5533, Michael C Price, Christian75, Nabokov, Garik, NorthernThunder, Santegeezhe, Voldemortuet, LarryQ, Tewapack, Moilforgold, Numen, Mattisse, Malleus Fatuorum, Thijs!bot, Epbr123, Marek69, A3RO, Jbl1975, Grayshi, Pcbene, Srose, LostNTheNoise, Dawnseeker2000, Mmortal03, Northumbrian, Ken Thomas, Dantheman531, Hmrox, AntiVandalBot, Seaphoto, QuiteUnusual, Bigtimepeace, Edokter, Mountolive, TimVickers, Manushand, Modernist, Dylan Lake, North Shoreman, Niki2006, HolyT, Woodstein52, JAnDbot, Gatemansgc, Eruedin, Aille, Galadron, The Transhumanist, Arch dude, Hello32020, Wmcewenjr, Greensburger, Frankie816, TAnthony, Jay1279, .anacondabot, Coffee2theorems, Nicransby, Freedomlinux, MiguelMunoz, Jmorrison230582, PvT, Freefry, Prestonmcconkie, BioShock2225, KConWiki, Dirac66, LorenzoB, Matt Adore, DerHexer, JaGa, KenyaSong, Bonneux, Patstuart, Lunakeet, Karengpve, MartinBot, Mattjs, Anaxial, Kateshortforbob, Fconaway, Zentropa77, Koplimek, Dinkytown, Pinot, AlphaEta, J.delanoy, Uncle Dick, Maurice Carbonaro, MrBell, BrokenSphere, McSly, Janus Shadowsong, Trumpet marietta 45750, Palealien, Gurchzilla, WHeimbigner, NewEnglandYankee, Molly-in-md, DadaNeem, 2help, Juliancolton, Cometstyles, HenryLarsen, Jarry1250, Frickeg, DASonnenfeld, Spitfire ch, Fbarton, Marlen Ffm, Deor, VolkovBot, TreasuryTag, Kerrow, Fences and windows, Blackpantha 91, Vincent Lextrait, LeilaniLad, Philip Trueman, TXiKiBoT, Ftocagni~enwiki, Fregle, Jkeene, A4bot, Rei-bot, Phjellming, Gmios, Unsorted, Yovinedelcielo, Qxz, Vanished user ikijeirw34iuaeolaseriffic, Steven J. 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James T. Kirk, Starzynka, Jean-Marie Lindén, Mahuna2, Mish149, Schwede66, Wbjones, J'88, Tyler19951995, Diannaa, 564dude, Norwoodplace, Reach Out to the Truth, Jesse V., Kelvinbaker8000, Lord of the Pit, BronzeSilvGold, Stefanjohnsrud, Rns890, DARTH SIDIOUS 2, RjwilmsiBot, Jmannc3, TjBot, Beyond My Ken, Hajatvrc, Aircorn, DASHBot, Richfrommich, EmausBot, Orphan Wiki, Immunize, Ajraddatz, Super48paul, RA0808, PoeticVerse, Tommy2010, Latowson, Djembayz, Savh, Bravo Foxtrot, Aramando, Ronk01, Illegitimate Barrister, AboutFaace, Shannonah, , Califa22651, Manfred-Stelter, Ora Stendar, Aftesk, Rockclaw1030, H3llBot, GrindtXX, Wingman4l7, Tolly4bolly, IGeMiNix, Brandmeister, L Kensington, Senjuto, Donner60, Efenna, Mystichumwipe, Hazard-Bot, Museomed, DASHBotAV, 28bot, 1007D, Gunbirddriver, ClueBot NG, Yoshi x3, Two Engineer, Suid-Afrikaanse, Bulldog73, Jim bobby dob, Dizztdesi, Reedman72, Mannanan51, Widr, Redveer02, Helpful Pixie Bot, The rakish fellow, BG19bot, Riverhugger, MaxxRenn, Dutchldy, Wzrd1, Alf.laylah.wa.laylah, Vampshoe36, Ella Plantagenet, Wtfsvi, CitationCleanerBot, Harizotoh9, 1&onlyJLB, OhNoMyFace, Polmandc, Glacialfox, MathewTownsend, Red Rose 13, Clancy at Central College, Andrewgprout, Stev za reaper, Rwarming97, Arizonatsunami, Hghyux, Andy stockton, Cloptonson, ZuluKane, Classifiedman12359, Dexbot, DFY889, Mogism, Lugia2453, Cheerioswithmilk, Bluebasket, Killuminator, Blaue Max, NimaBoscarino, Epicgenius, BreakfastJr, Jb1944, TwelvePawFarms, Cash434, Gravitycollapse, Megerler, BallenaBlanca, Boone jenner, Lacemaker427, Meiræ, ChrisP218, Craigrottman, ♥Golf, E.D.J. Muckenfuss, Garfield Garfield, Ratatosca, WordSeventeen, 0xF8E8, Julietdeltalima, Anonimeco, VexorAbVikipædia, Saturnoswald, Kaymandavis, Grammarian3.14159265359, KasparBot, Bullets and Bracelets, Max Paxman, Gaelan, Eric Pode lives, Barbara (WVS), InternetArchiveBot, Thonatas, Snowbird225, GreenC bot, Aryanshurvir, Nerdcorenet, Bender the Bot, Octoberwoodland, PrimeBOT, EggFriedReece, Gothicchicken and Anonymous: 1160 • 2009 flu pandemic Source: https://en.wikipedia.org/wiki/2009_flu_pandemic?oldid=790309972 Contributors: AxelBoldt, Jimbo Wales, The Anome, Ed Poor, Arcade~enwiki, Hajhouse, Rmhermen, William Avery, GrahamN, R Lowry, Leandrod, Bdesham, Infrogmation, Boud, Michael Hardy, Fred Bauder, Julesd, Jll, Jeandré du Toit, Conti, Hawthorn, Victor Engel, Guaka, Rob.derosa, Ike9898, Andrewman327, Flipper9, Tb, WhisperToMe, Tpbradbury, Thue, Earthsound, Wetman, Pakaran, Jeffq, Skybunny, Denelson83, Vt-aoe, Greystar, Chealer, Andrsvoss, Jwbrown77, Moncrief, Nurg, Naddy, Dodger~enwiki, Pifactorial, Angilbas, Guy Peters, Alan Liefting, Jasenlee, Centrx, Giftlite, Lee J Haywood, Lethe, Lazurs, Zigger, Markus Kuhn, LarryGilbert, Mike40033, BigBen212, Dmmaus, Kmsiever, Edcolins, OldakQuill, Gadfium, Andycjp, J~enwiki, Ljhenshall, Mike R, SarekOfVulcan, Antandrus, BozMo, Beland, Robert Brockway, Eregli bob, Nograpes, FelineAvenger, Kaldari, OwenBlacker, EBB, Mysidia, Willhsmit, TRS-80, Barnaby dawson, Ouro, Asbruckman, Rich Farmbrough, Stuart hc, Loganberry, Cacycle, Jwise77, MaxMad, Bishonen, LindsayH, Pavel Vozenilek, Bender235, Mykhal, Nabla, Art LaPella, Andreww, Causa sui, Diamonddavej, Viriditas, Ziggurat, Phansen, Ctrl build, RichardRothwell, Jojit fb, Rajah, Samulili, MARQUIS111, TheGridExe, 99of9, Sebastian Goll, Polylerus, Hectigo, Solid Reign, Nsaa, Espoo, Bob rulz, Alansohn, Jaroslavleff, Richard Harvey, Rd232, AzaToth, EquinoxeIV, Hinotori, Julianortega, Kurieeto, Wdfarmer, Avenue, Bart133, NTK, MattWade, Melaen, Ronark, BanyanTree, Super-Magician, Cromwellt, Paul1337, ReyBrujo, Amorymeltzer, A.K.R., Geraldshields11, Computerjoe, Pauli133, Arthur Warrington

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CHAPTER 20. INFLUENZA A VIRUS SUBTYPE H7N9

Thomas, Sleigh, Djsasso, Kazvorpal, Ling Kah Jai, Sesh, Zntrip, Jef-Infojef, Stemonitis, Angr, Joriki, Richard Arthur Norton (1958- ), Jamsta, Camw, LOL, Oliphaunt, BillC, Mazca, Jimbryho, Seanwong, Pol098, Pixeltoo, Rainmaker, Apokrif, Jok2000, Broc7, Mikintosh, GregorB, BlaiseFEgan, Jetpeach, Fugue~enwiki, Sega381, Laurap414, Ggonnell, Indahnesia, Joe Roe, Sherpajohn, RichardWeiss, Graham87, WBardwin, BD2412, Xavier114fch, Dpr, Mendaliv, Stdout, Edison, Sjö, Rjwilmsi, Markkawika, Jivecat, Jibco, XP1, SMC, Vegaswikian, Jehochman, LjL, Dianelos, Brighterorange, Yug, The wub, Notorious4life, Croperz, Fred Bradstadt, Syced, Titoxd, Ground Zero, Heyz, Dan Guan, Pfctdayelise, Nihiltres, Aeon17x, AlexCovarrubias, Tequendamia, TheDJ, Gussisaurio, SteveBaker, No Swan So Fine, Idaltu, Chobot, WriterHound, Wavelength, TheTrueSora, Sceptre, Wester, Brandmeister (old), Tznkai, SLATE, Geljamin, MMuzammils, RussBot, Athempel, Arjuna909, Spaully, Inkbacker, Mythsearcher, Rsrikanth05, Pseudomonas, Anomalocaris, Adidasx007, GSK, Madcoverboy, Petter Strandmark, Badagnani, Welsh, Trovatore, Mccready, RFBailey, Wolbo, Dbfirs, Historymike, Derek.cashman, Cinik, Ms2ger, Kelovy, Intershark, WAS 4.250, Sandstein, Mike Serfas, Jdjerich, Zzuuzz, Aremisasling, Rushyo, Icydesign, Nikkimaria, Th1rt3en, BytEfLUSh, BorgQueen, Tobixen, SV Resolution, Sitenl, Wechselstrom, Jonasfagundes, ViperSnake151, Jeffreymcmanus, Trickstar, John Broughton, Paul Erik, Zvika, Elliskev, Hsibley, Cappelle, Luk, Amalthea, A bit iffy, SmackBot, Ralphpukei, Unschool, F, Estoy Aquí, McGeddon, Saintyboy666, Praetor alpha, Blue520, Ikip, Jagged 85, ScaldingHotSoup, Stifle, Kintetsubuffalo, Kslays, BiT, Methedunker, Nil Einne, Flamarande, HalfShadow, Mauls, Hdstubbs, Lonelymiesarchie, Aij, Brianski, Ohnoitsjamie, Phizzy, Oscarthecat, D14852001, Durova, Tangamandapiou, GoneAwayNowAndRetired, Chris the speller, Dycotiles, Boggy1, LinguistAtLarge, Persian Poet Gal, Ryan Paddy, Dawd, Blacknail, Viewfinder, Rolypolyman, Quackslikeaduck, Wedian, Farry, Baronnet, Craig t moore, Da Vynci, Hengsheng120, Jdthood, Modest Genius, Xeryus, Chendy, Jahiegel, Jacob Poon, Rrburke, Nunocordeiro, WMXX, GrahameS, Wine Guy, JMAPGGGonzalo~enwiki, Freek Verkerk, Aldaron, Fuhghettaboutit, Cybercobra, Khukri, Coolbho3000, Nakon, Allan87, Dream out loud, Clean Copy, Pmbarros, Crd721, Leaflord, Scootdive, Daniel.Cardenas, Mostlyharmless, Drunken Pirate, Ceoil, Ohconfucius, CIS, DerekLee, ArglebargleIV, Mksword, Ser Amantio di Nicolao, Atkinson 291, Calvados~enwiki, John, Bruin79, Microchip08, SilkTork, Briantist, Park3r, Ngckmax, Gboyers, IronGargoyle, Arun.blue, BillFlis, Grapetonix, Korovioff, Anto475, Stwalkerster, Lampman, Beetstra, SQGibbon, Eric76, Samfreed, Hedleypanama, SandyGeorgia, TastyPoutine, NJA, Novangelis, Dfred, Fredwerner, Mohamed Abdel Mageed, Jcblackmon, Dl2000, Supaman89, Falc, Stephen B Streater, Levineps, Kencf0618, Nosimplehiway, Joseph Solis in Australia, Kernow, Wjejskenewr, Roblespepe, Tony Fox, EZio, HongQiGong, Makfan, Ellis2ca, Yacov, Valoem, Travisl, Agus elex 2005, Shadow86, MarkTB, Vitriden, JForget, Sketch051, Vargklo, Americasroof, Marthiemoo, Liam Skoda, Rainbow warrior, Ale jrb, Insanephantom, Nunquam Dormio, Leevanjackson, Runningonbrains, Ruslik0, MrRyanEinfeldt, Wilester, KnightLago, WikiRedPen, Jesse Viviano, Rockysmile11, Green caterpillar, AshLin, Vrysxy, Tex, Honghu, Cydebot, Fluence, Marqueed, Vanished user 2340rujowierfj08234irjwfw4, Reywas92, Grahamec, Crossmr, TomParys, UncleBubba, Kslotte, Mechem, Gogo Dodo, Jefft0, Sloth Loves Chunk, Daniel J. Leivick, Costelld, Eu.stefan, Scud133, Sp, The Lake Effect, Hontogaichiban, Jaerik, Xabier Cid, Viridae, Xanthis, Casliber, CieloEstrellado, Friera, Thijs!bot, Michiganfan1, HappyInGeneral, CopperKettle, Sry85, Pocus, Marek69, SGGH, Zzthex, Mr pand, Bagofants, Babytexcoco, Turkeyphant, Chandler, Esbullin, Eb.eric, Danigoni, Uruiamme, Dawnseeker2000, Escarbot, Mentifisto, Dookas27018, Chicgeek, Betdud, Bigtimepeace, Just Chilling, Orbzon, Dr. Blofeld, Willscrlt, Prince Vegeta, Madder, TimVickers, Smartse, Kovalski, Alphabet55, Yellowdesk, Trakesht, Borgarde, Didanio, Econprof, TRBlom, Daytona2, JAnDbot, Thomasmallen, Eruedin, DuncanHill, Felipe Menegaz, Mike D 26, MER-C, Skomorokh, Daniel Supreme, Arch dude, QuantumEngineer, Hello32020, Merumerume, VeronicaPR, Andonic, Xeno, Ojchase, Ecphora, TAnthony, Gavia immer, TofuMatt, Paf00, Acroterion, Achero, Dauphiné, Animaly2k2, Yurei-eggtart, Margamanterola~enwiki, VoABot II, SyG, AuburnPilot, Dentren, MastCell, Conor McManus, JamesBWatson, Samunoz1, Harelx, Kibblesworth, Jatkins, Kotsolis, Avicennasis, Dianaw654, Animum, Sourside21, Owenob1, BatteryIncluded, Emw, Ole.steen, Cpl Syx, Benjamintchip, Vssun, Shadiac, Cool Nerd, WLU, Acidbird, Seba5618, Alexandre linhares, Tracer9999, Oren0, Paul Gard, Tonicthebrown, Cliff smith, FlieGerFaUstMe262, Gandydancer, Monkeywarrior, Gkklein, Foncea, ARCG, Lithium57, Smilingsuzy, Jack007, R'n'B, Kateshortforbob, CommonsDelinker, Fconaway, Ash, Fpbear, Dinkytown, AlphaEta, J.delanoy, Abecedare, AstroHurricane001, Whaatt, Javawizard, Maurice Carbonaro, Xris0, Jesant13, Ginsengbomb, A Nobody, Icseaturtles, MaxWilder, Paris1127, NagamasaAzai, Shawn in Montreal, TomyDuby, Anguswalker, Little Professor, Collegebookworm, Mikael Häggström, Ipigott, SchirmerPower, Gombang, BeŻet, Colchicum, ParaDoctoral, Nwbeeson, Yawaraf, SriMesh, Flatterworld, Sculptorjones, Lanternix, Diablote, Juliancolton, Mlle thenardier, Oscargsol, Ja 62, Jarry1250, Andy Marchbanks, Useight, Wikipeterproject, Spitfire 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Ravensfire, CurranH, Yintan, LeadSongDog, Grundle2600, D'Ranged 1, Xenophon777, Flyer22 Reborn, ATC, BFritzen, PascalLeroy, BBKurt, Steven Crossin, Ryanpcollins, ConradWZ, LaidOff, Pcontrop, Azulsquall, WacoJacko, Eugen Simion 14, Zylox, KritonK, Svick, Flying hw, Rhyseh2007, Jóhann Heiðar Árnason, Vice regent, DragonZero, Johnson487682, Latics, The Four Deuces, KatiaRoma, OboeCrack, UB65, WikiLaurent, Hyperionsteel, Curtdbz, Drgarden, Arnos78, Explicit, Shawnnicholsonca, TheCoolOne99, Invertzoo, Llywelyn2000, Atif.t2, Blueliteway, Doom Fox, Church, Jiminezwaldorf, Rickemiller, Oneforlogic, ClueBot, SummerWithMorons, Fresh Prince Carlton, Artichoker, Shruti14, Quisqualis, Snigbrook, Analoguni, Fox, The Thing That Should Not Be, Taikanatur, Bsw123, Pi zero, Cochonfou, Gopher65, Saddhiyama, Ignorance is strength, Farolif, Mild Bill Hiccup, Cube lurker, Wikimike2007, Othmanskn, Tyberiuswp, Niceguyedc, Blanchardb, Block77129, LizardJr8, Piledhigheranddeeper, Trivialist, Counteraction, DragonBot, Hilmarwoy, Welsh-girlLowri, Cricket07jack, Nymf, Alexbot, Jusdafax, Tsukamoto, Tphscc, Ottre, John Nevard, Euronbaja, Danziger100, QuiteInteresting, Vanhoabui, Very neant, Rhododendrites, Sun Creator, NuclearWarfare, Cenarium, Aurora2698, Replysixty, Lipton sale, Micha, Bretonnia, Abhi2810, Sampsonite5, EivindJ, Boxter1977, DSWiiLOrd1o1, Jeff.johnson.au, La Pianista, Dp074, Yellwsub, Spiby, Light show, Canadianpaddy, Liberalcynic, BetoCG, PCHS-NJROTC, JTSomers, Adamfinmo, SoxBot III, Tehcrazybob, Trulystand700, 3193th, Vanished user uih38riiw4hjlsd, Ohio614, Tdslk, DumZiBoT, Nskrill, Aj00200, XLinkBot, Hotcrocodile, Fastily, Kormin, Cph003, EnWikinombre, TaalVerbeteraar, Messiisking, Jovianeye, Dthomsen8, ErgoSum88, Qwertluis, Facts707, Skarebo, SilvonenBot, Sarejo, Mbbl, Spoonkymonkey, Mm40, Kaiwhakahaere, WholeyMoley, Jens Martin, JCDenton2052, ESO Fan, Airplaneman, Bhockey10, Wyatt915, GDibyendu, Addbot, Cxz111, ConnorJack, Otterathome, JBsupreme, Roentgenium111, Willking1979, Roman888, Jojhutton, Landon1980, Friginator, Uktvhistory064, M.nelson, Ocdnctx, Yongjianrong, Totakeke423, Fieldday-sunday, Amrad, Refractions, Cognatus, Rayox, MrOllie, Download, SoSaysChappy, LaaknorBot, Ccacsmss, Bazza1971, Glasszone33, Chzz, Debresser, AlexW1122, Super duper jimbo, Kyle1278, Green Squares, DMMc, LinkFA-Bot, Lemonade100, Deemers, Numbo3-bot, Ehrenkater, Peridon, Iluvalar, HandThatFeeds, Kinou, Tide rolls, Saepe Fidelis, Canationalist, ‫ماني‬, Neurovelho, Zorrobot, MuZemike, JEN9841, Konandoar, Alpalfour, HerculeBot, Genius101, Sneaky Oviraptor18, Aslam646, Ten Thousand Bullets, Legobot, Alexander Widefield, WrcF1, Luckas-bot, Shannon1, Boyben10, Yobot, DerechoReguerraz, WikiDan61, Ht686rg90, Toushiro, Fraggle81, Grochim, Guessing Game, Yukarihiraiforever, Yng-

20.12. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES

141

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Barth, Asennott, MiraAroyo, J9mu83, 564dude, Antrikshy, Suffusion of Yellow, Moowax, DaleMu, FvdL2009, Accuracy-searcher, Tbhotch, Leaf16nut, Muminovs, YESHA-eevish, Neomed, Brianboone, 09wyatte, Ktshockey2, Totalportal, ZBlacK, Manifredtellew, Christaa123, Hoppihopp, RjwilmsiBot, Undescribed, Cplcecil, Andiggidy, Ninacows, Lovestomessthingsup, Beyond My Ken, Klltr, NerdyScienceDude, Jackhatchet, Aircorn, Duncanb1234, Myki Cassie, DASHBot, Whywhenwhohow, EmausBot, John of Reading, WikitanvirBot, Immunize, Gfoley4, Gotnothin11, Flutterbelle, Murmis, Brandonoppliger, OhSNAPPLE15987, Boredude, GoingBatty, Loooooooooo, Gotohelllol, Rt123rt, Mikeybinns, Aiden pollard, Wham Bam Rock II, Wikipelli, Dcirovic, Mt4928, Josve05a, LDAB, H3llBot, BSW-RMH, SporkBot, Donner60, Zpsmi, TruthSeekerT4C, Lguipontes, 1007D, Petrb, Xanchester, ClueBot NG, Manubot, Sm1l3yx85, Helpful Pixie Bot, Pumpie312121, BG19bot, Arshiamcs, Damm0050, OpenMind, Tatchell, Gorthian, Dainomite, MrBill3, Goltak, Polmandc, Nxd131, Minsbot, BattyBot, Cyberbot II, LHcheM, Padenton, Enterprisey, Dexbot, LightandDark2000, ComfyKem, BurritoBazooka, PC-XT, General lee100, Melonkelon, Mariasin, Hatagalow, Drchriswilliams, Daleslimnsaw, Stamptrader, Truebreath, Monkbot, , H.hussain24, Hy2rogenh2, Lime0life, Awesomeisprettyawesome, AlphaBetaGamma01, CV9933, Inr ayyanar, InternetArchiveBot, Fuortu, GreenC bot, Gurwinder Malhi, Bender the Bot, Octoberwoodland and Anonymous: 880 • Influenza A virus subtype H2N2 Source: https://en.wikipedia.org/wiki/Influenza_A_virus_subtype_H2N2?oldid=786917326 Contributors: Rmhermen, Twang, Moondyne, Ianeiloart, Tom harrison, Piotrus, Rich Farmbrough, MBisanz, Bobo192, Ziggurat, Espoo, Alansohn, DoctorWho42, Marudubshinki, Yug, Benjwong, Rupert Clayton, WAS 4.250, Niayre, G716, JohnM4402, Chipmunk15, Lucio Di Madaura, Daniel5127, Shrimp wong, Hucz, **mech**, Cydebot, Dekimasu, Dragfyre, Ciar, J.delanoy, Gunnar Guðvarðarson, Malinaccier, Gaelen S., Denisarona, ClueBot, Ah1270, Fyyer, The Thing That Should Not Be, Bretonnia, Addbot, MrOllie, Betty2006, Blaylockjam10, Austro, HistoryEditor1951, Jim1138, Rootmarm, Gigemag76, Date delinker, Cantons-de-l'Est, WebCiteBOT, Zanhe, Miracle Pen, Jynto, Jsanthara, ClueBot NG, Helpful Pixie Bot, Damm0050, Kooky2, Smalleditor, RotlinkBot, Tentinator, OrbitHawk, InternetArchiveBot, Bender the Bot, Octoberwoodland, Magic links bot and Anonymous: 38 • Influenza A virus subtype H3N2 Source: https://en.wikipedia.org/wiki/Influenza_A_virus_subtype_H3N2?oldid=775431242 Contributors: Gojomo, Earthsound, Centrx, Bluejay Young, Kaldari, Jiy, Rich Farmbrough, Kndiaye, Senori, Ziggurat, Woohookitty, LOL, Tckma, Edison, Rjwilmsi, Marasama, Benjwong, Jimp, AirWalker, Summitguy, WAS 4.250, Arthur Rubin, SmackBot, Ikip, Niayre, Kintetsubuffalo, Gilliam, CWesling, Akulkis, G716, SilkTork, Korovioff, Beetstra, Hkoala, General Eisenhower, Kencf0618, Lucio Di Madaura, HDCase, JForget, R0, Room101, Escarbot, AntiVandalBot, Secret Squïrrel, Cgingold, Asseverator, Ciar, Tracer9999, Peter2212, J.delanoy, Notreallydavid, Hvrwrstlr007, VolkovBot, Gunnar Guðvarðarson, Una Smith, Jackfork, Madhero88, Caltas, LeadSongDog, Anchor Link Bot, ClueBot, The Thing That Should Not Be, DragonBot, Alexbot, Ottre, Tealwisp, Jax 0677, Spitfire, WikHead, Jhjonesjr, Download, Tide rolls, Yobot, DerechoReguerraz, AnomieBOT, Götz, Materialscientist, Rootmarm, Gigemag76, Date delinker, FrescoBot, Pinethicket, Abductive, SpaceFlight89, Himypiedie, Weedwhacker128, Jamesshliu, Klbrain, Mz7, Hanjifi, ClueBot NG, Bulldog73, Helpful Pixie Bot, Anonymous Revolution, LightandDark2000, IamASIANyesIam, InternetArchiveBot, Bender the Bot, Octoberwoodland and Anonymous: 63 • 1968 flu pandemic Source: https://en.wikipedia.org/wiki/1968_flu_pandemic?oldid=768604316 Contributors: Rich Farmbrough, Kndiaye, Bender235, Ziggurat, BDD, Ahunt, DVdm, RussBot, NawlinWiki, WAS 4.250, Tim1965, NeilN, Ppntori, George Ho, French user, SilkTork, KrakatoaKatie, Seaphoto, STSC, Eruedin, Magioladitis, AstroHurricane001, NewEnglandYankee, Mannafredo, Goustien, Mx. Granger, Boneyard90, Rror, Facts707, ZooFari, Addbot, Ainali, OlEnglish, AnomieBOT, Rootmarm, RodrigoCruzatti, FrescoBot, Impala2009, Hazard-Bot, ClueBot NG, Helpful Pixie Bot, BG19bot, Cold Season, WarriorsPride6565, Mediran, Kitty1234567891011, Senpai Ben, BleffeIN, Xennis, Omni Flames, GreenC bot, Bender the Bot, PrimeBOT, Alexverb and Anonymous: 24 • Influenza A virus subtype H5N1 Source: https://en.wikipedia.org/wiki/Influenza_A_virus_subtype_H5N1?oldid=788411582 Contributors: AxelBoldt, Alex.tan, Danny, SimonP, Rickyrab, Stevertigo, Boud, Earth, Shyamal, Gabbe, Lemming, Ahoerstemeier, JWSchmidt, Bogdangiusca, Nikai, Llull, RodC, Fuzheado, Quux, Tpbradbury, Morwen, Lkesteloot, ZeWrestler, SEWilco, Joseaperez, Shizhao, Joy, Raul654, CBorges, Johnleemk, Denelson83, Donarreiskoffer, Vespristiano, Netizen, Gandalf61, Nach0king, Michael Snow, Mushroom, ElBenevolente, Diberri, Giftlite, Jacoplane, Awolf002, Nunh-huh, Marcika, Everyking, Curps, Michael Devore, Sublium, Jfdwolff, Fjarlq, Solipsist, Bobblewik, Toby Woodwark, Andycjp, Ran, Beland, Karl-Henner, Neutrality, DanBlick, Ukexpat, Surfingslovak, Discospinster, Rich Farmbrough, Silence, Fleung, Roodog2k, Paul August, Rubicon, Kaisershatner, Richard Taylor, Violetriga, Eric Forste, Clement Cherlin, Zscout370, El C, Chairboy, Aude, Shanes, Andreww, CDN99, Ce garcon, Circeus, Che fox, Davidruben, ZayZayEM, Brian McNeil,

142

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Arcadian, Sludge, Bawolff, 99of9, Ral315, Pearle, Jumbuck, Bob rulz, Rocketfairy, Mo0, Mackinaw, Atlant, Rd232, Ronline, Axl, MarkGallagher, Lightdarkness, Hu, Avenue, Snowolf, BanyanTree, ClockworkSoul, Knowledge Seeker, ReyBrujo, Quintin3265, Evil Monkey, Amorymeltzer, Randy Johnston, Cmapm, DrGaellon, Martinoei~enwiki, Instantnood, Grnch, Brookie, Zntrip, Snowmanmelting, MickWest, OleMaster, Richard Arthur Norton (1958- ), Kelly Martin, OwenX, Woohookitty, Simon Shek, Jamieli, Pol098, Ruud Koot, Chochopk, Duncan.france, Rickjpelleg, Uris, I64s, Paul Carpenter, Isnow, Fxer, Prashanthns, MarcoTolo, Rnt20, T34, Jack Cox, Draconiator, Amayzes, BD2412, MC MasterChef, DanielAmelang, Edison, Xerxes2k~enwiki, Rjwilmsi, Tangotango, R.O.C, Oblivious, Ligulem, Plastictv, Fred Bradstadt, AySz88, DirkvdM, Titoxd, Vietbio~enwiki, Doc glasgow, Winhunter, Nihiltres, Alhutch, Vsion, RexNL, Orborde, Preslethe, Dunemaire, M4f14b0y~enwiki, King of Hearts, Lifeischeese, Chobot, Roboto de Ajvol, YurikBot, Wavelength, Waitak, Midgley, Anonymous editor, Zafiroblue05, Splash, Ramallite, Zelmerszoetrop, Stephenb, Gaius Cornelius, MarcK, Gustavb, Thomas E. Goodwin, G.G., Wiki alf, Trimmer56, Hhamdy283, Barberio, American007, RFBailey, Raven4x4x, Leotohill, Mysid, Cinik, Haemo, Dododo, Yabbadab, -Tsugaru-, PGPirate, Bob247, Pegship, WAS 4.250, FF2010, Encephalon, Arthur Rubin, Ekstazo~enwiki, GraemeL, Reject, Kungfuadam, NeilN, Lewys, Zvika, Wallie, Saikiri, Harthacnut, Wai Hong, KnightRider~enwiki, SmackBot, Bormalagurski, XYaAsehShalomX, ChXu, CarbonCopy, Tarret, TestPilot, Mkaycomputer, Istvan, Cyphereng, Ikip, Jacek Kendysz, Btm, Midway, Jfurr1981, Delldot, Peloneous, Harrypmgaga, Edgar181, R.M. Brady, Gr3g1, Toddintr, G O T R, The Famous Movie Director, Oscarthecat, Skizzik, Dingar, Pseinstein, Dither, Kattenstoet, Bluebot, Ahmed Sammy, Bcore, Aleksei, Ian13, Dr bab, Stephen.frede, Vobios, Derodof, Quaque, Aviageek, Vulcanstar6, Xiner, Addshore, Megamix, Theonlyedge, Cybercobra, Nakon, TedE, Astrogeek, Lostart, Xyzzy n, Kirils, G716, Fitzhugh, DMacks, Wizardman, Rock nj, Lambiam, Rory096, Swatjester, Kuru, J. Finkelstein, Ian.desouza, Olin, Korovioff, Tripod2282, Hylobates, Bendzh, Spook`, Biwhite2, Sheherazahde, Opal-kadett, Monticus, Freakyguy, General Eisenhower, Hetar, Hiuwah, Iridescent, Patrea, JoeBot, SaintOfFeon, Tawkerbot2, Dlohcierekim, Shrimp wong, Andreas Willow, SkyWalker, Chrumps, CWY2190, Outriggr (2006-2009), Evilgohan2, Moreschi, OliverC123, Cydebot, Kazubon~enwiki, Hontogaichiban, Kozuch, Pascallanctot, Crimsonl, Thijs!bot, Epbr123, Yboord028, Picus viridis, AntiVandalBot, TimVickers, Drewk, Bridgeplayer, MECU, Gdo01, Zedla, Falconleaf, AtikuX, Beelaj., JAnDbot, Little Spike, Leolaursen, VoABot II, Ling.Nut, Prestonmcconkie, Johnbibby, Ciar, Allstarecho, Schumi555, Bilditup1, Tracer9999, Gandydancer, David Munch, Char561, EdBever, Rawa9999, Janus Shadowsong, Mikael Häggström, Oceanflynn, Bkeffer, Plasticup, Jeff F F, Dennis Myts, Flink the blind hemophiliac, AlnoktaBOT, Gunnar Guðvarðarson, Bjfcool, Philip Trueman, Trevorssister, Qxz, Asiatic Flu, Brianga, Theta00, Doc James, John Shaffer, Graham Beards, Gerakibot, Keilana, Oxymoron83, Senor Cuete, Jóhann Heiðar Árnason, DeborahADeal, Florentino floro, Wee Curry Monster, Beeper44, Muhends, ClueBot, Binksternet, Icarusgeek, Addie777, Showtime2009, Gabaking, Mspraveen, Provax, Shamshel~enwiki, Jikalaman, DumZiBoT, Karkiked, XLinkBot, Jgrulz94, Revancher, JCDenton2052, HexaChord, Cugerbrantstandfast, Addbot, IMEvids7, DOI bot, Mikeydyer, Fluffernutter, Diptanshu Das, MrOllie, LaaknorBot, PranksterTurtle, AnnaFrance, Bruce grant, 84user, Yobot, Cflm001, Thidewiki, AnomieBOT, Andrewrp, DemocraticLuntz, Hairhorn, IsabelleHubert, Jim1138, IRP, Citation bot, Frankenpuppy, Synaptophysin, Xqbot, Youngdones, Rootmarm, Gigemag76, Alfierise, Billydevil, Ymerino, Sophus Bie, Thehelpfulbot, Lawynholds, FrescoBot, Iamawoman, TC Murphy, Citation bot 1, AstaBOTh15, Abductive, MJ94, Ivs5982, Uad473, Full-date unlinking bot, Lotje, Sgt. R.K. Blue, Lugturn33, Draguvi, Peterson24, EmausBot, Immunize, Gfoley4, Stephanienox, Dcirovic, AsceticRose, Cung45, H3llBot, Abergabe, Mayur, ClueBot NG, Klopfleisch, Frietjes, Cassie72, Widr, Geofferybard, CasualVisitor, BG19bot, Makedonija, JoVEscied, Bobby7474, BattyBot, Cyberbot II, Dexbot, RachulAdmas, Eyesnore, Ebrown4109, Soffredo, Ss6j81avz, Aerolit, Stephendavion, Webredactie Erasmus MC, Monkbot, Zaixar, Ezrysm, Emily Temple-Wood (NIOSH), Thijs Kuiken, InternetArchiveBot, GreenC bot, Anubhav28singh, Bender the Bot, Octoberwoodland and Anonymous: 499 • Avian influenza Source: https://en.wikipedia.org/wiki/Avian_influenza?oldid=790239489 Contributors: Eloquence, The Anome, Stevertigo, GTBacchus, Gojomo, CamTarn, Ahoerstemeier, Smack, Schneelocke, Fuzheado, Furrykef, Paul-L~enwiki, HarryHenryGebel, Merovingian, Academic Challenger, Alan Liefting, Giftlite, Christopher Parham, Wizzy, Nunh-huh, Cobaltbluetony, Bkonrad, Jfdwolff, Micru, Ceejayoz, Utcursch, Slowking Man, Antandrus, Jossi, MacGyverMagic, DragonflySixtyseven, SimonLyall, Bepp, Expatkiwi, Mike Rosoft, Freakofnurture, Discospinster, Rich Farmbrough, Jarcanist, Cnwb, Wrp103, Xezbeth, Bender235, ESkog, El C, Femto, Bobo192, Longhair, Irrbloss, ZayZayEM, Arcadian, RazorChicken, Stephen G. Brown, Alansohn, Interiot, Snowolf, Wtmitchell, Melaen, BanyanTree, HenkvD, Geraldshields11, SteinbDJ, Saxifrage, OwenX, Henrik, Antiphon~enwiki, PoccilScript, Pol098, Nklatt, Deltabeignet, BD2412, P3on, FreplySpang, Zoz, BorgHunter, Edison, Rjwilmsi, Koavf, Саша Стефановић, Aroberts, Boccobrock, The wub, AySz88, Nivix, RexNL, Gurch, TheDJ, Mpradeep, Alphachimp, Chobot, Bdelisle, The Rambling Man, JarrahTree, Anonymous editor, Neilbeach, NawlinWiki, Mipadi, Robertvan1, RazorICE, Dureo, Apokryltaros, Cholmes75, RUL3R, Grafikm fr, Bucketsofg, DeadEyeArrow, Nlu, Wknight94, WAS 4.250, Zzuuzz, Closedmouth, Colin, Livitup, Sean Whitton, GraemeL, TBadger, Alias Flood, Fram, HereToHelp, Kungfuadam, NeilN, Lunch, DVD R W, Tom Morris, Luk, SmackBot, Hkhenson, Fff, Bomac, Nscheffey, Yamaguchi , Ohnoitsjamie, Themobman91, Dr bab, Jprg1966, Lollerskates, Tree Biting Conspiracy, Milalwi, The Thrillinator, SpookieWookie, Can't sleep, clown will eat me, Kevinyaun, Onorem, Jennica, Snowmanradio, TheKMan, Cybercobra, Khukri, Yrral, Thegraham, IrisKawling, G716, Weregerbil, DMacks, Kukini, JohnM4402, Xezlec, Luigi-ish, Kuru, Joelmills, PseudoSudo, Beetstra, AxG, Stizz, Totakeke, Novangelis, Avant Guard, Dodo bird, General Eisenhower, Nehrams2020, Kencf0618, JoeBot, Jihad cowboy, Linkspamremover, Tawkerbot2, Dlohcierekim, Globalmuseum, Emote, Torc421, Joostvandeputte~enwiki, King of the North East, Epicurus One, Dycedarg, Jorcoga, Mrperson27, Jjj444, Jonk512, Trasel, Michaelas10, Gogo Dodo, Travelbird, Anthonyhcole, Corpx, Pascal.Tesson, Strom, Chrislk02, Atom1, Jay32183, FastLizard4, Lee, Nsaum75, Crimsonl, Zzzmarcus, Tuxide, Gimmetrow, Epbr123, Judae1, Thebug44, Marek69, NorwegianBlue, Maitre~enwiki, Drugshome network, Petrosino, Wikipediauser1001, Mentifisto, Sidasta, Cyclonenim, AntiVandalBot, Opelio, Nipisiquit, Woodstein52, JAnDbot, Dan D. Ric, Apparent Logic, Hello32020, Kirrages, Montie5, Ecki~enwiki, Magioladitis, Bongwarrior, VoABot II, Weser, CTF83!, Prestonmcconkie, BBQ~enwiki, Ciar, 28421u2232nfenfcenc, Sabedon, Jeremybeardmore, Anthology51, Cool Nerd, Pax:Vobiscum, IvoShandor, Azure06, 0612, Jemijohn, Hdt83, MartinBot, Gandydancer, 52 Pickup, BetBot~enwiki, Artie1324, RP88, Nicko85, Keith D, Realdevilman, Sully2106, LedgendGamer, RockMFR, J.delanoy, Fowler&fowler, Dazzawheeler, JackAidley, RagnaParadise, Keesiewonder, Icseaturtles, Minderbinder~enwiki, Rod57, McSly, Mikael Häggström, Mle-mot-dit, Kilroy42, Igotlotsaquarters, SJP, SriMesh, Djandrews, Tygrrr, S (usurped also), Xiahou, Mellonbank, Idioma-bot, Althaea, Kookubura, Deor, VolkovBot, Cireshoe, TreasuryTag, Kwsn, Forest Garner, JustinHagstrom, Kakoui, Anthonee1230, Gunnar Guðvarðarson, Philip Trueman, JayEsJay, Trevorssister, Kittymalicious, Womenshealth, Vipinhari, JayC, Someguy1221, Annodeus, Littleblackboy~enwiki, Una Smith, Lradrama, Sintaku, Sanfranman59, LeaveSleaves, Whoohoo9876, JerFT, Digitalis101, Asiatic Flu, Coffeepot, BigDunc, @pple, Papelr13, Insanity Incarnate, Cliffmurphy, Doc James, In before, FlyingLeopard2014, Tbirdkid5000, Ispca, SieBot, Graham Beards, Caulde, JoshEdgar, Plinkit, Android Mouse, Bob98133, Cville roger, Oxymoron83, Alex.muller, Svick, Maelgwnbot, Correogsk, Mojoworker, DeborahADeal, Nimbusania, Mygerardromance, WordsExpert, Hariva, Susan118, Florentino floro, Escape Orbit, Beeper44, Boobz ere, ImageRemovalBot, Touchstone42, Elassint, ClueBot, Binksternet, The Thing That Should Not Be, Matdrodes, Ostmoe, Egoffman, Czarkoff, NPIC, WDavis1911, Sw258, Regibox, CounterVandalismBot, Pegibson, Bensci54, Chuchugecko, Puchiko, Harimawan, Tisdalepardi, Excirial, Boogereater123, Coralmizu, Monobi, Ahender, Tsmithnal, Jboltonnal, Butters x, Rbexter93, Nochrisgriswold, Heathspic, Alexadriagon, Faust921, Rui Gabriel Correia, Light show, Brookz1981, Proofer47, Thingg, Dunseath, Lubin5792, Matthew avent, Gnowor, Ladsgroup, Dark Mage, Cugerbrantstandfast, Cabayi, Addbot, DOI bot, DougsTech, Tanhabot, Cst17, MrOl-

20.12. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES

143

lie, Munchbox, Yourface12, Glass Sword, Bruce grant, Adityajuneja7, Numbo3-bot, David0811, Luckas-bot, Yobot, Senator Palpatine, TaBOT-zerem, Anypodetos, Nallimbot, Rogerb67, Worksafe, ChildSurvival, Masterchief 123456789, Raimundo Pastor, AnomieBOT, Andrewrp, Rubinbot, Berkeleyonian, IsabelleHubert, Ulric1313, Materialscientist, Citation bot, G6cid, ArthurBot, Xqbot, Lemmys61, AvianInfluenza, R0pe-196, Rootmarm, JimVC3, Brettporter, Capricorn42, Alfierise, Inferno, Lord of Penguins, Generalthanshwe, RibotBOT, Ymerino, Waldo1961, David471993, ADTS1, Dirkach, Lawynholds, Eksimaru, Editorveterinaryworld, Alex4827, TheLou75, Citation bot 1, Simulation18, Cflores81, Baconadvocate, Sir Jamie2, I dream of horses, Fatman94, 1v0odoo1, Skyerise, Datofm, JackLaros, HRW in 1899, Trappist the monk, ‫کاشف عقیل‬, Draguvi, Tbhotch, Dr.Claloisled, Hayley2600, Minimac, Sifi899, RjwilmsiBot, Missmimi123, Donutshankz, DASHBot, EmausBot, John of Reading, WikitanvirBot, Razor2988, Chuang.cdc, PoeticVerse, Dcirovic, Mt4928, Fæ, Health animal, L Kensington, Gsarwa, Donner60, ChuispastonBot, JonRichfield, Mjbmrbot, Farmjustice2010, ClueBot NG, Miilhan, Rdonis, Movses-bot, Lasanja14, Agrichuck2010, GlassLadyBug, Google1234321, Bobnob1234, JohnsHopkinsCCP, Helpful Pixie Bot, Martin of Sheffield, DBigXray, Mediator Scientiae, BG19bot, MKar, Toddtaylor81, Rcasey13, Jumbiewinston, JMtB03, Cyberbot II, Leo Hernandez14, FunnyKelpie, Dexbot, Bree’s Block, Lugia2453, ComfyKem, RotlinkBot, Echoblast53, Acorn Drains Cans, Huang1991, Meteloides, VeryCrocker, Suelru, Monkbot, 3primetime3, Juvrud, Zszabo81, GeorgiaMorrison, Emily Temple-Wood (NIOSH), Face too Face, JJMC89, Lemiha, InternetArchiveBot, Emilyjose, GreenC bot, J621e404, Banalitea, Kontort, Bender the Bot, Janeclay, Octoberwoodland, Zeddrepulsa, Mma201674822, Magic links bot and Anonymous: 614 • Influenza A virus subtype H7N7 Source: https://en.wikipedia.org/wiki/Influenza_A_virus_subtype_H7N7?oldid=754833333 Contributors: DocWatson42, Dbaron, Rich Farmbrough, ZayZayEM, Neilbeach, WAS 4.250, Niayre, RDBrown, G716, Ohconfucius, WhiteCat, Dl2000, Nehrams2020, VoABot II, Ciar, Tracer9999, Gunnar Guðvarðarson, Woowah, MystBot, Addbot, AkhtaBot, Yobot, Rootmarm, Dcirovic, Jsanthara, ComfyKem, Monkbot, Emily Temple-Wood (NIOSH), Bdbdd, Bender the Bot and Anonymous: 6 • Zoonosis Source: https://en.wikipedia.org/wiki/Zoonosis?oldid=792651699 Contributors: Carey Evans, The Epopt, Mav, Malcolm Farmer, Andre Engels, Dachshund, Josh Grosse, PierreAbbat, Anthere, Tem42, Heron, Rsabbatini, Camembert, DennisDaniels, Edward, Pit~enwiki, Minesweeper, Александър, ²¹², Samhiggins2001, Wik, Thue, Rhys~enwiki, Robbot, Fredrik, RedWolf, Nilmerg, Hadal, Tsavage, Dmn, Srtxg, DocWatson42, Noririty, J. 'mach' wust, Beland, Sam Hocevar, Neutrality, Punchi, Rich Farmbrough, FT2, Bender235, CanisRufus, Kwamikagami, Davidruben, Arcadian, Nachocab, Espoo, Arthena, Rodw, Melaen, Matthias5, Versageek, Abanima, LOL, Jason Palpatine, Ikescs, SETh, Hughcharlesparker, Hovea, Marudubshinki, Graham87, BD2412, Sci guy, Rjwilmsi, Koavf, FlaBot, Stevenfruitsmaak, WriterHound, YurikBot, Hairy Dude, Hede2000, Hydrargyrum, Gaius Cornelius, Proyster, JohJak2, Droxiang~enwiki, Tweeq, Jacklee, Imz, Eskimbot, AnOddName, BiT, MartinPoulter, Sadads, Hgrosser, Scray, Eschbaumer, Jjhjjh, Kevinpurcell, Krsont, AltheaJ, Wonderstruck, Overawe, WereWolf, Clicketyclack, Kuru, Breno, Korovioff, Hu12, Patrick Schwemmer, StvnLunsford, Nydas, Cryptic C62, Liam Skoda, Myasuda, Cydebot, Querencia, Nabokov, Alaibot, Thijs!bot, Sarichkaa, Headbomb, PaperTruths, Escarbot, Gioto, Molar5, Deepakthomas, JAnDbot, Deflective, Robina Fox, .anacondabot, Lucyin, M-1, Jacobko, Scottalter, Jmauck, Tonicthebrown, Mattjs, Kimse, Boghog, Mikael Häggström, Chiswick Chap, KylieTastic, Idioma-bot, VolkovBot, Philip Trueman, PDFbot, Razzmar3, Wiae, Robert1947, ARUNKUMAR P.R, Wikipedian Person, Synthebot, Dick Shane, Doc James, SieBot, Graham Beards, WereSpielChequers, Paradoctor, Suzanne Schreck, Nix D, Oxymoron83, Lightmouse, ClueBot, Userafw, Jackollie, Niceguyedc, MosheEmes, Coinmanj, Arjayay, Carriearchdale, Tom18, Berean Hunter, DumZiBoT, ChyranandChloe, Zodon, BhagyaMani, Addbot, Tigerbreath13, DOI bot, Zorrobot, Jarble, Munimvn, Legobot, Luckas-bot, Yobot, Alexkin, AnomieBOT, VanishedUser sdu9aya9fasdsopa, Rjanag, Jim1138, Sdason, Rebeccact, Materialscientist, Citation bot, Jmarchn, ArthurBot, V35b, Xqbot, Nappyrootslistener, ChildofMidnight, Matthewmazurek, Call me Bubba, Omnipaedista, RibotBOT, Citation bot 1, Ruthiedee, Jonesey95, Tom.Reding, RedBot, MDGx, VenomousConcept, Evakfisch, Animalparty, Science2science, TypoJohnson, Jguerrag, Emble64, Foxymamma, EmausBot, ScottyBerg, AManWithNoPlan, Crm1003, Manum56, Jesanj, MoonOwl2010, JonRichfield, ClueBot NG, Ktwest, Kotiyanimr, Frietjes, Cntras, Rezabot, Widr, YFV, AAMK1227, BG19bot, CityOfSilver, ElphiBot, Gorthian, Lkahnmd, Ayeeitskimm, Smoney95, KitsuneSorrow, ComfyKem, Me, Myself, and I are Here, Sbalfour, Iztwoz, Marilyn210, Froglich, Glaisher, Mandygyrl, Gubino, Nhj78992, JulianAragonMayer, Ngongclimber, Monkbot, Missisabella, Mvolz, Spiderjerky, Pathogenic Cyanide Piggy, Mypowerpuff, UsernameTBD, L0st H0r!z0ns, Jdcomix, KasparBot, BU Rob13, Barbara (WVS), InternetArchiveBot, GreenC bot, Marissa3, Dsatgameing174, PrimeBOT, The-TDE-guy, Justine Maganira (SLU) and Anonymous: 202 • Influenza A virus subtype H1N2 Source: https://en.wikipedia.org/wiki/Influenza_A_virus_subtype_H1N2?oldid=778646537 Contributors: Hike395, Rich Farmbrough, Xezbeth, Alansohn, Rjwilmsi, Grafen, WAS 4.250, SmackBot, Niayre, Chris the speller, RDBrown, Kingdon, James McNally, G716, WhiteCat, Eivind F Øyangen, Ciar, Tracer9999, Janus Shadowsong, Gunnar Guðvarðarson, RobertFritzius, Wilson44691, Magic9mushroom, DragonBot, Alexbot, MystBot, Addbot, AkhtaBot, Jncraton, MuZemike, Citation bot, Rootmarm, Rdawg466, JayJay, Full-date unlinking bot, Random44141, Dcirovic, Helpful Pixie Bot, Kooky2, Cyberbot II, Hmainsbot1, Monkbot, GreenC bot, John P. Sadowski (NIOSH) and Anonymous: 19 • Influenza A virus subtype H9N2 Source: https://en.wikipedia.org/wiki/Influenza_A_virus_subtype_H9N2?oldid=723096398 Contributors: Rich Farmbrough, JustinWick, Rjwilmsi, WAS 4.250, Niayre, RDBrown, G716, Ciar, Tracer9999, CommonsDelinker, Gunnar Guðvarðarson, Mikiwikipikidikipedia, Peteruetz, Addbot, Edhral, Yobot, LilHelpa, Rootmarm, A.amitkumar, Abductive, Full-date unlinking bot, Dcirovic, Zammy.butt, Plantdrew, Hmainsbot1, ComfyKem, Monkbot, MansiG123 and Anonymous: 7 • Influenza A virus subtype H7N2 Source: https://en.wikipedia.org/wiki/Influenza_A_virus_subtype_H7N2?oldid=760451230 Contributors: Zundark, Eddpayne, Klemen Kocjancic, Rich Farmbrough, Woohookitty, BD2412, WAS 4.250, SmackBot, Niayre, G716, Satmandu, BetacommandBot, Oldehen, Ciar, Tracer9999, Gunnar Guðvarðarson, Kathrinthomas, Niteshift36, Addbot, Dc2000dsl, AkhtaBot, Rootmarm, Hmainsbot1, GreenC bot and Anonymous: 7 • Influenza A virus subtype H7N3 Source: https://en.wikipedia.org/wiki/Influenza_A_virus_subtype_H7N3?oldid=673886436 Contributors: Rich Farmbrough, FlaBot, WAS 4.250, Niayre, Hmains, Harangutan, G716, Ciar, Tracer9999, LordAnubisBOT, Gunnar Guðvarðarson, Anatoly.bourov, Addbot, AkhtaBot, Rootmarm, Gigemag76, SassoBot, Full-date unlinking bot, John of Reading, Emily Temple-Wood (NIOSH) and Anonymous: 3 • Influenza A virus subtype H10N7 Source: https://en.wikipedia.org/wiki/Influenza_A_virus_subtype_H10N7?oldid=723388875 Contributors: Rich Farmbrough, Rjwilmsi, Cactus.man, Wavelength, WAS 4.250, SmackBot, Niayre, Hmains, G716, Podiggady, Dl2000, Ciar, Gunnar Guðvarðarson, Anna Lincoln, Addbot, DOI bot, AkhtaBot, Citation bot, Rootmarm, Cargoking, Ricardo Ferreira de Oliveira, Citation bot 1, Alex8th1996, Dcirovic, Jsanthara, ComfyKem and Anonymous: 5 • Influenza A virus subtype H7N9 Source: https://en.wikipedia.org/wiki/Influenza_A_virus_subtype_H7N9?oldid=788411598 Contributors: The Anome, Rmhermen, Stismail, Andrewman327, Davidcannon, Johnfreez, Geraldshields11, Rjwilmsi, Yug, Vsion, Bgwhite, Wavelength, Gerbil, Gzabers, Arthur Rubin, Mardus, Espresso Addict, Nickst, Typhoonchaser, Gobonobo, Minna Sora no Shita, IronGargoyle, Efficks, Kencf0618, Goldenowl, JohnInDC, Electron9, Widefox, Yellowdesk, Inks.LWC, Cool Nerd, Drm310, Gandydancer, RP88,

144

CHAPTER 20. INFLUENZA A VIRUS SUBTYPE H7N9

Scheuerm, CommonsDelinker, Thirdright, Technopat, Koine2002, Doc James, ImageRemovalBot, Martarius, Shaded0, Ottawahitech, Light show, Lx008~enwiki, Ladsgroup, Guillaume Filion, AnomieBOT, Citation bot, Jtamad, Synaptophysin, Melmann, 333dreamer, Anna Frodesiak, JoeCo0327, January2009, FrescoBot, Pinethicket, Abductive, Jonesey95, TedderBot, FrankDev, Some Wiki Editor, Reepy1, RjwilmsiBot, Ben H Wong, EmausBot, Peaceray, Dcirovic, Makecat, Brandmeister, Donner60, Mannix Chan, ClueBot NG, Alexandru M., William H. Depperman, BG19bot, Lieutenant of Melkor, BattyBot, XyZAn, Lorzusa97, ChrisGualtieri, Shwangtianyuan, Dexbot, LightandDark2000, Mysterious Whisper, Cerabot~enwiki, Jc86035, TheLedger, ComfyKem, Lemnaminor, Lihbrowne, Alexander95015, Rogal Dorm, Flat Out, EllenCT, New worl, Dr.alaagad, Exesop, Julius Know, Teamorangered, Comp.arch, Fairymystic, LewisAHoffman, Goodforak, GvacWP, BDLaw, Snowmass1, Lizia7, M.Haffner, Gglenn59, Fafnir1, Cdiesh, Dempr, Lemiha, InternetArchiveBot, Fawad mk89, Bender the Bot, Octoberwoodland, PrimeBOT, Baptisteg and Anonymous: 108

20.12.2

Images

• File:13238_2014_111_Fig1_HTML.jpg Source: https://upload.wikimedia.org/wikipedia/commons/a/ab/13238_2014_111_Fig1_ HTML.jpg License: CC0 Contributors: http://www.ncbi.nlm.nih.gov/pubmed/25384439 Original artist: Sun Y1, Liu J. • File:165-WW-269B-11-trolley-l.jpg Source: https://upload.wikimedia.org/wikipedia/commons/0/06/165-WW-269B-11-trolley-l.jpg License: Public domain Contributors: ? Original artist: ?

• File:165-WW-269B-25-police-l.jpg Source: https://upload.wikimedia.org/wikipedia/commons/c/c2/165-WW-269B-25-police-l.jpg License: Public domain Contributors: ? Original artist: ?

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20.12.3

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