8 www.eurosurveillance.org

Review articles

Influenza at the animal–human interface: a review of the literature for virological evidence of human infection with swine or avian influenza viruses other than A(H5N1)

G S Freidl1,2, A Meijer1, E de Bruin1, M de Nardi3, O Munoz3, I Capua3, A C Breed4, K Harris4, A Hill4,5, R Kosmider4, J Banks4, S von Dobschuetz5,6, K Stark5, B Wieland5, K Stevens5, S van der Werf7, V Enouf7, K van der Meulen8, K Van Reeth8, G Dauphin6, M Koopmans (marion.koopmans@rivm.nl)1,2, FLURISK Consortium91. National Institute for Public Health and the Environment (RIVM), Centre for Infectious Diseases Research, Diagnostics and

Screening (IDS), Bilthoven, the Netherlands2. Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands3. Istituto Zooprofilattico Sperimentale delle Venezie (IZSVe), OIE/FAO and National Reference Laboratory for Newcastle Disease

and Avian Influenza, OIE Collaborating Centre for Diseases at the Human–Animal Interface, Padova, Italy4. Animal Health and Veterinary Agency (AHVLA), Surrey, United Kingdom5. Royal Veterinary College (RVC), London, United Kingdom6. United Nations Food and Agricultural Organization (FAO), Rome, Italy7. Institut Pasteur, Paris, France8. Universtiy of Ghent, Ghent, Belgium9. http://www.izsvenezie.it/index.php?option=com_content&view=article&id=1203&Itemid=629

Citation style for this article: Freidl GS, Meijer A, de Bruin E, de Nardi M, Munoz O, Capua I, Breed AC, Harris K, Hill A, Kosmider R, Banks J, von Dobschuetz S, Stark K, Wieland B, Stevens K, van der Werf S, Enouf V, van der Meulen K, Van Reeth K, Dauphin G, Koopmans M, FLURISK Consortium. Influenza at the animal–human interface: a review of the literature for virological evidence of human infection with swine or avian influenza viruses other than A(H5N1). Euro Surveill. 2014;19(18):pii=20793. Available online: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20793

Article submitted on 01 August 2013/ published on 08 May 2014

Factors that trigger human infection with animal influ-enza virus progressing into a pandemic are poorly understood. Within a project developing an evidence-based risk assessment framework for influenza viruses in animals, we conducted a review of the literature for evidence of human infection with animal influenza viruses by diagnostic methods used. The review cov-ering Medline, Embase, SciSearch and CabAbstracts yielded 6,955 articles, of which we retained 89; for influenza A(H5N1) and A(H7N9), the official case counts of t he World Health Organization were used. An additional 30 studies were included by scan-ning the reference lists. Here, we present the findings for confirmed infections with virological evidence. We found reports of 1,419 naturally infected human cases, of which 648 were associated with avian influenza virus (AIV) A(H5N1), 375 with other AIV subtypes, and 396 with swine influenza virus (SIV). Human cases naturally infected with AIV spanned haemaggluti-nin subtypes H5, H6, H7, H9 and H10. SIV cases were associated with endemic SIV of H1 and H3 subtype descending from North American and Eurasian SIV lin-eages and various reassortants thereof. Direct expo-sure to birds or swine was the most likely source of infection for the cases with available information on exposure.

IntroductionInfluenza virus type A, a member of the fam-ily Orthomyxoviridae, is an enveloped virus with a

negative-sense, single-stranded RNA genome organ-ised in eight gene segments, which encode at least eleven proteins. Antigenic and genetic diversity of two surface glycoproteins, haemagglutinin (HA) and neu-raminidase (NA), is used to classify type A influenza viruses into subtypes; 18 HA and 11 NA subtypes are known to date [1-5]. Water- and shorebirds were iden-tified as reservoirs harbouring all subtypes, except A(H17N10) and A(H18N11) of which RNA was recently detected in bats from Guatemala and Peru, respectively [2,3]. Reservoir animals typically do not display symp-toms. In contrast, the diversity of influenza viruses in mammalian hosts is limited to specific subtypes. Human-adapted seasonal influenza viruses since the beginning of the 20th century have had HA subtypes H1, H2 and H3, combined with NA subtypes N1 and N2.

The segmented nature of the genome facilitates the exchange of genetic material if a host is co-infected with two genetically different type A influenza viruses. This reassortment process, also known as antigenic shift if it involves the gene segment encoding the HA, can result in the generation of viruses with surface antigens against which the human population may not have pre-existing, protective antibodies. Additional flexibility is conferred by the accumulation of muta-tions during replication, potentially resulting in amino acid substitutions that can affect pre-existing immunity if the HA is involved (antigenic drift), host range, viru-lence, and other factors [6]. If this results in sustained

9www.eurosurveillance.org

human-to-human transmission of a virus against which a large proportion of the world’s human population is immunologically naïve a pandemic can develop result-ing in a large number of human cases occurring simul-taneously worldwide [7,8]. Such novel introductions of reassorted viruses were at the root of four influ-enza pandemics in the last 100 years, and claimed the lives of millions of people, namely the ‘Spanish flu’ A(H1N1) in 1918, the ‘Asian flu’ A(H2N2) in 1957, the ‘Hong Kong flu’ A(H3N2) in 1968, and the recent pandemic caused by influenza A(H1N1)pdm09 in 2009 [9,10]. Influenza A(H1N1)pdm09 has replaced previous human seasonal A(H1N1) viruses [11] and, together with A(H3N2) and influenza B viruses, has been causing seasonal influenza epidemics in humans since 2009. With the emergence of the influenza A(H3N2) pandemic in 1968, influenza A(H2N2) viruses ceased to circulate in humans, but H2 subtypes are still present in birds

and were also recently isolated from diseased swine [12,13].

The factors that determine whether an animal influenza virus may acquire the ability to efficiently spread among humans are poorly understood [14]. Reassortment is not a necessary prerequisite for human infection, and there is clear documentation of direct transmission and human disease caused by animal influenza viruses, in particular avian (AIV) and swine (SIV) influenza viruses , such as AIV A(H5N1), A(H9N2) and various H7 sub-types, as well as European avian-like SIV A(H1N1) [15-22]. Early detection and in-depth investigation of such events may provide clues for (future) risk assessment of animal-to-human transmissions.

This review was conducted under the framework of the FLURISK project funded by the European Food Safety

Figure 1Search strategy for the literature review on animal influenza A virus infections in humans

AV: avian; SW: swine; EQ: equine; H: human.Selection step 1 extracted studies indicating information on human infection with animal influenza viruses in title and abstract. Selection

step 2 excluded papers as specified in Inclusion and exclusion criteria. Seven articles described virological as well as serological evidence of infection. These references were counted once in the total count and listed twice in the row ’Articles according to type of evidence’. The virological evidence of human infection is presented in this paper. The indirect serological evidence will be described elsewhere.

Complete search output:

Total after selection criterion 1:

Total after selection criterion 2:

Articles retrieved in addition to literature search:

19 AV-H8 SW-H3 EQ-H

TOTAL REFERENCES

INCLUDED: 119

Medline

4,905

185 AV-H86 SW-H

35 AV-H45 SW-H1 EQ-H

Embase

631

21 AV-H2 SW-H

0 AV-H1 SW-H

SciSearch

553

29 AV-H3 SW-H

3 AV-H0 SW-H

CabAbstracts

866

23 AV-H6 SW-H

2 AV-H2 SW-H

Virologicalevidence: 59

Serological evidence: 60

No serologic evidence found: 7

Articles according to type of evidence:

10 www.eurosurveillance.org

Tabl

e 1a

Vir

olog

ical

evi

denc

e of

hum

an in

fect

ion

with

avi

an in

fluen

za A

vir

uses

, exc

ludi

ng h

igh

path

ogen

icity

A(H

5N1)

Year

(Tes

ted)

a /co

nfirm

ed c

ases

Subt

ype

Sym

ptom

sM

etho

dPa

tient

info

rmat

ion

and

natu

re o

f exp

osur

eLo

catio

nRe

fere

nce

1959

1/1

H7N7

Unkn

own

Cultu

re in

em

bryo

nate

d ch

icke

n eg

gs; s

ubty

ping

with

spe

cific

an

tiser

a

Sour

ce u

nkno

wn;

isol

ated

from

pat

ient

su

ffer

ing

from

hep

atiti

sUn

ited

Stat

esCa

mpb

ell e

t al.

1970

[52]

1977

1/1

H7N7

Kera

toco

njun

ctiv

itsCu

lture

in e

mbr

yona

ted

chic

ken

eggs

Labo

rato

ry te

chni

cian

acc

iden

tally

infe

cted

w

ith fo

wl p

lagu

eM

elbo

urne

, Au

stra

liaTa

ylor

and

Tur

ner 1

977

[53]

1979

1/1

H7N7

Conj

unct

iviti

sVi

rus

isol

atio

n

Sour

ce: e

xper

imen

tally

infe

cted

har

bour

sea

l; Pr

ior t

o th

at c

ase,

four

add

ition

al p

ossi

ble

case

s w

ho p

erfo

rmed

aut

opsi

es o

n in

fect

ed

harb

our s

eals

sho

wed

con

junc

tiviti

s bu

t viru

s is

olat

ion

was

not

per

form

ed

Mas

sach

uset

ts,

Unite

d St

ates

Web

ster

et a

l. 19

81 [5

4,60

]

1991

11/2

14/3

15/6

H6N1

H4N8

H10N

7

Rang

ing

from

re

spira

tory

an

d so

me

cons

titut

iona

l sy

mpt

oms

to n

o sy

mpt

oms

Cultu

re in

em

bryo

nate

d ch

icke

n eg

gsEx

perim

enta

l inf

ectio

nUn

ited

Stat

esBe

are

and

Web

ster

199

1 [7

5]

1996

1/1

LP H

7N7

Conj

unct

iviti

sCu

lture

on

rhes

us m

onke

y ki

dney

ce

llsSo

urce

: str

aw c

onta

min

ated

with

duc

k fa

eces

Unite

d Ki

ngdo

mKu

rtz

et a

l. 19

96 [5

5]

1998

5/5

H9N2

Acut

e re

spira

tory

sy

mpt

oms

Cultu

re in

em

bryo

nate

d ch

icke

n eg

gs, H

I an

d NI

ass

ayPo

ultr

y co

ntac

tSh

anto

u (n

=3)

, Sh

aogu

an (n

=2),

Chin

aGu

o et

al.

1999

[70]

1999

2/2

H9N2

Mild

ILI

Cultu

red

by W

HO re

fere

nce

labo

rato

ry4-

and

1-y

ear-

old

girl;

one

pat

ient

pro

babl

y ha

d co

ntac

t with

live

pou

ltry

Hong

Kon

gbPe

iris

et a

l. 19

99 [1

6]

1999

1/1

H9N2

Feve

r, co

ugh,

br

onch

itis

MDC

K ce

ll cu

lture

, HI

and

NI-a

ssay

2-ye

ar-o

ld fe

mal

e w

ith p

roba

ble

poul

try

cont

act

Guan

gzho

u,

Chin

aGu

o et

al.

2000

[71]

2003

453/

89 (i

nclu

ding

on

e fa

talit

y)HP

H7N

7

Conj

unct

iviti

s, IL

I (fa

talit

y: fe

ver,

pneu

mon

ia,

mul

ti-or

gan

failu

re, r

espi

rato

ry

insu

ffic

ienc

y)

Cell

cultu

re (u

sed

for t

he fi

rst

25 c

onfir

med

cas

es, a

fter

war

ds

RT-P

CR u

sed

as s

cree

ning

m

etho

d), t

yped

and

sub

type

d by

HI

ass

ay (t

urke

y RB

C), R

T-PC

R

Poul

try

fam

er a

nd fa

mily

, cul

lers

, ve

terin

aria

ns, m

edic

al p

erso

nnel

, oth

ers

Geld

erla

nd,

Nort

h Br

aban

t, Li

mbu

rg, T

he

Neth

erla

nds

Koop

man

s et

al.

2004

; Fou

chie

r et

al.

2004

[17,

56]

2003

1/1

H9N2

Mild

ILI

Cultu

re in

em

bryo

nate

d ch

icke

n eg

gs. H

I and

NI a

ssay

, se

quen

cing

No h

isto

ry o

f con

tact

with

pou

ltry

Hong

Kon

gbBu

tt e

t al.

2005

[66]

2004

2/2

LP a

nd H

P H7

N3

Conj

unct

iviti

s,

mild

ILI

RT-P

CR, c

ell c

ultu

re, s

eque

ncin

gO

ccup

atio

nal e

xpos

ure

to in

fect

ed p

oultr

y (V

eter

inar

ian,

gen

eral

wor

ker)

Briti

sh

Colu

mbi

a,

Cana

daTw

eed

et a

l. 20

04 [1

8]

Whe

re m

ore

than

one

hum

an c

ase

is s

tate

d, d

iagn

ostic

test

s w

ere

perf

orm

ed fo

r all

case

s as

sta

ted

in th

e M

etho

ds s

ectio

n, u

nles

s ot

herw

ise

spec

ified

.

HI: h

aem

aggl

utin

atio

n in

hibi

tion;

HP:

hig

hly

path

ogen

ic; I

LI: i

nflu

enza

-like

illn

ess,

LP:

low

pat

hoge

nic;

MDC

K: M

adin

Dar

by c

anin

e ki

dney

; MN:

mic

rone

utra

lisat

ion;

n.a

.: no

t app

licab

le; N

I: ne

uram

inid

ase

inhi

bitio

n; P

CR: p

olym

eras

e ch

ain

reac

tion;

RBC

: red

blo

od c

ells

; RT-

PCR:

reve

rse

tran

scrip

tion

poly

mer

ase

chai

n re

actio

n; r

tRT-

PCR,

real

-tim

e re

vers

e tr

ansc

riptio

n po

lym

eras

e ch

ain

reac

tion;

WHO

: Wor

ld

Heal

th O

rgan

izat

ion.

a In

mos

t cas

es th

e nu

mbe

r tes

ted

refle

cts

only

the

conf

irmed

cas

es re

port

ed in

the

revi

ewed

pap

er w

here

the

auth

ors

did

not r

epor

t on

the

true

num

ber o

f sus

pect

ed c

ases

test

ed.

b Ho

ng K

ong

Spec

ial A

dmin

istr

ativ

e Re

gion

(SAR

), Ch

ina.

11www.eurosurveillance.org

Tabl

e 1b

Vir

olog

ical

evi

denc

e of

hum

an in

fect

ion

with

avi

an in

fluen

za A

vir

uses

, exc

ludi

ng h

igh

path

ogen

icity

A(H

5N1)

Year

(Tes

ted)

a /co

nfirm

ed c

ases

Subt

ype

Sym

ptom

sM

etho

dPa

tient

info

rmat

ion

and

natu

re o

f ex

posu

reLo

catio

nRe

fere

nce

2004

2/2

H10N

7'Il

lnes

s' (n

ot

furt

her s

peci

fied)

Viru

s is

olat

ion

Infa

nts

with

indi

rect

con

tact

to

poul

try

(fath

er o

f one

is p

oultr

y m

erch

ant)

Egyp

tPa

n Am

eric

an H

ealth

O

rgan

izat

ion,

200

4 [7

6]

2006

1/1

LP H

7N3

Conj

unct

iviti

sPC

R (n

o se

rolo

gica

l co

nfirm

atio

n re

port

ed)

Sour

ce: i

nfec

ted

poul

try

Unite

d Ki

ngdo

mNg

uyen

-Van

-Tam

et a

l. 20

06 [5

7]

2007

4/4

LP H

7N2

Conj

unct

iviti

s, IL

ICo

nfirm

ed in

fluen

za A

c So

urce

: inf

ecte

d po

ultr

yUn

ited

King

dom

Edi

toria

l tea

m, 2

007

[58]

2007

1/1

H9N2

Mild

ILI

Info

rmat

ion

not a

vaila

ble

Sour

ce: p

roba

bly

a bi

rd m

arke

tHo

ng K

ongb

Un

ited

Stat

es C

ente

rs fo

r Dis

ease

Co

ntro

l and

Pre

vent

ion

200

8 [6

7]

2008

, 20

092/

2dH9

N2IL

I, vo

miti

ng,

dysp

noea

Rapi

d te

st, R

T-PC

R;

MDC

K ce

ll cu

lture

; im

mun

oflu

ores

cenc

e as

say;

seq

uenc

ing

Imm

unoc

ompr

omis

ed p

erso

ns

(with

and

with

out p

oultr

y co

ntac

t)Sh

enzh

en a

nd H

ong

Kong

bCh

eng

et a

l., 2

011

[68]

2010

7/ 2

H10N

7Co

njun

ctiv

itis,

rh

inor

rhoe

a, s

ore

thro

at

PCR,

par

tial s

eque

ncin

g of

ha

emag

glut

inin

gen

es (n

o vi

rus

cultu

re);

no e

vide

nce

of s

eroc

onve

rsio

n

Abat

toir

wor

kers

exp

osed

to

infe

cted

pou

ltry

New

Sou

th W

ales

, Aus

tral

iaAr

zey

et a

l. 20

12 [2

0]

2011

1/1

H9N2

eFe

ver,

head

ache

, ru

nny

nose

, cou

gh,

snee

zing

Part

ial s

eque

ncin

g51

-mon

th-o

ld fe

mal

e ex

pose

d to

sl

augh

tere

d ch

icke

nsBa

ngla

desh

Inte

rnat

iona

l Cen

tre

for

Diar

rhoe

al D

isea

se R

esea

rch,

Ba

ngla

desh

201

1 [6

9]

2012

2/2

HP H

7N3

Conj

unct

iviti

s; n

o fe

ver o

r res

pira

tory

sy

mpt

oms

rtRT

-PCR

(n=2

), cu

lture

in

em

bryo

nate

d ch

icke

n eg

gs (n

=1),

sequ

enci

ng

(n=1

)

32- a

nd 5

2-ye

ar-o

ld fe

mal

e/m

ale

poul

try

wor

ker e

xpos

ed to

infe

cted

po

ultr

yJa

lisco

, Mex

ico

Unite

d St

ates

Cen

ters

for D

isea

se

Cont

rol a

nd P

reve

ntio

n 20

12 [5

9]

2013

251/

251

(incl

udin

g 56

fata

litie

s)f

LP H

7N9

Rang

ing

from

m

ild s

ympt

oms

and

reco

very

to

seve

re re

spira

tory

sy

mpt

oms

and

deat

h

Viru

s is

olat

ion,

PCR

Sour

ce: n

ot s

peci

fied

Shan

ghai

, Bei

jing,

Hon

g Ko

ngb ,

Anhu

i, Fu

jian,

Jian

gsu,

Jian

gxi,

Guan

gdon

g, G

uizh

ou, H

enan

, Hu

nan,

Heb

ei,

Shan

dong

, Zhe

ijang

, pro

vinc

es,

Chin

a; tw

o ca

ses

wer

e im

port

ed to

Ta

iwan

from

mai

nlan

d Ch

ina

Euro

pean

Cen

tre

for D

isea

se

Prev

entio

n an

d Co

ntro

l upd

ated

ra

pid

risk

asse

ssm

ent [

23]

Whe

re m

ore

than

one

hum

an c

ase

is s

tate

d, d

iagn

ostic

test

s w

ere

perf

orm

ed fo

r all

case

s as

sta

ted

in th

e M

etho

ds s

ectio

n, u

nles

s ot

herw

ise

spec

ified

.

HI: h

aem

aggl

utin

atio

n in

hibi

tion;

HP:

hig

hly

path

ogen

ic; I

LI: i

nflu

enza

-like

illn

ess,

LP:

low

pat

hoge

nic;

MDC

K: M

adin

Dar

by c

anin

e ki

dney

; MN:

mic

rone

utra

lisat

ion;

n.a

.: no

t app

licab

le; N

I: ne

uram

inid

ase

inhi

bitio

n; P

CR: p

olym

eras

e ch

ain

reac

tion;

RBC

: red

blo

od c

ells

; RT-

PCR:

reve

rse

tran

scrip

tion

poly

mer

ase

chai

n re

actio

n; r

tRT-

PCR,

real

-tim

e re

vers

e tr

ansc

riptio

n po

lym

eras

e ch

ain

reac

tion;

WHO

: Wor

ld

Heal

th O

rgan

izat

ion.

a In

mos

t cas

es th

e nu

mbe

r tes

ted

refle

cts

only

the

conf

irmed

cas

es re

port

ed in

the

revi

ewed

pap

er w

here

the

auth

ors

did

not r

epor

t on

the

true

num

ber o

f sus

pect

ed c

ases

test

ed.

b Ho

ng K

ong

Spec

ial A

dmin

istr

ativ

e Re

gion

(SAR

), Ch

ina.

c Au

thor

s as

sum

e th

at in

fluen

za A

-pos

itive

test

sug

gest

s in

fluen

za A

(H7N

2) in

fect

ion

beca

use

of c

lose

tem

pora

l-spa

tial l

inks

with

influ

enza

A(H

7N2)

-infe

cted

pou

ltry

and

low

sea

sona

l inf

luen

za a

ctiv

ity

at

that

tim

e.d

One

pat

ient

and

her

asy

mpt

omat

ic h

usba

nd s

how

ed a

titr

e of

80

in th

e m

icro

neut

ralis

atio

n as

say,

thre

e an

d tw

o w

eeks

aft

er o

nset

of i

llnes

s re

spec

tivel

y.e

Belo

ngs

to G

1 lin

eage

.f

At th

e tim

e of

writ

ing

(31

Janu

ary

2014

) the

num

ber o

f cas

es w

as s

till o

n th

e in

crea

se.

12 www.eurosurveillance.org

Tabl

e 1c

Vir

olog

ical

evi

denc

e of

hum

an in

fect

ion

with

avi

an in

fluen

za A

vir

uses

, exc

ludi

ng h

igh

path

ogen

icity

A(H

5N1)

Year

(Tes

ted)

a /co

nfirm

ed c

ases

Subt

ype

Sym

ptom

sM

etho

dPa

tient

info

rmat

ion

and

natu

re o

f ex

posu

reLo

catio

nRe

fere

nce

2013

1/1

H6N1

ILI,

mild

pn

eum

onia

Viru

s is

olat

ion,

full

geno

me

sequ

enci

ng20

-yea

r-ol

d fe

mal

e; n

o ex

posu

re

to p

oultr

yTa

iwan

Cent

ers

for D

isea

se C

ontr

ol 2

013

[79]

2013

1/1

H10N

8Se

vere

pne

umon

ia

and

deat

hNo

t spe

cifie

d73

-yea

r-ol

d im

mun

ocom

prom

ised

fe

mal

e w

ith u

nder

lyin

g ill

ness

; ex

pose

d to

live

pou

ltry

Jiang

xi p

rovi

nce,

Chi

naPr

oMED

201

3 [7

7]

2013

1/1

H9N2

Ches

t inf

ectio

n,

low

feve

r, ch

ills

and

coug

hNo

t spe

cifie

d86

-yea

r-ol

d m

ale

with

und

erly

ing

illne

ss; n

o re

cent

pou

ltry

expo

sure

Shen

zhen

/Hon

g Ko

ngb

ProM

ED 2

013

[72]

2014

1/1

H9N2

Illne

ss (n

ot

furt

her s

peci

fied)

; re

cove

red

Not s

peci

fied

7-ye

ar-o

ld m

ale

with

pou

ltry

expo

sure

Huna

n, C

hina

ProM

ED, 2

014

[73]

2014

1/1

H10N

8

Sore

thro

at,

dizz

ines

s, lo

ss o

f st

reng

th, s

ever

e pn

eum

onia

g

Not s

peci

fied

55-y

ear-

old

fem

ale;

vis

ited

agric

ultu

ral m

arke

tJia

ngxi

, Chi

naPr

oMED

201

4 [7

8]

Tota

l78

4/38

6 (3

75 w

hen

expe

rimen

tally

infe

cted

hum

an c

ases

are

sub

trac

ted)

29

Whe

re m

ore

than

one

hum

an c

ase

is s

tate

d, d

iagn

ostic

test

s w

ere

perf

orm

ed fo

r all

case

s as

sta

ted

in th

e M

etho

ds s

ectio

n, u

nles

s ot

herw

ise

spec

ified

.

HI: h

aem

aggl

utin

atio

n in

hibi

tion;

HP:

hig

hly

path

ogen

ic; I

LI: i

nflu

enza

-like

illn

ess,

LP:

low

pat

hoge

nic;

MDC

K: M

adin

Dar

by c

anin

e ki

dney

; MN:

mic

rone

utra

lisat

ion;

n.a

.: no

t app

licab

le; N

I: ne

uram

inid

ase

inhi

bitio

n; P

CR: p

olym

eras

e ch

ain

reac

tion;

RBC

: red

blo

od c

ells

; RT-

PCR:

reve

rse

tran

scrip

tion

poly

mer

ase

chai

n re

actio

n; r

tRT-

PCR,

real

-tim

e re

vers

e tr

ansc

riptio

n po

lym

eras

e ch

ain

reac

tion;

WHO

: Wor

ld

Heal

th O

rgan

izat

ion.

a In

mos

t cas

es th

e nu

mbe

r tes

ted

refle

cts

only

the

conf

irmed

cas

es re

port

ed in

the

revi

ewed

pap

er w

here

the

auth

ors

did

not r

epor

t on

the

true

num

ber o

f sus

pect

ed c

ases

test

ed.

b Ho

ng K

ong

Spec

ial A

dmin

istr

ativ

e Re

gion

(SAR

), Ch

ina.

g At

the

time

of w

ritin

g (3

1 Ja

nuar

y 20

14) t

he p

atie

nt w

as h

ospi

talis

ed a

nd in

crit

ical

con

ditio

n.

13www.eurosurveillance.org

Tabl

e 2a

Vir

olog

ical

evi

denc

e of

hum

an in

fect

ion

with

swin

e in

fluen

za A

vir

uses

Year

(Tes

ted)

a /co

nfirm

ed

case

sSu

btyp

eSy

mpt

oms

Met

hod

Patie

nt in

form

atio

n an

d na

ture

of e

xpos

ure

Loca

tion

Refe

renc

e

Not

spec

ified

7/3b

13/2

swH3

N2c

clH1

N1M

ild: c

oryz

aVi

rus

isol

atio

n (n

ot fu

rthe

r sp

ecifi

ed)

Expe

rimen

tally

infe

cted

hum

ans

(intr

anas

al, 1

05.5

egg

-infe

ctiv

e do

ses)

Not s

peci

fied

(a

ccor

ding

to

auth

or a

ffili

atio

ns:

Engl

and)

Bear

e et

al.

1972

[45]

1974

1/1

(fata

l)sw

H1N1

dPn

eum

onia

Cultu

re o

n W

I-38-

, HeL

a- a

nd

rhes

us-m

onke

y ki

dney

-cel

ls,

inoc

ulat

ion

of m

ice;

HI a

ssay

(g

uine

a pi

g RB

C)

16-y

ear-

old

Hodg

kin’

s di

seas

e pa

tient

livi

ng o

n sw

ine

farm

Min

neso

ta, U

nite

d St

ates

Smith

et a

l. 19

76 [4

2]

1976

20/5

(inc

ludi

ng

1 fa

talit

y)sw

H1N1

Acut

e re

spira

tory

ill

ness

, pne

umon

iaEm

bryo

nate

d ch

icke

n eg

g cu

lture

, HA

assa

yPr

evio

usly

hea

lthy

sold

iers

with

out k

now

n ex

posu

re to

sw

ine

New

Jers

ey, U

nite

d St

ates

Gayd

os e

t al.

1977

[28]

1976

1/1

swH1

N1e

Mild

ILI

Viru

s is

olat

ion;

HI a

ssay

22-y

ear-

old

swin

e w

orke

r exp

osed

to il

l, in

fluen

za-p

ositi

ve s

win

eW

isco

nsin

, Uni

ted

Stat

esUn

ited

Stat

es C

ente

rs fo

r Dis

ease

Co

ntro

l and

Pre

vent

ion

1976

[29]

1976

1/1

swH1

N1f

ILI

Viru

s is

olat

ion;

HI a

ssay

13-y

ear-

old

boy

livin

g on

sw

ine

farm

Wis

cons

in, U

nite

d St

ates

Unite

d St

ates

Cen

ters

for D

isea

se

Cont

rol a

nd P

reve

ntio

n 19

76 [3

0]19

79/8

02/

2sw

H1N1

fIL

IRh

esus

mon

key

kidn

ey c

ell

cultu

re; e

mbr

yona

ted

chic

ken

egg

cultu

re; H

I ass

ay

20-y

ear-

old

fell

ill a

fter

clo

se c

onta

ct w

ith

swin

e; 6

-yea

r-ol

d vi

sito

r of l

ives

tock

sho

w

with

out d

irect

con

tact

with

sw

ine

Texa

s, U

nite

d St

ates

Dacs

o et

al.

1984

[31]

1982

1/1

(fata

l)sw

H1N1

fPn

eum

onia

Cyno

mol

gus

mon

key

kidn

ey

cells

; em

bryo

nate

d ch

icke

n eg

g cu

lture

; RN

A-ol

igon

ucle

otid

e m

appi

ng

4-ye

ar-o

ld fe

mal

e le

ukem

ia p

atie

nt; n

o kn

own

expo

sure

to s

win

eNe

vada

, Uni

ted

Stat

esPa

tria

rca

et a

l. 19

84 [3

2]

1983

3/3

swH1

N1In

form

atio

n no

t av

aila

ble

Isol

atio

n65

-yea

r-ol

d m

ale

with

occ

upat

iona

l exp

osur

e to

sw

ine;

10-

year

old

fem

ale

and

27-y

ear-

old

mal

e w

ith u

nkno

wn

expo

sure

to s

win

e

Russ

iaCh

uvak

ova

et a

l. 19

85 [2

7]

1986

a) 1

/1b)

2/2

swH1

N1g,

ha)

Pne

umon

iab)

Mild

ILI

a) V

ario

us c

ell c

ultu

res;

em

bryo

nate

d ch

icke

n eg

g cu

lture

; HI a

nd N

I ass

ay

b) V

ario

us c

ell c

ultu

res;

HI a

ssay

, co

mpl

emen

t fix

atio

n as

say

a) 2

9-ye

ar-o

ld fa

rmer

exp

osed

to il

l, in

fluen

za-

infe

cted

pig

sb)

50-

year

-old

em

ploy

ee e

xpos

ed to

ill,

influ

enza

-infe

cted

pig

s, a

nd 3

-yea

r-ol

d w

ith n

o kn

own

cont

act w

ith p

igs

a) T

he N

ethe

rlan

ds

b) S

witz

erla

nd

De Jo

ng e

t al 1

988

[33]

Whe

re m

ore

than

one

hum

an c

ase

is s

tate

d, d

iagn

ostic

test

s w

ere

perf

orm

ed fo

r all

case

s as

sta

ted

in th

e M

etho

ds s

ectio

n, u

nles

s ot

herw

ise

spec

ified

.

BSL:

bio

safe

ty le

vel;

cl: c

lass

ical

sw

ine

linea

ge; H

A: h

aem

aggl

utin

atio

n; H

eLa:

Hen

riett

e La

cks

cerv

ical

can

cer c

ells

; HI:

haem

aggl

utin

atio

n in

hibi

tion;

ILI:

Influ

enza

-like

illn

ess;

MAb

: mon

oclo

nal a

ntib

odie

s;

MDC

K: M

adin

Dar

by c

anin

e ki

dney

; MN:

mic

rone

utra

lisat

ion;

n.a

.: no

t app

licab

le; N

I: ne

uram

inid

ase

inhi

bitio

n; R

BC: r

ed b

lood

cel

ls; R

T-PC

R: re

vers

e tr

ansc

ripta

se p

olym

eras

e ch

ain

reac

tion;

rtR

T-PC

R:

real

-tim

e re

vers

e tr

ansc

ripta

se p

olym

eras

e ch

ain

reac

tion;

sw

: sw

ine;

Sw

L: s

win

e-lik

e; tr

: trip

le re

asso

rtan

t; W

I-38:

hum

an e

mbr

yo lu

ng fi

brob

last

.a

In m

ost c

ases

the

num

ber t

este

d re

flect

s on

ly th

e co

nfirm

ed c

ases

repo

rted

in th

e re

view

ed p

aper

whe

re th

e au

thor

s di

d no

t rep

ort o

n th

e tr

ue n

umbe

r of s

uspe

cted

cas

es te

sted

.b

Num

ber o

f hum

ans

from

who

m v

irus

coul

d be

reis

olat

ed.

c Sw

ine/

Taiw

an/7

310/

70 re

late

d to

A/H

ong

Kong

/1/6

8.d

Nam

ed A

/May

o Cl

inic

/103

/74,

inhi

bite

d by

ant

iser

a ag

ains

t A/s

win

e/19

76/3

1 an

d A/

swin

e/W

isco

nsin

/67.

e A/

New

Jers

ey/8

/76.

f A/

New

Jers

ey/8

/76-

like

influ

enza

viru

s.g

A/Ne

ther

land

s/38

6/86

, A/G

enev

a/55

21/8

6, A

/Gen

eva/

5200

/86.

h Hi

ghes

t hom

olog

y w

ith E

urop

ean

swin

e-in

fluen

za v

iruse

s.

14 www.eurosurveillance.org

Tabl

e 2b

Vir

olog

ical

evi

denc

e of

hum

an in

fect

ion

with

swin

e in

fluen

za A

vir

uses

Year

(Tes

ted)

a /co

nfirm

ed

case

sSu

btyp

eSy

mpt

oms

Met

hod

Patie

nt in

form

atio

n an

d na

ture

of e

xpos

ure

Loca

tion

Refe

renc

e

1988

1/1

(fata

l)i

swLH

1N1

Pneu

mon

iaRN

A fin

gerp

rintin

g; p

artia

l seq

uenc

ing;

32

-yea

r-ol

d pr

egna

nt w

oman

exp

osed

to p

igs

at

coun

ty fa

ir sh

owin

g IL

IW

isco

nsin

, Uni

ted

Stat

esM

cKin

ney

et a

l. 19

90 [3

4]

1991

1/1

(fata

l)sw

LH1N

1jPn

eum

onia

Rhes

us m

onke

y ki

dney

cel

l cul

ture

; em

bryo

nate

d ch

icke

n eg

g cu

lture

; rt

RT-P

CR; o

ligon

ucle

otid

e m

appi

ng; H

I an

d NI

ass

ay; s

eque

ncin

g; e

xper

imen

tal

infe

ctio

n of

sw

ine

27-y

ear-

old

anim

al c

aret

aker

exp

osed

to s

win

e sh

owin

g re

spira

tory

sym

ptom

sM

aryl

and,

Uni

ted

Stat

esW

entw

orth

et a

l. 19

94 [3

5]

1992

/ 93

2/2

swH3

N2k

Mild

resp

irato

ry

sym

ptom

sVi

rus

isol

atio

n; H

I ass

ay; s

eque

ncin

g1-

and

2-y

ear-

old

with

no

know

n ex

posu

re to

sw

ine

The

Neth

erla

nds

Claa

s et

al.

1994

[41]

1993

1/1

swH1

N1h

Pneu

mon

iaTe

rtia

ry m

onke

y ki

dney

cel

l cul

ture

; RT

-PCR

; im

mun

oflu

ores

cenc

e as

say

on

MDC

K ce

lls; s

eque

ncin

g; H

I ass

ay

5-ye

ar-o

ld li

ving

on

swin

e fa

rm (h

ealth

sta

tus

of

swin

e no

t kno

wn)

The

Neth

erla

nds

Rim

mel

zwaa

n et

al.

2001

[36]

1994

2/2

swH1

N1l

Mild

ILI

Embr

yona

ted

chic

ken

egg

cultu

re;

MDC

K ce

ll cu

lture

; HI-

and

NI-a

ssay

; se

quen

cing

; RT-

PCR

and

othe

r PCR

-ty

pes;

Eex

perim

enta

l inf

ectio

n of

sw

ine

39- a

nd 3

0-ye

ar-o

ld B

SL3

labo

rato

ry w

orke

rs

expo

sed

to in

fluen

za-in

fect

ed p

igs

Wis

cons

in, U

nite

d St

ates

Wen

twor

th e

t al.

1997

[37]

1995

1/1

(fata

l)sw

H1N1

Seve

re p

neum

onia

Viru

s is

olat

ion

and

subt

ypin

g37

-yea

r-ol

d he

alth

y w

oman

wor

king

on

pig

farm

(h

ealth

sta

tus

of p

igs

unkn

own)

Min

neso

ta, U

nite

d St

ates

Kim

ura

et a

l. 19

98 [3

8]

1999

1/1m

H3N2

nM

ild IL

IM

DCK

cell

cultu

re; H

I an

d NI

ass

ay;

RT-P

CR; s

eque

ncin

g10

-mon

th-o

ld g

irl (n

eith

er s

he n

or h

er fa

mily

ha

d re

cent

con

tact

with

pig

s)Ho

ng K

ongo

Gr

egor

y et

al.

2001

[39]

2002

1/1

H1N1

pIL

IM

DCK

cell

cultu

re; H

I ass

ay (a

lso

sero

logi

cally

con

firm

ed b

y HI

)50

-yea

r-ol

d fa

rmer

(pos

sibl

y fr

om p

igs

show

ing

resp

irato

ry s

ympt

oms)

Switz

erla

ndGr

egor

y et

al.

2003

[21]

2004

, 20

051/

11/

1H1

N2q

H1N1

qM

ild IL

IM

DCK

cell

cultu

re; H

A as

say

(turk

ey

RBC)

; HI a

ssay

r ; ra

pid

test

ss; R

T-PC

R;

sequ

enci

ng

25- a

nd 4

-yea

r-ol

d m

ale;

nei

ther

had

dire

ct

cont

act t

o pi

gs (i

ncid

enta

l con

tact

with

ba

ckya

rd p

igs

coul

d no

t be

excl

uded

)

Phili

ppin

esTh

aila

ndKo

mad

ina

et a

l. 20

07 [8

5]

Whe

re m

ore

than

one

hum

an c

ase

is s

tate

d, d

iagn

ostic

test

s w

ere

perf

orm

ed fo

r all

case

s as

sta

ted

in th

e M

etho

ds s

ectio

n, u

nles

s ot

herw

ise

spec

ified

.

BSL:

bio

safe

ty le

vel;

cl: c

lass

ical

sw

ine

linea

ge; H

A: h

aem

aggl

utin

atio

n; H

eLa:

Hen

riett

e La

cks

cerv

ical

can

cer c

ells

; HI:

haem

aggl

utin

atio

n in

hibi

tion;

ILI:

Influ

enza

-like

illn

ess;

MAb

: mon

oclo

nal a

ntib

odie

s;

MDC

K: M

adin

Dar

by c

anin

e ki

dney

; MN:

mic

rone

utra

lisat

ion;

n.a

.: no

t app

licab

le; N

I: ne

uram

inid

ase

inhi

bitio

n; R

BC: r

ed b

lood

cel

ls; R

T-PC

R: re

vers

e tr

ansc

ripta

se p

olym

eras

e ch

ain

reac

tion;

rtR

T-PC

R:

real

-tim

e re

vers

e tr

ansc

ripta

se p

olym

eras

e ch

ain

reac

tion;

sw

: sw

ine;

Sw

L: s

win

e-lik

e; tr

: trip

le re

asso

rtan

t; W

I-38:

hum

an e

mbr

yo lu

ng fi

brob

last

.a

In m

ost c

ases

the

num

ber t

este

d re

flect

s on

ly th

e co

nfirm

ed c

ases

repo

rted

in th

e re

view

ed p

aper

whe

re th

e au

thor

s di

d no

t rep

ort o

n th

e tr

ue n

umbe

r of s

uspe

cted

cas

es te

sted

.h

High

est h

omol

ogy

with

Eur

opea

n sw

ine-

influ

enza

viru

ses.

i Pa

tient

’s h

usba

nd d

evel

oped

ILI s

ympt

oms

one

day

befo

re th

e pa

tient

(viru

s is

olat

ion

not d

one)

j A/

Mar

ylan

d/12

/91.

k Hu

man

-avi

an re

asso

rtan

ts: A

/Net

herl

ands

/5/9

3, A

/Net

herl

ands

/35/

93.

l St

rain

was

sim

ilar t

o st

rain

use

d in

sw

ine

expe

rimen

t and

clo

sely

rela

ted

to S

w/I

N an

d A/

WI/

3523

/88.

m P

atie

nt s

how

ed a

titr

e of

160

by

HI a

ssay

, the

pat

ient

’s m

othe

r a ti

tre

of 2

0, fa

ther

, bro

ther

and

gra

ndpa

rent

s tit

res

of le

ss th

an 1

0.n

Viru

s w

as c

lose

ly re

late

d to

viru

ses

circ

ulat

ing

in E

urop

ean

pigs

.o

Hong

Kon

g Sp

ecia

l Adm

inis

trat

ive

Regi

on (S

AR),

Chin

a.p

A/Sw

itzer

land

/880

8/02

(Eur

opea

n av

ian-

like

linea

ge).

q Sw

ine-

like

viru

ses:

HA

gene

tical

ly s

imila

r to

swin

e vi

ruse

s ci

rcul

atin

g in

sw

ine

in A

sia

at th

e tim

e an

d to

viru

ses

that

circ

ulat

ed in

Nor

th A

mer

ica

in th

e 19

90s,

whe

reas

NA

and

inte

rnal

gen

es w

ere

sim

ilar

to E

urop

ean

swin

e vi

ruse

s.r

Both

isol

ates

test

ed n

egat

ive

agai

nst h

uman

str

ains

.s

To d

eter

min

e w

heth

er is

olat

es b

elon

g to

influ

enza

A o

r B.

15www.eurosurveillance.org

Tabl

e 2c

V

irol

ogic

al e

vide

nce

of h

uman

infe

ctio

n w

ith sw

ine

influ

enza

A v

irus

es

Year

(Tes

ted)

a /co

nfirm

ed

case

sSu

btyp

eSy

mpt

oms

Met

hod

Patie

nt in

form

atio

n an

d na

ture

of e

xpos

ure

Loca

tion

Refe

renc

e

2005

1/1

trH1

N1t

Sore

thro

at, r

unny

/ st

uffe

d no

se,

coug

h, fe

ver

Cell

cultu

re, R

T-PC

R, s

eque

ncin

g50

-yea

r-ol

d sw

ine

farm

resi

dent

exp

osed

to il

l sw

ine

(not

influ

enza

con

firm

ed)

Iow

a, U

nite

d St

ates

Gray

et a

l. 20

07 [9

2]

2005

1/1u

trH1

N1v

Acut

e m

ild

resp

irato

ry il

lnes

s;

no fe

ver

MDC

K ce

ll cu

lture

; RT-

PCR;

se

quen

cing

Vacc

inat

ed o

ne m

onth

bef

ore

illne

ss; a

ssis

ted

in b

utch

erin

g sw

ine;

W

isco

nsin

, Uni

ted

Stat

esNe

wm

an e

t al.

2008

[89]

2005

1/1

trH3

N2w

ILI

Cultu

re o

n pr

imar

y rh

esus

m

onke

y ki

dney

cel

ls; s

eque

ncin

gPr

evio

usly

hea

lthy

swin

e fa

rmer

exp

osed

to

influ

enza

-pos

itive

pig

sCa

nada

Ols

en e

t al.

2006

[40]

2006

1/1x

sw tr

H3N2

wIL

IHI

ass

ay (g

uine

a pi

g RB

C)RT

-PCR

, seq

uenc

ing

7-m

onth

-old

chi

ld li

ving

on

com

mun

al fa

rm; n

o di

rect

exp

osur

e to

ani

mal

s, s

erop

ositi

ve s

win

e fo

und

on fa

rm

Cana

daRo

bins

on e

t al.

2007

[96]

2007

1/1y

trH3

N2w

Paro

titis

, nas

al

cong

estio

n; n

o fe

ver,

coug

h or

ph

aryn

gitis

Viru

s is

olat

ion;

HI a

ssay

(tur

key

RBC)

; seq

uenc

ing

6-ye

ar-o

ld b

oy li

ving

on

swin

e fa

rm (n

o ill

ness

in

sw

ine

obse

rved

)Ca

nada

Bast

ien

et a

l. 20

09 [9

5]

2007

26/2

zsw

H1N1

aaIL

IVi

rus

isol

atio

n; s

eque

ncin

gPe

ople

exp

osed

to il

l sw

ine

at c

ount

y fa

irO

hio,

Uni

ted

Stat

esVi

ncen

t et a

l. 20

09 [8

7]; Y

assi

ne

et a

l. 20

09 [8

8]20

05–0

9a)

10/

10b)

1/1

a) s

w tr

H1N1

bb

b) tr

H1N2

ccRa

ngin

g fr

om m

ild

ILI t

o pn

eum

onia

Rapi

d po

int o

f car

e te

st (n

=8)

; Vi

rus

cultu

re (n

=7)

; rt R

T-PC

R (n

=6)

; HI a

ssay

; com

plet

e ge

nom

e py

rose

quen

cing

Seve

n m

ales

(age

: 16

mon

ths–

36 y

ears

)ou

r fem

ales

(age

: 4–4

8 ye

ars)

; exp

osur

e ra

ngin

g fr

om u

nkno

wn

cont

act,

clos

e pr

oxim

ity

and

dire

ct c

onta

ct w

ith s

win

e (s

ome

pig

s w

ere

ill)

Wis

cons

in,

Mis

sour

i, Io

wa

(n=

3), O

hio

(n=2

), Ill

inoi

s, M

ichi

gan,

M

inne

sota

and

Te

xas,

Uni

ted

Stat

e

Shin

de e

t al.

2009

[93]

Whe

re m

ore

than

one

hum

an c

ase

is s

tate

d, d

iagn

ostic

test

s w

ere

perf

orm

ed fo

r all

case

s as

sta

ted

in th

e M

etho

ds s

ectio

n, u

nles

s ot

herw

ise

spec

ified

.

BSL:

bio

safe

ty le

vel;

cl: c

lass

ical

sw

ine

linea

ge; H

A: h

aem

aggl

utin

atio

n; H

eLa:

Hen

riett

e La

cks

cerv

ical

can

cer c

ells

; HI:

haem

aggl

utin

atio

n in

hibi

tion;

ILI:

Influ

enza

-like

illn

ess;

MAb

: mon

oclo

nal a

ntib

odie

s;

MDC

K: M

adin

Dar

by c

anin

e ki

dney

; MN:

mic

rone

utra

lisat

ion;

n.a

.: no

t app

licab

le; N

I: ne

uram

inid

ase

inhi

bitio

n; R

BC: r

ed b

lood

cel

ls; R

T-PC

R: re

vers

e tr

ansc

ripta

se p

olym

eras

e ch

ain

reac

tion;

rtR

T-PC

R:

real

-tim

e re

vers

e tr

ansc

ripta

se p

olym

eras

e ch

ain

reac

tion;

sw

: sw

ine;

Sw

L: s

win

e-lik

e; tr

: trip

le re

asso

rtan

t; W

I-38:

hum

an e

mbr

yo lu

ng fi

brob

last

.a

In m

ost c

ases

the

num

ber t

este

d re

flect

s on

ly th

e co

nfirm

ed c

ases

repo

rted

in th

e re

view

ed p

aper

whe

re th

e au

thor

s di

d no

t rep

ort o

n th

e tr

ue n

umbe

r of s

uspe

cted

cas

es te

sted

.t

H1 H

A, N

1 N

A, M

, NP,

NS

gene

s de

scen

ded

from

cla

ssic

al s

win

e-, P

B1 fr

om h

uman

- and

PA

and

PB2

from

avi

an in

fluen

za v

irus

linea

ges

u Pa

tient

sho

wed

a tw

o-fo

ld ti

tre

incr

ease

in M

N as

say

(not

in H

I ass

ay) a

nd fo

ur fa

mily

mem

bers

and

the

patie

nt’s

bro

ther

-in-la

w w

ere

sero

nega

tive

by M

N an

d HI

ass

ay.

v Pr

edom

inan

t gen

otyp

e of

sub

type

H1N

1 in

Nor

th A

mer

ican

pig

s.w S

ame

geno

type

as

hum

an/c

lass

ical

sw

ine/

avia

n re

asso

rtan

t tha

t em

erge

d in

199

8 in

Nor

th A

mer

ica.

x Fo

ur o

f sev

en h

ouse

hold

mem

bers

of t

he p

atie

nt a

nd fo

ur o

f 46

othe

r res

iden

ts o

f the

farm

sho

wed

ser

olog

ical

evi

denc

e of

infe

ctio

n.y

Hous

ehol

d m

embe

rs w

ere

only

ser

olog

ical

ly s

cree

ned.

z Vi

rus

from

at l

east

two

indi

vidu

als

was

isol

ated

and

seq

uenc

ed a

nd tu

rned

out

to b

e ne

arly

iden

tical

to th

e sw

H1N1

isol

ated

from

the

ill s

win

e; n

ot d

one

for a

ll hu

man

cas

es.

aa H

A re

late

d to

H1γ

clu

ster

(H1N

2-lik

e) o

f con

tem

pora

ry H

1-SI

V, N

A re

late

d to

sw

ine

N1 p

hylo

gene

tic c

lust

er a

nd in

tern

al g

enes

wer

e fr

om tr

iple

-rea

ssor

tant

SIV

line

age

and

grou

p w

ith c

lust

er IV

of A

(H3N

2)

viru

ses.

bb H

1N1:

HA,

NA,

NP,

NS,

M (c

lass

ical

sw

ine,

Nor

th-A

mer

ican

line

age)

, PB2

, PA

(avi

an, N

orth

Am

eric

an li

neag

e), P

B1 (h

uman

sea

sona

l H3N

2).

cc H

1N2:

HA

(hum

an s

easo

nal H

1N1)

, NP,

M, N

S (c

lass

ical

sw

ine,

Nor

th-A

mer

ican

line

age)

, PB2

, PA

(avi

an, N

orth

-Am

eric

an li

neag

e), P

B1, N

A (h

uman

sea

sona

l H3N

2).

16 www.eurosurveillance.org

Tabl

e 2d

Vir

olog

ical

evi

denc

e of

hum

an in

fect

ion

with

swin

e in

fluen

za A

vir

uses

Year

(Tes

ted)

a /co

nfirm

ed

case

sSu

btyp

eSy

mpt

oms

Met

hod

Patie

nt in

form

atio

n an

d na

ture

of e

xpos

ure

Loca

tion

Refe

renc

e

2008

1/1d

dSw

L tr

H1N1

eeIL

I, vo

miti

ng,

diar

rhoe

aRa

pid

test

; cul

ture

; rRT

-PCR

; se

quen

cing

19-y

ear-

old

mal

e ex

pose

d to

hea

lthy

appe

arin

g pi

gs (n

o ph

ysic

al c

onta

ct)

Sout

h Da

kota

, Uni

ted

Stat

esDa

woo

d et

al.

2011

[90]

2008

1/1

swH1

N1ff

ILI

MDC

K ce

ll cu

lture

; im

mun

oflu

ores

cenc

e us

ing

MAb

; PC

R; p

artia

l seq

uenc

ing

50-y

ear-

old-

fem

ale

with

dire

ct c

onta

ct to

as

ympt

omat

ic p

igs

Spai

nAd

iego

San

cho

et a

l. 20

09 [2

2]

2009

1/1g

gsw

trH3

N2Fe

ver,

coug

h,

sore

thro

atRa

pid

test

; rtR

T-PC

R; s

eque

ncin

g12

-yea

r-ol

d bo

y (to

uche

d he

alth

y ap

pear

ing

swin

e at

a c

ount

y fa

ir, p

igs

wer

e se

ropo

sitiv

e)

Kans

as, U

nite

d St

ates

Cox

et a

l. 20

11 [9

7]

2009

3/3h

hsw

trH1

N1ii

ILI

MDC

K ce

ll cu

lture

; rtR

T-PC

R; H

I as

say

(turk

ey R

BC)jj

, seq

uenc

ing

Swin

e w

orke

rs (o

ne w

as im

mun

ized

in

200

8, o

ther

two

neve

r rec

eive

d an

in

fluen

za v

acci

natio

n)kk

Sask

atch

ewan

, Can

ada

Bast

ien

et a

l. 20

10 [9

1]

2009

–11

3/3

swH1

N1ll

Not s

peci

fied

Not s

peci

fied

Thre

e ad

ult,

mal

e sw

ine

wor

kers

exp

osed

to

ill,

influ

enza

-con

firm

ed p

igs

Switz

erla

ndEu

rope

an C

entr

e fo

r Dis

ease

Pr

even

tion

and

Cont

rol 2

012

[86]

Aug-

Dec

20

11

2012

2013

12/1

2mm

309/

309

19/1

9oo

H3N2

vnn

ILI,

vom

iting

, di

arrh

oea

Rapi

d te

sts;

rtR

T-PC

R;

sequ

enci

ng50

% e

xpos

ed a

nd 5

0% n

ot e

xpos

ed to

sw

ine;

(11

child

ren,

one

adu

lt m

ale)

; Mos

t at

tend

ing

agric

ultu

ral f

air

Mos

t att

endi

ng a

gric

ultu

ral f

air

Haw

aii,

Illin

ois,

Indi

ana,

Io

wa,

Mai

ne, M

aryl

and,

M

ichi

gan,

Min

neso

ta,

Ohi

o, P

enns

ylva

nia,

Ut

ah, W

est V

irgin

ia,

Wis

cons

in, U

nite

d St

ates

Unite

d St

ates

Cen

ters

for D

isea

se

Cont

rol a

nd P

reve

ntio

n 20

12

[99]

,201

3 [2

5]

Tota

l45

5/40

133

Whe

re m

ore

than

one

hum

an c

ase

is s

tate

d, d

iagn

ostic

test

s w

ere

perf

orm

ed fo

r all

case

s as

sta

ted

in th

e M

etho

ds s

ectio

n, u

nles

s ot

herw

ise

spec

ified

.

BSL:

bio

safe

ty le

vel;

cl: c

lass

ical

sw

ine

linea

ge; H

A: h

aem

aggl

utin

atio

n; H

eLa:

Hen

riett

e La

cks

cerv

ical

can

cer c

ells

; HI:

haem

aggl

utin

atio

n in

hibi

tion;

ILI:

Influ

enza

-like

illn

ess;

MAb

: mon

oclo

nal a

ntib

odie

s;

MDC

K: M

adin

Dar

by c

anin

e ki

dney

; MN:

mic

rone

utra

lisat

ion;

n.a

.: no

t app

licab

le; N

I: ne

uram

inid

ase

inhi

bitio

n; R

BC: r

ed b

lood

cel

ls; R

T-PC

R: re

vers

e tr

ansc

ripta

se p

olym

eras

e ch

ain

reac

tion;

rtR

T-PC

R:

real

-tim

e re

vers

e tr

ansc

ripta

se p

olym

eras

e ch

ain

reac

tion;

sw

: sw

ine;

Sw

L: s

win

e-lik

e; tr

: trip

le re

asso

rtan

t; W

I-38:

hum

an e

mbr

yo lu

ng fi

brob

last

.a

In m

ost c

ases

the

num

ber t

este

d re

flect

s on

ly th

e co

nfirm

ed c

ases

repo

rted

in th

e re

view

ed p

aper

whe

re th

e au

thor

s di

d no

t rep

ort o

n th

e tr

ue n

umbe

r of s

uspe

cted

cas

es te

sted

.dd

Co

ntac

ts o

f the

pat

ient

and

peo

ple

expo

sed

to s

win

e du

ring

the

even

t wer

e se

rolo

gica

lly s

cree

ned.

ee D

istin

ct fr

om A

(H1N

1)pd

m09

and

sim

ilar t

o tr

iple

-rea

ssor

tant

sw

ine

viru

ses

circ

ulat

ing

in th

e Un

ited

Stat

es s

hort

ly b

efor

e .

ff

Phyl

ogen

etic

ally

clo

se to

A/S

witz

erla

nd/8

808/

02 (E

urop

ean

avia

n-lik

e lin

eage

) [19

].gg

In

addi

tion,

27

of 3

4 vi

sito

rs o

f the

cou

nty

fair

part

icip

ated

in a

sur

vey:

non

e re

port

ed IL

I.hh

No

hous

ehol

d m

embe

rs w

ere

ill a

t the

tim

e.ii

Dist

inct

from

A(H

1N1)

pdm

09: N

S, N

P, M

, PA,

PB1

and

PB2

wer

e si

mila

r to

a No

rth-

Amer

ican

sw

ine

trip

le re

asso

rtan

t and

HA

and

NA

wer

e m

ost s

imila

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Authority (EFSA). The main objective of FLURISK is the development of an evidence-based influenza risk assessment framework (IRAF) to assess the potential of animal influenza viruses to cross the species barrier and cause sustained infections in humans. The work presented here aims at describing available evidence for animal-to-human influenza virus transmissions.

Methods

Search strategyWe performed a literature search using Medline, Embase, SciSearch and CabAbstracts. Search terms included ‘influenza’, ‘influenza virus’, ‘animals’, ‘swine’, ‘birds’, ‘poultry’, ‘wild bird’, ‘water bird’, ‘waterfowl’, ‘goose’, ‘duck’, ‘chicken’, ‘turkey’, ‘envi-ronment’, ‘animal-to-human’, ‘transmission-to-humans’, ‘interspecies transmission’, ‘human’, ‘case’, ‘seroprevalence’, ‘serosurveillance’, ‘prevalence’, ‘incidence’, ‘risk factor’, ‘exposure’ and various subtypes of influenza virus; the terms were used alone or in combinations using Boolean opera-tors. Full search details are available from the corre-sponding author on request. Only articles published in English were included and the search covered all years available in the respective databases, Medline from 1946, Embase from 1947, SciSearch from 1980, CabAbstracts from 1973, all up to February 2012. The search algorithm automatically discarded duplicates. Newly published evidence that came to our attention between February 2012 and January 2014 was also included. Case counts of avian influenza A(H7N9) and A(H5N1) cases were updated on 31 January 2014 based on the latest figures reported by the European Centre for Disease Prevention and Control (ECDC) [23] and by the World Health Organization (WHO) [24]. Case counts of human infections with swine influenza variant A(H3N2)v were retrieved on 31 January 2014 from the website of the United States (US) Centers for Disease Control and Prevention (CDC) as posted on 18 October 2013 [25. Grey literature was searched in a non- sys-tematic way.

Inclusion and exclusion criteriaIncluded were papers indicating evidence of human infection with animal influenza viruses (selection cri-terion 1, Figure 1). Two investigators first screened all papers by title and, when necessary, by abstract. All articles meeting this first criterion were reviewed for details of the methods used to diagnose the infec-tion. Experimental and observational studies describ-ing human infection with animal influenza viruses other than influenza A(H5N1) were included. Articles solely describing human infection with A(H5N1) were excluded, and for influenza A(H5N1) and A(H7N9), the official WHO and ECDC statistics from notifications under the International Health Regulations were used for completeness. Commentaries, reviews, articles dealing with influenza in animals only, studies solely assessing human-to-human transmission of an animal influenza virus (i.e. most of the literature on influenza

A(H1N1)pdm09), and articles referring to study subjects described in prior original publications were excluded (selection criterion 2, Figure 1). Studies based on sero-logical evidence only were excluded to ensure high specificity of the findings. Papers were screened for information on the time period when the study was conducted, total number of people sampled, patient information, nature of exposure (e.g. occupational, recreational), possible exposure to diseased animals, influenza virus subtypes included in testing, number of virologically confirmed cases, information on vaccina-tion history if stated, methods used for confirmation, geographic region and study design. Available data were extracted and summarised in tables. Grey litera-ture such as ProMED, and reference lists from articles were screened for possible additional relevant papers. Virus detection by culture or (real-time) reverse tran-scription polymerase chain reaction (rtRT-PCR) and sequencing was considered to be definitive proof of infection, listed as virological evidence (Tables 1 and 2).

Search output and article selectionThe initial search yielded 6,955 articles, with 4,905 articles resulting from the Medline search, and the oth-ers from additional searches (Figure 1). Search outputs from Embase, SciSearch and CabAbstracts yielded 631, 553 and 866 references, respectively. After screening of titles, abstracts and application of the second selec-tion criterion, a total of 89 publications were selected. The majority of these would also have been identified solely through the Medline search.

Thirty additional studies were retrieved through scan-ning of reference lists of articles identified via the lit-erature review, were retrieved from grey literature or came to our attention after February 2012. Of these 119, 59 publications and reports described virologi-cal evidence for infection of humans and met all other inclusion criteria; 60 papers provided some evidence for human infection, but only based on antibody test-ing and will therefore be described elsewhere.. Seven publications containing both serological and viro-logical evidence were counted once in the total refer-ence count but were included twice in the subdivision according to type of evidence in Figure 1.

Most studies discussed in a review of case reports of SIV infections in humans by Myers et al. [26] were also identified in our literature search. For complete-ness of the human case count, virologically confirmed civilian (n=23) and military cases of Fort Dix (n=5), although discussed in detail in the review by Myers et al. [26], were also included in the current review [21,27-42] (Table 2). For two virus-confirmed cases from the review by Myers et al. [26], the reference could not be retrieved or did not provide full confirmation; these cases were therefore excluded from our listing in Table 2 [43,44].

18 www.eurosurveillance.org

ResultsThe evidence for virologically confirmed infections of humans with avian or SIV is listed in Tables 1, 2 and 3. The exposure status of infected patients is summa-rised in Table 4. A total of 386 cases of human infec-tion with non-A(H5N1) AIV were described, of which 375 were caused by natural infection and 11 were infected experimentally (Table1).

Regarding human infections with SIV, a total of 401 naturally (n=396) and experimentally (n=5) infected cases were detected in the published and grey lit-erature in English. This included, three virologically confirmed SIV A(H1N1) cases originally published in Russian by Chuvakova et al. [27] because they were listed in the review by Myers et al. [26]. The major-ity of cases (n=340) were naturally infected by a SIV variant A(H3N2)v [25]. Recognised in US swine in 2010, this variant combines seven genes from the contem-porary North-American A(H3N2) SIV lineage and has acquired the M gene of the A(H1N1)pdm09 virus [25]. The remaining 56 naturally infected, virologically con-firmed human cases were caused by different circulat-ing SIV or SIV reassortants (Table 2). Five persons were experimentally infected with SIV [45]. The majority of

AIV- and SIV-infected patients had been exposed to animals (Table 4).

Human infections with avian influenza viruses

Infections with highly pathogenic avian influenza virus A(H5N1)To date, highly pathogenic avian influenza (HPAI) A(H5N1) viruses are the most frequently diagnosed zoonotic influenza virus infections related to avian exposure [46], although this picture may change in the near future given the recent upsurge in low pathogenic avian influenza (LPAI) A(H7N9) cases. The HPAI A(H5N1) viruses first attracted major attention in the scientific community in 1996, when a large number of domestic waterfowl died in the course of an A(H5N1) outbreak in Guangdong province in southern China. In 1997, HPAI A(H5N1) resurfaced in Hong Kong SAR, China (in the fol-lowing referred to as Hong Kong); it caused a massive die-off in poultry and crossed the species barrier for the first time, infecting 18 humans, of whom six died [47,48]. From mid-2003 to March 2004, HPAI A(H5N1) spread to seven south-east Asian countries with out-breaks in poultry and waterfowl, and the first con-firmed human cases, were reported in Thailand and Vietnam in 2004 [49]. In 2005, HPAI A(H5N1) accounted

Table 3Humans naturally infected with avian influenza virus subtypes other than A(H5N1) and swine influenza virus subtypes, 1959–2014 (n=771)

Sourcevirus Number of human cases infected with

Avian

SubtypeLP

H6N1 H7N2HP

H7N3LP

H7N3HP

H7N7LP

H7N7LP

H7N9a H9N2 H10N7 H10N8 Total

1 4 3 2 89 4 251 15 4 2 375Swine

SubtypeH1N1 H1N2 H3N2 H3N2vb Total

47 2 7 340 396

HP: highly pathogenic; LP: low pathogenic.a as of 27 January 2014 [23].b as of 18 October 2013 [25].

Table 4Exposure status of patients infected with avian influenza virus, excluding 251 A(H7N9) and including 11 experimentally infected cases, and with swine influenza virus, 1959–2014 (n=536)

Source Number of cases

Exposed Not exposed Exposure status unknownLikely exposed

(H3N2v) Othera Total

Avian 114 3 5 n.a. 13 135Swine 45 20 2 328 6 401

n.a.: not applicable.

a Experimental (avian n=11, swine n=5) or laboratory exposure (avian n=2), or human-to-human transmission (swine n=1).

19www.eurosurveillance.org

for the death of a large number of migratory waterfowl at Qinghai lake, China. Shortly after this event, the virus rapidly spread to other Asian countries, Africa, Europe, the Middle East, Mongolia and Russia [50]. Over time, the viruses evolved into multiple lineages, some of which persisted and have become endemic in China, Bangladesh, Egypt, India, Indonesia and Vietnam [51].

As of 10 December 2013, the WHO has listed 648 HPAI A(H5N1) infected cases from 15 countries, confirmed according to WHO criteria and covering a time span of 10 years [24]. In total, 59% of the reported cases died [24]. Indonesia, Egypt and Vietnam reported 195, 173 and 125 cases, respectively, accounting for about 75% of the total influenza A(H5N1) human case count. These three countries also reported the majority of fatalities [24].

Infections with H7 subtype avian influenza virusesIn total, we identified 353 human cases with virologi-cally confirmed H7 infection (Table 1). The majority of these cases (n=251) were reported in China, followed by 95 cases in Europe, six in North America and one in Australia [17,18,23,52–59]. In China, all cases were caused by the recently emerged subtype A(H7N9) [23]. Of the remaining 102 cases, 93 cases had influenza A(H7N7), five had influenza A(H7N3) and four influ-enza A(H7N2) (Table 3). The first two human cases infected with influenza A(H7N7) were reported in 1959 and 1977. One of these patients had keratoconjunctivi-tis, thought to be caused by the AIV infection [52,53]. This predilection for the ocular mucosa was confirmed when a person involved in an experimental infection of a seal with an avian-like influenza A(H7N7) developed conjunctivitis, and virus was cultured from a conjuncti-val swab [54,60]. In the United Kingdom (UK) in 1996, LPAI A(H7N7) virus infection was associated with mild conjunctivitis in a woman who cleaned a duck house and mentioned getting a piece of straw in her eye [55].

Among European cases, 89 humans were infected in the course of a large outbreak with HPAI A(H7N7) in poultry in the Netherlands in 2003 [17]. In contrast to the severe consequences in poultry, only mild symp-toms were seen in 88 of the infected people. There was one exception. a veterinarian who died of acute respiratory distress syndrome and multiple organ fail-ure. This person had contracted a virus with several mutations, including a known virulence marker in PB2 [56]. Most of these mutations had accumulated dur-ing circulation of the virus in poultry, showing that the public health risk may change over the course of an outbreak [61]. In February 2004, a mixed LPAI and HPAI A(H7N3) virus outbreak was reported in poultry in British Columbia, Canada [18]. Enhanced surveillance for influenza-like illness (ILI) and conjunctivitis in the course of this outbreak led to the identification of two poultry workers showing symptoms of unilateral con-junctivitis. Neither had used the recommended gog-gles or taken prophylactic oseltamivir. Interestingly,

both virus types led to human infection: the isolate cultured from the first worker had the LPAI phenotype, whereas the strain retrieved from the second worker was classified as HPAI [19,62,63]. In 2006 and 2012, LPAI A(H7N3) was associated with one patient in the UK and HPAI A(H7N3) with two patients in Mexico. In both instances, exposure to infected poultry was docu-mented and all patients presented with conjunctivitis [57,59]. Finally, LPAI A(H7N2) was reported as the infec-tious agent causing mild influenza-like symptoms and conjunctivitis in four cases in the UK in 2007 [58].

The assumption that LPAI influenza viruses were mostly associated with mild disease was challenged with the emergence of influenza A(H7N9) viruses in March 2013, when China notified the WHO of three cases infected with LPAI A(H7N9) who were severely ill and eventu-ally died [64]. During the first wave of infections from February to May 2013, 133 human cases were reported and an additional two cases in July and August [23]. Phylogenetic studies concluded that all genes of this newly detected virus were of avian origin [64]. In October 2013, the second wave started and was still ongoing at the time of writing (31 January 2014) [23]. Between February 2012 and 27 January 2014, a total of 251 influenza A(H7N9) cases were reported, 56 of whom died [23]. Infections occurred in Anhui (n=4), Beijing (n=3), Fujian (n=15), Guangdong (n=32), Guizhou (n=1), Hebei (n=1), Henan (n=4), Hong Kong (n=3), Hunan (n=4), Jiangsu (n=31), Jiangxi (n=5), Shandong (n=2), Shanghai (n=42) and Zheijang (n=102). Two cases were imported from mainland China into Taiwan [23]. In response to these events, China culled thousands of birds and closed several poultry markets [65], although only 39 of 48,000 samples representing 1,000 poultry markets tested positive. Most human cases had a his-tory of exposure to birds or live bird markets [23]. As of 31 January 2014, no conclusive evidence of human-to-human transmission has been reported and the ecol-ogy of the viruses remains to be resolved.

Infections with H9 subtype avian influenza virusesIn total, we detected 15 human cases infected with AIV A(H9N2) (Table 1, Table 3). Since the mid-1990s, influ-enza viruses of the H9 subtype have established sta-ble lineages in poultry in Asia and have occasionally infected humans and swine (Table 1) [16,66-69]. As of 31 January 2014, human A(H9N2) cases have only been detected in Asia, particularly in China. Six cases were identified via the literature search [16,66-68]. O