Ibis (2007), 149 , 202–214 · 2017-11-08 · Ibis (2007), 149, 202–214 © 2007 The Authors...

Ibis

(2007)

149

202ndash214

copy 2007 The Authors Journal compilation copy 2007 British Ornithologistsrsquo Union

Blackwell Publishing Ltd

Review

Recent expansion of highly pathogenic avian influenza H5N1 a critical review

M GAUTHIER-CLERC

1

C LEBARBENCHON

12

amp F THOMAS

2

1

Station Biologique de la Tour du Valat Le Sambuc 13200 Arles France

2

GEMI UMR CNRSIRD 2724 IRD 911 av Agropolis BP 64501 34394 Montpellier cedex 5 France

Wild birds particularly waterfowl are a key element of the viral ecology of avian influenzaHighly pathogenic avian influenza (HPAI) virus subtype H5N1 was first detected in poultryin November 1996 in southeast China where it originated The virus subsequently dis-persed throughout most of Asia and also to Africa and Europe Despite compelling evidencethat the virus has been dispersed widely via human activities that include farming andmarketing of poultry migratory birds have been widely considered to be the primary sourceof its global dispersal Here we present a critical examination of the arguments both for andagainst the role of migratory birds in the global dispersal of HPAI H5N1 We conclude thatwhilst wild birds undoubtedly contribute to the local spread of the virus in the wild humancommercial activities particularly those associated with poultry are the major factors thathave determined its global dispersal

The highly pathogenic avian influenza H5N1 (HPAIH5N1) is an influenza A virus Influenza A viruses arewidespread in the animal kingdom occurring mainlyin birds humans horses pigs and sometimes in ceta-ceans and mustelids These viruses differ markedlygenetically according to their hosts and their geo-graphical origin Subtypes are defined on the basis ofthe antigenicity of the haemagglutinin and neurami-nidase proteins (Webster

et al

1992) The haemag-glutinin allows the virus to attach to the surface of acell while the neuraminidase allows the virus to bereleased Sixteen subtypes of haemagglutinin (H1ndashH16) and nine subtypes of neuraminidase (N1ndashN9)have been described (Fouchier

et al

2005) In thecase of human flu the haemagglutinins H1 H2 andH3 and neuraminidases N1 and N2 circulate orcirculated through human populations naturallyby evolving their own lineages (Manuguerra 2001)H5 H7 and H9 have also been observed in humansalthough in these cases humans were not the initialtargets These viruses crossed the species barrier butdid not become established in human populations In

contrast the diversity of influenza A viruses is greaterin birds All 16 haemagglutinins and nine neuramin-idases have been isolated from birds (Fouchier

et al

2005 Olsen

et al

2006) although the subtype H16has been described only very recently (Fouchier

et al

2005 Olsen

et al

2006) There are many genotypesof avian influenza viruses (AIV) varying geographi-cally and between years as well as between speciesand populations of birds In most cases AIV are notcontagious to humans but are actively evolvingand virulence for the animal host varies markedlySurface antigenic proteins undergo two types ofevolution drift and shift Shift induces major changesby replacement of gene segments (Webster 1998)

AIV have been isolated in wild birds worldwideunderlining the importance of wild birds in viralepidemiology (Alexander 2000) The role of birds inthe dispersal of AIV has been well established formany years and they are the central element of theviral ecology of avian influenza Every year in EuropeAIV circulate among domestic and wild birds just asdoes the virus of human flu in human populationsAIV have been found in at least 12 orders of birdsincluding ducks passerines waders gulls ternspheasants and falcons (Stallknecht amp Shane 1988

Corresponding author Email gauthier-clerctourduvalatorg

copy 2007 The AuthorsJournal compilation copy 2007 British Ornithologistsrsquo Union

Recent expansion of avian influenza H5N1

203

Alexander 2000) The majority of species concernedlive in aquatic environments Anseriforms (ducksgeese and swans) have a particularly wide variety ofsubtypes of viruses (Deibel

et al

1985 Webster

et al

1992 Alexander 2000) All subtypes have beenfound in wild ducks and geese with the exception ofH13 and H16 described only in gulls Among water-birds the Mallard

Anas platyrhynchos

is particularlyimportant because virtually all the subtypes havebeen isolated from it (Munster

et al

2005) A studyconducted in Italy from 1992 to 1998 isolated 22AI subtypes the subtype H1N1 being the most fre-quent (De Marco

et al

2003 2004) Fifty per cent ofducks carried antibodies against AIV which meansthey had been in contact with the viruses at sometime during the previous months or years Waterbirdsare so readily infected by AIV because their environ-ment provides an ideal mode of viral dispersal TheAIV are particularly abundant in the final part of thedigestive tract which explains why they are foundmainly in the faeces (Webster

et al

1992) and theycan remain alive in water for long periods (Ito

et al

1995) from few days in water at 35

deg

C to a monthat 4

deg

C (Stallknecht

et al

1990) Faeces spread in thewater and viruses can be transmitted to other water-birds (Webster

et al

1992) In a recent study howeverexperimental inoculation of HPAI H5N1 of domesticMallards showed that the digestive tract was not themain site of replication for this subtype virusesreplicated rapidly in the trachea suggesting an oraltransmission path (Sturm-Ramirez

et al

2005)It has been shown in wild ducks in North America

that co-infections by two different subtypes of viruscirculating simultaneously in the body of the animalwere frequent (Sharp

et al

1997 Hatchette

et al

2004)This phenomenon increases the possibility of geneticre-assortment and consequently the emergence ofnew viral subtypes This phenomenon has already beendescribed in waders in North America wild ducks inJapan and Common Guillemots

Uria aalge

in Sweden(Makarova

et al

1999 Liu

et al

2004 Wallensten

et al

2005) These studies involved exchanges of genesbetween American and European viral lineages whichthough rare probably happen occasionally where themigratory paths of American and European birds cross

Knowledge of the epidemiology of AIV in wildbirds is still lacking AIV evolve more slowly than thehuman Influenza A perhaps because they are in a stateof more stable coevolutionary balance with wild birdsthan is the case with human Influenza A with humans(Manuguerra 2001) We have little information on thespecificity of AIV in relation to bird species whether

there is competition between virus subtypes if thereare seasonal peaks of infection or if temperate regionsof Europe have their own endemic subtypes or arecolonized anew every spring by African subtypes orevery autumn by Siberian subtypes In America shore-birds mainly carry the viruses north during the springmigration while ducks carry the viruses south during theautumn (Olsen

et al

2006) Genetic analysis of virusesfrom ducks and shorebirds also suggests that their viralgenes pools are not separated (Olsen

et al

2006)

THE SYMPTOMS OF AVIAN INFLUENZA

Every host species interacts and evolves with its ownparasites including phases of crisis during which thehost may have difficulties resisting the parasite andmay develop sometimes fatal diseases In the case ofAIV two phenotypes of virulence have been describeda high virulence and a low virulence The low patho-genic (LP) subtypes are asymptomatic or lead tobenign respiratory symptoms The highly pathogenic(HP) subtypes are responsible for high levels ofmortality in poultry the so-called lsquofowl plaguersquo Atthe time of writing only subtypes H5 and H7 havebeen shown to be responsible for HP phenotypes(Alexander 2000) The majority of H5 and H7 sub-types are LP but have the potential to become HPThis shift from LP to HP subtypes is achieved by theintroduction of basic amino acids into the cleavagesite of the polypeptide precursor of the haemagglutinin(Alexander 2000 Olsen

et al

2006) During thelast 50 years 25 disease outbreaks due to HP sub-types have been identified in birds primarily frompoultry (Alexander 2000) These outbreaks havegenerally remained localized in limited geographicalareas except more recently in the United States in1983 in Mexico in 1994 in Pakistan in 1995 andof course since 2003 in Asia where large epizooticsoccurred causing the death of a considerable numberof domestic birds and important economic losses InEurope Italy was affected in 1997 by a HP H5N2(Capua

et al

1999) and in 1999 by the subtypes HPH7N1 and HP H7N3 (Capua

et al

2002 Stegeman

et al

2004) Having remained free for 75 years theNetherlands was affected by a HP H7N7 subtype inFebruary 2003 (Elbers

et al

2004)HP subtypes have rarely been isolated in wild birds

The majority of the described cases concerning wildbirds were in those living near infected chickens thetransmission being from domestic birds to wild birdsThis was the case of the HPAI H5N1 subtype whichevolved at first in poultry for several years Before the

204

M Gauthier-Clerc C Lebarbenchon amp F Thomas


Asian HPAI H5N1 outbreak there had been noevidence of the presence of HPAI in wild birds apartfrom a Common Tern

Sterna hirundo

in Africa and a fewbirds found dead near outbreaks in poultry despitenumerous surveys over many years This is in keepingwith the theory that mutation from LPAI to HPAItakes place in gallinaceous poultry species It is how-ever very likely that HP subtypes appear regularly inwild individuals The fact that epizootics are notdetected in the wild populations results probablyfrom an ecology unfavourable to the HP subtypes ofthe viruses in particular lower densities of hosts andstronger competition with other LP viruses This lowvirulence of subtypes in wild birds is doubtless theconsequence of a long coevolution allowing the virusesto remain in their hosts without destroying them

Current theories are that the mutation from LP toHP appeared after the introduction in domestic birdsWild birds constitute a permanent source of genefragments of LP subtypes which are sometimestransmitted to domestic birds How the virus subtypesin domestic populations then evolve depends onpoultry rearing practices When bird densities are lowa very virulent subtype leading to high host mortalitymay disappear because of the impossibility of trans-mitting quickly to healthy birds before the death ofsick ones In Asia densities of domestic birds areespecially high These ecological conditions favour thepreservation and the fast transmission of very virulentstrains This scenario seems to apply for example to theepizootic of the H5N2 subtype in 1994 in Mexico(Horimoto

et al

1995) LP H5N2 subtypes circulateat present in Europe simultaneously in wild birdsand poultry They do not raise economic problems aslong as they do not evolve towards more virulentphenotypes During an epizootic of a HP subtypethe situation becomes even more difficult for poultrywhen the virus acquires the capacity to remain incertain birds without activating symptoms Thesehealthy carriers can then spread the virus over longperiods and infect a large number of birds withoutbeing discovered This is the current situation for theHPAI H5N1 subtype in Asia where certain domesticducks are healthy carriers and are not detected whilechickens or turkeys continue to suffer high mortality(Li

et al

2004 Sturm-Ramirez

et al

2005)

THE ORIGIN OF THE HIGHLY PATHOGENIC H5N1 SUBTYPE

HPAI H5N1 evolved after the end of 1996 at leastin populations of domestic birds Although not

detected again for several years it started to spreadagain from 2003 It is now endemic in poultry farmsin southeast Asia (Chen

et al

2006) This subtypethus arises from domestic farms where conditionsallow it to remain and propagate Wild birds con-tacted this subtype only later

The term H5N1 in reality covers numerous differentgenotypes which are continually evolving and whosevirulence varies In autumn 2005 a LP H5N1 sub-type was discovered in Italy in a wild duck (ProMED2005a) HPAI H5N1 subtypes circulating at presentfrom Asia to Europe are very contagious and causehigh mortality in poultry Their peculiarity is that theyare sometimes able to cross the species barrier andlead to mortality in mammals notably humans Domesticcarnivores have died probably after ingestion of con-taminated birds Cases were reported in cats as earlyas 2004 in Thailand (Tiensin

et al

2005) but also byexperimental inoculation (Kuiken

et al

2004) beforenew cases were detected in Germany and Austria atthe beginning of 2006 A study conducted in Thai-land in an infected zone showed that 25 of dogsand 7 of cats carried antibodies indicating that theyhad been infected (Butler 2006a) Wild carnivorescan also be infected the Owstonrsquos Civet

Chrotogaleowstoni

a globally threatened viverrid in Viet Nam(Roberton

et al

2006) a Marten

Martes foina

inGermany on the island of Ruumlgen and a mink

Mustela

sp in Sweden (WHO 2006) have all been shown tohave died as a result of AIV infection The virus hasalso been passed to wild mammals in captivityincluding Ferret

Mustela putorius furo

Tiger

Pantheratigris

and Leopard

Panthera pardus

(Thanawongnu-wech

et al

2005 WHO 2006) In October 2004infection of tigers in Srinacha zoo in the east ofThailand apparently by ingestion of contaminatedchicken meat (tigers were fed whole carcasses ofinfected chickens) led to the euthanasia of 147tigers (Tiensin

et al

2005) A current hypothesis isthat cats can transmit the virus to other cats (Kuiken

et al

2004 2006) but there is still doubt as to theexistence of this transmission route in the wild Thisis however of great importance because it suggeststhat the virus may now be able to pass from onemammal to another The HPAI H5N1 subtype is notthe only subtype that can be transmitted from birdsto mammals Harbour Seals

Phoca vitulina

died as aresult of an H7N7 subtype in the United States in1980 (Lang

et al

1981) and farmed mink as a resultof an H10N4 subtype in Sweden in 1984 (Englund2000) Cases of transmission from domestic birds tohumans have been reported for H7N7 H7N2 H7N3



205

and H9N2 (Lin

et al

2000) In 2003 in Holland theH7N7 subtype caused the death of a veterinarianand several dozen cases of conjunctivitis In HongKong in 1999 two children infected by the H9N2subtype developed respiratory disorders (Lin

et al

2000) It is possible that LP AIV are regularly trans-mitted to humans who are frequently in contact withbirds In Europe millions of wild birds are shot cookedand consumed by hunters and their dogs every yearA recent study in Iowa United States showed trans-mission of H11N9 virus from wild birds to huntersand wildlife professionals (Gill

et al

2006)There are several hypotheses based on genetic

analyses to explain the origin of the HPAI H5N1subtype The progenitor HPAI H5N1 was discoveredin 1996 in domestic geese in the province of Guang-dong southern China (Chen

et al

2006) The lack ofprecise and long-term studies in domestic and wildbirds does not allow us to reconstitute exactly thephylogenetic origin of this subtype It seems to havecome from certain ancestral segments of LP subtypesfrom wild birds It shows segments of genes similarto those found in Hong Kong in an H9N2 subtype ofthe Japanese Quail

Coturnix coturnix japonica

and inan H6N1 subtype of a Green-winged Teal

Anas caro-linenis

(Webster

et al

2006) This last subtype itselfshows similarities to an H6N5 subtype isolated in ashearwater in Australia in 1973 (Hoffmann

et al

2000)The domestic goose virus would have been dispersedfrom the region of Guangdong to Hong Kong throughthe commercial movements of poultry Domesticchickens would then have become a new host in1997 From the year 2000 it seems that domesticducks frequently became hosts of the virus withoutexpressing the associated disease An experiment showsthat domestic ducks can excrete the virus for morethan 2 weeks (Li

et al

2004) This would have allowedthe virus to extend thanks to trade over a vast zonewithout being discovered This geographical expan-sion ended in the genetic differentiation of the virus(Chen

et al

2006) In 2001 seven different genotypeswere identified in poultry in Hong Kong and in theprovince of the Guangdong and in five other provincesin 2002 The major epizootic started between December2003 and January 2004 in chickens (more susceptiblethan domestic ducks) with episodes being reportedalmost simultaneously in eight countries in southeastAsia This outbreak was not due to a unique genotypebut to multiple genotypes which had gradually divergedgenetically The geographical extension and the geneticevolution of the virus since 1996 had probably takenplace without any link with the wild birds

THE HPAI H5N1 SUBTYPE IN WILD BIRDS

Until 2005 the number of cases of wild birdsreported as having contracted the HPAI H5N1 wasstill small compared with the geographical distribu-tion of the virus (Chen

et al

2006) In spite ofsearches for the virus in wild birds in Asia in 2003and 2004 very few individuals were found to be pos-itive In 2004 in Hong Kong the sampling of 2200wild birds showed only negative results (Sabirovic

et al

2005) The only wild birds in Asia found sickwere victims of the virus circulating in domesticbirds (FAO 2005) Sporadic cases were identified InSouth Korea for example three Magpies

Pica pica

were found dead in March 2004 near a farm withinfected chickens (Kwon

et al

2005) In Hong Kongthe virus was found in Tree Sparrow

Passer montanus

Peregrine Falcon

Falco peregrinus

and Grey Heron

Ardea cinerea

(FAO 2005 Kou

et al

2005) Wildspecies held in captivity were also affected as in azoo in Cambodia (FAO 2005) On 18 October 2004two smuggled Thai Eagles

Spizaetus nipalensis

wereseized at customs at Brussels international airportafter a flight from Bangkok (Van Borm

et al

2005)The birds were found to be infected with the HPAIH5N1 subtype The cause of their infection is not knownbut it is likely that they had been fed with carcassesof infected chickens Overall HPAI H5N1 is recordedas having caused mortality in more than 60 speciesof wild birds (Ellis

et al

2004 Olsen

et al

2006)Migratory birds had first been claimed as the

primary cause of the spread of this virus in Asia in2004 (Bangkok Post 2004) In the

New York Times

aspokesman for the World Health Organization statedthat lsquoMigratory birds are what carry the diseasesrsquo(Bradsher 2004) The assessment of the situationconcerning wild birds brought the World Organiza-tion for Animal Health (OIE) and the Food and Agri-culture Organization of the United Nations (FAO)to conclude in their report of the conference of Parisof 7 and 8 April 2005 that only localized infectionsand these limited to resident wild birds were provedand that the dispersal of the virus by migratory birdswas not established But this perception changedquickly during the ensuing weeks From the middleof 2005 in Russia and in Europe migratory wildbirds were again thought to be the main cause of thedispersal of HPAI H5N1 outside Asia This claim wasbased on the discovery in May 2005 that hundredsof wild birds had died on Lake Quinghaihu in theprovince of Qinghai on the high Asian plateau(Chen

et al

2005 Liu

et al

2005) In July 2005 the

206



virus crossed the Russian border According to offi-cial Russian reports wild birds were discovered tohave died from July onwards along the expansionroute of the virus In December 2005 the assess-ment for Russia stated that 62 sites of infection hadbeen recorded distributed across ten regions (OIE2006a) In only two of these sites were importantmortalities of wild birds mentioned totalling 840birds mainly swans These cases were reported latein the year at the end of November in the Astrakhanregion and in mid-December in the Kalmykiarepublic In October 2005 137 swans died in theTulcea region in Romania In Turkey at the end ofJanuary 2006 only two pigeons one Turtle Dove

Streptopelia turtur

a cormorant

Phalacrocorax

sp anda wild duck were reported to have died in the in-fected zones The most westerly point was reachedat the end of October in Croatia where swans werefound dead However no species of wild bird is knownto migrate routinely from China to Croatia Duringthis phase of expansion of the virus westward officialreports systematically indicated that the mode ofdistribution of the virus must be by way of mig-ratory wild birds (OIE 2006a)

New massive sampling campaigns of wild birdstook place in Asia in 2005 and 2006 In Hong Kongonly a Chinese Squacco Heron

Ardeola bacchus

wasdetected carrying the virus in 2005 among 9000 wildbirds sampled At the beginning of 2006 surveil-lance of dead birds discovered a Magpie Robin

Cops-ychus saularis

carrying the virus among 1600 analysesconfirming the rarity of the virus in wild birds (OIE2006a) A study based on samples taken from 13 100lsquomigratory ducksrsquo and lsquomigratory geesersquo betweenDecember 2002 and March 2005 in the zone infectedby the virus in eastern China showed that until2004 none of these wild birds was infected by HPAIH5N1 (Chen

et al

2006) The next winter betweenJanuary and March 2005 of 4674 lsquoapparently healthymigratory ducksrsquo six (01) were carrying the HPAIH5N1 Three species of ducks were caught ndash MallardFalcated Teal

Anas falcata

and Spot-billed Duck

Anas poecilorhyncha

ndash but the authors do not indicatewhich species were infected The Falcated Teal is amigrant on the coast of China Part of the Spot-billedDuck population is sedentary and some of the Mal-lards have a domestic origin The data in this studycould provide the strongest evidence for dispersal bymigratory birds but lack of precision in identifyingthe species infected prevents any conclusions beingdrawn (Feare amp Yasueacute 2006) Yasueacute

et al

(2006) high-lighted this frequent problem Essential information

on the sampling methodology and wild bird popula-tion is often missing while laboratory methods arereported in great detail A lack of better ecologicaldata can lead to unwarranted assumptions and con-clusions that affect public perception and manage-ment measures

By 31 January 2006 none of the sampling campaignsin the European Union (EU) had detected HPAIH5N1 either in wild or in domestic birds Neverthe-less millions of birds wintering in the EU crossedcontaminated zones in Russia during the autumnFrom February 2006 the virus began to spread furtherwest in Europe affecting numerous EU countriesThis time the great majority of reported cases con-cerned dead wild birds Most belonged to residentwaterbird species frequenting relatively deep waterincluding Mute Swan

Cygnus olor

Great CrestedGrebes

Podiceps cristatus

and Grey Herons In Franceand in Scandinavia Common Pochard

Aythya ferina

and Tufted Duck

A fuligula

were also discoveredThe majority of individuals of these two species aremigrants The species in which the virus was mostfrequently discovered was the Mute Swan as in FranceItaly Poland Hungary and Croatia This species isgenerally sedentary in western Europe but migratoryfurther east Dead Whooper Swans

Cygnus cygnus

were found in Germany Denmark and Scotland Birdpredators or scavengers were also listed among thevictims Peregrine Falcon Goshawk

Accipiter gentilis

and Common Buzzard

Buteo buteo So too weremammals that predate birds domestic cats on theisland of Ruumlgen in Germany and in Austria and amarten in Germany This expansion of the diseasewas caused by hard-weather movements of wild birdsduring a period of freezing winter conditions aroundthe Black Sea

Even though investigations in Europe have not yetdetected the existence of healthy wild birds carryingthe HPAI H5N1 their existence is highly likely par-ticularly in wild ducks of the genus Anas The virushas by now circulated for several years and is endemicin a large part of southeast Asia (Chen et al 2006)The number of domestic breeds infected by the virusas well as their wide geographical distribution increasesthe probability of contact between wild birds andthe virus However it is intriguing that the numberof wild birds contaminated by the virus seems sosmall and that the virus apparently passes fromdomestic birds to wild birds only with difficulty In2004 it was demonstrated that domestic Mallardducks which belong to the genus Anas could behealthy carriers of the virus and play a central role in


Recent expansion of avian influenza H5N1 207

the production and the preservation of HPAI H5N1(Li et al 2004 Sturm-Ramirez et al 2005) There isno reason why wild Mallards should not possess thesame capacities The official reports on cases of mor-tality by HPAI H5N1 in wild birds often lack preci-sion concerning the infected species In fact veryfew wild ducks of the genus Anas have been founddead even though they are the most abundantwaterbirds in winter whilst among the other Anati-dae ducks of the genus Aythya such as CommonPochard Tufted Duck and Greater Scaup A marilahave been reported repeatedly as well as geese andswans Despite tens of thousands of faecal samplesobtained from live Anas ducks in Europe or Africathe virus has not been found It seems that thefaecalndashoral route is not the main transmission pathof HPAI H5N1 (Sturm-Ramirez et al 2005) andthe lack of tracheal sampling may explain the lackof detection in wild birds

THE HYPOTHESIS OF DISPERSAL BY MIGRATING BIRDS

At the beginning of 2005 the virus was still confinedto southeast Asia Cases were reported from Indonesiato China including Cambodia Thailand and Viet-nam On the other hand Pakistan India Bangladeshand Burma were not infected In spring 2005 wildbirds were found dead from the virus in the centreof China in the zone of Lake Quinghaihu (Chenet al 2005 Liu et al 2005) The birds were mainlyBar-headed Geese Anser indicus Brown-headed GullsLarus brunnicephalus and Great Black-headed GullsLarus ichthyaetus The OIE indicated that the firstcase was detected on 4 May and deduced a primaryinfection by 15 April (OIE 2006a) The above threespecies reproduce in spring and in summer on thehigh plateau of Central Asia in China and Mongoliaand spend the winter further south in India and oncoasts and lakes of South Asia The Bar-headed Geesewinter in India Bangladesh Nepal and Pakistanfrom October and depart northwards at the end ofMarch In April 2005 these birds thus migratedfrom the uninfected south to Central Asia and it isseems extremely unlikely that they carried the virusto Lake Quinghaihu However by February 2004the virus was well established in China around aneastndashwest major highway from Shanghai on the eastcoast to the city of Urumqi in the province of Xin-jiang in the northwest by way of Liujlapu Jinguyanand Zhonghe (FAO 2006a) Quinghaihu Lake is sit-uated to the west of Zhonghe In spring 2005 migratory

birds thus arrived in this area which had alreadybeen infected for more than a year If Bar-headedGeese brought the virus to Lake Quinghaihu duringtheir spring migration it is necessary to postulatethat they contracted the virus during 2004 in Chinaand would thus have been likely to contaminateIndia during the autumn or winter of 200405 Itthus seems far more likely that these migratory birdswere the victims of the H5N1 by arriving in spring2005 on breeding areas which were already infectedby the virus The wild bird mortality at Quinghaihuwas an important basis for claims of the role ofmigratory birds in spreading H5N1 because the lakewas considered as remote However a year later inMay 2006 it was revealed that the main speciesaffected the Bar-headed Goose was artificially rearednear the lake raising the possibility that farmed birdswere the source of the outbreak (Butler 2006b)

If migratory wildfowl were a key agent of the dis-persal of H5N1 then it seems likely that the springmigrations of 2004 and 2005 would have infectedlarge areas of central Asia eastern Russia and SiberiaSimilarly autumn migration in 2005 of birds thathad nested in Siberia and central Asia would havespread the virus further to India Pakistan Bangladeshthe Middle East east Africa Australia and New Zea-land For example Bar-headed Geese Brown-headedGulls and Great Black-headed Gull the species founddead in China all have India as a key wintering area

In summer Siberia hosts breeding birds whichhave wintered in Europe Africa the Middle East Indiasoutheast Asia Australia and North America in par-ticular passerines waders ducks and geese So in summer2005 Siberia should have been a place of exchangeof the HPAI H5N1 virus if migratory birds were a keyagent of dispersal During autumn 2005 birds migratingsouth would in turn have dispersed the virus back tothe areas of winter origin of these species Duringtheir migrations wildfowl would also be likely tocontaminate stopover areas en route A new waveof contamination on a wide front from Europe toCentral Asia would then have begun in spring 2006

THE HYPOTHESIS OF DISPERSAL BY HUMAN ACTIVITY

During the previous epizootics of HP subtypes ofH5 and H7 it was shown that the expansion of theseviruses was due to human activities in particularmovements of poultry or their products (Webster1998 Alexander 2000) Does this same mechanismexplain the dispersal of HPAI H5N1

208 M Gauthier-Clerc C Lebarbenchon amp F Thomas


The first virus entered the EU in October 2004in two illegally imported Thai Eagles (Van Bormet al 2005) On 16 September 2005 a similar caseoccurred A Pionus Parrot Pionus sp native to Suri-nam kept in quarantine with Mesias Leiothrix spofficially stated to be from Taiwan was found deadand declared infected by the virus It appeared laterthat Mesias and not the parrot were infected by thevirus but the samples had been mixed by the UKauthorities (Defra 2005) Nevertheless Taiwan wasfree of the virus at this time Against these detectedcases how many may have been imported and goneunnoticed Millions of wild birds (Broad et al 2003)mostly passerines for aviculture are imported intoEurope both legally and illegally from Asia Forexample on 20 October 2005 the Taiwanese author-ities discovered 1000 exotic birds contaminated bythe virus HPAI H5N1 in a container forwarded illeg-ally for China (ProMED 2005b)

The virus started its westward expansion acrossEurasia in July 2005 in Novosibirsk Russia Thewestward road and railway links from areas of infec-tion in China provide the most obvious routes forthe initial spread of the virus if the main agent of dis-persal was human movement of birds Novosibirskis a road and railroad hub connected to MongoliaChina and Kazakhstan The trans-Siberian railwaypasses through this city and continues to the westpassing Omsk (Fig 1) The northern route passesTiumen and continues to Moscow The southernroute through the Urals passes Kurgan and Tcheliab-insk by Samara and to the south of Moscow towards

Tambov and Tula From Samara major main high-ways run southwards to Volgograd and Astrakhanand westwards to Rostov and Crimea The chrono-logy and the routes of the expansion of the HPAIH5N1 follow exactly this trajectory The first diag-nostic dates by administrative regions of Russia areon 22 July in the region of Novosibirsk on 23 Julyin the Territory of the Altai on 27 July in the regionof Omsk on 28 July in the region of Tiumen on 4August in the region of Kurgan on 13 August in theregion of Tcheliabinsk on 19 October in the regionof Tula on 24 October in the region of Tambovon 22 November in the region of Astrakhan and on12 December in the republic of Kalmykia alongthe Caspian Sea (OIE 2006a) In the hypothesis ofan expansion by human activities it was predictablethat the virus would continue on this trajectory Ifwe assume spread along major human transportroutes and continue according to the axes of virusdispersal in the year 2005 the virus would spreadfrom Turkey and Russia southwards into ArmeniaAzerbaijan Iran Iraq Syria Egypt and eastwardsinto Africa and westwards to Poland Byelorussiathe Balkans and then into western Europe Fromwestern China the virus would spread to TajikistanAfghanistan Pakistan Nepal and India and fromThailand towards Burma Bangladesh and India Inthis scenario the virus is most likely to be stoppedor at least slowed at the borders of countries withstricter controls by customs and more organized vet-erinarian services as is the case in the EU Export ofthe virus may not only occur via movements of live

Figure 1 Map showing the trans-Siberian railways



poultry The transport of droppings or waste to fer-tilize fish farms in Asia eastern Europe and Africacould also be a major route of dispersal (Melville ampShortridge 2006 Feare 2007) In the Qinghai Pro-vince the region of the wild bird outbreaks in May2005 such fisheries have been developed by theUnited Nations Development Programme and theFAO (FAO 1990)

Migratory birds do not recognize borders yet thevirus remained restricted to China and southeastAsia for some years The virus was in northwestChina from the beginning of 2004 It spread quicklytowards Europe once the Russian border wascrossed In January 2006 the virus was detected inthe impoverished Kurdish regions of Anatolia ineastern Turkey but subsequent epidemiologicalinquiries showed that the virus was already verywidespread in Turkey in particular along the mainhighway connecting Ankara to Anatolia Trade inlow-value poultry collected by truck and resoldthroughout Turkey to low-income farmers allowedthe virus to spread quickly (Rosenthal 2006) Theannouncement of the presence of the virus inNigeria on 6 February 2006 (the first infectionwould have been roughly 1 month before on about10 January) further reinforced belief that migratorybirds were the main agents of dispersal for the virusThe fact that the outbreak was very remote fromEuropean and Asian outbreaks and did not fit a pro-gressive dispersal of the virus strengthened this viewHowever the outbreak proved to originate on anindustrial farm of 46 000 laying hens in Jaji in theState of Kaduna hundreds of kilometres fromwetlands with wintering wildfowl This first Africanoutbreak was situated in one of the zones of mostextensive poultry industry in Africa and thus on thecommercial hypothesis of viral dispersal one of thezones most at risk The Nigerian Minister of Agricul-ture declared that the commercial trade had prob-ably brought the virus because in spite of bans onsuch movements the importation of poultry fromcontaminated zones had continued throughout2005 (Birdlife International 2006) Commercial avi-culture requires chicks that are just a few days oldbut Nigeria has to import them because it does nothave either adequate temperatures or technologiesto produce these for itself A recent study showedthat the HPAI H5N1 was introduced into Nigeria onat least three separate occasions (CIDRAP 2006Ducatez et al 2006) and although it did not drawconclusions about the means of introduction ifmigratory birds were the source it seems surprising

that other wintering areas of European and Asianwildfowl in Africa were not contaminated

A scenario of virus expansion identical to that insoutheast Asia in 2004 now ensued in Africa Thanksto the poultry trade the virus quickly spread through-out Nigeria and reached adjacent countries on 13February in the south of Niger on 21 February in thenorth of Cameroon in domestic duck farms and in Marchin guineafowl Numida sp farms in central Burkina Faso

This commercial scenario is the one that explainedthe expansion and the maintenance of the virus insoutheast Asia until 2004 via the legal and illegaltrade in poultry (Gilbert et al 2006a) In their studyconducted in the east of China Chen et al (2006)isolated the virus in 01 of wild ducks and geeseand 18 of domestic ducks and geese Phylogeneticstudies allowed the authors to show that southernChina was the epicentre of the disease from wherethe virus was repeatedly introduced into neighbour-ing countries such as Viet Nam (Nguyen et al 2005)by way of the poultry trade thus creating newgenetic lineages of the virus which are co-circulatingnow (Chen et al 2006) Even long-distance disper-sion of the HPAI H5N1 by live and dead poultry hasbeen highlighted (Melville amp Shortridge 2006) Itwas introduced from Lanzhou into Lhasa in Tibet1500 km away by live chickens Duck meat infectedby the virus has been discovered in Korea and Japanimported from China Neither is Europe protectedfrom illegal exchanges On 11 January 2006 theGerman Minister of Agriculture imposed strictcustoms controls notably on goods coming from in-fected countries From the first day of this operation200 kg of meat and live poultry were seized byGerman customs in Frankfurt On 19 February 200621 tonnes of poultry imported illegally from Chinawere seized crossing the province of Alicante Spainin trucks (Thinkspain 2006) Multiple sources of con-tagion associated with human movements are possible

THE SITUATION IN 2006

It is clear that the expansion of the virus HPAIH5N1 did not simply follow migratory routes FromFebruary 2004 the virus was present in northwestChina not far from the Russian Altai and border ofKazakhstan (Fig 2 FAO 2006a) The virus started itsprogress westward again in summer 2005 by crossingthe Russian border In July the virus progressedalong the southern border of Russia near the borderwith Kazakhstan between Novosibirsk and Omskthen during the two first weeks of August on the



other side of the border in Kazakhstan and at theend of August in the southeastern Urals aroundTcheliabinsk (OIE 2006a) In October it reached thesouth of Moscow Romania Croatia and the westernedge of Turkey In December the first cases werereported on the Crimean Peninsula in Ukraine andin eastern Turkey In January new outbreaks weredetected right across Turkey At the same time fromOctober to January outbreaks continued to bedetected in the original areas in Thailand in VietNam in China and in Indonesia The virus thus gradu-ally spread according to an eastndashwest linear axisduring summer and autumn 2005 from China towestern Russia then along two northndashsouth axesaround the Black Sea one from Crimea to Romaniaand western Turkey and the other from Astrakhan toeastern Turkey By the beginning of January 2006 nocase had yet been reported in India in Pakistan

Bangladesh the Middle East Africa America orAustralia although the southwards passage of mig-ratory birds had ended and they were beginning tostart their northward migration which takes placefrom February to June according to species

The summer of 2005 marked a new epidemiolog-ical phase with the fast progression of the virus west-wards to the Balkans (Fig 1) In numerous countriesthe epidemiological data are not reliable or preciseenough to allow us to understand the causes of theexpansion but the trajectory of the virus does notcorrespond with the main migration routes of wildbirds Gilbert et al (2006b) concluded that thespread of the virus is consistent in space and timewith the autumn migration of the Anatidae familyTheir study remains however correlative and shouldbe balanced by other explanations not investigatedsuch as important trade from Russia to the Black Sea

Figure 2 Map showing the outbreaks in 2004 and new areas infected in 2005 and 2006 Sources Emergency Prevention System(EMPRES) for Transboundary Animal and Plant Pests (httpwwwfaoorg) and World Organization for Animal Health (httpwwwoieint)



Two new stages in the progression of the virustook place at the beginning of 2006 the arrival of thevirus in sub-Saharan Africa in Nigeria and a newphase of progression westwards in Europe Indeednumerous sporadic outbreaks appeared in Europefrom February to March at first in southern Italy inGreece in Serbia-Montenegro in Hungary then inthe centre of Italy Slovenia Austria northernGermany eastern France then Slovakia the CzechRepublic the south of France the south of GermanyAlbania Poland Switzerland Denmark the southof Sweden and finally Scotland This stage involvingalmost exclusively mortality in wild birds corre-sponds very well with a movement of wild birdswestwards not during a migration season but pushedby a very cold spell in eastern Europe and the spo-radic contamination of water across a broad geo-graphical front The spread does not correspond tothe usual routes of migrants and it is still not possibleto determine which bird species were responsiblefor the spread of the virus because the mortality wasvery largely observed in resident species After thisphase it is remarkable that outbreaks remainedlocalized and did not extend like an epizootic aroundeach initial outbreak February and March are majorperiods of migration in particular for ducks towardstheir northern breeding areas In France outbreaksremained localized in some ponds in the south nearDombes and one pond in Bouches-du-Rhocircne whilstwild birds circulated between these lakes otherregions and other countries

At the beginning of 2006 the virus continuedits progressive extension in poultry but not wildbirds along several axes one from Turkey and thesouth of Astrakhan towards Azerbaijan Iraq IranIsrael Jordan the Gaza Strip and Egypt anotherfrom southern Russia and China towards KazakhstanAfghanistan Iran and northwestern India and a thirdfrom Nigeria towards Niger Cameroon and BurkinaFaso (OIE 2006a)

CONCLUSIONS

The phenology and geographical pattern of expan-sion of the HPAI H5N1 does not correspond to thepattern of bird migration First it took several monthsfor the virus to spread from China to the BalkansMigratory birds such as ducks and waders travel sev-eral hundred kilometres in a single day If migratingbirds mainly dispersed the virus the virus should alsospread by large jumps of thousands of kilometresthroughout the migratory stopping places of Asia

and Africa The observed expansion has rather beenby a progressive expansion from isolated outbreaksthe geographical pattern of which corresponds wellwith major routes and patterns of human commerceSecondly from July 2005 onwards if migratory birdswere a main agent of dispersal one would haveexpected massive mortalities of wild birds both inthe breeding areas and along all migratory routes asbird populations would have been encountering thisvirus for the first time However only sporadic caseswere observed The cases in Western Europe afterthe cold spell on the Black Sea showed that the viruscan spread through infected wild birds travellingshort distances (Feare 2007) but no evidence forlong-distance transmission during seasonal migrationhas yet been found (Feare 2007) Analysing 52 intro-duction events into countries Kilpatrick et al (2006)concluded that both poultry and the trade in wildbirds represent a larger risk than migratory birds forthe introduction of HPAI H5N1 to the Americas

In summary although it remains possible that amigratory bird can spread the virus HPAI H5N1 andcontaminate poultry the evidence overwhelminglysupports the hypothesis that human movements ofdomestic poultry have been the main agent of globaldispersal of the virus to date The occurrence of anoutbreak at a commercial turkey farm in SuffolkEngland in February 2007 fits this wider pattern

In spite of the absence of evidence that migratorybirds play a major role in the dispersal of the virusmany statements to this effect were made by inter-national institutions non-governmental organiza-tions and media and a debate between epidemiologistsand ecologists followed (eg Normile 2005 2006a2006b Fergus et al 2006) However from autumn2005 it was largely presented as fact that migratorybirds were the main potential agent of global dispersal(eg Derenne amp Bricaire 2005 FAO 2005) even asevidence emerged in Asia that spread was mainlymediated by human activities (Melville amp Shortridge2004) OIE reports (eg OIE 2005 2006a 2006c)indicated that the source of outbreaks was contactwith migratory birds but offered no evidence to sup-port this assertion and contributed to the inappro-priate emphasis on migratory birds thus reducingthe probability that alternative mechanisms such aspoultry movements were fully considered in indivi-dual cases In spite of the declarations of the NigerianMinister of Agriculture on the probability of theintroduction of the virus via the poultry trade (EuroSurveillance 2006) the FAO continued to implicatemigratory birds thus denying problems associated



with commercial exchanges The natural globaliza-tion of the exchanges of migratory birds seemed tohide the globalization ndash without strict health controlndash of the exchanges of poultry as the accepted mech-anism for disease spread By May 2006 an interna-tional conference in Rome had recognized that thevirus was mainly spread through the poultry tradeboth legal and illegal but OIE and FAO mediareleases (FAO 2006b OIE 2006b) continued to focuson the possible contribution of spread by wild birdsGiven that a key part of the remit of the FAO is todevelop international agricultural trade reticence toaccept that this trade is the main agent of global dis-persal of HPAI H5N1 is perhaps unsurprising

The OIE have pleaded for a resolution of thedebate over the cause of spread by acknowledgingthat the solution lies in the control of the epizooticdisease notably by training farmers the develop-ment of necessary veterinary infrastructure andespecially the provision of financial resources neces-sary for the countries affected For its part the WorldHealth Organization asked for urgent preparation ofplans to fight any pandemic and warned of the riskof human mortality which might run to hundreds ofmillions Because of the currently poor controls foranimals there is strong probability that the HPAIH5N1 subtype will become endemic near EuropeHowever comparisons between countries show thatit is possible to control the epizootic disease InTaiwan Japan and South Korea the virus has dis-appeared Control of trade and strong veterinariansurveillance were the keys to this success At the sametime migratory birds continue to pass through thesecountries in spring and in autumn Conversely inChina Viet Nam and Cambodia where means werenot implemented to control the epizootic diseasethe virus is now endemic

Fear of an immediate economic impact on poultryas a result of the dispersal of HP subtypes by migratorybirds could lead to keeping of poultry indoors Yetthe current major impact of the virus H5N1 hasbeen economic losses and the destabilization of food-producing farms of Asia where very high densities ofanimals and increased stress factors are particularlyfavourable for the maintenance and transmission ofvirulent agents in particular subtypes of highly patho-genic influenza Paradoxically the H5N1 viruscoupled with a fear of transmission by wild birds couldlead to a reversion to battery farming which increasesrisk of outbreaks rather than maintaining the currenttrend to better animal welfare resulting fromfree-range agriculture All the evidence suggests that

maintaining these trends whilst controlling diseasethrough strong veterinary scrutiny and control of tradeis more likely to be a successful strategy

We are grateful to Chistopher Perrins David Gremilletand Arnaud Bechet for helpful comments on this manu-script CL is supported by a lsquoReacutegion Languedoc-Roussillonndash Station Biologique de la Tour du Valatrsquo PhD grant

REFERENCES

Alexander DJ 2000 A review of avian influenza in differentbird species Vet Microbiol 74 3ndash13

Bangkok Post 2004 Scientists suspect migratory birds arecarriers of virus Bangkok Post 27 January 2004

Birdlife International 2006 Illegal imports probable cause ofNigeria flu httpwwwbirdlifeorg

Bradsher K 2004 Spread of flu across Asia laid to birds thatmigrate New York Times 27 January 2004 httpquerynytimescom

Broad S Mulliken T amp Roe D 2003 The nature and extentof legal and illegal trade in wildlife In Oldfield S (ed) TheTrade in Wildlife Regulation for Conservation 3ndash22 LondonEarthscan

Butler D 2006a Thai dogs carry bird-flu virus but will theyspread it Nature 439 773

Butler D 2006b Blogger reveals Chinarsquos migratory goosefarms near site of flu outbreak Nature 441 263

Capua I Marangon S Selli L Alexander DJ SwayneDE Dalla Pozza M Parenti E amp Cancellotti FM 1999Outbreaks of highly pathogenic avian influenza (H5N2) inItaly during October 1997 to January 1998 Avian Pathol 28455ndash460

Capua I Mutinelli F Pozza MD Donatelli I Puzelli S ampCancellotti FM 2002 The 1999ndash2000 avian influenza(H7N1) epidemic in Italy veterinary and human health impli-cations Acta Tropica 83 7ndash11

Chen H Smith GJD Li KS Wang J Fan XH Rayner JMVijaykrishna D Zhang JX Zhang LJ Guo CTCheung CL Xu KM Duan L Huang K Qin KLeung YHC Wu WL Lu HR Chen Y Xia NSNaipospos TSP Yuen KY Hassan SS Bahri SNguyen TD Webster RG Peiris JSM amp Guan Y 2006Establishment of multiple sublineages of H5N1 influenzavirus in Asia implications for pandemic control Proc NatlAcad Sci USA 103 2845ndash2850

Chen H Smith GJD Zhang SY Qin K Wang J Li KSWebster RG Peiris JSM amp Guan Y 2005 Avian fluH5N1 virus outbreak in migratory waterfowl Nature 436191ndash192

CIDRAP 2006 Report says avian flu entered Nigeria 3 timeshttpwwwcidrapumneducidrapcontentinfluenzaavianflunewsjul0606nigeriahtml

Defra (Department for Environment Food and Rural Affairs)2005 News Release Epidemiology report published onH5N1 in Essex quarantine 15 November 2005 httpwwwdefragovuknews2005051115bhtm

De Marco MA Campitelli L Foni E Raffini E Barigazzi GDelogu M Guberti V Di Trani L Tollis M amp Donatelli I2004 Influenza surveillance in birds in Italian wetlands(1992ndash98) is there a host restricted circulation of influenza



viruses in sympatric ducks and coots Vet Microbiol 98197ndash208

De Marco MA Foni GE Campitelli L Raffini E Di Trani LDelogu M Guberti V Barigazzi G amp Donatelli I 2003Circulation of influenza viruses in wild waterfowl wintering inItaly during the 1993ndash99 period evidence of virus sheddingand seroconversion in wild ducks Avian Dis 47 861ndash866

Deibel R Emord DE Dukelow W Hinshaw VS amp Wood JM1985 Influenza viruses and paramyxoviruses in ducks in theAtlantic Flyway 1977ndash83 including an H5N2 isolate relatedto the virulent chicken virus Avian Dis 29 970ndash985

Derenne J-P amp Bricaire F 2005 Pandeacutemie la grande men-ace Grippe aviaire 500 000 morts en France Paris Fayard

Ducatez MF Olinger CM Owoade AA De Landtsheer SAmmerlaan W Niesters HGM Osterhaus ADMEFouchier RAM amp Muller CP 2006 Avian flu multipleintroductions of H5N1 in Nigeria Nature 442 37

Elbers ARW Fabri THF de Vries TS de Wit JJPijpers A amp Kock G 2004 The highly pathogenic avianinfluenza (H7N7) virus epidemic in the Netherlands in 2003ndash Lessons learned from the first five outbreaks Avian Dis 48691ndash705

Ellis TM Bousfield RB Bissett LA Dyrting KC Luk GSTsim ST Sturm-Ramirez K Webster RG Malik Peiris JSamp Guan Y 2004 Investigation of outbreaks of highly patho-genic H5N1 avian influenza in waterfowl and wild birds inHong Kong in Late 2002 Avian Pathol 33 492ndash505

Englund L 2000 Studies on influenza viruses H10N4 andH10N7 of avian origin in mink Vet Microbiol 74 101ndash107

Euro Surveillance 2006 World avian influenza update H5N1could become endemic in Africa 11 (6) E0606223 httpwwweurosurveillanceorgew2006060622asp

FAO 1990 Fish feed formulation and production httpwwwfaoorgdocrepfield003U4173EU4173E00htm

FAO 2005 Wild birds and Avian influenza httpwwwfaoorgagagainfosubjectsenhealthdiseases-cardsavian_HPAIriskhtml

FAO 2006a httpwwwfaoorgagagainfoprogrammesenempresmapshtml

FAO 2006b Wild birdsrsquo role in HPAI confirmed httpwwwfaoorgnewsroomennews20061000312indexhtml

Feare CJ 2007 The role of wild birds in the spread of HPAIH5N1 Avian Diseases doi 1016377575-040106

Feare CJ amp Yasueacute M 2006 Asymptomatic infection withhighly pathogenic avian influenza H5N1 in wild birds howsound is the evidence Virology J doi 1011861743-422X-3-96

Fergus R Fry M Karesh WM Marra PP Newman S ampPaul E 2006 Migratory birds and avian flu Science 312 845

Fouchier RAM Munster V Wallensten A Bestebroer TMHerfst S Smith D Rimmelzwaan GF Olsen B ampOsterhaus ADME 2005 Characterization of a novelinfluenza A virus hemagglutinin subtype (H16) obtainedfrom black-headed gulls J Virol 79 2814ndash2822

Gilbert M Chaitaweesub P Parakamawongsa T Pre-mashthira S Tiensin T Kalpravidh W Wagner H ampSlingenbergh J 2006a Free-grazing ducks and highlypathogenic avian influenza Thailand Emerging InfectiousDis 12 227ndash234

Gilbert M Xiao X Domenech J Lubroth J Martin V ampSlingenbergh J 2006b Anatidae migration in the WesternPalearctic and spread of highly pathogenic avian influenzaH5N1 virus Emerging Infectious Dis 12 1650ndash1656

Gill JS Webby R Gilchrist MJR amp Gray GC 2006Avian influenza among waterfowl hunters and wildlife profes-sionals Emerging Infectious Dis 12 1284ndash1286

Hatchette TF Walker D Johnson C Baker A Pryor Pamp Webster RG 2004 Influenza A viruses in feral Canadianducks extensive reassortment in nature J Gen Virol 852327ndash2337

Hoffmann E Stech J Leneva I Krauss S Scholtissek CChin PS Peiris M Shortridge KF amp Webster RG2000 Characterization of the influenza A virus gene pool inavian species in southern China was H6N1 a derivative or aprecursor of H5N1 J Virol 74 6309ndash6315

Horimoto T Rivera E Pearson J Senne D Krauss SKawaoka Y amp Webster RG 1995 Origin and molecularchanges associated with emergence of a highly pathogenicH5N2 influenza virus in Mexico Virology 83 223ndash230

Ito T Okazaki K Kawaoka Y Takada A Webster RG ampKida H 1995 Perpetuation of influenza A viruses in Alaskanwaterfowl reservoirs Arch Virol 140 1163ndash1172

Kilpatrick AM Chmura AA Gibbons DW Fleischer RCMarra PP amp Daszak P 2006 Predicting the global spreadof H5N1 avian influenza Proc Natl Acad Sci USA 103doi101073pnas0609227103

Kou Z Lei FM Yu J Fan ZJ Yin ZH Jia CXXiong KJ Sun YH Zhang XW Wu XM Gao XB ampLi TX 2005 New genotype of avian influenza H5N1 virusesisolated from tree sparrows in China J Virol 79 15460ndash15466

Kuiken T Fouchier R Rimmelzwaan G Osterhaus A ampRoeder P 2006 Feline friend or potential foe Nature 440741ndash742

Kuiken T Rimmelzwaan G van Riel D van Amerongen GBaars M Fouchier R amp Osterhaus A 2004 Avian H5N1influenza in cats Science 306 241

Kwon Y-K Joh S-J Kim M-C Lee Y-J Choi J-GLee E-K Wee S-H Sung H-W Kwon J-H Kang M-Iamp Kim J-H 2005 Highly pathogenic avian influenza inMagpies (Pica pica sericea) in South Korea J Wildlife Dis 41618ndash623

Lang G Gagnon A amp Geraci JR 1981 Isolation of an influ-enza A virus from seals Arch Virol 68 189ndash195

Li KS Guan Y Wang J Smith GJ Xu KM Duan LRahardjo AP Puthavathana P Buranathai C NguyenTD Estoepangestie AT Chaisingh A Auewarakul PLong HT Hanh NT Webby RJ Poon LL Chen HShortridge KF Yuen KY Webster RG amp Peiris JS2004 Genesis of a highly pathogenic and potentially pan-demic influenza virus in eastern Asia Nature 430 209ndash213

Lin YP Shaw M Gregory V Cameron K Lim W Klimov ASubbarao K Guan Y Krauss S Shortridge KWebster R Cox N amp Hay A 2000 Avian-to-Human Trans-mission of H9N2 Subtype Influenza A Viruses Relationshipbetween H9N2 and H5N1 Human Isolates Proc Natl AcadSci 97 9654ndash9658

Liu JH Okazaki K Bai GR Shi WM Mweene A ampKida H 2004 Interregional transmission of the internal pro-tein genes of H2 influenza virus in migratory ducks fromNorth America to Eurasia Virus Genes 29 81ndash86

Liu J Xiao H Lei F Zhu Q Qin K Zhang X-WZhang X-L Zhao D Wang G Feng Y Ma J Liu WWang J amp Gao GF 2005 Highly pathogenic H5N1 influenzavirus infection in migratory birds Science 309 1206



Makarova NV Kaverin NV Krauss S Senne D ampWebster RG 1999 Transmission of Eurasian avian H2influenza virus to shorebirds in North America J Gen Virol80 3167ndash3171

Manuguerra J-C 2001 Ecologie biodiversiteacute et eacutevolution desvirus grippaux Virologie 5 195ndash205

Melville DS amp Shortridge K 2004 Reflection and reactionInfluenza time to come to grips with the avian dimensionLancet Infectious Dis 4 261ndash262

Melville DS amp Shortridge K 2006 Spread of H5N1 avianinfluenza virus an ecological conundrum Lett Appl Microbiol42 435ndash437

Munster VJ Wallensten A Baas C Rimmelzwaan GFSchutten M Olsen B Osterhaus ADME amp FouchierRAM 2005 Mallards and highly pathogenic avian influenzaancestral viruses northern Europe Emerging Infectious Dis11 1545ndash1551

Nguyen DC Uyeki TM Jadhao S Maines T Shaw MMatsuoka Y Smith C Rowe T Lu X Hall H Xu XBalish A Klimov A Tumpey TM Swayne DEHuynh LP Nghiem HK Nguyen HH Hoang LTCox NJ amp Katz JM 2005 Isolation and characterizationof avian influenza viruses including highly pathogenic H5N1from poultry in live bird markets in Hanoi Vietnam in 2001J Virol 79 4201ndash4212

Normile D 2005 Are wild birds to blame Science 310 426ndash428

Normile D 2006a Evidence points to migratory birds in H5N1spread Science 311 1225

Normile D 2006b Wild birds only partly to blame in spreadingH5N1 Science 312 1451

OIE 2005 Highly pathogenic avian influenza in Romania Follow-up report no 12 Disease Information Vol 18 ndash No 50 httpwwwoieintenginfohebdoAIS_40HTMSec5

OIE 2006a Update on avian influenza in animals (type H5)httpwwwoieInternationaldownldAVIAN 20INFLUENZAA_AI-Asiahtm

OIE 2006b Wild birdsrsquo role in HPAI crisis confirmed httpwwwoieintengpressfr_060602htm

OIE 2006c Highly pathogenic avian influenza in RussiaFollow-Up Report No 2 26 August 2005 18 ndash no 34 httpwwwoieintenginfohebdoAIS_56HTMSec2DiseaseInformation

Olsen B Munster VJ Wallensten A Waldenstroumlm JOsterhaus ADME amp Fouchier RAM 2006 Global pat-terns of influenza A virus in wild birds Science 312 384ndash388

ProMED 2005a Report on the H5N1 low pathogenic avianinfluenza (LPAI) isolate in Italy ndash November 2005 httpwwwpromedmailorg

ProMED 2005b Taiwan detects avian flu virus (H5N1) on smug-gled birds from China httpwwwpromedmailorg

Roberton SI Bell DJ Smith GJ Nicholls JM Chan KHNguyen DT Tran PQ Streicher U Poon LL Chen HHorby P Guardo M Guan Y amp Peiris JS 2006 Avianinfluenza H5N1 in viverrids implications for wildlife healthand conservation Proc R Soc Lond B 273 1729ndash1732

Rosenthal E 2006 UN aide urges flu transit checks Interna-tional Herald Tribune 17 January 2006 httpwwwihtcomarticles20060117healthsciencefluphp

Sabirovic M Raw L Hall S amp Coulson N 2005 Interna-tional disease monitoring October to December 2004 VetRecord 156 193ndash196

Sharp GB Kawaoka Y Jones DJ Bean WJ Pryor SPHinshaw V amp Webster RG 1997 Coinfection of wild ducksby influenza A viruses distribution patterns and biologicalsignificance J Virol 71 6128ndash6135

Stallknecht DE amp Shane SM 1988 Host range of avian influ-enza virus in free-living birds Vet Res Commun 12 125ndash141

Stallknecht DE Shane SM Kearney MT amp Zwank PJ1990 Persistence of avian influenza viruses in water AvianDis 34 406ndash411

Stegeman A Bouma A Elbers AR de Jong MCNodelijk G de Klerk F Koch G amp van Boven M 2004Avian influenza A virus (H7N7) epidemic in The Netherlandsin 2003 course of the epidemic and effectiveness of controlmeasures J Infectious Dis 190 2088ndash2095

Sturm-Ramirez KM Hulse-Post DJ Govorkova EAHumberd J Seiler P Puthavathana P Buranathai CNguyen TD Chaisingh A Long HT Naipospos TSPChen H Ellis TM Guan Y Peiris JSM amp Webster RG2005 Are ducks contributing to the endemicity of highlypathogenic H5N1 influenza virus in Asia J Virol 79 11269ndash11279

Thanawongnuwech R Amonsin A Tantilertcharoen RDamrongwatanapokin S Theamboonlers A Payung-porn S Nanthapornphiphat K Ratanamungklanon STunak E Songserm T Vivatthanavanich V Lekd-umrongsak T Kesdangsakonwut S Tunhikorn S ampPoovorawan Y 2005 Probable tiger-to-tiger transmission ofavian influenza H5N1 Emerging Infectious Dis 11 699ndash701

Thinkspain 2006 Infected meat detected at Benidorm Chineserestaurant Friday February 17 2006 httpwwwthinkspaincomnews-spain10555

Tiensin T Chaitaweesub P Songserm T Chaisingh AHoonsuwan W Buranathai C Parakamawongsa TPremashthira S Amonsin A Gilbert M Nielen M ampStegeman A 2005 Highly pathogenic avian influenza H5N1Thailand 2004 Emerging Infectious Dis 11 1664ndash1672

Van Borm S Thomas I Hanquet G Lambrecht BBoschmans M Dupont G Decaestecker M Snacken Ramp van den Berg T 2005 Highly pathogenic H5N1 influenzavirus in smuggled Thai eagles Belgium Emerging Infec-tious Dis 11 702ndash705

Wallensten A Munster VJ Elmberg J Osterhaus ADMEFouchier RA amp Olsen B 2005 Multiple gene segmentreassortment between Eurasian and American lineages ofinfluenza A virus (H6N2) in Guillemot (Uria aalge) Arch Virol150 1685ndash1692

Webster RG 1998 Influenza an emerging disease EmergingInfectious Dis 4 436ndash441

Webster RG Bean WJ Gorman OT Chambers TM ampKawaoka Y 1992 Evolution and ecology of influenza Aviruses Microbiol Rev 2 (56) 152ndash179

Webster RG Peiris M Chen H amp Guan Y 2006 H5N1 out-breaks and enzootic influenza Emerging Infectious Dis 12 3ndash8

WHO 2006 Influenza Research at the Human and Animal Inter-face Report of a WHO Working Group Released 1 November2006 httpwwwwhoint

Yasueacute M Feare CJ Bennun L amp Fiedler W 2006 The epi-demiology of H5N1 avian influenza in wild birds why we needbetter ecological data Bioscience 56 923ndash929

Received 17 February 2007 revision accepted 20 February 2007



203

Alexander 2000) The majority of species concernedlive in aquatic environments Anseriforms (ducksgeese and swans) have a particularly wide variety ofsubtypes of viruses (Deibel

et al

1985 Webster

et al

1992 Alexander 2000) All subtypes have beenfound in wild ducks and geese with the exception ofH13 and H16 described only in gulls Among water-birds the Mallard

Anas platyrhynchos

is particularlyimportant because virtually all the subtypes havebeen isolated from it (Munster

et al

2005) A studyconducted in Italy from 1992 to 1998 isolated 22AI subtypes the subtype H1N1 being the most fre-quent (De Marco

et al

2003 2004) Fifty per cent ofducks carried antibodies against AIV which meansthey had been in contact with the viruses at sometime during the previous months or years Waterbirdsare so readily infected by AIV because their environ-ment provides an ideal mode of viral dispersal TheAIV are particularly abundant in the final part of thedigestive tract which explains why they are foundmainly in the faeces (Webster

et al

1992) and theycan remain alive in water for long periods (Ito

et al

1995) from few days in water at 35

deg

C to a monthat 4

deg

C (Stallknecht

et al

1990) Faeces spread in thewater and viruses can be transmitted to other water-birds (Webster

et al

1992) In a recent study howeverexperimental inoculation of HPAI H5N1 of domesticMallards showed that the digestive tract was not themain site of replication for this subtype virusesreplicated rapidly in the trachea suggesting an oraltransmission path (Sturm-Ramirez

et al

2005)It has been shown in wild ducks in North America

that co-infections by two different subtypes of viruscirculating simultaneously in the body of the animalwere frequent (Sharp

et al

1997 Hatchette

et al

2004)This phenomenon increases the possibility of geneticre-assortment and consequently the emergence ofnew viral subtypes This phenomenon has already beendescribed in waders in North America wild ducks inJapan and Common Guillemots

Uria aalge

in Sweden(Makarova

et al

1999 Liu

et al

2004 Wallensten

et al

2005) These studies involved exchanges of genesbetween American and European viral lineages whichthough rare probably happen occasionally where themigratory paths of American and European birds cross

Knowledge of the epidemiology of AIV in wildbirds is still lacking AIV evolve more slowly than thehuman Influenza A perhaps because they are in a stateof more stable coevolutionary balance with wild birdsthan is the case with human Influenza A with humans(Manuguerra 2001) We have little information on thespecificity of AIV in relation to bird species whether

there is competition between virus subtypes if thereare seasonal peaks of infection or if temperate regionsof Europe have their own endemic subtypes or arecolonized anew every spring by African subtypes orevery autumn by Siberian subtypes In America shore-birds mainly carry the viruses north during the springmigration while ducks carry the viruses south during theautumn (Olsen

et al

2006) Genetic analysis of virusesfrom ducks and shorebirds also suggests that their viralgenes pools are not separated (Olsen

et al

2006)

THE SYMPTOMS OF AVIAN INFLUENZA

Every host species interacts and evolves with its ownparasites including phases of crisis during which thehost may have difficulties resisting the parasite andmay develop sometimes fatal diseases In the case ofAIV two phenotypes of virulence have been describeda high virulence and a low virulence The low patho-genic (LP) subtypes are asymptomatic or lead tobenign respiratory symptoms The highly pathogenic(HP) subtypes are responsible for high levels ofmortality in poultry the so-called lsquofowl plaguersquo Atthe time of writing only subtypes H5 and H7 havebeen shown to be responsible for HP phenotypes(Alexander 2000) The majority of H5 and H7 sub-types are LP but have the potential to become HPThis shift from LP to HP subtypes is achieved by theintroduction of basic amino acids into the cleavagesite of the polypeptide precursor of the haemagglutinin(Alexander 2000 Olsen

et al

2006) During thelast 50 years 25 disease outbreaks due to HP sub-types have been identified in birds primarily frompoultry (Alexander 2000) These outbreaks havegenerally remained localized in limited geographicalareas except more recently in the United States in1983 in Mexico in 1994 in Pakistan in 1995 andof course since 2003 in Asia where large epizooticsoccurred causing the death of a considerable numberof domestic birds and important economic losses InEurope Italy was affected in 1997 by a HP H5N2(Capua

et al

1999) and in 1999 by the subtypes HPH7N1 and HP H7N3 (Capua

et al

2002 Stegeman

et al

2004) Having remained free for 75 years theNetherlands was affected by a HP H7N7 subtype inFebruary 2003 (Elbers

et al

2004)HP subtypes have rarely been isolated in wild birds

The majority of the described cases concerning wildbirds were in those living near infected chickens thetransmission being from domestic birds to wild birdsThis was the case of the HPAI H5N1 subtype whichevolved at first in poultry for several years Before the

204




Sterna hirundo



et al


et al

2004 Sturm-Ramirez

et al

2005)




et al



et al


et al


Chrotogaleowstoni


et al

2006) a Marten

Martes foina


Mustela



Tiger

Pantheratigris

and Leopard

Panthera pardus

(Thanawongnu-wech

et al


et al


et al


Phoca vitulina


et al




205

and H9N2 (Lin

et al


et al


et al



et al




Anas caro-linenis

(Webster

et al


et al


et al


et al




et al


et al


Pica pica


et al


Passer montanus

Peregrine Falcon

Falco peregrinus

and Grey Heron

Ardea cinerea

(FAO 2005 Kou

et al




et al


et al

2004 Olsen

et al



New York Times


et al

2005 Liu

et al


206




Streptopelia turtur

a cormorant

Phalacrocorax



Ardeola bacchus


Cops-ychus saularis


et al


Anas falcata


Anas poecilorhyncha


et al




Cygnus olor

Great CrestedGrebes

Podiceps cristatus


Aythya ferina

and Tufted Duck

A fuligula


Cygnus cygnus


Accipiter gentilis

and Common Buzzard






































CONCLUSIONS












REFERENCES
























































































204




Sterna hirundo



et al


et al

2004 Sturm-Ramirez

et al

2005)




et al



et al


et al


Chrotogaleowstoni


et al

2006) a Marten

Martes foina


Mustela



Tiger

Pantheratigris

and Leopard

Panthera pardus

(Thanawongnu-wech

et al


et al


et al


Phoca vitulina


et al




205

and H9N2 (Lin

et al


et al


et al



et al




Anas caro-linenis

(Webster

et al


et al


et al


et al




et al


et al


Pica pica


et al


Passer montanus

Peregrine Falcon

Falco peregrinus

and Grey Heron

Ardea cinerea

(FAO 2005 Kou

et al




et al


et al

2004 Olsen

et al



New York Times


et al

2005 Liu

et al


206




Streptopelia turtur

a cormorant

Phalacrocorax



Ardeola bacchus


Cops-ychus saularis


et al


Anas falcata


Anas poecilorhyncha


et al




Cygnus olor

Great CrestedGrebes

Podiceps cristatus


Aythya ferina

and Tufted Duck

A fuligula


Cygnus cygnus


Accipiter gentilis

and Common Buzzard






































CONCLUSIONS












REFERENCES


























































































205

and H9N2 (Lin

et al


et al


et al



et al




Anas caro-linenis

(Webster

et al


et al


et al


et al




et al


et al


Pica pica


et al


Passer montanus

Peregrine Falcon

Falco peregrinus

and Grey Heron

Ardea cinerea

(FAO 2005 Kou

et al




et al


et al

2004 Olsen

et al



New York Times


et al

2005 Liu

et al


206




Streptopelia turtur

a cormorant

Phalacrocorax



Ardeola bacchus


Cops-ychus saularis


et al


Anas falcata


Anas poecilorhyncha


et al




Cygnus olor

Great CrestedGrebes

Podiceps cristatus


Aythya ferina

and Tufted Duck

A fuligula


Cygnus cygnus


Accipiter gentilis

and Common Buzzard






































CONCLUSIONS












REFERENCES
























































































206




Streptopelia turtur

a cormorant

Phalacrocorax



Ardeola bacchus


Cops-ychus saularis


et al


Anas falcata


Anas poecilorhyncha


et al




Cygnus olor

Great CrestedGrebes

Podiceps cristatus


Aythya ferina

and Tufted Duck

A fuligula


Cygnus cygnus


Accipiter gentilis

and Common Buzzard






































CONCLUSIONS












REFERENCES



























































































































CONCLUSIONS












REFERENCES

















































































































CONCLUSIONS












REFERENCES











































































































CONCLUSIONS












REFERENCES


































































































CONCLUSIONS












REFERENCES




























































































CONCLUSIONS












REFERENCES































































































REFERENCES






































































































































































































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