The claim that migratory birds are responsible for the
long-distance spread of highly pathogenic avian infl uenza
viruses of subtype H5N1 rests on the assumption that in-
fected wild birds can remain asymptomatic and migrate long
distances unhampered. We critically assess this claim from
the perspective of ecologic immunology, a research fi eld
that analyzes immune function in an ecologic, physiologic,
and evolutionary context. Long-distance migration is one of
the most demanding activities in the animal world. We show
that several studies demonstrate that such prolonged, in-
tense exercise leads to immunosuppression and that migra-
tory performance is negatively affected by infections. These
fi ndings make it unlikely that wild birds can spread the virus
along established long-distance migration pathways. How-
ever, infected, symptomatic wild birds may act as vectors
over shorter distances, as appears to have occurred in
Europe in early 2006.
highly pathogenic avian infl uenza (HPAI) caused by a vi-
rus of subtype H5N1 has repeatedly been portrayed as the
most prominent emerging disease threat faced by humanity.
In addition to its high mortality rate for infected humans
(currently 60%), a worrisome aspect of Asian lineage HPAI
(H5N1) is its rapid spread from East Asia to Central Asia,
Europe, and Africa in 2005–2006. In 2006–2007, Southeast
Asia remained the geographic center of outbreaks in ani-
mals and humans. Migratory birds as well as trade involv-
ing live poultry and poultry products have been suggested
as the most likely causes of dispersal of the virus (1–3).
Several outbreaks in Central Asia and Europe of HPAI
(H5N1) among wild bird populations that were apparently
not in contact with domestic birds led to an increased inter-
est in the potential role of wild migratory birds in the long-
distance dispersal of the virus.
ince its appearance in 1996 in a domestic goose in
Guangdong Province, People’s Republic of China,
Despite intensive research, the means by which this
spread was accomplished have remained extraordinarily
controversial. The divisiveness of this issue illustrates the
point that an evaluation of emerging disease threats re-
quires a broad interdisciplinary approach (4). It is thus dis-
appointing that ornithologic knowledge and methods have
not fi gured prominently in many high-profi le studies that
have shaped scientifi c, public, and political perceptions of
the threat posed by HPAI (H5N1). Premature verdicts can
have serious consequences. The view that disease transmis-
sion between wild birds and domestic poultry and humans
is likely can seriously undermine conservation efforts con-
cerning threatened migratory birds by eroding tolerance
of what the public is led to believe are potential disease
We agree with Yasué et al. (5), who considered data on
which migratory birds are considered responsible for long-
distance spread of HPAI (H5N1) to be incomplete, inad-
equate, and often incorrect. For example, in a large number
of cases involving wild birds in 2005 and early 2006, the
Organisation Mondiale de la Santé Animale (Paris, France)
did not report the species concerned. Lack of knowledge
of the species involved in outbreaks among wild birds is
just the tip of the iceberg. Even if species, age, and sex of
affected birds were recorded correctly, many other interpre-
tative issues often emerge. The ecology of infectious dis-
eases and the immune system is an innovative fi eld that has
stimulated the attention and interest of ecologists (6) but is
still struggling to be appreciated by the biomedical com-
munity. The fi eld relies on fundamental information on the
natural history and evolutionary ecology of the pathogens
and hosts involved. Work on the natural history of avian
migrants is published mainly in journals that easily escape
the attention of veterinarians, virologists, epidemiologists,
and molecular biologists. Relevant fi ndings published in
ecologic or physiologic journals are also easily missed by
the scientists who deal most closely with avian infl uenza.
An additional problem is that many important phenomena
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 13, No. 8, August 2007 1139
Ec ologic Immunology of Avian
Infl uenza (H5N1) in Migratory Birds
Thomas P. Weber* and Nikolaos I. Stilianakis*†
*Joint Research Centre, Ispra, Italy; and †University of Erlangen-
Nürnberg, Erlangen, Germany
1140 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 13, No. 8, August 2007
in avian movements are not well researched, e.g., move-
ments caused by cold weather and migratory connectivity.
Yasué et al. (5) and Feare and Yasué (7) have reported
numerous problems with the soundness of many results
concerning the involvement of wild birds in the spread of
avian infl uenza. We complement these criticisms by con-
centrating on the neglected topic of seasonal (and shorter
term) variation in the physiology of bird migration and
consider how this variation might affect and be affected by
immunocompetence. The immune function of migratory
birds has so far received little attention in relation to avian
infl uenza. We present pertinent and representative fi ndings
in this fi eld. We argue that the considerable physiologic
stresses of long-distance fl ights cast some doubts on the
assumption that migratory birds are capable of spreading
HPAI (H5N1) on a continental and transcontinental scale.
Ecologic Immunology of Migratory Birds
The hypothesis that migratory birds can transport HPAI
(H5N1) over long distances rests on the assumption that
some infected, virus-shedding wild birds show no or only
mild symptoms and migrate long distances unhampered.
There has been no direct test of this assumption, but several
fi ndings from ecologic immunology and exercise physiol-
ogy studies are not compatible with this conjecture.
The immune system operates in a complex physiologic
and ecologic context. The hormonal and nutritional states
of an animal infl uence the functions of the immune system
(8,9). These states are, in turn, affected by ecologic factors
such as food supply, density of competitors and predators,
energy expenditure, and injury. The fundamental idea of
ecologic immunology is that maintaining a responsive im-
mune system and mounting an immune response are ener-
getically and nutritionally costly and that these costs have
to be balanced against other expenses, such as reproduction,
molting, growth, and development, that contribute to an an-
imal’s fi tness (6,10). Thus, it is not only the direct negative
effects of parasites that determine the consequences of an
infection, but also the costs of the immune response. These
costs are likely to become visible in situations in which ani-
mals are resource-limited. Animals might, for example, al-
locate more resources to immune function if challenged by
an infection and expend less energy in other activities. Car-
ing for young is energy-demanding, and activation of the
immune response during breeding results in lower repro-
ductive success or parental effort (11). Birds give up some
of their current reproductive success to safeguard their sur-
vival and expected future reproductive success. Activating
the immune system without being challenged by parasites
can be costly. In a laboratory experiment with bumble-
bees (Bombus terrestris), Moret and Schmid-Hempel (12)
showed that activation of the immune system of starved
bumblebees resulted in lower survival rates. Hanssen et al.
(13) reported similar results with eiders (Somateria mollis-
sima, a migratory sea duck).
Long-distance migration is one of the most demanding
physiologic activities in the animal world, and an adaptive
resource allocation between concurrent physiologic pro-
cesses likely occurs. Birds migrate for hours or even days
at extremely high metabolic rates. During long fl ights, they
can sustain up to 10× the basal metabolic rate. The bar-
tailed godwit (Limosa lapponica baueri) may fl y 6,000–
8,600 km nonstop from New Zealand to stopover locations
in Southeast Asia (14). Ducks generally travel shorter dis-
tances between stopover sites. However, because of their
heavier bodies and shorter wings, ducks are less dynami-
cally effi cient and probably experience physiologic stress
during their shorter migratory fl ights. The periods between
fl ights are sometimes called resting phases, but this is clear-
ly a misnomer. These are periods of frantic energy acquisi-
tion and physical recovery. During these stopovers, birds
increase their body weight by 30%–50% of their lean mass
in a few days with mainly fat to fuel the next step in their
journey. Birds have evolved physiologic and behavioral ad-
aptations to deal with these extreme demands of both ener-
gy expenditure and acquisition. Birds, especially those that
migrate between widely separated stopover sites, adjust to
these demands by regularly and repeatedly rebuilding their
bodies. They increase the size of the digestive system and
decrease fl ight muscle mass in refueling periods, and they
go through the opposite adjustments before departure (15).
Migratory birds are well-adapted feeding and fl ying
machines, but the exertion involved still takes its physi-
ologic toll. Guglielmo et al. (16) reported that migratory
fl ights result in muscle damage. Macrophages and other
phagocytic cells invade the injured muscle cells and re-
move them. Migration and channeling of resources from
the immune system can release latent infections in song-
birds (17). Figuerola and Green (18) showed that the num-
ber of parasite species or genera reported per migratory
waterfowl host species is positively related to migration
distance. However, to infer that birds that migrate long dis-
tances are affected disproportionately by parasites, it would
be necessary to show that they host more parasite species
from each geographic region they pass through than resi-
dent waterfowl from the respective region.
Migratory birds have also evolved mechanisms to cope
with a greater diversity of parasites than resident species.
Møller and Erritzøe (19) found that migratory birds have
larger immune defense organs than closely related nonmi-
gratory birds. Owen and Moore (20) showed that 3 spe-
cies of thrushes migrating through mainland America (only
fl ying at night and resting and feeding during the day) are
immunocompromised during spring and autumn migration.
In humans, postexercise immune function depression is
most pronounced when exercise is continuous, prolonged,
Ecologic Immunology of Avian Infl uenza (H5N1)
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 13, No. 8, August 2007 1141
of moderate-to-high intensity, and performed without food
intake (21). However, whether similar mechanisms link-
ing exercise and immune function also apply to birds is not
These representative studies demonstrate that physi-
ologic demands of long-distance migration can suppress
the immune system. Far less information is available, how-
ever, on 1 important aspect: how do infected birds perform
during long-distance migration? Møller et al. (22) showed
that barn swallows (Hirundo rustica) with large energy re-
serves maintain better immune function during migration,
clear ectoparasites and blood parasites more effectively,
and arrive earlier at breeding grounds (which is an impor-
tant determinant of reproductive success) than birds with
poor energy reserves. Some indirect evidence shows how
exercise during migration, infection, and immune respons-
es could interact. As mentioned, Hanssen et al. (13) dem-
onstrated that in eiders, immune system activation can have
severe negative consequences. These researchers injected
females with 3 different nonpathogenic antigens (sheep
erythrocytes, diphtheria toxoid, and tetanus toxoid) early
in their incubation period. Mounting of a humoral immune
response against these antigens decreased the return rate
to the breeding grounds in northern Norway from 72% to
27%, which implied a high cost of the immune response.
However, it is not clear from these results whether birds
died during migration or during overwintering or whether
the reduced return rate refl ected only failure of birds to mi-
grate back to their breeding grounds. Also, the demands of
thermoregulation can be substantial. Liu et al. (23) reported
correlations between sudden temperature decreases and ac-
tivation of latent infection with infl uenza A virus.
The most direct evidence of interaction between de-
mands of migratory fl ights and infections was reported
by van Gils et al. (24). These authors found that Bewick’s
swans (Cygnus columbianus bewickii) infected with low
pathogenic avian infl uenza A viruses of the subtypes H6N2
and H6N8 performed more poorly in terms of foraging and
migratory behavior than uninfected birds (including birds
that had recovered from a previous infection). Infected
birds had lower bite rates, took more time to deposit the
energy reserves required for migration, departed later, and
made shorter journeys. The researchers suspect that the
swans might have traded off energy invested in immune
defense against energy invested in rebuilding their bodies
for effi cient fuel deposition and fl ight. However, as van
Gils et al. (24) also reported, only a controlled experimen-
tal study can establish whether this hypothesis is plausible.
However, such a study will probably never be done because
release of the H5N1 subtype of HPAI virus into the wild is
banned. A large number of studies of domestic and labora-
tory mammals show that many bacterial, viral, and parasit-
ic infections lead to anorexia in the host (25). The fi ndings
reported by van Gils et al. (24) are consistent with known
patterns of infection-induced anorexia in mammals.
These fi ndings do not offer a defi nite rebuttal, but they
cast some serious doubts on the frequently repeated claim
that wild birds can easily act as long-distance vectors for
infl uenza A viruses. However, some caveats need to be
addressed that make any quick judgment impossible. The
study by van Gils et al. (24) had a low sample size of in-
fected birds. Furthermore, it was conducted during spring
migration. In many migratory species, spring and autumn
migration are likely to occur under different conditions.
The considerable stress of spring migration may be ampli-
fi ed by energetically costly fl ights undertaken when food
resources are often still scarce along the migratory route, as
well as at breeding grounds at the time of arrival (26,27).
After arrival at breeding grounds, the birds’ energy must be
invested in display and, in females, in egg production. In
autumn, feeding conditions are generally better along mi-
gratory routes. If autumn migration, when infections with
infl uenza A viruses are more prevalent in waterfowl, pro-
ceeds under more benign feeding conditions, the immune
system of birds might be able to clear infections more ef-
fectively. This may mean that the birds can clear infections
quickly or that the infection is controlled by the immune
system but not entirely cleared, and virus-shedding still oc-
curs. Hasselquist et al. (28) showed in a wind-tunnel exper-
iment with the red knot (Calidris canutus), a long-distance
migratory bird, that long fl ights did not infl uence immune
responses. However, they also found that some birds with
low antibody responses against tetanus refused to fl y. This
suggests that there is a trade-off between the demands of
different physiologic systems and that only birds in good
condition with energy to spare may be willing to expend
Sparse fi ndings on immunocompetence and exercise in
migratory birds do not decisively rule out the possibility
that HPAI (H5N1) may be transported relatively short dis-
tances by wild birds. That wintering birds are leaving areas
with cold weather does not necessarily imply stressful long
fl ights and the physiologic adjustments that accompany
long-distance migration. Even birds incapacitated by an
infection may therefore manage to escape harsh weather.
However, causes and consequences of cold weather move-
ments have not been investigated in suffi cient detail (29).
An analysis by Feare (30) supported the view that long-
distance spread of virus by migratory birds is unlikely but
short-distance spread is possible. Feare (30) examined all
known major outbreaks in wild birds and concluded that
most occurrences refl ect local acquisition from a contami-
nated source, followed by rapid death nearby. Outbreaks in
Europe in 2006 indicate that infected wild birds can travel a
limited distance before dying of infl uenza and can pass the
virus to other wild or domestic birds.
1142 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 13, No. 8, August 2007
No convincing evidence has yet shown that infected,
asymptomatic wild birds can or do carry infl uenza virus
along established, seasonal long-distance migration routes.
Even infected dying swans do not shed HPAI (H5N1) in
large quantities; swans may thus constitute an end host and
not be carriers or effi cient transmitters (31,32). The contro-
versies surrounding HPAI (H5N1) and its likely mode of
spread show how little is known about some important top-
ics in the fi eld of emerging infectious diseases. These top-
ics include epidemiology of parasites with highly mobile
host species and function of the immune system of these
highly mobile host species who experience diverse climatic
and ecologic conditions and variable parasite faunas during
their annual cycle.
Recent work on the role of migratory Saiga antelopes
in livestock disease epidemiology has shown how host
movement, multiple host species, and temporal and cli-
matic variation must be included in population dynamics
models of parasites (33). However, studies must go beyond
such necessary and welcome modeling efforts. Research
in ecologic immunology has shown that the functionality
of the immune system has to be considered in an ecologic
and evolutionary life-history context. The immune system
shows complex and, from an evolutionary point of view,
often adaptive dynamics with multifaceted interactions
with nutritional, hormonal, and energetic states and other
physiologic processes. However, ecologic immunology is
a discipline in its infancy and still often works with rather
simplistic ideas. For example, the immune system is often
implicitly assumed to be a unifi ed system that competes
with other physiologic processes for energy and nutrients.
Long and Nanthakumar (34) showed this to be an unreal-
istic and naive assumption; they emphasize the necessity
of considering the differential effects of energy or nutrient
stress on specifi c subcomponents of the immune system.
It therefore remains a critical task to research the ca-
pacities and limitations of the immune system in wild birds
under natural conditions. Only then will it be possible to
judge how results from laboratory experiments can be
transferred to natural situations. For example, Hulse-Post et
al. (35) have shown that HPAI (H5N1) evolves to lowered
pathogenicity in captive laboratory-maintained mallards
(Anas platyrhynchos) but remains highly lethal for chick-
ens. This fi nding suggests that ducks may act as asymp-
tomatic carriers. However, it remains unclear whether free-
living, migratory wild ducks facing stressors such as food
shortages or long fl ights are as immunocompetent as their
laboratory counterparts or whether virus evolution takes the
same course under such conditions. The commercial move-
ment of asymptomatically infected domestic ducks, often
for pest control reasons and over longs distances, could be
a mechanism of spread.
Two of the major challenges in the 21st century are
emerging diseases and the protection of biodiversity. Sus-
tainable solutions for these challenges can be fostered only
in a respectful interdisciplinary atmosphere. Migratory
birds are already affected by habitat destruction and cli-
mate change; alarmist statements blaming migrants for the
spread of an emerging disease with pandemic potential and
ignoring or underplaying the role of the poultry industry
do not do justice to the complexity of the issues involved
Dr Weber works for the European Commission’s Joint Re-
search Centre (JRC) in Ispra, Italy. His research interests include
modeling of infectious diseases and evolutionary ecology and
physiology of avian migration
Dr Stilianakis is a biomathematician who works at the Eu-
ropean Commission JRC and an assistant professor of epidemiol-
ogy and biomathematics at the University of Erlangen-Nürnberg
Medical School in Erlangen, Germany. His research interests in-
clude development of models for pathogenesis and epidemiology
of infectious diseases.
1. Liu J, Xiao H, Lei F, Zhu Q, Qin K, Zhang XW, et al. Highly patho-
genic H5N1 infl uenza virus infection in migratory birds. Science.
2. Kilpatrick AM, Chmura AA, Gibbons DW, Fleischer RC, Marra PP,
Daszak P. Predicting the global spread of H5N1 avian infl uenza.
Proc Natl Acad Sci U S A. 2006;103:19368–73.
3. Gilbert M, Xiao X, Domenech J, Lubroth J, Martin V, Slingen-
bergh J. Anatidae migration in the Western Palaearctic and spread
of highly pathogenic avian infl uenza H5N1 virus. Emerg Infect Dis.
4. Kaplan DD, Bennett SN, Ellis BN, Fox F, Lewis ND, Spencer JH, et
al. Avian infl uenza (H5N1) and the evolutionary and social ecology
of infectious disease emergence. EcoHealth. 2006;3:187–94.
5. Yasué M, Feare CJ, Bennun L, Fiedler W. The epidemiology of
H5N1 avian infl uenza in wild birds: why we need better ecological
data. Bioscience. 2006;11:923–9.
6. Sheldon BC, Verhulst S. Ecological immunology: costly parasite de-
fenses and trade-offs in evolutionary ecology. Trends in Ecology and
7. Feare CJ, Yasué M. Asymptomatic infection with highly pathogenic
avian infl uenza H5N1 in wild birds: how sound is the evidence? Vi-
rol J. 2006;3:96–9.
8. Besedovsky HO, del Rey A. Immune-neuro-endocrine interactions:
facts and hypotheses. Endocr Rev. 1996;17:64–102.
9. Lochmiller RL, Vestley MR, Boren JC. Relationship between pro-
tein nutritional status and immunocompetence in northern bobwhite
chicks. Auk. 1993;110:503–10.
10. Lochmiller RM, Deerenberg C. Trade-offs in evolutionary immunol-
ogy: just what is the cost of immunity? Oikos. 2000;88:87–98.
11. Råberg L, Nilsson JÅ, Ilmonen P, Stjerneman M, Hasselquist D. The
cost of an immune response: vaccination reduces parental effort.
Ecology Letters. 2000;3:382–6.
12. Moret Y, Schmid-Hempel P. Survival for immunity: the price
of immune system activation for bumblebee workers. Science.
Ecologic Immunology of Avian Infl uenza (H5N1)
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 13, No. 8, August 2007 1143
13. Hanssen SA, Hasselquist D, Folstad I, Erikstad KE. Costs of immu-
nity: immune responsiveness reduces survival in a vertebrate. Proc
R Soc B-BiolSc. 2004;271:925–30.
14. Battley PF, Piersma T. Body composition and fl ight ranges of bar-
tailed godwits (Limosa lapponica baueri) from New Zealand. Auk.
15. Piersma T, Lindström Å. Rapid reversible changes in organ size as a
component of adaptive behaviour. Trends in Ecology and Evolution.
16. Guglielmo CG, Piersma T, Williams TD. A sport-physiological per-
spective on bird migration: evidence for fl ight-induced muscle dam-
age. J Exp Biol. 2001;204:2683–90.
17. Gylfe Å, Bergström S, Lundström J, Olsen B. Reactivation of Bor-
relia infection in birds. Nature. 2000;403:724–5.
18. Figuerola J, Green AJ. Haematozoan parasites and migratory behav-
iour in waterfowl. Evolutionary Ecology. 2000;14:143–53.
19. Møller AP, Erritzøe J. Host immune defence and migration in birds.
Evolutionary Ecology. 1998;12:945–53.
20. Owen CO, Moore FR. Seasonal differences in immunological condi-
tion of three thrush species. Condor. 2006;108:389–98.
21. Gleeson M. Immune system adaptation in elite athletes. Curr Opin
Clin Nutr Metab Care. 2006;9:659–65.
22. Møller AP, de Lope F, Saino N. Parasitism, immunity, and arriv-
al date in a migratory bird, the barn swallow. Ecology. 2004;85:
23. Liu CM, Lin SH, Chen YC, Lin KC, Wu TS, King CC. Temperature
drops and the onset of severe avian infl uenza A H5N1 virus out-
breaks. PLoS One. 2007;2:e191.
24. van Gils JA, Munster VJ, Radersma R, Liefhebber D, Fouchier RA,
Klaassen M. Hampered foraging and migratory performance in
swans infected with low-pathogenic infl uenza A virus. PLoS One.
25. Kyriazakis I, Tolkamp BJ, Hutchings MR. Towards a functional ex-
planation for the occurrence of anorexia during parasitic infections.
Anim Behav. 1998;56:265–74.
26. Ebbinge BS, Spaans B. The importance of body reserves accumu-
lated in spring staging areas in the temperate zone for breeding in
dark-bellied brent geese Branta b. bernicla in the high Arctic. Jour-
nal of Avian Biology. 1995;26:105–13.
27. Arzel C, Elmberg J, Guillemain M. Ecology of spring-migrating
Anatidae: a review. Journal of Ornithology. 2006;147:167–84.
28. Hasselquist D, Lindström Å, Jenni-Eiermann S, Koolhaas A,
Piersma T. Long fl ights do not infl uence immune responses of a
long-distance migrant bird: a wind-tunnel experiment. J Exp Biol.
29. Ridgill SC, Fox AD. Cold weather movements of waterfowl in
western Europe. International Waterfowl Research Bureau Special
Publication 13. Slimbridge (UK): International Waterfowl Research
30. Feare CJ. The role of wild birds in the spread of HPAI H5N1. Avian
31. Teifke JP, Klopfl eisch R, Globig A, Starick E, Hoffmann B, Wolf
PU, et al. Pathology of natural infections by H5N1 highly pathogen-
ic avian infl uenza virus in mute (Cygnus olor) and whooper (Cygnus
cygnus) swans. Vet Pathol. 2007;44:137–43.
32. Nagy A, Machova J, Hornickova J, Tomci M, Nagl I, Horyna B, et
al. Highly pathogenic avian infl uenza virus subtype H5N1 in mute
swans in the Czech Republic. Vet Microbiol. 2007;120:9–16.
33. Morgan ER, Lundervold M, Medley GF, Shaikenov BS, Torgersin
PR, Milner-Gulland EJ. Assessing risks of disease transmission be-
tween wildlife and livestock: the Saiga antelope as a case study. Bio-
logical Conservation. 2006;131:244–54.
34. Long KZ, Nanthakumar N. Energetic and nutritional regulation of
the adaptive immune response and trade-offs in ecological immunol-
ogy. Am J Hum Biol. 2004;16:499–507.
35. Hulse-Post DJ, Sturm-Ramirez KM, Humberd J, Seiler P, Govorkova
EA, Krauss S, et al. Role of domestic ducks in the propagation and
biological evolution of highly pathogenic H5N1 infl uenza viruses in
Asia. Proc Natl Acad Sci U S A. 2005;102:10682–7.
36. Gauthier-Clerc M, Lebarbenchon C, Thomas F. Recent expansion
of highly pathogenic avian infl uenza H5N1: a critical review. Ibis.
37. Feare CJ. The spread of avian infl uenza. Ibis. 2007;149:424–5.
Address for correspondence: Thomas P. Weber, Joint Research Centre,
European Commission, Via Enrico Fermi 1, TP 267, I-21020 Ispra, Italy;
The print journal is available at no charge to public health professionals
YES, I would like to receive Emerging Infectious Diseases.
Please print your name and business address in the box and return by fax to
404-639-1954 or mail to
1600 Clifton Road, NE
Atlanta, GA 30333
Moving? Please give us your new address (in the box) and print the number of
your old mailing label here_______________________________________