Simultaneous infection with multiple influenza virus strains can affect
virus fitness components, such as virus growth performance, and thus
affect virus pathogenicity, transmission, or recombination (
).
In a host infected with 2 closely related influenza viruses, the stains
can reassort, exchanging gene segments to produce new strains, some of
which might have increased virulence. Virulence might also trade off
with transmission such that more pathogenic viruses spread more slowly (
).
However, in some instances, a reassortant virus can have high
transmissibility and high pathogenicity. For example, reassortment
between influenza viruses of humans and birds resulted in the 1957 and
1968 pandemic viruses, each of which is estimated to have killed ≈1
million persons (
).
The exchange of genes between pairs of influenza virus subtypes
increased virulence in animal models, including reassortment between
subtypes H9N2 and H1N1, between H5N1 and H1N1, and between H3N2 and H5N1
(
Discussion
The spatial models presented here predict that a reassortant
influenza (H3N2/H5N1) virus is most likely to originate in the coastal
and central provinces of China or the Nile Delta region of Egypt. The
probability that subtypes H3N2 and H5N1 will co-occur in these regions
is high (
Figure 1;
Figure 3, panel C;
Technical Appendix 
[PDF - 1.61 MB - 9 pages]Figure 4,
panel C), which could lead to dual infection in mammalian hosts, such
as swine or humans in China or humans in Egypt. Co-infection could
subsequently result in in vivo reassortment. Although the influenza
A(H1N1)pdm09 virus is hypothesized to have originated from Mexico (
20), southern China remains a major hotspot for the generation of novel influenza viruses (
21).
Our spatial models are compatible with this longstanding observation
insofar as we predict that the southern coastal province of Guangdong is
a potential hotspot for the evolution of novel influenza viruses by
reassortment.
A caveat is that even if virus subtypes H3N2 and H5N1 were to
reassort in swine, the spread of the reassortant virus among humans
might require further virus adaptation events; for example, mutations
might be required for the virus to replicate efficiently in humans or to
be transmitted among humans (
22). Recent work has shown that as few as 5 aa substitutions are required for aerosol spread of subtype H5N1 among mammals (
23).
With these qualifications in mind, this analysis provides actionable
recommendations about which areas to target for intensified farm and
market surveillance. Such surveillance could enable early detection of a
reassortant influenza (H3N2/H5N1) virus, should it arise in swine, and
facilitate containment of the virus before it crosses the species
barrier to humans.
Our finding that in China the probability of subtype H3N2 infection
increases with human population density is compatible with previous
studies that detected a positive association between population,
influenza cases, and mortality rates (
12,
24). Reasons for this association could be that the number of susceptible human hosts increases with population (
11) or that surveillance efforts are greater in populous areas (
25).
Our results with regard to subtype H5N1 in birds are also largely
consistent with those of previous studies that mapped subtype H5N1
hotspots in China and Egypt. In China, several provinces identified as
having high ecologic suitability for subtype H5N1 (including Shandong,
Jiangsu, and Sichuan) were also identified as subtype H5N1 hotspots in a
previous study that used a different statistical model and different
predictor variables (
11). In China, previous analyses have concluded that risk for subtype H5N1 increases with the density of domestic ducks (
26).
In Egypt, earlier studies identified high-intensity crop production as a
statistically significant predictor of subtype H5N1 in poultry (
27).
Similarly, we found that subtype H5N1 infections in poultry were
associated with poultry density, which was highly correlated with crop
production. In a previous study, models constructed from satellite
images of vegetation predicted that the highest environmental
suitability for subtype H5N1 is along the Nile River and in the Nile
Delta (
28).
Our models were constructed from different predictor variables, such as
poultry density, but yielded similar results: the highest number of
subtype H5N1 cases in poultry were predicted to occur in districts in
the Nile Delta.
Efforts to contain the A(H1N1)pdm09 virus would have been more
effective if the virus had been detected in animal populations before it
was transmitted to humans (
29).
Continuous zoonotic influenza surveillance is needed in China and Egypt
and requires a network of laboratories to screen surveillance samples
and requires financial incentives to encourage poultry producers and
sellers to report outbreaks. One strategy for early detection of a
reassortant virus could involve increasing farm and market surveillance
in the identified areas (i.e., live-bird markets in 6 provinces in China
[Guangdong, Hunan, Jiangsu, Shanghai, Sichuan, and Zhejiang] that have a
>50% chance of subtype H3N2 and H5N1 co-occurrence and above average
swine density). Increased monitoring could identify hotspots where
subtype H5N1 is circulating, leading to more efficient targeted
vaccination of poultry, and could pinpoint prefectures at high risk for a
reassortant virus. In China, sanitary practices, such as cage
disinfection and manure disposal, would substantially reduce risk for
subtype H5N1 in live-bird markets (
30).
In Egypt, our results support increased surveillance of backyard
flocks near Benha, Cairo, Dumyat, El Faiyum, Shibin el Kom, and Tanta,
where suitability for subtypes H5N1 and H3N2 is predicted to be high.
Control measures could include compensation plans and vaccination of
poultry with a recently developed subtype H5N1 vaccine that is more
effective than previous vaccines against strains circulating in Egypt (
10). Reporting of poultry disease outbreaks in Lower Egypt is poor (
31),
probably because farmers fear loss of income if authorities cull their
flocks. Indeed, birds suspected to be infected with subtype H5N1 are
often sold quickly at a discount, resulting in virus transmission to
buyers’ flocks and families (
32).
If equitable compensation schemes were implemented, reporting of
subtype H5N1 might increase and outbreaks could be contained more
quickly, reducing opportunities for subtypes H5N1 and H3N2 to co-infect
humans or domestic animals and, thus, for reassortment.
In general, policies such as culling must have a scientific basis
because these measures have major effects on the economy and animal
welfare. For example, when part of a swine herd is culled to contain an
outbreak, it might become necessary to euthanize the entire herd,
including animals with no influenza exposure, because buyers will not
accept them (
33).
Furthermore, influenza outbreaks among livestock can trigger major
global declines in meat prices, and the nature and timing of veterinary
health authorities’ responses to an outbreak can affect the extent to
which demand recovers after the crisis. In particular, when control
measures such as culling are scientifically well justified and explained
to the public soon after the start of an outbreak, consumer confidence
is restored more quickly (
34).
Although our maps suggest a risk for reassortment in Lower Egypt and
eastern and central China, in vivo reassortment of subtypes H3N2 and
H5N1 has not been detected in humans in these areas. On the other hand,
numerous infections with influenza (H3N2)v, a reassortant virus that
contains genes from a subtype H3N2 virus circulating in swine and from
the A(H1N1)pdm09 virus, have been detected in humans in North America (
35,
36).
This finding raises the question of why subtype H3N2v has spread but
subtype H3N2/H5N1 reassortants have not. Spread of subtype H3N2v could
result from the fact that the reassortant virus contains the M gene from
the A(H1N1)pdm09 virus, which increases aerosol transmission (
35,
37).
Our models might explain why, in contrast with subtype H3N2v
reassortants, no subtype H3N2/H5N1 reassortants have been detected in
humans. For example, we predict that subtypes H3N2 and H5N1 occur in
Hunan, China, a province that has high swine density and was the
geographic origin of subtype H5N1 viruses in clade 2.1 (
38). Influenza (H3N2/H5N1) reassortants in which the nonstructural gene comes from a clade 2.1 virus replicate poorly in mice (
5).
Thus, subtype H3N2/H5N1 reassortants might not have emerged as often as
subtype H3N2v reassortants because the provinces where subtypes H3N2
and H5N1 overlap contain a clade of subtype H5N1, whose genes reduce the
fitness of reassortant viruses.
If this hypothesis is correct, if
subtypes H5N1 and H3N2 infect a pig in central China and exchange genes,
the hybrid virus might not replicate efficiently or transmit to other
hosts. Furthermore, a reassortant virus with surface proteins similar to
those of subtype H3N2 viruses that have circulated in humans recently
might have poor transmissibility because of preexisting immunity (18).
Applying our modeling framework to other zoonotic influenza subtypes,
such as H3N2v, could yield insight about geographic hotspots of
reassortment and the pattern of spatial spread of reassortants. To
accomplish this, 2 data limitations must be overcome. First, to be
incorporated into spatial models, influenza sequences submitted to
GenBank or GISAID should be accompanied by geographic data at relatively
high spatial resolution, for example, names of cities or counties where
sampling was conducted.
However, such sequences are often accompanied
by only the state or country of the sample, which reduces the usefulness
of the data for fine-scale spatial modeling (39).
For example, we searched online databases and confirmed that the
geographic data available for Indonesia are insufficient to construct a
spatial model to predict sites with a high risk for reassortment.
Second, more extensive surveillance of livestock is needed to provide
sufficient sample sizes to parameterize geographic models. Currently,
the number of influenza subtype H1, H3, and H5 viruses from swine in
major databases is an order of magnitude lower than that available for
humans (
Technical Appendix Table 3 [PDF - 1.61 MB - 9 pages]).
Additional surveillance of swine could lead to better predictions about
hotspots of influenza in livestock and sites of potential
swine-to-human transmission. Livestock surveillance campaigns should
sample large geographic areas and include regions where production is
high (35).
The potential for reassortment between human and avian influenza
viruses underscores the value of a One Health approach that recognizes
that emerging diseases arise at the convergence of the human and animal
domains (29,40).
Although our analysis focused on the influenza virus, our modeling
framework can be generalized to characterize other potential emerging
infectious diseases at the human–animal interface.
http://wwwnc.cdc.gov/eid/article/19/4/12-0903_article.htm?s_cid=eid-gDev-email
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