Influenza Infections
J. M. Daly1 and
A. Cullinane2
1School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, Leicestershire, UK. 2Irish Equine Centre, Johnstown, County Kildare, Ireland.
Classification of Equine Influenza Virus
Equine influenza viruses are classified as type A influenza viruses,
which also include viruses infecting man, birds and swine. Type A
influenza viruses are divided into subtypes according to the antigenic
characteristics of the surface antigens, haemagglutinin (HA) and
neuraminidase (NA). With the exception of the recently discovered H17N10
bat influenza virus [
1],
all the subtypes (combinations of H1 to H16 and N1 to N9) have been
isolated from aquatic birds, which act as a natural reservoir for
influenza A viruses. Two subtypes have established in equids (H7N7 and
H3N8, previously known as equi-1 and equi-2, respectively).
Epidemiology
Influenza virus was first isolated from horses in Czechoslovakia in 1956 [
2];
this was the prototype strain for the H7N7 subtype of equine influenza
virus A/equine/Prague/56 (H7N7). There has been no convincing evidence
for circulation of H7N7 viruses in horses for several decades.
Virus of the H3N8 subtype was first isolated in Miami in 1963 [
3].
Antigenic variants can give rise to large-scale disease epidemics in
regions where the virus is endemic, such as Europe and North America.
Only New Zealand and Iceland are known to have remained entirely free
from equine influenza. Some of the most devastating epidemics of equine
influenza have occurred when the virus has been introduced into areas
previously free of the disease. Outbreaks in South Africa (1986 and
again in 2003/4), India (1987), Hong Kong (1992), and Australia (2007)
highlighted the ease with which equine influenza can be introduced into
susceptible populations as a result of international movement of horses [
4-9].
The outbreak in Australia in 2007 particularly emphasised the potential
impact of introduction of equine influenza virus into an unvaccinated
population, with around 76,000 horses affected and an estimated
expenditure of 360 million Australian dollars to bring the outbreak
under control [
10].
A novel strain of equine influenza caused an epidemic in China in
1989 with an overall morbidity rate of 80% and a mortality rate of 20%.
The prototype virus from this epidemic (A/equine/Jilin/89) was shown to
be more closely related to influenza viruses infecting aquatic birds
than to contemporary equine influenza viruses, demonstrating that the
epidemic was the result of emergence of virus from the avian influenza
reservoir [
11].
A related avian-like virus, which had lost its ability to replicate in
birds, affected a few hundred horses in 1990, but seems to have neither
persisted in nor spread beyond China [
12].
Influenza A viruses are unpredictable by their very nature and
unlikely to ever be fully eradicated due to the reservoir of viruses
circulating in wild aquatic birds. Recently, donkeys in Egypt joined the
relatively long list of mammalian species to have been naturally
infected with highly pathogenic avian influenza virus of the H5N1
subtype [
13].
It was thought that there was no interchange of influenza virus
infections between horses and other mammalian species. However,
interspecies transmission of equine influenza virus to dogs has occurred
apparently independently in the USA, UK and Australia [
14-16].
Furthermore, the H3N8 virus has become endemic, with dog-to-dog
transmission, in North America. During surveillance of pigs in China,
two H3N8 isolates closely related to equine viruses circulating in the
1990s were isolated in 2005 and 2006 [
17]. Although human volunteers have been experimentally infected with equine influenza virus [
18], there is currently little evidence of zoonotic infection of people with equine influenza.
Clinical Signs and Pathology
Equine influenza is contracted by inhalation. The virus infects the
ciliated epithelial cells of the upper and lower airways and can cause
deciliation of large areas of the respiratory tract within 4 to 6 days (
Fig. 1a,
Fig. 1b,
Fig. 1c).
As a result, the mucociliary clearance mechanism is compromised and
tracheal clearance rates may be reduced for up to 32 days following
infection [
19].
Classic clinical signs of influenza infection in previously naïve
animals are easily recognisable, although some strains of equine
influenza are less virulent than others [
20].
In addition, the amount of virus to which the horse is exposed
influences the severity of the disease. Influenza is characterised by a
short incubation period of one to 3 days and rapid spread among
susceptible animals. The rapidity with which influenza spreads is a key
observation for differentiating influenza from other infectious
respiratory diseases. The first sign is an elevation of body temperature
(up to 41°C), which is usually followed by a deep dry cough that
releases large quantities of virus into the atmosphere. This is often
accompanied by a serous nasal discharge (
Fig. 2),
which may become mucopurulent. Other clinical signs that may be
observed include: depression, myalgia, inappetance, enlarged
submandibular lymph nodes, and oedema of the legs and scrotum.
Previously healthy adult horses usually recover from uncomplicated
influenza within 10 days, although coughing may persist for longer. If
secondary bacterial infection occurs it can prolong the recovery period.
On rare occasions more severe signs are observed, sometimes with fatal
outcome. Neurological signs were observed in two influenza-infected
horses during the 2003 outbreak in the UK [
21],
and broncho-interstitial pneumonia was observed in young foals without
maternal antibodies during the 2007 outbreak in Australia [
22].
The severity of the disease varies with the immune status of the
horse; in animals partially immune as a result of vaccination or
previous infection there may be little or no coughing or pyrexia [
23,24].
Whereas spread of infection throughout a group of naïve animals is
generally rapid, outbreaks have been described in which the infection
circulated sub-clinically in vaccinated horses for 18 days before
inducing recognisable clinical signs [
4].
There have also been positive diagnoses of a few animals infected with
equine influenza that have occurred without spread to other animals
within Thoroughbred racehorse training yards [
25]. In well-vaccinated Thoroughbreds, loss of performance may be the only indication that a horse is infected [
26].
Diagnosis
Various agents may cause outbreaks of infectious respiratory disease
in horses including: equine herpes, rhino, adeno, and arteritis viruses,
Streptococcus equi,
S. zooepidemicus, or
S. pneumoniae.
Therefore, a presumptive diagnosis of influenza based on clinical signs
should be confirmed by laboratory testing. Traditionally, laboratory
confirmation of a clinical diagnosis has been by isolation of virus from
nasopharyngeal swabs or retrospective serology, both processes that can
take several days if not weeks. Nowadays, a wide range of laboratory
tests are available that allow more rapid diagnosis of influenza
infection.
Nasopharyngeal swabs for virus isolation or detection should be taken
as promptly as possible. Results of experimental challenge studies
suggest that peak viral titres occur on the second or third day after
infection, and duration of viral shedding is usually not more than 4 or 5
days in naïve animals [
27].
Nasal swab samples are taken by passing a swab as far as possible into
the horse’s nasopharynx via the ventral meatus to absorb respiratory
secretions. Swabs should be transferred immediately to a container with
virus transport medium, which contains antibiotics, and kept cool to
maintain viability of the virus. Most equine diagnostic laboratories
will supply appropriate swabs and transport medium (
Fig. 3).
Virus is unlikely to survive if dry swabs are taken and there is
increased chance of contamination if bacterial transport medium is used.
Most laboratories only attempt virus isolation from samples that have
tested positive in a rapid diagnostic test. Virus isolation is essential
to surveillance programmes and provides isolates to update vaccine
strains when this becomes necessary to maintain vaccine effectiveness (
Fig. 4).
Where there are low levels of virus shedding, such as in vaccinated
horses, virus isolation may prove difficult and some strains are more
difficult to isolate than others.
Virus isolation has been largely replaced by rapid diagnostic tests
that detect the presence of viral antigens (enzyme-linked immunosorbent
assays, ELISAs) or viral nucleic acid (reverse-transcription and
polymerase chain reaction, RT-PCR) in nasal swab extracts. RT-PCR is the
test of choice in most laboratories as it is highly sensitive and can
provide a result in a matter of hours [
28-30].
An equine influenza-specific ELISA to detect viral nucleoprotein has
been in use at the Animal Health Trust, Newmarket, UK since 1989 [
31,32].
There are now commercial influenza detection kits available for the
diagnosis of human influenza that cross-react with equine influenza.
Although less sensitive than equine-specific assays, these kits are easy
to use by staff with little laboratory training and provide a rapid
result [
33-36].
Influenza infection can also be diagnosed by comparison of the
results of serological testing of an acute serum sample taken as soon as
possible after the onset of clinical signs and a convalescent serum
sample taken around 2 weeks later. There are two serological assays –
the haemagglutination inhibition (HI) test (
Fig. 5) and the single-radial haemolysis (SRH) test (
Fig. 6).
Both assays rely on measurement of antibodies to haemagglutinin, the
surface glycoprotein responsible for viral attachment and entry into
host cells and the primary target of virus neutralising antibodies. The
SRH test is more complicated and time-consuming to perform than the HI
test, but has the advantage of being easier to standardise between
laboratories and is therefore particularly useful for vaccine efficacy
and epidemiological studies. Serological detection of influenza virus
infection is rarely useful in immediate clinical management. However, it
is a useful surveillance tool and may be essential to establish a
diagnosis where virus detection has not been possible (virus may only be
shed for 1 or 2 days and at lower levels in partially immune animals).
ELISA tests that detect antibodies against the viral nucleoprotein have
recently become available. They are less sensitive than HI and SRH for
the detection of influenza in populations where the virus is endemic,
but were extremely useful in the control and eradication of equine
influenza in Australia [
37].
Most recently, a sensitive and quantitative assay to measure
neutralising antibodies was developed using an equine influenza
pseudotyped lentivirus [
38].
Vaccination
Traditional equine influenza vaccines consist of representative virus
strains either as inactivated whole virus or protein subunits and are
dependent on induction of antibodies to the surface glycoproteins, in
particular haemagglutinin. Levels of antibody required for protection of
horses have been determined through vaccination and challenge studies
and from field data [
39,40].
The vaccine-induced antibody response to HA is remarkably short-lived
in horses, therefore, adjuvants such as aluminium hydroxide, carbomer or
saponins are normally included to enhance the height and duration of
the immune response to whole virus or subunit [
41,42].
Live-attenuated and canarypox-vectored vaccines are now also
available against equine influenza in some countries. These vaccines are
intended to mimic the immune response to natural infection more closely
than the traditional vaccines. However, both second-generation vaccines
such as immune-stimulating complex (ISCOM)-based and canarypox
recombinant vaccines on the one hand, and a more traditional whole
inactivated vaccine on the other, have been shown to elicit a
cell-mediated immune response [
43-46].
Vaccination against equine influenza is mandatory for racehorses and
competition horses in several countries and it is important to comply
with the relevant regulations. This does not, however, guarantee
protection of individual horses, although vaccinated horses typically
have milder disease than non-vaccinated horses, are less likely to
develop secondary bacterial infections and can thus return to work
sooner. A few horses respond poorly to vaccination and have persistently
low antibody titres; such horses are often instrumental in starting an
influenza outbreak within a premise [
47]. Serological monitoring of antibody levels can be useful to determine whether additional booster vaccinations are required [
48].
Equine influenza outbreaks are frequently associated with sales or race
meets where horses from different regions congregate and mix. It may
therefore be advantageous to time additional booster vaccinations to be
given prior to such events.
It has been demonstrated that inclusion of an additional booster
vaccination to close the window of susceptibility between the second and
third vaccinations recommended by the vaccine manufacturers is of
benefit to young horses [
49].
Furthermore, it is advisable to vaccinate young horses, particularly
racehorses and other competition horses, at 4- to 6-month intervals for
several years after their primary course of vaccinations. An annual
booster will usually suffice for older horses such as show jumpers and
brood mares that have been vaccinated regularly since they were foals.
Brood mares should be vaccinated in the later stages of pregnancy,
but not later than 2 weeks prior to foaling, to ensure a good supply of
colostral antibodies for the foal. For most vaccines, vaccination in the
presence of maternal antibodies is not recommended as they interfere
with the response to vaccination and may even lead to the induction of
serotolerance [
49-51].
It is therefore advisable to monitor the antibody titres of foals and
start the vaccination programme when maternal antibody titres have
declined to negligible levels, usually at around 6 months of age (foals
from non-immunised dams should be vaccinated earlier). It has been
suggested that vaccination of foals with the canarypox-vectored
recombinant vaccine effectively primes the immune system despite the
presence of maternally-derived antibodies [
52].
Some existing vaccines are available as combination vaccines also
containing tetanus or herpes antigens. The immune response elicited by
tetanus toxoid is much more durable than that induced by influenza
antigen and it is inadvisable to administer tetanus toxoid more
frequently than the vaccine manufacturers recommend. In an intensive
influenza vaccination programme, vaccines containing influenza only
should be routinely administered.
Vaccine Strain Selection
It has been demonstrated in vaccination and challenge studies and in
the field that the ability of a vaccine to reduce virus shedding is
directly correlated with the antigenic relatedness of the vaccine strain
and the challenge virus [
53,54].
A European rapid licensing system for influenza vaccines containing
updated strains has been developed on the basis that accurate
standardisation of in vitro vaccine potency tests allows a reduction in
animal testing of the final product [
55]. It is nonetheless a major undertaking to update vaccine strains. An Expert Surveillance Panel was instigated at a meeting of
World Health Organisation and
OIE (World Organization for Animal Health) experts in 1995 [
56]. Human influenza vaccines are reviewed on an annual basis and in most years at least one of the 3 components is updated. The
equine influenza Expert Surveillance Panel
similarly reviews available data annually and reports whether changes
to vaccination composition are required. However, antigenic drift occurs
at a much lower rate in equine influenza viruses than in human
influenza viruses [
57],
therefore equine vaccines do not need to be updated so frequently. The
initial recommendation of the Expert Surveillance Panel was that
vaccines should contain one H3N8 virus representative of the
"American-like" lineage and a representative of the "European-like"
lineage [
56]. Prior to 1993, it was thought that equine influenza H3N8 viruses evolved in a single lineage [
58]. However, in 1993 viruses were isolated that revealed divergent evolution on the American and European continents [
57]; the American and European lineages (
Fig. 7).
In recent years, there has been little evidence of European lineage
viruses in circulation whereas the American lineage has continued to
evolve with the predominance of a "Florida sublineage", which has
further diverged into two distinct "clades" [
59,60].
The latest recommendations to have been published are that vaccines
should contain both clade 1 and clade 2 viruses of the Florida
sublineage but that it is not necessary to include either an H7N7 strain
or a "Eurasian lineage" strain [
61].
Management of an Influenza Outbreak
Treatments for equine influenza are aimed at ameliorating clinical signs; antiviral agents have only been used experimentally [
62-66].
Rest is essential to reduce the severity of clinical signs and the
recovery period, and minimise chronic sequelae. Ill animals should be
provided with plenty of fresh water. Electrolytes can be provided, in a
second bucket of water [
67].
A non-steroidal anti-inflammatory drug (NSAID) can be used in cases
with high fever to reduce pulmonary inflammation and in pregnant mares
to reduce the risk of abortion. Clinical signs should be monitored daily
and if secondary bacterial infection is suspected (indicated by coarse
crackles sounds in the lung and prolonged or rising fever), antibiotic
therapy should be initiated, and samples obtained for bacterial culture
and antibiotic sensitivity testing.
Immediate and effective quarantine of infected individuals is the
best way to minimise spread of influenza virus within premises. In order
for quarantine measures to be effective, infected individuals must be
rapidly identified and isolated. This can be achieved by regularly
taking temperatures and / or samples for rapid diagnostic tests.
Similarly, restricting movement from premises can limit spread of the
virus further afield. In Australia during the 2007 outbreak of equine
influenza outbreak, movement restrictions were put in place within and
between four different zones according to the level of infection already
observed within each zone [
9].
Precautions should be taken against the risk of spread by personnel or
shared equipment (including vehicles used for transportation); spread of
virus by fomites or people was implicated in both outbreaks of equine
influenza in South Africa [
7,8].
Vaccination in the face of an outbreak has also proven to be effective [
10,
68,69].
However, if horses are vaccinated in the face of infection it can be
difficult, using HI and SRH assays, to determine whether any increase in
antibody levels is due to vaccination or infection. In Australia, the
canarypox-vectored vaccine was used as part of the effort to contain the
outbreak in 2007. This vaccine expresses only the HA protein of equine
influenza virus, therefore using an ELISA to detect antibodies to
nucleoprotein (present in infectious virus) enables differentiation of
infected from vaccinated animals (the so-called DIVA strategy).
Conclusions
Although equine influenza is a self-limiting disease, it is highly
contagious in susceptible populations. There have been considerable
advances in development of sensitive and rapid diagnostic tests for
equine influenza virus in recent years. Nonetheless, it continues to be
imperative to obtain samples that allow characterisation and isolation
of new strains of equine influenza virus as effective vaccination
remains dependent on relevant strains being included in vaccines.
Different vaccine technologies are available for equine influenza; to
maximise their effectiveness, consideration must be given to the choice
of product and vaccination regimen.
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