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Published Date: 2009-02-20 17:00:46
Subject: PRO/AH/EDR> Influenza A(H1N1) virus, swine, human - Spain
Archive Number: 20090220.0715

INFLUENZA A(H1N1) VIRUS, SWINE, HUMAN - SPAIN
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[These articles from Eurosurveillance are posted in reverse order to their
presentation in the journal as the editorial makes any moderator comment
superfluous and places previous American data and European experience in
perspective. - Mod.CP]

[1]
Date: Thu 19 Feb 2009
Source: Eurosurveillance edition 2009; 14(7) [edited]
<http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19120>

Human case of swine influenza A (H1N1), Aragon, Spain, November 2008
--------------------------------------------------------------------
[Authors: B Adiego Sancho1, M Omenaca Teres2, S Martinez Cuenca1, P Rodrigo
Val1, P Sanchez Villanueva3, I Casas4, F Pozo4, P Perez Brena4
1. Direccion General de Salud Publica (Directorate General of Public
Health), Zaragoza, Spain
2. Hospital Miguel Servet, Zaragoza, Spain
3. Subdireccion de Salud Publica (Sub-directorate of Public Health),
Teruel, Spain
4. Centro Nacional de Microbiologia (National Microbiology Centre),
Majadahonda, Spain]

A human case of swine influenza A (H1N1) in a 50 year old woman from a
village near Teruel
---------------------------------------------------------------
Summary
-------
A human case of swine influenza A (H1N1) in a 50 year old woman from a
village near Teruel (Aragon, in the north east of Spain), with a population
of about 200 inhabitants, has been reported in November 2008.

Introduction
------------
On 8 Nov 2008, a 50 year old woman developed fever, cough, extreme
tiredness, myalgia, irritation of the nasal/oral mucosae, and shivers of
sudden onset. During a medical visit on 12 Nov 2008, the general
practitioner (GP) who treated the case and is a member of the sentinel
influenza surveillance system, took a throat swab sample and sent it to the
Microbiology Laboratory of the Miguel Servet University Hospital in
Zaragoza, Aragon in the context of the Spanish Influenza Surveillance
System. The patient, with no history of recent travel, did not need
specific treatment or hospitalisation and recovered fully.

Epidemiological investigation
-----------------------------
The case worked on a family swine farm and had direct and close exposure to
pigs. No other family members or co-workers reported flu-like symptoms
before or after this case and no symptoms were observed in the pigs.
However, the GP who took the throat swab sample reported influenza-like
illness (ILI) after visiting the patient. No samples from the GP were taken
at that time.

A low level influenza activity, with no activity for the geographical
spread indicator, was reported in Spain and specifically in the province of
Teruel during week [46/2009: 10-16 Nov 2008] when the case was notified.
The GP did not report any other influenza case for the whole season up to
week 53 [29 Dec 2008-4 Jan 2009].

After the initial report of a possible case of A(H1N1) of swine origin from
the National Influenza Reference Laboratory on 13 Jan [2009], the following
actions were taken: an active surveillance was implemented on site,
including collection of blood samples for serological investigations from
the case, the treating physician and the 4 household contacts of the case
on 20 Jan 2009. Informed consent was required from all of them and a
specifically designed questionnaire was used to interview the 6 mentioned
people. So far, no more cases related to the farm have been detected.
Following the requirements of the International Health Regulations (IHR,
2005), this event was notified to WHO as a human case of influenza caused
by an influenza virus different from those circulating in humans.

Laboratory investigation
------------------------
Respiratory secretions were first inoculated in cell cultures (MDCK) at the
Microbiology Laboratory of the Miguel Servet University Hospital. The cell
cultures were positive for influenza A virus, but the assays routinely used
in this laboratory (immunofluorescence with monoclonal antibodies and PCR
assay) failed to subtype the virus. After consulting the National Influenza
Reference Laboratory (National Influenza Centre-Madrid, Instituto de Salud
Carlos III, Spain) the specimen and influenza isolate were sent to this
laboratory for further characterisation. Different PCR approaches allowed
to partially sequence and identify the haemagglutinin gene. On 13 Jan 2009,
the Reference Laboratory reported an influenza A subtype H1
phylogenetically close to the human isolate A/Switzerland/8808/2002 of
swine origin (1) indicating a sporadic human infection of possible swine
origin.

Other genes (NA, M, NP, and NS) were also sequenced and analysed, which
confirmed that the influenza A virus was phylogenetically related to swine
H1N1 viruses. Partial sequences of the 5 genes have been submitted to the
GenBank database (accession numbers from FJ713784 to FJ713788) PPB.
Avian-like H1N1 swine influenza viruses are enzootic in the swine
population of Western Europe. In order to undertake a serological survey
and further virological studies the virus is being propagated in
embryonated hen eggs.

Discussion
----------
The epidemiological and virological information points towards a human
infection with an influenza virus of swine origin in a person with
professional exposure to pigs. No further cases have been identified
amongst family members or fellow workers. Sporadic human infections due to
influenza viruses of swine origin have been described previously, mostly in
young persons (younger than 25 years) in contact with pigs (2-4).
Transmission to humans for unknown reasons seems to be inefficient.
Although it is expected that similar cases could appear in the future this
event could not be considered unexpected. All these considerations have led
us to investigate this case in order to contribute to a better knowledge of
the interaction between swine and human influenza.

The treating physician reported mild influenza-like symptoms after contact
with the patient. Based on the available information, human to human
transmission could not be confirmed. Ongoing serological studies may be of
help to determine whether further transmission of the swine virus has taken
place. Human to human transmission has been reported before; however in
these cases transmission was limited to one generation (5).

To conclude, this event cannot be considered unexpected and does not pose a
public health risk which would require specific public health measures.

References
----------
1. Gregory V, Bennett M, Thomas Y, Kaiser L, Wunderli W, Matter H, et al.
Human infection by a swine influenza A (H1N1) virus in Switzerland. Arch
Virol 2003; 148(4): 793-802 [abstract available at
<http://www.ncbi.nlm.nih.gov/pubmed/12664301>].
2. The European Surveillance Network for Influenza in Pigs. ESNIP 2. Swine
influenza: variations on an old theme. Available from
<http://www.esnip.ugent.be/page6/page6.html>.
3. Myers KP, Olsen CW, Setterquist SF, Capuano AW, Donham KJ, Thacker EL,
et al. Are swine workers in the United States at increased risk of
infection with zoonotic influenza virus? Clin Infect Dis 2006; 42(1): 14-20
[abstract available from <http://www.ncbi.nlm.nih.gov/pubmed/16323086>].
4. Gray GC, McCarthy T, Capuano AW, Setterquist SF, Olsen CW, Alavanja MC.
Swine workers and swine influenza virus infections. Emerg Infect Dis 2007;
13(12): 1871-8 [available from
<http://www.cdc.gov/EID/content/13/12/1871.htm>].
5. Myers KP, Olsen CW, Gray GC. Cases of swine influenza in humans: a
review of the literature. Clin Infect Dis 2007; 44(8): 1084-8 [abstract
available from <http://www.ncbi.nlm.nih.gov/pubmed/17366454>].

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[Teruel can be located on the map of Spain at
<http://blog.willamette.edu/people/klutz/journal/archives/spain_map.jpg>.
The HealthMap/ProMED-mail interactive map of Spain is available at
<http://healthmap.org/promed/en?g=3108126&v=40.346,-2.106,6>. - CopyEd.MJ]

******
[2]
Date: Thu 19 Feb 2009
Source: Eurosurveillance edition 2009; 14(7) [edited]
<http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19124>

Editorial: a human case of swine influenza virus infection in Europe --
implications for health and research
----------------------------------------------------------------------
[Authors: K Van Reeth1, A Nicoll2
1. Laboratory of Virology, Faculty of Veterinary Medicine, Ghent
University, Belgium
2. European Centre for Disease Prevention and Control, Stockholm, Sweden]

Swine are susceptible to the same influenza A virus subtypes as humans --
H1N1, H3N2, and H1N2 -- and the histories of influenza in pigs and people
are closely linked (1). Many swine influenza viruses are a result of
reassortment and their genes are composed of human and avian and/or swine
virus genes. Indeed, it is known that both human and avian influenza
viruses occasionally transmit to pigs, and that pigs can serve as "mixing
vessels" for these viruses, meaning that viruses can exchange genetic
material and lead to the production of a new "hybrid" virus (2). This has
led to the thinking that perhaps pandemic viruses could emerge following
reassortment in pigs. However, since nobody has observed the start of a
pandemic, there remains no direct evidence to make this more than a theory.

Influenza is one of the major causes of acute respiratory disease in pigs,
but subclinical infections are also common. Unlike the non-zoonotic swine
fevers it is not a disease that comes under the European Union's harmonised
Animal Disease Notification System and there are no routine European
surveillance data. The symptoms and pathogenesis of influenza in pigs show
remarkable similarities with those of seasonal influenza in humans, but the
epidemiology is different. Part of this is due to the structure of the
swine industry and the extremely rapid turnover of the swine population,
with the constant introduction of immunologically naive animals into swine
herds. In swine-dense regions in particular, most pigs show serological
evidence of having been infected with influenza by the end of the
6-month-long fattening period, and many of them have undergone simultaneous
or consecutive infections with 2 or even 3 swine influenza subtypes (3).
Unlike human viruses in temperate climates, swine influenza viruses
circulate at comparable levels year round. Also, the viruses in Europe
differ significantly in their antigenic and genetic make-up from those
circulating in North America, even though they consist of the same H and N
subtypes, and hence findings in the United States should not necessarily be
extrapolated to Europe.

Humans in contact with pigs occasionally become infected by swine influenza
viruses (4). The Eurosurveillance report preceding this editorial describes
a case of swine influenza in a middle-aged woman in Spain (5), which came
to attention almost by chance. The woman worked with pigs and suffered a
mild self-limiting influenza-like illness for which few physicians would
have taken a swab. However the general practitioner (GP) she consulted
happened to be part of an active influenza surveillance scheme and a
specimen was taken. This was passed on to the laboratory as a regular
surveillance specimen and then recognised as being influenza A (H1N1)
phylogenetically close to European H1N1 swine influenza viruses.
Retrospective epidemiological investigations found no evidence of any
further cases apart from the GP who had experienced similar symptoms but
was not laboratory-confirmed (5).

Infection with swine influenza virus has been detected sporadically in
humans since the 1950s and the human disease is usually clinically similar
to disease caused by infections with human influenza viruses (4). However,
complications that include pneumonia and death have occasionally been
reported in the literature in otherwise healthy adults without underlying
disease (4). On the whole, human infections with swine influenza virus, to
date, have been different and much milder than those seen with avian
influenza A (H5N1) (6) and more similar to infections with low pathogenic
avian influenza viruses (7). Single generation person to person
transmission has been reported but appears to be rare and chains of
transmission have not been observed in general (4). Though it is not
entirely clear what measures public health authorities should pursue when
they discover such human infections, it seems reasonable to regard them as
comparable to low pathogenic avian influenza and so deserving a similar
approach (7).

There is one well-known exception to these generalisations. In 1976 an
outbreak of swine influenza virus infections in humans was detected in
recruits in a military camp in Fort Dix, New Jersey in the United States.
The presumed link to pigs was never discovered but there was extensive
human to human transmission, with over 200 infections resulting in 12
hospitalisations and one death (8). This was human to human transmission of
a novel influenza virus causing some significant human pathology, which
today might be described as WHO Pandemic Phase 4 (9). The unilateral
decision was made by the national authorities to develop, produce and
deploy a specific pandemic vaccine based on the new strain. However, the
infections petered out and the vaccine was seemingly associated with
occurrence of Guillain-Barre syndrome in a few recipients. Mass
immunisation was terminated but the incident remains part of public health
lore and has been reviewed extensively for its learning points (10,11).

While the reported case in this issue and other sporadic cases pose little
direct threat to humans, they expose important gaps in knowledge about
these zoonotic influenzas. The true incidence of swine influenza in humans,
for example, is unknown. Recent serologic studies in the United States,
where there has been more attention to zoonotic swine influenza than in
Europe, have consistently found higher seroprevalence rates and higher
antibody titres against all swine influenza viruses in those working with
pigs than in non-swine-exposed controls (12-15). This, and the fact that
the current infection was detected by accident, suggests that the few
reported cases of symptomatic swine influenza in humans represent a larger
number of undetected infections among those in contact with pigs. However,
there are no comparable data available for Europe and the prevalence of
swine influenza in humans cannot be estimated from such studies because of
the possibility of partial serologic cross-reactivity in the
haemagglutination-inhibition test between human and swine influenza virus
strains of the same subtype. Epidemiologists have tried to adjust for this
by statistical methods, but they agree "it is possible that the elevated
titers compared by proportional odds modeling do not correlate with
infection" (13). This stresses the need for combined serological and
virological surveillance in humans exposed to pigs to gain this
information. There have been recent developments in surveillance of
influenza in European swine populations, which is an essential starting
point for the monitoring of swine flu in humans. A fruitful initiative has
been the "European Surveillance Network for Influenza in Pigs (ESNIP)"
(2000-2009) a European Commission funded project that ends next month
[March 2009].

Even if the magnitude of the risk of swine influenza virus infections to
human health is unknown, it seems unlikely to be high. Two factors are
probably restricting infection of humans, though both are neglected
research areas. Firstly, the host range of influenza viruses is generally
very restricted by a limited fitness of a given virus in a different host
species. Studies on the infectivity of animal influenza viruses for cells
of the human respiratory tract, and the molecular determinants involved,
have however so far focused almost exclusively on avian influenza viruses
(16-18). Secondly, immunity to human H1 or H3 influenza viruses may
partially protect against infection with swine viruses. But animal model
experiments on this issue are lacking. This type of research is needed if
we want to understand the risk of zoonotic influenza based on
scientifically proven facts rather than hypotheses.

The unknown element is the risk of reassortment to produce a novel virus,
even a pandemic strain either in the pig "mixing vessel" or in a human
dually infected with a human and pig strain. In the United States there
have recently appeared triple reassortant swine influenza viruses with
avian, human, and swine genes and these have then transmitted to humans
(19,20). Fortunately, these and similar swine influenza viruses (21) that
can infect humans have not yet met any of the criteria to cause a human
pandemic. The true risk can only become clear if epidemiological
investigations are combined with experimental research. Some scientists
have advocated offering seasonal influenza vaccination to persons working
with pigs to reduce their risk of getting infected (15). However,
experience with workers with domestic poultry on this point is not
encouraging (22). In one audit attempt in Europe uptake of the vaccine was
low and those offered immunisation were confused as to what they were being
protected against. The possible efficacy of human influenza vaccines
against swine influenza virus infection, on the other hand, also remains
unknown.

Following the discovery in Spain it seems likely that more human infections
will be detected and reported as has happened in North America. While such
events will mean an improvement in surveillance rather than an increased
risk, they highlight another area where closer human and animal
surveillance is needed around a poorly understood zoonosis.

References
----------
1. Olsen CW, Brown I, Easterday BC, Van Reeth K. Swine influenza. In: Straw
BE, Zimmerman JJ, D'Allaire S, Taylor DJ, editors. Diseases of Swine. 9th
ed. Ames, Iowa: Iowa State University Press; 2006. pp 469-82.
2. Van Reeth K. Avian and swine influenza viruses: our current
understanding of the zoonotic risk. Vet Res 2007; 38(2): 243-60 [abstract
available from <http://www.ncbi.nlm.nih.gov/pubmed/17257572>].
3. Van Reeth K, Brown IH, Durrwald R, Foni E, Labarque G, Lenihan P, et al.
Seroprevalence of H1N1, H3N2 and H1N2 influenza viruses in pigs in seven
European countries in 2002-2003. Influenza and other respiratory viruses.
2008; 2(3): 99-105 [available from
<http://www.medscape.com/viewarticle/574904>.
4. Myers KP, Olsen CW, Gray GC. Cases of swine influenza in humans: a
review of the literature. Clin Infect Dis 2007; 44(8): 1084-8 [abstract
available from <http://www.ncbi.nlm.nih.gov/pubmed/17366454>].
5. Adiego Sancho B, Omenaca Teres M, Martinez Cuenca S, Rodrigo Val P,
Sanchez Villanueva P, Casas I, et al. Human case of swine influenza A
(H1N1), Aragon, Spain, November 2008. Euro Surveill 2009; 14(7): pii=19120.
Available from
<http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19120>.
6. Writing Committee of the Second WHO Consultation on Clinical Aspects of
Human Infection with Avian Influenza A (H5N1) Virus, Abdel-Ghafar AN,
Chotpitayasunondh T, Gao Z, Hayden FG, Nguyen DH, et al. Update on avian
influenza A (H5N1) virus infection in humans. N Engl J Med 2008; 358(3):
261-73 [available from <http://content.nejm.org/cgi/content/full/358/3/261>].
7. Influenza team (ECDC). Low Pathogenicity Avian Influenzas and human
health. Euro Surveill 2007; 12(22): pii=3209. Available from
<http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=3209>.
8. Hodder RA, Gaydos JC, Allen RG, Top FH Jr, Nowosiwsky T, Russell PK.
Swine influenza A at Fort Dix, New Jersey (January-February 1976). III.
Extent of spread and duration of the outbreak. J Infect Dis 1977; 136
Suppl: S369-75 [available from
<http://www.thefreelibrary.com/Swine%20influenza%20a%20outbreak,%20Fort%20Dix,%20New%20Jersey,%201976-a0141048443>].

9. WHO. WHO global influenza preparedness plan. The role of WHO and
recommendations for national measures before and during pandemics. Geneva:
WHO; 2005. Available from
<http://www.who.int/csr/resources/publications/influenza/WHO_CDS_CSR_GIP_2005_5.pdf>.

10. Neustadt RE, Fineberg HV. The swine flu affair: decision-making on a
slippery disease. Honolulu: University Press of the Pacific; 2005 [review
available from <http://www.bmj.com/cgi/content/full/331/7527/1276?rss>].
11. Sencer DJ, Millar JD. Reflections on the 1976 swine flu vaccination
program. Emerg Infect Dis 2006; 12(1): 29-33 [available from
<http://www.cdc.gov/ncidod/EID/vol12no01/pdfs/05-1007.pdf>].
12. Olsen CW, Brammer L, Easterday BC, Arden N, Belay E, Baker I, et al.
Serologic evidence of H1 swine Influenza virus infection in swine farm
residents and employees. Emerg Infect Dis 2002;8(8): 814-9 [available from
<http://www.cdc.gov/ncidod/eid/vol8no8/01-0474.htm>].
13. Myers KP, Olsen CW, Setterquist SF, Capuano AW, Donham KJ, Thacker EL,
et al. Are swine workers in the United States at increased risk of
infection with zoonotic influenza virus? Clin Infect Dis 2006; 42(1): 14-20
[abstract available from <http://www.ncbi.nlm.nih.gov/pubmed/16323086>].
14. Ramirez A, Capuano AW, Wellman DA, Lesher KA, Setterquist SF, Gray GC.
Preventing zoonotic influenza virus infection. Emerg Infect Dis 2006;
12(6): 996-1000 [available from
<http://www.cdc.gov/ncidod/eid/vol12no06/05-1576.htm>].
15. Gray GC, McCarthy T, Capuano AW, Setterquist SF, Olsen CW, Alavanja MC.
Swine workers and swine influenza virus infections. Emerg Infect Dis 2007;
13(12): 1871-8 [available from
<http://www.cdc.gov/EID/content/13/12/1871.htm>].
16. Matrosovich MN, Matrosovich TY, Gray T, Roberts NA, Klenk HD. Human and
avian influenza viruses target different cell types in cultures of human
airway epithelium. Proc Natl Acad Sci USA 2004; 101(13): 4620-4 [available
from <http://www.pnas.org/content/101/13/4620.full>].
17. Wan H, Perez DR. Amino acid 226 in the hemagglutinin of H9N2 influenza
viruses determines cell tropism and replication in human airway epithelial
cells. J Virol 2007; 81(10): 5181-91 [available from
<http://jvi.asm.org/cgi/reprint/81/10/5181.pdf>].
18. Bateman AC, Busch MG, Karasin AI, Bovin N, Olsen CW. Amino acid 226 in
the hemagglutinin of H4N6 influenza virus determines binding affinity for
alpha 2,6-linked sialic acid and infectivity levels in primary swine and
human respiratory epithelial cells. J Virol 2008; 82(16): 8204-9 [available
from <http://jvi.asm.org/cgi/content/full/82/16/8204>].
19. Olsen CW, Karasin AI, Carman S, Li Y, Bastien N, Ojkic D, et al. Triple
reassortant H3N2 influenza A viruses, Canada, 2005. Emerg Infect Dis 2006;
12(7): 1132-5 [abstract available from
<http://www.ncbi.nlm.nih.gov/pubmed/16836834>].
20. Newman AP, Reisdorf E, Beinemann J, Uyeki TM, Balish A, Shu B, et al.
Human case of swine influenza A (H1N1) triple reassortant virus infection,
Wisconsin. Emerg Infect Dis 2008; 14(9): 1470-2 [abstract available from
<http://www.ncbi.nlm.nih.gov/pubmed/18760023>].
21. Gregory V, Lim W, Cameron K, Bennett M, Marozin S, Klimov A, et al.
Infection of a child in Hong Kong by an influenza A H3N2 virus closely
related to viruses circulating in European pigs. J Gen Virol 2001; 82(Pt
6): 1397-406 [abstract available from
<http://www.ncbi.nlm.nih.gov/pubmed/11369884>].
22. Lyon AK, Davies T, Tahir M, Spraggett B. The English Seasonal Flu
Immunization Programme for Poultry Workers 2007: a challenging task. J
Public Health (Oxf) 2008; 30(3): 245-50 [abstract available from
<http://www.ncbi.nlm.nih.gov/pubmed/18567571>].

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