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Published Date: 2009-05-03 21:00:06
Subject: PRO/AH/EDR> Influenza A (H1N1) - worldwide (07)
Archive Number: 20090503.1658

INFLUENZA A (H1N1) - WORLDWIDE (07)
***********************************
A ProMED-mail post
<http://www.promedmail.org>
ProMED-mail is a program of the
International Society for Infectious Diseases
<http://www.isid.org>

In this update:
[1] Vaccine Logistics: Correction
[2] Multi-drug strategy
[3] Celia Alpuche interview
[4] 'Ground zero' village
[5] H5N1 in swine

******
[1] Vaccine logistics: Correction of "Influenza A (H1N1) - worldwide
(05)" 20090503.1657

The moderator comment from a report discussing the logistics of
production of a vaccine for the novel influenza A (H1N1) in the
ProMED report "Influenza A (H1N1) - worldwide (05)" 20090503.1657
stated: "infections with the novel H5N1 strain with few infections
have been mild" rather than "infections with the novel H1N1 strain
with few exceptions have been mild" The corrected full comment is
reproduced below. ProMED apologizes for the error. - Mod.LM

[A question which has still to be addressed in this debate is the
extent to which vaccination with seasonal influenza virus vaccine
will provide some degree of immunity or amelioration of symptoms in
vaccinees. The symptoms of the illness in those experiencing
infection with the novel H1N1 strain with few exceptions have been
mild (the Mexican population apart). It would be interesting to know
to what extent this relates to the seasonal influenza virus history
of patients. - Mod.CP]

******
[2] Multi-drug strategy
Date: Fri 1 May 2009
Source: The New Scientist [edited]
<http://www.newscientist.com/article/dn17069-multidrug-strategy-could-slow-pandemic-spread.html>

Multi-drug strategy could slow pandemic spread
----------------------------------------------
How individual countries deploy their flu drugs may be key to
determining the size of any pandemic that emerges from the current
H1N1 outbreak. That's the conclusion of a mathematical model of flu
transmission by an international team of researchers. The findings
also suggest that countries that stockpile just one of the 2 commonly
used flu drugs may have trouble controlling a major pandemic.

"If you can hold off using your primary drug until the cumulative
number of cases reaches a sufficiently high number, you reduce the
spread of resistance and the final number of cases," says team member
Joseph Wu at the University of Hong Kong. "The key is to make sure
the source population has good control of antiviral drugs, then all
countries downstream benefit. If the source loses control then these
strategies won't work," he says.

There are 2 anti-flu drugs that are commonly stockpiled for use in a
flu pandemic: oseltamivir, which is sold as Tamiflu, and zanamivir,
which is sold as Relenza. Both work by inhibiting an enzyme called
neuraminidase that the virus needs to replicate, but they act on
different parts of the enzyme and resistance to one drug does not
confer resistance to the other. The Mexican H1N1 strain is currently
sensitive to both drugs, but no one knows how long that will last.

The Wu team conducted their study after noticing that despite
concerns about resistance, many countries stockpile just one drug,
usually oseltamivir. There are some exceptions, however, including
Australia and the UK, which stockpile both drugs.

Viruses are notorious for their ability to develop resistance to
drugs. Last year (2008), an H1N1 flu strain that caused some seasonal
flu rapidly developed resistance to oseltamivir. By December, "close
to 100 percent of H1N1 in Australia and the US, and many other parts
of the world, were resistant to Tamiflu," says Raina MacIntyre, an
infectious disease expert at the University of New South Wales in
Sydney, Australia.

To work out whether initially treating patients from a smaller
stockpile of a secondary anti-flu drug could delay the emergence of
resistance, the Wu team ran a mathematical model of a flu outbreak in
a theoretical "closed" population of 6.8 million the size of Hong
Kong. In the model, doctors either prescribed just one drug, both
drugs in combination, or prescribed one, then switched to the other
when supplies of the 1st drug ran out.

The 2 strategies that used more than one drug decreased the number of
people who finally became infected from 68 to 58 percent. It also
reduced the chance of resistance emerging from 38 to just 2 percent,
which would translate into a significant number of lives saved, says
Wu.

When the model included international travel between the "index"
population and 105 large cities to take into account the possibility
that people might spread resistant strains, the 2 strategies that
used more than one drug reduced the final number of people infected
and the emergence of resistance to a similar degree.

As the safety of using 2 drugs together has not been assessed, the
most practical strategy would be to use a limited supply of one drug
1st, and then switch to the other, says Wu. Zanamivir, which is less
popular because it has to be inhaled, is the obvious drug of choice
for the limited-supply drug. However, it has not been approved to
treat young children.

"Cross-resistance to both drugs at the same time is highly unlikely,
so using the 2 drugs cleverly might be able to delay the emergence of
resistance," says epidemiologist Jodie McVernon at Melbourne
University, Victoria, Australia, who was not involved in the study.
McVernon's team have previously used mathematical modelling to show
that resistance can also be delayed by using one of the drugs to
treat active flu infections, and the other to prevent infection. "In
Australia, where the stock pile is enough for 40 percent of the
population, we are keen to use drugs to prevent cases and spread
early on, because it's far more effective at limiting the pandemic,"
she says.

The Wu model only considers drug resistance that is caused by
treatment with the drug, and not resistance that emerges from mixing
of viruses, or natural mutation. Wu points out that simply avoiding
using either drug until numbers of sick people had reached a certain
threshold would have the same effect as using 2 drugs in succession.
"But medically that would be unethical, so you need to use a 2nd
drug," he says. "In a scenario where lots of drugs are being used
over a short period of time, drug resistance will probably emerge,
and efficacy would be substantially weakened," says Wu.

The modelling study was carried with researchers from Harvard
University and the Health Protection Agency in London, as well as the
University of Hong Kong. (An account of this research will be
published in the journal PLoS Medicine)

[Byline: Rachel Nowak]

******
[3] Celia Alpuche interview
Date: Fri 1 May 2009
Source: ScienceInsider [abbreviated and edited]
<http://blogs.sciencemag.org/scienceinsider/2009/05/exclusive-inter.html>

[An Interview With Head of Mexico's Top Swine Flu Lab Microbiologist.
Celia Alpuche, who heads the laboratory in Mexico that has become
ground zero for the country's outbreak of swine flu, spoke to Science
yesterday from her office at the Instituto de Diagnpstico y
Referencia Epidemiologicos (InDRE) in Mexico City.]

Celia Alpuche: Many people have raised questions about whether Mexico
could have detected this outbreak earlier and contained it before it
spread elsewhere. But as Alpuche explains, InDRE had a confusing
situation because the virus surfaced in the middle of flu season --
and it may not have originated in Mexico anyway. Alpuche also sets
the record straight about why it took several weeks to link the
outbreak to the 1st case with symptoms, a 4-year-old boy from La
Gloria in Veracruz state. And she frankly describes the limitations
of her own lab.

InDRE has worked closely with the Public Health Agency of Canada and
the U.S. Centers for Disease Control and Prevention (CDC) to identify
the virus as the cause of the outbreak, and Mexico continues to
collaborate to test samples of suspected cases. As of 1 May 2009,
Mexico had 156 confirmed cases and 9 deaths, more than any country in
the world. Mexico has identified another 1918 suspected cases, as
described in the CDC's Morbidity and Mortality Weekly Report (MMWR)
yesterday [30 Apr 2009], and InDRE is rushing to sort out how many
are actually swine flu.

Influenza is caused by 2 strains, A and B, and several different
subtypes that are designated by the 2 proteins that stud the viral
surface, hemagglutinin and neuraminidase, followed by a number. The
outbreak is caused by an influenza A virus of the subtype H1N1.

Question by ScienceInsider: There have been many questions about the
origin and the timing. When was there an indication that there were
an unusual number of respiratory cases?

Alpuche: On 7 Apr 2009, we heard that the National Institute of
Respiratory Disease was having unusually severe cases of pneumonia in
young adults who were previously healthy. Immediately, we started to
get the data around this cluster. We also started to do a
retrospective analysis of the influenza data we had. We looked at all
data that we had regarding influenza detection since January [2009]
up to this month and also to compare to the past season of influenza.
In addition to the unusual pneumonia, we started to have rumors there
were other cases that were not pneumonia, it was like a respiratory
disease, an influenza-like illness. The 1st thing that it told us is
that we were still detecting influenza in the country, not just in
Mexico City. It was pretty much the same as we see every year except
it was a prolongation of the flu season. Then we analyzed the
subtypes of the strains of influenza, and one of the unusual things
we saw was that in this season, we had the 1st peak in the last part
of November and December and another one in February. Over the
season, we started having more influenza B than we had the year
before.

It was very confusing. We found that 37 percent of cases were B and
the year before we only found up to 15 percent were B. Then we looked
at data that they have in the influenza surveillance system at CDC to
see if were having something unusual. We saw also in United States
something kind of similar -- a prolonged period of influenza and
increases of strain B. So we thought that we were having something
related to influenza, and we were still concerned about the pneumonia
cases. We went back immediately to look at all the influenza
outbreaks we had in the country since the season started to see if
this was more related to the prolonged influenza or there was
something else we were seeing. We had small outbreaks in some states
in the central part of Mexico, Tlaxcala, and then the last outbreak
we had was in Veracruz state, in the town of La Gloria, near Perote.
That was in the last 2 weeks of March.

ScienceInsider question: Why didn't that trigger concern in the last
2 weeks of March?

Alpuche: It was influenza-like illness, no fatalities and no
pneumonia cases. This outbreak was deeply studied with state
epidemiologists. The secretary of health of Veracruz did a wonderful
job during the outbreak in the last 2 weeks of March.

ScienceOnsider: What capability did they have for typing subtypes?

Alpuche: The influenza, laboratory-based surveillance network in
Mexico is using immunofluorescence -- that's the screening test, and
it's using antibodies against A and B. So that's what the public
health state lab is doing.

ScienceInsider: So they don't have subtype tests and had to refer the
samples to you?

Alpuche: Yes. Not immediately, because if there's nothing unusual,
they wait to get accumulated cases and then send to the national
referral center. One of the interesting things in this outbreak is
they were testing, but the onset of symptoms was after 4 or 5 days.
The sensitivity of the immunofluorescence test is low after 72 hours.
Most of the tests, which were nasopharyngeal swabs, were negative. In
the last part of the outbreak in La Gloria, children started having
symptoms 1 Apr 2009. They took the samples 3 Apr 2009. They sent the
samples to the public health state lab, and they were processed 4 Apr
2009. These arrived at my lab on 8 Apr 2009. They only identified 3
influenza strains at the end of the period. One turned out be H3N2.
The other was A, but it was not heartening. Here at our lab, we were
considering that it could be H1, but it looked indeterminate. To be
honest, we were not able to type it. And then we had a B. At that
moment, we didn't have any information about the untypeable A's that
they saw in the California children.

ScienceInsider: In the surveillance program here in California, if
you cannot type it, you send it on to the CDC.

Alpuche: That's what we do. Our collaboration center is the CDC. We
have 3 different deadlines to do the accumulation of samples to send
to the CDC during the season. When we had that 1st indeterminate
strain from La Gloria, we were not worried. By that time, the
outbreak was controlled.

ScienceInsider: On 12 Apr 2009, Mexico notified the Pan American
Health Organization as per the International Health Regulations about
the influenza-like outbreak in Veracruz. Initially, did you think
these cases looked like influenza?

Alpuche: No, our initial thinking, as we reported according to the
International Health Regulations, was that we were having
intensification and prolongation of the influenza period. We thought
the outbreaks of Tlaxcala and Perote were nothing unusual in terms of
the pneumonia. Those were later on, and then we started to consider
that there was something unusual. Then we got a notification of an
isolated case, a 37-year-old woman, diabetic, who died because of
respiratory disease and pneumonia in Oaxaca. The woman had onset of
symptoms 4 Apr 2009. There was no connection at all with Perote. We
got samples, and it was a lung biopsy because the relatives didn't
allow an autopsy. They intensively investigated the contacts around
these deaths. They found some with respiratory diseases but no
fatalities. Nothing unusual. They were tested, and all were negative
for influenza and other viruses.

ScienceOnsider: When did you 1st contact Frank Plummer, head of the
National Microbiology Lab at the Public Health Agency of Canada?

Alpuche: I contacted him 17 Apr 2009 by e-mail, and he answered
immediately. He wanted to know more about this, and we had a long
conversation on Saturday, 18 Apr 2009.

ScienceInsider: Frank told me that he initially didn't think
influenza. He thought it would be an unknown pathogen.

Alpuche: Exactly. And we discussed that with Dr. Plummer. In fact, I
was the one who called him because I'm the lab person. I met him
through the Global Health Security Action Group. And we've been
talking about different collaborations, and immediately when we began
discussing this and the epidemiology, we wanted to rule out
everything we could. Canada had a lot of experience with the
screening of the severe acute respiratory syndrome, SARS, of unknown
pathogenesis.

ScienceInsider: When were samples sent to Canada and the CDC?

Alpuche: 21 Apr 2009. We asked for help from both at same time. The
CDC is my collaborating center in the WHO network. They always help
us, doing quality assessment for us, giving us reagents, doing
training, transferring technology. But to do shipping for both of
them, it was kind of hard. It was a little delayed to get all the
permission from the U.S.

ScienceInsider: Was your decision to send it to Canada also because
U.S. authorities were holding up your samples?

Alpuche: No, not at all. I sent these samples to the CDC because they
are my collaboration center. That's the way to do it. We get all the
help we need from the CDC.

Science Insider: When did you 1st hear back from Frank Plummer about
your samples?

Alpuche: We got the preliminary results 22 Apr 2009. Dr. Plummer got
the samples at 3:00 in the afternoon, and by midnight he was calling
me to say we had influenza A. Some of the samples I sent him, we knew
they were influenza A. That week, we started seeing the A's and we
started to change our mind about this influenza B prolongation of the
seasonal influenza.

ScienceInsider: When did you learn that they were positive for a new
swine flu virus?

Alpuche: I 1st learned that it was swine from Frank Plummer; that was
in the afternoon of 23 Apr 2009. And later that night Dr. Nancy Cox
[of CDC] in a teleconference we had with Mexican experts, we were
discussing this and she gave us the preliminary results that we have
some swine strains, the ones that just arrived that day at the CDC.

Science: Many laboratories in Mexico City I've visited are very
sophisticated. What are the limitations that prevented your lab from
identifying the new H1N1? What did the CDC and Canada have that you
didn't have?

Alpuche: The only place in Mexico doing subtyping is this lab here.
We are able to sequence and subtype, but we are overwhelmed with
samples of influenza and other things from all around the country.
It's a little bit slower than in the U.S. or Canada. Since this week,
we have experts from the CDC and Canada helping us to set up a
real-time PCR [polymerase chain reaction] technology to test for
swine H1N1 directly.

ScienceInsider: Is your lab the only lab in the country at this point
that can do the confirmatory test with the real-time PCR machines?

Alpuche: At this point, yes, but we're working with the CDC and
Canada to train molecular biologists in different institutions in 6
different states in Mexico. We have 2 real-time PCR machines we were
able to get immediately -- we borrowed one from the company. And now
we bought 10 more machines. We are working full-time to speed up the
diagnostics. Right now, we have a backlog of around 1000 tests that
we're rushing to do on time. We're having 3 shifts of people working,
during the morning, afternoon, and overnight.

ScienceInsider: A lot of Mexican press and now press outside of
Mexico has written about La Gloria and the large pig farm in nearby
Perote, Granjas Carroll. There are all these allegations and even
conspiracy theories. What about the boy in La Gloria who has received
so much attention?

Alpuche: It was mild disease, no problem.

ScienceInsider: Is it accurate that he is the index case?

Alpuche: We're not sure about that. By the onset of symptoms, he's
the 1st we're seeing in our database, that's all. The date of onset
was 1 Apr 2009

ScienceInsider: There have been all these stories of Perote as the
epicenter, or the originator. Do you believe that?

Alpuche: We've been asking agriculture authorities, and they ensured
us that they didn't detect any problems with outbreaks with animals
in these farms near Perote. And the farm is 80 kilometers [50 miles]
from La Gloria.

ScienceInsider: One of the theories is that this originated in the
United States or elsewhere and a human came to Mexico, possibly a
migrant. The assumption that it was a big pig farm could be very
misleading.

Alpuche: Could be. That's the same thought we have. We need more data
to prove it. One of the interesting thing is, we're seeing these
cases isolated in Oaxaca and Perote, they are well-known for
migration. And also the other state that we're seeing several cases
now during the active epidemic is San Luis Potosi, and it's like the
corridor for migration. It's hard to believe that it's going to be
associated with this farm, but I know that the authorities are
thoroughly investigated it.

ScienceInsider: Do you think if this surfaced somewhere other than
Mexico it would have been contained, or does influenza just move too
quickly anyway?

Alpuche: Considering it was the end of the season, maybe that
confused the fact a little that something else could grow, but
probably influenza moves too quickly anyway.

--
Communicated by;
Philip Henika
<philiphe@yahoo.com>

******
[4] 'Ground zero' village
Date: Sun 3 May 2009
Source: Haaretz newspaper [edited]
<http://www.haaretz.com/hasen/spages/1082555.html>

'Ground zero' swine flu village gets new facilities, but few answers
--------------------------------------------------------------------
At the end of a dirt road leading to the village of La Gloria in
Mexico's Veracruz State, 4 hours from Mexico City, the local
authorities hung a new sign in broken English welcoming visitors to
the village, attesting that it is swine flu-free. It is just one of
the changes that has occurred here in the past month.

In his cinder block home, with concrete floor and blue walls, hung
with pictures of Jesus and the Virgin of Guadalupe, Edgar Hernandez
shows no interest in speaking to any more of the reporters who have
been besieging his home for the past week. The 5-year-old, in his
Sponge Bob T-shirt, keeps to the other room, watching a video on a
broken-down television set. He leaves the reporters to his mother,
Maria Carmen. It all started, she says, on 1 Apr 2009. "Edgar had a
headache and a sore throat, and soon his whole body was hurting. By
night his fever was 40 degrees Celsius [104 degrees F]. I gave him a
sponge bath and in the morning I took him to the village clinic." La
Gloria, population 2243, has no doctor. The nurse sent Maria and
Edgar home with antibiotics and paracetemol. For 3 days, Edgar burned
up with fever, but 2 days later his fever was gone. The next day, he
returned to kindergarten, his mother says.

Then, 2 weeks ago, representatives of the Mexican Health Ministry
came to the village. "They told me that Edgar had been very sick with
flu. They took him to the clinic again, they did a biopsy and brought
him home. I am so angry; how could it be that I have a child at home
with such a serious illness and no one told me about it. Why did our
clinic not have the right medicine?" Maria said. Maria attributes the
fact that Edgar got better not to to antibiotics, but to the Virgin
Mary who she says blessed her and her husband with Edgar and his
brother Jonathan after years of trying to conceive.

There is a great deal of confusion in the homes along the unpaved
lanes of the poor village about the epidemic that might have visited
here. People say that before Edgar got sick, an 8-year-old girl had
died, although no one knows whether it was from swine flu. Last month
6 elderly villagers died, but some say they succumbed to a freak cold
snap in February. People in the village eke out a living raising
corn, and blue agave for tequila, but most work at odd jobs in
distant cities.

When the Mexican government released a report 10 days ago indicating
that the 1st person to contract swine flu was a boy from La Gloria,
health experts, followed by the media, began to try to track the
disease. One theory is that the virus spread from a huge industrial
pig farm near the village. Villagers who went to work in the big
cities spread the virus to the rest of Mexico, it was said.

Some people reported climate changes, strange clouds and odors from
one of the farms. The Mexican government hotly denies such a
connection, and is doing all it can to protect Granjas Carroll, which
operates the farms, 50 percent of which is owned by a large U.S. food
producer that is the biggest employer in the region. Granjas Carroll
is also conducting tours for journalists at one of its farms to show
its attentiveness to sanitation.

In addition to showing the world it is dealing effectively with the
disease, the government suddenly paved the 9-kilometer road
connecting La Gloria to the nearest town, Perote. Dozens of
government vehicles were brought in to build a new clinic, and an
abundance of antiviral medications have appeared in the old clinic,
which has been freshly painted. A field kitchen, a mobile cafe, an
information center and a tent with advanced communications equipment
has been put up for press conferences. Signs praising the
government's work in developing the area have also been installed.
All under the watchful eyes of soldiers armed with M-16s.

Dr. Jonathan Perez, in charge of Health Ministry activities in the
village, insists that there was "just one case of H1N1 flu in the
village - the boy Edgar." If that is the case, why were hundreds of
people been brought in to take care of the village? "We had to check
everyone and immunize them. We spread disinfectant powder and checked
all the pigs and birds raised here. But I can promise you that we
found no additional signs of the virus." Perez also denies that the
flu came from nearby pig farms and that the virus spread from La
Gloria to the rest of the country, since he says the farms are 8
kilometers [5 miles] away and no signs of the virus were found on it.
He also notes that almost immediately after Edgar Hernandez got sick
a woman in a town 1000 miles away also contracted the viruses.

[Byline: Anshel Pfeffer]

--
Communicated by;
ProMED-mail
<promed@promedmail.org>

******
[5] H5N1 in swine
Date: Thu 30 Apr 2009
Source: The Daily Shimbun online [edited]
<http://www.asahi.com/special/09015/TKY200905030162.html>

Study shows new H5N1 strain may mutate in pigs
----------------------------------------------
A high proportion of pigs in Indonesia carry the highly infectious
H5N1 avian influenza virus -- something that could mutate into a new
strain inside the pigs, according to research by the Kobe University
Center for Infectious Diseases. It is feared that if the virus
mutates inside pigs and becomes transmittable between humans, it
could pose a far greater threat to people than the current outbreak
of swine flu. The World Health Organization is taking precautions
regarding a likely scenario of a new strain that is highly contagious
between people being formed in this way.

The center detected the H5N1 virus in 52 pigs -- more than one in ten
of the 402 pigs it examined in 4 Indonesian provinces. Pigs are
capable of transmitting the virus to birds and people. On further
analysis of the H5N1 virus detected in the 52 pigs, the center found
a strain of a type of virus that could be transmitted to humans in
some cases. "It's a surprising result," said Yoshiyuki Nagai,
director of the Center of Research Network for Infectious Diseases.
"Perhaps we are looking at the process by which a new strain of
influenza becomes infectious [in humans?]. We need to be vigilant."

--
Communicated by:
correspondent Kunihiko Iizuka

[According to our correspondent a similar report published (in
Japanese) in the Sun 3 May 2009 issue of Asahi Shimbun
(see: <http://www.asahi.com/special/09015/TKY200905030162.html>)
states that the research was conducted with Airlannnga University in
Indonesia during 2005-07 in 4 states on Indonesia. 52 pigs were
infected with H5N1 among 402 pigs. One case [isolate?] was a type
able to infect both humans and birds.

An account of these investigations has been posted on ProMED-mail
previously; see Avian influenza (30): Indonesia, swine 20090403.1289.
These data need to be analyzed in detail. Further information would
be welcomed from anyone familiar with this research. The greater risk
will be co-infection of pigs with the 2009 H1N1 virus and the avian
H5N1 virus which potentially might accelerate the evolution of a
human-transmissible version of the H5N1 virus to which the human
population has no inherent immunity. - Mod.CP]

See Also