Page
101
1 However,
people with high-risk behaviors for
2 contracting
HBV infection frequently have
3 isolated core
antibody positivity, suggesting
4 that they were
indeed infected with HBV.
5 In the early
days of AIDS or GRID,
6 Hepatitis C
had not been identified, nor had
7 HIV. However,
the disease sweeping one
8 community, and
appearing with alarming
9 frequency in
ours, bore enough similarities to
10 a hepatitis that
clinicians were beginning to
11 use testing for
antibodies to HBV Core Antigen
12 as a surrogate for
one or both of these
13 conditions. Clearly
they were both blood-
14 transmissible. It
would not be too long
15 before clinicians
and regulators alike
16 realized that this
blood transmission was
17 coming from the
blood supply itself,
18 threatening the
entire nation.
19 However, clinician
astuteness was
20 not followed up by
Agency alertness. Anti-HBc
21 testing as a
surrogate marker for HCV and/or
22 HIV was never
mandated. The Committee members
Page 102
1 are well aware
of how many lives were lost in
2 our community
subsequently.
3 We developed
a healthy respect for
4 the certainty
that a positive Anti-HBc
5 conveyed, in
light of the marker value it had
6 at the time.
Therefore, there is still an
7 extent to
which we have a visceral reaction on
8 hearing a
person tests positive for it.
9 A positive
Anti-HBc test in the
10 past, when used as
a surrogate marker,
11 suggested
intravenous drug use. It did not
12 indicate that, of
course, but at the time,
13 when Non-A Non-B
and HIV were proliferating
14 though tests were
not available, the tendency
15 was to take any
suggestion of blood-borne
16 contagious
pathogens as a basis for excluding
17 donors.
18 Today that is far
less of a
19 concern as other
tests have been developed,
20 and especially
since the onset of widespread
21 PCR testing.
However, our earlier point
22 remains, that a
positive or indeterminate
Page 103
1 Anti-HBc test
may be triggered by other
2 factors. If we
no longer rely on this test,
3 which means
its use will be discontinued, we
4 will lose that
small indication of other
5 risks.
6 We encourage
the committee to
7 consider a six
to twelve months delay in
8 acting on this
proposal while further study
9 offers
clarification on the risk of loss of
10 informative data
should the Anti-HBc test be
11 discontinued.
12 Units testing
positive or negative
13 for key viruses are
then placed in appropriate
14 channels. We remind
FDA and CBER and the
15 blood industry that
humans run the computers,
16 humans move the
supplies around, so, humans
17 will still make
errors. The ongoing inability
18 of the American Red
Cross to fix its operating
19 procedures,
correctly screen donors and get
20 its overall blood
operations in order, even
21 after tens of
millions of dollars in fines,
22 proves our point.
COTT continues to counsel
Page 104
1 caution when
changes in donor screening and
2 eligibility
are proposed.
3 A key reason
for considering this
4 change is a
shortage of donors. We are
5 mindful of the
need to expand the nation's
6 donor pool all
the time. However, without the
7 political will
necessary to connect blood
8 donation to
good citizenship, the situation
9 will remain
difficult and the donor pool will
10 not grow
significantly enough to meet
11 projected demand.
The blood industry and our
12 political
leadership should teach our children
13 in the schools the
importance of regular blood
14 donations. And we
know that the age has been
15 lowered in many
cases and this has been going
16 on.
17 In this election
year we need to
18 put regular blood
donations on the political
19 table. If former
Presidents Bush and Clinton
20 can raise awareness
about Hurricane Katrina in
21 television spots,
then it is also possible for
22 our leaders to
regularly and repeatedly
Page 105
1 encourage
donation.
2 Thank you
very much.
3 CHAIR SIEGAL:
Thank you. It is
4 now time for
our break. Is there a comment?
5 DR. BISWAS: I
just, there may be
6 a
misunderstanding here. There is no
7 intention
whatsoever to drop Anti-core testing
8 of blood
donations, transfusable blood. That
9 is number
one.
10 Number two, you
know, the value of
11 the surrogate test
for Anti-HBc has been sort
12 of debated over the
years. However, you know,
13 we have recommended
it precisely really to
14 screen for
hepatitis B. And its value has
15 been shown and
demonstrated and there is no
16 intention of
dropping it.
17 MR. CAVENAUGH: Our
point about
18 decreasing the
focus on it, possibly leading
19 to, I used the term
atrophy earlier, stands.
20 DR. BISWAS: I
don't see that
21 happening all in
the case of this particular
22 test in the near
future or far future.
Page 106
1 MR.
CAVENAUGH: I heard it here.
2 CHAIR SIEGAL:
Okay because of the
3 lateness of
the hour, let's just take a ten
4 minute break.
Which means you should be back
5 here by about
nine minutes after the hour.
6 (Whereupon,
the meeting went off
7 the record at
10:00 a.m. and
8 resumed at
10:12 a.m.)
9 CHAIR SIEGAL:
Topic III: Options
10 for Blood Donor
Screening and Reentry for
11 Malaria. The first
speaker to introduce and
12 provide background
is Dr. Sanjai Kumar of FDA.
13 DR. KUMAR: Good
morning. I am
14 just looking at
people are still settling down
15 but I guess they
are.
16 My name is Sanjai
Kumar and I work
17 at Division of
Emerging and Transfusion
18 Transmitted
Diseases at Office of Blood
19 Research and Review
at CBER, FDA. So, it is
20 my task to give you
introduction and
21 background to the
issue at hand this morning.
22 So the question we
are here before this
Page 107
1 committee
today is options for donor screening
2 and reentry
for malaria. And to be specific
3 here, the
question FDA is seeking advice from
4 the BPAC on
options for blood donor screening
5 for the
presence of malarial antibodies as
6 evidence for
malaria exposure and on a
7 possible
mechanism to allow reentry of donors
8 who traveled
to Mexico.
9 So, with that
out of the way and I
10 must say that this
is an issue which is going
11 for a long time and
there has been a great
12 demand from the
blood banking industry to
13 address this issue.
So here we are. Let's
14 see where we
get.
15 I would like to
spend a few
16 minutes talking
about the global problem with
17 malaria because
what goes around, comes
18 around. So, if
there is Malaria globally,
19 that affects us
also.
20 I would like to
draw your
21 attention to these
different colors on the
22 global map here. So
look at the dark brown,
Page 108
1 almost
chocolate brown here. This is the
2 malaria
situation today or rather in 2002. So
3 what it tells
here is brown is rather dominant
4 so you will
not see the changing face of
5 malaria much
here. But if you go past,
6 really, in the
beginning of the last century
7 here, malaria
used to be a lot more prevalent
8 around the
world. It almost reached to the
9 Arctic Circle.
But if you look as close to
10 the in the 1940s,
malaria was deeply
11 entrenched in the
American southern states
12 here. And before
that, Washington right here
13 was the hottest
spot of malaria. But as I
14 said, change of
malaria is changing now. But
15 it is still today
more than half of the
16 world's population.
Probably now is 108
17 countries to be
exact where malaria is
18 transmitted. It is
about half of the world
19 population lives in
malaria endemic areas.
20 And as about as a
result five hundred million
21 cases every year
and more than one million
22 deaths every
year.
Page 109
1 Coming closer
to home here in the
2 United States,
malaria situation today,
3 natural
transmissions of malaria in U.S. are
4 rare. It does
happen but probably doesn't
5 have very
serious impact on malaria
6 epidemiology.
We do get approximately 1,500
7 cases of
malaria every year. And these
8 numbers remain
stable for the last many years.
9 Malaria
infections can be transmitted by
10 transfusion of
blood products of the infected
11 donor. And that is
the reason we are here
12 today, do discuss
this point. And that is
13 something I will
defer as transfusion
14 transmitted malaria
or TTM.
15 How malaria
infections reach in
16 the United States,
the sizable number of 1,500
17 here each year? So
there are an average of 30
18 million U.S.
residents that make trips to
19 malaria endemic
countries each year. And that
20 is almost ten
percent of the U.S. population
21 that gets
potentially exposed to malaria every
22 year.
Page 110
1 There is
another situation that we
2 need to pay
close attention to here. Almost
3 twelve million
U.S. residents travel to Mexico
4 every year,
however, closer to border mostly
5 to non-endemic
areas in Mexico. But that has
6 a serious
implication here for donor deferral
7 issues. A
significant proportion of malaria
8 in the U.S. is
brought by immigrants from
9 endemic
countries or people who visit endemic
10 countries. The rate
of malaria transmission
11 varies greatly
among different geographical
12 areas.
13 So, the risk of
malaria exposure
14 depends directly on
the area of travel or
15 residence. I mean,
that is the point I would
16 like to make again
and again here. So, these
17 are the areas here
but these boundaries are
18 still very flexible
here to variation.
19 I mean, one good
example here is
20 the malaria in the
Caribbean. So, we are
21 having too many
hottest spots of malaria
22 recently and the
areas which are considered to
Page 111
1 be full of
malaria now malaria is becoming
2 endemic there.
So, all of that relationship,
3 transmission
of malaria in relation to travels
4 and residence
in malaria endemic areas.
5 Looking at
the numbers here,
6 malaria cases
in the United States, as I said,
7 1,564 cases
last year, which was about two or
8 three percent
rise from the previous year.
9 But the
numbers are all very stable. This is
10 the species-wide
distribution for malaria
11 here. So, these
numbers, so between vivax and
12 falciparum, these
two species contribute to
13 about 90 percent
malaria infections globally.
14 So, equally
distributed among these two.
15
So the falciparum number is
16 reaching close to
what global distribution is
17 but the vivax is
slightly low. But the reason
18 being probably is
there is a big unknown here
19 about a 36 percent
of cases we don't know,
20 which species those
are. So probably these
21 numbers are
somewhere lost in here.
22 This is all CDC
data. Then also
Page 112
1 looking at
where the malaria is coming from
2 and who are
the population groups again in
3 relation to
the donor populations here. So
4 having
information about that. So out of
5 those 1564
cases in 2006, 930 cases we knew,
6 CDC knew that
they had data, who these people
7 are, whether
they are U.S. residents. So the
8 U.S.
residents, they do not discriminate
9 between legal
residents. Who is living is
10 considered U.S.
resident. And then the
11 foreign residents
and the is totally out. So,
12 from Africa, only
0.6 percent U.S. travel was
13 to Africa but it
still contributed to a
14 sizable number.
There are 642 cases out of
15 930 cases, known
cases.
16 So these are the
number of
17 travelers and these
are the foreign residents
18 who are possibly
are mostly immigrant
19 population
here.
20 Then the next
biggest contributor,
21 geographic wise,
was Asia here. And again, so
22 as you can see here
from all geographic areas
Page 113
1 are not
equally contributing to malaria in the
2 U.S. Although
the risks to exposure are
3 different,
although that may not be related to
4 directly the
number of travel. So, actually
5 that does
not.
6 So, the
disproportionate number of
7 malaria coming
to this country from different
8 continents or
different geographical areas.
9 And here
again, the point in case, our
10 southern neighbor,
not America, but out of
11 that only malaria
have been stabling in
12 Mexico. We had very
few cases of malaria
13 brought to this
country from Mexico.
14 There are a few
points I would
15 like to make here.
The two factors that
16 contribute towards
malaria infections and I
17 think they both
have more relevant activity in
18 the case of
transfusion transmitted malaria is
19 the parasite
virulence and host factors. So
20 the parasite
factors relates to parasite
21 validity and
parasite virulence. And then
22 host factors are a
host of susceptibility and
Page 114
1 prior immunity
in the host. And I think both
2 go hand in
hand, in many cases for the species
3 of Plasmodium.
And many of these things will
4 come again and
again in different talks that
5 you will hear
after me. But I would just like
6 to set the
stage, nonetheless.
7 For the
species the biology and
8 pathogenesis
is greatly dependent on
9 Plasmodium
species and intensity of
10 transmission. And I
talked about the
11 intensity of
geographical distribution, length
12 of liver stage
cycle varies for each species
13 has very important
implications for
14 transfusion
transmitted malaria. Some species
15 can establish
long-term infections or talk
16 about a little bit
more and then individuals
17 from endemic areas
may have chronic low-grade
18 parasitemia that is
clinical immunity.
19 So again, just
elaborating about
20 what I said here,
this I would have put in the
21 parasite factor
prepatency at the time between
22 the time of
sporozoite inoculation during a
Page 115
1 mosquito bite
to the first appearance of
2 parasite when
these human hosts or prospective
3 donors become
infectious for transfusion
4 transmitted
malaria. And this period varies
5 greatly here.
And there are no complexities
6 here vivax and
ovale have dormant liver form
7 stages,
causing relapse infections and those
8 are more
difficult to handle, actually. So
9 this time
could be 30 days or it could be
10 possibly month or
year or more, even.
11 Plasmodium malaria
can establish
12 chronic infection.
There is a host
13 susceptibility. It
could be 40 years reported
14 or could be
life-long possibility.
15 So and then
individuals born in
16 endemic area
expect, they become asymptomatic
17 carriers that is
mostly falciparum malaria.
18 Parasite burden, we
don't know any
19 asymptomatic
carriers. That is why it is very
20 difficult to have
direct parasite detection.
21 Infectious does of
intraerythrocytic
22 parasites of very
low. But some few incidents
Page 116
1 of this that
could be as low as ten infected
2 cells can
cause, form an infection.
3 So all of
these shows if there is
4 a chronic
infection from Plasmodium malaria up
5 to 40 years,
falciparum malaria can persist
6 for more than
five years or so. None of the
7 donor deferral
policies we have in place can
8 possibly take
care of these long-term
9 persistent
parasites. So, one has to be
10 cognizant of that.
There is always some risk
11 of
malaria.
12 So blood safety in
the U.S., how
13 do we do it? There
is no approval of routine
14 test in the U.S.,
at least, if we screen blood
15 donors of malaria.
And we do screen
16 prospective blood
donors for malaria risk
17 based on their
travel history and malaria risk
18 areas. And that is
how we determine the risk
19 of
exposure.
20 This is exact
policies here.
21 Three years
deferral for somebody who had
22 clinical malaria.
And the prior residents of
Page 117
1 endemic
countries are deferred for three years
2 as well. One
year deferral for U.S. residents
3 who had never
prior exposure to malaria and
4 run the risk
to malaria in endemic areas.
5 The
identification of malaria-
6 endemic areas,
so this is not country-wide
7 now, this is
the malaria-endemic areas within
8 each country
because outside Sub-Saharan in
9 Africa, every
part of another country is
10 malaria endemic.
This is maintained by CDC.
11 And we have Dr.
Paul Arguin here who will be
12 able to answer
those questions.
13 Looking at the
transfusion
14 transmitted malaria
in this United States,
15 this is a more
historical, long-term view
16 here, last 45
years, this is the data from
17 CDC, mostly CDC's
work here. A total of 96
18 cases in 45
years.
19 And if you look at
the species-
20 wide distribution
down here, this is very
21 close to what you
see falciparum malaria that
22 causes transfusion
transferred malaria, close
Page 118
1 to what you
see in the clinical cases that was
2 defined
numerically correctly 39 percent.
3 Vivax is also
close but not, I mean, rather
4 close, 19
percent was at 26 percent here. But
5 the numbers
don't match here. The malaria
6 here is 27
percent of all cases in the last 45
7 years cause
Malaria.
8 The global
transmission of malaria
9 probably, I
mean the hard numbers are
10 difficult to know.
But probably around in the
11 range of five to
ten percent at the most. So
12 what is happening
here, what is happening if
13 you remember with
the slide I showed you,
14 malaria can persist
to 40 years or more. So
15 those donors who
have been exposed to malaria
16 are just sitting
there without any chronic
17 infection. So they
are the major contributor
18 here, at least in
the U.S.
19 Looking at a more
closer view of
20 the recent cases of
transfusion transmitted
21 malaria in this
decade, rather, because in
22 part see what is
happening now. So the two
Page 119
1 things you
will notice here. So this is the
2 transfusion
transmitted malaria in 45 years.
3 This is not
number of infected blood units but
4 rather number
of infected donors who are
5 implicated at
2.18 mean average here in 45
6 years but in
last eight years, the numbers
7 have come down
to .37. So three cases
8 happened. One
malaria and two falciparum in
9 the last two
years, total three cases.
10 So what is
happening here is what
11 we are doing,
something is working. I mean,
12 it goes to both
regulatory agencies and to
13 blood banking
industry. So the number of this
14 has steadily
decline the number of transfusion
15 transmitted
malaria. But nonetheless, these
16 cases continue to
happen. We just can't tell
17 when the next case
will happen. I mean, this
18 is again a very
prime example. This person
19 had never left the
country for eight years or
20 so when contributed
to transfusion transmitted
21 malaria.
22 I would like to
summarize it here
Page 120
1 again, all 40
species have caused transfusion
2 transmitted
malaria in the U.S. If you look
3 at the
infectious blood units, so the more
4 than six-fold
increase in the number of donors
5 who implicated
more than nine-fold decline in
6 the incidence
of infections, in terms of
7 infected blood
units in these recent years
8 here.
9 So blood
safety is better than
10 ever but the issue
at hand here is not only
11 blood safety but
the number of donor
12 deferrals. So is
the donor availability is
13 the question here,
why we are here today,
14 mostly.
Approximately 150,000 donors are
15 deferred each year
for malaria risk. And if
16 you look a little
later, these numbers are
17 cited somewhere one
percent to three percent
18 here. But this
number seems to be coming
19 through more and
more recent data now.
20 They are
significant but we cannot
21 put exact numbers
on the unknown numbers of
22 self-deferrals.
These numbers could be very
Page 121
1 high but at
this time we do not like to put a
2 number because
we don't have hard data that we
3 would like to
have. And probably if we have
4 a liability
test that can predict or detect
5 malaria
exposure in at-risk donors, will allow
6 to bring back
if not all, but at least
7 majority of
these donors who are deferred for
8 malaria
risk.
9 I would just
like to recap it one
10 more time because
this is very important. The
11 number of clinical
malaria cases, because I
12 look at these
number of clinical malaria cases
13 in the
U.S.
14 What is happening
in the clinical
15 cases of the donor
populations come from these
16 same population. So
these numbers are very
17 stable in last four
or five years. And also
18 the species ratio,
the proportion that
19 contributes to
malaria has also been very
20 stable. So that is
one good thing we can look
21 at.
22 There is more
better and better
Page 122
1 information
through concerted efforts to
2 individual
governments, WHO and CDC. We have
3 more
information on ground information of
4 geographical
malaria transmission in unusual
5 countries,
actually. So that data helps,
6 actually, to
determine the prior history of
7 exposure or
potential exposure actually in the
8 travelers and
residents, prior residents.
9 Then this
allows us to identify
10 the donor
populations who are put in the
11 highest risk or
transmitting malaria by blood
12 transfusion and I
think that identifying these
13 risk populations is
most important, a critical
14 factor, in our
strategies to develop donor
15 testing matters
here.
16 So what we have in
doing about
17 this, in 1999,
there was informational BPAC
18 to discuss the
issue of testing blood donors
19 for malarial
antibodies to determine malaria
20 risk.
21 And then two years
ago we had a
22 workshop, highly
successful workshop, to
Page 123
1 discuss the
issue of testing for malarial
2 infections in
blood donors.
3 So, I would
like to just focus on
4 something that
happened more recently, 2006
5 malaria
workshop.
6 So these are
the common features
7 that appeared
and that mostly were the
8 consensus of
this independent panel also,
9 expert panel.
So, geographical area of travel
10 or prior residence
is the major determinant of
11 malaria risk in
prospective blood donors. And
12 I hope I have
sufficiently shown you data and
13 convinced you also
about that.
14 Laboratory testing
for malaria
15 parasites would be
a useful strategy to
16 identify at-risk
malaria donors and
17 potentially bring
those donors back in donor
18 pool. Then direct
parasite detection methods,
19 the microscopy, DNA
tests, lack the
20 sensitivity for use
as donor-risk screening
21 test. And for me,
it is not even a
22 sensitivity issue.
I mean, many of these
Page 124
1 tests, DNA
tests, can detect one parasite very
2 easily but the
problem is sampling how you are
3 going to look
for ten infected red cells in a
4 unit of donor
blood. It is like looking for
5 a needle in a
haystack.
6 The presence
of malarial
7 antibodies is
a reliable indicator of exposure
8 to malaria
parasites. There is sufficient
9 data to do,
accept that now.
10 And then what
others are doing.
11 So many European
countries, Australia and New
12 Zealand allow
testing of deferred at-risk
13 donors for the
presence of anti-malarial
14 antibodies. In
those countries, deferred at-
15 risk donors are
allowed to reenter the donor
16 pool after a
shortened deferral period. So
17 the donor
questionnaire, therefore, they ask
18 whether you have
been to malaria endemic area
19 or not. They
identify those donors, they
20 defer them for four
to six months period and
21 I will go into the
detail of why four to six
22 months period. And
then if they are found
Page 125
1 negative for
malaria antibodies, they are
2 allowed to
defer into the donor pool with a
3 reduced
deferral period.
4 We have two
speakers today from
5 Europe. They
are the chief manufacturers and
6 they are going
to share their experience in
7 detail with
their antibody test here. So we
8 will get to
hear a lot more about this later
9 in the
day.
10 So what is our
approach now?
11 Where are we
heading now? So, we would like
12 to know if you
implement an antibody test,
13 what effect will
you have, first in blood
14 safety and then
other donor availability.
15 We don't want to
rock the boat, to
16 say. We don't want
to change something which
17 is working very
well without knowing what
18 affects it will
have. So, to do that, we
19 along with our
colleagues in Office of
20 Strategics and
Epidemiology. And you will
21 hear two talks
about this by Dr. Hong Yang and
22 Dr. Mark Walderhaug
later on the risk
Page 126
1 assessment.
They have built a, or constructed
2 a risk benefit
assessment model to estimate
3 the effect of
antibody testing on donor
4 availability
and blood safety from the risk of
5 transfusion
transmitted malaria. So, we did
6 make certain
assumptions about that. And
7 there are
three major components in that model
8 and I will go
over those in detail.
9 So, first is
that we looked at the
10 different model
scenarios where tests could be
11 implemented. And
those models scenarios are
12 based on the level
of malaria risk acquired
13 during travel,
residence, and distinct
14 geographical areas
are no risk at all if you
15 stayed at home. The
model assumed the use of
16 ELISA with
FDA-defined sensitivity and
17 specificity. I will
give you some idea of
18 that and then you
will hear detail by Dr. Yang
19 and Dr. Walderhaug.
And then model assumed a
20 four-month deferral
for travel or residence in
21 endemic area before
antibody testing would be
22 implemented and
allowed.
Page 127
1 Looking at
the what kind of test
2 we have in
mind or what characteristics we are
3 looking at in
the assumed test, I will still
4 say this is an
assumed test. This is not
5 etched in
stone but this is what we used to
6 test our
model. It must be sensitive enough
7 that it
maintains at least the current level
8 of blood
safety of for transfusion transmitted
9 malaria. We
will not allow something which
10 will make us to
compromise the current level
11 of blood safety,
which is very good at this
12 time.
13 It must be highly
specific so that
14 we have minimal
donor loss of false-positive
15 reactions. And I
think this issue becomes
16 more important if
larger donor pools are
17 tested because
donor losses could be higher
18 than what we have
current level of donor loss.
19 Ideally, we would
like to have a
20 test that detects
all four species of
21 Plasmodium species
and must be practical to
22 use in different
blood banking settings.
Page 128
1 Another thing
I would like to say
2 at this time
is the test that are used in
3 European
countries I would rather like to say
4 contains
antigens from two species of
5 plasmodium
ordinarily, that is falciparum and
6 plasmodium
vivax. And it shows us again and
7 again that all
40 species contribute towards
8 transfusion
transmitted malaria.
9 This is
looking at this window
10 period of four to
six months deferral that
11 they are using in
Europe. This is CDC data
12 again and these
numbers remain stable. I
13 would just like not
to dwell on it but just to
14 very quickly say
that based on travel
15 residence, if
anyone malaria is brought in
16 this country,
clinical malarial, more than 90
17 percent of all
clinical malaria reveals itself
18 within three months
after coming to the
19 country. So whether
these are immigrants
20 coming back here,
expatriates coming back here
21 or travelers coming
back here. So it is a
22 three month period
allowed itself to recognize
Page 129
1 a great number
of malaria infections yourself.
2 But I must, I
have to qualify it here, this
3 does not
address the issue of asymptomatic
4 chronic
malaria infection. Plasmodium malaria
5 are individual
with clinical immunity against
6 falciparum
malaria.
7 So, just
thinking a little more
8 about what
other things do they contribute
9 here, how much
deferral should be allowed
10 here, there is a
time left, a window period
11 between sporozoite
inoculation by infected
12 mosquitoes and the
first appearance of blood
13 form parasites in
circulation resulting in
14 clinical symptoms.
I mean, a lot could be
15 said about this.
This period could be longer,
16 also but we need to
take the larger picture in
17 hand here, that
what is happening and where
18 the risk is coming
from. And we have some of
19 the world's
greatest experts in this area. We
20 have Dr. John
Barnwell here, Dr. Tom
21 McCutchan, who
know, who spend their life
22 studying these
things.
Page 130
1 But we have
to keep the focus on
2 the issue in
hand also. What this means in
3 terms of
transfusion transmitted malaria,
4 given the risk
of transfusion transmitted
5 malaria and
from where the exposure was
6 acquired.
7 Prior
anti-malarial immunity may
8 delay the
onset of parasitemia and clinical
9 disease. So,
obviously, the four-month
10 deferral will not
capture all cases. And as
11 the data I just
showed to you, 90 percent of
12 the clinical cases
of malaria are reported to
13 occur within 90
days of return from the CDC
14 data many
years.
15 There is the
question how much
16 time it takes after
exposure inoculation and
17 before the malarial
antibodies are evolved,
18 matured to
detectable level. And the only
19 data to my mind
which is available in the
20 world is
sporozoite, experimental sporozoite
21 challenge
experiment. It is a very well-
22 controlled
experiment which are done by Walter
Page 131
1 Reed as part
of their testing of malaria
2 vaccines.
3 So in the
controlled individuals
4 who were not
given any vaccine or drug
5 treatment,
when they are challenged with
6 malarial
sporozoite, this is the data from
7 Colonel Chris
Ockenhouse and Colonel Colin
8 Ohrt, they are
telling me that within 20 to 40
9 days, that
this is looking at an antibody
10 response to malaria
surface protein that most
11 of the volunteers
who do see that they can
12 work, they work
within day 20 to 40.
13 So, looking at all
of this, I
14 think it made us
pretty comfortable that most
15 of the cases who
did develop malaria after
16 coming from endemic
areas did experience
17 clinical malaria
within four months. And
18 also, this time, 20
to 40 days acquired to
19 develop antibody
responses, we felt that four
20 months' deferral
would be a quite comfortable
21 period. So at the
time we are going to be
22 using our risk
assessment model.
Page 132
1 Then again,
looking at the
2 geographical
risk assessment. And again the
3 question of
Mexico. Mexico is very important
4 for us 12
million were just there. Again,
5 doesn't mean
everybody went to malaria endemic
6 area. But
looking at the malaria situation,
7 it is very
interesting in Mexico. You have to
8 excuse
me.
9 This is
looking at the malaria
10 situation. And from
the reports we will hear,
11 we will hear a very
detailed talk from Dr.
12 Paul Arguin from
CDC on this. But just a
13 snapshot of here,
what he will present,
14 malaria, first of
all, I think the data we get
15 from Mexico is very
reliable. Within the last
16 20 years, there has
been a steady decline in
17 malaria cases in
Mexico. So in 1998, there
18 were 15,000 or so
cases of malaria there. Out
19 of those, there
were 21 cases of falciparum
20 malaria that have
survived. Either falciparum
21 alone or vivax
infections.
22 But if you look
over time,
Page 133
1 something
happened there. First, there was a
2 precipitous
drop in the following year. Then
3 the situation
became stable. There was a drop
4 again. And now
in 2007 for the time for which
5 complete data
is available now, only 2,200
6 cases -- And
something else happened there.
7 Falciparum has
almost disappeared from there.
8 So there are
around 2,000 cases in
9 the whole
country and no falciparum. So that
10 sort of looked
ideal to us to try in a
11 situation for which
we have a malaria antibody
12 test available,
which is definitely known to
13 detect antibodies
against falciparum and vivax
14 malaria.
15 So, looking at the
testing
16 situations here,
what are the donor testing
17 scenarios we will
use in our discussions as a
18 model. So, here is
the current policy here,
19 donor questions and
deferral.
20 The other model
that was tested in
21 the model was a
universal testing that
22 everybody gets
tested. But even those who get
Page 134
1 tested, there
will be donor questions in place
2 and a four
month deferral will be applied
3 here. And
those who answered positive to
4 travel to
malaria endemic areas, only those
5 will be
tested.
6 Donor
questions, and then again,
7 the next one
is the reentry testing of donors
8 who were
otherwise deferred for travel or
9 residence in
any endemic area around the
10 world.
11 And the fourth
scenario will apply
12 for four month
deferral and then reentry
13 testing of donors
who were deferred for travel
14 during endemic
areas in Mexico only.
15 So these are four
scenarios here,
16 which you will hear
a lot more about by Dr.
17 Hong Yang and Dr.
Mark Walderhaug.
18 So, I would just
set the
19 background here.
And this is the scientific
20 agenda. There will
be two talks here, both
21 from blood bank
industry, one by Bryan
22 Spencer, the second
one with Dr. Celso Bianco.
Page 135
1 Two different
establishments but they looked
2 at the
question of a geographical exposure
3 based deferral
of donors for malaria risk.
4 So, the data
coming from two
5 different
sources. Then Dr. Paul Arguin will
6 present data
about the risk of malaria in
7 travelers to
Mexico.
8 Then Dr.
David Leiby from American
9 Red Cross. He
has been using one of the test
10 cases available in
Europe to look at the
11 exposure rate in
American blood donors here.
12 He will share his
experience.
13 And then risk
analysis for malaria
14 exposure in blood
donors and its effect on
15 blood safety and
availability. Dr. Hong Yang
16 and Mark
Walderhaug.
17 And then during
the open public
18 hearing, we are
very fortunate to have two
19 speakers who were
kind enough to come overseas
20 from Europe and
they are, as I said earlier,
21 they represent the
blood test kit
22 manufacturers, and
they will show their data,
Page 136
1 their
experiences with the test kits in Europe
2 and then we will have a presentation from
3 Abbott here, I believe, on the test kit they
4 are working on.
5 Then, I will
come back after open
6 public hearing
and summarize the entire issue
7 and present
the question to the committee
8 again. But
before I go away, I would just
9 like to put
the question to the committee here
10 so when you hear
these presentations, you will
11 have the question
in mind that what we are
12 asking for here
today.
13 So, given the
historic risk of
14 transfusion
transmitted malaria from
15 Plasmodium malaria
and Plasmodium ovale is
16 testing for
antibodies only to falciparum
17 vivax after four
month deferral period
18 practical and
appropriate for use to screen
19 reentry donors
deferred for any risk of
20 malaria. But then
the real question here
21 comes to here is
can selective testing for
22 antibodies to
falciparum and vivax malaria
Page 137
1 four months
after possible exposure be used as
2 a criteria to
screen and reenter donors
3 deferred for
travel to Mexico.
4 I would like
to stop here, unless
5 you have any
questions. And then we will move
6 on to the next
speaker and I believe that is
7 Bryan
Spencer.
8 CHAIR SIEGAL:
Thank you, Dr.
9 Kumar. There
is a question but then we should
10 move to the rest of
the speakers.
11 DR. ZIMRIN: In the
personal
12 communication from
Ockenhouse about
13 seroconversion of
the experimental subjects.
14 I think you said
that most of them converted
15 with the 20 to 40
day window. What did you
16 mean by
most?
17 DR. KUMAR: Well,
those who
18 seroconverted, they
did convert to be done.
19 So not every person
who was exposed to
20 malaria did
seroconvert. So, the sensitivity
21 of the assay was
not 100 percent but perhaps
22 they included more
recombinant antigens.
Page 138
1 Probably they
will see more.
2 But the idea
was just to show you
3 that if the
test has one antigen, I mean, this
4 is bringing
back the question how many tests
5 I incorporated
by using a single protein
6 antigen
because you will hear about that
7 antigen again
and again. That is why it goes
8 to show the
data that those who did convert,
9 they did
convert within the time frame.
10 So, the issue was
not about
11 sensitivity but
more of an issue of how much
12 time it took from
exposure to exposure, known
13 exposure to
sporozoite and seroconversion.
14 DR. ZIMRIN: Thank
you.
15 DR. KUEHNERT: Just
a point of
16 information.
Chair?
17 CHAIR SIEGAL: Oh,
Dr. Kuehnert.
18 DR. KUEHNERT: For
a point of
19 information, I
didn't see the handout. Can
20 the handout be
distributed to the committee?
21 It would help for
the consideration of the
22 questions, if that
is possible.
Page 139
1 DR. KUMAR:
The questions are in
2 these.
3 DR. KUEHNERT:
No, I'm sorry. The
4 presentation,
is that in all of the packets?
5 DR. KUMAR:
There were some
6 changes but
the packet that is there, yes, it
7 should have
been there. Otherwise, we will
8 make sure that
you get it.
9 DR. KUEHNERT:
Okay, thank you.
10 DR. KUMAR: Yes,
sure. Okay. So
11 with that, I hand
it over to you.
12 CHAIR SIEGAL:
Okay, thank you.
13 Our next speaker is
Bryan Spencer, M.P.H. from
14 the American Red
Cross, evaluating risk for
15 malaria infection
in U.S. donors deferred for
16 travel to malaria
endemic areas. Dr. Spencer.
17 MR. SPENCER: So,
thank you for
18 the invitation to
speak here this morning.
19 the work that I
will present is the collective
20 effort of a group
funded by NHLBI, the REDS-II
21 group. So, I am
with the American Red Cross
22 in the New England
Region based in
Page 140
1 Massachusetts.
2 So, if we
were to survey the
3 epidemiology
of malaria across countries that
4 are endemic in
the Americas, Asia and Africa,
5 we would find
that the epidemiology is very
6 different from
one place to another, that the
7 level of
morbidity and mortality, the age
8 distribution,
whether the burden is borne
9 mostly by
infants or under five year-olds, or
10 whether adults
share in that burden, as well
11 as the type of
morbidity, principally severe
12 anemia versus
cerebral malaria. All of this
13 might vary quite a
bit from one place to
14 another. There are
complex associations
15 between the levels
of transmission and the
16 epidemiology in any
given spot.
17 As measured by
this, as estimated
18 by this theoretical
construct, the basic
19 reproductive rate
which is used to estimate
20 the number of
infections that would occur in
21 a non-immune
population with the introduction
22 of one infected
person, one can see that the
Page 141
1 estimates of
how malaria would manifest at the
2 population
level vary widely from one more
3 case, on
average, to over thousands of cases.
4 And this is
going to vary depending on local
5 factors that
include climate, the mosquito
6 vector, its
biting patterns. And so we know
7 that compared
to other infectious diseases,
8 malaria is
much more highly transmissible but
9 the main point
I want to make here is that it
10 is extremely highly
variable.
11 At the individual
level, however,
12 it is almost
axiomatic that if you have never
13 been infected
before, your first infection or
14 first few
infections are likely to be
15 clinically overt.
And that has significant
16 implications for us
in considering the risk
17 for TTM. And it is
worth pointing out that
18 this makes malaria
almost unique among the
19 main pathogens that
concern us in this field,
20 compared to
hepatitis B, West Nile Virus,
21 Chagas,
Leishmaniasis, toxo. Many other
22 pathogens have
patterns where there are tens,
Page 142
1 hundreds, even
thousands of clinically silent
2 infections for
each one that is clinically
3 overt.
4 So, this is
an important point for
5 us in thinking
about who might be at risk, not
6 just for
developing malaria infection but for
7 having a
silent asymptomatic infection when
8 they walk in
the door to donate blood. So the
9 FDA guidelines
of who may and may not donate
10 with respect to
potential risk for transfusion
11 transmitted malaria
are summarized here. You
12 are okay if you
have never had malaria
13 infection or not
within the past three years.
14 If you haven't
resided in malarial countries
15 or not within the
last three years, and if you
16 haven't traveled to
malarial areas within a
17 malarial country
within the last 12 months.
18 The 1994 guidance,
which is what
19 is currently the
standards that apply, 2000
20 draft guidance
never got finalized, doesn't
21 really define
residence within the Red Cross.
22 We follow the Draft
2000 Guidance that
Page 143
1 establishes a
five year period of residence
2 within a
malarial country for all three
3 categories.
Country of birth is not a factor
4 in determining
who may or may not donate.
5 Certainly,
that is an important
6 factor in
terms of who might or might not have
7 sufficient
exposure to malaria to have a
8 silent
infection.
9 So of course,
overlap is possible
10 across these
categories. And I think we will
11 see a bit of detail
on this in Dr. Leiby's
12 talk. This Venn
diagram is sized not to
13 reflect the
relative risks attached to each of
14 these three groups,
but rather the respective
15 impact attached to
each group. Travel history
16 being a much more
common cause for deferral
17 than for someone
who reports residence history
18 in the summary
materials for this talk. Dr.
19 Leiby's work is
cited that shows for the Red
20 Cross ten times as
many with travel history
21 deferral as
residence history. And then those
22 with residence
history being 40 times more
Page 144
1 common than
those who report a history of
2 malarial
illness among those deferred in the
3 Red Cross. So
this, being roughly 400 times
4 more common
that that, that is where the
5 impact is. The
risk, I would suggest, is much
6 the opposite
of that. So I think that will be
7 spelled out
more over my talk and subsequent
8 ones.
9 So, this
slide was presented by
10 Dr. Parise from the
CDC at the workshop two
11 years ago, which
shows the declining rates of
12 TTM in recent
years. It doesn't extend up to
13 the 2007 case that
was shown on Dr. Kumar's
14 slide but we do see
that three and four
15 decades ago, there
was quite a bit more TTM in
16 this country than
there currently is.
17 Now, it might be
that the
18 declining rates of
TTM are because the
19 deferral policies
are very effective but no
20 one has really made
that systematic evaluation
21 to determine if
that is the case. Within the
22 Red Cross over in
recent years, we see that
Page 145
1 the burden of
travel deferrals has increased
2 quite a lot,
that from 0.4 percent of donor
3 presentations
up to 0.65 percent of donor
4 presentations
over a seven year period,
5 resulted in
malaria travel deferral.
6 If you were
to make the
7 denominator
discreet donors presenting each
8 year, it would
be one percent of productive
9 donors
deferred per year. So, this is a
10 significant burden
the margin of other sorts
11 of deferrals that
happen at the blood centers.
12 So, this represents
a 50 percent increase in
13 relative terms, as
well as in absolute terms
14 just in the last
seven years alone.
15 So this data comes
from the New
16 England Journal
paper which Dr. Kumar showed
17 data from that as
well. And it shows that in
18 the most recent 25,
26 years, including what
19 has happened in the
current millennium, only
20 one U.S. civilian
traveler on routine travel
21 has been implicated
in a case of TTM that the
22 remainder have all
been people who either
Page 146
1 having been
born in or not born in but resided
2 for
significant periods of times in malarious
3 areas and who then immigrated to or came to
4 visit the U.S. And then others who are
5 residents of the U.S. who then returned to
6 their area of origin and subsequently came
7 back with malaria infection.
8 Prior to
that, U.S. military
9 personnel
returning from Vietnam were the
10 cause of a large
share of TTM cases but that
11 is not the case in
the most recent 25 years or
12 so. The primary
point here is that most non-
13 immune routine
travelers from the U.S. are not
14 the cause of
TTM.
15 So the objective
of our study was
16 to compare the
impact of the existing travel
17 deferral guidelines
with the likelihood that
18 a presenting donor
with malaria travel history
19 might be
parasitemic. So, we are focusing
20 here just on those
with a travel history, not
21 a residence
history, not a history of malarial
22 illness.
Page 147
1 So the
participating blood centers
2 in the REDS-II
program include two American
3 Red Cross
regions, Institute for Transfusion
4 Medicine in
Pittsburgh, Hoxworth in
5 Cincinnati,
Blood Center of Wisconsin, and
6 Blood Centers
of the Pacific. So we have two
7 centers on the
eastern coast, one on the West
8 Coast, three
in between. All together, we
9 account for
more than eight and a half percent
10 of the U.S. blood
supply. So, it is a large
11 sample and also
geographically diverse, with
12 diverse,
demographically diverse donor bases.
13 The coordinating
center for this
14 work is Westat in
Rockville.
15 So what we did was
try to define
16 the cohort of
donors who were deferred for
17 travel to malarial
areas, sampling,
18 systematically our
own records for the
19 calendar year 2006
to determine where had
20 those donors who
were deferred traveled.
21 Separately, we
developed estimates
22 of risk for malaria
acquisition in U.S.
Page 148
1 civilian
travelers. So, we are not looking at
2 military
personnel. We are looking at U.S.
3 civilian
travelers and we make the assumption
4 that people
who come to donate have equivalent
5 or at least
not a higher risk for malaria
6 infection as
all U.S. civilian travelers to
7 estimate the
risk that someone who comes to
8 donate at
different points in time might have
9 malaria
infection.
10 So, the external
data sources
11 include travel
information from the world
12 trade organization,
as well as the U.S.
13 Department of
Commerce and then Dr. Paul
14 Arguin at CDC
kindly provided greater detail
15 from the U.S.
annual malaria surveillance
16 summaries,
specifically breaking out data into
17 whether an imported
case of malaria was in a
18 U.S. civilian or a
foreign civilian.
19 This graph
represents similar data
20 to that which Dr.
Kumar showed, showing the
21 incubation periods
of malaria by the four
22 species, falciparum
malaria, ovale and vivax
Page 149
1 in U.S.
travelers.
2 So here we
can see specifically
3 that
falciparum malaria does indeed occur very
4 quickly. By the end of three months, fewer
5 than one percent of cases have yet to
6 manifest. So if you were to have a donor walk
7 in who had been to an area with exclusively
8 falciparum malaria and three months have
9 passed, whatever that risk of acquiring
10 malaria might be, you would say the odds that
11 there is an unrecognized infection have
12 already been reduced by two logs.
13
That risk is different for the
14 other three
species, where the incubation
15 period is quite a
bit more diverse. At the
16 end of the current
one-year deferral period,
17 only 0.1 percent of
falciparum infections have
18 yet to manifest.
About two and a half or so
19 of the other three
species have yet to
20 manifest. So this
comes into play in our
21 estimates of
residual risk at time T. And we
22 are making, and I
will show you estimates for
Page 150
1 three months
as a hypothetical alternate
2 deferral
period and for one year, the current
3 guidelines.
And so this equation reflects how
4 we made
estimates of residual risk.
5 So, this
slide summarizes the
6 number and
rate of malaria travel deferrals
7 across the six
blood centers. And it is worth
8 noting that
there was almost a four-fold
9 difference in
the level of impact. The
10 southern region of
the Red Cross had about six
11 deferrals per
thousand donations and blood
12 centers of the
Pacific more than 22. In the
13 aggregate, it was
about one percent, which
14 fits nicely with
estimates that we have seen
15 in the literature
recently. And all-tolled,
16 our six blood
centers had more than 13,000
17 malaria travel
deferrals in the calendar year
18 2006.
19 So this is a very
busy slide here.
20 I just, I mainly
want to make note of the fact
21 that for each of
the centers, Mexico was by
22 far the region to
which most malaria travel
Page 151
1 deferred
donors had visited. There is quite
2 a bit of
variability from one center to
3 another, which
one might expect. Blood
4 centers of the
Pacific, for example, had the
5 highest level
of deferrals for travel to Asia.
6 But using this
sample of 2,100 deferrals,
7 which is a 16
percent sample of our 13,000
8 deferrals, we
were able to project to the
9 country at
large how many deferrals there
10 might be annually
and where they had gone.
11 So, this is where
the 150,000
12 figure comes from.
About 40 percent of that
13 to Mexico and a
very small share due to travel
14 to Africa or other
high risk areas such as
15 Oceania. In fact,
our sample had none. We
16 used some
statistical techniques to estimate
17 what might be the
country level. So, just
18 barely more than
100 there.
19 So this table
summarizes risk for
20 malaria in U.S.
civilian travelers during
21 2005. So again,
this is a complicated slide
22 so I won't focus on
all of the data. But we
Page 152
1 estimated
here, using the external data on
2 numbers of
travelers to each region to try to
3 limit our
estimates, the denominators only to
4 people who had
visited countries that are
5 endemic for
malaria. Other reports one finds
6 in the
literature take all travel, for
7 example, to
the Caribbean, which includes many
8 areas that are
not endemic for malaria. So,
9 we tried to
make sure that we weren't
10 underestimating the
risk.
11 What we estimate
for Mexico is
12 that about four
million travelers to Mexico
13 might have gone to
areas that would trigger a
14 Malaria deferral.
So with this as the
15 denominator, we use
CDC information on
16 imported Malaria in
U.S. civilians to develop
17 a rate per hundred
thousand travelers for one
18 region versus
another.
19 Over on the right,
we see relative
20 risks setting
Mexico as one. So what is the
21 relative risk to
acquire malaria infection if
22 you go to Africa or
other regions as compared
Page 153
1 to Mexico. And
we see a three log difference
2 in Africa and
Oceania, as compared to Mexico
3 with most
other regions in between.
4 Because the
species of malaria
5 likely to be
imported from one region differs
6 from that to
another, these relative risks
7 shift somewhat
by 12 months. This reduction
8 in the risk
from Mexico to Africa reflect the
9 tighter
incubation periods of falciparum and
10 the fact that most
malaria imported from
11 Africa is
falciparum.
12 We can estimate
based on the
13 incubation periods
the pre-symptomatic
14 prevalence of
infection at three months and
15 twelve months per
100,000 travelers. So for
16 Mexico at 12
months, it is 0.003 per 100,000.
17 And at three
months, that might be 0.03.
18 So estimates on
residual risk then
19 says that we assume
that our deferral donor
20 cohort has
equivalent risk as U.S. travelers
21 overall. These are
the number of donors
22 deferred to each
region. How many infections
Page 154
1 might we
assume in each group? So, this is
2 assuming that
we have identified this cohort
3 before they
have traveled. At the moment they
4 walk in the
door, we know that the risk is not
5 this high
because time has already elapsed
6 since the
return and they haven't manifested
7 symptoms. But
again, to make a conservative
8 estimate, this
is the number of infections you
9 might expect
in each group and, in total,
10 about 13. Eleven
infections would have
11 manifested prior to
the donor's arrival at the
12 blood center. And
we use the actual interval
13 between return and
presentation to estimate
14 that. At the end of
12 months, perhaps one
15 infected donor
every six years might be there.
16 I think this is an
overestimate because it
17 assumes that they
come in on day 366, whereas
18 that risk would
continue to diminish with time
19 and donor
presentation intervals would
20 naturally
vary.
21 If we were to
shorten the deferral
22 period to three
months, we see what the
Page 155
1 residual risks
might be in this model. Nearly
2 all of it is
due to travel to high-risk Africa
3 or to
intermediate risk Asia but which has
4 lots of donors
deferred, or to Central
5 America, which
has also high numbers of
6 deferrals and
an intermediate risk.
7 Mexico
represents a risk of one
8 infected donor
every 50 years. If you look at
9 the change in
risk from current guidelines to
10 this alternate
model, you see a risk of one
11 infected donor for
travel to Mexico every 57
12 years and this is
without any serologic test
13 at
all.
14 So, what about if
there is no
15 deferral at all for
travel to Mexico? The
16 risk for collecting
a unit from an infected
17 donor would
increase by an additional unit
18 every 15 years. And
the number of donations
19 gained would be
about 100,000 per year,
20 assuming each donor
gives about 1.6, 1.7
21 donations per
year.
22 Compare that to
the three month
Page 156
1 deferral
period in the model, which again
2 shows
additional risk of one infected donation
3 every 57 years, with about 56,000 donations
4 more per year. And I think that there are
5 other countries that would present a cost
6 benefit ratio as attractive as
Mexico's.
7 So to
conclude, U.S. travelers who
8 go to
Sub-Saharan Africa and Oceania have a
9 risk for
malaria infection one thousand times
10 or more greater
than that than travelers to
11 Mexico but Mexico
accounts for ten times more
12 deferrals. So, on a
cost benefit or risk
13 benefit estimate,
that deferral to Mexico has
14 about one-ten
thousandth the value of one for
15 a donor who has
gone to Africa.
16 Shortening or
eliminating the
17 deferral period for
Mexico might add tens of
18 thousands of donors
each year at an
19 exquisitely small
additional risk. And then
20 finally, to hammer
home that point about semi-
21 immune donors
versus those who have no history
22 of malaria
infection, those who have no risk
Page 157
1 for being
semi-immune carriers of silent
2 infections
present a fairly straight-forward
3 opportunity to
estimate risk at time T,
4 following
return to the U.S.
5 Thank
you.
6 CHAIR SIEGAL:
Thank you very
7 much. Are
there questions of this speaker?
8 If not, let's
proceed.
9 We will next
hear from Celso
10 Bianco from
America's Blood Centers. Donor
11 Deferrals Due to
Travel to Malarial Areas
12 Among Members of
America's Blood Centers. Dr.
13 Bianco.
14 DR. BIANCO: Well
thank you very
15 much for the
opportunity to present these
16 data. This reflects
a survey that we carried
17 out among the
members of America's Blood
18 Centers about
malaria deferrals. For those of
19 you that are not
familiar with it, we are a
20 network of
community blood centers. They
21 provide advocacy
and a lot of group services
22 to these centers.
They include 75 U.S. blood
Page 158
1 centers, the
Canadian Blood Systems and Hema-
2 Quebec, and in
the aggregate, they collect
3 about 9.4
million donations. It is about half
4 of the U.S.
blood supply. And they provide
5 also a lot of
other blood services.
6 This survey
was conducted in the
7 months of
July/August of this year. And
8 invited every
one of the members in the U.S.
9 to respond,
but it was a voluntary survey.
10 The questions were
very simple to increase the
11 response. And we
asked what was the number of
12 donors that
presented to donate in 2007, how
13 many were deferred
because they traveled to a
14 malarial area, and
how many of those have been
15 deferred because
they were in Mexico, in an
16 area defined as
malarial, according to the
17 Yellow Book. And
the data was parsed
18 according to
geography.
19 Fifty-two of these
75 centers
20 responded to this
survey. And we had states
21 in the snow belt,
we had states in the Mexican
22 border, and we have
the rest of the country.
Page 159
1 One of the
large members got several centers
2 and they
provided an aggregate response so we
3 had to add
Arizona and New Mexico on the rest
4 of the
country, states.
5 These centers
collected, had 6.5
6 million donors
presenting. And they had an
7 aggregate
deferral of 1.1 percent. So, 72,000
8 donors were
deferred for a year because they
9 traveled to a
malarial area. And of those,
10 27,000 were
deferred because they traveled to
11 Mexico.
12 So the percent of
all deferrals
13 that can be
attributed to Mexico is, in our
14 calculation, 37
percent. That is very close
15 to the data that
was just presented from REDS.
16 And when we look
and we just rank all of the
17 deferrals,
certainly they have a wide
18 variability. There
are centers in which the
19 deferrals range up
to three percent of the
20 presenting donors,
while others will have 0.2,
21 0.3 percent. And
again, there is a lot of
22 variability on how
many of the donors traveled
Page 160
1 to Mexico or
not. And we could actually
2 divide the
centers where the proportion of
3 Mexican travel
was very high, for instance,
4 for seven
centers on top of the chart, 80 to
5 100 percent of
the deferrals related to travel
6 to Mexico. For
other centers, it is in the
7 bottom of the
chart. Ten centers had less
8 than ten
percent of their deferrals related to
9 Mexico.
10 If we divide in
these broad
11 regions of the
country, people in the snow
12 belt feel colder
and they go south more often.
13 About 1.4 percent
are deferred for malarial
14 risk, while in the
rest of the country is
15 about 0.8 percent.
But the differences are
16 not that
big.
17 And again, the
number of donors
18 varies, obviously,
by the size of the center
19 and by the area
where they are. And among
20 these 52 member
centers in 2007, there were
21 centers that lost
to that deferral about
22 11,000
donors.
Page 161
1 So, in
summary, in data from 2007,
2 about 6.5
million donors presented. 72,000
3 were deferred
for malarial risk. So, if we
4 were to
double, since we are about half of the
5 blood supply,
is 140,000, again matches very
6 well with the
data that we were just
7 presented.
8 The range of
deferrals varied from
9 0.3 to 3.2
percent. And the impact of
10 deferrals due to
travel to Mexico for each
11 center ranged from
four percent to 97 percent
12 of the malarial
deferrals. And 27,000
13 deferrals were due
to travel to Mexico,
14 representing about
37 percent of the malaria
15 deferrals. And that
represents about 1,000
16 donors a week for
the country. They are being
17 deferred because of
travel to Mexico and not
18 just a total of
malarias.
19 And the other
point that I just
20 want to make is
that we know very well that a
21 lot of the
deferrals lead to donors that get
22 discouraged and
don't return.
Page 162
1 I am close to
the end. I have
2 only one more
slide but I want to make a
3 comment. The
risk that we heard from Kumar is
4 currently
about one in 37 million for
5 transmission
of malaria. We defer over one
6 percent of the
donors because of travel. We
7 defer over
five percent of the donors, it
8 varies between
five and ten percent, because
9 of travel to
Europe or to the UK because of
10 mad cow disease,
where probably the smallest
11 epidemic ever
recorded in medical history but
12 with no cases in
the U.S.
13 And we are
considering applying a
14 test for something
that we defer so many
15 donors and that is
so much less than all the
16 other major issues
that we confront like we
17 did yesterday with
bacterial contamination,
18 where our test got
20, 30 percent sensitivity
19 and TRALI that we
have very limited means of
20 controlling.
21 My last slide is
just repeating
22 what was said at
the malaria workshop
Page 163
1 sponsored by
FDA in 2006 and something that
2 Dr. Katz very
wisely said. He said we could
3 take care of a
lot of the deferral problem if
4 we didn't
include Mexico as a malaria risk
5 area, even
though malaria occurs there. I
6 would
encourage further discussion on that.
7 I mean, you
guys have heard me say
8 this for
years. Give me back Mexico. That is
9 all I want is
Mexico. Thank you.
10 CHAIR SIEGAL:
Thank you, Dr.
11 Bianco. Are there
any questions? All right.
12 Very
good.
13 Now we are going
to hear from Paul
14 Arguin, M.D. from
the Centers for Disease
15 Control. The Risk
of Malaria in Travelers to
16 Mexico.
17 Jay? I'm sorry.
Jay had a
18 comment.
19 DR. EPSTEIN:
Actually, I did have
20 a question. Whether
we know the typical
21 interval between
the last at-risk travel,
22 particularly to
Mexico and when donors come in
Page 164
1 to donate.
Because the idea of deferral
2 versus reentry
testing, how much of a burden
3 it is to
losing a donor will depend whether
4 you actually
have to send that donor away.
5 And if donors
typically don't come in to
6 donate shortly
after travel, then it would
7 have a lot
less impact than if they typically
8 do. So, I am
just wondering whether any of
9 the surveys
have shed any light on that issue.
10 And in the
modeling, we simply
11 assume a random
stochastic relationship but
12 that may not be the
case.
13 DR. BIANCO: Well
unfortunately,
14 Dr. Epstein, we
don't have these data. I
15 believe that
through the REDS, they would be
16 able to try to mine
that data out. And you
17 may say something,
Bryan.
18 MR. SPENCER: I can
comment on
19 that. I didn't
present that just now but
20 about 40 percent of
donors, in aggregate
21 across all of the
regions, present within the
22 first three months.
So, it is not a uniform
Page 165
1 distribution
over twelve months. A three
2 month
deferral, you would still lose 40
3 percent.
4 CHAIR SIEGAL:
Okay. Go ahead.
5 DR. ARGUIN:
All right. Good
6 morning.
7 So, I have
been asked to describe
8 the risk of
acquiring malaria from travel to
9 Mexico. And so
I think we need to address
10 several, there are
several things we need to
11 know in order to
really talk about the true
12 risk in
travelers.
13 How many people go
to Mexico? How
14 many travelers get
malaria in Mexico? Where
15 in Mexico did they
travel? Where did they get
16 malaria while they
were in Mexico? How much
17 malaria is there in
Mexico? And where in
18 Mexico is that
malaria occurring? So, some
19 very key
points.
20 So, to address the
first one, how
21 many people go to
Mexico? You have heard some
22 numbers already and
there are many different
Page 166
1 sources of
data to try to characterize volume
2 of travel from
any one place to any one place.
3 So first of
all, WTO, World
4 Tourism
Organization, not trade, this is one
5 of the better
sources of information out there
6 describing the
volume of travel from one
7 country to
another. As you can imagine, being
8 that it is
sensitive data describing travel
9 from all the
different countries in the world,
10 quality of data is
going to vary country to
11 country, depending
on which of the two
12 countries involved
that data set.
13 Likewise,
different variables are
14 collected and I
will describe this a little
15 bit more in the
next slide, actually. So, it
16 may not be
comparable country-to-country.
17 Next, ITA, this is
the
18 International Trade
Administration, in the
19 office of travel
and tourism industries in the
20 U.S. Department of
Commerce. This is an
21 annual in-flight
survey that is conducted at
22 international
travelers. U.S. residents
Page 167
1 traveling to
other countries. So this is, it
2 helps
characterize air travel from the U.S. to
3 other countries. It is a very rich data
4 source. It has lots of variables collected,
5 mostly for economic purposes, but it is very
6 handy for public health as well.
7 NATS, North American
8 Transportation
Statistics, this is a U.S.
9 Canada Mexico
collaboration describing border
10 crossings between
the three countries. The
11 other data that I
am going to show you here is
12 from the Health
Styles survey. This is a
13 regularly conducted
survey that is a
14 population-based
sample of adults in the
15 United States
asking regular sort of health-
16 based questions.
And there is opportunities
17 for investigators
to add additional questions.
18 Questions have been
added to this survey about
19 international
travel. And I will show you
20 some of that data
as well.
21 And finally, I am
going to show
22 you a lot of
information from both the U.S. as
Page 168
1 well as the
Mexican National Malaria
2 Surveillance
Systems.
3 So, WTO. Here
are some of the
4 variables that
can be measured and reported
5 out. Arrivals
of non-resident tourists at
6 national
borders by nationality. They also
7 measure
arrivals of non-resident tourists at
8 national
borders by country of residence. So,
9 depending on
which country, which question you
10 are asking or which
data is available from
11 those countries to
report, you can get very
12 different
numbers.
13 Other surrogates
that they
14 sometimes use if
that specific border crossing
15 data isn't
available is overnight stays by
16 non-resident
tourists in hotels and similar
17 establishments by
country or residence. So
18 once again, it is a
surrogate marker for
19 volume of travel
and you can get very
20 different
numbers.
21 The other thing to
realize about
22 this is this is
crossings. It is not
Page 169
1 individual
people. So, one individual can go
2 into a country
ten times and be counted ten
3 times in these
statistics. And so you need to
4 be very
careful when you are using this data
5 that you don't
suddenly fall into a population
6 based, using
this to actually describe
7 individuals.
8 ITA, this is
U.S. resident air
9 travelers from
the U.S. to another country.
10 So once again, a
subset of the overall travel,
11 especially
considering there is a very large
12 volume of
pedestrian traffic across the U.S.
13 Mexico border, as
well as automobile traffic.
14 NATS, this is
probably the most
15 comprehensive set
of numbers and this does
16 include
pedestrians, cars, planes, etcetera,
17 cruise ships,
border crossings by U.S.
18 resident travelers
to another country. And
19 once again, this is
crossings, not
20 individuals.
21 And finally,
health styles, this
22 is a measure of
individuals. So adults who
Page 170
1 stayed at
least one night in another country.
2 So here are
some of these numbers.
3 And you can
see, the spread is huge. With
4 WTO, depending
on which variable you are
5 looking at for
travel to Mexico, 17 to 19
6 million. ITA
about almost seven million air
7 travelers,
these are U.S. residents. NATS,
8 overnight
travelers almost 20 million, same
9 day travelers,
almost 70 million. And once
10 again, these are
crossings not individuals.
11 I did it myself.
And Health Styles, 11.8
12 million adults that
were overnight travelers
13 in the previous
year.
14 So the next thing
to focus on
15 here, actually
before I move on to that, I
16 guess because of
that and because malaria may
17 not be endemic
throughout countries -- so the
18 data that you see
here, these numbers, these
19 describe everyone
or every crossing in to the
20 country. If there
are very focal pockets of
21 malaria within that
country, this could be a
22 gross
over-estimation of people that are
Page 171
1 actually
exposed.
2 So moving on
now to how many
3 travelers get
malaria in Mexico, and I am
4 going to be
showing you data here from the
5 U.S. Malaria
Surveillance System, it is
6 important to
note that it is a passive system.
7 We rely on
local and state health departments
8 to report
their cases of malaria to CDC.
9 There is a
very detailed case report form for
10 people to provide
information.
11 As you can see
from some of the
12 data that Sanjai
was showing you earlier, it
13 is not often
completed. So there are many
14 times that we
receive a case report form that
15 says 30-year-old
male acquired his infection
16 on January 10th and
it was vivax. And that is
17 all we got. They
may not report the country
18 of acquisition.
They may not even report the
19 species sometimes.
And so that is why you get
20 a lot of blanks in
there. And that can sort
21 of play a role as
you are trying to use some
22 of this data to do
precise calculations.
Page 172
1 So, in 2006,
there were 1564 cases
2 of malaria.
You can see almost of half of it
3 in U.S.
civilians. Sanjai presented this
4 information
before so I am not going to dwell
5 on it. We do
get country of acquisition. And
6 you can see
here the top five that we have,
7 countries in
Africa and Asia. I listed Mexico
8 at the bottom
of that so you can see in 2006
9 11 cases,
which represents less than seven
10 percent of the
malaria that we get in the
11 United States.
Limiting that data set just to
12 U.S. residents,
similar set of countries in
13 the top five and
you can see in 2006, we had
14 only four cases of
malaria reported in the
15 United States among
U.S. residents.
16 And looking at
this over time, you
17 can see in the
past, in the late 1990s, we
18 were having maybe
about 10 cases of malaria
19 per year. Now we
are currently experiencing
20 about four to five
cases of malaria a year
21 acquired by U.S.
residents traveling in
22 Mexico.
Page 173
1 Now, it is
very important as I
2 have been
alluding to, to use this travel data
3 with care. The
numerator is often an
4 underestimation. Cases can be unreported.
5 There are estimates that the U.S. malaria
6 surveillance system gets about 30 percent
7 under reporting. Even though it is a
8 reportable disease, everyone is required to
9 notify us of all their cases. Not all of them
10 always make it up to us.
11 Likewise, it is
not possible to
12 know the true
country of acquisition
13 sometimes. If
either it is not reported at
14 all, the form is
left blank. Another
15 possibility is when
someone has traveled to
16 multiple
destinations. If they have spent a
17 week in four
different countries in West
18 Africa and then
they come back and get
19 diagnosed with
falciparum, they could have
20 gotten it anywhere.
So, as a result, that is
21 one case that we
know of for a fact occurred,
22 but we cannot
ascribe it to any one country.
Page 174
1 And so the
numerator is going to be an
2 underestimate
when you are trying to use these
3 numbers.
4 Likewise, the
denominator can be
5 an
overestimation. Risk may not be the same
6 for all travelers to a destination, in
7 particular, if no malaria is occurring in the
8 majority of that country. And so we are
9 using very imprecise data to try and do
10 precise calculations and I think it can lead
11 us astray sometimes.
12 Why some places
appear to be low
13 risk, it could be
it is true. It could be
14 that the
probability of infection truly is low
15 because there is a
very low intensity of
16 transmission and
there also can be difference
17 in different types
of travelers. For some
18 destinations if it
is a certain type of
19 traveler, they may
take more or less
20 precautions for
that destination. Another
21 possibility is that
the probability of
22 infection appears
falsely low because of some
Page 175
1 of these
factors. Specifically, that malaria
2 doesn't occur
throughout the whole country or
3 that and also
that the U.S. travelers aren't
4 going to the
parts of the country where
5 malaria is
occurring.
6 So, let's see
if we can try and
7 get to this
question of where malaria is
8 acquired by
U.S. travelers in Mexico. And I
9 really am not
going to have a good answer to
10 this and so I am
going to show you some
11 information
here.
12 The surveillance
data that is
13 collected on cases
is limited to the country
14 level of
information. So, if a physician
15 diagnoses a case of
malaria, we ask them to
16 tell us what
country it was acquired in, we do
17 not get sub-country
level information. And so
18 that is a problem.
Occasionally, we do get
19 this information.
CDC and Malaria Branch does
20 run a malaria
hotline where clinicians can
21 call in to get
advice about diagnosis and
22 treatment of cases.
And in these instances
Page 176
1 where we have
a one-to-one connection with the
2 clinician in
real time, we can sort of get
3 some of that
additional information to find
4 out where
specifically they were in a country,
5 sometimes but
we don't collect that
6 information
systematically.
7 So,
destination is only one aspect
8 of risk to
consider. Duration of travel
9 certainly can
affect the risk of acquiring
10 malaria, the type
of traveler and certain
11 behaviors may
increase or decrease risk. And
12 certainly that is
the case for Mexico.
13 According to the
NATS data, about 80 percent
14 of travel to Mexico
to United States is same
15 day travel. This
includes both pedestrian,
16 automobile, as well
as cruise ship travel. So
17 only about 20
percent of the border crossings
18 are overnight
border crossings.
19 One particular
type of travel that
20 I would like to
call your attention to is VFR
21 travel. These are
first and second generation
22 immigrants who
returned to their countries of
Page 177
1 origin to
visit friends and relatives. It is
2 a concept in
travel medicine that has been
3 described
repeatedly because VFR travelers
4 tend to have
an excess morbidity and mortality
5 from many
infectious diseases, including
6 malaria.
Oftentimes VFR travelers tend not to
7 seek
pre-travel care, may not recognize it as
8 a risk, may not use prophylaxis, may stay
9 longer, may stay in higher risk settings. And
10 this was described by, there is the
11 GeoSentinel Surveillance System, which is a
12 network of travel clinics. And per patient
13 encounter, you can see that risk of acquiring
14 malaria was much higher amongst VFRs than
15 compared to people who travel for education,
16 business, tourism, etcetera.
17 Looking at some
ITA data, this is
18 the in-flight
survey, we can see that 20
19 percent of the U.S.
residents traveling to
20 Mexico were
actually born in Mexico,
21 suggesting that
these are a subset of VFR
22 travelers. And in
fact, that is one of the
Page 178
1 questions that
is asked on the ITA survey,
2 what was your
purpose of traveling? And about
3 a quarter did
report that they were returning
4 home to visit
friends and relatives. A
5 similar
proportion stayed in private homes.
6 So that is
compatible.
7 And if you
look at our cases of
8 malaria over
the past five years, over half of
9 the U.S.
residents traveling to Mexico who
10 acquired malaria
were VFR travelers. So, to
11 answer that other
question about where in
12 Mexico specifically
are they acquiring
13 malaria, we really
don't know but that really
14 is not the whole
issue.
15 So the next issue
is how much
16 malaria is there in
Mexico and where in Mexico
17 is the malaria
occurring? And I am going to
18 address these two
together. Here is a graph
19 that has two
separate axis. As you can see on
20 the left, that is
the number of cases reported
21 to the U.S.
Surveillance System that were
22 acquired in Mexico
from 1985 to 2006. On the
Page 179
1 right, you can
see the number of cases in
2 Mexico. Mexico
was experiencing probably
3 about 150,000
cases per year back in the mid-
4 1980s. That
has come down steadily over time
5 and as you can
see, the number of cases
6 amongst U.S.
residents who acquired their
7 disease in
Mexico follows it quite nicely.
8 And so I think
one of the biggest predictors
9 of how we can
reduce the amount of malaria we
10 get from Mexico is
as Mexico gets their
11 malaria problem
under better and better
12 control, we are
going to experience fewer and
13 fewer cases of
malaria.
14 Looking at a
closer look here,
15 Sanjai showed some
of this data. And you can
16 see now they are
currently experiencing about
17 2,000 cases per
year. I have 2008 data there
18 as well. And that
is year-to-date, that is as
19 of this week. So
they are on track to be
20 right about the
same level, maybe just a
21 little bit
below.
22 What is very good
news is that in
Page 180
1 2007, they
reported zero cases of falciparum
2 and so far for
2008, zero cases of falciparum
3 again. So it
appears now that they are down
4 to a single
species of malaria, Plasmodium
5 vivax, down to
about 2,000 or so cases per
6 year.
7 And in fact,
Mexico is able to
8 break down
their surveillance data by state
9 and there are
several states that previously
10 had been endemic
for malaria where over time
11 it has come down to
virtually zero and has
12 stayed at zero. So
these are parts of Mexico
13 that have been
removed as areas where
14 transmission
occurs. And in fact, if you look
15 over time, this was
the malaria situation in
16 Mexico in 1985.
Many of the states within
17 Mexico having
active transmission of malaria.
18 And I will just
flip through these, as you can
19 see, 2002, 2003,
coming up to present.
20 So the majority of
Mexico in green
21 has no active
transmission of malaria. We
22 have this little
square area here up in
Page 181
1 Sonora,
Chihuahua, Durango, Sinaloa, the state
2 right below
it, here I will point, Nayarit,
3 coming down
here to Oaxaca, Chiapas, Tabasco,
4 and Quintana
Roo are the places where there is
5 still malaria
transmission occurring.
6 Now, you will
notice I have
7 colored in
whole areas in red to indicate that
8 transmission
occurs within the state. And
9 that is
because we don't get information with
10 a finer granularity
than that. In reality, in
11 a state like
Quintana Roo, most of the
12 transmission is
probably occurring towards the
13 southern part of
the state but we really don't
14 know and it is
impossible to draw a line in
15 the sand and say I
can give you a 100 percent
16 guarantee that if
someone was in this beach
17 resort, they are
not going to get malaria but
18 in this beach
resort, they might. So, it is
19 a little bit
tricky.
20 Now, I am going to
show you some,
21 a series of graphs
here. And let me just do
22 a little bit of
description on the graph
Page 182
1 because I have
graphed two very different
2 things on each
one of these slides.
3 The green
line shows the number of
4 cases in the
Mexican surveillance system by
5 state. So here
is that area of Sonora,
6 Chihuahua,
Durango, that big square up in the
7 northwest
quadrant of Mexico. And this is the
8 number of
cases over time. And you can see
9 the green line
here coming down, coming from
10 about 900 cases in
2000 to now less than 100
11 cases so far in
2008. Very good news.
12 The line in blue,
on the other
13 hand, this is our
estimate of risk for the
14 U.S. travelers.
This is the proportion of
15 U.S. air travelers
to Mexico who are going to
16 this destination. I
said we are getting this
17 from the ITA data
set, a very rich data source
18 that asks the
question, please list every
19 destination you
plan on going to while you are
20 in Mexico. And so
they list all of the
21 specific towns. So,
for people who are going
22 to destinations
within this area, you can see
Page 183
1 it has been
less than one percent over these
2 several years.
There was a little blip here
3 in 2006, for
whatever reason. But even still,
4 it looks like
a big blip but all of this is
5 less than one
percent of travel. So, almost
6 nobody goes
here and fortunately, not much
7 malaria there
any more.
8 The state
right below that,
9 Sinaloa, also
coming down beautifully from
10 about 800 cases to
now about ten cases. There
11 is a reasonable
volume of travel there. This
12 is in the range of
about four percent now and
13 it is rising. So
even though larger volume of
14 travel going,
malaria is disappearing in this
15 area.
16 Nayarit, less than
one percent
17 forever, or at
least for the past several
18 years. And malaria
coming down nicely from
19 about 200 cases to
about ten or fewer for the
20 year so
far.
21 And I am just
going to run through
22 some of these other
ones. Tabasco also coming
Page 184
1 down nicely.
And very small volume of travel
2 for
U.S.
3 Now, here is
one of the problem
4 areas, Oaxaca
down in the south of Mexico.
5 They had about
600 cases in 2,000. It was
6 coming down
nicely like the rest of Mexico and
7 they
experience quite a resurgence, up to
8 about 1500
cases in 2005. It started to come
9 down now but
it appears to be plateauing or
10 rising again. So,
this is an area even though
11 in aggregate Mexico
appears to be getting
12 their malaria
situation under control, I think
13 there are still
pockets where transmission is
14 occurring. And as
you can see here it has
15 ranged, I think it
is just a coincidence that
16 these lines happen
to look very similar. One
17 way to interpret it
would be that people are
18 seeking out malaria
and they are only going to
19 Oaxaca when there
is a lot of malaria around.
20 But I don't think
that is the case.
21 Chiapas is another
sort of problem
22 area within Mexico.
It had the largest amount
Page 185
1 of cases for
quite a while, 3,500 cases coming
2 down
beautifully. Again, when was it down to
3 less than a
thousand cases rebounded up to
4 1500 cases. So
we need to keep an eye on that
5 as well. But
again, fortunately, almost
6 nobody goes
there.
7 And now here
is our big problem
8 one. Quintana
Roo. They have had relatively
9 few cases and
it has been coming down
10 beautifully staying
at very small numbers and
11 our volume of
travel has been climbing. Over
12 a quarter of U.S.
air travelers to Mexico have
13 a destination
within this state as one of
14 their destinations.
And so you think
15 incredibly low
risk, unlikely to be getting
16 any cases at
all.
17 Unfortunately, 50
percent of our
18 cases that we got
in U.S. travelers in 2007,
19 so two out of the
four cases acquired their
20 malaria here. And I
know this because I was
21 talking with their
physician who called the
22 malaria hotline. So
it was just complete
Page 186
1 serendipity
that I found out about this. They
2 were quizzed.
It was a husband and wife.
3 They swear
they went to a beach resort in the
4 northern part
of the state and did not do any
5 of the
traditional excursions down to the
6 south that are
considered to be higher risk.
7 And so this
bit of a disconnect
8 makes me a
little concerned. It makes me want
9 to not throw
this out even though it has been
10 low for so long, I
want to keep my eye on it
11 as an area of
potential concern. And here is
12 another reason to
sort of maintain vigilance
13 as well. Jalisco is
one of these areas that
14 we had removed as a
risk area. They had only
15 two cases reported
for three years in a row
16 with a huge volume
of travel. And this is
17 about 14 percent of
air travel in 2007 is
18 going to
destinations within Jalisco. And
19 this year, they are
experience a little bit of
20 a resurgence.
Keeping our eye on this to see
21 if it is real or
not or if it is just going to
22 be a blip. We may
end up having to actually
Page 187
1 add Jalisco
back as an area where transmission
2 occurs.
3 So putting it
all together on one
4 big map, you
can see most of Mexico does not
5 have active
transmission. The areas up here
6 that I showed
you, the Sonora, Chihuahua,
7 Durango,
Sinaloa, Nayarit, it is coming down
8 dramatically.
I would not be surprised if it
9 disappears all
together, within the next year
10 or two. And that
would be wonderful news.
11 The volume of
travel, however, going to this
12 area, isn't very
big and so it is not likely
13 going to have much
of an impact. We do need
14 to keep our eye
here on Jalisco, to make sure
15 that that doesn't
recur as well.
16 These areas right
here, Oaxaca and
17 Chiapas are the
areas with the largest amount
18 of malaria still
but still a relatively low
19 volume of travel
that goes there. And then
20 this is our other
sort of big problem one.
21 Apparently not a
lot of malaria but yet we
22 still have gotten
the two cases from there
Page 188
1 with the huge
volume of travel that is going
2 there.
3 And so, I
guess, my last comment,
4 I am just
going to talk about how to use some
5 of these
denominators a little bit carefully.
6 Because I
think if you use the NATS data with
7 all of the
border crossings, etcetera, there
8 is about 91
million border crossings. I would
9 say if you are
going to use let's say four
10 cases acquired in
2007 and you wanted to
11 divide that by a
number, you could be tempted
12 to use a huge
number like that. You could use
13 WTO data of
something like 19 million. You
14 could, the Health
Styles data of about 12
15 million. So once
again, just depending on how
16 you are doing it,
if you consider that maybe
17 it is just the
overnight travelers that are
18 the risk
population, the ones that travel by
19 plane are more
likely to be able to get all
20 the way down to the
risk areas, compared to
21 let's say the
pedestrians or the motor vehicle
22 traffic. You could
limit it to maybe six
Page 189
1 million.
2 So once
again, depending on who
3 you parse it,
and then with some of this ITA
4 data showing
where people are actually going
5 when they are
traveling by air, most of them
6 aren't even
going to risk areas. I think you
7 could probably
even get that number down to
8 one percent of
the air travel or 0.01 percent
9 of overall. So
maybe as low as 100,000 are
10 actually at risk.
So, it is a little tricky
11 and as you are
doing models or as you are
12 doing some of these
predictions to say, you
13 know, one case per
50 years or something like
14 that, I think you
need to be careful and maybe
15 have wide
confidence intervals on some of
16 these calculations.
Maybe run it with several
17 different
denominators to try and really
18 characterize
risk.
19 So, my summary
here. How many
20 people go to
Mexico? Millions but only a very
21 small percentage go
to areas where malaria is
22 transmitted.
One-quarter are VFR travelers,
Page 190
1 which tend to
be higher risk.
2 How many
travelers get malaria in
3 Mexico?
Currently only about five per year.
4 More than half
are VFR travelers. Where in
5 Mexico? We're
not really sure.
6 How much
malaria is there? Less
7 and less. And
that is very good news. And in
8 more and more
focal areas, that is going to be
9 a lot easier
to manage, hopefully, if things
10 continue along this
trend. And so it is
11 mostly in the south
but we do need to maintain
12 this vigilance to
make sure it is not
13 reestablished.
Thanks.
14 DR. McCOMAS: I
have a quick
15 question.
16 CHAIR SIEGAL:
Okay. Thank you,
17 Dr. Arguin. There
are questions.
18 DR. McCOMAS: Yes.
To what do you
19 attribute the
decrease in malaria? Is it
20 better public
healthcare or is it a decrease
21 in mosquito
population? Because that would
22 seem to have some
implications for how we
Page 191
1 review these
results.
2 DR. ARGUIN:
Yes, I think it is a
3 function of,
it is happening purposefully.
4 So, the
Mexican government has an active
5 malaria
control program. That does include
6 mosquito
interventions as well as healthcare
7 based
interventions. So they are actively
8 trying to
reduce their amount of malaria is
9 one
component.
10 So, there is
mosquito control as
11 well as there are
health interventions. I
12 don't think it is
an issue that health in
13 Mexico overall is
getting better but there is
14 a focused malaria
control program trying to
15 reduce the burden
of malaria.
16 CHAIR SIEGAL:
Louis?
17 DR. KATZ: Paul, is
there any way
18 to know, I presume
that these cases, the rates
19 in the states are
because it was diagnosed
20 there. And my
question is, is there a gap
21 between
transmission and diagnosis? Because
22 we know that there
is substantial internal
Page 192
1 migration in
Mexico from the hinterlands to
2 the places
where there are jobs, i.e.,
3 Quintana Roo
and others. Is there any way to
4 parse that at
all?
5 DR. ARGUIN:
You mean, for
6 example, let
me just, to restate that. If
7 there is a
person whose residence is in
8 Chiapas,
happens to go to Quintana Roo for a
9 job, gets
diagnosed with malaria there, I
10 mean, those sorts
of issues?
11 DR. KATZ: Yes, so
the difference
12 between the
diagnosis and actual transmission
13 occurring in the
state or wherever.
14 DR. ARGUIN: No.
Sorry.
15 DR. DI BISCEGLIE:
Could you
16 comment on the
CDC's recommendations for
17 malaria prophylaxis
for travelers visiting
18 Mexico and whether
those recommendations are
19 sort of based on
some of these data that you
20 have
shown?
21 DR. ARGUIN:
Absolutely. And so
22 we try and
determine where the risks would be
Page 193
1 for a traveler
and make those recommendations
2 appropriately.
And so, for example, if there
3 was a VFR
traveler planning on spending a
4 month visiting
family in Chiapas, yes, I want
5 that person on
chemoprophylaxis.
6 DR. DI
BISCEGLIE: I'm talking
7 about official
recommendations that I might
8 find on the
CDC website. Is that --
9 DR. ARGUIN:
Yes, absolutely.
10 DR. DI BISCEGLIE:
It is by area
11 like
that?
12 DR. ARGUIN: Yes.
The current
13 recommendations
lists the states within Mexico
14 where risk is
occurring, where transmission is
15 occurring.
16 CHAIR SIEGAL: Dr.
Goodman.
17 DR. GOODMAN: I was
wondering what
18 you know about
non-diagnosed acquisition of
19 infection. You
mentioned under reporting an
20 estimate of 30
percent. I am wondering how
21 robust that
estimate is because certainly
22 other public health
reportable diseases are
Page 194
1 under reported
a great deal more than that.
2 Now, maybe
because clinical malaria is often
3 traumatic that
there is less under reporting.
4 So I am
wondering if you know more about that.
5 Certainly,
and the other question
6 is sort of,
has there ever been a scientific
7 study of
returnees let's say from an area
8 where there is
known to be a lot of
9 transmission
going on where one looks not just
10 at the clinical
acquisition of malaria but for
11 example antibody
levels at three months.
12 Because we
certainly know, you know, those of
13 us who practice
medicine with travelers or in
14 endemic areas, that
the presentation of
15 malaria is not
always typical and that
16 certainly for vivax
infection may be self-
17 limited.
18 So, I am just
wondering what you
19 know about
that?
20 DR. ARGUIN: I
guess to take the
21 first one, the 30
percent that I threw out
22 there, that is, we
have conducted a capture,
Page 195
1 recapture
study comparing the national malaria
2 surveillance
system to data captured by the
3 NNDSS,
National Notifiable Disease
4 Surveillance
System. So, essentially right
5 now, it is a
point of annoyance to many states
6 that they have
to report their data twice or
7 that there is
dual reporting systems within
8 the U.S. And
so we use that to our benefit to
9 be able to
compare two different data systems
10 and to make that
calculation. So we came up
11 with 30 percent is
from that study. It is
12 actually on its way
to publication right now.
13 And I guess the
goal of this
14 actually is to get
a single reporting system
15 for states,
separate issue. Your issue about
16 has a serologic
study been done of return
17 travelers? I am not
aware of a study like
18 that.
19 I would say that,
you said that
20 vivax can be
self-limited. I think a lot of
21 patients with vivax
actually often feel much
22 sicker than people
with falciparum.
Page 196
1 So I don't
think a lot of it is
2 being lost
from people having a very mild
3 illness that
went away on its own and they
4 never sought
medical attention.
5 Certainly
incidents do happen
6 where someone
comes into a hospital. They get
7 treated
empirically with everything under the
8 sun. They got
better and you never know what
9 it was. So
yes, that happens.
10 DR. FINNEGAN: Is
there anyway you
11 can tell if any of
the cases in the last five
12 years have come
from the day travelers?
13 DR. ARGUIN: From
same day?
14 DR. FINNEGAN: From
same day
15 trips.
16 DR. ARGUIN: No.
No, that
17 variable wouldn't
be collected. I mean, if
18 someone filled out
a detailed surveillance
19 form and they
indicated the dates of travel,
20 we would know that
if they traveled for one
21 day only or less
than a day. Yes, I guess
22 that is knowable.
But I think the odds of
Page 197
1 getting that
level of detailed information are
2 slim.
3 CHAIR SIEGAL:
Question in the
4 back.
5 MR. SPENCER:
Bryan Spencer,
6 American Red
Cross. I am curious about your
7 conclusion
that only a small percent go to
8 areas where
malaria is transmitted and that
9 perhaps as few
as 100,000 really incur any
10 risk.
11 In our own study,
we took a look
12 at blood donation
records, you know, for every
13 donor over a period
of several days to see of
14 those donors who
reported travel to Mexico,
15 how many actually
triggered a deferral. And
16 for us, it was 22
percent. One of the other
17 blood centers did
the same thing. I think
18 they got closer to
30 or 35 percent.
19 Now, this may not
be week-long
20 travel or VFR
travel. It may just be someone
21 who was on a bus
for a few hours passing
22 through a malarial
area. But it is sufficient
Page 198
1 to trigger
deferral. So, we used a
2 conservative
estimate of 20 percent of
3 travelers to
Mexico who might actually trigger
4 a deferral,
which you know, should be a pretty
5 good estimate
of how many incurred any risk at
6 all.
7 But what we
found suggested that
8 it is quite a
bit more than 100,000 or even a
9 very small
percent.
10 DR. ARGUIN: Yes,
and I can tell
11 you, we have got a
telephone line at CDC where
12 we speak with blood
banks every day trying to
13 characterize should
this person be deferred or
14 not based on this
itinerary. And it is often
15 very tricky. And I
would tend to think if
16 that same call came
from a healthcare provider
17 that said should I
provide chemoprophylaxis
18 for this traveler,
the two groups, a blood
19 bank versus a
travel medicine provider might
20 arrive at very
different conclusions of risk.
21 A travel medicine
provider might say, yes, I
22 think they are
going into an area. But I bet
Page 199
1 if they just
use insect repellant, they would
2 probably be
just fine.
3 A blood bank
may set the bar a
4 little higher
and say we want absolutely no
5 transfusion
transmitted malaria. They skirted
6 the zone,
let's defer them. So, I mean, they
7 tend to be
more conservative. So, I think
8 that is a
reasonable guess at the number of
9 people that
went through areas where active
10 transmission is
occurring. But like I said,
11 there is a pretty
broad range of numbers that
12 are out
there.
13 DR. McCOMAS: I am
struck by the
14 sort of the axiom
that mosquitoes don't know
15 borders. And a lot
of the mosquitoes don't
16 know borders and so
a lot of the cases are
17 actually bordering
Central America, which has
18 a much higher
incidence of malaria, according
19 to some of the
numbers we have seen. And I am
20 just curious, are
you aware, is the Mexican
21 government or the
folks there, are they
22 spending a fair
amount of -- is anybody
Page 200
1 looking at
mosquito vector patterns and how
2 those may be
subject to change if, for
3 instance, the
climate changes. Is anybody
4 actively
looking at how these sort of patterns
5 may influence
the prevalence of malaria
6 bearing
mosquitoes in Mexico?
7 DR. ARGUIN:
That's not likely to
8 be an issue.
In fact, there are anopheline
9 mosquitoes
throughout a lot of the United
10 States. So it is
not an issue that the
11 mosquitoes are
traveling to different areas or
12 especially related
to climate but they are
13 already here. So,
it is an issue of infected
14 people that could
then infect the mosquitoes.
15 So, I think as
part of a malaria
16 control program,
you certainly do want to
17 control the
mosquito population, prevent
18 people from getting
bitten by the mosquitoes.
19 But the same
species that are there in
20 Guatemala are there
in Mexico already. So
21 that is not so much
the issue.
22 I can tell you we
recently, you
++