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
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  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
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  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.
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  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.
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  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,
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  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
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  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
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  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
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  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
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  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
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  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