FDA Workshop
Testing for Malarial Infections in Blood Donors
July 12, 2006
Sanjai Kumar, PhD, FDA, Workshop Chair
Welcoming Remarks
Jesse Goodman, MD, PMP, FDA
Introduction to the Workshop
Hira Nakhasi, PhD, FDA
Session I: Global Problem of Malaria and Its Impact on the US Blood Supply
Monica Parise, MD, CDC, Session Chair
Global Problem of Malaria, Biology of Malaria Parasites and Implications for Transfusion-Transmitted Malaria and Detection Methods
Sanjai Kumar, PhD, FDA
Malaria in the United States
Monica Parise, MD, CDC
Malaria in the United States Military and It's Implications for Safety of the Blood Supply
Christian F. Ockenhouse, MD, PhD
Walter Reed Army Institute of Research
Current Deferral Policies to Reduce the Risk of Transfusion-Transmitted Malaria and Their Impact on Donor Availability
Alan Williams, PhD, FDA
Session II: Testing For Malaria Infections
Peter Chiodini, MBBS, PhD, Session Chair
London School of Hygiene and Tropical Medicine, UK
Developing a Test to Detect Malaria Infections in Blood Donors
P. Nigel Appleton
Newmarket Laboratories Ltd., UK
Antigen/Antibody Diagnostic Assays for Malaria: A CDRH Perspective
Freddie Poole, FDA
CDC Experience with the Laboratory Tests Used to Investigate Incidents of Transfusion-Transmitted Malaria
Marianna Wilson, MS, CDC
Prospects for DNA-Based Tests to Detect Malaria Infections
Sanjai Kumar, PhD, FDA
Session III: Perspectives on Testing For Malaria Infections in Blood Donors
Roger Dodd, PhD, Session Chair
American Red Cross
United Kingdom Experience Regarding Malaria Antibody Tests and Their Contribution to Blood Safety
Peter Chiodini, MBBS, PhD
London School of Hygiene and Tropical Medicine, UK
French Experience with Malaria Antibody Testing
Olivier Garraud, MD, PhD
University of Saint-Etienne, France
Australian Experience with Malaria Antibody Testing and Feasibility of Implementing a Malaria Test for the US Blood Donors
Susan Stramer, PhD
American Red Cross
Enhancing US Blood Availability by Testing for Plasmodium Spp. Infection
David Leiby, PhD
American Red Cross
Estimated Risks and Benefits of Blood Donor Screening for Malaria Compared With Donor Deferrals for Geographical Exposure
Steven Anderson, PhD, MPP, FDA
WHO International Standards for P. Falciparum NIBSC Proposal
Peter Chiodini, MBBS, PhD
Session IV: Roundtable Discussions
Jay Epstein, MD, FDA, Moderator
Panelists: Hira Nakhasi, Monica Parise, Matthew Kuehnert, Alan Williams, Peter Chiodini, Roger Dodd, Jerry Holmberg, Tom McCutchan, Louis Katz, Olivier Garraud, Steven Anderson
Closing Remarks by Jay Epstein, MD
KEYNOTE: "---" denotes inaudible in the transcript.
"*" denotes word was phonetically spelled.
M O R N I N G S E S S I O N
(8:03 a.m.)
Welcoming Remarks
Jesse Goodman, MD, MPH
DR. KUMAR: My name is Sanjai Kumar, and I am a researcher and a regulatory scientist with the Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics at FDA, and it my great pleasure to invite Dr. Jesse Goodman to come up here and give the welcoming remarks and open the workshop. Dr. Goodman.
DR. GOODMAN: Good morning to so many familiar faces. I just want to thank everybody for attending and dealing with this, helping us deal with this important issue. I really want to stand between you and the scientific discussions; and I as usual have to run off, but I am looking forward to hearing more about this. The one comment I would make is I think this discussion here is an example of something we are dealing with in a number of areas, which is kind of the increasing globalization of everything that we do.
With respect to the things that we help oversee in CBER, you know, I sort of see this in two directions. One is that it has often been said we live in a global village with respect to infectious disease threats, and I think we all know that. Even if you look back to HIV, that was really a global emerging infectious disease, although we tend to think of it as US-onset disease, so that increasingly we are looking at things like whether it is avian influenza. Malaria has kind of been a stable or improving problem in a sense. It's been to some degree a success story in blood safety, but obviously what you are all concerned about and we are all concerned about is at cost of deferred donors, et cetera.
But I also don't think we should be too sanguine about it not being a potential transfusion transmitted disease problem or an emerging infectious disease, and I always -- I think people are aware of some of these clusters of transmission of malaria cases in the United States. I saw on one of Hira's slides one of the maps showing the extent of malaria zones at various global malaria zones at various times at history; but I always like to point out that of course CDC was originally, a US malaria control center and much of the southern United States was areas of active malaria transmission. So I think we shouldn't be too -- I mean, with issues like climate change and environmental change, we shouldn't be too secure about malaria.
So there may be advantages to have having improved tools at least in the blood area. I am not talking here about necessarily about implementation strategies, but there may be advantages to having improved tools in terms of our readiness as we try to be prepared.
Then of course there is the issue of travel, and again this has got, again, you got -- the blood bank operators certainly see this in terms of the growth in deferrals, et cetera. My personal story, I think I have affected the NIH blood supply because, you know, I was donating fairly frequently, and then I suddenly couldn't donate because of a trip I had taken. You know, I called up FDA and complained about.
(Laughter.)
But I didn't get anywhere, you know, so don't feel you are alone. But I think there are -- there clearly is on the level that we deal with health and donations, you know, tremendous room for improvement in what we do. Then, as I said, I think there is a -- it is not just a blood bank operation, but there are some public health issues here. Also I am sure many of you in your -- those in blood banking or clinical medicine like I have, you know, all you need to do is see one or two cases of transfusion transmitted malaria and you realize this isn't something trial either in non-immune individuals.
So with that I just say, you know, what I see happening here is obviously we are trying to work with you to assess and bring together a science, see what some of the possible approaches might be, what some of the policy and practical implications are, and sort of help things move forward in this area. You know, I would be very interested to hear the rumblings, you know, that this might be something that if we can improve or move forward on, you know, could actually be helpful even in the near future to the blood community.
You know, so with all that said, I again wish I could hang out for the day, and I appreciate everybody doing it, and I will look forward to hearing about this. Again, this is an area where I think collaboration and partnership with NIH, with the blood community, et cetera, is really going to be helpful to us and where we hope we can provide rational scientific and policy approaches. So thanks very much. Everybody have a great day.
DR. KUMAR: Now --- Dr. Hira Nakhasi, who is Division Director for Emerging and Transfusion Transmitted Diseases, and he is going to give you an introduction and overview for the workshop.
Introduction to the Workshop
Hira Nakhasi, PhD
DR. NAKHASI: Good morning. Thank you, Sanjai, for the introduction, and also I would like to put my welcome for all of you guys who came from different places, from the country as well as outside the country. I appreciate your coming here because this is a very important issue for us, and we would like to get the input from all of you.
I just wanted to say Jesse, if he is still around, he is not the only guy who got differed. Last two years back human health --- Tommy Thompson went to Afghanistan, you know, as ---, and so he called us and asked whether he can donate the blood, and we had to tell him, sorry, you went to visit Afghanistan so you can't. So anyway, so if it, you know, is some consolation to Jesse.
(Slide.)
Now the purpose of this workshop is --.
(Adjusting equipment.)
I just wanted to give you an overview of what, you know, the -- why we are talking about this --- today's workshop as well as what the discussion is going -- we would like you to focus on. The challenges for the blood and blood products for all of us, including you, is that we need to have the enhanced product safety, purity and potency in order to avoid product shortage, and that is exclusively mutual.
(Slide.)
And how do we achieve that? And FDA's approach to achieving the blood safety is based on five principles. As Jay would call it, five layers of blood safety. The one is the donor screening deferral based on geographical, behavioral, and risk factors, usually by donor education, self-donor, and donor interviews.
Then on top of that and very, very applicable we also have laboratory tests, and based on the outcome of those laboratory tests for particular pathogens, there will be a deferral. Such as currently a deferral for laboratory tests for HIV-1 and -2, HBV, HCV, HTLV-I and -II, West Nile, and syphilis.
In addition to that, we have deferral registries to prevent use of blood from different donors. That is, you know, people if they are differed at one place they can't go other places and donate the blood. Then we have the quarantine controls for the products, which before testing and everything they are not released, and so there is another layer of safety. Then lastly it is the investigations and corrections of deviations.
(Slide.)
Now having said that, you know, the impact on the blood safety because of both the safety and availability. Millions of units, as you know, are transfused annually, and luckily the risks of transmission of infectious disease has significantly decreased with the introduction of these tests.
(Slide.)
This is just to give you an example here how we have gone from no testing to now with the testing. So for some of these agents for example, for HIV, you know, we are now at 1- to 2-million risk of infection per unit transfused. Similarly for HBV, it is around approximately
1.5/1.6 million, and you know HBV also has one in 200,000. However, because we still have not instituted a highly sensitive HBV --- assay.
(Slide.)
Now to make people understand how we start when a pathogen comes in, you know, in the blood supply and, you know, how do we respond to that. So basically, as many of you know the West Nile story, how it evolved, and we first of all introduced the --- criteria based on epidemiology and determined the risk factors. That is the initial safety measures. Then wherever feasible tests are developed, and then based on the development and testing the people are deferred. So that was the case in the case of West Nile Virus we know. When the epidemic started in 2002, very -- in a broad, big-time epidemic, we first started the donor deferral; and after nine months of that in place the tests were developed, and under IND we have started testing the people and then deferring donors based on the positive test. Then what happens is as the sensitivity and specificity improves on these tests, because it usually takes -- you know, first-generation tests are not as highly sensitive and specific, even though we try to achieve that. However, then based on the risks, we keep both the testing as well as the deferral bases together so that to insure that we have an optimal level of safety.
(Slide.)
The primary goal of this workshop is to seek public input on scientific developments that might support two things. One, if we want to have universal donor screening for malaria; or just reenter donors, which are those people who have got infected or exposed, and then test them for infection, and if they are not then reenter those donors. SO those are the really two major issues here we would like to focus, and I would like to just give you a brief introduction about the malaria background here. I know Sanjai will talk about in detail the biology of this parasite. However, but what I am trying to, you know, give you is set the stage here.
(Slide.)
Transfusion transmission malaria is a public health concern as everybody knows it in the US as well as the world around, and four species of human plasmodium which have been shown to cause transfusion transmission in the US. So you need to keep those factors in mind.
(Slide.)
There is no laboratory test approved, FDA-approved laboratory test to screen donors for malaria infection existing at this time, and currently the blood safety of transfusion transmission malaria is mainly through deferral policies, which you will hear more very in detailed from Alan Williams, a based on the history of malaria infection and travel or residence in malaria endemic countries or regions.
(Slide.)
Now what are guidelines? Currently what we have in place, which is this 1994 memoranda, where we talk about -- we have said that there is a three-year deferral for anybody who has a history of clinical malaria, prior residents of endemic countries, and one-year deferral for a visit to malaria endemic countries by residents who are coming from -- going from non-endemic to endemic. For example, going from here to, you know, Africa or Latin America or Indian for that matter, and identification of malaria endemic areas as provided by the CDC. That is the website.
(Slide.)
So why are we so concerned? The risk of transfusion transmission in the US, each year there are 28 million Americans visiting this endemic areas, and several millions of immigrants from endemic countries to this country, and so they may be harboring some infections sometimes, and there are a significant number of local clinical cases.
(Slide.)
Now what is the impact, what are we doing now, the deferral polices and the impact on the blood supply? Incidents of transfusion transmission malaria in the US is at an all-time low. That is good news. That is down from three cases per year in 1995 to 0.6 cases per year, which is every-other year one case or so at this moment.
However, because of these good deferral policies we also have a significant donor loss because of that because if a person goes and visits these endemic countries and also, you know, also we differ just for the exposure as I told you the guidelines just now. So approximately, you know, from 100- to 150,000 donors per year are deferred on that basis. You know, the estimates vary. Then availability of blood screening tests --- and minimize the unnecessary donor loss, because if we had a test which would allow these people to be tested and a significant number of these people can be re-entered.
(Slide.)
Now one thing, also another point which people have to remember, that what is the biology of this parasite. Briefly, that infectious unit of blood from parasites is very low. That is according to -- you know, this slide was provided to me by Sanjai, and what he tells me is that as one parasite in case of murine, which is P. berghei, can cause the infection, and in the case of the vivax malaria 10 parasites in infected red blood cells can cause the infection. So one has to be --- we have to have an assay to detect that level of infection in the blood. Then on top of that, we have the -- you know, blood products are stored, and parasites can survey under the storage conditions, blood banking storage conditions, up to 20 days. So we have to be careful about that, too.
(Slide.)
So, so what are the topics of discussion I would like to focus you guys on today? And at the end of the day I am sure, you know, at every session we have discussion, and we will welcome from the public, welcome questions from the podium as well as from everybody else. But at the end we will have a round robin, so keep these points in mind. What we want to focus our discussion are what are the main sources of malaria to the US blood supply and how effective are the current safety interventions? You will hear quite a bit. That is the first session today, and you will hear quite a bit about that. Then we also need to keep in mind what are the risks and benefits of donor screening for malaria infection in lieu of risk-based deferrals. Okay? So keep that in mind. Then also we need to focus our attention on what are the pros and cons of universal donor screening compared with testing only for donor re-entry, because I think it is a very important question for us, for everybody here. Knowing what the incidence is, what the --- in this country? You know, we need to discuss the pros and cons of universal donor screening versus testing only for donor re-entry.
(Slide.)
Then with regard to tests. So what are the desirable characteristics of laboratory tests to detect malaria infection in blood donors? We need to discuss that. What kind of -- as I told you, that the infections, you know, what is the dose of infection, and therefore we need to have such tests which can detect that ---.
Then the next step is what are the prospects for the use of malaria antibody tests in the US to screen blood donors or to re-enter deferred blood donors. Because why am I saying that? In Europe and some of the European countries already testing is being done to have our screening people who are exposed in malaria infection using antibody tests. You will hear both from the European perspective as well as the Australian perspective, and also you will hear from some of the makers of this test and what their experiences are.
Then finally we also need mot to keep our mind closed about only the antibody. We would like to see what are the prospects for the use of DNA-based methods as blood screening tests in the US, is there a possibility. Because the reason why I am saying that is because the antibody tests, you know, you have large window period. By the time a person gets infected and develops antibody there is a large window period. The question is is there another --- method where you can look at all of the --- infection and can narrow the window period.
(Slide.)
So with that, I would like to thank you for you attention and I guess I will open the workshop for the discussion. Thank you very much.
DR. KUMAR: Thank you, Hira, for the introduction and overview. If anyone is standing, there are more seats in the front. Before we begin the scientific sessions I have a couple of announcements to make here. First of all, as you can see we are really full, an impressive lineup of speakers here. So to get the most of the workshop we request please, please, all the speakers stay within their time. So, otherwise we will be speaking over somebody else's time, so that is going to create a problem, and I request the session chairs to please keep a close eye on the timing. Also in the interest of time please hold your questions for the end of the session. We have open sessions for discussion in the end. A full transcript of the meeting will be made available, so if you miss something you will be able to catch up with that, and the majority of the presentations will be available online given that we have consent from the speakers. And with that, I would like to hand over the session to Dr. Monica Parise, who is Chief of the Parasitic Disease Program at CDC, and she will open her session.
UNIDENTIFIED: ---.
DR. KUMAR: Yes, and also just one more thing. In case the room gets full here we have an overflow room, Room D, and that is just the adjoining room there. So there will be a live telecast there, but hopefully we will be able to accommodate everyone here.
SESSION I: GLOBAL PROBLEM OF MALARIA AND ITS IMPACT ON THE US BLOOD SUPPLY
Monica Parise, MD, Session Chair
DR. PARISE: Thank you, Sanjai. Okay. We are going to move right into the first session which is the global problem of malaria and its impact on the US blood supply. Actually this is not the first talk in the session. The first talk is Sanjai Kumar's talk on the global problem of malaria. Can we switch the slides? This isn't the first talk.
(Adjusting equipment.)
Global Problem of Malaria, Biology of Malaria Parasites and Implications for Transfusion Transmission Malaria and Detection Methods
by Sanjai Kumar, PhD
DR. KUMAR: Good morning again, and it's me again, so you might see me through the day so you might get used to it. Actually this is not the first talk I want to give.
(Laughter.)
--- the AV person. Well, I just want to give the acknowledgments. Okay. I will do that a little later than. So what I am going to do here in this first talk of this session, I am going to review the global transmission of malaria parasite, the biology of malaria parasite, and acquisition of naturally-acquired immunity against malaria. We believe this sort of information is key to developing sensible donor deferral policies to identify donors at risk of malaria and also to develop tests that could be used to detect malaria infection in blood donors.
(Slide.)
This is the global transmission of malaria as of today. So with all the numbers here there a couple of things to keep in mind here. Currently there are about 3.2 billion people around the world who are risk of contacting malaria, 300- to 500-million clinical cases of malaria, and 1- to
2-million deaths. I mean, depending on who you are talking to. But there are a few things to keep in mind here. There are four different species of plasmodium. Those are transmitted all over the world, but there are certain things about them to remember. First of all, the vary in their virulence. So about 90 percent of the deaths you see here, they occur from falciparum infection. That is the most lethal malaria, and also the majority of the deaths, about 80 percent of deaths, occur in sub-Saharan African, the south and Saharan desert in Africa, and most of those are children under the age of five. They bear most of the burden of the disease. The other thing about this plasmodium species, their transmission, global transmission, is not even, and you will see that in the coming slides there, and the disease is transmitted almost around the world. There are 100 countries where the disease is transmitted, but still the transmission is not even. You will see that also.
(Slide.)
Okay. These are the representative distributions of the four species, and I guess this is important for us to know where this infection is coming from, where the risk is coming from. If you look in sub-Saharan Africa plasmodium falciparum is the predominant disease. In Asia it is the plasmodium vivax is the predominant disease. In Central America again plasmodium vivax, and South America you get quite a good number of falciparum as well. So if you think of the reasons why this is happening some things can be explained here. For example, in Africa mostly in central and west Africa, and to a large extent in eastern and southern Africa also, Africans there, they lack the --- antigen on the
--- red cell, and that is the receptor used by plasmodium vivax --- red cells. So it makes the vivax is almost absent there, and probably an evolutionary adaptation. Probably vivax --- disease that is --- cause too much problems there, so evolutionary that happened. But still I was rather surprised to see --- vivax is there. But why the falciparum is --- predominant species in most of the Africa and parts of Central and South America, I just do not understand that clearly. Look at plasmodium malariae, and that is one of the causes of major trouble in terms of transfusion transmission malaria, because ---. It is pretty much absent in Asia and big parts of Central and South America. It --- low numbers, but it is still there in Africa. Plasmodium ovale is present almost close to 10 percent in Africa, but also disease there is in the form of co-infections. Most of the time it is not the sole infection. It is present along with falciparum infection, just to keep that in mind.
(Slide.)
So the global reach of malaria, there is no credible transmission of malaria in this country, and Monica will talk about that in detail. But in today's interconnected world this infection comes to us in may ways. The problem of malaria is rising, and there are more cases today than there were 30 years ago, so malaria is going to stay here. So what are the major factors which contribute to the rise of malaria transmission globally? Well, environmental factors, human activities, and I guess the two are interconnected, drug resistance emerging and drug resistance in malaria parasites, and the vector populations. In terms of vector populations, the global population of the --- species, those high --- capacity for transmitting malaria parasites is globally increasing, and there is good evidence for that.
(Slide.)
So, but all is not gloomy about malaria. So this is the malaria mortality data which I got from this extract from a paper by Carter, Richard Carter and --- Mendis. If you look at the beginning of the 20th century, approximately 10 percent of all deaths globally used to happen because of malaria, but now those figures are significantly lower. So in Europe and North America close to one percent deaths used to happen because of malaria. It's almost --- now. But there is one disappointing place here in sub-Saharan Africa. So with all the advances in modern medicine, that has not helped people in Africa in terms of when it comes to malaria. It's still 10 percent of all deaths today. This is data from 1997, and I don't think figures have changed. They are still because of malaria. So that is mind boggling. The world minus sub-Saharan Africa used to be eight percent before, and the numbers have come down to close 0.1 percent now. So this is one place where the majority of the problem is in terms of mortality. Unfortunately I could not find similar sort of data for malaria transmission 100 years ago and now, but this is in terms of mortality of malaria.
(Slide.)
Okay, so making the case in point. So the majority of the malaria ---. It started in the late mid '50s and it was --- intervention through ---. So making the case in point in Indian here, around 1955 before DDT was introduced there were close to 10 million cases. With the introduction of DDT malaria almost disappeared in India, so it went from 10 million cases to very few cases. I am sure the transmission was still going on, but very ---. With time and the lack of --- and malaria education programs were lifted, and the resurgence of malaria began in the early '70s, and then the transmission peaked around here to six million more cases around 1975. Then interventions were introduced again and they came down again, a now there is a rise, and I did not put the --- here. This --- but the numbers are rising again here. But it makes a case of point here how malaria has made its comeback also and malaria intervention methods work out successfully also. This is simple matters by controlling mosquito populations. What was not happening in sub-Saharan Africa was they were completely left intact. DDT was not introduced during that time. Most of the efforts were placed in India, in --- and around that area and really paid off.
(Slide.)
So this is a part of the global environmental changes, what some might want to call inconvenient --- here.
So if you look, this the prediction in 2020 based on a projected two percent at two degrees Fahrenheit rise in global temperature. So how malaria may be introduced in the parts of the world, in the majority of Europe also where it is not there, and how the intensity of malaria is expected to change, and that is given that there will be no human interventions made, successful interventions made to control malaria. So if this prediction is true so you might brace ourselves as well to prepare for this.
There is another point I would like to make here. There are some --- studies that increase in global temperature will lead to increase in malaria parasite. Because clearly the data shows that a two- to three-degree increase in in temperature in laboratory conditions facilitates the faster development of malaria parasite in mosquitos, and eventually that will lead to more malaria transmission.
(Slide.)
This is the picture, global picture today of the drug --- drugs. The drug resistance is everywhere, and probably that is the major factor that is contributing to a rise in malaria, and that is why the intervention of --- in Africa have not been very successful.
(Slide.)
So looking at the life cycle of malaria parasites here, this is for those who don't think about malaria issues everyday. So this is upon inoculation. The parasite enter into your cell and the infection commences there. From single human this parasite develops into 10 to 40,000 ---. Those come out in --- cells where the parasite develops, and each parasite develops into somewhere between 16 to 32 blood --- and the infection continues here, and then it gets transmitted again into ---.
So there are several things here about malaria biology --- that are part of building on transfusion transmission malaria. First of all, the --- cycle is somewhere between six to 14 days, depending on the species, but there are several exceptions, and I will talk about that in a second. The blood stage continues for 48 to 72 hours, depending on the species. So here is this incubation period that is around 21 days. Then the primary infections, a person will experience different sort of clinical diseases, varying from the most serious form of malaria to this fever; and then there is the story of these adults from endemic areas who develop partial immunity, but they carry low-grade parasite ---, and those are the most important group of people for us to watch out for.
So looking at the malaria biology and immunity again, so the definition of incubation period, the time that it takes between the infection to the first appearance of blood form parasite. That varies between the species. In the cases, I just said, it can be somewhere between 14 days to 21 days. But in the case of plasmodium vivax and ovale they have the --- forms in the liver, and this all could take sometimes a month to a year, and some --- strains of plasmodium vivax are known to just do that, so this period could be up to nine months very easily.
So when you are talking about this primarily, malaria ---, we have to keep this in mind. The chronicity of infection in the case of plasmodium malariae, the parasites have been known to have been demonstratively present up to 40 years. In the asymptomatic carries in multiple exposures in individuals who are either born in endemic countries or expatriates who live for a long period of time develop partial immunity. They have no clinical disease, but the carry. The --- develop ---- immunity as well and they carry low-grade parasite burden. So something I will keep talking again and again in talk, the parasite burden in asymptomatic carries is not known how many parasites they carry. That presents a big problem in terms of their identification and exclusion. Here I mentioned the infectious does of blood from malaria parasites is very low.
(Slide.)
So talking about travelers, so they have no prior immunity. Infection can be acquired shortly before departure from an endemic area, and the come and become infectious while in this country or in a non-endemic country. Infection with a strain of plasmodium with prolonged latency, I talked about that. Residents born in an endemic area or had a prolonged residence, they become asymptomatic carriers, a good number of those, and parasite burden is not known. Then history of clinical malaria, those could be still infectious because of inadequate treatment, and then there is still the possibility of relapse from liver form parasites in the case of vivax and ovale malarias.
(Slide.)
What are the laboratory methods that have been used over time? Direct demonstration, microscopy or DNA detection is we have to worry about the window period in this and also the parasite burden in asymptomatic carriers. The other method is look for a surrogate exposure such as looking for the antibodies, but then you have to worry about the time lapse between the parasitic exposure and first appearance of parasites, and there are few early reports on --- presence and data that show that it doesn't take very long after the first appearance of blood form parasites to the seroconversion. Then the a screening test to whatever we might want to implement should be able to detect at least the predominant plasmodium species that are known to cause transfusion transmission malaria.
(Slide.)
Detection methods I will just pass through quickly. Microscopy, thick film, quantitative buffy coat method, then antigen detection, methods of --- look for circulating parasite antigens, nucleic acid --- detections, and then antibody methods.
(Slide.)
This is my favorite slide I like to show. This is Sir Ronald Ross. He published this paper in 1903, an improved method for the microscopical diagnosis of intermittent fever; and 103 years later this is the method that is used around the world to detect malaria parasite, and there has not been much improvement since then. The staining may be a little fancy. The filter may be a little nicer.
(Slide.)
So this is a thick smear. You can see the parasites here. This is the gametocytes here. There are the rings here, and the sensibility depending on the hands holding the --- could be five parasites per microliter to 500 parasites per microliter if it is done by --- experienced technician.
(Slide.)
This is the quantitative buffy coat method here. So it is simply it is a hematocritic tube where you apply the infected blood. Then it is centrifuged in a hematocritic centrifuge at a high speed, and based on the bugs here, the different cells and the densities, the infected red cells, the form a ring just next to the white cells and on top of the uninfected red cells under a microscope. In a florescent filter you can see the parasites there, --- gametocytes and different --- here. So this is modification of the --- microscopy, but from what I see here it is clear to be as sensitive ad microscopy, but it is not very much preferred by people out in the field
(Slide.)
There are antigen detection methods. So there antigens there --- malaria and there antigens from the --- parts where there are --- between different plasmodium species. So, but there is a word of caution. So there are all kinds of methods there, and there are commercial companies who make and cell these tests. But as a word of caution here, these antigens could be circulating around four weeks after completion of chemotherapy. So presence of these antigens does not always equate to the current infection. The sensitivities vary depending on who is testing them, and they are sold by many commercial companies. Just to avoid the appearance of any endorsement, I am not showing any commercial. But none of those are FDA approved, but they are available in the market in different countries nonetheless.
(Slide.)
These are DNA methods here. This is our own data here using a small subunit of ribosomal RNA. We can detect up to 0.2 parasites per microliter. That equates to 250 parasites per ml of blood, and this method, I will talk about this in much more detail in my second talk. But this is at least 20-fold superior to thick film method. You will see all kinds of these kinds of publications in the literature. There is another word of caution I would like to have, but which I will talk about in my next talk.
(Slide.)
Then there is antibody-based detection methods. So is the florescent IFA method here. It s a method of choice. It is sort of a gold standard that is used by different laboratories, and some countries, including France, until very recently have used to screen for at-risk malaria donors by IFA. But it has sort of becoming outdated now because the sensitivity in travelers with a single one-time infection is questionable. The method is cumbersome, and it is probably difficult to be adopted in an automated format. But nonetheless, the method has been used very effectively and the CDC still uses this for malaria diagnosis.
(Slide.)
This is the data I would like to show here from my own laboratory here. This is an ELISA, and you will hear all kind of ELISA later in the workshop, but I would like to show this. So one of the concerns we have is the pan species recognition. The test should be able to detect at least the major species of plasmodium, and this is the data we ---. This is falciparum --- protein two --- proteins here. These are recombinant proteins. These were provided to us by ---, and this protein was produced for clinical use. There is a highly --- protein here, so that is why we get very little background ---. This is a test done at --- dilution.
But I would like to show here the recombinant CS protein recognized down to only --- falciparum, but also recognizes all samples in vivax with one exception for OLER samples from plasmodium malariae. The same was true for AMA1's. The majority --- recognition across these species and then --- to us from Marianna Wilson from CDC.
So we were rather kind of surprised because if you look --- sequence homology at protein level we really --- similarity at least for CSP and the --- protein here. When you mix the three proteins in the same --- in ELISA everything gets recognized in a very nice way.
(Slide.)
Probably some people here in the audience would be very pleased to see this data, and again in Western here this same sort of thing appears here. It recognizes -- I am not sure how I am doing on time. This thing is jumping. Okay. Okay, I will done in five seconds.
So recombinant CS recognizes all PF samples, and also these recombinant proteins recognize vivax sera, malariae sera, and ovale sera. So that is sort of good news that if you have highly --- recombinant proteins from one or two species and in combination are --- even if we have done
--- characterization. But again the word of caution here is probably it would be much better for these assays to work with the endemic sera where people have multiple exposures. But we have to be a lot more careful when we are dealing with primary infection. The person has seen only one time a parasite, so sensitivity may not be seen.
(Slide.)
My collaborators here. They are the people from my lab. Hira, who has been always supportive, Dr. David Haynes always provides good parasites, Monica Parise and Marianna Wilson, we can't do without them, and then NIAID Malaria Vaccine Development Branch for giving us these wonderful recombinant proteins; and I will stop here.
Malaria in the United States
by Monica Parise, MD
DR. PARISE: Thank you, Sanjai. We are going to move right into the next talk on malaria in the United States.
(Slide.)
Okay. So today I am going to talk about traveler's malaria, locally-transmitted malaria and the special case of locally-transmitted malaria, that caused by transfusion-transmitted malaria. Thank you to Sanjai and the organizers for asking me to give this talk.
(Slide.)
The points that were already mentioned I am going to go over sort of rapidly. 1,000 to 1,500 cases reported in the US every year, 99 percent of them are imported infections in travelers and immigrants, and we have up to about 10 cases a year of locally-acquired infection.
(Slide.)
So locally-acquired infection can be induced by transfer of blood as occurs in blood transfusion or by the other methods listed on the slide. It can be congenital transmission, and, as was mentioned, we occasionally have outbreaks, usually very small, of local mosquito-borne transmission in the United States.
(Slide.)
This map shows where local mosquito-borne transmissions occurred over the last 50 years or so. It is not surprising. The vector is really almost everywhere in the United States except in the Rocky Mountains and up in the very northern part of New England. So these outbreaks are scattered around and they do tend to be particularly concentrated in areas where there are a lot of travelers and immigrants as one factor.
(Slide.)
This is data from the National Malaria Surveillance Summary that we put out at CDC every year. This is from '73 up to 2004, numbers of reported malaria cases. The total number is in red, the numbers in foreigners in green, and the number of travelers in magenta. Really the main points here is there was a large increase in the '70s due to immigration from southeast Asia, and then the cases have really been trending up over all, but there has been a recent decrease in the last couple of years. That decrease has been proportionally more in foreign residents than in US residence.
(Slide.)
SO we looked at that and asked, well, why might that be, and here is a graph that shows immigration to the US over the last two centuries or so. One thing you can see is in very recent years there was a very step drop-off in immigration. That is really since 2001. That is probably related to restrictions after 911. So that may be one factor that is causing this recent decrease in cases in foreign residents that we see in our overall surveillance.
(Slide.)
These are rates. So now I am going to move onto travelers. These are rates that we calculated using data from -- on denominators on numbers of travelers and malaria cases through our US surveillance system. There is one point, just an overall point I want to make about any of the rate data I am going to show today, is that you have to remember that the data in the travelers and then in the transfusion cases, those are really rates in the face of a program, probably a very effective program. For travelers, a lot of people take chemo prophylaxis. We have a program to limit risk in the blood supply. So these rates could very well be much higher, you know, in the absence of those programs.
So here you can see really there is an order of magnitude with the lower risk among travelers to Mexico. Highest risk is in the green in Africa, and then sort of intermediate is what we see in the rest of the Americas and in Asia. Sorry. Well, there is the intermediate.
(Slide.)
This is really the same. This is a snapshot of just '99 data. The main point I wanted to make here is that this is the risk we see in immigrants, refugees, asylees, versus travelers, and the rates are significantly higher in the immigrants versus the travelers, as one would expect, because they have less exposure probably.
(Slide.)
This is really more of the same. Highest risk in Africa. These are all travelers, immigrants, and refugees, and, you know, very low in Mexico, which you see in the light blue.
(Slide.)
This brings just one country case up. This is Mexico. Much higher risk in your immigrants as opposed to your travelers.
(Slide.)
Now, this is a meeting on basically donor screening by lab tests, but these are questions we always get, so I am just going to sort of address them up front. We are always asked. "What about the resorts? They have such low risks. Can't you just leave us alone on these resorts in the Caribbean in Mexico?"
Well, I guess a couple of points. You know, the risk is in resorts, but really largely this is resorts in rural areas. It is not all resorts. An except there is La Altagracia Province in the Dominican Republic. We have heard a lot of arguments. "Well, is a rural versus an urban resort? You guys are calling these rural resorts things that are big and urbanized."
We used to give an anecdote. I went on a consultation in Mexico about a year-and-a-half ago to a large resort. I won't name it, but we went. You know, this would have been an argument that there is no malaria here, but we saw cases in the town. So I think all of us really argues for the need for the best evidence-based recommendations we can do. You know, certainly as long as we are using the questions and also on the lab tests.
(Slide.)
So as far as, you know, just to give I think or opinion at this point on these resorts, you know, these are areas that we consider risks high enough to recommend prophylaxis for travelers. Now at some point we may change that recommendation and think about standby treatment for very low-risk situations, but we are not there yet. So we are putting travelers on preventive measures. It would seem risky not to defer blood donors to those areas.
This also, when we talked about these very low-risk situations, I think it raises a couple of interesting questions that we have really not dealt with adequately completely yet. So, you know, these questions are would you base recommendations on the endemic situation, which is what we do now, which is the conservative approach, or use traveler or transfusion data, for example. Well, if you chose to use sort of the latter, traveler data, given the micro-epidemiology of malaria, you need to consider that the assumptions based on an average traveler might not hold for all travelers across the board; and then we would also have to grapple with, well, what would be an acceptable level of risk, you know, both for travelers or for transfusion, whatever group you are talking about.
(Slide.)
Okay. So back to US data. This is malaria cases reported in the US by species. Highest number from falciparum, followed by vivax and then small percentages of the other species.
(Slide.)
This is trend data, and we really see a rise in the trend of more falciparum and less vivax over the last, you know, decade or so. Why might that be? Well -- oh, sorry. Anyway, just to hypothesize why might that be, one thing is probably, you know, the progressive loss of sensitivity of chloroquine. It is just not working anymore, and people are still using it. Two, travel to areas where, you know, countries are seeing more vivax, more falciparum. An example is there is India. Travel to India has increased. The ratio of falciparum to vivax in India has increased, so that would contribute as some possibilities.
(Slide.)
Where are people acquiring malaria? About 60 to 70 percent of our cases in the United States are acquired in Africa followed by Asia, and then Central America and the Caribbean.
(Slide.)
Travel to Africa accounts for only about 0.6 percent of US travel, 2003 data. Yet about two-thirds of all malaria infections and 86 percent of deaths of all falciparum were acquired in Africa, and in the last 15 years or so not surprisingly 93 percent of US deaths were due to falciparum; 73 percent of those were acquired in Africa.
(Slide.)
There is a lot of travelers to the Americas, including the Caribbean. So this data, this just shows our surveillance data species-wise, and pretty much what we see is, you know, we are seeing all these other species, falciparum, vivax and malariae, really from most of this area. This is probably an error. I think that is probably a mistaken diagnosis basically based on if you look at PAHOO data they also certainly report malariae in the Americas, no mention of ovale, and a big review article put out by Bill Collins last year was that in extensive literature review there was no mention of ovale in the Americas.
(Slide.)
The special case of VFR is these immigrants who return to their homeland to visit friends and relatives. This accounts for a lot of travel. This was the purpose of travel in 44 percent of the 26 million trips made in 2002, and the geosentinel network of travel medicine reported that these travelers have about eight times higher risk of acquiring malaria than tourists.
(Slide.)
Okay. I am going to move on to transfusion-transmitted malaria now. From 1963 to 2005 we had 96 cases reported, so these are the cases. About two-thirds were over 40 years old, about half male. A fatal outcome in 10 percent. That is much higher in comparison to what we see as sort of the overall rate of fatality rate due to malaria infections in the US, which is about one percent. Where we were able to implicate a blood product, whole blood, packed cells, platelets, this is skewed because remember this is data way back to the '60s. Certainly this would be shift more toward packed red cells now. Range of one to 192 donors per case with a mean of seven, and from -- these cases are not picked up right away. I mean, here you go. Time from symptom onset to diagnosis up to 180 days with a median of about nine. People just don't think of this because there is no travel history.
(Slide.)
Where we were able to implicate an infective donor this is sort of the profile: about 75 percent almost between 20 and 40 years old, 90 percent male, 60 percent foreign born. Area of acquisition, this is again the overall series, about half from Africa. I will show you recent data sort of at the end of the talk. This has shifted to more towards Africa now.
(Slide.)
We were able to do a complete investigation, this is some records, in about 62 cases. In about 60 percent there was a failure in the donor screening process, so that is why the case happened. In about 40 percent even, you know, the process as it is supposed to work worked fine, but cases slipped through. This is largely due to the biology of malaria, P. malariae. Two-thirds of those were P. malariae that could come up decades later as the issue there.
(Slide.)
This just shows sort of what I just told you in a flow diagram, and the point I wanted to make here is, you know, where the screening process worked. Again, two-thirds malariae, about one-third other species. If you calculate what the risk is here for where the screening process worked as it was supposed to, the risk is about 0.09 cases per million units transfused, and I will show you data overall on incidence in a minute.
(Slide.)
Sort of a special case, as I mentioned, are these VFR travelers, these prior residents of endemic areas. We were asked a couple of years ago to look at, well, should they be deferred longer. I mean, these people that now live in the United States, but used to live -- so they are US residents now, but they used to live overseas. Could these people, you know, be semi-immune and be carrying the parasites for longer? Should they be deferred for longer than on one-year US resident deferral?
So we find eight cases in this database, and five of them came up within a year anyway. Two of them came up over three years. They were P. malariae. Even if you changed it to three years you wouldn't get them. Then there was one, it had been one case that if the deferral guidelines had been changed you would have picked it up.
(Slide.)
Species involved in transfusion-transmitted malaria, overall most -- you know, more falciparum followed than by vivax and malariae. Not surprisingly where the screening process didn't work you see more falciparum. Where it did work, because malariae doesn't follow the three-year rule, that is the most predominant species.
(Slide.)
Here is species involved by region, and basically here what you see is from these three species we are really seeing from all -- you know, all of these three major regions, whereas in the transfusion cases we have seen the P. ovale come from Africa.
(Slide.)
There has been quite a change in sort of implicated donor profile, infective donor profile over the years, with over the last 20 years by far most of this is from immigrants.
(Slide.)
This slide shows the incidence of transfusion-transmitted malaria again over the last 40 years or so. The denominators come from data either published in the literature that I got from Lou Katz from -- actually from a donor. You guys know the data from the donors better than I do. I'm a malaria person, but -- but anyway, but what it shows is basically that the rate has come down and it has remained at a very stable low rate in recent years.
(Slide.)
So the last 15 years, he is what is happening most recently. We have had 16 cases from 1990. We have been able to implicate a donor in 14. I have to say the 2005 case where there were about 150 donors we have still not been able to complete the investigation. It is like pulling teeth to get all those donors back in, so we don't have an answer on that one yet. Twelve cases in immigrants, two of those were really people who were born here but have lived long periods oversees, so we group them there. One US traveler to Kenya, one VFR to Africa, 86 percent of these in the last 15 years acquired in Africa, two in China due to malariae, 71 percent P. falciparum, and a failure of the screening process in about 70 percent.
(Slide.)
So in summary, we are seeing a low incidence of transfusion-transmitted malaria using the current guidelines. We calculated a rate of about 0.23 cases per million units transfused; and, as I mentioned, where the screening process works it is about 0.09. Highest risk, as I mentioned, in immigrants and exposure in Africa.
(Slide.)
Acknowledgments to people who helped me technically or gave me data, and thank you. We will take questions after the session.
So we are going to move on to the next talk, which is going to be current deferral polices to reduce the risk of transfusion-transmitted malaria and their impact on donor availability by Dr. Alan Williams.
UNIDENTIFIED: Actually --
DR. PARISE: Oh, you switched? Oh, okay. Oh, I am sorry. I am very sorry. I --- up here. So we are going to have malaria in the United State military and its implications for safety of the blood supply by Dr. Chris Ockenhouse.
(Adjusting equipment.)
Malaria in the United States Military and Its Implications for Safety of the Blood Supply
by Christian F. Ockenhouse, MD, PhD
DR. OCKENHOUSE: Good morning. It is a pleasure to be here. I think I might be one of the lone voices out here. I don't have an agenda this morning. I don't represent a company that is trying to market an antibody or a nucleic acid based therapy, but I would like to maybe talk to you about what the situation is of malaria in the United States military, and specifically for blood transfusion-transmitted malaria.
(Slide.)
Now as all of you know, malaria infection in the US military has a long history. We spend a lot of money, millions of dollars each year, to develop new drugs and vaccines against malaria. Malaria, because of the deployment of our troops worldwide, is a constant concern. We take a lot of effort to try to prevent infection in our troops with proper prophylaxis, and it doesn't always work. We have about 35 to 100 cases of reported malaria every year. It is probably a little more. A lot of cases, we have malaria that don't get reported to the proper channels. Approximately about 60 percent of the cases are P. vivax and about 40 percent of the cases are P. falciparum.
Now historically, as many of you know, malaria has been in the US military, many militaries, because of the deployments around the world in Viet Nam, World War II, Somalia. In plasmodium vivax 300 cases occurred after troops returned to upstate New York, 300 cases after a couple of months in Somalia, and they all had P. vivax, and that is peculiar to east Africa. Just a couple of years ago a contingent of Marines went for only 100 hours into Liberia, Monrovia, to quell a disturbance. 126 went there for 100 hours, and 80 of them came down with malaria. Now that is a lack of command control on proper prophylaxis, and that commander should have been relieved of duty. He wasn't.
(Laughter.)
But that takes a lot of effort and a lot of -- because a couple of those Marines were deathly sick. We also have malaria in Iraq and Afghanistan. There isn't any actually in Iraq. It actually occurs from soldiers who pick it up when they are elsewhere, and most of the cases come from if they have been deployed to, for instance, Republic or Korea. Several months later they show up in Iraq and they come up with a --- illness. It turns out to be P. vivax and it can be genotyped as coming from Korea.
If Afghanistan there is transmission of malaria, and in the last five years we have had cases of severe and complicated malaria, a couple of deaths. But, you know, all these cases it has been found they have been non-compliant.
(Slide.)
But what does this tells us about the safety of the blood supply? How safe is the blood supply against malaria infection for US military personnel? I think it is extremely safe. I believe that the deferral policies, the policies that we have now, work. US military follows the recommendations on the donor deferral policy. The only exceptions are for fresh whole blood in emergencies in mass casualty. In Iraq when we have mass casualties and we don't have enough fresh blood, we will line up soldiers and ask them to donate blood. It happens, but we will test them for obviously HIV, hepatitis B and C.
And when I was asked to talk about this I didn't know very much about transfusion-transmitted malaria in the US military, ad we have a lot of -- we have a large blood program, Army blood program, ad we track all cases of infectious disease in transfusion over the last 10 years. Over the last 10 years we have found three cases of malaria that was of infection that was coincident with transfusion, and they are listed there, case one, two, and three. All the cases occurred -- two of the cases occurred after transfusion, 149 days and 720 days. The other one was coincident with blood transfusion from falciparum. But all the cases had a history consistent with malaria exposure. I don't believe that any of these cases were from transfusion-transmitted malaria. So our donor policy, our deferral policy works. We use the same deferral policy as recommended by the FDA and the American Association for Blood Banks.
(Slide.)
So this is deferrals by type. The Army Blood Banking Program gave it to me. In orange about six percent are deferrals. This is one year, from March '05 to '06, just in this past year. About six percent of the deferrals are due to malarial exposure of having traveled to malarias. As you can imagine, we have a lot of soldiers that have been deferred. However, if you look in the purple, actually a lot of these deferrals are low hemoglobin and hematocrit. The fact is if we are really worried about retaining the deferral pool, maybe we ought to look at individuals who have anemia; and there are other reasons for deferral.
(Slide.)
So let me go on. Is there evidence that the blood supply poises an unacceptable risk for malaria using the current policies of donor deferral? I would say that it all depends on what your level of risk is. This is where if you are risk adverse and you believe that there is no acceptable risk for a single case of malaria, then you think that all blood should be screened. However, if you feel that our current deferral policies work, then what is the problem? Is the problem not the safety of the blood, but is there something else that we should be concerned about? I think that is where some of the discussion today may lead.
Are we at risk of permanently losing potential blood donors; and, if so, how can you minimize that risk? How can you get some of these people who are deferred for one year or three years back into the pool? You could actually screen for malaria if you had a proper test, either a passive or active, but perhaps what you could do is you could change the policy, the current policy for deferral to retain potential donors that pose a low risk.
(Slide.)
Now the active -- I am not going to get into this. There are several talks later about the active detection. You know, there is obviously many groups are working on nucleic acid testing and testing for enzymatic reaction of parasite products, antigen detecting, or passive detection of malaria specific antibodies. Much of this in the US military's effort is for diagnosis, not for the screening of the blood per se.
(Slide.)
But, you know, we have looked at passive detection. What we do at Walter Reed in the context of a lot of drug and vaccine trials, we actually tend to use --- challenge of malaria in volunteers who hare non-immune volunteers, and we infect them with malaria as a part of vaccine and drug studies and control individuals as well. And we follow them daily, and as soon as we see a single malaria parasite, even if they are asymptomatic, we treat them. So these are individuals who are very, very low parasite densities, about approximately one parasite per microliter, much lower than what you would observe in an endemic area. We then continue to follow these individuals up, and we collect plasma and do thick blood smears to make sure they are negative.
But, you know, a couple of years ago we said, you know, if we wanted to measure the exposure of malaria in an individual who had already come down with malaria, who was potentially clinically ill, an AA non-immune clinically ill, could you detect antibodies and how quickly could you detect those antibodies. The answer is using a variety of assays, and there are many assays. We use a couple of recombinant proteins. We can detect the exposure of malaria in 96 percent of the individuals, 75 subjects, within certainly 30 days.
But does this help you in a non-immune population? You know, who is at most risk for transmitting malaria in the United States? My emphasis is in the United States.
(Slide.)
Now, non-immune travelers I believe are not high risk for transmitting malaria. It is highly unlikely that a non-immune asymptomatic blood donor carries malaria parasites in their blood. The only caveat is if that parasite threshold for density is less than the clinical threshold, and they would have to be in that window period. I think that is very highly unlikely.
So if you look at the current donor policies, who would be at risk in this country of transmitting malaria in their pool? Would it be a traveler, a non-immune traveler? Which think would be greater than 99 percent of the individuals who travel anywhere in the world. Are they at high risk for transmitting malaria in their blood? I say that they are really not.
Now residents from endemic countries that either live here or go back home may be asymptomatically infected with malaria, could be. It is usually mostly in children, and asymptomatic adults and adults who carry malaria parasites in their blood for prolonged periods of time is actually quite rare. Now if you really wanted to do something, you could actually continue the deferral policy for those individuals. Or you could alter the deferral policy. What is so special about the one-year deferral for travel or the three-year deferral for a clinical illness? Or you could do the easy thing, other people think would be the easy thing, screen all the blood if you had a good test for malaria. But there is a cost and there is a benefit. The costs are not only costs of losing permanent individuals from the pool of potential donors, but there are financial costs as well. In an era of increase in medical costs we need to be cognizant of trying to control medical costs, and perhaps we should be looking at deferral policies first before we undergo a prolonged screening of blood for all donors.
I think that is the last of my comments. I look forward to a discussion later. Thank you.
DR. PARISE: Thank you very much. Okay. Now we are going to move on to the last talk of this session, and then we will have a panel discussion. Now Alan Williams is going talk about current deferral policies.
Current Deferral Policies to Reduce the Risk of Transfusion-Transmitted Malaria and Their Impact on Donor Availability
by Alan Williams, PhD
DR. WILLIAMS: Sorry. I appear not to have gotten loaded here. This should just take a second. But in the meantime I am going to get started. I think in the previous talks you heard some interesting presentations about some of the scientific and epidemiologic parameters surrounding donor deferral policies, and all of these are obviously quite relevant and ---.
(Technical problems with AV equipment. Speaker still presenting, but not being recorded.)
There have been I think a total of four blood product advisory committee discussions related to malaria. I am going to present a couple of the key discussions that were voted on. In June 19th of 1999 the committee considered an exemption for daylight travel, particularly travel to Mexico on cruise ships and visiting resorts. Some of the discussion surrounded the fact that trying to distinguish between rural versus urban exposure and dusk to dawn versus daytime exposure would greatly increase the subjectivity of the donor screening questionnaire in context of which trying to screen for a travel history is complex as it is. Also certain of the vectors have certain times of the day that they feel one simply cannot totally rule out mosquito exposure during the fringes of daylight hours, again increasing some of the subjectivity for a donor to try to distinguish whether they were there only in the twilight or evening hours versus during the day. So the committee at that time in response to the question did the committee members support a change in the current blood donor policy to allow for travel when travel exposure was limited to hours of bright daylight did not vote in favor of that recommendation by a vote of nine to five.
(Slide.)
In June of 2000, the agency issued draft guidance entitled "Recommendations for Donor Questioning Regarding Possible Exposure to Malaria." That guidance, draft guidance, it was proposed that the 1994 recommendations be modified. One, to provide a definition of residence defined as five years in an endemic country, again not specified as cumulative or continuous. The draft guidance did provide specific donor travel questions. This included a capture question format to be followed and followup of a travel history. It did not distinguish time of day and rural/urban exposures. In other words, even on a cruise ship a passenger who made a daytime trip to an endemic area and then back to the ship by the evening was subject to deferral. And it provided a provision related to this concept of partial immunity from individuals who were residents in malaria endemic countries who then returned to that country might in fact be asymptomatically infected by the virtue of partial immunity. It provided that immigrants, refugees, citizens or residents of malaria endemic countries would be deferred for three years after the last visit to the endemic country.
(Slide.)
There is an additional discussion in March of 2001 around the plasma risk issue. The committee considered the question of are there available data sufficient to conclude that it is safe to prepare frozen plasma products for transfusion despite a history of malaria risk in the donor.
The committee did not support that on a routine basis plasma prepared by separation from whole blood should be exempt from malaria donor criteria. With some differences when that plasma is collected by automatic apheresis our specifically by an Autopheresis C procedure, which was a target of discussion based on a variance that was projected to be requested of the agency by an individual blood collection establishment.
The committee also voted whether the agency should continue to allow use of FFP when personal information from a donor indicates a history of malaria risk, and the committee voted in favor of that policy continuing.
(Slide.)
In terms of current considerations, there have been through the years a lot of discussions, a lot of interaction certainly with our colleagues at Centers for Disease Control and Prevention and with our blood collection colleagues, and recommendations that are currently under consideration and hopefully will publish soon as again draft guidance I am following because this will emerge as draft guidance. There will be plenty of opportunity for discussion and comment, but these are the current considerations.
That there is a distinction to be made between countries considered endemic for malaria versus areas within a country endemic for malaria, and this distinction comes --- considering residence versus travel. Travel to an area that is not endemic for malaria within a country that itself has endemic areas would not be a cause for deferral, whereas travel to an endemic area in a malaria endemic country would be cause for deferral. On the residency basis, residency defined on a country basis due to microchanges in the epidemiology of endemic malaria so that residence is defined on a country basis rather than an area basis.
The recommendations for specific donor travel questions is proposed to be removed from FDA recommendations, and instead because of the difficulty of collecting travel histories and the great deal of work that has gone into streamlining and improving the validity of the donor questionnaire process as is being done in several other donor eligibility areas, the agency is prepared to accept the organizational taskforce questionnaire which in fact uses a tiered approach to collecting travel history starting with capture questions and then working down to individual travel exposures. So instead of dictating questions, the FDA is prepared to accept that questionnaire and its subsequent modifications. --- time of day and rural/urban exposures are not distinguished.
One change is that immigrants, refugees, citizens or residents from malaria endemic countries are deferred for one year after last visit to the endemic country. You notice this is a change from the previous draft. This is acknowledging the point made by Monica that in fact most of the cases that returned to countries in fact would not have been -- the post-transfusions cases would not have been eliminated by a three-year deferral. So due to the difficulties of trying to distinguish this information as reported by a donor, this is simplified to match the residence of non-endemic countries as proposed.
Any future guidance will extensively reference the CDC travel website. The URL is provided here, and my understanding is that the CDC is working hard on a long-awaited geospacial map that could be used to actually pinpoint on a map hopefully electronically where a donor has traveled and then have a drop-down in terms of not only current, but hopefully historically exposure to malaria, which would create a pictorial screening environment that hopefully would help the confusion aspect of this screening procedure quite a bit.
(Slide.)
As mentioned, the revised recommendations would again be published as draft guidance. The recommendations would apply to cellular blood components for transfusion, red cells prepared for immunization of source plasma donors or manufactured injectable products, as well as plasma process from whole blood collected by apheresis and intended for transfusion or for the preparation of cryoprecipitate, but would not apply to source plasma. This is a specific exemption in the regulations.
(Slide.)
I am not going to address in great depth the concepts of donor loss related to deferrals. I know there are several speakers today that have data from their own experiences. Just borrowing from one figure that was put forward by Marcus Blood Centers, at least in their system there is a --- of about 1.2 percent overall loss of donors for potential malaria exposure. I think one thing to keep in mind in looking at donor loss issues really for any donor screening event is deferral onsite for which centers certainly have very good information, but doesn't necessarily address the larger group of donors who know they aren't eligible and simply don't come to the blood center, potentially a much larger population. But the range of the estimates provided from ABC, 0.2 to 3.1 percent, and as you saw even higher and double that in areas of the military.
This would translate to in the range of 120- to 150,000 potential donors per year known to be deferred. I believe that is onsite deferrals, representing up to 180,000 donations. There have been certainly a lot of observations as well as some publications that donors who once deferred are difficult to get back to the blood center. They don't fully understand that they are not eligible or they consider this as being, you know, an unfortunate and unpleasant experience in interacting with the blood center and they are simply tough to get back. So that combined with the fact that many of the deferred donors for some of these travel deferrals are repeat donor populations, some of them very valuable apheresis donors, is very costly from a donor loss standpoint.
Deferrals currently certainly reflect increased travel to malaria endemic countries that historically have not --- previously frequented, specifically areas of southeast Asia that are now becoming in vogue for travel. So that you are seeing some changes in the epidemiology of the deferrals as well.
There is a recognition now that deferral of repeat donors not only has the loss of the immediate loss of that donor, but a cumulative effect down the line that actually makes it more difficult years hence to maintain an intake donor population due to loss of well-established repeat blood donors. There was a publication in 2004 from Transfusion that travel deferrals disproportionately impact male donors in the 25- to 39-year-old age range, probably in large part due to business travel, and then that flattens out for older donors. So really impacting in large part a major portion of the current donor base.
(Slide.)
Some of the screening challenges that you have heard alluded to before. Travel histories are just difficult to obtain precisely, and I think in many cases to try to make the criteria as simple as possible helps improve the validity of a screening as well as prevent some of the false-negative and false-positive deferrals that plague some of these questions.
The definition of residency has been somewhat vague in current considerations in the agency. We are trying to simplify that to a one-year continuous exposure which should be an easily understood definition. Clearly donor screening doesn't capture all the exposure possibilities. Even considering that a proportion of post-transfusion exposures are due to false negative screens where he donor did not self-defer appropriately, there are some situations where one simply cannot identify exposure. An interesting case is published in Transfusion in 2001 by Charles de Gaulle Airport. A cabin mechanic --
(Laughter.)
Okay. A cabin mechanic was diagnosed with falciparum malaria. Sorry. I guess I hear that. As sometimes happens at international airports, this mechanic served flights coming in from Africa and specifically flights from Angola, and this individual had managed to contract falciparum malaria from working inside an airplane that had returned. Anecdotally he had been a blood donor eight days before he was diagnosed with his illness. That blood was retrieved and destroyed, but it shows some of the situations that it is simply impossible to control.
Obviously despite use in other areas of the world, currently in the US there is no test approved at this time for reentry of donors deferred. Formulary exposure, this would certainly be a great improvement to the situation and hopefully this workshop will take us closer to that reality. Absence in up-to-date mapping utility makes it difficult for blood establishments to actually sit down with a donor and pinpoint exactly where they traveled and whether or not they had exposure, and as most of your post-donation information related to trying to get a fairly complex travel history triggers costly operational measures. This can mean product retrieval and quarantine, consigning notifications, biologic deviation reports that need to be submitted to the agency when the --- is released, and all in the context that endemic areas for malaria are subject to change. This is not a static environment. It is a micro epidemiology where new areas of endemicity do pop up now and then.
(Slide.)
And this actually happened just this year where CDC in contact with the Bahamian government was made aware that there was an outbreak of P. falciparum malaria in Great Exuma Island in the Bahamas. It was actually documented for a couple of weeks during the month of June. Eighteen cases were identified, four of these were in travelers, and it was a self-limited epidemic. No cases since June 19th. This is in contrast for the past six years in Great Exuma where only one case had been identified. So CDC recommended prophylaxis to travelers to this area and contacted FDA and the blood community to make sure this information was known, and then AABB on one of its latest news reports just reminded establishments that a 12-month deferral for donor travel to an area identified by CDC as having endemic malaria was appropriate and defined April 1st as a conservative starting point for this outbreak.
That is all I am intending to present. I look forward to questions.
DR. PARISE: Thank you, Alan. Okay. I just now would like to ask all of the panelists who talked in this session to come up to the front and we will have the panel discussion
Session I Panel Discussion
DR. PARISE: Okay. We will open it up for questions. Hello? Can you hear me? Okay. We will open it up for questions. A few of the questions that the FDA had asked us to specifically address and people may have questions or things you want to comment on that about these subjects. What are the main sources of malaria risk to the US blood supply, and how effective are the current safety interventions?
DR. KUMAR: Well, I guess we would welcome questions from the audience first. Yes, Tom, please. Maybe if would be nice if we just move up here.
DR. PARISE: If you can identify yourself just before you speak.
DR. McCUTCHAN: Yes. My name is Tom McCutchan from the NIH. How statistically sound -- actually it was in Hira's talk -- is the evidence that we are actually having an effect over the last 10 or so years because of a deferral policy? I mean, one case in 100,000 or two cases in 100,000 shows up nicely on the graph, but I am sort of naive with regard to how statistically sound that is.
DR. PARISE: I guess that is my question. I haven't done any kind of statistical analysis saying comparing the right now back to 1960. I mean, if you look through, there clearly were more cases per year in those earlier years than we see now.
DR. McCUTCHAN: Well, in '60 there are, but when did the deferral -- I mean, what I am talking about is the last several years. We claim that it is a success, but I am not -- and I am sure it is, but statistically how sound? I mean, those curves flatten out pretty nicely. They are on a downward slope, but --.
DR. PARISE: I mean, I -- we haven't really analyzed defacto. You know, there are probably a number of factors. The donor policy hasn't really changed since '94, and if you look back, you know, it didn't even change that much since then for a number of years before. I can't remember. We had a table in the paper we wrote in the New England Journal several years back that defined what the ---. Well, at the very beginning it was just, you know, donor will be free of any communicable disease, and then, you know, later it became more malaria-specific, and there is probably a lot -- you know, there probably are different factors. I mean, if the donor policies as well as how well the blood banks are doing at implementing those policies. I mean, it is not just the specific change in policy per se. But all I can say is we are clearly seeing less cases than we used to see induced by transfusion.
DR. McCUTCHAN: Right. But what I am asking is, is that real?
DR. PARISE: I guess I would say yes. I think it is real.
DR. McCUTCHAN: Okay.
DR. SUBIANCO*: Sal Subianco from America's Blood Centers. It is a little bit of followup to the previous question. If about 60 percent you indicated of the individuals that transmitted malaria had failed or the questionnaire failed to catch them, and is there a reason for us to assume that at least 60 percent is focused in one group? Couldn't we consider that 60 percent of the questions are ineffective in general and that this would be an indication in a certain way that now despite this failure of 60 percent were are still having an extremely low incidence of malaria by transfusion? And as part of that, that is a question for you obviously, but as part of that question for Dr. Williams, if we have the evidence that the problem is smaller, if it is clearly related to immigrants from areas of very high prevalence like Africa, west Africa, why are you considering more rigorous donor deferral criteria like reducing the residence for five years to one year? What was the driver maybe for that?
DR. WILLIAMS: I am not sure I necessarily understand the first part, but I guess if, you know, a proportion of your screening processes are successful and you apply that to the relative proportion of donors capable of transmitting malaria that is -- you know, if a higher proportion are transmitted by prior immigrants and you have a certain failure rate, you have a higher likelihood of seeing, you know, a failure result in transmission than you would in a travel deferral where the potential to transmit is much lower to begin with. So that might be at play there.
In terms of the change in the residency definition, Sanjai might wish to comment on that further, but I think it's basically two considerations. One is scientific and the other simply trying to simplify the questioning process. From the scientific basis, I think it simply relates to the fact that one year in an endemic country is sufficient time to have multiple exposure to malaria that would result in partial immunity. That is the basis of the concern. From a screening standpoint, a five-year residency definition that could be variously interpreted as continuous versus cumulative is somewhat more complex to administer to a donor than a one-year continuous period, and at the same time the one year is somewhat more rigorous, but also would capture the individual who had been in fact a resident versus a five-year residence considered continuous where the donor may have gone somewhere for a short period and wouldn't have been caught by that residence.
All of these are, you know, basically best estimates of a deferral criteria that will give us the best ability to distinguish, but that is some of the thinking that went into that. Sanjai, do you have any additional --?
DR. KUMAR: Yes. Just comment very quickly on five years versus one years. Five-year deferral apparently comes from mostly children in sub-Saharan Africa who die of malaria. They die within the first five years of their age. So that was taken as an indication of evolution of partial immunity of clinical immunity, and along with that comes with an asymptomatic low-grade parasitemia. But there is very little that looks at how immunity evolves in adults and if you are worried about long-term residents, the adults who donate blood. So whatever linkage that is there it says that within one to two years continuous residence in a malaria endemic area is sufficient to induce partial immunity, and all it requires is sometimes somewhere between two to four exposures to malaria parasites. So immunity in adults is known to evolve a lot faster than in children, and that is why I think the five-year might be scientifically erroneous for adults.
DR. PARISE: Did that answer your question? Okay. Jerry, go ahead.
DR. HOLMBERG: Yes. Jerry Holmberg, HHS. Actually my question, I have multiple questions on one topic; and that is, you know, what we are really dealing with is addressing a geographical deferral, and we all know that geographical deferrals not only include malaria risk, but also other parasitic or viral risks such as --- or chick virus and some of the other emerging type of concerns that we might have. What I am concerned about is, first of all, the tiered question that you referred to. How would that -- Alan, you referred to the tiered question in the uniform standard questionnaire. Would that -- how would that affect some of the other organisms that we are concerned about? Then also I would like to follow up with you commented also on the yellow book and the webpage. How often is that updated? Is the yellow book still available and is the webpage updated? And then also what is the time table for the GIS improvements?
DR. WILLIAMS: So I will go ahead first with the question about the capture question approach. It really should reach the same end, and it should reach it in a more efficient manner. So that instead of asking a long list of potential travel areas, one starts out with a question, for instance, "Have you been out of the United States in the last three years?" This would then eliminate a large proportion of donors who would not have to go through the subsequent questions as far as, you know, where they have traveled, where they have resided and so forth. Given that some of the agents that you mentioned are also included, some of the --- viruses and other emerging agents from sub-Saharan Africa, we have seen, you know, potential protections from lhasa, ebolas, other agents which may or may not have asymptomatic carrier states. But the question process should certain get at these individuals who have had that exposure at least as well as the previous way of administering the question.
In addition, these questions I think importantly for the first time in -- since the genesis of the donor screening process have been looked at by the National Center for Health Statistic for donor understanding of the question and have been modified to try to optimize that.
DR. HOLMBERG: So has that been the validation process?
DR. WILLIAMS: What process? I'm sorry.
DR. HOLMBERG: Is that the validation process?
DR. WILLIAMS: It's a cognitive validation. It is not a validation from the standpoint are you really capturing the information you need to capture. That is much more difficult.
DR. PARISE: I will take the questions then on the updates of the yellow book and the website. We systematically -- and Paul --- is here who really knows more about this than me from the CDC. So, Paul, wherever you are, if you want to --
UNIDENTIFIED: Here.
DR. PARISE: okay. If you want to add anything if I get anything wrong, please feel free. We systematically update the yellow book every two years, and the website, too. I mean, we look at every -- across all countries and look at the data we get from WHO and other sources. If something comes up in the interim, for example as has happened in the Dominican Republic in the past or in the Bahamas now, you know, that would be cause for an immediate update. And although we can't alter the hard-copy yellow book, I mean, that would trigger changes to anything we put up on our website on the various pages, which include, you know, the website yellow book.
I guess as far as the mapping project, there are going to be discussions I think at lunch on some -- you know, in detail on that with a group of people. But one of the barriers at this point has been just identifying the resources to sort of take it to completion, and hopefully we have solved that problem. I no longer work in malaria actually, and Paul can correct me. I think they are going to try to get this up by the end of the year. I guess I would say, I mean, I think it is important that we are going to have a pilot phase to that first.
We have made some assumptions. You know, these data are not black and white, and what really isn't black and white is the urban versus rural, and it is hard to really completely ignore the urban versus rural because the risk areas in some cases are really defined by urban verus rural. I mean, the information we get from WHO and what we put out is that, you know, there is malaria risk in urban areas and none -- I mean in rural areas and none in urban areas. So we will have to define where cutoff is. That has been very difficult to do. We have made some assumptions, and I think the pilot is going to be important to make sure that that is working and that, you know, we get input from people before it totally goes live. Paul, anything to add?
UNIDENTIFIED: Sure. I will just add the time line partly for that, we are aiming at December, but we will see as time goes on. Another thing to add with regard to the book, certainly as there are temporary recommendations for
--- prophylaxis such as there were for the Bahamas, those are expected to be very short, so those do not get the -- the outbreak notice goes up onto the website, but it does not change the yellow pages section of the online yellow book when there are -- there has been one reprinting of this current addition of the yellow book, and we were able to add additional changes to the actual print version as well as to the online version such as we did with the Dominican Republic because that will be a longer term change to the --- nations.
Monica is correct. Every two years it does undergo a comprehensive change, and --- question is the book available, absolutely, including it is now available not just through government sources, but also through private sources. You can find it from online retailers as well as in book stores now.
DR. SAYERS: Merlyn Sayers from Carter Blood Care, Dallas, Fort Worth, and Waco. This may be a little big to the panel discussion, but I am prompted to ask the question because of the known risk in question one. I don't think it really matters whether one is talking about --- or --- disease or malaria. We are talking about transfusion-transmissible risks which are so rare that each new event inevitably justifies publication. So against that background, Monica, just to refer back to a point that you made which had to do with how you would base recommendations on the resort issue and would those recommendations be based on the endemic situation, which would be the conservative approach, or would you look at the traveler data, which would be the less conservative approach. Then you went on to say but then you would have to grapple with the question of acceptable risk. So I just wonder if any of the panel members think it would be worthwhile having a workshop in the not too distant future where we might address what exactly acceptable and non-acceptable risk is and then perhaps use those discussions to guide some of our deliberations about what new interventions might be to reduce the risk of remote likelihoods of infectious disease.
DR. PARISE: Let me just say one thing quickly, and then I will defer this to the FDA, who really has purview over this. I just again want to remind people the risk is low, but that is the risk in the face of effective programs. Then I guess as far as the question of acceptable risks I think I will defer that to Sanjai or Alan, if you have anything to --
DR. WILLIAM: Unless Jay wants to address it. I would say typically from a regulatory standpoint we make decisions on a scientific basis. Define the risks, the cost-benefit of interventions, and acceptability of risk often is determined at different levels.
DR. EPSTEIN: Well, I think that there is no magic number. That what we try to do is achieve the safest feasible blood supply, which means driving the risk as low as is practically attainable. So we are always looking at the sources of threat and the available interventions, and we are always constrained by issues of practicality. You know, there are limits to what can be done. But, you know, what is possible to do and practical to do we think should be done, even if the absolute level of the risk is low.
I think where the argument gets engaged is that there is an undefined domain of public health tradeoffs if you look at the, you know, dollar costs per infection or adverse event prevented in the blood system. We know that it is out of proportion to that kind of cost effectiveness metric applied in other areas of medicine, but that gets you into the whole question of what does society expect.
You know, we continue to respond to at least a perceived demand for the highest achievable level of blood safety, so I don't have an absolute answer except to say that it is not driven by an absolute number. In other words, there is no threshold for action that has ever been set or agreed upon. Dr.ÿOckenhouse, you seem to want to answer also.
DR. OCKENHOUSE: Well, yes. I happen to think that is the reason we have this problem. I mean, based on that philosophy you will exclude one case of -- if a solution was possible, let's say a technical solution of finding a parasite of blood in a transfused unit, we would exclude -- if there was one case that we would exclude we would institute that policy. I am not sure that is in good public health for the -- you know, a good public health practice, and I get back to I think there are two issues here, and I am not sure. One is safety, and I think the blood supply is quite safe for malaria risk, and I base that is if you didn't have that, you know, is this at a -- are individuals at risk for death? Perhaps, and why would they die? Probably in my opinion as a clinician probably poor medical care. They should have been diagnosed with malaria. This is a totally treatable illness. This is unlike some of the viruses.
On the other hand there is another thing, is this deferral and if this keeps coming up permanently losing individuals permanently from the deferral pool, and this comes up because there must be some type of -- what is driving this? What is driving this, one, we are not having enough blood -- if we defer individuals permanently that suggests that we are -- let me back up here. I'm sorry.
It seems to me that the impetus to retain blood donors is because we want to use those individuals for additional blood donations. So that is what drives a lot of this policy. I think that if we -- you can retain individuals by changing the policy. You know, who are at risk for transmitting malaria? It is for every donated blood in this country, it is -- for instance, if I was -- I am non-immune malaria. I go in to give a unit of blood. They will ask me have I traveled somewhere, and I say, yes, I have traveled to Africa last month; and they will say, "You are now deferred for one year." What is the evidence that that is good policy? I think there is very little scientific evidence that that is good policy. Perhaps it is very good that I was deferred for one month, because the chances of me if I was exposed to malaria coming down with malaria are very high in the first month, but not in the sixth or seventh month. So instead of losing me permanently for deferring me for a year, you may only need to defer individuals for a shortened period of time.
You could retain a lot of those individuals and keep the cost down without having to screen a lot of units of blood for malaria. On the other hand, if you think that the safety of the blood is not to the best that we can achieve, then you would argue that we need to sample all blood for antibodies of nucleic acid of the presence of parasites. It is this type of dichotomy, what is driving this issue. Is it the safety or is it deferral policy?
DR. KUMAR: Maybe I would like to one thing here. I think we have already --- deferral policy has been. If you go back --- numbers are not like not to be completely cited, but some of the data that is available there for --- days. The cases in transfusion-transmitted malaria used to be as high as 60 or so in each year, and those were days when there was much less travel to malaria endemic areas and much less immigration from endemic countries. We have to bear that in mind.
DR. PARISE: Go ahead, Jay.
DR. EPSTEIN: Well, I actually was going to raise the same issue, hoping that Monica would respond. Dr.ÿOckenhouse, you have basically put a challenge in front of us. You have said is the deferral policy for travelers overkill, and I think that is an important question. There is a scientific basis for the deferral period, which is the information about time to illness in travelers who become ill with malaria, and what we have done is we have tried to maximize safety by looking at about the 98 percent capture. Now it is true when you look at that curve, you know, the majority of cases are a lot earlier than one year. It is just that there is a tailing end, and so then the question is, well, do you address that or do you accept the risk.
So it begs two questions really. The first question -- and these are the things I had originally stood to ask. The first question is what do we know about the malaria risk in persons we defer, and I know there are some data. I don't know, Sanjai, if you were going to bring it up later, but we didn't hear it in the first panel. You know, do we have an estimate of the malaria incidence in travelers and in particular travelers who might qualify as donors, because that is important. It is a measure of the, you know, efficiency of the deferral.
Then the second question, which I think is even more provocative, you are really saying if a non-immune traveler contracts malaria, do we really think that there parasitemic and still asymptomatic. In other words, what is the likelihood that they actually will transmit, and I think that that is an answerable question. It comes back to how carefully have we scrutinized the donors who actually transmit it to find out how long was it from their exposure and was there any early evidence of symptoms. You know, were the actually donating say between febrile intervals.
So I think that those two pieces of information would help us put, you know, a scientific framework on the very provocative and reasonable question that you have asked. So I am hoping Monica can answer those questions.
(Laughter.)
DR. PARISE: I guess one thing now, you know, as Sanjai mentioned before and Jay has brought up before, I mean, we are basing this really on cases of malaria. So these are asymptomatics, and that is really being extrapolated to the asymptomatics that we don't have a handle on at all. So, you know, that is just one limitation of all of this. But we do know, and I didn't bring the slide, that when you look at people that live in non-endemic areas, I mean US residents, and look at how many of those, what percent of infections come up over a year, it's two percent. So I wasn't here when, you know, these donor deferral policies came up, but I am assuming that, you know, when the cost -- when the risk-benefit ratios come up numbers like what was discussed and this one-year and three-year were brought into being that those kinds of things were taken into consideration. The number for what comes up in foreign residents over three years is considerable lower, and I believe it is about 0.2 percent. I do have that calculation, but I have not looked at it for a little while.
I guess one just point that came up to me, you know, as we look at the deferral policies and who is ---, I mean, one thing that is possible that I don't know how much we know about either is that, you know, it just may well be true that, you know, these -- we are seeing most of these, you know, cases come across in immigrants as opposed to African. Part of that, you know, many of them that come from Africa, and one factor there could also be that the donor deferral guidelines are functioning better in our travelers and they are functioning in immigrants where there may be language barriers and other things.
I guess your last question there, what do we know about these donors and their symptoms. You know, unfortunately we don't know very much. It is a good point, and it is probably something that we should incorporate into the questions that we suggest be asked in these investigations. I think that is good idea. You know, much of this data we just took from surveillance reports.
You know, we only have a little more detail on the donors I would say from the last decade when we really started, you know, to try to do things more systematically, and we do have a list of somewhere between eight and 10 questions that we at CDC suggest that whoever is doing the investigation, the blood establishment or the State Health Department or in conjunction, ask to those donors. We have not asked them about their symptoms, but we certainly could do that.
DR. GORLIN: Gorlin, Minnesota. Alan was far too kind. I was responsible for the May 15th, 2001, submission to BPAC showing up from Minnesota in my snow boots since I forgot my shoes, and was very pleased to have the positive answer from BPAC suggesting that growing donors by plasma pheresis would be okay if they had gone to deferral areas since there are simply zero cases of transfusion transmission from a frozen plasma pheresis product. Only when I returned did I find out that the computer system had absolutely no way of accepting a donor for one product but deferring them for everything else, and so my QRA department chased me into the corner where I was of course -- had no courage to actually submit the variance.
We have just updated our computer system, which apparently we think now could do this. I am little well bereft that the contemplated guidance update is not going to accept that plasma pheresis exception, so I am just a little curious as to your current thinking.
Then a quick question for the military. I would -- I am naive as to logistics as to getting product routinely and rapidly into endemic areas, and if there were a large-scale engagement in an endemic area wouldn't it be a logistic advantage for the military to be able to draw soldiers in those areas and have a testing methodology? I'm just curious.
DR. OCKENHOUSE: Well, for your second question, that is exactly what we do. We draw -- the Army blood banking program has two components. They have a frozen packed cell component which has been going on for 20 years, and I don't think we have actually drawn on that. All the blood that we use for transfusion worldwide is either flown in on a daily logistical basis or is collected in country and screened using the currently accepted screening procedures.
DR. GORLIN: But which don't include a malarial screen.
DR. OCKENHOUSE: Right, no.
DR. GORLIN: So wouldn't it be an advantage if you were collecting in country to have a malarial screen?
DR. OCKENHOUSE: Well, not really. No, I don't think it would be an advantage at all. I don't think we would do that policy. I mean, if we are deployed in a malaria endemic area our soldiers will be on malaria prophylaxis. Malaria prophylaxis, there is a very small chance of them transmitting malaria, so I don't think we would do that.
DR. GORLIN: And Alan?
DR. WILLIAMS: I will just comment on your first question. I am glad to have the extra time here. In fact as you mentioned, the variance was never submitted, so the issue -- the question wasn't asked. The blood products advisory committee discussed that question carefully and took a vote. The nature of the variance request is a variance to a regulation, so --- regulation takes some time; and, you know, basically we didn't have to face the question at that time, but it certainly could reemerge in the future, and that might be a discussion for another day.
DR. EPSTEIN; If I could just add to that. It is true that we thought the issue mute because the variance request was withdrawn. It is also true that in reflecting on the discussion at the advisory committee we felt that there were two pieces of data that were missing. One is the residual red cell count in a variety of apheresis products prepared in different ways, and of course linked to that is the uncertainty about the minimum infectious dose of plasmodial, which might be an extremely small number.
Then the other issue is that a lot of the data that committee reviewed had to do with non-transmission by plasmas that were being infused in I guess the Minnesota area, but what we didn't have is an estimate for how many of those donors might have actually been incubating malaria. So we didn't know what to do with the non-transmission data because we couldn't answer the question of whether a malaria-infected donor had made -- been a donor of FFP what would have happened in a recipient. So, you know, we were a little bit disquieted by the gaps in the information, and so, you know, these just gave us cause for pause.
DR. NAKHASI: Thank you. I have two questions. One is for Dr. Ockenhouse. I just -- you know, which is basically following up on to what Jay and others asked. So when you were mentioning that there is no immune -- non-immune travelers are not at high risk, and it is highly unlikely that non-immune asymptomatic blood donors carry malaria parasite in blood. What kind of an evidence do you have, because that dovetails with the question you were posing to ask as an FDA, why should we different with people, you know, if they are only exposed ---.
DR. OCKENHOUSE: Well, I base that on the biology of the malaria parasite. It is I would think that if someone is coming in to donate a unit of blood they are going to come in probably fairly healthy. All right. They are not going to be ill. They are not going to have a fever. If they are, you will defer them on sight because they have a fever.
So the question then becomes if I am donating a unit of blood what is the likelihood that I am carrying a malaria parasite? I am a resident of the United States. The likelihood of me carrying a malaria parasite is extremely small because I am healthy, unless the level of parasites in blood are below the clinical threshold. The clinical threshold is about one parasite per microliter. All right?
Now, when would that occur? That would occur within a period of exposure. I could have been exposed two weeks ago. I could have traveled two weeks ago to Africa. I could have been bitten, and I could have malaria parasites in my blood. Yeah, and I come in now two weeks later and I am here for my regular donor time. I am going to give a unit of blood. Now I could have a malaria parasite. All right? And I could donate that blood, and that blood could be transfused and the recipient could come down with malaria.
However, now the alternative is if now I am six weeks out or two months out and I said I traveled two months ago, could I have a malaria parasite? It is highly unlikely, because 90 percent of the cases of malaria come out within the first 21 days because I am non-immune. Now for immune individuals who have been exposed previously all bets are off.
So the question comes, and I don't know the demographics of people who give blood in this country, how many of them are non-immunes? I suspect that the vast majority of individuals are non-immunes. They haven't been born outside of the country. They haven't lived in an endemic area for quite a while. So how many of those individuals that we defer really impact the blood supply and -- you know, these are demographic type of questions which I don't know. It would be very interesting. Because, you know, you could say we are going to defer individuals specifically on a few questions. You don't need a lot of questions.
The second thing is that I don't think geography makes any difference. GIS, you know, that is all well and good, but I could go to the most heavily endemic area in the world, western Kenya where I go all the time, and I could come back and I am off prophylaxis, and I am ready to give my unit of blood. The changes of me transmitting malaria is extremely small, and so if somebody goes to Mexico on a resort and we are deferring those individuals I think that is a ridiculous policy. You know, that is a personal opinion, and I would like to see the evidence to say that we are hurting the blood supply by deferring those types of individuals because I think that is the issue here. People say why are we doing this. It is a deferral issue. We lose people in blood bankers' case. We are deferring all these people. We are removing them permanently from donating, and I think part of that is by overkilling the policy, and I think we ought to use evidence-based policy based on the biology of the parasite. Now if other malariaologists in this room disagree about that, that would be very important. But I would like to find out if anything thinks if you are a non-immune that you are asymptomatically carrying malaria parasites. I would like to find you and study you, because that just doesn't occur.
DR. KUMAR: Chris, let me comment on something just very quickly here for what you said about a trip to western Kenya and --- prophylaxis. You presented that yourself a few minutes ago giving a military campaign in Liberia, 126 Marines came down with it 100 hours after landing there. Okay? What are the chances? I mean, how much can you trust a 21-year-old young man going to western Kenya that he will follow the chemo prophylaxis and how much compliance will be there? Certainly the issue is a lot more complicated than you ---.
DR. OCKENHOUSE: No, that has nothing to do with non-compliance. They could not ---.
DR. KUMAR: If the US military cannot enforce compliance on malaria chemo prophylaxis how can one be sure that the normal population, especially most of these young men and women going to --- will follow up and will consider
--- simply they have been considered --- malaria prophylaxis?
DR. OCKENHOUSE: No, I wouldn't even ask that question. I don't think it matters one bit whether an individual has been on prophylaxis or not. I would just ask how long have you been out of the country. If you have been less than a month your chances of having a malaria parasite incubating is probably higher than if you were out three or four months.
DR. NAKHASI: But the question is, which is again a question to the blood bankers here, how feasible is it to ask that question and how effective is that when people remember that he was one month back, there are three months ---. That is the question, and as Jay mentioned there is a risk versus benefit in that ---.
DR. OCKENHOUSE: Sure. I mean, if you ever donated blood you go in and, you know, some people just ask questions. They don't even listen to the answers. So, you know, that is obvious. All right? So --
(Laughter.)
DR. OCKENHOUSE: But the question is how serious do you take this. All right? And how serious is the training of the individuals who work in blood banks? All right? I can't control everything, but what I can control is understanding the biology in the context of how likely malaria is to be transmitted.
DR. NAKHASI: I would like to hear from biologists, too, how effective is that when it is one months or two months or three months.
DR. PARISE: Let me just say one thing. We have got about one minute, and then we are going to cut this off at 10:15. If people want to chat, then after --
DR. NAKHASI: Maybe we should hear John Barwell.
DR. PARISE: Yes, and then we will stop, and then people can come here and talk among themselves if they want to continue.
DR. BARNWELL: The exception to that is vivax and ovale, and that is because people going to endemic areas are on prophylaxis, and you are killing off your first malaria parasites that come out and you are worried about the relapse phenomenon. If in depending upon the strain of the parasite, the relapses could occur within one month, it could be six months, and it could be nine months to a year. That is one of the reasons I think that probably some of those policies were instituted for deferral of non-immune -- you know, from a non-endemic area for one year. Now if you look at the recent one in the last 15 years, there hasn't been a case due to vivax and there is one case of ovale.
DR. OCKENHOUSE: So that is my point. In the last 15 years we have one case of malaria transfusion per year; 10 years, you know, 10 cases, not one case of vivax. I would even say, you know, vivax is a non-fatal illness. It is an illness. Matter of fact, you don't even have to treat it. You can probably -- they are going to be sick. Individuals are going to become sick, and it is self-curing eventually. All right? Now the point is are you going to institute sampling and testing of every unit of blood to satisfy one case of malaria? And I am not sure that you need to go to that length when you might be able to just change in order to retain donors. Relook at this one-year versus three-year policy, and look at and base it on real evidence. Certainly you can go, you know, with the first couple of months and then, you know, double it, but --.
DR. NAKHASI: Yes. I think we will have more discussion on that at the end of the day. Just a quick question for Monica. I think, you know, I was surprised, maybe that is my naivety, that 90 -- you said out of the 69 implicated donors 90 percent were male. Why not females?
DR. PARISE: I don't know.
(Laughter.)
DR. PARISE: You know, I don't know.
UNIDENTIFIED: ---.
DR. PARISE: Some of that. I guess if I separated that out by decade that might be what comes out, because a lot of the earlier ones were in military from Viet Nam. That is probably what it is. I guess I just want to close with one thing. I mean, there are two percent -- we may be missing the first primary infection as John just said, but as you can consider this one year, I mean, two percent of these non-immune US residents come up over one year. So, I mean, that has to go in the equation I think.
All right. We are going to close. I am sorry. You know, we need about a 15-minute break, right? Okay, and if you have questions, I mean, there is going to be a larger panel discussion.
UNIDENTIFIED: The purpose is questions for the whole audience, not to come up to the front.
DR. PARISE: Well, I guess I am just trying to say that it is time for a break. We will have a time at the end of the day for another panel discussion, so you can get your questions in.
UNIDENTIFIED: I do think that you have a major misperception that perhaps the audience should know if they don't, and that is that perhaps the decline in cases of malaria in the last decade, that is probably totally unrelated to the screening policies. Because as most of the audience knows, we have been screening geographically for malaria for more than 30 days. This didn't start with the 1994 FDA policy. We have tweaked it a little bit. We actually have screened people for whether they took prophylaxis, different geographic areas. But screening has been going on for more than 30 years, and I think it would be foolhardy to believe that changes over the last 10 years have resulted in a decline of transfusion-transmitted malaria. Clearly there are a lot of other issues.
(Whereupon, a break was taken at 10:21 a.m.)
SESSION II: TESTING FOR MALARIA INFECTIONS
Roger Dodd, PhD, Session Chair
Technical problems with equipment. Introduction of first speaker not recorded.)
Developing a Test to Detect Malaria Infections in Blood Donors
by P. Nigel Appleton
MR. APPLETON: I have to say thanks for being invited. Sorry. I will get used to this technology eventually. I have to say thank you for being invited. It is an honor to be here and a pleasure. I am always rather surprised not to be booed and hissed because I'm commercial.
(Laughter.)
Thank you for that. Okay. To put me in context, New Market actually is a diagnostics company operated from the rural end of eastern England, and I am reliably informed that I keep my hands to myself.
(Laughter.)
I am reliably informed that the part of England we operate from is going to be thick with enough of these mosquitos by 2025 or dripping parasites, but there we go. Here I am.
(Slide.)
About 2001, the local blood transfusi