Graham Lecture 2013 (2 of 4)

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Graham Lecture 2013 (2 of 4)

MIKE KLAG: So thank you So it’s now my job to introduce the chair of the Department of International Health, who’s going to do the next introduction And the chair is Dr. David Peters, who is a professor in international health And he’s worked in health systems as a researcher, policy advisor, educator, recovering bureaucrat, manager, and clinician in low and middle income countries for over 25 years His research interests include the performance of health systems, the interaction of poverty and health systems, implementation of health services in low income countries, innovations in organization, technology, and financing of health systems, the role of the private sector in health systems, and institutional capacity strengthening in low income countries He’s a pioneer in the development of sector-wide approaches, which approach now commonly used to allocate aid in donor aid in developing countries And he developed the first national balanced scorecard to assess health services and implemented that in Afghanistan for nearly 10 years So David? DAVID PETERS: Thanks Thanks, Mike And I have the singular pleasure of introducing Dr. Klaus Kraemer But before that, I should let you know that I also learned about the role of the dean from Pierre You know, we have offices on the 8th floor together And in my first week in office, I was seeking some advice And we were standing in there in the hallway And I said, I have this very sensitive problem, a personnel problem And I think I need help, and I need nothing, nothing less than a dean And Pierre turns to me and says, David, there is nothing lower than a dean [LAUGHTER] Anyway, this is quite an elevated time, actually, to talk about the centennial celebration And you know, I’m struck by this story of discovery It’s a story of drive and determination And it’s also really a story of collaboration And it also has as a common theme this vision or goal of trying to improve nutritional health and the health of– particularly, of disadvantaged populations, of the poor And that’s something that’s remarkable But it’s also something that Dr. Klaus Kraemer embodies all of these attributes He is a scientist And as a scientist, he’s worked on, he’s done research on the development and identification of new micronutrient products But he’s also collaborated in field research, population research, and surveillance on disadvantaged populations around the world, and particularly in Bangladesh and Indonesia as well as refugee camps in Kenya He is a longtime educator, a technical advisor, and mentor And he continues to play important roles in this as well as in communications between scientists and practitioners, policymakers, and advocacy work So Dr. Kraemer is currently the Director of Sight and Life, a humanitarian nutrition agency of DSM that’s seeking to improve the quality of diet and nutritional health of the world through education, technical assistance, and advocacy As I learned yesterday, the editor of the Sight and Life magazine, and I’m very pleased to say that he is a recently appointed adjunct associate professor of Department of International Health here at the School of Public Health So with that, I’m pleased to introduce Dr. Klaus Kraemer [APPLAUSE] KLAUS KRAEMER: Good afternoon, Dr. Peters, Dean Klag, Dr. West I’m really thrilled about the honor of being adjunct faculty of the School of Public Health in the Department of International Health here in Baltimore I’m also not totally sure whether you were talking about me, Dr Peters, introducing me today And it is a difficult task now to follow the great Dr. Bruce Ames and speaking about hidden hunger around the globe It’s a broad topic Dr. West has charged me to speak about today And I ever believe that hidden hunger– the term was coined for the Ending Hidden Hunger conference in 1991 in Montreal, Canada But my dear colleague and friend, Dr. Richard Semba of the medical school, he passed on to me a book published in 1943 in the United States, entitled The National Malnutrition, Hidden Hunger,

Is It Starving Millions? And that is talking about the United States, not the developing countries that we are mainly focusing at Hidden hunger has been poorly defined in the past And we decided in 2009 to gather a group more casually, during the International Nutrition Conference in Bangkok, to start a discussion about developing a hidden hunger index We didn’t achieve that at this meeting, but we achieved then a definition of hidden hunger And we defined it as a lack or loss of dietary quality that leaves individuals or populations with deficiencies of essential micronutrients, which negatively impact on health, cognition, survival, function, and economic potential This was followed by another consultation about a year later And then I will talk a bit about– later in my presentation– a publication, and the first entitled, I believe, advocacy paper running a peer review process on a hidden hunger index We know that micronutrient deficiencies are widespread in the developing world, but also in the developed world We can follow Dr. Ames in this presentation And the number of people with micronutrient deficiencies, or hidden hunger, is meant to be in the range of 2 billion And these are primarily the big fives, like zinc, vitamin A, iodine, folate, and iron And more recently, and I’m just back from the [INAUDIBLE] meeting in Singapore, vitamin B-12 appears to be very important to fetal development, in reducing non-communicable diseases in later life This slide, this iceberg is slightly modified from Dr. West’s slide on the tip of the iceberg and the underlying reasons for severe micronutrient deficiencies If we look at the top here, I have a pointer We usually look at the top, which is above the surface And it’s about, just in the tens of millions of people who may be affected by overt deficiency diseases, like blindness, wickets, or scurvy But underneath the water surface, we have a number of effects, systemic effects, that lead to subclinical deficiency that can impair cognition, that can impair immune function, and it can, of course, result in birth defects like neural tube defects And that is a cause of tissue and plasma depletion, with micronutrients And the underlying causes are in low dietary quality, frequent infections and diarrhea, suboptimal breast feeding and complimentary feeding, endemic enteropathy– something very important, recently described, related to the gut microbiome And I think this is an area to focus at a lot in the future– and of course, environmental toxin, like aflatoxin and heavy metals And here, we have the invisible part, the hidden part which will lead to significant health consequences Just a snapshot about dietary intakes I’m personally not in favor of using dietary intakes to signify micronutrient deficiencies We need indicators that can measure nutrient status But here, a recent paper from Bangladesh using intakes of different vitamins and minerals in breast-fed children and lactating women, and this is the prevalence of adequacy And here we see that test for vitamin B-6– that’s almost 100% of the adequacy reached And for some nutrients, and I hardly can believe that calcium is at zero and vitamin A is at almost zero in this paper But it shows that there are still significant gaps in the nutrient supply of these micronutrients I was intrigued by a recent paper by Kay [INAUDIBLE] And Kay, from UC-Davis, she looked into the supply of iron and zinc as an example in breast milk only, reaching a percentage of the iron(I), and the red line is 100% iron(I) And then breast milk plus a typical cereal and [INAUDIBLE] based complementary food reaching just less than 40% of the iron(I) for iron

And breast milk and diverse complementary food that contains animal food is still not reaching 100% of the iron(I) And she compared that with a diet of the hunters and gatherers, apparently much more complete in providing iron as well as zinc This is from a paper from Richard Semba we published two years or one year back, a special edition in The Journal of Nutrition on multiple micronutrients and evidence based on history, on epidemiology, on basic science, and on randomized controlled trials And Richard Semba, he tried to compare the dietary diversity in different sorts of economic strata These are the not poor They have a number of diverse foods in their diet And here this is for an Asian population Rice is still the majority But going to the bottom with extremely poor, they eat very little of foods vegetable and all sugar They cannot afford animal food, which is rich in micronutrients And we have the highest risk of deficiencies in these poor populations Another important aspect to be considered in hidden hunger– these are high food prices They are particularly affecting the poor And here, I have torn from the FAO food price index– the time from 1990 to 2011 And here, you have extracted the time between 2004 and 2011 And here, we had the two high food price spikes and that affected significantly the nutrient status of the poor in this crisis in 2008 And more than 100 people got driven in the poverty range under $1.25 per day And with this low amount of income, it is almost impossible or it’s impossible to buy a balanced diet which provides rich varieties in fruits, vegetables, and animal food And here, based on the food price crisis in Asia and Indonesia, there was one study that shows that child underweight was not affected by the food price crisis in the years between 1997 and 2000 Likely because the mothers, they were balancing the intake of foods of the children and eating less food But at the same time, when child underweight was not significantly changing, hemoglobin levels were significantly dropping down This means that all of the children received a diet that was less rich in micronutrient or iron-rich components I don’t want to go into details with this table from the recent Lancet series And Dr. [INAUDIBLE] is the lead author on this paper And he has [? drawn, ?] with his colleagues, for a number of micronutrients– vitamin A, iodine, zinc, and iron– the prevalence of deficiencies globally and in different regions, just highlighted Africa and Asia, which are still the regions with the highest micronutrient deficiencies This paper was not published when we started to think about a hidden hunger index But we wanted to integrate these indicators– vitamin A, iodine, zinc, and iron deficiency in one index And this is a global map that was drawn from this index The countries with a dark orange color– they had an alarmingly high hidden hunger index going to mild And in many areas, we didn’t have the data We had to rely on global databases, national– representative data from WHO, UNICEF, [INAUDIBLE] and DHS surveys that were incorporated into this hidden hunger index And here we see, as anticipated, the most serious micronutrient deficiencies in sub-Saharan Africa and in South Asia In this slide, we have drawn– the DALYs derived from iron, vitamin A, and zinc deficiency And the data were provided by Dr. Black, who was co-author of this paper And here, we also see again that the DALYs related to micronutrient deficiencies are clustered in sub-Saharan Africa and in South Asia

Just as an overview, Nigeria had the highest hidden hunger index and Ghana the lowest of the 10 countries that were most severely affected Then we calculated a number of correlations And this correlation here shows our hidden hunger index with the Human Development Index, which is a composite for long and healthy life, education, and standard of living And here we see a strong negative correlation of the hidden hunger index with Human Development Index from the year 2007 And when we did the same, correlating hidden hunger with undernourishment– and the recent data of undernourished people in the world is over 840 million people– there we see that there’s a [INAUDIBLE] correlation And the undernourishment is just about caloric intake It’s the number of the people that can achieve 2,100 calories per day from the food that’s available in a country And what we still also see, at relatively low percentages of undernourishment, the hidden hunger index can be very high, as here in many of the African countries that are in the letters in black Just to briefly summarize, hidden hunger index correlates with the Human Development Index So people with a high Human Development Index have the low hidden hunger index And at low undernourishment, we even observe a high hidden hunger in the population Micronutrient deficiencies were responsible for 1.5 to 12% of total DALYs in the 36 high-burden countries Here, with 1.5% for South Africa and 12%, for example, for Ivory Coast But I would like to highlight a number of limitations There is a lack of biomarkers and outdated national data we had to rely upon, in particular, representative data We don’t have data for multiple micronutrients And we had even to use proxy indicators for zinc and for iron deficiency And I think this is really an issue that we have to address and improve the data quality we are working upon I was asked to talk about global micronutrient deficiencies or hidden hunger This is the only slide, other than the book from 1943 And this publication from Fulgoni in 2011 shows– here with the dark bars– that’s a natural occurring amount of micronutrients, or in this case, vitamins, in the diet And specifically for folic acid, we see that here a significant amount of folic acid is provided through fortified foods And the United States mandated flour fortification with folic acid in 1996 And since that time, neural tube defects and deficiencies in folic acid or folate have dramatically shrunken in this country I don’t want to speak about this specifically There are more speakers to come But we also have good news We have evidence-based interventions that we can use to address micronutrient deficiencies And Dr. Sommerville will certainly talk about vitamin A supplementation, and Dr. Black, I expect, will talk about some others of these 10 evidence-based nutrition-specific interventions that were published recently in The Lancet Just to come to an end, to conclude, single micronutrient deficiencies still persist in large parts of the developing world We can also demonstrate that there are multiple micronutrient deficiencies that always co-exist Usually if there is an iron deficiency, likely there’s also a vitamin B12 deficiency or zinc deficiency or vitamin A deficiency in the population But the true magnitude of micronutrient deficiencies remains hidden, with outdated, fragmented, and incomplete data And deficiencies are likely to have causes in their context– in the context people live And we need to understand, better understand, the context in order to effectively eradicate micronutrient deficiencies Otherwise, we won’t be successful

And of course, we’ll want to move more and more into programs and scaling up of programs But we need to continue to build the evidence in science and in programs And I would like to plea that scientists and program people would really work closely together in order to improve the program quality Also like to conclude we know that poverty [? abrogation ?] is important in reducing also micronutrient deficiency and improving nutrition and economic growth in countries But just rising incomes is not sufficient We have to address micronutrient deficiencies now We have a number of evidence-based, evidence-proven interventions that are available, that are on hand And they need to be taken to scale And I would also particularly plea that breastfeeding is extremely important, that we have to encourage women to breastfeed exclusively And then to introduce adequate complementary food after six months And we have to address micronutrient deficiencies through supplementation, through mandatory and voluntary fortification of staple foods, and of course, of using biofortification as new tools to address micronutrient deficiencies Thank you [APPLAUSE] MIKE KLAG: We have time for probably one or two short questions AUDIENCE: Hi I’m told you might have this coming It seems to me, in my great ignorance in this field, that there are deficiencies in just about everything And that a lot of the programs try the effect of A, the effect of E, the effect of C– why not give them the [INAUDIBLE] that is going to supplement everything and cause no damage for someone who might have enough of this or that? I’m just puzzled KLAUS KRAEMER: I cannot more than agree Giving a low dose multiple micronutrient supplement would really do the job And we know, in pregnant women, in the meantime that iron and folic acid is not as good as a multiple micronutrient And I think this is the way to go, moving towards multiple micronutrients AUDIENCE: We’ve learned about the deficiencies of micronutrients that are well-known– vitamin A, zinc, iron Are there information about trace minerals– selenium 10, vanadium– those trace minerals KLAUS KRAEMER: There is knowledge about trace minerals, particularly selenium, which follows, usually, the deficiency out of iodine And Finland started, many years ago, to add selenium to the fertilizer, so that selenium could be provided for the whole food chain [APPLAUSE] KEITH WEST: Thank you, Dr. Kraemer We’ve had two speakers that have given us a breadth of the issues that are challenging us in understanding this aspect of nutrition Our next speaker needs really no introduction But it is really a pleasure to do this We have a birthday vitamin, of course, that’s kicking this off And vitamin A was named A for that reason But we have a special speaker to address this vitamin– Dean Emeritus Alfred Sommer Professor Alfred Sommer, an ophthalmologist– he declares he knows little about nutrition But in fact, he knows a great deal about nutrition Dr. Ames, he’s an example of where nutrition and epidemiology meet We have several people on the program today So we hope to convince you that nutrition and epidemiology actually fit together very well when we have the facts on both sides Dean Sommer, Dean Emeritus Sommer– ALFRED SOMMER: Thank you KEITH WEST: –a long term mentor– would you like to speak, or shall I just keep on going? ALFRED SOMMER: I would rather sit down [LAUGHTER] He’s going to tee me up I am not going to tell any dean jokes, Klag, so don’t worry about it MIKE KLAG: You’re the only one

ALFRED SOMMER: Well, you know, they reverberate back on you OK, here we go So we’re going to do a fast review of– this is forward, I presume, right? SPEAKER 1: [INAUDIBLE] ALFRED SOMMER: Great Right –of vitamin A. So we can entitle this talk, GR, Gr, GR, just to keep you awake, or GIR, GI(W)R, GIR(A) So what does all that stand for? It means got it right, got it wrong, got it right, finally– or again So Got It Right– so who got it right? The early nutritionists got it right Discovery of vitamins, which we’re celebrating at this symposium, you know, Hopkins, accessory factors, vital amines, Osborne and Mendel’s butter fat, and of course, McCollum and Davies fat soluble A. They knew what they were talking about EV McCollum– I’m showing that for you, Pierre, since you didn’t show his picture It’s because it’s right outside this hall People can go and play obeisance during the break So famous EV McCollum, and even the more famous rat that the dean wouldn’t allow him to use, but he used anyway, the hooded rat which became the experimental model for nutrition back in the turn of the last century And of course, this was the famous paper by McCollum and Davies about the importance of certain lipins in the diet during growth And they all got it right They recognize that vitamin A deficiency lead to reduced growth, reduced resistance to infection, increased mortality And only near the end of that, did the ophthalmologists get involved with the disease of the eye called xerophthalmia And this is a curve drawn by Stevenson, clocking the deaths of deficient rat pops And what this is showing here is that they are dying off long before they’re dying off with the eye disease xerophthalmia And this is Professor Bloch, a famous pediatrician in Denmark, who did a series of landmark observations in humans about the relationship between something that was missing from their diet, presumably vitamin A, and then a series of consequences And following one of his earlier papers about xerophthalmia, even McCollum– again, now here, 1917– “We feel confident that these cases of xerophthalmia reported by Mori”– who was Japanese and reporting a similar syndrome from Japan– “and Bloch should be looked upon as a deficiency disease not hitherto recognized in its true relationship to diet.” And Bloch in 1924, after a series of observations, “[Vitamin A deficiency] is ushered in by failure to gain weight– an increased susceptibility and a diminished power of resistance to infection The eye lesion does not appear as a rule until late in the disease.” Green and Mellanby, of course, went on, following again a series of observations by others, and called vitamin A the anti-infective vitamin So essentially, by the 1930s, those brilliant nutritionists had the entire story worked out And then they got it all wrong And what happened was is that they generalized at a period when it was difficult to generalize So [? Ellis ?] then did this beautiful paper, which I’ll mention later on measles, showing you could treat acute severe measles in children in London who are hospitalized with severe measles in 1930 and reduce their case fatality rates in half Well, people then said, well, wow, this is anti-infective Let’s give it to anybody who has an infection And that’s where they went wrong So they tried it on puerperal sepsis They tried it on influenza They tried it on colds And of course, it didn’t work And it didn’t work– or they got inconsistent results– because the disease was not, one, amenable The context, the population in Europe, was not particularly vitamin A deficient anymore The methodologies were poor They were using as an acute treatment for an acute disease, as opposed to a prophylaxis by improving the vitamin A status so they could fend off the disease And their interest was overtaken by the sudden advent of anti-microbial agents And as I said, the nutrition of Europe started to improve So if you just compare, if one was going to do a randomized trial between penicillin and vitamin A, which nobody has ever done as far as I know I mean, here’s a treatment This is a prevention, so you have to do it more or less ahead of time Here you get an immediate impact Here it’s usually delayed This will impact what was then most of the infectious agents, the bacterial infectious agents of the times This only some conditions, 90% effective This was 70% failure, because it was the wrong diseases,

and that was only when it worked at all So the world of nutrition and pediatrics, basically from the 1930s onward, completely forgot about the importance of vitamin A in its many roles other than for xerophthalmia So along comes this ophthalmologist who knows absolutely nothing about nutrition other than as it affects the eye And I go off to study vitamin A deficiency as a cause of xerophthalmia and stumble onto some things that I hadn’t anticipated And we started to get it right again, but not without some resistance So many of you have seen this slide before This was basically following children in six villages in Indonesia, some of whom would develop night-blindness, some Bitot’s spots, some both together, and some whose eyes look normal at the beginning of a three month observational period We would re-examine them every three months for 18 months And much to our surprise, and we hadn’t been looking for this, was that the children who had night blindness at the beginning of a three month observational period died at three times the rate as the children who had normal looking eyes And these children were not normal vitamin A status It’s just that their eyes didn’t have xerophthalmia They were like those pups that died early, as it turns out, but without eye disease In children with a little bit more vitamin A deficiency, correlated with not only their clinical condition, they had Bitot’s spots, but also with their serum Vitamin A levels, died at six times the rate than those with both conditions together A pure group died at almost nine times the rate So from this data, when we published this– which nobody paid any attention to because it was so absurd to think that vitamin A status could impact on mortality by the very profession that had made the story completely validated 40, 50 years earlier, I had calculated– and see, it must all have to do with the severity of xerophthalmia And you have to have that severe Vitamin A deficiency to have increased mortality And in that original paper, I extrapolated the death rates and said, if we could rid the world of xerophthalmia in children who are Vitamin A deficient and have it, we could reduce child mortality by roughly 15% Because I thought all the mortality was associated with Vitamin A deficiency severe enough to cause xerophthalmia Well, we then went ahead into the first randomized trial, and we reduced mortality 35 percent, not 15% And that was the first clue I think we had to us then rediscovering the older literature that, in fact, where did those other half of the kids who didn’t die come from? They were the kids who were vitamin A deficient but not sufficiently deficient to develop xerophthalmia So half the deaths that were being prevented were kids who were getting xerophthalmia And half the kids’ deaths that were being prevented were kids who were vitamin A deficient, but much more mildly so So they didn’t develop xerophthalmia, but they were already at increased risk of severe infections and mortality And then as you know, lots of trials were done around the world And except for two very poorly done studies, which we won’t get into, the overall reduction rate was about 35% wherever you did it– Indonesia, India, Nepal, or Africa, which actually surprised me, that it was so uniform And this is just the Asian trials Which came up with an overall effective 34% reduction in mortality, which is pretty much the same thing we got in that first original study Now the vitamin A status is, of course, impacting on other diseases, essentially infectious diseases that are going to kill children because they can’t fend off those They have suppressed immune responses, and they’re more likely to die This was three of those prevention trials, where children were either given vitamin A prophylactically or given placebos And the children who were in the villages that were assigned to vitamin A, if you look at their measles mortality rate– so they got vitamin A, and some time over the next four to six months they got measles They were only half as likely to have died if they had been in the vitamin A group So that was prophylactic and prevention And interestingly, we that ended up doing some trials of treatment of children who had severe measles in hospital, randomizing them to get large doses of vitamin A in the first two days or not And you got exactly this same 50% reduction And then we went back and found that original paper om 19– it was done in 30 And we published it in 1932 in England So we had three studies in which you got a 50% reduction in case fatality rates treating kids with severe measles

They got a 50% reduction in measles mortality if you just improve the vitamin A status of children before they got measles So that’s about as good as it usually gets for epidemiologic research in the field So right after those trials, WHO-UNICEF came out with a joint recommendation that Vitamin A should be used for the treatment of measles anywhere in the world The American Academy of Pediatrics followed suit here in the US particularly for populations in the US who might be consuming a traditional diets where they come Still countries wanted more data Still a lot of scientists didn’t believe it And we finally decided we had done enough trials and enough other people had done enough trials We had to call a halt to this whole thing We organized a meeting at the Bellagio Center for Rockefeller Foundation, which is a nice place, you know, good food, good wine, beautiful scenery, hard to argue At least, that was the theory And we got about 22 people there who have been doing studies, who were experts in child survival and nutrition And after looking at all the data from four days, came out with only three– that’s all we asked for was three conclusions– that improving the vitamin A status of children in populations that were vitamin A deficient will reduce “all cause” mortality by a third It specifically reduces measles and diarrheal mortality And prompt treatment cuts measles case fatality rates in half And I asked everybody to go off and publish these findings and these conclusions in their favorite medical journal So I published it in The Lancet Someone else published it in The Medical Journal of South Africa, and so forth So the whole message sort of swept the medical world at once, that for the most part, there was scientific consensus around this So where do we stand today? These are some nice projections that Keith largely was responsible for Vitamin A deficiency disorder– that means any metabolic disturbance from deficiency probably effects 150 to 200 million children every year Xerophthalmia of some degree affects about 3 million children and 3 million pregnant women every year About half a million children would go blind every year And there are about one to two million preventable deaths every year– if we did not have vitamin A intervention programs Fortunately, by now we do have vitamin A intervention programs around the world One of the things is, once you have a message, you have to get the message out This was a visit of Hugh Downs and the TV program 20/20 that came to see the work and film it in the Philippines Hugh Downs was just enamored with this work He showed it three times– once on a regular program, once on the 20th anniversary of 20/20, which I didn’t watch, but my son watched So they were doing clips over the first 20 years, and my son told me the next day, “You were right up there with Vietnam, Dad.” So I’m not sure I wanted to be right up there with Vietnam, but anyway And then, his last program, he again showed the vitamin A story My Christmas present in 1997– this was a lead editorial in The New York Times– Malnutrition’s 20-Cent Treatment Scott Shane wasn’t working for the times at that point, I don’t think So I don’t know who was responsible for this They never talked to me They never talked to anybody that I know about And I don’t know where they got $0.20 from But nonetheless, it was a nice editorial One of the issues, and Dr Ames talked about mechanisms being important So this was not a molecular mechanism This was the thing that bothered me, was why was it so common for children anywhere in the developing world to be vitamin A deficient? We had something wrong I mean, no matter where you looked, they were deficient And the reason, turned out, when people looked at it– a colleague of mine, [INAUDIBLE] in Indonesia’s the first that I think of, but then are some of our Dutch colleagues– that in fact, the traditional– and I think it’s still the FAO and WHO conversion rate– is it takes six molecules of beta carotene in diet to make one molecule of vitamin A. And that is patently wrong And the IOM, always being a conservative group, decided it really took more They went to twelfths, that makes only half as much vitamin A in at least the vegetable food supply But in fact, if you look at the real data coming from the developing world, fruit and squash– which don’t have quite as much fibers, you need about 12 molecules of beta carotene to make one vitamin A Green leafy vegetables– they’re green, they’re colored, right? So they’re color-coded They take 26 molecules of beta carotene to make one of So what is the practical implications of that? Well, this is what we should have figured out a long time ago So the orange bars are how much vitamin A there is in the food supply using the 6 to 1 ratio So there’s plenty everywhere, basically If everybody gets their fair share– nobody

gets their fair share Some get too much I mean, some get too little But basically, there’s enough for everybody If you use the IOMs, 12 to 1 ratio Well, now, Africa is a little short South America is a little short And Asia is about 30% to 40% short And if you use the real data, which is 21 to 1 by Clive West’s calculations, well, now Africa is down about 45% South America is down about 40% And Asia only has about 40% of the vitamin A supply that they need So that’s why children are vitamin A deficient everywhere in the world, because there is not enough vitamin A in the food supply, if they got their fair share, in order to get as much as they need So this is the reconfiguration But really it’s reconfirming what everybody knew in the 1920s and ’30s And that is, as you get vitamin A deficient, the first manifestations are systemic There’s a reduction of immune competence, increase of infections, increase of mortality, anemia, decreased growth And then only later, with more severe deficiency, they actually get the ocular complications, which is what got me into the game to begin with And of course, there has been a long time UNICEF-sponsored program They estimate that there are 70 countries in the world that have vitamin A supplementation programs 50 of them claim to reach 80% of the children twice a year I suspect that’s not true I suspect that’s an overestimate But nonetheless, people are trying to do it We have persistent risks Not only were we not reaching all the children who need it, but the persistent risk is not using every alternative strategy, like diets, supplements, biofortification, “anesthesia” from success You know, every government has said, oh, we’ve controlled that problem Let’s move on to another one So you have the risk of things are going well, let’s forget it And why do we forget it? Well, let’s abandon it because there’s a new disease du jour that has just been identified by WHO-UNICEF as being the hottest new disease that we really have to tackle So where are you going to get the money from? You take it away from ongoing programs that are highly successful And of course, everything then implodes This is just to remind you there are these other interventions This is Potrykus, who came up with the golden rice thing It’s a long way from actually having any utility But if it does, and if you’re in a rice-eating country, and people eat yellow-looking rice, it could, in fact, make a big difference Lessons for the future– discovery and programmatic intervention of other micronutrients, like many of the ones that were discussed by Dr. Ames and Klaus You’ve got to follow up unexpected findings You have to reproduce the results in different populations, if you want different populations and countries to think that they’re important and willing to take some of their resources and put them into programs You have to bring other researchers along and reach a scientific consensus You have to work that scientific consensus And of course, you have to engage policymakers Be sure you understand the evidence Keep moving forward And bury the opposition in data Now that doesn’t necessarily get rid of all the opposition So this is Professor Michael Latham of recent memory, a very senior nutritionist at Cornell who, only a few years ago, very soon before he died– and there was, I think, not causally related to that– published a single article in this journal, Digital journal And it was a 12-page diatribe about why I was entirely wrong, and why Keith and the rest of us who have been working on vitamin A, called The Great Vitamin A Fiasco So you can’t always convince everybody You just have to convince people who have brains [LAUGHTER] We also have to acknowledge the fact that we were supremely lucky in our choice of micronutrient to study Vitamin A deficiency was ubiquitous among children in the developing world That’s not true of almost anything else It impacts commonly deadly infections So we’re able to identify there was something else going on– in this case, largely measles and diarrhea And you had a practical intervention– that is, a large capsule given only twice a year So it was like an immunization There were very few other micronutrients that meet all of those criteria I hate to show economic analyses because, you know, all economists are two-handed One of our former presidents here said give me a one-handed economist And so don’t pay any great attention to the actual number It’s just to give you a sort of an order of magnitude, which I found fascinating So this was the number of dollars that had to be spent in programs to prevent one death So vitamin A came in at $23, bed nets at $200,

and ORT, oral rehydration, at almost $4,000 And the reason there, of course, is because lots of kids are getting diarrhea all the time, only some of which are going to kill you But if you keep using ORT all the time, it’s going to be fairly costly The Copenhagen Consensus, which got under way by the economists back in 2004, was an attempt by leading economists to say, if we had– in those days, they’ve increased the number– $15 billion to invest in countries around the world to improve the lives of people, where would we invest it? And they repeatedly identified undernutrition in general and micronutrients, in particular– a number one best investment in 2008– micronutrient supplements for children, vitamin A and zinc And some of the people involved had more hair on their chin [LAUGHTER] We’re also thinner That’s Keith West, Joanne Katz, Jim Telch, and I even had hair in those days when we were getting going Thank you very much [APPLAUSE] DAVID PETERS: I think we’re going to save questions for the end Al, thank you Thank you very much That was compelling And tells the story that many micronutrients probably have to go through in one phase or another, shorter or longer There are some folks here in the audience that have played really important roles, who represent agencies that play important roles in this kind of work I see Nita Dalmiya from UNICEF in New York with us, Howdy Bouis and Fabiana Moura from Harvest Plus, Ellen Piwoz from Gates, and so many others who have been playing an important role in this kind of a story that needs to be learned from and may be shortened in the future So we go from vitamin A to vitamin D We go from a vitamin that has been through the trenches and through the wars, the 100 year wars, to get to where we are, to another vitamin that McCollum discovered And yet, has so far to go And so, consistent with that, we have a young investigator, Dr. Will Checkley, who is, Dr. Ames, a physician and epidemiologist and well-trained in nutrition, biostatistics, pulmonology What else? Have I missed anything? WILL CHECKLEY: You got it KEITH WEST: I got most of it I got about 50% of it Dr. Checkley is going to speak on Vitamin D And I understand the best century is yet to come I hope we all are around to observe it WILL CHECKLEY: Thank you very much, Dr. West [INAUDIBLE] SPEAKER 1: Yeah, [INAUDIBLE] WILL CHECKLEY: Well, thank you for that introduction And I’m honored to speak at the George Graham lecture, especially because I grew up in Peru And I learned how to become a physician scientist in Peru while a student here at Hopkins So Dr. West discharged me to whet your appetite about Vitamin D and chronic disease And that’s what I hope to do, and also to just talk about some of the current controversies also in the definition and in the health effects of Vitamin D But you can’t talk about vitamins without, again, mentioning it EV McCollum And as Dr. West mentioned, the story of Vitamin D starts with rickets Back in the 1600s, when there was a transition, it was increased urbanization, moving from rural to urban, rickets became a bigger problem And there was a lot of there was there was a lot of research thinking about this antirachitic substance and how to be able to stop it So this is where, again EV McCollum’s discovery of Vitamin A brought this idea that there could be substances that are helping diseases And Sir Mellanby started by creating, devising this diet that was free of a trace component that led to rickets But later on, it because he mentioned Vitamin A in this, got EV McCollum’s lab interested And through a series of elegant experiments, he went ahead, and his group went ahead and degraded Vitamin A from oils And then found that initiated the healing of rickets So that’s one side of the story of Vitamin D. Because later, it was also discovered that sunlight played a very important role and that irradiation, whether it was sunlight or UV exposure, led to the formation of Vitamin D

And that later on, it was kind of in the skin as well and the importance of sunlight to be able to activate Vitamin D, and that’s what led Adolf Windaus to get the Nobel Prize in relating this steroid hormone and its conversion to Vitamin D Is Vitamin D just about bones and calcium, and does it lead to just kind of a liver and kidney activation? I think we’ve learned so much more about Vitamin D in the last 30 to 40 years And it’s just more than bone and calcium So if you look at the literature, and you see what tissues express Vitamin D receptor, you can see it’s all throughout the body And as a matter of fact, there’s more than 2,000 genes that are up or down regulated by Vitamin D And there’s a recent GWAS study that looked at just what happens to genes in general when they’re in the setting of improved Vitamin D levels And they basically show that the improved serum Vitamin D was associated with a 1.5 fold alteration expression of at least 300 genes So it’s playing an important role And as a pulmonologist, I need to talk about the lungs And you can see that that Vitamin D is activated in multiple tissues, including the lungs So that in this study here, by Hansdottir et al., shows that the primary respiratory epithelial cells play a role in converting just the 25-hydroxyvitamin D to the active form of 125 And they did so by showing– just kind of taking two different cells, one was the cancer cell line, and another was a primary respiratory epithelial cell, showing this conversion And then they were able to actually show the quantitation compared against no cells And showing that indeed– and that respiratory epithelial cells have the presence of this activating one alpha hydroxylase So how is Vitamin D defined? And this, I think, has been a topic of controversy And there’s no clear consensus You have expert panels disagreeing on this And from the IOM and to the endocrine society So deficiency– I think the deficiency part, most people say, well, less than 20 is probably a bad thing I think it’s been more difficult to what defines sufficiency And there’s a big disagreement in this middle region and whether 30 is enough But that aside, if you just look at the global burden of Vitamin D deficiency, this is a big problem Just talking about one billion people are affected And if you look at numbers, and especially in high income countries, anywhere from 40 to 100% of elderly, apparently healthy, Americans and Europeans suffer from this deficiency And it’s also highly prevalent in children and adolescents, and especially in countries where you expect to have a lot of sunlight We had an opportunity to look at a population-based study And this was in Peru And we took two sites in Peru One was in Lima and the other in Tumbes It was about 1,400 kids and about 200 of them had Vitamin D measured And one of the things that we found and what we discovered was that, despite the fact that we’re talking about a very narrow range, Lima and Tumbes, in distance, there was a significant deficiency of Vitamin D in the Lima kids– about 50%, compared to the Tumbes kids And these are box percentile plots, basically What it shows is just an adaptation of a box plot in which the 50% percentile, 25% percentile, 10 percentile, 5% percentile, so on on the opposite side So one could see if you take the 20 nanograms per milliliter cut off, there is a significant deficiency of Vitamin A and Vitamin D in Lima versus Tumbes And a lot has to do, again, just going back to the 1600s as to how rickets started– urbanization, and what problems that urbanization bring, whether it’s just spending more time indoors, the increase in obesity And we know that fat cells sequester Vitamin D But also we know that there are race differences in Vitamin D levels So it is well-known that blacks have lower Vitamin D levels than do whites And part of the reason is skin pigmentation There’s less sun penetration But in a study that was recently done here in Baltimore– about 2,000 adults– that decided to look at this a little bit more carefully and think about what these data are saying So indeed, in these adults, Vitamin D levels were lower

Vitamin D binding protein was lower But bone mineral density was higher in blacks versus whites And more importantly, when they went ahead and they did a measure of what the bioavailable Vitamin D, there were exactly the same between blacks and whites And they went ahead and also stratified it by quintiles or parathyroid hormone And they just saw that there was basically no difference in bioavailable Vitamin D between blacks and whites So this brings the question, what are we measuring? What’s important? Another important finding of the study is that they showed there was an important difference in the polymorphisms of Vitamin D binding protein and that blacks showed more than 80% of one type, and whites show 80% of the other So could it be that– are we measuring the right biomarker to say that this is a deficiency? So thinking about health effects and Vitamin D, and we’re going to focus on chronic disease– so we’ve learned a lot about Vitamin D And more information just has come to light And you can see it affects multiple organ systems It goes anywhere from just generalized angiogenesis and apoptosis to prevent clonal proliferations, and in specific groups, like breast, colon, prostate In the kidney, it helps to regulate– decreases renin expression, which also helps with blood pressure In the pancreas, it helps to augment insulin and augment its sensitivity, as well In the immune system– it has many roles in the immune system All the way from microbial activity to cytokine regulation to immunoglobulin synthesis to hematopoiesis And in the vascular cells, it appears to decelerate atherosclerosis And in the lung– in the lung, there’s also data showing decreased asthma risk and severity, decreased pulmonary infections through the immune system And it corrects the steroid resistance in asthma and COPD But when you think about this, and I think I put the schematic here to remind us about the kind of the early origins of the disease, that much may actually start very early and that there may be fetal programming So there is good data to show that Vitamin D does up regulate many genes early in utero And it is also true in the lungs So the human fetal lung is very affected by how by Vitamin D regulation And we had an opportunity in Nepal to look at the nutritional consequences in lung development And in this study, in which we looked at 1,300 women who were receiving vitamin A, versus placebo And we were able to show that this plays a big role in lung development But Dr. West made me remember that Vitamin A and especially Vitamin A receptor, is coupled to Vitamin D And that a lot of the effects that Vitamin A are probably having are linked to how Vitamin D is working This schematic I took from a website that is a website on Vitamin D. And it’s a semi-quantitative interpretation of what’s available But basically, what I wanted to illustrate here is that, indeed it appears, and based on the evidence that, as you increase your levels of Vitamin D, many chronic diseases are affected And when you look at the literature and try to summarize information, it’s being mostly based on observational studies, I think, there’s been among randomized trials And a lot of these randomized trials come from [INAUDIBLE] in cardiology I think there’s been a good amount of evidence, a little bit more evidence in cardiology than a lot of other areas But at least in overall mortality, when they’ve actually looked at what Vitamin D does, it appears to do have a 6% to 8% decrease in mortality of Vitamin D supplementation And this is equivalent to about a 10 to 20 nanogram per ml increase in Vitamin D And in this one methanalysis, which included about 65,000 individuals, it basically shows there appears to be a plateau Seems to kind of level off somewhere here in the high ranges, anywhere beyond 50 to where– well, it kind of levels off somewhere a little bit over 50, 30– 30 nanograms per ml Now when you think about other chronic diseases, there’s been a good amount of methanalysis And these are all methanalyses that have anywhere from 8 to 8

to 50 studies And most of them, observational; several of them randomized, especially in the cardiovascular They all kind of show the trends that there’s a two-fold increase in depression risk, comparing lowest to highest levels of Vitamin D. There’s a little bit under a half a decrease in cardiometabolic disorders in the highest versus lower levels of Vitamin D. There’s a decreased risk of future diabetes as well, and about a 40% reduction in the highest versus lowest levels And chronic kidney disease mortality is also reduced And colon cancer is also reduced– I’d say about a 10 nanogram per ml increase in Vitamin D is associated with a reduction of about 26% in colon cancer in large population studies How about Vitamin D and asthma? So much of the evidence for Vitamin D in asthma is related, at the moment, in observational studies And while there are several trials that are ongoing to answer many of the questions, when you think about Vitamin D and asthma, Vitamin D insufficiency and asthma have many common factors One is obesity There’s migration to industrialized countries There’s also a component of race, where there’s more asthma in one group and more Vitamin D insufficiency in another And also, just living in the inner city itself has a big role And just going back to some of the areas that we talked about– this in utero programming– there has been some cohort studies that have looked at data of how Vitamin D, especially maternal Vitamin D, [? weigh ?] in just before and during pregnancy, how it affects asthma in offspring There have been at least four studies, reasonably sized, that have looked at this And the mothers who took maternal Vitamin D supplements versus those who didn’t had decreased odds of having a child that wheezed later in life And this was about by half And also other allergic diseases are affected, such as maternal vitamin– such as eczema So being shown that cord blood Vitamin D status is observed in infants who developed eczema and that the eczema risk was increased It was about almost tripled when cord blood levels were under 20, versus 30 or above Other outcomes– in thinking about asthma outcomes per log-unit increase in Vitamin D. Multiple outcomes, whether it’s use of anti-inflammatory medications, inhaled steroids, in the metacholine test, or hospitalizations are all reduced with increased Vitamin D And this is from our site in Peru– in which we had a chance again, the same Lima-Tumbes study– that we have, in this cross-sectional population they studied, we saw kind of a clear relationship between Vitamin D levels and asthma prevalence, especially when you stratify it by sight as well And when we had a chance to do an analysis in a multivariate approach, again, you see that there’s a high prevalence of Vitamin D deficiency in Lima versus Tumbes But what was interesting is that we found that the odds of asthma was pretty much in that group of children who had atopic disease or allergic disease that requires some immunomodulation, which probably is the role of Vitamin D. So here we’re speculating that probably it’s that group of children that have atopy that benefit the most from higher Vitamin D levels and how this affects their risk of asthma And kind of the last point I wanted to make is that that of Vitamin D and steroid resistance So there’s kind of good data already showing that Vitamin D deficiency may increase steroid resistance that is very important in obstructive lung diseases like asthma and COPD So that’s good There are some basic science data showing that putting cell cultures of CD4 cells with dexamethasone and with Vitamin D enhances IL-10 synthesis, that it’s a potent anti-inflammatory And then in a study, the CAMP study that looked at severe asthma, it basically showed that Vitamin D deficiency was associated with a slower increment in FEV1s, which is just lung size or lung function And in these kids, there was a much lower growth or poorer growth of lung function in these group of kids, which is also being seen in adults with COPD, according to levels of Vitamin D. But when they went ahead and they just analyzed it more just categorically, they saw that this group that was on inhaled corticosteroids and were Vitamin D sufficient had better outcomes than the rest of the groups You can see that the Vitamin D insufficient levels, even though they’re on inhaled corticosteroids, they had higher risks of having severe exacerbations

And then, Vitamin D plays a big role in the lungs So we know that it’s probably having some immune effects that lead to reversible steroid resistance It has an improved handling of respiratory infections, where it’s showing you that the Vitamin D is activated in the lungs and that it probably has an important [INAUDIBLE] role in the lungs And it probably also has a big role in allergic disease, or reducing allergic disease And also, it appears to have, through the kind of the Vitamin D receptor and the retinoic acid receptor complexes, it appears to also decrease airway smooth muscle proliferation, all benefiting multiple aspects of the disease in asthma And then finally, just to– should we be supplementing kids based on the evidence that we have for adults for many of these diseases? And the expert panels have not been convinced And they haven’t been convinced about the information yet They basically say that there’s insufficient evidence, other than for musculoskeletal health, mainly because many of these studies are observational We have some few, good randomized trials But I think more evidence is needed, especially in multiple diseases And just kind of the safe upper limits right now are 3,000 international units a day for children under nine, and then, 4,000 for those above nine And what are the future directions for Vitamin D? And what should we be thinking about, kind of the next steps? So there’s insufficient evidence to recommend supplementation at a larger level But it’s a potentially powerful intervention, given its simplicity of administration And we need more randomized clinical trials in this area to examine both the effects of Vitamin D in prevention and treatment and understand the mechanisms [INAUDIBLE] So thank you very much [APPLAUSE] KEITH WEST: We’re running a little bit late for our coffee But we can take one question while the coffee starts to get poured Who wants to be that person? Ingrid? AUDIENCE: Thanks for giving me a second chance to ask a question Great talk Well, thank you Questions about your own study– how do you tease apart the cause and effect to naysayers who say, oh, well, kids with asthma, especially in rural areas, don’t play outside because they have asthma How do you know that asthma isn’t the cause of the low Vitamin D, rather than the other way around? And in keeping with that, you’ve reported the elevation, the latitude, but not the altitude, elevation of those two sites And I know Michael Holick found out that seaports or urban areas tend to have fog and pollution that blocks and that may be more important than the latitude So how do you account for elevation, and also elevation’s contribution to asthma and pulmonary disease in general? WILL CHECKLEY: Two great questions, thank you So the first needs better evidence from longitudinal studies You’re right We did study that were cross-sectional in nature Now it’s a good segue, because we have an ongoing longitudinal study in which we’re following about 1,400 kids with and without asthma, in which we’ve characterized Vitamin D at baseline and are having an opportunity to look at longitudinal symptoms over time So hopefully this can give some of the temporal, temporality relationships Though it’s association based But I think the next step is to think about randomized trials and to think about supplementation of Vitamin D in children with and without asthma to see if this has an effect And luckily, we have at least four large trials that are ongoing in asthmatic children to see if that has an effect And hopefully, in the next year or two, we should hear the results from many of these trials So the question of urbanization, I think, is a critical one You’re correct that air pollution plays a very big role So the data that we had in our study– we didn’t show the data, but we had an opportunity– we teamed up with colleagues in environmental health sciences, especially Pat Breysse, and had an opportunity to do several measurements of air pollution, ambient air pollution, in both the sites, and found that Lima had at least three to four times higher rates of air pollution And you know Lima Lima is a horrible, foggy place, and smoggy place, and it probably does contribute a lot in this idea of urbanization Going back to how the problem of rickets started is the transition from rural environments

to urban environments, living indoors, and not as much exposure to the sun As for altitude, I haven’t had a chance to kind of explore the relationship of altitude and Vitamin D yet But I can say that just a little bit of time outside at high altitude– that gives you a good sunburn So well– and I know we have a tea and coffee break So don’t forget to add milk [LAUGHTER] OK? KEITH WEST: Thank you very much [APPLAUSE]