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Malaria: Interview With Dr Steve M. Taylor
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Malaria: Interview With Dr Steve M. Taylor
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>> This is Ed Livingston, Deputy Editor of Clinical Reviews in Education for JAMA, with this week's JAMA Evidence podcast about malaria. I'm talking to Dr. Steve Taylor who authored a chapter in the Rational Clinical Exam entitled, "Does this patient have malaria?" Dr. Taylor, could you tell us about yourself? >> Yeah. I'm an infectious disease clinician, an adult infectious diseases clinician. I currently see patients across the street from Duke at the Durham VA Medical Center, but I spend most of my time doing lab based malaria research on parasite genetics.
And I've been doing both of those for about five or six years now. >> Malaria's a hugely important problem in most of the world. Could you tell us a little bit about the disease and the organism that causes it, its lifecycle, and whatnot? >> Yeah. Malaria, I think for most of us that work on malaria all the time, we're fascinated by it but also appreciate what a horrible and emiserating disease it is for the folks who live in endemic countries. As many of your listeners probably know, malaria is a parasitic infection.
There are five species of plasmodium parasites that infect us humans. One of the interesting things about plasmodium parasites is there's a huge range of species that infect all sorts of vertebrates from penguins to reptiles and birds, but only five of those species infect us humans and cause diseases. >> Of the five, are any more important than the others or are they all important? >> Yeah, well they're all important for the folks that live in the areas where they circulate, but for the most part when we're talking about malaria causing a lot of human disease, we're generally talking about plasmodium vivax and plasmodium falciparum.
And for the most part, between those, when we're talking about people actually dying and getting really severe disease, mainly what we're talking about is plasmodium falciparum, which is really the most fulminant and dangerous form of malaria. >> Where do those live, the vivax and falciparum? >> Yeah, both are present throughout the tropics so on any tropical travel you're liable to pick them up. But the caveat to that is that plasmodium vivax is absent in most of sub-Saharan Africa. It's not believed that it's completely absent, but for the most part in most places in Africa you're mainly overwhelmingly likely to get plasmodium falciparum.
And in places like Southeast Asia, Oceania, and Central and South America, both species co-circulate. >> My recollection from medical school, which was now many, many years ago, was that these two organisms had slightly different lifestyle and that the periodic fevers that develop occur at different periods. Do I remember that correctly? >> Yeah, that's exactly right. That was described I think a couple of thousands of years ago that the different forms of malaria, depending upon the infecting species, have different clinical courses and tend to cause, or will cause, fevers every three days or every four days, or fluctuating fevers intermittently on no regular schedule, depending upon the species.
>> Which is which? >> Yeah. So falciparum tends to not follow a regular clock. I think that tends to have more intermittent unpredictable fevers. I'll admit the difference between quartan fevers and tertian fevers is these days lost upon me, but one of them is plasmodium malariae and one of them is plasmodium vivax. >> It's a leading question because my father was in prison in Uzbekistan during World War II. And when I was a medical student and I was learning about malaria and I asked him about having it, because he had it multiple times, he'd had different clinical syndromes.
And they knew that, you know, different bugs caused different syndromes and they were aware of that even during the war and in prison. So it was really kind of fascinating to talk to my dad. And he gave me the story and it was like, "Wow, this is right out of the textbook. How cool." >> Right out of the textbook. Wow. Hopefully they eventually got rid of it for him. Hopefully those repeated bouts didn't affect [inaudible]. >> No, he survived it eventually.
>> Yeah, yeah, yeah. >> So what about the mosquitoes? There's different mosquitoes that carry different organisms as well. Can you tell us about that? >> Yeah. So all forms of malaria are transmitted by anopheline mosquitoes. That's distinct from the aedes mosquitoes that'll transmit other infections like dengue or from [inaudible] mosquitoes. Anopheline mosquitoes are unfortunately present all over the world. I've been bit by quite a few of them this summer, I think here.
But the efficiency of those individual vectors, the efficiency with which they transmit malaria varies quite a bit between anopheline species, which have different epidemiologies depending upon what part of the tropics that you're in. But throughout sub-Saharan Africa, the most dangerous one is the one called Anopheles gambiae, which it's almost a missile perfectly suited to transmit malaria between human. >> Could you tell us a little bit about what happens between the time you get bit by a mosquito and you get the fever? >> Yeah. Yeah.
There's a few things that need to happen before you actually get sick with malaria. First, of course, you need to be in a place where the mosquitoes are transmitting these malaria parasites, usually plasmodium falciparum from one human to the other. And then you need to bit-you need to be a susceptible host and be bit by a mosquito which is carrying parasites, which are ready to be transmitted down from its salivary glands and into your skin. The parasites spend a very short amount of time in your skin. They pretty rapidly disseminate to some regional lymph nodes and then from there onwards to your liver.
And they take about 7 to 10, up to 14 days or so to mature within your liver. And during that period of time there are no symptoms. That's a clinically silent phase during which they're maturing within the liver. And then after that phase, inside hepatocytes, they burst forth from there and then carry on the asexual blood stage, which is the stage of the infection which actually causes symptoms. >> And so they all burst at once and that's what causes the fever? It's synchronized somehow, or? >> Yeah. Well, from the liver it's not entirely known.
It's not thought that that many hepatocytes actually get infected, but a single hepatocyte can produce scores of merozoites which then emerge from the liver. And then eventually it's thought that the cycling fevers and cycling chills and rigors do result from a synchronous rupture and release of merozoites during the asexual blood phase. That is in the history textbooks, but I'm not sure that that is that frequently observed clinically anymore. >> Okay. So one other fact, digging back to the dark recesses of my brain in medical school, relate to genetic predisposition or genetic resistance, certain genetic conditions that help resist malarial infection.
What are those? >> Yeah, there's quite a few of them and folks are continually describing more and more of them. That's a particular interest of mine because it seems like using these natural forms of immunity, we could try and figure out exactly how they protect humans and then try and do that ourselves with preventive measures or therapeutic measures. But the most well known one is sickle trait. Of course sickle cell anemia results from two mutated copies of hemoglobin, two copies of hemoglobin S. And those folks actually suffer worse morbidity in sub-Saharan Africa owing to malaria.
But their siblings who have sickle trait, so one copy of hemoglobin S, are nearly impervious. They're protected by about 90 or 95% from severe life threatening falciparum malaria. But it's not yet known exactly why that is. Although there is a few different hypotheses as to how they're protected. And in addition to that, hemoglobin C in West Africa, various forms of alpha and beta thalacemia, G6PD, and a few other red cell disorders have also been described as protecting folks innately and naturally from malaria.
>> In a recently published book called 1493, Charles Mann posited that the reason African Americans populated the south of the United States and not the north was that they were generally resistant to malaria. So when people were migrating from Europe and they were bringing them over as indentured servants essentially, all the white people from Europe died in the south from malaria. And so they tended to stay in the north where they didn't get that, and the blacks stayed in the south, where they tended to survive better because they were more resistant.
Are you familiar with that? Is that true? >> I would say the fact that he had a whole chapter on malaria, but that was a terrific book. And yeah. So another example of natural resistance to malaria is that plasmodium vivax is absent in most of sub-Saharan Africa and that's because most Africans lack the duffy receptor on their red blood cells. And plasmodium vivax uses that receptor on the surface of red blood cells to enter the red cells.
And so without that protein on the surface, it can't enter the red cells. And so most Africans are resistant to plasmodium vivax, but plasmodium vivax was endemic throughout North America up through southern Canada, actually even up until the early 20th century. And so yeah vivax malaria was quite a big killer in the American south even before it was America. And so folks who had increased fitness in that setting, including the Africans brought over as slaves and then their descendents, were more resistant to infection, therefore more able to stay alive.
But yeah, it really shaped the demographic and population structure of the United States back at that time. >> Yeah, I remember reading about it. It was fascinating to put those two facts together, the issues with malaria and how people migrate. Just fascinating. >> Yeah. And there's another book by Sonia Shah, name S-H-A-H, called The Fever. It's about five or six years old, I think, where she talks about the impact of malaria on various European wars, and on um-- both within Europe and then World War I and World War II.
And the patterns of European colonialisation of Southeast Asia and of sub-Saharan Africa. It's really like a sort of latent actor in a lot of the history that we learned in school. >> Yeah. >> Yeah. Anyway, malaria history is extremely interesting, at least to me. >> No, me too. I thought it was fascinating, because I think in the same book, maybe in the interview with the author, he talked about I think in the Spanish-American War that the leading cause of death was malaria, or one of those wars. >> Yeah. And I guess whenever I give talks, I just did one a couple weeks ago for like the masters students here in global health.
And you know malaria seems like this exotic thing which happens in other countries and you just hear about it when you go for your pre-travel consultation and whatnot. But to show the maps about how, you know, malaria was endemic in the United States and to tell them that the CDC is headquartered in Atlanta because it was founded as the Malaria Control in Wartime Areas Board, something like that, during World War II. And that the American south was still, you know, large parts of it were still endemic for malaria as recently as the 30s and the 40s. It kind of reinforces that this isn't some exotic problem which only happens to other people, but this is an actor in our recent past.
It makes it less foreign I think. >> Which means we all need to know about it. So let's get into the Rational Clinical Exam article itself. One of the things that struck me about it was when we think in terms of likelihood ratios for various clinical features that help establish a diagnosis, you think in terms of, if a positive likelihood ratio is greater than 10, then you have some disease. If a negative likelihood ratio is less than 0.1, then you don't have the disease.
That's kind of the general range people look at. And in looking at these clinical features, which again come from medical school as the typical features for malaria like fever, splenomegally, hepatomegally, things like that, none of these likelihood ratios really struck me as being huge. They seem to be relatively modest, especially those for the analyses done of patients in endemic areas, not returning travelers. Is that observation correct?
>> That's absolutely correct. And I think that may have been our um-- if we had formulated a hypothesis at the outset, the hypothesis would have been that the clinical signs and symptoms won't be terribly helpful in diagnosing malaria because that's, at least in endemic areas, that's been sort of an old saw for many decades, that it's just not reliable to try and diagnose it on clinical grounds. And I think that was part of the premise for just until recently. Let's see, until recently the WHO diagnosis and treatment guidelines for malaria in malaria endemic areas actually allowed one to forego any testing.
And it advocated for presumptive treatment based upon just fever alone. And I think the premise of that was that in a febrile patient it wasn't possible to differentiate febrile from other common causes of fever. And so because malaria can be so bad, they should just be treated presumptively. That's been changed recently because there's new diagnostics in endemic areas. But it is true that the clinical signs and symptoms and even basic laboratory values don't help one very much in terms of diagnosing malaria. >> Let's start with endemic areas. You mentioned that the various signs and symptoms that are classically attributed to malaria are not particularly reliable, and that there was a recommendation in the past at least to treat empirically.
And I ask this question because I was just talking to someone, I was in Norway a couple days ago, and I was talking to someone from Finland whose wife works in Africa and she's a lab tech in Africa. And he mentioned to me that she doesn't use prophylactic therapy. She's very fastidious about her mosquito nets. But when she gets a fever, she just treats herself for malaria empirically. And that seems to be a better thing. Now, the reason I ask this is that the signs and symptoms aren't reliable, but the endemic areas will tend not to have access to the testing strategies.
The tests are very good, but they may not be available in most of those areas. So I'm assuming that if the testing's not available, you just treat empirically? >> I think that's still pretty common practice. The time honored sort of gold standard way to diagnose malaria in anyone, I guess since it was first recognized that the plasmodium parasites were the bases of disease, is to demonstrate the parasites in a blood smear, which is fairly easy to do if you have a microscope and some stain and a slide and blood. So easy in fact that I can prepare a slide fairly effectively.
But unfortunately reading the slides is very operator dependent. It does take, which requires good training of operators, it requires a fair amount of time and in a lot of areas, even if one has the capacity to prepare slides, I think that the slide readers are just overwhelmed by the volume. Because of that, I think that the integrity of slide reading, particularly in normal operations, much less in clinical studies but in normal operations is pretty low. And so even when one can obtain results of a slide reading, I think that a lot of clinicians are fairly suspect of the results and will tend to treat folks anyway, even in the face of a negative study, negative result.
Because smears are believed to be unreliable, because that practice pattern is so hardwired into a lot of clinicians, rapid diagnostic tests have become quite an advance, a technological advance in malaria endemic areas. But the problem, as you alluded to, is that a lot of places, their stock outs of these are just not available. It does cost more money to obtain and use a rapid diagnostic test and it does use a smear. But when in the right hands and used in the right clinical setting, rapid diagnostic tests are really quite reliable for the diagnosis of malaria in endemic areas or in travelers.
>> We'll come back to this, but let me move on to returning travelers because you did a separate analysis for people returning from endemic areas to, I'm assuming the United States or Europe. And those likelihood ratios for the signs and symptoms were quite a lot higher, still not above the 10 threshold, but especially splenomegally. I think the likelihood ratio for that was 6.5 or something? >> That's right. Yeah. >> Why is it that the signs and symptoms are somewhat more reliable in returning travelers than in endemic areas?
>> You know, the main reason we did that, I guess there are two main reasons. One is that we thought that the readership would be fairly clearly split between those people interested in those two populations. Clearly the studies were. And the second is that biologically adaptive or acquired immunity to malaria plays a very large role in how malaria presents. Most of those folks in endemic areas will have been infected with malaria before and that's undoubtedly going to have an impact on how severe the infection presents. If you've had malaria ten times before, it's not likely to be quite as severe, one would think.
Whereas in travelers returning from an endemic area who have never been exposed to malaria parasites before or are less likely to have been exposed to malaria parasites before, probably not ten times either, it can often much more times be a more fulmanent or more severe presentation. >> Let me ask you about prophylaxis for travelers. What is recommended? >> Well that depends on what area you're going to and even-- well, what country you're going to and even within countries what area you're going to.
I usually direct folks to the CDC's yellow book online which has sections both for patients who are traveling and for clinicians. I do that myself even if I think I know about patterns of drug resistance in various areas. I still consult the book just to make sure that I'm not running afoul of what the officials recommend. But it depends mainly on -- the recommendations that the CDC puts in the yellow book are mainly governed by what are the prevailing patterns of parasite drug resistance in the places that folks are likely to visit.
>> So what drugs are used for prophylactic treatment? >> Yeah, let's see. If you're traveling to Central America, including Haiti, one could still use Chloroquine, which of course is a pretty old drug that's been around for a while, but that's one of the few places on earth where the parasites still appear to be susceptible to Chloroquine. Throughout sub-Saharan Africa, you have a number of options. You can't use Chloroquine but you can use Mefloquine. So a lot of folks will use Mefloquine, including myself, when I've gone.
Malarone, which is a combination pill of Atovaquone and Proguanil, is another common drug that folks use throughout sub-Saharan Africa. The main downside is it has to be taken daily, which sometimes limits its use. And then in Southeast Asia, Mefloquine resistance among the parasites is pretty widespread, and so there you're usually limited to Malarone or to Doxycycline I should say. Doxycycline is I believe pretty reliably effective as prophylaxis in all tropical areas.
But the nice thing about it is that the parasite is usually susceptible, and pharmacies will usually have the Doxycycline on hand so you can run and get it the day before you leave like a lot of folks do. I think the downsides of Doxycycline are you have to take it every day and because of the photosensitivity, some folks are skeptical of taking Doxycycline and sitting on the beach on their tropical vacations. >> If you get the disease, how do you treat it? >> Luckily there's as many options for treatment as there are for prevention when you travel. Let's see.
The CDC also maintains current lists of their recommended treatment options for malaria. So I usually go to that again just to make sure that I'm not running afoul of some common recommendation. I think the way you treat it, there's a few different medications that are active against the parasites. If you're in sub-Saharan Africa or in any malaria endemic area, the most common treatment people take are artemisin in combination therapies. Artemisin is an actual herbal remedy that was discovered by Chinese scientists some years ago.
And its first line therapy for vivax and falciparum malaria in just about every malaria endemic country on the globe. One of the artemisin in combination therapies named Coartem is available in the United States or at least is approved in the United States, but I think sometimes folks have trouble getting their hands on it. Other treatment options are Malarone, which is the same medication that you take for prevention, Quinine for severe disease, or Mefloquine, which is the same drug you take for prevention. >> Are there many complications from those drugs?
>> Let's see. Coartem, which is artemisin in combination therapy, is pretty well tolerated. Malarone is as well. Quinine is somewhat notorious for cinchonism which, you know, is a side effect, or tinnitus, which goes back many, many years. Mefloquine, the main concern with Mefloquine is neuropsychiatric side effects, which I believe are less common for short treatment doses rather than as weekly prophylaxis. >> So in general, when a patient has malaria in an endemic area, what is kind of the generic presentation?
What would you expect? >> Let's see, you expect folks to be febrile at least. Most research studies of malaria will use fever plus some degree of parasite density in the blood as a case definition of malaria. But I've gotten a sense from my collaborators and colleagues in endemic areas that in a lot of endemic areas, particularly in sub-Saharan Africa, the concept of malaria is thought about similar to the way that us Americans think about the flu, in the sense that a lot of us say that we had the flu, even in the absence of any microbiologic confirmation.
It's more of a sort of descriptive syndrome of like, "I feel bad. I have a headache. I have aches. I may or may not have a fever." When you have all that and you say to somebody, "I had the flu" that means okay that's why you weren't at work for a couple of days or don't come to my house. And in endemic areas, it's very common, particularly for adults who have some degree of acquired immunity, to have very nonspecific symptoms like that, a syndrome where they have some malaise, some aches, maybe a fever, maybe a history of a recent fever, maybe some chills and for that to be considered consistent with malaria.
And in a lot of those folks, since there's so much parasite transmission, particularly in sub-Saharan Africa, a lot of those folks will have parasites in their blood even when they feel well. And so that itself can be consistent with just having malaria. >> So one difference though is in the U.S. if you have the flu you don't treat it. So if you're in an endemic area and you have something that smells like malaria, do you just treat it empirically, if you don't have access to testing? >> Yeah. I think there are attempts to change those practice patterns, but I think it's still true that a lot of those folks will either go on their own to a pharmacy to obtain anti-malarials, which I would probably do as well, or will go to a provider.
Diagnostic testing may or may not be ordered. And if it's ordered, it may or may not be believed, but then the patients will be treated empirically anyway. >> So let's switch back to returning travelers from endemic areas. If you're a primary care clinician and a patient comes in and you need to worry about malaria, what is that patient going to look like? >> They'll almost always have a fever. And I've got to say the takeaway message from when we did this Rational Clinical Exam paper a few years ago, and what we really tried to emphasize, was that the number one job is just to put malaria on the differential diagnosis.
And in order to do that, usually people will have fever or will complain of recently had a fever. And they will have traveled to a malaria endemic area. And so taking a travel history, even briefly, not exhaustively but even just screening people for recent travel to tropical areas, in which they may have acquired malaria or a host of other potentially imported diseases, is really the most critical step. Because once you put malaria on the differential diagnosis, at that point then you can look up the CDC's tables about how to diagnose it.
If you want to, you can look up the CDC's tables about how to empirically treat it. But at first you've got to appreciate that the diagnosis is in play, and hopefully also appreciate that this infection could be fulminant and fatal, if I fail to diagnose it. Because another thing that comes out of the-- every year the CDC publishes, in MMWR, a report of the imported cases of malaria and it's usually about 1,300 or 1,500 every year in the United States. And they give much more granular data on a few separate cases of either severe or fatal cases.
And almost always there's a diagnostic delay in actually diagnosing malaria in the people who end up with some bad outcome, whether that bad outcome is death or if the bad outcome is just ending up in the ICU or even just ending up in the hospital. So the first thing to do is to appreciate that the patient might have malaria. And then from there you can obtain your diagnostic studies, or seek to try and increase the tempo of the workup, or even just refer them to another hospital for admission if you really believe that the likelihood is high.
>> So in the article, the features that were the most associated with malaria were fever, splenomegally, hyperbilirubanemia, and thrombocytopenia. >> Yeah. >> Is that right? Okay. So if you have those things, then you really need to worry about malaria. And then the next step then I guess in the U.S. would be to get a blood test or a smear. >> Yeah, that's exactly right, yeah, and I think most hospitals will have capacity to do blood smears. And a lot of them, the rapid diagnostic tests, at least one of them I believe is approved in the United States.
So a lot of them have those sitting around as well. Even without those other things, if you have a fever and you've recently returned from somewhere with malaria, I think you basically always will merit some type of formal diagnostic testing. >> So this may be a ridiculous or uninformed question, but I just went through customs yesterday and the one thing they ask you is did you come from western Africa, I think they ask you. And did you have a fever? So, if you come from western Africa and you have a fever, how do you know you have Ebola and how do you know you have malaria?
How do you approach that? >> Yeah. That's been a big issue, right? Because I mean there's been this remarkable public health response to detecting potential cases of imported Ebola into the United States. And the case definition has always been, you know, people returning from West Africa, you know, specific places in West Africa with a fever. But I think quite a few times those folks with possible Ebola, you know, they've been able to obtain some rapid testing for malaria parasites. And very frequently those folks have ended up having malaria instead of Ebola.
And of course I haven't seen the numbers, but I'd be willing to bet that the number of imported cases of malaria has exceeded the number of imported cases of Ebola in the past 12 months from West Africa. And there's even been, just recently, there have been a couple of studies which have focused on, or which have modeled, let's see, the number of missed cases of malaria in Liberia, and Sierra Leone. The number of cases of malaria that have either been missed or suboptimally managed owing to a rededication of resources to Ebola control.
So the Ebola epidemic in West Africa I think has really interrupted, you know, probably a lot of gains in malaria control in those areas. And I don't think clinically one can differentiate between the two either in endemic areas or reliably in a returning traveler. >> I was just thinking about that. I thought how would you know the difference? I mean you came from an endemic area and you got a fever. Are there any other diseases you need to worry about when you have that issue? You come from an area that's endemic for malaria and develop a fever.
>> Yeah. It kind of depends on where you've been. I mean malaria is almost always going to be on the list, but you know in West Africa, well most places in sub-Saharan Africa, I think malaria will probably be at the top of the list. But in Thailand it would probably not be at the top of the list. I know things like dengue, chikungunya, lepto, influenza, acute HIV, there's lots of things that are on the list. Malaria's almost always there, but it's, you know, it's really intense transmission of malaria in West Africa, central Africa, really intense transmission.
So it's very commonly going to be that. But in-- South America has malaria, but not that much. If you came back with a fever from South America, malaria should be on your list and you should test for it, but there's other things which come first I think in your differential diagnosis. My wife works for the Department of Public Health in North Carolina and so she was on call a lot of times for the Ebola response here in North Carolina. So many times in the middle of the night she received calls and I would hear about the cases and wonder gosh, it seems also likely that the guy might have malaria.
But of course people said Ebola, Ebola, Ebola. I would be willing to bet that a large fraction of those folks ended up having run of the mill malaria. >> Yeah, I could see where what you pointed out earlier would be a real problem because there's so much attention on Ebola, that once they've decided they don't have Ebola, they forget about everything else. Like, "Oh it's not Ebola. Go home." >> No. We really did worry about that.
I know my colleagues here at Duke were involved in setting up the institutional response and setting up, I don't know, a treatment unit for possible Ebola cases. But it's great for clinicians to be alert to the possibility of Ebola, but we're very much worried about people putting their blinders on, putting somebody in the back of an emergency department, and then not talking to them for 10 hours, while the sort of bureaucratic gears turn for their Ebola workup, while they might be sitting there with malaria parasites in their blood which need to be diagnosed and treated.
>> Thank you Dr. Taylor. I've been speaking with Dr. Steven Taylor from Duke University about malaria, who wrote a chapter in The Rational Clinical Exam on making the diagnosis of malaria from clinical features. Thank you for listening to this JAMA Evidence podcast. This is Ed Livingston, Deputy Editor of JAMA. Listen to our whole library of podcasts on the JAMA Evidence website or in the iTunes store or Stitcher.
Segment:0 .
>> This is Ed Livingston, Deputy Editor of Clinical Reviews in Education for JAMA, with this week's JAMA Evidence podcast about malaria. I'm talking to Dr. Steve Taylor who authored a chapter in the Rational Clinical Exam entitled, "Does this patient have malaria?" Dr. Taylor, could you tell us about yourself? >> Yeah. I'm an infectious disease clinician, an adult infectious diseases clinician. I currently see patients across the street from Duke at the Durham VA Medical Center, but I spend most of my time doing lab based malaria research on parasite genetics.
And I've been doing both of those for about five or six years now. >> Malaria's a hugely important problem in most of the world. Could you tell us a little bit about the disease and the organism that causes it, its lifecycle, and whatnot? >> Yeah. Malaria, I think for most of us that work on malaria all the time, we're fascinated by it but also appreciate what a horrible and emiserating disease it is for the folks who live in endemic countries. As many of your listeners probably know, malaria is a parasitic infection.
There are five species of plasmodium parasites that infect us humans. One of the interesting things about plasmodium parasites is there's a huge range of species that infect all sorts of vertebrates from penguins to reptiles and birds, but only five of those species infect us humans and cause diseases. >> Of the five, are any more important than the others or are they all important? >> Yeah, well they're all important for the folks that live in the areas where they circulate, but for the most part when we're talking about malaria causing a lot of human disease, we're generally talking about plasmodium vivax and plasmodium falciparum.
And for the most part, between those, when we're talking about people actually dying and getting really severe disease, mainly what we're talking about is plasmodium falciparum, which is really the most fulminant and dangerous form of malaria. >> Where do those live, the vivax and falciparum? >> Yeah, both are present throughout the tropics so on any tropical travel you're liable to pick them up. But the caveat to that is that plasmodium vivax is absent in most of sub-Saharan Africa. It's not believed that it's completely absent, but for the most part in most places in Africa you're mainly overwhelmingly likely to get plasmodium falciparum.
And in places like Southeast Asia, Oceania, and Central and South America, both species co-circulate. >> My recollection from medical school, which was now many, many years ago, was that these two organisms had slightly different lifestyle and that the periodic fevers that develop occur at different periods. Do I remember that correctly? >> Yeah, that's exactly right. That was described I think a couple of thousands of years ago that the different forms of malaria, depending upon the infecting species, have different clinical courses and tend to cause, or will cause, fevers every three days or every four days, or fluctuating fevers intermittently on no regular schedule, depending upon the species.
>> Which is which? >> Yeah. So falciparum tends to not follow a regular clock. I think that tends to have more intermittent unpredictable fevers. I'll admit the difference between quartan fevers and tertian fevers is these days lost upon me, but one of them is plasmodium malariae and one of them is plasmodium vivax. >> It's a leading question because my father was in prison in Uzbekistan during World War II. And when I was a medical student and I was learning about malaria and I asked him about having it, because he had it multiple times, he'd had different clinical syndromes.
And they knew that, you know, different bugs caused different syndromes and they were aware of that even during the war and in prison. So it was really kind of fascinating to talk to my dad. And he gave me the story and it was like, "Wow, this is right out of the textbook. How cool." >> Right out of the textbook. Wow. Hopefully they eventually got rid of it for him. Hopefully those repeated bouts didn't affect [inaudible]. >> No, he survived it eventually.
>> Yeah, yeah, yeah. >> So what about the mosquitoes? There's different mosquitoes that carry different organisms as well. Can you tell us about that? >> Yeah. So all forms of malaria are transmitted by anopheline mosquitoes. That's distinct from the aedes mosquitoes that'll transmit other infections like dengue or from [inaudible] mosquitoes. Anopheline mosquitoes are unfortunately present all over the world. I've been bit by quite a few of them this summer, I think here.
But the efficiency of those individual vectors, the efficiency with which they transmit malaria varies quite a bit between anopheline species, which have different epidemiologies depending upon what part of the tropics that you're in. But throughout sub-Saharan Africa, the most dangerous one is the one called Anopheles gambiae, which it's almost a missile perfectly suited to transmit malaria between human. >> Could you tell us a little bit about what happens between the time you get bit by a mosquito and you get the fever? >> Yeah. Yeah.
There's a few things that need to happen before you actually get sick with malaria. First, of course, you need to be in a place where the mosquitoes are transmitting these malaria parasites, usually plasmodium falciparum from one human to the other. And then you need to bit-you need to be a susceptible host and be bit by a mosquito which is carrying parasites, which are ready to be transmitted down from its salivary glands and into your skin. The parasites spend a very short amount of time in your skin. They pretty rapidly disseminate to some regional lymph nodes and then from there onwards to your liver.
And they take about 7 to 10, up to 14 days or so to mature within your liver. And during that period of time there are no symptoms. That's a clinically silent phase during which they're maturing within the liver. And then after that phase, inside hepatocytes, they burst forth from there and then carry on the asexual blood stage, which is the stage of the infection which actually causes symptoms. >> And so they all burst at once and that's what causes the fever? It's synchronized somehow, or? >> Yeah. Well, from the liver it's not entirely known.
It's not thought that that many hepatocytes actually get infected, but a single hepatocyte can produce scores of merozoites which then emerge from the liver. And then eventually it's thought that the cycling fevers and cycling chills and rigors do result from a synchronous rupture and release of merozoites during the asexual blood phase. That is in the history textbooks, but I'm not sure that that is that frequently observed clinically anymore. >> Okay. So one other fact, digging back to the dark recesses of my brain in medical school, relate to genetic predisposition or genetic resistance, certain genetic conditions that help resist malarial infection.
What are those? >> Yeah, there's quite a few of them and folks are continually describing more and more of them. That's a particular interest of mine because it seems like using these natural forms of immunity, we could try and figure out exactly how they protect humans and then try and do that ourselves with preventive measures or therapeutic measures. But the most well known one is sickle trait. Of course sickle cell anemia results from two mutated copies of hemoglobin, two copies of hemoglobin S. And those folks actually suffer worse morbidity in sub-Saharan Africa owing to malaria.
But their siblings who have sickle trait, so one copy of hemoglobin S, are nearly impervious. They're protected by about 90 or 95% from severe life threatening falciparum malaria. But it's not yet known exactly why that is. Although there is a few different hypotheses as to how they're protected. And in addition to that, hemoglobin C in West Africa, various forms of alpha and beta thalacemia, G6PD, and a few other red cell disorders have also been described as protecting folks innately and naturally from malaria.
>> In a recently published book called 1493, Charles Mann posited that the reason African Americans populated the south of the United States and not the north was that they were generally resistant to malaria. So when people were migrating from Europe and they were bringing them over as indentured servants essentially, all the white people from Europe died in the south from malaria. And so they tended to stay in the north where they didn't get that, and the blacks stayed in the south, where they tended to survive better because they were more resistant.
Are you familiar with that? Is that true? >> I would say the fact that he had a whole chapter on malaria, but that was a terrific book. And yeah. So another example of natural resistance to malaria is that plasmodium vivax is absent in most of sub-Saharan Africa and that's because most Africans lack the duffy receptor on their red blood cells. And plasmodium vivax uses that receptor on the surface of red blood cells to enter the red cells.
And so without that protein on the surface, it can't enter the red cells. And so most Africans are resistant to plasmodium vivax, but plasmodium vivax was endemic throughout North America up through southern Canada, actually even up until the early 20th century. And so yeah vivax malaria was quite a big killer in the American south even before it was America. And so folks who had increased fitness in that setting, including the Africans brought over as slaves and then their descendents, were more resistant to infection, therefore more able to stay alive.
But yeah, it really shaped the demographic and population structure of the United States back at that time. >> Yeah, I remember reading about it. It was fascinating to put those two facts together, the issues with malaria and how people migrate. Just fascinating. >> Yeah. And there's another book by Sonia Shah, name S-H-A-H, called The Fever. It's about five or six years old, I think, where she talks about the impact of malaria on various European wars, and on um-- both within Europe and then World War I and World War II.
And the patterns of European colonialisation of Southeast Asia and of sub-Saharan Africa. It's really like a sort of latent actor in a lot of the history that we learned in school. >> Yeah. >> Yeah. Anyway, malaria history is extremely interesting, at least to me. >> No, me too. I thought it was fascinating, because I think in the same book, maybe in the interview with the author, he talked about I think in the Spanish-American War that the leading cause of death was malaria, or one of those wars. >> Yeah. And I guess whenever I give talks, I just did one a couple weeks ago for like the masters students here in global health.
And you know malaria seems like this exotic thing which happens in other countries and you just hear about it when you go for your pre-travel consultation and whatnot. But to show the maps about how, you know, malaria was endemic in the United States and to tell them that the CDC is headquartered in Atlanta because it was founded as the Malaria Control in Wartime Areas Board, something like that, during World War II. And that the American south was still, you know, large parts of it were still endemic for malaria as recently as the 30s and the 40s. It kind of reinforces that this isn't some exotic problem which only happens to other people, but this is an actor in our recent past.
It makes it less foreign I think. >> Which means we all need to know about it. So let's get into the Rational Clinical Exam article itself. One of the things that struck me about it was when we think in terms of likelihood ratios for various clinical features that help establish a diagnosis, you think in terms of, if a positive likelihood ratio is greater than 10, then you have some disease. If a negative likelihood ratio is less than 0.1, then you don't have the disease.
That's kind of the general range people look at. And in looking at these clinical features, which again come from medical school as the typical features for malaria like fever, splenomegally, hepatomegally, things like that, none of these likelihood ratios really struck me as being huge. They seem to be relatively modest, especially those for the analyses done of patients in endemic areas, not returning travelers. Is that observation correct?
>> That's absolutely correct. And I think that may have been our um-- if we had formulated a hypothesis at the outset, the hypothesis would have been that the clinical signs and symptoms won't be terribly helpful in diagnosing malaria because that's, at least in endemic areas, that's been sort of an old saw for many decades, that it's just not reliable to try and diagnose it on clinical grounds. And I think that was part of the premise for just until recently. Let's see, until recently the WHO diagnosis and treatment guidelines for malaria in malaria endemic areas actually allowed one to forego any testing.
And it advocated for presumptive treatment based upon just fever alone. And I think the premise of that was that in a febrile patient it wasn't possible to differentiate febrile from other common causes of fever. And so because malaria can be so bad, they should just be treated presumptively. That's been changed recently because there's new diagnostics in endemic areas. But it is true that the clinical signs and symptoms and even basic laboratory values don't help one very much in terms of diagnosing malaria. >> Let's start with endemic areas. You mentioned that the various signs and symptoms that are classically attributed to malaria are not particularly reliable, and that there was a recommendation in the past at least to treat empirically.
And I ask this question because I was just talking to someone, I was in Norway a couple days ago, and I was talking to someone from Finland whose wife works in Africa and she's a lab tech in Africa. And he mentioned to me that she doesn't use prophylactic therapy. She's very fastidious about her mosquito nets. But when she gets a fever, she just treats herself for malaria empirically. And that seems to be a better thing. Now, the reason I ask this is that the signs and symptoms aren't reliable, but the endemic areas will tend not to have access to the testing strategies.
The tests are very good, but they may not be available in most of those areas. So I'm assuming that if the testing's not available, you just treat empirically? >> I think that's still pretty common practice. The time honored sort of gold standard way to diagnose malaria in anyone, I guess since it was first recognized that the plasmodium parasites were the bases of disease, is to demonstrate the parasites in a blood smear, which is fairly easy to do if you have a microscope and some stain and a slide and blood. So easy in fact that I can prepare a slide fairly effectively.
But unfortunately reading the slides is very operator dependent. It does take, which requires good training of operators, it requires a fair amount of time and in a lot of areas, even if one has the capacity to prepare slides, I think that the slide readers are just overwhelmed by the volume. Because of that, I think that the integrity of slide reading, particularly in normal operations, much less in clinical studies but in normal operations is pretty low. And so even when one can obtain results of a slide reading, I think that a lot of clinicians are fairly suspect of the results and will tend to treat folks anyway, even in the face of a negative study, negative result.
Because smears are believed to be unreliable, because that practice pattern is so hardwired into a lot of clinicians, rapid diagnostic tests have become quite an advance, a technological advance in malaria endemic areas. But the problem, as you alluded to, is that a lot of places, their stock outs of these are just not available. It does cost more money to obtain and use a rapid diagnostic test and it does use a smear. But when in the right hands and used in the right clinical setting, rapid diagnostic tests are really quite reliable for the diagnosis of malaria in endemic areas or in travelers.
>> We'll come back to this, but let me move on to returning travelers because you did a separate analysis for people returning from endemic areas to, I'm assuming the United States or Europe. And those likelihood ratios for the signs and symptoms were quite a lot higher, still not above the 10 threshold, but especially splenomegally. I think the likelihood ratio for that was 6.5 or something? >> That's right. Yeah. >> Why is it that the signs and symptoms are somewhat more reliable in returning travelers than in endemic areas?
>> You know, the main reason we did that, I guess there are two main reasons. One is that we thought that the readership would be fairly clearly split between those people interested in those two populations. Clearly the studies were. And the second is that biologically adaptive or acquired immunity to malaria plays a very large role in how malaria presents. Most of those folks in endemic areas will have been infected with malaria before and that's undoubtedly going to have an impact on how severe the infection presents. If you've had malaria ten times before, it's not likely to be quite as severe, one would think.
Whereas in travelers returning from an endemic area who have never been exposed to malaria parasites before or are less likely to have been exposed to malaria parasites before, probably not ten times either, it can often much more times be a more fulmanent or more severe presentation. >> Let me ask you about prophylaxis for travelers. What is recommended? >> Well that depends on what area you're going to and even-- well, what country you're going to and even within countries what area you're going to.
I usually direct folks to the CDC's yellow book online which has sections both for patients who are traveling and for clinicians. I do that myself even if I think I know about patterns of drug resistance in various areas. I still consult the book just to make sure that I'm not running afoul of what the officials recommend. But it depends mainly on -- the recommendations that the CDC puts in the yellow book are mainly governed by what are the prevailing patterns of parasite drug resistance in the places that folks are likely to visit.
>> So what drugs are used for prophylactic treatment? >> Yeah, let's see. If you're traveling to Central America, including Haiti, one could still use Chloroquine, which of course is a pretty old drug that's been around for a while, but that's one of the few places on earth where the parasites still appear to be susceptible to Chloroquine. Throughout sub-Saharan Africa, you have a number of options. You can't use Chloroquine but you can use Mefloquine. So a lot of folks will use Mefloquine, including myself, when I've gone.
Malarone, which is a combination pill of Atovaquone and Proguanil, is another common drug that folks use throughout sub-Saharan Africa. The main downside is it has to be taken daily, which sometimes limits its use. And then in Southeast Asia, Mefloquine resistance among the parasites is pretty widespread, and so there you're usually limited to Malarone or to Doxycycline I should say. Doxycycline is I believe pretty reliably effective as prophylaxis in all tropical areas.
But the nice thing about it is that the parasite is usually susceptible, and pharmacies will usually have the Doxycycline on hand so you can run and get it the day before you leave like a lot of folks do. I think the downsides of Doxycycline are you have to take it every day and because of the photosensitivity, some folks are skeptical of taking Doxycycline and sitting on the beach on their tropical vacations. >> If you get the disease, how do you treat it? >> Luckily there's as many options for treatment as there are for prevention when you travel. Let's see.
The CDC also maintains current lists of their recommended treatment options for malaria. So I usually go to that again just to make sure that I'm not running afoul of some common recommendation. I think the way you treat it, there's a few different medications that are active against the parasites. If you're in sub-Saharan Africa or in any malaria endemic area, the most common treatment people take are artemisin in combination therapies. Artemisin is an actual herbal remedy that was discovered by Chinese scientists some years ago.
And its first line therapy for vivax and falciparum malaria in just about every malaria endemic country on the globe. One of the artemisin in combination therapies named Coartem is available in the United States or at least is approved in the United States, but I think sometimes folks have trouble getting their hands on it. Other treatment options are Malarone, which is the same medication that you take for prevention, Quinine for severe disease, or Mefloquine, which is the same drug you take for prevention. >> Are there many complications from those drugs?
>> Let's see. Coartem, which is artemisin in combination therapy, is pretty well tolerated. Malarone is as well. Quinine is somewhat notorious for cinchonism which, you know, is a side effect, or tinnitus, which goes back many, many years. Mefloquine, the main concern with Mefloquine is neuropsychiatric side effects, which I believe are less common for short treatment doses rather than as weekly prophylaxis. >> So in general, when a patient has malaria in an endemic area, what is kind of the generic presentation?
What would you expect? >> Let's see, you expect folks to be febrile at least. Most research studies of malaria will use fever plus some degree of parasite density in the blood as a case definition of malaria. But I've gotten a sense from my collaborators and colleagues in endemic areas that in a lot of endemic areas, particularly in sub-Saharan Africa, the concept of malaria is thought about similar to the way that us Americans think about the flu, in the sense that a lot of us say that we had the flu, even in the absence of any microbiologic confirmation.
It's more of a sort of descriptive syndrome of like, "I feel bad. I have a headache. I have aches. I may or may not have a fever." When you have all that and you say to somebody, "I had the flu" that means okay that's why you weren't at work for a couple of days or don't come to my house. And in endemic areas, it's very common, particularly for adults who have some degree of acquired immunity, to have very nonspecific symptoms like that, a syndrome where they have some malaise, some aches, maybe a fever, maybe a history of a recent fever, maybe some chills and for that to be considered consistent with malaria.
And in a lot of those folks, since there's so much parasite transmission, particularly in sub-Saharan Africa, a lot of those folks will have parasites in their blood even when they feel well. And so that itself can be consistent with just having malaria. >> So one difference though is in the U.S. if you have the flu you don't treat it. So if you're in an endemic area and you have something that smells like malaria, do you just treat it empirically, if you don't have access to testing? >> Yeah. I think there are attempts to change those practice patterns, but I think it's still true that a lot of those folks will either go on their own to a pharmacy to obtain anti-malarials, which I would probably do as well, or will go to a provider.
Diagnostic testing may or may not be ordered. And if it's ordered, it may or may not be believed, but then the patients will be treated empirically anyway. >> So let's switch back to returning travelers from endemic areas. If you're a primary care clinician and a patient comes in and you need to worry about malaria, what is that patient going to look like? >> They'll almost always have a fever. And I've got to say the takeaway message from when we did this Rational Clinical Exam paper a few years ago, and what we really tried to emphasize, was that the number one job is just to put malaria on the differential diagnosis.
And in order to do that, usually people will have fever or will complain of recently had a fever. And they will have traveled to a malaria endemic area. And so taking a travel history, even briefly, not exhaustively but even just screening people for recent travel to tropical areas, in which they may have acquired malaria or a host of other potentially imported diseases, is really the most critical step. Because once you put malaria on the differential diagnosis, at that point then you can look up the CDC's tables about how to diagnose it.
If you want to, you can look up the CDC's tables about how to empirically treat it. But at first you've got to appreciate that the diagnosis is in play, and hopefully also appreciate that this infection could be fulminant and fatal, if I fail to diagnose it. Because another thing that comes out of the-- every year the CDC publishes, in MMWR, a report of the imported cases of malaria and it's usually about 1,300 or 1,500 every year in the United States. And they give much more granular data on a few separate cases of either severe or fatal cases.
And almost always there's a diagnostic delay in actually diagnosing malaria in the people who end up with some bad outcome, whether that bad outcome is death or if the bad outcome is just ending up in the ICU or even just ending up in the hospital. So the first thing to do is to appreciate that the patient might have malaria. And then from there you can obtain your diagnostic studies, or seek to try and increase the tempo of the workup, or even just refer them to another hospital for admission if you really believe that the likelihood is high.
>> So in the article, the features that were the most associated with malaria were fever, splenomegally, hyperbilirubanemia, and thrombocytopenia. >> Yeah. >> Is that right? Okay. So if you have those things, then you really need to worry about malaria. And then the next step then I guess in the U.S. would be to get a blood test or a smear. >> Yeah, that's exactly right, yeah, and I think most hospitals will have capacity to do blood smears. And a lot of them, the rapid diagnostic tests, at least one of them I believe is approved in the United States.
So a lot of them have those sitting around as well. Even without those other things, if you have a fever and you've recently returned from somewhere with malaria, I think you basically always will merit some type of formal diagnostic testing. >> So this may be a ridiculous or uninformed question, but I just went through customs yesterday and the one thing they ask you is did you come from western Africa, I think they ask you. And did you have a fever? So, if you come from western Africa and you have a fever, how do you know you have Ebola and how do you know you have malaria?
How do you approach that? >> Yeah. That's been a big issue, right? Because I mean there's been this remarkable public health response to detecting potential cases of imported Ebola into the United States. And the case definition has always been, you know, people returning from West Africa, you know, specific places in West Africa with a fever. But I think quite a few times those folks with possible Ebola, you know, they've been able to obtain some rapid testing for malaria parasites. And very frequently those folks have ended up having malaria instead of Ebola.
And of course I haven't seen the numbers, but I'd be willing to bet that the number of imported cases of malaria has exceeded the number of imported cases of Ebola in the past 12 months from West Africa. And there's even been, just recently, there have been a couple of studies which have focused on, or which have modeled, let's see, the number of missed cases of malaria in Liberia, and Sierra Leone. The number of cases of malaria that have either been missed or suboptimally managed owing to a rededication of resources to Ebola control.
So the Ebola epidemic in West Africa I think has really interrupted, you know, probably a lot of gains in malaria control in those areas. And I don't think clinically one can differentiate between the two either in endemic areas or reliably in a returning traveler. >> I was just thinking about that. I thought how would you know the difference? I mean you came from an endemic area and you got a fever. Are there any other diseases you need to worry about when you have that issue? You come from an area that's endemic for malaria and develop a fever.
>> Yeah. It kind of depends on where you've been. I mean malaria is almost always going to be on the list, but you know in West Africa, well most places in sub-Saharan Africa, I think malaria will probably be at the top of the list. But in Thailand it would probably not be at the top of the list. I know things like dengue, chikungunya, lepto, influenza, acute HIV, there's lots of things that are on the list. Malaria's almost always there, but it's, you know, it's really intense transmission of malaria in West Africa, central Africa, really intense transmission.
So it's very commonly going to be that. But in-- South America has malaria, but not that much. If you came back with a fever from South America, malaria should be on your list and you should test for it, but there's other things which come first I think in your differential diagnosis. My wife works for the Department of Public Health in North Carolina and so she was on call a lot of times for the Ebola response here in North Carolina. So many times in the middle of the night she received calls and I would hear about the cases and wonder gosh, it seems also likely that the guy might have malaria.
But of course people said Ebola, Ebola, Ebola. I would be willing to bet that a large fraction of those folks ended up having run of the mill malaria. >> Yeah, I could see where what you pointed out earlier would be a real problem because there's so much attention on Ebola, that once they've decided they don't have Ebola, they forget about everything else. Like, "Oh it's not Ebola. Go home." >> No. We really did worry about that.
I know my colleagues here at Duke were involved in setting up the institutional response and setting up, I don't know, a treatment unit for possible Ebola cases. But it's great for clinicians to be alert to the possibility of Ebola, but we're very much worried about people putting their blinders on, putting somebody in the back of an emergency department, and then not talking to them for 10 hours, while the sort of bureaucratic gears turn for their Ebola workup, while they might be sitting there with malaria parasites in their blood which need to be diagnosed and treated.
>> Thank you Dr. Taylor. I've been speaking with Dr. Steven Taylor from Duke University about malaria, who wrote a chapter in The Rational Clinical Exam on making the diagnosis of malaria from clinical features. Thank you for listening to this JAMA Evidence podcast. This is Ed Livingston, Deputy Editor of JAMA. Listen to our whole library of podcasts on the JAMA Evidence website or in the iTunes store or Stitcher.
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