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The Great Fever
Roundtable Discussion on Yellow Fever

On September 13, 2005, the one hundred and fifty-fifth birthday of Walter Reed, three medical doctors, all experts on aspects of yellow fever, discussed the history, science and future of the disease with American Experience Online. Dr. Margaret Humphreys teaches both history and medicine at Duke University and is the author of Yellow Fever and the South, 1992. Dr. Thomas Monath conducts research on infectious diseases and is the author of numerous scientific papers and books on the topic; he has served on World Health Organization (WHO) committees and was awarded the Walter Reed Medal from the American Society of Tropical Medicine and Hygiene. Dr. John R. Pierce, now with the Veteran's Administration health care system, is the author, with Jim Writer, of Yellow Jack: How Yellow Fever Ravaged America and Walter Reed Discovered Its Deadly Secrets, 2005, and is the historian of the Walter Reed Society.

Among the topics covered are:

  1. A description of the disease and an outbreak
  2. How historical events contributed to the rise and fall of yellow fever
  3. The mosquito species that transmits the disease
  4. Research on treatments and a vaccine
  5. Yellow fever as a biological weapon
  6. The science of the virus' life cycle
  7. The search for an end to yellow fever
  8. Jesse Lazear's self-experimentation
  9. Walter Reed's reputation
  10. The yellow fever vaccine
  11. The possibility of a return of yellow fever
  12. Are institutions prepared to deal with pandemics today

Participants

Margaret Humphreys Humphreys: I first trained in history of science and got a PhD in that and studied yellow fever in the American south for my PhD work. Then I went to medical school and I'm not sure we heard about yellow fever at all in medical school.

John Pierce Pierce: I spent 30 years in active duty in the army as a physician, about half that time, 15 years, at Walter Reed Army Medical Center and during that time I was interested in the history of Walter Reed, the hospital and the person. And you can't be interested in the history of Walter Reed the person without being interested in yellow fever.

Thomas Monath Monath: I'm a physician and I spent about 26 years in uniformed service also, much of it in the public health service. And I went in 1969 to Nigeria as a public health service officer to work on yellow fever, there was a big epidemic at that time, and I spent the rest of my career working in the laboratory at the CDC and then the army at Fort Detrick on yellow fever and other hemorrhagic fevers, and I did a lot of field investigations of outbreaks as well as laboratory research.

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Descriptions of the disease, and an outbreak

Monath: All the outbreaks that I experienced were in remote, rural areas of Africa, and a couple in South America. The thing I'd like to relate is that this disease, as it did in the times that I'm sure Dr. Humphreys and Dr. Pierce will allude to, created huge fear in the population at the time. All the schools were closed. There were makeshift hospitals. People were getting rudimentary care. The graveyards around the villages and town affected were filled up with fresh graves. Newspapers were filled with stories. People coming from elsewhere just driving through the area would roll their windows up -- in the tropics -- and drive straight through. There was a complete disruption of society; I'm talking about the last outbreak I worked in Nigeria in 1987, so we're talking about current events. This disease still occurs in epidemic form, particularly in Africa.

Pierce: It's a viral hemorrhagic fever and it attacks the liver and destroys the clotting mechanism and the people usually end up with what's called black vomit, toward the end of their life, and actually they're bleeding into their stomach. And the black vomit is just the blood that comes up from that. And they probably die from an overwhelming shock type syndrome.

Monath: People turn yellow because their liver stops functioning, they have bleeding, they go into shock, and they often go into coma towards the end and remember that the fatality rate, particularly among hospitalized people, people that come to medical attention can be as high as fifty percent. So this is a devastating, very rapidly fulminating fatal illness.

Pierce: Even now over a hundred years since the etiology of the spread of yellow fever was determined medical science still has difficulty treating the disease; there really is no cure for it and you end up treating the symptoms which, by the time people get to you sometimes, they're so far advance that you really can't bring them back.

Humphreys: Just one point about the mortality. If you look in the textbooks you'll see numbers of 10 to 20% mortality, but that includes all the light cases. And people, particularly in the 19th century, didn't see those people who were slightly ill, so the perception was that half the people who got it died. And it hit very rapidly.

There's a scene in a movie with Bette Davis, I think, where there's a man at the bar and he just crumples to the ground -- there's a yellow fever epidemic on and everybody backs away in horror, they know he's been struck down. So the panic component of it -- a quite reasonable panic -- was one of the major features of this disease in the 19th century. Even though tuberculosis, say, killed a lot more people, yellow fever is what caused the panic.

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American history and yellow fever

Humphreys: The main factor in yellow fever's spread in the nineteenth century has to do with shipping and commerce from the tropics. Cuba was a major source of it; you could ask where did it come from to Cuba, but in the United States, ships that came from Cuba, ships that came from Veracruz, or further south, Latin American ports, brought the fever in.

In Civil War and Reconstruction, there was much less yellow fever. There's a hiatus because of the federal blockade of the south, and the rigid control, particularly of New Orleans by Union troops from 1862. Yellow fever doesn't reemerge as a major problem in the South until the 1870s. So it's directly tied to trade and in the 1870s, the big epidemic of 1878 was directly tied to the resurgence of the railroad lines in the south, rebuilt after Sherman and his colleagues destroyed them, just in time for yellow fever to travel out of New Orleans as far north as Ohio, on boats and trains.

Monath: There really are two critical elements, one: the virus has to be introduced, as Dr. Humphreys said, the true endemic areas in tropical South America were the source and then it moved in on vessels to the United States, but the other critical element was simple sanitation. The transmission depends on a mosquito that breeds in close association with people, and man-made containers containing water. And so in the nineteenth century we had the situation where there was opportunity for the introduction of the virus, but then, because of just the low level of sanitation, an the exposure of people to mosquitoes that were breeding in close association around houses that allowed the spread of the virus in a city or town. So those are the two critical things, and of course both have changed over time, with respect to our means of transportation and also the level of sanitation that would allow epidemic spread in the United States.

Humphreys: The last major outbreak in the United States was in 1905 and I don't think we know a hundred percent why it disappeared. I think the main factor was the fact of the American military presence in Cuba and the very strong campaign against yellow fever that controlled the disease there. It's the control of yellow fever in the sources that is probably the major factor in controlling yellow fever in the United States. I mean nobody would say that New Orleans was all that clean in 1920 but the lack of importation I think was probably the major factor and it relates to what happened in those other places. Of course it's still there in Latin America. Dr. Monath could probably speak to that, but it's isolated in remote tropical jungle areas.

Monath: I would completely agree with Dr. Humphreys -- key centers in Latin American ports were the exit strategy for the virus. And there was an effort after Walter Reed to apply some rudimentary approaches to mosquito control and it focused on these key centers.

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Aedes aegypti: the mosquito

Monath: An interesting question we may come to is... well, there have been very interesting stories around the mosquito that carries yellow fever and attempts to control it and the failure to control it and what are the chances today, that yellow fever could be reintroduced in the United States because the mosquito is still here.

Humphreys: There is the presence, at least in Durham, North Carolina of a new "aedes." The aedes species [of mosquito] is the species that carries yellow fever, at least in the United States and the western hemisphere. And we now have the pleasure of the company of Aedes albopictus which is a Japanese aedes species that has been imported here, the so-called "Japanese Tiger Mosquito." And for a talk I gave several years ago, I sat on my front porch and captured eight of them easily to put in a peanut butter jar full of alcohol. So we've got the mosquito that can transmit it, it's a question of reintroduction.

Pierce: Do we know if that particular species can transmit yellow fever?

Monath: This was a great concern when this mosquito appeared in the [nineteen] eighties in the U.S. and spread rapidly. It is not a very efficient vector for the virus though. There have been a number of experiment studies but that does not at all exclude the possibility that it could play a role in transmission. Aedis aegypti is a much better vector, but the habits of the tiger mosquito are such that it could play an important role bridging the virus out of the jungle environment in South America to the urban cycle. So there are still a lot of unknowns, but it's an interesting sidelight to the history.

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A cure? And the vaccine

Pierce: [Yellow fever] is such a rare occurrence, in fact, has not occurred in the United States in over a hundred years -- except for a few people who traveled to South America and brought it back with them and fortunately there were no secondary cases -- that nobody's particularly interested in looking at [a cure]. It's not common enough to grab somebody's attention, to try to assess that problem. There has been a very effective vaccine for sixty years now, I guess and that is used widely and it does prevent the disease. Of course, you have to get the vaccine. The last gentleman that died in the United States went on a fishing trip to South America with his friends and several of his friends got the vaccine and he did not and unfortunately he contracted yellow fever from a mosquito bite and actually died from it.

Humphreys: I think it's worth pointing out, too, that's it's much harder to kill a virus that it is to kill bacteria. We don't have very many anti-viral drugs at all. There's a few, but -

Pierce: We can't kill the common cold, can we?

Humphreys: Exactly. We can't kill the common cold. Think of all the money that's poured into controlling the AIDS virus and they've got it controlled, but not dead. The drug companies don't spend much time worrying about malaria because of the lack of an American market with American insurance to pay for it; yellow fever even more so.

Monath: One thing to say is that, as Dr. Pierce pointed out, the availability of this vaccine has really been a tremendous component to control of this disease. However, if this virus were to come back to the United States, the supply of yellow fever vaccine in the United States would not cover half of a moderate sized city.

There are a number of different ways to go about controlling an outbreak, mosquito control and so on. But I can assure you that if that were to occur, or in a setting where yellow fever were epidemic a treatment would be a very nice thing to have. And there are a number of promising drugs but as was pointed out, there's no financial incentive for a drug company to complete that very expensive development of these compounds. There are some very closely related viruses to yellow fever where there is more of an incentive to develop a drug, and it's likely that a drug would work also against yellow fever virus, but I think it's correct that it's very unlikely that we'd have a treatment, even though it's feasible, that we'd have a treatment because of all those obstacles.

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Yellow fever as biological weapon

Pierce: There's been some speculation that yellow fever could possibly be used as a biologic warfare agent. Just wondered what Dr. Monath thought about that. Seems pretty far fetched to me.

Monath: We weaponized yellow fever in the United States.

The idea was to actually grow large numbers of Aedes aegypti mosquitoes, which was accomplished at Pine Bluff Arsenal, and to infect those mosquitoes with yellow fever -- a challenging point -- and then to release that. I think the point was that, whoever was the unfortunate recipient of this weapon would constitute the amplification cycle itself. Because, in an appropriate place you just need to start something, that all the elements, vector, host and so on were there, so that was the premise.

Now this was never used, fortunately, but like many other areas in biological warfare, it's nasty to talk about, but this actually was an intention of the United States government back in the Second World War time frame.

Pierce: How would you go about giving the yellow fever to large numbers of mosquitoes?

Monath: That's a very good point because presumably they were going to infect non-human primates and feed Aedes aegypti mosquitoes, you know, large numbers of them but all the technical bugs, no pun intended, weren't worked out at that point.

Pierce: The idea though, the government has looked at it, albeit years and years ago, the idea of being able to do that today, probably the same technical difficulties would be there.

Monath: Absolutely. There's actually a publication on this, maybe a couple publications on this effort by the United States government, but it's not widely known.

Humphreys: One of the points that Dr. Monath just made is that if you're going to grow yellow fever, you have to have primate species or higher, if you will. You can't grow yellow fever in guinea pigs, or mice, or frogs, or some other species that's easy to accumulate in the lab. And primates aren't cheap and they're not widely available in the United States unless they're people. So it does make it harder to do this, which I suppose is fortunate. But it was an obstacle in yellow fever research all through the twentieth century: finding an animal model to study the disease in.

Monath: But you're right. Fortunately this never got beyond the research stage.

[Laughs of relief]

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The incubation of yellow fever

Monath: The virus has to be ingested by the mosquito in a blood meal, on feeding, and then is replicated in the tissues of the mosquito and has to make its way to the salivary gland and then be secreted in saliva for transmission. The mosquito, in the meantime, is not induced to feed until some days later. That extrinsic incubation period is temperature dependent, but seven to ten days or so.

There are a number of important things that are happening in the mosquito. One is that the ovary of the mosquito, or the ova ducts, become infected and therefore the female mosquito is able to pass the virus in the egg to subsequent generations, which is critical to maintenance of the virus in nature. So there are two things happening, an ability to transmit by bite but also "vertically" through the egg.

Some of these mosquito borne viruses adversely affect the mosquito in subtle ways; I'm not aware that yellow fever virus does that to the yellow fever vector. So there doesn't seem to be a disadvantage to the vector but obviously the vector is playing a critical role in the maintenance of the [virus].

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The search for an end to yellow fever

Pierce: We had an occupying army in Cuba, and we had soldiers who were coming down and dying from yellow fever and so it was a political issue as well as just a health concern for everybody. General Sternberg who was the Army Surgeon General at the time, spent at least 25 years of his life studying yellow fever and he was very interested, not only to protect the troops, but he was scientifically curious about the cause [of the disease] and trying to get an answer to that question is the reason he sent Walter Reed down there.

Humphreys: In the early 1880s, the bacteriological revolution in medicine just burst onto the medical science scene, and very rapidly physicians found the germs for tuberculosis and meningitis and pneumonia and everyone was sure there was a yellow fever germ. And it got "discovered" over and over again in those two decades. Sternberg was one of the people who was a great debunker of those yellow fever germs and it really got to be a race to find it. Two researchers in the Marine Hospital Service (which would become the Public Health Service ) thought they had a handle on it and the army doctors, Walter Reed and his colleagues ,were sort of in competition with them. And Reed won.

But there was this great sense of a race, both for national pride (there were scientists in other countries who had their favored yellow fever germ) and even institutional pride within the Federal agencies to find the answer to this puzzle. And of course, they didn't know yet, about viruses. They knew about bacteria and you can see bacteria under the microscope, you can culture them, a lot of the other diseases the bacteria grew in laboratory animals like guinea pigs and rats. Whereas a virus you can't see under a regular microscope; they didn't even have a concept of an agent of disease that was that small until after 1900. And it proved to be particularly difficult to grow in lab animals, so it was a big race, both to find the organism, and then find how it spread, and of course Reed's group mainly found out how it spread.

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Jesse Lazear and self-experimentation

Pierce:I think that self-experimentation was much more common years ago than it is today. Dr. Lazear was a member of the yellow fever board. He was a civilian physician who was given a contract appointment in the army to go to Cuba and study infectious diseases. He had done some work with malaria and he was in his early thirties and trying to make a reputation for himself. He was interested in mosquitoes, had already collected mosquitoes before Walter Reed got there, and was very interested in them and was kind of disappointed when Reed got there, they originally started to try to find the germ. Spent about a month doing that and without success (which they didn't think they would have) and then they sort of turned toward the mosquito.

He was given the responsibility since he had some experience, of raising the mosquitoes that they got, mosquito eggs from Dr. Carlos Finlay, and over the course of time, he would raise the mosquitoes and actually did some experiments having them bite yellow fever patients in the hospital -- that was called "loading" the mosquito -- and having the mosquito incubate for a period, usually for a few days, and then bite a volunteer. He had actually had about nine volunteers bitten by mosquitoes, including himself, without any success.

And then he was a little discouraged by that but he continued the work and one of the other doctors, James Carroll, agreed to have a mosquito who was becoming weak and needed to have a blood meal bite him. The mosquito bit Dr. Carroll and a few days later, he became symptomatic and then it became pretty evident that he had yellow fever. Now he was not a really solid scientific case because he had not been isolated, quarantined away from mosquitoes or other people and could have picked up yellow fever some place else.

After Dr. Carroll got sick, Dr. Lazear went to the Army hospital and sought out a volunteer, a soldier who had been in the Army hospital for several months with apparently a relatively minor illness, there had been no yellow fever at the Army compound. This soldier whose name was Dean volunteered, he was bitten by the same mosquito that bit Dr. Carroll and he became sick with yellow fever and it was really the first, solid scientific case of mosquito transmission.

Walter Reed was not in Cuba at that time. And I think he certainly found out about Carroll's illness and probably found out about Dean's being bitten. Now Dr. Lazear was not a career army doctor and had only been in the army a few months as a contract physician, and Carroll was at that point sick.

The commander of the military post where the hospital was didn't even know about it so I'm sure that Reed didn't want Lazear sticking his neck out. Carroll was still sick -- the question was [whether] he might die -- and so my guess is that Reed communicated with Lazear in some way and said stop doing these experiments.

There is a notebook that came from the yellow fever board where on the 13th of September, 1900, Lazear wrote a note that said "guinea pig number 1" and then talked about doing an experiment with having a mosquito bite --several mosquitoes actually -- bite guinea pig number 1. Well the 13th is the date that Lazear, when he became ill on the 18th, told people that he was bitten by a stray mosquito in the yellow fever hospital in Havana. There is no evidence that the group did any animal experiments at all -- no one thought that animals could carry yellow fever, or were susceptible to it, and so my speculation is that this 13th of September note in this laboratory book is Lazear's notation of himself being the guinea pig.

He told a story that he was bitten on the 13th in what was called the Las Animas Hospital in Cuba, in Havana, that he became ill on the 18th, and died about a week later. During his illness he told people he had been in the Cuban hospital and had been bitten there. It's interesting that if there was a stray mosquito in the Cuban hospital that was loaded with yellow fever, no one else was bitten, and nobody else got sick. And all of the people that were there at the time that worked with Lazear were convinced he had done self-experimentation. There's not any real proof of that but I think the evidence sort of supports that.

He became ill, had a very serious illness, died from it, and then it was a couple of weeks before Walter Reed actually got back to Cuba.

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Walter Reed's reputation

Pierce: My speculation is that most of Walter Reed's reputation today is based on the hospital that's named after him. I usually asked the new interns that came into Walter Reed [Army Medical Center] what Walter Reed was known for and half of them would say yellow fever and half of them would say malaria. And so I don't think that, even in the scientific community, that Walter Reed is really known for his scientific accomplishments; I think he's known because the Army hospital is named after him and during course of wartime, a lot of casualties come through there and the hospital receives a lot of publicity.

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Vaccine

Monath: [Yellow fever] was one of the few of what were called "quarantinable diseases" that had the potential to spread across borders around the world. So [the World Health Organization (WHO)] actually played a fundamental role, going back to before the time it was actually called the WHO, in setting requirements for vaccine manufacturing, and distribution and so on.

The vaccine is a live, weakened virus and as such it's quite unstable. And even though improvements have been made, one of the concerns was that the virus would lose its potency if it wasn't handled properly. And so a system was developed of vaccinating centers which were approved by governments that insured the proper handling of and inoculation of this vaccine . And those vaccinating centers were approved by the World Health Organization and published as such. That responsibility was then delegated to governments and, in the United States, down to the state level. But the system still exists where you can only get this vaccine at an approved vaccinating center, where the government has made some assurances of proper handling.

So this is a vaccine that, although it's approved by the Food and Drug Administration, you can't find much information in the Physician's Desk Reference because this is for a very special population and distributed in a special way.

It's an old, kind of historical artifact. In today's world, the vaccine actually is quite stable and you could avoid all of this system of distribution if you wanted to.

Humphreys: I think that, from the perspective of being a primary care physician, if one patient a year, in my population which include Duke faculty, who are prone to world travel, if one person a year asks me about it, I'd be surprised. I certainly don't know the areas in Latin America or Africa where they need to have it, so we have a travel clinic and those people keep up with all that. You know, where in the world is malaria resistant to certain drugs? Where do people need to have yellow fever vaccine? And it's the kind of expertise that any individual primary care doctor is not likely to be able to keep up with.

I didn't know all this about the vaccine itself and what I would add to that that this not an area that most doctors have knowledge to properly administer the vaccine.

Monath: That's quite accurate. The other thing to say is, that this vaccine was considered one of the safest vaccines ever developed. And there were no real concerns about safety. That has now changed in the last decade and we now recognize that there are some really severe and significant, serious adverse events.

So you have the problem in deciding when to give it, whether the risk of the vaccine is outweighed by the risk of encountering yellow fever virus in the wild when you go on your trip. And as Dr. Humphreys points out, that judgment call, it's important that the physician be knowledgeable about the risk of the vaccine, and of the epidemiology. So people who run travel clinics generally have some knowledge about that. The vaccine is both underutilized, as has been pointed out, we've had deaths among travelers who don't get vaccinated because they don't know that they should be, and we also have over-utilization, the vaccine may be given to people who don't even travel where they have a risk of getting it.

Then there're the concerns about the safety of the vaccines. So it's a complicated area that really belongs in the hands of the travel medicine people who understand these issues, and so the vaccinating center is actually a good one currently.

Humphreys: I think during WWII, the yellow fever vaccine was contaminated with Hepatitis B at one point and some soldiers got that.

Pierce: That's true, there were actually thousands of soldiers who got Hepatitis B. Of course, they didn't call it that at that time and I think there were 84 deaths among those soldiers from that vaccine.

Humphreys: I wonder, perhaps Dr. Monath knows, perhaps it's classified: Are our soldiers who are vaccinated against bioterrorism -- targets if you will -- being vaccinated with yellow fever now, if they go to places like Iraq where of course there's no risk of yellow fever from a natural source.

Pierce: When I came on active duty in 1971, I received yellow fever vaccine. I never did get a booster dose like they recommend, every ten years, but I did get the initial vaccine in the early nineteen seventies. Of course, the Vietnam War was going on then but there's been no yellow fever in Southwest Asia but everybody that came on active duty got the vaccine.

Monath: On the biological weapons side, despite what we talked about earlier, none of the actors, they weren't really working on yellow fever as a biological weapon aside from this mosquito thing, which goes way back. No other state sponsored biological program that we knew about was working on yellow fever. There's such a good vaccine that this was not considered to be [effective].

The reason for military vaccination was that troops get deployed all over the world and even though you may be going to Korea on your assignment, a month later, it could be Africa or tropical America, so deployed military typically got vaccinated -- not because of biological weaponry threat, but because they may be moved to an endemic area.

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Does the presence of West Nile virus, Eastern Equine Encephalitis and other mosquito borne diseases predict a return of yellow fever?

Monath: I spend a great deal of time being asked this question and I'm happy to respond to it. [laugh]

What I can say is that I think most of us in the field of arthropod borne viruses consider that the risk is higher today, than it was, say, twenty years ago. For a lot of different reasons. One of them being rapid air travel. There are international flights from deep in the endemic areas now, such as [from] Aquitos in Peru, right in the heart of the Amazon, into Miami. And you can move from an endemic -- theoretically, move by air from an endemic area within the incubation period of the disease almost anywhere in the world.

The barrier is, most of the people who are traveling on international flights and so on are really not likely to be exposed to this virus which is in, still in pretty remote areas in the jungles of South America, or places in Africa where people aren't moving in and out of international airports.

It comes back to what Dr. Humphreys said, the risk in the old days were these key centers, the ports in which sailing ships could leave South America and reach North America, or leave Cuba and reach North America. So there's a fundamental barrier there, for people to get infected, to get on an airplane and move quickly.

The other thing is that if they land in Miami, even though the mosquitoes are there -- there are tremendous barriers between the mosquito and people. People live in screened houses, air conditioned, they're sitting indoors watching TV instead of sitting on the doorstep getting bitten.

We've had introductions of a related virus, dengue, into the United States on multiple occasions, and it's never taken off, even though it is much more capable than yellow fever of being transmitted person to person via this Aedes aegypti mosquito, so I think there are tremendous barriers. But air travel, and the reinvasion of South America by Aedes aegypti -- there was a time when there was a great effort to control this mosquito, because of the threat of yellow fever, driven by an interesting personality, Fred Soper, in the forties, fifties sixties -- but, with the growth of cities and the senescence of these vector control programs, Aedes aegypti is back in South America, in all of these key centers that we talked about before.

So, there are reasons why the risk is increased, there are also barriers, but most of us feel it's a matter of when -- not if -- yellow fever will reappear.

Humphreys: One of the issues is the balance between spraying insecticides and the risk of disease. We are, as a culture now, very sensitive to the risk from insecticides, unlike my childhood when we'd run around after the mosquito truck when it drove through the neighborhood spraying whatever toxic chemical it was spraying, perhaps DDT. With West Nile virus or Eastern Equine Encephalitis, we're talking a few cases, on the other hand, if we had a major yellow fever outbreak that was killing lots of people, the tip in the balance of fear of insecticide, fear of disease, is going to go way over to fear of disease and the planes would be in the air spraying, I would think, the insecticides that would stop the disease fairly quickly.

Plus, people would get so hyper about wearing their Deet [insect repellant] and not being outside... The fear of the mosquito is largely gone, people don't look down, see a mosquito biting them and think "I'm going to get sick," but if we returned to that fear, then I think the attack on the mosquito would be so vicious that the epidemic would be stopped, fairly quickly.

Monath: Unfortunately, we've had the same situation with dengue virus epidemics, same mosquito... not as fatal a disease fortunately, but in places like Puerto Rico. And the attempts to kill this mosquito by spraying is a dismal, absolute failure...

Humphreys: Oh!

Monath: It just doesn't work. Now, you're absolutely right, you'd do it, and it may have some impact, but I think yellow fever is such a dramatic disease that it would be recognized, if not the first case, the first cluster of a few cases, would be diagnosed rapidly because we have the tools to do that, and the contacts -- the source of the outbreak -- would be understood quite quickly, and with vaccination and some spraying and alerts to avoid mosquito bite, I seriously doubt we could ever see another 1905, for a lot of different reasons. Principally because we're on top of infectious diseases and we'd recognize it early in this country and it's unlikely that we'd have a dramatic, large epidemic.

Pierce: For a case to come into the country, an individual would have to be bitten by an active yellow fever mosquito somewhere overseas, would have to get on an airplane, get back to this country, become ill, the virus is only in the bloodstream, as I understand it, from just a few days so a mosquito that was able to carry yellow fever, the Aedes aegypti, would have to bite the patient during the third to fifth day of illness. That mosquito would have to incubate the virus for ten to twelve days or longer, having to survive that time, and then would be able to transmit that virus to other people that that mosquito bit.

And so as was said, the barriers of the mosquito getting to people, are much greater these days than they were before. Particularly if the person is sick, nowadays, if a person is sick, they are going to be indoors and it's unlikely that there are going to be any mosquitoes in the environment that they are in, either at home or in a hospital that would be able to get to them to be able to bite them at the time that they were still viremic. And so it would be very unusual for this disease. to spread even if a case came into this country, I think.

Monath: The other point is of course the virus is circulating in the blood before the illness reaches the stage at which it's easily recognizable. So the viremic period in which mosquitoes can get infected is a relatively early stage and before the jaundice appears, and so on. And added to that there are, for every person that gets a full blown illness, there are probably another six that have a milder form -- as Dr. Humphreys pointed out earlier, a milder form that can escape medical attention.

So it is possible that things could... if everything worked right: the person comes in on the airplane, he's in the viremic period, gets bitten by some mosquitoes, there's some infected mosquitoes in the environment, other people get bitten, things could get cranked up a while. But I think that as soon as the first person, with the full blown illness got sick, and got diagnosed, there would be a huge effort, to control the situation. So it's a little more complicated, but I think because of the features of this viremic period being early in the illness and some people having milder infection that could be the source of infection in mosquitoes -- an outbreak situation could occur.

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Institutional or governmental preparedness for pandemic disease?

Humphreys: One of the problems we saw with both SARS and bird flu is -- you see a similar situation with yellow fever in the nineteenth century that people in Louisiana wanted to hide their fever from people in Mississippi or in Texas because it affected trade. And then the people in Texas and Mississippi said the people in Louisiana are lying. One of the reasons justifications for Federal intervention was because the states couldn't be trusted. Well, you see a similar international situation where one country doesn't trust what another country's reporting and the country with an infection doesn't want to report it because it will affect tourism or trade or what have you. But we don't have an international body that is strong enough to take control of the situation. Whether we should or not is a political question. But the WHO does what it can, but it doesn't have that sort of international power.

Monath: The Chinese tried to hide the SARS epidemic for a long time. That's a good point. I think that's to avoid some of the stigma that's attached to the reporting of a specific disease. The WHO has recently gone to what they call "syndromic surveillance" so you can report an outbreak of diarrheal disease and so on without labeling it something that would lead to the kind of actions that Dr. Humphrey's described. But it's a very, very complicated issue.

Each infectious disease typically has its own specific features with respect to surveillance, control and prevention, all those things, so you have to develop some specific strategies. Of course there's a great deal of attention on the threat of pandemic flu right now and the federal government has a plan, they've now asked the states to create their own individual plans for containing and dealing with the whole range of health issues, social issues and so on that would come about in the event of an outbreak.

Overall I think we are dismally unprepared -- as a planet -- to deal with a threat of a true pandemic disease, influenza being the biggest threat of all, of course.

Pierce: I work for a federal agency and although the pandemic flu is not something I'm involved in, in the meetings I attend, it's mentioned at least every week, that our agency is working on their plan, they've got a plan, they're concerned about it, they're paying attention to it, and certainly, the agency I work for, it's high on our list of things we're concerned about.

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