Puerto Rico y el Tercer Planeta: Roundtable Discussion on Yellow Fever

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.

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:

Participants

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.

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.

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.

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.

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.

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 malariabecause 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.

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]

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].

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.

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 toCuba 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 Reedgot 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.

Puerto Rico y el Tercer Planeta

Monday, November 22, 2010

Roundtable Discussion on Yellow Fever

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