Epidemics in Western Society Since 1600

HIST 234 - Lecture 16 - Malaria (I): The Case of Italy

Chapter 1. Malaria: Relationships between Diseases and Genetics [00:00:00]

Professor Frank Snowden: I'd like to welcome you back, and hope that you all had really good breaks. We'll be talking this week about malaria, both today and on Wednesday. And I think I may be saying a couple of things that you may find surprising. I suppose — this may be an assumption — that when I mention malaria, that most of you think of it as an exotic tropical disease, and probably think that it's very distant from us, and has relatively little to do with the modern world, or with modern history, and probably nothing at all to do with the United States and with those of us here. But the point I'm wanting to make, this time and next, is that the reality of malaria is quite different from that; that when we've come to talk about this disease, I could say that of all human diseases it's one of the oldest; and some question, a question that some of you might ask me, is of all the diseases in our course, which is the one that, in the aggregate, has caused the most human suffering and death? And I think that of all of the diseases in our course, it's probably malaria which has that primacy.

The relationship of human beings to malaria has been so close, and so extensive, that we could also say that we, as a species, and malaria, as a disease, have evolved together, and that the human genome bears the imprint of our experience with malaria. Good examples of that are a couple of genetic diseases that I'd like to mention, one that may be familiar to you also, one being sickle-cell anemia, a second being thalassemia, and a third being what's called Duffy negativity. Now, all of these are genetic diseases, and they have in common the feature that there's a difference between the trait which — it's a recessive in all three cases, the recessive features.

And, so, a heterozygote — that is, a person who has just one X chromosome, rather than X and Y, expressing the trait for the disease — enjoys a protection from malaria. But if, in fact, you are a homozygote and have it on both X and Y chromosomes, and you develop the syndrome for sickle-cell anemia, instead you have a terrible disease that leads to — it causes sickle cell — it affects the quality of the hemoglobin and the red cells, and therefore it leads to anemia, occlusion of blood vessels, sometimes hypoxia, and serious respiratory diseases. So, it's a fatal illness in many cases. But if you have the trait, then in a highly malarial area you have a great selective advantage in enjoying a great deal of resistance or immunity.

In terms of human evolution, in intensely malarial areas there was a strong Darwinian pressure for the retention of the sickle cell trait. The same would be true of thalassemia, which affects not the quality of the red cells but rather their quantity, and leads to again terrible complications in homozygotes, and with asthma and terrible anemia, or Duffy negativity, which is another genetic disease that leads again to terrible diseases.

Chapter 2. Scope [00:04:45]

Another feature of malaria, apart from the fact that our genome has actually been strongly influenced by our history with malaria, is that until very recently it extended more or less across the globe, affecting not only the tropics in Africa, Asia and South America, but also the north, including most of Europe and North America. So, I thought I'd show you a map of malaria in the United States in the nineteenth century, just to give you an idea — this is 1882 — to show how extensively prevalent it was in this country, as recently as the late nineteenth century. And indeed it comes up — Oliver Wendell Holmes wrote a book on malaria in New England.

This is a map of 1912, when it's receded a great deal and is primarily a disease of the South. But remember that it had a major impact on public health in this country, until the end of the Second World War, which is when it was eradicated in the United States. It's sobering to remember, for example, that the Centers for Disease Control, the CDC, in Atlanta, was originally founded as an anti-malarial agency, and that the disease played a major role in the settlement of the West, and in the economic and social development of the South. And if you read Mark Twain, for example, you can read a great deal about shivering along the banks of the Mississippi River. In terms of our discussion of relationship of diseases to the big picture of history, malaria is also one of the diseases that I think helps us to make the case most effectively.

Malaria, it's now believed, played a major part in the fall, for example, of the Roman Empire, when an epidemic offalciparum malaria led to the disruption of agriculture and the Roman Legions. And I'm not trying to say that malaria caused the downfall of the Roman Empire. I'm saying that it was a major factor, leading to the kinds of military problems and social dislocation that we can't ignore in discussing that major series of events. It's led to major impacts on the outcome and on the conduct of warfare. One need go back only to the Second World War, when malaria was a major preoccupation of the armies on both sides of the conflict. It had an enormous role and impact on European expansion and colonization, and one of the great challenges to colonial expansion, in the Indian subcontinent, and in Africa, was what to do about the problem of malaria.

It's affected the pattern of human habitation and settlement, the way that cities and towns are built across the landscape, where human habitation often was a form of prophylaxis for malaria, and people lived far from swampy areas, and often on high ground, above dangerous wetlands low down. Malaria is also a major factor in economic development and under-development today, in ways that we'll be discussing. A decisive factor in its prevalence, and in its history, has always been the relationship of human beings to agriculture and the environment; that is to say that intensive forms of agriculture, with modern livestock raising practices, modern crop rotations, water management, ecological sanitation, with improved housing and conditions of diet, wages and clothing, have led, wherever they've been introduced, to a spontaneous recession of malaria and much better health outcomes.

And this has been a major factor in the divergence between the global North and the global South; the North with modernized intensive systems of agriculture, and in the South instead the persistence of extensive forms of practice that are conducive, for reasons we'll be examining, to the transmission of malaria. So, malaria both reflects and reinforces developmental differences and disparities. Now, let's remember that malaria is vitally important in our world today. Let me give you an example of some of the pictures that represent the global burden of malaria, and let me show you a map of where malaria is prevalent today; that is, in the twenty-first century. Indeed, at the moment, one can say the statistics are extraordinary.

About 500,000 people become seriously ill of malaria every year. Approximately a million people die of it, the majority of them being children under five, and pregnant women, concentrated particularly in Sub-Saharan Africa. In fact, one can say that a child dies of malaria, in Africa today, every thirty seconds, making this disease a global public health emergency, along with HIV/AIDS and tuberculosis. Let's look at more particularly the areas. This is the epicenter, if you like, of the present day resurgence of malaria as a major, major public health problem. And there are — malaria kills 3,000 children every day of the year. The burden of malaria though is greater than statistics for mortality and morbidity suggest. It is, for example, one of the worst possible complications of pregnancy. It leads to high rates of miscarriage; to maternal death through hemorrhaging and severe anemia, and all of the sequelae that follow from severe low birth rate.

Malaria also can be transmitted vertically; that is, trans-plancentally, from mother to fetus, and can lead to the birth of infants who are congenitally infected. We also need to remember, as we'll say in a moment, that malaria is a major immunosuppressive disease, and its victims therefore are highly susceptible to other opportunistic infections; especially respiratory infections, tuberculosis, influenza, pneumonia. In those areas of the tropical world where malaria is hyper-endemic, and transmission continues throughout the year, the population at risk can be infected, re-infected and super-infected every single year. If the victims of malaria survive, they possess a painfully acquired immunity. But it comes at a terrible price, because repeated bouts of malaria lead to severe neurological deficit and cognitive impairment. The results are ineradicable poverty, illiteracy and compromised economic growth, a stunted development of civil society and political instability.

We'll be talking in a moment about Ronald Ross, who was the Nobel Laureate, who was one of two people who discovered the mosquito theory of transmission for disease. And he wrote, quite movingly, that those malaria doesn't — in areas where malaria is prevalent — "those it doesn't kill it enslaves." Malaria, in other words, in our present world, is a major contributor to inequalities between North and South, and to the economic and political international dependency of third-world countries in the tropical world. Well, let's talk about the — malaria also will be of interest to us because it's an extremely complex disease, and so we need to spend a little bit of time talking about how it's transmitted, and about its effects on the human body, in order, after that, to talk about how the discoveries that led to our understanding of it, and to the impact on society and on history.

Chapter 3. Etiology [00:15:03]

Until the end of the nineteenth century, malaria was thought to be explained by a theory that you already know, by miasmatism. In other words, malaria was a form of bad air. In fact, that's what the word means, from the Italian mala, bad, and aria, air. So, malaria was bad air that somehow a susceptible person inhaled, and it got in his or her body, or was absorbed, perhaps, through the pores of the skin, and led, in susceptible people, to this terrible fever. It was also sometimes called paludisme, from the word for swamp; so it was swamp fever. So, the disease then was absorbed or breathed in, in some way.

In fact, malaria isn't one disease. It's a family of four different diseases, caused by a parasite, with an extremely complex lifecycle. The parasite is known as a plasmodium, and there are four species of plasmodium that cause human malaria. And I have them on your handout. They're Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, andPlasmodium ovale. For the purposes here, the first two, Plasmodium falciparum and Plasmodium vivax, are the most important, medically and historically, and the ones we'll be talking about mostly. Now, the plasmodia differ fundamentally from the other microbial pathogens we've examined so far in the course — bacteria, for example, and viruses — in that they're much more complex life forms, with complex lifecycles that we need to unravel.

Plasmodia were discovered in 1884 by Alphonse Laveran — there he is — a French Army doctor working in Algeria. It turns out that the plasmodia don't exist free in the environment at any stage of their lives. Instead, they're adapted to live either in the body of human beings, or in the gut of certain species of mosquitoes. And — there we are — this is an anopheles mosquito doing its thing; that is to say, having a blood meal, which is the way that malaria is transmitted from person to person. The plasmodia — this is again, in a more schematic way, it gets the point across about the relationship of human beings and the mosquito.

Plasmodia migrate in the body of the insect to the salivary glands in the biting apparatus. So, a biting mosquito, like this one, is in effect an extremely efficient vector. It's sometimes referred to as a flying syringe, because what it does, the mosquito does, is to inoculate the plasmodia directly into the bloodstream of the host. At this stage the parasite — we'll move to look at what happens next. The first thing we have is the mosquito taking a blood meal and inoculating the plasmodia directly into the bloodstream of the unfortunate victim.

At that stage — and here we'll see one of the points about the plasmodia, is that it undergoes a series of morphological changes in becoming distinct stages in its life, both in the human body and in the body of the insect. Initially when it's injected, it's known as a sporazoite, and what it does next is it migrates, after just a few hours after inoculation — say you were bitten right now, within a few hours the plasmodia in your bloodstream would have migrated to your liver. And this begins the incubation period in which the plasmodium reproduces — that is, asexually — in the liver. And you see its reproduction. And then after just a number of days or weeks, it's released again now in a new phase, this time known as a merozoite, into the bloodstream. So, it returns at that point to the bloodstream.

One of the points of the migration to the liver is that when it's in the liver, it's safely beyond the detection of the human immune system, and so it reproduces safely in the liver and then emerges, much more numerous, into the bloodstream in a new phase in its lifecycle. At this point in the bloodstream what happens is that the merozoites — that's what they're now called, the new name of the parasite for that phase — it enters into — it attaches itself to and enters into red blood cells or erythrocytes. Once safely inside the red blood cell — again it's not detected by the immune system — it reproduces asexually — and you can see it doing so — until at a certain point it has destroyed the red blood cell and ruptures the red blood cell, and the parasites return once again to the bloodstream. I have — this is a picture.

These are of the — by electron microscope — of the actual rupturing of red blood cells, and the emergence, once gain, of the parasites that have just reproduced, returning to the open bloodstream. At that point, the much more numerous merozoites keep repeating this process of invading red cells, reproducing, destroying the red blood cells, and then bursting them at periodic intervals. The interval of time that it takes is determined by the species of plasmodium. ForPlasmodium falciparum and vivax, it's every forty-eight hours. And so for Plasmodium malariae, it's every seventy-two.

Now, eventually, among the brood of merozoites — that is, let's see, again — after it's gone through a number of cycles, they produce among their offspring what are called — it's a new morphologically different stage in the lifecycle, and that is gametocytes, that are male and female; and these are in the open bloodstream. And then the next anopheline mosquito that takes a blood meal, as it does so it sucks up the male and female gametocytes that reproduce sexually this time — we see them here — in the gut, in the body of the female mosquito, and then that begins the phase of life in the body of the mosquito where once again we find it reproduces; and eventually it leads to the production of sporozoites that migrate, once again, to the biting apparatus, the salivary glands of the mosquito.

The mosquito again takes an infective bite and then — in its next blood meal — and the whole cycle, this complex cycle of both asexual reproduction in the body of man, and sexual reproduction in the body of the mosquito, the cycle is then complete. Now, let's return for a second to the plasmodia and to the insect. And let me just deal with the fact that in order — the reason that the female — and it's only female anophelines that take blood meals on human beings — and the reason that the female anopheline does that is that it needs blood in order to mature its eggs and to lay them. Having taken a blood meal, she's able to mature her eggs, and at that point lays them in water, and they pass through the cycle of larvae, pupae, and then the adult mosquito known as an imago.

Now, what happens at that point? It takes about a week for the eggs to develop as larvae, pupae and then adult mosquitoes, and then the mosquito is ready to take flight and to visit you and me. From the breeding site to the blood meal, the anopheles mosquitoes have delicate wings and are normally weak flyers. So, normally she flies about no more than three kilometers or so, from her birthplace. Most species of anopheles avoid sunlight, that dries up their wings, and they avoid strong winds. But as they take flight, they're able to orient themselves to places of human settlement. Why? Because on their antennae there are sensors that are highly stimulated by carbon dioxide in the air. And, so, this — the carbon dioxide plume arising from human settlements and human bodies, enables the mosquitoes to be attracted to them.

Having arrived at closer range, the mosquitoes then detect, with other sensors, odors emanating from sweat. They're also attracted by light. And then at close range they finally use their vision to settle on the site of the body most suitable for their feast. And human beings cooperate in this enterprise in that anopheline mosquitoes feast between dusk and dawn, and they thereby attack sleeping bodies, lying mostly motionless. Now, when you hear the buzz of the harmless culex mosquito that buzzes noisily around you and attracts your attention, you can be happy, because most anophelines that transmit malaria are silent and therefore don't disturb their hosts.

You're probably wondering, how is it that transmission is maintained if the vast majority of mosquitoes don't transmit malaria? Only the females of certain species of anophelines — and I've included two on your handout as being most important to us: Anopheles gambiae, which would be my candidate for the most deadly insect for human beings on our planet, and Anopheles labranchiae, which was one of the most important vectors of malaria in Europe and in parts of Africa. You're probably wondering if a female anopheline mosquito lives on average just a few weeks, and needs to be infected herself before transmitting the disease, how can transmission be maintained?

Well, there's a couple of facts that we need to remember. First, is the vast numbers of mosquitoes involved in areas where malaria is endemic. In most areas of high endemicity, no more than two percent or so of female mosquitoes are infected at any given time. But on average, a human being can be bitten thousands of time in a year. And it's also true that an insect like Anopheles gambiae is famished and doesn't feed a single time, but having entered a place of human settlement feasts repeatedly, moving from one body to another, thereby ensuring that in crowded conditions one malarial patient is a major source of danger to all of those around him or her.

Chapter 4. Symptomatology and Relationship to Poverty [00:30:17]

Well, that's the story from the standpoint of the mosquito. What happens to the human victim? What are the symptoms of malaria? How does the disease have its impact on the human body? After the incubation period, symptoms begin when the plasmodia have achieved a critical threshold number in the bloodstream. It's then that the classical symptoms of malaria begin, with their onset. Now, let's remember — return to our diagram. This process of reproduction, of entering — that is to say the parasite enters the blood cell, reproduces, bursts the blood cell and returns to the bloodstream — occurs simultaneously for an entire brood throughout the bloodstream. In other words, this is happening at the same time throughout the body. And it's when there are sufficient numbers of the parasite in the open bloodstream that the immune system of the body can detect the parasite, and it's then that symptoms begin.

The term for malaria also — it has many names, this disease. It was often called intermittent fever. This process of synchronicity was known as Golgi's law, after the malariologist Camillo Golgi, who discovered it; and he talked about the different timings of fever. Tertian fever, that is to say, every forty-eight hours; or Quartan fever, every seventy-two hours; or Quotidian fever. You can also have a bout of intense fever every twenty-four hours, and that means that you have more than one species of plasmodium in your bloodstream. You don't have to choose just one, you can have several species and several types in your bloodstream at once. If that occurs, you can have fever, intermittent fever, every twenty-four hours.

The recurring classic symptoms then are this intermittent fever, recurring at regular intervals, like a train schedule. You have recurring paroxysms of high temperature, plus chills, profuse sweating, headache, general malaise, exhaustion, and with it often nausea, vomiting and diarrhea. The precise symptoms depend on the species of plasmodium, and the most virulent is Plasmodium falciparum, which causes the most frequent life-threatening complications, and Plasmodium malariae and ovale are the most mild. You see that by entering the red and attacking red blood cells, the parasite initiates a cascade of consequences. The red cells can become misshapen, and they adhere to one another in clumps, thereby causing blockages in blood cells- blood vessels, that can be rapidly fatal, depending on the organ that's affected.

A frequent cause of mortality is cerebral malaria, in which there are blockages in the brain. But the heart can also be affected, or the gastrointestinal system; and if malaria attacks the gastrointestinal in particular, it mimics the symptoms of Asiatic cholera. Destruction of the red blood cells also is a cause of profound anemia. Another important symptom of the disease is — and this is a child who's a malaria patient, and what you see is a painful and pronounced swelling of the spleen. This is one of the classic signs of malarial infection. As I've said, also malaria is terrible in its effects on pregnant women, leading to hemorrhaging and miscarriage, and also to congenital malaria with infants born with the disease.

Malaria also is a disease that's a major immunosuppressive disease. It suppresses the immune system of the body, and therefore gives rise to complications, especially respiratory diseases; as I mentioned earlier, pneumonia, influenza and tuberculosis. So, we should say that the tuberculosis emergency in the present day, and the malaria emergency, are inter-locking and inter-related; malaria provides the substratum for rampaging re-emerging tuberculosis. I also said that recurring bouts of malaria lead to neurological damage, and in the worst cases to a state known as cachexia, in which a person is indifferent to his or her surroundings; is unable to learn to be productive, to take part in civil society.

Another feature of malaria is that it can lead to relapses; that is, with Plasmodium vivax. You remember that after the plasmodium is injected into the bloodstream, it migrates to the liver. Well in Plasmodium vivax, the parasite does emerge, but not all of the parasites. They continue to nestle in the liver, and they're beyond the detection of the immune system. And they can then — even after the patient thinks that he or she has recovered, there can be a relapse when the plasmodia, the parasites, re-emerge from the liver into the bloodstream. This can be months later, or even years later, after the initial infection. Immunity — that is, once you've had lots of bouts of malaria, and you survive, you develop a partial immunity, an acquired immunity. But it is short-term, and it's also at considerable cost in terms of neurological damage to the body.

Well, the impact on society, as you can imagine, is severe; and we'll be talking about that next time. But it leads, this disease — the symptoms, listing the symptoms, helps us to understand that someone like this as an adult, who's anemic, who has perhaps respiratory diseases, moves painfully and slowly, and is therefore not a productive worker in agriculture or in industry. So, malaria leads to backward systems of cultivation, low productivity, and lack of investment in agriculture. It leads to the desertion of whole- of some of the most fertile areas, land, because it's particularly dangerous, and known to be so. It leads then to poverty, to illiteracy.

Indeed, malaria and poverty are mutually reinforcing in a kind of vicious downward spiral. Poverty makes people vulnerable to the disease. Poverty, that is, makes people vulnerable because it causes them to live in poor housing, overcrowded housing; housing that's porous and vulnerable to flying insects. It also leads them to occupational hazards in having to work in areas where the disease is prevalent. It leads to poor diet, which makes people more vulnerable; to inadequate clothing, which makes them more vulnerable to biting insects. But malaria, in turn, then leads to further poverty. The burden of looking after the ill, that falls on families and communities; low productivity; low wages; limited education. This was what Ross meant when he says, "Those malaria doesn't kill, it enslaves."

Chapter 5. Mosquito Theory of Transmission [00:40:14]

Well, when was the mosquito theory of transmission unraveled, and how so? The idea that mosquitoes were involved in this disease wasn't at all obvious. It wasn't obvious because, well, first of all scientists and physicians knew that there are lots of places where there are gazillions of mosquitoes and no malaria. It was also clear that mosquitoes — there was no clear correlation between being bitten by mosquitoes and developing the disease. And so the dominant theory in the nineteenth century was of miasmatism as the cause of the disease. The unraveling of the disease — you'll remember this man, Patrick Manson, the father of tropical medicine. He was also one of the figures who was most closely associated in the development of tropical medicine, and of the mosquito theory of transmission, which he discovered for a different disease called filaria. And then he had the idea that perhaps if filaria could be transmitted by mosquitoes, possibly malaria could as well. And so he joined forces — he worked, Manson, in London.

This is Ronald Ross, who was a British military physician working in India. Now, India was a tremendously important place in terms of malaria. Let me just — there was a book that you might be interested in, and that I would recommend to those of you who are, which is the correspondence between Ronald Ross and Patrick Manson, that led them to the discovery of the mosquito theory of transmission. Now Ross worked in India, and he noted that malaria, amongst the general population of India in the 1890s, led to 5,000,000 deaths. And he said that it was the greatest problem of public health in India. "I think on the whole," he wrote, "that the Indian population of 400,000,000, it causes directly or indirectly 10,000 deaths a day. And apart from this amount of sickness, malaria is, of all diseases, the most important in political, agricultural and military affairs," he wrote, "since it renders large tracts of fertile land uninhabitable, impedes cultivation, planting and public works, and is the most fierce, vicious enemy that armies in the field have to contend against. On the whole I think we're justified in claiming that the malaria question is as important as famine or bubonic plague."

In India, what Ross and Manson did was to discover — let's go back to our picture of the lifecycle of malaria. They traced — through microscopy, were able to detect in the body of the mosquito after it had bitten, and they did experiments in which they — among not human beings but birds — and they discovered that it was possible to detect the plasmodia responsible for avian malaria, under the microscope, in the body of the mosquito. That was a first major insight, that the mosquito was in some way implicated. But then they went further and they followed the process by which it changed various phases in the body of the insect and reproduced, and they traced the migration of the parasite to the biting apparatus of the mosquito. And then they were able to take healthy birds and have mosquitoes, who were known to be infected, feast on them, and to produce malaria experimentally on birds.

And, so, in 1898, if you were reading this correspondence, there's a eureka moment in which Ross announces that he's discovered the mosquito theory of transmission, and proved it. And he claims that he feels like Captain Cook, the explorer, or possibly like Napoleon. And he was not, however, a naturalist, and he didn't know about the speciation of mosquitoes, and the mosquitoes he described, he described as dappled, brindled or light brown. He didn't know about the species of Anopheles mosquitoes.

It's at this point that we should mention then a second major figure — oops, anyway we'll see — it doesn't matter —Giovanni Battista Grassi, who was the next figure in the development of the mosquito theory of transmission, and he does so for human beings. And what he does is he discovers that it's possible — in a place called Capaccio he takes railroad workers, in the midst of a major malaria outbreak in the summer, and he introduces one variable in their lives, from a control group of railroad workers and the surrounding peasantry; and that is that one group he has living from dusk until dawn in well-screened houses; and this difference protecting them from the one factor, which is from the bites of mosquitoes, prevents their being contracting malaria. This was one place in which he did that.

And then he also did a different experiment, which was to use quinine, which kills malaria parasites in the open bloodstream. He gave it prophylactically to a series of workers, as a control group, in a place like Ostia, during the summer malaria season, and found that he could protect them as well from malaria by establishing a chemical barrier between the mosquitoes and human beings. And then he took the further step of actually taking mosquitoes who were known to have feasted on people ill of malaria, and took them to a hospital in Rome known as the Santo Spirito Hospital, where he had a volunteer on the second floor who was in a room where at night they released hundreds of intentionally infected mosquitoes, and a couple of weeks later they had their eureka moment when he had a spike and a temperature of 104, and they knew that they had successfully transmitted malaria by human experimentation to someone who had been healthy until mosquitoes infected with the disease had been allowed to feast upon him.

So, this then happens between 1898 and 1901. And this then is a powerful factor in the development of tropical medicine. But it also leads to programs to combat malaria. Having discovered the pathogen responsible to it, the plasmodia, and the vector, female anopheles mosquitoes, we see the development of public health programs to destroy the disease — either by attacking the plasmodia with chemical therapy, that is, through quinine; or by killing mosquitoes, that is, vector control — the idea of possibly being able to eradicate malaria. And next time what I'd like to do is to follow the practical application then of the discoveries we've talked about today, about the life cycle of plasmodia and of anopheline mosquitoes, and see how that leads to the development of public health strategies. And I'd like to talk about how those strategies are being used in the real world today to combat this crisis of this dreadful vector-borne disease.

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