The Coming Plague (79 page)
Authors: Laurie Garrett
In field trials in Malawi, David Heymann looked to see if it was possible to use drugs either to eliminate the parasites from pregnant women, thus at least decreasing the chances that babies would be born infected, or to boost maternal immunity so much that mothers would pass powerful antibodies
on to their breast-feeding babies. Clearing all parasites from a pregnant woman's body required over $10.00 worth of antimalarialsâtoo expensive in countries that spent less than $3.00 per capita annually for all health needs.
158
And giving chloroquine or quinine to newborns was fruitless, for Joe McCormick showed in Kenya that the average infant or toddler living in East African villages got 50 to 80 infectious mosquito bites
per month
. Other studies showed that half of all infectious bites ended up as malaria cases.
on to their breast-feeding babies. Clearing all parasites from a pregnant woman's body required over $10.00 worth of antimalarialsâtoo expensive in countries that spent less than $3.00 per capita annually for all health needs.
158
And giving chloroquine or quinine to newborns was fruitless, for Joe McCormick showed in Kenya that the average infant or toddler living in East African villages got 50 to 80 infectious mosquito bites
per month
. Other studies showed that half of all infectious bites ended up as malaria cases.
At the same time, the territory of the
Anopheles
mosquitoes was expanding. Usually the mosquitoes had very limited temperature and altitude flexibility; ideally, they preferred tropical sea-level conditions. But as the sheer density of the human population increased, and massive numbers of immune-naïve people moved back and forth between rural and urban areas, the mosquitoes braved their way into previously uncharted territory. Heymann witnessed the expansion of malaria in Rwanda, for example, where for centuries the disease and
Anopheles
mosquitoes were limited to lowland, densely populated areas. Similarly, in Swaziland he saw the expansion of the fruit-canning industry, located in the lowlands, draw people from the remote highland areas of the country, where
Anopheles
mosquitoes weren't found. They were recruited to work in the canneries in the malarial lowlands. Lacking any immunity and confronted with drug-resistant parasites, the highlanders died off in huge numbers. Those few lucky enough to survive carried the parasites in their blood back up to the mountainous communities where local mosquitoes picked up the microbes while feeding on the migrant workers.
Anopheles
mosquitoes was expanding. Usually the mosquitoes had very limited temperature and altitude flexibility; ideally, they preferred tropical sea-level conditions. But as the sheer density of the human population increased, and massive numbers of immune-naïve people moved back and forth between rural and urban areas, the mosquitoes braved their way into previously uncharted territory. Heymann witnessed the expansion of malaria in Rwanda, for example, where for centuries the disease and
Anopheles
mosquitoes were limited to lowland, densely populated areas. Similarly, in Swaziland he saw the expansion of the fruit-canning industry, located in the lowlands, draw people from the remote highland areas of the country, where
Anopheles
mosquitoes weren't found. They were recruited to work in the canneries in the malarial lowlands. Lacking any immunity and confronted with drug-resistant parasites, the highlanders died off in huge numbers. Those few lucky enough to survive carried the parasites in their blood back up to the mountainous communities where local mosquitoes picked up the microbes while feeding on the migrant workers.
Next door in Malawi, Heymann watched throughout the 1980s as the incidence of chloroquine-resistant malaria and malarial deaths rose steadily. In 1980 fewer than 5 percent of all child hospitalizations were due to acute anemia; by 1986 that percentage had tripled.
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Back at CDC headquarters in Atlanta, Campbell was still trying to answer his fundamental question: What is malaria? For much of their childhood virtually all Africans were infected with the parasitesâdid that constitute malaria? Clearly not, he decided. Was it malaria when an infected child developed fevers? Again, Campbell decided, the answer was no, as many ailments could produce fevers in young children. The presence of the malarial parasites did not necessarily mean that those particular bugs were responsible for a child's fever.
“Furthermore,” Campbell said, “we cannot continue to treat every fever as if it's malaria, because the roster of drugs is getting shorter.” He knew, however, that within twenty-four to forty-eight hours what appeared to be a vague fever could, after a single red blood cell reproduction cycle for the parasites, spell death.
Answering these questions became an obsession for Campbell, as well as the other old Africa hands at CDC: Joel Breman, Joe McCormick, and David Heymann. Stumping from one cluster of malariologists to another,
in Geneva and London, at Oxford and Harvard, before U.S. congressional subcommittees and in meetings with the Côte d'Ivoire Ministry of Health, Campbell would ask the same basic question: What is malaria?
in Geneva and London, at Oxford and Harvard, before U.S. congressional subcommittees and in meetings with the Côte d'Ivoire Ministry of Health, Campbell would ask the same basic question: What is malaria?
And everywhere he went the question was greeted first by disbeliefâhow could America's supposed leading malaria expert ask such a stupid question? Campbell didn't mind if he sounded naive. The tall, lanky marathon runner would stretch his long legs out from his seat, and in a style reminiscent of Jimmy Stewart's sly, falsely modest characters, repeat his question in a slow Tennessee drawl. Invariably the experts left these meetings shaking their heads and asking the same question: What is malaria?
Many other disease states were defined by the presence of antibodies against a particular microbe. A vague case of malaise, fever, and nausea could be ascribed to influenza if anti-flu antibodies were found in the ailing human's bloodstream. But here, too, Campbell saw difficulties with defining malaria, because of the strange and transient nature of immunity to the parasites.
When malarial parasites were injected through a female
Anopheles
proboscis into a human's bloodstream, they were in the form of small sporozoites. The sporozoites had a unique coating, bearing a set of specific protein antigens. At each stage in the parasites' life cycles thereafterâschizonts and merozoitesâthe organisms bore still another set of antigens on their cell membranes. Because the various stages of the parasite's growth presented different sets of antibodies, the human immune system was in a bind. It might make antibodies against one stage and not the others. Or it might mount a T-cell response against one, or none, of the stages.
Anopheles
proboscis into a human's bloodstream, they were in the form of small sporozoites. The sporozoites had a unique coating, bearing a set of specific protein antigens. At each stage in the parasites' life cycles thereafterâschizonts and merozoitesâthe organisms bore still another set of antigens on their cell membranes. Because the various stages of the parasite's growth presented different sets of antibodies, the human immune system was in a bind. It might make antibodies against one stage and not the others. Or it might mount a T-cell response against one, or none, of the stages.
The sporozoite stage of malaria elicited a particularly strange immune response: people could have millions of antibodies drifting through their bloodstreams, even attaching to the sporozoites, and still die of malaria. One key study involved Kenyan adults who were presumably “immune” to malaria because they were surviving constant exposure to the contaminating mosquitoes. The volunteers were given high doses of chloroquine and Fansidar (pyrimethamine/sulfadoxine) to rid their bodies of parasites. Their antisporozoite antibody levels were measured. And then the individuals were followed for ninety-eight days to see what transpired.
By the end of the study,
72
percent of the supposedly immune adults had become reinfected with
P. falciparum
parasites. In a similar study of small children, 100 percent were reinfected within ninety-eight days.
160
And there was
no
correlation between their likelihood of being reinfected and the levels of anti-malaria antibodies in their blood.
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72
percent of the supposedly immune adults had become reinfected with
P. falciparum
parasites. In a similar study of small children, 100 percent were reinfected within ninety-eight days.
160
And there was
no
correlation between their likelihood of being reinfected and the levels of anti-malaria antibodies in their blood.
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Laboratory and animal studies showed that T-cell responses were critical to controlling sporozoites, particularly the classes of T cells called CD4.
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The problem with such T-cell responses was that they were usually very specific, capable of recognizing a malaria enemy only if a very particular kind of antigen was present on the sporozoite surface. So narrow was the range of T-cell response that if a single amino acid building block in the
proteins protruding from a sporozoite's surface differed, the T cells wouldn't recognize the malarial invasion and no effective immune response would be mounted. Such specificities were called epitopes, and each different malaria epitope could be coded for by a single geneâor even a tiny part of one geneâin the parasite's DNA. That meant that one tiny mutation might be enough to allow the malarial parasite to evade the human T-cell immune responses.
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The problem with such T-cell responses was that they were usually very specific, capable of recognizing a malaria enemy only if a very particular kind of antigen was present on the sporozoite surface. So narrow was the range of T-cell response that if a single amino acid building block in the
proteins protruding from a sporozoite's surface differed, the T cells wouldn't recognize the malarial invasion and no effective immune response would be mounted. Such specificities were called epitopes, and each different malaria epitope could be coded for by a single geneâor even a tiny part of one geneâin the parasite's DNA. That meant that one tiny mutation might be enough to allow the malarial parasite to evade the human T-cell immune responses.
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As a result, a person whose T-cell system was able to control malarial parasites found in, say, Bujumbura in 1989 wouldn't be able to handle malaria in Kinshasa or Brazil or Thailand.
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Indeed, if the individual left Bujumbura and returned twelve months later, his or her T-cell system might not recognize the strains then present in Burundi's capital city.
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Indeed, if the individual left Bujumbura and returned twelve months later, his or her T-cell system might not recognize the strains then present in Burundi's capital city.
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These findings simply reinforced Kent Campbell's sense of perplexity. The parasites, despite the existence of proteins on their surfaces that clearly signaled alarms to the immune systems,
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managed to elude all the host's defenses, and nothing short of extraordinary doses of antimalarial drugs could dislodge the microbes.
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managed to elude all the host's defenses, and nothing short of extraordinary doses of antimalarial drugs could dislodge the microbes.
In the face of rising microbial resistance to the antimalarials, even the drugs were increasingly proving incapable of ridding human bodies of the parasites.
Oddly enough, as time wore on, Campbell reached the conclusion that it was a good thing, if one lived in an area with endemic malaria, to have some parasites in one's body at all times. In the absence of parasites there was soon no immunity whatsoever.
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If some malarial sporozoites inhabited one's liver, or merozoites one's red blood cells, the body made IgG antibodies. With luck, enough antibodies and activated T cells were present to create a condition of tolerance: each creature tolerated the other. The parasites put up with constant onslaughts from the immune system, and the human managed, most of the time, to accept the infection of some number of red blood cells and hepatocytes.
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If some malarial sporozoites inhabited one's liver, or merozoites one's red blood cells, the body made IgG antibodies. With luck, enough antibodies and activated T cells were present to create a condition of tolerance: each creature tolerated the other. The parasites put up with constant onslaughts from the immune system, and the human managed, most of the time, to accept the infection of some number of red blood cells and hepatocytes.
Once again the dogged Campbell queried: “What is malaria?” If not this state of chronic infection, which occasionally got out of balance to produce fevers and chills, what exactly was the disease that WHO claimed appeared in over 300 million people a year by 1990, killing 3.5 million?
Campbell liked to remind fellow malariologists of the old British colonial scourge, blackwater fever. It was the British who figured out how to mix quinine with water and cover the bitterness with Bombay gin. The result âthe gin and tonicâwent a long way to prophylaxing the British Army against malaria. But overuse of quinine, both medicinally and in heavy gin-and-tonic doses, created the new disease of blackwater fever. Victims urinated dark fluid, ran high fevers, felt miserable, and oftenâ25 to 50 percent of the timeâdied.
It was decades before British physicians figured out that blackwater fever was an iatrogenic disease. After repeated episodes of malaria, each of which was treated with escalating doses of quinine, the nonimmune Europeans
fell ill with what they thought was another infectious disease. Scientists eventually determined that quinine caused blackwater fever. Overuse of the powerful drug to counteract malaria led to quinine's attachment directly onto the membranes of red blood cells. The protruding quinine molecule attracted the attention of the immune system, which misinterpreted its presence on the red blood cells as an indication of an alien invasion. Antibodies and T-cell killers attacked the quinine-labeled red blood cells, killing them. The dying blackwater fever patient was, thus, the victim of his own medical attempts to cure malaria.
fell ill with what they thought was another infectious disease. Scientists eventually determined that quinine caused blackwater fever. Overuse of the powerful drug to counteract malaria led to quinine's attachment directly onto the membranes of red blood cells. The protruding quinine molecule attracted the attention of the immune system, which misinterpreted its presence on the red blood cells as an indication of an alien invasion. Antibodies and T-cell killers attacked the quinine-labeled red blood cells, killing them. The dying blackwater fever patient was, thus, the victim of his own medical attempts to cure malaria.
In the early 1980s researchers tentatively demonstrated that chloroquine could also have a deleterious effect on the human immune system. Test-tube studies indicated that the drug could hamper the immune system's ability to recognize some threats and properly stimulate antibody response.
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In 1983 a U.S. Peace Corps volunteer died of rabies while working in Kenya, though the twenty-three-year-old had previously been vaccinated against the disease. Because she had been taking chloroquine prophylaxis for malaria for several months prior to her death, CDC researchers decided to see if the drug's dampening effect seen on immune system cells in test-tube studies was hampering similar activities in human beings.
In 1984 CDC scientists tested the immune systems of Peace Corps volunteers working in eight countries, comparing responses to rabies vaccines among chloroquine users with the responses of those not taking the drug. Chloroquine, taken in recommended prophylactic doses, clearly diminished volunteers' ability to make antibodies against rabies following vaccination. Three months after vaccination, the chloroquine users had about half the antibody response to rabies seen in Peace Corps volunteers who didn't take the drug.
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Though nobody knew exactly how chloroquine worked, in terms of either limiting malaria or dampening the immune response, Campbell was certain by 1990 that the drug had little or no effect directly on the parasites.
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“It treats the fever without directly attacking the parasites,” Campbell said.
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He concluded that the pediatric malarial anemia syndrome sweeping across Africa in the 1990s was iatrogenic, as was the AIDS epidemic in that age group that stemmed from the emergency blood transfusions given to the gravely ill children. The first was a disease that resulted from overuse of chloroquine, the second from use of HIV-infected blood.
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He concluded that the pediatric malarial anemia syndrome sweeping across Africa in the 1990s was iatrogenic, as was the AIDS epidemic in that age group that stemmed from the emergency blood transfusions given to the gravely ill children. The first was a disease that resulted from overuse of chloroquine, the second from use of HIV-infected blood.
The parasites developed partial resistance to the chloroquine, and the drug dampened the children's immune responses. Though chloroquine kept down the kids' fevers, it did nothing to slow red blood cell damage. The children's hemoglobin counts steadily descended despite all treatments, until so few viable hemoglobin molecules remained that the children's bodies were starving for oxygen.
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The anemia syndrome, Campbell concluded, was not malaria. It, just
like blackwater fever, was a man-made disease that resulted from improper use of an antimalarial drug.
like blackwater fever, was a man-made disease that resulted from improper use of an antimalarial drug.
Improper
, by the way, was defined as precisely the use patterns suggested by World Health Organization policy. For over two decades WHO told African health planners to train mothers living in endemic areas to assume that all fevers in small children were due to malaria and immediately treat the youngsters with chloroquine.
, by the way, was defined as precisely the use patterns suggested by World Health Organization policy. For over two decades WHO told African health planners to train mothers living in endemic areas to assume that all fevers in small children were due to malaria and immediately treat the youngsters with chloroquine.
From all of this Campbell reached two conclusions:
“Life cannot be made into policy guidelines from Geneva,” and “Malaria is a disease that responds to antimalarial drugs.”
The definition of malaria, then, was that it was a disease whose existence was proven by reversing it with drug treatments.
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At least in the African context, when the disease no longer responded to chloroquine treatment because of resistance, it was transformed into a different syndrome.
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At least in the African context, when the disease no longer responded to chloroquine treatment because of resistance, it was transformed into a different syndrome.
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