to invade the cells. The parasite can’t spread effectively in populations in which most people are “Duffy-negative.” P. vivax is carried by at least 71 species of mosquitoes, which gives it another edge over P. falciparum. Many vivax vectors live happily in temperate climates—as far north as Finland. Some even prefer to bite outdoors or during the daytime, so in some regions indoor insecticide spraying and bed nets are less effective at preventing the dis-
Malaria as Lifesaving Therapy Vivax malaria was once familiar to doctors not only as a foe, but also as an ally. In the first half of the 20th century, people with tertiary syphilis, the phase of the disease in which Treponema pallidum bacteria attack the brain and nervous system, were doomed to a gruesome death: They would become increasingly neurotic and gradually paralyzed. Most were institutionalized, and there was no cure. So physicians drew on a theory that had gained prominence in the late 19th century—that high fever could help cure a variety of mental illnesses. Austrian psychiatrist Julius WagnerJauregg was one of the idea’s strongest proponents, but his initial experiments in the 1880s with fever-inducing pathogens and compounds such as tuberculin and salmonella toxin failed. He reasoned that the fevers they induced were not severe enough. In 1917, he tried again when a soldier who had caught malaria while fighting in the Balkans was admitted to his ward. Wagner-Jauregg used the soldier’s blood to inoculate nine neurosyphilis patients. Six of them got better. Soon, malariotherapy was seen as a miracle cure. It became a leading treatment for end-stage syphilis, quickly spreading across Europe and North America. Between 1917 and the rise of penicillin in the 1940s, tens of thousands of syphilis patients were infected with malaria. Different clinics used different parasites, but “after a few costly mistakes” with Plasmodium falciparum, a more lethal parasite, “most people settled on vivax,” says Nick White, professor of tropical medicine at Mahidol University in Bangkok and the University of Oxford in the United Kingdom. No one is sure exactly how it worked, but the high fevers that resulted seemed to help the patients’ immune systems fight off the bacteria. Roughly half recovered enough to resume normal activities; many were Radical treatment. In a 1934 image, Julius Wagner-Jauregg (center, able to resume independent in black suit) watches as blood from a malaria patient (in background on left) is injected into a neurosyphilis patient (center). lives. In 1927, WagnerJauregg won the Nobel Prize in physiology or medicine for his discovery. (The Austrian’s legacy has a darker side as well. He was an advocate of eugenics, and in the 1930s he was a Nazi supporter.) Because of malariotherapy, “the parasite’s biology was investigated in amazing detail,” White says. The result was a wealth of information about the disease process and how it differs depending on the strain of P. vivax. Those records are gaining some new attention today, as vivax starts to emerge from the shadow of its better-known cousin, falciparum (see main text, p. 684). But this medicinal use of the parasite is in part to blame for the later neglect of the disease it causes, says Kevin Baird of the Eijkman Oxford Clinical Research Unit in Jakarta. Because doctors used P. vivax as a medical treatment, he says, many people assumed that it must be relatively harmless. But Baird says that even at the height of the therapy’s use, that reputation was unfounded: Although malariotherapy saved lives, it also killed as many as 15% of the patients who received it, despite close monitoring and treatment of the infection. –G. V.
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ease. Several key vector species haven’t ever been grown in the lab for closer study, and it’s also unclear how widespread insecticide resistance might be. One bright spot is that, like falciparum malaria, vivax malaria is treatable. In fact, P. vivax has so far developed less resistance to common drugs. Chloroquine, which has lost most of its potency against P. falciparum, can still effectively treat acute infections of P. vivax in most regions. But those treatments are powerless against the parasite’s nastiest trick: its ability to lurk in the liver, making it much harder to cure than P. falciparum. Both parasites, when they are transmitted from mosquito to human host, go first to the liver. But unlike P. falciparum parasites, which undergo asexual reproduction in the liver and then burst out to infect red blood cells, some vivax parasites simply go into hiding. They form what are called hypnozoites (the name derives from “sleeping parasites”), an especially small form that nestles inside a liver cell. There they remain for weeks, months, or even years, waiting until chances are good that a recipient mosquito will be available to pass sexual stages on to the next victim. In fact, it is the hypnozoites that allow the parasite to survive in more temperate zones, where mosquitoes bite only part of the year. The parasite can bide its time for 9 months or even longer—enough time to wait out the winter and allow new vectors to hatch. (Another parasite, Plasmodium ovale, can also form hypnozoites, but it is much rarer than P. vivax.) Hypnozoites can’t be detected by blood tests, so the best strategy to eliminate the parasite from a region would be to mass-treat populations with a drug that could kill the sleeping pathogens. One drug can do that: Called primaquine, it was developed in the 1940s and early 1950s. It has two major drawbacks, however. The standard dose requires people to take a daily pill for 14 days—not an easy thing to enforce in people who don’t feel ill. And in people who have a genetic condition called G6PD deficiency, the drug causes red blood cells to burst open. In severe cases, the reaction, called hemolysis, can be fatal. G6PD stands for glucose-6-phosphate dehydrogenase, an enzyme that is especially important in red blood cell metabolism. There is no cheap, easy field test for G6PD traits, so any mass treatment campaign risks severe side effects in some people. The variant also seems to confer some protection against vivax malaria, so that regions in which the parasite is common tend to have more people with the trait.
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peared as countries became wealthier and housing conditions improved. (One of the most effective, though expensive, antimalaria measures is mosquito-proof housing with screens on the windows and doors.) Now, it is a plague of low- and middle-income countries, except those in sub-Saharan Africa, where the P. vivax map has a conspicuous hole. There, most of the population lacks the Duffy antigen, a protein on the surface of red blood cells that P. vivax uses
CREDIT: P. G. SHUTE AND M. E. MARYON, LABORATORY TECHNIQUE FOR THE STUDY OF MALARIA, J. & A. CHURCHILL LTD. (1966)
NEWSFOCUS
Malaria as Lifesaving Therapy Vivax malaria was once familiar to doctors not only as a foe, but also as an ally. In the first half of the 20th century, people with tertiary syphilis, the phase of the disease in which Treponema pallidum bacteria attack the brain and nervous system, were doomed to a gruesome death: They would become increasingly neurotic and gradually paralyzed. Most were institutionalized, and there was no cure. So physicians drew on a theory that had gained prominence in the late 19th century—that high fever could help cure a variety of mental illnesses. Austrian psychiatrist Julius WagnerJauregg was one of the idea’s strongest proponents, but his initial experiments in the 1880s with fever-inducing pathogens and compounds such as tuberculin and salmonella toxin failed. He reasoned that the fevers they induced were not severe enough. In 1917, he tried again when a soldier who had caught malaria while fighting in the Balkans was admitted to his ward. Wagner-Jauregg used the soldier’s blood to inoculate nine neurosyphilis patients. Six of them got better. Soon, malariotherapy was seen as a miracle cure. It became a leading treatment for end-stage syphilis, quickly spreading across Europe and North America. Between 1917 and the rise of penicillin in the 1940s, tens of thousands of syphilis patients were infected with malaria. Different clinics used different parasites, but “after a few costly mistakes” with Plasmodium falciparum, a more lethal parasite, “most people settled on vivax,” says Nick White, professor of tropical medicine at Mahidol University in Bangkok and the University of Oxford in the United Kingdom. No one is sure exactly how it worked, but the high fevers that resulted seemed to help the patients’ immune systems fight off the bacteria. Roughly half recovered enough to resume normal activities; many were Radical treatment. In a 1934 image, Julius Wagner-Jauregg (center, able to resume independent in black suit) watches as blood from a malaria patient (in background on left) is injected into a neurosyphilis patient (center). lives. In 1927, WagnerJauregg won the Nobel Prize in physiology or medicine for his discovery. (The Austrian’s legacy has a darker side as well. He was an advocate of eugenics, and in the 1930s he was a Nazi supporter.) Because of malariotherapy, “the parasite’s biology was investigated in amazing detail,” White says. The result was a wealth of information about the disease process and how it differs depending on the strain of P. vivax. Those records are gaining some new attention today, as vivax starts to emerge from the shadow of its better-known cousin, falciparum (see main text, p. 684). But this medicinal use of the parasite is in part to blame for the later neglect of the disease it causes, says Kevin Baird of the Eijkman Oxford Clinical Research Unit in Jakarta. Because doctors used P. vivax as a medical treatment, he says, many people assumed that it must be relatively harmless. But Baird says that even at the height of the therapy’s use, that reputation was unfounded: Although malariotherapy saved lives, it also killed as many as 15% of the patients who received it, despite close monitoring and treatment of the infection. –G. V.
686
8 NOVEMBER 2013
ease. Several key vector species haven’t ever been grown in the lab for closer study, and it’s also unclear how widespread insecticide resistance might be. One bright spot is that, like falciparum malaria, vivax malaria is treatable. In fact, P. vivax has so far developed less resistance to common drugs. Chloroquine, which has lost most of its potency against P. falciparum, can still effectively treat acute infections of P. vivax in most regions. But those treatments are powerless against the parasite’s nastiest trick: its ability to lurk in the liver, making it much harder to cure than P. falciparum. Both parasites, when they are transmitted from mosquito to human host, go first to the liver. But unlike P. falciparum parasites, which undergo asexual reproduction in the liver and then burst out to infect red blood cells, some vivax parasites simply go into hiding. They form what are called hypnozoites (the name derives from “sleeping parasites”), an especially small form that nestles inside a liver cell. There they remain for weeks, months, or even years, waiting until chances are good that a recipient mosquito will be available to pass sexual stages on to the next victim. In fact, it is the hypnozoites that allow the parasite to survive in more temperate zones, where mosquitoes bite only part of the year. The parasite can bide its time for 9 months or even longer—enough time to wait out the winter and allow new vectors to hatch. (Another parasite, Plasmodium ovale, can also form hypnozoites, but it is much rarer than P. vivax.) Hypnozoites can’t be detected by blood tests, so the best strategy to eliminate the parasite from a region would be to mass-treat populations with a drug that could kill the sleeping pathogens. One drug can do that: Called primaquine, it was developed in the 1940s and early 1950s. It has two major drawbacks, however. The standard dose requires people to take a daily pill for 14 days—not an easy thing to enforce in people who don’t feel ill. And in people who have a genetic condition called G6PD deficiency, the drug causes red blood cells to burst open. In severe cases, the reaction, called hemolysis, can be fatal. G6PD stands for glucose-6-phosphate dehydrogenase, an enzyme that is especially important in red blood cell metabolism. There is no cheap, easy field test for G6PD traits, so any mass treatment campaign risks severe side effects in some people. The variant also seems to confer some protection against vivax malaria, so that regions in which the parasite is common tend to have more people with the trait.
VOL 342 SCIENCE www.sciencemag.org Published by AAAS
Downloaded from www.sciencemag.org on December 4, 2013
peared as countries became wealthier and housing conditions improved. (One of the most effective, though expensive, antimalaria measures is mosquito-proof housing with screens on the windows and doors.) Now, it is a plague of low- and middle-income countries, except those in sub-Saharan Africa, where the P. vivax map has a conspicuous hole. There, most of the population lacks the Duffy antigen, a protein on the surface of red blood cells that P. vivax uses
CREDIT: P. G. SHUTE AND M. E. MARYON, LABORATORY TECHNIQUE FOR THE STUDY OF MALARIA, J. & A. CHURCHILL LTD. (1966)
NEWSFOCUS
