A Brief History of Malaria
MALARIA’S GLOBAL SAGA
Malaria occupies a unique place in the annals of history. Over millennia, its victims have included Neolithic dwellers, early Chinese and Greeks, princes and paupers. In the 20th century alone, malaria claimed between 150 million and 300 million lives, accounting for 2 to 5 percent of all deaths (Carter and Mendis, 2002). Although its chief sufferers today are the poor of sub-Saharan Africa, Asia, the Amazon basin, and other tropical regions, 40 percent of the world’s population still lives in areas where malaria is transmitted.
Ancient writings and artifacts testify to malaria’s long reign. Clay tablets with cuneiform script from Mesopotamia mention deadly periodic fevers suggestive of malaria. Malaria antigen was recently detected in Egyptian remains dating from 3200 and 1304 BC (Miller et al., 1994). Indian writings of the Vedic period (1500 to 800 BC) called malaria the “king of diseases.” In 270 BC, the Chinese medical canon known as the Nei Chin linked tertian (every third day) and quartan (every fourth day) fevers with enlargement of the spleen (a common finding in malaria), and blamed malaria’s headaches, chills, and fevers on three demons—one carrying a hammer, another a pail of water, and the third a stove (Bruce-Chwatt, 1988). The Greek poet Homer (circa 750 BC) mentions malaria in The Iliad, as does Aristophanes (445-385 BC) in The Wasps, and Aristotle (384-322 BC), Plato (428-347 BC), and Sophocles (496-406 BC). Like Homer, Hippocrates (450-370 BC) linked the appearance of Sirius the dog star (in late summer and autumn) with malarial fever and misery (Sherman, 1998).
Malaria’s probable arrival in Rome in the first century AD was a turning point in European history. From the African rain forest, the disease most likely traveled down the Nile to the Mediterranean, then spread east to the Fertile Crescent, and north to Greece. Greek traders and colonists brought it to Italy. From there, Roman soldiers and merchants would ultimately carry it as far north as England and Denmark (Karlen, 1995).
For the next 2,000 years, wherever Europe harbored crowded settlements and standing water, malaria flourished, rendering people seasonally ill, and chronically weak and apathetic. Many historians speculate that falciparum malaria (the deadliest form of malaria species in humans) contributed to the fall of Rome. The malaria epidemic of 79 AD devastated the fertile, marshy croplands surrounding the city, causing local farmers to abandon their fields and villages. As late as the 19th century, travelers to these same areas remarked on the feebleness of the population, their squalid life and miserable agriculture (Cartwright, 1991). The Roman Campagna would remain sparsely settled until finally cleared of malaria in the late 1930s.
In India and China, population growth drove people into semitropical southern zones that favored malaria. India’s oldest settled region was the relatively dry Indus valley to the north. Migrants to the hot, wet Ganges valley to the south were disproportionately plagued by malaria, and other mosquito- and water-borne diseases. Millions of peasants who left the Yellow River for hot and humid rice paddies bordering the Yangtse encountered similar hazards. Due to the unequal burden of disease, for centuries, the development of China’s south lagged behind its north.
Although some scientists speculate that vivax malaria may have accompanied the earliest New World immigrants who arrived via the Bering Strait, there are no records of malaria in the Americas before European explorers, conquistadores, and colonists carried Plasmodium malariae, and P. vivax as microscopic cargo (Sherman, 1998). Falciparum malaria was subsequently imported to the New World by African slaves initially protected by age-old genetic defenses (sickle cell anemia, and G6PD deficiency) plus partial immunity gained through lifelong exposure. Their descendants, as well as Native Americans and settlers of European ancestry, were more vulnerable, however. Deforestation and “wet” agriculture such as rice farming facilitated breeding of Anopheles mosquitoes. By 1750, both vivax and falciparum malaria were common from the tropics of Latin America to the Mississippi valley to New England.
Malaria, both epidemic and endemic, continued to plague the United States until the early 20th century. It struck presidents from Washington to Lincoln, weakened Civil War soldiers by the hundreds of thousands (in 1862, Washington, D.C., and its surroundings were so malarious that General McClellan’s Army en route to Yorktown was stopped in its tracks),
traveled to California with the Gold Rush, and claimed Native American lives across the continent. Until the Tennessee Valley Authority brought hydroelectric power and modernization to the rural South in the 1930s, malaria drained the physical and economic health of the entire region. Just as the United States was eradicating its last indigenous pockets of infection, malaria reclaimed Americans’ attention during World War II. During the early days of the Pacific campaign, more soldiers fell to malaria than to enemy forces. The United States’ premier public health agency—the Centers for Disease Control and Prevention—was founded because of malaria. By the time of the Vietnam War, the American military discovered that drug-resistant malaria was already widespread in Southeast Asia, a harbinger of the worldwide hazard it was destined to become.
But nowhere—past or present—has malaria exacted a greater toll than on Africa. A powerful defensive pathogen, it was a leading obstacle to Africa’s colonization. Portuguese traders who entered the African coastal plain in the late 1400s and early 1500s were the first foreigners to confront the killing fever. For the next 3 centuries, whenever European powers tried to establish outposts on the continent, they were repelled time and again by malaria, yellow fever, and other tropical scourges. By the 18th century, the dark specter of disease earned West and central Africa the famous epitaph, “the White Man’s Grave.”
Even stronger testimony to malaria’s ancient hold on Africa is the selective survival of hemoglobin S—the cause of the inherited hemoglobin disorder sickle cell anemia. Since individuals who inherit two copies of the hemoglobin S gene (one from each parent) are unlikely to survive and reproduce, the disease should be exceedingly rare. However, in those people who have inherited only one sickle cell gene (such individuals are sickle cell “carriers”—they suffer few if any complications of sickle cell disease), needle-shaped clumps of hemoglobin S within red blood cells confer strong protection against malaria (Bayoumi, 1987). Thus, the sickle cell gene is perpetuated in malarious regions by one set of individuals who reap its benefits while another set pays the price. In some parts of Africa, up to 20 percent of the population carry a single copy of the abnormal gene (Marsh, 2002).
In recent years, by virtue of climate, ecology, and poverty, sub-Saharan Africa has been home to 80 to 90 percent of the world’s malaria cases and deaths, although some predict that resurgent malaria in southern Asia is already altering that proportion.
Discovering the Malaria Parasite
Charles Louis Alphonse Laveran (1845-1922) was a French army doctor during the Franco-Prussian War. He later authored a treatise on mili-
tary medicine. In it he challenged the traditional wisdom regarding malaria’s ecology—namely, that the disease was restricted to low-lying humid plains. Laveran noted that malaria also could occur in temperate zones, and that not all tropical areas were plagued by the disease. Although malaria had been linked with swamps ever since the condition known as Roman fever inspired the name mal’aria (“bad air”), Laveran knew from contemporary scientific articles that many diseases previously ascribed to miasmas, or evil vapors, were in fact caused by microbes. Thus he predicted: “Swamp fevers are due to a germ” (Jarcho, 1984).
After transferring to a new post on Algeria’s North African coast, Laveran investigated his theory. On October 20, 1880, while looking through a crude microscope at the blood of a febrile soldier, he saw crescent-shaped bodies that were nearly transparent except for one small dot of pigment. In preceding decades the brownish-black pigment hemozoin (now known to be the product of hemoglobin digestion by the malaria parasite) had been found in cadaveric spleens and blood of malaria victims by several investigators including Meckel, Virchow, and Frerichs. Laveran subsequently examined blood specimens from 192 malaria patients and saw pigment-containing crescents in 148 sufferers (Laveran, 1978). He ultimately recognized four distinct forms in human blood that would prove to be the malaria parasite in different stages of its life cycle: the female and male gametocyte, schizont and trophozoite stages.
Although his findings were initially viewed with skepticism, 6 years later, Laveran was affirmed. Camillo Golgi (1843-1926) linked the rupture and release of asexual malaria parasites from blood schizonts with the onset of every third- and fourth-day fever due to P. vivax and P. malariae, respectively. Golgi was awarded the Nobel Prize in 1906 for unrelated studies of the central nervous system. One year later, Laveran received the Nobel Prize for discovering the single-celled protozoan that caused malaria.
Discovering Malaria’s Mosquito Stages
August 20, 1897, is the original “Mosquito Day”—so named by Surgeon-Major Ronald Ross (1857-1932) of the British Indian Medical Service. Although Ross had previously spent more than a year fruitlessly studying gray and brindled mosquitoes (probably Culex fatigans and Aedes aegypti, respectively) incapable of hosting malaria, on that date he discovered a clear, circular body containing malarial pigment in a dapple-winged Anopheles mosquito that had previously fed on an infected patient. The next day the doctor-cum-poet/composer/mathematician, who struggled to pass his own medical exams, dissected another Anopheles mosquito that had siphoned blood from the same patient on the same day. This time Ross observed even larger pigment-containing bodies. Convinced that malaria
parasites were growing in the mosquito, he published his observations (“On some peculiar pigmented cells found in two mosquitoes fed on malarial blood”) in the British Medical Journal in December 1897.
After transferring to Calcutta, Ross designed experiments involving Plasmodium relictum, the malaria parasite of sparrows and crows. Ross identified sporozoites in the salivary glands of mosquitoes that had previously fed on malarious birds. He subsequently infected 21 of 28 fresh sparrows through these mosquitoes (Sherman, 1998). He communicated all of his findings to Patrick Manson who shared them at a meeting of the British Medical Association at the University of Edinburgh in July 1898 (Harrison, 1978). In 1902, Ross received the Nobel Prize for discovering the mosquito stages of malaria.
Ross was not the only investigator who demonstrated the malaria life cycle in the mosquito, however. Credit for confirming that human malaria parasites pass through the same developmental stages in the mosquito as the avian parasites observed by Ross belongs to a group of Italian scientists—in particular, Giovanni Battista Grassi (1854-1925), Amico Bignami, Giovanni Bastianelli, Antonio Dionisi, and Angelo Celli. Following Ross’s publication, Grassi (an expert in mosquito taxonomy) not only identified Anopheles maculipennis as the vector of human disease in the marshy Roman Campagna, but transmitted the malaria parasite Plasmodium vivax to a healthy human volunteer. Because each claimed credit for discovering malaria’s life cycle in the mosquito, Grassi and Ross were bitter toward each other for the remainder of their careers.
Parenthetically, Ronald Ross owed much of his success to his teacher and mentor Sir Patrick Manson, considered by many the father of tropical medicine. While working in Amoy and Formosa, Manson was the first researcher to discover that mosquitoes siphon first-stage microfilariae from the bloodstreams of patients with the parasitic disease, filariasis. However, Manson never imagined the final step in the filarial life cycle; namely, that infected mosquitoes might inoculate third-stage filaria larvae back into humans through a subsequent bite. It was left to his protégé Ross to discover that parasites can travel two ways through the proboscis of a mosquito.
Discovering the Parasite in Human Tissue
The third piece of the human malaria puzzle—where sporozoites inoculated by mosquitoes undergo early development in the human host—was solved in 1948. Although previous researchers had found that bird malaria initially reproduced in tissues of the lymph system and the bone marrow, the sanctuary for primate and human malaria outside of red blood cells remained a mystery. Then H. E. Shortt, P. C. C. Garnham, and colleagues
at the Ross Institute of the London School of Hygiene and Tropical Medicine detected malaria parasites in the livers of rhesus monkeys infected with a primate malaria species. They subsequently found similar stages in liver biopsy specimens from human volunteers experimentally infected with P. vivax, and confirmed the same early sanctuary for P. falciparum (Garnham, 1966).
MILESTONES IN ANTIMALARIAL DRUG DISCOVERY AND DRUG RESISTANCE
“The Peruvian bark of which the Jesuites powder is made, is an excellent thing against all sorts of Agues,”
–William Slamon, Synopsis medicinae (1671)
The pharmaceutical compound known as quinine comes from the bitter bark of a high altitude tree native to South America. As legend has it, the Spanish Countess of Chinchon was treated with the tree’s bark in Peru in the 1600s. For many years, she was credited with bringing the bark—variously known as “Jesuit’s powder,” “Cardinal’s powder,” or “Peruvian bark”—back to Spain. However, since she later died in Peru, it is far more likely that Cardinal Juan de Lugo or another Jesuit priest introduced the remedy to Europe. In 1742, Linnaeus named the tree cinchona after the Countess, accidentally omitting the first “h” in her name (Meshnick, 1998).
In 1820, the French chemists Joseph Pelletier and Jean Biename Caventou isolated quinine from cinchona bark. Quinine quickly became a favored therapy for intermittent fever throughout the world. In the mid-19th century, British and Dutch botanical explorers combed the Andean cloud forest for cinchona in order to establish plantations in India, Ceylon, and the Dutch East Indies. However, many transplants produced only low-yield quinine crops. Eventually, for a few guilders, the Dutch government purchased 14 pounds of cinchona seed collected by Charles Ledger, an Englishman living in Peru. By grafting what was eventually named C. ledgeriana onto the hardier C. succirubra (McHale, 1986), the Dutch soon dominated cinchona cultivation, eventually producing 80 percent of the world’s quinine on the Indonesian island of Java before it was invaded during World War II.
Quinine remains an important and effective malaria treatment nearly worldwide to the present day, despite sporadic observations of quinine resistance. The earliest anecdotal reports of resistance date to 1844 and 1910 (Talisuna et al., 2004). Quinine resistance in P. falciparum was first documented in human volunteers in Brazil and in Southeast Asia in the
1960s (Peters, 1970). Loss of quinine sensitivity and treatment failures became more common in Southeast Asia in the 1980s (Bjorkman and Phillips-Howard, 1990), although, to this day, high-level quinine resistance has not yet been convincingly documented (Personal communication, N. White, Mahidol University, March 2004).
Because the Allies controlled Java and its valuable quinine stores during World War I, German troops in East Africa suffered heavy casualties from malaria. Determined never to lack for malaria drugs again, the German government commissioned a search for a quinine substitute following Armistice. The center of operations was I.G. Farben, part of the Bayer Dye Works. Farben chemists tested thousands of compounds until they found some that worked. The first promising agent was Plasmochin (pamaquine) in 1926, followed, in 1932, by Atabrine (quinacrine, mepacrine). Plasmochin, an eight-amino quinoline, was quickly abandoned due to toxicity, although its close structural analog primaquine is now used to treat latent liver parasites of P. vivax and P. ovale. Atabrine was in many ways superior, persisting in the blood for at least a week. However, it too had unacceptable side effects, including yellowing of the skin and, occasionally, psychotic reactions.
The breakthrough came in 1934 with the synthesis of Resochin (chloroquine), followed by Sontochin (3 methyl chloroquine). These compounds belonged to a new class of antimalarials known as four-amino quinolines. Although Farben scientists overestimated the compounds’ toxicity and failed to explore them further, ironically, they passed the formula for Resochin to Winthrop Stearns, Farben’s U.S. sister company, in the late 1930s. Resochin was then forgotten until the outbreak of World War II, when Allied forces were cut off from quinine—first by the German invasion of Holland, then by the Japanese occupation of Java. After French soldiers raided a supply of German-manufactured Sontochin in Tunis and handed it over to the Americans, Winthrop researchers made slight adjustments to the captured drug to enhance its efficacy. They called their new formulation chloroquine. Only after comparing chloroquine to the older and supposedly toxic Resochin did they realize that the two chemical compounds were identical (Honigsbaum, 2002).
Although the synthesis of chloroquine came too late to help malaria sufferers in the Pacific theater or Sicily (another malaria-ridden front), following World War II, chloroquine and DDT emerged as the two principal weapons in the WHO’s ambitious “global eradication” malaria campaign. Subsequently, chloroquine-resistant P. falciparum (CRPF) probably arose de novo from four independent geographic locations: the Thai-
Cambodian border around 1957 (Harinasuta et al., 1965); Venezuela and the nearby Magdalena Valley of Colombia around 1960 (Moore and Lanier, 1961); and Port Moresby, Papua New Guinea, in the mid-1970s (Grimmond et al., 1976). In Africa, CRPF was first found in 1978 in nonimmune travelers to Kenya and Tanzania (Lobel et al., 1985), spreading next to inland coastal areas and by 1983, to Sudan, Uganda, Zambia, and Malawi (Talisuna et al., 2004). Current evidence suggests that CRPF strains seen in Africa originated in Asia.
The pyrimidine derivative, proguanil, was another drug that emerged from the antimalarial pipeline during World War II. Proguanil’s success in treating humans (Curd et al., 1945) stimulated further study of its pharmaceutical class (agents that block folate synthesis in parasites and bacteria), and the development of pyrimethamine (Falco et al., 1951). However, as both monotherapies came into common use, it became apparent that malaria parasites could quickly alter the target enzyme of the two drugs, leading to resistance. Resistance to proguanil, for example, was observed within a year of introduction in Malaya in 1947 (Peters, 1987).
Sulfones and sulfonamides (drugs which act on another enzyme which helps the malaria parasite synthesize folic acid) were then combined with proguanil or pyrimethamine in the hopes of increasing efficacy, and forestalling or preventing the development of resistance (Cowman, 1998). P. falciparum strains resistant to pyrimethamine, and cross-resistant to proguanil and related compounds emerged in 1953 in Muheza, Tanzania; eight years later, these strains constituted 40 percent of P. falciparum isolates in a 15-mile radius (Clyde, 1966). Sulfadoxine-pyrimethamine (SP), today the most widely used antifolate antimalarial combination, was introduced in Thailand in 1967. Resistance to SP was first reported in Thailand later that year (Wernsdorfer and Payne, 1991). Although parasite resistance to SP spread quickly throughout Southeast Asia, it remained low in Africa until 5 or 6 years ago. Since then it has rapidly spread throughout Africa as well.
The development of mefloquine was a collaborative achievement of the U.S. Army Medical Research and Development Command, the World Health Organization (WHO/TDR), and Hoffman-La Roche, Inc. After World War II, about 120 compounds were produced at the Walter Reed Army Institute of Research (WRAIR) in an attempt to find replacements for quinine. Preclinical trials coincided with the appearance of chloroquine-
resistant falciparum malaria in areas of American military concern in Southeast Asia, and South America. Ultimately, WRAIR developed WR142490 (mefloquine), a 4-quinoline methanol. Mefloquine’s efficacy in preventing falciparum malaria when taken regularly was first reported in 1974 (Rieckmann et al., 1974). Soon after, it also was shown to be a successful treatment agent (Trenholme et al., 1975). Clinical evidence of parasites resistant to mefloquine began to appear in Asia around the time of the drug’s general availability in 1985 (Hoffman et al., 1985).
To reduce fever, “take a handful of sweet wormwood, soak it in a sheng of water, squeeze out the juice and drink it all.”
(Ge Hang, AD 340)
Artemisinin is the antimalarial principle isolated by Chinese scientists in 1972 from Artemisia annua (sweet wormwood), better known to Chinese herbalists for more than 2000 years as qing-hao (Klayman, 1985). Like other members of the family to which it is related (sagebrush, tarragon, absinthe), qing-hao is noted for its aromatic bitterness. The earliest report of its use appears in a Chinese book found in the Mawanhgolui Han dynasty tombs dating to 168 BC, where it was mentioned as a treatment for hemorrhoids. In Zhon Hon Bei ji Jang (Handbook of Prescriptions for Emergency Treatments) written by Ge Hang in 340 AD, it was recommended as treatment for chills and fevers (Trigg, 1990). Modern Chinese scientists found that an ethyl ether extract of qing-hao fed to mice infected with the lethal rodent malaria strain, Plasmodium berghei, was as effective as chloroquine and quinine at clearing the parasite (Honigsbaum, 2002). Soon after, Mao Tse Tung’s scientists began testing qing-hao in humans, publishing their findings in the Chinese Medical Journal in 1979.
From a historical perspective, there are several remarkable features to the story of qing-hao’s “rediscovery” as a potent antimalarial: 1) the structure of the drug was unlike any other known biological compound at the time; 2) within a few short years Chinese scientists had studied its antimalarial activity from test tube to patient, identified its active structure, then synthesized more active derivatives; and 3) the entire antimalarial drug discovery program resulted from an initial appeal for help from Ho Chi Minh to Zhou En Lai during the Vietnam War.
Today, artemisinin and other artemether-group drugs are the main line of defense against drug-resistant malaria in many areas of southeast Asia. To date, there have been no reported cases of stable, clinically relevant genetic resistance to artemisinin, although tolerance can be produced
through repeated in vitro culture of parasites in the presence of the drug (Meshnick, 2002).
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