The Coming Plague

by Laurie Garrett

  The definition of malaria, then, was that it was a disease whose existence was proven by reversing it with drug treatments.173 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.

  In 1992, having concluded that WHO policies were inadequate and the CDC’s analysis better reflected their situation, scientists within Malawi’s Ministry of Health recommended a change in policy. And Malawi became the first African nation to abandon chloroquine.

  Fortunately, Africa still had options. Though resistances to other antimalarials had emerged, they were not widespread, and alternative, albeit considerably more expensive, medications were available.174

  In southern Asia, however, where chloroquine resistance first appeared in the 1950s,175 the malarial parasites were often multiply resistant to all the readily available drugs.

  Though most Asian malaria was due to the less dangerous P. vivax parasite, the sheer density of parasite-carrying mosquito populations in tropical southern Asian areas was far greater than was seen in Africa with Anopheles gambiae and P. falciparum. In addition, many Asian nations had lively pharmaceutical black markets and/or over-the-counter sales of antimalarials as early as the 1950s. Finally, in some Asian regions both P. falciparum and P. vivax were present, creating a mixed malarial population.

  It wasn’t long after the first laboratory reports of chloroquine-resistant strains in Asia that treatment failures were correlated with the emerging mutants. In 1962, for example, three members of an American medical research team working in western Cambodia came down with severe malaria, despite taking prophylactic chloroquine. Analysis of the Cambodian P. falciparum strain, as well as a Malaysian strain, showed that they were resistant not only to chloroquine but also to pyrimethamine and proguanil. 176

  A team of National Institutes of Health researchers tested the drug-resistance capabilities of several Cambodian and Malaysian P. falciparum strains directly by injecting samples into prisoners confined in the federal penitentiary in Atlanta, Georgia. In this ethically questionable manner (due to the strong potential of coercion among alleged research volunteers in a research environment), the NIH scientists demonstrated that only one of the six Asian strains remained susceptible in 1963 to chloroquine and three strains were resistant to all four of the leading antimalarials of the day (chloroquine, proguanil, mepacrine, and pyrimethamine).177

  A decade later—still five years before the first resistant parasites emerged in East Africa—chloroquine resistance was widespread in Thailand, Burma, Bangladesh, India, Indonesia, the Philippines, Cambodia, Sri Lanka, Malaysia, Vietnam, Australia, Laos, Japan, Singapore, Papua New Guinea, the Solomon Islands, Vanuatu, and China.178

  To counter the trend toward nearly universal P. falciparum chloroquine resistance in Asia, WHO recommended the use of multiple-drug treatments. The thinking, which paralleled contemporary approaches to antibiotic resistance in bacteria, was that emerging resistance could be snuffed with simultaneous use of other drugs, one of which was sure to kill off the mutant strains.179

  But it wasn’t long before multiple resistance expanded in the P. falciparum parasites. In the wake of widespread social disruption, a mass refugee exodus, and a genocidal campaign conducted by the Khmer Rouge, a new malaria strain emerged in Cambodia that was strongly resistant to both chloroquine and Fansidar. The mutant strain struck a refugee camp located along the Thai-Cambodian border, causing widespread disease. The CDC responded by recommending a switch from standard chloroquine plus Fansidar treatments for malaria in the region to a combination of quinine and tetracycline.180

  Resistance spread and grew stronger all over Asia throughout the 1980s at a pace that was staggering.181

  During the same time period many of the Anopheles mosquito species that carried malarial parasites in Asia developed resistance to DDT, making insect control both more difficult and costly. Some of the insects expanded their territories, appearing in ecologies not previously thought to be suitable for their breeding and feeding.

  Even more troubling, the ratio of P. falciparum to its less dangerous cousin P. vivax changed in many places between the mid-1970s and the late 1980s. In India, where over 90 percent of all malaria was the milder P. vivax form in 1976, by 1989 only 65 percent were vivax, the remainder falciparum. In Sri Lanka, where falciparum had been virtually nonexistent, by 1990 close to half of all disease was due to the more dangerous parasite. Burma saw the percentage of falciparum jump from 60 percent to more than 90 percent.182

  One of the great tragedies was Nepal, which had been the success story of America’s earlier efforts to eradicate malaria. Between 1950 and 1970, Nepal’s malaria rate was reduced by an extraordinary 99 percent, from 2 million cases and 300,000 deaths per year to a mere 25,000 cases and fewer than 200 deaths. But by 1985 the country’s malaria incidence had doubled, and mortality had increased due to parasite resistance. Similar patterns were seen throughout southern and western Asia.183

  During the Vietnam War the U.S. Army invented mefloquine and in the early 1980s it was tested on civilians as an alternative to chloroquine. By 1987 mefloquine had supplanted most other antimalarials, becoming the drug of choice in much of Asia. It was a highly effective drug, offering minimal toxicity, at a time when no other agent appeared to guarantee protection against P. falciparum in Asia.184

  But in 1986, along the Thai-Cambodia border, malarial strains resistant to mefloquine alone, and in combination with chloroquine and Fansidar, emerged. In addition, strains appeared in the crucial area that were less responsive to quinine, rendering some malaria cases untreatable. By 1990 the mefloquine cure rate in Thailand had plummeted from 98 percent to 71 percent. And the following year halofantrine, the only remaining marketed drug, which had never even been used in the country, was rendered close to useless in Thailand by virtue of P. falciparum resistance.185

  When the new mefloquine-resistant P. falciparum strain emerged, Cambodia was in a state of civil war, a 16,000-strong United Nations peacekeeping force was poised to enter the area, and 360,000 refugees bivouacked across the border in Thailand were scheduled for imminent repatriation. It was an opportune moment for the microbe.

  The new strain was resistant to chloroquine, Fansidar, mefloquine, and their chemical cousins. That left only two available drugs, quinine and tetracycline. Neither was ideal. Quinine was a poor prophylactic drug, tetracycline a weak treatment.

  By March 1992, WHO estimated that more than half of all malaria cases in Cambodia involved the new strain, and control seemed impossible because years of civil war had left the country’s public health system in a state of ruin. The National Cambodian Malaria Control Office, such as it was, estimated that some 10,000 people died of the new malaria in that country in 1991. But officials conceded it was just a conservative guess.

  At her laboratory in the Harvard School of Public Health, Dyann Wirth worked at a feverish pace in 1992–93, trying to understand the nature of the mutation in the new strain and find a way to defeat it. She concluded that the parasite had produced a large, unique protein that nestled in its membrane. When the drugs entered the parasite’s environment, the protein acted as a pump, shunting the chemicals out of the P. falciparum. Though such a mechanism had previously been seen for chloroquine resistance, Wirth and several other scientists were convinced that the new strain had a pump that evicted nearly all the antimalarial drugs.186

  Evidence that such a pump existed was strong. A heart disease drug called verapamil, which blocked calcium pumping across cellular membranes, could reverse drug resistance. Some scientists urged WHO to release drugs that combined verapamil and chloroquine: one drug would shut down the pumps, the other would stop the parasite. Researchers saw evidence of such pumps in test-tube studies: when they compared resistant malaria to nonresistant, the resistant strains had forty to fifty times more chloroquine on the outside of the parasi
te.

  The pump mechanism was genetically controlled by at least two so-called mdr (multidrug-resistance) genes. No one knew how the malaria parasites got mdr genes—such genes had previously been seen operating in mammalian cancer cells, pumping out chemotherapy drugs. Nevertheless, Wirth was convinced that mdr genes not only were present in the super-resistant bugs but were amplified so that the parasite made huge numbers of the pumps.

  “Once this kind of mechanism occurs, it means resistance will emerge even before the drug can be invented,” Wirth said.

  It was tempting to conclude that the pump mechanism explained why the pace of resistance had so accelerated. Though chloroquine resistance first emerged in the 1950s, it and most of the other early antimalarials remained effective worldwide for decades. But in the 1980s resistance emerged at an extraordinary pace, seemingly from the moment drugs were introduced in some Asian areas, particularly Thailand and Cambodia. Most early mutant P. falciparum strains resulted from apparently random point mutations, and those strains were resistant to one drug at a time. But by the end of the 1980s, Indochina seemed to be awash in multidrug-resistant parasites.

  Perhaps, malariologists whispered nervously, the presence of a pump mechanism provided the parasites with a way to quickly outwit new drugs, by fine-tuning their pumps to adapt to each new agent. If that were so, the resistance trend would only worsen, and accelerate, wherever in the world the malaria parasites possessed such pumps.187

  In 1989, after forty years of effective trouble-free use, physicians treating people in Papua New Guinea who were infected with P. vivax parasites noticed that chloroquine no longer cured that type of malaria.188 Though resistance problems had been apparent with P. falciparum almost from the beginning of the chloroquine revolution, P. vivax had always remained vulnerable to the drug.

  Malariologists had hoped that the Papua New Guinea P. vivax cases were nothing more than an odd fluke—perhaps even a failure due to improper treatment—but in 1993 chloroquine-resistant P. vivax appeared in Indonesia (Irian Jaya).189 Because P. vivax had a more complicated life cycle inside humans, and spent far longer in the liver, the parasite’s vulnerability to drugs differed from that of P. falciparum.

  “There is no obvious replacement for chloroquine,” researchers said.190

  “We are in a crisis,” declared WHO’s parasitic disease expert Tore Godal. “The situation is truly alarming.”

  Only one alternative drug remained. For over two thousand years Chinese herbalists had treated malaria with extracts from the sweet wormwood, or Artemisia annua, plant—called qinghao in Chinese. The plant’s chemicals had long been used to bring down fevers. In 1972 Chinese scientists succeeded in isolating the responsible chemical in qinghao, giving it the name qinghaosu (or, alternatively, arteether and artemether). In the 1980s, as they witnessed the rapid rise of drug resistance throughout the malarial world, WHO and the Walter Reed Army Institute of Research teamed up to conduct studies of the drug. And in 1994, with much fanfare, WHO announced completion of successful field trials of the drug in Vietnam.

  WHO possessed the patent. And no drug company was interested. Critics wondered why WHO was embarking on such a mammoth project, given that synthesized slightly altered versions of the chemical were in development elsewhere.191

  Meanwhile, WHO officials spoke candidly about the need to “protect” the Chinese drug from the social conditions in Southeast Asia that led to the downfalls of chloroquine, halofantrine, mefloquine, quinine, Fansidar, proguanil, and every other antimalarial. But in late 1993 a French traveler picked up a strain of P. falciparum in Mali, West Africa, that was resistant to everything, including the new Chinese drug. Researchers discovered four strains of P. falciparum in Mali that were resistant to qinghaosu, though the drug wasn’t widely available in the country.192

  Insiders like Brinkmann and Campbell were skeptical. They had seen the conditions in Asian malarial regions up close, understood how the mosquitoes and parasites spread, and doubted that without strong political will in key countries any drug could be protected.

  Political will was in short supply. And biology was working against public health.

  Ten percent of Southeast Asia was rain forest, involving sixteen ecologically distinct types of forests. Malaria in the region was forest malaria, which meant that standard mosquito control measures were ineffective. How could one spray DDT in a wet, humid, dense tropical jungle?

  At least thirty major species of mosquitoes carried malaria in Asia, many of which fed on a range of other animals as well as humans. Among them, these mosquitoes had adapted to breed and feed in every possible Asian forest context: a bamboo stump filled with rainwater, an irrigation canal, jungle pools, puddles of muddy water left by the feet of marching soldiers, elephant footprints, wheel ruts, rice paddies, lagoons.

  These sturdy insects spanned most elevations of southern Asia. And they fed on people at all sorts of times of day and night. Many were resistant to the key pesticides, and most were “wild mosquitoes,” meaning that they stayed away from open spaces and human habitations, preferring the safety of dense tropical foliage.

  People who lived or worked in the forested areas were constantly bitten by mosquitoes. For centuries an ecological balance existed between the humans and the parasites, via the mosquitoes. A large percentage of the humans would die of the disease during infancy, but survivors, who were “vaccinated” every day by mosquitoes that injected parasites into their blood, were immune, or, as Kent Campbell would put it, tolerant.

  Efforts to eradicate malaria severely disrupted that balance. Temporarily successful mosquito control programs eliminated the daily “vaccinations,” and immunity immediately disappeared. Prophylactic use of antimalarials fended off disease, but also lowered immunity. In periodic times of drug scarcity, surges of malaria cases could be seen.

  The female mosquitoes, which fed voraciously on a range of creatures (from reptiles to humans), absorbed all kinds of microbes from animal blood. Different strains of malarial parasites co-inhabited the insect’s gut, and there was evidence of genetic exchange and shuffling occurring between the various microbes inside the mosquitoes.

  Entomologists felt certain that the roughly thirty identified species of malaria-carrying mosquitoes represented only a small percentage of all the Asian forest insects that were capable of serving as vectors for the parasites. It was, however, extremely difficult to study and taxonomically identify insects in such densely forested ecologies.

  “Malaria is an ecological disease,” wrote Indian scientist V. P. Sharma.193

  Human beings in these regions were highly mobile in the 1970s, 1980s, and 1990s. Warfare and civil strife, religious persecution, economic necessity, and natural disasters prompted tens of millions of families and individual laborers to migrate within countries and between nations. More than half a million Cambodians alone were refugees during the 1980s. The Indonesian government transplanted nearly seven million people in 1990 to colonize forested outer islands.

  With this mass movement came great risk for malaria. Most of the migrating humans either came from nonmalarious regions and had no immunity or were moving between areas inhabited by distinctly different strains or species of parasites. When a concentration of such immune-naïve Homo sapiens settled alongside a forest area, the mosquito population swelled and malaria was soon rampant.

  Warfare and civil strife, such as the Vietnam War or the long Khmer Rouge insurgency in Cambodia, not only produced mass human migrations but directly disrupted the ecology in ways that were advantageous to the mosquitoes. Rain-filled bomb craters, abandoned water-soaked military vehicles, and such leavings of war created ideal breeding sites for insects. As Asia’s human population exploded in the 1980s, desperate people pushed into forest lands, chopped and burned their way to the creation of farmlands. Public health and medical systems were nonexistent in mu
ch of Asia’s forested area because the human inhabitants were usually poor, often migratory, and increasingly resided in areas not previously inhabited by people.

  In many regions flagrant overuse of antimalarial drugs resulted, as adults and children alike swallowed whatever they could afford in an attempt to protect or cure themselves. Poorly trained paramedics widely dispersed drugs to anyone who was suspected of having malaria.

  “I have never seen such a low level of health infrastructure, even in Africa,” Ethiopian malariologist Awash Teklehaimont, a scientific consultant to Indochina for WHO, said. “Chloroquine injections are done openly, in the marketplaces, by quacks, under full view of the police,” he added, referring to Cambodia in 1992. With local physicians paid only five dollars a month, it was perhaps unremarkable that the shelves of government clinics seemed always to be empty, while the black market had no shortage of supplies.

  If there was a single Asian focus of all this social/ecological/medical interaction, a place where resistant strains most often appeared, it was the gem-mining area straddling the Thai-Cambodian border. On the Thai side were squadrons of underpaid police and soldiers, anxious to look the other way when fortune seekers illegally entered the area, and equally eager to grab them as they exited, taking a percentage of the ruby and emerald harvest. On the Cambodian side was the Khmer Rouge army of Pol Pot, which exacted their percentage from the gem miners to support continued insurgency.

  As word of the lawless access to fortunes spread during the 1980s, men poured into the area from all over Asia: Indians, Burmese, Thais, Cambodians, Lao, Vietnamese, Chinese. They moved surreptitiously, avoiding border patrols, police, soldiers, and, of course, health authorities. The area they moved into was one of dense rain forest inhabited by more than a dozen different species of wild, falciparum-carrying mosquitoes.