The Fever: How Malaria Has Ruled Humankind for 500,000 Years (17 page)

In 1944, Fairley announced the results at a high-level military conference, in Atherton, Queensland. “It has now been amply demonstrated to you that the control of this disease is in your own hands,” announced the director general of Australia’s Army Health Services.
“It is purely a matter of training and discipline in all antimalarial measures, particularly the taking of Atebrin [the brand name for quinacrine] . . . I have no hesitation in saying, most emphatically, Gentlemen—the ball is now in your court.”
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A few months later, more than seventeen thousand Australian soldiers landed along the northern coast of New Guinea. There was no ambiguity about what they were to do to avoid malaria. Quinacrine had the stamp of approval from the very highest authorities. It is hard to imagine, given the known malariousness of New Guinea and the weight of confidence in quinacrine, that the troops did not take it religiously. But just to make sure, if they didn’t, their platoon commanders were under threat of removal. And it worked. For months, the troops stayed healthful despite the swarms of malarial mosquitoes around them.

But then, about three months into the campaign, the troops started to advance alone the coast. Inexplicably, their antimalarial armor of quinacrine seemed to falter. Three hundred and fifty soldiers fell ill with malaria.
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News of this must have jolted the troops like a bolt of lightning. Nobody particularly liked taking quinacrine, and these infections could only have been seen as an utter betrayal. The hated drug had failed them! But the leadership, Fairley’s faith fresh in their minds, suspected just the opposite. Having worked so hard to implement the distribution of quinacrine, how could they think otherwise? For them it couldn’t be the drug that had failed. Rather, the troops had failed to take their medicine.

Amid the controversy over the three hundred and fifty fevered bodies, the troops’ commander, Major General J.E.S. Stevens, urged greater compliance. “Brigadier Fairley . . . is the most eminent malariologist in the world,” he announced.

He has devoted his whole life to this disease. He carried out the most extensive investigations and experiments made in the history of mankind and from that made a definite pronouncement that
1 tablet of Atebrin per day will suppress malaria. It would be presumptuous for us to suggest that this authority is not absolutely correct. There must be no weakening of our faith in his doctrine, otherwise the whole structure of antimalarial measures will collapse.
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To restore the drug’s reputation and the protection he believed it provided, Stevens cracked down even more heavily on the wilting troops. Not only did the troops have to line up to receive their tablet, he declared, but the commanding officer was to place the tablet in each mouth himself. After the soldiers drank some water and swallowed, they would be required to call out their names “in a loud voice,” and finally, to prove beyond a shadow of a doubt that the pill had in fact gone down their throats, they were to open their mouths for a thorough inspection.
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In addition, the soldiers were banned from taking off their long-sleeve shirts, trousers, and boots, even “for the purposes of ablutions.” Every two hours from dusk to nightfall, whistles were blown, signaling the troops to coat another layer of mosquito repellent onto their unwashed clothes and bodies.
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And yet despite the humiliating pill popping and the stinky repellent smearing, malaria rampaged. Every week, another seventy soldiers came down with the disease. The day before a brigadier visited, a falciparum-infected lieutenant colonel became so sick he had to be evacuated.
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It must have seemed to officers that the New Guinea troops were in the throes of some kind of willful defiance. The instructions to take the quinacrine had been clear and unequivocal. Such a dangerous breakdown of order would have been shameful enough. But what the higher-ups found, when they arrived to investigate, might have been even worse.

Utterly cowed, the soldiers weren’t just taking the drugs, they were wallowing in them, taking even more than required. They took twice the recommended dose. They took it not just to prevent malaria
but for aches and pains of all kinds. “One combatant officer said the troops preferred [quinacrine] to aspirin for headaches.”
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Finally, Fairley arrived on the scene to evacuate some infected troops to Cairns for study. Perhaps the quinacrine was not being absorbed properly, he thought. Or perhaps the troops had been infected by some new, more virulent kind of malaria. Or perhaps they didn’t have malaria at all and had been sickened by something else entirely. He’d study their blood, make sure they were getting enough drug, and pinpoint the pathogen that had struck them.

Back in Cairns, Fairley found that malaria parasites had infected at least seven out of nine soldiers. But all of them, incredibly, had quinacrine coursing through their veins. It was a finding, one malariologist later wrote, “without precedent in the history of man’s fight against malaria.”
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The obvious conclusion was that malaria parasites had achieved the ability to circumvent quinacrine’s killing mechanism. Perhaps a strain of the parasite had mutated.
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Most of the soldiers would have had no acquired immunity to
P. falciparum
, so the parasite inside their bodies would have been able to multiply prodigiously, providing ample opportunity for the development of mutations, which occur at a rate of one in a billion.
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Or perhaps the drug-resistant parasite had been there all along, its hidden abilities unnoticed until quinacrine came along.

Wherever this parasite came from, it rapidly spread, thanks to heavy quinacrine use among not only the Australians but also the similarly malaria-plagued enemy troops, positioned nearby. And the more religiously the soldiers took their quinacrine, the more successful the impervious parasite grew.

But Fairley could not bring himself to face what these findings meant. It was difficult enough getting the troops to take quinacrine without suggesting its abject failure. He still suspected that the troops—not the quinacrine—had played some role in diluting the drug’s killing power. After all, only half as many officers got infected
as troops. And why would the parasite defang the drug only in New Guinea and nowhere else? So Fairley did his best to protect the reputation of the drug he’d worked so hard to elevate. When he wrote up his results, he allowed that a few parasites circumvented quinacrine, but most of the cases of malaria had occurred, he said, because of failures of “discipline.”
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To be fair, there was no way for Fairley to have known how this quinacrine-resistant parasite incubating in New Guinea would fare elsewhere in the world, or even over time in New Guinea. It could have been a one-off occurrence, an instance of a strange mutant parasite that would never be seen again. Perhaps it would die out on its own, poisoned by some other mutation that came along with its drug-resisting capacities. Circumventing a drug designed to kill couldn’t be easy. Surely the ability placed some kind of compensatory burden on the parasite, the way, say, an Olympic swimmer might not be able to run very well. If the drug-resistant parasite had to compete for blood and mosquito with the usual array of malaria parasites, it would be hobbled, a world-class athlete in a neighborhood street fight. It wouldn’t be able to spread far.
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Which is why the international community—despite having formed, after World War II, a body to oversee global public health, the World Health Organization—equivocated over reports of malarias that resisted chloroquine, too.

The first hints of malaria’s retaliation against chloroquine emerged from Colombia and along the Thai-Cambodia border in 1957, just twelve years after the drug was introduced. One day two geologists who had been working for an oil company in Colombia staggered into a Dallas hospital. They were suffering falciparum malaria. But chloroquine, the king of antimalarial drugs, failed to cure them. Not long after, doctors in Bethesda treated a patient who contracted
P. falciparum
in Thailand. Chloroquine didn’t work for this patient,
either. “Oh my God, here we go,” the malariologist Robert G. Coatney remembers thinking.
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Chloroquine kills the malaria parasite by concentrating inside its food vacuoles, where the parasite digests its meal. The parasite attempts to expel the drug, but normally can’t do so fast enough. But parasites with a gene called pfmdr1 can spit chloroquine out of their food vacuoles fifty times faster than normal.
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Such parasites, commented the Centers for Disease Control’s Peter Bloland, could “eat chloroquine for lunch.”
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Not just chloroquine. Parasites endowed with pfmdr1 can resist other synthetic antimalarial drugs, including amodiaquine, introduced in the early 1950s,
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mefloquine, introduced in the mid-1970s,
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and halofantrine
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and quinidine,
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introduced for malaria in the early 1980s.
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One by one, the malaria parasite defanged each drug thrown at it. The more effective and widely used the drug, the faster the parasite subjugated it. The antimalarial drug proguanil begat the drug pyrimethamine. The parasite resisted both. Pyrimethamine was combined with a drug called sulfadoxine—a popular combination known as SP, or by its brand name, Fansidar. Parasites resistant to the drug emerged the same year they were introduced in Thailand.
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Hoffmann–La Roche launched the antimalarial drug mefloquine commercially in 1975. Parasites resistant to the drug emerged a year later.
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In 1961, WHO gathered its experts to consider the problem. They agreed that the implications of malaria’s resistance were “serious,” indeed. But like Fairley, they dragged their feet on sounding an alarm. First, the WHO experts wanted to know all the circumstances under which each “alleged” case of resistance had appeared. They wanted confirmation that the drug in question had, in fact, been appropriately consumed and absorbed. They wanted the allegedly resistant parasite to be captured, and for its passage into an uninfected, nonimmune person to be observed.

As serious as the silent spread of drug-impervious malaria was, the need for discretion, they decided, was even more serious. “It is
evident that this and other similar records demand the fullest and strictest investigation,” their final report advised, “before reports on them are circulated or published.”

After all, malaria’s drug resistance had not emerged as a coordinated strike, with all drugs failing everyone every where. It was more like guerrilla warfare, with rebellions confined by time and place. The old drugs still worked, at least a bit, for some people in some places some of the time. And so the drug war against malaria continued. Only the most exceptional ecological, demographic, and political circumstances could motivate the development of a new chemical weapon, one that could directly challenge the parasite’s insurrection.

As WHO cogitated, conditions in the wet jungles of Southeast Asia deteriorated. There, the chloroquine-resistant falciparum parasite enjoyed a fortuitous and unpredictable stroke of luck. Its edge over other parasites was not restricted to the interior of bodies dosed with chloroquine, however prevalent those may have been. Inside two malaria vectors, the Southeast Asian mosquito,
Anopheles stephensi
, and
Anopheles dirus
, from the western Pacific islands, the drug-resistant parasite was able to develop more effectively than drug-sensitive parasites.

What were the odds? But this was just the edge the drug-resistant parasites needed. Its numbers gained on those of its rivals until its descendants, uniformly endowed with the ability to repel chloroquine, had by the early 1960s become not just a pesky guerrilla tribe but the dominant strain in parts of Southeast Asia and western Oceania.
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The unlikely partnership between drug-resistant
P. falciparum
and Southeast Asian malaria mosquitoes happened to coincide with the political and geographical disruptions of the 1959–1975 conflict between communist North Vietnam and U.S.-supported South Vietnam. Just as the drug-resistant parasite achieved its hegemony, hundreds
of thousands of unwitting, nonimmune people from the lowlands poured into the malarious foothills of northern Vietnam, resettled by the North Vietnamese government to provide logistical support for the burgeoning war effort. For five to ten years, these people suffered “near-starvation and constant illness,” according to Pamela McElwee, an environmental historian of Vietnam,
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while their malaria-naïve bodies provided ample fodder for the drug-resistant parasite to feast. The Vietnamese jungle soon became the world’s premier incubator of drug-resistant malaria.

Had the impending epidemic been confined to the resettled villagers, the military authorities in Vietnam would not necessarily have done much about it. But the exigencies of battle soon turned that malarious jungle into the very lifeline of the war effort. The American bombs started falling in 1965. With the U.S. Navy blocking sea traffic, the North Vietnamese started using the jungle’s twelve thousand miles of shaded, mosquito-ridden track as a supply route, sending troops en masse to march through the jungle. They called it the Ho Chi Minh Trail.
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And it was a deadly one. Exposed to the bites of mosquitoes and fed by the malarious locals, the troops had ample contact with the drug-resistant malaria parasite. After one month-long journey down the trail, only 120 of a regiment of 1,200 Vietcong soldiers were fit to fight. “They had a saying,” one Vietnamese battlefield doctor remembers. “‘We fear no American imperialists, only malaria.’”
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The bodies of the people who died on the trail fill twenty-two cemeteries.
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