Malaria, drug resistance, and climate change
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Alex Adami, University of Connecticut School of Medicine

Scourge of humanity for millennia, malaria remains unconquered despite billions of dollars spent on prevention and treatment. Efforts to control the disease, including billions from the Gates Foundation and numerous intergovernmental organizations, still see over 200 million clinical episodes and over 650,000 deaths each year (WHO data for 2010). Unfortunately, some of the strongest weapons we have in the fight against malaria show signs of weakening, with resistance to the most powerful antimalarial drugs appearing in Southeastern Asia. While the temptation to dismiss the problem as one of the tropics alone may be strong in an era of shrinking research budgets, the developed world ignores malaria and similar diseases at its peril. World travel and increasing global temperatures threaten to bring diseases today confined to the tropics to the shores of the United States and Europe.

Malaria presents as an acute febrile illness, with subsequent clinical features depending on the causative Plasmodium parasite. For some, including P. vivax and P. ovale, chronic relapses may arise from dormant forms of the parasite present in the liver. The most severe form, driven by P. falciparum, can progress from the initial mild disease to a severe illness that risks death. Prompt treatment is vital to prevent clinical decline, but initial symptoms (from fever to headache) may be so mild as to escape suspicion. Successful therapeutic strategies must be both powerful and swift-acting. Fortunately for the millions facing P. falciparum malaria, nature provided a weapon in the form of the Chinese Artemisia annua, known for centuries to be a powerful antimalarial agent. The active ingredient, artemisinin, was purified in the 1970s (driven, in an interesting twist, by personal fiat of Mao Zedong[1]). Political chaos and bureaucratic squabbles kept the drug from wide use until the early 2000s, but it soon proved its worth. Where other antimalarial agents like chloroquine required lengthy periods of accumulation within the Plasmodium parasite to deliver the fatal blow, artemisinin acts rapidly, producing major clinical improvement within a few days of administration. Since 2000, the WHO estimates that malaria mortality rates have fallen by a quarter worldwide and by a third in Africa, driven by advances in prevention (such as widespread use of mosquito nets) and the availability of artemisinin combination therapy, or ACT.

Malaria sporozoite inside infected epithelial cell (false color)Malaria sporozoite inside infected epithelial cell
Electron micrograph by Ute Frevert; false color by Margaret Shear
PLoS Biology, Vol. 3(6) June 2005 doi:10.1371/image.pbio.v03.i06.g001.

Sadly, the success was short-lived. In 2008, the first report[2] of ACT-resistant malaria appeared in Cambodia. Subsequent evidence[3] in 2009 cast a further pall on control efforts. Initial hopes that resistance would remain confined to one country were soon dashed, with another group relating evidence of artemisinin-resistant disease on the Thailand-Myanmar (Burma) border in early 2012[4]. While resistance thus far remains mild, few expect this to last. In retrospect, the discovery of resistance is no surprise. The chloroquines, long a mainstay of antimalarial therapy, saw resistance develop as far back as the 1970s; today, few nations with endemic malaria can utilize the cheap chloroquines effectively. Similarly, resistance to antifolate treatment (e.g. sulfadoxine-pyrimethamine), long widespread in South America and Southeast Asia, is growing in Eastern Africa. Reasons behind appearance of artemisinin resistance are many, from simple evolutionary pressure on the part of Plasmodium to overuse of artemisininal monotherapy. New treatments are in development, but the most optimistic estimates of further antimalarial medication development put new therapies five or more years in the future.

In the United States or Europe, researchers, policy makers, and trainees may review these sobering reports and wonder just how concerned to be. Myriad demands and research directions tug at scientists and clinicians. Research budgets of the most fortunate seem stalled, while the less fortunate see cuts and curtailing of programs. Why target a disease long banished? In the United States, malaria was expunged in the 1950s, with many of the estimated 1500 cases today driven by travelers to endemic regions. However, lessons from the arboviruses (transmitted by arthropod vectors) provide a sobering reminder of our vulnerability. The explosion of West Nile virus from isolated bird kills to nationwide presence in the United States is one such warning. Others, such as the various equine encephalitis viruses, continue to bedevil residents of the US despite years of eradication efforts. For this author, it is not uncommon when visiting home in the Carolinas to hear the drone of mosquito spray trucks on summer nights. While the equine encephalitis viruses are long resident in the United States, West Nile only recently jumped from African roots. What if malaria were to follow suit?

Further cause for concern in the developed world arises from global warming. Reports from Australia’s Lowy Institute and the WHO warn of increasing warmth and changes in rainfall patterns that may permit the spread of the mosquitos that carry malaria to regions that have never seen the disease or that once conquered it. Dengue virus, another arboviral scourge of the tropics, provides a sobering lesson. Originally endemic to Southeastern Asia, dengue virus rode a combination of globalization and global warming to spread to the Americas and parts of Africa. The mosquito that carries dengue is already pushing northward into the southern United States, and the virus is likely not far behind.

What does this mean for policymakers and researchers? Diseases once dismissed as concerns of the tropics must be addressed in more temperate regions. There is strong incentive to focus on the diseases presently affecting the US, neglecting those affecting other regions. However, this misses the opportunity to prepare for diseases that may be on our shores in the next decade. What if researchers had examined West Nile virus in the early 1990s, when the disease first emerged as a deadly human pathogen? Perhaps they might have created tools to fight the virus before it had a chance to jump to North American shores. Will we wait until malaria again reaches American shores, leaving millions to suffer against an increasingly resistant disease, before devoting significant research energies to the battle? Fortunately, the tireless efforts of large organizations like the Gates Foundation have brought new weapons to our arsenals before this scenario comes to pass. Writing in the New England Journal of Medicine, an international group funded by the Gates Foundation described the progress of a new malaria vaccine[5]. While early results are disappointing, with only a third of newborns given the vaccine protected from later disease, they represent an important first step toward eradication of the disease.

Neglected diseases matter. This is the lesson of malaria and the host of other diseases of the poorer nations of the world that today spread relentlessly across the globe. Even if the developed world decides that research for the charitable purpose of helping the millions afflicted is too expensive, it should well consider the reality that those diseases may soon reach its borders. The importance of existing public health efforts to prevent malarial spread, such as distribution of cheap and highly-effective mosquito nets, is not to be understated. However, promotion of existing incomplete solutions must be complemented by an active search for more complete solutions. Public health efforts must go hand-in-hand with scientific research on new antimalarial drugs and effective vaccines. The scientific community in the developed world, both funding agencies and researchers, ignores malaria and other tropical diseases at its peril.

For more on the history of malaria, visit the CDC or the WHO.

Further reading:

  1. Jr, D. G. M. For Intrigue, Malaria Drug Artemisinin Gets the Prize. The New York Times (2012).at <http://www.nytimes.com/2012/01/17/health/for-intrigue-malaria-drug-artemisinin-gets-the-prize.html>
  2. Noedl, H. et al. Evidence of artemisinin-resistant malaria in western Cambodia. N. Engl. J. Med. 359, 2619–2620 (2008).
  3. Dondorp, A. M. et al. Artemisinin resistance in Plasmodium falciparum malaria. N. Engl. J. Med. 361, 455–467 (2009).
  4. Phyo, A. P. et al. Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study. The Lancet 379, 1960–1966 (2012).
  5. A Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Infants. N. Engl. J. Med. (2012).doi:10.1056/NEJMoa1208394