The Asia-Pacific Journal | Japan Focus Volume 13 | Issue 45 | Number 1 | Nov 09, 2015

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Malaria in the Asia-Pacific Region

J. Kevin Baird

Summary

Despite its relative invisibility to most peopleliving in the urban Asia-Pacific, endemicmalaria occurs across the region. The uniquecharacter of Asian-Pacific malaria includes aserious problem of drug resistance, dominanceof a particularly difficult species to control andtreat, and another that normally dwells inmonkeys but often infects humans. Mostnations in the region with endemic malariahave called for its elimination by the year 2030.Meeting that ambitious goal will requiremobilizing technical and financial resources,and social and political will. Malaria is aformidable foe fully capable of defeating half-hearted efforts to eliminate it.

Key Words: Malaria, public health, control,treatment, elimination

Introduction

Many well-educated people think of malaria asa single disease that is largely, if not entirely,isolated to the African continent. This includesmany living in the enormous urban centers ofthe Asia-Pacific. They go about their daily livesin gleaming modern cities with convenientaccess to professional clinical care. Some mayworry about dengue fever, and an unlucky fewwill actually contract it. Others will be moreanxious about threats like MERS-CoV orparticular strains of influenza that are muchless common than dengue, but with muchhigher fatality rates. There are no vaccines orcures for these viral infections. Malaria, bycomparison, is not only thought of as a distantthreat, but is also widely believed to becompletely preventable and curable withinexpensive simple therapies. This is an illusion

borne of a well-to-do urban worldview. In truth,the Asia-Pacific region is rife with endemicmalaria and it faces challenges in mitigatingand eliminating this serious problem.

The challenges are steep. There is no vaccineagainst malaria. Emerging strains of drug-resistant malaria threaten incurable infections.Some infections cannot be treated safely andpatients suffer repeated clinical attacks overmany months. Other infections derive fromforest-dwelling monkeys. About two billionthroughout the Asia Pacific live at risk of theinfection and tens of millions contract it eachyear.1 Unknown numbers, perhaps as many astwo hundred thousand each year, do notsurvive the malaria attack.2 This articleexplores the Asia-Pacific malaria problem andthe misplaced broad public complacencyregarding it.

The highest risk in urban centers is not malariaitself, but ignorance of or indifference to themalaria occurring in rural areas. The educated,empowered and endowed sectors of Asia-Pacific metropolises can act against malaria inthe region if they see and understand theformidable problem and the challenges faced ineliminating it from the region. This article aimsat such awareness.

What is Malaria?

Malaria is a term that encompasses a widevariety of diseases caused by single-celledparasites in the genus Plasmodium. There areover 170 species in this genus that infectparticular species of mammals, birds andreptiles. Only 5 species are known to routinelyinfect humans: Plasmodium falciparum,Plasmodium vivax, Plasmodium malariae,

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Plasmodium ovale, and Plasmodium knowlesi.Among these, P. falciparum and P. vivax causethe vast majority of infections. All of theseparasites follow a complicated life cycle thatdepends upon particular species of mosquitoesin the genus Anopheles. The ability to transmitmalaria by these species varies among themlike the ability to play chess among humans –from those who don’t know how to grandmasters. While it is true that mosquitoes carrymalaria from one person to another, in astrictly biological sense the parasites usehumans to carry malaria from one mosquito toanother – the plasmodia have sex in themosquito, which makes it, and not us, thedefinitive host for these parasites. Figure 1illustrates the life cycle of P. vivax, which isonly slightly different from the other species,but in an important way to be explained later inthis article.

Figure 1. The extraordinary complexity in the lifecycle of malaria parasites, with the human liver atlower left, the human blood stream at lower center,and the gut and salivary glands of anophelinemosquitoes at upper right. From the WHO as adaptedfrom Mueller et al.3

About a week or so after being bitten andinfected, people begin to show symptoms asparasites emerge from the liver and begininfecting red blood cells. The invasion, ruptureand reinvasion of red blood cells account for

the cyclical nature of the intense fever andchills of a malaria attack. If the infection is notproperly diagnosed, or the patient waits toolong before seeking treatment, the infectioncan progress to death in people who lack apartial immunity by prior chronic exposure tomalaria. This is true of all of the species ofmalaria, but especially P. falciparum, P.knowlesi, and P. vivax. Even with promptdiagnosis and appropriate treatment, theseinfections (excepting P. malariae) lead tointense illness with complete debilitation for atleast several days. It is a devastating illnessand fatal if not properly managed. The causesof death by malaria are many, including coma,severe anemia, respiratory distress, liver orkidney failure, and shock.

One of the primary reasons malaria tends to bealmost invisible is its affinity for impoverishedand isolated rural areas, and its aversion tourban environments. Access to qualityhealthcare in cities bodes poorly for parasitesurvival. Further, the anopheline mosquitovectors do not survive in urban environmentsand are not found there. The single knownexception to this rule is a particular species,Anopheles stephensi, which thrives in themassive cities of India and causes a great dealof malaria in them. That species adapted tobreeding in sunlit pools of clean rooftop watercreated by air conditioning units. Mostmosquito vector species, however, have notolerance of urban grime. Malaria victimizesthe poorest of the poor in rural settings, thosehaving limited access to rudimentary healthcare that governments struggle to deliver tothe many remote peripheries of moderncivilization. These people are among the mostinvisible to us, and they suffer tremendously invast numbers from malaria and other diseasesendemic to the Asia-Pacific.

Malarious Asia-Pacific

A glance at a world map of the levels of malariaprevalence reveals what most residents of the

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Asia-Pacific do not realize – that malaria is notsolely an African problem, it is all around usright here in the region, and quite a lot of it.The two maps of Figure 2 show the distributionof the two dominant species of parasites thatcause malaria, P. falciparum and P. vivax.Wherever there is color, even if blue, indicatesstable transmission of malaria, meaning it isalmost always present. The dark grey areasindicate unstable transmission, where malariais only sometimes present. Figure 3 zooms inon the As ia -Pac i f i c and revea ls theextraordinary patchwork of transmission, bothbroad swaths of persistent stable transmissionalong with a scattering of both very high riskand risk-free pockets.

Figure 2. Maps showing the distribution of malariarisk globally for Plasmodium falciparum (top)and Plasmodium vivax (bottom). See color keys inFigure 3. Courtesy of the Malaria Atlas Project(http://www.map.ox.ac.uk/browse-resources/),University of Oxford, United Kingdom.

Notice that the distribution of P. vivax reachesmuch farther north than P. falciparum. Thereare a couple of important reasons for this.First, this species develops quicker at lowerambient temperatures in its cold-bloodedmosquito host, allowing it to thrive intemperatures P. falciparum cannot tolerate.Secondly, P. vivax is able to place dormantforms in the human liver (called hypnozoites,see Fig.1), providing it a safe haven during theharsh winters on the Korean Peninsula, forexample, when there can be no mosquitoes totransmit them.

Figure 3. Maps showing the distribution of malariar i sk in the As ia Pac i f i c for Plasmodiumfalciparum (top) and Plasmodium vivax(bottom).“PR” indicates prevalence rate, or the percentage ofresidents found infected by malaria parasites inpopulation surveys of blood by microscopicexamination. The scales between P. falciparum and P.

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vivax differ for biological and epidemiologicalreasons. Courtesy of the Malaria Atlas Project(http://www.map.ox.ac.uk/browse-resources/),University of Oxford, United Kingdom.

The World Health Organization monitorsmalaria reporting globally, and in 2013 itestimated a total of 11.2 million cases of P.vivax in the Asia-Pacific, along with 25 millioncases of P. falciparum.4 That’s 36.1 millionattacks of malaria in the region. Somescientists believe these WHO estimates areunderest imated by a large degree . 5

Remarkably, in the instance of P. vivax, over80% of all attacks globally occur in the Asia-Pacific, making this principally a regionalproblem.

Malaria Problems of the Asia Pacific

Malaria as a public health problem variestremendously around the globe with respect todifficulties faced in striving to solve it.Malariologists in Africa wrestle with verydifferent technical issues from those managedby malariologists in the Asia-Pacific. It isimportant to understand that technicalprogress and health dividends in Africa will notnecessarily translate to the same in the Asia-Pacific. A brief exploration of three malariaproblems unique to the region will serve toemphasize that important point: artemisinin-resistant P. falciparum, primaquine therapyagainst P. vivax, and monkey malaria. Thechallenge in Africa is a very heavy burden ofinfection by a single species of parasite P.falciparum, which until today remains sensitiveto the frontline drugs against it. The species P.vivax is virtually absent from most of Africa, asare the malarias transmitted from monkeys orapes to humans.

Artemisinin-resistant P. falciparum

Forty years ago the drug chloroquine served asthe primary treatment for all malariasworldwide. The extraordinary history of thedevelopment of this workhorse drug includes

Nazi agents in Algiers and Allied capture of anexperimental formulation of the drug in 1943.6

Licensed in the USA in 1946, its useful lifebegan to unravel at the border betweenThailand and Cambodia in the 1960s. Theparasite P. falciparum evolved a means ofsurviving chloroquine, and with continued usethe resistant strains overwhelmed anddominated the sensitive strains. Over theensuing 20 years, those resistant strains spreadaround the globe. Millions are thought to havelost their lives to infections by resistant strainstreated with what had become a useless drug.7

Eventually, after a great deal of research andadvocacy for change, chloroquine was replacedwith a new c lass o f drugs ca l led theartemisinins – discovered by a medical scienceunit of the Chinese Army working in support ofthe North Vietnamese during the war with theAmericans (by the 2015 Nobel laureate Dr. Y.Tu).8 That warfare drives critical advances inmalaria therapy that cease in peacetime is asad testament to its low priority when it is onlyattacking and killing civilians. This is changing,however. In 1999, the Medicines for MalariaVenture at Geneva was created for taking upthe important business of discovering,evaluating and licensing medications affordableto the poor who are most affected by malaria.They have made great strides with generoussupport from sponsors and donors.9

The artemisinin combined therapies (ACTs,artemisinin plus a partner drug) todaycomprise the frontline against sickness anddeath caused by malaria. Thanks to their broadimplementation, along with many preventivemeasures like mosquito nets and practicaldiagnostics for malaria, global mortality due tomalaria has fallen by half since 2000.10

Unfortunately, the drug resistance drama thatplayed out in western Cambodia withchloroquine fifty years ago, is today repeatingitself – resistance to ACTs was detected in thesame area in 2008 and has since spread muchwider (Figure 4). No one understands exactlywhy, but western Cambodia seems to be a

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cradle of drug resistant malaria. It seems likelythat the decades-long unregulated use ofartemisinin alone during the strife and warfarein Cambodia, without the partner drug of ACTs(which is there in order to delay onset ofresistance) selected for those resistantmutants. The threat of this menace causing asurge in malaria mortality is not merehyperbole – it is real because we have nopractical therapeutic options in our globalmalaria medical kit. The specter of untreatablefalciparum malaria looms over the globe, and itis an Asian-Pacific responsibility to manage theproblem.

Figure 4. Map illustrates penetration of artemisinin-resistant P. falciparumin the Mekong of SoutheastAsia as of January 2014. Tiers refer to confirmedresistance (1, red), likely (2, yellow), absent (3,white). From the World Health Organization(http://www.who.int/malaria/publications/atoz/status-rep-artemisinin-resistance-sep2014.pdf).

Primaquine Therapy of P. vivax Malaria

As explained, P. vivax places dormant forms inthe human liver that can cause repeatedclinical attacks up to about 2 or 3 years after asingle infectious bite by a mosquito. The onlydrug that kills these dormant forms is calledprimaquine – another product of World War II,the Asia-Pacific War in particular.11 The Dutchon Java in 1941 produced over 95% of theworld’s supply of quinine, and when the Allieslost access to that supply they turned tosynthetic drugs. One of those caused the onlytherapy against dormant liver stages to becomeespecially toxic. The US Army then launched asearch for a new drug in 1943, and in 1952primaquine was licensed for this use.

In many respects, primaquine is woefullyinadequate as a drug. Its many problems arerooted in its toxicity to people with an inheritedblood disorder called glucose-6-phosphatedehydrogenase (G6PD) deficiency. Peoplehaving that disorder lead healthy lives ofnormal longevity, but become seriously ill whenexposed to specific drugs that destroy their redblood cells. Primaquine is one of those drugs,and the doses needed for treating P. vivax cancause death in the most severe types of G6PDdeficiency. Unhappily, G6PD deficiency is ahighly prevalent human genetic disorder(typically about 8% of people in malaria-endemic nations), impacting 400 million peopleglobally, most of them living in the Asia-Pacific(Figure 5). Even worse, the most severe typesof G6PD deficiency dominate those found in theAsia-Pacific.12

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Figure 5.Map illustrates the estimated frequencies ofG6PD deficiency in the Asia Pacific, with the darkestcolors indicating as high as 30% of residents. Theaverage prevalence of G6PD deficiency in malariaendemic nations is 8%. G6PD deficiency and theinability to diagnose it render the only treatmentagainst relapses of P. vivax with the drug primaquinea dangerous clinical decision. Courtesy oft h e M a l a r i a A t l a s P r o j e c t(http://www.map.ox.ac.uk/browse-resources/),University of Oxford, United Kingdom.

The diagnosis of G6PD deficiency is relativelysimple in a laboratory setting. If accomplished,the G6PD normal majority enjoys the enormousclinical benefit of primaquine therapy withoutrisk of harm. However, in the impoverishedrural tropics where the vast majority of malariapatients live, such services are almostuniversally absent. Recent work vigorouslystrives to address this serious problem thatdenies most patients with P. vivax access tosafe primaquine therapy.13

Another unfortunate fact is the strains of P.vivax occurring in the Asia- Pacific are amongthe most aggressive with respect to howfrequently and often they will cause repeatedattacks from the dormant liver stages.Scientists and doctors long thought P. vivaxinfection to be inherently benign and notthreatening, but over the past decade studiesat hospitals in rural areas revealed it as veryoften associated with severe illness and death.14

It is perhaps likely that most of those pooroutcomes derive from the repeated multipleattacks from the untreated liver forms of theparasite. In the absence of G6PD diagnostics,care providers must choose between risk ofserious harm caused by primaquine, or harmcaused by the infection by withholding thetreatment.

Monkey Malaria

Another problem of malaria unique to the Asia-Pacific is infection by P. knowlesi. This speciesis very different from the other four speciesinfecting humans because we are not its

natural host. Humans acquire P. knowlesi inforests inhabited by macaques, the animal thatP. knowlesi naturally infects. The first knownreport of human infection by this speciesappeared in 1965 – in an American CIA agentworking at night in the forests of peninsularMalaysia.15 He returned to Washington wherehe was correctly diagnosed only in a mostextraordinary series of coincidences worthy ofCIA intrigue. This lone infection for decadeswas considered a one-off event and it waswidely believed that P. knowlesi did notroutinely infect humans.

In 2004, Malaysian scientist Balbir Singh andhis colleagues at the University of Malaya atSarawak unveiled a serious threat from thisspecies.16 Not only was P. knowlesi infectinghumans, but it was doing so often and ending indeath for many.17 The infection had beendiagnosed as P. malariae (which it closelyresembles under the microscope). However,true P. malariae malaria is usually relativelybenign (although chronic infections can causeirreversible and ultimately fatal kidney failure).Patients were coming in with what seemed tobe that species but with very aggressiveinfections and acute disease states. ProfessorSingh and his team solved the mystery. Todaywe know that most of the malaria that occurson Malaysian Borneo is in fact P. knowlesi. Amap of the areas of known risk of P. knowlesiinfection reveals it to be uniquely Asian-Pacific(Figure 6).

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Figure 6. Map illustrates relative likelihood of humanexposure to infection P. knowlesi naturally occurringin forest-dwelling macaques. Courtesy of the MalariaA t l a s P r o j e c t(http://www.map.ox.ac.uk/browse-resources/),University of Oxford, United Kingdom.

Eliminate Malaria!

Beginning about a decade ago, momentumbegan building to mobilize resources toeliminate malaria transmission, leadingultimately to its eradication as a human healthproblem.18. Taking the personal encouragementand example of Bi l l & Mel inda Gatesexpressing malaria elimination as a vision,WHO Director General Margaret Chanannounced in 2008 that WHO would embark ona global malaria control strategy that aimed toeliminate malaria. This represented afundamental paradigm shift of strategy andtactics in malaria control as a public healthendeavor. Deliberately and aggressivelyattacking malaria where it was not highlyprevalent, or striving to interrupt transmissionwhere it was highly prevalent, had long beenviewed as impractical and even dangerous.19

The danger lies in failure. During the 1950sand 1960s the WHO (largely spurred by the USState Department and US funding) undertookthe Global Malaria Eradication Program(GMEP).20 Huge strides were made in reducingmalaria, especially in the Asia-Pacific.

However, in 1969 the WHO abandoned thecampaign, leaving behind malaria controlprograms that were no longer functional.Further, research on malaria effectively ceasedafter the program commenced due to optimismregarding successful global eradication.Between 1970 and 2000 global burdens ofmalaria morbidity and mortality surgedpowerfully due to technical, material, andpersonnel deficiencies spurred by the GMEP.Elimination strategy invites risk of rebounds ofmalaria in the wake of failure.

The year 2030 is the declared goal for theelimination of malaria transmission across theAsia-Pacific. In 2008 malaria technical expertsformed the Asia Pacific Malaria EliminationNetwork (http://www.apmen.org) that drawsthem together with the national malaria controlprograms of 18 nations with declared malariaelimination goals. They aimed to support thoseprograms in shifting from control to eliminationstrategy and tactics where deemed feasible.Mobilizing political and fiscal support andmomentum, the Asia Pacific Leader’s MalariaAlliance (http://www.aplma.org) was created in2013 by the heads of national governments inthe region. The risks of powerful rebounds ofmalaria with failure to achieve real eliminationare soberly acknowledged and impel theurgency of full commitment to the task.

The problems with malaria in the Asia-Pacificsummarized here will challenge eliminationgoals. Each of those three major challengesrequires solutions unique to the malaria of thisregion. Acknowledging these as problems ofthe Asia-Pacific appropriately focuses regionalattention, enthusiasm, and resources forattacking them vigorously. The temptation topassively wait for others in distant regions todeal with their own unique malaria problems topass along the technical fruit of their laborsmust be resisted. They cannot deliver the goodsthe Asia-Pacific requires. These are ourproblems to solve.

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Recommended citation: J. Kevin Baird, "Malariain the Asia-Pacific Region", The Asia-PacificJournal, Vol. 13, Issue 45, No.1, November 9,2015.

J. Kevin Baird served for 22 years on activeduty in the US Navy Medical Service Corps as amalaria specialist, principally in the Asia-Pacific, retiring in 2006 with the rank ofCaptain. He is currently Professor ofMalariology at the Centre for TropicalMedicine, Nuffield Department of Medicine,Oxford University and directs the Eijkman-Oxford Clinical Research Unit on behalf of thatuniversity and the Eijkman Institute forMolecular Biology in Jakarta, Indonesia. Prof.Baird has resided in Indonesia for over 20years and is co-author of the book War Crimesin Japan-Occupied Indonesia: A Case of Murderb y M e d i c i n e(http://www.amazon.com/dp/1612346448/?tag=theasipacjo0b-20), Potomac Books 2015, withSangkot Marzuki, former director of theEijkman Institute and current President of theIndonesian Academy of Science.

•Vivian Blaxell, Yellow Blood: Hepatitis C andthe Modern i s t Se t t l ement in Japan(https://apjjf.org/-Vivian-Blaxell/4112/article.html)

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2 Hay SI, Gething PW, Snow RW. India’sinvisible malaria burden. Lancet 2010; 376:1716-17.

3 Mueller I, et al. Key gaps in the knowledge ofPlasmodium vivax, a neglected human malaria

parasite. Lancet Infectious Diseases 2009; 9:555-66.

4 Ibid, WHO

5 Ibid, Hay SI, Gething PW, Snow RW

6 Coatney GR. Pitfalls in a discovery: thechronicle of chloroquine. American Journal ofTropical Medicine and Hygiene 1963; 12:121-8.

7 Attaran A, et al. WHO, the Global Fund, andmedical malpractice in malaria treatment.Lancet 2004; 363: 237-40.

8 Tu Y. The discovery of artemisinin (qinghaosu)and gifts from Chinese medicine. NatureMedicine 2011; 17: 1217-20.

9 See here (http://www.mmv.org/).

10 Murray CJ, et al. Global, regional andnational incidence of mortality for HIV,tuberculosis, and malaria during 1990-2013.Lancet 2014; 384: 1005-70.

11 Baird JK. Resistance to therapies for infectionby Plasmodium vivax. Clinical MicrobiologyReviews 2009; 22: 508-34.

12 Howes RE, et al. G6PD deficiency prevalenceand estimates of affected populations inmalaria endemic nations: a geostatisticalmodel-based map. Public Library of ScienceMedicine 2012; 9: e1001339.

13 World Health Organization. Control andelimination of Plasmodium vivax malaria: atechnical brief. Geneva. 2015.

14 Baird JK. Evidence and implications ofmortality with acute Plasmodium vivax malaria.Clinical Microbiology Reviews 2013; 26: 36-57.

15 Baird JK. Malaria zoonoses. Travel MedicineInfectious Diseases 2009; 8: e2780.

16 Singh B, et al. A large focus of naturally

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acquired Plasmodium knowlesi infections inhuman beings. Lancet 2004; 363: 1017-24.

17 Cox-Singh J, et al. Plasmodium knowlesi inhumans is widely distributed and potentiallylife threatening. Clinical Infectious Diseases2008; 46: 165-71.

18 Malaria: control vs elimination vs eradication.

Lancet 2011; 378: 1117.

1 9 S e e h e r e(http://www.nytimes.com/2008/03/04/health/04mala.html?pagewanted=all&_r=0).

2 0 Baird JK. Resurgent malaria at themillennium: control strategies in crisis. Drugs2000; 59: 719-43.