1Am. J. Trop. Med. Hyg., 64(1, 2)S, 2001, pp. 111Copyright 2001 by The American Society of Tropical Medicine and Hygiene

THE EARS OF THE HIPPOPOTAMUS: MANIFESTATIONS, DETERMINANTS, ANDESTIMATES OF THE MALARIA BURDEN

JOEL G. BREMANFogarty International Center, National Institutes of Health, Bethesda, Maryland

Abstract. Malarious patients experience asymptomatic parasitemia; acute febrile illness (with cerebral damage,anemia, respiratory distress, hypoglycemia); chronic debilitation (anemia, malnutrition, nervous systemrelated se-quelae); and complications of pregnancy (anemia, low birth weight, increased infant mortality). These manifestationsin patients, communities, and countries reflect intrinsic (human, parasite, mosquito) and extrinsic (environmental,social, behavioral, political, and economic conditions as well as disease-control efforts) determinants. At a minimum,between 700,000 and 2.7 million persons die yearly from malaria, over 75% of them African children. Between 400and 900 million acute febrile episodes occur yearly in African children under 5 yr of age living in endemic areas.Although about half of these children are parasitemic, all merit consideration of malaria-specific therapy, which isbecoming more problematic because of parasite resistance to drugs. These numbers will more than double over thenext 20 yr without effective control. Fewer than 20% of these febrile episodes and deaths come to the attention ofany formal health system. The relatively few ill patients who have any contact with the health services represent theears of the hippopotamus. Greatly intensified research activities and control of the intolerable burden of malariaare mandatory if economic development is to accelerate in Africa. In particular, support should be targeted to un-derstanding and preventing malaria-induced anemia, hypoglycemia, effects on pregnancy, and neurologic and devel-opmental impairment. To decrease and stop transmission of this intolerable scourge, there is an urgent need formalaria vaccines, newer drugs, and better vector control methods as well as the ability to improve current technologiesand use them more efficiently.

INTRODUCTION

The burden of malaria is a challenge to quantify becauseinfection may be asymptomatic in partially immune persons,may manifest in acute catastrophic cerebral illness and deathor permanent neurologic sequelae, or may appear in grada-tions between these clinical extremes. Many febrile illnessesin endemic areas mimic malaria, and confirmatory parasi-tologic diagnosis is not often available, reliable, or prompt,particularly in rural zones. Parasitemic patients can have oth-er illnesses, complicating matters even more. Most impor-tant, case detection and reporting are woefully incompletebecause of the poor state of surveillance in malarious coun-tries. This situation, whereby very little disease is perceivedor managed by health systems in the tropics, is analogous toa hippopotamus floating in deep water, with only the earsshowing; the largest and most dangerous part of the beastrests below the water.

With the recent increased support for malaria research andcontrol worldwide, particularly in Africa, it is urgent thatthere be more precise definition of malarias clinical, epi-demiologic, and economic burden. A recent review has con-cluded once again that about 1 million deaths (range,744,0001,300,000) from the direct effects of malaria occuryearly in Africa, more than 75% of them in children.1 Thisburden is determined by a wide variety of factors and isexpressed in several clinical and epidemiologic forms, manyof which are not usually considered in calculations of themalaria toll. This article will give an overview of the man-ifestations, important determinants, and estimates of the bur-den that dominate thinking about malarias impact as weattempt to understand, control, and prevent this scourge earlyin the 21st century. It will preface a series of articles thataddress specific expressions of the malaria burden, many ofwhich have been lamentably neglected.

MANIFESTATIONS OF MALARIA

Malaria is defined variably as acute febrile illness in en-demic areas, with or without parasitemia, depending uponlocal capability for parasitologic confirmation. Malaria in-fection can result in asymptomatic parasitemia; clinical ma-laria (febrile episodes, parasitemia); severe malaria (anemia,neurologic syndromes); and mortality.2 The major manifes-tations of acute febrile illness, chronic effects, and pregnan-cy-related complications are shown in Figure 1.320 Acutesevere illness can lead to cerebral malaria, with a high casefatality rate.36 Coma, severe anemia, and respiratory distressare ominous for children with acute malaria. One perilousbut eminently treatable complication of malaria is hypogly-cemia due to parasite metabolism in red blood cells (RBCs)and hyperinsulinemia secondary to use of quinine;7,8 preg-nant women with malaria have a high risk of hypoglycemia.Even when patients get to a hospital, differing malaria treat-ment regimens result in different outcomes in the hospitaland after discharge.910 The debilitating acute and chroniceffects of anemia and neurologic, cognitive, and develop-mental impairment are not well quantified.1116 Particularlydevastating to development are the long-duration effects ofmalaria, manifested in learning and behavioral disorders anddecreased capacity to work.14,15 The extent of the impact ofmalaria on the pregnant woman and her fetus, notable duringthe first and second pregnancies, have only recently beenappreciated.1720 In particular, low birth weight and subse-quent increased infant and childhood mortality result froman infected placenta.21,22 The economic devastation causedby malaria reflects health care costs, lost workdays andschooldays by patients and family members, and other directand indirect costs.2325 Retardation of the rate of long-termnational, regional, and continental economic growth as aconsequence of malaria has been appreciated only recently.26

Biologic, genetic, immunologic, and pathophysiologic

2 BREMAN

FIGURE 1. Manifestations of the malaria burden.

mechanisms predisposing malarious patients to severe dis-ease are beginning to be understood more completely. Tumornecrosis factor, cytoadhesion of parasitized RBCs (particu-larly in cerebral vessels), nitric oxide, lactic acidosis, andchondroitin sulfate A in the placenta are associated with ad-verse effects of malaria.27,28 The local epidemiologic profileof malaria and other diseases is very important for diagnos-ing and quantifying accurately the cause of febrile illness.29In areas with unstable malaria, the predictive values (positiveand negative) of fever will vary, depending upon season andother prevalent diseases.3037 Hence, to manage patientsproperly, particularly ill febrile children, it is necessary tohave a comprehensive understanding of the local pathologyand epidemiology.

DETERMINANTS OF THE MALARIA BURDEN

The manifestations of malaria in patients and the toll incommunities and countries reflect intrinsic and extrinsic de-terminants (Table 1). Of the intrinsic factors, host (human)immunity, parasite species, anopheline longevity, and avidityfor humans have the greatest impact on the malaria burden.38Among extrinsic factors, climate (mainly rainfall), economicconditions (poverty), political commitment, and effective-ness of control and prevention efforts are the most importantdeterminants of malarias burden (Figure 2).

Host factors. Human populations exposed to malaria in-fection may vary in their susceptibility to infection and se-verity of illness. Sickle cell (AS) and other traits that alterRBC structure limit parasite multiplication within RBCs.The protection of populations by their genetic makeup istermed balanced polymorphism, a concept strengthened bythe observation that the heterozygous (AS) trait is moreprevalent in African populations and may protect againstmalaria, particularly cerebral malaria.39 The presence of theDuffy blood factor on the surface of RBCs is required forPlasmodium vivax to enter RBCs; because over 90% of sub-

Saharan Africans lack the Duffy factor, P. vivax is essen-tially absent from most of this area.40 Hereditary ovalocy-tosis, and thalassemia, glucose-6-phosphate dehydroge-nase deficiency, spectrin, Lewis and Kid Is (a) red cell typemutations in the gene for the red blood cell membrane pro-tein and have also been associated with decreased suscepti-bility to severe malaria.41 A low frequency of the class Imajor histocompatibility complex molecule HLA-B53 hasbeen associated with severe malaria in the Gambia, possiblyassociated with immunity to liver stages of the parasite.42,43Other innate factors, such as ICAM-1, the putative receptorfor infected RBCs binding to brain endothelium, and a poly-morphism in the promoter region of tumor necrosis factor-appear related to the frequency of severe disease.44,45 Al-though knowledge of host and parasite genetics has addedgreatly to our understanding of susceptibility to malaria, theuse of genotype information for improved malaria treatmentsand prevention remains a challenge for the future.

The immune status of the individual and population playsthe most important role in the clinical response to infectionand transmission. Maternally derived antibody offers limitedand short-duration protection to the newborn.46 In heavilyendemic areas, over 30% of children acquire parasites by 3months of age.47 Researchers have identified humoral anti-bodies to sporozoites, intrahepatic parasites, merozoites, ma-laria toxins, parasite antigens on infected RBCs, intraeryth-rocytic parasites, and, within the mosquito, to parasite fer-tilization; cell-mediated immunity plays a role in the liverand RBC invasion and parasite development.48 Even withrepeated infection, protective immunity is incomplete; indi-viduals in malarious areas frequently have premunition, i.e.,parasitemia and antibodies without symptoms, and this is agedependent. There is recent evidence for a genetic basis forantibody and cellular responses to malaria proteins.49,50 Iden-tification of specific immunologic determinants of protectionwill lead to development of the most promising vaccine can-didates, including multistage vaccines.

3THE MALARIA BURDEN

TABLE 1Determinants of the malaria burden

Determinant Effect

Genetic susceptibilitySickle cell trait (AS), heredi-

tary ovalocytosisLimit parasite invasion/growth

in red blood cells (RBCs) thalassemia, HbE, fetal Hb,

glucose-6-phosphate dehy-drogenase deficiency, majorhistocompatibility antigensHLA-B53

Protect against severe disease

Duffy blood factor Surface receptor needed forPlasmodium vivax entry intoRBC

Immunologic statusMajor histocompatibility anti-

genAbsence on infected RBCs

limits T-cell recognitionICAM-1 Infected RBC receptor, binds

to brain endothelium, cere-bral malaria

Tumor necrosis factor polymor-phism

Linked to severe disease

Nave mother Susceptible newbornResidence in area of no or un-

stable transmissionNave/incompletely protected

populationResidence in area of stable

transmissionPremunition, partial protection

ParasitePlasmodium falciparum Severe illnessP. vivax, Plasmodium ovale RelapsesPlasmodium malariae Nephrotic syndrome, recrudes-

cenceAntigenic diversity New infections, not recrudes-

cenceResistance to drugs: P. falcipa-

rum (widespread); P. vivax(reports from Asia, SouthAmerica)

Inadequate patient managementand increased burden

MosquitoAnopheles gambiae complex Most efficient vector, wide-

spread in AfricaHigh entomologic inoculation

rateStable intense transmission and

severe disease in suscepti-bles

Resistance to insecticides Transmission maintained andincreased burden

EnvironmentalWarm temperatures, high rain-

fall and humidityIncreased mosquito longevity

Clear, still, sun-exposed watercollections

Good vector breeding sites

Engineering projects: dams,roads

New breeding sites, human-made malaria

Education, social, behavioral, political, and economicIlliteracy and poor knowledge

of disease cause, transmis-sion, and control

Uninformed, ineffective partici-pation in control and preven-tion

Community participation Necessary for proper preven-tion and control

Urbanization, economic oppor-tunity

Urban malaria

Natural disasters, civil and mil-itary disruption

Refugee movements to malari-ous areas

Poverty Inability to obtain and deploydrugs, insecticides, bed nets,and other measures

Political, economic commit-ment

Reflects high priority, spirit ofsuccess

TABLE 1Continued

Determinant Effect

InterventionsPolicies, strategies and tactics

well-definedGood program conception and

implementationSufficient infrastructure Ability to provide servicesGood training, implementation

and evaluationAbility to maintain effective

programDrugs, insecticides and bed

nets available and effectiveServices effective

Adequate financing Control and prevention

FIGURE 2. Intrinsic and extrinsic factors linked to the malaria toll.

Parasite. Of the 4 species of plasmodia affecting humans,Plasmodium falciparum, the most recently evolved species,is the most virulent, for reasons incompletely understood.51Although P. vivax, which can cause relapses months afteran infection, is widespread in Central and South Americaand Asia, it causes substantial morbidity but fewer severecomplications; recently, low birth weight was reported withplacental infection by P. vivax,52,53 a well-established resultof P. falciparum infection.1720 Plasmodium malariae is as-sociated with renal complications;54 if untreated, patientsmay remain parasitemic and asymptomatic for years. Plas-modium ovale, also a relapsing species, is a rare ( 0.5%)cause of infection; it is found principally in Africa. Evidenceis accruing that genetic diversity of parasites is frequentwithin species, patients, and localities, probably because ofrecombination and selection, and has an impact on clinicalpresentation in various age groups and on malaria transmis-sion.55,56 This may account for the lack of protective im-munity and the frequent repeat infections and clinical epi-sodes of malaria in persons, particularly young children, liv-ing in areas of intense and stable transmission, and it mustbe considered in the development of vaccines.

The development of P. falciparum resistance to drugs overthe past 20 yr has been a major cause of poor malaria pro-

4 BREMAN

FIGURE 3. Control of the malaria burden: current and future interventions.

gram performance and increasing burden; resistance to chlo-roquine is widespread, multidrug resistance is increasing,and new strategies are being developed for their use.5760Since 1980, following the demise of global malaria eradi-cation, use of effective drugs to reduce mortality and mor-bidity has been the major strategy for malaria control, par-ticularly in Africa.61 The increasing malaria burden reflectsthe inadequacy of this current strategy, which may becomefurther compromised by the projected increasingly wide-spread use of sulfamethoxazole-trimethoprim as prophylaxisfor patients with human immunodeficiency virus and ac-quired immune deficiency syndrome.62 Resistance to sulfa-methoxazole-trimethoprim may cross-react with a major an-timalarial drug and vice versa.63 This would have ominousimplications, because sulfadoxine-pyrimethamine is becom-ing a cost-effective first-line therapy in eastern and southernAfrica.64

Mosquito. Although there are about 400 species ofAnopheles, only 60 of them transmit malaria under naturalconditions, and only 30 are of major importance.65 Of these,the Anopheles gambiae complex and Anopheles funestus arethe most efficient vectors for P. falciparum transmission; thehighest rates of sporozoite development are in An. gambiae,the species that is widespread throughout tropical Africa. Ofall factors related to malaria transmission, apart from hostimmunity, the number (density), human-biting habits, andlongevity of anopheline mosquito vectors are the most im-portant. Transmission is directly proportional to the densityof the vector, the square of the number of human bites perday per mosquito, and the 10th power of the probability ofthe mosquitos surviving for 1 d.38,65 Mosquito longevity isparticularly important, because the portion of the parasiteslife cycle that takes place within the mosquitofrom ga-metocyte ingestion to subsequent inoculationcan takefrom 8 to 30 d, depending on ambient temperature. In gen-eral, sporogony within the mosquito is not completed at tem-peratures below 1618C, and transmission does not occur.The entomologic inoculation rate (EIR)the number of spo-

rozoite-positive mosquito bites per yearis the most com-mon measure of malarial transmission; this varies from 1in some parts of Latin America and Southeast Asia to 300in parts of tropical Africa. The relation between level ofexposure (the EIR) and the incidence of severe malaria anddeath remains controversial. A high EIR results in stable andintense transmission, with young children the most vulner-able for severe illness. Higher EIRs are, in general, associ-ated with increased frequency and density of parasitemia,febrile episodes, anemia and cerebral malaria in heavily en-demic areas.6669 The lower the EIR, the greater the numberof susceptible individuals who can develop severe infectionand illness.68,69

Because the health service delivery systems have been sopoor for malaria control and other diseases, vector controlhas had limited success in heavily endemic countries, espe-cially in Africa; indeed, outside of a few urban centers andresearch projects, vector control has not been a major strat-egy, with the exception of a few areas in southern Africa.There is increasing interest in attacking the mosquito bothwith classical vector control technologies to prevent andcontrol epidemics and with insecticide-impregnated bed netsand other materials for personal protection.7075 With the re-alization that the current drug-use strategy alone will have aminimal impact on transmission and limited success in de-creasing the malaria burden, newer vector-focused approach-es are needed.

Environmental. Tropical areas with warm temperatures,heavy rainfall, and high humidity are conducive to mosquitobreeding and longevity and parasite sporogony. An. gambiaemosquitoes breed readily in large and small collections ofsun-exposed still water, such as exist throughout tropical Af-rica. Human engineering projects, e.g., construction of dams,roads, and industrial and residential centers, can result indisruption of the terrain, allowing increased mosquito breed-ing. Geographic areas where populations are susceptible toepidemics are of particular importance; these zones are ofteninundated by unseasonal rains, influxes of migrants and ref-

5THE MALARIA BURDEN

FIGURE 4. Estimated world and regional malaria cases, 19871999.

FIGURE 5. Estimated world and regional malaria deaths, 19521999.

ugees, and breakdowns of malaria and other disease controland prevention programs. Epidemics linked to rainfall, tem-perature, geography, and, above all, population susceptibilityand unresponsiveness to incipient epidemics will becomemore frequent.7678 Recent mapping of malarious zones byendemicity and epidemic risk can help prevent medicallycatastrophic and disruptive malaria epidemics if realistic pro-gram objectives and indicators for action are established, pe-riodic monitoring and supervision occur, and corrective steps

are taken promptly when gaps are found.7982 The rapid trendtoward urbanization in developing countries will bring moremalaria to large cities and will expose susceptible popula-tions to outbreaks.83 Measures to prevent malaria can be eas-ier to implement and more cost-effective in urban and per-urban areas than in rural zones.

Social, behavioral, political, and economic. Over thepast 100 yr there has been a decrease in malaria transmissionin northern countries, including those with tropical areas,

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FIGURE 6. The Ears of the Hippopotamus where malaria patients are managed . . . and die.

FIGURE 7. Number and projected number of acute febrile episodes and malaria-associated febrile episodes in African children under 5 yrof age living in endemic areas, 19952020.

following an improvement in education and in social andeconomic conditions. The improvement of general hygieneand public health included the filling in of swamps, elimi-nation of open drainage ditches and other mosquito breedingsites, screening of windows and doors, widespread use ofair conditioning, and availability of rapid diagnosis anddrugs for acute illness. Alleviation of poverty has been as-sociated with a decrease in malaria endemicity. Economicand educational gains, along with the ability to manufacture,purchase, and deploy effectively DDT and other insecticides,may have had the greatest impact on the malaria burden intemperate zones.84,85 In some African countries, no associa-

tion was seen recently between socioeconomic status (SES)and severe malaria, anemia, and reinfection.86,87 Here, theSES may not reflect access to or use of malarial control orprevention measures or may reflect the relative ineffective-ness of those employed. Knowledge of which malaria con-trol strategies and interventions are most cost-effective isneeded because of the huge economic and medical toll ofmalaria. Recent attention given to malaria by the presidentsof several African countries and by the leaders of northerncountries has been very gratifying and, one hopes, reflectsthe political, financial, and other support for research andoperations that must continue to be forthcoming.88

7THE MALARIA BURDEN

Interventions. The current malaria control and preventionmeasures include personal protection, drug use, and vectorcontrol strategies (Figure 3). The correct and timely appli-cation of these strategies can result in decreases in malaria-specific and overall mortality, but this is difficult to achieveand sustain.61,8991 Experience in Sri Lanka during eradicationactivities in the 1960s and 1970s showed that malaria canresurge in epidemic form rapidly, even when transmission isalmost interrupted, if priorities change, field operations fal-ter, and maintenance activities and resources are inadequateor diverted.92

Because of the gaps in these strategies, difficulties inmounting and maintaining effective operational activities,and the peril of increasing parasite resistance to drugs andinsect resistance to insecticides, establishment of a soundmalaria research base, particularly in endemic countries, isessential; the focus is now on developing 1 or more vaccinesagainst malaria and on developing genetically altered anoph-elines unable to complete the sporogonic cycle.48,93 Devel-opment of new prevention and control tools requires greatlyincreasing the research and capacity of institutions in ma-larious areas and of partner institutions in the North.94 It isexpected that opportunities offered by, and collaboration be-tween, the Multilateral Initiative on Malaria (MIM), theTropical Diseases Research and Training Program (TDR)/World Health Organization (WHO), Wellcome Trust, RollBack Malaria/WHO, and other agencies, coupled with in-creasing private-sector interest and commitment, will accel-erate new discoveries, their translation into interventions,and their deployment operationally.

ESTIMATING THE BURDEN

Worldwide estimates of the number of patients with acutefebrile illness due to malaria have varied from 10 to 500million annually.1,61,95101 These estimates are imprecise, mis-leading, and low because of inadequate diagnosis and in-complete reporting. Some authors have tried to approximatethe number of febrile patients who might be parasitemic, anexercise that is difficult and has limited operational impor-tance in malarious areas without diagnostic capacity. Othershave designated 5,00010,000 parasites/L or anotherthreshold level for a malaria diagnosis in partially immunepatients living in endemic areas, a criterion that has someepidemiological but no clinical relevance. It is paradoxicaland regrettable that for many years Africa was not includedin WHO reporting of malaria morbidity and mortality be-cause of poor surveillance and lack of parasitologic diag-nosis, yet there is universal agreement that close to 90% ofcases globally occur in Africa (Figure 4), and virtually allare caused by P. falciparum. Early estimations of Africanmalaria deaths were based on the autopsy study by Bruce-Chwatt in Lagos, Nigeria;46 he concluded that approximately1 million African children died from malaria each year. Re-cent, more precise estimations of malaria mortality have re-mained surprisingly close to this number, varying between700,000 and 2.7 million, with well over 75% of deaths oc-curring in African children (Figure 5). It has not been ap-preciated that malaria-related anemia, hypoglycemia, respi-ratory distress, low birth weight, and other manifestationsare not usually included in defining the burden, and includ-

ing these may double the current estimates. Indeed, anemiaand low birth weight may contribute to 50% of the overallmalaria morbidity and mortality in children under 5 yr ofage in Africa.102,103 The acute and repeated effects of malariaon the brain and their sequelae remain to be quantified fully.

International and bilateral organizations (including WHO,the United Nations Childrens Fund [UNICEF], and the U.S.Agency for International Development [USAID]) and publichealth staff in malarious countries have advised that all fe-brile children under 5 yr of age in endemic areas be treatedfor malaria. Home treatment is encouraged initially becauseof the potential severe consequences of untreated illness, thelack of precise diagnosis, and the relative inaccessibility ofsecondary and tertiary health care facilities. Most febrilepersons do not come to the attention of the formal healthinfrastructure.1,61,104106 The ears of the hippopotamus rep-resent the fewer than 20% of patients who have any contactwith the formal health delivery service when they becomeill and die (Figure 6). The number of the most potentiallysevere malaria episodes can be approximated using the num-ber of young pediatric febrile episodes reported by parentsduring field surveys in rural and urban endemic areas: thesevary generally from 4 to 9 per year in children under 5 yrof age.61,106 Using this information, between 400 and 900million febrile episodes would have occurred annually inchildren less than 5 yr of age living in endemic areas inAfrica at the end of the 20th century; without effective in-terventions, by 2020 these numbers will have at least dou-bled (Figure 7). If 3060% of these children were parasitem-ic, as reported in some studies, about half would have truemalaria (200450 million annually).37,104,107 In many areas,the parasitemia rate for children is higher, particularly duringand just after the rainy season. These numbers do not con-sider febrile episodes and malaria infections in older childrenand adults in Africa and in endemic areas of the Americasand Asia. These older groups in Africa have between 0.4and 1 episode of malaria yearly and probably 2 or morefebrile episodes.1 Taking these older age groups and othercontinents into consideration, it is highly likely that world-wide well over 2 billion febrile episodes resembling malariaoccur annually and that a substantial portion are parasitemic,meriting effective treatment.

DISCUSSION

Malaria will be tamed only when its manifestations anddeterminants are understood more completely where theinfection and disease have special epidemiologic and clin-ical profiles and when current and more efficacious con-trol measures are applied more effectively. Study of theintrinsic factorsin particular the genetic profiles of thehuman host, parasite, and mosquito and their interrela-tionshipswill open new avenues for development of im-proved and new interventions. Relatively little can bedone now to enhance innate or acquired resistance to ma-laria, although more effective management of hospitalizedpatients susceptible to severe or cerebral malaria mightoccur by use of cytokines and, ultimately, vaccines. Par-asites and mosquitoes are the main targets of current andfuture interventions. Recent discoveries that plasmodialinfections are antigenically heterogeneous complicate at-

8 BREMAN

tempts to develop an effective blood-stage vaccine, but atleast 1 group has produced a multiantigenic construct.106The geographic spread and intensity of multidrug-resistantP. falciparum is ominous and mandates the developmentof newer drugs and trials of drug combinations.60 Im-proved understanding of the genetic and biologic basis ofparasite resistance to antimalarial drugs is leading to new-er diagnostic approaches.

An attack on the mosquitoby insecticide-impregnatedpersonal protection material (bed nets)is the main newapproach to malaria control, one that results in decreasingoverall mortality.75 This approach has the advantage of in-volving individuals, families, and communities in decisionmaking and implementation. Whether long-term use ofsuch materials will achieve the 50% decrease in malaria-related mortality and morbidity within 10 yrthe goal ofthe WHO Roll Back Malariaremains to be seen.109111 Re-newed effort in understanding Anopheles biology and ecol-ogy may lead to an original intervention that will preventparasite maturation in and transmission by the mosquito.

The recent sequencing of chromosome 2 of 1 isolate ofP. falciparum offers promise of increased understanding ofthe function of specific genes within the parasite and sitesfor newer drugs and vaccines;112114 of note is the recentfinding that a single gene in P. falciparum confers chlo-roquine resistance.114 Awaited with urgency is the devel-opment and field testing of the more effective antimalariadrugs, vaccines, and vector control methods that will cer-tainly follow these new discoveries. At the same time, moreeffective and efficient health care delivery systems need tobe developed to uncover and treat more of the hippopota-mus than is seen currently. Although falciparum malariacertainly merits our full and immediate preoccupation, theimportant burden of illness caused by P. vivax, as well asthe ill-defined effects of P. malariae and P. ovale, needfurther attention, as does their control.115

To better confront and solve the considerable malaria re-search and operational challenges, an increased number ofwell-trained and active scientists and institutions in the Southand North are joining the effort. The MIM is a coalition ofscientists and institutions in Africa and developed countriesthat aims to strengthen and sustain through collaborativeresearch and training, the capability of malaria endemiccountries in Africa to carry out research required to developand improve tools for malaria control.116 To achieve theneeded critical mass of malariologists in Africa and else-where and to achieve mastery over malaria, the MIM, RollBack Malaria, and similar programs must be nurtured andstrengthened.

Acknowledgments: I thank Drs. Louis Miller, Robert Snow, andKenneth Bridbord for constructive comments; Mr. Sean Murphy andMs. Kathleen Deren-Bernocchi for review of morbidity and mortal-ity data; and Ms. Melanie Rouse for manuscript assistance.Authors address: Joel G. Breman, Fogarty International Center, Na-tional Institutes of Health, Building 31, Room B2C39, 31 CenterDrive, MSC 2220, Bethesda, MD 20892-2220, Telephone: 301-496-1653, Fax: 301-402-0779 (e-mail: jbreman@nih.gov).

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Main MenuHelpVol. 64 Table of ContentsIssue 1 (Supplement) Table of ContentsExitINTRODUCTIONMANIFESTATIONS OF MALARIADETERMINANTS OF THE MALARIA BURDENESTIMATING THE BURDENDISCUSSIONREFERENCES