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10.1586/ERI.13.45 623ISSN 1478-7210© 2013 Expert Reviews Ltdwww.expert-reviews.com

Review

There has been an extraordinary scale-up ofmalaria control interventions over the last decade with significant increases in household owner-ship and individual use of insecticide-treatedbednets (ITNs), unprecedented growth in thenumber of houses protected by indoor residualspraying (IRS) and important improvements inaccess to effective treatment for clinical malaria. As a result, there has been an estimated 17%decline in the number of malaria cases and a 26%decrease in the malaria-specific child mortalityrate globally between 2000 and 2011 [1]. In thisoptimistic climate, the African Union, at its thirdsession of the Conference of Ministers of Health(Johannesburg, South Africa) in April 2007,advocated for eventual elimination of malariafrom the continent [2]; this was followed by acall in October of the same year from Bill andMelinda Gates [201], with support from the WHO[3], for global malaria eradication. As of 2011,36 of the 99 countries remaining with malariatransmission are pursuing elimination [4].

Despite the recent progress on reducingmalaria morbidity and mortality, there is empiri-cal and theoretical evidence that the current suiteof interventions will not be sufficient to elimi-nate malaria from many areas in sub-Saharan Africa with historically high levels of malaria

transmission. For example, in western Kenya,

despite more than 10 years with high coverage ofITNs, parasite prevalence in children <5 years ofage had declined from 83% in 1992 to only 41%by slide microscopy in 2009 [5,6]. Similar obser-vations have been noted in areas formerly consid-ered as high-transmission areas, such as Zambia[7] and Uganda [8]. A mathematical simulationof Plasmodium falciparum transmission in Africasuggested that only in areas with the lowest base-line level of transmission (<three infective bitesper person per year) could malaria be elimi-nated through a combination of ITNs, IRS andcase management with an artemisinin-basedcombination therapy (ACT) [9].

The situation in the Americas and Asia is somewhat different from Africa due to the higher pro-portion of malaria cases caused by Plasmodiumvivax , whose dormant liver stage poses an extrachallenge to elimination. Additionally, manyof the vectors in these areas are exophagic and,therefore, are less likely to be affected by theuse of ITNs or IRS. It is recognized that thesame malaria interventions successfully usedin sub-Saharan Africa may not work as well inP. vivax -endemic areas, and the technical feasi-bility of eliminating P. vivax from areas where itis currently endemic is not yet known [10].

As a result of the empirical and modeling data

suggesting that current interventions will need

Kim A Lindblade*,Laura Steinhardt,Aaron Samuels,S Patrick Kachur andLaurence Slutsker

Malaria Branch, Division of Parasitic

Diseases and Malaria, Centers for

Disease Control and Prevention,

1600 Clifton Rd. NE, MS A-06, Atlanta,

GA 30333, USA

*Author for correspondence:

Tel.: +1 404 718 4750

Fax: +1 404 718 4815

[email protected]

Scale-up of malaria control interventions has resulted in a substantial decline in global malariamorbidity and mortality. Despite this achievement, there is evidence that current interventionsalone will not lead to malaria elimination in most malaria-endemic areas and additional strategiesneed to be considered. Use of antimalarial drugs to target the reservoir of malaria infection is an

option to reduce the transmission of malaria between humans and mosquito vectors. However,a large proportion of human malaria infections are asymptomatic, requiring treatment that is nottriggered by care-seeking for clinical illness. This article reviews the evidence that asymptomaticmalaria infection plays an important role in malaria transmission and that interventions totarget this parasite reservoir may be needed to achieve malaria elimination in both low- andhigh-transmission areas.

The silent threat:

asymptomatic parasitemiaand malaria transmission

Expert Rev. Anti Infect. Ther. 11(6), 623–639 (2013)

KEYWORDS: antimalarial • asymptomatic • elimination • infection • interventions • malaria • parasite

mailto:[email protected]

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Review

to be supplemented by additional strategies for malaria to be elim-inated in most of sub-Saharan Africa, and the recognition thatthere is not yet a feasible technical strategy to eliminate P. vivax from Latin America and Asia, there is increased attention beingpaid to the human parasite reservoir [9,11]. The human parasite

reservoir consists of all malaria infections in people in a givenarea, including symptomatic and asymptomatic infections, andboth the sexual and asexual stages of the parasite (the special caseof dormant liver stages of P. vivax and Plasmodium ovale will notbe addressed in this review).

Improvements in case management through the use of moreeffective antimalarials have helped in reducing malaria transmissionin some areas [12], but low utilization of healthcare, suboptimal per-formance of healthcare workers, problems with patient adherenceto treatment regimens and drug stock-outs limit the ability of casemanagement strategies to significantly decrease the fraction of theparasite reservoir harbored in symptomatic individuals [13]. The

expansion of community case management may help to addressproblems of access, but health system issues are likely to remain achallenge in most areas. Additionally, case management, by defini-tion, only addresses symptomatic individuals, and there has beenincreasing recognition that a substantial proportion of the parasitereservoir may be found in persons who do not show symptoms andtherefore do not seek care [11]. In part, the use of molecular assayssuch as PCR to detect parasite DNA has improved the sensitivityof diagnostics to find subpatent (i.e., below the detection limits formicroscopy) infections that are more likely to be asymptomatic,and this has contributed to the understanding of the extent of theasymptomatic parasite reservoir [14].

As the magnitude of the asymptomatic parasite reservoir hasbeen revealed through increasing use of more sensitive molecu-lar diagnostic methods, new strategies to target individuals withsilent infections are being developed and evaluated. The objectiveof this review is to examine the data that support the hypothesisthat targeting the asymptomatic parasite reservoir will contributesubstantially to reductions in malaria transmission and eventualmalaria elimination.

How does Plasmodium infection cause acute clinical

symptoms?

Malaria sporozoites of the genus Plasmodium (comprising fourspecies that are transmitted between humans by Anopheles mos-quitoes: P. falciparum, P. vivax , P. ovale and Plasmodium malariae )are injected into humans through the bite of an infective femaleAnopheles mosquito. The malaria sporozoites pass rapidly to theliver, within 30 min of infection, where they mature into schizontswithin hepatocytes over 5–16 days, depending on the parasitespecies. The mature schizonts then rupture the cell and enter thebloodstream as merozoites. Merozoites infect red blood cells andover 2–3 days develop into eryrthrocytic schizonts, eventuallydestroying the erythrocyte, and releasing more merozoites andcellular debris into the bloodstream. The immediate impact of thisrupture is a significant decline in red cell mass, and cellular debrisand cytokines released by the host lead to the development of

acute clinical symptoms, including fever, rigors and myalgias [15].

How are malaria infections transmitted?

Gametocytes, the transmissible stage of the Plasmodium parasite,are produced by a small fraction of merozoites that differentiateinto gametocytes upon entering the red blood cell, althoughgametocytes of P. vivax , P. ovale and P. malariae can also arise

from emerging liver stage merozoites [16]. Whereas these three spe-cies produce gametocytes within the same time frame as asexualparasitemia, P. falciparum gametocyte production is delayed incomparison [17]. As a consequence, a higher proportion of P. vivax malaria patients are found with gametocytes shortly after devel-oping symptoms than in patients with P. falciparum [18], andP. vivax infections can be transmitted before becoming sympto-matic. Gametocytes are ingested by female Anopheles mosquitoesin a blood meal and they undergo sexual reproduction in themosquito midgut, eventually forming an ookinete that crossesthe midgut wall and develops into an oocyst. The oocyst pro-duces sporozoites that migrate into the mosquito salivary gland,

waiting to be injected into a susceptible host at the time of theanopheline’s next blood meal. The extrinsic incubation periodof the Plasmodium parasite within the mosquito is temperaturedependent and ranges from 10 to 14 days for P. falciparum [19] and 11 to 22 days for P. vivax [20].

Why are some malaria infections asymptomatic?

Partial immunity to malaria infections can lead to a reductionin the acute clinical symptoms of disease. Antidisease immu-nity is acquired from exposure to malaria infection and developsmore quickly with frequent exposure; most children in areas withmoderate-to-high levels of malaria transmission gain protectionfrom severe disease by a very young age, usually by 2–5 yearsof age, followed by a decrease in the rate of symptomatic ill-ness in early adolescence [21]. By contrast, antiparasite immunityincreases with maturation of the immune system and appearsto be somewhat independent of exposure frequency in areas ofmoderate-to-high transmission. By adulthood, parasite densitiesfollowing infection often remain at very low levels, frequentlyundetectable by microscopy, and most infected adults do notexhibit clinical symptoms. However, asymptomatic parasitemiacan occur at any age.

Development of partial immunity to clinica l malaria is antigen-specific, mediated by exposure to different genetically distinctparasite subpopulations, termed clones. Cross-protection can beconferred by antigenically similar clones [22]; in areas of hightransmission, residents are frequently exposed to a diversity ofclones, resulting in rapid development of antidisease immunityand asymptomatic infections [23]. In areas of low transmission,however, there is a lower rate of multiclonal infections andantidisease immunity develops more slowly [24].

Immunity to P. vivax is acquired more rapidly than toP. falciparum. In Papua, New Guinea, children aged 5–13 years were 21-times more likely to experience fever after infection withP. falciparum than P. vivax [25]. These findings were mirroredin children aged 1–4 years of age who showed an increasingability with age to keep parasite densities of P. vivax , but not

P. falciparum, below the pyrogenic threshold [26].

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How is asymptomatic parasitemia defined?

There is no standard definition of asymptomatic parasitemia, andprevious studies have used a range of definitions and diagnosticcriteria. Most definitions involve the detection of asexual or sexualparasites and an absence of any acute clinical symptoms of malaria

(usually fever) during a specified time frame. Whereas it is notalways explicit, asymptomatic parasitemia refers to bloodstreaminfections and does not include dormant liver stages.

A number of studies have used parasite density thresholds todefine cases of clinical malaria, that is, only cases of fever withparasite densities above a predetermined cutoff were consideredto be symptomatic malaria cases [27]. This results in a de facto classification of febrile infections with low density parasitemiaas asymptomatic, since their fever was not statistically attributedto malaria. While the use of parasite density threshold cutoffsprovides a more specific end point for studies of vaccines orclinical treatments [28], its converse should not be used to define

asymptomatic parasitemia for burden or impact assessments.Laishram et al. provide a list of diagnostic criteria that havebeen used in various studies to define asymptomatic malaria cases(T ABL E 1) [29]. The duration of time used to define an infectionas asymptomatic, both prior to and after the diagnosis, variesbetween studies; many have defined asymptomatic infectionas no measured fever at the time of the survey, whereas othershave required as many as 60 days of follow-up without clinicalsymptoms [30]. In some cases, fever is the only clinical symptomconsidered whereas other studies include a variety of additionalnonspecific disease symptoms. When follow-up periods are notmonitored for the development of symptoms, there may be aconcern that parasitemia detected during the malaria incubationperiod may be misclassified as an asymptomatic infection, butgiven the short duration of the time between the completion of theprepatent period and the end of the incubation period (~1 day forP. falciparum and 4 days for P. vivax ), this is likely an infrequentoccurrence. In some studies, cases have been excluded if theyreported prior use of antimalarial medication to avoid infectionsin the process of being cleared.

Gametocytes do not cause disease symptoms, and asympto-matic individuals may or may not have detectable gametocytes.The relationship between asexual parasite density and gametocytedensity is not straightforward; studies have found both positiveand negative associations [31]. Gametocytes may linger in peri-pheral blood up to several weeks after an asexual parasite infectionhas been cleared (whether by natural immunity or by drugs); onetrial demonstrated that gametocytes persist an average of 55 daysafter treatment with a non-ACT and 13.4 days after treatment with an ACT [32].

What factors are associated with asymptomatic

malaria infection?

Immunity is the factor that most strongly determines whethera malaria infection produces symptoms. An individual’s levelof immunity to infection is determined by past exposure his-tory and age. Increased immunity leads to improved control

over parasite multiplication and decreased parasite density,

which in turn lessens the severity of symptoms. In a nationalsurvey in Mozambique, children <10 years of age with low-density P. falciparum infections (1–499 parasites [p]/µl) had aprevalence of fever of 7.2%, compared with 42.1% among chil-dren whose asexual parasite densities were ≥50,000 p/µl [33]. In

Brazil, parasite density was compared between symptomatic (age12–78 years) and asymptomatic (age 4–56 years, with no fever ormalaria symptoms for 7 days prior to blood collection) individu-als infected with P. vivax and P. falciparum; lower asexual parasitedensities were found among the asymptomatic individuals forboth parasite species, although the difference was much greaterfor P. vivax [34].

Some asymptomatic infections may be residual or recrudescentparasitemia remaining after treatment for a clinical episode. In alow-transmission setting in Sudan, a higher proportion of people who experienced a clinical episode of malaria during the trans-mission season from September to December had an asympto-

matic infection detected by PCR in the following January thandid those without a prior clinical episode (35 vs 8%, respectively),despite having been clinically cured of their symptomatic infec-tion by treatment with chloroquine [35]. It is possible that drug-resistant parasites could persist at a low level after treatment, withdensities controlled by immunity developed during the initialinfection [36]. However, the parasites in these infections werenot genotyped to determine whether they were the same clonespresent during the clinical episode or new infections.

Coinfections may affect the development of symptoms by alter-ing immune system function. HIV-1 infection has been shownto increase rates of malarial fevers in a dose–response fashion, with declining CD4 T-cell counts [37]. The association betweensoil-transmitted helminths and development of clinical symptomsamong children with malaria parasitemia is less clear: hookworminfection appears to increase malaria symptoms, whereas infec-tion with Ascaris lumbricoides appears to decrease symptoms [38].Coinfection of malaria and schistosomiasis is a frequent occur-rence, but the effects on malaria immunity and transmission arecomplex. Some studies suggest that schistosomiasis coinfectionfavors development of antimalarial immunity [39,40], whereasothers have found lower levels of protective malaria antibodiesin Schistosoma haematobium carriers [41]. A recent prospectivestudy demonstrated that children coinfected with malaria andschistosomiasis were more likely to have detectable gameto-cytes and higher gametocyte densities than children infectedonly with malaria, potentially facilitating more intense malariatransmission [42].

The method used to diagnose infection will determine the num-ber of low density, asymptomatic infections that are identified. Thedetection limits of microscopy are typically estimated at 4–20 p/µlin a reference laboratory, but are more realistically 50–100 p/µlunder field conditions [43]. A few rapid diagnostic tests (RDTs)have been shown to have greater than 90% sensitivity and specific-ity for P. falciparum at parasite densities ≥200 p/µl [43–45] but mayoften fail to detect lower density infections. PCR is considered tobe the gold standard for detection of parasitemia with a limit of

detection of 0.02 p/µl for the most sensitive procedures [46].

Asymptomatic parasitemia & malaria transmission

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A review of studies reporting both PCR and microscopy resultsfor P. falciparum detection found that, on average, microscopyunderestimates the prevalence of Plasmodium infection asdetected by PCR by 50.8%, and this difference is greatest in low-transmission settings [14]. RDTs, with detection thresholds higherthan microscopy, would also be expected to underestimate theproportion of the population that has an infection, most of whichwill be asymptomatic. As a result, interpretation of estimates ofasymptomatic infections should consider the diagnostic methodused. Despite the increased sensitivity of PCR over microscopyand RDTs, there is still concern that it may not detect all malariacases with very low parasite densities [47].

Does the prevalence of asymptomatic parasitemia vary

by Plasmodium species?

All malaria species can infect without causing symptoms, butbecause P. falciparum and P. vivax are more prevalent globally,more asymptomatic infections of these two species occur than theother two human malaria species. Asymptomatic infections withP. ovale are rare but have been noted [48,49], whereas P. malariae isknown to persist in the bloodstream for decades without causing

any, or only mild, symptoms [48].

Individuals with P. vivax develop immunity more quicklythan with P. falciparum and consequently are able to controlparasite densities to a greater degree, but it is not clear whetherthis translates into a different proportion of infections that areasymptomatic by species. Few comparisons of the prevalence ofsymptoms among individuals infected with P. falciparum andP. vivax have been conducted in areas where the two speciesare sympatric, and results are contradictory. Using microscopyto diagnose infections, a larger proportion of P. falciparum infections (37.5%) compared with P. vivax infections (18.5%)in Brazil were asymptomatic (presenting with none of the13 malarial symptoms) [50]. In comparison, a greater propor-tion of P. vivax infections (97.1%) in the Solomon Islandscompared with P. falciparum infections (82.2%) were asymp-tomatic (axillary temperature: <38°C) [51]. Few studies havereported both the number of species-specific malaria cases andspecies-specific symptom rates, and diagnosed all infections byPCR; in Cambodia, 92% of the P. falciparum and 83% of theP. vivax infections were asymptomatic [52], whereas in Brazil,these proportions were 78 and 93%, respectively [53]. While itappears that the majority of prevalent infections of both species

are asymptomatic in cross-sectional surveys, there are no data

Table 1. Examples of diagnostic criteria used for defining malaria patients as asymptomatic.

Study (year),region

Criteria used for identifying asymptomatic malariacases

Study subjects,sample size (n)

Follow-up protocoland duration

Ref.

Africa

Abdel-Latif et al .(2003), Gabon

No clinical symptoms of malaria with a Plasmodium falciparum positive blood smear, asymptomatic for at least 5 days duringfollow-up

Children 6 months to10 years of age (60)

Examined once dailyfor 7 days; thereafter,once every 2 days

[92]

Rottmann et al .

(2006), Tanzania

Presence of P. falciparum on blood smear, axillary temperature

of <37.5°C and no other symptoms or signs of malaria

Children 4–59

months of age (127)

No follow-up [93]

South America

Alves et al . (2002),Brazilian Amazon

Individuals tested positive with microscopy and/or with PCR,and individuals tested negative with microscopy, which

subsequently became positive using PCR

All age groups (172) Follow-up on days 10and 60

[94]

Cucunubá et al .(2008), Colombia

Presence of patent asexual parasite stages of P. falciparum,Plasmodium vivax or Plasmodium malariae or of mixedinfections in blood, which persisted for at least 2 weeks

without causing any symptoms, or as the detection of parasiteDNA by PCR on day 0 in people who remained asymptomaticduring the follow-up period

Individuals 2–78 yearsof age (21)

Follow-up on days 14and 28

[95]

Asia

Boutlis et al .

(2003), Papua

No fever history or treatment for malaria within the past

week, no clinical evidence of malaria or other infection, nodiarrhea and no current pregnancy but bothP. falciparum- and P. vivax -positive individuals

Adults >16 years of

age (105)

Supervised overnight

at local health center.A third axillarytemperature wasrecorded the

following morning

[96]

de Mast et al .(2010), Indonesia

Presence of asexual P. falciparum or P. vivax parasitemia in theabsence of fever (temperature ≤37.9°C) and clinical signs or

symptoms that are suggestive for malaria or anotherinfectious disease

Children 5–15 yearsof age (381)

No follow-up [97]

A more comprehensive list of studies is given in the supplementary material of [29].


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to suggest that either species is associated with a larger reservoirof asymptomatic infections.

Do asymptomatic blood-stage infections eventually

become symptomatic?

Studies have suggested that a proportion of people with asympto-matic blood-stage malaria infection may become symptomatic,although reinfections or other causes of fever cannot always beruled out. In Brazil, 93 asymptomatic (presenting with none of13 malarial symptoms) infections in 33 persons aged 5 yearsand older were followed for 2 months after their infection wasidentified and ten (10.7%) became symptomatic during thatperiod [50]. However, the background transmission rate wouldsuggest that eight of those cases could have been the result ofnew infections. In a cohort study of asymptomatic (defined asno self-reported fever for the previous 24 h and axil lary tempera-ture <37.5°C) parasitemic Tanzanian children aged 1–5 years

who were followed over 31 days, 55.9% (19 out of 34) of thechildren eventually developed fever, which was associated withspikes in parasite density [23]. A prospective study of the riskof developing clinical malaria in a high-transmission area ofTanzania followed 265 parasitemic but asymptomatic (no feverduring previous 4 weeks or during 1 week after recruitment)residents aged 1–84 years of age over 40 weeks, and observed21 (7.9%) cases of fever in conjunction with a parasite density>400 p/µl [54].

Subpatent asymptomatic infections may be less likely tobecome symptomatic than infections detectable by microscopy.In Uganda, 25 out of 63 (39%) children aged 6 months to 5 years with subpatent infections who were asymptomatic (no malariatreatment in previous 2 weeks or fever in previous 48 h) devel-oped symptoms within 20 weeks of observation compared with43 out of 53 (82%) children with patent infections [55]. Thesefindings suggest that low-density malaria infections may persistfor long periods without causing symptoms if not treated.

It is not clear what triggers the appearance of symptoms inindividuals who have been parasitemic but remained asympto-matic for a period of time. It has been suggested that reinfection with new clones (to which the individual had not previously beenexposed) could trigger an increase in parasite density and thedevelopment of symptoms [56], but other studies have demon-strated that symptoms can appear without any change in clonaldiversity [55].

How long do asymptomatic infections last?

As described above, some portion of asymptomatic infectionsmay become symptomatic and receive appropriate antimalarialtreatment. However, many asymptomatic infections can per-sist for significant periods of time. Reports in the literature ofsoldiers returning home from malaria-endemic areas have dem-onstrated asymptomatic infections lasting up to 13 months forP. falciparum [57]. A statistical modeling approach combined withhighly sensitive molecular techniques using an all-age cohort inGhana – an area of high P. falciparum transmission – estimated

that untreated asymptomatic infections had a mean duration of

194 days (95% CI: 191–196) [58]. In areas of highly seasonaltransmission, low-density asymptomatic infections are believed topersist over the course of the dry season and to reseed transmission when mosquito populations increase along with wetter conditions[59,60]. P. malariae has been found in at least one case to remain

asymptomatic for decades [61].

Does the prevalence or density of gametocytes differ

between symptomatic & asymptomatic infections?

Several studies have shown that the presence of P. falciparum gametocytes is positively associated with an absence of symp-toms and low asexual parasite densities. While some anti-malarial treatments such as sulfadoxine–pyrimethamine (SP)may stimulate the production of gametocytes [62], this associa-tion has been detected even when non-gametocyte-stimulatingtreatments or no treatments have been used, and may arisefrom the natural concurrence between resolving infections and

the delay before gametocytes are produced in P. falciparum infections. On the western border of Thailand, being afebrileand having low P. falciparum asexual parasite densities wereindependently associated with increased prevalence of game-tocytemia [63]. Researchers in The Gambia evaluating children with P. falciparum infections at enrollment for antimalarial trialsfound that being afebrile at the time of examination increasedthe risk of gametocytemia by 67%, and having lower asexualparasite density (<100,000 p/µl) increased the risk fivefold [64].Similarly, in children with P. falciparum infections in Nigeria,being afebrile (axillary temperature 37.5°C) was associated witha 61% increase in gametocytemia, and having asexual parasitedensities <5000 p/µl more than doubled the odds of being game-tocytemic [65]. None of these studies used PCR to detect game-tocytes, suggesting that the prevalence of gametocytemia mayhave been underestimated; however, it is unlikely that this wouldhave changed the association described between asymptomaticinfections and the presence of gametocytes.

Wherea s a greater proportion of asymptomat ic infectionsmay have gametocytes, it is not clear whether gametocyte den-sity will be higher. As gametocytes in P. falciparum infectionsarise from asexual parasites (i.e., merozoites), there could be apositive correlation between the density of asexual and sexualparasite infections, leading to an association between low den-sity, asymptomatic infection and lower gametocyte densities.However, it is also possible that inflammatory and nonspe-cific immune factors related to symptomatic infections maynegatively affect gametocyte production, potentially leading tohigher gametocyte densities among asymptomatic infections.In Brazil, asymptomatic P. vivax gametocyte carriers had lowergametocyte densities as measured by PCR than symptomaticindividuals [66]. However, in Kenya, asymptomatic P. falciparum gametocyte carriers had higher gametocyte densities, but lowerasexual parasite densities than symptomatic individuals [67].These inconsistencies could be attributed to differences in thebiology of P. falciparum and P. vivax . No clear relationshipbetween asymptomatic infection and gametocyte density has

been established.


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How much do asymptomatic infections contribute to

transmission?

Gametocyte density appears to be a critical factor in determiningwhether a mosquito develops infection from an infective bloodmeal. An analysis of 930 transmission experiments showed a

largely log–linear positive relationship between gametocyte den-sity and the prevalence of infection in mosquitoes [68]. This sug-gests that if asymptomatic infections are associated with lowergametocyte densities, asymptomatic infections would be less likelyto result in mosquito infections. In a Brazilian study aimed atdemonstrating the viability and contribution of asymptomaticinfections to malaria transmission, 1.2% of the mosquitoes feed-ing on asymptomatic persons (n = 15) versus 22% of the mosqui-toes feeding on symptomatic persons (n = 17) developed oocystsin their midguts [30]. Different feeding techniques in the two pop-ulations may have affected the comparison but it is likely that thelower gametocyte density among the asymptomatic individuals

contributed to the observed differences in mosquito infection.Despite increasing probability of infection with increasinggametocyte density, numerous studies have demonstrated thatmosquitoes can become infected by blood from individuals withgametocyte densities as low as five gametocytes (g)/µl, and theo-retically as low as 1 g/µl [69]. To look at the relative transmissibilityof infections when gametocytes were detectable by microscopy,by PCR or were not detectable, researchers in western Kenyaused venous blood from children with and without gametocytesdetected by microscopy to feed mosquitoes through membranefeeders [70]. Blood from children with subpatent gametocytesinfected half as many mosquitoes as those with patent gameto-cytemia, but due to the frequency of subpatent gametocytemiain the sample of children, the end result was that both groupscontributed equally to the total number of infected mosquitoes.In this study, children with gametocytemia that was undetect-able even by PCR were still found to contribute to almost 10%of the overall number of infected mosquitoes, demonstratingthat gametocytes below detection thresholds can still result inmalaria transmission. P. vivax and other Plasmodium species aremore efficient at transmitting earlier in the infection and at lowerdensities than P. falciparum, and therefore a greater proportionof individuals infected with these species can transmit withoutdetectable gametocytemia [69].

There may be factors associated with the presence of symptomsthat alters infectivity to mosquitoes. In western Kenya, a signifi-cantly smaller proportion of mosquitoes that fed on blood fromsymptomatic individuals (0.6%) developed oocysts than thosethat fed on asymptomatic persons (12%) [67]. Although symp-tomatic individuals were found to have higher asexual but lowergametocyte densities than asymptomatic individuals, the authorsconcluded that the increased oocyst development in mosquitoesthat fed on asymptomatic individuals was not due solely to thehigher gametocyte densities, but also to an increased infectivityof these gametocytes. This increased ‘quality’ of gametocytes hasbeen postulated by others [29] and could be due to a variety offactors, including the stage of development of the gametocytes

(for P. falciparum, symptoms tend to occur earlier in infection

when gametocytes may not have reached a level of maturity to beoptimally infective), an inherent property of the parasite strain,a direct effect of symptomatology (i.e., the febrile response mayaffect the infectivity of gametocytes), or to a more specific hostimmune response, such as transmission-reducing antibodies [17].

Are individuals with asymptomatic infections more

likely to get bitten by malaria vectors?

There is no direct evidence that individuals with asymptomaticinfections are more likely to be bitten than symptomatic individu-als, but gametocyte carriers have been shown in one study to bemore attractive to mosquitoes than both uninfected individu-als and individuals with only asexual parasites. Comparing thesame children before and after they were cleared of P. falciparum gametocytes to control for inherent differences in individualattractiveness, researchers in Kenya were able to show that Anopheles gambiae were more attracted to children when they

were gametocytemic than when they were uninfected or whenthey harbored only asexual parasites [71]. As asymptomatic indi-viduals infected with P. falciparum may be more likely to begametocytemic than symptomatic individuals, it is possible thatasymptomatic persons have an increased likelihood of being bit-ten, but there is no clear evidence yet to support this hypothesis,nor is there any information on P. vivax infections.

How does transmission intensity affect the prevalence

of asymptomatic parasitemia?

It has long been held as conventional wisdom that in lowertransmission settings, the proportion of infected individuals whoare asymptomatic will be less than in high-transmission settingsbecause the population level of immunity is decreased [72]. FIGURE 1 (updated from data presented by Macauley [73] to include morerecent surveys that use PCR) shows the proportion of malariainfections (all species) that are asymptomatic across a wide rangeof transmission, prepared from 16 different sites in 14 countries.Only studies that measured the point prevalence of all malariainfections using a population-based cross-sectional survey designand included the number of infections that were asymptomatic were included, although the symptoms and the reference timeperiod used in the definition of asymptomatic differed betweenstudies. The data suggest that, while there is an increase in theproportion of the parasite reservoir that is asymptomatic as trans-mission increases, the majority (>60%) of prevalent infectionsare asymptomatic even at low transmission. Studies using PCRhad the highest rates of asymptomatic parasitemia, but evensome studies based on microscopy found greater than 80% ofthe cases of parasitemia to be asymptomatic. Many of the stud-ies did not report information allowing calculation of the pro-portion of asymptomatic infections by species, but seven studiesthat reported on P. falciparum found 73–98% of infections to beasymptomatic, and the five studies reporting on P. vivax found64–100% of infections to be asymptomatic.

The data presented by this graph challenge conventional wisdom and understanding of how immunity develops, but the

malaria cases reported in these studies were identified through


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active surveillance and are estimates ofpoint prevalence. Prevalence is a productof incidence and duration of infection; assymptomatic infections are more likelyto receive treatment, and the duration of

treated infections is significantly shorterthan untreated infections, it follows thatsymptomatic infections are less likely thanasymptomatic infections to be present atany one point in time. Similarly, onceappropriate treatment is provided, symp-toms may resolve more quickly than infec-tion. The few studies that have attemptedto capture all new infections over a periodof time, both symptomatic and asymp-tomatic, have found a lower proportionof asymptomatic infections using cumu-

lative incidence than point prevalence.Employing a combination of passive andactive case detection over a 14-monthperiod to identify all new malaria infec-tions in an area of Brazil, 326 episodesof malaria were identified, of which 96(29.4%) were asymptomatic at the time ofdiagnosis [50] – a proportion much lowerthan has been found in any cross-sectionalsurvey.

Without a strong association betweentransmission intensity and the proportion of infections thatare asymptomatic, the population prevalence of asymptomaticmalaria infection mirrors the overall transmission level. FIGURE 2 demonstrates the relationship between the prevalence of infec-tion, as detected by PCR, among asymptomatic individuals andtransmission intensity (as measured by the overall prevalence ofinfection) in 34 different studies in 38 sites in Latin America(n = 9), Asia (n = 10) and sub-Saharan Africa (n = 19). In thisanalysis, studies using a population-based cross-sectional surveydesign, in which the asymptomatic population could be identi-fied and malaria was confirmed using PCR, were included. Agegroups varied, but there is a positive correlation between trans-mission intensity and the prevalence of malaria infection amongasymptomatic individuals (T ABLE 2).

How does age affect the proportion of malaria

infections that are asymptomatic?

In areas of high malaria transmission, the proportion of the popu-lation that is parasitemic tends to decrease with age [31,74], althoughthis relationship may be somewhat muted when molecular assaysare utilized [75]. Conversely, the proportion of malaria infectionsthat are asymptomatic generally increases with age, presumablydue to acquired immunity and maturation of the immune system. After manipulating age categories to develop consistent groupingsbetween studies, FIGURE 3 presents the proportion of malaria infec-tions by age (0–4, 5–14 and 15+ years) across three studies in five

sites that used PCR for diagnosis. There is a consistent positive

trend in the proportions of infections that are asymptomatic withage across the five sites, but confidence intervals are wide. The lackof more significant differences by age could be a result of usingprevalent rather than incident infections, or the age groupings maybe too wide to detect differences between age categories.

What public health interventions target asymptomatic

parasitemia?

There are a number of drug-mediated strategies that implicitlyor explicitly target the asymptomatic parasite reservoir. By defi-nition, these strategies do not rely on any symptomatic trigger,and thus do not include health facility treatment, communitycase management, or fever surveys. Essentially, there are threeapproaches that will target drugs to the asymptomatic parasite res-ervoir: providing the population in a given geographic area withantimalarials irrespective of their infection or symptom status(mass drug administration [MDA]); universal screening of thepopulation with a malaria diagnostic test, followed by treatmentof those infected (mass screen and treat [MSaT], also referred toas aggressive-active case detection) [73]; and repeated treatment ofhigh-risk groups with an antimalarial not guided by diagnostictesting (intermittent preventive therapy). Whereas the primaryobjective of the first two approaches is a reduction of malariatransmission, intermittent preventive therapy strategies were con-ceived to reduce the burden of malaria and associated adverse con-sequences in high-risk groups, although theoretically, there may

be an impact on transmission if the high-risk group comprises a

Figure 1. The proportion of malaria infections that are asymptomatic comparedwith population prevalence of malaria across 16 sites in 14 countries. Error barscorrespond to the 95% CI. Hollow and filled shapes indicate diagnosis by microscopy andPCR, respectively. Diamonds, triangles and squares indicate surveys conducted in Asia,Latin America and Africa, respectively.Data taken from [35,36,51,52,94,114,120,124,126–132].

0

0

10 20 30 40 50

Prevalence of malaria (%)

P r o p o r t i o n o f m a l a r i a i n f e c t i o n

s

t h a t a r e a s y m p t o m a t i c ( % )

60 70 80 90 100

10

20

30

40

50

60

70

80

90

100


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significant proportion of the infective reservoir. These approachescan be modified by targeting smaller geographic areas (such ashotspots of transmission) or combined with other interventions,such as follow-up of passively detected cases, to fit different trans-mission settings and objectives [76]. Additionally, the frequencyof MDA and MSaT can be adjusted in light of the underlyingtransmission intensity, seasonality and type of antimalarial used.

What theoretical data suggest that these approaches

can reduce malaria transmission?

Several modeling attempts have demonstrated that targeting theasymptomatic parasite reservoir with MSaT or MDA could resultin reductions in malaria transmission, even though some of theeffects were modest [9,77,78] . Griffin et al. found that absolutereductions of 5–12% in parasite prevalence could be achieved inlow-to-moderate transmission settings (entomologic inoculationrates of 7–94 infective bites per person per year) with 80% cover-age of annual single rounds of MSaT using RDTs, in conjunctionwith 80% ITN coverage over 15 years of sustained program; theaddition of IRS would significantly improve the final outcome[9]. In areas with high malaria transmission (entomologic inocula-tion rates of 630 and 703 infective bites per person per year), themodeled impact of MSaT alone was marginal, with the ultimateoutcomes depending greatly on the initial transmission level aswell as the frequency and duration of the intervention and the

level of vector control established in conjunction.

Using the same basic underlying model,Okell et al. examined the impact of MDAand MSaT under different assumptions ofcoverage, drug choice, timing and screen-ing sensitivity, and found that MDA could

significantly improve chances for malariaelimination in small, concentrated pocketsof transmission [78]. In areas of moderatetransmission (baseline parasitemia preva-lence: 10–30%), single rounds of MDA would not have a lasting effect, but repeatedrounds could reduce malaria transmissionsubstantially. The authors found that inthese higher transmission settings, MSaTusing microscopy to identify infectionshad less of an impact than MDA, but theynoted that information on the infectivity

of subpatent infections is limited.

What empirical data suggest that

these approaches can reduce

malaria transmission?

Italy was the first country to implementMDA on a large scale beginning in 1900,through both quinine prophylaxis and cura-tive treatment [79]. This approach led to largereductions in malaria morbidity and mor-tality, but the country eliminated malariaonly after an IRS program using DDT

was added to the MDA with quinine after World War II. Sincethe 1930s, at least two dozen additional MDA interventions havebeen conducted [80]. Whereas many MDA interventions achievedtemporary reductions in malaria morbidity and transmission, fewhad rigorous study designs and MDA was often combined withother interventions. Only one project on the small, isolated islandof Aneityum in Vanuatu succeeded in permanently interruptingtransmission through a combination of weekly chloroquine, SPand primaquine, as well as high coverage of ITNs [81]. In 1981,70% of the Nicaragua population participated in a 3-day MDA with chloroquine and primaquine. The immediate impact of theMDA was substantial but the effect lasted only a few months [82].

The first large-scale community-randomized, placebo-con-trolled trial of MDA in Africa, which took place in The Gambiain 1999, found that one round of MDA with SP and single-dose artesunate in the dry season resulted in a brief reductionin malaria incidence that was not sustained over the 20-weekobservation period [83]. The only other recent trial of MDA in Africa attempted to interrupt malaria transmission in Tanzaniausing a treatment course of artesunate and SP plus primaquineto clear gametocytes [84]. However, despite achievement of highcoverage, transmission intensity was too low overall to demon-strate any impact. A recent trial of MDA with one round of afull course of dihydroartemisinin–piperaquine and a low dose ofprimaquine every 10 days for 6 months in 17 villages of Cambodia

found that parasite prevalence among both children and adults

Figure 2. Studies reporting on the proportion of the asymptomatic populationwith malaria parasitemia as diagnosed by PCR, by estimated malariatransmission intensity (n = 39). The top and bottom of the error bars indicate themaximum and minimum malaria prevalence, respectively; the dark line in the boxindicates the median prevalence; and the top and bottom of the box indicate the 75thand 25th percentile, respectively.Data taken from [51–53,77,91,95,98–126] .

0

Low Medium High

Transmission intensity

P r o p o r t i o n o f a s y m p t o m a t i c p o p

u l a t i o n

w i t h m a l a r i a p a r a s i t e m i a ( %

)

10

20

30

40

50

60

70

80

90

100


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Table 2. Studies reporting on malaria prevalence in asymptomatic individuals diagnosed using PCR.

Study (year),country

Study design Age group(years)

Patientstested (n)

Patientspositive formalaria (%)

Patientspositive forPlasmodiumfalciparum (%)

Patientspositive forPlasmodiumvivax (%)

Ref.

Low transmission

Fernando et al . (2009),Sri Lanka

Cross-sectional All agegroups

1854 0 [98]

Turki et al . (2012), Iran Cross-sectional 4–60 500 0 [99]

Zoghi et al . (2012), Iran Cohort of 500 patientsin each of two study

areas (three cross-sectional surveys)

2–60+ 1000 0 [100]

Atkinson et al . (2012),

Solomon Islands

Cross-sectional All age

groups

541 0.6 0 0.6 [101]

Kumudunayana et al .

(2011), Sri Lanka


groups

140 1.4 0 1.4 [102]

Hoyer et al . (2012),Cambodia

Focused screening andtreatment

All agegroups

6310 1.8 0.9 1.0 [52]

Congpuong et al .(2012), Thailand


475 1.9 [103]

Diallo et al . (2012),Senegal

Stratified urban sample 2–10 2231 2.2 [104]

Eisele et al . (2011),Haiti


647 2.2 2.2 0 [105]

Barracks et al . (2010),Vanuatu

Cross-sectional 2–12 4230 2.5 [106]

Hsiang et al . (2010),Uganda

Cohort 1–10 472 3.2 3.2 0 [107]

Harris et al . (2010),Solomon Islands


8107 3.6 [51]

da Silva et al . (2010),

Brazil

Cross-sectional 5+ 334 4.8 2.4 2.4 [108]

Kritsiriwuthinan andNgrenngarmlert(2011), Thailand

Cross-sectional Adults 241 6.2 3.3 2.5 [109]

Stresman et al . (2010),Zambia

Cohort All agegroups

176 7.4 7.4 0 [91]

Harris (2010), Solomon

Islands


groups

9,491 8.2 4.5 2.8 [51]

Roper et al . (1998),

Sudan

Serial cross-sectional

studies

All age

groups

77 10.4 10.4 0 [110]

Rodulfo et al . (2007),Venezuela


133 10.5 3.8 6.0 [111]

Gahutu et al . (2011),

Rwanda

Cross-sectional 0–5 529 13.2 13.2 0 [112]

Katsuragawa et al .(2010), Brazil

Cross-sectional 5+ 324 13.9 1.2 12.7 [113]

Cucunubá et al .

(2008), Colombia

Cross-sectional with

follow-up on days 14and 28

All age

groups

212 14.6 4.2 9.4 [95]


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Table 2. Studies reporting on malaria prevalence in asymptomatic individuals diagnosed using PCR (cont.).

Study (year),country

Study design Age group(years)

Patientstested (n)

Patientspositive formalaria (%)

Patientspositive forPlasmodiumfalciparum (%)

Patientspositive forPlasmodiumvivax (%)

Ref.

Low transmission (cont.)

Camargo et al . (1999),Brazil

Longitudinal All agegroups

169 14.8 0 14.8 [114]

Alves et al . (2002),Brazil


147 15.0 4.8 9.5 [53]

Färnert et al . (2009),Kenya

Cross-sectional surveywith follow-up

0–11 273 16.8 16.8 0 [115]

Moderate transmission

Ladeia-Andrade et al .(2009), Brazil

Five cross-sectionalsurveys (differentvillages)

All age

groups

644 9.6 3.4 6.2 [116]

Vafa et al . (2008),

Senegal

Cross-sectional survey

as part of cohort study

2–10 372 13.7 13.7 0 [117]

Suarez-Mutis andCoura (2007), Brazil


98 20.4 0 20.4 [118]

Baliraine et al . (2009),Kenya

Pooled data from 12monthly cross-

sectional surveys of acohort

5–14 81 22.6 22.6 0 [119]




5–14 81 25.8 25.8 0 [119]




5–14 2611 33.3 33.3 0 [119]

Pinto et al . (2000), São

Tome and Principe


groups

81 35.7 28.6 2.4 [120]

Kern et al . (2011),Kenya

Cross-sectional surveywith follow-up

0–11 264 36.7 36.7 0 [77]

Crookston et al .(2010), Ghana

Cross-sectional 0–5 84 51.9 51.9 0 [121]

Liljander et al . (2011),Kenya

Cross-sectional 1–6 360 58.9 58.9 0 [122]

High transmission

Koukouikila-Koussounda et al .

(2012), Congo

Cross-sectional surveyof cohort of children

1–9 313 16.3 16.3 0 [123]

Bereczky et al . (2007),Tanzania

Cross-sectional part ofcohort study

1–84 756 38.0 38.0 0 [124]

Dal-Bianco et al .

(2007), Gabon

Cross-sectional 18–51 470 51.9 51.9 0 [125]

Pinto et al . (2000), SãoTome and Principe


563 53.3 51.6 2.9 [120]

Owusu-Agyei et al .

(2002), Ghana


groups

297 82.5 82.5 0 [126]


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was dramatically reduced after 3 years from 52.3 to 2.6%, asmeasured by microscopy [85].

The Malaria Eradication Program of the 1950s and 1960s usedscreening of symptomatic individuals through mass fever surveysas an intervention, and in 1960, this approach was proposed to be

extended to asymptomatic carriers [86]. MSaT of asymptomaticcarriers was carried out on a large scale in Taiwan, India, Oman,Brazil, China and on one island of the Philippines, and led to largereductions in malaria and, in one case (Taiwan), elimination [73].In the USSR, significant declines in malaria cases to near-elim-ination levels resulted after the implementation of mass surveysin the late 1950s focused on asymptomatic parasite carriers [87].China was also able to achieve malaria elimination in a signifi-cant proportion of the country in the second half of the 20thcentury through rigorous active case detection focused on bothsymptomatic and asymptomatic individuals [88,89]. Despite theirapparent success, these early experiences with MSaT – from the

1950s to the 1990s – typically did not have a control group and were often implemented in combination with other interventions.One variation on MSaT is screening and treating only within

known malaria hotspots, also termed focal or focused screen andtreat (FSaT). Given the focalized nature of malaria, particularlyin low-transmission settings, FSaT has the potential to moreefficiently target screening and treatment resources to areas thatcould have a disproportionate impact on transmission reduction.The malaria control program of Zanzibar, conducted prior to thetransmission season, has experimented with FSaT in hotspots anddocumented significant decreases in malaria cases in the inter-vention areas over time and compared with control areas [90].FSaT using PCR was used in 20 villages of Cambodia in 2010,reaching 6931 (72.7%) residents over a 5-month period [52]. Atotal of 133 infections were detected and successfully treated, butthe impact on transmission is not yet known.

Using passively detected, symptomatic cases to identify high-risk households or geographic areas has been referred to as reac-tive or targeted case detection. In response to a household witha positive case, other household members along with the popu-lation within some distance of the index household would bescreened and treated [13]. Depending on how clustered or focalizedmalaria transmission is in the area, reactive case detection couldmore efficiently identify asymptomatic infections than MSaT.Using this approach in Zambia, members of RDT-positive house-holds, passively detected clinical malaria cases had a prevalenceof malaria parasitemia by nested PCR of 8.0% compared with0.7% in households in which no member had sought treatmentfor clinical illness [91]. The study was not designed to evaluate theimpact of the approach on malaria transmission. Both Zanzibarand selected areas of Zambia have implemented reactive casedetection in a programmatic fashion, although results are notyet available on the impact of this approach on malaria prevalenceand transmission.

Conclusion

Individuals who receive repeated malaria infections over time

eventually achieve increased immune control with a resultant

decrease in acute symptoms. Without clinical illness, these infec-tions are silent and remain untreated, resulting in chronic carriagethat can last for 6 months or longer. Asymptomatic infections maybe associated with a greater probability of gametocyte carriage,although there is also likely to be a lower density of gametocytes

in these individuals, and these effects may cancel themselves out with respect to altering the infectivity of asymptomatic infections.However, the proportion of mosquito infections that arise fromasymptomatic infections is likely to be high due to a combinationof the proportion of asymptomatic infected individuals in thepopulation at any given point in time and the duration of theirinfections. Evidence summarized in this report suggests that evenin areas of low transmission, the contribution of asymptomaticinfections to transmission is likely to be substantial, and in areas with seasonal transmission, asymptomatic infections may serveas the source of infections for a new generation of mosquitoesemerging after the start of the rains.

Lack of a standardized definition of asymptomatic infectionmay be limiting the ability to compare burden across space andtime, and to measure the impact of control or elimination pro-grams that target the asymptomatic parasite reservoir. Giventhat both P. falciparum and P. vivax have an approximately 48-hfebrile cycle, it seems reasonable to define asymptomatic infec-tions operationally as cases of malaria parasitemia of any density,preferably diagnosed using PCR, without current, measured feveror history of fever in the past 48 h that have not received appro-priate antimalarial treatment in the past 3 days. Increasing thetime without symptoms prior to diagnosis or adding an obser-vation period afterwards (often not feasible) would potentiallydecrease the specificity of the definition by increasing the prob-ability of encountering fever caused by another infection. It couldbe argued that including other symptoms besides fever mightimprove the specificity of the case definition, but there are noother symptoms commonly used to define clinica l malaria, anduse of fever alone greatly simplifies the definition of asymptomaticinfections.

Strategies targeting asymptomatic infections are available, butrigorous research efforts to compare the relative effectiveness ofdifferent approaches at varying levels of malaria transmission areneeded. The approaches that most efficiently and quickly findand eliminate asymptomatic parasite reservoirs may provide theendgame for malaria elimination in many areas.

Expert commentary

With the advent of molecular diagnostic techniques, there hasbeen increasing recognition that a significant proportion of theinfective reservoir across the spectrum of malaria transmission iscomprised of asymptomatic infections. Ultimately, it is the game-tocytes that are taken up in the blood meal of female Anopheles mosquitoes that go on to form sporozoites responsible for infect-ing other humans, but programmatic interventions to interruptthis transaction must focus on individuals with malaria infectionat any stage, as asexual parasitemia left untreated will eventuallyproduce gametocytes, and diagnostics for the sexual stage are

limited.


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Whereas our understanding of how par tial immunity tomalaria develops would suggest that malaria infections aremore likely to be symptomatic in low-transmission settings,data summarized in this report suggest that at any one pointin time, the majority of the parasite reservoir is likely to beasymptomatic. This finding is consistent across transmissionsettings and may be a result of symptomatic individuals receiv-ing treatment that reduces both the length of time they aresymptomatic as well as the time they are parasitemic, therebyremoving symptomatic infections from the parasite reservoirmore rapidly than asymptomatic infections. Regardless of whyprevalent infections are more likely to be asymptomatic, inter-ventions that are not linked to the presence of symptoms willbe needed, even in low-transmission settings, to significantlyreduce malaria transmission.

These data suggest several research questions that remain tobe answered. At least one study has found that prevalent, asymp-tomatic infections are associated with earlier episodes that wereclinically cured, albeit with an antimalarial medication (chlo-roquine) no longer recommended for sub-Saharan Africa [35].The extent to which asymptomatic parasitemia is associated withpartial treatment, treatment failures and residual populations ofresistant parasites should be investigated further. The relativecontributions of symptomatic and asymptomatic infections totransmission have been measured in very few studies; in particu-lar, the role played by subpatent asymptomatic infect ions should

be investigated further in both low- and high-transmission areas,

as this proportion of the asymptomatic res-ervoir is reached by MDA but not by MSaTand could help determine which of thesetwo strategies will be most efficacious in agiven setting. It is essential to rigorously

evaluate the cost–effectiveness of differentapproaches to target the parasite reservoir.Community-randomized controlled trialsof different strategies in areas with varyinglevels of P. falciparum and P. vivax trans-mission should be initiated to inform pro-gram managers and elimination strategiesof the best way forward. Care should betaken to monitor populations participatingin MSaT, FSaT and MDA interventionsfor safety issues and development of drugresistance, as well as to identify any poten-

tial rebound in clinical malaria that couldoccur as a result of eliminating asympto-matic infections. Finally, integrated drug-and insecticide-mediated interventionsshould be evaluated in the field to identifyoptimal mixes that will result in malariaelimination.

Five-year view

Strategies targeting the asymptomatic par-asite reservoir were used in the past, but

results did not always match expectations. In particular, MDAhas fallen out of favor because results were short lived and there was the potential for selection of drug-resistant strains. As a result,there is significant interest in evaluating MSaT approaches. MSaThas the additional advantage in that the location of malaria infec-tions can be mapped easily without additional effort, allowingfor more focused interventions to be layered on top. As we learnmore about the potential for infections missed by MSaT to sustaintransmission, MDA may prove to be a better option. Currently,there are a number of ef forts underway to evaluate MSaT, MDAand FSaT in a variety of transmission intensities and with slightlydifferent strategies for identification of cases and responses. Someevaluations will compare these approaches directly to case man-agement, and much information on the role of asymptomaticparasitemia in malaria transmission will be gleaned from com-parisons of strategies that target different segments of the parasitereservoir. Over the next 5 years, this research agenda is likely toexpand significantly and contribute to new strategies to find andeliminate malaria infections.

Financial & competing interests disclosure

The authors have no relevant af filiations or financial involvement with any

organization or entity with a financial interest in or financial conflict with

the subject matter or materials discussed in the manuscript. This includes

employment, consultancies, honoraria, stock ownership or options, expert

testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Figure 3. Proportion of malaria infections detected by PCR that areasymptomatic by age across three studies in five sites. The error bars correspond tothe 95% CI for the proportion.Data taken from [90,110,131].

Sudan (24) Brazil (45) Brazil (51)Burkina

Faso (31)

Burkina

Faso (69)

0

Location, malaria prevalence (%)

P r o p o r t i o n o f m a l a r i a i n f e c t i o n s

t h a t a r e a s y m p t o m a t i c ( % )

10

20

30

40

50

60

70

80

90

100

0–4 years

5–4 years

15+ years


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Key issues

• Advances in molecular diagnostic techniques have revealed a larger reservoir of asymptomatic human malaria infections than previouslyrecognized.

• Even in low-transmission settings, the majority of prevalent malaria infections are asymptomatic and may persist for weeks or months.

• With renewed focus on global malaria eradication, strategies targeting the human parasite reservoir are needed to continue to drivedown transmission and achieve elimination in malaria-endemic areas.

• Strategies to target asymptomatic parasitemia include mass drug administration (MDA), mass screen and treat (MSaT), and focusedscreen and treat (FSaT) in defined ‘hotspots’ of malaria.

• New research trials of MDA, MSaT and FSaT are underway in a number of countries. Findings from these studies will help informelimination efforts in a variety of transmission settings.

• Additional unanswered research questions on asymptomatic parasitemia include the extent to which asymptomatic parasitemia isassociated with partial treatment, treatment failures and resistant parasites; the relative contribution of asymptomatic infections to

malaria transmission; and the cost–effectiveness and safety of MSaT, FSaT and MDA interventions in different transmission settings.

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