Clin Infect Dis. 2002 Fischer 493 8

TRAVEL MEDICINE CID 2002:34 (15 February) 493

T R A V E L M E D I C I N EI N V I T E D A R T I C L ECharles D. Ericsson and John F. Modlin, Section Editors

Prevention of Malaria in Children

Philip R. Fischer1 and Ralf Bialek21Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota; and 2Institute for Tropical Medicine, University Hospital, Tuebingen, Germany

Although malaria kills 1 million children each year, preventive measures can be effective in limiting the mortality andmorbidity associated with malaria. Mosquito bites can be avoided by use of appropriate environmental control and use of

protective clothing, bed nets, repellents, and insecticide. Chemoprophylaxis is a mainstay of malaria prevention, and new,

effective agents are increasingly available. Rapid, accurate diagnosis and effective medical treatment can help people who

become ill with malaria despite their preventive efforts. With careful attention to preventive efforts, malaria should be

extremely rare in travelers; similarly, broader implementation of preventive measures could decrease the burden of malaria

on residents in areas where it is endemic.

Malaria kills 1 million children each year and is also a majorcause of illness, health care visits, and hospitalizations in many

areas of the world [1]. Although 2.4 billion people on the planet

live under the threat of malaria, most of the morbidity and

mortality with the disease is seen in sub-Saharan Africa [2, 3].

Like residents of regions where malaria is endemic, children

traveling in such areas are also at risk. Each year, 1000 casesof malaria are imported into the United States [4] and 7000are imported into Europe [5]; cases in children are well doc-

umented [6, 7] and comprise 5%10% of imported cases in

some unpublished reports.

Worldwide efforts to combat malaria have moved from the

unsuccessful eradication attempts of the 1950s through the con-

trol efforts of the 1980s to the current Roll Back Malaria pro-

gram (http://www.rbm.who.int) [8]. Spurred by widespread

publicity and fueled by newly mobilized resources, current con-

trol efforts have increased the optimism that malaria can be

subdued. However, what can be done now to prevent malaria

in children? Specific interventions are possible to avoid malaria

infection, to prevent malaria illness, and to preempt malaria-

associated mortality. These measures are easily implemented

for children whose families have the resources to travel to areas

where malaria is endemic, and similar efforts, when affordable,

could benefit young residents of these regions.

Received 3 July 2001; revised 1 October 2001; electronically published 2 January 2002.

Reprints or correspondence: Dr. Philip R. Fischer, Pediatric and Adolescent Medicine, MayoClinic, 200 First Street SW, Rochester, MN 55905 ([email protected]).

Clinical Infectious Diseases 2002; 34:4938 2002 by the Infectious Diseases Society of America. All rights reserved.1058-4838/2002/3404-0011$03.00

AVOIDING MALARIA INFECTION

The majority of cases of malaria are acquired via a bite from

an infected mosquito, although some cases are acquired trans-

placentally or via transfusion of blood products. Generally, to

avoid malaria infection, a child must avoid being bitten by an

infected mosquito. This can be accomplished by choosing ap-

propriate times and places for activities, controlling the physical

environment, blocking mosquitoes access to the skin, repelling

mosquitoes from the skin, and killing mosquitoes near the

child. Table 1 outlines practical advice about mosquito avoid-

ance for traveling children.

Malaria is transmitted by female anopheline mosquitoes,

which bite either outdoors or indoors during evening and night

hours. Thus, a child should spend the evening and night hours

in a mosquito-free environment, such as inside a house with

screened windows and closed doors. When they are in areas of

endemicity, travelers should schedule activities so that children

are not outside during evening hours, when anopheline mos-

quitoes are most likely to bite. In some areas, malaria trans-

mission is seasonal, and elective trips could be planned for the

dry season, when transmission is less common.

Mosquitoes spend their lives in and around standing water.

Human living areas should be free of persistent puddles and

open water-containers. In some areas, small fish that feed on

insect larvae are kept in fountains and water storage containers

as a means of mosquito control [9].

Given that mosquitoes and children do end up sharing the

same living areas, physical barriers should be used to block the

access of mosquitoes to childrens skin. Skin should be covered

with clothing (lightweight for comfort and light-colored to be

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494 CID 2002:34 (15 February) TRAVEL MEDICINE

Table 1. Practical advice for avoiding malaria infection.

Proactive protective actions

Schedule a visit to an area where malaria is endemic duringseasons of low transmission

Plan to spend evenings and nights in closed buildings

Impregnate clothes and bed nets with insecticide

Protective actions in area of endemicity

Eliminate standing water near housing

Cover skin with long-sleeved shirt and long pants or dress

Use bed nets

Apply concentrated DEET to skin, avoiding oral and ocularcontamination

NOTE. DEET, N,N-diethyl m-toluamide or N,N-diethyl-3-methylbenza-mide.

less attractive to insects). Sleeping children should be sur-

rounded by bed nets. Nets to fit various sizes and styles of beds

are available through the Internet, for example at the Travel

Medicine Web site (http://www.travmed.com).

Clothes and bed nets can be impregnated with an insecticide

to increase their effectiveness in protecting children. Products

such as 0.5% permethrin can be sprayed on clothes and nets

to moisten them; the material should then be allowed to air

dry for at least 6 h before use. Even if laundered, the impreg-

nated clothes will remain insecticidal for 26 weeks [10]. Im-

pregnated nets seem to retain their protective ability for 612

months and have been shown to decrease overall malaria mor-

tality and morbidity in communities [11].

Applied topically to skin, chemical repellents are effective in

reducing the number of mosquito bites received. DEET (N,N-

diethyl m-toluamide or N,N-diethyl-3-methylbenzamide) is the

gold standard; it has proven its safety and effectiveness for 140

years [12, 13]. Nonetheless, 13 serious adverse neurologic events

have occurred concurrent with DEET use. Details of these cases

were not fully recorded, but at least some were related to oral

ingestion or overapplication of DEET [14]. Despite myths to

the contrary, high concentrations of DEET have not been linked

to adverse effects, but higher concentrations have longer du-

rations of effectiveness [15]. Children can safely apply DEET

in concentrations of 30%, which will provide 46 h of re-

pellent activity. Use of newer formulations of DEET (such as

those incorporating DEET into liposomes) extends the duration

of protection to 12 h. DEET in any form is toxic if ingested

orally, and ocular contact will irritate the eyes and should be

avoided. Therefore, DEET should not be applied to the hands,

forearms, or faces of young children. DEET-containing repel-

lents can interact with concurrently applied sunscreens to limit

sunscreen effectiveness by 34% [16], but the insect-repellent

efficacy of DEET is unchanged by concurrent sunscreen use [17].

No insect repellent has yet been identified that is more ef-

fective than DEET [12]. Natural products that contain cit-

ronella have only a short-term (30 min) effect in repellingmosquitoes. Some perfumed repellents might actually attract

mosquitoes. A new topical insect repellent, 1-pipetidinecarbox-

ylic acid, 2-(2-hydroxyethyl)-,1-methylpropylester (trade name,

Bayrepel [Bayer]), is under development, and its effectiveness

is similar or superior to that of DEET in field studies. Its use

is recommended by the World Health Organization [18], and

it has been licensed in several countries for use on children

aged 12 years. Safety studies have not yet been performed for

younger children.

Environmental insecticides, such as those released by slowly

burning coils, seem to decrease indoor mosquito populations

by 50%75% [19, 20], but some cases of airway irritation have

been reported with the use of these products [21]. Ultrasonic

buzzers and devices that electrocute insects have not been found

to reduce bites from infected mosquitoes [19]. Community

spraying of insecticides is expensive but effective in limiting

mosquito populations.

PREVENTING MALARIA DISEASE

After the host is bitten by an infective mosquito, malaria par-

asites remain in the circulation for 30 min before gainingentry into hepatocytes. There, the parasites develop for at least

11.5 weeks before returning to the circulatory system to infect

RBCs and cause symptoms of malaria disease; some strains of

species other than Plasmodium falciparum, however, can persist

in the liver for months to years. Newer prophylactic medica-

tions, such as atovaquone-proguanil and primaquine, are able

to kill the parasites effectively before they return from the liver

to the blood system. Most chemoprophylactic agents, how-

ever, act by maintaining a concentration in the circulating blood

adequate to prevent the infection from becoming established in

RBCs. Thus, the infection is aborted before symptoms develop.

Chemoprophylaxis has been used effectively for decades, but

the increasing resistance of Plasmodium to medications has

limited the effectiveness of chemoprophylactic regimens used

in the past [22]. In areas of endemicity, chemoprophylactic

efforts have been hindered by cost and programmatic diffi-

culties. Nonetheless, mosquito avoidance and chemoprophy-

laxis are the mainstays of malaria prevention for children trav-

eling from areas where malaria is not endemic to areas where

it is.

Figure 1 shows countries and areas where there is risk of

acquiring malaria. As displayed in the figure, the selection of the

appropriate antimalarial medication should be individualized ac-

cording to the patterns of resistance in the geographical region

where exposure is anticipated. The Web sites of the Centers for

Disease Control and Prevention (http://www.cdc.gov) and the

World Health Organization (http://www.who.int) give specific

guidance. In general, chloroquine is the first choice for che-


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Figure 1. Map showing countries and regions where malaria occurs. The risk of malaria, however, is not uniform throughout the shaded areas.The Web sites of the Centers for Disease Control and Prevention (http://www.cdc.gov) and the World Health Organization (http://www.who.int) givespecific information identifying which parts of some countries actually are areas where malaria is endemic.

moprophylaxis for children going to areas where malaria is still

sensitive to chloroquine. Mefloquine is generally a good option

for children traveling to areas where chloroquine-resistant ma-

laria is prevalent; atovaquone-proguanil and (for children 8

years of age) doxycycline are good alternative choices. Children

who must travel to areas where there is mefloquine-resistant

malaria would usually receive atovaquone-proguanil or, if they

are 8 years old, doxycycline.

Table 2 notes medications effective in chemoprophylaxis and

details about recommended dosages. Clearly, the use of any

preventive medication must be customized on the basis of the

childs age, size, and health. There are not good data to specify

the duration of chemoprophylaxis in children, but continuous

use for 12 years is probably safe.

Chloroquine, a 4-aminoquinolone, was once the mainstay

of malaria chemoprophylaxis but has become less useful as the

parasites have developed resistance to its effects. As noted on

figure 1, its usefulness is limited to a few areas of Latin America,

the Mideast, and Asia. Chloroquine is rapidly absorbed and

becomes more concentrated in RBCs than in plasma. Approx-

imately one-half is secreted in the urine, and the other one-

half is biotransformed by the liver; metabolites are important

to the prophylactic effect, and the half-life is 610 days [23].

Toxicity is unusual with the dosages given as prophylaxis, but

pruritus is sometimes seen, especially in Africans and African-

Americans. There is some concern that the cumulative doses

achieved after 5 years of continual prophylaxis might be as-

sociated with a retinopathy and, therefore, periodic retinal ex-

aminations are sometimes recommended for children receiving

long-term prophylaxis. Chloroquine is generally safe for most

children. Overdosing, however, can be dangerous, and attention

should be paid to pill safety and the avoidance of inadvertent

ingestion of pills.

The addition of proguanil, given daily, to chloroquine, given

weekly, provides an effective prophylactic regimen in some parts

of the world. Nonetheless, malaria with increasing resistance

to this regimen has extended to East Africa and other areas,

and this combination of prophylaxis is no longer a first-line

choice for chemoprophylaxis. In addition, proguanil is not li-

censed for use in the United States. It is generally safe for

children, but transient hair loss, mouth sores, and mild gas-

trointestinal symptoms have been associated with its use.


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Table 2. Chemoprophylactic agents for malaria.

Agent(s) Dosage Comments

Chloroquine 5 mg/kg weekly; maximum dose, 300 mg; begin1 week before exposure, continue 4 weeksafter exposure

Mostly effective in Central America

Chloroquine plus proguanil Chloroquine as above; proguanil 4 mg/kg daily (or3 mg/kg per day in 2 divided doses); maximumdose, 200 mg

Increasing resistance has been noted

Mefloquine 5 mg/kg weekly; maximum dose, 250 mg; begin12 weeks before exposure and continue 4weeks after exposure

Effective in Africa, Asia, South America; no limitsto the age or size of the patient; do not administerif the patient has seizures, dysrhythmia, or psychi-atric problems

Atovaquone plus proguanil 1 pediatric pill (1/4 of an adult pill) per 10 kg daily;maximum dose, 4 pediatric pills (1 adult pill);begin 12 days before exposure and continue7 days after exposure

Alternative to mefloquine; dosage, 250 mg atova-quone 100 mg proguanil per adult pill

Doxycycline 2 mg/kg daily, maximum 100 mg Ineffective near some of the border areas of Thai-land; do not administer if patient is !8 years old;alternative to mefloquine

Primaquine 0.5 mg/kg daily; maximum dose, 30 mg Not yet recommended; there is some risk if thepatients G6PD level is low

Tafenoquine Pending Studies in progress; there is some risk if thepatients G6PD level is low

NOTE. G6PD, glucose-6-phosphate dehydrogenase.

Mefloquine, a quinoline-methanol compound, is effective

against malaria in most travel destinations, with the exception

of some regions near Thailands borders with Cambodia and

Myanmar. It is rapidly absorbed, and absorption might be im-

proved by taking it with a meal [23]. It is generally available

only in tablet form and has a taste that many children do not

enjoy. There are anecdotal reports that taking mefloquine after

eating and administration with either a cola drink or chocolate

seem helpful for some children. Emesis within 30 min of in-

gestion should prompt a second administration of the entire

dose. Mefloquine seems to have an adverse reaction profile that

is similar in children and in adults, but the exact risks for mild

side effects are not well understood, especially in young chil-

dren. In adults, bothersome effects (nausea, vomiting, insom-

nia, vivid dreams) occur in 10%15% of those who receiveit, and serious neuropsychiatric side effects have also been re-

ported; !5% of individuals treated need to discontinue treat-

ment because of side effects. Comparative studies suggest that

the frequency of side effects with mefloquine is similar to that

with other preventive antimalarial regimens [24]. Serious ad-

verse reactions are less likely with prophylactic than with cu-

rative dosages. Mefloquine does affect cardiac conduction and

can lower the seizure threshold. It should not be administered

to children with psychiatric problems or abnormalities of car-

diac rhythm. Children who require anticonvulsant therapy and

children aged !5 years who have a history of febrile seizures

should also avoid mefloquine.

The mixed combination of atovaquone and proguanil, re-

cently released into the US market, adds an additional agent

to the chemoprophylactic armamentarium. Atovaquone inhib-

its the parasites mitochondrial electron transport, and pro-

guanil acts on folate to hinder DNA synthesis by the parasite.

This combination product does have some effect during the

liver stage of malaria (causal prophylaxis), so it can be dis-

continued just a week after the traveling child leaves the area

of endemicity. It is effective and safe in children residing in

areas of endemicity [25] and in nonimmune adult travelers

[22], but detailed studies in pediatric travelers have not been

done. Pending further study, it is not yet recommended for

children who weigh !10 kg.

Doxycycline is contraindicated in children aged !8 years be-

cause of possible staining of developing teeth and because of

theoretical concerns about interference with bone growth. It

should be taken with plenty of liquid because inadequate swal-

lowing of capsules can lead to esophageal irritation. Photosen-

sitivity occurs in some children who are receiving doxycycline,

so use of sunscreen that blocks both ultraviolet A and B ra-

diation is advised for children who are receiving this agent.

Primaquine, an 8-aminoquinoline, has been used for decades

to treat persistent hepatic infection with Plasmodium vivax and

Plasmodium ovale. Recently, it has been proposed as causal

prophylaxis for all forms of malaria. If it were to be used, one

would need to rule out glucose-6-phosphate dehydrogenase

(G6PD) deficiency in the child, because the use of primaquine

in children with this deficiency can cause hemolytic crises. Pri-


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maquine is not yet generally accepted as a prophylactic agent

but does have potential for preventive use [26].

Tafenoquine, also an 8-aminoquinoline, is a newer investi-

gational antimalarial agent. As resistance to other prophylactic

agents increases, tafenoquine holds promise as a potential fu-

ture addition to the antimalarial armamentarium. Like pri-

maquine, it should only be used in children without G6PD

deficiency. A study in adolescents in an area of endemicity

showed a protective effect that persisted for 7 weeks after a 3-

day course of tafenoquine [27], which suggests that this agent

might have protective activity in short-term travelers who are

treated only before traveling.

Other antimalarial agents have been used in the past but are

not currently recommended as prophylactic agents. These other

agents are either inadequately effective (pyrimethamine and

azithromycin) or potentially toxic to children (sulfadoxine can

cause Stevens-Johnson syndrome, amodiaquine can suppress

bone marrow activity, and halofantrine can cause cardiac

rhythm disturbance).

The real hope for malaria control rests with the pursuit of

an effective vaccination. Initial efforts were disappointing, but

new methods of immunization hold potential for success. The

Spf66 vaccine includes amino acid sequences from 3 asexual

blood-stage proteins that are linked by repeat sequences from

the circumsporozoite protein. This product was developed in

South America and initially seemed to be effective there. In

field trials in other areas where different strains of Plasmodium

species were endemic, however, it was much less effective. Over-

all, there have been 9 clinical trials of this vaccine, which have

found that it has no statistically significant efficacy in decreasing

the rates of malaria infection or severe outcomes of malaria.

In the South American studies, there was a suggestion of a

decrease in episodes of malaria due to P. falciparum, but this

finding was not replicated elsewhere [28]. There have been 4

studies of a sporozoite-stage vaccine that uses a peptide se-

quence from a protein found on the surface of sporozoites.

None of these studies found that the vaccine had a significant

effect on the incidence of malaria [28].

The life cycle of malarial parasites is complex, and the human

immune response to malaria has not been completely char-

acterized. Even as the malaria genome is decoded, it seems that

successful vaccines will involve multiple antigens that affect

various stages of the parasite life cycle [29]. Vaccines can target

pre-erythrocytic stages in a way that would prevent infection

from becoming established, erythrocytic stages to moderate the

actual course of the infection, and gametocyte stages to block

subsequent transmission of parasites. DNA-based vaccines are

currently being evaluated, as are various combinations of prim-

ing and boosting vaccination strategies. Clinical studies in-

volving children have been launched in West Africa. It remains

to be seen how successful new immunizations will be, both in

residents of areas of endemicity and in visitors to malarial

regions of the world.

PREEMPTING MALARIA MORTALITY

In areas where malaria is endemic, efforts at mass chemopro-

phylaxis have not proved successful. This was primarily due to

programmatic problems that limited compliance with the dis-

tribution and regular administration of weekly medication. Be-

cause of ineffective prophylaxis and incomplete mosquito con-

trol measures, the emphasis in developing countries was placed

on prompt evaluation and treatment of febrile children who

possibly had malaria. Significant decreases in malaria-related

morbidity and mortality have not been achieved.

Nonetheless, the idea of administering early presumptive

treatment to avert serious complications of malaria is appealing.

In travelers who are careful to avoid mosquitoes when visiting

areas where the risk of acquiring malaria is relatively low, the

risk of side effects from chemoprophylactic medications might

be about the same as or even greater than the risk of suffering

adversely from malaria. In such cases, one might suggest that

chemoprophylaxis be withheld and that presumptive curative

therapy be readily available. The German Society of Tropical

Medicine and the Swiss Working Group on Travel Medicine

are now recommending this approach for travelers to low-risk

areas (i.e., parts of Thailand, Mexico, Peru, the Middle East,

and some other areas), and this is consistent with the World

Health Organization recommendations for travelers to low-risk

areas. In the United States, the Centers for Disease Control and

Prevention still recommends standard chemoprophylaxis.

However, dependence on presumptive treatment as a means

of preventing malaria-induced morbidity and mortality re-

quires that diagnostic methods be accurate and that therapeutic

interventions be available and rapidly effective. Clinical findings

(e.g., fever, pallor, and splenomegaly) alone have not been com-

pletely sensitive or specific in the detection of malaria, but

presumptive treatment by parents has sometimes been shown

to reduce mortality among children in areas of endemicity [30].

Blood tests that use rapid antigen-detection techniques have

been similarly incompletely reliable in field situations [31]. Even

in the United States, appropriate diagnostic evaluation of chil-

dren with malaria is often delayed [32]. Therapeutic interven-

tions are possible, but there can be some morbidity already by

the time malaria is suspected and treated. Options for pre-

sumptive treatment include chloroquine (for travelers to some

limited geographic areas), mefloquine, the combination of ato-

vaquone and proguanil, and quinine, but the side effects as-

sociated with therapeutic dosages and compliance challenges

can limit the proportion of patients who complete therapy.


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Newer rapid-acting antimalarial regimens that involved prod-

ucts such as the combination of artemether and lumefantrine

[33] might make even presumptive self-treatment more reliably

effective.

In addition, as much as possible, ready access to competent

medical care for ongoing monitoring and management must

be assured. For travelers to Africa, presumptive therapy cannot

replace chemoprophylaxis as the mainstay of malaria preven-

tion among children, especially because of the high risk of P.

falciparum malaria and because these diagnostic, therapeutic,

and management issues have not been resolved. Whether or

not a pediatric traveler received chemoprophylaxis while in an

area where malaria is endemic, any febrile illness in such a child

should stimulate a prompt and thorough evaluation by a com-

petent medical-care professional.

In conclusion, efforts aimed at the prevention of malaria in

children must be multifaceted. Insect avoidance is essential and

can prevent the acquisition of a malaria infection. Chemopro-

phylaxis is effective and usually well tolerated; this serves as a

means of preventing symptomatic malaria illness. Rapid treat-

ment of symptomatic malaria is useful in limiting malarias

morbidity and mortality among travelers who have break-

through malaria despite preventive efforts. At the same time,

children residing in areas where malaria is endemic continue

to suffer and die at alarming rates. Global efforts to combat

malaria are critical, and continued efforts to perfect an effective

vaccine are essential.

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