Tropical Medicine and International Health

volume 4 no 7 pp 469–470 july 1999

Editorial: Antimalarial drug resistance and mortality infalciparum malaria

Nicholas White

Wellcome Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand

Correspondence N.J. White, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road,

Bangkok 10400, Thailand. E-mail: fnnjw@diamond.mahidol.ac.th

Nobody knows the true mortality of untreated falciparum

malaria. It depends largely on age and previous exposure, but

even in nonimmune patients mortality is probably less than

5%, and may be much lower (Sudre et al. 1992). The mortality

of treated symptomatic drug-sensitive infections is ap-

proximately 0.1% (Meek et al. 1986; Luxemburger et al. 1996).

Antimalarial treatment therefore reduces the chances of dying

from falciparum malaria up to 50 fold. Once the infection has

progressed to the stage of severe malaria, the treated mortality

rises to between 15% and 20% (Waller et al. 1995; Hien et al.

1996; van Hensbroek et al. 1996; Newton & Krishna 1998). If

no antimalarial treatment is given, most authorities consider

severe malaria as a usually fatal condition. Thus in the context

of severe malaria, mortality is reduced up to fivefold by effec-

tive antimalarial treatment. It is evident that both in terms of

morbidity and mortality the greatest benefit is obtained by pre-

venting the progression from an uncomplicated to a severe

infection with effective antimalarial drugs. The likelihood of

progressing from uncomplicated to severe malaria, and ulti-

mately fatal infection, depends not only on the intervention

with antimalarial treatment, but also on the background level

of immunity and the age of the patient. What happens as anti-

malarial drug resistance develops?

In areas of low malaria transmission people have little or no

background immunity, and symptomatic malaria infections are

encountered at all ages. Resistance manifests itself as an

increase in the rate of recrudescence. Where there is some

background immunity, recrudescence rates increase first in chil-

dren and in pregnant women who have less immunity (ter Kuile

et al. 1995; Price et al. 1997). As resistance worsens, the mean

time to recrudescence shortens, symptom resolution becomes

slower, and eventually patients are encountered whose para-

sitaemia does not clear and whose symptoms do not resolve. In

this context quinine, or an artemisinin derivative, are usually

used for the treatment of severe malaria. Both are reliably

effective. Although there is some evidence of a slowing in the

clinical response to quinine in areas of resistance

(Pukrittayakamee et al. 1994), there is no evidence yet for an

increase in case-specific mortality in severe malaria. But even if

effective parenteral treatments for severe malaria are available

at health centres and hospital, there will still be an increase in

the number of patients who present with severe malaria if inef-

fective first-line oral treatments are used. Thus morbidity and

mortality rise, not because of ineffective treatment of severe

malaria, but because of ineffective first-line oral treatment

which causes an increasing proportion of patients to develop

severe disease. This situation is reflected well by conventional

in vivo antimalarial treatment assessments which show high-

level resistance (an increasing proportion of early R2 and R3

treatment failures). Persistent use of ineffective treatments may

lead to an increase in the overall incidence of falciparum

malaria and a change in epidemiology (Nosten et al. unpub-

lished observations). The transition from low to high-level

resistance is slow for the quinoline antimalarials (chloroquine,

amodiaquine and mefloquine), but may be more rapid for

pyrimethamine-sulphonamide combinations, and is particu-

larly abrupt for atovaquone. As adults are affected almost as

much, or in some epidemiological contexts, more so than chil-

dren, the impact of drug resistance on disease severity is obvi-

ous if there is surveillance. But areas labelled as having low or

unstable transmission are often located in remote regions, and

may conceal considerable heterogeneity of transmission of

intensities. Surveillance and thus reliable epidemiological infor-

mation is the exception, not the rule. Patients often cannot

reach treatment facilities, self-medication is usual, and the out-

come of the infection depends on the efficacy of available

drugs. Deaths frequently go unreported and mortality from

malaria is underestimated. This undocumented mortality will

rise as the available drugs become ineffective.

At higher levels of transmission and frequency of infection,

the impact of antimalarial drug resistance on mortality is also

underestimated. In this context nearly everybody is infected

with malaria all the time, but the majority of infections are

controlled at a level below that which causes illness. Severe dis-

ease is confined to childhood, and, at very high levels of trans-

mission, to the first three years of life (Marsh et al. 1996).

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© 1999 Blackwell Science Ltd 469

Tropical Medicine and International Health volume 4 no 7 pp 469–470 july 1999

N. White Editorial: Antimalarial drug resistance and mortality

Unfortunately in vivo assessments of drug efficacy are often

done in older children or sometimes in asymptomatic adults.

This provides misleading information as these age groups are

likely to self-cure. Many patients would have apparently good

responses to treatment, even if no active antimalarial drug

were given! Furthermore, as background immunity provides

such a large antiparasitic effect, only a small additional boost

from a relatively ineffective antimalarial drug may be sufficient

to drive the infection below the detection threshold, whereas

the same drug-resistant parasites causing an infection in a non-

immune patient could cause an early and potentially danger-

ous treatment failure. In a high stable transmission area only

young children (mainly in the first 3 years of life) would

demonstrate such an unsatisfactory response to ineffective

treatment, and even within this narrow age-range there may be

considerable variation as immunity is acquired rapidly through

continuous infection. Worsening antimalarial drug resistance

will go unnoticed unless trials are conducted specifically in

very young children.

Another point needs to be considered. There is considerable

variation in the multiplication of Plasmodium falciparum in

vivo. This results from intrinsic differences between parasites

in their multiplication rates, and their susceptibilities to den-

sity-dependent feedback control mechanisms, antimalarial

drugs and host immune responses. There is also considerable

variation between human hosts in terms of drug absorption

and disposition, red cell susceptibility to parasite invasion, the

speed and efficiency of induction of host immune defence

mechanisms and the reactions to the infecting parasites. This

results in significant differences in the severity of illness and the

therapeutic responses. In areas of high transmission where

infections are very frequent, even an unusual or aberrant

response will occur relatively frequently, whereas it will be a

rare event in a low-transmission area. In areas of intense trans-

mission heavy parasitaemias are common in the vulnerable age

group (i.e. young children), and the difference between a well-

controlled and a lethal infection may be a single multiplication

cycle. Lethal disease often develops rapidly and unpredictably.

Attributing the death of an infant living in a high transmission

area to malaria is also notoriously difficult. As resistance devel-

ops, death resulting from an inadequate initial treatment

response may represent initially only the very tail end of a wide

distribution of responses, but because infection is so common,

this is not a rare event. In contrast, in low transmission areas

the progression from first symptom to death is usually several

days, i.e. more than one asexual cycle, and there is more time

to detect an inadequate treatment response (WHO 1990). Thus

in areas of high transmission an increase in mortality in babies

and young children may be the first sign of significant anti-

malarial drug resistance. The recent detailed longitudinal epi-

demiological studies from Senegal reported by Trape et al.

(1998) indicate a dramatic increase in childhood mortality

attributed directly to chloroquine resistance, despite what, by

conventional assessment, would be considered ‘moderate’

levels of chloroquine resistance in the African context. In most

of the tropical world, the impact of antimalarial drug resis-

tance on malaria mortality is almost certainly underestimated.

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© 1999 Blackwell Science Ltd470