PLASMODIUM FALCIPARUM HYPERPARASITAEMIA I N CHILDREN

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PLASMODIUM FALCIPARUM HYPERPARASITAEMIA I N CHILDREN

Risk f a c t o r s , treatment outcomes, a n d gametocytaemia f o l l o w i n g treatment

SOWUNMI A., ADEDEJI A.A.. FATEYE B.A. & BABALOLA CP.

Summary:

The risk factors associated with hyperparasitemia at presentation and after treatment with different antimalarial drug regimens were evaluated in f , 0 4 8 children enrolled prospectively in seven antimalarial drug trials between July 1 9 9 6 and September 2 0 0 3 in a hyperendemic area of southwestern Nigeria. The outcomes of treatment of hyperparasitaemia, and gametocyte carriage following treatment were also evaluated. The children were assigned to one of seven treatment groups : chloroquine (CQ) only ; pyrimethamine-sulfadoxine (PS] only; amodiaquine (AQ) only; C Q plus chlorpheniramine (CQCP); PS combined with C Q or A Q (COM°); PS combined with probenecid (PPS); and

halofantrine (HF|. Hyperparasitaemia was found in 1 0 0 (9,5 %] of the 1 , 0 4 8 children at enrolment (day 0). Following oral therapy,

1.2 % of all patients (i.e. 1 3 patients) became hypeparasitaemic, which developed in all patients by day 1 of follow-up. In a multiple regression model, age < 5 years, and a core temperature (oral or rectal) > 39.5°C were found to be independent risk factors for hyperparasitaemia at enrolment. Following therapy, the cure rate on day 1 4 was significantly lower in those treated with C Q compared to other treatment groups. Severe resistance (RIII) response to treatment occurred significantly more frequently in those with hyperparasitaemia at enrolment than in those without, and was seen in five and one child with hyperparasitaemia w h o were treated with C Q and C Q C P , respectively. Gametocyte carriage was insignificantly lower at enrolment and at all times following treatment in children with hyperparasitaemia than in age- and gender- matched children without hyperparasitaemia w h o received the same treatment. The results are discussed in the light of management of uncomplicated hyperparasitaemia in children in endemic settings.

KEY WORDS : malaria, hyperparasitaemia, risk factors, gametocytaemia, children, Nigeria.

Résumé :

HYPERPARASITÉMIE À PLASMODIUM FALCIPARUM CHEZ DES ENFANTS : FACTEURS DE RISQUE ET GAMÉTOCYTÉMIE AVANT ET APRÈS TRAITEMENT

Les facteurs de risque associés à l'hyperparasitémie à Plasmodium falciparum à l'admission et après le traitement avec sept protocoles antipaludéens différents par voie orale ont été évalués chez I 048 enfants lors d'une étude prospective, menée entre juillet 1996 et septembre 2003 au Sud-Ouest du Nigeria, dans une zone hyperendémique. Les résultats du traitement

(hyperparasitémie et durée de la persistance des gamétocytes dans le sangl ont été évalués. Les groupes traités étaient : chloroquine ( C Q ) ; pyriméthamine-sulfadoxine (PS); amodiaquine (AQ) ; chloroquine plus chlorpheniramine (CQCP) ; pyriméthamine- sulfadoxine plus chloroquine ou amodiaquine ( C O M ) ; pyriméthamine-sulfadoxine plus probenecid (PPS) ; halofantrine (HF). L'hyperparasitémie a été retrouvée chez 100 enfants lors de l'admission 19.5 %). Après 24 heures de traitement, 1,2 % des enfants (n = 13) sont devenus hyperparasités. Avec un programme de régression multiple, nous avons montré qu'un âge ≤ 5 ans et une température centrale ≥ 39,5°C sont des facteurs de risque indépendants pour l'hyperparasitémie à l'admission. Après deux semaines de traitement, le poucentage de guérison est significativement plus bas dans le groupe CQ. Une résistance sévère à ce traitement (RIII) apparaît plus fréquemment chez ceux qui sont hyperparasités à l'admission. Le nombre de gamétocytes circulants était plus bas à l'admission et pendant le traitement chez les enfants hyperparasitémiques que chez ceux du même âge et de même sexe avec le même traitement, mais sans

hyperparasitémie. Les résultats sont discutés dans le but d'améliorer le traitement des accès palustres non compliqués avec

hyperparasitémie dans les zones d'endémie.

MOTS CLÉS :

paludisme, hyperparasitémie, facteur de risque, gamélocytémie, enfants, Nigeria.

INTRODUCTION

P

lasmodium falciparum infections may result in rapid multiplication o f asexual parasites and massive increases in circulating peripheral parasites particularly in the relatively n o n - i m m u n e or, less

* Department of pharmacology & therapeutics and Institute for medical research and training, and Department of pharmaceutical chemistry. University of Ibadan, Ibadan. Nigeria.

Correspondence : A. Sowunmi, Department of Clinical Pharmaco- logy. University College Hospital. Ibadan. Nigeria.

Tel. : 231-2-2412101. 23-1-2-2(1190-1 - Fax : +231-2 2411843 E-mail : malaria.iba@alpha.linkserve.com

akinsowunnii@hotmail.com

f r e q u e n t l y , in t h e s e m i - i m m u n e . T h e s e m a s s i v e increases may reach or surpass a threshold referred to as hyperparasitaemia. Hyperparasitaemia, defined as 5 % o r m o r e parasitized erythrocytes or a parasitaemia greater than 250,000/pI, blood, is considered o n e o f the several features o f severe malaria ( W H O , 1990, 2000 a).

Hyperparasitaemia not a c c o m p a n i e d by other features o f severe malaria ( u n c o m p l i c a t e d hyperparasitaemia) often p o s e m a n a g e m e n t p r o b l e m s in patients resident in e n d e m i c areas. Apart from a general r e c o m m e n d a - tion o f parenteral antimalarials ( W H O , 2 0 0 0 b ) , there are n o other clear-cut guidelines for the management o f uncomplicated hyperparasitaemia in children resident in such areas. However, it has b e e n suggested that

P a r a s i t e . 2 0 0 4 . 7 7, 3 1 7 - 3 2 3

M é m o i r e ³¹⁷

Article available athttp://www.parasite-journal.orgorhttp://dx.doi.org/10.1051/parasite/2004113317

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uncomplicated hyperparasitaemia in children in these e n d e m i c areas b e treated with oral antimalarial drugs providing the drug is rapidly a b s o r b e d and the para

sites are fully sensitive to the antimalarial drug(s) chosen ( S o w u n m i et al, 1992, 1996, 2000 a ) . Such a sugges

tion n e e d s review in view o f the increasing resistance in P. falciparum to many antimalarials drugs and the lack o f facilities to monitor drug sensitivity o f P . falci- parum in vitro and in vivo in many e n d e m i c areas.

T h e r e is little information on, for e x a m p l e , the risk fac

tors associated with u n c o m p l i c a t e d hyperparasitaemia or the time-course o f g a m e t o c y t a e m i a s following oral antimalarial treatment o f uncomplicated hyperparasitaemias in African children. Such information is n e c e s sary in view of the increasing resistance in P. falci

parum to c h l o r o q u i n e ( C Q ) a n d o t h e r c o m m o n l y available antimalarials and the increasing morbidity and mortality associated with drug resistance (Trape et al., 1 9 9 8 ; T r a p e . 2 0 0 1 ) . In addition, it may improve the overall m a n a g e m e n t o f these cases. T h e present study w a s d e s i g n e d to address these issues. T h e main aims o f the study w e r e : to evaluate the risk factors asso

ciated with hyperparasitaemia in a group o f children presenting with acute, symptomatic, apparently uncom

plicated, P. falciparum malaria in an e n d e m i c area; to assess the o u t c o m e s o f oral antimalarial treatment o f u n c o m p l i c a t e d hyperparasitaemia; and to follow the temporal c h a n g e s in g a m e t o c y t a e m i a s in children with hyperparasitaemias w h o w e r e treated with oral anti

malarial drugs.

PATIENTS A N D METHODS

PATIENTS

T

he study took p l a c e b e t w e e n July 1996 and S e p t e m b e r 2 0 0 3 in patients presenting at the University College Hospital in Ibadan, a hyper- e n d e m i c area for malaria in s o u t h w e s t e r n Nigeria (Salako et al., 1 9 9 0 ) . Ethical c l e a r a n c e was provided by the local ethics c o m m i t t e e . During the period, a series o f antimalarial drug studies w e r e c o n d u c t e d to evaluate the efficacy and safety- o f different treatment regimens. All antimalarial drugs w e r e given orally. T h e details o f the studies h a v e b e e n d e s c r i b e d b e f o r e ( S o w u n m i et al., 1 9 9 8 a, b, c, 2 0 0 0 a; Sowunmi. 2002, 2 0 0 3 ; Sowunmi & Fateye, 2 0 0 3 ) . Briefly, children with s y m p t o m s c o m p a t i b l e with acute falciparum malaria w h o fulfilled the following criteria w e r e enlisted in the study : a g e b e l o w 12 years, pure P. falciparum para- sitaemia greater than 2 0 0 0 asexual forms/uL b l o o d , negative urine tests for antimalarial drugs (Dill-Glazko and lignin tests), a b s e n c e o f concomitant illness, n o e v i d e n c e o f severe malaria ( W H O , 2 0 0 0 a ) and written

informed c o n s e n t given b y parents o r guardians. After enrolment and start o f treatment (day 0 ) , follow-up with clinical and parasitological evaluation was at days 1-7, and then o n days 14, and w h e n necessary, on days 21 and 2 8 , for e x a m p l e , in patients w h o received pyrimethamine-sulfadoxine ( P S ) [Fansidar®, Hoffmann La Roche] c o m b i n e d with c h l o r o q u i n e [Nivaquine®, May

& B a k e r Pic, Nigeria] or a m o d i a q u i n e [ C a m o q u i n e ® , Parke Davis, Senegal]. Clinical evaluation c o n s i s t e d o f a general clinical e x a m i n a t i o n including m e a s u r e m e n t o f weight, c o r e temperature and physical examination.

ASSESSMENT OF PARASITAEMIA

Thick and thin blood films prepared from a finger prick w e r e G i e m s a - s t a i n e d and w e r e e x a m i n e d by light m i c r o s c o p y u n d e r an o i l - i m m e r s i o n o b j e c t i v e , at x 1,000 magnification, b y two independent assessors.

Parasitaemia in thick films was estimated b y counting asexual parasites relative to 1,000 leukocytes, or 5 0 0 a s e x u a l forms, w h i c h e v e r o c c u r r e d first. F r o m this figure, the parasite density was calculated assuming an average l e u k o c y t e c o u n t o f 6,000, uL o f b l o o d ( S h a p e r 6 Lewis, 1 9 7 1 ; Ezeilo, 1 9 7 1 ; S o w u n m i et al., 1 9 9 5 ) . G a m e t o c y t e s w e r e also c o u n t e d in thick films against 1,000 leukocytes assuming an average l e u k o c y t e c o u n t of 6 0 0 0 / u L o f b l o o d at enrolment (day 0 ) and o n days 7 and 14. Fractional g a m e t o c y t e density ( F G D ) at enrolment was defined as g a m e t o c y t e count divided by total asexual and sexual count (Price et al., 1999).

Haematocrit was d o n e at e n r o l m e n t in 124 o f the patients treated with PS or CQPS, AQPS or PPS.

EVALUATION OF RESPONSE TO DRUG TREATMENT R e s p o n s e to drug treatment was a s s e s s e d using World Health Organization ( W H O ) criteria ( W H O , 1 9 7 3 ) as follows : S = sensitive, c l e a r a n c e o f p a r a s i t a e m i a without r e c u r r e n c e ; RI (mild resistance) = parasitaemia disappears but reappears within 7 to 14 d a y s ; RII ( m o d e r a t e resistance) = d e c r e a s e o f parasitaemia but n o c o m p l e t e c l e a r a n c e from peripheral b l o o d ; RIII ( s e v e r e r e s i s t a n c e ) = n o p r o n o u n c e d d e c r e a s e o r increase in parasitaemia at 4 8 hours after treatment. In those with sensitive or RI r e s p o n s e , parasite c l e a r a n c e time ( P C T ) was defined as the time elapsing from dnig administration until there was n o patent parasitaemia for at least 7 2 h. Asexual parasite reduction ratio [PRR]

(White, 1 9 9 7 ) was defined as the ratio o f day 0 / d a y 2 parasitaemia.

RE-TREATMENT OF TREATMENT FAILURES

All patients with RII and RIII r e s p o n s e s w e r e re-treated with intramuscular artemether ( 9 . 6 m g / k g , over five days). Patients with RI r e s p o n s e w e r e re-treated with oral mefloquine 25 m g / k g single d o s e and followed

3 1 8 M é m o i r e P a r a s i t e . 2 0 0 4 . 11, 3 1 7 - 3 2 3

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P. FALCIPARUM HYPERPARASITAEMIA IN CHILDREN

up for a n o t h e r M - 2 8 clays. Patients w e r e retreated w h e n e v e r they b e c a m e symptomatic or w h e n they s h o w profound clinical (hyperpyrexia, oral fluid into

l e r a n c e ) or parasitological deterioration.

STATISTICAL ANALYSIS

Data w e r e analysed using version 6 o f the Epi-Info soft

ware (Anon., 1994), and the statistical program SPSS for W i n d o w s version 10.01 (SPSS. 1 9 9 9 ) . Proportions w e r e c o m p a r e d by calculating X² with Y a t e s ' c o r r e c tion o r Fisher e x a c t test. Normally distributed, conti

n u o u s data w e r e c o m p a r e d by Student's t-tests and analysis o f variance (ANOVA). Data not conforming to a normal distribution w e r e c o m p a r e d by the Mann- W h i t n e y U-test and the Kruskal-Wallis test ( o r by Wil- c o x o n rank sum test). A multiple logistic regression model w a s used to test the association b e t w e e n hyperparasitaemia ( y e s o r n o at presentation or during follow u p ) and factors that w e r e significant at univa

riate analysis : age < 5 years, and p r e s e n c e o f fever (oral or rectal t e m p e r a t u r e ) > 3 9 . 5 " C. B e c a u s e the study was conducted over a period o f seven years, time w a s included as a covariate in the analysis. P-values o f < 0.05 w e r e taken to indicate significant differences.

RESULTS

T

he d e m o g r a p h i c characteristics o f the children enrolled in the study are summarized in T a b l e I.

At e n r o l m e n t , 3 0 3 . 1 7 3 , 104, 2 0 3 , 1 4 3 , 7 8 and

44 o f the 1,048 children w^rere allotted to, and were sub

sequently treated with c h l o r o q u i n e ( C Q ) o n l y ; pyrimethamine-sulfadoxine ( P S ) o n l y ; a m o d i a q u i n e ( A Q ) o n l y ; CQ plus c h l o r p h e n i r a m i n e ( C Q C P ) ; PS c o m bined with C Q or AQ ( C O M ) ; PS c o m b i n e d with pro

b e n e c i d ( P P S ) ; and halofantrine (HF) [Halfan®, GlaxoS- mithkline). respectively. Hyperparasitaemia w a s found in 100 ( 9 . 5 % ) o f the 1.048 children at enrolment.

RISK FACTORS FOR HYPERPARASITAEMIA AT ENROLMENT

Factors associated with hyperparasitaemia at enrol

ment are presented in T a b l e II. Age < 5 years, and oral or rectal temperature > 39.5" C w e r e independent risk factors for u n c o m p l i c a t e d hyperparasitaemia at enrol

ment.

T a b l e 1. - S u m m a r y o f d e m o g r a p h i c a n d o t h e r c h a r a c t e r i s t i c s o f t h e 1.048 c h i l d r e n e n r o l l e d in t h e studv.

OR, odds ratio.

a. x² with Yates correction.

CI. confidence interval.

Table II. - Risk factors for P. falciparum hyperparasitaemia at enrolment.

P a r a s i t e . 20()4. 11. 3 1 7 - 3 2 3 319

V a r i a b l e s V a l u e [ m e a n + s d ( r a n g e ) ]

Age ( y e a r s ) 5.5 + 2.5 ( 0 . 5 - 1 1 . 9 )

M : F 4 9 3 : 5 5 5

W e i g h t ( k g ) 15.1 + 4 . 8 ( 6 . 6 - 2 7 )

P r e s e n t i n g b o d y t e m p e r a t u r e ( ° C ) 3 8 . 6 ± 1.2 ( 3 6 . 4 - 4 0 . 8 ) D u r a t i o n o f illness ( d ) 3.0 + 1.5 ( l - l - i ) A s e x u a l p a r a s i t e d e n s i t y ( p e r p L )

G e o m e t r i c m e a n 3 0 . 1 2 9

R a n g e 2 , 0 9 0 - 2 . 3 - ) 1 . 0 0 0

No. > 2 5 0 0 0 0 100

Total no.

No. of children with hyperparasitaemia

Crude OR

(95 % CI) P. value

Adjusted OR

(95 % CI) P. value Age (years)

< 5

> 5

533 515

62 38

1.65

1 ( 1.06-2.6) 0.025

1.61

1 (1.05-2.4^-7) 0.026 Gender

male female

493 555

)5 55

1.1

1 (0.58-1.4) 0.7°

Duration of illness (d)

> 3

< 3

696 352

66 34

0.98

1. (0.62-1.56) 0.9 _ _

Fever*

> 39.5 °C

< 39.5 °C

214 834

31 69

1.88

1 ( 1.15-3.01) 0.008°

1.84

1 (1.17-2.89) 0.009 Gametocytes

Yes No

I2i 924

11 89

0.91

1 (0.43-1.78) 0.9°

M é m o i r e

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HYPERPARASITAEMIA DURING FOLLOW UP TREATMENT OUTCOMES OF HYPERPARASITAEMIA Following oral therapy, 1.2 % o f all patients (i.e. 13 o f

the 1.048 patients) b e c a m e hyperparasitaemic. which developed in all patients by day 1 o f follow-up. T h e 13 patients w e r e treated with CQ ( 1 0 patients) p s ( o n e patient) or COM (two patients), and following treatment, all but two had sensitive response. T h e two children in the COM group w h o b e c a m e hyperparasitaemic o n day 1 specifically received ps c o m b i n e d with CQ. T h e two children with resistance response (1 RI, 1Rii) w e r e treated with CQ. Compared with other treatment groups, there was a significant difference in the proportion o f children treated with CQ w h o b e c a m e hyperparasi

taemic on day 1 following treatment (p = 0.01).

T h e clinical and parasitological characteristics o f the 100 children w h o had hyperparasitaemia at enrolment and w e r e treated with oral antimalarial drugs are sum

marized in Table III. Despite enrolment at different per

iods, t h e s e c h a r a c t e r i s t i c s w e r e similar ( p r i m a r i l y b e c a u s e the criteria for enrolment into all studies w e r e similar). No child with hyperparasitaemia was treated with AQ a l o n e .

T h e responses o f the asexual hyperparasitaemia to drug treatment are s h o w n in T a b l e i v . T h e cure rate follo

wing treatment with CQ was significantly l o w e r than the other treatment groups.

CQ CQCP PS COM PPS* HF*

(n = 33) (n = 25) (n = 25) (11= 11) (li = 5) ( n = 1) P. value Age (years)

Mean + sd 4.3 ± 2.3 5.1 + 2.3 4.6 ± 2.8 1.9 ± 2.2 ^-. 5 + 1.5 5.0 0.6

Range 1.5-9 0.7-10.5 0.5-10.5 3-8.1 6.3-10

M : F 12 : 21 13 : 12 12 : 13 6 : 5 3 : 2 1 : 0 -

Duration of illness (d)

Mean 2.8 ± 1.2 3.2 ± 1.3 3.5 ± 2.5 3.0 ± 0.7 3.0 ± 0.0 3.0

Range 1-6 1-6 1-14 2-4 3-3

Parasitemia (uL)

Geometric mean 438,649 467.090 398.318 387,090 750.304 0,1

Range 253,091-1,500,000 253.600-2,341,000 253,091-1,254,000 250,145-716,000 414,750-1,388,000

PS, p y r i m e t h a m i n e - s u l f a d o x i n e ; C Q , c h l o r o q u i n e ; C Q C P , c h l o r o q u i n e p l u s c h l o r p h e n i r a m i n e : C O M . p y r i m e t h a m i n e - s u l f a d o x i n e c o m b i n e d with c h l o r o q u i n e o r a m o d i a q u i n e ;

PPS p y r i m e t h a m i n e - s u l f a d o x i n e c o m b i n e d with p r o b e n e c i d ; H F . h a l o f a n t r i n e .

* E x c l u d e d from m u l t i p l e c o m p a r i s o n b e c a u s e o f r e l a t i v e l y s m a l l n u m b e r o f p a t i e n t s .

** P a r a s i t a e m i a at e n r o l m e n t w a s 4 3 8 . 6 6 0 p e r uL.

T a b l e III. - Clinical a n d p a r a s i t o l o g i c a l c h a r a c t e r i s t i c s o f 1 0 0 c h i l d r e n with P. falciparum h y p e r p a r a s i t a e m i a w h o w e r e t r e a t e d with oral a n t i m a l a r i a l d r u g s .

C Q C Q C P P S C O M P P S * H F *

(n = 3 3 ) (n = 2 5 ) ( n = 2 5 ) ( 1 1 = 11) (n = S ) ( n - 1 ) P . v a l u e

F C T ( d )

M e a n + sd 2.0 + 0 . 9 2.3 ± 1.0 2.2 ± 1.2 1.6 ± 0 . 5 2.2 + 1.3 1.0 0.5

R a n g e l - i 1-4 1-4 1-2 1-4

-

PRR

M e d i a n ( x 1 0 ' ) 3 . 6 1.0 3 7 . 1 13.1 3 0 . 2 0 . 3

I n t e r q u a r t i l e r a n g e ( x 1 0 ' ) 0 . 0 0 6 - 7 2 . 2 0 . 0 3 - 4 4 . 6 2 7 . 3 - 7 7 . 6 0 . 0 9 - 4 5 . 1

-

P C T ( d )

M e a n 2.H + 1.1 3.2 ± 0 . 8 2.8 + 1.3 2 . 6 ± 0 . 5 2 . 6 ± 0 . 9 3 . 0 0 . 4

R a n g e 2 - 6 2-5 2 - 6 2 - 3 2-4

S ( n o . o f p a t i e n t s ) i s 2 2 2 2 1 1 5

-

RI S 1 3 0 0 0

RII 2 1 0 0 0 0

RIII 5 1 0 0 0 0

C u r e rate ( % ) 5 4 . 5 8 8 8 8 100 100

-

^{0 . 0 0 1}

PRR. parasite reduction ratio: FCT. fever clearance time: PCT. parasite clearance time; PS. pyrimethamine-sulfadoxine: CQ. chloroquine;

CQCP. chloroquine plus chlorpheniramine, COM. pyrimethamine-sulfadoxine combined with chloroquine or amodiaquine;

PPS pyrimethamine-sulfadoxine combined with probenecid; HF. halofantrine;

RI = parasitaemia disappears but reappears within 7 to 14 days; RII = decrease of parasitemia but no complete clearance from peripheral blood; RIII = no pronounced decrease or increase in parasitaemia at 48 hours after treatment. S = sensitive response.

* Excluded from multiple comparison because of relatively small number of patients.

Table IV. - Therapeutic responses of 100 children with acute P. falciparum malaria who had hyperparasitaemia at enrolment.

320 P a r a s i t e . 2 0 0 4 . 11. 3 1 7 - 3 2 3

M é m o i r e

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COMPARISON OF OUTCOMES OF TREATMENT

OF NON HYPERPARASITAEMIA AND HYPERPARASITAEMIA Sixteen o f 9 4 8 children without hyperparasitaemia had RIII r e s p o n s e to treatment c o m p a r e d to six o f 100 chil

dren with hyperparasitaemia. T h e difference b e t w e e n these proportions was significant (%² = 6.22. P = 0 . 0 0 1 ) . Four children (three treated with C Q and o n e with PS) aged < 3 years w h o had hyperparasitaemia progressed to cerebral malaria, while two o f the 9 4 8 children without hyperparasitaemia had the s a m e o u t c o m e . The difference b e t w e e n these two proportions was significant (P = 0 . 0 0 1 . by Fisher exact test). T h e two children without hyperparasitaemia w h o progressed to cerebral malaria w e r e treated with CQ. Adverse reac

tions reported following drug treatment w e r e similar in children with hyperparasitaemia and in age- and gender- matched children without hyperparasitaemia w h o w e r e treated with the s a m e drugs (data not s h o w n ) . For e x a m p l e , in those treated with CQ, pru

ritus occurred in five ( o f 3 3 ) and four ( o f 3 3 ) children with and without hyperparasitaemia. respectively.

GAMETOCYTE CARRIAGE AND GAMETOCYTAEMIA IN CHILDREN WITH HYPERPARASITAEMIA

In order to evaluate g a m e t o c y t e carriage and g a m e t o - cytaemia in those w h o w e r e hyperparasitaemic at pre

sentation, children with hyperparasitaemia w e r e mat

c h e d with those without hyperparasitaemia for time o f presentation, age, gender, and drug treatment.

At enrolment g a m e t o c y t e carriage w a s similar in chil

dren with hyperparasitaemia and in age- and gender- m a t c h e d c h i l d r e n without h y p e r p a r a s i t a e m i a w h o received the s a m e drug treatment ( 6 o f 100 vs 11 o f

100 children, X¹ = 1-03, P = 0 . 3 ) . Similarly following treatment, g a m e t o c y t e carriage was similar o n day 7 (16 o f 100 vs 27 o f 100 children, x2 = 2.9. P = 0 . 0 8 ) and on day 14 ( 9 o f 100 vs 17 o f 100 children, x2 = 2.2, P = 0 . 1 4 ) .

At enrolment g a m e t o c y t a e m i a was similar in children with hyperparasitaemia and in age- and gender- mat

c h e d children without hyperparasitaemia w h o received the s a m e drug treatment ( g e o m e t r i c mean 12, range 6-24/uL vs 14 range 6-72, P = 0 . 5 ) . Similarly following treatment, g a m e t o c y t a e m i a was similar on day 7 ( g e o metric mean 7 1 . range 6 - 1 3 2 0 / u L vs 6 6 , range 6 - 8 2 8 , P = 0 . 4 ) and o n day 14 ( g e o m e t r i c m e a n 57, range 12- 4 8 0 uL vs 7 0 range 1 2 - 3 6 0 , P = 0 . 7 ) .

Fractional gametocyte density was insignificantly lower in children with hyperparasitaemia c o m p a r e d with those without hyperparasitaemia (median 0 . 0 0 3 . range 0 . 0 0 1 - 0 . 0 0 5 vs 0 . 0 4 8 . range 0 . 0 0 1 5 - 2 . 3 %, P = 0 . 2 4 ) .

RE-TREATMENT OF TREATMENT FAILURES

All treatment failures responded to re-treatment with intramuscular artemether or oral mefloquine with clea

r a n c e o f fever and parasitaemia within 72 h o f c o m m e n c i n g re-treatment and with n o recurrence o f para

sitaemia during additional 14-28 days o f follow-up.

DISCUSSION

" T n c o m p l i c a t e d hyperparasitaemia is not uncommon in African children presenting with acute, symptomatic, falciparum malaria (Salako et al., 1990; Sowunmi el al., 1992, 1996, 2000 a). Prevalence rates in endemic and non endemic areas in Africa probably vary widely; in southwest Nigeria, the rate is approximately 10-12 % (Sowunmi.

unpublished data). The 10 % prevalence recorded in the present study was similar to that previously reported from the same area in the early 1990s (Salako

et al.. 1990).

The risk factors associated with uncomplicated hyper

parasitaemia at presentation are not frequently docu

mented. In falciparum infections, younger age (< 3 years) has been associated with hyperparasi

taemia and increased risk of progression to cerebral malaria (Sowunmi et al., 2000 a). In the present study, age < 5 years and oral or rectal temperature > 39.5" C were independent risk factors associated with hyper

parasitaemia at presentation. In falciparum infections in young children, the general trend is for parasi

taemia to increase with time, and more specifically, to be accompanied by increases in body temperature.

However, in severe infections there may be hypo

thermia. In practice many children with lower oral or rectal temperatures than our model found may be hyperparasitaemic. This would be so becaLise many parents or guardians have ready access to over the counter remedies including antipyretics before pre

sentation. This 'blunting' of presenting oral or rectal temperature may mislead the attending health care pro

vider and distract attention from the possible presence of hyperparasitaemia.

The responses of apparently uncomplicated hyperpa

rasitaemia to oral therapy are less frequently reported, probably because of the dangers associated with oral therapy in a condition that may rapidly progress to a fatal outcome, and probably also because of increa

sing resistance in P. falciparum to antimalarial drugs leading to reluctance to try oral therapy. Providing the parasites are fully sensitive to the oral drugs chosen, responses to drug therapy appears to be independent of parasite load. Thus in a comparative study, thera

peutic responses of those with and without hyperpa

rasitaemia were similar in children from an endemic

Parasite. 2 0 1) 4 . 1 1. 3 1 7 - 3 2 3

3 2 1

M é m o i r e

(6)

area in West Africa ( S o w u n m i et al., 2 0 0 0 a ) . In addi

tion, in drug sensitive infections, t h e disposition o f parasitaemia appears to follow a first order kinetics ( S o w u n m i et al.. 2 0 0 0 a. b ) . In our cohort o f children, CQ w a s the least effective drug in children with hyper- parsitaemia and clearly represented a significant decline in t h e sensitivity o f P. falciparum to this drug. Thus with prevailing d e g r e e o f CQ resistance, this dnig m a y not b e ideal for t h e treatment o f malaria irrespective of parasite load. T h e significantly higher proportions o f children without hyperparasitaemia w h o s u b s e quently d e v e l o p e d it following treatment with C Q o r PS c o m p a r e d with the other treatment groups suggest slow onset o f antimalarial action o r reduced sensitivity to these drugs and a risk for development o f post-treat

ment hyperparasitaemia.

The similar frequencies o f pruritus ( a n d o t h e r adverse drug reactions following treatment in those with a n d in those without hyperparasitaemia w h o w e r e treated with the s a m e drugs [data not s h o w n ] ) suggest that h y p e r p a r a s i t a e m i a d o e s n o t p r e d i s p o s e t o u n d u e adverse drug reactions following treatment ( S o w u n m i et al.. 2 0 0 0 a ) .

Relatively l o w asexual parasitaemia a n d a b s e n c e o f fever are s o m e o f t h e risk factors associated with g a m e t o c y t e carriage in falciparum infections (Price et al.. 1 9 9 9 ; Akim et al., 2 0 0 0 ; v o n Seidlein et al.. 2 0 0 1 ) . The l o w e r g a m e t o c y t e carriage a n d g a m e t o c y t a e m i a following treatment o f the children with hyperparasi

taemia indicate that oral therapy o f this condition is not associated with u n d u e generation o f g a m e t o c y t e s . However, it is not k n o w n w h e t h e r gametocytes arising from patients w h o had hyperparasitaemia are m o r e infectious to t h e m o s q u i t o than those arising from patients without hyperparasitaemia w h o w e r e treated with the s a m e drugs.

Hyperparasitaemia is a potentially life threatening condi

tion, a n d with or without other features o f s e v e r e malaria requires close clinical a n d parasitological moni

toring. Its occurrence in children from this endemic area without o t h e r overt features o f s e v e r e falciparum malaria suggests the presence o f s o m e degree o f immu

nity, although these children are, in general, considered relatively n o n - i m m u n e c o m p a r e d with adults from the s a m e e n d e m i c area, and are prone to multiple infec

tions (Happi et al.. 2 0 0 3 ) . Should oral C Q o r PS conti

nued t o b e used for a potentially life threatening situa

tion in view o f increasing resistance o f P. falciparum to these drugs in Africa? W e feel otherwise. A recent study suggests that AQ, a drug more effective than C Q in both CQ- sensitive and resistant- P. falciparum infec

tions, rapidly clears hyperparasitaemia (Ndounga &

B a s c o , 2 0 0 3 ) . In the small n u m b e r o f children treated with a c o m b i n a t i o n o f PS plus AQ in our study popu

lation, neither clearance nor parasite reduction ratio w a s

significantly faster o r higher, respectively than those o f other treatments. In view o f the fact that artemisinin and its derivatives clear parasitaemia m o r e rapidly than most o f the currently available antimalarials (Hien &

White, 1 9 9 3 ) , these drugs c o m b i n e d with, for e x a m p l e . AQ may b e tried for the management o f uncomplicated hyperparasitaemia in children from Africa. This sug

gestion is predicated o n the fact that A Q is a relatively safe d a i g (Olliaro et al., 1 9 9 6 ) , a n d m a y b e a suitable partner combination drug with the artemisinin deriva

tives, for e x a m p l e , artesunate for use in Africa (Adjuik et al., 2 0 0 2 ) . Studies to assess the efficacy o f such c o m  binations in uncomplicated and c o m p l i c a t e d hyperparasitaemias are under w a y in o u r study area.

ACKNOWLEDGEMENTS

T

h e study received financial support from t h e UNDP/World B a n k / W H O Special Programme for Research and Training in Tropical Diseases. AS was supported b y a W H O / T D R Career Development Grant.

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