epi.1993.hogh.actatropica.classification of clinical falciparum malaria and its use for evaluation...

8/14/2019 Epi.1993.Hogh.actaTropica.classification of Clinical Falciparum Malaria and Its Use for Evaluation of Chemo Suppre

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Acta Tropica, 5 4 (1 9 9 3 )1 0 5 -1 1 5 1 0 5 1 9 9 3 E l se v ie r Sc ie n c e Pu b l i sh e r s B .V . A l l r i g h t s r e se rv e d 0 0 0 1 -7 0 6 X /9 3 /$ 0 6 .0 0A C T R O P 0 0 2 9 7

C lass i f ica t ion o f c l in i ca l fa l c iparu m m alar ia and i tsu s e f o r t h e e v a l u a t i o n o f c h e m o s u p p r e s s i o n in

ch i ldren under s i x years o f age in L iber ia , WestA f r i c a

B i r t h e H o g h a 'b , N u a h n T . M a r b i a h a , E s k i ld P e t e r s e n " 'd , E u g e n eD o l o p a y e a, M i c h a e l W i ll c o x c, A n d e r s B j 6 r k m a n d, A l o y s i u s P .H a n s o n a a n d A d a m G o t t s c h a u e

aLiberian Institute or Biomedical Research, Liberia, bDepartment of lmmunology, University of Stockholm,Stockholm, Sweden, ~Department of Clinical Bacteriology, Giivle Hospital, Sweden, dDepartment ofInfectious Diseases, Karolinska Institute, Stockholm, Sweden and eDepartment of Biostatistics, StatensSeruminstitut, Copenhagen, Denmark(Re c e iv e d l0 Fe b ru a ry 1 9 9 3 ; a c c e p te d 3 1 Ma rc h 1 9 9 3 )

T h e p o s s i b le r o le o f m a l a r i a a s c a u s e o f m o r b i d i t y w a s a s s es s e d d u r i n g o n e y e a r i n 2 6 2 c h i ld r e n a g e d 6mo n th s t o 6 y e a r s l i v in g in tw o v i l l a g e s i n a ru ra l a re a o f L ib e r i a . Th e s tu d y p o p u la t io n w a s fo l lo w e d b yw e e k ly c l in i c s a n d th re e -mo n th ly su rv e y s a n d th e c h i ld re n w e re r a n d o mly a l lo c a t e d to r e c e iv e e i th e rc h lo ro q u in e o r p l a c e b o e v e ry 3 w e e k s . Th e mo rb id i ty o f t h e c h i ld re n w a s e v a lu a t e d b y c r i t e r i a b a se d o nth e h i s to ry a n d th e c l i n ic a l c o n d i t i o n in to fo u r d i f f e re n t s ta g e s , i n o rd e r t o d e sc r ib e th e p ro b a b i l i t y t h a t a no b se rv e d c l in i c a l e v e n t c o u ld b e a t t r i b u te d to ma la r i a i n fe c t io n , b a se d o n th e p re se n c e o f d e t e c t a b lep a ra s i t e s i n t h e b lo o d , t h e h i s to ry th e p re v io u s w e e k , a n d th e c l i n i c a l s t a tu s o f t h e c h i ld . Th e l e v e l o fa n a e m i a , s p l e n o m e g a l y a n d m e a s u r e d b o d y t e m p e r a t u r e s u p p o r t e d t h a t m a l a r i a w a s t h e m a j o r c o n t r i b u t o rto t h e o v e ra l l mo rb id i ty o b se rv e d . Ba se d o n th e s t a g e c l a ss i f i c a t io n o f c l i n i c a l i l l n e ss , c h i ld re n w e rec l a ss i f i e d a s h a v in g ' p o ss ib l e c l i n i c a l ma la r i a ' o r ' p ro b a b le c l i n i c a l ma la r i a ' . Ma la r i a a p p e a re d to b e a ni m p o r t a n t c a u s e o f f e b r il e e p i s o d es d u r i n g b o t h d r y a n d r a i n y s e as o n s . D u r i n g t h e r a i n y s e as o n m o r e t h a n6 0 % o f t h e c h i l d r e n e xp e r i en c e d a t l e a s t o n e cl in i c al m a l a r i a e p i so d e , a n d d u r i n g t h e d r y s e a s o n m o r e t h a n5 0 % o f t h e c h i ld re n e x p e r i e n c e d a t l e as t o n e c lin i c a l a t t a c k o f ma la r i a . Ch i ld re n r e c e iv in g c h e m o su p p re s -s io n h a d o v e ra l l f e w e r c l i n i c a l ma la r i a a t t a c k s , a n d th e e f fe c t o f t h e c h e mo su p p re ss io n w a s mo s t p ro -n o u n c e d i n t h e d r y s e a s o n , t h e o d d s r a t i o c o m p a r i n g c h i l d r e n r e ce i v in g re g u l a r c h e m o s u p p r e s s i o n w i t hc h i ld re n r e c e iv in g p re su mp t iv e t r e a tm e n t o n ly w a s e s t ima te d to 0 .3 9 (0 .2 5 -0 .6 2 ) .

K e y w o r d s : Plasmodiumfalciparum;M a l a r i a ; C l i n ic a l m a l a r i a ; C h i l d r e n ; C h e m o s u p p r e s s i o n

I n t r o d u c t i o n

T h e r e a r e n o u n i v e r s a l i n d i c a t o r s o f m a l a r i a m o r b i d i t y i n s e m i - i m m u n e i n d i v id u a l s .I n a m a l a r i a e n d e m i c a r e a a p r e s u m p t i v e d i a g n o s i s o f m a l a r i a i s o f t e n m a d e i n a n yi n f a n t o r y o u n g c h i l d , w h o h a s a f e b r i le i l l n es s . E v e n w h e n t h e d i a g n o s t i c c r i t e r i a i s

Correspondence to." B . H o g h , L a b o r a t o r y o f P a r a s i t o lo g y , S t a t e n s S e r u m i n s t i t u t , A r t i ll e r iv e j 5, D K - 2 3 0 0C o p e n h a g e n S , D e n m a r k . P h o n e + 4 5 3 2 6 8 3 7 2 2 ; F a x + 4 5 3 2 6 8 3 8 7 1 .


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b a s e d o n t h e h i s t o r y o f s y m p t o m s , c a r e f u l c li n i ca l e x a m i n a t i o n o f th e p a t i e n t t oe x c lu d e n o n - m a l a r i a l a e t i o l o g y , a n d c o m p e t e n t e x a m i n a t i o n o f t h e b l o o d t o d e t e c tp a r a s i t e m i a , t h e p r e s e n c e o f p a r a s i t e s in t h e p e r i p h e r a l b l o o d o f s e m i - i m m u n ei n d i v i d u a l s d o e s n o t n e c e s s a ri l y m e a n t h a t t h e i ll n es s m a n i f e s t e d b y t h e p a t i e n t isdue t o a m a l a r i a l i n f e c t i o n ( G r e e nw oo d , 1988 ; G i l l e s , 1988) .

E v e n t h e s e v e r e a n d c o m p l i c a t e d c a s e s o f m a l a r i a c a n b e d i ff i cu l t t o d i a g n o s e , a st h e r e a r e n o c l i n i ca l si g n s o r s y m p t o m s w h i c h a r e s p e ci fi c f o r m a l a r i a . F o r h o s p i t a l i -s e d p a t i e n t s a d e f i n i t io n o f se v e r e a n d c o m p l i c a t e d f a l c i p a r u m m a l a r i a a n d t h ed i f f er e n c e s b e t w e e n s e v e re m a l a r i a i n a d u l t s a n d c h i l d r e n h a s b e e n c o m p r e h e n s i v e l yc o n s i d e r e d b y t h e W H O ( W a r r e l l e t a l. , 1 9 9 0) .

R e p o r t s o n m a l a r i a m o r b i d i t y h a v e s u g g e st e d d if f er e n t p a t h o g e n i c o r p y r o g e n i ct h r e s h o l d s o f Plasmodiumfalciparum p a r a s i t e s r a n g i n g f r o m 1 0 0 0 - 1 5 0 0 0 p a r a s it e sla1-1 (Trape e t a l . , 1985; Baudon e t a l . , 1986; Benassani e t a l . , 1987; Snow e t a l . ,1988 ; M e n on e t al ., 1990 ; L y i om o e t a l ., 1991; V e l e m a e t a l ., 1991 ). T h e py r o ge n i ct h r e s h o l d w i ll , h o w e v e r , v a r y a c c o r d i n g t o t h e d e g r e e o f i m m u n i t y o f th e p o p u l a t i o n ,a n d r e fl e ct t h e a g e o f t h e h o s t a n d t h e t r a n s m i s s i o n c h a r a c t e r i s ti c s in t h e a r e a , a n di t is th e r e f o r e d if fi c u lt t o c o m p a r e d a t a o n m a l a r i a m o r b i d i t y b e t w e e n d i f f e r e n t a r e as .

I n e n d e m i c ar e a s , m o s t c a s e s o f m a l a r i a a r e d i a g n o s e d o n c li n ic a l g r o u n d s w i t h o u tl a b o r a t o r y c o n f i r m a t i o n o f p a r a s i t e m i a . A c l i n ic a l c a s e d e f i n i t i o n o f m a l a r i a b a s e do n f e v e r o r a h i s t o r y o f fe v e r a n d t h e c o n d i t i o n o f th e c h i ld i s o f t e n t h e o n l yi n f o r m a t i o n a v a i l a b le t o t h e h e a l t h w o r k e r t o d e c id e w h e t h e r t r e a t m e n t w i t h a n a n t i -m a l a r i a l d r u g i s n e e d e d . R e c o g n i s i n g t h a t n o s i n g l e d e f i n i t i o n w i l l b e s a t i s f a c t o r y o rr e l e va n t i n a l l c l i n i c a l s i t ua t i ons , w e de s c r i be t he l i ke l i hood t ha t a n obs e r ve d c l i n i c a le v e n t c a n b e a t t r i b u t e d t o m a l a r i a i n f e c t io n , b a s e d o n t h e p r e s e n c e o f d e t e c t a b l ep a r a s i t e s i n t h e b l o o d , t h e h i s t o r y o f fe v e r t h e p r e v i o u s w e e k a n d t h e c l in i c al s t a tu so f t h e c hi ld . W e u s e t h e l ev e l o f a n a e m i a , s p l e n o m e g a l y a n d m e a s u r e d b o d y t e m p e r -a t u r e t o s u p p o r t o u r s t a g e c l a s s i f i c a t i o n .

T h e s t a g e c l as s i fi c a ti o n w a s u s e d t o m e a s u r e t h e b u r d e n o f cl in i c al m a l a r i a e p i s o d e sa n d t h e i m p a c t o f 3 w e e k l y c h e m o s u p p r e s s i o n w i t h c h l o r o q u i n e .

M a t e r i a l a n d M e t h o d s

Study areaT h e s t u d y w a s p e r f o r m e d i n tw o v i l l ag e s i n a r u r a l a r e a o f t h e n o r t h - w e s t e r n p a r to f L i b e ri a , i n t h e M o u n t N i m b a r e g i o n c lo s e t o t h e b o r d e r s o f G u i n e a a n d I v o r yC o a s t . T h e c l i m a t e i s t r o p i c a l w i t h a r a i n y s e a s o n f r o m M a y t o O c t o b e r a n d a d r ys e a so n f r o m N o v e m b e r t o A p r il . T h e a n n u a l p r e c i p i ta t i o n v a ri es b e t w e e n 2 00 0 m ma n d 2 5 0 0 m m a n d t h e t e m p e r a t u r e is g e n e r a l l y b e t w e e n 2 1 C a n d 3 2 C . M a l a r i at r a n s m i s s i o n i s p e r e n n i a l , b u t i s m o s t i n t e n s e d u r i n g t h e r a i n y s e a s o n . N o h e a l t hc a r e s e r v ic e s w e r e a v a i l a b l e i n t h e s t u d y v i ll a ge s a n d t h e n e a r e s t d r u g s t o r e w a ss i t u a t e d 3 0 k m f r o m t h e v i ll ag e s.Study populationA c e n s u s w as p e r f o r m e d a n d a n o p e n c o h o r t o f c h i ld r e n a g e d 6 m o n t h s t o 6 y ea r si n t h e s t u d y v i l la g e s ( B e y t o n w e e n = 1 21 , B o n a h n - - 1 41 ) w e r e i n c l u d e d a f t e r i n f o r m e dc o n s e n t a n d f o l l o w e d b y w e e k ly c li ni cs a n d t h r e e - m o n t h l y s u r v ey s f r o m M a y 1 98 7t o A pr i l 1988 . T he s e x r a t i o m a l e / f e m a l e w a s 1 .06 .


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107Parasitological examinationEvery three-months and whenever the child was unwell and/or had a temperature>37.5C thick and thin blood films were made from finger-prick blood specimensand stained with Giemsa. Parasite density was calculated assuming 200 fields equalto 0.2 lal blood.Spleen examinationPalpation of the spleen was performed for children below 2 years of age with thechild lying down, and for children above 2 years of age the palpation was performedwith the child standing.Packed cell volumeEvery 3 months blood was collected in two 75 Ixl capillary tubes. The packed redcell volume was measured in percent of whole blood, recording the mean of the tworeadings.Haemoglobin typingSickle cell trai t (HbAS) was identified by electrophoresis and 13-thalassaemia (13T) wasdetected by an elevated HbA2 level as previously described Willcox et al. (1983).

Entomological investigationsEvery second month, pyrethrum spray collection of indoor-resting mosquitoes in10% of the houses was performed. The person-biting rate was calculated by dividingthe number of indoor-resting, human blood-fed mosquitoes by the number o f humansper room. The mosquitoes were examined for sporozoites by ELISA using monoclo-nal antibodies against P. fa lc iparum sporozoites. The entomological inoculation ratebeing the number of bites per person multiplied by the fraction of infectiousmosquitoes.

Morbidity measurementsThe cohort of children was followed by passive case detection during weekly clinicsand active case detection during three-monthly morbidity surveys by the researchteam including a medical doctor. Both at the weekly clinics (3871 encounters) andat the three-monthly surveys (730 encounters) a standardised clinical assessment wasmade by the medical doctor based on the history obtained from the child's attendant,usually the mother, by a registered nurse from the local tribe who asked specificquestions according to the questionnaire.

The mother or attendant was asked whether the child was (a) well, (b) unwell butable to cont inue normal activities, or (c) unwell and unable to continue normalactivities; and whether the child had had fever, had been vomiting, had had diarrhoeaor cough during the previous week. At each visit the temperature was measured byan axillary digital clinical thermometer (Terumo*).

Thick and thin blood films were made from finger-prick blood specimens wheneverthe child was unwell and/or had a temperature > 37.5C. Children found positivewere treated with chloroquine 25 mg/kg body weight.


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Chemosuppression2 6 2 ch i l d re n w e r e r a n d o m l y a l l o c a t e d i n t h e p r o p o r t i o n 3 :2 t o r e c ei v e c h e m o s u p p r e s -s i o n w i t h c h l o r o q u i n e , 5 m g / k g b o d y w e i g h t ( g r o u p 1 , n = 1 58 ) o r p l a c e b o ( g r o u p 0 ,n = 1 0 4) e v e r y 3 w e e k s . C h i l d r e n i n t h e p l a c e b o g r o u p w e r e g iv e n c h l o r o q u i n e w h e np a r a s i t e s w e r e d e t e c t e d i n a b l o o d s m e a r . I n g r o u p 1 a n d g r o u p 0 , 2 04 5 a n d 4 2 8d o s e s o f c h l o r o q u i n e w e r e g iv e n , r e s p ec t i v el y .A l l t h e c h i l d r e n w e r e a c t i v e l y s e a r c h e d f o r e v e r y 3 w e e k s i n o r d e r t o h a v e as u p e r v i s e d i n t a k e o f t h e t a b le t s . T h e f a c t t h a t o n l y 7 5 % o f t h e p l a n n e d d o s e s w e r ea c t u a l l y r e c e i v ed b y t h e c h i l d r e n r e f le c ts t h e m o b i l i t y o f t h e r u r a l p o p u l a t i o n i n t h es ec o m m u n i t i e s , w h e r e s t a y a t d i s t a n t f ie ld s o r w i t h r e l a ti v e s f o r a c o u p l e o f w e e k s a ta t i m e i s w i de l y p r a c t i s e d .Statistical methodsT h e e f f ec t o f t h e c h e m o s u p p r e s s i o n o n t h e o c c u r r e n c e o f cl in i c al m a l a r i a ( v a r ia b l e s:c l in i c al h i s t o r y o f fe v e r , c l in i c al s t a tu s , m e a s u r e d b o d y t e m p e r a t u r e , p a c k e d c el lv o l u m e , s p l e e n s i z e ) w a s a n a l y s e d . T h e v a r i a b l e s i n c l u d e d w e r e f u r t h e r m o r e s e a s o n( d r y , r a i n y ) , ag e g r o u p s ( < 2 y e a rs , > 2 y e ar s ) , h a e m o g l o b i n t y p e ( A A , A S , [3 T ) , se xa n d v i ll ag e . T h e d a t a i n c l u d e d 3 8 71 e n c o u n t e r s f r o m w e e k l y c l in i cs a n d 7 3 0e n c o u n t e r s f r o m t h r e e - m o n t h l y s u r v e y s o n 2 6 2 c h i ld r e n i n c lu d e d i n t h e o p e n c o h o r t .

W e e x p e c t s a m p l e s o n t h e s a m e c h i l d t o b e m o r e c o r r e l a t e d t h a n s a m p l e s o n t w od i f f e r en t c h i l d r e n , a n d a n o r d i n a r y l o g is t ic r e g r e s s io n a n a l y s i s w a s n o t s u i t a b l e.

T h e s t a t i s t i c a l s o f t w a r e p a c k a g e E G R E T v e r s i o n 0 . 2 6 . 6 ( S t a t i s t i c s a n dE p i d e m i o l o g y R e s e a r c h C o - o p e r a t i o n 1 99 1 ) w a s u s e d f o r t h e c o m p u t a t i o n s . I n it ia l lya ll e x p l a n a t o r y v a r i a b l e s w e r e i n c l u d e d w i t h o u t a n y i n t e r a c t i o n , a n d n o n s i g n i fi c a n tv a r i a b l e s w e r e r e m o v e d f r o m t h e m o d e l a c c o r d i n g t o M a u r i t s e n ( 1 9 8 4 ) . I n a t w o -w a y a n a l y s i s o f v a r i a n c e t h e e f f e c t o f cl i ni c a l s y m p t o m s a n d p a r a s i t o l o g i c a l g r o u p so n m e a n b o d y t e m p e r a t u r e , s p le e n r a te a n d m e a n p a c k e d c el l v o l u m e w e r e as se ss ed .T o t e s t w h e t h e r t h e e f f e ct o f t h e c h e m o s u p p r e s s i o n d e p e n d e d o n t h e d i f f e r e n t v a r i a b l e sc o n s i d e r e d , i n t e r a c t i o n s w e r e t h e n a d d e d .

R e s u l t s

Clinical measures of morbidityB a s e d o n t h e h i s t o r y o b t a i n e d f r o m t h e m o t h e r / g u a r d i a n c o n c e r n i n g f ev e r a n d t h eg e n e r a l c l in i c al s t a tu s , t h e c h i l d r e n w e r e g r o u p e d i n t o f o u r d i f f e r e n t s t ag e s , d e p e n d i n go n t h e p r e s e n c e o r a b s e n c e o f s i m p l e c l in i c al c r i t e r ia ( T a b l e 1 ).Indicators of malaria morbidityT o v a l i d a t e t h e p o s s i b l e b u r d e n o f m a l a r i a i n c a u s in g t h e m o r b i d i t y , t h e c l in i c als t a t u s a n d t h e h i s t o r y w e r e r e l a t e d t o t h e p a r a s i t e r a t e s a n d d e n s i t y c la s se s , b o d yt e m p e r a t u r e , s p l e e n ra t e s a n d m e a n p a c k e d c e ll v o l u m e i n c h i l d r e n w i t h p a r a s i te m i a .

T h e l i k e l i h o o d a n d s e v e r i ty o f c l in i c al m a l a r i a i n c r e a s e d f r o m s t ag e t w o t o s t a g ef o u r . T h e d i s t r i b u t i o n o f p a r a s i t e r a t e s a n d d e n s i ti e s in t h e f o u r s t a g es a r e i l l u s t ra t e di n F i g . 1 . S t a ge s t h r e e a nd f ou r ha d s i gn i f i c a n t l y h i ghe r pa r a s i t e r a t e s a nd de ns i t i e st h a n s t ag e o n e a n d t w o a n d a ll e n c o u n t e r s f o r c h i l d r e n in s t ag e t h r e e , w h o h a d


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109TABLE 1Staging o f general clinical condition o f the child based on the history obtain ed from the m other/g uardia nStage condition

Stage I:Stage II :Stage III :Stage IV:

Child is well , and had no fever during th e past weekChild is unwell , but ab le to continue norm al activit ies,and had no fever dur ing the pas t weekChild is unwell , but ab le to continue norm al activit ies,and had fever dur ing the pa s t weekChild is unwell , and unable to continue norm al activit ies,and had fever dur ing the pas t w eek

10 0

80n o

60 >0


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I10

, 010,000

1 2 3 4Clinical stages

Fig. 2. The mean body temperature at different parasite densities in. the four different stages.

100

90

z 80,. d

70

6 0

(141) (209)m (254)

!

1 2 3Clinical stages

(12

1210[ ] > 0 < 5 , 0 0 0 5-10,000 > I0,000

I

Fig. 3. The spleen rate at different parasite densit ies in the four different stages.

36 (141) (209) (254) (126)

34

i 3 o28

m] / i3Clinical stages

DO[] >0 I0,000

4

Fig. 4. The mean packed cell volume values at different parasite densities in the four different stages,


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il lmalaria'. The odds ratio comparing children receiving regular chemosuppressionwith children receiving presumptive treatment only was estimated to 0.49 (0.35-0.69).

The difference between the chemosuppression and placebo groups did not dependsignificantly (P= 14.1%) on the season, but there was a tendency towards largereffect in the dry season than in the rainy season, odds ratio in the chemosuppressiongroup for 'possible clinical malaria' was in the dry season 0.39 (0.25-0.62) and inthe rainy season 0.63 (0.39-1.04).For 'possible clinical malaria' the prevalence was higher in the rainy season thanin the dry season odds ratio 1.41 (1.02-1.96), but for 'pr obable clinical mala ria' nosignificant season-effect was seen, odds ratio 1.31 (0.83-2.06).

The effect of chemosuppression is illustrated in Fig. 5 and Fig. 6; however, ourestimated odds ratio cannot be derived directly from the proportions given in Fig. 5and Fig. 6, since we have used the random effect logistic regression model.Inoculation rateThe entomological data showed seasonal difference in the inoculation rate. In therainy season there was at maximum 0.5 infectious bites per person per night, thisrate decreased to 0.02 infectious bites per person per night late in the dry season.There was no difference in inoculation rates between the two villages.HaemoglobinopathiesThe sickle-cell trait was identified in 9.9% of the individuals, and 5.3% showed the13-thalassaemia trait. Subjects with haemoglobin AS compared to AA had a lower,

RAINY SEASON100806O

r . )

~. 4020

[ ][ ][]

Group 0 Group 1 Group 0 Group 16 mths-2 yrs >2 2 years -< 6 years. Group 1:children receiving chemosuppression.Group0: control children.Percentage of children who at one or more times of the samples had been having 'probable clinicalmalaria' (stage IV), and percentage of children having possible clinical malaria' (stage III) (Stages I andII) 'none and unlikely clinical malaria' have been combined.


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l l 2

100DRY SEASON

8 0

6Or,.)~ , 40

200

Group 0 Group Group 0 Gr ou p6 mths-2yrs >2 2 years - < 6 years.Group 1: children receiving chemosuppression.Group 0: control children.Percentage of children who at one or more times of the samples had been having 'probable clinicalmalaria' (stage IV), and percentage of children having "possible clinical malaria' (stage III). (Stages I andI1) 'none and unlikely clinical malaria' have been combined.

but not significantly lower risk of having experienced an attack of 'possible clinicalmalaria', odds ratio 0.70 (0.38-1.30), and the risk for subjects with 13-thalassaemiatrait was higher, but not significantly higher, odds ratio 1.60 (0.77-3.33). Thedifferences between the subjects with different haemoglobin types for 'probableclinical malaria' were even smaller. AS versus AA odds ratio 0.90 (0.37-2.19), 13-thalassaemia versus AA odds ratio 1.44 (0.51-4.00).

Discuss ion

There are no universal indicators o f malaria morbidity, and it is difficult to formulatea general and practical case definition for malaria disease in semi-immunes. Infectionwith P . f a l c i p a r u m is not always associated with clinical disease in subjects livingunder conditions of intense transmission, because of the development o f clinical andparasitological immunity.

The classification of morbidity stages three and four with detectable parasites as'possible clinical malaria' and 'probable clinical malaria', was supported by thehigher parasite rates and densities, higher mean body temperature and low packedcell volume. The high levels of parasitemia and low packed cell volume in stagesthree and fou r indicates that malaria pro babl y is the most impor tant cause of illhealth in this populati on of children.

The association between temperature and malaria parasitemia is not straightfor-ward. In a previous study in Liberia, Miller (1958) found that in children parasitecoun ts of < 11 000 ~tl- 1 were rarely associated with clinical symptoms, but the study


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included only 10 children aged 3 to 7 years, and was performed during the dryseason from February through April.In a study between 1978 and 1982 (911 children age range from new-born to 9years) of biocultural perceptions o f malaria illness (indigenous ethnomedical percep-tions of malaria-caused ill health) vs. clinical malaria (presence of parasites plus

selected symptoms) of disease in Liberian children, a significant positive linearcorrelation was observed between parasitological and clinical measures of malaria(Jackson, 1985). Among children, the most frequently reported sign or symptomexperienced in connection with malaria illness was fever.In The Gambia where malaria transmission is highly seasonal, there was foundno correlation between temperature and parasitemia during a cross-sectional survey

towards the end of the dry season, but at the end of the rainy season a significantcorrelation was found, but still many children with high parasitemias were afebrileand well. Many children aged 1 to 4 were anaemic and as expected, low packed cellvolumes were associated with malaria parasitemia, especially in children less than 3years (Greenwood et al., 1987).Individual indices of clinical malaria have been used in evaluation of differentcontrol strategies. In the Garki project it was possible to show reduction in pointprevalence of fever > 37.5C in the most susceptible group 37.5C in association with parasi-temia was sensitive enough to detect an effect of bed nets on a population in TheGambia (Bradley et al., 1986).In a recent study in Benin it was shown that children with parasitemia exceeding1000 parasites gl - 1 blood had fever ( > 37.9C) significantly more often than childrenwith lower levels of parasitemia (Velema et al., 1991).The clinical parameters chosen in this study showed a good correlation betweenincreasing severity of symptoms and increasing parasite density (Fig. 1), increasingmean body temperature (Fig. 2), increasing spleen rate (Fig. 3), and decreasing mean

packed cell volume (Fig. 4), which supports that the likelihood that an event ofclinical malaria has been encountered increases from stage one to stage four.In our study, a seasonal difference in the clinical condition stage four was found,indicating that the increased transmission in the rainy season results in an increasein clinical malaria indicated by the increase in 'probable clinical malaria' shownin Fig. 5.Applying the classification of clinical malaria developed here, we found thatchloroquine chemosuppression had most effect on 'possible clinical malaria', but

less effect on 'probable clinical malaria'. Mild attacks of clinical malaria will beclassified as "possible clinical malaria', and more severe clinical attacks will beclassified as 'probable clinical malaria' . The data thus shows that chloroquine chemo-suppression in this area is most effective in suppressing mild attacks of malaria.The da ta suggests that a certain degree of chloroquine resistance exists in the area,which was supported by a later study performed in December 1988, where chlo-roquine resistance was found in 34% of the isolates (Bjorkman et al., 1991).Chloroquine and immunity probably act in synergy, which may explain why thecombined effect is more pronounced in the dry season with few new inoculations.In the rainy season with more inoculations of parasites with presumably new anti-genic varieties, the immunity is not yet as fully developed, and episodes of 'probable

clinical malaria' develops and chloroquine is less effective.


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Our data are in agreement with a case-control study from the Republic of Niger,where there was a highly significant relation between the likelihood of fever and theparasite count during the rainy season, an association which was not found duringthe dry season (Rougemont et al., 1991).In a study in Tanzania chloroquine resistance increased between 1983 and 1989

in children under 5 years old, whereas in schoolchildren resistance decreased from1986 1989. It is suggested that antigenic differences between resistant and sensitivestrains may explain this age-specifc pattern (Koella et al., 1990).Peters (1987) suggested that chloroquine resistance is associated with the immuno-logical properties of P l a s m o d i u m f a l c i p a r u m which is in accordance with the generallyaccepted assumption that immunity against malaria is strain specific.Evidence for an association between chloroquine resistance of P l a s m o d i u m f a l c i-

p a r u m and its immunological properties has recently been reviewed by Koella (1993).The observations on the distribution of resistance suggest that selection on resistanceis frequency dependent. This may explain why resistance in areas with intensetransmission initially spreads very rapidly after which it is maintained at an interme-diate level.

It is unknown whether chloroquine chemosuppression may actually be able toinduce enhanced transmission which would be counterproductive to the intendedcontrol of malaria in the individuals. Indications for this have been seen in a recentstudy in Tanzania, where a 2.5 fold increase in human infectiousness has developedin the last 25 years. It has been argued that at least some of the increase may beattributed to the widespread use of chloroquine, and that chloroquine would beexpected to select for increased infectivity in the parasite (Lines et al., 199l).It is therefore of fundamental importance to determine the influence of drugson transmission dynamics, not only for the understanding of malaria as a disease,but also as a prerequisite for the development of an appropriate malaria controlstrategy.

The clinical stage classification used here based on the history and the clinicalcondi tion of the child as perceived by the mother, provides a tool for easy surveillanceof malaria morbidity without invasive techniques, and is therefore of special use inlarge scale operational community studies. Future malaria intervention strategiesneed to carefully consider the malaria burden, both at the individual and at thecommunity level.

AcknowledgementsWe wish to thank the parents and children in Beytonwee and Bonah without whosesupport this study would not have been possible. We are grateful to the staff at themalaria research unit of the Liberian Institute for Biomedical Research, Yekepa, fortheir invaluable assistance. Our study would not have been possible without con-tinuous support of the Liberian American-Swedish Minerals Company (LAMCO).We thank Professor Mario Coluzzi, Department of Parasitology, University ofRome, for assistance in the entomological aspects of this work. Professor PeterPerlmann is thanked for his encouraging support during the study. This investigationreceived financial support from the UNDP/World Bank/WHO Special Programmefor Research and Training in Tropical Diseases.


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