WORLD HEALTH ORGANIZATION ORGANISATION M O N D I A L E EXPERT COMMITTEE ON YELLOW FEVER Entebbe, 9-15 March 1971
VIR/YF/71.14 ENGLISH ONLY
DE L A SANTÉ
INDEXEO
EPIDEMIOLOGY AND Natural h i s t o r y of yellow by
ECOLOGY
fever i n the Americas
Wilbur G. Downs, M.D. Department of Epidemiology and Public Health Yale University School of Medicine
Yellow fever can f i r s t be i d e n t i f i e d with any degree of c e r t a i n t y i n the New World i n connexion with an outbreak of 1646 i n Guadaloupe and other islands of the French A n t i l l e s , and an outbreak i n 1648 i n Yucatan. This antedates any recognizable disease i n A f r i c a by a century. Carter, (1931) writes i n d e t a i l of his searches for evidence of pre-Colombian existence of the disease i n the New World. No convincing accounts e x i s t . Scott (1939) s t i l l did not wish to come to f i n a l grips with the question of whether YF was of Old World or New World o r i g i n . He provides a very useful l i s t i n g of YF outbreaks up to 1936, both i n A f r i c a and the New World. With the unfolding of the story of jungle yellow fever i n the Americas dramatically presented i n Soper's (1970) book, followed by recognition of a corresponding, although far from i d e n t i c a l cycle i n A f r i c a , from the mid-193q's on, the question of continent of o r i g i n of YF s t i l l remained unanswered, Clarke (1960) produced evidence that YF s t r a i n s o r i g i n a t i n g i n A f r i c a had an antigenic component absent from the South American s t r a i n studied. She acknowledges the l i m i t a t i o n s of the study, namely the small number of A f r i c a n (3) and American (1) s t r a i n s investigated. An extension of t h i s study at a l a t e r date provided evidence that an Ethiopian s t r a i n was not i d e n t i c a l with a West A f r i c a n s t r a i n . Further extension of these investigations of virus r e l a t i o n s h i p by antibody absorption, using several A f r i c a n virus s t r a i n s and several New World s t r a i n s i s needed. | The recognition of the jungle YF cycle i n the Americas led to investigations of s u s c e p t i b i l i t y of New World primate populations. Early investigations have been reviewed in the basic review and reference source "Yellow Fever" (Strode, 1951). The p o s i t i o n as outlined there has not changed remarkably. A number of species of marmosets were tested for s u s c e p t i b i l i t y and a l l species were susceptible, the i n f e c t i o n s often being f a t a l . Virus i s o l a t i o n s were made from C a l l i t h r l x p e n i c i l l a t a captured during the course of a yellow fever outbreak i n the Ilheus region of B r a z i l i n 1944. In studies of s u s c e p t i b i l i t y , i t was shown for two species that mortality was considerably higher following inoculation with South American s t r a i n s of virus than following i n o c u l a t i o n with A f r i c a n s t r a i n s . The howler monkeys (Alouatta), d i s t r i b u t e d widely i n several species from Argentina to southern Mexico are very susceptible, i n f e c t i o n often being f a t a l . It has been possible i n Ce document ne constitue pas une publication.
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VIR/YF/71.14
page 2 c e r t a i n e p i d e m i c s , ( C e n t r a l A m e r i c a i n the 1950's f o r example) t o f o l l o w t h e g e o g r a p h i c a l p r o g r e s s o f the e p i d e m i c by f i n d i n g dead monkeys. F o l l o w i n g an e p i d e m i c wave, h o w l e r monkey p o p u l a t i o n s may be m a r k e d l y r e d u c e d . N o n e t h e l e s s , immune a n i m a l s can be found, and i m m u n o l o g i c a l s t u d i e s o f the endemic howler monkey p o p u l a t i o n o f a r e g i o n a r e u s e f u l i n d e t e c t i n g a c t i v i t y o f the d i s e a s e i n the absence o f o v e r t d e c l a r a t i o n s o f d i s e a s e p r e s e n c e . I t has been shown t h a t v i r u s can be r e a d i l y r e c o v e r e d from the l i v e r or serum o f monkeys found dead i n the f o r e s t , even when c o n s i d e r a b l e a u t o l y s i s o f t i s s u e s has o c c u r r e d . This o b s e r v a t i o n presumably might be extended t o monkeys o f o t h e r s p e c i e s . Howler monkeys a r e e s s e n t i a l l y a n i m a l s o f deep f o r e s t , and i f space c o n s i d e r a t i o n s a r e not p r e s s i n g , a p p a r e n t l y p r e f e r t o r e m a i n w e l l s e p a r a t e d from human h a b i t a t i o n . The s a i m i r i monkeys o f n o r t h e r n r a t e s a p p r o a c h i n g 50%, South A m e r i c a a r e a l s o s u s c e p t i b l e t o YF, w i t h m o r t a l l t ;
The n i g h t monkeys ( A c t u s t r i v i r g a t u s ) o f the Amazon, O r i n o c o and Magdalena b a s i n s a l s o a r e r e a d i l y i n f e c t e d w i t h YF, and have a h i g h m o r t a l i t y r a t e . These monkeys a r e commoner t h a n was e a r l i e r s u s p e c t e d ( a l t h o u g h r e c e n t d e m o n s t r a t i o n s of s u i t a b i l i t y as a h o s t f o r human m a l a r i a p a r a s i t e s has made them i n demand, a f a c t o r w h i c h may a f f e c t p o p u l a t i o n d e n s i t i e s ) . The s p i d e r monkeys ( A t e l e s ) a r e s u s c e p t i b l e t o YF, r e s p o n d i n g w i t h h i g h m o r t a l i t y . W o o l l y monkeys ( L a g o t h r i x ) c o u l d be i n f e c t e d but l i m i t e d o b s e r v a t i o n s i n d i c a t e t h a t m o r t a l i t y r a t e s may not be h i g h . C a p u c h i n monkeys (Cebus s p . ) can be i n f e c t e d r e a d i l y w i t h YF, immunity, but m o r t a l i t y r a t e s a r e low. c i r c u l a t e v i r u s and develo
The dynamics o f t h e m a i n t a i n a n c e o f YF i n the v a s t endemic a r e a s o f S o u t h A m e r i c a a r e f a r from c l e a r l y u n d e r s t o o d t o d a y . In a broad g e n e r a l statement, i t can be s a f e l y s a i d t h a t YF, a t any g i v e n p o i n t i n time, i s on the move i n an e p i d e m i c or s u b - e p i d e m i c form, i n various l o c a l i t i e s . J u s t what p a r t i c u l a r l o c a l i t i e s are a f f e c t e d a t any g i v e n p o i n t i n t i m e i t i s not p o s s i b l e t o s a y . To r e f i n e the q u e s t i o n f u r t h e r , can we w i t h c e r t a i n t y s t a t e t h a t any g i v e n r e g i o n w h i c h has been known to have had a j u n g l e YF o u t b r e a k i n t i m e s p a s t does not have r e s i d u a l e n d e m i c i t y a t t h i s moment? A g a i n one has t o d e f i n e " r e g i o n " more p r e c i s e l y . I f we r e d u c e " r e g i o n " t o a 50 square m i l e a r e a , we can w i t h some c o n f i d e n c e say ( f o r T r i n i d a d f o r example) t h a t s i n c e 1959, the d a t e o f the l a s t r e c o g n i z e d o u t b r e a k , i t has not been p o s s i b l e t o d e t e c t any e v i d e n c e o f endemic d i s e a s e . S t u d i e s of t h a t r e g i o n a r e more t h o r o u g h t h a n f o r any o t h e r s i m i l a r o r much l a r g e r r e g i o n s . N o n e t h e l e s s , they a r e f a r from a d e q u a t e . A c o n t i n u i n g degree o f v i g i l a n c e i s m a i n t a i n e d , but not s u s t a i n e d at a h i g h l e v e l c o n t i n u o u s l y I n v e s t i g a t o r s i n Panama, c o v e r i n g a l l o f (Central A m e r i c a n o r t h o f D a r i e n , f e e l r e a s o n a b l y c e r t a i n t h a t f o l l o w i n g t h e e p i d e m i c YF sweep o f the 1950's, t h e r e i s now no endemic d i s e a s e i n the r e g i o n . The Belem V i r u s L a b o r a t o r y , the s o l e a d e q u a t e l y e q u i p p e d l i s t e n i n g p o s t f o r t h e whole Amazon r e g i o n , has YF s u r v e i l l a n c e as a n a t u r a l component o f i t s more g e n e r a l a r b o v i r u s programme. Over t h e p a s t 20 y e a r s , t h e y have uncovered seven e p i s o d e s o f y e l l o w f e v e r a c t i v i t y i n the r e g i o n i n c l o s e p r o x i m i t y t o the l a b o r a t o r y . I t i s c e r t a i n t h a t most o f t h e s e e p i s o d e s would have gone u n r e c o g n i z e d had the l a b o r a t o r y not been t h e r e . What may be g o i n g on t h e r e m a i n d e r o f the Amazon t e r r i t o r y cannot be even guessed at. In any d i s c u s s i o n o f e n d e m i c i t y , t h e p o s s i b l e r o l e o f n o n - p r i m a t e v e r t e b r a t e s comes up for d i s c u s s i o n . T h e r e have been a t t e m p t s t o e v a l u a t e r e c e p t i v e n e s s o f v a r i o u s m a r s u p i a l s , r o d e n t s , e d e n t a t e s and b a t s t o i n f e c t i o n and i t has been e s t a b l i s h e d t h a t v a r i o u s mammals can be i n f e c t e d , can c i r c u l a t e v i r u s and can d e v e l o p d e t e c t a b l e a n t i b o d i e s . Serological studies o f mammal populations however, have not y i e l d e d i n f o r m a t i o n w h i c h would l e a d one t o c o n c l u d e , o r even t o s u s p e c t , t h a t one o r a n o t h e r o f the s p e c i e s s t u d i e d i s i n v o l v e d i n an endemic c y c l e on other than a c a s u a l , even a c c i d e n t a l b a s i s .
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page 3 B i r d s and p o i k i l o t h e r m i c v e r t e b r a t e s have not been o v e r l o o k e d i n t h e quest f o r a nonp r i m a t e endemic c y c l e . I t has n o t been p o s s i b l e t o d e v e l o p t h e concept beyond t h e p o i n t o f l o w - l e v e l , s h o r t - t e r m v i r e m i a s and o c c a s i o n a l n e u t r a l i z a t i o n t e s t p o s i t i v e s , d i f f i c u l t t o evaluate. The v e c t o r s o f j u n g l e YF a r e d e a l t w i t h a t l e n g t h i n S t r o d e ' s " Y e l l o w F e v e r " . Mosquitos o f t h e genus Haemagogus a r e w i t h o u t doubt t h e p r i m a r y i m p o r t a n t v e c t o r s . Mosquitos o f other g e n e r a (Aedes, S a b e t h e s ) have been i n f e c t e d e x p e r i m e n t a l l y and can t r a n s m i t , and i n f e c t e d m o s q u i t o s have been c a p t u r e d i n n a t u r e . There i s no e v i d e n c e however t h a t non-Haemagogus mosquitos a r e i n v o l v e d i n other than a secondary f a s h i o n . I n t h e 1954 T r i n i d a d o u t b r e a k , i t was p o s s i b l e t o l o c a t e a s p e c i f i c t r e e h a r b o u r i n g a d y i n g A l o u a t t a monkey. C a p t u r e s o f Haemagogus m o s q u i t o s p o s i t i v e f o r YF v i r u s were made f o r more t h a n a week f o l l o w i n g t h i s e v e n t , from t h e canopy o f t h i s v e r y t r e e , A study o f A l o u a t t a monkeys c a r r i e d o u t i n T r i n i d a d i n t h e 1954 p e r i o d i n d i c a t e d a p r o b a b i l i t y g r e a t e r t h a n chance, t h a t a g i v e n monkey band would be composed o f monkeys a l l YF n e g a t i v e , a t one extreme, o r w i t h a h i g h p r o p o r t i o n o f p o s i t i v e s , on t h e o t h e r . These l i m i t e d f a c t s l e n d some s u p p o r t t o a concept t h a t i n t h e j u n g l e , t h e YF v i r u s may be c o n t i n u a l l y on t h e move, and t h a t one might c o n c e i v e o f an endemic focus as a f o c u s o f s e v e r a l hundred, o r even s e v e r a l thousand s q u a r e m i l e s , w i t h v i r u s somewhere i n t h e a r e a , a l w a y s , b u t w i t h no p o s s i b i l i t y s h o r t o f an e x t r e m e l y d e t a i l e d study, o f knowing e x a c t l y where. An i n f e c t e d monkey i n a band c o u l d i n f e c t many m o s q u i t o s i n a g i v e n t r e e . This tree would r e m a i n a danger spot f o r s e v e r a l weeks. I f i n v a d e d by monkeys o f a n o t h e r band ( i f t h e t r e e happened t o be i n a boundary zone where b a n d - t e r r i t o r i e s o v e r l a p ) w h i l e a danger s p o t , i n f e c t i o n would be passed on t o t h e next band. S e v e r a l new i n f e c t i v e f o c i m i g h t t h e n be e s t a b l i s h e d a few days l a t e r and s e v e r a l m i l e s d i s t a n t . A l t h o u g h s e v e r a l new danger s p o t s m i g h t be e s t a b l i s h e d , s u c c e s s f u l i n v o l v e m e n t o f a n o t h e r monkey band ( w i t h s u s c e p t i b l e monkeys t h e r e i n ) would o n l y be needed f o r one o f t h e danger s p o t s f o r t h e v i r u s t o be assured o f i t s c o n t i n u i n g maintainance i n the r e g i o n . The t e r r i t o r i a l b e h a v i o u r o f monkey bands i n t r o d u c e s an i m p o r t a n t f a c t o r t o be c o n s i d e r e d . O b v i o u s l y , when an i n t e n s e e p i d e m i c such as t h e C e n t r a l A m e r i c a n one o c c u r s , t h e v i r u s i s more t h a n o r d i n a r i l y s u c c e s s f u l i n i t s movement ( i n t o p o p u l a t i o n s presumably c o m p l e t e l y s u s c e p t i b l e ) , and v i r t u a l l y a l l monkeys a r e i n v o l v e d . Movement o f v i r u s from t h e monkey - Haemagogus c y c l e i n t o humans i s an a c c i d e n t a l phenomenon, s e c o n d a r y t o human i n v a s i o n o f t h e i n f e c t e d f o c u s . I n i n s t a n c e s where nonimmunized l a b o u r e r s a r e w o r k i n g i n t h e j u n g l e t h e r e may be s h a r p o u t b r e a k s . I t i s important t o remember i n c o n n e x i o n w i t h human-Haemagogus i n t e r - a c t i o n , t h a t t h e Haemagogus m o s q u i t o s a r e n o t r e s t r i c t e d t o canopy, b u t a r e o f t e n found b i t i n g a t ground l e v e l , i n sunny c l e a r i n g s , a t r o a d s i d e s , e t c , , and have a l s o been o b s e r v e d b i t i n g w i t h i n houses ( a l t h o u g h t h e y s h o u l d not be c o n s i d e r e d as h o u s e - h a u n t i n g m o s q u i t o s ) . The n a t u r a l h i s t o r y o f u r b a n y e l l o w f e v e r i n t h e A m e r i c a s can be r e s t r i c t e d t o Aedes aegypti-human c y c l e . F o r u r b a n a r e a s , where Aedes a e g y p t i has been e r a d i c a t e d , t h e r e i s no e v i d e n c e t h a t any o t h e r mosquito, even s p e c i e s shown i n e x p e r i m e n t a l s t u d i e s t o be c a p a b l e o f t r a n s m i t t i n g v i r u s , c a n s u c c e s s f u l l y f u n c t i o n t o m a i n t a i n endemic o r e p i d e m i c YF. Much r e m a i n s unknown about t h e urban y e l l o w f e v e r e p i d e m i c model. Recognizable v a r i a b l e s of m o s q u i t o d e n s i t y , p r o p o r t i o n o f s u s c e p t i b l e s i n t h e human p o p u l a t i o n , and l o n g e v i t y o f m o s q u i t o s under t h e i n f l u e n c e o f l o c a l c l i m a t i c f a c t o r s and l e s s u n d e r s t o o d v a r i a b l e s as t h e non-YF group B immune s t a t u s o f a g i v e n p o p u l a t i o n have t o be c o n s i d e r e d . I t i s n o t known, f o r example, under i d e a l c i r c u m s t a n c e s o f a c o m p l e t e l y s u s c e p t i b l e p o p u l a t i o n w i t h o u t o t h e r group B a n t i b o d i e s , what d e n s i t y o f Aedes a e g y p t i might be r e q u i r e d t o produce an e p i d e m i c . I t has a l s o been h y p o t h e s i z e d t h a t group B immunity (dengue has been p a r t i c u l a r l y s u s p e c t i n t h i s c o n n e x i o n ) might s e r v e t o m o d i f y t h e c o u r s e o f YF i n t h e i n d i v i d u a l , s h o r t e n i n g t h e
VIR/YF/71.14
page 4 v i r e m i c phase and d e p r e s s i n g the v i r u s t i t r e l e v e l s a t t a i n e d i n the i n d i v i d u a l . Such a p a t t e r n has been shovm i n a n i m a l models, and i f a p p l i c a b l e t o humans, would be a c o n s i d e r a b l e dampening i n f l u e n c e . C o n t i n u i n g Y F a c t i v i t y i n the t r o p i c a l and s u b t r o p i c a l j u n g l e areas o f t h e A m e r i c a s c a n be e x p e c t e d . Human i n v o l v e m e n t can be l e s s e n e d by e f f e c t i v e Y F v a c c i n a t i o n programmes, Aedes a e g y p t i had been e r a d i c a t e d o r reduced t o l e v e l s presumably below t h o s e n e c e s s a r y to produce urban Y F o u t b r e a k s i n many o f the C e n t r a l and South A m e r i c a n c o u n t r i e s and C a r i b b e a n islands. However, i n the p a s t two decades, i n s e c t i c i d e r e s i s t a n t Aedes have become e s t a b l i s h e d i n many s i t e s . Recent dengue o u t b r e a k s i n c i r c u m - C a r i b b e a n and n o r t h e r n S o u t h A m e r i c a n c o u n t r i e s have p r o v i d e d e v i d e n c e t h a t Aedes a e g y p t i d e n s i t i e s adequate t o cause an epidemic now e x i s t i n a number o f l o c a l i t i e s . T h i s i s a v e r y dangerous s i t u a t i o n . Chance i n t r o d u c t i o n o f v i r u s may l e a d t o an e x p l o s i v e o u t b r e a k , i f the s i t u a t i o n i s not r e c o g n i z e d f o r what i t i s e a r l y . I m m u n i z a t i o n o f p o p u l a t i o n s i n urban c e n t r e s where Aedes a e g y p t i i s known t o e x i s t can o f c o u r s e p r o v i d e adequate c o n t r o l . I t appears u n l i k e l y t h a t , i n the absence o f r e c o g n i z e d d i s e a s e , such i m m u n i z a t i o n w i l l be c a r r i e d o u t . S p o r a d i c mass v a c c i n a t i o n programmes i n absence o f r e c o g n i z a b l e d i s e a s e may i n d e e d upon o c c a s i o n be o r g a n i z e d by a c o n s c i e n t i o u s h e a l t h department, but i t i s u n l i k e l y t h a t c o n t i n u i n g programmes o f v a c c i n a t i o n of new s u s c e p t i b l e s w i l l be m a i n t a i n e d , Aedes a e g y p t i c o n t r o l or e r a d i c a t i o n i s o f c o u r s e a prime c o n s i d e r a t i o n f o r c o n t r o l o f urban y e l l o w f e v e r . The Pan A m e r i c a n H e a l t h O r g a n i z a t i o n has been much i n t e r e s t e d i n t h i s problem and has had r e c e n t c o n f e r e n c e s t o d e t e r m i n e f e a s i b i l i t y . C e r t a i n o f the c o u n t r i e s i n v o l v e d have a c h i e v e d e r a d i c a t i o n but a r e plagued by r e i n t r o d u c t i o n from n e i g h b o u r i n g countries. C e r t a i n o t h e r c o u n t r i e s w h i c h had had programmes aimed a t e r a d i c a t i o n , and w h i c h had a t l e a s t a r r i v e d a t a l e v e l o f a h i g h degree o f c o n t r o l , have i n r e c e n t y e a r s relaxed control e f f o r t s . The e r a d i c a t i o n programme on w h i c h the U n i t e d S t a t e s o f A m e r i c a had embarked i s now n o n - o p e r a t i v e . The problem i n the a d m i n i s t r a t i v e a r e a i s whether an e f f e c t i v e c o n t r o l programme i n any p a r t i c u l a r c o u n t r y i s l i k e l y t o be c o n t i n u e d a t an effective level indefinitely. The q u e s t i o n o f whether Y F v i r u s , i n r a p i d passage from human t o Aedes a e g y p t i t o human i n an u r b a n o u t b r e a k may undergo an enhancement o f v i r u l e n c e f o r the human h o s t i s one w h i c h gets r a i s e d p e r i o d i c a l l y . I t i s i m p o s s i b l e t o t e s t the h y p o t h e s i s i n t h e human h o s t under c o n d i t i o n s of a c o n t r o l l e d experiment. I t i s p o s s i b l e , a l t h o u g h i t has not been done, t h a t markers f o r v i r u l e n c e might be found under c o n d i t i o n s o f l a b o r a t o r y m a i n t a i n a n c e o f v i r u s , i n c e l l c u l t u r e systems or i n v i v o . The d i f f i c u l t y o f r e l a t i n g any such m a r k e r s back t o the human h o s t w i l l r e m a i n . D i f f e r e n c e s i n v i r u l e n c e of f i e l d i s o l a t e d s t r a i n s , of v i r u s , w i t h low o r no mouse passage, when t e s t e d i n Rhesus monkeys, a r e a l r e a d y known. Again r e l e v a n c e t o human d i s e a s e i s not c l e a r . A f u r t h e r d i f f i c u l t y l i e s i n r e c o g n i t i o n o f s p o r a d i c y e l l o w f e v e r c a s e s , w h i c h may have few o f the c h a r a c t e r i s t i c s o f the c l a s s i c a l d i s e a s e p i c t u r e . A s i n g l e s p o r a d i c case u n r e c o g n i z e d may be a l l t h a t i s needed t o g i v e r i s e t o an e p i d e m i c . The e p i d e m i c i t s e l f , w h i l e g a t h e r i n g headway, may not be r e c o g n i z e d as y e l l o w f e v e r u n t i l i n t h e second or t h i r d wave o f t r a n s m i s s i o n . The i d e a l s o l u t i o n l i e s i n t h e m a i n t a i n a n c e o f a s e r i e s o f l i s t e n i n g p o s t s , a b l e t o d i a g n o s e y e l l o w f e v e r q u i c k l y and c o r r e c t l y , by a p p l i c a t i o n o f a p p r o p r i a t e v i r o l o g i c a l techniques. Two such p o s t s , the T r i n i d a d l a b o r a t o r y and the Belem l a b o r a t o r y , f a c e t h e v e r y r e a l t h r e a t o f l o s s o f such competency t h r o u g h l a c k o f adequate c o n t i n u i n g financing.
VIR/YF/71.14
page
5
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