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ORGANISATION M O N D I A L E D E L A S A N T É

INDEXCD

TRAINING COURSE IN EPIDEMIOLOGY AND CONTROL OF COMMUNICABLE DISEASES P r a g u e , August 1970 - F e b r u a r y 1971 D e h l i , F e b r u a r y 1971 - May 1971

EPIDEMIOLOGY OF YELLOW FEVER by

P. Brès, MD

M e d i c a l O f f i c e r , V i r u s D i s e a s e s WHO h e a d q u a r t e r s , Geneva

L i k e a l l o t h e r a r b o v i r u s i n f e c t i o n s , y e l l o w f e v e r i s an a n t h r o p o z o o n o s i s : i t s n a t u r a l h i s t r o y i s f u n d a m e n t a l l y an a n i m a l - m o s q u i t o - a n i m a l c y c l e i n w h i c h man i s i n c i d e n t a l l y i n v o l v e d e i t h e r as a b i o l o g i c a l dead-end f o r t h e v i r u s o r a t t h e s t a r t i n g o f a man-to-man t r a n s m i s s i o n i f Aedes a e g y p t i , o r some o t h e r d o m e s t i c ( o r s u b - d o m e s t i c ) m o s q u i t o , i s p r e s e n t . G e o g r a p h i c a l d i s t r i b u t i o n

Y e l l o w f e v e r i s an endemic d i s e a s e between t h e t r o p i c s i n A m e r i c a and A f r i c a ( F i g s 1 and 2) T h i s endemic zone has been d e l i n e a t e d a c c o r d i n g t o t h e e v i d e n c e o f s p e c i f i c a n t i b o d i e s among t h e r e s i d e n t s . These r e g i o n s a r e a l s o t h o s e where t h e e c o l o g y i s f a v o u r a b l e t o t h e p e r s i s t e n c e o f t h e v i r u s : s u f f i c i e n t p o p u l a t i o n s o f r e c e p t i v e v e r t e b r a t e h o s t s and a d e q u a t e warmth and

h u m i d i t y f o r v e c t o r s .

B e f o r e 1900-1920, when measures were e f f e c t i v e a g a i n s t t h e t r a n s p o r t a t i o n o f i n f e c t e d Aedes a e g y p t i , o r i n f e c t e d t r a v e l l e r s , y e l l o w f e v e r e p i d e m i c s were r e p o r t e d d u r i n g summer u n d e r t e m p e r a t e c l i m a t e s , v e r y f r e q u e n t l y i n t h e U n i t e d S t a t e s o f A m e r i c a and even as f a r t o t h e n o r t h as B o s t o n , o r f r o m t i m e t o t i m e i n E u r o p e , as t h e famous e p i d e m i c i n C a d i x ( S p a i n ) w i t h 7000 d e a t h s i n 57 000 i n h a b i t a n t s i n 1800,

The r e c e p t i v i t y a r e a e x t e n d s e v e r y w h e r e Aedes a e g y p t i can c o l o n i z e even t e m p o r a r i l y , f a r b r o a d e r t h a n t h e endemic a r e a . I t i n c l u d e s , i n p a r t i c u l a r , t r o p i c a l a r e a s o f I n d i a and S o u t h - E a s t A s i a , where t h i s s p e c i e s i s a b u n d a n t . One r e a l i z e s t h e d a n g e r o f i n t r o d u c t i o n o f t h e v i r u s i n t h e s e c o u n t r i e s where no c a s e has been r e p o r t e d up t o now, t h e r e a s o n why i s s t i l l m y s t e r i o u s .

T r a n s m i s s i o n o f t h e v i r u s

The v i r u s i s t r a n s m i t t e d by f e m a l e m o s q u i t o s b e l o n g i n g t o d i f f e r e n t s p e c i e s o f A e d i n e s , d u r i n g t h e b l o o d meal w h i c h i s t a k e n on v e r t e b r a t e s and w h i c h i s n e c e s s a r y f o r o v i p o s i t i o n . They become i n f e c t e d w h i l e b i t i n g an a n i m a l , o r a man, d u r i n g t h e v i r a e m i c p e r i o d . The v i r u s i s p e r p e t u a t e d i n t h i s way t h r o u g h a s e q u e n c e o f c y c l e s o f t r a n s m i s s i o n , i n f e c t e d h o s t - v e c t o r - r e c e p t i v e h o s t , s e v e r a l o f w h i c h a r e now w e l l known.

V I R/ 7 1 . 1

The issue of this document does not constitute formal publication. It should not be reviewed, abstracted or quoted without the agreement of the World Health Organization. Authors alone are responsible for views expressed in signed articles.

Ce document ne constitue pas une publication.

Il ne doit faire l'objet d'aucun compte rendu ou r é s u m é ni d'aucune citation sans l'autorisation de l'Organisation Mondiale de la S a n t é . Les opinions e x p r i m é e s dans les articles s i g n é s n'engagent que leurs auteurs.

- 2 - I n f e c t i o n i n h o s t s and v e c t o r s

V i r a e m i a i n man b e g i n s around 10 days a f t e r b i t i n g by an i n f e c t e d m o s q u i t o and f r e q u e n t l y one day b e f o r e the f i r s t symptoms a p p e a r . V i r a e m i a may l a s t two to t h r e e d a y s , e x c e p t i o n a l l y more, up to s i x t o e i g h t d a y s . I f the p a t i e n t does not d i e , s p e c i f i c c i r c u l a t i n g a n t i b o d i e s a p p e a r between t h e f i f t h and t e n t h day a f t e r o n s e t . The d e l a y and l e n g t h o f v i r a e m i a i n o t h e r v e r t e b r a t e s may be more v a r i a b l e a c c o r d i n g t o the s e n s i t i v i t y o f the s p e c i e s and t h e a m o u n t o f

i n o c u l a t e d v i r u s .

A f t e r the i n f e c t e d b l o o d meal d u r i n g v i r a e m i a , the v i r u s u n d e r g o e s a m u l t i p l i c a t i o n p h a s e i n the a r t h r o p o d g u t s and hemolymph and r e a c h e s the s a l i v a r y g l a n d s by where i t w i l l be

e x c r e t e d d u r i n g b i t i n g . T h i s i n c u b a t i o n p e r i o d , the " e x t e n s i v e p h a s e " i s d e p e n d a n t on

t e m p e r a t u r e and l a s t s f r o m f o u r days a t 37°C t o 12 days at 23 C. There i s no m u l t i p l i c a t i o n under 18 C, but the v i r u s can m u l t i p l y a g a i n i f a f t e r f o u r weeks at 8°C the t e m p e r a t u r e r e a c h e s a c o n v e n i e n t l e v e l . The i n f e c t e d Aedes w i l l be i n f e c t i v e a l l i t s l i f e w i t h o u t any a p p a r e n t t r o u b l e f o r i t s e l f . D i f f e r e n t s p e c i e s o f Aedes are known as v e c t o r s o f y e l l o w f e v e r a n d t h e i r p a r t i c u l a r e c o l o g y w i l l d e t e r m i n e d i f f e r e n c e s i n t r a n s m i s s i o n c y c l e s .

T r a n s m i s s i o n c y c l e s

T r a n s m i s s i o n o f y e l l o w f e v e r f r o m man t o man by Aedes a e g y p t i i s known s i n c e i t s

d e m o n s t r a t i o n on v o l u n t e e r s by C a r l o s F i n l a y i n 1881 i n Cuba. T h i s has been c o n f i r m e d i n u r b a n y e l l o w f e v e r e p i d e m i c s by W a l t e r Reed i n 1900 i n Havana and Marchoux i n 1903 i n B r a z i l Y e l l o w f e v e r seemed f i r s t t o be dependant on man as a r e s e r v o i r and A. a e g y p t i as t h e o n l y v e c t o r Meanwhile, i n 1932, F r e d S o p e r s t u d i e d an e p i d e m i c i n B r a z i l i n an a r e a where A. a e g y p t i was c e r t a i n l y a b s e n t and, i n 1935, he d e s c r i b e d the j u n g l e y e l l o w f e v e r : man was c o n t a m i n a t e d by t h e v i r u s c i r c u l a t i n g i n f o r e s t s among a n i m a l s .

F u r t h e r r e s e a r c h e s began i n 1936 w h i c h have g i v e n e v i d e n c e of d i f f e r e n t t r a n s m i s s i o n c y c l e s i n A m e r i c a and A f r i c a .

In S o u t h A m e r i c a ( F i g . 3A) t h e f o r e s t c y c l e i n v o l v e s t r a n s m i s s i o n o f t h e v i r u s among Cebus monkeys l i v i n g i n the canopy, by m o s q u i t o s as Haemagogus s p c g a z z i n i i f a l c o . T h i s m a i n t a i n s e n d e m i c i t y i n Amazon, Orenogue (?) and Magdalena b a s i n s by w a n d e r i n g e p i z o o t i c s i n t h e f o r e s t s , at s h o r t i n t e r v a l s as Cebus do n o t d i e a f t e r i n f e c t i o n and r e p r o d u c e n o r m a l l y , b r i n g i n g a s u f f i c i e n t number o f r e c e p t i v e i n f a n t s . Man i s c o n t a m i n a t e d when e n t e r i n g t h e f o r e s t . Aedes l e u c o c e l a e n u s can p l a y an a c c e s s o r y r o l e . In C e n t r a l A m e r i c a , A t e l e s and A l o u a t t a monkeys d i e f r o m i n f e c t i o n s : e p i z o o t i c s a r e more s p a c e d than i n S o u t h A m e r i c a , e v e r y 20-30 y e a r s . In 1950, y e l l o w f e v e r went a c r o s s the Panama C a n a l , swept t o t h e n o r t h and r e a c h e d t h e M e x i c a n b o r d e r i n 1956. I t a p p e a r e d i n t h i s e p i z o o t i c t h a t o t h e r m o s q u i t o s and o t h e r v e r t e b r a t e s as marmosets c o u l d a l s o p l a y a r o l e .

In A f r i c a i t has been shown i n Uganda, t h a t the v i r u s i s t r a n s m i t t e d i n t h e c a n o p y among c e r c o p i t h e c u s by Aedes a f r i c a n u s ( F i g . 3 B ) . I n f e c t e d monkeys can l e a v e the f o r e s t and wander m a r a u d i n g i n n e a r b y p l a n t a t i o n s where they a r e b i t t e n by Aedes s i m p s o n i . I n f e c t e d A. s i m p s o n i w h i c h i s a s u b - d o m e s t i c s p e c i e s , can b i t e man, but i t s a n t h r o p o p h i 1 l i e f e e d i n g may v a r y f r o m ~ one a r e a t o t h e o t h e r . In some p l a c e s , m a i n l y i n savanna, o t h e r p o t e n t i a l v e c t o r s may a c t i n p l a c e o f A. s i m p s o n i , as A. l u t e o c e p h a l u s . A, v i t t a t u s , A, f u r c i f e r - t a y l o r i , G a l a g o s h a v e been s u s p e c t e d t o p l a y a r o l e as r e s e r v o i r s i n savanna a r e a s where they have y e l l o w f e v e r a n t i b o d i e s . As i n A m e r i c a , o t h e r v e r t e b r a t e s may be i n v o l v e d i n the n a t u r a l h i s t o r y of y e l l o w f e v e r i n A f r i c a , but monkeys a r e p r i n c i p a l l y a m p l i f i e r s and d i s s e m i n a t o r s o f t h e v i r u s . V e c t o r s o t h e r than m o s q u i t o s may a l s o be i m p l i c a t e d : one s t r e a m o f y e l l o w f e v e r v i r u s has been i s o l a t e d f r o m a p o o l o f p h l e b o t o m u s .

E p i d e m i o l o g i c a l s i t u a t i o n i n t h e p a s t d e c a d e

S p o r a d i c c a s e s o r s m a l l o u t b r e a k s o f j u n g l e y e l l o w f e v e r were n o t i f i e d f r o m 1960 t o 197o t h r o u g h o u t e a c h y e a r i n t r o p i c a l A m e r i c a p r i n c i p a l l y i n B o l i v i a , B r a z i l , C o l u m b i a , P e r u and V e n e z u e l a , A s m a l l o u t b r e a k o c c u r r e d i n N o r t h A r g e n t i n a i n 1966. The t o t a l number of n o t i f i e d c a s e s v a r i e s between 12 to 200 a y e a r .

The s i t u a t i o n i s q u i t e d i f f e r e n t i n A f r i c a where few c a s e s o f s m a l l o u t b r e a k s o f j u n g l e y e l l o w f e v e r a r e n o t i c e d e p i s o d i c a l l y i n f o r e s t e d a r e a s w h i l e l a r g e e p i d e m i c s may o c c u r a t t h e end o f t h e r a i n y s e a s o n i n s a v a n n a . D u r i n g t h e p a s t decade a s e v e r e e p i d e m i c o c c u r r e d i n t h e S o u t h - W e s t e r n p a r t o f E t h i o p i a ( 1 9 6 0 - 6 2 ) w i t h p r o b a b l y 100 000 c a s e s and 30 000 d e a t h s i n a one m i l l i o n p o p u l a t i o n a r e a . In 1965 t h e number o f v i c t i m s o f an e p i d e m i c i n W e s t e r n S e n e g a l c o u l d have been 2000-20 000 c a s e s w i t h 200-2000 d e a t h s . In 1969, t h r e e c o u n t r i e s w e r e a f f e c t e d by e p i d e m i c s : Ghana ( p r o b a b l y more t h a n f i v e c a s e s and two d e a t h s f o r w h i c h a d i a g n o s i s has been c o n f i r m e d ) ; Upper V o l t a ( a b o u t 3000 c a s e s w i t h 100-300 d e a t h s ) and

N i g e r i a ( e s t i m a t i o n o f 10 000 c a s e s and 1000 d e a t h s ) . D u r i n g t h e same d e c a d e , s p o r a d i c c a s e s w e r e n o t i f i e d i n t h e D e m o c r a t i c R e p u b l i c o f t h e Congo, Ghana, P o r t u g u e s e G u i n e a , Uganda, L i b e r i a , M a l i , Togo and Cameroon.

C o n t r o l o f y e l l o w f e v e r

P r o b l e m s r a i s e d by c o n t r o l o f y e l l o w f e v e r a r e d i f f e r e n t i n an e p i d e m i c s i t u a t i o n o r an i n t e r - e p i d e m i c s i t u a t i o n .

C o n t r o l o f y e l l o w f e v e r i n e m e r g e n c i e s

To be more e f f e c t i v e , e p i d e m i o l o g i c a l i n v e s t i g a t i o n s a r e u n d e r t a k e n by teams o f v i r o l o g i s t s , e n t o m o l o g i s t s and e p i d e m i o l o g i s t s i n s u f f i c i e n t numbers t o c o v e r t h e p r o b a b l e i n f e c t e d a r e a v e r y r a p i d l y i n a few d a y s . The e n t o m o l o g i s t w i l l i d e n t i f y v e c t o r s , t h e i r d i s t r i b u t i o n and b i t i n g a c t i v i t y . The e p i d e m i o l o g i s t w i l l do c a s e f i n d i n g s i n h o s p i t a l , d i s p e n s a r i e s and by d o o r - t o - d o o r v i s i t s . The v i r o l o g i s t w i l l t a k e s a m p l e s o f s u s p e c t e d c a s e s f o r i s o l a t i o n o f v i r u s o r s e r o l o g i c a l t e s t s f o r e v i d e n c e o f c o n v e r s i o n i n p a i r e d s e r a - l i v e r s p e c i m e n s o f s u s p e c t e d d e a t h s a r e s e n t f o r h i s t o p a t h o l o g y . One must remember t h a t e v i d e n t c l i n i c a l c a s e s , d y i n g i n " v o m i t o n e g r o " , a r e by f a r l e s s f r e q u e n t t h a n m i l d f o r m s , o r i n f l u e n z a - l i k e f o r m s . On t h e o t h e r s i d e , d i f f e r e n t a g e n t s may c a u s e i c t e r u s , t h e most f r e q u e n t b e i n g t h e h e p a t i t i s v i r u s .

P r e c u r s o r s i n e p i d e m i o l o g y knew w e l l t h a t s e c o n d a r y c a s e s t r a n s m i t t e d by A, a e g y p t i may a p p e a r i n a community s i x d a y s a f t e r t h e i n t r o d u c t i o n o f an i n f e c t e d m o s q u i t o o r 18 d a y s a f t e r t h e i n t r o d u c t i o n o f a y e l l o w f e v e r p a t i e n t . The p r o p a g a t i o n o f t h e e p i d e m i c depends on t h e p r o p o r t i o n o f non-immune p e o p l e and t h e number o f A. a e g y p t i . These two p a r a m e t e r s v a r y i n r e c i p r o c a l f u n c t i o n s . The number o f A, a e g y p t i may be e x p r e s s e d i n d i f f e r e n t i n d e x e s , t h e most common o f w h i c h i s t h e " B r e t e a u i n d e x " (number o f b r e e d i n g s i t e s w i t h A, a e g y p t i l a r v a e p e r 100 i n h a b i t e d p r e m i s e s ) c o n s i d e r e d as meaning a d a n g e r when above one p e r c e n t . An e p i d e m i c was c o n s i d e r e d a t an end o n l y 18 days a f t e r t h e l a s t c a s e .

V a c c i n a t i o n o f t h e i n f e c t e d a r e a and i t s s u r r o u n d i n g s must be i m m e d i a t e . The 17D v a c c i n e i s e a s i l y a d m i n i s t e r e d s i n c e t h e use o f " j e t - i n j e c t o r s " , a t a s p e e d o f 500 t o 3000 p e o p l e p e r h o u r . A c o l d c h a i n i s n e c e s s a r y t o k e e p t h e v a c c i n e b e l o w +4°C d u r i n g s t o r a g e and t r a n s p o r t a - t i o n . Humoral immunity a p p e a r s 10 d a y s a f t e r a f i r s t v a c c i n a t i o n but p r o t e c t i o n i s t h o u g h t t o be e f f e c t i v e e a r l i e r . P e o p l e a t s p e c i a l r i s k s , p r o f e s s i o n a l s , must be v a c c i n a t e d f i r s t , and t h o s e d e a l i n g w i t h c o n t a m i n a t e d s p e c i m e n s must be even r e v a c c i n a t e d ,

A d u l t A. a e g y p t i a r e c o n t r o l l e d e i t h e r by hand p o r t a b l e n e b u l i z e r s o r by a e r i a l d i s p e r s i o n . As A, a e g y p t i i s f r e q u e n t l y r e s i s t a n t t o o r g a n o c h l o r a t e compounds (DDT, HCH, d i e l d r i n ) , o r g a n o - p h o s p h o r o n s a r e u s e d ( m a l a t h i o n , f e n t h i o n , d i b r o m ) . A b a t e o r d u r s b a n a r e l a r v i c i d a l w h i c h may be u s e d i n d r i n k i n g w a t e r . A n t i - a d u l t s and l a r v a e measures a r e more e f f e c t i v e w i t h a permanent e f f e c t i f t h e y a r e c o n d u c t e d a t t h e same t i m e .

Permanent measures f o r c o n t r o l o f y e l l o w f e v e r

S u r v e i l l a n c e i s t h e k e y s t o n e f o r p r e v e n t i o n a g a i n s t e p i d e m i c s . E a r l y r e c o g n i t i o n o f c a s e s r e l i e s upon v i g i l a n c e o f p h y s i c i a n s i n h o s p i t a l s and members o f m o b i l e h e a l t h teams.

They must be s p e c i a l l y e d u c a t e d i n endemic a r e a s i n a s e n s i t i v e a t t i t u d e t o w a r d s s u s p i c i o n o f y e l l o w f e v e r . Samples f r o m i n f e c t e d c a s e s a r e s e n t t o n a t i o n a l l a b o r a t o r i e s s p e c i a l l y

- 4 -

e q u i p p e d f o r r a p i d d i a g n o s i s and, i f n e c e s s a r y , c o n f i r m a t i o n i s g i v e n by a s p e c i a l i z e d r e g i o n a l l a b o r a t o r y . Such a n e t w o r k has been o r g a n i z e d i n West A f r i c a by WHO a f t e r the e p i d e m i c i n S e n e g a l i n 1965. A WHO R e g i o n a l R e f e r e n c e C e n t r e may even g i v e a prompt a s s i s t a n c e i n s t a f f and equipment f o r e p i d e m i o l o g i c a l i n v e s t i g a t i o n s and most u r g e n t v a c c i n a t i o n s .

R e g u l a r v a c c i n a t i o n programmes may be c o n d u c t e d i n endemic a r e a s , e x t e n d e d t o a l l t h e p o p u l a t i o n o r l i m i t e d t o t h e l o w e s t age g r o u p a c c o r d i n g t o t h e immunity s t a t u s o f t h e p o p u l a t i o n and p o s s i b i l i t i e s o f h e a l t h s e r v i c e s .

S u r v e i l l a n c e o f v e c t o r s must a l s o be f o l l o w e d up and i s , i n d e v e l o p i n g c o u n t r i e s , a m a t t e r o f s a n i t a r y e d u c a t i o n o f p o p u l a t i o n s . One must r e c o g n i z e t h a t t h i s aim i s d i f f i c u l t

t o a c h i e v e and e x p e n s i v e t o o .

I f a competent l a b o r a t o r y i s i n v o l v e d , s u r v e i l l a n c e may be e x t e n d e d t o t h e d e t e c t i o n o f v i r u s c i r c u l a t i o n among v e c t o r s and monkeys o r o t h e r p o t e n t i a l h o s t s i n and a r o u n d known o r

s u s p e c t e d d e l i m i t e d endemic f o c i . Such l a b o r a t o r i e s a r e n o t i n s u f f i c i e n t number. D e t e c t i o n o f a c t i v i t y o f t h e v i r u s may be o b t a i n e d a t a low c o s t w i t h p e r i o d i c s e r o l o g i c a l s u r v e y s i n

monkeys and n o n - v a c c i n a t e d young c h i l d r e n . C o n c l u s i o n

Even w i t h a l l t h a t i s known nowadays i n t h e e p i d e m i o l o g y o f y e l l o w f e v e r , t h e d i s e a s e r e m a i n s a t h r e a t f o r l a r g e a r e a s u n d e r t h e t r o p i c s i n A f r i c a and A m e r i c a . W i t h p r o g r e s s i n t r a n s p o r t a t i o n , t h e v i r u s can a l s o a p p e a r o u t o f t h e endemic zone and o r i g i n a t e an o u t - b r e a k i f A, a e g y p t i i s p r e s e n t and becomes i n f e c t e d . S a n i t a r y r e g u l a t i o n s have made an o b l i g a t i o n f o r d e c l a r a t i o n o f c a s e s and v a c c i n a t i o n o f t r a v e l l e r s t o and f r o m endemic a r e a s and t h i s i s hoped t o a v o i d d i s s e m i n a t i o n o f t h e v i r u s .

FIG. 2 YELLOW-FEVER ENDEMIC AREA, AFRICAN CONTINENT 1970

r

A. Cycles In America

Jungle Cycle Urban Cycle