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ORGANISATION MONDIALE DE L A SANTE
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E X P E R T COMMITTEE ON V I R A L HAEMORRHAGIC F E V E R Geneva, Draft 19-23 M a r c h 1984 item 3.1
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E P I D E M I O L O G I C A L , C L I N I C A L AND P H Y S I O P A T H O L O G I C A L D E S C R I P T I O N OF YELLOW FEVER I N A F R I C A by '
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Dr P. Brès I n s t i t u t Pasteur,
Paris
A l t h o u g h t h e f i r s t e p i d e m i c w h i c h c o u l d r e a s o n a b l y be a t t r i b u t e d t o y e l l o w f e v e r w a s d e s c r i b e d i n S e n e g a l i n 1 7 7 8 , i t i s c e r t a i n t h a t t h i s d i s e a s e was w e l l e s t a b l i s h e d i n t h e A f r i c a n c o n t i n e n t b e f o r e t h a t t i m e , a n d was p a r t i c u l a r l y f e a r e d by E u r o p e a n s a i l o r s , t r o o p s and t r a d e r s . Several large o u t b r e a k s p e r i o d i c a l l y d e c i m a t e d t h e e x p a t r i a t e p o p u l a t i o n s o n t h e West C o a s t , b u t t h e d i s e a s e was w e l l k n o w n t o o c c u r i n t h e A f r i c a n s a s w e l l . I n 1972, d u r i n g o n e o f t h e p e r i o d i c a l o u t b r e a k s o f t h e d i s e a s e , t h e v i r u s was i s o l a t e d simultaneously by t h e R o c k e f e l l e r F o u n d a t i o n M i s s i o n a t A c c r a , Ghana, from t h e b l o o d o f a n A f r i c a n p a t i e n t named A s i b i , a n d by w o r k e r s a t t h e P a s t e u r I n s t i t u t e , D a k a r , S e n e g a l , f r o m t h e b l o o d o f a L e b a n e s e , by i n o c u l a t i o n o f t h e s u s c e p t i b l e I n d i a n r h e s u s monkey. T h e s t r a i n f r o m t h e P a s t e u r I n s t i t u t e was f u r t h e r a d a p t e d t o m o u s e b r a i n b y M. T h e i l e r a n d b e c a m e known a s t h e F r e n c h Neurotropic Virus. Apart from a d i f f e r e n t degree i n n e u r o t r o p i s m , both s t r a i n s a r e i d e n t i c a l b u t t h e y show a s l i g h t a n t i g e n i c d i f f e r e n c e c o m p a r e d w i t h t h e S o u t h - A m e r i c a n s t r a i n s a n d w i t h t h e 17D v a c c i n e s u b s t r a i n d e r i v e d f r o m t h e A s i b i s t r a i n a n d w h i c h was n o t p a s s a g e d i n mouse b r a i n . The m o l e c u l a r s t r u c t u r e o f y e l l o w f e v e r v i r u s has r e c e n t l y been s t u d i e d ana found somewhat s i m i l a r t o t h a t o f o t h e r v i r u s e s o f t h e F l a v i v i r u s g e n u s o f t h e Togaviridae family. In s p i t e o f s i m i l a r i t i e s with the American v i r u s , the epidemiology of y e l l o w f e v e r i s somewhat d i f f e r e n t i n A f r i c a . The c l i n i c a l p a t t e r n o f c l a s s i c a l severe forms o f the d i s e a s e has n o t changed s i n c e t h e f i r s t d e s c r i p t i o n s b y D u t r o u l e a u i n 1 8 5 8 , b u t m i l d c a s e s h a v e b e e n more f r e q u e n t l y recognized s i n c e 1930 o w i n g t o t h e p r o g r e s s i n l a b o r a t o r y diagnostic methods. However, t h e r e has been l i t t l e o p p o r t u n i t y i n Africa recently to add t o t h e c l a s s i c a l d e s c r i p t i o n s a n d i m p r o v e t h e k n o w l e d g e a v a i l a b l e o t t h e physiopathology of the disease.
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VIR/VHF/EC/84.6 Page 2
1.
EPIDEMIOLOGY 1.1 Geographical Distribution
The endemic, zone f o r y e l l o w f e v e r d e f i n e d by the I n t e r n a t i o n a l H e a l t h R e g u l a t i o n s l i e s between the 15th p a r a l l e l North and the 10th South and i n c l u d e s t o t a l l y or p a r t i a l l y 28 c o u n t r i e s . T h i s zone has been d e l i m i t e d on the b a s i s of n e u t r a l i z a t i o n t e s t s i n a s e r o l o g i c a l s u r v e y c a r r i e d out i n these c o u n t r i e s i n the 193ÛS under the R o c k e f e l l e r Foundation auspices. 1.2 Virus Transmission Chains
The f i r s t d a t a on the v i r u s t r a n s m i s s i o n c h a i n s i n A f r i c a were o b t a i n e d by the R o c k e f e l l e r M i s s i o n i n Bwamba County, Uganda, i n the 1930s. I t was proved t h a t the v i r u s was t r a n s m i t t e d between monkeys i n the f o r e s t canopy by the Aedes a f r i c a n u s m o s q u i t o ( s y l v a t i c y e l l o w fever). Monkeys i n f e c t e d i n the f o r e s t may r a i d banana p l a n t a t i o n s i n nearby v i l l a g e s and are b i t t e n by Aedes s i m p s o n i m o s q u i t o e s w h i c h b r e e d i n p l a n t a x i l s and a f t e r w a r d s can b i t e man ( j u n g l e y e l l o w fever). In v i l l a g e s , the v i r u s can be t r a n s m i t t e d from p e r s o n t o p e r s o n by Aedes a e g y p t i ; i f p r e s e n t , or by Aedes s i m p s o n i ( s o c a l l e d "urban" y e l l o w f e v e r ) . T h i s p a t t e r n , t y p i c a l of E a s t A f r i c a , was o b s e r v e d i n E t h i o p i a d u r i n g the l a r g e e p i d e m i c o f 1960-1962 w h i c h caused about 100,000 c a s e s , o f which 30,000 d i e d out of a p o p u l a t i o n of one m i l l i o n inhabitants. The a t t a c k r a t e was lower i n the D i d e s s a v a l l e y , where man was i n f e c t e d by Aedes a f r i c a n u s on e n t e r i n g the f o r e s t , t h a n i n the Omo v a l l e y where man was i n f e c t e d by Aedes s i m p s o n i i n v i l l a g e s . A s l i g h t l y d i f f e r e n t t r a n s m i s s i o n p a t t e r n has been found r e c e n t l y i n West A f r i c a i n v o l v i n g o t h e r m o s q u i t o s p e c i e s ( t a b l e 1 ) . A l t h o u g h Aedes s i m p s o n i i s a l s o p r e s e n t i n A f r i c a west of the Cameroons, i t does not b i t e man. S t u d i e s c a r r i e d out by the I n s t i t u t P a s t e u r and the O f t i c e de l a Recherche s c i e n t i f i q u e e t t e c h n i q u e Outre-mer have shown the same e n z o o t i c b a s i c maintenance c y c l e o f monkey-to-monkey t r a n s m i s s i o n i n the w e s t e r n s t r i p of the C o n g o l e s e G u i n e a n r a i n f o r e s t by Aedes a f r i c a n u s mosquitoes. T h i s c a u s e s e x c e p t i o n a l l y a few s p o r a d i c human cases ( s y l v a t i c y e l l o w f e v e r ) . From the f o r e s t c y c l e , the v i r u s can i r r a d i a t e p e r i o d i c a l l y a l o n g r i v e r i n e f o r e s t s which p e n e t r a t e i n t o the s u r r o u n d i n g savanna zone and i s t r a n s m i t t e d by d i f f e r e n t v e c t o r m o s q u i t o s p e c i e s a c c o r d i n g t o the type of savanna, humid (Guinean) or d r y ( S u n d a n e s e ) : t h i s i s the "emergency z o n e " ( t a b l e 1 ) . Sporadic human c a s e s r e f l e c t an e n z o o t i c s i t u a t i o n , or c i r c u m s c r i b e d o u t b r e a k s r e f l e c t an e p i z o o t i c s i t u a t i o n i n monkeys. Man-to-man t r a n s m i s s i o n may a l s o be caused by these m o s q u i t o e s , w h i c h p l a y the same r o l e as Aedes s i m p s o n i i n the E a s t ( j u n g l e y e l l o w f e v e r ) . I t has been shown t h a t the d e n s i t y of m o s q u i t o e s i n r i v e r i n e f o r e s t s i n c r e a s e s d u r i n g the second h a l f o f the r a i n y s e a s o n , f i r s t f o r Aedes l u t e o c e p h a l u s and soon a f t e r Aedes f u r c i i e r and Aedes t a y l o r i . The p r o p o r t i o n of i n f e c t e d mosquitoes a l s o increases r a p i d l y . Male m o s q u i t o e s have been found n a t u r a l l y i n f e c t e d w i t h y e l l o w f e v e r v i r u s which p r o v e s the " v e r t i c a l " ( t r a n s o v a r i a l ) t r a n s m i s s i o n t h r o u g h eggs w h i c h p e r s i s t
VIR/VHF/EC/8A.6 Page 3
b e t w e e n two r a i n y s e a s o n s . A l t h o u g h t h i s m e c h a n i s m may t r a n s m i t the v i r u s t h r o u g h the d r y s e a s o n o n l y t o a low p e r c e n t a g e o f the F l g e n e r a t i o n , i t may p e r p e t u a t e t h e v i r u s l o c a l l y f o r two o r t h r e e y e a r s i f t h e v i r u s c i r c u l a t i o n i s e n h a n c e d e a c h y e a r by i n f e c t i o n o f non-immune m o n k e y s w h i c h c a n be a s o u r c e o f v i r u s t o i n f e c t many m o r e mosquitoes. R.M. T a y l o r s t a t e d i n 1951 t h a t " f r o m t h e a s p e c t o f t h e t i m e e l e m e n t and t h e r e s e r v o i r o f t h e v i r u s , t h e m o s q u i t o q u a l i t i e s b e t t e r as a h o s t t h a n does the v e r t e b r a t e , f o r i t i s i n the m o s q u i t o t h a t the v i r u s f i n d s a more p e r m a n e n t a b o d e " ( 1 ) . In order to d e t e r m i n e the r i s k f o r n e a r b y v i l l a g e s , the e n z o o t i c o r e p i z o o t i c a c t i v i t y o f t h e v i r u s i n t h e r i v e r i n e f o r e s t c a n be m o n i t o r e d by c a p t u r e o f m o s q u i t o e s t o f i n d t h e p r e s e n c e o f v e c t o r s p e c i e s and monkeys t o f i n d s e r o l o g i c a l e v i d e n c e o f r e c e n t i n f e c t i o n . A t l o n g i n t e r v a l s , t h e v i r u s may p r o g r e s s f u r t h e r d u r i n g t h e r a i n y season towards v i l l a g e s i n the s e m i - a r i d zone where Aedes a e g y p t i c o l o n i z e s i n d o m e s t i c b r e e d i n g s i t e s , o r i n towns, where most o f t h e human p o p u l a t i o n no l o n g e r h a s a n y i m m u n i t y s i n c e t h e l a s t e p i d e m i c o r v a c c i n a t i o n c a m p a i g n , and t h i s may c a u s e s e v e r e and extended epidemics of urban y e l l o w f e v e r . The v i r u s may be t r a n s p o r t e d f r o m t h e j u n g l e c y c l e t o d i s t a n t p l a c e s by i n f e c t e d mosquitoes or p a t i e n t s . Incidence i n the Population
T h e r e i s no e t h n i c d i f f e r e n c e i n s u s c e p t i b i l i t y t o i n f e c t i o n s . M a t e r n a l i m m u n i t y , i f s t r o n g e n o u g h , may p r o t e c t a c h i l d u n t i l a b o u t s i x months o f age. I t seems t h a t r e p e a t e d i n f e c t i o n s w i t h c e r t a i n other f l a v i v i r u s e s closely r e l a t e d a n t i g e n i c a l l y to yellow fever virus s u c h a s Z i k a , W e s s e l s b r o n , U g a n d a S, m i g h t a f f o r d some d e g r e e o f c r o s s - p r o t e c t i o n by t h e age o f 15 y e a r s . E x p e r i m e n t a l l y , the v i r a e m i a a f t e r c h a l l e n g e w i t h y e l l o w f e v e r v i r u s i s lower i f the monkey has b e e n i m m u n i z e d w i t h d e n g u e , Z i k a and W e s s e l s b r o n v i r u s . However, w h e t h e r dengue w o u l d r e s u l t i n c r o s s - p r o t e c t i o n o f man a g a i n s t y e l l o w f e v e r i s not c e r t a i n , knowing that y e l l o w f e v e r v a c c i n a t i o n does not p r o t e c t a g a i n s t dengue. D u r i n g u r b a n o u t b r e a k s o f y e l l o w f e v e r i n t h e p a s t , i t was o b s e r v e d t h a t the e p i d e m i c " b u r n e d i t s e l f o u t " when a b o u t 6 0 - 8 0 % o f the p o p u l a t i o n had b e e n i n f e c t e d . T h e s e f i g u r e s c a n be t a k e n a s targets for v a c c i n a t i o n coverage. E p i d e m i c s w h i c h o c c u r r e d i n A f r i c a d u r i n g the p e r i o d 1965-1983 a r e i n d i c a t e d i n t a b l e 2. The n u m b e r s o f n o t i f i e d c a s e s a r e frequently under-estimated. By c o m p a r i s o n w i t h t h e r e g u l a r p a t t e r n o f y e a r l y o c c u r r e n c e o f y e l l o w f e v e r i n t h e A m e r i c a s i t may be s e e n that outbreaks occur at l e s s r e g u l a r i n t e r v a l s i n A f r i c a . Sporadic cases of j u n g l e y e l l o w f e v e r are r a r e l y d e t e c t e d i n A f r i c a b e c a u s e o f t h e s c a r c i t y o f e n t o m o l o g i c a l s u r v e y s and l a c k o f laboratory capabilities for virus isolation. Even outbreaks r e a c h i n g some i m p o r t a n c e may a l s o n o t be r e p o r t e d t o h e a l t h authorities. S i t u a t i o n s have been documented where an important e p i z o o t i c a c t i v i t y was g o i n g on i n r i v e r i n e f o r e s t s a n d sero c o n v e r s i o n s o c c u r r e d i n the c h i l d p o p u l a t i o n or nearby v i l l a g e s w i t h o u t any e v i d e n c e o f c l i n i c a l o u t b r e a k s . T h i s may be i n t e r p r e t e d as a low v i r u l e n c e o f the v i r u s i n t h e s y l v a t i c c y c l e , w h e r e a s i t c a n be e n h a n c e d a f t e r some m a n - t o - m a n t r a n s m i s s i o n c y c l e s .
VIR/VHF/EC/84.6 Page 4
2.
CLINICAL
FEATURES
C l a s s i c a l s e v e r e t o r m s o f y e l l o w f e v e r c a n e a s i l y be r e c o g n i z e d by their c l i n i c a l features. The i n c u b a t i o n p e r i o d i s 3-6 d a y s a f t e r the b i t e o f an i n f e c t e d m o s q u i t o . The o n s e t i s a b r u p t w i t h l u m b o s a c r a l and g e n e r a l i z e d muscular pains, intense headache, c o n j u n c t i v a l i n f e c t i o n , f l u s h e d f a c e , n a u s e a and v o m i t i n g . Faget's sign (slow pulse i n r e l a t i o n t o the f e v e r ) i s t y p i c a l . A f t e r a s h o r t r e m i s s i o n of f e v e r the t o x i c and haemorrhagic conditions develop; e p i s t a x i s , gum b l e e d i n g , b l a c k , s p o t s (as f l i e s ) i n v o m i t i n g w h i c h announce the m a s s i v e b l a c k v o m i t o f d i g e s t e d b l o o d , the a s c e n d i n g a l b u m i n u r i a (a good s i g n but sometimes of l a t e a p p e a r a n c e and n o t c o n s t a n t l y f o u n d ) , u r e m i a , the d e t e r i o r a t i o n o f c e n t r a l n e r v o u s s y s t e m f u n c t i o n s , coma and t e r m i n a l s h o c k s y n d r o m e . Jaundice is i n g e n e r a l m o d e r a t e and may e v e n n o t be v i s i b l e b e f o r e d e a t h . The case f a t a l i t y r a t i o v a r i e s b e t w e e n 20-80^. o f h o s p i t a l i z e d c a s e s . I n E t h i o p i a , t h e m a j o r i t y o f c a s e s d u r i n g t h e 1959 e p i d e m i c s h o w e d o n l y s i g n s and symptoms o f t h e c e n t r a l n e r v o u s s y s t e m ( 2 ) , s i m i l a r t o c a s e s w h i c h w e r e o b s e r v e d d u r i n g t h e Nuba m o u n t a i n e p i d e m i c i n S u d a n i n 1940. In E t h i o p i a a g a i n , d u r i n g the 1960-1962 e p i d e m i c , f u l m i n a n t forms w i t h o u t any h e p a t i c o r r e n a l s i g n s , a n d d e a t h o c c u r r i n g i n two t o t h r e e days were o b s e r v e d i n a c e r t a i n r e g i o n , whereas o n l y the c l a s s i c a l f o r m was s e e n i n o t h e r s ( 3 ) . M i l d c a s e s a r e more f r e q u e n t t h a n was f o r m e r l y t h o u g h t and e v e n s u b c l i n i c a l i n f e c t i o n s are not r a r e . B o t h c a n be c o n f i r m e d by a n i n c r e a s e o f I g G b e t w e e n a n e a r l y a n d a l a t e b l o o d s p e c i m e n o r by e a r l y d e t e c t i o n of s p e c i f i c IgM. W h e r e a s t h e r e i s no g r e a t d i f f i c u l t y d u r i n g a n e p i d e m i c , sporadic c a s e s may be c o n f u s e d w i t h m a l a r i a o r i n f l u e n z a when t h e y a r e m i l d , o r w i t h o t h e r h a e m o r r h a g i c f e v e r s when t h e y a r e s e v e r e . Ebola v i r u s i n f e c t i o n s were c o n f i r m e d s e r o l o g i c a l l y d u r i n g the y e l l o w f e v e r e p i d e m i c i n t h e G a m b i a i n 1978 and t h e r e h a s b e e n a p o s s i b i l i t y t h a t O r u n g o v i r u s could cause haemorrhagic signs during a yellow fever outbreak. Malaria i s p e r h a p s t h e m o s t f r e q u e n t c a u s e o f e r r o r f o r m i l a f o r m s and viral h e p a t i t i s f o r i c t e r i c forms. Erroneous d i a g n o s i s of i n f e c t i o u s h e p a t i t s c a n be s u s p e c t e d when l e t h a l i t y i n t h e o u t b r e a k o f j a u n d i c e , w h i c h o c c u r s u s u a l l y a t the b e g i n n i n g of the r a i n y s e a s o n , (as does y e l l o w f e v e r ) e x c e e d s 1%. However, t h i s l a t e d i f f e r e n t i a l d i a g n o s i s p r o v i d e s ample t i m e f o r t h e y e l l o w f e v e r v i r u s t o s p r e a d and p r o d u c e many more c a s e s . 3, P H Y S I O P A T H O L O G I C A L FEATURES T h e r e i s no s p e c i f i c f e a t u r e d i f f e r e n t i a t i n g y e l l o w f e v e r i n A f r i c a f r o m t h e same d i s e a s e i n t h e A m e r i c a s . The p a t h 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 t h e d i s e a s e h a v e b e e n k n o w n s i n c e t h e d e s c r i p t i o n by C o u n c i l m a n ( 1 8 9 0 ) o f t h e l i v e r l e s i o n s a n d t h e i s o l a t i o n o f t h e v i r u s i n 1927 e n a b l e d their o r i g i n t o be a s c e r t a i n e d by f u r t h e r s t u d i e s i n r h e s u s m o n k e y s . P r a c t i c a l l y n o t h i n g c o u l d be a d d e d s i n c e . In c o n t r a s t , l i t t l e i s known o n t h e d i a t h e s i s a s p e c t o f t h e d i s e a s e and i t s i m m u n o p a t h o l o g y . 3,1 Pathological Characteristics of Yellow Fever
L e s i o n s of the l i v e r mainly a t t r a c t a t t e n t i o n because of t h e i r d i a g n o s t i c s i g n i f i c a n c e , but l e s i o n s which are a l s o c o n s p i c u o u s i n o t h e r o r g a n s t e n d t o be f o r g o t t e n and c o u l d be o f i n t e r e s t f o r t h e f u r t h e r u n d e r s t a n d i n g o f the p h y s i o p a t h o l o g i c a l p r o c e s s . They a r e s u m m a r i z e d h e r e u n d e r f r o m J.G. B u g h e r ( 4 ) .
VIR/VHF/EC/84.6 Page 5
As a c o n s t a n t c h a r a c t e r i s t i c , t h e r e i s a m i l d , e x c e p t i o n a l l y i n t e n s e , i c t e r i c t i n t i n g o f o r g a n s and no i n f l a m m a t o r y response. N o t h i n g i s i n favour of a n e c r o t i z i n g a c t i v i t y of the v i r u s . (a) General appearance
The g e n e r a l a p p e a r a n c e i s u n i m p r e s s i v e and m o s t o f t h e time the i c t e r u s i s m i l d . S u b m u c o s a l and s u b e p i t h e l i a l p e t e c h i a l h a e m o r r h a g e s a r e common and t h e gums and m u c o u s membrane o f t h e m o u t h show p e r s i s t e n t haemorrhage. S u b c o n j u n c t i v a l haemorrhages may be found. O r g a n s show l i t t l e g r o s s c h a n g e e x e p t a n i c t e r i c tinct which i s g e n e r a l l y l i g h t , but m i c r o s c o p i c changes are important.
(b)
Liver There is little change i n the v o l u m e and aspect.
M i c r o s c o p i c l e s i o n s are c h a r a c t e r i s t i c but h e p a t i c f a i l u r e may n o t be t h e p r i m a r y c a u s e o f d e a t h . A d i f f u s e d i s o r g a n i z a t i o n of the parenchyma i s most marked i n the midzone of the l o b u l e : discontinuous c o a g u l a t i v e n e c r o s i s i n the c o r d s of l i v e r c e l l s , b e g i n n i n g by t u r g e s c e n c e o f t h e c e l l , f o r m a t i o n o f s m a l l and l a r g e d r o p l e t s o f f a t w i t h i n t h e n u c l e u s and c y t o p l a s m , f o l l o w e d by m i g r a t i o n o f c h r o m a t i n t o t h e n u c l e a r membrane, c y t o p l a s m a t i c e o s i n o p h i l i c c o a g u l a t i o n r e s u l t i n g i n a h y a l i n e mass f o r m i n g t h e C o u n c i l m a n body from w h i c h the c h r o m a t i n w i l l disappear. A c o l l a r of s u r v i v i n g c e l l s around the c e n t r a l v e i n of the l o b u l e i s the d i f f e r e n c e w i t h o t h e r forms of h e p a t i t i s . Haemorrhage i s not characteristic of the liver lesion.
K u p f e r c e l l s a r e i n c r e a s e d i n number, e n l a r g e d , c o n t a i n s m a l l a m o u n t s o t b i l e and i r o n p i g m e n t s . N u c l e u s p y k n o s i s and k a r y o r r h e x i s a r e s e e n i n f u l m i n a n t forms o f the d i s e a s e . D e p l e t i o n of glycogen r h e s u s monkey. has been demonstrated in the
In a v e r a g e , 6 0 % o f t h e l o b u l e i s a f f e c t e d ( S - l O O / i ) w i t h s o m e t i m e s m a r k e d d i f f e r e n c e b e t w e e n t h e l e f t and right lobes. T h e r e i s an o u t s t a n d i n g inflammatory reaction. absence of significant
T o r r e s i n t r a n u c l e a r e o s i n o p h i l i c b o d i e s have been d e s c r i b e d i n the n u c l e i of the s u r v i v i n g l i v e r c e l l s , somewhat s i m i l a r t o t h e i n c l u s i o n b o d i e s o f h e r p e s v i r u s i n f e c t i o n , b u t t h e y a r e l e s s f r e q u e n t i n humans t h a n i n the r h e s u s monkey. N o t h i n g i s known o t t h e i r virus content.
When d e a t h i s d e l a y e d , C o u n c i l m a n b o d i e s c a n n o t b e found i n most s p e c i m e n s . Ocher-coloured bodies ( V i l l e l a bodies ) are v i s i b l e i n the midzone w h i c h r e p r e s e n t an i n t e r m e d i a t e stage i n t h e c o m p l e t e d i s i n t e g r a t i o n of the Councilman bodies. There i s no inflammatory r e a c t i o n t o the n e c r o t i c c e l l s . When t h e p a t i e n t s u r v i v e s , r e g e n e r a t i o n o f l i v e r cells i s r a p i d and c o m p l e t e by t h e end o f c o n v a l e s c e n c e w i t h o u t any p r o l i f e r a t i o n o f s t r o m a . Intestinal Tract blood i s
An i m p r e s s i v e q u a n t i t y o f p a r t i a l l y d i g e s t e d found w i t h i n the c a v i t y of the stomach. The m u c o s a s h o w s a l a r g e number o f p e t e c h i a l h a e m o r r h a g e s , s u r r o u n d e d by p o l y m o r p h o n u c l e a r l e u k o c y t e s and l y m p h o c y t e s . Some h a e m o r r h a g e may be f o u n d none o c c u r s i n the small
i n t h e duodenum, b u t
intestine. a
-
There i s a p r o l i f e r a t i o n o f l a r g e round c e l l s w i t h d i m i n u t i o n o f mature lymphocytes i n the lymphoid t i s s u e s of the i n t e s t i n a l t r a c t . tract
Urinary
The k i d n e y f u n c t i o n i s p r o f o u n d l y a f f e c t e d a n d p l a y s an i m p o r t a n t p a r t i n c a u s i n g d e a t h . Albuminuria u s u a l l y makes i t s a p p e a r a n c e soon a f t e r t h e o n s e t o f f e v e r and r a p i d l y i n c r e a s e s i n i n t e n s i t y . Anuria i s one o f t h e s i g n s o f g r a v e s t p r o n o s s i s . U r e m i a may c a u s e p a r t o f t h e o b s e r v e d c e r e b r a l symptoms. The t u b u l a r e p i t h e l i u m shows more s e v e r e c h a n g e s t h a n the g l o m e r u l i , e s p e c i a l l y i n t h e c o n v o l u t e d tubules where a d i s c o n t i n u o u s d e g e n e r a t i v e f a t t y i n f i l t r a t i o n and n e c r o s i s p r o c e s s i s g e n e r a l l y o b s e r v e d . The l u m i n a o f m o s t t u b u l e s a r e f i l l e d w i t h g r a n u l a r d e b r i s d e r i v e d from the e p i t h e l i a l c e l l n e c r o s i s and c a l c a r e o u s masses a r e f r e q u e n t l y encountered. Renal c o n g e s t i o n i s part o f the general of the t e r m i n a l v a s c u l a r c o l l a p s e . manifestation
As i n t h e l i v e r , t h e r e i s a s t r i k i n g l a c k o f s t r o m a l r e a c t i o n , n o s u b s e q u e n t f i b r o s i s a n d t h e k i d n e y may r e t u r n t o a normal h i s t o l o g i c appearance d u r i n g recovery. Submucosal haemorrhages a r e found i n the b l a d d e r c o n t a i n s a s m a l l amount o f b l o o d - s t a i n e d u r i n e . which
VIR/VHF/EC/84.6 Page 7
(f)
Brain Y e l l o w f e v e r i s c h a r a c t e r i z e d by t h e r e l a t i v e m e n t a l c l a r i t y o f t h e p a t i e n t e v e n t h o u g h he may a c t u a l l y be n e a r o r a t the p o i n t o f d e a t h . Small p e r i v a s c u l a r haemorrhages are c o n s i s t e n t l y seen i n s p a c e s a r o u n d s m a l l a r t e r i e s , v e i n s and a r o u n d c a p i l l a r i e s a n d t h e i n v o l v e d v e s s e l s show c u f f s o f r e d c e l l s , w i t h m o d e r a t e oedema and no s i g n i f i c a n t cellular infiltration. A l t h o u g h the s m a l l h a e m o r r h a g e s a r e w i d e s p r e a d , t h e y are present i n c o n c e n t r a t i o n i n the mammillary bodies and the o p t i c t h a l a m u s . The b r a i n i n v o l v e m e n t i s r e l a t e d t o t h e g e n e r a l h a e m o r r h a g i c t e n d a n c y and t h e r e i s no t r u e e n c e p h a l i t i s , but the p e r i v a s c u l a r haemorrhage a l o n e may c a u s e d e a t h .
(g)
Spleen The e a r l y l e s i o n s a r e c h a r a c t e r i z e d by t h e a p p e a r a n c e o f l a r g e m o n o n u c l e a r c e l l s i n and a b o u t the f o l l i c l e and p r o g r e s s i v e d i m i n u t i o n i n t h e number o f l y m p h o c y t e s (a c o n s t a n t l y m p h o c y t o p e n i a i s e n c o u n t e r e d in yellow fever). T h e y a r e f o l l o w e d by a d i m i n u t i o n o f m o n o n u c l e a r s marked r e t i c u l o e n d o t h e l i a l h y p e r p l a s i a . and
(h)
Pancreas There i s c o n s i d e r a b l e pacchy haemorrage. bile s t a i n i n g of the organ and
(i)
Cardiovascular
tract
T h e r e i s a c l o u d y s w e l l i n g and degenerative i n f i l t r a t i o n o f the h e a r t m u s c l e f i b e r s , most s e v e r e beneath the endocardium. The n u c l e i o f t e n show h y d r o p i c changes l e a d i n g t o a c t u a l n e c r o s i s w i t h k a r y o l y s i s and v a c u o l i z a t i o n o f t h e cytoplasm. These l e s i o n s o c c u r a l s o i n the s i n o a u r i c u l o node, the b u n d l e o f H i s s , and t h e a u r i c u l o - v e n t r i c u l a r b u n d l e , w h i c h are i n a c c o r d a n c e w i t h the o b s e r v e d b r a d y c a r d i a and t h e a l t e r a t i o n s i n t h e e l e c t r o c a r d i o g r a m . The i n v o l v e m e n t o f t h e c o n d u c t i o n s y s t e m e x p l a i n s bradycardia during convalescence, myocardial i n s u f f i c i e n c y and s u d d e n d e a t h o c c u r r i n g d u r i n g exertion. D e g e n e r a t i v e changes of the m a j o r b l o o d v e s s e l s b e e n d e s c r i b e d w i t h no m e n t i o n o f c a p i l l a r i e s . The l u n g , a s w e l l a s o t h e r o r g a n s , i s c o n g e s t e d degree dependant upon the e x t e n t of the c a r d i a c the
have
to a damage.
VIR/VHF/EC/84.6 Page 8
(J)
Summary o f -
Lesions
In w h a t e v e r o r g a n i t i s p r e s e n t , the y e l l o w f e v e r lesion consists in a selective necrobiosis that a t t a c k s o n l y h i g h l y s p e c i a l i z e d e p i t h e l i a l or myocardial c e l l s . The c h a n g e s a r e f u n d a m e n t a l l y t o x i c i n c h a r a c t e r , the s t r o m a c e l l s a r e not i n v o l v e d a n d t h e r e i s no i n f l a m m a t o r y response to n e c r o s i s . The m o s t s i g n i f i c a n t l y i n v o l v e d o r g a n s a r e t h e liver and k i d n e y s . During convalescence the n e c r o t i c m a t e r i a l i s s l o w l y a b s o r b e d and t h e r e i s a c o m p l e t e r e p l a c e m e n t o f t h e l o s t t i s s u e by d i r e c t r e g e n e r a t i o n . findings in Africa
(k)
Further
Out o f 60 l i v e r s p e c i m e n s t a k e n p o s t - m o r t e m f r o m c h i l d r e n who d i e d d u r i n g t h e 1965 o u t b r e a k o f y e l l o w f e v e r i n S e n e g a l and w h i c h w e r e c o n s i d e r e d a s suspect, 14 ( 2 3 % ) h a d a j a u n d i c e c a u s e d by o t h e r a g e n t s a n d m a l a r i a was a s s o c i a t e d w i t h y e l l o w f e v e r i n 8 0 % o f children (5). Any p h y s i o p a t h o l o g i c a l s t u d y o f y e l l o w f e v e r s h o u l d f i r s t l o o k a t the p u r i t y o f the c a s e . S i m i l a r f i n d i n g s w e r e made d u r i n g t h e 1969 e p i d e m i c i n Upper V o l t a C6). D u r i n g t h e 1969 e p i d e m i c i n N i g e r i a , i t was f o u n d t h a t a s t h e d i s e a s e progresses towards convalescence the h i s t o l o g i c a l f e a t u r e s begin to resemble those of a n o n s p e c i f i c h e p a t i t i s ( 7 ) . 3.2 Evidence for Disseminated intravascular Coagulation
T o d a y , l i t t l e e v i d e n c e o f t h i s phenomenon has been o b t a i n e d i n human y e l l o w f e v e r ( 8 ) . The o c c u r r e n c e o f a n t i g e n - a n t i b o d y ( I g M ) c o m p l e x e s a r o u n d t h e f i f t h - s i x t h day a l t e r o n s e t h a s b e e n s h o w n i n man and monkey. The monkey m i g h t be a m o d e l f o r s t u d y . I n one study, e i t h e r t h e i n i t i a l a n t i b o d y r e s p o n s e was c o r r e l a t e d w i t h r a p i d c l e a r a n c e of v i r a e m i a , the l i m i t a t i o n of t r a n s a m i n a s e e l e v a t i o n and t h e l i m i t a t i o n o f C'3 d e p r e s s i o n , o r i n i t i a l a n t i b o d i e s d i d n o t get r i d o f v i r a e m i a and t h e s e p a r a m e t e r s a g g r a v a t e d u n t i l death.
VIR/VHF/EC/84.6 Page 9
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Sérié, C. e t a l . Etudes s u r l a fiève jaune en E t h i o p i e I n t r o d u c t i o n . Symptomatologie c l i n i q u e a m a r i l e . B u l l e t i n o f the World H e a l t h Organization. 38, 835-841, 1968. Bugher, J.C.; New Y o r k . The p a t h o l o g y o f y e l l o w f e v e r . 137-163, 1951. Yellow Fever, McGraw-Hill,
Group Study - Une épidémie de fiève jaune au Sénégal en J 9 6 5 . B u l l e t i n o f t h e World H e a l t h O r g a n i z a t i o n . 3 6 , 1 1 3 - 1 5 0 , 1 9 b / . Ricossé. J.-H. e t a l . Le d i a g n o s t i c anatome - p a t h o l o g i q u e de l a fiève j a u n e . A n n a l e s d'Anatomie P a t h o l o g i q u e . IT.' 21-3», l ^ ' ^ F r a n c i s T. I . e t a l . A c l i n i c o p a t h o l o g i c a l s t u d y o f ^ u ^ ^ " yello«/"«ver. B u l l e t i n o f t h e World H e a l t h O r g a n i z a t i o n . 4 6 , b 5 9 - t ) b / , i v / / 8. J o h n s o n , K. P e r s o n a l communication
T3 0)
< M
Table
1.
E p i d e m i o l o g i c a l F e a t u r e s o f Y e l l o w Fever
i n West A f r i c a
CWest ot Cameroons) O
< ^
PI
ECOLOGICAL ZONE
MOSQUITO VECTORS
TRANSMISSION CYCLES
EPIDEMIOLOGICAL ZONE
MODE OF OCCURRENCE
TYPE OF YELLOW FEVER
n
00
Wooded s t e p p e
(Sahel)
Ae. a e g y p t i
man-to-man
Invasion zone
Epidemic
Urban y e l l o w f e v e r (may o c c u r i n v i l lages)
Undifferentiated savanna o f d r y type
(Sudan savanna)
Ae. a e g y p t i
man-to-man
( Different iated ( savanna CU u o
( (
(Northern Guinea savanna) (Southern Guinea savanna) (Derived savanna)
Ae. f u r c i f e r Ae. t a y l o r i Ae. luteocephc Ae. a f r i c a n u s
monkey-to-man Emergency zone * man-to-man Endemic (sporadic or c i r c u m scribed outbreaks during epizootics)
!^ Q ) C •i-l
Undifferentiated savanna o f m o i s t type Forest savanna mosaic
Ae. opok Ae. a f r i c a n u s (Ae. s i m p s o n i East A f r i c a )
Jungle yellow fever (may o c c u r in villages)
u 0)
>
OS
Moist Forest
(rain forest)
Ae. a f r i c a n u s
monkey-to-man
Maintenance zone
Sporadic (enzootic)
Sylvatic fever
yellow
Note;
Aedes A e g y p t i t r a n s m i t t e d y e l l o w f e v e r may o c c u r i n any u r b a n i z e d a r e a where t h i s v e c t o r i s p r e s e n t , w h a t e v e r t h e g e o g r a p h i c a l l o c a t i o n .
T a b l e 2.
Y e l l o w F e v e r i n A f r i c a and A m e r i c a d u r i n g t h e p e r i o d 1965 - 1983
1965 1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 Angola E q u a t o r i a l Guinea Guinée équatoriale Ethiopia - Ethiopie . . . . Gambia - Gambie Ghana I v o r y C o a s t - C6te d ' i v o i r e L i b e r i a - Libéria N i g e r i a - Nigéria S e n e g a l - Sénégal S i e r r a Leone Tongo U n i t e d Rep. o f Cameroon Rép.-Unie du Cameroun ... Upper V o l t a - H a u t e - V o l t a . Z a i r e - Zaïre TOTAL 65 4 350 5 5 21 208 243 130 I 2 1 87 2 243 350 5 322 23 70 7 8 27 134 3 110 249 508 16 7 31 671 2 1 1 2 1 7 b 356 4 2 25 11 3 1 3 12 3 5 5 1 2 2 110 30 219 494 8 4 6 25 315
1965 1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 A r g e n t i n a - Argentine . . Bolivia - Bolivie . . . . B r a z i l - Brésil C o l o m b i a - Colombie . . . Ecuador - Equateur Guyana - Guyane Panama Paraguay P e r u - Pérou Suriname T r i n i d a d and Tobago T r i n i t -et-Tobago Venezuela TOTAL 2 19 14 2 51 69 167 3 1 2 5 1 27 2 11 l 4 9 2 8 4 7 2 2 7 8 11 9 9 12 3 86 70 16 12 13 36 151 1 12 3 19 1 22 1 2 9 9 11 27 105 1 10 12 51 14 45 27 11 2 1U2 22 6 2 95 24 2 11 5 1 5
45
9
3
5 1
28 1
75
7 2
33
1
1
82
93
97
30
98
19
25 n < !* < 1=:^
18 5 87 5 304 12 47 48 86 28 2 55 7 212 76 168 44 102 3 240 3 205 119 4 237 140 47
" OO
*-