é f ^ ^ l WORLD HEALTH ORGANIZATION
^iKJ' ORGANISATION MONDIALE DE LA SANTE
SCIENTIFIC GROUP ON ARTHROPOD- AND RODENT-BORNE VIRAL DISEASES
INDtXLiD VIR/SG/83.21 ENGLISH ONLY
Geneva, 28 F e b r u a r y - 4 M a r c h 1983 D r a f t agenda i t e m 9-2.2
ADVANCES IN IMMUNOPATHOGENESIS by
Dr K.M, J o h n s o n
U,S. Army M e d i c a l R e s e a r c h I n s t i t u t e of I n f e c t i o u s D i s e a s e s F o r t D e t r i c k , M a r y l a n d , USA
9.2 H a e m o r r h a g i c f e v e r s
9.2.2 O t h e r V i r a l H a e m o r r h a g i c F e v e r (VHF) 9.2.2.1 I n t r o d u c t i o n
E l u c i d a t i o n o f t h e Immunopathogenesis o f a c u t e i n f e c t i o u s d i s e a s e s d e r i v e s f r o m c a r e f u l and d e t a i l e d s t u d i e s i n p a t i e n t s a n d / o r i n a n i m a l m o d e l s w h i c h c l o s e l y m i m i c t h e d i s e a s e p r o c e s s i n man. A l t h o u g h r e a s o n a b l e d e s c r i p t i v e s t u d i e s have been done f o r a l l o f the VHF b o t h p l a c e and p a t t e r n o f d i s e a s e o c c u r e n c e have s e v e r e l y l i m i t e d o p p o r t u n i t y f o r d e t a i l e d s t u d y o f many o f t h e s y n d r o m e s . S i m i l a r l y a n i m a l m o d e l s a r e n o t a v a i l a b l e f o r some VHF and i n o t h e r c a s e s t h e r e q u i r e m e n t f o r s p e c i a l c o n t a i n m e n t l a b o r a t o r i e s r e s t r i c t s i n v e s t i g a t i o n of v i r a l p a t h o g e n e s i s .
I n g e n e r a l t e r m s i t i s a p p a r e n t t h a t many i f n o t most o f t h e HP v i r u s e s m u l t i p l y i n i t i a l l y i n l y m p h o i d t i s s u e s , a r e d i s s e m i n a t e d s y s t e m i c a l l y and may o r may n o t a t t a c k p a r a n c h y n e a l o r g a n s p a r t i c u l a r l y l i v e r , l u n g and o c c a s s i o n a l l y k i d n e y o r e v e n b r a i n . E v e n t u a l l y m i c r o c a p i l l a r y l e a k a g e w i t h e x t r a v a s a t i o n of e r y t h r o c y t e s o c c u r s , l e a d i n g t o c l i n i c a l h e m o r r h a g i c f e v e r and s h o c k . How t h i s happens i s s t i l l l a r g e l y a m y s t e r y ; p e r h a p s v i r a l d i r e c t damage t o c a p i l l a r y e p i t h e l i u m i n some c a s e s , p e r h a p s m o n o c y t e -
macrophage a c t i v a t e d k i n i n s s e c o n d a r y t o v i r a l i n f e c t i o n of t h e s e c e l l s i n o t h e r s , p e r h a p s a b l e e d i n g c a s c a d e , d i s s e m i n a t e d i n t r a v a s c u l a r c o a g u l a t i o n ( D I G ) , p r o d u c e d by l i v e r c e l l d e g r a d a t i o n p r o d u c t s i n o t h e r s . B e c a u s e a l l t h e s e d i s e a s e s r e p r e s e n t p r i m a r y v i r a l i n f e c t i o n s and b e c a u s e a l l a r e b e l i e v e d t o c o n f e r l i f e - l o n g immunity i t h a s b e e n
p o s t u l a t e d t h a t t h e y a r e n o t i n f a c t i m m u n o p a t h o l o g i c a l d i s e a s e s . L i t t l e d i r e c t e v i d e n c e , however, e x i s t s t o s u p p o r t t h i s c o n c l u s i o n , e x c e p t f o r t h e f a c t t h a t i n t h e g r e a t m a j o r i t y o f t h e VHF. V i r e m i a , w h i c h i s a h a l l m a r k o f a l l of them, g e n e r a l l y d i s a p p e a r s a t o r
b e f o r e t h e t i m e t h a t d e t e c t a b l e a n t i b o d i e s a p p e a r i n t h e c i r c u l a t i o n . T h i s p o i n t i n t h e e v o l u t i o n of t h e i n f e c t i o n , m o r e o v e r , u s u a l l y c o r r e l a t e s w e l l w i t h t e r m i n a t i o n of f e v e r and s u b s i d e n c e o f o t h e r s i g n s and symptoms.
D e s p i t e t h i s g e n e r a l l y u n s a t i s f a c t o r y summary, t h e r e h a s been s i g n i f i c a n t r e c e n t p r o g r e s s i n u n d e r s t a n d i n g t h e p a t h o g e n e s i s of s e v e r a l o f t h e VHF. S p e c i f i c e x a m p l e s
f o l l o w .
9.2.2.2 A r g e n t i n e • H a e m o r r h a g i c F e v e r (AHF)
A b o u t 20 y e a r s ago i t was p o s t u l a t e d t h a t b o t h B o l i v i a n HF and AHF were
i m m u n o s u p p r e s s i v e d i s e a s e s . T h i s s u g g e s t i o n r e s t e d on t h e r e l a t i v e l y l o n g i n t e r v a l
between t e r m i n a t i o n of a c u t e i l l n e s s and d e v e l o p m e n t o f n e u t r a l i z i n g a n t i - v i r a l a n t i b o d i e s (10-20 d a y s ) and t h e h i g h i n c i d e n c e of s e c o n d a r y b a c t e r i a l pneumonia w h i c h c h a r a c t e r i z e d b o t h s y n d r o m e s .
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 résumé ni d'aucune citation sans l'autorisation de l'Organisation mondiale de la Santé. Les opinions exprimées dans les articles signés n'engagent que leurs auteurs.
VIR/SG/83.21 page 2
I t has now been amply documented i n b o t h man and g u i n e a p i g t h a t J u n i n
v i r u s p r o d u c e s b o t h h u m o r a l and c e l l m e d i a t e d i m m u n o d e p r e s s i o n . The l a t t e r i s b o t h v i r u s s p e c i f i c and n o n - s p e c i f i c . O t h e r s t u d i e s have shown t h a t t h e r e i s complement a c t i v a t i o n b u t no a p p a r e n t c a s c a d e o f c l o t t i n g d e f e c t s , and t h e r e i s l i t t l e e v i d e n c e t o s u p p o r t t h e o c c u r r e n c e o f DIG. A l t h o u g h the p a t h o g e n e t i c t r i g g e r f o r hemorrhage and s h o c k r e m a i n s e l u s i v e , t h e s e new d a t a s u g g e s t t h a t f a t a l outcome i n AHF may c o r r e l a t e w i t h i n a b i l i t y t o
i n i t i a t e a c e l l - m e d i a t e d immune r e s p o n s e . I f t h i s were s o , and no s i g n i f i c a n t v a r i a t i o n i n v i r u s v i r u l e n c e e x i s t s , t h e n i t would seem t h a t a b o u t 15? o f p a t i e n t s have a f u n c t i o n a l d e f i c i e n c y i n t h e i r a b i l i t y t o r e s p o n d i m m u n o l o g i c a l l y t o J u n i n v i r u s .
Even more i n t e r e s t i n g , and c e r t a i n l y more i m p o r t a n t , i s t h e f a c t t h a t v i r u s - s p e c i f i c a n t i b o d i e s a d m i n i s t e r e d t o p a t i e n t s d u r i n g the f i r s t week o f i l l n e s s a r e a b l e t o r a p i d l y c l e a r v i r u s f r o m b l o o d and t o p r e v e n t d e a t h . Thus v i r u s i n c i r c u l a t i o n o r k i n i n s r e l e a s e d by i n f e c t i o n o f c e r t a i n as y e t unknown c e l l s may be the t r i g g e r ( s ) f o r h e m o r r h a g e a n d s h o c k . One must c o n c l u d e a l s o t h a t were i t n o t f o r the h u m o r a l i m m u n o s u p p r e s s i o n r e g u l a r l y i n d u c e d by J u n i n (and the r e l a t e d Machupo) v i r u s I l l n e s s i n man w o u l d be no worse t h a n a b r i e f n o n - s p e c i f i c i l l n e s s .
9.2.2.3 L a s s a f e v e r ( L F ) ( L a s s a v i r u s ) (LV)
T h i s d i s e a s e c o g e n t l y i l l u s t r a t e s t h a t h o s t r e s p o n s e s t o members o f a g i v e n v i r u s f a m i l y ( i n t h i s c a s e a r e n a v i r u s e s ) a r e n o t i d e n t i c a l . L i t t l e has y e t been done w i t h r e s p e c t t o c e l l - m e d i a t e d immunity i n L a s s a f e v e r . In a s m a l l number o f f a t a l c a s e s s k i n t e s t a n e r g y and c l e a r s u p p r e s s i o n o f c i r c u l a t i n g T - h e l p e r l y m p h o c y t e s has b e e n
d e m o n s t r a t e d . I t i s known t h a t LV r e p l i c a t e s i n v i t r o i n macrophages and i n v i v o i n l y m p h o b l a s t s o f i n f e c t e d r o d e n t s . F a i l u r e o f n o r m a l h o s t immune r e s p o n s e t o i n f e c t i o n i n p a t i e n t s w i t h s e v e r e d i s e a s e i s f u r t h e r i n d i c a t e d by the l o n g f e b r i l e c o u r s e o f i l l n e s s w i t h v i r e m i a l a s t i n g as l o n g as 3 weeks. I n d e e d , t h e amount o f v i r u s i n b l o o d t o g e t h e r w i t h t h e c o n c e n t r a t i o n o f c i r c u l a t i n g serum g l u t a m i c o x a l i c t r a n s a m i n a s e i n d i c a t i v e o f s e v e r i t y o f v i r a l i n d u c e d l i v e r damage r e l i a b l y p r e d i c t s d e a t h o r s u r v i v a l i n L F . I t i s e s t i m a t e d t h a t a b o u t 1$ o f LV human i n f e c t i o n s r e s u l t i n t h i s s e v e r e p a t t e r n o f
u n c o n t r o l l e d v i r u s r e p l i c a t i o n .
H u m o r a l a n t i b o d y r e s p o n s e t o LV i n f e c t i o n i s u n i q u e among VHF. A n t i b o d i e s a r e f o r m e d e a r l y i n c l i n i c a l d i s e a s e s u c h t h a t a b o u t >iO% o f p a t i e n t s a r e p o s i t i v e on a d m i s s i o n t o h o s p i t a l . B o t h M and G c l a s s e s a r e p r e s e n t and n e i t h e r o n s e t n o r t i t e r o f t h e s e p r o t e i n s a p p e a r t o d i f f e r i n f a t a l o r n o n - f a t a l d i s e a s e . These a n t i b o d i e s do n o t n e u t r a l i z e L V . V i r u s and a n t i b o d y a r e d e t e c t a b l e f o r s e v e r a l days i n a g i v e n s p e c i m e n w i t h o u t r e s o r t t o methods f o r d i s s o c i a t i o n o f v i r u s - a n t i b o d y c o m p l e x e s . V i r u s i s p r e c i p i t a t e d f r o m s e r u m b y a n t i - I g M b u t n o t a n t i - I g G a n t i b o d i e s i n d i c a t i n g t h a t LV i s c o a t e d w i t h n o n - n e u t r a l i z i n g and p o s s i b l y n o n - o p s i n i z i n g IgM a n t i b o d i e s . N e u t r a l i z i n g a n t i b o d i e s b e g i n t o a p p e a r a b o u t one month a f t e r o n s e t o f d i s e a s e . Q u a n t i t a t i v e e v o l u t i o n i s a s l o w p r o c e s s , ( i n c o n t r a s t t h e immune f l u o r e s c e n t n o n - n e u t r a l i z i n g a n t i b o d i e s r e a c h h i g h t i t e r by 30-50 d a y s a f t e r d i s e a s e o n s e t and d e c l i n e t h e r e a f t e r ) f r e q u e n t l y r e q u i r i n g 6 months o r more t o a c h i e v e h i g h e s t t i t e r s . I n a d d i t i o n s u c h a n t i b o d i e s a r e p o o r n e u t r a l i z e r s o f LV i n v i t r o . The c o n s t a n t s e r u m - v i r u s d i l u t i o n method y i e l d s b e s t r e s u l t s and i n d i c e s o f 10 a r e r e a c h e d
o n l y by a m i n o r i t y o f LF p a t i e n t s . "
A b a s i c a l l y s i m i l a r p a t t e r n i s o b s e r v e d f o l l o w i n g i n f e c t i o n o f r h e s u s monkeys o r
g u i n e a p i g s , b u t t h o s e a n i m a l s w h i c h s u r v i v e a c u t e i n f e c t i o n a c h i e v e n e u t r a l i z i n g a n t i b o d y t i t e r s o f a b o u t 10^ a t 6 months p o s t - i n o c u l a t i o n . I n t h e s e models r e a s o n a b l e d o s e s o f s u c h a n t i b o d i e s were f o u n d c a p a b l e o f p r e v e n t i n g d e a t h i n cynomolgous monkeys and s t r a i n 13 i n b r e d g u i n e a p i g s w h i c h o t h e r w i s e u n i f o r m l y succumb. T r e a t m e n t was s u c c e s s f u l when s t a r t e d 4 d a y s a f t e r i n f e c t i o n . T i t r a t i o n o f t h e s e a n t i b o d i e s r e v e a l e d t h a t on i n d e x o f
VIR/SG/83/21 page 3
10 ' was r e q u i r e d f o r e f f e c t i v e n e s s . Human p l a s m a s do n o t c o n t a i n t h i s much a n t i b o d y , b u t c o n c e n t r a t i o n o f s u c h m a t e r i a l p e r m i t t e d e s t a b l i s h m e n t o f a v i r t u a l l y e q u a l
t h e r a p e u t i c i n d e x i n g u i n e a p i g s .
These e x p e r i m e n t a l d a t a a r e c o m p a t i b l e w i t h r e s u l t s o f c o n t r o l l e d t r i a l s o f human p l a s m a i n t r e a t m e n t o f LF i n S i e r r a Leone. The f a t a l c o u r s e o f i l l n e s s i n p a t i e n t s a d m i t t e d w i t h h i g h v i r e m i a and m a j o r e l e v a t i o n o f SCOT was u n a f f e c t e d by s u c h t r e a t m e n t , and v i r e m i a was n o t r e d u c e d . In c o n t r a s t , p a t i e n t s w i t h l e s s e r v i r e m i a and h e p a t i t i s f r e q u e n t l y t e r m i n a t e d v i r e m i a i m m e d i a t e l y a f t e r r e c e i v i n g p l a s m a , a l t h o u g h a v e r a g e h o s p i t a l s t a y was n o t r e d u c e d . I t i s b e l i e v e d t h a t s u c h p a t i e n t s w o u l d n o t have d i e d i n any c a s e .
T a k e n t o g e t h e r t h e s e new f a c t s p e r h a p s e x p l a i n why p a s s i v e a n t i b o d y t h e r a p y f o r LF has had m i x e d r e s u l t s . T h e r e a r e c l e a r l y two s e t s o f h o s p i t a l i z e d p a t i e n t s and t h e r e a r e now o b j e c t i v e c r i t e r i a f o r t h e i r r e c o g n i t i o n . A v a i l a b l e a n t i b o d i e s a r e i n s u f f i c i e n t t o t r e a t t h e f a t a l s e t . A n o t h e r l e s s o n t o be r e l e a r n e d , and i t may have s p e c i f i c v a l u e f o r o t h e r HF, i s t h a t t h e g o a l i s t o a d m i n i s t e r a known amont o f v i r u s n e u t r a l i z i n g a n t i b o d i e s , n o t s i m p l y " p l a s m a . "
9.2.2.1» R i f t V a l l e y F e v e r
T h r e e c o m p l i c a t i o n s o f o t h e r w i s e b e n i g n f e b r i l e RVF have now been r e c o g n i z e d ; v a s c u l a r r e t i n i t i s , e n c e p h a l i t i s , and h e m o r r h a g i c f e v e r . The p a t h o g e n e s i s o f t h e s e phenomena r e m a i n s u n c l e a r . The t r u e i n c i d e n c e o f each syndrome i s a l s o n o t known a l t h o u g h l e s s t h a n 5 p e r c e n t o f i n f e c t i o n s p r o d u c e s r e t i n i t i s and p r o b a b l y l e s s t h a n 1 i n 1000 RVFV
i n f e c t i o n s l e a d s t o the more s e v e r e c o m p l i c a t i o n s . I n t e r e s t i n g l y , no p a t i e n t s have been o b s e r v e d t o have more t h a n one o f t h i s t r i a d o f t r o u b l e s .
The i n c u b a t i o n p e r i o d o f RVF i s s h o r t 3-6 d a y s , and i n f e c t i o n may o c c u r by a r t h r o p o d b i t e , d i r e c t c o n t a c t w i t h b l o o d o r c a r c a s s o f a n i m a l s , o r by a e r o s o l . H i g h v i r e m i a (10 - 10 /ml) i s t h e r u l e b u t p e r s i s t s o n l y 3-5 d a y s i n most c a s e s . R e t i n i t i s becomes
s y m p t o m a t i c 1-2 weeks l a t e r as a r u l e , and t h e r e i s a l s o a " l a t e n t " p e r i o d w i t h o u t v i r e m i a p r i o r t o t h e o n s e t o f c l i n i c a l e n c e p h a l i t i s . H i g h t i t e r s o f v i r u s - s p e c i f i c a n t i b o d i e s i n c e r e b r o s p i n a l f l u i d s o f s u c h p a t i e n t s document v i r u s r e p l i c a t i o n i n t h e b r a i n , b u t shed no l i g h t on how and when the v i r u s r e a c h e s t h i s o r g a n . The HF c o m p l i c a t i o n i n c o n t r a s t
u s u a l l y o c c u r s t o w a r d t h e end o f t h e f e b r i l e - v i r e m i a p h a s e o f i l l n e s s . T h e r e i s s e v e r e h e p a t i t i s w i t h c l i n i c a l j a u n d i c e , p e r s i s t e n t v i r e m i a , s o m e t i m e s i n t h e p r e s e n c e o f a n t i b o d i e s . H e m o r r h a g i c phenomena a r e g r a v e s i g n s and m o r t a l i t y i n t h i s syndrome i s e x t r e m e l y h i g h . W h a t e v e r , t h e p a t h o g e n e t i c m e c h a n i s m s , t h e v e r y low f r e q u e n c y o f o c c u r r e n c e o f c o m p l i c a t i o n s s u g g e s t s t h a t human g e n e t i c f a c t o r s a r e most l i k e l y t h e p r i n c i p a l d e t e r m i n a n t s o f i l l n e s s .
Such a p a t t e r n has now been documented f o r e x p e r i m e n t a l RVFV i n f e c t i o n u s i n g i n b r e d r a t s . W i s t a r - F u r t h r a t s a r e h i g h l y s e n s i t i v e t o t h e v i r u s and d i e w i t h f u l m i n a n t h e p a t i t i s w i t h i n 5 d a y s o f r e c e i v i n g a s l i t t l e as 3 p l a q u e u n i t s ( P U ) . L e w i s r a t s i n c o n t r a s t a r e c l i n i c a l l y r e s i s t a n t t o more t h a n 10 PU, w h i l e Maxx s t r a i n r a t s e x h i b i t e d a p a t t e r n o f s i l e n t o r l a t e e n c e p h a l i t i c i n f e c t i o n . R e s i s t a n c e t o l e t h a l h e p a t i c
n e c r o t i z i n g i n f e c t i o n was found t o s e g r e g a t e as a s i n g l e a u t o s o m a l d o m i n a n t g e n e t i c t r a i t . F u r t h e r m o r e , i t has been l e a r n e d t h a t macrophages f r o m r e s i s t a n t L e w i s r a t s a r e h i g h l y s e n s i t i v e t o i n t e r f e r o n w i t h t h e r e s u l t t h a t v i r u s r e p l i c a t i o n i n t h e s e c e l l s i s r e s t r i c t e d as compared t o macrophages f r o m W i s t a r - F u r t h r a t s . B e c a u s e the h e m o r r h a g i c f o r m o f RVF o c c u r s a f t e r o n l y a b r i e f e p i s o d e o f f e v e r and a p p e a r s t o r e s u l t from d i r e c t a t t a c k by v i r u s r e p l i c a t i n g a t a v e r y h i g h r a t e , i t i s r e a s o n a b l e t o s p e c u l a t e t h a t macrophage f u n c t i o n r a t h e r t h a n immune r e s p o n s e may w e l l r e p r e s e n t t h e c r i t i c a l e v e n t i n
VIR/SG/83.21 page 4
d e t e r m i n i n g the outcome o f i n f e c t i o n . Human p o p u l a t i o n s t u d i e s t o d e t e r m i n e p a t t e r n s o f r e s p o n s e o f c i r c u l a t i n g m o n o c y t e s t o i n t e r f e r o n and RVFV m i g h t p r o v e r e w a r d i n g .
9.2.2.5 H e m o r r h a g i c F e v e r w i t h R e n a l Syndrome (HFRS) and N e p h r o p a t h i c E p i d e m i c a (NE) The p a t h o g e n e s i s o f t h e s e d i s e a s e s i s f a r from u n d e r s t o o d . B u t the r e c e n t i s o l a t i o n o f t h e i r i m m u n o l o g i c a l l y r e l a t e d c a u s a t i v e v i r u s e s and t h e d e v e l o p m e n t o f a s s a y s f o r v i r u s - s p e c i f i c a n t i b o d i e s now p e r m i t work t o b e g i n on t h i s p r o b l e m . A c u t e r e n a l i n t e r s t i t i a l n e p h r i t i s , sometimes w i t h c o m p l e t e f u n c t i o n a l shutdown i s a m a j o r and r e l a t i v e l y l a t e m a n i f e s t a t i o n o f t h e s e d i s e a s e s . I s the l e s i o n i n d u c e d by a n t i g e n -
a n t i b o d y c o m p l e x e s ? As y e t t h e r e i s no answer b u t i t seems p o s s i b l e . I r a m u n o f l u o r e s c e n t and n e u t r a l i z i n g a n t i b o d i e s a r e found i n s e r a o f most p a t i e n t s e a r l y i n t h e f e b r i l e p h a s e o f i l l n e s s and i n c r e a s e s t e a d i l y f o r a b o u t 30 d a y s . Indeed i t has p r o v e n v e r y d i f f i c u l t t o r e c o v e r v i r u s f r o m a c u t e b l o o d specimens when p a t i e n t s e n t e r h o s p i t a l . A n t i b o d i e s a l s p e r s i s t f o r d e c a d e s a f t e r i n f e c t i o n , sometimes i n s u r p r i s i n g l y h i g h t i t e r s , and some ° p a t i e n t s show s i g n i f i c a n t i n c r e a s e s i n t i t e r s d u r i n g the i n t e r v a l o f 2 and 12 months a f t e i l l n e s s . F i n a l l y c i r c u l a t i n g a n t i g e n - a n t i b o d y c o m p l e x e s o f u n c e r t a i n s p e c i f i c i t y h a v e been found i n NE p a t i e n t s ; p e r s i s t e n t w e l l b e l o w the phase o f a c u t e i l l n e s s .
P r o g r e s s i n u n d e r s t a n d i n g t h e s e f a s c i n a t i n g p a t h o g e n s w i l l come most q u i c k l y i f a s u i t a b l e a n i m a l model can. be f o u n d . Sub-human p r i m a t e s a r e c u r r e n t l y u n d e r i n v e s t i g a t i o n 9.2.2.5 Y e l l o w F e v e r V i r u s (YFV)
D e s p i t e i t s v e n e r a b l e s t a t u s a s t h e o l d e s t o f the HF a g e n t s t h e r e r e m a i n s much t o
l e a r n c o n c e r n i n g p a t h o g e n e s i s o f t h i s v i r u s . I t has l o n g been known t h a t d e a t h due t o YFV i n f e c t i o n i s l a r g e l y a t t r i b u t a b l e t o e i t h e r an e a r l y f u l m i n a t i n g HF syndrome w i t h
h e p a t i t i s and c l i n i c a l j a u n d i c e o r t o a l a t e r e n a l t u b u l a r l e s i o n w i t h r e n a l i n s u f f i c l G n r e m i n i s c e n t o f t h a t seen i n HFRS.
Recent s t u d i e s i n r h e s u s monkeys d e m o n s t r a t e t h a t h i g h v i r e m i a and m a j o r h e p a t i t i s somehow r a p i d l y l e a d t o s e v e r e a c i d o s i s , h y p e r k a l e m i a , r e n a l i n s u f f i c i e n c y , and
h y p o t e n s i o n , the s o - c a l l e d h e p a t o - r e n a l syndrome. The t i m e c o u r s e o f monkey i n f e c t i o n i s compressed as compared t o t h a t o b s e r v e d i n human YF, t h u s c a s t i n g some d o u b t as t o w h e t h e
t h i s model t e l l s the e n t i r e s t o r y . F o r example t h e r e a r e v i r t u a l l y no d a t a on ^ q u a n t i t a t i v e e v o l u t i o n o f v i r e m j a i n YF. I n one f a t a l human c a s e d a i l y t i t r a t i o n s done i n
c e l l c u l t u r e s r e v e a l e d a b o u t 10 i n f e c t i o u s u n i t s / m l u n t i l t h e day o f d e a t h when t h e r e wa an a b r u p t d r o p t o 10 • S i m u l t a n e o u s measurement i n m o s q u i t o e s , h o w e v e r , showed t h a t a l l ^ s p e c i m e n s c o n t a i n e d =10 i n f e c t i o u s u n i t s . T h i s i s t a k e n as e v i d e n c e t h a t a n t i g e n -
a n t i b o d y c o m p l e x e s were formed d u r i n g t h e l a s t day o f U f e , and i t was f u r t h e r f o u n d t h a t t h e p a t i e n t ' s serum had s m a l l amounts o f n e u t r a l i z i n g a n t i b o d y a t the t i m e o f d e a t h .
H i s t o l o g i c a l l e s i o n s i n t h e l i v e r o f t h e Y F V - i n f e c t e d monkey were n o t o b s e r v e d u n t i l t h e day o f d e a t h . C o u l d i t be t h a t n e c r o s i s was m a s s i v e l y i n d u c e d by complement d e p e n d e n t immune c y t o l y s i s o f i n f e c t e d c e l l s h a v i n g v i r u s s p e c i f i c membrane a n t i g e n s a t t h e t i m e o f i n i t i a l a n t i b o d y r e s p o n s e ? And would s u c h an e v e n t l e a d t o r e n a l t u b u l a r d i s e a s e i f t h e l i v e r i n s u l t were somehow s u r v i v e d ? These a r e w o r t h w h i l e q u e s t i o n s b e c a u s e d e s p i t e t h e e x i s t e n c e o f YF v a c c i n e , d e s p i t e t h e new p h y s i o l o g i c k n o w l e d g e g a i n e d from e x p e r i m e n t a l work, p e o p l e s t i l l d i e from YF. What i s newly r e l e v a n t i s w h e t h e r c r n o t p a s s i v e
a n t i b o d i e s m i g h t be e f f e c t i v e i n t r e a t m e n t o f the d i s e a s e . Work done h a l f a c e n t u r y ago g a v e a n e g a t i v e v e r d i c t , b u t e x a m i n a t i o n o f t h o s e r e p o r t s r e v e a l s t h a t o n l y t r i f l i n g amounts o f a n t i b o d y were a d m i n i s t e r e d . I n the l i g h t o f d e v e l o p m e n t s w i t h o t h e r HF t h i s p r o b l e m s h o u l d be r e e x a m i n e d . S e a r c h f o r a v i r u s s t r a i n - h o s t c o m b i n a t i o n w h i c h s i m u l a t e s the c o u r s e o f human i n f e c t i o n i s i n d i c a t e d .
