OF CLINICAL ASPECTS
P. D. Marsden and R.R. Nonata*
IN T R O D U C T IO N
In 1 9 1 0 G a s p a r V ia n n a su gg este d a t a c o n fe re n c e in B e lo H o r iz o n te t h a t a n tim o n ia l th e r a p y w as e ffe c tiv e in th e tr e a tm e n t o f m u c o c u ta n e o u s le is h m a n ia s is a n d th is p ro v e d t o be th e case9 8 . In 1 9 2 6 , M o n te n e g ro e v a lu a te d a s k in te s t a n tig e n w h ic h is o f d ia g n o s tic v a lu e . I t is s o m e m e a su re o f th e s lo w d e v e lo p m e n t o f c lin ic a i re a sea rc h in th is im p o r ta n t h u m a n in f e c tio n t h a t to d a y b o th th e se d is c o v e rie s are s t ill b e in g a p p lie d as s ta n d a rd p ra c tic e a n d s t ill th e la b o r a to r y d ia g n o s is a n d tr e a tm e n t is fa r f r o m s a tis fa c to r y .
W e h ave w r it t e n th is re v ie w because in o u r c lin ic a i w o r k w e h a v e b e e n in d o u b ts o m e tim e s a b o u t w h a t is th e b e s t lin e o f m a n a g e m e n t f o r o u r p a tie n ts . T u r n in g t o th e lite r a tu r e w e d id n o t a lw a y s f in d th e a n s w e r t o o u r q u e s tio n s . T h is is, as th e t i t l e suggests, a re v ie w c o n c e m e d w it h th e p a tie n ts s id e o f th e p ro b le m a n d f o r th is rea son b e g in s w it h th e c lin ic a lly im p o r ta n t aspects. L a te r o n w e d is c iis s th e rele va n ce o f s o m e r e c e n t b io m e d ic a l re se arch t o o u r u n d e r s ta n d in g o f h o w th is in f e c tio n behaves in m a n .
C L I N I C A L F E A T U R E S
T h e le s io n s o f M u c o c u ta n e o u s le is h m a n ia s is are p o ly m o r p h ic a n d c a n c lo s e ly re s e m b le m a n y o th e r s k in diseases. T h is has ie d t o a n u m b e r o f c la s s ific a tio n s o f s k in a n d m u c o u s m e m b ra n e le s io n s b y d if f e r e n t w o rk e rs . F o r e x a m p le . A z u la y 5 in h is th e s is in 1 9 5 2 lis ts e ig h t c la s s ific a tio n s . A lth o u g h th e se c la s s ific a tio n s have v a lu e th e y h a v e b e c o m e e x tr a o r d in a r y c o m p le x a n d s in c e th e y are la rg e ly d e s c rip tiv e i t is n a tu ra l t o s e arc h f o r a s im p le r o n e .
W e sh all use a s im p le c la s s ific a tio n in th is d is c u s s io n . T h e s k in le s io n s w ill .be c o n s id e re d u n d e r th e g e n era l h e a d in g s o f c lo s e d a nd o p e n s in ce th e u su a l e v o lu tio n is f r o m a c lo s e d le sio n t o an o p e n u lc e ra te d o n e . F o r m u c o s a l le sio n s w e w ill use th e th re e e v o lu tio n a r y stages d e s c rib e d b y K lo tz e L in d e n b e rg 6 0 , n a m e ly (1) n o d u la t io n w it h o u t u lc e r a tio n ; (2 ) E a rly u lc e r a tio n a n d (3 ) L a te u lc e ra tio n .
A m a rk e d fe a tu re o f b o th o u r c lin ic a i o b s e rv a tio n s a n d th o s e in th e lite r a tu r e as reg a rd s th ese le s io n s is th e e x tre m e v a r ia b ility in th e c o u rs e o f th e disease. F o r e x a m p le in s o m e p a tie n ts severe m u c o s a l d am ag e appears r e la tiv e ly e a rly a n d c h ild re n m a y p re s e n t irr e p a ra b le fa c ia l d am ag e. O th e r p a tie n ts give a h is to r y o f a m in o r s k in le s io n m a n y years b e fo re th e o n s e t o f m u c o u s m e m b ra n e in v o lv e m e n t a n d y e t o th e rs o n ly h ave a m in o r s k in le s io n . H o s t im m u n it y a n d th e ty p e o f p a ra s ite p r o b a b ly p la y s an im p o r ta n t p a r t in th is a n d th e l i t t l e w e k n o w a b o u t th is s u b je c t is m e n tio n e d in o u r s u b s e q u e n t d is c u s s io n .
C U T A N E O U S L E S IO N S C L O S E D L E S IO N S
T h e s ite o f th e b ite o f th e s a n d fly is g e n e ra lly re g a rd e d as th e s ite o f th e in itia l le s io n . T h e fr e q u e n c y w it h w h ic h in n o c u la tio n o f p ro m a s tig o te s b y s a n d flie s p ro d u c e s a le sio n is n o t k n o w n . D e te r m in in g fa c to rs m a y in c lu d e th e n u m b e r o f fla g e lla te s in n o c u la te d , th e s tra in o f L e is h m a n ia a n d th e p re v io u s im m u n o lo g ic a l e x p e rie n c e a n d g e n e tic m a k e u p o f th e h o s t. Q u ite fr e q u e n tly p a tie n ts are seen w it h m u ltip le e a rly le s io n s a li a b o u t th e sam e stage a n d thes e p ro b a b ly re p re s e n t th e b ite s o f several in fe c te d s a n d flie s .
* University of
Brasília, Brazil
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L ik e K a la A z a r th e in c u b a tio n p e rio d m u s t b e v e r y v a r i a b l e . L a in s o n ( p e r s o n a l c o m m u n ic a tio n ) has w e ll d o c u m e n te d e v id e n c e i t m a y be as s h o r t as 1 5 d a y s. A z u la y and S a lga do , in 1 9 6 6 8 , n o te d 1 8 — 3 3 d a y s in p a ra tro o p e rs d ro p p e d in t o th e A m a z o n ia n fo re s t. G u im a rã e s, in 1 9 5 5 S 3 , c a lc u la te d th e average in c u b a tio n p e rio d in a fie ld " s tu d y as b e in g a b o u t 2 m o n th s .
I f a le s io n d o e s d e v e lo p i t in it ia lly ta k e s th e f o r m o f a n e ry th e m a to u s m a c u le w h ic h d e v e lo p s in t o a p a p u le a n d th e n g ro w s in t o a n o d u le . T h e s ite o f th e le s io n s is m o s t fr e q u e n tly th e lim b s o r fa c e p r o b a b ly because th e y are m o s t fr e q u e n tly e x p o s e d . In C e n tra l A m e ric a lesions o f th e p in n a o f th e e a r caused b y L eish m a nia m e x ic a n a are v e ry c o m m o n 1 2 .
T h e se le sio n s c a n ta k e a v a r ie ty o f fo r m s a n d m a y re s e m b le o th e r in fe c tio n s . T h e y c an be lis te d a s .fo llo w s :
1) P apules w it h a p u s tu la r e le m e n t — a ra re f o r m w h ic h c o u ld be c o n fu s e d w it h im p e tig o — th e r e fo r e c a lle d im p e tig in o u s .
2) F o llic u la r p a p u le s th e in d u r a tio n b e in g a t th e s ite o f th e f o llic le s .
3) A s m a ll fu r u n c u la r lik e n o d u le — has t o be d is tin g u is h e d f r o m a s im p le b o il o r a D e rm a to b ia h o m in is in fe c tio n .
4 ) D is c re e t n o d u le s m u ltip le a n d v a ria b le in size s o m e tim e s d i f f i c u l t t o d iffe r e n tia te o n s ig h t f r o m s k in tu b e rc u lo s is , s a rc o id o r le p ro s y . T he se are p ro b a b ly th e r e s u lt o f b lo o d s tre a m d i s s e m i n a t io n a n d h a v e b ee n te rm e d le is h m a n id s " a lth o u g h th is te r m has a ls o b een a p p lie d t o lic h e n o id , h y p o c h r o m ic le sio n s a p p e a rin g m a n y y e a rs a f t e r t h e in ití a l in f e c tio n . S u ch le s io n s h ave a tu b e r c u lo id h is to lo g y o fte n w it h o u t p a ra site s4 9 . S o m e tim e s o n a s m a lle r scale th e y m a y re s e m b le th e a p p le je lly n o d u le s o f lu p u s v u lg a ris (m o re c o m m o n in L. tro p ic a ) o r g iv e ris e t o a d iffu s e in f il t r a t io n w it h a rais ed m a rg in re s e m b lin g th e le s io n o f t u b e r c u lo id le p ro s y .
5) H y p e r k e r a to tic le s io n s — s u c h le s io n s w it h a h is to lo g ic a l a p p e a ra n c e o f m a rk e d e p ith e lia l a c tiv a tio n c a n p ro d u c e p a p illo m a to u s le sio n s re s e m b lin g th e fr a m b o e s ia o f s e c o n d a ry y a w s . C o n d y lo m e ty p e le s io n s as w e ll c a n be c o n fu s e d w it h th e tre p o n e m a to s e s . V e rru c o s e g r a n u l o m a t o u s le s io n s m a y r e s e m b le h is to p la s m o s is o r c h ro m o b la s to m y c o s is .
M a n y o f th e s e fo r m s a re u n c o m m o n a n d are p re s u m e a b ly g o v e rn e d b y th e tis s u e r e a c tio n t o th e in v a d in g p a ra s ite . T h e h is to p a to lo g y has b e e n s t u d i e d b y s e v e r a l g r o u p s o f
w o r k e r s 6 , S8, 1 s . a n d is e s s e n tia lly a p a ra s ite g ra n u lo m a o f th e d e rm is w it h s e c o n d a ry c h an ge s in th e e p id e rm is . T h e s e q u e n c e b y w h ic h in n o c u la te d p ro m a s tig o te s re s u lt in in tr a c e llu la r a m a s tig o te s in tis s u e m a cro p h a g e s has n o t b een d ir e c t ly o b s e rv e d in th e d e rm is . I t is n o t c le a r w h e th e r p ro m a s tig o te s p e n e tra te tis s u e ce lls o r w h e th e r th e y r o u n d u p t o f o r m a m a s tig o te s w h ic h a re th e n e h g u lfe d b y m a cro p h a g e s .
T h e in it ia l h is to lo g y c o n s is ts o f p a ra s itis e d m a cro p h a g e s a n d u n d iffe r e n tia te d h is tio c y te s . A f t e r a v a ria b le p e r io d ly m p h o c y te s a p p e a r in d ic a tin g th e a p p e a ra n c e o f a c e ll m e d ia te d im m u n e resp on se . T h e in t e n s it y o f th is re sp on se va ries g re a tly a n d is a m a jo r fa c to r in flu e n c in g th e c h r o n ic it y o f th e le s io n . U s u a lly th e ly m p h o c y t ic i n f ilt r a t io n b e c o m e s in te n s e w it h a s s o c ia te d p la sm a c e lls a n d e o s in o p h ils . A c tu a l in tra d e rm a l m ic r o abscess f o r m a tio n ca n o c c u r w it h p o ly m o rp -h in v a s io n . In c h r o n ic le s io n s w e ll d e fin e d g ra n u lo m a s w it h g ia n t c e lls m a y b e e n c o u n te d . V a s c u la r le s io n are a lso im p o r ta n t w it h e n d a r te ritis a n d n e w vessel f o r m a tio n . F ib r in o id n e cro sis o f v e n u le s w as re g a rd e d b y B itt e n c o u r t a n d A n d r a d e 1 5 t o be a p a r t o f w h a t th e y c o n s id e re d t o be a h is to lo g ic a l p ic tu r e s u g g e s tin g a h y p e r s e n s itiv ity re a c tio n . T h e e p id e rm is m a y s h o w irre g u la r a c a n th o s is , p s e u d o e p ith e lio m a to u s h y p e rp la s ia , h y p e rk e ra to s is , p a ra k e ra to s is , k e ra tin p lu g s o r p a r tia l a tr o p h y . O n o c c a s io n h y p e rp la s ia m a y be s o m a rk e d as t o s ugg est c a rc in o m a .
D iffu s e in d u r a tio n o f th e d e rm is w it h lit t l e a p p a r e n t s u rfa c e s k in le s io n h ave b een d e s c r ib e d . L y m p h g la n d e n la rg e m e n t is c o m m o n , u s u a lly in p r im a r y n o d e s d r a in in g th e s ite o f th e le s io n . S in c e s p re a d b y th e ly m p h a tic s t o th e c ir c u la tio n is b e lie v e d t o be th e m e th o d o f d is s e m in a tio n , s u c h e n la rg e m e n t is n o t s u p ris in g e ve n in c lo s e d le sio n s. In o p e n le sio n s s e c o n d a ry b a c te ria l in f e c tio n p la y s an im p o r ta n t ro le .
T h e ly m p h g la n d h is to lo g y e x ib its th e sam e b as ic processes a lr e a d y d e s c rib e d in th e s k in le s io n s . A n in it ia l le u c o c y tic in f ilt r a t io n is r a p id ly f o llo w e d b y a m a rk e d c e llu la r a c tiv a tio n o f ly m p h o c y te s , p la sm a c e lls a n d h is tio c y te s . O fte n le is h m a n ia c a n b e seen in th e la tte r . G ia n t c e lls a re less c o m m o n th a n in s k in le s io n s b u t w e ll d e fin e d tu b e r c u lo id g ra n u lo m a s m a y b e p re s e n t a n d th e se m a y e v en g o o n t o c a s e a tio n .
te g u m e n ta ria d iffu s a ) w h ic h is u s u a lly a c lo s e d ty p e o f le s io n a n d o n ly r a r e ly u lc e ra te s . T h e le s io n s ta k e th e f o r m o f e ry th e m a to u s n o d u le s w h ic h c lo s e ly res e m b le le p ro m a to u s le p ro s y b o th in th e ir in d iv id u a l a p p e a ra n c e a n d th e ir s y m m e tr ic a l d is t r ib u t io n w it h p r o m in e n t ear in v o lv e m e n t. F o r th is re a so n p a tie n ts o f d iffu s e c u ta n e o u s le is h m a n ia s is have b een in te rn e d in le p ro s a ria . S im ila r ear lo b e n o d u la tio n is a lso seen in L o b o 's K e lo id a l m y c o s is 9 6 . H is to lo g y s h o w s h is tio c y te s r ic h in le is h m a n ia w it h lit t le ly m p h o c y tic in f ilt r a t io n . T h e M o n te n e g ro te s t is n e g a tiv e . U s u a lly th e se p a tie n ts d o n o t r e s p o n d t o tr e a tm e n t b u t i f th e y d o ly m p h o c y tic in f ilt r a t io n o f th e s k in le s io n has b een n o te d t o b e g in a n d M o n te n e g ro te s t has c o n v e rte d in so m e in s ta n c e s f r o m n e g a tiv e t o p o s itiv e . T h e s ig n ific a n c e o f th is ra re f o r m o f le is h m a n ia s is is d is c us se d la te r .
O P E N L E S IO N S
T h e p ro cess o f u lc e r a tio n is p r o b a b ly d e p e n d a n t o n s u c h fa c to r s as tis s u e o e d e m a , fo c i o f n e c ro s is in areas o f h e a v y in f la m m a to r y c e ll in f ilt r a t io n a n d v a s c u la r o c c lu s io n d u e t o e n d a r te ritis . U lc e r a tio n is th e u su a l se qu ei t o t h e d e rm a l in f ilt r a t io n a n d u s u a lly th e u lc e r is s m a ll w it h a s u rfa c e c r u s t. H o w e v e r s u c h u lc e rs m a y b e la rge , m u ltip le a n d severe. In a n a n a ly s is o f 1 8 4 p a tie n ts in V ila Q u e ir o z S ão P a u lo S ta te Pessoa a n d B a r r e to 81 fo u n d a s in g le u lc e r in 4 6 .8 % , t w o in 2 5 ,7 % , 3 in 9 .7 % a n d in 6 .6 % m u ltip le u lc e rs u p t o 9 w e re seen in s m a lle r n u m b e rs o f p a tie n ts .
In h o s p ita l se ries th e p r o p o r t io n o f p a tie n ts w it h u lc e ra te d le s io n s is h ig h 97 p ro b a b ly because p a tie n ts o n ly p re s e n te d a t a r e la tiv e ly la te stage.
T h o u g h th e size , s ite a n d c o n fig u r a tio n o f th e u lc e r is v a ria b le i t o f t e n has a c h a r a c te r is tic m a r g i n . T h is is in f ilt r a t e d , ra is e d a n d e ry th e m a to u s . In fo r e s t y a w s (p ia n b o is ) f o r in s ta n c e th e le s io n iis c le a r ly p u n c h e d o u t w it h s te e p s ide s a n d b ecause o f th is c a n be c o n fu s e d w it h th e t e r t ia r y s ta ge o f a tre p o n e m a to s is . U lc e rs m a y a ls o re s e m b le th o s e o f v a ric o s e (stasis) u lc e rs , t r o p ic a l u lc e r a s s o c ia te d w it h v in c e n ts o rg a n is m s , a n d v è ld s o re (c u ta n e o u s d ip h th e r ia ) . A n e p id e r m o id o r basal c e ll c a rc in o m a m a y m im ic c u ta n e o u s le is h m a n ia s is .
O c c a s io n a lly le is h m a n ia l u lc e rs m a y f o l lo w th e lin e o f th e ly m p h a tic d ra in a g e a n d re s e m b le s p o ro tr ic h o s is . S o m e s k in u lc e rs c a n p e rs is t f o r y e a rs a n d b e c o m e larg e d e e p a n d f ib r o t ic . A t h is stage t h e y m a y re s e m b le B u r u li u lc e r
(M y c o ò a c te riu m u lce ra n s in fe c tio n ) . T h is e n tity has y e t t o be r e p o rte d in B ra z il b u t th e o v e rh a n g in g edge o f s k in so c h a ra c te ris tic o f B u r u li u lc e r is n o t a fe a tu re o f su c h le is h m a n ia l u lc e rs . A s c ro fu la lik e le s io n , s h o u ld be d is tin g u is h e d f r o m tr u e tu b e rc u lo u s s c ro fu la o r a c tin o m y c o s is .
M U C O S A L L E S IO N S
A v a rie ty o f m u c o u s m e m b ra n e s m a y be a ffe c te d . Pessoa a n d B a rre to , in 1 9 4 8 8 1 , s u m m a ris in g B a rbo s a's larg e series p r o d u c e s th e fo llo w in g in c id e n c e fig u re s — N asal lesions, 1 7 9 0 p a tie n te s ; b u c c a l le sio n s, 2 0 9 ; p h a ry n g e a l, 1 7 0 a n d la ry n g e a l, 5 0 . R a re r site s in c lu d e th e c o n ju n c tiv a a n d g e n ita ls . T h e o v e r a li in c id e n c e o f m u c o s a l in v o lv e m e n t in d if f e r e n t series varies w id e ly a n d A z u la y 5 c ite s 7 s ources w it h p e rce n ta g e s v a ry in g f r o m 8 % — 8 0 .9 % . S in ce th e nasal area is b y fa r th e m o s t c o m m o n ly a ffe c te d th e f o llo w in g d is c u s s io n re la te s t o th is s ite . S p e c ific c o m p lic a tio n s a t o th e r sites are c o n s id e re d la te r.
1 — N o d u l a t i o n w ith o u t u lc e ra tio n — T h e s e p tu m o f th e nose is th e c o m m o n e s t s ite f o r th is le s io n w h ic h m a y be v e ry s m a ll. I t m a y a lso o c c u r o n th e in f e r io r tu r b in a te s 5 6 . Because o f th is i t is e s s e n tia l t h a t e v e ry p a tie n t have a c a re fu l e x a m in a tio n o f th e nose o r m o u th o th e rw is e a s ig n ific a n t c o m p lic a tio n m a y be m isse d. V ille la e t a / 1 0 3 e n c o u n te re d le is h m a n ia in a p p a r e n tly n o r m a l nasal m u co sa o f p a tie n ts a n d i t is lik e ly t h a t i f a phase o f b lo o d s tre a m d is s e m in a tio n o c c u rs d u r in g th e c o u rs e o f th e disease o rg a n is m s re a ch th e nose w h e re th e y th e n lie d o r m a n t. T h is a sp e c t is fu r t h e r d isc u s s ed in th e la s t s e c tio n . W a lto n e t a/ 1 07 r e c o rd th e o n s e t o f m u c o s a l le sio n s in 4 p a tie n ts r e s id in g in a n o n e n d e m ic area f o r 1 1 , 1 8 , 1 9 a n d 2 4 y e a rs re s p e c tiv e ly b e fo re th e a p p e a ra n c e o f m u c o s a l disease. T h e m u c o s a 1 g ra n u lo m a m a y n o t be w e ll d e fin e d b u t ju s t ta k e th e f o r m o f a d iffu s e in f ilt r a t io n . F ra n k p o ly p s m a y o c c u r 69 w h ic h h ave t o be d i f f e r e n t i a t e d f r o m !b e n ig n p o ly p s o r r h i n o s p o r i d o s i s . P a tie n ts o f t e n p re s e n t c o m p la in in g o f n asa l o b s tr u c tio n . T h e le s io n m a y b e e n t ir e ly in tra n a s a l.
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a g e n e ra lise d in f ilt r a t io n o f th e n ose w h ic h m a y be e ry th e m a to u s a n d s u c c u le n t in a p p e a ra n c e . T h e d if fe r e n tia l d ia g n o s is h e re in c lu d e s le p ro s y a n d G c u n d o u o f s e c o n d a ry y a w s . A c o m b in a tio n o f th e se processes m a y g iv e rise t o a b ro a d d r o o p in g nose, th e so c a lle d ta p ir nose.
L a te u lc e ra tio n — T he se a d v a n c e d cases p re s e n t w it h m a rk e d tis s u e loss o fte n c a u s in g h id e o u s fa c ia l d is t o r tio n . T h e nose m a y be t o t a ll y lo s t a n d th e p a tie n t p re s e n t w it h a r o u g h ly c ir c u la r h o le m a k in g th e nasal passages a n d m o u th a c o m m o n c a v ity . T h e d if fe r e n tia l d ia g n o s is in c lu d e s tra u m a , gangosa ( t e r t ia r y y a w s ), le th a l m id lin e g ra n u lo m a a n d a la rg e basal c e ll c a rc in o m a . T h e a d v a n c in g b o r d e r o f th e le s io n m a y th re a te n th e lo w e r e y e lid s a n d i f th is is th e case n o tim e s h o u ld be lo s t in in s t it u tin g v ig o ro u s tr e a tm e n t.
O n e disease, a g a in p e rc u lia r t o S o u th A m e ric a w h ic h has n o t b ee n m e n tio n e d b u t w h ic h e n te rs in t o e v e ry d if fe r e n tia l d ia g n o s is o f m u c o sa l le is h m a n ia s is is S o u th A m e ric a n b la s to m y c o s is (P a ra co ccid io de s b ra z ilie n s is ). T h e im p o rta n c e o f th is d if fe r e n tia l d ia g n o s is c a n n o t be o v e re m p h a s iz e d . U s u a lly c u lt u r e a n d b io p s y w ill s e ttle th e q u e s tio n . A s a s h o r t c u t t o d ia gn o s is a P .A . c h e s t X ra y s h o w in g p u l m o n a r y i n f i l t r a t i o n u s u lly in d ic a te s b la s to m y c o s is unless severe le is h m a n ia s is is c o m p lic a te d b y a s p ira tio n p n e u m o n ia o r p u lm o n a r y tu rb e rc u lo s is . R h in o s c le ro m a , a ra re in fe c tio n d u e t o K le b s ie lla rh in o s c le ro m a to s is m a y a ls o c lo s e ly re s e m b le nasal le is h m a n ia s is 59.
O th e r site s — T h e s ite s a fte r th e n ose m o s t c o m m o n ly a ffe c te d a re s tr u c tu r e s o f th e m o u th s u c h as p a la te , to n g u e o r lip . A p a r t f r o m b la s to m y c o s is m e n tio n e d a b o ve n e o p la s m s are th e c h ie f d if fe r e n tia l d ia g n o s is . M o re r a r e ly th e le is h m a n ia l g ra n u lo m a to u s p ro ce s s m a y d es ce nd f r o m th e m o u th t o in v o lv e th e p h a r y n x a n d la r y n x th e p a tie n ts p re s e n tin g w it h d y s p h a g ia , d y s p h o n ia o r e ven a p h o n ia . G e n ita l le s io n s are r e la tiv e ly ra re . U lc e rs o f th e g la n s p e n is a n d th e fe m a le p e rin e u m h a ve t o be d is tin g u is h e d f r o m ve ne re al in fe c tio n s s u c h as s y p h ilis , s o ft s o re a n d p a r tic u la r ly g ra n u lo m a in g u in a le . G e n ita l le s io n s m a y be th e r e s u lt o f in fe c te d p h le b o to m u s b ite s o c c u r rin g w h e n th e g e n ita ls are e x p o s e a i-* th e fo re s t. O c u la r le s io n s a re a ls o u n c o m m o n n d h ave b e e n re v ie w e d b y A n d ra d e , in 1 9 3 2 2 .
C O M P L I C A I ! Q N S
1) M o n te n e g ro , in 1 9 2 4 7 4 d e m o n s tra te d th a t a u to in n o c u la tio n m a y o c c u r in p a tie n ts
w it h an o p e n le s io n . T h is is n o t fr e q u e n t a n d th e u su a l e x p la n a tio n f o r m u ltip le le s io n s is ly m p h a tic o r b lo o d s tre a m s p re a d . P ro b a b ly m o is t c o n tig u o u s s k in s u rfa c e s c re a te o p tim u m c o n d itio n s f o r th is ty p e o f s p re ad .
2) S e c o n d a ry b a c té ria I in f e c tio n o f o p e n u lc e rs is a lm o s t in e v ita b le ; a lth o u g h th e re have b een n o s p e c ific s tu d ie s th es e a re p r o b a b ly th e u su a l s k in flo r a (c. g. c o c c i) .
S u p e r in fe c tio n w it h v in c e n ts o rg a n is m s (B o rre lia v in c e n ti a n d B a c illu s fu s ifo rm is ) is r e p o r te d 8 1 . W h e n th e le s io n is in th e nose s e c o n d a ry b a c te ria l in fe c tio n m a y g iv e ris e t o a p u r u le n t r h in itis . S in u s itis m a y a ls o be a c o m p lic a tiò n a n d in th e t h r o a t a s p ira te d s e c re tio n m a y be re s p o n s ib le f o r a s e c o n d a ry p n e u m o n ia .
3 ) B u c c a l a n d p h a ry n g e a l le s io n s m a y g ive ris e t o s ia lo rrh e a a n d d if f ic u lt ie s in d e g lu titio n .
4 ) In a d v a n c e d la ry n g e a l le s io n s th e r e m a y be n o t o n ly loss o f s p e e ch b u t a ls o a c tu a l o b s tr u c t io n t o th e a ir w a y b y g ra n u lo m a o r s c a rrin g . T ra c h e o s to m y m a y be n ec essa ry.
5) C o n ju n tiv a l le sio n s m a y g iv e rise t o d is t o r t io n o f th e p a lp e b ra l fis s u re a n d in ra re in s ta n c e s loss o f th e e y e .
6 ) Severe c ic a tr iz a tio n in th e fa c e area m a y re d u c e th e m o u th o r nose a p e rtu re s t o s u ch s m a ll p r o p o r tio n s as t o p re ju d ic e b re a th in g o r a lim e n ta tio n .
7 ) L a rg e u lc e rs m a y b e th e s ite o f a s e c o n d a ry m yia s is.
8 ) L ik e a li larg e in fe c te d u lc e ra te d areas in th e c e n tre o f th e fa c e c a v e rn o u s s in u s th ro m b o s is m a y b e a c o m p lic a tio n .
9 ) E x te n s io n t o th e base o f b ra in w it h s e c o n d a ry b a c te ria l m e n in g itis is p e rh a p s m o re
lik e ly i f su c h a n u lc e r is t h e s e a t o f m y ia s is .
1 0 ) P u p o , in 1 9 4 6 8 7 , d e s c rib e d b o n e a n d jo i n t c o m p lic a tio n s as a r e s u lt o f le is h m a n ia s is . T he se u s u a lly a p p e a r t o be o f a n o n s p e c ific n a tu re a n d are a n a tu ra l se qu elae t o a n y d e e p u lc e r a tio n c o n tig u o u s t o a b o n e o r jo in t . F o r e x a m p le th e p e rio s ta l re a c tio n o f a tib ia b e n e a th th e s ite o f a d e e p u lc e r a tio n c a n be fo u n d in a v a ric o s e u lc e r. H o w e v e r r a r e ly a n o th e r ty p e o f b o n e le s io n m a y b e seen w it h a b s o rp tio n o f th e d is ta i p ha lan g e s . U s u a lly a s s o c i a t e d w i t h d i f f u s e c u t a n e o u s le is h m a n ia s is 95 i t re s e m b le s th e d is ta i b o n e c han ge s o f le p ro s y . T h e e x p la n a tio n is o b s c u re .
P R O G N O S IS
h e a lin g o f th e s k in u lc e r o c c u rs w it h o u t relap se . T h e scar o f a p re v io u s le is h m a n ia l le s io n is r e la tiv e ly c h a r a c te r is tic . U s u a lly o n th e lim b it is s lig h tly d ep re ssed , o f s m o o th a tr o p h ic s k in a nd o fte n h y p o p ig m e n te d in th e c e n tre . I t has to be d is tin g u is h e d f r o m th e s ca r o f a m o th e r y a w , b u r n , o r v a ric o s e u lc e r. R e a c tiv a tio n a fte r h e a lin g is d o c u m e n te d in L. tro p ic a in fe c tio n s o f th e m id d le e ast91 b u t is m o re fr e q u e n t in S o u th A m e ric a n le is h m a n ia s is . S o m e tim e s in a p a tie n t w it h m u c o s a l disease n o e v id e n c e o f a p re v io u s s k in s ore c a n be d e te c te d . I t is w ise n o t t o a fte r a f i r m p ro g n o s is . M a n y p a tie n ts are a w a re o f th e c o u rs e o f th e disease a n d w ill g o t o g re a t le n g th s t o e n s u re h e a lin g o f th e s k in u lc e r in t h e b e l i e f t h i s w i ll p re v e n t nasal c o m p lic a tio n s . T h e a u th o r s have seen p a tie n ts w i t h r e n a l d am a g e d u e t o p ro lo n g e d , u n s u p e rv is e d s e lf a d m in is te re d a n tim o n ia l th e r a p y f o r th is re a so n .
L A B O R A T O R V D IA G N O S IS
E v id e n c e f o r a d ia g n o s is o f m u c o c u ta n e o u s L e is h m a n ia s is is p ro v id e d b y th re e ty p e s o f la b o r a to r y e x a m in a tio n , n a m e ly ( 1 ) d ir e c t d e m o n s t r a t i o n o f t h e p a r a s i t e , ( 2 ) Im m u n o lo g ic a l e v id e n c e b y s k in te s t o r s e ro lo g y a n d (3 ) b io p s y . T h e p a th o lo g y has b ee n d e s c rib e d b u t th e f ir s t t w o a spe cts are c o n s id e re d b e lo w .
D e m o n s tra tio n o f th e p a ra s ite — A s F u r ta d o 48 p in ts o u t th e p e rc e n ta g e o f p o s itiv e is o la tio n s b y d ir e c t e x a m in a tio n o f m a te ria l f r o m th e u lc e r is in v e rs e ly re la te d t o th e d u r a tio n o f th e l e s i o n . M u l t i p l e a s p i r a t i o n s w it h an in tra m u s c u la r n e e d le w ill p ro v id e m a te ria l f o r sm ears. T h e se s ta in e d w it h g ie m sa d e m o n s tr a te le is h m a n ia w it h g re a te r c la r it y th a n th o s e id e n t if ie d in fo r m a lin fix e d H . a n d E. slide s. H o w e v e r im p re s s io n sm ea rs m a d e a t th e tim e o f s k in b io p s y a re b e tte r . B io p s y is b e s t d o n e f r o m th e b o rd e r o f th e le s io n u s in g a s k in p u n c h . S e v era l s p e c im e n s are ta k e n a n d o n e o f th e se c a n b e c u lt u r e d u s in g th e m e th o d d e s c rib e d b y H e rre r e t a l, in 1 9 6 6 5 5 . We have h ad p o o r re s u lts w it h c u lt u r e a n d h ave f o u n d i t d if f i c u l t t o p r e d ic t w h o m ig h t h ave le is h m a n ia d e m o n s tra b le in sm ears o r b io p s y . U s u a lly in la te le s io n s w it h m u c o s a l d a m a g e p a ra s ite s a re ra re . T h e m o s t e ffe c tiv e w a y o f is o la tin g th e p a ra s ite is t o in n o c u la te t r it u r a t e d b io p s y m a te r ia l in t o th e n ose a n d f e e t o f a h a m s te r6 3 . O fte n m o n th s la te r le s io n s a p p e a r a t th e s ite o f in n o c u la tio n c o n ta in in g p a ra s ite s. I f n o v is ib le le s io n a p p ea rs i t is s t ill w o r th w h ile e x a m in in g
sm ears f r o m th e in n o c u la tio n s ite a t s ix m o n th s a n d a y e a r a fte r in n o c u la tio n . A n o th e r p ossible t e c n i q u e f o r i s o l a t i n g le is h m a n ia is x e n o d ia g n o s is u s in g s p e c ific p h le b o to m in e s 3 2 . T h e d if f ic u lt ie s in re a rin g s a n d flie s m a ke i t u n lik e ly t h a t th is m e th o d can b e w id e ly used.
D l A G N O S T IC IM M U N O L O G V
The M o n te n e g ro re a c tio n — F u r ta d o 48 has ta b u la te d m a n y re p o r ts o f th e use o f th e M o n te n e g ro te s t a n d has discu s sed s o m e o f th e d if f ic u lt ie s in r e la tio n t o w h a t w o u ld a p p e a r t o be a s im p le te s t o f d e la y e d h y p e rs e n s itiv ity . U s u a lly th e a n tig e n c o n s is ts o f a s u sp e ns io n o f d e a d p ro m a s tig o te s o b ta in e d f r o m c u ltu r e in a p re s e rv a tiv e . T h e c o n c e n tr a tio n o f these fla g e lla te s p e r m l o f c u ltu r e is im p o r ta n t a n d g o v e rn s th e s e n s itiv ity o f th e te s t9 0 . A c o n c e n tr a tio n o f a t lea st 1 x 1 0 6 ís d e s ira b le a n d b e tte r re s u lts a re a c h ie v e d w it h even h ig h e r c o n c e n tr a tio n (1 x 1 0 7 ). U n fo r tu n a te ly th is in f o r m a t io n o n th e n a tu re o f th e p re p a ra tio n o f th e a n tig e n used in s k in te s t s tu d ie s is o fte n m is s in g f r o m p u b lis h e d s tu d ie s th u s lim it in g th e v a lu e o f t h e o b s e rv a tio n s . M o re r e fin e d a n tig e n s o b t a i n e d b y s o n ic a tio n 3 4 p o lv s a c c h a rid e e x tr a c tio n 4 4 o r s o lu b le e x tr a c tio n have been te s te d b u t re s u lts h ave o n ly been m a rg in a lly m o re a c c u ra te . T h e y d o have th e a dva ntag e h o w e v e r t h a t th e y c a n be s ta n d a rd is e d b y w e ig h t. R e c e n tly e x o a n tig e n s have been p re p a re d a n d te s te d a g a in st th e s ta n d a rd le is h m a n in a n tig e n . S u c h e x o a n tig e n s p ro d u c e a n im m e d ia te h y p e r s e n s itiv ity re a c tio n in t h ir t y m in u te s w it h w h e a l a n d fla r e . T. c r u z i e x o a n tig e n s p ro d u c e s a s im ila r im m e d ia te resp on se b u t in c o n tr a s t t o th e le is h m a n ia l e x o a tin g e n a d e la y e d h y p e r s e n s itiv ity response a fte r 4 8 h o u rs w as n o t seen in d ic a tin g th e g re a te r s p e c ific ity o f th e la t te r a n tig e n 9 4 .
314
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VOL. IX - NP 6
c h ild re n ) w it h o u t a n y c lin ic a i e v id e n c e o f leis h m a n ia s is . T h is raises th e p o s s ib ility th a t a v ir u le n t s tra in s o r s u b c lin ic a l in fe c tio n s m a y be re s p o n s ib le f o r s k in te s t c o n v e rs io n .
M u c h w o r k has b ee n d o n e in A f r ic a a lo n g s im ila r lin e s in areas o f L. d o n o v a n i in f e c tio n o f m an b u t r e s tr ic tin g o u r d is c u s s io n t o L. b ra zilie n s is th e re is s tro n g e v id e n c e n o t o n ly fr o m B ra z il b u t f r o m o th e r S o u th A m e ric a n a n d C e n tra l A m e ric a n c o u n tr ie s t h a t a p o s itiv e M o n te n e g ro te s t in in d iv id u a is w it h o u t signs o f le is h m a n ia s is is a c o m m o n f in d in g 3 , 1 4 ' 4 2 , 7 0 . A n e g a tiv e te s t has o c c u r re d in p a tie n ts in w h o m L. b ra z ilie n s is p a ra s ite s have b een fo u n d 72 a n d th is f in d in g is p re s u m e a b ly an in d ic a tio n o f a p o o r c e ll m e d ia te d im m u n e resp on se. H o w s o o n a fte r in f e c tio n th e M o n te n e g ro te s t b e c o m e s p o s itiv e is a ls o in d o u b t a n d is p r o b a b ly v a ria b le . T h e re h ave b een re p o rts o f p o s itiv e c o n v e rs io n o f th e re a c tio n in p a tie n ts u n d e r tr e a tm e n t2 7 , 3 6 . A p o s itiv e re a c tio n p ers is ts a fte r r e s o lu tio n o f th e c lin ic a i le s io n 80 b u t its r e la tio n t o p a ra s ite p e rs is te n c e in th e b o d y o f m a n is u n k n o w n . A lth o u g h th e M o n te n e g ro te s t is a r e fle c tio n o f c e ll m e d ia te d im m u n ity a n d has b ee n e m p lo y e d f o r m a n y y ears th e r e is l i t t le in f o r m a t io n o n o th e r p a ra m e te rs o f c ê
II
m e d ia te d im m u n it y . In1970,
T r e m o n t i a n d W a lto n 101 r e p o r te d b la s t tr a n s fo r m a tio n o f p e rip h e ra l ly m p h o c y te s o f p a t i e n t s w i j h A m e r i c a n c u t a n e o u s l e i s h m a n ia s is . W h e n t h e ly m p h o b la s t tr a n s fo r m a tio n te s t w as assessed in 2 0 p a tie n ts w it h c u ta n e o u s le is h m a n ia s is 73 th e p e rc e n ta g e o f b la s t tr a n s fo r m a t io n ra n g e d f r o m19-27%
b u t n o c o r r e la tio n c o u ld be fo u n d w it h th e in te n s ity o f th e s k in te s t. C o n v it a n d P in a r d i34 c la im t o have s h o w n a c le a r d iffe r e n c e in th e b e h a v io r o r c u lt u r e d ly m p h o c y te s s tim u la te d w it h le is h m a n ia l te g u m e n ta r ia d iffu s a . W h e re as p a tie n ts w it h a m a rk e d ly m p h o c y te re sp on se a n d a s tro n g M o n te n e g ro te s t s h o w e d a h ig h p e rc e n ta g e o f b la s t f o r m a tio n .
S e ro lo g y — T h e re h a v e b e e n a n u m b e r o f s tu d ie s o n th e v a lu e o f a c o m p le m e n t f ix a t io n te s t u s in g b o th L. b ra z ilie n s is a n d T. c r u z i a n tig e n s 4 , 4 9 . F u r ta d o has re v ie w e d e a rly w o r k o n th e in d ir e c t flu p r e s c e n t a n tib o d y te s t w h ic h because o f its c o m p a r a tiv e s im p lic it y is m o re lik e ly t o be e m p lo y e d in r o u tin e d ia g n o s is. H o w e v e r c ro s s re a c tio n s w it h T. c r u z i o c c u r2 4 a n d th e s e a u th o rs h a ve d e s c rib e d a flu o r e s c e n t in h ib it io n p ro c e d u re t o o v e rc o m e th is p ro b le m . C ross re a c tio n s w it h Chagas disease h a v e a ls o b e e n n o te d u s in g th e passive h a e m o g g lu tin a tio n te s t4 .
L a te r s tu d ie s b y C h ia ri e t a / 31 a n d G u im a rã e s e t a / 54 u s in g c u ltu r a l fla g e lla te a n tig e n s d id n o t f in d cross re a c tio n s su c h a s e rio u s p ro b le m as t o n eg ate th e u se fu ln e s s o f t h e i n d i r e c t flu o r e s c e n t a n tib o d y te s t. T ry p a n o s o m a c r u z i a n d L. d o n o v a n i in fe c tio n s o f m a n p ro d u c e sero p o s it iv it y w it h L. b ra z ilie n s is p a tie n ts . A s lid e o f a 8 d a y o ld c u ltu r e p ro m a s tig o te s tr e a te d w it h 2 % fo r m a lin c an b e k e p t a t — 2 0 ° C f o r th r e e y e a rs w it h o u t loss o f a n tig e n ic ity 5 4 . W a lto n e t a l 106 have c u t d o w n th e in c id e n c e o f c ross re a c tio n s t o o th e r in fe c tio n s b y u s in g an a n tig e n p re p a re d f r o m a m a s tig o te s in tis s u e c u ltu r e . T h e c h ie f v a lu e o f th e I F A f r o m a c lin ic a i p o in t o f v ie w w o u ld be i f i t c o u ld be d e v e lo p e d as a c r it e r io n o f c u re a n d u sed t o e v a lu a te c h e m o th e ra p y . T h e re is s o m e in d ic a t io n th is m a y b e p o s s ib le . W a lto n 1 0 5 a n d C h ia ri e t a lJ1 h ave n o te d t h a t th e I F A te s t b e c o m e s n e g a tiv e a fte r s u cce s sfu l th e r a p y .
T H E R A P Y
In a n y d is c u s s io n o f th is s u b je c t tw o im p o r t a n t m a tte rs m u s t be c o n s id e re d a t th e b e g in n in g . F ir s t w e s t ill have n o a c c e p te d c r ite r ia o f c u re . S in c e th is is s u c h an u n p r e d i c t a b l e d is e a s e w i t h f r e q u e n t s p o n ta n e o u s h e a lin g id e a lly e v e ry d ru g t r ia l s h o u ld h a ve a n a d e q u a te c o n tr o l g ro u p a n d th e t r ia l te r m in a te d w h e n s ta tis tic a lly s ig n ific a n t im p r o v e m e n t is a c h ie v e d in th e g ro u p u n d e r th e r a p y . F o r a v a r ie ty o f p ra c tic a l rea son s th is has n o t b e e n p o s s ib le t o d a te . A s m e n tio n e d e ls e w h e re in th is d is c u s s io n p e rs is te n c e o f le is h m a n ia a fte r h e a lin g o f th e s k in le s io n has b een d e m o n s tr a te d so t h a t th e p re s en ce o f p a ra s ite s d o e s n o t c o rr e la te w it h tis s u e resp on se . A z u la y 1 9 6 6 7 agrees th e r e a re n o a c c e p te d c r ite r ia o f c u re a n d fe e ls t h a t h e a lin g o f th e le s io n s d o e s n o t ju s t if y s u s p e n s io n o f th e r a p y . P o s s ib ily th e p re sen ce o f p a ra s ite s a fte r tr e a tm e n t d o e s n o t c o rr e la te w e ll w it h s u b s e q u e n t re lap se a n d tis s u e b r e a k d o w n . T h is q u e s tio n deserves s tu d y as d o e s th e v a lu e o f th e flu o r e s c e n t a n tib o d y te s t in assessing c u re .
o c c u r in a c o m m u n ity e x p o s e d t o in fe c tio n is u n k n o w n . I t is n o t k n o w n w h e th e r such c o m p lic a tio n s a re a fe a tu r e o f r e in fe c tio n . M o s t im p o r ta n t o f a li it is n o t k n o w n h o w th e r a p y m o d if ie s th is disease p a tte r n .
In s h o r t w e k n o w n o th in g o f th e > e v o lu tio n o f th e disease in a p o p u la tio n w it h o r w it h o u t th e r a p y a n d th is m a ke s i t v e ry d i f f i c u l t to devise a s o u n d sc he m e o f m a n a g e m e n t o f s uch p a tie s ts .
T h is is p a r tly because o f th e d if f i c u l t y o f f o llo w u p o f p a tie n ts d ia g n o s e d in h o s p ita l. T h is p ro b le m is illu s tr a te d b y an a tte m p t b y C a s tro 28 t o f o llo w u p 2 3 p a t ie n ts t r e a t e d w ith A m p h o te r ic in B. O n ly n in e p a tie n ts re tu rn e d f o r f o llo w u p o b s e rv a tio n s a fte r o n e y e a r a n d o n ly 4 a fte r 3 ye a rs.
M a n y d ru g s have b e e n t r ie d in th e tr e a tm e n t o f th is disease b u t n o n e have su p e rc e d e d a n tim o n ia ls as th e m a in s ta y o f th e r a p y . In cases r e s is ta n t t o a n tim o n ia ls th e lite r a tu r e suggests t h a t A m p h o te r ic in B has p ro d u c e d th e best re s u lts . T h e se t w o lin e s o f th e r a p y w ill be f ir s t d is c u s s e d a n d o th e r d ru g s s u b s e q u e n tly c o n s id e re d . B e fo re c o n s id e rin g d e ta ils o f t r e a tm e n t w it h th e m a in d ru g s used in th e r a p y i t is nece ssary t o m e n tio n t h e ir m a in t o x ic e ffe c ts . P e n ta v a le n t a n tim o n ia ls are m u c h less t o x ic th a n tr iv a le n t b u t lik e a li h e a v y m eta is th e y c an p ro d u c e c a rd ia c , h e p a tic , re n a l o r c e re b ra l c o m p lic a tio n s . A m p h o te r ic in B is a v e ry t o x ic d ru g . T h e m o s t im p o r ta n t t o x ic e ffe c t is re n a l d a m ag e . In o n e s tu d y m a n y y e a rs a fte r tr e a tm e n t w it h th is d ru g th e m a jo r ity o r p a tie n ts h ad e v id e n c e o f re n a l im p a ir m e n t2 3 . Id e a lly th e r e fo r e p a tie n ts s h o u ld be tr e a te d w it h th e s e d ru g s in h o s p ita l. A s e ru m tra n s a m in a s e a n d b ro m o s u lp h a le in te s t d o n e t o assess h e p a tic f u n c t io n , an e le c tr o c a rd io g ra m t o d e te c t c a rd ia c a b n o r m a litie s a n d a u rin e e x a m in e d a n d b lo o d u re a e s tim a te d t o e x c lu d e th e p o s s ib ility o f re n a l im p a ir m e n t b e fo re c o m m e n c in g tr e a tm e n t.
A N T I M O N I A L S
A z u la y 7 lis ts 1 8 a n tim o n ia l p re p a ra tio n s t h a t h a ve b e e n used in th e tr e a tm e n t o f th is disease. T a r ta r e m e tic th e t r iv a le n t a n tim o n ia l h a d t o b e a b a n d o n e d b ecause o f its s e rio u s t o x ic s id e e ffe c ts a n d th e n e c e s s ity f o r i n t r a v e n o u s a d m i n i s t r a t i o n . H o w e v e r p e n ta v a le n t a n tim o n ia ls have p ro v e d t o be e ffe c tiv e in th is as w e ll as o th e r fo r m s o f le is h m a n ia s is . T h e t w o m u s t w id e ly used
p re p a ra tio n s have b e e n a n tim o n y -n - m e th y l- g lu ta m in e , G lu c a n tim e (R h o d ia ) a nd s o d iu m a n tim o n y g lu c o n a te , P e n to s ta m (B u rro u g h s W e llc o m e ). S in c e th e fo r m e r is m a n u fa c tu re d in B ra z il i t has b ee n m u c h m o re w id e ly used in L b ra z ilie n s is in fe c tio n s th o u g h P e n to s ta m has a lso g iv e n g o o d re s u lts 4 5 . N o c o n tr o lle d t r ia l has b e e n d o n e o n w h ic h is b e s t b u t th e re is p r o b a b ly l it t l e d iffe re n c e . B o th d ru g s have th e a d v a n t a g e t h a t t h e y c a n b e g iv e n in tr a m u s c u la rly as w e ll as in tra v e n o u s ly w h ic h is p a r tic u la r ly h e lp fu l w h e n tr e a tin g s m a ll c h ild re n .
V a r io u s tr e a tm e n t sc h e d ule s h ave been re c o m m e n d e d . T h e o n e w e u s e is a s f o llo w s . T h e dose m u s t b e re la te d t o th e p a tie n ts w e ig h t a n d is c a lc u la te d o n th e basis o f a t o t a l d ose o f d ru g o f 1 g m / k i l o g r a m . T h is is a d m in is te re d in tra v e n o u s ly o v e r a 1 0 d a y s p e r io d w it h th e p a tie n t re s tin g in b ed a nd re c e iv in g o n e in je c tio n a d a y . A f t e r 1 m o n th 's , re s t th is tr e a tm e n t is re p e a te d a n d th e sam e process re p e a te d y e t a g a in t o g iv e a t o ta l o f th re e tr e a tm e n t c o u rs es w it h a fin a l to t a l dose 3 g m /k ilo b o d y w t. G lu c a n tim e is a v a ila b le in 5 c c a m p o u le s c o n ta in in g 1 .5g o f d ru g w h ic h c o n ta in s 4 2 5 m g o f a n tim o n y . T h e m e c h a n is m o f a c tio n o f s u c h a n a n tim o n ia l o n le is h m a n ia is s till p o o r ly u n d e rs to o d . I t is p o s s ib le it is b ro k e n d o w n in th e b o d y a n d a cts in th e t r iv a le n t f o r m . S tu d ie s in v itr o b e a r li t t l e re le v a n c e t o th e a c tio n in m a n . In v ie w o f th e r e la tiv e ly lo w t o x i c it y o f g lu c a n tim e a nd p e n to s ta m i t is p o ss ib le t o a d m in is te r th e r a p y o n a n o u tp a t ie n t basis.
A M P H O T E R IC IN B (F u n g iz o n e )
T h is d ru g c a n n e ve r b e u sed o n a n o u tp a tie n t basis. S t ill th e m a in d ru g e ffe c tiv e in th e d e e p s y s te m ic m y co se s its v a lu e in th e d e e p s y s te m ic m y c o s é s i t s v a lu e in m u c o c u ta n e o u s le is h m a n ia s is w as v e r ifie d s im u lta n e o u s ly b y F u r ta d o a n d Lacaz e t a l, in 1 95 9 . S in c e th e n i t has b e e n u sed w it h success b y v a rio u s S o u th A m e ric a n w o r k e r s 1 *>9 3 . P ra c tic e v a rie s w id e ly b o th as reg a rd s th e in itia l a n d s u b s e q u e n t d oses o f th is d ru g b u t a c o m m o n re g im e n is as fo llo w s .
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th a n in s y s te m ic fu n g a i in fe c tio n s . In o n e s tu d y su ch to ta l doses v a rie d b e tw e e n 4 .4 m g /k g a n d 5 5 .6 m g /k g w it h a m e a n o f 2 8 .7 m g /k g 8 . C u re w it h o u t re lap se has b e e n r e p o r te d in f o l lo w u p s u p t o te n ye a rs.
S id e e ffe c ts h o w e v e r are c o n s id e ra b le w it h fe v e r, a n o re x ia , nausea a lm o s t in v a ria b le . V e n o u s th ro m b o s is a t th e d r ip s ite is a n o th e r p ro b le m . T h is ca n be lessened b y s lo w d ilu te d i n f u s i o n s a n d a d d i n g 2 5 - 5 0 m g o f h y d r o c o rtis o n e s o d iu m s u c c in a te t o th e d r ip b o t t le . K id n e y t o x i c it y is s t r ic t ly dose d e p e n d e n t a n d re n a l f u n c t io n s h o u ld be m o n ito r e d tw ic e a w e e k u n t il a z o te m ia is s ta b le . B e n n e tt13 p re fe rs t o k e e p th e b lo o d u re a b e lo w 5 0 m g a n d th e s e ru m c re a tin in e b e lo w 3 .5 m g /1 0 0 m l. H y p o k a le m ia o c c u fs in 2 5 % o f p a t i e n t s a n d r e q u i r e s o r a l s u p p le m e n t i o n . P e rm a n e n t r e d u c tio n in g lo m e ru la r f i l t r a t io n ra te p r o b a b ly o c c u rs in a li p a tie n ts re c e iv in g a th e r a p e u tic c o u rs e o f A m p h o te r ic in B f o r fu n g u s in f e c tio n . O n e e le c tr o n m ic ro s c o p y s tu d y re v e a le d tu b u la r changes b u t th e g lo m e r u li a p p e a re d n o r m a l2 6 .
P a tie n ts m u s t be c a r e fu lly s e le c te d f o r A m p h o te r ic in B th e r a p y as th e tr e a tm e n t schem e in v o lv e s a p ro lo n g e d s ta y in h o s p ita l a n d a c a p a c ity t o to le r a te s ide e ffe c ts . T h is s itu a tio n s h o u ld be e x p la in e d t o th e p a tie n t a n d his c o lla b o r a tio n e n s u re d . T h is d r u g tr e a tm e n t w h ile u n d o u b te d ly e ffe c tiv e s h o u ld be res erve d f o r p a tie n ts w it h P ro g re ssive d e s tr u c tiv e le s io n s w h o h ave n o t re s p o n d e d t o a n tim o n ia l th e r a p y .
O T H E R D R U G S
A m u ltitu d e o f o th e r d ru g s h ave b e e n tr ie d in th is in f e c tio n b u t n o n e h ave p ro d u c e d c o n s is te n t s u c c e s s fu l re s u lts s u c h t h a t th e y ca n be re v ie w e d in th e sam e w a y as th e t w o p re v io u s ly m e n tio n e d . A z u la y 7 in h is c e v ie w m e n tio n s a n u m b e r o f d ru g s w h ic h h ave b e e n tr ie d w it h lit t le success a m o n g th e m s o d iu m a rs e n ite , b is m u th , a te b r in , y a tre n , g e rm a n in e , s u lp h a n ila m id e a n d fu r a z o lid in e . O n e g r o u p o f d ru g s he m e n tio n s , th e a ro m a tic d ia m id in e s s h o u ld p e rh a p s be re e v a lu a te d f o r use in c e rta in cases in v ie w o f its success in tr e a tin g d iffu s e c u t a n e o u s l e i s h m a n i a s is in E t h i o p i a . B ry c e s o n 2 0 re p o rte d c u re in 7 o u t o f 31 p a tie n ts tr e a te d w it h lo m id in e ( p e n ta m id in e d im e th a n s u lp h o n a te ). In d ru g r e s is ta n t cases o f Leish m a nia b ra z ilie n s is in f e c tio n th is m ig h t be w o r th a t r iã l. E s p e c ia lly as L o p e s a n d A lm e id a 68 f e lt i t w as e ffe c tiv e . H o w e v e r s o m e
n e w e r d ru g s have a ls o b e e n tr ie d a n d th ese w ill be b r ie f ly re v ie w e d here.
C y c lo g u a n il p a m o a te (C a m o la r) A d e p o s ito ry a n tim a la ria l re la te d t o p a lu d r in e , i t c o n ta in s 1 4 0 m g o f a c tiv e c o m p o u n d in e a c h cc . c o m - b in e d w it h m in e ra l o il a n d b e n z y l b e n z o a te . G iv e n in a s ing le d o s e b y d e e p in tra m u s c u la r in je c tio n . F o r c h ild r e n o f 4 -6 y e a rs o f age 1 4 0 m g is s u ffic ie n t, 2 8 0 m g f o r th o s e 5 -1 0 and 3 5 0 m g is th e a d u lt d o s e 1 9 ,', n ' 5 7,1 0 4 . T h e f ir s t 3 a u th o rs used th is d ru g in 5 0 , 2 6 a n d 2 0 p a tie n ts re s p e c tiv e ly in w h o m le is h m a n ia h a d b een fo u n d . T h e c r it e r io n o f c u re w as c lin ic a i h e a lin g o f th e le s io n a n d c u re ra te s o f 8 8 , 7 3 a n d 8 8 % re s p e c tiv e ly w e re o b ta in e d . B ry c e s o n e t a! 1 9 c o n c lu d e d , h o w e v e r, th a t th e d ru g h a d n o e ffe c t o n L. tro p ic a in fe c tio n s in E th io p ia . T h e d ru g has side e ffe c ts a t th e side o f in n o c u la tio n w it h p e rs is te n t m u s c le p a in and o c c a s io n a lly abscess fo r m a tio n .
N irid a z o le ( A m b ilh a r ) T h is a n tis c h is to s o m a l d ru g has b ee n u sed in th e dosage i t is u sed f o r th is in fe c tio n n a m e ly 2 5 m g /k ilo g r a m d a ily f o r 1 0 d a y s in th e f o r m o f o ra l ta b le ts 2 2 , 4 7 . B a ra n s k i22 re p e a te d th is tr e a tm e n t u p t o 5 tim e s , a d a n g e ro u s p o lic y in v ie w o f th e side e ffe c ts o f th is d ru g . A lth o u g h th e a u th o r s f e lt i t h ad s o m e a c t iv it y c le a r ly t o d a y th is d ru g has n o place.
D a r a p r i m ( P y r e m e t h a m in e ) A n o t h e r a n tim a la ria l a n d a fo lie a c id a n ta g o n is t i t has been t r ie d w it h o u t success in m u c o s a l le s io n s b y V ie g a s a n d F u r ta d o 1 0 2 a n d S o la n o a n d V a rga s1 0 0 .
F la g y l — A 5 n it r o im id a z o le w it h g o o d a c tiv it y a g a in s t T ric h o m o n a s v a g in a lis a n d in te s tin a l p ro to z o a th is has b een g iv e n in h ig h doses w it h o u t m u c h e f f e c t b y F u r ta d o a n d V ie g a s 4 6 . W a lto n e t a/ 1 10 h ave c o n fir m e d th is fin d in g . B a y e r 2 5 0 2 ( L a m p it, n if u r t im o x ) A c u r r e n t tr e a tm e n t f o r Chagas disease 6 p a tie n ts have been tr e a te d w it h a d ose o f 4 8 0 m g p e r d a y f o r 2 5 - 3 0 d a ys . In th e o n ly p a tie n t w it h m u c o s a l in v o lv e m e n t th e tr e a tm e n t w as c o n tin u e d u n t il th e 7 0 th d a y . A g o o d c lin ic a i re sp on se w as n o te d in a li p a tie n ts 8 9 . F u r th e r tr ia ls are in d ic a te d .
s im ila r dosage s o m e tím e s c o n tin u e d f o r several m o n th s . A lth o u g h n e ith e r in v e s tig a to r m e n tio n s id e e ffe c ts these are k n o w n t o be severe a n d in c lu d e h e p a titis , a c u te re n a l in s u ffic ie n c y , c o a g u la tio n d e fe c ts a n d a c u rio u s ty p e o f a u to im m u n e re s p o n s e 1 6 . T h e se a n d th e c o s t o f th e d ru g are lik e ly t o l i m i t its u s efu lne ss.
O th e r d ru g s w h ic h h ave been tr ie d w it h o u t e f f e c t i n c l u d e T h ia b e n d a z o le a n d N a g o x in 9 2 , n i . I t is o b v io u s f r o m th is s h o r t d is c u s s io n t h a t w o rk e rs have b een t r y in g t o f in d b e tte r d ru gs a n d th e se arch w ill c o n tin u e . H o w e v e r i t is d if f i c u l t t o e v a lu a te th e se re s u lts s in c e th e n u m b e r o f p a tie n ts tr e a te d is s o s m a ll, th e re is n o c o m p a ris o n w it h s ta n d a rd th e r a p y , a n d th e c r ite r ia o f c u re is o fte n c lin ic a i h e a lin g w h ic h c o u ld be s p o n ta n e o u s . I t can s a fe ly be sa id t o d a te t h a t n o n e w d ru g has b een so s u cc e s s fu l as t o b e c o m e s ta n d a rd th e r a p y .
H E A T T H E R A P Y
I t is w e ll e s ta b lis h e d t h a t le is h m a n ia a re h e a t s e n s i t i v e a n d t h a t s m a ll a lte ra tio n s in te m p e ra tu r e ca n p r o f u n d ly in flu e n c e th e b a h a v io r o f le is h m a n ia in c u lt u r e 6 7 . I t has been suggested t h a t th e c o m m o n s ite s o f s e c o n d a ry le sio n s in L e is h m a n ia b ra zitie n s is in fe c tio n , n a m e ly th e n ose o r e x te r n a i e a r, is d e te rm in e d b y th e lo w e r te m p e r a tu r e a t th e se s k in s u rfa c e s 1 . In a n im a is h e a lin g o f le s io n s has b een p r o d u c e d b y i n c r e a s i n g t h e r o o m te m p e r a tu r e 1 14 y e t s u p r is in g ly li t t l e w o r k has been d o n e o n u s in g h e a t o r fe v e r th e r a p y in tr e a tm e n t in m a n . B a k e r a n d G u tie rr e z B a lle s te ro s 9 u se d a v a p o u r h e a t p ro cess u sed f o r th e d e s tr u c tio n o f in s e c t larvae in f r u i t a n d r e p o r te d success in L. b ra z itie n sis in f e c tio n in m an a n d L. e n r íe t ti in th e g u in e a p ig . B ry c e s o n 20 in h is s tu d ie s o n d iffu s e c u ta n e o u s le is h m a n ia s is in E th io p ia n o te d t h a t an a tta c k o f m easles d r a m a tic a lly im p ro v e d th re e p a tie n ts w it h m a rk e d s k in in v o lv e m e n t a n d suggests t h a t th e fe v e r d u r in g th e m easles a tta c k c o u ld be re s p o n s ib le . B ra y a n d A s h f o r d 1 7 f o llo w in g u p th is s u g g e s tio n in d u c e d a P la s m o d iu m viv a x in f e c tio n in a p a tie n t w it h d iffu s e c u ta n e o u s le is h m a n ia s is a n d o b ta in e d a resp on se . R e c e n tly success has b een r e p o rte d w it h th e use o f h o t w a te r o r u lt r a v io le t a n d in fr a r e d ra y s in th e t r e a t m e n t o f e a s t A f r i c a n c u ta n e o u s le is h m a n ia s is 7 7 .
S U R G E R Y
C ic a tr iz a tio n o f o ro n a s a l le s io n s m a y re q u ire p la s tic s u rg e ry a fte r m e d ic a i tr e a tm e n t w it h r e c o n s tr u c tio n o f th e u p p e r lip a n d n ose . V e r y
s u c c es s fu l re s u lts have been o b ta in e d th o u g h lit t le has been p u b lis h e d t o d a te 5 . O ne d if f ic u l t y is t h a t a re lap se w ill re s u lt in loss o f th e g ra ft. Because o f th is b e fo re u n d e rta k in g re c o n s tru c tiv e s u rg e ry a w a itin g p e rio d o f 3 m o n th s t o a y e a r a fte r th e te r m in a tio n o f s u cc essfu l m e d ic a i tre a tm e n t is d e sira b le .
A S P E C T S O F R E S E A R C H O F C L I N I C A L R E L E V A N C E
In v o lv e m e n t o f th e m u c o u s m e m b ra n e s in c u ta n e o u s le is h m a n ia s is is c h a ra c te ris tic o f th e S o u th A m e ric a n in fe c tio n (L . b ra zilie ns is ). H o w e v e r th e re have been is o la te d re p o rts o f m u co s a l in v o lv e m e n t a s so c ia te d w it h v is c e ra l o r d e r m a l le is h m a n ia s is fr o m th e S u d a n 6 1 , Y u g o s l a v i a 52 a n d I r a n 1 1 2 . C u ta n eo u s le is h m a n ia s is o c c u rs in m o s t C e n tra l a n d S o u th A m e ric a n c o u n trie s w ith th e e x c e p tio n o f C h ile 3 3 . T h e p r o p o r t io n o f p a tie n ts in c lin ic a i s tu d ie s w it h m u c o u s m e m b ra n e in v o lv e m e n t is v e ry v a ria b le f r o m 8 0 % in so m e p a rts o f B ra z il to less th a n 5% in G u y a n a . L a in s o n (P e rso na l C o m u n ic a tio n ) e x p la in s th is o n th e basis o f o v e rla p p in g o f d if f e r e n t species. " A s y o u tra v e i s o u th w a r d in B ra z il th e in c id e n c e o f e s p u n d ia d u e t o L .b . b ra z ilie n s is increases as p ia n b o is (L .b . guyanensis) d ecrea se s". E a rly re p o rts o f t h e g e o g ra p h ic a l d is t r ib u tio n h ave b een re v ie w e d b y Pessoa a n d B a r re to 8 1 . T he se a u th o rs in th e ir e x te n s iv e m o n o g ra p h d o c u m e n t th e disease in m a n y B ra z ilia n S tate s . T h e disease p ro b a b ly e x is ts in S ta te s w h e re i t has y e t t o be d o c u m e n te d . F o r e x a m p le 1 0 7 cases o f m u c o c u ta n e o u s le ih m a n ia s is w e re c o lle c te d in G o ia s b y o n e h o s p ita l se rv ic e o v e r a p e rio d o f 4 y e a rs 1 ° . P re v io u s ly th e r e w e re n o re c o rd s f r o m th is s ta te . M u c o sa l in v o lv e m e n t seem s t o be rare in s o m e s u rv e y s . F o r e x a m p le in f ie ld s tu d ie s o f p a tie n ts in A m a p a 4 3 a n d in d ia n s in th e M a to G ro s s o 25 n o m u c o s a l le s io ns w e re o b s e n /e d . I t has been su gg este d t h a t th e In d ia n is m o re re s is ta n t t o th is ty p e o f le s io n . S in c e w e have l it t le in f o r m a t io n o n th e a c tu a l in c id e n c e o f m u c o s a l le s io n s in c o m m u n itie s i t c o u ld be t h a t th e y d o e x is t b u t a re s u ffic ie n tly ra re n o t t o be r e p r e s e n t e d i n s tu d ie s o f s m a ll ru ra l p o p u la tio n s . C o n v it a n d P in a r d i33 n o te t h a t in V e n e z u e la in areas w h e re m u c o s a l fo r m s a re n o t u s u a lly seen i f an e p id e m ic o c c u rs w it h a large n u m b e r o f cases m u o c u ta n e o u s le s io n s a p p e a r in a f e w p a tie n ts .
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in f o r m a tio n r e la tin g t o p ro g n o s is . G u im a rã e s 53 d escrib e s a c o m m u n ity w h e re a s m a ll e p id e m ic was a ss o c iate d w it h tr e e fe llin g . O f 3 0 6 p e rso n s e x a m in e d 3 9 had c h a ra c te ris tic le s io n s a n d o f these 3 4 o u t o f 3 6 h a d p o s itiv á M o n te n e g ro re a c tio n s . O n ly t w o p a tie n ts h a d nasal in v o lv e m e n t a n d th ese p ro v e d re s is ta n t t o tr e a tm e n t w it h ta r t a r e m e tic a n d fu a d in . In general th e in it ia l resp on se t o th es e d ru g s w as g o o d b u t th e re is n o in f o r m a tio n o n lo n g te rm f o llo w u p . In th re e p a tie n ts s p o n ta n e o u s c u re was n o te d .
P re s to n , in 1 9 7 4 8 6 , h a s 'p o in te d o u t t h a t th e in n o c u la tio n o f le is h m a n ia in t o m a n is fo llo w e d b y th re e ty p e s o f sequelae n a m e ly s u b c lin ic a l, s e lf h e a lin g le s io n , o r a n o n h e a lin g le s io n . N o n h e a lin g a p p ea rs t o be a ss o c iate d w it h t w o ty p e s o f h o s t resp on se, e ith e r a n e rg ic fo rm s c h a ra c te ris e d b y a supressed im m o n o g ic a l response as c h a ra c te ris e d b y th e ra re d iffu s e c u ta n e o u s le is h m a n ia s is o r m o re c o m m o n ly a lle rg ic fo rm s w it h a n e n h a n c e d im m u n o lo g ic a l response o n th e p a r t o f th e h o s t. T h e t w o m a in s ug g e stio n s t o e x p la in th e se d if f e r e n t responses are:
1. A n in n a te p r o p e r ty o f th e h o s t in te rm s o f h is a b ilit y t o m o u n t an im m u n e res pon s e.
2. T h e ty p e o f le is h m a n ia in n o c u la te d . T h e re is m u c h e v id e n c e t o s u p p o r t b o th s ug g e stio n s b u t a t th e tim e o f w r it in g i t is t o o e a rly t o c o n c lu d e w h ic h is th e m o re im p o r ta n t . In d e e d i t is lik e ly t h a t w h ile b o th m a y be re le v a n t th e ro le th e y p la y m a y v a ry w it h th e in d iv id u a l case.
T h e im m u n o lo g ic a l resp on se o f th e h o s t has been r e c e n tly re v ie w e d b y B ry c e s o n 21 a n d C o n v it a n d P in a r d i33 a n d th e se a u th o rs seem la rg e ly in a g re e m e n t. B ry c e s o n has p o in te d o u t t h a t th e h is to lo g ic a l p ic tu r e o f le is h m a n ia s is can be c la s s ifie d a lo n g th e lin e s o f th e R id le y J o p - lin g scale f o r le p ro s y a nd used as an in d e x o f th e h o s t's c e ll m e d ia te d im m u n ity . H is ta b le is re p ro d u c e d in ta b le I illu s tr a tin g th e se h is t o lo g i cal v a ria tio n s . T h e re is u s u a lly a close c o rre - la tio n b e tw e e n s k in s e n s itiv ity t o le is h m a n in a n d th e h is to lo g ic a l p ic tu r e . T h e im m u n o lo g ic a l d e f e c t in d iffu s e c u ta n e o u s le is h m a n ia s is appears t o be s p e c ific f o r s uc h p a tie n ts re s p o n d n o r m a lly t o tu b e r c u lin a n d le p r o m in . A ls o b o th C o n v it a n d P in a r d i33 in V e n e z u e la a nd B r a y 18 in 1 9 7 4 , in E th io p ia h ave d e m o n s tr a te d de- fe c tiv e ly n p h o c y te tr a n s fo r m a tio n in d iffu s e c u ta n e o u s le is h m a n ia s is . B ra y 's g ro u p h ave a lso s h o w n d e fe c tiv e le u c o c y te m ig r a tio n , an absen- ce o f ly m p h o c y te a c tiv a tio n p r o d u c ts c o n - ta in in g a m ito g e n ic fa c to r a n d in h ib it io n o f
m a c ro p h a g e m ig ra tio n . T h e p o o r c a p a c ity o f th e h o s t t o re s p o n d t o th e p a ra s ite in d iffu s e c u ta n e o u s le is h m a n ia s is is a lso s h o w n in th e bad resp on se to tr e a tm e n t. B ry c e s o n 20 in E th io p ia fo u n d p e n ta m id in e d im e th a n e s u lp h o n a te w as th e m o s t e ffe c tiv e d ru g a n d u n d e r th e in flu e n c e o f tr e a tm e n t th e le is h m a n in te s t fr e q u e n tly b ecam e p o s itiv e s u gg estin g th e b e g in in g s o f an c e ll m e d ia te d im m u n e resp on se. T h e cause o f th e d e fe c t in ce ll m e d ia te d im m u n e resp on se in d iffu s e c u ta n e o u s le is h m a n ia s is is u n k n o w n . A t o ne tim e a s p e c ific ty p e o f le is h m a n ia (L. p i-fa n o i) was h e ld re s p o n s ib le . H o w e v e r it a ppears t h e s a m e o r g a n is m can p ro d u c e s im p le c u ta n e o u s le is h m a n ia s is 1 8 a n d th e is o e n z y m e s tr u c tu r e o f E th io p ia n is o la te s f r o m d iffu s e c u ta n e o u s le is h m a n ia s is ( D .C .L .) is s im ila r to th o s e f r o m s im p le c u ta n e o u s le is h m a n ia s is 8 4 . Z e le d o n 115 o n these g ro u n d s has suggested t h a t L. m e xic a n a p if a n o i is a species in q u e - re n d a . L a in s o n a n d S h a w (p e rs o na l c o m m u n ic - a tio n ) have s h o w n D .C .L . in B ra z il to be d u e to
L. m e x ic a n a am azon ensis w h ic h p ro d u c e s u n - c o m p li c a t e d c u t a n e o u s le is h m a n ia s is in im m u n o lo g ic a lly c o m p e te n t p erso n s in th e sam e g e o g ra p h ic a l area. I t is p o s sib le L. p if a n o i is s y n o n y m o u s w it h L. m . am a zon ensis b u t since th e y have n o t e x a m in e d th e V e n e z u e la n m a te ria l d e s ig n a te d L. p if a n o i th e y p re fe r to use th e n am e L. m e x ic a n a p if a n o i f o r th e m o m e n t, b u t e v id e n c e is b u ild in g u p a g a in st c o n s id e rin g L p if a n o i as a d is t in c t species.
B ry c e s o n 20 n o te d in E th io p ia t h a t th e p r im a r y le s io n o f D .C .L . is fr e q u e n tly o n th e leg in c o n tr a s t t o o r ie n ta l sore w h e re 9 9 % w e re o n th e fa c e. H a lf th e p a tie n ts w it h leg le s io n s had in a d d itio n d e fe c tiv e ly m p h a tic fu n c t io n in th e leg. H e argues th a t th e in d u c tio n o f an im m u n e resp on se in a ly m p h n o d e w h ic h is d a m a g ed o r p re o c c u p ie d w it h c o m p e tin g a n tig e n s m ig h t be re d u c e d o r a llo w th e d e v e lo p m e n t o f a
