H U M A N M U C O C U T A N E O U S L E I S H M A N I A S I S I N T R Ê S
B R A Ç O S , B A H I A - B R A Z I L . A N A R E A O F
L E I S H M A N I A
B R A Z I L I E N S I S B R A Z I L I E N S I S
T R A N S M I S S I O N .
II. C U T A N E O U S D I S E A S E . P R E S E N T A T I O N A N D E V O L U T I O N
Elm er A. Llanos-Cuentas1, Philip D. Marsden1, Edinaldo L. Lago2,
Air C. Barreto1 , César C. C uba
1
and W arren D. Johnson
3
T h e c l i n i c a i r e c o r d s o f l 8 2 p a t i e n t s w i th c u t a n e o u s l e i s h m a n i a s i s p r o b a b l y d u e to L e is h m a n ia b r a z ilie n s is b r a z ilie n s is a r e a n a l y s e d . 6 8 % h a d a s i n g l e l e s i o n w h ic h w a s u s u a l l y a n u l c e r o n t h e l o w e r a n t e r i o r t i b i a l t h ir d . M a n y h a d s h o r t h i s t o r i e s o f o n e to t w o m o n t h s a n d a l i a g e g r o u p s w e r e r e p r e s e n t e d 1 3 % h a d c l o s e d l e s i o n s o f a v e r r u c o s e o r p l a q u e l i k e n a tu r e .
E v o l u t i o n o f t h e s e s k i n l e s i o n s a f t e r t r e a t m e n t w a s r e l a t e d to t h e r e g u l a r i t y o f a n t i m o n y th e r a p y . A l t h o u g h h e a l i n g u s u a l l y o c c u r r e d in th r e e m o n th s , th e t i m e to s c a r r i n g a f t e r c o m m e n c i n g t r e a t m e n t w a s v a r i a b l e a n d r e l a t e d to t h e s i z e o f t h e l e s io n ( p < 0 .0 1 ) . U s u a l l y i f s u f f i c i e n t a n t i m o n y t r e a t m e n t w a s g i v e n t h e l e s i o n c l o s e d .
S e v e n o f t h e te n p a t i e n t s w i th i n i t i a l l y n e g a t i v e l e i s h m a n i n s k i n t e s t s c o n v e r t e d to p o s i t i v e a f t e r t r e a t m e n t . A s i g n i f i c a n t d e c l i n e o f i n d i r e c t f l u o r e s c e n t a n t i b o d y t i t r e s
o c c u r r e d in p a t i e n t s f o l l o w e d , d u r i n g a n d a f t e r t h e r a p y .
K e y w o rd s : C u t a n e o u s le is h m a n ia s is . L e i s h m a n i a b r a z i l i e n s i s b r a z i l i e n s i s . C lin ic a i p r e s e n ta t io n . E v o lu t io n . T r e a t m e n t.
H e r e w e d e s c r ib e o u r fin d in g s in a t o t a l o f 1 8 2 p a tie n t s w it h c u t a n e o u s le is h m a n ia s is o b s e r v e d a n d f o llo w e d in o u r f ie ld c l in i c a t T r ê s B r a ç o s , B a h ia , B r a z il, fr o m 1 9 7 6 to 1 9 8 2 .
M A T E R I A L A N D M E T H O D S
D i a g n o s t i c c r ite r ia a n d m e t h o d s o f p a r a s ite d e t e c t io n h a v e a lr e a d y b e e n d e s c r ib e d in th e fir s t p a p e r o f th is s e r ie s ^ . A p a r t fr o m a c lin i c a i d ia g n o s is a n d c o m p a tib le h i s t o l o g y th e g r e a t m a jo r ity o f p a t ie n t s h a d a p o s it iv e M o n t e n e g r o r e a c t io n ( 9 3 % ) . In th e a n a ly s is a s im p le c l a s s if ic a t io n in to s in g le o r m u ltip le c u ta n e o u s l e s io n s is u s e d .
A s s e s s m e n t o f c u r e w a s b a s e d o n c lin i c a i e x a -m in a t io n a n d a d e c l in e in th e le v e i s o f a n tib o d ie s d e t e c t e d b y im m u n o f lu o r e s c e n c e , w h e n t h e s e w e r e p r e s e n t C lin ic a i h e a lin g w a s d e f in e d a s to ta l s c a r r in g o f t h e in it ia l le s i o n s w it h o u t in d u r a tio n or s a t e ll it e n o d u le s a n d w it h o u t th e a p p e a r a n c e o f o th e r l e s i o n s a t l e a s t s i x m o n t h s a n d u s u a ll y a y e a r a fte r th e e n d o f tr e a tm e n t , d e p e n d in g o n f o llo w up.
W e a t te m p te d to e x a m in e in d ir e c t im m u n o flu o -r e s c e n t a n tib o d y in p a tie n t s a t in te -r v a ls a fte -r h e a lin g . N e w k n o w le d g e o f t h e t a x o n o m y o f A m e r i c a n
h u m a n L e is h m a n ia 1 1 a n d n e w t e c h n iq u e s fo r id e n ti-fic a t io n o f in fe c t in g s p e c ie s im p l ie s fu r th er c lin i c a i s t u d ie s . U p to th e p r e s e n t s u c h s t u d ie s h a v e la c k e d th e n e c e s s a r y t e c h n o lo g y t o p r e c is e ly id e n ti fy th e c a u s a -t iv e o r g a n is m . T h e m a n y r e v ie w s o f c lin i c a i p r e s e n -ta tio n r e ly o n im p r e s s io n s o f h o w L . b r a z i l i e n s i s b r a z i l i e n s i s ( L b b ) b e h a v e s in m a n r a th e r t h a n in f a c t s 17 2 0 . F u r th e r m o r e , s in c e s u c h c l in i c a i s t u d ie s a re u s u a ll y b a s e d o n s h o r t te r m o b s e r v a t io n s o f h o s p it a li s e d p a tie n t s , w it h o u t a d e q u a t e f o llo w u p , t h e y h a v e lim it e d v a lu e .
1 . N ú c l e o d e M e d i c i n a T r o p i c a l e N u t r i ç ã o , U n i v e r s i t y o f B r a s í l i a , 7 0 9 1 0 B r a s í l i a , D F , B r a z i l .
2 . S U C A M , B r a z i l i a n M i n i s t r y o f H e a l t h . 3 . C o r n e l l M e d i c a i C o l l e g e , N e w Y o r k , U S A .
7 o r m a n y p a tie n t s d u e t o th e te r ra in a n d d if f ic u lt y o f i c c e s s in th e r a in s t h is w a s n o t p o s s ib le .
R e c o m m e n d e d tr e a t m e n t s in c e 1 9 7 8 h a s c o n -s i-s te d o f th r e e c o u r -s e -s o f g l u c a n ti m e , e a c h c o u r -s e d e liv e r in g 1 g r a m /k g b o d y w e ig h t o f d ru g in e a c h s e r ie s . T h is im p lie s a d a ily d o s e o f 2 8 m g /k g b o d y w e ig h t o f p e n ta v a le n t a n tim o n y . T h is d o s e is b a s e d o n o u r h o s p it a l e x p e r i e n c e 2 2 . T h e B r a z ilia n M in is tr y o f
H e a lt h p r o v id e s th e d r u g w it h o u t c o s t
T h e m a jo r ity o f in je c t io n s h a v e t o b e g iv e n in tr a m u s c u la r ly s in c e t h e y c a n n o t b e g iv e n u n d e r m e d ic a i s u p e r v is io n . I n s p it e o f e x t e n s iv e c h e c k in g in s o m e p a tie n ts w e c a n n o t b e su r e w h e th e r th e fu ll d o s e w a s ta k e n . T h e s e h a v e b e e n c l a s s if ie d a s ir re g u la r ( I R ) w h e n b o th in d iv id u a l d o s e a n d s e r ie s w a s in te r m itte n t,
p a r t ia lly r e g u la r ( P R ) w h e r e th e in te r v a l b e t w e e n s e r ie s w a s m o r e t h a n o n e m o n th , a n d r e g u la r ( R ) w h e n a t l e a s t t w o s e r ie s in th e m a n n e r p r e s c r ib e d w e r e c o m p le t e d .
W h e n fa ilu r e o c c u r r e d , p a tie n t s w e r e o f fe r e d h o s p it a l t r e a tm e n t e ith e r w it h fu r th er a n tim o n y o r a m p h o te r ic in B . B e fo r e 1 9 7 8 g lu c a n ti m e w a s n o t a v a ila b le a n d n if u r t im o x w a s u s e d . D o s a g e s c h e d u le s fo r th is d r u g h a v e b e e n p u b lis h e d e l s e w h e r e ^ I 5 .
I t w a s p o s s i b l e to f o llo w u p 1 4 6 p a t ie n t s w it h c u t a n e o u s d i s e a s e fo r a m in im u m o f s ix m o n t h s a n d a m a x im u m o f 8 0 m o n t h s . M e a n f o llo w u p tim e w a s 2 4 ± 1 8 m o n t h s . 8 9 % w e r e f o llo w e d fo r m o r e t h a n o n e y e a r , 4 3 % fo r t w o y e a r s a n d 7 % fo r m o r e t h a n 5 y e a r s .
T a b le 1 - C o m p a r i s o n o f 1 8 2 p a t i e n t s w i th c u t a n e o u s d i s e a s e a s r e g a r d s a g e a n d n u m b e r o f l e s io n s .
A g e
( i n y e a r s )
C u t a n e o u s d i s e a s e
T o t a l S i n g l e L e s i o n M u l t i p l e L e s i o n s
N
p %N
p %N
p %< 9 18 1 4 .5 1 9 3 2 .7 3 7 2 0 .3
1 0 - 1 9 5 4 4 3 .5 1 8 3 1 . 0 7 2 3 9 .6
2 0 - 2 9 1 4 1 1 .3 4 6 .9 I S 9 .9
3 0 - 3 9 8 6 .5 5 8 .6 13 7 .2
4 0 - 4 9 1 4 1 1 .3 7 1 2 .2 2 1 1 1 .6
5 0 - 5 9 1 2 9 .7 2 3 .4 1 4 7 .6
> 6 0 4 3 .2 3 5 .2 7 3 .8
T o ta l 1 2 4 1 0 0 .0 5 8 1 0 0 .0 1 8 2 1 0 0 .0
R E S U L T S
C l i n i c a i p r e s e n t a t i o n
T h e d is t r ib u t io n o f a c t iv e le s i o n s in p a t ie n t s r e la t e d to a g e a n d n u m b e r o f l e s io n s is g iv e n in T a b le 1. 6 0 % o f p a tie n t s w e r e u n d e r 2 0 y e a r s o f a g e a n d th e d is e a s e w a s u n c o m m o n u n d e r th e a g e o f fiv e . T h e y o u n g e s t p a tie n t a f fe c t e d w a s 1 8 m o n th s o ld a n d th e o ld e s t 7 3 y e a r s o f a g e . P a t ie n t s u n d e r 1 0 y e a r s o f a g e h a d m u lt ip le l e s io n s m o r e f r e q u e n tly ( p < 0 . 0 1 ) . G o v e r n m e n t s u r v e y d a ta g iv e s th e m a l e / f e m a l e r a tio fo r th e a r e a a s 4 8 / 5 2 Í 0 . T h e s e x r a tio o f d is e a s e n a m e ly 5 7 / 4 3 w a s n o t s ig n if ic a n t ly d if f e r e n t
D u r a ti o n o f th e d is e a s e in r e la tio n t o s in g le a n d m u ltip le s k in le s i o n s is s h o w n in T a b le 2 . I n 5 0 % o f p a tie n ts th is w a s t w o m o n t h s o r l e s s a n d in 7 1 % fo u r m o n th s o r le s s . M o r e s in g le l e s io n s w e r e n o t e d in th e fir s t m o n th o f th e d is e a s e ( p < 0 . 0 5 ) b u t o t h e r w is e
e v o l u t io n t im e s w e r e s im ila r fo r s in g le o r m u ltip le l e s io n s . O f th e 1 8 2 p a tie n t s 6 8 % h a d a s in g le le s io n s , 1 5 % t w o l e s i o n s , a n d 1 7 % t h r e e o r m o r e le s io n s . O n e p a tie n t h a d 5 6 l e s i o n s o f o n l y t w o m o n t h s d u r a tio n . M o s t o f th e m u lt ip le le s i o n s w e r e l o c a l i s e d o n th e s a m e b o d y s e g m e n t o r o n a d ja c e n t s e g m e n t s . I n 8 3 % o f p a t ie n t s th e l e s i o n s w e r e o n th e lim b s . T h e c o m m o n e s t a r e a w a s t h e lo w e r a n te r io r t ib ia l th ir d .
T a b le 2 - A n a l y s i s o f 1 8 2 p a t i e n t s w i t h c u t a n e o u s l e i s h m a n i a s i s a s r e g a r d s d u r a t i o n o f d i s e a s e a n d n u m b e r o f l e s i o n s
D u r a t i o n o f D i s e a s e
N u m b e r o f l e s i o n s
T o t a l S i n g l e l e s i o n M u l t i p l e l e s i o n s
y i f t i s f 11 f l ò J
N . ° %
N
p %N
p %< 1 3 9 3 1 .5 9 1 5 .6 4 8 2 6 . 4
2 2 7 2 1 . 8 1 6 2 7 . 6 4 3 2 3 .6
3 - 4 2 1 1 6 .9 17 2 9 .3 3 8 2 0 .9
5 - 6 1 9 1 5 .3 6 1 0 .3 2 5 1 3 .7
7 - 1 2 6 4 .8 6 1 0 .3 1 2 6 .6
> 13 1 2 9 .7 4 6 .9 16 8 .8
T o t a l 1 2 4 1 0 0 .0 5 8 1 0 0 .0 1 8 2 1 0 0 .0
F i g . 1 M o r p 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 s k i n l e s i o n s f r o m w h i c h L e i s h m a n i a b r a z i l i e n s i s b r a z i l i e n s i s w a s i s o l a t e d . A . T y p i c a l l e i s h m a n i a l u l c e r ( 4 c m s ) o n t h e l o w e r t i b i a l t h i r d C . P l a q u e l i k e i n f i l t r a t i v e l e s i o n o f 2 4 m o n t h s d u r a t i o n .
o f s i x w e e k s d u r a t i o n . C u r e w i t h g l u c a n t i m e ( L T B 1 7 8 ) . B . N o d u l a r i n f i l t r a t i v e l e s i o n o f t h e w r i s t o f s i x m o n t h s
d u r a t i o n . C u r e w i t h g l u c a n t i m e ( L T B 2 6 3 ) .
F a i l e d t o r e s p o n d t o p e n t a v a l e n t a n t i m o n i a l ( L T B 1 3 3 ) . D . V e r r u c o s e m u l t i p l e l e s i o n s o f 2 4 m o n t h s d u r a t i o n . C u r e d
T a b le 3 s h o w s th a t a r e la t io n s h ip e x i s t s b e t w e e n th e s iz e o f th e s k in le s i o n ( m e a s u r e d b y it s g r e a t e s t d ia m e te r in c m ) a n d th e e v o l u t io n tim e . I t is p o s s i b l e to fin d p a tie n ts w it h u lc e r s o f 4 c m a n d o n l y a 1 - 2 m o n th h is t o r y . T h e d ia m e t e r o f t h e l e s i o n s g r o w s r a p id ly in th e fir s t t w o m o n t h s . L e s i o n s o f m o r e t h a n s ix m o n th s d u r a tio n w e r e s ig n if ic a n t ly la r g e r th a n th e o t h e r s ( p < 0 . 0 1 ) .
T a b le 3 - C o m p a r i s o n o f 1 4 6 p a t i e n t a s r e g a r d s th e d u r a t i o n o f d i s e a s e a n d t h e i r s i z e a t t i m e o f i n i t i a l c o n s u l t a t i o n .
D u r a t i o n o f d i s e a s e ( m o n t h s )
N u m b e r o f p a t i e n t s
S i z e o f l e s i o n
( M e a n ± 1 S D ) p V a l u e ( a ) ( c m )
< 1 2
4 2 2 9
2 . 7 + 1 . 4 3
3 . 2 5 + 1 . 3 3 0 . 0 1
N . S . N . S . 0 . 0 1
3 - 4 2 0 3 . 1 8 ± 1 . 2 1
4 - 5 2 3 3 . 3 5 + 1 . 4 4
> 6 3 2 4 . 4 6 + 2 . 9 2
T o t a l 1 4 6
N .S . = N o t s i g n i f ic a n t ( a ) S t u d e n t 's t t e s t
E v o l u t i o n
I n a g r o u p o f 7 7 p a tie n t s w h e r e t h e ir t r e a tm e n t w a s c l o s e l y s u p e r v is e d o n l y 3 5 ( 4 5 % ) t o o k th e t w o c o u r s e s o f g lu c a n ti m e in th e p r e s c r ib e d m a n n e r ( R ) . T h e s e p a tie n t h e a le d in 3 .2 5 ± 2 .5 1 m o n t h s ( m e a n ± 1 s .d ) . T h is is a s ig n if ic a n t ly s h o r te r h e a lin g tim e ( p < 0 . 0 1 ) th a n t h o s e P R p a tie n t s in w h o m t h e r e w a s a lo n g d e la y b e t w e e n s e r ie s ( 4 . 7 6 ± 2 .5 1 m o n t h s ) o r th e I R p a t ie n t s w h o o n l y t o o k th e ir g lu c a n tim e ir r e g u la r ly ( 9 . 7 2 ± 5 .2 1 m o n t h s ) .
F ig u r e 2 s h o w s g r a p h ic a ll y th a t m o s t p a tie n t s w h o s e l e s i o n s r e m a in e d a c t iv e u s e d th e d r u g ir re g u la r ly . A lt h o u g h w e a l w a y s r e c o m m e n d e d th r e e s e r ie s d u e th e d a n g e r o f m e t a s t a s is in a c t u a l f a c t o n l y 1 8 % t o o k th is a d v ic e . E i g h t e e n p e r c e n t o f p a tie n t s a c c e p t e d o n l y o n e s e r ie s , 4 5 % t w o s e r ie s a n d 1 3 % fo u r o r m o r e s e r ie s . I n v a r ia b ly t h e in c e n t iv e t o c o n t in u e t h e r a p y w a s w h e n th e l e s i o n f a ile d t o h e a l r a th e r th a n a n y m e d ic a i a d v ic e . R e g u la r th e r a p y d u r in g th e s e r ie s ( P R ) w a s s u f f ic ie n t fo r h e a lin g in th e g r e a t m a jo r it y o f c a s e s i f o n l y o n e o r t w o s e r ie s w e r e g iv e n a l th o u g h it h a d to b e p r o lo n g e d t o t h r e e t r e a tm e n t s e r ie s in fiv e c a s e s a n d fo u r in t w o c a s e s t o a c h ie v e th is r e s u lt. T h e s e n io r
Number o f p a t i e n t s
I
PR IR1 se r i es
R PR IR 2 se r i e s
R PR IR 3 se r i e s
R PR IR 4 se r i e s
NIJÍBER OF SERIES OF GLUCANTIME
R = Re gu l ar d a i l y t r eat m ent w i t h l e ss t han one mont h bet ween se r i e s PR = Re gu l ar d a i 1y t r eat m ent but more t han one mont h bet ween se r i e s IR = Ir r e n u l a r t r eat m ent bot h i n d a i l y dose and t im es bet ween se r i e s
a u th o r p e r s o n a ll y o b s e r v e d h e a lin g in 6 6 p a tie n t s ( T a b le 4 ) . A s m i g h t b e e x p e c t e d s m a lle r l e s i o n s h e a le d q u ic k e r ( p < 0 . 0 1 ) . T h is h o ld s g o o d i f p a tie n t s w ith ir r e g u la r t r e a tm e n t a r e e x c lu d e d .
L e s i o n s o n t h e h e a d , tr u n k a n d a r m s t e n d e d to h e a l q u ic k e r a l t h o u g h t h is d id n o t r e a c h s t a t i s t i c a l s ig n if ic a n c e ( p = 0 . 0 7 ) . T h e f o llo w in g f a c t o r s d id n o t in fl u e n c e h e a lin g : a g e o f t h e p a tie n t , s e x , d u r a tio n o f d i s e a s e , n u m b e r o f l e s i o n s a n d h is t o lo g y .
S i x t e e n ( 1 1 % ) o f 1 4 6 p a t ie n t s in w h o m f o llo w u p w a s p o s s i b l e e ith e r f a ile d t o c l o s e t h e ir in it ia l le s i o n s ( 9 ) o r r e la p s e d ( 7 ) . O n ly s i x h a d r e c e iv e d g lu c a n ti m e t r e a tm e n t a n d in a li c a s e s th is d r u g w a s t a k e n ir r e g u la r ly . T h e o t h e r p a tie n t s h a d b e e n t r e a te d w it h o r a l d r u g s s u c h a s n if u r t im o x o r a llo p u r in o l. O n e p a t ie n t ( L T B 2 1 6 ) a fte r r e g u la r g lu c a n ti m e t r e a t m e n t h a s c o n t in u e d w it h a n o p e n u lc e r fo r 2 1 m o n t h s . I n a n o th e r p a t ie n t w it h n ip p le l e is h m a n ia s is a f te r fiv e s e r ie s o f g lu c a n t i m e w it h o u t s u c c e s s th e n ip p le w a s e x c i s e d ( L T B 2 5 0 ) . B o t h h a d p o s it iv e le is h m a n in s k in t e s t s . S i x o f t h e s e v e n p a t ie n t s w h o h a d s k in r e la p s e s d id s o in th e o r ig in a l s c a r u s u a ll y w it h in a y e a r o f in it ia l h e a lin g . T h e f o u r p a tie n t s w h o d e v e l o p e d m u c o s a l l e s i o n s a r e d i s c u s s e d in t h e th ir d p a p e r in th is s e r ie s .
T a b le 4 - R e l a t i o n b e t w e e n o f e x t e n s io n o f le s io n ( a r e a ) a n d s c a r r i n g t i m e in 6 6 p a t i e n t s w i th c u t a n e o u s l e i s h m a n i a s i s
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( a ) T i m e i n m o n t h s f r o m s t a r t o f t r e a t m e n t t o h e a l i n g . ( b ) S i n g l e S t u d e n t ’ s t t e s t .
T e n o f 1 2 p a t ie n t s w it h a n e g a t iv e M o n t e n e g r o r e a c t io n r e c o r d e d in T a b l e 1 o f th e p a p e r o n d ia g n o s is 5 h a d th e le is h m a n in s k in t e s t r e p e a t e d a fte r tr e a tm e n t a n d in 7 th e r e a c t io n b e c o m e p o s it iv e . T h e th r e e n e g a t iv e p a t ie n t s ( in t w o p a r a s it e s w e r e is o l a t e d ) w e r e s t ill n e g a t iv e o n e y e a r la te r a n d t w o h a d h e a le d th e ir s k in le s io n s . I n o n e p a t ie n t ( L T B 1 7 9 ) d e s p it e a d e q u a t e t r e a tm e n t l e s io n a c t iv i t y p e r s is t e d fo r 15 m o n t h s b e f o r e s c a r r in g a n d fiv e s e r ie s o f g lu c a n tim e w e r e n e e d e d . A l i w e r e w e ll n o u r is h e d .
T a b l e 5 - E v o l u t i o n o f t i t r e s o f i n d i r e c t i m m u n o f l u o r e s c e n t ( I g G ) a n t i b o d y in 3 6 p a t i e n t s w i th c u t a n e o u s l e i s h m a n i a s i s a f t e r t w o s e r i e s o f G l u c a n t i m e
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T e r m in a ti o n 3 6 11 6 3 7 7 1 1 6 9 .5 4 1 . 1 8 < 0 . 0 0 1 S c a r r in g 3 6 1 2 1 0 6 2 5 1 — 6 6 .5 2 7 . 7 4 < 0 . 0 0 1
3 - 6 m o n t h s a fte r s c a r r in g 3 6 2 1 7 7 1 — — — 4 1 . 7 1 5 .8 7
* M G T = M e a n g e o m e t r i c t i t r e . ( a ) U n p a i r e d s t u d e n t ’ s t t e s t .
A g r o u p o f 1 6 p a t ie n t s w it h a n in it ia lly p o s it iv e l e is h m a n in s k in t e s t w e r e f o llo w e d u p fo r 3 4 + 1 4 m o n t h s ( r a n g e 1 8 - 7 2 m o n t h s ) a fte r s c a r r in g a n d th e t e s t r e p e a t e d . T h e d iff e r e n c e b e t w e e n t w o r e a d in g s w a s 6 . 4 ± 5 . 7 m m ( c o n f i d e n c e lim it s 9 5 % : 3 . 5 6 to 9 . 1 9 ) s u g g e s t in g a s ig n if ic a n t d im in u ti o n in c u t a n e o u s h y p e r s e n s i t iv i t y .
T a b l e 5 s h o w s th e s e r o lo g i c a l titr e s in a g r o u p o f 3 6 p a t ie n t s w h o t o o k t w o s e r ie s o f g lu c a n ti m e w ith r e s u lt a n t s c a r r in g . A s i g n if ic a n t d e c l in e in t itr e s o f th e g r o u p a s a w h o le o c c u r r e d a fte r th is t r e a tm e n t A lt h o u g h o n l y 3 0 % h a d n e g a t iv e s e r o lo g y a t th e tim e o f s c a r r in g
th e r e is a s ig n if ic a n t d e c l in e in t itr e s a f te r tr e a tm e n t ( p < 0 . 0 0 1 ) . F o r t y p e r c e n t o f p a tie n t s 3 - 6 m o n th s a f te r s c a r r in g h a d t it r e s a t a lo w le v e i.
ti-b o d ie s a re s till p r e s e n t a fte r 3 o r 4 y e a r s . P a t ie n ts u s in g ir re g u la r t r e a tm e n t a re c o m m o n in th is c o h o r t.
W e h a v e o b s e r v e d fo u r d iffe r e n t p a t te m s o f titr es r is e a n d fa li in o u r p a tie n t s o v e r th e y e a r s in T r ê s B r a ç o s . T w o c o m m o n o n e s a re in it ia l p o s it iv e titr e s fa llin g t o n e g a t iv e w it h t r e a t m e n t a n d p e r s is t e n c e o f p o s it iv e titr e s in s p ite o f tr e a tm e n t. R a r e r a re p e r s is -t e n -tly n e g a -t iv e s e r o lo g y ( w h ic h c a n o c c u r in -th e p r e s e n c e o f r e c o v e r a b le p a r a s it e s ) a n d ra r er s till n e g a tiv e tu r n in g t o p o s it iv e w ith tr e a tm e n t .
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P a ti e n ts w it h s im u lt a n e o u s c u t a n e o u s a n d m u c o s a l d is e a s e a re c o n s id e r e d in th e th ir d p a p e r ' 6 in
t h is s e r ie s s in c e m u c o s a l d i s e a s e is m o r e im p o r ta n t a s tr e a tm e n t is m o r e d iffic u lt.
O f o u r 6 2 s t o c k s c h a r a c t e r is e d b y m o n o c lo n a l a n tib o d y im m u n o flu o r e s c e n t o r is o e n z y m e a n a ly s is to d a te o n l y t w o h a v e b e e n o f th e M e x i c a n a g r o u p . N e i t h e r o f t h e s e p a tie n t s a r e in c lu d e d in th is a n a ly s is a lt h o u g h th e ir s k in l e s io n s ( o n e s in g le , o n e m u lt ip le ) w e r e n o t r e m a r k a b ly d iff e r e n t fr o m w h a t w e g e n e r a lly s e e in T r ê s B r a ç o s . T h e ta s k o f id e n ti fy in g a li o u r s t o c k s w ill ta k e y e a r s p a r t ic u la r ly a s th e v a lu e o f th e v a r io u s t a x o n o m ic m e t h o d s is s t ill u n d e r d is c u s s io n . It is p o s s ib le th a t o t h e r M e x i c a n a in fe c t io n s a r e p r e s e n t in th e c o h o r t d is c u s s e d h e r e b u t t h e y w ill b e f e w b a s e d o n o u r r e s u lts . W e h a v e n e v e r s e e n a c a s e o f d iff u s e c u t a n e o u s le is h m a n ia s is in T r ê s B r a ç o s w h ic h h a s o n l y b e e n d o c u m e n t e d in B r a z il w it h M e x i c a n a in fe c t io n s .
T h e o v e r a ll c l in i c a i p ic tu r e fits w it h w h a t is o f te n c ite d a s th e c h a r a c t e r is t ic c u t a n e o u s le s i o n s o f L . b r a z i l i e n s i s b r a z i l i e n s i s in f e c t io n 2 . S in g le , d e s t r u c -tiv e , e x t e n s iv e a n d c h r o n ic u lc e r a t iv e l e s io n s b e in g th e m o s t c o m m o n p r e s e n ta t io n . T h e p r e d o m in a n c e o f s u c h le s io n o n th e lo w e r a n te rio r le g s u g g e s ts th a t a lo w fly in g P h le b o t o m in e v e c t o r is b itin g a fr e q u e n tly e x p o s e d s it e . I t is t e m p t in g to r e la t e th e r a p id u lc e r a -tio n t o th e f r e q u e n t n e c r o s is f o u n d o n h i s t o l o g y ^ 21 R id le y 2 1 is o f th e o p in io n th a t t h is n e c r o s is is d u e to th e p r e s e n c e o f th e p a r a s it e . T h is t y p e o f r e s p o n s e c o u ld b e th e m e c h a n is m o f d e s t r u c t io n o f th e p a r a s it e a n d th e s u r r o u n d in g t is s u e s . W h y v e r r u c o s e o r p la q u e lik e le s io n s o c c u r in s o m e p a tie n t fr o m w h o m w e r e c o v e r L b b is n o t c le a r a l th o u g h t h e s e le s i o n s a re u s u a ll y o f lo n g d u r a tio n 2 ® ( F i g u r e i ) .
T h e r e is s o m e in d ic a t io n o f e a r ly ly m p h a t ic s p r e a d in o u r c a s e s 2 . M u lt ip le l e s io n s a re ra r er in th e fir st m o n t h o f th e d is e a s e a n d c o m m o n e r in c h ild r e n .
W e h a v e r a r e ly d e t e c t e d in d u r a te d ly m p h a t ic a r o u n d th e s it e o f th e l e s i o n o r m a r k e d lo c a l ly m p h a d e n o p a t h y b u t t h e s e a re c r u d e m e a s u r e s . W e h a v e r e c o v e r e d p a r a s it e s in in d iv id u a l c a s e s fr o m b o th t h e s e s ite s . C lin ic a l ly th e s iz e a n d d u r a t io n o f m u lt ip le le s i o n s m a y b e a g u id e a s to w h e th e r m u ltip le in f e c t e d s a n d f ly b it e s a re r e s p o n s ib le . F o r in s t a n c e , in o u r p a t ie n t w it h 5 6 le s i o n s o f t w o m o n t h d u r a tio n t w o lo c a lis e d n e a r th e u p p e r t h o r a c ic v e r te b r a l a p p e a r e d in th e fir s t m o n t h a n d w e r e la r g e r t h a n th e o t h e r 5 4 le s i o n s s o m e o f w h ic h w e r e o f p im p le s iz e . T h e c o n c lu s i o n w a s h a e m a to g e n o u s sp r e a d . T o d a te in th is a n d o t h e r p a tie n t s w it h e v i d e n c e o f b lo o d s t r e a m d is s e m in a t io n w e h a v e n o t d e t e c t e d c i r c u la t in g p a r a s it e s b y in o c u la t in g p e r ip h e r a l b lo o d in to h a m s t e r o r c o n c e n t r a tin g w h ite c e l l s a n d s e e d in g c u ltu r e a n d h a m s t e r s . H o w fr e q u e n tly a n d w h e n m e t a s t a s is o c c u r a w a it s c l a r if ic a ti o n u s in g m o r e s e n s i t iv e t e c h n iq u e s fo r is o l a t in g L b b t h a n t h o s e c u r r e n tly a v a ila b le .
A n o t h e r a s p e c t o f m u lt ip le le s i o n s is th a t t h e y d o n o t a lw a y s f o l l o w l o c a l ly m p h a t ic d r a in a g e u n lik e L e i s h m a n i a b r a z i l i e n s i s g u y a n e n s i s ^ 2 b u t c a n a p p e a r in w id e ly d is s e m in a t e d s it e s ( 1 2 % o f o u r p a tie n t s ) . T h e r e is n o s u re w a y o f te ll in g i f th is is d u e to m u lt ip le in fe c t e d b it e s o r r a p id b lo o d s t r e a m d is s e m in a t io n . T h e s p o r o tr ic h o id p ic tu r e o f u lc e r s f o llo w in g ly m p h a tic d r a in a g e w e h a v e o n l y s e e n in th r e e p a tie n t s .
T h a t s in g le e a r ly c l o s e d s k in g r a n u lo m a s w e r e n o t s e e n is d u e p r o b a b ly t o a p a tie n t fa c t o r s in c e t h e y o n l y s e e k t r e a t m e n t w h e n a n u lc e r is e s t a b lis h e d . S u c h e a r ly le s i o n s m u s t o c c u r , s in c e w e s e e th e m in m u lt ip le l e s i o n in fe c t io n s .
A h ig h in c id e n c e in p a tie n t s u n d e r 2 0 y e a r s o f a g e m ig h t s u g g e s t a h ig h r isk o f t r a n s m is s io n . H o w e v e r 5 8 .6 % o f th e g e n e r a l p o p u la ti o n in o u r u n p u b lis h e d f ie ld s u r v e y w e r e in th is a g e g r o u p a n d d is e a s e e x p r e s s io n a p p e a r s t o r e f le c t th e a g e d is t r ib u t io n in o u r p o p u la ti o n . D o e s th e o c c u r r e n c e o f le is h m a n ia s is in c h ild r e n a n d o c c a s i o n a l l y in h o u s e b o u n d w o m e n w h o c l a im n o c o n t a c t w it h t h e c a c a o f a r m s in d ic a t e p e r id o m ic ilia r y tr a n s m is s io n ? W e s till k n o w s o little a b o u t th e e p id e m io lo g y o f th e t r a n s m is s io n o f le is h m a n ia s is in T r ê s B r a ç o s t h a t th is r e m a in s a s p e c u la t iv e q u e s ti o n . D e s p i t e m u c h f ie ld a c t iv it y w e h a v e s t ill to in c r im in a te th e s u s p e c t e d v e c t o r ( L u t z o m y i a w h i t m a n i ) o r fin d a n in f e c t e d a n im a l w it h L b b a p a r t fr o m th e d o m e s t i c d o g 3 .
la r g e s e r ie s w e h a v e h a d n o a b s o lu t e fa ilu r e , b u t its a p p lic a t io n in p a tie n t s liv in g in r e m o te ru ra l a r e a s r e q u ir e s g r e a t e ff o r t. W e h a v e p r o v id e d g la s s s y r in g e s , ta u g h t s t e r ilis a t io n p r o c e d u r e s a n d a t te m p te d t o in s t a ll a n e tw o r k o f p e o p l e w h o c a n g iv e a n in tr a m u s c u la r in je c tio n in s u c h a r e a s . F o r a s ix t y k ilo m a n to a c c e p t 2 0 m l o f d r u g in tr a m u s c u la r ly d a ily fo r te n d a y s is p ainful. W it h c h ild r e n s u c h in je ctio n r e g im e s c a n b e e v e n m o r e d i f f i c u l t I t is n o t s u p r is in g th a t p a tie n t s o f te n a b a n d o n t r e a tm e n t w h e n t h e y s e e a r e s p o n s e . In o u r c lin ic w e g iv e g lu c a n ti m e b y s l o w in tr a v e n o u s in je c t io n ( n o d i l u e n t i s n e c e s s a r y ) . W e a s k a li p a tie n t s t o r e s t f o r 3 0 m in u t e s b e f o r e w a lk in g h o m e . W e a re fo r t u n a te to h a v e h a d n o s e r io u s s id e e f f e c t s in th e a r e a .
T h e m a in c o n c l u s i o n o f o u r d e t a ile d a n a ly s is o f s u c h th e r a p y i s t h a t i f in je c t io n s a re t a k e n a s p r e s c r ib e d th e r e s p o n s e in t e r m s o f c l in i c a i h e a lin g is g o o d e n o u g h in c u t a n e o u s d i s e a s e t o u s e o n l y t w o t r e a tm e n t s e r ie s . A d is t in c t p o s s i b i l i t y e x i s t s t h a t in th e fu tu r e w e c o u ld g iv e n c o n t in u o u s t h e r a p y fo r 2 0 d a y s a t a d o s e o f 2 0 m g S b v / k i l o p e r d a y 2 . H o w e v e r a s d e m o n s t r a t e d b y o u r b r ie f d e s c r ip t io n s o f s o m e o f o u r p a tie n t s in th e r e s u lts s e c t io n , th e r e s p o n s e t o th e r a p y is v a r ia b le a n d s o m e p a tie n t s o n l y r e s p o n d t o m u c h m o r e a n tim o n y t h e r a p y t h a n is n o r m a l.
O u r d a ta a l s o s h o w th a t ir r e g u la r t h e r a p y w ith g lu c a n ti m e i n c r e a s e s s ig n if ic a n t ly ( p < 0 . 0 1 ) th e risk o f r e la p s e , o f s c a r r in g tim e a n d th e p o s s ib ilit y o f t h e r a p e u tic fa ilu r e . A l s o th a t o u r d e c i s i o n to a b a n d o n n ifu r t im o x a lo n e o r n ifu r t im o x p lu s g lu c a n ti m e g iv e n in o n e s e r ie s is ju s t if ie d s in c e th e m a jo r ity o f r e la p s e s h a v e o c c u r r e d in th is g r o u p . W it h n o a lt e m a t iv e d r u g in s ig h t w e m u s t c o n c e n t r a t e o n m o r e e f f ic i e n t g lu c a n ti m e s c h e d u le s fo r f ie ld u s e .
T h a t la r g e r l e s i o n s a r e s lo w e r t o h e a l c o m e s a s n o s u p r is e . A s w e o b s e r v e d e l s e w h e r e 13 it is u n fo r -tu n a te t h a t s o m a n y le s i o n s a r e o n th e lo w e r a n te r io r le g s in c e th is is a s it e o f p o o r v a s c u la r is a t io n w ith im p a ir e d h e a lin g p o w e r .
I n th e fir s t p a p e r in th is s e r ie s w e s h o w e d th a t 9 2 % o f p a t ie n t s h a d a p o s it iv e le is h m a n in s k in t e s t 5 w h e n fir s t s e e n . A lt h o u g h th e m a j o r it y o f t h o s e p a tie n t s w it h n e g a t iv e d e l a y e d s k in h y p e r s e n s i t iv i t y c o n v e r t e d a fte r t r e a t m e n t, o f th e th r e e p a tie n t s w it h p e r s is t e n t ly n e g a t iv e s k in t e s t t w o h e a le d . A lt h o u g h v a r io u s fa c to r s s u c h a s p a r a s it e lo a d , n u tr it io n a l s t a t e e t c . m a y in te r fe r e w it h t h is s k in t e s t 1 n o n e o f th e m c o u ld b e im p lic a t e d in t h e s e p a tie n t s .
I t is t h o u g h t b y s o m e th a t th e le is h m a n in s k in t e s t s r e m a in s p o s it iv e t h r o u g h o u t lif e p e r m it tin g a r e t r o s p e c tiv e d ia g n o s i s o f in fe c t io n in 1 0 0 % o f c a s e s 7 2 0 . T h e g r o u p o f 1 5 p a tie n t s in w h o m w e o b s e r v e d d im in u ti o n o f s k in t e s t r e a c t iv it y a fte r tr e a t m e n t is t o o s m a ll t o d r a w fir m c o n c l u s i o n s b u t o u r r e s u lt s s u g g e s t th a t c h a n g e s in th e le is h m a n in s k in te s t m a y o c c u r m o r e r a p id ly a fte r t r e a tm e n t th a n h a s b e e n n o te d b y o t h e r w o r k e r s 1** 1 9 . T h e p e r s is t e n c e o f s k in t e s t p o s it iv it y c o u ld in d ic a t e th e p r e s e n c e o f liv in g p a r a s it e s a n d th is t e s t m ig h t h a v e v a lu e in th e e v a lu a -t io n o f c u r e . F u r -th e r in v e s -t ig a -t io n is n e c e s s a r y .
D e c l i n e o r d is a p p e a r a n c e o f c ir c u la t in g a n tib o -d ie s is a b e t te r e s t a b lis h e -d c r it e r io n o f c u r e4 6 23 \ y e
h a b it u a lly u s e it in o u r t r e a tm e n t e v a lu a t io n s b o th in th e h o s p it a l2 2 a n d in th e f ie ld 5 a n d a s o u r r e s u lts s h o w t itr e s fa li o v e r tim e a fte r s u c c e s s f u l tr e a tm e n t ( p < 0 . 0 0 1 ) . H o w e v e r w e h a v e a r e la t iv e ly la rg e n u m b e r o f p a tie n t s in w h o m l o w titr e s p e r s is t . W e n e e d fu r th e r s t u d ie s to a s s e s s w h e th e r s u c h titr e s r e p r e s e n t p a r a s it e p e r s is t e n c e . S e r o l o g y is a ls o u s e f u l in p r ed ic t-in g r e la p s e . W e c a n o f fe r n o e x p la n a ti o n fo r w h y s o m e p a tie n t s , e v e n w it h d e t e c t a b le p a r a s it e s , d o n o t d e v e l o p d e t e c t a b le a n tib o d ie s a l th o u g h u s in g th e m o r e s e n s i t iv e E l i s a t e s t t h is n u m b e r is r e d u c e d .
T h e d iffe r e n tia l d ia g n o s is o f A m e r ic a n c u ta n e o u s l e is h m a n ia s is h a s b e e n d i s c u s s e d in d e t a il e l s e w h e -re® 1 7 . T r ê s B r a ç o s p a tie n t s fr e q u e n tly c o n f u s e l e is h m a n ia s is w it h v a s c u la r o r s t a s is u lc e r a lth o u g h t h e s e r a r e ly p r e s e n t d if f ic u lt ie s fo r th e c lin ic ia n . E p id e r m o id c a r c i n o m a s o f b o t h s k in a n d m u c o s a h a v e b e e n m is d ia g n o s e d b e f o r e h is t o lo g y b e c a m e a v a ila b le . F o r t u n a t e ly P a r a c o c c i d i o d e s b r a s i l i e n s i s is e a s ily s e e n in b io p s i e s . S o m e t im e s u lc e r s f o llo w in g tr a u m a ( i n s e c t b it e s , s c r a t c h in g , f o o t b a ll) c a n m im ic le is h m a n ia s is e s p e c i a l l y a s le is h m a n ia l u lc e r a t io n c a n a p p e a r a t th e s it e o f tr a u m a . P r a c t ic e in o u r c lin ic in T r ê s B r a ç o s s u g g e s t s t h a t a n e x p e r ie n c e d c l in i c ia n w ill b e r ig h in th e d ia g n o s i s m a d e o n c l in i c a i g r o u n d s in th e m a j o r it y o f p a tie n t s .
d iffic u lt d i s e a s e s o m e y e a r s a g o 1 5 . H i s t o l o g i c a l a n d p a r a s it o lo g ic a l c u r e a s s e s s m e n t n o t b e in g p o s s i b l e in v ie w o f th e d if f ic u lt y o f b i o p s y w e h a v e to r e ly o n c l in i c a i a n d s e r o lo g i c a l e v i d e n c e .
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F o r a m a n a l i s a d o s o s d a d o s c l í n i c o s d e 1 8 2 p a c i e n t e s c o m l e i s h m a n i o s e c u tâ n e a , p r o v a v e l m e n t e c a u s a d a p o r L e is h m a n ia b r a z i lie n s i s b r a z ilie n s is . S e s s e n t a e o i t o p o r c e n t o a p r e s e n t a v a m u m a ú n ic a le s ã o , u s u a l m e n t e u m a ú lc e r a , n a t e r ç a p a r t e i n f e r i o r a n t e r i o r d a tí b i a . T o d o s o s g r u p o s e t á r i o s e s t a v a m r e p r e s e n t a d o s e m u i t o s a p r e s e n t a r a m h i s t ó r i c o d e u m a d o i s m e s e s . T r e z e p o r c e n t o a p r e s e n t a v a m le s õ e s f e c h a d a s d e n a t u r e z a v e r r u c o s a o u e m p l a c a .
A p ó s t r a t a m e n t o , a e v o l u ç ã o d e s t a s l e s õ e s f o i r e l a c i o n a d a à r e g u l a r i d a d e d a t e r a p i a p o r a n t i m ô -n io . E m b o r a a c u r a u s u a l m e n t e o c o r r e s s e e m tr ê s m e s e s , o t e m p o d e c i c a t r i z a ç ã o , a p ó s o i n í c i o d e t r a t a m e n t o , f o i v a r i á v e l e r e l a t i v o a o t a m a n h o d a l e s ã o ( p < 0 . 0 1 ) . E m g e r a l a l e s ã o f e c h a v a q u a n d o e r a d a d o s u f i c i e n t e a n t i m ô n i o c o m o t r a t a m e n t o .
S e t e e n t r e d e z p a c i e n t e s q u e a p r e s e n t a v a m t e s t e c u t â n e o n e g a t i v o p a r a l e i s h m a n i a t o m a v a m p o s i t i v o s a p ó s o t r a t a m e n t o .
O b s e r v o u - s e p o r f l u o r e s c ê n c i a i n d i r e t a , u m d e c l í n i o s i g n i f i c a n t e n o s t í t u l o s d e a n t i c o r p o s e m p a c i e n t e s a c o m p a n h a d o s d u r a n t e e a p ó s a t e r a p i a .
P a la v r a s c h a v e s : L e i s h m a n i a b r a z i l i e n s i s b r a z i l i e n s i s . A p r e s e n t a ç ã o c l ín i c a . E v o l u ç ã o . T r a ta m e n to .
R E F E R E N C E S
1 . A n d r a d e T M , T e i x e i r a R , A n d r a d e J A F , P e r e i r a C , C a r v a l h o F i l h o E M . E s t u d o d a h i p e r s e n s i b i l i d a d e d o t i p o r e t a r d a d o n a l e i s h m a n i o s e v i s c e r a l . R e v i s t a d o I n s t i t u t o d e M e d i c i n a T r o p i c a l d e S ã o P a u l o 2 4 : 2 9 8 - 3 0 2 , 1 9 8 2 .
2 . A n o n y m o u s . T h e l e i s h m a n i a s e s . W o r l d H e a l t h O r g a - n i z a t i o n . T e c h n i c a l r e p o r t S e r i e s N o . 7 0 1 , G e n e v a , 1 9 8 4 .
3 . B a r r e t o A C , C u b a C C , M a r s d e n P D , V e x e n a t J A , M a g a l h ã e s A V . I d e n t i f i c a ç ã o d a L e i s h m a n i a b r a z i l i e n s i s b r a z i l i e n s i s e m c ã e s n a t u r a l m e n t e i n f e c t a d o s e m u m a r e g i ã o e n d ê m i c a d e l e i s h m a n i o s e c u t â n e o m u c o s a . I X R e u n i ã o A n u a l d e P e s q u i s a B á s i c a d e C h a g a s , p . 1 0 9 , C a x a m b u , M G , B r a s i l , 1 9 8 2 .
4 . C h i a r i C A . P e s q u i s a d e a n t i c o r p o s c i r c u l a n t e s n a l e i s h m a n i o s e t e g u m e n t a r a m e r i c a n a p e l a r e a ç ã o d e i m u n o - f l u o r e s c ê n c i a i n d i r e t a . T e s e d e M e s t r a d o . U n i v e r s i d a d e F e d e r a l d e M i n a s G e r a i s , B e l o H o r i z o n t e , M G , B r a s i l , 1 9 7 1 .
5 . C u b a C C , B a r r e t o A C , L l a n o s - C u e n t a s E A , M a g a l h ã e s A V , L a g o E L , R e e d S , M a r s d e n P D . H u m a n m u c o c u t a n e o u s l e i s h m a n i a s i s i n T r ê s B r a ç o s , B a h i a - B r a z i l . A n a r e a o f L e i s h m a n i a b r a z i l i e n s i s b r a z i l i e n s i s . I . L a b o r a - t o r y d i a g n o s i s . R e v i s t a d a S o c i e d a d e B r a s i l e i r a d e M e d i c i n a T r o p i c a l 1 7 : 1 6 1 - 1 6 7 , 1 9 8 4 .
6 . D e S o u z a W J S , C o u t i n h o S G , M a r z o c h i M C A , T o l e d o L M , G o t t l i e b M V . U t i l i z a ç ã o d a r e a ç ã o d e i m u n o f l u o - r e s c ê n c i a n o a c o m p a n h a m e n t o d a t e r a p ê u t i c a d a l e i s h m a n i o s e t e g u m e n t a r a m e r i c a n a . M e m ó r i a s d o I n s t i t u t o O s w a l d o C r u z 7 7 : 2 4 7 - 2 5 3 , 1 9 8 2 .
7 . F u r t a d o T . C r i t é r i o s p a r a o d i a g n ó s t i c o d a l e i s h m a n i o s e t e g u m e n t a r a m e r i c a n a . A n a i s B r a s i l e i r o s d e D e r m a t o l o g i a 4 7 : 2 1 1 - 2 2 8 , 1 9 8 0 .
8 . G o l d m a n L . T y p e s o f 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 i a s i s - d e r m a t o l o g i c a l a s p e c t s . T h e A m e r i c a n J o u r n a l o f T r o p i c a l M e d i c i n e 2 7 : 5 6 1 - 5 8 4 , 1 9 4 7 .
9 . G u e r r a M , M a r s d e n P D , C u b a C C , B a r r e t o A C . F u r t h e r s t u d i e s o f n i f u r t i m o x i n t h e t r e a t m e n t o f m u c o c u t a n e o u s l e i s h m a n i a s i s . T r a n s a c t i o n s o f t h e R o y a l S o c i e t y o f T r o p i c a l M e d i c i n e a n d H y g i e n e 7 5 : 3 3 5 - 3 3 7 , 1 9 8 1 .
1 0 . I n s t i t u t o B r a s i l e i r o d e G e o g r a f i a e E s t a t í s t i c a . S i n o p s e p r e l i m i n a r d o c e n s o d e m o g r á f i c o . I X R e c e n s e a m e n t o G e r a l d o B r a s i l . V o l u m e 1 , t o m o 1 , N o . 1 4 ( B a h i a ) . R i o d e J a n e i r o , 1 9 8 0 .
1 1 . L a i n s o n R . T h e A m e r i c a n L e i s h m a n i a s i s : s o m e o b s e r v a - t i o n s o n t h e i r e c o l o g y a n d e p i d e m i o l o g y . T r a n s a c t i o n s o f t h e R o y a l S o c i e t y o f T r o p i c a l M e d i c i n e a n d H y g i e n e 7 7 : 5 6 9 - 5 9 6 , 1 9 8 3 .
1 2 . L o w A C h e e R M , R o s e P , R i d l e y D S . A n o u t b r e a k o f c u t a n e o u s l e i s h m a n i a s i s i n G u y a n a . E p i d e m i o l o g y , c l i n i c a i a n d l a b o r a t o r y a s p e c t s . A n n a l s o f T r o p i c a l M e d i c i n e a n d P a r a s i t o l o g y 7 7 : 2 5 5 - 2 6 9 , 1 9 8 3 .
1 3 . L l a n o s - C u e n t a s E A , M a r s d e n P D , T o r r e D , B a r r e t o A C . A t t e m p t s u s i n g c r y o t h e r a p y t o a c h i e v e m o r e r a p i d h e a l i n g i n p a t i e n t s w i t h c u t a n e o u s l e i s h m a n i a s i s d u e t o L . b r a z i l i e n s i s b r a z i l i e n s i s . R e v i s t a d a S o c i e d a d e B r a s i l e i r a d e M e d i c i n a T r o p i c a l 1 6 : 8 5 - 8 9 , 1 9 8 3 .
1 4 . M a g a l h ã e s A V , C h i a r i n i L H , R a i c k A N . H i s t o p a t o l o g i a d a l e i s h m a n i o s e t e g u m e n t a r . R e v i s t a d o I n s t i t u t o d e M e d i c i n a T r o p i c a l d e S ã o P a u l o 2 4 : 2 6 3 - 2 7 6 , 1 9 8 2 .
1 6 . M a r s d e n P D , L l a n o s - C u e n t a s E A , L a g o E L , C u b a C C , B a r r e t o A C , C o s t a J M , J o n e s T C . H u m a n m u c o c u t a n e o u s l e i s h m a n i a s i s i n T r ê s B r a ç o s , B a h i a - B r a z i l . A n a r e a o f L e i s h m a n i a b r a z i l i e n s i s b r a z i l i e n s i s t r a n s m i s s i o n . I I I M u c o s a l d i s e a s e p r e s e n t a t i o n a n d i n i t i a l e v o l u t i o n . R e v i s t a d a S o c i e d a d e B r a s i l e i r a d e M e d i c i n a T r o p i c a l 1 7 : 1 7 9 - 1 8 6 , 1 9 8 4 .
1 7 . M a r s d e n P D , N o n a t a R N . M u c o c u t a n e o u s l e i s h m a n i a s i s - a r e v i e w o f c l i n i c a i a s p e c t s . R e v i s t a d a S o c i e d a d e B r a s i l e i r a d e M e d i c i n a T r o p i c a l 9 : 3 0 9 - 3 2 6 , 1 9 7 5 .
1 8 . M a r z o c h i M C A , C o u t i n h o S G , S a b r o z a P , D e S o u z a W J S . R e a ç ã o d e i m u n o f l u o r e s c ê n c i a i n d i r e t a e i n t r a - d e r m o r e a ç ã o p a r a l e i s h m a n i o s e t e g u m e n t a r a m e r i c a n a e m m o r a d o r e s n a á r e a d e J a c a r e p a g u á ( R i o d e J a n e i r o ) . E s t u d o c o m p a r a t i v o d o s r e s u l t a d o s o b s e r v a d o s e m 1 9 7 4 e 1 9 7 8 . R e v i s t a d o I n s t i t u t o d e M e d i c i n a T r o p i c a l d e S ã o P a u l o 2 2 : 1 4 9 - 1 5 5 , 1 9 8 0 .
1 9 . M a y r i n k W , R a s o P , M e l o M N , M i c h a l i c k M S M , M a g a l h ã e s P A , C o s t a C A , D i a s M . E p i d e m i o l o g y o f d e r m a l l e i s h m a n i a s i s i n t h e R i o D o c e V a l l e y , S t a t e o f
M i n a s G e r a i s , B r a z i l . A n n a l s o f T r o p i c a l M e d i c i n e a n d P a r a s i t o l o g y 7 3 : 1 2 3 - 1 3 7 , 1 9 7 9 .
2 0 . P e s s o a S B , B a r r e t o M P . L e i s h m a n i o s e t e g u m e n t a r a m e r i c a n a . I m p r e n s a N a c i o n a l , R i o d e J a n e i r o , 1 9 4 8 .
2 1 . R i d l e y D S , M a r s d e n P D , C u b a C C , B a r r e t o A C . A h i s t o l o g i c a l c l a s s i f i c a t i o n o f m u c o c u t a n e o u s l e i s h m a n i a s i s i n B r a z i l a n d i t s c l i n i c a i e v a l u a t i o n . T r a n s a c t i o n s o f t h e R o y a l S o c i e t y o f T r o p i c a l M e d i c i n e a n d H y g i e n e 7 4 : 5 0 8 - 5 1 4 , 1 9 8 0 .
2 2 . S a m p a i o R N R , R o c h a R A A , M a r s d e n P D , C u b a C C , B a r r e t o A C . L e i s h m a n i o s e t e g u m e n t a r a m e r i c a n a . C a s u í s t i c a d o H o s p i t a l E s c o l a d a U n B . A n a i s B r a s i l e i r o d e D e r m a t o l o g i a 5 5 : 6 9 - 7 6 , 1 9 8 0 .
2 3 . W a l t o n B C . E v a l u a t i o n o f c h e m o t h e r a p y o f A m e r i c a n l e i s h m a n i a s i s b y t h e i n d i r e c t f l u o r e s c e n t a n t i b o d y t e s t . T h e A m e r i c a n J o u r n a l o f T r o p i c a l M e d i c i n e a n d H y g i e n e 2 9 : 7 4 7 - 7 5 2 , 1 9 8 0 .
