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 2 1 ( 1 ) : 1 5 - 2 0 , J a n - M a r , 1 9 8 8 .
D O E S A S P O N T A N E O U S C U R E F O R C H A G A S ’ D I S E A S E E X I S T ?
Rodrigo Z e le d ó n 1, João Carlos P. Dias2, A. Brilla-Salazar3,
J. M arcondes de R ezende4, Luis G. Vargas
1
and Andrea U rbina1.
S i x C o s t a R i c a n C h a g a s ’ d i s e a s e p a t i e n t s , w i t h w e l l k n o w n a c u t e p h a s e h i s t o r y a n d n o s p e c i f i c t r e a t m e n t w e r e e x a m i n e d in s e v e r a l o c c a s i o n s d u r i n g 3 9 , 2 4 , 3 2 , 1 6 a n d
1 4 y e a r s , r e s p e c t i v e l y , f r o m t h e o n s e t. N o m e o f t h e p a t i e n t s p r e s e n t e d h e a r t a b n o r m a l i
t i e s a s r e v e a l e d b y t h e c o n v e n t i o n a l E K G a n d e r g o m e t r y , e x c e p t f o r o n e o f t h e m w i t h a n
i n c o m p l e t e b l o c k o f t h e r i g h t b u n d l e b r a n c h . A l s o , n o a l t e r a t i o n s o f t h e o e s o p h a g u s
m o t i l i t y w a s d e t e c t e d m a n o m e t r i c a l l y e x c e p t f o r a n o t h e r p a t i e n t w h o p r e s e n t e d a s l i g h t
h y p e r s e n s i v i t y r e a c t i o n to a p h a r m a c o l o g i c a l t e s t ( M e c h o l y l ) . T h r e e o u t o f s i x p a t i e n t s b e c a m e s e r o l o g i c a l l y n e g a t i v e i n 1 9 8 1 , r e m a i n i n g a s s u c h u n t i l 1 9 8 6 . B e s i d e s t h e
c o n v e n t i o n a l s e r o l o g y , t h e s e a r c h o f p r o t e c t i v e ( “l y t i c ”) a n t i b o d i e s w a s a l s o p e r f o r m e d
i n 1 9 8 5 a n d 1 9 8 6 , b e i n g c o m p l e t e l y n e g a t i v e in o n e o f t h e “c u r e d ” p a t i e n t s a n d d u b i o u s
i n t h e o t h e r tw o . T h e h y p o t h e s i s t h a t t h e s e t h r e e p a t i e n t s h a d a s s p o n t a n e o u s c u r e , b a s e d o n t h e c l i n i c a l , s e r o l o g i c a l a n d p a r a s i t o l o g i c a l f i n d i n g s i s d i s c u s s e d .
K e y w ords: A m e ric a n try p an o so m iasis. C h a g a s ’ disease. S p o n tan e o u s cure. L ongitu din al studies.
C h a g a s’ d isease, or A m e ric a n try p an o so m ia sis, is endem ic in m o st L a tin A m eric an coun tries w here i t is tra n sm itte d b y se v eral sp ecies o f triato m in e bugs. Its incidence a n d p rev a len c e varies w ithin dif fe re n t g eographical a re as an d this seem s to b e rela ted , as le a s t in p a rt, to th e relative ab u n d an ce, w ithin a ho u se, o f th e p a rtic u la r species o f v ec to r invol v e d 20 29 31 33
A fte r a n acu te p h ase, w hich is n o t alw ay s d etec ted , a ch ro n ic p h ase is stablished. In som e cases it m ay tak e as long as 2 0 y e a rs after th e acu te o n se t for the p ath o lo g ical m an ifestatio n s to ap p e ar (e.g. alteratio n s o f th e h e a r t o r th e digestive tr a c t) 2 8 JO 18 19 22 23.
S ince all p a tie n ts in th e asy m p to m a tic o r inde te rm in ate p h ase re m a in serologically positive for the specific antigen, th e y h av e b een co n sid ered p o te n tia l victim s for the tissu e d am ag e th a t leads to th e different m a n ifestatio n s o f th e d is e a s e 1 8 11 15 18 20 24 25
In th e follow ing p ara g ra p h s w e p re se n t evidence supporting c u rre n t o b se rv atio n s th a t several p atien ts
1. P ro y e c to d e Z o o n o sis, E s c u e la de M e d icin a V e terin ária , U n iv e rsid a d N a c io n a l, H e re d ia , C o s ta R ica.
2. F u n d a ç ã o O sw a ld o C ru z & U n iv e rsid ad e F e d e r a l d e M i n a s G e ra is. D iv isã o de D o e n ç a de C h a g as, S U C A M , M in is té rio d a S a ú d e , B ra sília , D F , B rasil.
3. S erv icio de C a rd io lo g ia, H o s p ita l M é x ico , S a n Jo s é , C o s ta R ica.
4. F a c u ld a d e d e M e d icin a, U .F . G o iá s, G o iâ n ia , G O , B rasil.
E n d ere ço : J o ã o C a rlo s P in to D ia s. S U C A M , M in istério d a
S a ú d e , E s p la n a d a dos M in istério s, B lo co G , a n ex o A , 7 0 0 5 8 B rasília.
R eceb id o p a ra p u b licação em 8 /6 /8 7 .
w ho h a d an ev id en t ac u te p h a s e an d no specific chem o th e ra p y rem a in asy m p to m a tic for long p eriods o f tim e. A lso , as a new h y p o th esis, th a t som e o f th e m m ay sud d en ly b eco m e serologically negative suggesting th a t th e y evolve to w ard s sp o n ta n eo u s cu re o f the in fectio n 3 4 7 17
22
.M E T H O D O L O G Y A N D H IS T O R Y O F T H E C A S E S
In a g eneral w a y this w o rk is a p a r t o f epidem io logical studies a b o u t C h a g a s ’ d ise ase th a t h av e b ee n c a rrie d o u t in C o s ta R ic a since several y e a rs by o ne o f us (Z .). T h e clinic an d la b o ra to ria l follow -up o f som e ca ses th a t h av e p re se n te d a ty p ic al acute p h ase consti tu te a ro u tin e th a t includes p h y sical ex am in atio n , elec- tro -c ard io g ram ( E K G ) , X -r a y o f the ch est, xenodiag- n o ses and c o n v en tio n al se ro lo g y 18 23 28. T h e x enodia- gnoses w ere in itially p erfo rm ed w ith ab o u t 10 th ird in sta r n ym phs o f T r i a t o m a d i m i d i a t a , b u t after 1981
Z e l e d o n R , D i a s J C P , B r i l l a - S a l a z a r A , V a r g a s L G , U r b i n a A . D o e s a s p o n t a n e o u s c u r e f o r C h a g a s ’ d i s e a s e e x i s t ? 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 2 1 : 1 5 - 2 0 , J a n - M a r , 1 9 8 8
D rs. A . K rettli and Z . Brener. The technique utilized was immunofluorescence with living trypomastigotes test (IT L T ), consisting of treating living T . c r u z i try pom astigotes pre-incubated with diluted sera in the presence o f sodium azide a t 4 °C then washed and fixed, plus a fluorescein-conjugated I g G 17.
In o r d e r t o d e t e c t incipient chagasic lesions of the h eart and oesophagus, in 1983 and 1984 these patients were respectively subm itted to ergometric tests, oesophagus m anom etry and m echolyl te sts11 12 13 24. Ergom etry was perform ed in a conventional track apparatus, through progressive tests m onitorized by E K G and blood pressu re11. M echolyl test is a phar m acological technique th at employs a cholinergic stim ulus (m etacholine chloride N .F .) w hich is able to p u t in evidence some alterations of the oesophagus intrinsic innervation12 13 24
In the following sum m arized description the main objective is to characterize the acute phase and the clinical and laboratorial evolution of each case.
A ll the six cases presented a typical picture of acute C hagas’ disease and four o f them had the R om ana sign. T he direct blood exam ination was posi tive for T. c r u z i in five patients, while xenodiagnoses were positive in all o f them during the acute onset. The patien t whose d irect exam ination w as negative was M .C .C h. (case n.° 2). She entered the hospital w ith fe ver, splenomegaly, tachicardia and generalized oede ma. A cute C hagas’ disease was suspected by D r. A r tu ro Rom ero, being confirmed by xenodiagnosis28.
T r i a t o m a d i m i d i a t a was found in the houses o f all the patients. N one of these patients h ad never received specific treatm ent against T . c r u z i . M ore detailed in form ation on clinical and laboratorial findings o f these cases as well as epidemiological data related to them
were presented in different publications28 29 32 34. T able 1 sum m arizes the m ain clinical, epide m iological and laboratorial d ata concerning this group of patients. T able 2 presents the traditional serology perform ed in 1985 and 1986 and table 3 shows the results of non-conventional serology (ITLT).
Z e l e d o n R , D i a s J C P , B r i l l a - S a l a z a r A , V a r g a s L G , U r b i n a A . D o e s a s p o n t a n e o u s c u r e f o r C h a g a s ’d i s e a s e e x i s t ? 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 2 1 : 1 5 - 2 0 , J a n - M a r , 1 9 8 8
T a b le 2 - R e c e n t r e s u l t s o f C o s t a R i c a n p a t i e n t s w i t h t w o c o n v e n t i o n a l s e r o l o g i c t e c h n i q u e s d o d e t e c t s p e c i f i c a n t i -T . cruzi a n t i b o d i e s *
P a tie n ts 1 0 /1 2 /1 9 8 5 2 5 /0 6 /1 9 8 6 F in a l F in a l
Np (in itials) I I F T I H T I I F T IH T In te rp re ta tio n
1 M .C .R .M . N eg . (1 :2 0 ) N e g . 1:8 1 8 N e g a tiv e
2 M .C .C h . 1: 1,024 P o s. 1:128 1 512 P o sitiv e
3 F .B . N eg . N e g . N eg . 1 16 N e g ativ e
4 J .R .M .A . N eg. N eg . 1:8 1 8 N eg ativ e
5 M .A . 1:256 P o s. 1:128 1 128 P ositive
6 F .C h .V . 1:512 1:16 1:32 1 32 P o sitiv e
I I F T : I n d ire c t im m u n o flu o rescen ce test. IH T : I n d ire c t h aem ag g lu tin a tio n test.
* Serology p e rfo rm e d by the S ero ep id em io lo g y L a b o ra to ry . E z e q u ie l D ia s F o u n d a tio n , B elo H o riz o n te , B razil
(D r. H élène D ’H ooge).
T ab le 3 - C h a g a s ’d i s e a s e . R e s u l t s o f t h r e e t e s t s p e r f o m e d i n C o s t a R i c a n s e r a w i t h t h e n o n - c o n v e n t i o n a l i m m u n o f l u o r e s c e n c e t e c h n i q u e m a d e w i t h l i v i n g t r y p o m a s t i g o t e s , 1 9 8 6 °
N .°
P a t i e n t s :
( i n i t i a l s ) T e s t 1
R e s u l t s
T e s t 2 T e s t 3
F i n a l
I n t e r p r e t a t i o n
1 M .C .R .M . P osit. N eg at. D u b io u s D u b io u s
2 M .C .C h . N eg at. P o sit. P o sit. P ositive
3 F .B . N eg at. N eg at. N eg a t. N eg a tiv e
4 J .R .M .A . P osit. D u b io u s N eg a t. D u b io u s
5 M .A . P osit. P osit. P osit. P ositive
6 F .C h .V . P osit. P osit. P o sit. P o sitiv e
* S era p erfo rm ed in th e la b o ra to ries o f R en é R a ch o u R e se a rc h C e n tre, B elo H o rizo n te , M G , B razil (D rs. Z ig m a n B ren er & A n to n ia n a U . K rettli).
D I S C U S S I O N
T h e fact th a t th ree o f th is special group o f six C o s ta R ic a n p atien ts b ec a m e serologically n egative after a c e rta in p e rio d o f tim e is a strong evidence, in our opin io n , th a t th e y ev olved to w ard s a sp o n ta n eo u s cure. I t is im p o rta n t to no te th a t all th e se p atien ts h av e a w ell d o cu m en te d ac u te p h a s e an d n ev e r rec eiv e d specific tre a tm e n t for C h a g a s’ d ise ase . M o re o v er all o f th e m h av e b ee n clinically w ell during all th e p erio d after the ac u te d ise ase , n o n e o f th e m p resen tin g an y evidence o f im m u n o d ép ressio n 6.
T h e p e rsis te n t an d definitive rev ersio n o f th e se rology from positive to n egative resu lts is co n sid ered now ad ay s as the m o st im p o rtan t cure criterion o f hum an C h a g a s ’ d is e a s e 7 9 1 6 1 7 19. S p o ra d ic negative te sts ca n b e o b se rv e d in a few ch ro n ic n o n -tre ated p atien ts, som etim es in the v ery sam e d a y in w ich xenodiagnoses w as found to b e p o sitiv e 19 26. N ev e rth ele ss, this fact is
e x c ep tio n al in lo n g itu d in al studies in endem ic areas w h ere n o rm ally th e serological te sts b eco m e positive again in fu rth er o b s e rv a tio n s3 410 22 23. In ex p erim en ta l la b o ra to ry m o d els sp o n tan eo u s cu re o f T . c r u z i
in fections w as re c e n tly o b se rv e d in o p o ssu n s, w ith p e rsis te n t n egative p ara sito lo g ica l an d serologieai te sts (including the re s e a rc h o f lytic a n tib o d ie s17 27. B y a n o th er w ay th e rev e rtio n o f th e serological te sts to n egative resu lts h a s b e e n o b se rv e d in h u m a n chagasic p atien ts tre a te d w ith specific c h e m o te ra p y in th e acu te p h a s e 7 9 17.
Z e l e d o n R , D i a s J C P , B r i l l a - S a l a z a r A , V a r g a s L G , U r b i n a A . D o e s a s p o n t a n e o u s c u r e f o r C h a g a s ’ d i s e a s e e x i s t ? 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 2 1 : 1 5 - 2 0 , J a n - M a r , 1 9 8 8
gy c a n p e rs is t p o sitiv e for u p to 4 y ea rs in such c a s e s 7 17. I t is im p o rta n t to o b serv e th a t o u r cases n.° 1 ,3 & 4 h a v e show n neg ativ e resu lts fo r co n v e n tio n a l serology since 1981, after m an y exam inations and using different techniques. T h e litres ab o u t 8 in som e recen t tests o f the p atien ts nP 1 & 4 are very inespecific and m u st be con sidered negatives according to cu rren t ex p e rien c e1 3 17
T h e diagn o stic v alu e o f n o n -co n v en tio n al se ro lo gy is v ery high, chiefly co nsidering th e negative resu lts (sen sib ility )6 17. Som e o p era tio n al problem s w ith false positive se ra m a y ex ist a n d m a y h av e o c c u rre d in o u r p atien ts N.°s 1 and 4 (T a b le 3). I t has b ee n frequently found som e dubious results, m ainly in pe rio d s im m ed iatly b efore the definitive co n v e rtio n o f the te s t to n egative o u tc o m es717. F o r th e p a tie n tn ? 3 b o th co n v en tio n al an d n o n -co n v en tio n al m e th o d s show ed co n s iste n t negative results, w h at strongly suggest the p o ssib ility o f s p o n ta n e o u s c u r e 5 7 9 17 19 rec en tly p o in te d o u t b y L u q u e tti19 th e sam e p o ssib ility exists for th e p a tie n ts N . os 1 & 4, w hose co n v en tio n al sero logy h av e p ersisted negative fo r 6 y ears o r m ore. I t is c o n v e n ie n t to follow th e se p atien ts for a t le a s t further tw o o r three y ears in o rd er to analyse the real behaviour o f th e ir clin ical an d im m unological p ic tu re s 7 17. N e v erth eless th e ca se N P 3 a t o n ce c a n be. co n sid ered cured, fa c t th a t ce rtain ly rep rese n ts an d ex c ep tio n in the n a tu ra l h isto ry o f h u m a n C h a g a s ’ d ise a ses 9 10 17 18 19 23 26.
T h e p atien ts n.° 2,5 & 6 still p re se n t positive se rology and co rresp o n d to the abso lu te m ajo rity o f the cases th a t are being stu d ied in endem ic are a s an d lon gitudinal stu d ie s3 7 10 19 23. N o n e o f th o se c a se s have show n any im p o rta n t path o lo g ical alteratio n attrib u ta b le to th e d isease resp ectiv ely after 39, 34 an d 32 y ears. T h e y re m a in in th e so called “ in d e term in a te” fo rm o f ch ro n ic C h a g a s’ d ise ase and p re se n t a v ery good p ro g n o sis2 10 11 18 22 25.
T h e b o rd er-lin e alteratio n s o b serv ed in the E K G o f patient N ? 1 and the mecholyl test o f patient N ? 4 are n o t to b e co n sid ered as signs o f active C h a g a s’ d ise a se 2 50, since b o th alteratio n s can b e se en in n on- infected people as w ell as in ch ag asic peo p le due to resid u a l lesions o cc u rre d in th e p a s t2 15 18. In the specific c a se o f h y p ersen sitiv ity to the m e ch o ly l te s t it o n ly rep rese n ts a m o d e ra te d en e rv atio n o f the intrinsic p ara -sy m p ath e tic p le x u s o f th e oeso p h ag u s, in depen d en tly o f th e aetio lo g ical fa c to r12 13 24.
C h a g a s’ d ise ase in C o s ta R ica h a s b e e n w ell d em o n strate d in sev eral p u b lic atio n s, w ith a serologi cal p rev alen ce o f 1 1 .7 % in a group o f 1 ,4 2 0 peo p le from an a re a infested w ith T r i a t o m a d i m i d i a t a34. So m e local peculiarities such as the absent (or extrem ely low) p rev a len c e o f digestive “ m e g a” syn d ro m es are being n ow studied in the sam e regional difference co n tex t o f C h a g a s ’ d is e a s e 20 21 28 30.
T h is p a p e r suggest th a t som e p atien ts could evolve to sp o n ta n eo u s cu re o f C h a g a s ’ d ise ase after m a n y y ea rs o f activ e infection. I t rem ain s to b e d e m o n stra ted w hether this phenom enon, here rep o rted for C o s ta R ica n p atien ts also o cc u rs in o th e r L atin am e ri- c a n are as w here th is try p an o so m iasis is endem ic. T h is p o ssib ility h as rec en tly b ee n co n sid ered b y A rrib a d a e t a l in C h ile 4 a n d L u q u etti, in B ra z il19, b u t how fre q u en t the fact occurs and the reaso n o f th a t occurrence rem ain to b e investigated.
R E S U M O
U m g r u p o d e p a c i e n t e s c o m d o e n ç a d e C h a g a s v e m s e n d o a c o m p a n h a d o d e s d e a f a s e a g u d a , n a
C o s t a R i c a , c o m t e m p o s d e e v o l u ç ã o e n t r e 1 4 e 4 4
a n o s ( m e d i a n a d e 3 2 a n o s ) . E m t o d o s a d o e n ç a
a g u d a f o i b e m c o m p r o v a d a , n ã o s e n d o r e a l i z a d o
t r a t a m e n t o e s p e c í f i c o e m n e n h u m d e l e s , c o n t r a o
T ry p a n o so m a cm zi. T o d o s a p r e s e n t a r a m p e l o m e n o s u m a s o r o l o g i a p o s i t i v a a o l o n g o d a f a s e c r ô n i c a , m a s
e m t r ê s d e l e s a s t é c n i c a s s o r o l ó g i c a s c o n v e n c i o n a i s s e
t o m a r a m p a r m a n e n t e m e n t e n e g a t i v a s e m d i v e r s o s
e x a m e s e a l i z a d o s e m d i f e r e n t e s l a b o r a t ó r i o s , e n t r e 1 9 8 1 e 1 9 8 6 . N e s t e s tr ê s p a c i e n t e s t a m b é m a p e s
q u i s a d e a n t i c o r p o s l í t i c o s f o i n e g a t i v a ( u m c a s o ) o u
n e g a t i v o d u v i d o s a ( d o i s c a s o s ) , p e r m a n e c e n d o c o n
-s i -s t e n t e m e n t e p o -s i t i v a n o -s t r ê -s o u t r o -s p a c i e n t e -s c o m
s o r o l o g i a c o n v e n c i o n a l r e a g e n t e . A t u a l m e n t e t o d o s o s s e i s p a c i e n t e s s e a p r e s e n t a m a s s i n t o m á t i c o s e c o m
x e n o d i a g n ó s t i c o n e g a t i v o . A p e n a s u m d e l e s a p r e s e n
t a d i s t ú r b i o e l e t r o c a r d i o g r à f i c o m í n i m o e i n e s p e c í f i c o
( b l o q u e i o i n c o m p l e t o d o r a m o d i r e i t o ) e, u m o u t r o , p e q u e n o r e t a r d o d o t r â n s i t o e s o f a g i a n o à p r o v a d e
m e t a c o l i n a . L e v a n t a - s e a h i p ó t e s e d e c u r a e s p o n
t â n e a d a d o e n ç a d e C h a g a s , f a t o q u e d e v e s e r r a r o e
q u e m e r e c e m a i o r i n v e s t i g a ç ã o .
P a la v ra s C h a v es: T rip a n o so m ia se am erican a. D o e n ç a d e C h agas. C u ra esp o n tân e a. E s tu d o longitudinal.
A C K N O W L E D G E M E N T S
Z e l e d o n R , D i a s J C P , B r i l l a - S a l a z a r A , V a r g a s L G , U r b i n a A . D o e s a s p o n t a n e o u s c u r e f o r C h a g a s ’d i s e a s e e x i s t ? 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 2 1 : 1 5 - 2 0 , J a n - M a r , 1 9 8 8
R E F E R E N C E S
I . A n d ra d e Z A . A s p e c to s p a to ló g ico s d a d o e n ç a d e C h a
gas. In te rc iê n c ia 8: 3 6 7 -3 7 3 , 1983.
A n d ra d e Z A , A n d ra d e S G . P a to lo g ia . I n : B re n e r Z , A n d ra d e Z (ed.) T r y p a n o s o m a c r u z i e d o e n ç a d e C hagas. G u a n a b a ra K oo g an E d . R io de Janeiro. 1979.
3. A p t W , A rrib a d a A , C a b re ra L. S an d o v al I. N a tu ra l h isto ry o f ch ag a sic c a rd io p ath y in C hile. F o llo w -u p o f
71 c a ses after 4 y e ars. Jo u rn a l o f T ro p ic a l M ed icin e. 86: 2 1 7 -2 2 2 , 1986.
4. A rrib a d a A , A p t W U g a rte IM . A four y e a r follow -up
su rv ey o f ch ag a sic c a rd io p a th y in C hile. P a n A m e ric a n H e a lth O rg a n iz a tio n B u lletin 20: 2 4 5 -2 6 6 , 1986.
5. B rener Z , A n d ra d e Z (ed.) T r y p a n o s o m a c r u z i e d o en ça de C h ag as, G u a n a b a ra K o o g an , E d . R io de Ja n e iro , 1979.
6. B re n ie re F , P o c h G , S e lae s H , T ib a y re n c M , L e m e s tre F L , A n te z a n a G , D e sje u x P . Specific h u m o ral d e p res sio n in c h ro n ic p a tie n ts in fected b y T r y p a n o s o m a c r u z i .
R e v ista do In stitu to de M e d ic in a T ro p ic a l de S ão P a u lo , 26: 2 5 4 -2 5 8 , 1984.
7. C a n ç a d o JR . T ra ta m e n to específico. I n : C a n ç a d o JR ., C h u ste r M . (e d .) C a rd io p a tia C h a g ásic a. F u n d a ç ã o C a rlo s C h a g as E d . B e lo H o riz o n te , 1985.
8. C a rra s c o H A , P a la c io s-P ru E , M e n d o n z a R V , D a g e rt de S co rz a C . A s p e c to s clínicos de la e n ferm ed ad de C hagas. D ia g n ó stic o de d a n o m io cárd ico . In terc ie n c ia , 8 :3 4 2 -3 5 2 , 1983.
9. C e riso la JA . V alo r dei im m unodiagnóstico en la infección chagásica. I n : Sim pósio In tern acio n al de E n ferm ed ad de C hagas. S o c ied a d eA rg en tin a de Parasitologia: E d. B ue nos A ires, 1972.
10. D ia s J C P . D o e n ç a d e C h a g a s em B am buí, M in a s G e ra is , B rasil. E s tu d o clínico-epidem iológico a p a rtir
d a fase aguda, entre 19 4 0 e 1982. T e s e , F a c u ld a d e de M edicina d a U niversidade F e d e ra l de M in a s G e rais, 1982. M in a s G e ra is, 3 7 6 p ., 1982.
I I . F a r ia C A F . E rg o m e tria n a a v aliaç ão c lín ica d a d o e n ç a de C h a g as crônica. I n : C an ça d o J R , C h u ste r M . (ed.) C a r d io p a tia C h a g ásic a. F u n d a ç ã o C a rlo s C h a g as E d ., B elo H o riz o n te , 1985.
12. G o d o y R A . E s tu d o d a e so fag o p a tia c h ag á sica c rô n ic a p o r m eio do m éto d o ele tro m a n o m é tric o e d a p ro v a d a m eta co lin a em p a c ie n te s com e sem d ila ta ç ã o do e sô fa go. R evista G o ia n a de M e d icin a 18: 1-73, 1972.
13. G o d o y R A ., V ie ira C B . E ffe c ts o f c h o lin erg ic drugs on th e oeso p h ag u s o f p a tie n ts w ith C h a g a s d ise ase. A c ta P h y sio lo g ia L a tin o a m e ric a n a 11: 1 0 7 , 1961.
14. G u im a rã e s M C S . C h a g a s ’ d ise ase serology: specifica tio n s a n d e v alu atio n s m eth o d s fo r im m unological re a
gents. P A H O /W H O W ash in g to n , 1984.
B razilian form s o f C h a g as’d ise ase? L a n c et, 1 :1 3 3 8 -1 3 4 0 ,
15. K o b e rle F . P a th o g en e sis o f C h a g a s ’ d ise ase. C ib a F o u n d atio n S im p o siu m 20: 1 3 7 -1 5 8 , 1974.
16. K re ttli A U . R e sp o sta im une h u m o ral n a d o e n ç a de C h ag as. In te rc ie n c ia 8: 3 7 4 -3 8 3 , 1983.
17. K re ttli A U , C a n ç a d o JR ., Z . B rener. C rite rio n o f cure o f h u m a n C h a g a s ’ d ise ase afte r specific trea tm e n t: re
c e n t a d v an ces. M e m o ria s d o In stitu to O sw a ld o C ru z, 7 9 (supl.): 1 5 7 -1 6 4 , 1984.
18. L a ra n ja F S , D ia s E , N ó b re g a G , M ira n d a A . C h a g a s ’ d ise ase. A clin ical, epidem iologic a n d p ath o lo g ic study. C irc u la tio n 14: 1 0 3 5 -1 0 6 0 , 1956.
19. L u q u e tti A O . C o n trib u iç ã o a o e stu d o epidem iológico, so rológico e p a ra sito ló g ic o d o m egaesôfago chagásico. D iss e rta ç ã o de m estra d o . In stitu to d e P a to lo g ia T ro p ic a l
e S a ú d e P ú b lic a , U n iv e rsid a d e F e d e ra l d e G o iá s , G o iâ nia, 1987.
20. M a e k e lt G A . L a epid em io lo g ia d e la e n ferm ed ad de C h ag as en re la ció n c o n el e co s is te m a d o m iciliário . In te r cie n cia 8: 3 5 3 -3 6 6 , 1983.
21. M ile s M A , C e d ilh o s R A , P o v o a M M , S o u z a A A ., P r a ta A , M a c e d o V . D o ra d ic a lly d issim ila r T r y p a n o s o m a c r u z i stra in s (Z y m o d e m e s) c au se V e n ezu elan and B razilian form s o f C hagas’ disease?. L ancet, 1:1338-1340, 1981.
22. P r a ta A , M a c e d o V O . M o rb id ity o f C h a g a s ’ h e a rt disease. M e m ó ria s d o In s titu to O sw a ld o C ru z 79 (S upl.): 9 3 -9 6 , 1984.
23. P u ig b o J J ,N a v a R h o d e J R , B a rrio s H G , Y e p ez C G . C u a tro an o s d e e stu d io lo n g itu d in al d e u n a c o m u n id a d ru ral c o n en d em icid ad c h ag á sica . B oletin de la O ficin a S a n ita ria P a n a m e ric a n a 4 8 :1 1 2 -1 2 0 , 1 9 6 9 .
24. R e z e n d e J M . C lín ica: M a n ife s ta ç õ e s digestivas. I n : B r e n e r Z . & A n d ra d e Z .(e d .) T ry p a n o s o m a c ru zi e D o e n ç a d e C h a g a s . G u a n a b a r a K o o g a n E d . R io d e Ja n e iro ,
1 9 7 9 .
25. R o se n b a u m M B ., C e ris o la J A . E p id e m io lo g ia de la e n ferm ed ad de C h a g a s e n la R e p ú b lic a A rg e n tin a . O H o s p ita l 6 0 :5 5 -1 0 0 , 1961.
26. S a lg ad o A A , M a y rin k W ., D ia s J C P . E s tu d o c o m p a ra tiv o e n tre re a ç ã o de fix aç ão de c o m p lem en to c o m os
a ntígenos b e n z e n o clo ro fo rm ad o e m etílico e o x e n o d ia g - n ó stico . R e v is ta d o In stitu to de M e d ic in a T ro p ic a l de S ã o P a u lo 12: 3 6 -4 0 , 1970.
27. T h o m a z N ., J a n s e n A M , D e a n e M P . T r y p a n o s o m a c r u z i: th e c o m p le m e n te -m ed iate d lysis (C o M L ) in ex p e rim e n tally in fec te d o p o ssu m s D i d e l p h i s m a r s u p i a l i s . X I R e u n iã o A n u a l so b re P e s q u is a B á sic a e m D o e n ç a de C h a g as (A b s tra c t 1-48). C a x a m b u , M G , B rasil, 1984.
28. W H O /U N D P /W B . W o rk sh o p on guidelines fo r m u lti d iscip lin ary re s e a rc h o n th e e p idem iology o f C h a g a s ’
d isease. D o c . T D R / E P I C H A 7 9 .1 . B ra s ilia /G e n e va, 1979.
2 9 . Z e le d ó n R . E l p ro b le m a d e la trip a n o so m ia s is a m e ric a n a o e n ferm ed a d de C h a g as e n C o s ta R ica . T e s is , M in is té rio de S a lu d P ú b lic a n.° 2 , 1952.
30. Z e le d ó n R . E p id e m io lo g y , m o d es o f tra n sm issio n an d reserv o ir h o sts o f C h a g a s ’ d ise a s e . In T ry p a n o s o m ia s is and L e ish m a n ia sis w ith sp e c ia l re feren ce to C h a g a s ’ d ise a s e . C ib a F o u n d a tio n S y m p o siu m 2 0 (N e w S eries), E ls e v ie r E x c e rp ta M e d ic a , p . 5 1 -7 7 , 1974.
31. Z e le d ó n R . E ffec ts o f T ria to m in e b eh av io r o n T ry p an o -
Z e l e d o n R , D i a s J C P , B r i l l a - S a l a z a r A , V a r g a s L G , U r b i n a A . D o e s a s p o n t a n e o u s c u r e f o r C h a g a s ’ d i s e a s e e x i s t ? 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 2 1 : 1 5 - 2 0 , J a n - M a r , 1 9 8 8
32. Z e le d ó n R , M e n a C . P rim e r c a s o de en ferm ed a d de C h a
gas de la P ro v ín cia de A lajuela. R ev ista d e B iologia T ro p i cal. 1: 5 5 -6 2 , 1953.
33. Z e le d ó n R , R a b in o v ic h J E . C h a g a s ’ d ise ase: A n e co lo
gical a p p ra isa l w ith sp e c ia l e m p h asis o n its in se ct vectors. A n n u a l R eview o f E ntom ology 2 6 :1 0 1 -3 3 , 1981. 34. Z e le d ó n R , S o la n o G , B u rstin L , S w artzw eld er J C . E p i
d em iological p a tte rn o f C h a g a s ’d ise a s e in a n endem ic
a re a o f C o s ta R ica . A m e ric a n Jo u rn a l T ro p ic a l M e d ic i ne a n d H y g ie n e 2 4 :2 1 4 -2 2 5 , 1975.
35. Z e le d ó n R , D ia s J C P , S a la z a r A B , R e z e n d e J M , V argas G u illen L. & U rb in a A . E vidências de c u ra e sp o n tân ea de d o e n ç a d e C h a g a s em C o s ta R ica. I I R e u n iã o A n u a l de P e s q u is a A p lic a d a em d o e n ç a d e C h a g a s , A ra x á , M G . B razil, R e su m o s d o s T ra b a lh o s , pág. 18, 1985.
