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 2 ( 3 ) : 1 4 7 - 1 5 6 , J u l - S e t , 1 9 8 9
T H E IN D E T E R M IN A T E F O R M OF H U M A N C H RO N IC C H A G A S ’ D IS E A S E A C L IN IC A L E P ID E M O L O G IC A L R E V IE W
João Carlos Pinto Dias
D a ta on the epidem iology a n d the n a tu ra l history o f the indeterm inate fo r m o f hu m a n chronic C hagas’ disease (IF C C D ) are discussed, revealing its g rea t im portance in endem ic areas o f B razil. The w ork show s th a t IF C C D p resen ts a g ra d u a l a n d very slow course, causing a benign p ictu re in the stu d ied patients. E v o lu tio n patterns, p ro g nostic a n d anatom o-pathological fea tu res are also d iscu ssed
F o r p ra c tic a l purposes, the classical concept o f IF C C D p ro v e d to be simple, operational a n d consistent, I t is defined by the absence o f sym p to m s a n d clinical fin d in g s in chronic infected p a tie n ts with p o sitive serology a n d /o r p a ra sito lo g ica l
exa m in a tio n s fo r Trypanosoma cruzi coupled w ith n o rm a l electrocardiographic a n d
radiological ex a m s (heart, oesophagus a n d colon X -R a ys). I f a p a tie n t is su b m itted to m ore rigorous a n d sophisticated tests, these can reveal so m e alterations, g enerally sm a ll ones a n d unable to interfere with the p rognosis o f the infection.
I t is suggested th a t research lines specially related to the evolution ary fa cto rs a n d im m u n o lo g ica l involvem ent during th is p h a se be adopted.
Key-words: Chagas’ disease. Indeterminante form. Prognosis. Evolution factors.«
The indeterminate form of human chronic Cha gas’ disease (IFCCD ) has had very great epidemiolo gical importance in endemic areas. In 1916, Carlos Chagas11 introduced the term “indeterminante”, to in dicate “the absence of predominant clinical syndro mes” while, in 1923, E. Villela^O wrote that “ the indeterminate form has no single description; it is recognized only as a temporary stage of the provisional classification of the cases that will be developing toward one of the clinical forms, or as a latent phase in which the lack of clinical signs will give the appearance of perfect health”. Also called “laboratorial form” or “latent phase”, or even “ sub-clinical” form, IFCCD generally comprises more than half of the infected population in Brazilian endemic areas18 29 32 38
The general concept of IFC C D has an “opera tional” nature, as pointed out by the Laranja’s et al. classic paper of 195629. “ The asymptomatic period, described as the chronic indeterminate form of the disease, comprises a long period, usually from 10 to 20 years, between the end of the acute stage and the establishment of the late heart disease of chronic
Federal University of Minas Gerais and Ministry of Health, Brazil. Work in part sponsored by TD R (UN D P/W B/W H O ) and CNPq, Brazil.
Address: Centro de Pesquisas R ené R a ch o u CP 1743, 30000, Belo Horizonte, MG, Brazil.
Recebido para publicação em 19/11/88.
infection. During the asymptomatic period indivi duals may be considered as belonging to the category of potential cardiac patients. In the endemic areas this group of asymptomatic chronic infection is the largest of the three groups of patients with T. cruzi infection. Although these patients are apparently healthy and asymptomatic, they most important from the epidemiological standpoint” . With the more recent descriptions of the chronic digestive forms of the d i s e a s e 2 2 42 this concept must incorporate the ab sence of the symptoms and signs of the major digestive “ pathies” , the oesophageal and colonic chagasic dysperistalsis^ 35 44
The present concept earned general acceptance with the beginning of the longitudinal studies of Chagas’disease in endemic and non-endemic Brazilian areas in the sixties13 21 31 and was formally discussed in official documents in 197135 and 197421. In November 1984, a very distinguished group of Brazi lian experts was brought together by the Conselho Nacional de Desenvolvimento Científico e Tecnoló gico to discuss IFCCD , and expressed the classical concept in the following terms41: “ Considering the existing controversies on the validity of the concept of the so-called indeterminate forms of Chagas’disease, and also unfavourable repercussion for the patient from the medical, social and laboural points of view, the participants of the First Meeting of Applied Research on Chagas’Disease, taking place in Araxá (MG, Brazil), from December 13th to 15th 1984,
D ias JC P . T h e in d eter m in a te fo r m o f h u m a n c h ro n ic C h a g a s ’ d isease. A c lin ic a l ep id e m io lo g ic a l review. R e v is ta d a S o c ie d a d e B ra s ile ir a d e M e d ic in a T ro p ica l 22: 1 4 7 -1 5 6 , Ju l-S e t, 1 9 8 9
decided to estab lish th e following as criteria fo r its ch aracterisation:
1. Serological a n d /o r parasitolo gical positivity; 2. A b sen ce o f sym ptom s a n d /o r signs o f the disease;
3. N o rm al conventional electrocardiogram ; 4. N o rm al h eart, oesophagus an d colon X -ra y images.
T h e G ro u p consid ered it convenient to m ain tain this co n cep t o f the indeterm inate form in clinical ev alu atio n an d epidem iological studies, takin g into acco u n t th e good pro gnosis fo r the cases.
F in ally , the G ro u p em ph asised that, w hen su b m itted to m ore sensitiv e exam in atio n m ethods, chaga- sic patients inclu ded in the criteria above can show som e changes, b u t this fac t d o es n o t invalidate the concept here ex p ressed ” .
I F C C D no rm ally show s its highest in cid ence in the first 10 o r 15 years o f the infection, im m edia tely after the acute phase; th is inclu des the younger group o f p atien ts in endem ic a re a s18 32. I t m u st be em phasi sed th a t the acute period o f th e disease passes unno ticed, w ith few o r no sym ptom , in the great m ajo rity o f the ca s e s1 8 20 29 T h is “ in ap p aren t” form o f acute
C h ag as’ d isease w as d escrib ed b y G . T eix eira ^ 8 in 1977, having A . T e ix e ir a ^ d etecte d im m unosuppre- sive ph en o m en a in th ese patients.
N ev erth eless, this in a p p a re n t acute C h ag as’ disease m u st no t be confused w ith IF C C D , since the p atien ts p re se n t a t le a st som e fever, an d positive fresh blood exam in ations. A s described b y L aran ja e t al29, the sim plest crite ria to distinguish the end o f acute phase are th e su bsid ence o f the acute clinical m anifes tations an d the red u ctio n o f the n u m b er o f try p an o so - m es in the blo o d to su ch levels th a t can no longer be
detected on fresh exam in ation. O ne very im p o rtan t co nsid eration a b o u t this tran sitio n al perio d b etw een the end o f the acute an d the beginning o f the chronic ph ase is the possib ility o f a parasitological cure for m any patien ts, since adequ ate specific treatm en t m ay be p erform ed at this time^ ^ .
G en erally , the I F C C D begins a few w eeks o r m onths after the acu te phase, as show n b y longitudinal studies. A m ong 317 sym ptom atic acute p atien ts followed in Bam bui (M G , B razil) the great m ajority o f the cases p a sse d to th e chronic “ laten t” perio d in the first six m onths after the beginning o f the infection; the fever an d clin ical p ictu re d isap p ea red first an d the norm alisatio n o f E C G and card iac X -ra y s w ere observed later. N ev ertheless, in a few p a tie n ts a p ersisten t card iac involvem ent could be observed after the acute episode, w ith E C G d istu rb an ces (P R enlarg em ent o r T w ave d istu rbances) a n d /o r p ersis ten t card iac enlargem ent fo r several years, even in the absence o f fever, card iac failu re o f o th er im p o rtan t sym ptom s. In a few o th er cases it w as n o ted th at I F C C D h ad a very sh o rt du ratio n (on e o r tw o years) after the acu te p hase, since h e a rt o f oesophagic chronic involvem ent w ere soon d e te c te d 18. F inally , in ano ther sm all g roup o f p atien ts, th ere w as a variable p erio d o f betw een tw o an d five years during w hich tra n sie n t episodes o f an acute h e a rt involv em ent (chiefly elec trocardio graphic d istu rb ances) a ltern ated w ith typical I F C C D , until the estab lish m en t o f persistent I F C C D o r definite chro nic form.
D ia s JC P . T h e in d e te rm in a te f o r m o f h u m a n c h ro n ic C h a g a s ’ d isea se. A c lin ic a l e p id e m io lo g ic a l review. R e v is ta d a S o c ie d a d e B r a s ile ir a d e M e d ic in a T r o p ica l 2 2 : 1 4 7 - 1 5 6 , Ju l-S e t, 1 9 8 9
In the m ajority o f p atien ts I F C C D persists fo r 10 to 20 y e a rs after infectio n w ith T . c r u z i l % 38 Som etim es individuals rem ain indefinitely in this “ laten t” stage, a n d it is com m o n to detect them living in endem ic areas w hen ov er 70 years o f a g e 2 2 .
A b o u t 2 -5 % o f p atien ts w ith I F C C D evolve tow ards the sym pto m atic d isease form each year. T he m ore com m on ev olution p a tte rn is an incipient chaga- sic cardiopathy, o r in to the initial degrees o f oesopha- gic involv em ent
1
%22 32
j
ab ie \ sum m arises the m ainIt seems th erefo re th a t individuals whith less car diac involv em ent during th e acute p h ase have a ten den cy to rem ain free o f card io p ath y durin g the chronic stage. T h ese d ata agree with recent experim ental works.
S chlem per Jr.46 verified in w hite m ice a positiv e correla tion betw een the m ore severe chronic cardio p ath y (esp ecially w ith histo lo gical fibrosis) an d the intensity o f acu te m yocard ial inflam m ation. Sim ilary, R am irez39 o b served m ore im p o rtan t chronic electro cardio graphic distu rb an ces in rab b its w hich had
clin ical fo rm s o f ch ronic C h ag as’ d isease in p atien ts ob served o v er sev eral y ears in th e endem ic a re a of B am bui, B ra z il18.
T h is T ab le show s th a t m o st young p atien ts generally p re sen t I F C C D w ith m o re th a n 8 0 % in this asy m ptom atic form in th e first te n y e a rs after infection, i.e. people from 10 to 2 0 years o f age, since the o n s e to f the acute p h ase occu rred in p eople betw een on e and ten y ears o ld 18.
Still considering this longitudinal study, som e facto rs related to the clin ical p ictu re m ay be ob serv ed 16 20. F irstly th e pre valence o f E C G alterations during th e chronic p h ase w as significantly higher in the patients w ho d isp lay ed abnorm al E C G ’s during the acute ph ase, th a n in tho se w ho h ad norm al tracings during this early stage o f th e disease (T ab le 2).
sh o w n E C G a ltera tio n s in the a c u te p h a se th a n in
th o s e th a t h a d n o su c h c h a n g es .
T h e pre valence o f digestive form s am ong p a tients w ho h ad a m ore severe acute p h ase w as significantly higher th an in those w ith m ore benign acute episode. A g re ater tend ency to p re sen t chronic card io p ath y w as o bserved in th o se p atien ts w hose acute p h ase o ccu rred a t lo w er ages (0 -2 y e a rs)18.
A n o th e r im po rta n t fa c to r in th e natural h is to ry o f C h a g a s ’ d is e a s e is th e p a ra s ite stra in in v o lv ed . S e v e ra l la b o ra to ries h a v e sh o w n d ifferen t e v o lu tio n
pa tterns o f th e d is e a s e in a n im a ls e x p e rim e n ta lly in fec te d w ith stra in s o f T. c r u z io f d iffe ren t v iru le n c e, including the degree o f parasitic histotropism 6 22 34 35 43
N e v e r th e le s s , it m u s t b e s tre ssed th at, in a pa rticu la r en d em ic a rea, th e e x p e c te d te n d e n c y is g e n e ra lly th at
o f a h o m o g e n o u s p o p u la tio n o f circ u la tin g p a ra site s, a s su g g es te d b y S . A n d ra d e 2 a n d D i a s 1 8 . T h e s e o b ser v a tio n s are still m o r e im po rta n t w h e n o n e ta k e s in to a cc o u n t th at, in a rea s in w h ic h th e v ecto r co n tro l prog ram m e sta rted , a c u te c a s e s b e c a m e m o r e and
m o re rare and s ev er e c a s e s in y o u n g p e o p le d isa p p ea red 18 2 ®. It s e e m s that, u nder stro ng v e cto ria l trans m is sio n p r essu r e, th e in c id e n c e o f s e v e r e a c u te c a s e s in y o u n g er p e o p le is h ig h er th a n in a rea s w h e re the tr a n sm is sio n rate is lo w ; th is o b ser v a tio n m a y p a rtly e x p la in th e d ifferen t d e g r ee s o f m o rb id ity o f the
ch ro n ic d is e a s e in e n d em ic a r e a s 1 8 .
T h e clin ical evolution o f p atien ts w ith I F C C D is generally slow an d benign. In the S ao F elip e pro ject, M a ced o 32 h as verified that, am ong 4 0 0 chagasic patients w ith this form, 96 (2 4 % ) pro gressed to an o th er clinical form in a period o f 10 years, as show n
D ia s JC P . T h e in d e te rm in a te f o r m o f h u m a n c h ro n ic C h a g a s ’ d isease. A c lin ic a l ep id e m io lo g ic a l review. R e v is ta d a S o cied a d e B ra s ile ir a d e M e d ic in a T ro p ica l 2 2 : 1 4 7 -1 5 6 , J u l-S e t, 1 9 8 9
in T ab le 3. T his study w as perform ed in a n endem ic a re a o f B ah ia S tate, B razil, w ith a n o n-selected general populatio n. T h e I F C C D group rep resen ted 5 0 % o f the ch agasic p atien ts o f the are a an d w as m ade u p o f individuals o f b o th sexes, m ostly you ng people (5 0 % under 2 0 y ears o f age).
D a ta are also very sim ila r in o ther endem ic B razilian a re a s 14 18 an d even in a longitudinal study perform ed in B uenos A ires33.
In M in as G e ra is S tate, C o u ra and P e re ira 14 have determ ined the ev olution o f 76 cases follow ed fo r 6 years in th e N o rth e a st an d 57 ca se s follow ed for 10 years in th e W e s t o f the S tate (T a b le 4).
T h e po ten tial o f I F C C D fo r determ in ing the evolution into the sym ptom atic form seem s to be higher am ong young m ale th an am ong fem ales patients up to 40 years^ 18 25 . A ccording to M aced o , 5 0 % o f the indeterm inate p atien ts w ho evolved into the sym p to m atic form w ere in the age group betw een 10 an d 20 years; 4 0 % betw een 21 an d 49 an d only 1 0% w ere under 5 0 y ears old32.
T h e long term evolution o f p atien ts with I F C C D is generally very favourable, and th ey usu ally die of causes o th er th an C h ag as’ disease. M o rtality d a ta on these p atien ts are available in som e longitudinal
studies su ch as those o f M a c ê d o 32, D ia s 18, D ias an d K lo etzel23 an d F o ric h o n 2^ show ing a very good q u o d v i t a m prognosis fo r the p atien t betw een f i v e an d ten years after th e diagnosis, in an y age group. F o r insta nce, in th e S ão F e lip e study o nly eight patients d ied am o n g st 4 0 0 in div iduals p resenting th e indeter m inate form , seven o f them d u e to no n-chag asic cau ses an d o n e b e c a u se o f acute chagasic m yo card itis d u e to reinfection32. In the B am bui study, none o f the 37 patients follo w ed u p since th e acute o n set w ho died in the chronic phase w as in the indeterm inate fo rm 18. F o rich o n 25, still in B am bui, verified th a t n o t m ore th an 3 % am on gst 885 ad u lt chagasic p atien ts w ithout cardiac inv olvem ent died durin g th e following 10 years, w hilst the general m o rtality rea ch ed 3 0 % for fem ale a n d 4 5 % fo r m ale p a tie n ts w ith chagasic chronic cardio p athy .
S im ilar d a ta w ere o b tain ed b y C o u ra an d P erei r a 14 w ho follo w ed 116 in determ inate p atien ts fo r six y ears a n d 130 fo r ten years, w ith n o deaths, in an endem ic a re a o f M in as G erais. T h e se d a ta suggest once m ore, as did v ery e a rly C a rlo s C h ag as’ an d L aranj a e t al th a t the m ain cau se o f d e a th from C h ag as’ disease is still the severe h e a rt in v o lv e m e n t T herefore, since the m o st com m on evolution p a tte rn o f I F C C D is to initial benign card io p ath y (T a b le 3), it is easy to u n d erstan d w hy the im m edia te an d m ediu m -term pro gnoses o f p atien ts are so good.
T h e general pre valence o f I F C C D is a b o u t5 0 % am ong all chagasic people in endem ic a re a s 1 4 3 8 . L ongitudinal and cross sectional specific studies m u st take in to acco u n t the age gro ups o f th e population, since th e m ajo r evolution p o ten tial belongs to the younger groups an d also b e cau se it is som etim es very difficult to rea ch conclusions ab o u t C h ag as’ d isease in older ag es18 33. In o th e r w ords, becau se o f th e evolu tive potential o f som e patients, those in I F C C D m u st be closely o b serv ed b y th e p rim ary h ealth services. E a rly d etection o f h e a rt involv em ent m akes th e clinical m anagem ent o f ch ronic chagasic card io p ath y m uch
e a s y1^ 2 6 U nfortunately, it seem s th a t specific treat m ent o f p atien ts in the indeterm in ate form resu lts neither in cure (ex cep t fo r som e young p atien ts)2 4^ n o r in the interrup tio n o f the evolution co u rse8. M an zu llo and D a rra id o u 33 o bserved 185 chronic patients durin g eight y ears o r m ore, p a rt o f them treated w ith N ifurtim ox and the o th e r p a rt untreated. B oth th e se groups h a d norm al E C G ’s and X -ra y s a t the beginning o f the study, an d electrocardiographic distu rb ances em erged a t a n annu al rate o f 6 .6 % and 6 .7 % respectiv ely.
R a c e , s e x , co n c o m ita n t o r intercurrent d is e a s e s , n u tritiona l sta tu s a n d a lc o h o lis m a re so m e g enera l fa ctors th a t m u st a ffe c t th e n atu ra l h isto ry o f the d is e a s e 2 3 6 13 18 19 2 0 25 38 W o r k is a v e r y im po r
D ia s JC P . T h e in d e te r m in a te f o r m o f h u m a n c h ro n ic C h a g a s ’ d isea se. A c lin ic a l ep id em io lo g ica l review. R e v is ta d a S o c ie d a d e B r a s ile ir a d e M e d ic in a T r o p ica l 2 2 : 1 4 7 - 1 5 6 , J u l-S e t, 1 9 8 9
w h o s h o w e d th e v e r y h ig h e x e r c is e p e rfo rm a n ce o f a du lt rural w o rk ers w ith I F C C D (g ro u p I) in c o m p a riso n w ith n o rm a l in d iv id u a ls and ch a g a sic p a tie n ts w ith c o m p le te right b u nd le b ran ch b lo c k (g ro u p s I I and
H I ). T a b le 5 su m m a r is es th e s e resu lts.
T h e g o o d w o rk p e rfo rm a n ce o f in d iv id u a ls w ith I F C C D is g en e ra lly a cc ep te d . T h e in ter feren ce o f w o rk w ith th e c lin ic a l co u r se o f th is fo rm is still n o t
c o m p le te ly clea r. It s e e m s th at so m e in d iv id u a ls ca n rem a in a sy m p to m a tic a ll th eir liv e s in en d e m ic a rea s, in sp ite o f v e r y ha rd p h y s ic a l w o r k 18 3 2 . B u t it is a ls o true th at h ig h p h y s ic a l effort c a n interfere in ca rd ia c eq uilib riu m p r o d u cin g p a th o p h y sio lo g ic ch a n g es in the
m y o ca rd ia l u n its th at, in c h a g a sic h earts, co u ld in d u c e
p ro g re ssiv e d e g r ee s o f ca rd ia c fa ilu re4 18 19 26 28
T h e e v o lu tio n to w a rd s th e “ c lin ic a l” fo rm s is d ir e c tly re la te d to th e d u ratio n o f th e d is e a s e . A s P ra ta a n d M a c e d o^ 8 h a v e o b s e r v e d “ th e lo n g er th is tim e th e m o re c h a n ce th ere is o f c a rd io p a t h y a pp ea ring ” .
P a r a site m ia p e r s ed o e s n o t a p p e a r to m o d ify th e
co u r se o f c h ro n ic C h a g a s ’ d is e a s e , a cco rd in g to C a s tro 10 a n d D i a s 1 8 . N e v e r t h e le s s P i f a n o ^ sta tes th at ca rd ia c in v o lv e m e n t is m o re lik e ly to a pp ear in in d iv id u a ls w ith a h ig h p a ra sitem ia , m ea su re d b y x e n o d ia g n o sis.
D i a s 16 a n d M a c e d o ^ 1 su g g e st th a t th e c lin ic a l
e v o lu tio n m a y a ls o b e in flu e n c ed b y rein fectio n s , b u t
Di a s J C P . T h e in d e t e r m in a t e f o r m o f h u m a n c h r o n ic C h a g a s ' d is e a s e . A c l i n i c a l e p i d e m i o l o g i c a l r e v ie w . 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 ic a l 2 2 : 1 4 7 - 1 5 6 , J u l- S e t , 1 9 8 9
this factor did not appear to be important in the longitudinal study in Bambui18.
As remarked above, the acute episode influen ces the clinical course of the chronic phase3 1 8 2 2 39. Andrade2 stresses that IFC C D generally means a general picture of inactive scarce inflammatory foci remaining from the acute phase, with few possibilities of evolution. As suggested by Koberle2 8 the autono mous denervation, chiefly occurring in the acute phase, can result in clinical chronic signs, which depend on the physiological balance between the involved functions and the number of neurons des troyed. In the chronic phase, the acute denervations is slowly increased by a slight chronic denervation and also by age-dependent physiological denervation3 84 2 The anatomical substrate of IFC C D was studied chiefly by Chapadeiro12, Andrade2 and Lopes et al30. Generally the digestive tract of the patients with this form presents some degree of intramural autonomous denervation, with or without scarce detectable chronic inflammatory foci3 2 8 44. General para-sympathetic denervation is nearly always present in Brazilian patients with IFCCD , but this condition is not fre quently detectable in some other endemic countries such as Venezuela and Central America1 8 44. On the other hand, as stressed by Rezende44, “ the greatest variation in the level of denervation seen among infected individuals belonging to the same community or the same family, points to the existence of important immunological factors linked to the host” .
In the heart, the systematic studies performed in asymptomatic individuals who have died in accidents can be summarised as follows1 2 3®:
a) The volume and the weight of these hearts are within normal limits.
b) Macroscopically, about 90% of the hearts present thick white pericardic formations sometimes presented as little plaques, or as tendinous spots, or even as rosary-form nodes; microscopically these formations represent an active chronic pericarditis that can reach some autonomic nervous intracardiac gan glia or threads;
c) The myocardium generally presents a ma croscopically normal aspect, but sometimes can be come thin (1 0%) and, more rearely, shows wall aneurysms. The myocardial features in IFC C D commonly consist of lympho-plasmocytic infiltra tions that are small and scarce, but sometimes can constitute larger foci with associated myocytolysis. There are frequent tiny fibrotic scars in some parts of the myocardium. In dogs that survived acute disease, Andrade1 verified several degrees of cicatricial lesions in the myocardium, in the conducting tissue of the heart and in intra-cardiac vagal neurons. He concluded that “it was apparent that the destructive changes occurring during acute infection and involving struc
tures that cannot regenerate will leave cicatricial areas in the heart and, presumably, elsewhere. Will such cicatricial lesions in the conducting tissue and auto nomic nervous system be responsible for the positivity of the refined tests when cardiac function is explored in asymptomatic Chagas’ patients?”
d) The inflammatory process is more evident in the region of the v e r te x ;
e) The endocardium is generally normal, but in a few cases may be thickened because of fibroblastic proliferation;
f) The finding of amastigote forms 6f the parasite is exceptional.
As a more general conclusion, Lopes et al3^. have stated that inflammatory lesions are always observed in all chagasic patients and that different levels of involvement in the heart of patients with IFC C D may explain at least in part, the clinical differences amongst the cases. These authors also stated that it is very difficult to establish the evolutive potential of the focal lesions observed in patients with IFCCD.
The long silent period between the acute in fection and the late cardiac manifestations of chronic Chagas’ disease still remains without an adequate explanation. When chronic myocarditis starts, it appa rently assumes a self-perpetuating mechanism and progresses until the death of the h o st Although it is not known the nature of the a n t i g e n s ^ responsible for the
Di a s J C P . T h e in d e t e r m in a t e f o r m o f h u m a n c h r o n ic C h a g a s ’ d is e a s e . A c li n i c a l e p id e m i o l o g i c a l r e v ie w . 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 ic a l 2 2 : 1 4 7 - 1 5 6 , J u l- S e t, 1 9 8 9
pathway depends on a delayed-type hypersensitive m echanism1 2.
In spite of the several evolutive possibilities of IF C C D1 5 19, or even the accumulated data about histological, haemodynamic and pharmacological dis turbances that can be detected in some of these ca ses1 5 1 8 it must be stressed that classical definition of IFC C D is above all, a practical and operational concept based on two main considerations:
a) This concept is sufficiently simple to be useful in any kind of area or medical service. Besides serological diagnosis, it demands no more than a good clinical examination, a conventional E C G and simple x-ray apparatus able to perform chest examinations, oesophagic barium meal transit studies and simple contrast examinations of the colon6 31 35 44
b) The concept itself is very consistent, since the patients labelled as “ indeterminate” really present very good work performance and an immediately favourable clinical evolution in m ost o f the reported cases13 14 18 24 32 33 38.
Nevertheless, using “ secondary” more sophis ticated methods, cardiac and oesophagic abnormali ties may appear in “ indeterminated” patients15 38 41 Therefore, within the classical concept o f IF CCD, two main groups o f patients can be distinguished: those individuals whose results remain normal and those who show some alterations with “ secondary” exa minations. A s stressed by P rata and M acedo38, it is difficult to determine whether these two groups have a different prognosis. Histopathological changes veri fied in cardiac biopsies15, small and transient atrio ventricular conduction abnormalities after vagolytic drug adm inistration38, echocardiographic36, vec- tocardiographic15, haem odynam ic15 and cardiac autonomic disturbances27 are some alterations that can be detected in patients with IF C C D . Also inci pient neuro-motor incordination m ay emerge in ma- nometric oesophagic studies43. Psychological distur bances can also be detected in the “ asymptomatic” patients, as pointed out by Vieira49, since autonomic denervation occurs in the acute phase and the day life tensions can induce them to be hyperreactive (stres sed) to the different environmental stimuli.
These considerations do not invalidate the clas sical concept of IFCCD , as mentioned in the Araxa document41. The really pertinent problems on the correct definition of the indeterminate form concern chiefly the operational aspects of the basic diagnosis, namely:
a) A consistent serologic diagnosis, involving, at least, two concordant serological tests;
b) A correct and detailed clinical examination, taking into account the basic aspects of the disease. Official guidelines for this examination have been
published by W HO and CNPq6 3 5 and must be used both in individual and population studies;
c) The precise and homogeneous interpretation of the ECG, in order to eliminate the concessions in interpretation pointed by Decourt et al15. (The same considerations can be applied to the radiological exami nation, concerning both interpretation and technical aspects). TD R and other institutions are trying to standardise specific criteria and guidelines to make these examinations comparable in every area;
d) The consistent differential diagnosis with other prevalent diseases. For this it is very important to establish the real “ chagasic component” of heart or digestive problems in individuals. For instance, young patients with IF C C D can be affected by idiopathic myocardiophaties, whilst old chagasic patients may present presbioesophagus, hypertensive or myocardic sclerotic lesions without any participation of Chagas’ disease in such disturbances1 7 29. In most epidemio logic and comparative studies the patients with other heart and/or digestive problems must be removed even it they are in IFCCD.
For practical purposes, the basic clinical exa mination of patients in IFC C D can be improved with minimal resources, even in field work. The various workshops of the TD R and the National Scientific Councils6 35, and the accummulated experience of the Brazilian longitudinal and crossectional studies sug gest the following simple procedures for patient ana lysis:
Clinical Examination: Anamnesis must be re liable. Heart and digestive symptoms are often under rated by the patients and must be correctly explored. It is also important to distinguish when hypocondriac patients (or people that are hoping for social security benefits) are stressing some general and/or vague symptoms. Clinical signs of the main chronic syn dromes must be looked for in detail, chiefly the initial heart failure and cardiac arrythmias, Apart from a long and detailed cardiac auscultation, observation of the pulse for one minute or more is useful in detecting incipient ectopic beats1 7 35. Some ambulatorial non-invasive procedures such as the Valsalva and hyperventilation manoeuvers are also very useful in detecting cardiac arrythmias in apparently heathy individuals1 7 24.
Basal ECG: This is the most important auxi liary method in the study of human chronic Chagas’ disease5 2 9 35. It is necessary to establish electrocar diographic normality, as well as to record a sufficient number of cardiac complexes to detect easily ectopic heart b e a t s 3 3 . EC G may be accompanied either by
Valsalva or hyperventilation manoeuvres or by simple pharmacological tests38.
Effort tests: They probably constitute the best non-invasive procedure to explore heart function in
Dia s JC P. T he indeterm inate fo r m o f h u m a n chronic C h a g a s’ disease. A clin ica l epidem iological review. R evista da Sociedade B rasileira de M ed icin a Tropical 2 2 :1 4 7 -1 5 6 , Jul-Set, 198 9
IFCCD. As verified by Faria et al24, ergometric tests can detect heart function degeneration earlier than resting ECG, X-ray studies and clinical examinations. Several years of using the cycloergometric test has proved its safety, but it must be emphasised that risks do exist and the procedure must be performed carefully and by trained personnel24.
Certainly the asymptomatic chagasic patients with a “negative” effort test will have much better prognosis q uo d v i t a m than those with increased
readings. The value of ergometry is unquestionable in Chagas’ disease. The use of this procedure must be stimulated both in research and clinical care services, in endemic countries.
The digestive forms of chronic Chagas’ disease are visually detected by anamnesis plus contrasted X- ray examinations1 7 3 5 4 4 Nevertheless some pro blems can be present for IFC C D characterisation, since border-line oesophagic or colonic dysperistalsis can occur1 8 43. Incipient colopathy without “mega” seems to be very frequent in some endemic areas, with a progressive and very slow evolution, presenting transitory periods of constipation and with a radiolo gical picture showing only some degree of sygmoid elongation18. Should these individuals be considered to be in the indeterminate form?
Autonomic denervation seems to appear in different degrees, in chagasic patients of different endemic areas32 7 2 8 44. Many patients with IFC C D may show signs of denervation when submitted to simple neurological tests2 7 28. Such neurological aspects might receive more attention and general research, but probably a low or moderate level of denervation will not interfere with the classical con cept of IFCCD . As a matter of fact, denervation phenomena in chronic Chagas’ infection generally progress very slowly or even remain stable, frequently being tolerated by the individual, with no clinical manifestations1 8 28. In terms of peripheral and central nervous systems, the usual neurological examinations are generally completely negative17.
F i n a l R e m a r k s
The epidemiological importance of IFCCD and the related laboral and medical aspects constitute a reason to vigorously strengthen the research on this form of American Trypanosomiasis.
The multicentric investigation must be obviou sly standardised looking for epidemiological, opera tional, clinical, anatomical, therapeutical and immu nological aspects.
The evolutionary aspects of the IF CCD must be investigated more completely including work on labo ratory models, in order to clarify the risk factors, and the possible therapeutic avenues.
The clinical management of these patients shoud be more completely detailed, giving special
attention to diagnostic aspects and operational pro cedures to be transferred to the primary health care system.
Laboral aspects of IFC C D also need more research, chiefly in order to determine up to what limit physical effort influences the natural history of the group.
Immunological and immunochemical studies must be stimulated along two main lines:
a) Attempts to discover a marker in the host able to indicate whether the disease is in evolution or n o t
b) Attempts to clarify the mechanism and elements of the disease evolution, in order to establish the basis for the prevention of this evolution.
RESUM O
A n a l i s a m - s e e p i d e m i o l o g i a e a h i s t ó r i a n a t u r a l
d a f o r m a i n d e t e r m i n a d a d a d o e n ç a d e C h a g a s ( F C I ) ,
c o n f i r m a n d o s e s u a g r a n d e i m p o r t â n c i a e p i d e m i o l ó
-g i c a e m á r e a s e n d ê m i c a s d a tr i p a n o s o m o s e , n o B r a s i l .
O s d a d o s m o s t r a m q u e a e v o l u ç ã o d a F C I é g e r a l
m e n t e le n ta , c o m b o m p r o g n ó s t i c o , d i s c u t i n d o - s e
a l g u n s f a t o r e s e v o l u t i v o s , o p r o g n ó s t i c o e o s u b s t r a t o
a n a t o m o p a t o l ó g i c o d e s t a e n t i d a d e .
S o b o p r i s m a p r á t i c o , v e r i f i c a - s e q u e o c o n c e i t o
c l á s s i c o d a F C I s e m o s t r a s i m p l e s , c o n s i s t e n t e e
o p e r a c i o n a l : d e f i n e s e n o p a c i e n t e c r ô n ic o e a s s i n
t o m á t i c o , p o r t a d o r d e p r o v a s s o r o l ó g i c a s e / o u p a r a s i
-t o l ó g i c a s p o s i -t i v a s p a r a T. cruzi, c o m e x a m e s clín i c o ,
e l e t r o c a r d i o g r á f i c o e r a d i o l ó g i c o ( á r e a c a r día c a , e s ó
f a g o e c ó l o n ) n o r m a i s . E x a m e s o u t r o s m a i s r i g o r o s o s
e s o f i s t i c a d o s p o d e m d e m o n s t r a r a l g u m a s a l t e r a ç õ e s e
a n o r m a l i d a d e s n e s t e s p a c i e n t e s , g e r a l m e n t e d i s c r e t a s
e p o u c o in te r f e r e n te s n o p r o g n ó s t i c o .
F a z e m - s e a l g u m a s s u g e s t õ e s d e p e s q u i s a s o b r e
a F C I , p r i n c i p a l m e n t e c o m r e l a ç ã o a o e n v o l v i m e n t o
i m u n o l ó g i c o e a f a t o r e s d e e v o lu ç ã o .
Palavras-chaves: D o e n ç a d e C h a g a s . F o r m a i n d e t e r m i n a d a . P r o g n ó s t i c o . F a t o r e s d e e v o lu ç ã o .
A CK NOW LEDGEM ENT
The author gratefully acknowledges Drs. Hum berto Guerra, Garret Capei-Williams and Stephen J. Hampson for their precious help in the final revision of this manuscript.
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