Initial studies
Knowledge about the disease: Carlos Chagas and the clinical characterization of American trypanosomiasis (1909-1934)
Simone Petraglia Kropf
Casa de Oswaldo Cruz/Fiocruz
Email: simonek@coc.fiocruz.br
The first characterization of the clinical condition of American trypanosomiasis, discovered in 1909, was presented by Carlos Chagas in October 1910, in a conference at the National Academy of Medicine. In addition to the clinical observation data performed in Lassance, the histopathological data produced by Gaspar Vianna, also a researcher from Manguinhos, were fundamental to its composition.
Chagas divided the infection into two modalities: acute and chronic. The acute phase was classified into two forms: 1) cases with severe brain disorders, such as meningo-encephalitis, derived from the action of T. cruzi on the central nervous system, and usually composed of children under one year old, who almost never survived; 2) cases without such manifestations, with a more benign prognosis, that, between 10 and 30 days, evolved to the chronic state, with the regression of the symptoms of the initial period. Due to the abundance of trypanosomes in the blood circulation during the acute period, the parasitological diagnosis was made by direct observation of the blood.
Of the symptoms of the acute period – continuous and intense fever, ganglia in the cervical region, armpits and inguinal region, splenomegaly, hepatomegaly, nervous system disorders (meningism phenomena), cardiac disorders and eye disorders -, Chagas highlighted some signs that, by their constancy should be privileged as elements of disease specificity and, consequently, as a basis for clinical diagnosis. Expressing what, according to him, was a thyroid disorder derived from the pathogenic action of T. cruzi on this gland, the main of these signs would be facial swelling (myxedema), which is very common in children since the early days of infection and conferred to the patients a characteristic facies.
The chronic phase comprised most patients and consisted of endocrine, cardiac and neurological elements. For Chagas, the most constant and salient clinical feature of the new trypanosomiasis was the functional thyroid disorders, expressed mainly by hypertrophy of the gland (goiter). In May 1910, he had published a note formulating the hypothesis of parasitic etiology of endemic goiter.
This thyroid disorder, which was associated with physical and mental disorders constituting endemic cretinism, has been known since ancient times and has been described above all in the mountainous regions of the European Alps. By the end of the nineteenth century, its etiology had not yet been fully elucidated. Some credited it with the chemical deficiency of iodine in water, while others considered the action of microorganisms. Endemic goiter had a high prevalence in Minas Gerais and, since the 18th century, attracted the attention of naturalists, travelers and doctors (Figures 1 and 2). The physical disfigurement it caused, especially when it reached large volumes, and the association with Cretinism, was considered one of the main reasons for the backwardness of the peasants in Minas.
According to Chagas, in Minas Gerais and other regions where there was T. cruzi transmission, endemic goiter was not the same nosological entity as in Europe, but a consequence of the action of this parasite on the thyroid. His conviction was based on three orders of evidence. First, he observed clinical signs of hypothyroidism in individuals with other signs of trypanosomiasis, both in the acute and chronic phase (including exclusively breastfed infants, which, he said, disproved the hypothesis related to chemical water deficiency). In addition, autopsies revealed thyroid lesions that, according to him and Vianna, would be caused by the parasite. Finally, the epidemiological data: “So far, from personal observations and information gathered, in the regions of Minas where goiter exists, there is also the insect transmitting schizotrypanosis”. Based on these arguments, he concluded: “Whether the European endemic goiter of water or infectious origin, ours, the one we have been studying in our home state, is undoubtedly a parasitic thyroiditis syndrome, a name very happily created by the illustrious Professor Miguel Pereira”.
Considering the effects of thyroid impairment on the organic development of individuals, this has become one of the main ways in which Chagas would affirm the medical and social importance of the disease, as a “chronic morbid condition that renders the individual unusable for vital activity” and as “an important factor of human degeneration.”
Endocrine disorders of the chronic phase, according to Chagas, varied in intensity and so he classified them into two clinical forms: pseudo-myxedematous and myxedematous. The first would be the most prominent, comprising the vast majority of carriers of the infection. These were children or young people who, having survived the acute phase, suffered the still mild effects of hypothyroidism. The “goiter” was still incipient, not characterized by the large volume that, after a progressive evolution, would have in some adults. The myxedematous form would cover the less common cases of greater severity of thyroid involvement. Instead of hypertrophy of the gland, its atrophy was observed, that is, the total destruction of the function, with extremely debilitating effects.
The third form of chronic infection would be the nervous form, whose signs, especially in children, would be motor disorders (such as diplegia), language (such as aphasia or dysarthria) and intelligence, such as idiocy (severe mental retardation) and dementia (Figure 3). Along with the “goiter”, such disorders, attributed to the action of the parasite on the central nervous system, would take great prominence in Chagas’ statements on the severity of the physical and social effects of the disease. Just as in the acute meningo-encephalic form, the allusion to “creatures condemned to the existence of monsters” would become frequent in this respect as well.
Another clinical syndrome of the chronic phase was the cardiac form. The most characteristic signs derived from parasitic localization in the “noble myocardial element” would be certain cardiac rhythm changes, such as extrasystoles (excitability disorder) and, to a lesser extent, disturbances in stimulus conduction, such as heart block. Unlike other forms, which preferentially affected children, Chagas observed the presence of these phenomena in individuals from about 16 years. The prognosis was generally severe, leading to heart failure and, in some cases, sudden death from asystole. This was one more aspect of the medical-social impact of the disease, he stressed, as it compromised the vitality of individuals at full working age.
As for the diagnosis, in the chronic modality, unlike in the acute phase, the parasites were not in the bloodstream, which prevented the parasitological demonstration by direct observation of the blood. The procedure used in these cases was the inoculation of “suspicious” blood in guinea pigs. Once the animal died, the identification of schizogonic forms in its lung (which Chagas considered evolutionary stages of T. cruzi) would determine the positivity of the diagnosis. This method would be abandoned in 1913.
Despite the incipient stage of the research, as early as 1910 Chagas pointed out that the presence of the “barber” had been attested in “almost the whole of northern Minas Gerais, in vast western regions of the same state, and also in the states of Mato Grosso and Goiás”, which allowed him to speculate that “the extent of the country where schizotrypanosis will rage” will be vast. These data came mainly from the studies of Arthur Neiva, who dedicated himself to entomological studies in Manguinhos (Neiva 1910).
From this first clinical design of the disease, the following fundamental features stand out: it was an essentially chronic infection, with progressive evolution, contracted in the early ages, by practically all those who lived in “barber”-infested dwellings and that, by reaching the individuals in the midst of physical and mental formation produced permanent impacts on their vitality and organic development. Its main clinical manifestations were endocrine (mainly thyroid), nervous and cardiac disorders.
Despite attaching importance to these three axes of the clinical condition, Chagas gave a clear emphasis to the first of them. One of the main indications of this primacy was the name, proposed by Miguel Pereira and widely used by Chagas, to refer to the disease: parasitic thyroiditis. In the expression of another renowned physician of the time, Miguel Couto, thyroid hypertrophy was the hallmark of the disease and became the most prominent feature in the visualization of the new medical entity. “Goiter” was thus seen as the primary sign for the clinical diagnosis of infection.
Since 1910, Chagas publicly defended the notion that the new trypanosomiasis was a disease of great medical and social importance. Using a rather recurring term in the intellectual debate of the time, it would lead to the physical and mental “degeneration” of rural populations, compromising the country’s productivity and progress. It should therefore be firmly opposed by the public authorities. At his conference at the National Academy of Medicine, he warned:
“It is very painful the impression brought by the morbid facts observed in those zones; painful for the doctor, who in the current resources of science does not yet find an effective means of combating the terrible enemy; painful for the statesman who is slow to reason about the obstacle fatally opposed by that morbid condition to any attempts at collective progress; painful, finally, to the altruist, who will have drawn human misery there in its fullest expression, whatever the fatality of a chronic disease, capable of rendering mentality, intelligence, vital activity, life normal condition necessary for human happiness”.
His statements had a big impact. They unveiled, before the medical and political elite of the federal capital, the portrait of the disease and misery of the interior of Brazil. The fundamental precept was then stated that, throughout the 1910s and especially after the outbreak of World War I, would be amplified in the so-called sanitary movement: the idea that overcoming the illnesses of Brazil depended on state intervention in for the sanitation of their backlands. By the end of his life, Chagas would emphasize the need to prevent and combat this and other inland endemics as a path to “health redemption” and the economic progress of the country’s rural populations.
In 1911, Chagas deepened his clinical classification, reiterating the primacy given to endocrine elements and his conviction regarding the parasitic etiology of endemic goiter. In addition to thyroid disorders, he pointed to the presence of ovarian and adrenal deficiencies, even proposing, for this last aspect, the creation of a specific clinical form.
From 1913 onwards, the process of defining and recognizing the new trypanosomiasis as a specific nosological entity would assume a new direction. Studies started by Henrique Aragão proved that the schizogonic forms found in the lung of experimentally infected guinea pigs (which Chagas thought were evolutionary stages of T. cruzi) corresponded to another parasite, Pneumocystis carinii. In addition to leading to a review of the parasite’s cycle, such studies invalidated the main parasitological diagnostic method used by Chagas for chronic forms of trypanosomiasis. From then on, despite the proposition of new diagnostic methods – such as the complement fixation-based serological test developed by César Guerreiro and Astrogildo Machado in 1913, and the xenodiagnosis proposed by Émille Brumpt in 1914 – the uncertainties regarding the confirmation parasitological analysis of chronic cases would raise questions about the clinical definition of this modality of infection.
In 1915/1916, studies in Argentina under the leadership of the microbiologist Rudolf Kraus of the University of Vienna confronted some statements by Chagas for the chronic forms of trypanosomiasis, especially the hypothesis of parasitic etiology of endemic goiter. Despite the proven distribution of infected vinchucas in Argentine territory, the researchers were concerned that no human cases of the disease were diagnosed. They reported that in provinces where vectors were present, goiter was often not identified; or when they were found, infection with that parasite could not be proven. Kraus and his colleagues then argued that the thyroid and nerve manifestations attributed to American trypanosomiasis corresponded in fact to the endemic goiter and cretinism already described in Europe, attributed by many to iodine deficiency.
In response to these questions, Chagas published in 1916 three important papers in which he reiterated his convictions about endocrine and neurological impairment in trypanosomiasis. However, even reaffirming his statements, Chagas began to give them new emphases and meanings, minimizing the primacy attributed to thyroid signals and reinforcing the importance of cardiac elements. In an extensive work published in 1916, he established new terminology for the classification of chronic forms, replacing the “pseudo-myxedematous” and “myxedematous” forms, respectively, with “indeterminate form” and “hypo-thyroid form”. In the first case, relatively recent chronic cases would be assembled, which did not yet manifest “the profound anatomical alterations that determine definitive clinical syndromes”. They would constitute, according to him, “forms of passage”, by indeterminacy in their clinical physiognomy.
Affirming that “in trypanosomiasis thyroid insufficiency is only one of the elements of the disease and is not in itself the nosological entity”, Chagas endeavored to ensure that even if such an aspect were discarded, this would not rule out the disease. existence of the disease as an “autonomous disease (…) characterized by well-determined symptomatology and well-grounded in histopathological lesions”.
In quite significant discursive operations of the movement whereby American trypanosomiasis was no longer characterized as a fundamentally endocrine disorder, endemic goiter – hitherto seen as the “seal of the disease” – has come to be described as’ a debatable problem attached to the clinical history of trypanosomiasis”. From then on, Chagas stopped using the term parasitic thyroiditis to refer to the disease.
The guideline adopted in this “new framework of the clinical picture of the disease”, begun in 1916, was the progressive appreciation of cardiac aspects. In 1922, in partnership with Eurico Villela, Chagas published extensive work on heart shape, which, according to the authors, should be seen as “the quintessential clinical feature of American trypanosomiasis.”
Ironically, in the same year of 1922, an intense controversy began at the National Academy of Medicine, in which a group of physicians challenged various aspects of Chagas’s work, restating the doubts cast in Argentina, especially the correlation with goiter and the idea derived from this association, that the disease was a vast endemic of great medical and social impact. Although Chagas has come since 1916, stating that the hypothesis about goiter could be revised, the great political visibility given to the American trypanosomiasis, between 1916 and 1919, within the scope of the sanitary movement had reinforced, by the social dramaticity that imposed to the clinical design of that endemic, precisely the aspects that were the object of dispute in the field of scientific discussion: the “goiter” and nervous disorders.
At the conference at the closure of this controversy, Chagas continued by stating that, even if one refuted the goiter statements and other formulations, one could not doubt the “inescapable signs” that underlie American trypanosomiasis as a real and specific clinical entity. Again, he pointed to the heart shape as “the most interesting and characteristic feature of American trypanosomiasis.”
Still less intense than the cardiac form, the nervous form, although contested, would still motivate the research of Chagas and his collaborators. Beginning in 1923, experiments by Eurico Villela and other researchers, who reproduced paralysis and other neurological disorders in dogs inoculated with T. cruzi, were seen as reinforcing the thesis of this protozoan’s special “predilection”, at least of some strains by the nervous system. Animal studies also demonstrated congenital intrauterine transmission of T. cruzi. At a time when the doctrines in neurology postulated that congenital infections were the most propitious to nervous system impairment, the notion that the pathogenic action of that parasite on such an organic system took place from embryonic life was strengthened.
In 1932, in his last scientific presentation on the disease, Chagas presented a systematization of the “current state of American trypanosomiasis”, whose objective was to highlight precisely the advances in the understanding of the nervous form. After expressing his enthusiasm with the impetus given to this aspect, the work addressed the heart shape, reaffirming its central importance:
“The different alterations of the heart rhythm constitute the most valuable symptomatic characteristic for the clinical diagnosis of this infection; (…) The endemic index of American trypanosomiasis should be appreciated mainly by the high percentage of individuals with heart rhythm disturbances.”
The other clinical modalities of the disease, including endocrine syndromes and goiter, were, according to him, “less enlightened aspects”. He said:
“Although persistent in the previous conviction, we must confess that the subject offers room for disagreement, being subject to challenge the formulated doctrine. … It is an open question, worthy of study and insight.”
After the death of Chagas (1934), it was confirmed that American trypanosomiasis and endemic goiter were overlapping and totally distinct endemics. Like its statements about endocrine forms, the chronic nervous form would also be abandoned.
However, his formulations of heart shape would be widely confirmed and expanded, especially from the research of his followers in Manguinhos, such as Evandro Chagas and Emmanuel Dias. The latter, director of the Chagas Disease Research and Prophylaxis Center – IOC, post created in 1943 in Bambuí, Minas Gerais -, produced, along with the cardiologist Francisco Laranja, works that would consolidate the characterization throughout the 1940s of the chronic chagasic heart disease as the main clinical expression of Chagas disease.
In the 1950s, based on the work of Joffre M. de Rezende and Fritz Koeberle, another statement that Chagas had proposed in 1916 (albeit deepening later) was proved: that the “choking disease” or megaesophagus is due to pathogenic action of T. cruzi. The digestive form (megaesophagus and megacolon) then became, together with the cardiac form and the undetermined form, the clinical picture of chronic infection.
Controversy
The controversy surrounding Chagas disease (1915-1923)
Simone Petraglia Kropf
Casa de Oswaldo Cruz/Fiocruz.
Email: simonek@coc.fiocruz.br
In his early work on clinical characterization of American trypanosomiasis, Carlos Chagas stated that the new morbid entity, discovered by him at Lassance in 1909, was defined by endocrine, neurological, and cardiac disorders. In its conception, in Minas Gerais and other regions where there was transmission by T. cruzi, endemic goiter (thyroid hypertrophy, popularly known as “goiter”) had a different etiology from that found in Europe, constituting a clinical manifestation of trypanosomiasis, due to of the action of the parasite on this gland. The emphasis on this and other thyroid signs led Chagas to refer to the disease as parasitic thyroiditis. This thesis was at the heart of the controversies that the disease became the object in the mid-1910s.
Studies conducted in Argentina under the leadership of the microbiologist Rudolf Kraus of the University of Vienna, in 1915/1916, confronted Chagas’s statements on chronic endocrine and nervous forms of trypanosomiasis, especially the parasitic etiology of endemic goiter. Despite the distribution of infected vinchucas in Argentine territory, no human cases of the disease had been diagnosed. Researchers reported that in provinces where vectors were present, goiter was often not identified; or when they were found, infection with that parasite could not be proven (Chagas’ method for parasitological demonstration of chronic cases – the detection of schizogonic forms in the lung of infected guinea pigs – had been refuted in 1913 when proved to correspond to another parasite).
Kraus and his colleagues then argued that the thyroid and neurological manifestations attributed to American chronic trypanosomiasis would in fact correspond to the endemic goiter and cretinism already described in Europe, the cause of which many credited to iodine deficiency. In an attempt to explain the absence of trypanosomiasis cases in the country, the researchers hypothesized that “la vinchuca infectada en la República Argentina, con mucha probabilidad, no produce la enfermedad de Chagas. La causa pode ser uma atenuación del tripanossoma por el clima.” Such statements cast doubt on the very definition of trypanosomiasis, especially in its chronic modality, as a differentiated clinical entity.
In September 1916, Carlos Chagas rebutted such allegations by taking part in the First National Medical Congress, held in the Argentine capital, annexed to which an International Conference on Bacteriology and Hygiene was held. He reiterated that even if he revised some of his ideas, none of the challenges threatened his general concept of the disease, which, he pointed out, was not restricted to the country in which it was discovered. However, while reiterating his main convictions, Chagas began an important process of “reframing” the clinical design of trypanosomiasis, minimizing the primacy he had previously given to thyroid signals and reinforcing the importance of cardiac elements.
In the new classification he proposed for chronic forms, presented in extensive work in 1916, it was softened the weight of endocrine elements and presented the parasitic etiology of endemic goiter as an “annexed problem” that could be revised. In a very significant indication of the movement by which American trypanosomiasis was no longer characterized as a fundamentally endocrine disorder, its discoverer ceased to use the term parasitic thyroiditis as one of its names.
The scientific controversy in Argentina had an impact on the Brazilian medical field, especially in the context of the nationalist debate – which intensified with the advent of World War I – about the precarious sanitary conditions of the interior of the country, formalized in the so-called rural sanitation movement in Brazil. In reception to Aloysio de Castro (director of the Faculty of Medicine of Rio de Janeiro) and Chagas, who were returning from the congress in Argentina, doctor Miguel Pereira issued the famous sentence that would become the symbol of this movement: “Brazil is a huge hospital.” One of the central motivations of his speech was precisely to draw attention to the seriousness and importance of that disease which, despite being questioned in the neighboring country, constituted, as Chagas said since the early 1910s, one of the main scourges of the country, along with malaria and hookworm infection.
While Chagas himself reviewed in his works the weight he had placed on endocrine disorders, the combative discourse of the sanitary movement – led by Belisario Penna – emphasized the social drama of American trypanosomiasis precisely because of the elements in question in the scientific controversy: physical deformities and mental problems materialized in the goiter and nervous form, which, according to Penna proclaimed, would reach about three million Brazilians.
This intertwining of science and politics, while giving public visibility to Chagas disease, created the conditions for some Brazilian doctors, in the heat of the nationalist debate of the 1920s, to confront Chagas’s scientific statements and to accuse of patriotic, pessimistic and exaggerated those who, like him, described Brazil as a sick country.
In July 1919, Henrique Aragão corroborated, in a speech at the Society of Medicine and Surgery of Rio de Janeiro (SMCRJ), the uncertainties about the disease discovered by his colleague of Manguinhos. Stating that the parasitic etiology of endemic goiter was unsustainable, he pointed to what he considered to be other weaknesses of Chagas’s propositions, such as the small number of proven cases, which would not reach four dozen. Based on Kraus’s arguments, Aragão stated that one explanation would be the low pathogenicity of T. cruzi to the human organism, especially in adults. Touching another point that would become controversial, he referred to Oswaldo Cruz as the “discoverer of T. cruzi”, in which he was supported by Henrique Figueiredo de Vasconcellos, also a researcher from Manguinhos. The speech provoked an immediate reaction. Belisario Penna challenged Vasconcellos to discuss the matter, stating that no one better than him, Penna, who had witnessed Chagas’ discovery in Lassance, to attest to his authorship in that process.
The following month Vasconcelos gave a conference at the SMCRJ in response to Penna. He reaffirmed that, because he was the author of the experimental infection that revealed the new parasite, it was up to Oswaldo Cruz to prioritize its discovery, and therefore the disease should be called “Cruz and Chagas disease.”
Another aspect in question was the medical and social importance of the disease. Vasconcellos explained that he did not doubt that the parasite had a pathogenic action, but could not accept the extent that many attributed to trypanosomiasis, due to its association with endemic goiter. It stated that, as in Argentina, in several Brazilian states where there were infected barbers the search for patients had been unsuccessful and the number of reported cases remained tiny. In evidence of the political meanings surrounding the subject, Vasconcellos stressed that he deemed it necessary “a reaction, not to destroy the work of Dr. Carlos Chagas, (…) but to place it within its true limits.” The “dull colors” with which many painted the disease discovered in Lassance would, he said, discredit the country, driving away the much-needed immigrants to national progress.
The controversy reached its maximum intensity in 1922. Upon receiving Figueiredo de Vasconcellos as honorary member of the National Academy of Medicine (ANM), the literary professor of hygiene at Rio de Janeiro Medical School, Afrânio Peixoto, launched the fuse of a fierce contend that it would unfold for a year. Referring to the services rendered by Vasconcellos to Manguinhos, he mocked:
“During your consulate you could have done more (….). You might have found some mosquitoes, invented a rare and unknown disease, a disease that was widely talked about, but almost no one knew the sick, cornered there in a “sertanejo” nursery in your province, which you would magnanimously distribute to some millions of your patrolmen, accused of cretins.”
In a letter to Miguel Couto, president of the Academy, Chagas stated that he was attacked in his personal and professional honor and requested that a special committee be appointed to take a position on some of the questions he formulated regarding the clinical and epidemiological characterization of the disease and the merit of his works. From the opinion of this commission, it would depend on his stay in that house.
Almost a year later, in November 1923, the matter returned to the plenary of the Academy, becoming the agenda of the session. Vasconcellos delivered a lecture stating that Chagas’s own initial publications on the discovery left no doubt that it was Oswaldo Cruz who first saw the forms of trypanosomes in the blood of monkeys under a microscope. It was therefore his priority the discovery of T. cruzi.
At the same session, the tone of the dispute was raised even more when Peixoto, by letter, reiterated his doubts about the “nosographic rarity” which he acidly called “Lassance’s disease.”
The professor at the Bahia School of Medicine and Chagas’s personal friend, Clementino Fraga, went on his defense. He said he had witnessed “sick people in abundance” in Lassance, as had the commission sent by the Academy in 1910, of which Vasconcellos himself had been a member. He observed that, even before the experimental infection, Chagas had been responsible for the “initial finding”, while observing, even in the Minas Gerais backlands, the flagellates inside the barber.
In reply, insisting on the need to remove exaggerations about the size of that morbid entity, Vasconcellos once again made clear the political dimension of the theme: “I do not want our land to be considered as the only country in the world where north to south, east to west, there is a terrible, horrible disease not known anywhere else in the world.”
Each stage of the controversy was recorded by the newspapers. One report stated that the doubts about Chagas’s discovery boiled down to “jealousy, enmity and nothing else” and expressed concern about the image of national science: “And what idea will make of us, of our scientists, the luminaries of foreign medicine, when they realize that in Brazil it is not known who made the important discovery in Brazil, denying the doctor who had discovered the glory of a liquid case?” (“Trypanosome and… jealous ”, Brazil, Rio de Janeiro, November 18 1923).
At the lecture by Paulo de Figueiredo Parreiras Horta, professor of parasitology at the School of Agriculture and Veterinary Medicine, the nature of the parasite and the spread of the disease were discussed. Reproducing Kraus’ argument, Horta said that in his travels around the country, he had observed the spread of barbers in several states, but despite the research, clinical cases of the disease had not been proven parasitologically. He defended the hypothesis that T. cruzi would be a saprophytic parasite (harmless), or that it would have a much lower virulence than intended, causing benign and sporadic infections. He concluded: “Well, the cases of authentic human trypanosomiasis, already noted, are few and limited to one part of the country. It is the unknown that remains”.
At the same session, Fraga made his formal defense of Chagas, presenting, in support of his argument, a letter in which Oswaldo Cruz’s own son, Bento, attested that his father had always attributed the discovery entirely to Chagas and protested against what he described as disrespect for the memory of the creator of Manguinhos.
On November 23, 1923, the long-awaited verdict was read at the Academy. On the issue of the priority of discovery, the position was favorable to Chagas:
“In the course of this coordinated series of facts, the discoverer of the parasite, which was not found by chance, but sought after in a logical conclusion, would not, therefore, be the person who first saw it by chance, but necessarily the person in that concatenation who arranged everything for it to be found. ”.
After denying Horta’s allegations about the innocuity of T. cruzi, the report addressed Chagas’s question about the characterisation and clinical individualisation of American trypanosomiasis. Highlighting the still existing difficulties regarding the diagnostic methods of chronic forms, both serological and parasitological, emphasized that the commission was not in a position to answer the question unequivocally, including the controversial point of the relationship with endemic goiter. The issue thus remained, as Chagas himself had admitted, an “open question”. Aiming a compromise, despite the “restrictive due to the very nature of the subject, still under study”, the commission considered to have “responded positively” to the point formulated by Chagas.
The report also left open the question of the social dimension of trypanosomiasis:
“(…) The new disease, which geographical extent and coefficient of morbidity, are beyond the means of investigation available to the Commission, but there are documents indicative of other outbreaks in the American continent, represent, whichever its diffusion within the country, a social problem of major importance, deserving the attention of the state ”.
As for the scientific value and the good repute of Chagas’ works, there would be no doubt: “The National Academy of Medicine cannot but fully preserve the concept that determined the inclusion of Dr. Carlos Chagas in his guild”.
The last act of the controversy at ANM was the conference pronounced by Chagas, in a crowded session on the evening of December 6, which gained prominence in the press (Figure 1). The discoverer of American trypanosomiasis pledged to synthesize the foundations of “an unshakable conviction,” but did not hide the hurt:
“It would not be worth the word of whoever, to safeguard the scientific heritage of a school, today find himself in the attitude of a defendant, guilty of misconduct and of demolishing the prerogatives of robustness and resistance of our country people.”
Figure 1 – Chagas lecturing at the session of the National Academy of Medicine.
Disputing his critics, Chagas presented what he considered the “inescapable signs” of the clinical characterization of trypanosomiasis, both in its acute and chronic phases. Following a trend already expressed in his works since 1916, he gave special emphasis to the heart shape, as the strongest and most well-characterized element of chronic infection.
His conference ended with strong criticism of Peixoto’s “false nationalism” and his spokesmen. Reiterating the social importance of studying and combating rural endemics, he protested against those who accused him of “disliking our land”:
“(…) I cannot enable, Mr. President, that this effort to deviate the State’s measures from one of the matters that are most important to our zeal as Brazilians constitutes sincere and true nationalism(…)I will continue to be resolute in my scientific convictions, and not one day will I withdraw from the zealous feelings for the life and health of my countrymen. It is my duty as a doctor, it is human solidarity that guides me.”
Pointing out Peixoto’s contradiction in denying the banners of the campaign for the sanitation of the hinterlands, of which he himself had been “one of the most authoritative voices” a few years earlier, Chagas challenged him to “personally verify” while traveling inland in his company, the truth or the error of his conclusions.
The episode of the Academy became a watershed in Chagas’s biography and in the path of the disease he discovered. Regarding the dispute with Kraus, many contemporaries close to Chagas (such as Eurico Vilella), while disregarding the raised objections, recognized in it an eminently scientific controversy. Chagas himself stressed the scientific nature of his Austrian colleague’s claims: “he is a researcher and his observations, naturally, are provenance. However, he stressed that those who, like Vasconcellos and Peixoto, were spokesmen for Kraus had, in fact, “secondary purposes” (“Chagas Disease. Its spread in Brazil and almost all of America”, A Rua, Rio de Janeiro, August 18, 1920).
Throughout this controversy, the idea that Chagas faced detractors, in a clash moved by rivalries and feelings of envy and spite, was consolidated. With his death in 1934, such an interpretation was reinforced by doctors and scientists who revered his memory. In 1944, the professor at the Belo Horizonte Medical School, Octavio de Magalhães, referred to the episode:
“Toda vez que oigo la expresión enfática, de que ‘la escuela es la vida’, recuerdo las vidas de Oswaldo y de Chagas, ambos flagelados en el via crucis de sus empeños por el bien colectivo, martirizados en las cumbres de sus Gólgotas”.
The notion that Chagas was victim of a defamation process, driven by personal grudges, is still present in the interpretations of this controversy. Many argue that this could have been the cause of being denied to him the Nobel Prize, for which he was nominated in 1920, and which was not, oddly, awarded to anyone that year.
Another recurrently emphasized aspect is that the contention at the Academy caused the disease to enter a period of “forgetfulness.” Chagas Filho stated that, after a “heroic period” of national and international recognition of studies on the new disease, doubts started in Argentina and, above all, the “great struggle” in the ANM set in motion a “phase of disenchantment and disagreement”. According to him, by bringing a “wave of suspicion and discredit to Chagas disease itself”, the controversy had disastrous consequences, as generations of Brazilian doctors graduated “without having properly focused on the importance of the disease”. Only in the 1950s would the period of “perfect national and international understanding of the problem posed by Chagas disease” have begun.
Chagas Filho points out what, according to him, were the main factors that motivated the dispute that, for his father, constituted “an intimate drama of great proportions”. The predominant motive would have been envy for its national and international recognition. However, he stressed, there would be more concrete reasons for resentment. In Peixoto’s case, it would have been the fact that he had been deprived of his post as director of the federal public health department, assumed by Chagas in 1919. Other sources of conflict would have been Chagas’s rise in the IOC hierarchy and tensions with the medical establishment. at the School of Medicine.
Historians Jaime Benchimol, Luiz Antonio Teixeira and Nara Britto also emphasize that the succession at Manguinhos director was a central aspect of the rivalries that fueled the controversy. Moreover, since the beginning of his administration at the Institute (1917-1934), Chagas has faced much criticism in the context of the internal crisis stemming from the financial constraints experienced during the 1920s. Political disputes within his administration in the Department National Public Health (1919-1926) also contributed to the attrition.
Stepan, in turn, points out that the conflict was related to the broader debates surrounding tropical medicine and its meanings for national identity. According to the author, in Peixoto’s reactions to the representation of Brazil as a nation of degenerates was expressed in the condemnation of the idea of the specificity of tropical medicine, which, according to him and other doctors, stimulated old stereotypes that confronted national pride, as well as climatic determinism incompatible with the redemptive prospects of hygiene.
Some authors, such as Coutinho, argue that the episode of the ANM, motivated mainly by rivalries and personal enmities with Chagas, would have led to the “deconstruction” of the disease as a scientific fact and a topic of medical and social relevance in the country, plunging it into a phase of discredit.
In our interpretation, we consider that the controversy surrounding American trypanosomiasis should be understood as a controversy that mobilized elements of a scientific nature (related to the doubts that in fact surrounded the clinical and epidemiological characterization of the disease) and also political, in many ways. Constituting a specific phase of the very trajectory of the construction of this scientific object, the controversy at the Academy had, as we see it, as a determining factor, the political dimension of the confrontation between different positions in the nationalist debate at the time, to which different ways of conceiving Chagas disease as a symbol of national identity, as “Brazil’s disease”.
Despite the new course followed since then, this trajectory would continue. The new paths Chagas had taken in 1916 were reinforced and would lead, after his death, under new institutional, social and political circumstances, to a new stage of what has been a long and collective process of consensus building since 1909, It mobilized different actors, institutions and interests, involved agreements and disputes and exhibited their peculiarities in different contexts.
Romaña
A contribuição de Salvador Mazza, Cecilio Romaña e dos médicos argentinos ao estudo da doença de Chagas
The contribution of Salvador Mazza, Cecilio Romaña and Argentine doctors to the study of Chagas disease
João Carlos Pinto Dias
Centro de Pesquisas René Rachou, Belo Horizonte
E-mail: jcpdias@cpqrr.fiocruz.br
The Argentinian contribution to the evolution of knowledge and the coping of American trypanosomiasis has been great and relevant, especially from the 1930s. There are old and important records about the presence of triatomines in rural dwellings, especially in the northwest and in the Chaco corridor, possibly due to the passive dispersal of Triatoma infestans, the main species domiciled in the country. Epicenter in the Cochabamba valleys, T. infestans spread through the migration of native and Spanish populations in the north-south direction, permeating the ravines and settling on primitive Jujuy, southern Peruvian and northern Chilean ranches. There are also reports of sudden death and mega among these populations, as there are mummies of two thousand years in Atacama, with traces of the parasite in suggestive visceral lesions. In the post-independence period, it appears that schizotrypanosis spread at least two-fifths of Argentina from time to time, reaching its maximum endemicity between the 1920s and 1950s. As early as 1911, Lozano and Maggio went on an official mission to Manguinhos, bringing to Buenos Aires slides, samples and boards alluding to Trypanosoma cruzi, disease and triatomines, provided by Chagas and Oswaldo. Soon, Maggio and Rosembuch will collect naturally infected T. infestans from various parts of the country without, however, detecting human cases, especially sought in individuals with goiter. It is also important to note Carlos Chagas’ presentation at a congress in Buenos Aires, 1916 (where he was accused by Kraus) and Mazza’s stay in Rio and Manguinhos, having contacts with Chagas in 1918. The first two acute cases described in Argentina will be detected in 1924 by Mulhens, Diós, Petrocchi and Zuccarini, respectively in Tucumán and Jujuy. A third case will be described a year later. At this time Salvador Mazza would be traveling with Charles Nicolle in the interior of the country, in recognition of the regional pathology and in frank elaboration of the dreams that would come to the founding of MEPRA (Misión of Argentine Regional Pathology Studios), in Jujuy, 192). From then on Mazza will become the leading Argentinian schizotrypanosis researcher, studying in MEPRA vectors and reservoirs, acute (about 1,400) and chronic human cases, performing more than 100 necropsies, making experimental infections and testing diagnostic methods and therapeutic procedures. It will train and excite countless doctors for the diagnosis and management of the disease, will tramp the country in its rail car, searching for cases and divulging the disease. Until his death in 1946, Mazza will publish more than 250 papers on different aspects of Chagas disease and participate in numerous scientific meetings, many of them organized by himself. There is much similarity in the trajectory of this great researcher with the life and work of the Brazilian pioneers. Like Oswaldo, Mazza studied at Pasteur and brought modern scientific concepts and techniques to his country, including starring in Argentina the fundamental visit of Charles Nicolle, as Cruz had done with Giemsa, Duerck, Max Hartmann and Von Prowazeck in Manguinhos. Like Chagas, he went to the backlands and settled there, in the path of what he found fundamental to his science, also living and working in a wagon, having also been extremely well trained in Parasitology, Experimental Medicine and Pathology. Like Emmanuel Dias, he called on doctors, authorities, the population and journalists to fight vinchuca, dwellings and disease. In fact, he lived intensely his Jujuy, for the exact same twenty years that lasted the first phase of Bambui. Visionary, Mazza predicted transfusion transmission, introduced complement fixation testing in his country, and described the first human case of oral transmission.
Mazza’s great contributions will begin in the most difficult and sad period of Carlos Chagas’s life, which begins in the 1920s, due to envious and detractors, within the National Academy of Medicine. Certainly, out of envy, unpreparedness, and resentment, the libel against Chagas was based on several misconceptions, such as details of the discovery of the parasite and the non-detection of human cases in triatomine areas, including the non-association of parasitosis with goiter and the total incompetence of the detractors to establish a link between chronic conditions (especially heart disease) and trypanosoma infection. In Brazil, especially between 1923 and 1933, there was a phase of discredit and cooling down in research on the entity, although Carlos Chagas continues to act and follow up on two projects of exceptional importance in the medium term: a) forming and maintaining a group of disciples who would follow the research, and b) deepen the study of chronic heart disease through electrocardiography. In such a context, the work of the Argentines, in particular Mazza, will be essential for the continuity of studies and interest in the disease. Not so much a rediscovery, as some think, but a major breakthrough, in line with several of Chagas’s postulates and yet an unambiguous contribution to the review of the endemic goiter issue. Moreover, the progressive detection of acute cases in Chaco, Santa Fe and the Argentine Northwest would in turn shape the wide spread and the medical and social importance of the disease at this stage of discredit.
In this regard, the question of the description of an extremely striking sign for acute cases, the ophthalmo-ganglionic complex, described by the Argentine physician and Mazza’s assistant, Cecílio Romaña in 1935, at the IX MEPRA meeting in Mendoza stands out.
The sign consists of an eye-catching entry point for acute Chagas disease. It is a bipalpebral edema, usually unilateral (one eye) involving satellite ganglion engorgement (usually preauricular), conjunctivitis and dacrioadenitis (inflammation of the accessory lacrimal gland). It has a warm temperature, is painless and usually not suppurative, evolving in a few weeks or months. It may occlude the entire eye and leave long-term, as “reliquat”, a slight closure of the affected eyelid (the overall picture may resemble insect bites, tersol, conjunctivitis, trauma etc).
Cecílio presented his work in plenary, in a precise and didactic manner, substantiated by observations that he had already made a year earlier in Norte Santafesino and Chaco, including originating two notes in MEPRA. According to Segura, “Mazza autorizo la publicación de Romaña sobre el complejo oftalmoganglionar, pero se sintió muy impresionado por la propuesta que hizo Emmanuel Dias en esa reunión para denominar a dicho complejo como “signo de Romaña”, porque consideró que eran signos ya sugeridos por Carlos Chagas”. The controversy lasted for several years, generating replicas and trebles between Mazza and his friends, Dias and Romaña himself, resulting in Cecilio’s removal from the team and a certain withdrawal of Mazza with Dias and Evandro Chagas. In fact, the signal had been seen (and photographed) by Mazza and Chagas himself (see photos in Chagas 1916) in Argentina and Lassance, but never systematized or given due attention as Cecilio had done. On the other hand, however, the heat of the debate and the sequence of its repercussion turned out to be an additional element to its disclosure, making the description of this signal a scientific and epidemiological hallmark of the disease, greatly facilitating the diagnosis of the acute phase not only in the Argentina as throughout the endemic area. According to Pick (1954), in the first 25 years after the discovery of Chagas only 34 acute cases were described, 29 of them by Chagas in Brazil, while hundreds were recorded after the description of Romaña. Pellegrino (1954), reinforces these data, informing that, only in the ten months that followed the description, 139 acute cases were published, mostly bearers of the Romaña sign. In the available reviews on the subject, the occurrence of the sign appears on average between 50 and 70% of acute cases by vectorial transmission detected in different endemic areas, and in Mazza’s case series, with 1,232 cases, 61.3% presented the sign. In other major series, Lugones describes the signal in 81.5% of 601 cases in Argentina, compared to 96% of Talice and Rial (in Uruguay, 100 cases); in Brazil, Rassi finds 57% in Goiás, H. Ferreira detects 39.2% in Uberaba and Dias et al. 49.2% in Bambuí, MG. There is now general agreement on the relative value of the ganglionic ophthalmic complex, in that it remains the most striking indicator frame for acute schizotrypanosis in vector-borne areas, with reasonable specificity, although a number of entities may cause a similar picture. In fact, in an endemic area the vast majority of acute cases go unnoticed, and the sign of Romaña should in fact affect a portion probably less than 50% of those who become infected. In fact, however, it is so striking and easy to associate (in addition to being so popular since its description) that its carriers are often referred to the doctor with the suspicion of the family or the first attendant, constituting in a way an iceberg tip in acute Chagas disease. Historically, it has even been speculated whether Romaña himself would have been influenced – in his first searches – by photos of some cases of Chagas and some of the first Argentine acute cases, which Mazza circulated in the country, trying to motivate the doctors in the country. about the disease. The controversy followed for some years, especially between Mazza and Emmanuel Dias, who had proposed the name of the sign and defended the precedence and accuracy of the description of Romaña, friend who welcomed in Manguinhos for some years. It was the sign of Romaña that triggered the important work of Bambuí, Brazil, which attracted the discovery of the first acute case in the area by Torres Sobrinho and Amílcar Martins, in October 1940. Cecílio continued working, mainly in Tucumán. He had described the first chronic case in Argentina, in 1941, and carried out work in epidemiology, pathological anatomy and prophylaxis, describing with Abalos in 1948 the effective action of BHC against triatomines, concurrently with the work of Dias and Pellegrino in Brazil. He deepened his studies of the ganglion ophthalmic complex and reproduced it experimentally in monkeys and other mammals. He loved Brazil, where he was always welcomed and respected, especially at the Oswaldo Cruz Institute. At the end of the 1950s, due to political pressures, he moved to Barcelona, teaching at the Faculty of Medicine. In 1963 he published the excellent compendium Enfermedad de Chagas. In 1979 he founded an International Committee to Fight the Disease. He died in February 1997 at the age of 96. Mazza remained active and productive until his unexpected death in Monterrey, Mexico, 1946. It was an international medical congress, an opportunity in which he was very tenderly and friendly reconciled with Emmanuel Dias. Feeling unwell, he was attended by him and Francisco Orange, unfortunately not surviving the extensive heart attack. He is considered the largest “Argentine chagologist”, undoubtedly responsible for the definitive resumption of studies on Chagas disease. MEPRA has not survived it, as it does for similar institutions that thrive only on the flashing flash of great men.
Following Mazza and Romaña, Argentina heroically followed its scientific production and its efforts to fight Chagas disease. Respectable and well-known names like Abalos, Rebosolán, Yanowsky, Cazzullo, Rosenbaum, Cerisola, Castagnino, Salica, Cichero, Segura, Bozzinni, Jörg, Basso, Storino, Manzullo, Madoery, Kuschnir, Alvarez, Lugones, Stopanni, Frash, Ripoll, Soza, Ledesma, Moya, W. Colli, Chiale, Cosio, Carcavallo, Sosa-Estani, Ortega, Salomón. Leguizamón, Ruiz, Sica, Freilij, Castagnino, Titto, Alderette, Zerba, Schmunis, Mouso, Marteleur, Yosa, Posse, Milei, Sgaminni, Rabinovich, Cura, Freire, Niño, Salica, Bravo, Zerba, Gurtler, Pérez, Brenner, Gonzalez-Cappa, Fatalla, Rowheder, Cura, Del Ponte, Berjarano, Bonet, Bocca Tourres, Wygodzinskyand many others have produced and continue to produce important contributions to knowledge and coping with schizotrypanosis. From Argentina came important improvements for parasitological and immunological diagnosis of the disease, as well as fundamental contributions to better knowledge and management of chronic chagasic heart disease. The national leadership of the Fatala Chaben Institute is uncontested in training for diagnosis and specific treatment for the whole country, as was Pilar Alderette’s Human Health Program, with the human and material resources throughout the regional endemic area, for ten years, to confront and prevent the disease. From this work, based on the International Committee created by Romaña in 1979, and the impressive unity of thought and purpose of the Latin American scientific community involved in trypanosomiasis, the 1991 Southern Cone Initiative against Chagas disease, launched at a meeting of area ministers and led by the delegations of Argentina and Uruguay. Extraordinary evolution has had studies on schizotrypanosis in Argentina in all sectors. It punctuates biochemical, molecular, genetic and specific treatment investigations, along with the great efforts to optimize and consolidate the anti-vector fight. About 100% of blood banks are controlled, but there are still pockets of vector and congenital transmission in the country. New generations of researchers are forming and interest in the disease has not declined, renewed each year in multiple study workshops and in the participation of researchers and health workers in regional seminars such as Uberaba and Caxambu. Finally, it is important to note the great impact and good service that the Argentine Federation of Cardiology has been rendering to the world with its “Virtual Forum on the Nursing of Chagas”, conducted continuously and effectively five years ago on the Internet by Edgardo Schapachnick and his colleagues.
Pathology
The history of Chagas disease pathology
Zilton A. Andrade
Laboratório de Patologia Experimental. Centro de Pesquisa Gonçalo Moniz/Fiocruz
E-mail: zilton@cpqgm.fiocruz.br
Shortly after Chagas made the discovery of Trypanosoma cruzi and the disease in 1909, Gaspar Vianna, in 1911, studied of its pathology as a crowning achievement for Chagas’ great scientific achievement. Subsequent studies by Magarinos Torres, Crowell, Jorg, and Mazza led to the consolidation of the fundamental data on the pathology of Chagas disease by the middle of the twentieth century. Since then, the contributions have not ceased, highlighting the great complexity of the disease pathogenesis, and serving as a stimulus for the development of our experimental science.
The historical development of knowledge about Chagas disease presents a curious aspect. Interest in each of the ways the disease presents itself has arisen separately over time, due to different causes. It seems that, at any given time, interest focuses on a phase or clinical form of the disease. This report uses this fact to briefly describe progress in the study of Chagas disease pathology, and seeks to show the reasons for this concentration of interest in different clinical forms at different times.
Acute form of Chagas disease
We can consider a first period, which runs from 1909 until the late 1930s, when interest in the study of the disease was centered on its acute form (Figure 1). Although Carlos Chagas began early on to investigate various clinical forms of the disease, including a nervous form, the publications that appeared gave the impression that it was concentrated in the countryside. The description of the eye sign or sign of Romaña (1935), as well as cutaneous and lipo-chagomas, facilitated the recognition of the case and served to illustrate the various publications from the 1930s. The study of the myocarditis diffuse, with its causal agent within the contractile fibers, was already accompanied by pathogenetic interpretations. When interest in the study of the new disease had inexplicably waned among Brazilians, it was the follow-up of acute cases made by Mazza’s group in Argentina that brought new encouragement for the resumption of studies.
The chronic cardiac form
Beginning in the mid-1930s, and extending over the next 30 years, interest focused on the chronic cardiac form of the disease (Figure 2). The major motivating factor for this trend was the increasingly common use of electrocardiographs in hospitals and doctors’ offices, coupled with the progressive detection of a frightening number of cases of chronic heart disease, even among the urban population. From the studies of Francisco Laranja and collaborators, cardiologists in the major cities of the American countries, where the disease is endemic, were surprised to find a chronic, progressive and severe myocardial pathology that exhibited a varied hue of arrhythmias, isolated or conjugated, as had not yet been seen in any other heart disease. Cardiac pathology was thoroughly investigated in autopsy material and the findings were correlated with clinical and electrocardiographic manifestations, with thromboembolic phenomena being highlighted. The rarity with which parasites were found in the sections, as opposed to the acute form, raised discussions for the histopathological diagnosis and interpretation of the pathogenesis.
The digestive form
Around the 1960s there was an outbreak of interest for the digestive form of the disease (Figure 3). Obtention of purified and well-standardized antigens, as well as introduction of new techniques, have improved serology to the point that many have become more confident in its results. This was a step in testing a theory long held by doctors in central Brazil who worked in an area where Chagas disease, megaesophagus, and megacolon were endemic: that the digestive megas were a manifestation of Chagas disease. They then added to the clinical and epidemiological evidence very reliable serological studies, and saw that the carriers of megaesophagus and megacolon did indeed systematically exhibit positive serology for Trypanosoma cruzi. This was followed by studies on pathogenesis, led by Fritz Koeberle, from Ribeirão Preto, focused on the possibility of a new pathology that diffused and primarily affected the autonomic nervous system. Although the fundamental postulates of this theory (which indicated Chagas disease as an autonomic nervous system disease and chronic heart disease as a neurogenic heart disease) have not been confirmed, anatomical studies have contributed decisively to the recognition of the digestive form of Chagas disease, precisely due to the wide debates that arose.
The indeterminate chronic form
Since 1983, when the official program to combat Triatoma infestans with residual action insecticides was installed in homes, we have seen a drastic reduction in transmission, which is reflected in the near disappearance of acute forms of infection, in low serological reactivity of schoolchildren in endemic areas, and a decrease in morbidity and mortality in chronic forms, as described by Dias and collaborators. The indeterminate form has now become the most common form of all (Figure 4). Although it is a relatively benign form, it is surprising how little we yet know about the meaning and pathogenesis of this form of Chagas disease. Therefore, their study in these times of transmission control is a priority for those interested in disease problems.
In fact, interest in the indeterminate form of Chagas disease has arisen since the early days of the studies, when infected individuals were found but without the disease. The initial idea was that they were “potential heart patient” who would suddenly die. This notion revealed the lack of a safe criterion for separating the indeterminate form of patients with asymptomatic Chagas disease. This criterion was set by the Brazilian Society of Tropical Medicine at its 1985 meeting, which came to represent progress in longitudinal, clinical and pathological studies (Figure 5). Anatomical studies have shown that asymptomatic Chagas’ disease patients, who died suddenly, actually belonged to the chronic cardiac form of the disease. True bearers of the indeterminate form usually present only a discrete focal myocarditis on microscopic examination. Experimental studies have shown that such foci of myocarditis have a cyclic evolution, arising after parasitic stimulation, resolving by apoptosis of inflammatory cells and re-absorption of excess extracellular matrix (Figure 6). This evolution may occur for a long time, without major repercussions on the patient, provided that there is no hitherto unpredictable change in the immunopathological pattern, as reviewed by Andrade et al. in 1997. The elucidation of the meaning of the indeterminate form and the mechanism of Its transition to the chronic cardiac form is one of the major challenges for the study of Chagas disease pathology today.
Cardiac
The cardiac form of Chagas disease – History
Anis Rassi
Faculdade de Medicina da Universidade Federal de Goiás, Goiânia, GO, Brasil
E-mail: anisrassi@arh.com.br
Simone Petraglia Kropf
Casa de Oswaldo Cruz/Fiocruz
Email: simonek@coc.fiocruz.br
Carlos Chagas, in his first works on the new human trypanosomiasis discovered by him in 1909, pointed out the importance of cardiac alterations derived from the pathogenic action of Trypanosoma cruzi, in the acute phase and, especially, in the chronic phase of infection. The histopathological data produced by Gaspar Vianna, also a researcher at the Manguinhos Institute, were fundamental for the characterization of these alterations. In the autopsies he performed, Vianna located large numbers of parasites inside cardiac cells, in acute cases, with intense inflammatory process around, after the parasite cell rupture.
By presenting, in 1910, the first detailed systematization of the clinical picture of the disease, Chagas designated the cardiac form as one of the forms of chronic infection, to be expressed by arrhythmias due to myocardial lesions caused by T. cruzi. Such a phenomenon, he said, was of “impressive frequency and certainly never observed” in other heart diseases. Its peculiar signs were, according to Chagas, certain excitability disorders, such as extrasystoles and, to a lesser extent, disturbances in stimulus conduction, such as complete heart block, published in the article “New Morbid Entity of Man” in Brasil Médico in 1910.
In 1911, the relevance of the cardiac form was again highlighted. Despite the emphasis on the thyroid elements that had been marking his formulations – which led him to refer to the new trypanosomiasis as “parasitic thyroiditis”, Chagas noted that in many cases heart rhythm irregularities were “the most easily appreciable phenomenon, that first hurts the observer’s attention, standing out as a key element in the data provided by physical semiotics”, as published by Chagas in 1911 in the Memórias do Instituto Oswaldo Cruz.
Chagas stressed the severity of the prognosis of this clinical form, which, at an unusual frequency, led to sudden death by asystole, young individuals who often appeared to be in good health. This aspect would be progressively valued as an element of specificity in the definition of the new nosological entity and as evidence of its medical and social impact, due to the loss of vitality that it caused among workers in their productive age, in rural areas affected by trypanosomiasis.
Carlos Chagas is recognized as a pioneer in the introduction of electrocardiography in Brazil, and in 1912 was the first reference in his works to the electrical recording of heartbeat. At the time, the electrocardiograph – invented in 1901 by the Dutchman William Einthoven – was a rope galvanometer, difficult to handle, especially with regard to the stability of the devices for obtaining the traces. In addition, the registration was made on photographic paper.
In 1916, as a result of questioning his theses on endocrine and neurological disorders attributed to T. cruzi infection (particularly the conception of the chagasic etiology of endemic goiter), Chagas undertook an important review of his studies. From then on, it would fall back on the role of thyroid aspects and progressively reinforce the cardiac aspects. In the context of the intensified nationalist debate with World War I, the so-called sanitary movement – of which Chagas was the leader, alongside Miguel Pereira, Belisário Penna and Monteiro Lobato – projected on the public scene the social importance of the Chagas endemic. The damage to rural labor caused by the heart shape was one of the elements that justified the claims for state intervention in favor of rural sanitation in Brazil.
In 1922, in partnership with Eurico Villela, Chagas published extensive work on the cardiac form of American trypanosomiasis, which presented in detail the main physical signs of progressive organ exhaustion (such as signs of heart failure and increased heart volume, for example), subjective symptoms referred to by patients (such as “avexume” or “baticum”), the evolution of pathological processes, and drug trials to treat arrhythmias. According to the authors, the cardiac form should be seen as “the quintessential clinical feature of American trypanosomiasis”; the characteristic arrhythmias of this heart disease, they said, constituted clinical elements sufficiently individualized to warrant the differential diagnosis of that nosological entity, as well as to “assess the endemic index of the disease,” as described by Chagas and Villela.
At his 1923 conference – at the end of the celebrated controversy at the National Academy of Medicine about his work – Chagas stated that, even if refuting the statements on goiter and other aspects of his formulations, one could not doubt “inescapable signs” that substantiated American trypanosomiasis as a real and specific clinical entity. Once again, he pointed to the cardiac form as “the most interesting and characteristic aspect of American trypanosomiasis”, to support the clinical specificity and epidemiological importance of the disease.
In the following years, and until his death in 1934, Chagas would continue his studies on this aspect of the disease that bears his name. An indication of the importance of this research path was the trajectory of his own son Evandro, who dedicated himself to the clinical and electrocardiographic study of chagasic heart disease, especially in the acute phase.
The idea that the study of the cardiac form was the preferred way to overcome the doubts surrounding the clinical definition and geographic dimension of American trypanosomiasis was expressed in a review by English parasitologist Warrington Yorke in 1937.
“There seems, on the whole, to be a prima facie case that American trypanosomiasis may actually be responsible for a good deal of the heart disease which is apparently so common in certain endemic areas in Brazil, Uruguay and the Argentine, and the cause of so many early deaths. (…) If this should eventually prove to be the case, then American trypanosomiasis will indeed assume a pathological significance of the first magnitude. The subject is obviously one which urgently requires much further work”.
This guideline was precisely one of the dimensions of the work carried out in the 1940s at the Center for Studies and Prophylaxis of Chagas Disease, a post of the Oswaldo Cruz Institute created in 1943 in the city of Bambuí in Minas Gerais. Advances in this direction were mainly due to research by Emmanuel Dias, Chagas’ disciple in Manguinhos and director of the post, Genard Nóbrega, from Evandro Chagas Hospital, and by Francisco Laranja, a cardiologist with extensive clinical and electrocardiographic experience. At the time, this was a field that was undergoing significant technical improvements, mainly due to the contribution of the American Frank Wilson, who established multiple precordial shunts as a procedure to give greater precision to the examination of electrical disorders of the heart. Cardiology itself lived an important process of institutionalization as a distinct specialty in the medical field. In 1943, the Brazilian Society of Cardiology was founded.
Performing systematic examinations on the possible carriers of the chagasic infection in Bambuí and neighboring western Minas Gerais, Laranja, Dias and Nobrega came to establish a detailed electrocardiographic picture of chronic chagasic heart disease, individualizing it as a clinical entity in the face of other heart diseases and ensuring the means its recognition not only by specialists but by clinicians in general.
In 1945, the first results of this electrocardiographic study, presented in a diverse universe in terms of age and time of infection, were presented. Of the 183 individuals classified as chronic cases by serological or xenodiagnostic testing, 90 (49.2%) had electrocardiograms showing myocardial injury. Such work, one of the main references of Bambuí’s contribution to the clinical study of Chagas disease, consolidated the notion that the chronic heart form constituted “the true clinical expression of the disease”. Even the indeterminate form, in which about 50% of the chronic patients were found, was then defined by reference to heart disease, as, according to these authors, asymptomatic individuals presented themselves as “potential cardiac patients”, which, at any given time, might be surprised by the effects of the action of the parasite on their heart, as described by Dias, Laranja and Nóbrega.
As the most indicative signs of chronic chagasic heart disease, Dias, Orange and Nóbrega pointed out (i) stimulus conduction disorders and, in addition to (ii) atrioventricular blocks (especially total AV block), they highlighted the importance of (iii) right bundle branch block (RBB) detection, which was made possible by modern electrocardiographic techniques. Besides these, another sign that would be pointed out, by the Bambuí studies, as “suggestive evidence” for the diagnosis of chronic chagasic heart disease were (iv) ventricular extrasystoles, already pointed by Chagas as a characteristic arrhythmia of chronic American trypanosomiasis.
As the number of cases identified by the Bambuí post increased, the knowledge on the cardiac form of Chagas disease was consolidating. In 1948, in another major review work, based on the analysis of more than 600 cases of the disease, Orange, Dias and Nóbrega provided new data on the specific electrocardiographic picture of this heart disease – “one of the most varied and curious in cardiopathology” – pointing to related clinical manifestations.
Surveys among individuals not previously selected reinforced the arguments regarding the specificity of this clinical entity, showing that the electrocardiographic pattern of the cases studied in Bambuí was found in other population groups in endemic areas. In 1947, Dias, Laranja and the Minas Gerais doctor José Pellegrino examined 312 individuals among workers of the Minas Gerais Road Network and their families, proving by electrocardiograms the high prevalence of the peculiar signs of chronic chagasic heart disease among those who had a positive serological reaction to T. cruzi infection. This study, published in 1948, was a pioneer in using the electrocardiographic method as a criterion for epidemiological investigation. The survey conducted by Pellegrino and Borrotchin in 1948 among patients at the Santa Casa de Misericórdia Hospital in Belo Horizonte also confirmed the importance of chagasic infection as an etiological factor of cardiovascular problems in areas with high frequency of triatomines.
In addition to the epidemiological argument, another important argument regarding the specificity of chagasic heart disease was the reproduction by Pellegrino in dogs experimentally inoculated with T. cruzi of a chronic heart disease with the same electrocardiographic, radiological and clinical characteristics found in humans. At the same time, the advances made in the methods of serological diagnosis, especially in the complement fixation reaction (Guerreiro and Machado reaction), facilitated the recognition of cases of chronic infection, corroborating the data of clinical research.
As a result of this set of researches, Orange, Dias and Nóbrega declared in 1948 that their experience in Bambuí allowed them to be convinced that American trypanosomiasis in its chronic phase “finds clinical expression essentially in a well-defined heart disease in its pathological, clinical, radiological and electrocardiographic characteristics, allowing them to be safely individualized”. Synthesizing the contribution of the Bambuí post, Orange considered it the beginning of a new phase in the “bumpy history” of Chagas disease, in which the recognition of chronic chagasic heart disease as a “clinical entity of indisputable reality” led to the overcoming of “skepticism” that had imposed itself on the subject after the initial phase of the discovery and the early studies of Chagas and his collaborators, as Orange described in 1949. The works of Orange, Dias, Nóbrega and Miranda were to be internationally published in 1956 in the prestigious magazine northern American Circulation, in an article that would be one of the most cited in the literature on Chagas disease.
In the 1950s, an important contribution to studies of chagasic heart disease was the work of the Austrian pathologist Fritz Köberle, hired in 1953 by the newly established Ribeirão Preto Medical School. His research contributed in part to explain the pathogenesis of the morphological and functional changes specific to chronic chagasic heart disease. According to him, such changes had as a determining factor a denervation process caused by damage to the autonomic nervous system of the heart, similar to what found in other organs, especially the esophagus and the colon.
The second half of the twentieth century was very lavish in the diagnostic and therapeutic progress of chronic chagasic heart disease, which, due to its potential for morbidity and mortality, represents a serious public health problem, and its manifestations are three syndromes: (i) arrhythmic, (ii) heart failure and (iii) thromboembolic disease, which are isolated or associated and which gradation depends on the evolutionary stage of the disease. In general, heart failure and thromboembolism syndromes behave like those of other myocardiopathies, however, the arrhythmic syndrome, due to its frequency, variety, quality and severity, makes chronic chagasic cardiopathy an unusual model for clinical, therapeutic, electrocardiographic, electrophysiological and prognostic research. Tiredness and dyspnea on less and less exertion, palpitation, presyncope and syncope are symptoms that are present in heart patients with Chagas disease. It should be noted that there are cases of heart disease (especially in its early stage) without any symptoms; in these cases, the diagnosis is remembered by the finding of electrocardiographic alterations suggestive of the etiology (such as right bundle branch block, left anterior hemiblock, ventricular extrasystole and atrioventricular block of the 1st, 2nd and 3rd degrees) and subject to confirmation by diagnostic serological tests. Thromboembolism is so much for the large circulation (brain, limbs, kidneys, spleen, etc.) as for the small circulation (lungs).
This advance was due to the introduction of laboratory methods, the invention of apparatus and the synthesis of pharmaceutical products to better and more thoroughly examine it and treat its different manifestations. They were so many and of such value that they made obsolete resources relatively new until then.
The electrocardiograph itself has received several improvements, such as direct inscription on thermosensitive paper, weight and size reduction – to make it portable – battery operated – very useful in rural population surveys – automotive etc.
Dynamic electrocardiography (Holter) and exercise testing (initially used for the study of ischemic heart disease) became, since the 1970s, unusual/special pieces to quantify and qualify the tachy and/or bradycardia arrhythmias, symptomatic and mainly, asymptomatic, correctly guiding the treatment. Such methods are also of great value in the therapeutic evaluation of antiarrhythmic drugs and in the detection of their eventual proarrhythmic effect, in the evaluation of the functioning of implanted artificial cardiac pacemakers, in the medical-labor evaluation and in the identification of patients at increased risk of sudden cardiac death.
Similarly, the echocardiogram, which in the early M-mode was soon perfected to two-dimensional and currently Doppler color, providing cardiac morphodynamical data, is not supplanted by any other noninvasive method of investigation. Echocardiography has become more valuable than radiological examination of the heart by allowing the study of contractility myocardial, by determining more accurately the cavity diameters, by reporting the value of the ventricular ejection fraction and by detecting ventricular aneurysm and intra thrombosis-cardiac. The radiological exam was left to the diagnosis of pulmonary vascular stasis.
The serological diagnosis of the chronic phase of Chagas disease has been modified. Guerreiro-Machado’s reaction, introduced in 1913, was replaced by simplified methods such as indirect hemagglutination, indirect immunofluorescence and ELISA, all with sensitivity and specificity around 98%. In parasitological diagnosis, xenodiagnoses has been modified to increase its sensitivity, being now better standardized and performed by artificial or indirect technique. At the same time, the blood culture also underwent significant advances, allowing even greater diagnostic sensitivity than xenodiagnoses. It should be emphasized that both xenodiagnoses and blood culture are, fundamentally, examinations performed in research laboratories in patients undergoing specific treatment to evaluate its results.
Another method, this semi-invasive, for investigation of chronic chagasic heart disease, which began to be used from 1980, is represented by the intracardiac electrophysiological, diagnostic and therapeutic study, performed through catheterization, to study the specific conduction system, whose main indications are assessment of sinus node function, study of atrial and intra-ventricular blocks, differential diagnosis between ventricular paroxysmal tachycardia and aberrant conduction supraventricular paroxysmal tachycardia, reproduction of arrhythmogenic focus and ablation of the same transcatheter using direct electric current.
From the point of view of drug treatment was also modeling the advance. Mercurial diuretics gave way, since the 1960s, to the more potent and less toxic furosemide and thiazides. In recent years, angiotensin-converting enzyme inhibitors, spironolactone, platelet anti-adhesives, anti-coagulants as well as beta-blockers have been incorporated into the clinical treatment of heart failure and thromboembolism. Also noteworthy is the introduction of new antiarrhythmic drugs, especially amiodarone, from the 1970s on in the treatment of ventricular arrhythmias, significantly improving the prognosis of chronic chagasic heart disease.
For bradyarrhythmias, sadly assisted until then by cardiologists, and culminating in sudden death, due to the ineffectiveness of clinical treatment, from the 1960s onwards, it was used the implantable artificial pacemaker (initially epimyocardial, requiring thoracotomy and then transvenous endocardial), which has undergone successive improvements over the years. There have been so many improvements that, in the jargon of experts, it is said that the pacemaker holder had to adapt to it, whereas today it is the pacemaker that adapts to the needs of the patient; in addition, its generator is small (3 cm in diameter and 0.5 cm thick) and light (10 g). For ventricular tachyarrhythmias (sustained ventricular tachycardia and ventricular fibrillation) another electrical resource was invented and used since the 1990s. It is the implantable cardioverter-defibrillator, which, according to programming, triggers a shock, hardly noticed by its carrier, due to paroxysmal tachycardia and, necessarily, during ventricular fibrillation, when the patient is unconscious (syncope). This apparatus too, primitively, as the pacemaker, was of great proportions and heavy. Today, however, its dimensions and weight have decreased to the point of allowing transvenous implantation, and more, they also have a pacemaker function to treat eventual bradyarrhythmia that, with relative frequency, is associated with tachyarrhythmia in chronic chagasic cardiopathy.
For terminal cases of chronic chagasic cardiopathy, especially irreducible heart failure, heart transplantation is presented as a solution. In its history there are two periods: (i) the first, from 1967 (when it was performed by Christian Barnard) to 1980, and (ii) the second, after 1980, when new immunosuppressive drugs were incorporated into the treatment, significantly improving the prognosis. The first heart transplantation in chronic chagasic patient dates back to 1985. To date, a few hundred cases have been performed in 57 accredited hospitals, with results as good or even better than those of heart disease of another etiology. In the context, T. cruzi should be considered, due to the use of immunodepressants, which may cause reactivation of the infection. There is no consensus on the prophylactic use of trypanosomicide before or after surgery. We are of the opinion, on an empirical basis, that it should be performed (preoperatively if the patient’s general conditions permit) or otherwise in the immediate postoperative period using benznidazole (5 mg/kg/day for 60 days).
Another resource for the treatment of severe chronic chagasic cardiopathy was recently adopted by a group of researchers from Bahia, led by Ricardo Ribeiro dos Santos, based on literature data, which consisted of implanting the patient’s own bone marrow stem cells. As the initial results of this study were promising, the Ministry of Health provided a national, double-blind, placebo-controlled trial, already underway, to ascertain the true value of the method. Three hundred patients with chronic chagasic heart disease (NYHA functional class III and IV) will be included, half of whom will be treated with intra-coronary injection bone marrow stem cells and the other half with placebo. Let’s wait for the result.
All these diagnostic and therapeutic advances gradually allowed the optimization of care for the patient, modifying the prognosis of chronic chagasic cardiopathy in the second half of the twentieth century, in favor of a better quality and longer life.
Parallel to all the symptomology and physical examination techniques and therapeutic achievements observed in the second half of the twentieth century, there was a great increase in the study of chronic chagasic cardiopathy in all its aspects, making it a mandatory and frequent subject in medical congresses and related meetings, as well as the formation of research groups in several centers: Ribeirão Preto (SP), Goiânia (GO), Belo Horizonte (MG), Uberaba (MG), São José do Rio Preto (SP), Sao Paulo (SP), Salvador (BA), Rio de Janeiro (RJ), Brasília (DF), Recife (PE), Uberlândia (MG) and Campinas (SP).
Digestive form of Chagas disease
Historical review
Joffre Marcondes de Rezende
Prof. Emérito da Faculdade de Medicina da Universidade Federal de Goiás
Membro titular fundador da Sociedade Brasileira de História da Medicina
E-mail: jmrezende@cultura.com.br
Since the discovery of Chagas disease in 1909, it has been considered one of the possible causes of choking disease, an endemic condition in Brazil, the symptoms of which are the same as those of universal esophageal achalasia. It is characterized by loss of esophageal peristalsis and lack of lower sphincter relaxation during swallows, which causes difficulty in eating foods, which are largely retained in the esophagus, causing the progressive dilation of this organ. The similarity of the two conditions led many authors to believe that it was the same and only morbid entity. What set them apart was the unusual frequency of choking disease in certain regions of Brazil, in contrast to the rarity of achalasia in any country in the world. To get an idea of the incidence of choking disease in Brazil, suffice it to say that the series reported in studies published by only five authors, between 1939 and 1993, reached the sum of 7,435 cases.
To explain this fact, several hypotheses were raised, admitting the action of environmental factors, toxic, infectious or food, which could be contributing to the endemic character of the disease. Toxic action of a variety of cassava consumed by the rural population, malaria and other infectious diseases, malnutrition in general or specific vitamin B1 deficiency in the diet was considered.
In the book Brazil and Brazilians, published in 1857, the authors, two American missionaries, based on the information of a physician who was practicing in Limeira, São Paulo State, described choking disease as “a new disease”, which was raging in the interior of the country, from “Limeira to Goiás”. The identity of this doctor has only recently been revealed.
Arthur Neiva and Belisário Penna, in their famous scientific trip to the interior of Brazil in 1912, described in great detail the choking disease from a clinical and epidemiological point of view; they even thought of an infectious cause for endemic disease, as is clear from their experiment injecting blood from a patient in a cavy, but they did not relate it to Chagas disease.
The first documented reference to the possibility of the chagasic etiology of choking disease is Carlos Chagas himself in his work on the acute form of trypanosomiasis, published in 1916. Suspecting the etiological relationship between the two endemics, the said: “choking would be one more element of the Brazilian Trypanosomiasis and this dysphagia of acute forms will translate the initial phase of the syndrome?”. And later, he concluded: “new research is needed to authorize the inclusion of choking disease in the multiform symptomatology of Trypanosoma cruzi infection.” It is noteworthy that Chagas referred to choking disease as a syndrome rather than a disease. For unexplained reasons, Chagas disease scholars at the time either ignored Chagas’s words or were not motivated to undertake the new research that was needed.
The years went by and only in the 30’s the first studies on the pathology of choking disease, carried out by researchers from São Paulo. Moacyr Amorim, Alípio Correa Netto and Eduardo Etzel have shed new lights to clarify the problem. They demonstrated the existence of degenerative lesions of Auerbach’s myenteric plexus in choking disease not only on the esophageal wall but throughout the digestive tract. This finding allowed to unify in one entity the choking disease and colon dilation, commonly found in the same patient.
Colon dilatation was called megacolon; by analogy, considering that the esophagus is also dilated, the name megaesophagus proposed by von Hacker in 1907 was adopted for cases of idiopathic achalasia. Since then, both conditions have been considered manifestations of the same condition.
Degenerative lesions of the enteric nervous system were attributed to vitamin B1 deficiency in food, according to the theory advocated by Eduardo Etzel in 1935, a theory that was well accepted by the national and international scientific community, lasting until the 1950s.
On the other hand, choking disease has always been the subject of investigation by physicians working in the interior, both clinically and epidemiologically. A frequent observation was the presence in the same patient of megaesophagus and chagasic heart disease. Epidemiological data indicated that choking disease was a rural endemic disease; the inhabitants of the cities afflicted with ilness, with very rare exceptions, had lived in farms or small villages.
In Goiânia, Joffre Rezende found that the condition was mainly in low-income families living in precarious houses built with barred walls, where hematophagous triatomines were colonized, and that the highest number of cases of megaesophagus treated in city hospitals came from municipalities in the interior of the state with a high rate of natural infection of triatomines by Trypanosoma cruzi, according to a survey by the National Department of Rural Endemics.
It seemed that, like heart disease, megaesophagus was a consequence of Chagas disease.
Another argument that corroborated the hypothesis of the chagasic etiology of endemic megaesophagus was the high positivity index of the Guerreiro and Machado complement fixation reaction in patients with megaesophagus or megacolon, much higher than that found in any unselected group of the population of endemic areas. The first research in this sense was performed by Eurico Vilela in 1930, in the city of Belo Horizonte. In 186 people investigated, 53 (28.5%) had a positive Guerreiro and Machado reaction, while in 13 patients with megaesophagus, eight were positive (61.5%). Also, in Belo Horizonte, Melo Alvarenga employed this technique in 16 cases of megaesophagus, finding it positive in eight (50%). The low percentages obtained were due to the low sensitivity of the antigen employed. With improvement of this reagent, in the 40’s, Pedreira de Freitas obtained 91.2% in 80 cases of megaesophagus and megacolon, and Laranja, Dias and Nóbrega, 97.0% in 81 cases. Several other authors reported a high positivity index of Guerreiro and Machado reaction in patients with megaesophagus and megacolon.
Despite all the clinical, epidemiological and serological evidences, there were still opponents to the chagasic etiology of the megas. They were based on the following theoretical arguments of apparent logic, namely: megaesophagus does not occur in all endemic regions of Chagas disease, such as Venezuela and the countries of Central America; the vast majority of patients with Chagas disease do not have megaesophagus or megacolon; the high positivity of the serological reaction can be explained by the overlapping of two endemic areas, as happened with Chagas disease and endemic goiter; no parasites were found in the esophageal or colon wall of autopsied cases; the megaesophagus is the same achalasia of the esophagus, found where there is no Chagas disease; megacolon may be due to other causes and also occurs in non chagasic regions.
At the Medical Congresses in Triângulo Mineiro and Central Brazil, held since 1947, the subject was much debated and the local doctors, grounded in their experience with the problem, always defended the chagasic etiology of the megas against all these arguments.
The importance given in these Congresses to Chagas disease and endemic megaesophagus can be appreciated in the article by Porto and Porto, entitled History of the megaesophagus in the Medical Congresses of Central Brazil. In this article, the authors refer, in chronological sequence, to the most relevant contributions and end with the following words:
“In these 13 Medical congresses in Triângulo Mineiro and Central Brazil held from 1947 to 1965 the megaesophagus theme was constant. It had the appearance of insubordination this constancy. It seemed like an attitude of protest against the chairs… which silenced for a long time about a common illness widespread in Brazil and of secular knowledge even by healers and blessers”.
In addition to the megaesophagus theme, the Triangulo Mineiro and Central Brazil Congresses also influenced the recognition of the severity of Chagas disease as a public health problem and the awareness of the country’s health authorities about the urgent need to start a prophylaxis campaign for this endemic disease. In this sense, the participation of Emmanuel Dias and other distinguished chagologists, including Amilcar Viana Martins, José Pelegrino, Humberto Ferreira, Pedreira de Freitas, was decisive.
For the definitive acceptance of the chagasic etiology of the megaesophagus and megacolon, however, anatomopathological evidence was lacking.
This proof was up to Fritz Koeberle. Austrian by birth, Koeberle came to Brazil at the end of 1953, hired to set up and direct for a period of three years, the Department of Pathology at the University of São Paulo at Ribeirão Preto Medical School. At the end of his contract, he decided to stay in Brazil; he became a naturalized Brazilian, revalidated his medical degree, and competed for a full professor position, becoming a full professor at the university until his retirement in 1976. Since the beginning he became interested in the problem of choking disease and its possible relationship with Chagas disease. After reviewing the existing literature, he was convinced that trypanosomiasis was the true cause of endemic megaesophagus and megacolon in Brazil. On the one hand, convincing clinical, epidemiological and serological data on the etiological relationship between the two endemics; on the other hand, the anatomopathological findings of degenerative Auerbach’s myenteric plexus lesions in autopsied megaesophagus cases are found not only in the dilated segments, but throughout the digestive tract.
The main function of the myenteric plexus in the digestive tract wall is to coordinate motility in its different segments. It remained to be proved that these lesions were primitive and the dilation secondary to the motor alterations resulting from the denervation produced by T. cruzi infection.
Koeberle developed his research on autopsies of patients with Chagas disease, naturally infected animals and experimental infection in laboratory animals. In the acute phase of infection, he observed parasitism of the muscular wall of the digestive tract and inflammatory process involving the myenteric plexus. In the chronic phase, he observed that denervation is irregular, with variable distribution and intensity. He then had the idea of carrying out quantitative study of esophageal neurons in autopsies of non-carriers and Chagas disease patients with and without megaesophagus. In the counting of neurons, which was done in the lower third of the esophagus, the reduction in the number of neurons was very variable. Denervation was a constant in patients with Chagas disease, but less intense in those cases of apparently normal esophagus. He concluded, after comparing cases with and without megaesophagus, that the evolution of chagasic esophagopathy to a typical megaesophagus only occurs when denervation reaches a threshold, which was estimated at 90%.
Quantitative studies were also done in relation to the colon, which showed that denervation is not restricted to the dilated segment, commonly straight and sigmoid, as was believed, and extends to the entire colon. The critical level of reduction in the number of neurons for megacolon onset was estimated at 55%.
Then, his collaborators proceeded with quantitative studies of other segments of the digestive tract: stomach, duodenum, small intestine, cecal appendix, and colon, demonstrating a significant reduction in the number of neurons in all of them. Studying chronic chagasic heart disease, Koeberle also found a reduction in the number of heart nerve cells.
From the series of works published by Koeberle on the pathology of the digestive tract in Chagas disease, reference should be madeto the Preliminary Note in collaboration with Stephen Nador and those of major relevance that followed.
Koeberle had initially admitted that neuronal destruction resulted from a neurotoxin released by the parasites after rupturing amastigote pseudocysts; he later recognized that it was related to an immune mechanism.
In view of the findings that formed an entirely new aspect in the pathology of T. cruzi infection, Koeberle established a new view of Chagas disease, conceptualizing it as a disease of the peripheral autonomic nervous system.
This concept proved to be very fertile and led to numerous researches that evidenced multiple disorders in different sectors of the organism in patients with Chagas disease.
Subsequently, other authors not only confirmed Koeberle’s studies, but also verified the existence of denervation in other organs.
Given the evidence of the chagasic etiology of endemic megaesophagus and megacolon and the intrinsic denervation throughout the digestive tract, it was necessary to review the classification of the clinical forms of Chagas disease, considering the large number of cases of megaesophagus and megacolon without heart disease, previously included in the indeterminate form and considered only as potential cardiac cases.
Joffre Rezende, in 1956, proposed the denomination of digestive form to characterize the manifestations resulting from “digestive tract lesions with consequent changes in motility”, a name that was well accepted by the scientific community. In 1959, the same author expanded the concept of digestive form to include, in addition to motor disorders, secretory and absorptive alterations of the digestive system, already known or to be described in the future, regardless of the presence or absence of esophageal or colon dilatation.
Many of the new aspects of Chagas disease pathology and its manifestations in the digestive tract were published by the Revista Goiana de Medicina. This journal, of modest pretensions, was founded by the Medical Association of Goiás in 1955 with the main objective, according to the editorial of its first issue, to improve the “standard of medicine practiced in Goiás, preparing the ground for our future Faculty of Medicine”. The Faculty was born in 1960 as a private entity, being federalized that same year with the creation of the Federal University of Goiás.
Since its inception, the Revista Goiana de Medicina has given priority in its editorial line to works related to regional pathology, especially Chagas disease, considered at the time the main endemic state of Goiás.
Graças aos artigos publicados, desde o seu primeiro número, sobre a doença de Chagas, a Revista se projetou no cenário médico nacional e internacional, granjeando a confiança de pesquisadores dos grandes Centros do País, que nela publicaram importantes trabalhos sobre a Tripanossomíase americana.
Over the 35-year period (1955 to 1990), out of 564 titles of original articles published, 201 (35.6%) refer to Chagas disease and of these, 85 (42.3%) relate to the digestive form in its different aspects, from pathology to surgical treatment of megaesophagus and megacolon.
Due to the acquired knowledge, the classification of Chagas disease is currently accepted in the following clinical forms: indeterminate, cardiac, digestive and mixed or associated (cardiac + digestive). The digestive form has been reported with a very variable prevalence, depending on the geographical region. In Brazil, the existing medical literature records the largest number of cases in the central region of the country, comprising part of the states of Minas Gerais, Goiás, São Paulo, Bahia and southern Piauí. Its occurrence is exceptional in countries above the equatorial line, such as Venezuela and the Central American countries where Chagas disease is well studied and recognized as a cause of heart disease.
In Brazil, the prevalence of the digestive form has been estimated based on the diagnosis of esophagopathy in radiological surveys made in chagasic populations of endemic areas, through the 35 and 70 mm abreugraphy. In seven of these surveys, totaling 2,073 cases, the prevalence ranged from 7.1 to 18.8, with an average of 8.8.
Chagasic esophagopathy was considered a good indicator of digestive form, given that many of the changes found in other sectors of the digestive system occur in association with megaesophagus.
On radiological examination, depending on the evolution of the disease, the esophagus may present different morphological aspects that were classified into four groups by Joffre Rezende and collaborators. The first two groups comprise the compensated phase of the megaesophagus, in which there is greater contractile activity of the esophageal muscle wall, while the last two correspond to the decompensated phase in which motor activity is minimal or nonexistent.
The motor changes recorded by manometry are very variable in the compensated phase and follow a uniform pattern in the decompensated phase, as demonstrated by Henrique Pinotti, Renato Godoy and Joffre Rezende.
In the digestive form, in addition to the megaesophagus and megacolon, several authors have described motor and or functional alterations in the stomach, duodenum, jejunum, ileum, bile ducts, salivary glands and pancreas, as recently reviewed by Joffre Rezende and Hélio Moreira.
The existence of a chagasic gastropathy had previously been suspected by Calil Porto based solely on clinical observation. Gastric abnormalities are found in about 20% of patients with megaesophagus. At radiological examination, the gastric volume is extremely variable and the absence of stomach air chamber in patients with advanced megaesophagus is characteristic. Hypersensitivity of the gastric wall musculature to cholinergic pharmacological stimulation, as well as motility and secretion disorders can be detected by different methods in patients with digestive form. In such cases, gastric emptying is accelerated to liquids and delayed to solids and there is a less adaptive relaxation of the gastric body to distension of the stomach. Recently an electrogastrographic study showed alteration of the electric rhythm of the stomach, with gastric dysrhythmia.
Studies of gastric secretion revealed hydrochloropeptic hyposecretion, both basal and under different stimuli: histamine, histalog, insulin, pentagastrin and calcium ion infusion. When one of these tests is associated with stimulation with a cholinergic substance such as methacholine or bethanechol, increased secretion of both hydrochloric acid and pepsin demonstrates that hyposecretion is mainly determined by intrinsic denervation of the stomach. and not by reducing the number of secretory cells. In parallel, there is fasting and postprandial hypergastrinemia.
In addition to these motor and secretory alterations, the presence of chronic gastritis in different degrees of intensity is frequent, whose etiopathogenic factors appear to be multiple, possibly including duodenogastric biliary reflux and Helicobacter pylori infection.
In cases with severe difficulty in gastric emptying, previously labeled as “pylorus achalasia”, pyloric muscle hypertrophy is found. In these cases, pyloroplasty is indicated as a complement to cardiomyotomy in the surgical treatment of megaesophagus.
After the esophagus and colon, the duodenum is the segment that is most often dilated. Almost always megaduodene is associated with other visceromegalies. Dilatation may be located only in the bulb (megabulum), in the second and third portions, or may compromise the entire duodenal arch. Even in cases where there is no dilation, dyskinesia and hyperreactivity to cholinergic stimulation due to denervation are frequent. The symptoms eventually caused by megaduodene may be confused with dysmotility-type dyspepsia of gastric origin.
In the small intestine, histopathological studies showed less severe denervation of the enteric nervous system than that of the esophagus and colon. Dilatation of the jejunum or ileum to the point of configuring the megajejunum and megaileum is a rare occurrence, with few cases reported.
The repercussions of chagasic enteropathy are less evident from the clinical point of view, but can be detected in investigations directed to this end. Motor changes have been proven in both radiological and manometric studies. The interdigestive migratory motor complex presents abnormalities in patients with other manifestations of the digestive form. Possibly as a result of this fact there is a greater growth of bacterial flora, which resembles, in certain cases, that found in stagnant loop syndrome.
Studies on intestinal absorption in patients with the digestive form revealed accelerated absorption of glucose and other sugars. As a result, oral glucose tolerance testing may show abnormal glycemic curves with transient hyperglycemia within the first hour. In addition to glycemic hyperabsorption, mild lipid hypoabsorption was observed, which did not change the fecal fat excretion content. Both described changes are attributed in part to gastric emptying disorders.
Colon dilation most often occurs in the distal segment, comprising the rectum and sigmoid colon.
The gallbladder also undergoes intrinsic denervation in the digestive form of Chagas disease, with motor changes in filling and emptying. Abnormalities were also recorded by Oddi sphincter manometry. Cholecystomegaly, however, is uncommon, as is choledochal dilation. There are data in the literature suggesting a higher incidence of cholelithiasis in patients with Chagas disease with megaesophagus and/or megacolon.
Salivary glands, notably parotid glands, are hypertrophied in patients with megaesophagus, which is common in any obstructive esophagopathy as a consequence of the esophagossalivary reflex, which produces hypersalivation. In patients with Chagas disease, however, there is greater sensitivity of the salivary glands to mechanical chewing stimulus and pharmacological stimulation by pilocarpine. Moreover, hypersalivation and parotid hypertrophy persist in esophagectomized patients, which demonstrates that it not just about the esophagosalivary complex but also the impairment of innervation of these glands in Chagas disease.
In relation to the exocrine pancreas, its functional capacity is preserved in relation to direct stimulation on the gland. However, there may be secretory deficiency due to indirect stimulation, resulting from changes in duodenojejunal hormone release.
Diagnostic
History of the diagnostic methods for Chagas disease
Alejandro Luquetti Ostermayer*
Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás
E-mail: luquetti@ufg.br
The diagnostic of the infection by Trypanosoma cruzi, etiologic agent of Chagas disease, as in other infectious disease, is based on three distinct parameters: the clinical manifestation, which, if present, allows the doctor to suspect the infection; the previous epidemiology, which also induce the suspicion; and the diagnostic methods, in general laboratory ones, which allow the confirmation or exclusion of the diagnostic suspicion in most of the situations. The clinical doctor, with the informations above, will have to decide if the individual is infected or not. It is important to note that the infection by a given agent is not a synonym of disease; many infections run without disease clinically ostensive. In the infection by T. cruzi, more than half the infected people does not present cardiopathy, megaesophagus or megacolon, the main manifestations of Chagas disease. In these cases in particular, the diagnostic is suggested by the antecedent epidemiology and confirmed or excluded by the results of the laboratorial tests.
As so, the diagnostic methods present particular importance in Chagas disease. Additionally, this infection displays only two phases, distinct by the chronology of the infection, the clinical manifestations and diagnostic methods. The acute phase, initial, with fever and inespecífic symptoms (sometimes with Romaña signal or inoculation chagoma) is diagnosed by parasitological methods, due to the elevated parasitemia, that defines this phase. In the chronic phase, that begins after the acute phase and that, as mentioned, is assymptomatic in more than half of the cases, the laboratorial diagnostic is based in the indirect search of signals of the infection, i.e., the presence of antibodies anti-T. cruzi.
The history of the diagnostic method can be divided in three periods, with diferente duration of time. The first period, since the discovery until 1969, is commented below.
The first developed diagnostic methods were the parasitological methods. Carlos Chagas based on the finding of T. cruzi in a child named Berenice affirmed that this agent was the responsible for the clinical condition. It consisted in an acute case of the disease, and the diagnostic, nowadays, more that 100 years, remains being performed in the same manner, the direct research of T. cruzi in the peripheral blood.
In the chronic phase of this trypanosomiasis, in the first years after its discovery, the laboratorial diagnosis was performed by the inoculation of the blood in guinea pigs. Chagas described the presence of parasitic esquizogonic forms in the lung of infected animals, believing that were T. cruzi. This finding was defined as the diagnostic method in the experimental infection of guinea pigs until 1913, when it was demonstrated that these forms, in reality, were from another parasite, Pneumocystis carini, and the method was abandoned.
In 1914, Brumpt described another type of parasitological diagnosis, the xenodiagnosis, that initially was not frequently employed. The first references about its use in the diagnostic of Chagas disease were from Torrealba, in Venezuela in 1934; Emmanuel Dias, in Brazil and Bacigalupo, in Argentina. This method was routinely used only after its standardization by Cerisola and collaborators in 1974.
The initial description of the research of antibodies was in 1913 by Guerreiro and Machado. It constituted the complement fixation reaction, soon known as the reaction of Guerreiro & Machado, which was the sole serological test available for more than 50 years, and that was performed routinely for the diagnostic till a few years ago. This test suffered multiple modifications and standardizations, highlighting the contribution of Almeida and Fife in 1976. The technical complexity, the utilization of several reagents requiring daily standardization and the time of reaction led to its gradual abandonment beginning in 1995, mainly due to the existence of simpler tests. In this period, a technical report of the Ministry of Health recommended its substitution by other tests. In this first period in the evolution of the knowledge about diagnostic, until 1960, there were only two tests for more than 50 years. The second period, from 1960 to 1975, was of substantial development, as will be discussed below.
Blood culture, introduced as a parasitological diagnostic method since the decade of 1940, presented results inferior to those of xenodiagnosis, and was not employed. After the work of Chiari and Brener in 1966 and with successive improvements (reviewed in Chiari, 1992) it was re-introduced and is employed until now, with results comparable to xenodiagnosis and the advantage of allowing parasite isolation.
The inoculation in experimental animals was also used for a long time, but it was abandoned as diagnostic method due to operational difficulties, and also due to low sensibility in the chronic phase.
Other tests were used, such as the detection of circulating antigen, antigenuria, tests of delayed hypersensibility, but were not incorporated into the routine and are not employed.
Several trials of the utilization of serological tests, employing other methods, such as precipitation test, latex agglutination, flocculation, did not fructified, sometimes due to low efficiency, or due to high costs. In 1962, Cerisola and collaborators reported the utilization of indirect hemagglutination test (IAT) for the serological diagnosis of the infection. This test, of simple execution and good performance, is employed until now, although it presents a sensibility lower than the immunofluorescence and ELISA assays, that will be described below. For such reason, it is not recommended for exclusion of blood donors.
In 1966, Camargo optimized the utilization of the indirect immunofluorescence test, initially reported by Fife and Muschel. This test, of high sensibility, was employed in the national serological survey using more than one million of samples in Brazil, determining, with good accuracy, the prevalence of Chagas disease. Due to its high sensibility, it is ideal for epidemiological studies as well as for diagnosis, although it exhibits cross reaction, in particular with leishmaniasis. This test is still employed, simultaneously with IAT and ELISA, constituting, the three together, the conventional tests, performed with great expertise in all the Latin America countries.
The direct agglutination test, improved by Vattuone & Yanovsy with the inclusion of the reducing agent 2-mercaptoethanol, was employed mainly in Argentina with good results, however its commercialization was interrupted.
In 1975, Voller and collaborators described the immunoenzimatic test ELISA in samples collected in filter paper. This method was improved and nowadays it is employed in the routine of hemotherapic and diagnostic services, existing in Brazil several brands, approved by the Agência Nacional de Vigilância Sanitária (ANVISA), displaying good performance.
As so, this second period in the evolution of diagnostic, in just 15 years we watched the development of methods that are still the base of the current diagnosis.
In the third period, from 1979 until now, the advances in molecular biology improved the existing methods and led to development of new ones, which will be discussed below. In successive studies, the aim was the better quality of the antigens employed, of total extracts (crude antigen) of the parasite, antigens purified by different techniques, in order to prevent cross reactions, usually observed in conventional diagnostic tests. In the decade 1980, were published studies employing glycoproteins of 25 kDa, 90 kDa and 72 kDa, among others, with a panel of sera of patients with different clinical forms. These reagents are not comercialized.
With the advancement of molecular biology knowledge, begining in 1980, recombinant proteins were obtained by different research groups in Brazil, Argentina and USA, with good results. Studies with synthetic peptides were also published (reviewed by Silveira and collaborators). Aiming the definition of those with higher applicability, the program TDR (Tropical Diseases Research) from the World Health Organization (WHO), sponsored a multicentric study that also included some purified antigens, defining some of them as suitable. Another study, developd by Levin and collaborators, confirmed some of these results, and also a third one, with an elevated number of sera, was performed by Umezawa and collaborators. After these studies, several rapid tests were developed, some of them aiming to perform the field diagnosis, using a single drop of blood. One test was validated in a mulitcentric study performed by Luquetti and collaborators. Later on, a study coordinated by the Medecins sans Frontieres compared the performance of 11 rapid tests available, demonstrating some of them good sensibility and specificity, with applicability in surveys and in emergency situations.
Other tests employed were based on flow cytometry and Western blot. Although, th later one was commercialized for some period of time (Tesa-blot®), both are not currently available.
In another approach, serological methods were developed for detection of specific antibodies against different populations of T. cruzi, aiming the identification of the parasite type (I to VI) that predominates in each infected individual. Some results have been already published by Bhattacharyya and collaborators in 2014.
In another phase of the laboratorial diagnosis, in the decade 1990, studies were directed for the amplification of nucleic acids of the parasite itself, aiming the parasitological diagnosis, by PCR. Nowadays, it is possible to verify the presence of one parasite in 10 mL of blood. The point is, that, as a verification method of the parasite presence, since the parasite could be not present in a chronic infection sample, a negative result does not have a diagnostic value. The sensibility is higher than that of hemoculture and xenodiagnosis, although there is a concern in relation to its specificity in routine services. Also, such method is still not commercialized (reviewed by Luquetti & Rassi). Please, see the following chapter.
A new commercial test, based on quimioluminescence, was developed in the last decade, with excellent sensibility, for application in hemotherapic services. This test of high utility in centers with a high demand of exams, is nowadays widely used.
Although several serological tests of good performance are at hand, it is necessary the verification of each batch and the availability of adequate technical instructions for the laboratoy personal. The Ministry of Health from Brazil demonstrated sensibility to this subject, promoting studies of the commercialized reagents. In partnership with the Management fo AIDS, manual and video about the disease diagnosis were elaborated. Also, in partnership with Biomanguinhos (Fiocruz), ANVISA develops, since 2001, an external quality program (AEQ), distributing three panels of sera each year, which is still in operation for the hemotherapic services in Brazil.
Although with all the advancements achieved, is still needed the use of two tests with different principles to assure the presence (or exclusion) of infection. However, for exclusion of a blood donor, following WHO recommendations (2002), the execution of a single test of high sensibility (ELISA or quimioluminescence) is enough if an external control of quality is operative.