American Trypanosomiasis Chagas Disease: One Hundred Years of Research

†Deceased

Preface

Francisco J. Ayala, University of California, Irvine, United States

In 1909, Carlos Chagas identified Trypanosoma cruzi as the agent of Chagas disease. In 1910, Chagas discovered that Triatoma bugs are vectors of the parasite and that various animals (first, the armadillo) are wild reservoirs for the parasite. The parasite was named in honor of Oswaldo Cruz, the great Brazilian epidemiologist of yellow fever, smallpox, and bubonic plague. In 1986, Michel Tibayrenc and collaborators discovered that the reproduction of the parasite is clonal, rather than sexual. The disease is, of course, much older than Chagas’ discovery. It may have been associated with humans shortly after they arrived in the Americas some 15,000 years ago. T. cruzi has been found in mummies from northern Chile and southern Peru that are nearly 9000 years old.

Chagas disease is endemic in Mexico and Central and South America, with significant prevalence of human infection in 22 Latin American countries, where it affects 10–12 million people and kills more than 10,000 humans each year. There are several hundred thousand people infected with T. cruzi in other parts of the world. Mostly, in the United States, Canada, Australia, Japan, Spain, and Portugal, where the carriers are typically Latin American immigrants, who are often unaware of their infection, but cause the infection of others through blood transfusions and otherwise. In the United States, the annual cost of treatment is about $900 million. The global cost is estimated to be more than $7 billion.

In spite of counting among mankind’s worst scourges, Chagas disease has received relatively little attention from investigators and institutions. Pharmaceutical corporations typically have little or no interest in diseases that affect the world’s poorest. In the United States, Europe, and other industrialized countries, Chagas is largely perceived as a foreign disease, which does not motivate government agencies, foundations, and other institutions to invest substantial resources to discover curative drugs and medical treatments.

This neglect has been changing. In 1943, the Oswaldo Cruz Institute’s Prophylaxis and Study Center for Chagas Disease was created in Bambuí, Brazil. In 1974, the World Health Organization set a special program for the study of Chagas disease. In 1991, Argentina, Bolivia, Brazil, Chile, Paraguay, and Uruguay started the Southern Cone initiative for vector control. The Drugs for Neglected Diseases Initiative (DNDi) was established the same year to promote research against Chagas and other tropical diseases. In 2013, the DNDi received the Carlos Slim Health Award, as well as a Next Century Innovator’s Award from the Rockefeller Foundation. The first complete genome sequence of T. cruzi was published in 2005, culminating an effort pioneered since 1998 by Björn Andersson and others. There are now very few treatment drugs in use, notably benznidazole and posaconazole, but research and testing of several other drugs are in the pipeline.

American Trypanosomiasis Chagas Disease: One Hundred Years of Research is a wonderful addition to current efforts. The coverage is broad, almost all-inclusive: from history and geography—through vectors and nonhuman hosts, the biology and modes of transmission of the parasite, and the host–parasite immune interactions—to the pathology, diagnosis, and treatment of the disease. I anticipate that this Second Edition will be hailed as a landmark in the history and control of Chagas disease, as the First Edition was also recognized.

1

History of the discovery of the American Trypanosomiasis (Chagas disease)

T. Araujo-Jorge¹, J. Telleria²,³ and J.R. Dalenz⁴,    ¹Fundação Oswaldo Cruz, Rio de Janeiro, Brazil,    ²Institute for Research for Development (IRD), Montpellier, France,    ³Pontifical Catholic University of Ecuador, Quito, Ecuador,    ⁴Universidad Mayor de San Andrés, La Paz, Bolivia

Abstract

American Trypanosomiasis was named Chagas disease in honor of its discoverer, Carlos Chagas (1878–1934). In 1909 he produced a unique and exceptional work in the history of medicine. He discovered a new species of flagellated protozoa (1) in the intestines of hematophageous insects, (2) in the blood of various domestic animals, and (3) in the blood of a little girl. This new species was called "Trypanosoma cruzi" in honor of Professor Oswaldo Cruz. His discovery gradually spread among different Latin America countries. Salvador Mazza (Argentina) profoundly marked this history. Cecilio Romanha discovered the early pathognomonic sign of Chagas disease (the Romanha sign) and Rafael Torrico is considered to be the father of Chagas disease in Bolivia. Chagas disease, 100 years later, is still the most neglected of kinetoplastid diseases, but affected people actively argue for their rights for diagnosis and treatment through new associations in many countries.

Keywords

History of science; parasitic disease; vectorial disease; biography; treatment

Chapter Outline

A beautiful history of life and work 1

The history of a significant discovery 6

Salvador Mazza: marked the history of the knowledge of his disease 10

Cecilio Romanha: his contribution to the identification of the disease 11

First evidence of Trypanosomiasis Americana (Chagas disease) in various countries of Latin America 12

Chagas disease 100 years after the discovery 16

Acknowledgments 18

References 18

A beautiful history of life and work

American Trypanosomiasis was named Chagas Disease in honor of its discoverer Carlos Ribeiro Justiniano Chagas,¹ who was born in a coffee farm at Oliveira (Fig. 1.1), state of Minas Gerais, on July 9, 1878.¹–⁴ His father was a tradesman named José Justiniano Chagas and his mother was Maria Ribeiro de Castro, born into a traditional family of coffee producers (Fig. 1.2).

Figure 1.1 The house in Oliveira, state of Minas Gerais, Brazil, where Carlos Ribeiro Justiniano Chagas was born (July 9, 1878) (Archives of the Instituto Oswaldo Cruz).

Figure 1.2 The parents of Carlos Ribeiro Justiniano Chagas: José Justiniano Chagas and Maria Ribeiro de Castro (Archives of the Instituto Oswaldo Cruz).

Carlos Chagas suffered three important family losses: his father and his two brothers. Soon, he assumed the responsibility as the head of the family, helping his mother and sister. He spent his childhood (Fig. 1.3) in the farm and his youth in a catholic school in São João del Rey, where the priest João Sacramento exerted an enormous influence on his education.²,³

Figure 1.3 Carlos at the age of about 5, in the farm where he was born (Archives of the Instituto Oswaldo Cruz).

His mother wanted him to be an engineer but he did not pass the entrance exams, and in consequence, he experienced a severe depression. Carlos Chagas then decided to break with his mother’s expectations and settled in Rio de Janeiro to study medicine, 3 years before the end of the 19th century. Two uncles from his mother’ family profoundly influenced him in finding his medical vocation.

During his childhood and youth, his curiosity was awakened; moreover, Sacramento introduced him to the delights of the discovery of the natural world and the art world.

Carlos Chagas exercised all the important mental tools for educating his imagination, as summarized in 1999 by Robert and Michelle Root-Bernstein⁵: to observe, to evoke images, to abstract, to recognize and to form patterns, to think with the body, to empathize, to think in a dimensional way, to establish analogies, to create models, to play, to transform, and to synthesize. These are some of the tools that explain how creative thinking emerges and we can recognize them in his scientific work.

Carlos Chagas graduated in Medicine in 1903, concluding his clinical training under the influence of Professor Miguel Couto and with a well-grounded laboratory experience in the Manguinhos Institute, where he studied malaria. He accepted the invitation of Oswaldo Cruz and got a contract to work as a doctor at the Hygiene and Public Health Office/Ministry, because of his expertise in malaria and also because he needed to take a job with a fixed salary to marry the woman he had fallen in love with, Miss Iris Lobo (Fig. 1.4) from a rich family in Rio de Janeiro. With her he had his two sons, Evandro and Carlos (Figs. 1.4 and 1.5).

Figure 1.4 The family founded by Carlos Ribeiro Justiniano Chagas [his wife, Iris Lobo (married in July 1904), and his two sons: Evandro and Carlos] (Archives of the Instituto Oswaldo Cruz).

Figure 1.5 Carlos Ribeiro Justiniano Chagas (in center) with a group of friends after a hunting expedition, on a property at Rio Pardo, Avaré, Sao Paolo (Archives of the Instituto Oswaldo Cruz).

He was then commissioned by Oswaldo Cruz to lead a campaign against malaria in Itatinga, state of São Paulo. In this and other situations, he advocated a strategy of prevention based on the intrahousehold combat of the mosquito and succeeded in his goal of controlling malaria. Thereafter, a series of events characterize a successful scientific career. Carlos Chagas became member of the Brazilian National Academy of Medicine in a place especially created for him, received numerous awards and titles of Doctor Honoris Causa (including Harvard, Paris, Lima, and Belgium Universities), was nominated twice for the Nobel Prize (in 1913 and 1921), directed the Oswaldo Cruz Institute for 17 years, and coordinated the campaign against the epidemic of Spanish influenza in Brazil. Several biographers registered these stories, but we especially like two books written by his son, Carlos Chagas Filho,³ where the human and emotional aspects of the scientist do appear very clearly. Two picturesque aspects have been reported by his son: Chagas loved to hunt (Fig. 1.6) and enjoyed football, supporting the football club Botafogo in Rio de Janeiro.

Figure 1.6 Carlos Ribeiro Justiniano Chagas’ sons: Evandro and Carlos (Archives of the Instituto Oswaldo Cruz).

The political, scientific, and cultural context in which Carlos Chagas was immersed and made his discovery was a very rich one. Politically, it was the end of the era of the Brazilian empire, with the abolition of slavery and the proclamation of the Republic of Brazil. Successive presidential elections and popular rebellions occurred.

The American Trypanosomiasis discovery also was determined by a peculiar health context in Brazil. In the Institute of Manguinhos, Oswaldo Cruz implanted a virtuous triad articulating assistance, research, and education. This public health model remains until now at the current Fiocruz, which continues today as an institution of science, technology, and innovation in health linked to the Ministry of Health. After the campaign against the Spanish flu in 1918, Chagas created the National Department of Public Health, giving rise to the future Ministry of Health, and implicating the presence of the State all over the Nation due to the creation of the Sanitary Code, thus expanding the assistance to other diseases such as tuberculosis, venereal diseases, and workers’ health, creating the School of Nursing and creating a program for prophylaxis in endemic areas with endemic guards. A strong cooperation with the Rockefeller Foundation was initiated. Formal science education started in 1911 with the first Course of Application at the Institute, and in 1925 Carlos Chagas began the first Special Course in Hygiene and Public Health. He became Professor of Tropical Medicine at the Faculty of Medicine in 1928.³

The history of a significant discovery

In 1987 the great science sociologist Bruno Latour⁶ said, The more controversy we articulate, the broader becomes the world. Carlos Chagas and his colleagues precisely articulated controversies and discovered a new world of research and of political action in public health.

The disease had already existed in the Americas for over 9000 years.⁷ Mummies were found in Peru with physical evidence of clinical signs of Chagas disease from which samples of Trypanosoma cruzi DNA were recovered. In Brazil, paleoparasitology studies conducted by Adauto Araujo, Luiz Fernando Ferreira, and his group have confirmed T. cruzi DNA in mummies dating back to 7000 years. These findings changed the assumptions about the emergence of Chagas disease in the Americas, dating it back to the contact of hunters and gatherers with mammalian reservoirs and insect vectors, much earlier than the period when Andean men started home breeding small animals, as it was thought previously. This means that the disease had already been in Latin America for 9000 years and that no one had seen or detected it before Carlos Chagas in 1909. Even Charles Darwin registered the presence of triatomines during his stay in South America in 1835 (Darwin 1899, cited in Neiva & Lent, 1943),⁸ but this was not associated to any specific disease: The night I experienced an attack (for it deserves no less a name) of the Vinchuca (a species of Reduvius) the great black bug of the Pampas. It is most disgusting to feel soft wingless insects, about an inch long, crawling over one’s body. Before sucking, they are quite thin, but afterwards became round and bloated with blood, and in this state they are easily crushed. One which I caught at Iquique was very empty. When placed on a table, and though surrounded by people, if a finger was presented, the bold insect would immediately draw its sucker, make a charge, and if allowed, draw blood. No pain was caused by the wound. It was curious to watch its body during the act of sucking, as it changed in less than 10 minutes, from being as flat as a wafer to a globular form. Darwin’s biographers suspect that he also had contacted Chagas disease in the Beagle voyage.⁹

Was Carlos Chagas different? Why and how could he make the triple discovery: the parasite, the vector, and the disease? All other parasitic diseases took years or decades to get their cycle completely elucidated, from the etiological agent, to the vector(s), the reservoir(s), and the clinical manifestations. How did Carlos Chagas do all that in less than 5 months?

First, Carlos Chagas was educated as a scientist, with a mind trained in the tools that educate the imagination, as we said before, in association with a lot of solid experience in scientific method and reasoning. Second, he had an excellent clinical training as a physician, associated with excellent training in the laboratory, being a skillful examiner of blood smears for the diagnosis of malaria that was the subject of his MD thesis. Third, the scientific environment of the Manguinhos Institute allowed him to follow the development of medical entomology and the development of literature on tropical medicine and microbiology. And finally, at the Institute, he had laboratories to do experimental animal testing under controlled conditions. That is why, while on a mission for malaria control in the region of Itatinga, São Paulo, then in Xerém, Rio de Janeiro, and later in Lassance, Minas Gerais (Figs. 1.7 and 1.8), he articulated the daily work of the prophylaxis of malaria with the work of an investigator.

Figure 1.7 Carlos Chagas with his work team at the railway station in Lassance—Minas Gerais, Brazil (1908) (Archives of the Instituto Oswaldo Cruz).

Figure 1.8 View of the railway station in Lassance—Minas Gerais (1908) (Archives of the Instituto Oswaldo Cruz).

Chagas worked in two ways, first as a health professional and second as a health researcher. He was trained embracing the idea of Patrick Manson’s School of Hygiene and Tropical Medicine in London¹⁰ that a tropical disease is a more convenient than accurate concept because bacteriology is cosmopolitan, with variations in climate and geography, and protozoa and helminths are prominent in tropical climates where many vectors and hosts live. According to him, the concept of tropical medicine in Brazil reconciles the microbiology laboratory with the entomological collection, based on the classification of naturalists. All this gave him a more holistic environmental approach.

With these ideas in mind, when Chagas studied the real health situation in the interior of Brazil, he transformed science and public health into a tool for building a Nation.⁴ He rethought the Nation among its hinterlands and its people. Carlos Chagas took advantage of the period of modernization of Rio de Janeiro, then the capital of the New Republic, to call for the integration of the entire country.

The discovery took place in the context of expanding Brazilian economic frontiers, following the need for installation of railways for transportation of agricultural production, along with the intense collection of biological material that Carlos Chagas promoted during his missions.⁴,¹¹ In Lassance the engineer of the train company showed him an insect. Carlos Chagas had already discovered a Trypanosoma when he examined the blood of monkeys in the region (it was not T. cruzi, but T. minasense¹²). He had sent the infected insects to Manguinhos, asking Oswaldo Cruz to perform experimental infections that confirmed that the parasite could cause disease in monkeys. After a train journey lasting more than 70 hours, Chagas went to the laboratory in the middle of the night. He had realized that the protozoon was not T. minasense but a new species, which he called T. cruzi in honor of the master Oswaldo Cruz.

His work described, with beautiful plates, all the stages of the evolution of T. cruzi in the insect, in cultures, and in organs of infected animals.¹ Chagas had a certainty in his mind: a new parasite, a vector, wild reservoirs, and only the human cases were missing. He then returned to Lassance and began to look careful at every febrile child, always examining blood smears. In his work,¹ he described the finding of a trypanosome in the blood of a cat, defining a domestic reservoir, and in the sequence he found T. cruzi in the blood of Berenice, case number 1 (Fig. 1.9).

Figure 1.9 Berenice, Carlos Chagas’ first patient (Archives of the Instituto Oswaldo Cruz).

In the article published in a medical journal in 1909,¹³ Chagas wrote: "In a febrile patient, deeply anaemic and with oedema, engorged with multiple ganglia, we found trypanosomes, whose morphology is identical to that of Trypanosoma cruzi. In the absence of any other aetiology for the morbid symptoms observed and in accordance with previous experiments in animals, we believe this is a human trypanosomiasis, the disease caused by Trypanosoma cruzi, transmitted by Conorrhinus sanguissuga."

Carlos Chagas examined many other children because he did not find circulating trypanosomes in adults. Berenice, his first patient, was found (Fig. 1.10) and restudied at the age of 78 by Lana et al.¹⁴ and still had circulating trypanosomes, remaining asymptomatic, in the indeterminate chronic form of Chagas disease, just as 75% of patients with Chagas disease. Berenice did not die from T. cruzi infection but from other causes.

Figure 1.10 Berenice, found again at the age of 78 for further clinical studies (Archives of the Instituto Oswaldo Cruz).

This was therefore the natural path traced by Carlos Chagas, in which the scientific fact was the result of a social construction caused by a public health problem. It begins with the identification of a vector, then the causative agent and the epidemiological characteristics, in the search for an associated disease without previous clinical evidence.

The disease was described in the initial period, without definitive evidence of etiological and epidemiological studies. Ten years after the description, only 40 cases had been confirmed by laboratory procedures. Carlos Chagas claimed that the disease was a major public health problem and a major obstacle to the country’s progress, but the final acceptance of the existence of a new disease led to a social and cognitive process which spanned over three decades. In publications such as in 1911,¹⁵ in photos and films, Carlos Chagas showed the whole country that this new trypanosomiasis reached vast areas of Minas Gerais and other Brazilian states, giving rise to a degenerate population seriously jeopardizing the vitality and productivity of rural persons in the country. And he made an error, associating the trypanosomiasis to the goiter, which was endemic in this area of iodine deficiency. That was later revised and corrected by several researchers.

From 1916 to 1920, Carlos Chagas led a large national campaign for rural sanitation, entering then into a phase of both glory and ordeal. In 1917, after the death of Oswaldo Cruz, Carlos Chagas at the age of 39 became director of the Oswaldo Cruz Institute.

Glory from 1909 to 1913, when Brazilian science was recognized internationally for its excellence, when the Oswaldo Cruz Institute was consolidated, when the flag of the Movement of Rural Hygiene was created, public health in Brazil was founded, and a Nation began to be built and prepared to face the health challenges for economic and social development. He was thus twice nominated for the Nobel Prize.

The ordeal began when part of the medical and political community doubted on clinical aspects, on epidemiological data, and on the scale of the disease, claiming that it was a rare disease entity and not a national evil. There was a political dimension concerning a possible negative image of Brazil abroad, questioning the project of tropical medicine.

During this period Carlos Chagas and his assistants worked hard to achieve a double translation of the parasitic thyroiditis,⁴ with multinodule goiter and cretinism, for the chronic heart and nervous disease.¹⁶ The acute and chronic diseases were also determined as two different entities. The silent indeterminate clinical form, the potential cardiac patients, was also described. So it then changed from a Brazilian disease into American Trypanosomiasis. To overcome these ordeals it was essential to develop clinical simplified diagnostic features such as the Romanha’s sign, which describes the swelling around the eyes and face,¹⁷ the reports of cases found by Mazza in Argentina,¹⁸ and the electrocardiogram.¹⁹ In the 1940s, after the identification of cases in Argentina, after several scientific expeditions to the interior of Brazil, after the creation of the Centre for the Study and Prevention of Chagas disease in 1943 in Bambuí, the prevalence and relevance of Chagas disease was finally proved and the strategic method to control transmission using insecticides and house improvement was implemented.²⁰,²¹

Carlos Chagas made many important discoveries such as the theory on the intradomicile transmission of malaria,²² which was fundamental for its prophylaxis, and the description of Pneumocysti carinii, which was confused with a cystic form of T. cruzi.¹,³ But, history will acknowledge him for this unique achievement in biomedical science: his 1909 description of a new etiological agent, the hemoflagellate T. cruzi, its life cycle, vectors, domestic and sylvatic reservoirs, and corresponding human disease.¹ This brilliant scientist was more than a member of the microbe hunter generation, but decades were required for international recognition of the dramatic epidemiological picture of Chagas disease. He died at the age of 56, after 32 years of a hard and fruitful scientific career and 17 years of active direction of the Oswaldo Cruz Institute.

Salvador Mazza: marked the history of the knowledge of his disease

In 1915 and 1916, Maggio and Rosenbusch with Kraus noticed the absence of a link between infected bloodsucking insects and the goiter and cretinism, which constituted the basis of a set of doubts relating to the pathogenic conceptions proposed by Carlos Chagas.

This decade saw the beginning of the work by Salvador Mazza (1886–1946) on Chagas disease, which profoundly marked the history of knowledge of the disease.

Mazza, born in Rauch, Buenos Aires, Argentina, graduated from the School of Medicine in 1910 and was a specialist in chemical and bacteriological pathology. During his career, he was a member of the National Department of Hygiene, Minister of Health, then, appointed professor of Bacteriology at UBA, and Director of the Central Laboratory of the Clinics Hospital in Buenos Aires. Thus, in 1926, he founded the Jujuy Scientific Society. Between 1926 and 1927, subsidiaries of the society were created in Salta, Tucumán, Catamarca, Santiago del Estero, La Rioja, and in Corrientes. The year 1928 saw the creation, with the support of Dr José Arce, of an official extension of the universities dependent on the Institute of Clinical Surgery of the Faculty of Medicine of the University of Buenos Aires, called MEPRA (Mission de Estudios de Patologia Régional Argentina). During this time, Mazza had met Carlos Chagas in Germany, and had been impressed by the clarity and strength of his arguments concerning the disease. Consequently, he initiated many studies which confirmed the existence and the importance of this pathology. In 1926, Mazza found a dog infected with T. cruzi and in 1927, he diagnosed clinically the first acute case in Argentina.¹⁸

During the 1930s, at the head of MEPRA, Mazza guided studies of this affection confirming its multiple aspects, the insect vectors, the mammal hosts, the epidemiology, and the pathogenesis. This work, carried out with tenacity, enabled the diagnosis of several hundred cases, both clinical and parasitological. Furthermore, the verification of Chagas disease in the zones where the goiter is endemic, enabled him to overcome the obstacles that Carlos Chagas had confronted. Following this work, Trypanosomiasis Americana was the main theme of the Sixth National Congress of Medicine in 1939. In 1940, Mazza and Jörg defined the three anatomo-clinical periods of the disease which remain valid to this day. In 1946 Mazza died from a heart attack. MEPRA, which had become a multidisciplinary team carrying out treatment, teaching, and research, was temporarily directed by Jörg. However, he was unable to overcome the institutional and political vicissitudes which finally led to its closure in 1958.

Cecilio Romanha: his contribution to the identification of the disease

Research carried out at MEPRA during the 17 years that Mazza worked for the mission, enabled him to observe men and animals in the zone infected by T. cruzi, also the infestation of the bloodsucking bugs in the homes, and, among the descriptions of the clinical manifestations of the disease, a crucial point in its identification, the observation of an ocular edema (known as the Romanha’s sign, in honor of the doctor—a disciple of Mazza—who suggested it) was crucial in the diagnoses of infected patients.

The Romanha’s sign¹⁷ is a pathognomonic early sign of Chagas disease: unilateral severe conjunctivitis and swelling of the eyelid for more than 30 days, inflammation of the tear gland, and swelling of regional lymph glands, caused by the entry of T. cruzi. The sign has proved of great value in the identification of the infection in its acute phase. It constituted a fundamental element to establish a rapid diagnosis and a clinical characterization of the disease and it enabled the confirmation of many cases, finally putting an end to doubts concerning its spread.

In 1946, the year of the transfer of MEPRA to Buenos Aires, Mazza and his collaborators had registered 1400 cases of Chagas disease of which the parasite in the blood could be proved for 1100.²³ During the same period, the Regional Medicine Institute had been founded at the National University of Tucuman, directed by Cecilio Romanha. The institute dealt with the more precise characterization of the clinical symptoms of the disease, as well as trials on the efficiency of hexachlorocyclohexane, an insecticide capable of killing the bloodsucking bug.

During the first Panamerican meeting of Chagas disease, organized by Romanha in Tucuman in 1949, a decision was taken to create, in 1950, a management committee for research and Prophylaxis on Chagas disease at the Ministry of Health and the coordination was entrusted to Cecilio Romanha. This was an important step because it constituted the first institutional organization concerning Chagas disease, outside the university research institutes already mentioned.²⁴

First evidence of Trypanosomiasis Americana (Chagas disease) in various countries of Latin America

Thus, slowly the discovery of Chagas disease spread across various countries of Latin America.

In Central America, the first report of human Trypanosomiasis Americana was made by Segovia in El Salvador in 1913.²⁵ Subsequently other Salvadorian researchers reported on new cases: Reina Guerra (1939),²⁶ Castro, Fasquelle, Garcia Montenegro. In 1956, renowned researchers²⁷ described in detail the epidemiological and clinical symptoms of this disease.

In Costa Rica, the disease was originally described in 1922 by Picado (doctoral thesis) and later studied by Von Bullon, Cespedes, Chen, and Zeledon. In Guatemala,²⁸ the disease was first encountered by Reichnow in 1933. Subsequently, the work of De Leon in 1935 highlighted the importance of this disease in this country.²⁹ However, it is important to emphasize the considerable contributions to the understanding of this disease realized by Montenegro, Esteres, Blanco, and Peñalver.

In Panama in 1931, the presence of the disease was proven with the report of 19 human cases in the area of the Panama Canal. Later on, other research was carried out by Calero, Johnson, and Rivas.

In Honduras, the disease was not officially reported until the first case came to light in 1960, on which the doctors A. Leon Gomez, A. Flores Fiallo, E. Poujeol, and M. Barilla reported in the Seventh Day of Honduran Medicine which took place in San Pedro Sula.²⁹ In 1961, the same authors communicated seven cases of Chagas’ chronic myocarditis³⁰ and in 1965, Duron, in a postmortem study, encountered numerous pseudocysts of Leishmania in the myocardium of a girl suffering from acute Chagasic myocarditis who died suddenly. Nevertheless, already in 1950, Zepada had observed the existence of a vector in various zones of the country and in 1939 an opossum infected with T. cruzi was discovered.³¹ In 1968, Fernandez and Lainez reported for the first time the first two cases of the acute form of the disease, with the discovery of T. cruzi in peripheral blood, whose clinical characteristics presented a unilateral conjunctive reaction, temperature above 39°C, palpebral edema, hemifacial edema, and cervical adenitis.

It was in 1949 that the first native case of the disease was described in Nicaragua and as recently as 1969 that Fray Bernadini de Schagen reported on the infestation of homes by vectors described as bloodsucking insects like cockroaches with wings and very poisonous (the Chagas Space Group).

In Mexico, Hoffman published in 1928 a document describing the great abundance and domiciliation of Triatoma dimidiata in Choapas, Veracruz and in 1938, the same author spoke of a case native of the same region that was described by Luis Mazzotti, who, in 1936 identified the first two officially recognized cases originating from Oaxaca as being abundantly infected with triatomine bugs.³² In 1938, Bernal Flandes published on transmitter insects and trypanosomatides in Veracruz, and in 1940 Palomo Eroso described two other new cases in Yutacan. But, it was only in 1972 that the first formal identification of the disease was carried out with reports by Eugenio Palomo and Luis Mazzotti.³³

In South America, the first case of Chagas disease reported in Venezuela was by Enrique Tejera, in the state of Zulia,³⁴ 10 years after Carlos Chagas discovery. Pioneer studies were carried out in Venezuela, directed by José Francisco Torrealba, who, from 1932, initiated studies in the state of Guàrico³⁵ and introduced the xenodiagnosis, invented by Emile Brumpt, while in 1941 Pifano³⁶ studied the epidemiology of the disease in the state of Yaracuy. Both authors highlighted its importance as a public health problem and a social one with the maintenance of this zooanthroponosis. In the Institute of Tropical Medicine of the Central University of Venezuela, Maekelt in 1960 had developed a protocol for the preparation of antigen which is still used in the country and Pifano in 1960 published the first figures of national prevalence. As recently as in 1961, the Ministry of Health and Social Welfare allocated budgets, effort, and expertise to fight Chagas Disease, and initiated the Campaign which in 1966 was officially proclaimed as the program to control Chagas disease.³⁷

In Colombia,³⁸ Ignacio Moreno Perez observed in Cali in 1939 for the first time, the pathogenic parasite provoking the disease, according to a report by Hernando Ucros in 1971. In 1947, J. Caicedo and C. Hernandez wrote a report describing the first proven chronic case of the disease in Colombia originating from Fusagasuga in Cundinamarca and in 1961, Marcos Duque began studies on Chagas’ cardiopathy. Ten years later, Hernando Rocha communicated his discoveries on the mega-esophagus which is a consequence of the disease.³⁸

The first research on the epidemiology of Chagas disease in Chile³⁹ is attributed to Prof. Juan Noe, who, in 1921, observed for the first time, the presence of T. cruzi in the evidence of many samples of Triatoma infestans, coming from the outskirts of the town of Santiago. Later, in 1931, Dr Miguel Massa, under the authority and direction of Prof. Noe, demonstrated the specificity of the parasite in cardiac fibers in animals used for experimentation. With the creation of the Department of Parasitology of the State Health Office in 1937, began the systematic investigations leading to the demonstration of the first human cases of this disease.³⁹

In Peru, in 1919, E. Escomel described the first human case demonstrating the presence of Trypanosoma in human blood, in a border zone between Brazil and Bolivia where species of the flora and fauna are very abundant. Escomel said that predecessors had described T. infestans in the Vitor and Majes valleys which was suspected of being the cause of certain patients’ clinical symptoms which were, in fact, those of trypanosomiasis; however, the confirmation of the parasite had not been able to be made.⁴⁰ Roughly 25 years after Escomel’s cited publication, the second human case of Chagas disease was verified in Peru, and at the same time the first epidemiological research was realized.

In Paraguay, in 1924 the first discoveries were made with studies by Lutz, Sousa, Araujo, de Fonseca, and Migone, which showed the first infected bloodsucking insects (the Chagas Space Group). In this way, Gamiro in Uruguay, carried out studies on the infection of these insects in his country.

In Bolivia, in the 16th century, when Bolivia was part of the Spanish Viceroyalty of Peru, a priest, Fray Reginaldo de Lizarraga traveling to inspect the convents of this region, noticed that in the valleys of Cochabamba bloodsucking insects like cockroaches, called vinchucas by natives, fell, during the night, from the ceiling of houses of the poor and bit the people while sleeping, particularly in the face and other exposed parts of the body. This was a description of the Triatominae, as was discovered later.⁴¹

In 1916, in Sococha, a small town of the Department of Potosi and near the border with Argentina, the Brazilian Artur Neiva, from the group of the Manguinhos Institute of Rio de Janeiro later named as the Oswaldo Cruz Institute, found these Triatominae, similar to the ones called barbeiros in Brazil, infected with the parasite T. cruzi.⁴² Later, in 1929, the Bolivian Felix Veintimillas, claimed that he found Triatominae with T. cruzi in the area of Yungas of La Paz as he reported in 1930.⁴³

The Argentinean Salvador Mazza who studied Chagas disease in the northern region of Argentina, did expeditions to several regions of Bolivia from 1937 to 1943 and found infected triatomine bugs, of the species T. infestans, in 22% of the cases studied in Vitichi, Potosi, 50% in the small village of Mollegrande, Potosi, and found a very thin 2-year-old girl, who died a few days later, with T. cruzi in smears of her blood.⁴⁴,⁴⁵

Rafael Torrico (Fig. 1.11) returned to Bolivia in 1943, after postgraduate studies at the Oswaldo Cruz Institute of Brazil, became Professor of Parasitology at the Medical School in Cochabamba and director of the Central Laboratory of Interamerican Cooperative Public Health Service of the Ministry of Health, where he did several studies on Chagas disease. With M. Dias he published work, in 1943, relating to infected triatomine bugs of the species T. infestans in several towns of the Department of Cochabamba.⁴²

Figure 1.11 Rafael Torrico, 1943, the father of Chagas disease in Bolivia.

In 1946 he described a 14-year-old girl from Capinota (Fig. 1.12), a rural area of the Department of Cochabamba, as the first case in Bolivia of an acute form of Chagas disease with edema on the eyelid, the site of the bite by a triatomine bugs, identified as T. infestans, and a preauricular lymphadenopathy as described by Romanha in Argentina.⁴⁶,⁴⁷

Figure 1.12 First case of Chagas disease in Bolivia, reported in a girl aged 14 in Capinota, Department of Cochabamba, Bolivia.

In this area, where the patient lived, Torrico found in 427 insects, of the species T. infestans, 84.9% infected with T. cruzi. However, a Bolivian student in Chile, C.L. Ponce Caballero,⁴⁸ published in 1946 a study of seven cases of Chagas disease from the town of Colcapirhua, Cochabamba, confirmed, as he claimed by xenodiagnosis, that did not have any clinical manifestations of the disease according to one of the participants of this study.⁴⁸ Romanha, in 1947, with students of the University of Chile, including Ponce Caballero, reported 122 cases, confirmed by xenodiagnosis, in several areas of Bolivia.⁴⁹

At the first Panamerican Meeting of Chagas disease, held in Argentina in 1949, Torrico presented a paper about the knowledge of Chagas disease in Bolivia up to that year. He stated that T. infestans was the principal and the most important vector because of its high infection index, its prevalence, and wide distribution, predominantly in the valleys, where it was an obliged host in most houses. He stated also that guinea pigs (Cavia cobaya), dogs, and cats were the only parasite reservoirs known of T. cruzi in Bolivia, particularly the guinea pigs that are seen in houses inhabited by peasants where they live together. Regarding human morbidity, he presented 211 cases collected, most of which were acute ones, either studied by him or published by others, diagnosed by blood examination and mostly by xenodiagnosis, from many areas of the country.⁵⁰

Finally, Torrico presented an up-to-date study of the situation of Chagas disease in Bolivia, at the International Congress of Chagas disease in 1959, held in Rio de Janeiro, confirming his observations of the vectors, the reservoirs, and human cases, acute or chronic, which had increased to 342 patients, including cases of Chagasic myocardiopathy, with its classic electrocardiography, studied by J. Rodriguez Rivas.⁵¹,⁵²

Chagas disease 100 years after the discovery

What is Chagas disease now, 100 years after its discovery? It remains a neglected and silent disease of poverty.⁵³ Millions of people are infected in Latin America and thousands of others in Europe, Asia, and North America.

The centenary of the discovery of Chagas disease⁵⁴ led us to reflect on the evolution of ideas and concepts about it.⁵⁵–⁵⁷ The first phase from 1909 to 1934, mainly through the work of Chagas and the team of scientists from Manguinhos, which ended immersed in controversies; the second phase, from 1935 to 1960, after the death of Chagas, when Mazza and Romanha confirmed acute Chagas disease in Argentina and when Evandro Chagas (Chagas’ elder son) and his student Emmanuel Dias deepened studies and confirmed the concept of endemic chronic disease; and finally a third phase, in which political awareness about Chagas disease, associated to the need for control and to the implementation of national and international policies of vector control and corresponding challenges, paved the way for more work to be done in the 21st century.

The control program brought many advances, because there were about 200,000 new cases per year in 2000 while in 1983 this picture was 700,000 per year.⁵⁸ Today there are less than 100,000 per year. These numbers are possibly underestimated due to lack of attention to Chagas disease in health information systems that mainly report injuries.

In recent years, the effectiveness of the two main drugs—benznidazole and nifurtmox—for the treatment of Chagas disease in the chronic phase, has produced a regain in interest due to (1) the new observational data, showing that nontreated chronic cases had worse clinical outcomes, higher serological levels, and a higher number of parasites recovered by hemoculture and detected by PCR⁵⁹; (2) the large studies conducted by Médicins sans Frontières showing much less incidence of side effects and higher evidence of effectiveness⁶⁰; and (3) the reviews indicating the emergence of a paradigm shift in the treatment of chronic Chagas disease.⁶¹ In 2015, a benefit trial (Benznidazole Evaluation for Interrupting Trypanosomiasis), a double-blind, placebo-controlled trial on cardiac patients, was conducted. This study (1) confirmed that the etiological treatment led to negative T. cruzi DNA blood detection and (2) confirmed the tolerability of the drug, but did not show an increase in the benefit of treatment in cardiac complications, probably due to the advanced heart disease stages of the cases included in the studied cohort.⁶² This will probably be the bottom line of many other studies needed to answer dozens of open questions raised in the first decade of precise clinical trials involving chronic Chagas disease patients. A new profile of oral transmission predominates in the scenario and, therefore, this disease still needs a lot of attention. With the Worldmapper tool⁶³ it is possible to display the country areas proportions comparing the relative burden of various diseases and the existing epidemiological data. The reality of cases of Chagas disease in the Americas can be seen at the site www.worldmapper.org/display_extra.php?selected=392.

A very important and new issue in the scenario of Chagas disease is the organization of many associations of patients and affected people, claiming to fight against negligence and for their rights to have access to diagnosis and treatment. In 2009, during the meeting celebrating 100 years of Chagas disease discovery in Uberaba, Brazil, a work group formed by almost a dozen associations worldwide decided to create the International Federation of Patients Associations, named FINDECHAGAS (http://www.findechagas.com), and supported by associations from every city where affected people found a way to meet and talk about their problems and the consequences of the different dimensions of Chagas disease as a neglected illness.⁶⁴,⁶⁵ These new protagonists on the Chagas disease scene will certainly influence research choices, priorities, and outcomes.

All Latin America has to honor the Carlos Chagas legacy and face such challenges. His old institution and many others on the continent are actively engaged in research on several topics concerning Chagas disease.

In 2009 the clinical trials website (www.clinicaltrials.gov) showed very few studies are devoted to infectious diseases clinical trials: 390 on malaria, 336 on tuberculosis, but only 10 on Chagas disease: 5 on diagnosis and 5 on treatment. This expresses the real definition of a neglected disease. Neglected by the pharmaceutical industry, which does not invest in research and technological development of drugs for the treatment of Chagas disease because it does not provide a rich market for buying future products. In 2016 those numbers changed respectively to 976 for malaria, 887 for tuberculosis, but only 98 for Chagas disease, thus confirming negligence.

Chagas disease is still the most neglected among the kinetoplastid infectious diseases (Leishmaniasis and African trypanosomiasis). From the total amount of resources invested in 2007 (over US$125 million) only 8% were for Chagas disease. This leads, of course, to a lack of research on interventions and therapeutic innovations in Chagas disease and emphasizes the need for public policies to help the affected countries to face their problems.

Chagas disease has poverty as its major social determinant and has the vector and the susceptibility of human host as its major biological determinants. The affected countries need policies not only for studies and development of drugs and vaccines, but also for the reduction of poverty and social disparities which expose the poor to risks of contamination. So here we highlight the words of Peter Hotez⁶⁶: We have the technology available to develop new drugs, vaccines and diagnostics to combat poverty. However, what is needed is more innovation to enable financial institutions to be able to lead the intensification of the process of developing manufacturing and clinical testing, in order to ensure global access to these new products. It is worth remembering the legacy of Carlos Chagas: his son Evandro Chagas⁶⁷ wrote in 1935 that for Chagas, science was valid only if it was directed toward the welfare of humanity.

Carlos Chagas began in 1909: the joy of broad social commitment. And the words of Chagas fill us with hope and renew our commitment to the struggle for control of the disease and care for people: It won’t take long for us to pass on a beautiful and strong science which creates art in the support of life.

Acknowledgments

We wish to extend our thanks to Paulo Ernani Vieira, the president of Fiocruz, for all his help in the writing of this chapter and acknowledge him as a coauthor. Equally to Tania Araujo-Jorge, Director of the Oswaldo Cruz Institute, Oswaldo Cruz Foundation—Fiocruz, Brazil and also attached to the Conselho Nacional de Pesquisas (CNPq) for productivity in science. Our thanks also to the following people: Joseli Lannes-Vieira, Maria de Nazaré Soeiro, Nara Azevedo, Simone Kropf, Lisabel Klein, Luiz Fernando Ferreira, Joao Carlos P. Dias, José R. Coura, and Rodrigo Correa-Oliveira.

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2

Chagas disease in pre-Colombian civilizations*

F. Guhl,    Universidad de los Andes, Centro de Investigaciones en Microbiología y Parasitología Tropical, Bogotá, Colombia

Abstract

Human Chagas disease is a purely coincidental occurrence. As humans came into contact with the natural foci of infection, they might have become infected as a single addition to the already extensive host range of Trypanosoma cruzi, which includes other primates and a diversity of sylvatic mammals. Thus began a process of adaptation and domiciliation to human habitations, through which the vectors had direct access to abundant food as well as protection from climatic changes and predators. In addition to insect transmission, Chagas disease could be acquired by ingestion of contaminated food. Historical evidence suggests that many pre-Hispanic cultures were in close contact with triatomine insect vectors in their dwellings before the arrival of European conquerors to the New World, and several reports also provide evidence of the antiquity of human T. cruzi infection in South America, Central America, and Mexico.

Keywords

Chagas disease; fossil DNA; pre-Colombian civilizations; human migrations; mummies

Chapter Outline

Introduction 23

Genetic variation 24

Archeology 25

Biochemistry (Bioarcheology) 25

The parasite transmission cycle 27

Insect vectors associated with the human habitats 29

Historical overview 32

Pre-Hispanic settlements in areas of transmission of T. cruzi 34

Argentine-Bolivian Altiplano, Northwest Argentina 36

Sierras Centrales 36

Sur del Perú 36

Meso-America, Mayan culture 37

Andean region, Northern South America 39

Oral infection by T. cruzi 39

Evidence of human T. cruzi infection in pre-Colombian civilizations 40

References 44

Introduction

Chagas disease caused by the parasite Trypanosoma cruzi is a complex zoonosis that is widely distributed throughout the American continent. More than 150 species of triatomine bugs and more than 100 species of mammals, mostly wild species, maintain T. cruzi infection in nature. The infection can be acquired by infected triatomine feces, blood transfusion, oral and vertical transmission. Chagas disease represents an important public health problem, with estimates by the World Health Organization in 2015 of at least 6 million people having T. cruzi infection in 21 Latin American countries and 25% of Latin America’s population being at risk due to the geographical distribution of insect vectors. Also, immigration of infected people from endemic countries is now making Chagas disease a relevant health issue in other regions, including Europe and the United States.¹

Chagas disease comprises two stages where the acute phase occurs about 1 week after initial infection, and about 30–40% of the infected patients develop the chronic phase of the disease when the cardiomyopathy is the most frequent and severe clinical manifestation.

Reconstruction of the behavior of a modern disease during antiquity is a formidable challenge. However, success in such an endeavor would allow for the creation of a new database, and this new information could then spawn new hypotheses. Their results could then be blended with our present knowledge to produce an unbroken history of infectious diseases from deep antiquity to the present. Paleoecological integration of such data could help explain chronological changes, whose causes could be exploited for novel modern therapeutic or preventive control of the condition.

However, there are currently only three methodological tools that can be used in such searches: genetic variation, archeology, and biochemistry.

Genetic variation

A nomenclature for T. cruzi has been adopted since 2009 and includes six discrete taxonomic units (DTUs), namely, T. cruzi I (TcI), T. cruzi II (TcII), T. cruzi III (TcIII), T. cruzi IV (TcIV), T. cruzi V (TcV), and T. cruzi VI (TcVI), based on different molecular markers and biological features.² Recently, T. cruzi bat has been described as an independent DTU, based on phylogenetic and phylogeographical analyses, multiple molecular markers, and degrees of sequence divergence between T. cruzi bat and the six already reported DTUs.³

Many eukaryotic pathogenic microorganisms that were previously assumed to propagate clonally have retained cryptic sexual cycles. The T. cruzi parasite comprises a heterogeneous population that displays clonal propagation due to the different cycles of transmission, and also the possibility of recombination exchange that can be found in nature. Several reports indicate that natural hybridization in T. cruzi may be frequent, potentially involving independent exchange of kinetoplast and nuclear genetic material as well as canonical meiotic mechanisms.⁴

Different molecular markers including a 48 set of microsatellite loci have shown the great diversity in TcI.⁵–⁷ Primers designed based on the sequences of TcI confirmed the existence of three genotypes (Ia, Ib, and Id) and a new genotype found in the Southern Cone countries named as TcIe.⁸ Genetic variability has also been clearly demonstrated, reporting homogeneous (TcII) and heterogeneous groups considered hybrids due to recombination events (TcIII–TcVI).⁹,¹⁰ Hybrids are considered within T. cruzi showing TcIII and TcIV probably as a product of recombination of TcI and TcII and TcIV–TcVI as a product of recombination of T. cruzi II and T. cruzi III/T. cruzi IV,¹¹ although this last statement is still controversial.

The molecular epidemiology and distribution of T. cruzi genotypes may have important implications on the disease features. However, a few correlations have been relating T. cruzi genetic variability and the disease outcome, showing T. cruzi I more related to patients with cardiomyopathy in Colombia and Venezuela and T. cruzi II–T. cruzi VI more related to patients with digestive syndrome.¹²

For triatomines, susceptibility or resistance to trypanosome infections seems to be modulated by the intestinal symbionts, which are vital for development. T. cruzi is considered to be subpathogenic to triatomines, whereas Trypanosoma rangeli is another species that commonly infects Rhodnius species and causes pathogenicity based on a reduction of the number of symbionts Some studies using different species of triatomines, such as R. pallescens, T. dimidiata, R. colombiensis, and P. geniculatus, have shown the affinity of TcI to infect these species in comparison with TcII transmitted by Triatoma infestans in the southern countries of South America.¹³

Archeology

The modern domestic cycle is the common environment in which humans are exposed to reduviid bugs, usually T. infestans and Rhodnius prolixus. These insects hide in the cracks and defects of a house’s roof and wall during the day, emerging at night to obtain a blood meal from their prey. That prey includes not only humans, but also domestic animals. Thatched roofs are especially attractive for these insects.¹⁴ Even today, many families supplement their meals by raising guinea pigs and