Commentary: Chagas disease: 100 years since ... - Oxford Journals

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Jun 3, 2008 - health, for which epidemiological thinking was one of the essential elements. .... the institution he and the Brazilian Government founded in 1900 to fight ..... Hippocrates, epidemiology was only acknowledged as an academic ...

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His achievement was a clear demonstration that scientific and technological development is possible outside the central hub of countries with strong science, by local researchers acting on an independently. However, like John Snow when he described the mode of transmission of cholera, Chagas’ work faced resistance for several decades, which supposedly hindered him from being awarded the Nobel Prize, for which he was nominated twice.4 The impact of his work gained even greater importance as American trypanosomiasis was proven to be disseminated throughout this continent, spreading from the south of the United States to the north of Argentina. Therefore, it is not by chance that the importance of his research is still used among Latin Americans as a great example of integration between scientific investigation and social policies in the field of public health, for which epidemiological thinking was one of the essential elements. His importance in this context can be compared to that of remarkable scientists such as Virchow and Snow in the European scenario. His memory remains alive and well-respected among Latin Americans. More than that, his scientific practice and thinking are still present. For instance, following his path and with the use of modern scientific methods, it has recently been possible, by examining the materials stored from his first case (the girl Berenice), to document that she was a carrier of two different strains of T. cruzi, the etiological agent of the disease, a fact that is important to understand its complex pathogenesis.5

After this remarkable achievement, Chagas became an example of a dedicated scientist concerned with building science and health policies at these pioneer times. With great dedication he held important position as the director of Instituto Manguinhos (today Fundac¸a˜o Oswaldo Cruz) and as the director of the National Department Of Public Health (today equivalent to the Ministry of Health) and as a professor of Tropical Diseases in the Medical School of Rio de Janeiro, thus fulfilling the example of a scientist who combined scientific investigation with action and the pursuit for solutions.

References 1

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Scliar M, Oswaldo Cruz, Carlos Chagas. O nascimento da cieˆncia no Brasil. Sa˜o Paulo. Odysseus Editora, 2002. Lewinsohn R. Carlos Chagas and the discovery of Chagas´ disease (American trypanosomiasis). J R Soc Med 1981;74:451–55. Punukollu G, Gowda RM, Kahn IA. Early twentieth century descriptions of the Chagas heart disease. Int J Cardiol 2004;95:347–49. Lewinsohn R. Prophet in his own country: Carlos Chagas and the Nobel Prize. Perspect Biol Res 2003;46:532–49. Lana M, Chiari CA, Ciari E et al. Characterization of two isolates of Trypanosoma cruzi obtained from the patient Berenice, the first human case of Chagas’ disease described by Carlos Chagas in 1909. Parasitol Res 1996;82:257–60.

Published by Oxford University Press on behalf of the International Epidemiological Association ß The Author 2008; all rights reserved.

International Journal of Epidemiology 2008;37:698–701 doi:10.1093/ije/dyn134

Commentary: Chagas disease: 100 years since discovery and lessons for the future ´ia Diotaiuti2 and Uriel Kitron3 Ricardo E Gu ¨ rtler,1* Lile

Accepted

3 June 2008

1

Department of Ecology, Genetics and Evolution, Universidad de Buenos Aires, Buenos Aires, Argentina.

2

Centro de Pesquisas Rene´ Rachou, FIOCRUZ, Belo Horizonte, Brazil.

3

Department of Environmental Studies, Emory University, Atlanta, USA.

* Corresponding author. Department of Ecology, Genetics and Evolution, Universidad de Buenos Aires, Buenos Aires, Argentina. E-mail: [email protected]

On April 14, 1909, the 29-year-old Brazilian physician Carlos Ribeiro Justiniano das Chagas (1879–1934) examined Berenice, a 2-year-old girl with signs of an acute infection including persistent fever and swollen face. Based on research conducted over the previous months, Berenice came to be the first human case of a new disease entity and a new parasite.1 In 1900, the Earth’s human population was 1.7 billion, and most people lived in rural areas.2,3 Much of the world population lived in poverty and this continued to

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be the case through the 20th century. Infectious diseases were rampant, and mean life expectancy was about 30 years. The vector-borne mode of transmission of malaria, yellow fever and sleeping sickness had recently been demonstrated by Ronald Ross, Carlos Finlay, Walter Reed, David Bruce and others. In Brazil, with 10 million inhabitants, yellow fever, malaria, plague and smallpox curtailed economic and social progress. Expansion of the railroad system gave birth to new villages whose populations died from a plethora of diseases that defied diagnosis and treatment with the very limited tools available. Houses rapidly became infested by large blood-sucking bugs called ‘barbeiros’, currently known as Panstrongylus megistus. After leading a successful antimalarial campaign in Santos, Carlos Chagas was sent by his mentor Oswaldo Cruz to duplicate these actions in Lassance, Minas Gerais.4 The exceptional sequence of research steps leading to the discovery of a new disease entity (from identifying the blood-sucking vectors to linking the trypanosomes detected in them and in mammals with the first human case) mainly appears to be a one-man epic based on curiosity, scientific rigor and perseverance while attending the health of the poor. But it is fair to say that this breakthrough was indissolubly linked to Oswaldo Cruz’s mentoring and the institution he and the Brazilian Government founded in 1900 to fight endemic diseases.5 Success rarely comes alone, and Carlos Chagas had to face strong opposition and envy from fellow colleagues.4 This resulted in interest and research on the new disease practically coming to a halt for almost 20 years until Salvador Mazza and others detected some 1400 cases of Chagas disease in the Argentine Chaco between 1926 and 1934, in a region where others had failed to identify a case in previous decades.4–6 A wider use of serodiagnostic methods during the 1940s revealed that human Trypanosoma cruzi (Chagas) infection was widespread in the Americas and had unsuspected magnitude and extent. Field trials demonstrating that the recently developed organochlorine insecticides eliminated domestic populations of triatomine bugs7,8 opened new inroads to vector-borne disease control. In 2002, 100 years after its discovery, the burden of Chagas disease in Latin America amounted to as much as 2.7 times the joint burden of malaria, schistosomiasis, leishmaniasis and leprosy, and accounted for 670 000 disability-adjusted life years through its impact on worker productivity, premature disability and death.9 By the turn of the 21st century, the world’s population has increased to 6 billion and nearly half of it lives in cities.2,3 Mean life expectancy reached 76 years in rich countries and 63 years in the poor countries. Despite a 4-fold increase in the average annual gross domestic product per person during the 20th century, economic inequality has increased and there were 2 billion people living in poverty.3 Chagas disease, a poverty-related and poverty-promoting disease, still remains an important and neglected tropical disease.

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With frequently quoted figures ranging from 8 to 15 million of people infected with T. cruzi, the actual magnitude of the disease is rather uncertain and geographically heterogeneous. The epidemiological profile of Chagas disease has been changing as a result of control efforts in a rapidly changing environmental and political scenario. Starting in the late 1950s, progress in Chagas disease prevention gained momentum during the 1980s and 1990s through large-scale vector control and screening of blood donors. A regional intergovernmental control programme was launched in 1991 with the original objectives of eliminating all domestic and peridomestic populations of the main vector Triatoma infestans and transmission of T. cruzi via blood transfusion in the Southern Cone countries by the year 2000.10,11 Other regional control initiatives were launched during the 1990s with similar objectives. Disease control programmes reduced the geographic range and infestation prevalence of major triatomine vectors and increased screening of blood donors, which led to the interruption of transmission in Uruguay, Chile and Brazil and significant improvements in eastern Paraguay, parts of Central America and elsewhere.10,11 These positive trends prompted some people to advance (in 1996) the premature notion that Chagas disease was ‘a disease whose days are numbered’.12 The 2005 target for interruption of transmission of Chagas disease set by the World Health Assembly in 1998 and others13 was not met, and neither is the 2010 target for elimination endorsed very recently likely to be met.14 Forecasts of disease elimination have frequently been contradicted by subsequent resurgence (e.g. malaria) or persistence (e.g. yellow fever). Active vector-borne transmission still persists in vast areas of Argentina, El Salvador and Colombia, among others, and several countries (Mexico, Peru, Colombia, Panama and Costa Rica) have no national programmes for the control of Chagas disease vectors, or have yet to implement them effectively.15 In the Gran Chaco (a 1.3 million km2 ecoregion extending over Argentina, Bolivia and Paraguay), recrudescence of transmission occurred in previously ‘controlled’ areas as soon as the intensity of residual insecticide spraying declined.16 The recent emergence of pyrethroid resistance in T. infestans causing control failures in northwestern Argentina and Bolivia further complicates the scenario. High-risk settings such as those in Bolivia and southern Peru depended on foreign loans to sustain the insecticide campaigns conducted in recent years. Some transfusion-related T. cruzi infections may have occurred in 12 of 17 Latin American countries between 2001 and 2002.17 Sustained emigration from Latin America to the developed world over the 1990s caused more frequent vertical, transplant- and transfusionrelated cases in the target destinations. There are still millions of chronically infected people who will be in need of medical treatment for decades to come.5,10,15 Fortunately, the evidence has served to raise awareness

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that ‘it is premature to believe that Chagas disease is conquered’.15 Current challenges to prevent and control Chagas disease are manifold but they are tractable.18 Challenges include recolonization of houses with triatomine bugs after insecticide application; reduced effectiveness of pyrethroid insecticides in peridomestic sites; the emergence of pyrethroid resistance in northern Argentina and Bolivia; the occurrence of many non-strictly domiciliated vector species (such as Rhodnius prolixus, Triatoma dimidiata, P. megistus and Triatoma brasiliensis), each with distinct invasion, colonization and transmission capacities, less susceptible to traditional control tactics than T. infestans; rising numbers of epidemic outbreaks through ingestion of contaminated food in the Amazon basin, and lack of consensus on the use of the currently available drugs (benznidazole and nifurtimox) for treating chronic infections in adult people. Although the available control tools (insecticides, diagnostics and drugs) are far from perfect, these are also grossly underused (drugs) or applied in suboptimal ways (insecticides) within the frame of less effective or misguided strategies. Some high-priority recommendations include: (i) active case detection and specific treatment of seropositive children 415 years of age should be more widely pursued to take advantage of the currently accepted window of opportunity for effective chemotherapy; (ii) though still controversial, aetiologic treatment of adults with chronic infections apparently cures a fraction of patients and moderates disease progression.19 Better management of infected adults with heart disease is possible.20 However, the supply of and access to benznidazole and nifurtimox in multiple endemic settings remain problematic, and so does the number of local physicians trained to conduct supervised treatment of children seropositive for T. cruzi. Lack of integration between vector and disease control programmes is a major cause of lost opportunities for minimizing the burden of disease and ensuring longterm sustainability of control programmes.16 Major obstacles to renewed, improved Chagas disease control and eventual elimination may also be found at the political level.5,10 Recurrent instability at political, social and economic levels pose major threats to disease control and elimination programmes in the regions most affected by Chagas disease. Roots of the neglect may also be traced to the fact that this mostly asymptomatic, inapparent disease affects vulnerable population groups with weak political representation and to the loss of visibility and political priority raised by the immediate success of vector control actions reducing disease incidence rates. All of these factors have conspired against sustained control or elimination efforts. Furthermore, the growing decentralization of health services to provincial and municipal levels (since the early 1980s in Argentina, since 2000 in Brazil) added the unmet challenge of coordinating efforts among districts differing in infestation, control status, resources and priorities, and between national,

provincial and municipal public health levels.21 Public health officials in charge of the decentralization process frequently failed to integrate experienced vector control staff who championed the era of vertically structured programmes. These programmes lost operational capacity and expertise, and moreover, became overburdened by the emergence or expansion of dengue and malaria in the region. Lack of research has also undermined disease control efforts. For example, it took nearly 40 years to realize that traditional vector control programmes conducted in the Gran Chaco region were not as effective as elsewhere and had to be revised [http:// www.paho.org/english/ad/dpc/cd/dch-incosur-xv.htm (Accessed September 19, 2007)]. The magnitude of congenital transmission of T. cruzi was underestimated by a factor of 6.3 in Argentina, and constitutes a sizable public health problem in the region.22 Various sources of heterogeneity (environmental and demographic), jointly with various political and institutional arrangements, determine the occurrence of ‘hot spots’ of infestation where traditional control actions are less effective than expected and where parasite transmission tends to persist at lower rates. The challenge of sustainable suppression of bug infestation and T. cruzi transmission can be met through integrated disease management, in which vector control is combined with case detection and treatment to increase impact, cost-effectiveness and public acceptance. For sustainable Chagas disease management, broad social participation and schoolbased health promotion in the frame of sustainable social, political and economic development are essential.16 To minimize the burden of disease and achieve long-term sustainability of disease management programmes, the tight links between research and disease control exemplified by the discovery of Chagas disease need to be re-established and strengthened.

Acknowledgements The ideas discussed in this article have benefited from the support by the Fogarty International Center and the National Institute of Environmental Health Sciences (US National Institutes of Health/National Science Foundation Ecology of Infectious Disease Program award (R01 TW05836 to U.K. and R.E.G.).

References 1

Chagas C. Nova tripanozomiaze humana. Estudos sobre a morfologia e o ciclo evolutivo do Schizotrypanum cruzi n. gen.,n.sp., agente etiologico de nova entidade morbida do homem - Ueber eine neue Trypanosomiasis des Menschen. Studien u ¨ ber Morphologie und Entwicklungszyklus des Schizotrypanum cruzi n. gen., n. sp., Erreger einer neuen Krankheit des Menschen. Mem Inst Oswaldo Cruz 1909;1:159–218.

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Cohen JE. Human population: the next half century. Science 1995;302:1172–75. Cohen JE. Population and planet: the twentieth century and the twenty-first. Harv Mag 1999;102:38–40. Lewinsohn R. Prophet in his own country. Carlos Chagas and the Nobel Prize. Perspect Biol Med 2003;46:532–49. Morel CM. Chagas disease, from discovery to control and beyond: History, myths and lessons to take home. Mem Inst Oswaldo Cruz 1999;94(Suppl I):3–16. Wendel S, Brenner Z. Historical aspects. In: Wendel S, Brener Z, Camargo ME, Rassi A (eds). Chagas Disease (American Trypanosomiasis): Its impact on Transfusion and Clinical Medicine. Sao Paulo: International Society for Blood Transfusion, 1992. pp. 5–12. Dias E, Pellegrino J. Alguns ensaios com o gammexane no combate aos transmissores da doenc¸a de Chagas. Brasil Me´d 1948;62:185–91. ´n del ‘Gammexane’ sobre los ˜ a C, Abalos JW. Accio Roman triatomideos. ‘Control’ domiciliario. An Inst Med Reg (Tucuma´n) 1948;2:95–106. World Health Organization. World Health Report 2004: Changing History. Geneva: World Health Organization, 2004. Available at: http://www.who.int/whr/2004/en/ (Accessed May 30, 2007). Dias JCP, Silveira AC, Schofield CJ. The impact of Chagas disease control in Latin America: a review. Mem Inst Oswaldo Cruz 2002;97:603–12. Silveira AC. El control de la enfermedad de Chagas en los paı´ses del Cono Sur de Ame´rica. Historia de una iniciativa internacional. 1991-2001. In: Silveira AC, Rojas de Arias A, Guille´n G, Russomando G, Schenone H (eds). Uberaba: Facultad de Medicina do Triangulo Mineiro, 2002. Division of Control of Tropical Diseases. Chagas Disease: A Disease whose Days are Numbered. Geneva: World Health Organization, 1996.

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World Health Organization. Control of Chagas Disease. Geneva: World Health Organization, 2002. Anonymous. New global effort to eliminate Chagas disease. Partners set out strategy against the ’kissing bug’ disease. Available at: http://www.who.int/media centre/news/releases/2007/pr36/en/index.html (Accessed December 27, 2007). Schofield CJ, Jannin J, Salvatella R. The future of Chagas disease control. Trends Parasitol 2006;22:583–88. Gu ¨ rtler RE, Kitron U, Cecere MC, Segura EL, Cohen JE. Sustainable vector control and management of Chagas disease in the Gran Chaco, Argentina. Proc Natl Acad Sci USA 2007;104:16194–99. Schmunis GA, Cruz JR. Safety of the blood supply in Latin America. Clin Microbiol Rev 2005;18:12–29. Tarleton RL, Reithinger R, Urbina JA, Kitron U, Gu ¨ rtler RE. The challenges of Chagas disease—grim outlook or glimmer of hope. PLoS Med 2007;4:1852–57. Viotti R, Vigliano C, Lococo B et al. Long-term cardiac outcomes of treating chronic Chagas disease with benznidazole versus no treatment: a nonrandomized trial. Ann Intern Med 2006;144:724–34. Rassi A Jr, Rassi A, Little WC et al. Development and validation of a risk score for predicting death in Chagas’ heart disease. N Engl J Med 2006;355:799–808. ´n ZE, Gu Yado ¨ rtler RE, Tobar F, Medici AC. Decentralization and Management of Communicable Disease Control in Latin America. Buenos Aires: Pan American Health Organization, 2007. Available at: http://www.paho.org/ English/ad/dpc/cd/res-descentralizacion.htm (Accessed November 4, 2007). Gu ¨ rtler RE, Segura EL, Cohen JE. Congenital transmission of Trypanosoma cruzi infection in Argentina. Emerg Infect Dis 2003;9:29–32.

Published by Oxford University Press on behalf of the International Epidemiological Association ß The Author 2008; all rights reserved.

International Journal of Epidemiology 2008;37:701–703 doi:10.1093/ije/dyn139

Commentary: Carlos Chagas—predecessor of Epidemiology in Brazil ´ da Rocha Carvalheiro* and Paulo Gadelha Jose

Three contextual points should be borne in mind when considering the texts Carlos Chagas wrote in 19091–4as an example of a significant contribution to epidemiology. First, even though its roots extend back Fundac¸a˜o Oswaldo Cruz, Rio de Janeiro, Brazil *Corresponding author. E-mail: [email protected]

to classical ancient history with the work of Hippocrates, epidemiology was only acknowledged as an academic discipline in the 20th century. Second, Chagas was not the only contributor. The method implemented in the early days of Manguinhos followed the ‘Pasteur model’ that spread throughout the world at the time. In America, Garcia5 pointed out that almost all scientific institutes founded at the turn