Campaign
The first Chagas disease prophylaxis campaign in Brazil (Uberaba, 1950)
Simone Petraglia Kropf
Casa de Oswaldo Cruz/Fiocruz.
Email: simonek@coc.fiocruz.br
Among the new technical resources produced, in the context of World War II, to combat infectious diseases were, besides antibiotics, residual action insecticides. Dichloro-diphenyl-trichloroethane (DDT), used since 1944 to protect Allied troops against typhoid and malaria vectors in southern Italy and the Pacific, was the main symbol of the new belief in victory over so-called tropical diseases. The DDT era consolidated the view that health interventions, especially the systematic fight against vectors, were the prerequisite for the economic and social development of countries.
The environment of sanitary optimism reinforced, in Brazil, the perspective of the Ministry of Education and Health (MES) to broaden its campaigns against the main endemic and epidemic diseases of the country and was an important impetus for those seeking to establish, for the first time in the country, prophylaxis measures against Chagas disease. Several elements of the more general historical context of the so-called Vargas era gave new meanings to the fight against rural endemics, which, under the management of Henrique Aragão at the Oswaldo Cruz Institute (1942-1949), was considered a priority.
Although the modernization project established in 1930 favored the urban-industrial world, the theme of occupation and development of the interior gained a new meaning, as a condition to ensure the supply of a domestic consumer market, capable of sustaining the new economic model. The centrality, given by the State to the theme of work as a primordial value for the construction of a new nation, came to support, politically and ideologically, projects that aimed to guarantee the existence of healthy, strong and productive workers, in the cities and in the countryside.
In Minas Gerais, in turn, the elite’s concern about the state’s economic stagnation made them sensitive to programs aimed at increasing productivity in the countryside, stopping the rural exodus and restoring the state’s traditional agricultural vocation as a “great granary” of the national domestic market.
All these factors created a favorable environment for the creation of the Chagas Disease Center Study for Prophylaxis (CEPMC), in 1943, at the IOC advanced post, the mining town of Bambuí, whose direction fell to Emmanuel Dias, disciple of Carlos Chagas and his godson of baptism. Following the international trend of the time, the goal was to enable the complete destruction of the American trypanosomiasis vectors, although it was recognized that, at that time, the eradication of triatomines was still a goal for the future. One strategy was the application of insecticides to dwellings. Dias tested several commercially available substances, such as kerosene, gasoline, formaldehyde, ammonia, phenic acid, among others. Fumigation of toxic gases and the use of flame-throwers to destroy insects by fire were also tested, which were not satisfactory.
The main challenge was to find a product that had the longest lethality for barbers, so as to avoid re-infestation of the household. In the case of triatomines, whose characteristic is to hide in the cracks in the walls and hard to reach places for the sprinkler pump jets, the residual action became even more necessary. The tests with DDT in Bambuí began in August 1944. Despite the positive results of the first experiments, the product was not effective against barbers.
In addition to insecticide purges, CEPMC has also tested housing improvement techniques such as plastering the walls to extinguish conditions for transmitter proliferation. As Dias stated, “The problem of Chagas disease is closely linked to the problem of rural housing and its solution will almost certainly bring the solution to the first one”. Fighting “cafua” is fighting trypanosomiasis.” In July 1947, an agreement was established with the Casa Popular Foundation for the construction of experimental houses in Bambuí, aiming at the general reform of the city’s houses.
Beginning this year, the prospect of attacking barbers with insecticides gained a major boost when the doctor José Pellegrino from Minas Gerais, who is linked to the State Department of Health, joined the Bambui post’s staff. Dias and Pellegrino began testing gamexane (hexa-chloro-cyclohexane gamma isomer or BHC). The first results were very positive and, in 1948, they published work on the action of the product against triatomines, from laboratory experiments. At the same time, the Argentineans Romaña and Abalos were also conducting experimental trials for the same purpose. Despite some technical restrictions, Dias and Pellegrino celebrated the fact that, almost forty years after the discovery, scientists had a concrete weapon against American trypanosomiasis. They then reinforced their demands for health organisations to promote a prophylaxis campaign based on household disinsectization.
In a lecture given on the 1st. Medical Congress of Central Brazil and Triangulo Mineiro held in Araxá, in September 1949, Dias stated that the National Malaria Service (SNM) from MES should be responsible for these actions, advised by the state health departments. Expressing the important alliance that IOC researchers had been establishing with inland clinicians, many of them scholars of Chagas disease, the congress participants formalized a motion addressed to the Minister of Education and Health, Clemente Mariani, requesting the support by the Department National Health and the SNM, for such campaign.
The following month, an agreement between the directors of IOC and SNM, Henrique Aragão and Mário Pinotti, began in Uberaba, experimental purges aimed at establishing the technical procedures for a household disinfection campaign in large areas. SNM has borne the costs of insecticides and material, as well as providing specialized personnel trained in anti-malarial campaigns. The CEPMC, in turn, sent its technicians, who moved with Dias to Uberaba, where they had the collaboration of local doctors. In addition to the trials in Uberaba, insecticides were also tested in Bambuí and in the Industrial City, near Belo Horizonte, also in preparation for a larger-scale campaign.
In December 1949, the MES entrusted the SNM, the Sanitary Organization Division and the IOC with the task of initiating a Chagas disease prophylaxis campaign by insecticides to be carried out by the SNM.
On May 7, 1950, the first American trypanosomiasis prophylaxis campaign was inaugurated in Uberaba. The region chosen for the purges comprised 123 municipalities of Minas Gerais, located in the Triângulo Mineiro and the southwest of the state, and 93 in the north of São Paulo, in the Rio Grande Basin, covering approximately 213,000 square kilometers and a population of about 3,460,000 inhabitants. In this region, where Triatoma infestans was the main transmitting species, insecticides were expected to be applied to around 200,000 dwellings.
The link between Chagas disease and impairment of rural productivity was a central argument to justify the campaign, including from the point of view of the choice of regions to benefit. According to Pinotti, such selection was based on “technical, economic and practical reasons”: better knowledge of the incidence of the disease by researchers, the opportunity to prevent T. infestans from expanding north and east, and the fact that the region had high population density, comprising “highly productive areas”.
With the presence of various political and health authorities, the inauguration ceremony had a great impact on the press. The optimism about the power of science and the state’s capacity for action for the “redemption of the sertanejos” was expressed in a ufanist tone. The occasion gave great public projection to the work of the Bambuí post, as well as the notions about the disease advocated by scientists, especially its characterization as a dangerous heart disease for the rural worker.
In the following years, the campaign started in the Triangulo Mineiro would be extended to other regions of Minas Gerais and to some other states of the country. The São Paulo State Malaria Prophylaxis Service also launched, in 1950, a campaign similar to that initiated by the SNM in the Triangulo Mineiro, aimed at covering regions of the state not covered by the federal service, especially the Ribeirão Preto area. The fight against the disease in São Paulo would count on the decisive collaboration of researchers from the Ribeirão Preto Medical School, created in 1952 and which would constitute an important center for studies on the disease.
The campaign started in Uberaba brought to the process of social recognition of Chagas disease a decisive new ally. The SNM was the most important body in the federal structure of Brazilian public health, with wide penetration in several states of the country, extensive staff and that has been in evidence since the post-war, due to the international importance given to malaria. Its director, Mário Pinotti, who was in charge of the service since its creation in 1941, would consolidate itself as a great political leader of the Brazilian public health, becoming Minister of Health between 1958 and 1960. Dias, at the inauguration of the campaign, stressed the importance of the alliance with the NMS, stating that that date was the most important in the history of Chagas disease since its discovery. He said: “Gentlemen, born with malaria, on the banks of the Rio das Velhas, the American trypanosomiasis. And with malaria it must begin to die here, in the fertile lands of the edge of Rio Grande.”
The beginning of the prophylaxis measures also meant the opportunity to reinforce the ties of researchers dedicated to the study of Chagas disease with the doctors of the interior, who took the opportunity to reaffirm their own identity around this theme. At the meeting of the Uberaba Society of Medicine and Surgery, held during the campaign’s inauguration, the president of that association, Sabino Vieira de Freitas, recalled the efforts of the city’s clinicians to draw the authorities’ attention to the severity of the chagasic endemic, calling for local doctors the direct responsibility for making the campaign viable.
The 1950 campaign brought major projection to Chagas disease in the medical, scientific and public health forums in Brazil and abroad, reinforcing the process of institutionalization of the theme as a subject of study and the public health agenda. At the 1951 Brazilian Hygiene Congress, for example, it was the subject that gathered the majority of the presentations. At the same time, this field of research was gaining new ground in universities, especially in medical schools created at the time in regions where the disease was endemic, such as Ribeirão Preto, Triângulo Mineiro and Goiânia. Another important milestone of this institutionalization was the first International Congress on Chagas Disease, in Rio de Janeiro, in 1959.
Throughout the 1950s, Dias was engaged in political mobilization to extend the scope of the campaign and, especially, for the Pan American Healh Organization (PAHO) to coordinate a plan to fight the disease on the continent. Despite facing resistance to his thesis that, similar to what was then spreading to malaria, it was possible to eradicate the vectors of Chagas disease, he promoted intense articulation with scientists and governments from various South American countries. In 1960, the OSP organized an expert meeting in Washington to discuss the prospects for prophylaxis.
Dias’ acting to expand the scientific interest in the disease and institutionalize it as an object of national and international health policies was directly related to the postwar scenario. The theme of the link between health and development gained new strength in a world under reconstruction that lived the dream of development. In the field of health, confidence was reinforced in the long-awaited victory against tropical diseases, which assumed not only economic importance as a factor for increased productivity in the so-called Third World, but political as a means of preventing the spread of communist ideology in this region. The creation of the World Health Organization in 1948 brought new institutional, political, and symbolic conditions for projects aimed at breaking what was then defined as the “vicious circle of disease and poverty”, such as the 1955 program for the global eradication of malaria.
In the Brazilian context of the 1945 redemocratization, the processes that had been shaping the new economic model focused on industrialization and urbanization were intensifying. The country lived, in many ways, the progressive conformation of what, under the second Vargas government, and especially during the JK years, constituted the national-developmental model. Health, especially the theme of combating rural endemics, gained new visibility, not only because of the expansion of the State’s administrative capacity – expressed in the creation of the Ministry of Health in 1953 as an autonomous ministry – and by the new technological resources then available to the campaigns, but also for the political and symbolic meaning it assumed, at a time when the goals of development were synthesized in the great operation of internalization of the country’s capital.
The control of Chagas disease throughout the Brazilian territory would be implemented by the Ministry of Health in the 1980s, as a result of the First National Survey, conducted between 1975 and 1980, to map the prevalence of infection and the distribution of transmissors in the country. In 2006, about 50 years after the Uberaba campaign and nearly 100 years after the discovery of the disease, the project by Carlos Chagas, Emmanuel Dias, achieved its objectives with PAHO’s certification of the interruption of transmission by the Triatoma infestans in Brazil.
Therapy
The history of Chagas disease therapy
José Rodrigues Coura
Departamento de Medicina Tropical, Instituto Oswaldo Cruz, Fiocruz
E-mail: coura@ioc.fiocruz.br
Joaquim Romeu Cançado
Universidade Federal de Minas Gerais e Fundação Carlos Chagas, Belo Horizonte, MG, Brasil
The history of specific therapy for Chagas disease can be divided into three periods: (i) from the discovery of the disease in April 1909 until the death of Carlos Chagas in November 1934, and shortly thereafter in 1935 the launch of the “Manual of Tropical and Infectious Diseases” by Evandro Chagas, on behalf of his father and himself as authors, where they say: “Trypanosomicidal drugs have been tried without any success”; (ii) from 1936 and 1960, when numerous drugs were empirically tried with controversial results; and (iii) from 1961 onwards, when Zigman Brener clearly demonstrated nitrofurazone activity in long-term regimens in curing experimental Trypanosoma cruzi mouse infection.
The chapter on American Trypanosomiasis in the Manual on Tropical and Infectious Diseases by Carlos Chagas and Evandro Chagas, published in 1935 in its 36 pages, devotes only a six-line paragraph to the topic of treatment, which says: “There is as yet no specific treatment for American trypanosomiasis”. Medications with trypanomycidal action have been tried by numerous researchers without any success. Some clinical syndromes may experience symptomatic therapeutic action, performed according to their manifestations and evolution.” Although they speak of “typanosomycidal-acting drugs have been tried by numerous researchers” they do not cite references to published works on these drugs. Possibly because the results were negative, the researchers, as usual at the time, did not want to publish them.
In an excellent review by Brener in 1968 in the chapter on “Experimental Therapy of Chagas Disease”, in the most complete work on the disease so far published, the book on Chagas Disease, organized by Cançado, with the collaboration of the leading Brazilian specialists on the disease, only two papers had been published on experimental therapy for Chagas disease until 1935. Mayer and Rocha Lima’s 1912 work on Atoxil (arsenical), fuchsin (a rosanylin dye) and emetic tartar (pentavalent antimonial) and from the same authors in 1914 on mercury chloride, both without favorable results. In the detailed 1968 review, Brener mentions 23 other chemotherapeutic drugs and more than 30 antibiotics used from 1936 to 1962, of which only the following had some suppressive effect on Trypanosoma cruzi infection: Bayer 7602 bisquinaldine, phenanthridines, 8-aminoquinolines, trivalent arsenicals (Bayer 9736 and Bayer 10557 also named spyrotrypan), “acromycin” or “stylomycin”, nitrofurans and “Flagyl” (acetamide-5-nitrotiazole imidazole) and particularly the nitrofurans, which we will discuss later.
In an analysis of the therapeutic attempts of Chagas disease in the 50 years since its discovery (1909-1959), Cançado, in his book published in 1968, says “the literature review on the treatment of Chagas disease immediately reveals extreme poverty”, and presents the following figures that confirm its assertion: Out of 96 papers presented to the International Congress on Chagas Disease, held in Rio de Janeiro in July 1959, only four refer to the treatment of the disease and of these only one to clinical therapy, and adds 1,369 studies on Chagas disease identified by the Brazilian Institute of Bibliography and Documentation (IBBD), in the same period (1909-1959), there were only 69 on treatment, 43 on experimental therapy and 26 on clinical therapy. Finally, he mentions the fact that has always impressed all of us who work with Chagas disease: none of the 64 works by Carlos Chagas cited by the IBBD is dedicated to treating the disease. Certainly, Carlos Chagas and/or his collaborators must have done therapeutic experiments for the disease, particularly with arsenicals and antimonials, used respectively since 1906 for syphilis (Paul Enrlich) and 1912 for leishmaniasis (Gaspar Vianna).
Still in the chapter on treatment of Chagas disease, Cançado makes a critical analysis of the literature, showing the methodological weakness of the vast majority of works on therapy. On the one hand because most of them are in the acute phase and using the remission of clinical signs and symptoms and parasitemia as parameters, which usually occurs in this phase even in untreated patients and on the other hand by the lack of systematization in cure control and the definitive test that would be serology negativation, revealed by complement fixation, a diagnostic method of the time, most of the time not applied or with inconsistent results.
Among the chemotherapeutic agents employed from 1936 to 1960 as an attempt to treat Chagas disease are quinolein derivatives and various other antimalarials, arsenobenzoles and other arsenicals, phenanthridines, salts of gold, bismuth, copper and zinc, sodium iodide. gentian violet, aminopterins, para-aminosalicylic acid, nicotinic acid hydrazide, sulfonamides, antihistaminics, ACTH and cortisone, stilomycin derivatives, amphotericin B and more than 30 antibiotics, and some nitrofurans with negative or arguable results, as reviewed by Coura e Silva, and by Brener and Cançado.
From 1961, when Brener reviewing nitrofurans experimentally studied by Packchanian in the experimental infection with T. cruzi, clearly and undoubtedly demonstrated that nitrofurazone (5-nitro-2-furaldeido-semicarbazone) in a scheme of prolonged duration (53 days) in the dose of 100 mg/kg/day cured more than 95% of chronically infected mice, a new era in the treatment of Chagas disease has been opened. Soon after, Ferreira and colleagues also treated 10 acute cases of nitrofurazone disease, “with good results and few side effects”, but then found that five of them later reverted to positive xenodiagnosis. Coura and colleagues report in studies published in 1961 and 1962 the treatment of 14 chronic cases with nitrofurazone (Furacin) at progressive doses of 10 mg/kg/day in the first week, 20 mg/kg/day in the second week and 30 mg/kg/day in the third week; the side effects in the first four cases were so intense (sensory polyneuropathy) that treatment had to be stopped. Treatment was restarted with 10 mg/kg/day in 10 other patients, with 5 tolerating treatment despite side effects (anorexia, weight loss, paresthesias and sensory polyneuropathy) for 60 days; one of these patients with recent chronic infection (18 months) tolerated treatment with 20 mg/kg/day for 53 days. Of the six patients treated for a prolonged period (more than 50 days), two were considered cured, based on persistent negative xenodiagnosis and complement fixation reaction (Guerreiro and Machado reaction), which never returned to positive. Cançado and collaborators in 1964 also treated five chronic patients with nitrofurazone at a dose of 10 mg/kg/day at varying periods with a tolerance of 10 to 34 days, with therapeutic failure. The final conclusion was that nitrofurazone could be curative, but patients did not tolerate side effects at the doses and time required to cure.
In the late 1960s and early 1970s two new drugs emerged with better prospects for treating Chagas disease both due to their healing potential, particularly for the acute phase, and their tolerance: nifurtimox, a nitrofuran: 3-methyl-4- (5′-nitrofurfurilidenoamino) tetrahydro-4H-1,4-thiazine-1,1-dioxide (Bayer 2502) marketed as Lampit and benznidazole (N-benzyl-2-nitroimidazole acetamide (RO 7-1051) marketed with the name of Rochagan® in Brazil and Radanil® in Argentina. Nifurtimox developed by Bock and collaborators and benznidazole developed by Richle were active in vitro and in vivo against T. cruzi. Nifurtimox production from the 1980s, has been discontinued, initially in Brazil and then Argentina, Chile and Uruguay and benznidazole in Brazil was passed by Roche to the Pernambuco State Pharmaceutical Laboratory (Lafepe). The lack of interest of the pharmaceutical industry in the production of medicines for Chagas disease, considered as “social medicines”, is linked to low demand, restricted only to some countries in Latin America, for low income population and therefore with low profit margin.
Nifurtimox and benznidazole have been widely used by several researchers, especially in Brazil, Chile and Argentina, including Cançado and collaborators, Cançado and Brener, Bocca-Tourres, Rubio and Donoso, Schenone and collaborators, Rassi and Ferreira, Rassi and Luquetti, Coura and collaborators, Macedo and Silveira, Viotti and collaborators, Andrade and collaborators, Sosa Estani and collaborators, Cançado, and Lacunza and collaborators, among many others who published their results.
Results obtained with both drugs varied according to the phase of the disease, the duration of treatment, the age of the patients, and the geographical area of origin. The best results were obtained in the acute phase of the disease in children and patients with recent infection using nifurtimox at a dose of 8 to 10 mg/kg/day or benznidazole 5 to 7.5 mg/kg/day for 60 to 90 days. In the chronic phase and in adult patients the best results were obtained in southern Brazil, Argentina and Chile, therefore in the Southern Cone, probably due to the type of T. cruzi strain in this region. In summary, it can be said that the cure rate was 60 to 80% in the acute phase and 10 to 20% in the chronic phase, according to the various authors and geographical areas. Some authors who achieved “high cure rates” in the chronic phase were based on negativity of xenodiagnosis or PCR, which may be negative in more than 50% of patients with parasitemia reduction, even if not cured.
The most common side effects with nifurtimox were anorexia, weight loss, psychic excitability or drowsiness and digestive manifestations such as nausea, vomiting and occasionally intestinal cramps. Side effects with benznidazole can be classified into three types: (i) hypersensitivity manifestations such as rash dermatitis (usually appearing between the 7th and 10th day of treatment), peri-orbital or generalized edema, fever, lymphadenopathy and muscular and articular pain; (ii) bone marrow depression, including neutropenia, agranulocytosis and thrombocytopemic purpura; (iii) peripheral polyneuropathy represented by paresthesias and polyneuritis.
Despite being a breakthrough in the treatment of Chagas disease, nifurtimox and benznidazole are far from being considered ideal drugs. The ideal drug for the treatment of Chagas disease should meet the following requirements: (i) produce parasitological cure of acute and chronic cases and prevent the evolution of the disease, being effective with few doses in the short term (10 to 15 days); (ii) do not produce significant side effects or teratogenic ones and do not induce parasitic resistance; (iii) be inexpensive, easy to apply and accessible to patients.
Since the 1990s, due to the limitations of nifurtimox and benznidazole, some drugs such as allopurinol, an analogue of xanthine oxidase inhibitor and purine synthesis, used for the treatment of gout and azole antifungals, such as ketoconazole, fluconazole. and itraconazole, which showed some in vitro activity against T. cruzi were used in experimental animals and in humans with controversial results, such as those published by the following authors and their collaborators: Lauria-Pires, Galerano, Brener, Castro, Apt and Molina.
The serious problem that leads to controversy and a huge waste of time is the lack of criteria in clinical and experimental evaluation in vivo in relation to the partial results obtained in in vitro. Of course, this is a necessary and indispensable first step, but it must be followed with a rigorous experimental animal study with different strains of T. cruzi, before any announcement and experimentation in humans, which in addition to the studies of toxicity, should be done with extreme scientific rigor before proclaiming positive results, most often false for lack of criteria in controlling parasitological cure and disease evolution and should always be done with a control group.
The development of an anti-parasitic drug may arise through experiments with natural or synthetic products that have similarity to compounds with recognized activity for other diseases or through specific metabolic targets for a particular parasite to be targeted, as reviewed by Coura & de Castro. As perspectives for the experimental treatment of Chagas disease, several targets are being revealed through metabolic and biochemical studies of T. cruzi, including the synthesis of sterols and enzymes essential for the development and multiplication of this parasite, as reviewed by Do Campo.
Considering that ergosterol is the main sterol of T. cruzi, in the last decade research has been oriented towards the development of an effective sterol inhibitor. Urbina and colleagues developed the DO870 which cured a high percentage of T. cruzi-infected animals in the short and long term. Molina and colleagues have shown that posoconazole triazole (SCH 56592 Schering-Plouch) inhibits the proliferation of T. cruzi epimastigotes and ergotenol synthesis by up to 100-fold more than DO870, including strains resistant to nifurtimox and benznidazole. Posoconazole is currently the great hope in the treatment of Chagas disease and is already in the early stages of experimentation in humans.
Vaccine
Background: Critical Requirements for a Chagas Disease Vaccine
Erney Plessmann Camargo
Instituto de Ciências Biomédicas, Universidade de São Paulo
E-mail: erney@usp.br
Just four years after Carlos Chagas’ discoveries, Emile Brumpt published the first essays on the induction of an “Immunité partielle dans les infections à Trypanosoma cruzi”. Brumpt’s work contained a statement that would mark ninety-odd years of history of the search for a vaccine against Chagas disease: the protection induced against experimental T. cruzi infections would always be partial, never accompanied by sterile immunity.
Let’s look at the history of this “immunité partielle” by recalling four basic requirements for a prophylactic or preventive Chagas vaccine:
1. A prophylactic vaccine should give full protection, ie sterile immunity to prime infections. As Zigman Brener and I already warned: “A vaccine which merely attenuates the acute phase of the infection – a procedure possibly acceptable for other infectious disease – would be of questionable value in Chagas disease.” That’s because, in the pathogenesis of the disease, the impairment of target organ damage is a chronic sequel to the long course of the disease, not an exclusive event of the acute phase. A few surviving trypanosomes from the acute phase could lead to chronic phase lesions. Hence the requirement of sterile immunity for a prophylactic vaccine against Chagas. Not to mention the fact that non-sterile immunities do not eliminate the source of infection. Notwithstanding this basic principle, most vaccine trials have taken into consideration only acute-phase mortality rates, without concern for residual parasitemia and chronic disease of vaccinated animals.
2. A vaccine should provide protection against all T. cruzi strains capable of infecting man. Since Brumpt, T. cruzi strains of greater or lesser virulence are known. Today we know more about T. cruzi strains that circulate in nature and we know that they can be grouped into zymodems or genotypes that exhibit distinct virulence and antigens. Potential vaccines should be tested at least against known and epidemiologically important T. cruzi genotypes and should be effective against all.
3. A vaccine could not induce autoimmune disease, a postulate that derived from evidence and beliefs that Chagas disease had a large autoimmune component and that T. cruzi fractions and antigens could induce pathological manifestations of disease. chronic in the absence of infections. Although the importance of this autoimmunity is questionable, just in case this possibility should be examined.
4. Finally, as the vaccine was intended for humans, it should be developed and tested in experimental models that mimic the pathogenesis and immune response of humans. Unfortunately, the universally adopted model was the murine model, which has proved to be a limited model. Just as an example, mice do not recognize as antigenic alpha-galactopyranosil epitopes from the surface of trypanosomes. These epitopes are responsible for the induction of lytic antibodies in human infections. Thus, an effective vaccine against T. cruzi infection in mice may not mean a vaccine against Chagas disease. Nevertheless, few alternative experimental models have been tested. Occasional, though promising, incursions were made in the rabbit and especially dog models, which were not followed up. The monkey was equally unexplored, and attention, Muniz, in 1947 showed that rhesus monkeys vaccinated with dead forms of trypanosomes developed “hyperergic” myocarditis, which in itself shows that distinct models can lead to absolutely dissonant observations. Surprisingly, the simple and affordable dog, which besides the monkey, is the only one that is infected with T. cruzi in the wild and exhibits a pathology in many respects similar to that of man, has been poorly tested.
Given these assumptions, the story of the search for a vaccine against Chagas disease would be a mismatch in the maze of Brumpt’s fateful “immunité partielle”.
What was first attempted in Chagas, following a practice common to vaccine attempts in other diseases, was to induce protection with prior immunizations of either sublethal doses of T. cruzi or of parasite strains of alleged attenuated virulence. These attempts began with Brumpt’s seminal work and lasted until the late 1970s. In the late 1960s, immunizations with several strains of T. cruzi, as well as other trypanosome species, and later with parasitic trypanosomatids of insects. All were unsuccessful and all limited to the measurement of mortality in the post-challenge phase with virulent T. cruzi strain.
Several attempts at vaccination have also been made with live T. cruzi culture forms, inactivated by radiation or multiplication-blocking chemicals, or culture forms killed by the most varied fixatives and antiseptics. The results obtained were always discouraging when, after various vaccination schedules, the animals were challenged with infective doses of T. cruzi. Mortality reduction was never accompanied by sterile immunity, and post-challenge parasitemia was always positive.
Numerous were the vaccine trials with cell subfractions, the most notorious of them with flagellar fractions. Although in some cases mortality rates were null after challenge with infectious forms, parasitemia, when properly investigated, never was.
A step forward was taken when purified antigens replaced cell fractions in vaccine trials. Not because the results were better than the previous ones toward sterile immunity. But because rational research for antigens, particularly surface ones, has replaced empirical demand with rationalistic demand for a vaccine. At the same time, we were moving to better understand the molecular organization of the surface of T. cruzi and its antigens, especially transialidase (TS, a unique T. cruzi enzyme). The association of antigen definition with immunological studies allowed significant advances in understanding the immune response to T. cruzi, especially in clarifying the role of CD8+ cells in the assembly of an organ-protective defense in chagasic infection.
Despite these advances in our knowledge of chagasic pathogenesis, available and prospective experimental vaccines could not overcome the stigma of “immunité partielle”.
In recent years new perspectives have been opened with DNA vaccines. The work developed by Rodrigues and collaborators which consists of the insertion of T. cruzi genes into plasmids and their injection into animals to be vaccinated. The primary genes chosen were surface genes and, among them transialidase. Early results have not escaped the stigma of “immunité partielle”. Recently, the choice of a T1-type immunity-stimulating plasmid (with production of proinflammatory cytokines such as interferon-gamma) carrying an association of two surface genes, transialidase among them, resulted in zero mortality rates after the challenge between mice vaccinated for six months of observation, although parasitemia persisted in most animals.
Either way, the outlook is optimistic, thanks to the properties of DNA vaccines of permanently producing vaccinating antigens, sometimes for the lifetime (at least) of mice. Thus, even if the infection is not fully eradicated (sterile immunity), constantly elicited defenses can keep the infection under control, reducing chronic tissue and organ damage. This fact, which still needs further investigation, opens possibilities for the use of DNA vaccines also as curative vaccines.
Another interesting perspective concerns mucosal protection, particularly because oral infections are becoming more frequent (or more frequently recorded), notably in the Amazon. In this sense, some works developed by Hoft and collaborators already point to the induction of mucosal immunity against T. cruzi antigens. However, without being pessimistic, it should always be remembered that the murine model serves the mouse and may not be suitable for man. As it should be remembered, too, that different T. cruzi strains express different epitopes of transialidases and possibly other antigens.
Finally, there is a last problem that is not even equated in terms of vaccine logistics. How to verify epidemiologically the effectiveness of a vaccine against Chagas disease? Which population to use in the vaccine testing phase? Considering that Chagas disease is late-chronic expression, how many years should the test population be expected to release the vaccine? To which population would a vaccine for Chagas disease in Brazil should be directed to?
Fortunately, these are just problems, not unavoidable obstacles, and science always finds solutions to its problems. However, while this does not occur, it is not possible to think in neglecting the services of control of vectors and blood banks.
Survey
First National Serological Survey for Chagas Disease (Brazil, 1975-1980)
João Carlos Pinto Dias
Centro de Pesquisas René Rachou, Belo Horizonte
E-mail: jcpdias@cpqrr.fiocruz.br
Aluízio Rosa Prata
Faculdade de Medicina da Universidade do Triângulo Mineiro
E-mail: a_prata@mednet.com.br
Carlos Chagas very early realized the great disproportion between the acute and chronic cases of American trypanosomiasis in endemic areas, the latter being extremely numerous and of much greater social medical impact. He also sensed that the disease should be widespread throughout the Americas, thanks to the rapid accumulation of evidence of infected triatomines in rural homes, from Mexico to Patagonia, recorded by his colleague and collaborator, the entomologist Arthur Neiva. Chagas knew of the difficulties at the time of diagnosing chronic infection, given the scarcity of circulating parasites and the lack of sufficiently specific and sensitive serum antibody detection techniques. It was a time when Immunology was just blossoming in the scientific setting, with very little accomplished in terms of parasitic diseases. The parallel between the triatomine-trypanosomal scenario and the social medical burden of schizotrypanosis had been the subject of much speculation by Chagas, in fact, one of the main motives of the celebrated controversy of the National Academy of Medicine in the 1920s. The disease would only receive attention, studies and prevention if objectively recognized to an extent that demonstrates its importance. The paths to such recognition would be through the clinic and the laboratory. Determined, Chagas embarked on both, calling for research and supportive studies by clinicians and pathologists such as Eurico Villela, Gaspar Vianna, Crowell, Evandro and Margarinos Torres, and clinical pathologists and parasitologists such as A. Machado, C. Guerreiro, Rocha Lima, E. Brumpt and Emmanuel Dias. Until the 1940s, xenodiagnosis was the main tool for detection of chronic infection, developed by Brumpt and perfected by E.Dias, restricted by its low sensitivity and the technical and logistical difficulties of its implementation in mass surveys. The Guerreiro e Machado complement fixation reaction (RFC), described in 1913, was very complex and presented sensitivity problems in pioneering works by Villela, among others. Chronic Chagas disease actually began to be recognized in the second half of the 1940s, thanks to work in the endemic area of Bambuí, by E. Dias and colleagues. In that focus, the Chagas chronic heart disease was re-studied and systematized by Orange, Dias, Nobrega and others, having been essential, a precise serological diagnosis. This was achieved thanks to the excellent RFC improvement work by Júlio Muniz, Gilberto de Freitas and José Lima Pedreira de Freitas, among others, providing studies in populations of endemic areas that also began with Bambuí. The first large-scale survey conducted in that area by Dias and collaborators was classic, followed by similar work in Sao Paulo, the Northeast, Rio Grande do Sul, Goias, and Rio de Janeiro, later in the Northeast and the Midwest. In the early sixties, Salgado and Pellegrino (1968) conducted an extensive school serological survey in Minas Gerais, which showed important rates of disease transmission. Systematic surveys in Bambuí and São Paulo were then used for the first time to measure the impact of control actions, a strategy also applied in Venezuela and Argentina. Surveys multiplied and improved, especially with the advent of modern laboratory techniques such as hemagglutination, immunofluorescence and, later, ELISA. Based on the evidence accumulated in the mid-1970s, a group of scientists and sanitarians, with the support of CNPq, the Ministry of Health and the University of São Paulo, understanding that it is highly opportune to carry out extensive research on trypanosomiasis in Brazil, planned and executed the First National Prevalence Survey (INP) which played a key role in prioritizing endemic control in our country.
From the historical point of view, the implementation of the INP resulted from the progressive articulation of the Brazilian scientific community with the health authorities during the 1970s. At the beginning of that decade there had been an institutional reform in Brazil that had drained out the Ministry of Health of technical staff and research, generating discomfort, competition and loss of scientific references, a negative situation that needed to be reversed. In contrast, an institutional academic process dating back to the early 1950s strengthened the national scientific community, especially marked by the creation of the National Research Council (CNPq), the World Health Organization, and, more particularly, the Brazilian Society of Tropical Medicine (SBMT). Chagas disease had been put on the agenda of these institutions in terms of congresses, technical meetings, research incentives and publications. As a background, Emmanuel Dias had called on the Pan American Health Organization (PAHO) at a 1958 Lisbon World Congress to give priority to genuinely Pan-American endemic control, receiving from Dr. Fred Soper, then director, the pragmatic response: “You must sell the idea…”. Indeed, the burden of the disease was suspected and even calculated, but the data on prevalence, morbidity and mortality that motivated and justified the necessary investments in its control, in a rational and continuous manner, were still lacking. In 1975, the ministerial program was revised and streamlined. The resources available at SUCAM reached approximately what was needed to cover 60% of the endemic area (anti-vector fight). At the time, in the recently created integrated endemic disease program (PIDE) from CNPq, a technical meeting between researchers and the Ministry resolved to trigger two epidemiological surveys that served to scale up the problem of Chagas disease in Brazil, to better direct and guide the control actions as well as to motivate and justify the necessary material, human and financial resources to allow full coverage of the endemic area. These would be a national survey of domiciled triatomines and the national prevalence survey for serum epidemiology. The triatomine survey covered more than 2,400 municipalities, being carried out entirely by SUCAM regional teams and financial resources, and was published by Silveira and collaborators in 1984.
As a fundamental basis for the INP, the systematization of epidemiological and serological methodologies was of high importance, in order to have a significant representation of the universe to be studied and that the serological technique was very reproducible, of high sensitivity and specificity. The practice of serology in chronic Chagas disease had evolved considerably, with the advent and improvement of simpler and reliable techniques than the classic test by Guerreiro and Machado. This was complex and presented discrepancies between different laboratories, although it provided excellent information for the serologists in various regional surveys. In the 1960s, among others, indirect haemagglutination and indirect immunofluorescence techniques, improved for the detection of anti-T. cruzi antibodies, would already be available. In particular, both techniques allowed an important simplification, as it was possible to collect blood on filter paper slides, facilitating field collection and transport, and being independent of venous puncture.
The survey was conducted from 1975 onwards, being the collection phase most intensive in the years 1976-79, with consolidation activities (including sub-regional repetitions) until the end of 1981. The entire operation was conducted and coordinated interinstitutionally and transdisciplinaryly with the general coordination by a collegiate formed by the Ministry of Health (SUCAM, Drs. Antonio Carlos Silveira and Pedro Tauil) and the University of São Paulo, through its Department of Preventive Medicine of the Faculty of Medicine of São Paulo (Profs, Drs. Guilherme Rodrigues da Silva and Euclydes A. Castilho) and from the Immunology Laboratory of the Tropical Medicine Institute of São Paulo (Prof. Mário E. Camargo). By simple sampling, teams of SUCAM agents collected more than 1.5 million blood samples by digital puncture and filter paper transport in rural locations of less than 2,500 inhabitants in all the Brazilian municipalities, except those in the State of São Paulo, which particularly developed its own control and evaluation actions. The sampling was calculated in a simple random way, in rural areas, with stratification of localities by the number of houses. The harvest was done on the general population of rural areas, covering all residents of the selected housing, using disposable lancets for digital pulp puncture. The support was made on a standardized area of filter paper (Whatmann number 1), which greatly facilitated the collection, storage and transport. Drying in the environment and packaging in plastic envelopes, for storage in common refrigerator and Styrofoam boxes until arrival at the regional laboratories. Seventeen of these laboratories were located in various Brazilian states (state, university, or research institute laboratories), having been set up, supervised and hosted by the Central Laboratory of the Institute of Tropical Medicine of São Paulo. The technique used was indirect immunofluorescence, with antigen and conjugate prepared by the Central Laboratory, using the 1:40 dilution as a cut. For quality control, each laboratory received a standardized panel of positive and negative sera prepared by the Tropical Medicine Institute of São Paulo. All positive sera and part of the negative ones of the regional laboratories were retested by the Central Laboratory, noting also several episodes of repetition in regions or municipalities with problems in the first collection (conservation, identification etc.).
The overall survey results were widely disseminated, being appropriated in terms of overall prevalence in the country, states and municipalities, by calculating the proportion of positive sera by age group. An overall prevalence of 4.2% of T. cruzi infection was estimated for the Brazilian rural general population, with higher prevalence rates in Minas Gerais and Rio Grande do Sul (8.8%), Goiás (7.4%), DF (6.1%), Sergipe (6.0%) and Bahia (5.4%). This was followed by Piaui and Parana (4.0%), Paraiba (3.5%), Pernambuco and Mato Grosso (2.8%), Alagoas and Mato Grosso do Sul (2.5%), Acre (2.4 %), Amazonas (1.9%), Rio Grande do Norte (1.8%), Rio de Janeiro (1.7%), Santa Catarina (1.4%), Ceará (0.8%), Pará (0.5%), Rondônia (0.4%), Roraima and Espírito Santo (0.3%) and Maranhão (0.1%), being negative in Amapá. In general, it was observed that the distribution of prevalence rates did not follow a continuity pattern, but showed the existence of more intense sub-regional transmission pockets, usually linked to higher triatomine-trypanosomal densities, revealed by the entomological survey. This fact has already been observed in previous sub-regional surveys. As the autochthonous data could not be disaggregated, unexpected prevalence rates such as in DF, Western Amazon and S. Catarina were later revised, possibly explained by internal migrations from areas of greater endemicity. Other situations, such as the municipality of Barcelos (Amazonas), have characterized a focal characteristic of higher triatomine density, in this case, Rhodnius brethesi.
As foreseen, this INP allowed for a better targeting of the control program and was a very important argument for the prioritization of actions by the government, which took place through supplementary financial resources from 1983, which allowed full coverage of the endemic area. It also yielded important fruits in the dissemination of the diagnosis of chagasic infection throughout the country, as well as leading to a relevant development by enabling a national electrocardiographic survey (1980-86), performed by appropriate methodology and pairing of positive and negative serum individuals, which revealed variable patterns of morbidity in different regions.The developed methodology has enabled numerous focal or regional studies, spreading the use of collection on filter paper and generating the use of regional serology laboratories as embryos of state reference systems and training for the diagnosis of Chagas disease in the Unified System of Health (SUS) in Brazil. Another good product was the measurement of the impact of control actions by SUCEN in São Paulo (1980s) and the Brazil Program (1990s), showing a huge reduction in the incidence of the disease in young age groups in the worked areas. The INP also served, at a distance, as a model and reference for similar studies in several other countries, such as Mexico, Honduras, Bolivia, etc. It was, above all, an important milestone of Brazilian Public Health, demonstrating competence, methodological excellence and political will, emulated by correct and coherent scientific motivation.
About thirty years later, the results of the INP are being reviewed by a group of researchers, associated with the Ministry of Health and the University of São Paulo, with a view to determining prevalence rates by age group, which will allow comparisons to be made, and cohort studies in subsequent studies, especially regarding the impact assessment of control actions. It will also enable, indirectly, to estimate the importance of congenital transmission of chagasic infection through the prevalence study in young children. To complement it, in both directions, a new national survey is underway for individuals from 0 to 5 years of age, in a sample study of about 150,000 Brazilians, covering all states of the Federation, already being finalized (Brazil 2002). As expected, the prevalence found is extremely low, indicating very low degrees of transmission. Preliminary results from almost one hundred thousand samples revealed only 21 positive cases, ie, 0.021% prevalence, with positive results in only six states so far (CE, PB, AL, BA, MG and RS). A significant number of seropositive children before six months of age were negative when the reaction was repeated after seven months, which shows passive transfer of maternal antibodies, and also indicates a very low level of congenital transmission in Brazil (except, perhaps, in Rio Grande do Sul). The negative results for the Amazon Region show, until now, absence or minimal incidence of transmission in the age group examined in that area. The new survey should end in 2007 and may indicate, in addition to the positive impact of control actions, operational failures or new epidemiological situations, represented by the persistence of some residual pockets of natural or congenital transmission of Chagas disease.
Southern Cone
The Southern Cone Initiative (Incosul)
João Carlos Pinto Dias
Centro de Pesquisas René Rachou/Fiocruz
E-mail: jcpdias@cpqrr.fiocruz.br
Christopher John Schofield
London School of Tropical Medicine & Hygiene, Inglaterra
E-mail: cj.schofield@wanadoo.fr
It is one of the largest international cooperation programs against a metaxenic disease, covering an area larger than six million km2 and covering seven countries (Argentina, Chile, Uruguay, Paraguay, Bolivia and Peru (southern region), where are found most of the patients with Chagas’ disease in the Americas. Its main antecedents include the development of weapons and strategies for the control in the area, the medical, social and economic dimensioning of the disease problem by researchers and institutions such as the World Bank, the Pan American Health Organization, the unity and consensus among scientists dedicated to trypanosomiasis and the good results of well-conducted actions at regional scale. On a more contextual level, an initiative by African countries against onchocerciasis had been successful, and a spirit of inter-country cooperation around common interests was emerging in Latin America, such as Mercosul. Launched in July 1991, by resolution of the Southern Cone Health Ministers, Incosul was the first in a series of other Chagas disease “Initiatives” in the Americas and can be considered as a scientific response to a problem. still little addressed politically. In part, although control tools and strategies have been defined and available since the 1950s, national programs have not demarcated or assumed the necessary coverage and continuity due to factors inherent in the disease itself and its knowledge (slow evolution, lack of data), to the population involved (poor, rural, politically non-significant),to the lack of human and financial resources, to political immaturity and successive government discontinuities. In fact, since pioneering claims by scholars such as Emmanuel Dias (1959) and Cecílio Romaña (1979), a possibility of an institutional political agenda was already outlined, based on the importance of the problem (high prevalence and estimated morbidity as severe, along with the proven vulnerability to control the main forms of transmission) and the growing governmental responsibility for the health of poor populations, developed in Alma Ata through increasing pressure from the scientific community, particularly conveyed and catalyzed by PAHO, important meetings and workshops began in the 1970s on the topic of disease control.
In 1986, at the first meeting of the Southern Cone Health Ministers (organized by PAHO), the problem had already been understood as a responsibility of the government, and appropriate multinational cooperation actions were foreseen. In the 1980s, there were also antecedents of technical and scientific cooperation, such as the Brazil-Uruguay border work, Brazil Paraguay, Argentina-Bolivia, and the Human Health Program (El Salvador University, B. Aires). Particularly noteworthy are the achievements of the Brazilian Control Program (reorganized in 1975 and prioritized in 1983) and notable events such as the International Congress on the disease in Rio de Janeiro, 1979. In 1990, at a Pan American Sanitary Conference, the schizotripanosis was included among the candidates to regional elimination. Ideas for a Regional Initiative took shape in 1991 at a scientific meeting in Uberaba, Brazil, and were brought to the PAHO Board in May this year, and also discussed at a special session of the Italian Research Council a month later. At the same time, the Argentine Government officialized the fight against the disease as a high priority, and it was up to this delegation to present to the Brasilia Regional Health Conference on July 30, 1991, together with the Uruguayan Minister, the definitive proposal for the implementation of Incosul. It was the resolution 04-3 CS, which established the creation of an Intergovernmental Commission for Chagas disease, charged with the development of a program and action plan, with two fundamental objectives:
1. Interrupting vector transmission of protozoosis by eliminating domestic and peridomestic populations of Triatoma infestans in the endemic area, together with controlling domestic populations of other vector species occurring in the same regions, and,
2. Interrupting transfusion transmission, especially through the improvement of blood donor serological screening actions in the countries of the region.
The rationality of the proposed actions and strategy was based on field findings and accumulated scientific knowledge about the disease and the most vulnerable points of intervention. The lack of effective specific treatment, especially for the millions of chronic infected, made transmission prevention a priority. In the absence of a vaccine, the program focused on the chemical fight against vectors and the selection of blood donors through pre-transfusion serology, and it is estimated that this should include the prevention of at least 98% of the transmission occurring in the dispersion area. target species, as happened in the state of São Paulo. The target triatomine had been highly vulnerable to the control strategy pioneered in pioneering work in Bambuí and São Paulo (Brazil), which allowed to envision its elimination and showed immediate and persistent impact on the incidence of schizotripanosis. Four factors justified the priority action on T. infestans, the main (and often the only) transmitter of human Chagas disease in the Southern Cone:
• Its limited number of habitats, with all stages confined to artificial ecotopes (houses and peridomicile);
• Slow population growth rate and consequently low level of genetic rearrangements;
• Extreme degree of specialization, with very low rates of genetic variability, conditioning a very limited genetic repertoire for further adaptation (eg in the development of pesticide resistance), and,
• Total vulnerability to modern pyrethroid insecticides.
At the time, the epidemiological and control landscape in the six countries that launched the Initiative showed important pockets of triatomine infestation and transmission of infection in all countries, largely dependent on T. infestans, and almost exclusively in Brazil, other species were also involved. Vector control was organized in four countries (Argentina, Brazil, Chile and Uruguay), but lacked uniformity and continuity of actions. On the other hand, it was very incipient and diminishing in Bolivia and Paraguay, and a program was totally lacking in Peru. In fact, it was very clear at the various meetings leading up to the launch that the Initiative should be – first and foremost – an international cooperation mechanism that could sustain and enhance vector control in the four countries already in action, but also, above all, to be able to launch a minimally efficient program in Bolivia and Paraguay, which had a very serious epidemiological situation. From an institutional angle, PAHO had greatly matured its political and integrative role in the area, prioritizing the most transcendent targets from the medical and social point of view and willing to reinforce the technical references and its intermediary role in the provision of inputs and strategies against the main problems. including assuming tasks such as international bidding.
The overall scope of the Initiative came from the formal commitment of countries, with PAHO’s seal, to continued and shared work, with the initial targets set for ten-year compliance. The intergovernmental committees of the respective Ministries of Health have been set up and have been operating on a regular basis, holding annual evaluation, information exchange and programming meetings, with countries being rotated as headquarters. In addition, as a mechanism of cooperation and shared activity, throughout the fifteen years of operation, the concepts, criteria and strategies of action were systematized and standardized. Several workshops on the disease and its control were conducted, and training and capacity building programs were developed. In several countries, regular international oversight was carried out in all countries for field assessments and exchanges, all taking into account the main anti-vector and transfusion control actions. Incosul also served as a parameter and motivation for the demarcation of similar Initiatives in the Andean Pact Region, Central America, Mexico and the Amazon, in this order. In particular, it stands out as a gain in the encouragement of the scientific body, which currently works very well in terms of medical attention, diagnosis and large-scale entomological studies, improving the scope of attention and control.
After ten years of operation, the Initiative was reevaluated: Bolivia and Paraguay had launched, the first with an important BDI loan, the second with extraordinary rationalization of its resources and involvement of its Malariology (SENEPA). In other countries, surveillance was underway and national programs were sustained (even under administrative difficulties and due to the transition to decentralization). Southern Peru had been inserted and blood bank control was over 90% in all countries except Bolivia (then about 40%). Uruguay, Chile, much of Brazil, and 20% of Argentina’s endemic area had been certified for the elimination of transmission by T. infestans, an intermediate but very significant target. A key role had been fulfilled by PAHO in the Secretariat and in articulating the activities of the Initiative, also substantially helping to fund intergovernmental or technical supervisions, workshops, and meetings. Today, Incosul is alive and active. Household infestation levels have been drastically reduced in all countries, particularly Bolivia and Paraguay, with transmission disruption detected in most regularly worked areas. Blood banks are still under control (above 95%, Bolivia reaching 70 or 80%), trying to improve entomological surveillance. New age-specific treatment actions are multiplying and cure rates are expected to be over 60%. Evaluation criteria and control strategies are homogenized, as are diagnostic laboratories and input procurement activities. The supply of benznidazole and nifurtimox is being equated with the cooperation of PAHO and WHO, including for production in Brazil and El Salvador, respectively. New partners such as Doctors Without Borders, ECLAT and International Cooperation (Japanese, Belgian, Canadian, etc.) are reinforcing the Initiative. New fields of activity such as congenital transmission, medical attention to the infected and the control of secondary species are being worked on. At the epidemiological level, transmission rates and, probably, morbidity and mortality rates are very low. At the political and institutional level, PAHO is greatly strengthened and somehow reinforces the self-esteem and identity of the sanitarians of the Region, in line with reactive advances in the greater integration of the countries under consideration. In practice, the character of international cooperation has made many operational advantages possible for national programs, in addition to the annual obligation to report and to charge the progress of activities. Also notable is the easier and more frequent access of national technicians to their ministers and senior authorities. Intergovernmental commissions have been received by the Ministers of Health and even Presidents of the Republic on several occasions, which has always led to constructive talks about Chagas disease and its control, naturally facilitating planning and budget adjustments. In particular, at successive regional or continental health conferences, the agenda for reporting on the Initiative was opened. From the initial dream, Incosul became a tangible reality and proved to be possible, even in a still immature political context and a market economy scenario (difficult to apply in chagasic areas).
The main concerns and future challenges can be summarized as follows (Dias 2007):
- Maintain interest and priority over Chagas disease and its control
- Maintain the cohesion of the Incosul system
- Adapting to health system decentralization
- Achieve triatomine control in the peridomicile
- Leverage Education and Participation Actions
- Achieve coverage and access for infected Chagas disease patients
- Maintain the operational investigation necessary for improvement and possible new epidemiological and control situations
- Keep PAHO at the heart of the Initiative.
Looking to the future, new scenarios are presented, starting with the positive impact of actions taken on other transmission routes, as well as probably on the morbidity and mortality of human disease. The concentration of infected will be in high age groups, complicating the disease with other chronic degenerative diseases. Progressively, the areas of residual transmission will be reduced (if there is no discontinuity in actions), probably remaining in pockets of poverty, isolation and political-sanitary precariousness. New areas of expansion (as in the Amazon) may survive at agricultural borders. Urban foci and alternative modes of transmission (orally, for example) may occur randomly and unpredictably. A progressive lack of interest in Chagas disease research across the region is expected. However, research into strategies for maintaining surveillance and improving the detection and treatment of human disease cases are future priorities. In particular, the plan for technical renewal and sustainability of actions in view of the natural aging of the staff and the reduction of the interest and visibility of disease, complicated by the emergence of other priorities, must be considered. The technical teams have been renewed with difficulties in all countries, and the complexity of articulation and training of municipal staff have also increased, as a requirement for decentralization. Finally, it is appropriate to consider that this Initiative has not only been successful epidemiologically and scientifically. In fact, it fits into the scenario of the possibilities of conformation and rescue of Latin America, as a region that seeks its identity and its best political and social expression.
Vector control
The certification of the interruption of Chagas disease transmission by Triatoma infestans in Brazil in 2006
João Carlos Pinto Dias
Centro de Pesquisas René Rachou/Fiocruz
E-mail: jcpdias@cpqrr.fiocruz.br
On June 9, 2006, the Minister of Health of Brazil received a World Health Organization certification for the virtual elimination of Chagas disease transmission by the main regional vector, Triatoma infestans, reported by Dias in 2006. Carlos Chagas’s greatest dream came true, when he said that one day we would not lack the necessary energy to beneficially solve the enormous problem of the disease he was discovering, as described by Chagas in 1912. Great and a consecrated achievement, the certification was the product of the tenacious work of tenacious of scientists and thousands of anonymous sanitary guards, a saga initiated in Minas by Emmanuel Dias in the 1940s, as revised by Dias in 2002.
As base data, it should be noted that in the 1970s the Brazilian endemic area of American trypanosomiasis covered more than 2,450 municipalities, of which 711 with detection of T. infestans. At the time there were in Brazil more than five million people affected by the disease, with an incidence of about 100,000 new annual cases and mortality of over 10,000 annual cases. Less than five percent of blood banks-controlled donors, and more than seven hundred municipalities had their homes infested with T. infestans. People died early, especially young men, and it is estimated that more than 10,000 Brazilians died annually from the disease, especially from advanced heart disease, as reviewed by Dias and Coura in 1997. There was no vaccine or effective treatment. The medical and social problem was enormous, multitudes of orphans and widows incapacitated by serious heart disease. The only vulnerable links in the epidemiological chain were the insect vector, housed in poor rural huts, and blood banks, where between 5 and 7 percent of donors were infected with T. cruzi.
In the 1980s, thanks to pioneering work in Bambuí and Triangulo Mineiro (soon followed by the State of São Paulo), the good results and great pressure from Brazilian scientists on the Government, managed to prioritize a national program against the disease, covering itself the entire endemic area with the appropriate insecticide and by law establishing the mandatory selection of blood donors throughout Brazil, as revised by Dias in 2002.
In 1991, a major step was taken, bringing together the six Southern Cone countries in the common struggle, achieving exceptional results in Uruguay, Chile and parts of Argentina and Paraguay with the INCOSUL Initiative. To be certified, Brazil had, for years, millions of houses purged and inspected, dropping T. infestans catches from over 80,000 in 1979 to just over forty copies in 2005. With the launch of the Cone Initiative South, in 1991, the Brazilian Program prioritized T. infestans dispersion areas, concentrating on research and spraying activities. The T. infestans species of the Chagas disease triatomine vector was the main target of the Program due to its (i) great epidemiological impact, (ii) as it was restricted to the domestic environment, (iii) because it was introduced in the country (therefore being for being introduced into the country (thus being an eliminable species), (iv) for its high vulnerability to the indicated insecticides, (v) for its very slow population recovery capacity and (vi) for its low genetic plasticity, as reviewed by Schofield & Dias. Thus, in 1991 in the municipalities with history of presence of the species in the last five years (therefore, since 1986), intensive household surveys were carried out, spraying with modern pyrethroid insecticides all the locations where the species was detected and the locations to these neighbors, in full disinfectant schemes with re-purging between sixty and one hundred and eighty days. Following the actions, the species became focused and the purge was repeated in all houses of the locations found positive, as reviewed by Dias in 2002.
As the actions improved, the acute cases disappeared as by a miracle, and virtually no more infected young people and children were found in dozens of serological surveys. Blood banks were gradually controlled, very close to 100%, in fact, due to the wake of the HIV/AIDS epidemic. Much less “Chagas disease sufferers” die today, and the remaining two million infected are surviving longer, due to advances in medicine and greater coverage of health and social security care, as reviewed by Dias and colleagues in 2002.
Aiming a well-documented certification granted under scientific and consistent criteria, the successive Intergovernmental Commissions of Iniciativa do Cone Sul mandated multiple rigorous entomological surveys and epidemiological serum across the endemic area, which were presented and discussed at successive annual meetings, and submitted several International and National Evaluation Committees, routinely occurring since 1992. The effort undertaken since the beginning of INCOSUL was outlined by the experts based on the strategy of the National Chagas Disease Control Program (PCChagas Disease) itself, prioritizing the areas infested by the target species in the last five years and reinforcing the insecticide actions, with full spraying of the municipalities through two initial purges between ninety and one hundred and eighty days, according to the technique described by Emmanuel Dias in 1958, followed by inspection. the annual of these municipalities and full spraying of positive localities and their bordering, as described by Dias in 2002. With such a concentrated effort, the rates of home infestation, the densities of the insects captured, and the municipalities and positive localities gradually declined in all the worked areas. This was observed in several pioneering works, which justified and based the PCChagas Disease/Brazil, including to allow the prediction of the elimination of the species in Brazil, by Emmanuel Dias in 1957. The continuity of the work produced the expected fruits: for example, from 711 municipalities infested by the species and 84,334 T. infestans specimens captured in 1983, in 1991 (INCOSUL base) there were 322 municipalities with 16,937 specimens captured; in 1997, 1,080 specimens were captured in 106 infested municipalities, and in 2000 there were 256 insects in 53 municipalities, according to Dias described in 2002. The official website of INCOSUL describes the evolution of vector control in Brazil from 1993 to 2001. As expected, the targeting and reduction of triatomine-trypanosomal density were progressively occurring in all worked areas, with variable responses according to the complexity, continuity and rigor of the actions.
At the turn of the millennium, INCOSUL accepted certification targets by Federative Unit, certifying the states of São Paulo, Rio de Janeiro, Mato Grosso, Mato Grosso do Sul, Goiás and Paraíba.
In the following year, Minas Gerais and Pernambuco were certified, followed by Tocantins. Between 2004 and 2006 the last three states (RS, PR and BA) were certified. Throughout the Initiative, serological surveys followed showed the progressive negativity of chagasic infection in young populations. In 2001 a large survey was initiated among more than 100,000 children from zero to five years of age, which has resulted in very small positivity data (preliminarily below 0.02%) according to Brazil in 2002. The possibilities for T. infestans to return to pre-1980 levels in Brazil are remote, the species has no natural (wild) outbreaks in Brazil, and re-infestation from other border countries even with household outbreaks such as Bolivia, Uruguay and Argentina is unlikely. To begin with, due to the levels of infestation in such countries had also declined immensely in recent years, but also due to human migrations to our country are generally occurring in urban areas of Brazil, where T. infestans has shown enormous difficulty in colonization, according to Dias & Coura and Rocha & Silva.
For fair reasons, the country and the scientific community celebrated the victory, coincidentally on the eve of the centenary of the discovery of Chagas. In view of the certification, institutions such as Opas, o Ministério da Saúde e a Fiocruz were well advised to publicize the fact, understanding that the achievement was due, but also as a way to discuss with the society the subsequent perspectives and the work of consolidation. Looking ahead, it is the duty of conscience and responsibility to warn that the matter is not over: there is much to do. The infestation by T. infestans will hardly return in the country, because it is a vector introduced in the past (coming from Bolivia) and it has wild natural foci in Brazil. Eventual outbreaks, very small and scattered, have sporadically appeared in Bahia, Rio Grande do Sul, Minas Gerais and even São Paulo in past years, having been detected by the entomological surveillance system and fumigated intensively and effectively, with modern insecticides. Fortunately, no resistance of the species to these insecticides was detected in the country, unlike a few foci of resistance observed in northern Argentina and southern Bolivia, according to Dias in 2002.
Among us, the transmission of American trypanosomiasis is not restricted to T. infestans. Other species of “barbers” persist in the Brazilian environment, which may occupy the niche of the eliminated species, in a progressive colonization process. The elimination of T. infestans itself requires a consolidation process to detect and promptly destroy any residual outbreaks. In this context, the key word is epidemiological surveillance. Above all, it is necessary to take into account that from the year 2000 onwards, the Health Reform decentralized the control actions carried out by FUNASA, transferring them to the states and municipalities, which are autonomous to carry out the necessary surveillance. The logic and systematics of surveillance work are the same, but the continuity of actions cannot be undone. Municipal and state secretariats have to equip themselves, maintain technical staff, allocate relevant human and material resources, under the necessary political will of their managers. As most municipalities are small, unequipped and with no tradition in vector control, a major task will be at the state and sub-regional levels (state secretariats and regional health directorates) in the fields of motivation, supervision and capacity building of municipalities, as described by Dias in 2006. Epidemiology instances should be empowered to address rare situations such as the recent outbreaks of oral disease transmission in Santa Catarina, Bahia and Ceará, as well as to monitor possible resistance of “barbers” to current insecticides. Any congenital cases should be taken care of and also properly treated for people who have become infected in the past. Blood banks must remain controlled. Clinical research needs to continue, seeking a more effective drug against chronic disease.
How long, and who will do all this? Surely two or three decades of surveillance are needed, and the Unified Health System (SUS) will be largely responsible for the continuity of actions. The research and services that resulted in the present victory should continue, not allowing the interest in the endemic to disappear and the achievements to be reversed, or to take care of new or unexpected epidemiological situations, as described by Dias in 2002 and 2006. Final clashes against Chagas disease in Brazil will from now on involve other protagonists besides the valiant guards of SUCAM, of longing and heroic memory. The entire Health System should be involved, holding up surveillance and taking care of appropriate medical and social security care for infected persons. Mayors, Secretaries and Educators, among others, are required for the success of the new phase. In particular, a good structure and high level of competence of thePC Chagas Disease command teams at national and state level is required to enable and supervise the Program in thousands of municipalities, ensuring the continuity and effectiveness of the surveillance. Particularly, a great insertion of the Society in this vigilance is also required, to be obtained mainly at the expense of organized and continuous actions of Education. Unfortunately, such actions are not yet on the agendas of the Ministry and State Secretariats of Education, which deserves and urges special commitment by sanitarians, politicians and rulers.