Futuro Do Controle Chagas

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The future of Chagas disease control Chris J. Schofield1, Jean Jannin2 and Roberto Salvatella3 1

London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK Neglected Tropical Diseases Department, World Health Organization (WHO), 1211 Geneva 27, Switzerland 3 Pan American Health Organization (PAHO), Montevideo CP 11300, Uruguay 2

In the past 15 years, there have been major advances in the control of Chagas disease in most of the countries endemic for this infection. Attention now turns to the future continuity of surveillance and control interventions – especially in regions where control has been so successful that the epidemiological significance of Chagas disease is in steep decline. The effort and expenditure of the recent past cannot continue indefinitely, but a degree of surveillance and selective intervention will be required because of the risk of new infestations and infections resulting from adventitious silvatic vectors accidentally entering houses. In this review, we summarize the progress of multinational control initiatives against Chagas disease. In addition, we suggest that the most sustainable approach to future surveillance involves both the primary healthcare system and university-based teams, with progressively greater attention given to case detection and treatment. Such an idea is not new, but we believe that it merits extensive discussion because of the different ways that research and health interventions are financed and because of the need to establish clearer reporting links between the research communities and the national health authorities. Is Chagas disease conquered? On 9 June 2006, at their 15th annual meeting, the Intergovernment Commission of the Southern Cone Initiative against Chagas disease formally declared Brazil to be free of Chagas disease transmission due to Triatoma infestans. This represents a remarkable achievement considering that this species had been the primary domestic vector infesting rural houses in >700 municipalities of the 12 most populated states of Brazil, in addition to vast areas of neighbouring countries of the Southern Cone (Figure 1). Throughout Latin America, the transmission of Trypanosoma cruzi, the causative agent of Chagas disease (American trypanosomiasis), has been steadily reduced through a series of multinational initiatives coordinated by the Pan American Health Organization (PAHO: http://www.paho.org). In addition to Brazil, transmission has been effectively eliminated in Uruguay (1997), Chile (1999), substantial areas of Argentina, Bolivia and Paraguay, and parts of Central America. Global disease prevalence has been reduced from the 1990 estimates of 16–18 million people infected to 9 million (Box 1) and can be expected to decline further through demographic changes and as a result of current control interventions. But the health advances come at a Corresponding author: Schofield, C.J. ([email protected]). Available online 16 October 2006. www.sciencedirect.com

price – sometimes known as ‘el castigo del e´xito’ (lit. punishment of success) – whereby success in reducing the epidemiological burden invariably also reduces political interest and operational budgets. Yet it is premature to believe that Chagas disease is conquered. Experience from the programmes and campaigns against Triatominae throughout the Americas demonstrates that all domestic populations of this subfamily can and should be eliminated. It is less clear whether peridomestic populations of Triatominae can be so readily eliminated [1] and whether interventions should be contemplated against silvatic populations [2]. Because available techniques sometimes fail to eliminate all bugs inhabiting peridomestic habitats and because silvatic populations of Triatominae are widespread in the Americas, even the successful elimination of domestic populations might not be sustained against occasional reinfestation from peridomestic or silvatic habitats. Even without re-establishment of the main domestic vectors such as T. infestans and Rhodnius prolixus, a low level of accidental transmission can be expected because of silvatic or peridomestic species entering houses. The resulting transmission risks might be substantially lower than those attributed to the original domestic vectors – as shown by comparing human prevalence in areas with Triatoma dimidiata, which was almost four times lower than in areas with R. prolixus [3] – but are not insignificant. Moreover, when an adventitious silvatic triatomine contaminates comestibles in a house, the consequent oral transmission can result in a localized ‘microepidemic’ of acute cases of Chagas disease – as has occurred frequently in the Amazon region and elsewhere in Brazil [4–6]. In such situations, in which transmission occurs without the establishment of domestic vector populations, vector control becomes of questionable priority compared with prompt diagnosis and specific treatment. The future scenario seems likely to involve a diverse range of peridomestic and silvatic populations of Triatominae, some of which might colonize houses and some of which might mediate the transmission of T. cruzi without establishing domestic colonies. Such risks cannot be ignored and will require adequate approaches to surveillance, selective vector control, and treatment of new human infections. However, this must be organized within the anticipated framework of reduced political interest and reduced operational budgets. The balance of success The Southern Cone Initiative against Chagas disease followed a resolution by the Ministers of Health of

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Box 1. The rise and fall of Chagas disease

Figure 1. Apparent distribution of Triatoma infestans. (a) The maximum predicted distribution (in the absence of control interventions) from a geographic information system (GIS) thematic analysis, which reveals a few points outside the Southern Cone region (and in southern Chile and around the Peru–Bolivia– Brazil border) that might be suitable for T. infestans but from where this species has never been recorded. The predicted maximum distribution of T. infestans covers 6 278 081 km2 [38]. (b) An estimate of current distribution based on reports from the Intergovernment Commission for the Southern Cone Initiative, from which the estimated distribution of T. infestans has been reduced to 913 485 km2. Part (a) provided by David E. Gorla.

Argentina, Bolivia, Brazil, Chile, Paraguay and Uruguay, meeting in Brasilia (Brazil) in 1991. It focused on the interruption of T. cruzi transmission by eliminating domestic vectors (particularly T. infestans), together with extended screening of blood donors to reduce the risk of transfusional transmission, and the promotion of maternal screening for infection followed by specific treatment of infected newborns. Similar initiatives were agreed in 1997 for the Central American and Andean Pact countries, and in 2004 a surveillance initiative was announced for the nine countries of the Amazon basin. The progress of these initiatives has been widely reviewed [7–12]. Extensive screening of blood donors for T. cruzi infection is now carried out in most countries of the Americas (Table 1), and the distribution of domestic vectors has been markedly reduced, with transmission interrupted over vast areas. Because the rate of new infection has declined to zero over such substantial areas, estimates of prevalence have been progressively reduced to a current figure of 9.8 million people infected (Box 1). Of the 100 million people thought to be at risk from Chagas disease in 1990, 60 million now sleep without the risk of infection and without the nuisance and chronic blood loss previously caused by domestic colonies of Triatominae. The medical benefits of the control initiatives are reflected in the progressive decline of hospitalizations for Chagas disease [9]. This is primarily because of the reduced numbers of new acute infections but also seems to reflect a declining severity of chronic disease. This decline in severity might be a result of halting reinfection, an idea recently endorsed by studies of chronically infected mice in which rates of severe cardiac lesions were significantly lower in mice infected only once compared with mice that were repeatedly reinfected [13]. A similar effect might be reducing the likelihood of congenital infection because the apparent rate of transplacental transmission from www.sciencedirect.com

Carlos Chagas first published his report of ‘a new human trypanosomiasis’ in 1909 [39]. In the following years, there was extensive argument about whether the discovery was important, or even real [40,41], with the unnecessary polemic continuing even to the end of the 20th century [42]. The arguments were trivial, at times scurrilous, but probably contributed to the successive negation of a well-deserved Nobel Laureate in recognition of Chagas’ outstanding and detailed studies [41,43]*. By 1960, Chagas disease had been reported from all countries of Latin America, and the first WHO Expert Committee meeting on Chagas disease estimated global prevalence of the infection to be 7 million people, with perhaps another 35 million at risk [44]. Successive reports revised these estimates steadily upwards to a peak of 24 million people thought to be infected in the mid-1980s [45]. By the end of the 1980s, data from wide-ranging serological surveys provided more detailed estimates for most countries, leading to the oft-quoted figures of 16–18 million people infected with Chagas disease, with a further 90–100 million at risk [46,47]. From the same dataset of seroprevalence, annual incidence could be calculated at 450 000 new infections per year in the absence of control interventions, and the World Bank (http://www.worldbank. com) ranked Chagas disease as the most important parasitic disease of the Americas in terms of its socioeconomic impact, estimated as disability-adjusted life years (DALYs) lost because of the infection [48]. With the success of the Southern Cone Initiative, launched in 1991, and similar initiatives launched in 1997 for Central America and the Andean Pact countries, prevalence estimates have been steadily declining. As early as 1994, from reports of reduced incidence in Argentina and Brazil, overall prevalence was estimated to be 14 615 000 [49]. Estimates for these two countries, and Chile and Venezuela were then further reduced, although prevalence estimates for Ecuador and Mexico were revised upwards as a result of more-extensive serological surveys, leading to an overall estimated prevalence of 11 253 375 in 1998 [50]. The most recent estimate, from the Disease Control Priorities Project of the NIH (http://www.nih.gov) and World Bank, indicates an overall prevalence of 9.8 million people [51]. *

Carlos Chagas was formally nominated twice for the Nobel Prize in Medicine, in 1913 and 1921.

chronically infected mothers seems to be declining in areas where vectorial transmission has been interrupted. The Chagas disease control interventions also seem to have been extremely beneficial in financial terms. In Brazil, for example, annual treatment costs for Chagas disease were estimated to be approximately US$200 million per year in 1996, compared with the annual investment in control of approximately US$20 million; in Chile, annual treatment costs were estimated to be US$14–19 million, compared with annual intervention costs of approximately US$300 000. For the Southern Cone countries as a whole, aggregate costs since 1991 have been approximately US$320 million [9], which is within the initial estimates of US$190–350 million [14]. The internal rate of return on this investment was initially predicted at just over 14% [11] but point studies show actual rates of return of 30% in Brazil [15] and >60% for the province of Salta in Argentina [16]. But, against the social, medical and financial successes of the Chagas disease control initiatives, some difficulties must be acknowledged. Although 60 million people no longer share their homes with blood-sucking Triatominae, 40 million people remain at risk. Although 5 million new infections of Chagas disease have probably been

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Table 1. Screening of blood donors for Trypanosoma cruzi in Latin Americaa Southern Cone countries Argentina Bolivia Brazil Chile Paraguay Uruguay Andean Pact countries Colombia Ecuador Peru Venezuela Central America Belize Costa Rica El Salvador Guatemala Honduras Nicaragua Panama

Coverage (%)

Seropositive (%)

100 86 100 75 b 99 100

4.50 9.90 0.61 0.47 2.80 0.47

99 100 99 100

0.98 0.15 0.26 0.67

100 100 100 100 100 100 98

0.40 0.34 2.46 0.79 1.40 0.49 0.90

a Table based on data from Ref. [26], with revisions from 2006 Intergovernment Commission reports. b 98% in endemic regions.

prevented, transmission is still apparent in several countries and might even be increasing in parts of Argentina [17], Venezuela [18] and the Amazon region [4]. Mexico, Peru, Colombia and Costa Rica still have no national programme for the control of Chagas disease vectors, and programmes for screening blood donors remain below targets in Bolivia and Mexico. But perhaps the greatest difficulty lies in the premature idea that Chagas disease has been conquered, and the consequent dismemberment of executive services responsible for surveillance and control. Today, only four countries in the Americas – Nicaragua, Ecuador, Paraguay and Panama – retain an executive structure with national responsibility for the control of Chagas and other vector-borne diseases. In the other countries, responsibility has been devolved to state, provincial and municipal authorities, with – at best – a centralized authority retained only for statistics and legislation. Such decentralization risks heterogeneity of action (and inaction), discontinuity of programme implementation (especially of surveillance) and inefficiencies due to duplication of administrative effort – precisely the problems that the multinational initiatives, with all countries working simultaneously within a coordinated framework, were designed to avoid. Vector control strategy When the Southern Cone programme was launched in 1991, it was believed that the main vector in the countries affected, T. infestans, could be eliminated over most of its range. This idea was based on historical reconstruction [19] progressively supported by genetic studies [20–22] indicating that, in most Southern Cone countries, T. infestans had been accidentally imported in relatively recent times, particularly during the past 100 years. The control interventions could be seen as correcting a historical accident and restoring the vector distribution to its origins. Similar arguments were implicit in the idea of eliminating www.sciencedirect.com

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R. prolixus from Central America, which seems to have been accidentally imported from a Venezuelan origin early in the 20th century [23,24]. Such arguments might also be applicable to populations of T. dimidiata in Ecuador and northern Peru, which seem to have been accidentally imported in pre-Columbian times [25,26], and to Rhodnius ecuadoriensis in parts of northern Peru, which might have been imported within the past 50 years [27]. To a large extent, however, much of what seemed possible in these elimination concepts has already been achieved. T. infestans does seem to have been eliminated over much of its range, R. prolixus is disappearing from Central America, and the recently launched national programme in Ecuador will probably have substantial success against domestic T. dimidiata. The imperative to eliminate all domestic populations of Triatominae derives not only from their capacity to transmit T. cruzi but also from their high nuisance value and contribution to chronic blood loss [28,29]. Although this must remain central to future programmes, the underlying rationale will be different. The idea of large-scale elimination was justified as a strategy to prevent future reinfestations by that species. However, where reinfestation is expected to be less frequent and probably due to local silvatic species, the more appropriate strategy will be of periodic intervention when householders report new infestations. The effectiveness of such an idea depends on three features: (i) a system to receive and acknowledge householder reports; (ii) a system to collate such reports with other information of operational and epidemiological relevance; and (iii) capacity to implement selective interventions in response to reports of individual and/or clustered infestations. Such a design has already been proposed and tested for the control of Chagas disease in areas of Central America where the main vector is T. dimidiata (Box 2). This species retains silvatic and peridomestic populations in many areas, from which it can gradually recolonize houses from which the original domestic population has been eliminated. The proposed strategy involves an initial programme to eliminate all existing domestic populations, followed by an annual cycle of accumulating reinfestation reports and an annual round of selective interventions in response. In parallel, progressively greater emphasis is given to active case detection and treatment, especially among school-age children. Case detection and treatment The change from an elimination strategy to one of continual selective intervention carries implicit acceptance that occasional accidental transmission might occur – chiefly due to adventitious silvatic vectors entering houses. In the past, such an idea was seen to be problematic because of the belief that treatment of human cases would be satisfactory only if administered within the early acute phase of infection, although accumulating experience begins to indicate otherwise. The two drugs available for specific treatment of T. cruzi infection are nifurtimox (Lampit1), launched by Bayer (http://www.bayer.com) in 1967, and benznidazole (Rochagan1, Radanil1), launched by Roche (http:// www.roche.com) in 1972. Initially shown to be effective

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Box 2. Steps in the proposed operational strategy for the control of Triatoma dimidiata in Central America The following information was adapted from Ref. [52]. 1. In each school in the endemic areas, serological testing of a random sample of 30 schoolchildren using the Chagas Stat-Pak1 and a questionnaire for possible recognition of Triatominae. (a) If all tests are negative and no child reports having seen T. dimidiata in their house, the school catchment area apparently has no active transmission. (b) If three or fewer children are positive for Chagas disease, the school catchment area is considered a medium priority for entomological survey and control interventions. All positive children given quantitative ELISA for confirmation, followed by specific treatment with benznidazole or nifurtimox. (c) If more than three children are positive, the school catchment area is considered a high priority for entomological survey and control interventions. All children in school are tested by Chagas Stat-Pak1, with all positives given quantitative ELISA for confirmation, followed by specific treatment with benznidazole or nifurtimox. 2. School catchment areas can now be ranked in terms of apparently active transmission. In this order, they can be visited for entomological surveys in each house, followed by residual spraying of all houses confirmed to be infested; all houses are identified by their geographical coordinates, and all householders are informed about T. dimidiata and asked to report all such insects to the local health centre. 3. Health centre reports are collated and mapped during the year. Isolated reports of infestation can be checked, with the houses sprayed if infestation is confirmed; if several reports indicate a cluster of infested houses, all houses in the apparent cluster can be checked and sprayed. 4. If, during a reporting year, no reports are received from houses in what was a previous infestation cluster, the cluster can be checked to make sure that the absence of reports is not due to a breakdown of the reporting system. 5. Steps 1 and 2 can be repeated in accordance with epidemiological assessment and available resources.

at curing acute infections, these drugs were largely discarded for treatment of chronic T. cruzi infections because of a high likelihood of serious side-effects combined with an apparently low likelihood of radical cure [30]. Such ideas are being challenged by evidence that serious side-effects are much less frequent in younger age-groups and that reversion to seronegativity after treatment can occur in a large proportion of patients – especially children – although this might not occur for several years [31,32]. National policy in several countries is now to offer specific treatment to all cases that occur in patients under 14–15 years of age, whether acute or chronic, and current research on adults in Argentina indicates that this policy could be extended to a much wider range of patients [33–35]. The World Health Organization (WHO: http:// www.who.int) is working in partnership with industry to ensure adequate supplies of both drugs. Nifurtimox is now manufactured by Bayer in El Salvador and can be made available free of charge through WHO and PAHO; the supply of benznidazole has been guaranteed by Roche until adequate production can be sustained by the Brazilian laboratory Laborato´rio Farmaceˆutico do Estado de Pernambuco (LAFEPE) – although neither the cost of the drug nor procedures for its distribution outside Brazil have been finalized. A further issue to be resolved concerns www.sciencedirect.com

the feasibility and the most appropriate techniques for active case detection of asymptomatic Chagas disease; this is actively pursued in Central America, using the Chagas Stat-Pak1 for a rapid assessment of schoolchildren [36], followed by quantitative ELISA to confirm positivity and monitor changes in serological titres after treatment (Box 2). In some countries, however, treatment is discouraged for non-acute cases, and may be authorized only after residual house spraying to remove vectors. Outline for the future The future scenario for Chagas disease control must continue to be based on the idea of eliminating all existing domestic populations of Triatominae but then accepting that reinfestation might occur or that adventitious silvatic Triatominae might enter a house and cause disease transmission without establishing a new domestic colony – as in Amazonia. In such a scenario, large-scale vector control campaigns of the style of the multinational initiatives would become progressively less relevant as existing domestic infestations are eliminated. However, surveillance and focal interventions against newly established domestic colonies of Triatominae would be required. In addition, improved parasitological surveillance would be warranted, with the idea of offering specific treatment to all new cases of infection and probably to asymptomatic chronic cases. The key issue is how to maintain entomological and parasitological surveillance, especially as the incidence of new infestation and infection declines. Much is written about the importance of community participation, and it is indeed a key component both of the initial interventions and of the subsequent surveillance, but community interest wanes when there is little to report, so an additional approach is required. This could be provided by university-based research teams [37] but would be of little relevance without a clear reporting structure so that data can be collated and selective interventions undertaken where necessary. Perhaps one of the greatest achievements of the multinational initiatives against Chagas disease is that surveillance and control of the disease and its vectors are currently on the agenda of all endemic countries, even those such as Belize, Guyana and Suriname, where the problem has been minimal. This means that a degree of vector and disease surveillance will be carried out in all of these countries so that, with adequate data collation, it should be possible to detect epidemiological trends and potential new outbreaks of transmission. But such an idea must emphasize the need for adequate collation of available data at national and regional levels, which at present is often lost between official reports and formal publication. There is currently no international system – beyond review articles – that can monitor and collate epidemiological data over a continental scale. Concluding remarks: towards a sustainable end-point The most consistently successful programme against Chagas disease has been that of the Brazilian state of Sao Paulo – a programme initiated with a state-wide ‘attack phase’ in 1964–1967 and continued through a series of strategic adjustments in accordance with the changing

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Box 3. Current and future phases in Chagas disease control Phase 1 1.1 Elimination of all existing domestic populations of Triatominae; this requires one or two spray rounds, designed to treat all houses in infested localities in the case of Triatoma infestans or Rhodnius prolixus, or targeting only those confirmed to be infested with other vectors. 1.2 Organization of community-based surveillance networks. These report the presence of residual (or new) domestic infestations to a local voluntary post (posto de informacion sobre triatomineos), with adequate reporting to the local health authorities, entomological confirmation and written acknowledgement of householder reports, followed by selective intervention where required or requested. 1.3 Improved and standardized screening of blood donors (with clinical follow-up and psychological counselling for those found to be infected). Phase 2 2.1 Continuation and support for community-based surveillance networks, with selective interventions carried out by local health authorities. 2.2 Development of the community networks as general health surveillance systems linked to the primary healthcare system of that locality. 2.3 Routine blood-slide microscopy from all febrile cases (combined with haemoconcentration techniques where possible) to diagnose new infections and offer prompt specific treatment as necessary. 2.4 Encouragement of university-based field teams to carry out investigative projects designed to evaluate the progress of Chagas disease control and study the biology of non-domiciliated vectors in specific regions (this could involve logistic support from the local health authorities and financial support from the national research councils). Phase 3 3.1 Development of a national database for epidemiological surveillance of Chagas disease using GIS techniques, with mandatory reporting of all new cases of infection and all findings of domestic, peridomestic and silvatic populations of Triatominae (such reporting could be a condition of research council support for academic research teams and of national support to local health centres). 3.2 Development of the Chagas database and reporting system for other pathologies, ideally linked to a small ‘rapid deployment force’ of highly trained professionals able to support emergency vector control or public health interventions in all parts of the country. Phase 1 is well advanced in most countries, and a small number – notably Brazil and some Central American countries – is advancing with phase 2. None, however, has yet advanced to phase 3.

epidemiological circumstances (D. Wanderley, PhD thesis, Universidade de Sao Paulo, Brazil, 1994). Although T. infestans was probably eliminated from Sao Paulo by 1990, a system of community-based surveillance is maintained for secondary vectors (e.g. Triatoma sordida and Panstrongylus megistus), together with centralized data assimilation and selective interventions where necessary. Sao Paulo has been effectively free of Chagas disease transmission since the early 1990s and offers a model for the various phases in Chagas disease control. This includes the essential idea that, although domestic vector populations can and should be eliminated, there will be a perennial need for surveillance, data assimilation and selective interventions. In addition, a primary healthcare approach is required to detect and treat new cases of Chagas disease (Box 3) – although this will require a consensus about the most appropriate diagnostics and treatment regime. www.sciencedirect.com

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At national and regional levels, however, the focus in recent decades has been on eliminating the primary domestic vectors. Less thought has been given to the design of an institutionally stable end-point to maintain the advances, prevent recrudescence of transmission and respond adequately to new cases that might occur. Such a system will depend crucially on a capacity to seek and assimilate georeferenced epidemiological data – from whatever source – and to organize serological screening, and treatment of new cases, together with selective vector control interventions where necessary. Medical professionals and the primary healthcare system, together with schools (Box 2), would have a fundamental role but only with adequate training and clear reporting lines to the epidemiological surveillance centre. In many countries, academic research teams also have a significant role in the surveillance and control of Chagas disease, and this should be encouraged as an important complement to the health surveillance structure. It is a way to accord national relevance to research, improve interactions between health and education authorities, and might come to represent the primary source of specific epidemiological information. Acknowledgements This review has benefited from international collaboration through the Latin American Network for Research on the Biology and Control of Triatominae (ECLAT). We also thank Sergio Sosa-Estani for additional information about current trials of specific treatment for Chagas disease in chronically infected adults, and David E. Gorla for access to unpublished geographic information systems (GIS) studies of Triatoma infestans distribution.

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