Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 94, Suppl. I: 103-121, 1999 103 The Evolution of Chagas Disease (American Trypanosomiasis) Control after 90 Years since Carlos Chagas Discovery JCP Dias/+, CJ Schofield* Centro de Pesquisas René Rachou-Fiocruz, Caixa Postal 1743, 30190-002, Belo Horizonte, MG, Brazil *Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Coordina- tor of the European Community & Latin America Network on Biology and Control of Triatomines (ECLAT), London WC1 E7TH, UK

Key words: Chagas disease - control - trypanosomiasis

INTRODUCTION AND HISTORICAL ASPECTS Chagas disease can be transmitted by several Chagas disease is one of the most serious para- mechanisms. Numerically however, vector-borne sitic diseases of Latin America, with a social and transmission is the most important, generally ac- economic impact far outweighing the combined counting for over 80% of all transmission of T. cruzi effects of other parasitic diseases such as malaria, to humans. Direct observations, and mathematical leishmaniasis and schistosomiasis. Serological data models, indicate that social and political develop- indicate well over 16 million people are infected ment of the endemic regions could be sufficient to with the causative agent, Trypanosoma cruzi, with control Chagas disease (and many associated prob- a further 100 million people considered at risk lems). Yet this route is complex in the less devel- (WHO 1991). The World Bank, in 1993, calcu- oped regions, largely because it involves rural ar- lated an annual loss due to Chagas disease of eas that traditionally receive little political priority 2,740,000 ‘disability-adjusted life years’ (DALYs), (Caldas Jr 1980, Litvoc 1985, Dias 1987). But the representing an economic loss to the endemic coun- epidemiological patterns of Chagas disease present tries of Latin America equivalent to over US$6.5 a series of vulnerable points that can be attacked billion per year (WHO 1997, Schofield & Dias through national or regional control programmes. 1999). Regrettably, neither vaccines to prevent infection, Control of Chagas disease is now given high nor drugs suitable for large-scale treatment, are cur- priority by Latin American governments, partly rently available, but techniques for the interrup- because of its high economic impact and conse- tion of transmission are now well established and quent financial benefits of effective control (eg. are being progressively implemented throughout Schofield & Dias 1991, Akhavan 1996, Basombrio the endemic areas of Latin America. et al. 1998) but also because of the technical feasi- Today, there is a general consensus that human bility of control through the interruption of trans- Chagas disease will be overcome through inter- mission. In 1991 a major regional initiative to ventions against different levels in the cycle of eliminate Chagas disease was launched by the gov- transmission (WHO 1991, Dias 1993a, b, ernments of Southern Cone countries (Argentina, Schofield 1994). At the primary level, interven- Bolivia, Brazil, Chile, Paraguay, and Uruguay) (cf. tions are designed to prevent transmission. At the Kingman 1991, Schofield & Dias 1999), which has secondary level, interventions are designed to pre- recently been followed by similar initiatives in vent or inhibit disease in cases where infection has Andean Pact countries (Colombia, Ecuador, Peru, occurred, while at the tertiary level the interven- and Venezuela) and Central America (El Salvador, tions seek to limit human incapacity and reinte- Guatemala, Honduras, Nicaragua) (Schofield & grate infected people into the community (Dias Dujardin 1997, WHO 1997). 1997). This paper presents a summarised overview of the control of Chagas disease, considering some historical aspects and the general context of the fight against the disease in endemic countries. The discovery of Chagas disease constitutes one of the most exciting pages of the history of medi- E-mail: [email protected] cal science. In parallel with the clinical, epidemio- Received 9 June 1999 logical, biological and pathological aspects that he Accepted 9 August 1999 studied, Carlos Chagas stated very early that, first 104 The Evolution of Chagas Disease • JCP Dias, CJ Schofield of all, control of the disease represented a “duty cific treatment would certainly present difficulties for the State”. In his admirable work, Chagas in trypanosomiasis. Because effective insecticides pointed out that control of transmission would be against triatomine bugs did not exist at that time the most desirable goal and the best strategy in the (in contrast with malaria, for which mosquito lar- fight against the disease which now bears his name. vicides were available and used by Chagas), his His comprehension about the problem was estab- attention was directed to housing improvement. lished in three basic points (Chagas 1911): (1) the One of Chagas’ disciples, HC Souza Araujo (1919), epidemiological and social impact of the disease had an important influence, proposing in the state would be extremely relevant, considering the very of Paraná (Brazil) a law making compulsory house large dispersion of the vector and the possibilities improvement in endemic areas to prevent HAT. of high prevalence of human infection in Brazil However, this law was never implemented during and other countries of Latin America; (2) the basic Chagas’ life, and there were no government or re- focus on governmental programmes against the gional efforts to break the disease transmission until disease would be of preventive nature, since the the end of the 1940s (Chagas died in 1934). But cure of human T. cruzi infection had many techni- Chagas was conscious of the difficulties of HAT cal problems and the control of transmission cer- control, in spite of his tremendous anxiety to face tainly would be the most vulnerable point to inter- the disease in all possible ways. Very soon he per- vention in the epidemiological chain, and; (3) the ceived that political will never would come unless fundamental point for intervention would involve the disease and its social and economical impact vector control. Nevertheless, Chagas suspected that were recognised. An entomological line of research other mechanisms of transmission existed, for in- at laboratory and field level was swiftly developed stance, congenital transmission. in “Manguinhos” and in several parts of the Ameri- Carlos Chagas very soon realised that political cas, providing important information about vector aspects might primarily be involved in disease and parasite distribution throughout the continent. control, since he perceived that human American But this line would not be sufficient, since the basic trypanosomiasis (HAT) was basically a disease af- political subject was not the parasite, but human fecting extremely poor rural populations who were disease. At this point, Chagas worked in several living in very bad housing conditions, such a situ- projects seeking to clarify the epidemiology of ation providing an ideal condition to vector HAT, particularly in relation to diagnosis and clini- colonisation. Chagas stated that the main frame for cal characterisation of the chronic phase of the dis- the HAT undoubtedly would the house infested ease – especially chronic heart disease (Laranja by triatomine bugs and clearly said in his famous 1949, Dias 1988). Nevertheless, during the first II Conference (Chagas 1911): 30 years after the discovery, knowledge of the dis- “Cumpre salientar que o principal facto ease remained polarised between entomological epidemiologico da moléstia é constituido por um aspects and the acute phase of HAT – reflecting insecto, companheiro constante do homem nos the fashion for microbiological research of that domicilios e, por isso mesmo, facilmente attingivel time. Another constraint was the lack of interest of às medidas de destruição....Medidas sanitarias European and North American researchers to study nesse sentido, visando, sobretudo, modificar as a strictly Latin American pathology. At that time, condições de habitabilidade .....importariam, sem Latin American countries were independent and dúvida, em acto administrativo do maior proveito”. their attractive mines of gold, silver and other pre- (“It is clear that the basic epidemiological fact cious minerals were rapidly becoming non-produc- of the disease is constituted by an insect, a con- tive. European attention was focused on their colo- stant companion of men in their houses, and thus nies in Asia and Africa, where classical institutes easily vulnerable to destruction....Sanitary mea- for tropical medicine were installed. Carlos Chagas sures in this sense, especially improvement of the and Oswaldo Cruz were conscious of these facts, living conditions, would certainly represent an but still sought to interest the international scien- administrative act of major importance”). tific community in the new pathology discovered Chagas was an excellent malariologist, prob- in Lassance. Chagas’ works were therefore pub- ably the most important in Brazil at that time. He lished in the USA, Europe and Argentina, written was in charge of an anti-malaria campaign in Minas in English, French, German and Spanish. Impor- Gerais when he discovered the trypanosomiasis. tant figures such as Hartmann, Prowazek, Nevertheless, since his first works he stated very Metchnikoff, Brumpt, Crowell and Laveran were clearly what were the main differences in clinical contacted, but Chagas reserved his greatest efforts and pathological aspects of these diseases, and also to prepare his own group at the national level. In discussed possible strategies of control. Vaccina- 1913 Chagas induced his assistants C Guerreiro tion was not feasible for either disease, and spe- and A Machado to apply the Bordet and Gengou Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 94, Suppl. I, 1999 105 technique to detect anti-T.cruzi antibodies in cre and jealous enemies aggressively questioned chronic patients. At the same time he began to de- Chagas) he never lost his hope in the force of sci- velop his own research on chronic disease, latterly ence to control diseases and to improve health for with the assistance of Eurico Villela and Evandro the people: Chagas who chiefly focused on chronic cardiopa- “The European nations, zealous of their colo- thy. For them, it soon became clear that chronic nies in the tropics, have organised the expertise - heart disease was the most relevant aspect of all in their universities and in their great research in- HAT (Dias 1988, Coura 1997). Once more Chagas stitutes - to the study and the teaching of pathol- was proved correct, but again he could not escape ogy in tropical countries. Here, not so much the from another personal frustration: in spite of his economic interests, but the most exalted duties and magnificent descriptions, the clinical and patho- provident nationalism oblige us to study and to logic aspects of chronic disease were not appreci- research the Brazilian nosology, in order to pro- ated by the majority of scientists of his time. In vide the improvement of our race, of rare native parallel, serological diagnosis of chronic infection attributes, and to reach, by the prophylactic method, only became generalised in the 1940s following the sanitary redemption of our large territory” successful work carried out in Bambuí (E Dias & (Chagas 1926). cols) and in São Paulo (P Freitas & cols); in the THE MODERN ERA OF CHAGAS DISEASE CON- same way, chronic chagasic cardiopathy only be- TROL came widely at the end of the 1940s, again fol- Vector control lowing detailed studies by the Bambuí group In the 1930s, an increasing number of acute (Laranja et al. 1956, Dias 1988, Coura 1997). Data cases were being detected in Argentina by Mazza, collected by Laranja (1949) about the evolution of Romaña, etc., and in Uruguay (by Talice & Rial) knowledge and the description of the chronic following important work by MEPRA in Argen- chagasic cardiopathy (CCC) can be summarised tina – particularly the description of Romaña’s sign as follows: (a) until 1930, cases of CCC were only as a diagnostic indication of acute infection. There described in Lassance, by Chagas and Villela; (b) were attempts at prevention, chiefly by Talice and from 1930 to 1944, only 45 new CCC cases were Mazza, focusing again the question of housing described in Brazil, all from Lassance; (c) the first improvement. But systematic control efforts only case of CCC described outside Brazil was pub- began to develop when a small branch of the lished in Argentina, 1934, where 133 other cases Oswaldo Cruz Institute was set in Bambuí, Minas were detected up to 1944; ( d) in Brazil, between Gerais, where dozens of acute cases were detected 1944 and 1948, another 600 cases of CCC were by Vianna Martins (a general parasitologist) and registered, mainly from Bambuí; (e) in contrast, subsequently by Emmanuel Dias (one of Chagas’ from 1909 to 1948, more than 2.000 acute cases disciples), in the beginning of the 1940’s. This were registered, the majority of them in Argentina, “Centro de Estudos e Profilaxia da Moléstia de Brazil and Uruguay. Chagas do Instituto Oswaldo Cruz “ represents the Chagas remained patient. In his last works and first institutional effort to promote Chagas disease conferences, he still emphasised the chronic as- control. It was promoted through the influence of pects of the disease, certainly waiting for confir- Evandro Chagas and Amilcar Vianna Martins and mation of his findings elsewhere. In 1932 (pub- implemented by Emmanuel Dias, under the deci- lished in 1934) he wrote: sion of the Institute Director, Dr Henrique Aragão. “Firstly verified in Brazil, in the hinterland of In 1943/44, Dias made a complete survey of the Minas Gerais, this other human trypanosomiasis municipality, finding astonishing epidemiological is not an exclusive disease of our country, since it indicators such as a house infestation rate of 70%, was also recognised in other countries of South natural infection of the bugs by T.cruzi around 30- and Central America. In Argentine, in Tucuman 40%, and 45% of positive serology among rural and Catamarca provinces, several clinical cases children under 10 years old (Dias 1944, 1997). Two were observed, with the verification of the para- basic research lines were established between 1943 site in their peripheral blood, as well as in Peru, and 1961: (a) control of transmission, focused Venezuela, San Salvador and, recently, in Panamá. mainly on vector control, and, (b) the study and But we still have little knowledge concerning the clinical characterisation of chronic heart disease. endemic index and the social importance of the The first line was immediately started by means of disease in these other American countries...” physical and chemical control of domestic vectors, (Chagas 1934). including house improvement and intensive health At the same time, in spite of the sad episode of education. The second line demanded development the National Academy of Medicine (where medio- of a complex research structure, involving cardi- 106 The Evolution of Chagas Disease • JCP Dias, CJ Schofield ologists (mainly Dr Francisco Laranja), general were available, at least at the experimental or theo- doctors (Dr Genard Nóbrega), serologists (particu- retical level. E Dias recruited to his group a bril- larly Dr Julio Muniz) and pathologists (Drs liant medicine student, José Pellegrino, who helped Magarinos Torres and A Miranda), all leaded by him very much in the work. Other research groups Emmanuel Dias. The first clinical studies were were also developing work on the control of performed between 1945 and 1956, resulting in Triatominae, chiefly in Brazil [Freitas (1963) in S. several publications about acute and chronic Paulo, Szumlewiecs (1953), in Rio] and in Ar- Chagas disease, focused particularly on cardiac gentina (Romaña & Abalos 1948). Nevertheless, pathology. The group also looked for experimen- large-scale control programmes could not start until tal models, succeeding in reproducing all aspects the beginning of the 1960s, because of the lack of of the human disease in dogs and monkeys (Laranja political decision and the absence of national struc- 1949, Dias 1993-c). In 1956 the group published tures capable of implementing control programmes. their conclusions about Chagas cardiopathy in Cir- For these reasons, Emmanuel Dias put his best ef- culation (the most important medical journal on forts to stimulate the national director of the Bra- cardiology, at that time), a work which is still con- zilian Endemic Diseases Programme (DNERu), Dr sidered as the definitive contribution about the Mário Pinotti, to launch a regional control trial in characteristics of chronic Chagas heart disease Uberaba in the State of Minas Gerais during 1951- (Laranja et al. 1956). In relation to disease preven- 1952. The results were excellent, and stimulated tion, Dias easily reached the conclusion that the other regional initiatives during the 1960s such as transmission of T. cruzi to man was directly de- the São Paulo State Programme (by Freitas, Rocha pendent on infected vector populations in human e Silva & others) and large scale trials carried out dwellings, realising the correlation between inci- in Argentine (by Cichero, Soler and Abalos), in dence and prevalence of human disease and the Chile (by Neghme & Schenone) and in Venezuela level of infested houses (Dias 1944, Hayes & (by Pifano & Gabaldón) (Dias 1993-b, 1988). Na- Schofield 1990). In his early attempts, Dias tried tional programmes followed, all based on chemi- everything he could imagine to kill or remove cal control methods against domestic Triatominae triatomines from human dwellings. His early ap- and using the rationale and strategies of the suc- proaches included throwing boiling water, caustic cessful malaria campaigns. In Venezuela, as well soda, or kerosene, over the walls of infested houses, as insecticide application, a national programme and even limited attempts using military flame to improve rural dwellings was implemented, capi- throwers. At that time, the best results were ob- talising on the strong economy and public health tained employing a mixture of rotenone and kero- expertise of the country at that time (Dias 1988). sene (C23 H22 O6), by which an enormous knock Through the 60s and 70s, a series of different con- down effect was obtained against domestic Tri- trol approaches were tested (Table 1) but insecti- atoma infestans and Panstrongylus megistus infes- cides remained the most effective and efficient tation. This gave an immediate reduction in the approach (Dias 1957, 1994, 1997, Rabinovich et number of acute cases, especially when houses al. 1979, Rocha e Silva 1979, WHO 1991). were also submitted to physical improvement (Dias The introduction of synthetic pyrethroids in the 1944). Several other approaches have been tried early 80s was a major advance in campaigns to but with the development of synthetic insecticides control domestic Triatominae. All those currently in the 1940s, chemical methods of vector control used are alpha-cyano-substituted pyrethroids, ap- have become the most widely used technique, plied as wettable powder (WP) or suspension con- backed by low-cost systems of house improvement centrate (flowable) (SC) formulations using con- and community health education. DDT was found stant pressure backpack sprayers, generally of 8 ineffective against most species of Triatominae or 10 l capacity. These pyrethroids are fast acting (although it does have a latent effect against some against the target Triatominae, and also provide species) but good results were obtained in early transient control of other domestic insect pests such trials with another organochlorine, gamma-BHC as fleas, cockroaches and houseflies. They are (also known as HCH, Lindane or Gammexane) considerably more expensive per kg than the pre- (Dias & Pellegrino 1948, Romaña & Abalos 1948). viously used organochlorine insecticides, but are BHC (and/or dieldrin) remained the most widely applied at much lower doses (Table II). Compara- used compound against domestic Triatominae un- tive studies show them to be considerably more til the late 1970s when it was progressively replaced cost effective (eg. Oliveira Filho 1989, Schofield with synthetic pyrethroids (Schofield 1994, Dias 1994) and they have the additional advantages of 1997). greater acceptability to householders (being By the end of the 1940s all the main tools and odourless and leaving no stains on the walls after strategies for the control of domestic Triatominae application) and safety (2500 times less toxic to Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 94, Suppl. I, 1999 107

TABLE I Methods of control tested against domestic Triatominae Conventional insecticides Organochlorine compounds (eg. BHC & Dieldrin), organophos- phates (eg, malathion, fenitrothion), carbamates (eg. propoxur) and modern pyrethroids (see Table II); advantages: cheap, effec- tive, available, safe for mammals; disadvantages: loss of residual activity on porous mud walls and peridomestic habitats Insect growth regulators Eg: juvenile hormone mimics, precocenes; advantages: highly specific; safe for mammals; disadvantages: slow acting, active against only a few stages Insect pathogens (eg. nematodes, fungi) Advantages: safe for mammals; disadvantages: greatly limited by climatic factors, difficult application Other biological control (eg. egg parasitoids) Advantages: safe for mammals; disadvantages: expensive, ineffective. Genetic control (eg. liberation of sterile Advantages: none; disadvantages: expensive, unethical to releas or substerile males) e potential vectors Traps (eg. baited with lights, kairomones) Advantages: none; disadvantages: ineffective Housing improvement (eg. wall plaster, Advantages: effective; general improvement of living standards; replacement of thatch roofs) disadvantages: difficult to implement on a large scale; tends to be costly Health education (eg. improve public Advantages: general improvement of education and living stan- awareness, support of vigilance programmes) dards; disadvantages: great expectations are not always fulfilled mammals than organochlorines). They are also of pyrethroids against Triatominae (Dias 1997). well accepted by spraymen, although they occa- Among all triatomine species, undoubtedly the sionally produce transient irritation of the eyes and most important has been T. infestans, responsible mucosa during application. Other formulations of for the majority of cases of Chagas disease in the conventional insecticides have been tried against Continent. It is present in the six countries of South- triatomines, chiefly looking for a more consistent ern Cone, and in southern Peru, and is almost en- residual effect. These include microencapsulated tirely domestic throughout its wide distribution. formulations of pyrethroids, and slow release PVC The spread of T. infestans to its current wide dis- matrices containing organochlorine or organophos- tribution appears to have been relatively recent, phate (malathion) compounds. These formulations associated mainly with human migration patterns tend to have more residual activity, but their final (Schofield 1988). Since Emmanuel Dias and Alina cost-effectiveness is usually no better than con- Szumlewics, in the 40s and 50s, the behavioural ventional pyrethroids. Other approaches using biology and population dynamics of this species ionised micro drops of active ingredient (Electro- have been intensively studied, and several com- dyne) and/or spatial ultra-low volume spraying prehensive reviews have been published. First of showed no advantages when compared with clas- all, the species became almost completely domi- sical spraying methods. Synergists such as PBO ciliated in all its area of dispersion, with the ex- (Piperonyl butoxide) seem not improve the action ception of some restricted rural areas of Bolivia

TABLE II Types of pyrethroid insecticide and recommended dose of active ingredient to be applied for the elimination of domestic Triatominae Formulation Dose rate (mg a.i./sq, m) Manufacturer Deltamethrin 2.5% SC (or 5% WP) 25 AgrEvo Cyfluthrin 10% WP 50 Bayer Beta-cyfluthrin 12.5% WP or SC 25 Bayer Cypermethrin 20-40% WP 125 Various Lambda-cyhalothrin 10% WP 30 Zeneca SC: suspension concentrate (flowable); WP: wettable powder. 108 The Evolution of Chagas Disease • JCP Dias, CJ Schofield where it can be found in sylvatic ecotopes If the post-spray evaluation indicates more than (Schofield 1994, Dias & Coura 1997). Of particu- 5% of the houses still appear to be infested with lar interest in relation to vector control interven- Triatominae, then the area is programmed for a tions is the insect’s relatively slow rate of popula- repeat application as in the original attack phase. tion regeneration and the susceptibility of nymphs If less than 5% of houses appear to be infested, and adult bugs to modern insecticides. In addition, then the area is placed under vigilance, whereby the bugs have a very specialised genetic system any premises still infested can be selectively re- with holocentric chromosomes and extremely low treated. The decision level at 5% house infesta- rates of genetic variability. The practical conse- tion rate has been determined on the basis of expe- quences of these facts in vector control correspond rience indicating that below this level new cases to the extreme difficulty these insects have in se- of T.cruzi infection are rare (Dias 1987). lecting insecticide resistance. In summary, T. The vigilance phase depends crucially on the infestans has at least four biological characteris- participation of the local community, and is pre- tics functioning as key factors favouring its con- pared from the start of the campaign through com- trol: (a) limited range of habitats, with all stages munity health education and discussion with local confined to houses and some peridomestic animal community officials. The idea is that all house- enclosures; (b) slow rate of population develop- holders are made aware of the objectives and ra- ment, and consequent low rate of genetic rearrange- tionale of the campaign, and can appreciate their ment; (c) extreme specialisation with a low rate of important role in its success. In this way they can genetic variability and consequently limited genetic assist the spraymen during the attack phase, and repertoire for further adaptation (including insec- then act as the ‘eyes’ of the control services during ticide resistance), and, (d) complete susceptibility the subsequent vigilance, reporting the presence to modern pyrethroid insecticides (Schofield & of triatomine bugs to the local information post, so Dias 1998). that the house can be rechecked and resprayed if Organisation of control campaigns against necessary. Triatominae is generally based on the administra- Following this general schedule, the results tive structures previously set up for campaigns have been very satisfactory in Brazil, Uruguay, against other insect pests - particularly mosquito Chile, and in large regions of Argentina, Venezu- vectors of yellow fever and malaria. And the op- ela, and parts of Bolivia and Paraguay. Where erational procedure is also similar, with three main vector control has been satisfactorily implemented phases of intervention: preparatory, attack, and in these countries, acute cases of Chagas disease vigilance. The preparatory phase mainly involves are no longer seen, and serology of young chil- arrangement of material and financial resources, dren (born since the launch of the control cam- recruitment and training of personnel, and sketch- paigns) shows very low rates of infection (Dias mapping of the area to be treated - including, where 1993a, Schmunis et al. 1996, WHO 1997). In ad- possible, baseline serological studies of the popu- dition, the prevalence of T. cruzi infection is also lation to determine initial infection rates. The at- decreasing amongst blood donors and women of tack phase generally involves large-scale spraying child-bearing age, bringing corresponding reduc- of all premises in the target area, regardless of tions in the risk of transfusional and congenital whether or not an individual house is known to be transmission (Dias 1997). Table III, from the offi- infested. This is because available sampling meth- cial reports of Southern Cone Initiative, shows the ods are imprecise, and may not detect low-density reduction of seropositivity over the last few years triatomine populations (Schofield 1978, Gurtler et (WHO 1997, Schofield & Dias 1999). al. 1993). Householders are advised to remove all Consolidation of successful vector control in- foodstuffs and animals, and asked to pull furniture terventions depends on two important concepts, away from the walls. All internal and external wall applicable to different epidemiological situations. surfaces are sprayed, together with the inside roof The objective is to ensure that treated premises surface and all peridomestic animal enclosures. remain free of triatomine bug infestations. Con- Following the attack phase, dwellings must be tinual retreatment with insecticides, as has been evaluated for the presence of Triatominae by teams carried out in the past against endophilic mosqui- of trained personnel using torch and forceps to toes, is neither practical nor desirable, especially examine cracks and crevices in the house. Some- given the slow rate of recolonisation of houses by times sheets of paper (Garcia Zapata et al. 1985) most triatomine species. Instead, the strategy is to or special cardboard boxes (Gómez-Nuñez 1965) inhibit reinfestations by: (a) eliminating all residual are placed on the walls as passive sampling de- foci of infestation that could give rise to new bug vices; subsequent deposits of bug faeces on the colonies, and (b) progressive socio-economic de- papers will indicate the presence of triatomine bugs. velopment and house improvement to render Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 94, Suppl. I, 1999 109

TABLE III Seroprevalence (in %) of Trypanosoma cruzi infection in five Southern Cone countries from large scale surveys before and after initiation of the Southern Cone Programme (Schofield & Dias 1999)a Country 1981 - 1985 1993 - 1995 Observations Argentina 4.8 1.2 18 year-old military recruits Brazil 4,5 (a) 0.2 (b) (a): general population; (b): 7-14 years old Chile 5.4 1.4 < 10 years old Paraguay 9.2 4.0 18 year-old military recruits Uruguay 2.4 0.2 < 12 years old a: values are percentage seropositive in the age groups shown. houses less amenable to bug infestations, although rally the necessary resources) in those regions for both scenarios the importance of community- where the disease impact fallen down; (b) to face based vigilance cannot be stressed too highly. In objectively the irreversible tendency to centraliza- the case of highly domestic species of Triatominae, tion. In other words, to maintain minimum central such as T. infestans in Southern Cone countries, and regional reference structures in order to im- new infestations arise primarily through passive prove the efficacy and continuity of finalistic ac- transport of bugs in the clothes and belongings of tivities at the peripheral level; (c) to control sec- people travelling from infested to non-infested ondary and ubiquitous species at the peri-domes- dwellings (Schofield 1988, Schofield & Dias tic level, and, (d) to maintain a high and perma- 1998). Consequently, the broad international strat- nent degree of community participation in order to egy (PAHO 1993, Schmunis et al. 1996) is to elimi- improve a continuous epidemiological surveillance nate all domestic foci of T. infestans throughout (Dias 1987, 1991, Schofield & Dias 1999). the region in order to eliminate the possibility of Control of transfusional transmission passive transport of bugs from one region to an- Blood transfusion transmitting T. cruzi was one other. In the case of species that retain silvatic of the few subjects not suspected by Carlos Chagas, ecotopes however, complete elimination is impos- but discovered at the end of the 40’s, after the ad- sible, so that greater emphasis is placed on adequate vertising of Salvador Mazza, Emmanuel Dias and surveillance, selective retreatment of new infesta- other pioneers. Transfusion is considered the sec- tions, and progressive improvement of rural hous- ond most important mechanism of transmission of ing (Schofield et al. 1990, Briceño-León 1993). Chagas disease to which currently accounts for The new scenery of Chagas disease control around 15% of all transmission. The required programmes is replacing the classical vertical by methods for control of transfusional transmission the horizontal approach, since most of the coun- have been available since the 1950s, but have only tries are turning their Public Health systems to the been adopted on a large scale since the emergence decentralised model. In the years 90, globalisation of the Aids pandemic in the 1980s. As HIV can and market controlled economies imposed the gen- also be transmitted by blood transfusion – along eral tendency to deliver resources and responsi- with other pathogens such as hepatitis and syphi- bilities to peripheral levels, in order to improve lis – there is now greater emphasis on improving small and efficient central and national structures. the quality of blood for transfusion to eliminate In matter of fact, considering the general condi- the risk of these infections. tions of the regions where Chagas disease exists, There are three basic strategies according to the the transition to decentralisation can be considered epidemiological situation (Wendel et al. 1992). In another new challenge, since the very poor mu- regions with high seroprevalence of T. cruzi infec- nicipalities and counties generally do not have tion amongst blood donors (20% or more) or where sufficient expertise, organisation and political will serological screening systems are unavailable or to carry on the programme. Technically, at the unreliable, the best approach is to add gentian vio- present time no major problems exist concerning let to stored blood (1:4000) for 24 hr in order to the fight against triatomines indoors: all the results kill any flagellates. This method has been very can be considered very optimistic in those areas or widely used for many years, and the blue regions where the programmes are being conducted colouration imparted to the transfused blood gen- with a minimum of quality, coverage and continu- erally disappears a few days after transfusion. In ity (WHO 1991, Schofield & Dias 1998). Never- areas with lower seroprevalence of T. cruzi infec- theless four other challenges emerge for the new tion the recommended approach is to screen all century: (a) to maintain political decision (and natu- potential blood donors using at least two serologi- 110 The Evolution of Chagas Disease • JCP Dias, CJ Schofield cal tests (usually Indirect Haemaglutination and Unfortunately, congenital transmission cannot Indirect Fluorescent Antibody tests); at the same be prevented during pregnancy because available time the blood can also be screened for HIV, hepa- drugs are toxic and teratogenic, and preventive titis and syphilis (Dias 1978, Schmunis 1991, WHO abortion is unacceptable. There is also no reliable 1991). The third approach, used in non-endemic way to detect intrauterine infections, so that the areas such as the USA, is based on a preliminary best procedure consists of early diagnosis of the questionnaire to see if the donor has any history of new-born followed by specific treatment with possible contact with T. cruzi or infected benznidazole (8-10 mg/kg/day during 60 days). Triatominae (eg. has previously lived in an endemic Serology can be carried out on pregnant women region), which may then be followed by appropri- with appropriate epidemiological history (eg. com- ate serological testing. ing from an endemic area), thus detecting those at For endemic Latin American countries, the risk. However, conventional serology is not diag- screening methods need to be complemented by nostic for new-bornes because the baby will re- adequate legislation obliging a standardised sys- main seropositive for 4-5 months due to passive tem of screening in all blood banks, and entirely transference of IgG antibodies from the infected prohibiting the use of paid blood donors. There is mother. Instead, parasites can be sought directly a corresponding need to promote correct clinical or by haemoculture or indirect xenodiagnosis from indications for the use of transfused blood and the new-bornes, especially in those who present haemoderivates, the correct and immediate notifi- continuous fever or other suggestive symptoms cation of transfusion accidents, and to stimulate such as myocarditis or hepato and splenomegaly. modern practices such as auto-haemotransfusion In countries such as Brazil where congenital cases (Wendel et al. 1992, Dias 1997). The research need are becoming rarer, the usual strategy is to use con- is to improve serological screening techniques to ventional serology when the babies reach 6 months achieve greater sensitivity and specificity at re- (when maternal antibodies will have disappeared) duced cost, and to develop a serological ‘gold stan- and immediately treat those who result positive dard’ for all reference laboratories. Improved (Dias 1987, WHO 1991). chemoprophylaxis for stored blood would also be Control of transmission by organ transplant helpful, because of the potential toxicity of Gen- Theoretically, transmission of T. cruzi can oc- tian Violet and its slow rate of action (Moraes de cur by the transplant of virtually any organ from Souza et al. 1997). infected donor to susceptible recipient. However, Additionally, it is worth emphasising the inte- most cases have been recorded as a result of kid- grated approach to Chagas disease control, in the ney transplantation, with rare cases attributed to sense that throughout the Americas blood banks transplants of heart, pancreas, and bone marrow. are now one of the most important sources of epi- Pre-surgery serology of both donor and recipient demiological information on the seroprevalence of should be obligatory in endemic areas, or when infection. Data from blood banks provide a useful either has an epidemiological history of possible baseline against which to judge the progress of contact with the parasite. Nevertheless, in urgent Chagas disease control programmes, offering an cases the transplant must proceed and the best strat- important index of the changes in seroprevalence egy is specific treatment of the infected donor as control programmes proceed. Serological (benznidazole 5-7 mg/kg/day) during the 10 days screening prior to blood donation also offers an preceding surgery, and similar treatment of the re- important opportunity to identify infected individu- cipient on the day before surgery and for 9 days als, who must be advised never to offer blood again afterwards. The rationale is to minimise circulat- and must be referred for clinical follow up, coun- ing parasites in the donor in order to inhibit their selling, and supportive treatment where required establishment n the recipient (Dias et al. 1986). In (Dias 1997, Moraes de Souza et al. 1997, Dias & cases where pre-surgical treatment of an infected Schofield 1998). donor is not possible, the recipient should be treated Control of congenital transmission immediately after surgery. This applies also to Congenital transmission of T. cruzi, although cases of transplant from an uninfected donor to an numerically small, is the third most important infected recipient, since reactivation of acute mechanism of transmission. Up to 4% of births Chagas disease can result from the use of immu- from infected mothers can result in infected ba- nosuppressants during transplant surgery (Ferreira bies due to parasites crossing the placenta et al. 1997). (Schmunis 1991, Dias & Coura 1997) suggesting Accidental transmission that up to 5000 new infections per year may be Accidental transmission of T. cruzi is regretta- due to this route of transmission. bly frequent in laboratories, and well over 50 cases Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 94, Suppl. I, 1999 111 have been recorded, generally as a result of acci- above, but also to those infected in rural settings dental puncture from infected needles or splash- prior to the implementation of large-scale vector ing with contaminated triatomine faeces or culture control interventions. Even if all transmission were material (Brener 1987). This problem must be immediately halted, there would remain some 16 addressed by very clear training of personnel and million people requiring clinical attention over the rigorous attention to good laboratory procedures. next 30 years or so. In the context of the overall Laboratories should have a restricted entrance, and Chagas disease control strategy, treatment of in- the use of gloves, protective eye-glasses, masks, fected individuals can be considered the second- closed shoes and long-sleeved gowns, should be ary level of intervention, designed primarily to halt obligatory for technicians working with the para- the progression of disease. site. Periodic serological checks of laboratory staff Specific treatment - There are two drugs that are also advisable. Immediate local sterilisation can be used for specific treatment of T. cruzi infec- must be provided after accidental contact with sus- tion. Nifurtimox manufactured by Bayer under the pect material, and silver nitrate eye washes are in- trade name Lampit® is given at 10-15 mg/kg body dicated if the eyes were contaminated. If a person weight per day, while benznidazole, manufactured seems likely to have been infected, then an imme- by Roche under the trade names Radanil®, diate presumptive course of treatment should be Rochagan® or Ragonil®, is given at 5-7 mg/kg given, using benznidazole (5-7 mg/kg/day) for at body weight per day. Treatment with either drug least 10 days. is indicated in acute or recent infections, and in congenital cases, with a good chance of radical Vaccination and chemoprophylaxis cure. Acute infections are generally treated for up Several forms of immunisation have been tested against T. cruzi, using attenuated strains, fraction- to 60 days, but Brazilian experience indicates that recent non-acute infections can be successfully ated parasites, antigenically similar trypa- treated with a 10 day regime, provided that treat- nosomatids, and synthetic molecules. None has been effective. ‘Live’ vaccines could not assure ment is started very soon after the initial infection. Abbreviated treatment regimes have the advantage safety, while ‘killed’ vaccines could not provide of reduced likelihood of side effects, which gener- total protection, and further research aimed at pro- ducing a vaccine against T. cruzi is no longer en- ally commence after 8-10 days of treatment. Side effects are dosage dependent, and include malaise, couraged (WHO 1991). Similarly there is no drug anorexia, loss of appetite and of concentration, that can be used for effective prophylaxis, for ex- ample to protect travellers who visit endemic ar- erythema, pruritus, and peripheral neuritis. In some cases, agranulocytosis and/or anaemia has been eas. In this context however, it is worth observed, requiring interruption of treatment. In emphasising that the risk of infection to travellers is extremely low. general, children tolerate treatment much better than adults. Reactivation of human Chagas disease Use of nifurtimox or benznidazole has given As mentioned for organ transplanted individu- variable results in different countries, which may als, some other situations involving immunologi- reflect parasite strain differences. In general how- cal depression can re-activate T. cruzi infection. ever, complete cure can be expected with immedi- The most common situation concerns to HIV su- ate treatment of accidental infections, and 30-70% perinfection in chagasic patients, chiefly when the cure for treatment of acute infections. Even if radi- level of CD4 cells is lower than 300, generally re- cal cure is not achieved, there is now strong evi- sulting in severe neurological pictures. More than dence that early treatment can prevent mortality 40 cases are known, most of them with fatal evo- during the acute phase of infection, and can re- lution. Adequate treatment with anti retroviral duce the progression of disease in the subsequent drugs are able to prevent reactivation in these cases. chronic phase - especially in relation to cardiac Recently, it was also suggested to treat them with lesions. Viotti et al. (1997) present results of a 10 benznidazole (5 mg/k/day three times weekly) in year follow-up of treated and non-treated individu- order to maintain a small number of circulating als in the chronic phase of infection, showing sig- parasites (Ferreira et al. 1997). nificantly improved clinical evolution in the treated Treatment of infection group, as well as reduced mortality. At the experi- Although the primary emphasis in Chagas dis- mental side, since the 70’s, important trials made ease control concerns the interruption of transmis- by Rowheder, Andrade (1999) and others have sion, there remains a need to treat people who are shown that both drugs were effective at the tissue already infected. This applies not only to specific level and that inflammatory response (and even cases such as transfusion and transplant surgery, initial fibrosis) is reversible when the parasite is congenital transmission and accidents as described killed throughout treatment. Specific treatment 112 The Evolution of Chagas Disease • JCP Dias, CJ Schofield of chronic infections should therefore be consid- or immediately corrected, although it is regrettable ered on a case-by-case basis, bearing in mind the that the mortality rate from megacolon surgery re- age of the patient since treatment is better toler- mains high, in spite of modern techniques. ated in younger individuals, and the age of infec- Reintegration of chagasic patients into the com- tion since greatest success is likely from more re- munity cent infections (WHO 1991). The modern ten- This is the last stage in the classical sequence dency, nevertheless, is to give to the patient the of preventive medicine. Often, a patient will panic “benefit of the doubt” treating specifically the cases or become severely depressed when a positive di- of indeterminate and initial cardiac and digestive agnosis is revealed, even in the absence of clinical chronic forms (Dias 1997). manifestations. The public image of Chagas dis- Symptomatic treatment - Symptomatic or sup- ease is commonly associated with sudden death portive treatment for chronic phase patients has and/or irreversible heart disease, an association that advanced greatly in recent years. Effective treat- has been progressively incorporated due to inap- ment presupposes adequate access to medical at- propriate and sensationalist reporting of a minor- tention, with periodic clinical checks. Patients with ity of severe cases. Nevertheless, a person with indeterminate (asymptomatic) chronic infections need a yearly check, whereas those with severe positive serology must be informed of this result arrhythmia or heart failure will require in order to avoid giving blood and to accept medi- hospitalisation and weekly or monthly clinical ex- cal attention. Clinicians and health workers must aminations. In general, about 85% of chronic phase give a realistic and non-sensationalist explanation patients can be followed through the primary health of Chagas disease, pointing out its natural history care system, with periodic medical consultations, and principal modes of transmission, as well as a serology and electrocardiograms (Dias 1990). balanced view of the patient’s clinical prognosis. Management of the principal clinical manifesta- Facing the chagasic individual, the role of the cli- tions can be summarised as follows: nician is to analyse carefully the case and discuss Chronic cardiopathy: arrhythmias must be con- objectively the particular situation with the patient trolled by adequate diagnosis and treatment - usu- and family. Most cases do not represent serious ally with amiodarone and other modern anti- clinical problems, and have little likelihood of se- arrhytmic drugs such as propaphenone and rious manifestations in the short and medium terms. mexilethine. Severe arrhythmias may require pace- Moreover, available medical resources are continu- maker implant or other surgery. Cardiac surgery in ously improving in terms of disease management, Chagas disease has being improved with the re- provided the patient is aware of the need for regu- section of aneurysms and of myocardium zones lar medical consultation and checks. A rarely dis- where arrhytmogenic foci are detected. Preven- cussed problem is the psychological behaviour of tion of heart failure is extremely important, and chagasic individuals, since most will suffer para- requires detection before the onset of cardiac en- sympathetic denervation, becoming hyper-reactive largement. In chronic Chagas disease, the final to common ambient stimuli – they become perma- phases of heart failure predict thrombi-embolic and nently stressed according Vieira (in Dias 1990). refractory situations based on severe weakness of At the operational level, a present tendency is to the cardiac muscles and advanced cardiac fibro- allocate psychological attention in those medical sis. In such cases, the only possible recourse may services where chagasic people are attended (e.g., be to heart transplantation. in Recife, São Paulo, Belo Horizonte, Goiânia and Chronic digestive tract involvement: although Campinas (Brazil) and in Cordoba (Argentina). intestinal megasyndromes are well recognised in At the community level also, correct and bal- many cases of advanced chronic infection, treat- anced information must be given, especially to ment should be conservative in the early stages. emphasise that Chagas disease is not contagious, At the oesophagus level, the Heller technique (ex- and that the prognosis for infected individuals is tra-mucosa miotomy) followed by plastic recon- generally good. This is particularly important in struction of the sphincter is considered the most terms of the basic rights of the chagasic individual, recommendable procedure for the cases up to 3rd the right to work (which is often refused to indi- degree, not only correcting disphagia and other viduals merely because they present positive se- current symptoms, but also preventing the evolu- rology), and the right to social security (which is tion of megaoesophagus in a large number of cases. sometimes denied in cases of advanced heart dis- More aggressive surgical procedures are indicated ease). These aspects require well-prepared clini- mainly for the most advanced cases with severe cians and health workers, clear practical guidelines, dilatation and ectasy. The worst manifestation of and an effective social security system. In prac- megacolon, sygmoid volvulus, must be prevented tice, the basic problem is to define the perspec- Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 94, Suppl. I, 1999 113 tives and conditions for chagasic individuals, tak- gentina, Brazil, Uruguay and Venezuela. ing into account their clinical state, their profes- Mazza warns about the risk of transfu- sion and general living conditions. Each case must sion and oral (mother milk) transmission be carefully evaluated, avoiding distress to the pa- 1943 Foundation of the Bambuí center in tient but equally avoiding false expectations. At Minas Gerais, Brazil, by Emmanuel present, millions of chagasic individuals from ru- Dias, where trials are made of several ral areas of Latin America are migrating into cit- available insecticides (including cya- ies, seeking work and better social conditions. nidegas), physical methods (flame- Most remain in the chronic indeterminate phase of thrower), housing improvement and infection, or in the initial stages of chronic heart or community participation digestive tract damage, and are physically quite 1944-46 Still in Bambuí, beginning of chronic car- capable of carrying out the majority of professions. diopathy systematization; failure of DDT On the other hand, some are in advanced stage of against triatomines; Dias warns against chronic impairment, requiring medical attention the risk of transfusion disease and a reduction in their physical labour in order to 1947-48 First laboratory trials against insects reduce the risk of cardiac failure or sudden death. (Busvine & Barnes 1947) and descrip- But since many of the people infected with T .cruzi tion of the action of HCH (gammexane) are illiterate or poorly educated, it remains the re- against triatomines (Dias & Pellegrino, sponsibility of the social security system and the Romaña & Abalos); first large scale sur- medical profession to provide the best conditions vey employing serology and EKG in for their survival and development (Dias 1997). non-selected population (Bambuí) 1949 First regional serological survey of blood SUMMARY OF THE PRINCIPAL EVENTS RELATED TO HUMAN CHAGAS DISEASE CONTROL FROM donors (Pellegrino, in Belo Horizonte, 1909 TO 1999 Brazil); L Dao confirms in Venezuela the congenital transmission of human In order to have a general and chronologic com- Chagas disease; Ramos and Freitas carry prehension of the facts appointed above, the fol- on a serological and EKG inquiry in lowing picture was prepared, showing the consid- Cássia dos Coqueiros, SP, Brazil ered most relevant facts concerning to the control 1950-52 In São Paulo, Brazil, Nussensweig, of human Chagas disease, since its discovery and Freitas and Amato Neto confirm trans- according to the consensus of the majority of the fusional transmitted Chagas disease. The authors (Dias 1988, Coura 1997, Schofield & Dias same group employs successfully gen- 1999): tian violet as chemoprophylactic agent YEARS SUBJECT/OBSERVATION in blood banks. First large-scale trial with 1909 Carlos Chagas discovers the disease gammexane against triatomines in 1911 Chagas proposes vector control and Uberaba, Minas Gerais, Brazil (E Dias, housing improvement and describes the Bustamante et al.) congenital transmission of Trypanono- 1955 First experimental trial attempting Tri- ma cruzi atoma infestans eradication in Bambuí 1913 Brumpt describes xenodiagnosis; (E Dias) Guerreiro and Machado develop comple- 1956 Publication of the definitive systemati- ment fixation test zation of chronic heart Chagas disease 1916 Chagas emphasizes chronic heart disease in Circulation by Laranja, Dias, Nóbrega 1918 Souza Araújo promotes a law con- and Miranda cerning house improvement in endemic 1957-58 Re-description of Chagas disease diges- areas tive forms by Köberle and others. Im- 1919-22 N Larrier and S Campos study congenit- portant serological and EKG survey in al transmission at experimental level the Córdoba region of Argentina, by 1926 Mazza begins the MEPRA project in Rosenbaum and Cerisola. Important re- Jujuy, Argentina gional epidemiological surveys in Ven- 1930-34 C Chagas and E Chagas employ EKG in ezuela, by Pifano et al. chronic Chagas heart disease 1959 Neghme and Schenone confirm in Chile 1932-36 Mazza claims for housing improvement the results obtained in Bambuí against and tries some classical drugs in Chagas T. infestans. E Dias emphasises the con- disease cept of T. infestans eradication 1935 IX MEPRA meeting; Romaña describes 1960-70 Beginning of vector control in São Paulo, his eye portal of entry sign Brazil, and in Venezuela (National 1935-44 Many acute cases are described in Ar- Programme: using insecticide plus hous- 114 The Evolution of Chagas Disease • JCP Dias, CJ Schofield ing improvement); regional actions in and Zilton Andrade as well as an Inter- Argentina and in various Brazilian states; national Congress on Chagas Disease P Freitas introduces his concept of se- (Rio de Janeiro), call the attention of lective spraying. Improvement of new se- authorities and scientific community to rological techniques for diagnosis (indi- the disease and its control; in New York, rect immunofluorescence, direct agglu- publication of Lent and Wygodzinsky’s tination and indirect haemagglutination); compendium about triatomines; in Ven- registration of low levels of resistance ezuela, Gomez-Nuñes develops a simple to organochlorine insecticides (dieldrin model of passive sensor to triatomines; and BHC) in part of Venezuela, promptly spreading of the HAI and IIFT serologi- resolved by changing the product to a cal tests in endemic countries, slowly re- carbamate compound (propoxur); first placing the pioneer CFT; first trials of optimistic results of nifurtimox, against pyrethroid insecticides in Minas Gerais acute forms of human Chagas disease; and Rio de Janeiro (Brazil) and in Ar- improvement of chemoprophylaxis in gentina blood banks of Argentina and Brazil, 1980-90 Aids emergence and dispersion, induc- besides the increasing of prevalence sur- ing the reformulation of haemotherapy veys among blood donors in the entire throughout the world, so making com- Continent; still timid improvement of pulsory the serological screening of blood bank serological control is ob- blood donors; progressive replacement served in endemic regions; the first posi- of ancient insecticides by modern pyre- tive serological results are registered in throids; mathematical simmulations (J worked areas of Brazil (Bambuí, São Rabinovich) show that vector control is Paulo), Venezuela (Belén, Eneal) and Ar- feasible mainly when insecticide, hous- gentina; beginning of the trials with new ing improvement and social progress are anti-arrhythmic drugs (amiodarone) for associated; first regional programmes in chronic cardiopathy Chile and Bolivia; political decision in 1970-80 Beginning of the national programme in Brazil, resulting in the allocation of re- Uruguay (1972); reformulation of the sources to expand programme coverage Brazilian programme in 1975, based on to entire endemic area, without disconti- E Dias’ ideas concerning a systemic ap- nuity; beginning of the annual meeting proach taking into account the continu- on applied research in Brazil (Araxá, ity of the actions in contiguous areas; then Uberaba) and some important peri- complete revision of transfusion trans- odical meetings in Argentina (Carlos mitted Chagas disease by Cerisola et al. Paz, La Falda, etc.); beginning of the (Argentina); first community based sur- “Programa de Salud Humana”, headed veillance against triatomines in Bambuí; by Dr Pilar Alderette in Argentina beginning of the national entomological (BIRD/Universidad El Salvador), stimu- and serological surveys in Brazil; im- lating several emergent regional groups provement of applied and basic research for the diagnosis and control of Chagas in Brazil supported by the Ministry of disease in Argentina, Uruguay, Chile, Health and Brazilian Research Council Brazil, Paraguay and Bolivia; the results [Integrated Programme of Endemic Dis- obtained by the control programmes in eases (PIDE, followed some years later São Paulo and other Brazilian parts call by TDR/UNDP-WB-WHO)]; first trials attention to vigilance strategies formerly with benznidazole; Alma-Ata meeting, developed in Bambuí; detailed studies bringing the concept of Public Health of the population dynamics of activities based on the primary health Triatominae developed in Venezuela care system; generalisation of the con- (Rabinovich), Brazil (Marsden, cept of the regional differences on Schofield) and Argentina (Gorla) help to Chagas disease morbidity; still a very improve new control strategies; impor- slow advance in the coverage of blood tant publications in Brazil about the ecol- banks with preventive serology and/or ogy of vectors and reservoirs (O Forattini chemoprophylaxis; beginning of the an- & M Barretto); a national electrocardio- nual meeting on basic research graphic survey is carried out in Brazil, (Caxambu, Brazil); at the end of the de- showing regional differences; financial cade, a book edited by Zigman Brener constraints result in the decreasing of Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 94, Suppl. I, 1999 115 Venezuelan programme; development of tion of the progression of chronic lesions; the ELISA technique for serology; gen- other endemic countries implement blood eral improvement in the medical atten- bank control; results of vector control in tion for acute and chronic patients, Brazil and Uruguay show a positive im- mainly at the level of cardiac arrythmias, pact on decreasing of transfusion and con- cardiac failure and mega-syndrome di- genital transmitted Chagas infection, as agnosis and surgery; important advances well as on the morbidity and mortality in cardiopathy studies with the patterns of the disease; new regional “ini- generalisation of ecocardiographic, tiatives” arise in Central America and holter, exercise tests and other investi- Andean Regions; Mexico starts a regional gation procedures; generalisation of car- pilot programme against domiciliated diac transplantation and pace-maker im- triatomines; the Global Conference on plantation; spreading of social and cost- Disease Elimination (Atlanta, USA), con- benefit studies about the disease and its siders Chagas disease as a clear candidate control; introduction of Aedes aegypti for elimination up to the year 2010; in and dengue fever in Brazil, resulting in 1999, Bolivia assumes an historical deci- relative disactivation of Chagas disease sion to implement a complete national programme; the entomological results control programme in all endemic areas, in Brazil Uruguay and Argentina make allocating external and national resources clear that elimination of T. infestans is to guarantee its continuity over the next an attainable goal, and that the surveil- five years; at the same time, national con- lance strategy, peridomestic Triatominae trol programmes start in Peru, Colombia and secondary species will constitute a and Central America (Honduras, El Sal- challenge for the next decade; in some vador, Nicaragua and Guatemala, and a countries (Argentina, Brazil, Uruguay), plan is made for Costa Rica); entomologi- a law about blood transfusion is imple- cal studies carried out through the ECLAT mented net work show the possibility of Rhodnius 1990-99 Preliminary studies at the scientific level prolixus elimination in Central America, and final resolution of the Ministries of since this species is out of its original dis- Health of Argentina, Bolivia, Brazil, persion centre Chile, Paraguay and Uruguay implement the “Southern Cone Initiative for elimi- This very short and simple summary reveals to nation of T. infestans and Control of us a history involving men, research, social poli- Transfusion Transmitted Chagas Dis- cies, political will and technological development. ease” (Brasília); progressive disacti- It must be emphasised that HCD never received a vation of PIDE and Chagas disease TDR high social priority because of several and differ- research programmes; ECLAT research ent factors such as the very weak socially involved network launched with support from EC population (poor, rural, isolated, non-organised, and Switzerland; improvements are made etc.) and the lacking of specific treatment for sev- in chemoprophilaxys of stored blood eral years, of medical interest on the disease, of banks in order to short the time of para- formal education involvement, of an effective site disactivation (Moraes Souza); pro- policy considering agriculture and rural housing gressive disactivation of the conventional in endemic countries, and also the very weak mar- vertical programmes in Argentina, Brazil ket concerning the main trade tools involved in and Venezuela, because of the transition HCD: insecticides and laboratory reagents for di- to horizontal peripheral systems and the agnosis. It is very peculiar the fact of scientific new model of “modern and small central community involvement in all this history, since structures”; improvement of the research Carlos Chagas, following his examples with a very to new areas, such as Amazon Region and clear social compromise, many times leaving the to other less well studied regions (Cen- hospitals and laboratories to push on political de- tral America, México); Paraguay begins cisions. In the history of Chagas disease control, national programme in 1994; longitudi- was necessary more than research and epidemio- nal, sectional and experimental studies logical data to move on national and regional show that treatment with benznidazole programmes. An additional work was required to and/or nifurtimox can be effective in sensitise the public opinion, to influence the na- young and even adult patients, providing tional governments and to stimulate leadership for- parasitological cure and even the interrup- mation and decision making (Morel 1998). 116 The Evolution of Chagas Disease • JCP Dias, CJ Schofield THE PRESENT SITUATION OF CHAGAS DISEASE 5% in non endemic regions, while the only con- CONTROL IN ENDEMIC COUNTRIES trolled blood bank is in Sta. Cruz City. Bolivia has In a general way, the endemic countries can be launched a new national programme, with Presi- considered according their epidemiological situa- dential backing, and – for the first time – adequate tion (vectors, transmission rate, prevalence and financial resources (more than US$ 30 million) to morbidity) and by the state of national control spray approximately 700,000 houses and to con- programmes. Serology of children and blood do- trol all blood banks within the next five years. nors provides useful epidemiological information, Paraguay has also an important level of transmis- as do electrocardiographical surveys of infected sion: in the Chaco Region the mean house infesta- and non-infected individuals (Schmunis 1991, Dias tion rate by T. infestans reaches more than 30%, & Coura 1997). Unfortunately, representative and while the prevalence of infection is over 25% comparable data are not available in the majority amongst pregnant women. The vector control of countries, chiefly those concerning morbidity. programme still remains in a phase of organisation. Chagas disease is not homogenously distributed Nevertheless, the control of blood banks and a na- in the endemic countries, but tends to be in micro- tional policy to detect and to treat congenital cases regional clusters that generally depend of the level are rapidly being improved in the country. Peru of domestic colonisation by vector species. Na- has an important endemic area (Arequipa and tional and regional control programmes prioritise Tacna regions), and is now developing a national chemical control of vectors, together with screen- programme for the elimination of T. infestans from ing of blood donors as the basic strategy to HAT the infested southern departments, and progressive control, supported by Health Education and com- control of blood banks. As a whole, the elimina- munity organisation. Chemoprophylaxis of trans- tion of T. infestans is now considered an attain- fused blood has not been implemented in recent able goal, since this insect has no wild foci (except years (WHO 1991, Dias 1997). In the Southern in limited areas of central Bolivia) and infestation Cone, chronic heart disease is the bigger problem rates decrease dramatically in all sprayed areas. among infected people of the region, being present In the Andean Pact region (Ecuador, Colom- in more than 20% of them, while digestive “megas” bia and Venezuela) the main vectors are R. affect up to 10%. Acute cases usually disappear prolixus, and T. dimidiata, with several other spe- immediately when a locality is treated. At present, cies of local importance. R. prolixus is the princi- Argentina, Bolivia, Brazil, Chile, Paraguay and pal regional vector in Venezuela and Colombia, Uruguay are implementing programmes for the where it is highly domesticated. The principal dis- elimination of T. infestans, as the best way to reach ease impact is due to chronic cardiopathy, which the minimum level of disease transmission. Nev- affects about 20% of infected Venezuelan individu- ertheless, secondary triatomines such as T. sordida, als, whereas, digestive chronic forms seem to be T. pseudomaculata and P. megistus can invade not observed in this region. Venezuela has imple- dwellings (chiefly in Brazil) and must be faced mented a large-scale programme of Chagas dis- throughout effective and continuous vigilance. The ease control, where during more than 20 years there most advanced programmes are in Uruguay, Chile, was intensive house spraying and more than Brazil and Argentina, where current levels of trans- 600,000 rural houses were improved in endemic mission are now low (see Tables III, V). In these areas. Unfortunately, the national programme has countries, the control of blood banks is also being weakened in the last decade, with progressive loss improved, with a high degree of coverage and very of human and financial resources, the complexi- low prevalence of infected blood donors. Finan- ties of decentralisation and the emergence of den- cial support of national programmes in these coun- gue. In 1997 however, following encouraging re- tries has been maintained in the last eight years, sults in the Southern Cone, a new Andean Pact but the availability of trained personnel is declin- initiative was agreed. Colombia has quickly de- ing, either because of the decentralisation policies veloped improved systems of blood bank control, or by the demand of other emergent problems, and is now implementing a national programme to chiefly dengue fever. Progressive disactivation of eliminate R. prolixus; Ecuador has begun vector traditional programme structures is leaving admin- control trials (especially in Guayaquil), and inten- istrative gaps at regional and municipal levels, sified vector control activities in Venezuela are which generally are not prepared to assume the expected. control activities and to maintain the consequent The Central American initiative, also launched surveillance. In Bolivia, original centre of disper- at the end of 1997, mainly involves Guatemala, sion of T. infestans, the epidemiological indicators Honduras, El Salvador and Nicaragua. In these are high, with a mean rate of infection in blood countries, the most important vector is R. prolixus, donors of around 40% in endemic areas, and over which is considered a feasible candidate for eradi- Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 94, Suppl. I, 1999 117 cation from the region since it appears to be exclu- maculata and P. geniculatus in islands close to the sively domestic. Moreover, genetic studies show mainland, and members of the T. flavida group in that it was probably imported some 80 years ago Cuba and Jamaica – but there appears to be no ac- from Venezuela, and now has an extremely lim- tive transmission of human Chagas disease on these ited genetic repertoire compared to the original islands. In the Guianas (Guyana, Suriname and Venezuelan and Colombian forms. R. prolixus is French Guiana) several species of Rhodnius and associated with very high rates of human infection Panstrongylus have been reported, occasionally (typically over 40% in Honduras and Guatemala) entering houses, and a few acute cases of Chagas but it has a limited and focal distribution. In con- disease have been reported from parts of French trast, T. dimidiata is extremely widespread in Cen- Guiana. At present however, there are no national tral America – even in periurban areas – but is gen- programmes for surveillance or control of the dis- erally associated with human infection rates of 8- ease in these countries, either in terms of vector 12%. T. dimidiata cannot be considered a candi- control or in monitoring of blood donors. date for eradication since it also has widespread sylvatic foci, so that its control will require the RESEARCH NEEDS AND FINAL CONSIDERATIONS development of continuous community-based vigi- The most visible framework shows that re- lance systems. The distribution of T. dimidiata search is still necessary either to solve some actual extends from southern Mexico throughout Central constraints or to prevent possible epidemiological America into Panama, Colombia, Ecuador and changes in the future. First of all, the basic control northern Peru. In Panama, the main vector of hu- strategies are available and can provide a good man Chagas disease is R. pallescens, with very chance that HAT transmission can be substantially low house colonisation. Although results from re- reduced within the next few years, in spite of some cent surveys have yet to be fully analysed, it seems constraints existing at each control level. At the that the highest prevalence rates are found in Gua- other side, about 16 million of yet infected indi- temala, Honduras and Nicaragua, with a mean rate viduals deserve medical attention, an important of infected blood donors between 4 and 8%. subject in which the researcher finds higher chal- Chronic Chagas heart disease seems less common lenges than in primary control. To the next future a and less severe compared to Southern Cone coun- very low level of transmission is expected, a fact tries, and digestive forms are rare. But the morbid- that claims for a better and long term sustained ity and prevalence of HAT in Central American epidemiological surveillance. Secondary vector countries are more intense in those areas infested species and an effective management of peri-do- by R. prolixus, rather than those where T. dimidiata mestic ambient require more and more attention. (or other species) dominate. Considering the different control levels, the more In Mexico, in spite of an excellent tradition of urgent research needs could be summarised as fol- Chagas disease research in the 1950s and 1960s, the lows (Table IV). importance of Chagas disease was largely overlooked Many accounts of Chagas disease present a dis- until the current decade. In 1992, a large scale sero- mal picture of incurable infection consigning mil- logical survey of blood donors and rural populations lions to chronic debility, ignored by all but a hand- indicated an overall infection prevalence of over ful of research workers and rural clinicians. But 500,000 cases, and subsequent surveys have con- this picture has changed dramatically in recent firmed high levels of infection, especially in the years. Advances in diagnosis, and improvements southern and central states. Since 1997, an improved in understanding and treating the infection, have system of screening of blood donors has been pro- led to much better disease management and in- gressively developed, although coverage remains creased awareness that chagasic individuals can incomplete. Vector control activities have yet to be generally fulfil an entirely normal role in society. implemented on a large scale, although the first tri- als using modern pyrethroids were begun in 1998. Most importantly perhaps, there is now wide rec- The main vectors are members of the T. protracta ognition that transmission of the parasite can be group of species (especially T. barberi) and mem- halted, with national, regional and international bers of the T. phyllosoma group (especially T. programmes designed to improve the screening of pallidipennis). All of these seem to have extensive blood donors and implement effective control of sylvatic ecotopes as well as colonising peridomestic the insect vectors. Today, over vast areas of the and domestic habitats, and are subject of major re- once endemic regions, acute cases of Chagas dis- search efforts to clarify the most appropriate meth- ease are no longer seen, and the risk of new infec- ods for control and surveillance. tion (of all transmission routes) is diminishing rap- Data on the remaining countries remains scarce. idly as the control programmes achieve wider geo- Amongst the caribbean islands, several report the graphical coverage. And vector control has brought presence of potential vectors – particularly T. additional advantages to rural communities, 118 The Evolution of Chagas Disease • JCP Dias, CJ Schofield

TABLE IV Research needs to Chagas disease control at present time, according to the different epidemiological levels Control level Required research General comments Vector control Better insecticide and methodology at the Community participation and the peri-domestic level maintenance of political will in Better triatomine trapping in low densities very low bug densities will be a Better organisation of epidemiological major challenge in the next future surveillance Monitoring of sylvatic-domestic triatomine migration Monitoring of triatomine resistance to insecticides Transfusion transmission More rapid, sensible and specific serology Cost-benefit relations worse in More rapid, effective and non toxic drug in advanced phases of the programme, chemoprophilaxis Institutional research when the level of transmission is about the quality of haemotherapy very low. In general, better indica- tion and quality of hemotherapy are required, mainly in smaller towns Congenital Transmission Development of tools to detect precociously Better organisation and coverage congenital transmission Immunoprophilaxis on peripheral primary health care (still not available) system are required Accident and organ More efficient drugs to chemoprophilaxis There is not adequate registration/ transplantation Studies on risk factors information Specific treatment More effective and less toxic drugs Indications for treatment are increasing to chronic cases Symptomatic treatment Cardiopathy: more efficient drugs and Precocious diagnosis and adequate procedures to control arrythmias, heart medical and social attention failure and trombo-embolic syndrome; remain the main challenge for improvement of precocious diagnosis of human Chagas disease management cardiopathy and immune modulation of fibrosis (not available); digestive: impro- vement of farmacologic and surgical treat- ment of digestive lesions Programme organisation How to improve the minimum continuity Improvement of regional reference and quality, as well as the information flow centres concerning control, in horizontal and decentralised operative epidemiology, medical care, structures? Analysis of causes, conse- diagnosis, entomology, etc., is quences and risk factors involving the required failure and weakening of national and regional programmes whereby families can now sleep undisturbed, in nomic return equivalent to 14% in medical savings even the poorest of dwellings, without the risk of alone (Schofield & Dias 1991). Since then, studies attack by blood-sucking Triatominae. The dilemma in Brazil have shown a real economic rate of return remains in the same social and biological factors of over 30% (Akhavan 1997) while studies in Ar- involved in HAT and very early detected by Carlos gentina indicate rates of return in excess of 60% (Del Chagas: poverty, and low political priority of af- Rey et al. 1995, Basombrio et al. 1998). For Brazil fected populations, by one side, and a terrible during the period 1983-1996, the analysis indicates a chronic disease transmitted by the opportunistic national expenditure on Chagas disease control of insect, at the other. about $400 million, producing savings of over $900 In addition to the social and medical benefits of million in terms of improved survivorship alone, pre- Chagas disease control, the financial benefits are also venting at least 277,000 new cases of infection and substantial. In planning the Southern Cone 85,000 deaths (Akhavan 1997). programme, it was estimated that an investment in The main challenge is to consolidate and extend Chagas disease control would produce an annual eco- these successes to implement control programmes Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 94, Suppl. I, 1999 119

TABLE V General situation of Chagas disease and programme control in different countries or regions Country/ Prevalence Infestation Main Blood Program/Observations Region (%) (%) vectors control (a) (b) Argentina 1.9 4.4 <5.0 Triatoma >90.0 Regular decentralised; lacking of human infestans resources (HR) Bolivia >30.0 5-55.0 >20.0 T. infestans <5.0 Starting 1999; decentralised Brazil 0.17 <0.8 <3.0 P. megistus/ >80.0 Regular; vertical>decentralised; more than T. brasiliensis 90% in surveillance Chile 1.1 0.9 <1.0 T. infestans >90.0 Regular decentralised; mainly surveillance Paraguay 5.0 5.7 >5.0 T. infestans ~30.0 Starting 1999; decentralised; HR Peru NA 0.4 NA T. infestans <20.0 Starting in Arequipa region 1999 Uruguay <1.0 0.62 <1.0 T. infestans 100.0 Regular-decentralised; only surveillance; HR Colombia NA 1.2 NA R. prolixus NA Starting regular programme Ecuador NA 0.2 NA T. dimidiata NA No regular programme; planning (1999) Venezuela <3.0 0.7 NA R. prolixus/ >70.0 Regular semi-disactivated programme T. maculata (vertical>decentralised); HR Guyanes <1.0 NA NA ? NA No programmes Panamá NA <3.0 NA R. pallescens NA No programme C. Rica NA 2.5 NA T. dimidiata NA No programme. Nicaragua NA <1.0 NA T. dimidiata NA Planning (1999) Honduras NA 1.2 >10.0 T. dimidiata/ <50.0 Starting regular actions (1998-1999) R. prolixus Guatemala NA >5.0 >10.0 T. dimidiata/ <50.0 Starting regular actions (1999) R. prolixus E Salvador NA 1.9 NA T. dimidiata/ NA No programme R. prolixus Belize NA <2.0 NA T. dimidiata NA No programme Mexico NA <5.0 NA T. pallidipennis/ <20.0 No programme; pilot trials beginning (1998) T. longipennis USA NA <0.05 <0.005 T. protracta <5.0 No programme; blood control to Latin American Caribe NA <0.1 NA ? NA No programmes (a): children (%); (b): blood donnors (%); NA: not available.

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