The Discovery of Chagas Disease

Infect Dis Clin N Am 18 (2004) 247–260

The discovery of Chagas disease:progress and prejudice

Michael A. Miles, DSc, PhDPathogen Molecular Biology Unit, Department of Infectious and Tropical Diseases,

London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK

The discovery of Chagas disease makes an extraordinary story. Itencompasses the pinnacle of scientific achievement. In addition, there isa background story line of controversy, jealousy, and power politics. Severalprevious accounts are available, in varying detail. This article providesa synopsis, in part adapted and updated from a chapter in The WellcomeTrust Illustrated History of Tropical Diseases [1].

Chagas disease is also known as American trypanosomiasis or NewWorld trypanosomiasis. It is caused by infection with the parasiticprotozoan Trypanosoma cruzi. Transmission is by contamination ofabraded skin or mucous membranes with infected feces of blood-suckingtriatomine bugs. The natural habitat of these insects is the nests and refugesof mammals and birds. Some species colonize poor-quality housing,however, where they feed from humans and their domestic animals.Transmission may also occur congenitally, by blood transfusion, or fromorgan donors, and occasionally orally by triatomine contamination of food.In mammalian hosts T cruzi multiplies inside cells, particularly of the heartand smooth muscle. In the chronic phase up to 30% of infected people maydevelop severe ECG abnormalities and chagasic cardiomyopathy. Some ofthese patients may also suffer enlargement and dysfunction of the intestinaltract, typically megaesophagus and megacolon. In terms of public healthand economic impact, Chagas disease is the most important parasiticinfection in Latin America; more than 10 million individuals are infectedwith T cruzi. None of the fundamental facts about this disease or thecausative agent were known before the pioneering work of Carlos Chagas(Fig. 1).

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248 M.A. Miles / Infect Dis Clin N Am 18 (2004) 247–260

Before Carlos Chagas

The disease

Armed with the present knowledge of Chagas disease one can lookbackward in time to search for records of the disease before the discoveries ofChagas. Chagas disease works from within, however, and there is no obviousand unequivocal external clinical marker. There will always be an element ofuncertainty about such early clinical records. There are two suggestive earlyclinical entities, both primarily relating to the possible intestinal symptoms ofChagas disease. The first of these, particularly reminiscent of megacolon, wasknown as ‘‘bicho,’’ with severe intestinal obstruction, as described inPimenta’s [2] book of 1707, based on his work experience in Pernambuco,Brazil. Later came clearer accounts of recognizable symptoms. Ferreira [3] in

Fig. 1. Carlos Chagas (1879–1934) the discoverer of Trypanosoma cruzi, its life cycle, and the

associated disease, American trypanosomiasis (Chagas disease). (Courtesy of the Archive of

Casa de Oswaldo Cruz, Department of Archives and Documentation, Rio de Janeiro, and the

Wellcome Trust Illustrated History of Tropical Diseases; with permission.)

249M.A. Miles / Infect Dis Clin N Am 18 (2004) 247–260

Minas Gerais, Brazil, writes ‘‘The corruption of bicho is nothing else but anenlargement and distension of the rectum, which is known by another namecoecum.’’ More graphically, Jobim [4] in 1844 wrote ‘‘Degeneration of thelayers of the stomach, duodenum and large intestine. These a few times arecontracted, on occasions very dilated, above all the descendent colon, to thepoint of resembling a second stomach.’’

The second clinical entity was known as ‘‘mal de engasgo,’’ whichconsisted of difficulty in swallowing or retention of food in the esophagus, asis now described as chagasic megaesophagus. Spix and Martius [5] refer to‘‘the peculiar disease engasgo, perhaps due to a hardening of the uppersphincter of the stomach.’’

Kidder and Fletcher [6] give a more detailed description, in 1857:

At Limeira I became aware of the new disease. . .which is widely prevalentin some portions of interior Brazil. . .. The Brazilians call it mal de engasgo.

The first indication of its existence is a difficulty in swallowing. The personthus affected appears to be in good health but in five or six years deathensues due to starvation. . .. The full extent of country over which the mal

the engasgo prevails is not known but to this physician’s certain knowledgeit exists from Limeira (200 miles from the sea coast) to Goyaz the distance,of 400 miles.

Langgaard, in 1865 [7] gives a very characteristic description:

. . .usually the food bolus only passes up to the cardia above the stomach. . ..Some patients are able to force the descent of the food into the stomach bydrinking a small amount of water after each mouthful of ingested food. . ..As a result of the imperfect nutrition the patients begin to lose weight,

become emaciated. . ..

Guerra [8] incorporates many oblique references to intestinal diseasewithin his detailed history of Chagas disease but some of these almostcertainly relate to different etiologies.

The insect vectors (triatomine bugs)

An attack by triatomine bugs can be an unforgettable and horrificexperience. It is not surprising that there are several graphic accounts oftriatomine bugs long before Chagas discovered their role as vectors of theprotozoan parasite T cruzi. This contrasts with the early vague andequivocal descriptions of what may or may not have been Chagas disease.Lizarraga was a Spanish Dominican who traveled extensively in Peru, Chile,and Paraguay. His account of attack by triatomine bugs, sometime between1608 and 1611, was published in 1909 [9]:

The valley of Cochabamba suffers from a plague, which occurs fromTapacari in all this province of Charcas. . .covers all Tucuman and reachesthe first villages of Chile. It is a sort of cockroach with wings. . .biting in

such a delicate way that it is not felt, at night after the light is turned off. . ..


These bugs are afraid of light but as soon as it is gone they come down the

walls or let themselves fall from the ceiling on to the face or head of thoseasleep. . .. They are clumsy because their legs are long and thin, and aftertheir belly is full of the blood they sucked they cannot walk.

Cobo from 1615 visited several areas of Bolivia and Peru; his descriptionof triatomine attack was published in 1890 to 1895 [10]:

Instead of ordinary bedbugs, up in some parts of this country (Peru) and itswarmer valleys. . .there are bugs bigger and more pernicious to the

inhabitants. . .. They are as big as the tip of the little finger, longer,brownish, and in the shape of beetles. They live in the ceiling of the housesand come out at night guided by the smell of people asleep; getting down on

to the beds they bite cruelly. . .sucking up to half a thimbleful of blood.

Gumilla in his account around 1702, published in 1741 [11], used thememorable phrase ‘‘they suck blood. . .with such care and sweetness that itcannot be felt.’’

Other accounts include those of Dobrizhoffer [12], published in 1822:

Flying bugs called binchuccas are common in Cordoba and other parts of

Tucuman. By day they lurk in the chinks of roofs and chests but fly out atnight and make bloody war upon sleepers.

The account of Azara [13] was published in 1809:

The vinchuca bothers greatly those travelling between Mendoza andBuenos Aires. . .. It is a beetle with a flat and oval body, which becomes fat

like a grape with sucked blood, but as soon as it has digested it defecatesand the stain makes an indelible spot on white linen. This insect onlyemerges at night; the adult insects with wings can fly but not the little ones.

These beetles can be found all over the plains in this country and whencrushed give out a strong stench of bed bugs.

The most famous account of all is that from the diaries of Darwin [14],published in 1839:

We slept in the village of Luxan, which is a small place surrounded bygardens, and formed the most southern uncultivated district in the provinceof Mendoza (Argentina) it is five leagues south of the capital. At night I

experienced an attack (for it deserves no lesser name) of the Benchuca,a species of Reduvius, the great black bug of the Pampas. It is mostdisgusting to feel soft wingless insects, about an inch long, crawling over

one’s body. Before sucking they are quite thin, but afterwards they becomeround and bloated with blood, and in this state are easily crushed. One,which I caught at Iquique, (for they are found in Chile and Peru) was very

empty. When placed on a table, and though surrounded by people, ifa finger was presented, the bold insect would immediately protrude itssucker, make a charge, and if allowed, draw blood. No pain was caused bythe wound. It is curious to watch its body during the act of sucking, as in

less than 10 minutes it changed from being as flat as a wafer to a globularform. This one feast, for which the Benchuca was indebted to one of the


officers, kept it fat during four whole months, but after the first fortnight it

was quite ready to have another suck.

Indeed it has been speculated that Darwin suffered from Chagas diseasebecause he suffered a prolonged chronic illness. Chagas disease is an unlikelydiagnosis for Darwin, however, because his clinical history and symptomsdo not correspond sufficiently well with those expected for chronic chagasiccardiomyopathy and megaesophagus. Furthermore, it is difficult to acquireChagas disease by limited exposure to triatomines: transmission usuallyinvolves contamination of the mucous membranes or abraded skin withinfected bug feces.

In 1773 the Swede de Geer wrote the first taxonomic description ofa triatomine bug, now renamed Triatoma rubrofasciata, and in 1811Latreille named two other species, now known as Triatoma dimidiata andPanstrongylus geniculatus. Several further descriptions followed in the earlynineteenth century [15].

Interestingly, the generic name Triatoma, meaning three-segments, wascreated in error in 1833 by Laporte, based on museum specimens withdamaged antennae. Recognizing his mistake the next year he renamed thegenus Conorhinus, which means cone-nosed. Conorhinus was used for nearlya century but, in accordance with the International Code of Zoologicalnomenclature, the name reverted by priority to Triatoma [15].

Carlos Chagas (1879–1934): the discovery of Trypanosoma cruzi andChagas disease

The discoveries of Chagas are remarkable. Indeed Lewinsohn [16] hasstated that they are unique in at least two senses. First, Chagas found thecausative agent of the disease in the insect vector, the triatomine bugPanstrongylus megistus (Fig. 2) before he described the clinical disease andisolated the organism from patients. Second, it is difficult to find an examplein which so many aspects of a disease have been understood, so rapidly,largely by the efforts of a single individual.

Chagas was a medical student in Rio de Janeiro, Brazil. In 1902 he joinedthe new medical institute at the Manguinhos farm, under the directorship ofOswaldo Cruz. In 1907 he was sent to Lassance [17], in the remote interiorof the state of Minas Gerais, with the task of controlling malaria, which wasimpeding construction of the railway linking Rio de Janeiro to central andnorthern Brazil. He became aware that a large blood-sucking insect, thetriatomine bug (Hemiptera: Reduviidae) infested local poor-qualityhousing. He knew that blood-sucking insects transmitted human diseases,such filariasis and malaria, and dissected the bugs to look for infectiousagents. In the triatomine feces he found a single-celled flagellate. Infectedbugs were sent back to Oswaldo Cruz in Rio de Janeiro, where marmosetsexposed to the bugs developed blood parasitemia of a previously unknowntrypanosome, which Chagas named T cruzi.


The best way of appreciating the simplicity and importance of thesediscoveries is to read the words of Carlos Chagas himself [18,19]:

In 1907 we were commissioned by the director Dr Oswaldo Goncalves Cruzwith the task of carrying out an anti-malarial campaign to support theconstruction of the central Brazilian railroad, in the northern region of

the State of Minas Gerais. We had information on the existence there of thehematophagous insect called barbero by the locals, which inhabits humandwellings, attacking man at night, after the lights are out, and hiding during

the day in the cracks of the walls. . .. Examining the hindgut contents ofsome examples of Conorrinos (bugs) collected in Minas Gerais, in theinterior of human dwellings, we confirmed there the presence of numerous

flagellates with the morphological characteristics of crithidias. . ..We therefore sent bugs to the Institute where our Director Dr Oswaldo

Cruz tried to infect a monkey (marmoset), of the species Callithrix

Fig. 2. Early drawings of a the triatomine bug Panstrongylus megistus, in which Carlos Chagas

first discovered the protozoan flagellate Trypanosoma cruzi. (Courtesy of the Memorias do

Instituto Oswaldo Cruz; with permission.)


penicillata, by having it bitten by several examples of the hemipteran.

Twenty or thirty days after the bite, large numbers of trypanosomes werefound in the peripheral blood of the monkey, with morphology that wasentirely distinct from any known species of the genus Trypanosoma. We

then began to study the flagellate, soon succeeding in infecting byinoculation several laboratory animals, guinea pigs, dogs, rabbits andother monkeys. The parasite was shown to be pathogenic for all these

animals. . ..

If this organism, isolated from P megistus infesting human dwellings,proved infectious and pathogenic to such a wide range of laboratoryanimals, might it not also be the agent of the human disease? Chagas beganto look for T cruzi parasitemia in sick people in Lassance. Here, in his ownwords [19,20], is what he found:

We were called to treat the seriously ill child, whose blood we had examinedpreviously, and on this occasion found flagellates in the peripheral blood.

Staining blood preparations by the method of Giemsa we concluded theobserved flagellate to be a trypanosome, with morphology identical to thatof Schizotrypanum cruzi, whose biology we were studying in the

laboratory. . ..

Chagas can be seen with one of his early infant patients in Fig. 3. Hewent on to give a detailed clinical history of the acute phase of infection,which included intermittent fever, edema, enlarged lymph nodes, andhepatosplenomegaly. Two acute cases were reported at the same time. InFig. 4 Chagas can be seen on the steps of the Lassance hospital with more

Fig. 3. Carlos Chagas in Lassance with one of his early infant patients, diagnosed as suffering

from acute Chagas’ disease. (Courtesy of the Archive of Casa de Oswaldo Cruz, Department of

Archives and Documentation, Rio de Janeiro, and the Wellcome Trust Illustrated History of

Tropical Diseases; with permission.)


of his patients. Unfortunately, Chagas included goiter, then of uncertainetiology, within the wide range of systemic, cardiac, and digestive symptomsattributable to Chagas disease. This may have contributed to subsequentcontroversy and acrimonious debate on the intrinsic value of his pioneeringwork (see later).

Remarkably, Chagas also described two morphologic forms of trypano-some in the blood. These are a highly motile slender form and a shorterbroader form, mobile in situ. The slender forms are associated with acutephase infections but often overlooked and still of uncertain biologicsignificance. Chagas also succeeded in culturing T cruzi using a blood agarmedium.

Fig. 4. Carlos Chagas with patients and staff on the steps of the hospital in Lassance (Minas

Gerais State, Brazil) where he discovered Chagas disease. (Courtesy of the Archive of Casa de

Oswaldo Cruz, Department of Archives and Documentation, Rio de Janeiro, and the Wellcome

Trust Illustrated History of Tropical Diseases; with permission.)


What were the natural hosts of T cruzi ? Astonishingly, Chagas went onto give the first account [21] of a silvatic reservoir host, the armadillo, nowknown as Dasypus novemcinctus.

Another conclusion from an observation, supposing the parasite of the

Tatu (armadillo) to be Trypanosoma cruzi, is that this animal may act as anout-of door carrier of the Brazilian trypanosomiasis.

This led to the description of many other silvatic reservoirs of infection,in accord with the wide host range demonstrated in the laboratory. Extractsfrom the work of Chagas and his colleagues are given in a selection of classicpapers on tropical medicine and parasitology [22], and a collection of hisscientific works has been reproduced [19].

Gaspar Vianna: the intracellular cycle

It is not appropriate to write an account of the discovery of Chagasdisease without special mention of the extraordinary contribution made byVianna.. . . Chagas had assumed that parasitic schizonts seen in the lungwere part of the life cycle of T cruzi, which explains why the organism wasfirst called Schizotrypanum cruzi, and the name of the subgenus remainsSchizotrypanum. It was later demonstrated by Delanoe and Delanoe [23],however, that these schizonts had nothing to do with the life cycle of T cruzibut were in fact the replicative stage of Pneumocystis carinii, now prominentas a fungal agent of opportunistic pneumonia in AIDS. Vianna describedthe true intracellular forms of the life cycle of T cruzi, in both heart andskeletal muscle. He also gives an account of the inflammatory reaction ininfected tissue. Here are some quotes from his work [24]:

The heart is one of the organs to which Schizotrypanum shows predilection inboth humans and animals. . .. These forms of the parasite vary numerically

inside the cardiac cell and one can see them in binary fission. Some cells havea reduced number of protozoan parasites; others have hundreds of them.In human cases, I verified the infection in large areas of the leg, and back,

arm muscles and other areas. The striated muscle cell as well as themyocardial cell contain a variable number of parasites. . ..On reachinga certain point of saturation, when the sarcolemma can no longer contain

the Schizotrypanosomes which have developed in its interior, it ruptures insome parts, and parasites—some still round, others already flagellated—arepushed into the interstices of the muscle fibres.There are cases in which quite peculiar degeneration of the cardiac cell is

present and in which the parasites are not seen at all while the infection ispositively verified in other cells of the organism. . .. Whenever a cardiacfibre ruptures, there is always a definite reaction of the connective tissue,

and other cells come into this area, obviously in defence of the organ.

The astonishing clarity of his observations can be seen in the drawingsfrom his original publication, examples of which are shown in Fig. 5.


Acclaim, scorn, and rediscovery

Chagas initially received local and international acclaim for his discoveryof T cruzi and American trypanosomiasis. He was awarded full membershipof the Brazilian Academy of Medicine in 1910. In an internationalcompetition he won the prestigious Schaudinn Prize, awarded every 4years, for the most important contribution to protozoology. He was twicenominated for the Nobel Prize. The first nomination was in 1913, when theprize was awarded to Richet for work on anaphylaxis. The secondnomination was for the 1921 prize, when no award was made.

The work of Chagas was also greeted by controversy and disbelief. Thisin part was attributable to genuine scientific enquiry. T cruzi replicatesintracellularly and was hard to find in the blood of those infected, even insome acute cases. It was difficult to diagnose and to associate with chronicclinical symptoms. Infected triatomines had been reported from Argentina

Fig. 5. Early drawings of the intracellular life cycle stages of Trypanosoma cruzi, seen

replicating as amastigotes in heart muscle and skeletal muscle. (Courtesy of the Memorias do

Instituto Oswaldo Cruz; with permission.)


but they had failed to find patients. Also Chagas assigned goiter asa symptom of Chagas disease, which proved not to be the case.

As reviewed by Coutinho et al [25] there was also an undercurrent ofjealousy and political rivalry. Chagas had to contend with scorn and openhostility. He was appointed Head of Service at the Manguinhos institute in1910, which no doubt displeased those who were passed over. When Cruzdied in 1917, Chagas became the director of the institute, alienating theacting director who had covered for Cruz during his illness. In 1920 theDepartment of Public Health was created and Chagas was appointed asdirector. This again created enemies, in particular the other primecompetitor for the post. The resultant hostilities culminated, between 1922and 1924, in debate within the Brazilian Academy of Medicine, challengingthe validity of the discoveries of Chagas. As quoted by Coutinho et al [25],in 1922 Chagas was viciously attacked at the Academy, in the followingterms:

You could have found some mosquitoes, you could have invented a rare

and unknown disease, about which much was said, but whose victimsalmost no one knew, hidden in a countryside dwelling of your province,a disease that you could magnanimously distribute among your fellowcountryman, accused of cretins.

A commission was established to investigate. More than a year later itsreport vindicated Chagas. It has been suggested that the acrimony and

Fig. 5 (continued )


investigation at home influenced the outcome of the Nobel Prize nomi-nations [25,26].

Chagas died in 1934, before the true extent of the distribution of Chagasdisease in Latin America had been established. Chagas disease was‘‘rediscovered’’ in the 1930s in Argentina by Mazza and Romana [27].Slowly it emerged that it was present throughout Latin America as a majorpublic health problem. Serologic surveys indicated that up to 18 millionpeople carried T cruzi, with a huge burden of morbidity and prematuremortality, and up to 100 million were exposed to infection. Interest ininterventions and in research on T cruzi began to grow.

Subsequent landmarks

The purpose of this article is to illuminate the discovery of Chagas diseaseand some of the events surrounding it. Interest in Chagas disease hasexpanded dramatically, particularly over the last two decades. Thisexpansion of interest in part arises from a realization that this infection isthe most important parasitic disease in Latin America, and is also caused byan international determination to control its transmission, particularly inthe southern cone countries of South America. In addition, trypanosomeshave become model organisms in the study of molecular biology and thisdrives much of the laboratory research on T cruzi [28].

The Wellcome Trust Illustrated History of Tropical Diseases [1] brieflydescribes some of the other early landmarks in the history of Chagas disease,such as the demonstration by Brompt that transmission of T cruzi is bycontamination of mucous membranes with infected triatomine feces; thedevelopment of xenodiagnosis, whereby T cruzi it is detected in mammalianhosts by feeding uninfected triatomines on them and subsequently dissectingthe bugs to detect the organism; the first serology for Chagas disease,a complement fixation test produced by Guerreiro and Machado in 1913;the description of unilateral conjunctivitis and edema (Romana’s sign) asa classical indicator of acute Chagas disease; the development of neuronalloss and autoimmunity theories to explain the pathogenesis of Chagasdisease; the perfection of surgical procedures to treat megacolon andmegaesophagus; the introduction of insecticide spraying to control domesticbug infestations; and the realization that blood transfusion is such animportant secondary mode of transmission.

Dias et al [29] gives a history of the Southern Cone Initiative andassociated efforts to control Chagas disease in the southern cone countriesof Latin America. This initiative has become a model for the role thatresearch collaboration can have in stimulating international co-operation, inmobilizing political will, and in driving international control programs.

One prominent theme of the last two decades has been resolution of thephenotypic and genotypic diversity of T cruzi, which is now known not to bea single entity but a heterogeneous complex of organisms. This genetic


diversity provides the likely explanation of the regional differences in theclinical manifestations of Chagas disease [28]. Molecular markers, for bothT cruzi and triatomine populations, can also help to unravel the complex-ities of transmission cycles and their epidemiologic significance [28].Furthermore, it has recently been shown that T cruzi has a capacity forgenetic exchange, by an unusual mechanism of hybridization [30]. Hybridstrains seem to be common among natural populations, and one such strain,CL Brener, has been selected for the T cruzi genome sequence project. Arecent book provides an update on research developments [31] and a WorldHealth Organization technical Report [32] gives a detailed account ofclinical aspects of Chagas disease and control strategies.

None of these recent findings erode the fundamental importance andastounding nature of the discoveries of Chagas and his distinguishedcolleagues. The work of Chagas is characterized by rapid progress involvingfew dedicated individuals. The international community has progresseda little further since then, by the effort of many. Chagas disease is still withus, although in retreat as a public health problem. There are still plenty ofunanswered questions concerning the pathogenesis of the disease and thebiology of the fascinating causative agent, T cruzi.

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The Discovery of Chagas Disease