Trypanosoma Cruzi, the Etiologic Agent of Chagas' Disease: Status in the Blood Supply in Endemic and Nonendemic Countries

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Reviews Trypanosoma cruzi, the etiologic agent of Chagas' disease: status in the blood supply in endemic and nonendemic countries

G.A. SCHMUNIS

AMERICANTRYPANOSOMIASIS (Chagas' disease) is a lation is infected with T. cruzi,l0 and limited studies7 of protozoan zoonotic disease caused by the hemoflagellate the populations of Guatemala and Honduras indicate that Trypanosoma cruzi (T. cruzi). It is transmitted to the 730,000 and 300,000 persons, respectively, are infected. vertebrate hosts by hematophagous insects of the genus These numbers represent approximately 8.4 and 6.2 per- Triatoma, the triatomine bugs. The infection is autoch- cent of the total populations of those respective coun- thonous in the Americas, where 16 to 18 million people tries. Similar prevalence has been found in some areas are infected.' Most of these people live in the poor rural of Mexico." In fact, infected individuals have been re- or suburban areas of South and Central America, from ported in all Central and South American countries in- Mexico in the north to Argentina and Chile in the south.2 cluding French Guiana, Guyana, and Suriname. The only The extent of human infection is related to the poor Spanish-speaking countries in the western hemisphere in socioeconomic conditions of the population and the do- which human T. cruzi infection has not been found are mestic nature of the vector.24 Cuba and the Dominican Republic. American tIypanosomiasis is more widespread as an Three transmission cycles of T. cruzi involving inter- enzootic disease than as a human infection. Its range vention of the vector are recognized. The domestic cycle, extends approximately from latitude 42 N (northern Cal- which is responsible for maintaining the infection in hu- ifornia to Maryland) to latitude 43 S (southern part of mans, occurs mostly in houses of rural or suburban areas Argentina and Chile).z In the United States (US), how- with bahareque or adobe walls and thatched roofs. The ever, the better living conditions of the population and vector lives and multiplies in cracks in the walls, in holes the sylvatic characteristics of the local species of tria- in the roof, under and behind furniture, behind pictures, tomines make human infection by the vector extremely and so on. The most important vectors are Triatoma un~sual.~-~ infestans in Argentina, Bolivia, Brazil, Chile, Paraguay, It is estimated that there are 2.6,7 5,* and l.27 million Peru, and Uruguay; T. sordida in Bolivia, Brazil, and infected individuals in Argentina, Brazil, and Vene- Paraguay; Panstrongylus megistus in Brazil; T. dimi- zuela, respectively. Data from B~livia,~Chile,7 Para- diata in Ecuador and Central America; Rhodnius palles- g~ay,~and Uruguay9 indicate that 500,000, 1,460,000, cens in Panama; and R prolizus in Colombia, Venezuela, 397,000, and 37,000 individuals, respectively, may be and Central America.14 They are well-adapted to houses, infected in those countries. These figures imply that 7.9 where they live in intimate contact with man and do- percent of the population of Argentina, 4.3 percent of mestic animals such as dogs and cats. that of Brazil, 6.2 percent of that of Venezuela, 7.2 The sylvatic cycle involves sylvatic triatomine bugs percent of that of Bolivia, 11.0 percent of that of Chile, that become infected and, in turn, infect rodents, mar- 9.8 percent of that of Paraguay, and 1.2 percent of that supials, and other wild animak2w4There is a peridomes- of Uruguay are infected with T. cruzi. Estimates from tic cycle in which mammals (domestic rodents, marsupials, El Salvador indicate that 20 percent of the rural popu- cats, dogs) and sylvatic bugs participate-mammals by moving freely from the outside to the inside of human ~~ dwellings, and sylvatic bugs by being attracted to lights Abbreviations: CF = complement fixation, DAT = direct agglutination test, ELISA = enzyme-linlred hmnnosorbent assay; in houses and to food. This cycle acts as a link between IHA = Indirect hemagglutination; IIF = Indirect the domestic and sylvatic cycles. immunofluorescnce. Most persons acquire the infection when their skin or From the Communicable Diseases Program, Pan American Sanitary mucosa comes in contact with feces of infected bugs. Bureau, Regional Office of the World Health Organization, Washing- ton, DC. The recent infection is usually not evident; the signs and Received for publication July 23, 1990; revision received January symptoms are so mild that they are not associated with 23, 1991, and accepted February 6, 1991. T. cm*infection. In the few cases in which symptoms

547 TRANSFUSION 548 SCH M U NI S Vol. 31. No. 6-1991 appear and are recognized as T. cruzi infection, the site Morbidity of T. cruzi in blood donors of entry of the parasite shows a primary chagoma char- Serologic surveys of T. cnui antibodies in blood do- acterized by a small, reddish, slightly painful nodule and nors have been made since 1949. Almost all surveys often accompanied by the swelling of satellite lymph between 1949 and 1980 have been reported else- nodes.7 These signs may be followed by fever and en- ~here.'~J~*~*~Surveys reported since 1980 are sum- largement of the liver and spleen. Young children may marized in Table 1 for Argentina;20*25*30*31Table 2 for show symptoms of an acute myocarditis or meningoen- Bra~il;~?-~~Table 3 for the Andean countries such as cephalitis. Mortality is usually low, except for children B~livia,~~~~Col~mbia,'~ Ecuador, and Venezuela; Ta- with cardiac or central nervous system inv~lvement.'~*'~ ble 4 for Costa Guatemala,& Hondura~,'~Mex- Even without treatment, most individuals recover from ico," and the US;& Table 5 for and Table 6 the acute stage of the infe~tion.'~-~~After a latent period for Uruguay.64s65The survey results are usually from the of years or decades, up to 20 percent of those infected capitals of countries, provinces, or states in which there in Argentina and Chile and up to 40 percent of those in is no vector transmission even though the area is en- central Brazil may develop the cardiac or gastrointestinal demic. In other instances, results are from cities in whose symptoms that characterize chronic Chagas' di~ease.'~ surrounding rural areas there are no bugs because ecol- ogic conditions do not allow them to survive, as in the T. cruzi and Blood Transfusion Chubut and Tierra del Fuego provinces in the southern tip of Argentina, or because domestic bugs have been Although most cases of human T. crua' infection are eliminated by control measures, as in the state of Slo still acquired through contact with contaminated feces Paulo, Brazil. In spite of the lack of vectors, there have of infected triatomine b~g~,~.~*~~other ways of acquiring been positive serologic tests in blood donors (Tables 1 the infection are becoming significant. It is believed that and 2). In the Argentinean provinces, migration alone an individual not receiving early treatment after infection could account for this situation. In the state of Slo Paulo, will remain infected throughout life. Parasitemia may be however, individuals infected in the rural areas before detected years after the infection took place in as many transmission-blocking strategies were implemented should as one-half of those infected.16 This parasitemia could be added to those who came to that state from endemic easily be transferred to a noninfected person by blood areas. transfusion, which is actually considered the second most Most of the surveys were made by using one serologic common way of acquiring the infection.17-19 test: for example, the data from Chile are mainly based The potential importance of this form of transmission on the indirect hemagglutination te~t4~~'and those from is related to the prevalence of infection in the population Colombia on the indirect immunofluorescence test.42 Data and to the profound social changes that have occurred from a few other surveys using two30*33*38*40or more3' in Latin America in recent decades. Economic hardship tests were obtained. An interesting trend is the decrease has stimulated migration to urban areas, where more in the number of donors in certain locations with positive than 60 percent of the population now lives." This has serologic te~ts.~~~~.~This change can be explained by increased the possibility of T. cnui infection of blood the successful implementation of control measures in ru- transfused in cities. Because of economic problems and ral areas, as seems to be the case in Argentina,30 Brazil,* political turmoil, migration has increased to other Latin and Venezuela.? Given the number of blood transfusions American countries as well as northward to the US and yearly in the Americas and the very few countries man- eastward to Europe. The United States is by far the main dating serologic tests for T. cnui in blood donor screen- destination of immigration from Latin America, and most ing, T. cruzi infection from transfusion is still a serious of these immigrants are from Mexico.2' Figure 1 shows problem, even when only some of those receiving in- the overall intranational and international migration pat- fected blood become infected-14 to 18 percent in Ar- terns in the Americas. gentina, Brazil, and Chile17-19*29and up to 49 percent in Because of immigration, it is not surprising to find in Bolivia.41 Washington, DC, individuals from El Salvador and Nic- aragua with positive serologic tests for T. cru~i2~or in Sweden a case of congenital T. cruzi infection.= In fact, Incidence it has been estimated that there are 100,000 individuals Although hard data on the incidence of transfusion- living in the US who are chronically infected with T. associated infection are not available, it is estimated that ~ruzi.~~Although the potential problem for the blood 10,OOO to 20,000 cases occur yearly in Brazil alone." supply in the US has been recognized for some time,= Information is also available in a report from Santa Cruz, the recent diagnosis of Chagas' disease acquired through Bolivia,"l where 62 percent of the donors and 70 percent blood transfusion in the USz6 and Canada27has height- of the recipients were seropositive for T. cnui. Assum- ened awareness of the seriousness of this problem.24*28 ing that 3400 transfusions are performed in Santa CIUZ TRANSFUSION 1991-Vd. 31. NO. 6 TRYPANOSOMA CRUZI IN THE BLOOD SUPPLY 549

Ro. 1. Overall pattern of migration in the Americas. The numbers of Latin Americans (in the thousands) who immigrated to the United States.” Because of illegal immigration, the numbers shown here arc probably an underestimation of the nal number of immigrants. annually and extrapolating from the reported data,” we that time, however, detection of specific IgM may be a can conclude that, of 1020 seronegative recipients, 26.9 confirmatory percent will become infected. Thus, the incidence would The practice of taking several samples of serum be 8 percent of the total number of transfusions accom- throughout a period is especially helpful. Decreasing ti- plished per year. Those persons in whom acute T. cruzi ters will tend to disprove the presence of the infection, infection acquired through blood transfusion is not di- and stable or rising titers will confirm it. The main prob- agnosed and treated may, years later, develop chronic lem is that most cases are asymptomatic or the symptoms Chagasic cardiopathy or megae~phagus.~*~’ are very mild and not recognized as T. cruzi infection. There is no obligation to report transfusion-associated Even in endemic countries, physicians sometimes do not cases; such reports would be of limited use. Most cases connect T. crua’ infection with late (4 weeks or more) are not diagnosed, even though confirmation of clinical persistent posttransfusion fever that does not respond to suspicion is not difficult. Detection of the parasite by antibiotics, even if the fever is accompanied by liver and microscopic observation of a blood sample may confirm spleen enlargement.69 Attempts to use the detection of the diagnosis, but a negative microscopic test does not specific IgM to identify recent transfusion-associated in- invalidate it. Serologic tests are also helpful, although, fections in asymptomatic, multiply transfused individu- if done soon after the transfusion, they could be positive als have not been successful.7o Therefore, it is not because of the transfer of antibodies from the donor. At unexpected that, in nonendemic countries, a diagnosis TRANSFUSION 550 SCHMUNIS Val. 31. No. 6-1991

Table 1. Positive serologic tests for T. cruzi in blood donors Table 3. Positive serologic tests for T. cruzi in blood donors in Argentina in several Andean countries Number of Prevalence of Number of Prevalence of Location (reference cited) Year' samples Infection (%) Country (province or city) Year' Samples infection (%) Buenos Ares (city)= 1987 12,991 1.7 Bolivia Buenos Ares (province)30 1987 58,284 4.89 Santa CNP 105 51 .O Thirteen provincess 1981 95,904 8.7 TariJaa 114 45.0 Catamarcaa.30 1987 1,594 8.6 Ctxhabambaa 286 28.0 1982 156 17.0 Sucrea 1988-1989 105 39.0 C15rdoba~~.~ 1987 19,259 11.7 La Psi? 432 4.9 1982 2,441 8.4 Oruroa 83 6.0 Chacoz6.J0 1987 3,044 23.9 PotoslQ 72 24.0 1982 480 20.9 Santa Cruz4' 1982-1983 280 62.1 ChubuP 1987 1,604 2.1 Entre Rlos" 1982 237 5.7 Formosa= 1987 6,922 7.2 Colombla42 Norte de Santanderl JujW 1987 11,734 17.5 La Pa~npa~.~' 1987 2,414 5.7 cucuta 1987 491 7.5 1982 248 7.2 Ecuadort La Riojaa.50 1987 939 19.2 Quito 1990 1,979 0.10 1986 588 20.4 Mendozazn.30 1987 4,288 12.0 Chone 1990 387 0.26 1982 81 8 12.4 Esmeraldas 1990 370 0.54 Rlo Negrow 1987 514 3.5 1988 566 0.35 Rosarioao 1987 12,000 15.0 Quevedo 1990 278 0.72 Salta2s.J0 1987 3,040 16.0 1986 23 1 0.43 1982 41 1 12.4 Sto. Domlngo de 10s 1990 398 0.00 San Luis= 1987 1,230 9.0 Colorados 1989 1,259 0.08 San Juans.W 1987 2,009 7.9 Loja 1989 1,245 0.16 1982 72 5.5 Machala 1989 2,004 0.09 Santa FeZs.= 1987 2,352 7.0 1988 2,052 0.05 1982 883 4.4 1987 838 0.83 Santiago del Esteros*W 1987 2,003 17.6 1986 2,004 0.29 1982 392 22.4 Babahoyo 1988 678 0.58 Tierra del Fuego30 1987 122 8.4 TucumAns,W 1987 6,675 7.3 Guayaquil 1986 11,878 0.33 1982 815 7.7 VenezuelaS 1989 195,476 1.33 'Year In which the samples were collected or the study was 1988 21 5,420 1.59 published. 1987 199,428 1.60 1986 187,589 2.08 1985 174,686 1.98 *Year In which the samples were collected or the study was Table 2. Posltive serologic tests for T. cruzl in blood donors published. in Brazil tlnformation provided by the Red Cross of Ecuador. Number of Prevalence of *Information provided by Dr. E. Brito, Transfusion and Blood Country (province or city) Year' samples infection (%) Bank, Ministry of Health and Welfare, Venezuela. Brazil Brasilia= 1984 2,413 14.6 Goias/Goiania= 1985-1989 62,814 3.3 Minas Gerals" In a hypothetical country of 30 million inhabitants, in Several cities 1984 2,300 5.7 which 8 percent of the population is infected and 600,ooO Minas Gerais/lJberabaS1983-1985 5,632 4.83 Uberaba" 1980-1988 4,923 5.0 units of blood are transfused yearly, we may expect 48,ooO ParaniVL~ndrina~~ 1981 3,000 7.5 of those units to be infected with T. cruzi. Considering Rlo Grande do Sull that 8 percent of the recipients are already infected and Port0 Aegre= 1981-1983 15,338 0.21 Sbo PaulolSAo Paulo" 1982 56,902 2.9 that about 20 percent of the noninfected individuals re- Sta. Catarind ceiving an infected Mit may become infected, there would FlorlanopolisSO 1985 3,540 0.09 be approximately 8800 yearly cases of transfusion-as- 'Year In which the samples were collected or the study was sociated T. cruzi infection. In a country with the above- published. mentioned population, these would be about 500,000 newborn infants per year. Of those births, 8 percent would be to Chagasic mothers. Because 2 to 3 percent of those of transfusion-associated infection is made in immuno- born to the 40,000 Chagasic mothers might be in- suppressed blood recipients having symptoms of an acute fected,7l approximately 800 to 1200 cases of congenital infection and whose blood shows 7'. cruzi on micro- infection could occur yearly. Therefore, if serologic tests scopic ~bservation.~~.~' are not used to discard infected units, there would prob- TRANSFUSION 1991-VoI. 31. No. 6 TRYPANOSOMA CRUZI IN THE BLOOD SUPPLY 55 1

Table 4. Positive serologic tests for T. cruzi in blood donors Table 6. Positive serologic tests for T. cruzi in blood donors in countries of Central and North America in Uruguay Number of Prevalence of Number of Prevalence of Country (province or clty) Year' samples infection (%) city Year' samples infection (%) Costa Rita- 1980-1984 40,774 0.92 Alajuela 1,306 0.8 1983-1984H 123 1.6 Heredia 1983-1985 666 0.9 1982 39,691 1.03 San Jose 602 1.6 Paysandu 445 4.7 GuatemalaU salt0 1983-1984s 71 4.22 Various cities 1987 1,260 5.0 Tacuarenbo 699 7.7 120 3.0 Various cities 1987 1,225 11.6 Cerro Largo 387 1.o 767 2.4 Paysandu 198M Mexico' Rivera ] 21 9 3.2 PuebldPuebla 1986 200 17.5 Salt0 51 9 1.5 USA Tacuarenbo 554 6.0 CaliforniaRos Angeies" 1988 1,027 0.097 'Year in which the samples were collected or the study was Washington, DCt 1983 200 0.0 published. 4Year in which the samples were collected or the study was tData from one hospital only. published. *information provided by Dr. L Calm, Blood Transfusion tinformation provided by Dr. Ana Szahan, George Washington Services, Ministry of Health, Uruguay. Unkersity Medical Center, Washington, DC. Samples from Red Cross Donors, Washington, DC.

If serologic testing were used in this hypothetical country to prevent transmission, there would still be the Table 5. Posltive serologic rests for T. cruzl In blood donors in Chile possibility of transmission by transfusion because of the percentage of false-negative results for the various se- Number of Prevalence of Location Year' samples infection (%) rologic te~ts.'~.~."If false-negative results are obtained from 2 percent of the tests, it could be assumed that 960 1985 1,035 1.3 1985 1,062 1.o units may have had parasites and that 8 percent of those 1985 1,017 1.o units could be transfused to already-infected individuals. Santiago47u 1984 260 0.8 By transfusing the remaining units, approximately 176 1984 429 2.8 1982 1BOO0 2.0 recipients would acquire the infection (0.5/100,000 1980 325 0.3 population). 1980t 314 3.16 The risk of receiving infected blood will increase in Region illquiqueM 1982-1983 1,278 1.6 proportion to the prevalence of the infection in the donor Arbm 1982-1983 1,064 2.5 population and the number of transfusions received. He- Region Ii/Calama57 1983-1984 1,Ooo 2.6 mophilic patients clearly are at greater risk. In Argen- Antofagasta5' 1983-1984 998 3.8 Catamam 1981 214 12.1 tina, up to 50 percent of hemophiliacs became infected after receiving 30 or more transfusions from a blood Region IiIICopiapo" 1982-1983 1,144 6.5 bank where 2 percent of the donors were infected by T. Region iVLa Serenam 1983-1985 1,000 1.2 CM..~~In a recent study in Chile,n 15 percent of per- @allem 1983-1985 498 7.6 iliapeim 1983-1985 357 9.2 sons who were multiply transfused because of hemo- Salaman&' 1981-1 982 202 29.0 philia, hematologic alterations, or dialysis had positive Reglon VlSan Feiipe" 1983-1984 999 2.7 serologic tests, while only 2 percent of the general pop- Los Andesw 1983-1984 996 3.6 ulation had positive serologic tests. The same study Region ViIRancagua- 1983-1989 1,041 1.7 showed that persons who received multiple transfusions San Fernando- 1983-1989 500 0.8 of blood from a blood bank where 2 percent of serologic Santa CruP 1983-1989 500 0.8 tests were positive for T. cruzi were 8.7 times more 4Year in which the samples were collected or the study was likely to be positive than persons who did not receive pubilshed. transfusions." On the other hand, the theoretic risk of tCombined information from three hospitals. transmission for individuals receiving only one transfusion may vary from 0.15 to 0.6 percent.s0 Potential danger may come not only from whole blood ably be a higher incidence of transfusion-associated cases but also from packed red cells, platelets, white cells, (24.5/100,000 population) than of congenital cases (2.6- fresh-frozen plasma, and ayoprecipitate, yet the parasite 4/100,000 population). may not survive in lyophilized produ~ts.~~.~~~~ TRANSFUSION 552 SCHMUNIS Vol. 31. No. 6-1991

Prevention itive serologic tests, which decreases the blood supply Endemic countries available for transfusion, or in hospitals where it is not possible to carry out serologic tests, the only way to Blood must be screened by serologic tests; positive prevent infection is to add a trypanocidal drug to the units must be discarded. Antigens for serologic tests are b100d.19.z*29 Early work indicated the in vitro activity made by public health laboratories or are commercially of crystal violet dye on T. cnui and stipulated its use to available. Two different serologic tests with the same prevent transmission through blood tran~fusion.~~(Crys- sample and stringent measures for quality control will tal violet and gentian violet are considered synonymous.) minimize the possibility of false results.z*M*a In areas Subsequent work showed the in vitro potential of anti- of high prevalence of the infection, if discarding sero- biotics such as amphotericin B,74 candicidin, nystatin, logically positive units will compromise the blood sup- doxorubicin, IMI30, and several amphiphilic cationic ply for transfusion, it may be necessary to implement drugs, including maprotiline, a tetracyclic antidepres- chemoprophylaxis of the blood. and 3-allyl-B-lapa~hone.~~Results of experi- Both measures are well known but not widely imple- mental work using gamma radiation were also mented. Few countries have mandated serologic tests for encouraging.78 However, none of these drugs were tested T. cnui in blood donors. However, for such testing to in the field69 and their potential toxicity when given in- be effective, the government must be prepared to enforce travenously in blood has in most cases not yet been its implementation. The medical profession is sometimes dete~mined.~~.~~ of little help. In a made among the staffs of At the present time, only crystal violet is used rou- health units from the endemic area of Brazil, between tinely in collection containers. This prevents transfusion- 74 and 77 percent believed that Chagas' disease was associated T. CIW' infection at a concentration of 200 frequent and of sociomedical importance, but only 2.8 p.g per mL (0.6 mM [0.6 mmoUL]) of blood stored at percent knew of transfusion-associated infections in that 4°C for 24 hours before use (125 mg crystal violeV500 region. Another survey" in the same Brazilian area in- mL blood).19*z*67*80Commercially available triphenyl- dicated that routine tests to exclude donors with T. cnui methane gentian violet dye is a purified mixture of three infection were done in only 40 percent of the 266 coun- rosaniline dyes: hexamethyl violet makes up 96 percent ties in which transfusions were performed (473 hospitals of the mixture and pentamethyl violet and tetramethyl- and 100 blood banks). The same survey"" indicated that pararosaniline (brilliant green) the remaining 4 percent. only one serologic method was used by 68 percent of A photodynamic action of gentian violet against T. cIuziB1- the centers in which serology was performed. When a 83 is probably mediated by oxygen-reduction similar study was done in Argentina,M 50 percent of the When the drug is exposed to light, the photoreduction 423 centers responding to the survey carried out only of gentian violet causes a carbon-centered free radicaP one serologic technique to reject positive donors. The that, in aerobic conditions, auto-oxidizes and produces number of transfusions is increasing in the Americas; a superoxide anion whose dismutation yields H2.82 The the overuse of hemotherapy has been mentioned as one redox cycling of this dye is enhanced with light by re- of the factors contributing to this increase." This pos- ducing cofactors such as ascorbate, that increase free sibility, in conjunction with the overall prevalence of the radical formation.82 It is worth mentioning that photoir- infection, suggests that transfusion-associated transmis- radiation with artificial light and sodium ascorbate re- sion is a real public health problem. duces both the effective dose of crystal violet and its Another hindrance to prevention is the existence of required time of contact for killing the parasite in in- paid blood d~nors,l~*~~whose blood has a higher risk of fected blood.79 This is of practical importance, as crystal being infected. Migrants from rural to urban areas are violet could be used in small health centers that lack the usually part of the unskilled labor force. As they are facilities to store blood or when quick sterilization of more likely, in a urban environment, to be unemployed potentially infecled blood is necessary. J3posure of blood or underemployed, they donate blood for money. Volun- to a combination of light (a 500-W lamp from a slide teer or directed donations may prevent transfusion-associ- projector) and 10 mM (10 mmol/L) ascorbate will kill ated transmission. It has been shown that, when relatives the parasite in 20 minutes.83 Encouraging results were donate blood for transfusion, there are significant decreases also obtained when a 75-W fluorescent lamp was used." in the prevalence of T. cm' in the blood bank." Although several mechanisms have been proposed to ex- chemoprophylaxis, serologic tests, education of health plain the effect of crystal violet in the dark, none has personnel, and the nonuse of paid donors are thus the yet been clearly identified.m There is evidence, how- basis for prevention. The first two will be discussed at ever, that in T. cnui the mitochondrion is the target for length. crystal violet toxicity.85 Blood chemoprophylaxis. In areas of high endem- The toxicity of gentian violet has been tested in dif- icity where potential donors are excluded because of pos- ferent ways. In vitro, it was showPsm to be a mutagen TRANSFUSION 1991-Vd. 31. No. 6 TRYPANOSOMA CRUZI IN THE BLOOD SUPPLY 553 of Escherichia coli and to cause frameshift mutations. It the other hand, the use of the CF is decreasing progres- also causes a severe cytogenetic toxicity, is a mitotic ~ively.~lEvaluation of the sensitivity of any of these poison, is clastogenic, and produces a chromatid ex- tests is initially made by using sera from individuals with change in cultured cell^.^*^ positive xenodiagnosis who are considered to be true In vivo, crystal violet was shown to be carcinogenic positives. In these circumstances, any of the above-men- in different organs in rodents in proportion to the dose tioned diagnostic techniques has a sensitivity of up to administered." In humans, after the drug is administered 100 percent.= When new antigens are used in a known intravenously, depressions of the white cell count in in- test or when a new test is being evaluated, the IIF has fants and of gastrointestinal irritation in adults have been become the reference test because of its high sensitivity reported. Other side effects included necrotic skin or (s98%), easy reproductibility, and standardization of mucous membrane reactions and keratoconjunctivitis. reagents.g1 Crystal violet was identified as a cause of nosebleeds in The host immune response recognized dozens of an- workers exposed to it.86*87 tigenic determinants of T. cnui. Some of them are stage- Crystal violet has been used in thousands of transfu- specific, others are present in all stages, and still others sions in Latin America without serious side are common to other trypanosomatids like leishmania even when 34 L were given to one patient in 74 trans- and T. rangekaW Sensitivity andlor specificity of a fusions during a &month period and 4 L were given given test will depend on the test itself and also on the once to another patient.s0 Although microagglutination antigen(s) used. For example, sensitivity in the CF may and rouleaux formation of red cells have been reported, vary from 90 to 99 percent, depending on the antigen.9o side effects seemed to be transitory and without conse- Antigens for the IIF and the DAT are whole epimasti- quences. The only real disadvantage is that the patient's gotes that were formalin-treated in the IIF, but treated blood may become blue-stained for a short period.s0 For with trypsin before treatment with formalin in the DAT. this reason, some physicians would prefer not to use the In the CF and ELISA, the parasites are broken, and all dye even if no other product is available. No study has or part of the homogenate is used in the test. In the IHA, yet been reported on the possible long-term toxicity of soluble antigens obtained from the supernatant of lysed transfused crystal violet, but a casecontrol study of its epimastigotes are used.J0p90 possible carcinogenic effect is underway in Brazil. Comparison among thousands of sera indicated a 98.8 Crystal violet does not seem to affect metabolism or percent correlation between the results of the CF and the the preservation of fresh red cells stored up to 28 days. IHA and a 98.9 percent correlation between those of the ATP and 2,3-DPG levels were similar to those found in IHA and IIF. On the other hand, a comparative study of untreated blood stored up to 21 days, but from 22 to 27 the results of the CF, IHA, and IIF showed that the CF days of storage, the levels decreased. However, until the confirmed 99.2 percent of the samples considered pos- 28th day, levels were still above the minimum accepted itive by the other two techniques but detected as positive for good preservation. The pOz, pCOz, and sodium and 0.1 percent of the samples considered negative by the potassium levels were considered normal.89 IHA and IIF. In general, the IIF detected as positive a Serologic tests of blood donors. It is highly unlikely slightly higher number of sera than the IHA, and both that an individual donating blood would have recently had more sensitivity than the CF.31*90*989In another been infected, which is the only situation in which the study,'O0 a correlation of 94.5 percent between the IIF detection of parasites in blood could be a useful tool in and the DAT was found. certification of the infection in the donor. The detection A recent comparative IIF and CF study' of 588 Sera of parasites to certify infection is not useful in blood from a blood bank 20 percent of whose serologic tests banking, because direct microscopy of blood in chronic were positive for T. cluzi indicated that CF had lower cases is usually negative and because hemwulture or sensitivity. The IHA at a 1-in-8 dilution of the serum xenodiagnosis is cumbersome and positive in no more sample had a sensitivity of 99.2 percent and a specificity than 50 percent of cases.16 of 73.1 percent; at a 1-in-16 dilution, a sensitivity of Several tests are available for the routine serologic 92.5 percent and a specificity of 85.9 percent; at a l-in- diagnosis of T. cmi infection: complement fixation (CF), 32 dilution, a sensitivity of 85.0 percent and a specificity indirect hemagglutination (IHA), indirect immunofluo- of 93.2 percent.31 Similar studies, including others based rescence (IIF), direct agglutination test with previous on larger surveys,mJo' suggest that a 1-in-8 dilution of treatment of the sera with Zmercaptoethanol (DAT), and sera tested by IHA could be used as a screening method enzyme-linked immunosorbent assay (ELISA).90 The CF, to discard presumably positive blood donors. This method IHA, and IIF are the most widely used tests. The ELISA would yield up to 5 percent false-positive results within is also being used with increasing frequency for T. cruzi the serologically negative population of Argentina.'O* diagnosis; increased testing for human immunodefi- When the IHA is routinely used for screening, a 1-in-8 ciency virus has made the equipment more available. On dilution of positive serum samples should be confirmed TRANSFUSION 554 SCHMUNIS Vol. 31, No. 6-lW1 by, at the least, the performance of another IHA test, at leishmaniasis or T. rangeli infection. The availability > 1411-16 dilution.101.102Undoubtedly, the discarding of of more sensitive and specific antigens is an attainable 5 percent of the units because of false-positive results is goal, and there is no doubt that recombinant antigens unacceptably high. have an important role to play."O To date, even without Latex agglutination tests for screening donors have these antigens, however, available tests allow for a se- also been developed; some laboratories have had good rologic diagnosis of T. cruzi infection with a high degree results with them, but others have not. In fact, low sen- of sensitivity and specificity."' sitivity and remarkable differences from lot to lot have From a practical, blood banking point of view, it is been reported.m*wJm unlikely that an individual with cutaneous or mucocu- The internal concordance of T. cruzi serologic tests, taneous lesions in uncovered areas of the body or with repeatedly krformed in the same laboratory, is good clinical visceral leishmaniasis would be asked or per- (>95%). On the other hand, the external concordance mitted to donate blood. In addition, if the test for T. is about 80 percent, which indicates a need for improved cruzi crossreacts with leishmania, detecting subclinical repr~ducibility.~~Therefore, because of variations in infections, or with T. rangeli, it could be argued that technical procedures and reagents as well as in the cri- this feature is desirable. Although T. rangeli is consid- teria for evaluating the results of the tests, discrepancies ered nonpathogenic, the possibility that it could be trans- in the results of different laboratories testing the same ferred by the blood should be taken into consideration. sera are not unexpected."*103 Discrepancies have oc- Moreover, the possibility that cross-reactivity with leish- curred even when reference laboratories tested the same mania or T. rangeli will eliminate enough blood donors serum panel with one or more of the following tests: CF, to compromise the blood supply remains to be proven. IHA, DAT, IIF, and ELISA. All of the laboratories con- Data on the serologic prevalence of T. crua' in blood sidered a sample positive even if only one of the tests donors from ArgentinaZJ" and Uruguay64.65 correlate was positive. The study indicated a wide range of dif- well, overall, with the results of the serologic surveys ferences, including differences in the criteria used to indicating morbidity in the general population of these evaluate a sera as positive or negative,lo3and concluded co~ntries.~*~J~'Similar findings were reported in one that ensuring the comparability of the results requires a Brazilian state.33 It could be hypothesized that the de- common standard reference sera and test cutoff levels termination of the prevalence of T. cnrzi antibodies in that reflect the local prevalence of the infection and the blood donors in a country where knowledge of the status distribution frequencies of titers in infected and unin- of human infection is lacking and where control mea- fected individ~a1s.l~~ sures are not implemented could provide information on Acute infections of different origins may produce IgM the prevalence of the infection in a given geographical antibodies that could react with T. cruzi, usually at low area. The prevalence would also indicate the need to serum dilutions, in the IIF test.w This could be avoided implement control strategies for the prevention of trans- by the use of a fluorescence-labeled, anti-human IgG in mission via transfusion. the test. The most important problem, however, is the false-positive results of sera from individuals infected Nonendemic countries with mucocutaneous and visceral leishmaniasis. Any of In most Latin American countries, the overall preva- the above-mentioned tests will show this cross-reactiv- lence of T. cruzi infection makes serologic tests a rea- ity.w.95 Differential immunodiagnosis is also needed in sonable control measure. For example, assuming that, infections with T. rangeli, a parasite that shares with T. in the city of Slo Paulo, 250,OOO units of blood are cruzi several antigens, some geographic areas, and host transfused yearly with a 2-percent prevalence of T. cruzi ranges and Cross-reactivity between T. antibodies, as determined by an IIF test with a sensitivity CM' and T. rangeli is detecied mainly with the IIF and and specificity of 98 percent, the test will have a positive not with the ELISA.lo5 False-positive results with the predictive value of 50 percent and a negative value of IIF and IHA for T. CM' diagnosis have also been re- 99.9 percent. The positive predictive value of a similar ported in patients with schistosomiasis,w although it was test will be much higher in areas of the highest preva- difficult to prove that the samples from these patients lence of infection, such as in Chaco, Argentina, or Santa did not belong to persons having a mixed infection. Cruz, Bolivia. One solution to the problem of cross-reactivity is to In the nonendemic countries, however, the positive increase the specificity of the test with T. cruzi-specific predictive value will be much lower because of the lower antigens, for example, by using glycoproteins or poly- prevalence. For example, in the US, 100,000 individuals peptides that do not react with leishmania.1"108 Another are suspected of being infected." Even where there is a approach is the substitution of a recombinant protein high concentration of immigrants, as in Los Angeles, that, when used as antigen, does not detect antibodies Chicago, Miami, or New York, the usefulness of blood in sera from persons with mucocutaneous or visceral screening is doubtful, except when there is a combina- TRANSFUSION 1991-Vd. 31, No. 6 TRYPANOSOMA CRUZI IN THE BLOOD SUPPLY 555 tion of factors, such as donors who have lived in en- 14. Coura JR. Evolutive pattern in Chagas’ disease and the life span of Tty~somacrua’ in human infection. Proceedings of an demic countries and recipients who are immunosup- international symposium: New Approaches in American Tlypa- pressed. As a preventive measure, it would be more nosomiasis Research. Scientific Publication No. 318. Washing- beneficial to avoid donors who have lived in endemic ton, DC Pan American Health Organization, 1976:378-83. IS. Carcavallo RU. Aspects of the epidemiology of Chagrs’ disease areas, not only Latin American immigrants but also cit- in Venezuela and Argentina. Pmcedings of M international izens of nonendemic countries who have lived in rural symposium: New Approaches in Amerian Ttypanosomiash Re- areas of endemic countries; have worked in farming, search. Scientific Publication No. 318. Washington. DC Pan American Health Organization, 197654748. timber, mining, oil exploration, or development proj- 16. Schenone H, Alfm E, Reyes H, Taucher E. [value of xcw ects; or have received transfusions in endemic countries. diagnosis in chronic Chagasic infection] (Eng abstract). Bol Chi1 If Darwin could have become infected by T. crun’ while Parasitol 1968;23:149-54. 17. Rohwedder RW. [Chagas’ infection in blood donors and the traveling in South America,l12 others could also suffer probability of its transmission by blood transfusion] (Eng ab- the same fate. Infected donors could be potentially iden- stract). Bol Chi1 Parasitol 1%9;24:88-93. tified by the inclusion in a medical history of questions 18. Cerisola JA, Rabinovich A, Alvarcz M, Di Corleto CA. Pruneda J. [Chagas’ disease and blood transfusion] (Eng abstract). Bol related to this subject. In addition, prevention must be Of Sanit Panam 1972;73:203-21. based on the education of health personnel and on their 19. Diaz JCP. MGcrnkmos de transmido. In: Brener Z. Andrade awareness of the potential transmission of the infection ZA,eds. Trypanaroma cncd e doenp de Chagas. Rio de Janeiro: Guanabara Koggan, 1979:152-74. by blood and of the symptoms associated with it. 20. Quinteros ZT, Troncow MC, Amesi N, Boggio G, Sanchez S. In any case, the few confirmed cases of transfusion- [Migrant behavior in blood donors and its relation with Chagas’ transmitted infection diagnosed to date (immunosup- infection]. Cuadernos Med Soc 1990;54:3-14. 21. Statistical abstract of the United States. 109th ed. Bureau of the pressed individuals) are probably the tip of the iceberg. Census document. Washington: US Department of Commerce, Infections in the nonimmunocompromised host will re- 1989:lO. main mostly undetected or undiagnosed. 22. Kirchhoff LV, Gam AA, Gillian FC. American trypanosomiasis (Chagas’ disense) in Central American immigrants. Am J Med 19&7;82915-20. 23. Pehrson PO, Wahlgren M, Bengtsson E. Asymptomatic congen- References ital Chagas’ disease in a fne-year-old child. Sand J Infect Dis 1981;13:307-8. 1. The diseases: Chagas disease. In: Tropical diseases. Progress in 24. Skolnick A. Does influx from endemic areas mean more trans- international research 1987-1988. Ninth Programme Report of fusion-associated Chagas’ disease? (news). JAMA 1989,2621433. the UNDPNorld Ba-0 Special Programme for Research 25. SchmuAis GA. Chagas’ diseasc and blood transfusion. Pmg Clin and Training in Tropical Diseasts. Geneva: World Health Or- Biol Res 1985;182:127-45. ganization, 1989:79-84. 26. Grant IH, Gold JWM, Wittner M. et al. Transfusion-associated 2. chagas’ distasc. Epidaniol Bull Pan Am Health Organ 1982;3:14. acute Chagas disease acquired in the United States. Ann Intern 3. Sherlock IA. Vetores. In: Brener Z, Andrade Z, eds. T- Med 198% 111~849-51. soma CM’ e doemg de Chagas. Rio de Janeiro: Guanabara 27. Nickerson P, Orr P. Schrocder ML, Sekla L, Johnston JB. Tnns- Koggan, 1979:42-88. fusion-associated Ttyjmnosoma clud infection in a non-cndemic 4. Baneto MP. Epidemiologia. In: Brener Z, Andrade Z, eds. Try- area. 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37. Mamhi MCA. [Chagas’ disease as an urban problem]. Ca- 56. Weinborn ME, Beltran R, Contreras MC, et al. [Chagas’ disease demos Saude Publica 1981;2:7-12. in Chile. Urban sectors. IV-Frequency of Chagas’ infection in 38. Waltrick de Liz AG. [Epidemiologic study of Chagas’ disease blood donors and in mothers and newborn infants under care at in the blood bank of the Hospital of Pronto Socorm of Port0 the Aria Hospital (Region I, 1982-1983)] (Eng abstract). Bol Alegre, RS]. Med Cir 19863227-9. Chil Parasitol 1983;38:73-5. 39. Schlemper BR Jr, Pacheco G, da Silva MS, Stainder M, Bazzo 57. Castillo S, Mardones C, Hormazabal G, et al. [Chagas’ disease ML, da Rosa R. [Chagas’ infection in blood donors at the uni- in Chile. Urban sectors. VI. Frequency of Chagas’ infection in versity hospital of Florianopolis, Santa Catarina] (abstract 072). blood donors and in mothers and newborn infants of the cities Presented at the 17th Congress of the Brazilian Society of Trop- of Antofagasta and Calama. Region 11 (1983-1984)] (Eng ab- ical Medicine, Belo Horizonte, Brazil, March 2-7, 1986. stract). Bol Chil Parasitol 1984,39:28-32. 40. Carrasco R, Miguez H, Camacho C, et al. Prevalence of Try- 58. Sagua H. Araya J, GonZalez J, Fuentes A. [Chagas seropositivity panaroma crwi infection in blood banks of seven departments in a blood bank in an endemic zone. Some epidemiological as- of Bolivia. Mem Inst Oswaldo CNZ 1990;85:69-73. pects of the blood donors] (Eng abstracts). Bol Chi1 Parasitol 41. Zuna H, La Fuente C, Valdez E, et al. [Prospective study of the 1982;37:24-6. transmission of Trypunosoma cm‘ by blood in Bolivia] (Eng 59. Rojas R, Contreras MC, Rojas J, et al. [Chagas’ disease in Chile. abstract). Ann Soc Belg Med Trap 1985;65(Suppl 1):107-13. Urban sectors. 11-Prevalence of Chagas’ infection in blood do- 42. Guhl F. Jaramillo C, Mogoll6n JH, Rodrlguez J, de Sanchez N, nors at the Hospital of Copiap6 (Region 111, Chile)] (Eng ab- Marinkelle U. [Seroepidemiologic tracing of chagasic blood do- stract). Bol Chil Parasitol 1983;38:M8. nors in an endemic zone (Norte de Santander, Colombia)] (Eng 60. Contrcras MC. de la Rivera J, Sandoval L, et al. [Chagas’ dis- abstract). Rev Latinoam Microbiol 1987;29:63-6. ease in Chile. Urban sectors. X. Frequency of Chagas’ infection 43. Urbina A, Vargas L, Rojas M, Retana F, Zeled6n R. [Serologic in blood donors and in mothers and newborn infants of the cities prevalence of infection with T. cnui in blood donors in Costa of La Serena, Ovalle e Illapel, 1983-19851 (Eng abstract). Bol Rica]. Cienc Med, in press, 1991. Chil Parasitol 1985;40:72-6. 44. cdceres A, Matta VL, Mazariegos R, Castillo AL, Ramirez JL. 61. Guajardo U, Silva J, Lorca M, Atias A. [Prevalence of Try- Sempidemiologia de la enfermedad de Chagas en Guatemala. punaromo cm’ infection in the blood bank of the hospital of Salamanca (Region Chile]. Parasitol Dia 1984;8:105-7. Presented at the 8th Latin American Congress on Parasitology, IV), Guatemala, November 17-22, 1987:273. 62. Villablanca E, brio L. Salinas P, et al. [Chagas’ disease in Chile. Urban sectors. VII. Incidence of Chagas’ infection in 45. Ponce C, Ponce E. Infecci6n por Trypanosoma cnui en dona- blood donors and in mothers and newborn infants of the cities dores de sangre de diferentes hospitales de Honduras. Presented of San Felipe and Los Andes. Region V, 1983-19841 (Eng ab- at the 8th Latin American Congress on Parasitology, Guatemala, stract). Bol Chi1 Parasitol 1984,39:72-4. November 17-22, 1987:260. 63. Valenzuela M, Pinto ME, Contreras MC, et al. [Chagas’ disease 46. Kerndt P. Waskin H, Steurer F. et al. Trypunosoma cruzi anti- in Chile. Urban sectors. VIII. Incidence of Trypunosomn cllui bodies among blood donors in Los Angeles (abstract 669). Pre- infection in blood donors and in mothers and newborn infants of sented at the Twenty-eighth Interscience Conference on the cities of Rancagua, San Fernando y Santa Cruz. Region VI, Antimicrobial Agents and Chemotherapy. Washington, DC 1983-19841(Eng abstract). Bol Chi1 Parasitol 1984;39:75-7. American Society for Microbiology, 1988. 64. Franca ME. [Chap’ disease in U~guayin the last twenty years]. 47. Liendo F. Salinas P, Contnras MC, et PI. [Chagas’ disease in Rev Med UNguay 1986;2125-31. Chile. Urban sectors. XIII. Prevalence of infection by Trypuno- 65. Arago A. [Transmission of Chagas’ disease by transfusion]. Rev somu cnui in blood donors of the southern sector of the met- Med UNguay 1986;2:193-7. ropolitan area of Santiago, 19851 (Eng abstract). Bol Chil Parasitol 66. Storino RA, Milei J. [Chronic chagasic myocardiopathy. [An 1985;40:82-4. approach for the clinician]. 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