Chagas Disease in the United States: a Public Health Approach

Global Burden of Chagas DiseaseThe Chagas disease control initiatives instituted throughout Latin America since 1991 constitute a major public health success story. Thanks to vector control programs, blood bank screening, and in some countries, congenital Chagas disease screening programs, global estimates have decreased from 18 million in 1991 to less than 6 million infected individuals in 2010 (Table 1) (3, 35). Incidence estimates have fallen from 500,000 in 1991 to 30,000 new T. cruzi infections per year in 2010 (3). As vectorial transmission has come under increasing control, the proportion attributable to other routes has grown: currently, 22.5% of incident infections are estimated to occur through congenital transmission, and in some areas, oral transmission may be more frequent than the traditional vector-borne route (3, 31).

Triatomine Vector BiologyMore than 130 triatomine species have been reported in the Western Hemisphere, many known to carry T. cruzi (16, 36). However, a few species are disproportionately responsible for T. cruzi transmission to humans, due to their propensity to colonize human houses and/or the peridomestic environment. These include Triatoma infestans and Panstrongylus megistus in the Southern Cone (Argentina, Bolivia, Brazil, Chile, Paraguay, and Uruguay), Triatoma dimidiata in southern Mexico and Central America, and Rhodnius prolixus in Central America and northern South America (16). These species have been the major targets of the regional control initiatives. The elimination of R. prolixus from Central America and the near elimination of domestic T. infestans from much of the Southern Cone are responsible for the steep decline in new infections and very low prevalence in children throughout most of the historic zone of endemicity (37, 38). However, in the Gran Chaco, an ecological zone that straddles southern Bolivia, northeastern Argentina, and parts of Paraguay, the prevalence of house infestation and transmission remains very high (39, 40).

The domestic environment is rich in blood meal sources, both human and animal. Crevices in adobe walls and dark spaces within animal corrals and poultry nests provide safe diurnal refuges for triatomines. Rhodnius species, which nest in palm crowns in the sylvatic environment, can infest thatch roofs. Triatomines of both sexes require at least one blood meal during each of the five nymphal stages, and females need a blood meal to lay eggs. Thus, both male and female nymphs and adults may carry T. cruzi, with infection rates increasing with age. Only adults have wings. Most domestic triatomine species feed nocturnally and complete their blood meals without waking the host (36). The major Latin American vectors defecate during or immediately after taking a blood meal (41). Many sylvatic triatomine species colonize the nests of their blood meal sources and are found in close association with specific rodent or marsupial species (16, 36). Sylvatic triatomine adults may be attracted by light to invade human dwellings, which can lead to sporadic human infections (42, 43). Some triatomine species, such as T. dimidiata, can infest both domestic and sylvatic sites (44).

Triatomine Distribution in the United StatesEleven triatomine species have been reported in the United States: Triatoma gerstaeckeri, T. incrassata, T. indictiva, T. lecticularia, T. neotomae, T. protracta, T. recurva, T. rubida, T. rubrofasciata, T. sanguisuga, and Paratriatoma hirsuta (Fig. 2 and Table 2) (9, 36). Triatomines are present from coast to coast across the southern two-thirds of the continental United States (Fig. 3). In field collections, vectors are often found in specific microenvironments (woodpiles, rock piles, rodent nests, livestock pens, and dog kennels) (9). Natural T. cruzi infections have been documented in all species except the rarely collected T. incrassata and P. hirsuta (9, 45).

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FIG 2

Photographs of U.S. triatomine species of the genera Triatoma and Paratriatoma. Image size relative to the scale bar represents the average length of each species. The Triatoma incrassata photo is courtesy of E. Barrera Vargas, the T. recurva and Paratriatoma hirsuta photos are courtesy of R. Hoey-Chamberlain and C. Weirauch, and the T. protracta protracta photo is courtesy of G. Lawrence (DPDM/CDC). All other images are from reference 9 (photos by S. Kjos).

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FIG 3

Ranges of the four most frequently identified triatomine species in the continental United States. Based on references provided in Table 2.

The two species with the widest geographic distribution in the United States are T. sanguisuga and T. protracta. The former has been reported from Texas to the Atlantic coast and as far north as Illinois, the latter from Texas to California (9, 46). A recent review by the Wheeling-Ohio County West Virginia Health Department turned up 10 specimens of T. sanguisuga archived since 1969 and adds this state (long assumed to have the vector) to the confirmed list (46). T. sanguisuga was also recently reported in Delaware (47). T. protracta has been extensively collected in association with its favored blood meal hosts, the woodrats (Neotoma spp.); the prominent above-ground nests of these rodents make sylvatic collection relatively straightforward for this species (9, 48). T. protracta includes three morphologically distinct subspecies in the United States, T. protracta protracta in California, Nevada, Utah, Arizona, and New Mexico, T. protracta woodi in Texas, and T. protracta navajoensis in the Four Corners area, where Colorado, Utah, Arizona, and New Mexico meet (49). Thousands of specimens of T. sanguisuga and T. protracta have been reported in literature dating back to the 1930s, and these species were found in or near the residences of humans with locally acquired T. cruzi infection in Tennessee, Louisiana, Mississippi (T. sanguisuga), and California (T. protracta) (9, 50–53). In field collections, both species frequently have T. cruzi infection, with rates generally in the 15 to 30% range (9, 48).

T. gerstaeckeri has a more limited range, encompassing south-central Texas and southeastern New Mexico, but is one of the most frequently collected species, perhaps in part because of its propensity to infest dog kennels and other peridomestic structures (54). T. gerstaeckeri constituted more than 70% of several thousand vectors submitted through a citizen science project based at Texas A&M University (55). Collections of T. gerstaeckeri show high rates of T. cruzi infection, often >60% (9, 55). Infected T. gerstaeckeri insects were collected in the house of a child with acute T. cruzi infection in south Texas in 2006 (56).

Texas and the southwestern states have the highest triatomine species diversity, with at least seven species in Texas and six in Arizona (Table 3) (9, 54). A spatial analysis of bugs submitted through the Texas citizen science initiative showed geographic overlap among species but with T. gerstaeckeri predominantly in south-central Texas, T. sanguisuga in the eastern portion, T. rubida in west Texas, and T. indictiva in a small area of central Texas (54). T. gerstaeckeri reports showed earlier seasonality than T. sanguisuga, possibly because of the earlier arrival of high temperatures in the southern part of the state. Like all passive surveillance, there may be reporting biases in these data. The authors observe that they received few submissions from west Texas (and perhaps for this reason, few T. protracta specimens). They attribute this to lower human population density and/or less effective outreach (54), but lower rates of Internet access in rural counties could also play a role.

The ranges of all United States species extend into Mexico, with the exception of T. rubrofasciata (49, 57). T. rubrofasciata is associated with rats and is thought to have been carried from North America globally on sailing ships in the 18th century (58). In the United States, this species has been reported in Jacksonville, Florida, and Honolulu, Hawaii, consistent with its predominant distribution in ports.

Allergic Reactions to Triatomine AntigensT. gerstaeckeri, T. protracta, T. recurva, T. rubida, and T. sanguisuga have been implicated in allergic reactions in the United States (59). Such reactions are due to vector salivary antigens, not the infection status of the vector. Most reactions consist of a pruritic welt where the bite occurred. Severe reactions may involve angioedema, urticaria, dyspnea, gastrointestinal symptoms, and/or anaphylaxis (59). Severe reactions may necessitate treatment with epinephrine (60). Reports are most frequent in Arizona and California; the most commonly identified species are T. protracta and T. rubida, and the most frequent scenario is house invasion by an adult triatomine (59). In a study in southern California, allergic reactions consistent with those provoked by triatomine exposure were reported by 13% of residents of desert areas with frequent triatomine sightings, compared to 4% of those living in suburban Los Angeles County (61).

Transmission Potential in the United StatesWith the exception of the rarely collected species T. neotomae, T. incrassata, and P. hirsuta, all U.S. vector species have been reported to invade human dwellings (54, 60). A total of 2,883 specimens of 7 different vector species were submitted to the Texas citizen science project (54). Of these, 17% were collected inside human dwellings; the highest proportions were for T. rubida and T. protracta. Houses with refuges like woodpiles, rock piles, and brush and those with structural gaps through which vectors can pass are more vulnerable to vector invasion (50, 60, 92). Rarely, the presence of T. protracta or T. recurva nymphs has been reported inside houses, suggesting possible colonization (60). Window screens, air conditioning, and caulking of gaps in house construction may be protective against such invasion (60).

Detection of human blood meals is frequent in tested triatomines, especially those collected in and around human dwellings and in other spaces where humans congregate. In a recent study in Texas, human blood was detected in 59% (30/51) of T. gerstaeckeri bugs; the second most frequent blood meal was canine (17/51, 33%), followed by more than a dozen other vertebrate hosts (93). In this study, collection sites were largely domestic or peridomestic, and human blood meals were found in 77% (17/22) of T. gerstaeckeri bugs collected inside homes; mixed blood meals were frequent. In another study from Texas, vectors were collected in dog kennels and woodrat nests, as well as domestic settings (91). In this study, dogs (10/33, 30%) were the predominant blood meal source for T. gerstaeckeri, followed by woodrats (Neotoma micropus) (7/33, 21%); human blood was identified in a single bug. All 40 T. protracta bugs were collected in woodrat nests and had fed exclusively from Neotoma micropus (91). In a Louisiana study conducted near the house of the 2006 autochthonous human infection, 43 T. sanguisuga bugs were collected; 53% had fed from American green tree frogs, 49% from humans, and 30% from raccoons; detection of blood from multiple host species was frequent (94). In the Arizona-Sonora Desert Zoo, human blood was detected in all 7 T. rubida bugs tested; 5 of 7 had other blood meal sources detected, including pig, sheep or goat, dog, mouse, rat, or woodrat (95). Human blood was also detected in 2 of 3 T. recurva bugs collected elsewhere in southern Arizona (95).

The coincidence of human blood meals and T. cruzi infection in triatomines has been described as indicating the “potential for Chagas disease” in the United States (93–95). Clearly, transmission to humans occurs; more investigation is needed to quantify the risk, since most infections likely go undetected. However, the small number of locally acquired T. cruzi infections detected in humans stands in contrast to the moderate to high T. cruzi prevalence rates in dogs, raccoons, opossums, and woodrats. Compared to major South American vectors, such as R. prolixus and T. infestans, North American vectors appear to have somewhat longer time intervals from blood meal to defecation and may be less likely to defecate on the host (96–99). Vectors rarely colonize houses in the United States, and well-constructed houses with window screens provide effective barriers against domestic invasion. Perhaps most importantly, stercorarian transmission is inefficient; mathematical models based on data from the Gran Chaco, where transmission to humans is the highest in the world, estimate that a single human T. cruzi infection requires on average 900 to 4,000 contacts with infected vectors (69).

Trypanosoma cruzi GenotypesTrypanosoma cruzi is a highly genetically diverse parasite, estimated to have diverged from its most recent common ancestor 3 to 4 million years ago (100). Scientific consensus currently defines a minimum of six genetic lineages, or discrete typing units (DTUs [TcI to TcVI]) (101), plus a potential seventh, bat-associated genotype (TcBat), most closely related to TcI (102–105). Multiple molecular markers confirm a largely clonal population structure, which maintains the identity of major DTUs, interspersed with recombination events (106). TcI through TcIV form monophyletic clades, while TcV and TcVI resulted from recent hybridization of TcII and TcIII (100, 107). Genomic data support this evolutionary model. TcI to TcIV display substantial allelic homozygosity resulting from long-term, recurrent, and dispersed gene conversion, whereas TcV and TcVI have natural heterozygosity and minimal distinction, with shared intact alleles from their parental DTUs (100, 107–111).

Each T. cruzi DTU is characterized by distinct but often overlapping transmission ecologies (112). TcI, TcII, TcV, and TcVI are commonly associated with domestic cycles and are the genotypes found in most human infections. Investigators have long observed that gastrointestinal Chagas disease is more frequent in the Southern Cone than further north in Latin America and hypothesized a connection to different circulating T. cruzi strains (113). However, there remains no clear, unequivocal evidence of influence of particular lineages on the progression or clinical outcome of human Chagas disease (reviewed in reference 114). Domestic TcI is distributed from the Amazon Basin northwards and is the principal DTU found in humans in Venezuela, Ecuador, and Colombia (115–117). TcI also circulates in arboreal ecotopes between Didelphis species and the triatomine tribe Rhodniini (118, 119), with secondary cycles among rodents and sylvatic Triatoma species in highland valleys in Bolivia, Peru, and Chile (120–123). Sylvatic TcI populations are characterized by high levels of genetic diversity (124–130), while human infections are associated with divergent, more genetically homogenous strains (128, 131–133). In contrast, TcII, TcV, and TcVI appear less variable overall (100) and are predominant in domestic cycles in the Southern Cone (112, 134, 135). However, recent whole-genome sequencing of clinical TcII isolates has revealed more extensive intra-DTU diversity than previously reported (110). Sylvatic reservoirs of TcII, TcV, and TcVI are less well delineated than for TcI, but TcII has been increasingly detected in Brazilian primates (130, 136, 137). In addition, TcV and TcVI have been demonstrated in domestic dogs from Argentina to as far north as Colombia (107, 138–141). TcIII is transmitted by Panstrongylus geniculatus to D. novemcinctus and other burrowing mammals in terrestrial transmission cycles from the Amazon Basin to Argentina (142–144). The known host range of this DTU has expanded to include dogs, grisons, and foxes in Brazil (145). TcIV, perhaps the most neglected DTU, circulates sympatrically with TcI in wild primates in the Amazon (146) and raccoons and dogs in the United States (147). TcIV can invade the domestic environment in Venezuela (113, 116) and has been isolated from patients during oral-infection outbreaks in the Brazilian Amazon (146, 148–151) and Colombia (152). Finally, TcBat has been isolated from Chiroptera species across Brazil (102), Panama (103), Colombia (105), and Ecuador (104) and is potentially infective to humans (153).

Trypanosoma cruzi Molecular Epidemiology in the United StatesThe majority of genotyping activities have concentrated on vectors and reservoir hosts. In an extensive analysis of U.S. vectors and mammalian hosts, all five autochthonous human cases were reported as TcI (online supplement in reference 119). In a more recent series of presumed-autochthonous chronic T. cruzi infections in Texas blood donors, the authors were limited by genetic marker resolution and therefore unable to distinguish among TcII, TcV, and TcVI (154).

To date, TcI and TcIV are the only DTUs detected among the six triatomine species examined, with no absolute associations between parasite genotype and vector (Table 4). Higher proportions of TcIV have usually been identified in T. sanguisuga, T. indictiva, and T. lenticularia, compared to a predominance of TcI in T. gerstaeckeri, T. protracta, and T. rubida (78, 87, 89, 119, 155–157). However, except for studies of vectors collected by the Texas citizen science initiative (156, 157), samples sizes were far too small to make any meaningful extrapolations. The observation of potential TcII/V/VI autochthonous human infections in Texas is noteworthy but challenging to interpret without clear evidence of these genotypes circulating in local vector species (154). Similarly, a study of T. protracta collected in California encountered issues distinguishing among TcII/V/VI and was unable to establish the presence of infections with these lineages (158). Further investigations are warranted to confirm the presence of these DTUs in the United States, using a larger panel of more highly resolutive markers, in conjunction with phylogenetic analyses incorporating all representative T. cruzi DTUs; neither of these studies examined parasite sequence homology to TcI (154, 158).

Among reservoir hosts, TcI and TcIV are the principal DTUs identified in United States (Table 5). Similar to vector surveys, sample sizes are insufficient to reveal any strict correlations between host and parasite genotype; current data demonstrate both lineages circulating among mammalian hosts in variable proportions. Finally, a few studies in Louisiana reported rodents harboring TcII, alongside other mixed TcI, TcIV, and TcVI infections (78). Additional sampling efforts will be necessary to delineate the frequency and ecology of TcII/V/VI in the United States.

Issues Underlying T. cruzi Genotyping Data CollectionTo accurately interpret T. cruzi genotypic data, biological and logistical limitations relating to both parasite infection dynamics and genotyping methodologies must be considered. Trypanosoma cruzi genotyping can be conducted on clinical samples (blood or tissue) or parasite axenic cultures, obtained through hemoculturing or xenodiagnosis. Due to low levels of peripheral parasitemia, especially in chronically infected patients, direct genotyping is insensitive but may be improved if multiple specimens are tested (159). The principal limitation of parasite isolation is selection bias for specific clones, due to higher growth rates or culture conditions to begin with (160–162) and, subsequently, by loss of diversity from long-term maintenance in axenic culture or animals (163–167). Hemoculture recovery rates are usually less than 30% among chronic patients (168) and are dependent upon parasite load and distribution in the initial inoculum. Xenodiagnosis can generally recover more parasite strains, but biases may result from variable vector permissibility to specific strains (169–171). Furthermore, circulating clones isolated by hemoculture or xenodiagnosis may be different from those sequestered in tissues due to differential strain tropisms (172–174) and can vary even between sequential blood samples (175). Similar biases affect sylvatic T. cruzi sampling, with certain reservoir species more heavily represented in survey data due to their relative ease of capture and the presence of detectable parasitemia.

The most commonly used genotyping techniques for clinical and field specimens involve analysis of size polymorphisms in multicopy genetic markers, particularly the nuclear spliced-leader intergenic region (SL-IR), 24α rRNA, and 18S ribosomal DNA (rDNA) (Tables 4 and 5) (176, 177). The major confounder associated with the use of any multicopy gene is the level of intraclone copy number and undefined chromosomal orthology, which can prevent direct comparability between strains. The SL-IR is present in many hundreds of copies per parasite genome; the copies are not necessarily identical and may instead comprise a predominant haplotype accompanied by a low abundance of minor paralogous sequence types more closely related in identity to other DTUs, likely resulting from their shared evolution (110, 178, 179). In this scenario, it is virtually impossible to distinguish between a monoclonal DTU infection containing multiple divergent SL-IR sequences and a polyclonal infection consisting of different major DTU parasites. This issue is minimized when using conventional PCR, as generally, the most common gene sequence is amplified in a reaction. However, recently, a number of deep sequencing studies reported results based on sequencing millions of copies of the SL-IR locus that seem to indicate the occurrence of almost all DTUs in infected rodents and primates in the United States (180, 181). Parallel deep sequencing of appropriate biologically cloned controls to exclude low-abundance haplotypes has thus far yielded equivocal evidence; further investigations are essential to define the applicability of this technique to characterize natural multiclonal infections (182, 183).

Acute T. cruzi InfectionThe acute phase begins 1 to 2 weeks after vector-borne transmission and lasts approximately 8 weeks. Patients are most commonly asymptomatic or experience mild, nonspecific symptoms such as fever. A T. cruzi abscess or chagoma may occur at the site of inoculation. Parasite entry via the conjunctiva may result in unilateral eyelid swelling (the Romaña sign) (184). However, eyelid swelling can be caused by an allergic reaction to triatomine salivary or fecal antigens; confirmed diagnosis of T. cruzi infection is obligatory, even in the setting of vector exposure and an apparent Romaña sign. Severe acute Chagas disease, including myocarditis, pericardial effusion, and/or meningoencephalitis, is rare, but when it occurs, the mortality risk is high (5, 185). In the absence of the Romaña sign or severe manifestations, individual infections are seldom diagnosed during the acute phase.

Orally transmitted T. cruzi infection has been reported to cause more severe acute morbidity and higher mortality than vector-borne infection (186, 187). Microepidemics appear to be fairly frequent in the Amazon basin, due to sylvatic vectors contaminating produce, such as açaì or sugarcane (31). In the Caracas outbreak, mentioned above, 103 people were infected, of whom 59% had electrocardiogram (ECG) abnormalities and 20% were admitted to hospital, and one person died from acute Chagas myocarditis (32, 34). Alterations in T. cruzi surface glycoproteins caused by exposure to gastric acid may increase parasite invasiveness, providing a possible explanation for the increased severity of orally acquired Chagas disease (188, 189).

Congenital Chagas disease is acute infection in the newborn. Most infected infants are asymptomatic or have mild findings, but a small percentage present with severe disease or die in utero (18, 190). Manifestations may include low birth weight, prematurity, low Apgar scores, hepatosplenomegaly, anemia, and thrombocytopenia (18, 190). Severely affected neonates may have meningoencephalitis, gastrointestinal megasyndromes, myocarditis, pneumonitis, and/or respiratory distress (18). Women who receive antitrypanosomal therapy prior to conception are significantly less likely to transmit T. cruzi to their infants (23, 191).

Chronic T. cruzi InfectionOne to 2 months after infection, parasitemia falls below levels detectable by microscopy, and the patient passes into the chronic phase of T. cruzi infection (2, 5). Chronic T. cruzi infection without signs or symptoms of Chagas disease is designated the indeterminate form (2, 5, 192). Over a period of years to decades, an estimated 20 to 30% of infected individuals develop cardiomyopathy (2, 5). A retrospective cohort analysis of Brazilian blood donors estimated progression to cardiomyopathy to occur at a rate of 1.85% per year (193). Chagas cardiomyopathy features chronic inflammation in all chambers and damage to the conduction system and cardiac muscle (194). The most frequent early signs are right bundle branch block or left anterior fascicular block and segmental left ventricular wall motion abnormalities (185, 194, 195). Later manifestations appear decades after infection and include ventricular arrhythmias, sinus node dysfunction and bradycardia, persistent or intermittent complete heart block, an apical aneurysm usually in the left ventricle, thromboembolic phenomena, and progressive dilated cardiomyopathy. Patients may experience palpitations, syncope, and systemic and pulmonary emboli, with high risk of sudden death or death from progressive heart failure. (185, 194, 195).

Gastrointestinal involvement is much less frequent than cardiomyopathy. Esophageal manifestations range from asymptomatic motility disorders through mild achalasia to megaesophagus (196). Patients may experience dysphagia, odynophagia, esophageal reflux, weight loss, aspiration, and regurgitation. Patients with colonic involvement may have prolonged constipation, fecaloma, volvulus, bowel ischemia, or megacolon. Symptomatic gastrointestinal disease, like symptomatic cardiac disease, usually appears several decades after infection.

MicroscopyIn acute, congenital, or reactivated infection, trypomastigotes may be detectable by light microscopy in thick and thin smears from whole blood or buffy coat with routine staining (e.g., Giemsa stain) (214). When acute or reactivation meningoencephalitis is suspected, cerebrospinal fluid samples should be concentrated by the thin-layer cell preparation technique, stained, and examined by light microscopy. Microscopy is useful due to fast turnaround time, wide availability, and high specificity, but its sensitivity is lower than that of molecular techniques (215, 216).

Molecular TechniquesThe most sensitive primer sequences originate from satellite or kinetoplast minicircle DNA (217–219). A recent publication from the CDC outlines an algorithm that incorporates testing by multiple primer sets in a quantitative assay to optimize performance and reliability (218). Several recent initiatives have addressed standardization of qualitative and quantitative PCR for clinical use (217, 220). In acute or early congenital infection, PCR has substantially higher sensitivity than microscopy and is the diagnostic test of choice (190, 219). PCR results are variably positive in chronic T. cruzi infection, depending on specimen volume, primers, DNA extraction methods, and level of experience of the laboratory (220). Blood clot or buffy coat preparations may provide higher sensitivity than whole blood, but these preparations may not be widely available in routine clinical laboratories (218, 221). PCR has recently been utilized in several clinical trials as an early indicator of treatment failure; use in this setting requires rigorous standardization and criteria for patient inclusion (for example, positive results by PCR in at least one of 3 pretrial 10-ml specimens) (222, 223). In chronically infected patients at risk because of immunosuppression, a rise in parasite load by quantitative PCR in serial specimens is the earliest indicator of reactivation, enabling treatment before onset of symptoms (224, 225).

Diagnostic SerologyDiagnosis in the chronic phase of Chagas disease relies on detection of host IgG against T. cruzi antigens (16). Currently, the main methods in use are enzyme-linked immunosorbent assays (ELISAs), immunofluorescence assays (IFAs), and immunochromatographic strip or cassette tests. Confirmed diagnosis requires positive results by at least two assays, preferably based on different antigens (for example, parasite lysate and recombinant antigens) (16). The sensitivities and specificities of the available assays are not sufficient for a single assay to be used alone for diagnosis, especially in a setting where prevalence is low and pretest probability is not high. The IgG trypomastigote excreted-secreted antigen immunoblot (TESA-blot) is used as a confirmatory test in blood banks and clinical practice in Brazil (226, 227). Preparation of the test strips using antigen from trypomastigotes in cell culture requires specialized infrastructure and may be prone to interbatch and laboratory variability. The banding pattern may differ by T. cruzi DTU, suggesting different antigenic characteristics between strains (228). Conventional serology in cord and infant blood reflects transferred maternal IgG until around 9 months of age.

IgM-based assays have been evaluated for the diagnosis of acute T. cruzi infection, with a special focus on use for congenitally infected infants in settings where molecular assays are not available (226). IgM TESA-blot showed sensitivity of 58% compared to a consensus definition of infection and 80% compared to PCR in congenitally infected infants in Bolivia; in these two analyses, the specificities were 98% and 94%, respectively (190, 229). The specificity of IgM assays utilizing whole T. cruzi lysate was <30% in a similar population of congenitally infected infants (230). In the United States, PCR is the assay of choice for the diagnosis of acute and congenital T. cruzi infection (216).

HCT/PSerological screening is recommended for donors of human cells, tissues, and tissue-based products (HCT/P) with epidemiological risk factors; for example, those who were born or lived in areas of endemicity or whose mothers were born in such areas. Two assays are approved by the U.S. Food and Drug Administration (FDA) for living and cadaveric donor screening, Ortho ELISA (Ortho-Clinical Diagnostics, Inc., Raritan, NJ) and Abbott PRISM (Abbott Diagnostics, Abbott Park, IL) (231). These tests are currently available only in blood donor testing laboratories. The Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) Disease Transmission Advisory Committee also recommends the use of an FDA-cleared diagnostic ELISA to test living donors (232, 233). For living donors, a positive screening test should prompt referral for appropriate diagnostic testing and clinical evaluation (192).

HistopathologyTrypanosoma cruzi causes tissue damage through cellular lysis, inflammatory response, and fibrotic replacement (234). The spectrum of histopathology related to T. cruzi infection has been the subject of several recent reviews (235–239). The most important target organ is the heart, where chronic pathology includes multichamber damage, most prominent in the ventricles and often severe enough to form an apical aneurysm (235, 236). The spectrum of microscopic pathology includes myofiber degeneration, interstitial fibrosis, and patchy inflammation predominantly comprised of lymphocytes, macrophages, plasma cells, and eosinophils; neutrophils are not commonly observed. The patterns of inflammation and fibrosis can be focal or diffuse throughout the layers of the myocardium. Fibrotic plaques may be observed on the epicardium (235, 236). Intracellular amastigote pseudocysts are rarely observed in chronic pathology, especially with limited tissue sampling, but demonstrable parasite persistence appears to be associated with higher-grade inflammation in the chronic phase (236, 240, 241). Histopathology can play an important diagnostic role in the setting of suspected reactivation. Careful examination of endomyocardial biopsy specimens for nests of intracellular parasites can help distinguish rejection from T. cruzi reactivation in cardiac transplant recipients (203, 242). In immunosuppressed patients with suspected skin manifestations of T. cruzi reactivation, histopathology may reveal the parasite and confirm the diagnosis (238). The diagnosis of T. cruzi reactivation was made on a brain biopsy specimen in a patient with HIV and cerebral lesions of unknown etiology (205).

Antitrypanosomal DrugsBenznidazole and nifurtimox are the only drugs with proven efficacy against Chagas disease (2). Benznidazole is considered the first-line treatment, because of better tolerance and more comprehensive efficacy data (1, 243). Benznidazole is a prodrug that requires metabolism by parasite enzymes to become active; metabolites appear to act through multiple mechanisms to interrupt T. cruzi glutathione and trypanothione pathways (243). Dermatologic side effects are frequent and consist of rashes and photosensitization (244, 245). Dermatitis occurs with significantly higher frequency in females than males (244). Most rashes are mild and can be managed with antihistamines or topical steroids without interrupting treatment (246). Treatment should be suspended immediately for severe or exfoliative dermatitis or dermatitis associated with fever and lymphadenopathy. Peripheral neuropathy is dose dependent, usually occurs late in the course of therapy, and should prompt immediate treatment interruption; resolution may take months. Bone marrow suppression is rare and requires immediate interruption of treatment. Clinical and laboratory monitoring for side effects should occur regularly throughout the course of treatment. Benznidazole tolerance is substantially better in children than in adults and in children younger than 7 years than in older children (247). This better safety profile correlates directly with more rapid elimination of the drug in younger age groups (248).

Benznidazole was approved by the FDA in August 2017 (249) and became commercially available in the United States as of 14 May 2018. The drug is marketed in the United States by Exeltis, a U.S.-based division of Insud Pharma (previously called Chemo Group) (250). The approval covers treatment of T. cruzi infection in children 2 to 12 years of age (250); usage for other age groups is off-label. As of 2019, prescriptions require submission of a completed order form to Exeltis FastAccess (https://www.benznidazoletablets.com/en/Treatment). Urgent requests for benznidazole should be made by telephone (877-303-7181).

Nifurtimox, a nitrofuran, impedes T. cruzi carbohydrate metabolism through the inhibition of pyruvic acid synthesis. The most common side effects are anorexia and weight loss, experienced by up to 70% of patients. Other frequent adverse effects include nausea, vomiting, irritability, and insomnia (251, 252). Rarely, patients develop peripheral neuropathy, usually manifested as paresthesias. The peripheral neuropathy is dose dependent, appears late in the course of therapy, and requires cessation of the drug. Nifurtimox is better tolerated by children than adults. As of 2019, nifurtimox is not approved by the FDA but is provided by the CDC under investigational protocols (https://www.cdc.gov/parasites/chagas/health_professionals/tx.html; telephone no., 404-718-4745).

Several new drug candidates (posaconazole and the ravuconazole prodrug E1224) have been tested in recent trials, but so far, none has shown acceptable efficacy (222, 223). All of the participants in these trials were from the Southern Cone. Although the posaconazole trial was carried out in Spain, 75 of the 78 subjects acquired their infections in Bolivia (223). Recent reviews have called for the inclusion of patients from diverse locations within Latin America, representing all of the major T. cruzi strains that infect humans (253). A novel aspect of these trials was the use of carefully standardized PCR assays to document treatment failure (254). Of those treated with posaconazole, 80 to 90% had detectable parasitemia by 12 months posttreatment, compared to benznidazole failure rates of 6% (per protocol) to 38% (intention to treat) (223). Similar results were demonstrated in a Bolivian trial of E1224, a related drug (222). These trials demonstrated that, with rigorous standardization, PCR may be useful as an early indicator of treatment failure, at least in populations of patients with infection acquired in the Southern Cone.

Acute and Congenital T. cruzi InfectionAcute infection has been an absolute indication for treatment since the drugs first became available in the 1970s (255). In acute and early congenital T. cruzi infection, antitrypanosomal therapy reduces the severity of symptoms, shortens the clinical course, and decreases the duration of detectable parasitemia (255, 256). In severe acute disease, treatment can be lifesaving. Cure rates in acute and congenital infection are estimated at 80 to 99% (255–258).

Treatment of Chronic T. cruzi InfectionEvaluation of antitrypanosomal drug efficacy in chronic T. cruzi infection is challenging. PCR, while a potential indicator of treatment failure, is not a true test of cure, since many persons with chronic T. cruzi infection will have circulating parasite levels below the threshold of detection of the assay. Conventional IgG serology is considered the only sensitive indicator of infection, but it requires years to decades to revert to negative after successful treatment (259). The longer the duration of infection, the more durable the antibody response, with women treated after age 15 taking a median of 27 years to revert to negative serology (191). Age is often used as a proxy for infection duration, since in communities where the disease is endemic, most infections are acquired in childhood. Testing using experimental lytic antibody assays shows conversion to negative results more quickly than with conventional serology but still requires years, even in children (260). In the 1990s, two placebo-controlled trials of benznidazole treatment in children with chronic T. cruzi infection showed approximately 60% cure rates based on lytic antibody assays 3 to 4 years after treatment (261, 262). These studies made early diagnosis and antitrypanosomal drug therapy the standard of care for children and prompted the establishment of large-scale pediatric screening programs in high-prevalence locations (16, 263).

Treatment of chronic infection in adults remains a topic of debate (264, 265). The fundamental question is whether antitrypanosomal therapy decreases the risk that an infected person will develop cardiac morbidity from T. cruzi. Observational data published in 2006 suggested that benznidazole treatment significantly decreased the progression of Chagas cardiomyopathy in adults (266). Since progression only occurs in 20 to 30% of those with infection and takes decades to become clinically evident, the ideal trial would require large study populations followed for 20 years or more, a virtually impossible clinical trial design. The design of the BENEFIT trial (Benznidazole Evaluation for Interrupting Trypanosomiasis; ClinicalTrials.gov registration no. NCT00123916), a randomized, double-blinded, placebo-controlled trial, was based on the observation that patients who already have cardiac morbidity are more likely to have further progression than those with normal cardiac status (267). Eligible patients were required to have cardiac findings consistent with established Chagas cardiomyopathy, and the primary outcome consisted of any of the following: death, resuscitated cardiac arrest, sustained ventricular tachycardia, insertion of a pacemaker or implantable cardioverter-defibrillator, cardiac transplantation, new heart failure, or other thromboembolic event. To the disappointment of many in the Chagas disease community, the trial showed no significant difference for the primary composite outcome, despite significantly higher conversion to negative PCR results in the treatment group compared to the results for the placebo group (268).

The patient populations in the observational and trial populations differed substantially. The nonrandomized study subjects had a mean age of 39, and two-thirds had normal cardiac function at baseline (266). In contrast, the BENEFIT trial population had a mean age of 55, all had cardiac damage based on electrocardiographic abnormalities, and nearly half had decreased ejection fraction at baseline, indicating ventricular dysfunction (268). The question of whether treatment provides clinical benefit for those with no or very early cardiac signs therefore remains unanswered (269). The only clear take-away messages are that the younger the patient the higher the probability of benefit and that active screening is essential to identify infected individuals before they become symptomatic. As in earlier publications (192), treatment recommendations remain stratified by age and clinical status and require balancing the risk of adverse effects with the probability and uncertainty of benefit (Table 7).

Management of the Immunocompromised HostIn organ transplant recipients with reactivation, a standard course of benznidazole or nifurtimox is effective in ameliorating clinical symptoms and shortening the duration of microscopically detectable parasitemia. Prior treatment or posttransplant prophylaxis has not been shown to decrease the risk of reactivation; posttransplant prophylaxis is not generally administered in heart transplant centers in Latin America (270). As no reliable test of cure exists, treated patients are considered to remain at risk for reactivation (225). Organ recipients at risk of reactivation should have regular monitoring of blood by quantitative PCR, with treatment based on demonstration of rising parasite load in blood (Table 6) (225, 271). T. cruzi reactivation should be included in the differential diagnosis of febrile episodes and apparent rejection crises, and endomyocardial biopsy specimens should be examined for evidence of T. cruzi myocarditis in the transplanted heart. Reactivation in an HIV-coinfected patient is treated with standard courses of antitrypanosomal treatment and optimization of antiretroviral therapy (272). The utility of and optimal regimen for secondary prophylaxis are unknown.

Disease Burden among Latin American ImmigrantsNo population-representative data exist to make an unbiased estimate of T. cruzi infection prevalence in the United States. Several studies of T. cruzi seroprevalence in convenience samples of Latin American immigrants have been conducted. In Los Angeles, 59 (1.24%) of 4,755 Latin-American-born residents had confirmed T. cruzi infection (273). The prevalence was higher among participants older than 40 than in those 18 to 40 (1.42% versus 0.95%), and it was higher among immigrants from El Salvador than those from Mexico (3.45% versus 0.79%) (273). A community health clinic-based program to screen Latin American immigrants in East Boston reported an overall prevalence of 0.87% (19/2,183), with prevalence rising with age (0/101 [0%] for age <20, 10/1,562 [0.64%] for age 20 to 39, and 9/507 [1.78%] among those 40 years or older) (274).

Based on the reported number of immigrants from countries of Chagas disease endemicity of Latin America and estimated national T. cruzi seroprevalence in their countries of origin, there were an estimated 240,000 to 350,000 infected persons in the United States in 2010; the upper end of the range includes an estimate for undocumented immigrants, whereas the lower end does not (7). All estimates of Chagas disease burden in the United States have major uncertainties, and the method used for these estimates carries several potential biases. The demographics of Latin American immigrants in the United States may not reflect those of the general population in their countries of origin, and their significant exposure risk ended when they left their home countries years earlier (275). Chagas disease prevalence is highly heterogeneous in countries of endemicity; depending on geographic sources of immigrants, the prevalence in immigrants could be either higher or lower than the national average. For example, in Spain, Bolivian immigrants appear to have a higher prevalence of Chagas disease than the estimated national prevalence, possibly because they are more likely to come from departments with high prevalence, such as Cochabamba and Santa Cruz, than from departments with low prevalence, such as Oruro or Potosí (3, 8). Similar systematic information for Mexican and Central American immigrants in the United States is lacking, although data from Los Angeles support the notion that infection prevalence is higher among immigrants from some Mexican states than others (273). Finally, the composition of migrant populations entering the United States has changed in recent years, with a higher proportion of families and children from Central America than in earlier migrations, in which adult men from Mexico predominated (275). National T. cruzi prevalences are higher in El Salvador, Guatemala, and Honduras than in Mexico (3), but the younger age of migrants would have the effect of decreasing the likely prevalence in migrants compared to that in earlier waves of older migrants. The success of vector control programs has dramatically decreased the prevalence of T. cruzi infection among children in Latin America over the past 30 years, and the limited data from Boston suggest that pediatric Chagas disease is infrequent in Latin American immigrants in the United States (274).

Autochthonous Vector-Borne Transmission to HumansAvailable data indicate that autochthonous vector-borne T. cruzi transmission to humans is rare in the United States (276, 277). A longitudinal study in repeat blood donors yielded a point estimate of zero incidence, with an upper 95% confidence limit of 0.61 per million (277). House colonization is rare, and vector-human contact occurs primarily in peridomestic areas, when vectors invade houses, or when humans spend time in sylvatic sites with enzootic T. cruzi transmission (9, 278).

Prior to initiation of blood bank screening in 2007, all reported vector-borne infections in the United States were detected because of acute symptoms and/or the presence of a vector in the vicinity of the case (Table 8). Four infections were reported in Texas and one each in California, Tennessee, and Louisiana. Five of seven cases occurred in infants or small children, and six were in the acute phase at the time of detection. In retrospect, one of the Texas infections, reported to be in a 2- to 3-week old infant with no other details provided, may actually have been congenital (279). In California, a contemporaneous survey demonstrated positive complement fixation results in 6 (2.5%) of 241 residents of the community associated with the 1982 case compared to 1 (0.2%) of 637 persons surveyed in a major urban area (53).

Since 2007, blood bank screening has resulted in the publication of an additional 35 putative autochthonous T. cruzi infections (50, 280–285). All were in the chronic phase and detected on serological screening by blood centers. States postulated to be sources of infection include Mississippi, Texas, Louisiana, Arizona, and California, but with the exception of the CDC investigation (50), all were either individual case reports or focused on a single state, raising the likelihood of sampling bias. The CDC investigation estimated that locally acquired T. cruzi infection was likely to account for between 5.5% and 7.5% of confirmed positive blood donations (50). Unlike earlier case reports, all of these putative autochthonous infections were in adults in the chronic phase; thus, the location and timing of transmission events are unknown. Some reports speculate on potential sources of triatomine contact, including hiking, camping, hunting, and peridomestic woodpiles and brush (50, 282, 283, 285). In other cases, infected individuals had exposure in multiple states with known sylvatic cycles and no hypotheses could be formed as to which was the most likely site of acquisition (280, 282).

Blood Donor Screening and Transfusion TransmissionPrior to the institution of blood donor screening, five transfusion-associated T. cruzi infections were documented in the United States, two in 1988, one in 1989, one in 1997, and one in 2002 (Table 9) (9, 286). Evaluation of the recipients of blood components from infected donors identified two additional transmission events in 2004 and 2006, from separate donations from the same donor (287). Most infected recipients had underlying malignancies and were immunosuppressed (9, 287). Donors from the Southern Cone were implicated in 5 of the 6 cases where the source was known. In two cases, the blood component was unknown; in all others, the implicated units were platelets. Based on tracing of 350 recipients of blood components from infected donors, the risk associated with a platelet unit was estimated to be 13.3% (95% confidence interval [CI], 5.6 to 25.7), compared to zero for packed red blood cells (RBCs) (95% CI, 0 to 0.15) and frozen plasma/cryoprecipitate (95% CI, 0 to 3.7) (286). Several of the acutely infected recipients had severe manifestations of Chagas disease, including acute myocarditis, acute atrioventricular block, severe congestive heart failure, pericarditis with T. cruzi in the pericardial fluid, and possible meningoencephalitis.

Blood donation screening began in January 2007 using the Ortho ELISA, which had been licensed by FDA the previous month, with the radioimmunoprecipitation assay (RIPA) as the confirmatory test (288). The FDA licensed the Abbott PRISM chemiluminescent immunoassay (ChLIA) as a screening test in 2010 and the Abbott enzyme strip assay (ESA) as a supplemental test in 2011. Guidance from the FDA in 2010 recommended screening of all donations, regardless of previous screening results (277). Universal screening enabled an analysis of results from two or more serial specimens from 4.22 million repeat donors representing 6.06 million person-years of follow-up (277, 290). No incident T. cruzi infections were detected, corresponding to zero autochthonous transmission incidence, with an upper 95% confidence limit of 0.61 incident cases per million person-years (277). In 2017, final FDA guidance endorsed a one-time screening approach, recommended against the use of donor questions to assess risk based on low sensitivity, and required further testing of screen-positive donations with the Abbott ESA (291, 292). Screening was estimated to cover 75 to 90% of the U.S. blood supply as of 2008 (293).

Several ancillary studies were conducted during the early years of blood donor screening. In an analysis of approximately 14 million blood donations in 2008, the overall seroprevalence was 1/27,500, with the highest rates in Florida (1/3,800), followed by California (1/8,300) (293). Of 104 T. cruzi-infected donors with epidemiological data, 29 (28%) were born in Mexico, 27 (26%) in the United States, 17 (16%) in El Salvador, and 11 (11%) in Bolivia; the remaining 20 donors were born in nine other countries of Central and South America. In a subsequent study of 22 million donations collected between 2007 and 2011, 717 donations were confirmed seropositive by RIPA, corresponding to a seropositivity rate of 1/31,000 (215). Among 263 donors who provided 30-ml blood specimens, 18 (6.8%) had positive results by hemoculture and 17 had parasite genotyping results. Only 2 (1.3%) of 157 donors from areas where TcI predominates (Mexico, Central America, and northern South America) had positive hemocultures (both TcI). In contrast, T. cruzi grew in cultures from 13 (34.2%) of 38 donors from the Southern Cone (1 TcII, 10 TcV, 1 TcVI, and 1 not typed). Three donors born in the United States had positive results by hemoculture, two TcV and one TcVI; no data were available to determine the likely source of their infections. Together with the predominance of Southern Cone donors implicated in recognized transfusion transmissions, these data support the hypothesis that TcII/V/VI infections result in higher parasite loads and, therefore, higher blood-borne transmission risk than TcI infections (215, 286).

As of 26 October 2019, a total of 2,435 confirmed seropositive donors in 47 states have been detected in screening (AABB Chagas Biovigilance Network, Chagas data reports through 26 October 2019; www.aabb.org/programs/biovigilance/Pages/chagas.aspx). Over the period from 2007 to 2016, the mean prevalence in first-time donors was 64 per million donors overall and 3.64 per 10,000 donors in southern California and showed a nonsignificant decreasing trend (277). The highest number of positive donations by calendar year was 420 in 2008; since 2014, yearly detections have ranged from 84 to 98 (Chagas data reports mentioned above).

Organ Donor-Derived Transmission and Organ Donor ScreeningA total of 14 investigations, involving organs from 14 T. cruzi-infected donors transplanted to 32 recipients between 2001 and 2011, were reported in a recent review (28). Transmission occurred to 9 recipients of organs from six donors; no transmission occurred from the remaining 8 donors (Table 10) (28). Transmission risk differs by organ type: 3 (75%) of 4 heart, 2 (20%) of 10 liver, and 2 (13%) of 15 kidney recipients became infected.

The earliest reported instances of transmission in 2001 and 2006 were not suspected until at least one recipient presented with symptomatic acute Chagas disease (294, 295). More recently, some organ procurement organizations have begun selective or universal screening of donated organs (30, 296). Four subsequent published transmission events (in a liver recipient in 2006, two heart recipients in 2006 and 2010, and a bilateral lung recipient in 2011) were detected through systematic laboratory monitoring. Three of these patients were treated and survived their T. cruzi infection (28). The bilateral lung transplant recipient died 2 years posttransplantation from respiratory failure; his T. cruzi PCR was intermittently positive despite prolonged benznidazole therapy, and Chagas disease was considered a possible contributing factor in his death (28, 297).

In the United States, screening of donors has been based largely on risk assessment; donors born in or with significant periods of residence in Latin America, born of women from Latin America, and/or noted to have clinical findings such as cardiomegaly consistent with Chagas disease should be screened by IgG serology (30). Some organ procurement organizations contract with a blood bank for donor testing, as the Abbott PRISM and Ortho ELISA have approval for use in specimens from living and cadaveric organ donors (231).

The recipient of an organ from an infected donor should be monitored by microscopy and/or PCR in serial specimens (28, 30). Seroconversion may be delayed or never occur in immunocompromised individuals. Positive results by PCR occur days to weeks before parasites are detectable by microscopy (218). The incubation period of transplant-transmitted T. cruzi infection is typically 2 to 3 months, but detection may be delayed as long as 6 months (28). A frequently recommended monitoring schedule consists of weekly specimens for 2 months, every 2 weeks up to 4 months, and then monthly afterwards (Table 6) (28, 30). In the absence of other indications and assuming no evidence of infection has been detected, the monitoring interval can be lengthened after 6 months posttransplantation.

Chagas Cardiomyopathy and Heart Transplantation for Chagas Heart Disease in the United StatesChagas heart disease has been recognized in U.S. health care facilities for nearly 30 years (298). Ten years ago, we estimated that there were 30,000 to 45,000 patients with Chagas cardiomyopathy in the United States (299). Recent studies have confirmed that Chagas disease is frequent among Latin American-born patients with cardiac signs, including 13% (5/39) of patients with left ventricular ejection fraction (LVEF) of <45% without evidence of ischemic heart disease in New York City (300), 19% (25/135) of patients with LVEF of <40% without evidence of ischemic heart disease in Los Angeles (301), 5.3% (17/327) of patients with any bundle branch block in Los Angeles (302), and 7.5% (6/80) of patients with pacemaker implantation in Los Angeles (303). As in studies from Latin America (304, 305), the most common conduction system abnormalities were right bundle branch block, left anterior hemiblock, and the combination of the two (302, 306), and Chagas cardiomyopathy was associated with more rapid progression than other cardiac etiologies to severe disease requiring transplantation or resulting in death (301, 306, 307). Data from 17 Texas blood donors suggest that locally acquired Chagas disease can also result in cardiomyopathy, but data are insufficient to assess the relative risk for autochthonous versus imported infection (281).

In Brazil and Argentina, heart transplantation is an accepted modality to treat end-stage Chagas cardiomyopathy, and survival for those transplanted for Chagas heart disease is the same or better than that of recipients of cardiac transplants for other etiologies (200, 201, 308, 309). The incidence of T. cruzi reactivation in Latin American heart transplant cohorts varies widely, from 20 to 90% (225). In the United States, data are published for 40 patients who underwent heart transplantation for end-stage Chagas cardiomyopathy since 2006 (199, 225). In one review from a Los Angeles medical center, 31 of 405 patients who received heart transplants between 2006 and 2012 were born in Latin America; 20 of the 31 had serological testing for T. cruzi and 11 (2.7% of the total number of 405) had positive results (199). Only two of the T. cruzi-infected transplant recipients received their diagnosis prior to the transplant, both in their home countries. Two (18.2%) patients were diagnosed with T. cruzi reactivation when they experienced dysfunction of the transplanted heart; their infections had not previously been suspected, and one died of cardiogenic shock. One additional patient was asymptomatic but treated based on the finding of parasites in the explanted heart. One of the patients in the Los Angeles cohort is included in the CDC’s comprehensive review of 31 patients that underwent heart transplantation for Chagas cardiomyopathy from 2012 to 2016; 19 (61%) had reactivation (225). In the CDC review, reactivation was defined by rising parasite load by quantitative PCR in peripheral blood, a finding that precedes both microscopically detectable parasitemia and the development of symptoms (218). Only one instance of reactivation was symptomatic at the time of diagnosis, and all patients with reactivation were alive at the end of follow-up.

Congenital Chagas Disease in the United StatesBased on births to Latin American-born women in the United States and T. cruzi infection prevalence in their home countries, it was estimated that between 60 and 315 congenitally infected infants are born in the United States each year (299). Nevertheless, only two congenital infections have been reported, both in infants of Bolivian women (310, 311). The first infant was delivered by caesarian section at 29 weeks gestation because of fetal hydrops (a classic presentation of severe congenital Chagas disease) (18). The diagnosis was not suspected until the mother reported a prior diagnosis of Chagas disease (311). The second infant was also delivered by caesarian section at 30 weeks due to placental abruption and had a pericardial effusion, ascites, and respiratory distress requiring intubation until the 10th day of life (310). The diagnosis was made on histopathological examination of the placenta. Both infants were successfully treated with antitrypanosomal therapy.

Physician AwarenessSurveys indicate that the majority of physicians practicing in the United States have limited knowledge of Chagas disease and seldom consider the diagnosis, even when caring for Latin American-born patients at high risk or with typical clinical syndromes (312, 313). In one survey, 23% of cardiologists, 47% of obstetrician/gynecologists, and 25% of transplantation specialists reported that they had never heard of Chagas disease (312). In a survey of more than 400 obstetrician/gynecologists, 78% reported that they never considered the diagnosis of Chagas disease in their Latin American patients and fewer than 10% were cognizant of the risk of vertical transmission to the infant (313).

Patient Awareness and AccessAwareness and knowledge of Chagas disease are also limited among those at risk. Of Latin American immigrants interviewed in community outreach settings in southern California, 86% had never heard of Chagas disease, even though 62% reported having seen triatomines in their countries of origin (314). Patients with Chagas disease encounter multiple barriers to health care access in general, not just for Chagas disease: these patients disproportionately live below the poverty line, have less than a high school education, lack health insurance, and have difficulty taking time off from work for medical appointments (315). Even legal immigrants have lower access than citizens to publicly funded health insurance in most states; concerns about revealing immigration status may make patients reluctant to seek care (315).

Diagnostic IssuesThere are currently four commercial IgG serological tests cleared by the FDA for diagnostic use in the United States, including three ELISA kits (Hemagen [Hemagen Diagnostics, Waltham MA], Chagatest Recombinante 3.0 [Wiener Laboratories, Rosario, Argentina], and Ortho [Ortho-Clinical Diagnostics, Inc., Raritan, NJ]) and one point-of-care test (ChagasDetectPlus [InBios International, Seattle, WA]) (316). With the exception of the Ortho ELISA, which is also licensed for blood donor screening (215, 277, 317), there is a paucity of data on the performance of these assays in specimens from populations in the United States or in the likely predominant countries of origin of infected U.S. residents (Mexico, El Salvador, Guatemala, and Honduras) (273, 293, 299). Discordant serology has been reported as a particular problem in Mexico (318). Some recombinant tests with excellent performance in the Southern Cone show discordance or low sensitivity when applied in some areas where TcI is predominant (319, 320). In addition, no commercial laboratory in the United States currently offers more than one validated IgG serological assay. The diagnosis of chronic T. cruzi infection requires positive results by two distinct IgG assays and is therefore not possible with commercial testing alone (16). Currently, the only laboratory that conducts multiple IgG serological assays under Clinical Laboratory Improvement Amendments (CLIA) is the CDC Division of Parasitic Diseases and Malaria (DPDM) laboratory.

FDA Approval of Benznidazole and Resulting ChangesUntil May 2018, when benznidazole became commercially available, prescribing antitrypanosomal treatment necessitated a consultation with CDC epidemiologists (321). Confirmation of the diagnosis, recommendations for treatment, and advice on monitoring and management of side effects were necessary components of these consultations, and reporting of adverse events was mandatory under the investigational protocol. Ensuring appropriate diagnostic confirmation, judicious treatment decisions, and adequate side effect monitoring going forward will require efforts to raise provider awareness and knowledge about Chagas disease and antitrypanosomal therapy.

From October 2011 to May 2018, the CDC released benznidazole for 365 patients with confirmed T. cruzi infection (321). Four (1.1%) patients had acute-phase infection, two organ derived, one congenital, and one presumed to be vector borne. Treatment was administered for T. cruzi reactivation in 35 (9.6%) patients, comprising 29 organ transplant recipients, 5 HIV-coinfected patients, and 1 on chemotherapy for malignancy. The vast majority of patients were adults, 236 (64.7%) aged 19 to 50 and 97 (26.6%) older than 50 years. Only 2 (0.5%) of 365 treated patients were aged 2 to 12 years, the age range for which the FDA approved benznidazole.

Insud Pharma’s approach to FDA approval and drug marketing represents a new paradigm in the United States, with patient access and affordability as central concerns (250). The FDA Priority Review Voucher (PRV) program was established in 2008 to provide an incentive for new drug development for neglected tropical diseases (NTD) but has had limited impact and unintended negative consequences (322). In one recent example, FDA approval of miltefosine, a drug used for leishmaniasis, was followed by an astronomical price increase, and the company ceased production after receiving and selling the PRV, leading to a global shortage (323). In contrast, the Insud Pharma/Exeltis Patient Assistance Program, funded in part by the benznidazole PRV, ensures that the cost to the patient will not exceed $60 per course (250).

Public Health Surveillance and ResponseAs of 2017, Chagas disease was a reportable condition in six states, Arizona, Arkansas, Louisiana, Mississippi, Tennessee, and Texas (324); Utah added Chagas disease to its notifiable disease list recently. All of these states except Arkansas and Utah have had published reports of locally acquired T. cruzi infection (50–52, 280, 282, 283). Most of the states focus on autochthonous transmission and incident cases, and several have provisions for submission of triatomines for identification (324). In Texas, the Department of State Health Services (DSHS) provides extensive on-line guidance and data to health care providers and the public, including a summary of reported Chagas disease case data; of 124 cases reported from 2013 to 2017, all were chronic infections and 22 were judged to have resulted from local transmission (325). These figures likely overlap substantially with the published locally acquired infections detected in blood donors in recent years (282, 283). The Texas Chagas Taskforce, which includes the DSHS and several universities, addresses many public health aspects of Chagas disease, including provider and patient resources and educational materials on local vectors (326).