Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is endemic in many parts of Mexico, Central America and South America. The most common mode of T. cruzi transmission is vector-borne, via the feces of infected triatomine bugs. T. cruzi parasites can also be transmitted by congenital and foodborne routes, transfusion and transplantation. Chronic infection persists for life in the absence of treatment, and reactivation in immunosuppressed patients may result in severe disease with increased risk of mortality (1). Currently, two drugs are available to treat Chagas disease (2). Nifurtimox and benznidazole are not approved by the Food and Drug Administration (FDA) but are available in the United States through the Centers for Disease Control and Prevention (CDC) Drug Service under FDA-approved protocols.

An estimated eight million people in the Americas have Chagas disease (3) and Chagas disease is now found in previously nonendemic urban areas of Latin America and other regions of the world (4). In the United States, an estimated 300,000 Latin American immigrants have Chagas disease (5). In addition, at least 23 U.S. residents and possibly many more have become infected via domestic vector-borne transmission (6). Documented human cases of T. cruzi infection have been acquired in the United States by vector-borne, congenital, transfusion and transplant transmission (7).

Three investigations of donor-derived T. cruzi infection in U.S. organ transplant recipients were previously reported (1,8,9), and published recommendations for screening and treatment of Chagas disease in organ transplant recipients in the United States exist (10). The evidence to support these recommendations included results of several previously unpublished potential transplant-transmission investigations.

The first documented case of transplant transmission was reported in the United States in 2001 (8). This report describes the cumulative CDC experience identifying chronically infected organ donors and prospectively monitoring recipients of transplanted organs from those donors with comparisons based on adherence to the recommended monitoring strategy. We also describe details of four previously unpublished transplant-transmitted T. cruzi infections in organ recipients from three donors, including the first successful heart transplantation in the United States from a T. cruzi seropositive donor.

CDC was notified of potential transplant transmission of T. cruzi when either infected donors or recipients were identified. Donor infections were identified retrospectively when transplant-associated transmission was suspected in organ recipients or prospectively as a result of risk-based organ donor screening. Recipient infections were identified either after the development of symptomatic disease or after monitoring recipients for acute infection posttransplant.

CDC requested samples for confirmatory testing for any suspected infection. The international standard for confirming the diagnosis of chronic Chagas disease requires positive results on at least two different format serologic tests, preferably using different antigen preparations. Acute Chagas disease is diagnosed by detection of T. cruzi parasite in blood smears or by polymerase chain reaction (PCR) testing of serial blood samples, documenting parasitemia. Serologic testing was performed on donor blood specimens to confirm T. cruzi infection status; most donors were tested with a CDC in-house immunofluorescence assay (IFA) based on fixed epimastigotes and the commercial Chagatest ELISA recombinante v.3.0 (Wiener Laboratorios, Argentina). Confirmation of chronic Chagas disease in the donor was determined by positive results on two or more serologic assays or, in cases with indeterminate serologic testing results, when transmission of T. cruzi was documented in recipients of organs from that donor. Recipients were tested for antibody to T. cruzi at or soon after transplantation to document baseline T. cruzi status.

Testing for acute infection in recipients included microscopic examination of peripheral blood, hemoculture and PCR testing at CDC. Serologic testing was also performed to detect any developing antibody response to the parasite. Acute infection was confirmed by positive hemoculture or detection of trypomastigotes in peripheral blood; confirmation based on PCR testing was considered sufficient evidence of infection in many cases. CDC PCR testing approaches changed over time as advances in T. cruzi PCR methods became available. Prior to 2006, a PCR assay targeting the kinetoplast (minicircle DNA) was used (11). Cloning and sequencing of amplicons was performed on some specimens. A positive PCR result for one specimen was considered sufficient to presume transmission. From 2006 to 2008, a PCR assay targeting the TCZ minisatellite was also used (12). Amplicons from specimens only positive by minicircle PCR were cloned and sequenced for confirmation. Positive PCR results for both assays on a single specimen were considered sufficient to presume transmission. Since 2008 the PCR testing algorithm was changed to include three PCR assays targeting the kinetoplast, the TCZ mini-satellite and the small subunit ribosomal RNA gene, respectively (13). Positive PCR results with at least two of these assays on two consecutive specimens were required for an organ recipient to be considered infected.

Recommended monitoring involved PCR testing of whole blood specimens collected at weekly intervals posttransplant for 8–12 weeks with concurrent hemoculture and serological testing at CDC. Clinicians caring for recipients were advised to examine peripheral blood smears and buffy coat preparations at the local facility. After the first 2–3 months of intensive monitoring, monthly testing was performed for a total of 6 months posttransplant. More frequent testing was recommended if the recipient developed illness or immunosuppression was increased for treatment of rejection. After the initial 6 months, additional testing to monitor for infection was also based on development of illness or increase in immunosuppression.

Adherence to the posttransplant monitoring recommendations varied among investigations. To demonstrate the impact of monitoring, investigations were categorized by intensity of monitoring. Investigations with recommended monitoring were those where (1) PCR monitoring was initiated promptly with testing of specimens collected within 2 weeks of transplantation, (2) intensive weekly testing was performed for 2–3 months and (3) biweekly to monthly testing was performed for 6 or more months or until T. cruzi infection was diagnosed. We defined adherence to recommended monitoring as complete if all three criteria for recommended monitoring were met; partial if two of the three criteria were met; and incomplete if only one criterion was met or no testing was performed prior to diagnosis at the time of symptom development in the recipient.

Donor histories were reviewed for potential risk factors for Chagas disease, including birth or residence in Latin America, mother’s immigration status and previous transplantation or transfusion. Recipients were interviewed regarding risk factors and clinical information was extracted from medical records.

From 2001 to 2011, CDC helped investigate potential transmission of T. cruzi from 14 seropositive organ donors to 34 solid organ transplant recipients who were seronegative at the time of transplantation (Tables 1 and 2). For 13 of 14 donors, birth country or mother’s birth country was in Latin America; one donor and his mother were both born in the United States (Table 3). The organs from the 14 donors were procured in the following states: California (4), New York (4), Florida (2), Pennsylvania (1), Georgia (1), Tennessee (1) and Texas (1). The 34 transplant recipients received the following organs: isolated kidney (14), isolated liver (11), isolated heart (4), combined liver-kidney (1), combined kidney-pancreas (1) and bilateral lung (1). Three corneas from two donors and pancreatic islet cells from one donor were transplanted but information about those recipients is not included in this analysis. Two organ recipients were excluded from further analysis due to insufficient data (Table 1). The following results are based on analysis of the remaining 32 organ recipients.

Transplant transmission of T. cruzi was confirmed in 9 of the 19 recipients of organs from 6 donors (investigations 1, 4–6, 12, 14) and included three heart, two liver, two kidney, one combined kidney-pancreas, and one bilateral lung recipients. Infection was diagnosed only after the development of symptomatic disease in four recipients, all of whom had positive hemocultures (1,8,9) (Table 2). T. cruzi infection in one kidney recipient (Table 1, investigation 1) was diagnosed by hemoculture after the other recipients in the investigation developed symptomatic illness. Infection was diagnosed in the absence of symptoms by PCR monitoring in the other four recipients, two of whom also had a positive hemoculture (Table 2). The median interval from transplantation to diagnosis of infection was 8 weeks (range: 3–29 weeks). All recipients who developed evidence of infection were treated with either nifurtimox or benznidazole, obtained through the CDC Drug Service. The other ten organ recipients in these six investigations did not develop evidence of infection during the period they were monitored (median: 29 weeks, range: 7–42 weeks).

In seven investigations (investigations 2, 3, 7, 9–11, 13), none of the 13 recipients developed evidence of infection during the monitoring period. The median duration of follow-up was 37 weeks (range: 12–145 weeks). Although monitoring was not always performed on a weekly basis as recommended, most of these recipients were tested at least monthly for 5 or more months following transplantation (Table 2). In investigation 3, the only organ recipient received chemoprophylactic treatment and complete monitoring (for 145 weeks) with no evidence of infection during the follow-up period.

Death within 1 year of transplantation was observed in six of the 32 recipients. All four of the recipients who developed symptomatic Chagas disease died; however, Chagas disease was reported as the cause of death for only one recipient (Table 1). Two recipients who were monitored by PCR died within 1 year. One was infected and her infection was detected by complete PCR monitoring. Chagas disease was not listed as the cause of death. The other recipient died without evidence of T. cruzi infection after partial monitoring. An additional death occurred more than 4 years after transplant, leading to a total of eight deaths reported in this case series (Table 1).

Three investigations involving four previously unreported cases of transplant-transmitted T. cruzi infection associated are described below. In all cases, donor infection status was recognized at the time of transplant and prospective monitoring led to prompt recognition of T. cruzi transmission with successful intervention of antitrypanosomal treatment to prevent clinical disease, including the first description of a successful outcome in a heart transplant recipient with donor-derived T. cruzi infection in the United States. The outcomes of the other investigations are summarized in Table 1.

Due to the increasing disparity between the number of organ transplant candidates on the waiting list and available organs, intense pressure exists to safely expand the donor pool. The use of organs from infected donors is considered acceptable when transmission can be easily monitored, detected and treated without compromising patient and graft survival. For example, organs from cytomegalovirus (CMV)-seropositive donors have been successfully transplanted in CMV-seronegative recipients with effective prophylaxis or preemptive strategies that that can minimize risk of disease in the recipient. T. cruzi seropositive donors are a potential source for organs. Although uninfected recipients who receive an organ from a T. cruzi-infected donor may develop acute T. cruzi infection, transmission under these circumstances is not universal. In the investigations summarized here, nine T. cruzi infections were diagnosed. Five infections were only diagnosed after development of symptomatic Chagas disease in four recipients in the absence of monitoring. The other four infections were identified by either complete or partial PCR monitoring. None of the 19 patients with complete or partial monitoring developed symptomatic Chagas disease (Figure 1). Our experience suggests that intensive monitoring and prompt T. cruzi therapy when transmission occurs may be a safe and effective management strategy for recipients of livers and kidneys from seropositive donors.

In 2011, published recommendations from the Chagas in Transplant Working Group advised targeted screening of donors from Mexico, Central America and South America and consideration of transplantation of liver and kidneys from infected donors with prospective monitoring for infection and prompt treatment. The data presented here provide further evidence to support the recommendations for donor screening and prospective recipient monitoring when organs from infected donors are transplanted. The prospective monitoring strategy is also recommended by the Chagas Disease Argentine Collaborative Transplant Consortium (14).

Although advocated by some authors (15,16,17), we agree with previously published guidelines that do not recommend chemoprophylaxis in transplant recipients from T. cruzi-seropositive donors. Our data suggest that preemptive monitoring identifies infection that can be treated before disease occurs. Although limited by sample size, preemptive monitoring appears to be a safe strategy. The rationale for recommending against prophylaxis also includes avoidance of potential drug toxicity and interactions. Furthermore, the efficacy of chemoprophylaxis remains undefined; parasitologic and molecular methods are not sufficiently sensitive to confirm that the recipients remain uninfected posttreatment and, as demonstrated by our data, immunosuppressed patients who become infected are unlikely to seroconvert. In this setting, the lack of detectable antibody to T. cruzi does not exclude infection.

Heart transplantation from T. cruzi seropositive donors is currently not recommended. In Argentina, hearts from T. cruzi-infected donors are discarded (14). The Chagas in Transplant Working Group also advises against heart transplantation from T. cruzi seropositive donors. In our investigations, four heart recipients were from seropositive donors. (Table 2) Of the three infected recipients, two were previously reported (1,9) and one is described here. The fourth recipient of a heart from a seropositive donor (investigation 10) has not developed detectable infection, but the donor was not an immigrant from Latin America and he was suspected to have acquired T. cruzi infection domestically. The donor was seropositive when tested at two commercial laboratories and was positive on ELISA but not IFA at CDC. The heart recipient in investigation 12 is one of two reports of a good outcome associated with heart transplantation from a confirmed T. cruzi seropositive donor with implementation of a prospective monitoring and treatment strategy (18). Infection was detected by PCR testing and clinical disease was prevented by a full course of benznidazole treatment. The results of follow-up testing have been negative to date. Although this case illustrates the potential efficacy of this strategy in heart transplantation, transmission did occur and we still favor avoiding this organ type. Furthermore, infection in the lung recipient from a T. cruzi seropositive donor (investigation 14) demonstrates that transmission may occur via lung transplantation as well. To our knowledge, this is the first reported transmission of T. cruzi via lung transplantation.

Before the publication of the guidelines from the Chagas in Transplant Working Group, a survey of all 58 U.S. organ procurement organizations (OPOs) revealed that only 11 (19%) OPOs performed any donor screening for Chagas disease (19). If the donor is known to be infected, transplant centers can make informed decisions and appropriately monitor recipients of organs from seropositive donors. Based on our investigations, the likelihood of transmission appears to vary by organ type. Transplanted organ types associated with infection included heart (3/4; 75%), liver (2/10; 20%), kidney (2/15; 13%), combined liver-kidney (0/1; 0%), combined kidney–pancreas (1/1; 100%) and bilateral lung (1/1; 100%). In the reported investigations, intensive monitoring of recipients led to prompt recognition and treatment of transplant-associated T. cruzi infection. This evidence supports the recommendation that the liver and kidneys from seropositive donors may be transplanted provided the transplant center and recipients are committed to appropriate prospective monitoring and advance planning for potential therapy (10,20). Further investigation is needed to understand the risk for transmission and the factors that affect outcomes associated with transplantation of organs from T. cruzi infected donors, by organ type and recipient characteristics.