Reactivation Chagas' disease in HIV/AIDS patients. Reactivation of T. cruzi infection in HIV/AIDS patients can cause severe clinical disease with a high risk of mortality. However, as in organ transplant recipients, reactivation is not universal, even in those with low CD4+ lymphocyte counts. The only published prospective cohort study followed 53 HIV-T. cruzi-coinfected patients in Brazil for 1 to 190 months; 11 (21%) had T. cruzi reactivation diagnosed based on symptoms and/or microscopically detectable parasitemia (260). Even among patients without clinical reactivation, the level of parasitemia is higher among HIV-coinfected than among HIV-negative patients (261). Symptomatic T. cruzi reactivation in AIDS patients is most commonly reported to cause meningoencephalitis and/or T. cruzi brain abscesses; the presentation may be confused with CNS toxoplasmosis and should be considered in the differential diagnosis of mass lesions on imaging or CNS syndromes in AIDS patients (70, 71, 88, 260). The second most commonly reported sign of reactivation is acute myocarditis, sometimes superimposed on preexisting chronic Chagas' cardiomyopathy (260, 297). Patients may present with new arrhythmias, pericardial effusions, acute cardiac decompensation, or accelerated progression of existing chronic heart disease (100, 260). Acute meningoencephalitis and myocarditis can occur simultaneously. In the Brazilian cohort, cardiac reactivation was as frequent as CNS disease; cardiac manifestations of reactivated Chagas' disease may pass undetected or mimic progression of chronic Chagas' cardiomyopathy (260). Less common manifestations of reactivation in HIV/AIDS patients include skin lesions, erythema nodosum, and parasitic invasion of the peritoneum, stomach, or intestine (100, 261).
Go to: DIAGNOSIS Appropriate diagnostic testing for T. cruzi infection varies depending on the phase of the disease and the status of the patient. In the United States, CDC provides consultation to health care providers concerning Chagas' disease diagnostic testing (contact information is listed in “Antitrypanosomal Drugs” below). Diagnosis of Acute T. cruzi Infection In the acute phase, motile trypomastigotes can be detected by microscopy of fresh preparations of anticoagulated blood or buffy coat (311). Parasites may also be visualized by microscopy of blood smears stained with Giemsa stain or other stains. Hemoculture in one of several types of standard parasitic medium (e.g., Novy-MacNeal-Nicolle) is relatively sensitive during the acute phase but requires 2 to 4 weeks to show replication. The level of parasitemia decreases within 90 days of infection, even without treatment, and becomes undetectable by microscopy in the chronic phase (306, 311). PCR is a sensitive diagnostic tool in the acute phase of Chagas' disease and may also be used to monitor for acute T. cruzi infection in the recipient of an infected organ or after accidental exposure (133, 134, 157). Diagnosis of Congenital T. cruzi Infection Early in life, congenital Chagas' disease is an acute T. cruzi infection and similar diagnostic methods are employed. Concentration methods yield better sensitivity than direct examination of fresh blood. The microhematocrit method is the most widely used technique in Latin American health facilities. Fresh cord or neonatal blood is collected, sealed in four to six heparinized microhematocrit tubes, and centrifuged, and the buffy coat layer is examined by light microscopy (108). Parasitemia levels rise after birth and peak at or after 30 days of life (32). Repeated sampling on several occasions during the first months of life increases the sensitivity but may not be acceptable to parents (14, 32, 197). Hemoculture can increase sensitivity, but the technique is not widely available, and results are not available for 2 to 4 weeks. Molecular techniques have higher sensitivity and detect congenital infections earlier in life than the microhematocrit method (32, 92, 247). Transient detection of parasite DNA has occasionally been reported in specimens from infants who subsequently are found to be uninfected (32, 211). For this reason, a positive PCR on samples collected on two separate occasions may be used as a criterion for confirmation of congenital infection (32). PCR is increasingly used for the early diagnosis of congenital Chagas' disease in Latin America and is the method of choice in industrialized countries (55, 140, 202, 247, 266). For infants not diagnosed at birth, conventional IgG serology (as outlined below for chronic T. cruzi infection) is recommended after 9 months of age, when transferred maternal antibody has disappeared and the congenital infection has passed into the chronic phase (32, 55, 56). Diagnosis of Chronic T. cruzi infection Diagnosis of chronic infection relies on serological methods to detect IgG antibodies to T. cruzi, most commonly the enzyme-linked immunosorbent assay (ELISA) and immunofluorescent-antibody assay (IFA). No single assay has sufficient sensitivity and specificity to be relied on alone; two serological tests based on different antigens (e.g., whole parasite lysate and recombinant antigens) and/or techniques (e.g., ELISA, IFA, and immunoblotting) are used in parallel to increase the accuracy of the diagnosis (311). Inevitably, a proportion of individuals tested by two assays will have discordant serological results and need further testing to resolve their infection status. Specimens with positive results but low antibody titers are more likely to show discordance because results obtained by less sensitive tests may be negative. Published data suggest that the sensitivity of serological assays varies by geographical location, possibly due to T. cruzi strain differences and the resulting antibody responses (275, 293, 299). The status of some individuals remains difficult to resolve even after a third test, because there is no true gold standard assay for chronic T. cruzi infection (283). Assays such as the radioimmunoprecipitation assay (RIPA) and trypomastigote excreted-secreted antigen immunoblot (TESA-blot) are promoted as reference tests, but even these do not have perfect sensitivity and specificity and may not be capable of resolving the diagnosis (168, 272). Options for diagnostic T. cruzi serological testing are relatively limited in the United States. Several ELISA kits based on parasite lysate or recombinant antigens are Food and Drug Administration (FDA) cleared for diagnostic application. Use of an assay with validation data (e.g., a commercial kit shown to have acceptable sensitivity and specificity in a thorough study) is preferable to reliance on in-house tests for which no performance data are available (31). Utility of PCR for Diagnosis or Monitoring PCR techniques provide the most sensitive tool to diagnose acute-phase and early congenital Chagas' disease and to monitor for acute T. cruzi infection in the recipient of an infected organ or after accidental exposure (32, 65, 133). PCR assays usually show positive results days to weeks before circulating trypomastigotes are detectable on peripheral blood smears (267). Quantitative PCR assays (e.g., real-time PCR) are useful to monitor for reactivation in the immunosuppressed T. cruzi-infected host. In these patients, a positive result on conventional PCR does not prove reactivation, but quantitative PCR assays that indicate rising parasite numbers over time provide the earliest and most sensitive indicator of reactivation (89, 92). In chronic T. cruzi infection, PCR is used as a research tool but is not generally a useful diagnostic test. Although PCR results will be positive for a proportion of patients, the sensitivity is highly variable depending on the characteristics of the population tested, as well as the PCR primers and methods (25, 142, 314). For these reasons, negative results by PCR do not constitute evidence for lack of infection.
Go to: TREATMENT Antitrypanosomal Drugs Nifurtimox and benznidazole are the only drugs with proven efficacy against Chagas' disease (73, 177). Neither drug is approved by the U.S. FDA, but both can be obtained from the CDC and used under investigational protocols. Consultations and drug requests should be addressed to the Parasitic Diseases Public Inquiries line [(404) 718-4745; e-mail, parasites@cdc.gov], the CDC Drug Service [(404) 639-3670], and, for emergencies after business hours and on weekends and federal holidays, the CDC Emergency Operations Center [(770) 488-7100]. Nifurtimox (Lampit, Bayer 2502), a nitrofuran, interferes with T. cruzi carbohydrate metabolism by inhibiting pyruvic acid synthesis. Gastrointestinal side effects are common, occurring in 30 to 70% of patients. These include anorexia leading to weight loss, nausea, vomiting, and abdominal discomfort. Neurological toxicity is also fairly common, including irritability, insomnia, disorientation, and, less often, tremors. Rare but more serious side effects include paresthesias, polyneuropathy, and peripheral neuritis. The peripheral neuropathy is dose dependent, appears late in the course of therapy, and should prompt interruption of treatment. Higher doses are often used in infants than in older children, and tolerance is better in children than in adults. Benznidazole (Rochagon, Roche 7-1051) is a nitroimidazole derivative, considered more trypanocidal than nifurtimox. Dermatological side effects are frequent, and consist of rashes due to photosensitization, rarely progressing to exfoliative dermatitis. Severe or exfoliative dermatitis or dermatitis associated with fever and lymphadenopathy should prompt immediate cessation of the drug. The peripheral neuropathy is dose dependent, usually occurs late in the course of therapy, and is an indication for immediate cessation of treatment; it is nearly always reversible but may take months to resolve. Bone marrow suppression is rare and should prompt immediate interruption of drug treatment. Patients should be monitored for dermatological side effects beginning 9 to 10 days after initiation of treatment. Benznidazole was well tolerated in two placebo-controlled trials with children (12% had a rash and <5% had gastrointestinal symptoms in one study; <10% had moderate reversible side effects in the other study) (7, 277). Side effects are more common in adults than in children. Treatment of Acute and Congenital T. cruzi infection In acute and early congenital Chagas' disease, both drugs reduce the severity of symptoms, shorten the clinical course, and reduce the duration of detectable parasitemia (53, 306). The earliest trials of antitrypanosomal drugs were conducted with patients with acute Chagas' disease in the 1960s and 1970s using nifurtimox (53, 306). Serological cure was documented at the 12-month follow-up in 81% of those treated in the acute phase (306). Treatment of Chronic T. cruzi Infection Until recently, only the acute phase, including early congenital infection, was thought to be responsive to antiparasitic therapy. However, in the 1990s, 2 placebo-controlled trials of benznidazole treatment in children with chronic T. cruzi infection demonstrated approximately 60% cure as measured by conversion to negative serology 3 to 4 years after the end of treatment (7, 278). Several follow-up studies suggest that the earlier in life that children are treated, the higher the rate of reversion to negative serology (6, 281). Together with growing clinical experience across Latin America, these studies revolutionized management of children with Chagas' disease, making early diagnosis and antitrypanosomal drug therapy the standard of care throughout the region (177, 311). There is currently a growing movement to offer treatment to older patients and those with early cardiomyopathy (30, 302, 311). In Latin America, most Chagas' disease experts now believe that the majority of patients with chronic T. cruzi infection should be offered treatment, employing individual exclusion criteria such as an upper age limit of 50 or 55 years and the presence of advanced irreversible cardiomyopathy (276). This change in standards of practice is based in part on nonrandomized, nonblinded longitudinal studies that demonstrate decreased progression of Chagas' cardiomyopathy and decreased mortality in adult patients treated with benznidazole (301, 302). A multicenter, randomized, placebo-controlled, double-blinded trial of benznidazole for patients with mild to moderate Chagas' cardiomyopathy is under way and will help to clarify treatment efficacy for this group (http://clinicaltrials.gov/show/NCT00123916). Management of the Immunocompromised Host Antitrypanosomal treatment for reactivation in organ transplant recipients follows standard dosage regimens and promotes resolution of clinical symptoms and parasitemia. There are no data to indicate that prior treatment or posttransplant prophylaxis decreases the risk of reactivation; posttransplant prophylaxis is not routinely administered in heart transplant centers in Latin America (52). Antitrypanosomal therapy is thought to achieve a sterile cure in few, if any, adults with longstanding chronic infection, and treated patients should be considered to be at risk for reactivation. Reactivation in an HIV-coinfected patient should be treated with standard courses of antitrypanosomal treatment; antiretroviral therapy should be optimized (143).
Go to: EPIDEMIOLOGY OF CHAGAS' DISEASE Since 1991, the estimated global prevalence of T. cruzi infection has fallen from 18 million to 8 million, due to intensive vector control and blood bank screening (87, 214). The Pan American Health Organization estimates that approximately 60,000 new T. cruzi infections occur each year (214). As other transmission routes have diminished, the proportion attributable to congenital infection has grown: an estimated 26% of incident infections now occur through mother-to-child transmission (214). In settings with endemic vector-borne transmission, T. cruzi infection is usually acquired in childhood. Because the infection is lifelong, the seroprevalence in an area with sustained vector-borne transmission rises with age, reflecting the cumulative incidence (98). Before widespread vector control was instituted in the early 1990s, it was common to find that >60% of adults in an community where the disease was endemic were infected with T. cruzi (200, 230). In cross-sectional community surveys, most infected individuals are asymptomatic; an estimated 70 to 80% will remain asymptomatic throughout their lives (176, 234). Because cardiac and gastrointestinal manifestations usually begin in early adulthood and progress over a period of years to decades, the prevalence of clinical disease increases with increasing age (178).
Go to: HUMAN CHAGAS' DISEASE IN THE UNITED STATES Autochthonous Transmission to Humans Seven autochthonous vector-borne infections (four in Texas and one each in California, Tennessee, and Louisiana) have been reported since 1955 (Table 6) (10, 90, 134, 151, 209, 265, 342). Most reported cases have been in infants or small children; six of the seven infections were in the acute phase at the time of identification, and the diagnosis was sought because of symptoms and/or the presence of triatomine vectors. A survey conducted in the community of residence of the 1982 California case demonstrated positive complement fixation results in 6/241 (2.5%) residents tested (203). The rarity of autochthonous vector-borne transmission in the United States is assumed to result from better housing conditions that minimize vector-human contact. In addition, North American vectors may have lower transmission efficiency, due at least in part to delayed defecation (153, 203, 228). However, given that the vast majority of acute T. cruzi infections in immunocompetent individuals pass undiagnosed in Latin America, where the index of suspicion is much higher, undetected cases of autochthonous vector-borne transmission are presumed to occur.
Chagas' Disease Burden among Latin American Immigrants The only direct assessments in Latin American populations living in the United States come from very limited local surveys and blood bank screening (see below) (42, 59, 148, 165, 167). No large representative surveys have ever been conducted, and blood bank data cannot be extrapolated with validity because donors are not representative of the larger population. The only recent data come from a survey of Latin American immigrants attending churches in Los Angeles County; a total of 10 (1%) of 985 adults tested had positive results by serological testing (290). Based on the reported number of immigrants from countries in Latin America where Chagas' disease is endemic and the estimated national T. cruzi seroprevalences in their countries of origin, there are an estimated 300,000 persons with T. cruzi infection currently living in the United States (29). Patients with clinical manifestations of Chagas' disease, especially cardiomyopathy, are assumed to be present but largely unrecognized in hospitals and health care facilities in the United States, but systematic data are sparse (126). Recent targeted studies in a Los Angeles hospital demonstrated positive results by T. cruzi serological tests among 15 (16%) of 93 Latin American patients with a diagnosis of idiopathic cardiomyopathy and 11 (4.6%) of 239 patients with conduction system abnormalities on ECG and at least 1 year of residence in Latin America (190, 291).
Blood-Borne Transmission and Blood Donor Screening A total of 5 transfusion-associated T. cruzi infections have been documented in the United States since the late 1980s (Table 7) (59, 67, 114, 166, 351). All infected recipients had underlying malignancies and were immunosuppressed. Platelet units from Bolivian donors were implicated in 3 of 5 cases. Several patients 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 (67, 114, 351). The recipient of a platelet unit detected as infected during a research study had T. cruzi infection detected by PCR and serology during prospective monitoring but never developed symptoms (166).
In December 2006, the FDA approved an ELISA to screen for antibodies to T. cruzi in donated blood (59). The radioimmunoprecipitation assay (RIPA) has been used as the confirmatory test (1, 31, 257). The American Red Cross and Blood Systems Inc. voluntarily began screening all blood donations in January 2007, and in subsequent months, many other blood centers starting screening as well. As of 2 September 2011, 1,459 confirmed seropositive donations have been detected in 43 states, with the largest numbers found in California, Florida, and Texas (1). A second T. cruzi antibody screening test was approved in April 2010. In December 2010, FDA issued specific guidance for appropriate use of the screening tests (103). Current FDA recommendations are to screen all blood donors initially, and if a donor's sample tests negative using one of the two FDA-approved screening tests, no testing of future donations by that donor is necessary. No supplemental test has been approved, and donors are deferred indefinitely on the basis of positive screening test results alone. This strategy will be reviewed by FDA at upcoming meetings of the Blood Products Advisory Committee; the risk of newly acquired blood donor infections, including results from longitudinal studies of repeat blood donors, will be considered. Screening of blood donations remains voluntary, although most blood centers are currently following FDA recommendations. In data from the first 16 months of screening, comprising >14 million blood donations, the overall seroprevalence was 1:27,500 based on donations screened, with the highest rates in Florida (1:3,800), followed by California (1:8,300) (31). Because large blood donor studies prior to FDA approval of the screening ELISA were conducted in southern California with permanent deferral of all repeatedly reactive donors, a substantial number of infected individuals were already removed from the local donor pool, and the reported prevalence in California is thought to represent an underestimate (42, 59, 165, 167). From preliminary data, 29 (28%) of 104 T. cruzi-infected donors 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 9 other countries of Central and South America (31). Among confirmed infected donors born in the United States, 10 individuals reported no specific risk factors for T. cruzi infection. All of these donors reported outdoor activities (e.g., hunting, camping, or extensive gardening) in the southern United States, which may indicate potential autochthonous exposure to the vector or animal reservoirs.
Organ Donor-Derived Transmission and Organ Donor Screening A total of five instances of organ-derived transmission from three donors are documented in the published literature in the United States (Table 8) (60, 61, 157). Four of the five recipients died. One patient died from acute Chagas' myocarditis; T. cruzi infection was not the primary cause of but may have contributed to the other deaths (61, 157). In all of these instances of transmission, donor infections were not suspected until at least one recipient presented with symptomatic acute Chagas' disease.
More recently, some organ procurement organizations have begun selective or universal screening of donated organs (65). Three transmission events (in two heart recipients in 2006 and 2010 and one liver recipient in 2006) were detected through systematic laboratory monitoring when their respective donors were identified as infected shortly after the transplants occurred. All three of these recipients were treated and survived their T. cruzi infection (65; S. Huprikar and B. Kubak, unpublished data). When an infected organ donor is detected, recipient monitoring relies primarily on detection of the parasite by microscopy, culture, and/or PCR, because seroconversion may be delayed or never occur in immunocompromised individuals (65, 238). Molecular techniques usually show positive results days to weeks before circulating trypomastigotes are visible by microscopy of peripheral blood. Transplant-transmitted T. cruzi infection may have a longer incubation period than vector-borne infection; parasitemia is usually detected within 2 to 3 months, but the delay can be as long as 6 months. A frequently recommended monitoring schedule consists of weekly specimens for 2 months, specimens every 2 weeks up to 4 months, and then monthly specimens afterwards (65, 238). 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.
Unanswered Questions and Priorities for Research and Programs The United States faces important public health challenges for the prevention, control, and management of T. cruzi infection and Chagas' disease (86). Patients with undiagnosed Chagas' cardiomyopathy go unrecognized, impeding their optimal management. The large number of undetected T. cruzi infections sustains the risk of transmission through blood and organ donation and from mother to child. Currently, obstetricians have limited knowledge of congenital T. cruzi transmission risk, and almost no screening of at-risk women is carried out (48). Many health care providers in all specialties fail to consider the diagnosis of Chagas' disease in patients at risk and are unaware that antitrypanosomal treatment is available (280, 300); the possibility that treatment could decrease the risk of progression of disease in infected individuals is therefore not realized. Worldwide, programs to control Chagas' disease are hampered by the lack of adequate tools, and these challenges are equally salient in the United States (283). Point-of-care diagnostic tests would allow physicians to make a rapid diagnosis in patients in whom Chagas' disease is suspected and provide a practical means to identify women at risk of transmitting the infection to their infants. However, the sensitivity of current T. cruzi rapid tests shows wide geographic variation (275, 299); there is a need for screening tests with high sensitivity, especially for T. cruzi infections originating in geographic areas such as Mexico and the United States, where current tests appear to have low sensitivity (275; CDC, unpublished data). Two other diagnostic needs are critical: a practical, timely test of cure and indicators to distinguish patients who are likely to develop clinical disease from those likely to remain asymptomatic. Unfortunately, neither of these tools is currently on the horizon. Pediatric formulations of existing drugs are of immediate concern and expected to be available soon (91). However, new treatment drugs with high efficacy and better safety profiles, especially in adults, are needed (295). To inform effective policy for Chagas' disease control in the United States, significant gaps in our knowledge must also be addressed. Systematic, rigorous population-based data to determine infection prevalence and morbidity are needed to inform prevention strategies. Pilot studies in hospitals with a high proportion of women born in Latin America would help to define practical methods to target screening for congenital transmission. More thorough identification of the T. cruzi strains circulating in the United States will add to our assessment of transfusion risk and understanding of the molecular epidemiology of the disease (164). More comprehensive assessment of the magnitude of local transmission risk and the factors influencing vector and reservoir host distribution and human contact are important to inform control efforts. Improved knowledge of the local epidemiology and ecology will allow more efficient, effective targeting of limited resources and raise awareness of Chagas' disease in the United States. As improved control of vector- and blood-borne T. cruzi transmission decreases the burden in countries where the disease is historically endemic and imported Chagas' disease is increasingly recognized outside Latin America, the United States—which confronts the challenges faced both by countries where the disease is endemic and by those where it is not—can play an important role in addressing the altered epidemiology of Chagas' disease in the 21st century
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