An approach to the management of Trypanosoma cruzi infection (Chagas' disease) in immunocompromised patients.

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An approach to the management of Trypanosoma cruzi infection (Chagas’ disease) in immunocompromised patients Expert Rev. Anti Infect. Ther. 12(3), 357–373 (2014)

Angela Martinez-Perez, Francesca F Norman, Begonã Monge-Maillo, Jose-Antonio Perez-Molina and Rogelio Lopez-Velez* Tropical Medicine and Clinical Parasitology, Infectious Diseases Department, Ramon y Cajal Hospital, Carretera Comenar 9.100 Km, 28034 Madrid, Spain *Author for correspondence: [email protected]

The epidemiology of Chagas disease has changed in the last decades due to migration movements, population ageing and the emergence of new transmission routes. In endemic countries, health facilities and access to healthcare are improving and T. cruzi infected patients are also benefiting from medical advances. The HIV epidemic has spread to both endemic and non-endemic areas for T. cruzi, organ transplant rates have increased recently, especially in Latin America, and other medical conditions affecting the immune system are increasing their global burden. The natural course of Chagas disease is mainly determined by the host’s cellular immune response. These conditions may therefore overlap with T. cruzi infection and alter the disease’s natural history which may present with atypical clinical forms and a higher associated morbidity and mortality in immunocompromised patients. The present review aims to contribute to the management of immunosuppressed patients with T. cruzi infection. KEYWORDS: autoimmune disease . Chagas disease . HIV . immunosupression . neglected diseases . neoplasm .

transplantation

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Trypanosoma cruzi

Overview of Chagas disease

Chagas disease is caused by the hemoflagellate parasite Trypanosoma cruzi, a protozoan with great genetic diversity. Six different ancestral lineages, named discrete typing or taxonomic units (DTUs), have been identified and labeled TcI–TcVI (a seventh DTU affecting bats has been named Tcbat). DTUs have a varied geographical distribution and are involved in different parasite life cycles [1]. Some authors have also associated these DTUs with clinical manifestations and transmission patterns [2–4]. T. cruzi is transmitted through the feces of hematophagous triatomine vectors (Hemiptera, Reduviidae, Triatominae), congenitally from mother to child or by oral consumption of contaminated food or beverages [5]. Other transmission mechanisms such as laboratory accidents, transfusion of infected blood components or transplantation of organs from infected donors have been described [6,7].

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10.1586/14787210.2014.880652

T. cruzi may therefore also be transmitted in areas where the vector is not present. Primary infection with T. cruzi may have a wide clinical spectrum. The incubation period ranges from 1 to 2 weeks. The acute phase may be asymptomatic or mildly symptomatic in the majority of cases, presenting with fever, malaise, palpitations or abdominal pain that usually disappear in few weeks or it may present as a life-threatening condition with acute myocarditis or meningoencephalitis (less than 1% of cases) [5,7]. Most patients then enter a chronic asymptomatic state known as the indeterminate period and may remain disease-free for many decades. Annually, around 2–3% of all infected patients will progress to a chronic symptomatic phase [8]. Patients in this late stage may have cardiac and/ or gastrointestinal involvement and an increased risk of stroke [9]. Chagas cardiomyopathy is the main cause of death and disability in this neglected disease [10].

2014 Informa UK Ltd

ISSN 1478-7210

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Martinez-Perez, Norman, Monge-Maillo, Perez-Molina & Lopez-Velez

Diagnosis in the acute phase relies on identification of parasites in peripheral blood or other body fluids. Standard techniques include direct observation of fresh blood samples or following concentration methods. Classical parasitological methods include xenodiagnosis and culture, but they are timeconsuming and have varying sensitivities. Some nucleic acid amplification assays detecting the presence of T. cruzi may also be used for diagnosis during this phase [11,12]. Parasites gradually clear from peripheral blood as the disease enters the intermediate phase and T. cruzi infection during this phase may only be confirmed with serological methods. The WHO recommends two positive serological tests using two different T. cruzi antigens, one of them being an ELISA, to confirm T. cruzi infection in chronic patients [13,14]. Different PCR techniques are also available but are not suitable for diagnosis of chronic T. cruzi infection as parasitemia fluctuates in this stage of the disease [15]. Conventional PCR techniques may be useful in congenital disease, in immunocompromised patients and to monitor treatment efficacy [12], especially if they remain positive after treatment. Recent quantitative PCR methods may be more accurate for such monitoring and some authors consider them a suitable tool to predict reactivation episodes [16,17]. Once the diagnosis of T. cruzi infection has been confirmed, an adequate assessment should include a complete history and physical examination and a resting 12-lead ECG with a 30-s rhythm strip. Transthoracic ecocardiography is recommended. Additional tests should be performed if there are cardiovascular symptoms/signs suggestive of Chagas disease, and/or ECG abnormalities suggestive of Chagas cardiac disease and/or symptoms/signs of gastrointestinal tract involvement [5]. Reactivation of Chagas disease is characterized by the presence of trypomastigotes in blood, cerebrospinal fluid or other fluids, with or without clinical manifestations, which may be detected using direct microscopy [18]. Amastigote forms with intense inflammatory infiltration may be seen on histological examination. Increased protein levels, reduced glucose levels and lymphocytic pleocytosis may be found in the cerebrospinal fluid [19,20]. Only two drugs are licensed for treatment of Chagas disease: benznidazole administered at doses of 5–8 mg/kg/day for 30–60 days and nifurtimox administered at doses of 8–10 mg/kg/day for 60–90 days. Both of them are administered orally. Efficacy of antiparasitic treatment has been demonstrated in the acute, congenital and early chronic stages of the disease, and use during the chronic phase is controversial due to its lower efficacy in this stage. However, some recent observational studies have shown that treatment may decrease disease progression in this phase, so it may generally be offered to patients in the chronic stage of the disease [21]. Poor tolerance and undesired events are common with both treatment options [22,23], but benznidazole is the more widely used drug, and nifurtimox may be considered a second-line drug as it has been associated with higher toxicity [22]. The most common side effects described have been skin hypersensitivity reactions, gastrointestinal complaints, and rarely, peripheral neuropathy, fever and leucopenia in the case of benznidazole and gastrointestinal symptoms, 358

weight loss, headache, skin rash and myalgia in the case of nifurtimox. Changes in the epidemiology of Chagas disease

Chagas disease was originally restricted to rural areas of Latin America. In this region, an estimated 7.8–8 million people are infected and 28 million are at risk of acquiring the disease [24]. In endemic areas, vector control initiatives launched in the last decades and blood donor screening programs have led to a substantial decrease in the number of new cases acquired through these two routes [24]. However, oral transmission is an emerging route for acquisition of Chagas disease in the Amazon region, and there are still some clusters of active vectorial transmission in remote areas of the Gran Chaco region of Argentina, Bolivia, Paraguay and Brazil [25,26]. In the last two decades, large population movements from rural to urban areas of endemic countries and global migration to nonendemic countries have spread T. cruzi infection beyond its natural boundaries [27,28]. Persons with chronic infection have migrated to North America, Europe, Japan and Australia. The majority of imported cases have been diagnosed in the USA and Spain where an estimated 325,000 and 42,000 persons with chronic infection, respectively, are currently living [29,30]. Many infected patients may benefit from better access to healthcare, which may lead to increased survival and paradoxically a larger number of patients with associated comorbidity. Aging and chronic diseases may add comorbidity in patients with Chagas disease [31]. Immunosuppressive conditions such as HIV infection, transplant related and other immunosuppressive therapies and neoplasia deserve special attention as they may alter the natural history of Chagas disease [18]. Data from several studies highlight the relevance of T. cruzi infection in these different settings: HIV is currently a pandemic. An estimated 1.4 million people were living with HIV in Latin America in 2011 compared with 1.2 million in 2001. In this region, HIV has spread to rural areas in the last decades overlapping with the natural geographical distribution of T. cruzi [32] and affecting mostly heterosexuals and young women in rural areas [33]. In the last 5 years, organ donation in Latin America has increased by 41% [34]. Spain has the highest organ donation rate in Europe and well-established transplantation programs. Around 9–10% of organ donors in this country are of foreign origin, one-quarter of them being from Latin America [35]. Patients with chronic T. cruzi infection may eventually develop advanced cardiomyopathy and need heart transplantation. A Spanish study of blood donors at risk for Chagas disease revealed a seroprevalence of 0.62% in 2008 and a similar study in France found a seroprevalence of 0.31% [36,37]. A recent retrospective analysis identified the first two cases of probable transfusion-transmitted T. cruzi infection in the USA since implementation of the screening program in 2007 [38]. An estimated 12.7 million new cancer cases were diagnosed worldwide in 2008. Lung, female breast, colorectal and stomach cancers were the most commonly diagnosed cancers, Expert Rev. Anti Infect. Ther. 12(3), (2014)

An approach to the management of T. cruzi infection (Chagas’ disease)

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Table 1. Trypanosoma cruzi infection in immunocompromised hosts: clinical manifestations and differential diagnosis. Clinical scenario

Clinical manifestations

Differential diagnosis

Acute infection in organ transplant recipients

Fever, hepatosplenomegaly, myocarditis, congestive cardiac failure

Acute rejection Infections occurring in post-transplant patients

Reactivation of infection in organ recipients

Fever, myocarditis, inflammatory panniculitis/skin nodules, CNS involvement

Acute rejection Infections occurring in post-transplant patients

Reactivation of infection in HIV/AIDS patients

Meningoencephalitis, space-occupying CNS lesions, myocarditis, skin lesions, parasitic invasion of GI tract

Toxoplasmosis, primary CNS lymphoma, cryptococcosis, tuberculosis

accounting for more than 40% of all cases. Leukemia and nonHodgkin lymphoma were among the 10 leading cancer diagnoses. Worldwide, an estimated 7.6 million deaths from cancer occurred in 2008. Treatment relies on antineoplastic chemotherapy, which is readily available in tertiary centers of urban areas of Latin America [39]. Autoimmune diseases are increasing worldwide and range from organ specific to systemic disorders including rheumatoid arthritis, systemic lupus erythematosus, primary Sjo¨gren’s syndrome, systemic sclerosis, idiopathic inflammatory myositis and the systemic vasculitis. The cornerstone of treatment is immunosuppressive drugs [40]. T. cruzi & immunosuppression

Natural control of T. cruzi depends mainly on the cellular immune system. During the acute phase of the infection, any nucleated cell may be invaded by T. cruzi, and inflammatory changes are marked due to rupture of infected cells. The natural immune response is triggered by parasite surface mucins, trans-sialidases, which are the main virulence factors for invasion and parasite DNA. In most infected individuals, an effective host cellular immune response, involving Th1, CD4+ and CD8+ lymphocytes and the production of cytokines (IFN-g, TNF-a and IL-12), develops within 2 months of infection and is able to effectively control parasitemia during the host’s lifespan. Intracellular amastigote nests remain in the host tissues producing a degree of local low-grade inflammation. Tissue damage has also been attributed to cross-reactivity between T. cruzi antigens and self-antigens and an imbalance between CD4+ and CD8+ T-lymphocyte responses leading to an excess of inflammatory cytokines [26]. Progression from the indeterminate form to clinically overt chronic Chagas disease may involve an imbalance in Th 1 and Th 2 lymphocytes, which leads to a greater cytokine production. Benznidazole has trypanocidal activity but also induces a shift in CD8 phenotype to a cluster of memory T cells with protective capacity against T. cruzi [5,26]. In the context of immunosuppression and Chagas disease, different scenarios may be found: primary-acquired T. cruzi infection in recipients of blood components/organs from an infected donor; or reactivation of pre-existing T. cruzi infection in patients with immunosuppression, mainly due to HIV infection, but also following transplantation or associated


with other causes of immunosuppression such as autoimmune disorders and lymphoproliferative diseases [18]. Chagas disease in the immunosuppressed host may present with severe manifestations, atypical clinical forms and high associated morbidity and mortality [18]. The clinical manifestations and differential diagnosis of T. cruzi infection in immunocompromised hosts are shown in TABLE 1. Chagas disease is a neglected tropical disease even outside endemic areas, and there is a general lack of adequate diagnostic and therapeutic tools. Many health professionals in nonendemic areas may have had little experience with the disease, probably leading to underdiagnosis of this infection. This is highlighted by a recent European study, which estimated that 94–96% of T. cruzi-infected people may remain undiagnosed in nonendemic areas [41]. The first congenital case of Chagas disease in the USA has been described recently, which also probably reflects many cases may not have been adequately diagnosed, given the large migrant population from endemic areas living in the country [42]. Chagas disease is now a worldwide problem that may coexist with other diseases that alter its natural history. Guidelines have been published to assess clinicians in the management of patients with T. cruzi infection and immunosuppression but unresolved matters and controversies remain [43]. The present review aims to address some of these issues providing updated recommendations on management in different situations. T. cruzi & HIV coinfection Epidemiology

The first case of T. cruzi and HIV coinfection was described as early as 1988 [44]. Most coinfections occur in patients previously infected with T. cruzi who then acquire HIV during adulthood, although primary acquisition of T. cruzi has been suggested as a route of infection in intravenous drug users previously infected with HIV [4,20]. Coinfection with T. cruzi and HIV occurs in both endemic and nonendemic areas with Latin American migrants. Coinfection rates in endemic countries may range from 1.3 to 7.1% [45,46]. Prevalence may be higher among specific population groups such as intravenous drug users, up to 8.9% described in one study [47]. Spain is the only nonendemic country with published data on coinfection rates and estimates range from 359


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1.9 to 3.9% [48,49]. Up to 21.2% of newly diagnosed HIV infections in 2011 were found to be in migrants from Latin America [50], while 42,000 migrants were estimated to be infected with T. cruzi in the same period [30]. Regarding T. cruzi DTU characterization, different DTUs have been detected in blood samples from HIV coinfected patients, and these are similar to those found in the general population [4]. Different tissue tropisms have been described, and TcI, TcII and TcV have been found in the CNS tissue from HIV patients. In some cases, different DTUs have been detected in blood samples from these patients [51–53], details summarized in TABLE 2. Although currently under investigation, these findings may have potential implications in the future management of these patients. Diagnosis

In immunosuppressed patients inconclusive or false-positive T. cruzi serology is more frequent [19,20]. In these cases, a third serological assay or other techniques such as Western blot may be useful. In an HIV-positive individual with severe immunosuppression, risk factors for T. cruzi infection and negative serology, close follow-up is a recommended option to allow early detection of possible episodes of reactivation. If antiretroviral treatment is started, then conversion to positive T. cruzi serology is possible. Coinfected patients are more likely to have T. cruzi parasitemia than HIV-negative individuals, and parasitemia is usually higher as determined by culture, xenodiagnosis and quantitative real-time PCR techniques, suggesting that parasitemia may increase prior to reactivation and clinical manifestations [16]. Parasite detection is uncommon in the indeterminate form of Chagas disease and would indicate active replication in the context of immunosuppression. Clinical manifestations

Most HIV-positive individuals with preserved cell immunity and latent T. cruzi infection in the indeterminate phase remain asymptomatic. Only six cases of acute infection with T. cruzi in HIV-positive patients have been described so far [19]. The majority of reported cases of HIV–T. cruzi coinfection are reactivations in the context of advanced immunosuppression [18,19]. Reactivation is considered an AIDS-defining condition [54] and may be the first clinical manifestation of Chagas disease. The risk of T. cruzi reactivation in patients with HIV ranges from 15 to 35% [45,55] although this may represent an overestimation as most available data are from specialized centers and most referred cases were due to symptomatic episodes of reactivation. However, up to 70–80% of coinfected patients will never develop Chagas disease [8]. In the absence of specific parasitological methods to detect T. cruzi, a low CD4 count, especially below 200 cells/mm3 may indicate patients at increased risk of reactivation. In a recent study, the majority of reactivation episodes were seen in patients with AIDS, whose mean CD4 cell count was 98 (1–340 cells/mm3), while HIV patients without reactivation had a mean CD4 count of 562 (44–1949 cells/mm3) [19]. In 360

other studies, higher levels of parasitemia were associated with increased HIV viral load, a deceased CD4 cell count and a decreased CD4/CD8 ratio [16]. There are no specific data regarding progression from the indeterminate to the chronic symptomatic form of Chagas disease in HIV patients. No differences have been reported regarding cardiac or gastrointestinal involvement in these cases. Therefore, follow-up recommendations are similar to those for HIV-negative individuals. The characteristic clinical manifestations of reactivation episodes may mimic an acute illness: malaise, fever, lymphadenopathy and hepatosplenomegaly. CNS involvement has been described in most cases (74%), followed by myocardial involvement (17%) [19]. Other sites may be involved such as the skin, digestive tract, pericardium and cervix [56–59]. Occasionally, involvement of multiple organs has been described [45,55]. If the CNS is affected, then the clinical symptoms/signs may include headache, confusion, seizures, motor signs and coma. Other AIDS-defining conditions affecting the CNS, which may present similarly, such as toxoplasmosis and primary brain lymphomas, should be excluded [60]. When the heart is involved, manifestations such as new arrhythmias, atrioventricular and fascicular blocks or congestive heart failure may appear [45,55]. The differential diagnosis should include natural progression of Chagas heart disease, which should be excluded as management differs for both (patent parasitemia should be absent in cases of Chagas cardiomyopathy). HIV–T. cruzi coinfection has been associated with higher mortality rates than HIV infection alone [61]. In a Brazilian study, mortality was mainly due to AIDS-defining conditions in up to 70% of cases and due to advanced Chagas cardiomyopathy in around 17% of cases. Reactivation episodes have a high mortality in the absence of antiparasitic treatment, and this may be reduced to around 20% if drugs are started promptly and maintained for a minimum of 30 days [18]. According to one review, the minimum survival observed from diagnosis of reactivation was 1 day, but may be as long as 5 years with a mean of 10.6 months. Mortality is higher when the CNS is involved, 89% according to one study and is around 19% when only the heart is affected [19,61]. Treatment & follow-up

Although data are scarce, some authors recommend specific treatment to prevent disease progression and possible reactivations in coinfected patients [14,18,43]. Standard therapeutic schedules are used for HIV-infected individuals with Chagas disease although longer courses may be recommended: up to 90 days for benznidazole and up to 120 days for nifurtimox. Antiparasitic therapy should be started as soon as possible in cases of reactivation to decrease mortality and long-term sequelae. If the patient has been treated previously, then options might include a second course of benznidazole or use of nifurtimox. Although data are scarce, tolerance and side effects are similar to those found in non-HIV individuals [20]. Expert Rev. Anti Infect. Ther. 12(3), (2014)


1

1

10

Burgos et al. (2005)


Bisio et al. (2009)

13

Unknown origin

Endemic and non-endemic areas (Argentina)

Endemic area (Bolivia)

Non endemic area (Argentina)

Endemic area (Brazil)

Patients’ suspected place of T. cruzi acquisition

M F M M M M M M M M M

46 61 42 45 59 45 54 39 43 39 56

I V II/V/VI II/VI I V I I II/V/VI V V

II/V/VI V II/V/VI

I II/V/VI I I

Blood,skin† Heart explant, skin Blood† Heart explant, Blood, skin† Heart explant Blood , skin† Heart explant, Blood, skin† Heart explant Blood, skin† Heart explant Blood† Blood† Blood† Blood† Heart explant Heart explant Blood† Blood†

Skin reactivation

Heart and cutaneous reactivation

Cutaneous reactivation

Heart reactivation

Cutaneous reactivation Cutaneous reactivation

Encephalitis (R) Cerebral mass (R)

Patients recruited in Argentina. Three patients from the original series not included as no DTU was detected

[2]

M M

36 54

F F

F M

Adult Adult

48 59

[4]

Largest series to date, Only patients in whom DTU was characterized are included. Two patients have been excluded data previously reported (see [52,53]) Encephalitis (R) Indeterminate phase Indeterminate phase Indeterminate phase Indeterminate phase Encephalitis (R)

ND Blood Blood Blood Blood Blood Brain necropsy Blood CSF Blood CSF Blood

II, V V V V V Indetectable V V Indetectable V II, V V

F F F M M M

Adult Adult Adult Adult Adult 39 Not specified Encephalitis (R)

[53]

[52]

[51]

Ref.

Reported in Buenos Aires (Argentina)

Suspected congenital transmission

–

Comments

Transverse myelitis (R)

Multiple cerebral mass lessions (R)

CNS ring-enhancing lesion (R)

Clinical presentation

CSF Blood

Brain biopsy Bloodstream

Blood and CSF

Sample source

I I, V

II/VI V

II

T. cruzi DTU‡

M

M

M

Sex

41

29

63

Age

These samples in transplant recipients were taken during follow-up. ‡ Please note every article referring to HIV patients characterized DTUs according to the previous nomenclature (DTUs reported here have been adapted to 2009 consensus nomenclature as reported by Zingales et al. [1]). CSF: Cerebrospinal fluid; DTU: Discrete typing unit; F: Female; M: Male; R: Reactivation.

†


Organ transplant recipients

1

Patients (n)

Lages-Silva et al. (2002)

HIV coinfected patients

Study (year)

Table 2. Most relevant publications on Trypanosoma cruzi DTU characterization in immunocompromissed patients.



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There are no data to support the use of primary prophylaxis with antiparasitic drugs if CD4 counts decrease below 200. Evidence for secondary prophylaxis after a first episode of reactivation is scarce, but this strategy is recommended by most experts [43]. The most frequently used prophylaxis schedules are benznidazole 5 mg/kg/day three-times a week or ketoconazole 400 mg/day [43,62] The recommended duration of prophylaxis is also based on expert opinion, but it is generally maintained until virological control and CD4 counts of 200–250 cells/mm3 in at least two determinations performed 3 months apart [43,62]. Improved access to antiretroviral therapy (ART) worldwide has made HIV infection a chronic disease in most cases. Antiretroviral treatment increases survival in HIV-infected and coinfected patients and also decreases associated mortality after reactivation. If ART is started early, general prognosis seems to improve especially in cases of reactivation [20,63,64]. According to UNIAIDS, 68% of HIV-infected people in Latin America were receiving ART in 2011 [32], and efforts are being made to improve these figures. Once ART is started in a T. cruzi coinfected patient, the theoretical possibility of an immune restoration syndrome should be considered. To date, only one case has been reported with this complication [65]. Both benznidazole and nifurtimox undergo NADPHdependent nitroreductive transformations. Although data on the pharmacokinetics of these two drugs are lacking, expected interactions with antiretrovirals are very low [66] Raltegravirbased regimens might be safer due to its low potential for interactions. Nevertheless, clinicians should use these combinations with caution. Management during pregnancy

Both T. cruzi and HIV have recognized deleterious effects on pregnancy outcomes. Different vertical transmission rates for T. cruzi have been found depending mainly on maternal parasitemia and estimates range from 1 to 13.8%, or even up to 31% for pregnant women with a positive PCR result [67,68]. Congenital HIV transmission rates range from 15 to 40% and decrease to 1% with antiretroviral treatment. Several safe ART schedules may be recommended for HIV-infected pregnant women and should be started as soon as possible, whether they are coinfected with T. cruzi or not. Concomitant vertical transmission of both organisms has also been described [69]. Although data are limited, in HIV-infected women, one study described a rate of congenital T. cruzi transmission as high as 75% [70]. The teratogenic potential of benznidazole and nifurtimox in humans remains unknown, but they should generally be avoided during pregnancy as they have been demonstrated to cross the placental barrier and bind to fetal proteins in animal models. Regarding the management of coinfected women of childbearing age, antiparasitic drugs should be advised before pregnancy in order to reduce potential parasitemia and possible congenital transmission [68]. After treatment, the patient should avoid pregnancy for a period of 3 months. 362

T. cruzi & transplantation Epidemiology

The integration of immigrants into the host country’s society results in use of national health services, and data from several countries indicate that immigrants also contribute to and participate in transplant systems [71,72]. Potential donors and recipients may originate from or may have resided in T. cruzi endemic countries, and therefore Chagas disease is an important consideration for health professionals in this field working both in endemic and nonendemic areas. T. cruzi may be transmitted through a contaminated blood transfusion or through transplantation of an infected organ. In recipients from endemic areas, the possibility of reactivation of latent infection due to immunosuppression arises. In several countries, these issues are modifying donor selection criteria and screening protocols for recipients [71–73]. Most data are available for solid organ transplantation although case reports and guidelines on management of Chagas disease in hematopoietic tissue transplantation programs also exist. Regarding T. cruzi DTU characterization in transplant recipients, data are limited. One study has reported molecular identification of T. cruzi DTUs in cardiac explant specimens and blood samples from a cohort of patients with chronic Chagas heart disease who underwent heart transplantation and from biopsy samples in patients who presented clinical reactivation. Data are summarized in TABLE 2. Diagnosis, screening potential donors & recipients for T. cruzi & contraindications to transplantation Donors

Serological screening of potential organ donors for T. cruzi infection is generally performed in transplant centers in endemic areas. In nonendemic countries, donor screening is usually performed if risk factors are present (donor was born or resided in endemic areas, donor’s mother was born in Latin America or donor received transfusion in an endemic country). Before deciding on transplantation, a comprehensive study of the donor should be performed. If acute Chagas disease was considered, then the cause of death of the donor should be excluded. In the context of cardiac transplantation, transplanting the heart from a T. cruzi-infected donor is contraindicated given the risk of myocarditis during the period of immune suppression, data suggesting a higher transmission risk of the infection and the known cardiac tropism of the parasite [71,74]. Small bowel transplantation from a T. cruzi-positive donor would also be contraindicated as the organ may be infected [73]. In Latin America, positive serology does not necessarily contraindicate donation (except in the case of heart transplantation) due to organ shortage, the high prevalence of the disease and the observation that not all transplants from T. cruzi-positive donors result in transmission. Most data are available for kidney and liver transplants from infected donors and clinical outcomes may be favorable with adequate monitoring and early treatment if necessary. Although there is no consensus on the possible use of other organs from infected patients, this practice Expert Rev. Anti Infect. Ther. 12(3), (2014)



may be considered, especially in urgent cases, if appropriate post-transplant monitoring is performed [71,75]. Potential recipients should be advised on the associated risks and benefits and provide written informed consent. Regarding allogeneic bone marrow transplantation (BMT), potential donors with risk factors should also be screened for T. cruzi infection. If positive, then these donors would generally only be accepted if another compatible donor is not available [73]. Recipients

Potential recipients with risk factors for Chagas disease should be screened with serological tests. If the patient is immunocompromised, then serological tests may be negative and parasitological tests should be performed [73,75]. Heart transplantation in patients with cardiomyopathy due to chronic Chagas disease raised concerns in the past due to the possibilities of reactivation and an increased incidence and severity of rejection episodes associated with active myocarditis. However, nowadays, heart transplantation is considered a valid treatment option for end-stage cardiac disease associated with Chagas disease. This may be the only therapy that can modify natural progression of the disease in its terminal phase [76], and data have shown a tendency toward improved survival in patients transplanted for Chagas cardiomyopathy compared with non-Chagas heart transplant recipients [77,78]. A recent systematic review found a similar incidence of rejection episodes in Chagas and nonChagas heart transplant recipients and T. cruzi reactivation episodes were associated with very low mortality rates [77]. In some endemic areas, this type of cardiomyopathy was the third most common cause for transplantation after ischemic and dilated cardiomyopathy [18,76]. According to some authors, potential T. cruzi-infected recipients with grade 2 or 3 cardiomyopathy of the Kuschnir classification and/or advanced megaesophagus or megacolon may be excluded from transplantation (except in the case of heart transplantation for patients with advanced chagasic cardiomyopathy). Patients in the indeterminate phase or early chronic phase (grade 0 or 1 cardiomyopathy according to the Kuschnir classification and/or early gastrointestinal involvement) of Chagas disease may receive an organ or hematopoietic cell transplant [73]. Clinical scenarios

In the context of transplantation, acute T. cruzi infection may occur if an organ from a positive donor is transplanted or if blood components from infected donors are transfused. Although reactivation of chronic infection does not occur in all patients with Chagas disease who undergo immunosuppression, renewed parasite replication may be observed in transplant recipients similar to that seen in the acute phase. Transplant professionals may be faced with different scenarios. Acute infection in transfusion recipients

Transmission of T. cruzi through an infected blood transfusion was first reported in Brazil in 1952 [79]. Blood componentinformahealthcare.com

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derived T. cruzi infection has been documented in both endemic and nonendemic areas, and the risk of transmission after transfusion of a contaminated blood unit has been estimated to be around 20% [74,80]. Blood screening programs have contributed to the decreased incidence of Chagas disease in endemic areas, but in nonendemic countries, screening is not universal. In certain nonendemic countries, screening has only been introduced in recent years (e.g., in the year 2005 in Spain and in 2007 in the USA), and some infections have occurred since the implementation of national screening programs. Acute infection in organ recipients

T. cruzi infection following solid organ transplantation was first described in 1981 in a renal transplant patient [81]. The risk of transmission of T. cruzi from an infected donor via the graft may only be estimated based on small series and case reports, but available data suggest that transmission does not occur in the majority of cases. In patients receiving renal transplants from seropositive donors reported transmission rates varied from 0 to 18.7%, and associated complications were generally not severe (in some cases, infection was diagnosed following detection of asymptomatic parasitemia). In some of the studies, patients received benznidazole prophylaxis on the first day post-transplantation, whereas others received treatment if infection was documented [75,82]. Although data are scarce, based on two series, the risk of transmission from transplanted livers may range from 0 to 29% (in some of the cases, benznidazole prophylaxis was administered) [71,83]. Data are limited regarding heart transplants, but rates may be higher as in the USA transmission has been documented in three out of four heart transplants from positive donors (75%) [84]. Acute infection in BMT recipients

In 1992, the first fatal case of acute Chagas disease in Europe was reported following a BMT [85]. Other isolated cases of acute Chagas disease following BMT have been described. In some of these cases, the source of the infection was an infected blood transfusion [86]. In a study in an endemic country evaluating the efficacy of pre-emptive therapy in bone marrow recipients in the context of Chagas disease, three negative recipients received an allogeneic BMT from T. cruzi-infected donors. Primary prophylaxis with benznidazole was administered (30 days) in two of the donors (one donor did not receive prophylaxis as emergency transplantation was performed). During the period of follow-up, no evidence of transmission of the infection through BMT was detected in any of the recipients [87]. Estimates of transmission risk in BMT recipients are difficult to obtain as data are limited. Reactivation of chronic Chagas in organ recipients due to immunosupression

The incidence of reactivation in organ recipients with prior T. cruzi infection may vary according to the transplanted organ and the degree and type of immunosuppression [72]. Reactivation occurs mainly in the first year post-transplantation when 363

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immunosuppression is more intense. Most data are available for renal transplants, and evidence is limited for other types of organ transplants. In the context of cardiac transplantation, rates may vary from 20 to 50% depending on the series although some authors have reported much higher rates [76,88]. Manifestations of reactivation in renal transplant patients are usually less severe and reported rates, based on two series, vary from 21.7 to 37% [75,89]. Reactivation of chronic Chagas disease in BMT recipients due to immunosuppression

Reactivation of chronic Chagas disease has been described in immunosuppressed patients following BMT. Isolated case reports and small series have been published [90]. In a series of five adult patients with Chagas disease who underwent BMT, trypomastigotes were detected in only one case 4 days before BM infusion during neutropenia, without symptoms of reactivation (20%). No prophylaxis was given to any of the patients. Benznidazole administered to the affected patient rapidly cleared parasitemia and after treatment the patient did not have relapsing T. cruzi parasitemia. The other patients showed no evidence of parasitemia or symptoms/signs of reactivation [91]. A further study by the same group, which included additional patients examined data for a total of 22 seropositive recipients and reactivation was detected in 6 patients (27.3%). Of these 2 of 12 (17%) were autologous hematopoietic cell transplant recipients, and 4 of 10 (40%) were allogeneic hematopoietic cell transplants (for the two patients who underwent autologous BMT, asymptomatic parasitemia was detected 4 and 20 days, respectively, prior to the BM infusion, during the period of immunosuppression) [87]. Treatment & follow-up

Recommendations for the management of Chagas disease in the context of organ or hematopoietic tissue transplantation in endemic and nonendemic areas have been recently published by expert groups [71,73]. Pretransplantation

As part of the pretransplant workup, potential donors and recipients should be screened as outlined above and possible contraindications should be considered. There are no prospective randomized data to support pretransplant trypanocidal treatment to prevent transmission in the case of T. cruzi-infected live donors or post-transplant reactivation in the case of recipients. Patients with hematological or endstage hepatic/renal disease may be particularly vulnerable to potential drug toxicities caused by antitrypanosomal therapy. Donors

Some studies report use of predonation treatment with benznidazole (30–60 days) with the aim of decreasing the potential inoculum of T. cruzi parasites [87] and in this context, although data are limited, this strategy may be recommended for infected living donors [14,73]. 364

Recipients

Pretransplant treatment is sometimes considered in infected potential recipients as studies have shown that treatment may affect disease progression in the chronic phase [92] although data are scarce for immunocompromised patients. Limited data in heart transplant recipients have shown that preoperative administration of benznidazole does not consistently prevent reactivation and protocols that recommend benznidazole both pre- and immediately post-transplant do not appear to have clear advantages [76,93]. This strategy should therefore probably be considered on an individual basis, taking possible risks and benefits into account. Given the risk of toxicity of trypanocidal treatment, some authors recommend only treating candidates with detectable parasitemia [73]. Treated adults with longstanding chronic infection are still at risk of reactivation as current antiparasitic treatment is not efficient at eradicating T. cruzi, and these patients would therefore have to be monitored accordingly in the post-transplant period [18]. Post-transplantation Monitoring recipients for acute infection or reactivation

When the donor’s or recipient’s positive infection status for T. cruzi is known before, or shortly after, transplantation, close prospective monitoring of the recipient and prompt therapy if infection or reactivation occurs may lead to better outcomes. In BMT candidates, monitoring for possible reactivation should commence in the chemotherapy phase prior to transplantation [87]. Serocoversion may not occur in immunocompromised individuals or may be delayed [75] and therefore parasitological tests should be performed. A standard monitoring schedule would include weekly T. cruzi PCR and microscopy of blood specimens for the first 2 months, then every 2 weeks up to the first 6 months and monthly thereafter [72]. Additional tests should be performed if fever or symptoms of rejection occur. Protocol biopsy specimens, such as endomyocardial biopsies, and other available tissue specimens should also be evaluated for the presence of amastigotes. If immunosuppression is intensified, then weekly monitoring should be resumed for at least 2 months. Reactivation would be considered if parasitemia is detected by parasitological techniques, even in the absence of symptoms [72]. A positive blood PCR in a patient with pre-existing T. cruzi infection does not demonstrate reactivation but an increase in parasitemia as detected by serial quantitative PCR would be an indicator [88]. Clinical manifestations

If recipients are closely monitored prospectively, acute infection may be detected before clinical manifestations develop. The incubation period for acute transplant-derived T. cruzi infection in recipients may be prolonged (up to several months) and severe manifestations may be observed (fever, acute myocarditis, congestive cardiac failure). In cases of reactivation, in addition to fever and acute myocarditis, which can occur in the Expert Rev. Anti Infect. Ther. 12(3), (2014)


Brazil

Argentina

Brazil

Salgado et al. (1996)

Di Lorenzo et al. (1996)

Metze et al. (1991)

49

9

73

42

F

M

M

F

F

F

M

F

F

F

Sex

ND†

ND†

Chagas myocarditis without heart failure

ND†

ND†

1996

IND

IND

K III

IND

IND

IND

KI

Chagas disease clinical form

IND

BZD (2006) for 19 days due to toxicity

BZD (2010) for 6 months

Not indicated

BZD (04/2010)

BZD (ND/2005)

BZD (02/2007)

ND

Chagas disease therapy/ date

BZD (Feb/ 1996)

1994

2006

2010 Previous serologic test 2008 negative

2007

2010

2005

2006

1997

Year Chagas disease diagnosed

ND nest of amastigotes was found in the myocardium in autopsy.

ND†

ND Flagellate form of T. cruzi observed in CSF

Positive

Micro hematocrit positive

Positive PCR

Positive PCR

Positive PCR

Positive PCR

Positive PCR

Findings

No

IDICE-G MTX int Mitix+ ARA-C

Hodgkin´s lymphoma/1991

ND†

ND†

Cloramucil (Feb/1996)

Lymphocytic leukemia/1994

Acute lymphoblastic leukemia/1996

CHOP + BLEO

6-MCP MTX p.o.

Docetaxel + radical mastectomy

Polymorphic ventricular extrasystoles and cardiac arrest

Cerebral chagoma

Cerebral chagoma

Atrial flutter 130 b.p.m., right bundle branch block. Acute chagasic myocarditis. Gastric esophageal and laryngeal Chagas involvement

Cerebral chagoma

No

No

No

R-MEGACHOP/RESHAP

VBCMP Zoledronate

No

Clinical presentation of Chagas disease reactivation

IDICE-G

Therapy for neoplasia

Non-Hodgkin lymphoma/2005


Breast adenocarcinoma/ 2007

Multiple myeloma (IgG k)/2010

Acute myeloid leukemia secondary to gastric adenocarcinoma/ 2005

High grade B-cell non-Hodgkin lymphoma/2006

Acute myeloid leukemia M1/2008

Type neoplasia/ year diagnosis

† ND: No data, only the abstract of the article available. 6-MCP: mercaptopurine; ARA-C: Etoposide; BZD: Benznidazole; IDICE: Iduracibin; IDICE-G: Idurabicin; IND: Indeterminate stage of Chagas disease; K: Kuschnir clasification; Mitox: Mitoxandrone; MTX int: Intrathecal methotrexate; ND: No data; R-ESHAP:Rituximab-ESHAP; R-MEGACHOP: Rituximab-MEGACHOP; VBCMP: Vincristine, carmustine, melphalan, cyclophosphamide, prednisone.

Brazil

37

Bolivia

Fontes Rezende et al. (2006)

44

Bolivia

15

50

Peru

Bolivia

50

Bolivia

Cohen et al. (2010)

52

Bolivia

Pinazo et al. (2013)

Age

Country origin

Study (year)

Table 3. Characteristics of patients with Trypanosoma cruzi infection and neoplastic disease.


[103]

[102]

[101]

[58]

[100]

[17]

Ref.


Review

365

366

† ND: No data, only the abstract of the article available. 6-MCP: mercaptopurine; ARA-C: Etoposide; BZD: Benznidazole; IDICE: Iduracibin; IDICE-G: Idurabicin; IND: Indeterminate stage of Chagas disease; K: Kuschnir clasification; Mitox: Mitoxandrone; MTX int: Intrathecal methotrexate; ND: No data; R-ESHAP:Rituximab-ESHAP; R-MEGACHOP: Rituximab-MEGACHOP; VBCMP: Vincristine, carmustine, melphalan, cyclophosphamide, prednisone.

[105]

Chagoma cerebral ND Diagnosis by cerebral biopsy 11 Corona et al. (1988)

Chile

M

1987

Nifurtimox during 2 months but continued when the article was published

IND


ND

[104]

Fever and peripheral neuropathy ND ND T. cruzi observed in peripheral blood smears. 14 El Salvador Kohl et al. (1982)

F

1980

Nifurtimox 90 days (03/ 1980)

ND


Ref. Therapy for neoplasia Findings Country origin

Age

Sex


Chagas disease therapy/ date


Type neoplasia/ year diagnosis

Clinical presentation of Chagas disease reactivation


Study (year)

Table 3. Characteristics of patients with Trypanosoma cruzi infection and neoplastic disease (cont.).


Review

transplanted heart other manifestations such as skin nodules and inflammatory panniculitis may be observed. CNS involvement is a less frequent manifestation of reactivation among transplant recipients than in HIV-positive patients with AIDS [94]. Reactivation should be included in the differential diagnosis of febrile and apparent rejection episodes. Treatment

Most authors do not recommend antitrypanosomal prophylaxis and treatment should be initiated if there is parasitological evidence of primary acute infection (organ-derived transmission) or reactivation [18,71,73]. Benznidazole (5 mg/kg/day) and nifurtimox (8 mg/kg/day) for 60–90 days may be used based on dosing schedules used for immunocompetent patients, although occasionally longer courses have been recommended in immunosuppressed patients, for example, if there is CNS involvement until clinical improvement and/or parasitological response. During reactivation, response to treatment is usually favorable, and parasitological tests should be performed weekly until at least two negative results are obtained [72]. Treatment should be interrupted in the event of serious adverse effects such as severe dermatitis, bone marrow suppression, significant hepatic toxicity or peripheral neuropathy. Interactions of benznidazole and nifurtimox with the main drugs used for immunosuppression have not been described [73]. No data are available on the efficacy of secondary prophylaxis following an episode of reactivation and continued monitoring and retreatment of new reactivation episodes should be performed [18,95]. Management of immunosuppression

Early immunosuppressive regimens that included high-dose cyclosporine and high-dose steroids have been associated with a higher risk of reactivation compared with regimens using lower doses of cyclosporine and a rapid reduction in steroids. The early reduction of immunosuppression, especially of steroid doses, is a currently accepted practice to reduce the incidence of reactivation episodes and of neoplasia [76]. The introduction of mycophenolate mofetil instead of azathioprine was also associated with an increase in risk in some studies, but this was not demonstrated when lower doses of mycophenolate mofetil were used, and further data are necessary before recommendations can be made regarding the use of this drug. As response to trypanocidal treatment is generally favorable in the event of an episode of reactivation, the possible benefits and risks of reducing maintenance immunosuppression (acute rejection in solid organ recipients or graftversus-host disease in allogeneic BMT recipients) should be considered on an individual basis. Chagas diseases & neoplasia Epidemiology

Patients with neoplasia may have a degree of immunosuppression, which may confer an increased risk of reactivation of Chagas disease. This may be due to the tumor itself, the Expert Rev. Anti Infect. Ther. 12(3), (2014)



antitumoral drugs used or a combination of both factors. Published cases of reactivation of T. cruzi infection in the context of neoplasia are scarce. All 12 cases reported in the literature, except for one [17,58], occurred in patients with hematological malignancies (TABLE 3). Cases were diagnosed in endemic countries of Latin America, most frequently in Bolivia. In only one case, the patient had negative serology for Chagas disease prior to the diagnosis of neoplasia. A recent infection coinciding with the diagnosis of acute lymphoblastic leukemia and prior to the administration of chemotherapy was suspected [96]. Some early reports raised the concern that Chagas disease may induce neoplasia as several observational studies described a higher prevalence of esophageal carcinoma and leiomyoma of the uterine cervix among patients with chronic Chagas disease [97]. However, no further studies have confirmed a correlation with the mentioned gynecological tumors. In the case of esophageal carcinoma, infection with T. cruzi alone does not explain this association but the presence of megaesophagus does increase the risk of esophageal carcinoma. The development of esophageal carcinoma has been described in individuals with idiopathic achalasia and could be due to stasis of food components in the dilated organ triggering chronic esophagitis and/or prolonged contact of carcinogenic agents with the mucosa [98]. In contrast, a higher incidence of colorectal cancer in patients with megacolon, despite fecal stasis, has not been reported [98,99]. Diagnosis

Screening for T. cruzi in oncological patients with risk factors for the infection is recommended. Reactivation is defined by detection of parasitemia using direct parasitological techniques. A rise in qPCR may be an indicator of reactivation [17]. Clinical manifestations

Review

of reactivation may not be described. Treatment with benznidazole was the most frequently used therapeutic option for Chagas disease reactivation. Nifurtimox was employed as a first-line option in cases reported more than two decades ago. There are no prospective data on the use of trypanocidal treatment to prevent possible reactivation episodes in oncological patients. Administration of trypanocidal treatment to oncological patients with Chagas disease who will undergo immunosuppression should be assessed on an individual basis due to the potential toxicity of the treatment and the controversial efficacy in patients with chronic disease. If antitrypanosomal treatment is administered ideally, then this should be before chemotherapy is initiated. Early treatment is recommended when reactivation is confirmed [17]. Due to the observed association between Chagas disease and esophageal cancer, regular follow-up in patients with megaesophagus is necessary and periodic endoscopies should be performed. Chagas diseases & systemic autoimmune diseases Epidemiology

Cases of Chagas disease reactivation have been described in patients with autoimmune disorders mainly in those receiving immunosuppressive drugs such as cyclosporine and azathioprine [106]. Although corticosteroids were initially associated with reactivation due to their immunosuppressive effect, in only one reported case, steroids were the only immunosuppressant drug administered (the patient was a child receiving dexamethasone following cranial trauma) [107]. Further studies have not demonstrated a clear association between immunosuppressive doses of corticosteroids alone and higher rates of Chagas disease reactivation [108,109]. Among the reported cases (TABLE 4), all except one patient with rheumatoid arthritis had systemic lupus erythematosus [17]. This relative lack of cases may be due to the low frequency of clinical reactivation in these patients or due to infradiagnosis of T. cruzi infections, which may not be suspected by the clinician and/or may not be screened for.

Reactivation of T. cruzi infection should be considered in patients with chronic Chagas disease and neoplasia; mainly hematological malignancies, and especially in those with intensive or long-term chemotherapy schedules. Among symptomatic patients with reactivation, neurological manifestations due to cerebral lesions were most frequently described. Most of the described cases were in the indeterminate stage of Chagas disease prior to reactivation [17,58,100–105]. The clinical manifestations observed in the published cases highlight the need for considering Chagas disease as a possible diagnosis in oncological patients with CNS nodular lesions and risk factors for T. cruzi infection. Presence of metastases and CNS lymphoma should be excluded as this may avoid treatment delays and use of other therapeutic options such as intrathecal chemotherapy which may worsen cerebral chagoma lesions. In some of the cases, a biopsy may be necessary to confirm the diagnosis.

As for immunocompetent patients, chronic T. cruzi infection may be diagnosed using serological tests. A positive T. cruzi PCR result supports the diagnosis. As described previously, negative serology for T. cruzi must be interpreted with caution in immunosuppressed patients with risk factors.

Treatment & follow-up

Treatment & follow-up

Due to the heterogeneity in the types of chemotherapy employed, possible associations between chemotherapy and risk

Benznidazole was administrated to prevent reactivation in four cases. In two cases, treatment was administered following


Diagnosis

Clinical manifestations

Published cases of concomitant autoimmune diseases and T. cruzi infection are scarce, and there is only one report describing a symptomatic episode of reactivation in a patient with cutaneous manifestations [106].

367

368

Bolivia

Argentina

Paraguay

Brasil




dos SantosNeto et al. (2003)

F

36

33

44

F

F

F

F

46

44

F

Sex

40

Age

1991

2012

1987

1997

2005

2000


BZD 5 mg/kg/day for 60 days/1992

BZD 250 mg/day for 2 months/at the moment of diagnosis 2012

BZD (doses ND)/at the moment of diagnosis 1987 and Posaconazole

BZD (doses ND)/at the moment of diagnosis 1997



Chagas diseases therapy/date

Positive

IND

ND Xenodiagnostic for T. cruzi in blood positive

Positive

IND

IND

ND

ND

ND

PCR at reactivation

Chagas chronic digestive

IND

Chronic Cardiac Disease


PD 50 mg/day and azathioprine 50 mg/day

PD 1 mg/kg/day plus monthly pulses CYC

SLE/1992

Pulses of MP followed by PDN 1 mg/kg/day plus 6 monthly pulses of CYC

None

PDN 10 mg/day

Pulses of MP followed by PDN 1 mg/kg/day plus 6 monthly pulses of CYC followed by 2 quarterly pulses of CYC

Immunosuppressive therapy

SLE/2008

SLE/2007

AR/2010

SLE/2008

SLE/2007

Type of autoimmune disease/year diagnosis

Asymptomatic

Nodular, erythematous, painful cutaneous lesions with progression to ulcers

Asymptomatic

Asymptomatic

[111]

[106]

[110]

[17]

Asymptomatic

Asymptomatic

Ref.

Clinical presentation of Chagas disease

AM: Acid mycophenolic; AZA: Azathioprine; BLEO: Bleomycin; CHOP: Cyclophosphamide, hydroxydaunorunicin, vincristine, prednisone; CSF: Cerebro espinal fluid; CYC: Cyclophosphamide; IND: Indeterminate stage of Chagas disease; MP: Methylprednisolone; PDN: Prednisone; RA: Rheumatoid arthritis; SLE: Systemic lupus erythematosus.

Country origin

Study (year)

Table 4. Characteristics of patients with Trypanosoma cruzi infection and neoplastic disease.


Review Martinez-Perez, Norman, Monge-Maillo, Perez-Molina & Lopez-Velez

Expert Rev. Anti Infect. Ther. 12(3), (2014)



diagnosis of reactivation. In one case, treatment with benznidazole was considered to have failed as T. cruzi qPCR in blood was persistently positive, although parasitemia had decreased. Posaconazole was then administrated as an alternative therapeutic option and parasitemia became undetectable [110]. Although experience in the management of these cases is limited, screening for Chagas disease in all patients at risk receiving immunosuppressive therapy may be recommended. There are no clinical studies regarding treatment to prevent reactivation of T. cruzi infection in these patients and decisions should be taken on an individual basis. Early treatment of confirmed episodes of reactivation is recommended. Follow-up with periodic T. cruzi PCR determinations would be recommended at least during the duration of immunosuppression. Expert commentary & five-year view

Global migration is an ongoing process, and the number of T. cruzi-infected patients is expected to increase in Latin American cities and in nonendemic countries where this disease was previously unknown. Most chronically infected patients outside endemic areas remain undiagnosed. In addition, the HIV pandemic is well established within T. cruzi’ s natural geographic boundaries, the burden of cancer and immunosuppressive conditions has increased, and patients with T. cruzi infection have better access to health facilities and new treatment options. In the near future, clinicians will have to manage more immunocompromised patients with Chagas disease. Currently, there are no means to determine which patients with T. cruzi infection will progress to overt Chagas disease. This would be important in order to select patients who would benefit most from treatment. Efforts are being made to detect biological markers of progression. Some autoantigens such as the b1-adrenergic receptor, miosine and Cha protein have been identified as possible immune markers, but their role in Chagas disease pathogenesis is still not clear. Another issue is the assessment of prognosis in patients with chagasic cardiomyopathy. A risk scale has been developed to assess likelihood of a fatal outcome in this disease. A more complete patient evaluation together with improved access to medical facilities should lead to a higher number of patients being evaluated for intracavitary device implantation and heart transplantation. Healthcare systems will face the challenge of providing sophisticated and costly cardiac care to patients in the later stages of the disease. Regarding antiparasitic treatment, several issues should be considered. Chagas disease has an excellent prognosis in childhood if treated and new pediatric formulations of the currently available drugs are urgently needed. The benefits of antiparasitic treatment during the chronic phase are under evaluation.


Review

A randomized clinical trial (RCT), the Benznidazole Evaluation for Interrupting Trypanosomiasis study, designed to assess benznidazole efficacy and safety during adulthood is ongoing and hopefully results will clarify the treatment indications in these patients. New drugs are in different phases of evaluation. Cruzapain inhibitors are experimental drugs targeting a key parasite protease, which are still under development. Results from a RCT using ergosterol biosynthesis inhibitors such as ravuconazole will soon be available and posaconazole efficacy has recently been questioned. Nevertheless, this drug is now being tested in combination with benznidazole in another RCT. Although allopurinol was initially proposed as a candidate drug to treat T. cruzi infection, it was associated with poor outcomes. This drug has now shown promising results in a pilot study combined with benznidazole. Fexinidazole is another antiparasitic agent under study for American and African Trypanosomiasis. Assessing treatment efficacy is another unresolved issue in the management of Chagas disease. Quantitative ultrasensitive PCR methods have recently been proposed as a tool to monitor treatment efficacy and to assess the risk of reactivation in immunocompromised hosts. A different approach would be to monitor the amount of serum g-IFN, which appears to decrease, in some cases, to undetectable levels, after successful treatment. Additional screening programs should be implemented in order to detect undiagnosed cases, especially in women of childbearing age, during pregnancy, in blood donors and in the context of organ transplantation programs. Access to healthcare including antiparasitic treatment should be guaranteed for every T. cruzi-infected patient. International efforts such as those led by the Drugs for Neglected Disease initiative and the WHO Neglected Tropical Diseases department, an increasing interest from the scientific community and private partners’ investments have been responsible for greater advances in this field in the last decade than in the whole of the past century. Strengthening of public health policies and increased political commitment are necessary to tackle this disease, which remains neglected more than 100 years after its discovery. Financial & competing interests disclosure

This manuscript has been supported by the ‘ Red de Investigacioń Cooperativa en Enfermedades Tropicales’ (RICET), VI PN de I+D+I 2008-2011, ISCIII -Subdireccioń General de Redes y Centros de Investigacioń Cooperativa. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

369

Review


Key issues .

Patients with HIV and risk factors should be screened for Trypanosoma cruzi infection.

.

T. cruzi in an HIV-infected patient may behave as an opportunistic parasite typically affecting the CNS and the heart, with high associated mortality.

.

Early diagnosis of HIV status and prompt antiretroviral therapy can improve prognosis and prevent reactivation in T. cruzi coinfected patients.


.

Specific antiparasitic therapy should be started as soon as possible in case of reactivation although specific treatment schedules have not clearly been defined.

.

Management of T. cruzi infection in the context of transplantation may be complex and updated reviews and guidelines are necessary as new data become available.

.

Potential donors and transplant candidates with risk factors should be tested for T. cruzi infection using serology (if the patient is immunocompromised and serology is negative, parasitological tests should be considered).

.

Transplanting the heart from a T. cruzi-infected donor is contraindicated; use of other organs (including bone marrow) may be considered with appropriate informed consent and adequate post-transplant monitoring with parasitological tests.

.

Predonation antitrypanosomal treatment may be administered to infected living donors to decrease the potential parasite inoculation.

.

Post-transplantation monitoring rather than prophylaxis is generally recommended and treatment with specific antiparasitic drugs should be initiated if there is parasitological evidence of acute infection (organ-derived transmission) or reactivation of pre-existing chronic infection.

.

Screening for T. cruzi should be performed in patients with neoplasia or autoimmune diseases and risk factors for the infection.

.

Patients with neoplasia or autoimmune disease with reactivation of T. cruzi infection should receive prompt antiparasitic therapy.

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