Screening for Chagas Disease Should Be Included in Entry-to-Care Testing for At-Risk People With Human Immunodeficiency Virus (HIV) Living in the United States

Abstract

Chagas disease screening of at-risk populations is essential to identify infected individuals and facilitate timely treatment before end-organ damage occurs. Coinfected people with human immunodeficiency virus (PWH) are at risk for dangerous sequelae, specifically Trypanosoma cruzi reactivation disease. Recently published national recommendations indicate that at-risk PWH, particularly those from endemic areas or born to women from endemic areas, should be screened via a sensitive anti-T. cruzi IgG assay. However, immunocompromised patients with negative serologic results may warrant further investigation. Reactivation should be suspected in at-risk, untreated PWH with low CD4 cell counts presenting with acute neurologic or cardiac symptoms; these patients should be promptly evaluated and treated. One pragmatic solution to improve Chagas disease screening among PWH and thereby reduce T. cruzi–related morbidity and mortality is to incorporate Chagas disease screening into the panel of tests routinely performed during the entry-to-care evaluation for at-risk PWH.

Chagas disease can have dangerous sequelae in coinfected people with HIV (PWH). Here we offer practical recommendations to improve diagnosis and care of coinfected PWH, including incorporating Chagas disease screening into the entry-to-care evaluation at HIV diagnosis.

For people with human immunodeficiency virus (HIV) infection (PWH), the entry-to-care evaluation is critical to enable prompt detection and treatment of potential opportunistic infections [1]. Current recommendations include screening for infections that can lead to severe acute or reactivated disease, including Toxoplasma gondii, Mycobacterium tuberculosis, and the hepatitis viruses. Like T. gondii, Trypanosoma cruzi reactivation can present with central nervous system (CNS) lesions and is rapidly lethal in the absence of immediate recognition and appropriate treatment [2]. Screening for T. cruzi infection has been part of routine entry-to-care recommendations for PWH in Brazil for more than a decade [3], as well as for Latin American immigrants living in Spain [4]. We propose that risk-based Chagas disease screening should also be incorporated into entry-to-care protocols for US PWH from continental Latin America or those born to a woman from continental Latin America.

WHAT IS CHAGAS DISEASE AND WHO IS AT RISK?

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi, which is usually acquired through contact with the feces of triatomine vectors infesting houses in rural Latin America [5]. Less frequent routes include congenital, oral, and blood- and organ-derived transmission [6]. The infection is presumed to be life-long without treatment. Most infected people are asymptomatic and unaware of their infection, but 20–30% will eventually develop clinically evident cardiac and/or gastrointestinal disease [5]. Active screening is therefore crucial to identify infected individuals and enable timely treatment prior to the development of end-organ damage [7]. An estimated 300 000 infected individuals currently live in the United States [5]. Despite T. cruzi infection prevalence as high as 1–4% among Latin American immigrant populations in some large US metropolitan areas [8–10], awareness is low among both healthcare providers and people at risk for Chagas disease; thus, most US cases go undiagnosed or have a delayed diagnosis [11]. Based on immigration patterns and volumes, Mexico, El Salvador, Guatemala, and Honduras are the predominant countries of origin identified among patients with Chagas disease in the United States, although the national prevalence of T. cruzi infection is highest in Bolivia and Argentina [5]. Because congenital transmission occurs in 1–10% of births to infected women, US-born people whose mothers immigrated from endemic countries are also at risk for T. cruzi infection [5, 12].

In recently published consensus recommendations, screening is strongly recommended for people with epidemiological risk of chronic T. cruzi infection [7] (Box 1), particularly any person born in or who lived for at least 6 months in an endemic country of continental Latin America. Recommended testing for PWH follows the same methodology as for the general population [7]—that is, a serum specimen is tested using a sensitive anti–T. cruzi IgG assay and, if the screening result is positive, the diagnosis is confirmed with a second test, preferably one using different 
T. cruzi antigens [7]. High priority is recommended for persons at risk for cellular immunosuppression (eg, PWH not on antiretroviral therapy [ART]) and women of reproductive age. Discordant results require the use of a third distinct assay as a tiebreaker. As discussed below, a high index of suspicion for Chagas disease in an immunocompromised patient may warrant further investigation despite negative or equivocal serologic results.

TRYPANOSOMA CRUZI–HIV COINFECTION

Iatrogenic or acquired cellular immunosuppression (eg, CD4⁺ cell count <200 cells/mm³) of T. cruzi–infected individuals may permit reactivation, characterized by a return to high levels of parasitemia similar to those seen in acute infection [13]. T. cruzi reactivation can cause serious clinical sequelae. Consequently, Chagas disease has been recognized as a potentially severe opportunistic infection since the late 1980s and was first reported as reactivation disease in a PWH at the crest of the HIV pandemic in 1990 (Supplementary Table 1) [14]. T. Cruzi reactivation is commonly reported in endemic countries, where prevalence estimates in cross-sectional studies of PWH range from 1% to 7% (Supplementary Table 2). The prevalence of T. cruzi–HIV coinfection in at-risk US PWH is unknown, although likely similar to that in US populations sharing the same epidemiological profiles. In 2 cohort studies spanning the pre-ART and ART eras in Brazil and Argentina, an estimated 15–20% of HIV–T. cruzi coinfected patients experienced reactivation over the course of follow-up [15, 16]. In a recent retrospective analysis of 241 coinfection cases (most [86.7%] from Brazil, but also including Spain, Argentina, and Chile), 24.9% experienced T. cruzi reactivation disease [17] (Supplementary Table 2). They found that CD4 count was significantly lower in coinfected PWH with reactivation disease than those without reactivation (73 cells/µL vs 260 cells/µL, P < .001), and 40% of those with reactivation disease died. Additionally, while data are sparse, untreated coinfected women likely are at high risk of transmitting 
T. cruzi transplacentally (Supplementary Table 3).

CLINICAL MANIFESTATIONS OF T. CRUZI REACTIVATION IN PEOPLE WITH HIV: NEARLY ALL MANIFEST AS CNS DISEASE, AND MOST ARE DETECTED TOO LATE TO SAVE

Symptomatic Chagas disease reactivation is predominantly reported as CNS mass lesions with or without meningoencephalitis [2, 18–21] (Supplementary Table 1). The typical presentation includes focal or generalized neurologic symptoms and abnormalities on head computed tomography (CT) or brain magnetic resonance imaging (MRI) in a PWH with a CD4⁺ cell count less than 200 cells/mm³. Frequently, Chagas disease reactivation in the CNS is misdiagnosed as toxoplasmosis 
[18, 20–23]. Rim-enhancing cerebral lesions are often present, although up to 15% of patients have normal brain imaging by both CT and MRI [24]. MRI is more sensitive than CT and is preferred if available [24]. Trypanosoma cruzi is reported to localize more often to white matter or the subcortex, while Toxoplasma tends to cause cortical or basal ganglia lesions, but the etiologies cannot be reliably distinguished based on imaging alone [25]. Central nervous system reactivation carries an extremely high mortality rate (79–100%) [4]. Prompt recognition, antiparasitic treatment, and timely optimization of ART are essential to maximize the likelihood of survival [2]. US case reports indicate that Chagas disease reactivation is often the presenting manifestation in a newly diagnosed PWH (Table 1). None of the 6 reported US reactivation patients was on effective ART at the time of presentation, and 4 (67%) died of their disease within days to weeks. Immune reconstitution inflammatory syndrome (IRIS) is a theoretical concern with ART initiation, but it has not yet been documented for T. cruzi coinfection, with the possible exception of 1 patient who developed erythema nodosum after initiating ART [26].

Table 1.

Published Reports of Trypanosoma cruzi Reactivation in People With HIV in the United States

Location of Admission	Country of Origin	Clinical Presentation	CD4+ Cell Count, cells/mm3	Imaging	Outcome	Reference
Los Angeles	El Salvador	33-year-old man presented 3 months after initial HIV diagnosis with fever, hemiparesis, and papilledema; brain biopsy interpreted as histoplasmosis	45	Irregular contrast enhancing left temporal lesion on CT	Died 14 days post-admission; postmortem T. cruzi diagnosis	Gluckstein, 1992 [18]
Los Angeles	El Salvador	22-year-old man with headaches, epistaxis, and new HIV diagnosis; improvement and disappearance of basal lesions with treatment for toxoplasmosis; 3 weeks later presented with ataxia, spastic hemiparesis, and new CNS lesions on MRI; T. cruzi on CSF	77	Abnormal high- intensity signal in posterior limb of left internal capsule on diffusion-weighted MRI	Died despite treatment with nifurtimox	Yoo, 2004 [23]
North Carolina	Mexico	56-year-old man with progressive paraparesis, urinary retention and new HIV diagnosis; treated for presumed CNS toxoplasmosis without response; T. cruzi on brain biopsy	37	Multiple enhancing lesions; worsened with new lesions 10 days later	Died despite treatment with nifurtimox	Lambert, 2006 [20]
Houston	Honduras	38-year-old woman with 10-day history of right-sided hemiparesis and headache, and new HIV diagnosis; initially diagnosed as toxoplasmosis; T. cruzi on brain biopsy	104	Multiple enhancing lesions on MRI	After several days of nifurtimox, ART was added; 4 days later mental status deteriorated, and required intubation; developed sepsis, worsening brain lesions; died on day 54	Campos, 2010
Houston	Honduras	49-year-old woman with 3-week history of altered mental status, headache, and hemiparesis; initially treated for toxoplasmosis at another hospital and discharged; admitted for worsening mental status; T. cruzi in CSF and review of brain biopsy (initially read as toxoplasmosis)	38	Ring-enhancing lesions in right superior gyrus and left parietal lobe	Treated with benznidazole followed 17 days later by addition of ART; alive 5 months later, clinically stable with residual hemiparesis and CD4 >350 cells/mm3	Yasukawa, 2014 [21]
Palo Alto	El Salvador	31-year-old man with fever, ataxia, and recent HIV diagnosis; T. cruzi on brain aspirate	60	Large mass in corpus callosum, right parietal and occipital lobes	Improved mentation and gait after 2 weeks of benznidazole and ART; no information on long-term outcome	Gomez, 2018 [19]

Abbreviations: ART, antiretroviral therapy; CNS, central nervous system; CSF, cerebrospinal fluid; CT, computed tomography; HIV, human immunodeficiency virus; MRI, magnetic resonance imaging.

Reactivation myocarditis is the second most reported manifestation (10–23% of cases) but is likely underdiagnosed [15, 17, 27]. Distinguishing between cardiac disease due to T. cruzi reactivation versus progression of chronic cardiomyopathy is important, as benznidazole treatment can be lifesaving in reactivation [28]. Rarely, reactivation disease presents as cervicitis, gastrointestinal disease, peritonitis, or skin lesions (Supplementary Table 1).

Importantly, T. cruzi serology may be negative in coinfected PWH who are severely immunocompromised (eg, serology was negative in 2 of 9 patients in Benchetrit et al [29]). A high index of suspicion should prompt further testing with molecular techniques. Even PWH with asymptomatic chronic Chagas disease have significantly higher parasitemia levels than immunocompetent people with chronic T. cruzi infection [30]. Impaired cellular immunity erodes control of parasite replication, illustrated by the inverse correlation between CD4 counts and parasitemia levels [30, 31]. Polymerase chain reaction (PCR) sensitivity is high in the setting of coinfection because of the higher parasite load [31].

DEFINITIONS AND DIAGNOSIS OF T. CRUZI REACTIVATION IN PEOPLE WITH HIV

In the published literature, a variety of definitions have been used for T. cruzi reactivation [13]. The most frequent criteria include presentation with clinical manifestations atypical for chronic Chagas disease, plus microscopic detection of T. cruzi parasites in blood, cerebrospinal fluid (CSF), or tissue specimens [3, 15]. Some authors define reactivation based on microscopically detectable parasitemia, even without a reactivation-defining syndrome [16, 31]. This range of definitions should be considered when comparing publications (Supplementary Table 1).

For patients with signs or symptoms suggestive of T. cruzi reactivation disease, methods of diagnosis vary depending on the clinical scenario. While microscopic detection of parasites in peripheral blood constitutes the classic criterion for confirmation [16], CNS reactivation with negative peripheral blood microscopy is not infrequent (Supplementary Table 1) [24, 27, 29, 32]. Detection by microscopy or, increasingly, PCR in CSF or brain tissue, independent of results in peripheral blood, confirms the diagnosis of CNS reactivation. In a patient with clinical signs of CNS disease, a high parasitemia level by quantitative PCR in blood is suggestive but not confirmatory. Strict confirmation of reactivation myocarditis depends on tissue histology [16], which is rarely available in clinical practice. Currently, the US Centers for Disease Control and Prevention (CDC) is the only US national reference laboratory that offers T. cruzi PCR for diagnostic application.

CHALLENGES AND STRATEGIES FOR OPTIMIZING CHAGAS DISEASE SCREENING AND CARE IN PEOPLE WITH HIV

Major challenges to optimal Chagas disease screening and management include low patient and provider awareness, insufficient access to care, a complex diagnostic landscape, and knowledge gaps regarding treatment. Most T. cruzi–HIV coinfected people are unaware that they might have Chagas disease [33] or HIV [34]. Many lack ready access to healthcare. More than 20% of documented and more than 45% of undocumented immigrants are uninsured (compared to 9% of immigrants who are US citizens), and therefore have limited options to meet their medical needs [35]. Whether insured, underinsured, or uninsured, many racial/ethnic minority community members have no regular primary care provider or a medical home [36]. The US political environment has exacerbated fear of deportation and of being labeled a “public charge” within at-risk immigrant communities [37]. Immigrants may fear that accepting any type of assistance, including free or reduced-cost testing and treatment, will preclude them from lawful permanent residence and future US citizenship [38].

US HIV clinics often serve as the medical home for PWH; thus, they serve as screening centers for many treatable diseases and are ideal locations where at-risk PWH could be screened for Chagas disease. However, screening for Chagas disease requires accurate and readily available laboratory testing. Despite the recent publication of US-focused recommendations [7], many clinicians are unaware of testing requirements and options [39]. In theory, serological diagnosis of chronic Chagas disease is straightforward [40], but in practice, US clinicians face multiple logistical challenges to obtain appropriate testing for their patients. The first step in screening for Chagas disease requires just 1 sensitive serologic test, but confirmation requires up to 3 assays in total (2 to confirm and a third as tiebreaker in the case of discordant results by the first 2) [7]. Only 4 US Food and Drug Administration (FDA)–cleared assays exist and, of those, several are unavailable or difficult to access [7, 41]. Commercial laboratories currently offer only a single serologic test, and the CDC has the only US reference laboratory offering confirmatory serology and T. cruzi PCR at this time. When the CDC Parasitic Diseases testing is offline, as it has been in recent months, clinicians are left without ready alternatives for both confirmatory and molecular testing [42]. Improved availability of current assays and additional FDA-cleared tests are needed. Test manufacturers should be encouraged to develop improved assays to enable reflexive testing and simplify the process of confirmation. Expansion of testing capacity at state public health and commercial laboratories will be crucial to support screening at facilities serving vulnerable populations.

Although current data are insufficient to assess the cost-effectiveness of screening at-risk PWH at entry-to-care, the documented reactivation cases and deaths provide a basis for bringing US recommendations into line with those of countries such as Brazil and Spain [3, 4]. The only US Chagas disease cost-effectiveness model addresses screening of women from endemic areas and the infants of infected women to enable treatment of congenital and maternal infection [43]. The model indicates that such screening is cost-saving compared with no screening program for maternal prevalence levels above 0.06%. A Spanish group modeled the cost-effectiveness of screening their Latin American migrant population and found screening to be more cost-effective than not screening at all prevalence levels above 0.05% [44]. Screening data collected over the coming years for US PWH will help generate the evidence base needed for a formal cost-benefit analysis in the future.

In a patient with symptomatic, especially CNS, reactivation, anti-trypanosomal treatment can be lifesaving and is strongly recommended [45]. No systematic data exist regarding the ability of anti-trypanosomal treatment to prevent reactivation. US opportunistic infection guidelines give a weak recommendation for a single course of treatment in coinfected patients without symptomatic reactivation [45]. However, sterile cure is thought unlikely for chronic Chagas disease, and treated patients are considered to remain at risk for reactivation. After initial treatment for symptomatic T. cruzi reactivation, secondary chemoprophylaxis is often prescribed in endemic countries [46]. In 1 Argentine case series, post-treatment for T. cruzi CNS reactivation disease, 2 PWH were given benznidazole secondary prophylaxis at 5 mg/kg/day for 3 days per week until achieving CD4 counts higher than 200 cells/mm³ and an undetectable HIV viral load, with good outcomes [47]. Even so, restoration of robust cellular immunity through consistent use of effective ART is the most important means to prevent reactivation. The question of whether a course of anti-trypanosomal treatment and/or secondary chemoprophylaxis add any benefit beyond the protection provided by effective ART remains unanswered.

While optimization of Chagas disease screening and management for at-risk PWH is beset by obstacles, including those that always complicate care for the underserved and undocumented in the United States [37, 38], several tangible solutions are within reach. We conclude by offering a series of practical steps to improve care for T. cruzi–HIV coinfected people living in the United States (Box 2). As a first step, incorporating Chagas disease screening into the panel of laboratory tests routinely performed during the entry-to-care evaluation for at-risk PWH would go a long way to increase recognition by providers and patients, and reduce T. cruzi–related morbidity and mortality. Catch-up testing for those already in care can be incorporated into follow-up visits; for PWH on effective ART, the risk of reactivation is low. The entry-to-care visit would thus serve as a systematic mechanism to screen a vulnerable population, educate them about Chagas disease, and provide referral for appropriate confirmatory testing and management.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Box 1. Recommended Populations That Should Undergo Chagas Disease Screening in the United States.

Chagas disease screening should be targeted to people with epidemiologic risk of infection, including the following:

• Born in or who lived for at least 6 months in an endemic country of continental Latin America

• Born to a woman with prolonged exposure and/or birth in an endemic country

• Born to a woman with confirmed T. cruzi infection

• With evidence of a bite or other exposure to a triatomine in Latin America or US regions with known enzootic cycles

High priority should be given to persons at risk for cellular immunosuppression and to women of reproductive age (either prenatally or during routine care).

Box 2. Recommendations to Improve Care for People Coinfected With HIV and Trypanosoma cruzi Living in the United States.

• Integration of Chagas disease screening into entry-to-care protocols for PWH born in (or whose mother was born in) continental Latin America

• Education of frontline healthcare providers including HIV providers on Chagas disease screening and diagnosis, and recognition and management of reactivation

• For PWH already in care, incorporation of catch-up screening for Chagas disease at follow-up visits

• Optimization of diagnostic algorithms for T. cruzi  infection, particularly for PWH with low CD4 counts

• Validation and optimization of diagnostic algorithms for T. cruzi  reactivation in PWH

• Expansion of testing capacity at state public health, commercial, and institutional clinical laboratories and support for evidence-based, multistep, confirmatory testing algorithms

• Assessment of the prevalence of and risk factors for HIV-T. cruzi coinfection to better target interventions within at-risk communities

• Implementation of Spanish-language Chagas disease and HIV education and screening campaigns in at-risk communities

• Establishment of free or reduced-cost, easily accessible, and Spanish-language-friendly centers for Chagas disease treatment and management in high-prevalence areas of the United States