Keywords

1 Triatomine Vector Biology and Ecology

Kissing bugs belong to the family Reduviidae, subfamily Triatominae. There are 138 described species, and all triatomine bugs have the potential to transmit the pathogen responsible for Chagas disease, Trypanosoma cruzi [1, 2]. The relationship between triatomine bugs, their hosts, and the Trypanosoma cruzi parasite is ancient, thought to have evolved over millions of years ago in the New World, millennia before humans arrived [3, 4]. In fact, morphometric evidence suggests that triatomine bugs originated in the New World, after which they spread throughout other regions of the globe [3, 5]. Triatomine bugs are thought to have been described first by Fray Reginaldo de Lizarraga around 1590 in Peru or Chile, and the first valid species described in the United States was Conorhinus sanguisugus by John LeConte in Georgia in 1855, which is known as Triatoma sanguisuga today [6, 7]. Since 1855, an additional ten species of kissing bugs have been described and documented in the United States: Triatoma gerstaeckeri, Paratriatoma hirsuta, T. incrassata, T. indictiva, T. lecticularia, T. neotomae, T. protracta, T. recurva, T. rubida, and T. rubrofasciata. These bugs are found throughout the central to southern states, roughly south of the Great Lakes.

Relative to the species found in Latin, Central, and South America, there are fewer studies describing the biology, behavior, and ecology of the kissing bugs in the United States. Thus, knowledge is somewhat lacking regarding the trypanosome disease ecology, sylvatic cycles, and human risk in the United States. A recent uptick in research has brought more attention to this neglected tropical disease and triatomines in the United States in the past decade, especially around the United States-Mexico border. The US kissing bug species’ biology and history are described below according to the most recent research on these 11 species.

1.1 T. gerstaeckeri (Ståhl)

As the most frequently studied and collected kissing bug in the United States, T. gerstaeckeri has contributed to much of the current knowledge of triatomines in the southwest and central United States, and it has only been recorded in New Mexico and Texas [8]. Historically, this species was recorded as a pest of livestock and humans—even invading rural homes in Texas [7, 9,10,11]. In more recent decades, T. gerstaeckeri is found in various peridomestic and sylvatic habitats including bird nests, dog kennels, livestock pens, chicken coops, woodrat nests, lights on human structures at night, and caves [7, 8, 12,13,14]. Hosts for this species can be wide-ranging as well from dogs, chickens, amphibians, livestock, and humans; however woodrats are considered their primary host [7, 13,14,15]. T. gerstaeckeri has been found to be naturally infected with T. cruzi anywhere from 26% to 64% of specimens tested [7, 8, 12, 14, 15]. Some work has been conducted on understanding the feeding to defecation interval of this species in order to estimate risk of T. cruzi parasite transmission. Martinez-Ibarra et al. recorded an average defecation time of 11.5 min (N = 733) for this species [16].

1.2 T. incrassata (Usinger)

This species of triatomine is largely understudied compared to T. gerstaeckeri. T. incrassata has only been collected on lights at night in two southern Arizona counties: Santa Cruz and Pima [7, 8, 17]. Even though little is known about this species, Klotz et al. inferred that the favored habitat of this species is woodrat nests based on similar species and their primary hosts would be woodrats and squirrels [13] T. incrassata has not been found naturally infected with T. cruzi, so its infection status is unknown in the United States [7, 8].

1.3 T. indictiva (Neiva)

Little is known about this US species of kissing bug as well; it has been found only in Arizona, New Mexico, and Texas in relatively small numbers [7, 8]. T. indictiva has been collected from woodrat nests and from lights at night [11, 18], and woodrats are known to be their primary host [13, 15]. However, Wozniak et al. collected one T. indictiva specimen inside of a house [14]. Of the relatively small number of bugs collected, between 0% and 50% test positive for T. cruzi parasites [14, 15, 18].

1.4 T. lecticularia (Ståhl)

T. lecticularia has been collected in multiple states including New Mexico, Texas, Kansas, Missouri, Tennessee, Georgia, South Carolina, and Florida; its distribution most likely includes the adjacent states of Oklahoma, Arkansas, Louisiana, Mississippi, and Alabama as well [8]. This species has been collected from human dwellings as early as 1940 to now, dog kennels, hollowed logs, lights at night, rock squirrel burrows, and woodrat nests [7, 8, 14, 15, 19,20,21,22,23]. Woodrats and squirrels are thought to be the primary hosts for T. lecticularia [13, 24], but like its sister species, these are generalist ectoparasites; a study in 2017 investigating triatominae blood meals found multiple T. lecticularia specimens had fed on turkey vultures (Georgieva et al. [30]). Studies investigating the T. cruzi infection prevalence have shown that this kissing bug is commonly infected with the parasite, with results ranging anywhere from 38% to 83% [11, 14, 15, 25]. Martinez-Ibarra et al. recorded an average defecation time of 8.3  min (N = 368) for this species [16].

1.5 T. protracta (Uhler)

This triatomid was first reported in the United States in 1860 as a pest of humans in central California [26] and has since been recorded in Nevada, Utah, Arizona, Colorado, New Mexico, and Texas [8, 27,28,29]. Because this species is attracted to lights at night, it has been commonly found in and around human dwellings, and it has also been collected from woodrat nests [7, 8, 14, 29] and potentially dog kennels [30]. The woodrat and closely related rodents are believed to be T. protracta ’s primary hosts [13]. The infection prevalence for this species varies widely through the literature from 18% to 100% of bugs tested [8, 14, 15]. Results of defecation time experiments have varied: Wood reported a defecation time of 30.6 min (N = 10) [31], while Martinez-Ibarra et al. reported 6.7 min (N = 475) [16]. Klotz et al. recorded that T. protracta defecate less often and typically further away from their host compared to their Latin American cousins [32].

1.6 T. recurva (Ståhl)

T. recurva , the largest kissing bug in the United States, has been recorded only in Arizona and Texas; however it has not been found in Texas since the single report in 1984 [8, 33, 34]. In 1940s Arizona, it was described as a frequent pest invader of human dwellings and miner tents [11, 35] and continues to invade homes as recently as this decade [13, 36, 37]. This species can be found in rodent nests; however the primary host is still unknown although T. recurva can be found associated with rock squirrels and readily feeds on various reptiles and guinea pigs in laboratory settings [7, 8, 13, 17, 35, 38,39,40]. This species has been found naturally infected with T. cruzi [7, 30]. Wood recorded an average defecation time of 75.7 min following a blood meal from this species (N = 3) [31].

1.7 T. rubida (Uhler)

In the United States, this species has been recorded in Texas, New Mexico, Arizona, and California [7, 8]. Commonly collected in woodrat nests throughout this range [7, 10, 11, 13, 20, 35], it has also been known to infest or be attracted to human houses and other peridomestic structures where it has bitten people [36, 37, 41]. In addition, T. rubida has been sometimes collected from fish-eating bat refuges [7, 13]. The infection prevalence of this triatomine ranges from 0% to 41% in the published literature [8, 15, 30, 37]. Of the few studies on T. rubida’s defecation time, most have documented relatively fast defecation times relative to feeding. Wood recorded an average defecation time of 1.6 min (N = 5) [31], and Reisenman et al. demonstrated that 93% of adult females (N = 15) defecated while feeding and 62% of immature stages (N = 75) defecated within 10 min of feeding less than 3 cm from the feeding site [42]. Klotz et al. reported that T. rubida defecated less often compared to Latin American species [32].

1.8 Paratriatoma hirsuta (Barber)

The documented range in the United States of this species covers Nevada, California, and Arizona where it has been collected from human dwellings and lights at night; however the natural setting most often associated with P. hirsuta is woodrat nests [8, 35, 43, 44]. In fact, no other known hosts are associated with this kissing bug in the United States [7, 8]. To date, no naturally T. cruzi-infected specimen has been collected in the United States [7, 8, 30, 35]. Wood recorded an average defecation time of 35 min (N = 2) following a blood meal for this species [31].

1.9 T. neotomae (Neiva)

Named for its primary host, Neotoma spp. woodrats, T. neotomae has been found almost exclusively in woodrat nests, with one unique report from a dog kennel [7, 8, 13, 15]. This species is believed to only inhabit Texas, and previous reports of this kissing bug found in other states are thought to be in error [8]. The literature is lacking in the reported infection prevalence of this species, with only two reports: 0% and 76% of specimens testing positive for T. cruzi [12, 15].

1.10 T. sanguisuga (LeConte)

Triatoma sanguisuga has one of the widest ranges of kissing bugs in the United States; this species has been found in Texas, Oklahoma, Kansas, Louisiana, Arkansas, Missouri, Mississippi, Tennessee, Kentucky, Illinois, Indiana, Alabama, Florida, Georgia, South Carolina, North Carolina, Virginia, Ohio, Pennsylvania, Maryland, and New Jersey [7, 8]. It is most likely also found in West Virginia, but no published records of this exist. In parallel with its wide range, T. sanguisuga can be found in a diverse amount of habitats ranging from sylvatic to domestic: human dwellings, lights at night, armadillo burrows, chicken coops, raccoon and opossum nests, dog kennels, horse stables, cotton rat nests, etc. [7, 8, 10, 11, 14, 15, 45,46,47,48]. Klotz et al. identified their primary hosts as raccoons, armadillos, opossums, frogs, woodrats, dogs, squirrels, and humans [13]. Historically, this species has been associated with human biting activity since the 1800s [6, 14, 15, 36, 49]. Infection prevalence for this species can vary from 17% to 70%; however in every state where T. sanguisuga has been tested, at least one specimen is positive for T. cruzi [8, 12, 14, 15, 50].

1.11 T. rubrofasciata (De Geer)

This is the only kissing bug species found in both the Eastern and Western Hemispheres; it is largely associated with human developments and was most likely distributed around the world through the shipping industry [8, 13]. In the United States, it has been found in Florida and Hawaii, commonly collected in chicken and pigeon coops [7, 8, 43, 51,52,53,54]. This species has been found naturally infected with T. cruzi parasites; however infection prevalence data is not published in the United States [7].

2 Clinical Aspects of Chagas Disease in the United States

In recent years, there has been growing awareness of the significant burden of Chagas disease in the United States. The National Notifiable Diseases Surveillance System (NNDSS) does not require the mandatory notification of Chagas disease to public health authorities, and only a few states, including Arizona, Arkansas, Louisiana, Mississippi, Utah, Texas, and Tennessee, consider Chagas disease a reportable diagnosis, making it difficult to accurately evaluate the prevalence and incidence of infection.

Historically, Trypanosoma cruzi transmission was concentrated in rural Latin America. However, in recent decades migration has brought infected individuals to cities in Latin America, as well as to the United States and other countries [55]. In contrast to countries outside of North America, Chagas disease has been able to take root in the United States because the disease vector is already established. The southern states provide habitats to several triatomine species and animal reservoirs such as woodrats, raccoons, opossums, and dogs that influence transmission to human hosts living in these areas. In fact, human disease has likely been occurring in the United States for more than a century [56]. The first official reports of human autochthonous T. cruzi infection occurred in 1955, when two Texas infants were diagnosed [57, 58]. The next report was from California in 1982 of an acute infection in an adult woman. Over the following 34 years, another four cases were reported. In five of the total seven cases, triatomines were found in or near the patient’s dwelling.

US blood banks began testing for Chagas disease in 2007. Subsequently, two studies investigated T. cruzi-positive blood donors [59, 60]. These studies were designed to exclude positive blood donors whose suspected infection had likely been acquired outside the United States, and they identified another 21 cases of likely autochthonous T. cruzi infection, bringing the total number of documented infections acquired in the United States to 28 during 1955–2015. Nevertheless, most individuals infected with T. cruzi are immigrants from endemic countries in Latin America.

The number of Chagas disease cases varies from state to state and reflects the distribution of Latin American immigrant populations. Manne-Goehler et al. provided an updated national estimate of Chagas disease prevalence in their 2016 study, which showed the first state-level estimates of cases of Trypanosoma cruzi infection in the United States using data from the American Community Survey and from the American Association of Blood Banks (AABB) [61]. Their study estimated 238,091 cases of T. cruzi infection in the United States as of 2012, a number which excludes undocumented immigrants who may account for as many as 109,000 additional cases. The state-level results show that four states (California, Texas, Florida, and New York) had more than 10,000 cases, and an additional seven states had over 5000 cases. In addition, the AABB has reported 1908 cases of T. cruzi infection between 2007 and 2016, identified through screening of blood donations [61].

Screening of blood donors for T. cruzi infection has led to increased awareness of Chagas disease because of the identification of chronic infections among asymptomatic individuals [11]. In addition, it has improved understanding of the geographic distribution of chronically infected people in the United States and may help to direct future public health efforts to improve diagnosis and management for those at risk for the manifestations of chronic Chagas disease. Currently, the Ortho T. cruzi enzyme-linked immunosorbent assay (ELISA) test system is the initial screening assay, and it has been approved by the US Food and Drug Administration. The ELISA result is subsequently confirmed using a radioimmune precipitation assay [62]. Between 2007 and 2015, 1908 confirmed seropositive donations were detected, with the largest numbers found in California, Florida, and Texas [61]. At this time individuals who test positive for T. cruzi in the United States are not permitted to donate blood in their lifetime, regardless of treatment status.

2.1 Congenital Chagas Disease in the United States

In the United States, there is great concern for potential congenital transmission of T. cruzi from infected mothers to infants [63]. The first documented case of congenital transmission in the United States occurred in 2012 [64]. The patient’s mother was a Bolivian woman who had been diagnosed with Chagas disease in Bolivia but never treated. As in this case, most individuals born in the United States with congenital Chagas disease are the children of foreign-born parents [65]; thus the prevalence of congenital Chagas disease varies. Two important congenital risk studies were performed in Texas, which is one of the states with the highest prevalence [66, 67]. The first, conducted from 1993 to 1996, found that 0.3% (11 out of 3765) of predominantly Hispanic pregnant women in Southern Texas were T. cruzi-positive [66]. Nine of these 11 women were of Hispanic origin. A similar study was repeated between 2011 and 2012 [66] and found a consistent perinatal infection rate of 0.25% (ten out of 4000). These studies indicate that Chagas disease occurs with sufficient frequency (0.25%) in the United States and warrants a need for perinatal screening to identify infected mothers and infants at risk for congenital infection.

2.2 Identifying and Treating Chagas Disease in the United States

Although Chagas disease is one of the five neglected parasitic infections in the United States that have been targeted for public health action, most healthcare providers are not familiar enough with Chagas disease to routinely include it among their differential diagnoses for cardiac and intestinal disease, even with epidemiologically at-risk patients [17, 18]. Improved provider education on diagnosis and treatment of Chagas disease is imperative; one study showed that only 11% of T. cruzi-positive blood donors in the United States sought or were offered treatment [68]. This finding was supported by another study that found that only 25% of positive blood donors received additional follow-up care for their disease [60]. Increasing provider awareness will lead to better diagnosis and management for all patients, regardless of where the infection was acquired.

Approximately 30,000–45,000 persons in the United States are estimated to have Chagas cardiomyopathy [69, 70]. A New York study of Latin American immigrants diagnosed with dilated cardiomyopathy found that 13% of these patients had Chagas disease [71]. A larger California study followed 135 Latin American immigrants with advanced non-ischemic cardiomyopathy [72]. Chagas disease was diagnosed in 19% of those patients.

Identifying Chagas disease in patients with cardiomyopathy not only helps with prognostication but also aids in clinical treatment decisions. Many treatment options are available for patients with T. cruzi infection that develop heart disease in the United States that are not available in most other endemic countries, ranging from anti-arrhythmic medication to advanced cardiac devices to heart transplantation. Several studies have been done in the United States evaluating various interventions in Chagas disease patients. Many investigators have noted that these patients have a higher burden of malignant ventricular arrhythmias, which is a crucial factor when considering implantation of cardioverter-defibrillator devices or radiofrequency ablation [73]. One study demonstrated that the anti-arrhythmic amiodarone has direct anti-T. cruzi effects [74]. Chagas cardiomyopathy patients in the United States seem to be more likely to be offered ionotropes as well as electrical (ICDs and cardiac resynchronization therapy ) and ventricular support devices, especially while awaiting heart transplant, than in other endemic countries, including countries with significant medical resources such as Brazil [75].

Heart transplantation for patients with Chagas cardiomyopathy has been done since the 1990s, even though early on, given the potential for reactivation of T. cruzi with immunosuppression, Chagas cardiomyopathy was initially considered to be a relative contraindication to heart transplantation. Subsequently, studies have shown that the outcome after heart transplantation for Chagas cardiomyopathy is acceptable [76], and it is now recognized that survival in patients with Chagas cardiomyopathy after heart transplant may be better than those patients with other forms of non-ischemic cardiomyopathy. T. cruzi post-transplantation reactivation rates are thought to be as high as 26.5–42.9% [72]; thus, screening for T. cruzi infection in all patients born in a Chagas disease endemic country and undergoing transplant evaluation for dilated cardiomyopathy is critical.

Reactivation of T. cruzi infection is a major concern because of the risk of allograft dysfunction [77]. One study of Chagas cardiomyopathy patients who underwent heart transplantation in the United States identified reactivation in five patients (45%), detected by clinical signs of reactivation with accompanying allograft dysfunction by echocardiography in two cases and whole blood PCR testing in three patients [75]. The T. cruzi reactivation rate in the Kransdorf study is higher than the rates of 21–39% that were reported by transplant centers in Brazil [76,77,78]. This difference is likely due to the use of the more potent immunosuppressive agents tacrolimus and mycophenolate mofetil in the United States, as compared to predominant use of cyclosporine and azathioprine in Brazil. Mycophenolate mofetil in particular has been associated with a higher rate of T. cruzi reactivation [78, 79].

Conversely, testing of potential organ donors for chronic T. cruzi infection is quite important due to the risk of donor-transmitted infection. Given the prevalence of T. cruzi infection in blood donors discussed previously, universal testing is necessary to prevent donor-transmitted T. cruzi infections, which led to the death of two heart transplant recipients in 2006 [80]. Kransdorf et al. found that only four of 11 organ donors underwent testing for T. cruzi infection [75]. The most common reason for omission of T. cruzi testing in their cohort was that the Organ Procurement Organization (OPO) did not routinely perform T. cruzi testing, even on at-risk donors. Recent data indicate that only 19% of OPOs in the United States performs testing for T. cruzi [79].

Another barrier to improving control of Chagas disease in the United States includes diagnostic testing. Better diagnostic tests are needed so that effective screening can be performed outside of formal laboratory settings. Currently, when a healthcare provider suspects Chagas disease, most health departments in endemic states recommend that specimens should first be screened at a commercial laboratory. Several types of serologic tests are used among commercial laboratories in the United States, including indirect hemagglutination (IHA) tests, indirect immunofluorescence (IIF) tests, and ELISAs. Most of these tests use a complex mixture of parasite antigens (IHA and ELISA) or the whole-parasite lysate (IIF). This increases the likelihood that the infection will be diagnosed, even when the antibody level is low; however, false-positive results can occur with Leishmania species or Trypanosoma rangeli. Samples that test positive should then be forwarded to the Centers for Disease Control and Prevention (CDC) for confirmatory testing. At the CDC, two serologic tests are performed to confirm the diagnosis, the Wiener recombinant antigen Chagatest ELISA and the TESA (trypomastigote excreted-secreted antigen) immunoblot [81, 82]. Although it is commonly accepted that polymerase chain reaction (PCR)-based tests for Chagas disease are more sensitive in acute Chagas infection, their results are highly variable in chronic infection. Thus, at this time PCR-based assays are only used as a clinical tool when transmission via blood transfusion, organ transplant, or congenital or laboratory exposure is suspected [83, 84].

Treatment is now recommended for asymptomatic patients of all ages who are diagnosed with Chagas disease [81]. Ideally, treatment should be started before the patient begins to develop complications of the disease. Two medications currently exist for the treatment of Chagas disease, benznidazole and nifurtimox. Benznidazole has been approved by the US Food and Drug Administration (FDA) for pediatric applications (aged 2–12 years); however, nifurtimox (all ages) and benznidazole for adult use are only available through investigational protocols from the CDC. Administrative requirements for participation under the protocols often are a barrier for the typical busy healthcare provider; thus FDA approval of these drugs would allow clinicians to access these drugs more easily for their patients.

Although benznidazole is the preferred treatment due to its lower incidence of adverse events and shorter treatment duration [81], due to supply chain issues, the most often prescribed treatment for Chagas disease in the United States is nifurtimox [85,86,87]. Only one study has been done to date to assess the safety of nifurtimox in patients with Chagas disease in the United States [88]. Forsyth et al. evaluated 53 adult Latin American immigrants with Chagas disease who underwent treatment with nifurtimox (8–10 mg/kg in three daily doses for 12 weeks) between 2008 and 2012. They recorded 435 adverse events among these 53 individuals, most (93.8%) of which were mild. The most common adverse events were gastrointestinal symptoms and weight loss, which has been shown in prior studies performed outside of the United States. Thus, while nifurtimox frequently causes side effects, the majority is mild and can be managed with dose reduction or temporary suspension of medication. Importantly, patients undergoing treatment should be closely monitored during the first few weeks of treatment due to the increased frequency of potentially severe adverse effects, including depression, rash, and anxiety.

3 Concluding Remarks

As an estimated 99% of patients in the United States diagnosed with Chagas disease remain untreated, there is a significant need for increased national attention to strategies to increase treatment availability for this disease. Investigation and production of new drugs targeting Trypanosoma cruzi, as well as increasing the supply of the existing effective medications, are essential to expand treatment of Chagas disease in the United States. With increased treatment of infected, asymptomatic individuals, many lives will be saved due to prevention of deaths and morbidity from the sequelae of Chagas disease, such as heart failure and arrhythmias.