Chagas disease: Acute and congenital Trypanosoma cruzi infection

INTRODUCTION — Chagas disease is caused by infection with the protozoan parasite Trypanosoma cruzi; the major manifestations are cardiomyopathy and gastrointestinal disease [1,2].

Issues related to acute and congenital Chagas disease will be reviewed here. Issues related to chronic Chagas infection are discussed separately. (See "Chagas disease: Chronic Trypanosoma cruzi infection".)

Issues related to acute Chagas myocarditis are discussed in detail separately. (See "Chagas heart disease: Acute myocarditis".)

Issues related to the epidemiology and prevention of Chagas disease are discussed separately. (See "Chagas disease: Epidemiology, screening, and prevention".)

Issues related to cardiac and gastrointestinal Chagas are discussed separately. (See "Chronic Chagas cardiomyopathy: Clinical manifestations and diagnosis" and "Chronic Chagas cardiomyopathy: Management and prognosis" and "Chagas gastrointestinal disease".)

TRANSMISSION ROUTES AND RISK GROUPS — Humans usually become infected when the triatomine vector defecates during its blood meal and fecal material containing the parasite is inoculated through the bite wound or intact mucous membranes (figure 1) [1,3]. T. cruzi–infected vectors have been found in some areas in all countries of the continental Americas, from the southern United States to Chile and Argentina, but vector-borne transmission risk is very low outside rural areas (in which vectors infest or regularly invade rustic houses) [1,4]. (See "Chagas disease: Epidemiology, screening, and prevention".)

Transmission can also occur congenitally from mother to infant, via transfusion of blood components, via transplantation of an organ from an infected donor, and via consumption of contaminated food or drink.

T. cruzi infection is characterized by an acute phase, which lasts 8 to 12 weeks, followed by the chronic phase, which, in the absence of successful antitrypanosomal treatment, lasts the rest of the patient's life (figure 2) [1].

ACUTE T. CRUZI INFECTION — T. cruzi infection is characterized by two phases, acute and chronic. Issues related to the acute phase are discussed below; issues related to the chronic phase are discussed separately. (See "Chagas disease: Chronic Trypanosoma cruzi infection", section on 'Natural history'.)

Clinical manifestations — The incubation period following vector-borne exposure is one to two weeks, after which the acute phase of Chagas disease begins [1,5]. In transfusion- and transplant-associated cases, the incubation period may be as long as four months [6,7].

The acute phase of T. cruzi infection lasts 8 to 12 weeks and is characterized by circulating trypomastigotes. Most patients have mild, nonspecific symptoms (such as malaise, fever, and anorexia) or are asymptomatic so do not come to clinical attention during the acute phase.

In a minority of patients, acute infection may be associated with inflammation and swelling at the site of inoculation, known as a chagoma. Chagomas typically occur on the face or extremities; in some cases, parasites can be demonstrated in the lesion. Inoculation via the conjunctiva may lead to the characteristic painless unilateral swelling of the upper and lower eyelid known as Romaña's sign (picture 1).

Severe acute disease occurs in less than 1 percent of patients; manifestations may include acute myocarditis, pericardial effusion, and/or meningoencephalitis [5,8]. Severe acute Chagas disease carries a substantial risk of mortality. Orally transmitted T. cruzi infection appears to be associated with more severe acute morbidity (especially myocarditis) and higher mortality rate than vector-borne infection [9].

Issues related to clinical manifestations of acute myocarditis are discussed further separately. (See "Chagas heart disease: Acute myocarditis", section on 'Clinical manifestations'.)

Diagnosis — Acute Chagas infection should be suspected in individuals who have lived or spent significant periods of time in areas of Latin America with vector-borne transmission, especially those who lived in houses with adobe walls and/or thatched roofs. However, T. cruzi infection is rarely detected during the brief acute phase, except in the context of specific screening programs (eg, congenital Chagas disease screening in maternity hospitals) or outbreaks (eg, clusters of orally transmitted infection). (See "Chagas disease: Epidemiology, screening, and prevention".)

In the acute phase, the level of parasitemia is high; motile trypomastigotes can be detected by microscopy of fresh preparations of anticoagulated blood or buffy coat, or by staining buffy coat smears (picture 2) [10,11]. The level of parasitemia decreases within 90 days of infection, even without treatment, and is undetectable by microscopy in the chronic phase [10,12].

Polymerase chain reaction (PCR) is a sensitive diagnostic tool in the acute phase of Chagas disease. It may also be used to monitor for acute T. cruzi infection in the recipient of an infected organ or after accidental exposure [7,13]. PCR assays generally demonstrate positive results days to weeks before circulating trypomastigotes are detectable on peripheral blood smears [14].

Direct demonstration of parasite by hemoculture or xenodiagnosis in a reliable laboratory indicates true infection, but these techniques are laborious and final results may not be available for one to two months [15]. Xenodiagnosis consists of feeding laboratory-reared uninfected triatomine bugs directly on the patient or on blood in a membrane-feeding device. For diagnostic purposes, hemoculture and xenodiagnosis have largely been replaced by PCR.

Issues related to prenatal or peripartum screening of at-risk women are discussed further separately [16]. (See "Chagas disease: Epidemiology, screening, and prevention", section on 'Vertical transmission'.)

The approach to clinical evaluation in patients with acute myocarditis is discussed further separately. (See "Chagas heart disease: Acute myocarditis", section on 'Diagnosis'.)

The United States Centers for Disease Control and Prevention (CDC) provides consultation to healthcare providers concerning Chagas disease diagnostic testing and acts as a reference laboratory for Chagas disease serology and PCR (Division of Parasitic Diseases Public Inquiries line, 404-718-4745; for emergencies after business hours, 770-488-7100; email [email protected]).

Differential diagnosis — The differential diagnosis of acute Chagas infection includes:

●Preseptal cellulitis – Preseptal cellulitis typically presents with ocular pain, eyelid swelling, and erythema. The Romaña sign may look similar to preseptal cellulitis but is usually not painful or tender. The diagnosis is generally based on clinical history and physical examination. (See "Preseptal cellulitis".)

●Infectious mononucleosis – Infectious mononucleosis can present with nonspecific symptoms including malaise, fever, and anorexia. It may be distinguished from acute Chagas disease by laboratory testing. (See "Infectious mononucleosis".)

●Acute HIV infection – Acute HIV infection can present with fever, myalgia, headache, sore throat, and rash. In most cases, patients with acute Chagas have nonspecific symptoms, such as fever, or are asymptomatic. Acute HIV infection and acute Chagas disease may be distinguished based on clinical exposure and laboratory testing. (See "Acute and early HIV infection: Clinical manifestations and diagnosis".)

CONGENITAL CHAGAS DISEASE

Clinical manifestations — Approximately 1 to 10 percent of infants of infected mothers are born with acute T. cruzi infection [17-21]. In a meta-analysis, the pooled transmission rate was 4.7 percent [22]. Most congenital infections are asymptomatic or cause nonspecific signs; laboratory screening is required for detection of these cases [18].

Low birthweight (<2500 g), anemia, and hepatosplenomegaly are significantly more frequent among infants with congenital Chagas infection than uninfected infants [21,23]. In a small proportion of patients, congenital infection causes severe morbidity, including meningoencephalitis, and/or respiratory insufficiency, with high mortality risk [21,24].

Infants who survive acute infection are presumed to have the same lifetime risk of cardiac or gastrointestinal disease as other infected individuals (20 to 30 percent), although direct data are lacking [25]. Uninfected infants of infected mothers have health status equivalent to infants of uninfected mothers [21,23].

Identification of T. cruzi infection in a mother should prompt testing of all of her children [16]. There are data suggesting that a woman with one infected infant may have a higher risk of transmitting to subsequent children [26]. Although some studies have reported a higher incidence of premature rupture of membranes among T. cruzi-infected women, other obstetric complications appear to be no more frequent among T. cruzi-infected than uninfected women [21].

Diagnosis — Congenital T. cruzi infection should be suspected in children born to women who have lived or spent significant periods of time in areas of Latin America with vector-borne transmission. In addition, a woman who herself was infected congenitally can transmit to her children. Pregnant women with relevant risk factors should undergo prenatal or perinatal serologic screening; identification of an infected woman should prompt infant screening (algorithm 1). In addition, arrangements should be made for maternal evaluation and treatment after completion of lactation. Screening should also be pursued for the infected woman's other children (if any). (See "Chagas disease: Chronic Trypanosoma cruzi infection".)

For the first several months of life, congenital T. cruzi infection is an acute phase infection, and thus demonstration of the parasite (or its DNA or antigen) forms the basis for diagnosis. Diagnosis is complicated by the fact that immunoglobulin (Ig)G serology in an infant reflects maternal antibody for up to nine months after birth [17].

The technique traditionally used to diagnose congenital T. cruzi infection is the micromethod (or microhematocrit method) [11,20,27,28]. This technique consists of centrifugation of fresh cord or neonatal blood sealed in four to six heparinized microhematocrit tubes (12,000 rpm for seven minutes), followed by light microscopic examination of the buffy coat layer [27]. However, the sensitivity of examination of a single infant specimen by this technique is less than 30 percent [17,18,29]. Parasitemia levels appear to rise in the first month after birth, thus repeated sampling (for example, at birth and at one month) may improve the detection rate [17,30].

Molecular techniques have substantially higher sensitivity compared with the micromethod, estimated at 65 to 70 percent in a single specimen and 85 percent when performed in multiple specimens [17,18,29,31,32]. Several investigators have reported transient detection of low quantities of T. cruzi DNA in very early specimens from a small percentage of uninfected infants of infected mothers; some researchers therefore require positive results in more than one specimen or by more than one technique for confirmation of diagnosis [23,33]. Positive results in a single specimen by polymerase chain reaction (PCR) with high parasite load (eg, >100 parasite equivalents/mL where estimated detection threshold is <1 parasite equivalents/mL) in an experienced laboratory is sufficient to make the diagnosis and begin treatment (algorithm 1) [18]. PCR is used increasingly for early diagnosis of congenital Chagas disease in Latin American cities and is the method of choice in industrialized countries, although it has not yet been implemented widely in the context of congenital Chagas disease screening programs [32-36].

An IgM immunoblot using trypomastigote excreted secreted antigens (TESA) demonstrates characteristic ladder-like shed acute-phase antigen (SAPA) bands in early congenital infection [37]. The sensitivity of the IgM TESA blot was estimated at 53 percent in cord blood and rose to 74 percent when carried out in 0- and 1-month specimens, compared with 69 percent and 84 percent for quantitative PCR in the same study [18]. However, the assay has proven challenging to perform reliably in a resource-constrained setting [18].

For infants not diagnosed at birth, conventional IgG serology is recommended after nine months of age, when transferred maternal antibody has mostly disappeared [5,17].

Issues related to prenatal or peripartum screening of at-risk women are discussed further separately [16]. (See "Chagas disease: Epidemiology, screening, and prevention", section on 'Vertical transmission'.)

MANAGEMENT OF ACUTE AND CONGENITAL T. CRUZI INFECTION

Clinical approach — Antitrypanosomal therapy is warranted for all patients with acute or congenital T. cruzi infection [11]. Antitrypanosomal drugs include benznidazole and nifurtimox; in general, benznidazole is better tolerated so is favored as the first-line treatment for Chagas disease. Dosing and adverse effects are outlined in the tables (table 1 and table 2). Issues related to antitrypanosomal drugs are discussed further separately. (See "Chagas disease: Antitrypanosomal drug therapy".)

Treatment reduces the severity of symptoms, shortens the clinical course, and reduces the duration of detectable parasitemia [5,25,38-40]. Parasitologic cure (as well as clinical cure) is thought to occur in 60 to 85 percent of patients treated during the acute phase [5,25,38,39].

Parasitologic cure is thought to occur in >90 percent of congenitally infected infants treated in the first year of life [32,38,39,41,42]. Treatment should be initiated as soon as the diagnosis is made; the drugs are well tolerated in infancy [24,32,43]. Successful treatment is assumed to decrease or eliminate risk of later complications, although longitudinal data are lacking [19,44].

The treatment of an infant or young child requires benznidazole or nifurtimox tablets to be crushed and prepared as a syrup or slurry to provide the appropriate dose. A pediatric formulation of benznidazole, consisting of tablets easily divided and dispersible in water, has been developed and is registered in Brazil, Argentina, and the United States [45], and is included on the WHO Essential Medicines List for Children [46,47].

Issues related to management of acute myocarditis are discussed further separately. (See "Chagas heart disease: Acute myocarditis", section on 'Management'.)

Issues related to treatment of chronic T. cruzi infection and Chagas disease in immunosuppressed hosts are discussed separately. (See "Chagas disease: Chronic Trypanosoma cruzi infection" and "Chagas disease in the immunosuppressed host".)

Assessing response to treatment — In the setting of acute and early congenital T. cruzi infection, treatment success can be monitored by polymerase chain reaction and IgG serology [48]. Individuals treated in the acute phase and infants treated in the first year of life generally revert to negative serology within months of completing treatment.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chagas disease".)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Chagas disease (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Transmission – Trypanosoma cruzi infection begins with an acute phase that lasts 8 to 12 weeks. T. cruzi infection is rarely detected during the acute phase, except in the context of specific screening programs (eg, congenital Chagas disease screening in maternity hospitals) or outbreaks (eg, clusters of orally transmitted infection). (See 'Transmission routes and risk groups' above.)

●Acute T. cruzi infection

•Incubation period – The incubation period following vector-borne exposure is one to two weeks, after which the acute phase of Chagas disease begins. In transfusion- and transplant-associated cases, the incubation period may be as long as four months. (See 'Clinical manifestations' above.)

•Clinical manifestations – The acute phase of T. cruzi infection lasts 8 to 12 weeks. Most patients with acute T. cruzi infection have nonspecific symptoms (such as malaise, fever, and anorexia) or are asymptomatic, so do not come to clinical attention. In a minority of patients, acute infection may be associated with inflammation and swelling at the site of inoculation; when the inoculation site is the conjunctiva, the patient may develop characteristic painless swelling of the eyelids, known as Romaña's sign (picture 1). Severe acute disease occurs in less than 1 percent of patients; manifestations may include acute myocarditis, pericardial effusion, and/or meningoencephalitis. (See 'Clinical manifestations' above.)

•Diagnosis

-When to suspect acute infection – Acute Chagas disease should be suspected in individuals who live or have recently spent significant periods of time in areas of Latin America with vector-borne transmission, especially those who lived in houses with adobe walls and/or thatched roofs. However, T. cruzi infection is rarely detected during the acute phase. (See 'Diagnosis' above.)

-Diagnostic tests – In acute T. cruzi infection, the level of parasitemia is high; motile trypomastigotes can be detected by microscopy of fresh preparations of anticoagulated blood or buffy coat (picture 2). Polymerase chain reaction (PCR) assays generally demonstrate positive results days to weeks before circulating trypomastigotes are detectable on peripheral blood smears. (See 'Diagnosis' above.)

●Congenital T. cruzi infection –

•Clinical manifestations – Most congenital Chagas infections are asymptomatic or cause nonspecific signs. Low birthweight (<2500 g), anemia, and hepatosplenomegaly are significantly more frequent among infants with congenital Chagas infection than uninfected infants. In a small proportion of patients, congenital infection causes severe morbidity, including meningoencephalitis, and/or respiratory insufficiency. (See 'Congenital Chagas disease' above.)

•Diagnosis

-When to suspect congenital infection – Congenital Chagas infection should be suspected in children born to women who have lived or spent significant periods of time in areas of Latin America with vector-borne transmission.

-Diagnostic tests – Polymerase chain reaction is used increasingly for early diagnosis of congenital Chagas disease in Latin American cities and is the method of choice in industrialized countries. The traditional technique for diagnosis of congenital T. cruzi infection consists of microscopic examination of the buffy coat layer of fresh cord or neonatal blood following centrifugation. For infants not diagnosed at birth, conventional immunoglobulin (Ig)G serology is recommended after nine months of age, when transferred maternal antibody has disappeared. (See 'Diagnosis' above.)

●Management – We recommend antitrypanosomal therapy for all patients with acute or congenital T. cruzi infection (Grade 1A). Antitrypanosomal drugs include benznidazole and nifurtimox; in general, benznidazole is better tolerated so is favored as the first-line treatment for Chagas disease. Dosing and adverse effects are outlined in the tables (table 1 and table 2). Issues related to antitrypanosomal drugs are discussed further separately. (See 'Management of acute and congenital T. cruzi infection' above and "Chagas disease: Antitrypanosomal drug therapy".)