Pathogenesis of T. cruzi The life cycle of T. cruzi is depicted in Figure 2.1 Although the true pathogenesis of Chagas disease is not fully understood, what remains incontestable is that T. cruzi invades various host cells (including macrophages, epithelial cells, and fibroblasts) and propagates as amastigotes.8 These amastigotes then give rise to pseudocysts, which are responsible for an inflammatory reaction; when the pseudocysts rupture, they cause scarring and fibrosis of the invaded cell. Ruptured pseudocysts also release non-replicative trypomastigotes that are expelled into the bloodstream. These extracellular trypomastigotes will continue to circulate and infect new cells, thus perpetuating the T. cruzi infectivity cycle.1,2,6
Vector-borne transmission is most common. Less frequent sources of Chagas disease infection include contaminated blood transfusions, in utero transmission from an infected mother to her fetus, organ transplantation from infected donors, consumption of foods contaminated with triatomine feces, accidental laboratory exposures, and venereal transmission (for example, through infected menstrual fluids or sperm, and open wounds during coitus). Although triatomine insects harboring Chagas disease have been found in the United States, the main modes of transmission in this country are organ transplantation, contaminated blood donations, and congenital transmission.2
WHO SHOULD BE SCREENED
The CDC recommends screening in the following patients:1
- symptomatic patients who have recently emigrated from or traveled to Latin America (Mexico, Central, and South America) and/or who have encountered triatomine insects
- newborns with known Chagas-infected mothers
- immediate family members of newborns recently diagnosed with Chagas disease
- symptomatic patients who have recently received a blood transfusion, undergone organ transplantation, or have become immunocompromised. (Since 2007, the FDA has screened the US blood supply using a sensitive lysate-based enzyme-linked immunosorbent assay [ELISA] screening test called the Ortho T. cruzi ELISA Test System.1)
Patients who need to be screened should be told of Chagas disease's life-threatening risk, potential maternal-fetal transmission, and high cure rates if diagnosed early.
MANIFESTATIONS OF CHAGAS DISEASE
The clinical manifestations of Chagas disease differ based on its diverse phases and forms:
- Acute phase. This phase, lasting 4 to 8 weeks, is normally asymptomatic, but may manifest as nonspecific symptoms such as fever, myalgias, headache, and fatigue that diminish with time. Physical examination signs include lymphadenopathy, swelling of the bite mark (chagoma), and mild hepatosplenomegaly. The only pathognomonic marker specific to the acute phase is Romana sign, a unilateral swelling of the eyelid caused by the insertion of T. cruzi-laden feces into the conjunctival sac.1,9 Romana sign (Figure 3) is differentiated from an allergic reaction to the vector's saliva that causes the inoculation site to become erythematous and pruritic, in addition to the edematous eyelid.1 Orbital and periorbital cellulitis may also mimic Romana sign due to similar unilateral eyelid pain and swelling. In rare cases (<5%), patients can die during the acute phase; most often, these patients are children who develop myocarditis or meningoencephalitis.1,6
- Chronic phase. After 8 to 12 weeks without treatment, Chagas disease becomes chronic, with patients remaining asymptomatic or progressing into symptomatic Chagas disease.3,6
- Indeterminate phase. This term describes the state in which a chronically infected patient remains asymptomatic despite having a positive anti-T. cruzi serology with no medical abnormalities; a normal radiological imaging of the chest, colon, and esophagus; and a normal 12-lead ECG. Due to T. cruzi's ability to remain dormant, 70% to 80% of infected patients remain in this phase for life.2
- Chagas heart disease. Cardiac complications develop in 20% to 30% of patients with chronic Chagas disease, usually within 10 to 30 years after initial infection.10 Chagas heart disease, the umbrella term for these complications, is considered the most common cause of cardiomyopathies in Latin America.10 Manifestations include conduction system abnormalities such as a right bundle-branch block, sinus node dysfunction, sustained or non-sustained ventricular tachycardia, thromboembolic phenomenon, and dilated cardiomyopathy. Long-term complications include heart failure and sudden cardiac death; these are the primary causes of death in patients with Chagas disease.
According to Tanowitz and colleagues, each year Chagas heart disease kills about 20,000 people in Latin America and 250 immigrants in the United States.3
- Chagas gastrointestinal (GI) disease. Less common than Chagas heart disease, Chagas GI disease predominately affects the esophagus and/or colon, causing either megaesophagus or megacolon. Esophageal complications include acid reflux, dysphagia, aspiration, coughing, regurgitation, and an increased risk of esophageal cancer. Colonic complications include prolonged constipation and abdominal pain.2
- Reactivated Chagas disease. A minority of patients with chronic Chagas disease become immunocompromised due to either acquiring HIV or through pharmacologic immunosuppression. This can lead to Chagas disease reactivating when the patient previously was asymptomatic. Although the frequency of reactivated Chagas disease is unclear, a cohort study conducted by Sartori and colleagues indicated that out of 53 patients coinfected with HIV and T. cruzi, 11 (21%) developed reactivated Chagas disease over a 6-year period.11 Patients on immunosuppressive therapy may manifest subcutaneous nodules, inflamed adipose tissue, weight loss, fatigue, and myocarditis. In patients with HIV infection, reactivated Chagas disease can manifest as meningioencephalitis or as central nervous system imaged nodules.2,6
- Congenital Chagas disease. In 1% to 10% of births in the United States, infected mothers transmit Chagas disease to their newborns.12 As stated by the Pan American Health Organization, each year, an estimated 2,000 neonates are infected in the United States.7 Risk factors increasing congenital transmission include younger maternal age, higher maternal parasitemia, and weak maternal immune responses to T. cruzi.6 Newborns are often asymptomatic or have manifestations such as low Apgar scores, hepatosplenomegaly, and anasarca. More severe neonatal complications include respiratory distress, cardiac failure, meningioencephalitis, and death.
The first US case of congenital Chagas disease was identified in August 2010 in an infant whose mother had recently emigrated from Latin America. The newborn was reported to have an Apgar score of 6 at 1 minute after birth, and 9 at 5 minutes; non-exudative ascites; pericardial effusion; and a pleural effusion.12
LABORATORY TESTING AND DIAGNOSIS
The diagnostic criteria of T. cruzi infection vary with disease phase.
- Acute phase diagnosis is made through microscopic examination of Giemsa-stained blood smears with fresh samples of anti-coagulated blood or buffy coat. The examination will reveal high levels of motile parasites alongside various blood cells (Figure 4).2 Regardless of treatment, the parasitemia level will decrease over 3 months, eventually becoming undetectable once the patient enters the chronic phase.
- Chronic phase diagnosis is based on serologic methods detecting specific T. cruzi antigens. These methods include immunofluorescent antibody testing and ELISA. Because both techniques have limited sensitivity and specificity, diagnosis confirmation requires at least two positive tests based on different techniques. The only FDA-approved serology tests are a lysate-based ELISA and an ELISA that uses recombinant antigens.3
- Congenital Chagas disease is diagnosed by examining Giemsa-stained smears of umbilical cord or peripheral blood at birth; detection of motile T. cruzi parasites indicates infection. Additional methods include the polymerase chain reaction (PCR) test, which has a higher sensitivity and detects congenital infections earlier then microscopy. However, a positive PCR always requires second specimen confirmation because in rare instances the extremely sensitive technique detects maternal T. cruzi DNA in uninfected newborns. Thus, PCR is used again in 4 to 6 weeks to assess changes in parasitemia.2,6
- Reactivated Chagas disease is also diagnosed through microscopic examination of blood smears for motile T. cruzi parasites.2
MANAGING CHAGAS DISEASE
Once Chagas disease is diagnosed, primary care providers can use a standard management sequence for patients. First, obtain a detailed medical history, specifically asking patients about recent travel to Latin America. During the physical examination, look for bite marks on the patient's face or Romana sign. Finally, obtain an ECG with a 30-second lead II rhythm strip and look for the previously mentioned abnormal findings such as right bundle-branch block. If this initial evaluation is normal, repeat the physical examination and ECG annually. If testing reveals cardiac manifestations suggestive of Chagas heart disease, a more extensive cardiac evaluation is required, consisting of 24-hour ambulatory ECG recording, exercise stress testing, and echocardiography. For GI manifestations, barium contrast studies may be used to assess esophageal or colonic involvement. See Table 1 for a step-by-step workup.
Because no ideal drug cures Chagas disease, treatment primarily relies on two antitrypanosomal medications, benznidazole and nifurtimox here, that are not FDA-approved and are available only on request from the CDC Drug Service (404-639-3670; after business hours, during weekends, or on federal holidays contact the CDC Emergency Operations Center at 770-488-7100).1 Drug efficacy varies depending on the patient's age, phase of the disease, dosage, and length of treatment. Peak potency is achieved in younger patients during the acute phase, initial chronic phase, and congenital infections. Drug limitations include undesirable adverse reactions and low cure rates in the chronic phase, especially in adults.13
Benznidazole, a first-line treatment for Chagas disease, covalently modifies T. cruzi DNA, proteins, and lipids through nitro reduction.13 Before starting therapy, patients should have laboratory testing including a complete blood cell (CBC) count, liver enzymes, and kidney function tests; hepatic and renal disease are contraindications to benznidazole therapy. The CBC count should be repeated every 2 to 3 weeks because of the risk of leukocytopenia.
Children experience fewer adverse drug reactions to benznidazole than adults and can tolerate higher doses. The most common adverse reactions to benznidazole are dermatitis and peripheral neuropathy. The dermatitis is characterized as a photosensitive rash occurring in 30% of patients and can be managed with a topical corticosteroid or drug discontinuation. Peripheral neuropathy is dose-dependent, seen in 30% of patients, and includes peripheral neuritis, paresthesias, and polyneuropathies. If neuropathic symptoms arise, immediate drug cessation is recommended and generally reverses the neuropathy. Other less common adverse effects include weight loss, anorexia, nausea, vomiting, insomnia, and bone marrow suppression. Because of the lack of evidence, benznidazole should not be taken during pregnancy or breast-feeding. Lastly, patients taking this drug should abstain from alcohol ingestion due to potential effects of flushing, headache, abdominal cramps, nausea, and vomiting.1,2
Nifurtimox, which has similar features to benznidazole, is considered an alternative for patients unable to take benz-nidazole. Nifurtimox causes oxidative damage to T. cruzi by producing highly toxic oxygen metabolites. Common adverse reactions, affecting 30% to 70% of patients, include anorexia, weight loss, nausea, vomiting, and abdominal discomfort. Less common adverse reactions include vertigo, mood changes, and myalgias. Central nervous system effects include insomnia, disorientation, irritability, and tremors. Nifurtimox has the same contraindications, recommendations against use during pregnancy and breast-feeding, and laboratory testing recommendations as benznidazole; discontinue the drug if the patient develops peripheral neuropathy and advise the patient to avoid alcohol during therapy.1,2,13 See Table 2 for the recommended dosages of both drugs based on patient age.1
Managing acute Chagas disease Benznidazole and nifurtimox are used to decrease and shorten symptom severity and disease course. The parasitological cure rates are estimated to range from 60% to 85% and are higher in children.2
Managing chronic Chagas disease Experts generally recommend antitrypanosomal therapy for chronically infected children under age 18 and for adults ages 19 to 50 who lack advanced Chagas-induced cardiomyopathy. For adults over age 50, therapy is considered optional due to the increased risks of drug toxicity and adverse reactions.
Before starting a patient on antitrypanosomal medications for chronic Chagas disease, consider adverse effects, overall patient health, reproductive age, lack of data showing therapeutic benefits, and the expense of using these drugs for prolonged periods of time.2
Managing Chagas heart disease The Benznidazole Evaluation for Interrupting Trypanosomiasis (BENEFIT) study is an ongoing double-blind, randomized, and placebo-controlled trial being carried out to determine the role of benznidazole in preventing progression of cardiac disease in patients with Chagas heart disease. The trial was scheduled to be complete in July 2013.14,15 Patients with advanced Chagas cardiomyopathy are unlikely to respond to antiparasitic drugs, so the focus of Chagas heart disease management relies on consultation with cardiac specialists to initiate supportive therapy.2 For instance, according to the Latin American guidelines for the management of patients with Chagas heart diseases and New York Heart Association (NYHA) Stage I or II heart failure, consider these drugs: beta-blockers, oral anticoagulants, amiodarone, nitrates, and angiotensin receptor blockers. If patients develop heart failure symptoms and progress into NYHA Stage III or IV heart failure, heart transplantation and drugs such as spironolactone, diuretics, and digitalis are recommended.3,16
Managing Chagas GI disease Surgery is frequently the only option to relieve Chagas-associated megaesophagus and megacolon. For instance, the Heller-Pinotti technique is the method adopted by Brazilian surgeons to treat Chagas-induced achalasia caused by megaesophagus; this method involves cutting along the esophagus and extending past the lower esophageal sphincter into the stomach, thus curing the achalasia. The Duhamel-Haddad technique is the surgical anastomosis method of choice used to restore continuity of the colon in patients with Chagas-induced constipation caused by megacolon.16–18
Managing congenital Chagas disease Antitrypanosomal drugs are highly effective in newborns, with cure rates greater than 90% when administered within the first year of life. Benznidazole and nifurtimox are especially well-tolerated in infants, so most clinicians recommend early treatment. The lack of pediatric formulations requires dosing discussions between providers and the pharmacy.2,12
Managing reactivated Chagas disease Although studies have shown that manifestations of reactivated Chagas disease resolve in patients treated with benznidazole, the optimal duration of therapy and practicality of prophylaxis in immunosuppressed patients has not been determined.2 Treatment with antitrypanosomal drugs usually is recommended after manifestations of Chagas disease reactivation have occurred, including skin lesions, fevers, headaches, or high levels of parasitemia revealed on microscopy in patients with known Chagas disease.
For consultation regarding the diagnostic tests, treatment, and specific dosage instructions for patients with Chagas disease based on age, contact the CDC division of parasitic diseases public inquiries line at 770-488-7775 or e-mail firstname.lastname@example.org.
CHALLENGES REQUIRING FUTURE RESEARCH
Chagas disease is a parasitic infection caused by the T. cruzi and is lifelong once the patient enters the chronic phase. Screening is indicated for symptomatic individuals who recently lived or traveled to Latin America, persons who have had contact with triatomine insects, or infants born to Chagas-infected mothers. Diagnosis is phase-dependent and made through microscopic visualization of parasitemia, serology, and PCR. The only proven Chagas disease treatment relies on antitrypanosomal drugs with low efficacies and a myriad of adverse effects. Although Chagas disease has become a growing concern in the United States, many challenges remain to halt this disease's progression and improve management of chronically infected patients. These issues include:
- vaccine development. Despite ongoing animal research studies, no vaccine exists for T. cruzi infections.3,19
- incomplete clarification of the pathogenesis of Chagas disease. Vital and unanswered questions regarding Chagas disease pathogenicity include why the majority of patients with chronic Chagas disease remain in the indeterminate form, others develop Chagas heart disease, and a few present with megacolon or megaesophagus.20,21
- no effective drug that provides shorter treatment courses, fewer adverse effects, and cures both acute and chronic phases. Because the only treatments are chemotherapy drugs with low efficacy and many adverse effects, novel antitrypanosomal medication are desperately needed.19,21
- no standardized methods to diagnose, determine disease progression, and monitor treatment response. Without such standardization, the disease will evolve into a larger American healthcare burden.19,21
- lack of US health policy to prioritize Chagas disease and develop strategies for control and elimination. For two decades, the CDC has participated in global efforts to develop insecticides for triatomine insect control, promote standardized testing, and implement screening strategies to identify infected children. However, current US health policies are still lacking in their ability to control Chagas disease progression.1,7
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3. Tanowitz HB, Machado FS, Jelicks LA, et al. Perspectives on Trypanosoma cruzi
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). Prog Cardiovasc Dis
4. Bern C, Montgomery S. An estimate of the burden of Chagas disease
in the United States. Division of Parasitic Diseases, National Center for Zoonotic, Vector-Borne and Enteric Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia. 2009:49(1 September).
5. Reisenman CE, Lawrence G, Guerenstein PG, et al. Infection of kissing bugs with Trypanosoma cruzi
, Tucson, Arizona, USA. Emerging Infectious Diseases
6. Bern C, Kjos S, Yabsley MJ, Montgomery SP.. Trypanosoma cruzi
and Chagas disease
in the United States. Clin Microbiol Rev
7. Hotez PJ, Dumonteil E, Woc-Colburn L, et al. Chagas disease
: the new HIV/AIDS of the Americas. PLoS Neglect Trop Dis
8. de Souza W, de Carvalho TM, Barrias ES. Review on Trypanosoma cruzi
: host cell interaction. Int J Cell Biol
. 2010. ePub 2010 July 29.
9. Hemmige V, Tanowitz H, Sethi A. Trypanosoma cruzi
infection: a review with emphasis on cutaneous manifestations. Int J Dermatol
10. Cortez H, et al. Emerging and under-recognized Chagas cardiomyopathy in non-endemic countries. World J Cardiol
11. Sartori AM, Ibrahim KY, Nunes Westphalen EV, et al. Manifestations of Chagas disease
) in patients with HIV/AIDS. Ann Trop Med Parasitol
12. Centers for Disease Control and Prevention. Morbidity and Mortality Weekly Report. Congenital transmission of Chagas disease
13. Alviano DS, Barreto AL, Dias Fde A, et al.. Conventional therapy and promising plant-derived compounds against trypanosomatid parasites. Front Microbiol
14. Marin-Neto JA, Rassi A Jr, Avezum A Jr, et al. BENEFIT Investigators. The BENEFIT trial: testing the hypothesis that trypanocidal therapy is beneficial for patients with chronic Chagas heart disease. Mem Inst Oswaldo Cruz
. 2009;104(Suppl I): 319–324.
16. Lopes LR, Braga Nda S, Oliveira GC, et al. Results of the surgical treatment of non-advanced megaesophagus using Heller-Pinotti's surgery: laparotomy vs. laparoscopy. Clinics (Sao Paulo)
17. Pallisera A, Ortiz-de-Z???rate L, Moral A, et al. Chagas disease
in the differential diagnosis of megacolon [letter]. Revista Espanola De Enfermedades Digestivas
18. Gomes de Silva R, Can???ado HR, da Luz MM, et al. Morbidity and mortality assessment of modified Duhamel operation with immediate mechanical end-to-side colorectal anastomosis for chagasic megacolon: the role of the diverting stoma [letter]. Int J Colorectal Dis
19. Lannes-Vieira J, de Araújo-Jorge TC, Soeiro Mde N, et al. The centennial of the discovery of Chagas disease
: facing the current challenges. PLoS Neglect Trop Dis
20. Coura J. Chagas disease
: what is known and what is needed—a background article. Mem Inst Oswaldo Cruz
21. Coura J, Borges-Pereira J. Chagas disease
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22. Maguire JH, Hoff R, Sherlock I, et al. Cardiac morbidity and mortality due to Chagas disease
: prospective electrocardiographic study of a Brazilian community. Circulation
23. Maguire JH, Mott KE, Souza JA, et al. Electrocardiographic classification and abbreviated lead system for population based studies of Chagas disease
. Bull Pan Am Health Organ
24. Lazzari JO, Pereira M, Antunes CM, et al.. Diagnostic electrocardiography in epidemiological studies of Chagas disease
: multicenter evaluation of a standardized method. Rev Panam Salud Publica
Keywords:© 2013 American Academy of Physician Assistants.
Chagas disease; trypanosomiasis; myocarditis; benznidazole; nifurtimox