Annals of Internal MedicineT

In the ClinicT

Chagas Disease
C
hagas disease, which is caused by infection
with the parasite Trypanosoma cruzi, is a
leading neglected tropical disease in the
United States. An estimated 240 000 to 350 000 Risk Factors and Causes
persons in the United States are infected, primarily
immigrants from Mexico, Central America, and
South America, where the disease is endemic. The Diagnosis
parasite is transmitted by the triatomine bug but
can also be passed through blood transfusion, via Treatment
organ transplant, or congenitally. Approximately
30% of infected persons later develop cardiac
and/or gastrointestinal complications. Health care Practice Improvement
providers should consider screening at-risk patients
with serologic testing. Early diagnosis and treatment
with benznidazole or nifurtimox can help prevent
complications.

CME/MOC activity available at Annals.org.

Physician Writers doi:10.7326/AITC202302210

Natasha S. Hochberg, MD, MPH
Susan P. Montgomery, DVM, MPH This article was published at Annals.org on 14 February 2023.
Boston University School of CME Objective: To review current evidence for risk factors, causes, diagnosis,
Medicine, Boston University treatment, and practice improvement of Chagas disease.
School of Public Health, and
Boston Medical Center, Boston, Funding Source: American College of Physicians.
Massachusetts (N.S.H.) Disclosures: All relevant financial relationships have been mitigated. Disclosures
Parasitic Diseases Branch, Centers can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.
for Disease Control and Prevention, do?msNum=M22-1848.
Atlanta, Georgia (S.P.M.)
Disclaimer: The findings and conclusions in this article are those of the authors
and do not necessarily represent the views of the Centers for Disease Control and
Prevention.

With the assistance of additional physician writers, the editors of Annals of

Internal Medicine develop In the Clinic using MKSAP and other resources of
the American College of Physicians.
In the Clinic does not necessarily represent official ACP clinical policy. For ACP
clinical guidelines, please go to https://www.acponline.org/clinical_information/
guidelines/.
© 2023 American College of Physicians

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 Chagas disease, also known as American in 2010 (3). About 1.2 million persons
trypanosomiasis, is a leading cause of are affected by Chagas cardiomyopathy,
parasitic infection in the United States, and up to 12 000 deaths are estimated
with an estimated 240 000 to 350 000 to be caused by Chagas disease each
1. Manne-Goehler J, Umeh cases (1, 2). In Latin America, an esti- year (4, 5), mostly due to severe cardiac
CA, Montgomery SP, et al.
Estimating the burden of mated 5.7 million people were infected complications (6–9).
Chagas disease in the
United States. PLoS Negl
Trop Dis. 2016;10:
e0005033. [PMID:
27820837]
2. Bern C, Messenger LA,
Risk Factors and Causes
Whitman JD, et al. Chagas How is Chagas disease transmitted? after feeding, thereby increasing the likeli-
disease in the United
States: a public health
Chagas disease is caused by infection hood of transmission.
approach. Clin Microbiol
Rev. 2019;33. [PMID: with Trypanosoma cruzi. This hemofla- Vector-borne transmission occurs only
31776135]
3. Chagas disease in Latin gellate protozoan parasite was discov- in the mainland parts of Mexico,
America: an
epidemiological update ered in 1909 by Carlos Chagas, for Central America, and South America.
based on 2010 estimates.
Wkly Epidemiol Rec.
whom the disease is named (10). There There are rare reports of local transmis-
2015;90:33-43. [PMID: are 6 distinct lineages of T cruzi classi- sion in the United States, mostly based
25671846]
4. Perez-Molina JA, Molina I. fied into discrete typing units (TcI to on investigations of blood donors with
Chagas disease. Lancet.
2018;391:82-94. [PMID:
TcVI) and a potential seventh bat-asso- positive screening results (14). Distri-
28673423] ciated genotype; these vary in their ge- bution of infected persons is expanding
5. Moncayo A, Silveira AC.
Current epidemiological ographic distribution, host preference, to nonendemic regions, including Europe,
trends for Chagas disease and clinical manifestations (11, 12).
in Latin America and future
due to population movement, and there
challenges in epidemiol- are many reported cases in Spain among
ogy, surveillance and
health policy. Mem Inst
Triatomine bugs are the primary vector Bolivian migrants (15). Even if migrants
Oswaldo Cruz. 2009;104 (4, 6). They are also known as kissing are from a nonendemic country (such as
Suppl 1:17-30. [PMID:
19753454] bugs, cone-nosed bugs, and blood Haiti), providers should consider the mi-
6. Bern C. Chagas' disease.
N Engl J Med. 2015;373:
suckers and have many names in gration route of individual patients, as
456-66. [PMID: 26222561] endemic countries, such as vinchuca, they may have spent time in endemic
7. Bestetti RB, Bocchi EA,
Bestetti R, et al. chinche, or barbeiros. Providers should countries en route to their destination.
Management of cardiovas-
cular disease in patients
familiarize themselves with these local The countries with the highest estimated
with COVID-19 and chronic names to facilitate communication prevalence include Bolivia, Argentina,
Chagas disease: implica-
tions to prevent a scourge about potential exposure with patients. Paraguay, Ecuador, El Salvador, and
still larger. Front Med
(Lausanne). 2022;9: An example of a triatomine, Triatoma Guatemala (3). A map of Chagas disease
910388. [PMID:
35847824]
sanguisuga, is shown in Figure 1 (13). vector transmission can be found at the
8. Rassi A Jr, Rassi A, Triatomine bugs vary in size and appear- Pan American Health Organization (PAHO)
Marcondes de Rezende J.
American trypanosomiasis ance, but they are generally dark in color website (16).
(Chagas disease). Infect Dis
Clin North Am. 2012;26:
with light abdominal stripes, and adults
275-91. [PMID: 22632639] are typically 1.3 to 3.8 cm long. Providers Less commonly, transmission can occur
9. Perez-Molina JA, Perez AM,
can ask about potential exposures, via blood transfusion. Risk for transmis-
Norman FF, et al. Old and
new challenges in Chagas including if the patient has noticed bugs sion varies by blood component, with
disease. Lancet Infect Dis. estimates ranging from 10% to 25% for
2015;15:1347-56. [PMID: similar to this inside their home, if the
26231478]
patient lives in a rustic rural home made whole blood or platelet transfusion (17,
10. Chagas C. Nova
tripanozomiaze humana: 18). Screening of the U.S. blood supply
estudos sobre a morfolojia e
from mud, or if the patient's home has a
became widespread starting in 2007
o ciclo evolutivo do thatched roof or walls or a roof with no-
Schizotrypanum cruzi n. and was nationwide by 2012 (17) after
gen., n. sp., ajente etiolojico ticeable cracks. The vectors generally
de nova entidade morbida the U.S. Food and Drug Administration
become active at night, feeding on
do homem. Mem Inst
(FDA) issued final guidance on recom-
Oswaldo Cruz. 1909;1: human and animal blood by biting an
159-218. mended donor screening (19). Blood cen-
11. Zingales B, Andrade SG, exposed area of skin or mucous mem-
Briones MR, et al.; ters reported screening results from 2007
Second Satellite Meeting branes (such as the lips or eyes). The bug
to 2019, with 2462 donors having positive
A new consensus for defecates near the bite, and feces of
Trypanosoma cruzi intraspe- results on FDA-approved tests (20).
cific nomenclature: second infected bugs allows for passage of the
revision meeting recom-
mends TcI to TcVI. Mem Inst parasite through breaks in the skin or Vertical transmission may occur from a
Oswaldo Cruz.
2009;104:1051-4. [PMID:
conjunctiva. Some species are particularly mother to a fetus. A systematic review
20027478] known for rapidly defecating during or of data on congenital transmission found

© 2023 American College of Physicians ITC18 In the Clinic Annals of Internal Medicine February 2023

Downloaded from https://annals.org by Camilo Duque on 04/08/2023.

 such as fever, lymphadenopathy, and
Figure 1. Triatoma sanguisuga.
hepatosplenomegaly (Table 1). Regard-
less of the route of transmission, severe 12. Marcili A, Lima L,
manifestations include myocarditis and Cavazzana M, et al. A new
genotype of Trypanosoma
encephalitis; severity of disease is likely cruzi associated with bats
evidenced by phyloge-
related to parasite burden. Most acute netic analyses using SSU
infections go unrecognized and are rDNA, cytochrome b and
Histone H2B genes and
rarely diagnosed (4, 6, 8). genotyping based on ITS1
rDNA. Parasitology.
2009;136:641-55.
If there are symptoms, onset is typically [PMID: 19368741]
7 to 14 days after infection via vector- 13. Centers for Disease
Control and Prevention.
borne transmission. A firm swelling Triatomine Bug FAQs.
Updated 13 April 2022.
(chagoma) associated with local inflam- 14. Cantey PT, Stramer SL,
Courtesy of James Gathany and the Centers for mation may develop at the site of para- Townsend RL, et al. The
United States Trypanosoma
Disease Control and Prevention. site entry into the body (29) (Figure 2). cruzi Infection Study: evi-
dence for vector-borne trans-
that it occurred in 4.7% (95% CI, The chagoma may persist for weeks. mission of the parasite that
3.9% to 5.6%) of infants born to infec- When inoculation occurs through the causes Chagas disease
among United States blood
ted pregnant women (21). Another sys- conjunctiva or a break in the skin close donors. Transfusion.
2012;52:1922-30. [PMID:
tematic review found that higher maternal to the eye, the resulting chagoma is 22404755]
known as the Romaña sign, which is 15. Perez-Ayala A, Perez-
parasitic loads were associated with Molina JA, Norman F, et
greater risk for vertical transmission defined as unilateral swelling of the al. Chagas disease in
Latin American migrants:
(22). One study conducted at a single palpebrae and periocular tissue (30). a Spanish challenge. Clin
hospital suggested that cesarean sec- Severe acute disease is rare and is Microbiol Infect.
2011;17:1108-13.
tion protects against congenital trans- more likely to occur in young children [PMID: 21073628]
16. Pan American Health
mission, but this association may reflect and older adults. Organization. Vector
Borne Diseases (VBD) in
socioeconomic factors and requires fur- Congenitally acquired acute infections the Region of the
ther study (23). The risk for transmission Americas. 2022.
also are generally clinically silent. In the 17. Bern C, Montgomery SP,
through breastfeeding has not been well approximately 10% to 40% of infected Katz L, et al. Chagas dis-
ease and the US blood
evaluated (24). newborns with illness, manifestations supply. Curr Opin Infect
Dis. 2008;21:476-82.
include low birthweight and prematur- [PMID: 18725796]
Transmission may also occur via solid 18. Cancino-Faure B, Fisa R,
ity with low Apgar scores. Hepato-
organ or bone marrow transplant. Donor- Riera C, et al. Evidence of
megaly with or without splenomegaly meaningful levels of
derived infection rates are highest for Trypanosoma cruzi in pla-
is commonly reported (31, 32). Two telet concentrates from
transplant of infected hearts (up to 75%), seropositive blood
cases of congenital infection were diag-
followed by livers and kidneys (0% to donors. Transfusion.
nosed in the United States in 2010 and 2015;55:1249-55.
19%) (25). Transmission has also been [PMID: 25683267]
2015; both infants were born to immi- 19. U.S. Department of
reported due to laboratory accident after Health and Human
grant mothers and had hydrops fetalis, Services; U.S. Food and
unintentional inoculation with a needle
a severe manifestation of congenital Drug Administration;
contaminated with T cruzi (26). Center for Biologics
infection (33, 34). Evaluation and Research.
Use of Serological Tests to
Sporadic outbreaks have occurred due In documented outbreaks of food- Reduce the Risk of
Transmission of
to oral transmission via uncooked food borne Chagas disease, symptomatic Trypanosoma cruzi
or water contaminated with infected tria- acute infections typically had faster Infection in Blood and
Blood Components.
tomine vectors. Ten outbreaks of orally onset and a more severe clinical course Guidance for Industry.
December 2017.
transmitted acute Chagas disease with attributed to the amount of infectious 20. Centers for Disease
249 cases and 10 deaths were reported parasite ingested (28, 35). Control and Prevention
(CDC) Blood donor
in Venezuela between 2007 and 2014 screening for Chagas
(27), and 776 cases of orally transmitted What are the different presentations disease—United States,
2006-2007. MMWR Morb
acute Chagas disease were reported in of chronic Chagas disease? Mortal Wkly Rep.
2007;56:141-3. [PMID:
Brazil between 2000 and 2010 (3, 28). If untreated, T cruzi infection is lifelong. 17318113]
Most patients present after acute infec- 21. Howard EJ, Xiong X,
Carlier Y, et al. Frequency
What are the signs and symptoms of tion has transitioned to chronic infection of the congenital trans-
acute Chagas disease? and are asymptomatic, in what is mission of Trypanosoma
cruzi: a systematic review
Most acute infections are asymptomatic or considered the indeterminate form and meta-analysis. BJOG.
2014;121:22-33. [PMID:
present with nonspecific manifestations, of chronic Chagas disease (Table 1). 23924273]

February 2023 Annals of Internal Medicine In the Clinic ITC19 © 2023 American College of Physicians

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 Table 1. Symptoms and Signs of Different Manifestations of Chagas Disease
Stage Symptoms and Signs on Physical Examination Potential Radiographic and Cardiac Findings
Acute Often asymptomatic with normal physical Evidence of myocarditis on electrocardio-
examination findings gram and echocardiogram (rare)
May have chagoma, fever, lymphadenop-
athy, or hepatosplenomegaly
Myocarditis or encephalitis (rare)
Congenital Often asymptomatic with normal physical —
examination findings
May have low birthweight, prematurity,
low Apgar scores, hepatomegaly, or
splenomegaly
Hydrops fetalis (rare)
Indeterminate Asymptomatic (no signs on physical Normal
examination)
Chronic (cardiac) Symptoms include palpitations, lighthead- Electrocardiogram: Conduction system
edness, chest pain, symptoms of heart abnormalities, including right bundle
failure (e.g., peripheral edema, orthopnea) branch block, left anterior fascicular block,
Physical examination may show irregular car- bifascicular block, first-degree atrioventric-
diac rhythm, signs of heart failure or stroke ular block, ventricular premature beats,
atrial fibrillation, bradyarrhythmia, tachyar-
rhythmia (e.g., atrial fibrillation, ventricular
tachycardia)
Echocardiogram: Regional wall motion
abnormalities, dilated cardiomyopathy,
reduced ejection fraction, apical aneurysm
Chronic (gastrointestinal) Symptoms include abdominal pain, dys- Barium swallow, barium edema, chest/
phagia, odynophagia, regurgitation, and abdominal CT scan: Megaesophagus or
constipation megacolon
Signs include weight loss
Symptoms of colonic torsion (rare)
Reactivation (patients with Symptoms and signs of May have central nervous system lesions on
HIV) meningoencephalitis imaging (CT, MRI)
Reactivation (transplant recipi- Cutaneous nodules, myocarditis, Echocardiogram may show myocarditis
ents, immunosuppressed meningoencephalitis
patients)

CT = computed tomography; MRI = magnetic resonance imaging.

22. Klein MD, Proaño A, Chronic infections are asymptomatic cardiography may reveal subtle wall
Noazin S, et al. Risk fac-
tors for vertical transmis- for years to decades, and most remain motion abnormalities. These changes
sion of Chagas disease: a
asymptomatic through the remainder of may be present in the absence of
systematic review and
meta-analysis. Int J Infect the untreated patient's life (6). Provider symptoms, but symptoms develop as
Dis. 2021;105:357-73.
[PMID: 33618005] awareness is critical for timely diagnosis the dilated cardiomyopathy typically
23. Klein MD, Tinajeros F, Del
and treatment of patients with chronic progresses through New York Heart
Carmen Menduiña M, et
Association functional classes I to IV.
al. Risk factors for mater- indeterminate Chagas disease, with the
nal Chagas disease and Chagas cardiomyopathy can cause
vertical transmission in a goal of preventing progression to car- stroke, heart failure, thromboembolic
Bolivian hospital. Clin
Infect Dis. 2021;73: diac and/or gastrointestinal disease. events, and death; heart failure, stroke,
e2450-e2456. [PMID:
33367656]
Diagnosis and treatment also are impor- and sudden death are frequently
24. Norman FF, López-Velez tant to prevent possible transmission reported as causes of death among
R. Chagas disease and
breast-feeding. Emerg through blood donation; via organ patients with Chagas disease (36).
Infect Dis. 2013;19:1561-
6. [PMID: 24050257]
donation; or, for women, congenitally Chronic Chagas disease should be
25. Pierrotti LC, Carvalho NB, to unborn children. considered in patients originally from
Amorin JP, et al. Chagas endemic areas of continental Latin
disease recommendations
for solid-organ transplant In approximately 30% of chronically America who present with nonische-
recipients and donors. infected patients, Chagas cardiomyop- mic cardiomyopathy.
Transplantation.
2018;102:S1-S7. [PMID: athy develops after years to decades
29381572]
(36). Conduction system abnormalities Less frequently, chronic infections can
26. Hofflin JM, Sadler RH,
Araujo FG, et al. (for example, right bundle branch present with gastrointestinal manifesta-
Laboratory-acquired
Chagas disease. Trans R block, left anterior fascicular block, or tions (37). As with cardiac disease, gas-
Soc Trop Med Hyg.
1987;81:437-40. [PMID:
ventricular premature beats) are the trointestinal symptoms develop years to
3120369] earliest clinical manifestations; echo- decades after infection in approximately

© 2023 American College of Physicians ITC20 In the Clinic Annals of Internal Medicine February 2023

Downloaded from https://annals.org by Camilo Duque on 04/08/2023.

 Which adults in the United States are 27. Noya BA, Díaz-Bello Z,
Figure 2. Image of a traveler returning from an Colmenares C, et al.
endemic country with the Romaña sign, a man- at risk for acute and chronic Chagas Update on oral Chagas
disease outbreaks in
ifestation of acute Chagas disease. disease? Venezuela: epidemiologi-
cal, clinical and diagnostic
In the United States, the majority of approaches. Mem Inst
infected persons are of Latin American Oswaldo Cruz. 2015;110:
377-86. [PMID: 25946155]
origin, have acquired infection in their 28. Shikanai-Yasuda MA,
Carvalho NB. Oral trans-
home countries, and have chronic mission of Chagas dis-
Chagas disease. Due to migration of ease. Clin Infect Dis.
2012;54:845-52. [PMID:
infected persons, prevalence is also 22238161]
29. Carter YL, Juliano JJ,
increasing in other nonendemic regions Montgomery SP, et al.
and countries, including Europe, Canada, Acute Chagas disease in a
returning traveler. Am J
Japan, and Australia. In Spain, an esti- Trop Med Hyg.
2012;87:1038-40.
mated 47 000 to 67 000 Latin American [PMID: 23091192]
immigrants are seropositive for T cruzi 30. Hemmige V, Tanowitz H,
Sethi A. Trypanosoma
infection, with the majority originating cruzi infection: a review
with emphasis on cutane-
from Bolivia, Ecuador, Argentina, and ous manifestations. Int J
Paraguay (38). The actual incidence and Dermatol. 2012;51:501-
8. [PMID: 22515575]
prevalence in the United States are 31. Messenger LA, Bern C.
Congenital Chagas dis-
unclear because diagnostic testing is ease: current diagnostics,
rarely performed and there are no popu- limitations and future per-
spectives. Curr Opin Infect
lation-level studies. Based on the number Dis. 2018;31:415-21.
[PMID: 30095485]
of immigrants from endemic countries 32. Edwards MS, Stimpert KK,
and the prevalence of Chagas disease in Bialek SR, et al.
Evaluation and manage-
those countries, an estimated 240 000 to ment of congenital
Chagas disease in the
Used with permission of the American Journal 350 000 persons are seropositive for United States. J Pediatric
of Tropical Medicine and Hygiene. From Carter T cruzi infection in the United States (1). Infect Dis Soc.
2019;8:461-9. [PMID:
YL, Juliano JJ, Montgomery SP, et al. Acute 31016324]
Chagas disease in a returning traveler. Am J Trop Risk factors for infection include a pro- 33. Centers for Disease
Med Hyg. 2012;87:1038-40. Permission conveyed Control and Prevention
longed stay in endemic areas, particu- (CDC) Congenital
through Copyright Clearance Center, Inc.
larly in rural areas with poor housing transmission of Chagas
disease—Virginia, 2010.
10% of chronically infected patients. (4). Cases of acute infection after short- MMWR Morb Mortal
Wkly Rep. 2012;61:477-
Patients can have both gastrointestinal term travel are extremely rare, with an 9. [PMID: 22763884]
and cardiac disease due to T cruzi infec- estimate of 0.8 case per 1000 travel 34. Alarcón A, Morgan M,
Montgomery SP, et al.
tion, although this is rare. Symptoms of days reported among 79 previously Diagnosis and treatment
of congenital Chagas dis-
gastrointestinal Chagas disease result uninfected travelers who traveled to ease in a premature

from parasite-caused damage to esoph- their endemic countries of origin, pri- infant. J Pediatric Infect
Dis Soc. 2016;5:e28-e31.
ageal and/or colonic mural neurons and marily to visit friends and relatives (39). [PMID: 27466398]
35. Alarcón de Noya B, Díaz-
resultant motility disruption. Patients may There is 1 report of acute Chagas dis- Bello Z, Colmenares C, et

report chest and/or abdominal pain, dif- ease in a traveler returning to the al. Large urban outbreak
of orally acquired acute
ficulty swallowing, or constipation. In United States from Costa Rica (29). A Chagas disease at a
school in Caracas,
advanced stages, megaesophagus and/ family history of Chagas disease sug- Venezuela. J Infect Dis.
gests increased risk; one study found a 2010;201:1308-15.
or megacolon develop. Manifestations [PMID: 20307205]
prevalence of 7.4% among persons 36. Nunes MCP, Beaton A,
include dysphagia, odynophagia, re- Acquatella H, et al.;
with a family history of Chagas disease
gurgitation, aspiration, and weight American Heart
(40). To date, at least 100 cases of locally Association Rheumatic
loss for esophageal involvement and Fever, Endocarditis and
acquired infection have been docu- Kawasaki Disease
severe constipation, fecaloma, colonic Committee of the Council
mented in the United States, with modes
torsion, and bowel ischemia for colonic on Cardiovascular Disease
of transmission including triatomine vec- in the Young; Council on
involvement. Providers should consider Cardiovascular and Stroke
tors, blood transfusion, and organ trans- Nursing; and Stroke
chronic Chagas disease in patients origi- Council Chagas cardiomy-
plant (1, 41, 42).
nally from endemic areas who present opathy: an update of cur-
rent clinical knowledge
with megaesophagus or megacolon. If The diagnosis should also be consid- and management: a sci-
entific statement from the
they are diagnosed with Chagas dis- ered in persons with other potential American Heart
ease, cardiac evaluation should also be sources of infection, including expo- Association. Circulation.
2018;138:e169-e209.
performed. sure to a triatomine, having an infected [PMID: 30354432]

February 2023 Annals of Internal Medicine In the Clinic ITC21 © 2023 American College of Physicians

Downloaded from https://annals.org by Camilo Duque on 04/08/2023.

 mother, and exposure to blood conta- screening of potential transplant donors
minated with the parasite in a labora- who were born in endemic regions and
tory or health care setting. Transfusion- recommends testing and, if indicated,
associated infection is extremely rare in treatment of recipients of organs from
the United States due to routine screen- infected donors (46).
ing of the blood supply. Infection asso-
For laboratory personnel who handle
ciated with organ transplant has been
blood from T cruzi–infected patients,
reported but is uncommon, possibly
T cruzi cultures, or T cruzi–infected triato-
due to increasing implementation of
37. Pinazo MJ, Cañas E,
mines, particularly in endemic countries,
organ donor screening.
Elizalde JI, et al. some experts recommend testing them
Diagnosis, management
and treatment of chronic What are strategies for prevention of yearly for infection and providing tech-
Chagas' gastrointestinal
disease in areas where acute Chagas disease? nical training and personal protective
Trypanosoma cruzi infec- Screening and preventive measures for equipment to avoid exposure. If expo-
tion is not endemic.
Gastroenterol Hepatol. Chagas disease include primary pre- sure occurs, local disinfection, testing,
2010;33:191-200. [PMID:
19837482] vention (measures to prevent infection and (if indicated) antiparasitic treatment
38. Gascon J, Bern C, Pinazo
in naive hosts). Preventive measures are recommended (47). No vaccine is
MJ. Chagas disease in
Spain, the United States center around vector avoidance in currently available, but several candidates
and other non-endemic
countries. Acta Trop. endemic countries. Strategies include that protect against disease but not infec-
2010;115:22-7. [PMID:
applying insecticides in and around tion are in development (48).
19646412]
39. Sánchez-Montalvá A, houses, improving home construction What is the role of screening in
Salinas C, Sullerio E, et al.
Risk of Trypanosoma cruzi to reduce triatomine infestation, using prevention of chronic Chagas disease?
infection among travellers
visiting friends and rela- bed nets at night to reduce exposure, Screening for Chagas disease also allows
tives to continental Latin and preparing and storing food prop- for secondary prevention (preventing pro-
America. PLoS Negl Trop
Dis. 2021;15:e0009528. erly to prevent contamination with gression in chronically infected persons).
[PMID: 34214087]
40. Hernandez S, Forsyth CJ, infected vectors (43). Detection of new or longer-standing infec-
Flores CA, et al.
Prevalence of Chagas dis- Measures for primary prevention also tions through screening allows for provi-
ease among family mem-
bers of previously include preventing infection in new- sion of antiparasitic therapy that may
diagnosed patients in Los
borns as well as blood, organ, or bone prevent development of Chagas cardio-
Angeles, California. Clin
Infect Dis. 2019;69:1226- marrow recipients. Recommendations myopathy and allows for initiation of
8. [PMID: 31220221]
41. Hernandez S, Flores CA, issued by a group of U.S. experts in Chagas-specific symptomatic treatment.
Viana GM, et al.
2021 strongly suggested screening Recommendations issued by a group of
Autochthonous transmis-
sion of Trypanosoma cruzi women of childbearing age who have U.S. experts in 2021 suggested screening
in southern California.
Open Forum Infect Dis. lived in endemic countries to prevent persons who were born or who lived for a
2016;3:ofw227. [PMID:
neonatal transmission, based on prolonged period (>6 months) in ende-
28018928]
42. Lynn MK, Bossak BH, moderate-quality evidence (44). A World mic countries (strong recommendation
Sandifer PA, et al.
Contemporary autochtho- Health Organization (WHO) technical based on low-quality evidence), first-degree
nous human Chagas dis-
group further recommended screening relatives of persons diagnosed with Chagas
ease in the USA. Acta
Trop. 2020;205:105361.
girls (before fertile age) and women disease (strong recommendation based on
[PMID: 32006523]
43. World Health Organization. (especially pregnant women) to identify low-quality evidence), and those with docu-
Chagas disease (also
those who are at risk for transmitting mented exposure to triatomines during
known as American
trypanosomiasis). World
infection to the fetus, including those travel or in states with known transmission-
Health Organization;
2021. who live in, those who were born in, and capable triatomines (conditional recommen-
44. Forsyth CJ, Manne-
those who previously lived in disease- dation based on low-quality evidence) (44).
Goehler J, Bern C, et al.
Recommendations for
endemic areas (45) (Box: Consi- The WHO also recommends screening
screening and diagnosis
of Chagas disease in the derations for Who Should Be Screened organ and tissue recipients who are at risk
United States. J Infect Dis.
and Tested for Chagas Disease in the for reactivation and neonates and children
2022;225:1601-10.
[PMID: 34623435] born to infected, untreated mothers (43).
45. Carlier Y, Torrico F, Sosa- United States).
Estani S, et al. Congenital The WHO recommendation to screen girls
Chagas disease: recom- The WHO recommends screening blood (before fertile age) and women (especially
mendations for diagnosis,
treatment and control of donors as well as organ and tissue pregnant women) also serves as secondary
newborns, siblings and
pregnant women. PLoS donors in endemic areas (43), and prevention to identify chronic infection and
Negl Trop Dis. 2011;5:
e1250. [PMID:
the FDA also recommends screening prevent progression to clinically apparent
22039554] blood donors (19). Experts recommend disease (45).

© 2023 American College of Physicians ITC22 In the Clinic Annals of Internal Medicine February 2023

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 Considerations for Who Should Be Screened and Tested for Chagas Disease in the United States*
Perform Screening
• Persons who were born or who lived for >6 mo in endemic areas (Mexico, Central America, South America), especially
women of childbearing age and HIV-infected persons
• First-degree relatives of persons diagnosed with Chagas disease, especially neonates and children born to infected,
untreated mothers
• Blood donors who have lived in endemic countries
• Organ and tissue donors and recipients who have lived in endemic countries
• Recipients of organs transplanted from infected donors
• Laboratory personnel who handle blood from infected patients, T cruzi cultures, or triatomines
Consider Screening
• Those with documented exposure to triatomines during travel or in states with known transmission-capable triatomines
Clinical Conditions That Warrant Diagnostic Testing in Persons From Endemic Countries
• Electrocardiographic or echocardiographic abnormalities that suggest infection (see Table 1)
• Evidence of thromboembolic phenomenon
• Symptoms or signs of gastrointestinal disease (see Table 1)
* From reference 45.

In the United States, the guidelines on infected person with epidemiologic

opportunistic infections from the Centers risk factors for T cruzi infection (49).
for Disease Control and Prevention Screening of blood donors can also be
(CDC), the National Institutes of Health used for secondary prevention because
46. La Hoz RM, Morris MI;
(NIH), and the Infectious Diseases donors with reactive screening results Infectious Diseases
Community of Practice of
Society of America (IDSA) include a are directed to consult their health care the American Society of
recommendation to screen any HIV- provider. Transplantation Tissue
and blood protozoa
including toxoplasmosis,
Chagas disease, leishma-
niasis, Babesia,
Risk Factors and Causes... Chagas disease is endemic in the mainland parts of Acanthamoeba,
Mexico, Central America, and South America, and approximately 240 000 to 350 000 Balamuthia, and
Naegleria in solid organ
persons living in the United States are infected. Providers should consider screening transplant recipients—
persons who were born or who lived for a prolonged period (>6 months) in endemic guidelines from the
countries and first-degree relatives of persons diagnosed with Chagas disease. Infection American Society of
Transplantation Infectious
can occur congenitally or after blood transfusion (although this is rare due to routine Diseases Community of
screening in the United States) or organ transplant. Practice. Clin Transplant.
2019;33:e13546. [PMID:
30900295]
47. Wooley DP, Byers KB.
CLINICAL BOTTOM LINE Protozoa and helminths.
In: Wooley DP, Byers KB,
eds. Biological Safety:
Principles and Practices,
5th Edition. ASM Pr;
2017.
48. Beaumier CM, Gillespie
Diagnosis PM, Strych U, et al. Status
of vaccine research and
How is acute Chagas disease mastigotes in peripheral blood. Testing development of vaccines
for Chagas disease.
diagnosed? should be timed for after the incubation Vaccine. 2016;34:2996-
3000. [PMID: 27026146]
period, when detectable parasitemia 49. Clinicalinfo. Guidelines
Patient history and clinical suspicion for the Prevention and
would be expected. Microscopic exami-
are critical to diagnosis of acute Chagas Treatment of
nation of Giemsa-stained blood smears Opportunistic Infections
disease. History of exposure to triato- in Adults and Adolescents
mine vectors in endemic regions, either or fresh buffy coat preparations to iden- with HIV. 2021.
50. Nunes MCP, Badano LP,
directly or through contamination of tify trypomastigotes can be performed Marin-Neto JA, et al.
Multimodality imaging
food or drink, is suggestive (4, 6). (2). Molecular testing using polymerase evaluation of Chagas dis-
Congenital Chagas disease should be chain reaction (PCR) detects parasite ease: an expert consensus
of Brazilian Cardiovascular
considered in infants born to mothers DNA and is more sensitive, although Imaging Department
(DIC) and the European
with confirmed infection (21). availability is limited. The differential Association of
Cardiovascular Imaging
diagnosis for acute Chagas disease (EACVI). Eur Heart J
Diagnosis of acute Chagas disease is includes other causes of nonspecific Cardiovasc Imaging.
2018;19:459-460n.
made by testing for T cruzi trypo- febrile syndromes. The Romaña sign is [PMID: 29029074]

February 2023 Annals of Internal Medicine In the Clinic ITC23 © 2023 American College of Physicians

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 a less common sign of acute Chagas peripheral blood because the parasite
disease, and other causes of periorbital is not consistently found in the blood.
or preseptal cellulitis should be consid- In the United States, many patients with
51. Whitman JD, Bulman CA,
ered, including bacterial sinus infections asymptomatic Chagas disease are first
Gunderson EL, et al.
Chagas disease serologi- and viral infections causing swelling of flagged through blood donor screen-
cal test performance in U. ing for T cruzi–specific antibodies.
S. blood donor speci- the eyelids or conjunctivitis. T cruzi–
mens. J Clin Microbiol. Currently, 3 tests are FDA-approved
2019;57. [PMID: specific antibody develops within the first
31511333]
for blood donor screening for Chagas
52. Gray EB, La Hoz RM,
few weeks of infection and becomes disease. These tests are not sufficient
Green JS, et al. detectable within months. Most avail- or appropriate for patient diagnosis,
Reactivation of Chagas
disease among heart able serologic tests are specific for and the blood collection agency notifi-
transplant recipients in
the United States, 2012- IgG, meaning that standard serologic cation regarding a donor's reactive test-
2016. Transpl Infect Dis.
2018;20:e12996. [PMID:
testing is not useful for diagnosis of ing results advises consulting a health
30204269] acute Chagas disease in the United care provider for further diagnostic
53. Bern C, Montgomery SP,
Herwaldt BL, et al. States (2). evaluation.
Evaluation and treatment
of Chagas disease in the
United States: a system- In congenitally infected infants, Chagas The standard for diagnosis of chronic
atic review. JAMA. disease is diagnosed by detection of Chagas disease is positive results on 2
2007;298:2171-81.
[PMID: 18000201] trypomastigotes or parasite DNA in or more different serologic tests that
54. Rodriques Coura J, de
cord blood or newborn blood; detec- each use a different antigen prepara-
Castro SL. A critical review
on Chagas disease chem- tion of T cruzi–specific antibody in new- tion and, preferably, different formats
otherapy. Mem Inst
Oswaldo Cruz. 2002;97:3- born blood can confirm maternal (for example, enzyme-linked immuno-
24. [PMID: 11992141]
infection but is not useful for newborn sorbent assay [ELISA] and immuno-
55. Altcheh J, Biancardi M,
Lapeña A, et al. diagnosis (32). Because the sensitivity blot). No single test has adequate
[Congenital chagas dis-
of detection can be low due to incon- sensitivity and specificity to diagnose
ease: experience in the
Hospital de Niños,
sistent and waning parasitemia levels in Chagas disease, and test performance
Ricardo Gutierrez, Buenos
Aires, Argentina]. Rev Soc the infected newborn, in babies whose tends to vary among endemic geo-
Bras Med Trop. 2005;38 graphic areas (2).
Suppl 2:41-5. [PMID: PCR results are negative at birth and/or
16482812] within 2 months of birth, their status
56. Cancado J, Brener Z, In a study of 500 seropositive and 300
Andrade Z. Trypanosoma should be confirmed by serologic test- seronegative plasma samples from blood
cruzi e doenca de Chagas.
Terapeutica. 1979;362- ing at age 9 to 12 months (after mater- donors, 4 assays were assessed: InBios
424.
57. Viotti R, Vigliano C,
nal antibody is gone). For symptomatic Chagas Detect Plus rapid test (sensitivity,
Lococo B, et al. Long-term newborns, the differential diagnosis for 97.4% to 99.3%; specificity, 87.5% to
cardiac outcomes of treat-
ing chronic Chagas dis- acute Chagas disease includes infec- 92.3%), Hemagen Chagas’ Kit ELISA
ease with benznidazole
versus no treatment: a
tion with other pathogens, such as Toxo- (sensitivity, 88.0% to 92.0%; specificity,
nonrandomized trial. Ann plasma gondii, cytomegalovirus, herpes 99.0% to 100.0%), Ortho T cruzi ELISA
Intern Med.
2006;144:724-34. [PMID: simplex virus, rubella, or syphilis. (sensitivity, 92.4% to 96.5%; specificity,
16702588] 98.8% to 100.0%), and Wiener Chagatest
58. Crespillo-Andújar C, How is chronic Chagas disease
Comeche B, Hamer DH, Recombinante v3.0 ELISA (sensitivity,
et al. Use of benznidazole diagnosed?
to treat chronic Chagas 94.0% to 97.1%; specificity, 96.7% to
Because management of Chagas heart
disease: an updated sys- 99.3%) (51).
tematic review with a disease differs somewhat from man-
meta-analysis. PLoS Negl
Trop Dis. 2022;16: agement of other causes of cardiomy- In the United States, serologic testing
e0010386. [PMID:
35576215] opathy and there is increased risk for for Chagas disease is offered by several
59. Morillo CA, Marin-Neto stroke, early recognition is important commercial diagnostic laboratories, al-
JA, Avezum A, et al.;
BENEFIT Investigators (36, 50). Patient history and clinical sus- though none of those laboratories cur-
Randomized trial of benz-
nidazole for chronic
picion are critical to diagnosing chronic rently use more than 1 test. To help
Chagas' cardiomyopathy. Chagas disease. History of birth or resi- confirm Chagas disease, CDC offers
N Engl J Med.
2015;373:1295-1306. dence in endemic regions or maternal confirmatory serologic testing, with the
[PMID: 26323937]
60. Rassi A, Rassi A, Marin-
origin in those regions should prompt Wiener Chagatest Recombinante v3.0
Neto JA. Antitrypanosomal testing for Chagas disease. During the ELISA and a laboratory-developed test
agents: treatment or
threat? – Authors' reply. chronic phase, diagnosis is made by (trypomastigote excreted–secreted anti-
Lancet. 2010;376:768-9. detection of T cruzi–specific antibodies gen immunoblot) used in parallel. If the
61. U.S. Food and Drug
Administration. Highlights of (2, 4). Chronic infections cannot be reli- CDC results are discordant, a second
Prescribing Information.
Benznidazole tablets, for oral
ably diagnosed by microscopic exami- specimen is requested for repeated test-
use. August 2017. nation or molecular (PCR) testing of ing, and if the results are discordant

© 2023 American College of Physicians ITC24 In the Clinic Annals of Internal Medicine February 2023

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again, a third test (a laboratory-devel- Reactivation is characterized by parasitemia
oped immunofluorescent antibody test) and manifestations that include cutaneous
is used. nodules, myocarditis, or meningoence- 62. Centers for Disease

What are the clinical manifestations phalitis. Meningoencephalitis or brain Control and Prevention.
Parasites - American
and symptoms of chronic Chagas abscesses, similar to those caused by Trypanosomiasis (also
known as Chagas
Toxoplasma gondii, are more common
disease in immunocompromised Disease). 2021.
in people living with HIV than patients 63. Molina I, Gómez i Prat J,
patients (reactivation)? Salvador F, et al.
with immunosuppression due to other Randomized trial of posa-
Patients with chronic Chagas disease conazole and benznida-
causes (49). Reactivation is diagnosed zole for chronic Chagas'
are at risk for reactivation of their infec-
by detection of trypomastigotes in pe- disease. N Engl J Med.
tion if they have immunosuppression. 2014;370:1899-1908.
ripheral blood, either through morpho- [PMID: 24827034]
Reactivation risk is important for chroni- 64. Torrico F, Gascón J,
cally infected heart transplant recipi- logic identification in blood smears or Barreira F, et al.; BENDITA
study group New regi-
ents, with estimated rates ranging from wet preparations of microhematocrit mens of benznidazole

27% to as high as 90% depending on buffy coat layers, or through molecular monotherapy and in com-
bination with fosravucona-
the study (25). Reactivation of chronic testing for parasite DNA. Because low zole for treatment of
Chagas disease
Chagas disease can occur in hemato- levels of T cruzi DNA may be intermit- (BENDITA): a phase 2,
double-blind, randomised
poietic stem cell transplant recipients, tently present in the blood in immuno- trial. Lancet Infect Dis.
patients living with HIV who have CD4 T- competent patients, laboratory diagnosis 2021;21:1129-40.
[PMID: 33836161]
lymphocyte cell counts below 0.200  109 of reactivation necessitates identifying 65. Altcheh J, Moscatelli G,
Moroni S, et al. Adverse
cells/L (49), and patients receiving immu- increased amounts of DNA over time. events after the use of
This is typically accomplished by PCR benznidazole in infants
nosuppressive chemotherapy for treat- and children with Chagas
ment of cancer or autoimmune conditions. testing of serial specimens (52). disease. Pediatrics.
2011;127:e212-8. [PMID:
21173000]
66. Crespillo-Andújar C,
Venanzi-Rullo E, López-
Diagnosis... Diagnosis of Chagas disease varies by phase of infection. Acute Chagas Velez R, et al. Safety pro-
disease is diagnosed by detection of the parasite either morphologically (identification file of benznidazole in the
treatment of chronic
in blood smears, buffy coat preparations, or tissues) or molecularly using PCR to detect Chagas disease: experi-
T cruzi DNA. Chronic Chagas disease is diagnosed by detection of T cruzi–specific anti- ence of a referral centre
bodies based on positive results on 2 or more different serologic tests. During chronic and systematic literature
review with meta-analysis.
infection in immunocompetent patients, the parasite is often not detectable in the Drug Saf. 2018;41:1035-
blood, but reactivation can occur when chronically infected patients become immuno- 48. [PMID: 30006773]
67. Forsyth CJ, Hernandez S,
suppressed. Reactivation is diagnosed by detection of parasites in the blood, either Olmedo W, et al. Safety
morphologically or by identifying increasing levels of parasite DNA. profile of nifurtimox for
treatment of Chagas dis-
ease in the United States.
Clin Infect Dis. 2016;63:
CLINICAL BOTTOM LINE 1056-62. [PMID: 27432838]
68. U.S. Food and Drug
Administration.
Highlights of Prescribing
Information. LAMPIT
(nifurtimox) tablets, for

Treatment oral use. August 2020.

69. Altclas JD, Barcan L,
Nagel C, et al. Organ
What is the role of primary care Who should be treated? transplantation and
Chagas disease [Letter].
providers in the management of Antitrypanosomal therapy should be JAMA. 2008;299:1134.
[PMID: 18334687]
Chagas disease? provided for all cases of acute infection 70. Ramírez JC, Parrado R,
Sulleiro E, et al. First
Primary care providers play an essential (IDSA grade A, level II), early congenital external quality assurance
role in screening patients for Chagas infection (IDSA grade A, level II), and program for bloodstream
Real-Time PCR monitoring
disease. Referral to specialists may be chronic infection in children aged 18 of treatment response in
clinical trials of Chagas
necessary to assist in evaluating and years or younger (IDSA grade A, level I disease. PLoS One.
treating Chagas disease and its compli- for children aged ≤12 years; IDSA 2017;12:e0188550.
[PMID: 29176887]
cations (as outlined in a later section). grade A, level III for children aged 13 71. Sguassero Y, Roberts KN,
Harvey GB, et al. Course
Primary care providers also play a key to 18 years) (2, 53). Because there is no of serological tests in
role in monitoring patients after treat- real test of cure and because PCR treated subjects with
chronic Trypanosoma cruzi
ment (with serial electrocardiograms, results may not be positive in persons infection: a systematic
review and meta-analysis
echocardiograms, and assessment of with low circulating levels of parasites, of individual participant
symptoms) as well as testing of family understanding treatment efficacy is dif- data. Int J Infect Dis.
2018;73:93-101. [PMID:
members. ficult. Studies on the effectiveness of 29879524]

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 treatment (based on parasitologic cure) In a trial of chronically infected adults,
estimate a cure rate of 60% to 99% in after a median follow-up of almost 10
patients with acute Chagas disease and years, fewer treated patients had dis-
congenitally infected infants treated ease progression or developed electro-
within a year of birth (54–56). Treatment cardiographic abnormalities (57).
should also be provided for reactivated
A meta-analysis of 17 studies of benzni-
72. Andrade JP, Marin-Neto Chagas disease in patients with HIV/AIDS
JA, Paola AA, et al.; dazole compared with placebo or no
Sociedade Brasileira de or other immunosuppression (IDSA grade
Cardiologia I Diretriz treatment for chronically infected patients
Latino Americana para o A, level II) and should generally be offered
Diagnóstico e Tratamento in the indeterminate phase or with vis-
to patients with impending immunosup-
da Cardiopatia Chagásica. ceral involvement showed odds ratios for
[I Latin American guide- pression (IDSA grade B, level II) according
lines for the diagnosis seroreversion of 38.3 (CI, 10.7 to 137) in
and treatment of Chagas to a 2007 systematic review and meeting
cardiomyopathy]. Arq Bras children and 17.1 (CI, 2.3 to 129.1) in
of experts (53).
Cardiol. 2011;97:1-48.
[PMID: 21952638]
adults (58).
73. Muratore CA, Batista Sa Treatment of women of childbearing
LA, Chiale PA, et al. In a study of 2854 patients with Chagas
Implantable cardioverter age with chronic Chagas disease should
defibrillators and Chagas' cardiomyopathy who received placebo
generally be offered (IDSA grade B,
disease: results of the ICD or benznidazole and were followed for
Registry Latin America. level III) or should always be offered if
Europace. 2009;11:164- a mean of 5.4 years, benznidazole was
8. [PMID: 19056745] future pregnancies are planned (strong
74. Garcia RL, Matos BM, associated with increased likelihood of
Feres O, et al. Surgical
recommendation based on moderate-
parasite clearance (conversion to nega-
treatment of Chagas meg- quality evidence) (2, 53).
acolon. Critical analysis of tive PCR results of 66.2% vs. 33.5%) but
outcome in operative
methods. Acta Cir Bras. Treatment of adults with chronic infec- did not reduce mortality or cardiac
2008;23 Suppl 1:83-92.
[PMID: 18516454]
tion requires further study. In a 2007 deterioration (59).
75. Zulantay I, Apt W, Ramos systematic review, expert recommen-
D, et al. The epidemiologi- Some experts argue that in light of the
cal relevance of family dations stated that treatment is consid-
study in Chagas disease. small number needed to treat to pre-
ered optional for adults older than 50
PLoS Negl Trop Dis. vent 1 case of cardiomyopathy, treat-
2013;7:e1959. [PMID: years without advanced cardiomyopa-
23457649] ment should be advised for adults in
76. Pan American Health thy (IDSA grade C, level III) and for
Organization. Guidelines the indeterminate stage (60). Because
patients with gastrointestinal disease
for the diagnosis and of the weakness of the evidence, fur-
treatment of Chagas but without advanced cardiomyopathy
disease. 2019. ther studies are needed to determine
77. Dias JC, Ramos ANJr, (IDSA grade C, level III) (53). Treatment
Gontijo ED, et al. 2nd whether treatment is beneficial in the
Brazilian Consensus on should generally be offered to adults
setting of early cardiac disease.
Chagas Disease, 2015.
Rev Soc Bras Med Trop.
aged 19 to 50 years who are in the
2016;49Suppl 1:3-60. chronic indeterminate stage or have Avoiding treatment of patients with
[PMID: 27982292]
78. World Health mild to moderate cardiomyopathy advanced cardiomyopathy and heart fail-
Organization; U.S. Centers
for Disease Control and
(IDSA grade B, level II) as per expert ure (IDSA grade D, level III) and patients
Prevention; International recommendations (53). More recent with megaesophagus and significant
Federation of Red Cross
and Red Crescent recommendations suggest the impor- impairment of swallowing (IDSA grade
Societies. Blood donor D, level III) is recommended. Those with
counselling:
tance of considering potential risks,
implementation benefits, uncertainties, and patient pre- severe renal or hepatic insufficiency also
guidelines. 2014.
79. World Health ference but state that treatment may should not be treated (IDSA grade E,
Organization. Blood
donor selection:
be offered to adults with normal elec- level III) (53).
guidelines on assessing trocardiograms and cardiac function
donor suitability for blood What pharmacologic treatment
donation. 2012. and those with early signs of cardiomy-
80. Mehra MR, Canter CE, options are available for Chagas
Hannan MM, et al.; opathy (based on discretionary and
disease?
International Society for weak evidence) (2).
Heart Lung Two medications are currently avail-
Transplantation (ISHLT)
Infectious Diseases, In adults with chronic indeterminate able for treatment of Chagas disease
Pediatric and Heart
Failure and (asymptomatic) Chagas disease, anti- (Table 2). Benznidazole is FDA-approved
Transplantation Councils trypanosomal therapy may improve for the treatment of Chagas disease in
The 2016 International
Society for Heart Lung parasite clearance and slow the devel- pediatric patients aged 2 to 12 years
Transplantation listing criteria
for heart transplantation: a opment of cardiomyopathy, but data (61), and nifurtimox is FDA-approved for
10-year update. J Heart
Lung Transplant. 2016;35:1-
are limited primarily to observational treatment of pediatric patients (weighing
23. [PMID: 26776864] studies (53, 57–59). ≥2.5 kg) from birth until they reach age

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18 years. Use of benznidazole or nifurti- from the previous recommendation of
mox to treat a patient outside the FDA- 90 days) (6, 62). As with benznidazole,
approved age ranges is based on clinical adverse effects are less common in
diagnosis and a decision by the treating young children than in adolescents or
physician under the practice of medicine adults (67). Adverse effects (in ≥5%)
(62). Although posaconazole may have include anorexia, nausea, vomiting, ab-
some antitrypanosomal activity, it has dominal pain, headache, dizziness or
not shown clinical effectiveness to date vertigo, and polyneuropathy. With nifur-
(63). timox, 6% to 75% of patients may require
treatment discontinuation due to adverse
Benznidazole is the first-line drug
effects (4, 67).
option for treatment of T cruzi infection
and is available in the United States (6, Alcohol increases the risk for and severity
8, 9, 62). The dosage regimen for of adverse effects, and consumption is
patients aged 2 to less than 12 years is contraindicated during treatment with
5 to 8 mg/kg of body weight per day benznidazole or nifurtimox. Full lists of
(53). This is also the recommended warnings and precautions can be found
dose for patients younger than 2 years on the FDA labels (61, 68).
and those aged 12 years or older. For
A sensitive and practical test of cure is 81. Acquatella H, Asch FM,
all patients, treatment is given orally in Barbosa MM, et al.
lacking to assess treatment response (8, Recommendations for
2 divided doses for 60 days (62). Some 9). Treatment failure, particularly among multimodality cardiac
imaging in patients with
studies suggest that treatment duration immunosuppressed patients (for exam- Chagas disease: a report
could be shortened, but additional data ple, posttransplant patients or those with
from the American
Society of
are needed (57, 64). Adverse effects are HIV), may be confirmed by positive PCR Echocardiography in col-
laboration with the
reported less often in infants and results (69), but a negative PCR result Interamerican Association
young children than in adolescents or does not necessarily indicate cure (49).
of Echocardiography
(ECOSIAC) and the
adults (65). Common adverse effects Drug candidate trials have used PCR as Cardiovascular Imaging
Department of the
include dermatitis in 29% to 50%; the an indicator of treatment failure, but such Brazilian Society of
rash or photosensitization usually app- testing requires rigorous standardization, Cardiology (DIC-SBC). J
Am Soc Echocardiogr.
ears in the first few weeks of treatment and results may vary by location and the 2018;31:3-25. [PMID:
29306364]
and is more common in females than parasite's discrete typing unit (70). Hemo- 82. Bozkurt B, Colvin M, Cook
males (66). Peripheral neuropathy occurs culture and examination of buffy coat or J, et al.; American Heart
Association Committee on
in 0% to 30%, generally later in the treat- blood can be used to assess treatment Heart Failure and
Transplantation of the
ment course; it is reversible but may last response in cases of reactivation or acute Council on Clinical
for months and should prompt imme- and early congenital infection. For patients Cardiology; Council on
Cardiovascular Disease in
diate discontinuation of benznidazole. with chronic disease who are not immuno- the Young; Council on
Cardiovascular and Stroke
Anorexia and weight loss (5% to 40%), compromised, repeating serologic testing Nursing; Council on
nausea or vomiting (0% to 5%), insomnia, at least once every year is recommended, Epidemiology and
Prevention; and Council
and bone marrow suppression (<1%) but the reversion to a negative result on Quality of Care and
Outcomes Research
may also occur, and patients should may take decades in chronically infected Current diagnostic and
undergo regular clinical and laboratory patients (71). All patients with chronic treatment strategies for
specific dilated cardiomy-
monitoring while receiving treatment Chagas disease should be monitored opathies: a scientific state-
ment from the American
(2). Overall, 7% to 30% of patients may annually with 12-lead electrocardiogra- Heart Association.
require treatment discontinuation due phy (53), or biannually in the setting of Circulation. 2016;134:
e579-e646. [PMID:
to adverse effects. reduced ejection fraction or major changes 27832612]
(36). The American Heart Association (AHA) 83. Bennett C, Straily A,
Haselow D, et al. Chagas
The FDA-approved dosage for nifurti- recommends repeating echocardiogra- disease surveillance activ-
mox in children from birth until age 18 phy every 1 to 2 years for patients with ities—seven states, 2017.
MMWR Morb Mortal
years varies by patient weight. The reduced ejection fraction and every 3 to Wkly Rep. 2018;67:738-
41. [PMID: 29975678]
dose is 10 to 20 mg/kg per day for 5 years for those with preserved ejection 84. Council of State and
those weighing at least 2.5 kg but less fraction (36). Additional repeated cardiac Territorial Epidemiologists
website. Accessed at
than 40 kg and 8 to 10 mg/kg per day evaluations (for example, 24-hour Holter www.cste.org on 13
December 2022.
for those weighing 40 kg or more. monitoring and exercise stress testing) 85. Utah Department of
Nifurtimox is taken orally with food 3 should be considered for those with clini- Health. Chagas Disease:
Disease Plan. Updated 5
times daily for 60 days (a decrease cal status changes or other manifestations, December 2019.

February 2023 Annals of Internal Medicine In the Clinic ITC27 © 2023 American College of Physicians

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 Table 2. Indications, Dosing, and Adverse Effects for Medications Used to Treat Chagas Disease
Medication Indications by Age and Pregnancy and Breastfeeding FDA Status Dosage Adverse Effects
Acute/Chronic Status Considerations

Benznidazole Approved for patients aged Pregnant patients should not Approved for pediatric 5–8 mg/kg of body weight Dermatitis, peripheral neu-
2–12 y be treated patients aged 2–12 y per day ropathy, anorexia, bone
Recommended for all acute Consider deferral of treatment Treatment for older Administered in 2 divided marrow suppression,
and chronic infections in until after breastfeeding has children and adults is doses, taken orally for 60 d nausea, vomiting
children aged ≤18 y, includ- stopped based on the decision
ing congenital infections of the treating physician
Recommended for patients
aged 19–50 y in chronic
indeterminate stage or
with mild to moderate
cardiomyopathy
Consider for patients aged
>50 y without advanced
cardiomyopathy
Avoid treating patients with
advanced cardiomyopathy
and heart failure
Nifurtimox Approved for patients from Pregnant patients should not Approved for pediatric Taken orally with food 3 Anorexia, nausea, vomiting,
birth to age 18 y be treated patients weighing ≥2.5 kg times daily for 60 d abdominal pain, headache,
Recommended for all acute, Treatment should be deferred from birth to age <18 y For patients from birth to dizziness, neuropathy
congenital, and chronic until after breastfeeding has Not approved for adults; age <18 y:
pediatric cases stopped treatment for adults is For those weighing ≥2.5
Recommended for patients based on the decision of to <41 kg: 10–20 mg/kg
aged 19–50 y in chronic the treating physician per day
indeterminate stage or with For those weighing ≥41
mild to moderate cardiomy- kg: 8–10 mg/kg per day
opathy
Consider for patients aged
>50 y without advanced
cardiomyopathy
Avoid treating patients with
advanced cardiomyopathy
and heart failure

FDA = U.S. Food and Drug Administration.

as outlined by the 2019 AHA and nifurtimox are not well under- and time available during the visit
guidelines (36). stood (53, 61, 68). However, treat- to address Chagas disease, they
ment should be considered if it may be able to manage the dis-
What are special considerations would be life-saving for the ease without referral to an infec-
for managing mother. Benznidazole treatment tious disease specialist. Referral
immunosuppressed patients? should be deferred until after can be helpful in confirming the
In HIV-infected persons with breastfeeding has stopped, and diagnosis, evaluating potential
Chagas disease, most cases of infants exposed to nifurtimox end-organ complications, consid-
through breastfeeding should be ering whom to treat, and moni-
T cruzi reactivation have occurred
monitored for adverse effects. toring patients during and after
in patients not taking antiretrovi-
ral therapy (ART). Optimization of When should primary care treatment. It is anticipated that
ART might help prevent T cruzi providers consider referring most primary care providers will
reactivation (CDC/NIH/IDSA grade patients to a specialist for want to refer patients to infec-
tious disease specialists until they
B-III) (49). In patients with evidence treatment?
become comfortable treating T
of reactivation, starting or optimiz- Patients infected with T cruzi cruzi–infected patients.
ing ART is recommended once the should be referred to appropri-
patient's Chagas disease is clinically ate specialists, including infectious Cardiologists
stable (CDC grade A-III) (49). disease specialists, cardiologists, Referral to a cardiologist de-
and gastroenterologists, to add- pends on the provider's comfort
What are special considerations with treating heart failure and
ress disease complications.
for managing pregnant patients? their need for help in managing
Infectious disease specialists complications of chronic Chagas
Treatment is not recommended
during pregnancy because the Depending on the primary care pro- heart disease in accordance with
teratogenic risks of benznidazole vider's comfort level, knowledge, standard guidelines. Treatment

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for heart failure associated with Chagas disease to prevent arrhyth- can be considered for those who
Chagas disease is based on mias and sudden cardiac death, have high surgical risk or serious
extrapolation of data from other particularly for secondary preven- concomitant diseases. Early stages
causes of heart failure (53, 72) tion (73). Heart transplant may be of colonic involvement may
and usually includes 1 or more required in patients with refractory respond to high-fiber diets
categories of medications, inclu- and laxatives or enemas, but sur-
heart failure (6).
ding b-blockers, angiotensin- gical resection may be needed
converting enzyme inhibitors, Gastroenterologists for late stages of megaesopha-
angiotensin-receptor blockers, Depending on the provider's gus and megacolon. Referral to
diuretics, digoxin, and anticoa- comfort with treating symptoms
a specialized center for surgical
gulants. Patients should be care- and the need for a surgical pro-
management is recommended
fully monitored for bradyarrhythmia cedure, referral to a gastroenter-
(37). Rates of symptom recurrence
if b-blockers or digoxin are given ologist or surgeon may be indi-
(6). Notably, patients with Chagas cated. Esophageal symptoms may vary by type of surgical procedure
heart disease are at higher risk be mitigated by drugs that relax (74).
for atrial fibrillation and cardiac the sphincter, although the relief What counseling or services
thrombus; anticoagulation is rec- may be short-lived (37). Surgical should be offered to family
ommended for those with atrial options include pneumatic bal- members?
fibrillation, a previous thrombo- loon dilatation (often performed
Family members of persons with
embolic event, or a cardiac throm- via endoscopy) and laparoscopic
Chagas disease are more likely
bus detected by echocardiography myotomy (Heller technique), both
and may be indicated in those of which may help in partial re- than the general population to
with apical aneurysms. Further covery of esophageal peristalsis. have the disease. Screening should
details are available in the AHA Additional surgical procedures, be offered to all persons who
guidelines (36). Pacemakers and including esophagectomy, have shared a household in an endemic
implantable cardioverter-defibril- been performed in advanced country with a patient with Chagas
lators may be used in patients cases. Endoscopic botulin toxin disease and to children of infected
with advanced chronic cardiac injection in the sphincter region mothers (4, 44, 75).

Treatment... Treatment should be offered to patients with acute infection, patients with congenital disease, immu-
nosuppressed patients or transplant recipients with reactivation, and children younger than 18 years with chronic
infection. Treatment should generally be offered to nonpregnant women of childbearing age and adults aged 19
to 50 years who are in the chronic indeterminate stage or have mild to moderate cardiomyopathy; treatment of
other patients with Chagas disease can be considered. Treatment for Chagas disease consists of either benznida-
zole or nifurtimox; however, these are currently FDA-approved only for children, and treatment of adults is under
the practice of medicine. The decision to treat should generally be made in conjunction with an infectious disease
specialist who can help monitor for the frequent adverse reactions. Cardiologists and gastroenterologists also can
assist in the evaluation and treatment of complications.

CLINICAL BOTTOM LINE

Practice Improvement
What do professional Chagas Disease both address the with the basic concepts outlined
organizations recommend for topic (76, 77). Although formal in the PAHO guidelines, including
prevention, screening, guidelines on screening and di- the use of 2 different serologic
diagnosis, and management of agnosis have not been issued by tests for diagnosis of chronic
Chagas disease? U.S. professional organizations Chagas disease. Recommen-
The 2019 PAHO guidelines for (such as IDSA or the American dations for treatment of chronic
the diagnosis and treatment of Society of Tropical Medicine and Chagas disease are not uniform;
Chagas disease and the 2015 Hygiene), a set of recommenda- the PAHO guidelines suggest
Brazilian Society of Tropical Medi- tions from U.S. experts was pub- trypanocidal therapy for adult
cine 2nd Brazilian Consensus on lished in 2021 (44) that agrees patients with chronic T cruzi

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infection and no specific organ What are the reporting What resources are available
damage (conditional recommenda- requirements? for providers?
tion, low-quality evidence), whereas In the United States, Chagas dis- Questions about treatment
the Brazilian guidelines suggest this ease is reportable in certain should be directed to CDC's
should be determined on a case- states (83). Providers should Parasitic Diseases Inquiries (404-
by-case basis. check their state health depart- 718-4745; e-mail, parasites@cdc.
ment website or the Council of gov). For emergencies (inclu-
Guidelines from the WHO exist for ding disease in a newborn or an
State and Territorial Epidemio-
blood donor counseling and selec- immunocompromised person or
logists website (84, 85). As of
tion (78, 79), and there are interna- acute Chagas disease with severe
tional and U.S. guidelines on organ 2022, Chagas disease was ex- manifestations) outside regular
transplantation (46, 80). Several plicitly reportable in 7 states business hours, providers should
Brazilian and U.S. guidelines address (Arizona, Arkansas, Louisiana, call CDC's Emergency Operations
the role of echocardiography and Mississippi, Tennessee, Texas, Center (770-488-7100) and ask
other cardiac testing for Chagas and Utah) and implicitly report- for the person on call for parasitic
disease (36, 50, 81, 82). able in several others (84, 85). diseases.

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 In the Clinic Patient Information

Tool Kit
www.cdc.gov/parasites/chagas
www.cdc.gov/parasites/chagas/es/index.
html
Information and resources in English and
Spanish from the Centers for Disease
Control and Prevention.
Chagas Disease
https://medlineplus.gov/chagasdisease.
html
Information and handouts from the
National Institutes of Health's
MedlinePlus.

In the Clinic
www.who.int/health-topics/chagas-
disease
Overview of Chagas disease from the World
Health Organization.

www.paho.org/en/topics/chagas-disease
Information from the Pan American Health
Organization.
Information for Health Professionals
www.who.int/publications/i/item/
9789275120439
Guidelines on the diagnosis and treatment
of Chagas disease in English and Spanish
from the Pan American Health
Organization.

www.scielo.br/j/rsbmt/a/
mNgRbrGjpwwc9dSF73PdMHt/?lang=en
2015 2nd Brazilian Consensus on Chagas
Disease.

https://academic.oup.com/jid/article/225/
9/1601/6384556
Recommendations for screening and diag-
nosis of Chagas disease in the United
States.

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 In the Clinic
WHAT YOU SHOULD KNOW Annals of Internal Medicine
ABOUT CHAGAS DISEASE
What Is Chagas Disease?
Chagas disease is caused by infection with the par-
asite Trypanosoma cruzi. Most commonly, peo-
ple are infected by exposure to the triatomine
bug in Mexico, Central America, or South
America. About 30% of infected people later de-
velop heart or gastrointestinal complications.

What Are the Risk Factors?

You may be at higher risk for Chagas disease if
you:
• Lived in or spent more than 6 months in endemic
areas of Mexico, Central America, or South risk for acute infection. Because acute infection
America and parts of the United States often has no symptoms, screening persons at
• Have a first-degree relative with Chagas disease high risk (people from endemic countries) is im-
• Were born to an infected, untreated mother portant in order to identify, treat, and prevent
• Consumed food or liquid contaminated with the complications of chronic disease.
triatomine vector
• Had a blood transfusion in the United States How Is It Treated?
before 2007
• Received a transplanted organ from an infected Antiparasitic medications (benznidazole and nifurti-
donor mox) are approved for treating children. Although
medications are not approved for adults, physi-
cians may choose to treat adults under the practice
What Are the Symptoms and of medicine. Treatment is recommended for
Long-Term Risks? people with acute infection, children, and
women of childbearing age and can be consid-
Most people have no or nonspecific symptoms, ered for those with chronic infection before de-
such as fever and lymph node swelling after
velopment of severe cardiac complications. Side
acute infection. A firm swelling at the site of para-
site entry, called a chagoma, may be present. effects include rash, gastrointestinal symptoms,
nerve problems, or dizziness. Alcohol should be

Patient Information
Infected people then enter an asymptomatic
(“indeterminate”) phase. After years to decades, avoided during treatment. Antibody test results
heart or gastrointestinal problems may develop. may take years to decades to revert to negative
Heart problems may include heart failure (cardio- after treatment.
myopathy), rhythm disturbances, or clots in the
heart leading to stroke. Symptoms include palpi- Questions for My Doctor
tations, chest pain, and shortness of breath.
Gastrointestinal problems due to nerve damage • Am I at risk for Chagas disease?
may cause difficulty swallowing, abdominal pain, • What is my risk for transmitting Chagas disease?
or constipation. • Should I be screened for Chagas disease?
• What is my risk for getting a more serious
condition?
How Can It Be Prevented? • What symptoms should I watch out for that may
When visiting endemic areas, sleeping under bed point to chronic Chagas disease?
nets, using insecticides, and avoiding consuming • How often should I get a follow-up checkup?
contaminated food or drink can help reduce the • Should I follow up with a specialist?

For More Information

Centers for Disease Control and Prevention
www.cdc.gov/parasites/chagas/resources/chagas_protect_your_
baby.pdf
www.cdc.gov/parasites/chagas/resources/es/poster_chagas_
protect_your_baby_es.pdf
www.cdc.gov/parasites/chagas/resources/es/informativa_breve.
pdf
Pan American Health Organization
www.paho.org/en/node/57390

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