Chagas Disease

Etiology

Chagas disease is a vector-borne illness most commonly transmitted through contact with the contaminated feces and urine of the reduviid or kissing bug. This insect, in turn, carries the causative agent—the parasite Trypanosoma cruzi. Over 140 species of triatomines have been identified, but only about 40 species are found in North America, where native infections occur. In the United States, at least 11 triatomine species have been confirmed to transmit the disease, along with 24 known hosts. The most common species in the southern United States are Triatoma sanguisuga and Triatoma gerstaeckeri. The primary vectors in Mexico, Central America, and South America are Rhodnius prolixus and Triatoma dimidiata. 

The insects often lay dormant during the daytime, hiding in cracks in housing or agricultural structures and emerging at night to feed. Both sexes of reduviid bugs feed in this way, and female kissing bugs must additionally take blood meals to lay their eggs. As it takes the meal or soon afterward, the insect defecates and expels parasites in the feces and urine near the feeding bite. Local irritation at the bite site causes the person to instinctively rub the area, smearing the parasite-laden excrement into the open wound. The parasite can also enter through contact with the mucous membranes if the person touches their mouth or eyes with contaminated skin. Feces of infected reduviid bugs carry the largest number of the infectious trypomastigote form.[7]

Other mode transmissions include:

• Vertical transmission from mother to fetus leading to congenital Chagas disease
• Organ transplantation
• Transfusion of blood and blood products [2][3][8][9][4]

Epidemiology

Chagas is endemic in Latin America, from the southern United States to northern Argentina and Chile.[10] However, the distribution of the disease is changing due to the relocation of individuals from the endemic countries. The World Health Organization (WHO) estimates that 6 to 7 million people are currently infected with T. cruzi, causing 12,000 deaths annually, with 75 million people at risk of contracting the disease. In endemic regions of the Americas, approximately 28,000 new cases are reported annually.[11] Of those infected with the parasite, 1 in 10 will develop cardiac manifestations.[12] In the most affected regions, countries (eg, Bolivia) have up to 6 cases per every 100 people. Chagas disease has traditionally been a disease that occurs in poor rural areas where the kissing bug thrives.[3]

Domestic and wild mammals are also common hosts for this parasite. The primary transmission route occurs through infected reduviid bugs, which can be found in cracks indoors or on the roofs of substandard housing made from mud, straw, or palm thatch. Outdoor locations include animal nests, agricultural buildings (eg, barns and chicken coops), and tree bark or logs.[13] Children are most commonly affected, followed by women and then men.

In the United States, more than 300,000 Latin American immigrants are estimated to be currently infected with Chagas disease.[11][14] Reduviid bugs are frequently found in border states (eg, Texas) and commonly test positive for T. cruzi.[15] Kissing bug bites have been confirmed as far north as Delaware, with reports stretching to Maine.[16][17] Factors that influence the spread of disease are a combination of vector-borne transmission of infected individuals and the migration of people from rural to urban areas.[9] Chagas cardiomyopathy in nonendemic regions like the United States is likely underestimated.[18]

The presence of T. cruzi in blood donors from United States samples is about 0.02%. If transfused with infected blood, approximately 10% to 20% of recipients will contract Chagas disease.[2] Trypanosoma cruzi infection can also be transmitted from organs transplanted from an infected individual. Transmission rates vary on the organ transplanted, ranging from 18% to 19% for the kidney and 29% for the liver. A heart transplant from infected donors is contraindicated. T. cruzi reactivation can occur in up to 20% of HIV-infected patients.

Pathophysiology

The T. Cruzi Parasite Life Cycle

T. cruzi, in its leishmanial (trypanomastigote) form, is ingested by the vector reduviid bug when it takes a blood meal from an infected host. The trypomastigotes transform into epimastigotes in the insect's midgut, where they multiply and become flagellated in the midgut. Finally, they mature to the infective form in the hindgut, where they are excreted to infect a new host after the insect bites again (see Image. T. Cruzi Parasite Life Cycle).

When the reduviid bug bites and takes a blood meal, the metacyclic trypomastigotes are passed in the insect's feces near the open bite wound. Local irritation causes the mammal to scratch or contact the area, introducing the trypomastigotes to the mammalian host's bloodstream through the open bite. Alternatively, the mammalian host may innoculate themselves later by touching mucous membranes with a contaminated appendage.

After the parasite enters through an open wound or mucous membrane, the metacyclic trypomastigote penetrates various host cells near the site of infection, where they transform into amastigotes intracellularly. The amastigote stage of the parasites is found mainly inside pseudocysts located in muscle or nerve cells, where they multiply via binary fission. The intracellular amastigotes transform into trypanomastigotes, resulting in cell rupture and the entrance of the trypanomastigotes into the host bloodstream. These circulating trypanomastigotes can then infect additional host cells, and this host auto-infection cycle repeats, leading to clinical disease. If such a host is then bitten by another reduviid bug, these circulating trypomastigotes are then uptaken with the blood meal by the reduviid vector, facilitating transmission to additional hosts.[19]

Clinical Phases

Chagas disease has 2 clinical phases: acute and chronic.

Acute infection

Signs and symptoms are directly related to the T. cruzi parasite's replication and the host immune response to this replication. During this phase, the cycle of replication and auto-infection results in circulating trypomastigotes in the bloodstream, and the host's immune system produces antibodies to combat the infection. This phase lasts several weeks after initial infection and is primarily driven by host immune cells targeting intracellular pathogens, eg, natural killer T-cells and macrophages.[3]

Chronic infection

In the absence of treatment, host immune responses will ultimately control the parasite replication and resolution of symptoms in 4 to 8 weeks.[9] These patients remain asymptomatic and carry the infection for life. However, untreated infection can lead to ongoing circulation and deposition of parasite trypomastigotes into various cells throughout the host's body, and clinical disease is the result of years of continuing replication, circulation, and immune response, ultimately leading to end-organ damage in the host.[20] 

After several decades in the chronically infected, approximately 30% will develop significant gastrointestinal or cardiac sequelae.[4][11] The parasites show a predilection for infecting striated muscle cells, with significant parasite load detectable in cardiac muscle early in the chronic infection course. Late in the chronic phase of infection, parasite levels drop to barely detectable levels as the number of viable myocardial cells decreases.[20][21] This leads to local immune response inciting fibrosis of the cardiac muscle, leading to cardiomegaly and an overall decrease of viable myocardium. Approximately 20% to 30% will develop cardiomyopathy.[9] Chagas cardiomyopathy can result in conduction delay, dysrhythmia, and dilated nonischemic cardiomyopathy.[9][18] 

A less common sequela from Chagas is gastrointestinal disorders. The parasite routinely infects nerve cells in the gastrointestinal tract, leading to a profound loss of nerve endings in the digestive system, leading to decreased peristalsis in the esophagus and loss of function in the esophagus, as well as in the colon, with this loss of neurologic control of these organs being the underlying cause of organ dysfunction, as well as interrupting the blood supply. Disorders of motility resulting in dilation, eg, achalasia or megacolon, can also result.[21][9]

Reactivation of Chagas disease following immunosuppression results in parasite replication, parasitemia, and a clinical picture similar to acute infection, which is often more severe.[22][23] Common predisposing conditions include organ transplantation, untreated human immunodeficiency virus (HIV), or chemotherapy.[22] Immunosuppression from corticosteroids does not appear to increase rates of reactivation.[23] 

Histopathology

Microscopic detection of T. cruzi parasites is diagnostic for Chagas disease. Motile parasites can be detected microscopically by examining fresh, anticoagulated blood or the buffy coat of a fresh blood sample (see Image. Chagas Disease).[9] Alternatively, both thick and thin peripheral blood smears can be stained with Giemsa, where parasites can be visualized with a sensitivity ranging from 34% to 85% (see Image. Trypanosoma Cruzi).[3][2] Microscopically, the T. cruzi parasite has an undulating cell membrane with a flagellum, a visible nucleus, and a hallmark kinetoplast structure, distinguishing T. cruzi from other Trypanosoma species.[24]

History and Physical

Clinical Features of Chagas Disease

The clinical features of Chagas disease depend on its phase: acute or chronic. In either case, though possible, it is rare for a patient to remember or report a reduviid bug bite. Therefore, the astute clinician must consider Chagas disease as part of a broad differential diagnosis, especially in endemic areas.

Acute phase

The acute phase of Chagas disease lasts for approximately 2 months following infection from a bite, and symptoms may be very mild or absent altogether. Patients may rarely present with a skin lesion or visible bite with local irritation but, more commonly, will experience fever, localized edema, lymphadenopathy, myalgias, pallor, shortness of breath, and abdominal or chest pains.[25][26]

Intense local inflammation with uniocular conjunctivitis, or a purplish discoloration of 1 eyelid, is known as a Chagoma or Romana's sign and is a hallmark of Chagas disease (see Image. Romana's Sign).[27] Thus, a comprehensive physical examination is required. Care should be taken to perform a thorough skin examination and diligent heart, lung, abdominal, and extremity examinations to assess for lymphadenopathy. A small subset of patients will experience an anaphylactic reaction to the kissing bug bite, with presenting signs and symptoms including acute onset of urticarial rash, flushing, difficulty breathing, wheezing, nausea, vomiting, diarrhea, tachycardia, and edema.[28][29] Congenital infections may cause premature birth, low birth weight, fever, anemia, and hypotonicity.[2][3]

Chronic phase

An estimated 30% of Chagas patients will have cardiac involvement and may thus present with fever, cardiomegaly, apical aneurysms, or electrocardiography (ECG) abnormalities. Patients may present with heart failure, and subsequent cardiac workup may lead to the initial diagnosis of Chagas. Approximately 10% of patients may have gastrointestinal tract involvement and may present with fever, megaesophagus, or megacolon due to the destruction of myenteric plexus and constipation. Such gastrointestinal complaints of chronic Chagas may also be the presenting/diagnostic complaints for the patient.[30] Clinical manifestations of Chagas reactivation often occur in the setting of immunosuppression and result in an acute illness that may include chagoma, panniculitis, myocarditis, or meningoencephalitis.[23] 

Patients living in or from endemic areas presenting with signs and symptoms worrisome for heart failure or with intractable constipation warrant a thorough physical examination with special attention paid to heart, lung, abdominal, and extremity examinations. Signs of cardiomegaly, eg, a displaced point of maximal impulse, diminished pulse pressures, or sinus tachycardia, may be present.[31] Features of right heart failure, including bibasilar pulmonary rales or bipedal pitting edema, may be present. Abdominal distention with a soft abdomen and diminished bowel sounds may be present. Digital rectal examination may reveal hardened or impacted stool.[32] The abdominal examination may also reveal hepatosplenomegaly, and the conjunctival exam may reveal pallor from chronic anemia.[33][34]

Evaluation

The presenting symptoms will guide the investigations when evaluating a patient for potential Chagas disease.

Laboratory Studies

Diagnosis is established during the acute phase by detecting the parasite microscopically, from a fresh preparation of anticoagulated blood or buffy coat due to the high level of parasitemia. However, levels may decrease within 90 days of infection and may be undetectable by microscopy as the sensitivity of the test decreases and as the disease progresses from acute to chronic. Polymerase chain reaction (PCR) is another diagnostic tool that may be used during the acute phase, monitoring for acute infection in organ transplant recipients or following accidental exposures. PCR assays can demonstrate positive results days to weeks before a peripheral blood smear detects circulating trypomastigotes.

Additional Diagnostic Studies

When examining a patient with suspected chronic Chagas disease, further investigations will focus on the organ system dysfunction being assessed. Long-term cardiac manifestations are most common; an initial workup will often entail an ECG, and chest x-ray and echocardiography may also be indicated. Signs of cardiomegaly will be evident on all 3, and diminished ejection fraction may be demonstrated on echocardiography.[35][36] Common ECG findings are right bundle branch block, left anterior fascicular block, first-degree AV node block, and atrial flutter/fibrillation.[37]

Similarly, if a patient presents with gastrointestinal complaints, a series of abdominal x-rays may demonstrate pseudo-obstruction of the bowels, and a megacolon may be evident.[38] Ancillary testing for those with gastrointestinal symptoms may consist of a barium swallow and barium enema. The diagnosis of Chagas is confirmed via the detection of IgG antibodies to T. cruzi in chronic infections.[39]

Treatment / Management

Acute Chagas Disease Treatment

Clinicians should consider antitrypanosomal treatment for acute, congenital, and reactivation infections, indeterminate forms, women of childbearing age, accidental high-risk exposures, and chronic infections in the pediatric population.[6] Treatment may also be indicated for immunosuppressed patients.[11] Treatments for Chagas disease include nifurtimox and benznidazole, with >80% success during the acute phase but with no effect on the amastigote stage.[40](B3)

Benznidazole and nifurtimox are the only approved antitrypanosomal drugs available. Based on the 2018 Pan American Health Organization guideline, evidence to suggest which medication should be used as the first-line option is lacking; however, in the United States, benznidazole is used more often due to availability.[11] Benznidazole was approved by the Food and Drug Administration (FDA) in 2017 with a recommended dosage of 5 to 10 mg/kg/day divided every 12 hours for 30 to 60 days.[9][11] Pediatric dosing also includes a 60-day weight-based regimen. A common adverse effect is dermatitis; more serious adverse effects include myelosuppression and peripheral neuropathy.[22] The presence of myelosuppression or neuropathy is an indication to discontinue treatment immediately. Nifurtimox is the other antitrypanosomal therapy but is not currently FDA-approved. However, nifurtimox can be obtained through the Centers for Disease Control and Prevention (CDC) under an investigational protocol. Dosing is 8 to 10 mg/kg/day divided into 3 doses for 60 to 120 days. Pediatric dosing also includes a weight-based regimen.[11] Gastrointestinal adverse effects are very common with nifurtimox and may include nausea and vomiting.[9] More serious adverse effects can include neurotoxicity, including neurocognitive effects or neuropathy.[22][9](B3)

Cure rates are variable and dependent on several factors, including the patient's age, disease stage, and infection duration. During the acute phase, cure rates range from 80% to 90% and 20% to 60% in chronic disease.[22][9] Children generally respond better to therapy; earlier screening and treatment lead to a higher negative seroconversion rate.[9][6] Transplant patients with prior infection should undergo monitoring at intervals similar to monitoring for rejection and if concerns for an acute infection or reactivation are present.[22](B3)

Management of Chronic Chagas Disease

Treatment for chronic Chagas disease is dependent on which organ is involved. Treatment of Chagas heart failure is largely symptomatic, with pacing and defibrillation used to ameliorate life-threatening arrhythmias. Simply treating the patients with antiparasitic medications does not halt or reverse the end-organ symptoms in chronic Chagas disease.[41] Trypanocidal therapy for established Chagas cardiomyopathy is controversial. In a randomized trial, trypanocidal treatment for patients with Chagas cardiomyopathy resulted in a higher negative seroconversion rate but did not appear to improve clinical outcomes.[42] Despite largely negative results, some authors continue to advocate for treating Chagas cardiomyopathy with trypanocidal therapy.[43] Current thinking revolves around a parasite-driven systemic immune response that leads to end-organ damage, and there is much ongoing research into the use of immunomodulating medications in the treatment of these patients.[44][45](A1)

End-stage cardiac disease from Chagas is treated in much the same way as other forms of end-stage heart failure, with rate and rhythm control, prophylaxis for thromboembolism, and implanted defibrillators. Chagas cardiomyopathy is not a contraindication for heart transplantation, though the required immunosuppression makes reactivation of the latent disease highly likely.[46]

End-stage colon dysfunction, also called chagasic megacolon, may require surgical intervention. The Duhamel-Haddad procedure involves resection of the dilated, hypofunctional sections of the colon and has also been described with frozen section controls to evaluate for subclinical neuronal loss.[47][48] Other operations have been described, including partial sigmoidectomy with loop interposition, all to avoid a permanent ostomy.[49][50]

Differential Diagnosis

Differential diagnoses may be broad since signs and symptoms of Chagas disease are nonspecific and may include dysfunction of multiple organ systems. During the acute phase, symptoms of fever and malaise can mimic many other febrile illnesses. Unilateral palpebral edema could be mistaken for periorbital cellulitis. A chagoma could be mistaken for another arthropod bite or other dermatologic conditions of localized inflammation. Differential diagnoses that should also be considered when evaluating Chagas disease include:

• Esophageal motility disorders
• Esophageal rupture
• Esophageal spasm
• Esophagitis
• Gastroesophageal reflux disease
• Leishmaniasis
• Malaria
• Meningitis
• Myocardial infarction
• Myocardial rupture
• Congestive heart failure

Prognosis

The overall prognosis depends upon when the disease is diagnosed and treatment begins. Those patients diagnosed and potentially cured in the acute phase, before end-organ damage has occurred, have an overall favorable prognosis. However, rare reports of death from acute Chagas exist, primarily due to acute myocarditis.[51] In the acute phase, 1% to 5% of patients will develop severe disease, with a mortality rate of 0.2% to 0.5%.[3] 

Patients with chronic Chagas disease have a prognosis dependent upon the organ function (especially cardiac) at the time of diagnosis and treatment. Patients with Chagas cardiomyopathy have higher mortality and morbidity when compared to other causes of nonischemic heart disease, and overall, lower quality of life and lower life expectancy than those not infected.[52] Of those who develop chronic infection, approximately 10% develop symptomatic organ dysfunction, and 20% develop asymptomatic organ involvement.[17] Studies estimate that approximately 12,000 people per year die from Chagas disease. Significant variability in morbidity and mortality based on the route of infection exists.[3] 

Complications

Chronic cardiomyopathy and heart failure are the principal complications of untreated Chagas disease, though megacolon and other chronic intestinal dysmotility are also well-described.[53] Other rarer complications include esophageal dilatation and dysmotility, as well as brain abscess formation.[54]

During the acute phase of infection, serious complications include:

• Myocarditis 
• Pericardial effusion
• Encephalitis 
• Meningoencephalitis 

During the chronic phase, complications include:

• Heart failure
• Arrhythmias
• Thromboembolic disease
• Megaesophagus
• Megacolon
• Neuropathy