Continuing Education Activity

Kissing bug bites and the subsequent development of Chagas disease is under-recognized and frequently go untreated. Chagas disease can be challenging to diagnose and chronic in nature leading to significant morbidity and mortality. This activity will review the epidemiology of Chagas disease and how kissing bugs spread the disease. It will highlight the classic symptoms of both acute and chronic Chagas disease, how it is diagnosed, and the benefits of an interprofessional team in managing complications and side effects of treatment.

Objectives:

• Summarize how Chagas disease is transmitted in various at-risk populations.
• Describe the characteristic features of acute and chronic Chagas disease.
• Outline laboratory testing to diagnose Chagas disease.
• Review interprofessional team strategies for identifying and managing complications of Chagas disease.

Introduction

The term kissing bug is a colloquial term that refers to a variety of species of insects in the Triatominae family (triatomines) that commonly seek out uncovered host mucosal surfaces and thus will frequently bite the face.[1][2][3] The kissing bug is of significance because it can transmit the parasitic organism Trypanosoma cruzi (T. cruzi), the causative agent of Chagas disease. While symptoms of Chagas disease were described as early as the 19th century, it was not until 1909 when Carlos Chagas formally described a case in his publication, thus imprinting his namesake on the disease.[4]

It is now recognized that Chagas disease can be difficult to diagnose and chronic in nature, leading to significant morbidity and mortality.[1][2] Furthermore, with recent globalization and concern for habitat proliferation of the causative vector, there is an increased need for awareness of this disease.[2][5]

Etiology

Chagas disease (American trypanosomiasis) is a parasitic infection caused by the parasite T. cruzi. It is a vector, and the triatomine becomes contaminated with the organism while taking a blood meal from an infected mammalian host. Greater than 24 mammalian hosts can carry T. cruzi infection and include humans, raccoons, opossums, wood rats, cats, and domestic dogs.[6][7][3] There are over 140 species of triatomines, but only about forty species in North America where autochthonous infections occur.[8] In the United States, there are at least eleven Triatomine species that can transmit the disease and 24 known hosts.[9][10]

After an incubation period, the parasite is located in the gut of the kissing bug. Transmission to subsequent hosts occurs when an infected kissing bug defecates while in contact with mucosa or non-intact skin.[2] Kissing bugs often defecate during or shortly after a meal, although only a fraction of those bitten become infected.[6] The infective form of T. cruzi enters the blood and travels to various tissues, and differentiates into an amastigote form and multiplies. They then transform back into the infective form and spread through blood and lymphatic systems, where they can be ingested by feeding kissing bugs.[7]

More recently, a variety of additional modes of transmission have been documented. These include blood donation, congenital infections, oral transmission from food contaminated with vector feces, organ transplantation from an infected donor, and the migration of Latin immigrants to non-endemic regions.[1][2][5][6][3]

Epidemiology

Chagas disease is estimated to be present in six to 8 million people worldwide, and most do not know they are infected.[1][11] It is endemic in many Central and South American Countries. The prevalence is variable depending on location but is highest in Bolivia and Argentina.[6] In endemic regions of the Americas, there are approximately 28000 new cases reported annually.[12]  In the most affected regions, countries such as Bolivia have up to six cases per every 100 people. It has traditionally been a disease that occurs in poor rural areas where the kissing bug thrives.[2]

In the United States, it is estimated that more than 300000 Latin American immigrants are currently infected with Chagas disease.[12][13] Kissing bugs are frequently found in border states such as Texas and commonly test positive for T. cruzi.[14] Kissing bug bites have been confirmed as far north as Delaware, with reports stretching up to Maine.[15][4]  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.[6] There is likely an underestimation of Chagas cardiomyopathy in non-endemic regions like the United States.[16]

The presence of T. cruzi in blood donors from U.S. samples is about 0.02%. If transfused with infected blood, approximately 10% to 20% of recipients will contract Chagas disease.[1] One US study conducted found that 0.3% of pregnant women were infected with T. cruzi. [9]  Trypanosoma cruzi infection can also be transmitted from organs transplanted from an infected individual.  Transmission rates vary on the organ transplanted and are approximately 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.[17]

Pathophysiology

There are a variety of proposed mechanisms for the characteristic changes that occur with Chagas disease. There are also key mechanistic differences between sequelae caused by the acute versus chronic phase.

In acute infection, there is direct cellular and organ damage caused by the parasitic organism. During this phase, the organism will invade host cells and ultimately cause cell lysis.[1][2] Animal models have shown that infection can occur in nearly all types of tissue.[1] There is a subsequent inflammatory response causing additional tissue damage.  

In the absence of treatment, host immune responses will ultimately control the parasite replication and resolution of symptoms in 4 to 8 weeks.[6] Those patients remain asymptomatic and carry the infection for life. After several decades in the chronically infected, approximately 30% will develop significant gastrointestinal or cardiac sequelae.[3][12]  Approximately 20% to 30% will develop cardiomyopathy.[6] Chagas cardiomyopathy can result in conduction delay, dysrhythmia, and dilated non-ischemic cardiomyopathy.[6][16] A less common sequela from Chagas is gastrointestinal disorders.  Dysfunction of the gastrointestinal tract can impact the esophagus and/or colon. Disorders of motility resulting in dilation such as achalasia or megacolon.[6]

The pathophysiology for the chronic phase of Chagas disease is less well understood. Current evidence suggests there is likely a persistent parasite infection of tissues that causes chronic inflammation resulting in organ dysfunction. There is also evidence that several T. cruzi antigens cross-react with normal tissue antigens and cause an autoimmune reaction.[1][2]  Chagas cardiomyopathy is complex and involved direct invasion by the parasite causing direct cellular necrosis as well as an autoimmune response and subsequent inflammation.[7]

Reactivation of Chagas disease following immunosuppression results in parasite replication, parasitemia, and clinical picture similar to acute infection, which is often more severe.[17][18] Common predisposing conditions include organ transplantation, untreated human immunodeficiency virus (HIV), or chemotherapy.[17] Immunosuppression from corticosteroids does not appear to increase rates of reactivation.[18] 

History and Physical

In most cases, the acute phase of Chagas disease is asymptomatic and goes undiagnosed. When symptomatic, the findings are typically non-specific and can easily be attributed to other etiologies. Typical findings include:

• Asymptomatic
• Fever
• Malaise
• Localized nodule at the inoculation site (chagoma)
• Unilateral palpebral edema (Romana sign)
• Lymphadenopathy 
• Hepatosplenomegaly 

These findings usually occur over four to eight weeks. If infected by oral transmission, symptoms may also include nausea, vomiting, diarrhea, abdominal pain, or gastrointestinal hemorrhage. In most cases, the acute infection resolves spontaneously. Severe but rare acute organ-specific manifestations can include myocarditis or meningoencephalitis.[6] Congenital infections may cause premature birth, low birth weight, fever, anemia, and hypotonicity.[1][2]

A small subset of patients will experience an anaphylactic reaction to the kissing bug bite. Presenting signs and symptoms can include acute onset urticarial rash, flushing, difficulty breathing, wheezing, nausea, vomiting, diarrhea, tachycardia, and edema.[8][19]

Approximately 30% to 40% will develop a chronic infection with subsequent organ damage.[2] Most individuals with chronic infection will develop heart disease or less commonly have gastrointestinal involvement.[1][2] The manifesting symptoms will depend on the location and degree of organ dysfunction. Cardiac manifestations can include heart block, bundle branch block, syncope.  With more severe disease, including dilated cardiomyopathy or dysrhythmia, symptoms may include shortness of breath, dyspnea, orthopnea, chest pain, or sudden cardiac death.[7] Gastrointestinal manifestations may include motility problems and include dysphagia, nausea, vomiting, abdominal distention, and abdominal pain.[6]

Clinical manifestations of Chagas reactivation often occur in the setting of immunosuppression and results in an acute illness that may include chagoma, panniculitis, myocarditis, or meningoencephalitis.[18] 

Evaluation

During the acute phase, parasitemia is high, and the diagnosis of Chagas disease is made by visualizing the parasite under microscopy.[7] This is typically done on a blood smear, but occasionally, other body fluids such as cerebrospinal fluid are options. Blood smears can detect parasites; however, polymerase chain reaction (PCR) is a more sensitive test.[6]  Quantitative PCR may also be used for periodic monitoring or suspected reactivation.[12] For suspected congenital exposure that is not identified at birth, serology can be obtained at approximately nine months.[6]

There is minimal parasitemia with the chronic phase; therefore, T. cruzi PCR is less reliable, and the detection of serum antibodies is necessary.  These tests are typically enzyme-linked immunosorbent assays (ELISA) or immunofluorescent antibody tests (IFAT) and rely on the detection of IgG antibodies against T. cruzi.[7][12] Due to limitations of assay sensitivity, a two-test regimen using different antigens is recommended.[6][12] In some circumstances, serologic tests can be unreliable. Examples include the diagnosis of early congenital infections and the diagnosis of infection from an organ transplant. In these cases, molecular testing targeted to identify specific DNA sequences is recommended.[1][2]

In patients diagnosed with Chagas disease, evaluation for visceral organ involvement should be performed. This is mainly done with a thorough history to identify early symptoms. Cardiac assessment for those with a history of Chagas disease includes electrocardiogram and echocardiogram.  Common electrocardiographic findings are right bundle branch block, left anterior fascicular block, first degree AV node block, atrial flutter/fibrillation.[20] Ancillary testing depending on the clinical circumstances, could include event monitoring and cardiac MRI.[16] In those with gastrointestinal symptoms, ancillary testing may consist of a barium swallow and barium enema.  

Treatment / Management

Clinicians should consider antitrypanosomal treatment for acute infections, congenital, reactivation, indeterminate form, women of childbearing age, accidental high-risk exposures, and chronic phase in the pediatric population (less than 18 years).[7] Treatment may also be indicated for immunosuppressed patients.[12] Treatment decision-making for adults with chronic phase or Chagas cardiomyopathy is less clear. There are only two medications currently used to treat Chagas disease. Benznidazole and nifurtimox are the only two approved antitrypanosomal drugs available. Based on the 2018 Pan American Health Organization guideline, there is no strict evidence to suggest which medication should be used as the first-line option; however, in the United States, benznidazole will be more often used due to availability.[12] In the United States, benznidazole was approved by the Food and Drug Administration (FDA) in 2017. Dosing is 5 to 10 mg/kg/day divided every 12 hours for 30 to 60 days.[6][12] Pediatric dosing also includes a 60-day weight-based regimen. A common side-effect is dermatitis; more serious side effects include myelosuppression and peripheral neuropathy.[17] The presence of myelosuppression or neuropathy is an indication to discontinue treatment immediately. Nifurtimox is the other antitrypanosomal therapy and is not currently FDA approved but 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 three doses for 60 to 120 days. Pediatric dosing also includes a weight-based regimen.[12] Gastrointestinal side-effects are very common with nifurtimox and may include nausea and vomiting.[6]  More serious side-effects can include neurotoxicity, including neurocognitive effects or neuropathy.[17][6]

Cure rates are variable and dependent on several factors such as the patient's age, stage of the disease, and duration of infection. During the acute phase, cure rates range from 80% to 90% and 20% to 60% in chronic disease.[17][6] Children generally respond better to therapy; earlier screening and treatment lead to a higher negative seroconversion rate.[6][7] Transplant patients with prior infection should undergo monitoring at intervals similar to monitoring for rejection and if there are concerns for an acute infection or reactivation.[17]

Treatment for organ-specific sequelae, such as Chagas rhythm disturbances and cardiomyopathy, should follow current recommended treatment for that particular disease (e.g., dilated cardiomyopathy). Conduction or rhythm disturbances are treatable with an implantable pacemaker and/or cardioverter-defibrillator. Amiodarone is recommended for recurrent ventricular dysrhythmias.[16] For those with end-stage cardiomyopathy, heart transplantation is a viable option.[6] 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.[21] Despite largely negative results, some authors continue to advocate for treating Chagas cardiomyopathy with trypanocidal therapy.[22]

Differential Diagnosis

Differential diagnosis may be broad since signs and symptoms of Chagas disease are non-specific 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.

• Achalasia
• Acute colonic pseudo-obstruction
• Angina pectoris
• Atrioventricular block
• Atrioventricular dissociation
• Chronic megacolon
• Colonic Obstruction
• Constipation
• Coronary artery atherosclerosis
• Dilated cardiomyopathy
• Esophageal motility disorders
• Esophagitis
• Gastroesophageal reflux disease
• Hypertrophic cardiomyopathy
• Leishmaniasis
• Malaria
• Meningitis
• Myocardial rupture
• Myocarditis
• Pulmonary regurgitation 
• Syncope
• Third-degree atrioventricular block
• Toxic megacolon
• Toxoplasmosis

Staging

There are three stages of the disease:

• Acute infection
• Indeterminate phase
• Chronic infection

The indeterminate phase occurs after an acute infection resolves, but there remains serologic evidence of an infection. This phase can last for years or even decades. During this time, a person will remain asymptomatic with normal organ function. Approximately 70% of these patients will stay in the indeterminate phase for the remainder of their life, while the remaining 30% will develop chronic disease.[1][2]

Prognosis

In the acute phase, 1% to 5% of patients will develop severe disease, with a mortality rate of 0.2% to 0.5%.[2] Of those who develop chronic infection, approximately 10% develop symptomatic organ dysfunction, and 20% develop asymptomatic organ involvement.[4] It is estimated that approximately 12,000 people per year die from Chagas disease. There is significant variability in morbidity and mortality based on the route of infection.[2] 

Complications

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 

Deterrence and Patient Education

The main form of deterrence is vector control. This is achievable with measures such as insecticides. There is also a large emphasis placed on improved housing. Protective strategies include the elimination of mud dwellings in developing countries and the use of bed nets. Other methods include screening blood products, organ donors, and pregnant patients.[1][2] 

Enhancing Healthcare Team Outcomes

Chagas disease is one of the neglected tropical diseases outlined by the World Health Organization. If left untreated, it can lead to significant morbidity and mortality.[4][2] With the concern of climate change, it is possible this disease could spread.[23] Additionally, with increasing human migration patterns, there may be an increased spread of Chagas disease in non-endemic areas such as Europe and the United States.[5][13]

An interprofessional team can enhance the care of patients with Chagas disease. Primary care and emergency department personnel need to have a high level of suspicion for those at risk for the disease. Pharmacists review prescribed medications and counsel patients and their families about the importance of compliance and potential side effect. A board-certified infectious disease pharmacist may also help with agent selection and help guide the treatment plan. Nurses are involved in the initial evaluation, facilitate communication among the interdisciplinary team, and provide patient information. These interprofessional measures can lead to improved patient outcomes. [Level 5]