Chagas disease overview

# Overview
Chagas disease (American trypanosomiasis) is an infectious disease caused by the flagellate protozoan parasite, T. cruzi. The global incidence of Chagas disease is estimated to be 5-8 million with global incidence of Chagas disease of approxiamtely 100-400 per 100,000 individuals. The majority of cases are reported in South America, where Chagas disease is considered the most common parasitic infection. The most common mode of transmission of Chagas disease is vectorborne via exposure to feces/urine of infected triatomine (Riduvid) insects. The incubation period of T. cruzi is 1-2 weeks following transmission. The majority (90%-95%) of infected individuals remain asymptomatic in the acute phase following Chagas disease infection. Nonetheless, patients typically remain chronically infected and demonstrate clinical manifestation several years/decades following infection. Approximately 1/3 of patients develop manifestations of the chronic Chagas disease, namely cardiac conduction system dysfunction, GI denervation with esophageal and/or colonic dysfunction (megaesophagus and megacolon). Acute Chagas disease is often diagnosed by peripheral blood smear following the visual detection of T. cruzi parasite. In contrast, the diagnosis of chronic Chagas disease is more difficult and requires serial serological or PCR testing. Benznidazole and nifurtimox are the only antimicrobial therapies with proven efficacy against T. cruzi infection. Neither drug is FDA-approved, but can be obtained under investigational protocol. Either benznidazole or nifurtimox may be used to manage congenital infection, acute infection, and chronic infection (only among young patients < 50-55 years) including those with early cardiomyopathy. Chronic Chagas' disease leads to congestive heart failure. These patients commonly have right bundle branch block and/or other arrhythmias. These hearts are dilated and hypertrophied, have areas of fibrosis especially in the apex, and often contain mural thrombi. The myocardium is infiltrated with lymphocytes and macrophages and there is interstitial edema and fibrosis. This inflammatory reaction is most severe around the area of the right bundle branch. Patients may also develop megaesophagus and/or megacolon.

# Historical Perspective
The discovery of T. cruzi, the parasite that causes Chagas disease, dates back to pre-Columbian times in South America. Carlos Chagas,a Brazilian bacteriologist, was the first to discover the association between the Riduvid insect and T. cruzi. Carlos Chagas named the pathogen T. cruzi in honor of his mentor, Oswaldo Cruz. In 1966, Benznidazole was introduced and was the first antimicrobial agent against T. cruzi infections.

# Pathophysiology
The most common mode of transmission of Chagas disease is vectorborne via exposure to feces/urine of infected triatomine insects. Nonetheless, other modes of transmission, such as via blood transfusion, organ transplant, oral ingestion, breast milk, and vertical transmission, are possible. The hallmark of Chagas disease is inflammation. Acutely following transmission, a state of parasitemia, characterized by parasitic replication and host immune responses, is responsible for the development of clinical manifestations. Following the acute phase, it is thought that Chagas disease causes a state of low-grade persistent inflammation that eventually results in the development of chronic disease, manifested by multisystem involvement. The pathogenesis of chronic Chagas disease is poorly understood, but is thought to be caused by either persistent parasites that were not eliminated by the host during the acute phase or development of autoimmune destructive processes. On gross pathology, acute Chagas disease is characterized by inflammation, whereas chronic disease often demonstrates tissue dilation and congestion, along with evidence of fibrosis and wall thickening. On microscopic histopathological analysis, acute Chagas disease demonstrates mononuclear and lymphocytic infiltration in infected tissue, which chronically result in tissue denervation and fibrous scar formation.
Chagas disease in the heart:
The histologic diagnosis of Chronic Chagas cardiomyopathy (CCM) consists of a diffuse and patchy chronic myocarditis, interstitial mononuclear cell infiltrates, and myocardial fiber destruction with fibrotic replacement. Grossly enlarged hearts have been found in autopsy studies in subjects with end stage of Chagas disease. Left ventricular apical aneurysms are also frequently found on autopsy.

# Causes
Chagas disease is a human tropical parasitic disease usually caused by Trypanosoma cruzi, a flagellate protozoa.

# Differentiating Chagas disease from other Diseases
Chagas disease must be differentiated from other diseases the cause cardiomyopathy, hepatosplenomegaly, or esophageal/colonic dysfunction, such as electrophysiological cardiac diseases, GI hypomotility disorders, and malignancies.

# Epidemiology and Demographics
The global incidence of Chagas disease is estimated to be 5-8 million with global incidence of Chagas disease of approxiamtely 100-400 per 100,000 individuals. The majority of cases are reported in South America, where Chagas disease is considered the most common parasitic infection. Individuals of all age groups may acquire Chagas disease, including neonates due to risk of vertical transmission. Elderly patients often demonstrate clinical manifestations of chronic Chagas disease. Although there is no evidence that suggests racial predilection to the acquisition of the disease, the majority of cases are reported among individuals of Hispanic origin due to the endemicity of the disease in South America. The majority of cases outside South America are among South American immigrants.

# Risk Factors
Risk factors for Chagas disease include residence in Central or South America, living in old houses with either mud and sticks wall constructions or straw roofs, ingestion of contaminated water, or receiving blood transfusions / organ donation from individuals in regions with high endemicity. Neonatal risk is highest among those who breastfeed from bleeding / cracked nipples of infected mothers and those who are delivered from seropositive mothers with active disease.

# Natural History, Complications and Prognosis
The incubation period of T. cruzi is 1-2 weeks following transmission. The majority (90%-95%) of infected individuals remain asymptomatic in the acute phase following Chagas disease infection. Nonetheless, patients typically remain chronically infected and demonstrate clinical manifestations several years/decades following infection. Approximately 1/3 of patients develop manifestations of the chronic Chagas disease, namely cardiac conduction system dysfunction, GI denervation with esophageal and/or colonic dysfunction (megaesophagus and megacolon). Chagas cardiomyopathy is the most common chronic manifestation of the disease and accounts for approximately 80-90% of chronic manifestations. The majority of patients with Chagas cardiomyopathy die within 2 years of symptom onset.

# Diagnosis

## Symptoms
The majority of patients with acute Chagas disease infection are asymptomatic. Clinical manifestations of the acute phase of infection commonly non-specific symptoms, such as fever, myalgia, fatigue, and anorexia. Less commonly, patients may present with more severe disease that may be suggestive of early Chagas myocarditis or meningoencephalitis. Chronic symptoms are generally manifestations of Chagas either cardiomyopathy or GI disease.

## Physical Examination
On physical examination, Chagas disease may manifest with fever, tachycardia, cardiac rhythm abnormalities, hepatosplenomegaly, and lymphadenopathy. Romana's sign, a classical sign of Chagas disease, is characterized by eyelid sweilling at the site of parasitic entry. Other signs on physical examination are usually due to either cardiac or GI manifestations of the disease.

## Laboratory Findings
Acute Chagas disease is often diagnosed by peripheral blood smear following the visual detection of T. cruzi parasite. Serology is often helpful for chronic cases only, where assay positivity of both "whole parasite lysate" and "recombinant antigen" is usually required for the diagnosis. Although PCR is sensitive in acute cases (e.g. exposure following organ transplantation), its sensitivity and specificity are variable in the chronic state and highly depend on the pre-test probability.

## Electrocardiography
RBBB and AV block are common findings on ECG among patients with Chagas disease cardiomyopathy.

# Treatment

## Medical Therapy
Benznidazole and nifurtimox are the only antimicrobial therapies with proven efficacy against T. cruzi infection. Neither drug is FDA-approved, but can be obtained under investigational protocol. Either benznidazole or nifurtimox may be used to manage congenital infection, acute infection, and chronic infection (only among young patients < 50-55 years) including those with early cardiomyopathy.

## Primary Prevention
Methods of primary prevention of Chagas disease include use of insecticides to control the vector, use of new construction compounds in building walls and roofs, and organ/blood testing prior to donation.

## Future or Investigational Therapies
Although novel investigational drugs are being studied for chronic Chagas disease, to date no new pharmacologic therapy has proven to be effective compared with the current standard of care (either benznidazole or nifurtimox therapy)