Chagas disease

Chagas disease, also known as American trypanosomiasis, is a tropical parasitic disease caused by '' Trypanosoma cruzi''. It is spread mostly by insects in the subfamily '' Triatominae'', known as "kissing bugs". The symptoms change over the course of the infection. In the early stage, symptoms are typically either not present or mild, and may include fever, swollen lymph nodes, headaches, or swelling at the site of the bite. After four to eight weeks, untreated individuals enter the chronic phase of disease, which in most cases does not result in further symptoms. Up to 45% of people with chronic infections develop heart disease 10–30 years after the initial illness, which can lead to heart failure. Digestive complications, including an enlarged esophagus or an enlarged colon, may also occur in up to 21% of people, and up to 10% of people may experience nerve damage.

is commonly spread to humans and other mammals by the bite of a kissing bug. The disease may also be spread through blood transfusion, organ transplantation, consuming food or drink contaminated with the parasites, and vertical transmission (from a mother to her baby). Diagnosis of early disease is by finding the parasite in the blood using a microscope or detecting its DNA by polymerase chain reaction. Chronic disease is diagnosed by finding antibodies for in the blood.

Prevention focuses on eliminating kissing bugs and avoiding their bites. This may involve the use of insecticides or bed-nets. Other preventive efforts include screening blood used for transfusions. , a vaccine has not been developed. Early infections are treatable with the medications benznidazole or nifurtimox, which usually cure the disease if given shortly after the person is infected, but become less effective the longer a person has had Chagas disease. When used in chronic disease, medication may delay or prevent the development of end-stage symptoms. Benznidazole and nifurtimox often cause side effects, including skin disorders, digestive system irritation, and neurological symptoms, which can result in treatment being discontinued. , new drugs for Chagas disease are under development, and experimental vaccines have been studied in animal models.

It is estimated that 6.5 million people, mostly in Mexico, Central America and South America, have Chagas disease as of 2019, resulting in approximately 9,490 annual deaths. Most people with the disease are poor, and most do not realize they are infected. Large-scale population migrations have carried Chagas disease to new regions, which include the United States and many European countries. The disease affects more than 150 types of animals.

The disease was first described in 1909 by Brazilian physician Carlos Chagas, after whom it is named. Chagas disease is classified as a neglected tropical disease.

Signs and symptoms

Chagas disease occurs in two stages: an acute stage, which develops one to two weeks after the insect bite, and a chronic stage, which develops over many years. The acute stage is often symptom-free. When present, the symptoms are typically minor and not specific to any particular disease. Signs and symptoms include fever, malaise, headache, and enlargement of the liver, spleen, and lymph nodes. Sometimes, people develop a swollen nodule at the site of infection, which is called "Romaña's sign" if it is on the eyelid, or a "chagoma" if it is elsewhere on the skin. In rare cases (less than 1–5%), infected individuals develop severe acute disease, which can involve inflammation of the heart muscle, fluid accumulation around the heart, and inflammation of the brain and surrounding tissues, and may be life-threatening. The acute phase typically lasts four to eight weeks and resolves without treatment.

Unless treated with antiparasitic drugs, individuals remain infected with after recovering from the acute phase. Most chronic infections are asymptomatic, which is referred to as ''indeterminate'' chronic Chagas disease. However, over decades with the disease, approximately 30–40% of people develop organ dysfunction (''determinate'' chronic Chagas disease), which most often affects the heart or digestive system.

The most common long-term manifestation is heart disease, which occurs in 14–45% of people with chronic Chagas disease. People with Chagas heart disease often experience heart palpitations, and sometimes fainting, due to irregular heart function. By electrocardiogram, people with Chagas heart disease most frequently have arrhythmias. As the disease progresses, the heart's ventricles become enlarged ( dilated cardiomyopathy), which reduces its ability to pump blood. In many cases the first sign of Chagas heart disease is heart failure, thromboembolism, or chest pain associated with abnormalities in the microvasculature.

Also common in chronic Chagas disease is damage to the digestive system, which affects 10–21% of people. Enlargement of the esophagus or colon are the most common digestive issues. Those with enlarged esophagus often experience pain ( odynophagia) or trouble swallowing ( dysphagia), acid reflux, cough, and weight loss. Individuals with enlarged colon often experience constipation, and may develop severe blockage of the intestine or its blood supply. Up to 10% of chronically infected individuals develop nerve damage that can result in numbness and altered reflexes or movement. While chronic disease typically develops over decades, some individuals with Chagas disease (less than 10%) progress to heart damage directly after acute disease.

Signs and symptoms differ for people infected with through less common routes. People infected through ingestion of parasites tend to develop severe disease within three weeks of consumption, with symptoms including fever, vomiting, shortness of breath, cough, and pain in the chest, abdomen, and muscles. Those infected congenitally typically have few to no symptoms, but can have mild non-specific symptoms, or severe symptoms such as jaundice, respiratory distress, and heart problems. People infected through organ transplant or blood transfusion tend to have symptoms similar to those of vector-borne disease, but the symptoms may not manifest for anywhere from a week to five months. Chronically infected individuals who become immunosuppressed due to HIV infection can have particularly severe and distinct disease, most commonly characterized by inflammation in the brain and surrounding tissue or brain abscesses. Symptoms vary widely based on the size and location of brain abscesses, but typically include fever, headaches, seizures, loss of sensation, or other neurological issues that indicate particular sites of nervous system damage. Occasionally, these individuals also experience acute heart inflammation, skin lesions, and disease of the stomach, intestine, or peritoneum.

Cause

Chagas disease is caused by infection with the protozoan parasite , which is typically introduced into humans through the bite of triatomine bugs, also called "kissing bugs". When the insect defecates at the bite site, motile forms called trypomastigotes enter the bloodstream and invade various host cells. Inside a host cell, the parasite transforms into a replicative form called an amastigote, which undergoes several rounds of replication. The replicated amastigotes transform back into trypomastigotes, which burst the host cell and are released into the bloodstream. Trypomastigotes then disseminate throughout the body to various tissues, where they invade cells and replicate. Over many years, cycles of parasite replication and immune response can severely damage these tissues, particularly the heart and digestive tract.

Transmission

''T. cruzi'' can be transmitted by various triatomine bugs in the genera ''Triatoma'', ''Panstrongylus'', and ''Rhodnius''. The primary vectors for human infection are the species of triatomine bugs that inhabit human dwellings, namely '' Triatoma infestans'', '' Rhodnius prolixus'', ''Triatoma dimidiata'' and ''Panstrongylus megistus''. These insects are known by a number of local names, including ''vinchuca'' in Argentina, Bolivia, Chile and Paraguay, ''barbeiro'' (the barber) in Brazil, ''pito'' in Colombia, ''chinche'' in Central America, and ''chipo'' in Venezuela. The bugs tend to feed at night, preferring moist surfaces near the eyes or mouth. A triatomine bug can become infected with when it feeds on an infected host. replicates in the insect's intestinal tract and is shed in the bug's feces. When an infected triatomine feeds, it pierces the skin and takes in a blood meal, defecating at the same time to make room for the new meal. The bite is typically painless, but causes itching. Scratching at the bite introduces the -laden feces into the bite wound, initiating infection.

In addition to classical vector spread, Chagas disease can be transmitted through consumption of food or drink contaminated with triatomine insects or their feces. Since heating or drying kills the parasites, drinks and especially fruit juices are the most frequent source of infection. This oral route of transmission has been implicated in several outbreaks, where it led to unusually severe symptoms, likely due to infection with a higher parasite load than from the bite of a triatomine bug.

''T. cruzi'' can be transmitted independent of the triatomine bug during blood transfusion, following organ transplantation, or across the placenta during pregnancy. Transfusion with the blood of an infected donor infects the recipient 10–25% of the time. To prevent this, blood donations are screened for in many countries with endemic Chagas disease, as well as the United States. Similarly, transplantation of solid organs from an infected donor can transmit to the recipient. This is especially true for heart transplant, which transmits ''T. cruzi'' 75–100% of the time, and less so for transplantation of the liver (0–29%) or a kidney (0–19%). An infected mother can pass to her child through the placenta; this occurs in up to 15% of births by infected mothers. As of 2019, 22.5% of new infections occurred through congenital transmission.

Pathophysiology

In the acute phase of the disease, signs and symptoms are caused directly by the replication of and the immune system's response to it. During this phase, can be found in various tissues throughout the body and circulating in the blood. During the initial weeks of infection, parasite replication is brought under control by production of antibodies and activation of the host's inflammatory response, particularly cells that target intracellular pathogens such as NK cells and macrophages, driven by inflammation-signaling molecules like TNF-α and IFN-γ.

During chronic Chagas disease, long-term organ damage develops over years due to continued replication of the parasite and damage from the immune system. Early in the course of the disease, is found frequently in the striated muscle fibers of the heart. As disease progresses, the heart becomes generally enlarged, with substantial regions of cardiac muscle fiber replaced by scar tissue and fat. Areas of active inflammation are scattered throughout the heart, with each housing inflammatory immune cells, typically macrophages and T cells. Late in the disease, parasites are rarely detected in the heart, and may be present at only very low levels.

In the heart, colon, and esophagus, chronic disease leads to a massive loss of nerve endings. In the heart, this may contribute to arrythmias and other cardiac dysfunction. In the colon and esophagus, loss of nervous system control is the major driver of organ dysfunction. Loss of nerves impairs the movement of food through the digestive tract, which can lead to blockage of the esophagus or colon and restriction of their blood supply.

Diagnosis

The presence of ''T. cruzi'' in the blood is diagnostic of Chagas disease. During the acute phase of infection, it can be detected by microscopic examination of fresh anticoagulated blood, or its buffy coat, for motile parasites; or by preparation of thin and thick blood smears stained with Giemsa, for direct visualization of parasites. Blood smear examination detects parasites in 34–85% of cases. The sensitivity increases if techniques such as microhematocrit centrifugation are used to concentrate the blood. On microscopic examination of stained blood smears, trypomastigotes appear as S or U-shaped organisms with a flagellum connected to the body by an undulating membrane. A nucleus and a smaller structure called a kinetoplast are visible inside the parasite's body; the kinetoplast of is relatively large, which helps to distinguish it from other species of trypanosomes that infect humans.

Alternatively, ''T. cruzi'' DNA can be detected by polymerase chain reaction (PCR). In acute and congenital Chagas disease, PCR is more sensitive than microscopy, and it is more reliable than antibody-based tests for the diagnosis of congenital disease because it is not affected by transfer of antibodies against from a mother to her baby ( passive immunity). PCR is also used to monitor levels in organ transplant recipients and immunosuppressed people, which allows infection or reactivation to be detected at an early stage.

In chronic Chagas disease, the concentration of parasites in the blood is too low to be reliably detected by microscopy or PCR, so the diagnosis is usually made using serological tests, which detect immunoglobulin G antibodies against in the blood. Two positive serology results, using different test methods, are required to confirm the diagnosis. If the test results are inconclusive, additional testing methods such as Western blot can be used.

Various rapid diagnostic tests for Chagas disease are available. These tests are easily transported and can be performed by people without special training. They are useful for screening large numbers of people and testing people who cannot access healthcare facilities, but their sensitivity is relatively low, and it is recommended that a second method is used to confirm a positive result.

''T. cruzi'' parasites can be grown from blood samples by blood culture, xenodiagnosis, or by inoculating animals with the person's blood. In the blood culture method, the person's red blood cells are separated from the plasma and added to a specialized growth medium to encourage multiplication of the parasite. It can take up to six months to obtain the result. Xenodiagnosis involves feeding the blood to triatomine insects, then examining their feces for the parasite 30 to 60 days later. These methods are not routinely used, as they are slow and have low sensitivity.

Prevention

Efforts to prevent Chagas disease have largely focused on vector control to limit exposure to triatomine bugs. Insecticide-spraying programs have been the mainstay of vector control, consisting of spraying homes and the surrounding areas with residual insecticides. This was originally done with organochlorine, organophosphate, and carbamate insecticides, which were supplanted in the 1980s with pyrethroids. These programs have drastically reduced transmission in Brazil