Chagas disease

• 1. Introduction

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  Chagas disease travels on the back of an insect with an affectionate-sounding nickname, the kissing bug. These triatomine bugs feed at night, and they prefer the moist skin near the eyes or mouth of a sleeping person. The parasite they carry, Trypanosoma cruzi, can then live in a human body for decades. In 2019, an estimated 6.5 million people had the disease, mostly in Mexico, Central America and South America. Most of them were poor, and most did not know they were infected. How does a bite that barely registers lead, years later, to a failing heart? How did one Brazilian physician identify a disease, its cause and its carrier? And why do blood banks in Spain and the United States now screen for an illness once tied to rural Latin America?

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• 2. How It Spreads

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  Vinchuca, barbeiro, pito, chinche and chipo are all local names for the same family of insects. Vinchuca is used in Argentina, Bolivia, Chile and Paraguay. Barbeiro, meaning the barber, is the Brazilian word, while pito is Colombian, chinche is heard in Central America, and chipo in Venezuela. Four species matter most for people because they live inside human homes: Triatoma infestans, Rhodnius prolixus, Triatoma dimidiata and Panstrongylus megistus.

  The infection depends on a quirk of the bug's digestion. A triatomine becomes infected when it feeds on an infected host, and the parasite multiplies in its gut and leaves in its feces. When that bug pierces skin for a blood meal, it defecates at the same moment to make room for the new meal. The bite is usually painless, but it itches. Scratching pushes the parasite-laden feces into the wound, and the infection begins.

  The bug is not the only route. A single crushed triatomine in a drink can hold about 600,000 infective parasites of the metacyclic trypomastigote form. Bug feces carry 3,000 to 4,000 of them per microliter. Heat and drying kill the parasites, so drinks, and fruit juices in particular, are the most frequent source. Outbreaks from food and drink have produced unusually severe illness, probably because the dose is larger than a bite delivers. People infected this way tend to fall seriously ill within three weeks, with fever, vomiting, shortness of breath, cough, and pain in the chest, abdomen and muscles.

  Transfusion with blood from an infected donor infects the recipient 10 to 25 percent of the time. Organ transplants carry a steeper risk. A transplanted heart passes on the parasite 75 to 100 percent of the time, a liver 0 to 29 percent, and a kidney 0 to 19 percent. Symptoms in these patients resemble those from a bug bite but can take anywhere from a week to five months to appear.

  A mother can also pass the parasite to her baby across the placenta, which happens in up to 15 percent of births to infected mothers. Most of these babies show few or no symptoms, though some have jaundice, breathing trouble or heart problems. By 2019-22.5 percent of all new infections were of this congenital kind.

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• 3. Inside the Body

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  Trypomastigotes are the swimming form of the parasite, and they enter the bloodstream where the bug's feces meet the wound. They then invade cells and turn into a second, replicating form called the amastigote. After several rounds of multiplication, the amastigotes change back into trypomastigotes and burst the cell. The freed parasites spread through the body to invade more tissue, and the cycle repeats.

  In the first weeks, the body fights back. Antibodies and inflammatory cells, including NK cells and macrophages, bring replication under control. Signaling molecules called TNF-alpha and IFN-gamma drive that response. The symptoms of this early phase come from both the parasite itself and the immune reaction to it.

  The long chronic phase is slower and more destructive. Early on, the parasite is often found in the heart's striated muscle fibers. Over years, large regions of heart muscle are replaced by scar tissue and fat, with scattered patches of active inflammation full of macrophages and T cells. Late in the disease, parasites in the heart are rarely detected and may be present only at very low levels.

  Nerves suffer too. In the heart, colon and esophagus, chronic disease causes a massive loss of nerve endings. In the heart, this may feed arrhythmias. In the esophagus and colon, losing nerve control is the main cause of failure, because food no longer moves properly through the digestive tract.

  The parasite also does something stranger. It can insert its kinetoplast DNA into the DNA of host cells, an example of horizontal gene transfer. Offspring of infected chickens carrying inserted kinetoplast DNA showed symptoms of disease even though they carried no live trypanosomes. In 2010, researchers found integrated kinetoplast DNA being passed down in five human families.

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• 4. Stages of Illness

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  One to two weeks after a bite, the acute stage can begin, though it is often completely silent. When symptoms appear, they are usually minor and fit many other illnesses: fever, malaise, headache, and enlarged liver, spleen and lymph nodes. Some people develop a swollen nodule at the infection site. Doctors call it Romaña's sign when it forms on the eyelid and a chagoma when it forms elsewhere on the skin. Fewer than 1 to 5 percent of people develop a severe acute illness, with inflamed heart muscle, fluid around the heart, or brain inflammation. The acute phase lasts four to eight weeks and ends without treatment.

  The parasite stays behind. Without antiparasitic drugs, people remain infected after recovering, and most chronic infections cause no symptoms. This silent form is called indeterminate chronic Chagas disease. Over decades, about 30 to 40 percent of people develop organ damage, most often in the heart or digestive system. Fewer than 10 percent move to heart damage directly after the acute phase.

  Heart disease is the most common long-term outcome, affecting 14 to 45 percent of people with chronic infection. Palpitations and sometimes fainting come from irregular heart function, and electrocardiograms most often show arrhythmias. The heart's ventricles then enlarge, a condition called dilated cardiomyopathy, which weakens its pumping. For many patients, the first sign is heart failure, a blood clot, or chest pain linked to damage in the smallest blood vessels.

  The digestive system is hit in 10 to 21 percent of chronic cases. An enlarged esophagus brings painful or difficult swallowing, acid reflux, cough and weight loss. An enlarged colon brings constipation and can lead to severe blockage of the intestine or its blood supply. Up to 10 percent of people also develop nerve damage, with numbness and altered reflexes or movement.

  Chronically infected people who become immunosuppressed through HIV face a different and harsher illness. It is most often marked by brain inflammation or brain abscesses, with fever, headaches, seizures and loss of sensation.

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• 5. Finding and Treating

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  Under a microscope, the parasite in a stained blood smear looks like an S or a U, with a flagellum attached along an undulating membrane. A relatively large kinetoplast helps distinguish it from other trypanosomes that infect humans. Smears find the parasite in 34 to 85 percent of acute cases, and spinning blood in a microhematocrit centrifuge raises the odds. Polymerase chain reaction, which detects parasite DNA, is more sensitive in acute and congenital disease. It also avoids a trap in babies, since antibody tests can be fooled by antibodies passed from the mother.

  In chronic disease, parasites in the blood are too scarce for either method. Doctors instead look for immunoglobulin G antibodies, and two positive results from different test methods are needed to confirm the diagnosis. Rapid tests are portable and need no special training, but their sensitivity is relatively low, so positives should be confirmed. Two older methods are rarely used. Blood culture can take up to six months, and xenodiagnosis feeds the patient's blood to triatomine bugs and checks their feces 30 to 60 days later.

  Two drugs treat the infection, benznidazole and nifurtimox, and benznidazole is the only one available in most of Latin America. Treatment typically means two to three oral doses a day for 60 to 90 days. Timing matters enormously. The drugs eliminate the parasite from 50 to 80 percent of people in the acute phase, but only 20 to 60 percent in the chronic phase. The cure rate for congenital disease approaches 100 percent when treatment starts in the first year of life.

  The side effects are heavy. Benznidazole is stopped in up to 29 percent of patients, usually because of rash, digestive problems, weakness or sleeplessness. Nifurtimox causes side effects in up to 97.5 percent of those taking it, including weight loss and mood changes, and treatment is stopped in up to 75 percent of cases. Resistance to both drugs had been reported by 2019. Neither is recommended in pregnancy or in liver or kidney failure.

  Killing the parasite does not repair a damaged heart or colon, so those problems are treated separately. Heart patients may receive beta blockers, ACE inhibitors, amiodarone, blood thinners or a pacemaker. Chagas heart disease is a common reason for heart transplantation, and recipients with Chagas disease survive longer than the average transplant patient. Looking ahead, fexinidazole, a drug approved for African trypanosomiasis, was in phase II trials for chronic Chagas disease in Spain as of 2019.

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• 6. A Disease Named

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  A 9000-year-old Chinchorro mummy from the Atacama Desert carries evidence of T. cruzi. So do remains of various ages in Minas Gerais, and an 1100-year-old mummy found as far north as the Chihuahuan Desert near the Rio Grande. The parasite likely circulated in South American mammals long before people arrived. Early written accounts describe symptoms consistent with the disease, and descriptions are sometimes credited to Miguel Diaz Pimenta in 1707, Luís Gomes Ferreira in 1735, and Theodoro J. H. Langgaard in 1842.

  The formal discovery came in 1909, when Carlos Chagas examined a two-year-old girl with fever, swollen lymph nodes, and an enlarged spleen and liver. In her blood he saw trypanosomes identical to those he had recently found in the hindgut of triatomine bugs. He named the organism Trypanosoma cruzi to honor his mentor, the Brazilian physician Oswaldo Cruz. Chagas sent infected bugs to Cruz in Rio de Janeiro, who showed that a bite from one could infect marmoset monkeys. Across 1908 and 1909, Chagas published the disease, the organism and the insect carrier.

  At the suggestion of Miguel Couto, a professor at the Faculdade de Medicina do Rio de Janeiro, the illness soon became widely known as Chagas disease. Fame brought a cost. By exposing the shortcomings of the Brazilian government's response, Chagas drew criticism onto himself and his disease. That criticism stifled research and likely frustrated his Nobel Prize nomination in 1921.

  Research revived in the 1930s, when Salvador Mazza described more than a thousand cases in Argentina's Chaco Province. In Argentina the illness is still called mal de Chagas-Mazza in his honor.

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• 7. Campaigns Against the Bug

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  Serological tests introduced in the 1940s showed that T. cruzi infection was widespread across Latin America. Combined with the success of insecticides against the malaria mosquito, that finding led to campaigns to spray houses and wipe out triatomine bugs. In the 1950s, researchers discovered that crystal violet could destroy the parasite in blood, and it became widely used in transfusion screening in Latin America.

  Large control programs took shape in the 1960s, first in São Paulo, then in parts of Argentina, then nationwide across Latin America. A major boost came in the 1980s, when pyrethroid insecticides replaced the older organochlorine, organophosphate and carbamate chemicals. Pyrethroids left no stains or odors and lasted longer at lower cost. With support from the Pan American Health Organization, regional bodies followed. The Southern Cone initiative launched in 1991, the Andean and Central American initiatives in 1997, and the Amazon initiative in 2004.

  The sprays worked. Triatoma infestans was eliminated from Brazil, Chile, Uruguay and parts of Peru and Paraguay, and Rhodnius prolixus was eliminated from Central America. Resistance to insecticides has slowed progress in some regions. Programs responded with other chemicals such as fenitrothion and bendiocarb in Argentina and Bolivia, treatment of domestic animals the bugs also feed on, and pesticide-impregnated paints. Bed nets and housing improvements that keep bugs from colonizing homes also protect people.

  Blood safety changed as well. T. cruzi survives refrigeration, freezing and thawing, so it can persist in whole blood, red cells, platelets and other products. Nearly all blood donations in Latin America are now screened. Several countries with large immigrant populations followed: the United Kingdom in 1999, Spain in 2005, the United States in 2007, France and Sweden in 2009, Switzerland in 2012 and Belgium in 2013.

  Mothers and organs are screened too. Treating infected mothers during pregnancy lowers the risk of congenital infection, and the World Health Organization recommends screening all children born to infected mothers. No vaccine exists. Experimental vaccines reduced parasite numbers in the blood and heart of infected animals, but none had entered human clinical trials as of 2016.

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• 8. Beyond Latin America

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  Each year, Chagas disease brings roughly 173,000 new infections and 9,490 deaths, and it costs over 800,000 years of healthy life. Its economic burden was estimated at US$7.2 billion in 2013, with 86 percent borne by endemic countries. Bolivia has the highest prevalence at 6.1 percent, followed by Argentina at 3.6 percent and Paraguay at 2.1 percent. The endemic zone stretches from the southern United States to northern Chile and Argentina, and covers 21 countries in continental Latin America.

  Progress has been real. From the 1980s peaks to 2010, annual infections fell by 67 percent and deaths by more than 73 percent. Transmission by bug and by blood transfusion was fully interrupted in Uruguay in 1997, in Chile in 1999, and in Brazil in 2006. Setbacks followed. During Venezuela's humanitarian crisis, bug-borne transmission returned to areas where it had been stopped. In Venezuela, 16 oral outbreaks were recorded between 2007 and 2018. Rates have also risen in the Gran Chaco and in the Amazon basin, where oral transmission is the driver, possibly because urbanization and deforestation bring people closer to triatomines.

  More than 100 mammal species across Latin America are commonly infected, among them opossums, armadillos, marmosets, bats, rodents and dogs. Eating infected bugs or infected animals can pass the parasite along. Opossums of the genus Didelphis are unusual, because they can complete the parasite's life cycle through their own urine and feces without any bug. Climate change will affect where the disease occurs, though the effects depend on the region, the carrier species and the climate scenario.

  Migration has carried the disease far from its rural roots. Around 300,000 infected people lived in the United States as of 2020, and in 2018 an estimated 30,000 to 40,000 of them had Chagas cardiomyopathy. In Europe, 68,000 to 123,000 people were affected as of 2019, with 50,000 to 70,000 in Spain. Italy has the second highest prevalence, followed by the Netherlands, the United Kingdom and Germany.

  The United States has eleven native triatomine species and southern states where parasites cycle between bugs and animals such as woodrats, raccoons and skunks. From 2000 to 2018-29 confirmed locally acquired cases were reported in eight states. Some scientists argue the country should be reclassified as "hypoendemic" for Chagas disease, a label meant to reflect how rarely transmission occurs.

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