For the majority of you, our students, the mention of Chagas’ disease will bring blank stares. A few may have some vague recollection of some far-off illness, perhaps even a hint of its Latin American origins. Most, though, will have no idea what it is or whether it is even of any importance to you. But, like so many other esoteric illnesses, it is now rearing its ugly head in the United States and becoming an American problem.
Chagas’ disease was named after Carlos Chagas, a Brazilian physician who in 1909 was the first to describe the disease and its cause. It is endemic in Latin America, where an estimated 8 million people are affected. Chagas’ disease is a life-long illness and, if untreated, it can result in life-threatening health conditions.
The cause is infection with the protozoan parasite, Trypanosoma cruzi, which is transmitted to people and animals by insects found only in the Americas. Chagas’ disease is also known as American trypanosomiasis. African sleeping sickness, or African trypanosomiasis, is spread by a different insect but also caused by a protozoa in the Trypanosoma genus (see the table below).
|Chagas’ disease (American trypanosomiasis) vs. African sleeping sickness (African trypanosomiasis) |
| ||Chagas’ disease ||African sleeping sickness |
|Infectious agent ||Trypanosoma cruzi ||Two subspecies of Trypanosoma brucei, T.b. rhodesiense and T.b. gambiense |
|Transmission ||Through feces of infected Triatomine insects when bug bites are scratched; also through blood transfusion, organ transplantation, and mother-to-infant. ||Bite of infected tsetse fly. Flies bite during the day and less than 1% are infected. Bloodborne and congenital transmission is rare. |
|Epidemiology ||Endemic in parts of Mexico and Central and South America; in the U.S., primarily a disease of immigrants from endemic areas of Latin America; risk to travelers is low. ||Endemic in rural sub-Saharan Africa. Cases imported to the U.S. are rare. |
|Clinical presentation ||Acute illness develops one week or more after exposure and lasts up to 60 days. Most infected people never develop symptoms. About 20%–30% of patients develop chronic manifestations that may affect the heart. Less common are chronic GI problems (megaesophagus and megacolon). ||Infection with T.b. rhodesiense: High fever, headache, chancre at the bite site, malaise, myalgia, other symptoms 1–3 weeks after infective bite. Central nervous system involvement may occur within a month and may result in sleep cycle disturbance, mental deterioration, and eventually death. |
Infection with T.b. gambiense: Nonspecific symptoms like fever, headache, malaise, and myalgia can appear months to years after an infective bite. Central nervous system involvement may occur several months to years after infection and is characterized by daytime somnolence, nighttime sleep disturbance, severe headaches, and other neurologic problems.
The clinical course of infection with T.b. gambiense is usually less severe than infection with T.b. rhodesiense.
|Treatment drugs ||Benznidazole (now FDA approved) and nifurtimox (available under a CDC investigational protocol). ||Suramin, melarsoprol, and eflornithine are available under CDC investigational protocol. Choice of treatment drug depends on whether disease is the result of T.b. rhodesiense or T.b. gambiense infection and the stage of the disease. |
| Source: CDC Health Information for International Travel (2018 Yellow Book). |
About a dozen different but related insects in the Triatominae subfamily are capable of transmitting T. cruzi. The Triatomine insects go by a variety of common names, some pleasant (kissing bugs), others not (assassin bugs, bloodsuckers), and some merely descriptive (cone-nosed bugs). The unpleasant names are suitable; these creatures survive by biting and sucking blood.
In this country, various members of the Triatominae are found throughout the South and north into the nation’s mid-section up to an imaginary line that could be drawn through Pennsylvania, Ohio, Indiana, Illinois, Missouri, Kansas, Colorado, Utah and northern California. The insects are commonly found inside homes in Latin America because houses there are open and constructed very simply. Chagas’ is endemic in many Latin American countries for that reason. In this country, doors, windows, screens, and finished walls keep the insects out. But not always: Pets and rodents bring them inside, and they are found where pets sleep, in and around the beds used by the human inhabitants, and any place where mice and other rodents nest.
The details of how the parasite gets into human beings are not pretty: The bugs typically defecate on or near people while they are feeding on blood and then the fecal material containing the parasite gets scratched or rubbed into the bite wound or into a mucous membrane when, for example, someone rubs his or her eyes. The parasite can also be transmitted from mothers to children, through contaminated blood, and when organs are transplanted.
Americans don’t need to worry too much about getting infected with insect-borne Chagas’ disease. Most of the estimated 300,000 people in the United States with Chagas’ were infected when they were visiting countries where the disease is endemic. But because of the possibility of transmission from blood transfusion, American blood banks routinely check for evidence of T. cruzi.
Sometimes fatal heart arrhythmias
Once a human is infected with T. cruzi, the symptoms and signs depend upon where the parasite entered the body. If the route of infection is the conjunctiva of the eye, intense swelling can result and close the eye shut. But if it enters through the skin, the swelling may be minor; some people may not even notice. The illness has an acute phase and a chronic phase (sometimes called chronic indeterminate).
Acute Chagas’ disease occurs immediately after infection and may last a few weeks or months. During this phase, the parasite may be identified in the blood and seen under an ordinary microscope. The symptoms are usually mild or nonexistent. Rarely, severe inflammation of the heart muscle or brain and brain lining may occur. After the early acute phase, most infected people enter into a long-term asymptomatic form of the disease when few, if any, of the parasites can be isolated from the blood. Luckily, most people remain asymptomatic.
The problem is that about one in four people with Chagas’ disease develop debilitating and sometimes life-threatening medical problems, including heart arrhythmias (which can be fatal) and heart failure. The disease can also result in gastrointestinal problems, such as an enlarged esophagus or colon. Immunosuppression, whether from illness such as HIV or from medical treatment such as chemotherapy, can reactivate a more aggressive form of Chagas’.
Approval based on three trials
Until recently, there was no treatment bearing the FDA’s stamp of approval for Chagas’ disease. That changed in late August 2017 when the FDA approved benznidazole, which is not a new drug and has been approved as a treatment for Chagas’ disease in other countries. Another drug, nufurtimox, is also used to treat Chagas’, but it has not been FDA approved.
Under the FDA approval, benznidazole is indicated for children ages 2 to 12 years with Chagas’ disease. The drug is administered in two divided doses approximately 12 hours apart for a duration of 60 days. It’s thought that benznidazole works by triggering secondary production of reactive metabolites in T. cruzi, which leads to alkylation and oxidative damage to the DNA and RNA in the parasite.
The safety and efficacy of benznidazole were established in two placebo-controlled clinical trials (Trials 1 and 2) in pediatric patients, ages 6 to 12. Further data were obtained in a small uncontrolled trial (Trial 3). Benznidazole was approved under an accelerated approval process. The primary endpoint was the percentage of patients with serologic clearance of antigens.
Both trials were similar in enrollment and outcome methodology. Trial 1 included 106 pediatric patients, ages 6 to 12, in Argentina with chronic indeterminate Chagas’ disease and serologic evidence of T. cruzi infection but without symptoms of cardiac or gastrointestinal disease. They were followed for four years; 55 patients received active drug and 51 received a placebo. Trial 2 included 129 patients, ages 7 to 12, in Brazil that were followed for three years; 64 received active drug, 65 received placebo. Both trials used conventional serologic tests (IHA, IFA, and/or ELISA) as well as unconventional assays (F29-ELISA and AT-chemiluminescence-ELISA that are based on detection of anti–T. cruzi IgG antibodies against the recombinant antigens, F29 and AT, from the flagella of T. cruzi parasites). The results showed a seronegative rate of 47%–50% in the patients treated with benznidazole compared with a rate of 4.6%–13% among those assigned to take the placebo pills.
The most frequently reported adverse reactions in pediatric patients treated with benznidazole in both trials were abdominal pain (about 25%), rash (about 16%), decreased weight (about 13%), and headache (about 7%).
Benznidazole has also been associated with some more severe but rare adverse events, including serious dermatologic reactions, bone marrow depression, and nervous system effects such as paresthesia, insomnia, and convulsions. Based on findings from animal studies, benznidazole could cause fetal harm when administered to a pregnant woman.
There are several interesting aspects to benznidazole. For starters, the Spanish company that got the approval, Chemo Group, has two strong not-for-profit partners, Mundo Sano, an Argentine nongovernmental organization, and Drugs for Neglected Diseases Initiative, a not-for-profit drug development organization. They have promised to keep benznidazole affordable and accessible and even promised aid to those with Chagas’ disease.
Martin Shkreli testifying before the House Committee on Oversight and Government Reform, 2016
This is especially notable because another company, Humanigen, was also in the running for the benznidazole approval. Humanigen, when it was named KaloBios, had been led by Martin Shkreli, the notorious “pharma bro” who is now awaiting sentencing on securities fraud. KaloBios had fired Shkreli but even with the name change to Humanigen it has had difficulty recovering its reputation and shaking the association with Shkreli. As head of another company, Turing Pharmaceuticals, Shkreli became infamous for buying up the rights to Daraprim, which like benznidazole is an antiparasitic medication, and jacking up the price from $13.50 a tablet to $750. At one point, Shkreli had similar plans for benznidazole.
But the bigger picture here is that we must expect increased exposure to previously unfamiliar infectious illnesses like Chagas’ disease. Trade, travel, immigration—they have made the world a much smaller place. Hardly any place in the world can be considered truly remote.
To their credit, the CDC and FDA have implemented proactive programs to identify, study, and approve drugs for these new health threats through a variety of initiatives. The threats won’t go away. We can’t let our collective guard down. But the approval of benznidazole shows we can respond to these new threats in both a medically and an economically responsible manner. And therein lies some cause for hope.