Chagas Disease

Introduction

Chagas disease is a neglected tropical disease named after the Brazilian scientist, Carlos Chagas, who first described the life cycle of the parasite – Trypanosoma cruzi (T. cruzi) that causes the disease. Chagas is primarily transmitted via the faeces of triatomine bugs (also known as 'kissing bugs') when they take a blood meal. Other forms of transmission include: blood transfusions, orally via ingestion of contaminated fluids, vertical transmission. Chagas is endemic to Latin America but increased migration of infected people has led to it spreading to non-endemic countries, consequently increasing the number of people susceptible to the disease and causing it to be a growing global concern.

Since the 1990s, strategies to reduce the impact of Chagas in endemic countries have largely focused on preventing transmission through vector control programmes and screening blood banks. Although these achievements have significantly reduced its incidence, they are not sufficient to combat the spread of the disease vertically from a mother to her child. Therefore, congenital Chagas disease is growing in epidemiological importance, as it is now one of the most persistent forms of the transmission among the human population, with prevalence in some rural areas of Bolivia being as high as 70.5%.

All life stages of T.cruzi secrete a specific protease, known as cruzipain, which allow the presence of the trypomastigotes to be detected by our biosensor. However, the levels of trypomastigotes in the human blood falls with time after infection, as shown in Figure 1.

Figure 1: Lifecycle of T. cruzi

Acute and chronic phases

Within 4-8 weeks of being bitten, adults move from the acute phase of Chagas disease to the chronic phase if untreated.

During the chronic phase, cruzipain levels are very low in the blood and cost effective diagnosis of adults focuses on detecting antibodies specific to T. cruzi. However, antibody based diagnosis is unsuitable for newborns who lack a fully developed immune system. Newborns infected with congenital Chagas disease remain in the acute phase for up to 9 months, during which period there is no cost-effective diagnostic currently available. We hope to fill this gap in the ability to diagnose congenital Chagas disease in newborns, using synthetic biology to create a specific protease detection system.

Figure 2: Scheme of evolution of T. cruzi trypomastigotes in the blood of a human host

Symptoms and current diagnosis

Diagnosis of Chagas disease is difficult, as the disease is mostly asymptomatic in the acute phase and for the majority of the chronic phase. However, prolonged onset of the chronic phase leads to 30% of patients developing cardiac disorders and up to 10% developing digestive, neurological or mixed alterations that cause 12,000 deaths per year. The main diagnostic methods currently used to diagnose Chagas are summarised in the table below:

Table 1: Main diagnostic methods currently used to diagnose Chagas disease

Test	How it works	Benefits	Limitations	Suitable for newborns
Whole parasite microscopy	Preparation of Giesma blood smears Visualised using light microscopy	Established method Carried out by already trained professionals	Not suitable for the when there is little T. cruzi in the blood Not always possible to differentiate between T. cruzi from T. rangeli, which does not cause disease in humans.	Yes
Polymerase Chain Reaction (PCR)	Molecular detection of T. cruzi DNA is performed using a combination of three real-time PCR assays. Acceptable specimen types are EDTA blood, heart biopsy tissue or cerebrospinal fluid.	Allows high sensitivity in the acute phase Allows the presence of T.cruzi to be accurately distinguished from T. rangeli Allows direct detection of infection and easy interpretation of results	High variation in accuracy and lack of international quality controls High cost and complexity means it is not practical to use in a clinical practice Further validation is needed to prove whether PCR is suitable to diagnose the chronic phase of Chagas	Yes
Serological tests	Detection of antibodies against T. cruzi Includes techniques such as indirect fluorescent antibody (IFA) test, a commercial enzyme immunoassay (EIA) and immunochromatographic tests	Can be used for acute phase and chronic phase High specificity and sensitivity Commercialised and approved for use by WHO Low-cost formats are available	Cross reactivity can occur with diseases, such as leishmaniasis and schistosomiasis Performance of these tests is lower than reported by their manufacturer, especially against specific strains of T. cruzi Not suitable for immunocompromised patients and newborns	No

The table highlights the lack of a rapid and feasible diagnostic for congenital Chagas disease. Moreover, in June 2016 the WHO and experts on Chagas disease based in Latin America regarded a point-of-care diagnostic for congenital Chagas as their top priority in terms of the diagnostic needs for Chagas disease. The diagnostic needs were ranked following considerations of existing diagnostic tools and the expected clinical and epidemiological scenario of Chagas disease in the next five years. Strategies to tackle Chagas disease in an optimal fashion using our diagnostic device in the current Latin American society in Bolivia is outlined in our public policy proposal that can be found below:

Treatment

An 8 week course of benznidazole or nifurtimox can be used to kill the parasite and treat Chagas disease. The younger the patient and the closer to acquisition of the infection, the higher the probability of parasitologic cure. Therefore, newborns with congenital Chagas disease have the greatest chance for cure, with data from Argentina indicating that the cure rate is higher than 90% if treatment is given within the first year of life. In most cases the potential benefits of medication in curing, preventing or delaying Chagas is balanced against the possible adverse reactions that occur in up to 40% of treated patients. However, newborns are least affected by side effects of benznidazole or nifurtimox, due to the lower weight-accounted dosage, making treatment a very viable option. If the chronic phase is left untreated, additional specific treatment for cardiac or digestive manifestations may be required.

References

Louis V Kirchhoff, 2017. Chagas Disease (American Trypanosomiasis) Treatment &
Management. [Online] Available at
[Accessed September 2017].

WHO, 2017. Chagas disease (American trypanosomiasis) - Control strategy. [Online]
Available at: [Accessed October 2017].

Ana María Cevallos and Roberto Hernández, 2014. “Chagas’ Disease: Pregnancy and
Congenital Transmission,” BioMed Research International, vol. 2014, Article ID 401864, 10
pages. doi:10.1155/2014/401864

Hemmige, V., Tanowitz, H., & Sethi, A., 2012. Trypanosoma cruzi infection: a review with
emphasis on cutaneous manifestations. International Journal of Dermatology, 51(5),
501–508. .

Marin-Neto, J. A., Cunha-Neto, E., Maciel, B. C., & Simões, M. V. 2007 Pathogenesis of
chronic Chagas heart disease. Circulation, 115(9), 1109-1123.

Team:Oxford/Chagas Disease