Assessing antibody decline after chemotherapy of early chronic Chagas disease patients

Niamh Murphy,Natalia P Macchiaverna,M Victoria Cardinal,Michael A Miles,Gustavo F Enriquez,Pascal Mertens,Ricardo E Gürtler,Tapan Bhattacharyya,Héctor Freilij,Alejandra Alvedro,Quentin Gilleman,Israel Molina,Pablo Martinez De Salazar

doi:10.1186/s13071-021-05040-6

Abstract

BackgroundChagas disease remains a significant public health problem in Latin America. There are only two chemotherapy drugs, nifurtimox and benznidazole, and both may have severe side effects. After complete chemotherapy of acute cases, seropositive diagnosis may revert to negative. However, there are no definitive parasitological or serological biomarkers of cure.MethodsFollowing a pilot study with seven Bolivian migrants to Spain, we tested 71 serum samples from chronic patients (mean age 12.6 years) inhabiting the Argentine Chaco region. Benznidazole chemotherapy (5–8 mg/kg day, twice daily for 60 days) was administered during 2011–2016. Subsequently, pre-and post-chemotherapy serum samples were analysed in pairs by IgG1 and IgG ELISA using two different antigens and Chagas Sero K-SeT rapid diagnostic tests (RDT). Molecular diagnosis by kDNA-PCR was applied to post-treatment samples.ResultsPilot data demonstrated IgG1 antibody decline in three of seven patients from Bolivia 1 year post-treatment. All Argentine patients in 2017 (averaging 5 years post-treatment), except one, were positive by conventional serology. All were kDNA-PCR-negative. Most (91.5%) pre-treatment samples were positive by the Chagas Sero K-SeT RDT, confirming the predominance of TcII/V/VI. IgG1 and IgG of Argentine patients showed significant decline in antibody titres post-chemotherapy, with either lysate (IgG, P = 0.0001, IgG1, P = 0.0001) or TcII/V/VI peptide antigen (IgG, P = 0.0001, IgG1, P = 0.0001). IgG1 decline was more discriminative than IgG. Antibody decline after treatment was also detected by the RDT. Incomplete treatment was associated with high IgG1 post-treatment titres against lysate (P = 0.013), as were IgG post-treatment titres to TcII/V/VI peptide (P = 0.0001). High pre-treatment IgG1 with lysate was associated with Qom ethnicity (P = 0.045). No associations were found between gender, age, body mass index and pre- or post-treatment antibody titres.ConclusionsWe show that following chemotherapy of early chronic Chagas disease, significant decline in IgG1 antibody suggests cure, whereas sustained or increased IgG1 is a potential indicator of treatment failure. Due to restricted sensitivity, IgG1 should not be used as a diagnostic marker but has promise, with further development, as a biomarker of cure.Graphical abstractWe show that following chemotherapy of early chronic Chagas disease, a significant decline in IgG1 antibody suggests cure, whereas sustained or increased IgG1 is a potential indicator of treatment failure. Due to restricted sensitivity, IgG1 should not be used as a diagnostic marker but has promise, with further development, as a biomarker of cure.

Highlights

Chagas disease remains a significant public health problem in Latin America
We show that following chemotherapy of early chronic Chagas disease, significant decline in IgG1 antibody suggests cure, whereas sustained or increased IgG1 is a potential indicator of treatment failure
We assess immunoglobulin G (IgG) and IgG1 antibody decline in treated early chronic Chagas disease patients living in the Argentine Chaco where domestic transmission was interrupted, using separately whole cell lysate and Lineage-specific TSSA peptide (TSSApep)-II/V/VI antigens, and we show that IgG1 is more discriminative as a biomarker for assessing cure than IgG, irrespective of antigen

Summary

Introduction

Chagas disease remains a significant public health problem in Latin America. There are only two chemotherapy drugs, nifurtimox and benznidazole, and both may have severe side effects. Chagas disease, caused by the protozoan Trypanosoma cruzi, remains a major cause of disability in the Americas, in the Gran Chaco region of Argentina, Bolivia and Paraguay. The initial acute phase of Chagas disease is often asymptomatic or without specific symptoms, fatalities may occur [2]. Infection can be cleared by a full course of chemotherapy with benznidazole (or nifurtimox). Both drugs require prolonged treatment (30–60 days), and can be interrupted by severe adverse effects, in adults. The potential for improving long-term prognosis and for controlling transmission is usually lost due to the lack of early diagnosis and treatment, and delay in delivering insecticide control of infested dwellings, respectively [9]

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