Letter to the editor: ‘Strategies to enhance access to diagnosis and treatment for Chagas disease patients in Latin America’

KEYWORDS:

• American trypanosomiasis
• anti-infective therapy
• diagnostic methods
• parasitology
• Trypanosoma cruzi

To the Editor,

In their review, Alonso-Padilla et al. [1] presented an updated and informative overview on the challenges related to the development of more efficient strategies for the management of Chagas disease. More than 100 years after the discovery of this neglected disease, which is a potentially fatal infection, the authors clearly address profound limitations at all levels of health care for Chagasic patients and those at risk of infection. From a comprehensive approach, the authors also reinforce the understanding that effective control of Chagas disease requires complex and integrated algorithms that consider health education, epidemiological surveillance, accurate diagnosis, etiological treatment, and appropriate clinical monitoring.

Taking into account the valuable approach presented by Alonso-Padilla et al. [1], we would like to provide an additional perspective and contribute to the discussion on diagnostic tools, treatment protocols, and markers of post-therapeutic efficacy. We agree with the concern of Alonso-Padilla et al. [1], that achieving an accurate and early diagnosis of Chagas disease is a great challenge to overcome. There is no doubt that more sensitive and specific methods such as conventional serology and Polymerase Chain Reaction (PCR) are recommended and desirable for the diagnosis of Chagas disease [2]. However, these methods are prohibitive in areas with low socio-economic development and limited access to specialized laboratories. In this context, parasitological methods may still be the only viable alternative in poor communities, where direct detection of circulating trypomastigotes is a definite proof of infection [3,4].

Although serological and PCR methods are more effective in the diagnosis of Chagas disease, these tools still carry intrinsic limitations that need to be urgently overcome. In serological methods, high antibodies titers could be detected in patients with other types of infection, determining false positives or non-specific results. A high number of these cases in population screening is worrying and may be linked to the cross-reaction with antigens of Leishmania spp. and Trypanosoma rangeli, which are pathogens that frequently share the same endemic areas with Trypanosoma cruzi [5]. In addition to include internal and external controls in serological methods, immunoblotting with T. cruzi antigens and PCR are needed for the accurate diagnosis of Chagas disease due to their high efficiency in distinguishing infections by different pathogens [2,5]. Since 2000, PCR has been increasingly used as a tool to diagnose Chagas disease. However, very low levels of T. cruzi DNA and genetic differences between parasite strains may limit parasite detection from blood samples of patients with late chronic infections [6]. Despite current biotechnological advances, new generation serological and molecular methods still present sub-optimal performance with specific Chagasic populations [4]. Thus, the use of at least two tests based on different analytical principles remains advisable to achieve an accurate diagnosis [4].

Although consensual methods and markers of therapeutic efficacy are not currently available, these same serological and PCR tools applied to diagnose Chagas disease have been repeatedly used as criteria for the post-therapeutic cure [3,7–9]. Accordingly, the most comprehensive, controlled and recent clinical trials BENEFIT [7], CHAGAZOL [8] and STOP-CHAGAS [9] have selected parasitic load and seroconversion as primary endpoints. Considering only the results of serology and PCR, the impact of the etiological treatment appears to be quite limited in chronic infections. However, it is critical to understand that the evaluation of therapeutic efficacy should not be limited to parasitological cure, since it is still controversial whether and to what extent reduced parasite load reflects a clinical benefit in the absence of parasitological cure. Therefore, it needs to be clarified whether chemotherapy is able to mitigate the progression of Chagas disease in uncured treated patients. As throughout the lifetime of a T. cruzi-infected person, 70–80% will have an undetermined chronic infection without any clinical manifestation, preventing the onset of a symptomatic disease can also be a remarkable and desirable endpoint [2]. In this context, we understand that the intensive search for the parasitological cure is not the only required goal, and there is still a long way to go before discouraging the etiologic treatment of patients with late chronic infection.

As paradigm shifting becomes more prominent in assessing efficacy or therapeutic failure, a review and rearrangement of treatment protocols are probably needed. Since the development of benznidazole (Bz) and nifurtimox (NFx) for more than 40 years, traditional chemotherapy protocols continue to be used in clinical trials (Bz, 5–10 mg/kg/day for 30–60 days vs. NFx, 8–10 mg/kg/day for 60–90 days) [2,10]. However, the evidence found from these protocols indicated controversial therapeutic effects in Chagasic patients with late chronic infection. Thus, we are faced with a propitious moment to explore different doses and times of chemotherapy, a proposition supported by preclinical evidence showing that long-term interventions may potentiate the effects of etiological treatment [11]. Until we face this clinical challenge, the therapeutic potential of the etiological treatment will remain uncertain.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.