The challenging problem of disease staging in human African trypanosomiasis (sleeping sickness): a new approach to a circular question

Abstract

Human African trypanosomiasis (HAT), also known as sleeping sickness, puts millions of people at risk in sub-Saharan Africa and is a neglected parasitic disease that is almost always fatal if untreated or inadequately treated. HAT manifests itself in two stages that are difficult to distinguish clinically. The problem of staging in HAT is extremely important since treatment options, some of which are highly toxic, are directly linked to the disease stage. Several suggested investigations for disease staging have been problematic because of the lack of an existing gold standard with which to compare new clinical staging markers. The somewhat arbitrary current criteria based on the cerebrospinal fluid (CSF) white blood cell (WBC) count have been widely used, but the new potential biomarkers are generally compared with these, thereby making the problem somewhat circular in nature. We propose an alternative 'reverse' approach to address this problem, conceptualised as using appropriate statistical methods to test the performance of combinations of established laboratory variables as staging biomarkers to correlate with the CSF WBC/trypanosomes and clinical features of HAT. This approach could lead to the use of established laboratory staging markers, potentially leading to a gold standard for staging and clinical follow-up of HAT.

Neural Damage in Experimental Trypanosoma brucei gambiense Infection: The Suprachiasmatic Nucleus

“…In conclusion, the present findings show that neurodegenerative events are caused in the SCN in a rodent model of infection with a causative agent of HAT. T. b. gambiense HAT is a chronic progressive disease with a mean duration of 3 years and, due to the nonspecific clinical signs and symptoms of the first stage, patients mostly present at the observation when the disease is already in the encephalitic stage (Büscher et al, 2017 ; Njamnshi et al, 2017 ), and the partial neuronal damage here documented in the SCN of an animal model might have already occurred. The outcome of an infection depends on the delicate and complex interplay between the pathogen and the host, and the potential translational implications of the present findings should, therefore, be regarded with caution.…”

Update on human African trypanosomiasis (sleeping sickness)

“…Although several reports have purported to show novel CSF criteria for defining CNS disease ( 1,9 ) these have all been compared to the WHO CSF criteria which certainly do not represent a gold standard. This 'circular argument problem' has persisted and has recently been discussed in detail (17 ).…”

Clinical and Neuropathogenetic Aspects of Human African Trypanosomiasis

“…Attempts to circumvent this staging problem using appropriate biomarkers of CNS disease have been made and have included, for example, levels of CSF IgM (61), neopterin (62), and combined panels of chemokines and proteins (63), but the central problem with this approach is that the results are compared with the WHO criteria which are themselves controversial and not a “gold standard.” This is the “circular argument” problem that investigators in this field have to contend with. A recent analysis of this issue has suggested a novel “reverse” approach in which statistical methods could be used to test the performance of combinations of established laboratory variables as staging biomarkers to correlate with the CSF WBC/trypanosomes and clinical features of HAT (64). It is hoped that in this way a particular CSF WBC can be identified as giving a more reliable indication of CNS involvement in HAT, thereby establishing the CSF WBC diagnosis on a firmer footing.…”