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Gambiense human african trypanosomiasis and immunological memory: effect on phenotypic lymphocyte profiles and humoral immunity.

ABSTRACT: In mice, experimental infection with Trypanosoma brucei causes decreased bone marrow B-cell development, abolished splenic B-cell maturation and loss of antibody mediated protection including vaccine induced memory responses. Nothing is known about this phenomenon in human African trypanosomiasis (HAT), but if occurring, it would imply the need of revaccination of HAT patients after therapy and abolish hope for a HAT vaccine. The effect of gambiense HAT on peripheral blood memory T- and B-cells and on innate and vaccine induced antibody levels was examined. The percentage of memory B- and T-cells was quantified in peripheral blood, prospectively collected in DR Congo from 117 Trypanosoma brucei gambiense infected HAT patients before and six months after treatment and 117 controls at the same time points. Antibodies against carbohydrate antigens on red blood cells and against measles were quantified. Before treatment, significantly higher percentages of memory B-cells, mainly T-independent memory B-cells, were observed in HAT patients compared to controls (CD20+CD27+IgM+, 13.0% versus 2.0%, p<0.001). The percentage of memory T-cells, mainly early effector/memory T-cells, was higher in HAT (CD3+CD45RO+CD27+, 19.4% versus 16.7%, p?=?0.003). After treatment, the percentage of memory T-cells normalized, the percentage of memory B-cells did not. The median anti-red blood cell carbohydrate IgM level was one titer lower in HAT patients than in controls (p<0.004), and partially normalized after treatment. Anti-measles antibody concentrations were lower in HAT patients than in controls (medians of 1500 versus 2250 mIU/ml, p?=?0.02), and remained so after treatment, but were above the cut-off level assumed to provide protection in 94.8% of HAT patients, before and after treatment (versus 98.3% of controls, p?=?0.3). Although functionality of the B-cells was not verified, the results suggest that immunity was conserved in T.b. gambiense infected HAT patients and that B-cell dysfunction might not be that severe as in mouse models.

SUBMITTER: Lejon V

PROVIDER: S-EPMC3946376 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Gambiense human african trypanosomiasis and immunological memory: effect on phenotypic lymphocyte profiles and humoral immunity.

Lejon Veerle V Mumba Ngoyi Dieudonné D Kestens Luc L Boel Luc L Barbé Barbara B Kande Betu Victor V van Griensven Johan J Bottieau Emmanuel E Muyembe Tamfum Jean-Jacques JJ Jacobs Jan J Büscher Philippe P

PLoS pathogens 20140306 3

In mice, experimental infection with Trypanosoma brucei causes decreased bone marrow B-cell development, abolished splenic B-cell maturation and loss of antibody mediated protection including vaccine induced memory responses. Nothing is known about this phenomenon in human African trypanosomiasis (HAT), but if occurring, it would imply the need of revaccination of HAT patients after therapy and abolish hope for a HAT vaccine. The effect of gambiense HAT on peripheral blood memory T- and B-cells ...[more]

PMID: 24603894

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Project description:BACKGROUND: Algorithms to diagnose gambiense human African trypanosomiasis (HAT, sleeping sickness) are often complex due to the unsatisfactory sensitivity and/or specificity of available tests, and typically include a screening (serological), confirmation (parasitological) and staging component. There is insufficient evidence on the relative accuracy of these algorithms. This paper presents estimates of the accuracy of five algorithms used by past Médecins Sans Frontières programmes in the Republic of Congo, Southern Sudan and Uganda. METHODOLOGY AND PRINCIPAL FINDINGS: The sequence of tests in each algorithm was programmed into a probabilistic model, informed by distributions of the sensitivity, specificity and staging accuracy of each test, constructed based on a literature review. The accuracy of algorithms was estimated in a baseline scenario and in a worst-case scenario introducing various near worst-case assumptions. In the baseline scenario, sensitivity was estimated as 85-90% in all but one algorithm, with specificity above 99.9% except for the Republic of Congo, where CATT serology was used as independent confirmation test: here, positive predictive value (PPV) was estimated at <50% in realistic active screening prevalence scenarios. Furthermore, most algorithms misclassified about one third of true stage 1 cases as stage 2, and about 10% of true stage 2 cases as stage 1. In the worst-case scenario, sensitivity was 75-90% and PPV no more than 75% at 1% prevalence, with about half of stage 1 cases misclassified as stage 2. CONCLUSIONS: Published evidence on the accuracy of widely used tests is scanty. Algorithms should carefully weigh the use of serology alone for confirmation, and could enhance sensitivity through serological suspect follow-up and repeat parasitology. Better evidence on the frequency of low-parasitaemia infections is needed. Simulation studies should guide the tailoring of algorithms to specific scenarios of HAT prevalence and availability of control tools.

Project description:Gambiense human African trypanosomiasis (gHAT) is a virulent disease declining in burden but still endemic in West and Central Africa. Although it is targeted for elimination of transmission by 2030, there remain numerous questions about the drivers of infection and how these vary geographically. In this study we focus on the Democratic Republic of Congo (DRC), which accounted for 84% of the global case burden in 2016, to explore changes in transmission across the country and elucidate factors which may have contributed to the persistence of disease or success of interventions in different regions. We present a Bayesian fitting methodology, applied to 168 endemic health zones (∼100,000 population size), which allows for calibration of a mechanistic gHAT model to case data (from the World Health Organization HAT Atlas) in an adaptive and automated framework. It was found that the model needed to capture improvements in passive detection to match observed trends in the data within former Bandundu and Bas Congo provinces indicating these regions have substantially reduced time to detection. Health zones in these provinces generally had longer burn-in periods during fitting due to additional model parameters. Posterior probability distributions were found for a range of fitted parameters in each health zone; these included the basic reproduction number estimates for pre-1998 (R0) which was inferred to be between 1 and 1.14, in line with previous gHAT estimates, with higher median values typically in health zones with more case reporting in the 2000s. Previously, it was not clear whether a fall in active case finding in the period contributed to the declining case numbers. The modelling here accounts for variable screening and suggests that underlying transmission has also reduced greatly-on average 96% in former Equateur, 93% in former Bas Congo and 89% in former Bandundu-Equateur and Bandundu having had the highest case burdens in 2000. This analysis also sets out a framework to enable future predictions for the country.

Project description:BackgroundIn recent years, a programme of vector control, screening and treatment of gambiense human African trypanosomiasis (gHAT) infections led to a rapid decline in cases in the Mandoul focus of Chad. To represent the biology of transmission between humans and tsetse, we previously developed a mechanistic transmission model, fitted to data between 2000 and 2013 which suggested that transmission was interrupted by 2015. The present study outlines refinements to the model to: (1) Assess whether elimination of transmission has already been achieved despite low-level case reporting; (2) quantify the role of intensified interventions in transmission reduction; and (3) predict the trajectory of gHAT in Mandoul for the next decade under different strategies.MethodOur previous gHAT transmission model for Mandoul was updated using human case data (2000-2019) and a series of model refinements. These include how diagnostic specificity is incorporated into the model and improvements to the fitting method (increased variance in observed case reporting and how underreporting and improvements to passive screening are captured). A side-by-side comparison of fitting to case data was performed between the models.ResultsWe estimated that passive detection rates have increased due to improvements in diagnostic availability in fixed health facilities since 2015, by 2.1-fold for stage 1 detection, and 1.5-fold for stage 2. We find that whilst the diagnostic algorithm for active screening is estimated to be highly specific (95% credible interval (CI) 99.9-100%, Specificity = 99.9%), the high screening and low infection levels mean that some recently reported cases with no parasitological confirmation might be false positives. We also find that the focus-wide tsetse reduction estimated through model fitting (95% CI 96.1-99.6%, Reduction = 99.1%) is comparable to the reduction previously measured by the decline in tsetse catches from monitoring traps. In line with previous results, the model suggests that transmission was interrupted in 2015 due to intensified interventions.ConclusionsWe recommend that additional confirmatory testing is performed in Mandoul to ensure the endgame can be carefully monitored. More specific measurement of cases, would better inform when it is safe to stop active screening and vector control, provided there is a strong passive surveillance system in place.

Dataset Information

Gambiense human african trypanosomiasis and immunological memory: effect on phenotypic lymphocyte profiles and humoral immunity.

Publications

Gambiense human african trypanosomiasis and immunological memory: effect on phenotypic lymphocyte profiles and humoral immunity.

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