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Understanding the relationship between egg- and antigen-based diagnostics of Schistosoma mansoni infection pre- and post-treatment in Uganda.

ABSTRACT: Schistosomiasis is a major socio-economic and public health problem in many sub-Saharan African countries. After large mass drug administration (MDA) campaigns, prevalence of infection rapidly returns to pre-treatment levels. The traditional egg-based diagnostic for schistosome infections, Kato-Katz, is being substituted in many settings by circulating antigen recognition-based diagnostics, usually the point-of-care circulating cathodic antigen test (CCA). The relationship between these diagnostics is poorly understood, particularly after treatment in both drug-efficacy studies and routine monitoring.We created a model of schistosome infections to better understand and quantify the relationship between these two egg- and adult worm antigen-based diagnostics. We focused particularly on the interpretation of "trace" results after CCA testing. Our analyses suggest that CCA is generally a better predictor of prevalence, particularly after treatment, and that trace CCA results are typically associated with truly infected individuals.Even though prevalence rises to pre-treatment levels only six months after MDAs, our model suggests that the average intensity of infection is much lower, and is probably in part due to a small burden of surviving juveniles from when the treatment occurred. This work helps to better understand CCA diagnostics and the interpretation of post-treatment prevalence estimations.

SUBMITTER: Prada JM

PROVIDER: S-EPMC5759883 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Understanding the relationship between egg- and antigen-based diagnostics of Schistosoma mansoni infection pre- and post-treatment in Uganda.

Prada Joaquín M JM Touloupou Panayiota P Adriko Moses M Tukahebwa Edridah M EM Lamberton Poppy H L PHL Hollingsworth T Déirdre TD

Parasites & vectors 20180108 1

<h4>Background</h4>Schistosomiasis is a major socio-economic and public health problem in many sub-Saharan African countries. After large mass drug administration (MDA) campaigns, prevalence of infection rapidly returns to pre-treatment levels. The traditional egg-based diagnostic for schistosome infections, Kato-Katz, is being substituted in many settings by circulating antigen recognition-based diagnostics, usually the point-of-care circulating cathodic antigen test (CCA). The relationship bet ...[more]

PMID: 29310695

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Project description:Schistosomiasis is a parasitic disease affecting over 240-million people. World Health Organization (WHO) targets for Schistosoma mansoni elimination are based on Kato-Katz egg counts, without translation to the widely used, urine-based, point-of-care circulating cathodic antigen diagnostic (POC-CCA). We aimed to standardize POC-CCA score interpretation and translate them to Kato-Katz-based standards, broadening diagnostic utility in progress towards elimination. A Bayesian latent-class model was fit to data from 210 school-aged-children over four timepoints pre- to six-months-post-treatment. We used 1) Kato-Katz and established POC-CCA scoring (Negative, Trace, +, ++ and +++), and 2) Kato-Katz and G-Scores (a new, alternative POC-CCA scoring (G1 to G10)). We established the functional relationship between Kato-Katz counts and POC-CCA scores, and the score-associated probability of true infection. This was combined with measures of sensitivity, specificity, and the area under the curve to determine the optimal POC-CCA scoring system and positivity threshold. A simulation parametrized with model estimates established antigen-based elimination targets. True infection was associated with POC-CCA scores of ≥ + or ≥G3. POC-CCA scores cannot predict Kato-Katz counts because low infection intensities saturate the POC-CCA cassettes. Post-treatment POC-CCA sensitivity/specificity fluctuations indicate a changing relationship between egg excretion and antigen levels (living worms). Elimination targets can be identified by the POC-CCA score distribution in a population. A population with ≤2% ++/+++, or ≤0.5% G7 and above, indicates achieving current WHO Kato-Katz-based elimination targets. Population-level POC-CCA scores can be used to access WHO elimination targets prior to treatment. Caution should be exercised on an individual level and following treatment, as POC-CCAs lack resolution to discern between WHO Kato-Katz-based moderate- and high-intensity-infection categories, with limited use in certain settings and evaluations.

Project description:BackgroundTwo Kato-Katz thick smears (Kato-Katzs) from a single stool are currently recommended for diagnosing Schistosoma mansoni infections to map areas for intervention. This 'gold standard' has low sensitivity at low infection intensities. The urine point-of-care circulating cathodic antigen test (POC-CCA) is potentially more sensitive but how accurately they detect S. mansoni after repeated praziquantel treatments, their suitability for measuring drug efficacy and their correlation with egg counts remain to be fully understood. We compared the accuracies of one to six Kato-Katzs and one POC-CCA for the diagnosis of S. mansoni in primary-school children who have received zero to ten praziquantel treatments. We determined the impact each diagnostic approach may have on monitoring and evaluation (M&E) and drug-efficacy findings.Method/principle findingsIn a high S. mansoni endemic area of Uganda, three days of consecutive stool samples were collected from primary school-aged children (six - 12 years) at five time-points in year one: baseline, one-week-post-, four-weeks-post-, six-months-post-, and six-months-one-week-post-praziquantel and three time-points in years two and three: pre-, one-week-post- and four-weeks-post-praziquantel-treatment/retreatment (n = 1065). Two Kato-Katzs were performed on each stool. In parallel, one urine sample was collected and a single POC-CCA evaluated per child at each time-point in year one (n = 367). At baseline, diagnosis by two Kato-Katzs (sensitivity = 98.6%) or one POC-CCA (sensitivity = 91.7%, specificity = 75.0%) accurately predicted S. mansoni infections. However, one year later, a minimum of three Kato-Katzs, and two years later, five Kato-Katzs were required for accurate diagnosis (sensitivity >90%) and drug-efficacy evaluation. The POC-CCA was as sensitive as six Kato-Katzs four-weeks-post and six-months-post-treatment, if trace readings were classified as positive.Conclusions/significanceSix Kato-Katzs (two/stool from three stools) and/or one POC-CCA are required for M&E or drug-efficacy studies. Although unable to measure egg reduction rates, one POC-CCA appears to be more sensitive than six Kato-Katzs at four-weeks-post-praziquantel (drug efficacy) and six-months-post-praziquantel (M&E).

Project description:BACKGROUND:Schistosomiasis is a neglected tropical disease caused by Schistosoma parasites. Intervention relies on identifying high-risk regions, yet rapid Schistosoma diagnostics (Kato-Katz stool assays (KK) and circulating cathodic antigen urine assays (CCA)) yield different prevalence estimates. We mapped S. mansoni prevalence and delineated at-risk regions using a survey of schoolchildren in Rwanda, where S. mansoni is an endemic parasite. We asked if different diagnostics resulted in disparities in projected infection risk. METHODS:Infection data was obtained from a 2014 Rwandan school-based survey that used KK and CCA diagnostics. Across 386 schools screened by CCA (N = 19,217). To allow for uncertainty when interpreting ambiguous CCA trace readings, which accounted for 28.8% of total test results, we generated two presence-absence datasets: CCA trace as positive and CCA trace as negative. Samples (N = 9,175) from 185 schools were also screened by KK. We included land surface temperature (LST) and the Normalized Difference Vegetation and Normalized Difference Water Indices (NDVI, NDWI) as predictors in geostatistical regressions. FINDINGS:Across 8,647 children tested by both methods, prevalence was 35.93% for CCA trace as positive, 7.21% for CCA trace as negative and 1.95% for KK. LST was identified as a risk factor using KK, whereas NDVI was a risk factor for CCA models. Models predicted high endemicity in Northern and Western regions of Rwanda, though the CCA trace as positive model identified additional high-risk areas that were overlooked by the other methods. Estimates of current burden for children at highest risk (boys aged 5-9 years) varied by an order of magnitude, with 671,856 boys projected to be infected by CCA trace as positive and only 60,453 projected by CCA trace as negative results. CONCLUSIONS:Our findings show that people in Rwanda's Northern, Western and capital regions are at high risk of S. mansoni infection. However, variation in identification of environmental risk factors and delineation of at-risk regions using different diagnostics likely provides confusing messages to disease intervention managers. Further research and statistical analyses, such as latent class analysis, can be used to improve CCA result classification and assess its use in guiding treatment regimes.

Project description:α-galactosidase (α-GAL) and α-N-acetylgalactosaminidase (α-NAGAL) are two glycosyl hydrolases responsible for maintaining cellular homeostasis by regulating glycan substrates on proteins and lipids. Mutations in the human genes encoding either enzyme lead to neurological and neuromuscular impairments seen in both Fabry- and Schindler/Kanzaki- diseases. Here, we investigate whether the parasitic blood fluke Schistosoma mansoni, responsible for the neglected tropical disease schistosomiasis, also contains functionally important α-GAL and α-NAGAL proteins. As infection, parasite maturation and host interactions are all governed by carefully-regulated glycosylation processes, inhibiting S. mansoni's α-GAL and α-NAGAL activities could lead to the development of novel chemotherapeutics. Sequence and phylogenetic analyses of putative α-GAL/α-NAGAL protein types showed Smp_089290 to be the only S. mansoni protein to contain the functional amino acid residues necessary for α-GAL/α-NAGAL substrate cleavage. Both α-GAL and α-NAGAL enzymatic activities were higher in females compared to males (p<0.05; α-NAGAL > α-GAL), which was consistent with smp_089290's female biased expression. Spatial localisation of smp_089290 revealed accumulation in parenchymal cells, neuronal cells, and the vitellaria and mature vitellocytes of the adult schistosome. siRNA-mediated knockdown (>90%) of smp_089290 in adult worms significantly inhibited α-NAGAL activity when compared to control worms (siLuc treated males, p<0.01; siLuc treated females, p<0.05). No significant reductions in α-GAL activities were observed in the same extracts. Despite this, decreases in α-NAGAL activities correlated with a significant inhibition in adult worm motility as well as in egg production. Programmed CRISPR/Cas9 editing of smp_089290 in adult worms confirmed the egg reduction phenotype. Based on these results, Smp_089290 was determined to act predominantly as an α-NAGAL (hereafter termed SmNAGAL) in schistosome parasites where it participates in coordinating movement and oviposition processes. Further characterisation of SmNAGAL and other functionally important glycosyl hydrolases may lead to the development of a novel anthelmintic class of compounds.

Dataset Information

Understanding the relationship between egg- and antigen-based diagnostics of Schistosoma mansoni infection pre- and post-treatment in Uganda.

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Understanding the relationship between egg- and antigen-based diagnostics of Schistosoma mansoni infection pre- and post-treatment in Uganda.

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