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• W2037274735 abstract "Objective To develop a simple and standard operational decision tool for the diagnosis of relapse after treatment for human African trypanosomiasis (HAT), by evaluating the performance of several criteria currently used by HAT control programs and research projects. Methods We identified 10 different criteria for relapse, based on trypanosome presence and/or white blood cell count in cerebrospinal fluid, and compared their specificity, sensitivity and time to diagnosis on a data set containing 63 relapsed and 247 cured T.b. gambiense patients. Results At any time point, the criterion ‘Trypanosomes present and/or a cerebrospinal white blood cell count ≥50/μl’ allowed accurate and timely detection of HAT relapse, irrespective of disease stage. This criterion was 13–25% more sensitive (P ≤ 0.013) than trypanosome detection alone and was >97% specific. Lumbar punctures at the end of treatment and at 3-month post-treatment provided limited clinical information. Conclusions Adequate detection of relapse was possible with a simple criterion but these findings should be validated in a prospective study before adoption in clinical practice. Objectif: Développer un outil opérationnel simple et standard de décision pour le diagnostic de la rechute après traitement de la trypanosomiase humaine africaine (THA), en évaluant la performance de plusieurs critères actuellement utilisés par les programmes et projets de recherche pour le contrôle de la THA. Méthodes: Nous avons identifié 10 critères différents de rechute basés sur la présence du trypanosome et/ou du taux de globules blancs dans le liquide céphalorachidien, et comparé leur spécificité, sensibilité et durée de diagnostic sur un ensemble de données comprenant 63 patients avec Tb gambiense qui ont rechuté et 247 patients guéris. Résultats: En tout temps, le critère “Trypanosomes présents et/ou taux de globules blancs céphalorachidiens ≥ 50/μl” a permis la détection précise et à temps de la rechute de THA, indépendamment du stade de la maladie. Ce critère était 13 à 25% plus sensible (P = 0,013) que de la détection seule du trypanosome et était spécifique à 97%. Les ponctions lombaires à la fin du traitement et à 3 mois après le traitement procuraient des informations cliniques limitées. Conclusions: La détection adéquate de la rechute était possible avec un critère simple, mais ces résultats doivent être validés dans une étude prospective, avant son adoption dans la pratique clinique. Objetivo: Desarrollar una herramienta de decisión operativa, simple y estándar, para el diagnóstico de la recaída tras el tratamiento de la tripanosomiasis humana Africana (THA), evaluando el desempeño de varios criterios actualmente utilizados en los programas de control de la THA y en proyectos de investigación. Métodos: Hemos identificado 10 criterios diferentes para recaída, basándose en la presencia de tripanosomas y/o el conteo de glóbulos blancos en el líquido cefalorraquídeo, y comparado su especificidad, sensibilidad y tiempo al diagnóstico con una base de datos de pacientes con T.b. gambiense que incluían 63 recaídas y 247 pacientes curados. Resultados: En cualquier punto en el tiempo, el criterio “Presencia de tripanosomas y/o conteo de glóbulos blancos en líquido cefalorraquídeo ≥50/μl” permitió la detección certera y a tiempo de una recaída de THA, sin importar el estadio de la enfermedad. Este criterio fue un 13-25% más sensible (p ≤ 0.013) que la detección de tripanosomas por si sola, y tenía una especificidad de >97%. Las punciones lumbares al final del tratamiento y a los 3 meses post-tratamiento proveían una información clínica limitada. Conclusiones: La detección adecuada de la recaída sería posible con un criterio simple, pero estos hallazgos deberían ser validados con un estudio prospectivo antes de adoptar una práctica clínica. Sleeping sickness or Human African Trypanosomiasis (HAT) is caused by Trypanosoma brucei gambiense in West and Central Africa. The infection progresses from the first, haemo-lymphatic stage to the second, meningo-encephalitic stage, once parasites reach the central nervous system. Pentamidine or suramin are currently used for treatment of first-stage HAT and melarsoprol or eflornithine for the second stage (Van Nieuwenhove 1999). Since none of these drugs is 100% efficacious (Robays et al. 2008), current guidelines recommend follow-up of patients for 2 years after treatment with control visits at 3 and 6 months, and every 6 months thereafter (WHO 1998). The detection of parasites in lymph, blood or cerebrospinal fluid (CSF) unequivocally identifies HAT treatment failure or relapse. However, not all HAT relapse cases show this feature early enough to allow for timely re-treatment, and many treated patients do not adhere to this demanding and invasive follow-up schedule. The limited sensitivity of parasitological techniques furthermore significantly delays diagnosis of relapse during follow-up. To avoid the risk for serious sequelae or even death, the number of white blood cells (WBC) in CSF is taken into account by many clinicians as an early marker of relapse, at times in combination with neurological symptoms. Currently, these WBC-based criteria are not standardised and it remains unclear how those empirical criteria perform in terms of sensitivity and specificity. This lack of evidence has led to widely varying clinical practice even within a single country and has hampered the establishment of a consensus for the conduct of clinical trials (WHO 2007). The objective of this study was to contribute to the evidence base for a simple and standard operational decision tool for the diagnosis of HAT relapse, by evaluating the sensitivity, specificity and time to relapse of several criteria in use. The ‘Study on inflammatory parameters in blood and cerebrospinal fluid before and after treatment in patients suffering from human African trypanosomiasis’ took place between February 1998 and May 2001, in a highly endemic T.b. gambiense focus around Bwamanda Hospital, Equateur Province, Democratic Republic (D.R.) of the Congo, and was approved by the National Ethical Committee of the Ministry of Health of D.R. Congo. Patients with newly diagnosed, parasitologically confirmed HAT were consecutively recruited and admitted to Bwamanda Hospital. They were classified as first, intermediate or second stage based on the CSF WBC count, and the presence of trypanosomes after double centrifugation of CSF (Cattand et al. 1988) (respectively 0–5 WBC/μl and no trypanosomes in CSF, 6–20 WBC/μl and no trypanosomes in CSF, and >20 WBC/μl or trypanosomes in CSF). Patients with hemorrhagic CSF were excluded. First-stage patients were treated with suramin as described elsewhere (Lejon et al. 2007). Intermediate-stage patients were treated with melarsoprol, two series of 3.6 mg/kg/day IV (maximum 180 mg/day) during 3 days. Second-stage patients were enrolled in a clinical trial (registration number ISRCTN36877262), and received standard melarsoprol therapy, 10-day incremental-dose melarsoprol therapy, nifurtimox monotherapy or melarsoprol-nifurtimox combination therapy, as described elsewhere (Bisser et al. 2007; Lejon et al. 2008). Informed consent was obtained from each patient or his/her guardian prior to enrolment. A check-up was scheduled within 24 h after the last drug dose [end of treatment examination (EoT)], at 3, 6, 12 and 18 months post-treatment (interim follow-up visits, interim FU), and 24 months after treatment [test of cure (ToC)]. It consisted of microscopic examinations for presence of trypanosomes of lymph node aspirate, blood, and CSF after double centrifugation; CSF WBC count and protein determination; screening for co-infections and a clinical assessment. Patients who did not appear spontaneously were actively traced back. To retrieve all operational criteria in recent use for HAT treatment outcome, we searched the Pubmed database with the key words ‘sleeping sickness, Trypanosoma brucei gambiense, clinical trial’. Additionally, we hand-searched grey literature obtained through key-informants and internet search. Only unequivocal definitions for relapse or cure were retained. Besides the detection of trypanosomes in blood, lymph or CSF (criterion A), nine criteria combining trypanosome detection with CSF WBC count (criteria B–J) were selected (Table 1). Neurological symptoms or signs were not taken into account in our analysis, as they may be subject to observer variability. For data analysis, tolerance windows of 2–4, 5–9, 10–16, 17–21 and ≥22 months were defined around the scheduled follow-up visits of 3, 6, 12, 18 and 24 months (WHO 2007). Patients who were not retreated, but had no follow-up examinations after >6 months were excluded from data analysis. Relapse was defined as the presence of trypanosomes in blood, lymph or CSF at any time during follow-up or a CSF WBC count >20/μl at 24 months. Those patients were retreated. One patient, who had no detectable trypanosomes at interim FU, was also considered as a relapse and retreated by the physician in charge. This patient showed a more than tenfold increase in cell count compared to pre-treatment in combination with recurrent clinical symptoms. This case was also included as a relapse case in the analysis (Figure 1). Study cohort with number of patients included and excluded from the study, number of patients examined at follow-up visits and number and type of relapses diagnosed (T+ = trypanosome positive). In this analysis, the total number of patients retreated was used as the fixed denominator for all sensitivity calculations, while the total number of patients not retreated was used as the fixed denominator for all specificity calculations. Our reference standard therefore corresponds to the decision to retreat by the physician in charge. Once a patient was fulfilling a relapse criterion, this was considered definitive and the patient was regarded as a relapse for that criterion at all subsequent time points. A patient missing an assessment retained his status from the previous assessment. At all interim FU and at ToC, sensitivity and specificity with 95% confidence intervals were determined, which were compared using McNemar chi-square tests with Yates correction. Times to detect relapses were compared using the Wilcoxon signed rank test with continuity correction. Files from 411 patients, of whom 73 were first-stage, 60 intermediate-stage and 278 second-stage, were available (Figure 1). A total of 101 patients who were not retreated but that had no case report forms (two) or no follow-up after >6 months (99) were excluded. Thus data from 310 patients were used for the analysis, of whom 63 were retreated and 247 were not (Figure 1). We retrieved 10 operational criteria in recent use for the diagnosis of HAT relapse in clinical practice or research. The sensitivity and specificity of these criteria is presented in Figure 2. Sensitivity and specificity with 95% CI of HAT relapse criteria at 3, 6, 12 and 18-month post-treatment. At 3 months, the specificities of criteria C–F dropped significantly (P = 0.041) to 97–98% (240/247–242/247); thereafter they remained constant up to the ToC visit. The specificities of criteria G–J were 92–96% (227/247–236/247) at 3 months post-treatment, and further decreased to 90–94% (223/247–231/247) at 24 months. The specificities of G-J were always significantly lower than that of trypanosome detection (P ≤ 0.002). The specificity of criterion B remained 100% until the 18 months FU visit, when it dropped to 99.2% (245/247, P > 0.5). At 3-month post-treatment, sensitivity of parasite detection was 14% (9/63, Table 2). All criteria except B and H had a significantly higher sensitivity of 30–38% (19/63–24/63, P ≤ 0.04). At 6 and 12-month post-treatment, criteria C–J were 48–63% (30/63–40/63) and 60–73% (38/63–46/63) sensitive, significantly more (P ≤ 0.002) than trypanosome detection which was 30 (19/63) and 43% (27/63) sensitive. At 18 months, follow-up stops for criterion B, and this criterion became more sensitive (71%, 45/63, P = 0.041) than trypanosome detection alone (62%, 39/63). At that moment, criteria C–J detected 78–83% (49/63–52/63) of the relapses, also significantly more than trypanosome detection (P ≤ 0.004). At 24-month post-treatment, trypanosome detection identified 87% of relapses (55/63), which is significantly less than criteria C–J identifying all relapses (63/63, P = 0.013). Three months post-treatment, all negative predictive values were 82–86% (247/301–230/269). They increased to 91–96% (247/272–224/235) 18-month post-treatment. At 24-month post-treatment, negative predictive values were 100% for criteria C–J, and 97% (247/255) for criterion A. Positive predictive values for criteria C–F were 74–81% (20/27–21/26) 3-month post-treatment, and gradually increased to 90–93% (63/70–63/68) 24-month post-treatment. The positive predictive value of criteria G–J never exceeded 80% (63/79). The number of relapses diagnosed at each time point by each criterion is shown in Table 2. Median time for diagnosis of relapse was 6 months for criteria C, D, F, G, I and J, 12 months for criteria E and H, and 18 months for criterion B and trypanosome detection. Criteria C–J detected relapses sooner than criterion A, trypanosome detection alone (Bonferroni corrected P-value < 0.001), criterion B did not. We assessed different operational criteria for treatment outcome in HAT, based on the combination of trypanosome detection and the absolute or relative WBC count in CSF. In view of toxicity of HAT drugs and the fatal outcome of relapse, selection of a criterion should be based on the best possible compromise between specificity and sensitivity and on its predictive values. Moreover, relapses should be detected with a minimum delay since patient’s compliance with the follow-up schedule decreases drastically in function of time, and risks for adverse events and sequelae increase while the disease advances. For post-treatment follow-up in HAT, the criteria with the highest diagnostic accuracy for relapse were C ‘presence of trypanosomes in blood, lymph or CSF and/or a CSF WBC count ≥50 WBC/μl’ (Milord et al. 1992), and the almost identical criterion D, where in addition, the WBC count should be higher than the previous determination (Pépin & Milord 1994; Pépin et al. 2000). Both criteria combined the early detection of a relapse with high sensitivity and high specificity. Also criterion E (Pépin et al. 1989; Burri et al. 2000; Schmid et al. 2004; Balasegaram et al. 2006), which is very similar to D, and criterion F, seem appropriate for treatment follow-up in HAT, but are slightly more complicated to interpret. Criteria G, H, I and J showed lowest specificity and bear the highest risk of unnecessary re-treatment (overall decrease in positive predictive values of at least 0.11 compared to criteria C–F while negative predictive values are similar). Criterion B is highly specific, but had a similar median time to diagnosis of relapse and similar low sensitivities as trypanosome detection alone, and offers only limited added value, except at its final 18 months time point. This might explain the observation in the recent nifurtimox–eflornithine combination trial performed in P.R. Congo where only three out of four relapses were detected at 18 months only, based on criterion B (Priotto et al. 2007). Lumbar punctures at the EoT and 3 months interim FU were performed in this trial but remain controversial. Trypanosomes are rarely detected in CSF at EoT (Burri et al. 2000; Bisser et al. 2007), even in areas with high treatment failure rates (D. Mumba, personal communication). Although CSF WBC count should not be interpreted at EoT (WHO 2007), it may provide a baseline value essential for subsequent assessments. When applying criterion C, the EoT CSF WBC count was redundant. At 3 months after treatment, a relatively low specificity was observed for criteria including the CSF WBC count. Disregarding the 3 months lumbar puncture, would result for criteria B–F in specificities of 99.2–100% (245–247/247) throughout time. Interpretation of the WBC count at 3 months thus may introduce false positives and should be avoided. As a result, it can be questioned if lumbar punctures at EoT and at 3-month post-treatment have clinical benefit. The final assessment of treatment efficacy in HAT control programmes is currently scheduled at 24 months (WHO 1986) and this has been advanced to 18 months for clinical trials (WHO 2007). Our findings show an overall sensitivity for relapse of only 83% at 18 months (WHO 2007), compared to the total number of relapses observed after 24 months. Although the 18 months sensitivity is underestimated due to absence of some relapsing cases at that time point, up to 6/63 (9.5%) relapsing cases had been seen at 18 months and were not detected by any criterion until 24 months FU. The true sensitivity at 18 months, based on CSF WBC count and trypanosome detection only is therefore maximally 90%. Although none of the criteria was originally proposed for use on first stage patients, we assessed them on a mixed group of first, intermediate and second stage HAT patients. If the CSF WBC count at 3 months is disregarded, all criteria have 100% specificity in the first stage group, which is identical to the criterion of >20 WBC/μl defined for first stage (WHO 2007). The only effect is a slight increase in median time to diagnosis of 15 months with the first stage criterion, to 18 months with criteria C, D, E and F (diagnosis after 18, 18 and 24 months in stead of 12, 12 and 18 months for 3/14 first stage relapses). Therefore the criteria recommended above seem to be independent of stage. Our study had the following limitations. Not all published relapse criteria were included in our assessment (Lourie 1942; WHO 2007), as we excluded those for which the provided definition of relapse or cure was too imprecise. Furthermore, we excluded clinical signs and symptoms from our assessment, even if some of the original relapse criteria included them, as we considered them too variable and too difficult to assess for health workers non-trained in neurology who have to apply these operational criteria in program settings. In clinical practice, trained neurologists and experienced physicians remain of course free to treat HAT patients at their discretion. Patients who are relapsing tend to show up for assessments because of symptoms, while asymptomatic patients rather miss assessments (Priotto et al. 2008). Use of the clinical status of a patient in decision making is therefore likely to reduce the time to diagnosis of a relapse, but carries an inherent risk to lower the specificity. Besides presence of trypanosomes, the proposed criteria rely on the WBC count in CSF, which may be subject to some variability (Emerson & Emerson 2005). Especially when the WBC increase is close to the cut-off of the proposed criteria, letting the patient come back 1-3 months later for an additional follow-up examination instead of immediately retreating would be an option, to correct for possible variability of the WBC count (WHO 2007). We used the decision to retreat by the physician in charge as a reference standard in this study, since it was taken only when trypanosomes were observed (with one exception) or at 24 months based on CSF WBC counts >20/μl. Trypanosome detection was the least sensitive of all criteria resulting for the true relapses in a delay in retreatment (median time of diagnosis 18 versus 6 months), which, on the other hand, offered a unique opportunity for retrospective assessment of CSF WBC count based relapse criteria. Due to the limited sensitivity of trypanosome detection, some real relapses may have remained unnoticed among the untreated group leading to an underestimation of the specificity. In total 24 patients were not retreated but were false positive for at least one criterion. Nineteen of those had a normal CSF WBC count of ≤5/μl at 24-month post-treatment and three had nearly normalised to 6–10 WBC/μl at their last FU visit. The remaining two first-stage patients had respectively 8 and 14 WBC/μl at their last 12 and 18 months FU visits but were clinically well. The risk of being a real relapse can therefore not be completely excluded but seems minimal. The risk that our group of retreated patients, which served as a reference standard for sensitivity calculations, contains false positives seems minimal. All eight relapsed patients retreated without finding of trypanosomes, were detected as relapses by criteria C–J. The assessment was limited to one data-set only, in one treatment site with a limited number of relapses. Combined with the limited number of patients within each treatment group, we therefore cannot comment on the possible impact of different drugs on performance of the various criteria, or kinetics of relapse. Ideally, validation of our findings in a prospective cohort in a HAT control program setting would be the next step before adopting this decision tool in practice. However, such study design may be difficult to adopt, since for proper evaluation, the reference standard for relapse should be based on the most specific criterion, trypanosome detection only, which can in fact hardly be justified in a disease control setting. Finally, our results and conclusions are valid only for T.b. gambiense and a similar assessment remains to be performed on patients treated for T.b. rhodesiense disease, which is more acute. The Centre de Développement Intégral (Bwamanda, D.R. Congo), Medische Missie Samenwerking (Itterbeek, Belgium), and the staff of Bwamanda Hospital, in particular the late sister J. Verbunt provided logistic, medical, and laboratory support in D.R. Congo. Joris Menten (ITM) is thanked for statistical support. This study received financial support from the Belgian Ministry of Foreign Affairs, Directorate General for Development Cooperation." @default.
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• W2037274735 title "Comparison of operational criteria for treatment outcome in<i>gambiense</i>human African trypanosomiasis" @default.
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