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Estimates of the duration of the early and late stage of gambiense sleeping sickness
Francesco Checchi, Jo?o AN Filipe, Daniel T Haydon, Daniel Chandramohan, Fran?ois Chappuis
BMC Infectious Diseases , 2008, DOI: 10.1186/1471-2334-8-16
Abstract: We first model the duration of stage 1 through survival analysis of untreated serological suspects detected during Médecins Sans Frontières interventions in Uganda and Sudan. We then deduce the duration of stage 2 based on the stage 1 to stage 2 ratio observed during active case detection in villages within the same sites.Survival in stage 1 appears to decay exponentially (daily rate = 0.0019; mean stage 1 duration = 526 days [95%CI 357 to 833]), possibly explaining past reports of abnormally long duration. Assuming epidemiological equilibrium, we estimate a similar duration of stage 2 (500 days [95%CI 345 to 769]), for a total of nearly three years in the absence of treatment.Robust estimates of these basic epidemiological parameters are essential to formulating a quantitative understanding of sleeping sickness dynamics, and will facilitate the evaluation of different possible control strategies.Human African trypanosomiasis (sleeping sickness, HAT) has historically been a predominant parasitic infection in Africa, causing many millions of deaths in the late 1800s through early 1900s, and has re-emerged in historical foci after breakdown of control programmes [1]. Two forms of HAT are recognised, due respectively to Trypanosoma brucei gambiense (a mainly human disease found mainly in western and central Africa) and Trypanosoma brucei rhodesiense (a zoonosis observed in eastern and southern Africa) [2]. Gambiense HAT has an insidious onset and progresses over years, while rhodesiense HAT is fulminant, causing death within a few months of infection [3]. In recent years, 10 000–15 000 HAT cases (mostly gambiense) are reported annually [4], but this is likely an underestimate of the true burden.Fundamental aspects of the pathogenesis, clinical profile and epidemiology of HAT remain poorly understood. Infecting trypanosomes first colonise the haemo-lymphatic system, evading specific immunity through antigenic variation, but causing only mild and intermittent symptoms –
Interleukin (IL)-6 and IL-10 Are Up Regulated in Late Stage Trypanosoma brucei rhodesiense Sleeping Sickness  [PDF]
Charles D. Kato?,Vincent P. Alibu?,Ann Nanteza?,Claire M. Mugasa?,Enock Matovu
PLOS Neglected Tropical Diseases , 2015, DOI: 10.1371/journal.pntd.0003835
Abstract: Background Sleeping sickness due to Trypanosoma brucei rhodesiense has a wide spectrum of clinical presentations coupled with differences in disease progression and severity across East and Southern Africa. The disease progresses from an early (hemo-lymphatic) stage to the late (meningoencephalitic) stage characterized by presence of parasites in the central nervous system. We hypothesized that disease progression and severity of the neurological response is modulated by cytokines. Methods A total of 55 sleeping sickness cases and 41 healthy controls were recruited passively at Lwala hospital, in Northern Uganda. A panel of six cytokines (IFN-γ, IL1-β, TNF-α, IL-6, TGF-β and IL-10) were assayed from paired plasma and cerebrospinal fluid (CSF) samples. Cytokine concentrations were analyzed in relation to disease progression, clinical presentation and severity of neurological responses. Results Median plasma levels (pg/ml) of IFN-γ (46.3), IL-6 (61.7), TGF-β (8755) and IL-10 (256.6) were significantly higher in cases compared to controls (p< 0.0001). When early stage and late stage CSF cytokines were compared, IL-10 and IL-6 were up regulated in late stage patients and were associated with a reduction in tremors and cranioneuropathy. IL-10 had a higher staging accuracy with a sensitivity of 85.7% (95% CI, 63.7%-97%) and a specificity of 100% (95% CI, 39.8%-100%) while for IL-6, a specificity of 100% (95% CI, 47.8%-100%) gave a sensitivity of 83.3% (95% CI, 62.2%-95.3%). Conclusion Our study demonstrates the role of host inflammatory cytokines in modulating the progression and severity of neurological responses in sleeping sickness. We demonstrate here an up-regulation of IL-6 and IL-10 during the late stage with a potential as adjunct stage biomarkers. Given that both cytokines could potentially be elevated by other CNS infections, our findings should be further validated in a large cohort of patients including those with other inflammatory diseases such as cerebral malaria.
Nifurtimox plus Eflornithine for Late-Stage Sleeping Sickness in Uganda: A Case Series  [PDF]
Francesco Checchi,Patrice Piola,Harriet Ayikoru,Florence Thomas,Dominique Legros,Gerardo Priotto
PLOS Neglected Tropical Diseases , 2007, DOI: 10.1371/journal.pntd.0000064
Abstract: Background We report efficacy and safety outcomes from a prospective case series of 31 late-stage T.b. gambiense sleeping sickness (Human African Trypanosomiasis, HAT) patients treated with a combination of nifurtimox and eflornithine (N+E) in Yumbe, northwest Uganda in 2002–2003, following on a previously reported terminated trial in nearby Omugo, in which 17 patients received the combination under the same conditions. Methodology/Principal findings Eligible sequential late-stage patients received 400 mg/Kg/day eflornithine (Ornidyl, Sanofi-Aventis) for seven days plus 15 mg/Kg/day (20 mg for children <15 years old) nifurtimox (Lampit, Bayer AG) for ten days. Efficacy (primary outcome) was monitored for 24 months post discharge. Clinical and laboratory adverse events (secondary outcome) were monitored during treatment. All 31 patients were discharged alive, but two died post-discharge of non-HAT and non-treatment causes, and one was lost to follow-up. Efficacy ranged from 90.3% to 100.0% according to analysis approach. Five patients experienced major adverse events during treatment, and neutropenia was common (9/31 patients). Conclusions/Significance Combined with the previous group of 17 trial patients, this case series yields a group of 48 patients treated with N+E, among whom no deaths judged to be treatment- or HAT-related, no treatment terminations and no relapses have been noted, a very favourable outcome in the context of late-stage disease. N+E could be the most promising combination regimen available for sleeping sickness, and deserves further evaluation.
Three Drug Combinations for Late-Stage Trypanosoma brucei gambiense Sleeping Sickness: A Randomized Clinical Trial in Uganda  [PDF]
Gerardo Priotto, Carole Fogg, Manica Balasegaram, Olema Erphas, Albino Louga, Francesco Checchi, Salah Ghabri, Patrice Piola
PLOS ONE , 2006, DOI: 10.1371/journal.pctr.0010039
Abstract: Objectives Our objective was to compare the efficacy and safety of three drug combinations for the treatment of late-stage human African trypanosomiasis caused by Trypanosoma brucei gambiense. Design This trial was a randomized, open-label, active control, parallel clinical trial comparing three arms. Setting The study took place at the Sleeping Sickness Treatment Center run by Médecins Sans Frontières at Omugo, Arua District, Uganda Participants Stage 2 patients diagnosed in Northern Uganda were screened for inclusion and a total of 54 selected. Interventions Three drug combinations were given to randomly assigned patients: melarsoprol-nifurtimox (M+N), melarsoprol-eflornithine (M+E), and nifurtimox-eflornithine (N+E). Dosages were uniform: intravenous (IV) melarsoprol 1.8 mg/kg/d, daily for 10 d; IV eflornithine 400 mg/kg/d, every 6 h for 7 d; oral nifurtimox 15 (adults) or 20 (children <15 y) mg/kg/d, every 8 h for 10 d. Patients were followed up for 24 mo. Outcome Measures Outcomes were cure rates and adverse events attributable to treatment. Results Randomization was performed on 54 patients before enrollment was suspended due to unacceptable toxicity in one of the three arms. Cure rates obtained with the intention to treat analysis were M+N 44.4%, M+E 78.9%, and N+E 94.1%, and were significantly higher with N+E (p = 0.003) and M+E (p = 0.045) than with M+N. Adverse events were less frequent and less severe with N+E, resulting in fewer treatment interruptions and no fatalities. Four patients died who were taking melarsoprol-nifurtimox and one who was taking melarsoprol-eflornithine. Conclusions The N+E combination appears to be a promising first-line therapy that may improve treatment of sleeping sickness, although the results from this interrupted study do not permit conclusive interpretations. Larger studies are needed to continue the evaluation of this drug combination in the treatment of T. b. gambiense sleeping sickness. Trial Registration ClinicalTrials.gov NCT00330148
The development of drugs for treatment of sleeping sickness: a historical review
Dietmar Steverding
Parasites & Vectors , 2010, DOI: 10.1186/1756-3305-3-15
Abstract: Human African trypanosomiasis or sleeping sickness is a disease caused by two subspecies of Trypanosoma brucei, T. b. rhodesiense and T. b. gambiense. The parasites live and multiply extracellularly in blood and tissue fluids of their human host and are transmitted by the bite of infected tsetse flies (Glossina spp.). The occurrence of sleeping sickness is restricted to the distribution of tsetse flies which are exclusively found in sub-Saharan Africa between 14°N and 20°S [1]. More than 250 discrete active sleeping sickness foci in 36 African countries are recognised most of which are in rural areas [2].Trypanosoma b. rhodesiense is found in East and southern Africa whereas T. b. gambiense occurs in West and Central Africa. The course of sleeping sickness is different depending on the subspecies. Infections with T. b. rhodesiense lead to an acute form of the disease while infections with T. b. gambiense give rise to a chronic infection. The symptoms of the first stage of the disease, defined by the restriction of trypanosomes to the blood and lymph system, include fever, headache, joint pain and itching [3,4]. The clinical signs of the second stage of the disease, characterised by the invasion of trypanosomes into the central nervous system, are neurological and endocrinal disorders [3,4]. If left untreated, sleeping sickness patients infected with T. b. rhodesiense will die within months whereas those infected with T. b. gambiense usually survive for several years.In the late 19th Century, Africa experienced several sleeping sickness epidemics the most devastating of which was an epidemic with 300,000 to 500,000 deaths between 1896 and 1906 which mainly affected the Congo Basin and the Busoga focus in Uganda and Kenya [5]. The disastrous effect of this epidemic persuaded the various colonial administrations to call for their medical scientists to develop a cure for sleeping sickness. At that time, the field of chemotherapy was developing and had begun to make use
Detection of trypanosomes in suspected sleeping sickness patients in Uganda using the polymerase chain reaction
Kyambadde,J.W; Enyaru,J.C.K; Matovu,E; Odiit,M; Carasco,J.F;
Bulletin of the World Health Organization , 2000, DOI: 10.1590/S0042-96862000000100018
Abstract: diagnosis of sleeping sickness (trypanosomiasis) is difficult because of the fluctuating levels of parasitaemia encountered in patients. in the present study we found that the polymerase chain reaction (pcr) demonstrated trypanosome infection in 20 out of 35 (57.1%) blood samples and in 21 out of 34 (61.7%) cerebrospinal fluid (csf) samples collected from an area endemic for sleeping sickness in north-west uganda. a total of 14 blood samples and 13 csf samples that were positive for trypanosomes by double centrifugation were also positive by pcr, demonstrating good concordance between the two methods. however, 6 (28.6%) of the 21 blood samples that were parasitologically negative were positive by pcr, while 8 (38.0%) out of 21 csf samples that were negative by double centrifugation were positive by pcr. these 14 negative samples could therefore be from sleeping sickness cases even though a positive pcr test is not evidence for the presence of trypanosomes. furthermore, of these 8 csf samples, 4 had been designated as early cases, based on the absence of trypanosomes and on a count of < 5 white blood cells (wbc) per ml. this suggests that some late-stage cases could potentially be missed according to the present criteria, and it is therefore important to perform clinical trials to determine whether these cases could be treated successfully with the first-stage drug alone. the remaining four csf samples had been classified as late-stage cases, based on a count of > 6 wbc per ml, even though trypanosomes could not be detected in these samples by either double centrifugation or pcr. a cut-off point of 5 wbc per ml, which is used as a rule of thumb to stage sleeping sickness patients, seems to leave some late-stage cases undetected since trypanosomes were detected in four csf samples from suspected cases with < 5 wbc per ml.
New biomarkers for stage determination in Trypanosoma brucei rhodesiense sleeping sickness patients
Natalia Tiberti, Enock Matovu, Alexandre Hainard, John Charles Enyaru, Veerle Lejon, Xavier Robin, Natacha Turck, Dieudonné Mumba Ngoyi, Sanjeev Krishna, Sylvie Bisser, Bertrand Courtioux, Philippe Büscher, Krister Kristensson, Joseph Mathu Ndung'u, Jean-Charles Sanchez
Clinical and Translational Medicine , 2013, DOI: 10.1186/2001-1326-2-1
Abstract: A population comprising 85 T. b. rhodesiense patients, 14 stage 1 (S1) and 71 stage 2 (S2) enrolled in Malawi and Uganda, was investigated. The CSF levels of IgM, MMP-9, CXCL13, CXCL10, ICAM-1, VCAM-1, neopterin and B2MG were measured and their staging performances evaluated using receiver operating characteristic (ROC) analyses.IgM, MMP-9 and CXCL13 were the most accurate markers for stage determination (partial AUC 88%, 86% and 85%, respectively). The combination in panels of three molecules comprising CXCL13-CXCL10-MMP-9 or CXCL13-CXCL10-IgM significantly increased their staging ability to partial AUC 94% (p value < 0.01).The present study highlighted new potential markers for stage determination of T. b. rhodesiense patients. Further investigations are needed to better evaluate these molecules, alone or in panels, as alternatives to WBC to make reliable choice of treatment.Human African trypanosomiasis (HAT), commonly known as sleeping sickness, is a neglected tropical disease caused by the Trypanosoma brucei parasite and transmitted to humans through the bite of the tsetse fly [1]. Two morphologically identical subspecies of parasites are responsible for the disease: Trypanosoma brucei gambiense and T. b. rhodesiense[2]. In both cases, the disease progresses from a haemolymphatic first stage (S1), to a meningo-encephalitic second stage (S2). The latter reflects invasion of the central nervous system (CNS) by the parasites across the blood–brain barrier (BBB) with severe neurological complications, which can ultimately lead to coma and death, when untreated [3]. The two forms of HAT differ in their clinical presentations and geographic distribution. The gambiense form is widespread in Central and Western Africa and is commonly considered to be a chronic infection, which slowly progresses from the first to the second stage. The rhodesiense form of sleeping sickness, that affects communities in Eastern Africa, is a more aggressive illness, which rapidly progresses
Civil conflict and sleeping sickness in Africa in general and Uganda in particular
Lea Berrang Ford
Conflict and Health , 2007, DOI: 10.1186/1752-1505-1-6
Abstract: Sleeping sickness re-emerged in Uganda in the 1970s, and continues to pose a public health and economic burden [1-3]. Similar re-emergence has been reported across sub-Saharan Africa since the 1970s, including outbreaks in the Democratic Republic of the Congo (DRC), Sudan [4], and Angola [5]. In many cases, sleeping sickness outbreaks have coincided with periods of civil conflict and instability in affected countries and regions. Conflict in this context refers to the occurrence of civil war, rebel insurgency, violent governance, political or military oppression of populations, and military combat. These temporal associations are not purely spurious; patterns and processes related to conflict have been identified as determinants of sleeping sickness incidence and outbreaks [4,5]. An improved understanding of the specific processes linking conflict to sleeping sickness incidence can guide geographical predictions of disease risk and optimization of intervention resources. This paper provides a review and characterization of the processes by which conflict has contributed to the occurrence of sleeping sickness outbreaks across sub-Saharan Africa, with a focus on south-eastern Uganda (Figure 1).Sleeping sickness is the name used to describe the human form of African trypanosomiasis (Trypanosoma spp.), a protozoan parasitic disease affecting humans, livestock, and a large number of sylvatic species in much of sub-Saharan Africa (Figure 1). Transmitted by the tsetse fly vector (Glossina spp.), trypanosomiasis represents an important public health and economic burden in sub-Saharan Africa [6-8]. Sleeping sickness is characterized by highly variable and non-specific symptoms in its early stages [9], which are often mis-diagnosed as malaria [10]. Late stage sleeping sickness includes body weakness, progressive emaciation, slurred speech, mental confusion, and coma leading to death in all untreated cases [9]. There are two sub-species of human-infectious trypanosomes, includ
TLTF in Cerebrospinal Fluid for Detection and Staging of T. b. gambiense Infection  [PDF]
Maha-Hamadien Abdulla, Moiz Bakhiet, Veerle Lejon, Jan Andersson, James McKerrow, Omar Al-Obeed, Robert A. Harris
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0079281
Abstract: Background Trypanosome-derived lymphocyte triggering factor (TLTF) is a molecule released by African trypanosomes that interacts with the host immune system, resulting in increased levels of IFN-γ production. Methodology/Principal findings TLTF and anti-TLTF antibodies were assessed in sera and cerebrospinal fluid (CSF) from patients infected with Trypanosoma brucei gambiense (T. b. gambiense) in an attempt to identify alternative markers for diagnosis and stage determination of human African trypanosomiasis or sleeping sickness. Seventy-four serum and sixty-one CSF samples from patients with parasitologically confirmed infection and known disease stage along with 13 sera and CSF from uninfected controls were tested. In serum the levels of anti-TLTF antibodies were unrelated to the disease stage. In contrast, levels of anti-TLTF antibodies in CSF were higher in intermediate/late stages than in early stage disease patients. Specificity of the detected antibodies was assessed by inhibition of TLTF bioactivity as represented by its ability to induce IFN-γ production. Additionally, TLTF was detected in CSF from late stage patients by Western blotting with the anti-TLTF specific monoclonal antibody MO3. Conclusions/Significance These findings suggest a new possibility for disease diagnosis with focus on involvement of the CNS through detection of TLTF and anti-TLTF antibodies in the CSF.
Cerebrospinal Fluid Neopterin as Marker of the Meningo-Encephalitic Stage of Trypanosoma brucei gambiense Sleeping Sickness  [PDF]
Natalia Tiberti, Alexandre Hainard, Veerle Lejon, Bertrand Courtioux, Enock Matovu, John Charles Enyaru, Xavier Robin, Natacha Turck, Krister Kristensson, Dieudonné Mumba Ngoyi, Gede?o M. L. Vatunga, Sanjeev Krishna, Philippe Büscher, Sylvie Bisser, Joseph Mathu Ndung’u, Jean-Charles Sanchez
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040909
Abstract: Background Sleeping sickness, or human African trypanosomiasis (HAT), is a protozoan disease that affects rural communities in sub-Saharan Africa. Determination of the disease stage, essential for correct treatment, represents a key issue in the management of patients. In the present study we evaluated the potential of CXCL10, CXCL13, ICAM-1, VCAM-1, MMP-9, B2MG, neopterin and IgM to complement current methods for staging Trypanosoma brucei gambiense patients. Methods and Findings Five hundred and twelve T. b. gambiense HAT patients originated from Angola, Chad and the Democratic Republic of the Congo (D.R.C.). Their classification as stage 2 (S2) was based on the number of white blood cells (WBC) (>5/μL) or presence of parasites in the cerebrospinal fluid (CSF). The CSF concentration of the eight markers was first measured on a training cohort encompassing 100 patients (44 S1 and 56 S2). IgM and neopterin were the best in discriminating between the two stages of disease with 86.4% and 84.1% specificity respectively, at 100% sensitivity. When a validation cohort (412 patients) was tested, neopterin (14.3 nmol/L) correctly classified 88% of S1 and S2 patients, confirming its high staging power. On this second cohort, neopterin also predicted both the presence of parasites, and of neurological signs, with the same ability as IgM and WBC, the current reference for staging. Conclusions This study has demonstrated that neopterin is an excellent biomarker for staging T. b. gambiense HAT patients. A rapid diagnostic test for detecting this metabolite in CSF could help in more accurate stage determination.
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