• Card Agglutination Test for Trypanosomiasis (CATT) End-Dilution Titer and Cerebrospinal Fluid Cell Count as Predictors of Human African Trypanosomiasis (Trypanosoma brucei gambiense) Among Serologically Suspected Individuals in Southern Sudan.

      Chappuis, F; Stivanello, E; Adams, K; Kidane, S; Pittet, A; Bovier, P A; Médecins Sans Frontières, Swiss Section, Geneva, Switzerland. francois.chappuis@hcuge.ch (Published by: American Society of Tropical Medicine and Hygiene, 2004-09)
      The diagnosis of human African trypanosomiasis (HAT) due to Trypanosoma brucei gambiense relies on an initial serologic screening with the card agglutination test for trypanosomiasis (CATT) for T. b. gambiense, followed by parasitologic confirmation in most endemic areas. Unfortunately, field parasitologic methods lack sensitivity and the management of serologically suspected individuals (i.e., individuals with a positive CATT result but negative parasitology) remains controversial. In Kajo-Keji County in southern Sudan, we prospectively collected sociodemographic and laboratory data of a cohort of 2,274 serologically suspected individuals. Thirty-three percent (n = 749) attended at least one follow-up visit and HAT was confirmed in 64 (9%) cases. Individuals with lower initial CATT-plasma (CATT-P) end-dilution titers had lowest risks (10.4 and 13.8/100 person-years for 1:4 and 1:8 titers, respectively) that significantly increased for higher dilutions: relative risks = 5.1 (95% confidence interval [CI] = 2.6-9.5) and 4.6 (95% CI = 2.8-9.8) for 1:16 and 1:32 titers, respectively. The cumulative yearly risk was also high (76%) in individuals found with 11-20 cells in the cerebrospinal fluid, but this involved only eight patients. Adjustment for potential confounders did not affect the results. In conclusion, treatment with pentamidine should be considered for all serologically suspected individuals with a CATT-P end-dilution titer >/= 1:16 in areas of a moderate to high prevalence of HAT.
    • Clinical Presentation and Treatment Outcome of Sleeping Sickness in Sudanese Pre-School Children.

      Eperon, G; Schmid, C; Loutan, L; Chappuis, F; Médecins Sans Frontières, Rue de Lausanne 78, 1202 Geneva, Switzerland. (2007-01)
      BACKGROUND: Existing data on human African trypanosomiasis (HAT) due to Trypanosoma brucei gambiense among children are limited. Here, we described the demographic, clinical, diagnostic, treatment and outcome characteristics of HAT in pre-school children from Kajo-Keji County, South Sudan in comparison with older patients. METHODS: We did a retrospective analysis of HAT patients treated at the Kiri Sleeping Sickness Treatment Centre (SSTC), Kajo-Keji County, from June 2000 to December 2002. RESULTS: Of 1958 HAT patients, 119 (6.1%) were pre-school children (<6 years) including 56 (47%) in first-stage illness and 63 (53%) in second-stage. The proportion of children in second-stage HAT was significantly higher in very young children (<2 years). Walking and speech disturbances were more frequent in second-stage HAT but other neurological symptoms and signs were not associated with disease stage. Pentamidine treatment for first-stage illness was very safe and effective among pre-school children. In contrast, 4.9% of pre-school children in second-stage illness died during melarsoprol treatment and 46% had > or = 1 severe adverse event(s). Macular rash, jaundice and skin necrosis on injection site were significantly more frequent in this age group (p<0.05). Melarsoprol-induced encephalopatic syndrome was less frequent but more severe than in older age groups. CONCLUSION: The clinical features of T. b. gambiense HAT among pre-school children are insufficiently stage-specific. Therefore, laboratory-based staging is mandatory to prevent unnecessary harm to HAT patients caused by the high toxicity of melarsoprol.
    • Estimates of the duration of the early and late stage of gambiense sleeping sickness.

      Checchi, F; Filipe, J A N; Haydon, D T; Chandramohan, D; Chappuis, F; Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E7HT, UK. francesco.checchi@lshtm.ac.uk (BioMed Central, 2008-02-08)
      BACKGROUND: The durations of untreated stage 1 (early stage, haemo-lymphatic) and stage 2 (late stage, meningo-encephalitic) human African trypanosomiasis (sleeping sickness) due to Trypanosoma brucei gambiense are poorly quantified, but key to predicting the impact of screening on transmission. Here, we outline a method to estimate these parameters. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
    • Field evaluation of the CATT/Trypanosoma brucei gambiense on blood-impregnated filter papers for diagnosis of human African trypanosomiasis in southern Sudan.

      Chappuis, F; Pittet, A; Bovier, P A; Adams, K; Godineau, V; Hwang, S Y; Magnus, E; Büscher, P; Médecins Sans Frontières (MSF) - Switzerland, Geneva, Switzerland. francois.chappuis@hcuge.ch (Wiley-Blackwell, 2002-11)
      Most Human African Trypanosomiasis (HAT) control programmes in areas endemic for Trypanosoma brucei gambiense rely on a strategy of active mass screening with the Card Agglutination Test for Trypanosomiasis (CATT)/T. b. gambiense. We evaluated the performance, stability and reproducibility of the CATT/T. b. gambiense on blood-impregnated filter papers (CATT-FP) in Kajo-Keji County, South-Sudan, where some areas are inaccessible to mobile teams. The CATT-FP was performed with a group of 100 people with a positive CATT on whole blood including 17 confirmed HAT patients and the results were compared with the CATT on plasma (CATT-P). The CATT-FP was repeated on impregnated filter papers stored at ambient and refrigerated temperature for 1, 3, 7 and 14 days. Another 82 patients with HAT, including 78 with a positive parasitology, were tested with the CATT-FP and duplicate filter paper samples were sent to a reference laboratory to assess reproducibility. The CATT-FP was positive in 90 of 99 patients with HAT (sensitivity: 91%). It was less sensitive than the CATT-P (mean dilution difference: -2.5). There was no significant loss of sensitivity after storage for up to 14 days both at ambient and cool temperature. Reproducibility of the CATT-FP was found to be excellent (kappa: 0.84). The CATT-FP can therefore be recommended as a screening test for HAT in areas where the use of CATT-P is not possible. Further studies on larger population samples in different endemic foci are still needed before the CATT-FP can be recommended for universal use.
    • Human African trypanosomiasis

      Brun, R; Blum, J; Chappuis, F; Burri, C; Swiss Tropical Institute, Basel, Switzerland; Geneva University Hospitals, University of Geneva, Switzerland; Médecins Sans Frontières, Geneva, Switzerland (2009-10-14)
      Human African trypanosomiasis (sleeping sickness) occurs in sub-Saharan Africa. It is caused by the protozoan parasite Trypanosoma brucei, transmitted by tsetse flies. Almost all cases are due to Trypanosoma brucei gambiense, which is indigenous to west and central Africa. Prevalence is strongly dependent on control measures, which are often neglected during periods of political instability, thus leading to resurgence. With fewer than 12 000 cases of this disabling and fatal disease reported per year, trypanosomiasis belongs to the most neglected tropical diseases. The clinical presentation is complex, and diagnosis and treatment difficult. The available drugs are old, complicated to administer, and can cause severe adverse reactions. New diagnostic methods and safe and effective drugs are urgently needed. Vector control, to reduce the number of flies in existing foci, needs to be organised on a pan-African basis. WHO has stated that if national control programmes, international organisations, research institutes, and philanthropic partners engage in concerted action, elimination of this disease might even be possible.
    • Melarsoprol Versus Eflornithine for Treating Late-stage Gambian Trypanosomiasis in the Republic of the Congo.

      Balasegaram, M; Harris, S; Checchi, F; Ghorashian, S; Hamel, C; Karunakara, U; Medecins Sans Frontieres, London, England. manica.balasigaram@london.msf.org (Published by WHO, 2006-10)
      OBJECTIVE: To compare the effectiveness of melarsoprol and eflornithine in treating late-stage Gambian trypanosomiasis in the Republic of the Congo. METHODS: We analysed the outcomes of death during treatment and relapse within 1 year of discharge for 288 patients treated with eflornithine, 311 patients treated with the standard melarsoprol regimen and 62 patients treated with a short-course (10-day) melarsoprol regimen between April 2001 and April 2005. FINDINGS: A total of 1.7% (5/288) of patients treated with eflornithine died compared with 4.8% (15/311) of those treated with standard melarsoprol and 6.5% (4/62) of those treated with short-course melarsoprol. Patients treated with eflornithine tended to be younger and were more likely to have trypanosomes or higher white blood cell counts in their cerebrospinal fluid. The cumulated incidence of relapse among patients who attended at least one follow-up visit 1 year after discharge was 8.1% (11/136) for those treated with eflornithine, 14% (36/258) for those treated with standard melarsoprol and 15.5% (9/58) for those treated with shortcourse melarsoprol. In a multivariate analysis, when compared with eflornithine, standard melarsoprol was found to be a risk factor for both death (odds ratio (OR) = 2.87; 95% confidence interval (CI) = 1.03-8.00) and relapse (hazard ratio (HR) = 2.47; 95% CI = 1.22-5.03); when compared with eflornithine, short-course melarsoprol was also found to be a risk factor for death (OR = 3.90; 95% CI = 1.02-14.98) and relapse (HR = 6.65; 95% CI = 2.61-16.94). CONCLUSION: The effectiveness of melarsoprol treatment appears to have diminished. Eflornithine seems to be a better first-line therapy for treating late-stage Gambian trypanosomiasis in the Republic of the Congo.
    • Nifurtimox-eflornithine Combination Therapy for Second-Stage Trypanosoma Brucei Gambiense Sleeping Sickness: A Randomized Clinical Trial in Congo.

      Priotto, G; Kasparian, S; Ngouama, D; Ghorashian, S; Arnold, U; Ghabri, S; Karunakara, U; Epicentre, Paris, France. gpriotto@epicentre.msf.org (Published by: Infectious Diseases Society of America, 2007-12-01)
      BACKGROUND: Human African trypanosomiasis caused by Trypanosoma brucei gambiense is a fatal disease. Current treatment options for patients with second-stage disease are either highly toxic or impracticable in field conditions. We compared the efficacy and safety of the nifurtimox-eflornithine drug combination with the standard eflornithine regimen for the treatment of second-stage disease. METHODS: A randomized, open-label, active-control, phase III clinical trial comparing 2 arms was conducted at the Sleeping Sickness Treatment Center, which was run by Medecins Sans Frontieres, in Nkayi, Bouenza Province, Republic of Congo. Patients were screened for inclusion and randomly assigned to receive eflornithine alone (400 mg/kg per day given intravenously every 6 h for 14 days) or eflornithine (400 mg/kg per day given intravenously every 12 h for 7 days) plus nifurtimox (15 mg/kg per day given orally every 8 h for 10 days). Patients were observed for 18 months. The study's outcomes were cure and adverse events attributable to treatment. RESULTS: A total of 103 patients with second-stage disease were enrolled. Cure rates were 94.1% for the eflornithine group and 96.2% for the nifurtimox-eflornithine group. Drug reactions were frequent in both arms, and severe reactions affected 25.5% of patients in the eflornithine group and 9.6% of those in the nifurtimox-eflornithine group, resulting in 2 and 1 treatment suspensions, respectively. There was 1 death in the eflornithine arm and no deaths in the nifurtimox-eflornithine arm. CONCLUSIONS: The nifurtimox-eflornithine combination appears to be a promising first-line therapy for second-stage sleeping sickness. If our findings are corroborated by ongoing findings from additional sites (a multicenter extension of this study), the new nifurtimox-eflornithine combination therapy will mark a major and multifaceted advance over current therapies.
    • Options for field diagnosis of human african trypanosomiasis.

      Chappuis, F; Loutan, L; Simarro, P; Lejon, V; Büscher, P; Travel and Migration Medicine Unit, Geneva University Hospital, 24 rue Micheli-du-Crest, 1211 Geneva 14, Switzerland. francois.chappuis@hcuge.ch (The American Society for Microbiology, 2005-01)
      Human African trypanosomiasis (HAT) due to Trypanosoma brucei gambiense or T. b. rhodesiense remains highly prevalent in several rural areas of sub-Saharan Africa and is lethal if left untreated. Therefore, accurate tools are absolutely required for field diagnosis. For T. b. gambiense HAT, highly sensitive tests are available for serological screening but the sensitivity of parasitological confirmatory tests remains insufficient and needs to be improved. Screening for T. b. rhodesiense infection still relies on clinical features in the absence of serological tests available for field use. Ongoing research is opening perspectives for a new generation of field diagnostics. Also essential for both forms of HAT is accurate determination of the disease stage because of the high toxicity of melarsoprol, the drug most widely used during the neurological stage of the illness. Recent studies have confirmed the high accuracy of raised immunoglobulin M levels in the cerebrospinal fluid for the staging of T. b. gambiense HAT, and a promising simple assay (LATEX/IgM) is being tested in the field. Apart from the urgent need for better tools for the field diagnosis of this neglected disease, improved access to diagnosis and treatment for the population at risk remains the greatest challenge for the coming years.
    • Sleeping sickness

      Malvy, D; Chappuis, F; Travel Clinics and Division of Tropical Medicine and Imported Diseases, Department of Internal Medicine and Tropical Diseases, University Hospital Centre, Bordeaux, France; Universite de Bordeaux, Faculty of Medicine, INSERM U897 and Centre Rene-Labusquiere (Tropical Medicine Branch), Bordeaux, France; Division of International and Humanitarian Medicine, Geneva University Hospital, Switzerland; Medecins Sans Frontieres, Operational Centre, Geneva, Switzerland (Wiley-Blackwell, 2011-04-04)
      Human African trypanosomiasis (HAT), or sleeping sickness, is a vector-borne disease that flourishes in impoverished, rural parts of sub-Saharan Africa. It is caused by infection with the protozoan parasite Trypanosoma brucei and is transmitted by tsetse flies of the genus Glossina. The majority of cases are caused by T. b. gambiense, which gives rise to the chronic, anthroponotic endemic disease in Western and Central Africa. Infection with T. b. rhodesiense leads to the acute, zoonotic form of Eastern and Southern Africa. The parasites live and multiply extracellularly in the blood and tissue fluids of their human host. They have elaborated a variety of strategies for invading hosts, to escape the immune system and to take advantage of host growth factors. HAT is a challenging and deadly disease owing to its complex epidemiology and clinical presentation and, if left untreated, can result in high death rates. As one of the most neglected tropical diseases, HAT is characterized by the limited availability of safe and cost-effective control tools. No vaccine against HAT is available, and the toxicity of existing old and cumbersome drugs precludes the adoption of control strategies based on preventive chemotherapy. As a result, the keystones of interventions against sleeping sickness are active and passive case-finding for early detection of cases followed by treatment, vector control and animal reservoir management. New methods to diagnose and treat patients and to control transmission by the tsetse fly are needed to achieve the goal of global elimination of the disease.
    • Treatment of human African trypanosomiasis--present situation and needs for research and development.

      Legros, D; Ollivier, G; Gastellu-Etchegorry, M; Paquet, C; Burri, C; Jannin, J; Büscher, P; Epicentre, Paris, France. dlegros@epicentre.msf.org (Elsevier, 2002-07)
      Human African trypanosomiasis re-emerged in the 1980s. However, little progress has been made in the treatment of this disease over the past decades. The first-line treatment for second-stage cases is melarsoprol, a toxic drug in use since 1949. High therapeutic failure rates have been reported recently in several foci. The alternative, eflornithine, is better tolerated but difficult to administer. A third drug, nifurtimox, is a cheap, orally administered drug not yet fully validated for use in human African trypanosomiasis. No new drugs for second-stage cases are expected in the near future. Because of resistance to and limited number of current treatments, there may soon be no effective drugs available to treat trypanosomiasis patients, especially second-stage cases. Additional research and development efforts must be made for the development of new compounds, including: testing combinations of current trypanocidal drugs, completing the clinical development of nifurtimox and registering it for trypanosomiasis, completing the clinical development of an oral form of eflornithine, pursuing the development of DB 289 and its derivatives, and advancing the pre-clinical development of megazol, eventually engaging firmly in its clinical development. Partners from the public and private sector are already engaged in joint initiatives to maintain the production of current drugs. This network should go further and be responsible for assigning selected teams to urgently needed research projects with funds provided by industry and governments. At the same time, on a long term basis, ambitious research programmes for new compounds must be supported to ensure the sustainable development of new drugs.
    • Treatment Outcomes and Risk Factors for Relapse in Patients with Early-stage Human African Trypanosomiasis (HAT) in the Republic of the Congo.

      Balasegaram, M; Harris, S; Checchi, F; Hamel, C; Karunakara, U; Medecins Sans Frontieres, London, England. manica.balasigaram@london.msf.org (Published by WHO, 2006-10)
      OBJECTIVE: In 2002-03, the Republic of the Congo increased the threshold separating stage 1 and 2 cases of human African trypanosomiasis (HAT) from a cerebrospinal fluid (CSF) white cell count of 5 cells/mm(3) to 10 cells/mm(3). We aimed to assess whether the increased threshold of 10 cells/mm(3) is a safe indicator of stage 2 disease. METHODS: We assessed patients treated for stage 1 HAT caused by Trypanosoma brucei gambiense in the Republic of the Congo between April 2001 and April 2005. Patients with 0-10 cells/mm(3) in CSF were classed as stage 1 and treated with pentamidine. Patients with CSF of > 10 cells/mm(3) were classed as stage 2 and treated with either melarsoprol or eflornithine. We did a retrospective analysis of all patients treated after the September 2002 increase in threshold for classification of HAT disease stage 2, and who were eligible for at least 1 year of follow-up. Primary outcome was survival without death or relapse within 1 year of discharge. Risk factors for treatment failure, in particular CSF white cell count on diagnosis, were assessed. FINDINGS: Between September 2002 to April 2004, 692 patients eligible for our analysis were treated with pentamidine. All were discharged alive. Relapse rate was 5% (n = 33). The only identified risk factor for relapse was a CSF white cell count of 6-10 cells/mm(3) rather than 0-5 cells/mm(3) (adjusted hazard ratio 3.27 (95% confidence interval, 1.52-7.01); P = 0.002). CONCLUSION: A threshold of 5 white cells/mm(3) in CSF is safer than 10 cells/mm(3) to determine stage 2 HAT and reduce risk of relapse.
    • Trypanosoma Brucei Gambiense Trypanosomiasis in Terego County, Northern Uganda, 1996: A Lot Quality Assurance Sampling Survey.

      Hutin, Y; Legros, D; Owini, V; Brown, V; Lee, E; Mbulamberi, D; Paquet, C; Epicentre Office in Uganda, Kampala, Uganda. (Published by: American Society of Tropical Medicine and Hygiene, 2004-04)
      We estimated the pre-intervention prevalence of Trypanosoma brucei gambiense (Tbg) trypanosomiasis using the lot quality assurance sampling (LQAS) methods in 14 parishes of Terego County in northern Uganda. A total of 826 participants were included in the survey sample in 1996. The prevalence of laboratory confirmed Tbg trypanosomiasis adjusted for parish population sizes was 2.2% (95% confidence interval =1.1-3.2). This estimate was consistent with the 1.1% period prevalence calculated on the basis of cases identified through passive and active screening in 1996-1999. Ranking of parishes in four categories according to LQAS analysis of the 1996 survey predicted the prevalences observed during the first round of active screening in the population in 1997-1998 (P < 0.0001, by chi-square test). Overall prevalence and ranking of parishes obtained with LQAS were validated by the results of the population screening, suggesting that these survey methods may be useful in the pre-intervention phase of sleeping sickness control programs.