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Background The extent to which neuropsychiatric sequelae affects the mental health status and quality of life of former gambiense human African trypanosomiasis (gHAT) patients is not known. Methods We assessed anxiety, depression and health-related quality of life (HRQoL) in 93 patients and their age- and sex-matched controls using the Hospital Anxiety and Depression Scale, Becks Depression Inventory and the 36-item Short Form Health Survey in structured interviews in the Vanga health zone in the Democratic Republic of Congo. Data were analysed using Stata version 14.0. The degree of association between neurologic sequelae and mental distress was evaluated using the Student's t-test and χ2 or Fisher's exact tests, where appropriate, with a p-value <0.05 deemed to be statistically significant. Results We found that neurological sequelae persisted in former patients at least 15 y after treatment. Depression (p<0.001) and anxiety (p=0.001) were significantly higher in former patients with neurologic sequelae. The mean quality-of-life (QoL) scores were significantly lower for patients than in controls in the physical, emotional and mental health domains. Conclusions The presence of neurological sequelae leads to mental distress and a diminished QoL in former gHAT patients. Minimising neurologic sequelae and incorporating psychosocial interventions should be essential management goals for gHAT. [ABSTRACT FROM AUTHOR]

Background The clinical presentation of gambiense human African trypanosomias (gHAT) is generally considered to be the same among children and adults. In general, when describing the clinical presentation of children with gHAT, no differentiation is made between congenital gHAT and gHAT acquired later. There is a lack of knowledge regarding the signs and symptoms attributable to congenital gHAT and its long-term sequelae. Methods Following an evaluation of the hospital register for gHAT, the authors observed that six children born to mothers with gHAT during their pregnancies still had sequelae of the infection. The six mothers were interviewed about their respective pregnancies and the developmental history of the children borne to the infected mothers. Furthermore, the children then underwent a complete physical examination with a focus on neuropsychiatric signs and symptoms. Results Five of the six patients are still seriously disabled. Behavioral changes are present in four patients, tremor, speech impairment, involuntary movements and pathologic the Barrés test and Mingazzini test in three patients and convulsions, pyramidal signs and decreased muscle tonus in two patients. Two patients cannot work and one has a sphincter disorder. Conclusions Our study suggests that congenital gHAT may lead to long-lasting sequelae in babies born to mothers treated after delivery. The risk of embryo toxicity of treatment of mothers with gHAT must be balanced against the risk of congenital gHAT with long-term sequelae. [ABSTRACT FROM AUTHOR]

Background: Sleeping sickness (human African trypanosomiasis [HAT]) is a neglected tropical disease with limited treatment options that currently require parenteral administration. In previous studies, orally administered pafuramidine was well tolerated in healthy patients (for up to 21 days) and stage 1 HAT patients (for up to 10 days), and demonstrated efficacy comparable to pentamidine. Methods: This was a Phase 3, multi-center, randomized, open-label, parallel-group, active control study where 273 male and female patients with first stage Trypanosoma brucei gambiense HAT were treated at six sites: one trypanosomiasis reference center in Angola, one hospital in South Sudan, and four hospitals in the Democratic Republic of the Congo between August 2005 and September 2009 to support the registration of pafuramidine for treatment of first stage HAT in collaboration with the United States Food and Drug Administration. Patients were treated with either 100 mg of pafuramidine orally twice a day for 10 days or 4 mg/kg pentamidine intramuscularly once daily for 7 days to assess the efficacy and safety of pafuramidine versus pentamidine. Pregnant and lactating women as well as adolescents were included. The primary efficacy endpoint was the combined rate of clinical and parasitological cure at 12 months. The primary safety outcome was the frequency and severity of adverse events. The study was registered on the International Clinical Trials Registry Platform at with the number . Findings/Conclusions: The overall cure rate at 12 months was 89% in the pafuramidine group and 95% in the pentamidine group; pafuramidine was non-inferior to pentamidine as the upper bound of the 95% confidence interval did not exceed 15%. The safety profile of pafuramidine was superior to pentamidine; however, 3 patients in the pafuramidine group had glomerulonephritis or nephropathy approximately 8 weeks post-treatment. Two of these events were judged as possibly related to pafuramidine. Despite good tolerability observed in preceding studies, the development program for pafuramidine was discontinued due to delayed post-treatment toxicity. [ABSTRACT FROM AUTHOR]

Background: Sleeping sickness (human African trypanosomiasis [HAT]) is caused by protozoan parasites and characterized by a chronic progressive course, which may last up to several years before death. We conducted two Phase 2 studies to determine the efficacy and safety of oral pafuramidine in African patients with first stage HAT. Methods: The Phase 2a study was an open-label, non-controlled, proof-of-concept study where 32 patients were treated with 100 mg of pafuramidine orally twice a day (BID) for 5 days at two trypanosomiasis reference centers (Angola and the Democratic Republic of the Congo [DRC]) between August 2001 and November 2004. The Phase 2b study compared pafuramidine in 41 patients versus standard pentamidine therapy in 40 patients. The Phase 2b study was open-label, parallel-group, controlled, randomized, and conducted at two sites in the DRC between April 2003 and February 2007. The Phase 2b study was then amended to add an open-label sequence (Phase 2b-2), where 30 patients received pafuramidine for 10 days. The primary efficacy endpoint was parasitologic cure at 24 hours (Phase 2a) or 3 months (Phase 2b) after treatment completion. The primary safety outcome was the rate of occurrence of World Health Organization Toxicity Scale Grade 3 or higher adverse events. All subjects provided written informed consent. Findings/Conclusion: Pafuramidine for the treatment of first stage HAT was comparable in efficacy to pentamidine after 10 days of dosing. The cure rates 3 months post-treatment were 79% in the 5-day pafuramidine, 100% in the 7-day pentamidine, and 93% in the 10-day pafuramidine groups. In Phase 2b, the percentage of patients with at least 1 treatment-emergent adverse event was notably higher after pentamidine treatment (93%) than pafuramidine treatment for 5 days (25%) and 10 days (57%). These results support continuation of the development program for pafuramidine into Phase 3. [ABSTRACT FROM AUTHOR]

Background: Trypanosoma brucei (T.b.) gambiense Human African trypanosomiasis (HAT; sleeping sickness) is a fatal disease. Until 2009, available treatments for 2nd stage HAT were complicated to use, expensive (eflornithine monotherapy), or toxic, and insufficiently effective in certain areas (melarsoprol). Recently, nifurtimox-eflornithine combination therapy (NECT) demonstrated good safety and efficacy in a randomised controlled trial (RCT) and was added to the World Health Organisation (WHO) essential medicines list (EML). Documentation of its safety profile in field conditions will support its wider use. Methodology: In a multicentre, open label, single arm, phase IIIb study of the use of NECT for 2nd stage T.b. gambiense HAT, all patients admitted to the trial centres who fulfilled inclusion criteria were treated with NECT. The primary outcome was the proportion of patients discharged alive from hospital. Safety was further assessed based on treatment emergent adverse events (AEs) occurring during hospitalisation. Principal Findings: 629 patients were treated in six HAT treatment facilities in the Democratic Republic of the Congo (DRC), including 100 children under 12, 14 pregnant and 33 breastfeeding women. The proportion of patients discharged alive after treatment completion was 98.4% (619/629; 95%CI [97.1%; 99.1%]). Of the 10 patients who died during hospitalisation, 8 presented in a bad or very bad health condition at baseline; one death was assessed as unlikely related to treatment. No major or unexpected safety concerns arose in any patient group. Most common AEs were gastro-intestinal (61%), general (46%), nervous system (mostly central; 34%) and metabolic disorders (26%). The overall safety profile was similar to previously published findings. Conclusions/Significance: In field conditions and in a wider population, including children, NECT displayed a similar tolerability profile to that described in more stringent clinical trial conditions. The in-hospital safety was comparable to published results, and long term efficacy will be confirmed after 24 months follow-up. Registration: The trial is registered at ClinicalTrials.gov, number NCT00906880. [ABSTRACT FROM AUTHOR]

Objective: Assessment of the safety and efficacy of a 10-day melarsoprol schedule in second stage T.b. rhodesiense patients and the effect of suramin-pretreatment on the incidence of encephalopathic syndrome (ES) during melarsoprol therapy. Design: Sequential conduct of a proof-of-concept trial (n = 60) and a utilization study (n = 78) using historic controls as comparator. Setting: Two trial centres in the T.b. rhodesiense endemic regions of Tanzania and Uganda. Participants: Consenting patients with confirmed second stage disease and a minimum age of 6 years were eligible for participation. Unconscious and pregnant patients were excluded. Main Outcome Measures: The primary outcome measures were safety and efficacy at end of treatment. The secondary outcome measure was efficacy during follow-up after 3, 6 and 12 months. Results: The incidence of ES in the trial population was 11.2% (CI 5–17%) and 13% (CI 9–17%) in the historic data. The respective case fatality rates were 8.4% (CI 3–13.8%) and 9.3% (CI 6–12.6%). All patients discharged alive were free of parasites at end of treatment. Twelve months after discharge, 96% of patients were clinically cured. The mean hospitalization time was reduced from 29 to 13 days (p<0.0001) per patient. Conclusions: The 10-day melarsoprol schedule does not expose patients to a higher risk of ES or death than does treatment according to national schedules in current use. The efficacy of the 10-day melarsoprol schedule was highly satisfactory. No benefit could be attributed to the suramin pre-treatment. Trial Registration: Current Controlled Trials ISRCTN40537886 Author Summary: Human African Trypanosomiasis (HAT) is a parasitic disease that occurs in a chronic form caused by T.b. gambiense in West and Central Africa and in an acute form caused by T.b. rhodesiense in East and South Africa. In the first stage of the disease parasites are detectable in blood and lymph. Once they enter the central nervous system, patients are in the so-called second stage, which is fatal if left untreated. Melarsoprol, an old and highly toxic drug, remains the only available treatment for second stage T.b. rhodesiense HAT. The empirically developed treatment regimens are a high burden to affected patients and health care providers due to very long hospitalization times and complicated dosing schemes. An improved 10-day melarsoprol treatment schedule was developed and tested in second stage T.b. gambiense patients from 1997–2004 and was approved for large-scale use by the International Scientific Committee for Trypanosomiasis Research and Control (ISCTRC) in 2003. To test its adequacy also in T.b. rhodesiense patients, a series of clinical trials were conducted from 2005–2009. Based on these results the ISCTRC has officially recommended the use of the 10-day melarsoprol schedule also for treatment of second stage Rhodesiense HAT in 2009. [ABSTRACT FROM AUTHOR]

The number of imported Human African Trypanosomiasis (HAT) cases in non-endemic countries has increased over the last years. The objective of this analysis is to describe the clinical presentation of HAT in Caucasian travelers. Literature was screened (MEDLINE, Pubmed) using the terms ''Human African Trypanosomiasis'', ''travelers'' and ''expatriates''; all European languages except Slavic ones were included. Publications without clinical description of patients were only included in the epidemiological analysis. Forty-five reports on Caucasians with T.b. rhodesiense and 15 with T.b. gambiense infections were included in the analysis of the clinical parameters. Both species have presented with fever (T.b. rhodesiense 97.8% and T.b. gambiense 93.3%), headache (50% each) and a trypanosomal chancre (T.b. rhodesiense 84.4%, T.b. gambiense 46.7%). While sleeping disorders dominate the clinical presentation of HAT in endemic regions, there have been only rare reports in travelers: insomnia (T.b. rhodesiense 7.1%, T.b. gambiense 21.4%), diurnal somnolence (T.b. rhodesiense 4.8%, T.b. gambiense none). Surprisingly, jaundice has been seen in 24.2% of the Caucasian T.b. rhodesiense patients, but has never been described in HAT patients in endemic regions. These results contrast to the clinical presentation of T.b. gambiense and T.b. rhodesiense HAT in Africans in endemic regions, where the presentation of chronic T.b. gambiense and acute T.b. rhodesiense HAT is different. The analysis of 14 reports on T.b. gambiense HAT in Africans living in a non-endemic country shows that neurological symptoms such as somnolence (46.2%), motor deficit (64.3%) and reflex anomalies (14.3%) as well as psychiatric symptoms such as hallucinations (21.4%) or depression (21.4%) may dominate the clinical picture. Often, the diagnosis has been missed initially: some patients have even been hospitalized in psychiatric clinics. In travelers T.b. rhodesiense and gambiense present as acute illnesses and chancres are frequently seen. The diagnosis of HAT in Africans living outside the endemic region is often missed or delayed, leading to presentation with advanced stages of the disease. [ABSTRACT FROM AUTHOR]

Background: A wide spectrum of disease severity has been described for Human African Trypanosomiasis (HAT) due to Trypanosoma brucei rhodesiense (T.b. rhodesiense), ranging from chronic disease patterns in southern countries of East Africa to an increase in virulence towards the north. However, only limited data on the clinical presentation of T.b. rhodesiense HAT is available. From 2006-2009 we conducted the first clinical trial program (IMPAMEL III) in T.b. rhodesiense endemic areas of Tanzania and Uganda in accordance with international standards (ICH-GCP). The primary and secondary outcome measures were safety and efficacy of an abridged melarsoprol schedule for treatment of second stage disease. Based on diagnostic findings and clinical examinations at baseline we describe the clinical presentation of T.b. rhodesiense HAT in second stage patients from two distinct geographical settings in East Africa. Methodology/Principal Findings: 138 second stage patients from Tanzania and Uganda were enrolled. Blood samples were collected for diagnosis and molecular identification of the infective trypanosomes, and T.b. rhodesiense infection was confirmed in all trial subjects. Significant differences in diagnostic parameters and clinical signs and symptoms were observed: the median white blood cell (WBC) count in the cerebrospinal fluid (CSF) was significantly higher in Tanzania (134cells/mm3) than in Uganda (20cells/mm3; p,0.0001). Unspecific signs of infection were more commonly seen in Uganda, whereas neurological signs and symptoms specific for HAT dominated the clinical presentation of the disease in Tanzania. Co-infections with malaria and HIV did not influence the clinical presentation nor treatment outcomes in the Tanzanian study population. Conclusions/Significance: We describe a different clinical presentation of second stage T.b. rhodesiense HAT in two distinct geographical settings in East Africa. In the ongoing absence of sensitive diagnostic tools and safe drugs to diagnose and treat second stage T.b. rhodesiense HAT an early identification of the disease is essential. A detailed understanding of the clinical presentation of T.b. rhodesiense HAT among health personnel and affected communities is vital, and awareness of regional characteristics, as well as implications of co-infections, can support decision making and differential diagnosis. [ABSTRACT FROM AUTHOR]

The article offers clinical information on human African trypanosomiasis or sleeping sickness, a condition caused by the protozoan parasite Trypanosoma brucei and its transmitted by blood-feeding tsetse flies. Sleeping sickness is prevalent in sub-Saharan Africa where habitats are suitable for the tsetse flies. It appears in haemolymphatic and meningocephalitic stages, with the later stage being characterized with central nervous system invasion. Patients with sleeping sickness may experience fever, inflammation, sleep disorder and cardiac problems. Therapeutic options for such condition include pentamidine, suramin and melarsoprol.

Summary: American trypanosomiasis (Chagas disease) and human African trypanosomiasis (HAT; sleeping sickness) are both caused by single-celled flagellates that are transmitted by arthropods. Cardiac problems are the main cause of morbidity in chronic Chagas disease, but neurological problems dominate in HAT. Physicians need to be aware of Chagas disease and HAT in patients living in or returning from endemic regions, even if they left those regions long ago. Chagas heart disease has to be taken into account in the differential diagnosis of cardiomyopathy, primarily in patients with pathological electrocardiographic (ECG) findings, such as right bundle branch block or left anterior hemiblock, with segmental wall motion abnormalities or aneurysms on echocardiography, and in young patients with stroke in the absence of arterial hypertension. In HAT patients, cardiac involvement as seen by ECG alterations, such as repolarisation changes and low voltage, is frequent. HAT cardiopathy in general is benign and does not cause relevant congestive heart failure and subsides with treatment. We review the differences between the American and African trypanosomiasis with the main focus on the heart. [Copyright &y& Elsevier]

Objectives To estimate the frequency and evolution of heart involvement in human African trypanosomiasis (HAT) using electrocardiogram (ECG) findings; to describe these findings and to assess the frequency and clinical relevance of symptoms and signs before and after treatment. Methods In a prospective cohort study ECG findings, signs and symptoms consistent with heart failure and cardiac laboratory parameters were studied at baseline, 2 days after the end of treatment and 3 months later. Results Major ECG alterations were significantly more frequent in HAT patients than in healthy controls (71% vs. 18%; P < 0.001); 31% were low voltage changes, 34% were repolarization changes. ECG signs of necrosis and conduction problems were rare. Symptoms consistent with heart failure such as exertional dyspnoea (19% vs. 1.7%; P = 0.002) or palpitations (18% vs. 5%; P = 0.28) occurred more frequently in patients than in controls. The median NT-proBNP was significantly higher in HAT patients than in controls (85.2 vs. 28 pg/ml; P < 0.001). Troponin levels were normal. At the end of treatment repolarization changes appeared or worsened in 33.4%. Such changes improved or disappeared at follow-up in 33.1% of the patients. Conclusions Cardiac involvement documented by ECG alterations is common in HAT patients, but cardiopathy rarely causes severe congestive heart failure and subsides after treatment. ECG alterations immediately after treatment and their improvement 3 months later may be the result of a treatment-induced inflammatory reaction. [ABSTRACT FROM AUTHOR]

Abstract: Symptoms consistent with hypothyroidism or adrenal insufficiency, such as lethargy, anorexia, cold intolerance, weakness, hypotension or paraesthesia, are frequently reported in the literature in patients with Human African Trypanosomiasis (HAT), but an endocrine origin for these symptoms has not yet been demonstrated. Thyroid and adrenocortical function were assessed in 60 patients with late-stage HAT and compared to those in 60 age- and gender-matched healthy controls. Clinical assessment and endocrine laboratory examinations were performed on admission, within 2 days after the end of treatment and at follow-up 3 months later. Signs and symptoms of hypothyroidism, such as fatigue, cold sensation, constipation, paraesthesia, peripheral oedema and dry skin, were significantly more frequent in HAT patients than in the controls. However, these signs and symptoms could not be attributed to hypothyroidism due to the lack of supporting laboratory data, and thus empirical replacement therapy for the clinically suspected hypothyroidism was not warranted. Signs and symptoms consistent with adrenal insufficiency, such as weakness, anorexia, weight loss or hypotension, were significantly more frequent in HAT patients than in controls, but they could not be associated with an insufficiency of the adrenocortical axis. Higher basal levels of cortisol were found in HAT patients than in controls, which can be viewed as a stress response to the infection. However, a transitory adrenal insufficiency was suspected in 8% of HAT patients at admission and in 9% at discharge. All values were normal at follow-up 3 months later. [Copyright &y& Elsevier]

Abstract: The clinical symptoms and signs of patients with second stage HAT are described for a large cohort of patients treated in a prospective multicentre, multinational study. Special emphasis is given to the influence of disease stage (duration, number of WBC in CSF) and patient age to the clinical picture. Even though the frequencies of symptoms and signs are highly variable between centres, the clinical picture of the disease is similar for all countries. Headache (78.7%), sleeping disorder (74.4%) and lymphadenopathy (56.1%) are the most frequent symptoms and signs and they are similar for all stages of the disease. Lymphadenopathy tends to be highest in the advanced second stage (59.0%). The neurological and psychiatric symptoms increase significantly with the number of WBC in the CSF indicating the stage of progression of the disease. Pruritus is observed in all stages and increases with the number of WBC in CSF from 30 to 55%. In children younger than 7 years, lymphadenopathy is less frequently reported (11.8–37.3%) than in older children or adults (56.4–61.2%). Fever is most frequently reported in children between 2 and 14 years of age (26.1–28.7%) and malnutrition is significantly more frequently observed in children of all ages (43–56%) than in adults (23.5%). [Copyright &y& Elsevier]