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Trypanosoma brucei gambiense African trypanosomiasis: differences between men and women in severity of disease and response to treatment.

To compare the characteristics of women and men with Trypanosoma brucei gambiense trypanosomiasis, all 3231 cases treated in Nioki hospital, Democratic Republic of Congo, from 1982 to 2000 were reviewed for demographic information, date and mode of diagnosis, pre-treatment cerebrospinal fluid (CSF) examination, treatment given and its adverse effects, and whether a diagnosis of relapse was made during post-treatment follow-up. Women had a higher apparent incidence of Gambian trypanosomiasis than men (1768 cases in females, 1463 in males), due to selective migration of males out of endemic foci and potentially to a higher exposure among females. Women presented with a less-advanced disease than men: 27% (384/1431) of women had CSF trypanosomes and 72% (1024/1431) had an abnormal CSF white cell count, while corresponding figures in men were 39% (431/1115) and 82% (910/1115) (P < 0.001 for both comparisons), presumably because of differences in health-seeking behaviour. Men (61/718, 8.5%) were more likely to relapse after melarsoprol treatment than women (41/857, 4.8%) (P = 0.004), even after adjustment for other independent risk factors in multivariate analysis. The cause of this higher risk of treatment failure among men treated with melarsoprol remains unclear.

Adolescent↗

TrypTect CIATT--a card indirect agglutination trypanosomiasis test for diagnosis of Trypanosoma brucei gambiense and T. b. rhodesiense infections.

A simple and rapid test, the card indirect agglutination trypanosomiasis test (TrypTect CIATT) is described, for detecting circulating antigens in persons suffering from Trypanosoma brucei gambiense and T. b. rhodesiense infection by latex agglutination. The sensitivity of the test (95.8% for T. b. gambiense and 97.7% for T. b. rhodesiense) was significantly higher than that of lymph node puncture, microhaematocrit centrifugation and cerebrospinal fluid examination after single and double centrifugation. The specificity of the test was also high: 106 blood donor sera as well as sera from 37 patients with malaria, 25 with visceral leishmaniasis, 10 with schistosomiasis, 5 with filariasis and 10 with hydatid disease, from trypanosomiasis-free areas, gave negative results. Eighteen clinical suspects from active disease transmission foci, without microscopically detectable parasitaemia but with a positive test result, were further examined by lumbar puncture and inoculation of blood into mice; 11 (61%) were found to be infected, suggesting that the test had a high positive predictive value. This study showed that TrypTect CIATT is a useful test for rapid diagnosis of both patent and non-patent T. b. gambiense and T. b. rhodesiense infections.

Agglutination Tests↗

Interactions between tsetse and trypanosomes with implications for the control of trypanosomiasis.

Tsetse flies (Diptera: Glossinidae) are vectors of several species of pathogenic trypanosomes in tropical Africa. Human African trypanosomiasis (HAT) is a zoonosis caused by Trypanosoma brucei rhodesiense in East Africa and T. b. gambiense in West and Central Africa. About 100000 new cases are reported per year, with many more probably remaining undetected. Sixty million people living in 36 countries are at risk of infection. Recently, T. b. gambiense trypanosomiasis has emerged as a major public health problem in Central Africa, especially in the Democratic Republic of Congo, Angola and southern Sudan where civil war has hampered control efforts. African trypanosomes also cause nagana in livestock. T. vivax and T. congolense are major pathogens of cattle and other ruminants, while T. simiae causes high mortality in domestic pigs; T. brucei affects all livestock, with particularly severe effects in equines and dogs. Central to the control of these diseases is control of the tsetse vector, which should be very effective since trypanosomes rely on this single insect for transmission. However, the area infested by tsetse has increased in the past century. Recent advances in molecular technologies and their application to insects have revolutionized the field of vector biology, and there is hope that such new approaches may form the basis for future tsetse control strategies. This article reviews the known biology of trypanosome development in the fly in the context of the physiology of the digestive system and interactions of the immune defences and symbiotic flora.

Animals↗

Indigenous knowledge system for treatment of trypanosomiasis in Kaduna state of Nigeria.

A survey was carried out in Kaduna State of Nigeria to establish the indigenous knowledge system for treating trypanosomiasis in domestic animals. Questionnaire and interviews were, respectively, administered to, or conducted with about 200 livestock farmers and traders spread around the state. Data obtained revealed the use of several plants either alone or in combination, for the treatment and management of trypasonomiasis. The most common plants encountered were Adansonia digitata, Terminalia avicennoides, Khaya senegalensis, Cissus populnea, Tamarindus indica, Lawsonia inermis, Boswellia dalzielli, Pseudocedrela kotschi, Syzyium quinensis, Sterculia setigera, Afzelia africana, Prosopis africana, Lancea kerstingii. The method of preparation and mode of administration of some of these plants in the treatment of trypanosomiasis are reviewed and discussed.

Animals↗

Human African trypanosomiasis: potential therapeutic benefits of an alternative suramin and melarsoprol regimen.

Treatment of late-stage human African trypanosomiasis is complicated by the presence of trypanosomes within the central nervous system (CNS). The regimen commonly prescribed to treat CNS-stage disease involves the use of the trypanocidal drugs suramin and melarsoprol. Suramin does not cross the blood-brain barrier efficiently and therefore, at normal dosages, will not cure CNS-stage infections. An initial treatment with suramin is given to eliminate the parasites from the peripheral tissues. This is followed by a course of intravenous melarsoprol, which can enter the CNS. However, melarsoprol not only produces severe adverse reactions but also is extremely painful to administer. One possible method to help alleviate these problems is to reduce the total amount of melarsoprol in the treatment regimen. This study indicates a synergism between suramin and melarsoprol and demonstrates that experimental murine CNS-trypanosomiasis can be cured with a single intraperitoneal dose of 20 mg/kg suramin followed almost immediately by 0.05 ml (4.5 micromol) topical melarsoprol. These dosages will not cure the infection when administered as monotherapies. Moreover, the timing of the drug administration appears to be crucial to the successful outcome of the regimen. If the interval between injection of suramin and application of topical melarsoprol is extended from 15 min to 3 or 7 days, the infections are not cured. Although extended relapse times occur following these regimens when compared with monotherapy approaches. Thus, there is strong evidence that injected suramin and topical melarsoprol should be given almost simultaneously to achieve the most effective combination of the two drugs.

Animals↗

Experimental therapy of African trypanosomiasis with a nanobody-conjugated human trypanolytic factor.

High systemic drug toxicity and increasing prevalence of drug resistance hampers efficient treatment of human African trypanosomiasis (HAT). Hence, development of new highly specific trypanocidal drugs is necessary. Normal human serum (NHS) contains apolipoprotein L-I (apoL-I), which lyses African trypanosomes except resistant forms such as Trypanosoma brucei rhodesiense. T. b. rhodesiense expresses the apoL-I-neutralizing serum resistance-associated (SRA) protein, endowing this parasite with the ability to infect humans and cause HAT. A truncated apoL-I (Tr-apoL-I) has been engineered by deleting its SRA-interacting domain, which makes it lytic for T. b. rhodesiense. Here, we conjugated Tr-apoL-I with a single-domain antibody (nanobody) that efficiently targets conserved cryptic epitopes of the variant surface glycoprotein (VSG) of trypanosomes to generate a new manmade type of immunotoxin with potential for trypanosomiasis therapy. Treatment with this engineered conjugate resulted in clear curative and alleviating effects on acute and chronic infections of mice with both NHS-resistant and NHS-sensitive trypanosomes.

Animals↗

Interferon-gamma and interleukin-12 genes are preferentially expressed during early experimental African trypanosomiasis and suppressed by denervation of the spleen.

The cross talk between the central nervous system (CNS) and the immune system includes among others, the modulation of immune responses by the autonomic nervous system. Here, we investigated the effects of a splenic denervation on cytokine induction in early experimental African trypanosomiasis. Profiles of the cytokine mRNA expression for interleukin (IL)-4, interleukin (IL)-6, interleukin (IL)-10, interleukin (IL)-12, tumour necrosis factor (TNF)-alpha, tumour necrosis factor (TNF)-beta, transforming growth factor (TGF)-beta and interferon (IFN)-gamma were examined at 4 h, 8 h and 12 h postinfection (p.i.), and in noninfected controls. Only IFN-gamma and IL-12 were significantly expressed over noninfected controls. Already at 4 h p.i. both cytokines were expressed and showed more increased levels at 12 h. Sympathetic denervation of the spleen markedly reduced the mRNA expression for both IFN-gamma and IL-12. Con A was used as a positive control and showed an enhanced mRNA expression, which was also suppressed by a splenic denervation. To demonstrate that the mRNA expression had resulted in a cytokine production, we looked for the protein level of IFN-gamma at 4 h p.i. by immunohistochemistry and found increased levels of IFN-gamma, which was also inhibited by the denervation. Sham-operated animals exhibited similar responses as the nondenervated controls. Our data present for the first time very early kinetics for a cytokine gene expression during an experimental African trypanosomiasis. Furthermore, the data suggest a regulatory role for the autonomic nervous system on cytokine responses at both the mRNA and the protein levels.

Animals↗

Topical chemotherapy for experimental African trypanosomiasis with cerebral involvement: the use of melarsoprol combined with the 5-nitroimidazole, megazol.

Megazol, one of a number of related 5-nitroimidazoles, can be dissolved in dimethylsulphoxide and the solution can be converted into a gel by the addition of hydroxypropylcellulose which facilitates the ease and accuracy of administration. This megazol gel, when used in combination with melarsoprol (3.6%) in propylene glycol gel, will cure experimental CNS-trypanosomiasis in mice. A single application of 0.1 ml of melarsoprol (3.6%) gel plus 0.1 ml of either 8 or 16 mg/ml megazol gel successfully treated experimental CNS-trypanosomiasis while two consecutive days' treatment with 0.05 ml melarsoprol and 0.1 ml of 16 or 32 mg/ml megazol gels also produced satisfactory cures.

Administration, Topical↗

Attitude towards CATT-positive individuals without parasitological confirmation in the African Trypanosomiasis (T.b. gambiense) focus of Quiçama (Angola).

Serologically positive individuals without parasitological confirmation constitute an important problem for trypanosomiasis control programmes because of epidemiological and therapeutical consequences. In July 1997, in the focus of Quiçama (Angola), 4753 individuals were screened using CATT/T.b.gambiense on whole blood. In CATT-positive but parasite-negative individuals, CATT titration on serum was performed. Sixteen individuals showing an end-titre lower than 1/4 were considered noninfected according to the results of a previous study of serological status of parasitologically confirmed cases; 86 individuals with end titres >/= 1/4 were considered suspected of trypanosomiasis and were followed-up from July 1997 to July 1998 with controls every three months. After one year, 32 individuals whose antibody titres dropped < 1/4 were considered noninfected, 22 were confirmed by demonstration of parasites, 17 were further followed-up because antibody titres remained >/= 1/8 but parasites could not be found. Fifteen individuals did not show up for testing. Following the usual criterion, only parasitologically confirmed cases were treated. However, if it had been decided to treat parasite-negative individuals with a CATT end-titre > 1/8, 22 initially unconfirmed but infected individuals would have been treated earlier, whereas 5 noninfected individuals would have been treated unnecessarily. CATT titration on diluted serum or plasma is useful for making therapeutical decisions.

Angola↗

Follow-up of Card Agglutination Trypanosomiasis Test (CATT) positive but apparently aparasitaemic individuals in Côte d'Ivoire: evidence for a complex and heterogeneous population.

The aetiological diagnosis of human African trypanosomiasis (HAT) is based on the detection of the parasite, but currently available parasitological tests have low sensitivity and are hampered by fluctuating parasitaemia. The identification of seropositive individuals on whom to focus parasitological examination is based on antibody detection by means of the Card Agglutination Trypanosomiasis Test (CATT/T.b.gambiense). A complicating phenomenon is the occurrence of serologically positive but parasitologically unconfirmed results (isolated CATT positivity). This work presents a two-year longitudinal serological, parasitological and molecular follow-up of CATT-positive individuals including repeated examinations of each individual, to study the evolution over time of seropositivity at both the population and the individual levels. At the population level, the rate of seropositivity decreased during the first months of the survey, and afterwards showed remarkable stability. At the individual level, the results reveal the extreme heterogeneity of this population, with subjects showing fluctuating results, others with a short transient CATT positivity, and subjects that maintain their seropositivity over time. The stability of seropositivity and the pattern of results obtained with both immunological and parasitological examinations support the view that individual factors, such as immune response to infection, might be involved in the isolated CATT positivity phenomenon.

Adolescent↗

Combination of eflornithine and melarsoprol for melarsoprol-resistant Gambian trypanosomiasis.

OBJECTIVE: To evaluate the efficacy and toxicity of a combination of eflornithine and melarsoprol among relapsing cases of Gambian trypanosomiasis. METHODS: Forty-two late-stage Trypanosoma brucei gambiense trypanosomiasis patients relapsing after initial treatment with melarsoprol were treated with a sequential combination of intravenous eflornithine (100 mg/kg every 6 h for 4 days) followed by three daily injections of melarsoprol (3.6 mg/kg, up to 180 mg). They were then followed-up for 24 months. RESULTS: Two (4.8%) patients died during treatment. Of the 40 surviving patients, two had a treatment failure, 13 and 19 months after having received the combination therapy. By Kaplan-Meier analysis, the 2-year probability of cure was 93.3% (95% confidence interval: 84.3-100%). CONCLUSION: This sequential combination has an efficacy and a toxicity similar to a 7-day course of eflornithine monotherapy, but is easier to administer. Whether such therapeutic success corresponds tosynergism between eflornithine and melarsoprol, or merely means that 4 days of eflornithine monotherapy suffices for such patients, will need to be determined in a comparative trial.

Adolescent↗

Field evaluation of the CATT/Trypanosoma brucei gambiense on blood-impregnated filter papers for diagnosis of human African trypanosomiasis in southern Sudan.

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.

Agglutination Tests↗

Treatment perspectives for human African trypanosomiasis.

Human African trypanosomiasis (HAT), or sleeping sickness, is currently on the rise. HAT develops in two stages, the first involving the hemolymphatic system, and the second, the neurological system. Left untreated, HAT is invariably fatal. There have been no therapeutic advances in more than 40 years. Stage 1 can be treated with pentamidine and suramin, but stage 2 can only be treated with melarsoprol, a toxic arsenic derivative that has a 2-12% incidence of fatal side-effects (encephalopathy). Eflornithine has never achieved widespread use because it is difficult to administer under field conditions. Nifurtimox has been used successfully in the treatment of American trypanosomiasis, or Chagas disease, but only in small studies or as a compassionate use treatment. There is little research and development for new drugs in this area: only one prodrug is in the clinical development phase, a pentamidine analog that offers hope for the replacement of injectable pentamidine with an orally administered drug. Current efforts appear to be focused on reevaluating older drugs. A course of treatment with melarsoprol for 10 days at 2.2 mg/kg/day is now in the multicenter evaluation phase. Orally administered eflornithine is also slated for reevaluation. In addition, studies of drug combinations are recommended to determine possible combined or synergistic effects and find ways to reduce toxicity.

Animals↗

[Contributions and limits of the diagnosis of human African trypanosomiasis].

Human African trypanosomiasis, or sleeping sickness, is still a worrying problem in Africa. Sleeping sickness is a disease for which a systematic monitoring is necessary, particularly for the trypanosomiasis caused by Trypanosoma brucei gambiense, which is characterized by a long asymptomatic stage. In the absence of specific clinical signs, mass screening of populations remains the only way to control the disease and to avoid its spreading. The lack of sensitivity and specificity of the diagnosis tests classically used led to the development of molecular tools. PCR amplification of parasite specific sequences has considerably improved the diagnostic of the parasitic infection, the stage diagnosis as well as the post-therapeutic follow-up. But there are limits with a use in routine and research is still necessary to make PCR a real tool for control of sleeping sickness.

Animals↗

Nitric oxide and cytokine synthesis in human African trypanosomiasis.

Plasma and cerebrospinal fluid (CSF) concentrations of nitrate and the cytokines interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-10, and IL-4 were measured in 91 African trypanosomiasis patients before and after treatment. Nitrate levels overall were not significantly elevated over those for control persons, but a marginal increase in plasma nitrate was detected in patients reporting illness of <40 days' duration. Plasma IFN-gamma and total TNF-alpha concentrations increased during infection, but free TNF-alpha levels were low in all patients. The most dramatic cytokine response was for IL-10, which was significantly elevated in both plasma and CSF during infection but returned to control levels after treatment. The results indicate that human African trypanosomiasis leads to the development of a strong anti-inflammatory cytokine response.

Animals↗

Effectiveness of a 10-day melarsoprol schedule for the treatment of late-stage human African trypanosomiasis: confirmation from a multinational study (IMPAMEL II).

BACKGROUND: Treatment of late-stage human African trypanosomiasis (HAT) with melarsoprol can be improved by shortening the regimen. A previous trial demonstrated the safety and efficacy of a 10-day treatment schedule. We demonstrate the effectiveness of this schedule in a noncontrolled, multinational drug-utilization study. METHODS: A total of 2020 patients with late-stage HAT were treated with the 10-day melarsoprol schedule in 16 centers in 7 African countries. We assessed outcome on the basis of major adverse events and the cure rate after treatment and during 2 years of follow-up. RESULTS: The cure rate 24 h after treatment was 93.9%; 2 years later, it was 86.2%. However, 49.3% of patients were lost to follow-up. The overall fatality rate was 5.9%. Of treated patients, 8.7% had an encephalopathic syndrome that was fatal 45.5% of the time. The rate of severe bullous and maculopapular eruptions was 0.8% and 6.8%, respectively. CONCLUSIONS: The 10-day treatment schedule was well implemented in the field and was effective. It reduces treatment duration, drug amount, and hospitalization costs per patient, and it increases treatment-center capacity. The shorter protocol has been recommended by the International Scientific Council for Trypanosomiasis Research and Control for the treatment of late-stage HAT caused by Trypanosoma brucei gambiense.

Adolescent↗

African trypanosomiasis in two travelers from the United States.

African trypanosomiasis is a rare but well-documented cause of fever in United States travelers returning from areas where it is endemic. We report two recently diagnosed cases that involved tourists who went on safari in Tanzania. Review of these and 29 other published cases indicates that disease in returning United States travelers is nearly always of the East African form, a fulminant illness for which prompt diagnosis is necessary. In the United States, timely and appropriate therapy for this disease has resulted in favorable outcomes for most patients. Chemoprophylaxis for East African trypanosomiasis is not recommended, but travelers visiting areas of endemicity should practice appropriate preventive measures to prevent tsetse fly bites.

Female↗