Miltefosine treatment of Leishmania major infection: an observational study involving Dutch military personnel returning from northern Afghanistan.

In a retrospective, observational study involving 34 patients with Leishmania major infection, 31 of whom had experienced unsuccessful treatment with intralesional antimony (ilSb(v)), miltefosine proved effective. Thirty patients experienced cure after receipt of miltefosine, 3 after receipt of additional ilSb(v), and 1 after 28 daily intravenous injections of antimony. Temporary diminution of ejaculate volume was reported by 21 patients.

Viral respiratory tract infections among patients with acute undifferentiated fever in Vietnam.

To investigate the proportion of viral respiratory tract infections among acute undifferentiated fevers (AUFs) at primary health facilities in southern Vietnam during 2001-2005, patients with AUF not caused by malaria were enrolled at twelve primary health facilities and a clinic for malaria control program. Serum was collected on first presentation (t0) and after 3 weeks (t3) for serology. After exclusion of acute dengue infection, acute and convalescent serum samples from 606 patients were using enzyme-linked immunoassays to detect IgA, as well as IgM and IgG antibodies against common respiratory viruses. Paired sera showed the following infections: human parainfluenza virus (HPIV, 4.7%), influenza B virus (FLUBV, 2.2%), influenza A virus (FLUAV, 1.9%) and human respiratory syncytial virus (HRSV, 0.6%). There was no association between type of infection and age, sex or seasonality; some inter-annual differences were observed for influenza. Antibody prevalence, indicative of previous infections, was relatively low: HPV, 56.8%, FLUBV, 12.1%; FLUAV, 5.9% and HRSV, 6.8%.

Visceral leishmaniasis in Aba-Roba, south-western Ethiopia: prevalence and incidence of active and subclinical infections.

Between August 1997 and February 2005, a prospective study of human visceral leishmaniasis (VL) was undertaken in two villages in the Konso district of south-western Ethiopia, to provide epidemiological indices of subclinical infection and active VL. Six cross-sectional surveys at 6-month intervals (ending in August 2000) were complemented by a single survey in February 2005. The prevalences and incidences of leishmanial infection and active VL, which were determined using leishmanin skin tests (LST), direct agglutination tests (DAT) and parasitological diagnosis, varied spatio-temporally and by age and gender. At baseline, when 1339 individuals were investigated, the overall prevalences of LST positivity, DAT positivity and active VL among the 1232 subjects who had not been treated previously were 30.0%, 5.4% and 0.49%, respectively. During the study, <10% of the subjects found DAT-positive at baseline progressed to active VL (with a mean of about nine cases of subclinical infection for every one of active VL). The median age of an incident VL case was 10.5 years. The highest rates of LST conversion occurred among the subjects aged 5-25 years. A subject who became LST-positive during the study was much less likely to develop active VL than the other subjects.

Cutaneous leishmaniasis with lymphadenopathy due to Leishmania donovani.

We describe a case of cutaneous leishmaniasis with lymphadenopathy due to Leishmania donovani, which was successfully treated with oral miltefosine. Given the increased prevalence of travelling, patients presenting with lymph-node enlargement should have leishmaniasis included in the differential diagnosis even in the absence of typical ulceration.

[The treatment of falciparum malaria]. / Behandeling van malaria tropica.

Only a few drugs are available for the treatment of malaria. Artemisinin combination treatment is advocated because of its efficacy and to prevent the development of resistance. In the Netherlands, falciparum malaria is treated with atovaquone-proguanil or artemether-lumefantrine, both registered as 3-day treatments. In a recent study, 21 patients were treated with artemether-lumefantrine for 5 days. There are arguments in favour of a 5-day course: absorption of lumefantrine is dependent on food intake and the serum levels of lumefantrine are higher on day 7 after a 5-day course than after a 3-day course. As shown by studies in Thailand, the serum level is related to the relapse rate, although these studies revealed no difference in relapse rate between the 3- and 5-day courses. In endemic countries, short courses of treatment are favoured to further patient compliance. Artesunate for i.v. administration is urgently needed.

Prevalence and severity of malnutrition and age at menarche; cross-sectional studies in adolescent schoolgirls in western Kenya.

OBJECTIVE: Nutritional status is an important marker of overall health and linear growth retardation has serious long-term physiological and economic consequences. Approximately 35 and 29% of preschool children in sub-Saharan Africa are stunted and underweight, respectively. There is relatively little information available about the nutritional status in adolescents, the age group with the highest growth velocity after infancy. We conducted a series of cross-sectional surveys to determine the prevalence and main risk groups for malnutrition and to describe the associations between age, sexual maturation and nutritional status in adolescent schoolgirls in western Kenya. DESIGN: Three cross-sectional surveys; one in Mumias, using random sampling in all schools, and two surveys in Asembo, using a multi-stage random sample design. SETTING: Public primary schools in two different rural malaria endemic areas in western Kenya with high levels of malnutrition in preschool children. SUBJECTS: In all, 928 randomly selected adolescent schoolgirls aged 12-18 y. RESULTS: Overall prevalence of stunting and thinness was 12.1 and 15.6%, respectively. Of the total, 2% were severely stunted. Menarche and start of puberty were delayed by approximately 1.5-2 y compared to a US reference population. The prevalence of stunting and thinness decreased with age and mean height for age z-scores converged towards the median of the US reference curve. Girls who had not yet started menstruating were more likely to be stunted than the girls of the same age who were post-menarche. CONCLUSIONS: Stunting and thinness are common in young adolescent schoolgirls in these poor rural settings in western Kenya, but the prevalence decreases with age, providing observational support that children catch up on incomplete growth attained earlier in life due to a maturational delay of 1.5-2 y allowing prolonged growth.

Nutritional status following malaria control in a Vietnamese ethnic minority commune.

OBJECTIVE: To study whether control of malaria leads to catch-up growth or an increase of obesity in a marginally nourished population. SETTING: A Vietnamese ethnic minority commune in southern Vietnam. DESIGN: Repeated annual anthropometric surveys were performed from 1995 to 2000. Z-scores for height, weight and BMI for age and weight-for-height were determined by using NCHS 1978 and CDC 2000 reference tables and by the LMS method. INTERVENTION: Active malaria control that reduced the parasite carrier rate from 50% in 1994 to practically nil in 1998. RESULTS: Inhabitants were generally of short stature and very thin. Using the US reference tables, the prevalence of moderate/severe stunting among children was 53/24% and of wasting 27/9% in the first survey in 1995. Physical condition and normal daily activities of most inhabitants were normal. The repeated LMS-Z-scores uncovered a significant recovery of stunting, extending into preadolescence, including the development of a pubertal growth spurt for girls and enhancement of pubertal growth in boys, after control of malaria. The mean (95% CI) annual increase of Z-height-for-age was 0.11 (0.09-0.12) for boys and 0.14 (0.13-0.15) for girls (P<0.001). As a consequence, weight-for-age and BMI Z-scores decreased without indication of developing obesity. CONCLUSION: Catch-up growth, extending into preadolescent age, was observed in a Vietnamese ethnic minority population with a chronic state of low food intake, without indication of developing obesity. The control of malaria was probably the most significant contribution to this catch-up growth.

Indomethacin stimulates glucose production in adults with uncomplicated falciparum malaria.

In healthy subjects, basal hepatic glucose production is (partly) regulated by paracrine intrahepatic factors. It is unknown if these paracrine factors also influence basal glucose production in infectious diseases with increased glucose production. We compared the effects of 150 mg indomethacin (n = 9), a nonendocrine stimulator of glucose production in healthy adults, and placebo (n = 7) on hepatic glucose production in Vietnamese adults with uncomplicated falciparum malaria. Glucose production was measured by primed, continuous infusion of [6,6-2H2]glucose. After indomethacin, the plasma glucose concentration and glucose production increased in all subjects from 5.3 +/- 0.1 mmol/L to a maximum of 7.1 +/- 0.3 mmol/L (P < .05) and from 17.6 +/- 0.8 micromol x kg(-1) x min(-1) to a maximum of 26.2 +/- 2.5 micromol x kg(-1) x min(-1) (P < .05), respectively. In the control group, the plasma glucose concentration and glucose production declined gradually during 4 hours from 5.4 +/- 0.2 mmol/L to 5.1 +/- 0.1 mmol/L (P < .05) and from 17.1 +/- 0.8 micromol x kg(-1) x min(-1) to 15.1 +/- 1.0 micromol x kg(-1) x min(-1) (P < .05), respectively. There were no differences in plasma concentrations of insulin, counterregulatory hormones, or cytokines between the groups. We conclude that indomethacin administration results in a transient increase in glucose production in patients with uncomplicated falciparum malaria in the absence of changes in plasma concentrations of glucoregulatory hormones or cytokines. Thus, this study indicates that in uncomplicated falciparum malaria, the rate of basal hepatic glucose production is also regulated by paracrine intrahepatic factors.

Trypsin-treated and coomassie blue-stained epimastigote antigen in a microagglutination test for Chagas' disease.

A microagglutination test using trypsin-treated and Coomassie blue-stained Trypanosoma cruzi epimastigote antigen was adapted for the diagnosis of Chagas' disease. When incorporated in the test, 2-mercaptoethanol treatment of chagasic sera had no influence on antibody titer. In contrast, titers in sera from patients with visceral leishmaniasis, African trypanosomiasis, and autoimmune disorders, subjected to similar treatment, showed remarkable decline. Accordingly, a lower cut-off point for Chagas' disease serological negativity could be taken resulting in a higher sensitivity (95.6%); the specificity was 94.7%. Similar specificities were obtained with Leishmania donovani chagasi and L. d. donovani antigens applied to homologous visceral leishmaniasis and heterologous Chagas' sera. Of 316 nonchagasic sera, only 3 with leptospirosis and 1 with leprosy showed seropositive titers prior to and after 2-mercaptoethanol treatment.

Testing for anti-circumsporozoite and anti-blood-stage antibodies for epidemiologic assessment of Plasmodium falciparum infection in travelers.

The purpose of this investigation was to assess the role of serology for establishing incidences of Plasmodium falciparum malaria and of exposure to P. falciparum in epidemiologic studies of travelers using chemoprophylaxis. The design was a prospective cohort study involving 548 short-term Dutch travelers to areas endemic for P. falciparum malaria. Sera were collected before departure and, together with the medical history, 2-6 weeks after return. All sera were tested for anti-circumsporozoite (CS) antibodies by an R32tet32-ELISA; sera of subjects reporting febrile illness during travel or after return or with anti-CS responses were tested for anti-blood-stage antibodies by an indirect fluorescence antibody test (IFAT). Five subjects (0.9%) reported P. falciparum malaria confirmed by thick blood smear examination (documented cases) and six (1.0%) reported treatment for malaria without a documented diagnosis (presumptive cases). Conversions in the IFAT were detected in six subjects, including all five documented cases and one presumptive case. Anti-CS antibodies were detected in seven subjects (1.3%), including three documented cases and four of 442 subjects with no history of fever or malaria treatment (0.9%). Incidence rates per 1,000 person-months of travel (95% confidence interval) of infection with P. falciparum, whether or not suppressed by chemoprophylaxis, were 16.9 (8-31) for all destinations and 91.6 (33-200) for West Africa. In epidemiologic studies of P. falciparum malaria in travelers, testing for antibodies to blood stages can increase the sensitivity and specificity of case detection; testing for antibodies to sporozoites may be useful for the assessment of exposure to P. falciparum in travelers using chemoprophylaxis, but the sensitivity is limited.

The response of Kenyan kala-azar to treatment with sodium stibogluconate.

Of 16 patients with kala-azar treated with sodium stibogluconate (0.1 ml/kg body weight a day), one died on the 12th day of treatment and nine were cured by a 30-day course, although two subsequently relapsed. Extending the course cured a further five patients, and in one patient allopurinol was used in addition before a cure was achieved. Clinical and hematological recovery began within a few days of the start of treatment, but parasites continued to be seen in splenic aspirates for 3 weeks or more.

Effect of grapefruit juice or cimetidine coadministration on albendazole bioavailability.

The assumed metabolic breakdown of albendazole by mucosal CYP3A4 enzymes was studied by coadministering albendazole (10 mg/kg) with grapefruit juice. Concentrations of albendazole sulfoxide (ABZSX), the active metabolite of albendazole, were compared with those after albendazole was administered with water, a fatty meal, or grapefruit juice plus cimetidine (10 mg/kg). In comparison to water, maximum ABZSX concentration (Cmax) was enhanced 6.5-fold by a fatty meal (from 0.24 +/- 0.09 mg/l to 1.55 +/- 0.30 mg/l; mean +/- SD; P < 0.001) and 3.2-fold by grapefruit juice (from 0.24 +/- 0.09 mg/l to 0.76 +/- 0.37 mg/L; P = 0.031). When grapefruit juice was combined with cimetidine, Cmax was significantly lower than with grapefruit juice alone (0.41 +/- 0.29 mg/l and 0.76 +/- 0.37 mg/l, respectively; P = 0.022). The area under the concentration-time curve from 0 to infinity (AUC(0-omega)) followed a comparable pattern. Half-life (T(1/2)) was 8.8 +/- 4.2 hr and 8.2 +/- 4.3 hr after administration with water or a fatty meal (P = 1.000). Grapefruit juice shortened T(1/2) by 46% (P = 0.026). We hypothesize that albendazole is metabolized by CYP3A4 enzymes in the intestinal mucosa. This process can be inhibited by grapefruit juice. Cimetidine decreased albendazole bioavailability.

The pharmacokinetics of a single dose of artemisinin in healthy Vietnamese subjects.

The pharmacokinetics of artemisinin was studied in 12 healthy male Vietnamese subjects after a single, 500-mg, oral dose. A total of 14 plasma samples per subject was obtained up to 48 hr after drug intake. Measurement of artemisinin concentration was performed by high-performance liquid chromatography with electrochemical detection. Tolerance was evaluated by recording subjective and objective findings including repeated physical examination, routine blood investigation, and electrocardiograms. Fitting of the concentration-time curve and pharmacokinetic calculations revealed the following results: a mean +/- SD volume of distribution/dose ratio of 19.4 +/- 6.9 L/kg, a mean +/- SD absorption half-life of 0.58 +/- 0.54 hr with a mean +/- SD calculated maximum concentration of 391 +/- 147 micrograms/L occurring at 1.81 +/- 0.73 hr after drug intake. Elimination was rapid, with a mean +/- SD elimination half-life of 2.59 +/- 0.55 hr. Peak concentrations were sufficient with regard to antimalarial activity although bioavailability appears to be very low. The relatively small interindividual variation in pharmacokinetics does not seem to be of clinical significance. Tolerance to the single dose of artemisinin was good: no adverse effects were detected. Based on these results, a treatment schedule of 2 x 500 mg of artemisinin (oral dose) per day can be advised. This will result in adequate antimalarial plasma concentrations, despite poor bioavailability, and rapid elimination.

Comparison of the parasitologic efficacy of amodiaquine and sulfadoxine-pyrimethamine in the treatment of Plasmodium falciparum malaria in the Bungoma District of western Kenya.

The efficacy of amodiaquine (AQ) and sulfadoxine-pyrimethamine (SP) was assessed in 310 symptomatic children from western Kenya with uncomplicated Plasmodium falciparum malaria. A non-blinded, randomized, 14-day study was performed and parasitologic criteria were used. Of 310 patients included, 238 (77%) completed the study: 120 received AQ and 118 received SP. In those treated with AQ, there were sensitive (S) infections in 107 patients (89.2%, 95% confidence interval [CI] = 82.2, 94.1%), RI resistance in 10 (8.3%, 95% CI = 4.1, 14.8%), RII resistance in 1 (0.8%, 95% CI = 0, 4.6%), and RIII resistance in 2 (1.7%, 95% CI = 0.2, 5.9%). In those treated with SP, there were S infections in 74 patients (62.7%, 95% CI = 53.3, 71.4%), RI resistance in 21 (17.8%, 95% CI = 11.4, 25.9%), RII resistance in 11 (9.3%, 95% CI = 4.7, 16.1%), and RIII resistance in 12 (10.2%, 95% CI = 5.4, 17.1%). Resistance rates were consistently higher in the SP-treated patients (P < 0.001). Resistance to SP in this area has reached such levels that it should no longer be the first-line treatment. Alternative treatment, such as SP plus AQ combination treatment or artemisinin combination treatment, is urgently needed.

The pharmacokinetics of artemisinin after administration of two different suppositories to healthy Vietnamese subjects.

Eight healthy Vietnamese male subjects received 400 mg artemisinin formulated into fatty suppositories (FS), and six different subjects received 500 mg of artemisinin formulated in polyethylene glycol suppositories (PEGS). Plasma concentrations were measured by high-performance liquid chromatography with electrochemical detection; concentration versus time curves were analyzed with nonparametric methods. No statistically significant differences were found between the two formulations. The maximum concentration (Cmax) was 100 +/- 102 microg/L (mean +/- SD, range = 24-330) microg/L (FS), the pharmacokinetic lag time (Tlag) was 1.3 +/- 1.0 hr (range = 0-3) (FS), and the time of the maximum concentration (Tmax) was 7.1 +/- 2.1 hr (range = 3-10) hr (FS). Because artemisinin is not available for intravenous dosage, absolute bioavailability cannot be assessed. However, compared with a previous study on oral artemisinin in healthy Vietnamese subjects, bioavailability relative to oral administration was estimated to be approximately 30%. We conclude that therapeutic blood concentrations of artemisinin can be reached after rectal dosage. The dose after rectal administration should probably be higher than after oral administration; doubling or tripling the oral dose might be necessary, which would imply a rectal dose of at least 20 mg/kg of body weight given twice a day.

Studies on the prevalence of leishmanin skin test positivity in the Baringo District, Rift Valley, Kenya.

The leishmanin skin test (LST) was applied in 26 clusters of an average of 97 individuals in Baringo District, Kenya. These clusters were centered around recent cases of visceral leishmaniasis (VL). Of 2,411 individuals tested, 254 (10.5%, 155 males and 99 females) had a positive reaction. Among cured VL patients, the frequency was approximately 30% and no sex difference was observed. In the population as a whole, LST positivity increased with age to a stable level from approximately 15 years of age, reflecting an endemic situation. The level of LST positivity was 25-30% and 10-15% in males and females, respectively. Uninfected household contacts of VL cases had a higher frequency of LST reactivity than the rest of the population. This relationship was significant only in females and children, the prevalence ratio being 2.3 (95% confidence interval 1.3-4.1), 1.9 (1.1-3.5), and 1.4 (0.8-2.5) for females, children, and males, respectively. The frequency of LST positivity was higher individuals living in wood houses than in individuals living in house with mud or stone walls. Again, this difference was significant only in females and children (P = 0.02 and P = 0.04), but not in males (P = 0.7). The results suggest that children and women are exposed to the parasite in or around their houses, whereas adult males are, in addition, exposed elsewhere.

Artemisinin for treatment of uncomplicated falciparum malaria: is there a place for monotherapy?

The efficacy of artemisinin monotherapy was studied in 227 patients with uncomplicated falciparum malaria. They all received artemisinin at t = 0 hr, t = 8 hr, and thereafter once daily; treatment was extended at random until they had taken either 5 days of artemisinin followed by 2 days of placebo (A5), or 7 days (A7) of artemisinin. The adult artemisinin dose was 500 mg; children aged < 15 years received 10 mg/kg per dose. The median (range) parasite clearance time was 39 (8-112) hr for A5 and 43 (38-104) hr for A7 (P = 0.085). The recrudescence rates were similar between the groups. The lowest parasite count achieved during treatment (Pterm) was associated with the occurrence of recrudescence (P = 0.046, Cox regression model); it was lower for patients with a radical cure or late recrudescence than for early recrudescence (P = 0.034, t-test). Artemisinin monotherapy may offer rapid recovery and fast parasite clearance, but recrudescence is frequent. Extending the duration of monotherapy from 5 days to 7 days does not reduce recrudescence.

Tolerance of mefloquine chemoprophylaxis in Dutch military personnel.

From June until October 1993, a battalion of Dutch marines was stationed in Cambodia for a United Nations deployment. In 73 volunteers who used mefloquine as malaria chemoprophylaxis, possible mefloquine-related adverse events were monitored with special emphasis on QT prolongation. All participants started mefloquine chemoprophylaxis with a loading dose (250 mg a day for three days) one week before departure, followed by a weekly dose (250 mg) for approximately 25 weeks. One month before (t - 1) and one (t + 1) and three (t + 3) months after mefloquine prophylaxis was started, an at rest electrocardiogram was made. Frequency, PR-, and QT-intervals were measured; blood samples for liver transaminases, total white blood cell count, and mefloquine concentration were obtained after one and three months. Adverse events such as dizziness, headache, coordination problems, and nausea were spontaneously reported in one (1.4%) and three (4.1%) persons at t + 1 and t + 3, respectively, while specific questioning revealed adverse events in nine (12.3%) and five (6.9%) persons, respectively, at the same time point. Three months after starting chemoprophylaxis, the heart rate at rest and total white blood cell count were lower (P < 0.05), while the QTc-interval was longer and levels of liver transaminases increased (P < 0.05), although both were still within the normal range. There was no extreme prolongation of the QTc-interval or increased levels of liver transaminases that resulted in a need to stop the chemoprophylaxis. No accumulation of mefloquine in the serum occurred, and no relationship was observed between the incidence of adverse events and serum mefloquine concentrations. The incidence of self reported mefloquine-related adverse events was low. In conclusion, mefloquine chemoprophylaxis was safe and well-tolerated in this group.

Efficacy and tolerance of artemisinin in short combination regimens for the treatment of uncomplicated falciparum malaria.

Two oral regimens comprising a single dose of 20 mg/kg of artemisinin followed by three days of quinine, 10 mg/kg three times a day (AQ), or doxycycline, 4 mg/kg once a day (AD), were compared with a standard seven-day course of oral quinine, 10 mg/kg three times a day (Q), in the treatment of uncomplicated falciparum malaria. Of 161 treated patients, 157 could be included in the analysis. The mean +/- SD parasite clearance time was 43 +/- 14 hr for AQ and 41 +/- 19 hr for AD, and significantly longer for quinine: 66 +/- 24 hr (P = 0.0001). Treatment failure occurred in one Q and in 3 AD patients. The recrudescence rate was 16% for Q, 28% for AQ, and significantly worse for AD: 67% (P = 0.0001). Adverse effects were mainly limited to cinchonism. The conclusion is that a seven-day course of quinine is still effective in the initial treatment of uncomplicated falciparum malaria in Vietnam, but one should pay attention to possible recrudescence. The addition of a single 20 mg/kg per os dose of artemisinin allows for shortening the duration of treatment, with faster parasite clearance, comparable efficacy, and better tolerance, but with no reduction of recrudescence. The combination of artemisinin with three days of doxycycline is also not effective in preventing recrudescence.

Prognostic significance of reduced red blood cell deformability in severe falciparum malaria.

Severe falciparum malaria is associated with microvascular obstruction resulting from sequestration of erythrocytes containing mature stages of the parasite. Since reduced red blood cell deformability (RBC-D) can contribute to impaired microcirculatory flow, RBC-D was measured in 23 patients with severe falciparum malaria (seven of whom subsequently died), 30 patients with uncomplicated malaria, and 17 healthy controls. The RBC-D, measured by ektacytometry, was significantly reduced in severe malaria and was particularly low in all fatal cases. At a low shear stress of 1.7 Pascal (Pa), a red blood cell elongation index less than 0.21 on admission to the hospital predicted fatal outcome with a sensitivity of 100% (confidence interval [CI] = 59-100%) and a specificity of 88% (CI = 61-98%). The reduction in the RBC-D appeared to result mainly from changes in unparasitized erythrocytes. Reduced deformability of unparasitized red blood cells in severe malaria may contribute to impaired microcirculatory flow and a fatal outcome in severe falciparum malaria.