Tolerance and efficacy of mefloquine as the first line treatment of uncomplicated P. falciparum malaria in children

INTRODUCTION: Given the national therapeutic guidelines in France, halofantrine represents the first line treatment of uncomplicated Plasmodium falciparum (P. falciparum) malaria in children. But several disadvantages exist using halofantrine in paediatrics. OBJECTIVES: The primary objective of this study is to evaluate the tolerance and the efficacy of mefloquine as the first line treatment of uncomplicated P. falciparum malaria in a paediatric emergency department. The secondary objective of the study is to evaluate whether symptomatic measures may improve the gastrointestinal tolerance of mefloquine. PATIENTS AND METHODS: This retrospective observational cohort study includes all the patients who have been treated for acute uncomplicated P. falciparum malaria in the paediatric emergency department of the Hospital Trousseau (Paris, France) in 2003. RESULTS: First line treatment was mefloquine in 35 children. Early vomiting occurred in 22 (63%) cases. All children responded to mefloquine therapy except two children who had persistent vomiting early after mefloquine therapy and required intravenous quinine. Those two children had initial vomiting. Light meal and metopimazine prophylaxis did not precede mefloquine intake in those two children. CONCLUSION: This study suggests that mefloquine treatment of uncomplicated P. falciparum malaria is effective and well tolerated in children. Furthermore, a light meal and metopimazine prophylaxis preceding mefloquine intake may improve its gastrointestinal tolerance.     

Exchange transfusion in complicated pediatric malaria: A critical appraisal

Complicated falciparum malaria is a killer disease resulting in high mortality in spite of appropriate treatment. Some workers have reported improved survival when adjunct exchange blood transfusion is included in the treatment modality while others opine against it. This review is an effort to address and critically appraise current evidence for the treatment mode for severe malaria. The literature was searched with a specified search strategy to identify reports of children who underwent exchange transfusion for severe malaria. Total 23 children who underwent exchange transfusion for severe falciparum malaria published by 9 authors were identified. Age ranged from 5 months to 16 years with a mean age of 6.4 years. The average preprocedure parasite index (PI) was 41.4% (95confidence interval [CI]; 31.2-51.4). The average blood volume exchanged was 118.6% (95% CI; 94.7-143) of the circulating blood volume. The average postexchange reduction in PI was 34.1% (95% CI; 25.4-42.8). Three out of 23 children encountered some complications. All the children survived     

Mortality and loss to programme before antiretroviral therapy among HIV-infected children eligible for treatment in The Gambia, West Africa

Background

HIV infection among children, particularly those under 24?months of age, is often rapidly progressive; as a result guidelines recommend earlier access to combination antiretroviral therapy (cART) for HIV infected children. Losses to follow-up (LTFU) and death in the interval between diagnosis and initiation of ART profoundly limit this strategy. This study explores correlates of LTFU and death prior to ART initiation among children.

Methods

The study is based on 337 HIV-infected children enrolled into care at an urban centre in The Gambia, including those alive and in care when antiretroviral therapy became available and those who enrolled later. Children were followed until they started ART, died, transferred to another facility, or were LTFU. Cox proportional hazards regression models were used to determine the hazard of death or LTFU according to the baseline characteristics of the children.

Results

Overall, 223 children were assessed as eligible for ART based on their clinical and/or immunological status among whom 73 (32.7%) started treatment, 15 (6.7%) requested transfer to another health facility, 105 (47.1%) and 30 (13.5%) were lost to follow-up and died respectively without starting ART. The median survival following eligibility for children who died without starting treatment was 2.8?months (IQR: 0.9 - 5.8) with over half (60%) of all deaths occurring at home. ART-eligible children less than 2?years of age and those in WHO stage 3 or 4 were significantly more likely to be LTFU when compared with their respective comparison groups. The overall pre-treatment mortality rate was 25.7 per 100 child-years of follow-up (95% CI 19.9 - 36.8) and the loss to programme rate was 115.7 per 100 child-years of follow-up (95% CI 98.8 - 137). In the multivariable Cox proportional hazard model, significant independent predictors of loss to programme were being less than 2?years of age and WHO stage 3 or 4. The Adjusted Hazard Ratio (AHR) for loss to programme was 2.06 (95% CI 1.12 ?C 3.83) for being aged less than 2?years relative to being 5?years of age or older and 1.92 (95% CI 1.05 - 3.53) for being in WHO stage 3 or 4 relative to WHO stage 1 or 2.

Conclusions

Earlier enrolment into HIV care is key to achieving better outcomes for HIV infected children in developing countries. Developing strategies to ensure early diagnosis, elimination of obstacles to prompt initiation of therapy and instituting measures to reduce losses to follow-up, will improve the overall outcomes of HIV-infected children.     

Sensitivity of Plasmodium falciparum to different antimalarials. A study in 1988 in a village in the Hauts-Plateaux of Madagascar

Since a few years, malaria has reappeared in the Central Highland Plateaux of Madagascar. From 1983 to 1987, Plasmodium falciparum resistance to chloroquine remained stable, with a low frequency of R2 therapeutic failures. In 1988, a study was conducted in the village of Manarintsoa, 15 km from Tananarive. Ninety-one WHO in vivo standard tests were performed. In vitro efficacy of amodiaquine and quinine was also studied. In vitro, the efficacy of chloroquine, quinine, and mefloquine was measured against 104, 64, and 23 P. falciparum isolates, respectively, by an isotopic semi-microtest.     

Polymorphism of proteins in malaria parasites following mefloquine treatment

Proteins in malaria parasites (Plasmodium falciparum) isolated from a patient in Thailand before treatment, and after recrudescence of infection subsequent to mefloquine treatment, were compared by two dimensional polyacrylamide gel electrophoresis (2D-PAGE) analysis. Nine 'pre-treatment' and six 'recrudescent' clones were studied. Variants of the enzyme glucose phosphate isomerase were also noted and mefloquine susceptibility of each clone was measured by in vitro tests. The 'pre-treatment' isolate was found to contain at least four genetically distinct clones, all sensitive to mefloquine, while the 'recrudescent' isolate contained at least two other types of clone, both showing increased tolerance to mefloquine. These two more tolerant types of clone differed from all the sensitive ones studied in regard to several different protein variants as shown by 2D-PAGE analysis. It is concluded that at least two (and probably more) genetically distinct clones of parasites with increased tolerance to mefloquine were present in the parasite population before mefloquine treatment was given, and were selected under mefloquine pressure.     

Pertinence of the 2000 WHO criteria in non-immune children with severe malaria in Dakar, Senegal

The relevance of World Health Organization (WHO) criteria for severe malaria has not been assessed in non-immune children. The objectives of this study were (i) to evaluate the significance of 1990 WHO definition reconsidered in 2000 on distribution and lethality of severe cases in children admitted with falciparum malaria, and (ii) to contribute to the study of relevance of the WHO severe criteria in Dakar, an hypoendemic area in Senegal. PATIENTS AND METHODS: The 1990 WHO criteria, respiratory distress and platelet counts were prospectively collected in 1997-99 from children admitted to H?pital Principal de Dakar, Senegal, with falciparum malaria diagnosed on a thick blood film. This method allowed also the definition of severe cases according to 2000 WHO criteria. RESULTS: Among 311 patients (median age: 8 years old), according to the 2000 WHO criteria, the frequency of severe malaria cases was increased by 23% (75% versus 52%) and case-fatality rates thereof were decreased by 5% (17% versus 12%) compared with 1990 WHO definition. One death occurred among cases defined as severe on admission only according to criteria modified by WHO in 2000. A multivariate logistic regression model identified several independent prognostic factors: cerebral malaria, hypoglycaemia, respiratory distress, renal failure, collapse, abnormal bleedings, pupillary abnormalities and thrombocytopaenia defined as a platelet count below 100,000/mm3. A significant association (p < 0.001) was observed between platelet count increase and consciousness level improvement, evaluated on day of first platelet count control (time from admission: 1-7 d). Among survivors, a lesser improvement in coma score was associated with a decrease in platelet counts (p < 0.04). CONCLUSIONS: The 1990 WHO criteria, which predicted death among malaria cases in children living under stable falciparum transmission, are relevant in this series of non-immune children living in a low and seasonal transmission. Nevertheless new WHO criteria showed poor prognostic significance. However, the 2000 WHO definition was highly sensitive to detect severe malaria cases. These findings should be considered for managing severe malaria in migrant children.     

Trial of halofantrine in the treatment of malaria attacks by Plasmodium falciparum in Dakar (Senegal)]

Halofantrine has been given to 14 children and 15 adults suffering from an acute attack of P. falciparum malaria and living in Dakar (Senegal) to a total dose of 24 mg/kg/body weight for the first group and 1,500 mg for the second in 3 times at 6-hourly intervals. This treatment has allowed the fever to clear in all cases within 36.3 +/- 19.9 hours and headache to disappear at D3 in 93.1% of cases. A reduction by 93.6% of the average parasite density which amounted before treatment to 27,710 trophozoites/mm3 of blood has been recorded from the day following the beginning of treatment and the parasite clearance obtained in all the patients of whom had chloroquine-resistant P. falciparum strains in mean time of 58.0 +/- 14.7 hours. In 3 cases (10.7%) a recrudescence of parasitemia has been noticed in D14. Only 1 of them was treated again with halofantrine which proved efficient from D2. The only adverse reactions have been nausea, vomiting, a slight diarrhoea and dizziness which affected only 13.8% of the patients. No abnormality has been noticed at a biological level. These results confirm the efficacy and good tolerance of halofantrine and allow to list it among the resource drugs used for the treatment of chloroquine-resistant P. falciparum malaria in our area.     

The treatment of multiresistant falciparum malaria in Southeast Asia

The spread of chloroquine resistant strains of P. falciparum requires new approaches to treatment especially in tropical Africa. A single dose of 3 tablets of sulfadoxine-pyrimethamine (Fansidar) is a suitable and relatively inexpensive alternative. But under drug pressure resistance to this compound has developed in some South-East Asian countries and in Brazil, giving rise to multiple resistant strains of P. falciparum. A similar pattern has arisen with quinine to which almost 50% of P. falciparum strains have become resistant in Thailand. However the combination treatment of quinine with tetracycline given for 7 days is still successful in most cases. Unfortunately compliance to this regimen is rather poor in out-patients. Mefloquine (Lariam), recently marketed, and if used as 750 mg dose in semi-immune adult patients weighing less than 60 kg, has made possible a single-dose treatment schedule for falciparum malaria. In controlled studies conducted in South-East Asia the success rate of mefloquine was 97% in 445 patients. Since there is some fear of the appearance of resistance of P. falciparum to mefloquine, a combination of this compound with sulfadoxine and pyrimethamine was developed (MSP or Fansimef). Various controlled studies in South-East Asia have shown a success rate of this compound of 97% in 278 patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Efficacy of chloroquine in treatment of non-complicated malaria with Plasmodium falciparum in children at the San Pedro dispensary in Côte d'Ivoire

A survey has been carried out in south-west of C?te d'Ivoire in order to study chloroquine resistance in treatment of malaria according to 14 days protocol of WHO (World Health Organisation) (1996) for evaluation of antimalarial drugs activity; 63 children, aged from 6 months to 15 years and suffering from noncomplicated malaria due to Plasmodium falciparum, received by oral way 25 mg/kg of chloroquine over three days (10-10-5). During the survey, they were subjected to a clinic and parasitologic (thick and thin blood film) follow up. We obtained, for 51 children (81%), a satisfactory clinical answer, for 8 children (13%) an early therapeutic failure and for the other 4 (6%) a late therapeutic failure. Moreover, we obtained 40% of failure in children of less than 24 months old, 25% between 24 months and 59 months and 7% beyond 6 years old.     

Clinical trial of amodiaquine in the community of Attécoubé (Abidjan, Côte d'Ivoire)(May-December 1955)

A prospective study in the municipality of Attécoubé (Abidjan, C?te d'Ivoire) evaluated the sensitivity of P. falciparum to amodiaquine with a posology of 35 mg/kg over 3 days (1st day: 15 mg/kg; 2nd day: 10 mg/kg; 3rd day: 10 mg/kg) as well as its tolerance of this dosage. One hundred five WHO in vivo standard tests were performed over 7 days on subjects aged > 15 years from May to December 1995. The subjects were carriers of varying number of trophozoites: between 1000 to 34,000 trophozoites were recorded with a mean of 5193 trophozoites by microliter. We divided the subjects into two groups: group A with 43 patients to whom we administered medication and group B with 62 subjects who took their medication on their own. Clinical and parasitological verifications were made on D0, D2 and D7. Biological verification was conducted for 31 subjects of group A by mean of SGOT and SGPT quantity determination on D0 and D2. This survey revealed that 1.9% of P. falciparum malaria patients had precocious therapeutic failure to amodiaquine (35 mg/kg over 3 days) in this area. Clinical and biological tolerance was good and there was no difference between the two groups. We suggest that amodiaquine might be used for uncomplicated malaria at first intention in Abidjan.     

Health care related factors associated with severe malaria in children in Kampala,Uganda

Background

Severe malaria is responsible for the high load of malaria mortality. It is not clearly understood why some malaria episodes progress to severe malaria.

Objective

To determine factors associated with severe malaria in children aged 6 months to 5 years living in Kampala.

Methods

Over a 6-month period, 100 children with severe malaria were matched by age and place of residence with 100 children with non-severe malaria. We collected health care information from care takers.

Results

Mean duration of illness before getting antimalarial treatment was shorter for controls than cases (8hours vs. 20hours, p 0.015). Children with severe malaria were less likely to have been treated with sulphadoxine-pyrimethamine in the preceding 2 weeks (OR 0.2, 95% CI 0.04–0.85, p 0.016). Odds of severe malaria were higher in those who reported lack of protective measures (mosquito coils (OR = 20.63, 95% CI 1.5–283.3, p=0.02 and insecticide sprays OR 10.93, 95% CI 1.13–105.64, p=0.03), although few reported their use.

Conclusions

Early anti-malarial treatment and use of barriers against mosquitoes prevent severe malaria in children. There is need to increase the use of barriers against mosquito bites and to scale up prompt treatment and community-based interventions to reduce the incidence of severe malaria in children.     

Chloroquine sensitivity of Plasmodium falciparum at the Gamkalley Clinic and the Nigerian armed forces PMI (Niamey, Niger)

In vivo tests for Plasmodium falciparum were carried out in 1998 during the rainy season among children in Niamey, in the Republic of Niger. Chloroquine was prescribed at 25 mg/kg for 3 days in febrile patients with uncomplicated P. falciparum malaria. Forty-five 1-5 year-olds and thirty-three 6-15 year-olds were included in the study. A group of 53 adult patients was also surveyed to evaluate the efficacy of chloroquine in semi-immune persons. Body temperature and blood smears including parasitemia were recorded on days 0, 3, 7 and 14. Less than 10% of the patients were delinquent. Around 75% of the patients were successfully treated in the 1-5 year-olds and 6-15 year old age groups. Relapses were observed in 20% of the 1-5 year-olds (early relapses 8.9%, late relapses 11.1%) and in 16.7% in the 1-15 year-olds (early relapses 6.4%, late relapses 10.3%). Among adults, successful treatment was obtained in 86.8% of the cases and early and late relapses were respectively observed in 3.8% and 1.9% of the cases. All the patients with malaria relapses were cured with second-line treatments (pyrimethamine-sulfadoxine or quinine). According to these results, chloroquine resistance appears to be moderate in Niamey. Therefore chloroquine should remain the first line treatment of uncomplicated P. falciparum malaria in this population.     

Hypoxemia predicts death from severe falciparum malaria among children under 5 years of age in Nigeria: the need for pulse oximetry in case management

Background

Oxygen saturation is a good marker for disease severity in emergency care. However, studies have not considered its use in identifying individuals infected with Plasmodium falciparum at risk of deaths.

Objective

To investigate the prevalence and predictive value of hypoxaemia for deaths in under-5s with severe falciparum malaria infection.

Methods

Oxygen saturation was prospectively measured alongside other indicators of disease severity in 369 under-5s admitted to a tertiary hospital in Nigeria. Participants were children in whom falciparum malaria parasitaemia was confirmed with blood film microscopy in the presence of any of the World Health Organization-defined life-threatening features for malaria.

Results

Overall mortality rate was 8.1%. Of the 16 indicators of the disease severity assessed, hypoxaemia (OR=7.54; 95% CI=2.80, 20.29), co-morbidity with pneumonia (OR=19.27; 95% CI=2.87, 29.59), metabolic acidosis (OR=6.21; 95% CI=2.21, 17.47) and hypoglycaemia (OR=19.71; 95% CI=2.61, 25.47) were independent predictors of death. Cerebral malaria, male gender, wasting, hypokalaemia, hyponatriaemia, azotaemia and renal impairment were significantly associated with death in univariate analysis but not logistic regression model.

Conclusions

Hypoxaemia predicts deaths in Nigerian children with severe malaria, irrespective of other features. Efforts should always be made to measure oxygen saturation as part of the treatments for severe malaria in children.     

Intravenous immunoglobulin in the treatment of paediatric cerebral malaria.

Hyperimmune globulin can inhibit and reverse the cytoadherence between Plasmodium falciparum-infected erythrocytes and melanoma cells in vitro. Cytoadherence is believed to mediate disease in cerebral malaria. Therefore we studied the efficacy of i.v. immunoglobulin, purified from the plasma of local semi-immune blood donors, as an adjunct to standard treatment for cerebral malaria in Malawian children. The immunoglobulin preparation (IFAT antimalarial antibody titre 1:5120) recognized erythrocyte-associated antigens of each of 22 Malawian P. falciparum isolates studied, and reversed binding of Malawian isolates to melanoma cells. Immunoglobulin did not reverse binding to human monocytes or to cells of the human histiocytic lymphoma cell line U937. Thirty-one children with P. falciparum parasitaemia and unrousable coma were enrolled. All were treated with i.v. quinine dihydrochloride; in addition patients were randomized to receive either immunoglobulin (400 mg/kg by i.v. infusion over 3 h) or placebo (albumen and sucrose by similar infusion) in a double blind trial with sequential analysis. Of 16 patients receiving immunoglobulin, five (31%) died and five survivors had neurological sequelae. Of 15 patients receiving placebo, one (7%) died and two had sequelae. Parasite clearance, fever clearance and coma resolution times in survivors were similar in the two groups. Although the difference in outcome between the two groups was not significant, the trial was stopped because immunoglobulin was demonstrated not to be superior to placebo.     

Low-dose trimethoprim-sulfamethoxazole treatment for pneumocystis pneumonia in non-human immunodeficiency virus-infected immunocompromised patients: A single-center retrospective observational cohort study

Background/Purpose

The efficacy of low-dose trimethoprim-sulfamethoxazole (TMP-SMX) may be acceptable for the treatment of pneumocystis pneumonia (PCP) in non-human immunodeficiency virus (HIV)-infected patients, with a low incidence of adverse reactions. This study is aimed to evaluate the efficacy and safety of such a regimen for the treatment of non-HIV PCP.

Lack of association between maternal antibody and protection of African infants from malaria infection

Maternally derived antibodies are believed to protect infants against infection, but there is little direct evidence for a protective role of passively acquired antibodies against malaria. A longitudinal study of malaria infection in 143 infants was conducted in a region of southern Ghana where Plasmodium falciparum is endemic. Infants born in the high-transmission season were less likely to become infected in the first 20 weeks of life than children born in the low-transmission season. Plasma, obtained at birth, was tested for immunoglobulin G (IgG) and IgG subclasses to P. falciparum schizonts and recombinant circumsporozoite antigen, MSP-1(19), MSP-2, AMA-1, and Pf155 (also called ring-infected erythrocyte surface antigen). Antibody levels at birth were not associated with resistance to malaria infection. On the contrary, antibodies at birth were positively associated with infection, indicating that high levels of maternally derived antibodies represent a marker for intensity of exposure to malaria infection in infants. However, all five children who experienced high-density infections (>100 parasites/microl of blood) were seronegative for MSP-1(19) at the time of infection.     

Thrombocytopenia in pregnant women with Plasmodium falciparum malaria in an area of unstable malaria transmission in eastern Sudan

ABSTRACT: BACKGROUND: Blood platelet levels are being evaluated as predictive and prognostic indicators of the severity of malaria infections in humans. However, there are few studies on platelets and Plasmodium falciparum malaria during pregnancy. METHODS: A case-control study was conducted at Gadarif Hospital in Eastern Sudan, an area characterized by unstable malaria transmission. The aim of the study was to investigate thrombocytopenia in pregnant women with P. falciparum malaria (cases) and healthy pregnant women (controls). RESULTS: The median (interquartile) platelet counts were significantly lower in patients with malaria (N=60) than in the controls (N=60), 61, 000 (43,000-85,000) vs. 249,000 (204,000-300,000)/uL, respectively, p < 0.001. However, there was no significant difference in the platelet counts in patients with severe P. falciparum malaria (N=12) compared with those patients with uncomplicated P. falciparum malaria (N=48), 68, 000 (33,000-88,000)/uL vs. 61, 000 (45,000-85,000)/uL, respectively, p=0.8. While none of the control group had thrombocytopenia (platelet count <75, 000/ uL), it was found that 6/12 (50%) and 27/48 (56.2%) (p <0.001) of the patients with severe malaria and uncomplicated malaria had thrombocytopenia, respectively. Pregnant women with P. falciparum malaria, compared with the pregnant healthy control group, were at higher risk (OR=10.1, 95% CI=4.1-25.18; p<0.001) of thrombocytopenia. Two patients experienced bleeding, and there was one maternal death due to cerebral malaria where the patient's platelet count was only 28,000/uL. CONCLUSION: P. falciparum malaria is associated with thrombocytopenia in pregnant women in this setting. More research is needed.     

Long-term treatment with tetrahydrobiopterin increases phenylalanine tolerance in children with severe phenotype of phenylketonuria

Hyperphenylalaninemia caused by phenylalanine hydroxylase (PAH) deficiency requires lifelong rigorous diet starting in early infancy to prevent severe neurodevelopmental handicap. In a considerable number of children with mild hyperphenylalaninemia, long-term tetrahydrobiopterin (BH4) treatment significantly improves phenylalanine (phe) tolerance, but it has never been investigated in classic phenylketonuria (PKU). We performed a BH4-loading test in 40 consecutive infants with phe serum concentrations exceeding 240 microM, who had been detected by newborn screening programs. Eighteen out of 40 infants were found to be BH4 responsive. Five of them, responding to the neonatal BH4-loading test, showed a phe tolerance of less than 20 mg/kg/day and a phe pretreatment level of >1000 microM. They were treated with BH4 (20 mg/kg/day) over a period of 24 months. All five children had a sustained response to BH4, allowing substantial easing of dietary restrictions. Before BH4 treatment daily phe tolerance was 18-19 mg/kg, increasing to 30-80 mg/kg on BH4 treatment and decreasing again to 12-17 mg/kg after termination of BH4 treatment. Mutation analysis revealed compound heterozygosity for a putative null and a variant PAH mutation in four patients and homozygosity for a variant PAH mutation in one patient. We conclude that BH4 sensitivity is not restricted to mild hyperphenylalaninemia and that long-term BH4 treatment may also improve phenylalanine tolerance in a considerable number of children with a more severe PKU phenotype.     

In vivo evaluation of chloroquine therapeutic efficacy in uncomplicated Plasmodium falciparum malaria in Central African Republic ine 1997 and 1998

The efficacy of oral chloroquine was assessed in 268 children aged from 6 to 59 months attending pediatric services in regional hospitals between September 1997 and December 1998, located in the five county towns of the sanitary regions of the Central African Republic. Chloroquine was prescribed at 25 mg per kg body weight, and administered over 3 days to patients suffering from uncomplicated malaria. Body temperature and blood smears including parasitaemia were recorded on days 0, 3, 7 and 14. The main objective of the present study was to evaluate the therapeutic efficacy of chloroquine in the treatment of uncomplicated malaria using in vivo tests according to the WHO protocol (1996). The secondary objective was to identify the predictive factors of chloroquine relapses. Early relapses rates were under 15% except in Bangui (40%). A recurrence of parasitaemia with fever, sign of late relapse, was noted in 9% of children in Bambari, 9% in Bangassou, 8% in Bangui, 5% in Bossangoa and 4% in Berberati. The rate of successfully treated patients was between 66% and 75% except in Bangui (36%). Only the places of study and anaemia in days 0 were significant predictive factors of therapeutic relapses. Since the emergence of chloroquine resistance cases to P. falciparum in 1983 in Central African Republic, the phenomenon has increased. According to our results, a strong chloroquine resistance appears in the capital Bangui. Therefore, chloroquine should be replaced there for the first line treatment of uncomplicated P. falciparum malaria. In the provinces, it doesn't seem necessary to change the current chloroquine-based first line treatment.