The cost-effectiveness of chemoprophylaxis with Maloprim administered by primary health care workers in preventing death from malaria amongst rural Gambian children aged less than five years old.

In recent trials in The Gambia, mass chemoprophylaxis with Maloprim administered over several years by primary health care workers to children aged 3-59 months has reduced both mortality and morbidity without inducing impairment of natural immunity or significant development of drug resistance. Taking expenditure of both time and money, by both public authorities and village volunteers, into account, the costs and the cost effectiveness of such mass chemoprophylaxis are estimated here. The cost per child protected per season was (1990 US) $2.84; the cost per childhood death averted was $143. Both costs compare favourably with those of permethrin bed net impregnation. So in some circumstances where malaria is holoendemic, control of childhood malaria by chemoprophylaxis may be more economically efficient than provision of impregnated bed nets.     

Cellular immune responses to Plasmodium falciparum antigens in children receiving long term anti-malarial chemoprophylaxis

Fifty-two Gambian children who had received fortnightly chemoprophylaxis with maloprim, (pyrimethamine and dapsone), and 45 receiving placebo, were studied. Cellular immune responses to malaria antigens, measured by lymphoproliferative responses and interferon production, were higher in children who had received prophylaxis than in controls, although the anti-malarial antibody levels were lower. During a one-year period after termination of prophylaxis, there was no increase in the frequency of clinical episodes of malaria in the children who had received Maloprim. These results suggest that chemoprophylaxis for 3 years may lower malaria antibody levels, but does not interfere with the development of protective immunity, perhaps by enhancing cell-mediated immune responses to malaria in protected children.     

Importance and prevention of malaria in pregnancy

Malaria in pregnancy is one of the most important preventable causes of low birthweight deliveries worldwide. It is also a major cause of severe maternal anaemia contributing to maternal mortality. It is estimated that 40% of the world's pregnant women are exposed to malaria infection during pregnancy. The clinical features of Plasmodium falciparum malaria in pregnancy depend to a large extent on the immune status of the woman, which in turn is determined by her previous exposure to malaria. In pregnant women with little or no pre-existing immunity, such as women from non-endemic areas or travellers to malarious areas, infection is associated with high risks of severe disease with maternal and perinatal mortality. Women are at particular risk of cerebral malaria, hypoglycaemia, pulmonary oedema and severe haemolytic anaemia. Fetal and perinatal loss has been documented to be as high as 60-70% in non-immune women with malaria. Adults who are long-term residents of areas of moderate or high malaria transmission, including large parts of sub-Saharan Africa, usually have a high level of immunity to malaria. Infection is frequently asymptomatic and severe disease is uncommon. During pregnancy this immunity to malaria is altered. Infection is still frequently asymptomatic, so may go unsuspected and undetected, but is associated with placental parasitization. Malaria in pregnancy is a common cause of severe maternal anaemia and low birthweight babies, these complications being more common in primigravidae than multigravidae. Preventative strategies include regular chemoprophylaxis, intermittent preventative treatment with antimalarials and insecticide-treated bednets.     

8. Effect of iron supplementation and malaria prophylaxis in infants on Plasmodium falciparum genotypes and multiplicity of infection

During a randomized placebo-controlled trial of chemoprophylaxis against Plasmodium falciparum malaria and iron supplementation, in infants living under conditions of intense transmission, all samples of P. falciparum obtained from children aged 5 and 8 months were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis for the msp2 locus. One hundred and six blood samples were analysed for the number of concurrent infections (multiplicity), and the allelic family of each msp2 genotype was determined. Mean multiplicity of infection was, overall, 2·76 infections/child, and it was significantly reduced in infants receiving chemoprophylaxis. This finding might help to explain the rebound effect in morbidity observed after prophylaxis was ended. Iron supplementation did not affect multiplicity of infection. In infants receiving placebo only, or placebo and iron supplementation, a significant positive association was observed between the number of infections and parasite densities (Spearman's ϱ = 0·25, P − 0·047). This association was lost in the group receiving chemoprophylaxis alone, or in combination with iron. This study showed a significant association of FC27-like msp2 alleles with prospective risk of clinical malaria in children (relative risk = 1·487, P = 0·013). Such an association was also found for the present risk of clinical malaria in infants receiving prophylaxis (odds ratio = 3·84, P = 0·026), which might imply that chemoprophylaxis may impair the development of premunition.     

Criteria of gravity of neurological malaria in children

Neurological malaria, characterized by significant cerebral involvement, is the most worrisome aspect of Plasmodium falciparum malaria, with a mortality rate of 10-30%. Neurological malaria is generally limited to immunodepressed subjects. Children aged 4 months to 4 years and foreigners who have neglected their chemical prophylaxis are at risk. In weakly endemic areas, native adults who have not built up immunity may also be at risk. 1844 children hospitalized for malaria were studied in 1995 for clinical indicators of gravity. The risk of death was evaluated for each of 10 criteria suggested by the World Health Organization and 5 simple additional parameters. An initial coma, cardiovascular collapse, and repeated convulsions were major factors in mortality. Acute anemia, acidosis, and elevated parasite levels did not worsen the prognosis, but severe hypoglycemia, severe respiratory distress, and jaundice were associated with poor outcomes. The majority of children who died suffered respiratory distress on admission to the hospital, which often complicated the diagnosis of malaria. Nearly all died within 24 hours of admission. Knowledge of the factors associated with mortality should facilitate referral of patients who need higher levels of care.     

Sustained protection against mortality and morbidity from malaria in rural Gambian children by chemoprophylaxis given by village health workers

Mortality and morbidity from malaria were measured in children for a one-year period in a rural area of The Gambia 3-4 years after the introduction of a primary health care programme into some villages in the study area. Among children resident in primary health care villages who received treatment for febrile illnesses from a village health worker resident in their village there was no reduction in overall mortality or in morbidity from malaria compared with levels found in villages without a primary health care worker. However, among children aged 3-59 months who received malaria chemoprophylaxis from a village health worker in addition to treatment there was a 49% reduction in mortality and a 73% reduction in attacks of clinical malaria. The level of protection against malaria achieved by chemoprophylaxis given by village health workers 3-4 years after the chemoprophylaxis programme was started was as high as that obtained shortly after the introduction of the primary health care programme.     

Imported malaria in children: a national surveillance in the Netherlands and a review of European studies

BACKGROUND: Falciparum malaria or malaria tropica is one of the leading causes of childhood mortality worldwide. Malaria-related deaths occur mainly in sub-Saharan Africa, where an estimated 365 million clinical cases of Plasmodium falciparum malaria occur each year. In Europe, imported malaria cases occur due to returning travellers or immigration mostly from African countries. Children are more at risk than adults. The objective of this study was to identify high risk groups for imported childhood malaria in Europe in order to guide development of strategies for prevention, early recognition and management. METHODS: In the period May 2003-January 2005 we reviewed all cases of paediatric malaria in the Netherlands notified by the Dutch Paediatric Surveillance System (Nederland Signalerings Centrum Kindergeneeskunde, NSCK) and the literature on imported malaria in children in Europe published between 1996 and 2006. RESULTS: Malaria occurred mainly in children of long-term (n = 15, 47%) and new (n = 8, 25%) immigrants and was mostly acquired in sub-Saharan Africa. The dominant species was P. falciparum. Only one quarter of children had used adequate malaria chemoprophylaxis. Complicated disease occurred in 10 (31%) of cases. We also reviewed the literature and found 6082 reported cases of imported malaria among children in Europe; among these, four died and only one was reported to develop neurological sequelae. CONCLUSION: Imported malaria in children remains an important problem and is unlikely to decrease unless the reasons for inadequate prophylaxis are addressed.     

A review of randomized controlled trials of routine antimalarial drug prophylaxis during pregnancy in endemic malarious areas.

Current global recommendations for routine malaria chemoprophylaxis in pregnant women living in endemic malarious areas are not clear. To assist in policy formulation, the evidence from randomized controlled trials was reviewed. The literature was extensively searched, and studies identified were systematically analysed in relation to outcomes in the mother and the baby. Routine chemoprophylaxis appears to have an effect on antenatal morbid episodes and packed cell volume. There is a trend towards higher birth-weight values in chemoprophylaxis groups, which reached statistical significance in some studies. Evidence of an effect on gestation was only examined in one study. The effects on perinatal and neonatal mortality have only been examined in a few studies, with small sample sizes. The analysis questions whether routine malaria chemoprophylaxis is the best use of scarce resources in developing countries, and suggests that chemoprophylaxis might be targeted at anaemic women and primigravidae. Large controlled trials, with treatment available to placebo groups, are required to test whether routine chemoprophylaxis has advantages over early, effective treatment of clinical malaria.     

Combating severe malaria in African children

An initiative to reduce childhood mortality due to malaria, diarrhoea and vaccine-preventable diseases, called the Africa Child Survival Initiative—Combatting Childhood Communicable Diseases (CCCD) project, was started in 1982 and is now operating in 13 African countries, 12 of which are endemic for malaria. The project''s malaria control strategy relies on the use of drugs, mainly chloroquine, to prevent severe illness and death in children less than 5 years of age; chemoprophylaxis for pregnant women is also advised to prevent low birth weight in newborns. The strategy is based on WHO recommendations which focus on improved diagnosis and treatment of cases and chemoprophylaxis for pregnant women.     

Evaluating a malaria intervention strategy using knowledge, practices and coverage surveys in rural Bolifamba, southwest Cameroon

We evaluated the impact of a malaria intervention in Bolifamba in rural Cameroon. The intervention consisted of educating the community on management of malaria and provision of a dispensary for early diagnosis and treatment. In July 2001, prior to the intervention, a questionnaire was used to obtain information on knowledge of and practices toward childhood malaria of 185 mothers of children aged 0-5 years. The same questionnaire was administered to 120 of the 185 mothers, one-year post-intervention. Clinical and laboratory investigations were carried out on children whose mothers were interviewed. A comparison of pre- and post-intervention data indicated significant changes in (i) the use of appropriate malaria treatment (from 50% to 81.7%); (ii) recognition of splenomegaly as a feature of malaria (from 18.4% to 80.8%); (iii) prevalence of splenomegaly (from 26.5% to 13.3%); (iv) prevalence of fever (from 27.8% to 13.3%); (v) parasite prevalence (from 60.5% to 44.2%) and (vi) severe malaria anaemia (from 2.6% to 0.0%). These findings revealed that proper education of villagers, particularly mothers, on malaria and the presence of health facilities, where treatment is readily available at affordable cost, close to villages, are important strategies that would reduce malaria morbidity and mortality significantly.     

Cost-effectiveness of iron supplementation and malaria chemoprophylaxis in the prevention of anaemia and malaria among Tanzanian infants

Prerequisites for effective interventions against severe anaemia and malaria among infants are economic evaluations to aid the setting of priorities and the making of health policy. In the present study we analysed the cost and effectiveness of three control strategies hypothetically delivered through the Expanded Programme on Immunization (EPI). For the prevention of severe anaemia and from the perspective of the health provider, the cost-effectiveness ratios were, respectively, US$ 8, US$ 9, and US$ 21 per disability-adjusted life year (DALY) for malaria chemoprophylaxis with Deltaprim (a combination of 3.125 mg pyrimethamine and 25 mg dapsone) + iron, Deltaprim alone, or iron supplementation alone. For malaria prevention, Deltaprim + iron cost US$ 9.7 per DALY and Deltaprim alone cost US$ 10.2 per DALY. From a sociocultural perspective the cost-effectiveness ratios ranged from US$ 9 to US$ 26 for severe anaemia prevention and from US$ 11 to US$ 12 for the prevention of clinical malaria. These ratios were highly cost-effective, as defined by the World Bank's proposed threshold of less than US$ 25 per DALY for comparative assessments. Furthermore, all the preventive interventions were less costly than the current malaria and anaemia control strategies that rely on clinical case management. This economic analysis supports the inclusion of both malaria chemoprophylaxis and iron supplementation delivered through EPI as part of the control strategies for these major killers of infants in parts of sub-Saharan Africa.     

A comparative study of Lapudrine (chlorproguanil) and Maloprim (pyrimethamine and dapsone) as chemoprophylactics against malaria in Gambian children

A comparison has been made of Lapudrine (chlorproguanil) and Maloprim (pyrimethamine +dapsone) as malaria chemoprophylactics when given every two weeks for 3 years to Gambian children under the age of 5 years. Both drugs produced falls in spleen and malaria parasite rates and an increase in packed cell volume. Maloprim, but not chlorproguanil, significantly reduced the incidence of episodes of fever accompanied by malaria parasitaemia. Children who received Maloprim, but not those who received chlorproguanil, grew better than children in the placebo group. This finding suggests that brief clinical episodes of malaria are more important in impairing growth than more prolonged periods of asymptomatic parasitaemia. No serious side-effect attributable to either drug was observed. After chemoprophylaxis had been given for 3 malaria transmission seasons the level of resistance of Plasmodium falciparum to pyrimethamine and to chlorproguanil was about 10%.     

Immunity to malaria in young Gambian children after a two-year period of chemoprophylaxis

A cohort of 48 Gambian children was protected against malaria by fortnightly administration of Maloprim (pyrimethamine and dapsone) for 2 years between their 3 and 5 birthdays. A matched cohort of 47 children received placebo. During the year following the termination of prophylaxis there was no increase in the frequency of clinical attacks of malaria in the protected children compared with the control children. Antibody levels to circumsporozoite protein were measured by a radioimmunoassay and that to blood-stage antigens by a variety of techniques including an ELISA to whole blood-stage Plasmodium falciparum antigen, immunofluorescent assays (IFAT) to acetone fixed, glutaraldehyde fixed and unfixed parasites, a merozoite inhibition test and an opsonizing assay. Antibody levels were, in general, lower in protected than in control children and several differences between the two groups were statistically significant. When antibody levels were measured by ELISA and IFAT at the end of the following rainy season, when malaria transmission was intense, those in protected children had increased to comparable levels to those found in control children. Our findings suggest that chemoprophylaxis given for 2 years lowers malaria antibody levels but that it does not interfere with the development of protective immunity.     

Malaria chemoprophylaxis, birth weight and child survival.

Study of the effects of malaria chemoprophylaxis given during pregnancy on birthweight and investigation of the influence of birthweight on child survival suggest that, in a rural area of The Gambia, chemoprophylaxis given during pregnancy might reduce infant mortality by about one-fifth in the children of primigravidae but by less than 5% in the children of multigravidae. In malaria endemic areas, primigravidae should be protected against malaria not only for their own sake but also for that of their infants.     

Effectiveness of primaquine terminal prophylaxis against late primary attacks of Plasmodium vivax malaria: a case-control study among troops of the Republic of Korea army

Plasmodium vivax malaria is an important cause of morbidity among troops operating in endemic areas near the Demilitarized Zone in the Republic of Korea (ROK). The ROK Army has been administering antimalarial chemoprophylaxis to those troops at greatest risk of malaria since 1997. The number of recipients increased from 15000 in 1997 to 90000 in 2001. We undertook a case-control study to estimate the effectiveness of primaquine prophylaxis against late primary attacks of P. vivax malaria in ROK Army troops. Microscopically confirmed cases of P. vivax malaria were identified through hospital-based surveillance. Controls were matched by unit. Between 1 November 2001 and 31 May 2002, 68 cases and 137 matched controls with confirmed chemoprophylaxis status were enrolled. The estimated effectiveness of primaquine prophylaxis was 32% (95% CI 23-63%). Our results suggest that the effectiveness of primaquine prophylaxis against late primary attacks of P. vivax malaria may be insufficient for soldiers of the ROK Army.     

A return of endemic malaria to the Netherlands is highly unlikely]

The Netherlands has been free from malaria since the early 1960, due to a combination of factors: active search and treatment of patients and parasite carriers, targeted use of insecticides, changes in farming and in housing of man and cattle, pollution of surface water with phosphates and the fact that surface waters became fresher. These factors reduced the mosquito population that is dependent on brackish water. The Dutch malaria mosquito cannot transmit the parasite of tropical malaria. The mosquito population could possibly increase due to measures to 'develop nature' but the number of parasite carriers, the acute disease manifestations, the quality and organization of the health care system make it extremely unlikely that local transmission will occur. Fears that malaria may become endemic and that the population in the western parts of the country will have to apply malaria chemoprophylaxis in the near future, are unfounded.     

Compliance and tolerability of mefloquine and chloroquine plus proguanil for long-term malaria chemoprophylaxis in groups at particular risk (the military).

An historical prospective study was performed on 5120 Italian soldiers deployed in Somalia and Mozambique in 1992-94, to determine compliance and tolerability of long-term malaria chemoprophylaxis with chloroquine plus proguanil (C + P) and with mefloquine. Compliance with C + P among 3734 soldiers on duty in Somalia for 3.8 +/- 1.8 months and with mefloquine among 1386 soldiers on duty in Mozambique for 3.4 +/- 1.5 months was 90.3% and 95.7%, respectively (P < 0.01). Chemoprophylaxis curtailment rate due to side-effects was 1.5% among C + P users and 0.9% among mefloquine users (P = NS). Compliance with chemoprophylaxis and medication curtailment rate due to side-effects did not change significantly for either C + P or mefloquine, even after 3 months of continuous prophylaxis. Chemoprophylaxis curtailment rate was significantly lower in subjects aged < or = 25 years than in older subjects (1.3% vs. 2.5% for C + P [P < 0.05] and 0.4% vs. 3.3% for mefloquine [P < 0.01]). These results further support the evidence that both C + P and mefloquine regimens may be safely used in long-term malaria chemoprophylaxis. Moreover, weekly mefloquine seems easier to perform than C + P and not to increase prophylaxis discontinuation due to side-effects. Mefloquine regimen should therefore be considered the elective chemoprophylaxis for groups at particular risk of chloroquine-resistant Plasmodium falciparum malaria and especially for young male subjects.     

Effects of insecticide-treated bednets during early infancy in an African area of intense malaria transmission: a randomized controlled trial

OBJECTIVE: Insecticide-impregnated bednets and curtains have been shown by many studies to be effective against malaria. However, because of possible interactions with immunity development, treated bednets may cause no effect at all or even an increase in malaria morbidity and mortality in areas of high transmission. To clarify this issue, we did a randomized controlled trial to assess the long-term effects of bednet protection during early infancy. METHODS: A total of 3387 neonates from 41 villages in rural Burkina Faso were individually randomized to receive either bednet protection from birth (group A) or from age 6 months (group B). Primary outcomes were all-cause mortality in all study children and incidence of falciparum malaria in a representative subsample of the study population. FINDINGS: After a mean follow-up of 27 months, there were 129 deaths in group A and 128 deaths in group B rate ratio (RR) 1.0 (95% confidence interval (CI): 0.78-1.27)). Falciparum malaria incidence was lower in group A than in group B, during early (0-5 months) and late infancy (6-12 months) (RR 3.1, 95% CI: 2.0-4.9; RR 1.3, 95% CI: 1.1-1.6) and rates of moderate to severe anaemia were significantly lower during late infancy (11.5% vs 23.3%, P = 0.008), but there were no differences between groups in these parameters in children older than 12 months. CONCLUSION: The findings from this study provide additional evidence for the efficacy of insecticide-treated nets in young children living in areas of intense malaria transmission.     

Malaria prophylaxis in long-term expatriate mineworkers in Ghana

The role of malaria chemoprophylaxis for long-term expatriateshas not been re-evaluated since the emergence of widespreadmultidrug resistance. A survey of 106 expatriates working ina mine in Ghana (holoendemic for malaria) was conducted to determinethe compliance with malaria chemoprophylaxis. Overall 64 percent took regular chemoprophylaxis. Of the long-term expatriates(5 or more years in areas with holoendemic malaria), 48.4 percent either took malaria prophylaxis very irregularly or notat all. The main reasons for failing to comply were fear oflong-term side effects and conflicting advice on prophylaxis.This reluctance to take long-term chemoprophylaxis highlightsthe need to re-emphasise the importance of anti-mosquito measures,prompt treatment of fevers, and perhaps consider abandoningchemoprophylaxis in those expatriate workers with ready accessto hospital care.