The effect of delivery mechanisms on the uptake of bed net re-impregnation in Kilifi District, Kenya.

The results of recently completed trials in Africa of insecticide-treated bed nets (ITBN) offer new possibilities for malaria control. These experimental trials aimed for high ITBN coverage combined with high re-treatment rates. Whilst necessary to understand protective efficacy, the approaches used to deliver the intervention provide few indications of what coverage of net re-treatment would be under operational conditions. Varied delivery and financing strategies have been proposed for the sustainable delivery of ITBNs and re-treatment programmes. Following the completion of a randomized, controlled trial on the Kenyan coast, a series of suitable delivery strategies were used to continue net re-treatment in the area. The trial adopted a bi-annual, house-to-house re-treatment schedule free of charge using research project staff and resulted in over 95% coverage of nets issued to children. During the year following the trial, sentinel dipping stations were situated throughout the community and household members informed of their position and opening times. This free re-treatment service achieved between 61-67% coverage of nets used by children for three years. In 1997 a social marketing approach, that introduced cost-retrieval, was used to deliver the net re-treatment services. The immediate result of this transition was that significantly fewer of the mothers who had used the previous re-treatment services adopted this revised approach and coverage declined to 7%. The future of new delivery services and their financing are discussed in the context of their likely impact upon previously defined protective efficacy and cost-effectiveness estimates.

PIP: Recent trials of insecticide-treated bednets (ITBN) in Africa sought to achieve high ITBN coverage together with high net retreatment rates. Following the completion of a randomized, controlled trial on the coast of Kenya, a series of delivery strategies were used to continue net retreatment in the area. Adherence to a free bi-annual, house-to-house retreatment schedule resulted in a more than 95% coverage of nets issued to children. During the year following the trial, sentinel dipping stations were situated throughout the community and household members informed of their locations and opening times. More than 85% of bednets were re-impregnated between October 1993 and October 1995, and 61-67% coverage of nets used by children for 3 years after the free retreatment service was launched beginning in 1996. The introduction of a social marketing approach at sentinel sites in 1997 to retrieve some of the costs of the net retreatment services caused coverage to drop to 7.1% among children still resident in the study area who had had nets since 1993. The future of new delivery services and their financing are discussed with regard to their likely impact upon previously defined protective efficacy and cost-effectiveness estimates.

The effects of malaria control on nutritional status in infancy.

Both malaria and undernutrition are major causes of paediatric mortality and morbidity in sub-Saharan Africa. The introduction of insecticide-treated bed nets (ITBN) during a randomized controlled trial on the Kenyan coast significantly reduced severe, life-threatening malaria and all-cause childhood mortality. This paper describes the effects of the intervention upon the nutritional status of infants aged between 1 and 11 months of age. Seven hundred and eighty seven infants who slept under ITBN and 692 contemporaneous control infants, were seen during one of three cross-sectional surveys conducted during a one year period. Standardized weight-for-age and mid-upper arm circumference measures were significantly higher among infants who used ITBN compared with control infants. Whether these improvements in markers of nutritional status were a direct result of concomitant reductions in clinical malaria episodes remains uncertain. Never-the-less evidence suggests that even moderate increases in weight-for-age scores can significantly reduce the probability of mortality in childhood and ITBN may provide additional gains to child survival beyond their impressive effects upon malaria-specific events.

Infant parasite rates and immunoglobulin M seroprevalence as a measure of exposure to Plasmodium falciparum during a randomized controlled trial of insecticide-treated bed nets on the Kenyan coast.

Repeated cross-sectional surveys among infants sleeping under insecticide-treated bed nets (ITBN) and contemporary control infants were used to estimate changes in Plasmodium falciparum exposure due to ITBN use on the Kenyan coast. Presence of P. falciparum parasites or total P. falciparum Immunoglobulin M (IgM) seropositivity were used independently and in combination in a constant risk catalytic conversion model to estimate the force of infection in ITBN and control communities. Such studies during infancy avoid problems of early saturation of prevalence due to high forces of infection and persistence of infection, minimize problems of self-treatment, and can be conducted among large populations covering a wide geographic area. These contrast previous parasitologic studies of ITBN among older children and the traditional entomologic studies of transmission that are logistically demanding. Our investigations demonstrated that parasite prevalence, IgM seropositivity, and the force of transmission were all significantly reduced by 50%. In addition, more infants under ITBN entered their second year of life without previous exposure to P. falciparum than control infants. These effects upon delayed acquisition of effective immunity require careful monitoring during future vector control programs using ITBN.

Insecticide-treated bednets reduce mortality and severe morbidity from malaria among children on the Kenyan coast.

New tools to prevent malaria morbidity and mortality are needed to improve child survival in sub-Saharan Africa. Insecticide treated bednets (ITBN) have been shown, in one setting (The Gambia, West Africa), to reduce childhood mortality. To assess the impact of ITBN on child survival under different epidemiological and cultural conditions we conducted a community randomized, controlled trial of permethrin treated bednets (0.5 g/m2) among a rural population on the Kenyan Coast. Between 1991 and 1993 continuous community-based demographic surveillance linked to hospital-based in-patient surveillance identified all mortality and severe malaria morbidity events during a 2-year period among a population of over 11000 children under 5 years of age. In July 1993, 28 randomly selected communities were issued ITBN, instructed in their use and the nets re-impregnated every 6 months. The remaining 28 communities served as contemporaneous controls for the following 2 years, during which continuous demographic and hospital surveillance was maintained until the end of July 1995. The introduction of ITBN led to significant reductions in childhood mortality (PE 33%, CI 7-51%) and severe, life-threatening malaria among children aged 1-59 months (PE 44%, CI 19-62). These findings confirm the value of ITBN in improving child survival and provide the first evidence of their specific role in reducing severe morbidity from malaria.

Response of Plasmodium falciparum to chloroquine and Fansidar in vivo and chloroquine and amodiaquine in vitro in Uganda.

The response of P. falciparum to chloroquine and pyrimethamine-sulfadoxine in vivo and chloroquine and amodiaquine in vitro was investigated in parasitaemic school children from six locations. Mean parasite sensitivity to chloroquine at day 7 was 74% (range 61-97) with parasite clearance rates between 2-3 days and complete defervescence in 85% of febrile children. Sensitivity declined in the four sites followed up to day 14 to 45% (range 37-53). Parasites were significantly more sensitive to pyrimethamine/sulfadoxine at 5/6 sites (100% day 7) but 5% of subjects became parasitaemic by day 14. In vitro isolates were significantly less sensitive to chloroquine than to amodiaquine with a mean 99% effective concentration of 348 mumol/L compared to 6.44 mumol/L. Clearly the role of chloroquine as the primary therapy for uncomplicated P. falciparum malaria should be reconsidered especially in the light of increasing disease severity and resurgence. Amodiaquine may be suitable alternative with pyrimethamine/sulfadoxine as second line and for more severe malaria prior to referral. The cost of alternative antimalarials and the dynamic and deteriorating pattern of resistance are powerful arguments for more objective slide diagnosis to minimise drug pressure and a regular drug sensitivity surveillance system. We believe that the latter should concentrate on measuring clinical drug efficacy in symptomatic outpatients rather than in asymptomatic children while the former needs more pragmatic and economical strategies possibly centred on seasonality and risk.

Severe childhood malaria in two areas of markedly different falciparum transmission in east Africa.

Malaria remains a major public health challenge in sub-Saharan Africa, yet our knowledge of the epidemiology of malaria in terms of patterns of mortality and morbidity is limited. We have examined the presentation of severe, potentially life-threatening malaria to district hospitals in two very different transmission settings: Kilifi, Kenya with low seasonal transmission and Ifakara, Tanzania with high seasonal transmission. The minimum annual rates of severe disease in children below five years in both populations were similar (46 per 1000 children in Kilifi and 51 per 1000 children in Ifakara). However, there were important differences in the age and clinical patterns of severe disease; twice as many patients were under one year of age in Ifakara compared with Kilifi and there was a four fold higher rate of cerebral malaria and three fold lower rate of malaria anaemia among malaria patients at Kilifi compared with Ifakara. Reducing malaria transmission in Ifakara by 95%, for example with insecticide-treated bed nets, would result in a transmission setting comparable to that of Kilifi and although this reduction may yield early successes in reducing severe malaria morbidity and mortality in young, immunologically naive children, place these same children at increased risk at older ages of developing severe and potentially different manifestations of malaria infection hence producing no net cohort gain in survivorship from potentially fatal malaria.

Daily chlorproguanil is an effective alternative to daily proguanil in the prevention of Plasmodium falciparum malaria in Kenya.

To test the efficacy of chlorproguanil prophylaxis, 156 malaria-free schoolchildren in the coastal region of Kenya were allocated at random to receive either 7.5 mg chlorproguanil daily, 50 mg chlorproguanil weekly, 100 mg proguanil daily, or 100 mg calcium lactate weekly (placebo). The children were followed up daily for 169 d, by which time Plasmodium falciparum parasitaemia had occurred in 92% of the placebo group, 31% of the daily proguanil group, 38% of the daily chlorproguanil group and 55% of the weekly chlorproguanil group. There was significant reduction (P < 0.001) in the risk of parasitaemia in all the groups receiving chemoprophylaxis. Daily chlorproguanil and daily proguanil were equally effective, and significantly more effective than weekly high dose chlorproguanil. No significant toxicity was reported or observed. Thus daily chlorproguanil 20 mg/60 kg is a cheap and effective alternative to proguanil for chemoprophylaxis.

A comparison of amodiaquine and chloroquine in the treatment therapy of falciparum malaria in Kenya.

During June to August 1989, 158 symptomatic outpatients with P. falciparum malaria were randomly treated with either amodiaquine or chloroquine 25 mg/kg, divided over three days. Amodiaquine (Camoquin, Parke-Davis) was significantly more effective in terms of the rate of parasite clearance, 2.4 versus 3.1 days; parasite clearance day 7; 87% versus 41%; and clinical amelioration, 98% versus 68%. Moreover, this study demonstrates the lack of therapeutic toxicity of amodiaquine. Globally, tolerance was better with amodiaquine than with chloroquine; in particular, cutaneous side effects were less frequent with amodiaquine. There was no evidence of granulocyte or gross hepatic toxicity. These results suggest that WHO recommendations concerning amodiaquine should be questioned. In view of its low cost, demonstrated efficacy and lack of proven therapeutic toxicity, amodiaquine should be considered as a viable replacement for chloroquine in areas with high levels of clinical chloroquine failure.

Nairobi Hospital, Kenya: the management of nonimmune P. falciparum malaria abroad.

A retrospective analysis of all malaria cases admitted to the Nairobi Hospital was performed by reviewing patient records. Six hundred and three cases were recorded between the period of January 1987 and July 1990 (43 months). The mean age of the patients was 32.5 years and 57.5% were male. Although 81.4% were permanent residents of Kenya, only 18.2% could be said to have lived in a malarial zone. One-quarter of the patients (25.6%) admitted having had a previous episode of malaria, and 57.7% were taking regular chemoprophylaxis. The most common presenting symptoms were fever, headache, vomiting and myarthralgia; the most commonly recorded accompanying signs were jaundice and splenomegaly. Sixty patients met the criteria for severe malaria. During their hospital stay, six patients (1%) died; five of whom were severely ill from the time of for the USA and UK, especially as it represents a selected population of the more serious malarial cases admitted to the hospital. Therefore, it may indeed represent clear evidence to support the hypothesis that a high index of suspicion combined with early diagnosis and treatment will result in improved outcome. Comparative features illustrating these points are presented. As the malaria parasite, P. falciparum, has dynamic antimalarial sensitivity and as more travelers are under threat from this disease, it is vital that ignorance of this danger should not be allowed to put individuals at risk for death. Continuing education of both the traveling public and the medical profession is the only way that both parties will shoulder their respective responsibilities.

A single dose of intramuscular sulfadoxine-pyrimethamine as an adjunct to quinine in the treatment of severe malaria: pharmacokinetics and efficacy.

It has been suggested that sulfadoxine-pyrimethamine (SD/PM) may be useful in the treatment of severe malaria since it could enhance the killing of parasites by quinine (QN) and it can be given as a single intramuscular injection. Eighty Kenyan children with severe malaria were allocated at random to receive either intramuscular QN alone (quinine dihydrochloride 20 mg salt/kg as a loading dose, followed by 10 mg salt/kg 12 hourly for a total of 6 doses) or the same QN regimen plus one intramuscular injection of SD/PM (sulfadoxine 25 mg/kg, pyrimethamine 1.25 mg/kg). There was no difference in time to defervescence, aparasitaemia, or 50% reduction in parasitaemia, parasite elimination half-life, or mortality between the 2 groups. In addition, the concentrations of SD and PM were measured in 14 children and of QN in 8 of these children. Concentrations needed to achieve synergy against PM-resistant strains of Plasmodium falciparum were achieved in all of the children with severe malaria within the first hour and maintained for more than 72 h. SD/PM did not perturb the pharmacokinetics of QN.

Daily low dose chlorproguanil is an effective alternative to daily proguanil in the prevention of P. falciparum malaria in Kenya

156 coastal schoolchildren participated in a placebo controlled trial. All the children were treated with chloroquine 25mg/kg over 3 days plus single dose pyrimethamine-sulfadoxine and then randomised to receive one of four regimens:- A:7.5 mg chlorproguanil daily; B: 50 mg chlorproguanil weekly; C: 100mg proguanil daily; D: 100 mg Calcium lactate weekly. The children were followed up daily for 169 days for P.falciparum parasitaemia. Each 'terminal' event for the construction of life table; was treated with single dose pyrimethamine-sulfadoxine and the child removed from the trial. At the end of the study; 34/37 children had suffered a terminal event in the placebo group compared to 12/39 in the daily proguanil 100 mg group; 15/39 in the daily chlorproguanil 7.5 mg group and 22/40 in the weekly chlorproguanil 50 mg group. Life table analysis found a significant reduction (P is greater than 0.001) in the risk of malaria in all the chemoprophylactic groups compared to the placebo group. Daily proguanil also gave greater protection than weekly chloroproguanil (P greater than 0.05); but there was no difference between daily proguanil and daily chlorproguanil (P less than 0.1). Daily chlorproguanil 7.5 mg; has a lower cumulative dose; greater in vitro activity and increased intracellular concentration of the metabolite. Compared to proguanil and increased intracellular concentration of the metabolite. Therefore; daily proguanil has significant potential as another chealp; effective; nontoxic chemoprophylactic addition to vector avoidance measures

Pyrimethamine-sulfadoxine (Fansidar) resistance in a non-immune Kenyan--a case report.

Drug resistance in an endemic zone is often difficult to prove. This case illustrating both chloroquine and pyrimethamine sulfadoxine resistance unfolded in an area without risk of reinfection. The long time lapse and hence danger, between exposure and clinical symptoms in those on chemoprophylaxis highlighted and emphasis is placed on adequate follow up to pick up resistance in long acting preparations.

Variability in the metabolism of proguanil to the active metabolite cycloguanil in healthy Kenyan adults.

Extensive metabolizers (EM) and poor metabolizers (PM) of the malaria chemoprophylactic drug proguanil have been identified by measuring the proguanil/cycloguanil ratio in urine following a single dose of the pro-drug. The pharmacokinetic characteristics of proguanil were similar in 8 EM and 8 PM subjects, but there were significant differences between the 2 groups with respect to cycloguanil pharmacokinetics. In none of the PM subjects could cycloguanil be detected in whole blood samples at any time after proguanil dosage. Plasma cycloguanil was measureable in only 2 of 8 PM subjects, despite an analytical sensitivity in the high-performance liquid chromatographic assay of 1 ng/ml cycloguanil. A comparatively high proportion of Black Kenyan adults appear to metabolize proguanil poorly, possibly because they lack the specific mixed function oxidase which will accept proguanil as substrate.

Malaria in Sub-Saharan Africa.

Malaria as a threat to health has remained undaunted in Sub-Saharan Africa (SSA). It has been mathematically modelled, vertically attacked and continuously appraised and yet it continues unabated. Malaria is an acute and chronic disease caused by intracellular protozoa of the genus Plasmodium which are transmitted by the bite of female Anopheles mosquitoes. Approximately 2.6 billion people are at risk worldwide resulting in at least 100 million clinical cases and of the order of 1 million fatalities. The social and economic consequences of such morbidity and mortality have not been adequately documented.

Comparison of mosquito nets, proguanil hydrochloride, and placebo to prevent malaria.

One hundred and ninety students aged 6 to 18 at a boarding school 120 km west of Nairobi in the Rift Valley participated in a comparative trial of malaria prophylaxis. Treatment with a combination of amodiaquine 25 mg/kg over three days plus doxycycline 100 mg twice daily for five days cleared their blood of Plasmodium falciparum. They were then randomly divided into the following three groups matched for age and sex: one group slept under mosquito nets; one group received one or two tablets (100 mg each) of proguanil hydrochloride daily according to weight; one group received one or two placebo tablets daily which were the same size and colour as the proguanil tablets. Malaria was diagnosed when asexual P falciparum were seen on blood films and was treated with pyrimethamine-sulphadoxine. At the end of one school term 188 of the 190 students had completed the study. One new infection was found during 3893 days of follow up in the mosquito net group, eight new infections over 3667 days in the proguanil group, and 35 new infections over 3677 days in the placebo group, representing a reduction of 97.3% and 77.1% in attack rates for the mosquito net method and for treatment with proguanil respectively. Both provide effective protection from malaria.

Chlorproguanil/dapsone for the treatment of non-severe Plasmodium falciparum malaria in Kenya: a pilot study.

Chlorocycloguanil, the active metabolite of chlorproguanil, was synergistic in vitro with dapsone against 2 culture-adapted Plasmodium falciparum isolates from Kenya; maximal synergy occurred at lower concentrations that it did with pyrimethamine and sulfadoxine. 48 children with asymptomatic P. falciparum infections were treated with chlorproguanil (at a target dose of 1.2 mg/kg) and dapsone (target dose of 1.2 or 2.4 mg/kg); all were free of parasitaemia by day 7. The following numbers had recurrences on days 14, 21, and 28, respectively: 1 of 48, 7 of 47, and 7 of 40. All 39 children treated with pyrimethamine (target dose 1.2 mg/kg) and sulfadoxine (target dose 24 mg/kg) were cleared of infection, while the following had recurrences on days 14, 21, and 28: 1 of 39, 2 of 38, and 2 of 36. The rate of decrease in parasitaemia was the same in the 2 groups, and there was no change in haematocrit or haemoglobin during the follow-up. The rate of recurrence in the children receiving chlorporguanil/dapsone was higher, probably because these drugs have a much shorter clearance time than pyrimethamine/sulfadoxine. Chlorproguanil/dapsone is an effective combination for treating P. falciparum malaria and deserves further study.