Biomedical subjects
R W Snow
Publications and source records attributed to R W Snow.
Malaria epidemiology and economics: the effect of delayed immune acquisition on the cost-effectiveness of insecticide-treated bednets.
An understanding of the epidemiology of a disease is central in evaluating the health impact and cost-effectiveness of control interventions. The epidemiology of life-threatening malaria is receiving renewed interest, with concerns that the implementation of preventive measures such as insecticide-treated bednets (ITNs) while protecting young children might in fact increase the risks of mortality and morbidity in older ages by delaying the acquisition of functional immunity. This paper aims to illustrate how a combined approach of epidemiology and economics can be used to (i) explore the long-term impact of changes in epidemiological profiles, and (ii) identify those variables that are critical in determining whether an intervention will be an efficient use of resources. The key parameters for determining effectiveness are the protective efficacy of ITNs (reduction in all-cause mortality), the malaria attributable mortality and the increased malaria-specific mortality risk due to delays in the acquisition of functional immunity. In particular, the analysis demonstrates that delayed immune acquisition is not a problem per se, but that the critical issue is whether it occurs immediately following the implementation of an ITN programme or whether it builds up slowly over time. In the 'worst case' scenario where ITNs immediately increase malaria-specific mortality due to reduced immunity, the intervention might actually cost lives. In other words, it might be better to not use ITNs. On the other hand, if reduced immunity takes two years to develop, ITNs would still fall into the category of excellent value for money compared to other health interventions, saving a year of life (YLL) at a cost of between US$25-30. These types of calculations are important in identifying the parameters which field researchers should be seeking to measure to address the important question of the net impact of delaying the acquisition of immunity through preventive control measures.
Acquired immunity and postnatal clinical protection in childhood cerebral malaria.
By analysing data on the age distribution of cerebral malaria among sites of different transmission intensities, we conclude that the most plausible explanation for the epidemiological patterns seen is that (i) cerebral malaria is caused by a distinct set of Plasmodium falciparum antigenic types; (ii) these antigenic types or 'CM strains' are very common and induce strong strain-specific immunity; and (iii) the postnatal period of protection against cerebral malaria is much longer than the period of protection against other forms of severe disease. The alternative hypothesis that cerebral malaria may be caused by any 'strain' of P. falciparum is compatible with the data only if a single exposure is sufficient to protect against further episodes. This is not consistent with observations on the history of exposure of patients with cerebral malaria. Finally, it is clear that although the delayed peak in incidence of cerebral malaria (with age) can be generated by assuming that subsequent exposures carry a higher risk of disease, such an explanation is not compatible with the observation that severe disease rates are low among infants and young children in areas of high transmissibility.
A preliminary continental risk map for malaria mortality among African children.
Approaches to global public health are increasingly driven by an understanding of regional patterns of disease-specific mortality and disability. Current estimates of disease risks associated with Plasmodium falciparum in sub-Saharan Africa remain poorly defined. Through the integration of high-resolution population and climate probability models of P. falciparum transmission, geographical information systems have been used to define the spatial limits of populations exposed to the risk of infection in Africa. These estimates were combined with a range of annual malaria-specific mortality rates, derived from a variety of epidemiological approaches, among children aged 0-4 years. The best estimates of malaria-attributable mortality using this approach ranged between 0. 43 million and 0.68 million deaths per annum among an exposed population of approximately 66 million children in 1990. Despite the limitations of modelled transmission and population distributions, these empirical approaches to probabilities of infection risk and epidemiological data on mortality provide a novel approach to present and projected burdens of malaria mortality, as discussed here by Bob Snow, Marlies Craig, Uwe Deichmann and Dave le Sueur.
A climate-based distribution model of malaria transmission in sub-Saharan Africa.
Malaria remains the single largest threat to child survival in sub-Saharan Africa and warrants long-term investment for control. Previous malaria distribution maps have been vague and arbitrary. Marlies Craig, Bob Snow and David le Sueur here describe a simple numerical approach to defining distribution of malaria transmission, based upon biological constraints of climate on parasite and vector development. The model compared well with contemporary field data and historical 'expert opinion' maps, excepting small-scale ecological anomalies. The model provides a numerical basis for further refinement and prediction of the impact of climate change on transmission. Together with population, morbidity and mortality data, the model provides a fundamental tool for strategic control of malaria.
Immunity to non-cerebral severe malaria is acquired after one or two infections.
In areas of stable transmission, clinical immunity to mild malaria is acquired slowly, so it is not usually effective until early adolescence. Life-threatening disease is, however, restricted to a much younger age group, indicating that resistance to the severe clinical consequences of infection is acquired more quickly. Understanding how rapidly immunity develops to severe malaria is essential, as severe malaria should be the primary target of intervention strategies, and predicting the result of interventions that reduce host exposure will require consideration of these dynamics. Severe disease in childhood is less frequent in areas where transmission is the greatest. One explanation for this is that infants experience increased exposure to infection while they are protected from disease, possibly by maternal antibody. They therefore emerge from this period of clinical protection with considerably more immunity than those who experience lower transmission intensities. Here we use this data, assuming a period of clinical protection, to estimate the number of prior infections needed to reduce the risk of severe disease to negligible levels. Contrary to expectations, one or two successful infective bites seem to be all that is necessary across a broad range of transmission intensities.
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.
Vector-related case-control study of severe malaria in Kilifi District, Kenya.
A case-control study examined vector-related and environmental parameters associated with severe malaria in Kilifi District along the coast of Kenya. Over an 11-month period, 119 children identified with severe malaria infections at the Kilifi District Hospital were matched by age with control children who reported to the outpatient clinic with nonsevere infections. Intensive mosquito sampling was done in each of the case-control houses over a four-day period, beginning within a week of index case admission. A total of 109 environmental, demographic, behavioral, and animal husbandry variables were characterized for each household. Vector species (Anopheles gambiae s.l. and An. funestus) were detected in 40.1% and 36.1% of case and control houses, respectively. The relative abundance of vectors in individual houses was stable over the two-week resampling periods (r = 0.9). Both the overall abundance of anopheline mosquitoes (odds ratio [OR] = 1.5) and P. falciparum sporozoite rates (OR = 1.5) were not significantly different between case and control houses. In a matched analysis, 11 of 109 house variables associated significantly with severe malaria were also associated with vector abundance, as determined by chi-square linear trend analysis. Under conditions of year-round, low-level transmission on the coast of Kenya, the risk of severe disease in children is multifactorial and not governed strictly by transmission intensity or environmental heterogeneity affecting vector abundance and distributions. This suggests that current interventions that appear to be achievable only in areas where transmission is already low to moderate should be appropriate. However, such interventions should be monitored so that inappropriate and possibly disastrous control activities can be avoided in Africa.
Estimating mortality, morbidity and disability due to malaria among Africa's non-pregnant population.
The contribution of malaria to morbidity and mortality among people in Africa has been a subject of academic interest, political advocacy, and speculation. National statistics for much of sub-Saharan Africa have proved to be an unreliable source of disease-specific morbidity and mortality data. Credible estimates of disease-specific burdens are required for setting global and national priorities for health in order to rationalize the use of limited resources and lobby for financial support. We have taken an empirical approach to defining the limits of Plasmodium falciparum transmission across the continent and interpolated the distributions of projected populations in 1995. By combining a review of the literature on malaria in Africa and models of acquired functional immunity, we have estimated the age-structured rates of the fatal, morbid and disabling sequelae following exposure to malaria infection under different epidemiological conditions.
The cost of treating paediatric malaria admissions and the potential impact of insecticide-treated mosquito nets on hospital expenditure.
OBJECTIVE: To calculate the costs at Kilifi District Hospital (KDH) and Malindi Sub-district Hospital (MSH) of treating paediatric malaria admissions including three common presentations of severe paediatric malaria, i.e. cerebral malaria, severe malaria anaemia and malaria-associated seizures; and to estimate the implications for hospital expenditure of a reduction in paediatric malaria admissions. METHODS: Patient data were obtained from hospital records. All costs were allocated to departments that provided direct patient care by a four-stage step-down procedure. Laboratory and drug costs of treating paediatric malaria admissions were separately identified. RESULT: Unit recurrent costs per admission in KDH ranged from US $57 for 'other' paediatric malaria to US $105 for cerebral malaria, and in MSH from US $33 to US $44 for the same categories. The annual recurrent cost of treating all paediatric malaria admissions to KDH prior to the trial was estimated at US $78 900. Adjusting for preintervention differences in malaria admission rates and age between intervention and control areas, the ITBN trial found a 41% reduction in paediatric malaria admissions. The reduction in admissions resulted in an estimated saving of US $6240 in the cost of treating paediatric malaria admissions from the intervention area. CONCLUSION: There would be a substantial reduction in costs of treating paediatric malaria admissions if the intervention were introduced in the whole catchment area of the hospital. Actual savings would depend on the proportion of potential savings that can in practice be realised, and on the effectiveness of the intervention when routinely implemented.
A community randomized controlled trial of insecticide-treated bednets for the prevention of malaria and anaemia among primigravid women on the Kenyan coast.
The effectiveness of insecticide-treated bednets (ITBN) in preventing malaria and anaemia among primigravidae living in Kilifi District, Kenya, was assessed by a randomized controlled trial between September 1994 and November 1995. All residents within 28 community clusters received ITBN in July 1993, whilst residents of another 28 clusters served as contemporaneous controls. All resident primigravid women with singleton pregnancies attending antenatal care at Kilifi District Hospital were eligible for recruitment. 503 primigravidae were recruited. 91.4% were anaemic antenatally (Hb < 11 g/dl): 91.0% from the intervention arm and 92.0% from the control arm. Severe anaemia (Hb < 7 g/dl) was found among 15.1% of intervention women and 20.1% of control women (P = 0.28). No significant differences were observed in reports of febrile illness or the presence of chloroquine in the serum or peripheral parasitaemia during the third trimester between the two groups. In the women delivering in hospital (n = 130), there was no association between placental malaria infection and the intervention: 77.4% of placentas from control women had evidence of past or active infection, compared with 72.0% of placentas from intervention women (P = 0.76). Similarly, in the women delivering in hospital, ITBN did not improve birth weight, and there were no differences in perinatal mortality between the two study groups. Despite ITBN having a great impact on paediatric severe malaria and mortality in this transmission setting, there was very little impact of ITBN on the morbidity associated with malaria infection in primigravidae. Alternative strategies are required to tackle this continued public health problem for pregnant women living in endemic areas similar to the Kenyan Coast.
Mapping malaria transmission intensity using geographical information systems (GIS): an example from Kenya.
That there are so few examples of the use of epidemiological maps in malaria control may be explained by the lack of suitable, spatially defined data and of an understanding of how epidemiological variables relate to disease outcome. However, recent evidence suggests that the clinical outcomes of infection are determined by the intensity of parasite exposure, and developments in geographical information systems (GIS) provide new ways to represent epidemiological data spatially. In the present study, parasitological data from 682 cross-sectional surveys conducted in Kenya were abstracted and spatially defined. Risks of infection with Plasmodium falciparum among Kenyan children, estimated from combinations of parasitological, geographical, demographic and climatic data in a GIS platform, appear to be low for 2.9 million, stable but low for another 1.3 million, moderate for 3.0 million and high for 0.8 million. (Estimates were not available for 1.4 million children.) Whilst the parasitological data were obtained from a variety of sources across different age-groups and times, these markers of endemicity remained relatively stable within the broad definitions of high, moderate and low transmission intensity. Models relating ecological and climatic features to malaria intensity and improvements in our understanding of the relationships between parasite exposure and disease outcome will hopefully provide a more rational basis for malaria control in the near future.
Risk of severe malaria among African infants: direct evidence of clinical protection during early infancy.
Little empirical evidence from field-based studies exists on the relative magnitude or duration of clinical protection from Plasmodium falciparum malaria in infancy. A prospective study was undertaken to examine the age distribution of hospital admissions in four geographically and demographically well-defined areas with differing intensities of P. falciparum transmission. Where transmission was perennial, significant clinical protection from severe morbidity was observed up to the third month of life; in the seasonal transmission area, disease rates rose after the sixth month of life. Infants exposed to the highest rates of P. falciparum exposure demonstrated significant declines in the risks of severe malaria from 6 months of age. These data provide direct evidence for the very early acquisition of clinical immunity and for the existence of a period of clinical protection, which together may explain why, in these communities, the cumulative risk of malarial disease throughout childhood appears to decline with increasing transmission intensity.
An analysis of the geographical distribution of severe malaria in children in Kilifi District, Kenya.
BACKGROUND: Although malaria is known to be a major cause of child mortality and morbidity throughout sub-Saharan Africa there are few detailed studies of malaria mortality rates and incidence of severe malarial disease in defined communities. We have studied the geographical pattern of admissions to hospital with severe malaria and the stability of this pattern over time in Kilifi District on the Kenyan Coast. METHODS: Over a 2-year period all children under 5 years of age with severe malaria admitted to the district hospital and living in a rural study population of about 50,000 people were identified. Annual censuses were carried out in the study area, and all households were mapped using a hand-held satellite navigation system. The resulting databases were linked using a geographical information system (GIS). RESULTS: Using methods originally developed for the study of the geographical distribution of childhood leukaemia we assessed the spatial pattern of hospital admission rates for severe malaria. As expected, admission rates were significantly higher in children with easier access to the hospital. For example, those living more than 25 km from the hospital had admission rates which were about one-fifth of those for children living within 5 km of the hospital. Those living more than 2.5 km from the nearest road had admission rates that were about half of those for children living within 0.5 km of a road. We also investigated short-term local fluctuations in severe malaria and found evidence of space-time clustering of severe malaria. CONCLUSIONS: Hospital admission rates for severe malaria are higher in households with better access to hospital than in those further away. The finding of space-time clusters of severe malaria suggests that it would be of value to conduct case-control studies of environmental, genetic and human behavioural factors involved in the aetiology of the disease.
New insights into the epidemiology of malaria relevant for disease control.
Despite over 100 years of scientific investigation, malaria remains the leading cause of death among children living in sub-Saharan Africa. Our understanding of the epidemiology of clinical malaria has, until recently, been hampered by a paucity of empirical data from endemic settings. A striking feature of Plasmodium falciparum malaria is that, compared to infection and mild disease, severe complications and death are rare. Perhaps the single most important factor which ameliorates the risk of asymptomatic infection progressing to life-threatening pathology is the development of clinical immunity. Examination of recent epidemiological evidence suggests that the speed with which clinical immunity is acquired is dependent upon the frequency of parasite exposure from birth. Consequently, the age at which disease presentation peaks, the clinical spectrum of disease and the life-time risks of disease appear to be a function of the intensity of transmission within a given community. These observations are discussed in relation to control measures aimed at reducing P. falciparum exposure and the need to understand better the processes by which children naturally acquire clinical immunity before more rational statements can be made about their wide-spread use in Africa.
Host-parasite interaction and morbidity in malaria endemic areas.
Severe morbidity due to Plasmodium falciparum is a major health problem in African children. The patterns of morbidity in endemic areas are modified by the immune response, and vary markedly with transmission intensity. Severe disease falls into three overlapping syndromes: coma, respiratory distress, and severe anaemia. Recently, it has become clear that metabolic acidosis plays a major role in the pathogenesis of severe disease and is particularly important in the overlap between the different clinical syndromes. We propose that the different manifestations of severe malarial morbidity arise from the interaction of a limited number of pathogenic processes: red cell destruction, toxin-mediated activation of cytokine cascades, and infected cell sequestration in tissue microvascular beds. The pattern of severe morbidity varies with age within any one endemic area, with severe anaemia predominating in the youngest children and coma having its highest incidence in older children. Between endemic areas there is a marked variation in mean age of children with severe malaria, and therefore in the importance of different clinical syndromes. The shift in mean age is due to a combination of increased challenge and more rapid development of immunity at higher levels of transmission. Recent comparative studies indicate that at higher levels of transmission the net effect of these shifts may be a paradoxical reduction in total severe malarial morbidity.
Relation between severe malaria morbidity in children and level of Plasmodium falciparum transmission in Africa.
BACKGROUND: Malaria remains a major cause of mortality and morbidity in Africa. Many approaches to malaria control involve reducing the chances of infection but little is known of the relations between parasite exposure and the development of effective clinical immunity so the long-term effect of such approaches to control on the pattern and frequency of malaria cannot be predicted. METHODS: We have prospectively recorded paediatric admissions with severe malaria over three to five years from five discrete communities in The Gambia and Kenya. Demographic analysis of the communities exposed to disease risk allowed the estimation of age-specific rates for severe malaria. Within each community the exposure to Plasmodium falciparum infection was determined through repeated parasitological and serological surveys among children and infants. We used acute respiratory-tract infections (ARI) as a comparison. FINDINGS: 3556 malaria admissions were recorded for the five sites. Marked differences were observed in age, clinical spectrum and rates of severe malaria between the five sites. Paradoxically, the risks of severe disease in childhood were lowest among populations with the highest transmission intensities, and the highest disease risks were observed among populations exposed to low-to-moderate intensities of transmission. For severe malaria, for example, admission rates (per 1000 per year) for children up to their 10th birthday were estimated as 3.9, 25.8, 25.9, 16.7, and 18.0 in the five communities; the forces of infection estimated for those communities (new infections per infant per month) were 0.001, 0.034, 0.050, 0.093, and 0.176, respectively. Similar trends were noted for cerebral malaria and for severe malaria anaemia but not for ARI. Mean age of disease decreased with increasing transmission intensity. INTERPRETATION: We propose that a critical determinant of life-time disease risk is the ability to develop clinical immunity early in life during a period when other protective mechanisms may operate. In highly endemic areas measures which reduce parasite transmission, and thus immunity, may lead to a change in both the clinical spectrum of severe disease and the overall burden of severe malaria morbidity.
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.