Subsequent to these earlier studies there has been a renaissance in the clinical epidemiology of severe paediatric malaria across a wide range of different transmission settings, leading to descriptions of severe paediatric malaria from Sudan [10], Mozambique [11], Tanzania [12,13], Mali [14], Niger [15], Kenya [16], Uganda [17,18], Yemen [19], Ghana [20,21] and Zambia [22]. In addition, there have been several further attempts to compare the epidemiological patterns of severe malaria between sites of different transmission intensity in Gabon [23], Burkina Faso [24], Uganda [17], Sudan [25], Tanzania versus Mozambique [26], and one study that compared severe malaria risks at different altitudinal transmission limits in Tanzania [13]. The consensus view of all studies is that as the intensity of P. falciparum transmission increases, the mean age of severe malaria decreases. Less consistent is the reported relationship between clinical syndromes of severe paediatric malaria and transmission intensity.

There are three limitations of many of the reported ecological comparisons. First, they often compare data from very few sites, reducing the contextual ranges of the observations and thus their wider validity. Second, the measures of transmission intensity used in most studies are often imperfect or assumed rather than measured [13,17,23,25]; or not matched to the period of clinical surveillance under review [11,26]. Finally, despite an increased number of observational studies of severe malaria, they often do not cover the same age range, nor do they use similar diagnosis and surveillance methods.

To examine the corresponding age-patterns of malaria admission against transmission intensity we computed the proportion of all malaria admissions by single years of age 0 to 9 years at each site, arranged in descending order of PfPR_2–10 in Figure Figure2.2. Across the 17 communities the tendency was toward a greater proportion of older children presenting as PfPR_2–10 estimates decreased and a greater proportion of younger children admitted where PfPR_2–10 was higher. It was nevertheless notable, that even at very low estimates of PfPR_2–10, the proportion of cases after the fourth birthday was lower than in early childhood (last five panels in Figure Figure22).

For a number of reasons, that are expanded on in the discussion, the public health and intervention significance of clinical risks in infancy is of programmatic importance. Among the six communities where the PfPR_2–10 estimate was ≥ 40%; approximately 40% of all malaria admissions were in children aged < 1 year. This compared with an average of 20% of all malaria admissions in infancy among the eight sites with a PfPR_2–10 between 5 and 39%, and 10% of all admissions at the three sites where PfPR_2–10 was recorded as < 5%. There is a direct and strong linear relationship between increasing PfPR_2–10 and the proportion of paediatric malaria admissions that are infants (R² = 0.73, p < 0.001; Figure Figure3a)3a) and the converse relationship with the proportion of admissions that are aged between 5–9 years (R² = 0.47, p = 0.002; Figure Figure3b).3b). A few outliers are worth identifying: first Junju, Kilifi South, Kenya with a PfPR_2–10 estimate of 26% had no admissions above 5 years of age during the observation period; second, at Kilifi North between 2004–07 PfPR_2–10 was recorded as 1% and Kilimanjaro with a PfPR_2–10 estimate of 6%, however, both had considerably more children admitted aged 0–4 years compared to those 5–9 years of age. Finally, the Kilifi South (Chonyi) admission series documented between 1999 and 2001 shows a high proportion of infants while transmission intensity is intermediary between two sites where the infant admissions are much lower.

The observations summarized in Figure Figure22 include overlapping communities seen at different times with very different estimates of PfPR_2–10 during each observation period: Kilifi North in the 1990s and 2000s and two closely located communities surveyed between 1999 and 2007 south of Kilifi District Hospital and corresponding to Kilifi South surveyed in 1990's. In the same communities over the two time periods transmission had dropped dramatically. In Kilifi North over ten years PfPR_2–10 dropped from 52% to 1% and at Kilifi South (1992–1995) and the nested area of Chonyi (1999–2001) corresponding PfPR_2–10 estimates were 77% and 43% respectively. In both areas the age patterns of malaria admissions had shifted toward older children as PfPR_2–10 declined but the most dramatic age-shift was observed at Kilifi North with the largest decline in PfPR_2–10 over a longer time frame.

There are very few serial, long-term clinical observations of severe paediatric malaria in areas where transmission intensity is in transition [41]. Thus to understand the relationships between transmission intensity and disease outcome we must default to cross-sectional estimations of risk and exposure from different settings to infer what might happen if single communities transitioned between exposure states. Ecological comparative observational epidemiology is not without its limitations. An attempt has been made to standardize observations across 17 communities to minimize methodological measurement differences in the study of the clinical epidemiology of hospitalized paediatric malaria and transmission. Here PfPR_2–10 estimates of transmission contemporary with the clinical observations were used to ensure congruence between exposure and outcome.

One of the most striking observations was the relationship between increasing transmission intensity and the predominant age of paediatric malaria admissions (Figures (Figures2,2, ,3a3a and and3b).3b). Among communities where PfPR_2–10 is ≥ 40% more than 40% of malaria admissions to paediatric wards were infants, compared to only 10% in areas where PfPR_2–10 is < 5%. These observations are consistent with the view that the speed of acquired clinical immunity scales with the frequency of parasite exposure since birth [3,4,45]. Interestingly from the sites where the intensity of transmission was very low (Figure (Figure2),2), there remains evidence of some acquired functional immunity as expressed by the continued decline after the fourth birthday in the proportion of overall malaria admissions. This was most notable at Taiz (PfPR_2–10 6%) and Bakau (PfPR_2–10 2%). These declining risks with age under very low parasite exposure from birth suggest that only a few parasite exposures might confer a degree of clinical immunity [46] or age itself modifies risks of hospitalized malaria [47].

Despite the overall linear pattern of proportions of admissions aged less than one year (Figure (Figure3a)3a) or greater than five years (Figure (Figure3b)3b) with increasing transmission intensity there were some interesting exceptions to this general pattern. At two coincidentally matched sites investigated between ten years apart (Kilifi North) and five years apart (Kilifi South versus Chonyi) on the Kenyan coast the age-patterns were not as one might have anticipated based on the age patterns of disease seen in areas with very similar PfPR_2–10 (Figure (Figure2).2). Both sites did show a changing age pattern of disease presentation with decreasing transmission intensity but had not resulted in an age pattern similar to those of historically similar transmission intensity in their second observation period. What these data might suggest is that the cross-sectional investigation of the clinical epidemiology of hospitalized malaria during a period of transmission transition, inevitably results in the study of older children exposed to different transmission intensity risks at different times in their young lives with a cohort effect of accumulated acquired immunity. Thus the "true" age pattern in a community would take some time to stabilize. This phenomenon might also explain the slightly divergent patterns seen at the two South Eastern sites in Tanzania (Magunga and Kilimanjaro) where scaled ITN coverage may also have resulted in a difference between "historical" estimations of PfPR_2–10 and the current values used to match the clinical surveillance period [48].

More importantly the differences in peak age of hospitalized malaria disease presentation and transmission intensity have implications for the design of suites of prevention strategies planned for the control of malaria in Africa. The benefit of targeted intervention in the use of bed nets for malaria control as currently recommended by the WHO is based on the reasoning that targeting bed nets to the highest risk groups; infants and pregnant women, achieves the highest public health impact. Following the same reasoning it is clear that the likely public health impact of intermittent presumptive treatment of infants (IPTi) coincidental with vaccine schedules [49], is likely to be greatest in areas of the transmission axis where the disease burden in concentrated in infancy (Figure (Figure3a).3a). As the estimate of PfPR_2–10 declines IPTi must adapt to include increasingly older age risk groups [50] until one considers adoption of IPT in school-aged children [51] (Figure (Figure3b).3b). It seems entirely plausible that with adequate scaling of ITN coverage in most areas of Africa where PfPR_2–10 starts at values <40% a dramatic reduction in transmission intensity is likely within 3–5 years [52], as this happens the age-patterns of severe malaria presenting to hospital will change and increasingly become less dominated by infants, making the adaptation of the IPTi rationale an immediate priority. Following the same reasoning, outpatient screening tools such as the WHO recommended IMCI guidelines currently in use across many African countries will need to be modified to accommodate expected changes in disease presentation. The current dogma is that across Africa hospitalized malaria is a young paediatric problem, however recent assemblies of PfPR_2–10 information from across the continent [34], suggest that the predominant transmission pattern is one approximating to areas closer to the left hand side of the X-axis of Figures Figures3a3a and and3b.3b. Areas of exceptionally high transmission are likely to be less common than previously thought and yet are often the choices of location for most clinical studies of hospitalized malaria in childhood.

In this study series, cerebral malaria appeared to be a more common presentation among children hospitalized with malaria from lower intensity transmission settings compared to areas of high transmission (Figure (Figure4a).4a). This observation has been made in other between site comparative studies [2,3,13,17,24,53]. The proportion of malaria admissions regarded as having a BCS ≤ 2 varied considerably under a wide range of transmission conditions from PfPR_2–10 1% to 33%, however, and may also reflect the difficulties in measuring cerebral malaria in very young children [54]. The proportion of children presenting with severe malaria anaemia showed little variation across the range of transmission conditions from 1–80% PfPR_2–10 (Figure (Figure4b)4b) with the exception of the highest recorded proportion of anemic children (50%) from Nyamawala/Michenga villages where PfPR_2–10 was 87%. The epidemiology of severe malaria anaemia may be more complex than previously thought [12,55] and while is a common feature in young hospitalized infants remains a clinical predictor in older children [30]. A recent study looking at severe anaemia in children indicates that the occurrence of SMA is more likely to be multi-factorial than is CM and importantly is also more likely to be context specific relating to nutrition, prevalence of HIV and prevalence of other diseases which are associated with severe anaemia [56], thus complicating direct comparisons between sites.