Malaria incidence (i.e. cases per 1000 population at risk) reduced from 80 in 2000 to 58 in 2015 and 57 in 2019 globally [1, 9]. Despite these gains, the malaria situation in sub-Saharan Africa (SSA) remains volatile [10]. During the COVID-19 pandemic, there was a reversal of earlier reported gains in a reduction in mortality, with an excess of 69,000 deaths reported in the SSA in 2020 [2, 11]. This vulnerability seems to be driven by multiple factors that have shaped the dynamics of the malaria epidemiological quartet of vector, agent, host and environment [12]. The emergence of novel malaria-transmitting mosquito Anopheles stephensi mosquito in SSA [13], has posed a new threat to malaria control measures. In addition, the recent emergence of independent malaria drug resistance in Rwanda [14], Tanzania [15], and Uganda [16] has caused challenges in malaria control using artemisinin combination therapies (ACTs). There are also changing characteristics of the host. In recent studies, whereas children remain vulnerable to malaria, the age strata and clinical disease picture have changed [17–19]. Furthermore, tropical weather patterns and topography of marshlands accentuated by global warmings seem to improve the breeding of Anopheles mosquito and enhanced efficiency for its disease transmission capabilities in the last decade [20–22]. A constellation of these factors seems to have ushered in a new era of malaria in SSA, associated with variations in the clinical spectrum of severe malaria, but this has remained hitherto poorly described.
We studied 300 children, randomly selected among children being recruited into a longitudinal malaria study. This is a much larger sample size compared to similar studies for the work we report here. Therefore, we believe that these new phenomena represent a more widespread change in malaria presentation during the malaria epidemic in the paediatric population of Eastern Uganda.
In our study, the common clinical features reported were prostration 236/300 (78.7%), jaundice 205/300(68.3%), severe malarial anaemia 158/300(52.7%), blackwater fever (BWF) 158/300 (52.7%), and multiple convulsions 51/300 (17.0%). Prolonged hospitalisation was found in 56/251(22.3%). Participants with acidosis were more likely to have prolonged hospitalisation P = 0.041. More than half 154/300 (51%) of the study participants had already been treated with either oral or parental antimalarials. Our data show that the proportion of patients with each clinical feature has changed with some increasing tremendously compared to similar data reported in the same setting a decade ago [5]. It is plausible that there was an exponential increase in cases of malaria during the malaria epidemic that the Uganda Ministry of Health declared in June 2022. However, this does not necessarily explain the change in the clinical spectrum from the predominant respiratory distress and severe malarial anaemia a decade ago [20] to a higher proportion of children with prostration and BWF in the current data. We have demonstrated a shift in age strata towards older children. Elsewhere, malaria presentation in older children is commonly associated with more cerebral and renal involvement compared to frequencies of these features in younger children [23]. We have previously highlighted that BWF is increasing in Eastern Uganda [19], but this time round, we report that it has become even more common. In the earlier and current data, we have seen an increase in the average age of children suffering from severe malaria. Even though BWF seems to be increasing, especially in Eastern Uganda [19], the pathophysiology is typically different and depends on clinical presentation. Our data demonstrate a triad of severe anaemia, jaundice and BWF, which point towards massive haemolysis.
Conversely, BWF associated with cerebral malaria [23, 24] is a pointer towards myolysis, as myoglobin has previously been detected in children with impaired consciousness and BWF [24]. The pathogenesis of cerebral malaria is due to damaged vascular endothelium by parasite sequestration, inflammatory cytokine production and vascular leakage, which result in brain hypoxia, as indicated by increased lactate and alanine concentrations [25]. We think the source of myoglobin in the children with cerebral malaria is multifactorial. Firstly, the muscle damage from sgeneralised tonic-clonic seizures. Secondly, vaso occlusive phenomenon occurs s in muscle blood supply following damaged vascular endothelium by parasite sequestration similar to cerebral malaria. In Eastern Uganda, we have consistently reported a low frequency of impaired consciousness in severe childhood malaria even with changes in age strata [5, 19, 26].
Other clinical observations in our current study may suggest that earlier treatment with antimalarials may be responsible for the variation in the clinical spectrum and outcomes we observed. We noted that over -half of the study participants had taken antimalarials before admission. In SSA, there is a paucity of data on the role of artemisinin combination therapies (ACTs) in the causation or prevention of BWF. Earlier data reported that BWF was associated with quinine, the first line drug for treating severe malaria two decades ago [27] or where it is still in use [28]. There have been postulations that ACTs' fast-acting intra-erythrocyte activity results in death to malaria parasites, causing pitting of the infected red blood cells and resulting in premature apoptosis, autoimmune and spleen-driven lysis, culminating in massive haemolysis [29]. In some settings, case studies have indicated that ACTs could be associated with BWF [30], but further research is needed in our setting.
In this study, we report a median age of 4.6 years and a proportion of children below five years of 164/300 (54.7%). We demonstrate a shift towards older children and a lower proportion of children under the age of 5 years compared to a similar study in the same settings by Olupot-Olupot et al., which reported an average age of 1.5 years for data collected a decade ago [5]. Elsewhere, Kalinga and colleagues, 2012 assessed clinical manifestations and outcomes of severe malaria in children admitted to district hospital in Rungwe and Kyela in south-western Tanzania [31]. In their study, 1371 children were selected as screening group of which 409 (29.8%) tested positive for malaria. The mean age of the children was 2.7 (95%CI = 2.5, 2.8) years, and the majority (86%) were under five years of age [31]. Our results may propose that the current epidemic of malaria-affected more older children with waned immunity compared to earlier studies in which younger nonimmune children were affected. We think these age differences are also responsible for the differences in the clinical spectra of the disease between earlier and current malaria series.
In most malaria series, low rates of clinical jaundice have been reported. In Eastern Uganda, for instance, in 2012 Olupot-Olupot and colleagues reported that jaundice accounted for 26.7% of children with severe malaria [5], and now we report a higher proportion 205/300 (68.3%) in the same settings. Therefore, we can only suggest that massive haemolysis is the underlying cause given the unique triad of severe anaemia, jaundice and BWF reported in our earlier studies [19] and the current data.
In Eastern Uganda, cerebral malaria has consistently remained low [19]. In the current data, we found cerebral malaria in 10/137(6.0%) despite the older age of children with severe malaria in this study population. On other features, we note a reversal in the rates for respiratory distress. We currently report that respiratory distress of 6.7% was much lower than in earlier series in the same settings [5, 19, 26]. The main difference is age, and it is well documented that respiratory distress is common in severe malaria in younger children [5].
On the outcomes, 52/251(22.3%) study participants had prolonged hospitalisation, similar to other series previously reported, participants with acidosis (P = 0.041), were more likely to have prolonged hospitalisation. The overall mortality was 6.3%, higher than the 4.6% reported in Tanzania [31] but lower than earlier reports by Olupot-Olupot et al. in the same settings [5, 19, 26].
We conducted a retrospective review of adherence to malaria case management at this study site. Based on a convenience sample of children discharged between June 2021 and March 2022. Poor adherence to malaria treatment resulted in higher morality at 40/147 (27%) [32]. The difference with the current data could be attributed to several factors and the review period corresponded to the tail end of the COVID-19 lockdown. During this period, it was observed that few, but mainly very critically sick children accessed referral services at this facility, few health workers were working, and drug supplies were erratic as an effect of COVID-19. This effect of COVID-19 on malaria outcomes has been reported previously [2]. Compared to pre-COVID-19 mortality of 4.6% in Tanzania in 2012 [31] and 63/662 (9.5%) for a similar study done May, 5 2011 until April ,30 2012 in Eastern Uganda [5], we think a mortality of 6.3% in the first post-COVID-19 lockdown year is an indication of improvement attributable to recovery in the case management process. In addition, the older average age of the study participants in the current data and high rates (> 50%) of pre-admission antimalarial treatment may have contributed to the observed outcomes.
Overall, the factors that were independently associated with mortality in this study acidosis (P = 0.027), impaired consciousness (P = 0.022). These same factors have been reportedly associated with poor outcomes in African children with severe malaria [33–35]. In addition, there were many runaways (self-discharges) that we could not ascertain outcomes in their community. Against this background, we think the data on outcomes is incomplete. However, we have demonstrated that in the post-COVID-19 malaria epidemic, the clinical spectrum of disease is unique and mortality outcomes remain poor.