Our large retrospective study provides a contribution to the descriptions of paediatric BWF in malaria high transmission settings in Eastern Uganda. The prevalence rate of BWF of 13% reported in our study was comparable to earlier descriptions of BWF in malaria endemic settings (1, 2, 31, 39–41).
The higher frequency of BWF in children aged > 5 years, 682/1241 (55.0%) compared to ≤ 5 years, 559/1241(45.0%); [95% CI (0.41–0.59); P = 0.0002], observed in this study was consistent with previous reports from Kinshasa in DRC, a similarly holo- hyperendemic malaria setting (31). This has led to questioning the link between BWF and malaria. If malaria was a direct driving factor, then children aged > 5 years who are expected to have acquired malaria immunity (1, 18, 42, 43), would be resilient to BWF. On the other hand, if it was an innate factor then either more of the ≤ 5year old children or a similar proportion across the various age strata would have been observed with BWF. Therefore, greater understanding is still needed to elucidate the aetiopathophysiology of BWF.
We found the clinical features in childhood BWF were similar to the adult BWF case definitions (10), the cases typically presented with passing dark urine (1241/1241 (100%)), high grade fever (332/1241 (26.8%)), clinical jaundice (369/1241(29.7%)), pallor (742/1241(59.8%)) and abdominal pain (494/1241(39.8%)). Severity features reported in this study including unconsciousness (5(0.4%)), convulsions (72/1241(5.8)), prostration (231/1241(18.6%)), severe pallor/anaemia (330/1241(26.6%)) and respiratory distress/acidotic breathing (16/1241(1.2%)) seem to be similar to those reported in severe malaria series given the fact that BWF is also a form of severe malaria (38, 44–47). Of specific significance was the finding of abdominal pains (494/1241(39.8%)) and tenderness (120/1241(9.7%)) in this study population. Few data, if at all any, have described this phenomenon in relation to severe malaria or specifically BWF in African children. We think the ischaemic process following sequestration of parasitized red blood cells (48, 49) in the small blood vessels supplying mesentery may possibly lead to mesenteric infarction and thus the abdominal pain/tenderness.
A number of speculations have been made to try and explain high prevalence of BWF in these settings. For instance, the coincidence of increased cases of BWF with a roll out of Artemesinin Combination Therapies (ACTs) for control of malaria has postulated but has not been well studied (34). Elsewhere, lumefantrine, a key drug in first line ACTs has been implicated in the causation of BWF, but descriptions in African children have not been done. Similarly, the role of repeated exposure to other antimarials (18, 31, 39), and blood transfusions in the causation of BWF in children have also not been explored in these settings. High rates of index and repeat blood transfusions, in a phenomenon similar to isoimmunisation in mother-baby situation may be underlying in some of the massive haemolysis observed in these populations, but needs further research. Conversely, whereas past epidemiological studies have indicated that the interaction between host response to repeated malarial attacks, use of antimalarials, and possibly glucose-6-phosphate dehydrogenase (G6PD) deficiency are trigger factors (50), more recent descriptions in Eastern Uganda do not associate the phenomenon to G6PD deficiency(34). Alternatively, other scholars have argued that the possible cause is likely a recent change in the malaria parasite population towards a strain with a greater propensity towards causing BWF (35, 36).
The seasonal trend of BWF admissions in 2018 showed one peak in the months of July to September. Eastern Uganda receives moderate rainfall with annual rainfall averages ranging from 1100-1200mm and this is distributed between two seasons (March to July and September to November) (51). A malaria surveillance study done in all the regions of Uganda between 2015 to 2019 showed the highest peaks in monthly trends in regional malaria incidence rates were in June–July, highest in June, 2017 (Range: 13.4– 95.6 cases per 1000) and July, 2019 and the lowest troughs in February–March of each calendar year(52). Teso region home to one of the study sites (Soroti RRH) was one of the regions that persistently recorded the highest monthly incidence rates across the entire study duration (52). Possibly, the malaria incidence rate peaks of June – July of 2018 may have coincided with the peak in BWF admissions reported in this study between July and September suggesting either similar risk factors or a cause-effect relationship between BWF and malaria in this setting.
Understanding paediatric BWF in Africa is very important for informing treatment options and plans. Currently, there are no specific treatment and prevention remedies for BWF. According to the Uganda clinical guidelines, all cases are treated as severe malaria and respective supportive treatment such as blood transfusion is given (53), which is plausible. However, with no specific management guidelines for BWF, inconsistences exist in patient care owing to the differences in clinician expertise/training, experience and acumen. This explains the variability in treatment reported in this study. The inappropriate use of antimalarial and antibiotics especially second line cephalosporin (ceftriaxone 616/1241 (49.6%)) poses a threat of antimicrobial resistance. Surprisingly, a considerable number of patients 388/1241 (31.3%) were treated with steroids mainly parenteral hydrocortisone 370/1241 (29.8%) this increases the likelihood of steroid induced side effects. Therefore, there is need to develop adjuvant treatment specific to the pathophysiology of BWF to contribute to better outcomes. In addition, the high frequency of blood transfusions among children with BWF suggests efforts and strategies should be focused on preventing severe anaemia in the post discharge period including the use of haematinics and insecticide treated mosquito nets (54, 55).
This retrospective study design had some limitations. Mainly, the diagnosis of BWF was done clinically using the Hillmen urine colour chart. No real-time laboratory investigations were done to elucidate the aetiopathophysiology of BWF in children including acute kidney injury, one of the unique features of BWF in children (56). There was no data on post discharge status and as such, repeat or late onset BWF which usually occurs after 28days was not reported, yet these data are important in understanding of the complete disease picture. Nonetheless, this study was pragmatic and done at two high volume tertiary hospitals. It made use of a large sample size, which imparts significant strength to the study findings and was based on the diagnostic capabilities of health facilities in resource-limited settings used for routine care. Therefore, this study highlights the socio-demographic characteristics, clinical features and routine care of BWF patients at two tertiary hospitals in Eastern Uganda. We describe these data in Eastern Uganda ahead of a Phase I/II trial on use of paracetamol for acute kidney injury in children with BWF (PARIST; ISRCTN84974248).