Endemic Burkitt lymphoma: a complication of asymptomatic malaria in sub-Saharan Africa based on published literature and primary data from Uganda, Tanzania, and Kenya

Abstract

Background: Endemic Burkitt lymphoma (eBL) is an aggressive B cell non-Hodgkin lymphoma associated with antigenic stimulation from Plasmodium falciparum malaria. Whether eBL risk is related to malaria parasite density is unknown. To address this issue, children with eBL, asymptomatic and clinical malaria, as a surrogate of malaria parasite density, were assessed.

Methods: Malaria-related laboratory results (parasite density, haemoglobin, platelet count, and white cell count [WBC]) count) were compiled for 4019 eBL cases and 80,532 subjects evaluated for asymptomatic malaria or clinical malaria (severe malaria anaemia, hyperparasitaemia, cerebral malaria, malaria prostration, moderate malaria, and mild malaria) in 21 representative studies published in Africa (mostly East Africa) and 850 eBL cases and 2878 controls with primary data from the Epidemiology of Burkitt Lymphoma in East African Children and Minors (EMBLEM) case-control study in Uganda, Tanzania, and Kenya. The average values of malaria-related laboratory results were computed by condition and trends across single-year age groups were assessed using regression and spline models.

Results: Overall, malaria infection or malaria was diagnosed in 37,089 of children compiled from the literature. Children with eBL and asymptomatic parasitaemia/antigenaemia, but not those with clinical malaria, were closest in their mean age (age 7.1-7.2 vs. 7.4-9.8 years), haemoglobin level (10.0-10.4 vs. 11.7-12.3 g/dL), malaria parasite density (2800 vs. 1827-7780 parasites/µL), platelet count (347,000-353,000 vs. 244,000-306,000 platelets/µL), and WBC count (8180-8890 vs. 7100-7410 cells/µL). Parasite density in these two groups peaked between four to five years, then decreased steadily thereafter; conversely, haemoglobin showed a corresponding increase with age. Children with clinical malaria were markedly different: all had an average age below 5 years, had dramatically elevated parasite density (13,905-869,000 parasites/µL) and dramatically decreased platelet count (< 159,000 platelets/µL) and haemoglobin (< 7 g/dL).

Conclusions: eBL and asymptomatic parasitaemia/antigenaemia, but not clinical malaria, were the most similar conditions with respect to mean age and malaria-related laboratory results. These results suggest that children with asymptomatic parasitaemia/antigenaemia may be the population at risk of eBL.

Keywords: Burkitt lymphoma (BL); East Africa; Epstein-barr virus (EBV); Malaria complications; Plasmodium falciparum.

Fig. 1

Flowchart of the stepwise evaluation of different malaria conditions

Fig. 2

Flowchart showing the pipeline used to search and evaluate literature with relevant data

Fig. 3

Multi-panel graph showing the mean values of malaria-related laboratory measures (parasite density, haemoglobin, platelet count, and white cell count) plotted according to the mean age of the malaria condition using data obtained from the literature and the EMBLEM Study. Dotted lines mark cut-off value for hyper-parasitaemia (a), for mild (11.0 g/dL), moderate (7.5 g/dL), and severe anaemia (< 5.0 g/dL) (b), for the lower range of platelet counts (c), and for elevated white blood cell count (d)

Fig. 4

Multi-panel graph showing the modelled and raw age-specific mean values of malaria-related laboratory measures (parasite density, haemoglobin, platelet count, and white cell count) in eBL cases and children without eBL in the EMBLEM Study

Fig. 5

Discrete and overlapping malaria conditions based on mean age and biomarker levels (see text)