This case-control study of childhood Burkitt lymphoma in Malawi has focused on the potential role played by three different infectious diseases in children: HIV, EBV and malaria. The positive association between Burkitt lymphoma and HIV found here is similar to that reported from a recent study conducted in Uganda 
. Most other reports addressing this issue in African children have been case series or based on routinely collected data and have not been able to adjust for important confounding factors such as child's age, sex and residence 
. HIV may be acting as an indirect co-factor in the etiology of Burkitt lymphoma by reducing the effectiveness of T cell based immune response to oncogenic viruses 
or by reducing the EBV-specific T cell function, leading to proliferation of EBV infected B cells and eventual tumor formation 
. These findings suggest that reducing HIV incidence, or treatment of HIV with antiretroviral drugs, may lead to a reduction in the incidence of Burkitt lymphoma in children. However, the number of HIV positive cases of Burkitt lymphoma reported to date is relatively small and considerable uncertainty therefore remains about the magnitude of association between HIV and Burkitt lymphoma among African children.
In accordance with results from previous epidemiological studies from sub-Saharan Africa, we have clear evidence to suggest that the risk of Burkitt lymphoma increases with increasing titers of antibodies against EBV in the child 
. Because Burkitt lymphoma is a systemic disease and because we have used a case-control design it is possible that the raised antibody titers against EBV were a result of the tumor rather than the cause of the disease (reverse causality). Nevertheless, the results of our case-control study are similar to those from a prospective investigation 
In contrast, previous evidence for an association between Burkitt lymphoma and malaria has been largely ecological 
. This case-control study also provides more direct evidence of an association between malaria antibodies in the child and risk of Burkitt lymphoma comparable to those recently reported from a similar study in Uganda 
. While anti-malarial antibodies are not thought to reflect current infection, but rather previous exposure, uncertainty still remains about the longevity of these antibodies post-infection 
There is clear evidence from clinical trials that use of bed nets reduces mortality from malaria among children 
and our findings raise the possibility that this preventive measure against malaria may have potential to decrease the risk of Burkitt lymphoma in African children. Reported use of household insecticides and mosquito nets were associated with a lower risk of Burkitt lymphoma in Uganda, lending support to the view that malaria prevention may impact on the incidence of this childhood cancer 
. However, it is important to note that our results were based on a small subset of cases and controls and could be explained by the effects of residual confounding by socio-economic status. In Malawi, widespread distribution of subsidized bed nets began in 2002, although the prevalence of use has been reported to be higher in urban households compared to those in rural areas 
. No decline in the frequency of Burkitt lymphoma has yet been reported.
In accordance with the Uganda case-control study 
, we also found evidence to suggest that EBV and malaria act jointly as risk factors for Burkitt lymphoma. Compared with those who had low levels of both EBV and malaria antibodies, our data suggest that children with high levels of both antibodies have 13 times the risk of developing the tumor. While EBV viral load in blood has been previously reported to be highest in children from malaria endemic areas 
, the specific nature of the relationship between EBV and malaria is unclear. Two hypotheses have been suggested to explain this. First, malaria leads to reactivation and proliferation of EBV latently infected B cells and second, that malaria may also lead to suppression of EBV-specific T cell immunity, which allows EBV to proliferate 
. The apparently synergistic effect suggests that infection with both EBV and malaria may be needed to facilitate tumor formation.
That the odds of Burkitt lymphoma increased with the number of children alive reported by mothers may be linked to exposure of the index child to EBV infection and re-infection from other family members 
. Further, the odds of Burkitt lymphoma increased significantly with increasing number of self-reported maternal lifetime sexual partners and an association with high EBV antibody titers in the mother was suggested. Although based on small numbers, these findings may suggest that mothers of Burkitt lymphoma cases are exposed to EBV (or perhaps multiple strains of EBV) through sexual contact 
. The mother may then pass on EBV to the child, predisposing tumor development. However, further analysis did not show any correlation between number of self-reported lifetime sexual partners and levels of EBV titers in the mother (results not shown), nor was there an association between prevalence of maternal syphilis (as a marker of sexual behavior) and risk of Burkitt lymphoma in the child. Consequently, the significance of the findings relating to maternal sexual and reproductive history is not clear.
It is possible that some case and control children might have been misclassified, 75% of cases and 74% of controls had a histological verification of diagnosis. This is a relatively high rate of verification for an African series 
. As described previously, the jaw was the most common site for primary tumor presentation, and the mean age at diagnosis was 7.1 years, also similar to other studies 
In conclusion, this case-control study of Burkitt lymphoma conducted among children in Malawi strengthens the evidence associating the tumor with HIV, EBV and malaria. Improved control of malaria, as well as the future development of EBV vaccines 
could play an important role in protecting African children from this common and often fatal malignancy.