Among children with severe malaria, comorbidities were common, frequently fatal and appeared to be biologically associated with true severe malaria disease, rather than alternative causes of disease in asymptomatically parasitized children.
An association between HIV infection and malaria is established in adults [13
] but not among children in malaria endemic areas. Cohort studies in Zaire during the 1980's found no association between HIV infection and malaria in young children.[27
] In South Africa, in an area of unstable transmission and consequently a high fraction of parasitemic disease attributable to malaria, HIV was associated with severe malaria, but not with parasite density.[12
] The study was too small to identify an association with mortality. More recently in Malawi, HIV infection was reported in 16% of children admitted with clinically defined severe malaria and there was no association with death.[5
] This prevalence appears higher than expected among children in the community, but no formal comparison was made.
In a malaria endemic area, we found that HIV infection was associated with admission with true severe malaria among children age above one year. This, and higher parasite density suggest a failure of acquired immunity, as has been proposed among adults.[26
] We found no evidence that HIV was associated with increased risk of malaria in infants, who have not yet acquired natural immunity to severe malaria. We may have underestimated the effects of HIV since deaths were over-represented among those not tested. An odds ratio of nearly 10 represents a profound effect of untreated HIV on severe malaria. HIV diagnosis is important in this context, because of the effectiveness of cotrimoxazole prophylaxis in preventing malaria.[29
Protein-energy malnutrition is associated with many life-threatening infections. However, early reports of effects on malaria suggested it might be protective.[10
] More recent studies suggest that malnutrition is a susceptibility factor.[6
] We found malnutrition was far commoner among true severe malaria cases than in the community. Some weight loss may occur with acute illness, but we believe this is unlikely to account for our observations.[32
] An odds of 6.5 for fatal admission, concords with estimates modelled from pooled data by Caulfield et. al
] Our findings strongly support the view that improving nutrition is likely to reduce malaria deaths.
There are several reports of IBI among children with severe malaria, especially due to Salmonella species.[2
] Some report no association between invasive IBI and mortality among children with severe malaria, suggesting IBI may be benign in this context. [5
] We found no evidence that severe malaria was associated with Streptococcus pneumoniae
and Haemophilus influenzae
. Rather, non-Typhoidal Salmonellae and other Gram negative organisms occurred more commonly than expected, and were associated with fatality. This is in contrast to the findings relating to mortality from Malawi and Gambia, [5
] and is likely to reflect our different approach of not excluding children with evidence of other infections from being classified as cases of severe malaria.
We did not collect data on bacteremia among healthy children in the community. However, among children attending the outpatient department at our hospital, we previously found a prevalence of bacteremia of 2%,[34
] and less than 1% amongst those without fever (A Brent, personal communication). We therefore expect the prevalence of bacteremia among healthy children in the community to be <1%, considerably lower than we found amongst children with severe malaria and high parasite density, where almost all disease if due to malaria.
Most IBI among children with severe malaria was not in the context of malnutrition or HIV. It is conceivable that IBI might result in loss of immunological control of an asymptomatic parasitemia. However, we believe that IBI is more likely to have occurred as a direct consequence of severe malaria. As well as immunoparesis,[35
] sequestration in the microvasculature of the gut[37
] and at other barriers may permit bacterial invasion. If so, some IBIs might be prevented by interventions that prevent severe malaria.
Could these apparent associations be simply reflect bias towards admission to hospital of children who have both parasitemia and co-morbidity? At health centers in our area, blood film microscopy was rarely available. Furthermore, evidence from East Africa suggests that microscopy has limited influence on practice.[39
] Once at hospital, we believe that parasitemia was unlikely to influence admission because the children were severely ill, clearly requiring admission. There was no HIV testing of children and little voluntary counseling and testing of adults at the time of the study. The presence of IBI would not have been known to parents or referring health workers. We therefore think that for HIV infection and IBI, bias is unlikely. Malnutrition is visible to parents and health workers, and could therefore have influenced presentation to hospital in either direction. Our experience is that parents seek care because their malnourished children are sick, rather than for malnutrition per se
. However, it is impossible to exclude significant bias in relation to malnutrition.
It is possible that the age and location weighted attributable fraction calculation did not accurately represent admissions. However, associations were strong at parasite densities ≥50,000/μl where almost all severe disease was attributable to malaria, reflecting the fact that these parasite densities very rarely occurred at any age or location in the community surveys, but were common among admissions.
By considering the fraction of severe disease attributable to malaria, we found that HIV infection (above one year of age), malnutrition and IBI occur more commonly among hospitalized children with true severe malaria than expected by chance. We conclude that these important comorbidities are true biological associations of severe malaria, rather than simply alternative reasons for admission in asymptomatically parasitized children.