Severe falciparum malaria in children: current understanding of pathophysiology and supportive treatment.

Blood and bone marrow changes in malaria

The pathophysiology of the anaemia of falciparum malaria is both complex and multifactorial, and results in a condition which is a major cause of mortality and morbidity in patients, especially children and pregnant women, living in malarial endemic areas. The importance of anaemia as a cause of death in malaria may well be underestimated because of difficulty in diagnosis, especially where parasitaemia may be low and the clinical picture may be confused with other causes of anaemia. Two clinical presentations predominate: severe acute malaria in which anaemia supervenes, and severe anaemia in patients in whom there have been repeated attacks of malaria. The major mechanisms are those of red cell destruction and decreased red cell production. Potential causes of haemolysis include loss of infected cells by rupture or phagocytosis, removal of uninfected cells due to antibody sensitization or other physicochemical membrane changes, and increased reticuloendothelial activity, particularly in organs such as the spleen. Decreased production results from marrow hypoplasia seen in acute infections, and dyserythropoiesis, a morphological appearance, which in functional terms results in ineffective erythropoiesis. The role of parvovirus B19 as a possible cause of bone marrow aplasia in a few cases is postulated. Finally, there is now evidence which points to genetic factors, HLA associated, which may protect against the development of malarial anaemia and which has become common in areas endemic for malaria.

Anaemia of Plasmodium falciparum malaria

Severe anaemia is an important cause of morbidity and mortality in African children, but the causes, particularly falciparum malaria, are difficult to determine. We assessed the contribution of falciparum malaria to anaemia in Kenyan children by clinical examination and measurement of parasitaemia and haemoglobin (Hb) concentration in 559 children in the community and in 2412 children admitted to Kilifi district hospital during a 2-year period. We also attempted to characterize severe malarial anaemia by examining the causes and pathophysiology of anaemia in 101 children admitted with Hb concentration < or = 50 g/l during a 1-year period. Plasmodium falciparum infection was associated with reduced Hb concentration in children in the community and in those admitted to hospital irrespective of diagnosis. Falciparum malaria was the primary cause in 46 cases (46%) of severe anaemia admitted to hospital. There was no difference in the frequency of haemolysis or dyserythropoiesis in the children with malarial anaemia and those with anaemia from other causes, such as iron deficiency or sickle cell disease. The mortality rate in the children with severe malarial anaemia was 8.6% compared with 3.6% in children with severe anaemia due to other causes. Falciparum malaria does not present with a characteristic clinical or haematological picture, but is a major cause of the morbidity and mortality in children with severe anaemia who live on the Kenyan coast, a malaria endemic area.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-3156.1997.d01-238.x

Severe anaemia in children living in a malaria endemic area of Kenya.

Decreased erythropoiesis and increased clearance of both parasitized and noninfected erythrocytes both contribute to the pathogenesis of anemia in falciparum malaria. Erythrocytes with reduced deformability are more likely to be cleared from the circulation by the spleen, a process that is augmented in acute malaria. Using a laser diffraction technique, we measured red blood cell (RBC) deformability over a range of shear stresses and related this to the severity of anemia in 36 adults with severe falciparum malaria. The RBC deformability at a high shear stress of 30 Pa, similar to that encountered in the splenic sinusoids, showed a significant positive correlation with the nadir in hemoglobin concentration during hospitalization (r = 0.49, P < 0.002). Exclusion of five patients with microcytic anemia strengthened this relationship (r = 0.64, P < 0.001). Reduction in RBC deformability resulted mainly from changes in unparasitized erythrocytes. Reduced deformability of uninfected erythrocytes at high shear stresses and subsequent splenic removal of these cells may be an important contributor to the anemia of severe malaria.

Red blood cell deformability as a predictor of anemia in severe falciparum malaria.

The direct antiglobulin test (DAT) was performed on 134 Gambian children with P. falciparum malaria. 52 children had a positive DAT and in 25 this was due to the adherence of C3 to their red cells whilst 13 had sensitization with IgG as well as C3. Sensitization with C4 alone or associated with IgG and/or C3 was only rarely found. The haemoglobin levels and reticulocyte counts were not significantly different in patients with a positive DAT from those with a negative DAT. The children with positive IgG DAT, however, were of a significantly older age group and had significantly higher parasitaemias at presentation than children with complement components only or with a negative DAT. In vitro assay of phagocytosis by peripheral blood monocytes (PBM) showed that PBM from malarious patients were less active in phagocytosis than normal male adult Caucasian PBM. Neither PBM from malarious patients nor normal adult Caucasians PBM showed phagocytosis of cells from DAT positive malarious children. The same in vitro assay was used to test for the presence of opsonizing anti-schizont antibodies in the sera of these children and in adult Gambians. This revealed the presence of a schizont specific opsonizing antibody in the sera of adult Gambians and in the sera of children with a positive DAT due to IgG but not in sera of patients with a negative IgG. These findings indicate that a positive IgG DAT in malaria does not necessarily lead to excess haemolysis of non-parasitized red cells. The presence of a schizont opsonizing antibody, leading to in vitro phagocytosis, in the sera of children with a positive DAT and in sera from adult Gambians indicates a relationship between the development of the positive DAT and acquisition of protective malarial immunity.

S. Abdalla

Papers

The direct antiglobulin test in P. falciparum malaria.