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Complement Activation in Ghanaian Children With Severe Plasmodium Falciparum Malaria

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Complement Activation in Ghanaian Children With Severe Plasmodium Falciparum Malaria

Gideon K Helegbe et al. Malar J.

Abstract

Background: Severe anaemia (SA), intravascular haemolysis (IVH) and respiratory distress (RD) are severe forms of Plasmodium falciparum malaria, with RD reported to be of prognostic importance in African children with malarial anaemia. Complement factors have been implicated in the mechanism leading to excess anaemia in acute P. falciparum infection.

Methods: The direct Coombs test (DCT) and flow cytometry were used to investigate the mean levels of RBC-bound complement fragments (C3d and C3balphabeta) and the regulatory proteins [complement receptor 1 (CD35) and decay accelerating factor (CD55)] in children with discrete clinical forms of P. falciparum malaria. The relationship between the findings and clinical parameters including coma, haemoglobin (Hb) levels and RD were investigated.

Results: Of the 484 samples tested, 131(27%) were positive in DCT, out of which 115/131 (87.8%) were positive for C3d alone while 16/131 (12.2%) were positive for either IgG alone or both. 67.4% of the study population were below 5 years of age and DCT positivity was more common in this age group relative to children who were 5 years or older (Odds ratio, OR = 3.8; 95%CI, 2.2-6.7, p < 0.001). DCT correlated significantly with RD (beta = -304, p = 0.006), but multiple regression analysis revealed that, Hb (beta = -0.341, p = 0.012) and coma (beta = -0.256, p = 0.034) were stronger predictors of RD than DCT (beta = 0.228, p = 0.061). DCT was also not associated with IVH, p = 0.19, while spleen size was inversely correlated with Hb (r = -402, p = 0.001). Flow cytometry showed similar mean fluorescent intensity (MFI) values of CD35, CD55 and C3balphabeta levels on the surfaces of RBC in patients and asymptomatic controls (AC). However, binding of C3balphabeta correlated significantly with CD35 or CD55 (p < 0.001).

Conclusion: These results suggest that complement activation contributed to anaemia in acute childhood P. falciparum malaria, possibly through induction of erythrophagocytosis and haemolysis. In contrast to other studies, this study did not find association between levels of the complement regulatory proteins, CD35 and CD55 and malarial anaemia. These findings suggest that complement activation could also be involved in the pathogenesis of RD but larger studies are needed to confirm this finding.

Figures

Figure 1
Figure 1
Clinical categories of children with severe malaria. Children admitted to the paediatric ward of the Korle-Bu teaching hospital, Accra, with severe malaria (SM). Symptoms of SM included coma (score ≤ 3 on the Blantyre coma scale), severe anaemia (SA) (haemoglobin [Hb] < 5.0 g/dL), intravascular haemoloysis (IVH, evidence of haemoglobinuria), and respiratory distress (RD). The number of children showing the various symptoms, as well as the mean (SEM) Hb (in g/dL) and parasitaemia (Para, in parasites per μL) plus prevalence of a direct Coombs' test (DCT) is shown. NP, no patient.
Figure 2
Figure 2
DCT results compared with flow cytometry using anti-C3d. RBC suspensions from 30 DCT positive and negative SM patients were stained with ethidium bromide and monoclonal antibodies to detect surface-bound C3d. Association between DCT results and flow cytometry results for C3d are shown by scatter plots with regression line. MFI, mean fluorescence intensity. DCT was graded as accordingly as +4 (complete agglutination), +3 (several large agglutinates, few cells), +2 (large agglutinates in a sea of smaller clumps and free cells), +1 (many small agglutinates), 0 (no sign of agglutination).
Figure 3
Figure 3
Association of CD55 and CD35 with C3αβ in children with severe malaria. Correlation between C3bαβ and complement regulatory proteins (CD35 (complement receptor type 1) and CD55 (decay accelerating factor)) measured by flow cytometry on surfaces of RBC from 30 children with SM. Solid line: C3bαβ vs CD55, r = 0.777, p < 0.001; dotted regression line: C3bαβ vs CD35, r = 0.624, p < 0.001. MFI, mean fluorescence intensity.

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