Abstract
BackgroundDiagnosis of malaria in pregnancy is problematic due to the low sensitivity of conventional diagnostic tests (rapid diagnostic test and microscopy), which is exacerbated due to low peripheral parasite densities, and lack of clinical symptoms. In this study, six potential biomarkers to support malaria diagnosis in pregnancy were evaluated.MethodsBlood samples were collected from pregnant women at antenatal clinic visits and at delivery. Microscopy and real-time PCR were performed for malaria diagnosis and biomarker analyses were performed by ELISA (interleukin 10, IL-10; tumor necrosis factor-α, TNF-α; soluble tumor necrosis factor receptor II, sTNF-RII; soluble fms-like tyrosine kinase 1, sFlt-1; leptin and apolipoprotein B, Apo-B). A placental biopsy was collected at delivery to determine placental malaria.ResultsIL-10 and sTNF-RII were significantly higher at all time-points in malaria-infected women (p < 0.001). Both markers were also positively associated with parasite density (p < 0.001 and p = 0.003 for IL-10 and sTNF-RII respectively). IL-10 levels at delivery, but not during pregnancy, were negatively associated with birth weight. A prediction model was created using IL-10 and sTNF-RII cut-off points. For primigravidae the model had a sensitivity of 88.9% (95%CI 45.7–98.7%) and specificity of 83.3% (95% CI 57.1–94.9%) for diagnosing malaria during pregnancy. For secundi- and multigravidae the sensitivity (81.8% and 56.5% respectively) was lower, while specificity (100.0% and 94.3% respectively) was relatively high. Sub-microscopic infections were detected in 2 out of 3 secundi- and 5 out of 12 multigravidae.ConclusionsThe combination of biomarkers IL-10 and sTNF-RII have the potential to support malaria diagnosis in pregnancy. Additional markers may be needed to increase sensitivity and specificity, this is of particular importance in populations with sub-microscopic infections or in whom other inflammatory diseases are prevalent.
Highlights
Diagnosis of malaria in pregnancy is problematic due to the low sensitivity of conventional diagnostic tests, which is exacerbated due to low peripheral parasite densities, and lack of clinical symptoms
Procedures and design This study aimed to identify host biomarkers that can be used to support malaria diagnosis
There were no differences in infection rates at enrollment between cases and controls, both by real-time polymerase chain reaction (PCR) (48.7 versus 46.9%, p = 0.799) and microscopy (30.4 versus 32.1%, p = 0.798)
Summary
Diagnosis of malaria in pregnancy is problematic due to the low sensitivity of conventional diagnostic tests (rapid diagnostic test and microscopy), which is exacerbated due to low peripheral parasite densities, and lack of clinical symptoms. The adult population in malaria endemic areas has acquired (partial) immunity against the parasite due to repeated exposure throughout their lives, suppressing clinical symptoms [5, 6] This immunity is for a great part directed against surface antigens of the P. falciparum-infected erythrocyte. During malaria in pregnancy a unique surface antigen on P. falciparum-infected erythrocytes is expressed, against which immunity is lacking [7] This surface antigen is the variant surface antigen 2-chrondroitin sulphate A (VAR2CSA) antigen, a member of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family of surface antigens. With this pregnancy specific antigen, P. falciparum parasites can sequester in the placenta by binding to chondroitin sulphate A on syncytiotrophoblasts, thereby evading splenic clearance [8, 9]. This is because antibodies against VAR2CSA antigens are low or absent in primigravidae who are exposed to the antigen for the first time, while women generally acquire VAR2CSA antibodies during successive pregnancies [7, 11, 15]
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