Cytokine Profiles at Birth Predict Malaria Severity during Infancy

BACKGROUND: Severe malaria risk varies between individuals, and most of this variation remains unexplained. Here, we examined the hypothesis that cytokine profiles at birth reflect inter-individual differences that persist and influence malaria parasite density and disease severity throughout early childhood. METHODS AND FINDINGS: Cytokine levels (TNF-α, IFN-γ, IL-1β, IL-4, IL-5, IL-6 and IL-10) were measured at birth (cord blood; N=783) and during subsequent routine follow-up visits (peripheral blood) for children enrolled between 2002 and 2006 into a birth cohort in Muheza, Tanzania. Children underwent blood smear and clinical assessments every 2-4 weeks, and at the time of any illness. Cord blood levels of all cytokines were positively correlated with each other (Spearman’s rank correlation). Cord levels of IL-1β and TNF-α (but not other cytokines) correlated with levels of the same cytokine measured at routine visits during early life (P < 0.05). Higher cord levels of IL-1β but not TNF-α were associated with lower parasite densities during infancy (P=0.003; Generalized Estimating Equation (GEE) method), with an average ~40% reduction versus children with low cord IL-1β levels, and with decreased risk of severe malaria during follow-up (Cox regression): adjusted hazard ratio (95% CI) 0.60 (0.39-0.92), P = 0.02. CONCLUSION: IL-1β levels at birth are related to future IL-1β levels as well as the risk of severe malaria in early life. The effect on severe malaria risk may be due in part to the effect of inflammatory cytokines to control parasite density

Placental Malaria is associated with reduced early life weight development of affected children independent of low birth weight

<p>Abstract</p> <p>Background</p> <p>Infection with <it>Plasmodium falciparum </it>during pregnancy contributes substantially to the disease burden in both mothers and offspring. Placental malaria may lead to intrauterine growth restriction or preterm delivery resulting in low birth weight (LBW), which, in general, is associated with increased infant morbidity and mortality. However, little is known about the possible direct impact of the specific disease processes occurring in PM on longer term outcomes such as subsequent retarded growth development independent of LBW.</p> <p>Methods</p> <p>In an existing West-African cohort, 783 healthy infants with a birth weight of at least 2,000 g were followed up during their first year of life. The aim of the study was to investigate if <it>Plasmodium falciparum </it>infection of the placenta, assessed by placental histology, has an impact on several anthropometric parameters, measured at birth and after three, six and 12 months using generalized estimating equations models adjusting for moderate low birth weight.</p> <p>Results</p> <p>Independent of LBW, first to third born infants who were exposed to either past, chronic or acute placental malaria during pregnancy had significantly lower weight-for-age (-0.43, 95% CI: -0.80;-0.07), weight-for-length (-0.47, 95% CI: -0.84; -0.10) and BMI-for-age z-scores (-0.57, 95% CI: -0.84; -0.10) compared to infants born to mothers who were not diagnosed with placental malaria (p = 0.019, 0.013, and 0.012, respectively). Interestingly, the longitudinal data on histology-based diagnosis of PM also document a sharp decline of PM prevalence in the Sukuta cohort from 16.5% in 2002 to 5.4% in 2004.</p> <p>Conclusions</p> <p>It was demonstrated that PM has a negative impact on the infant's subsequent weight development that is independent of LBW, suggesting that the longer term effects of PM have been underestimated, even in areas where malaria transmission is declining.</p

C5a Enhances Dysregulated Inflammatory and Angiogenic Responses to Malaria In Vitro: Potential Implications for Placental Malaria

Placental malaria (PM) is a leading cause of maternal and infant mortality. Although the accumulation of parasitized erythrocytes (PEs) and monocytes within the placenta is thought to contribute to the pathophysiology of PM, the molecular mechanisms underlying PM remain unclear. Based on the hypothesis that excessive complement activation may contribute to PM, in particular generation of the potent inflammatory peptide C5a, we investigated the role of C5a in the pathogenesis of PM in vitro and in vivo.Using primary human monocytes, the interaction between C5a and malaria in vitro was assessed. CSA- and CD36-binding PEs induced activation of C5 in the presence of human serum. Plasmodium falciparum GPI (pfGPI) enhanced C5a receptor expression (CD88) on monocytes, and the co-incubation of monocytes with C5a and pfGPI resulted in the synergistic induction of cytokines (IL-6, TNF, IL-1beta, and IL-10), chemokines (IL-8, MCP-1, MIP1alpha, MIP1beta) and the anti-angiogenic factor sFlt-1 in a time and dose-dependent manner. This dysregulated response was abrogated by C5a receptor blockade. To assess the potential role of C5a in PM, C5a plasma levels were measured in malaria-exposed primigravid women in western Kenya. Compared to pregnant women without malaria, C5a levels were significantly elevated in women with PM.These results suggest that C5a may contribute to the pathogenesis of PM by inducing dysregulated inflammatory and angiogenic responses that impair placental function

The Association between Malaria and Iron Status or Supplementation in Pregnancy: A Systematic Review and Meta-Analysis

Introduction Malaria prevention and iron supplementation are associated with improved maternal and infant outcomes. However, evidence from studies in children suggests iron may adversely modify the risk of malaria. We reviewed the evidence in pregnancy of the association between malaria and markers of iron status, iron supplementation or parenteral treatment. Methods and Findings We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Global Health Library, and the Malaria in Pregnancy library to identify studies that investigated the association between iron status, iron treatment or supplementation during pregnancy and malaria. Thirty one studies contributed to the analysis; 3 experimental and 28 observational studies. Iron supplementation was not associated with an increased risk of P. falciparum malaria during pregnancy or delivery in Africa (summary Relative Risk = 0.89, 95% Confidence Interval (CI) 0.66–1.20, I2 = 78.8%, 5 studies). One study in Asia reported an increased risk of P. vivax within 30 days of iron supplementation (e.g. adjusted Hazard Ratio = 1.75, 95% CI 1.14–2.70 for 1–15 days), but not after 60 days. Iron deficiency (based on ferritin and C-reactive protein) was associated with lower odds for malaria infection (summary Odds Ratio = 0.35, 0.24–0.51, I2 = 59.2%, 5 studies). With the exception of the acute phase protein ferritin, biomarkers of iron deficiency were generally not associated with malaria infection. Conclusions Iron supplementation was associated with a temporal increase in P vivax, but not with an increased risk of P. falciparum; however, data are insufficient to rule out the potential for an increased risk of P. falciparum. Iron deficiency was associated with a decreased malaria risk in pregnancy only when measured with ferritin. Until there is more evidence, it is prudent to provide iron in combination with malaria prevention during pregnancy