Auto-antibodies targeting brain antigens in Plasmodium falciparum infected patients as biomarkers of Cerebral Malaria

International audiencen.

Sulphadoxine/pyrimethamine versus amodiaquine for treating uncomplicated childhood malaria in Gabon: A randomized trial to guide national policy

<p>Abstract</p> <p>Background</p> <p>In Gabon, following the adoption of amodiaquine/artesunate combination (AQ/AS) as first-line treatment of malaria and of sulphadoxine/pyrimethamine (SP) for preventive intermittent treatment of pregnant women, a clinical trial of SP versus AQ was conducted in a sub-urban area. This is the first study carried out in Gabon following the WHO guidelines.</p> <p>Methods</p> <p>A random comparison of the efficacy of AQ (10 mg/kg/day × 3 d) and a single dose of SP (25 mg/kg of sulphadoxine/1.25 mg/kg of pyrimethamine) was performed in children under five years of age, with uncomplicated falciparum malaria, using the 28-day WHO therapeutic efficacy test. In addition, molecular genotyping was performed to distinguish recrudescence from reinfection and to determine the frequency of the <it>dhps </it>K540E mutation, as a molecular marker to predict SP-treatment failure.</p> <p>Results</p> <p>The day-28 PCR-adjusted treatment failures for SP and AQ were 11.6% (8/69; 95% IC: 5.5–22.1) and 28.2% (20/71; 95% CI: 17.7–38.7), respectively This indicated that SP was significantly superior to AQ (<it>P </it>= 0.019) in the treatment of uncomplicated childhood malaria and for preventing recurrent infections. Both treatments were safe and well-tolerated, with no serious adverse reactions recorded. The <it>dhps </it>K540E mutation was not found among the 76 parasite isolates tested.</p> <p>Conclusion</p> <p>The level of AQ-resistance observed in the present study may compromise efficacy and duration of use of the AQ/AS combination, the new first-line malaria treatment. Gabonese policy-makers need to plan country-wide and close surveillance of AQ/AS efficacy to determine whether, and for how long, these new recommendations for the treatment of uncomplicated malaria remain valid.</p

Self-Reactivities to the Non-Erythroid Alpha Spectrin Correlate with Cerebral Malaria in Gabonese Children

BACKGROUND: Hypergammaglobulinemia and polyclonal B-cell activation commonly occur in Plasmodium sp. infections. Some of the antibodies produced recognize self-components and are correlated with disease severity in P. falciparum malaria. However, it is not known whether some self-reactive antibodies produced during P. falciparum infection contribute to the events leading to cerebral malaria (CM). We show here a correlation between self-antibody responses to a human brain protein and high levels of circulating TNF alpha (TNFα), with the manifestation of CM in Gabonese children. METHODOLOGY: To study the role of self-reactive antibodies associated to the development of P. falciparum cerebral malaria, we used a combination of quantitative immunoblotting and multivariate analysis to analyse correlation between the reactivity of circulating IgG with a human brain protein extract and TNFα concentrations in cohorts of uninfected controls (UI) and P. falciparum-infected Gabonese children developing uncomplicated malaria (UM), severe non-cerebral malaria (SNCM), or CM. RESULTS/CONCLUSION: The repertoire of brain antigens recognized by plasma IgGs was more diverse in infected than in UI individuals. Anti-brain reactivity was significantly higher in the CM group than in the UM and SNCM groups. IgG self-reactivity to brain antigens was also correlated with plasma IgG levels and age. We found that 90% of CM patients displayed reactivity to a high-molecular mass band containing the spectrin non-erythroid alpha chain. Reactivity with this band was correlated with high TNFα concentrations in CM patients. These results strongly suggest that an antibody response to brain antigens induced by P. falciparum infection may be associated with pathogenic mechanisms in patients developing CM

Etude des anticorps auto-réactifs produits au cours de l'infection par Plasmodium falciparum (implication dans la protection ou la pathogenèse du neuropaludisme)

Les études antérieures traitant du rôle des auto-anticorps dans la protection ou la pathogenèse du paludisme grave sont peu nombreuses. Notre approche consiste a analyser l auto-réactivité globale des IgG et des IgE au cours de l infection par P. falciparum, chez des patients vivant en zone d endémie palustre repartis en cinq groupes: patients non infectés par P. falciparum (NI), porteurs asymptomatiques (IA), accès palustre simple (AS), accès palustre graves sans atteinte neurologique (AG), neuropaludisme (NP). Nos résultats mettent en évidence une réponse auto-réactive des IgG associée aux concentrations plasmatiques d IL-10 chez les IA, dont les IgE reconnaissaient particulièrement les protéines 14-3-3 et -spectrine non érythrocytaire; alors que la réponse pathogène est corrélée aux taux plasmatiques du TNF chez les patients développant un NP. Chez ces derniers, l auto-réactivité particulièrement dirigée contre l -spectrine cérébrale, était également associée aux concentrations de TNF . Ces observations suggèrent que la réponse auto-immune induite au cours de l infection par P. falciparum est impliquée aussi bien dans la protection contre la maladie que dans la pathogenèse du neuropaludisme. Les IgE anti-14-3-3 pourraient jouer un rôle important dans la protection contre la maladie, et la réactivité anti- -spectrine associée aux taux de TNF pourrait être un marqueur de gravité du paludisme.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Total and functional parasite specific IgE responses in <it>Plasmodium falciparum</it>-infected patients exhibiting different clinical status

Abstract Background There is an increase of serum levels of IgE during Plasmodium falciparum infections in individuals living in endemic areas. These IgEs either protect against malaria or increase malaria pathogenesis. To get an insight into the exact role played by IgE in the outcome of P. falciparum infection, total IgE levels and functional anti-parasite IgE response were studied in children and adults, from two different endemic areas Gabon and India, exhibiting either uncomplicated malaria, severe non cerebral malaria or cerebral malaria, in comparison with control individuals. Methodology and results Blood samples were collected from controls and P. falciparum-infected patients before treatment on the day of hospitalization (day 0) in India and, in addition, on days 7 and 30 after treatment in Gabon. Total IgE levels were determined by ELISA and functional P. falciparum-specific IgE were estimated using a mast cell line RBL-2H3 transfected with a human Fcε RI α-chain that triggers degranulation upon human IgE cross-linking. Mann Whitney and Kruskall Wallis tests were used to compare groups and the Spearman test was used for correlations. Total IgE levels were confirmed to increase upon infection and differ with level of transmission and age but were not directly related to the disease phenotype. All studied groups exhibited functional parasite-specific IgEs able to induce mast cell degranulation in vitro in the presence of P. falciparum antigens. Plasma IgE levels correlated with those of IL-10 in uncomplicated malaria patients from Gabon. In Indian patients, plasma IFN-γ , TNF and IL-10 levels were significantly correlated with IgE concentrations in all groups. Conclusion Circulating levels of total IgE do not appear to correlate with protection or pathology, or with anti-inflammatory cytokine pattern bias during malaria. On the contrary, the P. falciparum-specific IgE response seems to contribute to the control of parasites, since functional activity was higher in asymptomatic and uncomplicated malaria patients than in severe or cerebral malaria groups.</p

Are Energy and Protein Intakes Lower Than Requirements in Older Adults? An Urgent Issue in Hospitals and Nursing Homes

Energy and protein intakes lower than requirements are associated with worsening health outcomes. Here we set out to evaluate gaps between energy and protein intakes and requirements in older adults in hospitals and in nursing homes (NH). A cross-sectional study included 360 inpatients and residents aged 75 years and older in two acute care wards; i.e., a multidisciplinary care unit (MCU) and a geriatric care unit (GCU), a geriatric rehabilitation unit (GRU), and two NH. Intakes were measured for three days. Requirements were based on French National Health Authority recommendations. Energy and protein intakes were under the minimum requirement of 30 kcal/kg/day and 1.2 g/kg/day in 89.5% and 100% of MCU patients, respectively, 75.5% and 64.2% of GCU patients, 92.7% and 90.9% of GRU patients, and 83.8% and 83.8 of NH residents. Intake-to-requirement gaps were not significantly associated with malnutrition, except in the GCU group where non-malnourished patients had higher energy gaps than malnourished patients. Intakes fell dramatically short of requirements in older adults in both hospital and NH settings irrespective of malnutrition status. A new paradigm based on a patient-centered approach should be developed to adapt meals served in hospital and in NH

Correlation of plasma soluble Fas ligand levels with severe anaemia in Gabonese and Indian plasmodium falciparum malaria patients

A comparative analysis of the plasma concentrations of soluble Fas-L (sFas-L) and their correlation with hemoglobin levels and malaria severity was carried out in cohorts of P. falciparum-infected patients from Gabon and India. Young patients from Gabon had plasma levels of sFas-L that increased with disease severity. In contrast, in Indian adults plasmatic sFas-L levels were more elevated in UM and SNCM than in CM. In both Gabonese and Indian subjects, sFas-L concentrations were negatively correlated with haemoglobin rates, which were lower in SNCM than in UM or CM in both populations. We also observed a positive correlation between the level of plasmatic sFas-L with the level of circulating IL-2 receptor in the Indian patients. All these observations suggest a paradoxical role of sFas-L in CM pathogenesis when comparing Gabonese and Indian patients, while a similar role was found to be associated with severe anaemia

Handgrip strength as a valid practical tool to screen early-onset sarcopenia in acute care wards: a first evaluation

International audienc