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Background: Maternal malaria may restrict foetal growth. Impaired utero-placental blood flow due to malaria infection may cause hypoxia-induced altered skeletal muscle fibre type distribution in the offspring, which may contribute to insulin resistance and impaired glucose metabolism. This study assessed muscle fibre distribution 20 years after placental and/or peripheral in-utero malaria exposure compared to no exposure, i.e., PPM+, PM+, and M-, respectively. Methods: We traced 101 men and women offspring of mothers who participated in a malaria chemosuppression study in Muheza, Tanzania. Of 76 eligible participants, 50 individuals (29 men and 21 women) had skeletal muscle biopsy taken from m. vastus lateralis in the right leg. As previously reported, fasting and 30 min post-oral glucose challenge plasma glucose values were higher, and insulin secretion disposition index was lower, in the PPM+ group. Aerobic capacity (fitness) was estimated by an indirect VO2max test on a stationary bicycle. Muscle fibre sub-type (myosin heavy chain, MHC) distribution was analysed, as were muscle enzyme activities (citrate synthase (CS), 3-hydroxyacyl-CoA dehydrogenase, myophosphorylase, phosphofructokinase, lactate dehydrogenase, and creatine kinase activities. Between-group analyses were adjusted for MHC-I %. Results: No differences in aerobic capacity were found between groups. Despite subtle elevations of plasma glucose levels in the PPM+ group, there was no difference in MHC sub-types or muscle enzymatic activities between the malaria-exposed and non-exposed groups. Conclusion: The current study did not show differences in MHC towards glycolytic sub-types or enzymatic activity across the sub-groups. The results support the notion of the mild elevations of plasma glucose levels in people exposed to placental malaria in pregnancy being due to compromised pancreatic insulin secretion rather than insulin resistance.
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Glicemia , Resistência à Insulina , Gravidez , Masculino , Adulto , Humanos , Feminino , Glicemia/metabolismo , Filhos Adultos , Placenta , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologiaRESUMO
INTRODUCTION: Fetal malaria exposure may lead to intrauterine growth restriction and increase the risk of developing diabetes and cardiovascular diseases in adulthood. We investigated the extent to which fetal peripheral and placental malaria exposure impacts insulin sensitivity and secretion, body composition and cardiometabolic health 20 years after in utero malaria exposure. RESEARCH DESIGN AND METHODS: We traced 101 men and women in Muheza district, Tanga region whose mothers participated in a malaria chemosuppression during a pregnancy study in 1989-1992. All potential participants were screened for malaria, hepatitis B and HIV to ascertain study eligibility. Seventy-six individuals (44 men, 32 women) were included in this cohort study. The participants underwent a thorough clinical examination including anthropometric measurements, ultrasound scanning for abdominal fat distribution, blood pressure, 75 g oral glucose tolerance test, an intravenous glucose tolerance test followed by a hyperinsulinemic euglycemic clamp and a submaximal exercise test. RESULTS: Offspring exposed to placental malaria during pregnancy had significantly higher 30-minute plasma post-glucose load levels, but no significant difference in peripheral insulin resistance, insulin secretion or other cardiometabolic traits compared with non-exposed individuals. CONCLUSIONS: Using the state-of-the-art euglycemic clamp technique, we were unable to prove our a priori primary hypothesis of peripheral insulin resistance in young adult offspring of pregnancies affected by malaria. However, the subtle elevations of plasma glucose might represent an early risk marker for later development of type 2 diabetes if combined with aging and a more obesogenic living environment.
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Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Malária , Adulto , Filhos Adultos , Estudos de Coortes , Feminino , Humanos , Malária/epidemiologia , Masculino , Placenta , Gravidez , Tanzânia , Adulto JovemRESUMO
BACKGROUND: Preeclampsia is a serious pregnancy-related disease which may lead to adverse health effects to the mother and fetus. Besides many publications on the association of red cell distribution width (RDW) and preeclampsia, there has been no published meta-analysis. This necessitated the present systemic review and met-analysis to assess the RDW in relation to preeclampsia. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline was followed. Relevant published studies were searched in PubMed, Cochrane library, Google scholar, Scopus, Embase and CINAHL using the term "Preeclampsia OR eclampsia AND red cell distribution width OR red blood cells). Modified Newcastle - Ottawa quality assessment scale was used for critical appraisal of retrieved studies. Pooled Meta logistic regression was computed using OpenMeta Analyst software. Subgroup and meta-regression methods were performed to analyse the heterogeneity. RESULTS: Eleven case control studies were included in the met-analyses with a total of 951 cases (preeclampsia) and 2024 controls. The mean (SD) of the RDW level was significantly higher in women with preeclampsia compared to controls [15.10 (2.48) % vs. 14.26(1.71) %, P < 0.001]. The mean difference was 0.85, 95% CI = 0.26-1.43. Due to a high heterogeneity (I2 = 90.45, P < 0.001), the continuous random effect model was used.Eight studies compared RDW level in the mild (N = 360) with severe cases (N = 354) of preeclampsia. The RDW level was significantly higher in women with severe preeclampsia compared to those with mild preeclampsia [15.37 (2.48) % vs. 14.037(1.79) %, P < 0.001]. The mean difference was 1.07, 95% CI = 0.45-1.70. Since there is a high heterogeneity [I2 = 76.67, P < 0.001], the continuous random effect model was used.Through the met-regression model, except for the region of the study (P < 0.001), none of investigated variables (age, parity, quality of the study) was significantly associated with the investigated heterogeneity. The outliers (3studies) were removed to reduce the heterogeneity. The pooled meta-analysis of the remaining 8 studies showed a significant difference in the RDW between preeclamptic women compared with the controls. The mean difference was 0.93, 95% CI = 0.56-1.31, P < 0.001. Because of heterogeneity [I2 = 69.6, P = 0.002], the continuous random effect model was used. CONCLUSION: RDW level was significantly higher in women with preeclampsia compared to controls. Similarly, women with severe preeclampsia had significantly higher RDW than those with the mild form.
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AIMS: Gestational Diabetes Mellitus (GDM) remains a neglected cause of maternal and foetal morbidity and mortality in developing countries exacerbated by limited screening and management strategies. This study aimed to understanding how the RCH health system works in Tanzania, so as to provide opportunity for improving GDM screening and management. METHODS: A questionnaire was administered to facility staff and physical performance observed in 30 randomly selected public RCH facilities. RESULTS: Deficiencies identified included limited understaffing, late booking at ANC, and limited screening for GDM due to lack of equipment and supplies. Most women (96%) attending ANCs and postnatal care (87%) were managed at respective facilities with only 12% and 22% respectively being referred to higher levels of care. Facility staff were less trained or received fewer refresher courses in diabetes (0-5%), hypertension (4-6%), and other NCDs (0-16%) compared to training in PMCTC (39%), management of postpartum bleeding (31%) and HIV/AIDs (31%). CONCLUSION: Diabetes during pregnancy is rarely sought in public health facilities and its management is suboptimal. Training and refresher courses of staff in diabetes and hypertension should be uplifted and health systems should be strengthened to improve capacity and capability of facilities for better quality of care.
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Diabetes Gestacional/diagnóstico , Diabetes Gestacional/terapia , Instalações de Saúde/normas , Planejamento em Saúde/normas , Programas de Rastreamento/normas , Países em Desenvolvimento , Diabetes Gestacional/epidemiologia , Feminino , Humanos , Incidência , Gravidez , Tanzânia/epidemiologiaRESUMO
BACKGROUND: Information regarding the safety and efficacy of artemisinin combination treatments for malaria in pregnant women is limited, particularly among women who live in sub-Saharan Africa. METHODS: We conducted a multicenter, randomized, open-label trial of treatments for malaria in pregnant women in four African countries. A total of 3428 pregnant women in the second or third trimester who had falciparum malaria (at any parasite density and regardless of symptoms) were treated with artemether-lumefantrine, amodiaquine-artesunate, mefloquine-artesunate, or dihydroartemisinin-piperaquine. The primary end points were the polymerase-chain-reaction (PCR)-adjusted cure rates (i.e., cure of the original infection; new infections during follow-up were not considered to be treatment failures) at day 63 and safety outcomes. RESULTS: The PCR-adjusted cure rates in the per-protocol analysis were 94.8% in the artemether-lumefantrine group, 98.5% in the amodiaquine-artesunate group, 99.2% in the dihydroartemisinin-piperaquine group, and 96.8% in the mefloquine-artesunate group; the PCR-adjusted cure rates in the intention-to-treat analysis were 94.2%, 96.9%, 98.0%, and 95.5%, respectively. There was no significant difference among the amodiaquine-artesunate group, dihydroartemisinin-piperaquine group, and the mefloquine-artesunate group. The cure rate in the artemether-lumefantrine group was significantly lower than that in the other three groups, although the absolute difference was within the 5-percentage-point margin for equivalence. The unadjusted cure rates, used as a measure of the post-treatment prophylactic effect, were significantly lower in the artemether-lumefantrine group (52.5%) than in groups that received amodiaquine-artesunate (82.3%), dihydroartemisinin-piperaquine (86.9%), or mefloquine-artesunate (73.8%). No significant difference in the rate of serious adverse events and in birth outcomes was found among the treatment groups. Drug-related adverse events such as asthenia, poor appetite, dizziness, nausea, and vomiting occurred significantly more frequently in the mefloquine-artesunate group (50.6%) and the amodiaquine-artesunate group (48.5%) than in the dihydroartemisinin-piperaquine group (20.6%) and the artemether-lumefantrine group (11.5%) (P<0.001 for comparison among the four groups). CONCLUSIONS: Artemether-lumefantrine was associated with the fewest adverse effects and with acceptable cure rates but provided the shortest posttreatment prophylaxis, whereas dihydroartemisinin-piperaquine had the best efficacy and an acceptable safety profile. (Funded by the European and Developing Countries Clinical Trials Partnership and others; ClinicalTrials.gov number, NCT00852423.).
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BACKGROUND: Information regarding the safety and efficacy of artemisinin combination treatments for malaria in pregnant women is limited, particularly among women who live in sub-Saharan Africa. METHODS: We conducted a multicenter, randomized, open-label trial of treatments for malaria in pregnant women in four African countries. A total of 3428 pregnant women in the second or third trimester who had falciparum malaria (at any parasite density and regardless of symptoms) were treated with artemether-lumefantrine, amodiaquine-artesunate, mefloquine-artesunate, or dihydroartemisinin-piperaquine. The primary end points were the polymerase-chain-reaction (PCR)-adjusted cure rates (i.e., cure of the original infection; new infections during follow-up were not considered to be treatment failures) at day 63 and safety outcomes. RESULTS: The PCR-adjusted cure rates in the per-protocol analysis were 94.8% in the artemether-lumefantrine group, 98.5% in the amodiaquine-artesunate group, 99.2% in the dihydroartemisinin-piperaquine group, and 96.8% in the mefloquine-artesunate group; the PCR-adjusted cure rates in the intention-to-treat analysis were 94.2%, 96.9%, 98.0%, and 95.5%, respectively. There was no significant difference among the amodiaquine-artesunate group, dihydroartemisinin-piperaquine group, and the mefloquine-artesunate group. The cure rate in the artemether-lumefantrine group was significantly lower than that in the other three groups, although the absolute difference was within the 5-percentage-point margin for equivalence. The unadjusted cure rates, used as a measure of the post-treatment prophylactic effect, were significantly lower in the artemether-lumefantrine group (52.5%) than in groups that received amodiaquine-artesunate (82.3%), dihydroartemisinin-piperaquine (86.9%), or mefloquine-artesunate (73.8%). No significant difference in the rate of serious adverse events and in birth outcomes was found among the treatment groups. Drug-related adverse events such as asthenia, poor appetite, dizziness, nausea, and vomiting occurred significantly more frequently in the mefloquine-artesunate group (50.6%) and the amodiaquine-artesunate group (48.5%) than in the dihydroartemisinin-piperaquine group (20.6%) and the artemether-lumefantrine group (11.5%) (P<0.001 for comparison among the four groups). CONCLUSIONS: Artemether-lumefantrine was associated with the fewest adverse effects and with acceptable cure rates but provided the shortest post-treatment prophylaxis, whereas dihydroartemisinin-piperaquine had the best efficacy and an acceptable safety profile. (Funded by the European and Developing Countries Clinical Trials Partnership and others; ClinicalTrials.gov number, NCT00852423.).
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Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Malária Falciparum/tratamento farmacológico , Complicações Parasitárias na Gravidez/tratamento farmacológico , Adulto , África , Amodiaquina/uso terapêutico , Antimaláricos/efeitos adversos , Combinação Arteméter e Lumefantrina , Artemisininas/efeitos adversos , Combinação de Medicamentos , Etanolaminas/uso terapêutico , Feminino , Fluorenos/uso terapêutico , Humanos , Plasmodium falciparum/genética , Plasmodium falciparum/isolamento & purificação , Reação em Cadeia da Polimerase , Gravidez , Resultado da Gravidez , Quinolinas/uso terapêutico , Adulto JovemRESUMO
BACKGROUND: Asymptomatic and symptomatic malaria during pregnancy has consequences for both mother and her offspring. Unfortunately, there is insufficient information on the safety and efficacy of most antimalarials in pregnancy. Indeed, clinical trials assessing antimalarial treatments systematically exclude pregnancy for fear of teratogenicity and embryotoxicity. The little available information originates from South East Asia while in sub-Saharan Africa such information is still limited and needs to be provided. DESIGN: A Phase 3, non-inferiority, multicentre, randomized, open-label clinical trial on safety and efficacy of 4 ACT when administered during pregnancy was carried out in 4 African countries: Burkina Faso, Ghana, Malawi and Zambia. This is a four arm trial using a balanced incomplete block design. Pregnant women diagnosed with malaria are randomised to receive either amodiaquine-artesunate (AQ-AS), dihydroartemisinin-piperaquine (DHA-PQ), artemether-lumefantrine (AL), or mefloquine-artesunate (MQAS). They are actively followed up until day 63 post-treatment and then monthly until 4-6 weeks post-delivery. The offspring is visited at the time of the first birthday. The primary endpoint is treatment failure (PCR adjusted) at day 63 and safety profiles. Secondary endpoints included PCR unadjusted treatment failure up to day 63, gametocyte carriage, Hb changes, placenta malaria, mean birth weight and low birth weight. The primary statistical analysis will use the combined data from all 4 centres, with adjustment for any centre effects, using an additive model for the response rates. This will allow the assessment of all 6 possible pair-wise treatment comparisons using all available data. DISCUSSION: The strength of this trial is the involvement of several African countries, increasing the generalisability of the results. In addition, it assesses most ACTs currently available, determining their relative '-value-' compared to others. The balanced incomplete block design was chosen because using all 4-arms in each site would have increased complexity in terms of implementation. Excluding HIV-positive pregnant women on antiretroviral drugs may be seen as a limitation because of the possible interactions between antiretroviral and antimalarial treatments. Nevertheless, the results of this trial will provide the evidence base for the formulation of malaria treatment policy for pregnant women in sub-Saharan Africa.
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Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Malária/tratamento farmacológico , Complicações Parasitárias na Gravidez/tratamento farmacológico , Adulto , Amodiaquina/efeitos adversos , Amodiaquina/uso terapêutico , Antimaláricos/efeitos adversos , Combinação Arteméter e Lumefantrina , Artemisininas/efeitos adversos , Artesunato , Peso ao Nascer/efeitos dos fármacos , Burkina Faso , Combinação de Medicamentos , Etanolaminas/efeitos adversos , Etanolaminas/uso terapêutico , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Fluorenos/efeitos adversos , Fluorenos/uso terapêutico , Seguimentos , Gana , Humanos , Recém-Nascido , Malaui , Mefloquina/efeitos adversos , Mefloquina/uso terapêutico , Placentação/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Quinolinas/efeitos adversos , Quinolinas/uso terapêutico , ZâmbiaRESUMO
Artemether-lumefantrine is a fixed-dose combination containing 20 mg artemether/120 mg lumefantrine per tablet, used for treating uncomplicated malaria in patients weighing ≥5 kg. It is the first artemisinin-based combination registered in some European countries and in the USA. It is marketed in Europe as Riamet(®) (Novartis, Basel, Switzerland) and in malaria-endemic countries as Coartem(®) (Novartis). Safety concerns prevent early pregnancy usage, while limited postmarketing surveillance has delayed safety assessment and policy development. Large clinical studies, postmarketing surveillance and pharmacovigillance ongoing in some countries may soon bridge safety issues. Fatty diet requirements for optimal absorption, pregnancy-induced changes in pharmacokinetics, pregnancy-related anorexia and food taboos, and emerging reduced parasite sensitivity to artemisinin, challenges optimal artemether-lumefantrine dosing and efficacy during pregnancy. This evaluation addresses drug usage, safety concerns following early exposure, implications for changed pharmacokinetics and reduced parasite susceptibility. Clinical-use updates and strategies to address some knowledge gaps including key operational research are discussed.
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Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Etanolaminas/uso terapêutico , Fluorenos/uso terapêutico , Malária/tratamento farmacológico , Complicações Parasitárias na Gravidez/tratamento farmacológico , Antimaláricos/efeitos adversos , Antimaláricos/farmacologia , Combinação Arteméter e Lumefantrina , Artemisininas/efeitos adversos , Artemisininas/farmacologia , Combinação de Medicamentos , Etanolaminas/efeitos adversos , Etanolaminas/farmacologia , Feminino , Fluorenos/efeitos adversos , Fluorenos/farmacologia , Infecções por HIV/complicações , Humanos , Malária/complicações , Gravidez , Trimestres da GravidezRESUMO
The antifolate sulphadoxine-pyrimethamine (SP) has been used in the intermittent prevention of malaria in pregnancy (IPTp). SP is an ideal choice for IPTp, however, as resistance of Plasmodium falciparum to SP increases, data are accumulating that SP may no longer provide benefit in areas of high-level resistance. Probenecid was initially used as an adjunctive therapy to increase the blood concentration of penicillin; it has since been used to augment concentrations of other drugs, including antifolates. The addition of probenecid has been shown to increase the treatment efficacy of SP against malaria, suggesting that the combination of probenecid plus SP may prolong the useful lifespan of SP as an effective agent for IPTp. Here, the literature on the pharmacokinetics, adverse reactions, interactions and available data on the use of these drugs in pregnancy is reviewed, and the possible utility of an SP-probenecid combination is discussed. This article concludes by calling for further research into this potentially useful combination.
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Antimaláricos/administração & dosagem , Quimioprevenção/métodos , Malária Falciparum/prevenção & controle , Complicações Infecciosas na Gravidez/prevenção & controle , Probenecid/administração & dosagem , Pirimetamina/administração & dosagem , Sulfadoxina/administração & dosagem , Antimaláricos/efeitos adversos , Antimaláricos/farmacocinética , Quimioprevenção/efeitos adversos , Combinação de Medicamentos , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Feminino , Humanos , Malária Falciparum/tratamento farmacológico , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Probenecid/efeitos adversos , Probenecid/farmacocinética , Pirimetamina/efeitos adversos , Pirimetamina/farmacocinética , Sulfadoxina/efeitos adversos , Sulfadoxina/farmacocinética , Resultado do TratamentoRESUMO
BACKGROUND: Iron supplementation may increase malaria morbidity and mortality, but the effect of naturally occurring variation in iron status on malaria risk is not well studied. METHODS: A total of 785 Tanzanian children living in an area of intense malaria transmission were enrolled at birth, and intensively monitored for parasitemia and illness including malaria for up to 3 years, with an average of 47 blood smears. We assayed plasma samples collected at routine healthy-child visits, and evaluated the impact of iron deficiency (ID) on future malaria outcomes and mortality. RESULTS: ID at routine, well-child visits significantly decreased the odds of subsequent parasitemia (23% decrease, P < .001) and subsequent severe malaria (38% decrease, P = .04). ID was also associated with 60% lower all-cause mortality (P = .04) and 66% lower malaria-associated mortality (P = .11). When sick visits as well as routine healthy-child visits are included in analyses (average of 3 iron status assays/child), ID reduced the prevalence of parasitemia (6.6-fold), hyperparasitemia (24.0-fold), and severe malaria (4.0-fold) at the time of sample collection (all P < .001). CONCLUSIONS: Malaria risk is influenced by physiologic iron status, and therefore iron supplementation may have adverse effects even among children with ID. Future interventional studies should assess whether treatment for ID coupled with effective malaria control can mitigate the risks of iron supplementation for children in areas of malaria transmission.
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Deficiências de Ferro , Malária Falciparum/epidemiologia , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: Millions of African women receive sulfadoxine-pyrimethamine (SP) as intermittent preventive treatment during pregnancy (IPTp) to avoid poor outcomes that result from malaria. However, parasites resistant to SP are widespread in parts of Africa, and IPTp may perversely exacerbate placental infections that contain SP-resistant parasites. METHODS: The study used a cross-sectional design. We determined IPTp use in a delivery cohort of 880 pregnant women in Muheza, Tanzania, by report and by plasma sulfa measurements, and we examined its effects on maternal and fetal delivery outcomes. RESULTS: In the overall cohort, IPTp was not associated with decreased odds of placental malaria or with increased mean maternal hemoglobin or mean birth weight. Unexpectedly, IPTp was associated with decreased cord hemoglobin level and increased risk of fetal anemia, which may be related to in utero SP exposure. CONCLUSIONS: IPTp does not improve overall pregnancy outcomes in Muheza, Tanzania, where SP-resistant parasites predominate and may increase the odds of fetal anemia. As parasite resistance increases in a community, the overall effect of IPTp may transition from net benefit to neutral or net harm.
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Antimaláricos/administração & dosagem , Quimioprevenção/métodos , Resistência a Medicamentos , Malária/prevenção & controle , Plasmodium/efeitos dos fármacos , Complicações Infecciosas na Gravidez/prevenção & controle , Pirimetamina/administração & dosagem , Sulfadoxina/administração & dosagem , Adulto , Antimaláricos/farmacologia , Estudos Transversais , Combinação de Medicamentos , Feminino , Humanos , Lactente , Recém-Nascido , Malária/parasitologia , Masculino , Gravidez , Complicações Infecciosas na Gravidez/parasitologia , Pirimetamina/farmacologia , Sulfadoxina/farmacologia , Tanzânia , Resultado do TratamentoRESUMO
BACKGROUND: Plasmodium falciparum-infected erythrocytes sequester in the placenta and elicit an inflammatory response that is harmful to both fetus and mother. Histologic measurements during placental malaria might provide surrogate end points for interventional trials, but existing histologic schemes capture limited complexity and are not consistently used among study sites. METHODS: Using frozen-section histologic evaluation in Tanzania (high-transmission area), we established a novel grading scheme to separately quantify inflammation and pigment deposition during placental malaria (n = 102). To generalize this method, formalin-fixed, paraffin-embedded placental samples from Karen women in Thailand (low-transmission area) were selected from among women with documented antenatal parasitemia who were near term (n = 18). RESULTS: In the Tanzanian cohort, the inflammation and pigment-deposition scores were independently associated with birth weight, and the inflammation score was associated with chemokine levels. In the smaller cohort from Thailand, both inflammation and pigment scores were associated with birth weight, and the pigment score had an inverse trend with the number of antenatal clinic visits. CONCLUSIONS: This semiquantitative pathological grading scheme is simple to implement and captures information that is associated with outcomes in Asia and Africa; therefore, it should facilitate the comparison and standardization of results among clinical trials across areas of differing endemicity.
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Malária Falciparum/patologia , Doenças Placentárias/patologia , Doenças Placentárias/parasitologia , Placenta/patologia , Placenta/parasitologia , Plasmodium falciparum , Complicações Parasitárias na Gravidez/patologia , Estudos de Coortes , Eritrócitos/parasitologia , Feminino , Humanos , Gravidez , Tanzânia , TailândiaRESUMO
Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a variant antigen expressed on the surface of malaria-infected erythrocytes. PfEMP1 attaches to the vascular lining and allows infected erythrocytes to avoid filtration through the spleen. Each parasite genome encodes about 60 different PfEMP1 variants, each PfEMP1 comprises several domains in its extracellular region, and the PfEMP1 repertoire in different parasites contains domain types that are serologically cross-reactive. In this longitudinal study, we followed 672 children living in an area of high malaria transmission during the first years of life and compared the acquisitions of antibodies to 32 Duffy-binding ligand-like (DBL) domains representing different types. For each child, we determined whether an antibody response to each domain was acquired before, after, or at the same time as responses to each of the other domains. We next used this information to calculate population-level odds ratios to measure the odds that antibodies to a given domain were acquired before antibodies to other domains. Odds ratios for 269 of the 496 possible domain combinations were statistically significant. Thus, the sequence in which individuals acquire antibodies to different PfEMP1 domains is ordered, and children in areas of endemicity first acquire antibodies to particular PfEMP1 domains encoded by the so-called group A and B/A var genes. The results imply that anti-PfEMP1 antibodies effectively structure PfEMP1 expression and play a major role in limiting parasite multiplication in the blood.
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Anticorpos Antiprotozoários/sangue , Variação Genética , Malária Falciparum/imunologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/química , Proteínas de Protozoários/imunologia , Adolescente , Adulto , Animais , Eritrócitos/parasitologia , Feminino , Humanos , Lactente , Recém-Nascido , Malária Falciparum/parasitologia , Pessoa de Meia-Idade , Plasmodium falciparum/metabolismo , Estrutura Terciária de Proteína , Proteínas de Protozoários/genética , Tanzânia , Adulto JovemRESUMO
BACKGROUND: Plasmodium falciparum placental malaria (PM) contributes to 10,000 maternal deaths due to severe anemia (SA) each year in Africa, primarily among primigravid women who are most susceptible. Increased levels of proinflammatory cytokines like TNF-alpha are associated with maternal anemia in first time mothers but not in other women. Here we aimed to identify additional changes in the plasma proteome associated with pregnancy malaria that may contribute to the development of malaria-related maternal anemia. PRINCIPAL FINDINGS: A semi-quantitative mass spectrometry approach was used to compare the relative abundance of plasma proteins in anemic versus non-anemic women with PM. Levels of 24 proteins differed significantly between anemic and non-anemic primigravidae, including several lipid metabolism proteins and molecular transport proteins involved in the acute phase response signaling network. These differences were not observed in multigravid women who enjoy specific immunity that protect them from PM. In a confirmatory study of a larger cohort of primigravid women, levels of the lipid metabolism protein Apolipoprotein (Apo)-AI were significantly lower in PM+ women with SA. CONCLUSIONS: Apo-AI levels are significantly lower in severely anemic primigravidae with PM, and ApoA1 levels positively correlate with hemoglobin levels in primigravid but not multigravid women. Apo-AI is known to have anti-inflammatory effects, and thus Apo-AI reductions may contribute to the inflammatory processes that result in SA.
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Apolipoproteína A-I/sangue , Malária Falciparum/sangue , Complicações Parasitárias na Gravidez/sangue , Adulto , Proteínas Sanguíneas/metabolismo , Cromatografia Líquida , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Malária Falciparum/complicações , Gravidez , Proteoma , Espectrometria de Massas em TandemRESUMO
Nitric oxide (NO) mediates host resistance to severe malaria and other infectious diseases. NO production and mononuclear cell expression of the NO producing enzyme-inducible nitric oxide synthase (NOS2) have been associated with protection from severe falciparum malaria. The purpose of this study was to identify single nucleotide polymorphisms (SNPs) and haplotypes in the NOS2 promoter, to identify associations of these haplotypes with malaria severity and to test the effects of these polymorphisms on promoter activity. We identified 34 SNPs in the proximal 7.3 kb region of the NOS2 promoter and inferred NOS2 promoter haplotypes based on genotyping 24 of these SNPs in a population of Tanzanian children with and without cerebral malaria. We identified 71 haplotypes; 24 of these haplotypes comprised 82% of the alleles. We determined whether NOS2 promoter haplotypes were associated with malaria severity in two groups of subjects from Dar es Salaam (N = 185 and N = 250) and in an inception cohort of children from Muheza-Tanga, Tanzania (N = 883). We did not find consistent associations of NOS2 promoter haplotypes with malaria severity or malarial anemia, although interpretation of these results was potentially limited by the sample size of each group. Furthermore, cytokine-induced NOS2 promoter activity determined using luciferase reporter constructs containing the proximal 7.3 kb region of the NOS2 promoter and the G-954C or C-1173T SNPs did not differ from NOS2 promoter constructs that lacked these polymorphisms. Taken together, these studies suggest that the relationship between NOS2 promoter polymorphisms and malaria severity is more complex than previously described.
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Haplótipos/genética , Malária/genética , Óxido Nítrico Sintase Tipo II/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , Alelos , Sequência de Bases , Linhagem Celular Tumoral , Criança , Pré-Escolar , Frequência do Gene , Heterogeneidade Genética , Genótipo , Humanos , Lactente , Quênia , Desequilíbrio de Ligação , Malária/patologia , Dados de Sequência Molecular , Mutação , Análise de Sequência de DNA , Homologia de Sequência do Ácido Nucleico , Índice de Gravidade de Doença , TanzâniaRESUMO
Plasmodium falciparum-infected erythrocytes bind endothelial receptors to sequester in vascular beds, and binding to ICAM1 has been implicated in cerebral malaria. Binding to ICAM1 may be mediated by the variant surface antigen family PfEMP1: for example, 6 of 21 DBLbetaC2 domains from the IT4 strain PfEMP1 repertoire were shown to bind ICAM1, and the PfEMP1 containing these 6 domains are all classified as Group B or C type. In this study, we surveyed binding of ICAM1 to 16 DBLbetaC2 domains of the 3D7 strain PfEMP1 repertoire, using a high throughput Bioplex assay format. Only one DBL2betaC2 domain from the Group A PfEMP1 PF11_0521 showed strong specific binding. Among these 16 domains, DBL2betaC2(PF11_0521) best preserved the residues previously identified as conserved in ICAM1-binding versus non-binding domains. Our analyses further highlighted the potential role of conserved residues within predominantly non-conserved flexible loops in adhesion, and, therefore, as targets for intervention. Our studies also suggest that the structural/functional DBLbetaC2 domain involved in ICAM1 binding includes about 80 amino acid residues upstream of the previously suggested DBLbetaC2 domain. DBL2betaC2(PF11_0521) binding to ICAM1 was inhibited by immune sera from east Africa but not by control US sera. Neutralizing antibodies were uncommon in children but common in immune adults from east Africa. Inhibition of binding was much more efficient than reversal of binding, indicating a strong interaction between DBL2betaC2(PF11_0521) and ICAM1. Our high throughput approach will significantly accelerate studies of PfEMP1 binding domains and protective antibody responses.
Assuntos
Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/genética , Plasmodium falciparum/imunologia , Proteínas de Protozoários/genética , Adulto , Sequência de Aminoácidos , Animais , Pré-Escolar , Membrana Eritrocítica/imunologia , Humanos , Lactente , Molécula 1 de Adesão Intercelular/imunologia , Molécula 1 de Adesão Intercelular/metabolismo , Proteínas de Membrana/imunologia , Dados de Sequência Molecular , Estrutura Terciária de Proteína , Proteínas de Protozoários/metabolismo , Alinhamento de SequênciaRESUMO
BACKGROUND: Malaria in pregnancy is serious, and drug resistance in Africa is spreading. Drugs have greater risks in pregnancy and determining the safety and efficacy of drugs in pregnancy is therefore a priority. This study set out to determine the efficacy and safety of several antimalarial drugs and combinations in pregnant women with uncomplicated malaria. METHODS: Pregnant women with non-severe, slide proven, falciparum malaria were randomised to one of 4 regimes: sulfadoxine-pyrimethamine [SP]; chlorproguanil-dapsone [CD]; SP+amodiaquine [SP+AQ] or amodiaquine+artesunate [AQ+AS]. Randomisation was on a 1ratio2ratio2ratio2 ratio. Women were admitted for treatment, and followed at days 7, 14, 21, 28 after the start of treatment, at delivery and 6 weeks after delivery to determine adverse events, clinical and parasitological outcomes. Primary outcome was parasitological failure by day 28. RESULTS: 1433 pregnant women were screened, of whom 272 met entry criteria and were randomised; 28 to SP, 81 to CD, 80 to SP+AQ and 83 to AQ+AS. Follow-up to day 28 post treatment was 251/272 (92%), and to 6 weeks following delivery 91%. By day 28 parasitological failure rates were 4/26 (15%, 95%CI 4-35) in the SP, 18/77 (23%, 95%CI 14-34) in the CD, 1/73 (1% 95%CI 7-0.001) in the SP+AQ and 7/75 (9% 95%CI 4-18) in the AQ+AS arms respectively. After correction by molecular markers for reinfection the parasitological failure rates at day 28 were 18% for CD, 1% for SP+AQ and 4.5% for AQ+AS. There were two maternal deaths during the trial. There was no apparent excess of stillbirths or adverse birth outcomes in any arm. Parasitological responses were strikingly better in pregnant women than in children treated with the same drugs at this site. CONCLUSIONS: Failure rates with monotherapy were unacceptably high. The two combinations tested were efficacious and appeared safe. It should not be assumed that efficacy in pregnancy is the same as in children. TRIAL REGISTRATION: ClinicalTrials.gov NCT00146731.
Assuntos
Amodiaquina/uso terapêutico , Artemisininas/uso terapêutico , Dapsona/uso terapêutico , Malária/tratamento farmacológico , Complicações Parasitárias na Gravidez/tratamento farmacológico , Proguanil/análogos & derivados , Pirimetamina/uso terapêutico , Sulfadoxina/uso terapêutico , Adulto , Amodiaquina/administração & dosagem , Artemisininas/administração & dosagem , Artesunato , Dapsona/administração & dosagem , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Malária/complicações , Gravidez , Proguanil/administração & dosagem , Proguanil/uso terapêutico , Pirimetamina/administração & dosagem , Sulfadoxina/administração & dosagem , Tanzânia , Adulto JovemRESUMO
Placental malaria (PM) caused by Plasmodium falciparum contributes significantly to infant mortality in sub-Saharan Africa and is associated with pregnancy loss. We hypothesized that fetal genes that modify PM would be associated with fetal fitness. During PM, placental trophoblasts produce soluble fms-like tyrosine kinase 1 (sFlt1), also known as soluble VEGF receptor 1, an angiogenesis inhibitor associated with preeclampsia. Here we present a study examining the genotype of the fms-related tyrosine kinase 1 (FLT1) 3' UTR in Tanzanian mother-infant pairs. First-time mothers suffer the most PM, and newborn FLT1 genotype distribution differed by birth order, with newborns of first-time mothers outside of Hardy-Weinberg equilibrium (HWE) during peak PM season. Among first-time but not other mothers, maternal FLT1 genotype was associated with a history of prior pregnancy loss. During PM, newborn FLT1 genotype was associated with low birth weight and placental inflammatory gene expression. FLT1 genotype was also associated with Flt1 levels among study subjects and in vitro. Thus, FLT1 variants confer fetal fitness in utero and are associated with the maternal immune response during PM. This indicates that FLT1 is under natural selection in a malaria endemic area and that human exposure to malaria can influence the evolutionary genetics of the maternal-fetal relationship.
Assuntos
Alelos , Imunidade Inata/genética , Malária/genética , Complicações Parasitárias na Gravidez/genética , Seleção Genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Aborto Espontâneo/epidemiologia , Aborto Espontâneo/genética , Ordem de Nascimento , Repetições de Dinucleotídeos/genética , Feminino , Regulação da Expressão Gênica , Genótipo , Humanos , Recém-Nascido , Inflamação/epidemiologia , Inflamação/genética , Malária/epidemiologia , Paridade , Doenças Placentárias/epidemiologia , Doenças Placentárias/genética , Gravidez , Complicações Parasitárias na Gravidez/epidemiologia , Estações do Ano , Tanzânia/epidemiologia , Regiões não Traduzidas/genéticaRESUMO
Iron plus folate supplementation increases mortality and morbidity among children in areas of malaria endemicity in Africa, but the effects of supplementation on pregnant women in malaria-endemic areas remain unclear. In northeastern Tanzania, where malaria and iron deficiency are common, we found that placental malaria was less prevalent (8.5% vs. 47.3% of women; P< .0001) and less severe (median parasite density, 4.2% vs. 6.3% of placental red blood cells; P< .04) among women with iron deficiency than among women with sufficient iron stores, especially during the first pregnancy. Multivariate analysis revealed that iron deficiency (P< .0001) and multigravidity (P< .002) significantly decreased the risk of placental malaria. Interventional trials of iron and folate supplementation during pregnancy in malaria-endemic regions in Africa are urgently needed to ascertain the benefits and risks of this intervention.
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Deficiências de Ferro , Malária Falciparum/imunologia , Malária Falciparum/prevenção & controle , Plasmodium falciparum/patogenicidade , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/prevenção & controle , Animais , Feminino , Humanos , Imunidade Inata , Placenta/parasitologia , Placenta/patologia , GravidezRESUMO
Inflammation during placental malaria (PM) is associated with low birth weight (LBW), especially during the first pregnancy, but the relative contribution of maternal or fetal factors that mediate this effect remains unclear and the role of gamma interferon (IFN-gamma) has been controversial. We examined the relationship of maternal and cord plasma levels of IFN-gamma, tumor necrosis factor alpha, interleukin-10, ferritin, and leptin to birth weight for Tanzanian women delivering in an area where there is a high rate of malaria transmission. The placental levels of inflammatory cytokines, including IFN-gamma, increased significantly during PM in primigravid and multigravid women but not in secundigravid women. PM also increased maternal peripheral levels of all inflammatory markers except IFN-gamma but had strikingly little effect on cord levels of these proteins. In a multivariate analysis, placental IFN-gamma was negatively associated (P = 0.01) and cord ferritin was positively associated (P < 0.0001) with birth weight in infected (PM-positive [PM+]) first-time mothers. This relationship was not observed in other mothers, consistent with the epidemiology of PM and disease. Cord leptin had a strong positive relationship with birth weight in offspring of PM-negative women (P = 0.02 to P < 0.0001) but not in offspring of PM+ women (all differences were not significant) in the three gravidity groups. The results confirmed that placental IFN-gamma is related to LBW due to PM during first pregnancies and suggest that fetal ferritin plays a protective role. Because fetal cells are a source of placental IFN-gamma and cord ferritin, the fetal response to PM may modify the risk of LBW.