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Malaria can cause brain injury. Neurofilament light chain (NfL) is a biomarker of neuronal damage. Here we examined longitudinal plasma NfL levels in children aged 1-12 years with uncomplicated and severe malaria from Mozambique. NfL levels were similar in all malaria cases at hospital admission. However, levels increased over time and the increment was significantly higher in severe malaria cases with neurological manifestations (ie, coma, impaired consciousness, or repeated seizures). NfL may be useful to identify and quantify brain injury in malaria.
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Lesões Encefálicas , Malária , Criança , Humanos , Filamentos Intermediários , Proteínas de Neurofilamentos , Biomarcadores , ConvulsõesRESUMO
BACKGROUND: Current malaria diagnostic tests do not reliably identify children at risk of severe and fatal infection. Host immune and endothelial activation contribute to malaria pathogenesis. Soluble urokinase-type plasminogen activator receptor (suPAR) is a marker of these pathways. We hypothesized that measuring suPAR at presentation could risk-stratify children with malaria. METHODS: Plasma suPAR levels were determined in consecutive febrile children with malaria at presentation to hospital in Jinja, Uganda. We evaluated the accuracy of suPAR in predicting in-hospital mortality, and whether suPAR could improve a validated clinical scoring system (Lambaréné Organ Dysfunction Score [LODS]). RESULTS: Of the 1226 children with malaria, 39 (3.2%) died. suPAR concentrations at presentation were significantly higher in children who went on to die than in those who survived (P < .0001). suPAR levels were associated with disease severity (LODS: 0 vs 1, P = .001; 1 vs 2, P < .001; 2 vs 3, 0 vs 2, 1 vs 3, and 0 vs 3, P < .0001). suPAR concentrations were excellent predictors of in-hospital mortality (area under the receiver operating characteristic curve [AUROC], 0.92 [95% confidence interval {CI}, .91-.94]). The prognostic accuracy of LODS (AUROC, 0.93 [95% CI, .91-.94]) was improved when suPAR was added (AUROC, 0.97 [95% CI, .96-.98]; P < .0001). CONCLUSIONS: Measuring suPAR at presentation can identify children at risk of severe and fatal malaria. Adding suPAR to clinical scores could improve the recognition and triage of children at risk of death. suPAR can be detected with a point-of-care test and can now be evaluated in prospective trials.
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Malária , Receptores de Ativador de Plasminogênio Tipo Uroquinase , Humanos , Criança , Prognóstico , Uganda , Estudos Prospectivos , Malária/diagnóstico , BiomarcadoresRESUMO
BACKGROUND: A prospective observational cohort study of COVID-19 patients in a single Emergency Department (ED) showed that sTREM-1- and IL-6-based algorithms were highly predictive of adverse outcome (Van Singer et al. J Allergy Clin Immunol 2021). We aim to validate the performance of these algorithms at ED presentation. METHODS: This multicentric prospective observational study of PCR-confirmed COVID-19 adult patients was conducted in the ED of three Swiss hospitals. Data of the three centers were retrospectively completed and merged. We determined the predictive accuracy of the sTREM-1-based algorithm for 30-day intubation/mortality. We also determined the performance of the IL-6-based algorithm using data from one center for 30-day oxygen requirement. RESULTS: 373 patients were included in the validation cohort, 139 (37%) in Lausanne, 93 (25%) in St.Gallen and 141 (38%) in EOC. Overall, 18% (93/373) patients died or were intubated by day 30. In Lausanne, 66% (92/139) patients required oxygen by day 30. The predictive accuracy of sTREM-1 and IL-6 were similar compared to the derivation cohort. The sTREM-1-based algorithm confirmed excellent sensitivity (90% versus 100% in the derivation cohort) and negative predictive value (94% versus 100%) for 30-day intubation/mortality. The IL-6-based algorithm performance was acceptable with a sensitivity of 85% versus 98% in the derivation cohort and a negative predictive value of 60% versus 92%. CONCLUSION: The sTREM-1 algorithm demonstrated good reproducibility. A prospective randomized controlled trial, comparing outcomes with and without the algorithm, is necessary to assess its safety and impact on hospital and ICU admission rates. The IL-6 algorithm showed acceptable validity in a single center and need additional validation before widespread implementation.
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COVID-19 , Adulto , Humanos , Algoritmos , COVID-19/diagnóstico , Interleucina-6 , Estudos Prospectivos , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
BACKGROUND: Despite the global burden of pneumonia, reliable triage tools to identify children in low-resource settings at risk of severe and fatal respiratory tract infection are lacking. This study assessed the ability of circulating host markers of immune and endothelial activation quantified at presentation, relative to currently used clinical measures of disease severity, to identify children with pneumonia who are at risk of death. METHODS AND FINDINGS: We conducted a secondary analysis of a prospective cohort study of children aged 2 to 59 months presenting to the Jinja Regional Hospital in Jinja, Uganda between February 2012 and August 2013, who met the Integrated Management of Childhood Illness (IMCI) diagnostic criteria for pneumonia. Circulating plasma markers of immune (IL-6, IL-8, CXCL-10/IP-10, CHI3L1, sTNFR1, and sTREM-1) and endothelial (sVCAM-1, sICAM-1, Angpt-1, Angpt-2, and sFlt-1) activation measured at hospital presentation were compared to lactate, respiratory rate, oxygen saturation, procalcitonin (PCT), and C-reactive protein (CRP) with a primary outcome of predicting 48-hour mortality. Of 805 children with IMCI pneumonia, 616 had severe pneumonia. Compared to 10 other immune and endothelial activation markers, sTREM-1 levels at presentation had the best predictive accuracy in identifying 48-hour mortality for children with pneumonia (AUROC 0.885, 95% CI 0.841 to 0.928; p = 0.03 to p < 0.001) and severe pneumonia (AUROC 0.870, 95% CI 0.824 to 0.916; p = 0.04 to p < 0.001). sTREM-1 was more strongly associated with 48-hour mortality than lactate (AUROC 0.745, 95% CI 0.664 to 0.826; p < 0.001), respiratory rate (AUROC 0.615, 95% CI 0.528 to 0.702; p < 0.001), oxygen saturation (AUROC 0.685, 95% CI 0.594 to 0.776; p = 0.002), PCT (AUROC 0.650, 95% CI 0.566 to 0.734; p < 0.001), and CRP (AUROC 0.562, 95% CI 0.472 to 0.653; p < 0.001) in cases of pneumonia and severe pneumonia. The main limitation of this study was the unavailability of radiographic imaging. CONCLUSIONS: In this cohort of Ugandan children, sTREM-1 measured at hospital presentation was a significantly better indicator of 48-hour mortality risk than other common approaches to risk stratify children with pneumonia. Measuring sTREM-1 at clinical presentation may improve the early triage, management, and outcome of children with pneumonia at risk of death. TRIAL REGISTRATION: The trial was registered at clinicaltrial.gov (NCT04726826).
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Proteína C-Reativa , Pneumonia , Biomarcadores , Proteína C-Reativa/metabolismo , Criança , Estudos de Coortes , Humanos , Lactatos , Pneumonia/diagnóstico , Estudos Prospectivos , Medição de Risco , Uganda/epidemiologiaRESUMO
BACKGROUND: Acute kidney injury (AKI) and blackwater fever (BWF) are related but distinct renal complications of acute febrile illness in East Africa. The pathogenesis and prognostic significance of BWF and AKI are not well understood. METHODS: A prospective observational cohort study was conducted to evaluate the association between BWF and AKI in children hospitalized with an acute febrile illness. Secondary objectives were to examine the association of AKI and BWF with (i) host response biomarkers and (ii) mortality. AKI was defined using the Kidney Disease: Improving Global Outcomes criteria and BWF was based on parental report of tea-colored urine. Host markers of immune and endothelial activation were quantified on admission plasma samples. The relationships between BWF and AKI and clinical and biologic factors were evaluated using multivariable regression. RESULTS: We evaluated BWF and AKI in 999 children with acute febrile illness (mean age 1.7 years (standard deviation 1.06), 55.7% male). At enrollment, 8.2% of children had a history of BWF, 49.5% had AKI, and 11.1% had severe AKI. A history of BWF was independently associated with 2.18-fold increased odds of AKI (95% CI 1.15 to 4.16). When examining host response, severe AKI was associated with increased immune and endothelial activation (increased CHI3L1, sTNFR1, sTREM-1, IL-8, Angpt-2, sFlt-1) while BWF was predominantly associated with endothelial activation (increased Angpt-2 and sFlt-1, decreased Angpt-1). The presence of severe AKI, not BWF, was associated with increased risk of in-hospital death (RR, 2.17 95% CI 1.01 to 4.64) adjusting for age, sex, and disease severity. CONCLUSIONS: BWF is associated with severe AKI in children hospitalized with a severe febrile illness. Increased awareness of AKI in the setting of BWF, and improved access to AKI diagnostics, is needed to reduce disease progression and in-hospital mortality in this high-risk group of children through early implementation of kidney-protective measures.
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Injúria Renal Aguda , Febre Hemoglobinúrica , Injúria Renal Aguda/complicações , Injúria Renal Aguda/diagnóstico , Biomarcadores , Febre Hemoglobinúrica/complicações , Criança , Feminino , Mortalidade Hospitalar , Humanos , Lactente , Masculino , Prognóstico , Estudos ProspectivosRESUMO
BACKGROUND: The inability to identify individuals with acute fever at risk of death is a barrier to effective triage and management of severe infections, especially in low-resource settings. Since endothelial and immune activation contribute to the pathogenesis of various distinct life-threatening infections, we hypothesized that measuring mediators of these pathways at clinical presentation would identify febrile adults at risk of death. METHODS: Plasma concentrations of markers of endothelial (angiopoetin-1/2, soluble fms-like tyrosine kinase-1, soluble vascular cell adhesion molecule-1, soluble intercellular adhesion molecule-1) and immune (soluble triggering receptor expressed on myeloid cells [sTREM-1], interleukin-6, interleukin-8, chitinase-3-like protein-1, soluble tumor necrosis factor receptor-1, procalcitonin [PCT], C-reactive protein [CRP]) activation pathways were determined in consecutive adults with acute fever (≥38°C) at presentation to outpatient clinics in Dar es Salaam, Tanzania. We evaluated the accuracy of these mediators in predicting all-cause mortality and examined whether markers could improve the prognostic accuracy of clinical scoring systems, including the quick sequential organ failure assessment (qSOFA) and Glasgow coma scale (GCS). RESULTS: Of 507 febrile adults, 32 died (6.3%) within 28 days of presentation. We found that sTREM-1 was the best prognostic marker for 28-day mortality (area under the receiver operating characteristic [AUROC] 0.87, 95% confidence interval [CI] 0.81-0.92) and was significantly better than CRP (P < .0001) and PCT (P = .0001). The prognostic accuracy of qSOFA and the GCS were significantly enhanced when sTREM-1 was added (0.80 [95% CI 0.76-0.83] to 0.91 [95% CI 0.88-0.94; P < .05] and 0.72 [95% CI 0.63-0.80] to 0.94 [95% CI 0.91-0.97; P < .05], respectively). CONCLUSIONS: Measuring sTREM-1 at clinical presentation can identify febrile individuals at risk of all-cause febrile mortality. Adding severity markers such as sTREM-1 to simple clinical scores could improve the recognition and triage of patients with life-threatening infections in resource-limited settings.
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Proteína C-Reativa , Células Mieloides , Adulto , Algoritmos , Instituições de Assistência Ambulatorial , Biomarcadores , Proteína C-Reativa/análise , Humanos , Células Mieloides/química , Prognóstico , Tanzânia , Receptor Gatilho 1 Expresso em Células MieloidesRESUMO
BACKGROUND: Malaria in pregnancy is associated with adverse birth outcomes. However, the underlying mechanisms remain poorly understood. Tight regulation of angiogenic, metabolic, and inflammatory pathways are essential for healthy pregnancies. We hypothesized that malaria disrupts these pathways leading to preterm birth (PTB). METHODS AND FINDINGS: We conducted a secondary analysis of a randomized trial of malaria prevention in pregnancy conducted in Malawi from July 21, 2011, to March 18, 2013. We longitudinally assessed circulating mediators of angiogenic, metabolic, and inflammatory pathways during pregnancy in a cohort of HIV-negative women (n = 1,628), with a median age of 21 years [18, 25], and 562 (35%) were primigravid. Pregnancies were ultrasound dated, and samples were analyzed at 13 to 23 weeks (Visit 1), 28 to 33 weeks (Visit 2), and/or 34 to 36 weeks (Visit 3). Malaria prevalence was high; 70% (n = 1,138) had PCR-positive Plasmodium falciparum infection at least once over the course of pregnancy and/or positive placental histology. The risk of delivering preterm in the entire cohort was 20% (n = 304/1506). Women with malaria before 24 weeks gestation had a higher risk of PTB (24% versus 18%, p = 0.005; adjusted relative risk [aRR] 1.30, 95% confidence interval [CI] 1.04-1.63, p = 0.021); and those who were malaria positive only before week 24 had an even greater risk of PTB (28% versus 17%, p = 0.02; with an aRR of 1.67, 95% CI 1.20-2.30, p = 0.002). Using linear mixed-effects modeling, malaria before 24 weeks gestation was associated with altered kinetics of inflammatory (C-Reactive Protein [CRP], Chitinase 3-like protein-1 [CHI3L1], Interleukin 18 Binding Protein [IL-18BP], soluble Tumor Necrosis Factor receptor II [sTNFRII], soluble Intercellular Adhesion Molecule-1 [sICAM-1]), angiogenic (soluble Endoglin [sEng]), and metabolic mediators (Leptin, Angiopoietin-like 3 [Angptl3]) over the course of pregnancy (χ2 > 13.0, p ≤ 0.001 for each). Limitations include being underpowered to assess the impact on nonviable births, being unable to assess women who had not received any antimalarials, and, because of the exposure to antimalarials in the second trimester, there were limited numbers of malaria infections late in pregnancy. CONCLUSIONS: Current interventions for the prevention of malaria in pregnancy are initiated at the first antenatal visit, usually in the second trimester. In this study, we found that many women are already malaria-infected by their first visit. Malaria infection before 24 weeks gestation was associated with dysregulation of essential regulators of angiogenesis, metabolism, and inflammation and an increased risk of PTB. Preventing malaria earlier in pregnancy may reduce placental dysfunction and thereby improve birth outcomes in malaria-endemic settings.
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Malária Falciparum/complicações , Malária Falciparum/diagnóstico , Neovascularização Patológica , Complicações Infecciosas na Gravidez/diagnóstico , Nascimento Prematuro/prevenção & controle , Adulto , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Inflamação/complicações , Modelos Lineares , Malaui , Gravidez , Nascimento Prematuro/epidemiologia , Risco , Resultado do Tratamento , Ultrassonografia Pré-Natal , Adulto JovemRESUMO
Plasmodium falciparum resistance to artemisinin derivatives is emerging in Asia. We examined molecular markers of resistance in 78 children in Uganda who had severe malaria and were treated with intravenous artesunate. We observed in the K13-propeller domain, A578S, a low-frequency (3/78), nonsynonymous, single-nucleotide polymorphism associated with prolonged parasite clearance.
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Antimaláricos/farmacologia , Artemisininas/farmacologia , Malária Falciparum/parasitologia , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Criança , Pré-Escolar , Resistência a Medicamentos , Feminino , Genes de Protozoários , Humanos , Lactente , Malária Falciparum/tratamento farmacológico , Malária Falciparum/patologia , Masculino , Plasmodium falciparum/genética , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , UgandaRESUMO
The host immune response plays an important role in the onset and progression of cerebral malaria (CM). The complement system is an essential component of the innate immune response to malaria, and its activation generates the anaphylatoxin C5a. To test the hypothesis that C5a signaling contributes to the pathogenesis of CM, we investigated a causal role for the C5a receptors C5aR and C5L2 in a mouse model of experimental CM (ECM) induced by Plasmodium berghei ANKA infection, and using a case-control design, we examined levels of C5a in plasma samples from Ugandan children presenting with CM or uncomplicated malaria (UM). In the ECM model, C5aR(-/-) mice displayed significantly improved survival compared to their wild-type (WT) counterparts (P = 0.004), whereas C5L2(-/-) mice showed no difference in survival from WT mice. Improved survival in C5aR(-/-) mice was associated with reduced levels of the proinflammatory cytokines tumor necrosis factor (TNF) and gamma interferon (IFN-γ) and the chemokine, monocyte chemoattractant protein 1 (MCP-1) (CCL2). Furthermore, endothelial integrity was enhanced, as demonstrated by increased levels of angiopoietin-1, decreased levels of angiopoietin-2 and soluble ICAM-1, and decreased Evans blue extravasation into brain parenchyma. In the case-control study, the median levels of C5a at presentation were significantly higher in children with CM versus those in children with UM (43.7 versus 22.4 ng/ml; P < 0.001). These findings demonstrate that C5a is dysregulated in human CM and contributes to the pathogenesis of ECM via C5aR-dependent inflammation and endothelial dysfunction.
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Complemento C5a/imunologia , Malária Cerebral/imunologia , Receptores de Quimiocinas/imunologia , Receptores de Complemento/imunologia , Animais , Estudos de Casos e Controles , Criança , Pré-Escolar , Complemento C5a/deficiência , Modelos Animais de Doenças , Feminino , Humanos , Lactente , Inflamação/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor da Anafilatoxina C5a , Receptores de Complemento/deficiência , Receptores de Concanavalina ARESUMO
Background: Current prognostic tools do not reliably and objectively identify children with pneumonia at risk of a severe or life-threatening episode. Heparin-binding protein (HBP) is a host immune protein that is released in response to infection. We hypothesized that measuring HBP concentrations at hospital admission could help risk-stratify children with pneumonia and identify those at higher risk of an adverse prognosis. Methods: We evaluated the prognostic accuracy of HBP for predicting in-hospital mortality among children with respiratory distress, and whether HBP could improve the accuracy of validated composite clinical severity scores. Results: Of 778 Ugandan children under 5 years of age and presenting with clinically defined pneumonia, 60 (7.7%) died during hospital admission. HBP concentrations at presentation were significantly higher in children with fatal outcomes (median, 76 ng/mL [interquartile range {IQR}, 41-150]) compared to children who survived (median, 31 ng/mL [IQR, 18-57]) (P < .001). Children with HBP >41 ng/mL on admission had an elevated risk of death (hazard ratio, 5.3 [95% confidence interval {CI}, 2.9-9.5]; P < .0001). In receiver operating characteristic (ROC) curve analysis, HBP concentrations distinguished between fatal and nonfatal outcomes (area under the ROC curve, 0.75 [95% CI, .66-.84]) and significantly improved the prediction provided by the Respiratory Index of Severity in Children, a composite clinical severity score (P = .0026). Conclusions: Measuring HBP at presentation could help identify children at risk of severe and fatal pneumonia. Adding HBP to clinical scores could improve the recognition and triage of children with pneumonia at risk of death.
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OBJECTIVES: We tested the hypothesis that adjunctive rosiglitazone treatment would reduce levels of circulating angiopoietin-2 (Angpt-2) and improve outcomes of Mozambican children with severe malaria. METHODS: A randomized, double-blind, placebo-controlled trial of rosiglitazone vs placebo as adjunctive treatment to artesunate in children with severe malaria was conducted. A 0.045 mg/kg/dose of rosiglitazone or matching placebo were administered, in addition to standard of malaria care, twice a day for 4 days. The primary endpoint was the rate of decline of Angpt-2 over 96 hours. Secondary outcomes included the longitudinal dynamics of angiopoietin-1 (Angpt-1) and the Angpt-2/Angpt-1 ratio over 96 hours, parasite clearance kinetics, clinical outcomes, and safety metrics. RESULTS: Overall, 180 children were enrolled; 91 were assigned to rosiglitazone and 89 to placebo. Children who received rosiglitazone had a steeper rate of decline of Angpt-2 over the first 96 hours of hospitalization compared to children who received placebo; however, the trend was not significant (P = 0.28). A similar non-significant trend was observed for Angpt-1 (P = 0.65) and the Angpt-2/Angpt-1 ratio (P = 0.34). All other secondary and safety outcomes were similar between groups (P >0.05). CONCLUSION: Adjunctive rosiglitazone at this dosage was safe and well tolerated but did not significantly affect the longitudinal kinetics of circulating Angpt-2.
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Antimaláricos , Malária Falciparum , Malária , Humanos , Criança , Rosiglitazona/uso terapêutico , Moçambique , Malária/tratamento farmacológico , Artesunato/uso terapêutico , Método Duplo-Cego , Malária Falciparum/tratamento farmacológico , Antimaláricos/efeitos adversosRESUMO
Preterm birth is a leading cause of death in children under five years of age. We hypothesized that sequential disruptions to inflammatory and angiogenic pathways during pregnancy increase the risk of placental insufficiency and spontaneous preterm labor and delivery. We conducted a secondary analysis of inflammatory and angiogenic analytes measured in plasma samples collected across pregnancy from 1462 Malawian women. Women with concentrations of the inflammatory markers sTNFR2, CHI3L1, and IL18BP in the highest quartile before 24 weeks gestation and women with anti-angiogenic factors sEndoglin and sFlt-1/PlGF ratio in the highest quartile at 28-33 weeks gestation had an increased relative risk of preterm birth. Mediation analysis further supported a potential causal link between early inflammation, subsequent angiogenic dysregulation detrimental to placental vascular development, and earlier gestational age at delivery. Interventions designed to reduce the burden of preterm birth may need to be implemented before 24 weeks of gestation.
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BACKGROUND: Malaria in early pregnancy is a risk factor for preterm birth and is associated with sustained inflammation and dysregulated angiogenesis across gestation. This study investigated whether malaria is associated with increased gut leak and whether this contributes to systemic inflammation, altered angiogenesis, and preterm birth. METHODS: We quantified plasma concentrations of gut leak markers, soluble CD14 (sCD14) and lipopolysaccharide binding protein (LBP) from 1339 HIV-negative pregnant Malawians at <24 weeks gestational age. We assessed the relationship of sCD14 and LBP concentrations with markers of inflammation, angiogenesis, and L-arginine bioavailability and compared them between participants with and without malaria, and with and without preterm birth. FINDINGS: Plasma concentrations of sCD14 and LBP were significantly higher in participants with malaria and were associated with parasite burden (p <0.0001, both analyses and analytes). The odds ratio for preterm birth associated with one log sCD14 was 2.67 (1.33 to 5.35, p = 0.006) and 1.63 (1.07-2.47, p = 0.023) for LBP. Both gut leak analytes were positively associated with increases in proinflammatory cytokines CRP, sTNFR2, IL18-BP, CHI3L1 and Angptl3 (p <0.05, all analytes) and sCD14 was significantly associated with angiogenic proteins Angpt-2, sENG and the sFLT:PlGF ratio (p <0.05, all analytes). sCD14 was negatively associated with L-arginine bioavailability (p <0.001). INTERPRETATION: Malaria in early pregnancy is associated with intestinal barrier dysfunction, which is linked to an increased risk of preterm birth. FUNDING: Open Philanthropy, Canadian Institutes of Health Research, Canada Research Chair program, European and Developing Countries Clinical Trials Partnership, Bill & Melinda Gates Foundation.
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Malária Falciparum , Malária , Nascimento Prematuro , Gravidez , Feminino , Humanos , Recém-Nascido , Nascimento Prematuro/etiologia , Plasmodium falciparum , Estudos de Coortes , Receptores de Lipopolissacarídeos , Canadá/epidemiologia , Malária Falciparum/complicações , Malária Falciparum/epidemiologia , Inflamação/complicações , Malária/complicações , Arginina , BiomarcadoresRESUMO
Plasmodium falciparum malaria in Haiti is considered chloroquine susceptible, although resistance transporter alleles associated with chloroquine resistance were recently detected. Among 49 patients with falciparum malaria, we found neither parasites carrying haplotypes associated with chloroquine resistance nor instances of chloroquine treatment failure. Continued vigilance to detect emergence of chloroquine resistance is needed.
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Antimaláricos/uso terapêutico , Cloroquina/uso terapêutico , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Adolescente , Adulto , Criança , Resistência a Medicamentos/genética , Feminino , Haplótipos , Humanos , Malária Falciparum/diagnóstico , Malária Falciparum/parasitologia , Masculino , Proteínas de Membrana Transportadoras/genética , Mutação , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Adulto JovemRESUMO
Acute kidney injury (AKI) is a life-threatening complication. Malaria and sepsis are leading causes of AKI in low-and-middle-income countries, but its etiology and pathogenesis are poorly understood. A prospective observational cohort study was conducted to evaluate pathways of immune and endothelial activation in children hospitalized with an acute febrile illness in Uganda. The relationship between clinical outcome and AKI, defined using the Kidney Disease: Improving Global Outcomes criteria, was investigated. The study included 967 participants (mean age 1.67 years, 44.7% female) with 687 (71.0%) positive for malaria by rapid diagnostic test and 280 (29.1%) children had a non-malarial febrile illness (NMFI). The frequency of AKI was higher in children with NMFI compared to malaria (AKI, 55.0% vs. 46.7%, p = 0.02). However, the frequency of severe AKI (stage 2 or 3 AKI) was comparable (12.1% vs. 10.5%, p = 0.45). Circulating markers of both immune and endothelial activation were associated with severe AKI. Children who had malaria and AKI had increased mortality (no AKI, 0.8% vs. AKI, 4.1%, p = 0.005), while there was no difference in mortality among children with NMFI (no AKI, 4.0% vs. AKI, 4.6%, p = 0.81). AKI is a common complication in children hospitalized with acute infections. Immune and endothelial activation appear to play central roles in the pathogenesis of AKI.
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Identifying febrile children at risk of sepsis in low-resource settings can improve survival, but recognition triage tools are lacking. Here we test the hypothesis that measuring circulating markers of immune and endothelial activation may identify children with sepsis at risk of all-cause mortality. In a prospective cohort study of 2,502 children in Uganda, we show that Soluble Triggering Receptor Expressed on Myeloid cells-1 (sTREM-1) measured at first clinical presentation, had high predictive accuracy for subsequent in-hospital mortality. sTREM-1 had the best performance, versus 10 other markers, with an AUROC for discriminating children at risk of death of 0.893 in derivation (95% CI 0.843-0.944) and 0.901 in validation (95% CI 0.856-0.947) cohort. sTREM-1 cutoffs corresponding to a negative likelihood ratio (LR) of 0.10 and a positive LR of 10 classified children into low (1,306 children, 53.1%), intermediate (942, 38.3%) and high (212, 8.6%) risk zones. The estimated incidence of death was 0.5%, 3.9%, and 31.8%, respectively, suggesting sTREM-1 could be used to risk-stratify febrile children. These findings do not attempt to derive a risk prediction model, but rather define sTREM-1 cutoffs as the basis for rapid triage test for all cause fever syndromes in children in low-resource settings.
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Sepse , Triagem/métodos , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Biomarcadores , Pré-Escolar , Estudos de Coortes , Doenças Transmissíveis , Feminino , Humanos , Lactente , Masculino , Estudos Prospectivos , Receptor Gatilho 1 Expresso em Células Mieloides/genética , UgandaRESUMO
BACKGROUND: Ex vivo lung perfusion (EVLP) is an isolated organ assessment technique that has revolutionized the field of lung transplantation and enabled a safe increase in the number of organs transplanted. The objective of this study was to develop a protein-based assay that would provide a precision medicine approach to lung injury assessment during EVLP. METHODS: Perfusate samples collected from clinical EVLP cases performed from 2009 to 2019 were separated into development (nâ¯=â¯281) and validation (nâ¯=â¯57) sets to derive and validate an inflammation score based on IL-6 and IL-8 protein levels in perfusate. The ability of an inflammation score to predict lungs suitable for transplantation and likely to produce excellent recipient outcomes (time on ventilator ≤ 3 days) was assessed. Inflammation scores were compared to conventional clinical EVLP assessment parameters and associated with outcomes, including primary graft dysfunction and patient care in the ICU. RESULTS: An inflammation score accurately predicted the decision to transplant (AUROC 68% [95% CI 62-74]) at the end of EVLP and those transplants associated with short ventilator times (AUROC 73% [95% CI 66-80]). The score identified lungs more likely to develop primary graft dysfunction at 72-hours post-transplant (OR 4.0, pâ¯=â¯0.03). A model comprised of the inflammation score and ∆PO2 was able to determine EVLP transplants that were likely to have excellent recipient outcomes, with an accuracy of 87% [95% CI 83-92]. CONCLUSIONS: The adoption of an inflammation score will improve accuracy of EVLP decision-making and increase confidence of surgical teams to determine lungs that are suitable for transplantation, thereby improving organ utilization rates and patient outcomes.
Assuntos
Circulação Extracorpórea/métodos , Inflamação/diagnóstico , Lesão Pulmonar/diagnóstico , Transplante de Pulmão/estatística & dados numéricos , Disfunção Primária do Enxerto/prevenção & controle , Doadores de Tecidos/estatística & dados numéricos , Seguimentos , Humanos , Lesão Pulmonar/etiologia , Morbidade/tendências , Ontário/epidemiologia , Disfunção Primária do Enxerto/epidemiologia , Estudos RetrospectivosRESUMO
BACKGROUND: Malaria during pregnancy is a major contributor to the global burden of adverse birth outcomes including fetal growth restriction, preterm birth, and fetal loss. Recent evidence supports a role for angiogenic dysregulation and perturbations to placental vascular development in the pathobiology of malaria in pregnancy. The Angiopoietin-Tie2 axis is critical for placental vascularization and remodeling. We hypothesized that disruption of this pathway would contribute to malaria-induced adverse birth outcomes. METHODS: Using samples from a previously conducted prospective cohort study of pregnant women in Malawi, we measured circulating levels of angiopoietin-1 (Angpt-1) and Angpt-2 by Luminex (n=1392). We used a preclinical model of malaria in pregnancy (Plasmodium berghei ANKA [PbA] in pregnant BALB/c mice), genetic disruption of Angpt-1 (Angpt1+/- mice), and micro-CT analysis of placental vasculature to test the hypothesis that disruptions to the Angpt-Tie2 axis by malaria during pregnancy would result in aberrant placental vasculature and adverse birth outcomes. FINDINGS: Decreased circulating levels of Angpt-1 and an increased ratio of Angpt-2/Angpt-1 across pregnancy were associated with malaria in pregnancy. In the preclinical model, PbA infection recapitulated disruptions to the Angiopoietin-Tie2 axis resulting in reduced fetal growth and viability. Malaria decreased placental Angpt-1 and Tie2 expression and acted synergistically with reduced Angpt-1 in heterozygous dams (Angpt1+/-), to worsen birth outcomes by impeding vascular remodeling required for placental function. INTERPRETATION: Collectively, these data support a mechanistic role for the Angpt-Tie2 axis in malaria in pregnancy, including a potential protective role for Angpt-1 in mitigating infection-associated adverse birth outcomes. FUNDING: This work was supported by the Canadian Institutes of Health Research (CIHR), Canada Research Chair, and Toronto General Research Institute Postdoctoral Fellowship Award. The parent trial was supported by the European & Developing Countries Clinical Trials Partnership and the Malaria in Pregnancy Consortium, which was funded by the Bill & Melinda Gates Foundation. The funders had no role in design, analysis, or reporting of these studies.
Assuntos
Angiopoietinas/metabolismo , Malária/parasitologia , Neovascularização Patológica/metabolismo , Placenta/metabolismo , Placenta/patologia , Complicações Parasitárias na Gravidez/parasitologia , Receptor TIE-2/metabolismo , Adulto , Angiopoietina-1/genética , Angiopoietina-1/metabolismo , Angiopoietina-2/genética , Angiopoietina-2/metabolismo , Angiopoietinas/sangue , Angiopoietinas/genética , Animais , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Humanos , Malária/diagnóstico , Malaui , Camundongos , Camundongos Knockout , Neovascularização Patológica/genética , Placenta/parasitologia , Gravidez , Complicações Parasitárias na Gravidez/diagnóstico , Resultado da Gravidez , Receptor TIE-2/genética , Microtomografia por Raio-X , Adulto JovemRESUMO
Reducing adverse birth outcomes due to malaria in pregnancy (MIP) is a global health priority. However, there are few safe and effective interventions. l-Arginine is an essential amino acid in pregnancy and an immediate precursor in the biosynthesis of nitric oxide (NO), but there are limited data on the impact of MIP on NO biogenesis. We hypothesized that hypoarginemia contributes to the pathophysiology of MIP and that l-arginine supplementation would improve birth outcomes. In a prospective study of pregnant Malawian women, we show that MIP was associated with lower concentrations of l-arginine and higher concentrations of endogenous inhibitors of NO biosynthesis, asymmetric and symmetric dimethylarginine, which were associated with adverse birth outcomes. In a model of experimental MIP, l-arginine supplementation in dams improved birth outcomes (decreased stillbirth and increased birth weight) compared with controls. The mechanism of action was via normalized angiogenic pathways and enhanced placental vascular development, as visualized by placental microcomputerized tomography imaging. These data define a role for dysregulation of NO biosynthetic pathways in the pathogenesis of MIP and support the evaluation of interventions to enhance l-arginine bioavailability as strategies to improve birth outcomes.