RESUMO
The pathophysiology of severe falciparum malaria involves a complex interaction between the host, parasite, and gut microbes. In this review, we focus on understanding parasite-induced intestinal injury and changes in the human intestinal microbiota composition in patients with Plasmodium falciparum malaria. During the blood stage of P. falciparum infection, infected red blood cells adhere to the vascular endothelium, leading to widespread microcirculatory obstruction in critical tissues, including the splanchnic vasculature. This process may cause intestinal injury and gut leakage. Epidemiological studies indicate higher rates of concurrent bacteraemia in severe malaria cases. Furthermore, severe malaria patients exhibit alterations in the composition and diversity of the intestinal microbiota, although the exact contribution to pathophysiology remains unclear. Mouse studies have demonstrated that the gut microbiota composition can impact susceptibility to Plasmodium infections. In patients with severe malaria, the microbiota shows an enrichment of pathobionts, including pathogens that are known to cause concomitant bloodstream infections. Microbial metabolites have also been detected in the plasma of severe malaria patients, potentially contributing to metabolic acidosis and other clinical complications. However, establishing causal relationships requires intervention studies targeting the gut microbiota.
Assuntos
Microbioma Gastrointestinal , Enteropatias , Malária Falciparum , Malária , Humanos , Animais , Camundongos , Microcirculação , Malária Falciparum/parasitologia , Malária/parasitologia , Plasmodium falciparum/fisiologiaRESUMO
PURPOSE: Fluid management is challenging in malaria patients given the risks associated with intravascular fluid depletion and iatrogenic fluid overload leading to pulmonary oedema. Given the limitations of the physical examination in guiding fluid therapy, we evaluated point-of-care ultrasound (POCUS) of the inferior vena cava (IVC) and lungs as a novel tool to assess volume status and detect early oedema in malaria patients. METHODS: To assess the correlation between IVC and lung ultrasound (LUS) indices and clinical signs of hypovolaemia and pulmonary oedema, respectively, concurrent clinical and sonographic examinations were performed in an observational study of 48 malaria patients and 62 healthy participants across age groups in Gabon. RESULTS: IVC collapsibility index (CI) ≥ 50% on enrolment reflecting intravascular fluid depletion was associated with an increased number of clinical signs of hypovolaemia in severe and uncomplicated malaria. With exception of dry mucous membranes, IVC-CI correlated with most clinical signs of hypovolaemia, most notably sunken eyes (r = 0.35, p = 0.0001) and prolonged capillary refill (r = 0.35, p = 0.001). IVC-to-aorta ratio ≤ 0.8 was not associated with any clinical signs of hypovolaemia on enrolment. Among malaria patients, a B-pattern on enrolment reflecting interstitial fluid was associated with dyspnoea (p = 0.0003), crepitations and SpO2 ≤ 94% (both p < 0.0001), but not tachypnoea (p = 0.069). Severe malaria patients had increased IVC-CI (p < 0.0001) and more B-patterns (p = 0.004) on enrolment relative to uncomplicated malaria and controls. CONCLUSION: In malaria patients, POCUS of the IVC and lungs may improve the assessment of volume status and detect early oedema, which could help to manage fluids in these patients.
Assuntos
Malária , Edema Pulmonar , Humanos , Malária/complicações , Sistemas Automatizados de Assistência Junto ao Leito , Estudos Prospectivos , Edema Pulmonar/diagnóstico por imagem , Edema Pulmonar/etiologia , Ultrassonografia , Veia Cava Inferior/diagnóstico por imagemRESUMO
BACKGROUND: Severe metabolic acidosis and acute kidney injury are major causes of mortality in children with severe malaria but are often underdiagnosed in low resource settings. METHODS: A retrospective analysis of the 'Artesunate versus quinine in the treatment of severe falciparum malaria in African children' (AQUAMAT) trial was conducted to identify clinical features of severe metabolic acidosis and uraemia in 5425 children from nine African countries. Separate models were fitted for uraemia and severe metabolic acidosis. Separate univariable and multivariable logistic regression were performed to identify prognostic factors for severe metabolic acidosis and uraemia. Both analyses adjusted for the trial arm. A forward selection approach was used for model building of the logistic models and a threshold of 5% statistical significance was used for inclusion of variables into the final logistic model. Model performance was assessed through calibration, discrimination, and internal validation with bootstrapping. RESULTS: There were 2296 children identified with severe metabolic acidosis and 1110 with uraemia. Prognostic features of severe metabolic acidosis among them were deep breathing (OR: 3.94, CI 2.51-6.2), hypoglycaemia (OR: 5.16, CI 2.74-9.75), coma (OR: 1.72 CI 1.17-2.51), respiratory distress (OR: 1.46, CI 1.02-2.1) and prostration (OR: 1.88 CI 1.35-2.59). Features associated with uraemia were coma (3.18, CI 2.36-4.27), Prostration (OR: 1.78 CI 1.37-2.30), decompensated shock (OR: 1.89, CI 1.31-2.74), black water fever (CI 1.58. CI 1.09-2.27), jaundice (OR: 3.46 CI 2.21-5.43), severe anaemia (OR: 1.77, CI 1.36-2.29) and hypoglycaemia (OR: 2.77, CI 2.22-3.46) CONCLUSION: Clinical and laboratory parameters representing contributors and consequences of severe metabolic acidosis and uraemia were independently associated with these outcomes. The model can be useful for identifying patients at high risk of these complications where laboratory assessments are not routinely available.
Assuntos
Acidose/diagnóstico , Malária Falciparum/complicações , Uremia/diagnóstico , Acidose/parasitologia , África Subsaariana , Criança , Pré-Escolar , República Democrática do Congo , Feminino , Gâmbia , Gana , Humanos , Lactente , Quênia , Malária Falciparum/parasitologia , Masculino , Moçambique , Nigéria , Prognóstico , Estudos Retrospectivos , Ruanda , Tanzânia , Uganda , Uremia/parasitologiaRESUMO
BACKGROUND: Impaired microvascular perfusion is central to the development of coma and lactic acidosis in severe falciparum malaria. Refractory hypotension is rare on admission but develops frequently in fatal cases. We assessed cardiac function and volume status in severe falciparum malaria and its prognostic significance. METHODS: Patients with severe (N = 101) or acute uncomplicated falciparum malaria (N = 83) were recruited from 2 hospitals in India and Bangladesh, and healthy participants (N = 44) underwent echocardiography. RESULTS: Patients with severe malaria had 38% shorter left ventricular (LV) filling times and 25% shorter LV ejection times than healthy participants because of tachycardia; however, stroke volume, LV internal diameter in diastole (LVIDd), and LV internal diameter in systole (LVIDs) indices were similar. A low endocardial fraction shortening (eFS) was present in 17% (9 of 52) of severe malaria patients. Adjusting for preload and afterload, eFS was similar in health and severe malaria. Fatal cases had smaller baseline LVIDd and LVIDs indices, more collapsible inferior vena cavae (IVC), and higher heart rates than survivors. The LVIDs and IVC collapsibility were independent predictors for mortality, together with base excess and Glasgow Coma Scale. CONCLUSIONS: Patients with severe malaria have rapid ejection of a normal stroke volume. Fatal cases had features of relative hypovolemia and reduced cardiac index reserve.
Assuntos
Hipovolemia/parasitologia , Malária Falciparum/fisiopatologia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Adulto , Bangladesh , Estudos de Casos e Controles , Ecocardiografia , Feminino , Hemodinâmica , Humanos , Hipovolemia/fisiopatologia , Índia , Modelos Lineares , Modelos Logísticos , Malária Falciparum/diagnóstico por imagem , Malária Falciparum/mortalidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Disfunção Ventricular Esquerda/parasitologia , Função Ventricular Esquerda , Adulto JovemRESUMO
BACKGROUND: In severe falciparum malaria, unlike sepsis, hypotension on admission is uncommon. We hypothesized that low nitric oxide bioavailability due to the presence of cell-free hemoglobin (CFH) increases vascular tone in severe malaria. METHODS: Patients with severe malaria (n = 119), uncomplicated malaria (n = 91), or suspected bacterial sepsis (n = 56), as well as healthy participants (n = 50), were recruited. The systemic vascular resistance index (SVRI) was estimated from the echocardiographic cardiac index and the mean arterial pressure. RESULTS: SVRI and hematocrit levels were lower and plasma CFH and asymmetric dimethylarginine levels were higher in patients with malaria, compared with healthy participants. In multivariate linear regression models for mean arterial pressure or SVRI in patients with severe malaria, hematocrit and CFH but not asymmetric dimethylarginine were significant predictors. The SVRI was lower in patients with suspected bacterial sepsis than in those with severe malaria, after adjustment for hematocrit and age. Plasma CFH levels correlated positively with the core-peripheral temperature gradient and plasma lactate levels and inversely with the perfusion index. Impaired peripheral perfusion, as reflected by a low perfusion index or a high core-peripheral temperature gradient, predicted mortality in patients with severe malaria. CONCLUSIONS: CFH is associated with mean arterial pressure, SVRI, and peripheral perfusion in patients with severe malaria. This may be mediated through the nitric oxide scavenging potency of CFH, increasing basal vascular tone and impairing tissue perfusion.
Assuntos
Pressão Arterial , Hemoglobinas/metabolismo , Malária Falciparum/fisiopatologia , Fluxo Sanguíneo Regional , Resistência Vascular , Adulto , Arginina/análogos & derivados , Arginina/sangue , Bacteriemia/fisiopatologia , Estudos de Casos e Controles , Ecocardiografia , Feminino , Hematócrito , Humanos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico , Gravidade do Paciente , Adulto JovemRESUMO
BACKGROUND: Liberal fluid resuscitation has proved harmful in adults with severe malaria, but the level of restriction has not been defined. METHODS: In a prospective observational study in adults with severe falciparum malaria, restrictive fluid management was provided at the discretion of the treating physician. The relationships between the volume of fluid and changes in renal function or tissue perfusion were evaluated. RESULTS: A total of 154 patients were studied, 41 (26.6%) of whom died. Median total fluid intake during the first 6 and 24 hours from enrollment was 3.3 (interquartile range [IQR], 1.8-5.1) mL/kg per hour and 2.2 (IQR, 1.6-3.2) mL/kg per hour, respectively. Total fluid intake at 6 hours was not correlated with changes in plasma creatinine at 24 hours (n = 116; rs = 0.16; P = .089) or lactate at 6 hours (n = 94; rs = -0.05; P = .660). Development of hypotensive shock or pulmonary edema within 24 hours after enrollment were not related to the volume of fluid administration. CONCLUSIONS: Restrictive fluid management did not worsen kidney function and tissue perfusion in adult patients with severe falciparum malaria. We suggest crystalloid administration of 2-3 mL/kg per hour during the first 24 hours without bolus therapy, unless the patient is hypotensive.
Assuntos
Hidratação/métodos , Malária Falciparum/tratamento farmacológico , Injúria Renal Aguda/etiologia , Adulto , Feminino , Hidratação/efeitos adversos , Humanos , Testes de Função Renal , Ácido Láctico/sangue , Malária Falciparum/mortalidade , Masculino , Estudos Prospectivos , Edema Pulmonar/etiologia , Adulto JovemRESUMO
Natural killer (NK) cells provide the first line of defense against malaria parasite infection. However, the molecular mechanisms through which NK cells are activated by parasites are largely unknown, so is the molecular basis underlying the variation in NK cell responses to malaria infection in the human population. Here, we compared transcriptional profiles of responding and non-responding NK cells following exposure to Plasmodium-infected red blood cells (iRBCs) and identified MDA5, a RIG-I-like receptor involved in sensing cytosolic RNAs, to be differentially expressed. Knockout of MDA5 in responding human NK cells by CRISPR/cas9 abolished NK cell activation, IFN-γ secretion, lysis of iRBCs. Similarly, inhibition of TBK1/IKKε, an effector molecule downstream of MDA5, also inhibited activation of responding NK cells. Conversely, activation of MDA5 by liposome-packaged poly I:C restored non-responding NK cells to lyse iRBCs. We further show that microvesicles containing large parasite RNAs from iRBCs activated NK cells by fusing with NK cells. These findings suggest that NK cells are activated through the MDA5 pathway by parasite RNAs that are delivered to the cytoplasm of NK cells by microvesicles from iRBCs. The difference in MDA5 expression between responding and non-responding NK cells following exposure to iRBCs likely contributes to the variation in NK cell responses to malaria infection in the human population.
Assuntos
Micropartículas Derivadas de Células/imunologia , Eritrócitos/imunologia , Helicase IFIH1 Induzida por Interferon/metabolismo , Células Matadoras Naturais/imunologia , Malária Falciparum/imunologia , Plasmodium falciparum/imunologia , Sistemas CRISPR-Cas , Células Cultivadas , Citoplasma/metabolismo , Eritrócitos/metabolismo , Eritrócitos/parasitologia , Humanos , Helicase IFIH1 Induzida por Interferon/antagonistas & inibidores , Helicase IFIH1 Induzida por Interferon/genética , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/parasitologia , Ativação Linfocitária , Malária Falciparum/metabolismo , Malária Falciparum/parasitologia , Plasmodium falciparum/isolamento & purificaçãoRESUMO
BACKGROUND: Acidosis in severe Plasmodium falciparum malaria is associated with high mortality, yet the pathogenesis remains incompletely understood. The aim of this study was to determine the nature and source of metabolic acids contributing to acidosis in patients with severe falciparum malaria. METHODS: A prospective observational study was conducted to characterize circulating acids in adults with P. falciparum malaria (n = 107) and healthy controls (n = 45) from Bangladesh using high-resolution liquid chromatography-mass spectrometry metabolomics. Additional in vitro P. falciparum culture studies were performed to determine if parasites release the acids detected in plasma from patients with severe malaria acidosis. RESULTS: We identified previously unmeasured plasma acids strongly associated with acidosis in severe malaria. Metabolomic analysis of P. falciparum parasites in vitro showed no evidence that these acids are released by the parasite during its life cycle. Instead, 10 of the plasma acids could be mapped to a gut microbial origin. Patients with malaria had low L-citrulline levels, a plasma marker indicating reduced gut barrier integrity. Longitudinal data showed the clearance of these newly identified acids was delayed in fatal cases. CONCLUSIONS: These data suggest that a compromise in intestinal barrier function may contribute significantly to the pathogenesis of life-threatening acidosis in severe falciparum malaria. CLINICAL TRIALS REGISTRATION: NCT02451904.
Assuntos
Acidose/metabolismo , Ácidos/metabolismo , Malária Falciparum/metabolismo , Metabolômica , Plasmodium falciparum/fisiologia , Acidose/complicações , Acidose/parasitologia , Adulto , Biomarcadores/sangue , Cromatografia Líquida , Feminino , Humanos , Mucosa Intestinal , Malária Falciparum/complicações , Malária Falciparum/parasitologia , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
BACKGROUND: Severe falciparum malaria is a medical emergency characterised by potentially lethal vital organ dysfunction. Patient fatality rates even with parenteral artesunate treatment remain high. Despite considerable research into adjuvant therapies targeting organ and tissue dysfunction, none have shown efficacy apart from renal replacement therapy. Understanding the causal contributions of clinical and laboratory abnormalities to mortality is essential for the design and evaluation of novel therapeutic interventions. METHODS AND FINDINGS: We used a structural model causal inference approach to investigate causal relationships between epidemiological, laboratory, and clinical variables in patients with severe falciparum malaria enrolled in clinical trials and their in-hospital mortality. Under this causal model, we analysed records from 9,040 hospitalised children (0-12 years, n = 5,635) and adults (n = 3,405, 12-87 years) with severe falciparum malaria from 15 countries in Africa and Asia who were studied prospectively over the past 35 years. On admission, patient covariates associated with increased in-hospital mortality were severity of acidosis (odds ratio [OR] 2.10 for a 7-mEq/L increase in base deficit [95% CI 1.93-2.28]), renal impairment (OR 1.71 for a 2-fold increase in blood urea nitrogen [95% CI 1.58, 1.86]), coma (OR 3.59 [95% CI 3.07-4.21]), seizures (OR 1.40 [95% CI 1.16-1.68]), shock (OR 1.51 [95% CI 1.14-1.99]), and presumed pulmonary oedema (OR 1.58 [95% CI 1.04-2.39]). Lower in-hospital mortality was associated with moderate anaemia (OR 0.87 for a decrease of 10 percentage points in haematocrit [95% CI 0.80-0.95]). Circulating parasite density was not associated with mortality (OR 1.02 for a 6-fold increase [95% CI 0.94-1.11]), so the pathological effects of parasitaemia appear to be mediated entirely by the downstream effects of sequestration. Treatment with an artemisinin derivative decreased mortality compared with quinine (OR 0.64 [95% CI 0.56-0.74]). These estimates were consistent across children and adults (mainly representing African and Asian patients, respectively). Using inverse probability weighting, transfusion was not estimated to be beneficial in children with admission haematocrit values between 15% and 25% (OR 0.99 [95% CI 0.97-1.02]). Except for the effects of artemisinin treatment and transfusion, causal interpretations of these estimates could be biased by unmeasured confounding from severe bacterial sepsis, immunity, and duration of illness. CONCLUSION: These data suggest that moderate anaemia is associated with a reduced risk of death in severe falciparum malaria. This is possibly a direct causal association. The severe anaemia threshold criteria for a definition of severe falciparum malaria should be reconsidered.
Assuntos
Malária Falciparum/etiologia , Acidose/parasitologia , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Nitrogênio da Ureia Sanguínea , Criança , Pré-Escolar , Coma/etiologia , Feminino , Mortalidade Hospitalar , Humanos , Lactente , Recém-Nascido , Malária Falciparum/complicações , Malária Falciparum/mortalidade , Malária Falciparum/patologia , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Edema Pulmonar/etiologia , Estudos Retrospectivos , Convulsões/etiologia , Choque/etiologia , Adulto JovemRESUMO
BACKGROUND: Lactic acidosis with an elevated lactate-pyruvate ratio suggesting anoxia is a common feature of severe falciparum malaria. High lactate levels are associated with parasitized erythrocyte sequestration in the microcirculation. To assess if there is an additional contribution to hyperlactataemia from relatively inadequate total oxygen delivery, oxygen consumption and delivery were investigated in patients with malaria. METHODS: Adult Bangladeshi and Indian patients with uncomplicated (N = 50) or severe (N = 46) falciparum malaria or suspected bacterial sepsis (N = 27) and healthy participants as controls (N = 26) were recruited at Chittagong Medical College Hospital, Chittagong, Bangladesh and Ispat General Hospital, Rourkela, India. Oxygen delivery (DO2I) was estimated from pulse oximetry, echocardiographic estimates of cardiac index and haematocrit. Oxygen consumption (VO2I) was estimated by expired gas collection. RESULTS: VO2I was elevated in uncomplicated median (IQR) 185.1 ml/min/m2 (135-215.9) and severe malaria 192 ml/min/m2 (140.7-227.9) relative to healthy persons 107.9 ml/min/m2 (69.9-138.1) (both p < 0.001). Median DO2I was similar in uncomplicated 515 ml/min/m2 (432-612) and severe 487 ml/min/m2 (382-601) malaria and healthy persons 503 ml/min/m2 (447-517) (p = 0.27 and 0.89, respectively). The VO2/DO2 ratio was, therefore, increased by similar amounts in both uncomplicated 0.35 (0.28-0.44) and severe malaria 0.38 (0.29-0.48) relative to healthy participants 0.23 (0.17-0.28) (both p < 0.001). VO2I, DO2I and VO2/DO2 did not correlate with plasma lactate concentrations in severe malaria. CONCLUSIONS: Reduced total oxygen delivery is not a major contributor to lactic acidosis in severe falciparum malaria.
Assuntos
Acidose Láctica/metabolismo , Malária Falciparum/metabolismo , Consumo de Oxigênio/fisiologia , Sepse/metabolismo , Adulto , Bangladesh , Feminino , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Background: Acute kidney injury independently predicts mortality in falciparum malaria. It is unknown whether acetaminophen's capacity to inhibit plasma hemoglobin-mediated oxidation is renoprotective in severe malaria. Methods: This phase 2, open-label, randomized controlled trial conducted at two hospitals in Bangladesh assessed effects on renal function, safety, pharmacokinetic (PK) properties and pharmacodynamic (PD) effects of acetaminophen. Febrile patients (>12 years) with severe falciparum malaria were randomly assigned to receive acetaminophen (1 g 6-hourly for 72 hours) or no acetaminophen, in addition to intravenous artesunate. Primary outcome was the proportional change in creatinine after 72 hours stratified by median plasma hemoglobin. Results: Between 2012 and 2014, 62 patients were randomly assigned to receive acetaminophen (n = 31) or no acetaminophen (n = 31). Median (interquartile range) reduction in creatinine after 72 hours was 23% (37% to 18%) in patients assigned to acetaminophen, versus 14% (29% to 0%) in patients assigned to no acetaminophen (P = .043). This difference in reduction was 37% (48% to 22%) versus 14% (30% to -71%) in patients with hemoglobin ≥45000 ng/mL (P = .010). The proportion with progressing kidney injury was higher among controls (subdistribution hazard ratio, 3.0; 95% confidence interval, 1.1 to 8.5; P = .034). PK-PD analyses showed that higher exposure to acetaminophen increased the probability of creatinine improvement. No patient fulfilled Hy's law for hepatotoxicity. Conclusions: In this proof-of-principle study, acetaminophen showed renoprotection without evidence of safety concerns in patients with severe falciparum malaria, particularly in those with prominent intravascular hemolysis. Clinical Trials Registration: NCT01641289.
Assuntos
Acetaminofen/uso terapêutico , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/prevenção & controle , Artesunato/efeitos adversos , Artesunato/uso terapêutico , Malária Falciparum/tratamento farmacológico , Acetaminofen/administração & dosagem , Acetaminofen/farmacocinética , Adolescente , Adulto , Analgésicos não Narcóticos/administração & dosagem , Analgésicos não Narcóticos/farmacocinética , Analgésicos não Narcóticos/uso terapêutico , Antimaláricos/efeitos adversos , Antimaláricos/uso terapêutico , Área Sob a Curva , Feminino , Humanos , Masculino , Adulto JovemRESUMO
We conducted a yearlong prospective study of febrile patients admitted to a tertiary referral hospital in Chittagong, Bangladesh, to assess the proportion of patients with rickettsial illnesses and identify the causative pathogens, strain genotypes, and associated seasonality patterns. We diagnosed scrub typhus in 16.8% (70/416) and murine typhus in 5.8% (24/416) of patients; 2 patients had infections attributable to undifferentiated Rickettsia spp. and 2 had DNA sequence-confirmed R. felis infection. Orientia tsutsugamushi genotypes included Karp, Gilliam, Kato, and TA763-like strains, with a prominence of Karp-like strains. Scrub typhus admissions peaked in a biphasic pattern before and after the rainy season, whereas murine typhus more frequently occurred before the rainy season. Death occurred in 4% (18/416) of cases; case-fatality rates were 4% each for scrub typhus (3/70) and murine typhus (1/28). Overall, 23.1% (96/416) of patients had evidence of treatable rickettsial illnesses, providing important evidence toward optimizing empirical treatment strategies.
Assuntos
Febre/epidemiologia , Febre/microbiologia , Infecções por Rickettsia/epidemiologia , Infecções por Rickettsia/microbiologia , Rickettsia , Animais , Bangladesh/epidemiologia , Febre/diagnóstico , Humanos , Camundongos , Filogenia , Reação em Cadeia da Polimerase , Vigilância da População , Prevalência , Rickettsia/classificação , Rickettsia/genética , Infecções por Rickettsia/diagnóstico , Estações do Ano , Testes SorológicosRESUMO
BACKGROUND: In severe falciparum malaria metabolic acidosis and acute kidney injury (AKI) are independent predictors of a fatal outcome in all age groups. The relationship between plasma acids, urine acids and renal function was investigated in adult patients with acute falciparum malaria. METHODS: Plasma and urinary acids which previously showed increased concentrations in proportion to disease severity in patients with severe falciparum malaria were quantified. Patients with uncomplicated malaria, sepsis and healthy volunteers served as comparator groups. Multiple regression and multivariate analysis were used to assess the relationship between organic acid concentrations and clinical syndromes, in particular AKI. RESULTS: Patients with severe malaria (n = 90), uncomplicated malaria (n = 94), non-malaria sepsis (n = 19), and healthy volunteers (n = 61) were included. Univariate analysis showed that both plasma and creatinine-adjusted urine concentrations of p-hydroxyphenyllactic acid (pHPLA) were higher in severe malaria patients with AKI (p < 0.001). Multiple regression analysis, including plasma or creatinine-adjusted urinary acids, and PfHRP2 as parasite biomass marker as independent variables, showed that pHPLA was independently associated with plasma creatinine (ß = 0.827) and urine creatinine (ß = 0.226). Principal component analysis, including four plasma acids and seven urinary acids separated a group of patients with AKI, which was mainly driven by pHPLA concentrations. CONCLUSIONS: Both plasma and urine concentrations of pHPLA closely correlate with AKI in patients with severe falciparum malaria. Further studies will need to assess the potential nephrotoxic properties of pHPLA.
Assuntos
Acidose/metabolismo , Injúria Renal Aguda/metabolismo , Malária Falciparum/complicações , Fenilpropionatos/sangue , Fenilpropionatos/urina , Sepse/complicações , Acidose/parasitologia , Acidose/fisiopatologia , Ácidos/sangue , Ácidos/urina , Injúria Renal Aguda/parasitologia , Injúria Renal Aguda/fisiopatologia , Adulto , Bangladesh , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Control of malaria increasingly involves administration of 8-aminoquinolines, with accompanying risk of haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Few data on the prevalence and genotypic basis of G6PD deficiency are available from Bangladesh, where malaria remains a major problem in the South (Chittagong Division). The aim of this study was to determine the prevalence of G6PD deficiency, and associated G6PD genotypes, in adults with falciparum malaria in southern Bangladesh. METHODS: G6PD status was assessed via a combination of fluorescent spot testing (FST) and genotyping in 141 Bengali patients admitted with falciparum malaria to two centres in Chittagong Division from 2012 to 2014. In addition, an analysis of genomic data from 1000 Genomes Project was carried out among five healthy Indian subcontinent populations. RESULTS: One male patient with uncomplicated malaria was found to have G6PD deficiency on FST and a genotype associated with deficiency (hemizygous Orissa variant). In addition, there were two female patients heterozygous for deficiency variants (Orissa and Kerala-Kalyan). These three patients had a relatively long duration of symptoms prior to admission compared to G6PD normal cases, possibly suggesting an interaction with parasite multiplication rate. In addition, one of 27 healthy local controls was deficient on FST and hemizygous for the Mahidol variant of G6PD deficiency. Examination of 1000 Genomes Project sequencing data across the Indian subcontinent showed that 19/723 chromosomes (2.63%) carried a variant associated with deficiency. In the Bengali from Bangladesh 1000 Genomes population, three of 130 chromosomes (2.31%) carried deficient alleles; this included single chromosomes carrying the Kerala-Kalyan and Orissa variants. CONCLUSIONS: In line with other recent work, G6PD deficiency is uncommon in Bengalis in Bangladesh. Further studies of particular ethnic groups are needed to evaluate the potential risk of wide deployment of primaquine in malaria control efforts in Bangladesh.
Assuntos
Deficiência de Glucosefosfato Desidrogenase/epidemiologia , Deficiência de Glucosefosfato Desidrogenase/patologia , Malária Falciparum/complicações , Adulto , Bangladesh/epidemiologia , Testes Diagnósticos de Rotina , Etnicidade , Feminino , Técnicas de Genotipagem , Deficiência de Glucosefosfato Desidrogenase/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
BACKGROUND: Intravascular hemolysis is an intrinsic feature of severe malaria pathophysiology but the pathogenic role of cell-free hemoglobin-mediated oxidative stress in severe malaria associated acute kidney injury (AKI) is unknown. METHODS: As part of a prospective observational study, enrolment plasma cell-free hemoglobin (CFH), lipid peroxidation markers (F2-isoprostanes (F2-IsoPs) and isofurans (IsoFs)), red cell deformability, and serum creatinine were quantified in Bangladeshi patients with severe falciparum malaria (n = 107), uncomplicated malaria (n = 80) and sepsis (n = 28). The relationships between these indices and kidney function and clinical outcomes were examined. RESULTS: AKI was diagnosed at enrolment in 58% (62/107) of consecutive patients with severe malaria, defined by an increase in creatinine ≥1.5 times expected baseline. Severe malaria patients with AKI had significantly higher plasma cell-free hemoglobin (geometric mean CFH: 8.8 µM; 95% CI, 6.2-12.3 µM), F2-isoprostane (56.7 pg/ml; 95% CI, 45.3-71.0 pg/ml) and isofuran (109.2 pg/ml; 95% CI, 85.1-140.1 pg/ml) concentrations on enrolment compared to those without AKI (CFH: 5.1 µM; 95% CI, 4.0-6.6 µM; P = 0.018; F2-IsoPs: 27.8 pg/ml; 95% CI, 23.7-32.7 pg/ml; P < 0.001; IsoFs: 41.7 pg/ml; 95% CI, 30.2-57.6 pg/ml; P < 0.001). Cell-free hemoglobin correlated with markers of hemolysis, parasite burden (P. falciparum histidine rich protein 2 (PfHRP2)), and F2-IsoPs. Plasma F2-IsoPs and IsoFs inversely correlated with pH, positively correlated with creatinine, PfHRP2 and fractional excretion of sodium, and were higher in patients later requiring hemodialysis. Plasma F2-IsoP concentrations also inversely correlated with red cell deformability and were higher in fatal cases. Mixed effects modeling including an interaction term for CFH and time showed that F2-IsoPs, IsoFs, PfHRP2, CFH, and red cell rigidity were independently associated with increasing creatinine over 72 h. Multivariable logistic regression showed that admission F2-IsoPs, IsoFs and red cell deformability were associated with the need for subsequent hemodialysis. CONCLUSIONS: Cell-free hemoglobin and lipid peroxidation are associated with acute kidney injury and disease severity in falciparum malaria, suggesting a pathophysiological role in renal tubular injury. Evaluation of adjunctive therapies targeting cell-free hemoglobin-mediated oxidative stress is warranted.
Assuntos
Injúria Renal Aguda/etiologia , Hemoglobinas/metabolismo , Malária Falciparum/metabolismo , Estresse Oxidativo , Injúria Renal Aguda/mortalidade , Injúria Renal Aguda/terapia , Adulto , Antígenos de Protozoários/sangue , Biomarcadores/sangue , Creatinina/sangue , Eritrócitos/patologia , F2-Isoprostanos/sangue , F2-Isoprostanos/urina , Feminino , Humanos , Peroxidação de Lipídeos , Malária Falciparum/complicações , Malária Falciparum/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Proteínas de Protozoários/sangue , Diálise Renal , Sepse/sangue , Sepse/etiologiaRESUMO
INTRODUCTION: Severe falciparum malaria is commonly complicated by metabolic acidosis. Together with lactic acid (LA), other previously unmeasured acids have been implicated in the pathogenesis of falciparum malaria. METHODS: In this prospective study, we characterised organic acids in adults with severe falciparum malaria in India and Bangladesh. Liquid chromatography-mass spectrometry was used to measure organic acids in plasma and urine. Patients were followed until recovery or death. RESULTS: Patients with severe malaria (n=138), uncomplicated malaria (n=102), sepsis (n=32) and febrile encephalopathy (n=35) were included. Strong ion gap (mean ± SD) was elevated in severe malaria (8.2 mEq/L ± 4.5) and severe sepsis (8.6 mEq/L ± 7.7) compared with uncomplicated malaria (6.0 mEq/L ± 5.1) and encephalopathy (6.6 mEq/L ± 4.7). Compared with uncomplicated malaria, severe malaria was characterised by elevated plasma LA, hydroxyphenyllactic acid (HPLA), α-hydroxybutyric acid and ß-hydroxybutyric acid (all P<0.05). In urine, concentrations of methylmalonic, ethylmalonic and α-ketoglutaric acids were also elevated. Multivariate logistic regression showed that plasma HPLA was a strong independent predictor of death (odds ratio [OR] 3.5, 95 % confidence interval [CI] 1.6-7.5, P=0.001), comparable to LA (OR 3.5, 95 % CI 1.5-7.8, P=0.003) (combined area under the receiver operating characteristic curve 0.81). CONCLUSIONS: Newly identified acids, in addition to LA, are elevated in patients with severe malaria and are highly predictive of fatal outcome. Further characterisation of their sources and metabolic pathways is now needed.
Assuntos
Malária Falciparum/etiologia , Ácido 3-Hidroxibutírico/sangue , Acidose/complicações , Adolescente , Adulto , Idoso , Cromatografia Líquida , Feminino , Humanos , Hidroxibutiratos/sangue , Ácidos Cetoglutáricos/urina , Ácido Láctico/sangue , Malária Falciparum/sangue , Malária Falciparum/metabolismo , Malária Falciparum/mortalidade , Malária Falciparum/urina , Masculino , Malonatos/urina , Espectrometria de Massas , Ácido Metilmalônico/urina , Pessoa de Meia-Idade , Fenilpropionatos/sangue , Estudos Prospectivos , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: Little is known about the prevalence of antimicrobial resistance (AMR) amongst bacterial pathogens in sub-Saharan Africa (sSA), despite calls for continent-wide surveillance to inform empirical treatment guidelines. METHODS: We searched PubMed and additional databases for susceptibility data of key pathogens for surveillance, published between 1990 and 2013. Extracted data were standardized to a prevalence of resistance in populations of isolates and reported by clinical syndrome, microorganism, relevant antimicrobial drugs and region. RESULTS: We identified 2005 publications, of which 190 were analysed. Studies predominantly originated from east sSA (61%), were hospital based (60%), were from an urban setting (73%) and reported on isolates from patients with a febrile illness (42%). Quality procedures for susceptibility testing were described in <50% of studies. Median prevalence (MP) of resistance to chloramphenicol in Enterobacteriaceae, isolated from patients with a febrile illness, ranged between 31.0% and 94.2%, whilst MP of resistance to third-generation cephalosporins ranged between 0.0% and 46.5%. MP of resistance to nalidixic acid in Salmonella enterica Typhi ranged between 15.4% and 43.2%. The limited number of studies providing prevalence data on AMR in Gram-positive pathogens or in pathogens isolated from patients with a respiratory tract infection, meningitis, urinary tract infection or hospital-acquired infection suggested high prevalence of resistance to chloramphenicol, trimethoprim/sulfamethoxazole and tetracycline and low prevalence to third-generation cephalosporins and fluoroquinolones. CONCLUSIONS: Our results indicate high prevalence of AMR in clinical bacterial isolates to antimicrobial drugs commonly used in sSA. Enhanced approaches for AMR surveillance are needed to support empirical therapy in sSA.
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Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Infecções Bacterianas/microbiologia , Farmacorresistência Bacteriana , África Subsaariana/epidemiologia , Bactérias/classificação , Bactérias/isolamento & purificação , Infecções Bacterianas/epidemiologia , Humanos , PrevalênciaRESUMO
Histoplasmosis is a frequent cause of infections in people living with HIV/AIDS (PLWHA). This study introduces the application of a Histoplasma capsulatum urine antigen lateral flow assay (LFA) for diagnosing disseminated histoplasmosis in PLWHA in Suriname. The LFA's diagnostic accuracy was compared with the current diagnostic approach, aiming to assess whether this test resulted in improved early detection and management. Additionally, the prevalence of histoplasmosis among advanced stage HIV patients without clinical suspicion of infection was evaluated using the same LFA. In total, 98 patients were included in the study, of which 58 were classified as "possible disseminated histoplasmosis (DH)" based on clinical criteria and 40 as "controls". Of these possible DH cases, only 19 (32.7%) had a positive LFA. During the study, decisions for treatment were made without the treating physician being aware of the LFA result. Only 55% of the patients who started treatment for histoplasmosis based on clinical criteria had a positive LFA, and 21% of untreated patients had a positive LFA. This study shows that combining clinical signs with LFA results enhances diagnostic accuracy and is cost effective, resulting in better treatment decisions.
Assuntos
Infecções por HIV , Histoplasma , Histoplasmose , Humanos , Histoplasmose/diagnóstico , Masculino , Feminino , Adulto , Suriname , Histoplasma/isolamento & purificação , Infecções por HIV/complicações , Pessoa de Meia-Idade , Antígenos de Fungos/urina , Sensibilidade e Especificidade , Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Infecções Oportunistas Relacionadas com a AIDS/urina , Infecções Oportunistas Relacionadas com a AIDS/microbiologia , Imunoensaio/métodosRESUMO
Background: A growing global shortage of health workers is limiting access to health care, especially in resource-limited countries. Family participation in hospital care could enhance care while tackling health worker shortages. With the same resources, it might deliver additional and more personalised care. This review assessed the effect and safety of family participation interventions in the care of hospitalised adults in resource-limited settings and, ultimately, if it is a viable strategy to tackle health worker shortages. Methods: For this systematic review, Medline, Embase, CINAHL and the Global Health Library were searched from inception till April 7, 2022. Clinical studies were included if they described a family participation intervention for hospitalised adults, were performed in a low- or middle-income country and reported on a patient-related outcome. Data were collected on patient, family, staff and health service-related outcomes. Risk of bias was assessed with the ROB2 and ROBINS-I tool. Results: From 4444 studies, six were included for narrative synthesis, with a total of 1794 participants. Four studies were performed in Asia and two in Africa; all were published between 2017 and 2022. In-hospital family participation interventions aimed at medication administration and adherence, delirium prevention, and palliative cancer care were successful in significantly improving patient outcomes. Involving family in post-stroke rehabilitation interventions showed no significant effect on mortality and long-term disability. Few data were reported on participating family members' outcomes or hospital staffing issues. None of the included studies showed harm from family participation. Conclusions: The limited data suggest that family participation can be effective and safe in specific contexts. However, more research is needed to determine the effect of family participation and justify further implementation. Family participation research for enhancing care while tackling health worker shortages should be a collaborative priority of researchers, health care professionals, funding agencies and policymakers. Registration: PROSPERO registration No. CRD42020205878.
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Atenção à Saúde , Família , Recursos Humanos em Hospital , Adulto , Humanos , Atenção à Saúde/organização & administração , Hospitais , Países em Desenvolvimento , Recursos Humanos em Hospital/provisão & distribuiçãoRESUMO
Severe falciparum malaria has substantially affected human evolution. Genetic association studies of patients with clinically defined severe malaria and matched population controls have helped characterise human genetic susceptibility to severe malaria, but phenotypic imprecision compromises discovered associations. In areas of high malaria transmission, the diagnosis of severe malaria in young children and, in particular, the distinction from bacterial sepsis are imprecise. We developed a probabilistic diagnostic model of severe malaria using platelet and white count data. Under this model, we re-analysed clinical and genetic data from 2220 Kenyan children with clinically defined severe malaria and 3940 population controls, adjusting for phenotype mis-labelling. Our model, validated by the distribution of sickle trait, estimated that approximately one-third of cases did not have severe malaria. We propose a data-tilting approach for case-control studies with phenotype mis-labelling and show that this reduces false discovery rates and improves statistical power in genome-wide association studies.
In areas of sub-Saharan Africa where malaria is common, most people are frequently exposed to the bites of mosquitoes carrying malaria parasites, so they often have malaria parasites in their blood. Young children, who have not yet built up strong immunity against malaria, often fall ill with severe malaria, a life-threatening disease. It is unclear why some children develop severe malaria and die, while other children with high numbers of parasites in their blood do not develop any apparent symptoms. Genetic susceptibility studies are designed to uncover why such differences exist by comparing individuals with severe malaria (referred to as 'cases') with individuals drawn from the general population (known as 'controls'). But severe malaria can be a challenge to diagnose. Since high numbers of malaria parasites can be found in healthy children, it is sometimes difficult to determine whether the parasites are making a child ill, or whether they are a coincidental finding. Consequently, some of the 'cases' recruited into these studies may actually have a different disease, such as bacterial sepsis. This ultimately affects how the studies are interpreted, and introduces error and inaccuracy into the data. Watson, Ndila et al. investigated whether measuring blood biomarkers in patients (derived from the complete blood count, including platelet counts and white blood cell counts) could improve the accuracy with which malaria is diagnosed. They developed a new mathematical model that incorporates platelet and white blood cell counts. This model estimates that in a large cohort of 2,220 Kenyan children diagnosed with severe malaria, around one third of enrolled children did not actually have this disease. Further analysis suggests that patients with severe malaria are highly unlikely to have platelet counts higher than 200,000 per microlitre. This defines a cut-off that researchers can use to avoid recruiting patients who do not have severe malaria in future studies. Additionally, the ability to diagnose severe malaria more accurately can make it easier to detect and treat other diseases with similar symptoms in children with high numbers of malaria parasites in their blood. Watson, Ndila et al.'s findings support the recommendation that all children with suspected malaria be given broad spectrum antibiotics, as many misdiagnosed children will likely have bacterial sepsis. It also suggests that using complete blood counts, which are cheap to obtain and increasingly available in low-resource settings, could improve diagnostic accuracy in future clinical studies of severe malaria. This could ultimately improve the ability of these studies to find new treatments for this life-threatening disease.