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1.
J Infect Dis ; 221(9): 1518-1527, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-31693130

RESUMO

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 Jovem
2.
J Infect Dis ; 221(2): 285-292, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31504666

RESUMO

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 Jovem
3.
J Infect Dis ; 221(1): 127-137, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31693729

RESUMO

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 Jovem
4.
J Infect Dis ; 219(11): 1766-1776, 2019 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-30566600

RESUMO

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 Jovem
5.
Clin Infect Dis ; 67(7): 991-999, 2018 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-29538635

RESUMO

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 Jovem
6.
Malar J ; 16(1): 134, 2017 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-28356147

RESUMO

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 Prospectivos
7.
BMC Infect Dis ; 17(1): 313, 2017 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-28449641

RESUMO

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/etiologia
8.
BMC Med ; 13: 122, 2015 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-26018532

RESUMO

BACKGROUND: Microvascular obstruction and endothelial dysfunction have both been linked to tissue hypoperfusion in falciparum malaria, but their relative contributions to the disease's pathogenesis and outcome are unknown. METHODS: Microvascular blood flow was quantified in adults with severe falciparum malaria on their admission to hospital; plasma biomarkers of endothelial function were measured simultaneously. The relationship between these indices and the patients' clinical findings and in-hospital course was examined. RESULTS: Microvascular obstruction was observed in 119/142 (84 %) patients; a median (interquartile range (IQR)) of 14.9 % (6.6-34.9 %) of capillaries were obstructed in patients that died versus 8.3 % (1.7-26.6 %) in survivors (P = 0.039). The proportion of obstructed capillaries correlated with the estimated parasite biomass (rs = 0.25, P = 0.004) and with plasma lactate (rs = 0.38, P <0.0001), the strongest predictor of death in the series. Plasma angiopoietin-2 (Ang-2) concentrations were markedly elevated suggesting widespread endothelial activation; the median (IQR) Ang-2 concentration was 21.9 ng/mL (13.4-29.4 ng/mL) in patients that died versus 14.9 ng/mL (9.8-29.3 ng/mL) in survivors (P = 0.035). Ang-2 concentrations correlated with estimated parasite biomass (rs = 0.35, P <0.001) and plasma lactate (rs = 0.37, P <0.0001). Microvascular obstruction and Ang-2 concentrations were not significantly correlated with each other (rs = 0.17, P = 0.06), but were independently associated with plasma lactate (P <0.001 and P = 0.002, respectively). CONCLUSIONS: Microvascular obstruction and systemic endothelial activation are independently associated with plasma lactate, the strongest predictor of death in adults with falciparum malaria. This supports the hypothesis that the two processes make an independent contribution to the pathogenesis and clinical manifestations of the disease.


Assuntos
Capilares/patologia , Células Endoteliais/patologia , Malária Falciparum/sangue , Malária Falciparum/complicações , Malária Falciparum/patologia , Adulto , Células Endoteliais/metabolismo , Feminino , Humanos , Masculino , Microcirculação , Pessoa de Meia-Idade
9.
BMC Med ; 13: 97, 2015 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-25907925

RESUMO

BACKGROUND: Thrombocytopenia is a common finding in adults with severe falciparum malaria, but its clinical and prognostic utility is incompletely defined. METHODS: Clinical and laboratory data from 647 adults with severe falciparum malaria were analysed retrospectively to determine the relationship between a patient's platelet count on admission to hospital and their subsequent clinical course. RESULTS: On admission, 614 patients (94.9%) were thrombocytopenic (platelet count <150 × 10(9)/L) and 328 (50.7%) had a platelet count <50 × 10(9)/L. The admission platelet count was inversely correlated with parasite biomass (estimated from plasma PfHRP2 concentrations, rs = -0.28, P = 0.003), the degree of microvascular sequestration (measured with orthogonal polarizing spectral imaging, rs = -0.31, P = 0.001) and disease severity (the number of World Health Organization severity criteria satisfied by the patient, rs = -0.21, P <0.001). Platelet counts were lower on admission in the patients who died (median: 30 (interquartile range 22 to 52) × 10(9)/L versus 50 (34 to 78) × 10(9)/L in survivors; P <0.001), but did not predict outcome independently from other established laboratory and clinical prognostic indices. The 39 patients (6%) with profound thrombocytopenia (platelet count <20 × 10(9)/L) were more likely to die (odds ratio: 5.00, 95% confidence interval: 2.56 to 9.75) than patients with higher platelet counts, but these high-risk patients could be identified more rapidly with simple bedside clinical assessment. The admission platelet count did not reliably identify the 50 patients (7.7%) with major bleeding during the study. CONCLUSIONS: Thrombocytopenia is a marker of disease severity in adults with falciparum malaria, but has limited utility in prognostication, triage and management.


Assuntos
Malária Falciparum/complicações , Trombocitopenia/etiologia , Adulto , Biomarcadores/sangue , Feminino , Humanos , Malária Falciparum/mortalidade , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Prognóstico , Estudos Retrospectivos , Trombocitopenia/mortalidade , Adulto Jovem
10.
Malar J ; 14: 246, 2015 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-26081927

RESUMO

BACKGROUND: Severe falciparum malaria may be complicated by haemolysis after parasite clearance, however the mechanisms remain unclear. Recent reports describe a pattern of delayed onset haemolysis among non-immune travellers with hyperparasitaemia treated with intravenous artesunate, termed post-artesunate delayed haemolysis (PADH). The occurrence and clinical impact of PADH following severe malaria infections in areas of unstable transmission are unknown. CASE: A 45-year-old Bangladeshi male was initially admitted to a local hospital with severe falciparum malaria complicated by hyperparasitaemia and treated with intravenous artesunate. Twenty days from his first presentation he was readmitted with delayed onset haemolytic anaemia and acute kidney injury. Multiple blood transfusions and haemodialysis were required. Renal biopsy revealed acute tubular injury and haem pigment nephropathy. His haemoglobin and renal function recovered to baseline after 62 days from his second admission. DISCUSSION: This case highlights the differential diagnosis of post-malaria delayed onset haemolysis, including the recently described syndrome of post-artemisinin delayed haemolysis. The pathophysiology contributing to acute kidney injury in this patient and the limited treatment options are discussed. CONCLUSIONS: This report describes PADH complicated by acute kidney injury in an adult patient living in a malaria hypoendemic region who subsequently required blood transfusions and haemodialysis. This case emphasizes the importance of routine follow up of haemoglobin and renal function in artesunate-treated patients who have recovered from severe malaria.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Anemia Hemolítica/tratamento farmacológico , Artemisininas/uso terapêutico , Malária Falciparum/tratamento farmacológico , Parasitemia/tratamento farmacológico , Injúria Renal Aguda/parasitologia , Administração Intravenosa , Anemia Hemolítica/parasitologia , Artesunato , Bangladesh , Humanos , Malária Falciparum/complicações , Masculino , Pessoa de Meia-Idade , Parasitemia/complicações , Resultado do Tratamento
11.
Crit Care ; 19: 317, 2015 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-26343146

RESUMO

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 Jovem
13.
Infect Dis Clin North Am ; 33(1): 39-60, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30712767

RESUMO

The global burden of malaria remains high, with 216 million cases causing 445,000 deaths in 2016 despite first-line treatment with artemisinin-based combination therapy. Decreasing transmission in Africa shifts the risk for severe malaria to older age groups as premunition wanes. Prompt diagnosis and treatment with intravenous artesunate in addition to appropriate supportive management are critical to reduce deaths from severe malaria. Effective individual management is challenging in settings with limited resources for higher-level care. Adjunctive therapies targeting the underlying pathophysiological pathways have the potential to reduce mortality. Resistance to artemisinin derivatives and their partner drugs threaten malaria management and control.


Assuntos
Antimaláricos/uso terapêutico , Gerenciamento Clínico , Resistência a Medicamentos , Malária/tratamento farmacológico , Malária/prevenção & controle , Quimioterapia Combinada , Humanos , Malária/diagnóstico , Plasmodium/efeitos dos fármacos
14.
Trop Med Infect Dis ; 3(3)2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30274491

RESUMO

Here we estimated the accuracy of the InBios Scrub Typhus Detect™ immunoglobulin M (IgM) ELISA to determine the optimal optical density (OD) cut-off values for the diagnosis of scrub typhus. Patients with undifferentiated febrile illness from Chittagong, Bangladesh, provided samples for reference testing using (i) qPCR using the Orientia spp. 47-kDa htra gene, (ii) IFA ≥1:3200 on admission, (iii) immunofluorescence assay (IFA) ≥1:3200 on admission or 4-fold rise to ≥3200, and (iv) combination of PCR and IFA positivity. For sero-epidemiological purposes (ELISA vs. IFA ≥1:3200 on admission or 4-fold rise to ≥3200), the OD cut-off for admission samples was ≥1.25, resulting in a sensitivity (Sn) of 91.5 (95% confidence interval (95% CI: 96.8⁻82.5) and a specificity (Sp) of 92.4 (95% CI: 95.0⁻89.0), while for convalescent samples the OD cut-off was ≥1.50 with Sn of 66.0 (95% CI: 78.5⁻51.7) and Sp of 96.0 (95% CI: 98.3⁻92.3). Comparisons against comparator reference tests (ELISA vs. all tests including PCR) indicated the most appropriate cut-off OD to be within the range of 0.75⁻1.25. For admission samples, the best Sn/Sp compromise was at 1.25 OD (Sn 91.5%, Sp 92.4%) and for convalescent samples at 0.75 OD (Sn 69.8%, Sp 89.5%). A relatively high (stringent) diagnostic cut-off value provides increased diagnostic accuracy with high sensitivity and specificity in the majority of cases, while lowering the cut-off runs the risk of false positivity. This study underlines the need for regional assessment of new diagnostic tests according to the level of endemicity of the disease given the high levels of residual or cross-reacting antibodies in the general population.

15.
PLoS One ; 13(12): e0204832, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30540757

RESUMO

INTRODUCTION: Patients with severe malaria or sepsis are at risk of developing life-threatening acute respiratory distress syndrome (ARDS). The objective of this study was to evaluate point-of-care lung ultrasound as a novel tool to determine the prevalence and early signs of ARDS in a resource-limited setting among patients with severe malaria or sepsis. MATERIALS AND METHODS: Serial point-of-care lung ultrasound studies were performed on four consecutive days in a planned sub study of an observational cohort of patients with malaria or sepsis in Bangladesh. We quantified aeration patterns across 12 lung regions. ARDS was defined according to the Kigali Modification of the Berlin Definition. RESULTS: Of 102 patients enrolled, 71 had sepsis and 31 had malaria. Normal lung ultrasound findings were observed in 44 patients on enrolment and associated with 7% case fatality. ARDS was detected in 10 patients on enrolment and associated with 90% case fatality. All patients with ARDS had sepsis, 4 had underlying pneumonia. Two patients developing ARDS during hospitalisation already had reduced aeration patterns on enrolment. The SpO2/FiO2 ratio combined with the number of regions with reduced aeration was a strong prognosticator for mortality in patients with sepsis (AUROC 91.5% (95% Confidence Interval: 84.6%-98.4%)). CONCLUSIONS: This study demonstrates the potential usefulness of point-of-care lung ultrasound to detect lung abnormalities in patients with malaria or sepsis in a resource-constrained hospital setting. LUS was highly feasible and allowed to accurately identify patients at risk of death in a resource limited setting.


Assuntos
Pulmão/diagnóstico por imagem , Malária/diagnóstico por imagem , Sistemas Automatizados de Assistência Junto ao Leito , Síndrome do Desconforto Respiratório/diagnóstico por imagem , Sepse/diagnóstico por imagem , Adulto , Bangladesh , Feminino , Humanos , Masculino , Estudos Prospectivos , Índice de Gravidade de Doença , Ultrassonografia
16.
Sci Transl Med ; 9(397)2017 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-28679662

RESUMO

Artesunate, the recommended drug for severe malaria, rapidly clears the malaria parasite from infected patients but frequently induces anemia-called post-artesunate delayed hemolysis (PADH)-for which a simple predictive test is urgently needed. The underlying event in PADH is the expulsion of artesunate-exposed parasites from their host erythrocytes by pitting. We show that the histidine-rich protein 2 (HRP2) of the malaria parasite Plasmodium falciparum persists in the circulation of artesunate-treated malaria patients in Bangladesh and in French travelers who became infected with malaria in Africa. HRP2 persisted in whole blood (not plasma) of artesunate-treated patients with malaria at higher levels compared to quinine-treated patients. Using an optimized membrane permeabilization method, HRP2 was observed by immunofluorescence, Western blotting, and electron microscopy to persist in once-infected red blood cells from artesunate-treated malaria patients. HRP2 was deposited at the membrane of once-infected red blood cells in a pattern similar to that for ring erythrocyte surface antigen (RESA), a parasite invasion marker. On the basis of these observations, we developed a semiquantitative titration method using a widely available HRP2-based rapid diagnostic dipstick test. Positivity on this test using a 1:500 dilution of whole blood from artesunate-treated patients with malaria collected shortly after parasite clearance predicted subsequent PADH with 89% sensitivity and 73% specificity. These results suggest that adapting an existing HRP2-based rapid diagnostic dipstick test may enable prediction of PADH several days before it occurs in artesunate-treated patients with malaria.


Assuntos
Antígenos de Protozoários/sangue , Artemisininas/uso terapêutico , Hemólise , Malária/sangue , Malária/tratamento farmacológico , Plasmodium falciparum/metabolismo , Proteínas de Protozoários/sangue , Adolescente , Adulto , Idoso , Artemisininas/farmacologia , Artesunato , Citosol/metabolismo , Demografia , Membrana Eritrocítica/efeitos dos fármacos , Membrana Eritrocítica/metabolismo , Eritrócitos/efeitos dos fármacos , Eritrócitos/parasitologia , Eritrócitos/ultraestrutura , Feminino , Humanos , Malária/parasitologia , Masculino , Pessoa de Meia-Idade , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/patogenicidade , Quinina/farmacologia , Quinina/uso terapêutico , Adulto Jovem
17.
PLoS One ; 11(4): e0152965, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27054362

RESUMO

Delays in seeking appropriate healthcare can increase the case fatality of acute febrile illnesses, and circuitous routes of care-seeking can have a catastrophic financial impact upon patients in low-income settings. To investigate the relationship between poverty and pre-hospital delays for patients with acute febrile illnesses, we recruited a cross-sectional, convenience sample of 527 acutely ill adults and children aged over 6 months, with a documented fever ≥38.0 °C and symptoms of up to 14 days' duration, presenting to a tertiary referral hospital in Chittagong, Bangladesh, over the course of one year from September 2011 to September 2012. Participants were classified according to the socioeconomic status of their households, defined by the Oxford Poverty and Human Development Initiative's multidimensional poverty index (MPI). 51% of participants were classified as multidimensionally poor (MPI>0.33). Median time from onset of any symptoms to arrival at hospital was 22 hours longer for MPI poor adults compared to non-poor adults (123 vs. 101 hours) rising to a difference of 26 hours with adjustment in a multivariate regression model (95% confidence interval 7 to 46 hours; P = 0.009). There was no difference in delays for children from poor and non-poor households (97 vs. 119 hours; P = 0.394). Case fatality was 5.9% vs. 0.8% in poor and non-poor individuals respectively (P = 0.001)-5.1% vs. 0.0% for poor and non-poor adults (P = 0.010) and 6.4% vs. 1.8% for poor and non-poor children (P = 0.083). Deaths were attributed to central nervous system infection (11), malaria (3), urinary tract infection (2), gastrointestinal infection (1) and undifferentiated sepsis (1). Both poor and non-poor households relied predominantly upon the (often informal) private sector for medical advice before reaching the referral hospital, but MPI poor participants were less likely to have consulted a qualified doctor. Poor participants were more likely to attribute delays in decision-making and travel to a lack of money (P<0.001), and more likely to face catastrophic expenditure of more than 25% of monthly household income (P<0.001). We conclude that multidimensional poverty is associated with greater pre-hospital delays and expenditure in this setting. Closer links between health and development agendas could address these consequences of poverty and streamline access to adequate healthcare.


Assuntos
Febre/diagnóstico , Febre/psicologia , Comportamentos Relacionados com a Saúde , Comportamento de Busca de Ajuda , Pobreza , Classe Social , Adolescente , Adulto , Bangladesh/epidemiologia , Criança , Pré-Escolar , Estudos Transversais , Feminino , Febre/economia , Febre/epidemiologia , Gastos em Saúde , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Fatores Socioeconômicos , Adulto Jovem
18.
Clin Vaccine Immunol ; 22(10): 1130-2, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26291089

RESUMO

This study investigated the comparative accuracy of a recombinant 56-kDa type-specific antigen-based rapid diagnostic test (RDT) for scrub typhus for the detection of IgM antibodies by using conventional serology in well-characterized serum samples from undifferentiated febrile illness patients. The RDT showed high specificity and promising comparative accuracy, with 82% sensitivity and 98% specificity for samples defined positive at an IgM indirect immunofluorescence assay positivity cutoff titer of ≥1:1,600 versus 92% and 95% at ≥1:6,400, respectively.


Assuntos
Anticorpos Antibacterianos/sangue , Cromatografia de Afinidade/normas , Imunoglobulina M/sangue , Orientia tsutsugamushi/imunologia , Tifo por Ácaros/diagnóstico , Testes Sorológicos/normas , Idoso , Antígenos de Bactérias/sangue , Antígenos de Bactérias/imunologia , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Masculino , Kit de Reagentes para Diagnóstico , Tifo por Ácaros/imunologia , Sensibilidade e Especificidade
19.
Am J Trop Med Hyg ; 91(3): 493-495, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24935949

RESUMO

Malarial retinopathy allows detailed study of central nervous system vascular pathology in living patients with severe malaria. An adult with cerebral malaria is described who had prominent retinal whitening with corresponding retinal microvascular obstruction, vessel dilatation, increased vascular tortuosity, and blood retinal barrier leakage with decreased visual acuity, all of which resolved on recovery. Additional study of these features and their potential role in elucidating the pathogenesis of cerebral malaria is warranted.


Assuntos
Infecções Oculares Parasitárias/patologia , Malária Cerebral/patologia , Malária Falciparum/patologia , Doenças Retinianas/patologia , Vasos Retinianos/patologia , Infecções Oculares Parasitárias/parasitologia , Humanos , Índia , Malária Cerebral/complicações , Malária Falciparum/complicações , Masculino , Radiografia , Retina/patologia , Doenças Retinianas/parasitologia , Vasos Retinianos/diagnóstico por imagem , Adulto Jovem
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