Background. This study sought to describe and quantify microcirculatory changes in the mucosal surfaces of patients with severe malaria, by direct in

Background. World Health Organization treatment guidelines recommend that adults with severe malaria be admitted to an intensive care unit (ICU). How

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. 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. 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). 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.

The epidemiology, clinical presentation and management of melioidosis vary around the world. It is essential to define the disease’s local features to optimise its management. Between 1998 and 2016 there were 197 cases of culture confirmed melioidosis in Far North Queensland; 154 (78%) presented in the December-April wet season. 145 (74%) patients were bacteraemic, 58 (29%) were admitted to the Intensive Care Unit and 27 (14%) died; nine (33%) of these deaths occurred within 48 hours of presentation. Pneumonia was the most frequent clinical finding, present in 101 (61%) of the 166 with available imaging. A recognised risk factor for melioidosis (diabetes, hazardous alcohol use, chronic renal disease, chronic lung disease, immunosuppression or malignancy) was present in 148 (91%) of 162 patients with complete comorbidity data. Despite representing only 9% of the region’s population, Aboriginal and Torres Strait Island (ATSI) people comprised 59% of the cases. ATSI patients were younger than non-ATSI patients (median (interquartile range): 46 (38–56) years versus 59 (43–69) years (p<0.001) and had a higher case-fatality rate (22/117 (19%) versus 5/80 (6.3%) (p = 0.01)). In the 155 patients surviving the initial intensive intravenous phase of treatment, eleven (7.1%) had disease recurrence, despite the fact that nine (82%) of these patients had received prolonged intravenous therapy. Recurrence was usually due to inadequate source control or poor adherence to oral eradication therapy. The case fatality rate declined from 12/44 (27%) in the first five years of the study to 7/76 (9%) in the last five (p = 0.009), reflecting national improvements in sepsis management. Melioidosis in Far North Queensland is a seasonal, opportunistic infection of patients with specific comorbidities. The ATSI population bear the greatest burden of disease. Although the case-fatality rate is declining, deaths frequently occur early after hospitalisation, reinforcing the importance of prompt, targeted therapy in high-risk patients. Burkholderia pseudomallei is endemic to the tropics and is responsible for the disease melioidosis. Exposure rarely evolves to significant disease in the absence of specific comorbidities. Conversely, in susceptible hosts, the disease can be rapidly fatal if unrecognised. Patients require an extended course of intravenous and oral antibiotic therapy to treat the disease and to prevent its recurrence. This retrospective, case series describes the epidemiology, presentation and outcomes of 197 cases of melioidosis in Far North Queensland (FNQ), Australia. The study confirms that melioidosis is predominantly a seasonal, opportunistic infection occurring among patients with specific comorbidities that include diabetes mellitus, hazardous alcohol use, chronic kidney disease, chronic lung disease, malignancy and immunosuppressive therapy. Melioidosis is more common in the local Aboriginal and Torres Strait Islander (ATSI) population, which has a higher prevalence of these comorbidities. Although overall case-fatality rates are declining, they are higher in the ATSI population, reflecting ongoing socioeconomic disadvantage. Disease recurrence is more likely in patients with inadequate source control and suboptimal adherence, factors that are not necessarily mitigated by extending the duration of intravenous therapy.

Objective: To evaluate the efficacy and safety of liberal fluid resuscitation of adults with severe malaria. Design, Setting, Patients, and Methods: Twenty-eight Bangladeshi and Indian adults with severe falciparum malaria received crystalloid resuscitation guided by transpulmonary thermodilution (PiCCO) in an intensive care setting. Systemic hemodynamics, microvascular indices and measures of acidosis, renal function, and pulmonary edema were followed prospectively. Results: All patients were hypovolemic (global end-diastolic volume index < 680 mL/m²) on enrollment. Patients received a median (range) 3230 mL (390–7300) of isotonic saline in the first 6 hours and 5450 mL (710–13,720) in the first 24 hours. With resuscitation, acid-base status deteriorated in 19 of 28 (68%), and there was no significant improvement in renal function. Extravascular lung water increased in 17 of 22 liberally resuscitated patients (77%); eight of these patients developed pulmonary edema, five of whom died. All other patients survived. All patients with pulmonary edema during the study were hypovolemic or euvolemic at the time pulmonary edema developed. Plasma lactate was lower in hypovolemic patients before (r_s = 0.38; p = 0.05) and after (r_s = 0.49; p = 0.01) resuscitation but was the strongest predictor of mortality before (chi-square = 9.9; p = 0.002) and after resuscitation (chi-square = 11.1; p < 0.001) and correlated with the degree of visualized microvascular sequestration of parasitized erythrocytes at both time points (r_s = 0.55; p = 0.003 and r_s = 0.43; p = 0.03, respectively). Persisting sequestration was evident in 7 of 15 patients (47%) 48 hours after enrollment. Conclusions: Lactic acidosis—the strongest prognostic indicator in adults with severe falciparum malaria—results from sequestration of parasitized erythrocytes in the microcirculation, not from hypovolemia. Liberal fluid resuscitation has little effect on this sequestration and does not improve acid-base status or renal function. Pulmonary edema—secondary to increased pulmonary vascular permeability—is common, unpredictable, and exacerbated by fluid loading. Liberal fluid replacement of adults with severe malaria should be avoided.