Identifying prognostic factors of severe metabolic acidosis and uraemia in African children with severe falciparum malaria: a secondary analysis of a randomized trial.

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

Rickettsial illnesses as important causes of febrile illness in Chittagong, Bangladesh

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

Metabolomic characterisation of acidosis in severe falciparum malaria

Severe falciparum malaria is a potentially lethal parasitic infection for which the treatment remains suboptimal as the pathophysiology is incompletely understood. Acidosis is the strongest predictor of death, caused by an accumulation of acids of which some are known, such as L-lactate, while others remain unidentified. The aim of this thesis was to further characterise metabolic acidosis in severe falciparum malaria by establishing the identity and source of the unidentified non-lactate acid load. A prospective observational study was conducted among patients with falciparum malaria from Bangladesh to establish the identity of metabolites associated with acidosis through a metabolomic analysis of plasma of 152 participants (Chapter 3). Patients with acidosis had significantly elevated levels of organic acids in their plasma that could be traced to a potential microbial source, either parasitic or bacterial. Additionally, dysregulation of plasma free amino acids was observed. The clearance of newly identified microbial acids was impaired in fatal cases. Follow-up studies were conducted by performing an in vitro metabolomic analysis of the liquid culture medium of Plasmodium falciparum 3D7 strain parasites with the aim to determine if parasites produce any of the microbial acids identified in patients with severe malaria (Chapter 4). There was no evidence for the release of microbial acids by Pf 3D7 in vitro suggesting their source is unlikely to be parasitic. Alongside of this, a prospective study was done to determine factors related to plasma free amino acid dysregulation (Chapter 5). Amino acids were simultaneously quantified in the plasma of 295 participants in relation to clinical syndromes. It was observed that amino acid abnormalities were part of widespread fluctuations in nitrogen balance, whereby the direction of change was related to the severity of malarial disease and the presence of hyperlactataemia, reflecting underlying tissue hypoxia. Finally, the role of the gut microbiota was further investigated as a potential source of microbial acids in 86 participants, including cases with severe falciparum malaria acidosis, by measuring soluble markers of gut integrity in plasma and sequencing the V4 region of the 16S rRNA gene in faecal DNA (Chapter 6). Patients with malaria had signs of impaired gut barrier function with elevated levels of plasma D-lactate linked to an enrichment of lactate-producing species in the gut microbiota. In conclusion, acidosis in severe falciparum malaria is associated with microbial acids and plasma free amino acid derangements. Microbial acids are not produced by Pf3D7 in vitro but instead might derive from the gut microbiota. These findings point towards a leaky gut as a possible source of previously unidentified acids in severe falciparum malaria acidosis with potential implications for treatment.</p

Metabolomic characterisation of acidosis in severe falciparum malaria

Severe falciparum malaria is a potentially lethal parasitic infection for which the treatment remains suboptimal as the pathophysiology is incompletely understood. Acidosis is the strongest predictor of death, caused by an accumulation of acids of which some are known, such as L-lactate, while others remain unidentified. The aim of this thesis was to further characterise metabolic acidosis in severe falciparum malaria by establishing the identity and source of the unidentified non-lactate acid load. A prospective observational study was conducted among patients with falciparum malaria from Bangladesh to establish the identity of metabolites associated with acidosis through a metabolomic analysis of plasma of 152 participants (Chapter 3). Patients with acidosis had significantly elevated levels of organic acids in their plasma that could be traced to a potential microbial source, either parasitic or bacterial. Additionally, dysregulation of plasma free amino acids was observed. The clearance of newly identified microbial acids was impaired in fatal cases. Follow-up studies were conducted by performing an in vitro metabolomic analysis of the liquid culture medium of Plasmodium falciparum 3D7 strain parasites with the aim to determine if parasites produce any of the microbial acids identified in patients with severe malaria (Chapter 4). There was no evidence for the release of microbial acids by Pf 3D7 in vitro suggesting their source is unlikely to be parasitic. Alongside of this, a prospective study was done to determine factors related to plasma free amino acid dysregulation (Chapter 5). Amino acids were simultaneously quantified in the plasma of 295 participants in relation to clinical syndromes. It was observed that amino acid abnormalities were part of widespread fluctuations in nitrogen balance, whereby the direction of change was related to the severity of malarial disease and the presence of hyperlactataemia, reflecting underlying tissue hypoxia. Finally, the role of the gut microbiota was further investigated as a potential source of microbial acids in 86 participants, including cases with severe falciparum malaria acidosis, by measuring soluble markers of gut integrity in plasma and sequencing the V4 region of the 16S rRNA gene in faecal DNA (Chapter 6). Patients with malaria had signs of impaired gut barrier function with elevated levels of plasma D-lactate linked to an enrichment of lactate-producing species in the gut microbiota. In conclusion, acidosis in severe falciparum malaria is associated with microbial acids and plasma free amino acid derangements. Microbial acids are not produced by Pf3D7 in vitro but instead might derive from the gut microbiota. These findings point towards a leaky gut as a possible source of previously unidentified acids in severe falciparum malaria acidosis with potential implications for treatment.</p

Antimicrobial drug resistance among clinically relevant bacterial isolates in sub-Saharan Africa: a systematic review

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. 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. 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. 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 sS

Host innate immune responses to sepsis

The immune response to sepsis can be seen as a pattern recognition receptor-mediated dysregulation of the immune system following pathogen invasion in which a careful balance between inflammatory and anti-inflammatory responses is vital. Invasive infection triggers both pro-inflammatory and anti-inflammatory host responses, the magnitude of which depends on multiple factors, including pathogen virulence, site of infection, host genetics, and comorbidities. Toll-like receptors, the inflammasomes, and other pattern recognition receptors initiate the immune response after recognition of danger signals derived from microorganisms, so-called pathogen-associated molecular patterns or derived from the host, so-called danger-associated molecular patterns. Further dissection of the role of host-pathogen interactions, the cytokine response, the coagulation cascade, and their multidirectional interactions in sepsis should lead toward the development of new therapeutic strategies in sepsi

Family participation to enhance care and tackle health worker shortages in resource-limited hospitals: A systematic review

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

Common Bile Duct Dilatation in Drug Users With Chronic Hepatitis C Is Associated With Current Methadone Use

Objectives: Dilatation of the common bile duct (CBD) can be an ominous sign for malignancy of the pancreatobiliary tract; however, it has also been described as a presumably harmless side effect of opioid use. We investigated the prevalence and determinants of CBD dilatation among drug users receiving methadone maintenance therapy in the Netherlands. Methods: A cross-sectional study was conducted in a prospectively studied and well-defined cohort of drug users with chronic hepatitis C virus infection, attending the Public Health Service of Amsterdam, the Netherlands. Patients underwent abdominal ultrasonography as part of pretreatment screening. A multivariable logistic regression model was used to analyze potential demographic and drug use-related determinants of radiological CBD dilatation. Results: Between September 2004 and December 2011, 222 hepatitis C virus-infected drug users were evaluated. Dilatation of the CBD was found in 50 of 222 patients (22.5%), with a median diameter of 8.0 mm (interquartile range, 7.0 to 10.0; n = 43). Dilatation was associated with current use of methadone (adjusted odds ratio = 20.50; 95% confidence interval, 2.79 to 2.61 x 10(3)), independent of the current methadone dose, and with age per 10-year increase (adjusted odds ratio = 1.68; 95% confidence interval, 1.06 to 2.71). Regular use of heroin in the 6 months before ultrasonography was not found to be associated with dilatation. Conclusions: Dilatation of the CBD is common in drug users under methadone treatment and seems to be a harmless side effect of opioid agonist