Hypoxaemia in Mozambican children < 5 years of age admitted to hospital with clinical severe pneumonia: clinical features and performance of predictor models

OBJECTIVE: To determine the prevalence of hypoxaemia among under-five children admitted to hospital with clinical severe pneumonia, and to assess the performance to diagnose hypoxaemia of models based on clinical signs. METHODS: We conducted a hospital-based survey in a district hospital from Southern Mozambique. RESULTS: A total of 825 children were recruited after obtaining an informed consent. The prevalence of hypoxaemia on admission was 27.9%, and 19.8% of these children died (OR compared to non-hypoxaemic children 3.22, 95%CI 1.98 - 5.21, p<0.001). The model with larger area under the ROC curve (AUC-ROC) to predict hypoxaemia included cyanosis or thoracoabdominal breathing or respiratory rate >/= 70 breaths per minute. None of the models performed well when tested in different case scenarios of oxygen availability through mathematical modelling, with over 50% of hypoxaemic children not receiving oxygen even in favourable case scenarios. CONCLUSIONS: Clinical signs alone or in combination are not suitable to diagnose hypoxaemia. The use of pulse oximeters should be strongly encouraged. This article is protected by copyright. All rights reserved

Climate change and the kidney

The worldwide increase in temperature has resulted in a marked increase in heat waves (heat extremes) that carries a markedly increased risk for morbidity and mortality. The kidney has a unique role not only in protecting the host from heat and dehydration but also is an important site of heat-associated disease. Here we review the potential impact of global warming and heat extremes on kidney diseases. High temperatures can result in increased core temperatures, dehydration, and blood hyperosmolality. Heatstroke (both clinical and subclinical whole-body hyperthermia) may have a major role in causing both acute kidney disease, leading to increased risk of acute kidney injury from rhabdomyolysis, or heat-induced inflammatory injury to the kidney. Recurrent heat and dehydration can result in chronic kidney disease (CKD) in animals and theoretically plays a role in epidemics of CKD developing in hot regions of the world where workers are exposed to extreme heat. Heat stress and dehydration also has a role in kidney stone formation, and poor hydration habits may increase the risk for recurrent urinary tract infections. The resultant social and economic consequences include disability and loss of productivity and employment. Given the rise in world temperatures, there is a major need to better understand how heat stress can induce kidney disease, how best to provide adequate hydration, and ways to reduce the negative effects of chronic heat exposure.Published versio

Under treatment of pneumonia among children under 5 years of age in a malaria-endemic area: population-based surveillance study conducted in Manhica district- rural, Mozambique

BACKGROUND: Integrated Management of Childhood Illness (IMCI) guidelines were developed to decrease morbidity and mortality, yet implementation varies across settings. Factors associated with poor adherence are not well understood. METHODS: We used data from Manhica District Hospital outpatient department and five peripheral health centers to examine pneumonia management for children <5 years old from January 2008 to June 2011. Episodes of IMCI-defined pneumonia (cough or difficult breathing plus tachypnea), severe pneumonia (pneumonia plus chest wall in-drawing), and/or clinician-diagnosed pneumonia (based on discharge diagnosis) were included. RESULTS: Among severe pneumonia episodes, 96.2% (2,918/3,032) attended in the outpatient department and 70.0% (291/416) attended in health centers were appropriately referred to the emergency department. Age<1 year, malnutrition and various physical exam findings were associated with referral. For non-severe pneumonia episodes, antibiotics were prescribed in 45.7% (16,094/35,224). Factors associated with antibiotic prescription included age <1 year, abnormal auscultatory findings, and clinical diagnosis of pneumonia; diagnosis of malaria or gastroenteritis and pallor were negatively associated with antibiotic prescription. CONCLUSION: Adherence to recommended management of severe pneumonia was high in a hospital outpatient department, but suboptimal in health centers. Antibiotics were prescribed in fewer than half of non-severe pneumonia episodes, and diagnosis of malaria was the strongest risk factor for incorrect management

High prevalence of Pneumocystis jirovecii pneumonia among Mozambican children < 5 years of age admitted to hospital with clinical severe pneumonia

We aimed to describe Pneumocystis jirovecii pneumonia (PCP) prevalence and features in children from sub-Saharan Africa, and to investigate PCP-associated risk factors. During 2006-2007 we used molecular methods to test children younger than 5 years old admitted with severe pneumonia to a hospital in Southern Mozambique for Pneumocystis infection. We recruited 834 children. PCP prevalence was 6.8% and HIV prevalence was 25.7%. The in-hospital and delayed mortality were significantly higher among children with PCP (20.8% vs. 10.2 %, p=0.021, and 11.5% vs. 3.6%, p=0.044, respectively). Clinical features were mostly overlapping between the two groups. Independent risk factors for PCP were age less than a year (OR 6.34, 95%CI 1.86-21.65), HIV infection (OR 2.99, 95%CI 1.16-7.70), grunting (OR 2.64, 95%CI 1.04-6.73), and digital clubbing (OR 10.75, 95%CI 1.21-95.56). PCP is a common and life-threatening cause of severe pneumonia in Mozambican children. Mother-to-child HIV transmission prevention should be strengthened. Better diagnostic tools are needed

Fructokinase, Fructans, Intestinal Permeability, and Metabolic Syndrome: An Equine Connection?

Fructose is a simple sugar present in honey and fruit, but can also exist as a polymer (fructans) in pasture grasses. Mammals are unable to metabolize fructans, but certain gram positive bacteria contain fructanases and can convert fructans to fructose in the gut. Recent studies suggest that fructose generated from bacteria, or directly obtained from the diet, can induce both increased intestinal permeability and features of metabolic syndrome, especially the development of insulin resistance. The development of insulin resistance is driven in part by the metabolism of fructose by fructokinase C in the liver, which results in oxidative stress in the hepatocyte. Similarly, the metabolism of fructose in the small bowel by intestinal fructokinase may lead to increased intestinal permeability and endotoxemia. While speculative, these observations raise the possibility that the mechanism by which fructans induce laminitis could involve intestinal and hepatic fructokinase. Further studies are indicated to determine the role of fructanases, fructose and fructokinase in equine metabolic syndrome and laminitis.Keywords: Fructose, Laminitis, Fructans, Fructokinase, Equine Metabolic Syndrom

Biomarkers to Distinguish Bacterial From Viral Pediatric Clinical Pneumonia in a Malaria-Endemic Setting.

BACKGROUND: Differential etiologies of pediatric acute febrile respiratory illness pose challenges for all populations globally, but especially in malaria-endemic settings because the pathogens responsible overlap in clinical presentation and frequently occur together. Rapid identification of bacterial pneumonia with high-quality diagnostic tools would enable appropriate, point-of-care antibiotic treatment. Current diagnostics are insufficient, and the discovery and development of new tools is needed. We report a unique biomarker signature identified in blood samples to accomplish this. METHODS: Blood samples from 195 pediatric Mozambican patients with clinical pneumonia were analyzed with an aptamer-based, high-dynamic-range, quantitative assay (~1200 proteins). We identified new biomarkers using a training set of samples from patients with established bacterial, viral, or malarial pneumonia. Proteins with significantly variable abundance across etiologies (false discovery rate 90% sensitivity and >80% specificity, regardless of number of pathogen classes. Bacterial pneumonia was strongly associated with neutrophil markers-in particular, degranulation including HP, LCN2, LTF, MPO, MMP8, PGLYRP1, RETN, SERPINA1, S100A9, and SLPI. CONCLUSIONS: Blood protein signatures highly associated with neutrophil biology reliably differentiated bacterial pneumonia from other causes. With appropriate technology, these markers could provide the basis for a rapid diagnostic for field-based triage for antibiotic treatment of pediatric pneumonia

Endogenous Fructose Metabolism Could Explain the Warburg Effect and the Protection of SGLT2 Inhibitors in Chronic Kidney Disease.

Chronic low-grade inflammation underlies the pathogenesis of non-communicable diseases, including chronic kidney diseases (CKD). Inflammation is a biologically active process accompanied with biochemical changes involving energy, amino acid, lipid and nucleotides. Recently, glycolysis has been observed to be increased in several inflammatory disorders, including several types of kidney disease. However, the factors initiating glycolysis remains unclear. Added sugars containing fructose are present in nearly 70 percent of processed foods and have been implicated in the etiology of many non-communicable diseases. In the kidney, fructose is transported into the proximal tubules via several transporters to mediate pathophysiological processes. Fructose can be generated in the kidney during glucose reabsorption (such as in diabetes) as well as from intra-renal hypoxia that occurs in CKD. Fructose metabolism also provides biosynthetic precursors for inflammation by switching the intracellular metabolic profile from mitochondrial oxidative phosphorylation to glycolysis despite the availability of oxygen, which is similar to the Warburg effect in cancer. Importantly, uric acid, a byproduct of fructose metabolism, likely plays a key role in favoring glycolysis by stimulating inflammation and suppressing aconitase in the tricarboxylic acid cycle. A consequent accumulation of glycolytic intermediates connects to the production of biosynthetic precursors, proteins, lipids, and nucleic acids, to meet the increased energy demand for the local inflammation. Here, we discuss the possibility of fructose and uric acid may mediate a metabolic switch toward glycolysis in CKD. We also suggest that sodium-glucose cotransporter 2 (SGLT2) inhibitors may slow the progression of CKD by reducing intrarenal glucose, and subsequently fructose levels

Whole genome sequencing to evaluate the resistance landscape following antimalarial treatment failure with fosmidomycin-clindamycin

Novel antimalarial therapies are needed in the face of emerging resistance to artemisinin combination therapies. A previous study found a high cure rate in Mozambican children with uncomplicated Plasmodium falciparum malaria 7 days post treatment with a fosmidomycin-clindamycin combination. However, 28-day cure rates were low (45.9%), due to parasite recrudescence. We sought to identify any genetic changes underlying parasite recrudescence. To this end, we utilized a selective whole genome amplification method to amplify parasite genomes from blood spot DNA samples. Parasite genomes from pre-treatment and post-recrudescence samples were subjected to whole genome sequencing to identify nucleotide variants. We find that our data do not support the existence of a genetic change responsible for recrudescence following fosmidomycin-clindamycin treatment. Additionally, we find that previously described resistance alleles for these drugs do not represent biomarkers of recrudescence. Future studies should continue to optimize fosmidomycin combinations for use as antimalarial therapies

Hyperuricemia and chronic kidney disease: to treat or not to treat

Hyperuricemia is common in chronic kidney disease (CKD) and may be present in 50% of patients presenting for dialysis. Hyperuricemia can be secondary to impaired glomerular filtration rate (GFR) that occurs in CKD. However, hyperuricemia can also precede the development of kidney disease and predict incident CKD. Experimental studies of hyperuricemic models have found that both soluble and crystalline uric acid can cause significant kidney damage, characterized by ischemia, tubulointerstitial fibrosis, and inflammation. However, most Mendelian randomization studies failed to demonstrate a causal relationship between uric acid and CKD, and clinical trials have had variable results. Here we suggest potential explanations for the negative clinical and genetic findings, including the role of crystalline uric acid, intracellular uric acid, and xanthine oxidase activity in uric acid-mediated kidney injury. We propose future clinical trials as well as an algorithm for treatment of hyperuricemia in patients with CKD

Safety and immunogenicity of the RTS,S/AS01 malaria vaccine in infants and children identified as HIV-infected during a randomized trial in sub-Saharan Africa

Background: We assessed the safety and immunogenicity of the RTS,S/AS01 malaria vaccine in a subset of children identified as HIV-infected during a large phase III randomized controlled trial conducted in seven sub-Saharan African countries. Methods: Infants 6–12 weeks and children 5–17 months old were randomized to receive 4 RTS,S/AS01 doses (R3R group), 3 RTS,S/AS01 doses plus 1 comparator vaccine dose (R3C group), or 4 comparator vaccine doses (C3C group) at study months 0, 1, 2 and 20. Infants and children with WHO stage III/IV HIV disease were excluded but HIV testing was not routinely performed on all participants; our analyses included children identified as HIV-infected based on medical history or clinical suspicion and confirmed by polymerase chain reaction or antibody testing. Serious adverse events (SAEs) and anticircumsporozoite (CS) antibodies were assessed. Results: Of 15459 children enrolled in the trial, at least 1953 were tested for HIV and 153 were confirmed as HIV-infected (R3R: 51; R3C: 54; C3C: 48). Among these children, SAEs were reported for 92.2% (95% CI: 81.1–97.8) in the R3R, 85.2% (72.9–93.4) in the R3C and 87.5% (74.8–95.3) in the C3C group over a median follow-up of 39.3, 39.4 and 38.3 months, respectively. Fifteen HIV-infected participants in each group (R3R: 29.4%, R3C: 27.8%, C3C: 31.3%) died during the study. No deaths were considered vaccinationrelated. In a matched case-control analysis, 1 month post dose 3 anti-CS geometric mean antibody concentrations were 193.3 EU/mL in RTS,S/AS01-vaccinated HIV-infected children and 491.5 EU/mL in RTS,S/ AS01-vaccinated immunogenicity controls with unknown or negative HIV status (p = 0.0001). Conclusions: The safety profile of RTS,S/AS01 in HIV-infected children was comparable to that of the comparator (meningococcal or rabies) vaccines. RTS,S/AS01 was immunogenic in HIV-infected children but antibody concentrations were lower than in children with an unknown or negative HIV status