26 research outputs found
WCN24-2067 Regional differences in acute kidney injury in Ugandan children hospitalized for Hypoxemia
Introduction: Acute kidney injury (AKI) is associated with increased mortality in hospitalized patients and incidence is highest in resource limited settings. The objective of this study was to assess sub-National regional differences in the incidence of AKI in children \u3c5 years of age hospitalized with an acute febrile illness and hypoxemia.
Methods: This was a secondary analysis of a stepped wedge cluster randomized controlled trial, which enrolled children \u3c5 years of age hospitalized with hypoxemia between 2019 and 2021. At least one measure of kidney function was available in 1452 children. A single creatinine was measured at enrolment in a sub-set of 495 children with serum stored and AKI defined using KDIGO criteria where baseline creatinine was estimated using the age-based Pottel equation assuming a normal glomerular filtration rate of 120mL/min per 1.73m2. Markers were divided into structural (uNGAL positive, proteinuria, hematuria) or functional (AKI, saliva urea nitrogen (SUN)) measures of kidney injury.
Results: 1452 children were included in this AKI sub-study (Figure 1). The mean age of participants was 1.49 years (standard deviation (SD), 1.21) and 55.7% were male (809/1452). Overall 2.6% of children died (38/1452). The majority of participants enrolled were from the West (31.3%) followed by the East (25.3%), North (24.1%), and Central (19.4%) regions. In general, 48.5% of children had AKI (240/495), the prevalence was highest in Eastern Uganda with 62.4% of children having AKI compared to 25.0% of children in Western Uganda, 44% in Central region and 53% in Northern region (p\u3c0.001). Over a third of children had urine NGAL levels â„150ng/mL, a marker of structural damage, irrespective of site and rates comparable across sites (p=0.095). Other measures of functional and structural kidney injury varied across sites, proteinuria ranged from 6.3% to 14.0% with rates lower in Central and Eastern Uganda compared to Northern and Western Uganda. Hematuria was over two times more common in Eastern and Northern Uganda compared to Central and Western Uganda. Of all the children 49.0 % were positive for malaria based on rapid diagnostic test (RDT) either as positive pLDH or both pLDH and HRP-2. The presence of a single band positive RDT for HRP-2 alone was associated with increased risk of AKI, severe AKI, elevated BUN, a positive SUN test and urinalysis positive for hematuria or urobilinogen (unadjusted p\u3c0.05). Children with a 3-band positive RDT were more likely to have proteinuria, hematuria, bilirubinuria and urobilinogen by dipstick (unadjusted p\u3c0.05). Regional differences in AKI persisted after adjusting for malaria, age, and sex.
Conclusions: As we move towards the ISN 0by25 initiative which aims to eliminate preventable deaths from AKI worldwide by 2025. This study provides key in-country data from a resource limited setting, demonstrating marked regional differences in the incidence of AKI in children hospitalized with hypoxaemia and malaria remains an important predictor of AKI. The substantial within-country heterogeneity of AKI highlights the need for further studies to evaluate regional contributors to local patterns of AKI
WCN24-931 AKI Phenotypes in Ugandan children hospitalized with Hypoxemia and Malaria
Introduction: Acute kidney injury (AKI) is a frequent life-threatening complication in hospitalized children. Emerging data suggest AKI is a heterogeneous condition that varies based on the underlying cause and is composed of distinct phenotypes. The objective of this study was to define AKI phenotypes using proposed classification systems in Ugandan children hospitalized with hypoxemia and to evaluate differences in phenotypes by malaria infection.
Methods: Between 2019 and 2021, 2402 Ugandan children \u3c5 years of age hospitalized with hypoxemia were enrolled in a cluster randomized trial of solar powered oxygen delivery across 20 districts in Uganda. At enrollment, urine NGAL was measured using a point-of-care lateral flow test with a positive test defined as a level â„150ng/mL. Malaria was assessed using a threeband rapid diagnostic test. In an extended sub-study, 491 children had creatinine measured to define AKI. AKI was defined using a single creatinine measure at enrolment and phenotypically characterized using two acute dialysis quality initiative (ADQI) proposed AKI phenotypes. The AKI biomarker definition incorporated urine NGAL into the KDIGO definition[group 1, no AKI; group 2, subclinical AKI (biomarker positive); group 3, AKI; group 4, biomarker positive AKI]. The ADQI sepsis AKI phenotype groups stage 1 AKI as sepsis phenotype (SP)-1 irrespective of biomarker status and differentiates severe AKI (stage 2/3) based on biomarker positivity where severe AKI that is biomarker negative is (SP2) and severe biomarker positive AKI is SP3.
Results: Overall, 491 children were included in the extended study with AKI defined and uNGAL measured. The median age was 1.3 years (interquartile range, 0.7 to 2.3) and 53.8% of children were male. There were 4 deaths (0.8%) and 24 children required transfer to a higher-level health facility (4.9%). Among children included, 91.2% met a clinical definition of pneumonia and 49.5% were positive for malaria. The frequency of creatinine defined AKI was 32.0% (157/491) and 36.5% (179/491) were biomarker positive. AKI was associated with a 3.24-fold increase in mortality (95% CI 0.34 to 31.4) but underpowered to show a difference. In children without malaria, 17.7% were biomarker positive and AKI negative (subclinical AKI, 44/248) while 37.5% of children had AKI (93/284) of whom 39.8% (37/93) were biomarker positive. In children with malaria, 14.0% had subclinical AKI, 34/243), 59.3% had AKI (144/243) with 44.4% of AKI cases biomarker positive (64/144). Children with malaria had a higher frequency of AKI compared to children without malaria (59.6% vs. 37.6%, p\u3c0.001) but comparable frequency of a positive biomarker test (41.3% vs. 36.2%, p=0.10). Using the sepsis phenotype criteria, 16.3% of children had SP1, 17.9% were SP2 and 14.1% were SP3. When evaluating the sepsis phenotype by malaria status, children with malaria were more likely to have SP2 (23.1% vs. 12.9%) and SP3 (18.1% vs.10.1%) compared to children without malaria (p\u3c0.001).
Conclusions: In this population of children hospitalized with hypoxemia across 20 health centers in Uganda, KDIGO-defined AKI was more common in children with malaria. While there was no difference in the AKI-biomarker classification based on malaria status, children with malaria were more likely to have severe phenotypes of AKI
Dried blood microsampling-based therapeutic drug monitoring of antiepileptic drugs in children with nodding syndrome and epilepsy in Uganda and the Democratic Republic of the Congo
Nodding syndrome is a highly debilitating, generalized seizure disorder, affecting children in subregions of sub-Saharan Africa. Despite numerous efforts to uncover the etiology, the exact cause of this syndrome still remains obscure. Therefore, to date, patients only receive symptomatic care, including the administration of first-generation
antiepileptic drugs for seizure control. As data on the efficacy of drugs within this population are completely lacking, the aim of this study was to explore how therapeutic drug monitoring could help to understand the
differential response to therapy. Considering the challenging environment in which sampling had to be performed (remote areas, devoid of electricity, running water, etc), dried blood matrices [ie, dried blood spots (DBSs)] and volumetric absorptive microsampling (VAMS) were considered fit-for-purpose. In addition, owing to the similarities between the syndrome and other forms of epilepsy, samples originating from patients suffering from (onchocerciasis-associated) epilepsy were included. In total, 68 patients with Nodding syndrome from Uganda,
58 Ugandan patients with epilepsy, and 137 patients with onchocerciasis-associated epilepsy from the Democratic Republic of the Congo were included. VAMS samples and DBS were analyzed using validated methods, involving manual extraction or fully automated extraction, respectively, before quantification using liquid chromatography coupled with tandem mass spectrometry. Analysis revealed that serum concentrations (calculated from DBS) within the respective reference ranges were attained in only 52.9% of the 68 Nodding syndrome patients treated with valproic acid, in 21.4% of the 56 Ugandan epilepsy patients treated with carbamazepine, and in 65.7% of the 137 onchocerciasis-associated epilepsy patients from the Democratic Republic of the Congo treated with phenobarbital. In all other instances, concentrations were subtherapeutic. Furthermore, on comparing DBS with VAMS concentrations, an inexplicable overestimation was observed in the latter. Finally, no obvious link could be observed
between the obtained drug concentrations and the number of seizures experienced during the last month before sampling, elaborating the fact that the level of improvement in some patients cannot simply be linked
to reaching therapeutic concentrations
Epstein-Barr virus and malaria upregulate AID and APOBEC3 enzymes, but only AID seems to play a major mutagenic role in Burkitt lymphoma
Endemic Burkitt lymphoma (eBL) is characterized by an oncogenic IGH/c-MYC translocation and Epstein-Barr virus (EBV) positivity, and is epidemiologically linked to Plasmodium falciparum malaria. Both EBV and malaria are thought to contribute to eBL by inducing the expression of activation-induced cytidine deaminase (AID), an enzyme involved in the IGH/c-MYC translocation. AID/apolipoprotein B mRNA editing catalytic polypeptide-like (AID/APOBEC) family enzymes have recently emerged as potent mutagenic sources in a variety of cancers, but apart from AID, their involvement in eBL and their regulation by EBV and P. falciparum is unknown. Here, we show that upon inoculation with EBV, human B cells strongly upregulate the expression of enzymatically active APOBEC3B and APOBEC3G. In addition, we found significantly increased levels of APOBEC3A in B cells of malaria patients, which correlated with parasite load. Interestingly, despite the fact that APOBEC3A, APOBEC3B, and APOBEC3G caused c-MYC mutations when overexpressed in HEK293T cells, a mutational enrichment in eBL tumors was only detected in AID motifs. This suggests that even though the EBV- and P. falciparum-directed immune response triggers the expression and activity of several AID/APOBEC members, only the upregulation of AID has oncogenic consequences, while the induction of the APOBEC3 subfamily may primarily have immunoprotective functions
Bi-isotype immunoglobulins enhance antibody-mediated neutrophil activity against Plasmodium falciparum parasites
Background: Malaria remains a major global health priority, and monoclonal antibodies (mAbs) are emerging as potential new tools to support efforts to control the disease. Recent data suggest that Fc-dependent mechanisms of immunity are important mediators of protection against the blood stages of the infection, but few studies have investigated this in the context of mAbs. We aimed to isolate mAbs agnostic to cognate antigens that target whole merozoites and simultaneously induce potent neutrophil activity measured by the level of reactive oxygen species (ROS) production using an antibody-dependent respiratory burst (ADRB) assay. Methods: We used samples from semi-immune adults living in coastal Kenya to isolate mAbs that induce merozoite-specific ADRB activity. We then tested whether modifying the expressed IgG1 isotype to an IgGâIgA Fc region chimera would enhance the level of ADRB activity. Results: We isolated a panel of nine mAbs with specificity to whole merozoites. mAb J31 induced ADRB activity in a dose-dependent fashion. Compared to IgG1, our modified antibody IgGâIgA bi-isotype induced higher ADRB activity across all concentrations tested. Further, we observed a negative hook effect at high IgG1 mAb concentrations (i.e., >200 ”g/mL), but this was reversed by Fc modification. We identified MSP3.5 as the potential cognate target of mAb J31. Conclusions: We demonstrate an approach to engineer mAbs with enhanced ADRB potency against blood-stage parasites
Comparison of structural changes in nodding syndrome and other epilepsies associated with Onchocerca volvulus
Background and Objective: Nodding syndrome (NS) is a unique childhood-onset epileptic disorder that occurs predominantly in several regions of sub-Saharan Africa. The disease has been associated with Onchocerca volvulus (Ov)âinduced immune responses and possible cross-reactivity with host proteins. The aim of this study was to compare structural changes in the brain on MRI between NS and other forms of onchocerciasis-associated epilepsies (OAEs) and to relate structural changes to the Ov-induced immune responses and level of disability.
Methods:Â Thirty-nine children with NS and 14 age-matched participants with other forms of OAE from an endemic region in Uganda underwent detailed clinical examination, serologic evaluation (including Ov-associated antibodies to Ov-16 and Hu-leiomodin-1) and quantitative volumetric analysis of brain MRIs (1.5 T scanner) using Neuroreader, a cloud-based software.
Results: Cerebral and cerebellar atrophy were the predominant features in both NS and OAE. On quantitative volumetric analysis, participants with NS had larger ventricular volumes compared with participants with OAE, indicative of increased global cortical atrophy (pcorr = 0.036). Among children with NS, severe disability correlated with higher degree of atrophy in the gray matter volume (pcorr = 0.009) and cerebellar volume (pcorr = 0.009). NS cases had lower anti-Ov-16 IgG signal-to-noise ratios than the OAE cases (p < 0.01), but no difference in the levels of the Hu-leiomodin-1 antibodies (p = 0.64). The levels of Ov-associated antibodies did not relate to the degree of cerebral or cerebellar atrophy in either NS or OAE cases.
Discussion:Â This is the first study to show that cerebral and cerebellar atrophy correlated with the severity of NS disability, providing an imaging marker for these endemic epileptic disorders that until now have remained poorly characterized. Both NS and OAE have cerebral and cerebellar atrophy, and the levels of Ov-associated antibodies do not seem to be related to the structural changes on MRI
Doxycycline for the treatment of nodding syndrome (DONS); the study protocol of a phase II randomised controlled trial.
BACKGROUND: Nodding syndrome is a poorly understood neurological disorder of unknown aetiology, affecting several thousand children in Africa. There has been a consistent epidemiological association with infection by the filarial parasite, Onchocerca volvulus and antibodies to leiomodin and DJ-1, cross-reacting with O.volvulus proteins, have been reported. We hypothesized that nodding syndrome is a neuro-inflammatory disorder, induced by antibodies to O.volvulus or its symbiont, Wolbachia, cross-reacting with human neuron proteins and that doxycycline, which kills Onchocerca through effects on Wolbachia, may be used as treatment. METHODS: This will be a two-arm, double-blind, placebo-controlled, randomised phase II trial of doxycycline 100âmg daily for six weeks in 230 participants. Participants will be patients' agesâ„8âyears with nodding syndrome. They will receive standard of care supportive treatment. All will be hospitalised for 1-2âweeks during which time baseline measurements including clinical assessments, EEG, cognitive and laboratory testing will be performed and antiepileptic drug doses rationalised. Participants will then be randomised to either oral doxycycline (AzudoxÂź, Kampala Pharmaceutical Industries) 100âmg daily or placebo. Treatment will be initiated in hospital and continued at home. Participants will be visited at home at 2, 4 and 6âweeks for adherence monitoring. Study outcomes will be assessed at 6, 12, 18 and 24-month visits. Analysis will be by intention to treat. The primary efficacy outcome measure will be the proportion of patients testing positive and the levels or titires of antibodies to host neuron proteins (HNPs) and/or leiomodin at 24âmonths. Secondary outcome measures will include effect of the intervention on seizure control, inflammatory markers, cognitive function, disease severity and quality of life. DISCUSSION: This trial postulates that targeting O.volvulus through drugs which kill Wolbachia can modify the pathogenic processes in nodding syndrome and improve outcomes. Findings from this study are expected to substantially improve the understanding and treatment of nodding syndrome. TRIAL REGISTRATION: Registered with clinicaltrials.gov ID: NCT02850913 on 1st August, 2016
Systemic and cerebrospinal fluid immune and complement activation in Ugandan children and adolescents with longâstanding nodding syndrome: a caseâcontrol study
Objective
Nodding syndrome is a poorly understood epileptic encephalopathy characterized by a unique seizure typeâ head noddingâ and associated with Onchocerca volvulus infection. We hypothesized that altered immune activation in the cerebrospinal fluid (CSF) and plasma of children with nodding syndrome may yield insights into the pathophysiology and progression of this seizure disorder.
Method
We conducted a caseâcontrol study of 154 children (8 years or older) with longâstanding nodding syndrome and 154 healthy ageâmatched community controls in 3 districts of northern Uganda affected by nodding syndrome. Control CSF samples were obtained from Ugandan children in remission from haematological malignancy during routine followâup. Markers of immune activation and inflammation (cytokines and chemokines) and complement activation (C5a) were measured in plasma and CSF using ELISA or Multiplex Luminex assays. O. volvulus infection was assessed by serology for antiâOv16 IgG levels.
Results
The mean (SD) age of the population was 15.1 (SD 1.9) years and the mean duration of nodding syndrome from diagnosis to enrolment was 8.3 (SD 2.7) years. Majority with nodding syndrome had been exposed to O. volvulus 147/154 (95.4%) compared to community children 86/154 (55.8%), OR 17.04 (95% CI 7.33, 45.58), p<0.001. C5a was elevated in CSF of children with nodding syndrome compared to controls, (p<0.0001). The levels of other CSF markers tested were comparable between cases and controls after adjusting for multiple comparisons. Children with nodding syndrome had lower plasma levels of IL10, APRIL, CCL5 (RANTES), CCL2, CXCL13, MMPâ9 compared to community controls (p<0.05 for all; multiple comparisons). Plasma CRP was elevated in children with nodding syndrome compared to community children and correlated with disease severity.
Significance
Nodding syndrome is associated with exposure to O. volvulus. Compared to controls, children with longâstanding symptoms of nodding syndrome show evidence of complement activation in CSF and altered immune activation in plasma
Natural malaria infection elicits rare but potent neutralizing antibodies to the blood-stage antigen RH5
Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) is the most advanced blood-stage malaria vaccine candidate and is being evaluated for efficacy in endemic regions, emphasizing the need to study the underlying antibody response to RH5 during natural infection, which could augment or counteract responses to vaccination. Here, we found that RH5-reactive B cells were rare, and circulating immunoglobulin G (IgG) responses to RH5 were short-lived in malaria-exposed Malian individuals, despite repeated infections over multiple years. RH5-specific monoclonal antibodies isolated from eight malaria-exposed individuals mostly targeted non-neutralizing epitopes, in contrast to antibodies isolated from five RH5-vaccinated, malaria-naive UK individuals. However, MAD8-151 and MAD8-502, isolated from two malaria-exposed Malian individuals, were among the most potent neutralizers out of 186 antibodies from both cohorts and targeted the same epitopes as the most potent vaccine-induced antibodies. These results suggest that natural malaria infection may boost RH5-vaccine-induced responses and provide a clear strategy for the development of next-generation RH5 vaccines